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Hostrup A.,Copenhagen University | Christensen G.L.,Glostrup Research Institute | Christensen G.L.,Neurosearch | Christensen G.L.,Laboratory for Molecular Cardiology | And 14 more authors.
Cellular Physiology and Biochemistry | Year: 2012

Angiotensin II (AngII) is a key peptide in cardiovascular homeostasis and is a ligand for the Angiotensin II type 1 and 2 seven transmembrane receptors (AT1R and AT2R). The AT1receptor is a seven-transmembrane (7TM) G protein-coupled receptor (GPCR) mediating the majority of the physiological functions of AngII. The AT1R mediates its effects through both G protein-dependent and independent signaling, which can be separated by functionally selective agonists. In the present study we investigate the effect of AngII and the β-arrestin biased agonist [SII]AngII on ischemia-reperfusion injury in rat hearts. Isolated hearts mounted in a Langendorff perfused rat heart preparations showed that preconditioning with [SII]AngII reduced the infarct size induced by global ischemia from 46±8.4% to 22±3.4%. In contrast, neither preconditioning with AngII nor postconditioning with AngII or [SII]AngII had a protective effect. Together these results demonstrate a cardioprotective effect of simultaneous blockade of G protein signaling and activation of G protein independent signaling through AT1receptors. Copyright © 2012 S. Karger AG, Basel.

Andreasen L.,Danish National Research Foundation Center for Cardiac Arrhythmia | Andreasen L.,Laboratory for Molecular Cardiology | Andreasen L.,Copenhagen University | Nielsen J.B.,Danish National Research Foundation Center for Cardiac Arrhythmia | And 15 more authors.
Canadian Journal of Cardiology | Year: 2013

Background: Both shortening and prolongation of the QTc interval have been associated with atrial fibrillation (AF). We investigated whether 8 single nucleotide polymorphisms (SNPs) at loci previously shown to affect QTc interval duration were associated with lone AF. Methods: We included 358 patients diagnosed with lone AF (defined as onset of AF at < 50 years of age in the absence of traditional cardiovascular risk factors) and a control group consisting of 751 individuals free of AF. The 8 loci were genotyped using TaqMan assays. Genotype frequencies in lone AF cases and controls were compared using an additive logistic regression model. Results: Risk of the development of early-onset lone AF in individuals homozygous for the variant rs2968863 (7q36.1) was higher than in individuals with no copies of the risk allele (odds ratio [OR], 2.40; P= 0.001). The association was also significant after Bonferroni correction (P= 0.016). This polymorphism has been shown to decrease the QTc interval by 1.4 ms in genome-wide association studies (GWAS). The genetic variant is situated close to the long QT syndrome (LQTS) type 2gene KCNH2 that encodes the potassium channel Kv11.1 (hERG). Sanger sequencing of KCNH2 confirmed the known high linkage disequilibrium between rs2968863 and the nonsynonymous variant K897T in KCNH2. No novel mutations were found in the gene. Conclusions: The variant rs2968863 (7q36.1), reported in GWAS to shorten the QTc interval, was found to be associated with early-onset lone AF. This may have implications for the pathophysiological understanding of AF. © 2013 Canadian Cardiovascular Society.

Jabbari J.,Copenhagen University | Jabbari J.,Laboratory for Molecular Cardiology | Olesen M.S.,Copenhagen University | Olesen M.S.,Laboratory for Molecular Cardiology | And 19 more authors.
Circulation: Cardiovascular Genetics | Year: 2015

Background - Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r2=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. Methods and Results - SCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16-1.54]; P=2.3×10-5). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. Conclusions - The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF. © 2015 American Heart Association, Inc.

Nielsen J.B.,Danish National Research Foundation Center for Cardiac Arrhythmia | Nielsen J.B.,Laboratory for Molecular Cardiology | Graff C.,University of Aalborg | Pietersen A.,Copenhagen General Practitioners Laboratory | And 14 more authors.
Journal of the American College of Cardiology | Year: 2013

Objectives The aim of this study was to investigate whether the heart rate-corrected QT (QTc) interval on the electrocardiogram (ECG) is associated with the onset of atrial fibrillation (AF). Background Patients with hereditary short-QT or long-QT syndromes, representing the very extremes of the QT interval, both seem to have a high prevalence of AF. Methods A total of 281,277 subjects were included, corresponding to one-third of the population of the greater region of Copenhagen. These subjects underwent digital ECG recordings in a general practitioner's core facility from 2001 to 2010. Data on drug use, comorbidities, and outcomes were collected from Danish registries. Results After a median follow-up period of 5.7 years, 10,766 subjects had developed AF, of whom 1,467 (14%) developed lone AF. Having a QTc interval lower than the first percentile (≤372 ms) was associated with a multivariate-adjusted hazard ratio of 1.45 (95% confidence interval: 1.14 to 1.84; p = 0.002) of AF, compared with the reference group (411 to 419 ms). From the reference group and upward, the risk of AF increased with QTc interval duration in a dose-response manner, reaching a hazard ratio of 1.44 (95% confidence interval: 1.24 to 1.66, p < 0.001) for those with QTc intervals ≥99th percentile (≥464 ms). The association with respect to longer QTc intervals was stronger for the outcome of lone AF, as evidenced by a hazard ratio of 2.32 (95% confidence interval: 1.52 to 3.54, p < 0.001) for having a QTc interval ≥99th percentile (≥458 ms). Conclusions In this large ECG study, a J-shaped association was found between QTc interval duration and risk of AF. This association was strongest with respect to the development of lone AF.© 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.

Olesen M.S.,Copenhagen University | Olesen M.S.,Laboratory for Molecular Cardiology | Jabbari J.,Copenhagen University | Jabbari J.,Laboratory for Molecular Cardiology | And 10 more authors.
Europace | Year: 2011

Aims: The aim of this study was to screen KCNN3 encoding the small-conductance calcium-activated K + channel (SK3) in lone atrial fibrillation patients. Atrial fibrillation (AF) is the most common cardiac arrhythmia. A genome-wide association study has recently associated an intronic single-nucleotide polymorphism (SNP) in KCNN3 with lone AF. Methods and results: We sequenced the coding region and splice junctions of KCNN3 in 209 early-onset lone AF patients, screening for variations. A group of 208 healthy blood donors with normal ECGs and without cardiac symptoms were used as controls. All patients and controls were of Danish ethnicity. No mutations were found in the coding regions or splice sites of KCNN3. We found one known exonic synonymous SNP (rs1131820) in KCNN3 that was associated with AF. Both the genotype distribution and allele frequencies of SNP rs1131820 were significantly different between the AF cases and controls (PGenotype= 0.047 and PAllele= 0.027). Being a homozygous carrier of the major allele (GG) vs. the minor allele (AA) of rs1131820 was associated with an odds ratio of 2.85 (95% CI 1.13-7.18, P = 0.026) for lone AF. Conclusions: In this study of 209 young lone AF patients, we found no mutations in the exons or splice sites of KCNN3, but we found an association between the synonymous SNP rs1131820 in KCNN3 and lone AF. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011.

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