This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sager, P. T. Articles by Singh, B. N. Search for Related Content PubMed PubMed Citation Articles by Sager, P. T. Articles by Singh, B. N. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Fainting Hazardous Substances DB PROCAINAMIDE

Circulation, Vol 88, 1072-1082, Copyright © 1993 by American Heart Association

ARTICLES

Antiarrhythmic effects of selective prolongation of refractoriness. Electrophysiologic actions of sematilide HCl in humans

PT Sager, K Nademanee, M Antimisiaris, A Pacifico, C Pruitt, R Godfrey and BN Singh
Division of Cardiology, Veterans Affairs Medical Center of West Los Angeles, CA 90073.

BACKGROUND. Recent data have suggested that antiarrhythmic agents that act largely by delaying conduction may not be as effective in controlling ventricular arrhythmias as those that prolong repolarization. Recently, numerous "pure" class III agents have been developed. METHODS AND RESULTS. The antiarrhythmic and electrophysiologic profiles of sematilide, a "pure" class III agent, were determined in 27 patients with clinical ventricular arrhythmias and inducible sustained ventricular tachycardia during electrophysiologic study. After treatment with oral sematilide (mean dose, 133 +/- 29 mg every 8 hours), the patients underwent repeat 24- hour ambulatory ECG monitoring and electrophysiologic study. The baseline sinus cycle length and QT, QTc, JT, and JTc intervals were significantly increased 8 to 17% by sematilide (P = .001 to .029). There were no changes in the PR or QRS intervals. Sematilide (at a paced cycle length of 600 ms) significantly increased the atrial effective refractory period (238 +/- 32 to 264 +/- 32 ms; 11 +/- 16% increase from baseline; P = .013), atrioventricular nodal effective refractory period (296 +/- 74 to 354 +/- 71 ms; 20 +/- 19%; P = .029), and right ventricular effective refractory period (252 +/- 25 to 281 +/- 30 ms; 12 +/- 8%; P < .001) but did not significantly change the PA or HV intervals, the corrected sinus node recovery time, or the Wenckebach cycle length. Determination of the frequency-dependent effects of sematilide (n = 10) on the right ventricular monophasic action potential duration (APD90) during ventricular pacing at cycle lengths of 600 to 300 ms revealed that the APD90 was significantly prolonged by sematilide during ventricular pacing at 600 to 350 ms (APD90 increase of 40 +/- 17, 27 +/- 21, 18 +/- 18, and 14 +/- 15 ms, respectively) but not at 300 ms (APD increase of 13 +/- 19 ms). Sematilide significantly prolonged the APD90 to a greater degree at longer than at shorter cycle lengths (P = .02). The ventricular effective refractory period had a similar reverse frequency-dependent relation as the APD90. Sematilide had no effect on the ventricular effective refractory period-to-APD90 ratio or on ventricular conduction. Sematilide suppressed the induction of sustained ventricular tachycardia in 41% of all patients exposed to sematilide. Prolongation of ventricular refractoriness was correlated with ventricular tachycardia suppression. The right ventricular effective refractory period (at 600 ms) increased by 38 +/- 14 ms in patients whose sustained ventricular tachycardia was suppressed by sematilide and by 19 +/- 18 ms in patients not suppressed (P = .015). One patient developed short runs of pause-dependent nonsustained ventricular tachycardia. Eight patients were placed on long-term sematilide therapy, and during a mean follow-up period of 7.0 +/- 7.5 months, two patients developed sudden cardiac death, and one additional patient had recurrent sustained ventricular tachycardia. CONCLUSIONS. The electrophysiologic profile of sematilide is consistent with selective block of outward potassium currents and associated isolated lengthening of the ventricular effective refractory period and APD; sematilide demonstrates a significant degree of reverse frequency- dependence of the ventricular APD and effective refractory period; and suppression of ventricular tachycardia inducibility by sematilide appears to be correlated with increases in the right ventricular effective refractory period.

This article has been cited by other articles:

				F. Bode, P. Karasik, H. A. Katus, and M. R. Franz Upstream stimulation versus downstream stimulation: arrhythmogenesis based on repolarization dispersion in the human heart J. Am. Coll. Cardiol., August 21, 2002; 40(4): 731 - 736. [Abstract] [Full Text] [PDF]

				F. Bode, M. Kilborn, P. Karasik, and M. R. Franz The repolarization-excitability relationship in the human right atrium is unaffected by cycle length, recording site and prior arrhythmias J. Am. Coll. Cardiol., March 1, 2001; 37(3): 920 - 925. [Abstract] [Full Text] [PDF]

				E. Robert, A. G. M. Aya, J. E. de la Coussaye, P. Peray, J.-M. Juan, J. Brugada, J.-M. Davy, and J.-J. Eledjam Dispersion-based reentry: mechanism of initiation of ventricular tachycardia in isolated rabbit hearts Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H413 - H423. [Abstract] [Full Text] [PDF]

				A. Bril, M.-C. Forest, B. Cheval, and J.-F. Faivre Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency dependent increase in action potential duration: comparison between BRL-32872 and azimilide Cardiovasc Res, January 1, 1998; 37(1): 130 - 140. [Abstract] [Full Text] [PDF]