Abstract 16629: Cardiosphere-derived Cells Rescue T-tubule Microdomains in HFpEF Cardiomyocytes

Introduction: Patients with heart failure with preserved ejection fraction (HFpEF) die primarily of cardiovascular causes, with sudden death being the single leading mode of death. The key pathophysiology of heart failure with reduced EF (HFrEF) includes widened t-tubule and abnormal calcium transients. cBIN1 (cardiac isoform of Bridging Integrator 1) is a membrane scaffolding protein organizing t-tubule dyads which are critical for normal calcium cycling. cBIN1 is reduced in HFrEF, impairing microdomain formation and increasing arrhythmia risk. Hypothesis: Reduction of cBIN1 and related pathological remodeling of t-tubules contribute to HFpEF pathophysiology, and cardiosphere-derived cells (CDC) can reverse these abnormalities. Methods: Dahl Salt-sensitive rats were fed low-salt (control) or high-salt diets (a phenotype-verified HFpEF responsive to CDC therapy; Gallet et al., JACC BTS 2016). Cardiomyocytes were isolated from control and HFpEF rats treated 4 weeks earlier with either intracoronary placebo or CDCs. Confocal and super-resolution STORM imaging were used to analyze t-tubule morphology, cBIN1 expression, and the distribution of dyad proteins Cav1.2 and RyR (ryanodine receptors). Results: cBIN1 at t-tubules is reduced in HFpEF myocytes. The t-tubule remodeling occurs with reduced local Cav1.2 and RyR. Along with the functional rescue reported by Gallet et al., CDC treatment increased cBIN1 and corrected t-tubule remodeling, doubling Cav1.2 expression at t-tubules. Moreover, RyR localization to the junctional SR membrane is impaired in HFpEF cardiomyocytes, and normalized by CDC treatment (Figure 1). Conclusion: cBIN1 is reduced and cBIN1-microdomains at t-tubules are impaired in HFpEF, reducing Cav1.2-RyR colocalization. CDC treatment rescues cBIN1-microdomains to normalize Cav1.2-RyR couplons at dyads. These changes in cBIN1 and couplons underlie the contractile abnormalities and their rescue by CDCs in this model of HFpEF.