Recombinant DNA technologies have facilitated the development of a set of polymorphic DNA markers covering the human genome. General linkage analysis in families predisposed to inherited disease is now feasible. Linkage analysis can help identify a disease gene even when relatively little is known about the disorder.

A broad, scientific consensus supports the role of cholesterol as a risk factor for coronary heart disease and agrees that lowering cholesterol levels will reduce coronary heart disease incidence. Cost-effectiveness analysis is a potentially powerful method for measuring the benefits to be achieved by expenditures of health care dollars.

Adenosine is released from the myocardium in response to a decrease in the oxygen supply/demand ratio, as is seen in myocardial ischemia; its protective role is manifested by coronary and collateral vessel vasodilation that increase oxygen supply and by multiple effects that act in concert to decrease myocardial oxygen demand (i.e., negative inotropism, chronotropism, and dromotropism). During periods of oxygen deprivation, adenosine enhances energy production via increased glycolytic flux and can act as a substrate for purine salvage to restore cellular energy charge during reperfusion. Adenosine limits the degree of vascular injury during ischemia and reperfusion by inhibition of oxygen radical release from activated neutrophils, thereby preventing endothelial cell damage, and by inhibition of platelet aggregation. These effects help to preserve endothelial cell function and microvascular perfusion. Long-term exposure to adenosine may also induce coronary angiogenesis.

The functional significance of coronary collaterals in humans has been debated for many years. Correlations have now been made between the anatomic appearance of coronary collateral vessels visualized at the time of intracoronary thrombolytic therapy during the acute phase of myocardial infarction and the creatine kinase time--activity curve, infarct size, and aneurysm formation. These studies demonstrate a protective role of collaterals in hearts with coronary obstructive disease, showing smaller infarcts, less aneurysm formation, and improved ventricular function compared with patients in whom collaterals were not visualized. There is ample evidence that collaterals respond to myocardial ischemia by opening preexistent channels. When the cardiac myocyte is rendered ischemic, collaterals develop actively by growth with DNA replication and mitosis of endothelial and smooth muscle cells. Heparin-binding growth factors are present in the heart, but their biological activity is quiescent under normal physiological conditions. Once ischemia develops, these factors are activated and become available for receptor occupation, which may initiate angiogenesis after exposure to exogenous heparin. This characteristic of heparin to potentiate the mitogenic activity of acidic fibroblast growth factor has recently been used in the clinical setting as a possible therapeutic modality in patients with coronary artery disease. Patients performing 20 rounds of exercise serially after receiving intravenous injection of heparin showed significantly greater increases in exercise capacity and improvement of clinical symptoms compared with the control group who performed the same exercise without heparin. Further study of neovascularization may lead to a new therapeutic strategy for ischemic heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of G proteins in mediating the responses of the heart to circulating catecholamines and to the influences of the autonomic nervous system is of special interest to cardiologists. It is evident that G proteins are essential links in the cascade of biochemical events that ensure when neurotransmitters and hormones interact with receptors on myocardial cells. It is likely [corrected] that dysfunction of G proteins plays a role in cardiovascular pathophysiology. With current methodologies, especially molecular biological and recombinant DNA techniques, and with transgenic animal models that can relate physiological function and specific gene dosage, some cardiovascular diseases may be traced to G protein-related defects.

It is clear that cocaine has cardiotoxic effects. Acute doses of cocaine suppress myocardial contractility, reduce coronary caliber and coronary blood flow, induce electrical abnormalities in the heart, and in conscious preparations increase heart rate and blood pressure. These effects will decrease myocardial oxygen supply and may increase demand (if heart rate and blood pressure rise). Thus, myocardial ischemia and/or infarction may occur, the latter leading to large areas of confluent necrosis. Increased platelet aggregability may contribute to ischemia and/or infarction. Young patients who present with acute myocardial infarction, especially without other risk factors, should be questioned regarding use of cocaine. As recently pointed out by Cregler, cocaine is a new and sometimes unrecognized risk factor for heart disease. Acute depression of LV function by cocaine may lead to the presence of a transient cardiomyopathic presentation. Chronic cocaine use can lead to the above problems as well as to acceleration of atherosclerosis. Direct toxic effects on the myocardium have been suggested, including scattered foci of myocyte necrosis (and in some but not all studies, contraction band necrosis), myocarditis, and foci of myocyte fibrosis. These abnormalities may lead to cases of cardiomyopathy. Left ventricular hypertrophy associated with chronic cocaine recently has been described. Arrhythmias and sudden death may be observed in acute or chronic use of cocaine. Miscellaneous cardiovascular abnormalities include ruptured aorta and endocarditis. Most of the cardiac toxicity with cocaine can be traced to two basic mechanisms: one is its ability to block sodium channels, leading to a local anesthetic or membrane-stabilizing effect; the second is its ability to block reuptake of catecholamines in the presynaptic neurons in the central and peripheral nervous system, resulting in increased sympathetic output and increased catecholamines. Other potential mechanisms of cocaine cardiotoxicity include a possible direct calcium effect leading to contraction of vessels and contraction bands in myocytes, hypersensitivity, and increased platelet aggregation (which may be related to increased catecholamine). The correct therapy for cocaine cardiotoxicity is not known. Calcium blockers, alpha-blockers, nitrates, and thrombolytic therapy show some promise for acute toxicity. Beta-Blockade is controversial and may worsen coronary blood flow. In patients who develop cardiomyopathy, the usual therapy for this entity is appropriate.

