Smith J H, Green C R, Peters N S, Rothery S, Severs N J
Department of Anatomy and Developmental Biology, University College London, United Kingdom.
Am J Pathol. 1991 Oct;139(4):801-21.
Arrhythmias are a common and potentially life-threatening complication of myocardial ischemia and infarction in humans. The structural pathways for the rapid intercellular conduction of the electrical impulse that stimulates coordinated contraction in the myocardium are formed by the gap junctions situated at intercalated disks. By raising antibodies to cardiac gap-junctional protein, and using these antibodies in an immunohistochemical procedure in combination with the technique of laser scanning confocal microscopy, we have succeeded in localizing gap junctions, with a clarity not previously possible, through thick volumes of human myocardial tissue. To explore the structural basis for ischemia and infarction-related arrhythmogenesis, antibody labeling and laser scanning confocal microscopy were applied to study the organization, distribution, and other characteristics of gap junctions in the explanted hearts of patients undergoing cardiac transplantation for advanced ischemic heart disease. In areas of myocardium free from histologically detectable structural damage, there was no significant difference in the size of distribution of labeled gap junctions, or in their number per intercalated disk, between left ventricular tissue (in which functional impairment was severe) and right ventricular tissue (in which functional impairment was minimal). However, in myocytes at the border of healed infarcts--zones to which the slow conduction responsible for reentry arrhythmias has been localized--the organization of gap junctions was markedly disordered; instead of being aggregated into discrete intercalated disks, gap-junctional immunostaining was spread extensively over myocyte surfaces. Some infarct zones were bridged by continuous strands of myocytes, coupled to one another by gap junctions, thereby linking healthy myocardium on either side. At their thinnest, these bridges were in some instances no wider than a single attenuated myocyte. The conclusions are 1) a widespread, generalized derangement of gap junction organization does not appear to underlie functional impairment in the ischemic heart, 2) a disorderly arrangement typifies gap junctions in myocytes of the infarct border zone, and this may contribute to alterations in conduction that are capable of precipitating reentry arrhythmias, and 3) delicate chains of myocytes traverse some healed infarcts, apparently forming electrically coupled bridges across what would otherwise constitute blocked zones. The weakest link in this chain can be a single, degenerating myocyte; avoidance of arrhythmia may therefore depend on the continued survival of this single cell.
心律失常是人类心肌缺血和梗死常见且可能危及生命的并发症。刺激心肌协调收缩的电冲动在细胞间快速传导的结构通路是由位于闰盘处的缝隙连接形成的。通过制备针对心脏缝隙连接蛋白的抗体，并将这些抗体用于免疫组织化学程序，结合激光扫描共聚焦显微镜技术，我们成功地在厚层人类心肌组织中清晰地定位了缝隙连接，这是以前无法做到的。为了探究缺血和梗死相关心律失常发生的结构基础，应用抗体标记和激光扫描共聚焦显微镜来研究因晚期缺血性心脏病接受心脏移植患者的离体心脏中缝隙连接的组织、分布及其他特征。在无组织学可检测结构损伤的心肌区域，左心室组织（功能损害严重）和右心室组织（功能损害轻微）之间，标记的缝隙连接的大小分布或每个闰盘处的数量没有显著差异。然而，在愈合梗死灶边缘的心肌细胞中——折返性心律失常所涉及的缓慢传导已定位到这些区域——缝隙连接的组织明显紊乱；缝隙连接免疫染色不是聚集在离散的闰盘中，而是广泛分布在心肌细胞表面。一些梗死区域由连续的心肌细胞链连接，这些心肌细胞通过缝隙连接相互耦联，从而连接两侧的健康心肌。这些桥最细的时候，在某些情况下不宽于单个变细的心肌细胞。结论如下：1）缝隙连接组织的广泛、普遍紊乱似乎不是缺血性心脏功能损害的基础；2）梗死边缘区心肌细胞中的缝隙连接排列紊乱，这可能导致传导改变，进而引发折返性心律失常；3）细的心肌细胞链穿过一些愈合的梗死灶，显然形成了跨越原本会构成传导阻滞区域的电耦联桥。这条链中最薄弱的环节可能是单个退化的心肌细胞；因此，避免心律失常可能取决于这个单细胞的持续存活。
