Calcium antagonists block the entry of calcium into vascular smooth muscle cells, producing pharmacological vasodilation. Thus, it is not surprising that these drugs are effective in treating unstable angina that is often characterized by increased vasomotion and dynamic obstruction at the site of atheromatous plaques. Nifedipine, diltiazem, and verapamil are all highly and equally effective in reducing painful and painless ischemic episodes in Prinzmetal's variant angina. In patients with unstable angina who have known or suspected significant underlying coronary artery disease, a multipharmacological approach to therapy is warranted. Nifedipine used with beta-blocker drugs is more effective than nifedipine as monotherapy. Diltiazem and verapamil have been shown to be effective when given without beta-blockers in unstable angina patients. In many patients, thrombus formation rather than vasospasm is the major pathophysiological event resulting in progression of the syndrome to infarction or sudden death. In these patients, antiplatelet, antithrombotic, or antiplatelet and antithrombotic therapy is of utmost importance to maintain adequate coronary flow. Nonresponders to medical therapy with unstable angina have a high prevalence of eccentric and multiple coronary stenoses with a high incidence of thrombi. The best responders to calcium antagonist therapy are patients with concentric coronary stenoses. In summary, calcium antagonists are highly effective in reducing ischemic episodes in patients with Prinzmetal's angina and effective for therapy for unstable angina when used in conjunction with other forms of medical treatment aimed at the processes of platelet activation and thrombus formation.

Asymptomatic myocardial ischemia likely results from an imbalance between myocardial oxygen supply and demand. Although changes in coronary vasomotor tone probably are important in the genesis of asymptomatic ischemia, heart rate increases also play a critical role. Consequently, all three classes of antianginal agents, nitrates, beta-blockers, and calcium entry blockers, have been shown efficacious as monotherapy for silent ischemia. Comparative studies have demonstrated that agents or combination therapies that control heart rate increases during normal activities are superior to regimens that increase average heart rate. Consideration of the side-effect profile of any therapy for asymptomatic patients also is important. The ideal therapy would be with one drug that reduced coronary vasomotor tone and myocardial oxygen demand during normal activities and had no adverse effects. Currently, the calcium entry blockers, diltiazem and verapamil, most closely approximate this ideal. It has yet to be proven, however, that the treatment of asymptomatic myocardial ischemia improves the prognosis of patients with coronary artery disease, and the risk-benefit ratio of pharmacological therapy is not established.

The calcium channel blockers are useful in treating many cardiovascular disorders. Due to their anti-ischemic and spasmolytic properties, the cardioprotective effects of these agents have been studied in the setting of acute myocardial infarction. This paper will review this application with respect to limitation of infarct size, reduction of mortality, and incident morbidity rates. Of the agents currently available for clinical use, nifedipine has been studied most extensively. This agent shows no beneficial effects and its use can, in fact, be harmful in this setting. Of the few trials that have been conducted with verapamil, none have shown a preventive effect on death, reinfarction, or postinfarction angina. Both verapamil and diltiazem might limit infarct size although further confirmation is required. At the present time, diltiazem is the only agent shown to have short- and long-term benefits on clinical outcome in patients with acute myocardial infarction. The success of prophylactic diltiazem is, however, critically dependent on proper patient selection. In particular, those patients with non-Q wave infarction, normal left ventricular function, or both can be expected to derive the greatest benefit in terms of reduced mortality and incident morbidity.

The calcium entry-blocking drugs produce effects on the coronary vasculature that might be expected to exert anti-ischemia activity. Although these agents cause little vasodilation of the epicardial coronary arteries during basal conditions, they block vasoconstriction that can increase stenosis severity during isometric exercise and interrupt coronary artery spasm in patients with variant angina. Administration of the calcium blockers causes transient vasodilation of the coronary resistance vessels, followed by decreased responsiveness to a brief ischemic stimulus. This results in decreased coronary reactive hyperemia after transient coronary occlusion. By preventing excessive ischemic vasodilation of the resistance vessels, these agents can enhance perfusion of the subendocardium distal to a flow-limiting coronary stenosis. The calcium entry blockers have relatively little effect on the immature coronary collateral vessels that exist at the time of acute coronary occlusion. Diltiazem, however, has been demonstrated to increase collateral blood flow in animals in which chronic coronary occlusion has resulted in growth of moderately well-developed collateral vessels.