Sudden death in children as in adults is usually due to cardiac disease. Sudden death in the pediatric population may be divided into the sudden infant death syndrome, sudden death in previously apparently healthy children, and sudden death in patients with known cardiac disease. The sudden infant death syndrome is not proved to be due to a cardiac cause and may well be due to central nervous system and/or pulmonary causes. However, interest remains in the cardiac hypothesis. Recent work from our laboratory shows that screening for prolonged QT interval in normal infants is not likely to detect those prone to sudden infant death syndrome. In children with apparently normal hearts, symptoms of syncope or palpitation should be given close attention. Detailed electrocardiography and echocardiography will detect many, but not all, children with subtle forms of heart disease. Vigorous treatment may prevent sudden death in many of these children. Some sort of screening program should be devised for varsity athletes. Children with congenital heart defects are now, for the most part, corrected early in life, so that the congenital heart defect itself rarely causes sudden, unexpected death. The residua and sequelae of the heart defect and the surgery to repair it, however, may lead to sudden death. Improvements in surgical technique and earlier repair of congenital cardiac defects will ameliorate this problem. Prospective evaluation of postoperative patients and attention to dysrhythmias can prevent sudden deaths in those who are prone to them.

The analysis of the autonomic control of the heart, by means of indirect markers, may represent a new approach for identifying patients at higher risk for sudden cardiac death after a myocardial infarction. This possibility is based on the evidence that autonomic responses during acute myocardial ischemia are a major determinant of the outcome (i.e., occurrence of ventricular fibrillation or survival). Specifically, sympathetic activation can trigger malignant arrhythmias, whereas vagal activity may exert a protective effect. Several experimental observations have provided new insights on the relation between sympatho-vagal interactions and the likelihood for the occurrence of ventricular fibrillation. In an established experimental model for sudden death involving conscious dogs with a healed myocardial infarction, either depressed reflex chronotropic responses during a blood pressure rise or reduced variability of heart rate (respectively, markers of reflex and tonic cardiac vagal activity) identify dogs at greater risk to develop malignant arrhythmias during a new ischemic episode. In anesthetized cats, direct neural recording of vagal activity to the heart confirmed that vigorous reflex vagal activation during acute myocardial ischemia is associated with protection from ventricular fibrillation. Furthermore, in these experiments the reflex neural response to acute myocardial ischemia was predicted by the analysis of baroreflex sensitivity. The antifibrillatory effect of vagal activation is confirmed by the prevention of ventricular fibrillation during acute ischemia in dogs susceptible to sudden cardiac death by direct electrical stimulation of the right vagus. The clinical counterpart of these experimental data lies in three separate prospective studies showing a higher cardiac mortality in patients who after a myocardial infarction have a depressed baroreflex sensitivity or a decreased heart rate variability. A definitive answer on the role that the analysis of markers of cardiac vagal activity may play in risk stratification of patients with coronary artery disease should be provided by Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI), an ongoing prospective study. In ATRAMI, baroreflex sensitivity and heart rate variability will be assessed within 20 days after a myocardial infarction in 1,200 patients enrolled in Europe, U.S.A., and Japan with a minimum follow up of one year.

It is well known that changes in serum potassium cause ventricular arrhythmias as a result of clearly documented changes in the electrophysiological characteristics of single fibers. Hypopotassemia induced by thiazide and loop diuretics may contribute to the incidence of sudden cardiac death in patients with hypertension and those with congestive heart failure. In addition, hypopotassemia appears to be an independent risk factor for lethal ventricular arrhythmias occurring in the setting of acute myocardial infarction and contributes significantly to arrhythmias associated with starvation and alcoholism. The increase in myocardial extracellular potassium that occurs in the ischemic zone after coronary occlusion is clearly a major factor in the genesis of lethal ventricular arrhythmias that occur in this setting. A decrease in serum magnesium is also believed to be arrhythmogenic, and magnesium depletion is thought to play a role in many of the arrhythmias associated with hypopotassemia. Moreover, the administration of magnesium salts may be effective in the management of life-threatening ventricular arrhythmias. However, definite evidence establishing a causal relation between ventricular arrhythmias and hypomagnesemia or intracellular magnesium depletion is lacking. Changes in intracellular calcium contribute to the arrhythmias associated with acute ischemia and with reperfusion and may be important in the genesis of ventricular tachycardia induced by exercise and by digitalis. Thus, electrolyte and metabolic abnormalities clearly underlie lethal ventricular arrhythmias in a wide variety of clinical situations and should be routinely considered as potential etiologic factors in patients with life-threatening ventricular arrhythmias, particularly those with hypertension and congestive heart failure who are receiving thiazide and loop diuretics.

