Calcium antagonists and the ischemic myocardium

International Journal of Cardiology, 15 (1987) 267-285 Elsevier

261

IJC 00535

Review

Calcium antagonists and the ischemic myocardium Winifred

G. Nayler

Department of Medicine, lJniversi[v of Melbourne, Austin Hospttal, Heidelberg, Vwtoria, Aurtralla (Received

Nayler WG. Calcium 1987;15:267-285.

4 November

antagonists

1986; accepted

and

16 December

the ischemic

1986)

myocardium.

Int

J Cardiol

Recent laboratory studies have shown that the calcium antagonists (slow channel blockers) can protect the myocardium against the consequences of experimentally induced ischemia and reperfusion. With one recent exception, however, clinical trials relating to the effectiveness of these drugs in the management of patients with myocardial infarction have been disappointing. This paper explores this apparent discrepancy. Key words: Calcium antagonist; Ischemia; Infarction; Calcium overload; Verapamil; Nifedipine; Diltiazem

Reperfusion

injury:

Introduction Recent clinical trials with beta-adrenoceptor antagonists [1] and platelet aggregate inhibitors [2] have established their efficacy in the management of patients with ischemic heart disease. With one exception [3], however, comparable calcium antagonist trials have been disappointing [4-71. This apparent failure of the calcium antagonists is surprising, since many laboratory studies [8-161 have shown them to be effective. Even under controlled laboratory conditions, however, the calcium antagonists do not always provide protection [17-191. The critical question which needs to be answered, therefore, is not whether these drugs can protect but rather how and when to use them to achieve such an effect. The answer lies in the time course of the changes caused by ischemia [20], and the determinants of lethal and hence irreversible injury [21].

Correspondence to: Winifred G. Nayler, Department Hospital. Heidelberg, Victoria, 3084, Australia.

of Medicine,

0167-5273/87/$03.50

B.V. (Biomedical

0 1987 Elsevier Science Publishers

University

of Melbourne,

Division)

Austin

268

The Ischemic Myocardium A sudden, severe and sustained reduction in coronary flow has a profound effect on the myocardium (Fig. l), largely because adenosine triphosphate production is impaired [22]. The heart, however, continues using adenosine triphosphate - for electromechanical coupling, active tension generation, and as substrate for the various ATPases, including those concerned with maintaining ionic homeostasis. Within only a few minutes of ischemia aerobic metabolism ceases, leaving anaerobic metabolism as the major source of energy production [23]. Anaerobic metabolism, however, generates only 3 moles of adenosine triphosphate per mole of glucose, compared with 38 moles generated by aerobic metabolism. Moreover, the capacity of the myocardium to generate adenosine triphosphate by anaerobic metabolism is limited, the metabolic pathways being pH sensitive [23,24], and the glycogen supply limited. Under normothermic conditions, therefore, the ischemic myocardium is using its adenosine triphosphate faster than it can be replenished, and unless coronary perfusion is restored the levels of adenosine triphosphate progressively fall. At the same time the levels of adenosine diphosphate and inorganic phosphate increase [22]. To replenish its dwindling supply of adenosine triphosphate, the heart converts the accumulated adenosine diphosphate to adenosine triphosphate, producing adenosine monophosphate as a by-product and delaying adenosine triphosphate exhaustion. The adenosine monophosphate is not retained, however, but is dephosphorylated to adenosine, and then degraded to inosine and hypoxanthine (Fig. 2). Since the cell membrane is permeable to these degradation products they diffuse into the extracellular space [25,26] and are therefore lost from the tissue. The result is a progressive depletion not only of the energy-rich phosphates but also of the

ISCHEMIA

/\ MECHANICAL

BIOCHEMICAL

/\ Slowed

relaxation

r$

,-,-‘I\ Depletion of tissue ATP & CP

Activation glycolyris

I + Electrical instability

-

I

Mobilization of tissue catecholamines

Release of prostanoids

Acidosis

Failure of ionic homeortaris 1 Raised tissue Ca”

of

J)\. Inactivation

Activation

of Na’/Ca=+ exchanger

of lysosomal enzymes

1 Activation of Ca*+-sensitive ATPases, phospholipases & proteases

Fig. 1. Schematic representation blood flow.

of the consequences

of a sustained and severe reduction in coronary

269 Effect of ischemia on energy production

Interrupted coronary

Inhibition of oxidative phosphorylation

Activation of glycolysis /\ G Iycogen

ATP and CP depletion

H*accumulation

ADP accumulation 1 ATP + AMP

I Adenosine Inhibition of glycolysis

I + Hypoxanthine inosine xanthine

Fig. 2. The direct effect of ischemia

on the cardiac

adenine

nucleotides.

adenine nucleotide precursors. Once this happens, restoring coronary flow cannot trigger immediate adenosine triphosphate regeneration, even although the mitochondria may still be viable, because the precursors have been lost. Other changes have also occurred by this time. Tissue osmolarity will have increased [27], potassium efflux will have occurred [28], and the endogenous stores of norepinephrine will have been mobilized [29]. At the same time the circulating levels of catecholamines increase, reflecting activation of the sympathetic nervous system [30,31]. In summary, ischemia imposes a progression of metabolic changes on the myocardium, starting with the switch from aerobic to anaerobic metabolism and proceeding to a condition in which the affected tissue is depleted of adenosine triphosphate, creatine phosphate purine precursors and norepinephrine, has an increased intracellular osmolarity, is acidotic, and has lost its capacity to maintain ionic homeostasis. Once this condition has been reached, restoring coronary flow irrespective of whether this involves thrombolysis, angioplasty, surgical intervention, increased collateral flow, or spontaneous or drug-induced abolition of spasm - can trigger neither functional nor metabolic recovery, since the tissue is already irreversibly injured [20,22]. Naturally the metabolic consequences of a short period of ischemia are less severe. The increase in osmolarity is less marked [27], more adenosine triphosphate and creatine phosphate is retained, the tissue is less acidotic [28], and the endogenous stores of norepinephrine remain intact [29]. Under these conditions the ischemia-induced changes are not lethal, and reperfusion can therefore be expected to promote functional and metabolic recovery.

