Sudden Cardiac Death

HomeCirculationVol. 98, No. 21Sudden Cardiac Death Free AccessOtherPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessOtherPDF/EPUBSudden Cardiac Death Douglas P. Zipes and Hein J. J. Wellens Douglas P. ZipesDouglas P. Zipes From the Krannert Institute of Cardiology, Indiana University School of Medicine and the Roudebush Veterans Administration Medical Center, Indianapolis (D.P.Z.), and the Department of Cardiology, Academic Hospital Maastricht and the Interuniversity Cardiology Institute of the Netherlands, Utrecht (H.J.J.W.). Search for more papers by this author and Hein J. J. WellensHein J. J. Wellens From the Krannert Institute of Cardiology, Indiana University School of Medicine and the Roudebush Veterans Administration Medical Center, Indianapolis (D.P.Z.), and the Department of Cardiology, Academic Hospital Maastricht and the Interuniversity Cardiology Institute of the Netherlands, Utrecht (H.J.J.W.). Search for more papers by this author Originally published24 Nov 1998https://doi.org/10.1161/01.CIR.98.21.2334Circulation. 1998;98:2334–2351Sudden cardiac death describes the unexpected natural death from a cardiac cause within a short time period, generally ≤1 hour from the onset of symptoms, in a person without any prior condition that would appear fatal.12 Such a rapid death is often attributed to a cardiac arrhythmia, but with the advent of monitoring capabilities from implantable cardioverter-defibrillators (ICDs), it is now well recognized that classifications based on clinical circumstances can be misleading and often impossible, because 40% of sudden deaths can be unwitnessed.3 Only an ECG or a ventricular electrogram recorded from an implanted device at the time of death can provide definitive information about an arrhythmia. Prodromal symptoms are often nonspecific, and even those taken to indicate ischemia (chest pain), a tachyarrhythmia (palpitations), or congestive heart failure symptoms (dyspnea) can only be considered suggestive. For these reasons, total mortality, rather than classifications of cardiac and arrhythmic mortality, should be used as primary objectives for many outcome studies.Magnitude of the ProblemSudden cardiac death accounts for 300 000 to 400 000 deaths annually in the United States, depending on the definition used.12 When restricted to death <2 hours from the onset of symptoms, 12% of all natural deaths were classified as sudden in one study, and 88% of those were due to cardiac disease.1 Sudden cardiac death is the most common and often the first manifestation of coronary heart disease and is responsible for ≈50% of the mortality from cardiovascular disease in the United States and other developed countries. In less-developed countries, sudden cardiac death rates parallel the rates of ischemic heart disease as a whole and therefore are lower. Several population-based studies have documented a 15% to 19% decline in the incidence of sudden cardiac deaths caused by coronary heart disease since the early 1980s. However, the increasing incidence of congestive heart failure may halt this decline in the future.4Figure 1 places the problem into perspective by expressing the incidence of sudden cardiac death in different subgroups at varying risk while indicating the overall number of events per year for each. Thus, if one considers an overall incidence in the adult population of only 0.1% to 0.2% per year, when applied to the entire US population, that accounts for more than 300 000 events per year. In contrast, although ≈33% of patients in the convalescent phase after a large myocardial infarction experience sudden cardiac death in the year thereafter, overall they account for a small number of the total sudden cardiac deaths per year. The use of interventions that limit infarct size, such as thrombolytic agents, has reduced this number still further. These factors have an impact on the effects of therapeutic interventions because, although it is relatively easy to identify patients in the small high-risk subgroups and then to possibly prevent or reverse a ventricular tachyarrhythmia, the overall impact on the total number of sudden cardiac deaths will be small. It becomes obvious that, to significantly reduce the incidence of sudden cardiac death, more specific markers are needed for the general population to identify large numbers in subgroups that account for a bigger percentage of the more than 300 000 who die suddenly. The present risk factors (see below) generally identify the risk of developing the structural heart disease underlying sudden cardiac death rather than the proximate precipitator of the event. Because the risk of sudden cardiac death does not necessarily equate with the risk of developing structural heart disease, these risk factors have limited ability in identifying specific individuals at risk for sudden cardiac death. Nevertheless, their control, with concomitant reduction in death from