Abstract 5286: Human AV Junctional Pacemaker Shift Due to Cholinergic and Adrenergic Stimulations: Optical Imaging with a Novel Long Wavelength Voltage-Sensitive Dye

It is well known that under different physiological and pathologic conditions, the atrioventricular junction (AVJ) may become the pacemaker of the heart. However, unlike the well-characterized AVJ pacemaker in animal models, autonomic control of the human AVJ pacemaker has not been studied. Explanted human hearts with different types of cardiomyopathy (n=7) were obtained at the time of cardiac transplantation and perfused with cardioplegic solution. The AVJ was cannulated, isolated from the rest of the heart, immobilized with the excitation-contraction uncoupler blebbistatin (10 μmol/L) and optically mapped using the infrared voltage sensitive dye di-ANBDQBS. Imaging was conducted with 100x100 CMOS camera from endocardial field of view ranging 24x24 to 36x36mm 2 , which allowed to simultaneously map right side of intratrial and intraventricular septa, coronary sinus (CS) and His bundle regions. In control, we found AVJ rhythm of 31+/−15 bpm (2409+/−1264 ms) in all human preparations which originated in compact AV node (N-region, n=4) and/or region between AV node and His bundle (NH-region, n=3). Isoproternol (Iso, 1 μM) induced AVJ rhythm acceleration up to 68+/−12 bpm (913+/−192 ms), temporary pacemaker shift to CS region (n=2) and improved conduction in both slow and fast pathways, which induced reentrant arrhythmias in 3/5 preparations. Acetylcholine (ACh, 1–3 μM) slowed rhythm to 21+/−6 bpm (3130+/−1146 ms) and conduction in both pathways up to complete block, and induced temporary pacemaker shift to CS region in 3/4 preparations. Moreover, we found bifocal activation in 3/4 preparation when two main pacemakers (CS and compact AV node) worked asynchronously with different frequencies, accompanied by the exit block from AV node. We showed by high-resolution optical mapping for the first time that unlike in animal models (rabbit and rat) in isolated coronary perfused human AVJ leading pacemaker localized mostly in the N- or NH-regions. Beta-adrenergic (Iso) and cholinergic (ACh) stimulations of AVJ can significantly accelerate or slow rhythm and conduction, as well as induced pacemaker shift to CS, and result in reentrant arrhythmias. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

Downward gradient in action potential duration along conduction path in and around the sinoatrial node

Regional differences in electrical activity in rabbit sinoatrial node have been investigated by recording action potentials throughout the intact node or from small balls of tissue from different regions. In the intact node, action potential duration was greatest at or close to the leading pacemaker and declined markedly in all directions from it, e.g., by 74 ± 4% (mean ± SE, n = 4) to the crista terminalis. Similar data were obtained from the small balls. The gradient is down the conduction pathway and will help prevent reentry. In the intact node, a zone of inexcitable tissue with small depolarizations of <25 mV or stable resting potentials was discovered in the inferior part of the node, and this will again help prevent reentry. The intrinsic pacemaker activity of the small balls was slower in tissue from more inferior (as well as more central) parts of the node [e.g., cycle length increased from 339 ± 13 ms ( n = 6) to 483 ± 13 ms ( n = 6) in transitional tissue from more superior and inferior sites], and this may help explain pacemaker shift.

Vagal effects on sinoatrial and atrial conduction studied with epicardial mapping in dogs: the influence of pacemaker shifts on the measurement of sinoatrial conduction time

The influence of pacemaker shifts on sinoatrial conduction time (SACT) was studied by investigating the effects of vagal stimulation on SACT and atrial conduction in anesthetized open-chest dogs. Isochronal maps were drawn from unipolar electrograms simultaneously recorded at 60 epicardial sites on the right atrial free wall and the inferior and superior vena cava. Vagal stimulation caused atrial conduction velocity to increase from 0.99 ± 0.10 m/s (mean ± SD) to 1.23 ± 0.23 m/s (p < 0.01), and the pacemaker to shift to lower positions along the superior vena cava – right atrial junction. As a result of the changes, the distances and the atrial conduction times from the stimulating and recording electrodes to the pacemaker site varied, and hence, the SACT values obtained indirectly by premature atrial stimulation varied. The isochronal maps were used to measure the atrial conduction times from stimulating to recording electrodes (a), from stimulating electrode to pacemaker site (b), and from pacemaker site to recording electrode (c). Indirect SACT was lengthened by vagal stimulation from 43 ± 16 to 64 ± 22 ms (p < 0.02). After correcting by subtracting the atrial conduction time (b + c − a), these values became 26 ± 6 ms (control) and 40 ± 11 ms (vagal stimulation) (p < 0.01). SACT values measured directly from the electrograms were 27 ± 7 ms (control) and 42 ± 10 ms (vagal stimulation) (p < 0.01). Corrected indirect SACTs were closer to direct SACTs than were the uncorrected indirect SACTs. It was concluded that (i) vagal stimulation induced pacemaker shift, increased atrial conduction velocity, and prolonged SACT; (ii) constant atrial pacing induced a pacemaker shift toward the stimulating electrode; and (iii) atrial conduction time must be taken into account to correctly estimate SACT.