No abstract

1 The rate-dependent contributions of the rapid and slow components of the cardiac delayed rectifier K þ current (I Kr and I Ks , respectively) to repolarization are not fully understood. It is unclear whether the addition of I Ks block will attenuate reverse rate-dependence seen after I Kr block. 2 The individual and combined electrophysiological effects of selective I Kr and I Ks blockers, dofetilide and HMR 1556, respectively, were evaluated using Langendorff-perfused rabbit hearts. Monophasic action potential duration at 90% repolarization (MAPD 90 ) and ventricular effective refractory period (VERP) were determined at cycle lengths (CLs) of 200-500 ms (at 50 ms intervals). 3 Dofetilide (1-100 nM) prolonged MAPD 90 in a concentration-dependent manner (Po0.001, n ¼ 6) with reverse rate-dependence (Po0.0001). In contrast, HMR 1556 (10-240 nM) alone did not prolong MAPD 90 . However, in the presence of 7.5 nM dofetilide, HMR 1556 (100 nM) increased the extent of reverse rate-dependence by further prolonging MAPD 90 at CLs of 400, 450 and 500 ms (Po0.05, n ¼ 9) and, to a lesser extent, at shorter CLs (e.g. by 1774 ms at CL 500 vs 273 ms at CL 200 ms). 4 Effects of dofetilide and HMR 1556 on VERP were similar to those on MAPD 90 . The slope of the VERP vs CL relation was steeper after the combination (0.08170.013) than after dofetilide alone (0.02870.018, Po0.01, n ¼ 9). 5 Blockade of rabbit I Ks increased reverse rate-dependence of I Kr block.

Background— Abnormal intercellular communication caused by connexin dysfunction may contribute to atrial fibrillation (AF). The present study assessed the effect of the gap junction conduction–enhancing antiarrhythmic peptide GAP-134 on AF inducibility and maintenance in a dog model of atrial cardiomyopathy. Methods and Results— Twenty-four dogs subject to simultaneous atrioventricular pacing (220 bpm for 14 days) were randomly assigned to placebo treatment (PACED-CTRL; 12 dogs) or oral GAP-134 (2.9 mg/kg BID; PACED-GAP-134; 12 dogs) starting on day 0. UNPACED-CTRL (4 dogs) and UNPACED-GAP-134 (4 dogs) served as additional control groups. Change in left atrial (LA) systolic area from baseline to 14 days was calculated using transoesophageal echocardiography. At 14 days, animals underwent an open-chest electrophysiological study. PACED-CTRL dogs (versus UNPACED-CTRL) had a shorter estimated LA wavelength (8.0�1.4 versus 24.4�2.5 cm, P <0.05) and a greater AF vulnerability (mean AF duration, 1588�329 versus 25�34 seconds, P <0.05). Oral GAP-134 had no effect on AF vulnerability in UNPACED dogs. Compared with PACED-CTRL dogs, PACED-GAP-134 dogs had a longer estimated LA wavelength (10.2�2.8 versus 8.0�1.4 cm, respectively, P <0.05). Oral GAP-134 did not significantly reduce AF inducibility or maintenance in the entire group of 24 PACED dogs; in a subgroup of dogs (n=11) with less than 100% increase in LA systolic area, oral GAP-134 reduced AF induction from 100% to 40% and mean AF duration from 1737�120 to 615�280 seconds ( P <0.05). Conclusions— Oral GAP-134 reduces pacing-induced decrease in LA wavelength and appears to attenuate AF vulnerability in dogs with less atrial mechanical remodeling. Gap junction modulation may affect AF in some circumstances.