Pulmonary arterial hypertension is a severe disease for which diagnosis often is delayed. Matrix metalloproteinases have been suggested to play a role in vascular remodeling and pulmonary hypertension development. Our aim was therefore to investigate the potential role of matrix metalloproteinases as biomarkers in diagnosis and differentiation of pulmonary arterial hypertension in relation to various causes of dyspnea and pulmonary hypertension. Using proximity extension assays, 10 matrix metalloproteinases and associated proteins were analyzed in venous plasma from healthy controls (n = 20), as well as patients diagnosed with pulmonary arterial hypertension (n = 48), chronic thromboembolic pulmonary hypertension (n = 20), pulmonary hypertension due to heart failure with preserved (n = 33) or reduced (n = 36) ejection fraction, and heart failure with reduced ejection fraction and heart failure with preserved ejection fraction without pulmonary hypertension (n = 15). Plasma levels of matrix metalloproteinase-2, -7, -9, -12 and TIMP-4 were elevated (p < 0.01) in pulmonary arterial hypertension compared to controls. Plasma levels of matrix metalloproteinase-7 were furthermore lower (p < 0.0081) in pulmonary arterial hypertension than in all the other disease groups, but higher compared to controls (p < 0.0001). Receiver operating characteristic analysis of matrix metalloproteinase-7 resulted in sensitivity of 58.7% and a specificity of 83.3% for detecting pulmonary arterial hypertension among the other disease groups. Plasma matrix metalloproteinase-7 may provide a potential new diagnostic tool to differentiate pulmonary arterial hypertension from other causes of dyspnea, including heart failure with or without pulmonary hypertension and healthy controls. Matrix metalloproteinase-7 may furthermore be involved in the development of pulmonary hypertension and pulmonary arterial hypertension. Future studies investigating the clinical usefulness of matrix metalloproteinase-7 in the differentiation and earlier diagnosis of pulmonary arterial hypertension, as well as its relationship to pulmonary arterial hypertension pathogenesis, are encouraged.

Aims Remodelling of the extracellular matrix (ECM) is a key mechanism involved in the development and progression of heart failure (HF) but also functional in associated pulmonary hypertension (PH). Our aim was to identify plasma ECM proteins associated to end‐stage HF and secondary PH in relation to haemodynamics, before and after heart transplantation (HT). Methods and results Twenty ECM plasma proteins were analysed with proximity extension assay in 20 controls and 26 HF patients pre‐HT and 1 year post‐HT. Right heart catherization haemodynamics were assessed in the patients during the preoperative evaluation and at the 1 year follow‐up post‐HT. Plasma levels of prolargin and matrix metalloproteinase‐2 (MMP‐2) were elevated (P < 0.0001) in HF patients compared with controls and decreased (P < 0.0001) post‐HT towards controls' levels. The decrease in prolargin post‐HT correlated with improved mean right atrial pressure (rs = 0.63; P = 0.00091), stroke volume index (rs = −0.73; P < 0.0001), cardiac index (rs = −0.64; P = 0.00057), left ventricular stroke work index (rs = −0.49; P = 0.015), and N‐terminal pro brain natriuretic peptide (rs = 0.7; P < 0.0001). The decrease in MMP‐2 post‐HT correlated with improved mean pulmonary artery pressure (rs = 0.58; P = 0.0025), mean right atrial pressure (rs = 0.56; P = 0.0046), pulmonary artery wedge pressure (rs = 0.48; P = 0.016), and N‐terminal pro brain natriuretic peptide (rs = 0.56; P = 0.0029). Conclusions The normalization pattern in HF patients of plasma prolargin and MMP‐2 post‐HT towards controls' levels and their associations with improved haemodynamics indicate that prolargin and MMP‐2 may reflect, in part, the aberrant ECM remodelling involved in the pathophysiology of HF and associated PH. Their potential clinical use as biomarkers or targets for future therapy in HF and related PH remains to be investigated.

Aims Metabolic derangement is implicated in the pathophysiology of heart failure (HF) and pulmonary hypertension (PH). We aimed to identify the dynamics of metabolic plasma proteins linked to end-stage HF and associated PH in relation to haemodynamics, before and after heart transplantation (HT). Methods and results Twenty-one metabolic plasma proteins were analysed with proximity extension assay in 20 controls and 26 patients before and 1 year after HT. Right heart catheterizations were performed in the HF patients pre-operatively and 1 year after HT. Plasma levels of soluble receptor for advanced glycation end products (sRAGE) and insulin-like growth factor-binding protein 7 (IGFBP7) were higher in HF patients compared with controls (P < 0.0001) and decreased after HT (P < 0.0001), matching controls' levels. The decrease in sRAGE after HT correlated with improved mean pulmonary arterial pressure (r s = 0.7; P < 0.0001), pulmonary arterial wedge pressure (r s = 0.73; P < 0.0001), pulmonary vascular resistance (r s = 0.65; P = 0.00062), and pulmonary arterial compliance (r s = À0.52; P = 0.0074). The change in plasma IGFBP7 after HT correlated with improved mean right atrial pressure (r s = 0.71; P = 0.00011) and N-terminal pro-brain natriuretic peptide (r s = 0.71; P < 0.0001). Conclusions Our results indicate that plasma sRAGE may reflect passive pulmonary vascular congestion and the 'mechanical' state of the pulmonary vasculature in HF patients with or without related PH. Furthermore, sRAGE and IGFBP7 may provide additional insight into the pathophysiological mechanisms in HF and associated PH. Their potential clinical and therapeutic relevance in HF and associated PH need further investigation.