Risk Of Arrhythmic Death Research Articles

The Cardiac Arrhythmia Suppression Trial

The Cardiac Arrhythmia Suppression Trial (CAST) was instituted in 1986 by the National Heart, Lung, and Blood Institute (NHLBI) after the completion of a 502-patient pilot study (CAPS).1 2 3 The initial results of CAST I was published in 1989 and the CAST II results published in 1992.2 3 In both trials, antiarrhythmic drugs effectively suppressed asymptomatic ventricular arrhythmias but increased arrhythmic death. Because the suppression hypothesis was refuted, the common practice of using antiarrhythmic drugs to suppress asymptomatic arrhythmias in patients after acute myocardial infarction has been curtailed. In CAST I, encainide and flecainide-treated patients had a 3.6-fold excessive risk of arrhythmic death compared with placebo-treated patients. The CAST results have been extrapolated to include other antiarrhythmic drugs, resulting in a concern of lethal proarrhythmia when using all antiarrhythmic drugs. Consequently, there have been substantial changes in the labeling of antiarrhythmic drugs and significant changes in the regulatory guidelines from the Food and Drug Administration.4 There has also been a dramatic restructuring of antiarrhythmic drug development by the pharmaceutical industry. At least a decade before the initiation of CAST, it was recognized that myocardial infarction patients with frequent and complex ventricular premature depolarizations (VPDs) detected on ambulatory ECG monitoring had an increased risk of subsequent arrhythmic death as compared with patients without these arrhythmias.5 6 7 8 Like most noninvasive markers of increased risk, VPDs lack specificity (3% to 6% arrhythmic death rate in 1 year), meaning that most post–myocardial infarction patients with asymptomatic VPDs survive.9 Thus, for each 100 patients exposed to empiric antiarrhythmic therapy, only a few (3 to 6 in 100) can benefit (that is, prevention of arrhythmic death), while, unfortunately, all are at risk for potential lethal proarrhythmia from the antiarrhythmic drug. In the design of CAST, only patients whose …

New insights into the definition and meaning of proarrhythmia during initiation of antiarrhythmic drug therapy from the cardiac arrhythmia suppression trial and its pilot study

Objectives. This study was undertaken to determine the characteristics of worsening ventricular arrhythmia during antiarrhythmic drug titration.Background. Proarrhythmia is an evolving concept in cardiology. Its definition, incidence and clinical significance in various patient settings require refinement.Methods. The Impact of early proarrhythmia was analyzed in 3,840 patients in the Cardiac Arrhythmia Suppression Trial (CAST).Results. Drug therapy did not affect the incidence of new, sustained but nonfatal ventricular tachycardia (placebo 0.5%, active drug 0.4%). Nevertheless, there was a threefold increase in arrhythmic death (placebo 0.5% vs. active drug 1.6%). The incidence of increased ventricular premature depolarizations was equivalent (3% to 5%) for the three study drugs and indistinguishable from that seen with placebo. Patients with increased ventricular premature depolarizations on the first drag tested had fewer at baseline (65 ± 94 vs. 137 ± 260 per hour; mean ± SD) (p < 0.01). When increased ventricular premature depolarizations occurred with the first drug, they were much more likely also to be present with the second drag (for example, 42% vs. 5%, p < 0.001). Increased ventricular premature depolarizations during initiation of therapy independently predicted increased risk of subsequent arrhythmic death (independent relative risk 2.34, p = 0.0053) in the absence of continued antiarrhythmic drag therapy.Conclusions. The overall incidence of early worsening of arrhythmia in the present study was low. In the absence of placebo control, the incidence of proarrhythmia win be overestimated. Increased ventricular premature depolarizations had characteristics that suggest they often represent spontaneous variability rather than proarrhythmia. The main finding is that markedly increased ventricular premature depolarization during drug titration predict long-term increased risk of arrhythmic death in this patient population despite absence of long-term antiarrhythmic drug therapy.

Pharmacological therapy in coronary heart disease: prevention of life-threatening ventricular tachyarrhythmias and sudden cardiac death.

