Increased Serum Levels of Fetal Tenascin-C Variants in Patients with Pulmonary Hypertension: Novel Biomarkers Reflecting Vascular Remodeling and Right Ventricular Dysfunction?

Abstract

Pulmonary vascular remodeling is a pathophysiological feature that common to all classes of pulmonary hypertension (PH) and right ventricular dysfunction, which is the major prognosis-limiting factor. Vascular, as well as cardiac tissue remodeling are associated with a re-expression of fetal variants of cellular adhesion proteins, including tenascin-C (Tn-C). We analyzed circulating levels of the fetal Tn-C splicing variants B ⁺ and C ⁺ Tn-C in serum of PH patients to evaluate their potential as novel biomarkers reflecting vascular remodeling and right ventricular dysfunction. Serum concentrations of B ⁺ and C ⁺ Tn-C were determined in 80 PH patients and were compared to 40 healthy controls by enzyme-linked immunosorbent assay. Clinical, laboratory, echocardiographic, and functional data were correlated with Tn-C levels. Serum concentrations of both Tn-C variants were significantly elevated in patients with PH ( p < 0.05). Significant correlations could be observed between Tn-C and echocardiographic parameters, including systolic pulmonary artery pressure (B ⁺ Tn-C: r = 0.31, p < 0.001, C ⁺ Tn-C: r = 0.26, p = 0.006) and right atrial area (B ⁺ Tn-C: r = 0.46, p < 0.001, C ⁺ Tn-C: r = 0.49, p < 0.001), and laboratory values like BNP (B ⁺ Tn-C: r = 0.45, p < 0.001, C ⁺ Tn-C: r = 0.42, p < 0.001). An inverse correlation was observed between Tn-C variants and 6-minute walk distance as a functional parameter (B ⁺ Tn-C: r = −0.54, p < 0.001, C ⁺ Tn-C: r = −0.43, p < 0.001). In a multivariate analysis, B ⁺ Tn-C, but not C ⁺ Tn-C, was found to be an independent predictor of pulmonary hypertension. Both fetal Tn-C variants may represent novel biomarkers that are capable of estimating both pulmonary vascular remodeling and right ventricular load. The potential beneficial impact of Tn-C variants for risk stratification in patients with PH needs further investigation.