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Atrial Ca2+ signaling in atrial fibrillation as an antiarrhythmic drug target

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Abstract

Atrial fibrillation (AF) is the most frequent arrhythmia and is associated with increased morbidity and mortality. Current drugs for AF treatment have moderate efficacy and increase the risk of life-threatening antiarrhythmias, making novel drug development crucial. Newer antiarrhythmic drugs like dronedarone and possibly vernakalant are efficient and may have less proarrhythmic potential. Emerging evidence suggests that abnormal intracellular Ca2+ signaling is the key contributor to focal firing, substrate evolution, and atrial remodeling during AF. Accordingly, identification of the underlying atrial Ca2+-handling abnormalities is expected to discover novel mechanistically based therapeutic targets. This article reviews the molecular mechanisms of altered Ca2+ signaling in AF and discusses the potential value of novel approaches targeting atrial Ca2+-handling abnormalities.

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References

  • Acsai K, Kun A, Farkas AS, Fülöp F, Nagy N, Balázs M, Szentandrássy N, Nánási PP, Papp JG, Varró A, Tóth A (2007) Effect of partial blockade of the Na+/Ca2+-exchanger on Ca2+ handling in isolated rat ventricular myocytes. Eur J Pharmacol 576(1-3):1–6

    Article  PubMed  CAS  Google Scholar 

  • Allessie M, Ausma J, Schotten U (2002) Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 54:230–246

    Article  PubMed  CAS  Google Scholar 

  • Antos CL, Frey N, Marx SO, Reiken S, Gaburjakova M, Richardson JA, Marks AR, Olson EN (2001) Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase a. Circ Res 89:997–1004

    Article  PubMed  CAS  Google Scholar 

  • Ausma J, Wijffels M, Thone F, Wouters L, Allessie M, Borgers M (1997) Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation 96:3157–3163

    PubMed  CAS  Google Scholar 

  • Benardeau A, Fareh S, Nattel S (2001) Effects of verapamil on atrial fibrillation and its electrophysiological determinants in dogs. Cardiovasc Res 50:85–96

    Article  PubMed  CAS  Google Scholar 

  • Berenfeld O, Zaitsev AV, Mironov SF, Pertsov AM, Jalife J (2002) Frequency-dependent breakdown of wave propagation into fibrillatory conduction across the pectinate muscle network in the isolated sheep right atrium. Circ Res 90(11):1173–1180

    Google Scholar 

  • Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205

    Article  PubMed  CAS  Google Scholar 

  • Boknik P, Unkel C, Kirchhefer U, Kleideiter U, Klein-Wiele O, Knapp J, Linck B, Lüss H, Müller FU, Schmitz W, Vahlensieck U, Zimmermann N, Jones LR, Neumann J (1999) Regional expression of phospholamban in the human heart. Cardiovasc Res 43:67–76

    Article  PubMed  CAS  Google Scholar 

  • Bosch RF, Scherer CR, Rüb N, Wöhrl S, Steinmeyer K, Haase H, Busch AE, Seipel L, Kühlkamp V (2003) Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces ICa, L and Ito in rapid atrial pacing in rabbits. J Am Coll Cardiol 41:858–869

    Article  PubMed  CAS  Google Scholar 

  • Brette F, Orchard C (2003) T-tubule function in mammalian cardiac myocytes. Circ Res 92(11):1182–1192

    Article  PubMed  CAS  Google Scholar 

  • Brundel BJ, Van Gelder IC, Henning RH, Tieleman RG, Tuinenburg AE, Wietses M, Grandjean JG, Van Gilst WH, Crijns HJ (2001) Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation 103:684–690

    PubMed  CAS  Google Scholar 

  • Brundel BJ, Ausma J, van Gelder IC, Van der Want JJ, van Gilst WH, Crijns HJ, Henning RH (2002) Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation. Cardiovasc Res 54:380–389

    Article  PubMed  CAS  Google Scholar 

  • Brundel BJ, Kampinga HH, Henning RH (2004) Calpain inhibition prevents pacing-induced cellular remodeling in a HL-1 myocyte model for atrial fibrillation. Cardiovasc Res 62(3):521–528

