Notes on sudden cardiac death

Notes on Sudden Cardiac Death

Definitions

• Unexpected natural death from a cardiac cause within a short

time period (generally demise from cardiovascular collapse
<= 1 hour from onset of symptoms according to Framingham
Heart Study) in a person without any prior condition that
would appear fatal (Zipes and Wellens 1998; 98:2334-2351)
(Leor et al NEJM 1996; 334:413-419) (Marks and Greene
Cardiac Arrhythmias 1995)
• Other researchers use WHO definition of sudden death as
death occurring within 24 hours of the onset of acute
symptoms (Myers and Dewar Br Heart J 1975 37:1133-1143)

• Prodromal symptoms often non-specific, and chest pain

(ischaemia), palpitations (tachyarrhythmia) or dyspnoea
(cardiac failure) are suggestive only. (Zipes and Wellens
1998; 98:2334-2351)

Epidemiology

• Sudden cardiac death accounts for 300-400,000 deaths per

year in US, and is most common and often the first
presentation of CHD responsible for >50% of the mortality
from cardiovascular disease in US (Zipes and Wellens 1998;
98:2334-2351) or between 200,000 and 600,000 p.a. in US
(Marks and Greene Cardiac Arrhythmias 1995) (Hirsch and
Adams Spitz and Fisher) 80-90% of sudden cardiac death
patients have significant CAD (Chugh et al Circulation 2000
102(6):649-654)

• Sudden cardiac death in those with structurally normal heart

– 20% of sudden cardiac deaths (Brugada et al 2004
Circulation 109:30-35) 50% (Chugh et al Circulation 2000
102(6):649-654) 80% have CHD – smaller amount of non-
atherosclerotic coronary artery causes e.g. arteritis,
embolism, dissection and malformations such as anomalous
left coronary artery origin (Zipes and Wellens 1998; 98:2334-
2351)

• In Paris study, 72% of sudden cardiac death victims had no

cardiac history. 83% occurred at home (and at rest), 30% of
those were sleeping. Sudden cardiac death usually occurred
on a background of severe coronary disease with multivessels
stenosed, but rarely thrombosed (15%) (Fornes et al Journal
of Forensic Sciences 1993 38(5))

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 Notes on sudden cardiac death

Davies and Popple (Histopathology 1979 3:255-277) stated

that 33% have recent occlusive thrombus, whilst 66% have
stenosis only. Occlusive thrombus present in 30% cases of
sudden cardiac death, mural thrombus in 43% and plaque
fissuring in 8%. Davies 1992 Circulation 85: (Supl 1) 19-24).

New thrombotic event underlies 50-70% of sudden deaths

caused by IHD. (Davies Heart 2000 83:361-366) Occlusive
thrombus recognised by hospital pathologists in 23% of cases,
recent MI in 20% and old MI scar in 56%. Occlusive thrombus
more common in those with prodromal chest pain. 25% of
non-fatal infarctions are silent and medically unattended.
(Norris Heart 2000 83:726-730)

50-75% of sudden death cases have thrombus (remainder

have >75% cross sectional area luminal narrowing) (Kolodgie
Heart 2004 90: 1385-1391) New coronary plaque rupture
independent of old MI is major cause of sudden death in those
with old MI (recent thrombus/ plaque rupture in 55%,
arrhythmia in 24%, pump failure in 14%) (Takada et al Legal
Medicine 2003 5:S292-294)
• 4.1% in 16-64 age-group are unexplained (Sudden
Arryhthmic Death Syndrome) (Behr et al 2003 Lancet
362:1457-59)
• Incidence of sudden cardiac death in England in healthy
people 16-64 years is 11 per 100,000 (3500 deaths) per year
(Behr et al 2003 Lancet 362:1457-59)
• Most people who die of SADS are young males who die while
inactive or in sleep (Behr et al 2003 Lancet 362:1457-59)
• Ventricular fibrillation is the main mechanism of sudden
cardiac death – vast majority have structural heart disease,
those who do not have ‘idiopathic VF’. (Gaita F et al
Circulation 2003; 108:965-970)
• 80% occur at home and 40% are unwitnessed (Maastricht
study) (Zipes and Wellens 1998; 98:2334-2351)
• First-degree relatives of those suffering sudden cardiac death
identified 7 families with familial cardiac disease, with
probable Long QT syndrome predominating. (Behr et al 2003
Lancet 362:1457-59)
• Familial history of sudden cardiac death is associated with
major (resuscitated cardiac arrest, syncope) and minor
(palpitations, dizziness, atrial fibrillation) arrhythmic events
and inducible VF at programmed stimulation (Gaita F et al
Circulation 2003; 108:965-970)
• Myocardial fibrosis provides a predisposition to electrical
instability, re-entry circuits and fatal arrhythmias. (Lecomte D
et al Journal of Forensic Sciences 2003; 38(3)? Page)

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 Notes on sudden cardiac death

• Sudden death due to primary VF without evidence of

structural heart disease occurs in approximately 5% of cases.
(Zipes and Wellens 1998; 98:2334-2351)
• 33% of people present with CAD present with sudden cardiac
death (Chi and Kloner stress and MI)
• in sudden cardiac death 95% of hearts have an abnormality,
although in 30% this abnormality is non-specific e.g..
Interstitial fibrosis (Chugh et al Circulation 2000 102(6):649-
654)
• acute MI was the underlying mechanism of sudden cardiac
arrest (out-of-hospital) in 24/47 patients; ischaemic event or
primary arrhythmia due to old MI in 19/47 (de Vreede-
Swagemakers JJM et al Heart 1998 79:356-361)
• new thrombotic event underlies 50-70% of sudden deaths
caused by Ischaemic Heart Disease (Davies Heart 2000
83:361-366)

Risk Factors

• Generally identify risk of structural heart disease underlying

sudden cardiac death rather than the proximate precipitator
of the event. 80% of those who suffer sudden cardiac death
have CHD (Zipes and Wellens 1998; 98:2334-2351)

• Incidence of sudden cardiac death increases with age, sex

variation M>F (3-4 times higher), white=black (because
incidence of heart disease increases with age)
• Among people with CHD, the proportion of sudden deaths
decreases with age. Peaks of incidence birth-6 months (SIDS)
and 45-75 due to CHD
• Physical activity controversial. Vigorous activity – can trigger
sudden death and MI (increased platelet adhesiveness) but
decreased in moderate activity. Regular exercise in dogs
increases vagal activity and reduces ischaemia induced VF
and death. Vigorous activity in untrained people may have
adverse effects – relative risk in men with low levels of
habitual activity = 56 (95% CI 23-131) whilst in those with
high levels of habitual activity = 5 (95% CI 2-14) Myocardial
Infarction Onset Study 5 fold increase of risk of MI on heavy
exertion and 2 fold increase in Triggers and Mechanisms of
Myocardial Infarction Study (TRIMM) (Willich et al Circulation
1993 87(5):1442-1450). Maastricht Sudden Death study –
67% of sudden deaths were inactive at time of event. Sexual
activity doubles risk of MI (Chi and Kloner stress and MI)
• Anatomy – acute changes in plaque morphology (thrombus,
plaque disruption or both >50% of sudden cardiac deaths).
Plaque erosion is common. Rupture >older women. ?role of

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apoptosis in genesis of arrhythmias or conduction

disturbances?
• Hypertension
• LVH
• Impaired left ventricular function (particularly in men) – in
severe heart failure, non-sustained VT may be independent
marker of increased mortality due to sudden cardiac death.
Also major independent predictor of sudden death in
ischaemic and non-ischemic cardiomyopathies. 50% of those
who die due to heart failure do so suddenly.
• Intraventricular conduction block
• Elevated serum cholesterol – predisposition to vulnerable
plaque rupture?
• Glucose intolerance
• Decreased vital capacity
• Smoking –Framingham study 2.5 times risk of sudden death
in smokers of >20 per day (increased platelet adhesiveness,
catecholamine release?)
• Relative weight
• Heart rate
• Emotional stress/arousal –fear, anger, tension, sadness,
police questioning or arrest, altercations (verbal or physical)
(Lecomte et al 1996 79:1-10)
o role of emotional stress in coronary heart disease
suggested by John Hunter ‘my life is at the mercy of any
scoundrel who chooses to put me in a passion’.
(Lecomte et al For Sci Int 79:1-10)
o stressful cardiac sudden death occurs primarily in those
with severe heart disease (40/43 cases) with no
premonitory symptoms, and occurred instantaneously.
75% of cases occurred during the stress or within
minutes afterwards. (Lecomte et al For Sci Int 79:1-10)
o Reich et al (JAMA 1981 246(3):233-235) studied people
who had VF and identified preceding acute psychological
disturbances in the preceding 24 hours in 21% –
predominant affect was anger. Others included acute
depression, fear, anticipatory excitement and grief.
o Sporting events – increased mortality from CHD on day
of Netherlands v France 1996 European Football
Championship (penalty shoot out); increased
admissions for acute MI day of England v Argentina
1998 World Cup (penalty shoot out); reduction in
mortality from MI in men following France winning 1998
World Cup (Chi and Kloner stress and MI)
o Disasters – Los Angeles /Northridge earthquake 1994 –
sharp increase in sudden cardiac deaths on day of
earthquake (from a daily average of 4 in preceding

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 Notes on sudden cardiac death

week to 24 on day of earthquake – relative risk 2.4

(95% CI 1.9-3.0).

