Ryanodine receptor dispersion disrupts Ca(2+) release in failing cardiac myocytes

Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca(2+) release 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 Ca(2+) sparks (Ca(2+) release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented ‘silent’ Ca(2+) leak, 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 Ca(2+) spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca(2+) transient. Thus, nanoscale RyR reorganization during HF augments Ca(2+) leak and slows Ca(2+) release kinetics, leading to weakened contraction in this disease.