Effectors of Fatty Acid Oxidation Reduction: Promising New Anti-Ischaemic Agents

Alain      Grynberg

Abstract

The heart is a pump, but also a furnace able to produce at each moment a large amount of energy and to adapt fast enough to face the changes in both fuel supply and energy demand. The pharmacological treatment of angina has been largely focused on the “pump” through hemodynamic agents aimed at decreasing cardiac effort to decrease energy demand. A new concept arose focusing the “furnace” through metabolic agents aimed at decreasing the oxygen cost of ATP production. This goal can be achieved by shifting energy production from fatty acid β-oxidation to glucose oxidation. CPT1 inhibitors were developed to prevent the fatty acid entry into mitochondria but induced cardiac hypertrophy. Regulation of carnitine biology either by carnitine supply or by γ-butyrobetaine hydroxylase inhibitors have led to controversial data both in pharmacological and clinical concerns. Trimetazidine and ranolazine increase the glucose / fatty acid oxidation balance and exhibit benefical effects in animal studies as well as in clinical trials, both in monotherapy and in association with a traditional hemodynamic drug. The association of metabolic and hemodynamic agents brings additive benefits in angina, whereas associations of hemodynamics do not. The mecanism of these drugs has not been fully understood in terms of specific target. In animal studies, dietary docosahexaenoic acid allowed similar protection, through a mechanism related to membrane conformation without specific enzymic target. From the mechanistic research published in this field, enough has now been understood to foresee some future possible targets, mainly related to the cardiomyocyte fatty acid metabolism.

Keywords: atp, cardiac myocyte, pyruvate dehydrogenase, ischaemia, phosphorylation, respiratory chain, mitochondria, Carnitine Palmitoy