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Are Calcium Antagonists Cardioprotective?

? In each situation they appear to improve the prognosis. If calcium antagonists are to become first-line treatments for angina and hypertension, should they also have a cardioprotective role? Clinical data on cardioprotection can only be obtained from large-scale trials. In the case of calcium antagonists such data may not be available for many years. However, since these drugs are already in widespread use, it seems

phylactically to animals whose coronary arteries are to be occluded [l,2], to hypertensives [3], and, both acutely [4,5] and chronically [6,7], to patients after cardiac infarction. In each situation they appear to improve the prognosis. If calcium antagonists are to become first-line treatments for angina and hypertension, should they also have a cardioprotective role?
Clinical data on cardioprotection can only be obtained from large-scale trials. In the case of calcium antagonists such data may not be available for many years. However, since these drugs are already in widespread use, it seems reasonable to ask now: (a) Are there theoretical reasons for supposing they may reduce the adverse effects of ischaemic heart disease? (b) Are there animal data suggesting that these drugs reduce infarct size? (c) Are there any clinical data on the use of calcium antagonists in patients at or after a myocardial infarction? These questions will be considered in turn.

Possible Cardioprotective Actions of Calcium Antagonists
Calcium antagonists could reduce infarct size by their impact on the supply and demand imbalance in the myocardium. This may be achieved by improving coronary blood flow or by reducing heart work. Calcium antagonists might also reduce mortality by reducing the damage caused by hypoxia and by having an antiarrhythmic action. Coronary Blood Flow (a) Vasospasm. Calcium antagonists reduce coronary artery spasm [8,9] and act as vasodilators [10]. These effects have been of interest in recent years as it has been increasingly appreciated that angina and infarction are by no means always the result of a fixed obstruction. The fact that recurring anginal episodes occur at rest, when there is no increased demandfl 1-13], and take place despite considerable variability in fixed coronary lesions [14], shows that another, spontaneous, process is operating. Such vasospasm may be assumed to play a role in Prinzmetal's angina, in situations where angiographic evidence or ergonovine injection testing is positive and where anti-vasospastic drug treatment is helpful.
In their investigations into the pathophysiology of MI, Maseri's group [15] showed that infarction occurred in 37 of 76 patients with rest angina involving coronary spasm as shown by angiography. The infarcted area was closely associated with the region supplied by the vessel undergoing spasm. Calcium antagonists have been repeatedly shown to possess anti-vasospastic properties. Through their block of excitation-contraction coupling in coronary artery smooth muscle [8] they reduce vascular tone, and therefore resistance, with a subsequent increase in coronary blood flow [9].
(b) Platelets. Platelet aggregation exacerbates the effects of diseased coronary arteries by predisposing to occlusive thrombus formation [16] and by the release of vasoconstrictor substances [17,18]. Calcium antagonists reduce platelet aggregation, a calcium dependent process [19], an effect which has been demonstrated both in vitro [20] and in patients with angina [19,21]. (c) Viscosity and Flow. Some drugs are reputed to improve tissue perfusion by modifying the flexibility of red blood cells and thereby facilitating their flow down narrow blood vessels. There is evidence that an increase in red cell calcium decreases deformability [22] and that calcium antagonists increase it [23].

Heart Work
The ability of calcium antagonists to improve cardiac haemodynamic efficiency and thereby reduce demand on the heart is well known. By their actions on cardiac muscle and arterial smooth muscle, calcium antagonists may reduce wall tension and peripheral resistance. Of these, the dilating effect on the peripheral arteries is Protection from Hypoxic Damage At the onset of a myocardial infarct several processes may lead to an increase in intracellular calcium which may be the cause of cell death [24,25]. First, catecholamines released at this time will markedly increase calcium uptake into myocardial cells [26]; this causes activation of the calcium-dependent myofibrillar ATPase and results in an abnormally high consumption of energy-rich phosphates. In addition, the mitochondria try to take up calcium ions from the cytosol and so consume energy.
This causes decoupling of oxidative phosphorylation and structural damage. A reduction in the cellular uptake of calcium across the cell membranes could therefore be expected to produce a protective effect. This may be achieved by blockade of the slow calcium channels [10] and also by an effect on calmodulin [27,28]. If calcium antagonists have this effect on the hypoxic cells in a human myocardial infarct, it is possible that they might reduce muscle damage.

