Can J Cardiol Vol 21 Suppl A May 15, 2005 37A

Epidemiology and mechanisms of sudden cardiac death

Douglas P Zipes MD
Division of Cardiology and the Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
Correspondence: Dr Douglas P Zipes, Indiana University School of Medicine, 1800 North Capitol Avenue E475, Indianapolis, Indiana
46202-5305, USA. Telephone 317-932-0556, fax 317-962-0568, e-mail dzipes@iupui.edu
Received for publication December 28, 2004. Accepted February 14, 2005
DP Zipes. Epidemiology and mechanisms of sudden cardiac
death. Can J Cardiol 2005;21(Suppl A):37A-40A.
A particular challenge in preventing sudden cardiac death is our lim-
ited means of identifying individuals, rather than populations, at risk.
Genetic and molecular risk factors are among the new measures cur-
rently being explored. Until effective risk recognition and stratifica-
tion methods are available, general prevention including
cardioprotective therapies and the widespread availability of auto-
matic external defibrillators remains important.
Key Words: Implantable defibrillator; Risk factors; Ventricular
fibrillation; Ventricular tachycardia
Lpidmiologie et les mcanismes de la mort
cardiaque subite
Les moyens limits pour reprer les individus, plutt que les populations,
risque constituent un dfi particulier pour la prvention de la mort
cardiaque subite. Les facteurs de risque gntiques et molculaires font
partie des nouvelles mesures tre explores. En attendant laccs une
reconnaissance efficace des risques et des mthodes de stratification, la
prvention gnrale y compris les traitements cardioprotecteurs et
laccs gnralis aux dfibrillateurs externes automatiss demeure
essentielle.
S
udden cardiac death (SCD), typically defined as an unex-
pected death due to cardiac causes, involves an abrupt loss
of consciousness due to disruption in cerebral blood flow and
occurs within 1 h of the onset of acute symptoms. In addition,
SCD may occur in a previously stable patient in whom heart
disease may or may not have been recognized (1).
THE CHALLENGE OF IDENTIFYING
INDIVIDUAL RISK
Although it is a clinical and public health problem of substantial
magnitude, the true mortality burden of sudden death due to
cardiac arrhythmia is not well-established. In the United States,
various sources have estimated the annual number of deaths to
be between 184,000 and 462,000 (2-7). In Canada, deaths num-
ber in the tens of thousands (8). In the United States, it is gen-
erally accepted that SCD accounts for approximately 50% of
cardiovascular deaths (1) and, according to a recent prospective
study, 5.6% of total annual mortality (7). Although mortality
due to coronary disease has been decreasing, the incidence of
SCD appears to be rising in line with increasing global rates of
coronary disease and heart failure.
Figure 1 illustrates a crucial challenge for scientific and
clinical investigators of SCD. The patient group contributing
the highest number of sudden deaths is comprised not of indi-
viduals deemed at risk due to a prior acute coronary syndrome,
low ejection fraction (EF), ventricular tachyarrhythmia (VT),
or other identified disease processes (in whom the estimated
one-year risk reaches 30% or greater); rather, the group con-
tributing the highest number of sudden deaths is the popula-
tion at large (estimated risk 1/1000 to 2/1000). SCD is the first
manifestation of disease in almost 50% of patients with coro-
nary artery disease (1). For example, in the Quebec
Cardiovascular Study (9), 42% of all ischemic heart disease
deaths in men fulfilled the criteria for sudden death or were in
individuals found dead in bed. According to information
extracted primarily from trials of implantable cardioverter
defibrillators (ICDs), approximately one in three sudden
deaths occurs in patients with known risk markers. That the
majority of sudden cardiac arrests occur in individuals who
have not been identified as being at high risk necessitates new
measures and modalities for recognizing predisposition and
stratifying risk.
UNDERLYING DISEASE: EVOLVING PATTERNS
As noted in Figure 2, the bulk of SCDs occurs in patients
with coronary artery disease, whereas cardiomyopathy
accounts for much smaller numbers (10). Interestingly, there
has been an evolution in the causative arrhythmia.
According to data compiled in 1989, the underlying arrhyth-
mia in approximately 80% of cases of SCD was VT, with
bradyarrhythmias accounting for 15% to 20% (11). In several
recent reports, however, VT has been identified less fre-
quently, while there is evidence of increasing rates of asystole
and pulseless electrical activity. For example, a study con-
ducted in Rochester, New York (12) has determined that
annual rates of ventricular fibrillation in out-of-hospital car-
diac arrests have declined from 26/100,000 in 1985 to
7.7/100,000 in 2002. The reasons for this change are unclear.
Whatever the explanation, these epidemiological data have
important clinical implications because patients with VT are
SUDDEN CARDIAC DEATH
2005 Pulsus Group Inc. All rights reserved
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Zipes
Can J Cardiol Vol 21 Suppl A May 15, 2005 38A
most likely to respond to resuscitation, while those with
asystole and pulseless electrical activity are least likely to
respond to resuscitation.
