Atrioventricular nodal ablation and His-bundle pacing: an acute canine model for proarrhythmic risk assesment.
BACKGROUND
QT interval prolongation following drug exposure is considered a marker for increased risk of drug-induced arrhythmias. QT interval measurements are common components of the safety pharmacology assessment of new therapeutic compounds but are potentially confounded by concurrent changes in heart rate that also alter QT intervals. We describe an anesthetized canine model of AV dissociation with His-bundle pacing that overcomes the confounding effects of a change in heart rate.


RESULTS
Transvenous radiofrequency ablation of the AV node was performed in isoflurane-anesthetized dogs and followed by open chest implantation of bipolar pacing electrodes in the vicinity of the His bundle. Pace rates were adjusted from 50 to 190 in steps of 20 beats/min, holding each step for 30 seconds. At each paced rate, QT intervals were measured manually to the nearest 1 ms to construct paced QT interval-heart rate (QT-HR) relationships. Paired QT-HR relationships using identical ascending ramps of pace rates were compared to paired QT-HR relationships with an ascending and descending pace ramp to evaluate short-term reproducibility and hysteresis effects. For proof of concept, an additional QT-HR relationship was constructed in three dogs after intravenous administration of a compound known to alter QT intervals: one dog received terfenadine (0.48 mg/kg bolus followed by 0.017 mg/kg/min infusion), one dog received quinidine (20 mg/kg), and the third dog received sotalol (1 and 3 mg/kg). Substantial inter-dog variation was found for QT-HR, although short-term reproducibility was high within one dog (average absolute difference for paired ascending ramps < 5 ms). QT intervals measured during descending paced ramps were generally lower than the value for the corresponding paced rate on an ascending ramp. This hysteretic effect was small, averaging < 7 ms over the entire ramp. All test compounds prolonged QT intervals and shifted the QT-HR relationship upward. Maximal QT prolongation was 30 ms for terfenadine, 50 ms for quinidine, and 59 ms for sotalol.


CONCLUSIONS
AV nodal ablation and His-bundle pacing provide a sensitive animal model to identify acute effects of test compounds on indices of myocardial repolarization such as the QT interval. The model is devoid of confounding effects of changing heart rates while enabling identification of effects of drugs over a wide range of controlled rates.
Olivier
N Bari
NB
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA. Olivier@cvm.msu.edu
Eyster
George E
GE
Sanders
Rob
R
Cheng
Jie
J
Bohart
George
G
Girand
Mike
M
Bailie
Marc
M
D000208:Acute Disease; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000628:therapy; D001283:Atrioventricular Node / Q000601:surgery*; D002036:Bundle of His; D002304:Cardiac Pacing, Artificial; D017115:Catheter Ablation / Q000379:methods*; D004285:Dogs; D008133:Long QT Syndrome / Q000628:therapy*; D008297:Male; D011446:Prospective Studies; D018570:Risk Assessment