Research Article| Volume 154, ISSUE 2, P141-146, January 26, 2012

Download started.


The impact of rapid atrial pacing on ADMA and endothelial NOS

Published:October 06, 2010DOI:



      The endothelial nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine (ADMA) is a well-established risk factor for oxidative stress, vascular dysfunction, and congestive heart failure. The aim of the present study was to determine the impact of rapid atrial pacing (RAP) on ADMA levels and eNOS expression.

      Methods and results

      ADMA levels were studied in 60 age- and gender-matched patients. Thirty five patients had persistent atrial fibrillation (AF)4 months. In AF-patients, parameters were studied before and 24 h after electrical cardioversion. Moreover, ADMA, eNOS expression, and calcium-handling proteins were studied in pigs subjected to RAP as well as in endothelial cell (EC) cultures. ADMA level was significantly higher in AF compared to sinus rhythm patients (p=0.024). ADMA was highest in AF-patients, who also showed elevated troponin T (TnT) levels. Moreover, ADMA showed a significant linear correlation to TnT (r=0.47; p<0.01). After electrical cardioversion ADMA returned to normal within 24 h. In pigs, RAP for 7 h increased ADMA levels (p=0.018) and TnI (p<0.05), and reduced mRNA expression of ventricular and aortic eNOS (−80%; p<0.05) compared to sham-control. However, ADMA per se did not affect eNOS mRNA level in EC cultures.


