Effect of atrial fibrillation on plasma galectin-3 and soluble CD40 ligand levels in patients with ischemic cardiomyopathy

Abstract

Objective

To reveal the significance of plasma galectin-3 and soluble CD40 ligand (sCD40L) levels in patients with ischemic cardiomyopathy (ICM) combined with atrial fibrillation.

Methods

In this case–control study, the case group comprised 60 patients with ICM combined with atrial fibrillation and the control group comprised patients with ICM without atrial fibrillation. Plasma galectin-3 and sCD40L levels, left atrial diameter (LAD), left ventricular ejection fraction (LVEF), and left ventricular diameter (LVD) were compared.

Results

The plasma galectin-3 and sCD40L levels, LAD, and LVD were higher and the LVEF was lower in the case than control group. In the case group, the plasma galectin-3 and sCD40L levels were positively correlated with the LAD and LVD but negatively correlated with the LVEF. The area under the receiver operating characteristic curve of the plasma galectin-3 and sCD40L levels in the diagnosis of ICM combined with atrial fibrillation was 0.857 (95% confidence interval, 0.792–0.923) and 0.724 (95% confidence interval, 0.634–0.814), respectively.

Conclusion

The plasma galectin-3 and sCD40L levels are significantly elevated in patients with ICM combined with atrial fibrillation. Although both may have predictive value in the diagnosis of ICM combined with atrial fibrillation, galectin-3 may have the higher predictive value.

Keywords

Ischemic cardiomyopathy atrial fibrillation galectin-3 soluble CD40 ligand receiver operating characteristic curve diagnostic value

Introduction

Ischemic cardiomyopathy (ICM) is characterized by severe myocardial dysfunction secondary to chronic myocardial ischemia due to narrowing and occlusion of the coronary arteries.¹ ICM is a special type or advanced stage of coronary heart disease. Atrial fibrillation is the most common clinical arrhythmia.² ICM may be accompanied by a series of arrhythmias, mainly including atrial fibrillation and ventricular premature contraction.³ Atrial fibrillation may increase myocardial oxygen consumption and lead to a severe reduction in ventricular filling, which in turn increases the burden on the heart and readily leads to death.⁴ The pathogenesis of atrial fibrillation remains unclear. ICM may interact with atrial fibrillation, contributing to the progression and deterioration of the patients’ condition. Therefore, early diagnosis of atrial fibrillation in patients with ICM is beneficial.

Galectin-3 is an inflammatory factor that is closely associated with pathophysiological processes such as myocardial fibrosis and myocardial remodeling.^5,6 It is secreted by activated macrophages and is a key regulator of T-cell function.⁷ Disruption of galectin-3 reduces the severity of chronic myocardial fibrosis.⁸ Few reports have focused on the plasma galectin-3 expression level in patients with ICM combined with atrial fibrillation.

Soluble CD40 ligand (sCD40L) is an important glycoprotein expressed on the surface of macrophages, and it is associated with the risk of cardiovascular events.⁹ sCD40L may be involved in the development of atrial fibrillation and may be used to predict the prognosis of patients with atrial fibrillation.¹⁰ However, few reports have focused on the expression level of the plasma sCD40L level and its clinical significance in patients with ICM combined with atrial fibrillation.

The present study was performed to investigate the effect of atrial fibrillation on the plasma galectin-3 and sCD40L levels in patients with ICM and reveal the changes and clinical significance of these levels in patients with ICM combined with atrial fibrillation.

Methods

Clinical materials

This case–control study was approved by the medical ethics committee of the Eighth Hospital of Wuhan, China. We have de-identified all participants’ details. All patients provided written informed consent. The reporting of the study conforms to the STROBE guidelines.¹¹

The sample size was calculated using G*Power software at a significance level of 0.05 and power of 80% with a two-tailed test. The calculation indicated that approximately 51 patients should be enrolled in each group. However, based on the actual number of patients in our hospital, 60 patients with ICM combined with atrial fibrillation who were admitted from January 2018 to March 2022 were selected as the case group.

