Lianjun Gao

SNP rs3825214 in TBX5 Is Associated with Lone Atrial Fibrillation in Chinese Han Population

Background A prolonged PR interval is a sign of increased risk of cardiac arrhythmia. Recent genome-wide association studies found that the single-nucleotide polymorphism (SNP) rs3825214 in T-box 5 (TBX5) was positively associated with PR interval, QRS duration, QT interval, and common arrhythmia disorders such as atrial fibrillation (AF) and advanced atrioventricular block. However, other independent replication studies are required to validate the result. This study assessed associations between rs3825214 and ECG parameters, AF, and ventricular tachycardia (VT) in a Chinese Han population. Methodology/Principal Findings To assess the association between rs3825214 and AF and VT, we carried out case-control association studies with 692 AF patients (including 275 lone AF patients), 235 VT patients, and 856 controls. Genotyping was performed using a Rotor-Gene TM 6000 High Resolution Melt system. Statistical analyses of associations were adjusted for potential confounding factors. A moderate association was detected between rs3825214 and AF (P adj = 0.036, OR = 0.79) and a highly significant association was detected between the G allele of rs3825214 and lone AF (P adj = 0.001, OR = 0.65; genotypic P = 3.75×10−4 with a dominant model). We also found that rs3825214 showed a significant association with atrial-ventricular block (AVB; P = 0.028; P adj = 0.035, OR = 0.494). Conclusions Our results indicate that rs3825214 conferred a significant risk of lone AF in this Chinese Han population.

Synergistic association of DNA repair relevant gene polymorphisms with the risk of coronary artery disease in northeastern Han Chinese

Evidence is mounting suggesting that DNA damage is implicated in the development and progression of atherosclerosis. To yield more information, we focused on six well-characterized polymorphisms from four DNA repair-relevant candidate genes, viz. XRCC1 (rs1799782 and rs25487), XRCC3 (rs861539), MTHFR (rs1801133 and rs4846049), and NQO1 (rs1800566), to identify and characterize their potential gene-to-gene interactions in susceptibility to coronary artery disease (CAD) in Han Chinese. This was a hospital-based case-control study involving 1142 patients diagnosed with CAD and 1106 age- and gender-matched controls. All participants were angiographically confirmed. Risk estimates were expressed as odds ratio (OR) and 95% confidence interval (95% CI). All six examined polymorphisms met Hardy-Weinberg equilibrium. Overall there were significant differences in the genotype/allele distributions of MTHFR gene rs1801133 and rs4846049 (both P ≤ 0.005), and in the genotype distributions of XRCC1 gene rs1799782 (P = 0.002) between patients and controls. The adjusted risk of having CAD was more evident for rs1799782 (OR = 1.53; 95% CI: 1.16-2.02; P = 0.003), rs1801133 (OR = 1.54; 95% CI: 1.22-1.94; P < 0.001), and rs4846049 (OR = 1.74; 95% CI: 1.13-2.69; P = 0.013) under the recessive model. Interaction analyses indicated that the overall best multifactor dimensionality reduction (MDR) model included rs4846049, rs1801133, and rs1799782, and this model had a maximal testing accuracy of 0.6885 and a cross-validation consistency of 10 out of 10 (P = 0.0030). Further interaction entropy graph bore out the validity of this MDR model. Taken together, our findings demonstrate a contributory role of genetic defects in XRCC1 and MTHFR genes, both individually and interactively, in the development of CAD in Han Chinese.

An Interactive Association of Advanced Glycation End-Product Receptor Gene Four Common Polymorphisms with Coronary Artery Disease in Northeastern Han Chinese

Background Growing evidence indicates that advanced glycation end-product receptor (RAGE) might play a contributory role in the pathogenesis of coronary artery disease (CAD). To shed some light from a genetic perspective, we sought to investigate the interactive association of RAGE gene four common polymorphisms (rs1800625 or T-429C, rs1800624 or T-374A, rs2070600 or Gly82Ser, and rs184003 or G1704A) with the risk of developing CAD in a large northeastern Han Chinese population. Methodology/Principal Findings This was a hospital-based case-control study incorporating 1142 patients diagnosed with CAD and 1106 age- and gender-matched controls. All individuals were angiographically confirmed. Risk estimates were expressed as odds ratio (OR) and 95% confidence interval (CI). Overall there were significant differences in the genotype and allele distributions of rs1800625 and rs184003, even after the Bonferroni correction. Logistic regression analyses indicated that rs1800625 and rs184003 were associated with significant risk of CAD under both additive (OR = 1.20 and 1.23; 95% CI: 1.06–1.37 and 1.06–1.42; P = 0.006 and 0.008) and recessive (OR = 1.75 and 2.39; 95% CI: 1.28–2.40 and 1.47–3.87; P<0.001 and <0.001) models after adjusting for confounders. In haplotype analyses, haplotypes C-T-G-G and T-A-G-T (alleles in order of rs1800625, rs1800624, rs2070600 and rs184003), overrepresented in patients, were associated with 52% (95% CI: 1.19–1.87; P = 0.0052) and 63% (95% CI: 1.14–2.34; P = 0.0075) significant increases in adjusted risk for CAD. Further interactive analyses identified an overall best multifactor dimensionality reduction (MDR) model including rs1800625 and rs184003. This model had a maximal testing accuracy of 0.6856 and a cross-validation consistency of 10 out of 10 (P = 0.0016). The validity of this model was substantiated by classical Logistic regression analysis. Conclusions Our findings provided strong evidence for the potentially contributory roles of RAGE multiple genetic polymorphisms, especially in the context of locus-to-locus interaction, in the pathogenesis of CAD among northeastern Han Chinese.

