Professional Documents
Culture Documents
Alessandro Capucci
Editor
Clinical Cases in
Cardiology
A Guide to Learning and Practice
ERRNVPHGLFRVRUJ
Editor
Alessandro Capucci
Cardiology Clinic
Universit Politecnica delle Marche
Ospedali Riuniti Ancona
Ancona
Italy
v
vi Preface
vii
ERRNVPHGLFRVRUJ
viii Contents
Part IV Cardiomyopathy
11 Hypertrophic Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Marco Marchesini and Erika Baiocco
12 Cardiac Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Alessandro Barbarossa and Erika Baiocco
13 Left Ventricular Non-compaction Cardiomyopathy . . . . . . . . . 141
Alessandro Maolo and Simona Masiero
14 Arrhythmogenic Right Ventricular Cardiomyopathy . . . . . . . . 153
Michela Brambatti and Matilda Shkoza
ERRNVPHGLFRVRUJ
Contents ix
Part IX Miscellanea
27 Sudden Cardiac Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Laura Cipolletta
28 The Role of Home Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Laura Cipolletta and Jenny Ricciotti
29 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
Simone Maffei and Jenny Ricciotti
30 Difficult Interpretation of ECG: Small Clues May Make
the Difference. The Role of the P Wave. . . . . . . . . . . . . . . . . . . . 349
Alessandro Maolo and Daniele Contadini
ERRNVPHGLFRVRUJ
Part I
Acute Ischemic Heart Disease
ERRNVPHGLFRVRUJ
ST Elevation Related to the Site
of Coronary Occlusion 1
Maria Vittoria Matassini and Matilda Shkoza
ERRNVPHGLFRVRUJ
4 M.V. Matassini and M. Shkoza
Physical Examination were placed, and the cath lab team was advised.
Therapy with crystalloid and dopamine 5 gamma/
General appearance: well developed, well kg/min infusion was practiced with blood pres-
nourished, alert but confused, suffering from sure increase to 120/70 mmHg, and morphine
retrosternal pain, with pallor and cold sweat was administered for the transcutaneous pac-
Lungs: dyspnea; clear to percussion and ing pain. At 1:45 AM the patient was transferred
auscultation without rhonchi, wheezing, or to the cath lab to perform coronary angiography
diminished breath sounds; presence of bibasi- and to position a temporary pacing via the right
lar rales femoral vein. The angiography showed right coro-
Cardiovascular: normal S1 and S2; no S3, S4, nary artery dominance with thrombotic occlusion
or murmurs; regular rhythm; no vascular of its middle tract; no other stenosis was pres-
murmurs ent. At 2:05 AM the patient underwent manual
Abdomen: positive bowel sounds, soft and non- thrombus aspiration (EXPORT) and PTCA with
distended, no guarding or rebound, no masses medicated self-expanding stent (STENTYS DES
3.54.5 17 mm) implantation via the right radial
artery. A bolus of abciximab 0.25 mg/kg was
Routine Laboratory Test administered, and the patient was shifted to prasu-
grel with a loading dose of 60 mg administered in
White blood cells 17,000 mmc, total cholesterol the cath lab. The residual stenosis was <20 % and
338 mg/dl, triglycerides 853 mg/ml, AST 398 TIMI flow was 3. Continuous unfractionated hepa-
U/L, ALT 117 U/L, LDH 689 U/L, GT 60 U/L, rin infusion was administered during the 12 h fol-
troponin I highly specific 116 ng/ml, CKMB lowing the procedure. The transvenous pacing was
222.8 ng/ml, and uric acid 8.4 mg/ml. The removed 48 h later being the patient again in stable
remaining laboratory tests were normal. sinus rhythm. Continuous electrocardiographic
monitoring during the first 6 days did not show any
dangerous tachyarrhythmia or bradyarrhythmia.
Instrumental Examination Therapy with ASA 100 mg od, prasugrel 10 mg
od, atorvastatin 80 mg od, losartan 12.5 mg od,
The ECG at entrance (Fig. 1.1a, b) confirmed the and pantoprazole 40 mg od was started since the
previous one, already described. first day. Metoprolol tartrate 25 mg bid was added
A complete echocardiographic examination the second day. The patient was transferred to our
was performed and showed normal dimensions semi-intensive cardiology unit on the third day and
of the cardiac chambers, reduced systolic left then discharged on the seventh day with a follow-
ventricle function (EF 45 %) due to hypokinesia up visit, ECG, and echocardiography programmed
of the inferior and posterolateral wall, normal 2 months later. Therapy at discharge was ASA
right ventricular function (TAPSE 21 mm), and 100 mg od, prasugrel 10 mg od for 12 months,
mild mitral and tricuspid regurgitation with nor- atorvastatin 80 mg od, losartan 12.5 mg od, panto-
mal pulmonary artery systolic pressure. prazole 40 mg, and metoprolol tartrate 25 mg bid.
These findings all together were suggestive for Denition and Epidemiology
inferior ST elevation acute coronary syndrome
complicated by third-degree AV block. The last ESC guidelines published in 2012 define
As soon as possible, a transcutaneous pac- acute myocardial infarction (AMI) as the evi-
ing and a continuous electrocardiographic, blood dence of myocardial necrosis (elevation of
pressure, and oxygen saturation monitoring cardiac biomarkers, typical ECG alterations,
ERRNVPHGLFRVRUJ
1 ST Elevation Related to the Site of Coronary Occlusion 5
a b
Fig. 1.1 (a, b) Patient ECG: sinus rhythm, third-grade leads (DII, DIII, aVf) with specular ST-segment depres-
atrioventricular block, narrow QRS escape rhythm with a sion in DI and aVl, QRS axis of 105
heart rate of 33 bpm, ST-segment elevation in the inferior
imaging alterations, or autopsy evidence) in the The in-hospital mortality of unselected STEMI
presence of a clinical setting suggestive for myo- patients varies from 6 to 14 % [8]. Ejection frac-
cardial ischemia [1]. tion, the Killip class, age, time delay to treatment
Acute myocardial infarction with ST elevation and mode of treatment, prior myocardial infarc-
(STEMI) is a clinical syndrome characterized by tion history, renal dysfunction, diabetes mellitus,
the typical symptoms of myocardial ischemia and diseased coronary artery number are all fac-
with electrocardiographic ST elevation (persis- tors that influence mortality. Hospitals with a
tent for more than 20 min) and following release high clinical volume and high rate of invasive
of cardiac biomarkers [2]. procedures have lower mortality rates [11].
Coronary artery disease (CAD) is the most STEMI mortality significantly decreased thanks
common cause of death in the whole world. In to a frequency care increase [5, 7].
2012, 7.4 million people in Europe (which is
13.2 % of all deaths) died from CAD [3].
At present, up to 2540 % of AMI presenta- Pathology and Pathophysiology
tions are STEMI ones [47]. The incidence of
STEMI hospital admissions is different among Pathology
countries that belong to ESC [8]. In the last The causes of STEMI are different, but they can
decades there has been a STEMI incidence be divided into two principal groups:
decrease despite an NSTEMI incidence increase.
In the Sweden registry, which is probably the Coronary atherosclerosis complicated by cor-
most comprehensive STEMI registry, an inci- onary thrombosis, the main one
dence of 66 STEMI/100,000/year, similar to those Non-atherogenic forms that are rare such as
of other countries like the Czech Republic [9], arteritis, trauma to coronary arteries, coronary
Belgium [8], and the USA [10], has been reported. mural thickening with metabolic disease or
ERRNVPHGLFRVRUJ
6 M.V. Matassini and M. Shkoza
intimal proliferative disease, emboli to coro- Anatomically, two major types of MI can be
nary arteries, congenital coronary artery detected: transmural infarcts characterized by the
anomalies, myocardial oxygen demandsup- presence of a full ventricular wall thickness myo-
ply disproportion, hematologic, and miscella- cardial necrosis and nontransmural or subendo-
neous [12] cardial MI with necrosis involvement of the
subendocardium or intramural myocardium or
We will focus our attention on the first cause both. In the first case, there is a completely occlu-
of STEMI, the coronary atherosclerosis. sive thrombus of an epicardial coronary artery
A previous classification based on ECG evolu- that subtends the infarct area with a typical
tion divided patients with MI into two groups: ST-segment elevation. The transmural necrosis
patients with a Q-wave infarction, very often con- can cause a full wall thickness vital myocardial
sidered a transmural infarction, and patients with loss and subsequent fibrosis that is evidenced by
a non-Q-wave infarction. Currently, a new classi- Q-wave evolution in the leads overlying the
fication based on pathophysiology divides infarcted zone. In a few number of patients, there
patients into other two groups: those with STEMI is not a Q-wave evolution but an R-wave height
related to an acute thrombotic occlusion of an epi- reduction.
cardial coronary artery and those with NSTEMI/ There is a specific correlation between the
unstable angina, due to stenosis of a coronary coronary artery occluded, the myocardial area
artery without occlusive thrombi. When there is a developing necrosis, and the ECG derivation that
chronic total occlusion of the coronary artery, shows an ST elevation (Fig. 1.2).
patients do not always have an MI because of col-
lateral blood flow development and other factors.
The most important element on AMIs physio-
pathology is the atherosclerotic plaque. The
plaque evolution is an active process lasting years
that consists in intima lipoprotein accumulation,
lipoprotein oxidation and glycation, intima leu-
kocyte migration, foam cell development, intima
smooth cell migration with consequent extracel-
lular matrix accumulation, atherosclerotic plaque
growth, and a fibrofatty lesion formation with a
lipid core surrounded by an acellular fibrous cap-
sule. Cytokines and effector molecules like hypo-
chlorous acid and superoxide anion play an
important role in this process.
During this natural evolution, high-risk
plaques can undergo plaque disruption [13, 14] Fig. 1.2 Schematic representation of left ventricle
segments, Einthovens triangle with electrocardiogram
that is induced by stressors like intramural blood
derivations. LAD supplies segments nr 1, 2, 6, 7, 8, 12, 13,
pressure, coronary vasomotor tone, and tachycar- 14, 15, 16, and 17; LCX supplies segments nr 4, 5, 6, 10,
dia. So, thrombogenic substances are exposed 11, 12, 15, 16, and 17; RCA supplies segments nr 3, 4, 9,
with secondary activation and aggregation of 10, 11, 14, 15, 16, and 17. Areas of shared perfusion
between LAD, LCX, and RCA are shown in green. The
platelet; moreover, thrombin generation is pro-
infarct artery can be deduced identifying the leads with
moted with subsequent thrombus formation. ST-segment elevation and correlating these with the
There is seasonal and circadian variation of some segments that these leads explore and so with coronary
of these key physiologic variations, and that is arteries that supply these segments. For example, ST
segment elevated prominently in leads exploring seg-
why STEMI happens more frequently in the
ments 1, 2, 7, 8, 13, 14, and 17 which means that the
winter early morning hours and following natural occluded vessel is the LAD. LAD, left anterior descend-
disasters [15]. ing; RCA, right coronary artery; LCX, left circumflex
ERRNVPHGLFRVRUJ
1 ST Elevation Related to the Site of Coronary Occlusion 7
The earliest myocardial ultrastructural typical, and if the myocardial loss is >40 %, car-
changes occurring within the first 20 min are diogenic shock appears.
reversible. Changes become irreversible after Improvement is possible thanks to the recovery
20 min up to 120 min of ischemia [16]. After of the stunned (reversibly injured) myocardium
612 h of necrosis onset, myocardium gross after revascularization, but in some patients the
alteration can be identified. So, in the first 30 min infarcted LV may dilate causing LV remodeling.
after ischemia onset, myocardial injury is revers- This can be a compensatory mechanism restoring
ible; subsequently, a progressive viability loss a normal stroke at the expense of a reduced ejec-
occurs and usually completes at 612 h. That is tion fraction; however, dilation elevates afterload
the reason why the reperfusion therapy benefits (Laplaces law) that depresses LV stroke volume
are greatest when patients are treated early. and increments the consumption of myocardial
Generally, the right ventricle is less involved oxygen, intensifying myocardial ischemia. The
by infarction. It is interested in approximately infarct size, patency of the related coronary artery,
50 % of patients with transmural infarct of the and reninangiotensinaldosterone system
inferoposterior wall and posterior portion of the (RAAS) influence LV remodeling. For this rea-
septum [17]. The right ventricle shows an excel- son, LV remodeling can be reduced by an antago-
lent recovery of systolic function once reperfu- nist of RAAS. Even aldosterone inhibitors reduce
sion is restored [18]. collagen deposition and decrease ventricular
arrhythmia development [20].
Pathophysiology
When a coronary artery is occluded, immediate
myocardial contractile alteration occurs. There Clinical Features
are four sequential patterns of abnormal
contraction: Symptoms
The typical STEMI discomfort is a prolonged
Dyssynchrony (adjacent segments do not con- (more than 20 min), constricting, oppressing, or
tract at the same time) compressing pain of variable intensity. It has a
Hypokinesia (reduced contraction) retrosternal location and often radiates to the ulnar
Akinesia (cessation of contraction) side of the left arm, or rarely both arms; to the
Dyskinesia (the segment expansion is neck, jaw, and shoulders; and rarely to the
paradoxical) epigastrium or interscapular region. In some
patients, frequently those with an inferior STEMI,
As an acute compensation of these alterations, the location is the epigastrium simulating abdomi-
a hyperkinesia of the normal myocardium seg- nal disorders. In these patients nausea and vomit-
ments usually firstly develops. It results from ing may occur due to vagal reflex activation or LV
sympathetic nervous system activity increase receptor stimulation. Symptoms like cold perspi-
and FrankStarling mechanism and lasts up to ration, palpitations, profound weakness, dizziness,
2 weeks. and a sense of imminent death may be present.
If ischemic injury involves >15 % of the myo- In some cases there is an atypical presentation
cardium, the systolicdiastolic function of the LV of STEMI-like atypical location of the pain or
becomes depressed, and a decline of cardiac out- dyspnea, syncope, profound weakness, or acute
put, stroke volume, and blood pressure occurs. indigestion. Some patients are wholly asymp-
End-systolic volume and end-diastolic pressure tomatic, and STEMI can be unrecognized and
increase and diastolic dysfunction appears. The discovered in a subsequent routine electrocardio-
degree of end-systolic volume increase has been graphic examination. These patients have a simi-
shown to be an important predictor of STEMI lar prognosis of symptomatic ones.
mortality [19]. If ischemic injury involves >25 % In up to half of STEMI patients, a precipitat-
of the myocardium, clinical heart failure becomes ing factor like reduced oxygen supply to the
ERRNVPHGLFRVRUJ
8 M.V. Matassini and M. Shkoza
myocardium (hypotension, hypoxemia, pulmo- the first 2 weeks and most commonly on the sec-
nary embolism, etc.) or increased myocardial ond or third day.
oxygen demands (aortic stenosis, fever, agitation,
tachycardia, emotional stress, unusually heavy
exercise) can be identified. Diagnosis
ERRNVPHGLFRVRUJ
1 ST Elevation Related to the Site of Coronary Occlusion 9
ERRNVPHGLFRVRUJ
10 M.V. Matassini and M. Shkoza
In case of mechanical reperfusion, only the cul- guidelines suggest the administration of GP
prit lesion should be treated with PCI and stenting IIb/IIIa inhibitors for bailout therapy if there is
[24]. Primary multivessel revascularization in angiographic evidence of a massive thrombus,
addition to the supposed culprit lesion is indicated slow or no reflow, or thrombotic complication.
in case of cardiogenic shock or persistent isch- 2. Anticoagulant therapy in primary PCI-treated
emia, after the culprit lesion treatment [1, 25, 26]. patients may be achieved with unfractionated
In case of multivessel disease, staged multivessel heparin (UFH), enoxaparin, and bivalirudin,
PCI could be considered as recent meta-analysis with the aim to reduce acute vessel thrombosis
showed improvement in short- and long-term sur- risk. Anticoagulants should be started as soon
vival and reduction of repeated PCI [27]. However, as possible and stopped at the end of PCI pro-
other randomized trials should confirm the bene- cedure, except in the presence of other
fits of staged multivessel PCI in STEMI. conditions that require prolongation of antico-
agulants, such as atrial fibrillation or mechani-
Primary Percutaneous Coronary cal valve or left ventricular thrombosis.
Intervention: Pharmacotherapy Bivalirudin is a direct thrombin inhibitor,
The main stones of therapy in acute coronary nowadays, recommended by European guide-
syndrome are represented by antiplatelet and lines over unfractionated heparin and a GP IIb/
anticoagulant drugs. IIIa blocker (Ib) [1]. As previously reported,
when bivalirudin is preferred, addition of GP
1. Antiplatelet therapy consists of a combination IIb/IIIa blockers does not add adjunctive
of two antiplatelet agents: the first option is benefits, and bivalirudin alone is associated with
aspirin, both oral and IV, if patients are unable lower bleeding rates and reduced mortality [32].
to swallow, and the second one is an adenosine Enoxaparin (with or without routine GP
diphosphate (ADP) receptor blocker. For a long IIb/IIIa blocker) may be preferred over unfrac-
time, clopidogrel has been the only and pre- tionated heparin with a class II of indication,
ferred ADP blocker, while in the last years new level B; finally, unfractionated heparin with or
antiplatelet agents such as prasugrel and ticagre- without routine GP IIb/IIIa blocker must be
lor have been studied [28, 29] and currently used in patients not receiving bivalirudin or
accepted in guidelines and widely used in com- enoxaparin (I, C) [1].
mon clinical practice. Prasugrel and ticagrelor
present a more rapid onset of action and higher Fibrinolysis
efficacy when compared to clopidogrel. Fibrinolysis must be considered when mechani-
Therefore, clopidogrel is preferably used when cal revascularization is not available in recom-
prasugrel or ticagrelor is either not available or mended timelines [1]. Prehospital treatment with
contraindicated. Table 1.1 summarizes the main fibrinolytic drugs by emergency medical person-
features of old and new antiplatelet agents. nel is strongly suggested, when feasible: the ben-
The glycoprotein IIb/IIIa (GP IIb/IIIa) efits from fibrinolytic therapy are higher in the
antagonists are the most recent additions to the first 3 h from symptom onset and then rapidly
antiplatelet agents available that are given decline [33]. The delay from first patient contact
intravenously. Currently, three GPIIb/IIIa and initiation of fibrinolysis should be within
antagonists are available: abciximab, eptifiba- 30 min to improve treatment efficacy, in both
tide, and tirofiban. The role of these agents is hospital and prehospital settings.
debated: in the era of potent oral antiplatelet There are many absolute and relative contrain-
agents, the upstream use is uncertain; more- dications to fibrinolysis, as reported in Table 1.2.
over, if bivalirudin is chosen as an anticoagu- A fibrin-specific agent (tenecteplase, alteplase,
lant, its use does not add further benefits. On reteplase) is recommended (over non-fibrin-
the other side, if UFH or enoxaparin is specific agents).
administered, the association of GPIIb/IIIa Aspirin and clopidogrel must be administered
antagonists remains debatable. Current to treated patients. Parenteral anticoagulation is
ERRNVPHGLFRVRUJ
1 ST Elevation Related to the Site of Coronary Occlusion 11
Table 1.1 Old and new antiplatelet agent for acute coronary syndrome
Clopidogrel Ticagrelor Prasugrel
Trial CURE [30], PCI-CURE PLATO [28] TRITON-TIMI 38 [29]
[31]
Class Thienopyridine Nucleoside analog Thienopyridine
Doses 300600 mg loading 180 mg loading 60 mg loading
dose + 75 mg maintenance dose + 90 mg maintenance dose + 10 mg maintenance
dose dose bis in die dose
Mechanism of action Irreversible inhibition of Reversible and Irreversible inhibition of
P2Y12 subtype of ADP noncompetitive binding of P2Y12 subtype of ADP
receptors on the platelet P2Y12 subtype of ADP receptors on the platelet
surface receptors on the platelet surface
surface
Metabolism Prodrug activated through No metabolism for Prodrug with intestinal,
hepatic metabolism by activation serum, hepatic
cytochrome P450 metabolism (cytochrome
enzymes P450 enzymes)
Genetic variability in
enzyme function affects
drug efficacy
Onset of action Within 2 h Within 30 min Within 30 min
Excretion Renal (50 %), biliary Biliary Renal (68 %), biliary
(46 %) (27 %)
Side effect Dyspnea Increased rate of
Ventricular pauses bleedings
Increased rate of
bleedings
Contraindications Hypersensitivity Hypersensitivity Hypersensitivity
Active bleeding Active bleeding Active bleeding
Significant liver History of intracranial Prior stroke/transient
impairment hemorrhage ischemic attack
Cholestatic jaundice Moderate to severe Moderate to severe
hepatic impairment hepatic impairment
Concomitant use of
strong CYP3A4
inhibitors
Use with caution in Use with caution in Not recommended in
patients at high risk of patients at high risk of patients aged 75 years or
bleeding or with bleeding or with in patients with lower
significant anemia significant anemia body weight (<60 kg)
Use with caution in
patients at high risk of
bleeding or with
significant anemia
recommended until revascularization (if per- ischemia. Also patients with heart failure or car-
formed) or for the duration of hospital stay, from diogenic shock must undergo angiography [1].
at least 48 h up to 8 days. Enoxaparin is preferred
over UHF.
Patients treated with fibrinolysis must be Arrhythmia Management
transferred to a PCI-capable center: stable in Acute Phase
patients should be studied within 324 h. Rescue
PCI is indicated in case of treatment failure Arrhythmias are very frequent in the acute phase
(<50 % ST-segment resolution at 60 min), of STEMI, and every kind of arrhythmia could be
recurrence of ST-segment elevation, or recurrent seen [1].
ERRNVPHGLFRVRUJ
12 M.V. Matassini and M. Shkoza
Table 1.2 Contraindications to fibrinolysis bility or ongoing ischemia, urgent electrical car-
Absolute Previous intracranial hemorrhage, known dioversion is indicated, while pharmacological
cerebrovascular lesion or intracranial cardioversion could be achieved with amioda-
neoplasm, ischemic stroke within the last rone in stable patients with recent arrhythmia
6 months, aortic dissection, recent major
trauma/surgery/head injury, onset. For further details on atrial fibrillation
gastrointestinal bleeding within the past management, see Chap. 20.
month, known bleeding disorder, Ventricular arrhythmias (VA) vary from ven-
noncompressible punctures in the past tricular premature beats to non-sustained and
24 h
sustained ventricular tachycardias (VT) to ven-
Relative Poorly controlled hypertension
(Pas > 180 mmHg or Pad > 110 mmHg), tricular fibrillation. The prevalence of ventricular
transient ischemic attack in the last arrhythmias has been investigated in the fibrino-
6 months, current use of anticoagulant lytic era [35] and, later, in the primary percutane-
therapy, pregnancy or within 1 week
ous coronary intervention era [36]: VA remain
postpartum, advanced liver disease,
infective endocarditis, active peptic ulcer, fairly common even if the real incidence may be
prolonged or traumatic resuscitation underestimated because MI resulting in
prehospital sudden cardiac death could have not
been considered in evaluating studies.
As occurred in our patient, inferior myocar- Ventricular premature beats and non-sustained
dial infarction is frequently associated with VT are really common in the first days from
bradyarrhythmias, from sinus bradycardia to MI. Treatment is not recommended [1] unless non-
atrioventricular (AV) blocks. Sinus bradycardia, sustained VT causes hemodynamic instability.
first-degree AV block, and second-degree AV Sustained monomorphic VT are often not tol-
block type I usually do not require specific treat- erated, especially in the presence of worse left
ment; in case of symptoms or severe hypoten- ventricular dysfunction; moreover, they may pro-
sion, IV atropine should be administered, and if duce ischemia and degenerate in ventricular
not effective, temporary pacing should be fibrillation.
started. All medications interfering with In hemodynamically unstable patients, electri-
electrical conduction should be withheld. cal cardioversion is mandatory. In stable VT,
Second-degree, type II, and third-degree atrio- diagnosis and treatment should be prompt
ventricular blocks usually need temporary pac- because of the risk of rapid deterioration of clini-
ing, especially if concomitant hypotension or cal and hemodynamic conditions. If the patient is
heart failure is present. stable, IV amiodarone, sotalol, or lidocaine could
AV blocks developing during inferior infarc- be attempted, even if conversion rates are low.
tion are usually supra-Hisian and reversible with For polymorphic VT and ventricular fibrilla-
the restoration of coronary perfusion, and they tion, the first therapy consists of immediate defi-
carry a good prognosis. The ECG shows an brillation [37]. If polymorphic VT develop in the
escape rhythm with narrow QRS. In case of ante- setting of bradycardia, a temporary pacing at
rior MI, the presence of an AV block underlines higher rate should be started.
the existence of an extensive necrosis, interesting For further details in the management of ven-
electrical conduction ways; the block is usually tricular arrhythmias and long-term risk evalua-
infra-Hisian with a low escape, wide QRS tion for sudden death, see Chap. 18.
rhythm. A new bundle branch block or a new
hemiblock should be highly monitored because
they often precede a complete AV block. Long-Term Therapies for ST-Segment
Atrial fibrillation is also very common in Elevation Myocardial Infarction
STEMI patients, especially in the presence of
heart failure [34]. Anticoagulation should be Long-term management of patients with acute
started if not contraindicated, and effective rate coronary syndrome with ST elevation consists of
control achieved in order to reduce myocardial lifestyle changes, risk factor control, and long-
oxygen demand. In case of hemodynamic insta- term drug therapy.
ERRNVPHGLFRVRUJ
1 ST Elevation Related to the Site of Coronary Occlusion 13
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9. Widimsky P, Zelizko M, Jansky P, Tousek F, Holm F,
(EF < 40 %), with heart failure in the early phase, Aschermann M (2007) The incidence, treatment strat-
and with diabetes. However, they may be consid- egies, outcomes of acute coronary syndromes in the
ered in all STEMI patients for their modest effect reperfusion network of different hospital types in
the Czech Republic: results of the Czech evaluation
on mortality.
of acute coronary syndromes in hospitalized patients
Finally, aldosterone antagonists should be (CZECH) registry. Int J Cardiol 119:212219
considered for patients with at least mild left ven- 10. McManus DD, Gore J, Yarzebski J, Spencer F,
tricular dysfunction (EF 40 %) and heart failure Lessard D, Goldberg RJ (2011) Recent trends in the
incidence, treatment, and outcomes of patients with
or for diabetic patients, provided that no renal
STEMI and NSTEMI. Am J Med 124:4047
failure or hyperkalemia is present. 11. Birkhead JS, Weston C, Lowe D (2006) Impact of
specialty of admitting physician and type of hospi-
tal on care and outcome for myocardial infarction
in England and Wales during 20045: observational
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tors. Circulation 98(23):2567 advanced cardiovascular life support: 2010 American
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ERRNVPHGLFRVRUJ
Non-ST-Segment Elevation
Myocardial Infarction (NSTEMI) 2
Marco Marchesini, Marco Morelli,
and Luca Piangerelli
None
A 66-year-old man with no previous car-
diovascular disease was admitted to the
emergency department for worsening chest Medications
pain and dyspnea. The patient referred the
presence of intermittent chest pain a month Ramipril 5 mg, atorvastatin 20 mg, pantoprazole
ago mainly at rest. No history of fever was 20 mg, and insulin
present.
Vital Signs
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18 M. Marchesini et al.
all four quadrants, soft, non-distended/non- anterior hemiblock and ST depression (>0.1 mv)
tender, no rebound or guarding, no costoverte- in V3-6 and DII-avF with ST elevation in aVR
bral angle tenderness (Fig. 2.1).
Extremities: no cyanosis or clubbing, no Echocardiography: moderate concentric
peripheral edema hypertrophy (LV mass/BSA 135 g/m2, relative
wall thickness 0.45) with preserved LV global
function (estimated ejection fraction of 56 %)
Routine Laboratory Tests and hypokinesia of the middle and apical anterior
wall; normal dimension and function of the right
Complete blood count: normal ventricle (TAPSE 20 mm, FAC area 40 %);
Cholesterol (total, HDL, LDL) and TG: total impaired relaxation of the left ventricle
280 mg/dl, LDL 150 mg/dl (E/A < 0.75, E/E < 10); mild mitral and tricuspid
Hepatic function (GOT, GPT, -GT, ALP, regurgitation; systolic pulmonary artery pressure
total bilirubin, amylase, lipase): normal of 35 mmHg
Thyroid function (TSH, FT3, FT4): normal Chest x-ray showed the absence of pulmonary
Renal function (creatinine, BUN): creatinine congestion, lobe consolidation, or bronchograms.
1.5 mg/dl (eGFR 65 ml/min/1.73 mq)
Serum electrolytes: potassium 4.5 mEq/l,
sodium 139 mEq/l Clinical Course and Therapeutic
Biomarkers: troponin I 5.4 ng/ml, BNP 80 pg/ Management
ml, C-reactive protein 0.2 mg/dl, glycosylated
hemoglobin 81 mmol/l Clinical, instrumental, and laboratory data
allowed us to make diagnosis of SCA-NSTEMI:
ECG changes (ST depression >0.05 in more
Instrumental Examination than two contiguous leads), rise in cardiac bio-
marker levels, and normal left ventricle global
An ECG performed at patients admission function with regional hypokinesia no signs of
revealed a right bundle branch block with left myopericarditis.
ERRNVPHGLFRVRUJ
2 Non-ST-Segment Elevation Myocardial Infarction (NSTEMI) 19
According to guidelines, the patient was was performed 5 days later without procedural or
assessed with established risk scores for progno- bleeding complications. The patient was then
sis and bleeding (GRACE 120, intermediate risk; transferred on day 12 to a postsurgery rehabilita-
CRUSADE 30, low risk of bleeding). Antiplatelet tion center with a progressive improvement in
therapy with aspirin and ticagrelor (P2Y12 inhib- functional capacity and subsequently dismissed
itor) with a loading dose of 300 mg and 180 mg, after 7 days. The therapy at discharge was dual-
respectively, and anticoagulant therapy with antiplatelet therapy (aspirin 100 mg and ticagre-
fondaparinux 2.5 mg/die were started. Intravenous lor 90 bid), ramipril 5 mg, atorvastatin 80 mg,
nitrate treatment and beta-blocker therapy (meto- metoprolol 50 mg bid, pantoprazole 20 mg, and
prolol 2.5 mg ev.) were administered due to per- insulin therapy.
sistent angina and tachycardia. ACE inhibitor
(ramipril 5 mg) was continued, and high-dose
statin therapy (atorvastatin 80 mg) was initiated. 2.2 Non-ST-Segment Elevation
The patient remained asymptomatic in the Myocardial Infarction
subsequent hours despite an increase in cardiac (NSTEMI)
biomarkers (troponin I 15 ng/ml) at the labora-
tory analysis (6 h after patient admission). Given Denition and Epidemiology
a GRACE score of 120, an ECG suggesting a left
main or multivessel coronary artery disease (ST Coronary artery disease (CAD) is one of the
depression in many leads with ST elevation in major causes of deaths and morbidity in devel-
avR) and the presence of high-risk criteria (sig- oped countries with a prevalence that increases
nificant rise in troponin) an early invasive strat- with age [1]. Nearly 17.3 million deaths in 2013
egy was performed. Thus, the patient underwent worldwide were related to cardiovascular disease
a coronary angiography (<24 h) that showed [2]. Acute coronary syndrome (ACS) represents
triple-vessel disease with a SYNTAX score >22 one of the most frequent and life-threatening clin-
(Fig. 2.2). ical presentations of CAD and is related to plaque
Considering the clinical status (asymptomatic rupture or an ischemic imbalance between myo-
patient, progressive lowering in cardiac biomark- cardial oxygen supply and demand. The extensive
ers: Tn I 10 ng/ml 12 h after patient admission) use of high-sensitive troponin assay may have led
and the unfavorable coronary anatomy (SYNTAX to more diagnosis of myocardial infarction (MI)
score >22), the patient was sent for coronary hiding a possible reduction in the incidence of MI
artery bypass grafting (CABG, class I A). [3]. According to the most recent guidelines [4],
Ticagrelor was then discontinued, and CABG the term myocardial infarction should be used in
ERRNVPHGLFRVRUJ
20 M. Marchesini et al.
the presence of symptoms of ischemia and/or rise or erosion with acute thrombosis or vasoconstric-
in cardiac biomarkers (troponin I or T values tion leading to a sudden and critical reduction in
above the 99th percentile upper reference limit) blood flow. Inflammation plays a determinant role
with the following criteria: ST-segment or T-wave in plaque erosion and subsequent thrombus forma-
changes, imaging evidence of loss of viable myo- tion. Rarely ACS may be caused by other mecha-
cardium or regional motion abnormalities, and nisms such as arteritis, trauma, dissection,
intracoronary thrombus by angiography or congenital abnormalities, or drug abuse [8].
autopsy. Two different clinical presentations may
be encountered based on electrocardiogram
(ECG) findings and pathophysiology: Diagnosis
Myocardial infarction with persistent The diagnosis of NSTE is complex and more dif-
(>20 min) ST elevation (see Chap. 1). ficult than STEMI due to less obvious signs and a
Myocardial infarction without persistent ST wider differential diagnosis. Risk stratification
elevation includes ST-segment depression should be evaluated during the diagnostic phase
>0.05 mV in two contiguous leads, T-wave guiding the revascularization and treatment
inversion >0.1 mV in two contiguous leads, strategy.
pseudo-normalization of T wave, or no ECG
changes [4]. Two types of non-ST-elevation Clinical Presentation
ACS are recognized: NSTEMI or unstable The more frequent symptom of ACS is retroster-
angina (UA) based on the evaluation of car- nal chest pain irradiating to the left arm or to the
diac biomarkers. neck sometimes described as retrosternal pres-
sure or heaviness. Dyspnea, diaphoresis, or nau-
In the last years, it has been observed an sea is often associated. Atypical presentation is
increase in the rate of non-ST-elevation myocar- common in older patients, women, and patients
dial infarction (NSTEMI) in relation to with diabetes and may lead to a missed diagnosis
ST-elevation myocardial infarction (STEMI) [9]. Exacerbation of symptoms during physical
with an annual incidence of ~3 per 1,000 inhabit- exertion and reduction at rest is common. Relief
ants [5]. Hospital mortality is higher between of pain after administration of nitrates is also
STEMI patients, while in the long term death quite specific. UA is characterized by the pres-
rates are consistently larger in NSTEMI [6]. ence of new-onset angina, post-MI angina, or
NSTEMI patients are often older with significant crescendo angina. The presence of risk factors
comorbidities. These data suggest the need of should be carefully evaluated as it significantly
significant efforts both in the acute phase and in increases the probability of CAD diagnosis. The
long-term management to ensure better most common risk factors are male sex, family
outcomes. history of CAD, older age, peripheral artery dis-
ease, diabetes mellitus, renal failure, previous
cardiovascular disease, and dyslipidemia.
Pathophysiology
Physical Examination
Atherosclerosis is a multifocal disease caused by Physical examination shall evaluate the presence
lipid accumulation that affects large-sized and of NSTEMI complication such as heart failure
medium-sized arteries [7]. CAD is a dynamic pro- with pulmonary or systemic congestion and
cess that leads to a progressive reduction in the ves- establish the presence of precipitating factors
sel size due to plaque formation. NSTEMI is due to (i.e., anemia). Extracardiac (pneumonia, pneu-
complete or partial occlusion of a coronary artery mothorax, costochondritis) and nonischemic
or a mismatch between oxygen supply and demand. (valvular disease, pericarditis) causes of chest
ACS is generally precipitated by a plaque rupture pain may also be excluded.
ERRNVPHGLFRVRUJ
2 Non-ST-Segment Elevation Myocardial Infarction (NSTEMI) 21
ERRNVPHGLFRVRUJ
22 M. Marchesini et al.
The first option is the early invasive strategy, level of evidence A). Among all other patients
meaning that the patient is quickly sent to the with UA/NSTEMI, those who have at least one
cath lab for coronary angiography, followed by secondary high-risk criterion or recurrent symp-
the eventual PCI or surgical revascularization toms should be treated with an invasive strategy
based on the angiographic results. within 72 h (class I, level of evidence A).
The second option, called conservative strat-
egy, consists in medical therapy alone for the ini-
tial treatment, reserving cardiac catheterization Primary high-risk criteria:
only to those who have recurrent ischemia or (a) Relevant increase and fall of
other high-risk features. troponin
(b) Dynamic changes of the ST seg-
Conservative Strategy Versus Invasive ment and/or T wave
Strategy Secondary high-risk criteria:
Currently, the results of these alternative strate- (a) Diabetes mellitus
gies have been analyzed in several randomized (b) Renal impairment (eGFR <60 mL/
trials. A meta-analysis in which seven studies min/1.73 m2)
were included showed a significant benefit (c) Reduced left ventricular ejection
offered by the early invasive strategy in terms of fraction (<40 %)
reduction of 2-year mortality from all causes and (d) Early postinfarction angina
myocardial infarction (MI), with no increase in (e) Recent angioplasty (PCI)
adverse periprocedural events. Patients who have (f) Previous bypass surgery (CABG)
most benefited from an early invasive strategy (g) Intermediate- to high-GRACE-risk
were those with abnormal troponin values and score (108140)
high-risk features.
These results have been translated into the
European Society of Cardiology (ESC) NSTEMI
Guidelines published in 2011 that recommend a From this, it is clear that by definition NSTEMI
routine invasive strategy in almost the totality of ACS with elevation of myocardial necrosis mark-
patients with NSTEMI while highlighting the ers should be treated with an invasive strategy
crucial role of risk stratification. within 72 h, since the elevation of troponin alone
is considered a primary high-risk criterion.
NSTEMI Patients: Indications Therefore, a conservative strategy is now
in the Light of the Most Recent restricted to a narrow subgroup of patients: basi-
Guidelines cally not to those who have a NSTEMI, but only
Although, for ethics and safety reasons, patients to patients with unstable angina (then with nega-
with UA/NSTEMI at very high risk (refractory tive troponin) and without recurrent symptoms.
angina, severe heart failure, electrical and/or Moreover, even among patients with UA, only
hemodynamic instability) were excluded from those without high-risk characteristics should be
randomized clinical trials, it is universally approached with a conservative strategy, that is,
accepted that these patients must be sent within nondiabetics, those with normal global contrac-
2 h to the cath lab for an urgent invasive strategy, tile function of the left ventricle, those who have
regardless of risk stratification and the values of not been subjected in the past to PCI or CABG,
troponin (class I, level of evidence C). and those with a GRACE risk score <108. In this
Based on randomized clinical trials, patients small group of patients (low risk and without
at high risk who have a GRACE score >140 or recurrent symptoms), a noninvasive assessment
with at least one of the primary high-risk criteria of inducible ischemia is recommended (class I,
must be treated with an early invasive strategy, level of evidence A), which must be performed
within 24 h from the first medical contact (class I, before hospital discharge. Coronary angiography
ERRNVPHGLFRVRUJ
2 Non-ST-Segment Elevation Myocardial Infarction (NSTEMI) 23
should be performed only if the results of nonin- revascularization at both 1 month and 1 year.
vasive tests are positive for inducible ischemia. However, only 43 % of CABG patients could be
matched, and there was a strong trend for a higher
Revascularization Strategies rate of major adverse cardiac events (MACE) at
In approximately one-third of patients, angiogra- 1 year with PCI, compared with CABG (25.0 %
phy will reveal single-vessel disease, allowing ad vs. 19.5 %, respectively; p 0.05).
hoc PCI of the culprit lesion in most cases. In a Culprit-lesion PCI does not necessarily require
multivessel disease, the choice has to be made a case-by-case review by the Heart Team, when
between culprit-lesion PCI, multivessel PCI, the procedure needs to be performed ad hoc after
CABG, and a combined (hybrid) revasculariza- diagnostic angiography particularly in case of con-
tion [13, 14]. The distribution of PCI versus tinuing or recurrent ischemia, hemodynamic insta-
CABG in patients with multivessel disease suit- bility, pulmonary edema, recurrent ventricular
able for revascularization is approximately 80 % arrhythmias, or total occlusion of the culprit coro-
versus 20 % [15]. The revascularization strategy nary artery requiring urgent revascularization. For
in patients with multivessel CAD should be all other scenarios, revascularization should be
determined early by the Heart Team and based on discussed in a multidisciplinary setting. After cul-
the patients clinical status, as well as the severity prit-lesion PCI, patients should be discussed by
and distribution of the CAD and the characteris- the Heart Team, in the context of functional evalu-
tics of the lesion. The SYNTAX score has proven ation of the remaining lesions, patients comor-
to be strongly predictive of death, myocardial bidities, and individual characteristics.
infarction, and TVR [16]. Culprit-lesion PCI is
usually the first choice in most patients with Medical Therapy: The Importance
NSTE-ACS and multivessel disease; however, of Balancing the Ischemic
there are no prospective studies comparing and Hemorrhagic Risk
culprit-lesion PCI with early CABG. In stabi- The therapeutic management of NSTEMI
lized patients with multivessel disease and a high includes the use of anti-ischemic and antithrom-
SYNTAX score (>22), particularly when there is botic drugs in combination to coronary revascu-
no clearly identified culprit lesion, a strategy of larization. The timing and intensity of these
urgent CABG should be preferred. The strategy therapeutic interventions must be individualized
of multivessel PCI rather than culprit-lesion PCI for each patient in light of both the ischemic and
has not been evaluated in an appropriate random- the bleeding risk, since most of the antithrom-
ized clinical trial. In a large database including botic therapies increase the risk of bleeding. Risk
105,866 multivessel CAD patients with NSTE- assessment is an ongoing process that must begin
ACS, multivessel PCI was compared with single- with the first medical contact, until discharge
vessel PCI and was associated with lower from the hospital, because it can change the ther-
procedural success but similar in-hospital mortal- apeutic strategy at anytime.
ity and morbidity [17]. Complete revasculariza- Among the main ischemic risk factors, age and
tion at the time of the index procedure did not the presence of other comorbidity (anemia, diabe-
result in lower mortality rates over 3 years, as tes, etc.) have the greatest prognostic impact.
compared with a staged procedure strategy. Other factors consist in the characteristics and
However, incomplete revascularization appears mode of onset of pain (being worse angina at rest
to be associated with more 1-year adverse event and/or relapsing) and hemodynamic conditions.
rates. In the ACUITY trial, CABG was compared Other prognostic factors recognized and to which
with PCI among patients with multivessel disease attention should be paid are the electrocardio-
[15]. PCI-treated patients had lower rates of graphic changes and the elevation of a series of
stroke, myocardial infarction, bleedings, and biomarkers such as troponin, C-reactive protein
renal injury and similar 1-month and 1-year mor- (CRP), and the N-terminal fragment of the atrial
tality but significantly higher rates of unplanned natriuretic peptide (NT-proBNP).
ERRNVPHGLFRVRUJ
24 M. Marchesini et al.
From the integration of all these risk factors, Morphine 35 mg intravenously or subcutane-
several risk scores have been developed, among ously, if severe pain.
which the best known are the TIMI risk score and Patients who are taking chronic beta-blocker
the Global Registry of Acute Coronary Events therapy, admitted with ACS, should be contin-
(GRACE) score. The TIMI risk score is the most ued on beta-blocker therapy if not in Killip
used in the past due to its simplicity, but its dis- class III (I; C).
criminating power is significantly lower than that Oral beta-blocker treatment is indicated in all
of the GRACE score, basically because it does patients with LV dysfunction without contra-
not take into account parameters of crucial indications (I; B).
importance as hemodynamics. In contrast, the Calcium channel blockers are recommended
GRACE score includes the heart rate (HR), blood for symptom relief in patients already receiv-
pressure (BP), and the presence of heart failure, ing nitrates and beta-blockers (dihydropyri-
in addition to classical risk factors such as age, dine type) and in patients with
any prior MI or previous PCI, creatinine values, contraindications to beta-blockers (benzothi-
myocardial-specific enzymes, and ST changes on azepine or phenylethylamine type) (I; B).
ECG. Therefore, it provides a more accurate esti- Calcium channel blockers are recommended
mate of the risk both on admission and at dis- in patients with vasospastic angina (I; C).
charge. The calculation can be made online at Intravenous beta-blocker treatment at the time
http://www.outcomes-umassmed.org/grace/acs_ of admission should be considered for patients
risk/acs_risk_content.html. in a stable hemodynamic condition (Killip
To date, GRACE score remains the only isch- class <III) with hypertension and/or tachycar-
emic risk score considered in the ESC Guidelines. dia (IIa; C).
At the same time, it is crucial to perform an evalua- Nifedipine or other dihydropyridines are not
tion of the bleeding risk during the prognostic strati- recommended unless combined with beta-
fication. The CRUSADE bleeding score is a score blockers (III; B).
that is used to predict the risk of major bleeding in
light of eight parameters; patients with an increased
risk of bleeding are women, diabetics, and those Oral Antiplatelet Agents
with low hematocrit, with low values of creatinine
clearance, with signs of heart failure, with low (or ASA: loading dose of 150300 mg, mainte-
too high) blood pressure, with high heart rate, and nance dose of 75100 mg daily (I; A).
with history of other vascular disease. P2Y12 inhibitor should be added to aspirin
A score <21 identifies patients at very low risk, and maintained over 12 months (I; A).
between 21 and 30 configures a low risk, between Ticagrelor (180-mg loading dose, 90-mg twice
31 and 40 the risk is moderate, between 41 and 50 daily maintenance dose) is recommended for
the risk is high, and >50 configures a very high all patients at moderate-to-high risk of isch-
risk. The calculation can be made online at http:// emic events (I; B). Contraindications: previ-
www.crusadebleedingscore.org. The execution of ous hemorrhagic stroke, II or III degree
both scores is recommended by the ESC atrioventricular block, sick sinus syndrome,
Guidelines in class I, level of evidence B. bradycardia, syncope, and anticoagulant
therapy.
Prasugrel (60-mg loading dose, 10-mg daily
Anti-ischemic Agents maintenance dose) is recommended for
patients (especially diabetics) in whom coro-
Oxygen insufflation: (48 L/min) if oxygen nary anatomy is known and who are proceed-
saturation is <90 %. ing to PCI (I; B). Contraindications: previous
Nitrate treatment (sublingual, oral, or intrave- stroke or TIA, oral anticoagulant therapy,
nous) is indicated to relieve angina and/or in trauma or recent surgery, age >75 years, and
patients with signs of heart failure (I; C). low body weight <60 kg.
ERRNVPHGLFRVRUJ
2 Non-ST-Segment Elevation Myocardial Infarction (NSTEMI) 25
Secondary Prevention
Anticoagulants
Beta-blockers are recommended in all patients
Anticoagulation is recommended for all patients with reduced LV systolic function (LVEF <40 %)
(I; A). (I; A).
ACE inhibitors/ARB are indicated within 24 h
Fondaparinux (2.5 mg subcutaneously daily) in all patients with LVEF <40 % and in patients
is recommended as having the most favorable with heart failure, diabetes, hypertension, or
efficacy-safety profile (I; A). If the initial anti- CKD, unless contraindicated (I; A).
ERRNVPHGLFRVRUJ
26 M. Marchesini et al.
ACE inhibitors/ARB are recommended for all 8. Hamm CW et al (2011) ESC Guidelines for the man-
agement of acute coronary syndromes in patients pre-
other patients to prevent recurrence of ischemic
senting without persistent ST-segment elevation. Eur
events, with preference given to agents and doses Heart J 32:29993054
of proven efficacy (I; B). 9. Canto JG, Fincher C, Kiefe CI, Allison JJ, Li Q,
Aldosterone blockade with eplerenone is indi- Funkhouser E, Centor RM, Selker HP, Weissman NW
(2002) Atypical presentations among Medicare bene-
cated in patients after MI who are already being
ficiaries with unstable angina pectoris. Am J Cardiol
treated with ACE inhibitors and beta-blockers and 90:248253
who have an LVEF <35 % and either diabetes or 10. Wu AH, Feng YJ (1998) Biochemical differences
heart failure, without significant renal dysfunction between cTnT and cTnI and their significance for
diagnosis of acute coronary syndromes. Eur Heart J
(serum creatinine >2.5 mg/dL for men and
19(Suppl N):N25N29
>2.0 mg/dL for women) or hyperkalemia (I; A). 11. Chang SA, Choi SI, Choi EK, Kim HK, Jung JW,
Statin therapy with target LDL-C levels Chun EJ, Kim KS, Cho YS, Chung WY, Youn TJ,
<70 mg/dL initiated early after admission is rec- Chae IH, Choi DJ, Chang HJ (2008) Usefulness of
64-slice multidetector computed tomography as an
ommended (I; B).
initial diagnostic approach in patients with acute chest
Patients with NSTE-ACS and severe LV dys- pain. Am Heart J 156:375383
function should be considered after 1 month for 12. Jolly SS, Yusuf S, Cairns J, Niemela K, Xavier D,
device therapy (CRT and/or ICD) in addition to Widimsky P, Budaj A, Niemela M, Valentin V, Lewis
BS, Avezum A, Steg PG, Rao SV, Gao P, Afzal R,
optimal medical therapy (IIa; B).
Joyner CD, Chrolavicius S, Mehta SR (2011) Radial
versus femoral access for coronary angiography and
intervention in patients with acute coronary syn-
dromes (RIVAL): a randomised, parallel group, mul-
References ticentre trial. Lancet 377:14091420
13. Windecker S, et al. ESC/EACTS Guidelines on myo-
1. Nichols M, Townsend N, Scarborough P, Rayner M cardial revascularization (2014) Eur Heart J
(2014) Cardiovascular disease in Europe 2014: epide- 35:25412619
miological update. Eur Heart J 35:2950 14. Ben-Gal Y, Moses JW, Mehran R, Lansky AJ, Weisz
2. GBD 2013 Mortality and Causes of Death G, Nikolsky E, Argenziano M, Williams MR,
Collaborators (2015) Global, regional and national Colombo A, Aylward PE, Stone GW (2010) Surgical
age-sex specific all-cause and cause-specific mortality vs. percutaneous revascularization for multivessel dis-
for 240 causes of death, 19902013: a systematic ease in patients with acute coronary syndromes: anal-
analysis for the Global Burden of Disease Study 2013. ysis from the ACUITY (Acute Catheterization and
Lancet 385:117 Urgent Intervention Triage Strategy) trial. JACC
3. Parikh NI, Gona P, Larson MG et al (2009) Long-term Cardiovasc Interv 3(10):10591067
trends in myocardial infarction incidence and case 15. Palmerini T, Genereux P, Caixeta A, Cristea E,
fatality in the National Heart Lung and Blood Lansky A, Mehran R, Dangas G, Lazar D, Sanchez
Institutes Framingham Heart study. Circulation R, Fahy M, Xu K, Stone GW (2011) Prognostic
119:1203 value of the SYNTAX score in patients with acute
4. Thygesen K et al (2012) ESC/ACCF/AHA/WHF coronary syndromes undergoing percutaneous coro-
Expert Consensus Document: Third Universal nary intervention: analysis from the ACUITY (Acute
Definition of Myocardial Infarction. Eur Heart Journal Catheterization and Urgent Intervention Triage
33:22512567 StrategY) trial. J Am Coll Cardiol 57(24):23892397
5. Fox KA, Eagle KA, Gore JM, Steg PG, Anderson FA 16. Brener SJ, Milford-Beland S, Roe MT, Bhatt DL,
(2012) The Global Registry of Acute Coronary Events, Weintraub WS, Brindis RG (2008) Culprit-only or
1999 to 2009 GRACE. Heart 96:10951101 multivessel revascularization in patients with acute
6. Terkelsen CJ, Lassen JF, Norgaard BL, Gerdes JC coronary syndromes: an American College of
et al (2005) Mortality rates in patients with Cardiology National Cardiovascular Database
ST-elevation vs. non -ST elevation acute myocardial Registry report. Am Heart J 155(1):140146
infarction: observations from an unselected cohort. 17. Hannan EL, Samadashvili Z, Walford G, Jacobs AK,
Eur Heart J 26:1826 Stamato NJ, Venditti FJ, Holmes DR Jr, Sharma S,
7. Hamm C, Heeschen C, Falk E, Fox KAA (2006) Acute King SB 3rd (2013) Staged vs one-time complete
coronary syndromes: pathophysiology, diagnosis and revascularization with percutaneous coronary inter-
risk stratification. In: Camm AJ, Luescher TF, Serruys vention for multivessel coronary artery disease
PW (eds) The ESC textbook of cardiovascular medi- patients without ST-elevation myocardial infarction.
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ERRNVPHGLFRVRUJ
Part II
Mimicking Ischemic Heart Disease
ERRNVPHGLFRVRUJ
Pericarditis
3
Alessia Urbinati and Marco Flori
None
A 43-year-old man was admitted to our car-
diology department, reporting a progressive
chest pain which referred to the neck and Vital Signs
left shoulder within the last 7 days.
Temperature: 36 C
Heart rate: 82 bpm
Arterial blood pressure: 140/80 mmHg
Medical History and Cardiovascular Respiratory rate: 12 breaths/min
Risk Factors Oxygen saturation: 99 %
ERRNVPHGLFRVRUJ
30 A. Urbinati and M. Flori
ERRNVPHGLFRVRUJ
3 Pericarditis 31
Fig. 3.3 Control ECG showing T-wave inversion in DI, aVL, V3, V4, V5, and V6
ERRNVPHGLFRVRUJ
32 A. Urbinati and M. Flori
ERRNVPHGLFRVRUJ
3 Pericarditis 33
Assessment of cardiovascular risk factors and pre- demanding physical activity help to minimize the
vious heart diseases may help in the diagnosis. symptoms.
Different characteristics of acute pericarditis and When pericardial effusion is present and clini-
ACS are shown in Table 3.1. Pneumothorax, acute cal examination and echocardiography suggest
pulmonary embolism, and acute aortic syndrome hemodynamic impairment of cardiac function
are other causes of acute chest pain with high (cardiac tamponade), pericardiocentesis should
mortality if undiagnosed and have to be excluded. be considered.
Other conditions that may simulate pericarditis Prognosis of acute pericarditis depends on eti-
are respiratory disorders (pneumonia, bronchitis, ology and comorbidities. Conditions such malig-
asthma), musculoskeletal diseases, herpes zoster, nancy, uremia, and HIV have the worse prognosis.
anxiety, and others, but ECG and cardiac bio- Viral or idiopathic pericarditis is usually a benign
marker alterations are rare in these conditions. condition with very low mortality.
Relapsing pericarditis is one of the most chal-
lenging complications of acute pericarditis, and
Therapy and Prognosis no optimal treatment for this disorder of the peri-
cardium has been definitively established. One or
Nonsteroidal anti-inflammatory drugs (NSAIDs) more recurrences arise up to 30 % of patients
are the first-line therapy in acute pericarditis. after an initial episode of acute pericarditis, usu-
High-dose aspirin, ibuprofen, or indomethacin ally within the first 18 months. Findings are simi-
may be used for 13 weeks, but no single NSAID lar to the initial episode, including pleuritic chest
appears to be more effective than the other [2]. pain, diffuse ST-segment elevation, and elevated
Colchicine has shown to be safe and effec- serum markers of inflammation [11]. Recurrences
tive in reducing recurrences [10]. Pericarditis must be differentiated from episodes of chest dis-
symptoms respond promptly to corticosteroid comfort with the patient reminiscent of prior
therapy. Nonetheless, corticosteroids are associ- pericardial pain but no other sign of recurrence
ated with increased recurrences and should only (no elevation of inflammatory markers, no ECG
be used when other therapies have shown to be alterations, pericardial rubs, or pericardial
ineffective. Concurrently, rest and avoidance of effusion).
ERRNVPHGLFRVRUJ
34 A. Urbinati and M. Flori
In the absence of specific clinical trials, 3. Zayas R, Anguita M, Torres F et al (1995) Incidence
of specific etiology and role of methods for specific
NSAIDs should be the first-line therapy of
etiologic diagnosis of primary acute pericarditis. Am
recurrences with a prolonged administration for J Cardiol 75(5):378382
24 weeks. Colchicine associated to NSAIDs 4. Maisch B, Ristic AD (2002) The classification of peri-
has shown to reduce episodes of recurrent peri- cardial disease in the age of modern medicine. Curr
Cardiol Rep 4:1321
carditis of additional 50 % [12]. If refractory
5. Imazio M et al (2011) Prevalence of C-reactive pro-
pericarditis is present, corticosteroid therapy tein elevation and time course of normalization in
should be considered using lower effective dose acute pericarditis. Circulation 123(10):10921097
for their side effects in long-term therapies. 6. Spodick DH (2003) Acute pericarditis: current con-
cepts and practice. JAMA 289:11501153
Immunosuppressors (methotrexate, azathioprine)
7. Holzmann M (1965) Klinische Elektrokardiographie.
have shown symptom improvement in a small Georg Thieme, Stuttgart, pp 511525
number of patients not respondent to steroids. 8. Casale PN, Deveraux RB, Kligfield P et al (1984)
Finally, few data of pericardiotomy in continuous Pericardial effusion: relation of electrocardiographic
finding. J Electrocardiol 17:115
relapsing pericarditis showed variable efficacy
9. Spodick DH (1974) The electrocardiogram in acute
with some patients reporting complete remission pericarditis: distributions of morphologic and axial
but others continuing to be plagued with ongoing changes in stages. Am J Cardiol 33:470474
symptoms [13]. 10. Imazio M et al (2005) Colchicine in addition to con-
ventional therapy for acute pericarditis. Circulation
112:20122016
11. Imazio M et al (2010) Controversial issues in the
References management of pericardial diseases. Circulation
121:916928
1. Imazio M, Cecchi E, Demichelis B et al (2008) 12. Imazio M, CORP (COlchicine for Recurrent
Myopericarditis versus viral or idiopathic acute peri- Pericarditis) Investigators et al (2011) Colchicine for
carditis. Heart 94(4):498501 recurrent pericarditis (CORP): a randomized trial.
2. Khandaker MH, Espinosa RE, Nishimura RA, Sinak Ann Intern Med 155:409414
LJ, Hayes SN, Melduni RM, Oh JK (2010) Pericardial 13. Khandaker MH et al (2012) Pericardiectomy vs medi-
disease: diagnosis and management. Mayo Clin Proc cal management in patients with relapsing pericardi-
85:572593 tis. Mayo Clin Proc 87:10621070
ERRNVPHGLFRVRUJ
Intracranial Bleeding
4
Alessia Urbinati and Michela Brambatti
ERRNVPHGLFRVRUJ
36 A. Urbinati and M. Brambatti
Fig. 4.2 Rest ECG showing incomplete right bundle block and normal repolarization
ERRNVPHGLFRVRUJ
4 Intracranial Bleeding 37
What Are the Possible Causes for ST coronary artery. In the following 48 h, ST eleva-
Elevation? tion gradually resolved, and waves were inverted
in DII, DIII, aVF, V4, V5, and V6 (Fig. 4.3).
A repeated head CT scan revealed a partial
Acute ST-segment elevation myocardial reduction of the encephalic bleeding. The patient
infarction (STEMI) was extubated and transferred to a spoke inten-
Coronary spasm sive care unit.
Pericarditis
Left ventricular aneurysm
Brugada syndrome 4.2 ECG Correlation
Left bundle branch block and Intracranial Bleeding
Left ventricular hypertrophy
Early repolarization ECG Abnormalities
Drugs (e.g., cocaine, digoxin, quinidine,
tricyclics, and many others) In patients with acute cerebrovascular events,
Electrolyte abnormalities (e.g., especially intracranial hemorrhage (ICH) and
hyperkalemia) ischemic stroke, electrocardiographic repolariza-
Neurogenic factors (e.g., stroke, hemor- tion abnormalities are frequently observed
rhage, trauma, tumor, etc.) regardless of the presence or absence of previous
Metabolic factors (e.g., hypothermia, cardiac diseases. Repolarization abnormalities
hypoglycemia, hyperventilation) warrant attention as they increase the vulnerable
period during which an extrasystole is more
likely to result in ventricular tachycardia or fibril-
What Are the Possible Causes lation. Repolarization abnormalities thus may
of Increased Troponin Level? explain the higher risk of arrhythmias and sudden
death following acute neurological disorders
[14].
Acute coronary syndrome The exact incidence of ECG abnormalities is
High blood pressure in lung arteries still unclear but ranges from 50 to 98 % and
(pulmonary hypertension) includes QT prolongation, T wave inversion,
Blockage of a lung artery by a blood prominent U wave, ST segment elevation or
clot, fat, or tumor cells (pulmonary depression, peaked P waves, and transient patho-
embolus) logical Q waves [1]. A typical, but not pathogno-
Congestive heart failure monic, pattern is characterized by giant T
Myocarditis waves, abnormally wide T waves of increased
Prolonged exercise amplitude (mostly negative than positive); eleva-
Trauma that injures the heart tion or depression of the ST segment is less fre-
Weakening of the heart muscle quent [4].
(cardiomyopathy) However, as in our case, these ST changes are
Long-term kidney disease particularly important since they may simulate
acute myocardial ischemia and therefore mislead
physicians in the initial diagnosis. In fact, uncon-
In a setting of acute coronary syndrome and scious patients with ICH and ST segment eleva-
ST elevation, the patient has been promptly tion may be misdiagnosed with acute myocardial
treated with metoprolol and acetylsalicylic acid infarction and could be incorrectly treated with
intravenous and a percutaneous coronary angiog- antiplatelet and anticoagulative drugs with devas-
raphy was urgently performed which showed just tating consequences. Also, in the setting of cere-
a non-critical stenosis (<30 %) of the right brovascular events, changes in ST segment have
ERRNVPHGLFRVRUJ
38 A. Urbinati and M. Brambatti
Fig. 4.3 Control ECG showing ST elevation in DII, DIII, aVF, V4, V5, and V6 and ST depression in aVR, aVL, V1, V2,
and V3
generally the same polarity of T wave, and among patients who have developed brainstem or
rarely, ST elevation is diffuse simulating acute peri-insular hematomas [8].
pericarditis. As a consequence of repolarization abnormal-
The ECG abnormalities usually reverse after ities, especially with prolonged QT interval,
the neurological clinical recovery. malignant ventricular arrhythmias, including
ventricular tachycardia, torsades de pointes, and
ventricular fibrillation, may also be observed [9].
Arrhythmias So, it is very important to check for QTc prolon-
gation and to select drugs that do not prolong QT
In a prospective study, serious arrhythmia in the interval.
first 72 h after admission with acute stroke was
detected in 25 % of 501 patients [5]. The risk for
cardiac arrhythmia was highest during the first Mechanisms Leading to ECG
24 h of care and declined with time during the Abnormalities
first 3 days. In previous series, cardiac arrhyth-
mias were detected in 625 % of patients after The mechanism through which cerebrovascular
stroke [6, 7]. events lead to these ECG abnormalities is still
Atrial fibrillation is the most common cardiac unknown; however, autoptic findings reported
arrhythmia accounting for nearly 60 % of all that over 50 % of patients had cardiac muscle
events of arrhythmia [5]. However, transient contraction band necrosis. The most plausible
atrial fibrillation is more common among patients hypothesis suggests that ECG changes result as a
with ischemic stroke than with ICH; in this latter consequent alteration of the autonomic nervous
setting, atrial fibrillation occurs more frequently system control on cardiac electrophysiology that
ERRNVPHGLFRVRUJ
4 Intracranial Bleeding 39
results in catecholamine release at the terminal 3. Korpelainen JT, Sotaniemi KA, Huikuri HV (1997)
MyllylVV Circadian rhythm of heart rate variability
nerve at the cardiac myocyte [2, 3]. Increase of
is reversibly abolished in ischemic stroke. Stroke
adrenergic stimulus increases myocardial oxygen 28(11):2150
demand, reduces coronary perfusion time, and 4. Byer E, Ashman R (1947) Toth La Electrocardiograms
also has a direct cardiotoxic effect with general- with large, upright T waves and long Q-T intervals.
