Abstract 2311: The Relationship Between Gap Junction Conductance and Conduction Velocity in Intact Myocardium
Several murine connexin-gene knockout studies have led to the concept that myocardial conduction velocity (CV) slowing occurs only under conditions of extreme cellular uncoupling and near-complete connexin deletion. Uncoupling to this extent has not been reported to occur naturally, and other transgenic studies refute this concept. To examine the hypothesis that there is a continuous relationship between CV and gap-junction coupling requires direct measurement of both gap-junction conductance and action potential propagation in the same preparations. We used oil-gap impedance and microelectrode measurements to examine this relationship in guinea-pig atrial and ventricular preparations before and during pharmacological uncoupling with carbenoxolone, in human left ventricular myocardium, and, during electrophysiology study in the intact human heart, examined the effects of carbenoxolone uncoupling on the clinically accessible measure of microscopic myocardial conduction - electrogram duration. Carbenoxolone increased gap junction resistivity by 28±9, 26±16, and 25±14% and slowed CV by 17±3, 23±8, and 11±4% (p<0.05 vs. control) in guinea-pig left ventricle (LV), left atrium (LA), and right atrium (RA) respectively. In LV, CV slowed preferentially in the transverse direction (by 25±15%), increasing the anisotropy ratio from 3.8±0.4 to 4.8±1.1 (p<0.05). There was a consistent and uniform linear relationship between junction resistivity and CV in both human and guinea-pig myocardium, and consistent with this, carbenoxolone prolonged electrogram duration from 39.7±4.2 to 42.3±4.3ms (p=0.01) and from 48.1±2.5 to 53.3±5.3ms (p<0.01) in intact human RA and RV respectively during clinical electrophysiology study. These results demonstrate that moderate uncoupling of intact myocardium, results in significant reductions of action potential propagation velocity suggesting no significant redundancy in naturally occurring gap-junction conductance in determining CV.