Anti-arrhythmic Action
Beta-blockers reduce the risk of sudden death from myocardial re-infarction and this might be due to their ability to reduce the extent of ischaemia and to block the development of arrhythmias [29]. This is of interest since beta-blockers do not have a major therapeutic role in the treatment of ventricular tachyarrythmias. The hope that calcium antagonists may reduce mortality in the same way has received little attention.
Correction of calcium influx into ischaemic myocardial cells can retard the development of ventricular fibrillation [30]. Originally, the retardation was ascribed to increased coronary blood flow and reduced cardiac work, as shown by studies of verapamil in dogs with com-plete^ 1] or temporary [32] coronary artery occlusion. Recently, however, it has been demonstrated that calcium antagonists can directly suppress ventricular fibrillation induced by ischaemia [30,33,34]. Nifedipine, widely thought to have few anti-arrhythmic actions, reduces the incidence of ventricular fibrillation, ventricular tachycardia and ventricular ectopic activity in rats [35] and inhibits calcium-dependent myocardial excitability in dogs with one-day-old infarcts [36].

Evidence of Cardioprotection from Animal Studies
The three major calcium antagonists currently in clinical use?verapamil, nifedipine and diltiazem?have all been investigated in a wide variety of animal models. The data from these have to be interpreted with caution. Drugs which act as vasodilators must be expected to have different effects in animals which readily form a collateral circulation, such as dogs [37], compared with those which do not, such as pigs and baboons [38]. Second, where infarct size is the end point, care must be taken to ensure that the time allowed for its development is compar-able^]. Third, the effects of surgery and anaesthesia have to be considered [40]. Finally, different calcium blockers have very different actions [41][42][43]. Nifedipine causes coronary and peripheral vasodilatation while having few chronotropic effects. Verapamil and diltiazem prolong atrioventricular nodal conduction and have less effect on vascular smooth muscle. In addition, verapamil and nifedipine are negative inotropic agents, while diltiazem is probably not.

Verapamil and its Analogues
In open chest anaesthetised dogs, pre-treatment with verapamil reduces the extent of tissue necrosis as measured histologically following left circumflex artery occlusion [44]. DaLuz [45] found that treatment both before and after occlusion increased collateral blood flow to the ischaemic myocardium, reduced heart rate, thus reducing metabolic demand, and reduced ST elevation, indicating a decrease in infarct size. In addition, Wende [46] demonstrated that verapamil infusion during coronary artery ligation reduced infarct size as measured by epicardial ST segment changes. Verapamil also selectively depressed ischaemic myocardium, thereby reducing injury to the ischaemic tissue [47]. However, the favourable effects of intravenous verapamil treatment after ligation have been challenged [48,49].
In conscious dogs, DeBoer [50,51] was the first to find that verapamil administered one hour after infarction produced a short-term significant decrease in infarct size. Yellon [52] extended this by showing the longer term tissue sparing effect of verapamil treatment. Urquhart [40], using physiologically equipotent doses of verapamil, nifedipine and diltiazem, showed that all three drugs caused coronary and systemic vasodilatation, reduced heart rate and reduced myocardial contractility following left circumflex artery ligation. Two other studies have yielded negative results [53,54].
Cardioprotective effects have also been demonstrated in other animals including the open chest anaesthetised baboon [55], rabbits [56] and in the isolated rat heart [34].
Verapamil and its analogues clearly appear to have significant cardioprotective effects in most animal models, but a number of studies [47,57] have emphasised the need to use low doses of verapamil since higher doses will precipitate heart failure with consequent extension of the infarcted area.