Calcium antagonists are potent arterial vasodilators that do not lead to relevant chronic sympathetic reflex activation and sodium and volume retention. This favorable hemodynamic profile renders them suitable for monotherapy of hypertension in which they can reduce the calcium influx-dependent functional component of elevated vascular resistance that may be enhanced by altered vascular muscle cation handling and increased intracellular free calcium concentrations. Clinical studies have proved their efficacy, safety, and good tolerability alone or in combination with other drugs in uncomplicated hypertension in which they are particularly effective in older, low renin, and possibly, black patients. These properties and their efficacy in the treatment of severe and accelerated hypertension or hypertensive emergencies make them a valuable addition to already available drug therapy.

The calcium ion is recognized as having a ubiquitous role in a wide range of physiological responses. The calcium entry blockers have assumed a greater role than first thought possible in the management of cardiovascular disorders. As a group, they have multiple effects and can be tailored to meet specific needs. The drugs are well tolerated, thus making them useful for chronic administration. The efficacy of the calcium entry blockers can be enhanced when combined with other therapies such as beta-adrenoceptor antagonists and inhibitors of angiotensin converting enzyme as applied to patients with hypertension, angina pectoris, or both. The range of indications and potential uses of the calcium entry blockers demands an understanding of the role of the slow inward current in cardiac and vascular smooth muscle. This review focuses on the pharmacological actions of the calcium entry blockers and relates these events to their clinical applications in an effort to achieve an understanding of their multiple therapeutic uses.

Left ventricular hypertrophy (LVH) is a structural adaptation of the heart and is a response to increased hemodynamic and metabolic demands, which are most commonly caused by systemic hypertension. LVH induced by hypertension is associated with reduced myocardial compliance, structural alterations, and changes in coronary perfusion. Calcium entry blockers have caused LVH regression both in experimental studies and in clinical trials. Although their efficacy as antihypertensive agents is primarily due to their vasodilating properties, the mechanisms by which calcium entry blockers accomplish LVH regression are complex and include various hemodynamic and neurohumoral factors. Calcium entry blockade has decreased LVH with no apparent deterioration of left ventricular function. Because LVH is a major risk factor for sudden cardiac death and other cardiac morbidities, it is possible that the regression of LVH can improve the prognosis in hypertensive patients.

Left ventricular hypertrophy (LVH) is a common sequela of long-standing essential hypertension. LVH cannot be considered, however, an adaptive process only serving to normalize wall stress but can be considered one that significantly increases the risk of sudden death, myocardial ischemia, congestive heart failure, and other cardiovascular diseases. Patients with LVH exhibit impaired ventricular filling, ventricular arrhythmias, and myocardial ischemia even in the absence of coronary artery disease. LVH can be prevented or reversed by a variety of antihypertensive agents including calcium channel blockers and angiotensin converting enzyme inhibitors. Calcium channel blockers, more than angiotensin converting enzyme (ACE) inhibitors, suppress ectopic impulse generation, improve ventricular compliance, and alleviate myocardial ischemia while preserving or improving the contractile state. In contrast, ACE inhibitors can be particularly useful in patients with LVH and diminished ventricular contractility and in preventing chamber dilatation after myocardial infarct. These favorable cardiovascular effects of both calcium channel blockers and ACE inhibitors are a reason for optimism that carefully tailored therapy will ultimately diminish the well-documented risk of cardiovascular morbidity and mortality associated with LVH.

