A Novel Treatment for Heart Failure by Stabilizing Tetrameric Structure of Cardiac Ryanodine Receptor

Abstract

Aberrant diastolic Ca2+ leak through the cardiac ryanodine receptor（RyR2）is an important cause of heart failure（HF）and lethal arrhythmia. Dantrolene directly binds to the Leu601-Cys620 region of RyR2, corrects defective inter-subunit interactions between the N-terminal domain and the central domain within RyR2, and then enhances the binding affinity of calmodulin（CaM）to RyR2, thus subsequently inhibiting diastolic Ca2+ leakage（zipping/unzipping hypothesis）．We demonstrated the anti-HF and anti-arrhythmic effects of dantrolene in a chronic-phase pressure-overloaded HF model or a catecholaminergic polymorphic ventricular tachycardia（CPVT）-associated RyR2（R2474S/+）knock-in mouse model. Furthermore, our single-center, interventional, open-label, uncontrolled study reported the acute effect of an intravenous injection of dantrolene in the context of a VT storm or sustained VT（sVT）in patients with HF resistant to guideline-directed medical therapy with β-blockers and class III anti-arrhythmic drugs. Thus, dantrolene, a RyR2 stabilizer, is a new type of anti-arrhythmic drug without negative inotropic action and QT prolongation. These beneficial effects are different from those of other anti-arrhythmic drugs such as beta-blockers or amiodarone. Hence it would be useful and appropriate for the treatment of patients with HF.