European Heart Journal Advance Access originally published online on June 7, 2006
European Heart Journal 2006 27(14):1640-1641; doi:10.1093/eurheartj/ehl076
Do genetics help to better understand the underlying mechanisms of atrial fibrillation?
Department of Pharmacology and Toxicology, Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany
* Corresponding author. Tel: +49 351 4586279; fax: +49 351 4586315. E-mail address: dobrev{at}rcs.urz.tu-dresden.de
This editorial refers to ‘Analysis of minK and eNOS genes as candidate loci for predisposition to non-valvular atrial fibrillation’
by C. Fatini et al., on page 1712
Atrial fibrillation (AF) commonly occurs in the context of structural heart disease and is accompanied by atrial remodelling. The latter refers to any change in atrial function that promotes AF or occurs as a consequence of the arrhythmia.1 Atrial remodelling in the aged heart and during heart failure is characterized by pronounced fibrosis leading to heterogeneous slowing conduction of and prolongation of effective refractory period (ERP). In contrast, atrial remodelling induced by tachycardia is associated with shorter ERP and impaired rate adaptation. Nevertheless, atrial remodelling cannot be an absolute prerequisite for AF because the arrhythmia may also occur in structurally normal hearts, alluding to the existence of acquired or genetically determined predisposing factors. Current knowledge of the molecular identity of the predisposing factors is, however, limited.
Fatini et al.2 provide evidence that susceptibility to non-valvular AF (NVAF) may be enhanced in association with certain single nucleotide polymorphisms in the genes encoding the accessory K+ channel subunit minK and the endothelial nitric oxide synthase (eNOS). They studied a serine to glycine exchange in position 38 of minK protein (minK S38G) and several polymorphisms in the eNOS gene including G894T nucleotide exchange in exon 7, a T/C exchange in the promoter region (–T786C), and the eNOS 4a/4b polymorphism. In more than 300 consecutive patients with NVAF, distribution of allele frequencies for minK S38G and eNOS –T 786C, but not for eNOS G894T and 4a/4b polymorphisms, was significantly different when compared with healthy volunteers. However, only the minK 38G allele was significantly associated with enhanced susceptibility to NVAF. Interestingly, the contemporary presence of minK 38G and eNOS –786C alleles resulted in stronger predisposition for NVAF than the minK gene variant alone. Do these findings contribute to a better understanding of the mechanisms for AF?
Interaction of the minK (KCNE1) protein with the pore-forming K+ channel subunits KvLQT1 (KCNQ1) and HERG (KCNH2) enhances activity of the slow (IKs) and rapid (IKr) component, respectively, of delayed rectifier potassium current. If KvLQT1 is co-expressed with minK 38G instead of minK S38, the amplitude of IKs is reduced without alterations in current kinetics.3 Provided that native atrial channels containing minK 38G behave similarly, the presence of the minK 38G variant will prolong the action potential (AP).3 Prolongation of atrial AP in patients with long QT syndrome is associated with higher incidence of polymorphic atrial tachyarrhythmias.4 In analogy, the presence of minK 38G could predispose to the initiation of AF. In contrast, protein levels of minK are low in patients with chronic AF,5 and mice that lack minK protein develop spontaneous episodes of AF associated with high IKs amplitudes and short atrial AP.6 Possible explanations for these apparently contradictory findings are unconcealed differences between heterologous expression systems and native atrial myocytes, accumulation of abnormal IKs current at high atrial rates, or interaction of KvLQT1 with other accessory subunits in native cells.6 Ion channels and their subunits are generally accepted to be organized as macromolecular complexes including regulatory proteins. Hence, by assembling with additional proteins, minK may influence function of large molecular complexes and genetically determined variant of the subunit could produce an arrhythmogenic substrate that promotes the initiation of AF. Thus, the minK-associated alterations in atrial function are complex and may predispose to NVAF even via mechanisms unrelated to IKs function.
NO modulates cardiac function by nitrosylation of target proteins and by increasing cyclic guanosine monophosphate production,7 which in turn enhances activation of L-type Ca2+ channels.8 Conversely, reduced NO production may result in less Ca2+ influx via L-type Ca2+ channels and hence the shortening of atrial AP. In the presence of the eNOS –786C allele, eNOS promoter activity is halved leading to low eNOS expression and reduced cellular NO production. Short AP due to low NO level could contribute to the associated predisposition for NV-AF in conjunction with minK 38G allele. In pigs, development of AF is in fact associated with decreased eNOS activity.9
As part of the ryanodine receptor Ca2+ channel (RYR2) complex, eNOS modulates intracellular Ca2+ concentration, because NO decreases the open probability of RYR2 via channel nitrosylation.10 In patients with AF, RYR2 become ‘leaky’,11 which is consistent with low NO production and RYR2 Ca2+ release unopposed by nitrosylation. Diastolic Ca2+ leak from RYR2 induces late after-depolarizations that trigger AF. In support of this hypothesis eNOS-deficient mice exhibit increased susceptibility to triggered activity mediated by late after-depolarizations.12 Finally, reduced NO release into the coronary circulation of eNOS –786C allele carriers promotes severe coronary spasm.13 As coronary artery disease is a significant risk factor for AF and acute atrial ischaemia triggers AF in dogs,14 episodes of acute ischaemia may contribute to predisposing eNOS –786C allele carriers to AF.
