UNLABELLED: Previous studies have shown that two linked polymorphisms within regulatory regions of the gene for connexin40 (Cx40), at nucleotides -44 (G --> A) and +71 (A --> G) occur in about 7% of the general population. Cx40 is abundant in the atrium, and homozygosity for the linked polymorphisms combined with an SCN5A mutation appeared to be responsible for familial atrial standstill. We hypothesized that these polymorphisms are associated with the atrial electrophysiologic substrate favoring reentrant mechanisms for initiation of atrial fibrillation (AF). Reentry is promoted by spatial dispersion of refractoriness that can be expressed as a coefficient of dispersion (CD). METHODS: CD was calculated from the standard deviation of 12 local mean fibrillatory intervals recorded at right atrial sites during induced AF in 30 patients without structural heart disease (14 sporadic AF episodes, 16 no AF history). CD <or= 3.0 was considered normal. Cx40 genotypes were determined by DNA sequencing. RESULTS: Mean CD in AF patients was 5.96 +/- 0.70 and without AF 1.59 +/- 0.18 (p < 0.001). Thirteen of fourteen patients with AF had enhanced CD. Carriers of -44 AA genotype had higher CD compared with those with -44 GG genotype (6.37 +/- 1.21 vs. 2.38 +/- 0.39, p = 0.018), whereas heterozygotes showed intermediate values (3.95 +/- 1.38, NS). CONCLUSION: The rare linked Cx40 polymorphisms are associated with enhanced CD and thus with the substrate for reentry in AF.
UNLABELLED: Previous studies have shown that two linked polymorphisms within regulatory regions of the gene for connexin40 (Cx40), at nucleotides -44 (G --> A) and +71 (A --> G) occur in about 7% of the general population. Cx40 is abundant in the atrium, and homozygosity for the linked polymorphisms combined with an SCN5A mutation appeared to be responsible for familial atrial standstill. We hypothesized that these polymorphisms are associated with the atrial electrophysiologic substrate favoring reentrant mechanisms for initiation of atrial fibrillation (AF). Reentry is promoted by spatial dispersion of refractoriness that can be expressed as a coefficient of dispersion (CD). METHODS:CD was calculated from the standard deviation of 12 local mean fibrillatory intervals recorded at right atrial sites during induced AF in 30 patients without structural heart disease (14 sporadic AF episodes, 16 no AF history). CD <or= 3.0 was considered normal. Cx40 genotypes were determined by DNA sequencing. RESULTS: Mean CD in AFpatients was 5.96 +/- 0.70 and without AF 1.59 +/- 0.18 (p < 0.001). Thirteen of fourteen patients with AF had enhanced CD. Carriers of -44 AA genotype had higher CD compared with those with -44 GG genotype (6.37 +/- 1.21 vs. 2.38 +/- 0.39, p = 0.018), whereas heterozygotes showed intermediate values (3.95 +/- 1.38, NS). CONCLUSION: The rare linked Cx40 polymorphisms are associated with enhanced CD and thus with the substrate for reentry in AF.
Authors: Eliseo A Eugenin; Daniel Basilio; Juan C Sáez; Juan A Orellana; Cedric S Raine; Feliksas Bukauskas; Michael V L Bennett; Joan W Berman Journal: J Neuroimmune Pharmacol Date: 2012-03-23 Impact factor: 4.147
Authors: Luc Leybaert; Paul D Lampe; Stefan Dhein; Brenda R Kwak; Peter Ferdinandy; Eric C Beyer; Dale W Laird; Christian C Naus; Colin R Green; Rainer Schulz Journal: Pharmacol Rev Date: 2017-10 Impact factor: 25.468
Authors: Heather C Mefford; Andrew J Sharp; Carl Baker; Andy Itsara; Zhaoshi Jiang; Karen Buysse; Shuwen Huang; Viv K Maloney; John A Crolla; Diana Baralle; Amanda Collins; Catherine Mercer; Koen Norga; Thomy de Ravel; Koen Devriendt; Ernie M H F Bongers; Nicole de Leeuw; William Reardon; Stefania Gimelli; Frederique Bena; Raoul C Hennekam; Alison Male; Lorraine Gaunt; Jill Clayton-Smith; Ingrid Simonic; Soo Mi Park; Sarju G Mehta; Serena Nik-Zainal; C Geoffrey Woods; Helen V Firth; Georgina Parkin; Marco Fichera; Santina Reitano; Mariangela Lo Giudice; Kelly E Li; Iris Casuga; Adam Broomer; Bernard Conrad; Markus Schwerzmann; Lorenz Räber; Sabina Gallati; Pasquale Striano; Antonietta Coppola; John L Tolmie; Edward S Tobias; Chris Lilley; Lluis Armengol; Yves Spysschaert; Patrick Verloo; Anja De Coene; Linde Goossens; Geert Mortier; Frank Speleman; Ellen van Binsbergen; Marcel R Nelen; Ron Hochstenbach; Martin Poot; Louise Gallagher; Michael Gill; Jon McClellan; Mary-Claire King; Regina Regan; Cindy Skinner; Roger E Stevenson; Stylianos E Antonarakis; Caifu Chen; Xavier Estivill; Björn Menten; Giorgio Gimelli; Susan Gribble; Stuart Schwartz; James S Sutcliffe; Tom Walsh; Samantha J L Knight; Jonathan Sebat; Corrado Romano; Charles E Schwartz; Joris A Veltman; Bert B A de Vries; Joris R Vermeesch; John C K Barber; Lionel Willatt; May Tassabehji; Evan E Eichler Journal: N Engl J Med Date: 2008-09-10 Impact factor: 91.245