Abstract 18556: Sinus Node-Like Pacemaker Phenotype is the Basis of Ectopic Activity Originating in Atrioventricular Rings
Introduction: The atrioventricular (AV) ring surrounding the tricuspid valve orifice is a hotbed of ectopic activity in patients with focal atrial tachycardia. The AV ring shares embryological ancestry with nodal tissue and is capable of pacemaking. Currently, experimental data offering mechanistic insights into the initiation and maintenance of the ectopic foci is lacking. We have investigated pacemaker mechanisms in the rat AV rings and the autonomic modulation of ectopic activity.
Methods: Multi-electrode arrays and sharp microelectrodes were used for electrophysiology (n = 19). Gene and protein expression were studied by qPCR and immunohistochemistry, respectively (n = 12). Conditions favouring ectopic foci in the AV ring were assessed by computer simulations. Data are presented as mean ± SEM.
Results: In right atria devoid of sinus node, pacemaker activity originated in the AV ring and propagated to the terminal crest. Pacemaker action potentials were sinus node-like with prominent diastolic depolarization (Max. diastolic potential, -50 ± 3 mV), slow upstroke velocity (7 ± 1 V/s) and short amplitude (49 ± 3 mV). The time to 50% and 90% repolarization was 46 ± 5 ms and 87 ± 8 ms, respectively and the spontaneous cycle length was 620 ± 84 ms. Blocking the pacemaker current, If with 2 mM Cs+ prolonged cycle length, indicating a role for If in pacemaking. Similar effects were observed after disrupting intracellular Ca2+ release with 2 μM ryanodine. The adrenergic agonist isoproterenol (0.05 μM) shortened cycle length by 35% and muscarinic agonist carbachol (0.1 μM) prolonged it. AV rings immunolabelled with neurofilament-M revealed abundant nerve endings similar to sinus node. Consistent with our electrophysiology, mRNA levels for receptors (β2 adrenergic and M2 muscarinic), HCN4 channel (for If) and Ca2+ handling proteins (RyR2, SERCA2 and NCX1) in the AV ring was similar to levels in sinus node. Computer simulations of action potential propagation in the right atrium with intact sinus node demonstrated overdrive suppression of the AV ring; however, a sick sinus node unveiled the AV ring ectopic foci and increased arrhythmic propensity.
Conclusions: Pacemaking in AV rings is dependent on If and intracellular Ca2+ release and is prone to autonomic modulation.
- Atrial arrhythmias
- Ablation, radiofrequency
- Beta-adrenergic receptor agonists
- Cellular Electrophysiology
Author Disclosures: S.R. Logantha: None. A.J. Atkinson: None. S.R. Kharche: None. H. Dobrzynski: None.
- © 2016 by American Heart Association, Inc.