Correcting Inter-domain Interaction of Cardiac Ryanodine Receptor Inhibits Aberrant Ca2+ Release in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy Mouse Model

Abstract

Cardiac troponin T (cTnT) mutations causes Familial Hypertrophic Cardiomyopathy (FHC), which leads to sudden cardiac death in young age. However, the underlying mechanism by which the cTnT mutations leads to lethal arrhythmia remains elusive. Here, we hypothesized that aberrant Ca2+ release could be altered arrhythmogenesis in FHC. To verify this hypothesis, we investigated the pathogenic role of aberrant Ca2+ release via the cardiac ryanodine receptor (RyR2) in transgenic mouse (TG) model with FHC-related cTnT mutation (δ160E). There was no appreciable structural difference of the hearts between wild-type (WT) mice and TG in 6th month of age. In response to isoproterenol (ISO; 10 nmol/L), the Ca2+ spark frequency was much higher in TG cardiomyocytes than in WT (TG (n=5): 7.8±0.9; WT (n=5): 3.6±0.4; p<0.01), whereas it was largely reversed by dantrolene (1μM), which was found to correct the defective inter-domain interaction in failing hearts (TG(n=5): 5.0±0.3; p<0.05). ISO-treated TG cardiomyocytes (but not ISO-treated WT: 0/14; n=14) showed spontaneous Ca2+ transient (sCaT) after 5 Hz pacing (8/13; n=13). The sCaT was again attenuated by dantrolene (4/14; n=14). In FHC-linked cTnT mutated hearts, aberrant local Ca2+ release through defective RyR2 induced by beta-adrenergic stimulation could be attenuated by correcting the inter-domain interaction of RyR2.