Modulation of Fatty Acids Oxidation in Heart Failure by Selective Pharmacological Inhibition of 3-Ketoacyl Coenzyme-A Thiolase

Gabriele      Fragasso; Roberto      Spoladore; Amarild      Cuko; Altin      Palloshi

Abstract

A direct approach to manipulate cardiac energy metabolism consists in modifying substrate utilization by the heart. Pharmacological agents that directly inhibit fatty acid oxidation include inhibitors of 3-ketoacyl coenzyme A thiolase (3-KAT), the last enzyme involved in β-oxidation. The most extensively investigated agents of this group of drugs are trimetazidine and ranolazine. Clinical studies have shown that these agents can substantially increase the ischemic threshold in patients with effort angina. However, the results of current research is also supporting the concept that shifting the energy substrate preference away from fatty acid metabolism and toward glucose metabolism by 3-KAT inhibitors could be an effective adjunctive treatment in patients with heart failure, in terms of left ventricular function and glucose metabolism improvement. In fact, these agents have also been shown to improve overall glucose metabolism in diabetic patients with left ventricular dysfunction. In this paper, the recent literature on the beneficial effects of this new class of drugs on left ventricular dysfunction and glucose metabolism is reviewed and discussed.

Keywords: 3-ketoacyl coenzyme A thiolase inhibitors, trimetazidine, ranolazine, heart failure, left ventricular function, diabetes