Galectin-3 is known to play an important role in a number of fibrotic conditions, including cardiac fibrosis. Many studies have focused on the association between galectin-3 levels and cardiac fibrosis in heart failure. However, the role of galectin-3 in the pathogenesis of atrial fibrillation (AF) has not been evaluated thoroughly yet. The aim of this study was to determine whether serum galectin-3 levels were elevated in patients with AF and preserved left ventricular function. Seventy-six patients with paroxysmal or persistent AF and preserved left ventricular systolic function and 75 age- and gender-matched control subjects were enrolled in this observational study. Galectin-3 levels were measured by enzyme-linked immunosorbent assay. Serum galectin-3 (median 0.6 ng/ml [interquartile range 0.2 to 1.4] vs 0.5 ng/ml [interquartile range 0.1 to 0.7], p <0.001) and left atrial volume index (LAVI) (mean 29.5 ± 3.5 vs 26.5 ± 2.5 ml/m 2 , p <0.001) were significantly greater in patients with AF compared with the control group. Serum galectin-3 levels were also significantly higher in patients with persistent AF than those with paroxysmal AF (median 0.8 ng/ml [interquartile range 0.4 to 1.4] vs 0.5 ng/ml [interquartile range 0.2 to 0.9], p <0.001). Multivariate regression analysis demonstrated that serum galectin-3 (odds ratio 87.53, 95% confidence interval 6.06 to 1,265.03, p = 0.001) and LAVI (odds ratio 1.38, 95% confidence interval 1.19 to 1.60, p <0.001) were independent predictors of AF. Only LAVI was independently correlated with serum galectin-3 levels in patients with AF in linear regression analysis. In conclusion, serum galectin-3 is significantly elevated and is also significantly correlated with LAVI in patients with AF with preserved left ventricular function.
Galectin-3 is an α-galactoside-binding lectin that appears to play an important role in a number of fibrotic conditions, including cardiac fibrosis. The role of galectin-3 in the pathogenesis of cardiac fibrosis involves the recruitment of macrophages, myofibroblasts, and fibroblasts into the myocardium, resulting in cellular proliferation and collagen deposition. Many studies have focused on the association between galectin-3 levels and cardiac fibrosis in heart failure. In clinical studies, elevated galectin-3 has been found to be associated with incident heart failure. Galectin-3 has also been shown to be an independent predictor of adverse outcome in patients with heart failure. Although the association between atrial fibrillation (AF) and atrial fibrosis has been highlighted in several studies, the role of galectin-3 in the pathogenesis of these 2 conditions has not yet been evaluated thoroughly. In a recent study, higher circulating galectin-3 concentrations were found to be associated with increased risk for AF development over the subsequent 10 years in age- and gender-adjusted analyses. In this study, we aimed to determine whether serum galectin-3 levels were elevated in patients with AF and preserved left ventricular (LV) function.
Methods
Seventy-six patients with paroxysmal or persistent AF and preserved LV function and 75 age- and gender-matched control subjects were enrolled in this observational study. AF episodes either lasting >7 days or requiring termination by cardioversion, either with drugs or by direct-current cardioversion, were defined as persistent, whereas AF episodes self-terminating within 7 days were defined as paroxysmal. The control group consisted of subjects without histories of any disease who underwent routine screening visits in the outpatient clinics.
Patients who were pregnant and those with histories of hypertension, diabetes mellitus, moderate to severe valvular disease, congenital heart disease, alcohol consumption, abnormal thyroid function, coronary artery disease, serum creatinine >1.20 mg/dl, autoimmune disease, recent infection, or attempted AF ablation were excluded from the study. Furthermore, patients with left atrial (LA) diameters >55 mm or systolic LV dysfunction were not included in the study.
