-
Florian Rader,
Akshat C Pujara,
Gregory Pattakos,
Jeevanantham Rajeswaran,
Liang Li,
Laurie Castel,
Mina K Chung,
A Marc Gillinov,
Otto Costantini, David R Van Wagoner,
Eugene H Blackstone
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Postoperative atrial fibrillation (POAF) is common and associated with poor outcomes. Perioperative ischemia can alter arrhythmic substrate. OBJECTIVE: To demonstrate an association between perioperative measurement of heart-type fatty acid binding protein (HT-FABP), a sensitive marker of ischemic myocardial injury. METHODS: Blood samples from 63 inpatients undergoing coronary artery bypass surgery (CABG), valve surgery or both were obtained before and up to four days after surgery. Continuous telemetry monitoring was used to detect POAF. 59 patients had at least 3 HT-FABP measurements. The relation of ELISA-measured HT-FABP to POAF was assessed using joint logistic regression adjusted for age and surgery type. RESULTS: Thirty five patients (55%) developed POAF; these were on average older (69.3 ± 10 vs. 60 ± 11 years, p=0.0019), with a higher prevalence of heart failure (43% vs. 17%, p=0.034), chronic obstructive lung disease (26% vs. 4%, p=0.017), preoperative calcium channel blocker use (29% vs. 7%, p=0.031) and more likely to undergo combined surgery (21% vs. 11%, p=0.049). The joint age- and CABG-adjusted model revealed that postoperative but not preoperative HT-FABP levels predicted POAF (coefficient 1.9 ± 0.87, p=0.03). Longer bypass time, prior infarction and worse renal function were all associated with higher postoperative HT-FABP. CONCLUSIONS: A greater rise of HT-FABP is associated with atrial fibrillation after cardiac surgery, suggesting that ischemic myocardial damage is a contributing underlying mechanism. Interventions that decrease perioperative ischemic injury may also decrease the occurrence of POAF.
Heart rhythm: the official journal of the Heart Rhythm Society 10/2012; · 4.56 Impact Factor
-
Masahide Harada,
Xiaobin Luo,
Xiao Yan Qi,
Artavazd Tadevosyan,
Ange Maguy,
Balazs Ordog,
Jonathan Ledoux,
Takeshi Kato,
Patrice Naud,
Niels Voigt,
Yanfen Shi,
Kaichiro Kamiya,
Toyoaki Murohara,
Itsuo Kodama,
Jean-Claude Tardif,
Ulrich Schotten, David R Van Wagoner,
Dobromir Dobrev,
Stanley Nattel
[show abstract]
[hide abstract]
ABSTRACT: Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)-promoting remodeling. Here, we investigated fibroblast regulation by Ca(2+)-permeable transient receptor potential canonical-3 (TRPC3) channels.
Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents (I(NSC)) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L). Pyrazole-3 suppressed angiotensin II-induced Ca(2+) influx, proliferation, and α-smooth muscle actin protein expression in fibroblasts. Ca(2+) removal and TRPC3 blockade suppressed extracellular signal-regulated kinase phosphorylation, and extracellular signal-regulated kinase phosphorylation inhibition reduced fibroblast proliferation. TRPC3 expression was upregulated in atria from AF patients, goats with electrically maintained AF, and dogs with tachypacing-induced heart failure. TRPC3 knockdown (based on short hairpin RNA [shRNA]) decreased canine atrial fibroblast proliferation. In left atrial fibroblasts freshly isolated from dogs kept in AF for 1 week by atrial tachypacing, TRPC3 protein expression, currents, extracellular signal-regulated kinase phosphorylation, and extracellular matrix gene expression were all significantly increased. In cultured left atrial fibroblasts from AF dogs, proliferation rates, α-smooth muscle actin expression, and extracellular signal-regulated kinase phosphorylation were increased and were suppressed by pyrazole-3. MicroRNA-26 was downregulated in canine AF atria; experimental microRNA-26 knockdown reproduced AF-induced TRPC3 upregulation and fibroblast activation. MicroRNA-26 has NFAT (nuclear factor of activated T cells) binding sites in the 5' promoter region. NFAT activation increased in AF fibroblasts, and NFAT negatively regulated microRNA-26 transcription. In vivo pyrazole-3 administration suppressed AF while decreasing fibroblast proliferation and extracellular matrix gene expression.
TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca(2+) influx that activates extracellular signal-regulated kinase signaling. AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, TRPC3 blockade prevents AF substrate development in a dog model of electrically maintained AF. TRPC3 likely plays an important role in AF by promoting fibroblast pathophysiology and is a novel potential therapeutic target.
