Sudden Cardiac Death
Epidemiology and Genetics of Sudden Cardiac Death
Rajat Deo, MD, MTR; Christine M. Albert, MD, MPH
Sudden cardiac death (SCD) generally refers to an unexpected
death from a cardiovascular cause in a person with or without
preexisting heart disease. The specificity of this definition varies
depending on whether the event was witnessed; however, most
studies include cases that are associated with a witnessed
collapse, death occurring within 1 hour of an acute change in
clinical status, or an unexpected death that occurred within the
previous 24 hours.13 Further, sudden cardiac arrest describes
SCD cases with resuscitation records or aborted SCD cases in
which the individual survived the cardiac arrest.
The incidence of SCD in the United States ranges between
180 000 and 450 000 cases annually.4 These estimates vary
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owing to differences in SCD definitions and surveillance meth-
ods for case ascertainment.4,5 In recent prospective studies using
multiple sources in the United States,6,7 Netherlands,8 Ireland,9
and China,10 SCD rates range from 50 to 100 per 100 000 in the
general population.3 Despite the need for multiple sources of
surveillance to provide a more accurate estimate of SCD
incidence, it is clear that the overall burden in the population
remains high. Although improvements in primary and secondary
prevention have resulted in substantial declines in overall coro-
nary heart disease (CHD) mortality over the past 30 years,11,12
SCD rates specifically have declined to a lesser extent.1316 SCD
still accounts for 50% of all CHD deaths and 15% to 20% of
all deaths.17,18 For some segments of the population, rates are not
decreasing19 and may actually be increasing.14,19 As a result,
SCD prevention represents a major opportunity to further reduce
mortality from CHD.
Despite major advances in cardiopulmonary resuscitation20
and postresuscitation care, survival to hospital discharge after
cardiac arrest in major metropolitan centers remains poor.21
Survival to hospital discharge was recently estimated to be only
7.9% among out-of-hospital cardiac arrests that were treated by
emergency medical services personnel.6 In addition, the majority
of SCDs occur at home, often where the event is unwitnessed.8,22
As a result, automated external defibrillators, which improve
resuscitation rates for witnessed arrests,21 may have limited
effectiveness on reducing overall mortality from SCD. There-
fore, substantial reductions in SCD incidence will require effec-
tive primary preventive interventions. Since the majority of
SCDs occur in the general population, an in-depth understanding
of the epidemiology of SCD may lead to possible low-risk
interventions that could be applied broadly to populations. In
addition, recent data emerging related to the genetics of SCD
From the Section of Electrophysiology, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, PA (R.D.); Division of
Preventive Medicine and Cardiovascular Medicine, Center for Arrhythmia Prevention, Brigham and Womens Hospital, Boston, MA (C.M.A.).
Correspondence to Christine M. Albert, MD, MPH, Division of Preventive Medicine and Cardiovascular Medicine, Center for Arrhythmia Prevention,
Brigham and Womens Hospital, 900 Commonwealth Ave E, Boston, MA 02215-1204. E-mail calbert@partners.org.
(Circulation. 2012;125:620-637.)
2012 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
620
may eventually aid in the identification of high-risk subsets
within the general population or provide new molecular targets
for intervention.
Demographics: Age, Sex, and Race
The incidence of SCD increases markedly with age regardless of
sex or race (Figure 1). For example, the annual incidence for
50-year-old men is 100 per 100 000 population compared with
800 per 100 000 for 75-year-old men.23 Although SCD increases
with age, the proportion of deaths that are sudden is larger in the
younger age groups2,24,25 in which the socioeconomic impact of
SCD is greater. At any age,26 women have a lower incidence of
SCD than men, even after adjustment for CHD risk factors.27
This discrepancy may be decreasing over time.7,16 The decline in
SCD rates among women has been less than that observed for
men, in particular in the younger age groups.14 This may be due,
in part, to a lower overall burden of CHD in women with SCD.
Approximately two-thirds of women who present with SCD
have no known history of heart disease compared with 50% of
men.8,24,28 In addition, among cardiac arrest survivors29 and SCD
patients,30 women appear to have a higher prevalence of struc-
turally normal hearts (Figure 2).
There are also racial differences in the incidence of SCD
that are not well understood. Black men and women appear to
experience out-of-hospital cardiac arrest several years earlier
than whites do. In 2 American cities, blacks had higher rates
(relative risk1.32.8) of cardiac arrest than whites (Figure
3).23,31 Data from death certificates also suggest that SCD is
more common among black Americans than other ethnicities,
and Hispanic Americans may have lower SCD rates than
non-Hispanic populations.14,32 In addition, survival rates after
cardiac arrest are lower for African blacks.23,33 In Chicago,
the overall survival rate after an out-of-hospital cardiac arrest
among blacks was only 31% of that among whites.23 Blacks
are more likely to have an unwitnessed arrest with an
unfavorable rhythm such as pulseless electric activity docu-
mented at the time of the arrest.23,34 However, the disparity in
survival does not appear to be entirely due to the initial
rhythm at time of arrest. Even when limited to cardiac arrests
due to ventricular fibrillation (VF) or pulseless ventricular
tachycardia, rates of survival to hospital discharge are 27%
lower among black patients.35 In the National Registry of
Cardiopulmonary Resuscitation, much, but not all, of this
disparity appeared to be explained by black patients receiving
DOI: 10.1161/CIRCULATIONAHA.111.023838

Figure 1. Incidence of sudden cardiac arrest according to age,
sex, and race in the Chicago CPR project. The study population
was comprised of 6451 patients including 3207 whites and 2910
blacks. Adapted from Albert et al,23 with permission from the pub-
Downloaded from http://circ.ahajournals.org/ by guest on May 18, 2017
lisher. Copyright Massachusetts Medical Society, 1993.
treatment at hospitals with worse outcomes.35 As in all studies
of racial differences, it is difficult to separate socioeconomic
influences from a true genetic predisposition.
Underlying Pathophysiology
The pathophysiology of SCD is complex and is believed to
require the interaction between a transient event and under-
lying substrate. This process induces electric instability and
lethal ventricular arrhythmias followed by hemodynamic
collapse. Although the challenge remains to predict when
such interactions prove harmful, a variety of risk factors have
been proposed (Figure 4).
CHD is the most common substrate underlying SCD in the
Western world, being responsible for 75% of SCDs.8,18,36,37
Figure 2. Structural heart disease in cardiac arrest survivors.
These pie charts depict the proportions of underlying cardiac
disease among men and women who survive out-of-hospital
cardiac arrests. The mean age was 5812 years for men and
5517 years for women. Coronary artery disease was the prin-
cipal diagnosis in the majority of men. In contrast, women had
more nonischemic heart disease than men, including dilated
cardiomyopathy (19%) and valvular heart disease (13%).29 CAD
indicates coronary artery disease; DCM, dilated cardiomyopa-
thy; VHD, valvular heart disease; SPASM, coronary vasospasm;
and RV, right ventricular. Adapted from Albert et al,29 with per-
mission from the publisher. Copyright American Heart Associ-
ation, Inc., 1996.
Deo and Albert Sudden Cardiac Death 621
Figure 3. Relative risk of cardiac arrest in blacks in comparison
with whites by age group. The bars represent 95% confidence
intervals. Adapted from Albert et al,23 with permission from the
publisher. Copyright Massachusetts Medical Society, 1993.
Cardiomyopathies (dilated, hypertrophic, and arrhythmo-
genic right ventricular cardiomyopathy) and primary electric
disorders related to channelopathies account for most of the
remainder.18 In 5% of SCDs or cardiac arrests, a significant
cardiac abnormality is not found after extensive evaluation or
at autopsy.29,38,39 CHD predisposes to SCD in 3 general
settings: (1) acute myocardial infarction, (2) ischemia without
infarction, and (3) structural alterations such as scar forma-
tion or ventricular dilatation secondary to prior infarction or
chronic ischemia. In those who die suddenly of CHD, 19% to
27%40,41 have pathological evidence for myocardial necrosis,
and only 38% of cardiac arrest survivors will develop
enzymatic evidence of myocardial infarction.42 In autopsy
studies, stable plaques and chronic changes alone are found in
50% of SCD patients with CHD41,43,44 suggesting that
plaque rupture and acute mycoardial infarction (MI) is
present in some, but not the majority, of SCD cases.
Presumably, the mechanism of SCD in cases without acute
MI is an electric event due to a ventricular arrhythmia triggered
by ischemia or other arrhythmogenic stimuli in the setting of a
chronically diseased heart.45 This hypothesis is difficult to prove,
because most deaths are not monitored, and those that are
constitute a highly selected population. Ventricular fibrillation
degenerates to asystole over the course of several minutes; as a
result, the majority of SCD patients demonstrate asystole or
pulseless electric activity when first examined by rescue teams.34
In cases where there has been a relatively short delay between
collapse and the initial determination of rhythm, the proportion
with documented ventricular tachyarrhythmias increases to 75%
to 80% (Figure 5).42,46 49 Studies in epidemiological cohorts of
men50 and women24 from the 1970s to 1990s suggest that 88%
to 91% of deaths that occur within 1 hour of symptom onset are
arrhythmic in nature. However, the proportion of SCD deaths
due to VF may be decreasing over time. VF is less often
encountered as the initial rhythm in recent emergency medical
services series,19 and the decline does not appear to be entirely
accounted for by changing resuscitation patterns or patient
characteristics.51
 622 Circulation January 31, 2012
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Figure 4. Critical pathways leading to electric instability and sudden cardiac death. HTN indicates hypertension; CHD, coronary heart
disease; CHF, congestive heart failure; LV, left ventricular; PUFA, polyunsaturated fatty acids; NEFA, nonesterified fatty acids; SCD,
sudden cardiac death.
Risk Factors
Structural Heart Disease
Coronary heart disease or congestive heart failure markedly
increases SCD risk in the population.52 In the Framingham
Study, preexisting CHD was associated with a 2.8- to 5.3-fold
increase in risk of SCD, and congestive heart failure was
associated with a 2.6- to 6.2-fold increased risk.27 After
experiencing an MI, women and men have a 4- to 10-fold
higher risk of SCD, respectively.24,28 The absolute rate is
Figure 5. First cardiac rhythm documented at time of sudden
arrhythmic death.46 VT indicates ventricular tachycardia; VF,
ventricular fibrillation. Adapted from Bayes de Luna et al,46 with
permission from the publisher. Copyright Elsevier, 1989.
highest in the first 30 days after MI and decreases gradually
with time.53,54 The incidence of SCD after MI has declined in
parallel with CHD mortality over time,54 and rates as low as
1% per year in patients receiving optimal medical therapy and
revascularization have been documented.55,56 However, rates
are still high in certain subsets of post-MI patients with
SCD.53 Both left ventricular dysfunction and New York Heart
Association class are powerful risk factors for SCD in
patients with either ischemic or nonischemic cardiomyopa-
thy,57 and implantable cardioverter defibrillators prolong life
in these high-risk patients.58,59 Other markers of structural
heart disease associated with elevated SCD risk include left
ventricular hypertrophy,60,61 QTc prolongation,62 and abnor-
mal heart rate profile during exercise.63 At the present time,
none of these markers have been incorporated into risk
stratification algorithms.
Although overt structural heart disease markedly increases
SCD risk, most patients who experience a cardiac arrest will not
have a left ventricular ejection fraction 35% documented
before SCD.2,18,30,64 This finding presents a major challenge
when designing SCD preventive strategies, because those most
at risk by current criteria make up a small percentage of the total
number of SCDs in the population. One recent study among
postmenopausal women with overt CHD and relatively pre-
served systolic function raised the possibility that a combination
of easily accessible clinical and epidemiological risk factors
might be able to better reclassify SCD risk into clinically
meaningful risk categories in comparison with left ventricular
ejection fraction alone.65 However, as is the case for left
ventricular ejection fraction and most other clinical predictors,
high risk patients identified by this approach were also at a

similarly high risk for competing forms of cardiovascular
death.53,66 The high risk for competing causes of death limits the
effectiveness of therapies such as the implantable cardioverter
defibrillators that are specifically targeted toward SCD preven-
tion. In addition, SCD is often the first manifestation of cardio-
vascular disease, and risk stratification in high-risk patients will
not address the majority of SCDs that occur in the population.
Therefore, a more thorough understanding regarding risk factors
for SCD in the general population is also needed.
CHD Risk Factors
Because 80% of men who experience SCD have underlying
CHD, it follows that the standard CHD risk factors are
predictive of SCD in the general population. Modifiable CHD
risk factors that have been demonstrated to predict SCD in
diverse cohorts include hypertension, hypercholesterolemia,
diabetes mellitus,67 69 kidney dysfunction,70,71 obesity, and
smoking. 24,27,72,73 Although the prevalence of CHD among
female SCD patients may be lower than among male SCD
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patients,29,30 conventional CHD risk factors still appear to
predict SCD in women.24,28,65 Smoking, in particular, is an
important risk factor for SCD with risk elevations in the
general population similar to that conferred by MI.24,43,44
Continued smoking increases the risk of recurrent cardiac
arrest,74 and smoking cessation is associated with a prompt
reduction in SCD risk among patients with CHD.26,75,76 Diabetes
mellitus and hypertension are also strong risk factors for
SCD,67 69 and recent evidence has highlighted the potential
importance of diabetes as a potential risk stratifier for SCD even
in high-risk populations.77 Serum cholesterol appears to be more
strongly related to SCD at younger ages.24,28
All of the risk factors discussed above predict CHD in
general and are not specific for SCD, and with the exception
of diabetes,65,77 kidney disease,65,70,71 and smoking,75 do not
appear to predict SCD risk once overt CHD has been
established.52 However, modification of traditional CHD risk
factors will have an impact on SCD incidence at the popula-
tion level. Reduced incidence rates of all manifestations of
CHD including SCD since the mid-1960s provide indirect
evidence of the success of CHD risk factor modification.
Electrocardiographic Measures of Risk
Standard 12-lead electrocardiographic measures including
heart rate, QRS duration, QT interval, and early repolariza-
tion have been assessed as risk factors for SCD. Population-
based studies have demonstrated that an elevated resting heart
rate78 and prolonged QT interval increase SCD risk in the
general population.62,79 Similarly, a prolonged QRS duration
has also been associated with SCD.80,81 Recent interest has
focused on early repolarization (ER) as a novel risk factor for
SCD and cardiovascular death. ER is defined as an elevation
of the junction between the end of the QRS complex and the
beginning of the ST segment (J point), and its presence in the
inferior or lateral ECG leads has been associated with a
history of sudden cardiac arrest and idiopathic VF in case-
control studies.82 84 In a population-based study from Fin-
land, ER patterns associated with 0.2 mV elevations in the
inferior leads were associated with marked elevations in the
risk of death from cardiac causes or from arrhythmia.85 In a
Deo and Albert Sudden Cardiac Death 623
follow-up analysis from this same cohort, ER was associated
with arrhythmic death only when horizontal or descending ST
segments were present.84 Individuals with ER and rapidly
ascending/upsloping ST segment were not at elevated risk.
Nutritional Risk Factors
Dietary intake and blood-based measures of selected nutrients
have been specifically associated with SCD in observational
studies (Table 1).70,86 101 Several epidemiological studies sug-
gest that increased consumption of n-3 polyunsaturated fatty
acids is inversely associated with SCD to a greater extent than
nonfatal MI.102106 In 4 observational studies, consuming fish
1 to 2 times per week was associated with 42% to 50%
reductions in SCD risk.102105 -Linolenic acid, which is an
intermediate chain n-3 polyunsaturated fatty acids found in
foods of plant origin, has also been associated with a reduced
risk of SCD in 1 observational study of women.106 These data
from relatively healthy observational cohorts support experi-
mental data demonstrating a protective effect of these nutrients
on arrhythmia susceptibility.107 Data from randomized clinical
trials, however, have not consistently supported this hypothesis.
The Gruppo Italiano per lo Studio della Sopravvivenza
nellInfarto miocardico (GISSI) Prevenzione trial, which tested
supplementation with n-3 polyunsaturated fatty acids (combina-
tion of 850 mg eicosapentaenoic acid and docosahexaenoic acid
daily) in an open-label fashion among 11 324 patients with
recent MI, found a significant 45% reduction in SCD without
any benefit on nonfatal MI or stroke.108 More recently, however,
2 randomized, blinded trials of n-3 polyunsaturated fatty acids
performed in post-MI populations were unable to confirm these
benefits on SCD.109,110 The SCD event rates in both of these
post-MI populations were much lower than expected, and the
studies were likely underpowered. As a result, it will be
challenging to test whether interventions reduce SCD rates in
lower-risk populations.
Alcohol and magnesium intake may also have a selective
effect on SCD risk. Heavy alcohol consumption (5 drinks
per day) is associated with an increased risk of SCD73 but not
nonfatal MI.111 In contrast, light-to-moderate levels of alco-
hol consumption ( 12 to 1 drink per day) may be associated
with reduced risks of SCD.112114 Magnesium intake may also
be related to SCD rates. In the Nurses Health Study, the
relative risk of SCD was significantly lower among women in
the highest quartile of dietary magnesium intake. In addition
each 0.25 mg/dL (1 SD) increment in plasma magnesium was
associated with a 41% reduced risk of SCD.87 A similar
inverse association between serum magnesium and SCD was
also found in the Atherosclerosis Risk in Communities study;
however, a single measure of dietary magnesium intake was
not associated with SCD risk.88
Finally, there is some evidence that certain dietary patterns
that account for additive and interactive effects of multiple
nutrients 115 are associated with lower SCD risk. A
Mediterranean-style diet consisting of higher intake of vege-
tables, fruits, nuts, whole grains, fish, moderate intake of
alcohol, and low intake of red/processed meat, has been
associated with lower risks of cardiovascular disease in
clinical trials116 and observational studies.117 The association
appears stronger for fatal in comparison with nonfatal events,
 624 Circulation January 31, 2012