    Article  PubMed  CAS  Google Scholar 

  • Bukowska A, Lendeckel U, Hirte D, Wolke C, Striggow F, Röhnert P, Huth C, Klein HU, Goette A (2006) Activation of the calcineurin signaling pathway induces atrial hypertrophy during atrial fibrillation. Cell Mol Life Sci 63(3):333–342

    Article  PubMed  CAS  Google Scholar 

  • Cardin S, Libby E, Pelletier P, Le Bouter S, Shiroshita-Takeshita A, Le Meur N, Léger J, Demolombe S, Ponton A, Glass L, Nattel S (2007) Contrasting gene expression profiles in two canine models of atrial fibrillation. Circ Res 100(3):425–433

    Article  PubMed  CAS  Google Scholar 

  • Carnes CA, Janssen PM, Ruehr ML, Nakayama H, Nakayama T, Haase H, Bauer JA, Chung MK, Fearon IM, Gillinov AM, Hamlin RL, Van Wagoner DR (2007) Atrial glutathione content, calcium current, and contractility. J Biol Chem 282:28063–28073

    Article  PubMed  CAS  Google Scholar 

  • Cha TJ, Ehrlich JR, Zhang L, Nattel S (2004) Atrial ionic remodeling induced by atrial tachycardia in the presence of congestive heart failure. Circulation 110(12):1520–1526

    Article  PubMed  Google Scholar 

  • Cha TJ, Ehrlich JR, Chartier D, Qi XY, Xiao L, Nattel S (2006) Kir3-based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias. Circulation 113:1730–1737

    Article  PubMed  CAS  Google Scholar 

  • Chelu MG, Wehrens XH (2007) Sarcoplasmic reticulum calcium leak and cardiac arrhythmias. Biochem Soc Trans 35:952–956

    Article  PubMed  CAS  Google Scholar 

  • Chelu MG, Sarma S, Sood S, Wang S, van Oort RJ, Skapura D, Li N, Santonastasi M, Müller FU, Schmitz W, Schotten U, Anderson ME, Valderrabano M, Dobrev D, Wehrens XHT (2009) Calmodulin kinase II-mediated sarcoplasmic reticulum calcium leak promotes atrial fibrillation in mice. J Clin Invest 119:1940–1951

    PubMed  CAS  Google Scholar 

  • Chen YJ, Chen YC, Wongcharoen W, Lin CI, Chen SA (2008) Effect of K201, a novel antiarrhythmic drug on calcium handling and arrhythmogenic activity of pulmonary vein cardiomyocytes. Br J Pharmacol 153:915–925

    Article  PubMed  CAS  Google Scholar 

  • Christ T, Boknik P, Wöhrl S, Wettwer E, Graf EM, Bosch RF, Knaut M, Schmitz W, Ravens U, Dobrev D (2004) Reduced L-type Ca2+ current density in chronic human atrial fibrillation is associated with increased activity of protein phosphatases. Circulation 110:2651–2657

    Article  PubMed  CAS  Google Scholar 

  • Comtois P, Kneller J, Nattel S (2005) Of circles and spirals: bridging the gap between the leading circle and spiral wave concepts of cardiac reentry. Europace 7(Suppl 2):10–20

    Article  PubMed  Google Scholar 

  • Dixen U, Ravn L, Soeby-Rasmussen C, Paulsen AW, Parner J, Frandsen E, Jensen GB (2007) Raised plasma aldosterone and natriuretic peptides in atrial fibrillation. Cardiology 108(1):35–39

    Google Scholar 

  • Dobrev D (2007) Cardiomyocyte Ca2+ overload in atrial tachycardia: is blockade of L-type Ca2+ channels a promising approach to prevent electrical remodeling and arrhythmogenesis. Naunyn Schmiedebergs Arch Pharmacol 376(4):227–230

    Article  PubMed  CAS  Google Scholar 

  • Dobrev D, Ravens U (2003) Remodeling of cardiomyocyte ion channels in human atrial fibrillation. Basic Res Cardiol 98:137–148

    PubMed  Google Scholar 

  • Dobrev D, Nattel S (2008) Calcium handling abnormalities in atrial fibrillation as a target for innovative therapeutics. J Cardiovasc Pharmacol 52(4):293–299

