Electrical remodeling


Electrical remodeling and effects of pharmaceuticals on chronic atrial fibrillation

Coordinating Investigator

Prof. Dobromir Dobrev, Essen, Germany

Overall Responsibility

Atrial Fibrillation NETwork (AFNET), Münster, Germany

Current Status



German Federal Ministry of Education and Research


The changes in the electrical properties of the atrial tissue (electrical "remodeling") in atrial fibrillation are attributed to cellular remodeling processes that are associated with a changed activity of atrial ion currents. The aim of the research project was to elucidate the molecular mechanisms of electrical remodeling in paroxysmal and chronic atrial fibrillation and to find out whether electrical remodeling by pharmaceuticals can be reversed. The changes in ion channels and calcium channel proteins were examined in patients with atrial fibrillation and in various animal models.


The project has resulted in numerous publications on the changes in atrial ion currents during remodeling. Experiments in pigs f. e. have shown that atrial fibrillation leads to the development of oxidative stress in the left ventricle via the activation of angiotensin II, which is associated with disturbances in the microcirculation and an increase in troponin-I. Irbesartan prevents these effects and may help prevent ventricular dysfunction during atrial fibrillation. See also sub-project C7



Dobrev D. Is Altered Atrial microRNA-ome a Critical Contributor to Pathophysiology of Atrial Fibrillation? Basic Res Cardiol 2012; 107: 284-287

Dobrev D, Carlsson L, Nattel S. Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov 2012; 11(4): 275-91

Dobrev D, Singh BN. Antiarrhythmic drugs. In “Electrophysiological Disorders of the Heart”. Eds. Sanjeev Saksena, A John Camm, 2nd edition, 2012; pp. 1133-1157, Elsevier Science, Waltham, MA, USA

Heijman J, Dobrev D. Systems approaches to post-operative atrial fibrillation – do they help us to better understand the ionic basis of the arrhythmogenic substrate? J Mol Cell Cardiol 2012; 53: 320-322

Heijman J, Voigt N, Nattel S, Dobrev D. Atrial Ca2+ handling and atrial fibrillation. Wien Med Wochenschr 2012; 162(13-14): 287-291

Nattel S, Dobrev D. The multidimensional role of cellular calcium signaling in atrial fibrillation pathophysiology: Mechanistic insights and therapeutic opportunities. Eur Heart J 2012; 33(15): 1870-1877

Voigt N, Dobrev D. Cellular and Molecular Correlates of Ectopic Activity in Patients with Atrial Fibrillation. Europace 2012; 14 (Suppl. 5). v97-v105

Voigt N, Li N, Wang Q, Wang W, Trafford AW, Abu-Taha I, Sun Q, Wieland T, Ravens R, Nattel S, Wehrens XHT, Dobrev D: Enhanced Sarcoplasmic Reticulum Ca2+ Leak and Increased Na+-Ca2+ Exchanger Function Underlie Delayed Afterpolarizations in Patients with Chronic Atrial Fibrillation.
Circulation 2012, 125:2059-70, doi: 10.1161/CIRCULATIONAHA.111.067306

Voigt N, Nattel S, Dobrev D. Proarrhythmic Atrial Calcium Signalling in the Diseased Heart. Adv Exp Med Biol 2012; 740: 1175-1192

Zhou XB, Dobrev D. Voltage-gated Na+ channels: novel players in fibroblast-to-myofibroblast transition with a potential role in atrial arrhythmogenesis? J Physiol 2012; 590 (20): 4975

Boontje NM, Merkus D, Zaremba R, Versteilen A, de Waard M, Mearini G, de Beer VJ, Carrier L, Walker LA, Niessen HW, Dobrev D, Stienen GJM, Duncker DJ, van der Velden J. Enhanced myofilament responsiveness upon β-adrenergic stimulation in post-infarct remodeled myocardium. J Mol Cell Cardiol 2011, 50(3): 487-99.

Cunha SR, Hund TJ, Hashemi S, Voigt N, Li N, Wright P, Koval O, Li J, Gudmundsson H, Schott JJ, Probst V, Le Marec H, Karck M, Anderson ME, Dobrev D, Wehrens XH, Mohler PJ. Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation. Circulation 2011, 124(11): 1212-1222. (Editorial in Sci Transl Med, 2011 Sept 14, 3(100): 100ec149).

