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

详细信息    查看全文

• 作者：Simon Sedej ; PhD^&lowast ; ; ^&dagger ; ; ^{simon.sedej@medunigraz.at" class="auth_mail} ; Albrecht Schmidt ; MD^&lowast ; ; Marco Denegri ; PhD^&Dagger ; ; Stefanie Walther ; MD^&lowast ; ; Marinko Matovina^&lowast ; ; Georg Arnstein ; MD^&lowast ; ; Eva-Maria Gutschi ; MSc^&lowast ; ; ^&dagger ; ; Isabella Windhager ; MD^&lowast ; ; Senka Ljubojevi膰 ; PhD^&lowast ; ; ^&dagger ; ; Sara Negri ; MSc^&Dagger ; ; Frank R. Heinzel ; MD ; PhD^&lowast ; ; ^&dagger ; ; Egbert Bisping ; MD^&lowast ; ; ^&dagger ; ; Marc A. Vos ; PhD^§ ; ; Carlo Napolitano ; MD ; PhD^&Dagger ; ; ^鈥?/sup> ; Silvia G. Priori ; MD ; PhD^&Dagger ; ; ^鈥?/sup> ; Jens Kockskä ; mper ; PhD^¶ ; ; Burkert Pieske ; MD^&lowast ; ; ^&dagger ; ; ^{burkert.pieske@medunigraz.at" class="auth_mail}
• 关键词：calcium ; heart failure ; hypertension ; remodeling ; sarcoplasmic reticulum
• 刊名：Journal of the American College of Cardiology
• 出版年：22 April, 2014
• 年：2014
• 卷：63
• 期：15
• 页码：1569-1579
• 全文大小：1980 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

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聽of spontaneous SR Ca²⁺ release events, reduced Ca²⁺ transient peak amplitude, and SR Ca²⁺ content as聽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.