Heart and Vascular Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Hamann 3, Cleveland, OH 44109-1998, USA.
Circulation. 2012 Oct 23;126(17):2095-104. doi: 10.1161/CIRCULATIONAHA.111.071480. Epub 2012 Sep 27.
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.
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).
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).
最近，我们报道了肌浆网 Ca(2+)ATP 酶 2a（SERCA2a）在分子机制中起着中心作用，该酶负责舒张期细胞浆内钙的重摄取。心力衰竭（HF）与心肌钙处理受损、SERCA2a 缺乏以及对心脏电交替的易感性增加有关。因此，我们假设通过基因转移来恢复缺乏的 SERCA2a 将显著降低衰竭心脏中的心律失常性心脏电交替。
成年豚鼠分为 3 组：对照组、HF 组和 HF+AAV9.SERCA2a 基因转移组。HF 导致左心室分数缩短率降低（与对照组相比，P<0.001）。如预期的那样，与对照组相比，分离的 HF 心肌细胞显示出较慢的肌浆网钙摄取、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 中 SERCA2a、心脏兰尼碱受体 2 和钠钙交换蛋白表达降低（P<0.05）。如预测的那样，HF 增加了心脏电交替的易感性，这表现为 V(m)电交替和 Ca 电交替的心率阈值均低于对照组（P<0.01）。有趣的是，在衰竭心脏中体内基因转移 AAV9.SERCA2a 改善了左心室收缩功能（P<0.01），抑制了心脏电交替（P<0.01），并降低了兰尼碱受体 2 P(o)，这是由于兰尼碱受体 2-P(S2814)减少（P<0.01）。这最终导致可诱导性室性心律失常的发生率降低（P=0.05）。
这些数据表明，衰竭心脏中的 SERCA2a 基因转移不仅改善了收缩功能，而且通过改善关键心律失常性底物（即心脏电交替）和触发因素（即肌浆网 Ca(2+)泄漏）直接恢复了电稳定性。
