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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Abrogation of ventricular arrhythmias in a model of ischemia and reperfusion by targeting myocardial calcium cycling.
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Abrogation of ventricular arrhythmias in a model of ischemia and reperfusion by targeting myocardial calcium cycling.

机译：通过靶向心肌钙循环，在缺血和再灌注模型中消除室性心律失常。

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摘要

Abnormal intracellular Ca(2+) cycling plays an important role in cardiac dysfunction and ventricular arrhythmias in the setting of heart failure and transient cardiac ischemia followed by reperfusion (I/R). We hypothesized that overexpression of the sarcoplasmic reticulum Ca(2+) ATPase pump (SERCA2a) may improve both contractile dysfunction and ventricular arrhythmias. Continuous ECG recordings were obtained in 46 conscious rats after adenoviral gene transfer of either SERCA2a or the reporter gene beta-galactosidase (beta gal) or parvalbumin (PV), as early as 48 h before and 48 h after 30 min ligation of the left anterior descending artery by using an implantable telemetry system. Sham-operated animals were used for comparison for hemodynamic measurements, whereas within-animal baseline was used for electrocardiographic and echocardiographic parameters. All episodes of nonsustained ventricular tachycardia (VT) and ventricular fibrillation (VF) were counted, and their durations were summed by telemetry.I/R decreased regional cardiac wall thickening as well as the maximal rate of left ventricular pressure rise (+dP/dt) and ventricular pressure fall (-dP/dt). SERCA2a restored regional wall thickening and +dP/dt and -dP/dt to levels seen preoperatively. Regional-wall motion and anterior-wall thickening were improved in the SERCA2a animals, as assessed by echocardiography and piezoelectric crystals. To assess whether these effects are SERCA2a specific, we overexpressed a skeletal-muscle protein, PV, to examine whether Ca(2+) buffering alone can mitigate ventricular arrhythmias. During the first hour after I/R, the rate of nonsustained VT plus VF was 16 +/- 5 episodes per h (n = 6) in the Ad.beta gal group, 22 +/- 6 in the Ad.PV group, and 4 +/- 2(n = 6, P < 0.01) in the Ad.SERCA2a group. The decrease in VT plus VF in the Ad.SERCA2a group was consistent throughout the 48 h of monitoring. These results show that improving intracellular Ca(2+) handling by overexpression of SERCA2a restores contractile function andreduces ventricular arrhythmias during I/R.
机译：异常的细胞内Ca（2+）循环在心力衰竭和短暂性心脏缺血再灌注（I / R）的设置中，在心脏功能障碍和室性心律失常中起重要作用。我们假设，肌浆网Ca（2+）ATPase泵（SERCA2a）的过表达可能会改善收缩功能障碍和室性心律失常。在腺病毒基因转移SERCA2a或报告基因β-半乳糖苷酶（beta gal）或小白蛋白（PV）的腺病毒基因转移后，连续46次获得了连续的心电图记录，最早于结扎左前前30分钟之前48小时和48小时之后通过使用植入式遥测系统下降动脉。将假手术动物用于血液动力学测量的比较，而将动物体内基线用于心电图和超声心动图参数。计数所有非持续性室性心动过速（VT）和心室纤颤（VF）的发作，并通过遥测对它们的持续时间进行累加。 ）和心室压下降（-dP / dt）。 SERCA2a使区域壁增厚以及+ dP / dt和-dP / dt恢复到术前水平。通过超声心动图和压电晶体评估，SERCA2a动物的局部壁运动和前壁增厚得到改善。若要评估这些效果是否是SERCA2a特异的，我们过表达了骨骼肌蛋白PV，以检查Ca（2+）单独缓冲是否可以减轻室性心律失常。在I / R后的第一个小时，Ad.beta gal组的非持续性VT加VF的发生率为每小时16 +/- 5次发作（n = 6），Ad.PV组为22 +/- 6次，在Ad.SERCA2a组中为4 +/- 2（n = 6，P <0.01）。在整个监测的48小时中，Ad.SERCA2a组的VT和VF降低是一致的。这些结果表明，通过过度表达SERCA2a改善细胞内Ca（2+）处理可恢复收缩功能并减少I / R期间的室性心律失常。

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