Table 1. Biological Markers and Sudden Cardiac Death in Prospective Studies

Biomarker Mechanism Study Findings
Dietary markers
Long-chain n-3 fatty Ionic channel stabilization, Physicians Health Study86 (n278) Baseline level of long-chain n-3 fatty acids were inversely related
acids inflammation to the risk of SCD
Magnesium Repolarization, membrane Nurses Health Study87 (n88 735) Higher plasma concentrations and dietary magnesium intake were
stabilization associated with lower risks of SCD
ARIC study88 (n14 232) Participants in the highest quartile of serum Mg were at a
significantly lower risk of SCD compared with those in the lowest
one
Nonesterified fatty Membrane stabilization Paris Prospective Study89 (n5250 Fasting plasma NEFA measurements at baseline were
acids men) independently associated with SCD after a 22-y follow-up period
Trans-fatty acids Inflammation, endothelial Cardiovascular Health Study90 Higher plasma phospholipid trans-18:2 fatty acids were associated
dysfunction (n428) with higher risk of SCD. Higher trans-18:1 levels were associated
with lower SCD risk
Inflammatory markers
CRP, IL-6, Inflammation, oxidative PRIME Study91 (n9771 men) Baseline concentrations of IL-6, but not CRP or fibrinogen, were an
fibrinogen stress, insulin resistance independent risk factor for SCD after 10 y of follow-up
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CRP Inflammation, oxidative Nurses Health Study92 (n121 Baseline concentrations of CRP were not associated with SCD
stress 700 women) events after 16 y of follow-up
CRP Inflammation, oxidative Physicians Health Study93 (n22, Baseline CRP levels were associated with an increased risk of SCD
stress, apoptosis 071 men) over a 17-y follow-up period
ST2 Interleukin-1 receptor, MUSIC Registry,94 ambulatory heart Over a 3-y follow-up period, elevated soluble ST2 concentrations
myocardial fibrosis failure patients (n99) at baseline were independently associated with SCD
Metabolic markers
Aldosterone Myocardial tension, STEMI population95 (n356) Among patients referred for primary PCI for STEMI, high
fibrosis, electrical aldosterone levels at admission were associated with death or
remodeling resuscitated cardiac arrest during a 6-mo follow-up period
Cystatin C Marker of glomerular Cardiovascular Health Study,70 Over a median follow-up of 11.2 y, elevated cystatin C
filtration rate excluded participants with concentrations at baseline had an independent association with
prevalent cardiac disease SCD in elderly people without prevalent cardiovascular disease
(n4482)
Renin Fibrosis and electrical LURIC study,96 patients referred for Baseline plasma renin is associated with long-term cardiovascular
remodeling coronary angiography (n3303) mortality including both SCD and death due to heart failure.
Vitamin D and Fibrosis, electrical Cardiovascular Health Study,97 The combination of lower vitamin D and higher PTH concentrations
parathyroid remodeling, metabolic excluded participants with was an independent risk factor for SCD among older adults
hormone effects prevalent cardiac disease without cardiovascular disease
(n2312)
Vitamin D Fibrosis and electrical German Diabetes and Dialysis Over a median follow-up of 4 y in this dialysis cohort with
remodeling Study98 (n1108) diabetes, severe vitamin D deficiency was associated with SCD
Neurohormonal markers
BNP Increased myocardial Nurses Health Study92 (n121 Increased baseline NT-pro-BNP concentrations were independently
NT-pro-BNP tension 700 women) associated with SCD events after 16 y of follow-up
Cardiovascular Health Study99 Elevated baseline NT-pro-BNP levels were associated with SCD
(n5447) after a median 12.5 y follow-up period
Vienna Heart Failure cohort (LVEF After 3 y of follow-up, elevated BNP levels at baseline were an
35%)100 (n452) independent risk factor for SCD in patients with CHF
Multiple Risk Factor Analysis Trial During a 3.5-y follow-up period, elevated baseline BNP levels were
(MRFAT, post-MI population) 101 associated with SCD after adjustment for clinical risk factors and LVEF
(n521)
SCD indicates sudden cardiac death; ARIC, Atherosclerosis Risk in Communities; NEFA, nonesterified fatty acids; IL-6, interleukin 6; CRP, C-reactive protein; PRIME,
Etude PRospective de lInfarctus du Myocarde; MUSIC, MUerte Sbita en Insuficiencia Cardaca; STEMI, ST segment elevation myocardial infarction; PCI, percutaneous
coronary intervention; LURIC, Ludwigshafen Risk and Cardiovascular Health; PTH, parathyroid hormone; BNP, brain natriuretic peptide; NT pro-BNP, amino-terminal
pro-B type natriuretic peptide; and LVEF, left ventricular ejection fraction.

and may be driven partially through protection against ven-
tricular arrhythmias and SCD.118 Recent data from the
Nurses Health Study suggest that women whose dietary
habits most resemble the Mediterranean dietary pattern have
a significantly lower risk of SCD.119
Biological Markers
In addition to the nutrient biomarkers described above,
multiple epidemiological investigations have evaluated dys-
regulation in inflammatory, metabolic, and neurohormonal
pathways as predisposing factors for SCD (Table 1). Several
 Deo and Albert Sudden Cardiac Death 625
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Figure 6. Sports engaged in at the time of the SCD events among 820 SCD events associated with exertion in France. N refers to the abso-
lute number of SCD events that occurred during the specified sport. The percentage refers to the percent of deaths engaged in the specific
activity. The pink-shaded region represents the number of women.137 SDs indicate sudden deaths; SCD, sudden cardiac death. Adapted
from Marijon et al,137 with permission from the publisher. Copyright American Heart Association, Inc., 2011.

epidemiological studies have assessed biomarkers at a time
when the majority of participants are free of significant
clinical cardiovascular disease. As a result, abnormal concen-
trations may reflect subclinical changes in cardiovascular
processes that eventually predispose individuals to SCD
risk. The early stages of hemodynamic stress, atheroscle-
rotic plaque instability, and cardiac remodeling may only
be detectable with biomarkers that are associated with
inflammatory processes, metabolic factors, and neurohor-
monal regulation. Experimental evidence suggests that
these markers regulate pathophysiologic mechanisms im-
plicated in CHD, heart failure, and cardiac arrhythmias.
Although many of the prospective epidemiological studies
on which these inferences are based have enrolled many
participants, they contain only a limited number of SCD
events. Future studies will require larger samples of SCD
cases with prospectively collected blood samples to vali-
date these findings and to determine whether biomarkers
have a diagnostic role120 in identifying high-risk individ-
uals in the general population.
Triggers
SCD risk in the population is not only a function of the
underlying substrate and its vulnerability to arrhythmias but also
the frequency of exposure to acute precipitants or triggers
(Figure 4). These triggers tend to increase sympathetic activity,
which in turn may precipitate arrhythmias and SCD.
Diurnal/Seasonal Variation
Several studies have demonstrated a circadian pattern to the
occurrence of SCD and out-of-hospital cardiac arrest.121 The
peak incidence occurs in the morning hours from 6 AM to
noon122 with a smaller peak in the late afternoon for out-of-
hospital VF arrests.123,124 This morning peak in SCD is blunted
by -blockers,125 supporting the concept that excessive activa-
tion of the sympathetic nervous system in the morning hours
may be responsible. Weekly and seasonal patterns to SCD onset
have also been appreciated. The risk of out-of-hospital cardiac
arrest126 and SCD127 appears to be highest on Monday with a
nadir over the weekend.126 These patterns of onset suggest that
activity and psychological exposures play roles in triggering
SCD. There have also been reports of seasonal variation in SCD
rates with lower rates in the summer and higher rates in winter
months in both hemispheres.127,128 SCD may be associated with
endogenous rhythms and environmental factors including tem-
perature,128,129 sunlight exposure, and other climatic conditions.
Physical Activity
Physical activity has both beneficial and adverse effects on SCD
risk. Most studies,65,73,130 133 but not all,134,135 have found
inverse associations between increasing regular physical activity
and SCD or sudden cardiac arrest. Results are most consistent
for moderate levels of exertion,65,73,131133 where the majority of
studies have documented favorable associations. Despite the
long-term benefits of exercise, it is also well known that SCD
occurs with a higher-than-average frequency during or shortly
after vigorous exertion.136 Case-control and case-crossover stud-
ies performed among men have demonstrated that vigorous
exertion can trigger cardiac arrest130 and SCD.135 Regular
vigorous exertion diminishes the magnitude of this excess risk;
however, the risk remains significantly elevated even in the most
habitually active men.137 The magnitude of the risk associated
with exertion appears to be lower among women133 where
exertion-related SCD is much less common (Figure 6).137 The
 626 Circulation January 31, 2012
effect of exertion on plaque vulnerability138 and the sympathetic
nervous system could account for both the transiently increased
risk of SCD during a bout of exertion and the ability of habitual
vigorous exercise to modify this excess risk.139,140 Acute bouts
of exercise decrease vagal activity leading to an acute increase in
susceptibility to ventricular fibrillation,139 whereas habitual ex-
ertion increases basal vagal tone, resulting in increased cardiac
electric stability.
Despite these transiently elevated relative risks, the abso-
lute risk of SCD during any particular episode of exertion is
extremely low in most series,141 and exertion-related SCDs
are felt to be relatively rare outcomes. A recent national
survey in France estimated that the incidence of exertion-
related SCD in the population may be as high as 17 cases per
million population per year.137 In this study, the absolute
number of SCDs associated with exertion in the general
population (n770) far exceeded that observed among young
competitive athletes (n50), where the majority of the public
attention has been directed.
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Psychosocial Determinants
Lower socioeconomic status, depression, anxiety, social isola-
tion, and psychological stress have all been linked to an increase
in cardiovascular mortality in diverse populations.142,143 Al-
though arrhythmic mechanisms have been postulated to partly
underlie these associations, there are few studies that have
prospectively examined associations with SCD. The incidence
of SCD is higher in regions with lower socioeconomic status,
and this gradient in risk is more exaggerated below age 65.144
Chronic psychological stressors such as anxiety disorders and
depression have also been associated with SCD in population-
based studies. Phobic anxiety has been directly associated with
SCD, but not nonfatal MI risk, in 3 separate populations of
men145 and women.146 Depression has also been associated with
elevated risks of cardiac arrest147 and SCD among women
without CHD.148 In addition to the chronic effects of psychos-
ocial stress, it appears that acute mental stress can trigger SCD
as well. Acute increases in the incidence of SCD have been
documented in populations experiencing disasters such as earth-
quakes or wars.149,150 In addition to disasters, life stresses such as
death of a spouse and loss of a job have been associated with an
increase in total mortality151 and SCD152 in healthy populations.
Genetic Predisposition to SCD
Over the past decade, investigations focused on the genetic
bases of rare, inherited arrhythmic diseases (IADs) have
provided insight into understanding the heritability of vulner-
ability to ventricular arrhythmias.153 The discovery of novel
genes implicated in IADs and the effects of mutant alleles on
basic electrophysiology raised the possibility that common
genetic variants or polymorphisms in these same regions may
account for part of the familial component of SCD risk
observed in epidemiological studies. Subsequently, comple-
tion of the Human Genome Project provided the foundation
to identify novel genes and biological pathways implicated in
conduction system disease, cardiac arrhythmias, and SCD.
Familial Studies
Several studies have demonstrated a familial predisposition to
SCD.72,154 156 SCD events and fatal arrhythmias such as VF are
often the initial manifestation of an acute myocardial infarction
and appear to cluster in families. Two case-control studies
demonstrate that a history of SCD in a first-degree relative is an
independent risk factor for VF155 or SCD156 in the setting of an
acute myocardial infarction (AMI). Similar results have been
documented in a prospective population-based study, where
parental history of SCD was ascertained before death. Over a 20
plus year follow-up period,72 parental history of SCD was an
independent risk factor for SCD (RR1.80; 95% CI 1.112.88),
but not for fatal MI. Conversely, a parental history of fatal MI
was only associated with an increased risk of fatal MI and had no
effect on risk of SCD. These data in aggregate suggest that the
familial aggregation of SCD or ischemic VF may be distinct
from the familial risk pattern of MI or CHD. The consistent
associations implicating a family history of arrhythmic death as
an independent risk factor for SCD in the general population has
led to several studies focused on identifying genetic variants that
may influence vulnerability to ventricular arrhythmias and SCD
in the population.
Intermediate Phenotypes for SCD:
ECG Variables
As discussed previously, quantitative measures obtained from
ECGs, including those for heart rate, QRS duration, and QT
interval, have been associated with SCD. These measures are
heritable and have multiple environmental and genetic contrib-
utors.157161 As a result, genetic working groups across the world
have partnered to identify common genetic variations associated
with these quantitative traits through genome-wide association
studies (GWAS). These genetic variants, which usually confer
modest effects, may provide further insight, not only into the
cardiac conduction system, but also into arrhythmic diseases
including SCD. Novel variants identified through this mecha-
nism may also eventually serve as susceptibility alleles for SCD
in the population.
QT Interval
Three GWAS focused on variation in the QT interval among
individuals of European ancestry have been completed.162164 In
total, these studies evaluated almost 30 000 individuals.163,164
Approximately half the loci identified in these unbiased
analyses map near the monogenic longQT-syndrome genes
(KCNQ1, KCNH2, KCNE1, and SCN5A) (Table 2). The
strongest and most consistent signal is within the NOS1AP
gene, which encodes a nitric oxide synthase 1 adaptor
protein.162 This gene has been demonstrated to be a modula-
tor of myocardial repolarization in translational models,165
and variants in NOS1AP also modulate risk in the long-QT
syndrome.166,167 Approximately half the genetic variants
identified in these GWAS were in loci not previously impli-
cated in cardiac electrophysiology or recognized to regulate
myocardial repolarization. In combination, these variants
explain 5% to 6% of variation in QT interval.
QRS Interval
A recent genome-wide meta-analysis of 14 studies including
a total of 40 407 individuals of European descent has identi-
fied 22 loci associated with QRS duration (Table 2).168 Some
of these loci map within or near genes implicated in ventric-
 Deo and Albert Sudden Cardiac Death 627

Table 2. Genetic Variants of ECG Traits Identified Through Genome-Wide Association Studies
Coded Allele
Chr Gene/Region SNP Freq. Eff. (ms) Findings/Notes
QT interval
1p36 RNF207 rs846111 0.29 1.5 The function of this locus is unknown
1q24 ATP1B1 rs10919071 0.87 2.0 ATP1B1 encodes a transmembrane protein that maintains Na and
K gradients across the membranes
1q23 NOS1AP rs12143842 0.24 3.2 Neuronal nitric oxide synthase 1 regulates calcium cycling in the
sarcoplasmic reticulum
3p22 SCN5A rs12053903 0.34 1.2 Rare variants in SCN5A result in long-QT syndrome type 3 and the
Brugada syndrome
6q22 c6orf204, SLC35F1, rs11756438 0.47 1.4 PLN inhibits cardiac sarcoplasmic reticulum Ca2-ATPase.
PLN Increased PLN activity is linked to cardiomyopathy and ventricular
tachycardia
7q36 KCNH2 rs2968864 0.25 1.4 Rare variants in KCNH2 are associated with congenital long-QT
7q36 KCNH2 rs4725982 0.22 1.6 syndrome type 2 and short-QT syndrome type 1