The impact of hypertension on the electromechanical properties and outcome of catheter ablation in atrial fibrillation patients

BACKGROUND Although hypertension is associated with atrial fibrillation (AF), the impact of hypertension on the electromechanical properties and outcome of catheter ablation in AF patients is unclear. METHODS AF patients [n=213, 136 paroxysmal AF (PAF) patients and 77 persistent AF patients] undergoing circumferential pulmonary vein (PV) isolation guided by CARTO mapping were enrolled, and then were divided into normotension group and hypertension group. Several left atrial (LA) electroanatomical parameters determined by the CARTO system were compared between groups. RESULTS The LA bipolar voltage was lower in PAF patients with than without hypertension (1.44±1.09 vs. 1.92±0.76 mV, P=0.048); a significant difference was also observed in persistent AF patients. Hypertension significantly increased the size of the LA scar and low-voltage zones (LVZs) in both PAF and persistent AF patients. However, hypertension did not significantly affect recurrence in either PAF or persistent AF patients. The LA bipolar voltage was higher in PAF patients without recurrence than in those with recurrence (1.77±1.01 vs. 1.29±0.93 mV, P=0.048); a significant difference was also observed in persistent AF patients. PAF and persistent AF patients with AF recurrence had significantly larger LA scar and LVZs than patients without recurrence. CONCLUSIONS Hypertension has a significant impact on the LA electromechanical properties in AF patients, and the LA substrate has an important influence on the outcome of catheter ablation.

Association between insomnia and atrial fibrillation in a Chinese population: A cross‐sectional study

Insomnia is the most prevalent sleep disorder; however, little research has explored the link between insomnia and atrial fibrillation (AF).

Increased plasma corin levels in patients with atrial fibrillation

BACKGROUND NPPA mutations/polymorphisms were associated with atrial fibrillation (AF), and plasma proatrial natriuretic peptide (proANP) concentrations were increased in AF patients. Corin, as a transmembrane protease that processes proANP in the heart, may play a potential role in AF. METHODS To test whether corin concentrations are altered in AF patients, we used ELISA to measure corin and N-terminal proANP (NT-proANP) concentrations in plasma samples from control (n=127) and AF patients (n=141), including paroxysmal AF (PAF, n=83) and persistent AF (PeAF, n=58). RESULTS In patients with AF, plasma corin concentrations were 1209±510pg/ml, which were significantly higher than in the controls (973±528pg/ml, P<0.001). The increased plasma corin concentrations were found in both male and female patients. Plasma NT-proANP concentrations in AF patients were 3.1±2.42nmol/l, which were higher than in the controls (1.77±1.04nmol/l, P<0.001). Gender (P=0.003), weight (P=0.016) and PR interval (P=0.028) were independent predictors of plasma corin concentrations in AF patients. A positive correlation was found between corin concentrations and left atrial diameter/PR interval in AF patients. CONCLUSION High plasma corin concentrations in AF patients suggest that corin may play an important role in the pathology of AF.

Association between modifiable lifestyle and the prevalence of atrial fibrillation in a Chinese population: Based on the cardiovascular health score.

The Cardiovascular Health (CVH) Score was comprised of a series of modifiable lifestyle and health factors, which was published by American Heart Association in 2010. Its relationship with atrial fibrillation (AF) remains unclear.

The Early Stage of the Atrial Electroanatomic Remodeling as Substrates for Atrial Fibrillation in Hypertensive Patients

