Asymmetric Dimethylarginine and NT-proBNP Levels Provide Synergistic Information in Pulmonary Arterial Hypertension.

BACKGROUND: Plasma asymmetric dimethylarginine (ADMA) is elevated in pulmonary arterial hypertension (PAH) and is associated with unfavorable outcomes. OBJECTIVES: The aim of this study was to assess changes in ADMA plasma levels for monitoring disease progression and outcomes during PAH-specific therapy. METHODS: ADMA was measured at baseline and after at least 6 months of follow-up using enzyme-linked immunosorbent assay and high-performance liquid chromatography. Changes in ADMA were analyzed in relation to changes in established PAH markers, including hemodynamic status, N-terminal pro-brain natriuretic peptide (NT-proBNP) and risk assessment scores. Impact on survival was assessed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Between 2008 and 2019, ADMA samples were collected prospectively from 215 patients with PAH. Change in ADMA plasma level was a predictor of disease progression and survival. ΔADMA (median -0.03 µmol/L; 95% CI: -0.145 to 0.0135) was correlated with change in mean pulmonary arterial pressure (P < 0.005; rS = 0.287) but was not significantly correlated with ΔNT-proBNP (P = 0.056; rS = 0.135). Patients with decreased ADMA plasma levels at follow-up had better 3-year and 5-year survival rates (88% and 80%, respectively, vs 72% and 53% in those without decreases in ADMA) (P < 0.005; pulmonary hypertension-related mortality or lung transplantation). Patients with decreases in both ADMA and NT-proBNP had better survival rates compared with patients in whom only 1 parameter improved (P < 0.005). ΔADMA was a significant predictor of survival in Cox regression analysis and also when corrected for ΔNT-proBNP (HRs: 1.27 and 1.35, respectively; P < 0.005). CONCLUSIONS: ADMA and NT-proBNP provide synergistic prognostic information for patients with PAH. ADMA could be used as an objective and distinct biomarker for monitoring treatment response in PAH.

Efficacy and safety of the Aria pulmonary endovascular device in pulmonary hypertension.

AIMS: A common feature of various forms of pulmonary hypertension (PH) is progressive decline of pulmonary arterial compliance (CPA), which correlates with reduced survival. In this acute study, we evaluated feasibility, safety and haemodynamic performance of the Aria pulmonary endovascular device in patients with PH associated with left heart disease (PH-LHD) and chronic lung disease (PH-CLD). METHODS AND RESULTS: Eight patients with PH-LHD and 10 patients with PH-CLD were included in this study. The device was placed in the main pulmonary artery via the right femoral vein and was connected by a catheter to a gas-filled reservoir outside the body. During systole, gas shifts from the balloon to the reservoir, leading to deflation of the balloon. In diastole, the gas returns from the reservoir to the balloon, leading to balloon inflation and enhancing diastolic blood flow to the distal pulmonary capillary bed. Haemodynamics were assessed at baseline, and again with device off, device on and device off. The primary safety endpoint was the incidence of serious adverse events through 30 days after the procedure. No complications or investigational device-related serious adverse events occurred. Device activation in PH-LHD and PH-CLD patients decreased pulmonary arterial pulse pressure by 5.6 ± 4.2 mmHg (-12%; p = 0.003) and 4.2 ± 2.2 mmHg (-11%; p < 0.001), increased CPA by 0.4 ± 0.2 ml/mmHg (+23%; p = 0.004) and 0.4 ± 0.3 ml/mmHg (+25%; p = 0.001), and increased right ventricular-to-pulmonary vascular (RV-PV) coupling by 0.24 ± 0.18 (+40%; p = 0.012) and 0.11 ± 0.07 (+21%; p = 0.001), respectively. CONCLUSIONS: Temporary implantation of the Aria endovascular device was feasible and safe. Device activation resulted in acute improvement of CPA and RV-PV coupling.

Recognition, diagnosis, and operability assessment of chronic thromboembolic pulmonary hypertension (CTEPH): A global cross-sectional scientific survey (CLARITY).