The inclusion criteria for the case group were fulfillment of the clinical diagnostic criteria for ICM and the presence of atrial fibrillation as confirmed by electrocardiography on admission, atrial fibrillation mainly in the form of paroxysmal atrial fibrillation (atrial fibrillation duration of <7 days) or persistent atrial fibrillation (atrial fibrillation duration of ≥7 days), age of >18 years, and provision of informed consent for participation. The exclusion criteria for the case group were coronary artery disease and relevant complications; an enlarged heart and heart failure due to other heart diseases; an unknown history of ICM; oncological diseases, autoimmune defects, cerebrovascular diseases, or hematological diseases; diseases resulting in persistent atrial fibrillation or paroxysmal atrial fibrillation, such as coronary artery disease, hyperthyroidism, or rheumatic heart disease; concurrent infection; and a history of medication use (antithrombotics, anticoagulants, statins, or others) within 4 weeks prior to enrollment.

The control group comprised 60 patients with ICM without atrial fibrillation who were admitted to this hospital during the same period. The patients in the control group were matched to those in the case group in terms of sex and age, and they had no history of atrial fibrillation.

Detection of indicators

All patients were required to fast for 10 hours after admission, and 5-mL fasting blood samples were then collected from the antecubital vein at 8:00 the next morning. The samples were anticoagulated with EDTA and centrifuged at 4°C, and the plasma was retained and stored in a −80°C freezer for subsequent measurement. The plasma galectin-3 and sCD40L levels were measured by enzyme-linked immunosorbent assay (Shanghai Hengyuan Biotechnology Co., Ltd., Shanghai, China).

Within 24 hours of admission, the patients were examined using a color Doppler ultrasound diagnostic instrument (ACUSON X300 PE; Siemens Healthineers, Erlangen, Germany). The left atrial diameter (LAD), left ventricular ejection fraction (LVEF), and left ventricular diameter (LVD) were measured in all patients using the area–length method.

Statistical analysis

IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp., Armonk, NY, USA) was used for the data analysis. Measurement data with a normal distribution are expressed as mean ± standard deviation, and the independent-samples t-test was used for comparison. Pearson’s correlation analysis was used to analyze the correlation between the two variable factors. The predictive value of galectin-3 and sCD40L in the diagnosis of ICM with atrial fibrillation was evaluated using a receiver operating characteristic (ROC) curve. A P value of <0.05 was considered statistically significant.

Results

There were no significant differences in sex, age, body mass index, hypertension, diabetes, or smoking between the control group and the case group, as shown in Table 1.

Table 1.

Demographic and clinical characteristics of the patients.

Variables	Control group (n = 60)	Case group (n = 60)	P value
Male sex	37 (61.67)	38 (63.33)	0.850
Female sex	23 (38.33)	22 (36.67)	0.850
Age, years	66.75 ± 4.69	66.72 ± 4.43	0.968
Body mass index, kg/m²	27.27 ± 2.10	27.44 ± 2.28	0.669
Hypertension	25 (41.67)	28 (46.67)	0.581
Diabetes	18 (30.00)	20 (33.33)	0.695
Smoking	16 (26.67)	15 (25.00)	0.835

Data are presented as n (%) or mean ± standard deviation.

In the case group, 36 (60%) patients had paroxysmal atrial fibrillation and 24 (40%) had persistent atrial fibrillation. A study flowchart is shown in Figure 1.

Figure 1.

Flowchart of the present study.

The plasma galectin-3 and sCD40L levels, LAD, and LVD were significantly higher in the case group than in the control group (all P < 0.001) (Table 2), whereas the LVEF was significantly lower in the case group than in the control group (P < 0.001) (Table 2).

Table 2.

Comparison of relevant indexes between the two groups.

