Skip to main content

Genetics of Atrial Fibrillation and Standstill

  • Chapter
  • First Online:
Electrical Diseases of the Heart

Abstract

Atrial fibrillation (AF) is the most common arrhythmia and is associated with an unfavorable prognosis. Monogenetic forms of AF, however, represent a rare AF subtype. Although the identified mutations in affected family members have large effects, they do not seem to play a major role in more common AF present in the majority of the patients. The majority of patients have AF in association with concomitant (cardiovascular) conditions. In the last few years increasing data have been reported supporting the notion that there is a genetic component to more common AF. Recently, GWAS of the common AF phenotype have been successful in identifying three genetic loci associated with AF.

In this chapter we will focus on single mutations causing familial forms of AF, and discuss single nucleotide polymorphisms associated with AF in the general population, and lastly, we will discuss the genetic aspects of atrial standstill. Identification of the genes that play a role in the initiation of the arrhythmia may give new insights into the development of AF, and eventually lead to novel therapeutic options. Also, early recognition of patients at risk may, eventually, prevent AF and reduce morbidity and mortality.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98:946–52.

    Article  PubMed  CAS  Google Scholar 

  2. Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waclawiw MA, Stevenson LW. 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. Studies of left ventricular dysfunction. J Am Coll Cardiol. 1998;32:695–703.

    Article  PubMed  CAS  Google Scholar 

  3. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham heart study. JAMA. 1994;271:840–4.

    Article  PubMed  CAS  Google Scholar 

  4. Kirchhof P, Lip GY, Van Gelder IC, Bax J, et al. Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options – a report from the 3rd Atrial Fibrillation Competence Network/European Heart Rhythm Association consensus conference. Europace. 2011;14(1):8–27.

    Article  PubMed  Google Scholar 

  5. Fox CS, Parise H, D’Agostino Sr RB, Lloyd-Jones DM, Vasan RS, Wang TJ, et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004;291:2851–5.

    Article  PubMed  CAS  Google Scholar 

  6. Arnar DO, Thorvaldsson S, Manolio TA, Thorgeirsson G, Kristjansson K, Hakonarson H, et al. Familial aggregation of atrial fibrillation in Iceland. Eur Heart J. 2006;27:708–12.

    Article  PubMed  Google Scholar 

  7. Ellinor PT, Yoerger DM, Ruskin JN, MacRae CA. Familial aggregation in lone atrial fibrillation. Hum Genet. 2005;118:179–84.

    Article  PubMed  Google Scholar 

  8. Darbar D, Herron KJ, Ballew JD, Jahangir A, Gersh BJ, Shen WK, et al. Familial atrial fibrillation is a genetically heterogeneous disorder. J Am Coll Cardiol. 2003;41:2185–92.

    Article  PubMed  Google Scholar 

  9. Sinner MF, Lubitz SA, Pfeufer A, Makino S, et al. Lack of replication in polymorphisms reported to be associated with atrial fibrillation. Heart Rhythm. 2011;8(3):403–9.

    Article  PubMed  Google Scholar 

  10. Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir S, Holm H, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–7.

    Article  PubMed  CAS  Google Scholar 

  11. Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010;42:240–4.

    Article  PubMed  CAS  Google Scholar 

  12. Benjamin EJ, Rice KM, Arking DE, Pfeufer A, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet. 2009;41:879–81.

    Article  PubMed  CAS  Google Scholar 

  13. Van Gelder IC, Haegeli LM, Brandes A, Heidbuchel H, et al. Rationale and current perspective for early rhythm control therapy in atrial fibrillation. Europace. 2011;13(11):1517–25.

    Article  PubMed  Google Scholar 

  14. Wolff L. Familial auricular fibrillation. N Engl J Med. 1943;229:396–8.

    Article  Google Scholar 

  15. Brugada R, Tapscott T, Czernuszewicz GZ, Marian AJ, et al. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med. 1997;336:905–11.

    Article  PubMed  CAS  Google Scholar 

  16. Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, et al. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA. 2005;293:447–54.

    Article  PubMed  CAS  Google Scholar 

  17. McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, et al. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation. 2004;110:2163–7.

    Article  PubMed  CAS  Google Scholar 

  18. Schoonderwoerd BA, Smit MD, Pen L, Van Gelder IC. New risk factors for atrial fibrillation: causes of ‘not-so-lone atrial fibrillation’. Europace. 2008;10:668–73.

    Article  PubMed  Google Scholar 

  19. Ellinor PT, Shin JT, Moore RK, Yoerger DM, MacRae CA. Locus for atrial fibrillation maps to chromosome 6q14-16. Circulation. 2003;107:2880–3.

