title: 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.
abstract: 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).
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.).
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: 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.).
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Csepe
authors.affiliation: 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.).
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hansen
authors.affiliation: 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.).
authors.forename: Lidiya V
authors.initials: LV
authors.lastname: Sul
authors.affiliation: 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.).
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kalyanasundaram
authors.affiliation: 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.).
authors.forename: Stanislav O
authors.initials: SO
authors.lastname: Zakharkin
authors.affiliation: 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.).
authors.forename: Jichao
authors.initials: J
authors.lastname: Zhao
authors.affiliation: 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.).
authors.forename: Avirup
authors.initials: A
authors.lastname: Guha
authors.affiliation: 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.).
authors.forename: David R
authors.initials: DR
authors.lastname: Van Wagoner
authors.affiliation: 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.).
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kilic
authors.affiliation: 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.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: 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.).
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: 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.).
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Biesiadecki
authors.affiliation: 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.).
authors.forename: John D
authors.initials: JD
authors.lastname: Hummel
authors.affiliation: 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.).
authors.forename: Raul
authors.initials: R
authors.lastname: Weiss
authors.affiliation: 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.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Fedorov
mesh_terms: D000241:Adenosine / Q000633:toxicity*; D000328:Adult; D000368:Aged; D001281:Atrial Fibrillation / Q000139:chemically induced* / Q000378:metabolism*; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects; D006325:Heart Atria / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D006329:Heart Conduction System / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D000072078:Positron Emission Tomography Computed Tomography; D043682:Receptor, Adenosine A1 / Q000096:biosynthesis*
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D043682:Receptor, Adenosine A1; D000241:Adenosine
keywords: G protein-coupled inwardly rectifying potassium channels; adenosine; atrial fibrillation; optical mapping; receptor, adenosine A1; tertiapin