Subclinical abnormalities in sarcoplasmic reticulum Ca2+ release promote eccentric myocardial remodeling and pump failure death in response to pressure overload.

OBJECTIVE: We explored whether subclinical alterations of sarcoplasmic reticulum (SR) Ca2+ release through cardiac ryanodine receptors (RyR2) aggravate cardiac remodeling in mice carrying a human RyR2R4496C+/- gain-of-function mutation in response to pressure overload. BACKGROUND: RyR2 dysfunction causes increased diastolic SR Ca2+ release associated with arrhythmias and contractile dysfunction in inherited and acquired cardiac diseases, such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and heart failure (HF). METHODS: Functional and structural properties of wild-type (WT) and CPVT-associated RyR2R4496C+/- hearts were characterized under conditions of pressure overload induced by transverse aortic constriction (TAC). RESULTS: WT and RyR2R4496C+/- hearts had comparable structural and functional properties at baseline. After TAC, RyR2R4496C+/- hearts responded with eccentric hypertrophy, substantial fibrosis, ventricular dilatation and reduced fractional shortening, ultimately resulting in overt HF. RyR2R4496C+/--TAC cardiomyocytes showed increased incidence of spontaneous SR Ca2+ release events, reduced Ca2+ transient peak amplitude and SR Ca2+ content as well as reduced SR Ca2+-ATPase2a and increased Na+/Ca2+-exchange protein expression. HF phenotype in RyR2R4496C+/--TAC mice was associated with increased mortality due to pump failure, but not tachyarrhythmic events. RyR2-stabilizer K201 markedly reduced Ca2+ spark frequency in RyR2R4496C+/--TAC cardiomyocytes. Mini-osmotic pump infusion of K201 prevented deleterious remodeling and improved survival in RyR2R4496C+/--TAC mice. CONCLUSIONS: The combination of subclinical congenital alteration of SR Ca2+ release and pressure overload promotes eccentric remodeling and HF death in RyR2R4496C+/- mice, and pharmacological RyR2 stabilization prevents this deleterious interaction. These findings imply potential clinical relevance for patients with acquired or inherited gain-of-function of RyR2-mediated SR Ca2+ release.