© 2000 American Heart Association, Inc.
Cellular Biology |
Electrophysiological Effects of Remodeling Cardiac Gap Junctions and Cell Size
Experimental and Model Studies of Normal Cardiac Growth
From the Departments of Pediatrics (M.S.S., J.F.H.), Cell Biology (M.S.S.), and Biomedical Engineering (R.C.B.), Duke University Medical Center, and Department of Surgery (P.C.D.), Veterans Affairs Medical Center, Durham, NC.
Correspondence to Madison S. Spach, Box 3475, Duke University Medical Center, Durham, NC 27710. E-mail cspach{at}acpub.duke.edu
Abstract—The increased
incidence of arrhythmias in structural heart disease is
accompanied by remodeling of the cellular distribution of gap junctions
to a diffuse pattern like that of neonatal cardiomyocytes.
Accordingly, it has become important to know how remodeling of gap
junctions due to normal growth hypertrophy alters
anisotropic propagation at a cellular level (
max) in
relation to conduction velocities measured at a macroscopic level. To
this end, morphological studies of gap junctions (connexin43) and in
vitro electrical measurements were performed in neonatal and adult
canine ventricular muscle. When cells enlarged, gap
junctions shifted from the sides to the ends of ventricular
myocytes. Electrically, normal growth produced different patterns of
change at a macroscopic and microscopic level. Although the
longitudinal and transverse conduction velocities were greater in adult
than neonatal muscle, the anisotropic velocity ratios were the same. In
the neonate, mean max was not different during
longitudinal (LP) and transverse (TP) propagation. However, growth
hypertrophy produced a selective increase in mean TP
max (P<0.001), with no significant
change in mean LP max. Two-dimensional neonatal and
adult cellular computational models show that the observed increases in
cell size and changes in the distribution of gap junctions are
sufficient to account for the experimental results. Unexpectedly, the
results show that cellular scaling (cell size) is as important (or more
so) as changes in gap junction distribution in determining TP
properties. As the cells enlarged, both mean TP max
and lateral cell-to-cell delay increased. max
increased because increases in cell-to-cell delay reduced the electric
current flowing downstream up to the time of max,
thus enhancing max. The results suggest that in
pathological substrates that are arrhythmogenic, maintaining cell size
during remodeling of gap junctions is important in sustaining a maximum
rate of depolarization.
Key Words: gap junctions • structural remodeling • max • cellular scaling • anisotropic propagation
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