Dichloroacetate as metabolic therapy for myocardial ischemia and failure.
This article critically reviews the pharmacologic effects of the investigational drug dichloroacetate (DCA), which activates the mitochondrial pyruvate dehydrogenase enzyme complex in cardiac tissue and thus preferentially facilitates aerobic oxidation of carbohydrate over fatty acids. The pharmacologic effects of DCA are compared with other interventions, such as glucose plus insulin, inhibitors of long chain fatty acid oxidation and adenosine, that are also thought to exert their therapeutic effects by altering myocardial energy metabolism. Short-term clinical and laboratory experiments demonstrate that intravenous DCA rapidly stimulates pyruvate dehydrogenase enzyme complex activity and, therefore, aerobic glucose oxidation in myocardial cells. Typically these effects are associated with suppression of myocardial long chain fatty acid metabolism and increased left ventricular stroke work and cardiac output without changes in coronary blood flow or myocardial oxygen consumption. Although long-term studies are lacking, short-term parenteral administration of DCA appears to be safe and capable of significantly improving myocardial function in conditions of limited oxygen availability by increasing the efficient conversion of myocardial substrate fuels into energy.
Bersin
R M
RM
Sanger Clinic and the Department of Medicine, University of Florida College of Medicine, Gainesville 32610, USA.
Stacpoole
P W
PW
D000105:Acetyl Coenzyme A / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D004734:Energy Metabolism / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D008929:Mitochondria, Heart / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy; D009206:Myocardium / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism
D011768:Pyruvate Dehydrogenase Complex; D000105:Acetyl Coenzyme A; D003999:Dichloroacetic Acid