270

Even when the ischemic episode is prolonged to such an extent as to lethally injure the tissue, its ultrastructural appearance prior to reperfusion may still appear to be relatively unaltered. Some cell swelling (Fig. 3) will be apparent, but unless the ischemic episode extends well beyond twenty minutes, the myofibrils remain in regular array and the sarcolemma appears to be intact and contiguous. By this time, however, glycogen (Fig. 3) has usually disappeared from the cytosol, the nuclear chromatin is peripherally aggregated, and some mitochondria are swollen. As with the metabolic changes that occur during ischemia the severity of the changes in morphology progress with time, so that after hours of inadequate perfusion the ultrastructure becomes severely disturbed, the myofibrils disarrayed, the mitochondria swollen and the sarcolemma disrupted [27].

Reperfusion Upon reperfusion, the previously oxygen, metabolic precursors, water,

ischemic tissue is presented with unlimited sodium and calcium. How the tissue reacts

Fig. 3. Electron micrographs showing the changes in ultrastructure caused by either an ischemic episode or an ischemic episode followed by reperfusion. A. After 60 minutes of aerobic perfusion the myofibrils are relaxed, there is abundant glycogen. the nuclear chromatin is dispersed and the sarcolemma intact. B. After 60 minutes of global ischemia. Note the contracted myofibrils. clumped nuclear chromatin, the loss of glycogen and the accumulation of fluid beneath the sarcolemma ( *). C. After 60 minutes of global ischemia followed by 15 minutes of reperfusion there is a loss of myofibrillar material and the sarcolemma is discontinuous (arrows). Bars represent 0.5 pm.

27

Fig. 3 (continued).

272

depends largely upon the duration and severity of the preceding ischemic episode, and the ability of any intervention which may have been introduced during or before that episode to delay the progression of damage caused by the inadequate perfusion. In isolated hearts, if reperfusion occurs within 20 minutes, adenosine triphosphate slowly regenerates [21], sarcolemma integrity is retained [27] and functional recovery ultimately occurs. Under these circumstances sufficient ATP was probably available at the moment of reperfusion to ensure that ionic homeostasis could be maintained, even when sodium (Na+) and calcium (Ca*‘) ions become freely available in the extracellular fluid. Reperfusion under these conditions must be beneficial, because without it the cells in the affected area would ultimately have died. An entirely different picture emerges if the duration of the ischemic episode extends until the tissue reserves of adenosine triphosphate (and creatine phosphate) are exhausted, the adenine nucleotide precursor pool is depleted, protons have accumulated intracellularly, the intracellular osmotic pressure has increased and the sarcolemma has either been disrupted or weakened. Under these conditions reperfusion alone is of doubtful benefit, because it presents energy-depleted tissue with unlimited water, sodium and calcium ions at a time when its capacity to maintain homeostasis has been lost. The sodium and calcium ions flow along their concentration gradients and accumulate intracellularly [32]. The gain in sodium ions is of importance both because of its osmotic effect and because these ions exchange for calcium ions (Fig. 4), the exchange mechanisms surviving prolonged periods of ischemia and reperfusion [33]. The reperfusion-induced gain in calcium (Table 1) is catastrophic. Some of this calcium accumulates in the mitochondria, where it interrupts oxidative phosphorylation, and hence adenosine triphosphate production [9]. It will also cause energy wastage (Fig. 5), if any energy (as adenosine triphosphate) is still available, and almost certainly contributes to the development of sustained contraction and hence to a sustained increase in left ventricular end-diastolic pressure. A raised left ventricular end-diastolic pressure is highly undesirable, because it will physically constrict coronary blood vessels which are still patent, stress the already fragile sarcolemma, and limit left ventricular filling. The whole situation is made worse by 3 Na*

T

t tt

/E;,+KAtt

LA\ ADP

Ca2+

3 Na*

ATPase

/rr

ATP

Caz+]Na+ TTTTT Exchanwr

4

4

2 K+

Ca2+

Fig. 4. Schematic representation across an intact sarcolemma.

Na+ of the various

mechanisms

Ca2+ involved

in transporting

Na+

and Ca*+

Effect of uncontrolled Ca2+ influx

Ca2’-overload

Activation of Ca2+- dependent pathways

ATPases

Contracture

Proteases

Phospholipases

Membrane disruption

Arachidonic acid accumulation

J\ Prostacyclin

Platelet aggregation

Thromboxane+

1

1

\&

Coronary constriction

Thrombus formation

.++educe

..

‘coronary flo

., .

