Peters N S, Severs N J, Rothery S M, Lincoln C, Yacoub M H, Green C R
Department of Cardiac Medicine, National Heart & Lung Institute, London, England.
Circulation. 1994 Aug;90(2):713-25. doi: 10.1161/01.cir.90.2.713.
The growing postnatal human heart maintains electromechanical function while undergoing substantial changes of cellular topology and myocardial architecture. The capacity for growth and remodeling of ventricular myocardium in adaptation to the hemodynamic changes of early infancy later declines. This decline is associated with changes in electromechanical properties of the myocardium, which suggest that the electrical and mechanical interactions between the myocytes may change in an age-dependent manner. Thus, reduction in the capacity for myocardial growth and adaptability may relate to age-dependent alterations in the patterns of the intercellular junctions that mediate electrical and mechanical coupling. We therefore examined the hypotheses that (1) age-dependent changes in the distribution patterns of gap junctions and fasciae adherentes, the intercellular junctions responsible, respectively, for electrical and mechanical coupling, accompany postnatal development in the human heart and that (2) such changes continue into the first few years of childhood. Further, the spatial relation between the two types of junction, for which a close association has been hypothesized as necessary, was explored.
Ventricular myocardial gap-junction distribution was investigated in 23 pediatric surgical patients (4 weeks to 15 years old) by quantitative immunohistochemical localization of the principal cardiac gap-junctional protein, connexin43, using confocal microscopy. Immunolocalization of fascia adherens junctions by labeling N-cadherin, and correlative immunogold and standard electron microscopy, were performed in parallel. In the neonate, connexin43 gap junctions have a punctate distribution over the entire surface of the ventricular myocytes. With advancing age, gap junctions become progressively confined to the transverse terminals of the cell, ie, toward the distribution within the intercalated disk characteristic of the adult ventricle. The transversely arrayed proportion of gap-junctional label showed a linear increase with age (R = .88, P < .001), reaching the adult pattern at about 6 years, and the fascia adherens junctions showed a similar progression. Electron microscopy confirmed the changing pattern of junctional contacts and demonstrated that initially gap junctions and adhering junctions are frequently not closely adjacent but become increasingly so with maturation of the intercalated disk.
Changes in the spatiotemporal patterns of the intercellular junctions responsible for electrical and mechanical coupling are closely coordinated in postnatal human ventricular myocardium and continue to about 6 years of age. Over this period there is a close and increasing association between the gap junctions and fascia adherens junctions. These changes in the distribution of intercellular electrical and adhering junctions may parallel the changing functional requirements of the ventricle, from a distribution that facilitates the remodeling necessitated by rapid growth and changing hemodynamics to that of the relatively stable and rapidly conducting adult myocardium. These age-related changes may also diminish the ability for appropriate myocardial remodeling in response to physiological, pathological, or surgical hemodynamic alterations.
出生后不断生长的人类心脏在经历细胞拓扑结构和心肌结构的显著变化时仍维持着机电功能。婴儿早期心室心肌适应血流动力学变化的生长和重塑能力随后会下降。这种下降与心肌机电特性的变化相关，这表明心肌细胞之间的电和机械相互作用可能会随年龄而改变。因此，心肌生长能力和适应性的降低可能与介导电和机械偶联的细胞间连接模式的年龄依赖性改变有关。我们因此检验了以下假设：（1）负责电偶联和机械偶联的细胞间连接，即缝隙连接和黏着小带的分布模式的年龄依赖性变化伴随着人类心脏的出生后发育，且（2）这种变化会持续到儿童期的头几年。此外，还探究了两种连接之间的空间关系，此前曾假设它们紧密关联是必要的。
通过使用共聚焦显微镜对主要心脏缝隙连接蛋白连接蛋白43进行定量免疫组织化学定位，研究了23例儿科手术患者（4周龄至15岁）的心室心肌缝隙连接分布。通过标记N-钙黏着蛋白对黏着小带连接进行免疫定位，并同时进行相关的免疫金和标准电子显微镜检查。在新生儿中，连接蛋白43缝隙连接在心室肌细胞的整个表面呈点状分布。随着年龄的增长，缝隙连接逐渐局限于细胞的横向末端，即朝着成人心室特征性闰盘内的分布方向发展。缝隙连接标记的横向排列比例随年龄呈线性增加（R = 0.88，P < 0.001），在约6岁时达到成人模式，黏着小带连接也显示出类似的进展。电子显微镜证实了连接接触的变化模式，并表明最初缝隙连接和黏着连接通常不紧密相邻，但随着闰盘的成熟而变得越来越紧密相邻。
负责电和机械偶联的细胞间连接的时空模式变化在出生后的人类心室心肌中密切协调，并持续到约6岁。在此期间，缝隙连接和黏着小带连接之间存在紧密且不断增加的关联。细胞间电连接和黏着连接分布的这些变化可能与心室不断变化的功能需求平行，从有利于快速生长和血流动力学变化所需重塑的分布，到相对稳定且传导迅速的成人心肌的分布。这些与年龄相关的变化也可能会降低心肌对生理、病理或手术血流动力学改变进行适当重塑的能力。
