Abstract

HomeCirculationVol. 125, No. 4Epidemiology and Genetics of Sudden Cardiac Death Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBEpidemiology and Genetics of Sudden Cardiac Death Rajat Deo and Christine M. Albert Rajat DeoRajat Deo 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 Women's Hospital, Boston, MA (C.M.A.). Search for more papers by this author and Christine M. AlbertChristine M. Albert 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 Women's Hospital, Boston, MA (C.M.A.). Search for more papers by this author Originally published31 Jan 2012https://doi.org/10.1161/CIRCULATIONAHA.111.023838Circulation. 2012;125:620–637IntroductionSudden 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.1–3 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 owing to differences in SCD definitions and surveillance methods 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 coronary heart disease (CHD) mortality over the past 30 years,11,12 SCD rates specifically have declined to a lesser extent.13–16 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. Therefore, substantial reductions in SCD incidence will require effective 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 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 RaceThe 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 structurally normal hearts (Figure 2).Download figureDownload PowerPointFigure 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 publisher. Copyright © Massachusetts Medical Society, 1993.Download figureDownload PowerPointFigure 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 58±12 years for men and 55±17 years for women. Coronary artery disease was the principal 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 cardiomyopathy; VHD, valvular heart disease; SPASM, coronary vasospasm; and RV, right ventricular. Adapted from Albert et al,29 with permission from the publisher. Copyright © American Heart Association, Inc., 1996.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 risk=1.3–2.8) 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 documented 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 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.Download figureDownload PowerPointFigure 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.Underlying PathophysiologyThe pathophysiology of SCD is complex and is believed to require the interaction between a transient event and underlying 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).Download figureDownload PowerPointFigure 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.CHD is the most common substrate underlying SCD in the Western world, being responsible for ≈75% of SCDs.8,18,36,37 Cardiomyopathies (dilated, hypertrophic, and arrhythmogenic 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 formation 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.51Download figureDownload PowerPointFigure 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.Risk FactorsStructural Heart DiseaseCoronary 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 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 cardiomyopathy,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 abnormal 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 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 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 FactorsDietary 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 suggest that increased consumption of n-3 polyunsaturated fatty acids is inversely associated with SCD to a greater extent than nonfatal MI.102–106 In 4 observational studies, consuming fish ≈1 to 2 times per week was associated with 42% to 50% reductions in SCD risk.102–105 α-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 experimental 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 nell'Infarto miocardico (GISSI) Prevenzione trial, which tested supplementation with n-3 polyunsaturated fatty acids (combination 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.Table 1. Biological Markers and Sudden Cardiac Death in Prospective StudiesBiomarkerMechanismStudyFindingsDietary markers Long-chain n-3 fatty acidsIonic channel stabilization, inflammationPhysicians' Health Study86 (n=278)Baseline level of long-chain n-3 fatty acids were inversely related to the risk of SCD MagnesiumRepolarization, membrane stabilizationNurses' Health Study87 (n=88 735)Higher plasma concentrations and dietary magnesium intake were associated with lower risks of SCDARIC study88 (n=14 232)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 acidsMembrane stabilizationParis Prospective Study89 (n=5250 men)Fasting plasma NEFA measurements at baseline were independently associated with SCD after a 22-y follow-up period Trans-fatty acidsInflammation, endothelial dysfunctionCardiovascular Health Study90 (n=428)Higher plasma phospholipid trans-18:2 fatty acids were associated with higher risk of SCD. Higher trans-18:1 levels were associated with lower SCD riskInflammatory markers CRP, IL-6, fibrinogenInflammation, oxidative stress, insulin resistancePRIME Study91 (n=9771 