BACKGROUND:Recently, we reported that sarcoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a), the pump responsible for reuptake of cytosolic calcium during diastole, plays a central role in the molecular mechanism of cardiac alternans. Heart failure (HF) is associated with impaired myocardial calcium handling, deficient SERCA2a, and increased susceptibility to cardiac alternans. Therefore, we hypothesized that restoring deficient SERCA2a by gene transfer will significantly reduce arrhythmogenic cardiac alternans in the failing heart. METHODS AND RESULTS:Adult guinea pigs were divided into 3 groups: control, HF, and HF+AAV9.SERCA2a gene transfer. HF resulted in a decrease in left ventricular fractional shortening compared with controls (P<0.001). As expected, isolated HF myocytes demonstrated slower sarcoplasmic reticulum calcium uptake, decreased Ca(2+) release, and increased diastolic Ca(2+) (P<0.05) compared with controls. Moreover, SERCA2a, cardiac ryanodine receptor 2, and sodium-calcium exchanger protein expression was decreased in HF compared with control (P<0.05). As predicted, HF increased susceptibility to cardiac alternans, as evidenced by decreased heart rate thresholds for both V(m) alternans and Ca alternans compared with controls (P<0.01). Interestingly, in vivo gene transfer of AAV9.SERCA2a in the failing heart improved left ventricular contractile function (P<0.01), suppressed cardiac alternans (P<0.01), and reduced ryanodine receptor 2 P(o) secondary to reduction of ryanodine receptor 2-P(S2814) (P<0.01). This ultimately resulted in a decreased incidence of inducible ventricular arrhythmias (P=0.05). CONCLUSIONS:These data show that SERCA2a gene transfer in the failing heart not only improves contractile function but also directly restores electric stability through the amelioration of key arrhythmogenic substrate (ie, cardiac alternans) and triggers (ie, sarcoplasmic reticulum Ca(2+) leak).

译文

背景:最近,我们报告肌浆网Ca(2)ATPase 2a(SERCA2a),负责舒张期期间细胞内钙的再摄取的泵,在心脏交替分子的分子机制中起着核心作用。心力衰竭(HF)与心肌钙处理受损,SERCA2a不足以及对心脏交替素的敏感性增加有关。因此,我们假设通过基因转移恢复有缺陷的SERCA2a将显着减少衰竭心脏中的致心律失常性心脏交替链。
方法与结果:成年豚鼠分为3组:对照组,HF和HF AAV9.SERCA2a基因转移。与对照组相比,HF导致左心室缩短缩短的减少(P <0.001)。如预期的那样,与对照组相比,孤立的HF心肌细胞显示出较慢的肌质网钙摄取,减少的Ca(2)释放和增加的舒张期Ca(2)(P <0.05)。此外,与对照组相比,HF患者的SERCA2a,心脏ryanodine受体2和钠钙交换蛋白表达降低(P <0.05)。正如预测的那样,HF对心脏交替素的敏感性增加,与对照组相比,V(m)交替素和Ca交替素的心率阈值降低证明了这一点(P <0.01)。有趣的是,在衰竭心脏中,AAV9.SERCA2a的体内基因转移改善了左心室收缩功能(P <0.01),抑制了心脏交替素(P <0.01),并降低了瑞丹碱受体2继而降低了瑞丹碱受体2 P(o)。 -P(S2814)(P <0.01)。这最终导致可诱发的室性心律失常的发生率降低(P = 0.05)。
结论:这些数据表明,SERCA2a基因在衰竭心脏中的转移不仅改善了收缩功能,而且还通过改善关键的心律失常性底物(即心脏交替神经)和触发因素(即肌浆网Ca(2)泄漏)直接恢复了电稳定性。 。

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