Ryanodine receptor dispersion disrupts Carelease in failing cardiac myocytes.

Abstract

Reduced cardiac contractility during heart failure (HF) is linked to impaired Carelease from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters. Functional groupings of RyR clusters which produce Casparks (Carelease units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented 'silent' Caleak, not visible as sparks. Larger multi-cluster CRUs common in HF also exhibited low fidelity spark generation. When successfully triggered, sparks in failing cells displayed slow kinetics as Caspread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Catransient. Thus, nanoscale RyR reorganization during HF augments Caleak and slows Carelease kinetics, leading to weakened contraction in this disease.