Metabolic therapy for the treatment of ischemic heart disease: reality and expectations

Abstract

Ischemic heart disease is a major cause of morbidity and mortality in the world. Most of the existing therapeutic strategies used to treat ischemic heart disease aim at either increasing the oxygen supply to the heart (thrombolysis, revascularization, angiotensin converting enzyme inhibition and antiplatelet therapy) or decreasing the oxygen demand of the heart (β-blockers and nitrates). Despite the fact that a compromised energy supply to the heart muscle is central to the pathology of ischemic heart disease, therapeutic approaches that focus on altering cardiac energy metabolism have not seen major clinical use. Therapeutic strategies in which the efficiency of oxygen utilization by the heart is enhanced could theoretically benefit the ischemic heart, and could have an additive benefit to existing therapeutic strategies. The energy supply for the heart (in the form of ATP) is normally provided by the balanced metabolism of both fatty acids (major part) and carbohydrates (minor part) oxidation. During reperfusion, this balance is broken by the dramatic enhancement of fatty acid oxidation and attenuation of carbohydrate oxidation, which results in intracellular H⁺ accumulation and Ca²⁺ overload. This article reviews the alterations in cardiac energy metabolism that occur in the ischemic heart, and discusses the existing and proposed pharmacologic therapies to optimize the balance of fatty acids and carbohydrate oxidation for the treatment of ischemic heart diseases.

Keywords::

• CPT1 inhibitors
• dichloroacetate
• fatty acid oxidation
• glucose oxidation
• insulin
• malonyl-CoA decarboxylase inhibitors
• trimetazidine

Financial & competing interests disclosure

Gary D Lopaschuk is the President and CEO of Metabolic Modulators Research Ltd, a company involved in the development of metabolic agents to treat heart disease. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.