Cardiomyocyte Ca 2+ homeostasis as a therapeutic target in heart failure with reduced and preserved ejection fraction

Abstract

Heart failure is a highly prevalent syndrome of multiple etiologies and associated comorbidities, and aberrant intracellular Ca2+ homeostasis is a hallmark finding in heart failure patients. The cyclical changes in Ca2+ concentration within cardiomyocytes control cycles of cardiac contraction and relaxation, and dysregulation of Ca2+ handling processes leads to systolic dysfunction, diastolic dysfunction, and adverse remodeling. For this reason, greater understanding of Ca2+ handling mechanisms in heart failure is critical for selection of appropriate treatment strategies. In this review, we summarize the mechanisms of altered Ca2+ handling in two subsets of heart failure, heart failure with reduced ejection fraction and heart failure with preserved ejection fraction, and outline current and experimental treatments that target cardiomyocyte Ca2+ handling processes.

Western Diet-Fed, Aortic-Banded Ossabaw Swine

“…This contradiction also existed at the cellular level in WD-AB animals, as individual cardiomyocytes displayed normal absolute calcium transient and shortening amplitude, yet had an associated reduction in kinetic reserve capacity in response to adrenergic challenge with dobutamine. Such findings were consistent with those in rodent models of hypertrophy, in which cardiomyocyte functional parameters are maintained or enhanced 72, 73, which may serve as an initial compensatory mechanism used by the heart to maintain systolic function at rest (74). However, such functional adaptations might consume a large portion of the cardiac reserve that normal healthy hearts typically maintain.…”

Heart failure with preserved ejection fraction: an update on pathophysiology, diagnosis, treatment, and prognosis

“…Cardiomyocyte Ca 2+ accumulation in the absence of concomitant enhancement of SERCA activity leads to elevated diastolic Ca 2+ , Ca 2+ transients with preserved or enhanced amplitude, and slower Ca 2+ reuptake kinetics with impaired relaxation. The inability of SERCA to expeditiously resequester Ca 2+ becomes particularly evident at elevated stimulation frequencies, which may in part explain the chronotropic intolerance of the myocardium and reduced exercise capacity of HFpEF patients (11). Preclinical studies and clinical trials indicate that combining SERCA2a activation and Na + /K + -ATPase (NKA) inhibition may increase contractility and facilitate active relaxation, improving systolic as well as diastolic heart function, both of which would be beneficial effects in the treatment of chronic HF (12).…”

RUNX1: an emerging therapeutic target for cardiovascular disease

“…Thus far, the direct mechanisms linking RUNX1 to changes in cardiomyocyte Ca 2+ handling are unknown and require further study. Given the preponderance of Ca 2+ dysregulation across cardiac pathologies, including diabetic and hypertensive heart disease, 88 , 89 and its contribution to heart failure progression, 90 it will be useful to establish whether manipulation of RUNX1 in other cardiac disease contexts improve cardiac function.…”