INHIBITION OF PYRUVATE DEHYDROGENASE KINASE DECREASES THE SEVERITY OF HEART FAILURE



Gary D. Lopaschuk, Ph.D., University of Alberta, Edmonton, Alberta, Canada

In heart failure, changes in cardiac mitochondrial energy metabolism contribute to this contractile dysfunction and to a decrease in cardiac efficiency. The failing heart has defects in energy metabolic processes that compromise ATP production necessary to maintain contractile function. Normal oxidative phosphorylation is impaired in the failing heart, oxygen consumption is depressed, and the heart has compromised ATP production. With reduced oxidative phosphorylation, the heart increases its reliance on the highly inefficient process of ATP generation via glycolysis (glucose metabolism occurring outside of the mitochondria). Alterations in energy substrate metabolism accompanying heart failure are complex, and are partly dependent on the stage/severity of the syndrome. However, an elevation in glycolytic rates in relation to glucose oxidation in the failing heart is a consistent finding. We showed an increased uncoupling of glycolysis from glucose oxidation, accompanied by an enhanced H+ production and decreased efficiency in mouse and rat hearts subjected to permanent myocardial infarction. Studies involving heart failure secondary to pressure overload also show a depressed overall oxidative metabolism, as well as a decrease in glucose oxidation. We have shown that heart failure secondary to an abdominal aortic constriction, a transverse aortic constriction, or Ang II infusion in mice inhibits cardiac glucose oxidation. Pharmacological stimulation of glucose oxidation in both rat and mouse hearts improves overall cardiac energetic and cardiac function. In the failing heart, a decrease in pyruvate dehydrogenase (PDH) activity (the rate-limiting enzyme involved in glucose oxidation), and an increase in PDH kinase (PDK) expression (which phosphorylates and inhibits PDH) occurs. Genetic deletion of PDK can prevent this decrease in glucose oxidation in the failing heart, and is associated with improved cardiac function. This supports the concept that inhibition of cardiac glucose oxidation may be a promising approach to treat heart failure.