Kenneth M. Kessler

Sudden Cardiac Death: Epidemiology, Transient Risk, and Intervention Assessment

Despite recent progress in the management of cardiovascular disorders generally, and cardiac arrhythmias in particular, sudden cardiac death remains both a problem for the practicing clinician and a major public health issue [1-3]. Although the absolute number of sudden cardiac deaths has decreased in parallel with a reduction in overall cardiovascular mortality [1, 2], the proportion of all cardiovascular deaths that are sudden and unexpected remains constant at approximately 50% [2-4]. Information about the causes and mechanisms of the sudden cardiac death syndrome suggests that a specific reduction will require the development of new and multifaceted approaches. We have integrated data from several disciplines to generate a broad view of three components of this problem. These include the clinical epidemiology of sudden cardiac death and its application to preventive medicine; identification and control of transient risk factors that have proximate responsibility for the initiation of fatal arrhythmias; and analysis of therapeutic outcome data by means that provide appropriate interpretations of the potential benefits of interventions. Sources of data exist that address each of these issues, and we merged these disparate sets of data and concepts into a statement on current perspectives of and future approaches to the problem of sudden cardiac death. Applied Clinical Epidemiology Epidemiologic information that is clinically applicable to the problem of sudden cardiac death extends beyond the collection and analysis of mortality data across various demographic subgroups. The problem is dynamic and so is its epidemiology. Three areas of particular importance include the relation between absolute numbers of events and incidence of sudden cardiac death within defined population pools; the time dependence of risk; and the efficiency of therapeutic interventions. Risk in Population Subgroups When sudden cardiac death is measured as the absolute number of events per year in a defined population, it becomes clear that the highest-risk subgroups commonly cited in clinical studies (for instance, patients with low ejection fractions, patients with a history of heart failure, and survivors of out-of-hospital cardiac arrest) do not account for the majority of the events. This statement does not mean that commonly held perceptions about high-risk patients are wrong but rather that the predictive power of these high-risk characteristics applies only to small subgroups. The greater part of the risk for sudden cardiac death is hidden within the larger, more general population pools. These populations have smaller excesses in incidence but generate more events because of the larger size of the population bases from which they emerge. In Figure 1, the magnitude of the risk, expressed as incidence, is compared with the total number of events per year under six different conditions. The estimates are based on published epidemiologic and clinical data [4, 5]. When the more than 300 000 sudden cardiac deaths that occur annually among the unselected adult population in the United States [2, 3] are expressed as a fraction of the total adult population, the overall incidence is 0.1% to 0.2% per year. This calculation includes the 20% to 25% of sudden cardiac death victims whose cardiac arrest is the first clinical manifestation of previously silent or unrecognized heart disease [6-8] plus those with various degrees of increased risk identified by established clinical characteristics or risk factor profiles. When the more easily recognized, very-high-risk subgroups are removed from this population base, the calculated incidence for the remaining patients decreases, further amplifying the problem of identifying specific persons at risk among the general population. On the basis of these estimates, a preventive intervention designed for the general adult population must be applied to the 999 of 1000 people who will not have an event in order to reach and potentially influence the unidentified 1 of 1000 who will. Such limited efficiency impedes application of many active interventions and highlights the need for identifying specific markers of major increases in risk, even among groups with identified risk factors, in order to achieve more effective preventive efforts. Although escalation from a subgroup with several coronary risk factors in the absence of previous clinical events (risk, 1% to 2%/y) to higher-risk subgroups provides the ability to identify high-risk persons with progressively increasing power (Figure 1), the absolute number of persons who can be identified decreases with each escalation of risk. Thus, the challenge is not to focus more attention on the highest-risk clinical subgroups that are already clearly profiled but rather to develop new methods that will allow the identification of high-risk clusters within larger subgroups that have lesser degrees of increased risk. The first step toward this goal requires knowledge of the total number of sudden cardiac deaths within a specified population, the fraction of deaths that are sudden within that population, and the total mortality. For example, Kjekshus [9] analyzed a group of studies of heart-failure-related deaths, contrasting the probability of death and the ratio of sudden to total deaths as they relate to functional classification. In studies in which the mean functional class was between class I and class II, the overall death rate was relatively low, but 67% of the deaths were sudden [9]. In contrast, among studies with mean functional classifications close to class IV, the overall death rate was high, but the fraction of sudden deaths was only 29%. In the former circumstance, a therapeutic intervention targeted to all-cause mortality would be less efficient (that is, only a small fraction of the total population exposed to the intervention would have the potential to benefit from it), whereas, for the latter, efficiency would be high. For an intervention specific to the problem of sudden cardiac death, however, efficiency in the former case would be relatively high (67% of all deaths are sudden), whereas for the latter, efficiency for sudden cardiac death would be low because of the dominance of nonsudden deaths. Figure 1. Sudden cardiac deaths among population subgroups. Time Dependence of Risk The risk for death after surviving a major change in cardiovascular status is not linear over time for most conditions [5]. Survival curves for both sudden and total cardiac deaths show that the most rapid rate of attrition occurs during the first 6 to 18 months after an index event. By 24 months, the slope of the survival curve begins to approach the configuration of one describing a similar population that has remained free of the interposed major cardiovascular event (Figure 2). Further, the shapes of the curves are likely to be influenced by the magnitude of the increased risk after the index cardiovascular event. For instance, data from the Cardiac Arrhythmia Suppression Trial (CAST) [10, 11] show a linear attrition among the relatively low-risk, randomized placebo group during long-term follow-up of these patients with myocardial infarctions complicated by postinfarction arrhythmias but having relatively good mean ejection fractions. Data from the Multicenter Post-Infarction Program [12, 13], however, showed that subgrouping patients according to interactions between frequency of premature ventricular complexes (PVCs) and ejection fractions after they have survived acute myocardial infarction resulted in progressively increasing risk as the number and cumulative power of risk factors increased. The low-risk subgroups generated linear survival curves, whereas the added mortality in higher-risk subgroups tended to be expressed early (Figure 2). The time dependence of risk within the higher-risk groups limits the opportunity for effective intervention strategies to the early periods after the conditioning cardiovascular event. Curves showing these characteristics have been generated from among survivors of out-of-hospital cardiac arrest [14] Figure 2, from patients with new-onset heart failure, and from patients who have had high-risk markers after myocardial infarction [12, 15]. This property of risk must be integrated into strategies designed to intervene in such patients. Controlled intervention trials that allow enrollment of patients more than 12 to 18 months after the cardiovascular event to which the study is indexed might be confounded by a lower-than-anticipated event rate if such entrants are heavily represented in the study group. When the temporal property of risk is applied to individual patients, moreover, the probability of benefit from a secondary preventive intervention is also a function of time of implementation. Figure 2. Time-dependence of risk after cardiovascular events. Top. Middle. Bottom. Identification and Control of Transient Risk Factors The PVC hypothesis assumes that PVCs serve as triggers for the initiation of ventricular tachycardia or fibrillation (VT/VF) and that suppression of PVCs protects against sudden cardiac death by eliminating this triggering function. This concept gained popularity from early observations in coronary care units among patients with acute ischemic events [16, 17], and the view of PVCs as primary triggering events for fatal arrhythmias expanded and became ingrained into clinical dogma. However, the clinical application of the PVC hypothesis remained uncertain in clinical settings of chronic risk. Despite the existence of consistent data supporting chronic PVCs as a risk factor in long-term studies [12, 18-21], special circumstances are required to show the initiation of spontaneous life-threatening clinical arrhythmias by PVCs. Incidental ambulatory recordings have shown that the spontaneous onset of ventricular fibrillation may be preceded by a tendency toward increases in sinus rate and PVC frequency [22-2

