From Antianginal Drugs to Myocardial Cytoprotedive Agents

Charles Knight, MA, MRCP, and Kim Fox, MD, FRCP

The existing major classes of antianginal drugs emia. Any therapy that increases myocardial resis- improve quality of life in patients with coronary tance to ischemia will protect against cell death and artery disease, but mortality in these patients re- prolong the life of the myocyte, and possibly the mains unacceptably high. In order to limit the com- patient. The mechanisms of cell damage during plications of the disease, it is vital to limit myocyte ischemia, and possible therapeutic interventions, loss. Potentially, this can be achieved not only by arediscussed. prophylaxis, but also by protection, against isch- (Am J Cardioll995; 76:4B-7B)

M any different drugs have been proposed for the relief of angina over the last century. Some, the results of prize-

winning research, have dramatically improved the quality of life for patients with coronary artery disease. Others, poorly developed and evaluated, have been both ineffective and rapidly discarded.

ANTIANGINAL DRUGS The significance of Lauder Brunton’s descrip-

tion of the usefulness of nitrates for angina pectoris in 1857 is clear when placed in the context of the host of remedies that have passed out of use in the intervening years. Nitrates remain first-line therapy for angina. Their effectiveness is the result of a number of hemodynamic actions.* Initial smooth muscle relaxation reduces afterload, and subse- quent venodilation causes pooling of blood periph- erally, reducing the filling pressure of the left ventricle and hence myocardial wall stress and oxygen consumption. Capillary blood flow to the ischemic area is also increased via a fall in left ventricular end-diastolic pressure. Blood flow to ischemic myocardium may also be enhanced by redistribution and increased collateral flo~,~ and dilation of the large coronary arteries.4

Nitrates occupied a preeminent position as antianginal agents until the development of the 8 blocker by Sir James Black in the 1950s and early 1960s. This work subsequently earned him the Nobel Prize. Blockade of the Br-adrenergic recep- tor acts to slow the heart rate and reduce myocar- dial contractility, leading to a reduction in myocar- dial oxygen demand. These hemodynamic actions translate into important clinical benefits, p block- ers being effective agents for the prophylaxis of angina.5

From the Royal Brompton Hospital, London, United Kingdom. Address for reprints: Charles Knight, MA, MRCP, Royal Brompton

Hospital, Sydney Street, London SW3 6NP, United Kingdom.

48 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 76

The third major class of antianginal drugs, the calcium antagonists, were developed in the subse- quent decade by Flekenstein6 and others. These compounds inhibit the slow influx of calcium that is required for the contraction of myocardial and vascular smooth muscle. Although a more hetero- geneous group than nitrates and B blockers, with variations in the extent of their negatively chrono- tropic and ionotropic effects, they act principally by smooth muscle relaxation, causing a reduction in afterload and hence reducing myocardial oxygen demand. In addition they may improve coronary blood supply by coronary vasodilation.7

A number of newer agents are also being developed that appear to have antianginal action, affecting either myocardial oxygen demand or coro- nary blood supply. Examples include the potassium channel activator nicorandil, which also has nitrate effects, and the potassium channel blocker tedisa- mil, which acts as a negatively chronotropic agent and sinus node blocking agent.

Although treatment with the 3 major classes of antianginal drugs has dramatically improved the quality of life of patients with angina, their effect on prognosis is less clear, and mortality from coronary artery disease remains unacceptably high. The aim of treatment in coronary artery disease should be to limit not only pain, but also complica- tions. Preservation of the myocyte is crucial to the preservation of life and myocardial function. The endpoints of myocardial infarction, left ventricular failure, and death can only be prevented by treat- ments directed toward the limitation of myocyte loss. There are a number of stages in the disease process of atherosclerosis at which such therapy can be targeted. Lipid-lowering therapy can be instituted in an attempt to render the atheroscle- rotic plaque quiescent and less likely to undergo rupture, the initiating event for coronary thrombo- sis.8 The hematologic reaction to plaque rupture