coronary artery disease, is probably at least in part responsible for the reduction in overall sudden cardiac death. Figure 1B shows idealized curves of survival from sudden cardiac death for a population free of major cardiovascular events versus a population that has survived a major cardiovascular event. After an initial high attrition rate for the high-risk group in the first 6 to 18 months, the curves then become parallel, illustrating the modulating effects of time on the incidence of sudden cardiac death. Ultimately, risk stratification will be important only if it can be coupled with a therapeutic intervention that reduces the risk of dying.Risk Factors of Sudden Cardiac DeathInfluence of Age, Race, and SexBecause up to 80% of individuals who suffer sudden cardiac death have coronary heart disease, the epidemiology of sudden cardiac death to a great extent parallels that of coronary heart disease. As such, the incidence of sudden cardiac death increases with age in both men and women, whites and nonwhites, because the prevalence of ischemic heart disease increases with age (Figure 2). However, among patients with coronary heart disease, the proportion of coronary deaths that are sudden decreases with age. Sudden cardiac death has a much higher incidence in men than women, reflecting sex differences in the incidence of coronary heart disease as well. Thus, ≈75% of sudden cardiac deaths occur in men, with an annual incidence 3 to 4 times higher than in women. The peaks in incidence of sudden cardiac death occur between birth and 6 months of age because of the sudden infant death syndrome, and then again between 45 and 75 years of age as a result of coronary artery disease. Sudden cardiac death accounts for 19% of sudden deaths in children between 1 and 13 years of age and 30% between 14 and 21 years of age.5ActivityThe impact of physical activity on sudden cardiac death is somewhat controversial. Although vigorous exercise can trigger sudden cardiac death and acute myocardial infarction,6 in part possibly by increasing platelet adhesiveness and aggregability, moderate physical activity may be beneficial by decreasing platelet adhesiveness and aggregability.7 In cardiac rehabilitation programs, cardiac arrests occur at a rate of 1 in 12 000 to 15 000, and during stress testing, cardiac arrest occurs at a rate of 1 per 2000, at least 6 times greater than the general incidence of sudden cardiac death for patients known to have heart disease. Experimentally, it appears that regular exercise in dogs prevents ischemia-induced ventricular fibrillation and death by increasing vagal activity.8 Thus, it may be that regular exercise decreases cardiovascular morbidity and mortality, whereas vigorous exercise, particularly in untrained individuals, may have an adverse effect. The annual incidence of sudden cardiac death during exercise is 1 per 200 000 to 250 000 healthy young people,1 whereas in competitive athletes, sudden cardiac death is very rare, despite the publicity, with only 20 to 25 sports-related sudden cardiac deaths from cardiac causes annually in the United States.9 In young athletes (Figure 3), sudden cardiac death most often occurs from hypertrophic cardiomyopathy, and in older athletes, from coronary heart disease.10 Interestingly, in Europe, particularly in northern Italy, arrhythmogenic right ventricular dysplasia, possibly congenital, is the predominant anatomic finding in athletes with sudden cardiac death.11 Commotio cordis, that is, concussion of the heart from nonpenetrating blunt trauma to the anterior chest, can lead to fatal cardiac arrest, due to either myocardial trauma or the mechanoelectrical triggering of a ventricular tachyarrhythmia during the vulnerable period of the T wave.12 As with some other risk factors, the overall impact of activity on sudden cardiac death may be small. In the Maastricht Sudden Death study, 67% of the sudden death victims were physically inactive at the time of the event.3AnatomyAnatomic findings at autopsy include acute changes in coronary plaque morphology, such as thrombus, plaque disruption, or both, in >50% of cases of sudden coronary death, whereas in hearts with myocardial scars and no acute infarction, active coronary lesions are identified in 46% of cases. Erosion of proteoglycan-rich and smooth muscle cell–rich plaques lacking a superficial lipid core, or plaque rupture, is a frequent pathological finding.13 Plaque rupture appears to be more common in older women.14 Apoptosis may participate in the genesis and pathophysiology of some cardiac arrhythmias or conduction disturbances responsible for sudden cardiac death.15 However, these anatomic abnormalities are not represented by specific clinical risk factors different from those that identify patients with coronary heart disease in general. In addition, because mechanisms responsible for sudden cardiac death depend in part on anatomic substrate, which naturally