Am Heart J 33(6):796
ized spasm of the coronary arteries. Some evi-
5. Kallmnzer B, Breuer L, Kahl N, Bobinger T, Raaz-
dence suggests also that sympathetic Schrauder D, Huttner HB, Schwab S, Khrmann M
stroke-related activity causes calcium overload in (2012) Serious cardiac arrhythmias after stroke: inci-
ventricular myocytes and consequently arrhyth- dence, time course, and predictors--a systematic, pro-
spective analysis. Stroke 43(11):28922897. Epub
mias. Furthermore, the type and location of the
2012 Sep 6
cerebrovascular event may correlate with the type 6. Goldstein DS (1979) The electrocardiogram in stroke:
of arrhythmia as each cerebral hemisphere seems relationship to pathophysiological type and compari-
to have a different influence on cardiac functions. son with prior tracings. Stroke 10(3):253
7. Rem JA, Hachinski VC, Boughner DR, Barnett HJ
Indeed, injury of the right insula may cause bra-
(1985) Value of cardiac monitoring and echocardiog-
dycardia and vasodepressor effects, while the left raphy in TIA and stroke patients. Stroke 16(6):950
insular region may pose a higher risk for tachy- 8. Yamour BJ, Sridharan MR, Rice JF (1980) Flowers
cardia and hypertension [10, 11]. NC Electrocardiographic changes in cerebrovascular
hemorrhage. Am Heart J 99(3):294
9. Cruickshank JM, Neil-Dwyer G, Brice J (1974)
Electrocardiographic changes and their prognostic
References significance in subarachnoid haemorrhage. J Neurol
Neurosurg Psychiatr 37:755759. doi:10.1136/
1. Dimant J, Grob D (1977) Electrocardiographic jnnp.37.6.755
changes and myocardial damage in patients with 10. Hachinski VC, Oppenheimer SM, Wilson JX et al
acute cerebrovascular accidents. Stroke 8(4): (1992) Asymmetry of sympathetic consequences of
448455 experimental stroke. Arch Neurol 49:697
2. Hachinski VC (1993) The clinical problem of brain 11. Lane RD, Wallace JD, Petrosky PP et al (1992)
and heart. Stroke 24(12 Suppl):I1I2; discussion Supraventricular tachycardia in patients with right
I102 hemisphere strokes. Stroke 23:362
ERRNVPHGLFRVRUJ
Takotsubo Cardiomyopathy
5
Giulia Pongetti and Azzurra Fabbrizioli
ERRNVPHGLFRVRUJ
42 G. Pongetti and A. Fabbrizioli
ERRNVPHGLFRVRUJ
5 Takotsubo Cardiomyopathy 43
A pulmonary embolism is unlikely for the low angina) although it may consider a possible
pretest probability (the patient has never suffered posterior ST elevation with anterior ST depres-
previous pulmonary embolism or deep vein sion as a mirror image.
thrombosis; she didnt have previous surgery, A phlogistic damage (myocarditis, myopericar-
trauma, long immobilization, or cancer; and she ditis) is unlikely because the EKG modifications
never used hormone replacement therapy). are not typical and not widely represented in all the
Furthermore, the normal D-dimer level excludes EKG leads; moreover, the patient didnt report flu
this affection with high sensitivity. or gastrointestinal disease, and the laboratory tests
Pneumothorax and thoracic fractures can be did not show clear signs of a phlogistic state.
excluded because physical examination and chest The chest pain referred by the patient was
x-ray were normal. quite typical for angina or also could suggest
The EKG shows ST segment depression in an aortic damage caused by car accident. An
anterior leads which ruled out coronary spasm, echocardiography was done to evaluate those
usually characterized by ST elevation (Prinzmetal possible diagnostic alternatives.
ERRNVPHGLFRVRUJ
44 G. Pongetti and A. Fabbrizioli
a b
Fig. 5.2 Echocardiographic picture recorded at rest dur- akinesis in the apical to mid-segments circumferentially
ing systole (a) and during diastole (b); typical LV balloon- of the left ventricle with relative compensatory hypercon-
ing during systole is visible, characterized by complete tractility in the basal segments
ERRNVPHGLFRVRUJ
5 Takotsubo Cardiomyopathy 45
a b
Fig. 5.3 Coronary angiography of left coronary artery (a) and right coronary artery (b); right coronary dominance and
absence of significant coronary artery stenosis are shown
a b
Fig. 5.4 Left ventriculography recorded during diastole (a) and systole (b); complete apical akinesis and mid-ventric-
ular akinesis are shown, with systolic apical ballooning and moderate systolic dysfunction
apical ballooning and moderate systolic dys- presentation and with low plasma levels of car-
function. No spasm was recorded (Fig. 5.4). diac biomarkers, disproportionate with the sever-
ity of ventricular dysfunction, could suggest the
Conclusion diagnosis of Takotsubo cardiomyopathy. This
Absence of significant culprit coronary artery diagnosis is confirmed by findings on imaging
stenosis or intracoronary thrombosis (echocardiography and ventriculography) of
Apical ballooning pattern transient apical- to mid-ventricular ballooning
with compensatory basal hyperkinesis, without
coronary stenosis.
Final Diagnosis Subsequent blood tests have shown normaliza-
tion of cardiac biomarkers (max values: troponin I
The clinical presentation that mimics an acute 2.45 ng/mL, CK MB 6.7 ng/mL), and echocar-
myocardial infarction triggered by emotional diography has displayed progressive recovery of
stress (car accident) with modest EKG changes at contractile function until complete normalization.
ERRNVPHGLFRVRUJ
46 G. Pongetti and A. Fabbrizioli
Subsequent EKGs performed during hospital- branch block (QTS 140 ms), and normal ST seg-
ization showed the typical evolution described in ment with deep inverted T waves from V1 to V6
TC with new onset of negative and deep T waves and DI, DII, AVL, and AVF (QTc interval of
and marked QTc interval prolongation and then 624 ms) (Fig. 5.5).
slow and complete regression of these abnormali- The patient was discharged with the following
ties after about 15 days. therapy:
Fig. 5.5 EKG at rest during the third day of hospitalization while the patient was asymptomatic
ERRNVPHGLFRVRUJ
5 Takotsubo Cardiomyopathy 47
ERRNVPHGLFRVRUJ
48 G. Pongetti and A. Fabbrizioli
neck. When present, a typical aspect useful for lar name: it resembles a typical pot (called
diagnosis is that the chest pain usually occurs exactly Takotsubo) used for a long time in
after mental or physical stress, such as the unex- Japan to capture octopuses, which has a round
pected death of a relative or friend or receiving bottom and a narrow neck.
news of serious diagnosis or having a great Other patterns of wall motion abnormality
fright [13]. However, recently an international have been reported less frequently, involving
meta-analysis (COUNTS study) has shown that the basal-mid segment (apical sparing variant
these stressors have a limited impact occurring or inverted Takotsubo) or the right ventricle.
in about only 36 % of patients [14]. In men, Typically, the wall motion abnormality
physical stress rather than emotional stress is involves regions which are incongruent to a
much more associated with the occurrence [4]. particular coronary artery supply; instead dur-
Dyspnea, nausea, and diaphoresis can accom- ing an AMI, it is more common to find these
pany chest pain. hypokinetic/akinetic areas supplied by a par-
Comorbidities: A high number of patients ticular coronary artery.
affected by TS present cardiovascular risk fac-
tors like hypertension (54 %), dyslipidemia
(32 %), diabetes mellitus, obesity, and history Clinical Course and Complications
of smoking, similar to that seen in patients with
AMI [14]. Moreover, it has been noted that Clinical course of TC is usually characterized by
sometimes TS can occur in patients affected by the progressive lowering of chest pain and gradu-
comorbidities that are usually associated with ally complete resolution of the wall motion
an excess of catecholamine systemic produc- abnormality after some days; less frequently it
tion like obstructive pulmonary disease, sepsis, needs some weeks or months, but differently
thyroid (thyrotoxicosis), or neurological dis- from AMI, there arent permanent areas of hypo-
ease (cerebrovascular accidents, subarachnoid kinesis/akinesis of the left ventricle motion.
haemorrhage, etc.) [3], malignancy, or psycho-
logical disorders (22 %) [14]. EKG evolution: The EKG abnormalities show
12-Lead EKG: During the acute phase, it usu- a slower progression than during AMI, with a
ally shows ST segment depression or tran- specific evolution: gradually during the first
sient/persistent ST segment elevation in hours from symptom onset, there is the com-
anterior leads, perfectly mimic king acute plete resolution of ST segment elevation/
myocardial infarction [1518]. Sometimes it depression. Negative T waves usually occur
can show also T-wave inversion or Q waves. after 2472 h and then gradually deepen pro-
In subsequent days, the EKG abnormalities gressively during the days/weeks following
follow a distinctive time sequence [19]. [20]. Abnormal Q waves could be seen in pre-
Cardiac biomarkers: Troponin, creatinine cordial leads, but these are transient in most
kinase, and BNP are usually increased. patients and generally resolve within a few
Echocardiography: It plays a central role days to several weeks.
during diagnostic process because it shows a QTc interval becomes prolonged (>500 ms)
typical pattern of wall motion abnormality: progressively as the negative T wave deepens,
complete akinesis or hypokinesis in the apical and this could favor life-threatening ventricu-
to mid-segments circumferentially of the left lar arrhythmias such as torsades de pointes
ventricle with relative compensatory hyper- and ventricular fibrillation [18].
contractility in the basal segments (LV bal- After some weeks, there is usually the
looning during systole). During left complete restoration of the ECG pattern prior
ventriculography, this particular systolic left to the acute event [15].
ventricular shape is more evident and explains Recurrences: These may occur with a rate
the reason why this syndrome has this particu- range from 0 to 15 % after the first episode
ERRNVPHGLFRVRUJ
5 Takotsubo Cardiomyopathy 49
and may show the typical apical ballooning or first diagnostic criteria in 2004, which have been
even different patterns of wall motion abnor- modified recently (2008) and included [25, 26]:
malities [21].
Acute complication: Despite the most com- 1. Transient hypokinesis, dyskinesis, or akinesis
mon general favorable course, the in-hospital of the left ventricular midsegments, with or
death ranges from 0 to 8 % because of possi- without apical involvement; the regional wall
ble acute complications [22]. Congestive heart motion abnormalities extend beyond a single
failure is one of the most common acute com- epicardial vascular distribution, and a stress-
plications (approximately 346 %) occurring ful trigger is often, but not always, present.
more frequently in patients with right ventric- 2. Absence of obstructive coronary disease or
ular involvement [22]. angiographic evidence of acute plaque
As already mentioned, during the acute and rupture.
subacute phases, corrected QT (QTc) interval is 3. New ECG abnormalities (either ST segment
markedly prolonged (usually >500 ms), and this elevation or T-wave inversion) or modest ele-
is a potential risk factor for life-threatening vation in cardiac troponin.
arrhythmias such as torsades de pointes and 4. Absence of pheochromocytoma or
ventricular fibrillation that could require exter- myocarditis.
nal defibrillation [23]. Bradycardia, hypokale-
mia, hypomagnesemia, and the use of Patients were assigned this diagnosis when
antiarrhythmic drugs may favor arrhythmias they satisfied all these criteria.
when there is QTc prolongation, so they have to Japanese investigators have recently presented
be quickly corrected. The reversible nature of diagnostic guidelines [27].
the cardiomyopathy suggests that the use of sys- There is not a single shared diagnostic test so
tematic device implantation after a ventricular TC is currently a diagnosis of exclusion.
arrhythmias isnt recommended at the moment. Furthermore in addition to clinical features,
Apical thrombosis may occur during the acute EKG, and echocardiography abnormalities,
phase when the wall motion abnormalities are coronary angiography is mandatory to exclude
more evident, due to low blood flow within the coronary plaque rupture (culprit lesion) which
apical segment. This could become a potential would need angioplasty and stent implantation or
source of emboli especially when the resolu- multivessel epicardial coronary spasm. Most
tion of the apical akinesis/dyskinesis occurs patients have angiographically normal coronary
[24]. Prophylactic anticoagulation therapy arteries or mild atherosclerosis (considering
should be considered to prevent apical throm- advanced age and several coronary risk factors). In
bosis and embolic events until the resolution fact, many authors have attempted to find unique
of the apical ballooning. ECG criteria capable of distinguishing between
Hypotension occurs frequently and can result Takotsubo and STEMI patients during the acute
from LVOT obstruction associated with basal phase, but actually no criteria have been found,
hypercontractility, complicated by systolic and ECG keeps a limited diagnostic role [18, 20].
anterior movement of the mitral valve anterior Cardiac magnetic resonance is a suitable
leaflet and mitral regurgitation. method to establish TC diagnosis. It allows to
Cardiogenic shock and ventricular rupture are evaluate the global systolic function and the area
rare complications described in literature. of wall motion abnormalities; moreover, it shows
the area of myocardial edema, which is a typical
finding in TC, inflammation, and fibrosis.
Diagnosis Contrary to myocardial infarction or myocarditis,
there arent areas of delayed enhancement
There is yet no consensus on the diagnostic criteria because in TC there isnt an irreversible damage
for TC: researchers at the Mayo Clinic proposed [28, 29].
ERRNVPHGLFRVRUJ
50 G. Pongetti and A. Fabbrizioli
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5 Takotsubo Cardiomyopathy 51
infarction with minimal enzymatic release. Circ J 23. Madias C, Fitzgibbons TP, Alsheikh-Ali AA et al
68(1):7781 (2011) Acquired long QT syndrome from stress
16. Kosuge M, Kimura K (2014) Electrocardiographic cardiomyopathy is associated with ventricular
findings of takotsubo cardiomyopathy as compared arrhythmias and torsades de pointes. Heart Rhythm
with those of anterior acute myocardial infarc- 8(4):555561. doi:10.1016/j.hrthm.2010.12.012
tion. J Electrocardiol 47(5):684689. doi:10.1016/j. 24. Kurisu S, Inoue I, Kawagoe T et al (2011) Incidence
jelectrocard.2014.03.004 and treatment of left ventricular apical thrombosis in
17. Johnson NP, Chavez JF, Mosley WJ, Flaherty JD, Fox Tako-tsubo cardiomyopathy. Int J Cardiol 146(3):e58
JM (2013) Performance of electrocardiographic criteria e60. doi:10.1016/j.ijcard.2008.12.208
to differentiate Takotsubo cardiomyopathy from acute 25. Prasad A, Lerman A, Rihal CS (2008) Apical balloon-
anterior ST elevation myocardial infarction. Int J Cardiol ing syndrome (Tako-Tsubo or stress cardiomyopathy):
164(3):345348. doi:10.1016/j.ijcard.2011.07.029 a mimic of acute myocardial infarction. Am Heart J
18. Guerra F, Rrapaj E, Pongetti G et al (2013) Differences 155(3):408417. doi:10.1016/j.ahj.2007.11.008
and similarities of repolarization patterns during hos- 26. Prasad A (2007) Apical ballooning syndrome: an
pitalization for Takotsubo cardiomyopathy and acute important differential diagnosis of acute myocardial
coronary syndrome. Am J Cardiol 112(11):1720 infarction. Circulation 115(5):e56e59. doi:10.1161/
1724. doi:10.1016/j.amjcard.2013.07.036 CIRCULATIONAHA.106.669341
19. Mitsuma W, Kodama M, Ito M et al (2007) Serial elec- 27. Kawai S, Kitabatake A, Tomoike H (2007) Guidelines
trocardiographic findings in women with Takotsubo for diagnosis of takotsubo (ampulla) cardiomyopathy.
cardiomyopathy. Am J Cardiol 100(1):106109. Circ J 71(6):990992, http://www.ncbi.nlm.nih.gov/
doi:10.1016/j.amjcard.2007.02.062 pubmed/17527002. Accessed January 11, 2015
20. Duran-Cambra A, Sutil-Vega M, Fiol M et al (2014) 28. Kohan AA, Levy Yeyati E, De Stefano L et al
Systematic review of the electrocardiographic (2014) Usefulness of MRI in takotsubo cardio-
changes in the takotsubo syndrome. Ann Noninvasive myopathy: a review of the literature. Cardiovasc
Electrocardiol 20:16. doi:10.1111/anec.12228 Diagn Ther 4(2):138146. doi:10.3978/j.issn.2223-
21. Elesber AA, Prasad A, Lennon RJ, Wright RS, 3652.2013.10.03
Lerman A, Rihal CS (2007) Four-year recurrence 29. Eitel I, Behrendt F, Schindler K et al (2008)
rate and prognosis of the apical ballooning syndrome. Differential diagnosis of suspected apical balloon-
J Am Coll Cardiol 50(5):448452. doi:10.1016/j. ing syndrome using contrast-enhanced magnetic
jacc.2007.03.050 resonance imaging. Eur Heart J 29(21):26512659.
22. Kurisu S, Kihara Y (2012) Tako-tsubo cardiomy- doi:10.1093/eurheartj/ehn433
opathy: clinical presentation and underlying mecha- 30. Kurisu S, Kihara Y (2014) Clinical management of
nism. J Cardiol 60(6):429437. doi:10.1016/j. takotsubo cardiomyopathy. Circ J 78(7):15591566.
jjcc.2012.06.015 doi:10.1253/circj.CJ-14-0382
ERRNVPHGLFRVRUJ
Early Repolarization Pattern
6
Azzurra Fabbrizioli and Giulia Pongetti
Allergies
None
Medications
None
ERRNVPHGLFRVRUJ
54 A. Fabbrizioli and G. Pongetti
ERRNVPHGLFRVRUJ
6 Early Repolarization Pattern 55
Normal both atria size (LA diameter Complete blood count: normal.
M-mode = 3.6 cm; area 4c = 18 cm2, RA area Cholesterol (total, HDL, LDL) and TG:
4c = 16 cm2). Normal size and wall thickness of normal.
the left ventricle (iLVEDV 42 ml/m2), which Hepatic function (GOT, GPT, -GT, ALP, total
shows a preserved systolic function (ejection bilirubin, direct and indirect): normal.
fraction with Simpsons method 0.67). Normal Thyroid function (TSH, FT3, FT4): normal.
size and global function of the right ventricle Renal function (creatinine, BUN): normal.
(TAPSE 23 mm). Electrolytes (Na+, K+, Ca++, Mg++, Cl):
Normal morphology of the cardiac valves; normal.
mild tricuspid regurgitation and normal systolic Fasting blood glucose: 102 m/dl
pressure gradient (PASP = 25 mmHg). Normal (5.67 mmol/L).
size of the aortic root (24 mm) and of the proxi- Troponin I-hs: 0.012 ng/ml (n.v < 0.055 ng/ml)
mal ascending aorta (28 mm); normal size of the Inflammation index: VES 35 mm/h (n.v < 27
aortic arch (26 mm) and the descending thoracic mm/h), CRP 0.2 mg/dl (n.v <0.6 ng/ml)
aorta (22 mm) in the explored segments too. The D-dimers: 150 ng/mL (n.v. < 280 ng/mL)
inferior vena cava has also a normal size (12 mm)
and physiological collapsing during inspiration. The echocardiographic findings are com-
Normal diastolic pattern without increased filling pletely normal, so we can rule out cardiomyopa-
pressure (E/A 0.9, E/E 6, E dec time 210 m/s). thies and any severe valvular disease as previously
Absence of pericardial effusion. supposed.
Conclusion: normal echocardiographic find- Similarly, the aortic size is normal, and there
ings for a 38-year-old man. are no signs of acute aortic dissection (intimal
ERRNVPHGLFRVRUJ
56 A. Fabbrizioli and G. Pongetti
flap) or intramural hematoma. Furthermore, the amplitude or disappear in the leads in which the
biomarkers are normal (D-dimer and troponin), ST elevation is observed (see Chap. 1).
and the symptoms referred by the patients are not The repolarization abnormalities in our patient
typical of acute aortic syndrome. Moreover, he were not typical of an acute pulmonary embolism,
didnt present any cardiovascular risk factor, with which is usually characterized by sinus tachycar-
the exception of the smoking habit. He did not dia, or other atrial arrhythmias, complete or incom-
have any familial history of arterial disease. plete right bundle branch block, pulmonary P
The EKG recorded while the patient was wave, ST-segment abnormalities, and/or inverted
asymptomatic showed ST-segment elevation in T wave in right precordial leads. Clinical signs and
precordial leads (V2V6), with positive T wave symptoms and the normal D-dimer level highly
and a concave pattern, without any reciprocal contribute to exclude pulmonary embolism.
ST-segment changes in the other leads. There were no peaked T waves (tended) in
right precordial leads as we could expect during
hyperkalemia; moreover, the laboratory tests
The Most Common Causes ruled out any electrolyte abnormality.
of ST-Segment Elevation The EKG pattern was also not typical of
in a Young Man Brugada type 1 pattern (ST-segment elevation
2 mm descending with an upward convexity,
inverted T wave in at least one right precordial
Acute coronary syndrome with ST- lead); the clinical history was also negative for
segment elevation (ACS-STEMI) with syncope or tachyarrhythmic episodes.
or without possible coronary spasm Acute pericarditis could be more likely, espe-
Myocarditis/pericarditis cially according to chest pain, early recurrence,
Early repolarization pattern and its characteristics. Usually in this pathology,
Acute pulmonary embolism the ST-segment elevation is diffuse in all the leads
Hyperkalemia and little pronounced; QRS complex generally
Brugada syndrome shows a reduction in amplitude, and PR can be
Acute aortic dissection depressed in many leads. In myocarditis, the most
common EKG finding is diffuse T wave inver-
sion, whereas ST-segment displacement is less
common. The absence of flu during the days/
The first hypothesis we have to exclude is weeks before, the normal values of the logistic
ACS-STEMI. Even though there was an index at the laboratory tests together with the
ST-segment elevation in more than one precor- absence of pericardial effusion or wall motion
dial lead, it should be 0.25 mV when measured abnormalities made those hypotheses unlikely.
at the J point in a man under 40 years. Moreover,
the upward concavity is not typical of STEMI;
the limb leads showed an essentially normal Final Diagnosis
repolarization pattern, and there were no recipro-
cal EKG changes. By considering also normal According to the clinical history, echocardio-
echocardiography and laboratory results and the graphic findings, and laboratory tests, we con-
clinical history (previous recent coronary angiog- cluded that the EKG abnormalities were due to
raphy was completely normal), we excluded the an early repolarization pattern.
ACS hypothesis. An exercise testing was performed showing a
The EKG pattern in possible coronary spasms complete normalization of the ST-segment eleva-
is also different because in addition to the tion during exercise with a slow and progressive
ST-segment modification the R wave may return during recovery (Fig. 6.2). That confirmed
become taller and the S wave may decrease in our diagnostic hypothesis.
ERRNVPHGLFRVRUJ
6 Early Repolarization Pattern 57
Fig. 6.2 EKG recorded during exercise testing showing the ER pattern at rest (a), normalization of the ST-segment
elevation during exercise (b); slow return to the baseline and then progressive return of the ER pattern (c, d)
ERRNVPHGLFRVRUJ
58 A. Fabbrizioli and G. Pongetti
ERRNVPHGLFRVRUJ
6 Early Repolarization Pattern 59
ERRNVPHGLFRVRUJ
60 A. Fabbrizioli and G. Pongetti
(Ito), which starts the repolarization phase [10, BRUGADA SYNDROME: in Brugada type 1
11]. In this way, there is a voltage gradient pattern, there is typical coved J wave- ST seg-
between the epicardium and endocardium which ment elevation 2 mV and an inverted T wave
produces the J wave on the surface EKG. When in at least one right precordial lead [11]. The J
this voltage gradient occurs later in the action wave may be accentuated by increased vagal
potential, it is responsible for the ST-segment tone and fever and may be unmasked by the
elevation. class I antiarrhythmic drugs (flecainide, ajma-
line, and procainamide) [11, 12].
One of the key points about ER is to discriminate Exercise or isoproterenol test may cause
this benign condition from other disorders regression of the ST-segment elevation, pre-
presenting ST-segment elevation and requiring sumably as a result of a diminished difference
specific medical treatment. between ventricular action potential durations
during sympathetic stimulations. This phe-
ACS-STEMI: the diagnosis of ACS-STEMI is nomenon may be clinically useful to diagnose
clinical and electrocardiographic. The typical ER pattern in patients with low suspect of
ischemic EKG changes usually show acute myocardial infarction or acute pericardi-
ST-segment elevation 0.25 mV in men below tis [9].
the age of 40 years and 0.2 mV in men over
40 years or 0.15 mV in women, when mea-
sured at the J point in at least two contiguous Clinical Features and Risk
leads, and reciprocal changes. The lack of Stratications
reciprocal changes (without changes except
aVR) and the isolated ST-segment elevation The main question about early repolarization is
reduce the positive predicted value for STEMI; its possible relation to an arrhythmic risk eventu-
anyway, it can be useful in the comparison ally causing sudden cardiac death (SCD) in
with previous EKG and the evaluation of young subjects.
symptoms, cardiovascular history, echocar- A first report in 1984 showed an association
diography, cardiac biomarkers, and serial between an ER pattern and ventricular fibrillation
EKG monitoring. (VF) [13]. More recently in 2008, Haissaguerre
Acute Pericarditis: the typical EKG modifica- et al. demonstrated in a large study that ER pat-
tions during an acute pericarditis are diffuse tern is six times more common in patients who
concave ST-segment elevation with positive T suffered previous VF than in matched controls;
waves and no reciprocal ST-segment depression moreover, these patients have more likely an
(except in aVR and V1). In about 50 % of cases, increased risk of recurrent SCD [2].
PR segment depression may be visible which In particular, it seems that the ER pattern in
usually occurs in all leads except aVR and V1, inferior leads is the one with the most increased
and it is pathognomonic of acute pericarditis. arrhythmic risk of SCD, especially when the J
To achieve the right diagnosis of acute point is >2 mm (three-fold risk increased), as
pericarditis, the comparison with previous demonstrated in a control study with over 10,000
EKG is useful, considering symptoms, pres- patients, followed for 30 years [4].
ence of pericardial rubbings, pericardial effu- In 2011, Tikkanen et al. analyzed the different
sion, positive cardiac biomarkers, and serial electrocardiographic phenotypes in ER and their
EKG monitoring to evaluate the typical time long-term outcome, distinguishing between
modification. benign and malignant forms. In the benign
ERRNVPHGLFRVRUJ
6 Early Repolarization Pattern 61
ERRNVPHGLFRVRUJ
62 A. Fabbrizioli and G. Pongetti
arrhythmia death: a meta-analysis. J Am Coll Cardiol syndrome. Pacing Clin Electrophysiol 35:e234e238.
61(6):645650. doi:10.1016/j.jacc.2012.11.023. doi:10.1111/j.1540-8159.2012.03460.x
Epub 2013 Jan 2 18. Kalla H, Yan GX, Marinchak R (2000) Ventricular
16. Rosso R, Kogan E, Belhassen B et al (2008) J-point fibrillation in a patient with prominent J (Osborn)
elevation in survivors of primary ventricular fibrilla- waves and ST segment elevation in the inferior elec-
tion and matched control subjects incidence and trocardiographic leads: a Brugada syndrome variant?
clinical significance. J Am Coll Cardiol 52: J Cardiovasc Electrophysiol 11:9598
12311238 19. The ACC/AHA/HRS (2008) guidelines for device-
17. Myojo T, Sato N, Nimura A, Matsuo A, Taniguchi O, based therapy of cardiac rhythm abnormalities: their
Nakamura H et al (2012) Recurrent ventricular fibril- relevance to the cardiologist, internist and family phy-
lation related to hypokalemia in early repolarization sician. J Invasive Cardiol 2009;21(5):234237.
ERRNVPHGLFRVRUJ
Part III
Heart Failure and Resynchronization
Therapy
ERRNVPHGLFRVRUJ
Acute Heart Failure
and Pulmonary Edema 7
Andrea Romandini and Simone Maffei
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66 A. Romandini and S. Maffei
ERRNVPHGLFRVRUJ
7 Acute Heart Failure and Pulmonary Edema 67
ERRNVPHGLFRVRUJ
68 A. Romandini and S. Maffei
function including pericardial disease, myocar- gradual body weight gain [8]. Volume over-
dial disease, endocardial disease, valvular heart load is only one of the possible hemodynamic
disease, arrhythmias and conduction disorders, perturbations that may explain the elevated
congenital heart disease, high output state, or vol- filling pressure. Additional pathophysiologic
ume overload state. These patients may present mechanisms are afterload mismatch (increased
with reduced or preserved left ventricular (LV) afterload) and abnormal end-ventricular dia-
systolic function. LV ejection fraction (LVEF) is stolic pressure (related to ventricular diastolic
considered important in classification of patients dysfunction/abnormal compliance and valvular
with HF because of differing patient prognosis regurgitation). Pulmonary congestion, with or
and response to therapies and because most clini- without associated systemic signs, may be the
cal trials selected patients based on LV ejection results of two different pathways. The cardiac
fraction (LVEF). For this reason, patients with HF (central) pathway is the mechanism by which a
are broadly categorized (with some difference low cardiac output (usually an acute decrease
among major international guidelines) in HF with induced by a variety of precipitant mecha-
preserved EF (normal or mildly reduced LVEF nisms including ischemia, arrhythmia, inflam-
and LV not dilated) and HF with reduced EF matory activation or progression of underlying
(LVEF usually 3540 %). An episode of acute HF process induced by progressive myocardial
heart failure or acute heart failure syndrome dysfunction) leads to a further neurohormonal
(AHFS) is usually defined as a rapid or gradual activation, lower renal perfusion (cardiorenal
onset (or change) of symptoms and signs of heart syndrome), and fluid accumulation with sys-
failure (HF) requiring immediate medical atten- temic congestion (overload fluid retention) [9,
tion (unplanned hospitalization or office room 10]. The vascular (peripheral) pathway is related
visit). Patients with AHFS are generally classified to increased vascular stiffness/resistance with
into those presenting with HF for the first time (de acute afterload mismatch impairing systolic per-
novo AHF) and those with worsening chronic HF. formance and resulting in redistribution of fluid
from systemic to pulmonary circulation rather
than in general fluid retention [2, 9, 10]. Venous
Pathophysiology of AHFS volume mobilization of the splanchnic circula-
tion has also been proposed as complementary
Regardless of the underlying cause or superim- mechanism [11]. Although in most cases both
posed precipitating factor, pulmonary and sys- pathways are active during an AHF event, the
temic congestion (due to increased left- and/or magnitude of one pathway may predominate in
right-side heart filling pressures), with or without each patient and is usually suspected according
low cardiac output, is the unifying finding in the to AHF initial clinical presentation.
broad spectrum of hemodynamic models in
AHFS [2, 3]. Congestion and not low cardiac
output is the main cause for AHFS [47]. Precipitants of Acute Heart Failure
High left-side filling pressure results in pul-
monary hypertension (pulmonary congestion) Approximately 80 % of acute decompensated
with increased pulmonary capillary wedge pres- heart failure (ADHF) patients have a worsening
sure (PCWP) that preceded the subsequent clini- of chronic heart failure. In such patients with pre-
cal congestion with pulmonary interstitial and existing HF, one or more identifiable exacerbat-
alveolar edema. ing factors not necessarily related to the evolution
High right-side filling pressure results in of the underlying HF disease can be often identi-
systemic venous hypertension (systemic con- fied (up to 70 %) (Table 7.1). Detection and treat-
gestion) with increased central venous pres- ment of precipitating factors is necessary both for
sure (CVP) leading to jugular vein distension acute management of an episode of AHF and pre-
and often subsequent peripheral edema and vention of its recurrence.
ERRNVPHGLFRVRUJ
7 Acute Heart Failure and Pulmonary Edema 69
Table 7.1 Precipitants of acute heart failure Table 7.2 Common physical findings in HF
Precipitants and causes of acute heart failure syndromes Possible physical findings in heart failure
(AHFSs) More specific
Rapid deterioration Gradual deterioration Third heart sound (S3)
Rapid arrhythmias Arrhythmias Jugular venous distension
Acute coronary syndromes Infections (including Hepatojugular reflux
(ACSs) endocarditis)
Laterally displaced apical impulse
Mechanical complications Exacerbation of COPD/
Cardiac murmurs
of ACS asthma
Less specific
Acute pulmonary Anemia
embolism Pulmonary rales
Hypertensive crisis Renal failure Decreased breath sounds at lung bases (pleural
effusion)
Cardiac tamponade Use of drugs that
increase Na+ retention Peripheral edema and ascites
(steroids, NSAIDs, etc.) Hepatomegaly
Additional acute CV Nonadherence with HF Tachycardia
disorders (acute aortic medications or diet Tachypnea
dissection, myocarditis) regimen (including Irregular rhythm (ectopic beats or atrial fibrillation)
alcohol abuse)
Muscle wasting (cachexia)
Peripartum Poor controlled
cardiomyopathy hypertension Data from McMurray et al. [1]
Acute mechanical valve Endocrine abnormalities
dysfunction
On the basis of typical clinical and hemody-
Modified and reproduced with permission from McMurray namic characteristics, AHF patients may present
et al. [1]
with one of several distinct clinical profiles con-
sidering that some overlap between groups may
Clinical Proles at Presentation exist [8]. The main clinical profiles and relative
features are summarized in Table 7.3.
The two major classes of symptoms in HF are Another classification scheme has been previ-
those due to volume overload (dyspnea, orthop- ously proposed (Forrester classification) and is
nea, paroxysmal nocturnal dyspnea, cough, gas- based on the severity of disease at presentation
trointestinal symptoms) and those due to a rather than on the cause of HF [12, 13]. It is a
reduction in CO (fatigue and weakness). The simple strategy to classify patients into specific
most common are dyspnea and fatigue. Dyspnea hemodynamic profiles that may be helpful to
(at exertion or at rest) is related to complex physi- guide the initial management strategy.
ological mechanisms involving both pulmonary Accordingly, a patient presenting with AHFS
venous congestion and a buildup of lactic acid by may be classified into one of the four specific
working muscle increasing the ventilatory hemodynamic profiles based on the absence or
response to exercise. On the other hand, low car- presence of signs of congestion (wet or dry) and
diac output state often results in fatigue and the adequacy of peripheral perfusion (warm or
weakness due to reduced skeletal muscle perfu- cold): warm and dry, warm and wet, cold and dry,
sion or atrophy. Elevated systemic venous pres- and cold and wet.
sures like those occurring in volume overload or
right ventricular dysfunction states are responsi-
ble for abdominal discomfort (liver congestion Clinical Assessment and Diagnosis
and abdominal ascites), anorexia, and peripheral of AHF
edema. Common physical findings are summa-
rized in Table 7.2. The most common clinical Traditionally, the diagnosis of HF is a clinical
findings are dyspnea (approximately 90 %), rales, diagnosis combining characteristic symptoms
and peripheral edema (65 %). with physical findings, and still today no single
ERRNVPHGLFRVRUJ
70 A. Romandini and S. Maffei
tests can absolutely establish its presence or sions. Radiographic evidence of signs of pulmo-
absence. Unfortunately, signs and symptoms of nary congestion in a patient with dyspnea makes
HF often overlap with those of other common the diagnosis of heart failure more likely; how-
medical conditions (especially with chronic lung ever, the absence of radiographic pulmonary con-
disease), and those more specific are also less gestion does not exclude diagnosis of
common (like orthopnea and paroxysmal noctur- AHF. Patients with chronic heart failure, despite
nal dyspnea) or less reproducible (third heart AHF symptoms and elevated PCWP, may have
sound and jugular venous distension) so that sev- few radiographic signs because of enhanced lym-
eral ancillary tests, also contributing to determine phatic drainage. Electrocardiography (ECG) is
mechanisms underlying the AHF, are usually not useful for diagnosis but offers possible clues
needed to support the clinical diagnosis of AHF. to identify both specific treatable precipitating
A chest radiography should be performed ini- factors of AHF (acute myocardial ischemia and
tially because it may aid in diagnosis of HF as arrhythmias) and also possible etiology of HF
well as in ruling out other differential diagnoses (e.g., Q wave in ischemic cardiomyopathy).
(e.g., pneumonia). Findings suggestive of HF Laboratory tests (blood chemistry and hema-
include cardiomegaly (cardiac-to-thoracic width tological tests) are useful to guide initial therapy,
ratio above 50 %), upper zone vascular redistri- to detect reversible cause of HF (e.g., hypocalce-
bution (cephalization), interstitial edema with mia, thyroid dysfunction) and comorbidities
Kerley B-lines, alveolar edema, and pleural effu- (anemia), and to obtain prognostic information.
ERRNVPHGLFRVRUJ
7 Acute Heart Failure and Pulmonary Edema 71
Serial monitoring of myocardial necrosis bio- function, and pulmonary artery pressure). The
markers (troponin) is recommended initially for TD-derived E/Ea parameter is being used to non-
diagnostic (exclude acute coronary syndrome) invasively estimate LV filling pressures. In addi-
and prognostic purpose. Troponin elevation in tion, especially for those with hypotensive AHFS,
acute HF does not necessarily indicate the pres- echocardiographic assessment of inferior vena
ence of an acute coronary syndrome. A signifi- cava (IVC) diameter and its respiratory variation
cant number of patients with AHFS have aid to determine the patient volume status.
increased levels of troponin as a result of myocar-
dial injury during AHF episode resulting from
ischemic injury and myocyte apoptosis. Such tro- AHFS Management
ponin elevation is associated, however, with poor
long-term prognosis. The main goal of short-term therapy (hours to
Measurement of natriuretic peptide (NP) lev- days) for AHFS has been to achieve the lowest
els is helpful especially when the diagnosis is in left ventricular filling pressure possible without
question. Natriuretic peptides (BNP and decreasing cardiac output (especially renal perfu-
NT-proBNP) are a family of hormones released sion), increasing heart rate, or further activating
in increased amounts from myocytes (especially neurohormones because these factors have been
ventricular) secondary to myocardial stretch and associated with a worse prognosis [2]. The physi-
elevated end-diastolic filling pressure as occurs cians challenge is that many of the current medi-
in AHFS. Increased NP levels are indicators of cations that improve hemodynamics and
both the presence and severity of illness. symptoms may have potential deleterious effect
Accordingly, European guidelines recommend on such variables [8].
measurement of NP levels both to exclude alter- Currently, the use of available pharmacologi-
native causes of dyspnea and to obtain prognostic cal agents for the acute management of AHFS is
information. Patient presenting with acute onset largely empirical. None of the employed agents
or worsening of symptoms suggestive of HF with would meet todays standards for approval based
a plasma BNP level <100 pg/ml or NT-proBNP on evidence for clinical efficacy and safety.
<300 pg/ml is unlikely to have AHFS. For However matter, no major clinical practice guide-
patients presenting in nonacute way (slow onset lines include any therapeutic class I, level-of-
of symptoms), a lower exclusion NP cutoff point evidence A recommendations for the
should be used to avoid false-negative diagno- pharmacological treatment of AHFS [1].
sis (35 pg/ml for BNP and 125 pg/ml for Evaluation and management of AHFS include
NT-proBNP). Results of NP tests should be three main phases: the initial or early phase (sta-
always interpreted in the context of all available bilization phase), the in-hospital phase, and the
clinical data and should not be used in isolation discharge phase. The main goals of each phase
to diagnose HF. A variety of conditions associated are summarized in Table 7.4.
with myocardial stretch even in the absence of
AHF can still be associated with NP elevation
(e.g., atrial fibrillation, pulmonary hypertension, Initial Management Strategy
and pulmonary embolism). In addition, NP levels
are falsely increased in renal failure and tend to After treatment of life-threatening conditions,
be lower in obese patients. improving hemodynamics and correlated symp-
An initial bedside transthoracic echocardiog- toms are the key goals in early management. This
raphy is recommended both to support the diag- requires a basic understanding of pathophysio-
nosis of AHFS and to determine its etiology logic mechanisms underlying an episode of acute
through an assessment of cardiac anatomy and HF and how potential overt precipitants adversely
function (left and right ventricular systolic func- affect the cardiovascular system. These condi-
tion and wall motion, diastolic function, valvular tions and all HF precipitants should be targeted
ERRNVPHGLFRVRUJ
72 A. Romandini and S. Maffei
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7 Acute Heart Failure and Pulmonary Edema 73
may be considered as a bridge to decision respiratory and metabolic improvement, its early
therapy. use can also prevent the need for endotracheal
Approximately 80 % of patients are hospital- intubation. However, in the recent Cardiogenic
ized with worsening of HF. For those with new- Pulmonary Oedema trial (3CPO), no differences
onset HF who stabilize after initial management, other than an improvement in dyspnea were seen
a chronic HF should be considered, and they in the rates of death or intubation between
should be treated according to recommendation patients treated with NIV compared to standard
of current guidelines. Initiation or implementa- oxygen therapy [16]. Currently, according to
tion of evidence-based pharmacological thera- ESC guidelines, NIV should be considered in
pies for chronic heart failure such as beta- blockers, such dyspneic patients generally when SBP is not
ACE inhibitors, aldosterone-blocking agents, below 85 mmHg (class of recommendation IIa,
ARB, and electrical device should occur soon level of evidence B).
during this phase after stabilization. This topic
will be extensively addressed in the chapter on
chronic heart failure. For the acute setting, it is Opiates
important to underline that the outpatient oral HF
medications should be always carefully reviewed Opiates such as morphine sulfate may be benefi-
at admission. Generally, HF therapy should be cial in pulmonary edema because it is thought to
continued at same doses during an AHFS episode induce mild venodilatation (thereby reducing
unless the patient has hypotension or contraindi- preload) and reduce anxiety and distress associ-
cations (such as hyperkalemia and severe renal ated with dyspnea.
failure for ACE inhibitors, angiotensin receptor Despite wide empiric use, small previous trial
blockers, aldosterone antagonists) that may raised concern about the safety of morphine,
require dose reduction or complete withholding. because its use has been associated with increased
Several reports have shown that continuation of need for invasive ventilation and greater in-
HF medical therapy with ACE inhibitors (or hospital mortality [17, 18]. At present, according
angiotensin receptor antagonists) and with beta- to the latest European guidelines, an i.v. opiate,
blockers for most patients is usually well toler- along with antiemetic medication, may be con-
ated and results in better outcomes [14, 15]. sidered in particularly restless and distressed
patients to relieve anxiety and improve breath-
lessness. Patients should be carefully monitored
Ventilation because opiates can induce respiratory
depression.
Oxygen supplementation should be titrated in
order to keep the patient comfortable achieving
arterial oxygen saturation above 90 %; caution is Diuretic Therapy
required in patients at risk of CO2 retention. In
the presence of significant respiratory distress, Diuretics are the mainstay of therapy in manag-
noninvasive positive-pressure ventilation (CPAP ing congestion in ADHS. Although safety and
or BiPAP) may be immediately considered to efficacy of diuretics have not been established in
relieve dyspnea and to improve hypoxia, meta- randomized controlled trials, long observational
bolic disturbance, and hemodynamic parameters experience has shown their efficacy in relieving
(reduced LV wall stress and cardiac work) in the congestive symptoms. By reducing intravascular
absence of contraindications (hypotension, vom- volume, diuretic therapy in ADHF lowers CVP
iting, depressed consciousness, pneumothorax). and PCWP reducing pulmonary and peripheral
Previous studies and meta-analysis support edema often increasing forward-stroke volume
the use of noninvasive ventilation (NIV) in car- and CO. In addition, when given intravenously,
diogenic pulmonary edema showing that besides loop diuretics may act as vasodilators (principally
ERRNVPHGLFRVRUJ
74 A. Romandini and S. Maffei
venodilators) with additional benefit on renal and Suggested maximum effective doses of loop
pulmonary congestion. Despite the demonstrated diuretics in heart failure and renal insufficiency
efficacy in managing congestion, the use of have been previously described [22]. Regarding
aggressive diuretic regimens may be associated the use of furosemide, in patients with HF and
with neurohormonal activation, worsening renal normal renal function, suggested maximal intra-
function, electrolyte abnormalities, and arrhyth- venous doses are 4080 mg, but in the presence
mias and so with adverse clinical outcomes [19, of renal insufficiency, larger staring doses may be
20]. required up to 160 or 200 mg in moderate and
Current guidelines recommend administering severe renal impairment, respectively. Doses of
the lowest dosage in order to achieve and main- 250 mg or above should be given by infusion
tain euvolemia avoiding volume depletion and over 4 h.
dehydration. From a pharmacokinetic and pharmacody-
Loop diuretics have the most rapid onset and namic perspective, there are potential benefits of
most powerful effect. In acute setting, like AHFS, continuous infusion versus intermittent bolus.
intravenous rather than oral administration is rec- Continuous infusion results in more constant
ommended because of greater drug bioavailabil- delivery of diuretics to the tubule with increased
ity and more rapid onset of action. Diuretic diuresis probably minimizing intermittent periods
dosing should be individualized and titrated of the known postsodium retention effect. After a
according to patient status and initial response. starting loading dose, suggested starting infusion
Considering the bolus therapy, usually the rate of loop diuretics varies with the level of renal
diuretic effect begins within 30 min with a peak function (GFR or creatinine clearance). For furo-
at 12 h [21]. Common suggested initial doses of semide, suggested doses are 10 mg/h with a
intravenous loop diuretics are 40 mg for furose- GFR > 75 ml/min, 1020 mg/h with a GFR
mide, 0.51 mg for bumetanide, and 510 mg for 2575 ml/min, and 2040 mg if GFR < 25 ml/min.
torsemide in patients who are not receiving loop If an adequate response has not occurred within
diuretics [22]. In patients who have been already 1h, a loading dose should be repeated and then the
taking a loop diuretic, the dose should be almost infusion rate uptitrated [22].
equal or greater (i.e., 2.5 times) than the mainte- However, existing data still does not allow
nance oral dose (in ESC guidelines, the greater definitive recommendations for clinical practice
dose is advocated) [1]. As discussed above, poor because even in a recent trial, no clear benefit or
response to the diuretic is a common cause of harms with intermittent bolus versus continuous
inadequate response to initial therapeutic infusion strategy have been demonstrated [24].
approach in AHFS. Now a widely accepted defi- Several strategies can be tried to overcome
nition of diuretic resistance in HF is still lacking. such diuretic resistance especially during in-
In HF patients, the diuretic doseresponse curve hospital phase. A common method for treating
may be shifted downward and to the right because diuretic resistance is the sequential nephron
of a reduction in both renal drug delivery and blockade by adding a thiazidic or thiazide-like
natriuretic response. So higher doses are required diuretic (DCT diuretics) [25, 26]. Metolazone
to achieve a given diuretic response, and the max- and hydrochlorothiazide are the most common
imal effect may be bunted [23]. Once a single molecules used in combination with loop diuret-
effective dose has been determined, it should be ics. Many clinicians prefer metolazone, a
administered multiple times per day (two or three thiazide-like diuretic, because it has a longer
times) according to the magnitude of diuresis half-life and a preserved efficacy in advanced
needed. If there is little or no response, experts renal failure (GFR below 20 ml/min) [27].
recommend dose doubling at 2 h intervals as However, such combination therapy is associated
needed (until effective diuresis is demonstrated) with significant increase in adverse effect espe-
up to the maximum effective doses (ceiling doses cially when high doses of DCT diuretics are used
over which no further diuresis will be achieved). compared to either therapy alone [28].
ERRNVPHGLFRVRUJ
7 Acute Heart Failure and Pulmonary Edema 75
It is advisable to start with lower dose of DCT with loop diuretics, the ultrafiltrate (or volume
diuretic (hydrochlorothiazide 12.525 mg or removed) is isotonic to plasma and therefore
metolazone 2.55 mg) and maintain a daily regi- removed more sodium (and less potassium). In
men for a short period with careful monitoring of addition, UF allows a better control of plasma
electrolyte balance and fluid depletion [29]. water removal rate that can be tuned to match the
putative refilling rate from the interstitium
(approximately 15 ml/min) avoiding intravascu-
Additional Strategy to Enhance lar depletion and the vicious cycle of further neu-
Diuresis rohormonal activation [31].
ERRNVPHGLFRVRUJ
76 A. Romandini and S. Maffei
Table 7.5 Doses of intravenous vasodilators in AHFS the true incidence of clinically significant coro-
Suggested intravenous vasodilator doses in AHFS nary steal remains unknown.
Agent Doses
Nitroglycerine Start with 1020 mcg/min and
then increase up to 200 mcg/ Inotropes and Vasopressors
min
Isosorbide dinitrate Start with 1 mg/h and then
Despite the hemodynamic benefits in the short-
increase up to 10 mg/h
Nitroprusside Start with 0.3 mcg/kg/min and
term management, positive inotropic agents have
then increase up to 5 mcg/kg/ not demonstrated improved outcomes in patients
min with HF in both hospital and outpatient settings.
Modified and reproduced with permission from McMurray Rather, data from some registries and post hoc
et al. [1] analyses of RCT suggest an increased morbidity
and mortality with inotrope use in HF. In fact, as
opposed to hemodynamic benefits, inotropes
despite a graded doseresponse curve, a variable may cause sinus tachycardia and precipitate
interindividual response exists also related to myocardial ischemia and arrhythmias [3739].
baseline levels of systemic vascular resistance. In AHFS, the use of intravenous inotropic
A process of careful uptitration is always needed agents may be helpful to improve CO in patients
to avoid sudden BP reduction or hypotension. A with severe LV dysfunction with hypotension
significant drawback for intravenous nitrate par- (PAS < 85 mmHg) and/or low-output syndrome.
ticularly with NTG is the phenomenon of tachy- In such patients, the marginal systemic perfusion
phylaxis that may occur in 1530 % of patients may limit institution and adequate response to
within 24 h probably related to strong counter- the other pharmacological treatment like diuret-
regulatory neurohormonal activation that leads to ics. On the other hand, at the cost of increasing
sodium and water retention [34]. afterload and decreasing cardiac output, drugs
Sodium nitroprusside (SNP) is the sodium salt with arterial vasoconstriction action (e.g., norepi-
of a complex molecule that breaks down in the nephrine or dopamine at high doses) may be a
blood interacting with oxyhemoglobin and temporizing measure to redistribute CO from
directly releasing NO and cyanide into circula- extremities to vital organs, and their use is
tion. SNP is a potent vasodilator with the faster restricted to patients with persistent hypoperfu-
onset of action (within 6090 s). Its short half- sion despite optimization of cardiac filling pres-
life (approximately 2 min) facilitates early estab- sure and the concomitant use of inotropes. The
lishment in the intensive care unit of an individual use of inotropic/vasopressor agents will be
patients optimal level of vasodilation. Even low addressed in the chapter on the management
doses produce an equivalent venous and arterio- shock. In the 2102 ESC guidelines, the use of
lar dilatation resulting in balanced vasodilation inotropes is in class IIa of recommendation, level
of both sides of the circulation [35]. Because of evidence C, and the use of vasopressor in class
SNP can cause significant hypotension, it is usu- IIb, level of evidence C [1].
ally used in intensive care settings even with Calcium sensitizers such as levosimendan are
invasive arterial monitoring. It is postulated that a new category of inotropic agents that exert pos-
SNP may potentially increase the risk of a coro- itive inotropic effects by increasing the affinity of
nary steel phenomenon: as opposed to nitroglyc- troponin C for calcium. Levosimendan exertion
erins preferential effect on larger conductance also has a vasodilatory effect by blocking ade-
vessels, SNP dilates smaller resistance vessels nosine triphosphate-dependent potassium chan-
creating a low-pressure system distal to occluded nels in the vascular smooth muscle cells. Such
vessels that diverts critical pressure-dependent inotropic and vasodilator effects may result in
flow from ischemic areas [36]. The clinical sig- increased CO and reduced filling pressures in
nificance of these observations is uncertain, and AHF patients. Compared to the classic inotropic
ERRNVPHGLFRVRUJ
7 Acute Heart Failure and Pulmonary Edema 77
agents, calcium sensitizers have two major phar- 2. Gheorghiade M, De Luca L, Fonarow GC, Filippatos
G, Metra M, Francis GS (2005) Pathophysiologic tar-
macodynamic advantages: first, increase in con-
gets in the early phase of acute heart failure syn-
tractile force occurs without increasing calcium dromes. Am J Cardiol 96(6A):11G17G
loading that is associated with enhanced myocar- 3. Yancy CW (2008) Vasodilator therapy for decompen-
dial oxygen consumption, increased heart rate, sated heart failure. J Am Coll Cardiol 52(3):208210
4. Gheorghiade M, Vaduganathan M, Fonarow GC,
and arrhythmias; second, the inotropic effect is
Bonow RO (2013) Rehospitalization for heart failure:
not attenuated by concomitant treatment with problems and perspectives. J Am Coll Cardiol
beta-blockers. At present, the real risk/benefit 61(4):391403
ratio of levosimendan in AHFS is still debated in 5. Cleland JG, Swedberg K, Follath F et al (2003) The
EuroHeart Failure survey programmea survey on
light of less favorable outcomes observed in a
the quality of care among patients with heart failure in
recent study compared to placebo [40]. Currently, Europe. Part 1: patient characteristics and diagnosis.
levosimendan is approved in Europe as a second- Eur Heart J 24:442463
line agent for severe low-output HF refractory 6. Adams KF Jr, Fonarow GC, Emerman CL et al, for
the ADHERE Scientific Advisory Committee and
standard therapy, and according to ESC guide-
Investigators (2005) Characteristics and outcomes of
lines its use may be considered (recommendation patients hospitalized for heart failure in the United
class IIb, level of evidence C) especially in States: rationale, design, and preliminary observa-
patients with chronic beta-blocker therapy to tions from the first 100,000 cases in the Acute
Decompensated Failure National Registry
overcome the beta-blockade effect.
(ADHERE). Am Heart J 149:209216
7. Fonarow GC, Abraham WT, Albert NM et al (2004)
Organized program to initiate lifesaving treatment in
Thromboembolism Prophylaxis hospitalized patients with heart failure (OPTIMIZE-HF):
rationale and design. Am Heart J 148:4351
8. Gheorghiade M, Pang PS (2009) Acute heart failure
Several mechanisms like increased systemic syndromes. J Am Coll Cardiol 53(7):557573
venous pressure, low cardiac output, and proco- 9. Cotter G, Felker GM, Adams KF, Milo-Cotter O,
agulant blood changes may increase the risk of OConnor CM (2008) The pathophysiology of acute
heart failureis it all about fluid accumulation? Am
venous thromboembolism in patients with
Heart J 155(1):918
HF. For this reason, in the absence of contraindi- 10. Metra M, Felker GM, Zac V, Bugatti S, Lombardi C,
cation to anticoagulation, thromboembolism pro- Bettari L, Voors AA, Gheorghiade M, Dei CL (2010)
phylaxis (e.g., LMWH) is currently recommended Acute heart failure: multiple clinical profiles and
mechanisms require tailored therapy. Int J Cardiol
when HF patients are hospitalized (if not already
144(2):175179
anticoagulated) to reduce the risk of deep vein 11. Fallick C, Sobotka PA, Dunlap ME (2011)
thrombosis and pulmonary embolism (recom- Sympathetically mediated changes in capacitance:
mendation class I, level of evidence A) [1]. redistribution of the venous reservoir as a cause of
decompensation. Circ Heart Fail 4:669e75
12. Nohria A, Tsang SW, Fang JC, Lewis EF, Jarcho JA,
Mudge GH, Stevenson LW (2003) Clinical assess-
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Semigran MJ, Goldsmith SR, Bart BA, Bull DA, jchf.2012.12.004. Epub 2013 Apr 1
ERRNVPHGLFRVRUJ
Chronic Heart Failure
8
Simona Masiero and Marco Morelli
Medications
ERRNVPHGLFRVRUJ
80 S. Masiero and M. Morelli
ERRNVPHGLFRVRUJ
8 Chronic Heart Failure 81
Fig. 8.1 (a, b) Routine EKG at rest. Despite correct tried assessing EKG and echocardiographic findings in
biventricular pacing (axis directed upper right), the QRS order to find the best stimulation without success
complex is wide. Several lead configurations have been
ERRNVPHGLFRVRUJ
82 S. Masiero and M. Morelli
ERRNVPHGLFRVRUJ
8 Chronic Heart Failure 83
a b
Fig. 8.3 (a, b) Chestabdomen CT with contrast, with completely normal appearance
destination therapy. For this purpose the patient signs (e.g., elevated jugular venous pressure, pul-
underwent to a new coronary angiography and monary crackles) resulting from an abnormality
chestabdomen CT with contrast which were of cardiac structure or function [1].
completely normal (Fig. 8.3a, b). Chronic heart failure (CHF) can be caused by
In order to perform a complete evaluation several types of cardiac dysfunction and is most
before the left ventricular assist device implant, commonly due to left ventricular dysfunction. An
we performed a right heart catheterization which isolated right ventricular (RV) dysfunction is
showed: very rare, and generally RV involvement is sec-
ondary to left ventricular (LV) dysfunction.
Normal pressures in the right atrium, right Demonstration of an underlying cardiac cause
ventricle, pulmonary artery, and wedge is essential to diagnose HF as the precise pathol-
Slight increase in total pulmonary resistance ogy determines the specific treatment used. More
Arteriolar resistance at the upper limit of normal recently, CHF has been classified into two cate-
gories: HF due to LV dysfunction even called HF
By the investigations carried out during the with reduced ejection fraction (HF-REF or sys-
hospitalization, the patient has been judged suit- tolic heart failure) and HF where only a diastolic
able for LVAD as a destination therapy and added dysfunction is detectable called HF with pre-
to the waiting list at a referral center for the served ejection fraction (HF-PEF or diastolic
implant. heart failure). 1 HF-REF is the best understood
Until the LVAD implant, on top therapy to type of HF in terms of pathophysiology and treat-
chronic heart failure including loop diuretic, ment and is the focus of this chapter.
aldosterone antagonist, ACE inhibitor, and beta- Furthermore, HF can present either as a
blocker, the patient underwent cyclic intravenous chronic condition or acutely, occurring de novo,
inotropic therapy. or as a decompensation of CHF. The purpose of
this chapter is to cover CHF, while acute heart
failure is discussed in another section of this
8.2 Heart Failure book.
Denition
Epidemiology
Heart failure (HF) can be clinically defined as a
syndrome in which patients have typical symp- CHF prevalence is 12 % of the population, and
toms (e.g., breathlessness, ankle swelling) and the prevalence increases to approximately 15 %
ERRNVPHGLFRVRUJ
84 S. Masiero and M. Morelli
in the elderly [2]. At least half of patients with symptoms of HF are due in part to compensatory
HF have a low EF, and approximately 50 % of mechanisms utilized by the body in an attempt to
patients with significant LV systolic dysfunction adjust for a primary deficit in cardiac output.
have no symptoms or signs of heart failure. HF Many of the processes involved in sustaining HF
occurs more frequently in male rather than are maladaptive which means that they were
female sex. originally designed to maintain blood pressure
and vital organ perfusion.
Etiology
Changes in Hemodynamics
The causes of CHF are listed in Table 8.1. There
is a geographical variation regarding the etiology Decrease of cardiac output leads to an increase of:
of CHF. In Western countries two-thirds are sec-
ondary to ischemic disease, and other important Left ventricular end-diastolic pressure
contributors are hypertension, valve disease, and Pulmonary capillary wedge pressure
alcohol. Rheumatic disease still remains the most
common cause of CHF in the developing coun- Based on the FrankStarling law, the initial
tries, while Chagas disease is frequent in South increase of left ventricular end-diastolic pressure
America. is initially compensated by an increase of con-
tractility, but as the increase persists, the myocar-
dium fails and cardiac output drops.
Pathophysiology
ERRNVPHGLFRVRUJ
8 Chronic Heart Failure 85
Increase in heart rate, blood pressure, and mones. The types of natriuretic peptide hormones
myocardial oxygen demand which circulate in high concentration in HF are:
A toxic damage on the myocardium leading to Brain natriuretic peptides
cell apoptosis
A downregulation of beta-1 receptors in the heart BNP, the active peptide
NT-proBNP, the inactive N-terminal fragment
The decrease of cardiac output leads to a reduc-
tion of renal afferent arteriolar blood flow causing Atrial natriuretic peptides (ANP and NT-ANP)
secretion of renin and, subsequently, production of These peptides cause:
angiotensinogen and angiotensin I. The angioten-
sin I is then converted by the ACE present in the Natriuresis
lung to angiotensin II. There is also evidence that Vasodilatation
angiotensin II can be synthesized locally at a vari- Offset in the activation of RAAS
ety of tissue sites including the kidney, blood ves-
sels, adrenal gland, and brain [6]. Plasma ANP levels rise early in the course of
Angiotensin II increases aldosterone release, the disease and have been used as a marker for
inducing systemic and renal vasoconstriction. the diagnosis of asymptomatic left ventricular
Furthermore, angiotensin II can act directly on dysfunction.
myocytes and in the myocardium to promote All these processes are responsible for
pathologic remodeling as myocyte hypertrophy, sodium and water retention and a progressive
re-expression of fetal protein isoforms, myo- depression of myocardial function. The last step
cyte apoptosis, and alterations in the interstitial of this fall is an adverse remodeling of the left
matrix. Aldosterone-mediated effects are ventricle involving myocyte hypertrophy, death,
sodium and water retention and hypokalemia and fibrosis.
resulting in pulmonary and peripheral edema
and increased afterload. Activation of the
carotid sinus and aortic arch baroreceptors by Diagnosis
the low cardiac output in heart failure leads to
enhanced release of antidiuretic hormone and Clinical Symptoms and Signs
stimulation of thirst. Elevated levels of ADH The three most common symptoms and signs of
may contribute to the increase in systemic vas- HF are:
cular resistance in HF via stimulation of the
V1A receptor, which is found on vascular Breathlessness
smooth muscle cells, and also promote water Fatigue
retention via the V2 receptor by enhancing Peripheral edema
water reabsorption in the collecting tubules.
The combination of decreased water excretion Breathlessness is induced by exercise, and
and increased water intake via thirst often leads only in case of advanced heart failure, it appears
to a fall in the plasma sodium concentration. at rest. Symptoms that are more specific (i.e.,
The degree of hyponatremia is an important orthopnea and paroxysmal nocturnal dyspnea)
predictor of survival in these patients. are less common, especially in patients with
milder form of HF and who are, therefore, insen-
sitive [7, 8].
The Natriuretic Peptide System Many of the symptoms of HF are nonspecific
and do not, therefore, help discriminate between
The increased LV and left atrium wall stretch due HF and other problems.
to raised left ventricular end-diastolic pressure Symptoms are used to assign NYHA class to
leads to secretion of the natriuretic peptide hor- patients as listed in Table 8.2.
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86 S. Masiero and M. Morelli
Table 8.2 Since many of the symptoms of HF are non- To diagnose HF both of the following criteria
specific and do not, therefore, help discriminate between
should be present:
heart failure and other problems, patients are usually
assigned an NYHA class
Symptoms and/or signs of heart failure
New York Heart Association functional classification
based on the severity of symptoms and physical activity Cardiac dysfunction at rest
Class No limitation of physical activity. Ordinary
I physical activity does not cause undue The presence of cardiac dysfunction must be
breathlessness, fatigue, or palpitations proved to make the diagnosis of heart failure.
Class Slight limitation of physical activity. As stated in the current guidelines 1, investi-
II Comfortable at rest, but ordinary physical
gations that should be considered in all patients
activity results in undue breathlessness,
fatigue, or palpitations are:
Class Marked limitation of physical activity.
III Comfortable at rest, but less than ordinary
physical activity results in undue
A 12-lead ECG, to determine heart
breathlessness, fatigue, or palpitations
rhythm, heart rate, QRS morphology,
Class Unable to carry on any physical activity
VI without discomfort. Symptoms at rest can be and QRS duration and to detect other
present. If any physical activity is undertaken, relevant abnormalities. HF is rare in the
discomfort is increased presence of a normal ECG. The predic-
tive value of the ECG is >90 %.
Measurement of natriuretic peptide
(BNP, NT-proBNP) to exclude alterna-
tive causes of dyspnea. If the value is
Physical signs can be related to the presence within a normal range, HF is very
of either fluid retention or poor cardiac output. unlikely. Natriuretic peptide measure-
They usually include: ment has an extremely high negative
predictive value (>98 %).
A chest radiograph (X-ray), to detect/
exclude certain types of lung disease
Elevated jugular venous pressure (e.g., cancer, asthma/COPD). It may
Orthopnea allow also to identify pulmonary con-
Hepatojugular reflux gestion/edema. A normal X-ray does not
Third heart sound (gallop rhythm) exclude a diagnosis of heart failure.
Laterally displaced apical impulse Transthoracic echocardiography is the
Cardiac murmur key exam in the diagnostic process of
Peripheral edema (ankle, sacral, HF. It allows to evaluate cardiac struc-
scrotal) ture and function, to measure LV ejec-
Wheezing, pulmonary crepitations tion fraction, and to understand the
Weight gain (>2 kg/week) cause of cardiac dysfunction.
Reduced air entry and dullness to per- Measurement of blood chemistry
cussion at lung bases (pleural effusion) (including sodium, potassium, calcium,
Tachycardia urea/blood urea nitrogen, creatinine/
Bloated feeling, irregular pulse estimated glomerular filtration rate,
Tachypnea (>16 breaths/min) liver enzymes and bilirubin, ferritin/
Hepatomegaly total iron blood capacity) and thyroid.
Ascites A complete blood count to detect ane-
Palpitations mia, which may be a cause or effect of
Tissue wasting (cachexia) CHF.
