Ventricular rate determines early bradycardic electrical remodeling.

OBJECTIVES: The purpose of this study was to isolate chronic ventricular rate as the primary determinant of early bradycardic ventricular electrical remodeling. BACKGROUND: Ventricular repolarization delay predisposing to potentially lethal tachydysrhythmias occurs during chronic bradycardia. Prolonged QT intervals and torsades de pointes are associated with down-regulated ventricular myocyte delayed rectifier potassium (K(+)) currents. METHODS: Transcatheter AV node ablation in rabbits was followed by chronic right ventricular pacing at either 140 bpm (n = 16) or the near-physiologic rate of 280 bpm (n = 9). ECG QT intervals were assessed in vivo at days 0 and 8 of paced AV block. Repolarizing currents in isolated left and right ventricular myocytes were assessed using whole-cell patch clamp technique. RESULTS: Bradycardic rabbits had increased steady-state QT intervals (230 +/- 6 ms vs 206 +/- 7 ms [mean +/- SE], day 8 vs day 0; P < .001). Biventricular myocyte expression of the delayed rectifier K(+) currents I(Kr) and I(Ks) was down-regulated in bradycardic rabbits, with no change in the transient outward current I(to) or inwardly rectifying current I(K1). None of these changes were observed in rabbits paced at 280 bpm. Pause-dependent torsades de pointes was documented in one bradycardic animal on day 8. No heart failure or ventricular hypertrophy was apparent. CONCLUSIONS: Bradycardic ventricular electrical remodeling proceeds independently of structural remodeling, heart failure, or AV synchrony and is prevented by maintenance of near-physiologic ventricular rate.

Propafenone and its metabolites preferentially inhibit IKr in rabbit ventricular myocytes.

Propafenone is an antiarrhythmic agent with recognized cardiac myocyte repolarizing K+ current inhibitory effects. It has two known electropharmacologically active metabolites, 5-hydroxy- and N-depropylpropafenone, whose K+ current inhibitory effects are less thoroughly elucidated than those of the parent compound. This study characterizes and directly compares the pharmacologic interaction of all three compounds with two key repolarizing K+ currents, the rapidly activating delayed rectifier IKr and the transient outward current Ito, using the whole-cell patch-clamp technique in isolated rabbit ventricular myocytes. All three agents potently inhibited IKr with IC50 values of 0.80 +/-0.14, 1.88 +/-0.21, and 5.78 +/-1.24 microM for propafenone, 5-hydroxypropafenone, and N-depropylpropafenone, respectively, based on reduction of peak tail current amplitude following repolarization from +50 mV to -30 mV. IKr inhibition was concentration- and weakly voltage-dependent, with a time course from channel activation that was well described by a single exponential model and consistent with open channel block. Propafenone and its 5-hydroxy and N-depropyl metabolites also blocked Ito with IC50 values of 7.27 +/-0.53, 40.29 +/-7.55, and 44.26 +/-5.73 microM, respectively, at +50 mV. No significant drug effects were observed with respect to Ito voltage dependence of steady-state inactivation or time course of recovery from inactivation. The preferential interaction of propafenone and its metabolites with IKr relative to Ito in ventricular myocytes sheds new light on the anti- and proarrhythmic activity of propafenone in vivo.

A novel rabbit model of variably compensated complete heart block.

Complete heart block (CHB) provides a useful substrate for study of bradycardia-dependent ventricular arrhythmias and cardiac function. Existing CHB animal models are limited by surgical recovery time and reliance on intrinsic escape rhythms. We describe a novel closed-chest rabbit model of CHB involving transcatheter radiofrequency (RF) atrioventricular (AV) node ablation and ventricular rate control with chronic transvenous pacing. Permanent CHB was achieved in 34 of 38 attempts overall. Procedural mortality due to cardiac tamponade (n = 2), airway complications (n = 2), and unknown causes (n = 5) occurred in nine animals. Survivors with CHB (n = 28) were maintained for < or = 22 days, during which there were three late deaths related to infection (n = 1) or respiratory distress (n = 2). None of the survivors with CHB showed recovery of AV conduction or pacemaker capture loss during chronic ventricular pacing at about one-half normal sinus rates, and 25 animals surviving to death showed no overt signs of hemodynamic compromise such as lethargy, poor feeding, or respiratory distress. This approach provides a reproducible nonsurgical CHB model with adjustable ventricular rate control.