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.