This article reviews controlled trials of medical therapy for coronary artery spasm. The calcium antagonists, either alone or in combination with long-acting nitrates, are effective therapy for patients with coronary artery spasm. These drugs definitely decrease angina and the frequency of ischemic ST shifts recorded during continuous electrocardiographic monitoring. Therapy is still relatively nonspecific, however, since the mechanism(s) that lead to spasm remain unknown. Interestingly, the initial response to therapy is similar regardless of the presence or absence of severe coronary artery disease accompanying spasm. Drugs that block adrenergic or serotonin receptors or that alter platelet aggregability or prostaglandin production have been ineffective in relieving angina or decreasing the frequency of ischemic ST shifts. Patients with resting angina syndromes are a heterogeneous group; many do not have coronary spasm since other mechanisms also precipitate ischemic episodes at rest. Prevention of angina or ischemic ST shifts may not necessarily prevent acute myocardial infarction and sudden cardiac death. Both initial and long-term therapies should be individualized according to a detailed clinical and angiographic assessments of each patient.

Whether or not the kidney is involved in the genesis of hypertension in an individual patient, it becomes a major determinant of the response to antihypertensive therapy once a treatment strategy is adopted. The major mechanisms through which the kidney influences blood pressure are renin release and sodium retention, either together or separately, but additional mechanisms may also contribute. When sodium intake is restricted or a diuretic is used, the reactive increase in plasma renin activity makes a substantial contribution to limiting the decrease in blood pressure. When vasodilators or agents that block the sympathetic nervous system are used, sodium retention plays an important role. Among newer agents, the effectiveness of calcium-channel blockers, converting-enzyme inhibitors, and perhaps dopamine analogs reflects, for reasons that differ from one class of agent to another, a special action on the kidney that limits the reactive renal response to the reduction in blood pressure. Treatment strategies that address the problem of the renal response are more likely to be effective than approaches that avoid or ignore it.

The increasing use of the calcium-entry blockers has led to an enhanced potential for drug interactions with a variety of different drugs. Interactions with cardiovascular agents are of great concern because of the consequences of synergistic negative dromotropism or inotropism. We therefore assessed the concomitant use of calcium-entry blockers and cardiac glycosides, beta-blockers, antiarrhythmic agents, and other chemical types of calcium-entry blockers from a standpoint of clinical relevance. We also evaluated reported drug interactions with H2-receptor antagonists, anticonvulsants, lithium carbonate, general anesthetics, cytostatic drugs, rifampin, and sulfinpyrazone with regard to clinical implications, along with the modification of calcium-entry blocker dose for concurrent social drug use, such as cigarette smoking and ethanol intake. Although a myriad of potential drug interactions exists for these agents, combination therapy is still a reasonable alternative if doses are adjusted appropriately.

The use of calcium-channel blockers to treat essential hypertension is increasing, and in the United States several new drug applications for this indication are under consideration by the Food and Drug Administration. Although the ability of the calcium-channel blockers to lower blood pressure has been established, their efficacy and safety in relation to current therapy require further clarification. This article reviews studies in which calcium-channel blockers and beta-blockers have been compared, including seven with verapamil, four with nifedipine and nitrendipine and two with diltiazem. These studies indicate that the two classes of agents produce similar antihypertensive effects and are associated with a comparable incidence of adverse reactions. In addition, the preliminary findings of a multicenter trial in which 50 subjects with mild or moderate hypertension were treated with diltiazem (60 to 180 mg bid) or propranolol (80 to 240 mg bid) for 4 to 6 months are presented. Both medications significantly lowered blood pressure (from 148 +/- 17/101 +/- 5 to 133 +/- 25/88 +/- 9 mm Hg on diltiazem and from 154 +/- 22/104 +/- 6 to 146 +/- 23/91 +/- 11 mm Hg on propranolol). Fifty-nine percent of the patients on diltiazem and 40% of those on propranolol achieved the treatment goal of a supine diastolic blood pressure under 90 mm Hg together with minimum 10 mm Hg reduction. In a similar study, exercise blood pressure and exercise capacity were also examined, with the most important finding being a reduction in maximal oxygen consumption and exercise duration on propranolol without a significant change on diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)

Despite the proven effectiveness of calcium-channel and beta-blockers as monotherapy in patients with chronic stable angina pectoris, some patients remain symptomatic. Such patients have been shown to benefit from the application of combined treatment with beta-blockers and nitrates or, more recently, beta-blockers plus calcium-channel blockers. There have been few studies evaluating the long-term effectiveness of the combination of calcium blockers and nitrates, but available evidence suggests that symptoms of excessive vasodilation such as orthostatic hypotension may limit the usefulness of this approach. Recently, the additional benefit of adding a calcium blocker to therapy of patients with chronic stable angina who remain symptomatic on beta-blockers and nitrates has been demonstrated. Side effects related to vasodilation were the major limiting feature of this triple therapy. Thus, a triple therapy regimen may be of value in selected patients who do not respond to the combination of beta-blockers and nitrates or beta-blockers plus calcium blockers. However, caution must be exercised in patients with reduced left ventricular function and conduction system disease, since such patients have been excluded from the reported studies.