ERRNVPHGLFRVRUJ
8 Chronic Heart Failure 87
ERRNVPHGLFRVRUJ
88 S. Masiero and M. Morelli
minimum dose necessary to render the patient Table 8.3 Suggested dosage for ACEi and ARBs with
proved clinical efficacy for HF based on randomized clini-
euvolemic. The most common side effects are
cal trials
renal dysfunction, hypokalemia, hyponatremia,
hyperglycemia, and gout. ACE inhibitors Starting dose Target dose
(mg) (mg)
The usual starting dose in outpatients with HF
Captopril 6.25 t.i.d. 50 t.i.d
is 2040 mg of furosemide or its equivalent.
Enalapril 2.5 b.i.d. 1020 b.i.d.
Subsequent dosing is determined by the diuretic Lisinopril 2.55.0 o.d. 2035 o.d.
response. In patients who are volume overloaded, Ramipril 2.5 o.d. 5 b.i.d.
a reasonable goal is weight reduction of 1.0 kg/ Trandolapril 0.5 o.d. 4 o.d.
day. If a patient does not respond, the diuretic ARB Starting dose Target dose
dose should initially be increased to find the sin- (mg) (mg)
gle effective dose, rather than giving the same Candesartan 4 or 8 o.d. 32 o.d.
dose twice a day. Valsartan 40 b.i.d. 160 b.i.d.
Intravenous diuretics (either as a bolus or a Losartan 50 o.d. 150 o.d.
continuous infusion) are more potent than their
equivalent oral doses and may be required for
unstable or severe disease.
Some patients can develop a loop diuretic over, ACEi can induce cough (510 %) and
resistance if they are treated for a long time. In angioedema. ARB can be used in case of ACEi
this category of patients, it is useful to add a thia- intolerance.
zide diuretic (i.e., metolazone 2.55 mg/day) These drugs are usually started at low doses
instead of increasing the dose of loop diuretics and then titrated. ACEi and ARBs with proven
(i.e., >80 mg b.i.d. furosemide) to block differing clinical efficacy in HF based on randomized clin-
sites in the nephron and overcome the ical trials with their suggested dosing are listed in
resistance. Table 8.3.
ERRNVPHGLFRVRUJ
8 Chronic Heart Failure 89
Table 8.4 Beta-blockers with proven efficacy in clinical Table 8.5 Approved dosages for mineralocorticoid
trials and approved dosages receptor antagonists
Starting dose Target dose MRA Starting dose Target dose
Beta-blocker (mg) (mg) Eplerenone 25 o.d. 50 o.d.
Bisoprolol 1.25 o.d. 10 o.d. Spironolactone 25 o.d. 2550 o.d.
Carvedilol 3.125 b.i.d. 2550
b.i.d.
Nebivolol 1.25 o.d. 10 o.d.
Metoprolol succinate (CR/ 12.5/25 o.d. 200 o.d.
creatinine be checked 12 weeks after starting
XL) spironolactone or eplerenone and periodically
thereafter. Patients with poor renal function are
particularly at risk for hyperkalemia. For these
Mineralocorticoid Receptor reasons they should be used with caution in
Antagonist (MRA) elderly.
The approved doses are listed in Table 8.5.
Spironolactone and eplerenone, which compete
with aldosterone for the mineralocorticoid
receptor, prolong survival in selected patients Other Drug Options
with HF as demonstrated in randomized con-
trolled trials [11]. Ivabradine
MRAs are recommended to treat HF in It should be considered for patients in NYHA II
patients who have NYHA functional class II and IV heart failure with a heart rate 70/min in sinus
a left ventricular ejection fraction (LVEF) 30 % rhythm and LVEF 35 % despite treatment with
or NYHA functional classes III to IV and an evidence-based doses of:
LVEF <35 %, who can be carefully monitored for
serum potassium and renal function. MRAs are ACEi (or ARB)
also recommended for patients post ST elevation Beta-blocker
myocardial infarction who are already receiving MRA
therapeutic doses of ACE inhibitor, have an
LVEF 40 %, and have either symptomatic HF It may be also considered for patients in
or diabetes mellitus and who can be carefully NYHA IIIV heart failure with a heart rate 70/
monitored for serum potassium and renal func- min in sinus rhythm and LVEF 35 % who are
tion. The serum potassium should be <5.0 mEq/L unable to tolerate beta-blockers (true
and estimated glomerular filtration rate should be asthmatics).
30 mL/min per 1.73 m. The endocrine side
effects of spironolactone result from nonselective
binding to androgen and progesterone receptors; Hydralazine Plus Nitrates
eplerenone has greater specificity for the miner-
alocorticoid receptor and therefore has a lower In African-American population the addition of
incidence of endocrine side effects (1 versus hydralazine plus oral nitrate therapy is recom-
10 % in clinical trials). Although eplerenone is mended for patients with persistent NYHA
associated with fewer endocrine side effects than classes IIIIV and LVEF <40 % despite optimal
spironolactone (i.e., painful gynecomastia), this therapy including a beta-blocker, ACEi (or ARB),
advantage must be weighed against the marked MRA (if indicated), and diuretics. Although the
difference in cost between the two drugs. It may evidence of benefit is stronger in blacks, the addi-
be reasonable to begin with spironolactone (25 tion of hydralazine plus oral nitrate may be con-
50 mg/day) and switch to eplerenone (25 and sidered in non-blacks who have persistent NYHA
after 4 weeks 50 mg/day) if endocrine side effects class II or IV despite optimal conventional
occur. It is essential that serum potassium and therapy.
ERRNVPHGLFRVRUJ
90 S. Masiero and M. Morelli
Digoxin is given to patients with HF and sys- Implantable cardiac defibrillators (ICDs) have
tolic dysfunction to control symptoms (such as revolutionized the management of heart failure.
fatigue, dyspnea, and exercise intolerance) and An ICD is an advanced form of pacemaker that
to patients with atrial fibrillation to control the can detect and treat arrhythmias. Several types of
ventricular rate. As demonstrated in the DIG ICDs can be implanted: a single bipolar lead
trial, 12 digoxin therapy was associated with a placed in the right ventricular apex or a dual-
significant reduction in hospitalization for HF chamber device with a further atrial lead to
but no benefit in terms of overall mortality. improve detection of atrial from ventricular
Digoxin is indicated in patients with left ven- arrhythmias. ICDs use the following criteria to
tricular systolic dysfunction (LVEF <40 %) who distinguish ventricular tachycardia or fibrillation:
continue to have NYHA functional class II, III,
and IV symptoms despite appropriate therapy Rate detection zone.
including an ACE inhibitor, a beta-blocker, an Rate stability based on the principle that ven-
aldosterone antagonist if indicated, and an addi- tricular tachycardia is a stable rhythm without
tional diuretic if necessary for fluid control. The a significant inter-beat variation.
usual daily dose of digoxin is 0.125 mg or less, Sudden onset: ventricular arrhythmias usually
based upon renal function. Based upon the data have a sudden onset.
from the DIG trial, the recommended serum
digoxin concentration is maintained between According to the current guidelines 1, recom-
0.5 and 0.8 ng/mL. mendations for the use of ICDs in patients with
It is a useful drug in patients with atrial HF are resumed in Table 8.6.
fibrillation to reach an adequate rate control. It
should be avoided in patients with ventricular
arrhythmias. Resynchronization Therapy
ERRNVPHGLFRVRUJ
8 Chronic Heart Failure 91
Table 8.6 Current guideline recommendations for the use of ICDs in patients with HF [1]
Recommendations Recommendation class Recommendation level
Secondary prevention IA A
An ICD is recommended in a patient with a ventricular
arrhythmia causing hemodynamic instability, who is expected to
survive for >1 year with good functional status, to reduce the
risk of sudden death
Primary prevention IA A
An ICD is recommended in a patient with symptomatic HF
(NYHA classes IIIII) and an EF 35 % despite 3 months of
treatment with optimal pharmacological therapy, who is
expected to survive for >1 year with good functional status, to
reduce the risk of sudden death
(i) Ischemic etiology and >40 days after acute myocardial IA
infarction
(ii) Nonischemic etiology IB B
apex, and coronary sinus. CRT functioning will Extracorporeal ventricular support (useful for
be discussed more in detail in a separate section a short-term time support)
of this book.
Based on the current guidelines 1, the current Intra-aortic balloon pump
indications for CRT implant are listed in Table 8.7. Pulsatile ventricular assist device (VAD)
Non-pulsatile VAD
ERRNVPHGLFRVRUJ
92 S. Masiero and M. Morelli
Table 8.8 Terms describing various uses of mechanical circulatory support (MCS)
Bridge to decision Use of MCS in patients with drug-refractory acute circulatory collapse and at immediate
(BTD) risk of death to sustain life until a full clinical evaluation can be completed and additional
therapeutic options can be evaluated
Bridge to candidacy Use of MCS to improve end-organ function in order to make an ineligible patient eligible
(BTC) for transplantation
Bridge to Use of MCS to keep a patient at high risk of death before transplantation alive until a donor
transplantation organ becomes available
(BTT)
Bridge to recovery Use of MCS to keep patient alive until intrinsic cardiac function recovers sufficiently to
(BTR) remove MCS
Destination therapy Long-term use of MCS as an alternative to transplantation in patients with end-stage heart
(DT) failure ineligible for transplantation
for transplantation is very restrictive; indeed patients Lip GY, Maggioni AP, Parkhomenko A, Pieske BM,
Popescu BA, Rnnevik PK, Rutten FH, Schwitter J,
have to be able to face the major cardiac surgery and
Seferovic P, Stepinska J, Trindade PT, Voors AA,
the massive immunosuppressive regime. Cardiac Zannad F, Zeiher A, Task Force for the Diagnosis and
transplantation is not a cure but is the last Treatment of Acute and Chronic Heart Failure 2012 of
chance even because 1 year mortality is approxi- the European Society of Cardiology, Bax JJ,
Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard
mately 17 % with a median survival of 10.9 years.
R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P,
Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu
BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M,
Torbicki A, Vahanian A, Windecker S, McDonagh T,
References Sechtem U, Bonet LA, Avraamides P, Ben Lamin HA,
Brignole M, Coca A, Cowburn P, Dargie H, Elliott P,
1. McMurray JJ, Adamopoulos S, Anker SD, Auricchio Flachskampf FA, Guida GF, Hardman S, Iung B,
A, Bhm M, Dickstein K, Falk V, Filippatos G, Merkely B, Mueller C, Nanas JN, Nielsen OW, Orn S,
Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kber L, Parissis JT, Ponikowski P, ESC Committee for
ERRNVPHGLFRVRUJ
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Practice Guidelines (2012) ESC guidelines for the 7. Davie AP, Francis CM, Caruana L, Sutherland GR,
diagnosis and treatment of acute and chronic heart McMurray JJ (1997) Assessing diagnosis in heart fail-
failure 2012: The Task Force for the Diagnosis and ure: which features are any use? QJM 90:335339
Treatment of Acute and Chronic Heart Failure 2012 of 8. Kelder JC, Cramer MJ, van Wijngaarden J, van
the European Society of Cardiology. Developed in Tooren R, Mosterd A, Moons KG, Lammers JW,
collaboration with the Heart Failure Association Cowie MR, Grobbee DE, Hoes AW (2011) The diag-
(HFA) of the ESC. Eur J Heart Fail 14:803869 nostic value of physical examination and additional
2. Mosterd A, Hoes AW (2007) Clinical epidemiology testing in primary care patients with suspected heart
of heart failure. Heart 93:11371146 failure. Circulation 124:28652873
3. Francis GS, Goldsmith SR, Levine TB et al (1984) 9. Exner DV, Dries DL, Waclawiw MA et al (1999)
The neurohumoral axis in congestive heart failure. Beta-adrenergic blocking agent use and mortality in
Ann Intern Med 101:370 patients with asymptomatic and symptomatic left ven-
4. Dzau VJ (1987) Renal and circulatory mechanisms in tricular systolic dysfunction: a post hoc analysis of the
congestive heart failure. Kidney Int 31:1402 Studies of Left Ventricular Dysfunction. J Am Coll
5. Benedict CR, Johnstone DE, Weiner DH et al (1994) Cardiol 33:916
Relation of neurohumoral activation to clinical vari- 10. Cleland JG, McGowan J, Clark A, Freemantle N
ables and degree of ventricular dysfunction: a report (1999) The evidence for beta blockers in heart failure.
from the Registry of Studies of Left Ventricular BMJ 318:824
Dysfunction. SOLVD Investigators. J Am Coll 11. Zannad F, McMurray JJ, Krum H et al (2011)
Cardiol 23:1410 Eplerenone in patients with systolic heart failure and
6. Dzau VJ, Colucci WS, Hollenberg NK, Williams GH mild symptoms. N Engl J Med 364:11
(1981) Relation of the renin-angiotensin-aldosterone 12. Digitalis Investigation Group (1997) The effect of
system to clinical state in congestive heart failure. digoxin on mortality and morbidity in patients with
Circulation 63:645 heart failure. N Engl J Med 336:525
ERRNVPHGLFRVRUJ
Cardiogenic Shock
9
MariaVittoriaMatassini, LucaPiangerelli,
andMatildaShkoza
ERRNVPHGLFRVRUJ
96 M.V. Matassini et al.
The patient was evaluated and accepted for Cardiovascular: irregular and tachycardic
mitral valve surgery. rhythm, apical soft proto-mesosystolic mur-
2001: mitral valve replacement with mechani- mur (2/6 at Levine scale)
cal prosthesis. Surgical atrial fibrillation abla- Lungs: decreased tactile fremitus and dullness
tion was ineffective. to percussion at right pulmonary basis, bilat-
2006: hospital admission for hypotensive acute eral medio-basal rales
heart failure with renal and hepatic impairment Abdomen: moderate hepatomegaly, no spleno-
treated with IV diuretics and inotropes. The megaly, no ascites, no pulsatile masses, normal
echocardiogram revealed correct prosthesis bowel sounds in all four quadrants, no high-
function but further worsening of left ventricu- pitched or tinkling sounds, resonant to percus-
lar function (FEVS 30 %). The patient referred sion, soft, non-distended/non-tender, no rebound
an NYHA class III. The patient was discharged or guarding, no costovertebral angle tenderness
on optimal medical therapy with indication to Extremities: cold, mild cyanosis, peripheral
a follow-up visit after 3 months. edema
2007: cardiac resynchronization therapy with
defibrillator (CRT-D) implantation.
20102013: frequent hospital admissions for Laboratory Tests
acute heart failure. An evaluation for heart trans-
plantation was proposed, but the patient refused. White blood cells 8800/mmc, hemoglobin
10.5 g/l, hematocrit 32 %, platelets 138,000/
mmc, creatinine 2.4 mg/dl, blood urea nitrogen
Allergies 112 mg/dl, AST 288 U/L, ALT 204 U/L, GT
110 U/L, total bilirubin 2.1 mg/dl with direct bili-
None. rubin of 1.6 mg/dl, INR 4.2, uric acid 9.4 mg/ml,
potassium 4.8 mEq/l, sodium 134 mEq/l, magne-
sium 1.2 mg/dl, blood glucose 254 mg/dl
Medications
ERRNVPHGLFRVRUJ
9 Cardiogenic Shock 97
Fig. 9.1 ECG showing atrial fibrillation with rapid ventricular response
a b
Fig. 9.2 Echocardiographic images: apical four-chamber view (a) and parasternal short axis at papillary level (b) show-
ing chamber dilation, mitral valve prosthesis, and presence of lead in right chambers
ERRNVPHGLFRVRUJ
98 M.V. Matassini et al.
for drug infusions, measurement of central Considering the end-stage HF despite optimal
venous pressure and blood sampling, and deter- pharmacological and device treatment and the
mination of central venous oxygen saturation. recent episode of cardiogenic shock, the possibil-
Clinical, instrumental, and laboratory data ity to an evaluation for advanced treatment
(hypotension <90 mmHg, tissue hypoperfusion options, as heart transplant or left ventricular
with increase in arterial lactate and renal and assistive device implantation, was offered to the
hepatic impairment, cardiac index of 1.3 l/min/ patient who agreed, and a visit in a national refer-
m2) allow us to make the diagnosis of cardiogenic ence hospital was therefore planned. The patient
shock in a patient with advanced heart failure. was discharged on day 25.
Inotropic support with dopamine (5 mcg/kg/
min) was continued, and also adrenaline was
started at a dose of 0.05 up to 0.08 mcg/kg/min 9.2 Cardiogenic Shock
because of persistent hypotension, increase in
arterial lactate (7.8 mmol/l), and oliguria. Definition andEpidemiology
Continuous infusion of loop diuretics (furose-
mide, 500 mg/24 h) was started with progressive Cardiogenic shock (CS) is a complex clinical
improvement in diuresis. Intravenous digoxin condition characterized by inadequate end-organ
was administered in the acute phase for AF rate perfusion due to the inability of the heart to pro-
control, and unfractionated heparin was intro- vide adequate flow. The tissue hypoperfusion, if
duced. Insulin infusion was started to correct prolonged, could result in end-organ damage and
hyperglycemia and on the following days finally in multiorgan failure. Cardiogenic shock
switched to bolus insulin injection. is a fatal condition if not early diagnosed and
The patients clinical status gradually treated. The in-hospital mortality approaches
improved, with normalization of arterial lactate 50 % and is related to the severity of hemody-
on day 2 and also the central venous oxygen satu- namic impairment, the promptness of diagnosis,
ration (from baseline 5663 % on day 2). On day and the type of management (medical therapy,
5, pulmonary congestion significantly improved mechanical support) [1]. Mortality decreased sig-
and the patient was extubated. The patient was nificantly during the last years because of the
gradually weaned from inotropes until interrup- wide use of revascularization.
tion on day 7. Therefore, an echocardiography The diagnosis of CS results from multipara-
was repeated confirming severe left ventricular metric evaluation and could be made in the pres-
dysfunction (FEVS 25 %) and mild to moderate ence of:
right ventricle dysfunction (TAPSE 15 mm, FAC
area 32 %), reducing pulmonary artery pressure Hypotension defined as systolic blood pres-
(35 mmHg). sure 90 mmHg or when vasopressors are
A beta-blocker and an angiotensin-converting required to maintain SBP 90 mmHg or mean
enzyme inhibitor were started on day 8 and up- arterial pressure is 30 mmHg lower than
titrated (ramipril 2.5 mg o.d., bisoprolol 3.75 mg baseline
o.d.). Loop diuretics were switched from IV to oral Evidence of organ hypoperfusion: resting tachy-
administration (furosemide 125 mg b.i.d., spirono- cardia, altered mental status, oliguria, poor cap-
lactone 100 mg o.d.). Oral digoxin was continued illary refill, cold/diaphoretic extremities
to achieve a better rate control. Oral anticoagula- A reduction in cardiac index (<1.8 L/min/mq
tion was reintroduced on day 9. Laboratory tests without support or <2.2 l/min/mq with sup-
showed improvement of kidney and hepatic func- port) with evidence of increase in pulmonary
tion (creatinine 1.4 mg/dl, total bilirubin 1.3 mg/dl, capillary wedge pressure (>18 mmHg)
normalization of AST, ALT, and GT).
Cardiac rehabilitation was started on day 12 with Any cause of severe left or right ventricle dys-
progressive improvement of functional capacity. function may cause cardiogenic shock; however,
ERRNVPHGLFRVRUJ
9 Cardiogenic Shock 99
acute coronary syndrome (ACS) with left ventricu- mechanisms. The initial response to a decrease in
lar failure is mostly involved. The incidence of CS blood pressure is mediated by arterial barorecep-
complicating ACS is approximately 7 % in ST ele- tors that cause an enhancement in sympathetic
vation myocardial infarction (STEMI) and 2.5 % in activity (via IX and X cranial nerves) with a con-
non-STEMI [2]. In those patients presenting with sequent increase in HR, myocardial contractility,
ACS and CS, mechanical complications as ventric- and SVR. More slowly acting mechanisms are
ular septal or free wall rupture and papillary muscle the activation of renin/angiotensin/aldosterone
rupture should be suspected and searched. system and fluid retention. The reduction in tis-
Other less frequent causes are acute myoperi- sue perfusion leads to a reduced oxygen delivery
carditis, stress-induced cardiomyopathy, acute with a shift to anaerobic metabolism and an
valvular regurgitation or prior severe valvular increase in lactate levels with a possible conse-
disease, hypertrophic cardiomyopathy, dilated quent metabolic acidosis.
cardiomyopathy, drugs and medications, arrhyth- Cardiogenic shock (CS) may be precipitated
mias, and traumatic cardiac injury. by different cardiac and extracardiac causes as
Cardiogenic shock due exclusively to right listed below:
ventricle involvement represents only 5 % of
cases, and it is characterized by a similar mortal- Cardiomyopathies: acute myocardial infarc-
ity to LV shock [3]. tion (MI) involving >40 % of the left ventricu-
In the ischemic setting, CS could be present lar myocardium or dilated cardiomyopathy
acutely or could develop later, within the first days. with cardiac pump failure.
It seems that later CS is associated with a higher Arrhythmias: supraventricular arrhythmias
mortality than earlier development of CS [4]. may cause cardiogenic shock through an
Different risk factors for CS in ischemic impairment of left ventricular filling.
patients have been recognized: anterior STEMI, Bradyarrhythmias or ventricular tachycardia/
multivessel disease, advanced age, female sex, fibrillation may reduce or abolish CO due to
previous diagnosis of diabetes and hypertension, an ineffective cardiac contraction.
prior cardiovascular disease, heart failure at Mechanical: valvulopathies (mitral or aortic
admission, systolic blood pressure <120 mmHg, regurgitation) or intracardiac shunt.
heart rate >90 bpm, and presence of left branch Extracardiac: any condition that causes a sig-
block [5, 6]. nificant reduction in preload or acute increase
in afterload (i.e., cardiac tamponade, pulmo-
nary embolism, tension pneumothorax, con-
Pathophysiology strictive pericarditis).
Systemic perfusion and blood pressure are related The CS pathophysiology is very complex with
to cardiac output (CO) and systemic vascular differences from patient to patient. Cardiogenic
resistance (SVR): shock evolves through different stages that repre-
sent a physiologic continuum from an initially
MAP ( mean arterial pressure ) = CO SVR compensated status (pre-shock or shock impend-
SVR =8hL / p r 4 ing) till multiorgan failure.
CO = SV HR Regardless of the precipitating cause, the main
feature consists of a reduction of cardiac output
= viscosity, L = vessel length, r = vessel radius, with consequent hypotension, unable to maintain
SV = stroke volume, HR = heart rate an adequate systemic perfusion (Fig. 9.3). The
reduction of blood pressure triggers the activa-
The stroke volume depends on the preload, tion of compensatory mechanisms through sym-
afterload, and myocardial contractility as pathetic system and renin/angiotensin/
explained by the FrankStarling and Hill aldosterone system with consequent tachycardia,
ERRNVPHGLFRVRUJ
100 M.V. Matassini et al.
Myocardial dysfunction
Inotropes/
vasopressors Inflammatory cytokines Systolic Diastolic
Mechanical IL-6, TNF-
support: Cardiac output
IABP/LVAD stroke volume LVEDP
Pulmonary
iNOS/eNOS Hypotension congestion
Bleeding/ Systemic
perfusion Coronary
transfusion perfusion pressure Hypoxemia
NO
Peroxynitrite Ischemia
Perfusion:
PCI/CABG
Compensatory vasoconstriction Progressive
Vasodilation myocardial
SVR Fluid retention
dysfunction
MOF
Death
Fig. 9.3 Concept of CS pathophysiology. This is the (TNF)) production and consequent endothelial and induc-
downward spiral, induced by left ventricle (LV) systolic ible nitric oxide synthase (eNOS, iNOS) activation leads
dysfunction that leads to reduced stroke volume and car- to nitric oxide (NO) and peroxynitrite production that
diac output with consequent hypotension. Coronary blood causes reduced systemic vascular resistance (SVR) with
flow is therefore reduced with ischemia and further myo- vasodilatation and further myocardial depression.
cardial dysfunction. Even diastolic dysfunction with Bleeding complications and subsequent transfusions have
increased left ventricular end-diastolic pressure (LVEDP) a negative role in the shock spiral. If there is not a prompt
and pulmonary edema leads to hypoxemia and consequent intervention with treatment options shown in red (inotro-
ischemia. The reduced systemic perfusion activates com- pes/vasopressors, mechanical support with intra-aortic
pensatory mechanisms that cause vasoconstriction and balloon pumping (IABP) and left ventricular assist device
fluid retention, increasing left ventricle after- and preload (L-VAD), reperfusion by percutaneous coronary interven-
and aggravating myocardial dysfunction. The systemic tion (PCI) or coronary artery bypass (CABG)), the vicious
inflammatory response syndrome (SIRS) characterized by circle leads to multiorgan failure (MOF) and death
cytokine (interleukin-6 (IL-6) and tumor necrosis factor
increased contractility, a marked systemic vascu- Pump failure causes diastolic dysfunction
lar resistance (SVR) elevation increasing LV with increased ventricular diastolic pressure
afterload, and fluid retention with increase in pre- that further reduces coronary perfusion pres-
load. These compensatory mechanisms in the sure, worsening ischemia. The increased ven-
long term become maladaptive and result in a fur- tricular diastolic pressure increases left atrial
ther marked reduction in tissue perfusion. pressure which may cause pulmonary conges-
Hypotension, vasoconstriction, tachycardia, and tion leading to hypoxia, further exacerbating
increased myocardial contractility reduce myo- myocardial ischemia. Ischemia worsening
cardial perfusion and increase myocardial oxy- aggravates myocardial dysfunction and begins
gen demand, exacerbating ischemia. a vicious cycle that leads to progressive
ERRNVPHGLFRVRUJ
9 Cardiogenic Shock 101
ERRNVPHGLFRVRUJ
102 M.V. Matassini et al.
associated with low mixed venous oxygen artery catheterization has never shown to
saturation. improve patients outcomes in clinical trials [2,
3, 15]. The diagnosis of cardiogenic shock is
Electrocardiogram confirmed in the presence of a reduced cardiac
Electrocardiogram (ECG) suggests the diagnosis index (<2.2 l/min with inotropic support or <1.8
of acute MI in the presence of ST-T alterations. without therapy), an increased PCWP (>15
Supraventricular and ventricular tachy- or brady- 18 mmHg), and/or a reduction in SvO2/SvcO2
arrhythmias may cause shock and can be diag- (<70 % and <65 %, respectively). A fall in SvO2
nosed by ECG monitoring. Shocked patients is suggestive for a reduced oxygen delivery or an
usually present sinus tachycardia. increase in oxygen consumption and may reflect
inadequate tissue perfusion even in a pre-shock
Echocardiogram stage. According to guidelines [12], an invasive
Echocardiography may confirm the diagnosis of hemodynamic monitoring is recommended in a
cardiogenic shock, showing marked depression patient with persistent hypotension refractory to
of left or right ventricular function with low pharmacological treatment with uncertain left
stroke volume and elevated filling pressures. It is filling pressures.
also useful in evaluating cardiac chambers,
regional wall motion, the pericardium, and Laboratory Evaluation
valves: it could detect causes or contributing fac- Laboratory tests are useful in identifying causes
tors as regional wall motion abnormalities, the of shock and in evaluation of organ failure. Basic
presence of cardiac tamponade, or severe mitral chemistry tests, complete blood count, liver and
or aortic regurgitation. In acute MI, echocardio- renal function tests, amylase and lipase, and arte-
gram should be repeated to exclude the presence rial blood gas should be evaluated. Cardiac bio-
of mechanical complications as ventricular sep- markers (troponin T/I, CK-MB) are useful in the
tal, free wall, or papillary muscle rupture [12]. diagnosis of acute MI and correlate with infarc-
Transthoracic echocardiography (TTE) is the tion extension. Arterial or venous lactates com-
first step, but transesophageal echocardiography plete the picture because an increased serum
(TEE) should be used when TTE images are sub- lactate level may correlate with a reduced oxygen
optimal especially in patients with mechanical delivery with a shift to anaerobic metabolism.
ventilation. Elevated lactate serum levels (>1.5 mmol/l at
TTE plays also a role as a less invasive tool for admission, >1 mmol/l after 24 h) are also associ-
evaluating hemodynamic parameters with ated with increased mortality [16].
Doppler-based methods. Small ventricles (kiss-
ing ventricles) usually suggest the use of fluid Coronary Angiography
challenge, while a dilated and hypokinetic right Coronary angiography should be performed
ventricle should be related to pulmonary early in patients with suspected acute MI.
embolism. Revascularization with percutaneous coronary
intervention (PCI) or coronary artery bypass graft
Hemodynamic Monitoring surgery (CABG) is also recommended without
Hemodynamic monitoring through a pulmonary any delay in patients with cardiac pump failure
artery catheter adds further details in the diagno- related to an ischemic cause [12].
sis, establishing cardiac output, pulmonary
artery occlusion pressure (PCWP), systemic vas-
cular resistance, and continuous mixed venous Differential Diagnosis
oxygen saturation (SvO2) [13]. These parameters
are also helpful in guiding inotropic/vasopressor The differential diagnosis for shock may be chal-
therapy or fluid resuscitation and in assessing lenging and must be focused on underlying
mechanical ventilation settings [14]. Pulmonary causes of inadequate tissue perfusion.
ERRNVPHGLFRVRUJ
9 Cardiogenic Shock 103
ERRNVPHGLFRVRUJ
104 M.V. Matassini et al.
contractility and modifying vascular tone. The dopamine as the first-line inotropic therapy
principal inotropes and vasopressors that we in CS.
commonly use in CS are (Table 9.2): Epinephrine (adrenaline): It is a potent agonist
Dobutamine: It is predominantly a of all adrenoreceptors. Its use results in HR, SV,
-adrenergic agonist with a 1/2 ratio of 3:1. It CO, and coronary blood flow increase. At low
increases HR, SV, and CO with a modest decrease doses, a passive pulmonary vessel stretching
in blood pressure and SVR [20]. It also has a mild accommodates CO increase, but at high doses, it
1-adrenergic agonism, and this is the reason determines a pulmonary vascular resistance
why vascular resistance decrease does not persist increase and so a right ventricle afterload increase.
at higher doses. These beneficial effects are lim- Even adrenaline increases myocardial oxygen con-
ited by myocardial oxygen consumption increase sumption due to increase in HR and stroke work. It
that worsens myocardial ischemia, precipitates has metabolic effects like increased plasma glucose
tachyarrhythmias, and increases mortality. The and lactate concentration. The lactate concentra-
ESC guidelines recommend dobutamine and tion increase seems not to be harmful.
Norepinephrine (noradrenaline): It is a potent
Table 9.1 Location and response of adrenergic -agonist that also stimulates 1 receptors, with
receptors an increase in blood pressure, SVR, and SV. Like
Receptor Location Activity adrenaline, it increases right ventricle afterload.
1 Vascular smooth Contraction Either cerebral circulation or coronary circulation
muscle Increase force of is protected to a certain extent from these vaso-
Heart contraction constrictor effects due to the relative paucity of
2 Vascular smooth Contraction the vascular adrenoreceptors, while pulmonary,
muscle
renal, splanchnic, and cutaneous blood flow is not
1 Heart Increase force of
contraction spared. The ESC guidelines recommend nor-
Increase AV nodal adrenaline as second-line therapy in CS patients.
conduction velocity Dopamine: It has a dose-dependent action.
2 Smooth muscle Relaxation At low doses (2 /kg/min), it activates dopami-
(vascular,
nergic receptors with splanchnic and renal vaso-
bronchial, GI, and
GU) dilatation. At medium doses (510 /kg/min), it
D Vascular smooth Relaxation activates 1 receptors with HR and CO increase.
muscle At intermediate doses (25 /kg/min), either dopa-
AV node atrioventricular node, GI gastrointestinal, GU minergic or 1 receptors are stimulated. At high
genitourinary doses, it predominates -adrenergic action with
ERRNVPHGLFRVRUJ
9 Cardiogenic Shock 105
vasoconstriction and increase in SVR that may reverse beta-blocker effects if the last ones are
cause a CO decrease. De Backey et al. showed in thought to contribute to hypotension.
a subgroup analysis that in CS patients dopamine Phenylephrine: It is an 1-selective agonist
increased 28-day mortality rate compared with that causes an increase in SVR and blood pres-
norepinephrine, but in this study dopamine doses sure and a reflex bradycardia that determines a
in CS patients are not specified, and this may be decrease in CO. This is the reason why its utiliza-
a reasonable explanation of these results because tion in CS is very rare.
high-dose dopamine causes a CO decrease [21]. Vasopressin: It activates V1 vascular smooth
Milrinone: It inhibits phosphodiesterase-3 and receptors and causes vasoconstriction. In refrac-
prevents cyclic adenosine monophosphate tory CS, vasopressin has been utilized, increasing
(cAMP) degradation that activates protein kinase MAP without effects on CI, pulmonary capillary
A which results in increased calcium influx into wedge pressure, or urine output [24].
the cardiomyocyte with increased contractility. In Assessment and optimization of cardiac filling
the smooth muscle, elevated cAMP causes relax- pressure enhance hemodynamic improvement in
ation (vasodilatation) because it inhibits myosin CS. Hypovolemia should be treated with intrave-
light-chain kinase. Milrinone has a similar car- nous fluid replacement, and this should be guided
diovascular profile to dobutamine. In fact it by PCWP, systemic arterial pressure, arterial
increases HR, SV, and CO and decreases mean oxygen saturation, central venous pressure (tar-
blood pressure, SVR, and pulmonary artery resis- get value 810 mmHg if there is no right ventri-
tances, reducing preload and afterload and conse- cle (RV) dysfunction, 1012 mmHg if RV
quently ventricular wall stress. Although dysfunction), and cardiac output measurement.
milrinone affects hemodynamics, the OPTIME- When hypervolemia with pulmonary and periph-
CHF trial did not show a difference in days of eral edema is present, diuretics (loop diuretics or
hospitalization between decompensated heart combining loop with thiazide diuretic when patient
failure patients treated with 48 h administration becomes resistant to the first ones) should be used.
of milrinone and placebo. In this study, there was Actually the intra-aortic balloon pumping
not an increase in in-hospital mortality in the mil- (IABP) may be considered in patients with acute
rinone group [22]. Actually milrinone is recom- myocardial infarction complicated by CS. The
mended only for refractory CS patients. evidence does not support the IABP routine use
Levosimendan: It is a calcium-sensitizing because the IABP SHOCK II trial did not show a
agent that binds troponin C, at systolic calcium 30-day mortality difference between the IABP
concentrations, and prolongs myosinactin inter- and control groups in patients with CS compli-
action due to troponin I inhibition. So levosimen- cating MI, probably due to high rate of patient
dan does not increase cellular calcium shift from the control to the IABP group [25].
concentration and consequently does not impair In patients with refractory shock, LV mechan-
diastolic function and cardiac rhythm. It has phos- ical device may be considered. The percutaneous
phodiesterase III inhibitory effects and causes circulatory support devices can be distinguished
blood pressure decrease. Levosimendan has an in four categories:
active metabolite so its inotropic effects continue
even after infusion is stopped. The SURVIVE Mechanical left ventricle support that unloads
study did not show a 180-day mortality rate LV pressure (IABP)
through short-term levosimendan and dobutamine Mechanical left ventricle support that unloads
infusion in acute decompensated heart failure LV volume (TandemHeart and Impella
[23], but deaths in the first weeks were signifi- Recover 2.5 l/min or 4 l/min)
cantly fewer in the levosimendan group. There are Mechanical biventricular support (combina-
only few data (limited to case reports) on the role tion of right and left ventricle support)
of levosimendan in CS patients. The ESC guide- Mechanical biventricular support with mem-
lines recommend levosimendan infusion to brane oxygenation (ECMO)
ERRNVPHGLFRVRUJ
106 M.V. Matassini et al.
Oxygen or mechanical respiratory support is 12. OGara PT, Kushner FG, Ascheim DD et al (2013)
ACCF/AHA Guideline: 2013 ACCF/AHA Guideline
indicated according to clinical and blood gas
for the Management of ST-Elevation Myocardial
asset. Infarction: A Report of the American College of
Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. Circulation
128:1810
References 13. Mueller HS, Chatterjee K, Davis KB et al (1998) ACC
expert consensus document. Present use of bedside
1. Reynolds HR, Hochman JS (2008) Cardiogenic right heart catheterization in patients with cardiac dis-
shock: current concepts and improving outcomes. ease. J Am Coll Cardiol 32:840
Circulation 117:686697 14. Mimoz O, Rauss A, Rekik N et al (1994) Pulmonary
2. Holmes DR Jr, Berger PB, Hochman JS, Granger CB, artery catheterization in critically ill patients: a pro-
Thompson TD, Califf RM et al (1999) Cardiogenic spective analysis of outcome changes associated with
shock in patients with acute ischemic syndromes with catheter-prompted changes in therapy. Crit Care Med
and without ST-segment elevation. Circulation 22:573
100(20):20672073 15. Harvey S, Harrison DA, Singer M et al (2005)
3. Jacobs AK, Leopold JA, Bates E, Mendes LA, Sleeper Assessment of the clinical effectiveness of pulmonary
LA, White H, Davidoff R, Boland J, Modur S, Forman artery catheters in management of patients in inten-
R, Hochman JS (2003) Cardiogenic shock caused by sive care (PAC-MAN): a randomized controlled trial.
right ventricular infarction: a report from the SHOCK Lancet 366:472
registry. J Am Coll Cardiol 41:12731279 16. Smith I, Kumar P, Molloy S et al (2001) Base excess
4. Carnendran L, Abboud R, LA Sleeper R, Gurunathan and lactate as prognostic indicators for patients admit-
J, Webb G, Menon V, Dzavik V, Cocke T, Hochman ted to intensive care. Intensive Care Med 27:7483
JS, for the SHOCK Investigators (2001) Trends in 17. Hochman JS, Sleeper LA, Webb JG, Sanborn TA,
cardiogenic shock: report from the SHOCK Study. White HD, Talley JD, Buller CE, Jacobs AK, Slater
Eur Heart J 22:472478 JN, Col J, McKinlay SM, LeJemtel TH, Early revas-
5. Lindholm MG, Kober L, Boesgaard S et al (2003) cularization in acute myocardial infarction compli-
Cardiogenic shock complicating acute myocardial cated by cardiogenic shock. SHOCK Investigators
infarction: prognostic impact of early and late shock (1999) Should We Emergently Revascularize
development. Eur Heart J 24:258265 Occluded Coronaries for Cardiogenic Shock. N Engl
6. Goldenberg EJ, Frederisk AS, Gore JM, Lessard D, J Med 341:625634
Yarzebski J (2009) Thirty-year trends (1975 to 2005) 18. Hussain F, Philipp RK, Ducas RA, Elliott J, Dzavik
in the magnitude of management of, and hospital V, Jassal DS, Tam JW, Roberts D, Garber PJ, Ducas
death rates associated with cardiogenic shock in J (2011) The ability to achieve complete revascu-
patients with acute myocardial infarction. A larization is associated with improved in-hospital
population-based perspective. Circulation survival in cardiogenic shock due to myocardial
119:12111219 infarction: Manitoba cardiogenic SHOCK Registry
7. Kohsaka S, Menon V, Lowe AM et al (2005) Systemic investigators. Catheter Cardiovasc Interv 78:
inflammatory response syndrome after acute myocar- 540548
dial infarction complicated by cardiogenic shock. 19. Steg PG, James SK, Atar D, Badano LP, Blmstrom-
Arch Intern Med 165:16431650 Lundqvist C, Borger MA, Di Mario C, Dickstein
8. Shah AM (2000) Inducible nitric oxide synthase and K, Ducrocq G, Fernandez-Aviles F, Gershlick
cardiovascular disease. Cardiovasc Res 45:148155 AH, Giannuzzi P, Halvorsen S, Huber K, Juni P,
9. Ferdinandy P, Danial H, Ambrus I et al (2000) Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW,
Peroxynitrite is a major contributor to cytokine-induced Valgimigli M, vant Hof A, Widimsky P, Zahger
myocardial contractile failure. Circ Res 87:241247 D (2012) ESC Guidelines for the management of
10. Geppert A, Dorninger A, Delle-Karth G et al (2006) acute myocardial infarction in patients present-
Plasma concentrations of interleukin- 6, organ failure, ing with ST-segment elevation. Eur Heart J 33(20):
vasopressor support, and successful coronary revascu- 25692619
larization in predicting 30-day mortality of patients 20. Colucci WS, Wright RF, Jaski BE et al (1986)
with cardiogenic shock complicating acute myocar- Milrinone and dobutamine in severe heart failure: dif-
dial infarction. Crit Care Med 34:20352042 fering hemodynamic effects and individual patient
11. Menon V, White H, LeJemtl T et al (2000) The clini- responsiveness. Circulation 73:III175III183
cal profile of patients with suspected cardiogenic 21. De Backer D, Biston P, Devriendt J et al (2010)
shock due to predominant left ventricular failure; a Comparison of dopamine and norepinephrine in the
report from the SHOCK Trial Registry. Should we treatment of shock. New Engl J Med 362:779789,
emergently revascularize Occluded Coronaries in car- Clinical trial comparing two vasopressors in several
diogenic shock? J Am Coll Cardiol 36:1071 types of shock. Subgroup analysis suggests better
ERRNVPHGLFRVRUJ
9 Cardiogenic Shock 107
mortality in patients with cardiogenic shock treated 24. Jolly S, Newton G, Horlick E et al (2005) Effect of
with norepinephrine vasopressin on hemodynamics in patients with refrac-
22. Cuffe MS, Califf RM, Adams KF Jr et al (2002) tory cardiogenic shock complicating acute myocar-
Outcomes of a Prospective Trial of Intravenous dial infarction. Am J Cardiol 96:16171620
Milrinone for Exacerbations of Chronic Heart 25. Thiele H, Zeymer U, Neumann F-J, Ferenc M, Olbrich
Failure I. Short-term intravenous milrinone for acute H-G, Hausleiter J, Richardt G, Hennersdorf M,
exacerbation of chronic heart failure: a randomized Empen K, Fuernau G, Desch S, Eitel I, Hambrecht R,
controlled trial. JAMA 287:15411547 Fuhrmann J, Bhm M, Ebelt H, Schneider S,
23. Mebazaa A, Nieminen MS, Packer M et al (2007) Schuler G, Werdan K, for the IABP-SHOCK II Trial
Levosimendan vs dobutamine for patients with acute Investigators (2012) Intraaortic balloon support for
decompensated heart failure: the SURVIVE random- myocardial infarction with cardiogenic shock. N Engl
ized trial. JAMA 297:18831891 J Med 367:12871296
ERRNVPHGLFRVRUJ
Cardiac Resynchronization
Therapy and Possible 10
Dysfunctions
None
A 65-year-old man had been diagnosed
with congestive heart failure (HF) due to
dilated cardiomyopathy in 2013. He had Medications
been in chronic AF since 2012. He was
referred to the hospital with worsening HF Bisoprolol 5 mg, valsartan 40 mg b.i.d., furose-
in May 2014; however, his HF symptoms mide 40 mg t.i.d., spironolactone 50 mg q.d.,
remained New York Heart Association warfarin according to INR values
(NYHA) class III despite the administra-
tion of appropriate medical therapy. So he
was referred to our clinic for cardiac resyn- Vital Signs
chronization therapy (CRT).
Temperature: 36 C
Heart rate: 76 bpm
Arterial blood pressure: 130/75 mmHg
Medical History and Cardiovascular Respiratory rate: 14 breaths/min
Risk Factors Oxygen saturation: 96 %
ERRNVPHGLFRVRUJ
110 L. Cipolletta and M. Brambatti
ERRNVPHGLFRVRUJ
10 Cardiac Resynchronization Therapy and Possible Dysfunctions 111
ERRNVPHGLFRVRUJ
112 L. Cipolletta and M. Brambatti
a b
Fig. 10.3 (a) Posteroanterior chest X-ray showing the left ventricular lead displacement. (b) Latero-lateral chest X-ray
confirming the left ventricular lead displacement
a b
Fig. 10.4 (a) Coronary sinus angiography on right anterior oblique projection. (b) Coronary sinus angiography on left
anterior oblique projection
mortality [2]. LBBB often correlates with chrony can further worsen the pump function of
mechanical dyssynchrony also called interven- a failing LV. CRT, through the reestablishment
tricular delay, a nonphysiological timing of LV of a more physiological ventricular activation,
and RV contraction. There may also be abnor- improves cardiac performance and reduces HF
mal contraction of individual segments of the symptoms and also determines a reverse remod-
LV, causing intraventricular delay. In an HF eling of the LV along with mortality and hospi-
patient, the inter- and intraventricular dyssyn- talization reduction [37].
ERRNVPHGLFRVRUJ
10 Cardiac Resynchronization Therapy and Possible Dysfunctions 113
ERRNVPHGLFRVRUJ
114 L. Cipolletta and M. Brambatti
ERRNVPHGLFRVRUJ
10 Cardiac Resynchronization Therapy and Possible Dysfunctions 115
Non-capture is defined as the release of an All major malfunctions, including loss of cap-
atrial or ventricular pacing stimulus without ture, undersensing, and oversensing, can be asso-
capture. The left ventricular lead of CRT sys- ciated with a rupture in lead insulation or
tem is separated from the myocardium by the conductor failure. A marked drop in the mea-
vein wall and by any epicardial fat that may sured stimulation impedance is a sign of lead
coat the vein. When loss of capture occurs, the insulation break, while a significant increase in
capture threshold of the left ventricular lead impedance conductor is a sign of lead fracture.
may be higher than values measured at the
implantation procedure. In modern CRT
devices, the right and left ventricular leads can
References
be assessed independently if loss of capture is
suspected. Widening of the QRS complex or a 1. European Society of Cardiology (ESC), European
more elusive change in QRS morphology may Heart Rhythm Association (EHRA), Brignole M,
be a sign of loss of capture of LV lead. However, Auricchio A, Baron-Esquivias G, Bordachar P,
Boriani G, Breithardt OA, Cleland J, Deharo JC,
only pacemaker interrogation will confirm the
Delgado V, Elliott PM, Gorenek B, Israel CW,
issue or a chest X-ray in presence of a signifi- Leclercq C, Linde C, Mont L, Padeletti L, Sutton R,
cant displacement. Vardas PE (2013) 2013 ESC guidelines on cardiac
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116 L. Cipolletta and M. Brambatti
pacing and cardiac resynchronization therapy: the cardiac resynchronization in mildly symptomatic
task force on cardiac pacing and resynchronization heart failure patients and in asymptomatic patients
therapy of the European Society of Cardiology (ESC). with left ventricular dysfunction and previous
Developed in collaboration with the European Heart heart failure symptoms. J Am Coll Cardiol 52(23):
Rhythm Association (EHRA). Europace 15(8):1070 18341843
1118. doi:10.1093/europace/eut206, Epub 2013 Jun 8. Sipahi I, Carrigan TP, Rowland DY, Stambler BS,
24 Fang JC (2011) Impact of QRS duration on clinical
2. Shamim W, Francis DP, Yousufuddin M, Varney S, event reduction with cardiac resynchronization ther-
Pieopli MF, Anker SD, Coats AJ (1999) apy: meta-analysis of randomized controlled trials.
Intraventricular conduction delay: a prognostic Arch Intern Med 171(16):1454
marker in chronic heart failure. Int J Cardiol 70(2):171 9. Delgado V, van Bommel RJ, Bertini M et al (2011)
3. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass Relative merits of left ventricular dyssynchrony, left
DA, De Marco T, Carson P, DiCarlo L, DeMets D, ventricular lead position, and myocardial scar to pre-
White BG, DeVries DW, Feldman AM, Comparison dict long-term survival of ischemic heart failure
of Medical Therapy, Pacing, and Defibrillation in patients undergoing cardiac resynchronization ther-
Heart Failure (COMPANION) Investigators (2004) apy. Circulation 123:7078
Cardiac-resynchronization therapy with or without an 10. Kass DA (2003) Predicting cardiac resynchronization
implantable defibrillator in advanced chronic heart response by QRS duration: the long and short of it. J
failure. N Engl J Med 350(21):2140 Am Coll Cardiol 42:21252127
4. Cleland JG, Daubert JC, Erdmann E, Freemantle N, 11. European Heart Rhythm Association, European
Gras D, Kappenberger L, Tavazzi L, Cardiac Society of Cardiology, Heart Rhythm Society, Heart
Resynchronization-Heart Failure (CARE-HF) Study Failure Society of America, American Society of
Investigators (2005) The effect of cardiac resynchro- Echocardiography, American Heart Association,
nization on morbidity and mortality in heart failure. N European Association of Echocardiography, Heart
Engl J Med 352(15):1539 Failure Association, Daubert JC, Saxon L, Adamson
5. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown PB, Auricchio A, Berger RD, Beshai JF, Breithard O,
MW, Daubert JP, Estes NA, Foster E, Greenberg H, Brignole M, Cleland J, Delurgio DB, Dickstein K,
Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Exner DV, Gold M, Grimm RA, Hayes DL, Israel C,
Zareba W, MADIT-CRT Trial Investigators (2009) Leclercq C, Linde C, Lindenfeld J, Merkely B, Mont
Cardiac-resynchronization therapy for the prevention L, Murgatroyd F, Prinzen F, Saba SF, Shinbane JS,
of heart-failure events. N Engl J Med 361(14):1329 Singh J, Tang AS, Vardas PE, Wilkoff BL, Zamorano
6. Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon JL (2012) 2012 EHRA/HRS expert consensus state-
R, Connolly S, Hohnloser SH, Nichol G, Birnie DH, ment on cardiac resynchronization therapy in heart
Sapp JL, Yee R, Healey JS, Rouleau JL, failure: implant and follow-up recommendations
Resynchronization-Defibrillation for Ambulatory and management. Heart Rhythm 9(9):15241576.
Heart Failure Trial Investigators (2010) Cardiac- doi:10.1016/j.hrthm.2012.07.025
resynchronization therapy for mild-to-moderate heart 12. Biffi M, Moschini C, Bertini M, Saporito D, Ziacchi
failure. N Engl J Med 363(25):2385 M, Diemberger I, Valzania C, Domenichini G, Cervi
7. Linde C, Abraham WT, Gold MR, St. John Sutton M, E, Martignani C, Sangiorgi D, Branzi A, Boriani G
Ghio S, Daubert C, REVERSE (REsynchronization (2009) Phrenic stimulation: a challenge for cardiac
reVErses Remodeling in Systolic left vEntricular dys- resynchronization therapy. Circ Arrhythm
function) Study Group (2008) Randomized trial of Electrophysiol 2:402410
ERRNVPHGLFRVRUJ
Part IV
Cardiomyopathy
ERRNVPHGLFRVRUJ
Hypertrophic Cardiomyopathy
11
Marco Marchesini and Erika Baiocco
A 57-year-old man presented to the emer- The family history revealed that his mother
gency room complaining palpitations that was affected by hypertrophic cardiomyopathy
started suddenly few hours before, during a (HCM). There was not any case of sudden car-
moderate walking. Palpitations were diac death in the family.
accompanied by dyspnea and mild dizzi- At 20 years old, HCM was incidentally diag-
ness. Symptoms lasted for about 10 min, nosed during a sport screening and since pre-
forcing the patient to rest. The episode participation screening and since then he was
interrupted abruptly and spontaneously, and regularly followed up.
the patient did not remember if heartbeat He was a smoker.
was regular during the episode. He never
had arrhythmias before and he denied syn-
cope or angina. Allergies
The patient presented completely
asymptomatic to the emergency room. None
Medications
Verapamil 80 mg BID
Vital Signs
Temperature: 36.3 C
Resting heart rate: 58 bpm
M. Marchesini (*) E. Baiocco
Clinica di Cardiologia e Aritmologia, Universit Blood pressure: 125/90 mmHg
Politecnica delle Marche, Respiratory rate: 18 breaths per minute
Via Conca, 71, Ancona 60126, Italy Oxygen saturation while breathing in room
e-mail: marche9584@gmail.com; erikabaiocco@ air: 99 %
libero.it
ERRNVPHGLFRVRUJ
120 M. Marchesini and E. Baiocco
The patient appeared in good clinical condition. Complete blood count: normal
At physical examination, the relevant findings Cholesterol (total, HDL, LDL) and TG: normal
were the following: Fasting blood glucose: 78 m/dl (4.33 mmol/L)
Cardiovascular: Apical precordial impulse Hepatic function (GOT, GPT, -GGT, ALP, total
was forceful but not displaced laterally. Regular bilirubin, direct and indirect): normal
rate and rhythm; S1 and S2 were normal with an Thyroid function (TSH, FT3, FT4): normal
adjunctive S4. Systolic ejection late-peaking Renal function (creatinine, BUN): normal
murmur was best heard between the apex and left Electrolytes (Na+, K+, Ca++, Mg++, Cl):
sternal border without radiation to the neck, and normal
it was increased by Valsalva maneuver. Mild dia-
stolic decrescendo murmur was detected in Erb
auscultator focus. EKG
Lungs: No rales at auscultation neither rhon-
chi nor wheezes bilaterally. A routine EKG at rest was performed (Fig. 11.1).
Abdomen: Plain and tractable; no The initial EKG showed sinus rhythm at 58 bpm,
hepatosplenomegaly. normal atrioventricular conduction (PR interval 160
Extremities: No lower limb edema. s), normal QRS duration (0.08 s), absent Q wave,
ERRNVPHGLFRVRUJ
11 Hypertrophic Cardiomyopathy 121
Hyperthyroidism
Fever
Anxiety
Anemia
Use of medications containing stimu-
lant, caffeine, or nicotine
Strenuous exercise, poor training
He did not report any specific stress condition or Fig. 11.3 Parasternal short-axis ventricle view
recent changes in his lifestyle. He was walking
slowly, when the arrhythmia occurred, which there-
fore can be excluded a physiologic activity response
and poor training. According to physical examina-
tion, fever was excluded, and the laboratory tests
did not show any anemia and thyroid dysfunction.
The most probable cause of symptoms was
spontaneous arrhythmia.
Transthoracic
Echocardiography (TTE)
ERRNVPHGLFRVRUJ
122 M. Marchesini and E. Baiocco
asymmetrical hypertrophy with septal wall point to a hemodynamic distress that is often
thickness that reached 35 mm; the posterior related to sustained ventricular tachycardias.
wall was 15 mm with a septum to posterior In adult patients with HCM, most recent data
wall ratio of 2.4. report on an annual incidence of cardiovascular
Ejection fraction with the biplane Simpson death near 12 % with sudden cardiac death
method was 65 % without regional wall being (SCD) the most common.
motion abnormalities.
Diastolic dysfunction grade II with normal
Major clinical features associated with an
estimated filling pressure (E/E 6).
increased risk of SCD are:
Severe left atrial enlargement (LA diameter
55 mm, iLAV >40 mL/m2). Young age
Systolic anterior motion (SAM) of the ante- Non-sustained ventricular tachycardia
rior mitral valve leaflet, without LVOT (NSVT)
obstruction at rest, but with mild flow Maximum left ventricular wall thickness
acceleration during Valsalva (peak gradient Family history of sudden cardiac death
15 mmHg). Syncope
Normal size and function of right atrium and Left atrial diameter
ventricle. Left ventricular outflow tract obstruction
Normal aortic tricuspid valve with mild cen- Exercise blood pressure drop
tral regurgitation
Normal tricuspid and pulmonic valves.
Normal dimension of inferior vena cava (IVC) The patient had no family history of SCD and
with >50 % inspiratory collapse. denied syncope, but the risk assessment com-
No pericardial effusion. prised also of a 24-h ambulatory ECG and an
exercise test.
According to ESC guidelines, HCM is defined
as a wall thickness >15 mm in one or more LV
myocardial segments, as measured by any imag- Exercise Testing with Treadmill
ing technique (echocardiography, cardiac mag-
netic resonance imaging (CMR), or computed Exercise testing was terminated for asthenia and
tomography (TC)), that is not explained solely by muscular weakness at a heart rate corresponding
chronic loading conditions. to 93 % of maximal heart rate predicted for age.
Echocardiographic findings were suggestive Neither symptoms nor ST-segment depression or
of hypertrophic cardiomyopathy: the patient had elevation occurred. During exercise, arrhythmias
no history of hypertension or valve disease with were not detected except for two isolated poly-
elevated afterload. Infiltrative cardiomyopathy morphic ventricular ectopic beats (VE) and one
was excluded, because the ventricular thickening VE couple. Systolic blood pressure and heart rate
is usually concentric with characteristic pattern response were normal.
of granular sparkling and different degrees of
pericardial effusion.
In a patient with HCM, a sustained episode of 24-h Ambulatory ECG
palpitation lasting more than few minutes is often
caused by supraventricular arrhythmias, espe- 24-h ambulatory ECG was performed to detect
cially in the presence of left atrium enlargement; atrial or ventricular arrhythmias. The total num-
atrial fibrillation is the most common arrhythmia ber of beats analyzed was 82,105. Sinus rhythm
in this population. In our patient, we could not at average heart rate of 64 bpm, with minimum of
exclude the hypothesis of a ventricular origin, 50 bpm and a maximum of 95 bpm. Two hundred
particularly because the symptoms associated fifty total ventricular ectopic (VE) beats of differ-
with palpitation (dyspnea and dizziness) could ent morphologies with six VE couples and one
ERRNVPHGLFRVRUJ
11 Hypertrophic Cardiomyopathy 123
Clinical Course
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124 M. Marchesini and E. Baiocco
Moreover, at discharge, the patient was disorders due to inborn errors of metabolism
advised to abstain from competitive athletic (e.g., Pompe disease, Fabry disease) or deposi-
activity and strenuous physical exertion and was tion of anomalous misfolded proteins (different
given clinical and echocardiographic follow-up types of amyloidosis). Other genetic causes could
appointments. be mithocondrial diseases, neuromuscular disor-
ders (Friedreichs ataxia), or malformative syn-
dromes like Noonan or LEOPARD [4].
11.2 Hypertrophic The true hypertrophic cardiomyopathy is a
Cardiomyopathy genetic disease with an autosomal dominant trait
caused by mutations in cardiac sarcomere protein
Introduction and Epidemiology genes. In general, patients with a sarcomere pro-
tein mutation present earlier and report a higher
The most recent expert consensus on cardiomy- prevalence of family history of HCM and sudden
opathies has adopted a new classification system cardiac death (SCD) than those without a muta-
no more based on primary or secondary involve- tion. They also tend to have more severe hypertro-
ment of the heart but in which cardiomyopa- phy, microvascular dysfunction, and myocardial
thies are defined by specific morphological and fibrosis.
functional phenotypes as they present for the
first time to the observer: mainly hypertrophic,
dilated, arrhythmogenic cardiomyopathy and Incidence
restrictive phenotype. Only in the second time,
cardiomyopathies are grouped into familial/ A number of studies worldwide report a preva-
genetic and nonfamilial/nongenetic subtypes, lence of HCM in the range of 0.020.23 % in
irrespective of the presence of extra-cardiac dis- adults. In pediatric registries, the prevalence of
ease [1, 2, 3]. HCM in children is unknown, but population-
based studies report an annual incidence of 0.3
0.5 per 100,000. Most studies report a small male
Hypertrophic cardiomyopathy (HCM) is preponderance, while the prevalence in different
defined by the presence of increased left racial groups is similar.
ventricular (LV) wall thickness that is not
solely explained by abnormal loading con-
ditions. Many are the secondary causes of Diagnosis and Denition
hypertrophy (in particular left ventricular
hypertrophy) that should be considered in In an adult, HCM is defined by a wall thick-
differential diagnosis: ness 15 mm in one or more LV myocardial
segmentsas measured by any imaging tech-
1. Athletes heart nique such as echocardiography, cardiac mag-
2. Hypertensive cardiomyopathy netic resonance imaging (CMR), or computed
3. Valve diseases imposing increased tomography (CT)that is not explained
afterload (mainly aortic stenosis) solely by loading conditions.
4. Isolated basal septal hypertrophy in In children as in adults, the diagnosis of HCM
elderly people requires a LV wall thickness more than two
standard deviations greater than the predicted
mean z-score.
Moreover hypertrophic phenotype (variable The clinical diagnosis of HCM in first-degree
grade and distribution of ventricular wall thick- relatives of patients with unequivocal disease
ening) could represent a common picture of dif- (LVH 15 mm) is based on the presence of
ferent pathologic conditions such as infiltrative otherwise unexplained increased LV wall
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11 Hypertrophic Cardiomyopathy 125
thickness 13 mm in one or more LV myocar- and Danon disease in adolescent males. Different
dial segments. degrees of concentric hypertrophy with left ven-
tricular systolic impairment is a clue to infiltra-
tive diseases, because the hypokinetic end-stage
Variants phases of a true HCM more often pass through a
dilation of left ventricle.
A particular variant is apical hypertrophic cardio-
myopathy (AHCM) that is a rare form of HCM,
which usually involves the apex of the left ventricle A New Diagnostic Tool: Cardiac
and rarely involves the right ventricular apex or Magnetic Resonance
both. Historically, this condition was thought to be
confined to the Japanese population, but it is also Cardiac magnetic resonance (CMR) is particu-
found in other populations. Of all the HCM patients larly useful for characterizing the presence, loca-
in Japan, the prevalence of AHCM was 15 %, tion, and extent of LV hypertrophy, which can be
whereas in the USA and Europe, the prevalence limited to one or two left ventricle (LV) seg-
was only 3 %. The diagnostic criteria for AHCM ments. In those cases, CMR offers a superior
included demonstration of asymmetrical LV hyper- visualization and a higher diagnostic accuracy
trophy, confined predominantly to the LV apex, respect to 2D echocardiography, particularly
with an apical wall thickness 15 mm and a ratio when the only segments involved are the basal
of maximal apical to posterior wall thickness 1.5. anterolateral free wall or the apex.
In contrast with the common variant of HCM, up Recent study showed that diffuse hypertrophy,
to 54 % of patients with AHCM are symptomatic. involving >50 % of the left ventricle and 8 or
This entity should be well known because of its more segments, is present in 54 % of patients
difficult recognition (the apical position of hyper- with HCM, whereas only 10 % of patients pres-
trophic segments represents a limitation for a rou- ent with single segment involvement [6, 7].
tine 2D echocardiography) and its high prevalence During an exam directed to distinguishing the
of complications such as atrial fibrillation, myocar- possible origin of a hypertrophic phenotype found
dial infarction, apical aneurysm, embolic events, with echocardiography, CMR could add diagnos-
and congestive heart failure [5]. tic clues, demonstrating a constellation of sugges-
tive features of genetic HCM: such as anomalies
in papillary muscles, right ventricle, subclinical
Differential Diagnosis features, and particularly tissue characterization.
