Comparing the effects of long-term beta-blocker trials on nonfatal myocardial infarction (MI) is difficult because of differences in diagnostic criteria and in methods of reporting and classifying events. Analysis of available data indicates that the relative effect of beta blockers on the incidence of nonfatal MI is not different among the reviewed long-term trials. Pooling of trial results indicates that beta-blocker therapy has a beneficial effect on nonfatal MI incidence that is of the same magnitude (25%) as that for all-cause mortality.

Treatment with oral beta 1 blockade started after recovery from acute myocardial infarction and continued for approximately 2 years reduces total mortality by about 25%. It is unclear how long oral treatment should be maintained, nor is it known if stopping beta blockade increases the risk of sudden death or reinfarction. Acute i.v. administration of beta blockers has been shown to reduce indexes of infarct size. The effect of this reduction on short- and long-term survival is promising, but not conclusive.

It seems clear that beta blockers can limit infarct size in man and reduce mortality after a myocardial infarction. Early mortality also seems to be reduced by beta blockade in patients in whom infarct size was not limited. Thus, infarct size limitation is not the only mechanism for an effect of beta blockade on early infarction mortality. The favorable effect of early initiation of beta blockade on long-term survival might, however, suggest an importance of infarct size limitation for prognosis. More studies are needed to evaluate the role of infarct size limitation for long-term prognosis.

Morbidity and mortality differences between populations, between ethnic groups and between individuals are not satisfactorily explained by the variation of risk factors. Differences in genetic susceptibility might be responsible for a part of the unexplained variation of coronary heart disease (CHD) rates. Genetic factors are also significant in determining the level of risk factors in individuals. Ample evidence links genetic factors to the levels of serum cholesterol, blood pressure and diabetes. Marked sex differences in CHD mortality also indicate the role of heredity in the development of the disease. The male:female ratio varies widely between different countries, as well as between different ethnic groups. These variations are difficult to explain by variation in environmental and behavioral differences between males and females alone. The degree of atherosclerosis in males and females varies, depending on the anatomic location of the atherosclerosis. Inherited disorders of metabolism and the variability of anatomic patterns provide additional indications of the role of genetics. The data accumulated in the Israeli Ischemic Heart Disease Study over 15 years reveal an ethnic variation of risk factors coupled with remarkably larger variation in disease rates. Patterns of incidence assessed in the national mortality data of the Israeli study and in histologic findings in the coronary arteries of infants from different ethnic groups are compatible with a hypothesis that ethnic and sex differences in early structural changes of the coronary arteries partly determine the susceptibility of the latter to the development of atherosclerosis. In conclusion, findings from our studies and the review of the evidence from genetic epidemiologic investigations indicate a significant role of genetics in determining the degree, time course and severity of the atherosclerotic process and of the occurrence of symptomatic CHD. This important role of the genetic component is relevant to preventive strategies offered as tools for reducing the burden of CHD. Research into genetic determinants of both susceptibility to atherosclerosis or clinical manifestation of CHD and individual response to preventive measures should be encouraged.

Myocardial ischemia has, for many decades, been viewed as an all-or-none process that causes myocardial necrosis when prolonged and severe, but whose effects are transient when it is brief or mild. In view of the evidence that the ischemic process may "hit, run and stun," perhaps our thinking about the consequences of myocardial ischemia should be expanded. According to this formulation, an ischemic insult not of sufficient severity of duration to produce myocardial necrosis may acutely affect myocardial repolarization and cause angina (hit); but these changes wane rapidly (run), when the balance between myocardial oxygen supply and demand has been reestablished. However, the ischemia may interfere with normal myocardial function, biochemical processes and ultrastructure for prolonged periods (stun). The severity and duration of these postischemic changes depend on the length and intensity of the ischemia, as well as on the condition of the myocardium at the onset of the ischemic episode. Furthermore, it is likely that when the myocardium is repeatedly stunned, it may exhibit chronic postischemic left ventricular dysfunction, an ill-defined condition. If prolonged, chronic postischemic left ventricular dysfunction can progress to myocardial scarring and ischemic cardiomyopathy, it may be important to determine how often it can be ameliorated by permanent improvement of myocardial perfusion by surgical treatment.

This paper provides guidelines for the optimal, rather than minimal, performance of ultrasonic examination of the heart for current clinical applications using conventional echocardiographic equipment. Since the original report of this Inter-Society Commission on Heart Disease Resources Committee in 1975, M-mode echocardiography has continued to be a valuable clinical tool, and two-dimensional echocardiography has been developed. Guidelines are presented for optimal physician and cardiac sonographer training, case loads, space and support systems, equipment design features and performance testing, and administrative considerations. The developing area of Doppler ultrasound and the competitive technologies are noted.

Angina pectoris results from a deficiency in myocardial oxygen supply. The rate-pressure product is an important predictor of myocardial oxygen requirements in patients with ischemic heart disease and in normal persons. The rate-pressure product at the onset of angina pectoris is reproducible under a variety of circumstances with a suitable protocol. In some patients, coronary artery spasm may reduce myocardial blood flow and contribute to the development of angina pectoris. Lidoflazine is a synthetic drug that appears to be a calcium-entry blocker and results in symptomatic improvement in patients with angina pectoris. Lidoflazine reduces the exercising rate-pressure product by its effect on heart rate and by decreasing systemic vascular resistance. It decreases coronary vascular resistance and antagonizes processes leading to an increase in coronary vasomotor tone.

