SPATIOTEMPORAL RELATION BETWEEN GAP-JUNCTIONS AND FASCIA ADHERENS JUNCTIONS DURING POSTNATAL-DEVELOPMENT OF HUMAN VENTRICULAR MYOCARDIUM

Background The growing postnatal human heart maintains electromechanic al 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 ea rly infancy later declines. This decline is associated with changes in electromechanical properties of the myocardium, which suggest that th e electrical and mechanical interactions between the myocytes may chan ge in an age-dependent manner. Thus, reduction in the capacity for myo cardial growth and adaptability may relate to age-dependent alteration s in the patterns of the intercellular junctions that mediate electric al and mechanical coupling. We therefore examined the hypotheses that (1) age-dependent changes in the distribution patterns of gap junction s and fasciae adherentes, the intercellular junctions responsible, res pectively, for electrical and mechanical coupling, accompany postnatal development in the human heart and that (2) such changes continue int o the first few years of childhood. Further, the spatial relation betw een the two types of junction, for which a close association has been hypothesized as necessary, was explored. Methods and Results Ventricul ar myocardial gap-junction distribution was investigated in 23 pediatr ic surgical patients (4 weeks to 15 years old) by quantitative immunoh istochemical localization of the principal cardiac gap-junctional prot ein, connexin43, using confocal microscopy. Immunolocalization of fasc ia adherens junctions by labeling N-cadherin, and correlative immunogo ld and standard electron microscopy, were performed in parallel. In th e neonate, connexin43 gap junctions have a punctate distribution over the entire surface of the ventricular myocytes. With advancing age, ga p 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 propor tion 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 c onfirmed 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 in tercalated disk. Conclusions Changes in the spatiotemporal patterns of the intercellular junctions responsible for elecfrical and mechanical coupling are closely coordinated in postnatal human ventricular myoca rdium and continue to about 6 years of age. Over this period there is a close and increasing association between the gap junctions and fasci a adherens junctions. These changes in the distribution of intercellul ar electrical and adhering junctions may parallel the changing functio nal requirements of the ventricle, from a distribution that facilitate s the remodeling necessitated by rapid growth and changing hemodynamic s to that of the relatively stable and rapidly conducting adult myocar dium. These age-related changes may also diminish the ability for appr opriate myocardial remodeling in response to physiological, pathologic al, or surgical hemodynamic alterations.