varies from one individual to another, the usefulness of risk assessment modalities varies from one patient and particular type of anatomic substrate to another. Furthermore, in addition to interpatient variations, there may be intrapatient variation due to temporal changes in specific diseases (Figure 1).Other Risk FactorsAge, hypertension, left ventricular hypertrophy, intraventricular conduction block, elevated serum cholesterol, glucose intolerance, decreased vital capacity, smoking, relative weight, and heart rate identify individuals at risk for sudden cardiac death (Figure 4). Smoking is an important risk factor. In the Framingham study, the annual incidence of sudden cardiac deaths increased from 13 per 1000 in nonsmokers to almost 2.5 times that for people who smoked >20 cigarettes per day. Stopping smoking promptly reduced this risk, which may be mediated by an increase in platelet adhesiveness, release of catecholamines, and other mechanisms. Elevated serum cholesterol appears to predispose patients to rupture of vulnerable plaques, whereas cigarette smoking predisposes patients to acute thrombosis.16 Female survivors of cardiac arrest are less likely to have underlying coronary artery disease, even though coronary artery disease status is the most important predictor of cardiac arrest in women; impaired left ventricular function appears to be the most important predictor in men.17 In patients with severe heart failure, nonsustained ventricular tachycardia may be an independent marker of increased mortality due to sudden cardiac death.18 According to one study,19 sudden coronary deaths are less likely to occur at home than nonsudden coronary deaths, whereas individuals who die of sudden coronary death are more likely to have been current cigarette smokers. However, in the Maastricht study,3 80% of sudden cardiac deaths occurred at home. Emotional stress can be an important trigger for sudden cardiac death, as shown by the Northridge earthquake that struck the Los Angeles area at 4:31 am January 17, 1994.20 Depression in a patient in the hospital after myocardial infarction is a significant predictor of the 18-month post–myocardial infarction cardiac mortality, and the risk associated with depression was greatest among patients with frequent premature ventricular complexes. Socioeconomic factors are also important; sudden cardiac death after myocardial infarction increases 3-fold in men with low levels of education and complex ventricular ectopy compared with better educated men who have the same arrhythmias.History can provide clues to the high-risk patient. For example, in patients with ventricular tachycardia after myocardial infarction, on the basis of clinical history, the following 4 variables identify patients at increased risk of sudden cardiac death: (1) syncope at the time of the first documented episode of arrhythmia, (2) NYHA class III or IV, (3) ventricular tachycardia/fibrillation occurring early after myocardial infarction (3 days to 2 months), and (4) history of previous myocardial infarctions.21 In some patients, family history can be important.22Left ventricular dysfunction is a major independent predictor of total and sudden cardiac mortality in patients with ischemic and nonischemic cardiomyopathy.23 For example, in survivors of cardiac arrest who have a left ventricular ejection fraction <30%, the risk of sudden cardiac death exceeds 30% over 1 to 3 years if the patients do not have inducible ventricular tachycardia, whereas it ranges between 15% and 50% in those who have inducible ventricular tachyarrhythmias despite therapy with drugs that suppress the inducible arrhythmias or with empirical amiodarone.2425 Whether an ICD will reduce total mortality in patients with severe left ventricular dysfunction alone is the subject of several prospective trials, including the Multicenter Automatic Defibrillator Implantation Trial (MADIT II) and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).26 These patients have competing causes of death, and unless death is caused primarily by a ventricular tachyarrhythmia that can be terminated by prompt defibrillation, the ICD may not have an important impact. Although prompt defibrillation generally restores sinus rhythm with a very high success rate, it may not be as successful in patients with very advanced ventricular dysfunction.Certain ECG abnormalities can help identify patients at increased risk for sudden cardiac death. These include the presence of AV block or intraventricular conduction defects and QT prolongation, an increase in resting heart rate to >90 bpm, and increased QT dispersion in survivors of out-of-hospital cardiac arrest. A recent study failed to support the usefulness of QT dispersion in predicting risk in patients after myocardial infarction.27 The presence of complex ventricular arrhythmias, such as nonsustained ventricular tachycardia, is also a marker1 (Figure 5).Transient Risk