263 Junctional tachycardia in the mouse can be prevented by pacemaker channel (If) blockade with Ivabradine hydrochloride

Abstract

Atrioventricular nodal re-entrant tachycardia (AVNRT) and junctional tachycardia (JT) are common, electrocardiographically similar, arrhythmias. AVNRT is described as re-entry conduction between the fast (FP) and slow (SP) AV nodal pathways. JT occurring following cardiac surgery in neonates increases mortality risk by 5.6-14%. JT mechanisms are unknown, but may include autonomic nervous system involvement. Pacemaking mechanisms utilize a membrane clock, involving the pacemaker funny channel (If), and an intracellular calcium clock involving rhythmic oscillations in calcium release from ryanodine receptors. The SP, formed by the inferior extension of the compact AV node (INE), contains the dominant AVN pacemaker, expresses If, and may be involved in JT. We investigated the mechanisms of junctional arrhythmia in male wild type C57BL/6 mice. Studies utilized an intracardiac octapolar electrode catheter in anaesthetized mice. Programmed electrical stimulation elicited antegrade AVN conduction and SP conduction in 8/18 mice, single re-entrant beats in 3/18, but rarely AVNRT (1/18). Rapid ventricular pacing (RVP, 50 Hz, 400 ms, 10-30 bursts), induced junctional arrhythmia in 14/18 mice (83%) producing a 32% increase in rate (325 ± 15 vs 429 ± 19 BPM, P < 0.001). Response of arrhythmia to single premature atrial stimuli distinguish AVNRT from JT. Premature FP activation did not terminate the arrhythmia (0/14) indicating JT. RVP caused decreases (46 ± 2.6%) in minimum end-diastolic blood pressure and enhanced nodal conduction following 10 bursts (pre-pacing AH = 31 ± 1ms vs post-pacing AH = 28 ± 1ms, P < 0.001, n = 14) prior to JT initiation, suggesting involvement of a baroreflex response. Vagal nerve stimulation (5/5, X2 = 10, P < 0.002) and propranolol (7/7, X2 = 14, P < 0.001) prevented JT induction, confirming a role for the autonomics. Ivabradine hydrochloride, a selective If blocker, prevented JT (8/9, X2 = 14.4, P < 0.001). Ruthenium red, a potent inhibitor of intracellular calcium release also prevented JT (5/5, X2 = 10,P < 0.002). Forskolin (an adenylyl cyclase activator) and caffeine (a stimulator of intracellular calcium release) together produced long lasting (>2 mins) spontaneous JT (5/5, X2 = 10, P < 0.002) that was terminated by Ivabradine (5/5, X2 = 10,P < 0.002). AVNRT was infrequent, but the mouse is susceptible to JT. JT may rely on an interaction of membrane and intracellular events which can be prevented by If channel blockade. Ivabradine might be useful in neonatal patients with post-operative JT.