Life-threatening ventricular arrhythmias in patients with silent myocardial ischemia due to coronary-artery spasm.

BACKGROUND Silent myocardial ischemia in patients with coronary atherosclerosis is associated with an increased risk of adverse cardiac events, including sudden death. The relation between silent ischemia and the initiation of potentially fatal ventricular arrhythmias has not been defined, however. METHODS As part of a long-term study of sudden cardiac death, data on arrhythmias, coronary anatomy, and responses to ergonovine testing to provoke coronary-artery spasm were collected prospectively among survivors of out-of-hospital cardiac arrest who had no flow-limiting coronary-artery lesions, prior myocardial infarctions, or other structural causes of cardiac arrest and no angina pectoris. Associations between silent myocardial ischemia due to coronary-artery spasm and the occurrence and characteristics of life-threatening ventricular arrhythmias were studied by both invasive and noninvasive techniques. RESULTS Silent ischemic events were associated with the initiation of life-threatening ventricular arrhythmias in five patients with induced or spontaneous focal coronary-artery spasm (or both). These patients were identified among a group of 356 survivors of out-of-hospital cardiac arrest who were evaluated between 1980 and 1991. In two of the five patients reperfusion, rather than ischemia itself, correlated with the onset of the ventricular arrhythmia. Only one of the five had an inducible arrhythmia during electrophysiologic testing. Titration of the dose of a calcium-entry-blocking agent (verapamil, diltiazem, or nifedipine) against the ability of ergonovine to provoke spasm was successful in preventing both the provocation of spasm and arrhythmias in all four patients who were tested. CONCLUSIONS Silent myocardial ischemia due to coronary-artery spasm can initiate potentially fatal arrhythmias in patients without flow-limiting structural coronary-artery lesions. The role of silent ischemia, reperfusion, or both in the initiation of fatal arrhythmias in larger groups of patients with advanced coronary-artery lesions remains to be defined.

