Enhancement of Gap Junction Function During Acute Myocardial Infarction Modifies Healing and Reduces Late Ventricular Arrhythmia Susceptibility.
Enhancement of Gap Junction Function During Acute Myocardial Infarction Modifies Healing and Reduces Late Ventricular Arrhythmia Susceptibility.
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DOI：
10.1016/j.jacep.2016.03.007
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发表时间：
2016-10
影响因子：
7
通讯作者：
Peters, Nicholas S
中科院分区：
文献类型：
--
作者：
Ng, Fu Siong;Kalindjian, Jeremy M;Cooper, Simon A;Chowdhury, Rasheda A;Patel, Pravina M;Dupont, Emmanuel;Lyon, Alexander R;Peters, Nicholas S
本研究旨在探讨急性心肌梗死（MI）时增强间隙连接（GJ）偶联对梗死后瘢痕愈合形态和MI后晚期心律失常易感性的影响。MI后心肌瘢痕形成的异质性增加与心律失常易感性增加相关。我们假设，急性心肌梗死期间GJ耦合的短期增强可以产生更均匀的梗死瘢痕，降低心肌梗死后心律失常的晚期易感性。在大鼠MI后4周模型（n = 24）的药理学表征之后，将另外27只Sprague-Dawley大鼠随机接受罗替加肽以增强GJ偶联（n = 13）或生理盐水对照（n = 14），其在手术诱导的MI之前即刻和之后的前7天通过渗透微型泵进行。在MI后4周，将心脏进行体外程序电刺激（PES）和光学标测。梗死边缘区（IBZ）瘢痕的异质性通过组织形态计量学进行定量。尽管MI后4周时梗死面积没有检测到差异，但在PES期间，罗替加肽治疗的心脏降低了心律失常的易感性。（罗替加肽诱导评分：2.4 ± 0.8;对照组：5.0 ± 0.6; p = 0.02）和较少的异质性IBZ瘢痕形成（IBZ复杂性评分的离散度：罗替加肽：1.1 ± 0.1;对照组：1.4 ± 0.1; p = 0.04），与IBZ传导速度的改善相关（罗替加肽：43.1 ± 3.4 cm/s;对照组：34.8 ± 2.0 cm/s; p = 0.04）。在急性心肌梗死时仅增强GJ偶联7天，可产生更均匀的IBZ瘢痕，并在心肌梗死后4周降低心律失常易感性。MI时的短期GJ调节可能代表了一种新的治疗策略，以改变愈合的梗死瘢痕形态并降低MI后晚期心肌梗死的风险。
The purpose of this study was to investigate the effects of enhancing gap junction (GJ) coupling during acute myocardial infarction (MI) on the healed infarct scar morphology and late post-MI arrhythmia susceptibility. Increased heterogeneity of myocardial scarring after MI is associated with greater arrhythmia susceptibility. We hypothesized that short-term enhancement of GJ coupling during acute MI can produce more homogeneous infarct scars, reducing late susceptibility to post-MI arrhythmias. Following arrhythmic characterization of a rat 4-week post-MI model (n = 24), another 27 Sprague-Dawley rats were randomized to receive rotigaptide to enhance GJ coupling (n = 13) or to saline control (n = 14) by osmotic minipump immediately prior to and for the first 7 days following surgically induced MI. At 4 weeks post-MI, hearts were explanted for ex vivo programmed electrical stimulation (PES) and optical mapping. Heterogeneity of infarct border zone (IBZ) scarring was quantified by histomorphometry. Despite no detectable differences in infarct size at 4 weeks post-MI, rotigaptide-treated hearts had reduced arrhythmia susceptibility during PES (inducibility score for rotigaptide: 2.4 ± 0.8; for control: 5.0 ± 0.6; p = 0.02) and less heterogeneous IBZ scarring (dispersion of IBZ complexity score: rotigaptide: 1.1 ± 0.1; control: 1.4 ± 0.1; p = 0.04), associated with an improvement in IBZ conduction velocity (rotigaptide: 43.1 ± 3.4 cm/s; control: 34.8 ± 2.0 cm/s; p = 0.04). Enhancement of GJ coupling for only 7 days at the time of acute MI produced more homogeneous IBZ scarring and reduced arrhythmia susceptibility at 4 weeks post-MI. Short-term GJ modulation at the time of MI may represent a novel treatment strategy to modify the healed infarct scar morphology and reduce late post-MI arrhythmic risk.