Papillary muscle involvement in HCM con-
Genetic and nongenetic disorders causing hyper- sists in apical displacement of its insertion and
trophic phenotype can present with lesser the presence of multiple or bifid papillary mus-
degrees of wall thickening (1314 mm); in these cles with increased mass. All these variants could
cases, the diagnosis of true HCM requires evalu- favor SAM and outflow tract obstruction perturb-
ation of other features including family history, ing the normal activity of mitral valve apparatus.
noncardiac symptoms and signs, electrocardio- In 1/3 of patients with HCM, right ventricular
gram (ECG) abnormalities, laboratory tests, and wall thickness and/or mass is increased, includ-
multimodality cardiac imaging. In any situation, ing about 10 % of patient with extreme right ven-
the age of presentation is a fundamental clue to tricle (RV) wall hypertrophy (>10 mm). Finally
the differential diagnosis. Severe (maximal in preclinical (genotype [+]/phenotype [])
thickness more than 30 mm or equivalent in chil- patients with HCM, CMR may show the pres-
dren) and concentric ventricular hypertrophy in ence of crypts. Myocardial crypt is a deep fissur-
a child, adolescent, or young adult should rise ing of the muscle orthogonal to the endocardial
suspicion of metabolic or storage disorders, in border (often visualized also in angiography),
particular Pompe disease in the infantile period localized predominately in the inferior septum,
ERRNVPHGLFRVRUJ
126 M. Marchesini and E. Baiocco
although the etiology of these structural abnor- The latter group can be further divided into those
malities remains uncertain. who develop outflow tract obstruction and those
Moreover, CMR is able to accurately define who do not.
ventricular volume and function, being the gold Outflow tract obstruction at rest with exer-
standard for ejection fraction measurement. tional limitations is present in 25 % of all affected
Frequently in patients with HCM, the ventricular patients; an additional 25 % present inducible
volumes are reduced, and the hyperkinetic outflow tract obstruction; other groups of symp-
appearance of systolic contraction translates into tomatic patients are those with restrictive physi-
a supernormal ejection fraction. This is true until ology and frequent tachyarrhythmias and who
the end stage of cardiomyopathy is reached, may experience exertional limitation because of
when the diastolic dysfunction, present from the diastolic dysfunction and those who are at risk or
beginning and related to myocardial thickness have already experienced ventricular arrhythmias
and rigidity, is accompanied by a reduced sys- and sudden cardiac death. At last, there is a small
tolic thickening [8, 9, 10]. proportion of patients (up to 5 %) who may
In 3-chamber view with cine imaging, CMR is develop the end-stage phase of hypertrophic car-
able to elucidate the precise mechanism of outflow diomyopathy with left ventricular dilation and
tract obstruction demonstrating turbulent flow systolic impairment.
generated by systolic movement of anterior mitral
leaflet, chordae, and papillary muscle toward the Left Ventricular Outow Tract
interventricular septum [11]. Obstruction
Contrast-enhanced CMR with LGE Treatment of outflow obstruction should be
sequences can detect areas of focal abnormality restricted to patients who exhibit the associated
in approximately 5080 % of patients. There is symptoms. Recognition of obstruction-related
no specific pattern of LGE characteristic for symptoms may be made challenging by both a
HCM, although the distribution of LGE in HCM patients restriction in physical activity and by
does not correspond to a coronary vascular terri- the presence of latent obstruction (obstruction
tory. LGE is most often located in the most not present at rest but only under provocative
hypertrophied segment with an intramyocardial conditions such as exercise, Valsalva maneuver).
distribution (focal spot or linear deposit). First-line therapy consists in pharmacologic
Moreover, recent studies have demonstrated a approach with -blockers or disopyramide to
significant association between the presence of reduce left ventricular inotropism and to prolong
LGE and ventricular tachyarrhythmias on ambu- diastolic filling time.
latory 24-h Holter electrocardiography. Patients who cannot tolerate or who are refrac-
However, it is not clear whether the presence of tory to medical therapy are candidates for surgi-
LGE provides a strong predictive value in iden- cal or catheter-based treatment of outflow
tifying patients with HCM at risk for sudden obstruction. In experienced centers, both proce-
death, so much so the last ESC guidelines, pub- dures are associated with low rates of complica-
lished in 2014, do not include LGE in risk strati- tions and high successful rate. There is debate
fication algorithm [1217]. over which procedure is best, but concerns are
emerging about the potential for creation of an
arrhythmogenic focus with percutaneous septal
Treatment ablation, as well as the increased risk of complete
heart block with that procedure. The routine per-
Treatment depends on disease expression, which formance of CMR after septal reduction therapy
can differ greatly among individuals, even within is not recommended, but it can be of value when
a single family. The natural history of hypertro- questions arise about LV residual function or
phic cardiomyopathy includes those who remain when gradients do not resolve or recur late after
asymptomatic and those who develop symptoms. the procedure.
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11 Hypertrophic Cardiomyopathy 127
Table 11.1 Major clinical features associated with an increased risk of sudden cardiac death in adults according to the
2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy
Risk factor Comment
Age The effect of age on SCD has been examined in a number of studies, and two have shown a
significant association, with an increased risk of SCD in younger patients
Some risk factors appear to be more important in younger patients, most notably, NSVT severe
LVH and unexplained syncope
Non-sustained NSVT occurs in 2030 % of patients during ambulatory ECG monitoring and is an independent
ventricular predictor of SCD
tachycardia There is no evidence that the frequency, duration, or rate of NSVT influences the risk of SCD
Maximum left The severity and extent of left ventricular hypertrophy measured by TTE are associated with the
ventricular wall risk of SCD
thickness Several studies have shown the greatest risk of SCD in patient with a maximum wall thickness
of 30 min, but there are few data in patients with extreme hypertrophy (35 mm)
Family history While definitions vary, a family history of SCD is usually considered clinically significant when
of sudden one or more first-degree relatives have died suddenly aged <40 years with or without a
cardiac death at diagnosis of HCM or when SCD has occurred in a first-degree relative at any age with an
a young age established diagnosis of HCM
Left atrial Two studies have reported a positive association between LA size and SCD. There are no data
diameter on the association between SCD and LA area and volume. Measurement of LA size is also
important in assessing the risk of AF
Left ventricular A number of studies have reported a significant association with LVOTO and SCD. Several
outflow tract unanswered questions remain, including the prognostic importance of provable LVOTO and the
obstruction impact of treatment (medical or invasive) on SCD
Exercise blood Approximately one third of adult patients with HCM have an abnormal systolic blood pressure
pressure response to exercise characterized by progressive hypotension or a failure to augment the
response systolic blood pressure that is caused by an inappropriate drop in systemic vascular resistance
and a low cardiac output reverse
Various definitions for abnormal blood pressure response in patients with HCM have been
reported; for the purposes of this guideline, an abnormal blood pressure response is defined as a
failure to increase systolic pressure by at least 20 mmHg from rest to peak exercise or fall of
>20 mmHg from peak pressure
Abnormal exercise blood pressure response is associated with a higher risk of SCD in patient
aged 40 years, but its prognostic significance in patients aged >40 years is unknown
HCM hypertrophic cardiomyopathy, LA left atrium, LVH left ventricular hypertrophy, LVOT left ventricular outflow
tract obstruction, NSVT non-sustained ventricular tachycardia, SCD sudden cardiac death, TTE transthoracic
echocardiography
Ventricular Arrhythmias and Sudden ful risk factor. Multiple risk factors in an
Cardiac Death individual strengthen the case for an implantable
Ventricular arrhythmias and sudden cardiac death defibrillator, as stated by the most recent interna-
remain dreaded outcomes of HCM, occurring in tional guidelines (Table 11.1).
young, otherwise healthy individuals. Well-known
clinical risk factors for sudden cardiac death allow
clinicians to target implantable cardioverter defi- References
brillator therapy to those who are at the highest
risk. Not all risk factors predict this outcome 1. Elliot PM et al (2014) 2014 ESC guidelines on diagno-
equally, and placement of this type of device in sis and management of hypertrophic cardiomyopathy:
young patients is associated with an important the task force for the diagnosis and management of
hypertrophic cardiomyopathy of the European Society
lifetime risk of complications [1822]. of Cardiology (ESC). Eur Heart J 35(39):27332779
A personal history of cardiac arrest or sus- 2. Maron BJ, McKenna WJ et al (2003) American col-
tained ventricular arrhythmia is the most power- lege of cardiology/european society of cardiology
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clinical expert consensus document on hypertrophic 13. Elliott PM, Anastasakis A et al (2014) ESC guidelines
cardiomyopathy. Eur Heart J 24:19651991 on diagnosis and management of hypertrophic cardio-
3. Rapezzi C, Arbustini E et al (2013) Diagnostic work- myopathy. Eur Heart J. doi:10.1093/eurheartj/ehu284
up in cardiomyopathies: bridging the gap between 14. Ellims AH, Iles LM et al (2014) A comprehensive
clinical phenotypes and final diagnosis. A position evaluation of myocardial fibrosis in hypertrophic car-
statement from the ESC working group on myocardial diomyopathy with cardiac magnetic resonance imag-
and pericardial diseases. Eur Heart J 34:14481458 ing: linking genotype with fibrotic phenotype. Eur
4. Nagueh SF (2014) Anderson-fabry disease and other Heart J Cardiovasc Imaging 15:11081116
lysosomal storage disorders. Circulation 15. Kellman P, Hansen MS (2014) T1-mapping in the
130:10811090 heart: accuracy and precision. J Cardiovasc Magn
5. Yusuf SW, Bathina JD et al (2011) Apical hypertro- Reson 16:120
phic cardiomyopathy. World J Cardiol 3(7):256259 16. Maron SM (2012) Clinical utility of cardiovascular
6. Nagueh SF, Bierig SM et al (2011) American society magnetic resonance in hypertrophic cardiomyopathy.
of echocardiography clinical recommendations for J Cardiovasc Magn Reson 14:13
multimodality cardiovascular imaging of patients 17. Shiozaki AA, Kim RJ (2007) Cardiovascular mag-
with hypertrophic cardiomyopathy. J Am Soc netic resonance in hypertrophic cardiomyopathy. Arq
Echocardiogr 24:473498 Bras Cardiol 88(2):216221
7. To ACY, Dhillon A et al (2011) Cardiac magnetic 18. Christiaans I, van Engelen K et al (2010) Risk stratifi-
resonance in hypertrophic cardiomyopathy. JACC cation for sudden cardiac death in hypertrophic car-
Cardiovasc Imaging 4(10):11231137 diomyopathy: systematic review of clinical risk
8. Noureldin RA, Liu S et al (2012) The diagnosis of markers. Europace 12:313321
hypertrophic cardiomyopathy by cardiovascular mag- 19. Bruder O, Wagner A et al (2010) Myocardial scar
netic resonance. J Cardiovasc Magn Reson 14:17. visualized by cardiovascular magnetic resonance
http://www.jcmr-online.com/content/14/1/17 imaging predicts major adverse events in patients with
9. Pedrotti P (2013) La risonanza magnetica cardiaca hypertrophic cardiomyopathy. J Am Coll Cardiol
nella cardiomiopatia ipertrofica. Cardiol Sci 56:875887
11:7081 20. Maron MS, Appelbaum E et al (2008) Clinical profile
10. Hundley WG, Bluemke DA et al (2010) ACCF/ACR/ and significance of delayed enhancement in hypertro-
AHA/NASCI/SCMR 2010 Expert Consensus phic cardiomyopathy. Circ Heart Fail 1:184191
Document on Cardiovascular Magnetic Resonance: A 21. OHanlon R, Grasso A et al (2010) Prognostic signifi-
Report of the American College of Cardiology cance of myocardial fibrosis in hypertrophic cardio-
Foundation Task Force on Expert Consensus myopathy. J Am Coll Cardiol 56:867874
Documents. Circulation 121:24622508 22. Rubinshtein R, Glockner JF et al (2010) Characteristics
11. Ibrahim M, Rao C et al (2012) Modern management and clinical significance of late gadolinium enhance-
of systolic anterior motion of the mitral valve. Eur J ment by contrast-enhanced magnetic resonance imag-
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Cardiol 100:12931298
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Cardiac Amyloidosis
12
Alessandro Barbarossa and Erika Baiocco
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130 A. Barbarossa and E. Baiocco
Physical Examination
Heart diseases
General: fatigued, no acute distress, alert, Heart failure (HF)
awake, and oriented. Well developed and well Tachyarrhythmias and bradyarrhythmias
nourished Pulmonary embolism
Head, eyes, ears, nose, and throat: normoce- Anemia
phalic, atraumatic, mucous membranes moist, Poor training
extraocular muscles intact, pupils equally round
and reactive to light and accommodation bilater-
ally, bilateral tympanic membrane intact, bilateral Symptoms arose quite recently and therefore
sclera anicteric, and no conjunctival injection we can exclude a poor training condition.
Neck: supple, no jugular venous distention, no The patient does not refer fever, and chest
lymphadenopathy, and no carotid bruit X-ray didnt show pulmonary consolidations, so
Cardiovascular: regular rate and rhythm; S1 the hypothesis of a pneumonitis seems also
and S2 are normal; no murmurs, rubs, or gal- unlikely.
lops; point of maximal intensity nondisplaced According to the physical exam (bi-basal rales),
and nonsustained; no hepatojugular reflux; the most probable cause is heart failure. COPD
and capillary refill less than 2 s exacerbation is also unlikely (chest X-ray), but
Lungs: rales to auscultation at the bases bilat- cannot be excluded because of his smoking habit.
erally, no rhonchi or wheezes, no egophony, Pulmonary embolism and anemia could not be
no alterations in tactile fremitus, and normal excluded only according to physical exam.
percussion
Abdomen: mild overweight, no pulsatile masses,
normal bowel sounds in all four quadrants, no Routine EKG at Rest (Fig. 12.1)
high-pitched or tinkling sounds, resonant to per-
cussion, soft, non-distended/non-tender, no Conclusions: sinus rhythm, normal atrioventricu-
rebound or guarding, no cost vertebral angle lar conduction, counterclockwise rotation on
tenderness, and no hepatosplenomegaly horizontal axis, low voltages on limb leads, and
Extremities: no cyanosis or clubbing, with diffuse nonspecific alterations in repolarization
mild peripheral edema
Neurological: cranial nerves II through XII
intact, no focal deficit Routine Laboratory Tests
Psychiatric: normal affect, no hallucinations,
normal speech, and no dysarthria Complete blood count: normal
Skin: intact, no rashes, no lesions, and no Cholesterol (total, HDL, LDL) and TG:
erythema normal
Hepatic function (GOT, GPT, -GGT, ALP,
total bilirubin, direct and indirect bilirubin):
Which Are the Possible Causes normal
for Dyspnea on Exertion and Atypical Thyroid function (TSH, FT3, FT4): normal
Chest Pain? Renal function (creatinine, BUN): normal
Electrolytes (Na+, K+, Ca++, Mg++, Cl):
normal
Lung diseases Fasting blood glucose: 78 m/dl (4.33 mmol/L)
Chronic obstructive pulmonary Troponin I-hs: 0.16 ng/ml (n.v. < 0.055 ng/ml)
disease (COPD) BNP: 1195 pg/ml (n.v. <100 pg/ml)
Pneumonitis Inflammation index: VES 3 mm/h (n.v. < 27 mm/h),
Bronchitis CRP 0.3 mg/dl (n.v. <0.6 ng/ml)
D-dimers: 213 ng/ml (n.v. <230 ng/ml)
ERRNVPHGLFRVRUJ
12 Cardiac Amyloidosis 131
ERRNVPHGLFRVRUJ
132 A. Barbarossa and E. Baiocco
a b
Fig. 12.2 (a, b) PLAX and apical 4-CH short axis showed left ventricular hypertrophy with granular sparkling
appearance and pericardial effusion
ERRNVPHGLFRVRUJ
12 Cardiac Amyloidosis 133
Fig. 12.3 (a, b) Magnetic resonance showed areas of delayed enhancement (DA), diagnostic for amyloidosis and
pleuropericardial effusion
ERRNVPHGLFRVRUJ
134 A. Barbarossa and E. Baiocco
Red Flags
ERRNVPHGLFRVRUJ
12 Cardiac Amyloidosis 135
ERRNVPHGLFRVRUJ
136 A. Barbarossa and E. Baiocco
dosis (both senile and familial), and a pacemaker Nuclear imaging: scintigraphy with 99 mTc-
implantation is often required [8]. 3,3-diphosphono-1,2-propanodicarboxylic
acid (99mTc-DPD) may be useful in differen-
Extracardiac Manifestation tial diagnosis between AL and ATTR amyloi-
Neurological (peripheral and autonomic neurop- dosis [12].
athy, carpal tunnel syndrome), dermatological Serum electrophoresis: the presence of a serum
(periorbital purpura, nail dystrophy), macroglos- or urine monoclonal paraprotein in the setting of
sia (typical of AL form). a typical echocardiogram is suggestive of
Senile cardiac amyloidosis (ATTRwt), which AL-related amyloidosis, but it alone does not
is different from AL and ATTRm amyloidosis, firmly establish the diagnosis. In fact, as demon-
usually is not associated with other major organ strated in some studies, older males with clini-
involvements [3]. cally isolated cardiac involvement and a small
monoclonal gammopathy may have senile car-
diac amyloid and unrelated MGUS [13].
Diagnosis Tissue biopsy: the final diagnosis of cardiac
amyloidosis requires demonstration of amyloid
Physical examination: signs and symptoms deposits in the heart with endomyocardial biopsy
of heart failure (rales, high jugular venous or, in patients with appropriate imaging cardiac
pressure, hepatomegaly); usually systolic findings, demonstration of amyloid deposits at
BP is low (<100 mmHg); purpura may be histologic examination of other tissues, like the
present. abdominal fat pad, rectum, or kidney.
EKG: low voltage in the limb leads is one of Abdominal fat pad aspirate staning with Congo
the most common electrocardiogram (EKG) red will result positive in more of 70 % of
abnormalities in AL cardiac amyloidosis patients with AL-related amyloidosis, but it is
(occurring in approximate 50 %), although it subject to false positive especially in center
is less common in the other forms of cardiac with low expertise. Instead, bone marrow
amyloidosis, being reported in about 25 % of biopsy should be the test of choice to confirm
patients with familial disease (ATTRm) and in the suspect of AL-related amyloidosis, because
about 40 % of patients with senile cardiac it demonstrates evidence of a plasma cell dys-
amyloidosis (ATTRwt) [1, 3]. crasia in >80 % of patients and shows amyloid
Echocardiography: thickness of the atrium deposits in about 60 % [14].
and ventricular walls (which may or may not
be associated with increased echogenicity) as
well as thickened valve leaflets and interatrial Prognosis and Therapy
septum. Diastolic dysfunction and reduction
in longitudinal systolic function precede AL-related cardiac amyloidosis is associated
reduction in left ventricular ejection fraction. with a worse prognosis and more rapid progres-
Atrial dysfunction is frequently present and sion of heart failure (mainly due to diastolic dys-
may be associated with appendage thrombus function) compared with the other forms [1],
even in the absence of a history of atrial fibril- with a median survival of 6 months without spe-
lation [911]. cific therapy [3]. ATTRm forms, differently, have
Cardiovascular magnetic resonance: cardio- a better long-term survival [15].
vascular magnetic resonance (CMR) imaging
can provide evidence strongly suggestive of
amyloid cardiomyopathy, particularly a dis- Treatment
tinctive pattern of global left ventricular late
gadolinium enhancement (LGE) rarely seen in Treatment requires a twofold approach: manage-
other cardiomyopathies. ment of cardiac-related complications due to
ERRNVPHGLFRVRUJ
12 Cardiac Amyloidosis 137
amyloid deposition (which is similar regardless of amyloid cardiomyopathy, free from other comor-
the specific type of amyloid) and treatment of the bidities [20, 21].
underlying disease to suppress new amyloid for-
mation (which is tailored for each specific form). Specic Therapy
AL-related amyloidosis: the specific therapy
Cardiac-Related Therapy aims to stop the production of abnormal light
Standard drugs used for the treatment of conges- chains by the plasma cells. This can be achieved
tive heart failure are not useful and poorly toler- with a specific chemotherapy. Because each
ated or in some cases may be dangerous in patient is different, the dosage and choice of
patients with amyloidosis. drug require assessment by a hematologist in
Beta-blockers (BBs) and calcium channel order to minimize any adverse side effects.
blockers (CCBs) are deleterious because they Measuring the free light chains in the blood
decrease heart rate, which is the only mechanism assesses the response to AL-related amyloido-
that can maintain cardiac output in these patients sis treatment. The levels will normalize in suc-
with severe diastolic dysfunction; moreover, they cessful treatment, usually before there is a
may also aggravate autonomic dysfunction like definite improvement in the symptoms. The
angiotensin-converting enzyme inhibitors (ACE- initial therapy is often changed if there is no
i) and angiotensin receptor blockers (ARB) [16]. clear response over the first 23 cycles [18].
Moreover, these drugs may increase the risk of ATTRm (familial amyloidosis): because the
hypotension. main source of mutant transthyretin is the
Digitalis has been shown to accumulate in car- liver, transplantation is currently the treatment
diac amyloid deposits in in vitro studies; for this of choice in carefully selected patients.
reason its use may be harmful in patients with Intensive investigation is underway to develop
cardiac amyloidosis [17]. and test drugs that can prevent the production
Loop diuretics (e.g., furosemide), given at of amyloid in patients with the abnormal
high dosage in patients with severe fluid reten- genes [18].
tion, are the mainstay of therapy for ATTRwt (senile amyloidosis): no specific ther-
amyloid-related symptoms, although they dont apy currently exists.
reduce mortality. When fluid retention is severe,
a booster diuretic (metolazone) can be used inter- Conclusion
mittently. Furthermore, daily use of spironolac- Although cardiac amyloidosis is uncommon,
tone in addition to loop diuretics could help to knowledge of typical clinical and instrumental
keep normal potassium level [18]. features is essential for the diagnosis in order
In case of arrhythmias, amiodarone should be to start the correct treatment and to avoid
considered as the first-line therapy. unnecessary, and sometimes harmful,
Anticoagulation therapy is mandatory in therapies.
patients with supraventricular arrhythmias and The distinction between the major amyloi-
may be considered in patients with sinus rhythm dosis forms is fundamental because specific
but with severe contractile atrial dysfunction. therapies and prognosis differ greatly from
Pacemaker implantation may be indicated in one another. Moreover, early diagnosis is criti-
patients with symptomatic bradycardia or con- cal because patients with advanced disease are
duction disorders, while the utility of implantable usually too compromised for intensive
cardioverter defibrillators (ICDs) is still contro- chemotherapies.
versial because electromechanical dissociation Despite recent progress in knowledge of
seems to be the more frequent cause of sudden the disease mechanism, cardiac amyloidosis is
cardiac death in these patients [19]. a severe disease with a poor prognosis and few
Finally, heart transplantation could be a solu- therapeutic possibilities. For this reason fur-
tion in selected young patients, with advanced ther studies and investigation are necessary.
ERRNVPHGLFRVRUJ
138 A. Barbarossa and E. Baiocco
ERRNVPHGLFRVRUJ
12 Cardiac Amyloidosis 139
20. Mignot A, Varnous S, Redonnet M, Jaccard A, Epailly 21. Sattianayagam PT, Gibbs SDJ, Pinney JH, Wechalekar
E, Vermes E, Boissonnat P, Gandjbakhch I, Herpin D, AD, Lachmann HJ, Whelan CJ, Gilbertson JA,
Touchard G, Bridoux F (2008) Heart transplantation Hawkins PN, Gillmore JD (2010) Solid organ trans-
in systemic (AL) amyloidosis: a retrospective study of plantation in AL amyloidosis. Am J Transplant
eight French patients. Arch Cardiovasc Dis [Internet] [Internet] 10:21242131. [cited 2014 Nov 19].
101:523532. [cited 2014 Nov 19]. Available from: Available from: http://www.ncbi.nlm.nih.gov/pub
http://www.ncbi.nlm.nih.gov/pubmed/19041836 med/20883547
ERRNVPHGLFRVRUJ
Left Ventricular Non-compaction
Cardiomyopathy 13
Alessandro Maolo and Simona Masiero
Medications
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142 A. Maolo and S. Masiero
ERRNVPHGLFRVRUJ
13 Left Ventricular Non-compaction Cardiomyopathy 143
Fig. 13.1 Routine ECG. Notice the normal sinus rhythm without abnormalities in conduction or repolarization
Myocardial disease
Coronary artery disease
Fig. 13.2 Chest x-ray performed for the worsening dys-
pnea. The bronchovascular marking is evident Hypertension
Cardiomyopathy
Routine Laboratory Tests Familial (hypertrophic, dilated,
Complete blood count: normal ARVD, restrictive, left ventricular
Cholesterol (total, HDL, LDL) and TG: normal non-compaction)
Hepatic function (GOT, GPT, -GT, ALP, total
ERRNVPHGLFRVRUJ
144 A. Maolo and S. Masiero
ERRNVPHGLFRVRUJ
13 Left Ventricular Non-compaction Cardiomyopathy 145
a b
Fig. 13.3 Echocardiogram: (a) apical four-chamber view. The marked trabeculae of the apex can be noticed. (b) Apical
two-chamber view. Apex trabeculae are visible also in this view
ERRNVPHGLFRVRUJ
146 A. Maolo and S. Masiero
a b
d
c
e f
Fig. 13.4 (af) Cardiac RMN, short-axis view of the left ventricle in different levels (T1-weighted black blood imag-
ing). In these images, trabeculas extension to the side wall is visible
ERRNVPHGLFRVRUJ
13 Left Ventricular Non-compaction Cardiomyopathy 147
The overall prevalence of LVNC in the general Clinical manifestation of LVNC is very heteroge-
population is not well known, but it seems to be neous. The major clinical manifestations of LVNC
ranged between 1 and 3 % [1, 2]. This percentage are three, and they can appear simultaneously or
is probably an underestimate. The described separately: heart failure, supraventricular or ven-
prevalence of LVNC is 34 % among patients tricular arrhythmias, and thromboembolic events.
with heart failure [3, 4]. In the pediatric population, heart failure is the pre-
dominant clinical manifestation, while in the
adult population, there is an overlap between the
Genetics three clinical manifestations as first clinical pre-
sentation without a clear predominance of one
Non-compaction cardiomyopathy is a heteroge- over the other [6].
neous disease from the genetic point of view
which includes either familiar or sporadic forms
[5]. Familiar forms are more frequent in the male Diagnosis
sex, while sporadic forms are equally distributed
in both sexes. The most common form of inheri- ECG
tance is autosomal dominant compared to either ECG is often abnormal in patients with LVNC,
X-linked or autosomal recessive forms [6]. but changes of the ECG are not enough spe-
So far, have been reported mutation in several cific to allow an accurate screening of the pop-
genes in patients with LVNC and the most frequent ulation. The most common changes that can be
mutations involve genes encoding: proteins of the seen include right or left bundle branch block,
cytoskeleton, sarcomere, and mitochondria [7]. fascicular block, atrial fibrillation, ventricular
tachycardia, increased left ventricular volt-
Tafazzin Mutations in the tafazzin gene (aka ages, and left axial deviation. Wolff
G4.5 or TAZ) lead to cardiolipin deficiency in the ParkinsonWhite syndrome has been described
mitochondrial membrane and are responsible for in up to 18 % of pediatric patients affected by
Barth syndrome [1, 810], an X-linked disorder LVNC [14].
which usually causes cardiomyopathy, neutrope-
nia, and skeletal myopathy. Echocardiography
Although there is no consensus on the diagnostic
Alpha-Dystrobrevin (DTNA) Alpha-dystrobrevin criteria, echocardiography still remains the main
is a cytoskeleton protein. A mutation in the gene diagnostic tool. The echocardiographic criteria
coding for alpha-dystrobrevin has been identified are illustrated in Table 13.1.
in patients with LVNC, occasionally related to The first diagnostic criteria were published by
congenital heart disease [8, 11]. Chin et al. in 1990. They defined for the first time
the ratio between X/Y 0.5 as fundamental for
Sarcomeric Protein Genes Mutations related to the diagnosis of LVNC where X is the distance
sarcomeric proteins seem to be linked to several dis- from the epicardial surface to the base of the tra-
tinct cardiomyopathies, including LVNC, with a becular recess and Y is the distance from the epi-
common molecular base. The pE96K in the tropo- cardial surface to peak of trabeculation. These
nin T gene is more frequent, and it was described criteria, based on the observation of eight
for the first time in a family with LVNC and with patients, can be applied only at the level of left
reduced ejection fraction [12]. The E101K mutation ventricular apex on the subxiphoid or apical four-
in the alpha-cardiac actin gene (ACTC) has been chamber views at end diastole [5].
described in families with LVNC, septal defects, Afterwards, Jenni et al. [15] in 2001 pro-
and apical hypertrophic cardiomyopathy [13]. posed the following criteria that can be applied
ERRNVPHGLFRVRUJ
148 A. Maolo and S. Masiero
only in patients without coexisting cardiac CMR features in seven patients with LVNC with
abnormalities: 170 healthy volunteers, athletes, or patients with
dilated or hypertrophic cardiomyopathy, hyper-
1. A maximum ratio of non-compacted to com- tensive heart disease, or aortic stenosis. They
pacted myocardium >2:1 at end systole in the found that the best distinguishing feature for
parasternal short-axis view LVNC was a maximum ratio in diastole of non-
2. Color Doppler evidence of flow within the compacted to compacted myocardial thickness of
deep intertrabecular recesses >2.3 as assessed in three long-axis views (sensi-
tivity 86 % and specificity 99 %). In another
Stllberger et al. [16] proposed different crite- study, Jacquier [18] evaluated the diagnosis of
ria to diagnose LVNC based on the hypertrabecu- LVNC based on the ventricular mass: a volume
lation of the myocardial tissue. of the non-compacted tissue >20 % of the total
myocardial tissue is a criterion to diagnose
1. More than three trabeculations protruding from LVNC. Another important aspect related to CMR
the left ventricular wall, apically to the papil- is the possibility to use gadolinium which per-
lary muscles, visible in a single image plane mits to identify delayed enhancement areas
2. Intertrabecular spaces perfused from the ven- which are expression of myocardial fibrosis. The
tricular cavity, visualized on color Doppler number and the distribution of these areas seem
imaging to be related to the severity of the disease.
Furthermore, it is not rare to find delayed
Cardiovascular Magnetic enhancement areas far from the trabeculae, which
Resonance (CMR) may suggest that LVNC is a widespread cardio-
The importance of CMR as a diagnostic tool for myopathy involving all the myocardial tissue.
LVNC is increasing in the last few years. CMR
offers a good spatial resolution of the left
ventricular apex and lateral wall, and it permits Prognosis
better visualization of trabeculations and recesses.
CMR criteria to diagnose LVNC are slightly LVNC is associated with high rates of morbidity
different from the above-described echocardio- and mortality in children and adults. Outcomes
graphic criteria. Petersen et al. [17] compared are more closely related to the severity of the
ERRNVPHGLFRVRUJ
13 Left Ventricular Non-compaction Cardiomyopathy 149
disease at clinical presentation than to the diagno- increased mortality, especially if they involve an
sis per se. Sudden cardiac death is relatively com- already disfunctional left ventricle [21, 22].
mon among patients with LVNC, and it causes half For this reason, only bicameral ICD should be
of all deaths that occur in the adult population. implanted in this setting because they allow a
reliable discrimination between atrial and ven-
tricular arrhythmias. Regarding CRT-D, due to
Therapy the lack of randomized studies in LVNC popula-
tion, the indications for their implantation are the
There is no specific therapy for LVNC, even same as the current guidelines [20].
because data on treatment of LVNC are limited
and there are not guidelines. Medical manage- Prevention of Thromboembolism
ment varies with the clinical manifestations: Patients with LVNC with or without atrial fibril-
heart failure, the presence or absence of arrhyth- lation are at high risk for thromboembolism in
mias, and perceived risk of thromboembolism. the presence of impaired left ventricular function
or symptomatic presentation [23]. Therefore,
Heart Failure anticoagulation with warfarin is recommended in
Patients with LVNC and heart failure symptoms patients with LVNC without atrial fibrillation
should be treated according to the current guide- with LVEF <40 %. Patients with LVNC and atrial
lines [19]. Patients with LVNC and heart failure fibrillation who meet standard criteria for antico-
should receive the standard medical therapy used agulation should be anticoagulated according to
in heart failure with LV dysfunction that is mainly standard guidelines.
based on ACE inhibitors, beta-blockers, miner-
alocorticoid receptor antagonist, and diuretics.
Clinical Course and Therapeutic
Arrhythmias Management of the Clinical Case
Since patients with LVNC are at risk for atrial
and ventricular arrhythmias, an annual Holter For the specific clinical case discussed above, the
monitoring to detect asymptomatic arrhyth- medical therapy for heart failure was adminis-
mias is advisable. Patients with LVNC should tered including ramipril 5 mg a day, bisoprolol
receive ICD therapy according to standard indi- 2.5 mg a day, furosemide 25 mg 2 mg twice daily,
cations for ICD therapy in patients with non- and eplerenon 25 mg once daily.
ischemic cardiomyopathy. Patients with history According to the findings described above in
of sustained ventricular tachycardia or sudden this patient, we thought that a ventricular tachy-
cardiac arrest (SCA) should receive an implant- cardia was the most probable cause of the syn-
able cardioverterdefibrillator (ICD) therapy for cope and therefore the patient was at sudden
secondary prevention of SCA. ICD implantation death danger. A bicameral endocavitary ICD was
for primary prevention is indicated in patients implanted. The classical ICD was preferred
with LVNC with an LVEF 35 % and NYHA because of the possibility in upgrading to CRT-D
class II to III HF [20]. The efficacy of receiv- in case of a worsening of the cardiomyopathy
ing an ICD for the prevention of SCA is not despite an optimal medical therapy.
well proved because in patients with LVNC,
the arrhythmic substrate is increased due to the
dysfunction of the microvasculature and is not
confined to the areas with trabeculations, but References
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the high prevalence of supraventricular arrhyth- Clinical characterization of left ventricular noncom-
mias in these patients implies a high percent- paction in children: a relatively common form of car-
age of inappropriate shocks, which can lead to diomyopathy. Circulation 108:2672
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2. Stanton C, Bruce C, Connolly H et al (2009) Isolated ciation with additional cardiac abnormalities and
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Cardiol 104:1135 17. Petersen SE, Selvanayagam JB, Wiesmann F, Robson
3. Kovacevic-Preradovic T, Jenni R, Oechslin EN et al MD, Francis JM, Anderson RH, Watkins H, Neubauer
(2009) Isolated left ventricular noncompaction as a S (2005) Left ventricular non-compaction: insights
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Echocardiography 25:898 mass using cardiac magnetic resonance imaging in the
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R (1990) Isolated noncompaction of left ventricular Heart J 31:10981104
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Pagotto LT, Carey JC, Pysher TJ, Ward K, Chin TK Lip GY, Maggioni AP, Parkhomenko A, Pieske BM,
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8. Ichida F, Tsubata S, Bowles KR et al (2001) Novel Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu
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Arrhythmogenic Right Ventricular
Cardiomyopathy 14
Michela Brambatti and Matilda Shkoza
Vital Signs
M. Brambatti (*) M. Shkoza
Clinica di Cardiologia e Aritmologia, Universit
Politecnica delle Marche, Temperature: 36.3 C
Via Conca, 71, Ancona 60126, Italy Heart rate: 60 bpm
e-mail: michelabrambatti@gmail.com; matilda_ Arterial blood pressure: 130/70 mmHg
shkoza@libero.it
ERRNVPHGLFRVRUJ
154 M. Brambatti and M. Shkoza
Respiratory rate: 17 breaths/min observed. The left ventricle was mildly enlarged
Oxygen saturation: 99 % with an ejection fraction of 50 % without regional
wall motion abnormalities.
In order to better evaluate the right ventricular
Physical Examination size, motility, and ejection fraction, the patient
underwent cardiac MRI that revealed right ven-
General appearance: well developed, well tricular dilatation with wall thickening and mod-
nourished, alert, and cooperative erate dyskinesia in the mid- and apical segments.
Lungs: clear to auscultation bilaterally Right ventricular ejection fraction was deeply
Heart: regular rate and rhythm without mur- reduced, nearly 35 %. Left ventricle was mildly
murs, gallops, or rubs dilated with normal ejection fraction (Fig. 14.2).
Extremities: no peripheral edema, cyanosis or Unfortunately, the patient refused gadolinium
pallor. Warm and well perfused injection.
Abdomen: Nontender, nondistended, normo-
active bowel sounds throughout, no hepato-
splenomegaly, and no bruits Clinical Course and Therapeutic
Management
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14 Arrhythmogenic Right Ventricular Cardiomyopathy 155
Fig. 14.1 ECG sinus rhythm (heart rate 56 bpm), first- inferior lead and leads V2V6, with prolonged QT
degree atrioventricular block, anterior fascicular block, interval (corrected QTQTc = 463 ms). The right bundle
incomplete right ventricular block, characteristic epsilon is very abnormal with fractionation throughout the right
waves in leads V1V4, and also inverted T-waves in bundle in keeping with a cardiomyopathic process
a b
Fig. 14.2 Two axial FIESTA images (a, diastolic, and b, systolic) clearly depict a dilation of the four cardiac cham-
bers, especially right ones. Wall of RV is prominently thinned
ERRNVPHGLFRVRUJ
156 M. Brambatti and M. Shkoza
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14 Arrhythmogenic Right Ventricular Cardiomyopathy 157
and initial or absent left ventricular abnormali- Classic: primarily affects the right ventricle
ties; and (4) biventricular failure, with severe and, only in advanced stages, the left ventricle
systolic dysfunction of both ventricles similar to (39 %).
a cardiomyopathy [2]. Dominant left: characterized by early and
severe involvement of the left ventricle and
Ventricular/Supraventricular relatively mild disease of the right ventricle. It
Tachyarrhythmias and Sudden is very insidious variant as fibroadipose
Cardiac Death replacement involves initially only the epicar-
VTs in patients with ARVC range from single dium of the left ventricle without causing wall
extra beats to complex VT, symptomatic and not, motion abnormalities. The use of MRI con-
and the frequency appears to be proportional to trast medium allows the identification of non-
the severity of the disease. The most common VT transmural scar.
is generally monomorphic with origin from the Biventricular: characterized by a parallel
right ventricle and left bundle branch block mor- involvement of both ventricles.
phology. The arrhythmic episodes may origin
from the apex, the inflow tract, or the outflow
tract; when the site of origin is the right outflow Diagnosis
tract, a differential diagnosis with idiopathic VT
is required [2]. The diagnosis of ARVC is complex and
Unfortunately, the SCD may be the first mani- requires a high degree of clinical suspicion. To
festation of the disease. The estimated mortality date, no single diagnostic test is enough sensi-
rate for SCD varies from 0.08 to 9 % per year [1]. tive and specific to confirm or rule out the dis-
Exercise, especially the endurance sport, is ease; thus multiple parameters need to be
considered a precipitating factor for arrhythmias considered.
in patients with ARVC. This trigger effect is The Task Force of the Working Group on
likely related to the increased right ventricular Myocardial and Pericardial Disease of the
stimulation by catecholamine exposure; in addi- European Society of Cardiology has developed
tion, data from literature suggest that the exer- the ARVC diagnostic criteria that take into
cise itself contributes to the right ventricle account structural, histologic, arrhythmic, and
dilatation and consequently to the disease pro- genetic features. The original version of 1994 [8]
gression [2]. that the revised version of 2010 [9] includes
Supraventricular tachyarrhythmia (SVT), major and minor criteria collected in six main
such as atrial fibrillation, atrial tachycardia, and categories (Table 14.1). Based on this classifica-
atrial flutter, in association with ventricular tion, definite diagnosis of ARVC requires two
arrhythmias, is present in up to 25 % of patients major criteria or one major and two minor or
with ARVC; less commonly, SVT may be the four minor criteria from different categories
only arrhythmia present [6]. (Table 14.1).
In the suspicion of ARVC, as a general
Left Ventricular Involvement approach, it is recommended to go through a
The wider use of cardiac MRI has allowed to careful personal and family medical history, a
appreciate a more common involvement of the 12-lead ECG, and a transthoracic echocardiogra-
left ventricle in ARVC [7]. phy in all patients. Additional tests should be per-
In a study of 200 patients undergoing MRI, formed according to the clinical scenario or when
three patterns of disease expression were the results of initial tests are not conclusive.
identified: Recommended tests are as follows:
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158 M. Brambatti and M. Shkoza
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14 Arrhythmogenic Right Ventricular Cardiomyopathy 159
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160 M. Brambatti and M. Shkoza
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14 Arrhythmogenic Right Ventricular Cardiomyopathy 161
endomyocardial biopsy is a class IIb recommen- diagnosis of ARVC. In contrast, -blockers are
dation in the diagnostic workup for ARVC [13]. not usually recommended in mutation carriers
who do not express the ARVC phenotype.
Antiarrhythmic medications, in association
Differential Diagnosis for ARVC with -blockers or alone, may be useful to reduce
ventricular arrhythmias frequency and symptoms
Dilated cardiomyopathy: biventricular dilated in patients with ARVC. Although there is no evi-
and congestive heart failure may be similar to dence to suggest a specific antiarrhythmic treat-
ARVC with left ventricle involvement. ment, class III drugs as amiodarone and sotalol
Uhl anomaly: total lack of right ventricular are the drugs of choice [1]. However, any antiar-
myocardium. In ARVC, the myocardium is rhythmic medication has demonstrated to reduce
not completely absent but replaced by a vari- the risk of SCD; as a result, antiarrhythmic drug
able degree of fibrosis. therapy should not be considered an equivalent
Idiopathic VT: Left bundle branch block mor- alternative to ICD implantation in ARVC patients.
phology VT in a structurally healthy heart and
absence of SCD familiarity. ICD Implantation and Arrhythmic Risk
Stratication
In patients with ARVC and documented sus-
Therapy and Prognosis tained ventricular fibrillation or VT (PV), ICD
implantation for secondary prevention is strongly
The therapeutic approach in ARVC patients is recommended. In these patients, appropriate ICD
addressed to SCD prevention and relief of symp- intervention occurs in about 10 % of cases per
toms of arrhythmias related, as well as improve- year, and the estimated survival benefit is about
ment in terms of functional capacity and survival 2530 % at 3 years follow-up [2].
in patients who develop heart failure. To achieve On the contrary, due to the relatively low prev-
these goals, available treatment options include alence of the disease and lack of randomized con-
lifestyle changes, pharmacological therapy with trolled trials, the indications for ICD implantation
-blockers, antiarrhythmic and heart failure for primary prevention are still object of intense
drugs, transcatheter ablation, ICD implantation, debate among experts.
and cardiac transplantation. Prognostic stratification and indications for
ICD implantation for primary prevention are cur-
Lifestyle Changes rently based on several arrhythmic risk factors,
Given the well-known association between mostly identified from retrospective studies or
endurance sports and five-time increased risk of autopsy data, such as unexplained syncope; pro-
SCD, patients with a definitive diagnosis of band status; young age; physical activity; family
ARVC and asymptomatic mutation carriers history for SCD, QRS, and QT dispersion; severe
should not participate in any competitive activity right ventricular dysfunction; left ventricular
[14]. No absolute contraindications in practicing involvement; and inducible VT [15]. However,
low-intensity physical activity are established, not all these risk factors should be taken into
especially for ARVC patients treated with account when an ARVC patient is evaluated for
-blockers. ICD implant.
An interesting pyramidal representation of the
-Blockers and Antiarrhythmic Therapy relationship between the arrhythmic risk and cur-
With the assumption that the adrenergic stimula- rent ICD implant indications for ARVC patients
tion during exercise triggers arrhythmias, treat- was proposed by Corrado and colleagues [4]. At
ment with -blockers currently represents a the apex of the pyramid, there are the high-risk
first-choice therapy in patients with a definitive patients who are most likely to benefit from an
ERRNVPHGLFRVRUJ
162 M. Brambatti and M. Shkoza
Table 14.2 Our approach to patients with ARVC according to the arrhythmic risk
Subgroups Risk markers Recommendations ICD indication
High risk (810 %/ Aborted SCD Avoid competitive sport Recommended
year) Hemodynamically unstable -blockers
sustained VT
Moderate risk Unexplained syncope Avoid competitive sport Consider
(12 %/year) Hemodynamically stable -blockers
sustained VT Annually FU including:
Non-sustained VT ECG
Cardiac imaging (ECHO vs.
CMR)
Holter
Exercise stress testing
Moderate risk (?%/ Severe dilatation and/or Avoid competitive sport Consider
year) dysfunction of RV, LV, or -blockers
both Annually FU including:
Early onset structurally ECG
severe disease (age < 35 Cardiac imaging (ECHO vs.
years) CMR)
Holter
Exercise stress testing
Low risk (<1 %/ Asymptomatic mutation Reduce physical exercise Not recommended
year) carriers Avoid competitive sport
ARVD patients without risk Annually FU including:
factors ECG
Cardiac imaging (ECHO vs.
CMR)
Holter
Exercise stress testing
ARVD arrhythmogenic right ventricular dysplasia, FU follow-up, CMR cardiac magnetic resonance, LV left ventricle,
RV right ventricle, SCD sudden cardiac death, VT ventricular tachycardia, ICD internal cardiac defibrillator
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14 Arrhythmogenic Right Ventricular Cardiomyopathy 163
ERRNVPHGLFRVRUJ
Part V
Valvular Heart Disease
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Aortic Stenosis
15
LorenaScappini, SimoneMaffei,
andAlessioMenditto
Allergies
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168 L. Scappini et al.
aspirin 100 mg at 12:00 a.m., allopurinol 150 mg The routine laboratory tests were performed:
at 3:00 p.m., amlodipine 5 mg at 8:00 p.m., and
ezetimibe/simvastatin 10/20 mg at 10:00 p.m Complete blood count: normal (hemoglobin
13 g/dl)
Inflammatory markers (ESR, CRP): normal
Vital Signs Hepatic function (GOT, GPT, -GT, ALP, total
bilirubin, direct and indirect): normal
Temperature: 36 C Impaired renal function (creatinine 6.61 mg/
Heart rate: 53 bpm dl, BUN 146 mg/dl)
Blood pressure: 140/80 mmHg Electrolytes (Na+, K+, Ca++, Mg++, Cl):
Respiratory rate: 16/min normal
Oxygen saturation while breathing in ambient Fasting blood glucose: 55 mg/dl
air: 97 % Myocardial necrosis markers (CK-MB and
Hs-TnI): negative in two different samples
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15 Aortic Stenosis 169
Fig. 15.2 Echocardiography. Concentric left ventricular hypertrophy (left side). Severe aortic valve stenosis with high
trans-aortic valve gradient (right side)
ERRNVPHGLFRVRUJ
170 L. Scappini et al.
a b
Fig. 15.3 Coronary angiography: right coronary (a); left coronary (b)
Symptomatic severe aortic stenosis has sur- Calcific aortic valve disease is the most com-
gery correction indication; although the last mon cause of AS among adults in the Western
PTCA was done in the previous 4 months, an world [2]. Prevalence increases with age [1, 3],
invasive coronary angiography was performed and severe AS, if left untreated, is fatal a few
because the angina symptoms show a LAD 70 % years from symptom onset [4].
diameter stenosis (intrastent), severe stenosis of
the first diagonal branch (D1) and second diago-
nal branch (D2), and a severe stenosis of the pos- Etiology
terior descending artery (PDA) (Fig. 15.3a, b).
The patient was admitted to the cardio-surgery AS is a hereditary or acquired disease that causes
department to replace the aortic valve and for the a progressive obstruction to left ventricular
heart to be revascularized through coronary outflow. Obstruction may be valvular, subvalvu-
artery bypass graft (CABG). A bioprosthetic aor- lar, or supravalvular.
tic valve was implanted, and an artery graft with Valvular stenosis is the most common cause of
the left internal mammary artery to LAD and a aortic obstruction. Its etiology may be age
saphenous vein graft to PDA were performed. related: patients younger than 20 usually have a
congenital abnormality.
Patients aged 4060 usually have a calcified
15.2 Aortic Stenosis bicuspid valve or a valve previously damaged by
rheumatic heart disease.
Epidemiology The most common cause of AS in patients 7080
years old is degenerative AS; this is an active pro-
Valvular aortic stenosis (AS) is the second most cess characterized by lipid accumulation, inflam-
prevalent adult valve disease in the USA. The mation, and calcification of aortic valve cusps that
prevalence of AS increases with age: it occurs in provokes a valve degeneration [57].
4 % of patients older than 75 years [1] and Subvalvular AS occurs in less than 10 % of all
approximately in 2 % of population aged 65 patients with obstruction of left ventricular outflow
years old. and is frequently associated with aortic regurgitation
ERRNVPHGLFRVRUJ
15 Aortic Stenosis 171
due to valve damage. This kind of obstruction can point, both the high afterload and the intrinsic
be due to a subvalvular ridge or diffuse tunnellike myocardial disease significantly increase wall
narrowing of the entire outflow tract. If severe stress, and a vicious cycle of deterioration in ven-
hypertrophy of the left ventricle is present, addi- tricular function ensues.
tional dynamic outflow obstruction from systolic A death spiral may occur: if systemic hypo-
anterior motion of the mitral valve may occur. tension will occur (due to either drugs or a vaso-
Supravalvular AS is an uncommon (less than vagal reaction), perfusion of the coronary arteries
1 % of patients with aortic stenosis) congenital may decrease; this increases the myocardial oxy-
abnormality, consisting of narrowing of the gen supplydemand mismatch and results in
ascending aorta (immediately over the aortic myocardial ischemia. The myocardial ischemia,
valve) secondary to a single stenosis or a long in turn, reduces forward cardiac output, and aor-
tubular lesion of the entire ascending aorta. This tic diastolic pressure decreases, further decreas-
type of stenosis is often associated with some ing coronary perfusion pressure. Unless
congenital abnormalities like coronary dysplasia, immediate steps are taken to increase perfusion
elfin facies, mental retardation, coarctation of the pressure, progressive hemodynamic deterioration
aorta, hypercalcemia, peripheral pulmonary ste- and death may occur.
nosis, and Williams syndrome.
Clinical Manifestation
Physiopathology
The clinical presentation of AS varies. Many
AS represents a continuum disease: (1) an increase patients will remain asymptomatic for decades.
in afterload, (2) a decrease in systemic and coro- The diagnosis of AS is usually made in these
nary blood flow from obstruction, and (3) progres- patients on the basis of a systolic murmur on aus-
sive hypertrophy. These mechanisms result in the cultation and confirmed by echocardiography.
classic symptom triad of dyspnea, angina, and syn- Symptoms usually consist of one or more of
cope. Left ventricular cavity size and systolic func- the classic triad of exertional dyspnea, angina,
tion are initially maintained; in fact, the increase in and syncope. The cause of syncope may include
left ventricular wall thickness acts as a compensa- ventricular arrhythmias, a sudden decrease in
tory mechanism to normalize wall stress. So at the systemic flow caused by the obstruction, or
beginning, hypertrophy is a beneficial adaptation. abnormal vasodepressor reflexes caused by the
However, this phenomenon may cause a high left ventricular intracavitary pressure. Albeit
reduced coronary flow reserve and oxygen sup- rare, sudden death may be the initial manifesta-
plydemand mismatch [8]. Hypertrophic hearts tion of aortic stenosis.
are more sensitive to diffuse subendocardial isch- Uncommonly, patients with end-stage AS and
emic injury, which may result in both systolic concomitant left ventricular dysfunction present
and diastolic dysfunctions. The latter occurs from with anasarca and cardiac cachexia.
prolonged ventricular relaxation and decreased The development of symptoms is a critical
compliance and is caused by myocardial isch- point in the natural history of patients with AS. In
emia, a thick noncompliant left ventricle, and fact, after symptom onset, the average survival is
increased afterload [9, 10]. 23 years.
The so-called reversible phase is characterized by
an obstruction progression to a higher level that pro-
vokes a decrease of left ventricle systolic function. Physical Examination
If afterload excess was continued, myocyte
degeneration and fibrosis would occur (irrevers- The physical examination of a patient with AS
ible left ventricular systolic dysfunction). At this reveals classic, characteristic findings that are
ERRNVPHGLFRVRUJ
172 L. Scappini et al.
important for diagnosis and estimation of sever- T wave inversion, or a left bundle block can be
ity of this valvular disease. present.
The characteristics of the carotid upstroke are
a reliable indicator of the severity of AS in most
patients. There will be both parvus (small pulse) Chest Radiography
and tardus (slow upstroke) in patients with severe
AS. These typical findings couldnt be present on Chest radiography may demonstrate enlargement
carotid palpation in older patients with a of the ascending aorta and a left ventricular pre-
noncompliant vasculature. When there is a thrill dominance. Aortic calcification is frequently seen
felt in the right carotid artery but not in the left on lateral chest radiographs (i.e., porcelain aorta).
carotid artery, the diagnosis of supravalvular AS This find implies high risk for operation [11].
should be suspected. This phenomenon is due to
the high-velocity jet of blood directed toward the
innominate artery. How toAssess Aortic Stenosis
A sustained bifid left ventricular impulse indi-
cates concomitant left ventricular hypertrophy. A Echocardiography
systolic thrill, if present, indicates the presence of In addition to physical examination, electrocardi-
severe AS (mean gradient >50 mmHg). ography, and chest radiography, various imaging
Accurate auscultation is an essential compo- modalities may be used to confirm the presence
nent of evaluating patients with AS. An absent of aortic stenosis.
aortic component of the second heart sound indi- Transthoracic echocardiography is the gold
cates severe calcification of the aortic valve. A standard modality for initial diagnosis and subse-
delayed murmur apex is also present in severe AS. quent evaluation of aortic stenosis; with this
A fourth heart sound is frequently audible. The ultrasound technology, the physician can also
turbulence across the aortic valve always produces determine the level of obstruction (supravalvular,
a systolic ejection murmur. It is not necessarily the valvular, or subvalvular), the number of aortic
intensity but the timing of the murmur that deter- cusps, and the degree of cusp fusion.
mines the severity of AS. In patients with mild AS, The severity of aortic stenosis cannot be
the murmur is characterized by an early peak, and determined by visualization of valve motion
the duration ends before the second heart sound. alone, and Doppler echocardiography must be
As AS becomes more severe, the peak intensity of used to further assess the severity of aortic valve
the murmur occurs in mid-to-late systole, and the disease [12].
murmur extends into the second heart sound. The The main hemodynamic parameters recom-
murmur of AS must be differentiated from that of mended for clinical evaluation of AS severity
hypertrophic obstructive cardiomyopathy or mitral with transthoracic echocardiography are [13]:
regurgitation due to a flail posterior leaflet. A
Valsalva maneuver may be of help in this case. 1. AS jet velocity
So we can say that severe AS is characterized 2. Mean transaortic gradient
by (1) a dampened upstroke of the carotid artery, 3. Valve area by continuity equation
(2) a sustained bifid left ventricular impulse, (3)
an absent A2, and (4) a late-peaking systolic ejec- The antegrade systolic velocity across the nar-
tion murmur. rowed aortic valve, or aortic jet velocity, is mea-
sured using continuous-wave (CW) Doppler
(CWD) ultrasound [1416].
Electrocardiography AS jet velocity is defined as the highest veloc-
ity signal obtained from any window after a care-
The electrocardiography usually shows sinus ful examination. Color Doppler is also helpful to
rhythm with left ventricular hypertrophy and left avoid recording the CWD signal of an eccentric
atrial enlargement. An ST interval depression, a mitral regurgitation (MR) jet.
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15 Aortic Stenosis 173
A smooth velocity curve with a dense outer The aortic valve area can be calculated by
edge and clear maximum velocity should be Doppler echocardiography using the continuity
recorded. The maximum velocity is measured at equation.
the outer edge of the dark signal. To get the veloc- From the parasternal long-axis view, the
itytime integral (VTI) for the continuity equa- operator must get the left ventricular outflow
tion and the mean gradient, it is necessary to tract (LVOT) diameter and convert it to the
draw the outer edge of the dark envelope of the LVOT area. The LVOT velocity is obtained and
velocity curve (Fig. 15.4) [13]. traced to derive the timevelocity integral (TVI)
To distinguish the level and severity of from an apical approach with pulsed-wave
obstruction, the shape of the CW Doppler veloc- Doppler.
ity is helpful; the maximum velocity occurs later Continuity equation
in systole, and the curve is more rounded in shape
with more severe obstruction [13].
( LVOTTVI ) ( LVOTarea )
Aortic valve area =
To determine the fixity or the dynamism of ( AVTVI )
obstruction, the shape of the CWD velocity curve
also can be helpful. A characteristic late-peaking Significant errors in the area calculation may be
velocity curve is shown by a dynamic obstruc- caused by small errors in diameter measurement;
tion, with a concave upward curve in early sys- for this reason the calculation of aortic valve area
tole (Fig. 15.5), in a patient with severe anemia. with continuity equation does require a skilled
Transaortic pressure gradient (P) is calcu- echocardiographist to ensure accurate measure-
lated from velocity (v) using the Bernoulli equa- ment of the LVOT diameter.
tion as When LVOT diameter is squared for calcula-
tion of cross-sectional area, it becomes the great-
DP = 4v 2
est potential source of error in the continuity
The maximum gradient is calculated from maxi- equation [13].
mum velocity To reduce the errors associated with the
measurements of the LVOT, this ratio can be
DPmax = 4v 2 max
used:
and the mean gradient is calculated by averaging
VLVOT
the instantaneous gradients over the ejection Velocity ratio =
period [13]. VAV
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174 L. Scappini et al.
This dimensionless velocity ratio expresses the Table 15.1 Recommendations for classification of AS
size of the valvular effective area as a proportion severity
of the cross-sectional area of the LVOT [13]. In Aortic
the absence of valve stenosis, the velocity ratio sclerosis Mild Moderate Severe
approaches 1. If the velocity ratio is 0.25 or less, Aortic jet 2.5 2.62.9 3.04.0 >4.0
severe stenosis is present [17]. velocity
(m/s)
Aortic valve area planimetry may be an
Mean <20 2040b >40b
acceptable alternative when Doppler estimation gradient (<30a) (3050a) (>50a)
of flow velocities is unreliable. When valve calci- (mmHg)
fication causes shadows or reverberations limiting AVA (cm2) >1.5 1.51.0 <1.0
identification of the orifice, planimetry may be Index AVA >0.85 0.850.6 <0.6
inaccurate. (cm2/m2)
Severe aortic stenosis can be diagnosed if a Velocity >0.50 0.50 <0.25
ratio 0.25
patient has these features:
ESC guidelines
a
AHA/ACC guidelines
b
Clinical findings consistent with severe aortic
stenosis
A mean gradient greater than 40 mmHg
AVA less than 1.0 cm2 (<0.6 cm2/m2 when Aortic valve effective orifice area (EOA)
indexed for body surface area) <1.0 cm2 or <0.6 cm2/m2 when indexed for
body surface area
Recommendations for classification of AS Low mean transvalvular gradient (i.e.,
severity are listed in Table 15.1. <40 mmHg)
Low LVEF (<40 %), causing an LF state [18]
ow-Flow, Low-Gradient Aortic
L
Stenosis withLow Left Ventricular The diagnostic problem in this kind of pathol-
Ejection Fraction (LVEF) ogy is to distinguish true severe from pseudose-
Low LVEF, LF-LG severe AS is characterized by vere aortic stenosis. In true severe AS, the LV
the combination of these features: dysfunction is a secondary or concomitant
ERRNVPHGLFRVRUJ
15 Aortic Stenosis 175
phenomenon, while the primary culprit is deemed resulting in low cardiac output (i.e., stroke vol-
to be the valve disease. Instead, the main factor in ume index <35 ml/m2) and lower than expected
pseudosevere AS is deemed to be myocardial dis- transvalvular gradients (i.e., <40 mmHg); this
ease, and AS severity is overestimated due to clinical entity was defined as paradoxical
incomplete opening of the valve in relation to the LF-LG AS [26, 27].
LF state. Distinction between these two entities is The prevalence of this entity increases with
essential: patients with true severe AS generally older age, female gender, and concomitant pres-
will benefit from aortic valve replacement (AVR), ence of systemic arterial hypertension.
whereas those with pseudosevere AS may not Paradoxical LF-LG AS is characterized by a
benefit [18]. restrictive physiology, whereby left ventricular
Dobutamine infusion is helpful in differentiat- pump function and thus stroke volume are mark-
ing pseudosevere from true severe AS. edly reduced despite a preserved LVEF. Other
True severe AS is characterized by little or distinctive features are:
absent increase in effective orifice area and an
increase in gradient that is congruent with the Marked reduction in intrinsic LV systolic
relative increase in flow; pseudosevere AS shows function, not evidenced by the LVEF.
an increase in effective orifice area (EOA) and Longitudinal shortening is reduced to a larger
relatively little increase in gradient in response to extent in these patients due to more advanced
increasing flow [18]. fibrosis in the subendocardial layer.
Some parameters and criteria have been pro- More pronounced LV concentric remodeling
posed to identify patients with pseudosevere AS and myocardial fibrosis both contributing to
during dobutamine stress echocardiography: reduce the size, compliance, and filling of the
LV [26, 2830].
Peak stress mean gradient <30 or <40 mmHg
(depending on studies) Several studies reported that these patients
Peak stress EOA >1.0 or 1.2 cm2 have a worse prognosis than those with moderate
An absolute increase in EOA >0.3 cm2 AS or normal flow severe AS [26].
Characteristics of low-flow low-gradient AS,
The optimal cutoff values remain to be deter- paradoxical low-flow low-gradient, and pseudos-
mined. The prevalence of pseudosevere AS is evere AS are shown in Table 15.2.
reported to be between 20 and 30 % [1924].
A high plasma B-type natriuretic peptide
(BNP) level (>550 pg/ml) appears to be a pow- Natural History
erful predictor of mortality in patients with
LF-LG AS regardless of treatment (medical vs. Calcific AS is a chronic disease. Patients may be
surgical) or the presence and/or absence of flow asymptomatic for a long period of time [19, 22,
reserve [25, 38]. 36, 37], and the duration of the asymptomatic
phase varies a lot between individuals. Sudden
Low-Flow, Low-Gradient cardiac death seems to be rare in the truly asymp-
ASwithNormal LVEF (Paradoxical tomatic (<1 % per year), even in very severe AS,
Low-Flow Low-Gradient Aortic while it is a frequent cause of death in symptom-
Stenosis) atic patients. In asymptomatic patients with
Some authors [26] reported that a substantial severe AS, reported average event-free survival at
proportion of patients with severe aortic steno- 2 years ranged from 20 % to more than 50 % [19,
sis (EOA <1.0 cm2 and/or indexed EOA 22, 32, 36, 37].
<0.6 cm2/m2) and a preserved LVEF (i.e., There are clinical and echocardiographic pre-
>50 %) might develop a restrictive physiology, dictors of symptom development and adverse
ERRNVPHGLFRVRUJ
176 L. Scappini et al.
Table 15.2 Characteristics of low-flow low-gradient AS, paradoxical low-flow low-gradient, and pseudosevere AS
Mean gradient
EOA (cm2) Index EOA (cm2/m2) (mmHg) LVEF
Low-flow low-gradient aortic <1.0 cm2 <0.6 cm2/m2 <40 mmHg <40 %
stenosis
Paradoxical low-flow <1.0 cm2 <0.6 cm2/m2 <40 mmHg >50 % with
low-gradient aortic stenosis stroke volume
index < 35 ml/m2
Pseudosevere aortic stenosis Peak stress Absolute increase in Peak stress mean
(during dobutamine stress EOA > 1.0 or EOA > 0.3 cm2 gradient <30 or
echocardiography) 1.2 cm2 40 mmHg
outcomes in asymptomatic patients: older age, [31, 35, 40]. Treadmill testing may be appropri-
presence of atherosclerotic risk factors, peak aor- ate for stratifying patients with asymptomatic
tic jet velocity [19, 22, 36, 37], LVEF [22], rate of severe aortic stenosis, but it is contraindicated in
hemodynamic progression, increase in gradient a symptomatic patient.
with exercise, excessive LV hypertrophy, and
abnormal tissue Doppler parameters of systolic
and diastolic LV function [33, 34]. Indications forIntervention
When the symptoms appear, the prognosis of
severe AS is poor, with survival rates of only ortic Valve Replacement
A
1550 % at 5 years. Early valve replacement should be recommended
in all patients with severe aortic stenosis and
ymptomatic andAsymptomatic
S symptoms. As long as the mean gradient remains
Patients >40 mmHg, there is virtually no lower EF limit
Patients with severe aortic stenosis and symp- for surgery [22]. Paradoxical low-flow, low-
toms should be considered for aortic valve gradient aortic stenosis requires special attention.
replacement (AVR). Concomitant coronary In such cases, surgery should be performed only
artery bypass grafting should be performed for when symptoms are present and if comprehen-
coronary atherosclerosis when epicardial lesions sive evaluation suggests significant valve obstruc-
are >50 % [40], and age should not be consid- tion. The management of patients with
ered a contraindication to surgery [39]. The asymptomatic aortic valve stenosis still remains a
treatment of the asymptomatic patient with topic of discussion. Recent studies do not provide
severe aortic stenosis is more controversial. convincing data to support the general recom-
Surgery is reasonable to consider in asymptom- mendation of early AVR, even in patients with
atic patients when there is critical aortic asymptomatic, very severe AS [22].
stenosis:
Balloon Valvuloplasty
Gradient >60 mmHg In patients who will be undergoing surgery or
Valve area <0.6 cm2 TAVI, balloon valvuloplasty may be considered
Expected operative mortality <1.0 % as a bridge to these types of intervention. It may
also be considered in patients with symptomatic
If there is evidence of a high probability of severe AS who require urgent major noncardiac
rapid progression (Doppler peak velocity surgery, in hemodynamically unstable patients
increases by >0.3 m/s per year or when the valve who are at high risk for surgery, and as a pallia-
area decreases by >0.1 cm2 per year), aortic tive measure in selected individual cases when
valve replacement may also be considered for surgery is contraindicated and TAVI is not an
adults with severe asymptomatic aortic stenosis option [22].
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15 Aortic Stenosis 177
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178 L. Scappini et al.
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15 Aortic Stenosis 179
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180 L. Scappini et al.
the individual risk profile and anatomic 8. Julius BK, Spillmann M, Vassalli G et al (1997)
Angina pectoris in patients with aortic stenosis and
suitability.
normal coronary arteries. Mechanisms and patho-
physiological concepts. Circulation 95:892
9. Gaasch WH, Levine HJ, Quinones MA et al (1976)
ontraindications forTranscatheter
C Left ventricular compliance: mechanisms and clinical
implications. Am J Cardiol 38:645653
Aortic Valve Implantation [22] 10. Hess OM, Ritter M, Schneider J et al (1984) Diastolic
stiffness and myocardial structure in aortic valve dis-
Absolute contraindications: Estimated life expec- ease before and after valve replacement. Circulation
tancy <1 year, improvement of quality of life 69:855865
11. Schreiber C, Lange R (2006) Porcelain aorta: thera-
by TAVI unlikely because of comorbidities,
peutical options for aortic valve replacement and con-
inadequate annulus size (<18 mm, >29 mm), comitant coronary artery bypass grafting. Ann Thorac
thrombus in the left ventricle, active endocar- Surg 82:381
ditis, plaques with mobile thrombi in the 12. Wang A, Bashore TM (2009) Valvular heart disease.
