InsP 3 R-RyR Ca 2+ channel crosstalk facilitates arrhythmias in the failing human ventricle.

Dysregulated intracellular Ca 2+ handling involving altered Ca 2+ release from intracellular stores via RyR channels underlies both arrhythmias and reduced function in heart failure (HF). Mechanisms linking RyR dysregulation and disease are not fully established. Studies in animals support a role for InsP 3 receptor Ca 2+ channels (InsP 3 R) in pathological alterations in cardiomyocyte Ca 2+ handling but whether these findings translate to the divergent physiology of human cardiomyocytes during heart failure is not determined. Using electrophysiological and Ca 2+ recordings in human ventricular cardiomyocytes, we uncovered that Ca 2+ release via InsP 3 Rs facilitated Ca 2+ release from RyR and induced arrhythmogenic delayed after depolarisations and action potentials. InsP 3 R-RyR crosstalk was particularly increased in HF at RyR clusters isolated from the T-tubular network. Reduced SERCA activity in HF further facilitated the action of InsP 3 . Nanoscale imaging revealed co-localisation of InsP 3 Rs with RyRs in the dyad, which was increased in HF, providing a mechanism for augmented Ca 2+ channel crosstalk. Notably, arrhythmogenic activity dependent on InsP 3 Rs was increased in tissue wedges from failing hearts perfused with AngII to promote InsP 3 generation. These data indicate a central role for InsP 3 R-RyR Ca 2+ signalling crosstalk in the pro-arrhythmic action of GPCR agonists elevated in HF and the potential for their therapeutic targeting.