angiotensinogen and Atrial-Fibrillation

The M235T polymorphism in the angiotensinogen gene has been reported to be associated with the development of atrial fibrillation (AF).However, results from observational studies are conflicting.. PubMed, google scholar and China National Knowledge Infrastructure database(2000.1-2013.4) were searched for eligible articles; four separate studies with 2580 subjects on the relationship between M235T polymorphism and AF were analyzed by meta-analysis. The associations between M235T polymorphism and AF risk were estimated by pooled odds ratio (OR) and 95% confidence interval (CI) using a fixed or random-effects model.. There was a significant association between M235T polymorphism and AF. The pooled OR for the recessive model in the total population was 2.17 (95% CI: 1.39-3.38, I(2)=0%). In a subgroup analysis by nationality, the pooled OR for TT vs. MM genotype was 0.55 (95% CI: 0.32-0.95, I(2)=0%) and the pooled OR for the recessive model was 1.86 (95% CI: 1.08-3.20, I(2)=0%) in Asians.. The current meta-analysis suggested that the M235T polymorphism in the angiotensinogen gene might be related to the increased risk of AF in Asians. Conclusive evidence on the effects of the variants in AF should be addressed in further studies.

Topics: Angiotensinogen; Atrial Fibrillation; Confidence Intervals; Genes, Recessive; Genetic Heterogeneity; Genetic Predisposition to Disease; Humans; Odds Ratio; Polymorphism, Single Nucleotide; Publication Bias

Heart chymase rather than angiotensin (Ang)-converting enzyme has higher specificity for Ang I conversion into Ang II in humans. A new pathway for direct cardiac Ang II generation has been revealed through the demonstration that Ang-(1-12) is cleaved by chymase to generate Ang II directly. Herein, we address whether Ang-(1-12), chymase messenger RNA (mRNA), and activity levels can be differentiated in human atrial tissue from normal and diseased hearts and if these measures associate with various pathologic heart conditions.. Atrial appendages were collected from 11 nonfailing donor hearts and 111 patients undergoing heart surgery for the correction of valvular heart disease, resistant atrial fibrillation, or ischemic heart disease. Chymase mRNA was analyzed by real-time polymerase chain reaction and enzymatic activity by high-performance liquid chromatography using Ang-(1-12) as the substrate. Ang-(1-12) levels were determined by immunohistochemical staining.. Chymase gene transcripts, chymase activity, and immunoreactive Ang-(1-12) expression levels were higher in left atrial tissue compared with right atrial tissue, irrespective of cardiac disease. In addition, left atrial chymase mRNA expression was significantly higher in stroke versus nonstroke patients and in cardiac surgery patients who had a history of postoperative atrial fibrillation versus nonatrial fibrillation. Correlation analysis showed that left atrial chymase mRNA was positively related to left atrial enlargement, as determined by echocardiography.. As Ang-(1-12) expression and chymase gene transcripts and enzymatic activity levels were positively linked to left atrial size in patients with left ventricular heart disease, an important alternate Ang II forming pathway, via Ang-(1-12) and chymase, in maladaptive atrial and ventricular remodeling in humans is uncovered.

Topics: Aged; Angiotensinogen; Animals; Atrial Fibrillation; Chymases; Echocardiography; Female; Gene Expression Profiling; Heart Atria; Heart Valve Diseases; Heart Ventricles; Humans; Immunohistochemistry; Male; Middle Aged; Myocardial Ischemia; Peptide Fragments; RNA, Messenger; Stroke; Ventricular Remodeling

Heart chymase rather than angiotensin converting enzyme has higher specificity for angiotensin (Ang) I conversion into Ang II in humans. A new pathway for direct cardiac Ang II generation has been revealed through the demonstration that Ang-(1-12) is cleaved by chymase to generate Ang II directly. We address here whether Ang-(1-12) and chymase gene expression and activity are detected in the atrial appendages of 44 patients (10 females) undergoing heart surgery for the correction of valvular heart disease, resistant atrial fibrillation or ischemic heart disease.. Immunoreactive Ang-(1-12) expression was 54% higher in left atrial compared with right atrial appendages. This was associated with higher abundance of left atrial appendage chymase gene transcripts and chymase activity, but no differences in angiotensinogen mRNA. Atrial chymase enzymatic activity was highly correlated with left atrial but not right atrial enlargement as determined by echocardiography, while both tyrosine hydroxylase and neuropeptide Y atrial appendage mRNAs correlated with atrial angiotensinogen mRNAs.. Higher Ang-(1-12) expression and upregulation of chymase gene transcripts and enzymatic activity from the atrial appendages connected to the enlarged left versus right atrial chambers of subjects with left heart disease defines a role of this alternate Ang II forming pathway in the processes accompanying adverse atrial and ventricular remodeling.