Early recognition and diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) is crucial for improving prognosis and reducing the disease burden. Established clinical practice guidelines describe interventions for the diagnosis and evaluation of CTEPH, yet limited insight remains into clinical practice variation and barriers to care. The CTEPH global cross-sectional scientific survey (CLARITY) was developed to gather insights into the current diagnosis, treatment, and management of CTEPH and to identify unmet medical needs. This paper focuses on the recognition and diagnosis of CTEPH and the referral and evaluation of these patients. The survey was offered to hospital-based medical specialists through Scientific Societies and other medical organizations, from September 2021 to May 2022. Response data from 353 physicians showed that self-reported awareness of CTEPH increased over the past 10 years among 96% of respondents. Clinical practices in acute pulmonary embolism (PE) follow-up and CTEPH diagnosis differed among respondents. While 50% of respondents working in a nonexpert center reported to refer patients to an expert pulmonary hypertension/CTEPH center when CTEPH is suspected, 51% of these physicians did not report referral of patients with a confirmed diagnosis for further evaluation. Up to 50% of respondents involved in the evaluation of referred patients have concluded a different operability status than that indicated by the referring center. This study indicates that early diagnosis and timely treatment of CTEPH is challenged by suboptimal acute PE follow-up and patient referral practices. Nonadherence to guideline recommendations may be impacted by various barriers to care, which were shown to vary by geographical region.

Longitudinal analysis of chest Q-SPECT/CT in patients with severe COVID-19.

INTRODUCTION: Patients with COVID-19 have an increased risk for microvascular lung thrombosis. In order to evaluate the type and prevalence of perfusion defects, we performed a longitudinal analysis of combined perfusion single-photon emission and low-dose computed tomography (Q-SPECT/CT scan) in patients with COVID-19 pneumonia. METHODS: Consecutive patients with severe COVID-19 (B.1.1.7 variant SARS-CoV-2) and respiratory insufficiency underwent chest Q-SPECT/CT during hospitalization, and 3 months after discharge. At follow-up (FU), Q-SPECT/CT were analyzed and compared with pulmonary function tests (PFT), blood analysis (CRP, D-dimers, ferritin), modified Medical Research Council (mMRC) dyspnea scale, and high-resolution CT scans (HRCT). Patients with one or more segmental perfusion defects outside the area of inflammation (PDOI) were treated with anticoagulation until FU. RESULTS: At baseline, PDOI were found in 50 of 105 patients (47.6 %). At FU, Q-SPECT/CT scans had improved significantly (p < 0.001) and PDOI were recorded in 14 of 77 (18.2 %) patients. There was a significant correlation between mMRC score and the number of segmental perfusion defects (r = 0.511, p < 0.001), and a weaker correlation with DLCO (r = -0.333, p = 0.002) and KCO (r = -0.373, p = 0.001) at FU. Neither corticosteroid therapy nor HRCT results showed an influence on Q-SPECT/CT changes (p = 0.94, p = 0.74). CRP, D-Dimers and ferritin improved but did not show any association with the FU Q-SPECT/CT results (p = 0.08). CONCLUSION: Segmental mismatched perfusion defects are common in severe COVID-19 and are correlated with the degree of dyspnea. Longitudinal analyses of Q-SPECT/CT scans in severe COVID-19 may help understand possible mechanisms of long COVID and prolonged dyspnea.

Left Ventricular Filling Pressure in Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by obstruction of major pulmonary arteries with organized thrombi. Clinical risk factors for pulmonary hypertension due to left heart disease including metabolic syndrome, left-sided valvular heart disease, and ischemic heart disease are common in CTEPH patients. OBJECTIVES: The authors sought to investigate prevalence and prognostic implications of elevated left ventricular filling pressures (LVFP) in CTEPH. METHODS: A total of 593 consecutive CTEPH patients undergoing a first diagnostic right and left heart catheterization were included in this study. Mean pulmonary arterial wedge pressure (mPAWP) and left ventricular end-diastolic pressure (LVEDP) were utilized for assessment of LVFP. Two cutoffs were applied to identify patients with elevated LVFP: 1) for the primary analysis mPAWP and/or LVEDP >15 mm Hg, as recommended by the current pulmonary hypertension guidelines; and 2) for the secondary analysis mPAWP and/or LVEDP >11 mm Hg, representing the upper limit of normal. Clinical and echocardiographic features, and long-term mortality were assessed. RESULTS: LVFP was >15 mm Hg in 63 (10.6%) and >11 mm Hg in 222 patients (37.4%). Univariable logistic regression analysis identified age, systemic hypertension, diabetes, atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume as significant predictors of elevated LVFP. Atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume remained independent determinants of LVFP in adjusted analysis. At follow-up, higher LVFPs were measured in patients who had meanwhile undergone pulmonary endarterectomy (P = 0.002). LVFP >15 mm Hg (P = 0.021) and >11 mm Hg (P = 0.006) were both associated with worse long-term survival. CONCLUSIONS: Elevated LVFP is common, appears to be due to comorbid left heart disease, and predicts prognosis in CTEPH.

