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

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

doi:10.1161/CIRCULATIONAHA.115.021165

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

Circulation. 2016 Aug 9;134(6):486-98. doi: 10.1161/CIRCULATIONAHA.115.021165. Epub 2016 Jul 26.

Authors

Ning Li¹, Thomas A Csepe¹, Brian J Hansen¹, Lidiya V Sul¹, Anuradha Kalyanasundaram¹, Stanislav O Zakharkin¹, Jichao Zhao¹, Avirup Guha¹, David R Van Wagoner¹, Ahmet Kilic¹, Peter J Mohler¹, Paul M L Janssen¹, Brandon J Biesiadecki¹, John D Hummel¹, Raul Weiss¹, Vadim V Fedorov²

Affiliations

¹ From Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus (N.L., T.A.C., B.J.H., L.V.S., A. Kalyanasundaram, S.O.Z., A.G., P.J.M., P.M.L.J., B.J.B., V.V.F.); Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (N.L., T.A.C., B.J.H., L.V.S., A. Kalyanasundaram, A. Kilic, P.J.M., P.M.L.J., B.J.B., J.D.H., R.W., V.V.F.); Auckland Bioengineering Institute, The University of Auckland, New Zealand (J.Z.); Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus (A.G., A. Kilic, P.J.M., P.M.L.J., J.D.H., R.W.); Department of Molecular Cardiology, Cleveland Clinic, OH (D.R.V.W.); and Department of Surgery, Division of Cardiac Surgery, Wexner Medical Center, The Ohio State University, Columbus (A. Kilic, J.D.H., R.W.).
² From Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus (N.L., T.A.C., B.J.H., L.V.S., A. Kalyanasundaram, S.O.Z., A.G., P.J.M., P.M.L.J., B.J.B., V.V.F.); Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (N.L., T.A.C., B.J.H., L.V.S., A. Kalyanasundaram, A. Kilic, P.J.M., P.M.L.J., B.J.B., J.D.H., R.W., V.V.F.); Auckland Bioengineering Institute, The University of Auckland, New Zealand (J.Z.); Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus (A.G., A. Kilic, P.J.M., P.M.L.J., J.D.H., R.W.); Department of Molecular Cardiology, Cleveland Clinic, OH (D.R.V.W.); and Department of Surgery, Division of Cardiac Surgery, Wexner Medical Center, The Ohio State University, Columbus (A. Kilic, J.D.H., R.W.). vadim.fedorov@osumc.edu fedorov.2@osu.edu.

Abstract

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 (IK,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 µmol/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.

Keywords: G protein-coupled inwardly rectifying potassium channels; adenosine; atrial fibrillation; optical mapping; receptor, adenosine A1; tertiapin.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adenosine / toxicity*
Adult
Aged
Atrial Fibrillation / chemically induced*
Atrial Fibrillation / metabolism*
Female
G Protein-Coupled Inwardly-Rectifying Potassium Channels / biosynthesis*
Gene Expression Regulation
Heart / diagnostic imaging
Heart / drug effects
Heart Atria / diagnostic imaging
Heart Atria / drug effects
Heart Atria / metabolism*
Heart Conduction System / diagnostic imaging
Heart Conduction System / drug effects
Heart Conduction System / metabolism
Humans
Male
Middle Aged
Organ Culture Techniques
Positron Emission Tomography Computed Tomography
Receptor, Adenosine A1 / biosynthesis*

Substances

G Protein-Coupled Inwardly-Rectifying Potassium Channels
KCNJ5 protein, human
Receptor, Adenosine A1
Adenosine

Abstract

Publication types

MeSH terms

Substances

Grants and funding