Humana Press, Dordrecht/New York
ascending aorta or aortic arch, and inadequate
13. Baumgartner H, Hung J, Bermejo J et al (2008)
vascular access (vessel size, calcification, Echocardiographic assessment of valve stenosis:
tortuosity). EAE/ASE recommendations for clinical practice.
Relative contraindications: Bicuspid or noncalci- Eur J Echocardiogr 10:125
14. Currie PJ, Seward JB, Reeder GS et al (1985)
fied valves, untreated coronary artery disease
Continuous-wave Doppler echocardiographic assess-
requiring revascularization, and LVEF <20 % ment of severity of calcific aortic stenosis: a simulta-
hemodynamic instability. neous Doppler catheter correlative study in 100 adult
patients. Circulation 71:11621169
15. Smith MD, Kwan OL, DeMaria AN (1986) Value and
limitations of continuous wave Doppler echocardiog-
raphy in estimating severity of valvular stenosis.
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16. Burwash IG, Forbes AD, Sadahiro M et al (1993)
1. Nkomo VT, Gardin JM, Skelton TN et al (2006) Echocardiographic volume flow and stenosis severity
Burden of valvular heart diseases: a population-based measures with changing flow rate in aortic stenosis.
study. Lancet 368:10051011 Am J Physiol 265(5 Pt 2):H1734H1743
2. Kurtz CE, Otto CM (2010) Aortic stenosis: clinical 17. Oh JK, Taliercio CP, Holmes DR Jr et al (1988)
aspects of diagnosis and management, with 10 illus- Prediction of the severity of aortic stenosis by Doppler
trative case reports from a 25-year experience. aortic valve area determination: prospective Doppler-
Medicine (Baltimore) 89:349379 catheterization correlation in 100 patients. J Am Coll
3. Lindroos M, Kupari M, Heikkila J et al (1993) Cardiol 11:12271234
Prevalence of aortic valve abnormalities in the elderly: 18. Pibarot P, Dumesnil JG (2012) Low-flow, low-
an echocardiographic study of a random population gradient aortic stenosis with normal and depressed
sample. J Am Coll Cardiol 21:12201225 left ventricular ejection fraction. J Am Coll Cardiol
4. Schueler R, Hammerstingl C, Sinning JM et al (2010) 60(19):18451853. Qubec City, Qubec, Canada
Prognosis of octogenarians with severe aortic valve 19. Vahanian A, Alfieri O, Andreotti F et al (2012)
stenosis at high risk for cardiovascular surgery. Heart Guidelines on the management of valvular heart dis-
96:18311836 ease (version 2012): the Joint Task Force on the
5. OBrien KD, Reichenbach DD, Marcovina SM et al Management of Valvular Heart Disease of the
(1996) Apolipoproteins B, (a), and E accumulate in European Society of Cardiology (ESC) and the
the morphologically early lesion of degenerative European Association for Cardio-Thoracic Surgery
valvular aortic stenosis. Arterioscler Thromb Vasc (EACTS). Eur Heart J 33:24512496
Biol 16:523532 20. De Filippi CR, Willett DL, Brickner E et al (1995)
6. Rajamannan NM, Subramaniam M, Rickard D et al Usefulness of dobutamine echocardiography in dis-
(2003) Human aortic valve calcification is associated tinguishing severe from nonsevere valvular aortic ste-
with an osteoblast phenotype. Circulation nosis in patients with depressed left ventricular
107:21812184 function and low transvalvular gradients. Am J
7. Olsson M, Dalsgaard CJ, Haegerstrand A et al (1994) Cardiol 75:191194
Accumulation of T lymphocytes and expression of 21. Schwammenthal E, Vered Z, Moshkowitz Y et al
interleukin-2 receptors in nonrheumatic stenotic aor- (2001) Dobutamine echocardiography in patients
tic valves. J Am Coll Cardiol 23:11621170 with aortic stenosis and left ventricular dysfunction:
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Mitral Regurgitation
16
MarcoFlori, LorenaScappini, andLucaPiangerelli
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184 M. Flori et al.
Physical Examination The patient didnt refer fever and cough was
mild and without expectoration. Furthermore the
General: no acute distress, alert, awake, and symptoms arose 3 months before, so the hypothe-
oriented. Well developed and well nourished sis of a pneumonitis or bronchitis seemed unlikely.
Head, eyes, ears, nose, and throat: normal Myocardial ischemia was possible even with-
Neck: supple, mild jugular venous distention, out chest pain; dyspnea could have been an angi-
no lymphadenopathy, and no carotid bruit nal equivalent.
Cardiovascular: regular rate and rhythm, S1 According to the physical exam (rales at the
and S2 normal, third tone audible, blowing bases bilaterally, peripheral edema, mild jugular
crescendo-decrescendo holosystolic murmur distension, third tone, and cardiac murmur), the
grade IV in Levine scale, and best audible at most probable cause seemed to be heart failure.
the fifth left midclavicular intercostal space
and irradiated to the armpit
Lungs: harsh breath sounds with rales on hat Kind ofDisease Is Suggested
W
auscultation at the bases bilaterally, no rhon- fromCardiac Physical Examination?
chi or wheezes, no alterations in tactile fremi-
tus, and normal upercussion Aortic stenosis
Abdomen: mild overweight, no pulsatile Aortic regurgitation
masses, normal bowel sounds in all four quad- Mitral stenosis
rants, no abdominal rebound or guarding, no Mitral regurgitation
costovertebral angle tenderness, and no
hepatosplenomegaly There was a left apical at the fifth left intercos-
Extremities: no cyanosis or clubbing. Mild tal space toward the anterior axillary line. Systolic
peripheral pitting edema at ankle murmur was located in the mitral region and radi-
Neurologic: cranial nerves II through XII ated to the armpit. Its quality (holosystolic, blow-
intact and no focal deficit ing) suggested a mitral regurgitation over aortic
Psychiatric: normal stenosis.
Skin: intact, no rashes, no lesions, and no
erythema
What Should theFamily Doctor Do?
ERRNVPHGLFRVRUJ
16 Mitral Regurgitation 185
After 5 days, the patient was seen by a cardi- quence of either hypertension or mitral insuffi-
ologist which confirmed the diagnosis of MR; a ciency. These alterations led to the development
routine EKG at rest (resulting normal) and echo- of heart failure. The presence of cardiac remodel-
cardiography were performed. ing suggested a chronic valve disease, and even if
the symptoms arose 3 months before, severe
insufficiency was probably present since several
Echocardiography (Fig.16.1) months or years. Myxoid degeneration of valve
apparatus (Barlow disease) was the probable
Normal and trileaflet aortic valve. Normal aorta. mechanism of valve disease. No alterations sug-
Moderate dilatation of the left atrium (LA diam- gesting endocarditis were found. Ventricle was
eter M-mode = 4.5 cm; area 4c = 26 cm2). dilated, but the extent of dilatation wasnt suffi-
Eccentric hypertrophy of the left ventricle (with cient to consider valve insufficiency as
end diastolic diameter 60 mm). Normal systolic secondary.
function (ejection fraction 60 % measured with
Simpsons biplane) without focal hypokinesia or
akinesia. Thickened mitral leaflet with severe Final Diagnosis
prolapse of the posterior leaflet and mild prolapse
of the anterior leaflet. Severe eccentric mitral Congestive heart failure due to a severe mitral
regurgitation (vena contracta 7.5 mm, PISA valve prolapse and regurgitation
1.1 cm, effective regurgitant orifice area (EROA)
0.5 mm2). Normal right atrium (area 4c = 17 cm2).
Restrictive mitral inflow pattern (grade III dia- What Should theCardiologist Do?
stolic dysfunction). Normal tricuspid valve. Mild
tricuspid regurgitation which was centrally Refer the patient for cardiac surgery.
directed with an estimated PASP = 50 mmHg. Treat the patient for heart failure.
Normal pulmonic valve. Normal interatrial sep- Treat the patient with drugs and reevaluate
tum. Normal pericardium. Normal aorta. Slightly after 3 months.
dilated inferior vena cava. Less than 50 % inspi-
ratory collapse of the IVC. Cardiac surgery in primary mitral regurgitation
Mitral regurgitation had major hemodynamic is curative and the occurrence of symptoms is a
consequences in this patient and led to atrial major indication for surgery. The presence of
enlargement due to chronic volume overload. increased PASP is a further indication for surgery.
Ventricular hypertrophy was probably the conse- Medical therapy may alleviate symptoms, but
Fig. 16.1 Echocardiography, four-chamber view. From swirling toward interatrial septum and reaching the
left to right: two-dimensional imaging shows thickened pulmonary veins (Coand effect, arrow point). Nyquist
mitral leaflet with posterior leaflet prolapse (arrow). Color limit is shifted downward to detect proximal isovelocity
Doppler shows severe eccentric mitral regurgitation surface area (PISA) >1 cm (star)
ERRNVPHGLFRVRUJ
186 M. Flori et al.
reduction of valve regurgitation is unlikely (which and the left ventricular wall [2]. When one of
is possible in secondary MR). Hence evaluation these portions of the apparatus becomes abnor-
for cardiac surgery, including coronary angiogra- mal, MR may develop. Also left ventricle dilata-
phy for the detection of asymptomatic coronary tion or papillary muscle displacement can
artery disease, is the right choice. Concurrent provoke the dysfunction of the mitral valve
medical therapy for heart failure, including diuret- apparatus.
ics, beta-blockers, and ACE inhibitors or ARBs, As seen above, the etiology of MR can be
is important until cardiac surgery is undertaken. stratified into nonischemic and ischemic.
Nonischemic etiologies include:
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16 Mitral Regurgitation 187
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188 M. Flori et al.
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16 Mitral Regurgitation 189
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190 M. Flori et al.
Acute MR carries a poor prognosis and in most replacement and ring annuloplasty with excellent
cases requires surgery after hemodynamic stabi- outcomes in experienced centers [23]. The major
lization. Chronic severe MR, even if asymptom- benefits in valvular repair are the preservation of
atic, reduces the patients prognosis to 5 years subvalvular apparatus and the absence of
[18]. The management of MR largely depends on prosthetic valves. Preoperative echocardiography
pathophysiology, severity, and the presence of is needed to correctly evaluate the anatomy of the
indications to surgery. Two mitral surgery tech- regurgitant valve and to choose the appropriate
niques are available: valve repair and valve surgical approach. TOE is also recommended
replacement. Recently a percutaneous edge-to- intraoperatively to enhance surgery outcomes.
edge procedure has been proposed with good The durability of mitral repair is a potential
clinical results [22] and may be performed in limitation. In experienced centers with appropri-
inoperable patients who meet the echocardio- ate patients screening, the rate of freedom from
graphic criteria. reoperation is similar to valve replacement.
Extensive calcifications, prolapse of more than
rimary Mitral Regurgitation
P one-third of the leaflet, or complete muscle rup-
Acute MR due to papillary or chordal rupture is ture usually suggests replacement over repair.
an emergency and often requires surgical treat-
ment after medical stabilization with an intra- Mitral Valve Replacement
aortic balloon pump and inotropes or vasodilators. Mitral valve replacement requires the use of a
According to the most recent guidelines on val- prosthetic valve. The choice between mechanical
vular disease, mitral valve repair should be pre- or bioprosthetic valves and issues about prosthetic
ferred when feasible [18]. In chronic MR, surgical valves will be best developed in Chap. 17.
treatment is indicated in symptomatic patients According to ESC guidelines [18], a bioprosthetic
with no contraindications for surgery. Indications valve must be preferred in patients with contrain-
for surgery as suggested by the guidelines are dication to warfarin or >65 years. Chordal preser-
reported in Table 16.2. vation should be preferred if possible (i.e.,
subvalvular scarring or calcification) due to the
Mitral Valve Repair negative impact of left ventricular function.
Valve repair should be the preferred surgical
treatment in primary MR when feasible. Current Medical Therapy
techniques include the use of artificial chord Management of acute MR with hemodynamic
instability should be pointed on reduction of fill-
ing pressures and reduction of the regurgitant
Table 16.2 Indications for mitral valve surgery in
primary MR according to the 2012 ESC guidelines blood volume. Sodium nitroprusside should be
used to reduce afterload and regurgitant fraction
Class I evidence or agreement that mitral valve
surgery is indicated as intra-aortic balloon pump (IABP). IABP and
Patients with severe MR undergoing CABG and LVEF inotropes may be added in case of hypotension or
>30 % shock. Theres no evidence about the use of vaso-
Class IIa weight of evidence favors mitral surgery dilators in chronic MR.
Patients with moderate MR undergoing CABG
Patients with severe MR, LVEF <30 %, and the need unctional Mitral Regurgitation
F
for revascularization with evidence of myocardial In functional or secondary MR, mitral valve
viability
apparatus is normal and the regurgitant volume
Class IIb weight of evidence less well established
results from a disproportion between closing and
Symptomatic severe MR with LVEF >30 % despite
medical treatment, low comorbidity, and no need for tethering forces. The ischemic etiology carries a
revascularization poor prognosis. Severe tricuspidal regurgitation
LVESD left ventricular end systolic diameter, LVEF left is often associated, and right ventricular dysfunc-
ventricular ejection fraction tion may be a predictor of worse outcome [24].
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16 Mitral Regurgitation 191
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192 M. Flori et al.
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Prosthetic Valve Dysfunctions
17
Alessia Urbinati, Marco Marchesini,
and Ilaria Mazzanti
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194 A. Urbinati et al.
Chest X-Ray
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17 Prosthetic Valve Dysfunctions 195
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196 A. Urbinati et al.
endocarditis that could damage a biologic valve the commissures and at the base of the leaflets,
even more frequently than a native one. reducing the excursion movement.
Prosthetic valve detachment is the most dra- A different scenario is the patient-prosthesis
matic complication that should be monitored mismatch, more frequently viewed with aortic
after the recognition of a true perivalvular regur- stented bioprosthesis, where the increased after-
gitation. It is commonly due to an infective endo- load of the left ventricle is due to a normal func-
carditis, frequently with an early onset within 1 tioning valve that is however undersized in
year from the implant and related to the implant relation to the patients body surface area [7].
itself. The infective process disrupts the sewing This situation occurs mainly in patient with a
ring directly generating a perivalvular regurgita- small native aortic annulus in which it is possible
tion or creating a periprosthetic aneurysm that to lodge only a small prosthesis. The clinical sce-
could be silent until its emptying, when a loss of nario consists of a patient with a valvular stenosis
tissue occurs and the valve anchorage is lost. that is not solved [812].
Beside regurgitation that could range from mod- For patients with prosthetic valves, regardless
erate to severe leading to heart failure manifesta- of the type or model, most recent international
tions, we can see the rocking movement of the guidelines and experts consensus recommend a
valve that is a sign of a more extensive detach- visit, a chest X-ray, a 2D echocardiography
ment with a more urgent indication to surgery. within 4 weeks from the implant in order to
The most dreadful consequence is prosthetic obtain a picture in a moment in which the valve is
valve embolization. thought to work at best, and be able to register
On the opposite side, we can face prosthetic any modifications from this optimal condition.
valve obstruction generating valve stenosis of Then the follow-up consists of an annual cardiol-
different severity [3]. In this setting, knowing the ogy visit, with adjunctive controls with echocar-
exact type (mechanical, single disk, bileaflet or diography in case of symptoms variations or new
biologic, stented/stentless, etc.), model, and cardiac murmur discovery [2, 8]. If any dysfunc-
dimension of the valve is of paramount impor- tion is detected, a 2D echocardiography should
tance because the normal values reported by the be performed every 3 or 6 months in relation to
manufacturers differ in relation to these factors. the severity of the valve dysfunction. On the other
Moreover, it is essential, at every follow-up, to side, to perform an echocardiogram every 12
know the early post-implant gradient values in months, as a routine in a patient with stable clini-
order to avoid an incorrect diagnosis of prosthetic cal conditions, is not recommended [1320].
valve dysfunction. In mechanical valves, the
obstruction could be suspected in the presence of
a gradient higher than expected for the specific
prosthesis. Sometimes the cause is evident such References
as the presence of a voluminous mass (thrombus
or vegetation) occupying space and then reducing 1. Pibarot P, Dumesnil JG (2009) Valvular heart disease:
changing concepts in disease management.
the effective orifice area or blocking an occluder Circulation 119:10341048
in close position; sometimes the cause consists of 2. Vesey JM, Otto CM (2004) Complications of pros-
a small pathologic process that interferes with the thetic heart valves. Curr Cardiol Rep 6:106111
hinges that is not directly visible with 2D echo- 3. Roudaut R et al (2007) Thrombosis of prosthetic heart
valves: diagnosis and therapeutic considerations.
cardiography. In those cases, we must look for an Heart 93:137142
anomalous or incomplete opening of the occlud- 4. Ruel M et al (2004) Late incidence and determinants
ers, although it is often difficult to see without the of reoperation in patients with prosthetic heart valves.
use of fluoroscopy. Eur J Cardiothorac Surg 25:364370
5. ORourke DJ et al (2001) Outcome of mild peripros-
In biologic prosthesis, the main clue of suspi- thetic regurgitation detected by intraoperative trans-
cion is the presence of increased thickness esophageal echocardiography. J Am Coll Cardiol
(>3 mm) and extensive calcification, beginning at 38:163166
ERRNVPHGLFRVRUJ
17 Prosthetic Valve Dysfunctions 197
6. Habets J et al (2012) Imaging of prosthetic heart valve 13. Dumesnil JG et al (1990) Validation and applications
dysfunction. J Am Coll Cardiol Img 5(9):956961 of indexed aortic prosthetic valve areas calculated by
7. Botzenhardt F et al (2005) Hemodynamic perfor- Doppler echocardiography. J Am Coll Cardiol
mance and incidence of patient-prosthesis mismatch 16:637643
of the complete supraannular Perimount Magna bio- 14. Pibarot P, Dumesnil JG (2006) Prosthesis-patient mis-
prosthesis in the aortic position. Thorac Cardiovasc match: definition, clinical impact, and prevention.
Surg 53:226230 Heart 92:10221029
8. Vahanian A et al (2007) Guidelines on the management 15. Jamieson WR et al (2004) Surgical management of
of valvular heart disease: the Task Force on the valvular heart disease 2004. Can J Cardiol 20(Suppl
Management of Valvular Heart Disease of the European E):7E120E
Society of Cardiology. Eur Heart J 28:230268 16. Heras M et al (1995) High risk of thromboemboli
9. Butchart EG et al (2005) Working Groups on Valvular early after bioprosthetic cardiac valve replacement. J
Heart Disease, Thrombosis, and Cardiac Am Coll Cardiol 25:11111119
Rehabilitation and Exercise Physiology, European 17. Davila-Roman VG (2004) et all. Prevalence and
Society of Cardiology. Recommendations for the severity of paravalvular regurgitation in the Artificial
management of patients after heart valve surgery. Eur Valve Endocarditis Reduction Trial (AVERT) echo-
Heart J 26:24632471 cardiography study. J Am Coll Cardiol
10. Pibarot P, Dumesnil JG (2000) Hemodynamic and 44:14671472
clinical impact of prosthesis-patient mismatch in the 18. Akins CW et al (2005) Early and late results of the
aortic valve position and its prevention. J Am Coll surgical correction of cardiac prosthetic paravalvular
Cardiol 36:11311141 leaks. J Heart Valve Dis 14:792799
11. Kunadian B et al (2007) Meta-analysis of valve hemo- 19. Verheugt FWA (2013) The new oral anticoagulants in
dynamics and left ventricular mass regression for atrial fibrillation: an update. Neth Heart J
stentless versus stented aortic valves. Ann Thorac 21:480484
Surg 84:7378 20. Eikelboom JW, Connolly SJ, Brueckmann M (2013)
12. Dumesnil JG et al (1990) Validation and applications Dabigatran versus warfarin in patients with mechani-
of mitral prosthetic valvular areas calculated by cal heart valves. N Engl J Med 369:12061214
Doppler echocardiography. Am J Cardiol
65:14431448
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Part VI
Rhythm Disorders: Tachyarrhytmias
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Wide QRS Complex Tachycardias
18
Alessandro Barbarossa, Daniele Contadini,
and Marco Flori
Arterial hypertension.
Hypercholesterolemia (LDL 98 mg/dl on drug Allergies
therapy).
Stage 3 chronic kidney disease (GFR 40 ml/ None
min).
Previous inferior myocardial infarction
(STEMI) 9 years ago with consequent coro- Social History
nary artery bypass graft (CABG) surgery:
sequential venous graft (VG) between ascend- He never smoked.
ing aorta and right coronary artery (RC) and He never used illicit drugs.
first left marginal artery (LMA1) and VG He has a sedentary lifestyle.
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202 A. Barbarossa et al.
Vital Signs at ER Entrance Hepatic function (GOT, GPT, -GT, ALP, total
bilirubin, direct and indirect): normal
Temperature: 36.7 C Renal function: creatinine 1.71 mg/dl, BUN
Heart rate: 120 bpm 25.2 mg/dl
Blood pressure: 105/70 mmHg Electrolytes (Na+, K+, Ca++, Mg++, Cl):
Respiratory rate: 16 breaths/min normal
Oxygen saturation while breathing in ambient Thyroid function (TSH, fT3, fT4): normal
air: 91 % Fasting blood glucose: 131 mg/dl
HbA1C: 7.0 % (53 mmol/mol)
Physical Examination Hs-TnT: 12 pg/ml (highest value)
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18 Wide QRS Complex Tachycardias 203
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204 A. Barbarossa et al.
Moreover, the heart rate (120 bpm) is too slow At echocardiography: mild dilatation of the
for a 2:1 atrial flutter. Even if P wave is not visi- left atrium. Moderate dilatation of the left ventri-
ble, hypothesis of a sinus tachycardia is unlikely cle (iEDV 92 ml/m2). Severe left ventricular sys-
because there were not physiological reasons for tolic dysfunction (EF 40 %). Akinetic and thinned
having an elevated rest heart rate. inferior wall of the left ventricle. Normal dimen-
There are not fusion or capture beats (diagnos- sions of the right ventricular dimension and sys-
tic for VT). tolic function (TAPSE 19 mm). II grade diastolic
There was hemodynamic stability, and there- dysfunction. Moderate mitral regurgitation. Mild
fore we performed carotid sinus massage that did tricuspid regurgitation with normal pulmonary
not modify the tachycardia cycle. The QRS com- arterial pressure. No pericardial effusion.
plexes in the precordial leads were not concor- There were not any clues attributable to acces-
dant: V1 positive and negative from V2 to V6 sory AV pathways or to channelopathies (e.g.,
(concordance is high suggestive of ectopic ven- Brugada syndrome or long and short QT syn-
tricular beats, if negative specifically for VT). We drome). Also, cardiomyopathies like hypertro-
measured the distance from the onset of QRS to phic cardiomyopathy, arrhythmogenic right
the nadir of S wave in a precordial lead (we chose ventricular dysplasia, or non-compacted myocar-
V2), and it is about 120 ms (when this interval is dium were excluded. Finally, the presence of an
more or equal to 100 ms, you should consider inferior wall necrosis was confirmed.
VT). Finally, our ECG analysis ends with QRS Because of the low EF unknown in previous
morphological criteria: we are in front of a controls, we repeated a coronary arteriography
RBBB-type wide QRS tachycardia. In V1 the that showed occlusion of VG between RC and
QRS complex morphology is Rr and in V6 LMA1, occlusion of VG between aorta artery
rS. This morphological pattern is suggestive for and LAD, and a good flow on LIMA to LAD.
VT. The QRS axis at 160 and the QRS duration Amiodarone therapy was started (400 mg/die for
of 200 ms are other adjuvant criteria for VT. the 1st week then 200 mg/die) to prevent recur-
Owing these criteria, we postulated the diag- rences. During hospitalization at ECG monitor, a lot
nosis of ventricular tachycardia. of premature ventricular beats (PVBs), couple of
The patient, after sedation with midazolam PVBs, non-sustained VT (nsVT), and another VT
5 mg IV, was successfully treated with electric (which required cardioversion with DC shock) were
cardioversion (DC shock 200 J) with an immedi- recorded. All these ventricular arrhythmias had the
ate return to sinus rhythm (Fig. 18.2). same QRS morphology of the first VT episode.
At sinus rhythm, the QRS complex had a com- An invasive electrophysiological study (EPS)
plete different morphology. The signs of the pre- was performed and documented:
vious inferior MI were visible. [] easy induction by programmed ventricular
pacing of a ventricular tachycardia coming from
the inferior wall of left ventricle. A catheter abla-
Admission to the Arrhythmology tion of the site of origin of ventricular tachycardia
was performed successfully with no more induc-
Department tion of arrhythmia after programmed ventricular
pacing of the area. []
The patient was then admitted to our cardiology
and arrhythmology department to seek the cause The final diagnosis was ventricular tachycar-
of arrhythmia. dia starting from the inferior wall of the left ven-
Electrolytec imbalance, hyper- or hypothyroid- tricle due to macro-reentrant circuits secondary
ism, and coronary acute syndrome were excluded. to a myocardial scar.
ECG: sinus rhythm, normal AV conduction, VT did not return during hospitalization.
QRS axis +30, Q wave in inferior leads as a pre- One month after discharge, we performed a
vious inferior myocardial infarction, normal 7-day-long ECG-Holter monitoring that did not
repolarization. document any VT recurrence.
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18 Wide QRS Complex Tachycardias 205
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206 A. Barbarossa et al.
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18 Wide QRS Complex Tachycardias 207
18.2 Ventricular Tachycardia cardia (VT) has to be taken into account. The
mainstay of differential diagnosis is the ECG
Denition itself, but there are other elements that may help
the diagnosis.
VT is a tachycardia that rises from the ventricles
and lasts at least 3 beats. Non-sustained VT ECG in Wide QRS Tachycardias
(nsVT) is a VT that lasts less than 30 s; contrarily,
a VT that lasts longer than 30 s is called sustained
ventricular tachycardia (sVT). Wide QRS complex tachycardias are one
of the most challenging questions of
ECG. A regular wide QRS complex tachy-
Epidemiology and Etiology cardia may represent one of the following
rhythms:
VTs are associated with a structural heart dis-
ease, but can occur also in its absence. Ischemic
heart disease is the most common cause of
VT. During the acute phase of ischemia, a poly- Aberrant atrioventricular conduction of
morphic VT or a ventricular fibrillation (VF) is supraventricular tachycardia (SVT)
the principal cause of sudden cardiac death Ventricular tachycardia (VT)
(SCD). Preexisting right (RBBB) or left (LBBB)
Monomorphic VT is usually a consequence of bundle branch block with SVT
a myocardial scar zone that became a reentrant Anterograde conduction over the bypass
substrate in patients with structural heart disease. tract of atrioventricular connection in
The scars can derive from an old myocardial patients with Wolff-Parkinson-White
infarction but also from nonischemic cardiomy- (WPW) syndrome
opathies, including idiopathic dilated cardiomy-
opathy, hypertrophic cardiomyopathy (HCM),
infiltrative heart disease (e.g., amyloidosis), and
arrhythmogenic right ventricular dysplasia Irregular wide QRS complex tachycar-
(ARVD). dia may represent one of the following
Moreover, some genetic syndromes (chan- rhythms:
nelopathies) are mainly associated with polymor-
phic ventricular arrhythmias: Brugada syndrome,
long and short QT syndromes, and catecholamin-
ergic polymorphic ventricular tachycardia (see Atrial fibrillation with aberrant ventric-
specific chapters). ular conduction
Finally, a VT that occurs in the absence of Atrial fibrillation with ventricular
structural heart disease and genetic conditions is pre-excitation
referred to as idiopathic VT. This form of VTs Torsade de pointes
usually originates from the right ventricular out- Polymorphic VT
flow tract (RVOT) and is associated with good
prognosis [1].
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208 A. Barbarossa et al.
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18 Wide QRS Complex Tachycardias 209
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210 A. Barbarossa et al.
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18 Wide QRS Complex Tachycardias 211
Antiarrhythmic drug therapy may be consid- 7. Neumar RW, Otto CW, Link MS, Kronick SL, Shuster
M, Callaway CW, Kudenchuk PJ, Ornato JP, McNally
ered as the second choice in patients who cannot
B, Silvers SM, Passman RS, White RD, Hess EP, Tang
receive ICD therapy or in patients with recurrent W, Davis D, Sinz E, Morrison LJ (2010) Part 8: adult
VT/VF associated with ICD shocks [9]. advanced cardiovascular life support: 2010 American
Heart Association Guidelines for Cardiopulmonary
Resuscitation and Emergency Cardiovascular Care.
Supraventricular Tachycardia
Circulation [Internet] 122:S729S767. [cited 2013
WCTs due to SVT should be treated as SVT with Nov 6]. Available from: http://www.ncbi.nlm.nih.gov/
narrow QRS complex (see Chap. 19). pubmed/20956224
8. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NAM,
Freedman RA, Gettes LS, Gillinov AM, Gregoratos G,
Hammill SC, Hayes DL, Hlatky MA, Newby LK,
Page RL, Schoenfeld MH, Silka MJ, Stevenson LW,
Sweeney MO, Tracy CM, Darbar D, Dunbar SB,
References Ferguson TB, Karasik PE, Link MS, Marine JE,
Shanker AJ, Stevenson WG, Varosy PD (2013) 2012
1. Koplan BA et al (2009) Ventricular tachycardia and ACCF/AHA/HRS focused update incorporated into
sudden cardiac death. Mayo Clin Proc 84(3):289297 the ACCF/AHA/HRS 2008 guidelines for device-
2. Surawicz B, Knilans T (2008) Chous electrocardiog- based therapy of cardiac rhythm abnormalities: a
raphy in clinical practice, 6th edn, Saunders (elsevier). report of the American College of Cardiology
pp 440455 Foundation/American Heart Association Task Force
3. Bauernfeind RA et al (1978) Retrograde block during on Practice Guide. J Am Coll Cardiol [Internet] 61:e6
dual pathway atrioventricular nodal reentrant paroxys- e75. [cited 2014 Nov 21]. Available from: http://www.
mal tachycardia. Am J Cardiol 42:499 ncbi.nlm.nih.gov/pubmed/23265327
4. Wellens HJ et al (1978) The value of electrocardio- 9. Blomstrom-Lundqvist C, Scheinman MM, Aliot EM
gram in the differential diagnosis of a tachycardia with et al (2003) ACC/AHA/ESC guidelines for the man-
widened QRS complex. Am J Med 64:27 agement of patients with supraventricular arrhythmias:
5. Kindwall K et al (1988) Electrocardiographic criteria executive summary: a report of the American College of
for ventricular tachycardia in wide complex left bun- Cardiology/American Heart Association Task Force on
dle branch block morphology tachycardia. Am J Practice Guidelines and the European Society of
Cardiol 61:1279 Cardiology Committee for Practice Guidelines (Writing
6. Gupta AK, Thakur RK (2001) Wide QRS complex Committee to Develop Guidelines for the Management
tachycardias. Med Clin North Am [Internet] 85:245 of Patients With Supraventricular Arrhythmias) devel-
266, ixx. [cited 2015 Jan 26]. Available from: http:// oped in collaboration with NASPE-Heart Rhythm
www.ncbi.nlm.nih.gov/pubmed/11233948 Society. J Am Coll Cardiol 42:14931531
ERRNVPHGLFRVRUJ
Supraventricular Reentrant
Tachycardias 19
Daniele Contadini and Alessio Menditto
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214 D. Contadini and A. Menditto
extraocular muscles intact, pupils equally were not clearly visible. ST segment depression
round and reactive to light and accommoda- was present in I, II, aVF, and V3V6 leads. ST seg-
tion bilaterally, bilateral tympanic membrane ment elevation was present in aVR and V1 leads.
intact, bilateral sclera anicteric, and no con-
junctival injection
Neck: supple, no jugular venous distention, no What Are the Possible Types
lymphadenopathy, no carotid bruit of Supraventricular Arrhythmias?
Cardiovascular: regular rhythm, tachycardia
rate, S1 and S2 normal, and no murmurs
Lungs: no rales, rhonchi, or wheezes, no Sinus tachycardia
egophony, no alterations in tactile fremitus, Reentrant supraventricular tachycardias
and normal percussion Atrioventricular reciprocating
Abdomen: overweight, no pulsatile masses, tachycardia
normal bowel sounds in all four quadrants, no Atrioventricular nodal reciprocating
high-pitch or tinkling sounds, resonant to per- tachycardia
cussion, soft, non-distended/non-tender, no Focal atrial tachycardia
rebound or guarding, no costovertebral angle Atrial flutter
tenderness, and no hepatosplenomegaly Atrial fibrillation
Extremities: no cyanosis or clubbing and no
edema
Neurologic: cranial nerves I through XII intact
and no focal deficit The presence of a regular rhythm excludes the
Psychiatric: normal affect, no hallucinations, hypothesis of atrial fibrillation. There isnt a
and normal speech clearly visible P wave, probably because it is
Skin: intact, sweaty, and no rushes, and no lesion inside the terminal part of the ventricular com-
plexes. The atrioventricular ratio is 1:1. Heart
rate (200 bpm) is too low for a 1:1 atrial flutter, so
Routine Laboratory Tests this hypothesis is unlikely. Even if the morphol-
ogy of the P wave is not assessable, we can
Complete blood count: normal (hemoglobin exclude the hypothesis of a sinus tachycardia
13 g/dl) because there were no physiological causes for
Inflammatory markers (ESR, CRP): normal having high heart rate at rest. RP interval was
Hepatic function (GOT, GPT, -GT, ALP, total shorter than PR and longer than 70 ms. The most
bilirubin, direct and indirect): normal likely diagnoses left are therefore atrioventricular
Renal function (creatinine, BUN): normal reciprocating tachycardia, atrioventricular nodal
Electrolytes (Na+, K+, Ca++, Mg++, Cl): reciprocating tachycardia, and atrial tachycardia.
normal Vagal maneuver response may allow to distin-
Thyroid function (TSH, fT3, fT4): normal guish between the different forms of supraven-
Fasting blood glucose: 93 mg/dl tricular tachycardias. Atrial tachycardia generally
HbA1C: 7.0 % (53 mmol/mol) is conducted with a transitory high-grade atrio-
Hs-TnT: 120 pg/ml (highest value) ventricular block. Reentrant supraventricular
tachycardias end suddenly. In this case, the sinus
carotid massage caused a sudden tachycardia
Routine 12-Lead ECG at Rest (Fig. 19.1) interruption (Fig. 19.2).
Therefore, the diagnosis was reentrant supra-
The ECG showed a narrow QRS complex tachy- ventricular tachycardia. The high heart rate
cardia. Heart rate was 200 beats per minute (RR (about 200 bpm) was more suggestive for an
300 ms). The QRS axis is about + 20. P waves
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19 Supraventricular Reentrant Tachycardias 215
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216 D. Contadini and A. Menditto
Fig. 19.3 Electrophysiological study. Endocavity ECG during tachycardia. A atrium, H His, V ventricle
ERRNVPHGLFRVRUJ
19 Supraventricular Reentrant Tachycardias 217
the peak exercise with a heart rate of 154 bpm nodal pathways (dual AV nodal pathways). The
(96 % of theoretical maximum heart rate) and a fast pathway, which conducts more rapidly (PR
systolic blood pressure of 170 mmHg (double interval 100150 ms and AH <220 ms) and has a
product: 26,180). Heart rate and blood pressure long refractory period, appears to be located near
showed a normal behavior. There were no symp- the apex of Kochs triangle. The slow pathway,
toms of ischemic ECG changes. which conducts more slowly (PR interval
We conclude for nonischemic ST alteration. >220 ms) and has a short refractory period,
The abnormal repolarization may be the conse- extends inferoposterior to the compact AV node
quence of a distinct pattern of retrograde atrial tissue and extends along the septal margin of the
activation through accessory pathway. This phe- tricuspid annulus at the level of the coronary
nomenon (ST depression >2 mm) is more fre- sinus. The fast pathway constitutes the normal,
quent in AV reentrant tachycardia than in AV physiological, AV conduction axis [6].
nodal reentrant tachycardia. Indeed, in ortho- AVNRT has been categorized into typical or
dromic AV tachycardia, atrial retrograde activa- atypical. This categorization is based on the ret-
tion, as assessed by intracardiac electrograms, rograde limb of the circuit: if it is the fast path-
occurs during the ST segment on the surface way, it is defined typical; if it is the slow pathway,
ECG. In contrast, in AV nodal reentrant tachycar- it is atypical. Typical atrioventricular nodal reen-
dia, the retrograde atrial activation is most fre- trant tachycardia is the more common type
quently simultaneous with the QRS complex and (90 %) and involves the slow pathway for ante-
therefore does not interfere with repolarization grade conduction and the fast pathway for retro-
[14]. grade conduction (slow-fast variant). Atypical
atrioventricular nodal reentrant tachycardia is
less common (10 %) and includes fast-slow and
19.2 Atrioventricular Nodal slow-slow variants [6].
Reentrant Tachycardia An atrial premature complex that is blocked in
(AVNRT) the fast pathway and is conducted through the
slow pathway generally initiates typical
Denition and Epidemiology AVNRT. If the fast pathway has recovered excit-
ability, the impulse can conduct retrogradely over
Atrioventricular nodal reentrant tachycardia is the fast pathway, resulting in an atrial echo. If the
the most common form of regular paroxysmal impulse reenters into the slow pathway, typical
supraventricular tachycardia. Although it was AVNRT may be initiated. Seldom it is initiated
classically described more often in the young and by a ventricular premature complex (Fig. 19.4).
women, it can be detected at any age and sex. The Atypical AVNRT (fast-slow variant) initiates
overall prevalence of atrioventricular nodal reen- with a ventricular premature complex that is
trant tachycardia is 23 cases per 1000 persons. blocked in the fast pathway. The impulse then
Atrioventricular nodal reentrant tachycardia is conducts to the atrium via the slow pathway and
not usually associated with structural heart dis- returns to the ventricle via the fast pathway.
ease [57]. Seldom an atrial premature complex initiates
tachycardia (Fig. 19.5).
In AVNRT, neither the atrium nor the ventricle
Physiopathology and Classication has a critical role in the reentrant circuit [6].
ERRNVPHGLFRVRUJ
218 D. Contadini and A. Menditto
Atrium S
E
Slow Fast
SP
AV node FP
Ventricle
Fig. 19.4 Typical AVNRT (slow-fast) mechanism. FP fast pathway, SP slow pathway, S sinus beat, E extrasystoles
Atrium S
Slow Fast
SP
AV node FP
Ventricle E
Fig. 19.5 Atypical AVNRT (fast-slow) mechanism. FP fast pathway, SP slow pathway, S sinus beat, E extrasystoles
include palpitations, neck pulsations, dizziness, way so the atrium and ventricle are activated
and in some cases chest pain or dyspnea. simultaneously during tachycardia; the retro-
Tachycardia can last a few minutes or hours, and grade P wave is either hidden within the QRS or
the termination can be spontaneous or not. embedded in the terminal portion of the QRS,
Sometimes precipitating factors (drugs, physical resulting in RP < PR (usually RP is less or equal
and psychological stress, menstruation, anemia, to 70 ms) with pseudo-r waves in lead V1 and
hyperthyroidism, etc.) can be found [57]. pseudo-s waves in inferior leads. Comparison
A 12-lead ECG is fundamental for the diagno- with the QRS in sinus rhythm can help in identi-
sis. ECG, during AVNRT, shows in most cases a fying pseudo-r and pseudo-s waves. In atypical
regular narrow QRS complex tachycardia; some- AVNRT, the conduction to the atrium is through
times the QRS complex can be wide with the the slow pathway; the atrium is activated late
typical bundle branch block morphology (LBBB relative to the ventricle, so the retroconducted P
or RBBB). Rate of tachycardia is more often wave is away from the previous QRS and it is
between 140 and 250 per minute. The AV rela- near the following QRS (RP > PR) [6].
tionship is practically in all cases 1:1. Atrial acti- Invasive electrophysiological investigation
vation is concentric type because the (EPS) allows to detect the presence of dual AV
retroconducted stimulus comes from the AV nodal pathways, to induce and identify AVNRT
node, so the retroconducted P wave is narrow and (typical or atypical), and to perform catheter
negative in inferior leads. In typical AVNRT, the ablation of tachycardia. Dual pathway can be
impulse conducts to the atrium via the fast path- demonstrated with delivery of a premature atrial
ERRNVPHGLFRVRUJ
19 Supraventricular Reentrant Tachycardias 219
complex that results in a jump in AH conduc- QRS complex, and orthodromic AVRT ends
tion curve (defined as an increase >50 ms in AH with a retroconducted by accessory pathway P
interval with a 10 ms increase in atrial extrastim- wave [5, 6].
ulus prematurity). This jump is due to ante-
grade block in the fast pathway with the
conduction through the slow pathway. The elec- Treatment
trophysiological characteristic of AVNRT is the
concentric retrograde activation of the atrium, Acute treatment: patients with hemodynamic
with a short ventriculoatrial (VA) interval or with compromise should be electrically cardioverted
a A on V (simultaneous activation of the atrium without delay. Usually, AVNRT does not cause
and ventricle) in typical AVNRT or with a long significant hemodynamic compromise. Vagal
VA time in atypical (fast-slow) AVNRT [6]. maneuvers (Valsalva maneuver, dive reflex,
carotid sinus massage) can be used to terminate
the tachycardia. These maneuvers increase the
Differential Diagnosis vagal tone resulting in slow pathway conduction
blockage. If vagal maneuvers are ineffective,
Surface ECG can make differential diagnosis medications known to prolong refractoriness of
between AVNRT and the other narrow QRS com- the slow pathway of the AVNRT circuit can be
plex tachycardia during tachycardia, by the used. These agents include adenosine, calcium
induction and termination of tachycardia and by channel blocker (verapamil or diltiazem), and
the response to vagal maneuvers [5]. beta-blockers (metoprolol, atenolol, propranolol,
ECG features to assess are shown in Fig. 19.6. esmolol). Intravenous administration of these
The response to vagal maneuvers or to ade- drugs should be performed with continuous ECG
nosine can help to distinguish between the differ- monitoring. These agents are very effective in
ent types of supraventricular tachycardia. Gradual terminating the AVNRT [5, 6].
slowing then reacceleration of rate is typical of Long-term treatment: in patients with recur-
sinus tachycardia or focal atrial tachycardia. rent sustained episodes of AVNRT, we have two
Sudden termination is typical of AVNRT and strategies of long-term treatment, catheter abla-
AVRT. Persisting tachycardia with transient high tion and oral drug therapy. For oral therapy, the
grade of AV block is typical of atrial flutter or first choice includes AV nodal blocking agents
atrial tachycardia [5]. like nondihydropyridine calcium channel block-
Termination of tachycardia is due to block in ers (verapamil, diltiazem) or beta-blockers. The
slow pathway in AVNRT and in AV node in use of other antiarrhythmic agents like class IC
AVRT. Thus, typical AVNRT ends with a retro- (flecainide, propafenone) or class III (sotalol,
conducted P wave, atypical AVNRT ends with a amiodarone) is not common for treating AVNRT
RP<PR
3rd: assess RP and PR RP>PR
RP<70ms RP>70ms
ST; AT; Aflu with
4th: most probable diagnosis atypical Aflu; AT AF different AV
Typical AVNRT AVRT; AT MAT
AVNRT; conduction
PJRT
Fig. 19.6 ECG features to assess. AVNRT atrioventricu- tachycardia, PJRT permanent junctional reciprocating
lar node reentrant tachycardia, AVRT atrioventricular tachycardia, Aflu atrial flutter, AF atrial fibrillation, MAT
reentrant tachycardia, AT atrial tachycardia, ST sinus multifocal atrial tachycardia
ERRNVPHGLFRVRUJ
220 D. Contadini and A. Menditto
today; these are used only when the AV nodal syndrome. The expression WPW pattern defines
blocking agents have failed to prevent recurrence the ventricular preexcitation in the absence of
of tachycardia and patient refuses catheter abla- tachycardias symptoms and signs [5, 7].
tion. Radiofrequency catheter ablation is the non- The prevalence in the general population is
pharmacologic treatment option. Success rates about 13 per 1000 people. Men have an higher
for this technique are approximately 90 %. The incidence of ventricular preexcitation than
major procedural risk is the AV complete block. women (M/F = 2.2:1), and there is a higher inci-
The ablation of slow pathway, rather than the dence of multiple accessory pathways in men,
ablation of the fast pathway, reduces the risk of too. Some cases of WPW are inherited. Parents
AV complete block (1 % vs 8 %) and results in who have accessory pathways may pass them
the absence of hemodynamic consequences of onto their children. The incidence of preexcita-
marked prolongation of PR interval that derives tion in first-degree relatives could be as high as
from fast pathway ablation. Therefore, slow path- 5.5 per 1000 people. In a recent clinical study, a
way ablation represents the first choice today [5]. mutation to the gene that codifies for PRKAG2
(-2 regulatory subunit of AMP-activated protein
kinase) was identified to be responsible for a syn-
Prognosis drome associated with ventricular preexcitation
and early onset of atrial fibrillation and conduc-
Atrioventricular nodal reentrant tachycardia has tion disease. About 720 % of patients with
a good prognosis, and it is not usually associated WPW also have congenital defects within the
with structural heart disease. In some patient, heart [57].
AVNRT coexists with atrial fibrillation, and
recent reports suggest that it may serve as a trig-
ger for atrial fibrillation and its eliminations can Accessory Pathways Anatomy
help to treat atrial fibrillation [6].
The anatomical substrate of ventricular preex-
citation is an accessory pathway. There are four
19.3 Ventricular Preexcitation different types of them. The most common acces-
and Atrioventricular sory pathway is the bundle of Kent (more of 96 %
Reentrant Tachycardia of cases). This is an atrioventricular bypass: the
(AVRT) electrical impulse from the atria directly reaches
the ventricles. The bundle of Kent is made of
Denition and Epidemiology common myocardial cells. They are sodium-
dependent cells, and for this reason, they have
Ventricular preexcitation is a congenital alteration a faster conduction of the electrical impulse than
of the normal conduction of the electrical impulse the specialized cells of the heart conduction sys-
in the heart. In this pathology, an accessory tem that are calcium dependent. The electrical
pathway is present through which the electrical conduction through the bundle of Kent is often
impulse can activate an area of the myocardium frequency-independent and occurs with an all-or-
more rapidly bypassing the normal conduction nothing mode (non-decremental conduction). It
system. In 1930, Louis Wolff, John Parkinson, means that an electrical impulse can be conducted
and Paul Dudley White described a series of through the accessory pathway or blocked, and
young patients who experienced paroxysms of when conducted, it isnt slowed down. The bundle
tachycardia and had characteristic abnormali- of Kent can conduct the electrical impulse in dif-
ties on electrocardiography (ECG) of ventricular ferent ways: both directions (anterograde and ret-
preexcitation. When ventricular preexcitation is rograde, about 68 % of cases), only in retrograde
associated to symptoms and signs of tachycardias, direction (from ventricles to atria, about 21 % of
it is defined as Wolff-Parkinson-White (WPW) cases), or only in anterograde direction (from atria
ERRNVPHGLFRVRUJ
19 Supraventricular Reentrant Tachycardias 221
ERRNVPHGLFRVRUJ
222 D. Contadini and A. Menditto
ERRNVPHGLFRVRUJ
19 Supraventricular Reentrant Tachycardias 223
a b
Fig. 19.8 Accessory pathway axis. Peripheral leads (a) and precordial leads (b). LL lateral left, PostL posterolateral, P
posteroseptal, PL posteroseptal left, PR posteroseptal right, LR lateral right, A anteroseptal
Atrium S
AP E
NAV
HIS bundle
AP H
Ventricle
Fig. 19.9 Orthodromic AVRT mechanism. NAV atrioventricular node, AP accessory pathway, S sinus beat, E extrasys-
toles, H His bundle
atrial or ventricular complexes. Diagnostic not sinus P wave, when visible; and (4) P/
criteria on the ECG are (1) wide QRS regular QRS ratio always 1:1; an AV block during
tachycardia; (2) QRS morphology identical tachycardia rules out the AV reentrant one
to that of the fully preexcited complex; (3) (Fig. 19.10).
ERRNVPHGLFRVRUJ
224 D. Contadini and A. Menditto
S
Atrium
E
AP
NAV
HIS bundle AP H
Ventricle
Fig. 19.10 Antidromic AVRT mechanism. NAV atrioventricular node, AP accessory pathway, S sinus beat, E extrasys-
toles, H His bundle
ERRNVPHGLFRVRUJ
19 Supraventricular Reentrant Tachycardias 225
AF
Atrium
AP
H
NAV AP
HIS bundle
Ventricle
Fig. 19.11 Preexcited atrial fibrillation mechanism. NAV atrioventricular node, AP accessory pathway, AF atrial fibril-
lation, H His bundle
mias. Invasive EPS allows overstimulating the In fact a P wave at the end of the tachycardia is sug-
atria to identify if there is another way (in addi- gestive for AVRT or AVNRT. Continuation of
tion to the AV node) for the electrical impulse to tachycardia with AV block rules out AVRT. In case
reach the ventricles and overstimulating the all the maneuvers for the termination of the tachy-
ventricles to identify if there is another way to cardia are not effective, electrical cardioversion
reach the atria. In addition, studying the first acti- should be considered. In patients with a regular
vated and the last activated area is possible to wide QRS complex tachycardia, if a differential
localize exactly the position of the accessory diagnosis of ventricular tachycardia (VT) is
pathway. In some cases, it is possible to induce unclear, the arrhythmia should be treated as VT. In
tachycardia, too [57, 10]. case of preexcited tachycardias, AV nodal blocking
The differential diagnosis has already been agents should be used cautiously. It is preferable to
discussed in the AVNRT paragraph. treat preexcited AF with IV ibutilide, flecainide, or
procainamide.
Chronic treatment: in patients with WPW
Treatment syndrome, the first-line therapy is catheter abla-
tion of the accessory pathway. This approach is
Acute treatment: if the patient, during the arrhyth- recommended in patients with preexcitation and
mia, is hemodynamically unstable, an immediate symptomatic arrhythmias, mostly in the case of
electrical cardioversion is mandatory. In the case of preexcited tachycardias or when the arrhythmic
a regular narrow QRS complex tachycardia, in a episodes are frequent or poorly tolerated. In
hemodynamically stable patient, it is important to these patients, when catheter ablation is not pos-
do vagal maneuvers (Valsalva, carotid sinus mas- sible, a prophylactic antiarrhythmic therapy
sage, and facial immersion) to terminate the should be considered. The advised drugs are fle-
arrhythmia. If these fail, IV antiarrhythmic drugs cainide or propafenone or sotalol or amiodarone.
should be administered. Adenosine or nondihydro- AV-blockers (nondihydropyridine calcium chan-
pyridine calcium channel antagonists are the drugs nel antagonists or beta-blockers) should not be
of choice (the first one should be avoided in patients used as single therapy in patients with preexcited
with severe bronchial asthma). Second-choice tachycardia (especially AF) because there is con-
drugs are IV calcium channel blockers or beta- crete risk to favor the conduction through the
blockers. An ECG should be recorded during the accessory pathway. In case of rare episodes of
maneuvers for the termination of the tachycardia. AVRT without preexcitation or in asymptomatic
ERRNVPHGLFRVRUJ
226 D. Contadini and A. Menditto
patients with preexcitation, catheter ablation 3. Nelson SD, Kou WH, Annesley T et al (1988)
Significance of ST segment depression during parox-
should be considered. In such cases, patients
ysmal supraventricular tachycardia. J Am Coll Cardiol
choice should be taken into consideration. In this 12(2):383387
case, a pharmacological pill in the pocket 4. Rivera S, Conde D et al (2014) The retrograde P-wave
therapy (taking an antiarrhythmic drug only at theory: explaining ST segment depression in supra-
ventricular tachycardia by retrograde AV node con-
the onset of a tachycardia episode) could be
duction. Pacing Clin Electrophysiol 37:11001105
made with verapamil, diltiazem, or beta-blocker. 5. Blomstrom-Lundqvist C, Scheinman MM, Aliot EM
Sometimes none therapy could be another strat- et al (2003) ACC/AHA/ESC guidelines for the man-
egy, too [5, 6, 10]. agement of patients with supraventricular arrhyth-
miasexecutive summary: a report of the American
College of Cardiology/American Heart Association
Task Force on Practice Guidelines and the European
Prognosis Society of Cardiology Committee for Practice
Guidelines (writing committee to develop guidelines
for the management of patients with supraventricular
The risk of sudden cardiac death due to the pres-
arrhythmias). Circulation 108:18711909
ence of accessory pathway has been estimated to 6. Lee KW, Badhwar N, Scheinman MM (2008)
range from 0.15 to 0.39 % over 310 years fol- Supraventricular tachycardia part I. Curr Probl
low-up. If the risk of sudden cardiac death after Cardiol 33:467546
7. Bonow RO, Mann DL, Zipes DP, Libby P (2012)
accessory pathway ablation is the same or less is
Braunwalds heart disease: a textbook of cardiovascu-
debated yet [5, 10]. lar medicine, 9th edn. Saunders Elsevier, Philadephia,
pp 799850
8. Surawicz B, Knilans T (2008) Chous electrocardiog-
raphy in clinical practice, 6th edn. Saunders Elsevier,
References Philadelphia, pp 481508
9. Oreto G (2010) Lelettrocardiogramma: un mosaico a
1. Riva S, Della Bella P, Tondo C et al (1996) Value of 12 tessere, 1st edn. Edi. Ermes, Milano, pp 223242
ST segment changes during tachycardia in determin- 10. Cohen MI, Triednman JK et al (2012) PACES/HRS
ing type of narrow QRS complex tachycardia. J Am expert consensus statement on the management of the
Coll Cardiol 27(6):14801485 asymptomatic young patient with a Wolff-Parkinson-
2. Gle S, Ertab F et al (1999) Value of ST-segment white (WPW, ventricular preexcitation) electrocardio-
depression during paroxysmal supraventricular graphic pattern. Heart Rhythm 9(6):10061024
tachycardia in the diagnosis of coronary artery dis-
ease. Am J Cardiol 83:458460
ERRNVPHGLFRVRUJ
Atrial Fibrillation and Related
Disorders 20
Jenny Ricciotti and Alessio Menditto
No home medications
A 51-year-old man was admitted to the
emergency room for exertional dyspnea,
orthopnea, and edemas at lower limbs. He Vital Signs
reported a constrictive chest pain at rest
lasting almost 2 h. He denied any recent Temperature: 36.4 C
episodes of fever or infection diseases. Heart rate: irregular, about 130 beats per
There is negative anamnesis for previ- minutes
ous diseases. Cardiovascular risk factors Blood pressure: 120/95 mmHg
were absent. Respiratory rate: 24/min
Oxygen saturation while breathing in ambient
air: 93 %
Allergies
Physical Examination
No allergy was referred.
General: alert, awake, and oriented
Head, eye, ear, nose, and throat: normoce-
Social History phalic, atraumatic, mucous membranes moist,
extraocular muscles intact, pupils equally
The patient worked in a bakery, never smoked, round and reactive to light and accommoda-
and did not use illicit drugs. tion bilaterally, bilateral tympanic membrane
intact, bilateral sclera anicteric, and no con-
junctival injection
Neck: supple, jugular venous distention, and
no lymphadenopathy
J. Ricciotti A. Menditto (*)
Clinica di Cardiologia e Aritmologia, Cardiovascular: irregular rhythm, about
Universit Politecnica delle Marche, 130 beats per minutes, and no murmurs
Conca, Ancona 60100, Italy Lungs: bilateral rales at medium-basal lung
e-mail: jen.ricciotti@tiscali.it; fields, no rhonchi or wheezes, no egophony,
alessiomenditto@hotmail.it
ERRNVPHGLFRVRUJ
228 J. Ricciotti and A. Menditto
no alterations in tactile fremitus, and normal He was treated with a diuretic (furosemide)
upon percussion and rate-control agents (digoxin and metoprolol)
Abdomen: no pulsatile masses, normal bowel with an improvement of symptoms after 24 h.
sounds in all four quadrants, no high-pitched Echocardiography was recorded and showed
or tinkling sounds, resonant on percussion, the following findings: normal-sized left ventri-
soft, non-distended/nontender, no rebound or cle (60 ml/m2) with severe depression of global
guarding, no costovertebral angle tenderness, systolic function (EF less than 20 %) due to dif-
and no hepatosplenomegaly fuse hypokinesia. Severe dilatation of the left
Extremities: no cyanosis or clubbing, with atrium (index volume 40 ml/m2). High filling
lower limb edema pressure. Normal right ventricle size with reduced
Neurologic: cranial nerves I through XII systolic function (TAPSE 12 mm). Moderate dil-
intact, no focal deficit atation of the right atrium. No pericardial effu-
Psychiatric: normal affect, no hallucinations, sion. No gradients. Mild to moderate mitral
and normal speech regurgitation. Moderate to severe tricuspid regur-
Skin: intact, no rashes, and no lesion gitation with high pulmonary arterial pressure
(40 mmHg) (Fig. 20.3).
ERRNVPHGLFRVRUJ
20 Atrial Fibrillation and Related Disorders 229
Fig. 20.1 ECG shows atrial fibrillation with high ventricular rate
ERRNVPHGLFRVRUJ
230 J. Ricciotti and A. Menditto
a b
Fig. 20.4 Coronary angiography. Right coronary angiography (a) and left coronary angiography (b)
Fig. 20.5 Electrical cardioversion. Synchronized biphasic shock at 150 J restores sinus rhythm
ERRNVPHGLFRVRUJ
20 Atrial Fibrillation and Related Disorders 231
Fig. 20.6 Echocardiography. Normal left ventricular global systolic function (a). ECG with sinus rhythm (b)
ERRNVPHGLFRVRUJ
232 J. Ricciotti and A. Menditto
More than six million in Europe have this episodes of AF long enough (>524 h) are associ-
form of arrhythmia, and its prevalence is expected ated with an increased risk of thromboembolism
to double over the next 50 years with the aging [8, 9].
population. The European Heart Rhythm Association had
proposed a new classification for assessing symp-
toms during AF (EHRA score) [10, 11]: class I,
Classication related to no symptoms; class II mild symptom,
with no impairment of normal daily activities;
AF is classified according to the modality of pre- class III, severe symptoms that affected normal
sentation, its duration and the possibility of resto- daily activity; and class IV, disabling symptoms
ration of sinus rhythm into: with disruption of normal daily activity.
The diagnosis of AF requires an ECG per-
formed during the arrhythmia. ECG provides
1. First diagnosed AF, in patients present- information not only on heart rhythm but also
ing with the arrhythmia for the first time on the presence of ventricular hypertrophy, ven-
2. Paroxysmal AF, in general, self-termi- tricular pre-excitation, bundle branch block,
nating within 48 h, but with a maximum myocardial necrosis, and concomitant
duration up to 1 week arrhythmias.
3. Persistent AF, when an episode of AF Transthoracic echocardiography (TTE) is
lasts more than 7 days or requires car- extremely useful for assessing the existence of an
dioversion to restore sinus rhythm underlying heart disease; it helps to define the
4. Long-standing persistent AF if AF lasts presence of a valvular disease and its severity to
more than a year when an attempt is evaluate chamber dimension and left ventricular
made to restore the rhythm systolic and diastolic function and estimate pul-
5. Permanent AF if it is chronic and no monary pressure.
more attempts to restore normal heart Transesophageal echocardiography (TEE) is
rhythm will be made [3] used to assess the presence of e.g., left atrial
appendage thrombi before cardioversion of non-
datable AF.
Chest X-ray is useful in particular in cases of
Clinical Presentation and Diagnostic AF associated to symptoms of heart failure for
Evaluation the evaluation of the state of pulmonary circula-
tion. It can reveal the presence of concomitant
The most common symptoms in patients with AF AF-associated pulmonary diseases (e.g.,
are palpitations (54 %), which are more common COPD).
in paroxysmal forms, and dyspnea (44 %), which Laboratory tests to be performed are tests for
is prevalent in permanent type. Other common thyroid hormones (TSH, FT4), serum electro-
symptoms are easy fatigability and asthenia lytes, blood counts, and renal and hepatic func-
(14 %), chest pain (10 %), and dizziness and syn- tions that help in choosing antiarrhythmic and
cope (10 %) [4, 5]. anticoagulant drugs.
AF may be also asymptomatic and conse- ECG monitoring system as ambulatory ECG
quently silent; the frequency of silent FA varies Holter or external loop recorder may be used in
depending on the method used for recording, case of palpitations suspicious for paroxysmal
reaching up to 5174 % if considering the memo- AF but without previous electrocardiographic
ries of pacemakers and ICD [6, 7]. documentation of arrhythmia and for the diagno-
The high prevalence of asymptomatic AF has sis of asymptomatic episodes of AF.
implications on the need to start the oral antico- Performing other imaging studies should be
agulant therapy; various trials showed that only evaluated case by case.
ERRNVPHGLFRVRUJ
20 Atrial Fibrillation and Related Disorders 233
ERRNVPHGLFRVRUJ
234 J. Ricciotti and A. Menditto
First choice F, P, D, S F, P, D, S D S, D D A
Second choice A A A A A
Fig. 20.7 Antiarrhythmic drugs for rhythm control. HT hypertension, CAD coronary artery disease, HF heart failure,
F flecainide, P propafenone, D dronedarone, S sotalol, A amiodarone
ERRNVPHGLFRVRUJ
20 Atrial Fibrillation and Related Disorders 235
remains symptomatic or if tachycardiomyopathy the other side, the increased filling pressures in
occurs despite lenient rate control. If the rate con- heart failure favor wall stress and atrial dilatation
trol has failed, despite maximum tolerated medi- and fibrosis; the increase in adrenergic tone and
cal therapy, the ablate and pace (radiofrequency neurohumoral activation typical of chronic heart
ablation of atrioventricular node and pacemaker failure determines changes in the electrical sub-
implant) is a non-pharmacological strategy to strate, which are responsible for AF onset.
obtain rate control. Therefore the coexistence of AF and heart fail-
There are no differences in terms of mortality, ure leads to increased mortality and quality of life.
quality of life, and stroke rate between rhythm-
and rate-control strategies; the choice depends on
symptoms, structural heart disease, patients age, AF and Stroke
number of previous episodes, and comorbidity [3].
Stroke is the most important complication in
patients with AF. It is estimated that up to 25 %
20.3 Atrial Fibrillation of strokes in the elderly are a result of AF, which
and Related Disorders increases its risk fivefold [14].
Cardioembolic strokes due to AF are the result
AF is correlated with an increased risk of mortal- of emboli originating from the left atrium and the
ity, ischemic events, and heart failure. left auricle; they are often very large, with a
In the Framingham Heart Study, AF resulted in higher risk of disability [15] and an increased
an increased risk of mortality of 1.5-fold in men poststroke mortality than other types of strokes;
and 1.9-fold in women, independently from the moreover AF is an independent risk factor for
presence of concomitant cardiovascular disease stroke severity and recurrence [16].
[12]. Moreover, AF has a significant impact on the Therefore proper stratification and prevention
quality of life, with a lower score of 1630 % of of thromboembolic risk are a very important part
all the parameters commonly examined. The dete- in the management of AF patients. Actually ESC
rioration of the quality of life in AF patients is AF guidelines recommend to use the CHADS2
similar or even more pronounced than in patients score and more recently the CHA2DS2-VASc
with myocardial infarction or heart failure and score that consider various major and minor clin-
patients undergoing coronary angioplasty [13]. ical risk factor predictors of stroke for evaluating
the indication for anticoagulation treatment (see
Antithrombotic Therapy).
AF and Heart Failure Several randomized clinical trials and meta-
analyses have shown that oral anticoagulation
AF and heart failure are two conditions that often therapy is highly effective in the primary and sec-
coexist. About a third of AF patients have a his- ondary prevention of stroke in patients with AF;
tory of congestive heart failure, and 10 to 30 % of anticoagulation therapy reduced the relative risk
patients with heart failure have a history of of stroke by 64 %, corresponding to an absolute
AF. The prevalence of AF in heart failure increases annual risk reduction in all strokes (2.7 %) [17].
with the progression of the NYHA functional
class (from 4 % in class I to 50 % in class IV).