Indexes	Control group (n = 60)	Case group (n = 60)	P value
Plasma galectin-3, ng/mL	16.01 ± 1.04	17.15 ± 1.10	<0.001
Plasma sCD40L, μg/L	1.95 ± 0.15	2.49 ± 0.20	<0.001
LAD, mm	41.19 ± 3.18	49.46 ± 3.89	<0.001
LVD, mm	42.33 ± 3.27	52.70 ± 4.14	<0.001
LVEF, %	40.02 ± 3.09	35.86 ± 2.83	<0.001

Data are presented as mean ± standard deviation.

sCD40L, soluble CD40 ligand; LAD, left atrial diameter; LVD, left ventricular diameter; LVEF, left ventricular ejection fraction.

Pearson’s correlation analysis results showed that in the case group, the plasma galectin-3 level in patients with ICM combined with atrial fibrillation was positively correlated with the LAD and LVD (r = 0.572, P < 0.001 and r = 0.663, P < 0.001, respectively) (Table 3) but negatively correlated with the LVEF (r = −0.859, P < 0.001) (Table 3).

Table 3.

Correlation analysis between relevant indexes in the case group.

Indexes	LAD (mm)		LVD (mm)		LVEF (%)
Indexes	r	P value	r	P value	r	P value
Plasma galectin-3	0.572	<0.001	0.663	<0.001	−0.859	<0.001
Plasma sCD40L	0.543	<0.001	0.639	<0.001	−0.836	<0.001

sCD40L, soluble CD40 ligand; LAD, left atrial diameter; LVD, left ventricular diameter; LVEF, left ventricular ejection fraction.

In the case group, the plasma sCD40L level in patients with ICM combined with atrial fibrillation was positively correlated with the LAD and LVD (r = 0.543, P < 0.001 and r = 0.639, P < 0.001) (Table 3) but negatively correlated with the LVEF (r = −0.836, P < 0.001) (Table 3).

The area under the ROC curve of plasma galectin-3 and sCD40L in the diagnosis of ICM combined with atrial fibrillation was 0.857 (95% confidence interval, 0.792–0.923) and 0.724 (95% confidence interval, 0.634–0.814), respectively. The area under the curve of plasma galectin-3 was larger than that of plasma sCD40L, as shown in Table 4 and Figure 2.

Table 4.

Application value of plasma galectin-3 and sCD40L in diagnosis of ICM combined with atrial fibrillation.

Indexes	AUC	95% CI	P value	Cutoff value	Sensitivity (%)	Specificity (%)
Plasma galectin-3	0.857	0.792–0.923	<0.001	16.32 ng/mL	88.30	70.00
Plasma sCD40L	0.724	0.634–0.814	<0.001	2.00 μg/L	80.00	46.70

sCD40L, soluble CD40 ligand; AUC, area under the receiver operating characteristic curve; CI, confidence-interval.

Figure 2.

Receiver operating characteristic curves of plasma galectin-3 and sCD40L in the diagnosis of ischemic cardiomyopathy combined with atrial fibrillation.

Discussion

Primary cardiovascular diseases such as ICM and atrial fibrillation are closely related to and affect each other.¹¹ Under the effect of myocardial ischemia, hypoxia, and nutrient metabolism disorders, patients with ICM develop diffuse myocardial fibrosis, reduced left ventricular function, increased left atrial pressure, and bioelectrical instability of the atrial myocardium, further leading to atrial fibrillation.^12,13

The left atrium plays an important role in the development of atrial fibrillation.¹⁴ An increased LAD may promote the development of atrial fibrillation. The occurrence of atrial fibrillation is positively correlated with the LAD. The degree of structural remodeling of the left atrium in patients with atrial fibrillation affects the magnitude of the LVEF.¹⁵ The present study showed that the LAD and LVD were higher and the LVEF was lower in the case than control group, suggesting that patients with ICM combined with atrial fibrillation have an altered cardiac structure, significantly increased LAD and LVD, and significantly decreased LVEF compared with patients with ICM.