Although the study of Fatini et al.2 do not address the cellular mechanisms of increased susceptibility to NVAF in minK 38G and eNOS –786C allele carriers, they provide strong evidence that genetic variants in these regulator proteins may promote the induction of NVAF. Currently, our understanding of the causative mechanisms of AF is incomplete. The identification of susceptibility genes for AF induction may help to identify subjects at risk for AF development.
Acknowledgements
The authors' research is supported by the German Federal Ministry of Education and Research (BMBF) through the Atrial Fibrillation Competence NETwork (AFNET, project C4 to D.D., grant 01Gi0204), the Deutsche Forschungsgemeinschaft (DOB 769/1-1, 2) and Roland Ernst Stiftung für Gesundheitswesen.
Conflict of interest: the authors have no conflict of interest.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehl087 
References
- Nattel S. (2002) New ideas about atrial fibrillation 50 years on. Nature 415:219–226.[CrossRef][Medline]
- Fatini C, Sticchi E, Genuardi M, Sofi F, Gensini F, Gori AM, Lenti M, Michelucci A, Abbate R, Genuini GF. (2006) Analysis of minK and eNOS genes as candidate loci for predisposition to non valvular atrial fibrillation. Eur Heart J 27:1712–1718 First published on June 7, 2006, doi:10.1093/eurheartj/ehl087.
[Abstract/Free Full Text] - Ehrlich JR, Zicha S, Coutu P, Hebert TE, Nattel S. (2005) Atrial fibrillation-associated minK38G/S polymorphism modulates delayed rectifier current and membrane localization. Cardiovasc Res 67:520–528.
[Abstract/Free Full Text] - Kirchhof P, Eckardt L, Franz MR, Monnig G, Loh P, Wedekind H, Schulze-Bahr E, Breithardt G, Haverkamp W. (2003) Prolonged atrial action potential durations and polymorphic atrial tachyarrhythmias in patients with long QT syndrome. J Cardiovasc Electrophysiol 14:1027–1033.[CrossRef][Web of Science][Medline]
- 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.
[Abstract/Free Full Text] - Temple J, Frias P, Rottman J, Yang T, Wu Y, Verheijck EE, Zhang W, Siprachanh C, Kanki H, Atkinson JB, King P, Anderson ME, Kupershmidt S, Roden DM. (2005) Atrial fibrillation in KCNE1-null mice. Circ Res 97:62–69.
[Abstract/Free Full Text] - Saraiva RM and Hare JM. (2006) Nitric oxide signaling in the cardiovascular system: implications for heart failure. Curr Opin Cardiol 21:221–228.[Web of Science][Medline]
- Kirstein M, Rivet-Bastide M, Hatem S, Benardeau A, Mercadier JJ, Fischmeister R. (1995) Nitric oxide regulates the calcium current in isolated human atrial myocytes. J Clin Invest 95:794–802.[Web of Science][Medline]
- Cai H, Li Z, Goette A, Mera F, Honeycutt C, Feterik K, Wilcox JN, Dudley SC Jr, Harrison DG, Langberg JJ. (2002) Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: potential mechanisms for atrial thrombosis and stroke. Circulation 106:2854–2858.
[Abstract/Free Full Text] - Zahradnikova A, Minarovic I, Venema RC, Meszaros LG. (1997) Inactivation of the cardiac ryanodine receptor calcium release channel by nitric oxide. Cell Calcium 22:447–454.[CrossRef][Web of Science][Medline]
- 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.
[Abstract/Free Full Text] - Kubota I, Han X, Opel DJ, Zhao YY, Baliga R, Huang P, Fishman MC, Shannon RP, Michel T, Kelly RA. (2000) Increased susceptibility to development of triggered activity in myocytes from mice with targeted disruption of endothelial nitric oxide synthase. J Mol Cell 32:1239–1248.
- Nakayama M, Yoshimura M, Sakamoto T, Abe K, Yamamuro M, Shono M, Suzuki S, Nishijima T, Miyamoto Y, Saito Y, Nakao K, Yasue H, Ogawa H. (2006) A -786T>C polymorphism in the endothelial nitric oxide synthase gene reduces serum nitrite/nitrate levels from the heart due to an intracoronary injection of acetylcholine. Pharmacogenetics 16:339–345.
- Sinno H, Derakhchan K, Libersan D, Merhi Y, Leung TK, Nattel S. (2003) Atrial ischemia promotes atrial fibrillation in dogs. Circulation 107:1930–1936.
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Related articles in EHJ:
- Analysis of minK and eNOS genes as candidate loci for predisposition to non-valvular atrial fibrillation
- Cinzia Fatini, Elena Sticchi, Maurizio Genuardi, Francesco Sofi, Francesca Gensini, Anna Maria Gori, Meri Lenti, Antonio Michelucci, Rosanna Abbate, and Gian Franco Gensini
EHJ 2006 27: 1712-1718.[Abstract] [FREE Full Text]
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