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

卷:63

Article

Sedej, Simon^1,2  Schmidt, Albrecht¹  Denegri, Marco^3,4  Walther, Stefanie¹  Matovina, Marinko¹  Arnstein, Georg¹  Gutschi, Eva-Maria^1,2  Windhager, Isabella¹  Ljubojevic, Senka^1,2  Negri, Sara^3,4  Heinzel, Frank R.^1,2  Bisping, Egbert^1,2  Vos, Marc A.⁵  Napolitano, Carlo^3,4,6  Priori, Silvia G.^3,4,6  Kockskaemper, Jens⁷  Pieske, Burkert^1,2 

[1] Med Univ Graz, Dept Cardiol, A-8036 Graz, Austria

[2] Ludwig Boltzmann Inst Translat Heart Failure Res, Graz, Austria

[3] Univ Pavia, IRCCS Salvatore Maugeri Fdn, I-27100 Pavia, Italy

[4] Univ Pavia, Dept Mol Med, I-27100 Pavia, Italy

[5] Univ Med Ctr Utrecht, Dept Med Physiol, Utrecht, Netherlands

[6] NYU, Sch Med, Leon H Charney Div Cardiol, New York, NY USA

[7] Univ Marburg, Inst Pharmacol & Clin Pharm, Marburg, Germany

关键词: calcium;    heart failure;    hypertension;    remodeling;    sarcoplasmic reticulum;   

DOI  :  10.1016/j.jacc.2013.11.010

来源: Elsevier

【 摘 要 】

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 RyR2(R4496C+/-) hearts were characterized under conditions of pressure overload induced by transverse aortic constriction (TAC). Results Wild-type and RyR2(R4496C+/-) 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. RyR2(R4496C+/-)-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 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 RyR2(R4496C+/-)-TAC cardiomyocytes. Mini-osmotic pump infusion of K201 prevented deleterious remodeling and improved survival in RyR2(R4496C+/-)-TAC mice. Conclusions The combination of subclinical congenital alteration of SR Ca2+ release and pressure overload promoted eccentric remodeling and HF death in RyR2(R4496C+/-) 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. (C) 2014 by the American College of Cardiology Foundation

【 授权许可】

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