Experimental animal models of ventricular arrhythmias have been developed to elucidate mechanisms of arrhythmogenesis in humans. Studies of animal models have enabled the vulnerable period of the ventricles to be discovered and characterized and should eventually lead to improved techniques of defibrillation. Animal models of ischemic heart disease and myocardial infarction have also helped investigators elucidate the mechanisms of arrhythmias occurring at each stage of infarct development and healing. Data obtained from the experimental studies have been shown to apply to the clinical situation.

Ventricular arrhythmias may result from abnormalities of impulse initiation and/or impulse propagation. The former include automatic arrhythmias, which may occur at high (normal) levels of membrane potential or at low (abnormal) levels of membrane potential. They also include triggered activity, which may result from early (occurring before complete repolarization) or delayed (occurring after complete repolarization) afterdepolarizations. Arrhythmias resulting from abnormal impulse propagation may be reentrant, determined in part by anatomic or functional conduction block, or the result of reflection. The factors determining various arrhythmogenic mechanisms are discussed.

Sudden cardiac death (SCD) remains a major unresolved clinical and public health problem, accounting for more than 300,000 of the deaths in the United States annually. The ability to identify potential SCD victims is limited by the large size of the population subgroups that contain the majority of SCD victims and by the apparent time dependence of risk of sudden death. The latter refers to the tendency for SCD to follow other cardiovascular events within a high-risk period of 6-18 months after a primary cardiovascular event, with risk decreasing thereafter. The combination of time dependence and denominator pool size provides a basis for future studies to identify the higher risk individuals. Pathophysiologically, SCD can be viewed as an interaction between structural abnormalities of the heart, transient functional disturbances, and the specific electrophysiological events responsible for fatal arrhythmias. Structural abnormalities provide the anatomic substrate for chronic risk and include the myocardial consequences of coronary artery disease, left ventricular hypertrophy, myopathic ventricles, and specific electrophysiological anatomic abnormalities such as bypass tracts. The functional factors responsible for destabilizing a chronic electrophysiological abnormality include transient ischemia and reperfusion, systemic factors (e.g., electrolyte disturbances, acidosis, and hemodynamic dysfunction), autonomic fluctuations (both systemic and at a tissue level), and myocardial toxic influences such as proarrhythmic effects of various drugs. Each of these changes is able to destabilize myocardial membrane integrity, some regionally and some globally, making the heart susceptible to an electrical triggering event for ventricular tachycardia or fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)

Study of the detailed pathology of the myocardium and coronary arteries in ambulatory subjects dying suddenly of coronary heart disease shows that they can be divided into two groups. In one group, there is atherosclerosis with a new vascular event involving coronary thrombosis, which initiates acute myocardial ischemia. In the other group, there is chronic high-grade stenosis due to atherosclerosis, but there is no recent vascular change; the myocardium in this group shows scarring from a previously healed infarction acting as a substrate for reentrant ventricular arrhythmias. A study of 168 consecutive cases of sudden coronary death in London showed 73.3% to have had a recent coronary thrombotic lesion, giving a ratio of 2.7:1 for patients with versus patients without new acute myocardial ischemia. The widely differing ratios reported in the literature probably reflect the patterns of case selection. Prodromal pain immediately before the onset of ventricular fibrillation in a patient without previous known coronary disease selects for a thrombotic cause and acute myocardial ischemia. Absence of pain in a patient known to have had a previous infarction selects for a primary arrhythmia on the basis of preexisting myocardial hypertrophy and/or scarring.

The purpose of the present review is to suggest future approaches to the problem of sudden cardiac death. Short-term efforts should be directed toward delivering cardiopulmonary resuscitation and electrical therapy as soon as possible after the onset of an arrest. Long-term efforts encompass four interrelated, stepwise objectives that include identification of individuals at risk, mechanisms responsible for the arrhythmias, and interventions to prevent the arrhythmias. This is then followed by large-scale testing of the interventions in high-risk populations. Present funding for such research is inadequate, and the National Heart, Lung, and Blood Institute should be encouraged to consider supporting a major research initiative to combat the problem of sudden cardiac death.