    Article  PubMed  CAS  Google Scholar 

  • Dobrev D, Graf E, Wettwer E, Himmel HM, Hála O, Doerfel C, Christ T, Schüler S, Ravens U (2001) Molecular basis of down-regulation of G-protein-coupled inward rectifying K + current (IK, ACh) in chronic human atrial fibrillation. Decrease in GIRK4 mRNA correlates with reduced IK, ACh and muscarinic receptor-mediated shortening of action potentials. Circulation 104:2551–2557

    Article  PubMed  CAS  Google Scholar 

  • Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Christ T, Knaut M, Ravens U (2005) The G protein-gated potassium current IK, ACh is constitutively active in patients with chronic atrial fibrillation. Circulation 112:3697–3706

    Article  PubMed  CAS  Google Scholar 

  • Duytschaever M, Blaauw Y, Allessie M (2005) Consequences of atrial electrical remodeling for the anti-arrhythmic action of class IC and class III drugs. Cardiovasc Res 67(1):69–76

    Article  PubMed  CAS  Google Scholar 

  • Eckstein J, Verheule S, de Groot N, Allessie M, Schotten U (2008) Mechanisms of perpetuation of atrial fibrillation in chronically dilated atria. Prog Biophys Mol Biol 97:435–451

    Article  PubMed  Google Scholar 

  • Ehrlich JR, Nattel S (2009) Novel approaches for pharmacological management of atrial fibrillation. Drugs 69(7):757–774

    Article  PubMed  CAS  Google Scholar 

  • Ehrlich JR, Cha TJ, Zhang L, Chartier D, Villeneuve L, Hébert TE, Nattel S (2004) Characterization of a hyperpolarization-activated time-dependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium. J Physiol 557:583–597

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Fareh S, Benardeau A, Nattel S (2001) Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs. Cardiovasc Res 49:762–770

    Article  PubMed  CAS  Google Scholar 

  • Fenelon G, Shepard RK, Stambler BS (2003) Focal origin of atrial tachycardia in dogs with rapid ventricular pacing-induced heart failure. J Cardiovasc Electrophysiol 14:1093–1102

    Article  PubMed  Google Scholar 

  • Gaborit N, Steenman M, Lamirault G, Le Meur N, Le Bouter S, Lande G, Léger J, Charpentier F, Christ T, Dobrev D, Escande D, Nattel S, Demolombe S (2005) Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation. Circulation 112:471–481

    Article  PubMed  Google Scholar 

  • Gaspo R, Sun H, Fareh S, Levi M, Yue L, Allen BG, Hebert TE, Nattel S (1999) Dihydropyridine and beta adrenergic receptor binding in dogs with tachycardia-induced atrial fibrillation. Cardiovasc Res 42:434–442

    Article  PubMed  CAS  Google Scholar 

  • Gassanov N, Brandt MC, Michels G, Lindner M, Er F, Hoppe UC (2006) Angiotensin II-induced changes of calcium sparks and ionic currents in human atrial myocytes: potential role for early remodeling in atrial fibrillation. Cell Calcium 39:175–186

    Article  PubMed  CAS  Google Scholar 

  • George CH (2008) Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance? Cardiovasc Res 77:302–314

    Article  PubMed  CAS  Google Scholar 

  • Goette A, Arndt M, Röcken C, Staack T, Bechtloff R, Reinhold D, Huth C, Ansorge S, Klein HU, Lendeckel U (2002) Calpains and cytokines in fibrillating human atria. Am J Physiol Heart Circ Physiol 283:H264–H272

    PubMed  CAS  Google Scholar 

  • Greiser M, Halaszovich CR, Frechen D, Boknik P, Ravens U, Dobrev D, Lückhoff A, Schotten U (2007) Pharmacological evidence for altered src-kinase regulation of ICa, L in patients with chronic atrial fibrillation. Naunyn Schmiedebergs Arch Pharmacol 375:383–392

