Subclinical Abnormalities in Sarcoplasmic Reticulum Ca2+ Release Promote Eccentric Myocardial Remodeling and Pump Failure Death in Response to Pressure Overload

Objectives tudy sought to explore 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. ound ysfunction causes increased diastolic SR Ca2+ release associated with arrhythmias and contractile dysfunction in inherited and acquired cardiac diseases, such as catecholaminergic polymorphic ventricular tachycardia and heart failure (HF). s onal and structural properties of wild-type and catecholaminergic polymorphic ventricular tachycardia–associated RyR2R4496C+/– hearts were characterized under conditions of pressure overload induced by transverse aortic constriction (TAC). s ype and RyR2R4496C+/– hearts had comparable structural and functional properties at baseline. After TAC, RyR2R4496C+/– hearts responded with eccentric hypertrophy, substantial fibrosis, ventricular dilation, 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+-ATPase 2a and increased Na+/Ca2+-exchanger 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. sions mbination of subclinical congenital alteration of SR Ca2+ release and pressure overload promoted eccentric remodeling and HF death in RyR2R4496C+/– mice, and pharmacological RyR2 stabilization prevented this deleterious interaction. These findings suggest potential clinical relevance for patients with acquired or inherited gain-of-function of RyR2-mediated SR Ca2+ release.