Life-threatening ventricular tachyarrhythmias are the main reason for sudden cardiac death in coronary heart disease. In the majority of survivors of cardiac arrest, malignant tachyarrhythmias generate from a structurally fixed arrhythmogenic substrate following myocardial infarction without evidence of acute ischaemia. Thrombolysis in acute myocardial infarction improves the electrical stability as elucidated by electrophysiological studies and the signal averaged surface ECG. In post-infarction patients, beta-blockers provide significantly beneficial effects on arrhythmic outcome, particularly in the presence of impaired left ventricular function, whereas calcium antagonists and vasodilators are of no affect or may worsen the prognosis. In survivors of myocardial infarction, the prophylactic use of class I antiarrhythmic agents, which are able to suppress frequent single or complex premature ventricular contractions, cause worsening of the prognosis due to their proarrhythmic properties. However, arrhythmia suppression by antiarrhythmic agents selects patients who are at very low risk for arrhythmic death. Pilot trials using class III antiarrhythmic agents suggest beneficial effect on the reduction of sudden death mortality. As regards secondary prevention of malignant tachyarrhythmias in survivors of ventricular tachycardia or fibrillation, there is controversy about the importance of Holter monitoring or invasive electrophysiological testing in the evaluation of drug efficacy. In patients with severely impaired left ventricular function, pharmacological treatment is of limited efficacy. Even in cases of significant suppression of spontaneous or inducible tachyarrhythmias documented by Holter recording or programmed ventricular stimulation, the arrhythmic outcome is considerably poorer, but it could be influenced by implantable defibrillators. Amiodarone, as a potential alternative to class I antiarrhythmic agents, particularly in patients refractory to conventional antiarrhythmic drugs, shows only limited effects on long-term outcome, which is in part caused by the toxicity of this agent. There is substantial need for new drugs without proarrhythmic properties and particularly for those that correct abnormalities of the automatic nervous system.

Frequency domain measures of heart rate variability before the onset of nonsustained and sustained ventricular tachycardia in patients with coronary artery disease.

Low heart rate variability (HRV) is associated with an increased risk of arrhythmic death and ventricular tachycardia (VT). The purpose of this study was to examine whether there is a temporal relation between changes in HRV and the onset of spontaneous episodes of VT in patients at high risk of life-threatening arrhythmias. Components of HRV in the frequency domain were analyzed before the onset of 28 episodes of nonsustained VT (more than four impulses; duration < 30 seconds) and 12 episodes of sustained VT (> 30 seconds or requiring defibrillation) in 18 patients with coronary artery disease. Seven patients had survived cardiac arrest not associated with acute myocardial infarction, and 11 had a history of sustained VT. All frequency domain measures of HRV, i.e., total power (p < 0.001), high-frequency power (p < 0.05), low-frequency power (p < 0.01), very-low-frequency power (p < 0.01), and ultralow-frequency power (p < 0.05), were significantly lower before the onset of sustained VT than before nonsustained VT. Total power of HRV was also lower during the 1-hour period before the onset of sustained VT than the average 24-hour HRV (p < 0.05). An indirect correlation existed between the length of VT and the total power of HRV analyzed during the 15 minutes before the onset of VT (r = 0.54, p < 0.01). HRV had a trend toward increasing values before the onset of nonsustained VT (p < 0.01) but not before the sustained VT episodes. The ratio between low-frequency and high-frequency powers increased substantially before both nonsustained and sustained VT episodes (p = 0.06 and p = 0.05, respectively). The rate of VT or the coupling interval initiating the VT did not differ significantly between the nonsustained and sustained VT. Spontaneous episodes of VT are preceded by changes in HRV in the frequency domain. Divergent dynamics of HRV before the onset of nonsustained and sustained VT episodes may reflect differences in factors that can facilitate the perpetuation of these arrhythmias.

Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation

Background and Objectives.The relation between cardiac mortality and antiarrhythmic drug administration has not been fully determined. This relation was analyzed in 1,330 patients enrolled in the Stroke Prevention in Atrial Fibrillation Study, a randomized clinical trial comparing warfarin, aspirin and placebo for the prevention of ischemic stroke or systemic embolism in patients with nonvalvular atrial fibrillation.Methods.Patients who received antiarrhythmic drug therapy for atrial fibrillation in this study were compared with patients not receiving antiarrhythmic agents. The relative risk of cardiac mortality, including arrhythmic death, in patients receiving antiarrhythmic drug therapy was determined and adjusted for other cardiac risk factors.Results.In patients receiving antiarrhythmic drug therapy, cardiac mortality was increased 2.5-fold (p = 0.006, 95% confidence interval [CI] 1.3 to 4.9) and arrhythmic death was increased 2.6-fold (p = 0.02, 95% CI 1.2 to 5.6). Among patients with a history of congestive heart failure, Shose given antiarrhythmic medications had a relative risk of cardiac death of 4.7 (p < 9.001, 95% CI 1.9 to 11.6) compared with that of patients not so treated; the relative risk of arrhythmic death in the treated group was 3.7 (p = 0.01, 95% CI 1.3 to 10.4). Patients without a history of congestive heart failure had no increased risk of cardiac mortality (relative risk 0.70, 95% CI 0.2 to 3.1) during antiarrhythmic drug therapy.After exclusion of 23 patients with documented ventricular arrhythmias and adjustment for other variables predictive of cardiac death, patients receiving antiarrhythmic drugs were not at increased risk of cardiac death or arrhythmic death. However, in patients with a history of heart failure who received antiarrhythmic drug therapy, the relative risk of cardiac death was 3.3 (p = 0.05, 95% CI 0.99 to 11.1) and that of arrhythmic death was 5.8 (p = 0.009, 95% CI 1.5 to 21.7) compared with the risk in patients not taking antiarrhythmic medications.Conclusions.Although antiarrhythmic drug therapy was not randomly determined in this trial, the data suggest that in patients with artrial fibrillation and a history of congestive heart failure, the risk of such therapy may outweigh the potential benefit of maintaining sinus rhythm.

Early and late proarrhythmia from antiarrhythmic drug therapy.

Antiarrhythmic drug therapy is used with the hope of suppressing arrhythmias and therefore decreasing their associated symptoms or prolonging life. Unfortunately, many antiarrhythmic drugs have the opposite effect of exacerbating or provoking arrhythmias, a phenomenon that is termed proarrhythmia when such an event is specifically due to the drug in use. Early proarrhythmic events (within 30 days of initiation of drug use) have been reasonably well characterized and are predicted by either type of drug employed or the nature of the patient's cardiac disease and arrhythmia type. Late proarrhythmic events, as defined by placebo-controlled trials, have now been recognized as an increased risk of arrhythmic death in patients on antiarrhythmic drugs after many months of therapy. Initially, this late proarrhythmic event was identified with encainide and flecainide, but now several new studies have demonstrated that the risk of late proarrhythmia of comparable magnitude may be present in patients subjected to commonly used drugs, such as quinidine, mexelitine, etc. At present, only moricizine and the class II drugs (beta-adrenergic blockers) appear not to have this potential late proarrhythmic response. Therefore, before instituting antiarrhythmic drug therapy, the physician must be able to quantitate the degree of proarrhythmia and other risks of such therapy, as compared to their potential benefit, to define the proper indications for these agents.

Events in the cardiac arrhythmia suppression trial: Baseline predictors of mortality in placebo-treated patients

Patients randomized to placebo in the encainide and flecainide arms of the Cardiac Arrhythmia Suppression Trial (CAST) have been found to have a relatively low 1-year mortality rate of 3.9% in comparison with previous studies of patients in the postmyocardial infarction period. To determine the comparability of CAST with previous studies, baseline variables were examined in the 743 patients randomized to placebo in the flecainide and encainide arms of CAST. Twenty-three baseline characteristics were correlated with major outcome events: arrhythmic death (16 events), total mortality (26 events) and congestive heart failure (51 events).On multivariate analysis the risk of new or worsening congestive heart failure was significantly associated with diuretic use, diabetes, high New York Heart Association functional class, age, prolonged QRS duration and low ejection fraction. The risk of arrhythmic death or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, history of heart failure, use of digitalis, diabetes and prolonged QRS duration. Total mortality or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, diabetes, ST segment depression, high functional class, prolonged QRS duration and low ejection fraction.The variables at baseline associated with mortality from all causes or arrhythmic death or resuscitated cardiac arrest and heart failure in the CAST placebo-treated patients are similar to those identified in previous postmyocardial infarction studies. Thus, the observation of increased mortality in CAST associated with the administration of encainide and flecainide for suppression of ventricular premature depolarizations is probably applicable to any comparably defined group of patients in the postmyocardial infarction period.

