Primary Effect of SERCA 2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction.
Primary Effect of SERCA 2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction.
复制标题
SERCA 2a 基因转移对慢性心肌梗死传导储备的主要影响。
DOI：
10.1161/jaha.118.009598
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发表时间：
2018
影响因子：
5.4
通讯作者：
Akar,FadiG
中科院分区：
文献类型：
--
作者：
Motloch,LukasJ;Cacheux,Marine;Ishikawa,Kiyotake;Xie,Chaoqin;Hu,Jun;Aguero,Jaume;Fish,KennethM;Hajjar,RogerJ;Akar,FadiG
背景SERCA2a 基因转移 (GT) 改善非缺血性心力衰竭动物模型的机电功能 SERCA2a GT 是否能逆转缺血性心力衰竭晚期预先确定的重塑尚不清楚。我们试图揭示腺相关病毒血清型 1.SERCA2a GT 在心肌梗死 (MI) 后的电生理效应。方法和结果猪在前壁 MI 后 1 个月出现机械功能障碍，此时它们接受冠状动脉内腺相关病毒血清型 1.SERCA2a (MI+SERCA2a) 或盐水 (MI) 并维持 2 个月。年龄匹配的幼猪作为对照（对照）。在多巴酚丁胺应激前后评估体内心电图和血流动力学特性。使用对照、MI 和 MI+SERCA2a 制剂中的光学动作电位 (AP) 绘图来测量电生理底物。体内心电图测量显示各组之间的 QT 持续时间相当。相反，相对于对照组，MI 猪中存在 QRS 持续时间延长和 R' 波频率增加，但 MI+SERCA2a 猪中则没有。 SERCA2a GT 因多巴酚丁胺反应而减少体内心律失常。来自 MI 的离体制剂（而非 MI+SERCA2a 或对照猪）容易发生起搏引起的室性心动过速和颤动。这些心律失常的背后是 MI 与 MI+SERCA2a 相比传导速度明显减慢，导致室性心动过速和颤动。 MI+SERCA2a 猪对室性心动过速和颤动的易感性降低与血流动力学功能、收缩储备、纤维化或 Cx43 和 Nav1.5 的表达无关。相反，SERCA2a GT 使磷酸活性 CAMKII-δ 水平降低了 50% 以上，从而提高了快速兴奋性。结论 SERCA2a GT 可能通过防止 CAMKII 过度激活来增加传导速度储备。我们的研究结果表明 SERCA2a GT 对心肌兴奋性的主要影响与机械功能的改变无关。
BackgroundSERCA2a gene transfer (GT) improves mechano‐electrical function in animal models of nonischemic heart failure Whether SERCA2a GT reverses pre‐established remodeling at an advanced stage of ischemic heart failure is unclear. We sought to uncover the electrophysiological effects of adeno‐associated virus serotype 1.SERCA2a GT following myocardial infarction (MI).Methods and ResultsPigs developed mechanical dysfunction 1 month after anterior MI, at which point they received intracoronary adeno‐associated virus serotype 1.SERCA2a (MI+SERCA2a) or saline (MI) and were maintained for 2 months. Age‐matched naive pigs served as controls (Control). In vivo ECG‐and‐hemodynamic properties were assessed before and after dobutamine stress. The electrophysiological substrate was measured using optical action potential (AP) mapping in controls, MI, and MI+SERCA2a preparations. In vivo ECG measurements revealed comparable QT durations between groups. In contrast, prolonged QRS duration and increased frequency of R′ waves were present in MI but not MI+SERCA2a pigs relative to controls. SERCA2a GT reduced in in vivo arrhythmias in response to dobutamine. Ex vivo preparations from MI but not MI+SERCA2a or control pigs were prone to pacing‐induced ventricular tachycardia and fibrillation. Underlying these arrhythmias was pronounced conduction velocity slowing in MI versus MI+SERCA2a at elevated rates leading to ventricular tachycardia and fibrillation. Reduced susceptibility to ventricular tachycardia and fibrillation in MI+SERCA2a pigs was not related to hemodynamic function, contractile reserve, fibrosis, or the expression of Cx43 and Nav1.5. Rather, SERCA2a GT decreased phosphoactive CAMKII‐delta levels by >50%, leading to improved excitability at fast rates.ConclusionsSERCA2a GT increases conduction velocity reserve, likely by preventing CAMKII overactivation. Our findings suggest a primary effect of SERCA2a GT on myocardial excitability, independent of altered mechanical function.