Most deaths occurred in those with CAD and the team

estimate that 41% of sudden deaths in persons with
atherosclerotic cardiovascular disease that occur under
ordinary circumstances are related to a triggering
mechanism.

In 2/3rds symptoms developed or the victim died

immediately or within the first hour after the
earthquake. Unusual physical exertion contributed in
only 3 cases. Hospital admissions for acute MI increased
by 35% in California in week after earthquake, and
those with implantable cardioconvertors experienced an
increase in VT /VF in 2 weeks following quake. (Leor et
al NEJM 1996; 334:413-419)

1981 Athens earthquake – increase in deaths due to

atherosclerosis (Trichopoulos et al Lancet 1983 26:441-
443); Massachusetts Blizzards 1974-78 increase of 22%
deaths due to atherosclerosis. (Glass and Zack Lancet
1979 1:485-487)
o War – initial days of 1991 Gulf War – missile strike in
Israel, sharp increase in sudden cardiac deaths (Meisel
et al Lancet 1991 338:660)
o Life events – on impact of collapse and death of close
person, during period of acute grief (within 16 days),
threat or loss of close person, during mourning or
anniversary, loss of status or self esteem, personal
danger or threat of injury, real or symbolic, after danger
is over, reunion, triumph, happy ending (peak ages
affected men 45-55, women 70-75).

Common denominators = overwhelming excitement,

loss of control over situation/ self, giving up/
hopelessness/ helplessness (Engel Folklore or folk
wisdom?) Cardiac Arrhythmia Pilot Study (CAPS) –
depression, type B behaviour and low pulse-rate
reactivity to challenge all significant predictors of
cardiac arrest.

Recurrent Coronary Prevention Project – type A

behaviour significant predictor of sudden cardiac death
(in post- MI follow up). (Willich et al Circulation 1993
87(5):1442-1450)-

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 Notes on sudden cardiac death

o Day of week – stress of returning to work – increased

MI incidence on Mondays (Chi and Kloner stress and MI)
• Time of day – circadian rhythm (Chi and Kloner stress and MI)
(Willich et al Circulation 1993 87(5):1442-1450)- more
sudden deaths (three-fold increase), strokes and MIs,
episodes of transient myocardial ischaemia, ventricular and
supraventricular arrhythmias in morning on wakening/ hours
immediately after arising from bed ? sympathetic discharge in
response to venous pooling which triggers increased heart
rate, systemic arterial blood pressure and increased blood
coagulability (viscosity and platelet aggregation), decreased
fibrinolytic activity? (Leor et al NEJM 1996; 334:413-419)
sudden deaths associated with the evening (6-10pm) (Myers
and Dewar Br Heart J 1975 37:1133-1143) (Willich et al
Circulation 1993 87(5):1442-1450)
• Relationship with food –association of sudden death with the
hour after a meal (Myers and Dewar Br Heart J 1975
37:1133-1143)
• Type of water - Davies and Popple (Histopathology 1979
3:255-277) reported an excess of sudden cardiac deaths in
areas with soft water
• post MI – whole set of predictive factors (MADIT trial
population (Multicentre Automatic Defibrillator Implantation
Trial) – spontaneous non-sustained VT, inducible VT not
suppressed by iv procainamide and an ejection fraction of
<35%
• Alcohol – heavy drinking (>6 drinks daily) can induce cardiac
arrhythmias and VT and have a 2 fold increase in risk
compared to other drinking categories combined, particularly
in older drinkers (50-59). This association was clearer in those
with no evidence of prexisting ischaemic heart disease. Heavy
drinking raises blood pressure. Heavy drinking is associated
with an increase in incidence of sudden death as well as the
suddenness of death. (Wannamethee and Sharper Br Heart J
1992 68:443-8) Arrhythmias described in heavy drinkers after
binges include isolated ectopic beats, AF, paroxysmal atrial
tachycardia, junctional tachycardia and VT. Mechanism
unknown. Conduction defects known in overt alcoholic
cardiomyopathy. (Ettinger et al Am Heart J 1978 95(5): 555-
562) alcohol increases blood pressure. (Hirsch and Adams)
Sudden death also recorded in alcoholic fatty liver (Sheppard
and Davies).
• ECG abnormalities – AV block or intraventricular conduction
defects and QT prolongation in survivors of out-of hospital
cardiac arrest and non-sustained VT.
• Autonomic state – sinus node activity taken as surrogate for
autonomic activity within ventricles - baroreflex sensitivity,

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reflecting a vagal response to acute blood pressure elevation

is reduced in patients at risk of sudden death. Heart rate
variability reflects tonic vagal action and baroreflex activity
reflects reflex vagal activity.

Chaos theory – apparently irregularly irregular events, such

as ventricular ectopy, are non-randomly distributed in time,
and their clustering can be quantified by fractal geometric
analysis, which could help identify at risk patients.

Myocardial infarction produces regional cardiac sympathetic

and parasympathetic dysfunction in infracted area and in
regions apical to infarct (disruption of fibres crossing area of
infarction). Denervated regions are more sensitive to
catecholamines, resulting in differential conduction/
refractoriness, predisposing to arrhythmias. (Similar situation
also seen in heart failure and ventricular dilatation). I.e.
Creates electrical heterogeneity, favouring development of VF.

Vagal stimulation is profibrillatory to atria, but may mitigate

ventricular arrhythmias. Increase in basal tone or acute
stimulation of the CNS by drugs or electrical stimuli lowers the
threshold for cardiac electric instability and may evoke a
variety of arrhythmias, including VF (Willich et al Circulation
1993 87(5):1442-1450)

Deaths from vagal inhibition have been described by Simpson

(1949 Lancet 558-560) – afferent stimulation from sensory
nerves of the skin, pharynx, glottis, pleura, peritoneum
covering viscera and extending into the spermatic cord, of the
cervix, of the urethra, and of the peritoneum via spinal cord
lateral tracts to the vagal nucleus to exert their effect via
efferent fibres. Particularly important in any pressure to the
neck or during medical procedures without adequate sedation/
anaesthesia. Blow to larynx or upper abdomen, kick to
scrotum, pressure on carotid sinus, cannulation of cervix etc
implicated in sudden death due to vagal reflex (Hirsch and
Adams).
• Carotid sinus pressure – usually used to elucidate underlying
mechanism and prompt treatment of various supraventricular
tachycardias and their differentiation from ventricular
arrhythmias. Case reports of VT arising as a result of coronary
sinus pressure, mechanism unknown. Ventricle appears to be
influenced by vagal stimulation, and increased vagal tone as
part of the carotid sinus reflex produces a negative inotropic
effect on the left ventricle. ? do those who experience
problems have an unusually rich ventricular cholinergic

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innervation? After release of CSP there is a reflex sympathetic

stimulation, and catecholamines released come from
myocardial stores rather than those of sympathetic nerve
endings, allowing possible asymmetric distribution of
catecholamines contributing to genesis of ventricular ectopics
and arrhythmias. Also, CSP induces AV block, and decreased
heart rate, associated with increased asynchrony of recovery
of excitability of ventricular muscle. (Cohen Am Heart Journal
1972 84(5):681-686)
• One group has reported the apparent association of sudden
death in adults with a common mitochondrial DNA deletion
(mtDNA4977 deletion), with cardiac muscle being particularly
affected (Polisecki et al J Forensic Sci 2004 49(6):1-4)