FactorsUnfortunately, most of these more stable risk factors lack sufficient sensitivity, specificity, and predictive accuracy to pinpoint the patient at risk with a degree of accuracy that would permit using a specific therapeutic intervention before an actual event. This probably relates, at least in part, to the transient nature of many risk factors, such as myocardial ischemia and reperfusion; hemodynamic dysfunction; abnormalities in electrolytes, such as hypokalemia and hypomagnesemia, often due to diuretics; changes in pH or Po2; the influence of central and peripheral neurophysiological actions; and the transient effects of toxins such as drugs28 or alcohol.12 Structural cardiac abnormalities of the myocardium, coronary arteries, or cardiac nerves provide the substrate on which a transient risk factor operates. Although it is possible that intense functional changes alone may create electrical instability of the normal heart to the degree that a ventricular tachyarrhythmia can be provoked, the vast majority of cardiac arrests occur in patients with hearts that have structural abnormalities. One group that was identified before a cardiac arrest with sufficient accuracy to warrant ICD placement was the MADIT population,29 who were post myocardial infarction and had spontaneous nonsustained ventricular tachycardia, inducible sustained ventricular tachycardia not suppressed by intravenous procainamide, and an injection fraction <35%.As noted earlier, the most common structural abnormality is coronary atherosclerosis and its consequences, such as myocardial infarction. Interestingly, only ≈20% of patients who survive cardiac arrest develop features of a transmural myocardial infarction, and it is assumed that transient myocardial ischemia, perhaps caused by coronary spasm or unstable platelet thrombi,1330 plays an important role in precipitating a lethal ventricular tachyarrhythmia. Myocardial hypertrophy, congestive heart failure, and cardiac dilation,3132 as well as regional autonomic dysfunction,3334 all may be important. Although almost 50% of deaths in heart failure patients are sudden, among patients with cardiomyopathies, those with better-preserved functional capacity (NYHA functional classes I and II) have lower total death rates, but the fraction of all deaths that are sudden and unexpected is higher; among class IV patients, total death rates are higher, but the fraction of sudden deaths is lower; thus, the impact of reducing sudden cardiac death in this population will be influenced by competing causes of other mechanisms of death.12 Time of day is also important, with more sudden cardiac deaths, strokes, and myocardial infarctions occurring in the morning on arising from bed, perhaps related to increased sympathetic discharge in response to venous pooling that then triggers increased blood viscosity and platelet aggregation.35 The lack of association between the times of day in almost 600 patients who had at least 2 separate cardiac arrests supports the hypothesis that a person’s activity may also play a role in triggering the cardiac arrest.36Thus, if structural factors for the most part only create a substrate on which the transient factors operate to initiate a ventricular tachyarrhythmia, risk identification requires finding those subjects whose inherent physiological characteristics make the initiation of electrophysiological instability more likely when these conditions are met. This requires clinically identifiable, genetically based or acquired, individual differences in the responses of membrane channels, receptors, exchangers, and pumps in the susceptible individual,2 a formidable challenge at present. Patients with the congenital long-QT syndrome (see below) serve as the prototypic example of the interaction between a molecular myocardial abnormality, an “ionopathy,” and an inciting event, eg, exercise in LQT1 and sleep/rest in LQT3.37 Some patients may have a non–clinically manifest abnormality in repolarization, a latent form of long-QT syndrome, that becomes provoked only by exposure to certain drugs.37 Thus, molecular abnormalities in the long-QT syndrome, as well as in conditions such as hypertrophic cardiomyopathy,38 help provide genetic markers of patients at increased risk.An antiarrhythmic drug can create the abnormality on which a transient risk event, such as ischemia, interacts to provoke a lethal arrhythmia.39 For example, in the CAST experience, despite the increased risk of sudden cardiac death established by the presence of complex forms of ventricular ectopy, particularly in older age groups and in patients post myocardial infarction, suppression of those ventricular arrhythmias with encainide and flecainide conferred an increased risk of death and/or no improvement in survival with moricizine.40 Death among those treated with an antiarrhythmic drug may have resulted from an interaction between the substrate of coronary artery disease, the