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<p>Box plot analysis of serum concentrations of sRAGE (A), esRAGE (B), S100A9 (C) and HMGB1 (D) in patients with CTEPH (n = 26) and controls (n = 33). Independent Student’s t-test was used to compare groups. <i>RAGE</i> receptor for advanced glycation endproducts, <i>sRAGE</i> soluble RAGE, <i>esRAGE</i> endogenous secretory RAGE, <i>S100A9</i> member of S100 family of Ca+ binding proteins, <i>HMGB1</i> high mobility group box1, <i>CTEPH</i> chronic thromboembolic pulmonary hypertension.</p

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Pulmonary pressure recovery in idiopathic, hereditary and drug and toxin-induced pulmonary arterial hypertension. determinants and clinical impact

Over the past two decades randomized controlled trials of combination treatments for Pulmonary Arterial Hypertension (PAH) have demonstrated improvements of clinical status but only modest reductions in mean pulmonary arterial pressure (mPAP). Recent experiences with upfront combination treatments including parenteral prostacyclins have shown more substantial mPAP reductions, and have provided grounds for reconsiderations of treatment

The risk profile change in patients with severe chronic thromboembolic pulmonary hypertension treated with subcutaneous treprostinil

Abstract Chronic thromboembolic pulmonary hypertension (CTEPH) is successfully treatable with pulmonary endarterectomy (PEA), balloon pulmonary angioplasty, and medical therapy. Registry to Evaluate Early and Long‐Term Pulmonary Arterial Hypertension Disease Management risk score (RRS) is able to predict long‐term outcome in inoperable patients or in patients with residual PH after surgery. We performed a post hoc analysis of RRS in patients who were enrolled in the CTREPH study (NCT01416636), a randomized, double‐blind clinical trial comparing high‐dose and low‐dose subcutaneous (SC) treprostinil in patients with severe CTEPH that was classified by an interdisciplinary CTEPH team as nonoperable, or as persistent or recurrent pulmonary hypertension after PEA. Baseline mean RRS was similar in both treatment groups (8.7 in high‐dose arm vs. 8.6 in low‐dose arm), but mean RRS change from baseline to Week 24 was greater in the high‐dose treprostinil group than in the low‐dose treprostinil group (−0.88 vs. −0.17). The difference in RRS change from baseline to Week 24 between high dose versus low dose was statistically significant with mean difference of −0.70 (95% confidence interval: −1.36 to −0.05, p = 0.0352), and was driven mainly by improvement of World Health Organization functional class and N‐terminal pro‐brain natriuretic peptide concentration. SC treprostinil therapy administered in standard dose had positive effect on the risk profile measured by RRS in patients with inoperable or persistent/recurrent severe CTEPH. Although our study was limited by the small sample size and post hoc nature, assessment of risk profile is of great importance to this particular patient population with very poor prognosis

Local and systemic RAGE axis changes in pulmonary hypertension: CTEPH and iPAH.

OBJECTIVE:The molecular determinants of chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH) remain poorly understood. The receptor for advanced glycation endproducts (RAGE) and its ligands: HMGB1 and S100A9 are involved in inflammatory disorders. We sought to investigate the role of the RAGE axis in patients with CTEPH undergoing pulmonary endarterectomy (PEA), iPAH undergoing lung transplantation (LuTX). The high pulmonary vascular resistance in CTEPH/iPAH results in pressure overload of the right ventricle. We compared sRAGE measurements to that of patients with aortic valve stenosis (AVS) - pressure overload of the left ventricle. METHODS:We enrolled patients with CTEPH(26), iPAH(15), AVS(15) and volunteers(33). Immunohistochemistry with antibodies to RAGE and HMGB1 was performed on PEA specimens and lung tissues. We employed enzyme-linked immunosorbent assays to determine the concentrations of sRAGE, esRAGE, HMGB1 and S100A9 in serum of volunteers and patients with CTEPH, iPAH, AVS before and after PEA, LuTX and aortic valve replacement (AVR). RESULTS:In endarterectomised tissues from patients with CTEPH RAGE and HMGB1 were identified in myofibroblasts (α-SMA+vimentin+CD34-), recanalizing vessel-like structures of distal myofibrotic tissues and endothelium of neointima. RAGE was differentially expressed in prototypical Heath Edwards lesions in iPAH. We found significantly increased serum concentrations of sRAGE, esRAGE and HMGB1 in CTEPH. In iPAH, sRAGE and esRAGE were significantly higher than in controls. Serum concentrations of sRAGE were significantly elevated in iPAH(p<0.001) and CTEPH(p = 0.001) compared to AVS. Serum sRAGE was significantly higher in iPAH compared to CTEPH(p = 0.042) and significantly reduced in AVS compared to controls(p = 0.001). There were no significant differences in sRAGE serum concentrations before and after surgical therapy for CTEPH, iPAH or AVS. CONCLUSIONS:Our data suggest a role for the RAGE pathway in the pathophysiology of CTEPH and iPAH. PEA improves the local control of disease but may not influence the systemic inflammatory mechanisms in CTEPH patients through the RAGE pathway

RAGE expression in pulmonary vascular changes of patients with iPAH.

<p>Representative examples of immunohistochemical analyses of pathognomonic lesions in lung of patients with iPAH according to the modified Heath Edwards classification in PA vessels smaller than 500 µm in diameter are shown (3 patients per every Heath Edwards group were analysed). RAGE expression in (A) a morphologically regular small PA - stage 0 and (B) a stage 1 histological change in lung of a patient operated for pneumothorax (COPD 0, centriacinar emphysematous changes). RAGE expression in characteristic stage 2 changes in a lung of a patient with iPAH (C). Scale bar in A, B and C: 80 µm. Adjacent sections of H&E (D) and EvG (E) and RAGE staining (F) for stage 3 changes in iPAH. Scale bar in D, E and F: 40 µm. Stage 4, angiomatoid (insert with adjacent H&E section, G), and stage 5, plexiform (H) PA vessel changes are shown. Scale bar in G and H: 80 µm. <i>iPAH</i> idiopathic pulmonary arterial hypertension, <i>PA</i> pulmonary artery, <i>RAGE</i> receptor for advanced glycation endproducts, <i>COPD</i> chronic obstructive pulmonary disease, <i>H&E</i> hematoxylin and eosin staining, <i>EvG</i> Elastica van Gieson staining.</p