• Transient Risk Factors (Zipes and Wellens 1998; 98:2334-

2351) – structural cardiac abnormalities provide substrate
upon which transient risk factors operate.

o Myocardial ischaemia – assumed that in CHD transient

ischaemia, perhaps caused by coronary artery spasm or
platelet thrombi precipitate lethal arrhythmia (because
20% only of cardiac arrest survivors develop transmural
infarction). Perhaps it is combination of ischaemia,
hypertrophy, CCF and cardiac dilatation as well as
regional autonomic dysfunction? May be caused/
exacerbated in certain circumstances by anti-arrhythmic
drugs e.g.. Flecanide in CAST ( Cardiac Arrhythmia
Suppression Trial)
o Reperfusion
o Haemodynamic dysfunction
o Abnormalities in electrolytes (hypokalaemia and
hypomagnesaemia)
o Changes in Ph or P02
o Influence of central and peripheral neurophysiological
actions
o Transient effects of drugs, toxins or alcohol

Degree of coronary artery atherosclerosis and sudden

cardiac death

• Coronary blood flow begins to reduce with stenosis >50% and

decreases rapidly when it exceeds 70%. Calculation of %
diameter stenosis doesn’t take into account other factors
influencing physiological impact of the stenosis e.g. lesion
length or geometry. PM studies using perfusion-fixed material
(at or near diastolic pressure levels) have shown stenotic

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lumen to be usually circular, even in advanced lesions. The

problem with determining % stenosis is that adjacent areas
are used as a reference, but these are not usually free of
disease, and the effect of arterial remodelling (to conserve
lumen diameter) will result in underestimation. (Stary et al
Circulation 1995 92: 1355-1374)
• The heart receives 1/20th of the cardiac output under basal
conditions. This increases 3-4 fold with exercise, to
accommodate the increase in oxygen demand. Increase in
blood flow is needed by myocardium due to the near complete
oxygen extraction under basal conditions. Coronary artery
disease of epicardial vessels incorporates a new pathological
resistance to coronary blood flow;
o Stenosis of <50% is unlikely to be of haemodynamic
significance
o Stenoses >50% - there is a complex and curvilinear
relation to reduction in maximum coronary flow
o Longer lesions produce greater haemodynamic changes
(studies now use PET to measure coronary flow) (Aikaw
and Libby. Cardiovascular Pathology 2004 13: 125-138)
• Prinzmetal’s variant angina – mild coronary stenoses
displaying vasoconstrictive responses, sufficient to occlude
artery, causing ST elevation, which can resolve by the
administration of nitrates. The reason for the sensitivity of the
arteries is unknown. (Aikaw and Libby. Cardiovascular
Pathology 2004 13: 125-138)
• Microvascular angina – instability of microvascular tone on
exercise (Aikaw and Libby. Cardiovascular Pathology 2004 13:
125-138)
• 33% of sudden cardiac deaths are caused by acute total
coronary occlusion by thrombus (Willich et al Circulation 1993
87(5):1442-1450) others say very many fewer thrombi will be
found but that sudden cardiac death occurs on a background
of severe coronary artery disease (Myers and Dewar Br Heart
J 1975 37:1133-1143)
• episodes of symptomatic or asymptomatic myocardial
ischaemia with underlying chronic coronary artery disease are
associated with increased risk of sudden arrhythmia (Willich
et al Circulation 1993 87(5):1442-1450)
• 40-86% of those surviving cardiac arrest have >75% stenosis
• recent occlusive thrombus found in 15-64% of sudden cardiac
death
• minimum degree of disease reasonably associated with
sudden death is one area of 85% stenosis (pinpoint) Davies
and Popple (Histopathology 1979 3:255-277). They go on to
say that 75% is the least degree of stenosis reasonable to
cause death, when taken in conjunction with circumstances of

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death. In a later article Davies (Histopathology 1999 34:93-

98) states that 75% is ‘pinpoint’.
• For practical reasons, Davies and Popple (Histopathology
1979 3:255-277) state that ‘it is reasonable to assume that
under 65 yrs-of-age heavy calcification is likely to be
associated with enough stenosis to cause death – over 65 the
correlation of calcification with stenosis is far less good.
• no specific pattern of coronary artery lesions favour sudden
death (Zipes and Wellens 1998; 98:2334-2351) although
Myers and Dewar (Br Heart J 1975 37:1133-1143) found
sudden death to be associated with recent occlusion of the
right coronary artery and with posterior infarction than of the
left anterior descending and anterior infarction.

• acute ischaemia can be provoked by spasm (e.g. at the site of

an eccentric coronary plaque in which a segment of normal
media is retained (Davies Histopathology 1999 34:93-98)),
platelet thrombi, dissection, plaque rupture or other
vasoactive event

• platelet activation and aggregation followed by thrombus

formation on fissured plaque can have direct effect on
electrophysiological properties of the heart and provoke
arrhythmias

• chronic ischaemia and collateral formation mitigates extent of

ischaemia produced by sudden coronary occlusion

• thrombosis of the right coronary artery is clinically associated

with transient AV block beginning some 24 hours after onset
of pain and lasting 3-4 days before sinus rhythm returns.
Davies and Popple (Histopathology 1979 3:255-277).

• Some called right coronary artery as artery of sudden death,

others called left coronary artery that due to occlusion of this
causes infarction of over 60% of the left ventricle, and is often
rapidly fatal from cardiogenic shock. Davies and Popple
(Histopathology 1979 3:255-277).
• Visual aid for assessment of coronary artery stenosis (Champ
and Coghill J Clin Path 1989 42(8):887-8) – a narrowing of
75% reduces coronary blood flow at times of stress and
exertion and narrowing of 90% means that coronary blood
flow is severely reduced at rest. One could do planimetry of
multiple cross sections of vessels that have been fixed,
decalcified and stained for elastin, and give a good estimation
of luminal area narrowing. Vessels that have been perfused
and fixed at physiological pressures before dissection give the

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most meaningful results. But we use the more simple

subjective measure of slicing and estimation. Estimate
pictures given for concentric round, eccentric round and slit
shaped lumena.
• Major cause of acute coronary thrombosis is plaque rupture
(Kolodgie Heart 2004 90: 1385-1391)

Role of Ischaemia

• pH drops to <6, interstitial potassium levels increase to >15

mmol/L, intracellular calcium levels rise and neurohumoral
changes contribute to electrophysiological changes – slowed
conduction, reduced excitability and prolonged refractoriness,
cell-to-cell uncoupling and the generation of spontaneous
electrical activity
• the accumulation of free fatty acids and their metabolites, the
formation of lysophosphoglycerides and impaired myocardial
glycolysis may all contribute to electrical instability leading to
cardiac arrhythmias.
• Development of VF? Re-entry is dominant mechanism, but
also regional changes in automaticity and triggered activity
due to after-depolarisations
• Reperfusion may be arrhythmogenic
• Global myocardial dysfunction in severely diseased hearts is
more likely to lead to bradycardia, asystole or EMD/ PEA
• Electrical heterogeneity is key to development of VF – all
hearts demonstrate some degree of heterogeneity e.g.
conduction velocities and refractoriness etc between different
cell types (ventricular muscle versus Purkinje fibres) –
therefore must be extreme heterogeneity e.g. if one region
becomes ischaemic etc
• Myocardial necrosis caused by either proximal coronary artery
occlusion or intramyocardial platelet aggregation and
microemboli can create a substrate for VF (Willich et al
Circulation 1993 87(5):1442-1450)
• Scarred myocardium is associated with electrical instability
(Willich et al Circulation 1993 87(5):1442-1450) (Lecomte et
al For Sci Int 1996 79:1-10)
• Ischaemia is the common basis of arrhythmias in sudden
death. The ischaemia is produced by fixed atheromatous
obstructions compounded by transient risk factors e.g.
transient elevations in blood pressure, which increase
afterload, increase oxygen demand; or sympathomimetic
irritation of the heart e.g. by caffeine, cocaine and
epinephrine; coronary artery spasm at site of fixed but eroded
obstruction; platelet embolisation from an ulcerated plaque
leading to localised myocardial ischaemia and irritability;

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transient thrombosis at the site of a fixed but eroded

obstruction. (Hirsch and Adams)
• Only a small amount of cardiac arrest survivors go on to
develop signs of an infarct, just electrical instability (Hirsch
and Adams) 4/5ths of patients with CAD do not have evidence
of Q wave infarcts after cardiac arrest, although 38% have
elevated cardiac enzymes consistent with myocardial damage.
19% of patients with CAD have a new Q-wave MI associated
with the episode of VF. (Marks and Greene Cardiac
Arrhythmias 1995)
• Cause of death in those with coronary stenosis but no recent
occlusion can be regarded as pathophysiological due to
enhanced ventricular electrical instability. Examination of the
conduction system often unrewarding. Davies and Popple
(Histopathology 1979 3:255-277).
• Old scarring from previous infarcts is present in 16-55% of
sudden ischaemic deaths Davies and Popple (Histopathology
1979 3:255-277).

