799-2 Left Ventricular (LV) and Myocyte Electrophysiology with the Development of Dilated Cardiomyopathy (DCM); Effects of Angiotensin II Receptor (AT 1 AT-II) Blockade

Ventricular arrhythmias are a significant cause of morbidity and mortality with DCM, and AT1 AT-II receptor activation has been implicated to play a role in arrhythmogenesis. However, the effects of AT1, AT-II receptor activation on changes in LV function and myocyte electrophysiology during the progression of DCM remain unexplored. Accordingly, this study measured weekly changes in LV function (ejection fraction, LVEF; peak systolic wall stress, LVWS) and surface electrocardiography (R-R interval, QRS duration, QTc interval), and myocyte action potentials (resting membrane, RM; upstroke velocity, Vmax; duration at 90% repolarization, APD90) at terminal study in 3 groups of dogs (n = 6/group): DCM, chronic pace (216 bpm, 4 weeks); DCM/AT-BLOCK, chronic pace and treatment with a specific non-peptide AT1 AT-II antagonist (SR 47436 (BMS 186295); 30 mg/kg BID); and control (CON). All measurements were made with the pacemaker deactivated. LVEF (%) LVWS (g/cm2) R-R (ms). QRS (ms). QTc (ms) Week 2: CON 68.7 ± 3.2 133 ± 14 646 ± 99 58.4 ± 1.3 291 ± 13 DCM 40.9 ± 4.1 * 184 ± 16 * 519 ± 40 60.7 ± 1.9 316 ± 9 DCM/AT-Block 44.1 ± 3.7 * 138 ± 10 + 540 ± 56 6.32 ± 1.2 * 325 ± 9 Week4: CON 73.1 ± 2.4 127 ± 10 629 ± 45 57.6 ± 1.4 314 ± 9 DCM 35.2 ± 3.5 * 223 ± 16 * 505±41 * 62.0 ± 1.9 313 ± 9 DCM/AT-Block 35.2 ± 2.7 * 160 ± 13 * , + 578 ± 48 65.7 ± 1.5 * 296 ± 6 * p l 0.05 vs CON + p l 0.05 vs DCM With DCM, RM (-71 ± l* vs -78 ± 1 mV) and APD90 (257 ± 9* vs 226 ± 7 ms) increased, and Vmax decreased (121 ± 5* vs 158 ± 9V/s) compared to CON. In contrast, with AT-BLOCK, RM became more negative (-76 ± 1+ mV), APD90 was reduced (183 ± 14*+) and Vmax increased (165 ± 13+). Summary AT1 AT-II receptor blockade during the progression of DCM caused significant changes in LV myocardial conduction and myocyte action potentials. These results suggest that AT1 AT-II receptor activation plays a contributory role toward the changes in LV electrophysiology with DCM.