transient risk factor of acute myocardial ischemia, and the exacerbation of ischemia-induced conduction slowing produced by drugs with negative dromotropic actions, such as encainide or flecainide.41 The results of CAST taught us at least 3 important lessons: (1) that mechanisms responsible for premature ventricular complexes, which were suppressed, were different from mechanisms that caused sudden cardiac death, presumably from a ventricular tachyarrhythmia, which was increased; (2) that proarrhythmia from an antiarrhythmic agent could occur months after drug initiation and was not always an early event; and (3) that antiarrhythmic drugs could become a risk factor when the myocardial substrate changed, presumably when ischemia developed.Electrophysiological End PointsTwo tests that reflect autonomic actions on the sinus node can also be useful risk stratifiers. Baroreflex sensitivity, reflecting a vagal response to acute blood pressure elevation, is reduced in patients at risk of sudden cardiac death,42 and heart rate variability, a measure of beat-to-beat variations of sinus-initiated RR intervals, with its Fourier-derived parameters, is also blunted in these patients.43 It is important to stress that both of these parameters judge autonomic modulation at the sinus node, which is taken as a surrogate for autonomic actions at the ventricular level. Autonomic effects at the sinus node and ventricle can easily be dissociated experimentally44 and may possibly be a cause of false-positive or false-negative test results.According to chaos theory, apparently irregularly irregular events, such as ventricular ectopy, are nonrandomly distributed in time, and their clustering can be quantified by fractal geometric analysis, which may help identify patients at risk for sudden cardiac death.45 Late potentials, which are electrical activity in the microvolt range extending the duration of a filtered QRS complex and detected by signal-averaged ECG, has good negative predictive value but low positive predictive value in patients after myocardial infarction.1 More recently, late potentials were not found to be useful in identifying patients who might benefit from ICD implantation and who were undergoing coronary artery bypass surgery.46 T-wave alternans, that is, T-wave changes in alternate beats, can at times be visible in the scalar ECG and, when present, denote patients with an electrically unstable ventricle. Recently, T-wave alternans detectable only by computer averaging techniques has been used to identify patients at risk for subsequent ventricular arrhythmias.47 Finally, electrophysiological studies to induce sustained ventricular arrhythmias can be useful to help select appropriate therapy, including drug therapy, catheter ablation, surgery, or ICD implantation, and in identifying high-risk patients such as those suitable for treatment with an ICD.29Disease StatesCoronary Artery DiseaseAs indicated earlier, at least 80% of patients who experience sudden cardiac death have coronary artery disease as the underlying anatomic substrate due to atherosclerotic changes of the coronary arteries. Nonatherosclerotic coronary artery abnormalities are important in only a very small number of sudden cardiac deaths and include problems such as coronary arteritis, embolism, dissection, and congenital malformations of anomalous origin of a left coronary artery from the pulmonary artery or of a left coronary artery from the right or noncoronary aortic sinus of Valsalva, passing between the aortic and pulmonary artery roots.12In survivors of cardiac arrest, coronary heart disease with vessels exhibiting more than 75% cross-sectional stenosis are found in ≈40% to 86% of patients, depending on age and sex of the population studied. Although <50% of the patients resuscitated from ventricular fibrillation evolve evidence of myocardial infarction by elevated cardiac enzymes and <25% have Q-wave myocardial infarction, autopsy studies have reported that a recent occlusive coronary thrombus was found in 15% to 64% of victims of sudden cardiac death, caused by ischemic heart disease, with many hearts showing plaque fissuring, hemorrhage, and thrombosis.48 There appears to be no specific pattern of distribution of coronary artery lesions that favors the development of sudden cardiac death. Abrupt changes in regional myocardial blood flow due to alterations in coronary artery structure and/or function, such as spasm, platelet thrombi, dissection, plaque rupture, or other vasoactive events can provoke acute ischemia.1330 Transition of stable atherosclerotic plaques by fissuring that leads to platelet activation and aggregation followed by thrombosis formation, as well as other biochemical events that can have a direct effect on electrophysiological properties of the heart, may be important in provoking ventricular arrhythmias.1330 Healed infarctions are present in ≥50% of hearts of sudden cardiac death