men)Baseline concentrations of IL-6, but not CRP or fibrinogen, were an independent risk factor for SCD after 10 y of follow-up CRPInflammation, oxidative stressNurses' Health Study92 (n=121 700 women)Baseline concentrations of CRP were not associated with SCD events after 16 y of follow-up CRPInflammation, oxidative stress, apoptosisPhysicians' Health Study93 (n=22, 071 men)Baseline CRP levels were associated with an increased risk of SCD over a 17-y follow-up period ST2Interleukin-1 receptor, myocardial fibrosisMUSIC Registry,94 ambulatory heart failure patients (n=99)Over a 3-y follow-up period, elevated soluble ST2 concentrations at baseline were independently associated with SCDMetabolic markers AldosteroneMyocardial tension, fibrosis, electrical remodelingSTEMI population95 (n=356)Among patients referred for primary PCI for STEMI, high aldosterone levels at admission were associated with death or resuscitated cardiac arrest during a 6-mo follow-up period Cystatin CMarker of glomerular filtration rateCardiovascular Health Study,70 excluded participants with prevalent cardiac disease (n=4482)Over a median follow-up of 11.2 y, elevated cystatin C concentrations at baseline had an independent association with SCD in elderly people without prevalent cardiovascular disease ReninFibrosis and electrical remodelingLURIC study,96 patients referred for coronary angiography (n=3303)Baseline plasma renin is associated with long-term cardiovascular mortality including both SCD and death due to heart failure. Vitamin D and parathyroid hormoneFibrosis, electrical remodeling, metabolic effectsCardiovascular Health Study,97 excluded participants with prevalent cardiac disease (n=2312)The combination of lower vitamin D and higher PTH concentrations was an independent risk factor for SCD among older adults without cardiovascular disease Vitamin DFibrosis and electrical remodelingGerman Diabetes and Dialysis Study98 (n=1108)Over a median follow-up of 4 y in this dialysis cohort with diabetes, severe vitamin D deficiency was associated with SCDNeurohormonal markers BNP NT-pro-BNPIncreased myocardial tensionNurses' Health Study92 (n=121 700 women)Increased baseline NT-pro-BNP concentrations were independently associated with SCD events after 16 y of follow-upCardiovascular Health Study99 (n=5447)Elevated baseline NT-pro-BNP levels were associated with SCD after a median 12.5 y follow-up periodVienna Heart Failure cohort (LVEF 5 drinks per day) is associated with an increased risk of SCD73 but not nonfatal MI.111 In contrast, light-to-moderate levels of alcohol consumption (≈ ½ to 1 drink per day) may be associated with reduced risks of SCD.112–114 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.88Finally, there is some evidence that certain dietary patterns that account for additive and interactive effects of multiple nutrients115 are associated with lower SCD risk. A Mediterranean-style diet consisting of higher intake of vegetables, 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, and may be driven partially through protection against ventricular 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.119Biological MarkersIn addition to the nutrient biomarkers described above, multiple epidemiological investigations have evaluated dysregulation in inflammatory, metabolic, and neurohormonal pathways as predisposing factors for SCD (Table 1). Several epidemiological studies have assessed biomarkers at a time when the majority of participants are free of significant clinical cardiovascular disease. As a result, abnormal concentrations may reflect subclinical changes in cardiovascular processes that eventually predispose individuals to SCD risk. The early stages of hemodynamic stress, atherosclerotic plaque instability, and cardiac remodeling may only be detectable with biomarkers that are associated with inflammatory processes, metabolic factors, and neurohormonal regulation. Experimental evidence suggests that these markers regulate pathophysiologic mechanisms implicated 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 validate these findings and to determine whether biomarkers have a diagnostic role120 in identifying high-risk individuals in the general population.TriggersSCD 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 VariationSeveral 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 β-blockers,125 supporting the concept that excessive activation 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 temperature,128,129 sunlight exposure, and other climatic conditions.Physical ActivityPhysical 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,65,73,131–133 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 studies 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 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 exertion increases basal vagal tone, resulting in increased cardiac electric stability.Download figureDownload PowerPointFigure 6. Sports engaged in at the time of the SCD events among 820 SCD events associated with exertion in France. N refers to the absolute 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 de