      The current study shows that acute and persistent episodes of atrial tachyarrhythmia are associated with elevated ADMA levels accompanied by increased ischemic myocardial markers. Moreover, RAP increases ADMA and down-regulates eNOS expression in an ADMA-independent manner. We conclude that the combination of these two separate and potentially synergistic mechanisms may contribute to long-term vascular injury during atrial tachyarrhythmia.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to International Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Wyse D.G.
        • Waldo A.L.
        • DiMarco J.P.
        • et al.
        A comparison of rate control and rhythm control in patients with atrial fibrillation.
        N Engl J Med. 2002; 347: 1825-1833
        • Van Gelder I.C.
        • Hagens V.E.
        • Bosker H.A.
        • et al.
        Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation.
        N Engl J Med. 2002; 347: 1834-1840
        • Kochiadakis G.E.
        • Skalidis E.I.
        • Kalebubas M.D.
        • et al.
        Effect of acute atrial fibrillation on phasic coronary blood flow pattern and flow reserve in humans.
        Eur Heart J. 2002; 23: 734-741
        • Brown A.M.
        • Sease K.L.
        • Robey J.L.
        • Shofer F.S.
        • Hollander J.E.
        The risk for acute coronary syndrome associated with atrial fibrillation among ED patients with chest pain syndromes.
        Am J Emerg Med. 2007; 25: 523-528
        • Goette A.
        • Bukowska A.
        • Dobrev D.
        • et al.
        Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor mediated oxidative stress and microvascular flow abnormalities in the ventricles.
        Eur Heart J. 2009; 30: 1411-1420
        • Boger R.H.
        • Bode-Boger S.M.
        • Szuba A.
        • et al.
        Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia.
        Circulation. 1998; 98: 1842-1847
        • Bode-Böger S.M.
        • Scalera F.
        • Ignarro L.J.
        The l-arginine paradox: importance of the l-arginine/asymmetrical dimethylarginine ratio.
        Pharmcol Ther. 2007; 114: 295-306
        • Miyazaki H.
        • Matsuoka H.
        • Cooke J.P.
        • et al.
        Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis.
        Circulation. 1999; 99: 1141-1146
        • Feng Q.
        • Lu X.
        • Fortin A.J.
        • et al.
        Elevation of an endogenous inhibitor of nitric oxide synthesis in experimental congestive heart failure.
        Cardiovasc Res. 1998; 37: 667-675
        • Saitoh M.
        • Osanai T.
        • Kamada T.
        • et al.
        High plasma level of asymmetric dimethylarginine in patients with acutely exacerbated congestive heart failure: role in reduction of plasma nitric oxide level.
        Heart Vessels. 2003; 18: 177-182
        • Stuhlinger M.C.
        • Oka R.K.
        • Graf E.E.
        • et al.
        Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine.
        Circulation. 2003; 108: 933-938
        • Hasegawa K.
        • Wakino S.
        • Tatematsu S.
        • et al.
        Role of asymmetric dimethylarginine in vascular injury in transgenic mice overexpressing dimmethylarginine dimethylaminohydrolase 2.
        Circ Res. 2007; 1001: e2-e10
        • Suda O.
        • Tsutsui M.
        • Morishita T.
        • et al.
        Asymmetric dimethylarginine produces vascular lesions in endothelial nitric oxide synthase-deficient mice: involvement of renin–angiotensin system and oxidative stress.
        Arterioscler Thromb Vasc Biol. 2004; 24: 1682-1688
        • Meinitzer A.
        • Seelhorst U.
        • Wellnitz B.
        • et al.
        Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (The Ludwigshafen risk and cardiovascular health study).
        Clin Chem. 2007; 53: 273-283
        • Hammwöhner M.
        • Ittenson A.
        • Dierkes J.
        • et al.
        Platelet expression of CD40/CD40 ligand and its relation to inflammatory markers and adhesion molecules in patients with atrial fibrillation.
        Exp Biol Med. 2007; 232: 581-589
        • Martens-Lobenhoffer J.
        • Bode-Böger S.M.
        Fast and efficient determination of arginine, symmetric dimethylarginine, and asymmetric dimethylarginine in biological fluids by hydrophilic interaction liquid chromatography–electrospray tandem mass spectrometry.
        Clin Chem. 2006; 52: 488-493
        • Tsikas D.
        Simultaneous derivatization and quantification of the nitric oxide metabolites nitrite and nitrate in biological fluids by gas chromatography/mass spectrometry.
        Anal Chem. 2000; 72: 4064-4072
        • Goette A.
        • Bukowska A.
        • Lendeckel U.
        • et al.
        Angiotensin II receptor blockade reduces tachycardia-induced atrial adhesion molecule expression.
        Circulation. 2008; 117: 732-742
        • Scalera F.
        • Kielstein J.
        • Martens-Lobenhoffer J.
        • Postel S.
        • Täger M.
        • Bode-Böger S.M.
        Erythropoietin increases asymmetric dimethylarginine in endothelial cells — role of dimethylarginine dimethylaminohydrolase.
        J Am Soc Nephrol. 2005; 16: 892-898
        • Bukowska A.
        • Lendeckel U.
        • Hirte D.
        • et al.
        Activation of the calcineurin signaling pathway induces atrial hypertrophy during atrial fibrillation.
        Cell Mol Life Sci. 2006; 63: 333-342
        • Shinbane J.S.
        • Wood M.A.
        • Jensen D.N.
        • Ellenbogen K.A.
        • Fitzpatrick A.P.
        • Scheinman M.M.
        Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies.
        J Am Coll Cardiol. 1997; 29: 709-715
        • Bers D.M.
        Altered cardiac myocyte Ca regulation in heart failure.
        Physiology (Bethesda). 2006; 21: 380-387
        • Miyasaka Y.
        • Barnes M.E.
        • Gersh B.J.
        • et al.
        Coronary ischemic events after first atrial fibrillation: risk and survival.
        Am J Med. 2007; 120: 357-363
        • El-Armouche A.
        • Pohlmann L.
        • Schlossarek S.
        • et al.
        Decreased phosphorylation levels of cardiac myosin-binding protein-C in human and experimental heart failure.
        J Mol Cell Cardiol. 2007; 43: 223-229
        • Cengel A.
        • Sahinarslan A.
        • Biberoğlu G.
        • et al.
        Asymmetrical dimethylarginine level in atrial fibrillation.
        Acta Cardiol. 2008; 63: 33-37
        • Xia W.
        • Yin Z.
        • Li J.
        • Song Y.
        • Qu X.
        Effects of rosuvastatin on asymmetric dimethylarginine levels and early atrial fibrillation recurrence after electrical cardioversion.
        Pacing Clin Electrophysiol. 2009; 32: 1562-1566
        • Nijveldt R.J.
        • Siroen M.P.
        • Teerlink T.
        • van Leeuwen P.A.
        Elimination of asymmetric dimethylarginine by the kidney and the liver: a link to the development of multiple organ failure?.
        J Nutr. 2004; 134: 2848S-2852S
        • Nijveldt R.J.
        • Teerlink T.
        • Van Der Hoven B.
        • et al.
        Asymmetrical dimethylarginine (ADMA) in critically ill patients: high plasma ADMA concentration is an independent risk factor of ICU mortality.
        Clin Nutr. 2003; 22: 23-30
        • Benjamin E.J.
        • Wolf P.A.
        • D'Agostino R.B.
        • Silbershatz H.
        • Kannel W.B.
        • Levy D.
        Impact of atrial fibrillation on the risk of death: the Framingham Heart Study.
        Circulation. 1998; 98: 946-952
        • Dries D.L.
        • Exner D.V.
        • Gersh B.J.
        • Domanski M.J.
        • Waclawiw M.A.
        • Stevenson L.W.
        Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials.
        J Am Coll Cardiol. 1998; 32: 695-703
        • Liu H.
        • Qu X.
        • Liang Z.
        • Chen W.
        • Xia W.
        • Song Y.
        Variance of DDAH/PRMT/ADMA pathway in atrial fibrillation dogs.
        Biochem Biophys Res Commun. 2008; 377: 884-888
        • Nerheim P.
        • Birger-Botkin S.
        • Piracha L.
        • Olshansky B.
        Heart failure and sudden death in patients with tachycardia-induced cardiomyopathy and recurrent tachycardia.
        Circulation. 2004; 110: 247-252
        • Akoum N.
        • Hamdan M.H.
        Atrial fibrillation and congestive heart failure: a two-way street.
        Curr Heart Fail Rep. 2007; 4: 78-83
        • Kelly R.A.
        • Balligand J.L.
        • Smith T.W.
        Nitric oxide and cardiac function.
        Circ Res. 1996; 79: 363-380
        • Fraccarollo D.
        • Widder J.D.
        • Galuppo P.
        • et al.
        Improvement in left ventricular remodeling by the endothelial nitric oxide synthase enhancer AVE9488 after experimental myocardial infarction.
        Circulation. 2008; 118: 818-827
        • Nicholls S.J.
        • Wang Z.
        • Koeth R.
        • et al.
        Metabolic profiling of arginine and nitric oxide pathways predicts hemodynamic abnormalities and mortality in patients with cardiogenic shock after acute myocardial infarction.
        Circulation. 2007; 116: 2315-2324
        • Minamino T.
        • Kitakaze M.
        • Sato H.
        • et al.
        Plasma levels of nitrite/nitrate and platelet cGMP levels are decreased in patients with atrial fibrillation.
        Arterioscler Thromb Vasc Biol. 1997; 17: 3191-3195
        • Coats A.J.
        Ethical authorship and publishing.
        Int J Cardiol. 2009; 131: 149-150