Circulation 09/2012; 126(17):2051-64. · 14.74 Impact Factor
-
Patrick T Ellinor,
Kathryn L Lunetta,
Christine M Albert,
Nicole L Glazer,
Marylyn D Ritchie,
Albert V Smith,
Dan E Arking,
Martina Müller-Nurasyid,
Bouwe P Krijthe,
Steven A Lubitz, [......],
Bruno H Ch Stricker,
Stephan B Felix,
Alvaro Alonso,
Dawood Darbar,
John Barnard,
Daniel I Chasman,
Susan R Heckbert,
Emelia J Benjamin,
Vilmundur Gudnason,
Stefan Kääb
[show abstract]
[hide abstract]
ABSTRACT: Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
Nature Genetics 04/2012; 44(6):670-5. · 35.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The left and right atria have different susceptibilities toward developing arrhythmias, with left atrial arrhythmias more commonly observed. To understand the molecular basis for such differences, we catalogued micro (mi)RNA and mRNA expression differences by next generation sequencing.
Four human left-right atrial pairs were subjected to whole-genome expression analyses via next-generation sequencing of small RNAs, including miRNAs, and poly-A-enriched mRNAs. Using a paired sample design, significant differences in the expression of 32 miRNAs were found in between the left and right atria at a probability value of <0.01. Hsa-miR-143 was the most highly expressed miRNA in the atria, as quantified by RNA sequencing. There were 746 and 2292 differentially expressed mRNAs between the left and right atria at false discovery rates of <0.001 and <0.05, respectively. Transcription factor binding elements within 2 kb of RefSeq genes were determined and specific motifs were identified that were enriched in differentially expressed genes. Similarly, specific miRNA target sequences in 3' UTRs were also enriched in differentially expressed genes. In addition, 11 novel noncoding RNAs of unknown function were found to be differentially expressed between the left and right atria.
There are significant differences in miRNA and mRNA expression profiles between the left and right atria, which may yield insight into increased the arrhythmogenesis of the left atria.
Circulation Cardiovascular Genetics 04/2012; 5(3):327-35. · 6.11 Impact Factor
-
The Canadian journal of cardiology 02/2012; 28(2):158-9. · 3.36 Impact Factor
-
Christine M Albert,
Peng-Sheng Chen,
Mark E Anderson,
Michael E Cain,
Glenn I Fishman,
Sanjiv M Narayan,
Jeffrey E Olgin,
Peter M Spooner,
William G Stevenson, David R Van Wagoner,
Douglas L Packer
Heart rhythm: the official journal of the Heart Rhythm Society 12/2011; 8(12):1992-3. · 4.56 Impact Factor
-
Christine M Albert,
Peng-Sheng Chen,
Mark E Anderson,
Michael E Cain,
Glenn I Fishman,
Sanjiv M Narayan,
Jeffrey E Olgin,
Peter M Spooner,
William G Stevenson, David R Van Wagoner,
Douglas L Packer
Heart rhythm: the official journal of the Heart Rhythm Society 10/2011; 8(12):e1-12. · 4.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Despite having fewer risk factors for atrial fibrillation (AF), white patients have a greater prevalence of AF in the community than black patients, and a genetic basis has been postulated. However, it is unknown whether occurrence of new-onset AF after cardiac surgery is different in white versus black patients, and secondarily, other non-Caucasian patients.
From 1995 through 2005, 20 282 white, 1323 black, and 1919 other non-Caucasian patients in sinus rhythm underwent coronary artery bypass grafting with or without valve surgery. To adjust for clinical and socioeconomic confounders, we performed propensity-adjusted analyses; 7093 white patients (35%) had postoperative AF, compared with 255 (22%) black patients and 550 (29%) other non-Caucasians (P<0.0001). Whites were older than black patients, had higher socioeconomic position, and greater left atrial size but were less likely to have hypertension or congestive heart failure. In 847 propensity-matched patient pairs, postoperative AF occurred more frequently in white than in black patients (odds ratio, 1.74; 95% confidence interval, 1.7-1.78). Other than higher occurrence of bradycardia requiring pacing and reintubation in white patients, occurrence of other postoperative complications, hospital mortality, and length of postoperative stay were similar. Age and valvular surgery were the strongest predictors of AF irrespective of race.
White patients had a markedly higher risk of postoperative AF than black and other non-Caucasian patients. The cause for racial differences of arrhythmic risk is unknown, but a genetic predisposition is plausible. Our results have implications for risk stratification and mechanistic understanding of postoperative AF.
