Levosimendan May Prevent Postoperative Atrial Fibrillation Through Anti-inflammatory and Antioxidant Modulation

Abstract

We are very interested in a recent report by De Hert et al1De Hert S.G. Lorsomradee S. vanden Eede H. et al.A randomized trial evaluating different modalities of levosimendan administration in cardiac surgery patients with myocardial dysfunction.J Cardiothorac Vasc Anesth. 2008; 22: 699-705Abstract Full Text PDF PubMed Scopus (52) Google Scholar that showed levosimendan started before cardiopulmonary bypass was associated with a lower risk of postoperative atrial fibrillation (POAF). We would like to provide a potential underlying mechanism for the beneficial effects of levosimendan on POAF. Recently, the role of inflammation and oxidative stress in the pathogenesis of atrial fibrillation (AF) has been widely evaluated.2Korantzopoulos P. Kolettis T. Siogas K. et al.Atrial fibrillation and electrical remodeling: The potential role of inflammation and oxidative stress.Med Sci Monit. 2003; 9: RA225-RA229PubMed Google Scholar, 3Liu T. Li G. Is atrial fibrillation an inflammatory disease?.Med Hypotheses. 2005; 64: 1237-1238Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 4Korantzopoulos P. Kolettis T.M. Galaris D. et al.The role of oxidative stress in the pathogenesis and perpetuation of atrial fibrillation.Int J Cardiol. 2007; 115: 135-143Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar The AF inflammatory hypothesis was first supported by Bruins et al.5Bruins P. te Velthuis H. Yazdanbakhsh A.P. et al.Activation of the complement system during and after cardiopulmonary bypass surgery: Postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia.Circulation. 1997; 96: 3542-3548Crossref PubMed Scopus (658) Google Scholar They showed that the peak incidence of POAF on the second to third postoperative day coincided with the peak elevation in C-reactive protein levels. Our previous meta-analyses also have shown that increased baseline C-reactive protein levels are associated with a greater risk for immediate failure of electrical cardioversion6Liu T. Li L. Korantzopoulos P. et al.Meta-analysis of association between C-reactive protein and immediate success of electrical cardioversion in persistent atrial fibrillation.Am J Cardiol. 2008; 101: 1749-1752Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar and AF recurrence after successful electric cardioversion.7Liu T. Li G. Li L. et al.Association between C-reactive protein and recurrence of atrial fibrillation after successful electrical cardioversion: A meta-analysis.J Am Coll Cardiol. 2007; 49: 1642-1648Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar In the past few years, several nonchannel-blocking interventions aiming at the modulation of inflammatory substrate have shown beneficial effects on AF prevention and treatment. These include statins, blockers of the renin-angiotensin system, corticosteroids, dietary antioxidants, n-3 fatty acids, thiazolidinediones, and others.8Liu T. Li L. Korantzopoulos P. et al.Statin use and development of atrial fibrillation: A systematic review and meta-analysis of randomized clinical trials and observational studies.Int J Cardiol. 2008; 126: 160-170Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 9Liu T. Korantzopoulos P. Li G. et al.The potential role of thiazolidinediones in atrial fibrillation.Int J Cardiol. 2008; 128: 129-130Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 10Murray K.T. Mace L.C. Yang Z. Nonantiarrhythmic drug therapy for atrial fibrillation.Heart Rhythm. 2007; 4: S88-S90Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 11Dorian P. Singh B.N. Upstream therapies to prevent atrial fibrillation.Eur Heart J. 2008; 10: H11-H31Crossref Scopus (27) Google Scholar On the other hand, levosimendan is a novel inotropic and vasodilator agent used in decompensated heart failure. It improves myocardial contractility by stabilizing troponin C and enhancing calcium sensitivity of cardiac myofilaments.12Parissis J.T. Filippatos G. Farmakis D. et al.Levosimendan for the treatment of acute heart failure syndromes.Expert Opin Pharmacother. 2005; 6: 2741-2751Crossref PubMed Scopus (34) Google Scholar Recent studies showed that levosimendan could reduce inflammatory cytokines and oxidative stress profiles. Parissis et al13Parissis J.T. Adamopoulos S. Antoniades C. et al.Effects of levosimendan on circulating proinflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure.Am J Cardiol. 2004; 93: 1309-1312Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar showed that levosimendan caused a significant reduction in interleukin-6 and a slight decrease in tumor necrosis factor-α in patients with decompensated advanced heart failure after 48 hours compared with placebo. Avgeropoulou et al14Avgeropoulou C. Andreadou I. Markantonis-Kyroudis S. et al.The Ca2+-sensitizer levosimendan improves oxidative damage, BNP and proinflammatory cytokine levels in patients with advanced decompensated heart failure in comparison to dobutamine.Eur J Heart Fail. 2005; 7: 882-887Crossref PubMed Scopus (90) Google Scholar also showed that a 24-hour infusion of levosimendan in contrast to dobutamine decreased malondialdehyde levels, an endproduct of lipid peroxidation, indicating a possible antioxidant effect of levosimendan. With the important role of inflammation in the genesis of AF in postcardiac surgery patients, we propose that the beneficial effects of levosimendan on POAF may be partly related to its anti-inflammatory and antioxidant properties. We are very interested in a recent report by De Hert et al1De Hert S.G. Lorsomradee S. vanden Eede H. et al.A randomized trial evaluating different modalities of levosimendan administration in cardiac surgery patients with myocardial dysfunction.J Cardiothorac Vasc Anesth. 