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EXPERIMENTAL STUDY

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

Jocelyn Mérot, DVM, PhD^* , Vincent Probst, MSc^*, Michèle Debailleul, Uwe Gerlach, PhD, N. Sydney Moise, DVM, Hervé Le Marec, MD, PhD^* and Flavien Charpentier, PhD^*

^* INSERM U 533, Physiopathologie & Pharmacologie Cellulaires & Moléculaires, Nantes, France
Laboratoire de Médecine, Ecole Vétérinaire de Nantes, Nantes, France
the Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
Hchst Marion Roussel, Frankfurt, Germany

Manuscript received June 4, 1999; revised manuscript received March 1, 2000, accepted April 12, 2000.

Reprint requests and correspondence: Dr. Flavien Charpentier, INSERM U 533 Physiopathologie & Pharmacologie Cellulaires & Moléculaires, CHU Hôtel-Dieu, 44093 Nantes cedex, France
flavien.charpentier{at}nantes.inserm.fr

OBJECTIVES

This study sought to determine whether abnormal ventricular repolarization is implicated in cardiac arrhythmias of German shepherd dogs with inherited sudden death.

BACKGROUND

Moïse et al. (9) have identified German shepherd dogs that display pause-dependent lethal ventricular arrhythmias.

METHODS

Ventricular repolarization was studied both in vivo using electrocardiogram recordings on conscious dogs and in vitro with a standard microelectrode technique performed on endomyocardial biopsies and Purkinje fibers. Pharmacological manipulation was used to evaluate the role of potassium channels.

RESULTS

In control conditions, electrocardiogram parameters were similar in both groups of dogs, except for the PR interval (18% longer in affected dogs, p < 0.05). Injection of d,l-sotalol (2 mg/kg) prolonged QT interval more 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 (APD₉₀) of endomyocardial biopsies and Purkinje fibers were significantly longer in affected dogs (respectively 209 ± 3 ms, n = 30 and 352 ± 15 ms, n = 17) than they 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 APD₉₀ to a change in PCL was faster in affected dogs. D,l-sotalol (10^–5 and 10^–4M) increased APD₉₀ in both groups of dogs, but this increase was greater in affected dogs, with the occurrence of triggered activity on Purkinje fibers. E-4031 (10^–7 and 10^–6 M), an I_Kr-blocker, increased APD₉₀ similarly in both groups of dogs. Chromanol 293B (10^–6 and 10^–5M), an I_Ks-blocker, increased significantly APD₉₀ in unaffected dogs but had no effect in affected dogs.

CONCLUSIONS

These results support the hypothesis of an abnormal cardiac repolarization in affected dogs. The effects of 293B suggest that I_Ks may be involved in this anomaly.

Abbreviations and Acronyms   ANS = autonomic nervous system   AP = action potential   APD = action potential duration   EADs = early afterdepolarizations   ECG = electrocardiogram   HR = heart rate   IV = intravenous   PCL = pacing cycle length   TA = triggered activity

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