Randomized, placebo-controlled trials have documented that both streptokinase and rt-PA given early are associated with limitation of infarct size, improved ventricular function, and reduced mortality. Other concerns, however, documented experimentally include myocardial hemorrhage, the "no-reflow" phenomenon, myocardial "stunning," reperfusion-induced injury, and clinically, rethrombosis that occurs at a rate of 20% and reinfarction at 8-10%. Thus, even with the ideal thrombolytic agent, adjunctive therapy to prevent rethrombosis will remain a requisite to obtaining long-term benefit. Calcium blockers in association with reperfusion have been shown experimentally to be protective, resulting in limitation of infarct size and improved ventricular function. There is no data on the role of calcium blockers in conjunction with thrombolysis in patients. Results are available from two randomized trials with the calcium blocker, diltiazem, in patients with non-Q wave infarction. In the short-term trial involving 576 patients with non-Q wave infarction, the incidence of early reinfarction was reduced by 50%, and in the long-term study (non-Q wave infarction, n = 634), reinfarction and death were reduced by 40% after 1 year and by 34% after 4.5 years. Non-Q wave infarction is believed to undergo early spontaneous reperfusion based on the following: small infarct size, contracture necrosis at postmortem, early peaking of plasma CK, coronary patency on angiography, residual ischemia, and a high incidence of reinfarction. Thus, thrombolysis occurring spontaneously or induced therapeutically is associated with a high incidence of reinfarction. The implications of these clinical studies together with the experimental data suggests that the hypothesis of a calcium blocker being important adjunctive therapy following thrombolysis is worthy of clinical evaluation.

CAD is a complex disease with multiple etiologies and aggravating events. Yet, elevated plasma cholesterol levels, chiefly in the form of LDL, are essential for the progression of the atherosclerotic lesion. Any total plasma cholesterol level above an ideal of 180 mg/dl (and an LDL cholesterol level of 100 mg/dl) must be considered atherogenic in the presence of other risk factors. In patients at high risk for death from CAD, combined diet and drug therapy should have as a goal the attainment of ideal lipoprotein values. Drug therapies are now available that make it possible to substantially lower elevated LDL levels in almost all patients and even to achieve ideal levels in those at highest risk.

Oxygen free radicals are known to be generated during periods of ischemia followed by reperfusion. There is still some controversy, however, concerning the use of electron paramagnetic resonance spectroscopy to accurately detect and identify the free radical species that are formed. There is no doubt that oxygen radicals are deleterious to the myocardium; free radicals cause left ventricular dysfunction and structural damage to myocytes and endothelial cells in both in vitro and in vivo preparations. Potential sources of these cytotoxic oxygen species include the xanthine oxidase pathway, activated neutrophils, mitochondria, and arachidonate metabolism, yet the crucial source of free radicals in the setting of ischemia and reperfusion is unresolved. There is little doubt that oxygen radicals play a role in the phenomenon of stunned myocardium induced by brief periods of ischemia followed by reperfusion; numerous studies have consistently observed that pretreatment with free radical scavengers and antioxidants enhances contractile function of stunned, postischemic tissue. Whether oxygen free radical scavengers administered only during reperfusion enhance recovery of stunned myocardium in models of brief ischemia remains to be determined. In models of prolonged ischemia (2 hours) followed by reperfusion, we have not observed a beneficial effect of scavengers on stunned myocardium. The issue of whether oxygen free radical scavengers are capable of reducing so-called irreversible or lethal reperfusion injury remains, in our opinion, unresolved. Although some studies have observed that agents such as superoxide dismutase and catalase reduce infarct size in ischemia and reperfusion models, many others have reported negative results. Additional studies will be needed to resolve this ongoing controversy. Oxygen free radicals may also contribute to reperfusion-induced arrhythmias in rodent heart preparations; however, less data are available in other animal models. The concept of reperfusion injury should not be considered a deterrent to reperfusion for the treatment of acute myocardial infarcts in the clinical setting. Thrombolytic therapy reduces myocardial infarct size, enhances recovery of left ventricular function, and improves survival. Whether incremental beneficial effects on these parameters will be obtained when oxygen radical-scavenging agents are used as adjuvant therapy to thrombolysis in patients remains to be determined.