Calcium-entry blockers depress the myogenic activity and the responsiveness to vasoconstrictor stimuli of the smooth muscle cells of the precapillary vessels. Thus, they can reduce the afterload of the heart and have antihypertensive properties. Their inhibitory effect on the contractile responses of the vascular smooth muscle cells of large arteries also results in the reduction or the abolition of vasospastic episodes. By inhibiting the constrictor responses of the splanchnic capacitance vessels to the sympathetic nervous outflow, they reduce the preload of the heart. However, different calcium-entry blockers differ in their ability to affect different cardiovascular variables and in the onset and duration of their effect; they also have different degrees of tissue selectivity. This variability must reflect differences in pharmacodynamic and pharmacokinetic properties.

The membranes that separate the myocardial cell interior from the extracellular space and delimit compartments within the myocardial cell represent ion-impermeable phospholipid barriers. Embedded in these phospholipid membranes are intrinsic membrane proteins, some of which serve as ion channels. The voltage-sensitive ion channels that control the sarcolemmal action potential appear to be highly regulated intrinsic membrane proteins that contain "gates" that respond to changing membrane potential by opening and closing an ion-selective "pore" that allows specific ions to cross the membrane. Pharmacologic blockade of the sarcolemmal ion channels is selective, not only for individual classes of ion channels, but also for specific states of a given type of channel. The basis for this selectivity remains unclear, but may derive from a preferential interaction between a given drug and a specific type of ion-channel protein, or a selective drug action on a structurally specific region of the membrane phospholipid that is in intimate contact with the ion-channel protein.

Many basic concepts of cardiac output and arterial pressure control have changed considerably in the past few years. In general, each tissue controls its own local resistance and blood flow regardless of the level of arterial pressure; the sum of the local flows then determines the venous return and cardiac output. However, the arterial pressure is normally controlled by separate mechanisms that do not significantly alter the cardiac output. During acute circulatory stresses, such as exercise, the arterial pressure is controlled almost entirely by nervous reflex mechanisms; but over long periods, there reflex mechanisms fade away because they adapt. The arterial pressure is then controlled mainly by a renal-volume-endocrine pressure control system, in which the blood volume and total peripheral resistance are manipulated slowly to adjust the pressure.

Pulmonary vascular disease, a serious complication of many congenital heart lesions, has three major components: increased muscularity of small pulmonary arteries; intimal hyperplasia, scarring and thrombosis; and reduced numbers of intraacinar arteries. The muscularity is due to increased stress on the vessel wall, and is reversible. The intimal changes may be due to endothelial damage, causing an imbalance between prostacyclin and thromboxane A2 production and leading to local platelet aggregation. This, in turn, may stimulate migration and division of myointimal cells, which thicken the intima and lead to scarring and thrombosis. Extensive intimal changes are probably irreversible, but the possibility of preventing them by use of agents that inhibit platelet aggregation needs to be considered. The mechanism of a decrease in numbers of intraacinar arteries is unexplained. The potential for growth of new vessels after corrective surgery of the cardiac defect is an important factor in restoring pulmonary vascular resistance to normal. Available evidence suggests that this growth potential is reduced after 2 years of age and argues for early surgical relief of pulmonary vascular stresses.

The realization that bias in patient selection may influence the results of clinical studies has helped to establish the randomized controlled clinical trial in medical research. However, bias can be equally important at other stages of a trial, especially at the time of analysis. Withdrawing patients from consideration in the analysis because of ineligibility on account of study entry criteria, lack of compliance to the protocol, or data of poor quality may be a source of systematic error. Examples to illustrate the possible consequences are taken from trials in the cardiovascular field. We recommended that reported study results should include outcome data from all subjects randomized in the group to which they were originally assigned.

The cardiovascular reflexes, by regulating the traffic in the sympathetic nerves, govern the amount of norepinephrine released from the nerve endings. However, the final adjustments in the amount of neurotransmitter available to activate the beta 1 receptors in the heart and the alpha receptors in the blood vessels take place at the sympathetic neuroeffector junction. Thus, a decrease in pH, hyperosmolarity, moderate increases in the concentration of K+ ion, adenosine and adenine nucleotides depress the release of norepinephrine at any given level of sympathetic nerve activity. These metabolic changes, which occur in active tissues, and in particular in adenosine, have been proposed as mediators of the accompanying local hyperemia. In addition, they apparently facilitate this local dilatation by disconnecting the blood vessels in the active tissues from sympathetic control. Acetylcholine, histamine and 5-hydroxytryptamine are present in and around certain blood vessels and can activate specific receptors on the prejunctional fibers and cause vasodilatation by reducing the output of neutrotransmitter. Some of the norepinephrine released into the synaptic cleft may depress its continued release by activating prejunctional alpha receptors. In contrast, angiotensin II, by a local action on the nerve endings, can augment the release of transmitter. Decreases in local temperature reduce transmitter release but augment the affinity of the postjunctional alpha receptors for norepinephrine. The role of these local events at the neuroeffector junction, their physiologic significance and potential clinical importance are discussed in this review.