AUGUST 24, 1995

can be modified to decrease the extent of intralumi- nal coronary thrombosis; antiplatelet therapy can be effective in the secondary prevention of myocar- dial infarction.9 Once obstructive coronary throm- bosis has occurred, the prompt restoration of vessel patency with thrombolytic therapy is effec- tive in reducing the mortality and morbidity associ- ated with myocardial infarction.‘O Although signifi- cant, these advances alone are not enough to eliminate myocyte damage and death. Unfortu- nately, as many as 33% of infarctions are silent,” preventing their prompt detection and treatment. Further, restoration of blood flow following isch- emia does not immediately bring ischemic damage to an end, as reperfusion itself may be associated with further myocardial injury, arrhythmias, and postischemic stunning. In addition, even a smooth, nonulcerated plaque, by critically limiting coronary blood flow, may impair myocardial performance in the absence of plaque rupture by the induction of chronic ischemia and hibernation. For all these reasons, any cytoprotective therapy that made the myocardium more resistant to ischemia would be a valuable addition to the treatment of coronary artery disease. Such a treatment would have an additional role, allowing the heart to withstand better the ischemic insults that are an inevitable part of both coronary artery surgery and angio- plasty.

ISCHEMA The human myocyte is very sensitive to the

effects of ischemia, and a reduction in its blood supply induces a complex series of ionic and metabolic changes and a rapid arrest of contrac- tion. These changes include alterations in meta- bolic “fuel” supply, despite which the myocyte is unable to generate sufficient adenosine triphos-

phate (ATP) to maintain ionic gradients and con- trol intracellular calcium-a fundamental variable in determining myocyte viability during ischemia and reperfusion. Toxic metabolic products accumu- late, promoting cell death via membrane damage. Oxygen free radicals are formed both within the cell and from infiltrating activated neutrophils, which may also alter membrane function via activa- tion of lipid peroxidation.

The myocyte is usually dependent on aerobic metabolism and contains large numbers of mito- chondria. Although it is capable of responding to mild-to-moderate ischemia by increasing its glu- cose uptake, and hence its production of ATP, thus withstanding the insult, more profound ischemia induces an inhibition of glycolytic ATP production with resulting irreversible cellular damage’* (Fig- ure 1).

Ischemia shifts the use of energy-giving sub- strates away from glucose toward free fatty acids13 (FFA). This has deleterious consequences: first, oxygen requirement is stimulated without an in- crease in mechanical contractility; second, unoxi- dized FFA products, such as detergent lipids, accumulate, which can result in membrane dam- age. Ischemia is also associated with catecholamine release, which worsens the metabolic situation by activating adipose tissue lipolysis and inhibiting insulin secretion, thus decreasing the plasma glu- cose:FFA ratio.

The ionic changes induced by ischemia are mainly a result of ATP depletion. This causes activation of the ATP-sensitive potassium channel, which has 2 principal effects. First, it results in action potential shortening, reducing the trigger for sarcoplasmic reticular calcium release, and consequently contraction; and, second, it allows a rise in the extracellular potassium concentration,

FIGURE 1. lschemia and cell death. The myocyte is able to respond to and withstand, mild or moderate ischemia by increasing glucose uptake, but severe ischemia in- duces a deleterious fall in alucose uptake. The cell becomes &table to generate sufficient energy to maintain ionic gradients, and in- tracellular calcium rises. These changes lead to the death of the myocyte. NADH = reduced nico- tinamide-adenine dinucleotide. (Reprinted with permission from

Pasteur effect

/ Mild to moderate

lschemia .