    Article  PubMed  CAS  Google Scholar 

  • Greiser M, Neuberger HR, Harks E, de Haan S, Verheyen F, Boknik P, El-Armouche A, Schmitz W, Ravens U, Nattel S, Allessie MA, Dobrev D, Schotten U (2009) Distinct contractile and molecular difference between two goat models of atrial dysfunction: AV-block-induced atrial dilatation and atrial fibrillation. J Mol Cell Cardiol 46:385–394

    Article  PubMed  CAS  Google Scholar 

  • Herzig S, Neumann J (2000) Effects of serine/threonine protein phosphatases on ion channels in excitable membranes. Physiol Rev 80:173–210

    PubMed  CAS  Google Scholar 

  • Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ, ATHENA Investigators (2009) Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 360(7):668–678

    Article  PubMed  CAS  Google Scholar 

  • Hove-Madsen L, Llach A, Bayes-Genis A, Roura S, Rodriguez Font E, Arís A, Cinca J (2004) Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes. Circulation 110:1358–1363

    Article  PubMed  CAS  Google Scholar 

  • Iwamoto T, Watanabe Y, Kita S, Blaustein MP (2007) Na+/Ca2+ exchange inhibitors: a new class of calcium regulators. Cardiovasc Hematol Disord Drug Targets 7:188–198

    Article  PubMed  CAS  Google Scholar 

  • Kim YM, Guzik TJ, Zhang YH, Zhang MH, Kattach H, Ratnatunga C, Pillai R, Channon KM, Casadei B (2005) A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation. Circ Res 7(7):629–636

    Article  CAS  Google Scholar 

  • Kirchhof P, Bax J, Blomstrom-Lundquist C, Calkins H, John Camm A, Cappato R, Cosio F, Crijns H, Diener HC, Goette A, Israel CW, Kuck KH, Lip GY, Nattel S, Page RL, Ravens U, Schotten U, Steinbeck G, Vardas P, Waldo A, Wegscheider K, Willems S, Breithardt G (2009) Early and comprehensive management of atrial fibrillation: executive summary of the proceedings from the 2nd AFNET-EHRA consensus conference research perspectives in AF. Eur Heart J (in press)

  • Kraft R (2007) The Na+/Ca2+ exchange inhibitor KB-R7943 potently blocks TRPC channels. Biochem Biophys Res Commun 361(1):230–236

    Article  PubMed  CAS  Google Scholar 

  • Kumagai K, Nakashima H, Gondo N, Saku K (2003) Antiarrhythmic effects of JTV-519, a novel cardioprotective drug, on atrial fibrillation/flutter in a canine sterile pericarditis model. J Cardiovasc Electrophysiol 14:880–884

    Article  PubMed  Google Scholar 

  • Lafuente-Lafuente C, Mouly S, Longás-Tejero MA, Mahé I, Bergmann JF (2006) Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled trials. Arch Intern Med 166(7):719–728

    Article  PubMed  CAS  Google Scholar 

  • Lee KW, Everett TH, Rahmutula D, Guerra JM, Wilson E, Ding C, Olgin JE (2006) Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation 114:1703–1712

    Article  PubMed  CAS  Google Scholar 

  • Lehnart SE, Terrenoire C, Reiken S, Wehrens XH, Song LS, Tillman EJ, Mancarella S, Coromilas J, Lederer WJ, Kass RS, Marks AR (2006) Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias. Proc Natl Acad Sci USA 103:7906–7910

    Article  PubMed  CAS  Google Scholar 

  • Lehnart SE, Mongillo M, Bellinger A, Lindegger N, Chen BX, Hsueh W, Reiken S, Wronska A, Drew LJ, Ward CW, Lederer WJ, Kass RS, Morley G, Marks AR (2008) Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and suddencardiac death in mice. J Clin Invest 118(6):2230–2245

    PubMed  CAS  Google Scholar 

  • Li D, Fareh S, Leung TK, Nattel S (1999) Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 100:87–95

    PubMed  CAS  Google Scholar 

  • Li D, Melnyk P, Feng J, Wang Z, Petrecca K, Shrier A, Nattel S (2000) Effects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation 101(22):2631–2638

    PubMed  CAS  Google Scholar 

  • Liang X, Xie H, Zhu PH, Hu J, Zhao Q, Wang CS, Yang C (2008) Ryanodine receptor-mediated Ca2+ events in atrial myocytes of patients with atrial fibrillation. Cardiology 111(2):102–110

