Elevated serum levels of HIF-1α and VEGF as potential biomarkers in connective tissue disease-associated pulmonary arterial hypertension

Abstract

Abstract We to measure the serum levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in patients diagnosed with connective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) (CTD-PAH) and to analyze their clinical implications. Thirty patients who were diagnosed with CTD-PAH via right heart catheterization (RHC) were enrolled in the observation group. Additionally, twenty CTD patients without PAH (CTD-non-PAH) were enrolled in the CTD-non-PAH group, and twenty healthy participants were enrolled in the healthy control group. Additional data on CTD-PAH patients, including demographic characteristics, laboratory parameters, and hemodynamic measurements, were obtained. The serum levels of HIF-1α and VEGF in all participants were measured using an enzyme-linked immunosorbent assay (ELISA). Pearson correlation was utilized to determine the correlation between the expression levels of these factors and clinical data. Receiver operating characteristic (ROC) curves were constructed, and the area under the curve (AUC) was calculated to evaluate the diagnostic efficacy of expression of HIF-1α and VEGF for diagnosing CTD-PAH. Participants in the three groups were age-matched. The CTD-PAH group included 29 females and 1 male, and systemic lupus erythematosus (SLE) was the most prevalent CTD diagnosis (17/30). Serum levels of VEGF and HIF-1α were significantly greater in both CTD-PAH and CTD-non-PAH patients compared to the healthy controls (P < 0.01). In addition, the serum concentration of HIF-1α in the CTD-PAH group was significantly greater than that in the CTD-non-PAH group (248.86 ± 18.85 and 224.64 ± 12.22, respectively, P = 0.0022). Similarly, the serum concentration of VEGF in the CTD-PAH group was significantly greater than that in the CTD-non-PAH group (251.11 ± 48.37 and 222.120 ± 18.57, respectively, P = 0.0026). In patients with CTD-PAH, the concentrations of HIF-1α and VEGF are significantly positively correlated with mPAP (r = 0.81, r = 0.88). Both HIF-1α and VEGF concentrations were positively correlated with BNP levels (r = 0.5340, r = 0.6472) and negatively correlated with the 6-Minute Walk Distance (6MWD) (r=-0.46, r=-0.47, respectively, P < 0.01). When VEGF and HIF-1α were combined, the diagnostic ROC curve yielded an AUC of 0.933. Increased serum levels of HIF-1α and VEGF were observed in CTD-PAH patients compared to CTD-non-PAH patients and healthy controls, which, along with their positive correlations with mPAP and BNP levels and negative correlations with the 6MWD, indicate their potential as biomarkers for diagnosing CTD-PAH.

Keywords

• Connective tissue disease
• Pulmonary arterial hypertension
• Hypoxia-inducible Factor-1α
• Vascular endothelial growth factor
• 6-Minute walk distance