Plasma proteoglycan prolargin in diagnosis and differentiation of pulmonary arterial hypertension

Abstract

Aims Right ventricular dysfunction may arise because of pulmonary arterial hypertension (PAH). Development of new diagnostic methods able to identify PAH and allow for earlier treatment initiation, before the development of vascular remodelling and manifest right heart failure (HF), could potentially improve prognosis. Proteoglycans and inflammatory proteins are involved in vascular remodelling. We aimed to investigate their potential as biomarkers to differentiate PAH in a dyspnoeic population. Methods and results Plasma from 152 patients with PAH (n = 48), chronic thrombo-embolic pulmonary hypertension (n = 20), pulmonary hypertension due to HF with reduced (n = 36) or preserved (n = 33) ejection fraction, and HF without pulmonary hypertension (n = 15) and 20 healthy controls were analysed with proximity extension assays. Haemodynamics were assessed in the patients with right heart catheterization. Plasma prolargin levels in PAH were lower compared with all the other studied disease groups (P < 0.001) but higher than the controls' levels (P = 0.003). Receiver operating characteristic curve of prolargin as a PAH-differentiating marker in a pooled population, encompassing all the other studied disease groups, had a sensitivity of 74% and a specificity of 83.3% (area under the curve = 0.84, P < 0.001). Prolargin correlated with the mean right atrial pressure (r s = 0.65, P < 0.001), N-terminal pro-brain natriuretic peptide (r s = 0.64, P < 0.001), cardiac index (r s = À0.31, P = 0.029), stroke volume index (r s = À0.41, P = 0.004), right ventricular stroke work index (r s = À0.31, P = 0.032), six-minute walking distance (r s = À0.41, P = 0.005), and mixed venous blood oxygen saturation (r s = À0.42, P = 0.003). Conclusions Plasma prolargin levels differentiate PAH patients from controls and the other investigated dyspnoea groups including HF. Its potential in PAH differentiation may be enhanced by inclusion in a multi-marker panel. Larger studies are needed to evaluate its discriminative ability of PAH in relation to other dyspnoea aetiologies and its potential role in PAH risk stratification and pathobiology.

Plasma matrix metalloproteinase 2 is associated with severity and mortality in pulmonary arterial hypertension

“…In the present PAH cohort, glypican‐1 levels at follow‐up were increased compared to baseline. This indicates that the change in glypican‐1 levels may be related to PAH‐specific treatment, as we previously have found glypican‐1 levels to be decreased at PAH diagnosis compared to healthy individuals 14 . Glypican‐1 is a mediator of flow‐induced endothelial nitric oxide synthase activation 32 .…”

“…Consequently, ECM proteins could be of interest as prognostic markers in PAH. The present study, therefore, investigated ECM‐related proteins that we previously had found to be altered in the plasma of patients with PAH compared to healthy controls 13,14 . Among the ECM proteins evaluated in the present study, MMP‐2 was the most promising prognostic marker of outcome in PAH.…”

“…All included proteins except MEPE and glypican-1 had previously been found to have higher levels in PAH compared to healthy controls, whereas MEPE and glypican-1 had been found to have lower levels in PAH compared to healthy controls. 13,14 Risk scores Patients' 1-year mortality risk scores were calculated using ERS/ESC 2015 guidelines risk assessment tool. 4 WHO-FC, 6MWD, NT-proBNP, MRAP, CI, and SvO 2 were graded as 1 "low risk," 2 "intermediate risk," and 3 "high risk" according to the guidelines cut-offs.…”

“…11,12 Previous studies have investigated MMPs and proteoglycans as diagnostic markers for PAH differentiation and found that several ECM-related proteins were altered in PAH including MMP-7 and prolargin. 13,14 We hypothesized that ECM-related proteins with known abnormal expression in PAH patients may serve as biomarkers with prognostic value in PAH. Our aim was to study the relationship between ECM-related plasma protein levels in PAH patients in relation to survival and ERS/ESC risk stratification score.…”

“…One proteoglycan, decorin, inhibits the fibrotic effect of transforming growth factor‐beta 11,12 . Previous studies have investigated MMPs and proteoglycans as diagnostic markers for PAH differentiation and found that several ECM‐related proteins were altered in PAH including MMP‐7 and prolargin 13,14 …”