EGR1 Is Implicated in Right Ventricular Cardiac Remodeling Associated with Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a vasoconstrictive disease characterized by elevated mean pulmonary arterial pressure (mPAP) at rest. Idiopathic pulmonary arterial hypertension (iPAH) and chronic thromboembolic pulmonary hypertension (CTEPH) represent two distinct subtypes of PH. Persisting PH leads to right ventricular (RV) hypertrophy, heart failure, and death. RV performance predicts survival and surgical interventions re-establishing physiological mPAP reverse cardiac remodeling. Nonetheless, a considerable number of PH patients are deemed inoperable. The underlying mechanism(s) governing cardiac regeneration, however, remain largely elusive. METHODS: In a longitudinal approach, we profiled the transcriptional landscapes of hypertrophic RVs and recovered hearts 3 months after surgery of iPAH and CTEPH patients. RESULTS: Genes associated with cellular responses to inflammatory stimuli and metal ions were downregulated, and cardiac muscle tissue development was induced in iPAH after recovery. In CTEPH patients, genes related to muscle cell development were decreased, and genes governing cardiac conduction were upregulated in RVs following regeneration. Intriguingly, early growth response 1 (EGR1), a profibrotic regulator, was identified as a major transcription factor of hypertrophic RVs in iPAH and CTEPH. A histological assessment confirmed our biocomputational results, and suggested a pivotal role for EGR1 in RV vasculopathy. CONCLUSION: Our findings improved our understanding of the molecular events driving reverse cardiac remodeling following surgery. EGR1 might represent a promising candidate for targeted therapy of PH patients not eligible for surgical treatment.

The Roles of S100A4 and the EGF/EGFR Signaling Axis in Pulmonary Hypertension with Right Ventricular Hypertrophy.

Pulmonary hypertension (PH) is characterized by increased pulmonary arterial pressure caused by the accumulation of mesenchymal-like cells in the pulmonary vasculature. PH can lead to right ventricular hypertrophy (RVH) and, ultimately, heart failure and death. In PH etiology, endothelial-to-mesenchymal transition (EndMT) has emerged as a critical process governing the conversion of endothelial cells into mesenchymal cells, and S100A4, EGF, and EGFR are implicated in EndMT. However, a potential role of S100A4, EGF, and EGFR in PH has to date not been elucidated. We therefore quantified S100A4, EGF, and EGFR in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH). To determine specificity for unilateral heart disease, the EndMT biomarker signature was further compared between PH patients presenting with RVH and patients suffering from aortic valve stenosis (AVS) with left ventricular hypertrophy. Reduced S100A4 concentrations were found in CTEPH and iPAH patients with RVH. Systemic EGF was increased in CTEPH but not in iPAH, while AVS patients displayed slightly diminished EGF levels. EGFR was downregulated in all patient groups when compared to healthy controls. Longitudinal data analysis revealed no effect of surgical therapies on EndMT markers. Pulmonary thrombo-endarterectomized samples were devoid of S100A4, while S100A4 tissue expression positively correlated with higher grades of Heath-Edwards histopathological lesions of iPAH-derived lung tissue. Histologically, EGFR was not detectable in CTEPH lungs or in iPAH lesions. Together, our data suggest an intricate role for S100A4 and EGF/EGFR in PH with right heart pathology.

Efficacy and Safety of Percutaneous Pulmonary Artery Subtotal Occlusion and Chronic Total Occlusion Intervention in Chronic Thromboembolic Pulmonary Hypertension.

[Figure: see text].

Chronic Thromboembolic Disease and Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic pulmonary vascular disease (CTED) are rare manifestations of venous thromboembolism. Presumably, CTEPH and CTED are variants of the same pathophysiological mechanism. CTEPH and CTED can be near-cured by pulmonary endarterectomy, balloon pulmonary angioplasty, and medical treatment with Riociguat or subcutaneous treprostinil, which are the approved drugs.