These two conditions (AF and heart failure) AF and Tachycardiomyopathy
share the same risk factors, and the presence of
one predisposes to the development of the other: Tachycardiomyopathy or tachycardia-induced
the loss of atrial contribution to ventricular fill- cardiomyopathy (TIC) is defined as a condition
ing, the high heart rate, the irregularity of cardiac of systolic and/or diastolic dysfunction second-
cycles, and the reduced duration of diastole dur- ary to chronic or frequent recurrent tachyarrhyth-
ing AF lead to a reduction in cardiac output; in mias. It is characterized by ventricular dilatation
ERRNVPHGLFRVRUJ
236 J. Ricciotti and A. Menditto
and signs and symptoms of heart failure, com- rhythmic drugs. The return to sinus rhythm
pletely or partially reversible after normalization improves cardiac output, ejection fraction, and
of heart rate and/or heart rhythm abnormality. ventricular volumes and also restores AV syn-
TIC may result from various types of chronic chrony and the atrial contribution to ventricular
or frequent paroxysmal supraventricular and ven- filling.
tricular tachyarrhythmias, even if the most fre- In general, the choice of pharmacological
quent etiology is AF. therapy depends on the type of the arrhythmia.
The incidence of TIC is not exactly known but Class IC antiarrhythmic drugs should be used
it can occur at any age. In selected studies of with caution in these patients because of their
patients with AF, based on retrospective series, it negative inotropic effect. Beta-blockers and class
was reported that 25 to 50 % of patients with left III antiarrhythmic drugs (amiodarone, sotalol) are
ventricular dysfunction and AF can have some the drugs of choice in patients with atrial fibrilla-
degree of TIC [18]. tion, ventricular tachycardia, and frequent PVCs.
The time needed to the onset of ventricular However when the medical treatment is not
dysfunction and its extent vary from subject to effective, a non-pharmacological approach must
subject; many variables must be considered as the be considered; these include catheter radiofre-
type of arrhythmia, its rate and duration, the age quency ablation by electrical isolation near the
of the patient, drugs, the presence of pre existing ostia of the pulmonary veins and ablate and pace
heart disease, or other comorbidities [19]. strategy with radiofrequency ablation of the AV
The diagnosis of TIC is often made retrospec- node with pacemaker implantation.
tively, after the recovery of ventricular function The recovery of contractile function may be
once the normalization of cardiac rhythm and/or complete, partial, or totally absent. This can
heart rate is obtained. result from the prolonged duration of the arrhyth-
Diagnostic tests include an EKG that may mia, which causes irreversible histopathological
show the responsible arrhythmia. Chest X-ray alterations, and from the concomitant presence of
can reveal a dilated cardiac silhouette and inter- an underlying heart disease. The time required
stitial edema in the pulmonary circulation. for recovery of left ventricular function is very
Echocardiogram shows dilatation of the left and variable; in experimental animal models, the
right ventricles with systolic and/or diastolic dys- range is about 2 weeks after the end of the cardiac
function and signs of elevated filling pressure; stimulation; in clinical studies, the time neces-
mitral insufficiency secondary to valvular annu- sary for the improvement of ventricular function
lus dilatation is often present. can range from 1 month up to a maximum of 68
Other causes of hypokinetic dilated cardiomy- months.
opathy must be excluded, as idiopathic, ischemic,
and post-myocarditis types. TIC can occur also in
patients with underlying heart disease and worsen AF and Acute Coronary Syndromes
the preexistent systolic function.
The treatment of TIC aims to control heart AF is common in patients with ischemic heart
rate and/or normalization of the rhythm. This can disease, and its a frequent complication in acute
be achieved through non-pharmacological and coronary syndrome (ACS), with a reported inci-
pharmacological approaches. dence of new-onset AF in patients hospitalized
In patients with AF, the initial approach is the for ACS varying from to 2 to 23 % [20].
control of the heart rate, which can be achieved The prevalence of AF in the setting of ACS
with drugs that affect the AV node slowing the reduced in the last years, as a consequence of the
ventricular response (beta-blockers, digitalis, increasing use of revascularization strategies
calcium-channel blockers). (PCI in the acute phase).
Subsequently restoration of sinus rhythm can Several risk factors are associated with inci-
be achieved with DC cardioversion or antiar- dence of AF in ACS patients, including advanced
ERRNVPHGLFRVRUJ
20 Atrial Fibrillation and Related Disorders 237
age, infarct size and severity (ST-segment eleva- have also been postulated as responsible of tropo-
tion myocardial infarction), higher Killip class nin and BNP release during increased heart rates
and left ventricular dysfunction, female gender, [22, 23].
and poorer renal function [21]. Some trials reported that troponin elevation
In the management of patients with AF during may help in the risk stratification in patients with
ACS first of all in case of severe hemodynamic AF. In the biomarker substudies of two recent
instability, if an adequate rate control cant be and larger AF trials, RE-LY (randomized evalua-
obtained with pharmacological therapy, urgent tion of long-term anticoagulant therapy) and
DCC is indicated. In the choice of antiarrhythmic ARISTOTLE (apixaban for reduction in stroke
drugs, patient underlying comorbidities must be and other thromboembolic events in atrial fibril-
considered; current guidelines recommend the lation), including a total of 21,081 patients, ele-
use of amiodarone, sotalol, and dronedarone in vated troponin levels were associated with an
the presence of ischemic heart disease; class I increased risk of stroke or systemic embolism
antiarrhythmic drugs are contraindicated during and of cardiovascular death, independently from
acute ischemia. other clinical characteristics [24, 25].
In AF patients undergoing revascularization
(PCI) during ACS with stent implant, triple ther-
apy (warfarin, aspirin, and clopidogrel) must be AF and Cognitive Dysfunction
administered in the initial period (36 months)
and subsequently replaced by warfarin plus clop- It has suggested that AF may be a risk factor for
idogrel up to 12 months; after that, warfarin can the development of cognitive impairment.
be continued alone. For patients at high bleeding In the prospective, population-based
risk, bare metal stents instead of drug-eluting Rotterdam Scan Study [26], dementia and
stents must be considered to reduce the duration Alzheimers disease were correlated with the
of antiplatelet therapy [3]. presence of AF in the elderly, and a subsequent
In patients with ACS complicated with AF, an substudy [27] revealed an association between
increase in hospital and long-term mortality and silent brain infarcts with the risk of dementia
an increased risk of ischemic stroke were and decline in cognitive function in older patients.
observed; in the large multinational GRACE reg- Other possible causes are concomitant heart fail-
istry, a decline in short-term mortality over the ure and microcirculatory dysfunction, secondary
study period in AF patients (between 2000 and to hypertension.
2007), as a reflex of improvements in ACS ther- In a recent review [28], the incidence of cogni-
apy, was reported. tive impairment and/or dementia in patients with
and without AF was compared. It was observed
that patients with AF had a greater risk of cogni-
AF and Troponin Elevation tive impairment and a 2.3-fold (95 % CI 1.43.7)
increased risk of dementia, compared with
In patients presenting with AF and high heart patients in sinus rhythm.
rate, mild elevation of troponin is frequent, also
in the absence of other signs and symptoms of
ischemic heart disease. AF and Pericarditis
Potential mechanisms of troponin elevation in
AF patients, other than coronary syndromes, are A great number of studies have reported that
related to supply-demand mismatch secondary to inflammation has an important role in AF etiol-
increased heart rate, with shorter diastolic filling ogy. AF is observed between 2 and 3 days after
time, that can lead to a reduction in coronary flow cardiac surgery; this time coincides with the peak
and possible subendocardial ischemia. Increased of inflammatory proteins (C-reactive protein,
left ventricular wall strain and myocardial stretch IL-6). In acute pericarditis, the inflammation of
ERRNVPHGLFRVRUJ
238 J. Ricciotti and A. Menditto
pericardial sack can induce AF. In this case, AF is and the control of heart rate may be difficult in
secondary to inflammation and generally resolves this setting. In case of AF during an acute respira-
after the acute phase [29]. tory decompensation, treatment of underlying
A different mechanism is responsible for the pulmonary disease is the primary target, as resto-
onset of AF in constrictive pericarditis. Altered ration of sinus rhythm may be ineffective until
filling pressure for a long time leads to remodel- respiratory failure is corrected.
ing of heart chamber and atrial dilatation. This
atrial dilatation increases the possibility of AF
onset; about one-third of patients with constric- References
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Atar D, Colonna P, De Caterina R, De Sutter J, Goette
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cations on the projections for future prevalence.
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prognosis with higher mortality. Heart Survey Investigators (2005) Atrial fibrillation
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lation duration predicts arterial embolic events in 21. Lau DH, Huynh LT, Chew DP et al (2009) Prognostic
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ERRNVPHGLFRVRUJ
Atrial Flutter
21
Erika Baiocco and Azzurra Fabbrizioli
Medical History
and Cardiovascular Risk Factors Vital Signs
ERRNVPHGLFRVRUJ
242 E. Baiocco and A. Fabbrizioli
Head, eyes, ears, nose, and throat: normoce- Differential Diagnosis for Narrow
phalic, atraumatic, mucous membranes moist, QRS Complex Tachycardia
pupils equally round and reactive to light and
accommodation bilaterally, normal sclera and (see Chap. 19)
conjunctiva, and normal tympanic membranes
and external auditory canal
Neck: movable without resistance, no jugular Sinus tachycardia
venous distention, no lymphadenopathy, and Reentrant supraventricular tachycardias
no carotid bruit. No thyroid enlargement Atrioventricular reciprocating
Cardiovascular: regular rhythm tachycar- tachycardia
dia; S1 and S2 normal in intensity; no mur- Atrioventricular nodal reciprocating
murs, rubs, or gallops; point of maximal tachycardia
intensity non-displaced and non-sustained; Focal atrial tachycardia
no hepatojugular reflux; and capillary refill Atrial flutter
less than 2 s Atrial fibrillation
Lungs: no rales on auscultation in the lung
bases bilaterally, no rhonchi or wheezes, no
egophony, no alterations in tactile fremitus,
and normal upon percussion The regular RR interval excludes atrial fibril-
Abdomen: mild overweight, no pulsatile lation. The presence of an organized atrial rhythm
masses, normal bowel sounds in all areas, no at a rate of 300 bpm, with no isoelectric segment
high-pitched or tinkling sounds, resonant on between the typical sawtooth waves, best seen
percussion, soft, non-distended/non-tender, in inferior leads, suggests the diagnosis of typical
no rebound or guarding, no costovertebral atrial flutter.
angle tenderness, and no hepatomegaly or The two-to-one conduction makes difficult to
splenomegaly recognize the atrial waves superimposed on the
Extremities: no cyanosis, clubbing, or edema QRS complex or T waves, but the cardiologist per-
Neurologic: cranial nerves IIXII intact and formed vagal maneuvers (carotid massage) to
no focal deficit reveal atrial waves increasing AV block (Fig. 21.2).
Psychiatric: normal affect, no hallucinations, The presence of AV block and the ineffective-
normal speech, and no dysarthria ness of carotid massage to terminate the tachy-
Skin: normal in appearance, texture, and cardia exclude the hypothesis of supraventricular
temperature reentrant tachycardia. The atrial tachycardia may
be excluded because of higher atrial rate and the
absence of isoelectric baseline between regular
Routine EKG at Rest (Fig. 21.1) atrial activations.
At the end, the cardiologist concluded a diag-
Conclusions: regular tachycardia, heart rate nosis of typical atrial flutter.
150 bpm, incomplete right bundle branch block
(100 ms), QRS axis +10, apparent atrial
rhythm at a rate of 300 bpm and 2:1 AV con- Routine Laboratory Tests
duction, ST stretch segment from V4 to V6
with flat T waves, and normal corrected QT Complete blood count: normal (Hgb
segment duration 14.6 g/ dl)
The cardiologist was called to analyze the Cholesterol (total, HDL, LDL) and TG:
arrhythmia. normal
The presence of narrow QRS (100 ms) com- Hepatic function (GOT, GPT, -GT, ALP, total
plex indicates supraventricular tachycardia. bilirubin, direct and indirect): normal
ERRNVPHGLFRVRUJ
21 Atrial Flutter 243
a b
c d
Fig. 21.1 Clockwise-type typical atrial flutter with 2:1 ventricular response
Fig. 21.2 ECG strip of leads I, II, and III shows carotid sinus massage with progressive increase in atrioventricular
block
ERRNVPHGLFRVRUJ
244 E. Baiocco and A. Fabbrizioli
Thyroid function (TSH, FT3, FT4): normal abnormalities. Normal right ventricle size with
Renal function (creatinine, BUN): normal normal function. Mild mitral and tricuspid regur-
Electrolytes (Na+, K+, Ca++, Mg++, Cl): gitation with normal pulmonary arterial pressure
normal (PAPs = 30 mmHg). No pericardial effusion.
Fasting blood glucose: 90 mg/dl Slightly dilated inferior vena cava (24 mm) with
HbA1c: 5.0 % >50 % respiratory collapse. Monophasic dia-
TnI-hs and CK-MB: 0.25 ng/ml (normal stolic flow pattern with initial increase of esti-
<0.055 ng/ml) mated filling pressure.
BNP: 127 pg/ml (normal 1100 pg/ml) Conclusions: hypertensive cardiomyopathy
(HCM). The absence of any signs of ventricular
The routine laboratory did not show any dysfunction excludes a tachycardiomyopathy.
reversible proarrhythmic trigger such as electro- The patient was a young active person and he
lyte imbalance, anemia, and thyroid dysfunction. had never had heart rhythm problems before; in fact
The troponin I-hs value was slightly increased this episode of arrhythmia was the first in his life.
due to the tachyarrhythmia. The high myocardial Furthermore it could be triggered by bronchitis.
rate may cause an imbalance between myocardial For these reasons, and in consideration of the
oxygen supply and demand by enhancing myo- presence of only mild left atrium enlargement,
cardial oxygen requirements and reduces the dia- the cardiologist chose a rhythm-control strategy.
stolic coronary filling time. Also the BNP value The patient was electrically cardioverted.
was slightly increased as a result of initial atrial Catheter ablation is indicated for recurrent,
increased filling pressure. symptomatic, or drug-refractory arrhythmia and
therefore was not performed in this case.
The exact duration of atrial flutter was
Chest X-Ray unknown and lasted longer than 48 h. The patient
had a CHA2DS2-VASc score of 2, suggesting a
Both lung fields and costophrenic angles are considerable risk of stroke.
clear. The mediastinum is within normal limits. Many risks and complications of cardiover-
Cardiac size and shape are normal. sion are associated with thromboembolic events,
In agreement with patients symptoms and so effective anticoagulation for at least 3 weeks is
physical examination, chest X-ray did not show mandatory for AFL of >48 h or AFL of unknown
radiographic signs of pulmonary stasis. duration, unless the patient was hemodynami-
cally unstable (LGAF).
At this point, the cardiologist proposed to per-
Echocardiography Performed form a transesophageal echocardiography (TEE)
to Assess Cardiac Function as an alternative to 3 weeks of adequate pre-
and the Presence of Structural Heart cardioversion anticoagulation.
Disease In the meantime, a good control of ventricular
rate was achieved by administrating a calcium-
Normal trileaflet aortic valve and normal aorta channel blocker (verapamil).
dimension (aortic root dimension = 2.7 cm; Transesophageal echocardiography was
ascending aorta = 3.1 cm; aortic arch = 3.1 cm; performed.
thoracic aorta = 2.8 cm; abdominal aorta = 1.8 cm). Conclusion: TEE excluded the presence of
Mild enlarged left atrium (LA diameter M-mode thrombus in the left atrium or left atrial appendage.
41 mm; LA indexed volume 36 ml/m2). Normal The patient was fully informed about the risk
right atrium. No atrial septal defect. Mild left of cardioversion procedure.
ventricular hypertrophy with normal systolic He was sedated with a light anesthetic (mid-
function (mass indexed volume 70 ml/m2; EF azolam). Two electrode paddles were placed on
0.65) in the absence of regional wall motion his chest: the anterior patch was placed under the
ERRNVPHGLFRVRUJ
21 Atrial Flutter 245
Fig. 21.3 Electrical cardioversion. The atrial flutter is converted to sinus rhythm after one synchronized biphasic elec-
trical shock at 50 J
Fig. 21.4 Sinus rhythm, 85 bpm, normal atrio and inter- ventricular conduction, normal ripolarization
right clavicle and the apical patch was placed at patient had a considerable risk of thromboem-
the apex (anterior-apical paddle position). bolism (CHADS2VASc = 2) and a low risk of
Electrical cardioversion was performed during a bleeding (HAS-BLED = 1). In this case, oral
close oxygen level, blood pressure, and heart anticoagulant (OAC) therapy is indicated not
rhythm monitoring. Atrial flutter was success- only for 4 weeks after cardioversion (atrial
fully converted to sinus rhythm after one syn- stunning-related risk), but it should continue
chronized biphasic electrical shock at 50 J, lifelong irrespective of an apparent mainte-
without complications (Figs. 21.3 and 21.4). nance of sinus rhythm. The cardiologist
explained pros and cons of the OAC therapy
and following the patients preferences pre-
21.2 Atrial Flutter scribed a new oral anticoagulant (NOAC).
Catheter ablation and chronic prophylactic
Atrial flutter (AFL) management includes anti- antiarrhythmic therapy were not recommended
thrombotic and antiarrhythmic therapy, correc- because it was the patients first episode of AFL
tion of possible underlying causes, and and his AFL was probably due to a respiratory
treatment of associated comorbidities. The trigger (bronchitis). It was also well tolerated.
ERRNVPHGLFRVRUJ
246 E. Baiocco and A. Fabbrizioli
ERRNVPHGLFRVRUJ
21 Atrial Flutter 247
ERRNVPHGLFRVRUJ
248 E. Baiocco and A. Fabbrizioli
with a dominant negative flutter wave char- response. Patients with AFL are usually more
acterized by a sharp steep ascent followed by symptomatic than those with just AF because the
a gradual descent. Lead V1 shows positive heart rate is more rapid during AFL and because
flutter wave, with an isoelectric component AF is usually associated with increased AV nodal
between the oscillations. The positive deflec- penetration and slower ventricular responses.
tion progressively becomes inverted across Atrial flutter with one to one AV conduction may
the precordium, and the flutter wave is com- be life-threatening. Rapid ventricular rate may be
pletely negative in V6. This type of AFL is caused by antiarrhythmic treatment (IA and IC)
characterized by a rate of 250350 bpm [4, that slows the atrial rate or precipitated by
1214]. increased sympathetic stimulation such as during
Typical clockwise atrial flutter shows sym- exercise or induced by anesthesia. Another high-
metrical flutter waves in the inferior leads, risk condition is present in patient with accessory
with the same ascent and descent segments AV pathways capable of rapid conduction and
without isoelectric line between oscillations. excessive ventricular rate. Moreover, in patients
Lead V1 is characterized by negative deflec- with impaired cardiac function, the hemodynamic
tions, and the flutter waves show a gradually instability may be due to loss of regular atrial rate
transition across the precordium to an upright and diastolic atrial contribution even if the ven-
deflection in V6 [4, 9, 14, 15]. tricular rate is not excessively rapid.
Sometimes thromboembolism with transient
Some people may present both typical AFLs ischemic attack or stroke can be the first mani-
with either counterclockwise or clockwise right festation of arrhythmia. Polyuria is another typi-
atrial macro-reentrant circuit. cal symptom; it is caused by the release of atrial
Atypical atrial flutter shows a more variable natriuretic peptide in response to increased
surface ECG appearance depending on macro- atrial pressure during atrial contraction against a
reentry anatomical location, direction of rotation, closed AV valve, and that indicates a sustained
and the presence of more loop circuits, some- arrhythmia [4].
times mimicking a focal atrial tachycardia. In the Atrial flutter typically has a sudden onset. As
inferior leads, the morphology of flutter waves is atrial fibrillation, this arrhythmia can be clini-
not typically sawtooth and usually the isoelec- cally distinguished into [4]:
tric line is present. The surface ECG findings are
often similar for different underlying substrates,
making the localization within the LA based on Paroxysmal form: when it is transient
the ECG difficult. The flutter wave usually shows and ends spontaneously
a prominent positive deflection in lead V1 and Persistent form: when AFL is present
uncommonly is flat or isoelectric. The flutter and either lasts longer than 7 days or
waves in leads II, III, and aVF may be upright but requires termination by cardioversion
are frequently of low amplitude. LA AFL may (either with drugs or by direct current
sometimes mimic a focal atrial tachycardia [14]. cardioversion)
Permanent form: when the presence of
the arrhythmia is accepted by the patient
Clinical Presentation and the physician and the rhythm-con-
trol strategy is, by definition, not carried
Patients with atrial flutter can be asymptomatic, out
but more commonly, they present with palpita- Long-standing persistent AFL form:
tions, shortness of breath, dizziness, and fatigue. when AFL is present for at least 1
Patients with underlying heart or lung disease year when it is decided to pursue a
may complain also of syncope and chest pain. The rhythm-control strategy
hemodynamic stability depends on ventricular
ERRNVPHGLFRVRUJ
21 Atrial Flutter 249
Diagnosis Tachycardiomyopathy
AFL with persistent high ventricular rate (120
The surface EKG usually allows to diagnose 130 bpm), if untreated, may induce reversible
AFL; it is essential to obtain documentation of ventricular dysfunction (ventricular tachycardio-
the arrhythmia for the choice of treatment. When myopathy) [4].
the ventricular response is one to one or two to
one, EKG analysis may be difficult, because flut-
ter waves are superimposed on the QRS complex Treatments
and T waves. In these cases, vagal maneuvers or
intravenous adenosine administration can be The treatment of atrial flutter should be directed
used to unmask atrial activity. When arrhythmia to relief symptoms, prevention of complications,
is only suspected, it is necessary to perform achieving control of ventricular rate, conversion
Holter ECG monitoring (24 h to 7 days) or to to sinus rhythm, and maintenance of sinus
implant a loop recorder to establish the diagnosis rhythm.
and to choose the strategies of treatment.
Sometimes, the surface EKG is limited to define Acute Therapy
anatomical localization of macro-reentrant cir- Acute management of patients with atrial flutter
cuits, so the endocardial mapping can be used to depends on clinical presentation. The main goals
identify precise anatomical circuit. are to reduce symptoms and to prevent AFL-
related complications. It includes the management
of antithrombotic therapy, achieving control of
Differential Diagnosis ventricular rate through the administration of AV
nodal-blocking agent, conversion to sinus rhythm
See Chap. 19. through electrical or chemical cardioversion, or
atrial overdrive pacing.
If the patient is hemodynamically compro-
Complications mised or complains of significant symptoms (chest
pain, congestive heart failure), like often occurred
Thromboembolic Events in case of one-to-one AV conduction, urgent rate
AFL presents an increased risk for the develop- control or DC cardioversion is required.
ment of thromboembolic events. In non-antico- There are four options possible for the acute
agulated patients, the incidence of atrial treatment of AFL:
echo-dense material or clots increases with atrial
flutter duration longer than or equal to 48 h, and Emergent synchronized external DC cardio-
the risk of embolism was 2.2 % [16]. This is due version (CV), performed under anesthesia, is
to the high atrial rate that determines the paraly- the treatment of choice because of very high
ses of either the RA or LA with consequent blood likelihood of success (terminates AFL in
stasis and development of thrombus. Clots are >90 % of episodes) and safety (class I with
more frequently observed in the appendage level of evidence C). DC cardioversion is very
where the blood velocity is lower. effective because of rapid homogeneous depo-
Risk factors related to these complications are larization of the entire atrium. The necessary
similar to those described for atrial fibrillation, energy to revert AFL to sinus rhythm is less
and the CHADS2VASc score remains the sim- than 50 J using monophasic shocks and with
plest scheme of stroke risk stratification [15]. less energy using biphasic shocks [4, 17].
Furthermore AF and AFL often coexist in the Unsuccessful conversion is usually associated
same patient (2030 %), so the same manage- with prolonged period of the tachycardia, and
ment of antithrombotic therapy is recommended a higher CV energy is necessary that may
(see Chapter 20 AF and related disorders). compromise left ventricular function or
ERRNVPHGLFRVRUJ
250 E. Baiocco and A. Fabbrizioli
increase left atrial size. One option is pretreat- acting (about 30 min), and it is highly effec-
ing patient with an antiarrhythmic agent (ibu- tive in slowing ventricular rate response but
tilide is the most effective) and then the lower may provoke hypotension (10 %) especially in
CV energy may be sufficient. patients with significant left ventricular dys-
Atrial overdrive pacing by transesophageal function. Verapamil is just effective as diltia-
route or with atrial electrodes should be con- zem for rate control but with higher incidence
sidered as an option for conversion to sinus of symptomatic hypotension in particular in
rhythm, mainly in patients with implantable patients with left ventricular dysfunction. The
devices and after cardiac surgery, because beta-blockers are effective as class IV drugs,
these patients frequently have epicardial atrial but they should be avoided in patients at risk
pacing wires. It does not require anesthesia. for reactive airway disease exacerbation.
Nevertheless, high-frequency atrial pacing Digoxin and amiodarone are favored for rate
can induce sustained atrial fibrillation. control in patients with significant congestive
Pretreatment with antiarrhythmic agents may heart failure since other drugs (classes II and
reduce the risk of inducing AF with atrial IV) may worsen cardiac decompensation.
overdrive [4]. This method has a success rate
of about 80 %. Overdrive atrial pacing is pre- However, these are not a permanent solution
ferred in patients who have a history of sick and the arrhythmia may come back.
sinus syndrome with risk for significant bra- If the patient is hemodynamically stable and
dycardia after conversion. atrial flutter presents higher grades of AV block,
Chemical cardioversion is another method to conversion to sinus rhythm should be deferred,
terminate AFL without the need for anesthe- especially with arrhythmia of more than 48 h in
sia. The effect is not instantaneous but the suc- duration, because in these cases, anticoagulant
cess is recorded within 1 h after start of drug therapy is a priority. When a patient is adequately
infusion. The drug necessary to pharmacolog- anticoagulated, the DC cardioversion is the first
ical CV should prolong the refractory period choice (class I with level of evidence B).
within the tachycardia circuit, inhibiting con-
tinuation of the circulating wave front. Class Prevention of Recurrence and Chronic
III agents, such as amiodarone and ibutilide, Therapy
are typically used because they prolong refrac- Chronic pharmacological treatments in patient
toriness and may terminate the arrhythmia with AFL include:
because the circulating wave front encounters
tissue that is refractory. Intravenous amioda- For pharmacological prevention of recurrence,
rone has longer latency period. Ibutilide is class IA drugs such as quinidine and class III
more effective (70 % of success) and rapid drugs are used because they can prevent atrial
(about 30 min), but it may produce torsades de premature beats, reduce the excitable gap, and
pointes arrhythmias in 25 % of cases, and increase atrial refractoriness. Class IC drugs
ECG monitoring for at least 6 h is necessary. alone are usually ineffective and dangerous
But ibutilide should not be used in patients and should be combined with AV nodal-
with structural cardiac diseases, prolonged QT blocking agents [5].
interval, or underlying sinus node disease [5].
The administration of drugs to slow AV nodal When currently available antiarrhythmic
conduction and ventricular response (rate con- drugs for the prevention of AFL are not efficient
trol) is another pharmacological strategy. It and poorly tolerated (in particular IC or sotalol),
should be achieved with class II, III, and IV dronedarone can be used that decreases the risk
drugs [4, 5]; also if in AFL, the rate control of arrhythmic recurrence [18].
may be more particularly difficult to achieve In 60 % of patients, AFL is triggered by exac-
than in AF. Intravenous diltiazem (IV) is rapid erbation of pulmonary disease, postoperative
ERRNVPHGLFRVRUJ
21 Atrial Flutter 251
cardiac or pulmonary surgery, or during acute electrodes that form a Cartesian reference system
myocardial infarction. In this clinical condition, (X-Y-Z) are used. The myocardial virtual anatom-
the use of chronic therapy is not required [5]. ical map is created by moving the electrophysio-
The preferred therapies of poorly tolerated logical catheter in the heart chamber and recording
(also first episode) and recurrent or persistent the precise point of the electrophysiological cath-
atrial flutter is radiofrequency and cryotherapy eters electrodes rather than the surface electrodes,
catheter ablation (class I with level of evidence B) thanks to the recorded voltage gradient. The sys-
[4]. The typical flutter can be mapped with multi- tem analyzes the voltage of each myocardial point
polar catheter (e.g., halo) located in the anterolat- and identifies the sequence of activation com-
eral area of RA that allows to record the direction pared with the reference electrodes recording
of the cavo tricuspid isthmus macro-reentrant cir- more points of the same camera (electric map of
cuit and to distinguish between typical clockwise voltage and activation). The sequence of activa-
and counterclockwise AFL circuits. Diagnosis by tion time is shown with color map and is inte-
this endocavity electrophysiological study is sim- grated with the scar areas recorded with voltage
ple and usually more complex techniques such as map. The macro-reentrant circuit identified by
NavX are not necessary. Radiofrequency ablation these techniques can be interrupted by linear RF
of CTI-dependent AFL involves creating a linear lesion. For pharmacological prevention of recur-
lesion from the inferior vena cava (IVC) to the rence, class IA drugs such as quinidine and class
tricuspid ring to eliminate the critical isthmus in III drugs are used because they can prevent atrial
the macro-reentrant circuit. Successful ablation premature beats, reduce the excitable gap, and
interrupts macro-reentrant circuit and it is demon- increase atrial refractoriness. Class IC drugs alone
strated by bidirectional conduction block. For are usually ineffective and dangerous and should
diagnosis of atypical atrial flutter, typical flutter in be combined with AV nodal-blocking agents [5].
RA is necessary to exclude and to identify the Long-term anticoagulation is advised for
location of macro-reentrant circuit. This is not patients with persistent or paroxysmal atrial flut-
possible with conventional electrophysiological ter, whereas after successful catheter ablation,
study, and it is necessary to use CARTO or NavX anticoagulation can be stopped 46 weeks later if
techniques. The CARTO technique records an sinus rhythm is still present.
electroanatomic map of the RA and LA in sinus For several reasons, follow-up is very impor-
rhythm showing scar area. This system uses a tant for patients with AFL. The risk profile can
magnetic field generated around the patients change as well as the indication for anticoagula-
chest which allows to identify the specific tip tion, for example, when a new diagnosis of diabe-
position of the electrophysiological catheter in the tes or hypertension will be done or when a renal
RA or LA showing three-dimensional anatomical dysfunction occurred. Because of the potential
reconstruction of the heart chambers (anatomical side effects and proarrhythmic risk related to
virtual map). At the same time, the system records chronic antiarrhythmic therapy, patients that
the electric signal from each point using color receive these drugs should be monitored through
code (electric map). Then the two maps are inte- 12-lead ECG, laboratory tests, and echocardio-
grated. Moreover the activation and propagation gram at regular intervals [15].
map recorded with a color scale identifies the
macro-reentrant circuit, the direction, and the
point with slower conduction target for ablation.
The NavX technique uses an electric current References
between two surface electrodes that generates a
voltage gradient between the two electrodes. This 1. Surawicz B, Knilans T (2008) Chous electrocardiog-
raphy in clinical practice, Adult and pediatric. Sixth
voltage gradient is recorded by a standard electro- Edition. Elsevier Health Sciences, London
physiological catheter located in the heart cham- 2. DeStefano F et al (1996) Epidemiologic research in
bers. Usually, in NavX technique, three surface an integrated regional medical care system: the
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252 E. Baiocco and A. Fabbrizioli
Marshfield Epidemiologic Study Area. J Clin electrocardiographic characteristics of right and left
Epidemiol 49(6):643652 atrial flutter. Circulation 108:6066
3. Wellens HJJ (2002) Contemporary management of 11. Scheinman MM et al (2004) Atrial flutter: part II
atrial flutter. Circulation 106:649665 nomenclature. Pacing Clin Electrophysiol
4. Blomstrm-Lundqvist C, Scheinman MM et al (2003) 27(4):504506
ACC/AHA/ESC guidelines for the management of 12. SippensGroenewegen A, Lesh MD, Roithinger FX,
patients with supraventricular arrhythmias. American Ellis WS, Steiner PR, Saxon LA et al (2000) Body
College of Cardiology Foundation, American Heart surface mapping of counterclockwise and clockwise
Association, Inc., and European Society of Cardiology typical atrial flutter: a comparative analysis with
5. Delise P et al (2008) Aritmie. Fisiopatologia e diag- endocardial activation sequence mapping. J Am Coll
nosi: dallecg al mappaggio tridimensionale. Cardiol 35:12761287
Sciantifica Internazionale, CESI 13. Cosio FG, Arribas F, Lopez-Gil M, Gonzalez HD
6. Saoudi N et al (2001) Classification of atrial flutter (1996) Radiofrequency ablation of atrial flutter.
and regular atrial tachycardia according to electro- J Cardiovasc Electrophysiol 7:6070
physiologic mechanism and anatomic bases: a state- 14. Medi C, Kalman JM (2008) Prediction of the atrial
ment from a joint expert group from the Working flutter circuit location from the surface electrocardio-
Group of Arrhythmias of the European Society of gram. Review. Europace 10:786796. doi:10.1093/
Cardiology and the North American Society of Pacing europace/eun106
and Electrophysiology. J Cardiovasc Electrophysiol 15. ESC/EHRA 2011 (2010) Guidelines for the manage-
12(7):852866 ment of atrial fibrillation. Eur Heart J 31:23692429.
7. Yang Y, Cheng J, Bochoeyer A, Hamdan MH, Kowal doi:10.1093/eurheartj/ehq278
RC, Page R et al (2001) Atypical right atrial flutter 16. Pengo V, Rampado E, Iliceto S (2006) La terapia anti-
patterns. Circulation 103:30923098 coagulante nel flutter atriale. G Ital Aritmol Cardiostim
8. Tai CT, Liu TY, Lee PC, Lin YJ, Chang MS, Chen SA 3:151156
(2004) Non-contact mapping to guide radiofrequency 17. Stec S, Kryski T, Kuakowski P (2011) Efficacy of
ablation of atypical right atrial flutter. J Am Coll low energy rectilinear biphasic cardioversion for reg-
Cardiol 44:10801086 ular atrial tachyarrhythmias. Cardiol J 18(1):3338
9. Ricard P, Imianitoff M, Yaici K, Coutelour JM, 18. Guerra F, Capucci A et al (2014) Efficacy and safety
Bergonzi M, Rinaldi JP et al (2002) Atypical atrial of dronedarone in patients previously treated with
flutters. Europace 4:229239 other antiarrhythmic agents. Wiley Online Library
10. Bochoeyer A, Yang Y, Cheng J, Lee RJ, Keung EC, 37(12):717724
Marrouche NF et al (2003) Surface
ERRNVPHGLFRVRUJ
Part VII
Rhythm Disorders: Bradyarrhytmias
ERRNVPHGLFRVRUJ
Sinoatrial Exit Block
22
Andrea Romandini and Lorena Scappini
ERRNVPHGLFRVRUJ
256 A. Romandini and L. Scappini
Fig. 22.1 The figure shows the patients ECG when he arrived at the emergency room: it was characterized by type II
sinoatrial block; biphasic T waves were present in V4, V5, and V6, and negative T waves in III and aVF
Vital Signs
Instrumental Examination
Temperature 36.5 C, heart rate 35 bpm, arterial
blood pressure 95/55 mmHg, respiratory rate A complete echocardiogram was performed and
20 breaths/min, and oxygen saturation 98 % showed upper limits of normality for LVM index
ERRNVPHGLFRVRUJ
22 Sinoatrial Exit Block 257
(LV diastolic volume/BSA 75 ml/m2) with a A follow-up visit was performed 1 month
slightly reduced ejection fraction (EF 48 %) due later. The patient was completely asymptomatic.
to hypokinesia of interventricular septum and Physical examination was normal. The ECG
apical segments of the anterolateral wall. Normal showed a sinus rhythm (heart rate of 62 bpm).
dimensions and function of right cardiac cham- Holter monitoring did not record any arrhythmia.
bers, a mild mitral regurgitation, a calcification of Laboratory blood tests were normal, including
the aortic valve without regurgitation nor steno- the values of potassium (4 mEq/l) and creatinine
sis, a slightly enlarged tubular ascending aorta (1.4 mg/dl). Blood pressure level was
(38 mm), and a mild tricuspid regurgitation with 145/95 mmHg, so it was decided to resume
32 mmHg pulmonary artery systolic pressure administration of ramipril 2.5 mg cp bid. It was
were already shown by the echocardiogram that also recommended to perform periodic checks of
the patient underwent 1 month before. renal function and echocardiographic follow-up
A chest radiograph was done and disclosed of the tubular ascending aortic dimensions.
normal cardiac and pulmonary findings.
22.2 Electrocardiographic
Clinical Course and Therapeutic Diagnosis of Sinoatrial
Management Exit Block
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258 A. Romandini and L. Scappini
ERRNVPHGLFRVRUJ
22 Sinoatrial Exit Block 259
observation of a sudden heart rate doubling dur- with a collection of cardiac rhythm disturbances
ing atropine test. marked by sinus node inability (sinus node dys-
High-degree type II sinoatrial block occa- function) to generate an atrial rate matching the
sionally more than one sinus impulse in bodys physiologic requirements [5]. When SND
succession fails to reach the atrium, and two or is associated with symptoms or prolonged asys-
three successive P waves are dropped, giving a tole, it is referred as SSS. Sick sinus syndrome is
3:1 or 4:1 exit block and a long pause. The diag- not a disease with a single etiology and
nosis is possible only in the presence of pause pathogenesis.
exactly multiple of an underlying regular sinus Abnormalities encompassed in this syndrome
cycle. Usually it is difficult because this long include various bradyarrhythmias such as sinus
pause is interrupted by the intervention of escaped bradycardia, sinus arrest with or without escape
beats/rhythm. rhythm, or sinus exit block, associated or not
The third-degree (or complete) SA exit block is with supraventricular tachyarrhythmias.
a term used to describe a complete absence of P When complicating supraventricular arrhyth-
waves because no SA node impulse is conducted mias are present, the condition is termed the
to the atria. ECG shows an escape rhythm from a syndrome of alternating bradycardia and tachy-
lower pacemaker site after a sinus pause, and so it cardia or simply the bradycardia-tachycardia
is not distinguishable from a sinus arrest. syndrome (BTS) [6]. This syndrome is more
The occurrence of a sinus pause (or a long P-P common in older patients with advanced sick
interval) on ECG may result also from mecha- sinus syndrome. The most common tachyar-
nisms that should be differentiated: marked sinus rhythmias are atrial fibrillation and atrial flutter
arrhythmia, sinus suppression after ectopic pre- [7, 8]. It is argued that different electrophysiolog-
mature (often atrial) impulses even blocked or ical mechanisms may be responsible for BTS:
conducted, overdrive suppression after ectopic bradycardia associated with SND may favor
tachycardia, and single reciprocating echo P reentrant beats and related tachycardias, while
waves. many evidences suggest that atrial fibrillation and
Respiratory sinus arrhythmia can be easily atrial flutter can lead to atrial remodeling and
recognized because the cyclic lengthening of P-P subsequent SND [9, 10].
interval is usually gradual and phasic; on the Clinically, SSS may produce a variety of ECG
other hand, non-respiratory sinus arrhythmia manifestations consisting in inappropriate sinus
presents variable and unpredictable long P-P bradycardia, SA exit block or sinus arrest, pro-
intervals with different durations and no mathe- longed sinus arrest with failing ectopic pace-
matical relationship with short P-P intervals. maker, persistent atrial or atrioventricular escape
rhythm, episodes of alternating supraventricular
tachyarrhythmias with bradyarrhythmias, and
Clinical Presentation: The Sick Sinus long pause following cardioversion of atrial
Syndrome tachyarrhythmia.
Chronotropic incompetence (CI) is another
SA exit block may be chronic but often occurs as manifestation of SSS. It is defined as a failure to
intermittent episodes, so patients may have nor- achieve 85 % of the maximum predicted heart
mal sinus rhythm for several days or weeks rate during exercise testing.
between episodes. Furthermore, patients with SA
block usually have additional rhythm disturbance Prevalence of Sinus Node Dysfunction
because this arrhythmia is included in a broader and SSS
clinical scenario, the so-called sinus node dys- Bradycardia is frequently seen in healthy indi-
function or sick sinus syndrome. viduals, especially in trained subjects, with a
Sick sinus syndrome (SSS) is a term used to waking hour rate usually >40 bpm [11]. In highly
describe the clinical manifestations associated trained athletes, a slower heart rate (3035 bpm)
ERRNVPHGLFRVRUJ
260 A. Romandini and L. Scappini
may be seen, so that only profound sinus brady- symptoms for months or years like dizziness,
cardia and/or marked sinus arrhythmia (heart rate light-headedness, confusion, exertional fatigue,
less than 30 bpm and/or pauses 3 s during wake dyspnea, weakness, nocturnal wakefulness, and
hours) needs to be distinguished from sinus node vague digestive disturbance. Patients with BTS
disease [12]. may have also palpitations or peripheral throm-
Heart rate between 30 and 35 bpm, asymp- boembolic accidents related to atrial flutter or
tomatic sinus pauses lasting between 2 and 3 s, atrial fibrillation episodes.
escape junctional beats or rhythms (with func-
tional AV dissociation), and first- and second- Causes of SSS
degree atrioventricular nodal block are normal Sometimes SND is associated with abnormalities
variants during sleep [11]. intrinsic to the sinus node that include degenera-
Even if asystole longer than 3 s and heart rate tive age-related fibrosis (idiopathic SSS),
<20 bpm are usually secondary to SND [13], this ischemia-induced fibrosis (e.g., coronary artery
condition per se is not sufficient to define a clini- disease, arteritis), infiltrative disease process
cal disorder like SSS (a pause of at least 6 s is (amyloidosis, sarcoidosis, connective tissue dis-
necessary to cause symptoms) [14, 15]. ease, hemochromatosis, tumors), remodeling of
The exact incidence of SND is unknown. It the SA node associated with heart failure or atrial
may develop at any age, but it is primarily fibrillation, primary ion channel dysfunction
diseased in the elderly with the average age of (familiar or congenital form), and surgical injury.
occurrence being about 68 years [16, 17]. In Moreover, many extrinsic factors, usually
young patients it is often related to underlying transient and reversible, can alter SA node func-
heart disease or previous cardiac surgery. The tion, mimicking the SSS (or exacerbating an
natural history of SND may be highly variable, underlying subclinical intrinsic SA node dys-
although it tends to be progressive. SSS approxi- function): autonomic dysfunction of vagal reflex
mately affects 1 in 600 cardiac patients older than (vasovagal, situational, carotid sinus hypersensi-
65 years [18] and for this reason is more preva- tivity), increased vagal tone (training, sleep,
lent in countries with longer life expectancies. anesthesia, and surgical interventions), metabolic
Currently, in Europe, SSS represents the second disturbances (electrolyte abnormalities like
leading cause of permanent pacemaker implanta- hypo-/hyperkalemia, hypocalcemia, hypother-
tion after AV block [1924]. mia, hypoxia, hypothyroidism), obstructive sleep
apnea, drugs (beta-blockers, calcium channel
Sign and Symptoms blockers, digoxin, antipsychotic agents,
All symptoms would be uncommon in the early membrane-active antiarrhythmics like class I and
disease course. They are related to low cardiac preferentially IA and IC, amiodarone, sympatho-
output that occurs with brady- and/or tachyar- lytic medication, morphine), increased intracra-
rhythmias, causing acute end-organ hypoperfu- nial pressure, and temporal lobe seizure.
sion or worsening preexisting organ failure (heart
failure, angina pectoris, or cerebral vascular acci- Clinical Diagnosis: Diagnostic Workup
dent). The extent of bradycardia or length of The cornerstone for the diagnosis of SSS is the
pause that results in symptoms however varies correlation of end-organ perfusion symptoms with
among individuals because stroke volume, the occurrence of bradyarrhythmias, with or with-
peripheral resistance, and local vascular patency out tachycardia. The presence of the sinus node
also contribute to the extent of regional blood dysfunction should always trigger a proper workup
flow at any heart rate. to rule out reversible extrinsic causes before the
Cerebral hypoperfusion is the most common definitive diagnosis of SSS is made. For this pur-
manifestation often causing abrupt symptoms pose, a full review of systemic conditions and
like near fainting or syncopal episodes. However, medications used is necessary as these conditions
many patients may have mild and nonspecific could be potential reversible causes of SSS.
ERRNVPHGLFRVRUJ
22 Sinoatrial Exit Block 261
Since manifestations of SSS may be erratic steadily stored, with the oldest ECG samples
especially in the early stages, the resting ECG being overwritten by the newest (typically
could not reveal abnormal heart rhythm. 1020 min in duration). When activated
Furthermore, symptoms are often nonspecific (patient activated or by auto-trigger algo-
(e.g., dizziness, fatigue, weakness, or heart fail- rithm), data are stored for a programmable
ure) and in common with other disorders occur- fixed amount of time before and after the acti-
ring with progressive aging. vation. Recently, a new generation of wear-
Depending on the severity of symptoms and able garment-inserted ECG system has been
the overall clinical risk stratification, this can be developed (Nuubo system).
done by in-hospital telemetry or by outpatient Mobile cardiac outpatient telemetry (MCOT)
cardiac monitoring devices. systems are devices made up of an external
The true challenge in SSS is to capture a loop recorder with a portable receiver that
recording of the cardiac rhythm during symp- allows wireless transmission of ECG data
toms, so that the type of device that has to be cho- (non-real time or in real time) to a remote
sen depends on the frequency of symptoms. operating center or to a dedicated website
Ambulatory Holter monitoring that allows via the mobile telephone line or Internet.
recording for 2448 h may be sufficient for Typical duration use is 14 weeks. However,
patients with almost daily symptoms. In other nowadays appropriate use guidelines for this
patients with intermittent symptoms, longer mon- type of ECG monitor have not yet been
itoring is often necessary. Recently, several new developed.
external long-term devices have been developed:
Implantable loop recorders (ILR) are leadless
Patch-type long-term external Holter recorders subcutaneously implanted arrhythmia monitor-
using comfortable adhesive patches that enable a ing devices requiring a minor invasive procedure
continuous single-lead monitoring up to 14 through a small skin incision of about 2 cm in the
days. left precordial region. A single-lead ECG signal
Event recorders (post-event/symptom) are is recorded through two electrodes within the
small portable devices applied to the patients device. The memory loop is activated by the
skin and manually activated whenever symp- patient through an external activator or even
toms are experienced. These devices usually automatically (auto-trigger algorithm). ILR can
provide one-lead electrocardiographic record- be used by patients for a long period of time (up
ing for 3090 s (with up to 610 min of mem- to 3 years with the newest devices) until a diag-
ory storage capacity) that needs to be nosis is reached or the battery runs down. This
transmitted transtelephonically or via mail to type of monitoring is considered when all other
a central monitoring site (healthcare provider) investigation results are inconclusive.
for validation and analysis. Recently, a new Other tests to identify the presence of SND
generation of event recorder smartphone- may include the exercise testing and intracardiac
based device has been launched for this pur- electrophysiologic tests.
pose (AliveCor). However, this type of Exercise testing may confirm the diagnosis of
monitoring has several limitations because its chronotropic incompetence but is not useful for
useless in patients with syncope or short detecting the arrhythmias that occur in SSS.
arrhythmias and has no pre-event data. Electrophysiological study (EPS) may be
External loop recorders (looping memory sys- sometimes helpful in patients with highly sus-
tem or continuous loop recorder) are devices pected SSS and no symptom-rhythm correlation
connected continuously to the patient by demonstration after prolonged cardiac monitor-
means of skin ECG electrodes and equipped ing. It is no longer routinely recommended for
with a memory loop. The device has a built-in diagnosis because of its poor sensitivity and
looping memory in which the ECG signal is specificity (about 50 %) [25]. The two most
ERRNVPHGLFRVRUJ
262 A. Romandini and L. Scappini
common EPS tests for sinus node function severity and frequency of symptoms and the
measure are: overall clinical risk stratification.
D. In a symptomatic patient in whom ECG
1. The sinus node recovery time (SNRT), i.e., the events compatible with SSS fail to correlate
time taken for the sinus rhythm to resume with symptoms, consider implantable loop
after 30 s or 1 min of overdrive atrial pacing. recorder or additional laboratory testing
This interval is measured in the high lateral (exercise stress testing, electrophysiological
right atrium from the last paced beat to the study, carotid sinus massage, tilt test).
first spontaneous sinus beat. This test is based
on the assumption that automaticity sup-
pressed by overdrive recovers less rapidly Treatment
when the SA node is dysfunctional, so the lon-
ger the sinus node takes to recover, the more Nowadays there are no medications that reliably
abnormal sinus node function is evident. Its increase the heart rate in patients with bradyar-
poor diagnostic yield may be due to the fact rhythmias. Cardiac pacing therapy through an
that sinus recovery time is a more complex artificial pacemaker is the only choice.
event and many factors besides automaticity As discussed above, early identification of a
are involved. A delay of longer than 1500 ms potential reversible cause is the first step of
is abnormal. The corrected value (CSNRT) treatment. Discontinuation or dose reduction of
can be determined by subtracting the intrinsic nonessential concomitant drugs affecting sinus
sinus cycle length from the SNRT value: val- node function is recommended to see whether
ues longer than 550 ms suggest sinus node normal sinus function returns. All other medical
dysfunction. conditions which may precipitate the SSS should
2. The other EPS test for sinus node function be treated.
measure is the sinoatrial conduction time If bradyarrhythmia persists, indications for
(SACT) used for detecting delayed conduc- cardiac pacing therapy should be evaluated. The
tion between the sinus node and surrounding cause-effect correlation between symptoms and
atrial tissue. This technique involves resetting bradyarrhythmias is an essential critical step
the sinus node by an eight-beat period of atrial when positive effects of pacemaker placement
pacing at rates just above sinus (Narula proto- are evaluated. Indeed, there is no evidence that
col): the difference between the post-pacing cardiac pacing prolongs survival in patients with
pause and the sinus cycle length would equal SND [2628]. The primary goals of pacemaker
to the SACT. SACT values greater than placement are symptom relief and improved
120 ms are considered abnormal. quality of life.
However, in clinical practice some patients
Our approach to the diagnosis of SSS is sum- affected by sinus node disease may not have a
marized as follows: clear symptom-ECG correlation because of the
slow and erratic course of syndrome and frequent
A. Perform a comprehensive history and physi- comorbidities. In such circumstances, in the
cal examination. absence of other symptoms clearly attributable to
B. Carefully review for systemic conditions and SND, the mechanism of intermittent clinical
medications used as potential remediable significant events like syncope remains uncertain
causes for apparent SSS. as other competitive causes (e.g., autonomic dys-
C. Obtain a resting ECG and if nondiagnostic function) may play an important role. From a
proceed with in-hospital telemetry or ambu- practical perspective, when a competitive
latory ECG monitoring to identify episode of diagnosis can be ruled out (after head-up tilt
bradycardia and eventually correlated symp- testing, carotid sinus massage, and eventually an
toms. The type of monitoring depends on the EPS excluding a very prolonged csnrt, i.e.,
ERRNVPHGLFRVRUJ
22 Sinoatrial Exit Block 263
Table 22.1 The following table is a summary of the main recommendations in the European Society of Cardiology
guidelines on cardiac pacing (ESC guidelines on cardiac pacing 2013)
Recommendations Class Level
Pacing is indicated when symptoms can clearly be attributed to persistent bradycardia or to I B
documented (intermittent) sinus arrest or sinoatrial block
Pacing may be indicated when symptoms are likely to be due to bradycardia, even if the IIb C
evidence is not conclusive
Pacing is not indicated in patients with bradycardia which is asymptomatic or due to III C
reversible causes
Dual-chamber pacing mode with preservation of spontaneous AV conduction is indicated I A (vs. VVI)
for reducing the risk of AF and stroke, avoiding PM syndrome and improving quality of life B (vs. AAI)
>800 ms), cardiac pacing may be reasonable in 4. Oreto G (1997) I disordini del ritmo cardiaco. 2nd
patients with syncope and intrinsic node disease edition. Torino: Centro Scientifico Editore
5. Rubenstein JJ et al (1972) Clinical spectrum of the
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Table 22.1 lists the latest practice recommen- cardia and tachycardia. Br Heart J 16:208
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Coexistence of sick sinus rhythm and atrial flutter-
Society of Cardiology task force on cardiac fibrillation. Circulation 63:8086
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45:2630 26. Alboni P, Menozzi C, Brignole M et al (1997) Effects
19. Coma Samartin R, Sancho-Tello de Carranza MJ, of permanent pacemaker and oral theophylline in sick
Ruiz Mateas F et al (2011) Spanish pacemaker regis- sinus syndrome the THEOPACE study: a randomized
try. Eighth official report of the Spanish Society of controlled trial. Circulation 96(1):260266
Cardiology Working Group on Cardiac Pacing (2010). 27. Shaw DB, Holman RR, Gowers JI (1980) Survival in
Rev Esp Cardiol 64:11541167 sinoatrial disorder (sick-sinus syndrome). Br Med J
20. Cunningham D, Charles R, Cunningham M, de Lange 280:139141
A (2010) Cardiac rhythm management: UK National 28. Sutton R, Kenny RA (1986) The natural history of
Clinical Audit. http://www.ucl.ac.uk/nicor/audits/car- sick sinus syndrome. Pacing Clin Electrophysiol
diacrhythmmanagement/publicreports/pdfs/ 9:11101114
Heartrhythm10 29. Nielsen JC, Thomsen PE, Hojberg S et al (2011) A
21. Markewitz A (2010) The German Pacemaker Register. comparison of single-lead atrial pacing with dual-
Herzschrittmacherther Elektrophysiol 21:248255 chamber pacing in sick sinus syndrome. Eur Heart J
22. Proclemer A, Ghidina M, Gregori D et al (2010) 32:686696
Trend of the main clinical characteristics and pacing 30. Andersen HR, Thuesen L, Bagger JP et al (1994)
modality in patients treated by pacemaker: data from Prospective randomised trial of atrial versus ventricu-
the Italian Pacemaker Registry for the quinquennium lar pacing in sick-sinus syndrome. Lancet
200307. Europace 12:202209 344:15231528
23. Swedish ICD and Pacemaker Register (2010) Annual 31. Castelnuovo E, Stein K, Pitt M et al (2005) The effec-
statistical report 2010. www.pacemakerregistret.se tiveness and cost-effectiveness of dual-chamber pace-
24. Tuppin P, Neumann A, Marijon E et al (2011) makers compared with single-chamber pacemakers
Implantation and patient profiles for pacemakers and for bradycardia due to atrioventricular block or sick
cardioverter defibrillators in France (20082009). sinus syndrome: systematic review and economic
Arch Cardiovasc Dis 104 evaluation. Health Technol Assess 9:iii, xixiii, 1246
25. Brignole M, Auricchio A, Baron-Esquivias G et al 32. Nielsen JC, Kristensen L, Andersen HR et al (2003) A
(2013) Guidelines on cardiac pacing and cardiac randomized comparison of atrial and dual-chamber
resynchronization therapy: the task force on car- pacing in 177 consecutive patients with sick sinus
diac pacing and resynchronization therapy of the syndrome: echocardiographic and clinical outcome. J
European Society of Cardiology (ESC). Developed in Am Coll Cardiol 42:614623
ERRNVPHGLFRVRUJ
Atrioventricular Blocks
23
Andrea Romandini and Marco Morelli
Allergies
Medical History and Cardiovascular
Risk Factors None
ERRNVPHGLFRVRUJ
266 A. Romandini and M. Morelli
General appearance: well developed, well ECG (Fig. 23.1a, b) shows a third-degree
nourished, alert, and cooperative atrioventricular block with slow ventricular
Lungs: clear to auscultation and percussion escape rhythm (35 bpm); There is a clear atrio-
without rales, rhonchi, wheezing, or dimin- ventricular dissociation with atrial rate faster
ished breath sounds than the ventricular. QRS has a left bundle branch
Cardiovascular: Normal S1 and S2. No S3, block (LBBB) pattern.
S4, or murmurs. Regular bradycardic rhythm.
No peripheral edema, cyanosis, or pallor. Echocardiogram showed normal dimensions
Warm and well-perfused extremities and function of cardiac chambers (ejection frac-
Abdomen: Positive bowel sounds. Soft, non- tion 5560 %), aortic valve prosthesis normally
distended. No guarding or rebound. No masses functioning, mild mitral regurgitation, and mild
tricuspid regurgitation with a normal pulmonary
artery systolic pressure.
Routine Laboratory Tests
a b
Fig. 23.1 (a, b) A third-degree atrioventricular block the ventricular rate is clearly visible. QRS has a left
with slow ventricular escape rhythm (35 bpm) is shown. bundle branch block (LBBB) pattern
Atrioventricular dissociation with atrial rate faster than
ERRNVPHGLFRVRUJ
23 Atrioventricular Blocks 267
a b
Fig. 23.2 (a) Atrial flutter with third-degree atrioventricular block and junctional escape rhythm. (b) The same patient
after cardioversion: sinus rhythm with AV dissociation is shown
ERRNVPHGLFRVRUJ
268 A. Romandini and M. Morelli
or more consecutive impulses. Retrograde con- group) is longer than the cycle preceding the
duction can occur in the presence of anterograde blocked impulse [5].
AV block [1, 2]. Type II AV block is often a precursor of syn-
cope and complete AV block, because it is more
likely to be sub-Hisian. Type I AV block with a
First-Degree AV Block normal QRS complex generally does not prog-
ress to more advanced forms of AV conduction
During first-degree AV block, every atrial impulse disturbances. In elderly people, type I AV block
conducts to the ventricles and a regular ventricu- may be associated with a clinical course similar
lar rate is present. The prolonged PR interval to that seen in type II.
exceeds 200 ms in adults. The conduction delay In the acute coronary syndromes (ACS), type
can be located within the AV node (AH interval I AV block generally develops with inferior
prolonged), in the HisPurkinje system (HV infarction, is transient, and does not require tem-
interval prolonged), or both. If the QRS complex porary pacing [4].
has a normal width, the AV delay most likely Type II AV block occurs usually in the setting
resides within the AV node and rarely within the of an anterior myocardial infarction, can require
His bundle. On the contrary, if the QRS has a temporary or permanent pacing, and is associated
bundle branch block pattern, the conduction with a high mortality rate.
delay may be within the AV node or HisPurkinje A high-degree AV block can occur also in
system as well. Enhancement of vagal tone by patients with acute inferior myocardial infarction
carotid massage can cause first-degree AV nodal (MI) and is associated with an extended myocar-
block to progress to type I second-degree AV dial damage and a higher mortality rate than
block [2]. those without AV block. All types of AV blocks
in the setting of an acute MI can be reversible
within 1421 days.
Second-Degree AV Block In type I AV block with a normal QRS dura-
tion, the conduction delay is likely to be at the AV
In second-degree AV block, the nonconducted P node level proximal to the His bundle. A type I
wave can be intermittent and the preceding PR intra-Hisian block is uncommon. Type II AV
interval duration may be fixed or prolonged. In block, particularly in association with a bundle
this type of block, the PQRS relationship is not branch block, may be localized within or below
random. Mobitz type I (LucianiWenckebach) is the HisPurkinje system. Type I AV block in a
characterized by progressive PR prolongation patient with a bundle branch block can be caused
until a nonconducted P wave. In contrast, in by a block in the AV node or in the HisPurkinje
Mobitz type II, the PR interval remains constant system as well [2].
before a P wave is blocked [3, 4]. Type 2:1 AV block can be due to type I or type
During Mobitz type I block, the conduction II AV block.
time delay is longer in the second beat of the Abrupt transient alterations in autonomic tone
Wenckebach group; meanwhile, prolonged con- can also cause sudden block of one or more P
duction time decreases progressively in the sub- waves without altering the PR interval of the con-
sequent beats. The consequence is that the ducted P wave before or after the block. Such
interval between the successive beats progres- condition is a typical normal finding at night dur-
sively decreases, although the conduction time ing sleep. Thus, apparent type II AV block would
increases. The RR interval produced by the block be produced at the AV node. Increased vagal
is shorter than the double of the RR interval that tone, producing an AV block, usually lengthens
precedes the block impulse (the shortest inter- the PP interval at the same time [4].
val). The RR interval that follows the noncon- Vagal stimulation generally increases and
ducted beat (the first beat of the new Wenckebach vagolytic agents decrease the extent of type I AV
ERRNVPHGLFRVRUJ
23 Atrioventricular Blocks 269
block. Atropine can minimally improve conduc- lar rate is less than 40 beats/min. A hereditary
tion in the AV node and markedly faster sinus form caused by degeneration of the His bundle
rate, which may result in higher AV block degree. and bundle branches has been linked to the
Counterwise, carotid sinus massage generally SCN5A gene [2].
improves and atropine worsens AV conduction in Paroxysmal AV block can be caused by a too
patients with a conduction block within or below strong response of the AV node to vagotonic
the His bundle. reflexes. Surgery, electrolyte disturbances, myo-
Similarly, exercise or isoproterenol by increas- endocarditis, tumors, Chagas disease, rheumatoid
ing the sinus rate and improving AV conduction nodules, calcific aortic stenosis, myxedema, poly-
may resolve the supra-Hisian block and impair myositis, infiltrative processes (e.g., amyloidosis,
sub-Hisian one [2]. sarcoidosis, scleroderma), and many other com-
First-degree and type I second-degree AV mon and unusual conditions can produce AV
block can occur in normal healthy children; a block.
Wenckebach AV block can be also normal in In children, the most common cause of AV
well-trained athletes, probably related to a higher block is congenital. Children are most often
vagal tone at rest. asymptomatic, but in some cases symptoms
develop and pacemaker implantation becomes
necessary. Mortality from congenital AV block is
Third-Degree AV Block highest in the neonatal period, decreases during
childhood and adolescence, and increases slowly
In the total AV block, no atrial activity is con- later. Syncope can occur in patients with congen-
ducted to the ventricles; the atria and ventricles ital heart block at any age. It is difficult to predict
are controlled by independent pacemakers the prognosis. A persistent heart rate at rest of
(atrioventricular dissociation) [4]. The atrial 50 beats/min or less correlates with the incidence
pacemaker can be sinus or ectopic (tachycardia, of syncope in children with congenital complete
flutter, or fibrillation) (Fig. 23.4). AV block [2].
Complete AV block may arise at AV node
level (usually congenital), within the bundle of
His, or distally below the His (usually acquired). The association of a long PR plus a right
The ventricular focus that arise below the bundle branch block and left anterior hemi-
region of the block. Sites of ventricular pacemaker block is called bifascicular block.
activity that are in or closer to the His bundle are
more stable and can produce a faster escape rate
than those located distally in the ventricular con-
duction system. The ventricular escape rate in General Management
acquired total heart block is less than 40 beats/
min but can be faster in congenital complete AV First- or second-degree AV blocks are usually
block [5]. asymptomatic. Sometimes clinical manifesta-
Blocks proximal to the His bundle generally tions of first- and second-degree AV block consist
exhibit normal QRS complexes and rates of of palpitations or subjective feelings of the hearts
4060 beats/min. missing a beat. Persistent 2:1 AV block can
In patients with AV nodal block, atropine usu- produce symptoms of chronic bradycardia.
ally speeds both atrial and ventricular rates. Complete AV block can be accompanied by signs
Exercise can reduce the extent of AV nodal block. and symptoms of reduced cardiac output, syn-
An acquired complete AV block is more often cope or presyncope, angina, or palpitations from
distal to the bundle of His because of trifascicular ventricular tachyarrhythmias [2].
conduction disturbance. The QRS complex is Death in patients with untreated atrioventricu-
abnormal (wide QRS complex), and the ventricu- lar (AV) block is due not only to heart failure
ERRNVPHGLFRVRUJ
270 A. Romandini and M. Morelli
Fig. 23.4 The ventricular rate arise below the region of the block. The atrial pacemaker can be (a) ectopic (tachycardia,
flutter, or fibrillation) or (b) sinus
(HF) secondary to low cardiac output but mainly During early in-hospital phase, when conduc-
to sudden cardiac death caused by prolonged tion blocks are likely to be evanescent, vagolytic
asystole or bradycardia-triggered ventricular agents (such as atropine) are useful for patients
tachyarrhythmia [3]. who have AV nodal disturbances, whereas cate-
ERRNVPHGLFRVRUJ
23 Atrioventricular Blocks 271
cholamines (such as isoproterenol) can be used The diagnosis of AV block is usually made
transiently to treat patients who have heart block from standard ECG when persistent. Prolonged
at any site. Isoproterenol should be used with electrocardiogram monitoring strategy [standard
extreme caution in patients who have acute myo- 24 h Holter ECG or implantable loop recorder
cardial infarction. The use of transcutaneous or (ILR)] may be needed to diagnose an intermittent
temporary transvenous pacing is preferable [2]. AV block (Table 23.1). When an AV block is
For symptomatic AV block or high-grade AV suspected but not documented, provocative
block (e.g., infra-Hisian, type II AV block, third- testing or an electrophysiological study (EPS)
degree heart block not caused by congenital AV may also be needed (Table 23.2). Since there is
block), permanent pacemaker is the treatment of no defined heart rate below which treatment is
choice. indicated, correlation between symptoms and
bradyarrhythmia is essential to give the indica-
tion for permanent cardiac pacing.
