Abstract
Atrial fibrillation is the most common cardiac arrhythmia. The presence of the arrhythmia is associated with significant impairment of quality of life, morbidity, and mortality. Currently available antiarrhythmic strategies are often inefficient, with enough unpleasant side effects explaining the frequent lack of adherence to treatment. The limited success in the therapy of atrial fibrillation is highly due to the fact that the precise mechanisms underlying this arrhythmia are poorly understood. Recent studies assessing the molecular mechanisms linked to atrial fibrillation provided further insights into understanding ion channel function, regulation, and remodeling, and indicated potentially new therapeutic targets.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Scherf D. Studies on auricular tachycardia caused by aconitine administration. Proc Soc Exp Biol Med. 1947;4:233–9.
Haïssaguerre M, Marcus FI, Fischer B, et al. Radiofrequency catheter ablation in unusual mechanisms of atrial fibrillation: report of three cases. J Cardiovasc Electrophysiol. 1994;5:743–51.
Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92:1954–68.
Van Wagoner DR, Pond AL, Lamorgese M, et al. Atrial L-Type Ca2+ currents and human atrial fibrillation. Circ Res. 1999;85:428–36.
Ehrlich JR. Inward rectifier potassium currents as a target for atrial fibrillation therapy. J Cardiovasc Pharmacol. 2008;52(2):129–35.
Cha TJ, Ehrlich JR, Zhang L, et al. Atrial tachycardia remodeling of pulmonary vein cardiomyocytes: comparison with left atrium and potential relation to arrhythmogenesis. Circulation. 2005;111(6):728–35.
Gaspo R, Bosch RF, Bou-Abboud E, et al. Tachycardia-induced changes in Na + current in a chronic dog model of atrial fibrillation. Circ Res. 1997;81:1045–52.
Bosch RF, Zeng X, Grammer JB, et al. Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc Res. 1999;44:121–31.
Nyberg MT, Stoevring B, Behr ER, et al. The variation of the sarcolipin gene (SLN) in atrial fibrillation, long QT syndrome and sudden arrhythmic death syndrome. Clin Chim Acta. 2007;375:87–91.
Mohler PJ, Schott JJ, Gramolini AO, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003;421(6923):634–9.
Olson TM, Alekseev AE, Liu XK, et al. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet. 2006;15(14):2185–91.
Feng J, Wible B, Li G, et al. Antisense oligodeoxynucleotides directed against Kv1.5 mRNA specifically inhibit ultrarapid delayed rectifier K + current in cultured adult human atrial myocytes. Circ Res. 1997;80:572–9.
Makiyama T, Akao M, Shizuta S, et al. A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation. J Am Coll Cardiol. 2008;52(16):1326–34.
Olson TM, Alekseev AE, Moreau C, et al. KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation. Nat Clin Pract Cardiovasc Med. 2007;4(2):110–6.
Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007;115(4):442–9.
Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299(5604):251–4.
Tsai CT, Lai LP, Hwang JJ, et al. Molecular genetics of atrial fibrillation. J Am Coll Cardiol. 2008;52(4):241–50.
Wakili R, Voigt N, Kääb S, et al. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest. 2011;121(8):2955–68.
Yang Y, Xia M, Jin Q, et al. Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am J Hum Genet. 2004;75:899–905.
Fatini C, Sticchi E, Genuardi M, et al. Analysis of minK and eNOS genes as candidate loci for predisposition to non-valvular atrial fibrillation. Eur Heart J. 2006;27(14):1712–8.
Ma KJ, Li N, Teng SY, et al. Modulation of KCNQ1 current by atrial fibrillation-associated KCNE4 (145E/D) gene polymorphism. Chin Med J (Engl). 2007;120(2):150–4.
Ravn LS, Hofman-Bang J, Dixen U, et al. Relation of 97T polymorphism in KCNE5 to risk of atrial fibrillation. Am J Cardiol. 2005;96(3):405–7.
Olson TM, Michels VV, Ballew JD, et al. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA. 2005;293(4):447–54.