Circulation Arrhythmia and Electrophysiology 08/2011; 4(5):644-52. · 6.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Pathological conditions such as diabetes, insulin resistance, and obesity are characterized by elevated plasma and myocardial lipid levels and have been reported to exacerbate the progression of heart failure (HF). Alterations in cardiomyocyte Ca(2+) regulatory properties and myofilament proteins have also been implicated in contractile dysfunction in HF. However, our prior studies reported that high saturated fat (SAT) feeding improves in vivo myocardial contractile function, thereby exerting a cardioprotective effect in HF. Therefore, we hypothesized that SAT feeding improves contractile function by altering Ca(2+) regulatory properties and myofilament protein expression in HF. Male Wistar rats underwent coronary artery ligation (HF) or sham surgery (SH) and were fed normal chow (SHNC and HFNC groups) or a SAT diet (SHSAT and HFSAT groups) for 8 wk. Contractile properties were measured in vivo [echocardiography and left ventricular (LV) cannulation] and in isolated LV cardiomyocytes. In vivo measures of contractility (peak LV +dP/dt and -dP/dt) were depressed in the HFNC versus SHNC group but improved in the HFSAT group. Isolated cardiomyocytes from both HF groups were hypertrophied and had decreased percent cell shortening and a prolonged time to half-decay of the Ca(2+) transient versus the SH group; however, SAT feeding reduced in vivo myocyte hypertrophy in the HFSAT group only. The peak velocity of cell shortening was reduced in the HFNC group but not the HFSAT group and was positively correlated with in vivo contractile function (peak LV +dP/dt). The HFNC group demonstrated a myosin heavy chain (MHC) isoform switch from fast MHC-α to slow MHC-β, which was prevented in the HFSAT group. Alterations in Ca(2+) transients, L-type Ca(2+) currents, and protein expression of sarco(endo)plasmic reticulum Ca(2+)-ATPase and phosphorylated phospholamban could not account for the changes in the in vivo contractile properties. In conclusion, the cardioprotective effects associated with SAT feeding in HF may occur at the level of the isolated cardiomyocyte, specifically involving changes in myofilament function but not sarcoplasmic reticulum Ca(2+) regulatory properties.
AJP Heart and Circulatory Physiology 07/2011; 301(4):H1438-46. · 3.71 Impact Factor
-
N A Mark Estes,
Ralph L Sacco,
Sana M Al-Khatib,
Patrick T Ellinor,
Judy Bezanson,
Alvaro Alonso,
Charles Antzelevitch,
Randall G Brockman,
Peng-Sheng Chen,
Sumeet S Chugh, [......],
Richard Lee,
Douglas L Packer,
Sunny S Po,
Eric N Prystowsky,
Susan Redline,
Yves Rosenberg, David R Van Wagoner,
Kathryn A Wood,
Lixia Yue,
Emelia J Benjamin
Circulation 06/2011; 124(3):363-72. · 14.74 Impact Factor
-
Nature Reviews Cardiology 03/2011; 8(3):126-8. · 8.83 Impact Factor
-
Fadia Mayyas,
Seiichiro Sakurai,
Rashmi Ram,
Julie H Rennison,
Eui-Seock Hwang,
Laurie Castel,
Beth Lovano,
Marie-Luise Brennan,
Douglas Bibus,
Bill Lands,
John Barnard,
Mina K Chung, David R Van Wagoner
[show abstract]
[hide abstract]
ABSTRACT: Pre-treatment with dietary ω3 polyunsaturated fatty acids (ω3-PUFA) has been reported to reduce the incidence of new-onset atrial fibrillation (AF) following cardiac surgery. In a canine cardiac surgery model, we evaluated the impact of dietary ω3-PUFA on atrial electrophysiological properties, inflammatory markers, the atrial endothelin-1 (ET-1) system, and the expression and distribution of connexin 43.
Adult mongrel dogs received either normal chow (NC, n = 11) or chow supplemented with fish oil (FO, 0.6 g ω3-PUFA/kg/day, n = 9) for 3 weeks before surgery. A left thoracotomy was performed, and the left atrial appendage (LAA) was excised. Atrial pacing/recording wires were placed, and the pericardium/chest was closed. The atrial ratio of ω6/ω3 lipids decreased from 15-20 in NC to 2-3 in FO. FO treatment lowered pre-surgical and stabilized post-surgical arachidonate levels. Peak neutrophil to lymphocyte ratio was lower and decayed faster in FO-treated animals. Extensive inflammatory cell infiltration was present in NC atria, but was reduced in FO-treated dogs. FO-treated animals had lower post-surgical atrial expression of inducible nitric oxide synthase (iNOS) and reduced plasma ET-1. Expression of ET-1 and inositol trisphosphate receptor type-2 proteins in the LAA was also reduced. FO treatment prolonged post-operative atrial effective refractory period, slowed heart rate, and enhanced heart rate variability. Importantly, AF (>30 s) was inducible in four of six NC dogs, but no FO dogs.