NEW RISK FACTORS MAY ASSIST DETECTION
As shown in Table 1, there are numerous recognized risk fac-
tors for SCD. The difficulty is that most risk factors lack sensi-
tivity, specificity and predictive accuracy for individuals as
opposed to population assessment. For example, although it is
clear that a reduced EF is associated with increased risk, it is
difficult to determine which individuals with low EF would
most benefit from an ICD. In addition, standard risk factors
reflect the risk of developing structural heart disease rather
than the mechanism or proximate precipitator of SCD.
A number of additional factors are currently being explored
for their potential in identifying individuals at risk of SCD
(Table 2). The clarification of genetic risk an area of sub-
stantial progress is critical. It is becoming increasingly clear,
for instance, that genetic factors may play a role in the devel-
opment of the myocardial substrate associated with predisposi-
tion to thrombosis and arrhythmia. In addition, it has been
hypothesized that single nucleotide polymorphisms affecting
potassium channels may predispose to a long QT interval and,
therefore, higher risk.
Perfusion patterns observed on positron emission tomogra-
phy may also be employed as risk markers. The authors labora-
tory has conducted preclinical testing of this modality and is
initiating a trial in which sympathetic, vagal and myocardial
blood flow images will be assessed. Other promising investiga-
tions focus on mitochondrial defects, cytokines, C-reactive
protein and other markers of inflammation, and molecular
markers such as beta receptor subtypes.
TIMING AND TRIGGERS
Interesting and intriguing data have emerged on the timing
and trigger factors for SCD. Traditionally, it was believed that
the greatest risk for patients post-myocardial infarction (MI)
was in the first six months following the acute event. As shown
in Figure 3, the Multicenter Automatic Defibrillator
Implantation Trial-II (MADIT-II) (13) clearly demonstrated
that risk increases as a function of time in contemporary post-
MI patients with an EF of 30% or less. This trial, which was
conducted over a period of 10 years, found a progressive
increase in mortality due to sudden death in post-MI patients
treated with either an ICD or conventional therapy (corre-
spondingly, survival benefit from the ICD increased signifi-
cantly with time, up to 15 years following MI). Similarly,
according to data from the Maastricht Circulatory Arrest
Registry, the median time from MI to SCD (occurring in 92 of
224 patients [41%]) was nine years (14).
The particular factors that precipitate ventricular arrhythmia
and SCD appear to constitute an intersection among numerous
anatomical and functional factors, transient initiating factors
and arrhythmia mechanisms, as illustrated in Figure 4.
80%
Coronary Artery
Disease
Adapted from Heikki et al. N Engl J Med, Vol. 345, No. 20, 2001.
* ion-channel abnormalities, valvular or congenital heart disease, other causes
15%
Cardiomyopathy
5% Other*
Figure 2) Underlying causes of fatal arrhythmias. Reproduced/adapted
with permission from reference 10
TABLE 1
Standard risk factors for sudden cardiac death
Male sex
Smoking
Obesity
Diabetes
Inactivity
Previous myocardial infarction/history of coronary artery disease
Decreased left ventricular ejection fraction and heart failure
Previous sudden cardiac arrest or prior episode of ventricular tachycardia
Ventricular ectopy in chronic ischemic heart disease
Premature ventricular complexes during recovery from treadmill exercise
Atrial fibrillation
Electrophysiological parameters (eg, QTc, QRS duration, QT dispersion,
heart rate variability, T wave alternans, baroreflex sensitivity)
TABLE 2
Potential new risk factors for sudden cardiac death
Fatty acid metabolism: Mitochondrial defects
Serum biomarkers: Cytokines, other proteins
Inflammation: C-reactive protein, troponin
Molecular markers: Beta receptor subtypes
Genetics: Control of substrate, thrombosis precipitators, inherited arrhythmias
Single nucleotide polymorphisms: Ion channels, other
Temperature
Perfusion patterns
Heart rate turbulence
Myerburg RJ. Circulation.1998;97:1514-1521.
GROUP
300,000
Patients with high
coronary-risk profile
Patients with previous
coronary event
Patients with ejection
fraction < 35%,
congestive heart failure
Patients with previous
out-of-hospital cardiac
arrest
Patients with previous
myocardial infarction,
low ejection fraction, and
ventricular tachycardia
General population
200,000 100,000 0
No. of Sudden Deaths
Per Year
30 25 20 15 10 0
Incidence of Sudden Death
(% of group)
5
Figure 1) Incidence of sudden cardiac death in specific populations and
annual sudden cardiac death numbers. Reproduced/adapted with
permission from reference 10
zipes_8701.qxd 5/10/2005 11:25 AM Page 38
Interestingly, the right combination of factors may exist rela-
tively harmlessly in a given individual for many years, only to
be activated when the factors intersect and interact. A case
published several years ago cited the example of a 40-year-old
man whose congenital concealed accessory pathway was not
operative until he developed supraventricular tachycardia after
post-MI cardiac remodelling and development of a right bun-
dle branch block (15). Recent work has suggested that it may
be possible to combine several noninvasive techniques, includ-
ing body surface mapping and computerized tomography, to
identify such anomalies and the risk associated with them
(16).
