RyR2-targeting therapy prevents left ventricular remodeling and ventricular tachycardia in post-infarction heart failure

Background: Dantrolene binds to the Leu⁶⁰¹-Cys⁶²⁰ region of the N-terminal domain of cardiac ryanodine receptor (RyR2), which corresponds to the Leu⁵⁹⁰-Cys⁶⁰⁹ region of the skeletal ryanodine receptor, and suppresses diastolic Ca²⁺ leakage through RyR2.

Objective: We investigated whether the chronic administration of dantrolene prevented left ventricular (LV) remodeling and ventricular tachycardia (VT) after myocardial infarction (MI) by the same mechanism with the mutation V3599K of RyR2, which indicated that the inhibition of diastolic Ca²⁺ leakage occurred by enhancing the binding affinity of calmodulin (CaM) to RyR2.

Methods and results: A left anterior descending coronary artery ligation MI model was developed in mice. Wild-type (WT) were divided into four groups: sham-operated mice (WT-Sham), sham-operated mice treated with dantrolene (WT-Sham-DAN), MI mice (WT-MI), and MI mice treated with dantrolene (WT-MI-DAN). Homozygous V3599K RyR2 knock-in (KI) mice were divided into two groups: sham-operated mice (KI-Sham) and MI mice (KI-MI). The mice were followed for 12 weeks. Survival was significantly higher in the WT-MI-DAN (73%) and KI-MI groups (70%) than the WT-MI group (40%). Echocardiography, pathological tissue, and epinephrine-induced VT studies showed that LV remodeling and VT were prevented in the WT-MI-DAN and KI-MI groups compared to the WT-MI group. An increase in diastolic Ca²⁺ spark frequency and a decrease in the binding affinity of CaM to the RyR2 were observed at 12 weeks after MI in the WT-MI group, although significant improvements in these values were observed in the WT-MI-DAN and KI-MI groups.

Conclusions: Pharmacological or genetic stabilization of RyR2 tetrameric structure improves survival after MI by suppressing LV remodeling and proarrhythmia.