Metabolic mechanisms associated with antianginal therapy.

Abstract

Laboratory investigations into preserving viability of the ischemic myocardium or to promote recovery during reperfusion have often focused on the intermediary pathways of energy metabolism. However, in the clinical treatment of angina, the application of metabolic therapies has generally lagged behind or has been incidental to other approaches, such as a vasodilators, calcium antagonists, and negative inotropes. A study published in this issue of Circulation Research has demonstrated that the antianginal agent trimetazidine (1-[2,3,4-trimethoxybenzyl] piperazine dihydrochloride [TMZ]) inhibits the activity of one of the enzymes of the β-oxidation pathway in cardiac mitochondria with direct increases in glucose oxidation.1 These findings confirm in an intact, functioning heart model the well-documented, anti-ischemic properties of TMZ2 3 4 and the inhibitory effects of TMZ on long-chain fatty acid oxidation5 with reciprocal enhancement of glucose uptake.6 The study localizes the inhibition of β-oxidation to a specific enzyme, the mitochondrial long-chain 3-ketoacyl coenzyme A (CoA) thiolase. The suggestion by the authors is that the effectiveness of TMZ as an antianginal agent is directly linked to this inhibitory effect on long-chain fatty acid oxidation. Although studies on the isolated heart preparation can neither specifically nor conclusively identify an antianginal mechanism, the findings of the University of Alberta group1 are consistent with the known effectiveness of TMZ as an antianginal agent7 8 9 that reduces long-chain fatty acid oxidation, while lacking both vasodilator activity and negative inotropic effects.9 The inhibitory effects of TMZ on long-chain fatty acid transport into rat heart mitochondria, via inhibition of carnitine palmitoyltransferase 1 (CPT 1) enzyme, have already been demonstrated, but TMZ was also found to be much less potent than two other proven antianginal drugs, perhexiline and amiodarone.5 10 However, TMZ does not induce the confounding vasoactive, …