Galectin-3 is secreted by activated macrophages and induces macrophage infiltration in the heart, which may reflect cardiac fibrosis.¹⁶ Galectin-3 is a potential mediator of cardiac fibrosis. The serum level of galectin-3 was shown to be correlated with left atrial appendage remodeling in patients with atrial fibrillation.¹⁷ Galectin-3 has also been shown to be an independent risk factor for the development of atrial fibrillation in patients with cardiomyopathy.¹⁸ The present study showed that the plasma galectin-3 level was higher in the case than control group, suggesting that galectin-3 is highly expressed in the plasma of patients with ICM combined with atrial fibrillation. The findings of this study are generally consistent with the results of previous studies.¹⁹

sCD40L is hydrolyzed by membrane-bound (CD40 ligand) CD40L and is expressed in immune cells, blood vessel walls, and platelets.²⁰ sCD40L is closely associated with atrial fibrillation.²¹ Patients with atrial fibrillation at high risk of stroke develop high levels of sCD40L.²² The present study showed that the plasma sCD40L level was higher in the case than control group, suggesting that sCD40L is highly expressed in the plasma of patients with ICM combined with atrial fibrillation.

Our further analysis revealed that the plasma galectin-3 and sCD40L levels in patients with ICM combined with atrial fibrillation were positively correlated with the LAD and LVD but negatively correlated with the LVEF. These findings suggest that galectin-3 and sCD40L are closely associated with cardiac remodeling, that the plasma galectin-3 and sCD40L concentrations are higher in patients with ICM combined with atrial fibrillation, and that a larger LAD is associated with a lower LVEF. We speculate that the left atrium and left ventricle in patients with ICM combined with atrial fibrillation are enlarged and remodeled, which in turn promotes the secretion of galectin-3 and sCD40L in the body.

Early monitoring and diagnosis of atrial fibrillation are key to treating ICM combined with atrial fibrillation and improving the prognosis. Studies have shown that the preoperative sCD40L level predicts the risk of atrial fibrillation in patients after nonstop coronary artery bypass grafting.²³ In the present study, the area under the ROC curve of plasma galectin-3 was larger than that of plasma sCD40L, meaning that the sensitivity of plasma galectin-3 in the diagnosis of ICM combined with atrial fibrillation was higher but that its specificity in the diagnosis of ICM combined with atrial fibrillation was lower. This suggests that the detection of both galectin-3 and sCD40L has certain clinical application value in the determination of ICM combined with atrial fibrillation, but the diagnostic efficacy of galectin-3 is greater than that of sCD40L. By contrast, previous studies have suggested that galectin-3 may not be used to predict the risk of atrial fibrillation in patients with heart failure.²⁴ Plasma sCD40L might be expected to better predict atrial fibrillation after cardiac surgery.²⁵

Importantly, our findings suggest that increased plasma galectin-3 and sCD40L levels in patients with ICM combined with atrial fibrillation are the result of atrial fibrillation in ICM. However, these increased levels may also predict the occurrence of atrial fibrillation in patients with ICM. Additionally, plasma galectin-3 and sCD40L might serve as predictive markers that help assess the risk of atrial fibrillation in the context of ICM.

This study has three main limitations. First, the sample size was relatively small, and the results may have been affected by confounding factors. A larger sample size and a multicenter study design would help to minimize this limitation. Second, we did not explore the specific mechanisms underlying the relationship between atrial fibrillation and the plasma galectin-3 and sCD40L levels in patients with ICM. Further studies are needed to elucidate the mechanisms involved. Third, further subgroup analysis based on the different forms of atrial fibrillation would provide valuable insights into the specific impact of each subtype on ICM. However, because of the limitations in our sample size and the available data, we were unable to conduct such a subgroup analysis in this particular study.

Conclusion

Galectin-3 and sCD40L are significantly elevated in patients with ICM combined with atrial fibrillation. Both galectin-3 and sCD40L may have predictive value in the diagnosis of ICM combined with atrial fibrillation, but galectin-3 may have higher predictive value.

Footnotes

Availability of data and materials

The dataset of this article is not openly available. However, it can be accessed upon reasonable request from the corresponding author.

Authors’ contributions

CZ: Acquired the data, drafted the manuscript, and revised the manuscript.

HL: Collected the samples and examined the manuscript.

MH: Revised the manuscript and read and approved the final manuscript.

Declaration of conflicting interests

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

ORCID iD

Chi Zhang

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