Fig. 5. Schematic

consequences

of the uncontrolled

activation

of Ca’+-dependent

mechanisms

the fact that many of the endogenous proteases and phospholipases are Ca2+-dependent and therefore will be activated as cytosolic Ca2+ rises. The end result is a severely contracted myocardium which is ‘overloaded’ with calcium, has a damaged and by now discontinuous sarcolemma (Fig. 3) and is no longer capable of regenerating its own energy-rich phosphates, despite a restored supply of oxygen and glucose. Cell death and tissue necrosis is the inevitable consequence [34,35].

Route of Calcium Entry During Post-Ischemic Reperfusion and the Effect of the Calcium Antagonists Whereas ischemic hearts which are not yet lethally injured can be reperfused without becoming overloaded with calcium, lethally injured hearts gain excess calcium upon reperfusion (Table 1). If (Fig. 5) this uncontrolled calcium gain is the final mediator of cell death and tissue necrosis it is appropriate to consider the possible route(s) of calcium entry. Probably there is no single route but rather a progression of routes. During the first few seconds of reperfusion, when the sarcolemma may still be intact, although fragile, calcium may enter through normal physiological pathways, which include exchanging for sodium and through the Ca2+-selective ionic channels (Fig. 4). If the tissue triphosphate is already severely depleted, however, then the mechanisms for maintaining homeostasis with respect to any calcium that enters - even if it enters through a normal pathway - will be

274 TABLE

1

Effect of post-ischemic

reperfusion

on tissue calcium

hearts.

Cell Ca*+ a mol/g dry wt (mean f SEM, n = 6)

Experimental

30 min aerobic perfusion 30 min aerobic perfusion, followed by 30 min global ischemia, and then (a) 5 mm reperfusion, or (b) 15 mm reperfusion 30 min aerobic perfusion, followed by 60 min global ischemia, and then (a) 5 mm reperfusion, or (b) 15 min reperfusion Experiments 37°C.

in isolated

performed

in isolated

Sprague-Dawley

3.5 + 0.1

6.6 f 0.4 18.5 f 0.8

11.5+1.4 18.0&1.2 rat hearts

perfused

in the Langendorff

mode

at

inoperative. Under these conditions the entry of even a small amount of calcium may be sufficient to trigger the cascade of events shown in Pig. 5, and which has uncontrolled calcium gain as its end point. When used in therapeutically relevant concentrations, the calcium antagonists have no effect on the sarcolemmal sodium/calcium exchanger, nor will they restrict calcium influx through sarcolemmal discontinuities. They are, however, highly potent inhibitors of calcium ion entry through the Ca2+-selective, voltage activated channels [36] and therefore may slow the entry of calcium through this route. It is improbable, however, that the beneficial effect the calcium antagonists exert on the ischemic heart is due simply to a direct inhibitory effect on slow channel calcium entry during post-ischemic reperfusion. If this was the case then these drugs would be effective when added only upon reperfusion, and they are not [37], although their binding sites survive [3,8]. Even when used prophylactically the calcium antagonists have a complex mode of action that involves both vascular and myocardial components (Fig. 6). They are coronary vasodilators and some, by increasing collateral flow, improve the supply of oxygen and substrate to the area at risk. They also reduce myocardial oxygen consumption [39], by dilating the peripheral vasculature, decreasing contractility and in some instances decreasing heart rate. They have other properties, including an ability to slow the loss of the adenine precursors [26], to attenuate the ischemiareperfusion induced release of myocardial norepinephrine [29], and, at least one of them - diltiazem - inhibits the sodium-induced displacement of mitochondrial calcium. In summary, there are many reasons why the calcium antagonists should be useful in the management of ischemic heart disease: they are energy sparing, they slow Ca2+ entry, they attenuate norepinephrine overflow, they are coronary dilators and they slow the loss of adenine precursors. They also inhibit platelet aggregation,

275 Caz+antagonists and the ischemic myocardium

Increased collateral flow

Slowed Peripheral purine loss vasodilatation

Negaiive inotropism

Slowed heart rate

Sloweb CaZ+ influx

1 Increased 0, SUPPlY

Fig. 6. Schematic representation of the ischemic myocardium.

Energy preservation

of the mechanisms

involved

,

Reduced Na+ gain

in the Ca*+ antagonist-induced

protection

and protect the coronary vascular endothelial cells, thereby maintaining microvascular integrity [40]. Taking all of these properties into account it seems likely that the calcium antagonists should slow the progression of ischemia-induced damage, provided that they are used prophylactically. This, in turn, should increase the likelihood of spontaneous reperfusion occurring before the jeopardized cells in the area at risk are lethally damaged. It should also prolong the time interval during which other interventions - such as thrombolysis or angioplasty - can be usefully introduced.

Laboratory Studies: What Have They Shown Lack of Protection Irrespective of whether the protective effect of the calcium antagonists has been quantitated in terms of creatine kinase, creatine kinase release, ST elevation, calcium gain, contractility, infarct size, preservation of adenine precursors or maintenance of mitochondrial function, laboratory studies in which these drugs have been introduced after coronary artery occlusion have usually failed to provide evidence of protection (Table 2). This could have been anticipated, because in such studies the drugs were being added at a time when the ischemia-induced damage

2

2hr 2 hr 24 hr 3 hr 2 hr 1 hr 1 hr 60 min 75 min 2 hr

Regional Regional Regional Regional Regional Regional Global Low-flow Regional Regional

Dog

V V V V V N V V D N

Drug 15 min post-occlusion 5 hr post-occlusion 2 hr 55 min post-occlus. Post-occlusion 1 hr post-occlusion Post-occlusion Post-occlusion Post-occlusion Post-occlusion Pre-occlusion

Administration

4 day 24 hr 3 hr 3 hr 30 min 2.5 hr 30 min 60 min 4 hr 24 hr

Follow-up time

42 17 14 42 54 19 37 53 55 18

Ref.

refers to cardiac levels of adenosine

Infarct size Creatine/kinase Infarct size Infarct size ST elevation NADH Histology; Ca’+ gain Ca’+ gain; functional reco Ivery Adenosine triphosphate Infarct size

Criteria

V = verapamil; N = nifedipine; D = diltiazem. Creatine kinase refers to plasma creatine kinase. Adenosine triphosphate triphosphate.

