Adenosine-Induced Atrial Fibrillation Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart

作者：Li Ning; Csepe Thomas A; Hansen Brian J; Sul Lidiya V; Kalyanasundaram Anuradha; Zakharkin Stanislav O; Zhao Jichao; Guha Avirup; Van Wagoner David R; Kilic Ahmet; Mohler Peter J; Janssen Paul M L; Biesiadecki Brandon J; Hummel John D; Weiss Raul; Fedorov Vadim V

来源：Circulation, 2016, 134(6): 486-+.

DOI：10.1161/CIRCULATIONAHA.115.021165

• adenosine
• atrial fibrillation
• G protein-coupled inwardly rectifying potassium channels
• optical mapping
• receptor, adenosine A1
• tertiapin

BACKGROUND: Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor and its downstream GIRK (G protein-coupled inwardly rectifying potassium channels) channels (I (K, Ado)). METHODS: We applied biatrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and nonfailing human hearts (n=37). RESULTS: Optical mapping of coronary-perfused atria (n=24) revealed that adenosine perfusion (10-100 mu mol/L) produced more significant shortening of action potential durations in RA (from 290 +/- 45 to 239 +/- 41 ms, 17.3 +/- 10.4%; P< 0.01) than LA (from 307 +/- 24 to 286 +/- 23 ms, 6.7 +/- 6.6%; P< 0.01). In 10 hearts, adenosine induced AF (317 +/- 116 s) that, when sustained (=2 minutes), was primarily maintained by 1 to 2 localized reentrant drivers in lateral RA. Tertiapin (10-100 nmol/L), a selective GIRK channel blocker, counteracted adenosine-induced action potential duration shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher adenosine A1 receptor (2.7 +/- 1.7-fold; P< 0.01) and GIRK4 (1.7 +/- 0.8-fold; P< 0.05) protein expression than lateral/posterior LA. CONCLUSIONS: This study revealed a 3-fold RA-to-LA adenosine A1 receptor protein expression gradient in the human heart, leading to significantly greater RA versus LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest adenosine A1 receptor/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine.

• 出版日期2016-8-9