    Article  PubMed  Google Scholar 

  20. Bowles KR, Gajarski R, Porter P, Goytia V, Bachinski L, Roberts R, et al. Gene mapping of familial autosomal dominant dilated cardiomyopathy to chromosome 10q21-23. J Clin Invest. 1996;98:1355–60.

    Article  PubMed  CAS  Google Scholar 

  21. Sylvius N, Tesson F, Gayet C, Charron P, et al. A new locus for autosomal dominant dilated cardiomyopathy identified on chromosome 6q12-q16. Am J Hum Genet. 2001;68:241–6.

    Article  PubMed  CAS  Google Scholar 

  22. Bowles KR, Abraham SE, Brugada R, Zintz C, et al. Construction of a high-resolution physical map of the chromosome 10q22-q23 dilated ­cardiomyopathy locus and analysis of candidate genes. Genomics. 2000;67:109–27.

    Article  PubMed  CAS  Google Scholar 

  23. Chen YH, Xu SJ, Bendahhou S, Wang XL, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299:251–4.

    Article  PubMed  CAS  Google Scholar 

  24. Grunnet M, Jespersen T, Rasmussen HB, Ljungstrom T, Jorgensen NK, Olesen SP, et al. KCNE4 is an inhibitory subunit to the KCNQ1 channel. J Physiol. 2002;542:119–30.

    Article  PubMed  CAS  Google Scholar 

  25. Angelo K, Jespersen T, Grunnet M, Nielsen MS, Klaerke DA, Olesen SP. Kcne5 induces time- and voltage-dependent modulation of the KCNQ1 current. Biophys J. 2002;83:1997–2006.

    Article  PubMed  CAS  Google Scholar 

  26. Ellinor PT, Moore RK, Patton KK, Ruskin JN, Pollak MR, Macrae CA. Mutations in the long QT gene, KCNQ1, are an uncommon cause of atrial fibrillation. Heart. 2004;90:1487–8.

    Article  PubMed  CAS  Google Scholar 

  27. Das S, Makino S, Melman YF, Shea MA, Goyal SB, Rosenzweig A, et al. Mutation in the s3 segment of KCNQ1 results in familial lone atrial fibrillation. Heart Rhythm. 2009;6:1146–53.

    Article  PubMed  Google Scholar 

  28. Yang Y, Xia M, Jin Q, Bendahhou S, et al. Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am J Hum Genet. 2004;75:899–905.

    Article  PubMed  CAS  Google Scholar 

  29. Jiang M, Zhang M, Tang DG, Clemo HF, Liu J, Holwitt D, et al. KCNE2 protein is expressed in ventricles of different species, and changes in its expression contribute to electrical remodeling in diseased hearts. Circulation. 2004;109:1783–8.

    Article  PubMed  CAS  Google Scholar 

  30. Xia M, Jin Q, Bendahhou S, He Y, et al. A kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun. 2005;332:1012–9.

    Article  PubMed  CAS  Google Scholar 

  31. Ellinor PT, Petrov-Kondratov VI, Zakharova E, Nam EG, MacRae CA. Potassium channel gene mutations rarely cause atrial fibrillation. BMC Med Genet. 2006;7:70.

    Article  PubMed  CAS  Google Scholar 

  32. Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M, et al. Kv1.5 channelopathy due to kCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet. 2006;15:2185–91.

    Article  PubMed  CAS  Google Scholar 

  33. Yang Y, Li J, Lin X, Hong K, et al. Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation. J Hum Genet. 2009;54:277–83.

    Article  PubMed  CAS  Google Scholar 

  34. Yang T, Yang P, Roden DM, Darbar D. Novel KCNA5 mutation implicates tyrosine kinase signaling in human atrial fibrillation. Heart Rhythm. 2010;7:1246–52.

    Article  PubMed  Google Scholar 

  35. Ravn LS, Aizawa Y, Pollevick GD, Hofman-Bang J, et al. Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation. Heart Rhythm. 2008;5:427–35.

    Article  PubMed  Google Scholar 

  36. Laitinen-Forsblom PJ, Makynen P, Makynen H, Yli-Mayry S, Virtanen V, Kontula K, et al. SCN5A mutation associated with cardiac conduction defect and atrial arrhythmias. J Cardiovasc Electrophysiol. 2006;17:480–5.

    Article  PubMed  Google Scholar 

  37. Groenewegen WA, Firouzi M, Bezzina CR, Vliex S, van Langen IM, Sandkuijl L, et al. A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ Res. 2003;92:14–22.

