Dysregulation of intracellular pH in the failing heart.

Abstract

Despite significant advances in the therapeutic armamentarium, heart failure (HF) remains a deadly disease. Metabolic derangement occurs in HF, with a decrease in the overall ATP synthesis and alterations in substrate utilization. Our recent studies demonstrate beat-to-beat intracellular acidification, namely “intracellular pH (pHi) transient”, in cardiomyocytes, which is coupled to the contraction, myofilament ATP hydrolysis, and mitochondrial electron transport chain function, essential for ATP synthesis. However, the regulation of pHi in HF cardiomyocytes remains less understood. We hypothesize that pHi and pHi transients in HF cardiomyocytes may be subjected to dysregulation as a response to metabolic changes in HF.A HF mouse model was generated using transverse aortic constriction for eight weeks. We quantified pHi and sarcomere lengths simultaneously in single ventricular myocyte. We demonstrate that the baseline pHi and pHi transients are significantly reduced in HF cardiomyocytes compared to sham. Moreover, there are significant cell-to-cell variabilities in pHi and pHi transients in the HF mouse model. Similar alterations were observed in a rabbit model with pressure- and volume-overload induced HF. The phasic pHi during cardiac contraction dovetails with the prevailing dynamic electrical, Ca2+ and mechanical systems defining the heart as an efficient pump. Indeed, the dynamic acidification of pHi may serve as negative feedback to provide the needed relaxation during cardiac contraction. Therefore, the reduced amplitude in pHi transients may significantly contribute to the decrease in lusitropy in HF, well documented in HF. Our study demonstrates dysregulated cardiac pHi and pHi transients in HF ventricular myocytes with significantly increased variabilities. The abnormal pHi and pHi transients suggest significant dysregulation of acid-base balance in HF, which may contribute to cardiac dysfunction. Our study may help to unravel new therapeutic strategies targeting pHi and pHi transients to ameliorate cardiac dysfunction in the failing heart.