Published online before print November 11, 2002, doi: 10.1161/01.CIR.0000039327.11661.16
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;106:2854.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Downregulation of Endocardial Nitric Oxide Synthase Expression and Nitric Oxide Production in Atrial Fibrillation
Potential Mechanisms for Atrial Thrombosis and Stroke
From the Division of Cardiology, Emory University School of Medicine (H.C., Z.L., A.G., F.M., C.H., K.F., S.C.D., D.G.H., J.L.L.); Atlanta VAMC (Z.L., S.C.D.); and The Winship Cancer Institute, Emory University (J.N.W.), Atlanta, Ga.
Correspondence to Jonathan Langberg, MD, Emory University Hospital, Suite F-414, 1364 Clifton Rd, NE, Atlanta, GA, 30322. E-mail jonathan_langberg{at}emory.org
Background— In the arterial endothelium, laminar flow and cyclical stretch induce expression of NO synthase (NOS). We hypothesized that atrial fibrillation (AF) causes a downregulation of atrial endocardial NOS expression and NO·production. Because NO·has antithrombotic properties, this may contribute to thromboembolism in AF.
Methods and Results— In pigs, AF was produced with rapid atrial pacing at 600 bpm for 1 week, whereas controls had atrial pacing at 100 bpm. All animals had catheter ablation of the AV junction and ventricular pacing at 100 bpm. NO·production from freshly isolated tissue was measured by a NO·-specific microelectrode. Left atrial basal and stimulated NO·production was decreased in AF by 73% and 71% (P<0.01). Endocardial NOS expression, determined by Western analysis, was also significantly decreased by 46%. Expression of the prothombotic protein plasminogen activator inhibitor 1 (PAI-1) is known to be regulated by NO·and was increased in the left atrium by 1.8-fold in AF (P<0.05). NO·concentration was decreased in the left atrial appendage, although NOS expression was not affected. Neither NOS concentration, NO·levels, nor PAI-1 expression were altered in the aortas or right atria of animals with AF.
Conclusions— AF is associated with a marked decrease in endocardial NOS expression and NO·bioavailability and an increase in PAI-1 expression in the left atrium. These data suggest that organized atrial contraction is needed to maintain normal endocardial expression of NOS. It is likely that loss of this antithrombotic enzyme contributes to the thromboembolic phenomena commonly observed in AF.
Key Words: nitric oxide • arrhythmia • thrombosis • fibrillation • plasminogen activators
Related Article:
Circulation 2002 106: 2764-2766.
This article has been cited by other articles:
 |
|
 |
|
  E. Anter and D. J. Callans Pharmacological and Electrical Conversion of Atrial Fibrillation to Sinus Rhythm Is Worth the Effort Circulation, October 6, 2009; 120(14): 1436 - 1443. [Full Text] [PDF]
|
|
|
|
 |
|
 C N Pellegrini, E Vittinghoff, F Lin, S B Hulley, and G M Marcus Statin use is associated with lower risk of atrial fibrillation in women with coronary disease: the HERS trial Heart, May 1, 2009; 95(9): 704 - 708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M Guazzi and R Arena Endothelial dysfunction and pathophysiological correlates in atrial fibrillation Heart, January 15, 2009; 95(2): 102 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Gomez, L. Nunez, M. Vaquero, I. Amoros, A. Barana, T. de Prada, C. Macaya, L. Maroto, E. Rodriguez, R. Caballero, et al. Nitric oxide inhibits Kv4.3 and human cardiac transient outward potassium current (Ito1) Cardiovasc Res, December 1, 2008; 80(3): 375 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Adam, H.-R. Neuberger, M. Bohm, and U. Laufs Prevention of Atrial Fibrillation With 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Circulation, September 16, 2008; 118(12): 1285 - 1293. [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Van Wagoner Is homocysteine a mediator of atrial dysfunction or just another marker of endothelial dysfunction? Europace, August 1, 2008; 10(8): 899 - 900. [Full Text] [PDF]