Dobrev D. Prevention of atrial fibrillation complications with antiarrhythmic drugs: a still unmet need in the clinical practice. Expert Opin Pharmacother 2011, 12(8): 1195-1199.

Dobrev D, Nattel S. New insights into the molecular basis of atrial fibrillation: mechanistic and therapeutic implications. Cardiovasc Res 2011, 89(4): 689-691.

Dobrev D, Voigt N, Wehrens X. The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implications. Cardiovasc Res 2011, 89(4): 734-743.

Ehrlich JR, Dobrev D. Atrial-selective sodium channel block by dronedarone: sufficient to terminate atrial fibrillation? Naunyn Schmiedebergs Arch Pharmacol. 2011;384(2):109-14. DOI:10.1007/s00210-011-0647-5.

Le Quang K, Naud P, Qi XY, Duval F, Shi YF, Gillis MA, Comtois P, Tardif JC, Li D, Levesque PC, Dobrev D, Charpentier F, Nattel S. Role of T-type calcium current subunits in post myocardial infarction cardiac remodeling probed with genetically engineered knockout mice. Cardiovasc Res 2011, 91(3): 420-428. (Editorial in Cardiovasc Res, 91(3): 373-375).

Makary S*, Voigt N*, Maguy A*, Wakili R, Nishida K, Harada M, Dobrev D, Nattel S. Differential PKC Isoform Regulation and Increased Constitutive Activity of Acetylcholine-regulated Potassium Channels in Atrial Remodeling. Circ Res 2011, 109(9): 1031-43. *equally contributed first authors

Nishida K, Qi XY, Wakili R, Comtois P, Chartier D, Harada M, Iwasaki YK, Romeo P, Maguy A, Dobrev D, Michael G, Talajic M, Nattel S. Mechanisms of atrial tachyarrhythmias associated with coronary artery occlusion in a chronic canine model. Circulation. 2011;123:137-46. DOI:10.1161/CIRCULATIONAHA.110.972778

Richards MA, Clarke JD, Saravanan P, Voigt N, Dobrev D, Eisner DA, Trafford AW, Dibb KM.  Transverse t-tubules are a common feature in large mammalian atrial myocytes including human. Am J Physiol Heart Circ Physiol 2011, 301(5): H1996-2005.

Swaminathan PD, Purohit A, Soni S, Voigt N, Singh M, Glukhov A, Gao Z, He JB, Luczak ED, Joiner ML, Kutschke W, Yang J, Donahue JK, Weiss RM, Grumbach IM, Ogawa M, Chen PS, Efimov I, Dobrev D, Mohler PJ, Hund TJ, Anderson ME. Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J Clin Invest, 121(8): 3277–3288 (Commentary in J Clin Invest 2011, 121(8): 2975-2977).

Tsuji Y, Hojo M, Voigt N, El-Armouche A, Inden Y, Murohara T, Dobrev D, Nattel S, Kodama I, Kamiya K.  Ca2+-related Signaling and Protein Phosphorylation Abnormalities Play Central Roles in a New Experimental Model of Electrical Storm. Circulation 2011, 123: 2192-2203. (Editorial in Circulation, 123: 2183-2186).

Voigt N, Dobrev D. Ion channel remodeling in atrial fibrillation. European Cardiology 2011, 7(2): 97–103.

Wakili R, Voigt N, Kääb S, Dobrev D, Nattel S. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest. 2011;121:2955-68. DOI:10.1172/JCI46315. Review. 

Wittköpper K, Dobrev D, Eschenhagen T, El-Armouche A. Phosphatase-1-inhibitor-1 in physiological and pathological β-adrenoceptor signalling. Cardiovasc Res 2011, 91(3): 392-401.

Dobrev D, Wehrens XH. Calmodulin kinase II, sarcoplasmic reticulum Ca2+ leak, and atrial fibrillation. Trends Cardiovasc Med. 2010 Jan;20(1):30-4. Review

Dobrev D, Voigt N, Wehrens XH. The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implications. Cardiovasc Res. 2010 Nov 3. [Epub ahead of print].

Nishida K, Michael G, Dobrev D, Nattel S. Animal models for atrial fibrillation: clinical insights and scientific opportunities. Europace. 2010 Feb;12(2):160-72.