Invasive electrophysiological testing has contributed importantly to the objective evaluation and management of patients at high risk for sudden cardiac death. The clinical application of the technique is based on the hypothesis that the reproducible induction of ventricular arrhythmias by programmed cardiac stimulation constitutes a marker of risk for spontaneous ventricular arrhythmias and sudden death as well as an objective end point to guide the selection of antiarrhythmic therapy. The value of electrophysiological testing is well established in patients with ischemic heart disease and a history of sustained ventricular tachycardia or fibrillation and in some subsets of patients with unexplained syncope. More recently, the technique has been used by some investigators to identify individuals at high risk for sudden death among patients with recent myocardial infarction and those with left ventricular dysfunction and recurrent nonsustained ventricular tachycardia. The predictive value of the technique in patients with nonischemic heart disease is unknown. In addition to its use as an objective end point in the selection of antiarrhythmic drug therapy, invasive electrophysiological testing has advanced our knowledge of the mechanisms of life-threatening ventricular arrhythmias and contributed importantly to the development of new therapies, such as implantable arrhythmia control devices and catheter ablation techniques.

Signal-averaged electrocardiography allows the detection of late potentials, which have been associated with delayed and disorganized ventricular activation. This article reviews the technique, describes the findings recorded from patients with ventricular tachyarrhythmias, and assesses the prognostic value of late potentials for ventricular tachyarrhythmias and sudden cardiac death in patients after an acute myocardial infarction. The role of signal-averaged electrocardiography in the evaluation of patients with syncope and cardiomyopathies is also briefly discussed.

Cardiovascular mortality from ventricular tachycardia (VT) and ventricular fibrillation (VF) continues to be a major health problem. Several therapeutic approaches are now available to treat patients with known VT/VF. Among the various therapeutic options are antiarrhythmic drugs, catheter or surgical ablation of VT focus, and implantable cardioverter defibrillator (ICD). The overall 2-year cardiovascular mortality is significantly reduced by ICD therapy. The ICD is particularly useful in patients with 1) no inducible but clinical VT/VF, 2) drug refractory VT/VF, and 3) VT/VF in association with left ventricular ejection fraction of less than or equal to 30%. Significant improvements in ICD therapy have already been made; these improvements include tiered antitachycardia therapy, antibradycardia pacing, lower defibrillation threshold, and longer life of generator. Further improvements are expected, including nonthoracotomy approach to defibrillation, pectoral implant, and dual chamber sensing. It is likely that with all of the advances in ICD therapy its acceptance as a therapeutic option will increase.

Ventricular tachyarrhythmias are the most common arrhythmias documented at the time of sudden cardiac death. Since pharmacological therapy often does not completely suppress these arrhythmias, surgical procedures have been developed to provide an alternative mode of therapy. Coronary artery revascularization in patients with ischemic heart disease is associated with decreased sudden death mortality in patients with left ventricular dysfunction who have no history of prior cardiac arrest or ventricular tachycardia. In sudden death survivors, coronary revascularization appears effective chiefly for patients without inducible ventricular tachycardia or with inducible ventricular fibrillation. Cardiac arrest survivors with sustained monomorphic ventricular tachycardia at electrophysiological study require an ablative procedure that is usually guided by electrophysiological mapping. Current technique should permit elective operations to be carried out with a less than 10% mortality and a greater than 85% rate for suppressing ventricular tachycardia. Nonsurgical catheter ablation techniques have already shown promise in patients with slower, well-tolerated tachycardias that allow extensive catheter mapping. Application of these techniques in patients with the rapid tachycardias associated with sudden death has, to date, been very limited, but as catheter mapping and energy delivery techniques continue to evolve, they may be feasible even in these patients.