Dietary FO attenuated AF inducibility following cardiac surgery by modulating autonomic tone and heart rate. FO also reduced atrial inflammation, iNOS, and ET-1 expression.
Cardiovascular research 03/2011; 89(4):852-61. · 5.80 Impact Factor
-
David R Van Wagoner
European Heart Journal 11/2010; 32(7):788-90. · 10.48 Impact Factor
-
Robert C Wirka,
Shamone Gore, David R Van Wagoner,
Dan E Arking,
Steven A Lubitz,
Kathryn L Lunetta,
Emelia J Benjamin,
Alvaro Alonso,
Patrick T Ellinor,
John Barnard,
Mina K Chung,
Jonathan D Smith
[show abstract]
[hide abstract]
ABSTRACT: A common single-nucleotide polymorphism (SNP) in the promoter of the Connexin-40 (Cx40) gene GJA5 was suggested to affect Cx40 promoter activity and the risk of atrial fibrillation (AF), but the role of other common Cx40 polymorphisms is unknown.
Eight SNPs within the Cx40 gene region were tested for association with Cx40 levels measured in atrial tissue from 61 individuals. The previously described Cx40 promoter SNP (rs35594137, -44G→A) was not associated with Cx40 mRNA levels. However, a common SNP (rs10465885) located in the TATA box of an alternative Cx40 promoter was strongly associated with Cx40 mRNA expression (P<0.0001) and displayed strong and consistent allelic expression imbalance in human atrial tissue. A promoter-luciferase assay in cultured murine cardiomyocytes demonstrated reduced activity of the promoter containing the minor allele of this SNP (P<0.0001). Both rs35594137 and rs10465885 were tested for association with early-onset lone AF (≤60 years of age) in 384 cases and 3010 population control subjects. rs10465885 was associated with the AF phenotype (odds ratio, 1.18; P=0.046). This result was confirmed in a meta-analysis including 2 additional early-onset lone AF case-control cohorts (odds ratio, 1.16, P=0.022). rs35594137 was not associated with the lone AF phenotype in any of the cohorts studied or in a combined analysis.
A previously described Cx40 promoter SNP was not found to influence Cx40 expression or risk of AF. We describe an alternate promoter polymorphism that directly affects levels of Cx40 mRNA in vivo and is associated with early-onset lone AF.
Circulation Arrhythmia and Electrophysiology 11/2010; 4(1):87-93. · 6.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Atrial fibrillation (AF) promotes atrial remodeling and can develop secondary to heart failure or mitral valve disease. Cardiac endothelin-1 (ET-1) expression responds to wall stress and can promote myocyte hypertrophy and interstitial fibrosis. We tested the hypothesis that atrial ET-1 is elevated in AF and is associated with AF persistence.
Left atrial appendage tissue was studied from coronary artery bypass graft, valve repair, and/or Maze procedure in patients in sinus rhythm with no history of AF (SR, n=21), with history of AF but in SR at surgery (AF/SR, n=23), and in AF at surgery (AF/AF, n=32). The correlation of LA size with atrial protein and mRNA expression of ET-1 and ET-1 receptors (ETAR and ETBR) was evaluated. LA appendage ET-1 content was higher in AF/AF than in SR, but receptor levels were similar. Immunostaining revealed that ET-1 and its receptors were present both in atrial myocytes and in fibroblasts. ET-1 content was positively correlated with LA size, heart failure, AF persistence, and severity of mitral regurgitation. Multivariate analysis confirmed associations of ET-1 with AF, hypertension, and LA size. LA size was associated with ET-1 and MR severity. ET-1 mRNA levels were correlated with genes involved in cardiac dilatation, hypertrophy, and fibrosis.
Elevated atrial ET-1 content is associated with increased LA size, AF rhythm, hypertension, and heart failure. ET-1 is associated with atrial dilatation, fibrosis, and hypertrophy and probably contributes to AF persistence. Interventions that reduce atrial ET-1 expression and/or block its receptors may slow AF progression.