23.3 Guidelines Tilt table testing and carotid sinus massage are
indicated when reflex syncope is suspected in the
Diagnosis setting of an atypical presentation. Exercise
testing is indicated in patients who experience
Early identification of a potentially reversible syncope during or shortly after exertion.
cause (drug effects, acute myocardial infarction,
intoxication, electrolyte disorders) is the first step
toward treatment.
As long as the stroke volume increases in
Table 23.1 Prolonged electrocardiogram monitoring strat-
order to compensate for the decrease in heart egy (standard 24 h Holter ECG or implantable loop recorder)
rate, patients with bradycardia can remain com- may be needed to diagnose an intermittent AV block
pletely asymptomatic. First-degree AV block and Prolonged
type I second-degree AV block with marked PR electrocardiogram
prolongation (0.3 s) can lead to symptoms, monitoring strategy Provocative test strategy
because atrial contraction occurs very early in Holter Carotid sinus massage
diastole overlapping with early diastolic filling External loop recorder Tilt table test
and diastolic mitral regurgitation may occur Remote at-home Electrophysiological study
telemetry
between the end of atrial filling and the onset of
Implantable loop Exercise test
ventricular contraction. recorder
While the permanent forms of AV blocks are
caused by an intrinsic disease of the AV conduc-
tion system, the etiology of intermittent block Table 23.2 When an AV block is suspected but not docu-
can be difficult to determine. The diagnosis of mented, provocative testing or an electrophysiological
intermittent AV block is often only presumed but study (EPS) may also be needed
not documented by ECG [6]. Frequency of Suggested ECG monitoring
AV block can be asymptomatic in young, symptoms technique
healthy individuals or during sleep, but patients Daily 24 h Holter, in-hospital
telemetric monitoring
with sustained or frequent bradyarrhythmia are
Every 23 days 4872 h Holter, in-hospital
often symptomatic (e.g., easy fatigability,
telemetric monitoring
reduced exercise capacity, symptoms of HF, irri- Every week 7day Holter or external loop
tability, lassitude, and inability to concentrate). recorder
Dizziness, presyncope, and syncope, due to a Every month 1430-day external loop
sudden decrease in cerebral blood flow, are com- recorder
mon symptoms with intermittent severe forms of Less than once per Implantable loop recorder
AV block. month
ERRNVPHGLFRVRUJ
272 A. Romandini and M. Morelli
ERRNVPHGLFRVRUJ
23 Atrioventricular Blocks 273
Electrophysiological study (EPS) should mea- BBB, unexplained syncope, and abnor-
sure the Hisventricular (HV) interval at baseline mal EPS: Pacing is indicated in patients
and during stress by incremental atrial pacing. with syncope, BBB, and positive EPS
The progression rate to AV block at 4 years was defined as interval of 70 ms, or sec-
4 % in patients with HV interval <70 ms, 12 % ond- or third-degree HisPurkinje block
in those with HV interval of 70100 ms, and demonstrated during incremental atrial
24 % in those with HV interval >100 ms. The pacing or with pharmacological stress
development of intra- or infra-His block at incre- (I; B).
mental atrial pacing is highly predictive of Alternating BBB: Pacing is indicated in
impending AV block but is rarely observed [3]. patients with alternating BBB with or
In patients with unexplained syncope and without symptoms (I; C).
bifascicular block, EPS is highly sensitive in BBB, unexplained syncope, and nondi-
identifying patients with intermittent or impend- agnostic investigations: Pacing may be
ing high-degree AV block, though a negative considered in selected patients with
electrophysiological investigation cannot rule out unexplained syncope and BBB [old
intermittent/paroxysmal AV block as the cause of patients with unpredictable (no or very
syncope. Indeed, in patients with negative elec- short prodromes) and recurrent syncope
trophysiological studies, intermittent or stable that expose them to high risk of trau-
AV block was still documented by ILR in about matic injury] (IIb; B).
50 % of cases [3]. Asymptomatic BBB: Pacing is not indi-
The alternating bundle branch block is defined cated for BBB in asymptomatic patients
as block in all three fascicles detected on succes- (III).
sive ECGs: right bundle branch block (RBBB)
and left bundle branch block (LBBB) or RBBB
with associated left anterior fascicular block on
one ECG and associated left posterior fascicular Choice of Pacing Mode
block on another ECG]. These patients progress
quickly toward complete AV block. Therefore, a Dual-chamber pacing is superior over ventricular
PM is usually implanted as soon as possible, even pacing as regards symptom improvement, while
in the absence of a history of syncope [3]. there is evidence of non-superiority about sur-
Only half of patients with unexplained syn- vival and morbidity (hospitalization, HF). On the
cope, basal bundle branch block, and nondiag- other hand, bicameral pacing increases complica-
nostic investigations had a documented AV block tion risk and costs [3].
ERRNVPHGLFRVRUJ
274 A. Romandini and M. Morelli
References
Acquired AV block: In patients with sinus
rhythm, dual-chamber PM should be 1. Lee S, Wellens HJ, Josephson ME (2009) Paroxysmal
preferred over single-chamber ventricular atrioventricular block. Heart Rhythm 6(8):12291234
2. Bonow RO, Mann DL (2012) Braunwalds Heart
pacing for avoiding PM syndrome and Disease: a textbook of cardiovascular medicine. 9th
improving quality of life [IIa; A]. edition. Philadelphia: Saunders; pp 818823
3. Brignole M, Auricchio A, Baron-Esquivias G,
Bordachar P, Boriani G, Breithardt OA, Cleland J,
Deharo JC, Delgado V, Elliott PM, Gorenek B, Israel
CRT should be considered if clinical symp- CW, Leclercq C, Linde C, Mont L, Padeletti L, Sutton
toms of HF (NYHA IIIII), a wide QRS complex R, Vardas PE (2013) ESC guidelines on cardiac pacing
(>120 ms with appearance left BBB like), and a and cardiac resynchronization therapy: the task force
on cardiac pacing and resynchronization therapy of
severely reduced LVEF (<35 %) are present [3]. the European Society of Cardiology (ESC). Developed
It is advisable that mode-switch algorithm be in collaboration with the European Heart Rhythm
activated; episodes of AF during follow-up Association (EHRA) 15(8):10701118
should be assessed (to anticoagulant therapy). 4. Pietro D (2008) Aritmie. Fisiopatologia e diagnosi.
Roma: Cesi editor: 6567
In patient with AF associated with AV block, 5. Rolands DJ (2004) Interpretazione dellelettro-
rate-responsive pacing is associated with better cardiogramma. Treviso: Pro.med editor: 502547
exercise performance, improved daily activities, 6. El-Sherif N, Jalife J (2009) Paroxysmal atrioventricu-
decreased dyspnea, reduced chest pain and palpi- lar block: are phase 3 and phase 4 block mechanisms
or misnomers? Heart Rhythm 6(10):15141521
tations, and improved quality of life, compared
with fixed-rate pacing [3].
ERRNVPHGLFRVRUJ
Part VIII
Channelopathies
ERRNVPHGLFRVRUJ
Brugada Syndrome
24
Alessandro Barbarossa and Giulia Pongetti
24.1 Case Report The patient had a previous (5 years ago) syn-
copal episode also at rest, without prodromes,
that was not deeply evaluated.
A 35-year-old man was referred to the
emergency room (ER) for acute syncope, at
rest, during a febrile state. Its onset was Allergies
sudden and without any prodromic symp-
tom or convulsion. There was a rapid None
recovery of consciousness without any
neurological impairment and loss of urine.
The patient was admitted to our hospital for Medications
further investigations.
None
Physical Examination
A. Barbarossa (*) G. Pongetti
Clinica di Cardiologia e Aritmologia, Universit General: No acute distress, alert, awake, and well
Politecnica delle Marche, oriented. Normally developed and nourished
Via Conca, 71, Ancona 60126, Italy Head, eyes, ears, nose, and throat: Normo-
e-mail: alessandro.barbarossa@hotmail.it; cephalic, atraumatic, mucous membranes moist,
giuliapongetti@gmail.com
ERRNVPHGLFRVRUJ
278 A. Barbarossa and G. Pongetti
extraocular muscles intact, pupils equally round tion) and the patient was at rest and did not
and reactive to light and accommodation complain of any prodromic symptom (like
bilaterally, bilateral tympanic membrane intact, dizziness, headache, sweating, pallor, and nau-
bilateral sclera anicteric, and no conjunctival sea). Syncope due to orthostatic hypotension
injection seems also unlikely because he was sitting when
Neck: Supple, no jugular venous distention, no the episode occurred; moreover, he was not tak-
lymphadenopathy, and no carotid bruit ing any drug therapy.
Cardiovascular: Regular rate and rhythm; S1 A neurogenic cause of the loss of conscious-
and S2 are normal; no murmurs, rubs, or gal- ness (like epilepsy) could be a possible hypothe-
lops; point of maximal intensity non-displaced sis if we consider the young age and the sudden
and non-sustained; no hepatojugular reflux; onset, but the absence of other signs (tongue bite,
and capillary refill less than 2 s tonic-clonic seizures, typical aura, urinary incon-
Lungs: No rales, rhonchus, or wheezes; no tinence, rapid recover without neurological
egophony; no alterations in tactile fremitus; impairment) made it less likely.
and normal percussion According to these clinical features, cardiac
Abdomen: Mild overweight, no pulsatile masses, syncope was the most likely diagnosis. ECG and
normal bowel sounds in all four quadrants, no echocardiogram were performed during hospital-
high-pitched or tinkling sounds, resonant to per- ization together with routine laboratory tests.
cussion, soft, non-distended/non-tender, no
rebound or guarding, no costovertebral angle
tenderness, and no hepatosplenomegaly ECG (Fig. 24.1)
Extremities: No cyanosis or clubbing and mild
peripheral edema Sinus rhythm, heart rate 95 bpm, normal atrio-
Neurological: Cranial nerve II through XII ventricular conduction (PQ 150 ms), cardiac
intact and no focal deficit electrical axis +60, and coved-type ST-segment
Psychiatric: Normal affect, no hallucinations, elevation about 4 mm, followed by a negative T
normal speech, and no dysarthria wave in V1 and an ST-segment elevation with a
Skin: Intact, warm, no rashes, and no lesions saddleback appearance in V2 with a biphasic T
wave. QTc 450 ms
ERRNVPHGLFRVRUJ
24 Brugada Syndrome 279
Normal diastolic pattern without increased Inflammation index: VES 30 mm/h (n.v
filling pressure (E/A 0.8, E/E 3.7, E dec time <27 mm/h) and CRP 0.9 mg/dl (n.v <0.6 ng/ml)
193 m/s).
What Are the Possible Causes
Conclusion There are normal echocardiography of Cardiac Syncope?
findings for a 35-year-old man.
Arrhythmia
ERRNVPHGLFRVRUJ
280 A. Barbarossa and G. Pongetti
ERRNVPHGLFRVRUJ
24 Brugada Syndrome 281
Epidemiology
ECG Patterns
Prevalence of type 1 Brugada ECG pattern ranges
Initial classification considered three main ECG from 0.012 to 1.0 % in different population regis-
patterns [4], but in the last consensus, this classi- tries [810]. A meta-analysis reports an event
fication was changed unifying types 2 and 3 into rate of 10 % at 2.5 years in patients with type 1
a unique pattern (Fig. 24.2) [5]: ECG pattern [11].
ERRNVPHGLFRVRUJ
282 A. Barbarossa and G. Pongetti
Genetic Brugada syndrome demonstrates the syndrome are sudden cardiac arrest or syncope
autosomal dominant inheritance with variable (due to a tachyarrhythmia). Palpitations are rare
expression of mutation in the cardiac sodium and usually are caused by an episode of atrial fibril-
channel genes (mainly SCN5A) [12]. The lation that is common in Brugada syndrome [18].
ST-segment elevation and T wave inversions seen
in the right precordial leads seem to be due to a Sudden cardiac arrest (SCA) and syn-
different length of the action potentials in the epi- cope One-third of patients have SCA or syncope
cardial compared to the endocardial cells of the as the first manifestation of Brugada syndrome.
right ventricle [3, 13]. Usually these manifestations are more common
during the night and during sleep but not during
Arrhythmias The cells with impaired sodium physical exercise [19].
channel function may fail to propagate the action
potential, resulting in localized conduction Atrial fibrillation Patients with Brugada have an
blocks. Due to the abbreviation of phase two, increased incidence of atrial fibrillation (1020 %).
these cells have a much shorter refractory period Its presence has been associated also with an
and recovery of excitability compared to the sur- increased risk of ventricular fibrillation (VF) [20].
rounding cells. This combination (short refrac-
tory periods and localized conduction blocks) Nocturnal agonal respiration As abovemen-
provides the substrate for localized reentry (phase tioned, ventricular arrhythmias are frequent dur-
2 reentry) between epicardium and endocardium ing sleep; the clinical manifestation of these
as arrhythmia substrate [14]. arrhythmias may be nocturnal agonal respiration
associated with a gasping breath.
Structural abnormalities Historically, Brugada
syndrome is not associated with structural heart
disease. However, new evidence suggests the pres- Diagnosis and Risk Stratication
ence of microscopic area of fibrosis in the right
ventricular output tract (RVOT). Nevertheless, Drug Challenge
further investigations in this filed are necessary. In patients with type 2 Brugada pattern, a type 1
pattern may be unmasked by sodium channel
Fever Data from a retrospective review of blocker drugs (e.g., flecainide, procainamide,
patients with Brugada syndrome suggest that ajmaline). The importance of unmasking the type
fever is a main trigger for ECG changes and also 1 Brugada ECG pattern relates to its relevance in
possibly cardiac arrest [15]. confirming the diagnosis of Brugada syndrome,
particularly in patients without symptoms [4]. The
Autonomic tone An imbalance between sympa- test may be useful in patients with type 2 pattern,
thetic and parasympathetic activation seems to be asymptomatic, and with familiar history for SCD.
also present in the Brugada syndrome, as sug-
gested by frequent nocturnal occurrence of the Flecainide: 2 mg/kg over 10 min
tachyarrhythmias (torsades de pointes) and ST intravenously
elevation occurrence during the recovery phase Procainamide: 10 mg/kg over 10 min
of exercise tests (vagal rebound) [16, 17]. intravenously
Ajmaline: 1 mg/kg over 10 min intravenously
ERRNVPHGLFRVRUJ
24 Brugada Syndrome 283
an area of investigation and debate in which there Class IIb: ICD implantation may be considered
is discordant evidence [21, 22]. Despite this, 2005 in patients with a diagnosis of Brugada syn-
guidelines recommended EPS test in asymptom- drome who develop VF during programmed
atic patients with type 1 pattern [4]. A recent electrical stimulation (inducible patients).
study founded a short refractory period recovery Class III: ICD implantation is not indicated in
(<200 ms) as an adjunctive parameter to possibly asymptomatic patients with a drug-induced
indicate an ICD implantation [21]. type 1 ECG and on the basis of a family his-
tory of SCD alone.
Genetic Testing [12]
Comprehensive or BrS1 (SCN5A) targeted Pharmacological therapy plays a marginal role
BrS genetic testing can be useful particularly in Brugada syndrome; quinidine has been shown
for the patients in which there is a clinical to prevent induction of VF and suppress spontane-
index of suspicion for BrS based on examina- ous ventricular arrhythmias in a clinical setting.
tion of the patients clinical history, family However, quinidine is recommended only as [23]:
history, and expressed electrocardiogram
(resting 12-lead ECGs and/or provocative Class IIa: patients with ICD and multiple shocks
drug challenge testing). Class IIa: patients with contraindication to ICD
Genetic testing is not indicated in the setting
of an isolated type 2 Brugada ECG pattern. Conclusions
Brugada syndrome is one possible cause of
Prognostic Factors SCD in the young population with an incidence
The major risk factor for patients with the Brugada that is probably underestimated. ECG is funda-
ECG pattern is a history of ventricular tachyar- mental for diagnosis; however, it is important to
rhythmias leading to SCA or syncope; these remember that the typical pattern may not
patients should be considered at high risk [4, 22]. always be founded in all the consecutive ECGs
Atrial fibrillation, positive familiar history for in the same subject, because it can vary in rela-
SCD, and male gender are less powerful predic- tion to different environmental conditions.
tors of future events. About risk stratification, medical history plays
a central role because history of syncope or
SCA is so far the only major risk criteria.
Treatment ICD implantation is the only effective
therapy for these patients at the moment.
To date, the only proven effective therapeutic S-ICD could be chosen because of the exter-
strategy for the prevention of SCD in BrS patients nal lead in a relative young patient not needing
is the implantable cardioverter defibrillator ATP therapy or cardiac pacing.
(ICD), and this therapy is principally guided by
the clinical history.
Recommendation [23] are as follows: References
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New electrocardiographic leads and the procainamide 14. Aiba T, Shimizu W, Hidaka I, Uemura K, Noda T,
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pubmed/18355654 med/23916535
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Long QT Syndrome
25
Maria Vittoria Matassini and Alessandro Maolo
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288 M.V. Matassini and A. Maolo
Fig. 25.1 Holter ECG recording showing a torsade de pointes. The smaller trace below shows the spontaneous sinus
rhythm recovering
ERRNVPHGLFRVRUJ
25 Long QT Syndrome 289
a b
Fig. 25.2 (a, b) Standard rest 12-lead ECG showing a prolonged QT interval (600 ms)
showed a prolonged QT interval. They both were ECG with or without T wave [1]. These abnormal-
not taking any medications which could alter the ities of ventricular repolarization can be present in
QT interval, and laboratory findings did not show other family members of the affected subject.
electrolyte abnormalities. The natural history of LQTS is characterized
by the development of life-threatening ventricu-
lar arrhythmias such as torsade de pointes (TdP).
Final Diagnosis This arrhythmia can be self-limiting and asymp-
tomatic or they can manifest with syncope or
These findings altogether were suggestive for sudden cardiac death (SCD) [2].
hereditary long QT syndrome. Genetic assessments The prevalence of this genetic disorder is esti-
were therefore performed and it is still underway. mated to be at least 1:5,000 subjects. Considering
that the affected subject can be asymptomatic and
there are cases of sudden cardiac death with no
25.2 Long QT Syndrome defined etiology, the real prevalence of LQTS
may be considerably higher [1, 2].
Epidemiology Moreover, 1040 % of affected patients pres-
ent a nondiagnostic QT interval at rest because of
Hereditary long QT syndrome (LQTS) is a con- an intermittent nature of the ECG abnormalities
genital disorder characterized by a prolongation of or a borderline QT value that make the diagnosis
the QT interval detectable on the standard 12-lead challenging [3].
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290 M.V. Matassini and A. Maolo
Long QT syndrome more often manifests feet, phenotype known as Timothy syndrome
before puberty in males and after puberty in (LQT8)
females, and the probability of a cardiac event Cavelolin-3 gene, with increase in late sodium
depends on the degree of QT prolongation. current (LQT9)
Among untreated symptomatic patients, mor- SCN4B gene, with increase in late sodium
tality is high, with 20 % of deaths in the first year current (LQT10)
after the first cardiac event and approximately
50 % within 10 years [2]. In addition, 1520 % of affected patients pres-
ent a negative genetic assessment.
The majority of LQTS is inherited as an autoso-
Pathophysiology mal dominant trait: the Romano-Ward syndrome
affects 1 per 5,000 persons. Sporadic (or de novo)
Since the discovery of the first LQTS-responsible alterations occur 510 % of the time. The autosomal
genes in 1990s, a lot more genes have been recessive form of LQTS, also known as Jervell and
related to the syndrome and more than 500 muta- Lange-Nielsen syndrome, was firstly described in
tions are described nowadays, resulting in 10 dif- 1957. It probably affects less than 1 per million peo-
ferent phenotypes (LQTS 110). ple and results from complete loss of Kv7.1 channel
In about 75 % of patients, mutations involve function, which precipitates sensorineural deafness
three main causative genes: in addition to LQT1 or LQT5 mutation [2, 4].
II
aVF
V5
Fig. 25.3 Distinctive ECG patterns of the three main LQTS genotypes. (With permission from Prof. Arthur Moss with
the consens of the original publisher (Circulation))
findings have consistent clinical implications and Moreover, every genotype has a different
explain why these patients have less or no benefit response to exercise. LQT1 patients fail to appro-
at all from beta-blocker therapy. priately shorten their QT interval during exercise
Age of first manifestations varies from one and QTc may further lengthen. This effect is due
genotype to another. In fact, generally, the age of to IKs that in normal subjects is responsible for
first events is lower in LQT1 than in LQT2 and the abbreviation of the action potential at higher
LQT3 [4]. heart rates. On the contrary, patients with LQT3
Some differences can be noticed on the stan- show shortening of QT interval during exercise.
dard 12-lead ECG too. Each one of the three In LQT2, QTc duration behavior is variable [4].
major genotypes (LQT1 to LQT3) seems to have Finally, LQT1 patients have a peculiar response
a distinctive T-wave repolarization pattern on the to epinephrine. Epinephrine infusion has an excel-
ECG, as shown in Fig. 25.3. lent performance in the detection of LQTS1
because it provokes a significant and stable pro-
longation of the QTc in these patients [10, 12].
LQT1: T waves are broad-based with a Table 25.1 shows the characteristics of differ-
high amplitude. ent genotypes of LQTS.
LQT2: ST-T segment has a low ampli-
tude in the limb leads and a biphasic
pattern in the precordial leads. Clinical Presentation
LQT3: T waves are narrow, with late-onset
peak or biphasic and preceded by a long The long QT syndromes main manifestations are
isoelectric ST-T segment [1, 2, 4]. electrocardiographic anomalies, syncope, cardiac
arrest, and sudden cardiac death.
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292 M.V. Matassini and A. Maolo
Table 25.2 Scoring system to evaluate the probability of Some useful tests have been proposed to
LQTS
unmask the concealed forms of LQTS, and ongo-
ECG QTc 480 ms 3 ing clinical trials are evaluating and validating
findings QTc = 460470 ms 2 them. These tests are:
QTc = 450 ms (in males) 1
Torsade de pointes 2 Exercise test: patients with LQT1 mutation
T wave alternans 1 seem to have a more marked QT prolongation
Notched T waves (three leads) 1 during exercise (burst and gradual exercise
Rest heart rate below the second 0.5 showed the same results), while those with
percentile for age
LQT2 mutation have an exceeding hysteresis
Clinical Syncope with stress 2
history of the QT interval (difference between QT
Syncope without stress 1
interval measured during exercise and 2 min in
Congenital deafness 0.5
the recovery phase at similar heart rates)
Family Family members with LQTS 1
history (score 4) [1719].
Unexplained sudden cardiac death 0.5 Changing position: sudden changes from
below age 30 among immediate supine to standing position can provoke a pro-
family members longation of the QT interval mostly in LQT1
and LQT2 patients. This can be explained by
The ECG anomalies are very different and they the complex mechanism involving sympa-
depend in part on the type of QT syndrome. The thetic and vagal systems and their recruitment
main alteration is the prolongation of the QT inter- of IKs and IKr currents for an adequate inotropy
val, but is not always present at rest. In a certain and chronotropy response [17, 18, 20, 21].
percentage of patients, the QT interval can even be Epinephrine test: epinephrine infusion showed
normal (10 % in LQT3 and 37 % in LQT1) [12]. excellent results in unmasking concealed
In these cases, the QT intervals prolongation can forms of LQTS, but the clinical trials available
be evident during exercise test or infusion of epi- by now have few patients, and this test cannot
nephrine [4, 911]. Furthermore, repolarization be used as a routine exam so far.
can have strange aspects. For example, notches on
the T wave are typical of LQT2. According to the latest consensus paper, the
Syncope, cardiac arrest, and sudden death are presence of a pathogenic mutation in LQTS
the result of ventricular arrhythmias due to the genes per se can be a diagnostic criterion [22].
arrhythmogenic condition strictly linked to the A scoring system was created to evaluate the
genetic and electrical disorders of the disease. probability of LQTS when QT interval is normal
These arrhythmias are most of all torsade de or the genetic mutation is not unequivocal [23].
pointes VT that become clinically manifest This scoring system is still used and is shown in
depending on their duration. Sudden death occurs Table 25.2.
when the arrhythmia is not self-limiting and Thats why according to the latest HRS/
degenerates into ventricular fibrillation. EHRA/HPRS consensus document, diagnosis of
LQTS can be surely done if:
ERRNVPHGLFRVRUJ
25 Long QT Syndrome 293
ERRNVPHGLFRVRUJ
294 M.V. Matassini and A. Maolo
Other channel-specific therapies such as mex- frequent episodes of atrial fibrillation requiring
iletine, flecainide, and ranolazine (all sodium electrical cardioversion. Moreover, they
channel blockers) have been used in high-risk described the clinical case of a 37-year-old man
patients with recurrent events despite optimal with history of malignant ventricular arrhythmias
dosed beta-blockers, ICD, and LCSD. Their and a short QT interval on the ECG who died
effectiveness is encouraging, but they are still not suddenly at home [30].
considered as a routine therapy.
Genotypes-Phenotypes
25.3 Clinical Course
and Therapeutic The SQTS was associated with mutations of
Management some genes encoding the potassium channels
of the Clinical Case (KCNH2, KCNQ1, KCNJ2). These genes are
involved also in the pathogenesis of LQTS (in
For the specific clinical case discussed above, we particular LQT1 and LQT2), but on the contrary,
finally decided implanting one-chamber endo- in SQTS, the mutations are responsible for a gain
cavitary ICD. This choice was due to torsade de of function of the potassium channels. In few
pointes occurrence unrelated to secondary rea- patients with SQTS, mutations in the genes
sons. Furthermore, the classical ICD was pre- CACNA1C and CACNB2 (encoding the alpha-
ferred to S-ICD because we thought that the and beta-subunits of the L-type calcium channel
anti-tachycardia and anti-bradycardia pacing of the myocardium) responsible for a loss of
could have been useful in this patient. function of the channel were identified. These
Nadolol 40 mg once daily was also adminis- genes are usually involved also in the pathogen-
tered as starting dose. When employing a beta- esis of Brugada syndrome (in particular mani-
blocker, the choice is usually between two drugs: festing with type 1 ECG pattern).
nadolol and sustained-release propranolol. As The different genotypes correspond to dif-
explained above, these two drugs were demon- ferent phenotypes and different channels func-
strated to be superior to metoprolol in preventing tion disturbances (loss or gain of function), and
arrhythmic events in patients with LQTS. Nadolol they manifest with different ECG patterns
40 mg once a day is the starting dose, but the dos- [3135].
age could be increased up to 160 mg/day. The classification of the different forms of
A follow-up visit was performed 3 months short QT syndrome according to the genes muta-
later. The patients were completely asymptom- tions, the channel involved, and the ECG expres-
atic. The physical examination was normal. At sion is summarized in Table 25.3.
the ICD interrogation, any arrhythmia was
recorded.
Clinical Presentation
ERRNVPHGLFRVRUJ
25 Long QT Syndrome 295
Table 25.3 Summary table of genes and channels involved, channels function modifications and ECG patterns in
SQTS
Gene Channel Function disturbance ECG
SQTS1 KCNH2 IKr Gain
ERRNVPHGLFRVRUJ
296 M.V. Matassini and A. Maolo
have documented spontaneous sustained VT 10. Shimizu W, Noda T, Takaki H et al (2004) Diagnostic
value of epinephrine test for genotyping LQT1,
with or without syncope
LQT2, and LQT3 forms of congenital long QT syn-
ICD implantation (considered, Class IIb) in drome. Heart Rhythm 1:276283
asymptomatic patients with a diagnosis of 11. Vyas H, Hejilik J, Ackerman MJ (2006) Epinephrine
SQTS and a family history of SCD QT stress testing in the evaluation of congenital long
QT syndrome: diagnostic accuracy of the paradoxical
Quinidine (considered, Class IIb) in asymp-
QT response. Circulation 113(11):13851392
tomatic patients with a diagnosis of SQTS and 12. Zipes DP, Camm AJ, Borggrefe M et al (2006) ACC/
a family history of SCD AHA/ESC 2006 guidelines for management of
Sotalol (considered, Class IIb) in asymptom- patients with ventricular arrhythmias and the
prevention of sudden cardiac death A report of the
atic patients with a diagnosis of SQTS and a
American College of Cardiology/American Heart
family history of SCD Association Task Force and the European Society of
Cardiology Committee for Practice Guidelines (Writing
Finally, it is important to remember the pri- Committee to Develop Guidelines for Management of
Patients With Ventricular Arrhythmias and the
mary importance of an appropriate ICD program-
Prevention of Sudden Cardiac Death) Developed in col-
ming to avoid inappropriate shocks due to laboration with the European Heart Rhythm Association
oversensing of tall T waves present in the ECG and the Heart Rhythm Society. Europace 8:746837
pattern of SQTS. 13. Priori SG, Schwartz PJ, Napolitano C et al (2003)
Risk stratification in the long-QT syndrome. N Engl J
Med 348(19):18661874
14. Moss AJ, Zareba W, Benhorin J et al (1995) ECG
T-wave patterns in genetically distinct forms of the
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29. Chockalingam P, Crotti L, Girardengo G et al (2012) QT syndrome: clinical findings and diagnosticthera-
Not all beta-blockers are equal in the management of peutic implications. Eur Heart J 27:24402447
long QT syndrome types 1 and 2: higher recurrence of 38. Giustetto C, Schimpf A (2011) Lon term follow-up of
events under metoprolol. J Am Coll Cardiol 60(20): patients with short QT syndrome. J Am Coll Cardiol
20922099 58(6):587595
30. Schwartz PJ, Priori SG, Cerrone M et al (2004) Left 39. Gaita F, Giustetto C, Bianchi F et al (2004) Short QT
cardiac sympathetic denervation in the management syndrome: pharmacological treatment. J Am Coll
of high-risk patients affected by the long-QT syn- Cardiol 43(8):14941499
drome. Circulation 109(15):18261833
ERRNVPHGLFRVRUJ
Catecholaminergic Polymorphic
Ventricular Tachycardia: 26
A Challenging Case of Epilepsy
Laura Cipolletta
26.1 Introduction
had a period of incoherent speech, followed
Cardiac channelopathies are potentially malig- by sleepiness lasting for several hours. He
nant conditions caused by mutations in the chan- suffered from urinary incontinence during
nels that alter ion transit across the cardiac episodes. These events occurred approxi-
myocyte cell membrane. The clinical presenta- mately every month, although they had
tion of these mutations is variable, ranging from increased in frequency over the past
isolated abnormalities on electrocardiogram 2 months.
(ECG) to sudden cardiac death. The episodes were triggered by anxiety
and never occurred during physical efforts,
although he had no active lifestyle.
26.2 Case Report Several anticonvulsant medications
were not effective, so inpatient EEG moni-
toring was performed. EEG demonstrated
frequent, independent, temporal intermit-
A 17-year-old boy was referred to the car- tent rhythmic delta activity, indicating an
diology clinic by a neurologist for evalua- increased risk for focal seizures; however,
tion of potential arrhythmia. He was treated the typical episode was not recorded during
for resistant focal epilepsy for 4 years. admission. A second EEG recorder cap-
During a typical event, he fell off, with tured a typical event. It showed a high-
generalized shaking, lasting several min- amplitude diffuse slowing waves
utes. Then he gasped and in few seconds (suggestive of extracerebral artifact), fol-
later he appeared to stop breathing. He also lowed by an abrupt, and diffuse, attenua-
tion lasting 60 s, and finally a slow recovery
to diffuse polymorphic delta frequencies.
There was no ECG recording during the
episode. The EEG pattern suggested cere-
bral hypoperfusion, so the patient was
L. Cipolletta referred to a cardiologist. At admission to
Clinica di Cardiologia e Aritmologia, Universit
Politecnica delle Marche, the cardiology department, he became anx-
Via Conca, 71, Ancona 60126, Italy ious and lost consciousness.
e-mail: lauracipo2006@libero.it
ERRNVPHGLFRVRUJ
300 L. Cipolletta
Medical History and Cardiovascular potassium 3.9 mEq/l, sodium 140 mEq/l,
Risk Factors magnesium 1.8 mg/dl).
Medications
Clinical Course and Therapeutic
Valproic acid Management
26.3 Catecholaminergic
Physical Examination Polymorphic Ventricular
Tachycardia (CPVT)
General appearance: Well developed, well
nourished, alert, and cooperative Epidemiology
Lungs: Clear to auscultation and percussion
without rales, rhonchi, wheezing, or dimin- The prevalence of CPVT is about 1:10,000. The
ished breath sounds mean age of onset is between 7 and 9 years,
Cardiovascular: Normal S1 and S2. No S3, although later onset has been reported.
S4, or murmurs. Regular rhythm. No periph- Approximately 30 % of patients have a family
eral edema, cyanosis, or pallor. Warm and history of stress-related syncope, seizure, or SCD
well-perfused extremities before age 40 years. There is a high level of pen-
Abdomen: Positive bowel sounds. Soft and non- etrance of the disease (7580 %) [1].
distended. No guarding or rebound. No masses
Clinical Presentation
Routine Laboratory Test
Syncope triggered by exercise or emotion is the
Tests were normal (hemoglobin 13.4 g/dl, white typical clinical presentation of CPVT patients
blood cells 6,290/mmc, creatinine 0.7 mg/dl, and sometimes a reproducible, stress-related,
ERRNVPHGLFRVRUJ
26 Catecholaminergic Polymorphic Ventricular Tachycardia: A Challenging Case of Epilepsy 301
I
II
III
aVR
aVL
aVF
V1
V2
V3
V4
V5
V6
1000ms
Fig. 26.1 Onset of polymorphic VT symptomatic for syncope, converted to sinus rhythm after cardiopulmonary
resuscitation
ERRNVPHGLFRVRUJ
302 L. Cipolletta
not quickly stopped. On the recovery phase, VT reasonable [1, 4]. Invasive EP testing is of no
rate and VT duration progressively diminish until value in the diagnosis or risk stratification in
arrhythmias disappear. During exercise, at a patients with CPVT. Programmed electrical
range of heart rates similar to or slower than that stimulation is not useful to arrhythmia induction
of ventricular arrhythmias, isolated premature [1, 3]. Genetic testing should be performed in all
atrial complexes, nonsustained supraventricular definitive CPVT probands (see Fig. 26.3).
tachycardia, and short runs of AF usually are
observed [3, 4].
Genetics of CPVT
ERRNVPHGLFRVRUJ
26 Catecholaminergic Polymorphic Ventricular Tachycardia: A Challenging Case of Epilepsy 303
Echocardiogram:
Exclusion of structural heart disease
Treadmill test/ epinephrine test:
Ventricular arrhythmia that increases in frequency and
complexity while increases the exercise threshold/ epinephrine
infusion and decreases until it disappears during recopevy
With/without:
Holter:
Ventricular arrhythmia related to exercise/emotion
CPVT diagnosis
channels in the cell membrane permit Ca2+ influx calcium adenosine triphosphatase (SERCA)
during the action potential plateau that triggers resequesters most of the surplus Ca2+ in the cytosol
more Ca2+ release (Ca2+ transients) from the sarco- into the sarcoplasmic reticulum, controlled by the
plasmic reticulum into the cytosol via activation of phosphoprotein phospholamban. Additionally, to
Ca2+ release channels (RyR2). This amplifying balance the Ca2+ that enters with the Ca2+ current,
process, known as Ca2+-induced Ca2+ release, Na+Ca2+ exchanger extrudes from the cell some
causes a quick raise in cytosolic Ca2+ concentration of the Ca2+.
to an optimal level required for binding of Ca2+ to RyR2 mutations alter the physiological prop-
troponin C and induction of contraction [5]. During erties and function of RyR2 using some molecular
diastole, the sarcoplasmic/endoplasmic reticulum mechanisms not fully understood. It has been
ERRNVPHGLFRVRUJ
304 L. Cipolletta
suggested that the binding affinity of RyR2 for the arrhythmias related with intracellular Ca2+
regulatory protein calstabin-2 is reduced by overload and the DADs documented during digi-
CPVT mutations in RyR2. The closed conforma- talis toxicity. Mutations in RyR2 or CASQ2 lead
tional state of the RyR2 channel is stabilized by to the activation of the Na+Ca2+ exchanger
calstabin-2, which enables the channel to close enhanced by cytosolic Ca2+ overload. This mech-
completely during diastole (at low intracellular anism generates a net inward current (the so-
Ca2+ concentrations) and prevents aberrant Ca2+ called transient inward current) that provokes
leakage from the sarcoplasmic reticulum, ensur- DADs and if they reach the threshold for Na+
ing muscle relaxation. The binding affinity of cal- channel activation can trigger abnormal beats [1,
stabin-2 is worsened by PKA phosphorylation 3]. Low-amplitude DADs usually are not clini-
(induced by beta-adrenergic stimulation) of the cally significant. A decrease in the initiating
mutant RyR2 channels, increasing the probability cycle length probably is the most important fac-
of an open state at diastolic Ca2+ concentrations. tor that leads subthreshold DADs to reach thresh-
So, diastolic Ca2+ leak from the sarcoplasmic old; indeed fast heart rates increase both the
reticulum during stress or exercise is the result of amplitude and rate of the DADs. Moreover, cat-
the incomplete closure of the mutant RyR2 chan- echolamines can facilitate the development of
nel during diastole [1, 6]. Other groups have sug- DADs because the stimulation of beta-adrenergic
gested that in CPVT the mutated RyR2 channel is receptors and subsequently cAMP increases the
more sensitive to luminal (sarcoplasmic reticu- L-type Ca2+ current and leads to an increase in
lum) Ca2+. So under baseline conditions, where transsarcolemmal Ca2+ influx and intracellular
sarcoplasmic reticulum load is normal, there is no Ca2+ overload; also the enhancement of the activ-
Ca2+ leak, but under beta-adrenergic (sympa- ity of the Na+Ca2+ exchanger increases the like-
thetic) stimulation, sarcoplasmic reticulum Ca2+ lihood of DAD-mediated triggered activity;
concentration raises above the reduced threshold, finally, the enhancement of the uptake of Ca2+ by
causing Ca2+ to leak out of the sarcoplasmic retic- the sarcoplasmic reticulum leads to a greater
ulum. A third hypothesis for RyR2-related CPVT amount of Ca2+ stored in the sarcoplasmic reticu-
is that the intermolecular interactions between lum and the subsequent major release of Ca2+
discrete RyR2 domains necessary for proper fold- from the sarcoplasmic reticulum during contrac-
ing of the channel and self-regulation of channel tion. The increased susceptibility to ventricular
gating are impaired by the mutations in RyR2 [6]. arrhythmias in CPVT patients during exercise
The most important Ca2+ storage protein in the and emotional stress is associated with increased
sarcoplasmic reticulum is calsequestrin (CASQ2) sympathetic stimulation and higher heart rates.
and forms a part of a quaternary complex with Sometimes in CPVT, spontaneous Ca2+ release
RyR2, triadin, and junction, which play a major and DADs can happen without Ca2+ overload. For
role in regulating intracellular Ca2+. Calsequestrin, example, mutations in RyR2 or CASQ2 provoke
as a high-capacity, low-affinity Ca2+-binding pro- defective Ca2+ signaling that lowers the sarcoplas-
tein, is able to bind luminal Ca2+ during diastole, mic reticulum Ca2+ threshold for spontaneous
buffering Ca2+ within the sarcoplasmic reticulum Ca2+ release below the normal baseline level caus-
and preventing diastolic Ca2+ release via RyR2 to ing the so-named perceived Ca2+ overload [6].
the cytosol. For effective termination of sarco-
plasmic reticulum Ca2+ release and prevention of
spontaneous Ca2+ release during diastole, the Mechanism of the Bidirectional
control of RyR2s by luminal Ca2+ is required. Morphology of Ventricular
CASQ2 mutations lead to diminished Ca2+ sig- Tachycardia
naling refractoriness and generation of arrhyth-
mogenic spontaneous Ca2+ releases [6]. The main The EP mechanisms leading to the characteristic
arrhythmogenic mechanism in CPVT is DADs bidirectional morphology of the VT are not
and triggered activity because the bidirectional fully understood. Some of the proposed mecha-
ECG pattern of this VT corresponds to the nisms are the following: changes in conduction
ERRNVPHGLFRVRUJ
26 Catecholaminergic Polymorphic Ventricular Tachycardia: A Challenging Case of Epilepsy 305
direction from a single ventricular focus, one VT twisting of the points of the QRS complexes),
focus that triggers another focus, and firing from frequent in LQTS patients [13].
double ventricular foci (i.e., the right and left api- Bidirectional VT can also occur in patients
cal portions of the heart) [2, 6]. with type 7 LQTS (LQT7, AndersenTawil syn-
Others showed that left posterior inferior drome) linked to mutations in the KCNJ2 gene,
origin accounts for the majority of cases. which may be considered a CPVT phenocopy,
Additionally, the site of origin of bidirectional particularly in patients with AndersenTawil
VT has been recognized in the Purkinje network, syndrome having borderline QT interval prolon-
with alternating firing from the right and left gation. SCD is rare among AndersenTawil syn-
branches of the Purkinje fibers [3]. drome and KCNJ2 mutation carriers [8].
A recent experimental model identified a Furthermore, typical of AndersenTawil syn-
ping-pong mechanism as etiology of ventricu- drome are the extracardiac features such as peri-
lar arrhythmias in CPVT, so in different regions odic paralysis and facial dysmorphism [13].
of the HisPurkinje system (HPS) or ventricles, Ankyrin-B syndrome can also manifest with
DAD-induced triggered activity develops at dif- catecholamine-mediated ventricular arrhythmias.
ferent heart rate thresholds. First, if the heart rate Cardiac ankyrin-B is a structural membrane
rises above a certain threshold, ventricular adapter protein encoded by ANK2 gene. Loss-of-
bigeminy appears from a single site in the HPS or function mutations result in increased intracellular
ventricular myocardium. Ventricular bigeminy concentration of Ca2+ and a greater risk of fatal
shortens the RR cycle length that induces DAD- arrhythmia. This syndrome has been categorized
triggered beats from a second focus within the under LQTS (LQT4), but the QT interval prolon-
HPS, with the latter reciprocally activating PVCs gation is inconsistent and the degrees of cardiac
from the first focus; this process is repeated back dysfunction and arrhythmias observed (including
and forth, in a ping-pong pattern. The bidirec- bradycardia, sinus arrhythmia, idiopathic VF,
tional VT characteristic of CPVT is produced by adrenergically mediated VT, and SCD) are vari-
the reciprocating bigeminy from the two sites. able, so ankyrin-B syndrome is considered as a
When three or more sites concurrently develop different clinical entity compared to classic LQTS.
bigeminy, the result is the development of poly- The typical ECG pattern and the structural
morphic VT, whereas when repetitive DADs gen- abnormalities of the RV distinguish ARVD from
erate a run of triggered activity from a single site, CPVT despite the development of exercise-
the result is the development of monomorphic provoked arrhythmias. The typical arrhythmia in
VT [7]. ARVD is monomorphic VT with a left bundle
branch block (LBBB) pattern that is totally different
from the polymorphic PVCs or VT in CPVT [4].
Differential Diagnosis In contrast to CPVT, arrhythmias in Brugada
syndrome appear usually at rest or during sleep so
The first step is the exclusion of other inherited patients with Brugada syndrome do not manifest
arrhythmogenic cardiac disorders that can cause polymorphic PVCs on physical effort. Moreover,
malignant ventricular tachyarrhythmias. Measure Brugada syndrome shows the characteristic ST
of QT interval excludes the diagnosis of SQTS (if segment elevation in the precordial ECG leads at
QTc interval less than 320 ms) or LQTS (if QTc baseline and after provocation testing with Na+
interval more than 450 ms). The first syncope in channel blockers, absent in CPVT [4].
CPVT patients more often occurs during child-
hood, whereas clinical symptoms of LQTS typi-
cally start around puberty. Risk Stratication
Furthermore, the typical arrhythmia in CPVT
patients is bidirectional VT with a beat-to-beat Because of the relatively small number of
180 rotation of the QRS complex, in contrast to patients, reported risk stratification for SCD in
the torsades de pointes (characterized by the CPVT is difficult. CPVT patients with prior
ERRNVPHGLFRVRUJ
306 L. Cipolletta
cardiac arrest and those in whom pharmacologi- Table 26.1 Treatment of catecholaminergic polymor-
phic ventricular tachycardia (CPVT)
cal therapy does not suppress are considered at
high risk for SCD. Programmed electrical stimu- Catecholaminergic polymorphic ventricular tachycardia
lation typically fails in inducing ventricular (CPVT) treatment
arrhythmias and is of no value for risk stratifica- Genotype, if available
Beta-blockers (BB) at maximum tolerated doses:
tion. Furthermore, the predictive value of
In patients with CPVT clinical diagnosis (Class I
inducibility of ventricular arrhythmias by cate-
indication, level of evidence: C) [11]
cholamine infusion or exercise for risk stratifica- In patients without clinical symptoms of CPVT but
tion has not been confirmed. with genetic diagnosis of CPVT during childhood
(Class IIa indication, level of evidence: C) [11]
In patients with CPVT and genetic diagnosis in adult
Pharmacological Therapy age without any symptoms of tachycardia (Class IIb
indication, level of evidence: C) [11]
Nadolol 40 and 80 mg:
The first line of treatment for CPVT is beta-
Kids: 12.5 mg/kg/die, q.d.
blockers and should be promptly initiated to pre- Adults: maximal doses 160 mg/die, q.d.
vent the occurrence of ventricular Propranolol:
tachyarrhythmias. Untreated CPVT has a poor Kids: 2.53.5 mg/kg/die, t.i.d. (every 8 h)
prognosis, so drug therapy is indicated for all Adults: 160 mg/die (q.d.)
clinically diagnosed patients and also for all Treadmill test could help titrate beta-blocker doses
silent carriers of a CPVT mutation. The most (target heart rate of <85 % of maximum heart rate,
significant reduction of ventricular arrhythmia burden
widely used beta-blockers are nadolol (12.5 mg/
during exercise test)
kg/day) and propranolol (2.53.5 mg/kg/day).
Left thoracic sympathectomy [24]
Intravenous propranolol is the treatment of choice Kids with syncope during beta-blocker therapy,
for acute management of CPVT (Table 26.1). to delay/avoid ICD implantation
Exercise stress testing and Holter monitoring ICD patients with frequent ICD therapy (ATP/
can help determine the adequate beta-blocker shock/electrical storm)
dosage for arrhythmia control, but the absence of Flecainide [9]:
exercise-provoked arrhythmias does not com- On top of maximum tolerated doses of beta-
blockers and ICD [patients with high burden of
pletely exclude the risk of arrhythmia recurrence, complex ventricular arrhythmias in the exercise test
and the maximum tolerated dose of beta-blockers during follow-up or frequent ICD therapy (ATP/
should be prescribed to optimize control of shock/electrical storm)]
arrhythmias with the aim of avoiding the achieve- Doses: 150200 mg/die; range: 100300 mg/die
ment of the threshold rate for CPVT [3, 4]. ICD: CPVT + resuscitated sudden cardiac death (Class
I indication, level of evidence: C) [11]
Recent studies demonstrate that the addition
ICD + BB in CPVT patients with syncope and/or
of flecainide to beta-blocker therapy can effec- sustained VT during treatment with BB (Class IIa
tively reduce exercise-induced ventricular indication, level of evidence: C) [11]
arrhythmias in CPVT patients not controlled by Absolute contraindication to competitive sports [13]
beta-blocker therapy alone [9]. Direct blockade Relative contraindication to recreational sports [13]
of RyR2 channels and reduction of Ca2+ spark Avoid other arrhythmia triggers: loud noises,
amplitude rather than Na+ channel blockade emotional stress
mediate the flecainide effects [10]. If the patient is implanted with ICD: periodic
follow-up to monitor recorded arrhythmias or ICD
Limited data suggest that verapamil (an inhibi- therapy
tor of RyR2) can be an alternative option for the Urgent medical consultation in case of syncope or
treatment of CPVT. Also, verapamil used in com- nocturnal agonal respiration
bination with beta-blockers can provide additional Evaluation recommended to first-degree family
protection. However, there is no conclusive members
ERRNVPHGLFRVRUJ
26 Catecholaminergic Polymorphic Ventricular Tachycardia: A Challenging Case of Epilepsy 307
evidence for recommending verapamil alone or in high mortality of CPVT, it is important to study
combination with beta-blockers because of the both first- and second-degree relatives to find
small number of patients and the limited follow-up potential CPVT patients [14]. Exercise testing
and also its impact on prognosis is not known [4]. and Holter monitoring are used for screening
family members. Moreover, some CPVT patients
Implantable Cardioverter Debrillator may not have arrhythmias in the exercise stress
ICD therapy is recommended for CPVT patients test during early childhood, but later in life, a
who have survived a cardiac arrest or those who change in the phenotype may occur. Therefore,
continue to have symptoms (syncope or sustained follow-up with repeated exercise stress tests is
or hemodynamically unstable VT) despite ade- indicated. When a gene mutation has been identi-
quate beta-blocker therapy [11]. fied in the proband, genetic testing is recom-
Approximately half of ICD recipients mended to screen family members [3].
experience an appropriate shock to terminate VT
during 2 years of follow-up. It is important to
maintain the maximum tolerated dose of
References
beta-blockers in ICD patients to help reduce the
risk of arrhythmic storms and ICD shocks [1, 2]. 1. Liu N, Ruan Y, Priori SG (2008) Catecholaminergic
polymorphic ventricular tachycardia. Prog Cardiovasc
Catheter Ablation Dis 51:2330
When ventricular arrhythmias are triggered by 2. Mohamed U, Napolitano C, Priori SG (2007)
Molecular and electrophysiological bases of catechol-
monomorphic PVCs, catheter ablation of the aminergic polymorphic ventricular tachycardia. J
focus of PVCs may be attempted to reduce Cardiovasc Electrophysiol 18:791797
the burden of arrhythmias and ICD shocks. The 3. Napolitano C, Priori SG (2007) Diagnosis and treat-
initiating beat of VT usually shows an LBBB ment of catecholaminergic polymorphic ventricular
tachycardia. Heart Rhythm 4:675678
inferior axis pattern, suggestive of a ventricular 4. Ylanen K, Poutanen T, Hiippala A et al (2010)
outflow tract origin [12]. Catecholaminergic polymorphic ventricular tachycar-
dia. Eur J Pediatr 169:535542
Sympathetic Denervation 5. Wehrens XH (2007) The molecular basis of catechol-
aminergic polymorphic ventricular tachycardia: what
Small case series suggest the effectiveness of left are the different hypotheses regarding mechanisms?
cardiac sympathetic denervation in patients with Heart Rhythm 4:794797
recurrent symptoms despite beta-blocker therapy 6. Gyorke S (2009) Molecular basis of catecholaminer-
or those experiencing intractable arrhythmic gic polymorphic ventricular tachycardia. Heart
Rhythm 6:123129
storms or frequent ICD shocks [2]. 7. Baher AA, Uy M, Xie F et al (2011) Bidirectional
ventricular tachycardia: ping pong in the His-Purkinje
Participation in Sports system. Heart Rhythm 8:599605
All CPVT patients with documented exercise- or 8. Tsuboi M, Antzelevitch C (2006) Cellular basis for
electrocardiographic and arrhythmic manifestations
isoproterenol-induced VT should avoid all competi- of Andersen-Tawil syndrome (LQT7). Heart Rhythm
tive sports. A less restrictive approach may be pos- 3:328335
sible for the genotype-positive/phenotype-negative 9. Van der Werf C, Kannankeril PJ, Sacher F et al (2011)
(asymptomatic, no inducible VT) athlete [13]. Flecainide therapy reduces exercise-induced ventricu-
lar arrhythmias in patients with catecholaminergic
polymorphic ventricular tachycardia. J Am Coll
Cardiol 57(22):22442254
Family Screening 10. Hwang HS, Hasdemir C, Laver D et al (2011)
Inhibition of cardiac Ca2+ release channels (RyR2)
determines efficacy of class I antiarrhythmic drugs in
After a diagnosis of CPVT in a family member catecholaminergic polymorphic ventricular tachycar-
because of the severe clinical manifestations and dia. Circ Arrhythm Electrophysiol 4:128135
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11. Zipes DP, Camm AJ, Borggrefe M et al (2006) ACC/ 12. Sy RW, Gollob MH, Klein GJ et al (2011) Arrhythmia
AHA/ESC 2006 guidelines for management of patients characterization and long-term outcomes in catechol-
with ventricular arrhythmias and the prevention of sud- aminergic polymorphic ventricular tachycardia. Heart
den cardiac death: a report of the American College of Rhythm 8:864871
Cardiology/American Heart Association Task Force and 13. Zipes DP, Ackerman MJ, Estes NA III et al (2005)
the European Society of Cardiology Committee for Task Force 7: arrhythmias. J Am Coll Cardiol
Practice Guidelines (writing committee to develop 45:13541363
Guidelines for Management of Patients With Ventricular 14. Ackerman MJ, Priori SG, Willems S et al (2011)
Arrhythmias and the Prevention of Sudden Cardiac HRS/EHRA expert consensus statement on the State
Death): developed in collaboration with the European of Genetic Testing for the channelopathies and cardio-
Heart Rhythm Association and the Heart Rhythm myopathies. Heart Rhythm 8:13081339
Society. Circulation 114(10):e385e484
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Part IX
Miscellanea
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Sudden Cardiac Death
27
Laura Cipolletta
L. Cipolletta
Clinica di Cardiologia e Aritmologia, Universit Allergies
Politecnica delle Marche,
Via Conca, 71, Ancona 60126, Italy None
e-mail: lauracipo2006@libero.it
ERRNVPHGLFRVRUJ
312 L. Cipolletta
Fig. 27.1 Onset of polymorphic VT symptomatic for syncope, converted to sinus rhythm after cardiopulmonary
resuscitation
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27 Sudden Cardiac Death 313
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314 L. Cipolletta
subcutaneously from the pocket in the left pacing. Sudden cardiac death should not be used to
describe events that are not fatal [1].
midaxillary region to the right side of the
xiphoid process. The tip was then advanced up
to the manubriosternal junction, 1 cm to the
right of the midsternal line (Fig. 27.3). At the Epidemiology
end of the procedure, a defibrillation test was
performed: Clinical VT was induced, correctly SCD accounts for approximately 15 % of the
sensed, and treated after 12.5 s with a 65 J total mortality in the industrialized countries [4].
shock (conventional polarity configuration). At The incidence of SCD increases as a function
2-month follow-up examination, the patient of advancing age. The prognosis of patients expe-
did not have any complications, and no signifi- riencing SCA varies significantly according to the
cant events were recorded. initial rhythm, although the outcome remains poor,
despite advances in the treatment of heart disease.
The incidence of experiencing SCA is
27.3 Sudden Cardiac Death increased by age, sex, and underlying cardiac dis-
ease [5]. Indeed, men are two to three times more
Denitions likely to experience SCA than women. In the
Womens Health Initiative, 161,808 postmeno-
Various criteria have been used to define SCA pausal women were followed for an average of
and SCD in the medical literature [3]. It is diffi- 10.8 years, and the incidence rate of SCD was 2.4
cult to find a specific definition for several main per 10,000 women/year, and nearly one-half of
reasons: First of all, only two-thirds of events are women who experienced SCD did not have prior
witnessed, making the diagnosis difficult to clinically recognized coronary heart disease [6].
establish; secondly, the cardiac rhythm at clinical The presence of clinically recognized heart
presentation is unknown in many cases, so it is disease and of coronary heart disease (CHD) risk
not possible to restrict the definition of SCA to factors, respectively, increases six- to tenfold and
documented cases of VF; finally, the suddenness two- to fourfold the risk of SCA [7].
of death is generally defined by the duration of
symptoms prior to SCA, but in approximately
one-third of cases, the duration of symptoms is Etiology
not clearly defined.
For these reasons, the criteria proposed do not SCA is more frequent in male with structural
rely upon the cardiac rhythm at the time of the heart disease, especially CHD. The most frequent
event. The criteria focus on the sudden pulseless cause of SCA is CHD that amounts up to 70 % of
event occurred out of hospital and on the absence SCAs. It is possible that SCA occur during an
of a noncardiac condition (e.g., pulmonary embo- acute coronary syndrome (ACS) such as in
lism, intracranial hemorrhage, central airway patients with a chronic, stable CHD [8]. Usually
obstruction) as the cause of cardiac arrest. in this setting, prior myocardial damage and scar
The following definitions of SCA and SCD act as a substrate for SCA. On the contrary, SCD
were presented by the 2006 American College of occurs more commonly in the absence of an iden-
Cardiology/American Heart Association/Heart tifiable acute cardiac event.
Rhythm Society (ACC/AHA/HRS): Ten percent of cases of out-of-hospital SCA is
Sudden cardiac arrest is the sudden cessation of represented by other forms of structural heart dis-
cardiac activity so that the victim becomes unre- ease, both acquired and hereditary. Examples of
sponsive, with no normal breathing and no signs of such disorders include the following:
circulation. If corrective measures are not taken
rapidly, this condition progresses to sudden death.
Cardiac arrest should be used to signify an event as 1. SCD is responsible for approximately one-
described above, that is reversed, usually by CPR third of deaths in heart failure and
and/or defibrillation or cardioversion, or cardiac cardiomyopathy.
ERRNVPHGLFRVRUJ
27 Sudden Cardiac Death 315
2. Left ventricular hypertrophy due to hyperten- hypomagnesemia), and the proarrhythmic effect
sion or other causes. of some antiarrhythmic drugs. The mortality is
3. Myocarditis. highest in the first month after acute myocardial
4. Hypertrophic cardiomyopathy. infarction (MI) in patients with ejection fraction
5. Arrhythmogenic right ventricular (EF) of less than 30 % [1].
cardiomyopathy. In addition, direct trauma over precordium
6. Congenital coronary artery anomalies. precipitated SCA that results from commotio
7. Mitral valve prolapse. cordis.
The cumulative risk of SCD has been esti-
Data from different reports documented mated at 1520 % of adults with aortic stenosis,
approximately 1012 % of cases of SCA among with the risk being higher in symptomatic patients
subjects without structural heart disease, under and equal to or less than 5 % in asymptomatic
age 45, while a lower value of about 5 % has patients. Mitral valve prolapse is usually non-
been described when older patients are included life-threatening, and its link with SCD has never
[9, 10]. been definitely demonstrated. Reported SCD
Hereditary factors that contribute to coro- rates in patients with Wolff-Parkinson-White
nary heart disease risk have been thought to (WPW) syndrome have been 0.15 %, due in most
operate nonspecifically for the SCD syndrome. to the development of atrial fibrillation (AF) with
However, several studies have identified muta- a rapid ventricular response that degenerates to
tions and relevant polymorphisms along the VF. Genetic influences modulate the risk of SCD
cascade from atherogenesis to plaque destabili- in the setting of CHD. The Paris Prospective
zation, thrombosis, and arrhythmogenesis, each Study I, analyzing more than 7,000 men followed
of which is associated with a risk of a coronary for an average of 23 years, found that a parental
event. history of SCD increased the relative risk of SCD
for offspring to 1.8, without elevating the risk for
MI. When both parents had SCD, the relative risk
for SCD in offspring was 9.4. Genetic influences
SCA in the absence of apparent structural
may act through multiple mechanisms, such as
heart disease can occur in different
modulation of the substrate, atherothrombosis,
settings:
electrogenesis impulse propagation, neural con-
trol, and regulation [1].
1. Brugada syndrome
Some individuals can have inherited abnor-
2. Idiopathic VF
malities that are not manifest until triggered by
3. Congenital or acquired long QT
an external event. For example, autonomic mod-
syndrome
ulation associated with certain types of activity,
4. Arrhythmogenic right ventricular cardio-
as well as drugs that affect cardiac repolariza-
myopathy
tion, can convert a subclinical genetic abnor-
5. Catecholaminergic polymorphic VT
mality to SCD. Among the genetic factors, the
6. Familial SCD of uncertain cause
most common are DNA variants called poly-
7. Wolff-Parkinson-White syndrome
morphisms that may be present in a large pro-
portion of the population and create susceptibility
for SCD. Single nucleotide polymorphisms
A major role in the pathogenesis of SCA, in (SNPs) are DNA variants that can be associated
addition to the presence of the above underlying with a functional consequence. For example, a
disorders, is played by acute superimposed trig- polymorphism identified in the alpha 2b adren-
gers. These include ischemia, autonomic nervous ergic receptor is associated with an increased
system activation, psychosocial factors, electro- risk of MI and SCD [1]. Nevertheless, to create
lyte disturbances (particularly hypokalemia and a risk for SCD, a combination of polymorphisms
ERRNVPHGLFRVRUJ
316 L. Cipolletta
in different genes may be required, interacting Anyway, regular exercise should be encouraged
with a specific trigger or substrate, because mil- for the primary prevention of coronary heart dis-
lions of SNPs are present in the DNA of each ease and consequently SCA. Despite a small
individual [1]. transient increase in risk during and shortly after
strenuous exercise, rate of SCD is lower among
exercisers compared with sedentary men [17]. A
Risk Factors reduced risk of SCD is associated with a lower
resting heart rate and increased heart rate vari-
An increased risk of SCA is associated with a ability, characteristics which developed after
number of clinical characteristics and other regular exercise.
factors among patients without prior clinically Patients should be advised to pay attention to
recognized heart disease [11, 12]. Coronary heart possible symptoms of coronary heart disease,
disease and SCA have a lot of risk factors in even if they are trained exercisers.
common. These include family history of myo- Hypertrophic cardiomyopathy, anomalous
cardial infarction, hypertension, dyslipidemia, coronary artery of wrong sinus origin, myocardi-
diabetes mellitus, obesity, cigarette smoking, and tis, and arrhythmogenic right ventricular cardio-
physical inactivity [13, 14]. myopathy [18, 19] are an exception to the lower
The risk of SCA in patients with coronary overall risk associated with intensive exercise
heart disease is strongly related to current ciga- that occurs in patients with certain, often unrec-
rette smoking and the number of cigarettes ognized underlying heart diseases.
smoked per day. In the Nurses Health Study, A family history of SCA, which could be
101,018 women were followed for 30 years, and associated with myocardial infarction, is related
current smokers had a significantly greater risk of to a 1.5- to 1.8-fold increased risk of SCA [20].