    Article  PubMed  CAS  Google Scholar 

  38. Watanabe H, Yang T, Stroud DM, Lowe JS, et al. Striking in vivo phenotype of a disease-­associated human SCN5A mutation producing minimal changes in vitro. Circulation. 2011;124:1001–11.

    Article  PubMed  CAS  Google Scholar 

  39. Ellinor PT, Nam EG, Shea MA, Milan DJ, Ruskin JN, MacRae CA. Cardiac sodium channel mutation in atrial fibrillation. Heart Rhythm. 2008;5:99–105.

    Article  PubMed  Google Scholar 

  40. Makiyama T, Akao M, Shizuta S, Doi T, et al. A novel SCN5A gain-of-function mutation m1875t associated with familial atrial fibrillation. J Am Coll Cardiol. 2008;52:1326–34.

    Article  PubMed  CAS  Google Scholar 

  41. Watanabe H, Darbar D, Kaiser DW, Jiramongkolchai K, Chopra S, Donahue BS, et al. Mutations in sodium channel beta1- and beta2-subunits associated with atrial fibrillation. Circ Arrhythm Electrophysiol. 2009;2:268–75.

    Article  PubMed  CAS  Google Scholar 

  42. Olesen MS, Jespersen T, Nielsen JB, Liang B, et al. Mutations in sodium channel beta-subunit SCN3B are associated with early-onset lone atrial fibrillation. Cardiovasc Res. 2011;89:786–93.

    Article  PubMed  CAS  Google Scholar 

  43. Zhang X, Chen S, Yoo S, Chakrabarti S, et al. Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell. 2008;135:1017–27.

    Article  PubMed  CAS  Google Scholar 

  44. Oberti C, Wang L, Li L, Dong J, Rao S, Du W, et al. Genome-wide linkage scan identifies a novel genetic locus on chromosome 5p13 for neonatal atrial fibrillation associated with sudden death and variable cardiomyopathy. Circulation. 2004;110:3753–9.

    Article  PubMed  CAS  Google Scholar 

  45. Gollob MH, Jones DL, Krahn AD, Danis L, et al. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med. 2006;354:2677–88.

    Article  PubMed  CAS  Google Scholar 

  46. Yang YQ, Zhang XL, Wang XH, Tan HW, Shi HF, Jiang WF, et al. Connexin40 nonsense mutation in familial atrial fibrillation. Int J Mol Med. 2010;26:605–10.

    PubMed  CAS  Google Scholar 

  47. Yang YQ, Liu X, Zhang XL, Wang XH, Tan HW, Shi HF, et al. Novel connexin40 missense mutations in patients with familial atrial fibrillation. Europace. 2010;12:1421–7.

    Article  PubMed  Google Scholar 

  48. Hodgson-Zingman DM, Karst ML, Zingman LV, Heublein DM, Darbar D, Herron KJ, et al. Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. N Engl J Med. 2008;359:158–65.

    Article  PubMed  CAS  Google Scholar 

  49. Cunha SR, Hund TJ, Hashemi S, Voigt N, et al. Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation. Circulation. 2011;124:1212–22.

    Article  PubMed  CAS  Google Scholar 

  50. Le Scouarnec S, Bhasin N, Vieyres C, Hund TJ, et al. Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc Natl Acad Sci USA. 2008;105:15617–22.

    Article  PubMed  Google Scholar 

  51. Sebillon P, Bouchier C, Bidot LD, Bonne G, et al. Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations. J Med Genet. 2003;40:560–7.

    Article  PubMed  CAS  Google Scholar 

  52. Pan H, Richards AA, Zhu X, Joglar JA, Yin HL, Garg V. A novel mutation in lamin A/C is associated with isolated early-onset atrial fibrillation and progressive atrioventricular block followed by cardiomyopathy and sudden cardiac death. Heart Rhythm. 2009;6:707–10.

    Article  PubMed  Google Scholar 

  53. Gruver EJ, Fatkin D, Dodds GA, Kisslo J, Maron BJ, Seidman JG, et al. Familial hypertrophic cardiomyopathy and atrial fibrillation caused by arg663his beta-cardiac myosin heavy chain mutation. Am J Cardiol. 1999;83:13H–8.

    Article  PubMed  CAS  Google Scholar 

  54. van Spaendonck-Zwarts KY, van Tintelen JP, van Veldhuisen DJ, van der Werf R, Jongbloed JD, Paulus WJ, et al. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy. Circulation. 2010;121:2169–75.