Watanabe H, Darbar D, Kaiser DW, et al. Mutations in sodium channel beta1- and beta2-subunits associated with atrial fibrillation. Circ Arrhythm Electrophysiol. 2009;2(3):268–75.
Bedi M, McNamara D, London B, et al. Genetic susceptibility to atrial fibrillation in patients with congestive heart failure. Heart Rhythm. 2006;3(7):808–12.
Hagendorff A, Schumacher B, Kirchhoff S, et al. Conduction disturbances and increased atrial vulnerability in Connexin40-deficient mice analyzed by transesophageal stimulation. Circulation. 1999;99(11):1508–15.
Gollob MH, Jones DL, Krahn AD, et al. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med. 2006;54(25):2677–88.
Li DQ, Feng YB, Zhang HQ. The relationship between gap junctional remodeling and atrial fibrillation in patients with rheumatic heart disease. Zhonghua Yi Xue Za Zhi (abstract). 2004;84(5):384–6.
Tziakas DN, Chalikias GK, Stakos DA, et al. Effect of angiotensin-converting enzyme insertion/deletion genotype on collagen type I synthesis and degradation in patients with atrial fibrillation and arterial hypertension. Expert Opin Pharmacother. 2007;8(14):2225–34.
Cao FF, Chen XD, Wang QS, et al. Associations of the genetic polymorphisms in CYP11B2 gene with nonfamilial structural atrial fibrillation. Zhonghua Liu Xing Bing Xue Za Zhi (abstract). 2009;30(10):1069–72.
Wang QS, Li YG, Chen XD, et al. Angiotensinogen polymorphisms and acquired atrial fibrillation in Chinese. J Electrocardiol. 2010;43(4):373–7.
Gai X, Lan X, Luo Z, et al. Association of MMP-9 gene polymorphisms with atrial fibrillation in hypertensive heart disease patients. Clin Chim Acta. 2009;408(1–2):105–9.
Gai X, Zhang Z, Liang Y, et al. MMP-2 and TIMP-2 gene polymorphisms and susceptibility to atrial fibrillation in Chinese Han patients with hypertensive heart disease. Clin Chim Acta. 2010;411(9–10):719–24.
Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–7.
Gudbjartsson DF, Holm H, Gretarsdottir S, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet. 2009;41:876–8.
Chinchilla A, Daimi H, Lozano-Velasco E, et al. Pitx2 insufficiency leads to atrial electrical and structural remodelling linked to arrhythmogenesis. Circ Cardiovasc Genet. 2011;4(3):269–79.
Tessari A, Pietrobon M, Notte A, et al. Myocardial Pitx2 differentially regulates the left atrial identity and ventricular asymmetric remodeling programs. Circ Res. 2008;102(7):813–22.
Wang J, Klysik E, Sood S, et al. Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting leftsided pacemaker specification. Proc Natl Acad Sci U S A. 2010;107(21):9753–8.
Kirchhof P, Khar PC, Kaese S, et al. PITX2c is expressed in the adult left atrium, and reducing Pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression. Circ Cardiovasc Genet. 2011;4(2):123–33.
Lozano-Velasco E, Chinchilla A, Martinez-Fernandez S, et al. Pitx2c modulates cardiac specific transcription factor networks in differentiating cardiomyocytes from murine embryonic stem cells. Cells Tissues Organs. 2011;194(5):349–62.
Hjalt TA, Amendt BA, Murray JC. PITX2 regulates procollagen lysyl hydroxylase (PLOD) gene expression: implications for the pathology of Rieger syndrome. J Cell Biol. 2001;152(3):545–52.
Barth AS, Merk S, Arnoldi E, et al. Reprogramming of the human atrial transcriptome in permanent atrial fibrillation: expression of a ventricular-like genomic signature. Circ Res. 2005;96:1022–9.
Smith ML, Joglar JA, Wasmund SL, et al. Reflex control of sympathetic activity during simulated ventricular tachycardia in humans. Circulation. 1999;100:628–34.