Microvascular Disease in Chronic Thromboembolic Pulmonary Hypertension: Hemodynamic Phenotyping and Histomorphometric Assessment.

BACKGROUND: Pulmonary endarterectomy (PEA) is the gold standard treatment for patients with operable chronic thromboembolic pulmonary hypertension. However, persistent pulmonary hypertension (PH) after PEA remains a major determinant of poor prognosis. A concomitant small-vessel arteriopathy in addition to major pulmonary artery obstruction has been suggested to play an important role in the development of persistent PH and survival after PEA. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence and severity of small-vessel arteriopathy. Using the pulmonary artery occlusion technique, we sought to assess the presence and degree of small-vessel disease in patients with chronic thromboembolic pulmonary hypertension undergoing PEA to predict postoperative outcome before surgery. METHODS: Based on pulmonary artery occlusion waveforms yielding an estimate of the effective capillary pressure, we partitioned pulmonary vascular resistance in larger arterial (upstream resistance [Rup]) and small arterial plus venous components (downstream resistance) in 90 patients before PEA. For validation, lung wedge biopsies were taken from nonobstructed and obstructed lung territories during PEA in 49 cases. Biopsy sites were chosen according to the pulmonary angiogram still frames that were mounted in the operating room. All vessels per specimen were measured in each patient. Percent media (%MT; arteries) and intima thickness (%IT; arteries, veins, and indeterminate vessels) were calculated relative to external vessel diameter. RESULTS: Decreased Rup was an independent predictor of persistent PH (odds ratio per 10%, 0.40 [95% CI, 0.23-0.69]; P=0.001) and survival (hazard ratio per 10%, 0.03 [95% CI, 0.00-0.33]; p=0.004). Arterial %MT and %IT of nonobstructed lung territories and venous %IT of obstructed lung territories were significantly increased in patients with persistent PH and nonsurvivors. Rup correlated inversely with %MT (r=-0.72, P<0.001) and %IT (r=-0.62, P<0.001) of arteries from nonobstructed lung territories and with %IT (r=-0.44, P=0.024) of veins from obstructed lung territories. Receiver operating characteristic analysis disclosed that Rup <66% predicted persistent PH after PEA, whereas Rup <60% identified patients with poor prognosis after PEA. CONCLUSIONS: Pulmonary artery occlusion waveform analysis with estimation of Rup seems to be a valuable technique for assessing the degree of small-vessel disease and postoperative outcome after PEA in chronic thromboembolic pulmonary hypertension.

Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial.

BACKGROUND: Treprostinil, a prostacyclin analogue, is effective for the treatment of pulmonary arterial hypertension. However, information is scarce regarding treprostinil for treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to examine the efficacy and safety of subcutaneous treprostinil in this setting. METHODS: In this 24-week, randomised, double-blind controlled trial, we enrolled patients with CTEPH, classified as non-operable, or with persistent or recurrent pulmonary hypertension after pulmonary endarterectomy, in six European expert centres in Austria, Czech Republic, Germany, and Poland. Patients in WHO functional class III or IV with a 6-min walk distance of 150-400 m were randomly assigned at a 1:1 allocation ratio to continuous high-dose subcutaneous treprostinil (target dose around 30 ng/kg per min at week 12) or low-dose subcutaneous treprostinil (target dose around 3 ng/kg per min at week 12). The primary endpoint was the change from baseline in 6-min walk distance at week 24. All patients who received at least one dose of the study drug were included in the intention-to-treat efficacy and safety analyses based on assessment of adverse events. The trial was registered at ClinicalTrialsRegister.eu EudraCT number 2008-006441-10 and ClinicalTrials.gov, number NCT01416636. FINDINGS: From March 9, 2009, to June 9, 2016, 105 patients were enrolled with 53 (50%) patients randomly assigned to high-dose and 52 (50%) patients to low-dose subcutaneous treprostinil. At week 24, marginal mean 6-min walk distance improved by 44·98 m (95% CI 27·52 to 62·45) in the high-dose group, and by 4·29 m (95% CI -13·34 to 21·92) in the low-dose group (treatment effect 40·69 m, 95% CI 15·86 to 65·53, p=0·0016). 12 serious adverse events were reported in ten (19%) of 52 patients from the low-dose group and 16 serious adverse events were reported in nine (17%) of 53 patients from the high-dose group. The most common treatment-related adverse events in both groups were infusion site pain and other infusion site reactions. INTERPRETATION: Treatment with subcutaneous treprostinil was safe, and improved exercise capacity in patients with severe CTEPH. Subcutaneous treprostinil provides a parenteral treatment option for patients of WHO functional class III or IV and those who do not tolerate other therapies or need combination treatment. FUNDING: SciPharm Sàrl.