Recent clinical observations have extended our classification of unstable angina to include new groups of patients now recognized at high risk of subsequent infarction. Patients with non-Q wave myocardial infarction and those with early postinfarction ischemia share a prognosis similar to that of patients with crescendo angina or with acute coronary insufficiency. Unstable angina after coronary angioplasty and after coronary artery surgery also form particular subsets of patients. Pathologic, coronary angiographic, and coronary angioscopic studies have extended the role of the obstructive atherosclerotic plaque to include a dynamic component to explain the unstable state. Recognized dynamic components are rapid progression of the disease, active vasomotion, plaque fissuring, and thrombus formation. Activation of platelets and blood coagulation factors may play a major role in triggering the syndrome. Our therapeutic approach has also become more specific for the correction of the cause of the disease. Our understanding of unstable angina now appears to be at a turning point, and a pathophysiologic basis for its clinical classification and for its management may soon be available.

In recent years therapy with the calcium entry-blocking drugs nifedipine, verapamil, and diltiazem has made a major impact on the treatment of cardiovascular disease. Although all three of these drugs are approved for the treatment of angina pectoris, some are effective in treating supraventricular tachyarrhythmias and all appear to be effective in the treatment of mild-to-moderate hypertension. Reports of their therapeutic potential, however, are not confined to the cardiovascular system, which reflects the ubiquity of calcium ions as stimulus-effect couplers in a wide variety of organ systems. Although chemically heterogeneous, all three drugs produce similar negative inotropic effects in the myocardium and similar relaxant effects in vascular smooth muscle. From a review of the excitation-contraction coupling process in cardiac and smooth muscle it is apparent that "calcium blockade" could occur at any one of several loci. Our present understanding is that the effect of nifedipine, verapamil, and diltiazem is confined to an inhibitory one on channel-mediated membrane calcium influx. There is, in fact, a close parallel between their ability to decrease slow-channel calcium influx in the myocardium and the negative inotropic action of the drugs. Similarly, in vascular smooth muscle their ability to inhibit voltage- or receptor-mediated calcium influx parallels their vasorelaxant properties. With the use of radiolabeled ligands, particularly of the dihydropyridines (nifedipine, nitrendipine, nicardipine, nisoldipine) it has been shown that the drugs show high-affinity stereospecific binding to vascular smooth muscle channels in the same concentration range as their relaxant properties. In contrast, it was originally thought that myocardial binding was of a lower affinity and correlated poorly with the negative inotropic effect. More recent data, however, have cast some doubt on the validity of these observations. Attempts to define specific drug receptors are incomplete at this time. It appears that the dihydropyridine receptor is a 30-60 K D peptide subunit of the calcium channel. Distinct receptors for verapamil and diltiazem are poorly defined, but appear to be allosterically related to the dihydropyridine receptor. By their interactions with the calcium channel, the calcium entry-blocking drugs modulate excitation-contraction coupling, which produces their negative inotropic and vasorelaxant effects. They also interact with other slow channel-dependent functions in the specialized conducting tissues of the heart to slow the spontaneous sinus rate and decrease atrioventricular conduction.(ABSTRACT TRUNCATED AT 400 WORDS)

Patients with chronic heart failure have a high incidence of both complex ventricular arrhythmias and sudden death. Therefore administration of antiarrhythmic agents to these patients to prevent lethal ventricular arrhythmias is theoretically appealing. However, at present there are no prospective randomized studies supporting this approach, whereas retrospective studies have yielded conflicting results. Moreover, the use of antiarrhythmic agents in patients with heart failure has two potentially serious side effects: worsening of ventricular pump function and exacerbation of ventricular arrhythmias. Such information suggests that the use of antiarrhythmic agents to treat patients with heart failure who do not have symptomatic ventricular arrhythmias is currently not indicated.

