Electropharmacological characterization of cardiac repolarization in German shepherd dogs with an inherited syndrome of sudden death: Abnormal response to potassium channel blockers

Objectives This study sought to determine whether abnormal ventricular repo larization is implicated in cardiac arrhythmias of German shepherd dogs wit h inherited sudden death. Background Moise et al. (9) have identified German shepherd dogs that displ ay pause-dependent lethal ventricular arrhythmias. Methods Ventricular repolarization was studied both in vivo using electroca rdiogram recordings on conscious dogs and in vitro with a standard microele ctrode technique performed on endomyocardial biopsies and Purkinje fibers. Pharmacological manipulation was used to evaluate the role of potassium cha nnels. Results In control conditions, electrocardiogram parameters were similar in both groups of dogs, except for the PR interval (18% longer in affected do gs, p < 0.05). Injection of d,1-sotalol (2 mg/kg) prolonged QT interval mor e in affected dogs (+14%, n = 9) than it did in unaffected dogs (+ 6%, n = 6, p < 0.05) and increased the severity of arrhythmias in affected dogs. In vitro, in control conditions, action potential duration (APD(90)) of endom yocardial biopsies and Purkinje fibers were significantly longer in affecte d dogs (respectively 209 +/- 3 ms, n = 30 and 352 +/- 15 ms, n = 17) than t hey were in unaffected dogs (197 +/- 4 ms, n = 25 and 300 +/- 9 ms, n = 30) at a pacing cycle length (PCL) of 1,000 ms. This difference increased with PCL. The kinetics of adaptation of APD(90) to a change in PCL was faster i n affected dogs. D,1-sotalol (10(-5) and 10(-4)M) increased APD(90) in both groups of dogs, but this increase was greater in affected dogs, with the o ccurrence of triggered activity on Purkinje fibers. E-4031 (10(-7) and 10(- 6) M), an I-Kr-blocker, increased APD(90) similarly in both groups of dogs. Chromanol 293B (10(-6) and 10(-5)M), an I-Ks-blocker, increased significan tly APD(90) in unaffected dogs but had no effect in affected dogs. Conclusions These results support the hypothesis of an abnormal cardiac rep olarization in affected dogs. The effects of 293B suggest that IK, may be i nvolved in this anomaly. (C) 2000 by the American College of Cardiology