Published Online
on August 25, 2003

A more recent version of this article appeared on September 16, 2003

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Submitted on March 5, 2003
Revised on May 8, 2003
Accepted on May 9, 2003

Heterogeneous Ventricular Repolarization Provides a Substrate for Arrhythmias in a German Shepherd Model of Spontaneous Arrhythmic Death

Maria N. Obreztchikova PhD, Eugene A. Sosunov PhD, Evgeny P. Anyukhovsky PhD, N. Sydney Moïse DVM, Richard B. Robinson PhD, and Michael R. Rosen MD^*

From the Department of Pharmacology and Pediatrics, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY (M.N.O., E.A.S., E.P.A., R.B.R., M.R.R.), and the Department of Clinical Science, College of Veterinary Medicine of Cornell University, Ithaca, NY (N.S.M.).

^* To whom correspondence should be addressed. E-mail: mrr1{at}columbia.edu.

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.

Methods and 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, I_Kr and I_Ks, in single anteroseptal and anterobasal LV myocytes with the use of a whole-cell voltage clamp. There were no differences in I_Kr and I_Ks between anteroseptal and anterobasal regions in unafflicted dogs, whereas in afflicted dogs, I_Kr was smaller anterobasally (P<0.05). Isoproterenol produced a more prominent leftward shift in I_Ks voltage-dependent activation in anterobasal regions of afflicted than unafflicted dogs.

Conclusions--Spatial heterogeneity in expression and catecholamine responsiveness of I_Kr and I_Ks results in heterogeneous LV repolarization in afflicted German shepherd dogs, contributing importantly to the arrhythmogenic substrate.

Key words: arrhythmia • death, sudden • electrophysiology • ion channels

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