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(Circulation. 1999;100:2184.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Rate- and Site-Dependent Effects of Propafenone, Dofetilide, and the New I_Ks-Blocking Agent Chromanol 293b on Individual Muscle Layers of the Intact Canine Heart

Alexander Bauer, MD; Ruediger Becker, MD; Kirsten D. Freigang, MD; Julia C. Senges, MD; Frederik Voss, MD; Alexander Hansen, MD; Matthias Müller, MD; Hans Jochen Lang, PhD; Uwe Gerlach, PhD; Andreas Busch, PhD; Patricia Kraft, RN; Wolfgang Kübler, MD; Wolfgang Schöls, MD

From the Department of Cardiology, University of Heidelberg (A. Bauer, R.B., K.D.F., J.C.S., F.V., A.H., M.M., P.K., W.K., W.S.), and Hoechst Marion Roussel, Cardiovascular Pharmacology, Frankfurt (H.J.L., U.G., A. Busch), Germany.

Correspondence to Dr Alexander Bauer, Abteilung Innere Medizin III, Medizinische Universitätsklinik, Bergheimerstraße 58, 69115 Heidelberg, Germany. E-mail alexander_bauer{at}med.uni-heidelberg.de

Background—Recent in vitro studies have demonstrated regional differences in electrophysiological properties of individual left ventricular muscle layers. Controversy exists on the relevance of these findings for the situation in vivo. Thus, this study was designed to determine whether the in vivo canine heart exhibits regional differences in left ventricular refractoriness and in the susceptibility to sodium and potassium channel blockers.

Methods and Results—In 16 dogs, 36 needle electrodes (12 mm long, 4 bipolar electrodes, interelectrode distance 2.5 mm) were inserted into the left ventricular wall. By use of a computerized multiplexer-mapping system, the spread of activation in epicardial, endocardial, and midmyocardial muscle was reconstructed during ventricular pacing at 300- and 850-ms basic cycle length (BCL). Effective refractory periods (ERPs) were determined at baseline and after application of propafenone (2 mg/kg), dofetilide (30 µg/kg), or chromanol 293b (10 mg/kg) by the extrastimulus technique (BCL 300 and 850 ms). At baseline, activation patterns and ERPs were uniform in all muscle layers. Propafenone homogeneously decreased conduction velocity and moderately prolonged ERPs without any regional differences. Dofetilide and chromanol 293b did not affect the spread of activation. Dofetilide exhibited reverse use-dependent effects on ERP, still preserving transmural homogeneity of refractoriness. Chromanol 293b led to a regionally uniform but more pronounced increase in local ERPs at faster than at slower pacing rates.

Conclusions—At the heart rates applied, the in vivo canine heart does not exhibit regional differences in electrophysiological properties. Given the homogeneity of antiarrhythmic drug effects, induction of local gradients of refractoriness is obviously not a common mechanism of proarrhythmia in normal hearts.

Key Words: antiarrhythmia agents • arrhythmia • electrophysiology • mapping

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