Swine Baboon

Cat Rabbit

Duration

Ischemia

Species

Laboratory studies showing absence of protection with calcium antagonists.

TABLE

277

would have already progressed to the irreversible state. In a few experiments, however, even pretreatment was ineffective. This applies (Table 2) for example, to experiments with baboons [18]. Baboon hearts, however, have little or no collateral circulation, and since some calcium antagonists act, in part at least, by increasing oxygen delivery to the ischemic zone [41], the presence of a poorly developed collateral circulation could account for this failure. The extent of the collateral circulation may be equally important in the clinical situation, it being relatively poorly developed in the hearts of ‘healthy’ young patients but well developed in patients who have suffered repeated episodes of mild ischemia or in whom, often because of hypertension, the heart has been continuously subjected to a high work load. Evidence of Protection Evidence of a protective role for the calcium antagonists has been relatively easy to obtain in the experimental laboratory, provided that the drugs have been introduced prior to the ischemic insult, and the duration of the ischemic episode has not been so long as to lethally damage the entire area at risk [42]. This ability to protect applies to verapamil, nifedipine and diltiazem alike (Table 3) and is independent of the experimental model (regional, global or low flow ischemia). Again, many different indices of protection have been employed (Table 3). In only two studies (Table 3) has protection been obtained with calcium antagonists that were added after the occlusive event, and in both studies the model was that of mild regional ischemia. Hence, as well as considering the need for early interventions, it seems probable that not only the duration but also the severity of the ischemic episode determines whether the calcium antagonists will be beneficial. Quantification

of Protection

Collating laboratory and clinical trial data presents some difficulties, because of the different criteria used to quantitate protection. Of these criteria, creatine kinase washout is probably the least reliable, the drugs themselves altering the washout pattern. Preservation of mechanical function, maintenance of the energy-rich phosphates and adenine nucleotide precursors, attenuation of calcium overloading, maintenance of electrical stability, infarct size (measured histologically), and maintenance of mitochondrial function have all been used in the experimental studies. Under clinical conditions, however, the situation is more difficult. Improved ejection fraction and segmental shortening, mortality, and altered creatine kinase release have been used. However, if, as the laboratory findings suggest, these drugs act by preventing or slowing the progression of ischemic damage, then frequency of re-infarction may be the more useful marker - unless the drugs are administered prophylactically to patients who are at risk. Relevance of the Model Before comparing the clinical trial data with that obtained in the laboratory the relevance of the experimental models should be considered. In the majority of the

Regional Global Global Regional Global Global Low flow ischemia V/N V N D V N V

Infarct size ECG; mito. function Mito. and mech. function ATP Mito. function Mito. function CK release Segmental wall motion Mech. function; ATP/ADP ATP; Mech. function Infarct size; ATP Reduced Ca’+ Reduced Ca’+; ATP Mech. function: CaZi gain; ATP

Criteria

4 days 105 min No reper. 24 hr No reper. 10 min 24 hr 1 hr 30 min 40min 4 hr 30 min 30 min 60 min

Follow-up time

42 56 16 57 58 10 11 14 12 26 55 37 15 53

Ref.

V = verapamil; N = nifedipine; D = diltiazem. Mite. function refers to mitochondrial respiratory activity. ATP refers to preservation of cardiac adenosine triphosphate (ATP). CK release refers to plasma creatine kinase. Mech. function refers to contractility. Ca2+ gain refers to increase in cardiac Ca2+.

Swine Rabbit

Rat

Pre-occlusion Pre-occlusion Pre-occlusion Pre-occlusion Pre-occlusion Pre-occlusion 30 min post-occlus. 20 min post-occlus. Pre-occlusion Pm-occlusion Pre-occlusion Pre-occlusion Pre-occlusion Pre-occlusion

V N V V D D V

40min l-2 min 1 hr 15 min 5-10 mm 60 min 60 min 20-80 min 21 min 15 min 75 min 60 min 60 min 60 min

Regional Regional Regional Regional Regional Regional

Dog

antagonists. Administration

by calcium Drug

protection Duration

studies showing

Ischemia

3

Species

Laboratory

TABLE

279

experimental studies the ischemic insult has involved the abrupt cessation or severe reduction of flow through otherwise healthy arteries. The clinical relevance of this can be questioned. For example, if the naturally occurring ischemic event is due to persistent coronary artery spasm, then by abolishing the spasm the calcium antagonist may directly prevent the progression of ischemia-induced damage. On the other hand, if the ischemic episode is of thrombotic or atherogenic origin the calcium antagonists may improve regional perfusion by augmenting collateral flow [41], but they will neither lyse the thrombus nor remove the plaque. There are other differences between the laboratory-induced and naturally occurring ischemic episode, including the degree of activation of the sympathetic nervous system and the duration of follow up [42]. In the laboratory, the period of follow up seldom extends beyond 24 hours, and usually is much shorter (Tables 2, 3). In the clinic. however, the follow up period must, of necessity, extend for months or years. In summary, laboratory studies indicate that when used prophylactically, the calcium antagonists ameliorate the damage caused by ischemia and reperfusion, but that when added after coronary artery occlusion has already caused widespread and severe injury, they are of little benefit.