Atherosclerotic plaque factors

• Picture of histological lesion types based on American Heart

Association Committee on Vascular lesions. (Fayed and Fuster
Circ Res 2001; 89: 305-316)
• Erosion of proteoglycan-rich and smooth muscle cell rich
plaques lacking a superficial lipid core or plaque rupture is a
frequent finding in sudden death due to coronary thrombosis
(44%). Occurs more often in younger individuals, women,
with less luminal stenosis, less calcification and less often
have foci of macrophages and T cells in comparison with
plaque ruptures. (Farb et al Circulation 1996 93:1354-1363)
• Plaque rupture in 60-75% of patients with acute coronary
syndromes. ACS (unstable angina, acute MI and sudden
death) precipitated by luminal thrombi
o Rupture – lesion with necrotic core, overlying thin
disrupted fibrous cap infiltrated by macrophages and T
lymphocytes. The luminal thrombus forms due to
physical contact between platelets and thrombogenic
necrotic core.
o Erosions – luminal thrombus superimposed on
proteoglycan rich plaque containing mostly smooth
muscle cells with few inflammatory cells (25-40% of all
coronary thrombi). Most lack necrotic core, but when
present, there is no direct communication with luminal
thrombus as overlying fibrous cap is intact and thick.
o Calcified nodule – least common (2-7%) of lesions that
cause coronary thrombi. Contain calcified plates with

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bony nodules that penetrate lumen, which contains

disrupted endothelium. (Kolodgie Heart 2004 90: 1385-
1391)
• Plaque progression beyond 40-50% cross sectional luminal
stenosis occurs secondary to repeated ruptures, which are
clinically silent. The % of healed plaque ruptures mirrors %
stenosis. (Kolodgie Heart 2004 90: 1385-1391)
• Thin cap fibroatheromas cause less severe narrowing, but
sudden death is the 1st presentation of their coronary disease.
They are primarily located in the proximal coronary arteries
especially the LAD. Risk factors for TCFAs – increased total
cholesterol, increased total cholesterol/ HDL-C ratio, women
>50 yrs, patients with increased CRP levels. (Kolodgie Heart
2004 90: 1385-1391)
• The vulnerable atherosclerotic plaque – often no severe
stenosis, large lipid pool (core >50% of overall plaque
volume), inflammatory cell accumulation (high density of
macrophages, T lymphocytes), thin fibrous cap (in which
collagen structure is disorganised), smooth muscle cell loss
(‘low density’), collagen loss, overexpression of metallo-
proteinases, tissue factors and PAI-1. (Tissue factor +ve
expressed by macrophages in atheroma, and potently initiates
blood coagulation cascade. PAI-1 also macrophage expressed
– inhibits fibrinolysis). (Aikaw and Libby. Cardiovascular
Pathology 2004 13: 125-138) (Davies Heart 2000 83: 361-
366)
• Atherosclerotic plaque (Davies Heart 2000 83: 361-366)
o Core of lipid (extracellular mass of lipid containing
cholesterol and its esters) surrounded by capsule of CT
and macrophages, many of which are lipid laden ‘foam
cells’. These macrophages are circulating monocyte
derived, which have crossed the arterial lumen and are
highly activated, producing procoagulant tissue factor
and inflammatory cell mediators e.g. TNF alpha,
interleukins and metalloproteinases. The connective
tissue capsule surrounding the inflammatory mass is
predominantly collagen, synthesised by smooth muscle
cells. The portion of the capsule separating the core
from the arterial lumen is the plaque cap.
o Plaque progression – endothelium over and between
plaques shows enhanced replication, implying
endothelial cell immaturity and abnormal physiological
function. Focal denudation allows exposure of
underlying CT matrix and platelet adhesion, contributing
to plaque smooth muscle cell growth by release of
platelet derived growth factor.

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 Notes on sudden cardiac death

• Mechanisms of thrombosis (Davies Heart 2000 83: 361-366)

o Extension of denuded area with thrombus adherence
(endothelial erosion). Linked to proximity of
macrophages which cause endothelial cell death by
apoptosis and by production of proteases which cut
loose the endothelial cells from their adhesion to the
vessel wall. Occurs in 50% of major thrombi in women.
o Plaque disruption/ fissuring/ rupture – plaque cap tears,
exposing lipid core to arterial blood. The core is highly
thrombogenic, containing tissue factor, collagen
fragments and crystalline surfaces to accelerate
coagulation. Thrombus forms in the plaque and expands
and distorts to extend into the lumen. The CT matrix in
the cap is constantly being replaced and maintained by
the smooth muscle cells. Collagen synthesis is reduced
by inflammation by inhibiting the SMCs and causing
death by apoptosis. Macrophages also produce wide
range of MMPs capable of degrading all components of
the CT matrix (they are activated by plasmin). MMPs
are upregulated by inflammatory cytokines e.g. TNF
alpha and the plaque is disrupted (‘auto destruct
phenomenon associated with enhanced inflammatory
activation’). Occurs in >85% of major coronary thrombi
in white men with increased LDL and reduced HDL.
• Sequence of thrombotic events (Davies Heart 2000 83: 361-
366)
o Platelet thrombus in core, protrudes into lumen and
fibrin component increases. Covering with activated
platelets, which are swept downstream in clumps into
distal intra-myocardial arteries as microemboli.
Thrombus may occlude artery leading to final stage in
which there is a loose network of fibrin containing large
numbers of entrapped RBCs. This can propagate distally
after the onset of myocardial infarction. The final stage
thrombus has structure making it susceptible to natural/
therapeutic lysis, but this will expose the deeper/ earlier
thrombus, which is more resistant to lysis.
• Symptoms in relation to coronary thrombi (Davies Heart 2000
83: 361-366)
o Thrombi which project into the lumen but do not
occlude (mural thrombi) are the basis of unstable
angina. The balance between prothrombotic and
antithrombotic factors ensures that the thrombus
neither progresses to occlude, or resolves to heal.
Plaque disruption associated with intraplaque thrombus
are associated with onset/ exacerbation of stable angina
by sudden increase in plaque volume.

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 Notes on sudden cardiac death

o Mechanisms of myocardial ischaemia attacks – changes

in thrombus size for short periods of time; intense local
vasoconstriction/ spasm (many disrupted plaques are
eccentric, with retention of arc of normal vessel wall in
which constriction can reduce blood flow); platelet
deposition is known potent stimulus for local smooth
muscle constriction; embolisation of platelet aggregates
into myocardial vascular bed both block smaller arteries
and cause vasoconstriction within the myocardium
(platelet thrombi associated with microscopic foci of
myocyte necrosis).
• Significant proportion of thrombotic occlusions causing
infarction don’t develop at sites where there was pre-existing
high grade stenosis or even a plaque identified at all (Davies
Heart 2000 83: 361-366)
• 68% of occlusions leading to acute infarction were judged to
have caused <50% stenoses previously; 14% developed on
high grade stenoses of >70% diameter. (Davies Heart 2000
83: 361-366)
• artery responds to plaque growth by increasing its cross
sectional area while maintaining normal lumen dimensions
(remodelling) (Davies Heart 2000 83: 361-366)
• 24% of lesions occluding >80% diameter will progress to
chronic total occlusion by 5 years (Davies Heart 2000 83:
361-366)
• transmural regional acute MI is caused by occlusion which
develops after a short time (few hours) and persists for at
least 6-8 hours (Davies Heart 2000 83: 361-366)
• non transmural (non Q wave) regional infarcts have areas of
necrosis of different ages, i.e. following repetitive episodes of
short lived occlusion, platelet embolisation or both. (Davies
Heart 2000 83: 361-366)
• Further factor in limiting spread of necrosis and preserving
subendocardial zone is the existence of prior collateral flow in
the affected area (Davies Heart 2000 83: 361-366)
• Dyslipidaemia increases risk of ACS – hypercholesterolaemia
promotes accumulation of oxidatively modified LDL (oxLDL) in
arterial wall, promoting endothelial cell dysfunction and
leucocyte invasion. OxLDL and its components are highly pro-
inflammatory and pro-atherogenic. Oxidative stress induces
activation of vascular cells e.g. that promote monocyte
recruitment and proliferate into macrophages. Expression of
VCAM 1 (vascular cell adhesion molecule) and chemokines
e.g. MCP-1 (monocyte chemoattractant protein 1) giving rise
to the leucocyte invasion of the intima. Dyslipidaemia
therefore induces oxidative stress, leading to vascular
inflammation and initiation, progression and complications of