|
|
|
|
|
|
G. M. Marcus and J. E. Olgin Preventing Atrial Fibrillation After Cardiac Surgery: A New Method Using an Old Tool Circulation, July 29, 2008; 118(5): 467 - 468. [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Akar, W. Jeske, and D. J. Wilber Acute Onset Human Atrial Fibrillation Is Associated With Local Cardiac Platelet Activation and Endothelial Dysfunction J. Am. Coll. Cardiol., May 6, 2008; 51(18): 1790 - 1793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Roldan, F. Marin, and G. Y.H. Lip Letter by Roldan et al Regarding Article, "Plasminogen Activator Inhibitor-1 as a Predictor of Postoperative Atrial Fibrillation After Cardiopulmonary Bypass" Circulation, February 26, 2008; 117(8): e169 - e169. [Full Text] [PDF]
|
|
|
|
|
|
A. Goette, A. Bukowska, U. Lendeckel, M. Erxleben, M. Hammwohner, D. Strugala, J. Pfeiffenberger, F.-W. Rohl, C. Huth, M. P.A. Ebert, et al. Angiotensin II Receptor Blockade Reduces Tachycardia-Induced Atrial Adhesion Molecule Expression Circulation, February 12, 2008; 117(6): 732 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Carnes, P. M. L. Janssen, M. L. Ruehr, H. Nakayama, T. Nakayama, H. Haase, J. A. Bauer, M. K. Chung, I. M. Fearon, A. M. Gillinov, et al. Atrial Glutathione Content, Calcium Current, and Contractility J. Biol. Chem., September 21, 2007; 282(38): 28063 - 28073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pretorius, B. S. Donahue, C. Yu, J. P. Greelish, D. M. Roden, and N. J. Brown Plasminogen Activator Inhibitor-1 as a Predictor of Postoperative Atrial Fibrillation After Cardiopulmonary Bypass Circulation, September 11, 2007; 116(11_suppl): I-1 - I-7. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. T. Range, M. Schafers, T. Acil, K. P. Schafers, P. Kies, M. Paul, S. Hermann, B. Brisse, G. Breithardt, O. Schober, et al. Impaired myocardial perfusion and perfusion reserve associated with increased coronary resistance in persistent idiopathic atrial fibrillation Eur. Heart J., September 2, 2007; 28(18): 2223 - 2230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yamashita, A. Sekiguchi, T. Kato, T. Tsuneda, Y.-k. Iwasaki, K. Sagara, H. Iinuma, H. Sawada, and T. Aizawa Angiotensin type 1 receptor blockade prevents endocardial dysfunction of rapidly paced atria in rats Journal of Renin-Angiotensin-Aldosterone System, September 1, 2007; 8(3): 127 - 132. [Abstract] [PDF]
|
|
|
|
|
|
O. Adam, G. Frost, F. Custodis, M. A. Sussman, H.-J. Schafers, M. Bohm, and U. Laufs Role of Rac1 GTPase Activation in Atrial Fibrillation J. Am. Coll. Cardiol., July 24, 2007; 50(4): 359 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. C. Aird Phenotypic Heterogeneity of the Endothelium: II. Representative Vascular Beds Circ. Res., February 2, 2007; 100(2): 174 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Oak and H. Cai Attenuation of Angiotensin II Signaling Recouples eNOS and Inhibits Nonendothelial NOX Activity in Diabetic Mice Diabetes, January 1, 2007; 56(1): 118 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guazzi, M. Berti, S. Belletti, G. Reina, and M. D. Guazzi Exercise metaboreflex activation and endothelial function impairment in atrial fibrillation Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2396 - H2402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Baro Atrial fibrillation: Is NO an answer for refractoriness? Cardiovasc Res, October 1, 2006; 72(1): 7 - 8. [Full Text] [PDF]
|
|
|
|
|
|