Clinical Trials: What Have They Shown? In general, the data obtained from clinical antagonists have been used in the management

TABLE

4

Clinical

trials with calcium

Calcium antagonists

Patient number

Verapamil

717 719 25 25 29 25 115 112 89 82 64 68 595 562 289 282

Nifedipine

Diltiazem

-

antagonists

verapamil placebo verapamil placebo verapamil placebo nifedipine placebo nifedipine placebo nifedipine placebo nifedipine placebo diltiazem placebo

in myocardial

trials (Table 4) in which calcium of patients with myocardial infarc-

infarction

patients. Ref.

Time to treat

Index of response

Follow-up time

4 hr

Mortality

6 months

8 hr

CK-release

2 weeks

CK-release

2 days

5

5.5 f 2.9 hr

CK-release

6 weeks

7

4.6*0.1

hr

6 months

I

8.0+2.5

hr

CK-release; mortality Mortality: re-infarction Mortality

8 weeks

6

1 month

47

Re-infarction

14 days

3

7*5

hr

Admission to ecu 24-72 hr

Time to treat refers to time interval between onset of severe chest pain antagonist therapy. CK-release refers to plasma creatine kinase.

and introduction

4.52 45

of calcium

280

tion confirms the conclusion that these drugs are most useful phylactically, to slow or prevent the progression of ischemia-induced

when used damage.

pro-

Verapamil The first of the calcium antagonist myocardial infarction trials was the Danish Multicentre Verapamil Trial [4]. It involved 717 patients in the verapamil-treated and 719 in the placebo group, with therapy being started about four hours after the onset of severe chest pain and continued for up to 180 days (Table 5). On the basis of the data obtained over 180 days of treatment verapamil failed to reduce the incidence of mortality. At first sight this result is discouraging, but if the trial data is dissected out a little further, then an interesting pattern of response emerges. In the first week of treatment (Table 5) the incidence of death was actually higher in the verapamil, compared to the placebo-treated group. Death was due to cardiac failure, cardiogenic shock and atrioventricular block (4). However, if the data that relate only to the 22-180 days treatment period are considered, then both mortality (P < 0.03) and re-infarction rate (P < 0.05) were reduced (Table 5). This trial showed, therefore, that verapamil therapy may actually increase the death rate if the drug is administered during the first few hours of an ischemic episode, but for those patients who survive their first infarct and who are maintained on therapy, the risk of re-infarction is reduced. In retrospect these data may be interpreted as meaning that the calcium antagonists benefit those patients with ‘mild’ myocardial infarction, who survive their initial myocardial infarction episode. Verapamil is known to have a negative inotropic effect [39] which is exacerbated during ischemia [43]. Why this should happen is unknown, but an ischemia-induced increase in the number of verapamil binding sites has been excluded as a cause [44]. Irrespective of its cause, this increased sensitivity to the negative inotropy of verapamil may explain the increased early death rate in the Danish verapamil study. An increase in early deaths in verapamil-treated patients is not peculiar to the Danish study, a similar effect being detected by Crea et al. [5], in a relatively small group of patients with transmural infarctions (Table 4). Here treatment started

TABLE Mortality

5 and re-infarction

in the Danish

Multicentre

Verapamil

Study.

Treatment period

Mortality Verapamil

Placebo

Verapamil

Placebo

1 week 2 weeks 3 weeks 22-180 days

6.4 1.8 1.5 3.1

5.6 2.1 0.6 6.4 (P < 0.05)

3.2 1.0 0 3.9

2.1 0.9 0.8 6.1 (P -C 0.03)

Data taken from the latest report sample number.