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 Notes on sudden cardiac death

atherosclerosis. (Aikaw and Libby. Cardiovascular Pathology

2004 13: 125-138)
o LDL cholesterol leads to increased oxidised LDL
accumulation, reactive oxygen species production,
endothelial cell activation/ dysfunction, macrophage
accumulation/ proliferation and smooth muscle cell
activation/ apoptosis (Aikaw and Libby. Cardiovascular
Pathology 2004 13: 125-138)
• Atherosclerosis pathogenesis (Kumar et al Robbins 2005) –
‘response to injury hypothesis’ (chronic inflammatory
response of the arterial wall initiated by injury to the
endothelium. Lesion progression is sustained by the
interaction between modified lipoproteins, macrophages, T
lymphocytes and the normal constituents of the arterial wall.
o Chronic endothelial injury (due to
hypercholesterolaemia, haemodynamic disturbances
that accompany normal circulatory function (giving rise
to tendency for plaques to develop at ostia of vessels,
branch points and along the posterior wall of the
abdominal aorta, where there are disturbed patterns of
flow – areas of disturbed turbulent flow and low sheer
stress are prone to atherosclerosis while those with
smooth laminar flow seem to be protected),
inflammatory cytokines, cigarette smoke and ?infectious
agents) – with resultant endothelial cell dysfunction,
yielding increased permeability, leucocyte adhesion and
thrombotic potential
o Accumulation of lipoproteins, mainly LDL with its high
cholesterol content in the vessel wall
o Modification of lesional lipoproteins by oxidation
o Adhesion of blood monocytes (and other leucocytes) to
the endothelium, followed by their migration into the
intima and their transformation into macrophages and
foam cells
o Adhesion of platelets
o Release of factors from activated platelets (platelet
derived growth factor), macrophages or vascular cells
that cause migration of smooth muscle cells from the
media into the intima
o Proliferation of smooth muscle cells in the intima, and
elaboration of extracellular matrix, leading to the
accumulation of collagen and proteoglycans
o Enhanced accumulation of lipids both within cells
(macrophages and smooth muscle cells) and
extracellularly

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 Notes on sudden cardiac death

Cardiomyopathies

• second largest patient group experiencing sudden cardiac

death

• Hypertrophic cardiomyopathy – prevalence 2 in 1000

young adults, incidence of sudden cardiac death 2-4% per
year in adults and 4-6% per year in children and adolescents.
Risk of sudden death – sustained tachycardia, family history
of sudden cardiac death, diverse genotype, recurrent syncope,
multiple episodes of non-sustained VT, massive LVH.
Mechanisms? Arrhythmias, abrupt haemodynamic
deterioration, and/or ischaemia

• Idiopathic dilated cardiomyopathy – 10% of sudden

cardiac deaths in adults. Mortality 10-50% annually. Risk of
sudden death – non-sustained VT, bundle branch re-entry
causing VT and syncope. Triggers in heart failure – myocardial
stretch, neuroendocrine factors, electrolyte disturbances, pro-
arrhythmic effects of anti-arrhythmics and excessive
stimulation of sympathetic and rennin-angiotensin systems.

• Arrhythmogenic Right Ventricular Dysplasia – young

individuals and adults – gene defect on chromosomes 1 and 4
q23-q24. 30% familial (AD). Exercise can precipitate VT with
annual incidence of 2% sudden death. Fatty and fibro fatty
forms. 50% have involvement of left ventricle and septum.
Predilection sites for fatty degeneration reflect ECG
abnormalities, and slowed intraventricular conduction
(prolonged QRS interval).

Left Ventricular Hypertrophy

• Strong independent risk factor for cardiovascular deaths, and

particularly sudden death in those with history of
hypertension. Sheppard and Davies.
• Possible mechanism? Altered intramyocardial blood flow,
particularly subendocardial zone (wall stress at highest), seen
as increased subendocardial fibrosis. Metabolic demand
outstrips oxygen supply. Sheppard and Davies.
• Hypertensive hearts have prolonged QT interval
• Other triggers – myocardial ischaemia, interstitial fibrosis and
electrolyte disturbances generating tachyarrhythmias
• A heavy heart is usually an electrically unstable heart (Hirsch
and Adams) – associated with ectopic beats, VT and sudden
death. Aetiology unknown. Concentric hypertrophy –

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 Notes on sudden cardiac death

increased afterload and? Increased sympathetic tone,

activation of rennin-angiotensin system or both – in arterial
hypertension. (or less often, aortic valvular stenosis,
thyrotoxicosis and isometric exercise). Eccentric hypertrophy
(LVH with ventricular dilatation) – increased afterload and
increased preload (volume of blood drained from central veins
and pumped into ventricles by atria). Seen in obesity (blood
volume increases end diastolic pressure of left ventricle). LVH
with dilatation can also reflect decompensation of
atherosclerosis, valvular insufficiency, myocarditis or other
cardiomyopathies. (Hirsch and Adams)
• Hearts over 550g in total weight will have LV enlargement of
a degree to be reasonably associated with death. Davies and
Popple (Histopathology 1979 3:255-277). The risk is greatest
with pressure overload on the left ventricle as in aortic
stenosis or systemic hypertension.
• Gross right ventricular hypertrophy is also associated with
sudden death since it virtually always reflects significant
pulmonary hypertension. Davies and Popple (Histopathology
1979 3:255-277).
• Structural changes in hypertension – increased pressure
exerts an increased load on thin walled chambers or tubes by
increasing wall tension (by Laplace’s law). The rise in tension
results in increased wall tensile stress. Normalisation of this
stress can be achieved by either increasing wall thickness or
by decreasing chamber/ lumen diameter, or both. Patterns of
LV wall remodelling depends on; age, genetic influences,
haemodynamics, 24 hour blood pressure profile, arterial
stiffness, plasma volume, myocardial performance,
neurohormonal status. (Mayet and Hughes Heart 2003 89:
1104-1109)
• Hypertensive changes are either hypertrophy (increased LV
mass) or remodelling (normal LV mass but abnormal relative
wall thickness). Hypertrophy also involves interstitial fibrosis.
(Mayet and Hughes Heart 2003 89: 1104-1109)
• LVH predicts poor prognosis (3 fold increase risk independent
of blood pressure level). Possibly due to heterogenous
electrical conduction due to myocardial interstitial fibrosis, or
impaired coronary perfusion. (Mayet and Hughes Heart 2003
89: 1104-1109)
• Consequences of hypertrophy/ remodelling – impaired
relaxation and coronary reserve, leading to ischaemia even in
absence of coronary artery disease. Impaired relaxation
results in longer LV filling time, more blood in atria and
increase force of atrial contraction. Diastolic function is
impaired, and as it progresses, LV compliance reduces
(increased fibrosis), and heart becomes stiffer. Pressure in all

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 Notes on sudden cardiac death

chambers increases, and LV end diastolic volume decreases,

with a resultant reduction in Stroke volume and leads to low
output symptoms, e.g. fatigue. (Mayet and Hughes Heart
2003 89: 1104-1109)
• As LV filling pressure become very high, pulmonary
congestion can occur. (Mayet and Hughes Heart 2003 89:
1104-1109)
• Arterial remodelling and stiffness also occurs. (Mayet and
Hughes Heart 2003 89: 1104-1109)

Valvular Disease

• Risk of sudden death in aymptomatic aortic valve disease is

low
• Valve replacement? Risk of sudden death due to arrhythmias,
prosthetic valve dysfunction, co-existing CAD
• 20% of post-op deaths and incidence of 2-4% over 7 year
follow up
• mitral valve prolapse? – may be coincidental finding as so
common. If have MR and LV dysfunction or myxomatous
degeneration of valve – more risk of complications e.g.
infective endocarditis, cerebro-embolic events and sudden
cardiac death.

