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.

BackgroundPulmonary arterial hypertension (PAH) is a serious disease exhibiting unspecific symptoms, as a result of which diagnosis is often delayed and prognosis is poor. The underlying pathophysiology includes vasoconstriction and remodelling of small pulmonary arteries. As receptor tyrosine kinases (RTKs) and their ligands have been shown to promote PAH remodelling, our aim was to evaluate if their plasma levels may be utilised to differentiate between various causes of pulmonary hypertension.Methods28 biomarkers involved in RTK signalling were measured using proximity extension assays in venous plasma from patients with PAH (n=48), chronic thromboembolic pulmonary hypertension (CTEPH) (n=20), pulmonary hypertension due to diastolic (n=33) or systolic (n=36) heart failure and heart failure patients without pulmonary hypertension (n=15), as well as healthy controls (n=20).ResultsPlasma proto-oncogene tyrosine-protein kinase receptor Ret (RET) was decreased (p<0.04) in PAH compared with all disease groups and controls. RET generated a sensitivity of 64.6% and a specificity of 81.6% for detecting PAH from other disease groups. PAH and the other pulmonary hypertension groups showed elevated plasma tyrosine-protein kinase MER (p<0.01), vascular endothelial growth factor (VEGF)-A (p<0.02), VEGF-D (p<0.01), placental growth factor (p<0.01), amphiregulin (p<0.02), hepatocyte growth factor (p<0.01) and transforming growth factor-α (p<0.05) and decreased VEGF receptor-2 (p<0.04) and epidermal growth factor receptor (p<0.01) levels compared with controls.ConclusionPlasma RET differentiates patients with PAH from those with CTEPH, systolic or diastolic heart failure with or without pulmonary hypertension as well as healthy controls. Future studies would be of value to determine the clinical usefulness of RET as a biomarker and its link to PAH pathophysiology.

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.