Usefulness of thrombosis and inflammation biomarkers in chronic thromboembolic pulmonary hypertension-sampling plasma and surgical specimens.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) results from persistent pulmonary vascular obstructions, presumably due to inflammatory thrombosis. Because estimates of thrombus volume at diagnosis have no predictive value, we investigated the role of the thrombosis marker, D-dimer, and the inflammation marker, C-reactive protein (CRP), for predicting outcomes in CTEPH. METHODS: A total 289 consecutive patients with CTEPH were followed for 57 (median 45 to 69) months. One hundred fifty-seven of these patients underwent surgical pulmonary endarterectomy (PEA). D-dimer and CRP were collected at the time of CTEPH diagnosis and their impact on outcome was analyzed using Cox and logistic regression models. Their association with thrombus composition was analyzed utilizing HistoQuest. RESULTS: D-dimer and CRP levels were separately and independently predictive of death or need for lung transplantation (p = 0.012 and p = 0.025, respectively). For example, 5-year survival was 90% (confidence limits 84% to 96%) in patients with D-dimer levels <0.5 µg/ml and CRP <1 mg/dl at diagnosis, as compared with 50% (36% to 64%) for patients with D-dimer ≥0.5 µg/ml and CRP ≥1 mg/dl (p < 0.001). D-dimer and CRP both decreased significantly after PEA (p < 0.01). The amount of fresh red thrombus in thrombendarterectomy specimens correlated positively with D-dimer levels at diagnosis (r = 0.37, p = 0.003). CONCLUSIONS: D-dimer and CRP at the time of diagnosis are independent and significant predictors of outcome in CTEPH, available at the time of diagnosis. This observation suggests an important role for fibrin turnover and inflammation in the pathogenesis of CTEPH and the associated complications.

Subcutaneous treprostinil in congenital heart disease-related pulmonary arterial hypertension.

OBJECTIVE: To assess the efficacy and safety of subcutaneous treprostinil in adult patients with congenital heart disease (CHD)-associated pulmonary arterial hypertension (PAH) after 12 months of treatment. METHODS: Consecutive adult patients with CHD-PAH received subcutaneous treprostinil to maximum tolerated doses in an observational study. RESULTS: Advanced CHD-PAH patients with WHO class III or IV disease (n=32, age 40±10 years, 20 females) received treprostinil for suboptimal response to bosentan (n=12), WHO functional class IV disease (FC, n=7) or prior to bosentan approval (n=13). In the multivariate mixed model, mean increase in 6 min walk distance (6-MWD) from baseline to 12 months was 114 m (76; 152) (P<0.001). WHO FC improved significantly (P=0.001) and B-type brain natriuretic peptide decreased from 1259 (375; 2368) pg/mL to 380 (144; 1468) pg/mL (P=0.02). In those 14 patients who had haemodynamic data before and after initiation of treprostinil, pulmonary vascular resistance decreased significantly (from 18.4±11.1 to 12.6±7.9 Wood units, P=0.003). The most common adverse events were infusion-site erythema and pain. One patient stopped treatment because of intolerable infusion-site pain after 8 months of treatment. No other major treatment-related complications were observed. Five patients died during early follow-up, having experienced a decrease in their 6-MWD prior. CONCLUSIONS: Subcutaneous treprostinil therapy is generally safe and effective for at least 12 months and may be used in CHD-related PAH class III and IV.

Hemodynamic Thresholds for Precapillary Pulmonary Hypertension.