11p15 KCNQ1 rs2074238 0.06 7.9 Rare variants in KCNQ1 are associated with long-QT syndrome
11p15 KCNQ1 rs12576239 0.13 1.8 type 1 and short-QT syndrome type 2
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16p13 LITAF rs8049607 0.49 1.2 This gene has no known association with myocardial repolarization
16q21 NDRG4 rs7188697 0.74 1.7 Novel locus associated with myocardial repolarization
17q12 LIG3 rs2074518 0.46 1.1 LIG3 encodes DNA ligase III repair; the mechanism of modulating
repolarization is unknown
17q24 KCNJ2 rs17779747 0.35 1.2 Rare variants are associated with Anderson syndrome, which is
characterized by periodic paralysis, dysmorphic features and
ventricular arrhythmias
21q22 KCNE1 rs1805128 0.01 0.88 Rare variants in KCNE1 result in long-QT syndrome type 5
QRS interval
1p31 NFIA rs9436640 0.46 0.59 The association of Nuclear Factor One with QRS duration is
unclear
1p32 CDKN2C rs17391905 0.05 1.35 This gene is a cyclin-dependent kinase inhibitor and regulates cell
growth
1p13 CASQ2 rs4074536 0.29 0.42 Calsequestrin 2 is a calcium-handling protein that regulates
opening of the ryanodine receptor. Mutations in CASQ2 have been
implicated in CPVT
2p22 HEATR5B, STRN rs17020136 0.21 0.51 Striatin is a calmodulin-binding protein. It has recently been
implicated in a dog model of ARVC
2p21 CRIM1 rs7562790 0.40 0.39 CRIM1 is expressed in cardiac tissues and encodes a
transmembrane protein that may bind to various members of the
TGF- superfamily of ligands
3p22 SCN10A, SCN5A rs9851724 0.33 0.66 Both genes encode voltage-gated Na channels and are important in
cardiac conduction. SCN5A is also associated with the QTc interval
3p14 TKT, PRKCD, rs4687718 0.14 0.63 TKT is an enzyme used in multiple metabolic pathways
CACNA1D
3p14 LRIG1, SLC25A26 rs2242285 0.42 0.37 LRIG1 is upregulated in malignancies
5q33 HAND1, SAP30L rs13165478 0.36 0.55 HAND1 encodes a transcription factor essential to cardiac
development. Mutations have been associated with septal defects
and ventricular arrhythmias
6p21 CDKN1A rs9470361 0.25 0.87 CDKN1A is a cyclin-dependent kinase inhibitor that is important for
cardiac conduction system development. It can also aid with gap
junction assembly
6q22 C6orf204, SLC35F1, rs11153730 0.49 0.59 Cardiac PLN regulates calcium uptake into the sarcoplasmic
PLN reticulum by SERCA2a. This locus is also associated with the QTc
and left ventricular end diastolic dimension
7p14 TBX20 rs1362212 0.18 0.69 TBX20 demarcates the left and right ventricles
7p13 IGFBP3 rs7784776 0.43 0.39 The function of this locus is unknown
10q25 VTI1A rs7342028 0.27 0.48 The function of this locus is unknown
(Continued)
 628 Circulation January 31, 2012

Table 2. Continued
Coded Allele
Chr Gene/Region SNP Freq. Eff. (ms) Findings/Notes
10q11 DKK1 rs1733724 0.25 0.49 DKK1 is involved with axial development during embryological
development. It also inhibits the Wnt signaling pathway, which is
an important modulator of connexin43 activity
12q24 TBX5 rs883079 0.29 0.49 TBX3 and TBX5 encode transcription factors found in the cardiac
12q24 TBX3 rs10850409 0.27 0.49 conduction system. TBX5 (activator) competes with TBX3
(repressor) for the regulation of myocardial genes such as GJA1.
Mutations in TBX3 and TBX5 have been associated with rare
inherited syndromes manifested by structural and conduction
defects
13q22 KLF12 rs1886512 0.37 0.40 The association of this transcription factor with QRS duration is
unclear
14q24 SIPA1L1 rs11848785 0.27 0.50 It contributes to Wnt signaling and cardiac development
17q22 PRKCA rs9912468 0.43 0.39 Protein kinase C alters sarcoplasmic reticulum Ca2 loading.
17q21 GOSR2 rs17608766 0.16 0.53 The function of this locus is unknown
18q21 SETBP rs991014 0.42 0.42 The function of this locus is unknown
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RR interval
1q32 CD46, LOC148696 rs12731740 0.03 5.9 This locus has an unclear association with heart rate. It has been
observed in both white and nonwhite studies
6q22 GJA1 rs9398652 0.49 12.7 GJA1 encodes Cx43, a connexin family protein and component of
cardiac gap junctions. It is responsible for synchronized cardiac
contractions. Mutations in GJA1 have been implicated in
hypoplastic left heart syndrome
6q22 SLC35F1, PLA rs281868 0.44 1.50 This locus is 3 Mb away from GJA1. It is also associated with
QTc. PLN is also involved in excitation-contraction coupling and
intracellular calcium signaling
7q22 SLC12A9 rs314370 0.94 9.65 It encodes a Cl cotransporter interacting protein
7q22 UfSp1 rs12666989 0.07 9.31 The function of this locus is unknown
11q12 FADS1 rs174547 0.91 4.20 FADS1 was previously associated with cholesterol levels
12q24 GPR133 rs885389 0.30 14 This locus encodes a G-protein-coupled receptor and is expressed
in both the atria and ventricles
14q12 MYH6 rs452036 0.62 9.65 Two different sarcomeric MYHC isoforms are present: -MYHC
14q12 MYH6 rs365990 0.38 9.80 (encoded by MYH6) and -MYHC (encoded by MYH7). Mutations in
these genes have been implicated in various cardiomyopathies
14q12 MYH7 rs223116 0.77 4.47
Chr indicates chromosome; SNP, single-nucleotide polymorphism; Freq., frequency; Eff., effectiveness; PLN, phospholamban; CPVT, catecholaminergic polymorphic
ventricular tachycardia; ARVC, arrhythmogenic right ventricular cardiomyopathy; TGF-, transforming growth factor beta; TKT, transketolase; and MYHC, myosin heavy
chain.

ular conduction, such as sodium channels, transcription fac- RR Interval

tors, and calcium-handling proteins. In addition, several loci
are associated with previously unidentified biological pro-
cesses. Several of these loci also exhibit associations with PR
interval and QT interval, but most often in the inverse
direction for the latter. Overall, these loci in combination
explain 5.7% of the observed variance in QRS duration.
The strongest association signal mapped in or near 2 genes,
SCN5A and SCN10A, which encode the -subunit of the
Nav1.5 and Nav1.8 sodium channels, respectively. The
SCN5A locus is well established as a susceptibility locus for
a variety of IADs, but the involvement of SCN10A in cardiac
conduction was previously unrecognized until an initial
GWAS identified associations with PR interval and QRS
duration.169,170 Experimental models suggest that the SCN10A
transcript and product are expressed in mouse and human
hearts169 and localize to the mouse His-Purkinje system.168
GWAS have identified 9 loci associated with heart rate in
populations of European ancestry (Table 2).170,171 Two of these
loci have been identified in participants of East Asian ances-
try.172 One of the variants described in both Europeans and East
Asians is located on chromosome 6q22 and is located near the
GJA1 gene. GJA1 encodes gap junction protein and is critical for
synchronized contraction of the heart. It is a major component of
cardiac gap junctions173 and is known to play a role in
arrhythmogenesis.174,175
Genetic Determinants of ECG Phenotypes as
Susceptibility Alleles for SCD
Several of the single-nucleotide polymorphisms (SNPs) and
related loci associated with variations in ECG phenotypes
have been evaluated for specific associations with SCD.
NOS1AP variation has been associated with SCD risk in 3

separate studies.176 178 In a combined analysis of 334 SCDs
among white individuals participating in the Atherosclerosis
Risk In Communities Study and Cardiovascular Health
Study, a tagging SNP approach identified 2 intronic variants
in NOS1AP that were associated with SCD even after
controlling for QT interval. Interestingly, the variant with the
strongest association (rs12567209) was not associated with
QT-interval duration. A follow-up study in the Rotterdam
cohort found evidence for replication for this latter variant in
analyses limited to witnessed SCDs177; however, a case-
control study from Oregon did not.178 The latter study
reported another variant, which was correlated with the
rs12567209 SNP, to be nominally significant. A recent study
examined 49 independent loci, including NOS1AP, associated
with intermediate ECG traits of QT interval, QRS duration,
and heart rate in 1283 SCD cases.179 Only one locus,
TKT/CACNA1D/PRKCD, which had been previously associ-
ated with QRS duration, was associated with SCD after
adjustment for multiple testing. However, the QRS-
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prolonging allele was associated with a reduction in risk,
which was opposite to that predicted based on associations
between QRS duration and SCD.
All of the above common variants individually confer rela-
tively modest effect sizes on ECG characteristics, and, thus, may
not display detectable associations with SCD even with large
sample sizes. Therefore, attempts have been made to combine
variants into a genetic risk score to increase the power to detect
associations. Recently, all genome-wide significant SNPs asso-
ciated with the QT interval were entered into a QT genotype
score, which was then evaluated for an association with SCD in
2 Finnish cohort studies.180 The QT genotype score was linearly
associated with QT interval and explained 8.6% of the variance
in the QT interval within these populations. A linear relationship
between the genotype score and SCD risk, however, was not
detected for the combined 116 SCD cases within these cohorts,
which may have been underpowered. From these data, it has
become clear that genetic variants identified in genome-wide
studies on ECG markers can provide important information for
future translational and experimental work, but will not be
sufficient to explain the heritability of SCD.
Intermediate Phenotypes for SCD: CHD
Given the high prevalence of CHD, often undiagnosed in
SCD patients, genetic variants that are associated with CHD
may also serve as susceptibility alleles for SCD in the general
population. Shared variants for both traits may further our
understanding regarding biological processes that predispose
to SCD in the setting of CHD. International consortiums have
meta-analyzed GWAS to enhance the power of identifying
loci associated with CHD in European, African American,
and South Asian populations.181183 The most recent meta-
analysis included 22 000 cases of CHD in both the discov-
ery and replication phase and identified 10 previously recog-
nized and 13 novel loci associated with CHD.181 The majority
of these loci reside in gene regions that were not previously
suspected in the pathogenesis of coronary disease. The
strongest association signal remains a region on chromosome
9p21 that has been documented to regulate expression of 2
cyclin-dependent kinase inhibitor genes CDKN2A and
Deo and Albert Sudden Cardiac Death 629
CDKN2B,184 known to have critical roles in cell proliferation,
aging, senescence, and apoptosis.185 SNPs that tag the 9p21
region have been specifically associated with SCD in a
meta-analysis involving 492 SCDs among white individuals
from 6 prospective cohort studies.186 None of the other loci
associated with CHD in GWAS have been reported to be
associated with SCD.
Candidate Genes Analyses of SCD
These examinations of genetic variation associated with
intermediate phenotypes have been complemented by studies
using a candidate gene approach to identify susceptibility
alleles for SCD. This hypothesis-driven approach has focused
on several biological pathways implicated in the monogenic
arrhythmia disorders and SCD within the population.
Common Variants
Polymorphisms in genes fundamental to electric propagation,
cardiac conduction, sympathetic activation, thrombosis, athero-
genesis, and the renin-angiotensin-aldosterone system have been
assessed for associations with SCD in isolated studies using a
variety of designs and definitions (Table 3).178,187200 The prev-
alence of allelic variants in these studies is at least 5% and
often extends to 50% to 60% of the control population. As a
result, it is expected that these variants will have a modest
effect on SCD risk, because a particularly deleterious variant
would evolve over time to a rare variant/mutation in the
human gene pool (Figure 7). The vast majority of these
associations have not been independently replicated. Of the
candidates studied, genetic variants encoding for amino acid
polymorphisms in the 2-adrenergic receptor (Gln27Glu in
2AR) in whites191,193 and the -subunit of the Nav1.5 cardiac
sodium channel (Y1102A in SCN5A) in African Ameri-
cans189,190,201 have been associated with SCD or arrhythmic
events in 1 study; however, results have not been entirely
consistent.192
Rare Variants
Given the high lethality of SCD, it is possible that the genetic
architecture might be more similar to that underlying the rare
IADs, which is characterized by rare alleles associated with
variable penetrance. Such rare alleles are best detected by direct
sequencing, which is rapidly becoming more accessible because
of the development of next-generation sequencing technologies.
To our knowledge, very few studies have used sequencing to
examine rare variation in unselected SCD cases from adult
populations.188,202 The entire coding sequence and splice junc-
tions of 5 ion channel genes associated with IADs, SCN5A,
KCNE1, KCNE2, KCNQ1, and KCNH2, were directly se-
quenced in 113 cases of SCD.202 No unique or rare coding
sequence variants were identified in any of the ion channel genes
in 53 men.188 In 60 women with SCD, 6 rare missense variants
(10%) were identified in the cardiac sodium channel gene
(SCN5A).202 The overall frequency of these rare variants in
SCN5A was significantly higher in the SCD cases than in 733
controls from the same population (1.6%; P0.001), and subtle
alterations in ion channel function were observed for 4 of the 5
variants. Although not a common cause of SCD, these data
suggest that functionally significant mutations and rare variants
 630 Circulation January 31, 2012

Table 3. Candidate Genes for SCD in the General Population

N (SCD
Frequency of Cases/
Study Gene Variant Allele Population Controls) Findings/Notes
Ion channels
Westaway et al 2011178 CASQ2 GPD1L 1045% Americans of European 670/299 Polymorphisms in these genes are associated
ancestry, general population with SCD
Albert et al 2010187 KCNQ1 KCNH2 6070% Americans of European 516/1522 2 intronic variants (1 in KCNQ1 and 1 in
SCN5A KCNE1 ancestry, general population SCN5A) were associated with SCD
KCNE2
Stecker et al 2006188 SCN5A 14% Americans of European 67/91 No association was observed between SCN5A
ancestry with coronary disease polymorphisms or mutations with SCD
Burke et al 2005189 SCN5A (Y1102A) 9% Blacks, general population 182/107 Y1102A was associated with unexplained
arrhythmic death and SCA
Splawski et al 2002190 SCN5A (Y1102A) 13% Blacks, general population 23/100 Variant is associated with an increased risk
of SCD or medication induced QTc
prolongation
Autonomic nervous system
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Gavin et al 2011191 2AR (Gln27Glu) 45% Americans of European 492/1388 When combined with the 2 analyses below,
ancestry, general population the 2AR polymorphism is associated with
SCD
Tseng et al 2008192 2AR and 1AR 3040% (2AR) Aborted SCD and history of 107/388 No association was observed between any of
1030% (1AR) MI/CAD, 75% Americans of the AR polymorphisms and SCD
European ancestry
Sotoodehnia et al 2006193 2AR (Gln27Glu) 43% whites, American cohort (4441 195/5249 The 2AR variant is associated with SCD in
19% blacks European ancestry, 808 whites but not blacks
Blacks)
Snapir et al 2003194 Alpha2B-AR 48% Finnish, population based 278/405 The deletion/deletion genotype of the
2B-adrenoceptor gene increased the risk for
SCD in middle-aged men
Thrombotic and atherogenic
factors
Hernesniemi et al 2008195 IL-18 26% Finnish, population based 275/388 The IL-18 polymorphism is associated with
SCD
Mikkelsson et al 2002196 GPIa 3540% Finnish, population based 275/369 Polymorphisms on the glycoprotein Ia
receptor are not associated with SCD
Reiner et al 2002197 Factor V Leiden 69% American cohort (93% 145/592 Mutations in these genes are not associated
and PT 20210A European ancestry) with SCD
Mikkelsson et al 2001198 GPIb 23% Finnish 255/367 The variant was associated with coronary
thrombosis, fatal MI, and SCD in middle-aged
men
Mikkelsson et al 2000199 GPIIIa 3040% Finnish, population based 281/385 The PlA1/A2 polymorphism of GPIIIa is a risk
factor for coronary thrombosis and SCD in
middle age
Angiotensin-converting
enzyme pathway
Sotoodehnia et al 2009200 REN 15% Americans of European 211/730 Variations in AGTR1 and AGTR2 are
AGTR1 ancestry, population based associated with SCA risk in a
population-based case-control study
AGTR2
ACE2
BDRK2
AGT
ACE
KNG1
SCD indicates sudden cardiac death; SCA, sudden cardiac arrest; 1AR, 1-adrenergic receptor; 2AR, 2-adrenergic receptor; MI, myocardial infarction; CAD,
coronary artery disease; and IL-18, interleukin 18.