Sudden death is an important facet of the natural history of hypertrophic cardiomyopathy. Issues related to the nature and etiology of sudden death and the prospective identification of those patients at increased risk have been the subject of intense study, and consequently, our concepts and knowledge have continued to evolve. Occurrence of sudden death has been reported to be about 2-3% per year in a hospital-based referral population and, although described in most age groups, is most common in older children and young adults. The typical profile is that of a young asymptomatic patient with substantially increased left ventricular wall thickness who dies while performing sedentary or modest physical activities; however, a substantial minority die suddenly during or just after severe exertion, including those participating in competitive athletics. Other risk factors that have been identified in patients with hypertrophic cardiomyopathy include nonsustained ventricular tachycardia on ambulatory electrocardiogram, a strong family history of sudden death, and prior occurrence of syncope (or cardiac arrest). Electrophysiological studies have shown that most patients judged at increased risk for sudden death have sinoatrial or His-Purkinje conduction disease or inducible supraventricular or ventricular tachycardia; inducibility of a sustained ventricular arrhythmia is associated with prior occurrence of syncope or cardiac arrest. Hemodynamic and electrophysiological studies in patients with hypertrophic cardiomyopathy have demonstrated several potential mechanisms for cardiac arrest or sudden death, including atrial arrhythmias associated with hypotension, bradyarrhythmias, and ventricular tachyarrhythmias, all of which can be exacerbated in the presence of left ventricular outflow tract obstruction or myocardial ischemia.

Although both asymptomatic ventricular arrhythmias and sudden death are common in patients with chronic heart failure, there is little evidence that patients who have frequent or complex ventricular arrhythmias are at increased risk of sudden death. Two hypotheses may explain the lack of an arrhythmia-sudden death relation in this disorder. First, complex ventricular arrhythmias may be a nonspecific manifestation of a dying left ventricle rather than an indication of a specific arrhythmogenic substrate. In fact, during long-term follow-up, patients with mild heart failure who have nonsustained ventricular tachycardia are more likely to develop clinical progression of the disease rather than sudden death. Second, sudden death may be related to events other than a malignant ventricular arrhythmia. The most common myocardial ischemia, whereas the terminal event in patients with an idiopathic dilated cardiomyopathy is commonly a severe bradyarrhythmia or electromechanical dissociation. Neither outcome can be predicted by a prior history of ventricular arrhythmias on ambulatory electrocardiographic monitoring. If asymptomatic ventricular arrhythmias do not lead to sudden death, then there would appear to be little reason to expect that antiarrhythmic drugs could prevent cardiac arrest in patients with chronic heart failure. This may explain why drugs that suppress ambulatory arrhythmias do not prevent sudden death in these patients, whereas interventions may reduce the risk of unexpected circulatory collapse in this disorder without suppressing ventricular ectopic activity. To make matters more complicated, the desirable actions of antiarrhythmic drugs are attenuated and their negative inotropic and proarrhythmic actions are enhanced in patients with severe cardiac dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Sudden cardiac death (SCD) is responsible for 300,000-400,000 deaths per year with a recurrence rate of up to 40% in survivors within the first 2 years. SCD often occurs in patients with chronic coronary artery disease, which is manifested by myocardial infarction and left ventricular dysfunction but is infrequently associated with acute infarction. SCD may be the initial symptom of coronary artery disease. Primary or rapid ventricular tachycardia are the most common arrhythmic causes of SCD. Endocardial mapping studies during electrophysiological study have shown areas of slowed conduction with abnormal endocardial electrograms in SCD patients with moderately damaged ventricles. SCD increases with age and occurs more frequently in men with coronary artery disease as a significant risk factor. Complex ventricular ectopy, once thought of as an independent risk factor, is not as good a predictor as poor left ventricular function for recurrence of SCD. While signal-averaged electrocardiograms can identify patients with slowed conduction, their positive predictive value for SCD is poor. Initial evaluation should be aimed at the identification of ischemia, since those patients with SCD and acute myocardial infarction do well when treated for their ischemia. The arrhythmias that are inducible during electrophysiological study are rapid and poorly tolerated. Patients with inducible ventricular tachycardia who are rendered noninducible pharmacologically have a good prognosis, whereas those who are still inducible or have no inducible arrhythmias have a high recurrence rate of SCD and should be considered for subendocardial resection when appropriate or for placement of an implantable defibrillator.