Circulation, Vol 90, 713-725, Copyright © 1994 by American Heart Association
NS Peters, NJ Severs, SM Rothery, C Lincoln, MH Yacoub and CR Green
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
ARTICLES
Spatiotemporal relation between gap junctions and fascia adherens junctions during postnatal development of human ventricular myocardium
Department of Cardiac Medicine, National Heart & Lung Institute, London, England.
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