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Background Survivors of myocardial infarction are at increased risk of late ventricular arrhythmias, with infarct size and scar heterogeneity being key determinants of arrhythmic risk. Gap junctions facilitate the passage of small ions and morphogenic cell signaling between myocytes. We hypothesized that gap junctions enhancement during infarction-reperfusion modulates structural and electrophysiological remodeling and reduces late arrhythmogenesis. Methods and Results Infarction-reperfusion surgery was carried out in male Sprague-Dawley rats followed by 7 days of rotigaptide or saline administration. The in vivo and ex vivo arrhythmogenicity was characterized by programmed electrical stimulation 3 weeks later, followed by diffusion-weighted magnetic resonance imaging and Masson's trichrome histology. Three weeks after 7-day postinfarction administration of rotigaptide, ventricular tachycardia/ventricular fibrillation was induced on programmed electrical stimulation in 20% and 53% of rats, respectively (rotigaptide versus control), resulting in reduction of arrhythmia score (3.2 versus 1.4, =0.018), associated with the reduced magnetic resonance imaging parameters fractional anisotropy (fractional anisotropy: -5% versus -15%; =0.062) and mean diffusivity (mean diffusivity: 2% versus 6%, =0.042), and remodeling of the 3-dimensional laminar structure of the infarct border zone with reduction of the mean (16° versus 19°, =0.013) and the dispersion (9° versus 12°, =0.015) of the myofiber transverse angle. There was no change in ECG features, spontaneous arrhythmias, or mortality. Conclusions Enhancement of gap junctions function by rotigaptide administered during the early healing phase in reperfused infarction reduces later complexity of infarct scar morphology and programmed electrical stimulation-induced arrhythmias, and merits further exploration as a feasible and practicable intervention in the acute myocardial infarction management to reduce late arrhythmic risk.

背景

心肌梗死后患者发生晚期室性心律失常的风险增加，梗死面积和瘢痕异质性是心律失常风险的关键决定因素。缝隙连接促进小离子和形态发生细胞信号在心肌细胞之间传递。我们假设，在再灌注性梗死期间增强缝隙连接会调节结构和电生理重塑，减少晚期心律失常的发生。

方法和结果

在雄性 Sprague-Dawley 大鼠中进行梗死再灌注手术，随后进行 7 天的罗替戈汀或生理盐水治疗。3 周后通过程控电刺激来评估体内和体外的致心律失常性，随后进行弥散加权磁共振成像和 Masson 三色组织学检查。在再灌注性梗死后 7 天给予罗替戈汀治疗 3 周后，程序性电刺激分别诱发 20%和 53%的大鼠发生室性心动过速/心室颤动（罗替戈汀与对照组相比），导致心律失常评分降低（3.2 比 1.4，=0.018），与磁共振成像参数各向异性分数（各向异性分数：-5%比-15%，=0.062）和平均扩散系数（平均扩散系数：2%比 6%，=0.042）降低相关，并且梗死边缘区的 3 维层状结构重塑，心肌纤维横切角的平均值降低（16°比 19°，=0.013）和离散度降低（9°比 12°，=0.015）。心电图特征、自发性心律失常或死亡率没有变化。