Congenital heart disease

• Increased risk in tetralogy of Fallot, transposition of great

arteries, aortic stenosis, pulmonary vascular obstruction.
• Late complication of surgery for complex repairs
• In tetralogy of Fallot QRS prolongation relates to right
ventricular size and is a predictor for sudden cardiac death

Drugs

• Direct capability of provoking ventricular tachyarrhythmias

e.g. Class 1A anti-arrhythmics (procainamide, quinidine),
class 1C (flecanide)
• Non anti-arrhythmic drugs e.g. Antihistamines
• Polydrug interactions e.g.. Phosphodiesterase inhibitors and
positive inotropic agents
• Hypokalaemia e.g.. Potassium-wasting diuretics

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 Notes on sudden cardiac death

(Source: Zipes and Wellens 1998 p.2344)

Primary electrophysiological abnormalities/ inherited ion

channelopathies

• Ion channel proteins are responsible for the currents that

generate the cardiac action potential, and alterations of their
function are known to be associated with a variety of
phenotypes – the final outcome being similar, an alteration in
ion channel activity and the development of an
arrhythmogenic substrate.. (Brugada et al 2004 Circulation
109:30-35) NB. SCN5A mutations all cause deaths occurring
in sleep including SUNDS, SIDS, Brugada, LQTS and
conduction system disease, and therefore could be the same

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 Notes on sudden cardiac death

disease with variable penetrance (Vatta M et al 2002 Human

Molecular Genetics 11(3):337-345)

o However, Long QT syndrome and other channelopathies

have variable penetrance (Behr et al 2003 Lancet
362:1457-59)
o 68% of patients with Long QT syndrome have an
identifiable disease-causing mutation (Behr et al 2003
Lancet 362:1457-59)
o QT interval represents ventricular repolarisation –
prolonged QT interval associated with increased risk of
life threatening ventricular arrhythmias. The QT interval
is related to the effective refractory period of the
myocardium, and changes to this period leave the
myocardium vulnerable to fibrillation both at atrial and
ventricular levels. (Gaita F et al Circulation 2003;
108:965-970)
o Structural normality is normally identified by fairly gross
means, such as ECG and catheterisation. However, PET
scans, genetic testing and MRI is beginning to identify
structural abnormalities and/ or genetic defects in
previously described ‘idiopathic ventricular arrhythmias’.
(Zipes and Wellens 1998; 98:2334-2351)

• Long QT syndrome – characterised by prolonged period of

recovery from depolarisation and a tendency to syncope and
sudden death mediated by VT. Prolongation of QT interval first
associated with congenital deafness in the AR Jervell and
Lang-Nielson syndrome and without deafness in the AD
Romano-Ward syndrome. (Hirsch and Adams)cardiac
electrophysiological dysfunction without structural disease –
gain of function in SCN5A (gene encoding for α subunit of
cardiac sodium channel (late INa)) is associated with LQT3
form, other forms of long QT linked to loss of function of IKs
and IKr (prolongation of cardiac action potential and
lengthened QT interval which can lead to early after
depolarisations) (Brugada et al 2004 Circulation 109:30-35)
(Zipes and Wellens 1998; 98:2334-2351)
o Other genes implicated in long QT – KCNQ1, KCNH2,
KCNE1, KCNE2, SCN5A (Behr et al 2003 Lancet
362:1457-59)
o DNA mapping studies confirmed the genetic substrate
encoding defective ion channel proteins, but only 60-
70% of patients have a genetic defect confirmed at
screening (Gaita F et al Circulation 2003; 108:965-970)

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 Notes on sudden cardiac death

o AD mode of inheritance (Gaita F et al Circulation 2003;

108:965-970)
o A specific kind of VT called Torsade de Pointes occurs in
LQTS (Zipes and Wellens 1998; 98:2334-2351)
o Seven genetic loci identified, 6 described (all ion-
channel encoding genes). 5 encode potassium channel
proteins (LQT1, LQT2, LQT5, LQT6 and LQT7 encoding
KVLQT1, mink, HERG, MiRP1 and Kir2.1 respectively),
whereas LQT3 encodes cardiac sodium channel gene
SCN5A (Vatta M et al 2002 Human Molecular Genetics
11(3):337-345)
o LQT1/ LQT2 – incidence of cardiac events is higher than
LQT3, but lethality of events is higher in LQT3 (Zipes
and Wellens 1998; 98:2334-2351)
o LQT1 related to exercise trigger, whilst LQT3 related to
sleep/ rest trigger (Zipes and Wellens 1998; 98:2334-
2351)
o It has been proposed that long QT syndrome is due to
deficient adrenergic innervation by the stellate ganglion
and upper thoracic sympathetic ganglia on the right
side. Ablation of the right stellate ganglion reduces the
fibrillation threshold of the ventricles, whereas ablation
of the left side renders the heart more resistant to
fibrillation. The sympathetic current from the right side
is primarily chronotropic whereas the innervation from
the left is inotropic. An imbalance between signals from
each side, caused by some defect (?in brain, cord,
sympathetic nerves or ganglia) results in sympathetic
imbalance (Hirsch and Adams)

(Source: Zipes and Wellens 1998 p.2341)

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 Notes on sudden cardiac death

• Short QT syndrome
o Genetically heterogenous disorder – characterised by
marked abbreviation of QT interval (<300 ms) and high
incidence of atrial and ventricular arrhythmias and
sudden death in young patients? Gain of function
mutation of KCNE2 (IKr) (shortens action potential and
QT interval) (Brugada et al 2004 Circulation 109:30-35)
o Clinical manifestations wide – range from palpitations
and dizziness to sudden death. AD mode of inheritance.
(Gaita F et al Circulation 2003; 108:965-970)
o QT interval is shortened by increases in heart rate,
hyperthermia, increased calcium or potassium plasma
levels, acidosis or alterations of autonomic tone (Gaita F
et al Circulation 2003; 108:965-970)
o Lone AF in young individuals might be related to short
QT syndrome (Gaita F et al Circulation 2003; 108:965-
970)

• Brugada syndrome – First described in 1992. Specific ECG

pattern of right bundle-branch block, ST segment elevation in
leads V1-V3 associated with sudden death in those with no
demonstrable structural heart disease (Brugada et al 1998
Circulation 97:457-460). Due to decrease in function of
cardiac sodium channel – SCN5A gene on chromosome 3 but
with different biophysical properties to mutant channel in
LQT3 (Brugada et al 2004 Circulation 109:30-35), 10-20% of
patients have an identifiable disease-causing mutation (Behr
et al 2003 Lancet 362:1457-59). AD mode of inheritance
(Vatta M et al 2002 Human Molecular Genetics 11(3):337-
345)
• Catecholaminergic polymorphic ventricular tachycardia
– effort/ stress induced ventricular arrhythmia in young
children which can degenerate into cardiac arrest and cause
sudden death. The ECG pattern resembles arrhythmias
associated with calcium overload and delayed after
depolarisations observed during digitalis toxicity. (Priori S et
al 2001 Circulation 103:196-200). 2 genetic variants – 1 AD
caused by mutations in gene encoding the cardiac ryanodine
receptor (RyR2) and 1 recessive form caused by mutations in
human cardiac calsequestrin (CASQ2), both of which are
calcium binding proteins located in the sarcoplasmic reticulum
and are involved in the excitation coupling complex. (Mutation
reduces calcium storage capacity and release functions of SR
and destabilises calcium transport predisposing to adrenergic

