Investigating the Link Between Specific Signaling Molecules (CCL5, CCR5, CXCR4, BMPR2) and Cardiac Health Indicators...

Persistent systemic inflammation is a hallmark of rheumatoid arthritis (RA) and contributes to increased cardiovascular disease (CVD) risk, a major cause of morbidity and mortality. Given the need for reliable biomarkers for cardiovascular risk stratification, this study aimed to evaluate the association between key signaling molecules (CCL5, CCR5, CXCR4, and BMPR2) and cardiovascular-related biomarkers in RA patients.

This cross-sectional study was conducted between April and October 2022 and included 90 participants: 60 RA patients (30 treatment-naïve and 30 receiving disease-modifying anti-rheumatic drugs) and 30 age- and sex-matched healthy controls. Plasma CCL5 levels were measured using ELISA, and CCR5, CXCR4, and BMPR2 gene expression was assessed in peripheral blood mononuclear cells (PBMCs) using real-time PCR and the Pfaffl method. Outcomes included high-sensitivity C-reactive protein (HS-CRP), NT-proBNP, disease activity (DAS-28), and cardiovascular risk scores (FRS and SCORE). Group comparisons were performed using one-way ANOVA with Tukey's post-hoc test, and correlations were assessed using Pearson or Spearman methods as appropriate. Given the exploratory nature of the study, a Benjamini-Hochberg false discovery rate (FDR) correction was additionally performed as a sensitivity analysis for multiple correlation testing.

Plasma CCL5 levels did not differ significantly among groups (p = 0.48). However, gene expression differed significantly for CCR5 (F[2,87] = 5.2, p = 0.006), CXCR4 (F[2,87] = 5.4, p = 0.005), and BMPR2 (F[2,87] = 3.9, p = 0.02), with higher expression in treatment-naïve patients. Among RA patients (n = 60), CXCR4 expression correlated positively with DAS-28 (r = 0.29, p = 0.02), HS-CRP (r = 0.32, p = 0.01), and NT-proBNP (r = 0.40, p = 0.002). Additionally, CCL5 (r = 0.39, p = 0.002) and CCR5 (r = 0.26, p = 0.046) showed positive correlations with NT-proBNP. After FDR correction, the associations of CXCR4 with NT-proBNP and HS-CRP, and CCL5 with NT-proBNP remained statistically significant, whereas borderline associations should be interpreted cautiously.

CXCR4, CCL5, and CCR5 were associated with cardiovascular-related biomarkers in RA patients. These findings provide preliminary evidence supporting further investigation of these molecules as potential biomarkers of cardiovascular involvement in RA. However, the observed associations are exploratory and observational in nature, do not imply causation, and require confirmation in larger prospective longitudinal studies before clinical risk-stratification utility can be established.