Baseline demographic and clinical characteristics, including age, gender, body mass index, and smoking history, were recorded for all patients. Careful histories were taken from all patients to exclude any cardiac or noncardiac systemic disease. Data related to the diagnosis of AF, including date of first diagnosis, oral anticoagulation, rate-controlling drugs, and antiarrhythmic medications, were also recorded. Symptomatic severity of the patients was recorded according to the European Heart Rhythm Association score. All patients underwent transthoracic echocardiographic examination to assess LA size and LV function and to exclude valvular and structural heart disease. LA volume was derived using the biplane area-length method. LA volume index (LAVI) was calculated on the basis of the patient’s body surface area. LV systolic function was quantified from LV end-diastolic and end-systolic dimensions. Informed consent was obtained from each patient before enrollment. The study was in compliance with the principles outlined in the Declaration of Helsinki and approved by the institutional ethics committee.
After an overnight fast, blood samples were collected and immediately centrifuged and stored at −80°C until assayed. The frozen serum samples were rapidly thawed and brought to room temperature and assayed for the presence of human galectin-3 by using enzyme-linked immunosorbent assay kits (eBioscience, Europe/International, Vienna, Austria), according to the manufacturer’s instructions. Serial dilutions of known concentrations of human galectin-3 were used to construct a standard curve of the analytes. The serum levels of galectin-3 from the samples were estimated by extrapolation from a log-log linear regression curve determined from the serially diluted human recombinant galectin-3, ranging from 25 to 0.39 ng/ml.
Normally distributed continuous parameters are presented as mean ± SD and skewed continuous parameters as median (interquartile range [IQR], defined as minimum to maximum). Categorical data are presented as frequencies and percentages and were compared using chi-square test. Comparisons between baseline characteristics were performed by independent Student’s t , Mann-Whitney rank-sum, Fisher’s exact, and chi-square tests as appropriate. Univariate and multivariate logistic regression analyses were performed to determine the independent predictors of AF. Spearman’s correlation analysis was performed to investigate factors related to levels of galectin-3. Linear regression analysis was used to identify risk factors for predicting serum galectin-3 levels. Statistical analyses were performed using SPSS version 21.0 (SPSS, Inc., Chicago, Illinois). A 2-tailed p value <0.05 is considered statistically significant.
Results
Seventy-six patients with AF with preserved LV function and 75 age- and gender-matched control subjects were included in the study. Baseline demographic, clinical, laboratory, and echocardiographic parameters of the study population are listed in Table 1 . Serum galectin-3 (median 0.6 ng/ml [IQR 0.2 to 1.4] vs 0.5 ng/ml [0.1 to 0.7], p <0.001) and LAVI (mean 29.5 ± 3.5 vs 26.5 ± 2.5 ml/m 2 , p <0.001) were significantly elevated in patients with AF compared with the control group.
| Control group (n=75) | Atrial fibrillation group (n=76) | p value | |
|---|---|---|---|
| Men n | 35 (46.7%) | 36 (47.4%) | 1.000 |
| Age (years) | 57.6± 11.1 | 58.6± 9.2 | 0.556 |
| Body mass index (kg/m 2 ) | 24.2± 1.5 | 24.3± 1.7 | 0.811 |
| Active smoker n | 29 (38.7%) | 26 (34.2%) | 0.614 |
| White blood cell count (X10 6 /μl) | 7.1± 2.0 | 7.6± 2.0 | 0.125 |
| Serum creatinine (mg/dl) | 0.8± 0.2 | 0.8± 0.2 | 0.712 |
| Galectin-3 (ng/ml) | 0.5 (0.1- 0.7) | 0.6 (0.2- 1.4) | <0.001 ∗ |
| Left atrial volume index (ml/m 2 ) | 26.5± 2.5 | 29.5± 3.5 | <0.001 ∗ |
| Left ventricular end- diastolic diameter (cm) | 4.7± 0.4 | 4.7± 0.4 | 0.475 |
| Left ventricular ejection fraction (%) | 65.9± 3.5 | 65.9± 3.1 | 0.979 |
| E/ E′ ratio | 8.6± 1.7 | 8.8± 1.7 | 0.403 |
| Interventricular septal thickness (mm) | 9.6± 1.3 | 9.7± 1.2 | 0.684 |
Serum galectin-3 levels (median 0.8 ng/ml [IQR 0.4 to 1.4] vs 0.5 [IQR 0.2 to 0.9], p <0.001) ( Figure 1 ) and LAVI (mean 31.0 ± 4.0 vs 28.4 ± 2.6 ml/m 2 , p = 0.002) were significantly higher in patients with persistent AF compared with those with paroxysmal AF ( Table 2 ).