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 Notes on sudden cardiac death

mediated arrhythmias) (Viatchenko-Karpinski et al 2004

Circulation Research 94:471-477)
• Sudden unexpected nocturnal death syndrome –
disorder found in southeast Asia – abnormal ECG with ST-
segment elevation in leads V1-V3 and sudden death due to VF
– identical to Brugada syndrome. Called lai-tai (sleep death,
Laos), pokkuri (sudden and unexpected death, Japan),
bangungut (to rise and moan in sleep, Philippines). (Zipes and
Wellens 1998; 98:2334-2351). Genetic studies confirm that
the disease is phenotypically, genetically and functionally the
same disorder (SCN5A mutation) (Vatta M et al 2002 Human
Molecular Genetics 11(3):337-345) recent study shows that
the responsible arrhythmias occur during night terrors which
occur in non-REM sleep from which the victim cannot be
aroused. There is a sudden surge of catecholamines, and
precipitous rises in blood pressure.
• Progressive conduction system disease (Lev-Lenegre
syndrome) – decrease in function of cardiac sodium channel –
SCN5A mutation (Brugada et al 2004 Circulation 109:30-35)
(Vatta M et al 2002 Human Molecular Genetics 11(3):337-
345)
• Familial atrial fibrillation – increase in IKs current caused by
mutation in α subunit KCNQ1
• Wolff-Parkinson-White syndrome – risk of sudden death
<1 per 1000 patient years of follow up. Usually have
symptomatic arrhythmias before event, 10% first
presentation is sudden death. AF is rapidly conducted to
ventricles over accessory pathway to produce rapid
ventricular rates, which degenerate into VF. (Zipes and
Wellens 1998; 98:2334-2351) (Marks and Greene Cardiac
Arrhythmias 1995)
• Congenital complete AV block
• Idiopathic ventricular tachycardias with monomorphic and
polymorphic contours – sporadic and familial forms.
Paroxysmal and frequently precipitated by stress/ emotion

Mechanisms in sudden cardiac death

• Sudden cardiac death is an electrical accident as only a small

proportion of people at risk develop sudden death
• Many other individuals have the anatomical substrates and
functional substrates conducive to developing VT or VF
• Transient events perturb the balance
• The interplay between all factors is crucial
• VF is self electrocution/ turning the switch off (Hirsch and
Adams)

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 Notes on sudden cardiac death

• Combination of triggering event and susceptible myocardium

has evolved as a biological model for the initiation of lethal
arrhythmia (Chugh et al Circulation 2000 102(6):649-654)
• Arterioscerotic heart disease usually kills by pump failure or
sudden arrhythmia. (Hirsch and Adams) Pump failure is more
likely in dilated heart, infarcts, global subendocardial fibrosis.
When congestive failure is severe, all organs are
underperfused, including the heart. The left ventricle suffers
global hypoxia, and can lead to ectopics and bradycardia.
Electrical or sudden deaths are due to electrical instability,
increased by hypertension and LVH.
• The fundamental difference between living and dead
organisms is functional (electrochemical intercellular
communication) rather than structural, the pathologist who
focuses exclusively on anatomic causes of death is doomed to
fail. (Hirsch and Adams)
• Thrombus seen by naked eye in a coronary artery provides
good evidence of acute myocardial ischaemia even if the
artery is not completely occluded, as distal emboli of small
clumps of platelets from the thrombus cause microscopic foci
of myocardial necrosis and therefore a substrate for re-entry
tachycardias. (Davies Histopathology 1999 34:93-98)
• Sudden cardiac deaths are mediated by acute derangements
of physiologic function. (Hirsch and Adams) The functional
derangement is sometimes obvious, e.g. cardiac rupture, but
usually electrical. It is thus inferred from the presence of
chronic cardiac disease. Destabilisation of the heart and
production of arrhythmias occurs as product of predisposing
anatomical substrate and acute transient risk factors such as
altered autonomic tone, coronary artery spasm and increased
platelet adhesiveness. (Hirsch and Adams) Where functional
disturbances are severe enough, death can occur without the
anatomical substrate. Lown demonstrates that psychological
stress can lower the fibrillation threshold by means of
increased sympathetic tone, and that stimulation of the
hypothalamus can induce cardiac arrhythmias.
• The orderly propagation of the contractile wavefront depends
on the continuous overriding of the potential ectopic
pacemakers and on the absence of re-entry pathways, either
within the ventricles or between atria and ventricles. (Hirsch
and Adams)
• When an ectopic ventricular focus takes over and drives the
rest of the myocardium in an orderly fashion, premature
ventricular contractions or sustained VT are produced. In the
presence of re-entry pathways, the ectopic signal can
generate an uncoordinated wavefront and VF ensues. Because

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 Notes on sudden cardiac death

no net forward pumping of blood is produced, VF and certain

forms of VT are lethal. (Hirsch and Adams)
• Ventricular ectopy = ventricular irritability – increased by
hypertrophy, ischaemia, sympathetic discharge, ethanol
intoxication, hyperthyroidism, drugs including MAO inhibitors,
TCAs, caffeine, theophylline and other sympathomimetic
drugs, agents found in diet pills and nasal decongestants.
(Hirsch and Adams)
• Myocardial depression on the other hand leads to delayed AV
conduction and block, potentially leading to cardiac standstill
and death. E.g. parasympathetic discharge, myoedema,
hypothermia, hyperkalaemia (Hirsch and Adams)
• The electrochemical discharge from the CNS to the heart and
blood vessels can be strong enough or imbalanced enough to
produce standstill, VF or emptying of the heart by virtue of
vascular redistribution. (Hirsch and Adams).
• The exact areas of the brain of vasomotor centres are
unknown, but critical areas are region of 3rd ventricle,
midbrain, medulla oblongata. (Hirsch and Adams)
• Sympathetic discharge flows down interomediolateral columns
of the spinal cord, leaving the cord in the thoracic and lumbar
regions by way of the chains of sympathetic ganglia running
adjacent to the vertebral column. From the upper thoracic
ganglia and from the stellate ganglion in particular, efferent
branches pass into the mediastinum and along the base of the
heart to innervate the myocardium and cardiac blood vessels.
• Parasympathetic discharges originating in the vasomotor
centres exit the brain by way of the vagus nerves, which
descend into the mediastinum and innervate the heart.
• Mechanical trauma along these pathways can induce profound
electrical disturbances in the heart. Transverse fractures of
the floor of the skull running near the base of the 3rd
ventricle, fractures of the posterior fossa, dislocations of the
neck, forceful facial impacts that cause hyperextension of the
head with pontomedullary lacerations and gunshot wounds to
the spine or brain can all give rise to instantaneous death
(central cardiac concussion) (Hirsch and Adams)
• Spontaneous subarachnoid haemorrhages can cause
instantaneous death due to tamponade of blood in cisterns at
base of 3rd ventricle and along the medulla.
• In respiratory arrest, the first response to hypoxia is
tachycardia, then bradycardia until a slow pacemaker takes
over. When cellular metabolism is so disturbed that
electromechanical dissociation takes place, there is no flow/
output.

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 Notes on sudden cardiac death

Interaction of various anatomic/ functional and transient factors

that modulate potential arrhythmogenic mechanisms capable of
causing sudden cardiac death. (Source: Zipes and Wellens 1998)

• Willich et al (Circulation 1993 87(5):1442-1450) model of

‘triggering of sudden cardiac death’ – external trigger causes
increase in sympathetic nervous activity, this activity may act
on coronary arteries, myocardial tissue or the conduction
system, or a combination. The effect on the artery occurs
when haemodynamic forces cause a vulnerable plaque to
rupture. Transformation of stable to vulnerable plaque? Could
be accumulation of lipid pool covered by thin fibrous cap,
increased collagenase activity. Exposed collagen can lead
directly to occlusive thrombus formation and fatal MI. Gradual
growth of thrombus may lead to reduced blood flow, micro
emboli and myocardial ischaemia or small areas of myocardial
necrosis (both of which have been shown to be associated
with reduced threshold for VF. Damage of myocardial tissue or
conduction system by necrosis, fibrosis, hypertrophy or other
changes may increase risk of acute electric instability. The
diversity of findings suggests that many potential triggers
may interact, synergistically or alone, with structural and
functional abnormalities to produce a common clinical end-
point – sudden cardiac death.
• Mechanisms? Increased sympathetic discharge and circulating
catecholamines. Raise heart rate and BP, and thus oxygen
demand. Alpha sympathetic receptors stimulated, increasing
coronary tone reducing relative oxygen supply. Increased

