Objectives: This study 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 RyR2 R4496C+/- 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 and heart failure (HF). Methods: Functional 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). Results: Wild-type and RyR2R4496C+/- hearts had comparable structural and functional properties at baseline. After TAC, RyR2 R4496C+/- 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+/Ca 2+-exchanger protein expression. HF phenotype in RyR2 R4496C+/--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 Ca 2+ 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.
- heart failure
- sarcoplasmic reticulum
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine