Electrophysiologic mechanisms of antiarrhythmic efficacy of a sotalol and class Ia drug combination: elimination of reverse use dependence

Division of Cardiology, St. Michael's Hospital, Toronto, Ontario, Canada.

OBJECTIVES: We sought to determine the electrophysiologic mechanisms explaining the efficacy of combination therapy with DL-sotalol and a type Ia drug in the treatment of ventricular tachycardia (VT). BACKGROUND: Combination antiarrhythmic drug therapy with low dose DL-sotalol plus a type Ia antiarrhythmic agent has been shown to prevent spontaneous and induced VT. The mechanisms underlying the efficacy of this drug combination have not been fully elucidated. METHODS: We studied 32 patients with spontaneous sustained VT by using programmed electrical stimulation in the drug-free condition and after treatment with DL-sotalol (average dose [mean +/- SE] 151 +/- 8 mg/day) and a class Ia agent (quinidine, 1,337 +/- 59 mg/day, or procainamide, 2,083 +/- 327 mg/day). Sustained VT was induced in all patients at baseline study, and induction was reattempted during drug therapy. Monophasic action potential duration at 90% repolarization (APD90) and ventricular effective refractory period (ERP) were recorded with use of a contact electrode. RESULTS: Ventricular ERP increased from 258 +/- 4 ms at baseline to 310 +/- 6 ms at a 600-ms drive cycle length (DCL600) with treatment (p < 0.001). APD90 increased from 288 +/- 6 ms by +10.1% at DCL600 and from 267 +/- 7 ms by +13.3% at a 400-ms drive cycle length (DCL400) (p < 0.001). Paced QRS duration increased from 141 +/- 3 to 158 +/- 6 ms at DCL400 (p < 0.05). At baseline, the shortest achieved coupling interval between successive propagated extrastimuli decreased progressively with respect to the first extrastimulus, following double and triple extrastimuli, at both DCL600 (-14.0% and -20.0%, respectively) and at DCL400 (-16.4% and -22.4%, respectively). This "peeling back" of refractoriness was attenuated on therapy with sotalol plus a class Ia antiarrhythmic agent to -6.7% and -10.5% (DCL600, p < 0.05), and -8.1%, -9.5% (DCL400, p < 0.05), for double and triple extrastimuli, respectively. The absolute prolongation of functional refractory periods by the drug combination increased with successive extrastimuli, from 55 +/- 6 ms for the V1V2 interval to 75 +/- 6 ms for V2V3 and 67 +/- 6 ms for V3V4 at DCL600, and from 51 +/- 5 ms for V1V2 to 69 +/- 6 ms for V2V3 and 74 +/- 7 ms for V3V4 at DCL400 (p < 0.001). CONCLUSIONS: The combination of low dose sotalol and a class Ia agent greatly prolongs refractoriness. The magnitude of the effect increases at shorter coupling intervals.

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