Figure 7. Overview of genetic studies. Genome-wide associa-
tion studies aim to identify common allelic variants that have a
low relative risk of disease. Evolution will select for variants that
carry a high relative risk of disease; as a result, they will be rare.
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in SCN5A may contribute to SCD risk among women in whom
the prevalence of structural heart disease is lower.29,39
GWAS of SCD
In addition to these candidate gene studies for SCD, GWAS
have been performed directly on SCD cases to identify novel
genetic variants associated with SCD risk. This unbiased ap-
proach has the potential to discover previously unsuspected
genetic variants and novel biological pathways involved in the
genesis of lethal ventricular arrhythmias. The number of vali-
dated loci achieving genome-wide significance for SCD, how-
ever, is much smaller than for other complex diseases. This
finding is likely due, in large part, to the smaller numbers of
SCD cases available for genetic analyses and greater heteroge-
neity with respect to underlying pathology and case definitions
in comparison with other complex phenotypes.
One recent study sought to minimize heterogeneity by focus-
ing on a highly specific arrhythmic phenotype. In the AGNES
case-control study,203 a GWAS was performed among 505 cases
of VF and 457 controls, all presenting with a first ST-elevation
MI. SNPs on chromosome 21q21 were associated with VF at a
level of genome-wide significance. The strongest signal, which
was found at rs2824292, remained significantly associated with
VF (OR1.51; 95% CI, 0.30 0.76; P0.005) after adjustment
for baseline characteristics and was replicated in another 156
cases of VF arrest in the setting of an acute MI from the
ARREST study. The genetic locus is situated near the CXADR
gene, which encodes the coxsackievirus and adenovirus receptor
(CAR) protein.204,205 These proteins have a recognized role in
the pathogenesis of viral myocarditis206 and may also be in-
volved in connexin localization at intercalated discs of AV nodal
myocytes.207
Another recently published GWAS used a broader spectrum
of SCD cases from case-control and cohort studies.179 A
genome-wide approach was implemented to identify variations
among 1283 SCD cases from 5 separate studies and 20 000
controls, all of European ancestry. The most significant SNPs in
this discovery phase were then genotyped in an additional 1730
SCD and VF cases and 10 530 controls of European ancestry.
The combined meta-analyses of all discovery and replication
Deo and Albert Sudden Cardiac Death 631
populations resulted in the discovery of a novel marker at the
BAZ2B locus (bromodomain adjacent zinc finger domain 2B)
which reached genome-wide significance with a relatively
strong effect size (OR1.92; 95% CI1.572.34). The putative
risk allele was rare (minor allele frequency 1.4%) and in strong
linkage disequilibrium with genes critical in cardiogenesis and
formation of the autonomic nervous system. This finding of a
rare variant, which is unusual for GWAS, highlights the poten-
tial role that rare variants may play in SCD risk.
It should be noted that an unbiased evaluation of variants
associated with SCD in these 2 genome-wide studies did not
identify the same variants. This lack of replication, which is
commonly seen in genetic studies related to SCD, probably
relates to heterogeneity in the case definition. Although the case
definition used in the AGNES study is highly specific, it is also
quite selective and would not apply to the majority of SCDs in
the community.40 42 In contrast, the majority of cases in the
population-based samples were out-of-hospital SCD events de-
fined broadly. However, the heterogeneity both within and
between studies probably limited the power to detect associa-
tions, even with a larger number of cases. Phenotypic homoge-
neity, therefore, is critical across studies, especially when pool-
ing results in a genome-wide analysis to detect variants with
small effects. Larger sample sizes and a greater effort toward
establishing homogenous subphenotypes will be needed to
identify and replicate additional genetic variants associated with
SCD.
Future Directions
Although much is known regarding risk factors for SCD, there is
still a paucity of data for important subgroups within the
population, and established racial and sex differences are poorly
understood. In addition, our ability to accurately identify indi-
viduals most at risk for SCD within the population remains poor.
Unlike global CHD risk prediction, where there are widely
accepted predictive models, there are no similar models for SCD
risk prediction among the general population, despite multiple
studies reporting on individual risk factors. Risk stratification
algorithms based on findings from epidemiological studies that
evaluate traditional cardiovascular risk factors, lifestyle and
dietary habits, biological markers, and genetic variants in com-
bination may aid in the identification of susceptible subgroups
within the population. It will also be critical to determine
whether novel markers associate with SCD to a greater extent
than with other manifestations of heart disease. Such markers
will not only improve risk stratification, but will also provide
insights into arrhythmic mechanisms within the population that
could lead to novel preventive and therapeutic strategies.
The heritability of SCD remains poorly understood with the
current data. Although candidate gene and genome-wide analy-
ses have enlightened our appreciation for the intricacies of
cardiac electrophysiology, arrhythmias, and SCD, many ques-
tions remain. Very few of the SNPs identified or assessed in
these studies have been replicated, and many do not have clear
functional implications as of yet. Because of the rapid develop-
ment of next-generation sequencing technologies, large-scale
sequencing projects are becoming possible that will allow the
examination of rare genetic variation as a component of SCD
risk. It is also possible that structural variations, including
 632 Circulation January 31, 2012
copy-number variants, inversions, and translocations, may con-
tribute to SCD risk and will not be identified with standard
GWAS and sequencing techniques. To address this potential
complexity of the genetic architecture, large-scale collaborations
involving populations with synchronized definitions of SCD will
be necessary.
SCD is a complex disorder that has been a research and
clinical focus for several decades. As our understanding of
this condition continues to improve with epidemiological
studies, experimental investigations, and clinical trials, strat-
egies to reduce the incidence and lethality of SCD across the
population remain important priorities. Low-risk interven-
tions and therapies that are directed toward cardiovascular
disease in general and SCD specifically will likely help
reduce the burden of SCD in the population. In addition,
continued campaigns in SCD education and awareness
among the population remain important steps in reducing the
impact of this condition.
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Sources of Funding
Dr Deo is supported by National Institutes of Health grant
K23DK089118. This work was also funded by an Established
Investigator Award from the AHA to Dr. Albert and HL091069 from
the NHLBI to Dr. Albert.
Disclosures
Dr Albert is the Principal Investigator on research grants received
from National Heart, Lung, and Blood Institute, and St. Jude Medical
Inc, as well, to study genetic and biological markers as risk
predictors of sudden cardiac death. Dr Albert has previously received
funding from National Heart, Lung, and Blood Institute, and Boston
Scientific, as well, to study triggers and predictors of ventricular
arrhythmias in patients with implantable cardioverter-defibrillators,
and from Siemens Healthcare Diagnostics to study biomarkers and
prediction of sudden cardiac death.
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KEY WORDS: death, sudden epidemiology genetics
 Epidemiology and Genetics of Sudden Cardiac Death
Rajat Deo and Christine M. Albert

Circulation. 2012;125:620-637
doi: 10.1161/CIRCULATIONAHA.111.023838
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 Page 346

Mort subite

Epidmiologie et gntique de la mort subite

Rajat Deo, MD, MTR ; Christine M. Albert, MD, MPH

e terme de mort subite (MS) se rapporte gnralement
L un dcs de cause cardiovasculaire survenu de manire
totalement imprvisible chez une personne atteinte ou non
dune affection cardiaque prexistante. La spcificit de cette
dfinition varie selon que lvnement sest ou non produit en
prsence dun tmoin ; cela tant, la plupart des tudes ont
port sur des cas dans lesquels le collapsus avait t constat
par un tiers (la personne tant dcde dans lheure ayant
suivi une modification brutale de son tat clinique) ou sur
des dcs survenus brutalement au cours des prcdentes
24 heures.13 Par ailleurs, on parle darrt cardiaque subit
dans le cas dune MS rcupre grce une procdure de
ranimation documente ou dune MS qui a spontanment
avort, lintress ayant survcu larrt cardiaque.
Lincidence annuelle des MS aux Etats-Unis est comprise
entre 180 000 et 450 000 cas.4 Les variations dans les
estimations tiennent aux diffrences en matire de dfinitions
de la MS et de mthodes de suivi employes pour documenter
les cas.4,5 Dans les tudes prospectives rcemment menes
partir des informations recueillies aux Etats-Unis,6,7 aux
Pays-Bas,8 en Irlande9 et en Chine,10 les taux de MS varient de
50 100 cas pour 100 000 individus.3 Bien quil apparaisse
ncessaire de multiplier les observatoires afin de pouvoir
tablir des estimations plus prcises de lincidence des MS,
il est nanmoins indubitable que le poids global de ces
vnements au sein de la population demeure lev. Alors que
les progrs accomplis dans le domaine de la prvention
primaire et secondaire ont notablement rduit la mortalit
globale imputable aux affections coronaires au cours des
trente annes coules,11,12 limpact sur lincidence des MS a
t plus limit.1316 Ces vnements reprsentent aujourdhui
encore plus de 50 % des dcs de causes coronaires et entre
15 et 20 % de la mortalit globale.17,18 Dans certaines strates de
la population, loin de diminuer,19 les taux semblent en fait
augmenter.14,19 Cest pourquoi il apparat essentiel de prvenir
les MS si lon veut que la mortalit de cause coronaire
continue diminuer.
En dpit des progrs majeurs raliss en matire de
ranimation cardiorespiratoire20 et de soins ultrieurs, les taux
de survie aprs hospitalisation pour arrt cardiaque dans
les grandes mtropoles demeurent mdiocres.21 Selon une
estimation rcente, ils ne dpasseraient pas 7,9 % pour les
arrts cardiaques survenus en milieu extrahospitalier et pris
en charge par le personnel urgentiste.6 De plus, les MS se
produisent majoritairement au domicile, en labsence de tout
tmoin.8,22 De ce fait, la mise disposition de dfibrillateurs
externes automatiques, qui a permis damliorer le taux
de rcupration des arrts cardiaques survenus sur la voie
publique,21 na quun impact limit en termes de diminution
de la mortalit globale par MS. Cest pourquoi, si lon veut
significativement diminuer lincidence de ces accidents, il y a
lieu de se doter de moyens de prvention primaire efficaces.
Etant donn que la majorit des MS survient dans la
population gnrale, la connaissance approfondie de
lpidmiologie de ces vnements peut permettre didentifier
certains types dinterventions faible risque susceptibles
dtre mises en uvre large chelle. De plus, les donnes
rcemment acquises sur la gntique de la MS pourraient,
terme, faciliter lidentification des sous-groupes haut
risque au sein de la population gnrale ou rvler de
nouvelles cibles molculaires accessibles une intervention.
Caractristiques dmographiques :
ge, sexe et origine ethnique
Lincidence de la MS augmente fortement au cours de
lavance en ge indpendamment du sexe ou de lorigine
ethnique (Figure 1). Ainsi, lincidence annuelle chez
lhomme est denviron 100 cas pour 100 000 50 ans, mais
atteint 800 cas pour 100 000 75 ans.23 Bien que le risque
de MS augmente avec lge, le taux de dcs de survenue
brutale est plus lev dans les tranches dge infrieures,2,24,25
o la MS a un impact socio-conomique plus important.
Quel que soit lge,26 lincidence de la MS est plus faible chez
les femmes que chez les hommes, cela mme aprs ajustement
en fonction des facteurs de risque coronaire.27 Il semblerait
toutefois que lcart tende se resserrer avec le temps.7,16
Les taux de MS ont, en effet, moins diminu chez les femmes
que chez les hommes, en particulier dans les tranches
dge infrieures.14 Cela pourrait en partie tenir au fait
que les femmes victimes de MS sont globalement moins
sujettes que les hommes aux coronaropathies. Prs des
deux tiers des femmes qui dcdent de MS nont aucun
antcdent connu daffection cardiaque, contre seulement
50 % des hommes.8,24,28 De plus, que lon considre aussi
bien les personnes ayant survcu un arrt cardiaque29
que celles ayant prsent une MS,30 il semblerait que la
proportion dvnements survenus en labsence danomalie

Laboratoire dElectrophysiologie, Service de Mdecine Cardiovasculaire, Universit de Pennsylvanie, Philadelphie, Pennsylvanie, Etats-Unis (R.D.) ;
Service de Mdecine Prventive et Cardiovasculaire, Centre de Prvention des Troubles du Rythme Cardiaque, Brigham and Womens Hospital, Boston,
Massachusetts, Etats-Unis (C.M.A.).
Correspondance : Christine M. Albert, MD, MPH, Division of Preventive Medicine and Cardiovascular Medicine, Center for Arrhythmia Prevention,
Brigham and Womens Hospital, 900 Commonwealth Ave E, Boston, MA 022151204, Etats-Unis. E-mail : calbert@partners.org.
(Traduit de langlais : Epidemiology and Genetics of Sudden Cardiac Death. Circulation. 2012;125:620637.)
2012 American Heart Association, Inc.

