Ryanodine Receptor Stabilization Therapy Suppresses Ca2+- Based Arrhythmias in a Novel Model of Metabolic HFpEF

Abstract

Heart Failure with preserved ejection fraction (HFpEF) is the most prevalent form of heart failure worldwide and its significant mortality is associated with a high rate of sudden cardiac death (SCD; 30% - 40%). Chronic metabolic stress is an important driver of HFpEF, and clinical data show metabolic stress as a significant risk factor for ventricular arrhythmias in HFpEF patients. The mechanisms of SCD and ventricular arrhythmia in HFpEF remain critically understudied and empirical treatment is ineffective. To address this important knowledge gap, we developed a novel preclinical model of metabolic-stress induced HFpEF using Western diet (High fructose and fat) and hypertension induced by nitric oxide synthase inhibition (with L-NAME) in wildtype C57BL6/J mice. After 5 months, mice display all clinical characteristics of HFpEF and present with stress-induced sustained ventricular tachycardia (VT). Mechanistically, we found a novel pattern of arrhythmogenic intracellular Ca2+ handling that is distinct from the well-characterized changes pathognomonic for heart failure with reduced ejection fraction. In addition, we show that the transverse tubular system remains intact in HFpEF and that arrhythmogenic, intracellular Ca2+ mobilization becomes hyper-sensitive to {beta}- adrenergic activation. Finally, in proof-of-concept experiments we show in vivo that the clinically used intracellular calcium stabilizer dantrolene, which acts on the Ca2+ release channels of the sarcoplasmic reticulum (SR), the ryanodine receptors, acutely prevents stress-induced VT in HFpEF mice. Therapeutic control of SR Ca2+ leak may present a novel mechanistic treatment approach in metabolic HFpEF.