SCD than women who had never smoked Traditional risk factors that tend to aggregate in
(adjusted hazard ratio 2.44, 95 % CI 1.803.31), families, such as hypercholesterolemia, hyper-
and the risk was increased even among women tension, diabetes mellitus, and obesity, do not
who smoked 1 to 14 cigarettes per day (adjusted explain the increase in risk. However, it is likely
hazard ratio 1.84, 95 % CI 1.162.92) [15]. In that interactions of mutations or polymorphisms
this study, the risk of SCD declined over time in in specific genes and environmental factors influ-
a linear fashion after quitting smoking, reaching ence this risk.
the same risk of SCD as never smokers 20 years Elevated serum C-reactive protein (CRP) is
after quitting [15]. also associated with an increased risk of SCA
The risk of SCA is particularly high among [21]. Higher serum concentrations of CRP could
current smokers and declines rapidly after stop- be an expression of chronic inflammation that has
ping smoking, to reduce the risk of SCA and a been implicated as a risk factor for cardiovascu-
multitude of other complications. lar diseases (including acute coronary syndromes
During and up to 30 min after strenuous exer- and stroke).
cise, the risk of SCA is transiently increased com- Heavy alcohol consumption (six or more
pared to other times [16]. In fact, the actual risk drinks per day) or binge drinking increases the
during any one episode of vigorous exercise is risk for SCD [22, 23]. In fact, moderate alcohol
very low (1 per 1.51 million episodes of exercise) intake (e.g., one to two drinks per day) is related
[17]. Also, the magnitude of the transient increase to a reduction of the risk of SCD [22].
in risk during acute exercise is lower for people Clinical observations have suggested that
who perform regular exercise compared with peo- acutely stressful situations could have a possible
ple for whom exercise is unusual [16, 17]. relation with a higher risk of SCA. For example,
Data from long-term exercise intervention tri- major disasters, such as earthquakes and war,
als among apparently healthy persons that focus result in a rapid transient increase in the rate of
upon major disease end points are absent. SCA in populations [15]. Social support from
ERRNVPHGLFRVRUJ
27 Sudden Cardiac Death 317
others may reduce the risk associated with stress- Class I and III antiarrhythmic agents were not
ful life events. able to reduce total and SCD mortality in
Excessive caffeine intake has been investi- patients at risk for SCD [30]. In fact, both
gated as a potential risk factor for SCA [24], but classes do not direct their actions on cardiac
no significant association with SCA has been muscle or specialized conducting tissues that
found. have been shown effective for prevention of
After a myocardial infarction, elevated plasma SCD. Beta-blockers, ACE inhibitors, angioten-
nonesterified fatty acid (free fatty acid) concen- sin receptor-blocking agents, lipid-lowering
trations were associated with ventricular arrhyth- agents, spironolactone, and fibrinolytic and
mias and SCD [25]. However, in the antithrombotic agents were judged likely effec-
Cardiovascular Health Study, in a population- tive especially in primary prevention. Since
based cohort of older adults [26], nonesterified SCD is for the most part the result of a ventricu-
fatty acids were not associated with SCD. lar tachyarrhythmia, these drugs act on the bio-
Moreover, in a population-based case-control chemical, ischemic, and fibrotic processes that
study among people without prior clinically underlie the onset or maintenance of life-threat-
recognized heart disease, cases of SCA had ening ventricular arrhythmias.
higher concentrations of trans isomers of linoleic The mechanisms of cardiac arrest are repre-
acid in red blood cell membranes [27]. sented by electromechanical dissociation, asys-
In contrast, in several studies, a higher dietary tole and heart block, and VF. More permanent
intake and higher plasma levels of long-chain n-3 changes could also occur, such as plaque rup-
polyunsaturated fatty acids (eicosapentaenoic ture, but it is likely that transient factors inter-
acid and docosahexaenoic acid) are associated act with a fixed substrate to precipitate the
with a lower risk of SCD [28]. arrhythmia. The possibilities include physical
activity, transient ischemia, hypoxia, stretch,
ion channel abnormalities, pH and electrolyte
Mechanisms of Sudden Cardiac Death changes, inflammation, neuroendocrine actions,
and drugs.
The rhythm most often recorded at the time of
sudden cardiac arrest is VF. Previous studies
suggest that up to 80 % occur via this mecha-
Management
nism and up to 20 % are attributed to bradyar-
rhythmias, including advanced atrioventricular
(AV) block and asystole [1]. Bayes de Luna
et al. [31] reported that in 157 ambulatory The acute management of survivors of
patients who had SCD while undergoing Holter SCA includes the following:
recording, 62.4 % had VF, 16.5 % had bradyar-
rhythmias, 12.7 % had torsades de pointes, and 1. Identification and treatment of acute
8.3 % had primary VT. The true incidence of reversible causes
bradyarrhythmias is not easy to understand 2. Evaluation for structural heart disease
since a rhythm beginning as VF may appear to 3. Evaluation for primary electrical dis-
be asystole during the first ECG recording. eases in patients without identifiable
Advanced AV block or significant bradycardia arrhythmic triggers or cardiac structural
can provoke VF. It is difficult to identify clearly abnormalities
the electrophysiological mechanism responsible 4. Neurologic and psychologic assessment
for SCD. Mechanisms may be multifactorial 5. Evaluation of family members in
and are different depending on the specific car- selected patients with a suspected or
diac abnormality, and a rhythm can begin via confirmed heritable syndrome
one mechanism and proceed via a different one.
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318 L. Cipolletta
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27 Sudden Cardiac Death 319
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320 L. Cipolletta
myocardial infarction, patients with heart failure evaluation, such as with an electrocardiogram or
and cardiomyopathy, and patients with one of the echocardiogram.
congenital disorders associated with an increased
risk of SCA (e.g., Brugada syndrome, congenital Risk factor reduction: As mentioned above,
long QT syndrome, WPW). the majority of the traditional risk factors
associated with coronary heart disease are
General Population also associated with SCA.
Two approaches could be applied to reduce the
risk of SCA in the general population: screening
and risk stratification to identify individuals who
Thus, reduction of these risk factors may
may benefit from specific interventions (e.g.,
affect the incidence of SCA in the gen-
stress testing, screening ECGs) and behavior that
eral population. Such interventions
target the underlying disorders that predispose to
include:
SCA and reduce the risk in any individual (e.g.,
smoking cessation or other lifestyle Effective treatment of hypercholestero-
modifications). lemia
Effective treatment of hypertension
Screening and risk stratification: In patients Heart-healthy diet
with known elevated risk of SCA (e.g., Regular exercise
patients with a prior myocardial infarction), Smoking cessation
further risk stratification can identify sub- Moderation of alcohol consumption
groups that benefit from specific therapies, Effective treatment of diabetes
such as an ICD. On the contrary, in the gen-
eral population without known cardiovascu-
lar disease, routine screening with 12-lead
electrocardiography, exercise stress testing, There is no definitive evidence that risk fac-
or Holter monitoring hardly or ineffectively tor reduction in the general population lowers
identifies populations at an increased risk the rate of SCA. On the contrary, several studies
of SCA. have demonstrated that treatment of risk factors
can lower total cardiovascular and coronary
mortality. Reduction of cardiovascular risk fac-
Key point in risk stratification of the gen- tors may reduce SCA rates as well because the
eral population could be the following: majority of CHD mortality is due to SCD.
In observational studies of populations at low
Identifying risk factors for cardiovascu- cardiovascular risk, greater dietary fatty fish
lar disease according to standard intake was associated with lower cardiac mortal-
guidelines ity [36]. This benefit is partially due to a reduced
Screening for coronary heart disease in risk of SCD. From these results, subsequent ran-
selected patients domized trials evaluated the benefit of fish oil
supplements in high-risk populations [37].
Routine additional testing for the SCA risk The benefit of pharmacologic doses of n-3
stratification is not recommended. polyunsaturated fatty acids is little compared to
the intake of one to two servings of fatty fish per
week. The pharmacologic use of fish oil supple-
A complex topic matter of debate is the pre- ments should be restricted to patients with refrac-
participation evaluation of athletes. There are tory hypertriglyceridemia in whom the periodic
conflicting opinions regarding the appropriate- monitoring of apolipoprotein B levels is recom-
ness of screening and, if so, the optimal screening mended [37].
ERRNVPHGLFRVRUJ
27 Sudden Cardiac Death 321
Post-myocardial Infarction status for more than 1 year (class I, level of evi-
The risk of SCA is increased in patients who have dence: B) [1].
had a myocardial infarction (MI), and this risk var- Ventricular arrhythmias and SCD are common
ies significantly according to a number of factors. in patients with symptomatic acute and chronic
The strategies to the prevention of SCA in HF and LV systolic dysfunction. In the setting of
such patients include the following: acute HF, ventricular arrhythmias may be poorly
tolerated and early cardioversion should be per-
Standard medical therapies: Both beta- formed, rather than attempting pharmacological
blockers and ACE inhibitors (or angiotensin termination of arrhythmia.
II receptor blockers) reduce overall mortality In addition, standard medical therapies for HF
after an MI and are routinely administered. (beta-blockers, ACE inhibitors or angiotensin II
These agents also lower the incidence of receptor blockers, and aldosterone inhibitors
SCD. such as spironolactone or eplerenone) may lower
Risk stratification: To identify those patients the risk of SCA [1].
at the highest risk of SCA.
ICD implantation in selected patients: ICD
therapy is recommended for primary preven- Secondary Prevention
tion to reduce SCD in patients with LV dys-
function due to prior MI who are at least 40 ICD Therapy
days post-MI, have an LVEF less than or equal An implantable cardioverter defibrillator (ICD)
to 3040 %, are NYHA functional class II or is the preferred therapeutic modality in survi-
III, are receiving chronic optimal medical vors of SCA. The ICD does not prevent the
therapy, and have a reasonable expectation of recurrence of malignant ventricular arrhyth-
survival with a good functional status for more mias, but it effectively terminates these arrhyth-
than 1 year (class I, level of evidence: A) [1]. mia recurrences.
ICD patients who have frequent arrhythmia
In patients with LV dysfunction due to prior recurrences and device discharges may benefit
MI who are at least 40 days post-MI, have an from adjunctive therapies, such as antiarrhythmic
LVEF of less than or equal to 3035 %, are drugs or catheter ablation.
NYHA functional class I on chronic optimal Coronary revascularization reduces the risk
medical therapy, and have a reasonable expecta- of SCD in patients with VF when evidence of
tion of survival with a good functional status for acute myocardial ischemia is documented to pre-
more than 1 year, implantation of an ICD is rea- cede the onset of VF (class I, level of evidence:
sonable (class IIa, level of evidence: B) [1]. B) [1]. With evidence of prior MI and significant
LV dysfunction, if coronary revascularization
Heart Failure and Cardiomyopathy cannot be realized, the primary therapy of
Patients with heart failure and left ventricular sys- patients resuscitated from VF should be the ICD
tolic dysfunction, regardless of the etiology, are at in patients who are receiving chronic optimal
an increased risk of SCA. Primary prevention with medical therapy and those who have a reason-
an ICD is recommended in selected patients with able expectation of survival with a good func-
either ischemic or nonischemic cardiomyopathy tional status for more than 1 year (class I, level
(NICM). ICD therapy is recommended for primary of evidence: A) [1].
prevention to reduce total mortality by a reduction In patients with LV dysfunction due to prior
in SCD in patients with nonischemic heart disease MI with hemodynamically unstable sustained
who have an LVEF less than or equal to 3035 %, VT, receiving chronic optimal medical therapy,
are NYHA functional class II or III, are receiving with a reasonable expectation of survival for
chronic optimal medical therapy, and have a reason- more than 1 year, ICD is the effective therapy to
able expectation of survival with a good functional reduce SCD (class I, level of evidence: A) [1].
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322 L. Cipolletta
ICD therapy is recommended for secondary causes. ICD implantation is indicated in patients
prevention of SCD in patients who survived VF who are receiving chronic optimal medical ther-
or hemodynamically unstable VT or VT with apy and who have a reasonable expectation of
syncope and who have an LVEF less than or survival with a good functional status for more
equal to 40 %, who are receiving chronic optimal than 1 year (class I, level of evidence: B) [1].
medical therapy, and who have a reasonable Congenital heart disease represents a spectrum
expectation of survival with a good functional of anatomical and physiological defects with an
status for more than 1 year (class I, level of evi- intrinsic risk of arrhythmias and late SCD. Overall,
dence: A) [1]. congenital heart defects are the principal cause of
Amiodarone is a reasonable therapy to reduce infant mortality (less than 1 year of age) in the
symptoms due to recurrent hemodynamically sta- industrialized world. About all defects can now be
ble VT for patients with LV dysfunction due to repaired or palliated, with greater than 1 million
prior MI who cannot have or refuse to have an ICD worldwide long-term survivors after surgery for
implanted (class IIa, level of evidence: C) [1]. congenital heart disease [38].
ICD implantation is a reasonable treatment of Due to the low incidence of late SCD in post-
recurrent ventricular tachycardia in patients post- operative congenital heart disease patients, pro-
MI with normal or near-normal ventricular func- spective randomized clinical trials do not exist to
tion who are receiving chronic optimal medical identify either risk factors for SCD or the role of
therapy and who have a reasonable expectation of primary prevention therapies.
survival with a good functional status for more During infancy and childhood, greater than
than 1 year (class IIa, level of evidence: C) [1]. 75 % of deaths in patients with congenital heart
disease are in-hospital events, during the periop-
Antiarrhythmic Drugs erative period [39].
Antiarrhythmic drugs are less effective than an The remaining deaths often occur in patients
ICD for secondary prevention of SCD. Thus, their with other congenital anomalies in an out-of-
use is limited to the adjunctive role in frequent ven- hospital setting.
tricular arrhythmia recurrences or in patients who Beyond 20 years of age, a progressive increase
do not want or are not candidates for an ICD (e.g., in the incidence of sudden and total cardiac mor-
due to marked comorbidities or end-stage heart tality occurs in postoperative congenital heart
failure with a life expectancy less than 1 year). disease patients [40].
Amiodarone, sotalol, and/or other beta- Congenital heart defects associated with the
blockers are recommended pharmacological greatest risks of late SCD are tetralogy of Fallot,
adjuncts to ICD therapy to suppress symptomatic D- and L-transposition of the great arteries, aortic
ventricular tachyarrhythmias in optimally treated stenosis, and functional single ventricle [41].
patients with HF (class I, level of evidence: C) [1]. The additional factors most likely associated
Curative catheter ablation or amiodarone may with an increased risk of SCD due to ventricular
be considered in place of ICD therapy to improve arrhythmias appear to be volume overload due to
symptoms in patients with LV dysfunction due to pulmonary insufficiency and QRS duration
prior MI and recurrent hemodynamically stable greater than 160 ms [42]. EPS for risk stratifica-
VT whose LVEF is greater than 40 % (class IIb, tion in these patients is not useful, in part due to
level of evidence: B) [1]. variable study protocols and response to such
testing [1].
The mechanism of SCD appears to be atrial flut-
Congenital Heart Disease ter with 1:1 AV conduction, followed by myocar-
dial ischemia resulting in polymorphic VT or VF or
ICD implantation is indicated in patients with progressive ventricular dysfunction that results in
congenital heart disease who are survivors of car- ventricular arrhythmias [42]. Moreover, a positive
diac arrest after exclusion of any reversible response to EPS, independent of the clinical indica-
ERRNVPHGLFRVRUJ
27 Sudden Cardiac Death 323
tion, may identify patients with a high risk of late that is not manageable by reprogramming or
SCD [42]. Also, there are non-arrhythmic causes of changing drug therapy or who do not wish long-
late sudden death in postoperative patients, includ- term drug therapy (class I, level of evidence: C)
ing cerebral or pulmonary embolism, endocarditis, [1]. Finally, ablation is indicated in patients with
and aneurysm rupture [40]. WPW syndrome resuscitated from sudden car-
Coronary artery abnormalities are another diac arrest due to rapidly conducted atrial fibrilla-
class of congenital anomalies that may result in tion causing VF (class I, level of evidence: B) [1].
SCD. The most common congenital coronary Less evidence exists regarding ablation of
artery anomaly leading to SCD in the young is Purkinje fiber potentials that may be considered
anomalous origin of the left coronary artery from in patients with ventricular arrhythmia storm
the right sinus of Valsalva. The mechanism of consistently provoked by PVCs of similar mor-
SCD is that acute angulation of the coronary phology (class IIb, level of evidence: C) [1].
ostium or compression of the left coronary artery Also ablation of asymptomatic PVCs may be
on the region between the aortic wall and RVOT considered when the PVCs are very frequent to
results in acute myocardial ischemia and the sub- avoid or treat tachycardia-induced cardiomyopa-
sequent VT or VF. The risk of SCD is greatest thy and when PVCs are trigger of untolerated
during the first three decades of life. Diagnosis VT/VF [1] (class IIb, level of evidence: C).
may be difficult because only one-third of
patients have exertional syncope or angina.
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The Role of Home Monitoring
28
Laura Cipolletta and Jenny Ricciotti
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326 L. Cipolletta and J. Ricciotti
Fig. 28.1 Episode marked as VT/VF. The far-field electrogram (A) is present on the top, the near-field ventricular
sense channel (V) is present in the middle tracing, and the marker channel is on the bottom
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28 The Role of Home Monitoring 327
Fig. 28.2 VF episode secondary to T-wave oversensing (top). Capture test (bottom)
The episodes marked as VF are likely to be an Figure 28.2 shows another episode labeled as
artifact with the characteristics of high amplitude VF, inappropriately treated with ATP, and capaci-
and low frequency, not constant but intermittent, tors charging subsequently aborted; in reality it is
which suggest a problem in the integrity of ven- not a real VF but an oversensing phenomenon
tricular lead. from double T-wave counting.
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328 L. Cipolletta and J. Ricciotti
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28 The Role of Home Monitoring 329
Fig. 28.3 EKG. Conclusions: sinus rhythm, normal atrioventricular conduction, type 1 Brugada syndrome pattern
saddleback in V2
aorta, aortic arch, and abdominal aorta. Left exclude a macroscopic failure of the lead, a flu-
atrium of normal size (LA diameter oroscopy was made, which showed no images
M-mode = 30 mm, area 14 cm2). Right atrium was related to fractures or insulation defects of the
normal (area 4c = 14 cm2). Prolapse of the anterior conductors.
mitral leaflet. The tricuspid valve was normal. Given the sensing defect of the ventricular
Normal Dimensions and Thicknesses of the lead, we have reprogrammed sensitivity parame-
Left Ventricle. Normal contractile function (ejec- ters, in order to reduce the oversensing phenom-
tion fraction 60 % with Simpsons biplane enon; when sensitivity parameters of an ICD are
method) and normal wall motion. Right ventricle changed, it is always advisable to perform a defi-
of normal size and with normal contractile func- brillation threshold test (DFT).
tion (TAPSE = 29 mm). Inferior vena cava of nor- During the DFT (Fig. 28.4) after the first
mal size (13 mm), with normal collapse during shock at 2 J to induce VF, some noise entered the
inspiration. The pericardium is normal. Color ventricular channel hiding the real VF; when the
Doppler: mild mitral regurgitation. Normal dia- noise has stopped, the VF signal was very low
stolic function. Minimal tricuspid regurgitation. and unclassified beats were recorded. The shock
PAPs about 20 mmHg. was effectively delivered late by the device, and
There are a lot of factors that should be during the pacing post-shock, every paced beat
weighed in the management of a failed ICD was followed by noise and ICD began to recharge
lead. already the capacitors. To avoid that other
First, the suspected mechanism of lead fail- inappropriate shocks were delivered, ICDs were
ure should be evaluated; for this reason to turned off.
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330 L. Cipolletta and J. Ricciotti
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28 The Role of Home Monitoring 331
Fig. 28.5 Indications to transvenous lead extraction in patients with nonfunctional leads [1]
Fig. 28.6 Chest X-ray postimplantation of the S-ICD (posteroanterior and lateral views)
ERRNVPHGLFRVRUJ
332 L. Cipolletta and J. Ricciotti
vice center. The physician enters a personal low-up, the use of remote pacemaker interrogation
username and password in a specific website to detected actionable events that are potentially
access to data sent. A transmission is made by the important more quickly and more frequently than
patient connecting the RM device to the tele- transtelephonic rhythm strip recordings [7].
phone plug to establish the first connection with Several other clinical studies showed the ben-
the cardiac implantable electronic device (CIED) efits related to the use of RM such as the reduc-
and pressing the button to start the data transfer. tion of outpatient clinic workload, better patient
The CareLink website immediately allows the quality of life, improved implanted system sur-
consultation of exactly the same actualized data veillance, and continuous patient monitoring to
observed in the office. It is always possible to early detect harmful clinical events and to
consult every transmission from the file archive improve patient outcome [812].
on the website. All more recent Medtronic CIED
are compatible with CareLink. The parameters Latitude (Boston Scientic)
showed in the website are the following: This system also utilizes wireless transmission
from the device to a communicator and then to a
Complete program of the CIED central repository. From there, the data is made
Initial report available on an Internet platform. As with the
21 s of EGM recorded at the moment of send- other systems, the Internet site is the same as the
ing data respective manufacturers programmer in order
Battery voltage and estimated remaining life to make the system easier. With this system
of CIED scheduled appointments for remote controlling
Percentage of pacing can be programmed. Additionally, a red light on
Atrioventricular conduction the communicator prompts the patient to initiate
Atrial and ventricular impedance on-demand transmission if an alert has been
Atrial and ventricular automatic threshold detected. Furthermore, the Latitude System
High ventricular rate episodes optionally allows for connection of a blood pres-
High atrial rate episodes sure cuff and a weighing scale for ambulatory
Transthoracic impedance monitoring of heart failure patients.
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334 L. Cipolletta and J. Ricciotti
function system to the patient and appropriate cli- ity of impedance testing early after implant. The
nicians. Using this information, a cardiologist can sensitivity to predict HF events was at best 42 %
monitor disease progression and determine with a positive predictive valve of 38 %. The
whether the implant needs to be reprogrammed. DOT-HF trial [18] studied the clinical utility of
Installation of the SMARTVIEW remote monitor- the OptiVol to track changes in intrathoracic
ing system at the patients home is assisted by a impedance. All-cause mortality and rehospitaliza-
dedicated help desk provided by Sorin. tions did not change from control to
impedance-monitored therapy. The OptiVol is
being used to provide physicians with wireless
Clinical Utility alerts of threshold deviations for worsening car-
diac status in the OptiLink-HF trial [19]. To
Early AF Episodes Detection increase the predictive ability of a diagnostic
Rhythm disturbances can readily be identified in all algorithm, Whellan et al. in the PARTNERS-HF
of these devices allowing early detection of the trial [20] combined more device variables.
developmentofatrialfibrillation.Arrhythmia-related Utilizing data from an independent dataset, the
severe adverse events, caused by long-lasting unde- authors identified a fluid index >100 days or
tected atrial fibrillation, may be avoided by the any two of the following as criterion: (1) long
early detection of atrial fibrillation occurrence as atrial fibrillation duration, (2) rapid ventricular
soon as arrhythmia has been stored in the device rate during atrial fibrillation, (3) a high (60) fluid
memory because of the prompt clinical reaction of index, (4) decreased patient activity, (5) high
the physician. That is particularly meaningful in night heart rate, (6) low heart rate variability, (7)
asymptomatic patients, because this permits timely low CRT pacing, or (8) ICD shocks. Patients with
decisions concerning antithrombotic or anticoagu- positive device diagnostics had a hazard ratio of
lant therapy [22]. Remote monitoring has been also 5.5 (95 % CI 3.48.8; P<0.0001) of HF hospital-
associated with a reduced hospitalization rate for ization with pulmonary congestion within a
atrial fibrillation and a potential lower risk for month. More recently, Landolina et al. [10] in the
stroke [12]. EVOLVO study randomized 200 patients with a
Medtronic wireless ICD/CRT-D along with the
Heart Failure Monitoring CareLink network; half had remote transmission
The majority of these patients suffer from con- on, while the rest had remote transmission off.
comitant heart disease, reduced left ventricular In the control group, audible alerts were turned on
ejection fraction, and symptomatic heart failure. with no transmission of data, while in the inter-
Thoracic impedance can be measured with these vention group, all alerts were transmitted with no
implanted devices and has been considered as a audible alerts. The primary endpoint was emer-
surrogate marker of pulmonary congestion. When gency department or urgent in-office visits, and
a current is passed between the intracardiac lead the secondary endpoint was the number of visits
and the generator, the impedance to the conduc- related to worsening HF and arrhythmias or ICD-
tion of this current is inversely related to the fluid related events. Patients in the remote monitoring
content of the lungs. In a validation study, Yu et al. arm had significantly less events (0.59 vs. 0.93
[6] found that the impedance started to decrease events per year; incident rate ratio 0.65; 95 % CI
15 days prior to worsening heart failure symp- 0.490.88; P = 0.005). As expected for the directed
toms. In a more recent study of HF patients, intervention, the median time from the alert to
Abraham et al. showed that the sensitivity of ICD data review was 24.8 days for the standard
intrathoracic impedance monitoring was far supe- care arm compared with 1.4 days in the remote
rior to daily weight monitoring for predicting monitoring arm. The audible alerts from the ICD/
worsening HF events [16]. On the contrary, the CRT-D devices did not make much of a differ-
SENSE-HF trial failed to show utility of the same ence. In fact, also prior studies have indicated that
technology [17] and also revealed the unreliabil- many alerts go unnoticed by patients [21].
ERRNVPHGLFRVRUJ
28 The Role of Home Monitoring 335
PVC, NSVT, and Slow VT Episode the management of the huge workload that
Monitoring manufacturers advisory causes. The findings
Early detection of an high burden of PVC or in remote monitoring systems can be used to
NSVT/slow VT in CRT patients with heart fail- avoid clinical problems, but in their absence,
ure allows for early treatment, pharmacological nothing can be done [6, 7].
or ablative, of these conditions, and there is evi-
dence that hospitalization rates can be reduced, Early Identication of Device
as the biventricular pacing reduction and worsen- Troubleshooting
ing heart failure could be prevented. Oversensing, electromagnetic interferences, loss
of capture, undersensing, pacemaker-mediated
VT/VF Therapy tachycardia, and prompt starting of therapeutic
Remote monitoring permits to verify earlier measures are used for the early identification of
device therapies and decide a strategy device troubleshooting [23].
personalized for each patient. If the patient had
only an appropriate shock, he will be reassured Improving of Quality of Life
and hospital admission is avoided. In case of 2 While ICDs are highly effective in lowering the
shocks, the RM is useful to guarantee ER admis- rate of arrhythmic deaths in high-risk patients,
sion. RM has been also associated with less the delivery of shocks, especially when repeti-
appropriate and inappropriate ICD shocks [12] tive, remains a major cause of discomfort, anxi-
explained by the early suppression of inappropri- ety, depression, and poor quality of life. RM
ate therapies prompted by recurrent supraven- makes possible the very early detection of causes
tricular tachyarrhythmias or by oversensing and of appropriate and inappropriate ICD interven-
prevention of appropriate therapies by the early tions and rapid implementation of preventive
introduction of antiarrhythmic measures. measures. This may confer important advantages
for the quality of life of patient and device lon-
Monitoring of Lead Performance gevity [24].
Five-year failure rates have been reported to be
between 2 and 15 % [13], and lately problems
with high-profile ICD lead performance Infrastructure and Organization
(Medtronic Sprint Fidelis and St. Jude Medical of Remote Monitoring
Riata) have concerned the medical world [14].
For that purpose, some remote monitoring sys- Two-thirds of the centers in Europe do not have a
tems can report daily lead integrity measure- specific unit for RM, and the RM program is a
ments of more than 90 % of the time in most of part of their traditional device follow-up clinics.
cases [15]. However, lead alert system and The organization for RM in Europe is based
CareLink helped to identify the major defibril- primarily on nursing with easy communication
lator lead problems experienced with with the responsible physician for medical deci-
Medtronic Sprint Fidelis lead [3]. sions. Many centers, however, conduct only spo-
Unfortunately, contrary to other reports, not radic reviews or have no specific protocol, so the
always finding a lead failure with RM is pos- risk exists that some events may be undetected
sible. Several case reports warn that some- and that the opportunity to adjust therapy may
times the Riata leads can fail to deliver therapy not be undertaken [25].
although normal electrical parameters have
been recorded during in-office visits [4].
However, in the report of Hauser et al. [5], References
87 % of the leads analyzed, in a late stage of
disintegration, had shown electrical abnormal- 1. Wilkoff BL et al (2009) Transvenous lead extraction:
Heart Rhythm Society expert consensus on facilities,
ities, which may have been detected by remote
training, indications, and patient management. Heart
monitoring. Remote monitoring offers help for Rhythm 6(7):10851104
ERRNVPHGLFRVRUJ
336 L. Cipolletta and J. Ricciotti
2. Dubner S, Auricchio A, Steinberg JS, Vardas P, Stone P, able cardioverter defibrillator patients in clinical prac-
Brugada J et al (2012) ISHNE/EHRA expert consensus tice: impact on medical management and health-care
on remote monitoring of cardiovascular implantable resource utilization. Europace 10(2):164170
electronic devices (CIEDs). Europace 14:278293 16. Abraham WT, Compton S, Haas G, Foreman B,
3. Wilkoff BL, Auricchio A, Brugada J, Cowie M, Canby RC, Rishel R et al (2011) Intrathoracic imped-
Ellenbogen KA, Gillis AM et al (2008) HRS/EHRA ance vs daily weight monitoring for predicting wors-
expert consensus on the monitoring of cardiovascular ening heart failure events: results of the Fluid
implantable electronic devices (CIEDs): description Accumulation Status Trial (FAST). Congest Heart
of techniques, indications, personnel, frequency and Fail 17(2):5155
ethical considerations. Heart Rhythm 5:907925 17. Conraads VM, Tavazzi L, Santini M, Oliva F, Gerritse
4. Krebsbach A, Alhumaid F, Henrikson CA, Calkins H, B, Yu CM et al (2011) Sensitivity and positive predic-
Berger RD, Cheng A (2011) Premature failure of a tive value of implantable intrathoracic impedance
Riata defibrillator lead without impedance change or monitoring as a predictor of heart failure hospitaliza-
inappropriate sensing: a case report and review of the tions: the SENSE-HF trial. Eur Heart J 32(18):
literature. J Cardiovasc Electrophysiol 22:10701072 22662273
5. Hauser RG, McGriff D, Retel LK (2012) Riata 18. van Veldhuisen DJ, Braunschweig F, Conraads V,
implantable cardioverter-defibrillator lead failure: Ford I, Cowie MR, Jondeau G et al.; DOT-HF
analysis of explanted leads with a unique insulation Investigators (2011) Intrathoracic impedance moni-
defect. Heart Rhythm 9:742749 toring, audible patient alerts, and outcome in patients
6. Yu CM, Wang L, Chau E, Chan RH, Kong SL, Tang with heart failure. Circulation 124(16):17191726
MO et al (2005) Intrathoracic impedance monitoring 19. Brachmann J, Bhm M, Rybak K, Klein G, Butter C,
in patients with heart failure: correlation with fluid Klemm H et al (2011) Fluid status monitoring with a
status and feasibility of early warning preceding hos- wireless network to reduce cardiovascular-related hos-
pitalization. Circulation 112(6):841848 pitalizations and mortality in heart failure: rationale
7. Crossley GH, Chen J, Choucair W et al (2009) Clinical and design of the OptiLink HF Study (Optimization of
benefits of remote versus transtelephonic monitor- Heart Failure Management using OptiVol Fluid Status
ing of implanted pacemakers. J Am Coll Cardiol Monitoring and CareLink). Eur J Heart Fail
54(22):20122019. doi:10.1016/j.jacc.2009.10.001 13(7):796804
8. Varma N, Epstein A, Irimpen A, Schweikert R, Shah 20. Whellan DJ, Ousdigian KT, Al-Khatib SM, Pu W,
J, Love CJ, TRUST Investigators (2010) Efficacy and Sarkar S, Porter CB et al.; PARTNERS Study
safety of automatic remote monitoring for ICD fol- Investigators (2010) Combined heart failure device
low-up: the TRUST trial. Circulation 122:325332 diagnostics identify patients at higher risk of subse-
9. Crossley GH, Boyle A, Vitense H, Chang Y, Mead quent heart failure hospitalizations: results from
RH, CONNECT Investigators (2011) Clinical PARTNERS HF (Program to Access and Review
Evaluation of Remote Notification to Reduce Time to Trending Information and Evaluate Correlation to
Clinical Decision (CONNECT) Trial: the value of Symptoms in Patients With Heart Failure) study. J Am
wireless remote monitoring with automatic clinician Coll Cardiol 55(17):18031810
alerts. J Am Coll Cardiol 57:11811189 21. Simons EC, Feigenblum DY, Nemirovsky D, Simons
10. Landolina M, Perego GB, Lunati M, Curnis A, GR (2009) Alert tones are frequently inaudible among
Guenzati G, Vicentini A et al (2012) Remote monitor- patients with implantable cardioverter-defibrillators.
ing reduces healthcare utilization and improves quality Pacing Clin Electrophysiol 32(10):12721275
of care in heart failure patients with implantable defi- 22. Healey JS, Connolly SJ, Gold MR, IsraelCW, Van
brillators: the EVOLVO (Evolution of Management Gelder IC Capucci A et al.; for the ASSERT
Strategies of Heart Failure Patients with Implantable Investigators (2012) Subclinical atrial fibrillation and
Defibrillators) Study. Circulation 125:29852992 the risk of stroke. N Engl J Med 366:120129
11. Ricci RP, Morichelli L, Santini M (2009) Remote con- 23. Guedon-Moreau L, Lacroix D, Sadoul N, Clementy J,
trol of implanted devices through Home Monitoring Kouakam C, Hermida JS et al (2013) A randomized study
technology improves detection and clinical manage- of remote follow-up of implantable cardioverter defibril-
ment of atrial fibrillation. Europace 11:5461 lators: safety and efficacy report of the ECOST trial. Eur
12. Mabo P, Victor F, Bazin P, Ahres S, Babuty D, Da Heart J 34(8):605614. doi:10.1093/eurheartj/ehs425
Costa A et al (2012) A randomized trial of long-term 24. Schron EB, Exner DV, Yao Q, Yao Q, Jenkins LS,
remote monitoring of pacemaker recipients (The Steinberg JS, Cook JR, Kutalek SP, Friedman PL,
COMPAS trial). Eur Heart J 33:11051111 Bubien RS, Page RL, Powell J (2002) Quality of life
13. ECkstein J, Koller MT, Zabel M, Kalusche D, Schaer in the antiarrhythmics versus implantable defibrilla-
BA, Osswald S et al (2008) Necessity for surgical revi- tors trial: impact of therapy and influence of adverse
sion of defibrillator leads implanted long-term: causes symptoms and defibrillator shocks. Circulation
and management. Circulation 117(21):27272733 105:589594
14. Maisel WH, Kramer DB (2008) Implantable 25. Hernndez-Madrid A, Lewalter T, Proclemer A, Pison
cardioverter-defibrillator lead performance. Circulation L, Lip GY, Blomstrom-Lundqvist C (2014) Remote
117(21):27212723 monitoring of cardiac implantable electronic devices
15. Ricci RP, Morichelli L, Santini M (2008) Home in Europe: results of the European Heart Rhythm
Monitoring remote control of pacemaker and implant- Association survey. Europace 16(1):129132
ERRNVPHGLFRVRUJ
Drug-Related Adverse Events
29
Simone Maffei and Jenny Ricciotti
Temperature: 36.5 C
A 58-year-old woman presented to the Heart rate: 36 beats per minute
emergency department accompanied by Blood pressure: 150/90 mmHg
her family members for complaints of agi- Respiratory rate: 22 breaths/min; oxygen satu-
tation and dyspnea. She had a history of ration while breathing in ambient air, 97 %
bipolar disorder that required lithium, and General: awake but agitated and disoriented
there were no history of suicidal ideation, with aimless movements
recent medication changes, and improper Head, eyes, ears, nose, and throat: normoce-
medication administration and no family phalic, atraumatic, mucous membranes dehy-
history of sudden cardiac death. There drated, extraocular muscles intact, and pupils
were unknown cardiovascular risk factors equally round and reactive to light and accom-
or allergies. Home medication: only lithium modation bilaterally
(but the patient didnt remember the dosage Cardiovascular: regular bradycardia rhythm,
of the drug). S1 and S2 normal, and no pathological heart
According to the relatives, the patient murmurs
had been suffering from gastroenteritis Lungs: no rales, rhonchi, or wheezes; no alter-
with significant diarrhea few days before. ations in tactile fremitus; normal percussion
Abdomen: overweight, no pulsatile masses,
soft, nondistended/nontender, no hepatospleno-
megaly, slightly sore upon deep palpation in the
lower quadrants, and lively peristalsis
Extremities: no cyanosis or clubbing, no
edema, and dehydrated skin
ERRNVPHGLFRVRUJ
338 S. Maffei and J. Ricciotti
Hepatic function (GOT, GPT, -GT, ALP, and In this case, gastroenteritis has led to a state of
total, direct, and indirect bilirubin): normal dehydration which resulted in the deterioration of
Impaired renal function (creatinine 2.10 mg/ dl) renal function and an increase of lithium serum
Electrolytes: Na+ 133 mEq/l and K+ 3.4 mEq/l levels.
Myocardial necrosis markers: CK-MB 2.3 ng/ The patient was monitored and a fluid infusion
ml and TnI 0.30 ng/ml was set up with saline to restore an adequate
Lithium level: 3.7 seq/l blood volume and hydration state.
After a few hours, there was a gradual
A routine 12-lead resting ECG was performed reduction in blood creatinine and lithium levels
(Fig. 29.1ad). with the regression of the electrocardiographic
ECG showed marked sinus bradycardia (heart changes shown above (Fig. 29.2ad).
rate was 36 b/min), normal atrioventricular and The patient was discharged completely
intraventricular conduction, and diffuse altera- asymptomatic the next day, with a normal elec-
tions of ventricular repolarization with negative trocardiogram and with good renal function. We
T waves from V1 to V5; QTc = 435 msec. advised a further psychiatric check for a possible
optimization of the specific medical therapy.
ERRNVPHGLFRVRUJ
29 Drug-Related Adverse Events 339
Fig. 29.1 (ad) Image 1 ECG: sinus bradycardia, heart rate of 36 b/min, and negative T waves from V1 to V5
ERRNVPHGLFRVRUJ
340 S. Maffei and J. Ricciotti
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29 Drug-Related Adverse Events 341
a b
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342 S. Maffei and J. Ricciotti
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29 Drug-Related Adverse Events 343
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344 S. Maffei and J. Ricciotti
in the case of toxicity, with light-headedness, Table 29.3 Calcium channel blockers
seizures, confusion, hallucinations, and comatose Dihydropyridines 1st generation:
state. At cardiac level, there is a slowing of con- nicardipine, nifedipine
duction and reduction in myocardial contractility, 2nd generation:
felodipine, isradipine,
and with very high doses, asystole, advanced nimodipine
heart block, and refractory hypotension may 3rd generation:
occur [5]. amlodipine, nitrendipine
Class Ic antiarrhythmic drugs (flecainide, 4th generation:
lercanidipine, lacidipine
propafenone, encainide) bind to sodium channels
Phenylalkylamine Verapamil
in the activated state. At high plasma concentra-
Benzothiazepine Diltiazem
tions, these agents have a potent negative inotro- Diarylaminopropylamine Bepridil
pic effect; the PR interval and QRS duration are ether
prolonged, and QT interval generally is not very
affected.
Propafenone unlike the other drugs in this
class also possesses subclinical beta-blocker generation of action potential in the pacemaker
properties [5]. cells and for the contraction of smooth muscle
Cyclic antidepressants block sodium channels cells of the peripheral vessel walls.
in a manner similar to quinidine, slowing the rise Verapamil and diltiazem have a major affin-
of phase 0 of the action potential; in case of toxic- ity for cardiac calcium channels and in toxic
ity, an increase in duration of QRS and QT inter- states may induce sinus node and AV node dys-
val can occur, with a depression of myocardial function and depression of myocardial contrac-
contractility [6]. tility. Bradycardia, various degrees of AV
Block of the reuptake of catecholamines in the blocks, and accelerated junctional rhythms are
presynaptic nerve terminal and the antagonist common, and in most severe cases, asystole is a
effect on alpha-adrenergic receptors can cause possible complication; enlargement of QRS
hypotension. A study [7] suggested that an R complex may be an expression of a ventricular
wave in aVR 3 mm and a rightward terminal escape rhythm or a consequence of sodium
vector are predictive factors of cardiotoxicity channel block with a delay in the depolarization
from cyclic antidepressants and correlated with phase 0.
the risk of rhythm disturbances and seizures. At the systemic level, common manifestations
The initial management of all drug intoxica- are hyperglycemia and metabolic acidosis, nau-
tion is based on circulatory and airway support. sea and vomiting, lethargy, confusion, dizziness,
The mainstay treatment of sodium channel and slurred speech.
blocker toxicity is the intravenous administration Dihydropyridines have a major affinity for
of sodium bicarbonate that increases the extracel- vascular smooth muscle cells and, in overdoses,
lular sodium concentration and blood pH. may produce vasodilation, with severe hypoten-
Lidocaine is indicated in case of refractory sion and reflex tachycardia with palpitations and
ventricular arrhythmias. Gastric lavage and acti- flushing [5, 8].
vated charcoal may be effective in limiting Specific treatment of CCB intoxication
absorption if administrated early after drug inges- involves intravenous administration of calcium
tion (12 h). salts (calcium gluconate), the use of glucagon
that promotes calcium entry into cells, and the
Calcium Channel Blockers (CCB) use of vasopressors and inotropes in case of
CCBs block (see Table 29.3) the transport of cal- hypotension and shock; also insulin therapy may
cium ions into the cell from the extracellular be indicated, with a hyperinsulinemia/euglycemia
space, inhibiting voltage-sensitive L-type Ca2+ protocol because it can improve inotropy and
channels; these channels are responsible for the increase peripheral vascular resistance.
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29 Drug-Related Adverse Events 345
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346 S. Maffei and J. Ricciotti
Drugs and Toxins Acting Overdose with agents with intrinsic sympa-
on the Autonomic Nervous System thomimetic activity can be expressed with hypo-
tension and tachycardia.
Beta-Blocker Antagonists Other manifestations of beta-blocker poison-
Pharmacodynamic properties of beta-blockers ing are bronchospasm, lethargy, coma, and
differ in relation to their affinity for beta- hypoglycemia.
adrenergic receptor (see Table 29.5): block of 1 In the management of patients with beta-
receptors has negative chronotropic and inotropic blocker intoxication, glucagon via IV infusion is
effects and reduces renin secretion, while inhibi- used that induces an increase in cAMP levels and
tion of 2 receptors induces relaxation of smooth an influx of calcium in the intracellular space,
muscle cells in the vessels, bronchial apparatus, secondary to the stimulation of a membrane
and gastrointestinal tract and influences glucose receptor in a different site of action compared to
metabolism (inhibition of glycogenolysis and that of beta-blockers. Other therapeutic interven-
gluconeogenesis) [15]. tions are the infusion of atropine, calcium, and
The most common manifestations of beta- catecholamines [5].
blocker toxicity include cardiovascular system
symptoms, with disorders of the conduction sys- Other Drugs Acting on the Sympathetic
tem (sinus node dysfunction, various degrees of Nervous System (Table 29.6)
AV blocks, intraventricular conduction delay) Drugs acting on alpha-adrenergic receptors are
and hypotension, secondary to altered myocar- classified as central and peripheral, with agonist
dial contractility and block of peripheral and antagonist properties.
receptors. Alpha-2 central agonists (clonidine,
Sotalol is the only beta-blocker with class III -methyldopa) and peripheral alpha-1 blockers
antiarrhythmic properties, via blockade of potas- (doxazosin, prazosin, terazosin) are principally
sium channels, causing an increase in the dura- used as antihypertensive drugs; overdose states
tion of repolarization phase, with QTc can be associated with rhythm disturbances
prolongation on ECG and risk of ventricular (sinus, atrial, junctional, and ventricular bradyar-
tachyarrhythmias and TdP. Also propanolol and rhythmias; first-degree AV block; ventricular
acebutolol can induce prolongation of the QTc tachyarrhythmias), severe hypotension, and car-
interval [16, 17]. diac failure.
ERRNVPHGLFRVRUJ
29 Drug-Related Adverse Events 347
Table 29.6 Sympathomimetic drugs and toxins At high dosage, they commonly induce sinus
Drugs Beta-adrenergic agonists (albuterol, tachycardia, but in case of poisoning, we should
dobutamine, epinephrine, isoproterenol, assess for serious supraventricular and ventricu-
norepinephrine, ritodrine, terbutaline) lar arrhythmias.
Theophylline
Ergot alkaloids Clinical manifestations of anticholinergic
Phenylpropanolamine and other over-the- toxic syndrome are flushing, dry skin and mucous
counter sympathomimetics (decongestants membranes, mydriasis, altered mental status,
containing phenylephrine, sinus tachycardia with hypertension, and urinary
pseudoephedrine, ephedrine)
Monoamine oxidase inhibitors retention [19].
Caffeine
Chloral hydrate (sedative and hypnotic Cholinomimetic Toxicity
drug) The most common cause of toxicity from drugs
Illicit Cocaine
and toxins with cholinomimetic properties is
drugs Amphetamines
Phencyclidine the intoxication with organophosphate and
Delta-tetrahydrocannabinol (cannabis) carbamate pesticides. Organophosphorus pesti-
Psilocybin and other hallucinogens cides inhibit esterase enzymes (acetylcho-
Lysergic acid diethylamide
linesterase) with consequent accumulation of
Toxins Ethanol
acetylcholine and stimulation of acetylcholine
Hydrocarbon solvents (e.g., toluene,
benzene, chloroform, etc.) receptors in synapses of the autonomic nervous
Freon (and other fluorocarbon aerosols) system, central nervous system, and neuromus-
cular junctions.
In the early phase, tachycardia is present sec-
A lot of drugs and toxins can cause signs of ondary to the stimulation of nicotinic receptors,
hyperactivity of the sympathetic nervous system followed by the development of bradycardia by
both centrally and peripherally, with positive ino- the stimulation of muscarinic receptors; subse-
tropic and chronotropic stimulation (Table 29.6). quently, even after a few days, in cases of severe
At ECG, sinus tachycardia is very common; at intoxication, AV blocks and asystole may appear
high dosage, supraventricular and ventricular [5], with QT prolongation, ventricular tachycar-
arrhythmias may also occur. Cocaine can induce dia, and TdP.
vasospasm and platelet activation, causing myo- Cases of myocardial infarction have been
cardial ischemia and infarction also in young reported, secondary to parasympathetic hyperac-
subjects with no other cardiovascular risk factors tivity with coronary vasospasm and direct dam-
[18, 19]. age of pesticides on the myocardium [19].
Peripheral alpha-1 agonist drugs (imidazoline
derivatives) are used as nasal decongestants; at
References
high doses by topical administration, they can
induce systemic toxicity, hypertension, and 1. Sabharwal MS, Annapureddy N, Agarwal SK,
tachycardia. Ammakkanavar N, Kanakadandi V, Nadkarni GN
(2013) Severe bradycardia caused by a single dose of
Anticholinergic Toxicity lithium. Intern Med 52:767769
2. Roden DM (2001) Antiarrhythmic drugs. In: Hardman
A lot of drugs, toxins, and other natural sub- JG, Limbird LE (eds) The pharmacologic basis of
stances have anticholinergic properties: antihista- therapeutics, 10th edn. McGraw-Hill, New York,
mines, tricyclic antidepressants, antipsychotics pp 933970
(e.g., phenothiazines, clozapine, olanzapine), 3. Kim SY, Benowitz NL (1990) Poisoning due to class
Ia antiarrhythmic drugs. Drug Saf 5:393420
atropine, scopolamine, toxic plants from 4. Mathis AS, Gandhi AJ (2002) Serum quinidine con-
Solanaceae family containing belladonna alka- centration and effect on QT dispersion and interval.
loids, and toxic mushrooms (Amanita muscaria). Ann Pharmacother 36:11561161
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5. Jeremias A et al (2010) Cardiac intensive care, 2nd 14. Ma G, Brady WJ, Pollack M et al (2001) Electro-
edn. Elsevier Saunders, Philadelphia cardiographic manifestations: digitalis toxicity. J Emerg
6. Lewin NA, Nelson LS (2006) Goldfranks toxicologic Med 20(2):145152
emergencies, 8th edn. McGraw-Hill, New York 15. Bird SB (2007) Beta-adrenergic antagonists. In:
7. Liebelt EL, Francis PD, Woolf AD (1995) ECG lead Shannon MW et al (eds) Haddad and Winchesters
aVR versus QRS interval in predicting seizures and clinical management of poisoning and drug overdose,
arrhythmias in acute tricyclic antidepressant toxicity. 4th edn. Saunders Elsevier, Philadelphia, pp 975982.
Ann Emerg Med 26(2):195201, ISSN 0196-0644 ISBN 978-0-7216-0693-4
8. Pearigen PD, Benowitz NL (1991) Poisoning due to 16. Anderson AC (2008) Management of beta-adrenergic
calcium antagonists: experience with verapamil, blocker poisoning. Clin Pediatr Emerg Med 9:416
diltiazem and nifedipine. Drug Saf 6:408430 17. Delk C, Holstege CP, Brady WJ (2007) Electro-
9. Yap YG, Camm AJ (2003) Drug induced QT prolonga- cardiographic abnormalities associated with poison-
tion and torsades de pointes. Heart 89(11):13631372 ing. Am J Emerg Med 25(6):672687, ISSN
10. Sides GD (2002) QT interval prolongation as a bio- 0735-6757. Emerg Med 9(1), (March, 2008):416,
marker for torsades de pointes and sudden death in ISSN 1522-8401
drug development. Dis Markers 18(2):5762 18. Vincent GM, Anderson JL, Marshall HW (1983)
11. Nelson LS (2002) Toxicologic myocardial sensitiza- Coronary spasm producing coronary thrombosis and
tion. J Toxicol Clin Toxicol 40(7):867879 myocardial infarction. N Engl J Med 309:220239
12. Holstege CP, Eldridge DL, Rowden AK (2006) ECG 19. Murphy NG, Benowitz NL, Goldschlager N (2007)
manifestations: the poisoned patient. Emerg Med Clin Cardiovascular toxicology. In: Shannon MW et al (eds)
North Am 24(1):159177, ISSN 0733-8627 Haddad and Winchesters clinical management of poi-
13. Irwin J (2003) Intensive care medicine. In: Kirk M, soning and drug overdose, 4th edn. Saunders Elsevier,
Judge B (eds) Digitalis poisoning, 5th edn. Lippincott Philadelphia, pp 133165. ISBN 978-0-7216-0693-4
Williams & Wilkins, Baltimore
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Difcult Interpretation of ECG:
Small Clues May Make 30
the Difference. The Role
of the P Wave
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350 A. Maolo and D. Contadini
a b
Fig. 30.1 (a, b) Standard 12-lead ECG at rest. See the chapter for the description
P wave is apparently increased in amplitude part is high and narrow and its followed by a sec-
and duration; however, watching carefully, we ond part that is smaller and larger than the first
can notice that the amplitude of the P wave one. This is a likely sign of biatrial enlargement.
doesnt reach a pathologic value. In fact the max- P wave axis is 90, being negative in aVR and
imum amplitude is 0.20 mV in II lead. Also the aVL leads, biphasic in I lead, and positive in II,
duration is mildly prolonged, with the maximum II, and aVF leads. A negative P wave in aVL is
P wave duration of 120 milliseconds (ms) reached something to think about.
in II lead. P wave morphology can be considered PQ interval is normal (160 ms).
pathological: if we pay attention on the P wave in QRS complex is clearly enlarged (160 ms)
II, III, and aVF leads, we can notice that the first with a normal amplitude. However, it decreases
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30 Difficult Interpretation of ECG: Small Clues May Make the Difference. The Role of the P Wave 351
progressively from V1 to V6. Looking at precor- underwent a surgical correction when she was a
dial leads, the morphology is typical for right child.
bundle branch block. In the limb leads, the QRS Taking a new look to the previous ECG, we
complex has a strange morphology. A deep S can now relate some findings with the anatomic
wave, typical for RBBB, in I and aVL leads is abnormalities.
missing, and the intraventricular and interven- First of all, the axis of the P wave is not nor-
tricular conduction disturbance seems to be more mal. The notch on the apex of the P wave is not a
complex than in a simple RBBB. Also the rS sign of an atrial enlargement. In fact in young
morphology in aVR lead and the rSR in aVL people, the P wave duration can be normal up to
leads are not typical for RBBB. Axis is 130 ms. The notch is a sign of interatrial conduc-
indeterminable. tion disturbance compatible also with the previ-
Repolarization is not abnormal because this is ous surgical intervention.
secondary to the conduction disturbance. The QT The previously diagnosed RBBB is a left bun-
interval measures 400 ms and the QTc 447 ms. dle branch block. In dextrocardia, the morpho-
logical left bundle branch is placed on the right,
Conclusions and its conduction disturbance could be due to
ECG shows sinus rhythm, normal heart rate, right the interventricular septal defect that is always
and left atrial enlargement, normal atrioventricu- present in tetralogy of Fallot. The other intraven-
lar conduction, right bundle branch block, and tricular and interventricular conduction distur-
secondary repolarizations abnormalities. bances could be linked to the previous surgical
Looking at a previous chest X-ray, something intervention.
unexpected was found (Fig. 30.2). The atypical morphology of QRS complex in
The patient had a situs viscerum inversus with aVR and aVL leads can be related to dextrocardia
dextrocardia (please note the cardiac apex and too. In fact, in RBBB, rSR and qR morphol-
the gastric bubble placed on the right side). ogies in aVR lead and a deep or large S wave in
Moreover, the patient had tetralogy of Fallot and aVL lead are common findings, and in this case,
the morphologies are inverted between the two
leads.
By comparing the previous ECG with the fol-
lowing, it is visible that in the typical RBBB
(ECG from another patient below), the QRS mor-
phologies in aVR and aVL are switched
(Fig. 30.3a,b).
A sign that could suggest the presence of dex-
trocardia is the decreasing amplitude of the QRS
complex from V1 to V6 together with the nega-
tive P wave in aVL. This happens because the
electrodes are placed on the left part on the chest
and the electric signal from the heart is progres-
sively going farther from the precordial leads, in
particular from the left ones.
ERRNVPHGLFRVRUJ
352 A. Maolo and D. Contadini
a b
Fig. 30.3 (a, b) Standard 12-lead ECG at rest from another patient having a situs solitus and an RBBB. Please compare
with the ECG in Fig. 30.1
atrium first and then through the interatrial sep- cordial leads from V3 to V6, the P wave is gener-
tum to the left atrium. ally positive. Conversely in V1 and V2, normal P
Its normal duration varies from 70 to 140 ms wave is often diphasic and sometimes even
even in normal subjects [1]. A P wave lasting negative.
more than 110 ms can be considered abnormal. Talking about the normal amplitude of the P
The P wave axis is the result of the electrical wave, we have to say that its affected by many
activation of the right atrium (directed anteriorly factors such as the distance of electrodes from the
first and then posteriorly when involving the infe- heart and the level of atrial fibrosis. In the limb
rior wall) and of the left atrium (directed posteri- leads, a P wave inferior or equal to 0.25 mV or
orly). Therefore, on the limb leads, the normal P 25 % of the following R wave is considered as
wave range is 0 to +75. Thats why the normal normal amplitude. In the precordial leads, the
P wave is positive in I and II leads and always normal amplitude is a bit lower and doesnt
negative in aVR lead. Moreover, also in the pre- exceed 0.15 mV [1].
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30 Difficult Interpretation of ECG: Small Clues May Make the Difference. The Role of the P Wave 353
30.3 Interatrial Conduction Delay ectopic focus can cause P waves of different mor-
phology related to the presence of intra-atrial or
Atrial depolarization begins in the sinus node; interatrial conduction disturbances. Likewise,
from here, the electrical impulse goes through the ectopic P waves originating from different foci
internodal fascicles (fibers that connect sinus can have similar or the same morphology [1, 3].
with the AV node). There are three bundles: the Despite this wide variability, some ectopic
Bachman fascicle (anterior), the Thorel fascicle foci are identifiable with fairly good precision.
(in an intermediate position), and the Wenckebach For example, if the ectopic impulse originates
fascicle (posterior). The last one conducts the from a focus close to the AV node, a negative P
impulse from the right to the left atrium, too. So, wave can be visible in II, III, and aVF leads,
the atria activation begins from the right atrium while it is positive in aVL and aVR leads. On the
and then reaches the left one. The normal dura- contrary, if the ectopic focus is located in the left
tion of P wave is from 50 to 80 ms. A P wave atrium, the P wave is negative in aVL and posi-
duration superior to 110 ms is pathological and tive in aVR (similarly to the P wave in dextrocar-
related to interatrial conduction delay. This con- dia), while in the inferior leads, it can be positive
dition is caused by a complete or partial interrup- or negative depending on the part of the left
tion of the Bachman fascicle or other connecting atrium in which the focus is placed.
atria fibers. Usually the interatrial conduction
delay is associated with a modification of the axis
of the terminal part of P wave. It is more negative 30.5 Right Atrial Enlargement
(from 30 to 60) with a caudal-cranial activa-
tion of the left atrium. This pattern of activation is Right atrial enlargement (RAE) is a common con-
visible as a biphasic P wave (positive-negative, sequence of various cardiopulmonary diseases. As
with terminal negative component evident in we already said, the atrial depolarization firstly
inferior leads) lasting more than or equal to involves the right atrium, so it is easy to understand
100 ms. The interatrial conduction delay is highly that RAE alterations interest the initial portion of P
specific of left atrium enlargement [1, 2]. wave with voltage increase but without modifica-
tion in terms of P wave duration (Fig. 30.4a, b).
Some typical P wave modifications can help to rec-
30.4 P Wave Other Than That ognize RAE: P wave (or initial positive P wave
from the Sinus Node deflection) > 0.15 mV (more specific 0.20 mV)
in V1 and V2 leads; an initial positive part > 40 ms
The P wave is defined not to be sinusal when it in V1 when P wave is biphasic in this lead; high
originates from an ectopic focus that can be and sharp P wave in inferior leads (II, III,
located in variable parts of the atria. A non-sinus aVF) 0.25 mV; and P wave axis +75 (it can
P wave can be present as a premature atrial reach +90 too). The last modification is very
impulse (isolated or in pairs), as an ectopic atrial strictly associated with COPD. Sometimes the
tachycardia (heart rate 100 bpm), or as an ecto- RAE correlated P wave modifications can be asso-
pic atrial rhythm (heart rate < 100 bpm). ciated with QRS modification as increased volt-
In all these cases, the P wave has a different ages of right ventricle electrical vectors or delayed
morphology and axis compared with the sinusal right ventricle depolarization [1, 2].
P wave. Analyzing its characteristics on the sur-
face ECG can help us to identify the location of
the ectopic focus, but it isnt always accurate. 30.6 P Pulmonale
This variability depends on the possible presence
of ectopic focus close to the sinus node and there- A P wave is defined pulmonale when it
fore originating P wave very similar to that pres- appears as a tall and peaked P wave in the
ent in normal sinus rhythm. Moreover, a single inferior limb leads (II, III, and aVF) and
ERRNVPHGLFRVRUJ
354 A. Maolo and D. Contadini
consequently having an axis superior to 70 [1]. severe COPD is responsible for alterations of
This finding on the ECG has different correla- the P wave axis more than its morphology. This
tions, but its usually associated with pulmonary axis deviation over 70 is due to the hyperinfla-
hypertension. The P pulmonale is most fre- tion of lungs, always present in these kinds of
quently associated with congenital heart disease patients.
such as tetralogy of Fallot, pulmonic stenosis, Despite all, the P pulmonale pattern isnt
tricuspid atresia, or interatrial septum defects strictly correlated with the increase of right atrial
and interventricular septal defects in the pres- volume, and it can be present even in healthy sub-
ence of Eisenmenger syndrome. Furthermore, in jects. In these cases, usually a sympathetic stimu-
patients with chronic cor pulmonale, this ECG lation, resulting in a stronger and synchronous
pattern has an incidence of about 20 %. [1] As atrial contraction, or the vertical position of the
expected, the P pulmonale is a marker of chronic heart can explain abnormalities in P wave axis
lung disease, but it is mostly associated with and morphology similar to those present in the P
COPD and then pulmonary fibrosis. Moreover, pulmonale pattern [1].
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30 Difficult Interpretation of ECG: Small Clues May Make the Difference. The Role of the P Wave 355
Left atrial enlargement (LAE) is a common con- A prolonged P wave can be related to echocardio-
sequence of left ventricular or mitral valve dis- graphic findings of left or biatrial enlargement
eases. The left atrial depolarization is the last and consequently help us to identify patients with
part of atrial activation, so the LAE modifica- a high risk of developing atrial fibrillation. In a
tions involve the final component of P wave with clinical trial of 660 patients, who underwent
durations increase but without significant volt- dual-chamber pacemaker implantation, P wave
age alterations (Fig. 30.4a, c). Some typical P duration was measured using the standard 12-lead
wave modifications can help to recognize LAE: ECG (50 mm/s velocity). A P wave duration
P wave duration more than or equal to 120 ms in superior to 100 ms was identified in a group of
limb leads; left deviation of P wave axis more patients with a higher risk for developing persis-
negative than +30; and biphasic P wave in V1 tent atrial fibrillation and atrial fibrillation-related
with negative terminal component more than or hospitalization [4].
equal to 40 ms and with a minimum of 1 mV The P wave duration analysis can be more
bifid P wave (usually in dII, dI, aVL, V3, V4, V5, accurate using signal-averaged ECG (SAECG).
or V6), with an interval between the two peaks SAECG is a particular ECG technique using
longer than 40 ms. A more peak-to-peak prolon- cardiac electric signals from many surface elec-
gation could be the sign of a mitral disease, often trodes. The values measured with all the leads
a severe stenosis. This pattern is also defined as are averaged to minimize interference and to see
P mitrale [1, 2]. even the smallest alterations. A prolonged
signal-averaged P wave duration compared to
the standard 12-lead ECG was found to be a
30.8 Biatrial Enlargement more precise marker for the development of
atrial fibrillation [5].
The P wave abnormality during biatrial enlarge- Other important findings detectable using
ment can be simply considered as the summa of SAECG are atrial late potentials. Late potentials
the RAE and LAE alterations (Fig. 30.4a, d). are very-low-amplitude electric signals not visi-
ECG findings could be a P wave duration more ble with the standard 12-lead ECG. The QRS
than or equal to 120 ms associated with an ampli- late potentials originally were studied to esti-
tude more than or equal to 2.5 mV; a diphasic P mate the ventricular arrhythmia risk. Similarly
wave (positive-negative) in V1 with the positive the P wave (or atrial) late potential can be useful
component of at least 1.5 mV and a negative to stratify the risk for paroxysmal atrial fibrilla-
component longer than 40 ms with an amplitude tion. Budeus et al. hypothesized that atrial late
of 1 mV or more; and the presence of notched P potentials found on P wave SAECG could have a
wave in left precordial leads and high P wave in role in the development of paroxysmal atrial
right precordial leads [1, 2]. fibrillation [6]. However, the predictive value of
atrial late potentials has not been demonstrated
univocally yet.
30.9 P Wave and Arrhythmias
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356 A. Maolo and D. Contadini
be considered as the sign of abnormal atrial elec- affect accuracy and reliability of P wave
trical impulse propagation. In the literature, the dispersion as a noninvasive predictor of paroxys-
most used cutoff value for high P wave dispersion mal atrial fibrillation.
is considered to be 40 ms [7]. This value has been
demonstrated to have a sensitivity of 83 % and a
specificity of 85 % with a positive predictive value References
of 89 % in detecting subjects who had history of
1. Surawicz B, Knilans TK (2008) Chous electrocardi-
paroxysmal lone atrial fibrillation [8]. Calculating
ography in clinical practice, 6th edn. Saunders
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3. Wu D, Denes P, Amat-y-Leon F et al (1975)
fibrillation [8]. Moreover, other studies demon-
Limitations of the surface electrocardiogram in diag-
strated that the P wave dispersion calculated on nosis of atrial arrhythmias. Am J Cardiol 336:91
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postoperative period (after CABG) and in patients
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with hypertension [9, 10]. 5. Steinberg SA, Guidera JS (1993) The signal-averaged
For a more accurate evaluation of P wave P wave duration: a rapid and noninvasive marker of risk
dispersion, SAECG was also used and some of atrial fibrillation. J Am Coll Cardiol 21:16451651
6. Budeus M et al (2003) Detection of atrial late poten-
more precise markers were studied. In particu-
tials with P wave signal-averaged electrocardiogram
lar, P wave dispersion index (P wave duration among patients with paroxysmal atrial fibrillation. Z
standard deviation/P wave duration mean value Kardiol 92(5):362369
100) calculated in 40 subjects was demon- 7. Dilaveris PE, Jalavos JE (2001) P wave dispersion: a
novel predictor of paroxysmal atrial fibrillation. Ann
strated to have an 83 % sensitivity and 81 %
Noninvasive Electrocardiol 6(2):159165
specificity values in the identification of 8. Dilaveris PE, Gialafos EJ, Sideris SK et al (1998)
patients with a history of paroxysmal atrial Simple electrocardiographic markers for the predic-
fibrillation [11]. tion of paroxysmal idiopathic atrial fibrillation. Am
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The rationale for using P wave dispersion as a
9. Kloter Weber U, Osswald S, Huber M et al (1998)
predictor of atrial fibrillation is that a high dis- Selective versus nonselective antiarrhythmic approach
persion could be considered the electric sign of for prevention of atrial fibrillation after coronary sur-
nonhomogeneous atrial conduction and conse- gery: is there a need for preoperative risk stratifica-
tion? A prospective placebo-controlled study using
quently may reflect an electrical instability of the
low-dose sotalol. Eur Heart J 19:794800
atria. 10. Ciaroni S, Cuenoud L, Bloch A (2000) Clinical study
Nevertheless, the techniques used for ECG to investigate the predictive parameters for the onset
recording and P wave duration and dispersion of atrial fibrillation in patients with essential hyper-
tension. Am Heart J 139(5):814819
measurement were not standardized in the differ-
11. Villani GQ, Piepoli M, Rosi A, Capucci A (1996)
ent trials. Finally, we have to consider an interob- P-wave dispersion index: a marker of patients with par-
server and intraobserver variability that may oxysmal atrial fibrillation. Int J Cardiol 55(2):169175
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