% Re-infarction

on the Danish

Multicentre

Trial [52]. Mortality

is expressed

as %I of

281

7 f 3 hours after infarction was diagnosed and, as with the Danish study, early complications included heart failure and atrioventricular block. Another verapamil study is that of Bussmann et al. [45]. This was a small study, and observations were restricted to the first 48 hours post-myocardial infarction. Verapamil was given by continuous intravenous infusion, starting 8 f 5 hours after infarction. Based on creatine-kinase washout data this trial provides evidence of protection (P < 0.05), but it is worth noting that the trial was restricted to a particular subset of patients - that is, patients without left ventricular failure. This may explain why the early deaths encountered in the earlier verapamil studies were avoided, and substantiate the hypothesis that these drugs can be beneficial in cases of ‘mild’ infarction. Nifedipine Several nifedipine trials have been undertaken. In one of these studies, The Norwegian Multicentre Study [7], therapy was initiated 5.5 f 2.9 hours after the onset of symptoms, and infarct size was assessed on the basis of calculated creatine-kinase release. The trial was for 6 weeks, with 10 mg oral nifedipine being given five times daily during the first two days and four times daily thereafter. Over the treatment period neither mortality nor enzyme release was altered by the nifedipine therapy. Another study with nifedipine, that of Gottlieb et al. [46], yielded similar results to those obtained in the Norwegian study. Treatment was initiated 8.0 + 2.5 hours after the onset of severe chest pain, and progress was monitored on the basis of creatine-kinase release. With a daily dose of 120 mg nifedipine no evidence of protection was obtained. Another nifedipine study [6], in which 20 mg of the drug was administered every 4 hours, with treatment starting 4.6 + 0.1 hours after the onset of chest pain, also failed to provide evidence of protection. During the 6 months of treatment mortality was unchanged but, as with the Danish verapamil study, there was a significant increase in the death rate (2.5% for placebo, 7.5% for nifedipine) within the first 2 weeks of treatment. There are other nifedipine studies, including the ‘Trent’ study [47], in which patients were treated with placebo or nifedipme immediately after admission to the coronary care unit. This study also revealed an increase in early deaths associated with nifedipine therapy. Another nifedipine study, the ‘Sprint’ study, involved the use of a low dose of nifedipine (10 mg, 3 times daily) in extremely low risk patients. Because of the abnormally low death rate (even in the placebo group) this trial has been superseded by another using higher risk patients, and a higher dose of nifedipine. There is one other nifedipine trial which warrants attention. This is the prospective double-blind randomized trial of Gerstenblith et al. [48], which was based on the assumption that persistent angina often progresses to infarction in patients who are placed on traditional medical treatment (beta-blockade and long-acting nitrates). Based on a 4-month follow up period this study showed that adding nifedipine to the conventional medication was beneficial in that it reduced the incidence of death,

282

myocardial infarction or need for bypass surgery (P < 0.03) in a group of patients with unstable angina. This study is of particular interest, because the nifedipine was being used prophylactically to slow or prevent the progression of ischemia-induced damage. The trial conditions, therefore, mimic those of the laboratory, in which the drugs, when used prophylactically, either prevent ischemia from causing irreversible injury or delay the onset of that injury. Diltiazem The recently completed randomized, double-blind trial in which diltiazem was used for the management of infarct patients [3], differs in two important aspects from the earlier trials with verapamil or nifedipine. Firstly, a particular subset of patients was used - those with non-Q wave infarction and who therefore had ‘mild’ infarcts. Secondly, treatment was not initiated until 24-72 hours after infarction. The trial extended over 14 days, and used re-infarction as its end point. Whilst mortality was unaltered, frequency of re-infarction was reduced (P < 0.03). This is significant, in that it shows that in this particular subset of patients who are a high risk group for recurrent infarction [49-511, prophylactic therapy with a calcium antagonist can slow or prevent the progression of damage caused by inadequate perfusion. This trial, therefore, would seem to substantiate the conclusion reached from the experimental studies and from the Gerstenblith trial [48] - that the calcium antagonists can ‘protect’ potentially jeopardized myocardium provided that therapy is initiated in time to slow or abolish the progression of damage caused by inadequate perfusion.

Choice of Calcium Antagonists Clearly, the questions which need to be resolved now include the optimal time for introducing these drugs, which particular drug to use, its route of administration and which particular subset of patients will benefit. The answer to the former question will probably emerge from clinical trials which are in progress. Whether one calcium antagonist provides better protection than another remains to be established. In the case of diltiazem it might be argued that its relative lack of negative inotropy is advantageous, particularly when combined with its potent coronary vasodilator activity. Conversely, the potent peripheral vasodilator activity of nifedipine may be considered to be a disadvantage, because of the possibility of further underperfusing an already compromised ‘risk’ region [59]. Undoubtedly further clinical trials will resolve these problems but until diltiazem is administered to a broad spectrum of infarction patients within 4-8 hours of the onset of chest pain we will not know whether it, like verapa& and nifedipine, enhances the incidence of early death under these conditions. The existing trial [3] does not address this problem. In conclusion, therefore, if, as seems likely, prophylactic therapy with calcium antagonists reduces the likelihood of re-infarction in patients with ‘mild infarction then the results of the laboratory investigations are in complete harmony with the

283

clinical trial data. Whether the newly developed long-acting calcium antagonists will provide better protection than their parent compounds, and whether the individual calcium antagonists differ in their capacity to protect against re-infarction are the questions which now need to be solved. In this context the recent development of long-acting calcium antagonists is of great interest, because this should ensure that sufficient drug is available to provide protection whenever coronary perfusion becomes inadequate.

Acknowledgement This paper was prepared during the tenure of a grant from the National Health and Medical Research Council of Australia. I am deeply indebted to Jennifer Elz. who prepared the electron micrographs.