Circulation est disponible sur le site http://circ.ahajournals.org

346

10:00:26:07:12 Page 346

 Page 347
Figure 1. Incidence de la mort subite selon lge, le sexe et
lorigine ethnique dans le programme de ranimation
cardiorespiratoire de Chicago. La population de ltude comptait
6 451 patients, dont 3 207 Blancs et 2 910 Noirs. Adapt dAlbert
et al23 avec lautorisation de lditeur. Copyright Massachusetts
Medical Society, 1993.
structurale cardiaque soit plus leve parmi les femmes
(Figure 2).
Il existe galement, dans lincidence de la MS, des diffrences
interethniques que lon sexplique mal. Les hommes et les
femmes noirs semblent tre victimes darrts cardiaques
extrahospitaliers un ge de plusieurs annes infrieur
celui des sujets blancs. Dans deux villes amricaines, les taux
darrts cardiaques se sont rvls plus levs chez les Noirs
(risque relatif compris entre 1,3 et 2,8) que chez les sujets
blancs (Figure 3).23,31 Les donnes fournies par les certificats
de dcs suggrent galement que la MS est plus rpandue
parmi les Noirs amricains que dans les autres groupes
ethniques, alors que les taux sont plus faibles chez les
Amricains dorigine hispanique que dans les autres
communauts.14,32 De plus, les taux de survie aprs arrt
cardiaque sont infrieurs chez les Africains.23,33 A Chicago, il a
t tabli que le taux global de survie aprs arrt cardiaque
extrahospitalier chez les sujets noirs atteignait seulement
31 % de celui observ chez les sujets blancs.23 Les sujets noirs
sont davantage exposs aux arrts cardiaques survenant
en labsence de tmoin et qui ont pour origine immdiate
documente un trouble du rythme tel quune activit
lectrique sans pouls.23,34 Cela tant, la diffrence de taux de
survie ne semble pas seulement due au type danomalie
rythmique sous-tendant larrt cardiaque. Mme si lon ne
retient que les vnements imputables une fibrillation
ventriculaire (FV) ou une tachycardie ventriculaire sans
pouls, les taux de survie intrahospitalire sont de 27 %
infrieurs chez les sujets noirs.35 Selon le registre national
amricain des ranimations cardiorespiratoires, cette
disparit semblerait tre lie en grande partie (mais pas
totalement) au fait que les patients noirs sont pris en charge
dans des hpitaux moins efficients en termes de rsultats.35
Comme dans toute tude ayant trait aux diffrences
interethniques, il est difficile de faire la part entre les
facteurs socio-conomiques et la prdisposition gntique
relle.
10:00:26:07:12 Page 347
Deo et Albert La mort subite 347
Figure 2. Pathologies cardiaques structurales chez les personnes
ayant survcu un arrt cardiaque. Ces diagrammes secteurs
dcrivent les pourcentages daffections cardiaques sous-jacentes
chez les sujets des deux sexes ayant survcu un arrt
cardiaque survenu en milieu extrahospitalier. Lge moyen tait de
58 12 ans pour les hommes et de 55 17 ans pour les femmes.
La maladie coronaire a t le diagnostic principal chez la majorit
des hommes. En revanche, les femmes ont t plus souvent
sujettes que les hommes des troubles cardiaques dorigine non
ischmique, notamment type de cardiomyopathie dilate (19 %)
ou de valvulopathie cardiaque (13 %).29 MC : maladie coronaire ;
CMD : cardiomyopathie dilate ; VC : valvulopathie cardiaque ;
C. cong. : cardiopathie congnitale ; spasme : spasme coronaire ;
VD : ventricule droit. Adapt dAlbert et al29 avec lautorisation de
lditeur. Copyright American Heart Association, Inc., 1996.
Figure 3. Comparaison des risques relatifs darrt cardiaque
encourus par les Noirs et par les Blancs en fonction de la tranche
dge. Les barres figurent les intervalles de confiance 95 %.
Adapt dAlbert et al23 avec lautorisation de lditeur.
Copyright Massachusetts Medical Society, 1993.
Mcanismes physiopathologiques
La physiopathologie de la MS est complexe et semble
ncessiter une interaction entre un vnement transitoire
et un substrat sous-jacent. Ce processus gnre une instabilit
lectrique et un trouble du rythme ventriculaire ltal, cela
tant suivi dune dfaillance hmodynamique. Bien quil soit
difficile de prvoir quel moment ce type dinteraction est
appel devenir dangereux, divers facteurs de risque peuvent
jouer un rle (Figure 4).
La maladie coronaire est le principal substrat pourvoyeur
de MS dans les pays occidentaux, en cause dans prs de
75 % des cas.8,18,36,37 Les cas restants sont pour lessentiel
imputables aux cardiomyopathies (dilate, hypertrophique et
 Page 348
348 Circulation Septembre 2012
Figure 4. Elments physiopathologiques majeurs responsables de linstabilit lectrique et de la survenue dune mort subite. HTA :
hypertension artrielle ; Eco : vnement coronaire ; ICC : insuffisance cardiaque congestive ; VG : ventriculaire gauche ; AGPI : acides gras
polyinsaturs ; AGNE : acides gras non estrifis ; MS : mort subite.
ventriculaire droite arythmogne) et aux troubles lectriques
primitifs en rapport avec lexistence de canalopathies.18
Dans prs de 5 % des MS et des arrts cardiaques, aucune
anomalie cardiaque notable nest dcele lors dune enqute
approfondie ou lautopsie.29,38,39 La maladie coronaire pr-
dispose la MS dans trois contextes gnraux : (1) linfarctus
aigu du myocarde, (2) lischmie sans infarctus et (3) les
anomalies structurales consistant, par exemple, en la
formation dune cicatrice ou en une dilatation ventriculaire
secondaire un infarctus ou une ischmie chronique. Parmi
les individus qui dcdent brutalement dun trouble coronaire,
19 27 %40,41 prsentent des lsions anatomopathologiques
en faveur dune ncrose myocardique et seulement 38 % des
personnes ayant survcu un arrt cardiaque sont sujettes
une lvation de leurs paramtres enzymatiques tmoignant
de la survenue dun infarctus du myocarde.42 Dans les tudes
post-mortem, des plaques stables et des remaniements
chroniques isols ont t mis en vidence chez environ 50 %
des patients coronariens victimes de MS,41,43,44 ce qui tend
indiquer que lvnement peut parfois tre secondaire la
rupture dune plaque dathrosclrose ou un infarctus du
myocarde (IDM) en phase aigu, mais que cela nest pas
lventualit la plus frquente.
Il est permis de penser que, lorsquelle ne survient pas dans
un contexte dIDM aigu, la MS est cause par une anomalie
lectrique engendre par un trouble du rythme ventriculaire,
lui-mme provoqu par une ischmie ou un autre stimulus
arythmogne sur fond de cardiopathie chronique.45 Cette
hypothse est difficilement vrifiable sachant que la plupart
des dcs se produisent en labsence de toute surveillance
mdicalise et que les individus qui font lobjet dun tel
10:00:26:07:12 Page 348
monitorage forment une population hautement slectionne.
La fibrillation ventriculaire volue en asystolie en lespace de
quelques minutes, de sorte que, chez la majorit des patients
victimes dune MS, lexamen immdiat effectu par le
personnel urgentiste met en vidence une asystolie ou une
activit lectrique sans pouls.34 Lorsque la dtermination
initiale du rythme peut tre ralise dans un dlai relativement
court aprs la survenue du collapsus, le taux de tachy-
arythmies ventriculaires documentes augmente jusqu 75
80 % (Figure 5).42,4649 Des tudes pidmiologiques menes
dans les annes 1970 1990 sur des cohortes dhommes50 et de
femmes24 suggrent que 88 91 % des dcs qui se produisent
dans lheure qui suit lapparition de symptmes seraient dus
un trouble du rythme cardiaque. Cela tant, la proportion des
MS imputables une FV semble diminuer au fil du temps.
Selon de rcentes donnes manant de services durgences
mdicales,19 la FV constituerait moins souvent le trouble du
rythme inaugural, sa diminution dincidence ne semblant pas
tre totalement imputable lvolution des protocoles de
ranimation ou des caractristiques des patients.51
Facteurs de risque
Cardiopathies structurales
La maladie coronaire et linsuffisance cardiaque congestive
augmentent notablement le risque de MS encouru par les
individus.52 Dans ltude de Framingham, lexistence dune
coronaropathie a t associe un risque de MS 2,8 5,3 fois
suprieur et celle dune insuffisance cardiaque congestive a un
risque 2,6 6,2 fois plus lev.27 Aprs un IDM, le risque de
MS est quadrupl chez la femme et dcupl chez lhomme.24,28
 Page 349
Figure 5. Premier vnement arythmique document lors
dune mort subite lie un trouble du rythme cardiaque.46
TV : tachycardie ventriculaire ; FV : fibrillation ventriculaire.
Adapt de Bayes de Luna et al46 avec lautorisation de lditeur.
Copyright Elsevier, 1989.
Le risque absolu est maximal au cours des 30 premiers jours
qui suivent lIDM et diminue ensuite progressivement au fil du
temps.53,54 Lincidence de la MS post-IDM connat toutefois
une diminution parallle celle de la mortalit de cause
coronaire,54 des taux nexcdant pas 1 % par an tant
dsormais rapports chez les patients ayant bnfici
dun traitement mdical optimal et dune intervention de
revascularisation.55,56 Malgr tout, les taux de MS post-IDM
demeurent encore levs dans certains sous-groupes de
patients.53 La dysfonction ventriculaire gauche et la classe
de la New York Heart Association sont de puissants facteurs
de risque de MS chez les patients atteints dune cardio-
myopathie, que celle-ci soit ou non de type ischmique,57 la
pose dun dfibrillateur automatique implantable ayant pour
effet dallonger lesprance de vie de ces patients haut
risque.58,59 Les autres marqueurs datteinte structurale du
muscle cardiaque qui contribuent augmenter le risque
de MS sont lhypertrophie ventriculaire gauche,60,61 lallonge-
ment de lespace QTc62 et la rponse anormale de la frquence
cardiaque leffort.63 Pour lheure, aucun de ces marqueurs
na encore t incorpor aux algorithmes de stratification
des risques.
Bien que la prsence dune cardiopathie structurale
manifeste augmente fortement le risque de MS, chez la
plupart des patients qui sont victimes dun arrt cardiaque,
celui-ci ne se produit pas dans un contexte de diminution
documente de la fraction djection ventriculaire gauche en
de de 35 %.2,18,30,64 Cette observation rend compte de la
difficult quil y a concevoir des stratgies de prvention de
la MS, car les individus qui, selon les critres actuels,
encourent le risque le plus lev ne reprsentent quune
faible fraction des MS qui surviennent dans la population.
Les rsultats dune rcente tude mene chez des femmes
mnopauses atteintes de maladie coronaire patente mais
dont la fonction systolique tait relativement prserve
suggrent quune combinaison de facteurs de risque cliniques
et pidmiologiques faciles rechercher pourrait permettre
10:00:26:07:12 Page 349
Deo et Albert La mort subite 349
une reclassification des risques de MS en catgories clinique-
ment plus pertinentes que celles fondes sur la seule fraction
djection ventriculaire gauche.65 Pour autant, comme cela est
le cas pour la fraction djection ventriculaire gauche et pour
la plupart des autres facteurs prdictifs cliniques, les patients
identifis par cette approche comme tant haut risque
se sont rvls encourir un risque tout aussi lev de dcs
dorigine cardiovasculaire revtant une forme autre que la
MS.53,66 Cet important risque de dcs li des causes
concurrentes limite lefficacit des traitements qui, telle la
pose dun dfibrillateur automatique implantable, visent
exclusivement prvenir la MS. De plus, celle-ci constitue
souvent la premire manifestation dune maladie cardio-
vasculaire, de sorte que la stratification des niveaux de risque
chez les seuls patients haut risque conduit ignorer la
majorit des MS qui se produisent au sein de la population.
Cest pourquoi il est galement ncessaire dacqurir une
meilleure connaissance des facteurs de risque de MS prsents
dans la population gnrale.
Facteurs de risque coronaire
Etant donn que prs de 80 % des hommes victimes de MS
prsentent une maladie coronaire sous-jacente, il ressort que
les classiques facteurs de risque coronaire sont prdictifs
de MS dans la population gnrale. Les facteurs de risque
coronaire sur lesquels il est possible dagir et dont la valeur
prdictive en termes de survenue dune MS a t tablie dans
diverses cohortes comprennent lhypertension artrielle,
lhypercholestrolmie, le diabte,6769 linsuffisance rnale,70,71
lobsit et le tabagisme.24,27,72,73 Bien que la prvalence de la
maladie coronaire semble plus faible chez les femmes qui sont
victimes de MS que chez les hommes,29,30 les facteurs de risque
coronaire conventionnels demeurent nanmoins prdictifs
de MS parmi la population fminine.24,28,65 Le tabagisme
est notamment un important facteur de risque de MS, car
laugmentation du risque quil induit dans la population
gnrale est du mme ordre que celle imputable lIDM.24,43,44
La poursuite du tabagisme augmente le risque de nouvel
arrt cardiaque,74 alors que larrt du tabac est rapidement
suivi dune diminution du risque de MS chez les sujets
coronariens.26,75,76 Le diabte et lhypertension artrielle sont
galement de puissants facteurs de risque de MS,6769 de
rcentes donnes ayant, de plus, montr que le diabte
pourrait tre un intressant lment prendre en compte
dans la stratification des risques de MS, y compris dans
les populations haut risque.77 Il semblerait que la
cholestrolmie soit surtout corrle avec le risque de MS
chez le sujet jeune.24,28
Tous les facteurs de risque qui viennent dtre mentionns
favorisent la survenue dvnements coronaires considrs
dans leur globalit et ne sont pas spcifiquement prdictifs de
MS ; de plus, hormis le diabte,65,77 latteinte rnale65,70,71 et
le tabagisme,75 ils ne semblent pas prdire le risque de MS
lorsquil existe une maladie coronaire avre.52 Cela tant,
la modification des facteurs de risque coronaire connus a un
impact sur lincidence de la MS lchelon de la population.
La diminution dincidence des diverses manifestations de la
maladie coronaire, dont la MS, qui est observe depuis le
 Page 350
350 Circulation Septembre 2012
milieu des annes 1960 constitue une preuve indirecte du
succs des mesures visant agir sur les facteurs de risque
coronaire.
Paramtres lectrocardiographiques dvaluation
du risque
Des travaux ont t mens pour dterminer si les caractris-
tiques de llectrocardiogramme standard douze drivations,
telles que la frquence cardiaque, la dure des complexes
QRS, lespace QT et la repolarisation prcoce, pouvaient tre
retenues en qualit de facteurs de risque de MS. Des tudes de
populations ont ainsi montr quune frquence cardiaque de
repos leve78 et un espace QT de dure allonge augmentent
tous deux le risque de MS dans la population gnrale.62,79
Lallongement de la dure des complexes QRS est, lui aussi,
associ au risque de MS.80,81 Lattention sest depuis peu
porte sur la repolarisation prcoce (RP) en tant quautre
facteur de risque de MS et de dcs de cause cardiovasculaire.
La RP est dfinie par lascension de la zone de jonction entre
la fin du complexe QRS et le dbut du segment ST (point J),
la prsence dune telle anomalie dans les drivations lectro-
cardiographiques infrieures ou latrales de lECG ayant t
rattache la survenue darrts cardiaques subits et de FV
idiopathiques dans des tudes cas-tmoins.8284 Dans une
tude de population finlandaise, lexistence dune RP donnant
lieu un sus-dcalage de plus de 0,2 mV dans les drivations
infrieures sest montre corrle avec une forte augmentation
du risque de dcs li une cause cardiaque ou un trouble du
rythme.85 Dans une analyse de suivi de cette mme cohorte, la
RP nest apparue associe au dcs par survenue dun trouble
du rythme que dans les cas o le segment ST tait horizontal
ou descendant.84 Les individus qui prsentaient une RP mais
chez lesquels le segment ST dessinait une pente rapidement
ascendante nencouraient pas de risque important.
Facteurs de risque dorigine alimentaire
Des tudes observationnelles ont permis de rattacher
spcifiquement la consommation et le taux sanguin de
certains nutriments au risque de MS (Tableau 1).70,86101
Plusieurs tudes pidmiologiques tendent indiquer que la
consommation plus importante dacides gras polyinsaturs
n-3 diminuerait le risque de MS de faon inversement
proportionnelle et ce, plus fortement encore que le risque
dIDM non fatal.102106 Dans quatre tudes observationnelles,
la consommation de poisson environ une ou deux fois par
semaine a eu pour effet dabaisser le risque de MS de 42
50 %.102105 Lingestion dacide -linolnique, un acide gras
polyinsatur n-3 chane intermdiaire prsent dans les
aliments dorigine vgtale, a galement contribu diminuer parat plus puissant pour les vnements fatals que pour
le risque de MS dans une tude observationnelle mene chez
la femme.106 Ces observations recueillies au sein de cohortes
dindividus en relativement bonne sant corroborent les
donnes exprimentales ayant objectiv un effet protecteur de
ces nutriments lgard de la sensibilit aux troubles du
rythme.107 Nanmoins, les essais cliniques randomiss nont
pas tous valid cette hypothse. Lessai de prvention du
GISSI (Gruppo Italiano per lo Studio della Sopravvivenza
nellInfarto miocardico [groupe italien dtude de la survie
aprs infarctus du myocarde]), qui visait valuer sur un
10:00:26:07:12 Page 350
mode ouvert les effets de la supplmentation en acides gras
polyinsaturs n-3 (prise journalire de 850 mg dacide
deicosapentanoque et dacide docosahexanoque) chez
11 324 patients ayant des antcdents dIDM rcent, a montr
que ce traitement avait induit une diminution significative de
45 % de lincidence des MS, mais navait, en revanche, eu
aucun impact bnfique sur les taux dIDM et daccidents
vasculaires crbraux non fatals.108 Toutefois, deux essais
randomiss en double aveugle mens plus rcemment sur les
acides gras polyinsaturs n-3 dans des cohortes de patients en
post-infarctus nont pas permis de confirmer cette influence
favorable sur le risque de MS.109,110 Dans les deux populations
tudies, lincidence de la MS a t nettement infrieure
ce qui tait attendu, ce qui porte penser que ces essais
manquaient probablement de puissance. Cela signifie quil
sera encore plus difficile dvaluer la capacit dinterventions
dittiques rduire les taux de MS dans les populations chez
lesquelles le risque est plus faible.
Lingestion dalcool et celle de magnsium pourraient
galement exercer un effet slectif sur le risque de MS. Une
forte consommation dalcool (au-del de 5 verres par jour)
augmente le risque de MS,73 mais pas celui dIDM non
fatal.111 Il semblerait, en revanche, que lingestion dalcool en
quantits faibles modres (cest--dire nexcdant pas un
demi-verre un verre par jour) ait pour effet de diminuer le
risque de MS.112114 La prise de magnsium pourrait galement
influer sur la propension la MS. Dans la Nurses Health
Study (tude amricaine sur ltat de sant des infirmires), le
risque relatif de MS sest rvl significativement abaiss chez
les femmes dont la ration alimentaire en magnsium se situait
dans le quartile le plus lev. En outre, chaque augmentation
de 0,25 mg/dl (1 ET) de la magnsmie a correspondu une
diminution de 41 % du risque de MS.87 La mme relation
inverse entre magnsmie et MS a t rapporte dans
ltude Atherosclerosis Risk in Communities (risque dathro-
sclrose dans les communauts ethniques) ; cela tant, aucune
corrlation na t mise en vidence entre la mesure isole de
la ration alimentaire en magnsium et le risque de MS.88
Pour terminer, des observations tendent indiquer que
certains schmas alimentaires qui associent des nutriments
ayant des effets additifs et/ou synergiques115 contribuent
rduire le risque de MS. Aussi bien des essais cliniques116 que
des tudes observationnelles117 ont dmontr la diminution du
risque cardiovasculaire associe ladoption dun rgime de
type mditerranen, consistant en une consommation plus
importante de fruits et lgumes, de fruits cale, de crales
compltes et de poisson, une ingestion modre dalcool et
une faible consommation de viande rouge ou cuisine. Le lien
ceux nentranant pas la mort et pourrait en partie tenir la
protection exerce lgard des troubles du rythme
ventriculaire et de la MS.118 Les rcentes donnes de la Nurses
Health Study suggrent que les femmes ayant des habitudes
alimentaires proches de ce rgime dit mditerranen
encourent un risque de MS significativement abaiss.119
Marqueurs biologiques
Au-del des biomarqueurs nutritionnels dcrits ci-dessus, de
nombreux travaux pidmiologiques ont valu le rle jou
 Tableau 1. Liens relevs entre les marqueurs biologiques et la mort subite dans les tudes prospectives

10:00:26:07:12
Biomarqueur Mcanisme Etude Rsultats

Marqueurs dorigine alimentaire

Acides gras n-3 Stabilisation des canaux Physicians Health Study86 Une corrlation inverse a t objective entre le taux dacides gras n-3 longue chane mesur lentre dans ltude
longue chane ioniques, inflammation (n = 278) et le risque de MS
Magnsium Repolarisation, stabilisation Nurses Health Study87 Llvation de la magnsmie et laugmentation de la ration alimentaire en magnsium ont toutes deux contribu
membranaire (n = 88 735) rduire le risque de MS
Etude ARIC88 (n = 14 232) Le risque de MS est apparu significativement plus faible chez les participants dont la magnsmie se situait dans le
quartile le plus lev que chez ceux qui prsentaient des valeurs sinscrivant dans le quartile le plus bas
Acides gras non Stabilisation membranaire Paris Prospective Study89 Les taux plasmatiques dAGNE mesurs jeun lentre dans ltude se sont montrs corrls de faon indpendante
estrifis (n = 5 250 hommes) avec le risque de MS aprs une priode de suivi de 22 ans
Acides gras Inflammation, dysfonction Cardiovascular Health Study90 Llvation du taux plasmatique de phospholipides du type des acides gras trans-18:2 a eu pour effet daugmenter le
trans endothliale (n = 428) risque de MS. En revanche, llvation du taux dacides gras trans-18:1 a exerc leffet inverse
Marqueurs inflammatoires
CRP, IL-6, Inflammation, stress oxydatif, Etude PRIME91 Le taux dIL-6 mesur lentre dans ltude est apparu comme un facteur indpendant de risque de MS au terme dun
fibrinogne insulinorsistance (n = 9 771 hommes) suivi de 10 ans, ce qui na pas t le cas des taux de CRP et de fibrinogne
CRP Inflammation, stress oxydatif Nurses Health Study92 Il na pas t objectiv de corrlation entre le taux de CRP mesur lentre dans ltude et laugmentation du risque
(n = 121 700 femmes) de MS sur une priode de suivi de 16 ans
Page 351