2008; 22: 699-705Abstract Full Text PDF PubMed Scopus (52) Google Scholar that showed levosimendan started before cardiopulmonary bypass was associated with a lower risk of postoperative atrial fibrillation (POAF). We would like to provide a potential underlying mechanism for the beneficial effects of levosimendan on POAF. Recently, the role of inflammation and oxidative stress in the pathogenesis of atrial fibrillation (AF) has been widely evaluated.2Korantzopoulos P. Kolettis T. Siogas K. et al.Atrial fibrillation and electrical remodeling: The potential role of inflammation and oxidative stress.Med Sci Monit. 2003; 9: RA225-RA229PubMed Google Scholar, 3Liu T. Li G. Is atrial fibrillation an inflammatory disease?.Med Hypotheses. 2005; 64: 1237-1238Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 4Korantzopoulos P. Kolettis T.M. Galaris D. et al.The role of oxidative stress in the pathogenesis and perpetuation of atrial fibrillation.Int J Cardiol. 2007; 115: 135-143Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar The AF inflammatory hypothesis was first supported by Bruins et al.5Bruins P. te Velthuis H. Yazdanbakhsh A.P. et al.Activation of the complement system during and after cardiopulmonary bypass surgery: Postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia.Circulation. 1997; 96: 3542-3548Crossref PubMed Scopus (658) Google Scholar They showed that the peak incidence of POAF on the second to third postoperative day coincided with the peak elevation in C-reactive protein levels. Our previous meta-analyses also have shown that increased baseline C-reactive protein levels are associated with a greater risk for immediate failure of electrical cardioversion6Liu T. Li L. Korantzopoulos P. et al.Meta-analysis of association between C-reactive protein and immediate success of electrical cardioversion in persistent atrial fibrillation.Am J Cardiol. 2008; 101: 1749-1752Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar and AF recurrence after successful electric cardioversion.7Liu T. Li G. Li L. et al.Association between C-reactive protein and recurrence of atrial fibrillation after successful electrical cardioversion: A meta-analysis.J Am Coll Cardiol. 2007; 49: 1642-1648Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar In the past few years, several nonchannel-blocking interventions aiming at the modulation of inflammatory substrate have shown beneficial effects on AF prevention and treatment. These include statins, blockers of the renin-angiotensin system, corticosteroids, dietary antioxidants, n-3 fatty acids, thiazolidinediones, and others.8Liu T. Li L. Korantzopoulos P. et al.Statin use and development of atrial fibrillation: A systematic review and meta-analysis of randomized clinical trials and observational studies.Int J Cardiol. 2008; 126: 160-170Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 9Liu T. Korantzopoulos P. Li G. et al.The potential role of thiazolidinediones in atrial fibrillation.Int J Cardiol. 2008; 128: 129-130Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 10Murray K.T. Mace L.C. Yang Z. Nonantiarrhythmic drug therapy for atrial fibrillation.Heart Rhythm. 2007; 4: S88-S90Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 11Dorian P. Singh B.N. Upstream therapies to prevent atrial fibrillation.Eur Heart J. 2008; 10: H11-H31Crossref Scopus (27) Google Scholar On the other hand, levosimendan is a novel inotropic and vasodilator agent used in decompensated heart failure. It improves myocardial contractility by stabilizing troponin C and enhancing calcium sensitivity of cardiac myofilaments.12Parissis J.T. Filippatos G. Farmakis D. et al.Levosimendan for the treatment of acute heart failure syndromes.Expert Opin Pharmacother. 2005; 6: 2741-2751Crossref PubMed Scopus (34) Google Scholar Recent studies showed that levosimendan could reduce inflammatory cytokines and oxidative stress profiles. Parissis et al13Parissis J.T. Adamopoulos S. Antoniades C. et al.Effects of levosimendan on circulating proinflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure.Am J Cardiol. 2004; 93: 1309-1312Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar showed that levosimendan caused a significant reduction in interleukin-6 and a slight decrease in tumor necrosis factor-α in patients with decompensated advanced heart failure after 48 hours compared with placebo. Avgeropoulou et al14Avgeropoulou C. Andreadou I. Markantonis-Kyroudis S. et al.The Ca2+-sensitizer levosimendan improves oxidative damage, BNP and proinflammatory cytokine levels in patients with advanced decompensated heart failure in comparison to dobutamine.Eur J Heart Fail. 2005; 7: 882-887Crossref PubMed Scopus (90) Google Scholar also showed that a 24-hour infusion of levosimendan in contrast to dobutamine decreased malondialdehyde levels, an endproduct of lipid peroxidation, indicating a possible antioxidant effect of levosimendan. With the important role of inflammation in the genesis of AF in postcardiac surgery patients, we propose that the beneficial effects of levosimendan on POAF may be partly related to its anti-inflammatory and antioxidant properties. RETRACTED: A Randomized Trial Evaluating Different Modalities of Levosimendan Administration in Cardiac Surgery Patients With Myocardial DysfunctionJournal of Cardiothoracic and Vascular AnesthesiaVol. 22Issue 5PreviewThis article has been retracted: please see Elsevier Policy on Article Withdrawal ( http://www.elsevier.com/locate/withdrawalpolicy ). This article has been retracted at the request of the author. It was brought to the attention of Dr. De Hert that some of the outcome data on postoperative mortality in this paper are very similar to those reported in an earlier paper by Dr. De Hert, based on an earlier study, and published in Anesth. Analg., 104 (2007) 766–773. Upon further investigation Dr. De Hert and his co-authors determined that some of the data from the first study were inadvertently included in Groups A and C of the second study, published in Journal of Cardiothoracic and Vascular Anesthesia. Full-Text PDF