Upregulation of adenosine A1 receptors facilitates sinoatrial node dysfunction in chronic canine heart failure by exacerbating nodal conduction abnormalities revealed by novel dual-sided intramural optical mapping.
BACKGROUND
Although sinoatrial node (SAN) dysfunction is a hallmark of human heart failure (HF), the underlying mechanisms remain poorly understood. We aimed to examine the role of adenosine in SAN dysfunction and tachy-brady arrhythmias in chronic HF.


RESULTS
We applied multiple approaches to characterize SAN structure, SAN function, and adenosine A1 receptor expression in control (n=17) and 4-month tachypacing-induced chronic HF (n=18) dogs. Novel intramural optical mapping of coronary-perfused right atrial preparations revealed that adenosine (10 μmol/L) markedly prolonged postpacing SAN conduction time in HF by 206 ± 99 milliseconds (versus 66 ± 21 milliseconds in controls; P=0.02). Adenosine induced SAN intranodal conduction block or microreentry in 6 of 8 dogs with HF versus 0 of 7 controls (P=0.007). Adenosine-induced SAN conduction abnormalities and automaticity depression caused postpacing atrial pauses in HF versus control dogs (17.1 ± 28.9 versus 1.5 ± 1.3 seconds; P<0.001). Furthermore, 10 μmol/L adenosine shortened atrial repolarization and led to pacing-induced atrial fibrillation in 6 of 7 HF versus 0 of 7 control dogs (P=0.002). Adenosine-induced SAN dysfunction and atrial fibrillation were abolished or prevented by adenosine A1 receptor antagonists (50 μmol/L theophylline/1 μmol/L 8-cyclopentyl-1,3-dipropylxanthine). Adenosine A1 receptor protein expression was significantly upregulated during HF in the SAN (by 47 ± 19%) and surrounding atrial myocardium (by 90 ± 40%). Interstitial fibrosis was significantly increased within the SAN in HF versus control dogs (38 ± 4% versus 23 ± 4%; P<0.001).


CONCLUSIONS
In chronic HF, adenosine A1 receptor upregulation in SAN pacemaker and atrial cardiomyocytes may increase cardiac sensitivity to adenosine. This effect may exacerbate conduction abnormalities in the structurally impaired SAN, leading to SAN dysfunction, and potentiate atrial repolarization shortening, thereby facilitating atrial fibrillation. Atrial fibrillation may further depress SAN function and lead to tachy-brady arrhythmias in HF.
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Qing
Q
Lou
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Brian J
BJ
Hansen
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Olga
O
Fedorenko
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Thomas A
TA
Csepe
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Anuradha
A
Kalyanasundaram
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Ning
N
Li
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Lori T
LT
Hage
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Alexey V
AV
Glukhov
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
George E
GE
Billman
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Raul
R
Weiss
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Peter J
PJ
Mohler
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Sándor
S
Györke
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Brandon J
BJ
Biesiadecki
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.).
Cynthia A
CA
Carnes
From the Department of Physiology and Cell Biology (Q.L., B.J.H., O.F., T.A.C., A.K., N.L., L.T.H., A.V.G., G.E.B., P.J.M., S.G., B.J.B., V.V.F.), Davis Heart & Lung Research Institute (Q.L., A.K., G.E.B., R.W., P.J.M., S.G., B.J.B., C.A.C., V.V.F.), and Department of Internal Medicine (R.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Mental Health Research Institute and National Research Tomsk Polytechnic University, Tomsk, Russia (O.F.); and College of Pharmacy, The Ohio State University, Columbus (C.A.C.). vadim.fedorov@osumc.edu fedorov.2@osu.edu.
Vadim V
VV
Fedorov
D000200:Action Potentials / Q000187:drug effects; D000241:Adenosine / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000503:physiopathology; D001919:Bradycardia / Q000209:etiology / Q000503:physiopathology*; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology*; D043682:Receptor, Adenosine A1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012849:Sinoatrial Node / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D013610:Tachycardia / Q000209:etiology / Q000503:physiopathology*; D013806:Theophylline / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation; D056969:Voltage-Sensitive Dye Imaging / Q000379:methods*; D014970:Xanthines / Q000494:pharmacology / Q000627:therapeutic use
D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000241:Adenosine
adenosine; adenosine A1 receptor; atrial fibrillation; heart failure; optical imaging; sick sinus syndrome; sinoatrial node