Electrophysiological effects of remodeling cardiac gap junctions and cell size - Experimental and model studies of normal cardiac growth

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 ((V) over dot(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 (V) over dot(max) was not different during longitudinal (LP) and transverse (TP) propagation. However, growth hypertrophy produced a selective increase in mean TP (V) over dot(max) (P<0.001), with no significant change in mean LP (V) over dot(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 (V) over dot(max) and lateral cell-to-cell delay increased. (V) over dot(max) increased because increases in cell-re-cell delay reduced the electric current flowing downstream up to the time of (V) over dot(max), thus enhancing (V) over dot(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.