| Background and Objective:Atrial fibrillation (AF) is one of the most common arrhythmias in clinical practice, which may lead to heart failure, stroke, peripheral arterial embolism and other complications, resulting in more hospitalization, mortality and disability, and thus making greater economic burden for the individual and society. Atrial fibrillation occurs not only in patients with organic heart diseases but also in a small number of individuals without evidence of cardiac and systemic diseases, the latter known as lone (or isolated) atrial fibrillation. Although many cardiovascular diseases such as rheumatic heart disease, coronary arterial disease, myocardial infarction, congenital heart disease, cardiomyopathy can lead to atrial fibrillation, animal experiments and population epidemiological data indicated that essential hypertension (EH) is still the most important and independent risk factor for the occurrence and maintenace of atrial fibrillation. The age, occupation,24-hour ambulatory blood pressure level, left ventricular mass and left atrial diameter (LAD) of hypertensive patients have a crucial influence on atrial fibrillation, and high sensitive C-reactive protein also plays a certain role in the development of atrial fibrillation. However, such factors mentioned above are far from enough to explain all the reasons for the pathogenesis of atrial fibrillation in hypertensive patients. To explore the etiology of atrial fibrillation is becoming the research focus, and the relationship between genetic factors, single nucleotide polymorphism (SNP), molecular markers and atrial fibrosis as well as atrial fibrillation is paid much more attention to.TGFβ1 is an important profibrotic cytokine that regulates the synthesis of extracellular matrix such as collagen, fibronectin and proteoglycan and promotes the atrial fibrosis. Recent studies indicated that TGFβ1 was expressed highly in myocardium of some patients with cardiovascular diseases. TGFβ1 was not only found highly in blood and myocardium of patients with cardiomyopathy, valvular heart disease and arrhythmia, but also had an obvious effect on atrial fibrillation in patients with rheumatic heart disease. Clinical researches have demonstrated that serum TGFβ1 level was high in hypertensive patients, especially in those with hypertensive target organ damage (TOD), but the relationship between TGFβ1 and atrial fibrillation remains unknown in these patients.In 2004, epidemiological data of familial atrial fibrillation were reported firstly in Framingham study, and relationship between genetic factors and atrial fibrillation has become the focus of clinical researches since then. Approximately 5% of patients with atrial fibrillation have a tendency of familial aggregation which is more obvious in those with lone atrial fibrillation. At present, the etiological role of genetic factors have been basically confirmed in the development of atrial fibrillation by epidemiological studies, and lots of associated genes with atrial fibrillation have been screened out, of which angiotensin converting enzyme (ACE) gene polymorphisms gained much more attention early in association with atrial fibrillation. However, most of these studies were only limited to familial or lone atrial fibrillation. It is rarely studied whether ACE gene polymorphisms have related with the development of atrial fibrillation in hypertension. A few small-scale studies about relationship between ACE gene polymorphisms and atrial fibrillation got the different results even opposite conclusions.In this study we tested serum TGFβ1/connective tissue growth factor (CTGF) levels and detected ACE gene insertion/deletion (I/D) polymorphisms in hypertensive patients with atrial fibrillation or sinus rhythm in order to analyze the correlation between TGFβ1 and CTGF or LAD and explore the influence of different ACE I/D genotypes on serum TGFβ1 level in these patients, and thus look for new targets of intervening the occurrence of atrial fibrillation at molecular biological level and genetics in hypertensive patients.Objects and Methods:From March to November in 2013,166 patients with atrial fibrillation were admitted to our adult cardiology ward, among whom 75 cases with essential hypertension and documented atrial fibrillation were enrolled in this study and further divided into two subgroups according to AF duration:the paroxysmal AF group (EH+pAF) and the chronic AF group (EH+cAF, AF lasting≥6 months). Hypertension was defined as systolic blood pressure (SBP)≥140 mmHg, and/or diastolic blood pressure (DBP)≥90 mmHg in supine position, after 20 min of rest on 2 separate days. Atrial fibrillation was determined by 12-lead electrocardiogram (ECG) and/or 24-h Holter monitoring. Of these patients,44 cases in the EH+pAF group consisted of 28 men and 16 women whose mean age was 67.3±8.4 years and 31 cases in the EH+cAF group consisted of 19 men and 12 women whose age was 68.6±9.5 years. In addition, 37 EH patients with sinus rhythm (SR) from the same ward were consecutively selected into the EH+SR group as controls and consisted of 23 men and 14 women whose age was 66.7±8.3 years, and 36 healthy subjects from our medical examination center were selected as normal controls (NC group) and consisted of 22 men and 14 women whose age was 64.7±9.8 years. Patients with secondary hypertension, acute coronary syndrome (including unstable angina pectoris, non-ST segment elevation myocardial infarction and ST segment elevation myocardial infarction), old myocardial infarction, and/or other severe heart problems such as valvular heart disease, dilated or hypertrophic cardiomyopathy, congential heart disease, pulmonary heart disease and other types of cardiac arrythmia, were excluded. Patients with lung or liver fibrosis, malignant tumor, renal damage, stroke, and those aged more than 80, with secondary hypertension, taking ARB or ACEI for controlling high blood pressure and having atrial fibrillation occurred before the establishment of hypertension, were also ruled out. Clinical characteristics such as hypertensive levels and duration, smoking status, blood glucose (Glu), lipid profiles