Heterogeneous ventricular repolarization provides a substrate for arrhythmias in a German shepherd model of spontaneous arrhythmic death.
BACKGROUND
German shepherd dogs with inherited arrhythmias and sudden death appear to be a model for catecholamine-dependent ventricular tachycardias in human subjects. We tested the hypothesis that heterogeneity of left ventricular repolarization creates an arrhythmogenic substrate for pause-dependent ventricular tachycardia in these animals.


RESULTS
We used microelectrode techniques to record action potentials (AP) from midmyocardial sections of anteroseptal, anterobasal, and posterobasal left ventricular (LV) wall of unafflicted and afflicted dogs. There were no differences in AP duration to 90% repolarization (APD) among LV regions in unafflicted dogs. In contrast, in afflicted dogs, there was significant heterogeneity, with the longest APD in anterobasal and shortest in anteroseptal regions. Isoproterenol did not affect repolarization in unafflicted dogs, whereas in afflicted dogs, it shortened APD anterobasally and prolonged APD anteroseptally. We studied the repolarizing currents, IKr and IKs, in single anteroseptal and anterobasal LV myocytes with the use of a whole-cell voltage clamp. There were no differences in IKr and IKs between anteroseptal and anterobasal regions in unafflicted dogs, whereas in afflicted dogs, IKr was smaller anterobasally (P<0.05). Isoproterenol produced a more prominent leftward shift in IKs voltage-dependent activation in anterobasal regions of afflicted than unafflicted dogs.


CONCLUSIONS
Spatial heterogeneity in expression and catecholamine responsiveness of IKr and IKs results in heterogeneous LV repolarization in afflicted German shepherd dogs, contributing importantly to the arrhythmogenic substrate.
Obreztchikova
Maria N
MN
Department of Pharmacology and Pediatrics, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Sosunov
Eugene A
EA
Anyukhovsky
Evgeny P
EP
Moïse
N Sydney
NS
Robinson
Richard B
RB
Rosen
Michael R
MR
D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004285:Dogs; D004553:Electric Conductivity; D006321:Heart / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D017180:Tachycardia, Ventricular / Q000150:complications / Q000503:physiopathology*; D018879:Ventricular Premature Complexes / Q000150:complications / Q000503:physiopathology*
D007473:Ion Channels; D007545:Isoproterenol