A Metabolic Approach to the Management of Ischemic Heart Disease

Abstract

Myocardial ischemia occurs when there is a supply and demand imbalance between the delivery of oxygenated blood to the myocardium and the needs of the myocardium to maintain normal cardiac function at any level of activity. The commonest cause of the imbalance is obstructive coronary artery disease. A pharmacologic hemodynamic approach to therapy principally focuses on reducing demand (slowing heart rate, lowering blood pressure, reducing contractility and increasing peripheral venous and arterial vasodilatation), with a variable effect on supply (coronary vasodilatation). This is a proven and highly effective approach indirectly improving myocardial metabolism. An alternative and complementary strategy avoids any effect on hemodynamics, but by direct action at the cellular level minimizes the ischemic disruption of cardiac metabolism. Trimetazidine inhibits the fatty acid oxidation enzyme long-chain 3-ketoacyl-coenzyme A thiolase (3-KAT), thereby decreasing fatty acid oxidation and increasing the combustion of glucose and lactate. This switch back from ischemia-induced fatty acid oxidation to glucose oxidation has been shown to be of significant clinical benefit, both subjectively and objectively, independent of or in combination with conventional hemodynamic agents.

Novel inhibitors of fatty acid oxidation as potential metabolic modulators

“…However, introduction of a substituted phenyl group instead of the 2-methyl group in 10 restored the inhibitory activity and resulted in compounds (13-15) with IC 50 's comparable to that of 4. Among the three 2-phenylbenzoxazole compounds (13)(14)(15) only 14 showed liver S-9 stability that satisfied our criteria (40% parent remaining) and this was probably due to the presence of the trifluoromethyl group at the 4-position blocking that important site of metabolism. In this class of 2-substituted benzoxazole compounds and considering the limited number of compounds that were made, it seems that a 4-substituted aromatic ring might be optimal for Palm CoA oxidation inhibitory activity and liver S-9 stability.…”

“…Ranolazine 10,11 (1) and trimetazidine 12,13 (2) are two examples of this new class of anti-anginal drugs. Both compounds are believed to exert their anti-anginal effects in part by shifting myocardial energy metabolism from fatty acids towards glucose (through inhibition of b oxidation of fatty acids) as the substrate for production of ATP.…”

“…The synthesis of racemic analogues (4,(8)(9)(10)(11)(12)(13)(14)(15) is outlined in Scheme 1. Reaction of epichlorohydrin with 2-substituted benzoxazole or benzthiazole of the general formula 29 in acetone using K 2 CO 3 as a base afforded the corresponding epoxide 30.…”

Casses of Antianginal Compounds: Old and New—Therapeutic Implications

“…An evolution of extensive clinical data from controlled clinical trials (19,20) has confirmed the antianginal effectiveness of ranolazine in chronic stable angina. The initial studies were with the short-acting agents; however, the definitive studies with the longer-acting compound as monotherapy have indicated that the drug reduces anginal frequency, increases the time to the development of angina during the treadmill test, and prolongs the duration of exercise of a magnitude (21,22) comparable to that induced by Iadrenergic blocking compounds (23).…”

“…A number of controlled studies have established that trimetazidine decreases angina attacks, minimizes the time to the occurrence of angina during treadmill exercise, and prolongs the overall duration of exercise. The data have recently been summarized in a seminar-in-print (17) and in other reviews (18,19).…”