L. Nunez, M. Vaquero, R. Gomez, R. Caballero, P. Mateos-Caceres, C. Macaya, I. Iriepa, E. Galvez, A. Lopez-Farre, J. Tamargo, et al. Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism Cardiovasc Res, October 1, 2006; 72(1): 80 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. de Haan, M. Greiser, E. Harks, Y. Blaauw, A. van Hunnik, S. Verheule, M. Allessie, and U. Schotten AVE0118, Blocker of the Transient Outward Current (Ito) and Ultrarapid Delayed Rectifier Current (IKur), Fully Restores Atrial Contractility After Cardioversion of Atrial Fibrillation in the Goat Circulation, September 19, 2006; 114(12): 1234 - 1242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Guazzi, S. Belletti, E. Bianco, L. Lenatti, and M. D. Guazzi Endothelial dysfunction and exercise performance in lone atrial fibrillation or associated with hypertension or diabetes: different results with cardioversion Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H921 - H928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fatini, E. Sticchi, M. Genuardi, F. Sofi, F. Gensini, A. M. Gori, M. Lenti, A. Michelucci, R. Abbate, and G. F. Gensini Analysis of minK and eNOS genes as candidate loci for predisposition to non-valvular atrial fibrillation Eur. Heart J., July 2, 2006; 27(14): 1712 - 1718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Dobrev and U. Ravens Do genetics help to better understand the underlying mechanisms of atrial fibrillation? Eur. Heart J., July 2, 2006; 27(14): 1640 - 1641. [Full Text] [PDF]
|
|
|
|
|
|
A. Shiroshita-Takeshita, B. J.J.M. Brundel, J. Lavoie, and S. Nattel Prednisone prevents atrial fibrillation promotion by atrial tachycardia remodeling in dogs Cardiovasc Res, March 1, 2006; 69(4): 865 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. M. Kim, T. J. Guzik, Y. H. Zhang, M. H. Zhang, H. Kattach, C. Ratnatunga, R. Pillai, K. M. Channon, and B. Casadei A Myocardial Nox2 Containing NAD(P)H Oxidase Contributes to Oxidative Stress in Human Atrial Fibrillation Circ. Res., September 30, 2005; 97(7): 629 - 636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Dudley Jr, N. E. Hoch, L. A. McCann, C. Honeycutt, L. Diamandopoulos, T. Fukai, D. G. Harrison, S. I. Dikalov, and J. Langberg Atrial Fibrillation Increases Production of Superoxide by the Left Atrium and Left Atrial Appendage: Role of the NADPH and Xanthine Oxidases Circulation, August 30, 2005; 112(9): 1266 - 1273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yoshizawa, G. E. Kissling, J. A. Johnson, N. P. Clayton, N. D. Flagler, and A. Nyska Chemical-Induced Atrial Thrombosis in NTP Rodent Studies Toxicol Pathol, August 1, 2005; 33(5): 517 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Chalupsky and H. Cai Endothelial dihydrofolate reductase: Critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase PNAS, June 21, 2005; 102(25): 9056 - 9061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. J. Kim and R. Arora Emerging Role of Direct Thrombin Inhibitors in Nonvalvular Atrial Fibrillation: Potential and Peril Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2005; 10(1): 11 - 21. [Abstract] [PDF]
|
|
|
|
|
|
A. Shiroshita-Takeshita, G. Schram, J. Lavoie, and S. Nattel Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Promotion by Atrial-Tachycardia Remodeling in Dogs Circulation, October 19, 2004; 110(16): 2313 - 2319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamashita, A. Sekiguchi, Y.-k. Iwasaki, K. Sagara, S. Hatano, H. Iinuma, T. Aizawa, and L.-T. Fu Thrombomodulin and Tissue Factor Pathway Inhibitor in Endocardium of Rapidly Paced Rat Atria Circulation, November 18, 2003; 108(20): 2450 - 2452. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Bergfeldt and Y. Haga Power spectral and Poincare plot characteristics in sinus node dysfunction J Appl Physiol, June 1, 2003; 94(6): 2217 - 2224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. T Sie, W. P Beukema, A. Elvan, and A. R Ramdat Misier New strategies in the surgical treatment of atrial fibrillation Cardiovasc Res, June 1, 2003; 58(3): 501 - 509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rubart and D. P. Zipes NO Hope for Patients With Atrial Fibrillation Circulation, November 26, 2002; 106(22): 2764 - 2766. [Full Text] [PDF]
|
|