Efficacy of pentamidine analogue 6 in dogs with chronic atrial fibrillation

Abstract

BackgroundThe inward rectifier inhibitor pentamidine analogue 6 (PA‐6) is effective in cardioversion of goats with persistent rapid pacing induced atrial fibrillation (AF) and is not proarrhythmic in dogs with experimental chronic 3rd‐degree AV block. Efficacy and safety in the clinical setting are unknown.HypothesisThat PA‐6 would be effective in converting AF to sinus rhythm (SR) in dogs with naturally occurring AF, without the presence of overt adverse effects.AnimalsTen client‐owned large and giant breed dogs.MethodsAnimals with persistent or permanent AF were recruited for our prospective study. PA‐6 was administered IV as a bolus of 2.5 mg/kg 10 min−1 followed by a maintenance infusion of 0.04 mg/kg min−1 for a maximum of 50 minutes in conscious dogs. Standard 6 lead limb ECG was recorded during the infusion. Visible and audible signs of adverse effects were scored during the entire procedure.ResultsPA‐6 did not induce changes in QRS duration (54.7 ± 4.6 versus 56.7 ± 6.1 ms, P = .42), QTc interval (241.1 ± 19.5 versus 258.7 ± 19.8 ms, P = .061) or RR interval (363.4 ± 84.6 versus 440.8 ± 96.3 ms, P = .072) at the end of the bolus. No cardioversion to SR was observed in any dog. Three dogs displayed no adverse effects. Five dogs had premature ventricular depolarizations during PA‐6 infusion on the ECG. Respiratory distress with laryngeal stridor, subtle muscle twitching, and mild generalized muscular weakness were noncardiac adverse effects observed in 5 dogs. Adverse effects resolved spontaneously.Conclusions and Clinical importanceChronic naturally occurring AF in large and giant breed dogs could not be cardioverted to SR by PA‐6.

Investigational Anti–Atrial Fibrillation Pharmacology and Mechanisms by Which Antiarrhythmics Terminate the Arrhythmia: Where Are We in 2020?

“… 31 Specific inhibition of I K1 (with PA-6) effectively cardioverts persistent AF in a goat AF model, 32 but does not stop chronic, naturally occurring AF in dogs. 33 Specific inhibition of I K1 did not promote proarrhythmias in these studies. Further research is needed for evaluation of specific I K1 inhibition for AF suppression.…”

Anti‐arrhythmic investigations in large animal models of atrial fibrillation

“…Persistent AF in humans, horses, and dogs was recorded following naturally occurring AF, while the recordings of persistent AF in goats and pigs are obtained following tachypacing‐induced AF. Human ECGs were kindly provided by Steen Pehrson, Rigshospitalet, Denmark, goat ECGs by Sander Verheule, Maastricht, dog sinus rhythm and induced AF recordings from Juhász et al (2018), dog persistent AF from Szatmári et al (2018) and pig ECGs by Jonas Diness, Acesion Pharma, Denmark…”

Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease

“…Whereas much knowledge on K ir 2.x function has been derived from experimental in vitro studies and transgenic mice, insights on the physiological contributions of I K1 in larger organisms can only be deduced from a few experimental large animal studies using specific inhibitors [10,11] and patients with gain-or loss-of-function mutations [5]. For example, specific I K1 inhibition in awake dogs induced adverse effects like premature ventricular contractions, respiratory distress, and mild generalized muscle weakness [11]. On the contrary, the effects of specific I K1 activation have not been investigated in large animals.…”