\ Severe + glucose uptake& + I I

loss of control of cell Ca++

Eur HeartJ.lZ)

Other mechanisms

IW H+, lactate, NADH accumulation

A SYMPOSIUM: MANAGEMENT OF MYOCARDIAL ISCHEMIA 58

which induces membrane depolarization and may trigger arrhythmias. ATP depletion also causes a rise in intracellular sodium as the activity of the Na+:K+-ATPase is reduced. Ionic calcium concen- trations in the cell rise as the sodium-calcium exchange reverses. l4 Further rises in cytosolic cal- cium are promoted by the intracellular acidosis, consequent on ischemia, which, by stimulating the Na+:H+ exchange, causes a rise in intracellular sodium and activates the sodium-calcium ex- change pump. Acidosis may also affect contractile function as calcium is displaced from contractile proteins by protons, although this may not be the principal mechanism behind the rapid reduction in contraction seen after ischemia, as this occurs prior to a fall in intracellular pH.15 Catecholamine re- lease also results in calcium overload as a result of p-receptor-mediated elevation of intracellular cy- clic adenosine monophosphate.

The effects of calcium overload are fundamen- tal during myocardial ischemia, reperfusion, and “stunning.” During ischemia, the rise in calcium causes ischemic contracture, further reducing blood flow to the ischemic muscle, and also promotes additional ATP depletion, as ATP is consumed by the mitochondrial Ca++:H+ exchange, activated in an attempt to lower cytosolic calcium. Calcium overload also activates phospholipases, which dam- age the cell membranes. The level of ionic calcium concentration developed during ischemia seems to be a marker for the subsequent fate of the myocyte on reperfusion. l6 After a short period of ischemia, reoxygenation of a previously anoxic single myo- cyte results in full structural and functional recov- ery, whereas an anoxic insult of 220 minutes results in hypercontracture and disruption of the cytoskeleton on reoxygenation. There is evidence that abnormalities persist in the myocyte for sev- eral days following a brief ischemic insult, despite adequate reperfusion. These abnormalities, such as ATP and glycogen depletion, mitochrondrial edema, and clumping of nuclear chromatin, corre- late with the impaired myocardial function follow- ing ischemia that is known as “myocardial stun- ning.” The metabolic basis for stunning may also relate to the level of calcium at ischemia, possibly via myofilament desensitization to calcium as a result of transient exposure to high levels during ischemia.17

THERAPY There are, therefore, a number of possible ways

in which the myocyte might be metabolically ma- nipulated to withstand ischemia and reperfusion.

Such cardioprotective strategies include control of the catecholamine response, enhancement of gly- colysis, inhibition of fatty acid metabolism, improv- ing intracellular buffering, limiting free radical production, and membrane stabilization.

Beta blockers may exert a cytoprotective effect via the first mechanism, in addition to a possible role in plaque stabilization.8 They have been shown to exert a metabolic effect that is independent of their hemodynamic actions.r8 By antagonizing the effects of catecholamine stimulation described above, p blockers improve glucose utilization19 by shifting tissue metabolism toward a greater use of carbohydrates and a lesser use of FFAs. This cytoprotective effect may be, at least in part, the basis for the favorable effects of this class of compound in secondary prevention following myo- cardial infarction.*O Newer compounds have also been developed that have potential as cytoprotec- tive agents: L-carnitine enhances carbohydrate uti- lization by stimulating glycolysis. It also improves pyruvate metabolism, reduces acidosis, and acts as a scavenger for the toxic products of FFA metabo- lism.*l In addition to these metabolic effects, it has been shown to improve exercise tolerance and increase the ischemic threshold.**

Trimetazidine, another new compound, appears to have a number of potentially useful cytoprotec- tive features. It has been reported to limit intracel- lular acidosis and sodium and calcium accumula- tion,23 also preserving contractile function and limiting cytolysis. These changes appear to be independent of alteration in oxygen supply or demand. Trimetazidine may also limit membrane damage induced by oxygen free radicals” and inhibit neutrophil infiltration into reperfused myo- cardium.25 In vivo, it has an antianginal effect that is independent of hemodynamic changes.26

Agents such as these hold promise for the future development of cytoprotective strategies for isch- emit heart disease. The translation of favorable laboratory effects into clinically important reduc- tions in mortality and morbidity can only be achieved using carefully conducted large-scale clini- cal trials. Such trials will allow us to determine the correct use of these exciting new therapies.

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68 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 76 AUGUST 24, 1995

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