Effect of the Cardioselective, Sarcolemmal KATP Channel Blocker HMR 1098 on Atrial Electrical Remodeling During Pacing-Induced Atrial Fibrillation in Dogs

PURPOSE: The progressive shortening of the atrial effective refractory period (ERP) during atrial fibrillation (AF) might be due to the activation of the KATP channels by rapid atrial rates. We tested the hypothesis that the cardioselective, sarcolemmal KATP channel blocker HMR 1098 would prevent atrial ERP shortening during AF. METHODS AND RESULTS: Nine dogs were treated with HMR 1098 (3 mg/kg bolus injection followed by a continuous intravenous (i.v.) infusion at 17 microg/kg/min rate maintained throughout the study) and 7 dogs served as controls receiving i.v. saline. Pharmacological autonomic blockade was induced by i.v. administration of atropine (0.04 mg/kg) and propranolol (0.2 mg/kg) and maintained throughout the study by continuous i.v. infusion of atropine (0.007 mg/kg/h) and propranolol (0.04 mg/kg/h). Rapid right atrial pacing at 50 msec cycle length (CL) was initiated and maintained for 6 hours. High right atrial ERP (HRA-ERP) and corrected sinus node recovery time (HRA-cSNRT), coronary sinus ERP (CS-ERP) and corrected SNRT (CS-cSNRT) at three (400, 300, 200 msec) CLs were measured before and after pacing at different time points. Baseline values were not different between control and treated dogs. In the control group the HRA-ERP progressively shortened (from 179 +/- 21 msec at baseline to 161 +/- 23 msec at 360 min at 400 msec CL) ( p = 0.002), with a gradual decrease, loss or inversion of ERP rate adaptation at shorter (300, 200 msec) CLs. HMR 1098 treatment did not prevent the shortening of HRA-ERP during the first 2 to 3 hours of rapid atrial pacing. However, beginning at 180-240 min, HMR 1098 increased the HRA-ERP ( p = 0.01) to baseline by 360 min. HMR 1098 treatment did not prevent another feature of atrial electrical remodeling, the flattening or inversion of ERP rate adaptation. In neither group did CS-ERP shortening occur. The maximum cSNRT at 360 min prolonged significantly in both groups during HRA and CS pacing as well compared with baseline. CONCLUSIONS: HMR 1098 treatment did not prevent the shortening of HRA-ERP, the salient feature of atrial electrical remodeling in the first 2 to 3 hours of rapid atrial rates, but did prevent it thereafter. Another characteristic feature of atrial electrical remodeling, the flattening or inversion of physiological ERP rate adaptation was not prevented by HMR 1098 treatment. Sinus node depression was detectable after short-term (6 hours) rapid atrial pacing and was not affected by HMR 1098.