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 Notes on sudden cardiac death

ventricular inotropy and changes in coronary tone may alter

shear stress of blood against vulnerable atherosclerotic
plaque, contributing to fracture. Raised catecholamines
triggering arrhythmias directly, and increasing platelet
aggregation. (Leor et al NEJM 1996; 334:413-419) (Chi and
Kloner stress and MI) (Reich et al JAMA 1981 246(3):233-
235) Excitation causing sinus tachycardia/ ventricular
irritability; rapid shifts between sympathetic/ parasympathetic
effects e.g. uncertainty causing shift between ‘fight-flight’ and
‘conservation-withdrawal’ systems. Combination of neurogenic
adrenergic and cholinergic activity in conjunction with local
myocardial factors leading to escape rhythms. Vagal
stimulation causing slow heart rate and facilitation of re-
entrant ectopic activity and thus VF. QT prolongation,
premature beats and VF have all been experimentally
demonstrated by cortical and sub cortical CNS stimulation
therefore higher neural mediating control systems exist
(psych-neuro-cardiovascular circuit). (Engel Folklore or folk
wisdom?) (Reich et al JAMA 1981 246(3):233-235)
• Mechanism defined for both out-of-hospital and in-hospital
settings – 3 common rhythm disturbances – VF, asystole and
EMD. Relative proportions depend on patient population.
33%-50% have VF as initial rhythm recorded. (Marks and
Greene Cardiac Arrhythmias 1995)
• Ambulatory monitoring shows 85% of sudden cardiac deaths
due to VT rapidly degenerating into VF. After prolonged VF the
voltage of the signal decreases to fine VF and then to ‘flat line’
or asystole. (Marks and Greene Cardiac Arrhythmias 1995)
• Davies and Popple (Histopathology 1979 3:255-277) point out
that in those with a macroscopic normal heart, and where
ECGs were found, no conduction system abnormality was
found anatomically in those with long QT, inverted T waves,
episodic supraventricular tachycardias, multifocal ventricular
and atrial ectopics.
• Probability of sudden death being due to IHD when no other
cause can be found on macroscopic examination in hearts
with coronary atherosclerosis (Davies Histopathology 1999
34:93-98);

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 Notes on sudden cardiac death

Pathology Approximate probability of

death being due to IHD
Pericardial tamponade 100%
Rupture of acute infarct
Coronary thrombus
Acute MI/ coronary thrombus 90%
Coronary thrombosis alone
Healed previous infarct scar – no
thrombus
No thrombus – no scars 70%
X3 vessels with >75% stenosis
X2 vessels with >75% stenosis
X1 vessel with >75% stenosis
Stenosis <75% alone Less than 50%

• Modified in Sheppard and Davies (Practical Cardiovascular

pathology) – high probability for acute infarct with coronary
thrombosis and atherosclerosis, through medium probability
for high grade stenosis (>75% diameter) with old infarction
and/or LVH to low probability for high grade stenoses but
normal myocardium and very low probability for <50%
stenosis, no scars or LVH.

Homicide by heart attack

Davis criteria (J For Sci; 1978;23(2):384-7)

1. The criminal act should be of such severity and have such

sufficient elements of intent to kill or maim, either in fact or in
statute, so as to lead logically to a charge of homicide in the
event that physical injury had ensued.
2. The victim should have realised that the threat to personal
safety was implicit. A logical corollary would be a feared
threatening act against a loved one or friend.
3. The circumstances should be of such a nature as to be
commonly accepted as highly emotional.
4. The collapse and death must occur during the emotional
response period, even if the criminal act had already ceased.
5. The demonstration of an organic cardiac disease process of a
type commonly associated with a predisposition to lethal
cardiac arrhythmia is desirable.

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 Notes on sudden cardiac death

Modified Davis criteria (Turner et al 2004 49(3):1-5);

1. The action of the perpetrator towards the victim should be of

such severity and have sufficient elements of intent to
frighten, injure or kill, either in fact or in statute, so as to lead
logically to a charge of homicide in the event that the death
resulted from physical injury.
2. The victim should have realised that the threat to personal
safety was implicit. A logical corollary would be a feared
threatening act against a loved one or friend.
3. The circumstances should be of such a nature as to be
commonly accepted as highly emotional.
4. The collapse (and subsequent death, in most cases) must
occur within the emotional response period, even if the
criminal act had already ceased. In certain circumstances,
death may be delayed, typically via medical intervention.
5. Autopsy should demonstrate an organic cardiac disease
process of a type commonly associated with a predisposition
to lethal cardiac arrhythmia. In the absence of a grossly or
microscopically identifiable organic cardiac disease, the case
may involve a functional cardiac disorder (such as a
conduction system disorder) that has no anatomic correlation.

• Modified criteria take into account cases where injury

has occurred (unlike Davis) and incorporates NAME
guidelines.
• National Association of Medical Examiners NAME ‘Guide
for Manner of Death Classification’ – deaths resulting
from fear or fright that is caused by verbal assault,
threats of physical harm, or via acts of aggression
intended to instil fear may be classified as homicide, as
long as there is a close temporal relationship between
the incident and the death.
• Recovery after initial collapse, then death following
decompensation would not be homicide (Turner et al
2004 49(3):1-5);
• If coronary arteries poor, defence could reasonably
claim that death could have occurred at any time
(Knight and Saukko 2004)
• Standard of proof must be attained
• Easier to claim that emotional stress associated with
traumatic event caused increased demands upon a
weakened heart and caused it to fail (Knight and
Saukko 2004)
• May sometimes have morphological evidence of the
effects of catecholamines on the myocardium in form of

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 Notes on sudden cardiac death

contraction bands in myofibrils, especially subepicardial

layers (Knight and Saukko 2004)
• Average jury is likely to think it too much of a
coincidence that a man drops dead on the spot, even if
the extent of coronary artery disease is of long standing
(but he has not suffered any symptoms) (Knight and
Saukko 2004)
• Strict test is ‘would he have died when he did die if the
assault had not taken place?’ – may only be answerable
when considering all the circumstances (with a common
sense view of coincidence in terms of immediacy in time
and apply the ‘beyond reasonable doubt’ test) (Knight
and Saukko 2004)
• The fact that a person is in a poor state of health and
might die from minimum trauma is no defence – ‘an
assailant must take his victims as he finds them’ (Knight
and Saukko 2004)
• The prevalence of CAD is so widespread that a close
association in time must be shown before any causal
connection can be accepted. (Knight and Saukko 2004)

Commotio cordis/ cardiac concussion

• First described in 1930s

• Registry in US – 140 cases in 5 years (mean age 14 years,
male), 5-10 cases p.a. no data for UK.
• sudden death in young athletes with trivial non-penetrating
impacts to anterior chest, leaving no visible trauma, and in
which resuscitation attempts unsuccessful despite early
cardioversion (survival now approx 15% due to rapid
defibrillation)
• no pathological changes seen, and no cardiac enzyme rise
?troponins?
• syncopal events now also recognised due to chest wall impact
• mechanism – animal research using ECG/ cardiac cycle gated
impact studies show impact directly over precordium at
>30mph gives rise to increasing risk of VF (30% at 30 mph,
70% at 40 mph) with impact occurring at vulnerable part of
cycle (30ms prior to T wave peak). Thump in cycle at other
times gives rise to ST elevation and transient heart block.
Multifactorial – altered myocardial substrate with premature
ventricular depolarisation as the trigger. Change in substrate?
Not vagal inhibition, could be rise in left ventricular pressure,
activating stretch activated channels (potassium and others),
or effect of K/ATP channel (which are responsible for ST
elevation and contribute to risk of VF in ischaemia) as blocker
(glibeclamide) reduces ST elevation and incidence of VF

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 Notes on sudden cardiac death

following induced chest blows. Clinical colloraly – R on T

phenomenon (VF caused by premature ventricular
contractions falling on vulnerable portion of T wave, in
ischaemic conditions (acute MI/ coronary ischaemia) but not
non-ischaemic conditions such as continuous ventricular
pacing). (Link 2003 Progress in Biophysics and Molecular
Biology 82:175-186) (Koehler et al Am J For Med and Path
25(3):205-208) (Maron BJ et al JAMA 2002 287(9):1142-
1146) (Link et al NEJM 338(25):1805-1811) Cardiac
concussion involves absorbtion of mechanical energy from
blunt impact as harmonic oscillations which are dampened out
and converted to heat. A small part of the imparted kinetic
energy may be converted to electrical impulses. (Hirsch and
Adams)
• Resuscitation Council – precordial thump can convert
pulseless VT to perfusing rhythm - termination of VF less
common. Can also convert bradycardic rhythms or VT with
pulse to pulseless VT or VF, accelerated VT or complete heart
block – therefore only recommended for pulseless person
whose rhythm is monitored

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 Notes on sudden cardiac death

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