Retrospective studies have shown that patients with severe chronic heart failure who receive long-term treatment with positive inotropic agents have a high mortality rate, but in the absence of controlled trials it remains unclear whether the high incidence of fatal cardiovascular events in these patients is related to treatment or to the severity of the underlying disease. Most of the evidence that suggests a detrimental effect of positive inotropic therapy on survival remains circumstantial. The pooling of data from long-term studies of patients after an acute myocardial infarction suggests that use of digitalis may be associated with an unfavorable effect on survival. The prolonged administration of intravenous or oral catecholamines is associated with a high mortality rate, which may not be seen in similar patients treated conventionally. The presence of intrinsic sympathomimetic activity appears to neutralize the benefits of beta-blockade during the first year after an acute myocardial infarction; treatment with such agents after the first year may increase mortality. Long-term treatment with phosphodiesterase inhibitors is associated with a high mortality rate, which exceeds that reported in earlier years with vasodilator therapy. Nevertheless, most of these studies of positive intropic agents were not performed to evaluate the issue of survival and did not randomly assign patients to treatment groups. Hence, we do not know that the patients entered into these studies were truly comparable to their proposed control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with congestive heart failure have a high incidence of sudden cardiac death that is attributed to ventricular arrhythmias. The mortality rate in a group of patients with class III and IV heart failure is about 40% per year, and half of the deaths are sudden. Half of the patients with New York Heart Association class III or IV heart failure have unsustained ventricular tachycardia detected on a 24 hr continuous electrocardiographic recording. The presence of ventricular tachycardia in patients with congestive heart failure increases the probability of dying; in class III or IV heart failure, the presence of unsustained ventricular tachycardia on a 24 hr continuous ECG recording increases the odds of dying about threefold over a 1 to 2 year follow-up period. Many electrical, mechanical, humoral, and electrolyte abnormalities may promote ventricular arrhythmias in patients with heart failure. Correction of these predisposing factors could reduce the risk of lethal ventricular arrhythmias and therefore every effort should be made to do so. Because there has been no definitive study of the impact of antiarrhythmic drug treatment on the survival of patients with heart failure and ventricular arrhythmias, the role of therapy with antiarrhythmic drugs remains uncertain at the present time.

The high mortality of heart failure is associated with hemodynamic abnormalities, depressed cardiac function, and reduced exercise capacity. That these factors can be modified by drug treatment is of potential prognostic significance. Hemodynamic variables are related to survival, and long-term prognosis is better in patients with only midly abnormal cardiac output or ventricular filling pressures. Indexes of left ventricular function such as ejection or shortening fraction tend to be higher in patients who survive for longer periods. The relation between exercise capacity and survival, however, is unclear. Those patients with severe exercise intolerance (maximal oxygen uptake below 10 ml/min/kg) or with severe symptoms are at great risk of dying. However, exercise capacity and functional class are not related to prognosis when all classes of patients are considered together, especially if class IV patients are excluded. Most of the available data derive from retrospective analyses of trials involving heterogeneous patient populations and aimed at improving left ventricular performance or functional capacity. Large prospective trials aimed primarily at affecting mortality in a broad spectrum of patients are needed to learn more about determinants of survival in heart failure.

Over the past several decades, pharmacologic advances have made it possible to markedly alleviate symptoms in most patients with congestive heart failure. However, the prognosis for these patients remains poor. Five years after the onset of congestive heart failure, only approximately 50% of patients are alive; when cardiac failure develops after myocardial infarction mortality is even higher. Survival rates are only 40% to 60% after 1 year in patients with advanced symptoms who are followed in referral centers. Thirty to fifty percent of deaths are sudden and unexpected. Mortality is highest in patients with severe or progressive symptoms, but it appears to be unrelated to the cause of heart failure or its duration. In general, rate of survival is lowest in patients with the most severe depression of left ventricular function, but no hemodynamic index is capable of providing prognostic information in individual patients. Survival is also reduced in patients with frequent ventricular arrhythmias, marked electrolyte disturbances, and elevated plasma catecholamines, but again, none of these measurements are powerful discriminators between survivors and nonsurvivors. A number of pharmacologic and other interventions have the potential to alter the prognosis of congestive heart failure, either by improving or perhaps even by worsening survival. The pooled data from several short-term controlled trials have raised the possibility that the angiotensin converting-enzyme inhibitors may have a beneficial effect on survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased ventricular volume is one of the most powerful predictors of reduced survival in patients with heart disease. Despite its well-documented prognostic significance, the magnitude of the progression of ventricular dilatation from the acute to the chronic phase of myocardial infarction has only recently been appreciated. In an experimental preparation of myocardial infarction in rats, left ventricular cavitary volume increased progressively even after histologic resolution of the infarct region. We hypothesized that this remodeling of the infarcted left ventricle was a response to an increase in both systolic and diastolic wall stresses and that captopril, by reducing wall stress, would attenuate the process. For comparably sized infarcts, the captopril-treated rats had smaller ventricular volumes at common distending pressures, yet they had maintained or improved cardiac output. Most importantly, long-term captopril therapy also prolonged the survival of these rats with experimental myocardial infarction. The implication of these animal studies is that the potential exists for the attenuation of progressive ventricular enlargement and improvement of survival of patients recovering from a myocardial infarction. At the present time, no information is available in patients as to the therapeutic potential of interrupting this insidious process of ventricular dilatation in order to improve survival. Clinical trials are required to determine whether salutary benefits similar to those observed in animals can be provided to patients recovering from a myocardial infarction.