| Paroxysmal atrial fibrillation (n=42) | Persistent atrial fibrillation (n=34) | p value | |
|---|---|---|---|
| Men | 47.2% | 52.2% | 0.689 |
| Age (years) | 58.6± 9.5 | 58.6± 9.4 | 0.995 |
| Body mass index (kg/m 2 ) | 24.1± 2.0 | 24.5± 1.3 | 0.360 |
| Active smoker | 41.5% | 34.8% | 0.539 |
| Duration of atrial fibrillation (years) | 5 (1-12) | 8 (3-24) | <0.001 ∗ |
| White blood cell count (X10 6 /μl) | 7.9± 2.2 | 7.2± 1.7 | 0.145 |
| Serum creatinine (mg/dl) | 0.8± 0.2 | 0.8± 0.1 | 0.814 |
| Galectin-3 (ng/ml) | 0.5 (0.2- 0.9) | 0.8 (0.4- 1.4) | <0.001 ∗ |
| Left atrial volume index (ml/m 2 ) | 28.4± 2.6 | 31.0± 4.0 | 0.002 ∗ |
| Left ventricular end- diastolic diameter (cm) | 4.7± 0.4 | 4.8± 0.4 | 0.285 |
| Left ventricular ejection fraction (%) | 66.2± 3.4 | 65.7± 2.7 | 0.470 |
| E/ E′ ratio | 8.6± 1.6 | 9.0± 1.8 | 0.352 |
| Interventricular septum thickness (mm) | 9.5± 1.3 | 9.9± 1.1 | 0.155 |
The univariate regression analysis model showed that serum galectin-3 (odds ratio [OR] 177.89, 95% confidence interval [CI] 17.30 to 1,829.19, p <0.001) and LAVI (OR 1.37, 95% CI 1.21 to 1.55, p <0.001) were associated with AF ( Table 3 ). Multivariate regression analysis demonstrated that serum galectin-3 (OR 87.53, 95% CI 6.06 to 1,265.03, p = 0.001) and LAVI (OR 1.38, 95% CI 1.19 to 1.60, p <0.001) were independent predictors of AF in this patient group ( Table 3 ).
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p value | OR | 95% CI | p value | |
| Galectin-3 (ng/ml) | 177.89 | 17.30- 1829.19 | <0.001 ∗ | 87.53 | 6.06- 1265.03 | 0.001 ∗ |
| Left atrial volume index (ml/m 2 ) | 1.37 | 1.21- 1.55 | <0.001 ∗ | 1.38 | 1.19- 1.60 | <0.001 ∗ |
| White blood cell count (X10 6 /μl) | 1.00 | 1.00- 1.00 | 0.128 | 1.00 | 1.00- 1.00 | 0.381 |
In Spearman correlation analysis, age (r = 0.185, p = 0.023), duration of AF (r = 0.351, p = 0.002), and LAVI (r = 0.283, p <0.001) ( Figure 2 ) were found to be significantly correlated with serum galectin-3 levels in patients with AF ( Table 4 ). Among age, duration of AF, and LAVI, only LAVI was independently correlated with serum galectin-3 levels in patients with AF in linear regression analysis (B ± SE 0.031 ± 0.006, 95% CI 0.018 to 0.044, p <0.001) ( Table 4 ).