    Article  PubMed  Google Scholar 

  • Luss I, Boknik P, Jones LR, Kirchhefer U, Knapp J, Linck B, Lüss H, Meissner A, Müller FU, Schmitz W, Vahlensieck U, Neumann J (1999) Expression of cardiac calcium regulatory proteins in atrium v ventricle in different species. J Mol Cell Cardiol 31:1299–1314

    Article  PubMed  CAS  Google Scholar 

  • MacLennan DH, Kranias EG (2003) Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4:566–577

    Article  PubMed  CAS  Google Scholar 

  • Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101:365–376

    Article  PubMed  CAS  Google Scholar 

  • Mayr M, Yusuf S, Weir G, Chung YL, Mayr U, Yin X, Ladroue C, Madhu B, Roberts N, De Souza A, Fredericks S, Stubbs M, Griffiths JR, Jahangiri M, Xu Q, Camm AJ (2008) Combined metabolomic and proteomic analysis of human atrial fibrillation. J Am Coll Cardiol 51(5):585–594

    Article  PubMed  CAS  Google Scholar 

  • Mihm MJ, Yu F, Carnes CA, Reiser PJ, McCarthy PM, Van Wagoner DR, Bauer JA (2001) Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation 104:174–180

    PubMed  CAS  Google Scholar 

  • Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB, Tsang TS (2006) Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 114(2):119–125

    Article  PubMed  Google Scholar 

  • Miyata A, Zipes DP, Hall S, Rubart M (2002) Kb-R7943 prevents acute, atrial fibrillation-induced shortening of atrial refractoriness in anesthetized dogs. Circulation 106:1410–1419

    Article  PubMed  CAS  Google Scholar 

  • Nakaya H, Furusawa Y, Ogura T, Tamagawa M, Uemura H (2000) Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea-pig hearts. Br J Pharmacol 131:1363–1372

    Article  PubMed  CAS  Google Scholar 

  • Nattel S, Burstein B, Dobrev D (2008) Atrial remodelling and atrial fibrillation: mechanisms and implications. Circ Arrhythmia Electrophysiol 1(1):62–73

    Article  Google Scholar 

  • Niu CF, Watanabe Y, Ono K, Iwamoto T, Yamashita K, Satoh H, Urushida T, Hayashi H, Kimura J (2007) Characterization of SN-6, a novel Na+/Ca2+ exchange inhibitor in guinea pig cardiac ventricular myocytes. Eur J Pharmacol 573(1–3):161–169

    Article  PubMed  CAS  Google Scholar 

  • Okumura Y, Watanabe I, Nakai T, Sugimura H, Hashimoto K, Masaki R, Ohkubo K, Takagi Y, Shindo A, Ozawa Y, Saito S, Kanmatsuse K (2005) Recurrence of atrial fibrillation after internal cardioversion of persistent atrial fibrillation: prognostic importance of electrophysiologic parameters. Circ J 69(12):1514–1520

    Article  PubMed  Google Scholar 

  • Ouardouz M, Zamponi GW, Barr W, Kiedrowski L, Stys PK (2005) Protection of ischemic rat spinal cord white matter: Dual action of KB-R7943 on Na+/Ca2+ exchange and L-type Ca2+ channels. Neuropharmacology 48(4):566–575

    Article  PubMed  CAS  Google Scholar 

  • Ozdemir S, Bito V, Holemans P, Vinet L, Mercadier JJ, Varro A, Sipido KR (2008) Pharmacological inhibition of Na/Ca exchange results in increased cellular Ca2+ load attributable to the predominance of forward mode block. Circ Res 102(11):1398–1405

    Article  PubMed  CAS  Google Scholar 

  • Patterson E, Jackman WM, Beckman KJ, Lazzara R, Lockwood D, Scherlag BJ, Wu R, Po S (2007) Spontaneous pulmonary vein firing in man: relationship to tachycardia-pause early afterdepolarizations and triggered arrhythmia in canine pulmonary veins in vitro. J Cardiovasc Electrophysiol 18:1067–1075

