The canine chronic atrioventricular block model in cardiovascular preclinical drug research

Abstract

Ventricular cardiac arrhythmia is a life threating condition arising from abnormal functioning of many factors in concert. Animal models mirroring human electrophysiology are essential to predict and understand the rare pro-and antiarrhythmic effects of drugs. This is very well accomplished by the canine chronic atrioventricular block (CAVB) model. Here we summarize canine models for cardiovascular research, and describe the development of the CAVB model from its beginning. Understanding of the structural, contractile and electrical remodelling processes following atrioventricular (AV) block provides insight in the many factors contributing to drug-induced arrhythmia. We also review all safety pharmacology studies, efficacy and mechanistic studies on anti-arrhythmic drugs in CAVB dogs. Finally, we compare pros and cons with other in vivo preclinical animal models. In view of the tremendous amount of data obtained over the last 100 years from the CAVB dog model, it can be considered as man's best friend in preclinical drug research.

How good are our models of cardiovascular disease?

“…The review by Saljic et al (2021) focuses on antiarrhythmic investigations in large animals, including spontaneous atrial fibrillation in small and large mammals followed by a short presentation of frequently used methods for inducing short and long‐term atrial fibrillation with a major focus on antiarrhythmic compounds used in the human clinic or promising new candidates. Moreover, Loen et al (2021) provide us with a description of the canine model of ventricular cardiac arrhythmia by chronic atrioventricular block and its value for preclinical drug research. Those authors provide an explanation of the structural, contractile and electrical remodelling processes following atrioventricular block and thus offer insight into several factors contributing to drug‐induced arrhythmia.…”

Autonomic modulation of ventricular electrical activity: recent developments and clinical implications

“…Secondly, canine models have been of great value to the field of ventricular arrhythmogenesis, a significant advantage being that all major currents that are present in human myocytes are also found in dogs, resulting in a very similar action potential morphology [ 19 , 20 ]. Moreover, the social nature of dogs allows for awake experiments, which might be especially beneficial when studying the autonomic nervous system, as anesthesia can pose a confounding factor in such experiments [ 21 ].…”

“…However, canine models also come with various disadvantages and limitations. For example, dogs have a shorter action potential duration and a higher resting heart rate and respiratory rate [ 20 ]. Moreover, though parasympathetic tone is dominant in resting humans, the resting autonomic tone in dogs is even more heavily influenced by the parasympathetic nervous system, which is also reflected in their more pronounced respiratory sinus arrhythmia and increased heart rate variability [ 22 ].…”

“…This difference in autonomic tone must thus be carefully considered in the setting of preclinical studies in neurocardiology. Lastly, dogs are a costly, time-consuming and labor-intensive animal model, which greatly limits their use [ 20 ].…”

PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model

“…The sensitive atrioventricular (AV) block dog model has been used for the last three decades to test potential pro- and antiarrhythmic effects of pharmacological compounds ( 26 ). A combination of AV block-induced cardiac remodeling, anesthesia, bradycardia, and infusion of I Kr blocker dofetilide as the final hit, predisposes the heart to Torsade de Pointes (TdP) ventricular arrhythmias ( 27 ).…”