Voigt N, Trausch A, Knaut M, Matschke K, Varró A, Van Wagoner DR, Nattel S, Ravens U, Dobrev D. Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation. Circ Arrhythm Electrophysiol. 2010 Oct 1;3(5):472-80.

Wakili R, Yeh YH, Yan Qi X, Greiser M, Chartier D, Nishida K, Maguy A, Villeneuve LR, Boknik P, Voigt N, Krysiak J, Kääb S, Ravens U, Linke WA, Stienen GJ, Shi Y, Tardif JC, Schotten U, Dobrev D, Nattel S. Multiple potential molecular contributors to atrial hypocontractility caused by atrial tachycardia remodeling in dogs. Circ Arrhythm Electrophysiol. 2010; 3:530-41.

Chelu MG, Sarma S, Sood S, Wang S, van Oort RJ, Skapura DG, Li N, Santonastasi M, Müller FU, Schmitz W, Schotten U, Anderson ME, Valderrábano M, Dobrev D, Wehrens XH. Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. J Clin Invest. 2009;119(7):1940-51.

Dobrev D. Ion channel portrait of the human sinus node: useful for a better understanding of sinus node function and dysfunction in humans? Circulation, 119(12): 1556-1558, 2009

Dobrev D, Goette A, Ravens U. Stroke prevention versus risk of bleeding of vitamin-K antagonists: a double-edged sword in patients with atrial fibrillation who require surgery. Cardiovasc Ther (formerly Cardiovascular Drug Reviews), 27: 223-225, 2009

Dobrev D, Teos LY, Lederer WJ. Unique atrial myocyte Ca2+ signaling. J Mol Cell Cardiol. 2009; 46(4):448-51.

Gemein C, Schauerte P, Hatam N, Rana OR, Saygili E, Meyer C, Eickholt C, Schmid M, Knackstedt C, Zarse M, Mischke K. Targeting of cardiac autonomic plexus for modulation of intracardiac neural tone. Europace. 2009; 11(8):1090-6.

Goette A*, Bukowska A*, Dobrev D*, Pfeiffenberger J, Morawietz H, Strugala D, Wiswedel I, Röhl FW, Bergmann S, Bramlage P, Ravens U, Lendeckel U. Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor mediated oxidative stress and microvascular flow abnormalities in the ventricles. Eur Heart J, 05.03.2009; *shared first authorship

Greiser M, Neuberger HR, Harks E, El-Armouche A, Boknik P, de Haan S, Verheyen F, Verheule S, Schmitz W, Ravens U, Nattel S, Allessie MA, Dobrev D, Schotten U. Distinct contractile and molecular differences between two goat models of atrial dysfunction: AV block-induced atrial dilatation and atrial fibrillation. J Mol Cell Cardiol. 2009; 46(3):385-94.

Nattel S, Burstein B, Dobrev D. Molecular remodeling and chronic atrial fibrillation. In ”Cardiac Electrophysiology: From Cell to Bedside”. Eds. Douglas Zipes, Jose Jalife. 5th edition, Chapter 43, pp 453-465, Saunders, Elsevier, USA. 2009

Christ T, Wettwer E, Voigt N, Hála O, Radicke S, Matschke K, Várro A, Dobrev D, Ravens U. Pathology-specific effects of the IKur/Ito/IK,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation. Br J Pharmacol. 2008 Aug;154(8):1619-30.

Dobrev D, Nattel S. Calcium handling abnormalities in atrial fibrillation as a target for innovative therapeutics. J Cardiovasc Pharmacol. 2008 Oct;52(4):293-9.

Dobrev D, Teos LY, Lederer WJ. Unique atrial myocyte Ca(2+) signaling. J Mol Cell Cardiol. 2008 Dec 25. [Epub ahead of print]

Dobrev D, Wettwer E. Four and a half LIM protein 1: a novel chaperone for atrium-specific Kv1.5 channels with a potential role in atrial arrhythmogenesis. Cardiovasc Res. 2008 Jun 1;78(3):411-2.

Dobrev D. New concepts in understanding and modulating atrial repolarisation in patients with atrial fibrillation. J Interv Card Electrophysiol. 2008 Aug;22(2):107-10. Epub 2008 Mar 11. Review.