Heart transplantation involves chronic effects due to denervation, rejection, and treatment of rejection. The chronically denervated dog heart provides a model for the effects of denervation alone. These hearts have been shown to contain intrinsic neurons with VIP and NPY as possible neurotransmitters. Myocardial tissue noradrenaline concentration falls to very low levels after degeneration of postganglionic sympathetic neurons, but dopamine remains in near-normal concentration and is probably synthesized extraneuronally. ANP is present and released normally; however, the natriuretic response to atrial distension is blunted, suggesting that this response is mainly due to a reflex mechanism. Chronically denervated myocardial tissue exhibits increased oxygen consumption in vitro and increased Na-K, ATPase activity but has normal tissue levels of ATP and creatine phosphate. Glucose oxidation is inhibited in vivo, associated with increased levels of fructose-6-phosphate but normal glucose-6-phosphate, suggesting inhibition of phosphofructokinase activity. However, the enzyme protein concentration of phosphofructokinase, as judged by maximal in vitro activity, is normal. Maximal in vitro activities of succinate dehydrogenase, cytochrome oxidase, monoamine oxidase, calcium-dependent ATPase, and glyceraldehyde-3-dehydrogenase are also normal. From these findings, we would predict that patients with transplanted hearts are likely to show myocardial metabolic inefficiency.

Proarrhythmia defined as the exacerbation of existing arrhythmias or the genesis of new arrhythmias de novo may result from any antiarrhythmic agent. The two general clinical syndromes of sustained arrhythmias that result appear to have distinct clinical properties that are consistent with the proposed basic mechanisms of arrhythmogenesis. Torsades de points occurs most commonly in association with administration of type Ia antiarrhythmic agents and has characteristics most consistent with triggered activity mediated by early after depolarization. Conversely, incessant, sustained, monomorphic, wide complex ventricular tachycardia occurs most commonly in association with type Ic antiarrhythmic agents and has characteristics most consistent with incessant reentry. These general subdivisions are probably oversimplified, and in fact, much overlap likely exists. In addition, these proposed mechanisms may not apply to other forms of proarrhythmia such as an increased frequency of isolated ventricular premature couplets or repetitive forms. Furthermore, proarrhythmia may also occur during treatment of supraventricular arrhythmias; although some of these described syndromes are consistent with incessant reentry, the clinical syndromes are not sufficiently defined to better characterize potential mechanisms. Further investigation, therefore, is needed to better define the mechanisms in question, but the mechanisms proposed in this article help to provide a rational approach toward understanding and dealing with clinical proarrhythmia.

Reperfusion injury includes a spectrum of events, such as reperfusion arrhythmias, vascular damage and no-reflow, and myocardial functional stunning. The concept of reperfusion injury remains controversial with many proposed mechanisms when applied to humans, whereas in animal models, there are two main proposed mechanisms: calcium over-load and formation of oxygen free radicals. To prove that reperfusion injury is specifically caused by reperfusion would require evidence that an intervention given at the time of reperfusion can diminish or abolish the injury as in the case of arrhythmias, which are thought to be mediated by excess recycling of cytosolic calcium with delayed afterdepolarizations and ventricular automaticity. In the case of myocardial stunning, the phenomenon may be mediated, at least in part, by a burst of free radicals formed within the first minute of reperfusion and improved by free radical scavengers given at the time of reperfusion. The alternate hypothesis is that cytosolic calcium overload damages mechanisms for normal intracellular calcium regulation so that the stunned myocardium responds to agents that are thought to increase intracellular cytosolic calcium, such as beta-receptor agonists. A further component of reperfusion injury, under active investigation, is microvascular damage with alterations at the level of platelets, leukocytes, and endothelial integrity. From the therapeutic point of view, the divergent results of experimental interventions and the possibility that the abrupt onset of reperfusion in animals differs from the situation in humans with thrombolysis means that the best way currently available to limit reperfusion injury is by minimizing the ischemic period by early reperfusion and by optimizing the metabolic status of the ischemic myocardium at the end of the ischemic period.