Background Hypertension is one of the most important risk factors for atrial fibrillation (AF). Recent studies suggest right atrial remodeling in hypertensive patients may be associated with increased inducibility of AF. This study sought to characterize the electroanatomic features of left and right atria and pulmonary veins (PVs) in hypertensive patients. Methods and Results A prospective observational study was conducted on patients who underwent ablation for paroxysmal supraventricular tachycardia or paroxysmal AF. Electrophysiological features of the PVs and atria, including event‐related potentials, conduction time, and inducibility and vulnerability of AF, were characterized during cardiac catheterization. Anatomic and hemodynamic features were assessed by using echocardiographic and computer tomography imaging. When 15 hypertensive patients with paroxysmal supraventricular tachycardia were compared with 17 normotensive patients with paroxysmal supraventricular tachycardia, the hypertensive patients had significantly shortened PV event‐related potentials with increased dispersions (P<0.001) but slightly prolonged atrial event‐related potentials (P=NS) and had prolonged interatrial and intra‐atrial conduction times (P<0.001). Additionally, the hypertensive patients had increased vulnerability and inducibility of AF and prolonged duration of induced AF (P<0.01). All of these changes were more pronounced in hypertensive patients with paroxysmal AF. Anatomically, compared with the normotensive patients, the diameters of 4 PVs in the hypertensive patients with paroxysmal supraventricular tachycardia were significantly enlarged (P<0.01) and became more remarkable in hypertensive patients with paroxysmal AF (P<0.0001), although the diameter and volume index of the left atrium among 3 groups were similar. Conclusions The hypertensive patients showed electroanatomic changes associated with increased vulnerability to AF, including shortened event‐related potentials with increased dispersion, prolonged conduction time, and increased PV diameter, but these changes were not appreciated in the atria. Additionally, these changes became more dramatic in hypertensive patients with paroxysmal AF.

Common Variants in the TBX5 Gene Associated with Atrial Fibrillation in a Chinese Han Population

Background PR interval variations have recently been associated with an increased risk of long-term atrial fibrillation (AF), heart block and all-cause mortality. Genome-wide association studies have linked the PR interval with several common variants in the TBX5 gene. Several variants in the TBX5 gene, including rs7312625 and rs883079, have been associated with AF. The purpose of this study was to determine the association of single-nucleotide polymorphisms (SNPs) in the TBX5 gene, rs7312625 and rs883079, with AF in Chinese Han patients. Methodology/Principal Findings In this case-control association study, large cohorts of AF patients (n = 1132) and controls (n = 1206) were recruited from different hospitals. The genotyping was performed using a Rotor-Gene TM 6000 high-resolution melt system. Rs7312625, rs3825214 and rs883079 were analyzed. We found that SNP 3825214 was significantly associated with AF (P-obs = 0.002, odds ratio [OR] = 0.82), and lone AF (P-obs = 6.77x10-5, odds ratio [OR] = 0.71). SNP rs7312625 was significantly associated with lone AF (P-obs = 0.015, odds ratio [OR] = 1.27), although its association with AF was not significant. No significant association of SNP rs883079 with AF or lone AF was observed. Thus, we analyzed the interaction among these three loci. We demonstrated significant interaction among rs3825214, rs7312625 and rs883079. Four-locus risk alleles showed the highest odds ratio in combined rs3825214 and rs7312625 (P-obs<0.0001, odds ratio [OR] = 2.21). Six-locus risk alleles showed the highest odds ratio in combined rs3825214, rs7312625 and rs 883079(P-obs<0.0001, odds ratio [OR] = 2.35). Significance was established with the trend test (P<0.0001). Conclusions For the first time, we report the strong association of SNP rs3825214 in the TBX5 gene with AF and lone AF in a Chinese Han population. Rs7312625 was significantly associated with lone AF, and snp-snp interaction increased the risk of atrial fibrillation. Our data might provide new insights into understanding AF pathogenesis and designing novel genetic therapies for AF patients.

Elevated Circulating Fibrocytes Is a Marker of Left Atrial Fibrosis and Recurrence of Persistent Atrial Fibrillation

Background In atrial fibrillation (AF), a more extensively fibrotic left atrium (LA) provides a substrate for arrhythmias and increases risk of relapse following ablation. Fibrocytes are bone marrow–derived circulating mesenchymal progenitors that have been identified in the atrium of patients with AF who have valvular diseases. The present study investigates the associations between circulating fibrocytes and LA fibrosis or the prevalence of recurrence after ablation in patients with persistent AF. Methods and Results We measured the proportion, differentiation, and migration of circulating fibrocytes from patients with persistent AF (n=40), those with paroxysmal AF (n=30), and sinus rhythm controls (n=30). LA low‐voltage (fibrosis) area was identified by an electroanatomic mapping system, and patients were followed up for 1 year after ablation. The relationship between circulating fibrocyte percentage and LA low‐voltage area or recurrence was assessed by multivariate regression analysis. Circulating fibrocyte percentage positively associated with LA low‐voltage area in the persistent AF group, and circulating fibrocyte (≥4.05%) was a significant predictor of 1‐year recurrence after ablation. Cultured fibrocytes exhibited enhanced potential of differentiation in the persistent AF group (67.58±1.54%) versus the paroxysmal AF group (56.67±1.52%) and sinus rhythm controls (48.43±1.79%). Furthermore, expression of fibroblast activation markers and cell migratory ability were also elevated in differentiated fibrocytes from patients with persistent AF. Transforming growth factor β1 and stromal cell–derived factor 1 were elevated in the plasma of patients with persistent AF and were shown to promote fibrocyte differentiation and migration, respectively. Conclusions In patients with persistent AF, increased circulating fibrocytes served as a marker of LA fibrosis and recurrence.