Inability of the Signal‐Averaged Electrocardiogram to Determine Risk of Arrhythmia Recurrence in Patients with Implantable Cardioverter Defibrillators

Signal-averaged electrocardiography has been used to identify patients at risk for arrhythmic death after myocardial infarction. Since patients with implantable cardioverter defibrillators (ICDs) are at high risk for arrhythmic events, they should also be expected to have a high incidence of abnormal signal-averaged electrocardiograms (SAECGs). However, whether the SAECG can discriminate patients who will have arrhythmia recurrence and receive appropriate ICD shocks from those who will have no recurrence and no shocks is unknown. This study examines the usefulness of the SAECG to separate appropriate users from non-users of the ICD. Fifty patients with ICDs participated in this study. Those who received a shock preceded by symptoms, a shock without preceding symptoms but with electrocardiographic documentation of ventricular fibrillation or ventricular tachycardia, or a shock while asleep were classified as ICD users. All other patients were classified as nonusers. The SAECG was classified as normal if the QRS duration on the standard electrocardiogram was less than or equal to 110 msec and if the total filtered QRS duration was less than 120 msec, the root-mean square voltage of the terminal 40 msec was greater than 25 muV, and the terminal low amplitude signal duration measured less than 38 msec. The SAECG was classified as abnormal if the QRS duration on the standard electrocardiogram was less than or equal to 110 msec and any one of these three criteria were outside the "normal range." The SAECG was classified as indeterminate if the QRS duration on the standard 12-lead electrocardiogram was greater than 110 msec. For the entire group of 50 patients, 8 (16%), 12 (24%), and 30 (60%) had normal, abnormal, and indeterminate SAECGs, respectively. Of the 22 ICD users, 1 (5%), 5 (23%), and 16 (73%) patients had normal, abnormal, and indeterminate SAECGs, respectively. Of the 28 ICD nonusers, 7 (25%), 7 (25%), and 14 (50%) patients had normal, abnormal, and indeterminate SAECGs, respectively. ICD users had lower left ventricular ejection fractions (P = 0.0002), a higher incidence of ventricular tachycardia (P = 0.04), prior exposure to a greater number of antiarrhythmic drugs (P = 0.04), and a lower likelihood for survival (P = 0.02) compared to the ICD nonusers. There was no statistically significant difference between the ICD users and nonusers as stratified by SAECG classification regardless of whether or not the interminate studies were included or excluded from the analysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Events in the cardiac arrhythmia suppression trial (CAST): Mortality in patients surviving open label titration but not randomized to double-blind therapy

The patient characteristics and outcomes were studied in the 318 patients who survived open label drug titration in the Cardiac Arrhythmia Suppression Trial (CAST) and who were not randomized to double-blind therapy and in 942 patients, who were randomized to double-blind placebo therapy. The patients randomized to placebo therapy had a lower total mortality or resuscitated cardiac arrest rate (4% vs. 8.5%). However, at baseline, nonrandomized patients were dissimilar from patients randomized to placebo in the following ways: older; lower left ventricular ejection fraction; greater use of digitalis, diuretic drugs and antihypertensive agents; lesser use of beta-adrenoceptor blocking agents and more frequent prior cardiac problems, including runs of ventricular tachycardia and left bundle branch block. A matched comparison that took these inequities into account showed no significant differences in mortality or rate of resuscitation from cardiac arrest between nonrandomized patients and clinically equivalent patients randomized to placebo. Cox regression analysis indicated that two factors significantly increased the hazard ratio for arrhythmic death or resuscitated cardiac arrest in the nonrandomized patients: female gender (4.7, p less than 0.05) and electrocardiographic events (ventricular tachycardia, proarrhythmia, widened QRS complex, heart block, bradycardia) during open label titration (7.0, p less than 0.005). However, some potentially important differences between men and women were not included in the Cox regression model. Of the nonrandomized patients, approximately 70% were not randomized because of lack of suppression of ventricular premature depolarizations or adverse events, or both, and the remaining 30% because of patient or private physician request with no indication of another reason.(ABSTRACT TRUNCATED AT 250 WORDS)

Surgery for control of recurrent life-threatening ventricular tachyarrhythmias within 2 months of myocardial infarction