    Article  PubMed  Google Scholar 

  55. Horne BD, Rasmusson KD, Alharethi R, Budge D, et al. Genome-wide significance and replication of the chromosome 12p11.22 locus near the PTHLH gene for peripartum cardiomyopathy. Circ Cardiovasc Genet. 2011;4:359–66.

    Article  PubMed  CAS  Google Scholar 

  56. Cox MG, van der Zwaag PA, van der Werf C, van der Smagt JJ, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study. Circulation. 2011;123:2690–700.

    Article  PubMed  Google Scholar 

  57. van Spaendonck-Zwarts K, van Hessem L, Jongbloed J, de Walle H, Capetanaki Y, van der Kooi A, et al. Desmin-related myopathy. Clinical Genetics. 2011;80:354–66. doi: 10.1111/j.1399-0004.2010.01512.x.

    Google Scholar 

  58. Taylor M, Graw S, Sinagra G, Barnes C, et al. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation. 2011;124:876–85.

    Article  PubMed  Google Scholar 

  59. Ohkubo R, Nakagawa M, Higuchi I, Utatsu Y, Miyazato H, Atsuchi Y, et al. Familial skeletal myopathy with atrioventricular block. Intern Med. 1999;38:856–60.

    Article  PubMed  CAS  Google Scholar 

  60. Sakata K, Shimizu M, Ino H, Yamaguchi M, et al. High incidence of sudden cardiac death with conduction disturbances and atrial cardiomyopathy caused by a nonsense mutation in the STA gene. Circulation. 2005;111:3352–8.

    Article  PubMed  Google Scholar 

  61. Postma AV, van de Meerakker JB, Mathijssen IB, Barnett P, et al. A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation. Circ Res. 2008;102:1433–42.

    Article  PubMed  CAS  Google Scholar 

  62. Schott JJ, Charpentier F, Peltier S, Foley P, Drouin E, Bouhour JB, et al. Mapping of a gene for long QT syndrome to chromosome 4q25-27. Am J Hum Genet. 1995;57:1114–22.

    PubMed  CAS  Google Scholar 

  63. Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, et al. Ankyrin-B mutation causes type 4 long-qt cardiac arrhythmia and sudden cardiac death. Nature. 2003;421:634–9.

    Article  PubMed  CAS  Google Scholar 

  64. Bartos DC, Duchatelet S, Burgess DE, Klug D, et al. R231c mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation. Heart Rhythm. 2011;8:48–55.

    Article  PubMed  Google Scholar 

  65. Hong K, Piper DR, Diaz-Valdecantos A, Brugada J, et al. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc Res. 2005;68:433–40.

    Article  PubMed  CAS  Google Scholar 

  66. Hong K, Bjerregaard P, Gussak I, Brugada R. Short qt syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol. 2005;16:394–6.

    Article  PubMed  Google Scholar 

  67. Giustetto C, Di Monte F, Wolpert C, Borggrefe M, et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J. 2006;27:2440–7.

    Article  PubMed  Google Scholar 

  68. Morita H, Kusano-Fukushima K, Nagase S, Fujimoto Y, et al. Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome. J Am Coll Cardiol. 2002;40:1437–44.

    Article  PubMed  Google Scholar 

  69. Gillmore JD, Booth DR, Pepys MB, Hawkins PN. Hereditary cardiac amyloidosis associated with the transthyretin ILE122 mutation in a white man. Heart. 1999;82:e2.

    PubMed  CAS  Google Scholar 

  70. Gutierrez-Roelens I, De Roy L, Ovaert C, Sluysmans T, Devriendt K, Brunner HG, et al. A novel CSX/NKX2-5 mutation causes autosomal-dominant AV block: are atrial fibrillation and syncopes part of the phenotype? Eur J Hum Genet. 2006;14:1313–6.

    Article  PubMed  CAS  Google Scholar 

  71. Posch MG, Boldt LH, Polotzki M, Richter S, Rolf S, Perrot A, et al. Mutations in the cardiac transcription factor GATA4 in patients with lone atrial fibrillation. Eur J Med Genet. 2010;53:201–3.

    Article  PubMed  Google Scholar 

  72. Gollob MH, Seger JJ, Gollob TN, Tapscott T, Gonzales O, Bachinski L, et al. Novel PRKAG2 mutation responsible for the genetic syndrome of ventricular preexcitation and conduction system disease with childhood onset and absence of cardiac hypertrophy. Circulation. 2001;104:3030–3.

    Article  PubMed  CAS  Google Scholar 

  73. Schoonderwoerd BA, Van Gelder IC, Van Veldhuisen DJ, Van den Berg MP, Crijns HJ. Electrical and structural remodeling: role in the genesis and maintenance of atrial fibrillation. Prog Cardiovasc Dis. 2005;48:153–68.

