Antiarrhythmic effects of selective prolongation of refractoriness : electrophysiologic actions of sematilide HCl in humans

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. 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 susta