Reproducibility and circadian rhythm of heart rate variability in healthy subjects

Low heart rate (HR) variability, expressed as the standard deviation of cardiac cycle lengths, has been shown to be associated with increased mortality in patients with coronary artery disease.1,2 HR variability can be easily measured from 24-hour electrocardiographic recordings using recently developed software.1,2 However, reference values for HR variability and their reproducibility in normal persons are not well studied. We estimated the reproducibility and circadian rhythm of HR variability, measured from repeated 24-hour electrocardiographic recordings, in young healthy adults to establish normal values and determine patterns of reproducibility.

Congestive heart failure: Echocardiographic insights

This study was designed to assess the role of echocardiography in the evaluation and management of patients with the congestive heart failure syndrome. Fifty consecutive patients with congestive heart failure referred for echocardiography were evaluated. Thirty patients (60 percent) had ejection fractions under 50 percent (mean +/- SD 30 +/- 9 percent), left ventricular dilatation (6.5 +/- 0.7 cm), and normal wall thicknesses (1.0 +/- 0.2 cm). The echocardiographic findings were predictable on clinical grounds in 18 of the 30 patients (60 percent) and worse than clinically expected in 12 patients (40 percent). Management changes after echocardiography were indicated in 11 of 30 patients (37 percent). The remaining 20 of the 50-patient cohort (40 percent) had ejection fractions above 50 percent (mean 70 +/- 9 percent, p less than 0.01), and, as a group, were characterized by normal left ventricular size (5.1 +/- 0.8 cm, p less than 0.01) and borderline wall thicknesses (1.1 +/- 0.2 cm, p less than 0.01). The largest subgroup of these 20 patients had hypertensive heart disease (seven patients, 35 percent) associated with the congestive heart failure syndrome presumably related to left ventricular diastolic (compliance) dysfunction. The normal ejection fraction was unexpected clinically in 18 of these 20 patients (90 percent). Recommended management after echocardiography changed in all 18 patients. Since standard clinical findings (history, physical examination, and chest roentgenography) failed to separate patients with normal and abnormal ejection fractions, or those in need of changes in management, echocardiography was a useful and, at times, essential part of the evaluation of these patients with the congestive heart failure syndrome.

Circadian rhythm of heart rate variability in survivors of cardiac arrest

Reduced heart rate (HR) variability is associated with increased risk of cardiac arrest in patients with coronary artery disease. In this study, the power spectral components of HR variability and their circadian pattern in 22 survivors of out-of-hospital cardiac arrest not associated with acute myocardial infarction were compared with those of 22 control patients matched with respect to age, sex, previous myocardial infarction, ejection fraction and number of diseased coronary arteries. Survivors of cardiac arrest had significantly lower 24-hour average standard deviation of RR intervals than control patients (29 +/- 10 vs 51 +/- 15 ms, p less than 0.001), and the 24-hour mean high frequency spectral area was also lower in survivors of cardiac arrest than in control patients (13 +/- 7 ms2 x 10 vs 28 +/- 14 ms2 x 10, p less than 0.01). In a single cosinor analysis, a significant circadian rhythm of HR variability was observed in both groups with the acrophase of standard deviation of RR intervals and high-frequency spectral area occurring between 3 and 6 A.M. which was followed by an abrupt decrease in HR variability after arousal. The amplitude of the circadian rhythm of HR variability did not differ between the groups. Thus, HR variability is reduced in survivors of cardiac arrest but its circadian rhythm is maintained so that a very low HR variability is observed in the morning after awakening, corresponding to the time period at which the incidence of sudden cardiac death is highest.

