Study of Heart Mitochondria and Glycolytic Metabolism in Experimentally Induced Cardiac Failure

Abstract

Studies were made on the biochemical activity of mitochondria and of homogenates obtained from normal hearts and from hearts after experimentally induced failure. The principal types of failure investigated were: "chronic" congestive failure and acute failure in the guinea pig. The "chronic" failure was induced in from 2 to 10 days by a partial constriction of the ascending aorta, while the acute type of failure was induced by a more severe aortic constriction of a similar type. Various physiological parameters were studied. The "chronic" animals exhibited tachycardia, elevated right ventricular systolic pressure and a significant depression of myocardial contractility. In addition, a highly significant increase in cardiac tissue mass was observed. Passive congestion of the liver, spleen, kidneys, and lungs was evident. Mitochondria isolated from the hearts of guinea pigs in "chronic" failure exhibited a significant depression of metabolic activity. Thus phosphorylation associated with the oxidation of glutamate, succinate, or α-ketoglutarate was uncoupled in mitochondria isolated from the "failed" heart. Cardiac glycosides administered to animals with experimental cardiac failure did not alter the uncoupled state of the mitochondria, although these agents effected a significant improvement in cardiac contractility. The ATPase activity of the "failed" mitochondria was normal. Experiments concerning the localization of the site or sites of uncoupling of oxidative phosphorylation in the "failed" mitochondria revealed that the defect probably resided in the phosphorylation step associated with the electron transfer between cytochrome C to oxygen. Homogenates prepared from hearts of chronically failing animals were markedly depressed with respect to oxygen and glucose consumption and lactic acid formation. Mitochondria isolated from acutely failed guinea pig hearts exhibited a "mild" uncoupling of oxidative phosphorylation manifested as a decrease in responsiveness to a phosphate acceptor system. This was a graded effect, increasing in severity with increasing duration of aortic constriction. On the basis of the present study, it is possible that uncoupling of oxidative phosphorylation in heart mitochondria may play a role in the development of congestive cardiac failure.