victims at autopsy and in those of survivors of cardiac arrest. Interestingly, chronic ischemia may exert a protective effect by causing the development of coronary collaterals that can help mitigate the extent of ischemia produced by sudden coronary occlusion. Therefore, an acute occlusion of a minimally stenosed coronary artery can result in a more disastrous outcome than occlusion of a severely stenosed coronary artery with the jeopardized myocardium protected by collaterals.CardiomyopathyCardiomyopathies represent the second largest group of patients who experience sudden cardiac death. Hypertrophic cardiomyopathy has a prevalence of ≈2 in 1000 young adults and an incidence of sudden cardiac death of 2% to 4% per year in adults and 4% to 6% per year in children and adolescents49 (Figure 3). In patients with hypertrophic cardiomyopathy, a history of sudden cardiac death or sustained ventricular tachycardia, family history of sudden cardiac death, a diverse genotype, recurrent syncope, multiple episodes of nonsustained ventricular tachycardia, and massive left ventricular hypertrophy are the strongest risk factors for sudden cardiac death.3849 Multiple mechanisms may be responsible, including arrhythmias, abrupt hemodynamic deterioration, and/or ischemia. Hemodynamic and echocardiographic variables are generally not useful in identifying patients at high risk for sudden cardiac death, and the results of ambulatory ECG monitoring and invasive electrophysiological study are controversial.49 The presence of mutations in the α-tropomyosin as well as in the β-myosin heavy chain gene has been associated with sudden cardiac death.3849Idiopathic dilated cardiomyopathy is a substrate for ≈10% of sudden cardiac deaths in the adult population. Mortality in patients with idiopathic dilated cardiomyopathy ranges from 10% to 50% annually, depending on the severity of the disease. In a compilation of 14 studies including 1432 patients, mean mortality rate after a follow-up of 4 years was 42%, with 28% of deaths classified as sudden.50 The presence of nonsustained ventricular tachycardia in this group identifies a population at high risk of sudden death, presumably on the basis of a ventricular tachyarrhythmia.18 Bundle-branch reentry can be an important cause of ventricular tachycardia in patients with dilated cardiomyopathy.51 The terminal event can also be asystole or electromechanical dissociation, particularly in patients with advanced left ventricular dysfunction.23 Multiple triggering events in heart failure patients include myocardial stretch, neuroendocrine factors, electrolyte abnormalities, proarrhythmic effects of antiarrhythmic drugs, and excessive activation of the sympathetic and renin-angiotensin systems.31 Syncope in heart failure patients appears to be an important clinical variable that also identifies patients with a higher risk of sudden cardiac death.50Arrhythmogenic right ventricular dysplasia is a particular kind of cardiomyopathy responsible for sudden death in young individuals and adults, with a gene defect recently localized to chromosomes 1 and 14 q23-q24.1152 It occurs as a familial disorder in ≈30% of cases, with autosomal dominant inheritance. Exercise can precipitate ventricular tachycardia in these patients, with an annual incidence of sudden death estimated to be ≈2%. Two pathological patterns, fatty and fibrofatty myocardial infiltration, have been identified. In the fibrofatty variety, myocardial atrophy appears to be the consequence of acquired injury and myocyte death and repair by fibrofatty replacement, mediated by patchy myocarditis. Apoptosis may be important. The left ventricle and ventricular septum can be involved in 50% to 67% of cases, often later in the disease, confirming a poor prognosis.52 ECG during sinus rhythm often exhibits T-wave inversion in V1 to V3 or complete or incomplete right bundle-branch block, and the ventricular tachycardia has a left bundle-branch block contour, with the frontal-plane axis reflecting the site of origin in 1 of 3 predilection sites for ventricular fatty degeneration: right ventricular inflow and outflow tracts and apex, the so-called “triangle of dysplasia.” During sinus rhythm, intraventricular conduction may be sufficiently slow as to produce a terminal notch on the QRS complex that Fontaine called an epsilon wave (Figure 6).Left Ventricular HypertrophyLeft ventricular hypertrophy, whether established by ECG or by cardiac echo, is a strong independent risk factor for cardiovascular deaths and, in particular, sudden cardiac death in patients who also had a history of hypertension. Multiple disease states can result in hypertrophy, including valvular heart disease, obstructive and nonobstructive hypertrophic cardiomyopathy, primary pulmonary hypertension with right ventricular hypertrophy, and various congenital heart disorders. Although ventricular repolarization (QT interval) is prolonged in hypertensive