Quinidine Elimination in Patients with Congestive Heart Failure or Poor Renal Function

Abstract Plasma quinidine half-life values, determined by a relatively specific double extraction method in eight patients with poor renal function, eight with congestive heart failure, and nine controls were similar for all groups. When quinidine was measured by a nonspecific fluorescent method, the half-life values calculated for the uremic patients were longer than those for the controls. The nonspecific method does not differentiate slow biotransformation of quinidine from normal biotransformation but slow excretion of metabolites. Steady-state plasma quinidine concentrations were measured in 14 patients treated for arrhythmias and 12 with congestive heart failure. Therapeutic effectiveness was associated with concentrations of 2.3 to 5.0 μg per milliliter and ineffectiveness with lower levels or complicating illnesses. The relation of dose to steady-state blood level was similar for the two groups. Quinidine elimination appears to be grossly normal in patients with congestive heart failure or poor re...

Long-term survival after prehospital cardiac arrest: Analysis of outcome during an 8 year study

We analyzed long-term follow-up data accumulated during an 8 year study of survivors of prehospital cardiac arrest. All patients included in this study were primary entrants via community-based rescue systems; patients who were tertiary referrals (survivors of cardiac arrest from other hospitals) were not included in this analysis. In the group of 61 patients entering our study between 1975 and 1980, with a follow-up to 1983, there have been a total of 24 deaths (39%). Sixteen of the 24 deaths were the result of recurrent cardiac arrest; eight were nonsudden cardiac deaths or noncardiac deaths. The mean duration from entry to death in the nonsurvivors was 27.5 +/- 19.7 months, and the time from the index event to last follow-up in the long-term survivors was 59.9 +/- 19.4 months. Life table analysis demonstrated a 10% rate of recurrence of cardiac arrest in the first year, with a 5% per year rate in each of the subsequent 3 years. Left ventricular ejection fractions at entry were not significantly different between survivors (mean = 45.3 +/- 13.6%) and nonsurvivors (mean = 37.6 +/- 12.6%), and the severity of ejection fraction abnormality at entry did not correlate with time to death in the nonsurvivors. However, ejection fraction was significantly lower in patients who died from causes other than recurrent cardiac arrest than in those who died of cardiac arrest (24.5 +/- 9.1% vs 42.7 +/- 9.2%; p less than .002).(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in heart rate variability and its circadian rhythm in hypertensive patients with left ventricular hypertrophy free of coronary artery disease

Heart rate variability (HRV) and its circadian rhythm were evaluated in 22 patients with treated hypertension and left ventricular hypertrophy in whom coronary artery disease was excluded by stress thallium or angiography. By using 24-hour Holter monitoring, HRV and its spectral components were measured. Findings were compared with 11 age-matched normal controls. The difference between mean R-R intervals during sleep (11 PM to 7 AM) and while awake (9 AM to 9 PM) (73 +/- 33 vs 263 +/- 63 msec, p < 0.0001) and the mean 24-hour SD of the R-R intervals (55 +/- 6.3 vs 93 +/- 11, p < 0.0001) were lower among the hypertensive patients compared with controls. The percentage of difference between successive R-R intervals that exceeded 50 msec, a measure of parasympathetic tone, was also lower among the hypertensive patients (6.8 +/- 7.1 vs 13.6 +/- 8.9, p < 0.002); it increased at night and decreased during the day among the controls, and this circadian rhythm was blunted among the patients. Spectral analysis showed that power in the high-frequency range (0.15 to 0.40 Hz) was lower among the hypertensive patients during 21 of 24 hours but that the difference was statistically significant only during 9 hours (p ranging from < 0.05 to 0.009). Power in the low-frequency range (0.04 to 015 Hz) was lower at night, increased in the morning, and higher during the day among controls; this circadian rhythm was absent among hypertensive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A biological approach to sudden cardiac death: Structure, function and cause

S udden cardiac death (SCD) remains a major clinical problem and complex pathophysiologic mystery, despite major advances in experimental and clinical electrophysiology during the past 20 years. The subject has been of interest to clinicians, epidemiologists, physiologists and pathologists for many years, and information derived from each of these disciplines has enlightened understanding and focused clinical approaches. As more data accumulate, it has become increasingly clear that the SCD syndome is best understood in terms of a biologic model, with elements derived from both structural pathology and functional pathophysiology.

Cardiovascular findings in quadriplegic and paraplegic patients and in normal subjects

Abstract Seven normal, 7 paraplegic and 7 quadriplegic patients underwent cross-sectional cardiovascular evaluation, including recording of sitting heart rate, blood pressure and echocardiography. Quadriplegic patients had a 26% lower left ventricular (LV) mass index (75 ± 13 g/m 2 , p 2 ) or paraplegic patients (110 ± 26 g/m 2 ). Six quadriplegic patients and 3 paraplegic patients had an unusual pattern of LV posterior wall asynergy, which was associated with a significant rightward shift of the frontal-plane QRS axis (92 ± 22 ° vs 42 ± 41 °, p