References 1 Yusuf S, Peto R, Lewis J, Collins R. Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-371. 2 Klimt CR. Knatterud GL, Stamler J. Meier P. Persantine-aspirin reinfarction study. Part II. Secondary coronary prevention with persantine and aspirin. J Am Co11 Cardiol 1986;7:251-269. 3 Gibson RS, Boden WE, Theroux P, et al. Diltiazem and reinfarction in patients with non-Q-wave myocardial infarction. N Engl J Med 1986;315:423-429. 4 Danish Multicenter Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. Am J Cardiol 1984:54:24E_28E. 5 Crea F, Deanfield J, Crean P, Sharom M, David G. Maseri A. Effects of verapamil in preventing postinfarction angina and reinfarction. Am J Cardiol 1985;55:900-904. 6 Muller JE, Morrison HJ, Stone PH. et al. Nifedipine therapy for patients with threatened and acute myocardial infarction: a randomized, double-blind. placebo-controlled comparison. Circulation 1984;69:740-747. 7 Simes PA, Overskeid K. Pedersen TR, et al. Evolution of infarct size during the early use of nifedipine in patients with acute myocardial infarction: The Norwegian Nifedipine Multicenter Trial. Circulation 1984;4:638-644. 8 Reimer KA, Lowe JE. Jennings RB. Effect of the calcium antagonist verapamil on necrosis following temporary coronary artery occlusion in dogs. Circulation 1977;55:581-587. 9 Nayler WG, Ferrari R, Williams A. Protective effect of pretreatment with verapamil. nifedipine and propranolol on mitochondrial function in the ischemic and reperfused myocardium. Am J Cardiol 1980;46:242-248. 10 Weishaar RE, Bing RJ. The beneficial effect of a calcium channel blocker, diltiazem. on the ischemic-reperfused heart. J Mol Cell Cardiol 1980;12:993-1009. 11 Henry PD, Shuchleib R, Clark RE, Perez JE. Effect of nifedipine on myocardial ischemia: analysis of collateral flow. pulsatile heat and regional muscle shortening. Am J Cardiol 1979;44:817-824. 12 Watts JA, Maiorano LJ, Maiorano PC. Protection by verapamil of globally ischemic rat hearts: energy preservation, a partial explanation. J Mol Cell Cardiol 1985;17:797-804. 13 Ferrari R. Albertini A, Cure110 S. et al. Myocardial recovery during post-ischaemic reperfusion: effects of nifedipine, calcium and magnesium. J Mol Cell Cardiol 1986:18:487-498. 14 Perez JE, Sobel BE, Henry PD. Improved performance of ischemic canine myocardium in response to nifedipine and diltiazem. Am J Physiol 1980:239:H658-H663. 15 Nayler WG. Protection of the myocardium against post-ischaemic reperfusion damage. J Thorac Cardiovasc Surg 1982;84:897-905. 16 Yoon SB. McMillin-Wood JB, Michael LH, Lewis RM. Entman ML. Protection of canine cardiac mitochondrial function by verapamil-cardioplegia during ischemic arrest. Circ Res 1985:56:704-708.

284 of ischemic myocardium by verapamil in 17 Karlsberg RP, Henry PD, Ahmend SA. Lack of protection conscious dogs. Em J Pharmacol 1977;42:339-346. JJ. Failure of nifedipine therapy to reduce myocardial 18 Geary GS, Smith GT, Suehiro GT, McNamara infarct size in the baboon. Am J Cardiol 1982;49:331-338. to reduce infarct 19 Foster E, DeJong D, Connelly C, Apstein CS. Failure of nifedipine and reperfusion size relative to region at risk as measured by NADH fluorophotography. Circulation 1984;70:506-512. injury: laboratory artifact or clinical dilemma. Circulation 20 Nayler WG, Elz JS. Reperfusion 1986;74:215-221. 21 Jennings RB, Schaper J. Hill ML, Steenbergen C, Reimer K. Effect of reperfusion late in the phase of reversible ischemic injury. Circ Res 1985;56:262-278. 22 Jennings RB, Steenbergen CJ. Nucleotide metabolism and cellular damage in myocardial ischemia. Annu Rev Physiol 1985;47:727-749. pH of 23 Neely JR, Whitmer JT, Rovetto MJ. Effect of coronary flow on glycolytic flux and intracellular isolated rat hearts. Circ Res 1975;37:733-741. 24 Rovetto MJ, Lamberton WF, Neely JR. Mechanisms of glycolytic inhibition in ischemic rat hearts. Circ Res 1975;37:742-751. 25 Reibel DK, Rovetto MJ. Myocardial adenosine salvage rates and restoration of ATP content following ischemia. Am J Physiol 1979;237:H247-H252. 26 DeJong JW, Harmsen E. DeTombe PP, Keijzer E. Nifedipine reduces adenine nucleotide breakdown in ischemic rat heart. Eur J Pharmacol 1982;81:89-96. C. Myocardial ischemia revisited. The osmolar load, mem27 Jennings RB, Reimer KA, Steenbergen brane damage, and reperfusion. J Mol Cell Cardiol 1986; in press. extracellular K+ and H+ 28 Hirche HJ, Franz C, Bos L, Bissig R, Lang R, Schramm M. Myocardial increase and noradrenaline release as possible cause of early arrhythmias following acute coronary artery occlusion in pigs. J Mot Cell Cardiol 1980;12:579-586. effect of calcium antagonists on the depletion of cardiac 29 Nayler WG, Sturrock WJ. The inhibitory norepinephrine during postischemic reperfusion. J Cardiovasc Pharm 1985;7:581-587. RP, Cryer PE, Roberts R. Serial plasma catecholamine response early in the course of 30 Karlsberg clinical acute myocardial infarction: Relationship to infarct size and mortality. Am Heart J 1981;102:24-29. B, Wananabe E, Satake T. Plasma level of norepinephrine 31 Konda T, Ogawa K, Ban M, Ogasawara and cyclic nucleotides following acute myocardial infarction. Jpn Heart J 1981;22:593-603. calcium and magnesium in acute ischemic injury. Am J Path01 32 Shen AC. Jennings RB. Myocardial 1972;67:417-433. enzymes and Na+-Ca2+ exchange in hypoxic, ischemic 33 Daly MJ, Elz JS, Nayler WG. Sarcolemmal and reperfused rat hearts. Am J Physiol 1984;247:H237-H243. WG, Grinwald P. Calcium entry blockers and myocardial function. Fed Proc 34 Nayler 1981;40:2855-2861. 35 Cheung JY, Bonventre JV. Mahs CD, Leaf A. Calcium and ischemic injury. N Engl J Med 1986;314:1670-1676. A. Specific pharmacology of calcium in myocardium. cardiac pacemakers, and vascular 36 Fleckenstein smooth muscle. Annu Rev Pharmacol Toxic01 1977;17:149-166. PA. The effects of verapamil, quiescence, and cardioplegia on calcium 37 Bourdillon PD, Poole-Wilson exchange and mechanical function in ischemic rabbit myocardium. Circ Res 1982;50:360-368. 38 Nayler WG, Dillon JS, Elz JS, McKelvie MM. An effect of ischemia on myocardial dihydropyridine binding sites. Eur J Pharmacol 1985;115:81-89. 39 Nayler WG, Szeto J. Effect of verapamil on contractility, oxygen utilization and calcium exchangeability in mammalian heart muscle. Cardiovasc Res 1969;3:30-36. 40 McDonagh PF, Roberts DJ. Prevention of transcoronary macromolecular leakage after ischemia-reperfusion by the calcium entry blocker nisoldipine. Circ Res 1986;58:127-136. 41 Malacoff RF, Lore11 BH, Mudge GH, et al. Beneficial effects of nifedipine on regional myocardial blood flow in patients with coronary artery disease. Circulation 1982;65:1-32-I-37. 42 Reimer KA, Jennings RB. Verapamil in two reperfusion models of myocardial infarction. Temporary protection of severely ischemic myocardium without limitation of ultimate infarct size. Lab Invest 1984;51:655-667.

