Electropharmacological characterization of cardiac repolarization in German shepherd dogs with an inherited syndrome of sudden death: abnormal response to potassium channel blockers.
OBJECTIVE
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(-4)M) 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(-5)M), 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.
Mérot
J
J
INSERM U 533, Physiopathologie & Pharmacologie Cellulaires & Moléculaires, Nantes, France.
Probst
V
V
Debailleul
M
M
Gerlach
U
U
Moise
N S
NS
Le Marec
H
H
Charpentier
F
F
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology / Q000662:veterinary*; D002839:Chromans / Q000627:therapeutic use; D016757:Death, Sudden, Cardiac / Q000662:veterinary*; D004283:Dog Diseases / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D004285:Dogs; D004562:Electrocardiography; D004699:Endocardium / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D009206:Myocardium / Q000473:pathology; D010880:Piperidines / Q000627:therapeutic use; D026902:Potassium Channel Blockers; D011690:Purkinje Fibers / Q000503:physiopathology; D011725:Pyridines / Q000627:therapeutic use; D012016:Reference Values; D013015:Sotalol / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D002839:Chromans; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D013449:Sulfonamides; C063968:E 4031; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D013015:Sotalol