ANTIARRHYTHMIC EFFECTS OF SELECTIVE PROLONGATION OF REFRACTORINESS - ELECTROPHYSIOLOGIC ACTIONS OF SEMATILIDE HCL IN HUMANS

Background. Recent data have suggested that antiarrhythmic agents that act largely by delaying conduction may not be as effective in control ling ventricular arrhythmias as those that prolong repolarization. Rec ently, numerous ''pure'' class III agents have been developed. Methods and Results. The antiarrhythmic and electrophysiologic profiles of se matilide, a ''pure'' class III agent, were determined in 27 patients w ith clinical ventricular arrhythmias and inducible sustained ventricul ar tachycardia during electrophysiologic study. After treatment with o ral sematilide (mean dose, 133+/-29 mg every 8 hours), the patients un derwent repeat 24-hour ambulatory ECG monitoring and electrophysiologi c study. The baseline sinus cycle length and QT, QT(c), JT, and JT(c) 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 atria l effective refractory period (238+/-32 to 264+/-32 ms; 11+/-16% incre ase from baseline; P=.013), atrioventricular nodal effective refractor y period (296+/-74 to 354+/-71 ms; 20+/-19%; P=.029), and right ventri cular effective refractory period (252+/-25 to 281+/-30 ms; 12+/-8%; P <.001) but did not significantly change the PA or HV intervals, the co rrected sinus node recovery time, or the Wenckebach cycle length. Dete rmination of the frequency-dependent effects of sematilide (n=10) on t he right ventricular monophasic action potential duration (APD90) duri ng 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 APD'' to a greater deg ree at longer than at shorter cycle lengths (P=.02). The ventricular e ffective refractory period had a similar reverse frequency-dependent r elation as the APD90. Sematilide had no effect on the ventricular effe ctive refractory period-to-APD90 ratio or on ventricular conduction. S ematilide suppressed the induction of sustained ventricular tachycardi a in 41% of all patients exposed to sematilide. Prolongation of ventri cular refractoriness was correlated with ventricular tachycardia suppr ession. The right ventricular effective refractory period (at 600 ms) increased by 38+/-14 ms in patients whose sustained ventricular tachyc ardia was suppressed by sematilide and by 19+/-18 ms in patients not s uppressed (P=.015). One patient developed short runs of pause-dependen t 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 a dditional patient had recurrent sustained ventricular tachycardia. Con clusions. The electrophysiologic profile of sematilide is consistent w ith selective block of outward potassium currents and associated isola ted lengthening of the ventricular effective refractory period and APD ; sematilide demonstrates a significant degree of reverse frequency-de pendence of the ventricular APD and effective refractory period; and s uppression of ventricular tachycardia inducibility by sematilide appea rs to be correlated with increases in the right ventricular effective refractory period.