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

Simon Sedej, Albrecht Schmidt, Marco Denegri, Stefanie Walther, Marinko Matovina, Georg Arnstein, Eva Maria Gutschi, Isabella Windhager, Senka Ljubojević, Sara Negri, Frank R. Heinzel, Egbert Bisping, Marc A. Vos, Carlo Napolitano, Silvia G. Priori, Jens Kockskämper, Burkert Pieske

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1569-1579
Number of pages11
JournalJournal of the American College of Cardiology
Volume63
Issue number15
DOIs
Publication statusPublished - Apr 22 2014

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Keywords

  • calcium
  • heart failure
  • hypertension
  • remodeling
  • sarcoplasmic reticulum

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Sedej, S., Schmidt, A., Denegri, M., Walther, S., Matovina, M., Arnstein, G., Gutschi, E. M., Windhager, I., Ljubojević, S., Negri, S., Heinzel, F. R., Bisping, E., Vos, M. A., Napolitano, C., Priori, S. G., Kockskämper, J., & Pieske, B. (2014). Subclinical abnormalities in sarcoplasmic reticulum Ca2+ release promote eccentric myocardial remodeling and pump failure death in response to pressure overload. Journal of the American College of Cardiology, 63(15), 1569-1579. https://doi.org/10.1016/j.jacc.2013.11.010