Rate-dependent changes in intraventricular conduction produced by procainamide in anesthetized dogs. A quantitative analysis based on the relation between phase 0 inward current and conduction velocity.

Abstract

Antiarrhythmic drug effects on maximal upstroke velocity (V^,) are frequency dependent, which implies that the effects of these drugs on conduction should also be rate dependent. Previous in vivo studies have been limited by assumptions about unchanging propagation pathway, and by the empirical use of a first-order recovery model. To explore time-dependent antiarrhythmic drug-induced conduction slowing in vivo, we used 56-electrode epicardial mapping in chloralose-anesthetized dogs with formalin-induced atrioventricular block. Intervaldependent changes in conduction time were assessed under control conditions and then after three loading and maintenance infusions of procainamide. Under control conditions, epicardial activation time (86±26 msec at a basic cycle length of 300 msec) was unchanged (87±24 msec) by pauses up to 6.6 ±2.2 seconds. Procainamide caused conduction slowing that dissipated as a function of recovery interval, with 94±6% recovery over a maximum pause of 6.7±1.5 seconds, but did not alter activation pattern. Drug-induced changes in conduction were evaluated by use of a mathematical model assuming phase 0 inward current proportional to conduction velocity squared. Conduction changes were better fitted by this "quadratic model" (least sum of squared deviations 3.9 xlO~3 by mapping in five dogs, 2.7 xlO~2 by use of QRS duration in nine dogs) than by a monoexponential model (sum of squared deviations 5.7xlO" 3 by mapping, 3.4xlO~2 with QRS;/7<0.01 vs. quadratic model for each). As predicted by theoretical analysis, recovery time constants from the quadratic model were similar to time constants for procainamideinduced changes in V^ In vitro, and significantly longer than values obtained with a monoexponential model. Drug-induced changes in QRS duration were highly correlated with simultaneous changes measured by epicardial mapping (r=0.95,p<0.001), indicating that QRS duration is a valid index of drug effects on ventricular conduction. We concluded that procainamide causes interval-dependent changes in ventricular conduction in vivo that are consistent with a proportional relation between phase 0 inward current and the square of conduction velocity. These observations have important potential implications for the dosedependent and heart rate-dependent effects of antiarrhythmic drugs. Antiarrhythmic drug effects on conduction have been shown to be qualitatively frequency dependent in man for procainamide, 4 calcium channel blockers, 5 and a variety of sodium channel blockers.

Direct quantification of apparent binding indices from quinidine-induced in vivo conduction delay in canine myocardium.

“…The peak amplitude of monophasic waves and the peak of the largest deflection of triphasic waves were taken as the local activation time. ( 14). Furthermore, consistency ofactivation sequence was indicated qualitatively by similarities in isochronal activation patterns observed on the epicardial maps (14).…”

“…( 14). Furthermore, consistency ofactivation sequence was indicated qualitatively by similarities in isochronal activation patterns observed on the epicardial maps (14).…”

“…The estimation of fractional QUIN-induced Na' channel block from changes in conduction is based on assumptions previously applied and validated by Packer et al (5) in vitro and by Nattel and coworkers in vivo (14,15). It was assumed that 02 was a linear function of gN.…”

“…Nattel and coworkers showed, however, that when the activation sequence and, therefore, conduction pathway under control and experimental conditions are constant, relative conduction velocities may be estimated in vivo by comparing conduction times under control and experimental conditions (14,15). 02(N) was therefore derived using available data generated under control and drug conditions for each heartbeat:…”

“…Physiologic heart rates precluded a quantification of the relatively long time constants describing QUIN recovery kinetics. In a more recent analysis, Nattel and Jing (14) estimated Tr for procainamide recovery in the intact canine heart. In addition, in a study from the same institution, Villemaire et al (15) used a theoretical framework developed by Starmer and Grant (16) and Starmer et al (17) to estimate fundamental rate constants describing procainamide action in the intact heart.…”