Antiarrhythmic drugs may be used as primary therapy to prevent recurrent cardiac arrest or as adjunctive treatment in patients given an implantable cardioverter defibrillator. In the latter instance, drugs are given to suppress nonlethal arrhythmias that are capable of initiating defibrillator discharge or to slow and/or decrease the number of episodes of sustained ventricular tachyarrhythmias. When used as primary therapy, drug efficacy should be judged by nonempirical methods, preferably serial electrophysiological testing. Although no study has compared noninvasive with invasive testing to determine antiarrhythmic drug effectiveness in a substantial number of cardiac arrest survivors, several investigations have demonstrated that electrophysiological testing is useful for this purpose. One important limitation of serial electrophysiological testing is that nearly 40% of cardiac arrest survivors do not have a sustained ventricular tachyarrhythmia initiated at baseline study; nonpharmacological treatment would appear preferable in these patients. Further, since a relatively high arrhythmic recurrence rate has been noted in individuals with suppressible sustained ventricular tachycardia/fibrillation during drug therapy and a left ventricular ejection fraction less than 30%, we recommend serial electrophysiological/pharmacological testing primarily for patients with inducible sustained ventricular tachyarrhythmias with an ejection fraction greater than or equal to 30%.

Extensive atherosclerotic coronary artery disease is by far the most common pathological finding in patients with sudden cardiac death, and acute myocardial ischemia is often a contributing factor. Clinical trials using beta-blockers in postinfarction patients and bypass coronary artery surgery in patients with stable coronary artery disease have demonstrated a reduction in both sudden and total cardiac mortality after intervention. Information concerning the presence and extent of coronary artery disease, global and regional ventricular function, the presence or absence of ventricular aneurysms, and whether or not ischemia is inducible influences therapeutic management. Myocardial revascularization should be considered a primary therapy in patients with critical coronary artery stenosis, significant regions of myocardium at risk, and no inducible ventricular arrhythmias at electrophysiological testing. In patients with inducible polymorphic ventricular tachycardia or ventricular fibrillation, postoperative testing is essential, since only 50% will be suppressed by coronary artery surgery alone. In patients with inducible sustained monomorphic ventricular tachycardia and scars due to prior myocardial infarction, surgical revascularization alone will usually not be sufficient to prevent postoperative induction of the same arrhythmia. There are no data to support percutaneous transluminal coronary angioplasty as the sole therapy for post-sudden death patients who have inducible ventricular tachycardia or ventricular fibrillation on electrophysiological testing.

There is growing evidence to support the existence of a dynamic interaction in vivo between cardiac myocytes and adjacent microvascular endothelial cells in the regulation of both cardiac myocyte and possibly endothelial cell phenotype and function. Endothelins may be only one of several endogenous cytokines or autocoids that are released by the cardiac microvascular and/or endocardial endothelium and transported vectorially to adjacent myocytes that could modify cardiac contractile state, perhaps in response to changes in microvascular blood flow. Similarly, cardiac myocytes themselves could release cytokines that could directly affect endothelial cell proliferation or angiogenesis and indirectly elicit or modify the release of endothelium-derived cytokines and autocoids. Thus, in addition to modifying function, endothelial cell-cardiac myocyte interactions may also be of importance in the dynamic events that lead to myocardial wall remodeling and angiogenesis during hypertrophic growth and in the response to cardiac injury.

Long QT syndrome (LQTS) is an infrequently occurring familial disorder in which affected members have electrocardiographic QT interval prolongation and a propensity to syncope and fatal ventricular arrhythmias. This review of the current literature includes discussions of inheritance, clinical presentation, diagnosis, and treatment of LQTS. At present, there are three modalities of treatment for LQTS patients: beta-blockers, pacemakers, and left cervicothoracic sympathetic ganglionectomy. Because the clinical course of LQTS is quite variable, therapy must be individualized for each patient.