Twenty-seven patients (mean age 57 ± 7 years) underwent surgery for control of recurrent drug-refractory ventricular tachyarrhythmias (uniform ventricular tachycardia alone in 9 patients, ventricular tachycardia and ventricular fibrillation in 15 and ventricular fibrillation alone in 3) within 2 months of acute myocardial infarction. The mean number of major arrhythmic episodes per patient was 15 (range 2 to 200) and of drug failures 4 ± 2. Left ventricular function was severely impaired in the majority (ejection fraction 29%; range 14% to 47%) and 18 patients (66%) had a left ventricular aneurysm.Endocardial resection guided by a combination of endocardial activation mapping during tachycardia and fragmentation mapping during sinus rhythm was performed in all patients. All electrically abnormal left ventricular endocardium was excised. Eight patients (29.6%) died within 30 days of surgery. Death was not related to age, time of surgery after infarction, ventricular function, bypass time or type of arrhythmia. Patients requiring emergency surgery had a higher early postoperative mortality rate than did those undergoing planned surgery (43% versus 15%). During a follow-up period of 32 ± 20 months, there have been no arrhythmic deaths and only three patients (16%) have required antiarrhythmic drug therapy.When required in the early weeks after infarction, surgery for ventricular arrhythmias offers a high cure rate at a risk related to the patient's preoperative arrhythmia frequency, which in turn relates to the risk of arrhythmic death.

The cardiac arrhythmia suppression trial: Background, interim results and implications

The Cardiac Arrhythmia Suppression Trial (CAST) was designed to test the hypothesis that suppression of ventricular premature complexes (VPCs) in survivors of acute myocardial infarction would reduce arrhythmic death risk. Instead, a preliminary finding from the CAST was that the encainide and flecainide groups had a 3.6-fold increase in arrhythmic death compared with their placebo group. These unfortunate results were especially surprising in that the CAST population represented patients in whom the risk of arrhythmic death was only moderate and the risk of proarrhythmia was thought to be low. In contrast, the arrhythmic death rate of the CAST placebo group was unusually low, to the extent that it paralleled the arrhythmic death rate in previous clinical trials of patients surviving myocardial infarction with no ventricular arrhythmia. The excessive arrhythmic death rate in patients taking encainide and flecainide occurred over the duration of the CAST, implying a proarrhythmic effect that may be due to mechanisms that are unique in this population, and thus challenging traditional concepts of proarrhythmia. The existing knowledge regarding the proarrhythmic and negative inotropic effects of encainide and flecainide are reviewed. The previous pharmaceutical database experience with these 2 antiarrhythmic drugs exceeded 3,000 patients; however, there was no indication of this serious proarrhythmic effect. In contrast, the CAST population taking encainide and flecainide totaled only 725 patients who were followed for 10 months and had an extremely high proarrhythmic event rate. The reasons for this discrepancy are discussed. The results of the CAST emphasize the power of a randomized, placebo-controlled clinical trial to uncover previously unsuspected benefits or liabilities of traditional therapies.

The efficacy of amiodarone in the treatment of ventricular tachycardia or ventricular fibrillation

T HE HISTORY OF the introduction of amiodarone into the United States is considerably different from the history for other antiarrhythmic drugs. Because amiodarone had been used in other countries and appeared to have a reasonable antiarrhythmic effect, many physicians sought to evaluate the drug here. Many Investigational New Drug permits were issued by the US Food and Drug Administration, and there was very little drug company sponsorship or control over evaluation of this agent. No standard protocol was used in the many centers testing this agent, and each investigator studied relatively few patients with limited follow-up (commonly 1 year or less). Patients treated with the drug had diverse diseases and arrhythmia histories, and investigators used different endpoints for evaluation of this drug. Virtually all patients had serious arrhythmias that required treatment, there were no drug-free controls included in any studies, and the investigators were not blinded with regard to therapy when they determined the efficacy of the treatment. Because all patients treated with amiodarone in these early studies had been unsuccessfully controlled with other antiarrhythmic agents, most authors concluded that these patients were highly prone to have antiarrhythmic failure and arrhythmic death in follow-up. It is unclear from all available studies whether the highest risk for arrhythmic death exists in patients who have had an aborted episode of ventricular fibrillation (VF) or in patients who have had recurrent sustained ventricular tachycardia (VT). In fact, it is possible that a patient with multiple recurrences of sustained VT (often without cardiac arrest or ventricular fibrillation) may be more hemodynamically stable during their arrhythmias and less prone to sudden cardiac death than other patient populations with ventricular arrhythmias. A final problem that must be considered in the evaluation of studies that report on the efficacy of amiodarone is the fact that many studies ignore the arrhythmia experience in the first weeks or months of treatment with amiodarone because of the long latency before amiodarone exerts its full antiarrhythmic effect. This censoring of patient information is inappropriate, because it simply represents a deficiency of this drug due to its pharmacokinetics early during therapy. Selection of patients who have survived the first few weeks of a drug therapy eliminates those patients with the most severe arrhythmias who were most likely to succumb to their arrhythmias irrespective of treatment. Thus, studies that evaluate the electrophysiologic effects of amiodarone from four to 12 weeks after initiation of therapy select a group of patients who have a lower risk of recurrence of arrhythmias from the outset of treatment.