Support for the concept that neurohormonal mechanisms play an important role in determining the survival of patients with severe chronic heart failure is derived from two lines of evidence: circulating levels of neurohormones are markedly elevated in patients who have a poor long-term prognosis and the survival of high-risk patients may be favorably modified by treatment with specific neurohormonal antagonists. Plasma norepinephrine is a major prognostic factor in patients with severe chronic heart failure, the most markedly elevated levels being observed in patients with the most unfavorable long-term prognosis. Data from uncontrolled studies suggest that low-dose beta-blockade may improve the survival of patients with dilated cardiomyopathy. Similar trends were noted in the Beta-Blocker Heart Attack Trial, in which patients with congestive heart failure before or accompanying their acute myocardial infarction experienced a significant reduction in sudden death when treated with beta-blockers. In contrast, there appeared to be little selective benefit in patients without heart failure, who presumably had low circulating levels of catecholamines. Similarly, serum sodium concentration is a major prognostic factor in patients with severe chronic heart failure, the shortest survival being observed in patients with the most severe hyponatremia. The poor long-term outcome of hyponatremic patients appears to be related to the marked elevation of plasma renin activity in these individuals, since (in retrospective studies) hyponatremic patients appeared to fare significantly better when treated with converting-enzyme inhibitors than when treated with vasodilator drugs that did not interfere with angiotensin II formation. In contrast, there appeared to be no selective benefit of converting-enzyme inhibition on the survival of patients with a normal serum sodium concentration, in whom plasma renin activity was low. These data suggest that neurohormonal systems may exert a deleterious effect on the survival of some patients with severe chronic heart failure, which may be favorably modified by long-term treatment with specific neurohormonal antagonists.

A series of neurohumoral systems are activated in congestive heart failure that contribute to the increased vascular resistance and sodium retention that characterize this disorder. Abnormalities in baroreceptor function are intrinsic to the pathophysiology of heart failure and may subserve the vasoconstrictive and volume overloaded state that defines patient morbidity. Blunted baroreceptor responses to high cardiac filling pressures or depressed cardiac function reduce afferent signals that normally inhibit sympathetic efferent activity, vasopressin release, and indirectly, renin secretion. The resulting increase in neurohumoral activity mediates the redistribution of blood flow that occurs in this disorder. Limb blood flow is usually reduced and may be responsible for exercise intolerance. Decreased renal blood flow and altered intrarenal hemodynamics contribute to sodium retention. In addition, renal vasoconstriction and elevated circulating levels of angiotensin II and vasopressin may contribute to hyponatremia by influencing free water intake and excretion. Hence, baroreceptor dysfunction may be a principal mechanism that contributes to neurohumoral activation and subsequent alteration in vascular resistance and sodium and water balance in congestive heart failure. It may not be coincidental that two principal markers of an unfavorable prognosis in patients with heart failure, high plasma norepinephrine levels and hyponatremia, share baroreceptor dysfunction as a common theme.

CBV for adults with aortic and mitral stenosis is investigational at the present time and should usually be performed within the guidelines of clinical investigation. The technology is an evolving one with regard to types of catheters and balloons, methods of catheter insertion and placement, and patients and valves that are suitable for and will respond well to CBV. The initial results range from disappointing to excellent and must be kept in perspective. The procedure is clearly a palliative one; ideal results are not being achieved at present. Some of the complications are very serious. Nevertheless, CBV is a most promising catheter interventional technique for patients with valvular heart disease. Proper selection of patients and complete reporting of results is important.