Experimental Cardiology, University of Leuven, Herestraat 49 box 911, Leuven, Belgium.
Institute of Cardiovascular Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
J Physiol. 2020 Jul;598(14):2875-2895. doi: 10.1113/JP278839. Epub 2020 Feb 11.
Ventricular arrhythmias are a major complication after myocardial infarction (MI), associated with sympathetic activation. The structurally heterogeneous peri-infarct zone is a known substrate, but the functional role of the myocytes is less well known. Recordings of monophasic action potentials in vivo reveal that the peri-infarct zone is a source of delayed afterdepolarizations (DADs) and has a high beat-to-beat variability of repolarization (BVR) during adrenergic stimulation (isoproterenol, ISO). Myocytes isolated from the peri-infarct region have more DADs and spontaneous action potentials, with spontaneous Ca release, under ISO. These myocytes also have reduced repolarization reserve and increased BVR. Other properties of post-MI remodelling are present in both peri-infarct and remote myocytes. These data highlight the importance of altered myocyte adrenergic responses in the peri-infarct region as source and substrate of post-MI arrhythmias.
Ventricular arrhythmias are a major early complication after myocardial infarction (MI). The heterogeneous peri-infarct zone forms a substrate for re-entry while arrhythmia initiation is often associated with sympathetic activation. We studied the mechanisms triggering these post-MI arrhythmias in vivo and their relation to regional myocyte remodelling. In pigs with chronic MI (6 weeks), in vivo monophasic action potentials were simultaneously recorded in the peri-infarct and remote regions during adrenergic stimulation with isoproterenol (isoprenaline; ISO). Sham animals served as controls. During infusion of ISO in vivo, the incidence of delayed afterdepolarizations (DADs) and beat-to-beat variability of repolarization (BVR) was higher in the peri-infarct than in the remote region. Myocytes isolated from the peri-infarct region, in comparison to myocytes from the remote region, had more DADs, associated with spontaneous Ca release, and a higher incidence of spontaneous action potentials (APs) when exposed to ISO (9.99 ± 4.2 vs. 0.16 ± 0.05 APs/min, p = 0.004); these were suppressed by CaMKII inhibition. Peri-infarct myocytes also had reduced repolarization reserve and increased BVR (26 ± 10 ms vs. 9 ± 7 ms, P < 0.001), correlating with DAD activity. In contrast to these regional distinctions under ISO, alterations in Ca handling at baseline and myocyte hypertrophy were present throughout the left ventricle (LV). Expression of some of the related genes was, however, different between the regions. In conclusion, altered myocyte adrenergic responses in the peri-infarct but not the remote region provide a source of triggered activity in vivo and of repolarization instability amplifying the substrate for re-entry. These findings stimulate further exploration of region-specific therapies targeting myocytes and autonomic modulation.
室性心律失常是心肌梗死（MI）后的主要并发症之一，与交感神经激活有关。结构上不均匀的梗死周边区是已知的底物，但心肌细胞的功能作用知之甚少。在体内记录单相动作电位显示，在肾上腺素刺激（异丙肾上腺素，ISO）下，梗死周边区是延迟后去极化（DAD）的来源，并具有较高的复极变异性（BVR）。从梗死周边区分离出的心肌细胞在 ISO 下具有更多的 DAD 和自发性动作电位，并伴有自发性钙释放。这些心肌细胞的复极储备减少，BVR 增加。MI 后重构的其他特性存在于梗死周边区和远隔区的心肌细胞中。这些数据突出了 MI 后心律失常的改变心肌细胞的肾上腺素反应作为梗死周边区再入的来源和底物的重要性。
室性心律失常是心肌梗死（MI）后早期的主要并发症。不均匀的梗死周边区形成折返的底物，而心律失常的发生通常与交感神经激活有关。我们在体内研究了这些 MI 后心律失常的触发机制及其与区域性心肌细胞重构的关系。在慢性 MI（6 周）的猪中，在体内肾上腺素刺激异丙肾上腺素（ISO）期间，同时记录梗死周边区和远隔区的单相动作电位。假手术动物作为对照。在体内 ISO 输注期间，梗死周边区的迟发性后去极化（DAD）和复极变异性（BVR）的发生率高于远隔区。与远隔区的心肌细胞相比，从梗死周边区分离出的心肌细胞具有更多的 DAD，并与自发的钙释放相关，当暴露于 ISO 时自发性动作电位（AP）的发生率更高（9.99±4.2 vs. 0.16±0.05 AP/min，p=0.004）；这些可被钙调蛋白依赖性蛋白激酶 II 抑制所抑制。梗死周边区的心肌细胞还具有较低的复极储备和增加的 BVR（26±10 ms vs. 9±7 ms，P<0.001），与 DAD 活性相关。与 ISO 下的这些区域性差异相比，基线时钙处理和心肌细胞肥大的改变存在于整个左心室（LV）。然而，一些相关基因的表达在区域之间是不同的。总之，梗死周边区心肌细胞的肾上腺素反应改变提供了体内触发活动的来源和复极不稳定的放大，增强了折返的底物。这些发现促使进一步探索针对心肌细胞和自主神经调节的区域特异性治疗。