Circulation Arrhythmia and Electrophysiology 08/2010; 3(4):369-79. · 6.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Preoperative use of angiotensin-blocking drug therapy (ABDT) with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and its link to occurrence of postoperative atrial fibrillation (POAF), a common marker of poor outcomes after cardiac surgery, remain controversial.
From 1997 to 2003, 10,552 patients underwent coronary artery bypass grafting with or without valve surgery. To adjust for differences of clinical characteristics between patients who received ABDT within 24 hours before surgery compared with those who did not, propensity score analyses were conducted.
Angiotensin-blocking drug therapy was prescribed in 4,795 (45%) before surgery, of which 1,725 (36%) developed POAF before discharge versus 1,908 (33%) of 5,757 patients who did not receive ABDT (unadjusted odds ratio 1.13, 95% CI 1.05-1.25, P < .01). In 6,744 propensity score-matched patients with well-balanced comorbidity profiles, ABDT was not associated with POAF (odds ratio 1.05, CI 0.95-1.16, P = .38). Stratified analysis within quintiles of propensity score and propensity-adjusted logistic multivariable regression confirmed these findings.
In this large observational study, we found no evidence of an association between preoperative angiotensin blockade and the occurrence of POAF. Adequately powered randomized studies are needed to clarify the best strategy of perioperative ABDT in patients with and without guideline-based indications.
American heart journal 08/2010; 160(2):329-336.e1. · 4.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Atrial fibrillation (AF) has been linked to inflammatory factors and obesity. Epicardial fat is a source of several inflammatory mediators related to the development of coronary artery disease. We hypothesized that periatrial fat may have a similar role in the development of AF.
Left atrium (LA) epicardial fat pad thickness was measured in consecutive cardiac CT angiograms performed for coronary artery disease or AF. Patients were grouped by AF burden: no (n=73), paroxysmal (n=60), or persistent (n=36) AF. In a short-axis view at the mid LA, periatrial epicardial fat thickness was measured at the esophagus (LA-ESO), main pulmonary artery, and thoracic aorta; retrosternal fat was measured in axial view (right coronary ostium level). LA area was determined in the 4-chamber view. LA-ESO fat was thicker in patients with persistent AF versus paroxysmal AF (P=0.011) or no AF (P=0.003). LA area was larger in patients with persistent AF than paroxysmal AF (P=0.004) or without AF (P<0.001). LA-ESO was a significant predictor of AF burden even after adjusting for age, body mass index, and LA area (odds ratio, 5.30; 95% confidence interval, 1.39 to 20.24; P=0.015). A propensity score-adjusted multivariable logistic regression that included age, body mass index, LA area, and comorbidities was also performed and the relationship remained statistically significant (P=0.008).
Increased posterior LA fat thickness appears to be associated with AF burden independent of age, body mass index, or LA area. Further studies are necessary to examine cause and effect, and if inflammatory, paracrine mediators explain this association.
Circulation Arrhythmia and Electrophysiology 06/2010; 3(3):230-6. · 6.46 Impact Factor
-
Patrick T Ellinor,
Kathryn L Lunetta,
Nicole L Glazer,
Arne Pfeufer,
Alvaro Alonso,
Mina K Chung,
Moritz F Sinner,
Paul I W de Bakker,
Martina Mueller,
Steven A Lubitz, [......],
Bruce M Psaty,
Dan M Roden,
Thomas Meitinger,
H-Erich Wichmann,
Jacqueline C M Witteman,
John Barnard,
Dan E Arking,
Emelia J Benjamin,
Susan R Heckbert,
Stefan Kääb
[show abstract]
[hide abstract]
ABSTRACT: Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.
Nature Genetics 02/2010; 42(3):240-4. · 35.53 Impact Factor
-
Arne Pfeufer,
Charlotte van Noord,
Kristin D Marciante,
Dan E Arking,
Martin G Larson,
Albert Vernon Smith,
Kirill V Tarasov,
Martina Müller,
Nona Sotoodehnia,
Moritz F Sinner, [......],
Thomas Meitinger,
Daniel Levy,
Vilmundur Gudnason,
Patrick T Ellinor,
Serena Sanna,
Stefan Kääb,
Jacqueline C M Witteman,
Alvaro Alonso,
Emelia J Benjamin,
Susan R Heckbert
[show abstract]
[hide abstract]
ABSTRACT: The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.
Nature Genetics 02/2010; 42(2):153-9. · 35.53 Impact Factor
-
Circulation Arrhythmia and Electrophysiology 08/2009; 2(4):460-9. · 6.46 Impact Factor
