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

Qing Lou, Brian J. Hansen, Olga Fedorenko, Thomas A. Csepe, Anuradha Kalyanasundaram, Ning Li, Lori T. Hage, Alexey V. Glukhov, George E. Billman, Raul Weiss, Peter J. Mohler, Sándor Györke, Brandon J. Biesiadecki, Cynthia A. Carnes, Vadim V. Fedorov

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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. METHODS AND 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.

Original languageEnglish
Pages (from-to)315-324
Number of pages10
JournalCirculation
Volume130
Issue number4
DOIs
Publication statusPublished - 22 Jul 2014

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Adenosine A1 Receptors
Sinoatrial Node
Canidae
Up-Regulation
Heart Failure
Adenosine
Atrial Fibrillation
Dogs
Cardiac Arrhythmias
Adenosine A1 Receptor Antagonists
Theophylline
Cardiac Myocytes

Keywords

  • adenosine
  • adenosine A1 receptor
  • atrial fibrillation
  • heart failure
  • optical imaging
  • sick sinus syndrome
  • sinoatrial node

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

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. / Lou, Qing; Hansen, Brian J.; Fedorenko, Olga; Csepe, Thomas A.; Kalyanasundaram, Anuradha; Li, Ning; Hage, Lori T.; Glukhov, Alexey V.; Billman, George E.; Weiss, Raul; Mohler, Peter J.; Györke, Sándor; Biesiadecki, Brandon J.; Carnes, Cynthia A.; Fedorov, Vadim V.

In: Circulation, Vol. 130, No. 4, 22.07.2014, p. 315-324.

Research output: Contribution to journalArticle

Lou, Q, Hansen, BJ, Fedorenko, O, Csepe, TA, Kalyanasundaram, A, Li, N, Hage, LT, Glukhov, AV, Billman, GE, Weiss, R, Mohler, PJ, Györke, S, Biesiadecki, BJ, Carnes, CA & Fedorov, VV 2014, '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', Circulation, vol. 130, no. 4, pp. 315-324. https://doi.org/10.1161/CIRCULATIONAHA.113.007086
Lou, Qing ; Hansen, Brian J. ; Fedorenko, Olga ; Csepe, Thomas A. ; Kalyanasundaram, Anuradha ; Li, Ning ; Hage, Lori T. ; Glukhov, Alexey V. ; Billman, George E. ; Weiss, Raul ; Mohler, Peter J. ; Györke, Sándor ; Biesiadecki, Brandon J. ; Carnes, Cynthia A. ; Fedorov, Vadim V. / 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. In: Circulation. 2014 ; Vol. 130, No. 4. pp. 315-324.
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abstract = "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. METHODS AND 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.",
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T1 - 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

AU - Lou, Qing

AU - Hansen, Brian J.

AU - Fedorenko, Olga

AU - Csepe, Thomas A.

AU - Kalyanasundaram, Anuradha

AU - Li, Ning

AU - Hage, Lori T.

AU - Glukhov, Alexey V.

AU - Billman, George E.

AU - Weiss, Raul

AU - Mohler, Peter J.

AU - Györke, Sándor

AU - Biesiadecki, Brandon J.

AU - Carnes, Cynthia A.

AU - Fedorov, Vadim V.

PY - 2014/7/22

Y1 - 2014/7/22

N2 - 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. METHODS AND 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.

AB - 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. METHODS AND 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.

KW - adenosine

KW - adenosine A1 receptor

KW - atrial fibrillation

KW - heart failure

KW - optical imaging

KW - sick sinus syndrome

KW - sinoatrial node

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