New insights into myocardial arrhythmogenesis: Distribution of gap-junctional coupling in normal, ischaemic and hypertrophied human hearts - Glaxo/MRS Young Investigator Prize
New insights into myocardial arrhythmogenesis: Distribution of gap-junctional coupling in normal, ischaemic and hypertrophied human hearts - Glaxo/MRS Young Investigator Prize
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DOI：
10.1042/cs0900447
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发表时间：
1996-06-01
期刊：
影响因子：
6
通讯作者：
Peters, NS
中科院分区：
文献类型：
--
作者：
Peters, NS
1. 缺血性和肥厚性心脏病与室性心律失常有关，其中异常细胞偶联被认为具有致病作用。本系列研究的目的是表征正常人心室心肌的间隙连接组织，并探讨心肌间隙连接表达的数量和模式在缺血和肥厚性心肌疾病中发生改变的假设。一种针对connexin43的抗体被用于共聚焦激光扫描显微镜检查的心肌的免疫组织化学标记，允许通过完整的心脏组织体积对间隙连接进行高度敏感和可量化的免疫荧光成像。正常成人心室心肌的Connexin43间隙连接高度组织成荧光标记簇，作为大连接的外围环，中心有较小的连接，其表面积为0.005 μ m(2)/ μ m(3)肌细胞体积。新生儿心肌的连接蛋白（connexin43）在整个心室肌细胞表面呈点状分布，间隙连接向成熟间插盘的位置呈渐进式极化，在大约6岁时达到成人模式。在梗死愈合后瘢痕的心肌界面，连接蛋白43间隙连接的分布受到严重干扰，沿退变但存活的肌细胞之间的横向界面呈纵向定向排列，这可能是由于先前存在的连接群重新分布所致。这种改变的分布早在冠状动脉闭塞后4天就出现在犬模型中，它定义了引起室性心动过速的回路的位置。缺血性心脏病患者远离梗死的心肌具有正常的连接蛋白43间隙连接分布模式，但每单位细胞体积的间隙连接表面积减少47%，每个细胞减少30%。在慢性压力负荷的人左心室肥厚心肌中，每肌细胞的connexin43间隙连接表达与正常心肌细胞没有显著差异，但每单位体积肌细胞的connecin43间隙连接表达减少了40%。豚鼠心肌对肾血管性高血压的肥厚反应的早期阶段显示，与对照组相比，在每个细胞（增加45%）和每单位体积的心肌细胞（增加30%）的测量中，连接蛋白43间隙连接的表达显著增加，因此显示出明显与慢性肥厚的人类心室心肌相反的变化。在这一系列的研究中，正常成人心室心肌和出生后发育变化的特征是关于connexin43间隙连接的含量，并观察到在缺血和肥厚心脏中分布和数量的变化，预计将影响心肌传导和心律失常底物。
1. Ischaemic and hypertrophic heart diseases are associated with ventricular arrhythmias, in which abnormal cellular coupling is implicated as having a causative role. The aim of this series of studies was to characterize gap-junctional organization in normal human ventricular myocardium, and to investigate the hypothesis that alterations in the quantity and patterns of expression of myocardial gap junctions occur in ischaemic and hypertrophic myocardial disease.2. An antibody raised against connexin43 was used for immunohistochemical labelling of myocardium examined by confocal laser scanning microscopy, permitting highly sensitive and quantifiable immunofluorescent imaging of gap junctions through volumes of intact cardiac tissue.3. Connexin43 gap junctions in normal adult human ventricular myocardium are highly organized into clusters of fluorescent label confined to the intercalated disks as a peripheral ring of larger junctions, with smaller junctions centrally, and occupy a surface area of 0.005 mu m(2)/mu m(3) myocyte volume.4. Neonatal human myocardium has a punctate distribution of connexin43 over the entire surface of the ventricular myocytes, with a progressive polarization of the gap junctions towards the positions of the mature intercalated disks, reaching the adult pattern at about 6 years.5. At the myocardial interface with the scar of a healed infarct, connexin43 gap junction distribution is grossly disturbed, being strewn in longitudinally orientated arrays along the lateral interfaces between degenerated but viable myocytes, which may he due to a redistribution of the pre-existing population of junctions. This altered distribution is present as early as 4 days after coronary occlusion in a canine model, in which it defines the location of circuits causing ventricular tachycardia.6. Myocardium distant from infarction in patients with ischaemic heart disease has a normal pattern of connexin43 gap junction distribution, but has a 47% reduction in gap junction surface area per unit cell volume, and a 30% reduction per cell.7. in hypertrophied myocardium from chronically pressure-loaded human left ventricles, connexin43 gap junction expression per myocyte is not significantly different from normal, but is reduced by 40% per unit volume of myocyte.8. The early phases of the hypertrophic response of myocardium to renovascular hypertension in guinea pigs revealed a substantially increased connexin43 gap junction expression compared with controls, both when measured per cell (increased by 45%) and per unit volume of myocyte (increased by 30%), and therefore showed an alteration apparently contrary to that observed in chronically hypertrophied human ventricular myocardium.9. In this series of studies, normal adult human ventricular myocardium and the post-natal developmental changes have been characterized with respect to connexin43 gap junction content, and the observed alterations of both distribution and quantity in ischaemic and hypertrophied hearts would be expected to influence myocardial conduction and the arrhythmogenic substrate.