Topics: Aged; Angiotensin I; Angiotensin II; Angiotensinogen; Atrial Fibrillation; Chymases; Echocardiography; Female; Gene Expression Regulation, Enzymologic; Heart Atria; Heart Valve Diseases; Humans; Male; Middle Aged; Myocardial Ischemia; RNA, Messenger; Up-Regulation; Ventricular Remodeling

Previous studies showed that genetic variants of the angiotensinogen (AGT) gene conferred higher risk for acquired atrial fibrillation (AF). The present study investigated whether AGT variants correlate with the clinical outcome in patients with acquired AF after catheter ablation (CA).. A total of 150 acquired symptomatic drug-refractory AF patients (mean age 63.7±11.0 years, 24.6% non-paroxysmal AF) with acquired AF underwent a single CA procedure in our department and were included in this retrospective analysis. Eight tagging single nucleotide polymorphisms (tSNPs) in the AGT gene were genotyped. Standard electrocardiographs (ECGs) and 24-hour Holter recordings were performed during a median follow-up period of 57.5 months to detect AF recurrence.. Sixty-one patients (40.7%) suffered AF recurrences after a single CA procedure during follow up. Of the eight tSNPs, the frequency of the M allele of M235T was significantly higher in the recurrence group (28%) compared to the non-recurrence group (18%) (p=0.042). The recurrence rates of patients with the TT, MT, and MM genotypes were 34.4%, 50%, and 55.6%, respectively (ptrend=0.049). After adjusting for age, sex, body mass index, hypertension, left atrial volume index (LAVI) and other covariates, M235T increased the risk of AF recurrence in additive and dominant models with odds ratios of 2.023 (95% confidence interval (CI): 1.034-3.926, p=0.033) and 2.601 (95% CI: 1.102-6.056, p=0.025), respectively. However, in multiple correction analyses, the p values of multiple comparisons were not statistically significant (pcorrect>0.05).. The M allele of M235T might be associated with an increased risk of AF recurrence after CA. Genotyping may thus be helpful on identifying patients with higher risks of AF recurrence after CA and developing optimal follow-up strategies. These strategies may differ and should be individualized according to patients' genotype. Future studies are warranted to validate the potential effect of AGT M235T on AF recurrence post CA.

Topics: Angiotensinogen; Atrial Fibrillation; Catheter Ablation; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Recurrence

Activation of the renin-angiotensin system (RAS) is associated with atrial fibrillation (AF). The aim of this study was to investigate the relation between AF and polymorphisms in RAS. One hundred and fifty patients with AF, 100 patients with no documented episode of AF and 100 healthy subjects were consecutively recruited into the study. The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism, and the M235T, A-20C, and G-6A polymorphisms of the angiotensinogen gene were genotyped. Patients with AF had significantly lower frequency of II genotype of ACE I/D and higher frequency of angiotensinogen M235T polymorphism T allele and TT genotype and G-6A polymorphism G allele and GG genotype compared with the controls. AF patients had significantly larger left atrium, higher left ventricular mass index (LVMI) and higher frequency of significant valvular pathology. ACE I/D polymorphism II genotype, angiotensinogen M235T polymorphism TT genotype and G allele and GG genotype of angiotensinogen G-6A polymorphism were still independently associated with AF when adjusted for left atrium, LVMI and presence of significant valvular pathology. Genetic predisposition might be underlying the prevalence of acquired AF. Patients with a specific genetic variation in the RAS genes may be more liable to develop AF.

Topics: Aged; Alleles; Angiotensinogen; Atrial Fibrillation; Female; Genetic Predisposition to Disease; Humans; Male; Multivariate Analysis; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Regression Analysis; Ultrasonography

To test the association between renin-angiotensin system gene variants and atrial fibrillation (AF) using a regression approach.. A total of 1,236 consecutive patients (227 with AF and 1,009 with normal sinus rhythm as controls) were recruited. Angiotensin-converting enzyme (ACE) gene I/D polymorphism; T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen (AGT) gene, and A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects and to detect gene-gene interactions by incorporating interaction terms in the model.. In single-locus analyses, no locus was associated with AF. After adjustment for AF risk factors, we found significant differences in the global AGT gene haplotype profile (the global score statistic = 30.364, p = 0.001) and individual haplotype frequencies between AF patients and controls. Furthermore, significant 2-way gene-gene interactions between ACE I/D polymorphism and AGT gene haplotypes and between AT1R A1166C polymorphism and AGT gene haplotypes, and 3-way interaction between ACE I/D, AT1R A1166C and AGT gene haplotypes were detected.. These results are compatible with the concept of multilocus and multigene effects in determining the risk of complex diseases such as AF, which would be missed with conventional single-locus approaches.

