Metabolic flux in the driver's seat during cardiac health and disease

Cardiac function is a dynamic process that must adjust efficiently to the immediate demands of physical state and activity. So too, the metabolic support of cardiac function is a dynamic process that must respond, in time, to the demands of cardiac function and viability. Flux through metabolic pathways provides chemical energy and generates signaling molecules that regulate activity among intracellular compartments to meet these demands. Thus, flux through metabolic pathways provides a dynamic mode of support of cardiomyocytes during physiological and pathophysiological challenges. Any inability of metabolic flux to keep pace with the demands of the cardiomyocyte results in progressive dysfunction that contributes to cardiac disease. Thus, the priority in maintaining and regulating flux through metabolic pathways in the cardiomyocyte cannot be understated. Great potential exists in current efforts to elucidate metabolic mechanisms as therapeutic targets for the diseased heart. As a consequence, detecting metabolic flux in the functioning myocardium of the heart, under normal and diseased conditions, is essential in elucidating the metabolic basis of contractile dysfunction. As a companion to the 2022 ISHR Research Achievement Award lecture, this review examines the use and applications of stable isotope kinetics to quantify metabolic flux through intermediary pathways and the exchange and transport of intermediates across the mitochondrial membrane and sarcolemma of intact functioning hearts in determining how these intracellular events are coordinated to support cardiac function and health. Finally, this work reviews recently demonstrated metabolic defects in diseased hearts and the potential for metabolic alleviation of heart disease.