Effect of Substrate on Adult Human Cardiomyocytes Contractility

Abstract

Prior in vivo studies have reported that the development of heart failure is accompanied by a transition from the normal preferential metabolism of free fatty acids (FFA) to increases in glucose utilization and even ketone bodies, which normally provide a modest contribution to energy balance. However, the functional significance of the altered substrate utilization in the failing heart is poorly understood. Recognizing that nearly all prior studies examining isolated cardiomyocyte physiology have used glucose as the sole metabolic substrate, we initiated studies to examine the impact of alternative metabolic substrates on contractility in isolated human cardiomyocytes. We employed freshly isolated adult human left ventricular cardiomyocytes from non-failing hearts obtained from organ donors (NF, N=11 hearts, N=110 cells) and failing hearts obtained from transplant recipients (HF, N=13 hearts, n=130 cells). Cardiomyocytes were resuspended in a conventional 5mM Glucose Tyrode solution with alternative substrates (Glucose, FFA, R-3-Hydroxybutyrate (3-OHB) or Mix (Glucose + FFA + 3-OHB)). Myocytes were field stimulated at 1 Hz and sarcomere length, fractional shortening, contraction velocity and relaxation velocity were measured using a video-based sarcomere length detection system (IonOptix Corp). Studies using isolated cardiac myocyte contractility as readout confirm that myocytes from NF human hearts are omnivorous: high levels of myocyte fractional shortening (FS) can be achieved under unstressed conditions (1 Hz, unloaded) with any substrate (FSGlucose: 0.132±0.012; FSFFA: 0.143±0.013; FS3OHB: 0.134±0.014; FSMIX: 0.155±0.020). In the failing heart, glucose alone is insufficient to produce normal unstressed myocyte fractional shortening (FSGlucose: 0.088±0.009***, p