285 43 Smith HJ, Goldstein RA, Griffith JM. Kent KM, Epstein SE. Regional contractility. Selective depression of ischemic myocardium by verapamil. Circulation 1976;54:629-635. 44 Dillon JS, Nayler WG. Binding of [ 3H]verapamil to rat cardiac sarcolemmal membrane fragments: an effect of ischaemia. Br J Pharmacol 1986; in press. 45 Bussmann WD, Seher W, Gruengras M. Reduction of creatine and kinase and creatine kinase-MB indexes of infarct size by intravenous verapamil. Am J Cardiol 1984;54:1224-1230. 46 Gottlieb SI. Weiss JL, Flaherty JT, et al. Effect of nifedipine on clinical course and left ventricular function in low risk acute myocardial infarction: a double-blind randomized trial. Circulation 1984;70:11-257. 47 Wilcox RG. Hampton JR, Banks DC, et al. Trials of early nifedipine treatment in patients with suspected myocardial infarction (the TRENT study). Proc Br Cardiol Sot 1986;506. 48 Gerstenblith G, Ouyang P, Achuff SC, et al. Nifedipine in unstable angina. A double-blind, randomized trial. N Engl J Med 1982;306:885-890. 49 Marmor A. Geltman EM, Schechtman K, Sobel BE. Roberts R. Recurrent myocardial infarction: clinical predictors and prognostic implications. Circulation 1982;66:415-421. 50 Geltman EM, Ehsani AA, Campbell MK, Schechtman K, Roberts R, Sobel BE. The influence of location and extent of myocardial infarction on long-term ventricular dysrhythmia and mortality. Circulation 1979;60:805-814. 51 Gibson RS, Beller GA, Gheorghiade M. et al. The prevalence and clinical significance of residual myocardial ischemia 2 weeks after uncomplicated non-Q-wave infarction: a prospective natural history study. Circulation 1986;73:1186-1198. 52 The Danish Study Group on Verapamil in Myocardial Infarction. The Danish studies on verapamil in acute myocardial infarction. Br J Clin Pharmacol 1986;21:1975-2045. 53 Bersohn MM, Shine KI. Verapamil protection of ischemic isolated rabbit heart: Dependence of pretreatment. J Mol Cell Cardiol 1983;15:659-671. 54 Lefer AM, Polansky EW, Bianch CP. Narayan S. Influence of verapamil on cellular integrity and electrolyte concentrations of ischemic myocardial tissue in the cat. Basic Res Cardiol 1979;74:555-567. 55 Klein HH. Schubothe M, Nebendahl K, Kreuzer H. The effect of two different diltiazem treatments on infarct size in ischemic, reperfused porcine hearts. Circulation 1984;69:100%1005. 56 Fujibay Y, Yamazaki S, Chang B. Rajagopalan RE. Meerbaum S. Corday E. Comparative echocardiographic study of recovery of diastolic versus systolic function after brief periods of coronary occlusion: Differential effects of intravenous nifedipine administered before and after occlusion. J Am Co11 Cardiol 1985;6:1289-1298. 57 Lange R. Ingwall J, Hale SL, Alker KJ, Braunwald E, Kloner RA. Preservation of high-energy phosphates by verapamil in reperfused myocardium. Circulation 1984;70:734-741. 58 Nagao T. Matlib MA, Franklin D, Millard RW, Schwartz A. Effects of diltiazem, a calcium antagonist. on regional myocardial function and mitochondria after brief coronary occlusion. J Mol Cell Cardiol 1980;12:29-43. 59 Selwyn AP, Welman E, Fox K. Horlock P, Pratt T, Klein M. The effects of nifedipine on acute experimental myocardial ischemia and infarction in dogs. Circ Res 1979;44:16-23.