Dihydropyridines (nifedipine and related compounds)
Using open chest anaesthetised dogs to assess cardioprotection, the dose of dihydropyridines, like that of verapamil, was found to be important. Low doses improve regional myocardial blood flow and cause reduced creatine kinase (CK) release while higher doses cause an increased heart rate and hypotension, with resultant extension of the infarcted area [58][59][60]. Heart rate and blood pressure readings should therefore be used to monitor dosage. Henry [61] demonstrated the efficacy of nifedipine in producing increased collateral perfusion to ischaemic myocardium and reduced vascular resistance distal to the occlusion, and Clarke [62] showed a reduction in the injury volume. Weintraub [63] emphasised the direct effects of nifedipine on myocardial cells and found an increase in sub-endocardial blood flow in non-ischaemic tissue with improved muscle function in the ischaemic zone.
In conscious dogs it has been shown that nifedipine increased collateral blood flow to ischaemic myocardium and reduced ischaemic injury as measured by enzyme losses [64,65], Melin [66] attempted to mimic the clinical situation further by delaying nifedipine intervention until three hours after coronary artery occlusion. Even then there was a reduction in infarct size combined with an increased collateral blood flow.
As with verapamil, studies using the baboon, rabbit and rat hearts [67][68][69]  In chronically instrumented dogs, Franklin [75] showed that diltiazem improved collateral blood flow to the ischaemic tissue. Clozel [76] reinforced this finding by demonstrating improved function of hypokinetic muscle segments after treatment with diltiazem.
Confirmatory studies on the efficacy of diltiazem have also been performed on pigs [77], rats [78] and isolated preparations [79]. These studies and those in dogs indicate that diltiazem is a useful protective agent. A number of authors have actually stressed the advantages of diltiazem over the other calcium antagonists. In comparative studies, Urquhart [40] examined left ventricular function in healthy conscious dogs and showed that at equipotent doses diltiazem did not alter the indices of left ventricular contractility, whereas verapamil and nifedipine reduced them.

Evidence from Clinical Trials
Verapamil Several studies have been reported, but as yet no longterm clinical trial has been completed. Over a threemonth period Hansen[80] Heikkila and Neiminen[85] conducted the first study of the effect of verapamil on myocardial contractile performance in patients. They found that verapamil given intravenously caused increased regional contractile function without inducing a more widespread depression of normal myocardial tissue.
Finally, one study [86] has shown that intravenous treatment in the range of 0.5-12 hours (with a mean of 4 hours) after onset of pain produced no evidence of a reduction in infarct size (as measured by CK release) in 119 patients. The authors attributed this negative finding to the delay in treatment.

Dihyd.ropyrid.ines
Several studies of nifedipine given to patients soon after infarction[87-89] have shown that the drug is well tolerated and tends to have beneficial haemodynamic effects, but the studies have been too small to demonstrate any cardioprotective effect.
Muller et al. [90] have conducted the only randomised double-blind, placebo-controlled multicentre trial, using a 20 mg oral dose of nifedipine. In 181 patients selected from a sample size of 3,143, no prevention of progression of threatened myocardial infarction or limitation of necrosis in patients with acute MI was found. The study sample was not large enough to make any estimates of effects on mortality. This discouraging result may have been because treatment was not given early enough (4.6 ? 0.1 hr after onset of pain). As previously described, early treatment is required to obtain myocardial salvage.

Conclusion
On the basis of the evidence considered in this review the following conclusions may be drawn about the possible cardioprotective actions of the calcium antagonists. First, there are a number of well-documented mechanisms by which these drugs might reduce the size of an infarct and the complications that may result from it. They may improve flow, reduce demand and help to control potentially lethal ventricular arrhythmias. Second, in the majority of animal studies, calcium antagonists have successfully reduced infarct size. Finally, some of the small-scale clinical trials have yielded encouraging results. These, of course, must be interpreted with some caution since the relationship between various measures of infarct size, such as ECG changes and enzyme release, the amount of myocardial damage and the prognosis may not be a close one. Furthermore, the only study of any size yielded a negative result and further data based on much larger double-blind controlled trials are needed. Nevertheless, taken overall, the evidence must suggest that calcium antagonists may have a cardioprotective role, and interest in this subject is certain to continue and probably to increase.