    Article  PubMed  Google Scholar 

  • Pedersen OD, Abildstrom SZ, Ottesen MM, Rask-Madsen C, Bagger H, Køber L, Torp-Pedersen C, TRACE Study Investigators (2006) Increased risk of sudden and non-sudden cardiovascular death in patients with atrial fibrillation/flutter following acute myocardial infarction. Eur Heart J 27:290–295

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Roy D, Talajic M, Dorian P, Connolly S, Eisenberg MJ, Green M, Kus T, Lambert J, Dubuc M, Gagné P, Nattel S, Thibault B (2000) Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 342(13):913–920

    Article  PubMed  CAS  Google Scholar 

  • Sanders P, Morton JB, Davidson NC, Spence SJ, Vohra JK, Sparks PB, Kalman JM (2003) Electrical remodeling of the atria in congestive heart failure: electrophysiological and electroanatomic mapping in humans. Circulation 108(12):1461–1468

    Article  PubMed  Google Scholar 

  • Schotten U, Ausma J, Stellbrink C, Sabatschus I, Vogel M, Frechen D, Schoendube F, Hanrath P, Allessie MA (2001) Cellular mechanisms of depressed atrial contractility in patients with chronic atrial fibrillation. Circulation 103:691–698

    PubMed  CAS  Google Scholar 

  • Schotten U, Greiser M, Benke D, Buerkel K, Ehrenteidt B, Stellbrink C, Vazquez-Jimenez JF, Schoendube F, Hanrath P, Allessie M (2002) Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort. Cardiovasc Res 53:192–201

    Article  PubMed  CAS  Google Scholar 

  • Schotten U, Haase H, Frechen D, Greiser M, Stellbrink C, Vazquez-Jimenez JF, Morano I, Allessie MA, Hanrath P (2003) The L-type Ca2+-channel subunits alpha1C and beta2 are not downregulated in atrial myocardium of patients with chronic atrial fibrillation. J Mol Cell Cardiol 35:437–443

    Article  PubMed  CAS  Google Scholar 

  • Sheehan KA, Blatter LA (2003) Regulation of junctional and non-junctional sarcoplasmic reticulum calcium release in excitation-contraction coupling in cat atrial myocytes. J Physiol 546:119–135

    Article  PubMed  CAS  Google Scholar 

  • Shinagawa K, Shi YF, Tardif JC, Leung TK, Nattel S (2002) Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs. Circulation 105:2672–1678

    Article  PubMed  Google Scholar 

  • Sood S, Chelu M, Van Oort R, Skapura D, Santonastasi M, Dobrev D, Wehrens XHT (2008) Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation. Heart Rhythm 5(7):1047–1054

    Article  PubMed  Google Scholar 

  • Stambler BS, Fenelon G, Shepard RK, Clemo HF, Guiraudon CM (2003) Characterization of sustained atrial tachycardia in dogs with rapid ventricular pacing-induced heart failure. J Cardiovasc Electrophysiol 14:499–507

    Article  PubMed  Google Scholar 

  • Sun H, Gaspo R, Leblanc N, Nattel S (1998) Cellular mechanisms of atrial contractile dysfunction caused by sustained atrial tachycardia. Circulation 98:719–727

    PubMed  CAS  Google Scholar 

  • Szentandrássy N, Birinyi P, Szigeti G, Farkas A, Magyar J, Tóth A, Csernoch L, Varró A, Nánási PP (2008) SEA0400 fails to alter the magnitude of intracellular Ca2+ transients and contractions in Langendorff-perfused guinea pig heart. Naunyn Schmiedebergs Arch Pharmacol 378(1):65–71

    Article  PubMed  CAS  Google Scholar 

  • Tanaka H, Nishimaru K, Aikawa T, Hirayama W, Tanaka Y, Shigenobu K (2002) Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger, on myocardial ionic currents. Br J Pharmacol 135(5):1096–1100

    Article  PubMed  CAS  Google Scholar 

  • Tanaka K, Zlochiver S, Vikstrom KL, Yamazaki M, Moreno J, Klos M, Zaitsev AV, Vaidyanathan R, Auerbach DS, Landas S, Guiraudon G, Jalife J, Berenfeld O, Kalifa J (2007) Spatial distribution of fibrosis governs fibrillation wave dynamics in the posterior left atrium during heart failure. Circ Res 101:839–847