Topics: Aged; Aged, 80 and over; Angiotensinogen; Atrial Fibrillation; Female; Haplotypes; Humans; Linear Models; Male; Middle Aged; Multifactorial Inheritance; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1

The renin-angiotensin system may play a role in the pathogenesis of atrial fibrillation, and renin-angiotensin system blockers reduce the risk of atrial fibrillation. We hypothesized that polymorphisms in the angiotensinogen and angiotensin-converting enzyme (ACE) genes encoding proteins in this system predict risk of atrial fibrillation.. We genotyped 9235 individuals from the Danish general population, The Copenhagen City Heart Study, for the a-20c, g-6a, T174M, and M235T polymorphisms in the angiotensinogen gene and the insertion/deletion (I/D) polymorphism in the ACE gene; rare allele frequencies were 0.16, 0.40, 0.12, 0.41, and 0.49, respectively. Participants had sinus rhythm at inclusion. During 26 years of follow-up, 968 individuals developed atrial fibrillation. Multifactorially adjusted hazard ratios for atrial fibrillation for a-20c ac and cc versus aa genotype were 1.1(95% confidence interval: 1.0-1.3; P=0.05) and 1.5(1.1-2.1; P=0.01). Compared with double noncarriers (angiotensinogen -20aa and ACE II), double heterozygotes (ac-I/D genotype), and double homozygotes (cc-DD) had hazard ratios for atrial fibrillation of 1.2(0.9-1.6; P=0.06) and 2.4(1.4-4.1; P=0.001). a-20c cc homozygotes above 70 years of age who were overweight, severely hypertensive, and had heart failure, had an absolute 10-year risk of atrial fibrillation of 61%.. Angiotensinogen a-20c genotype alone and in combination with ACE I/D genotype predicts an increased risk of atrial fibrillation. Therefore, genetic variation in the renin-angiotensin system may influence effect of renin-angiotensin system blockers on atrial fibrillation.

Topics: Adult; Aged; Alleles; Amino Acid Sequence; Angiotensinogen; Atrial Fibrillation; Base Sequence; Denmark; DNA; Female; Genetic Predisposition to Disease; Heterozygote; Homozygote; Humans; Linkage Disequilibrium; Longitudinal Studies; Male; Middle Aged; Molecular Sequence Data; Peptidyl-Dipeptidase A; Pharmacogenetics; Polymorphism, Genetic; Renin-Angiotensin System; Risk Factors; Sequence Homology, Amino Acid; Sequence Homology, Nucleic Acid

The activated local atrial renin-angiotensin system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation (AF). We hypothesized that RAS genes might be among the susceptibility genes of nonfamilial structural AF and conducted a genetic case-control study to demonstrate this.. A total of 250 patients with documented nonfamilial structural AF and 250 controls were selected. The controls were matched to cases on a 1-to-1 basis with regard to age, gender, presence of left ventricular dysfunction, and presence of significant valvular heart disease. The ACE gene insertion/deletion polymorphism, the T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen gene, and the A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In multilocus haplotype analysis, the angiotensinogen gene haplotype profile was significantly different between cases and controls (chi2=62.5, P=0.0002). In single-locus analysis, M235T, G-6A, and G-217A were significantly associated with AF. Frequencies of the M235, G-6, and G-217 alleles were significantly higher in cases than in controls (P=0.000, 0.005, and 0.002, respectively). The odds ratios for AF were 2.5 (95% CI 1.7 to 3.3) with M235/M235 plus M235/T235 genotype, 3.3 (95% CI 1.3 to 10.0) with G-6/G-6 genotype, and 2.0 (95% CI 1.3 to 2.5) with G-217/G-217 genotype. Furthermore, significant gene-gene interactions were detected by the multifactor-dimensionality reduction method and multilocus linkage disequilibrium tests.. This study demonstrates the association of RAS gene polymorphisms with nonfamilial structural AF and may provide the rationale for clinical trials to investigate the use of ACE inhibitor or angiotensin II antagonist in the treatment of structural AF.

Topics: Aged; Aged, 80 and over; Angiotensinogen; Atrial Fibrillation; Epistasis, Genetic; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Heart Atria; Heart Valve Diseases; Humans; Linkage Disequilibrium; Male; Middle Aged; Mutagenesis, Insertional; Promoter Regions, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Sequence Deletion; Taiwan