The autonomic nervous system plays a very important role
in the timing and incidence of arrhythmia and SCD. For
example, the incidence of sudden death due to ventricular fib-
rillation (as well as MI and stroke) increases between 6:00 and
12:00. Morning hours are associated with a peak in VT, a
decrease in ventricular refractoriness, and increased difficulty
in achieving successful defibrillation. Peaks in mortality inci-
dence are observed Saturday through Monday and during the
first week of any month. Mortality due to SCD is also highest
during winter months. As documented in a recent report, mor-
tality in December through February was 111% of the expected
rate, while the rate for the other months of the year was 96.5%
of that expected. Because the difference could be eliminated
with an ICD, the investigators hypothesized that the winter
increase in SCD was due to VT (17). It has previously been
suggested that the seasonal relationship may be explained by
the relative lack of sunlight in the winter months (18).
GENERAL PREVENTION REMAINS KEY
New approaches to sudden death prevention may include gene
therapy to convert atrial or ventricular muscle cells to pace-
maker cells. Other therapies under investigation include spinal
cord stimulation, which is already used in Europe to treat
refractory angina (19), and intrathecal clonidine (20).
No pharmacological therapies aimed at reducing arrhyth-
mia, with the possible exception of amiodarone (although
recent data from the Sudden Cardiac Death in Heart Failure
Trial failed to show any survival benefit) (21), have been
shown to reduce mortality. Conversely, a mortality benefit has
been observed with numerous other agents, including beta-
blockers, acetylsalicylic acid, statins, angiotensin-converting
enzyme inhibitors and spironolactone (22). Their mecha-
nisms, although unknown, may result in a positive impact on
upstream events that would otherwise trigger ischemia.
The wide-scale availability of automatic external defibrilla-
tors (AEDs) is critical to allow immediate response to individ-
uals experiencing potentially fatal arrhythmias/sudden death.
These devices have been installed extensively in public venues
such as airports and sports arenas. However, it remains true
that at current rates of installation and use, only one in five
events is treated with an AED; the other four events occur in
the home (23). Programs such as the Neighborhood Heart
Watch, which ensures access to an AED to a group of resi-
dences in a prescribed area, form an integral part of the current
answer to community-based prevention (24).
While the investigation of new modalities for risk identifi-
cation, risk stratification and treatment for potentially fatal
arrhythmias is advancing, such population-based strategies
remain important for the prevention of SCD.
Epidemiology and mechanisms of sudden cardiac death
Can J Cardiol Vol 21 Suppl A May 15, 2005 39A
2 6 . 7
2 2 . 1
1 5 . 8 1 5 . 6
1 6 . 9
1 5 . 3
9 . 8
1 3 . 8
0
5
1 0
1 5
2 0
2 5
3 0
1 -1 7 m o 1 8 -5 0 m o 5 1 - 1 2 1 m o > 1 2 1 m o
Conv
ICD
(n = 296) (n = 284) (n = 290) (n = 289)
Hazard Ratio 1.08
(p = 0.81)
0.56
(p < 0.001)
0.56
(p< 0.001)
0.56
(p < 0.001)
David J. Wilber MD, NASPE 2003. Abstract ID. 100865
Time from MI
M

%
o
a
t
r
l
i
t
y
Figure 3) Time dependence of mortality risk postmyocardial infarc-
tion: The Multicenter Automatic Defibrillator Implantation Trial-II
(MADIT-II). Conv Conventional therapy; ICD Implantable car-
dioverter defibrillator; MI Myocardial infarction; mo Months.
Reproduced/adapted with permission from reference 13
ANATOMIC/FUNCTIONAL
SUBSTRATE
TRANSIENT INITIATING
EVENTS
ARRHYTHMIA MECHANISMS
Coronary arterydisease
Cardiomyopathy
Dilated
Hypertrophic
Rightventricular dysplasia
Valvular
Congenital
Primary electrophysiological
Neurohumeral
Developmental
Inflammatory, infiltrative,
neoplastic, degenerative,toxic
Neuro/endocrine
Drugs
Electrolytes, pH, pO2
Ischemia/reperfusion
Hemodynamic
Stretch
Arising/Stress/Sleep
Alcohol
EMD
Asystole
VT
VF
Reentry
Automaticity
Triggeredactivity
Block/cell-to-cell
uncoupling
Zipes and Wellens Circ 1998; 98:2334
Figure 4) Factors that precipitate ventricular arrhythmia: Intersection
of numerous anatomic and functional factors and transient initiating
factors. EMD Electromechanical dissociation; pO2 Partial pressure of
oxygen; VF Ventricular fibrillation; VT Ventricular tachycardia.
Reproduced/adapted with permission from reference 4
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