CRP Inflammation, stress oxydatif, Physicians Health Study93 Une corrlation a t mise en vidence entre le taux de CRP mesur lentre dans ltude et laugmentation du risque

Page 351
apoptose (n = 22 071 hommes) de MS sur une priode de suivi de 17 ans
ST2 Rcepteur linterleukine-1, Registre MUSIC,94 patients insuffisants cardiaques Sur une priode de suivi de 3 ans, lexistence dun taux lev de ST2 soluble lentre dans ltude sest rvle tre
fibrose myocardique non hospitaliss (n = 99) un facteur indpendant favorisant la MS
Marqueurs mtaboliques
Aldostrone Tension myocardique, fibrose, Population de patients atteints dIDM-ST+95 Chez les patients hospitaliss en vue de faire lobjet dune ICP premire pour un IDM-ST+, lexistence dun taux
remodelage lectrique (n = 356) daldostrone augment ladmission a t corrle avec la survenue dun dcs ou dun arrt cardiaque rcupr sur
une priode de suivi de 6 mois
Cystatine C Marqueur du dbit de Cardiovascular Health Study,70 exclusion des individus Au cours dune priode mdiane de suivi de 11,2 ans, lexistence dun taux lev de cystatine C lentre dans ltude
filtration glomrulaire prsentant dj une affection cardiaque (n = 4 482) est apparue comme un facteur indpendant favorisant la MS chez le sujet g indemne de toute affection
cardiovasculaire
Rnine Fibrose et remodelage Etude LURIC,96 patients adresss en vue dune La rninmie mesure lentre dans ltude sest montre corrle avec la mortalit cardiovasculaire long terme,
lectrique coronarographie (n = 3 303) cela englobant notamment la MS et le dcs li une insuffisance cardiaque
Vitamine D et Fibrose, remodelage lectrique, Cardiovascular Health Study,97 exclusion des individus Lassociation dun faible taux de vitamine D et dun taux augment de PTH a constitu un facteur indpendant de risque
parathormone effets mtaboliques prsentant dj une affection cardiaque (n = 2 312) de MS chez le sujet dge avanc indemne de toute affection cardiovasculaire
Vitamine D Fibrose et remodelage German Diabetes and Dialysis Au cours dune priode mdiane de suivi de 4 ans de cette cohorte de patients dialyss et atteints de diabte,
lectrique Study98 (n = 1 108) lexistence dune carence svre en vitamine D sest montre corrle avec le risque de MS
Deo et Albert

Marqueurs neuro-hormonaux
BNP Augmentation de la tension Nurses Health Study92 Les concentrations leves de NT-pro-BNP linclusion ont t indpendamment lies aux vnements de MS aprs
NT-Pro-BNP myocardique (n = 121 700 femmes) un suivi de 16 ans
Cardiovascular Health Study99 (n = 5 447) Lexistence dun taux lev de NT-pro-BNP lentre dans ltude est apparue comme un facteur indpendant de
risque de MS au terme dune priode mdiane de suivi de 12,5 ans
Cohorte de la Vienna Heart Failure (FEVG <35 %)100 Aprs 3 ans de suivi, lexistence dun taux augment de BNP lentre dans ltude sest rvle tre un facteur
(n = 452) indpendant de risque de MS chez les patients coronariens
Multiple Risk Factor Analysis Trial (MRFAT, Au cours dune priode de suivi de 3,5 ans, lexistence dun taux augment de BNP lentre dans ltude sest
patients en post-IDM)101 (n = 521) montre corrle avec la survenue dun MS aprs ajustement en fonction des facteurs de risque cliniques et de la FEVG
La mort subite

AGNE : acides gras non estrifis ; ARIC : Atherosclerosis Risk in Communities ; BNP : peptide natriurtique de type B ; CRP : C-ractive protine ; FEVG : fraction djection ventriculaire gauche ; IDM : infarctus du
myocarde ; IDM-ST+ : infarctus du myocarde avec sus-dcalage du segment ST ; IL-6 : interleukine-6 ; LURIC : Ludwigshafen Risk and Cardiovascular Health ; MS : mort subite ; MUSIC : MUerte Sbita en Insuficiencia
351

Cardaca ; NT Pro-BNP : fragment N-terminal du propeptide natriurtique de type B ; ICP : intervention coronaire percutane ; PRIME : tude prospective de lInfarctus du Myocarde ; PTH : parathormone.
 Page 352

352 Circulation Septembre 2012

par les perturbations des voies inflammatoires, mtaboliques hmisphres.127,128 Le risque de MS pourrait tre influenc par
et neuro-hormonales en tant que facteurs prdisposant la certains rythmes endognes et par des facteurs environ-
MS (Tableau 1). Dans plusieurs tudes pidmiologiques, les nementaux tels que la temprature, lexposition au rayonne-
taux de marqueurs biologiques ont t mesurs alors que les ment solaire128,129 et autres conditions climatiques.
participants taient en majorit indemnes de toute pathologie
cardiovasculaire cliniquement significative. Lexistence de
Lactivit physique
concentrations anormales pouvait, ds lors, constituer la
Lexercice physique a sur le risque de MS des effets la fois
traduction daltrations infracliniques de processus cardio-
bnfiques et nfastes. La plupart des tudes,65,73,130133
vasculaires ayant pour effet de prdisposer lindividu concern
mais pas toutes,134,135 ont objectiv une relation inverse entre
la MS. Les premiers stades du stress hmodynamique, de
laugmentation de lactivit physique rgulire et le risque
linstabilit des plaques dathrosclrose et du remodelage
de MS ou darrt cardiaque subit. Les donnes les plus
cardiaque ne sont dcelables que par la mesure des bio-
concordantes concernent lentranement physique de degr
marqueurs qui sont le reflet des processus inflammatoires,
modr,65,73,131133 que la majorit des travaux crditent dun
des voies mtaboliques et de la rgulation neuro-hormonale.
impact bnfique. Sil est dmontr que lexercice physique
Certaines donnes exprimentales suggrent que ces
exerce un effet favorable long terme, il est tout aussi
marqueurs moduleraient les mcanismes physiopathologiques
clairement tabli que la MS connat une frquence de
qui sous-tendent la maladie coronaire, linsuffisance
survenue suprieure la moyenne pendant ou peu de temps
cardiaque et les troubles du rythme cardiaque. Toutefois, bien
aprs les efforts intenses.136 Des tudes cas-tmoins et de cas
que nombre des tudes pidmiologiques prospectives partir
croiss menes chez des hommes ont montr quun effort
desquelles ont t formules ces conclusions aient port sur de
physique nergique peut provoquer un arrt cardiaque130 ou
vastes cohortes, elles nont permis denregistrer quun nombre
une MS.135 Lorsque de tels efforts intenses sont pratiqus
limit de MS. Les futures tudes devront tre menes sur des
sur une base rgulire, cela attnue la majoration du risque ;
chantillons runissant un nombre plus lev de cas de MS
celui-ci demeure nanmoins significativement augment,
avec recueil de prlvements sanguins sur un mode prospectif
mme chez les hommes les plus rompus aux efforts
pour pouvoir valider ces observations et tenter dtablir si
physiques.137 Le risque engendr par leffort semble tre plus
les marqueurs biologiques prsentent ou non un intrt
faible chez les femmes,133 celles-ci tant beaucoup moins
diagnostique120 pour le dpistage des individus haut risque
souvent victimes de MS loccasion dactivits physiques
au sein de la population gnrale.
(Figure 6).137 Leffet exerc par les efforts sur la vulnrabilit
des plaques dathrosclrose138 et sur le systme nerveux
sympathique pourrait expliquer tout la fois laugmentation
Facteurs dclenchants transitoire du risque de MS engendre par les efforts aigus et
Le risque de MS auquel la population est soumise dpend
lattnuation de ce sur-risque associe la pratique rgulire
non seulement du substrat sous-jacent et de sa vulnrabilit
dexercices physiques vigoureux.139,140 Les efforts de courte
aux arythmies, mais aussi de la frquence dexposition
dure diminuent lactivit vagale, ce qui provoque une
aux lments favorisants de survenue aigu ou facteurs
augmentation aigu de la sensibilit la fibrillation
dclenchants (Figure 4). Ces facteurs tendent augmenter
ventriculaire,139 alors quun entranement physique rgulier
lactivit sympathique, ce qui est susceptible de provoquer
augmente le tonus vagal de base, ce qui renforce la stabilit
un trouble du rythme cardiaque et une MS.
lectrique du cur.
En dpit de ces risques relatifs transitoires levs, le risque
absolu de MS au cours dune activit physique quelle quelle
Variations diurnes et saisonnires
soit est extrmement faible dans la plupart des sries,141 ce
Plusieurs tudes ont montr que les MS et les arrts
qui porte penser que la survenue dune MS imputable
cardiaques qui surviennent en milieu extrahospitalier
lexercice physique constitue une ventualit relativement
obissent un rythme circadien.121 Lincidence maximale est
rare. Dans une rcente enqute nationale mene en France,
observe entre 6 h du matin et midi,122 les arrts cardiaques
lincidence annuelle des MS lies lactivit physique au sein
secondaires une FV connaissant un second pic, moins
de la population a nanmoins t estime 17 cas par million
marqu, en fin daprs-midi.123,124 Ce pic matinal de survenue
dhabitants.137 Dans ltude en question, le nombre absolu
de la MS est aboli par les btabloquants,125 ce qui conforte le
de MS imputables lactivit physique enregistr dans
rle imput lhyperactivation matinale du systme nerveux
la population gnrale (n = 770) sest rvl trs suprieur
sympathique. Les variations dincidence de la MS au cours de
celui rapport parmi les jeunes athltes de comptition
la semaine et selon les saisons ont galement t tudies.
(n = 50) et sur lequel le public focalise lessentiel de son
Le risque darrt cardiaque126 et de MS127 en milieu extra-
attention.
hospitalier semble tre maximal le lundi et prsenter un nadir
pendant le week-end.126 Ces schmas de survenue portent
supposer que lactivit et les influences psychologiques Les facteurs psychosociaux
pourraient jouer un rle dans linduction dune MS. Il Le statut socio-conomique mdiocre, la dpression, lanxit,
a galement t fait tat de variations saisonnires dans lisolement social et la tension psychologique sont autant de
lincidence des MS, celle-ci tant plus faible en t et en facteurs dont il a t tabli, dans diverses populations, quils
augmentation pendant les mois dhiver dans les deux augmentent la mortalit cardiovasculaire.142,143 Bien que

10:00:26:07:12 Page 352

 Page 353
Figure 6. Sports pratiqus lors des MS survenues leffort chez 820 sportifs franais. N dsigne le nombre absolu de MS survenues
pendant la pratique du sport considr. Le pourcentage est celui des dcs imputables la pratique de ce sport. Les parties plus claires
reprsentent les nombres de femmes.137 MS : mort subite. Adapt de Marijon et al137 avec lautorisation de lditeur. Copyright American
Heart Association, Inc., 2011.
certains aient suppos que les corrlations observes
pouvaient tre en partie sous-tendues par des mcanismes
arythmiques, quelques tudes ont examin par une approche
prospective les liens unissant ces facteurs la MS. Lincidence
de la MS est plus leve dans les zones gographiques o le
niveau socio-conomique est faible, le gradient de risque tant
encore plus marqu chez les individus gs de moins de
65 ans.144 Des tudes de populations ont, par ailleurs, montr
que les facteurs de tension psychologique chronique tels que
les troubles anxieux ou la dpression favorisent galement la
MS. Dans trois cohortes distinctes dhommes145 et de
femmes,146 un lien direct a t objectiv entre lexistence dune
anxit phobique et le risque de MS, mais pas avec celui
dIDM non fatal. La dpression a galement t associe
une augmentation des risques darrt cardiaque147 et de MS
chez la femme non coronarienne.148 Outre les effets chroniques
des tensions psychosociales, un stress psychique aigu peut
lui aussi provoquer une MS. De brusques augmentations de
lincidence des MS ont ainsi t observes dans des
populations confrontes des catastrophes telles quun
tremblement de terre ou une guerre.149,150 Au-del des
catastrophes, les vnements traumatisants comme le dcs
du conjoint ou la perte de son emploi contribuent galement
augmenter la mortalit globale151 et les MS152 parmi les
individus en bonne sant.
Prdisposition gntique la MS
Au cours des dix annes coules, les recherches menes sur
les fondements gntiques des arythmies hrditaires (AH)
rares ont permis de mieux comprendre la transmissibilit de la
vulnrabilit lgard des troubles du rythme ventriculaire.153
10:00:26:07:12 Page 353
Deo et Albert La mort subite 353
La dcouverte de nouveaux gnes impliqus dans ces AH
ainsi que des effets exercs par les allles mutants sur
llectrophysiologie basale a conduit supposer que des
variants ou des polymorphismes gntiques courants sigeant
dans ces mmes rgions pouvaient en partie rendre compte
de la composante familiale du risque de MS mise en vidence
par les tudes pidmiologiques. Par la suite, la finalisation
du Projet sur le gnome humain a jet les bases de lidentifi-
cation dun nouvel ensemble de gnes et de voies biologiques
impliqus dans les troubles de la conduction, les arythmies
cardiaques et la MS.
Etudes familiales
Plusieurs tudes ont montr quil existe une prdisposition
familiale la MS.72,154156 Celle-ci ainsi que les troubles
du rythme fatals tels que la FV sont souvent la premire
manifestation dun infarctus aigu du myocarde et semblent
prsenter une tendance lagrgation dans certaines familles.
Deux tudes cas-tmoins ont ainsi montr que la survenue
dune MS chez un parent du premier degr constitue un
facteur indpendant de risque de FV155 ou de MS156 chez les
individus victimes dun infarctus myocardique aigu (IMA).
Des observations similaires ont t rapportes dans une
tude de population prospective, au cours de laquelle les
antcdents parentaux de MS ont t documents avant mme
la survenue des dcs. Sur une priode de suivi de plus de
20 ans,72 lexistence de tels antcdents est apparue comme un
facteur indpendant de risque de MS (RR : 1,80 ; IC 95 % :
1,112,88), mais non dIDM fatal. En revanche, un
antcdent familial dIDM fatal a seulement eu pour effet
daugmenter le risque dIDM fatal sans modifier le risque de
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354 Circulation Septembre 2012
MS. Considres dans leur globalit, ces donnes suggrent
que lagrgation familiale de la MS ou de la FV dorigine
ischmique pourrait tre distincte de la prdisposition
familiale lIDM ou la maladie coronaire. Les liens
constants mis en vidence entre les antcdents familiaux
de dcs par trouble du rythme cardiaque et le risque de MS
dans la population gnrale ont conduit plusieurs tudes
dont lobjectif tait de rechercher les variants gntiques
susceptibles dinfluer sur la vulnrabilit lgard des troubles
du rythme ventriculaire et de la MS au sein de la population.
Phnotypes intermdiaires de la MS :
les paramtres lectrocardiographiques
Comme cela a dj t voqu plus haut, des liens ont t
tablis entre le risque de MS et les mesures quantitatives
des paramtres lectrocardiographiques, dont la frquence
cardiaque et les dures des complexes QRS et des espaces QT.
Ces caractristiques lectrocardiographiques sont trans-
missibles et sous-tendues par de nombreuses influences
environnementales et gntiques.157161 Cela a conduit des
quipes de gnticiens du monde entier sunir pour
rechercher les variations gntiques courantes lorigine de
ces traits quantitatifs par la ralisation dtudes dassociations
pangnomiques (EAPG). Ces variants gntiques, dont
les effets sont gnralement modestes, peuvent fournir de
nouveaux clairages non seulement sur le systme de
conduction cardiaque, mais aussi sur les vnements
pathologiques lis des troubles du rythme, dont la MS.
Les nouvelles mutations identifies par cette approche
pourraient galement tre ensuite employes comme allles
de susceptibilit la MS dans la population.
Lespace QT
Trois EAPG entreprises pour analyser la variabilit de
lespace QT parmi les individus dascendance europenne
sont rcemment parvenues leur terme.162164 Au total, ce sont
prs de 30 000 personnes qui ont t ainsi tudies.163,164
Environ la moiti des loci dcouverts grce ces analyses non
biaises se situent au voisinage des gnes (KCNQ1, KCNH2,
KCNE1 et SCN5A) responsables du syndrome du QT long,
qui est une affection monognique (Tableau 2). Le signal la
fois le plus puissant et le plus constant sige au sein du gne
NOS1AP, qui code pour une protine adaptatrice de la
monoxyde dazote synthtase de type 1.162 Lemploi de
modles traductionnels a permis dtablir que ce gne module
la repolarisation myocardique,165 les variants de NOS1AP
influant, par ailleurs, sur le risque de syndrome du QT
long.166,167 Prs de la moiti des variants gntiques identifis
par ces EAPG sont ports par des loci auxquels il navait
jusqualors t attribu aucun rle dans llectrophysiologie
cardiaque ni dans la rgulation de la repolarisation
myocardique. Conjointement, ces mutations rendent compte
denviron 5 6 % de la variabilit de lespace QT.
Le complexe QRS
Une rcente mta-analyse pangnomique de 14 tudes ayant
port sur un total de 40 407 individus dorigine europenne a
identifi 22 loci ayant une influence sur la dure des complexes
10:00:26:07:12 Page 354
QRS (Tableau 2).168 Certains de ces loci sigent au sein ou
proximit des gnes impliqus dans la conduction
ventriculaire, tels ceux codant pour les canaux sodiques,
les facteurs de transcription et les protines de transport du
calcium. En outre, diffrents loci interviennent dans des
processus biologiques qui navaient pas t identifis
jusqualors. Plusieurs de ces loci influent galement sur
lespace PR et lespace QT, mais leffet exerc sur ce dernier est
le plus souvent de direction oppose. Lensemble de ces loci
rend compte denviron 5,7 % de la variance observe dans la
dure des complexes QRS. Le signal le plus puissant sige au
sein ou au voisinage de deux gnes, SCN5A et SCN10A, qui
codent respectivement pour les sous-units des canaux
sodiques Nav1.5 et Nav1.8. Le locus associ SCN5A est
connu pour favoriser divers types darythmies hrditaires ;
en revanche, le rle jou par SCN10A dans la conduction
cardiaque na t dcouvert quaprs quune premire EAPG
a eu objectiv linfluence quil exerait sur les dures
de lespace PR et du complexe QRS.169,170 Des modles
exprimentaux suggrent que le transcrit et le produit de
SCN10A seraient exprims dans les tissus cardiaques tant
chez la souris que chez lhomme,169 leur localisation tant
suppose tre le faisceau de His chez la premire.168
Lespace RR
Les EAPG ont permis didentifier 9 loci qui influent sur la
frquence cardiaque dans les populations dascendance
europenne (Tableau 2).170,171 Deux de ces loci ont t
dcouverts chez des individus originaires dAsie de lEst.172
Lun des variants dcrits aussi bien chez les Europens que
chez les Asiatiques sige sur le chromosome 6q22, proximit
du gne GJA1. Ce dernier code pour la protine des jonctions
communicantes et est indispensable au synchronisme des
contractions cardiaques. Il sagit dun lment majeur des
jonctions communicantes cardiaques,173 dont il apparat,
en outre, quil est impliqu dans la gense des troubles du
rythme.174,175
Facteurs gntiques sous-tendant les variations des
phnotypes lectrocardiographiques lorigine
dune prdisposition alllique la MS
Plusieurs des polymorphismes mononuclotidiques (PMN) et
des loci lorigine de variations des phnotypes lectrocardio-
graphiques ont t tudis quant leurs liens particuliers avec
la MS. Des variants de NOS1AP ont ainsi t identifis
comme contribuant au risque de MS dans trois tudes
distinctes.176178 Dans une analyse groupe de 334 MS
survenues chez des participants blancs lAtherosclerosis
Risk In Communities Study (tude sur le risque dathro-
sclrose dans les communauts ethniques) et la Cardio-
vascular Health Study (tude sur la sant cardiovasculaire),
le marquage des PMN a permis didentifier deux variants
introniques de NOS1AP qui se sont rvls responsables de
MS, y compris aprs ajustement en fonction de lespace QT. Il
est dailleurs intressant de noter que le variant pour lequel la
relation sest rvle la plus forte (rs12567209) nexerce
aucune influence sur la dure de lespace QT. Une tude de
suivi de la cohorte de Rotterdam a confirm la responsabilit
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Deo et Albert La mort subite 355