    Article  PubMed  CAS  Google Scholar 

  • Tessier S, Karczewski P, Krause EG, Pansard Y, Acar C, Lang-Lazdunski M, Mercadier JJ, Hatem SN (1999) Regulation of the transient outward K+ current by Ca2+/calmodulin-dependent protein kinases II in human atrial myocytes. Circ Res 85:810–819

    PubMed  CAS  Google Scholar 

  • Thijssen VL, Ausma J, Liu GS, Allessie MA, van Eys GJ, Borgers M (2000) Structural changes of atrial myocardium during chronic atrial fibrillation. Cardiovasc Pathol 9:17–28

    Article  PubMed  CAS  Google Scholar 

  • Tieleman RG, Van Gelder IC, Bosker HA, Kingma T, Wilde AA, Kirchhof CJ, Bennekers JH, Bracke FA, Veeger NJ, Haaksma J, Allessie MA, Crijns HJ (2005) Does flecainide regain its antiarrhythmic activity after electrical cardioversion of persistent atrial fibrillation? Heart Rhythm 2(3):223–230

    Article  PubMed  Google Scholar 

  • Tsang TS, Miyasaka Y, Barnes ME, Gersh BJ (2005) Epidemiological profile of atrial fibrillation: a contemporary perspective. Prog Cardiovasc Dis 48(1):1–8

    Article  PubMed  Google Scholar 

  • Uemura N, Ohkusa T, Hamano K, Nakagome M, Hori H, Shimizu M, Matsuzaki M, Mochizuki S, Minamisawa S, Ishikawa Y (2004) Down-regulation of sarcolipin mRNA expression in chronic atrial fibrillation. Eur J Clin Invest 34:723–730

    Article  PubMed  CAS  Google Scholar 

  • Van Wagoner DR (2008) Oxidative stress and inflammation in atrial fibrillation: role in pathogenesis and potential as a therapeutic target. J Cardiovasc Pharmacol 52(4):306–313

    Article  PubMed  CAS  Google Scholar 

  • Van Wagoner DR, Pond AL, McCarthy PM, Trimmer JS, Nerbonne JM (1997) Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation. Circ Res 80(6):772–781

    Google Scholar 

  • Van Wagoner DR, Pond AL, Lamorgese M, Rossie SS, McCarthy PM, Nerbonne JM (1999) Atrial L-type Ca2+ currents and human atrial fibrillation. Circ Res 85:428–436

    PubMed  Google Scholar 

  • Venetucci LA, Trafford AW, Eisner DA (2007) Increasing ryanodine receptor open probability alone does not produce arrhythmogenic calcium waves: threshold sarcoplasmic reticulum calcium content is required. Circ Res 100(1):105–111

    Article  PubMed  CAS  Google Scholar 

  • Vest JA, Wehrens XH, Reiken SR, Lehnart SE, Dobrev D, Chandra P, Danilo P, Ravens U, Rosen MR, Marks AR (2005) Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation 111:2025–2032

    Article  PubMed  CAS  Google Scholar 

  • Wakili R, Yeh YH, Chartier D, Qi XY, Kääb S, Ravens U, Nattel S, Dobrev D (2008) Substrate-dependent mechanisms of impaired contractility in atrial fibrillation. Heart Rhythm 5(Suppl):S13 abstract AB6-6

    Google Scholar 

  • Watanabe Y, Kimura J (2008) Acute inhibitory effect of dronedarone, a noniodinated benzofuran analogue of amiodarone, on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes. Naunyn Schmiedebergs Arch Pharmacol 377(4–6):371–376

    Article  PubMed  CAS  Google Scholar 

  • Watanabe H, Chopra N, Laver D, Hwang HS, Davies SS, Roach DE, Duff HJ, Roden DM, Wilde AA, Knollmann BC (2009) Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med 15(4):380–383

    Article  PubMed  CAS  Google Scholar 

  • Wehrens XH, Marks AR (2004) Novel therapeutic approaches for heart failure by normalizing calcium cycling. Nat Rev Drug Discov 3:565–573