El-Armouche A, Wittköpper K, Degenhardt F, Weinberger F, Didié M, Melnychenko I, Grimm M, Peeck M, Zimmermann WH, Unsöld B, Hasenfuss G, Dobrev D, Eschenhagen T.  Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy. Cardiovasc Res. 2008 Dec 1;80(3):396-406.

Greiser M, Neuberger HR, Harks E, El-Armouche A, Boknik P, de Haan S, Verheyen F, Verheule S, Schmitz W, Ravens U, Nattel S, Allessie MA, Dobrev D, Schotten U. Distinct contractile and molecular differences between two goat models of atrial dysfunction: AV block-induced atrial dilatation and atrial fibrillation. J Mol Cell Cardiol. 2008 Nov 27. [Epub ahead of print]

Nattel S, Burstein B, Dobrev D. Atrial remodelling and atrial fibrillation: mechanisms and implications. Circ Arrhythmia Electrophysiol. 2008; 1: 62-73.

Qi XY, Yeh YH, Xiao L, Burstein B, Maguy A, Chartier D, Villeneuve LR, Brundel BJJM, Dobrev D, Nattel N. Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current. Circ Res. 2008; 103(8): 845-854.

Sood S, Chelu M, Van Oort R, Skapura D, Santonastasi M, Dobrev D, Wehrens XHT. Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation. Heart Rhythm 2008; 5(7): 1047-54.

Voigt N, Maguy A, Yeh YH, Qi X, Ravens U, Dobrev D, Nattel S. Changes in IK,ACh single-channel activity with atrial tachycardia remodelling in canine atrial cardiomyocytes. Cardiovasc Res. 2008; 77: 35-43.

Yeh Y-H, Wakili R, Qi X, Chartier D, Boknik P, Kääb S, Ravens U, Coutu P, Dobrev D, Nattel S. Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure. Circ Arrhythmia Electrophysiol. 2008; 1: 93-102.

Dobrev D, Christ T, Boknik P, Wöhrl S, Bosch RF, Ravens U: Regulation of left atrial L-type Ca2+ channels in patients with chronic atrial fibrillation; J Mol Cell Cardiol, 42 (Suppl. 1): S20 (doi:10.1016/j.yjmcc.2007.03.057)

El-Armouche A, Pohlmann L, Schlossarek S, Starbatty J, Yeh YH, Nattel S, Dobrev D, Eschenhagen T, Carrier L: Decreased phosphorylation levels of cardiac myosin binding protein-C in human and experimental heart failure; J Mol Cell Cardiol 2007; 43:223-229

Greiser M, Halaszovich CR, Frechen D, Boknik P, Ravens U, Dobrev D, Lückhoff A, Schotten U: Pharmacological evidence for altered src-kinase regulation of ICa,L in patients with chronic atrial fibrillation., Naunyn Schmiedeberg’s Arch Pharmacol, 2007 375(6):383-92.

Voigt N, Christ T, Wettwer E, Bock M, Knaut M, Strasser RH, Ravens U, Dobrev D: Differential phosphorylation-dependent regulation of constitutively active and muscarinic-receptor activated IK,ACh channels in patients with chronic atrial fibrillation, Cardiovasc Res. 2007 74(3):426-43

Voigt N, Maguy A, Yeh YH, Qi X, Ravens U, Dobrev D, Nattel S.: Changes in lK, ACh single-channel activity with atrial tachycardia remodelling in canine atrial cardiomyocytes; Cardiovasc Res. 2007 Oct 26; [Epub ahead of print]

Wetter E, Christ T, Dobrev D, Ravens U: Novel antiarrhythmic agents for treatment of atrial fibrillation, Curr Opin Pharmacol 2007, 7(2): 214-218

El-Armouche A, Bednorz A, Pamminger T, Ditz D, Didie M, Dobrev D, Eschenhagen T: Role of calcineurin and protein phosphatase-2A in regulation of phosphatase inhibitor-1 in cardiac myocytes.; Biochem Biophys Res Commun 2006; 346(3): 700-6

El-Armouche A, Boknik P, Eschenhagen T, Carrier L, Knaut M, Ravens U, Dobrev D; Molecular determinants of altered Ca2+-handling in human chronic atrial fibrillation.; Circulation 2006; 114; 670-680