    Article  PubMed  Google Scholar 

  74. Lubitz SA, Yin X, Fontes JD, Magnani JW, et al. Association between familial atrial fibrillation and risk of new-onset atrial fibrillation. JAMA. 2010;304(20):2263–9.

    Article  PubMed  CAS  Google Scholar 

  75. Christophersen IE, Ravn LS, Budtz-Joergensen E, Skytthe A, Haunsoe S, Svendsen JH, et al. Familial aggregation of atrial fibrillation: a study in Danish twins. Circ Arrhythm Electrophysiol. 2009;2:378–83.

    Article  PubMed  Google Scholar 

  76. Lai LP, Su MJ, Yeh HM, Lin JL, Chiang FT, Hwang JJ, et al. Association of the human minK gene 38g allele with atrial fibrillation: evidence of possible genetic control on the pathogenesis of atrial fibrillation. Am Heart J. 2002;144:485–90.

    Article  PubMed  CAS  Google Scholar 

  77. Ehrlich JR, Zicha S, Coutu P, Hebert TE, Nattel S. Atrial fibrillation-associated minK38g/s polymorphism modulates delayed rectifier current and membrane localization. Cardiovasc Res. 2005;67:520–8.

    Article  PubMed  CAS  Google Scholar 

  78. Fatini C, Sticchi E, Genuardi M, Sofi F, Gensini F, Gori AM, et al. Analysis of minK and eNOS genes as candidate loci for predisposition to non-valvular atrial fibrillation. Eur Heart J. 2006;27:1712–8.

    Article  PubMed  CAS  Google Scholar 

  79. Ravn LS, Hofman-Bang J, Dixen U, Larsen SO, Jensen G, Haunso S, et al. Relation of 97t polymorphism in KCNE5 to risk of atrial fibrillation. Am J Cardiol. 2005;96:405–7.

    Article  PubMed  CAS  Google Scholar 

  80. Sinner MF, Pfeufer A, Akyol M, Beckmann BM, et al. The non-synonymous coding Ikr-channel variant KCNH2-k897t is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG). Eur Heart J. 2008;29:907–14.

    Article  PubMed  CAS  Google Scholar 

  81. Wang QS, Wang XF, Chen XD, Yu JF, Wang J, Sun J, et al. Genetic polymorphism of KCNH2 confers predisposition of acquired atrial fibrillation in Chinese. J Cardiovasc Electrophysiol. 2009;20:1158–62.

    Article  PubMed  Google Scholar 

  82. Chen LY, Ballew JD, Herron KJ, Rodeheffer RJ, Olson TM. A common polymorphism in SCN5A is associated with lone atrial fibrillation. Clin Pharmacol Ther. 2007;81:35–41.

    Article  PubMed  CAS  Google Scholar 

  83. Darbar D, Kannankeril PJ, Donahue BS, Kucera G, Stubblefield T, Haines JL, et al. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation. 2008;117:1927–35.

    Article  PubMed  CAS  Google Scholar 

  84. Firouzi M, Ramanna H, Kok B, Jongsma HJ, Koeleman BP, Doevendans PA, et al. Association of human connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation. Circ Res. 2004;95:e29–33.

    Article  PubMed  CAS  Google Scholar 

  85. Juang JM, Chern YR, Tsai CT, Chiang FT, Lin JL, Hwang JJ, et al. The association of human connexin 40 genetic polymorphisms with atrial fibrillation. Int J Cardiol. 2007;116:107–12.

    Article  PubMed  Google Scholar 

  86. Wirka RC, Gore S, Van Wagoner DR, Arking DE, et al. A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation. Circ Arrhythm Electrophysiol. 2011;4:87–93.

    Article  PubMed  CAS  Google Scholar 

  87. Thibodeau IL, Xu J, Li Q, Liu G, Lam K, Veinot JP, et al. Paradigm of genetic mosaicism and lone atrial fibrillation: physiological characterization of a connexin 43-deletion mutant identified from atrial tissue. Circulation. 2010;122:236–44.

    Article  PubMed  CAS  Google Scholar 

  88. Bedi M, McNamara D, London B, Schwartzman D. Genetic susceptibility to atrial fibrillation in patients with congestive heart failure. Heart Rhythm. 2006;3:808–12.

    Article  PubMed  Google Scholar 

  89. Yamashita T, Hayami N, Ajiki K, Oikawa N, Sezaki K, Inoue M, et al. Is ACE gene polymorphism associated with lone atrial fibrillation? Jpn Heart J. 1997;38:637–41.