    Article  PubMed  CAS  Google Scholar 

  • Wehrens XH, Lehnart SE, Reiken SR, Marks AR (2004a) Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor. Circ Res 94:e61–e70

    Article  PubMed  CAS  Google Scholar 

  • Wehrens XH, Lehnart SE, Reiken SR, Deng SX, Vest JA, Cervantes D, Coromilas J, Landry DW, Marks AR (2004b) Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science 304:292–296

    Article  PubMed  CAS  Google Scholar 

  • Wettwer E, Hála O, Christ T, Heubach JF, Dobrev D, Knaut M, Varró A, Ravens U (2004) Role of IKur in controlling action potential shape and contractility in the human atrium: influence of chronic atrial fibrillation. Circulation 110:2299–2306

    Article  PubMed  Google Scholar 

  • Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA (1995) Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92:1954–1968

    PubMed  CAS  Google Scholar 

  • Wongcharoen W, Chen YC, Chen YJ, Chang CM, Yeh HI, Lin CI, Chen SA (2006) Effects of a Na+/Ca2+ exchanger inhibitor on pulmonary vein electrical activity and ouabain-induced arrhythmogenicity. Cardiovasc Res 70:497–508

    Article  PubMed  CAS  Google Scholar 

  • Workman AJ, Kane KA, Rankin AC (2001) The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation. Cardiovasc Res 52:226–235

    Article  PubMed  CAS  Google Scholar 

  • Workman AJ, Kane KA, Rankin AC (2008) Cellular bases for human atrial fibrillation. Heart Rhythm 5(6 Suppl):S1–S6

    Article  PubMed  Google Scholar 

  • Xu L, Kappler CS, Mani SK, Shepherd NR, Renaud L, Snider P, Conway SJ, Menick DR (2009) Chronic administration of KB-R7943 induces upregulation of cardiac NCX1. J Biol Chem. (in press)

  • Yano M, Ono K, Ohkusa T, Suetsugu M, Kohno M, Hisaoka T, Kobayashi S, Hisamatsu Y, Yamamoto T, Kohno M, Noguchi N, Takasawa S, Okamoto H, Matsuzaki M (2000) Altered stoichiometry of FKBP12.6 versus ryanodine receptor as a cause of abnormal Ca2+ leak through ryanodine receptor in heart failure. Circulation 102:2131–2136

    PubMed  CAS  Google Scholar 

  • Yano M, Ikeda Y, Matsuzaki M (2005) Altered intracellular Ca2+ handling in heart failure. J Clin Invest 115:556–564

    PubMed  CAS  Google Scholar 

  • Yeh YH, Wakili R, Qi XY, Charter D, Boknik P, Kääb S, Ravens U, Coutu P, Dobrev D, Nattel S (2008) Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure. Circ Arrhythmia Electrophysiol 1(2):93–102

    Article  CAS  Google Scholar 

  • Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S (1997) Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res 81:512–525

    PubMed  CAS  Google Scholar 

  • Yue L, Melnyk P, Gaspo R, Wang Z, Nattel S (1999) Molecular mechanisms underlying ionic remodeling in a dog model of atrial fibrillation. Circ Res 84:776–784

    PubMed  CAS  Google Scholar 

  • Zalk R, Lehnart SE, Marks AR (2007) Modulation of the ryanodine receptor and intracellular calcium. Annu Rev Biochem 76:367–385

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The author thanks Ursula Ravens for critical reading of the manuscript and the German Federal Ministry of Education and Research (Atrial Fibrillation Competence Network grant 01Gi0204), German Research Foundation (DFG, Do 769/1-3), and Fondation Leducq (07 CVD 03, “European North American Atrial Fibrillation Research Alliance”) for research support.

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The author has no potential conflicts of interest to disclose.

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  1. Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany

    Dobromir Dobrev

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Dobrev, D. Atrial Ca2+ signaling in atrial fibrillation as an antiarrhythmic drug target. Naunyn-Schmied Arch Pharmacol 381, 195–206 (2010). https://doi.org/10.1007/s00210-009-0457-1

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