Tableau 2. Variants gntiques des traits lectrocardiographiques identifis par les tudes dassociations pangnomiques

Frquence de
Chromosome Gne/rgion PMN lallle cod Eff. (ms) Commentaires

Espace QT
1p36 RNF207 rs846111 0,29 1,5 On ignore la fonction de ce locus
1q24 ATP1B1 rs10919071 0,87 2,0 ATP1B1 code pour une protine transmembranaire qui maintient les
gradients transmembranaires dions Na+ et K+
1q23 NOS1AP rs12143842 0,24 3,2 La monoxyde dazote synthtase neuronale de type 1 rgule le cycle du
calcium dans le rticulum endoplasmique
3p22 SCN5A rs12053903 0,34 1,2 Des variants rares de SCN5A sont responsables de syndromes du QT
long de type 3 et de syndromes de Brugada
6q22 c6orf204, rs11756438 0,47 1,4 Le PLN inhibe la Ca2+ ATPase au sein du rticulum endoplasmique cardiaque.
SLC35F1, Laugmentation dactivit du PLN est implique dans le dveloppement de
PLN cardiomyopathies et de tachycardies ventriculaires
7q36 KCNH2 rs2968864 0,25 1,4 Des variants rares de KCNH2 sont responsables de syndromes congnitaux
7q36 KCNH2 rs4725982 0,22 1,6 du QT long de type 2 et de syndromes du QT court de type 1
11p15 KCNQ1 rs2074238 0,06 7,9 Des variants rares de KCNQ1 sont responsables de syndromes du QT long de
11p15 KCNQ1 rs12576239 0,13 1,8 type 1 et de syndromes du QT court de type 2
16p13 LITAF rs8049607 0,49 1,2 Ce gne na aucune influence connue sur la repolarisation myocardique
16q21 NDRG4 rs7188697 0,74 1,7 Locus nouvellement identifi comme agissant sur la repolarisation myocardique
17q12 LIG3 rs2074518 0,46 1,1 LIG3 code pour la rparation de lADN ligase III ; le mcanisme de
modulation de la repolarisation est inconnu
17q24 KCNJ2 rs17779747 0,35 1,2 Des variants rares provoquent la maladie de Fabry (ou syndrome dAnderson),
qui se caractrise par une paralysie priodique, une dysmorphie et des
troubles du rythme ventriculaire
21q22 KCNE1 rs1805128 0,01 0,88 Des variants rares de KCNE1 sont responsables de syndromes du
QT long de type 5
Complexe QRS
1p31 NFIA rs9436640 0,46 0,59 Linfluence exerce par le facteur nuclaire I sur la dure des complexes
QRS demeure mal cerne
1p32 CDKN2C rs17391905 0,05 1,35 Ce gne inhibe les kinases cycline-dpendantes et rgule la croissance
cellulaire
1p13 CASQ2 rs4074536 0,29 0,42 La calsquestrine 2 est une protine de transport du calcium qui rgule
louverture des rcepteurs la ryanodine. Des mutations de CASQ2
ont t reconnues responsables de TVPC
2p22 HEATR5B, rs17020136 0,21 0,51 La striatine est une protine de liaison de la calmoduline qui a rcemment t
STRN mise en cause dans le dveloppement de CVDA dans un modle canin
2p21 CRIM1 rs7562790 0,40 0,39 CRIM1 est exprim dans les tissus cardiaques et code pour une protine
transmembranaire susceptible de se lier divers membres de la
superfamille des ligands du TGF-
3p22 SCN10A, rs9851724 0,33 0,66 Ces gnes codent tous deux pour des canaux sodiques voltage-dpendants
SCN5A et jouent un rle important dans la conduction cardiaque. SCN5A
influe galement sur lespace QTc
3p14 TKT, PRKCD, rs4687718 0,14 0,63 TKT est une enzyme qui intervient dans de multiples voies mtaboliques
CACNA1D
3p14 LRIG1, SLC25A26 rs2242285 0,42 0,37 LRIG1 est activ dans les affections malignes
5q33 HAND1, SAP30L rs13165478 0,36 0,55 HAND1 code pour un facteur de transcription indispensable au dveloppement
cardiaque. Certaines mutations ont t identifies comme responsables de
malformations septales et de troubles du rythme ventriculaire
6p21 CDKN1A rs9470361 0,25 0,87 CDKN1A est un inhibiteur des kinases cycline-dpendantes qui joue un rle
important dans le dveloppement des voies de conduction cardiaque. Il pourrait
galement faciliter la constitution des jonctions communicantes
6q22 C6orf204, rs11153730 0,49 0,59 Le PLN cardiaque rgule lentre du calcium dans le rticulum endoplasmique
SLC35F1, PLN mdie par SERCA2a. Ce locus influe galement sur la dure de lespace QTc
et sur le diamtre tldiastolique du ventricule gauche
7p14 TBX20 rs1362212 0,18 0,69 TBX20 rgit le dveloppement des ventricules gauche et droit
7p13 IGFBP3 rs7784776 0,43 0,39 On ignore la fonction de ce locus
10q25 VTI1A rs7342028 0,27 0,48 On ignore la fonction de ce locus
(Suite)

10:00:26:07:12 Page 355

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356 Circulation Septembre 2012

Tableau 2. Suite

Frquence de
Chromosome Gne/rgion PMN lallle cod Eff. (ms) Commentaires

10q11 DKK1 rs1733724 0,25 0,49 DKK1 intervient dans le dveloppement axial de lembryon. Par ailleurs,
il inhibe la voie de signalisation de Wnt, qui est un important
modulateur de lactivit de la connexine 43
12q24 TBX5 rs883079 0,29 0,49 TBX3 et TBX5 codent tous deux pour des facteurs de transcription prsents
12q24 TBX3 rs10850409 0,27 0,49 dans les voies de conduction cardiaque. TBX5 (activateur) soppose TBX3
(rpresseur) dans la rgulation de gnes myocardiques tels que GJA1. Des
mutations de TBX3 et TBX5 sont lorigine de syndromes hrditaires rares
caractriss par des anomalies structurales et des troubles de la conduction
13q22 KLF12 rs1886512 0,37 0,40 Linfluence exerce par ce facteur de transcription sur la dure des
complexes QRS demeure mal cerne
14q24 SIPA1L1 rs11848785 0,27 0,50 Contribue la signalisation de Wnt et au dveloppement cardiaque
17q22 PRKCA rs9912468 0,43 0,39 La protine kinase C modifie la charge du rticulum endoplasmique en ions Ca2+
17q21 GOSR2 rs17608766 0,16 0,53 On ignore la fonction de ce locus
18q21 SETBP rs991014 0,42 0,42 On ignore la fonction de ce locus
Espace RR
1q32 CD46, rs12731740 0,03 5,9 Linfluence exerce par ce locus sur la frquence cardiaque demeure
LOC148696 mal cerne. Celui-ci a t identifi dans des tudes menes aussi bien
chez des sujets blancs que dans dautres groupes raciaux
6q22 GJA1 rs9398652 0,49 12,7 GJA1 code pour Cx43, une protine de la famille des connexines qui est lun des
lments constitutifs des jonctions communicantes cardiaques. Ce gne rgit le
synchronisme des contractions cardiaques. Des mutations de GJA1 ont t
identifies comme impliques dans le syndrome dhypoplasie du cur gauche
6q22 SLC35F1, PLA rs281868 0,44 1,50 Ce locus, qui est situ plus de 3 Mb de GJA1, influe galement sur la dure de
lespace QTc. Le PLN intervient galement dans le couplage excitation-
contraction et dans la signalisation calcique intracellulaire
7q22 SLC12A9 rs314370 0,94 9,65 Ce gne code pour une protine qui interagit avec le cotransporteur des ions Cl
7q22 UfSp1 rs12666989 0,07 9,31 On ignore la fonction de ce locus
11q12 FADS1 rs174547 0,91 4,20 FADS1 a t prcdemment dcrit comme influant sur le taux de cholestrol
12q24 GPR133 rs885389 0,30 14 Ce locus code pour un rcepteur coupl la protine G et est exprim
la fois dans les oreillettes et dans les ventricules
14q12 MYH6 rs452036 0,62 9,65 Il existe deux isoformes diffrentes du MYHC sarcomrique : l-MYHC
14q12 MYH6 rs365990 0,38 9,80 (cod par MYH6) et le -MYHC (cod par MYH7). Des mutations de ces
14q12 MYH7 rs223116 0,77 4,47 gnes ont t reconnues responsables de diverses cardiomyopathies

PMN : polymorphisme mononuclotidique ; Eff. : efficience ; PLN : phospholamban ; TVPC : tachycardie ventriculaire polymorphe catcholaminergique ; CVDA :
cardiomyopathie ventriculaire droite arythmogne ; TGF- : facteur de croissance transformant bta ; TKT : transktolase ; MYHC : chane lourde de la myosine.

du variant en question dans les analyses limites aux MS
survenues en prsence de tmoins177 ; en revanche, cette
observation na pas t corrobore par une tude cas-tmoins
mene dans lOregon.178 Les investigateurs de cette dernire
ont dcrit un autre variant, corrl avec le PMN rs12567209 et
pour lequel le lien dpassait peine le seuil de significativit.
Une rcente tude ayant port sur 1 283 cas de MS a examin
le rle jou dans la survenue de tels vnements par 49 loci
indpendants, dont NOS1AP, qui conditionnent les phno-
types lectrocardiographiques intermdiaires reprsents par
lespace QT, la dure des complexes QRS et la frquence
cardiaque.179 Parmi ces diffrents loci, seul TKT/CACNA1D/
PRKCD (dont il avait dj t tabli quil influe sur la dure
des complexes QRS) sest montr corrl avec le risque de MS
aprs ajustement en fonction des variables multiples. Il est
toutefois apparu que lallle lorigine de llargissement des
complexes QRS contribue rduire le risque, ce qui est
loppos de ce que lon prvoyait sur la base du lien existant
entre la dure desdits complexes et la MS.
Les variants courants qui viennent dtre voqus exercent
tous des effets relativement modestes sur les paramtres
lectrocardiographiques, de sorte que leurs liens avec la MS
peuvent tre difficiles objectiver, mme en analysant de
vastes populations. Certains ont donc tent de combiner les
variants en un score de risque gntique afin daugmenter
la puissance de dtection des associations. Rcemment, la
totalit des PMN recenss dans le gnome entier comme
exerant une influence significative sur lespace QT ont t
incorpors un score de gnotype QT, qui a t ensuite valu
quant sa valeur prdictive du risque de MS dans deux tudes
de cohortes finlandaises.180 Ce score gnotypique sest rvl
corrl de faon linaire avec lespace QT et a expliqu 8,6 %
de la variance de ce paramtre au sein des populations
tudies. Aucune relation linaire na, en revanche, t
objective entre le score gnotypique et le risque de MS pour
les 116 cas de MS quont totaliss les deux cohortes, qui
noffraient peut-tre pas une puissance suffisante. De ces
donnes, il ressort clairement que les variants gntiques

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 Page 357
identifis par les tudes pangnomiques menes sur les
marqueurs lectrocardiographiques peuvent fournir des
informations dun grand intrt pour de futures recherches
traductionnelles et exprimentales, mais ne suffiront pas
expliquer lhritabilit de la MS.
Phnotypes intermdiaires de la MS :
la maladie coronaire
Compte tenu de la prvalence leve des coronaropathies,
souvent mconnues chez les sujets victimes de MS, les variants
gntiques associs la maladie coronaire peuvent galement
tre recherchs en tant quallles de prdisposition la MS
dans la population gnrale. Lidentification des variants qui
influent sur les deux traits la fois peut, en effet, permettre de
mieux cerner les processus biologiques qui prdisposent les
individus coronariens la MS. Des groupes de collaboration
internationaux ont ralis des mta-analyses partir dEAPG
afin daugmenter la puissance didentification des loci qui
sous-tendent la maladie coronaire dans des populations
europennes, noires amricaines et dAsie du Sud-Est.181183 La
mta-analyse la plus rcente, qui a port sur plus de 22 000 cas
de maladie coronaire tant en phase de recherche que de
rplication, a confirm lexistence de 10 loci dj connus
comme associs au risque de coronaropathie et en a identifi
13 nouveaux.181 La plupart de ces loci sigent dans des
rgions gniques dont, jusqualors, on ne souponnait pas
limplication dans la pathogense de la maladie coronaire. Le
site pour lequel lassociation demeure la plus puissante est une
rgion du chromosome 9p21 qui tait dj connue pour
rguler lexpression de CDKN2A et CDKN2B, deux gnes
inhibiteurs des kinases cycline-dpendantes184 dont on sait
quils jouent un rle majeur dans la prolifration, la
snescence et lapoptose cellulaires.185 Les PMN localiss la
rgion 9p21 ont t directement rattachs au risque de MS par
une mta-analyse ayant port sur 492 cas survenus chez des
individus blancs dans six tudes de cohortes prospectives.186
Aucun des autres loci dont les EAPG avaient tabli la
responsabilit dans la maladie coronaire ne sest rvl
impliqu dans le risque de MS.
Analyses des gnes candidats
potentiellement pourvoyeurs de MS
Ces recherches des variants gntiques associs aux
phnotypes intermdiaires ont t compltes par des
tudes fondes sur la mthode des gnes candidats afin
didentifier les allles de prdisposition la MS. Cette
approche, qui consiste formuler des hypothses, a t
applique plusieurs voies biologiques impliques dans
la survenue de troubles du rythme cardiaque et de MS
fondement monognique au sein de la population.
Variants courants
Des tudes menes indpendamment les unes des autres et en
employant des mthodologies et des dfinitions diffrentes
(Tableau 3) ont recherch les influences potentiellement
exerces sur le risque de MS par les polymorphismes des gnes
jouant des rles essentiels dans la propagation des influx
lectriques, la conduction cardiaque, lactivation sympathique,
10:00:26:07:12 Page 357
Deo et Albert La mort subite 357
la thrombose, lathrogense et le systme rnine-
angiotensine-aldostrone.178,187200 Dans ces travaux, la
prvalence des variants allliques a t dau moins 5 % et
a souvent atteint 50 60 % de la population tmoin. Cela
autorise considrer que ces variants ne doivent que
modestement influer sur le risque de MS dans la mesure o
un variant particulirement dangereux est appel voluer
au cours du temps en une mutation rare dans le patrimoine
gntique humain (Figure 7). Dans leur immense majorit,
les liens rapports nont pas t confirms par des tudes
ultrieures. Parmi les gnes candidats explors, les variants qui
codent pour les polymorphismes affectant les acides amins
des rcepteurs 2-adrnergiques (Gln27Glu dans 2AR)
chez les Blancs191,193 et de la sous-unit du canal sodique
cardiaque Nav1.5 (Y1102A dans SCN5A) chez les Noirs
amricains189,190,201 ont t identifis comme impliqus dans
la MS ou les vnements arythmiques dans au moins
deux tudes ; toutefois, les rsultats nont pas toujours t
concordants.192
Variants rares
Etant donn la ltalit leve de larrt cardiaque subit, il nest
pas exclu que son architecture gntique soit plus proche de
celle des arythmies hrditaires peu courantes, qui repose sur
des allles rares ayant une pntrance variable. La meilleure
mthode didentification de ces allles rares est le squenage
direct, qui, grce aux techniques de seconde gnration, est
rapidement en train de devenir beaucoup plus largement
accessible. A notre connaissance, trs peu dtudes ont t
menes en employant le squenage pour rechercher les
variations rares parmi les cas non slectionns de MS
survenus dans des populations dadultes.188,202 Dans 113 cas de
MS, il a t possible deffectuer le squenage direct de
la totalit de la squence codante et des jonctions dpissage
de cinq gnes, SCN5A, KCNE1, KCNE2, KCNQ1 et KCNH2,
codant pour des canaux ioniques et impliqus dans la
survenue darythmies hrditaires.202 Chez 53 hommes, ce
squenage na objectiv aucune variation isole ou rare de la
Figure 7. Synopsis des tudes gntiques. Les tudes
dassociations pangnomiques visent identifier les variants
allliques courants qui induisent un faible risque relatif de
morbidit. Lvolution tend ne conserver que les variants
lorigine dun haut risque relatif de morbidit, ce qui rend compte
de leur raret.
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358 Circulation Septembre 2012