The failure of encainide and flecainide to reduce mortality after infarction in the Cardiac Arrhythmia Suppression Trial and the failure of low-dose amiodarone to prevent sudden cardiac death in patients with a low left ventricular ejection fraction has shifted attention to other strategies, such as beta-adrenergic blocking agents, to prevent sudden cardiac death. Evidence suggesting that beta-adrenergic blocking agents might be useful, especially in patients with low left ventricular ejection fraction, is accumulating. Previous data from studies using beta-adrenergic blocking agents and the mechanisms by which beta-adrenergic blocking agents might be of value in preventing sudden cardiac death are reviewed. These considerations and the availability of new investigational beta-adrenergic blocking agents with vasodilator properties provide a new opportunity to test the hypothesis that beta-adrenergic blocking agents are useful in preventing sudden cardiac death, especially in patients with a low left ventricular ejection fraction.

Although the benefit of beta-adrenergic blocking agents in acute coronary ischemia has been well documented, it is unclear whether the responsible mechanisms include the modification of platelet function. In recent studies, metoprolol appeared to reduce the total number and duration of episodes of silent ischemia in patients with stable coronary artery disease throughout the day. This effect was not associated with a change in baseline or circadian variability of the platelet aggregability. Since the treatment caused significant decreases in heart rate and blood pressure, the drug effect is more likely to be based on reduction of myocardial oxygen demand. Metoprolol, however, prevented a platelet aggregability increase and intracellular cAMP decrease during exercise stress testing in patients with stable angina pectoris. We speculate that this effect of beta 1-adrenergic blockade may be due to hemodynamic and neurohormonal changes, or possibly also to an increase in synthesis or release of platelet inhibiting substances.

Hypertension is associated with an increased risk of clinical cardiovascular complications due to atherosclerosis. However, attempts to reduce that risk with antihypertensive treatment have not always been successful. Therefore, it may be significant to discuss antihypertensive treatment in view of the cellular pathogenesis of atherosclerosis. Endothelial and smooth muscle cells are found in both normal and atherosclerotic arterial tissue, but cellular characteristics appear to be affected during atherogenesis. Lymphocytes and monocytes are found primarily in the atherosclerotic lesion and may be of critical importance for both cell proliferation and lipid accumulation. In the present review, processes involved in the regulation of functional properties of the various cell populations in the atherosclerotic lesions are discussed. The significance of the smooth muscle population as a quantitatively dominating cell constituent in both the atherosclerotic lesion and in the resistance vessels of hypertensives is emphasized. Two different mechanisms possibly involved in the increase of size of the smooth muscle population are discussed. Proliferation of a stem cell population or of differentiated medial smooth muscle cells might be involved. In addition, generalized, possibly genetically determined changes in cellular reactivity to adrenergic stimuli and growth factors may be implicated. If so, hypertension and atherosclerosis might perhaps be regarded as two independent expressions of the same cellular defect. This would have implications in attempts to prevent coronary heart disease by antihypertensive drugs.

The aim of this review is to present an overview of the results of randomized primary preventive trials with beta-blockers in patients with hypertension. For statistical and biological reasons, any preventive effect on coronary events is hard to demonstrate in women in these primary preventive trials because of the low incidence of coronary events in middle-aged, white women. Therefore, special attention will be focused on the effect in men. Four beta-blockers have been studied: propranolol, oxprenolol, atenolol, and metoprolol. Results from the Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) trial showed that the risk for coronary events was 24% lower in patients receiving beta-blockade compared with patients receiving diuretics (p less than 0.001). In men, three beta-blockers (propranolol, oxprenolol, and metoprolol) have shown significantly lower risk for coronary events (fatal and nonfatal) in the nonsmoking subgroup. Results from the MAPHY study also indicated a reduction in total and coronary mortality with the beta-blocker as compared with thiazide diuretics. The observed reduced risk for coronary events with beta-blockers as compared with diuretics is probably independent of the reduction in blood pressure. Mechanisms currently under study include antiatherosclerotic effects, antithrombotic effects, anti-ischemic effects, and antifibrillatory effects. It is not possible to judge, with present evidence, if all beta-blockers are equally effective in preventing sudden death and other coronary events.