    Article  PubMed  CAS  Google Scholar 

  90. Tsai CT, Lai LP, Lin JL, Chiang FT, Hwang JJ, Ritchie MD, et al. Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation. 2004;109:1640–6.

    Article  PubMed  CAS  Google Scholar 

  91. Ravn LS, Benn M, Nordestgaard BG, Sethi AA, Agerholm-Larsen B, Jensen GB, et al. Angioten­sinogen and ACE gene polymorphisms and risk of atrial fibrillation in the general population. Pharmacogenet Genomics. 2008;18:525–33.

    Article  PubMed  CAS  Google Scholar 

  92. Fatini C, Sticchi E, Gensini F, Gori AM, Marcucci R, Lenti M, et al. Lone and secondary nonvalvular atrial fibrillation: role of a genetic susceptibility. Int J Cardiol. 2007;120:59–65.

    Article  PubMed  Google Scholar 

  93. Huang M, Gai X, Yang X, Hou J, Lan X, Zheng W, et al. Functional polymorphisms in ace and cyp11b2 genes and atrial fibrillation in patients with hypertensive heart disease. Clin Chem Lab Med. 2009;47:32–7.

    PubMed  CAS  Google Scholar 

  94. Watanabe H, Kaiser DW, Makino S, MacRae CA, Ellinor PT, Wasserman BS, et al. ACE i/d polymorphism associated with abnormal atrial and atrioventricular conduction in lone atrial fibrillation and structural heart disease: implications for electrical remodeling. Heart Rhythm. 2009;6:1327–32.

    Article  PubMed  Google Scholar 

  95. Smit MD, Van Gelder IC. Upstream therapy of atrial fibrillation. Expert Rev Cardiovasc Ther. 2009;7:763–78.

    Article  PubMed  Google Scholar 

  96. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines.Part I: primary prevention. Europace. 2011;13:308–28.

    Article  PubMed  Google Scholar 

  97. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part II: secondary prevention. Europace. 2011;13:610–25.

    Article  PubMed  Google Scholar 

  98. Schreieck J, Dostal S, von Beckerath N, Wacker A, Flory M, Weyerbrock S, et al. C825t Polymorphism of the G-protein beta3 subunit gene and atrial fibrillation: association of the TT genotype with a reduced risk for atrial fibrillation. Am Heart J. 2004;148:545–50.

    Article  PubMed  CAS  Google Scholar 

  99. Siffert W, Rosskopf D, Siffert G, Busch S, Moritz A, Erbel R, et al. Association of a human G-protein beta3 subunit variant with hypertension. Nat Genet. 1998;18:45–8.

    Article  PubMed  CAS  Google Scholar 

  100. Ommen SR, Odell JA, Stanton MS. Atrial ­arrhythmias after cardiothoracic surgery. N Engl J Med. 1997;336:1429–34.

    Article  PubMed  CAS  Google Scholar 

  101. Bruins P, Te Velthuis H, Yazdanbakhsh AP, Jansen PGM, et al. Activation of the complement system during and after cardiopulmonary bypass surgery. Circulation. 1997;96:3542–8.

    Article  PubMed  CAS  Google Scholar 

  102. Aviles RJ, Martin DO, Apperson-Hansen C, Houghtaling PL, et al. Inflammation as a risk factor for atrial fibrillation. Circulation. 2003;108:3006–10.

    Article  PubMed  Google Scholar 

  103. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation. 1997;96:1180–4.

    Article  PubMed  CAS  Google Scholar 

  104. Nakamura Y, Nakamura K, Fukushima-Kusano K, Ohta K, Matsubara H, Hamuro T, et al. Tissue factor expression in atrial endothelia associated with nonvalvular atrial fibrillation: possible involvement in intracardiac thrombogenesis. Thromb Res. 2003;111:137–42.

    Article  PubMed  CAS  Google Scholar 

  105. Gaudino M, Andreotti F, Zamparelli R, Di Castelnuovo A, et al. The -174g/c interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation. 2003;108 Suppl 1:II195–9.

    PubMed  Google Scholar 

  106. Kato K, Oguri M, Hibino T, Yajima K, et al. Genetic factors for lone atrial fibrillation. Int J Mol Med. 2007;19:933–9.

    PubMed  CAS  Google Scholar 

  107. Gai X, Zhang Z, Liang Y, Chen Z, Yang X, Hou J, 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;411:719–24.

    Article  PubMed  CAS  Google Scholar 

  108. Gai X, Lan X, Luo Z, Wang F, Liang Y, Zhang H, et al. Association of MMP-9 gene polymorphisms with atrial fibrillation in hypertensive heart disease patients. Clin Chim Acta. 2009;408:105–9.