Tableau 3. Gnes candidats potentiellement responsables de MS dans la population gnrale

Frquence de N (cas de
Etude Gnes variation alllique Population MS/tmoins) Commentaires

Canaux ioniques
Westaway et al 2011178 CASQ2, GPD1L 1045 % Amricains dascendance 670/299 Les polymorphismes de ces gnes sont
europenne, population impliqus dans la MS
gnrale
Albert et al 2010187 KCNQ1, KCNH2, 6070 % Amricains dascendance 516/1 522 Deux variants introniques (intressant
SCN5A, KCNE1, europenne, population respectivement KCNQ1 et SCN5A) ont
KCNE2 gnrale t reconnus responsables de MS
Stecker et al 2006188 SCN5A 14 % Amricains dascendance 67/91 Aucun lien na t identifi entre les
europenne atteints de polymorphismes ou les mutations de
maladie coronaire SCN5A et la MS
Burke et al 2005189 SCN5A (Y1102A) 9% Noirs, population gnrale 182/107 Un lien a t tabli entre Y1102A et la
survenue de dcs inexpliqus
fondement arythmique et dACS
Splawski et al 2002190 SCN5A (Y1102A) 13 % Noirs, population gnrale 23/100 Le variant contribue augmenter les
risques de MS et dallongement de
lespace QTc dorigine
mdicamenteuse
Systme neurovgtatif
Gavin et al 2011191 2AR (Gln27Glu) 45 % Amricains dascendance 492/1 388 En combinant les donnes avec celles
europenne, population des deux analyses ci-dessous, le
gnrale polymorphisme de 2AR contribue
augmenter le risque de MS
Tseng et al 2008192 2AR et 1AR 3040 % (2AR) MS avorte et antcdents 107/388 Aucun des polymorphismes des gnes
1030 % (1AR) dIDM ou de maladie AR na pu tre reli au risque de MS
coronaire, 75 % dAmricains
dascendance europenne
Sotoodehnia et al 2006193 2AR (Gln27Glu) 43 % chez les Blancs, Cohorte amricaine 195/5 249 Le variant 2AR est responsable de MS
19 % chez les Noirs (4 441 sujets dascendance chez les Blancs mais pas les Noirs
europenne, 808 Noirs)
Snapir et al 2003194 Alpha2B-AR 48 % Finlandais, tude de 278/405 Le gnotype dltion/dltion du gne
population codant pour les rcepteurs 2B-
adrnergiques augmente le risque de
MS chez lhomme dge moyen
Facteurs thrombotiques et athrognes
Hernesniemi et al 2008195 IL-18 26 % Finlandais, tude de 275/388 Le polymorphisme du gne IL-18 est
population responsable de MS
Mikkelsson et al 2002196 GPIa 3540 % Finlandais, tude de 275/369 Les polymorphismes du gne codant
population pour les rcepteurs la glycoprotine
Ia nont pas dinfluence sur le
risque de MS
Reiner et al 2002197 Facteur V de 69 % Cohorte amricaine (93 % 145/592 Les mutations de ces gnes ne sont pas
Leiden et dindividus dascendance responsables de MS
PT 20210A europenne)
Mikkelsson et al 2001198 GPIb 23 % Finlandais 255/367 Le variant a t reconnu responsable de
thrombose coronaire, dIDM fatal et de
MS chez lhomme dge moyen
Mikkelsson et al 2000199 GPIIIa 3040 % Finlandais, tude de 281/385 Le polymorphisme PIA1/A2 du gne GPIIIa
population est un facteur de risque dinfarctus du
myocarde et de MS chez les individus
dge moyen
Voie de lenzyme de conversion de langiotensine
Sotoodehnia et al 2009200 REN 15 % Amricains dascendance 271/730 Les mutations dAGTR1 et dAGTR2 ont
AGTR1 europenne, tude de t identifies comme des facteurs
AGTR2 population daugmentation du risque dACS dans
une tude de population cas-tmoins
ACE2
BDRK2
AGT
ACE
KNG1

ACS : arrt cardiaque subit ; 1AR : rcepteur 1-adrnergique ; 2AR : rcepteur 2-adrnergique ; IDM : infarctus du myocarde ; IL-18 : interleukine-18 ;
MS : mort subite.

10:00:26:07:12 Page 358

 Page 359
squence codante de lun quelconque des gnes codant pour
des canaux ioniques.188 Chez 60 femmes victimes de MS,
six mutations faux-sens rares (10 %) ont t identifies, qui
intressaient le gne des canaux sodiques cardiaques
(SCN5A).202 La frquence globale de ces variants rares de
SCN5A sest rvle significativement plus leve dans les cas
de MS que chez 733 tmoins issus de la mme population
(1,6 % ; p = 0,001) ; de plus, quatre des cinq variants taient
lorigine de discrtes altrations de la fonction des canaux
ioniques. Ces observations permettent de penser que, mme
si elles ne constituent pas des causes courantes de MS, les
mutations fonctionnellement consquentes et les variations
rares de SCN5A pourraient contribuer au risque de MS
chez les femmes, population dans laquelle la prvalence des
cardiopathies structurales est plus faible.29,39
EAPG de la MS
A ct de ces tudes menes sur les gnes candidats de la MS,
des EAPG ont t directement effectues sur des cas de MS
afin de rechercher de nouveaux variants gntiques impliqus
dans la survenue de tels vnements. Cette approche non
biaise peut permettre de dcouvrir des variants encore
mconnus ainsi que de nouvelles voies biologiques impliques
dans la gense des troubles du rythme ventriculaire fatals. Le
nombre de loci valids comme sous-tendant le risque de
MS de faon statistiquement significative lchelon
pangnomique est toutefois beaucoup plus faible que pour
les autres maladies complexes. Cela est probablement en
grande partie li au fait que les cas de MS disponibles pour
les analyses gntiques sont en nombre plus rduit et que les
dfinitions des pathologies sous-jacentes et des cas sont plus
htrognes que pour les autres phnotypes complexes.
Les investigateurs dune rcente tude ont tent de limiter le
plus possible cette htrognit en concentrant leur analyse
sur un phnotype arythmique trs prcis. Dans cette tude
cas-tmoins baptise AGNES,203 une EAPG a t ralise
sur 505 cas de FV et 457 tmoins, les deux groupes tant
constitus dindividus qui avaient tous prsent un premier
IDM avec sus-dcalage du segment ST. Des PMN ports par
le chromosome 21q21 ont t identifis comme significative-
ment pourvoyeurs de FV lchelle pangnomique. Le signal
le plus puissant, qui correspondait au PMN rs2824292, est
demeur significativement corrl avec le risque de FV (odds
ratio [OR] : 1,51 ; IC 95 % : 0,300,76 ; p = 0,005) aprs
ajustement pour les caractristiques initiales et a pu tre
rpliqu, dans ltude ARREST, dans 156 autres cas darrt
cardiaque conscutif une FV survenus chez des individus
prsentant un IDM aigu. Le locus gntique est situ au
voisinage du gne CXADR, qui code pour la protine du
rcepteur aux virus Coxsackie et aux adnovirus (CAR).204,205
Cette protine, qui joue un rle connu dans la pathogense des
myocardites virales,206 pourrait galement tre implique
dans la localisation des connexines au niveau des disques
intercalaires des myocytes du nud auriculo-ventriculaire.207
Une autre EAPG rcemment publie a t ralise sur une
gamme plus large de cas de MS issus dtudes cas-tmoins et
de cohortes.179 Les investigateurs ont eu recours cette
approche pangnomique pour rechercher les variations parmi
1 283 cas de MS enregistrs dans cinq tudes distinctes ainsi
10:00:26:07:12 Page 359
Deo et Albert La mort subite 359
que chez 20 000 tmoins, les individus ainsi analyss tant
tous dascendance europenne. Les PMN identifis comme
ayant t les plus statistiquement significatifs dans cette phase
de dcouverte ont ensuite t gnotyps dans 1 730 autres cas
de MS et de FV et chez 10 530 tmoins qui, l encore, taient
tous dascendance europenne. Les mta-analyses combines
de lensemble des populations des phases de dcouverte et de
rplication ont permis didentifier un nouveau marqueur
sigeant au niveau du locus BAZ2B (bromodomaine adjacent
au domaine doigt de zinc 2B) qui a atteint la significativit
statistique lchelle pangnomique et dont leffet est apparu
de taille relativement importante (OR : 1,92 ; IC 95 % :
1,572,34). Lallle suppos risque sest rvl rare
(frquence alllique mineure : 1,4 %) et en fort dsquilibre
de liaison avec les gnes qui jouent un rle crucial dans la
formation du cur et celle du systme neurovgtatif. La mise
en vidence dun tel variant rare, qui est inhabituelle dans
les EAPG, met en lumire limpact que peut avoir ce type de
variant sur le risque de MS.
Il convient de noter que les recherches non biaises
des variants associs la MS effectues dans le cadre de ces
deux tudes pangnomiques nont pas identifi les mmes
mutations. Cette absence de reproductibilit, qui est courante
dans les tudes gntiques menes sur la MS, est probable-
ment lie aux diffrences de dfinitions des cas. Bien que, dans
ltude AGNES, les cas aient t dfinis sur des critres
extrmement prcis, la dfinition tait toutefois relativement
slective et, donc, non applicable la majorit des MS
observes en milieu communautaire.4042 A linverse, les cas
analyss dans les tudes de populations taient pour lessentiel
des MS extrahospitalires dfinies de faon sommaire. Cela
tant, lhtrognit des cas tant dans une mme tude que
dun travail lautre a probablement limit la puissance
de dtection des associations, mme lorsque les analyses
ont port sur un nombre de cas plus lev. Il est donc
indispensable que les phnotypes explors dans les diffrentes
tudes soient homognes, surtout si lon veut pouvoir
regrouper les rsultats dans une analyse pangnomique en
vue de rechercher les variants ayant des effets rduits. Pour
identifier et rpliquer les autres variants gntiques impliqus
dans la MS, les tudes devront la fois porter sur des
chantillons plus vastes et sur des sous-phnotypes dont
lhomognit aura t mieux assure.
Orientation futures
Bien que nous en sachions dj beaucoup sur les facteurs
de risque de MS, les donnes disponibles ce jour sur
dimportantes sous-populations sont encore tnues et les
diffrences observes selon lorigine ethnique et dun sexe
lautre demeurent mal lucides. De plus, notre capacit
dpister prcisment, au sein de la population, les individus
exposs un risque de MS maximal reste faible. Alors que
pour le risque coronaire global il existe des modles prdictifs
largement reconnus, aucun modle quivalent na encore t
dvelopp pour valuer le risque de MS dans la population
gnrale et ce, malgr les multiples tudes ayant mis en
lumire diffrents facteurs de risque. Lidentification des sous-
groupes prdisposs au sein de la population pourrait tre
facilite par llaboration dalgorithmes de stratification des
 Page 360
360 Circulation Septembre 2012
risques partir des donnes des tudes pidmiologiques
menes pour valuer tout la fois limpact des facteurs
de risque cardiovasculaire tablis, du mode de vie et des
habitudes alimentaires, des marqueurs biologiques et
des variants gntiques. Il sera galement important de
dterminer si de nouveaux marqueurs sont plus puissamment
corrls avec la MS quavec les autres manifestations de la
maladie cardiaque. De tels marqueurs contribueraient non
seulement amliorer la stratification des risques, mais aussi
mieux cerner les mcanismes arythmiques dans la population,
ce qui pourrait ouvrir la voie de nouvelles stratgies
prventives et thrapeutiques.
Lhritabilit de la MS demeure mal comprise compte tenu
des donnes dont nous disposons. Bien que les analyses
fondes sur les gnes candidats et les tudes pangnomiques
aient permis de mieux comprendre les intrications entre
llectrophysiologie cardiaque, les troubles du rythme et la
MS, de nombreuses questions demeurent encore sans rponse.
Seul un trs petit nombre des PMN identifis ou valus dans
ces tudes ont pu tre confirms et, pour beaucoup dentre
eux, on ignore encore quelles sont les influences fonctionnelles
quils exercent. Du fait du rapide dveloppement des
techniques de squenage de nouvelle gnration, il devient
dsormais possible dentreprendre des programmes de
squenage grande chelle qui permettront lidentification
de variants gntiques rares jouant un rle dans le risque de
MS. Il est galement possible que ce dernier soit sous-tendu
par des mutations structurales consistant, par exemple, en
des variations du nombre de copies, des inversions ou des
translocations et que ni les EAPG ni les mthodes de
squenage classiques ne permettent didentifier. Cette
complexit potentielle de larchitecture gntique ne
pourra tre matrise quen entreprenant de vastes tudes
collaboratives sur des populations dans lesquelles la dfinition
de la MS repose sur des critres homognes.
La MS est un vnement complexe qui fait lobjet de
recherches et dtudes cliniques depuis plusieurs dcennies.
Alors que notre comprhension de ce trouble ne cesse de
progresser grce aux tudes pidmiologiques, aux tudes
exprimentales et aux essais cliniques, rduire lincidence et la
ltalit de la MS au sein de la population demeure au cur des
priorits. Les interventions et traitements faible risque axs
sur les affections cardiovasculaires en gnral et sur la MS en
particulier permettront trs certainement de diminuer le tribut
pay par les populations cette dernire. En outre, les
campagnes rgulires dducation et de sensibilisation du
public la MS demeurent dimportantes mesures mettre en
uvre si lon veut rduire limpact de ce type daccident.
Sources de financement
Le Dr Deo a bnfici dune bourse K23DK089118 des National
Institutes of Health des Etats-Unis. Ltude a galement t finance
par un Established Investigator Award de lAHA dcern au
Dr Albert et par une bourse HL091069 octroye par le National
Heart, Lung, and Blood Institute (NHLBI) des Etats-Unis au
Dr Albert.
Dclarations
Le Dr Albert a bnfici de bourses de recherche manant du NHLBI
et de St. Jude Medical Inc. en sa qualit dinvestigateur principal dans
10:00:26:07:12 Page 360
des tudes destines valuer des marqueurs gntiques et
biologiques quant leur valeur prdictive du risque de mort subite. Le
Dr Albert a, par ailleurs, bnfici de dotations du NHLBI et de
Boston Scientific en vue dtudier les lments dclencheurs et les
facteurs prdictifs de troubles du rythme ventriculaire chez les
patients munis de dfibrillateurs automatiques implantables et a
reu le soutien financier de Siemens Healthcare Diagnostics en vue de
ltude des biomarqueurs et des facteurs prdictifs de mort subite.
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