including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c) were collected. LAD, left ventricular diameter (LVD), interventricular septal (IVS) thickness, left ventricular posterior wall (LVPW) thickness and left ventricular eject fraction (LVEF) were assessed by transthoracic echocardiographic examination. The serum TGFβ1/CTGF level were measured by enzyme-linked immunosorbent assay (ELISA) method, and the genotypes of ACE (I/D) genes were identified by polymerase chain reaction (PCR) and PCR restricted fragment length polymorphism assay. Serum TGFβ1/CTGF level and ACE I/D genotypes were compared within different groups:the EH+pAF group, the EH+cAF group, the EH+SR group and the NC group. For the EH patients with AF, serum TGFβ1/CTGF level was also compared within different ACE I/D genotypes:DD genotype, DI genotype and II genotype. Linear correlation analysis was used to test relationships between serum TGFβ1 level and CTGF or LAD in all EH patients, and stepwise multiple regression analysis was used to detect statistically significant associations between TGFβ1 and a number of parameters. Patients in the EH+AF group were given regular follow-up. Drug treatment of atrial fibrillation and ECG were recorded for further analysis. Follow-ups of the patients included embolic complications, the prognosis and outcome of atrial fibrillation and rehospitalization.Results:1. Clinical findingsThere were no significant differences in age, sex, hypertensive duration, SBP, DBP, serum TG, TC, HDL-c, LDL-c, Glu, IVS, LVPW and LVEF among three EH groups. However, LAD and LVD were markedly higher in the EH+cAF group than in the EH+SR group (p<0.0001 and p<0.05, respectively), and LAD was also obviously higher in the EH+cAF group than in the EH+pAF group (p<0.005).2. Comparison of serum TGFβ1 and CTGF levelThe serum TGFβ1 levels in all EH groups were significantly higher than that in the NC group (p<0.001). Among the EH groups, TGFβ1 levels in the cAF group (49.6 ±29.5ng/ml) and the pAF group (39.5±31.1ng/ml) were higher than that in the SR group (28.3±8.6ng/ml) (p<0.005). However, there was no significant difference in TGFβ1 levels between the cAF group and the pAF group, as well as the SR group and the NC group (25.2±13.0ng/ml) (p>0.05).Like the serum TGFβ1 level, the serum CTGF levels in all EH groups were obviously higher than that in the NC group (p<0.001). CTGF levels in the cAF group (8.16±0.21ng/ml) and the pAF group (7.87±1.30ng/ml) were also higher than that in the SR group (1.14±0.38ng/ml) (p<0.001). The serum level of CTGF in SR group (1.14±0.38ng/ml) was markedly higher than that in the NC group (0.26±0.09ng/ml) (p<0.001). There was no significant difference in serum CTGF levels between the cAF group and the pAF group either (p>0.05).3. Correlation analysis Among all EH patients including those with atrial fibrillation and with sinus rhythm, LAD was increased and correlated positively with the serum TGFβ1 and CTGF levels. There was a positive correlation between LAD and TGFβ1(r=0.468, p<0.0001), LAD and CTGF (r= 0.391,p<0.005). Moreover, there was also a positive correlation between LVD and TGFβ1level (r= 0.256, p<0.05).4. Stepwise multiple regression analysisStepwise multiple regression analysis was use to detect statistically significant association between a dichotomous-dependent variable and a number of independent variables. The results of stepwise of regression analysis for all AF patients showed that TGFβ1 was an independent risk factor of developing AF in hypertension. The serum TGFβ1 level in AF patients was independently correlated with LAD, the presence of AF, aldosterone, CTGF and age.5. Comparison of ACE I/D gene polymorphismsFrequency analysis of ACE I/D gene polymorphisms in the EH+AF group revealed that DD, DI and II genotype was 36.0%,41.3% and 22.7%, respectively. In spite of no significant difference of ACE I/D genotypes among the three groups (the EH+AF group, the EH+SR group and the NC group), allele D genotype frequency in EH+AF group (56.7%) was significantly higher than that in EH+SR group (41.9%) and in NC group (38.9%) (p<0.05).6. Comparison of serum TGFβ1 and CTGF level within different ACE I/D genotypes in hypertensive patients with atrial fibrillationAmong the patients in EH+AF group, the serum TGFβ1 level in patients with DD genotype (54.03±26.92ng/ml) was obviously higher than that in those with DI genotype (37.81±11.79ng/ml) and II genotype (32.43±24.08ng/ml) (p<0.05 and p<0.01, respectively), and the serum CTGF level in patients with DD genotype (8.25± 0.19ng/ml) was also markedly higher than that in those with DI genotype (8.03± 0.10ng/ml) and II genotype (7.99±0.69ng/ml) (p<0.05 and p<0.01, respectively). There was no significant difference of TGFβ1 and CTGF level between patients with DI genotype and those with II genotype in this group.7. Follow-up results of hypertensive patients with atrial fibrillationPatients in the EH+AF group were followed up for 1.5 to 2 years. There was an increased tendency of cerebral embolism and rehospitalization in AF patients with DD genotype, but no significant difference compared to those with DI genotype and II genotype (p>0.05). In pAF group, there was also an increased tendency of developing persistent AF in patients with DD genotype, but no significant difference compared to those with DI genotype and II genotype (p>0.05). Conclusion: 1. TGFβ1 and ACE I/D gene polymorphism are possibly associated with the development of atrial fibrillation in patients with essential hypertension. 2. Results from Stepwise multiple regression analysis shows that TGFβ1 is an independent risk factor of atrial fibrillation, which may play an important role in the pathogenesis of atrial fibrillation in hypertensive patients by promoting CTGF synthesis and causing left atrial enlargement and remodeling. 3. The allele D is a susceptible gene of atrial fibrillation in hypertensive patients. 4. Serum TGFβ1 and CTGF levels were significantly elevated in hypertensive patients with DD genotype, which may be one of the important causes of leading to the occurrence of atrial fibrillation in hypertension. |
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