BACKGROUND: Hemodynamic differentiation between pulmonary arterial hypertension (PAH) and postcapillary pulmonary hypertension (PH) is important because treatment options are strikingly different for the two disease subsets. Whereas patients with PAH can be treated effectively with targeted therapies, their use in postcapillary PH is currently not recommended. Our aim was to establish an algorithm to identify patients who are likely to experience a significant hemodynamic treatment response. METHODS: We determined hemodynamic cutoffs to discriminate between idiopathic PAH and postcapillary PH in a large database of 4,363 stable patients undergoing first diagnostic right and left heart catheterizations. In a second step, we performed a patient-level pooled analysis of four randomized, placebo-controlled trials including 541 patients with PAH who received treprostinil or placebo, to validate hemodynamic cutoffs with regard to treatment response. RESULTS: Receiver operating characteristic analysis identified mean pulmonary arterial wedge pressure (mPAWP) < 12 mm Hg and diastolic pulmonary vascular pressure gradient (DPG) ≥ 7 mm Hg as the best hemodynamic discriminators between idiopathic PAH and postcapillary PH. In our treatment study, only patients with mPAWP < 12 mm Hg, DPG > 20 mm Hg or a combination of both had a significant placebo-corrected improvement in hemodynamics. CONCLUSIONS: mPAWP < 12 mm Hg and DPG > 20 mm Hg identify patients with PAH who are likely to have significant hemodynamic improvement with prostacyclin treatment.

Extended-release oral treprostinil for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance ultimately resulting in progressive right heart failure. Although new specific treatments have demonstrated improvements in various end points including morbidity/mortality, prognosis remains unfavorable with an on-treatment yearly mortality rate of 10%. Due to complex delivery systems, the use of parenteral prostanoids has been limited to patients with advanced disease. While inhaled prostanoids have had little effect, an oral prostacyclin analog is a desired initial treatment for PAH patients. To that end, UT-15C was synthesized as a sustained-release tablet. FREEDOM-M in treatment-naïve PAH patients resulted in significant improvements of 6-min walk distance supporting the use of oral treprostinil as initial monotherapy in PAH patients with class II or III symptoms. A further study targeting patients on combination treatments is currently exploring a morbidity/mortality end point in a large patient population.

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.

Selexipag for the treatment of pulmonary arterial hypertension.

INTRODUCTION: Selexipag is a first-in-class orally available selective non-prostanoid IP receptor agonist. This review was based on a PubMed search and focuses on the potential role of selexipag in the treatment of pulmonary arterial hypertension (PAH). AREAS COVERED: Selexipag is rapidly hydrolyzed to an active metabolite, ACT-333679. Both selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors. This selectivity for the IP receptor offers the potential for improved tolerability with selexipag, as side effects (e.g., nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimized. In addition, the selexipag metabolite has a half-life of 7.9 h, thus permitting oral dosing twice daily. Selexipag showed effects on pharmacodynamic end points obtained with right heart catheterization in a Phase II trial in patients with PAH, and is being evaluated in the ongoing Phase III trial (GRIPHON trial, Clinicaltrials.gov NCT01106014). EXPERT OPINION: The signal of a beneficial effect of selexipag on disease progression may become more robust for long term under prolonged exposure. Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.

Surgical specimens, haemodynamics and long-term outcomes after pulmonary endarterectomy.

BACKGROUND: Chronic thromboembolic pulmonary hypertension is surgically curable by pulmonary endarterectomy (PEA). It is unclear whether PEA impacts primarily steady state right ventricular afterload (ie, pulmonary vascular resistance (PVR)) or pulsatile right ventricular afterload (ie, pulmonary arterial compliance (C(PA))). Our objectives were to (1) quantify PEA specimens and measure the impact of PEA on PVR and C(PA) in a structure/function study and (2) analyse the effects of haemodynamic changes on long-term survival/freedom of lung transplantation in an outcome study. METHODS: Thrombi were laid out, weighed, photographed and measured. PVR, C(PA) and resistance times compliance (RC-time) were assessed at baseline, within 4 days after PEA ('immediately postoperative') and 1 year after PEA, in 110 consecutive patients who were followed for 34.5 (11.9; 78.3) months. RESULTS: Lengths and numbers of PEA specimen tails were inversely correlated with immediate postoperative PVR (p<0.0001, r=-0.566; p<0.0001, r=-0.580). PVR and C(PA) normalised immediately postoperatively while RC-time remained unchanged. Immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation (p<0.0001). Patients with immediate postoperative PVR<590 dynes.s.cm(-5) had better long-term outcomes than patients with PVR≥590 dynes.s.cm(-5) (p<0.0001, respectively). CONCLUSIONS: PEA immediately decreased PVR and increased C(PA) under a constant RC-time. However, immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation. Our study confirms the importance of a complete, bilateral surgical endarterectomy. Low PVR measured immediately postoperative predicts excellent long-term outcome.