Subclinical Abnormalities in Sarcoplasmic Reticulum Ca2+ Release Promote Eccentric Myocardial Remodeling and Pump Failure Death in Response to Pressure Overload
Subclinical Abnormalities in Sarcoplasmic Reticulum Ca2+ Release Promote Eccentric Myocardial Remodeling and Pump Failure Death in Response to Pressure Overload
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DOI：
10.1016/j.jacc.2013.11.010
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发表时间：
2014-04-22
影响因子：
24
通讯作者：
Pieske, Burkert
中科院分区：
文献类型：
--
作者：
Sedej, Simon;Schmidt, Albrecht;Pieske, Burkert
目的探讨心肌Ryanodine受体（RyR 2）介导的肌浆网（SR）Ca 2+释放的亚临床改变是否会加重小鼠心肌重构（R4496 C +/-）功能获得性突变对压力超负荷的反应。背景RyR 2功能障碍导致舒张期SR Ca 2+增加在遗传性和获得性心脏病中与心律失常和收缩功能障碍相关的释放，如儿茶酚胺能多态性室性心动过速和心力衰竭（HF）。结果野生型和RyR 2（R4496 C +/-）心脏的结构和功能基本相似。TAC后，RyR 2（R4496 C +/-）心脏反应为离心性肥大、实质性纤维化、心室扩张和缩短分数降低，最终导致明显HF。RyR 2（R4496 C +/-）-TAC心肌细胞显示自发性SR Ca 2+释放事件发生率增加，瞬时Ca 2+峰值幅度降低，SR Ca 2+含量降低，SR Ca 2 +-ATPase 2a表达减少，Na_/Ca 2 +-exchange蛋白表达增加。RyR 2（R4496 C +/-）-TAC小鼠的HF表型与泵故障导致的死亡率增加相关，但与快速性心律失常事件无关。RyR 2稳定剂K201显著降低RyR 2（R4496 C +/-）-TAC心肌细胞中的Ca 2+火花频率。结论亚临床先天性SR Ca 2+释放改变和压力超负荷联合作用促进了RyR 2（R4496 C +/-）小鼠的离心重构和HF死亡，而药物稳定RyR 2可防止这种有害的相互作用。这些发现表明，潜在的临床意义的患者获得性或遗传性功能获得性RyR 2介导的SR钙释放。(C)2014年美国心脏病学会基金会
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