    Article  PubMed  CAS  Google Scholar 

  109. Ren X, Xu C, Zhan C, Yang Y, et al. Identification of NPPA variants associated with atrial fibrillation in a Chinese geneid population. Clin Chim Acta. 2010;411:481–5.

    Article  PubMed  CAS  Google Scholar 

  110. Roberts JD, Davies RW, Lubitz SA, Thibodeau IL, et al. Evaluation of non-synonymous NPPA single nucleotide polymorphisms in atrial fibrillation. Europace. 2010;12:1078–83.

    Article  PubMed  Google Scholar 

  111. Samani NJ, Thompson JR, O’Toole L, Channer K, Woods KL. A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. Circulation. 1996;94:708–12.

    Article  PubMed  CAS  Google Scholar 

  112. Wang WY, Barratt BJ, Clayton DG, Todd JA. Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet. 2005;6:109–18.

    Article  PubMed  CAS  Google Scholar 

  113. Kaab S, Darbar D, van Noord C, Dupuis J, et al. Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation. Eur Heart J. 2009;30(7):813–9.

    Article  PubMed  CAS  Google Scholar 

  114. Viviani Anselmi C, Novelli V, Roncarati R, Malovini A, et al. Association of rs2200733 at 4q25 with atrial flutter/fibrillation diseases in an Italian population. Heart. 2008;94:1394–6.

    Article  PubMed  CAS  Google Scholar 

  115. Body SC, Collard CD, Shernan SK, Fox AA, et al. Variation in the 4q25 chromosomal locus predicts atrial fibrillation after coronary artery bypass graft surgery. Circ Cardiovasc Genet. 2009;2:499–506.

    Article  PubMed  CAS  Google Scholar 

  116. Husser D, Adams V, Piorkowski C, Hindricks G, Bollmann A. Chromosome 4q25 variants and atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol. 2010;55:747–53.

    Article  PubMed  CAS  Google Scholar 

  117. Shi L, Li C, Wang C, Xia Y, et al. Assessment of association of rs2200733 on chromosome 4q25 with atrial fibrillation and ischemic stroke in a Chinese Han population. Hum Genet. 2009;126:843–9.

    Article  PubMed  Google Scholar 

  118. Gudbjartsson DF, Holm H, Gretarsdottir S, Thorleifsson G, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet. 2009;41:876–8.

    Article  PubMed  CAS  Google Scholar 

  119. Mommersteeg MT, Brown NA, Prall OW, de Gier-de Vries C, Harvey RP, Moorman AF, et al. PITX2c and NKX2-5 are required for the ­formation and identity of the pulmonary myocardium. Circ Res. 2007;101:902–9.

    Article  PubMed  CAS  Google Scholar 

  120. Mommersteeg MT, Hoogaars WM, Prall OW, de Gier-de VC, et al. Molecular pathway for the localized formation of the sinoatrial node. Circ Res. 2007;100:354–62.

    Article  PubMed  CAS  Google Scholar 

  121. Wang J, Klysik E, Sood S, Johnson RL, Wehrens XH, Martin JF. PITX2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification. Proc Natl Acad Sci USA. 2010;107:9753–8.

    Article  PubMed  CAS  Google Scholar 

  122. Kirchhof P, Kahr PC, Kaese S, Piccini I, 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;4:123–33.

    Article  PubMed  CAS  Google Scholar 

  123. Kohler M, Hirschberg B, Bond CT, Kinzie JM, Marrion NV, Maylie J, et al. Small-conductance, calcium-activated potassium channels from mammalian brain. Science. 1996;273:1709–14.

    Article  PubMed  CAS  Google Scholar 

  124. Tuteja D, Xu D, Timofeyev V, Lu L, et al. Differential expression of small-conductance ca2+ -activated k+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. Am J Physiol Heart Circ Physiol. 2005;289:H2714–23.

    Article  PubMed  CAS  Google Scholar 

  125. Xu Y, Tuteja D, Zhang Z, Xu D, et al. Molecular identification and functional roles of a Ca(2+)-activated K+ channel in human and mouse hearts. J Biol Chem. 2003;278:49085–94.

    Article  PubMed  CAS  Google Scholar 

  126. Tuteja D, Rafizadeh S, Timofeyev V, Wang S, et al. Cardiac small conductance Ca2+ -activated K+ channel subunits form heteromultimers via the coiled-coil domains in the C termini of the channels. Circ Res. 2010;107:851–9.