Bouzegrhane F, Thibault G. Is angiotensin II a proliferative factor of cardiac fibroblasts? Cardiovasc Res. 2002;53(2):304–12.
Dhein S, Polontchouk L, Salameh A, et al. Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40. Biol Cell. 2002;94(7–8):409–22.
Shinagawa K, Shi YF, Tardif JC, et al. Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs. Circulation. 2002;105:2672–8.
Anyukhovsky EP, Sosunov EA, Plotnikov A, et al. Cellular electrophysiologic properties of old canine atria provide a substrate for arrhythmogenesis. Cardiovasc Res. 2005;54:462–9.
Kistler PM, Sanders P, Dodic M, et al. Atrial electrical and structural abnormalities in an ovine model of chronic blood pressure elevation after prenatal corticosteroid exposure: implications for development of atrial fibrillation. Eur Heart J. 2006;27:3045–56.
Wang TJ, Parise H, Levy D, et al. Obesity and the risk of new-onset atrial fibrillation. JAMA. 2004;292:2471–7.
Xiao HD, Fuchs S, Campbell DJ, et al. Mice with cardiac-restricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death. Am J Pathol. 2004;165:1019–32.
Li D, Shinagawa K, Pang L, et al. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation. 2001;104:2608–14.
Okazaki H, Minamino T, Tsukamoto O, et al. Angiotensin II type 1 receptor blocker prevents atrial structural remodeling in rats with hypertension induced by chronic nitric oxide inhibition. Hypertens Res. 2006;29:277–84.
Anand K, Mooss AN, Hee TT, et al. Meta-analysis: inhibition of rennin-angiotensin system prevents new-onset atrial fibrillation. Am Heart J. 2006;152:217–22.
Fang WT, Li HJ, Zhang H, et al. The role of statin therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Br J Clin Pharmacol. 2012;74(5):744–56.
Khawaja O, Gaziano JM, Djoussé L. A meta-analysis of omega-3 Fatty acids and incidence of atrial fibrillation. J Am Coll Nutr. 2012;31(1):4–13.
Kaneko N. New 1,4-benzothiazepine derivative, K201, demonstrates cardioprotective effects against sudden cardiac cell death and intracellular calcium blocking action. Drug Dev Res. 1994;33(4):429–38.
Kohno M, Yano M, Kobayashi S, et al. A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure. Am J Physiol Heart Circ Physiol. 2003;284(3):H1035–42.
Hilliard FA, Steele DS, Laver D, et al. Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass. J Mol Cell Cardiol. 2010;48:293–301.
Neef S, Dybkova N, Sossalla S, et al. CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation. Circ Res. 2010;106:1134–44.
Dobrev D, Nattel S. Calcium handling abnormalities in atrial fibrillation as a target for innovative therapeutics. J Cardiovasc Pharmacol. 2008;52:293–9.
Dobrev D. 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. 2007;376:227–30.
Blomström-Lundqvist C, Blomström P. Safety and efficacy of pharmacological cardioversion of atrial fibrillation using intravenous vernakalant, a new antiarrhythmic drug with atrial selectivity. Expert Opin Drug Saf. 2012;11(4):671–9.
Shiroshita-Takeshita A, Sakabe M, Haugan K, et al. Model-dependent effects of the gap junction conduction-enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs. Circulation. 2007;115:310–8.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer-Verlag London
About this chapter
Cite this chapter
Scridon, A., Dobreanu, D. (2014). Inside Molecular Mechanisms and Pharmacological Targets of Atrial Fibrillation. In: Dan, GA., Bayés de Luna, A., Camm, J. (eds) Atrial Fibrillation Therapy. Current Cardiovascular Therapy. Springer, London. https://doi.org/10.1007/978-1-4471-5475-4_2
Download citation
DOI: https://doi.org/10.1007/978-1-4471-5475-4_2
Published:
Publisher Name: Springer, London
Print ISBN: 978-1-4471-5474-7
Online ISBN: 978-1-4471-5475-4
eBook Packages: MedicineMedicine (R0)