The risk factors for arrhythmic death in a sample of men followed for 20 years.

In a sample of 301 men, aged 54-62 years, who were employed in the telephone industry in New Jersey, and who were followed prospectively from 1963/1964 to 1984, 65 of 148 deaths were manifested by the abrupt occurrence of fatal ventricular arrhythmias. On multivariate analysis, the factors present at the initial examination that were significantly related to the subsequent occurrence of arrhythmic deaths were: abnormal patterns of QRS conduction; the level of blood pressure; the number of cigarettes currently being smoked; chronic myocardial ischemia; chronic airway disease; and failure to engage in any exercise or heavy physical activity. Among 28 other potential risk factors representing myocardial disorders, ventricular dysrhythmias, other disorders of cardiac rate, rhythm, conduction, and repolarization, and non-cardiac risk factors (including cholesterol level, serum uric acid level, diabetes mellitus, alcohol intake, general arteriosclerosis, other non-cardiac disease, and social, behavioral, and attitudinal variables), none significantly added to risk for arrhythmic death. The risk factors related to the subsequent occurrence of other deaths, manifested by the gradual development of circulatory failure, were significantly different from the risk factors related to arrhythmic deaths.

Beneficial Effects of Vagal Stimulation and Bradycardia During Experimental Acute Myocardial Ischemia

It is commonly believed that vagally-mediated bradycardia predisposes to ventricular fibrillation (VF) during acute myocardial ischemia. Recent experimental studies, however, have shown that bradycardia and vagal stimulation independently raise the threshold for electrically induced VF in the ischemic canine heart. To determine the influence of vagal stimulation on the spontaneous development of VF occurring during acute myocardial ischemia, open-chest dogs with acute coronary occlusion were observed with and without electrical vagal stimulation. When heart rate was allowed to fall, mean time to VF was 14.7 ± 2.1 min ( se ) in the control dogs (heart rate about 180/min), 23.4 ± 1.9 ( P &lt; 0.01) in the dogs with low intensity vagal stimulation (heart rate about 100/min), and 28.6 ± 0.9 ( P &lt; 0.001) in dogs with high intensity vagal stimulation (heart rate about 60/min). Only 10% of the control animals survived after 30 min of occlusion compared with 40% (NS) of the dogs with low intensity vagal stimulation and 71% ( P &lt; 0.05) of the dogs with high intensity vagal stimulation. Thus, vagal stimulation and bradycardia were associated with a postponement or prevention of VF. In a second series of animals with heart rate maintained constant by right ventricular pacing, vagal stimulation continued to exert a protective effect against the development of VF. Time to VF was increased from 11.0 ± 2.0 min in control animals to 22.6 ± 2.5 in dogs with vagal stimulation ( P &lt; 0.005), and percent survival was enhanced (12% in control animals versus 57% in the vagally stimulated group, P &lt; 0.02). Similar results were observed in a third series of dogs in which electrical stimulation was applied to the peripheral ends of the cut cervical vagi. We conclude that vagal stimulation, with or without accompanying bradycardia, reduces the incidence of spontaneous VF in experimental coronary occlusion. Thus, enhanced vagal tone might act to reduce, rather than increase, the risk of arrhythmic death occurring during acute myocardial ischemia in man.