    Article  PubMed  CAS  Google Scholar 

  127. Effendy FN, Bolognesi R, Bianchi G, Visioli O. Alternation of partial and total atrial standstill. J Electrocardiol. 1979;12:121–7.

    Article  PubMed  CAS  Google Scholar 

  128. Talwar KK, Dev V, Chopra P, Dave TH, Radhakrishnan S. Persistent atrial standstill – clinical, electrophysiological, and morphological study. Pacing Clin Electrophysiol. 1991;14:1274–80.

    Article  PubMed  CAS  Google Scholar 

  129. Ruff P, Leier CV, Schaal SF. Temporary atrial standstill. Am Heart J. 1979;98:413–20.

    Article  PubMed  CAS  Google Scholar 

  130. Boriani G, Gallina M, Merlini L, Bonne G, et al. Clinical relevance of atrial fibrillation/flutter, stroke, pacemaker implant, and heart failure in Emery-Dreifuss muscular dystrophy: a long-term longitudinal study. Stroke. 2003;34:901–8.

    Article  PubMed  Google Scholar 

  131. Liu YB, Chen WJ, Lee YT. Atrial standstill in a case of Kugelberg-Welander syndrome with cardiac involvement: an electrophysiologic study. Int J Cardiol. 1999;70:207–10.

    Article  PubMed  CAS  Google Scholar 

  132. Fazelifar AF, Arya A, Haghjoo M, Sadr-Ameli MA. Familial atrial standstill in association with dilated cardiomyopathy. Pacing Clin Electro­physiol. 2005;28:1005–8.

    Article  PubMed  Google Scholar 

  133. Pierard LA, Henrard L, Demoulin JC. Persistent atrial standstill in familial Ebstein’s anomaly. Br Heart J. 1985;53:594–7.

    Article  PubMed  CAS  Google Scholar 

  134. Carballal J, Asensio E, Hernandez R, Narvaez R, et al. Ebstein’s anomaly, atrial paralysis and atrio-ventricular block: an uncommon association. Europace. 2002;4:451–4.

    Article  PubMed  CAS  Google Scholar 

  135. Takehara N, Makita N, Kawabe J, Sato N, Kawamura Y, Kitabatake A, et al. A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill. J Intern Med. 2004;255:137–42.

    Article  PubMed  CAS  Google Scholar 

  136. Harrison Jr WH, Derrick JR. Atrial standstill: a review, and presentation of two new cases of familial and unususal nature with reference to epicardial pacing in one. Angiology. 1969;20:610–7.

    Article  PubMed  Google Scholar 

  137. Ward DE, Ho SY, Shinebourne EA. Familial atrial standstill and inexcitability in childhood. Am J Cardiol. 1984;53:965–7.

    Article  PubMed  CAS  Google Scholar 

  138. Shah MK, Subramanyan R, Tharakan J, Venkitachalam CG, Balakrishnan KG. Familial total atrial standstill. Am Heart J. 1992;123:1379–82.

    Article  PubMed  CAS  Google Scholar 

  139. Balaji S, Till J, Shinebourne EA. Familial atrial standstill with coexistent atrial flutter. Pacing Clin Electrophysiol. 1998;21:1841–2.

    Article  PubMed  CAS  Google Scholar 

  140. Disertori M, Guarnerio M, Vergara G, Del Favero A, Bettini R, Inama G, et al. Familial endemic persistent atrial standstill in a small mountain community: review of eight cases. Eur Heart J. 1983;4:354–61.

    PubMed  CAS  Google Scholar 

  141. Makita N, Sasaki K, Groenewegen WA, Yokota T, Yokoshiki H, Murakami T, et al. Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms. Heart Rhythm. 2005;2:1128–34.

    Article  PubMed  Google Scholar 

  142. Roberts JD, Gollob MH. Impact of genetic discoveries on the classification of lone atrial fibrillation. J Am Coll Cardiol. 2010;55:705–12.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Isabelle C. van Gelder MD, PhD .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag London

About this chapter

Cite this chapter

Rienstra, M., van Tintelen, J.P., Vermond, R.A., Schoonderwoerd, B.A., Wiesfeld, A.C.P., van Gelder, I.C. (2013). Genetics of Atrial Fibrillation and Standstill. In: Gussak, I., Antzelevitch, C. (eds) Electrical Diseases of the Heart. Springer, London. https://doi.org/10.1007/978-1-4471-4881-4_35

Download citation

  • DOI: https://doi.org/10.1007/978-1-4471-4881-4_35

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-4471-4880-7

  • Online ISBN: 978-1-4471-4881-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics