Worldwide CTEPH Registry: Long-Term Outcomes With Pulmonary Endarterectomy, Balloon Pulmonary Angioplasty, and Medical Therapy.

BACKGROUND: The European Chronic Thromboembolic Pulmonary Hypertension (CTEPH) registry, conducted between 2007 and 2012, reported the major impact of pulmonary endarterectomy (PEA) on the long-term survival of patients with CTEPH. Since then, 2 additional treatments for inoperable CTEPH have become available: balloon pulmonary angioplasty (BPA), and an approved oral drug therapy with the guanylate cyclase stimulator riociguat. The current registry aimed to evaluate the effect of these new therapeutic approaches in a worldwide context. METHODS: Participation in this international global registry included 34 centers in 20 countries. Between February 2015 and September 2016, 1009 newly diagnosed, consecutive patients were included and followed until September 2019. RESULTS: Overall, 605 patients (60%) underwent PEA and 185 (18%) underwent BPA; 76% of the 219 remaining patients not receiving mechanical intervention (ie, neither PEA nor BPA) were treated with pulmonary hypertension drugs. Of patients undergoing PEA and BPA, 38% and 78% also received drugs for pulmonary hypertension, respectively. Median age at diagnosis was higher in the BPA and No PEA/BPA groups than in the PEA group: 66 and 69, respectively, versus 60 years. Pulmonary vascular resistance (PVR) was similar in all groups, with an average of 643 dynes.s.cm-5. During the observation period (>3 years; ≤5.6 years), death was reported in 7%, 11%, and 27% of patients treated by PEA and BPA, and those receiving no mechanical intervention (P<0.001). In Kaplan-Meier analysis, 3-year survival was 94%, 92%, and 71% in the 3 groups, respectively. PEA 3-year survival improved by 5% from that observed between 2007 and 2012. There was no survival difference in patients receiving vitamin K antagonists and non-vitamin K oral anticoagulants (P=0.756). In Cox regression, reduced mortality was associated with: PEA and BPA in the global cohort; history of venous thromboembolism and lower PVR in the PEA group; lower right atrial pressure in the BPA group; and use of pulmonary hypertension drugs, oxygen therapy, and lower right atrial pressure, as well as functional class in the group receiving no mechanical intervention. CONCLUSIONS: This second international CTEPH registry reveals important improvement in patient survival since the introduction of BPA and an approved drug for pulmonary hypertension. The type of anticoagulation regimen did not influence survival. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02656238.

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.

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.

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

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.

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

BACKGROUND: 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. OBJECTIVES: To evaluate the possibility of achieving mPAP <25 mmHg with current treatments, its determinants and the prognostic impact of mPAP reduction. METHODS: 267 consecutive idiopathic, hereditary and drug and toxin-induced PAH patients treated with targeted therapies from three expert centers were followed with periodic clinical and hemodynamic assessments for survival detection. RESULTS: Fifty-four (20.2%) patients achieved a mPAP <25 mmHg over 58 months (IQR 27-90) of treatment. Determinants of mPAP <25 mmHg were mPAP at diagnosis (HR 0.96, 95C.I. 0.93-0.98, p = 0.002) and an upfront combination strategy (double oral combination: HR 2.3, 95C.I. 1.10-4.76, p = 0.02; one oral plus parenteral prostanoid: HR 3.6, 95C.I. 1.39-9.37, p = 0.008; triple combination employing parenteral prostanoids: HR 12.9, 95C.I. 4.9-33.2, p = 0.0001). Seventy-three patients (27.3%) died. Survival rates were 90%, 79%, 70%, 55%, and 42% at 1, 3, 5, 10, and 15 years, respectively. Mean PAP during follow-up, days from diagnosis to prostanoid initiation and prostanoid maximum dose emerged as independent predictors of survival (Uno-C-index: 0.85). A mPAP ≤35 mmHg during follow-up was identified as the best cutoff value for prediction of survival. CONCLUSIONS: Reduction to a mean PAP ≤ 35 mmHg appears to be a meaningful treatment target in idiopathic, hereditary and drug and toxin-induced pulmonary arterial hypertension.

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.

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

[Figure: see text].

Current strategies for managing chronic thromboembolic pulmonary hypertension: results of the worldwide prospective CTEPH Registry.

BACKGROUND: Pulmonary endarterectomy (PEA), pulmonary arterial hypertension (PAH) therapy and balloon pulmonary angioplasty (BPA) are currently accepted therapies for chronic thromboembolic pulmonary hypertension (CTEPH). This international CTEPH Registry identifies clinical characteristics of patients, diagnostic algorithms and treatment decisions in a global context. METHODS: 1010 newly diagnosed consecutive patients were included in the registry between February 2015 and September 2016. Diagnosis was confirmed by right heart catheterisation, ventilation-perfusion lung scan, computerised pulmonary angiography and/or invasive pulmonary angiography after at least 3 months on anticoagulation. RESULTS: Overall, 649 patients (64.3%) were considered for PEA, 193 (19.1%) for BPA, 20 (2.0%) for both PEA and BPA, and 148 (14.7%) for PAH therapy only. Reasons for PEA inoperability were technical inaccessibility (n=235), comorbidities (n=63) and patient refusal (n=44). In Europe and America and other countries (AAO), 72% of patients were deemed suitable for PEA, whereas in Japan, 70% of patients were offered BPA as first choice. Sex was evenly balanced, except in Japan where 75% of patients were female. A history of acute pulmonary embolism was reported for 65.6% of patients. At least one PAH therapy was initiated in 35.8% of patients (26.2% of PEA candidates, 54.5% of BPA candidates and 54.1% of those not eligible for either PEA or BPA). At the time of analysis, 39 patients (3.9%) had died of pulmonary hypertension-related causes (3.5% after PEA and 1.8% after BPA). CONCLUSIONS: The registry revealed noticeable differences in patient characteristics (rates of pulmonary embolism and sex) and therapeutic approaches in Japan compared with Europe and AAO.

Pulmonary vascular reactivity and prognosis in patients with chronic thromboembolic pulmonary hypertension: a pilot study.

BACKGROUND: Surgical pulmonary endarterectomy is the preferred treatment for chronic thromboembolic pulmonary hypertension. Persistent pulmonary hypertension after pulmonary endarterectomy has been recognized as a major determinant of poor outcome. We tested whether acute vasoreactivity identifies chronic thromboembolic pulmonary hypertension patients prone to develop persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and whether the degree of acute vasoreactivity affects survival or freedom from lung transplantation. METHODS AND RESULTS: Right-sided heart catheterization at baseline and after inhalation of 40 ppm nitric oxide for 20 minutes was performed in 103 patients (56.3+/-15.3 years old, 53 women). Reductions in mean pulmonary arterial pressure (DeltamPAP; -8.8+/-12.6%; P<0.0001) and pulmonary vascular resistance (-16.1+/-18.1%; P<0.0001) and an increase in mixed venous saturation during inhaled nitric oxide (9.1+/-11.6%; P<0.0001) were observed. Sixty-two patients underwent pulmonary endarterectomy after a median of 49 days (25th and 75th percentiles: 24 and 123 days). Operated patients were followed up for a median of 70.9 months (25th and 75th percentiles: 14 and 97 months). Change in mPAP during inhaled NO was identified as a predictor of persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. Patients experiencing a reduction in mPAP >10.4% with nitric oxide inhalation had a better postoperative outcome. A significant correlation was found between DeltamPAP and immediate postoperative pulmonary vascular resistance (r=0.5, P<0.0001). CONCLUSIONS: A total of 80 (77.7%) of 103 patients demonstrated acute pulmonary vascular reactivity of some degree. A decrease in mPAP >10.4% under inhaled nitric oxide is a predictor of long-term survival and freedom from lung transplantation in adult patients with chronic thromboembolic pulmonary hypertension who are undergoing pulmonary endarterectomy.

Treprostinil for the treatment of chronic thromboembolic pulmonary hypertension.

Introduction: Parenteral treprostinil for patients with pulmonary arterial hypertension has resulted in improvement of exercise capacity, functional class, hemodynamics, and survival. Recently, a first randomized trial performed in patients with chronic thromboembolic pulmonary hypertension confirmed the efficacy of subcutaneous treprostinil in this subset of pulmonary hypertension. Areas covered: Treprostinil sodium is a prostacyclin analog produced synthetically. Drug characteristics include potent systemic and pulmonary vasodilatory effects. Local side-effects of subcutaneous treprostinil have been an obstacle for its use. However, in contrast to other prostacyclins, treprostinil has favorable features. We performed a literature survey by searching PubMed for clinical trials published in any language, investigating medicinal treatments for CTEPH. We used the search terms 'inoperable', and 'chronic thromboembolic pulmonary hypertension' with 'randomized clinical trial', and have put treprostinil for CTEPH in the contest of published literature. Expert opinion: Drugs approved for PAH have recently shown excellent efficacy in patients with non-operable CTEPH. Rather than head-to-head comparisons of drugs, combination treatments are to be expected in the near future. Furthermore, drugs will have to be tested alongside with pulmonary endarterectomy (PEA), and alongside balloon pulmonary angioplasty, a promising percutaneous mechanical treatment for CTEPH that is not suited for PEA.

Neutrophil extracellular traps and monocyte subsets at the culprit lesion site of myocardial infarction patients.

Neutrophils release their chromatin into the extracellular space upon activation. These web-like structures are called neutrophil extracellular traps (NETs) and have potent prothrombotic and proinflammatory properties. In ST-elevation myocardial infarction (STEMI), NETs correlate with increased infarct size. The interplay of neutrophils and monocytes impacts cardiac remodeling. Monocyte subsets are classified as classical, intermediate and non-classical monocytes. In the present study, in vitro stimulation with NETs led to an increase of intermediate monocytes and reduced expression of CX3CR1 in all subsets. Intermediate monocytes have been associated with poor outcome, while non-classical CX3CR1-positive monocytes could have reparative function after STEMI. We characterized monocyte subsets and NET markers at the culprit lesion site of STEMI patients (n = 91). NET surrogate markers were increased and correlated with larger infarct size and with fewer non-classical monocytes. Intermediate and especially non-classical monocytes were increased at the culprit site compared to the femoral site. Low CX3CR1 expression of monocytes correlated with high NET markers and increased infarct size. In this translational system, causality cannot be proven. However, our data suggest that NETs interfere with monocytic differentiation and receptor expression, presumably promoting a subset shift at the culprit lesion site. Reduced monocyte CX3CR1 expression may compromise myocardial salvage.

Chronic thromboembolic pulmonary hypertension in Austria and Japan.

OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by one or more of the following features: intraluminal thrombus organization, fibrous stenosis, and complete obliteration of major pulmonary arteries, amenable to significant improvement by pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty, and medical treatments with vasodilators. Because treatment practices and outcomes differ in Europe versus Japan, we hypothesized that population-based characteristics of pulmonary vascular phenotypes may exist in Austria compared with Japan. The objectives of this study were to analyze clinical characteristics, hemodynamics, and PEA specimens in consecutive patients with CTEPH undergoing PEA in Austria and Japan. METHODS: Clinical features, hemodynamics, and PEA specimens were collected and analyzed in patients with CTEPH undergoing PEA, and clinical features and hemodynamics were collected and analyzed in patients with not-operated CTEPH and in patients with nonthromboembolic pulmonary arterial hypertension. RESULTS: Apart from key differences between Austrian and Japanese patients regarding body size, lung function vital capacity, cardiac output, and serum high-density lipoprotein levels, Austrian patients were more likely to be obese, have greater hematocrits and greater white blood cells counts, greater C-reactive protein levels, and significantly elevated serum myeloperoxidase levels compared with Japanese patients with CTEPH. Analysis of PEA specimens demonstrated more proximal thrombus and more fresh red thrombus components in Austrian patients. CONCLUSIONS: This study documents an inflammatory thrombotic phenotype in Austrian compared with Japanese patients with CTEPH that may be a determinant of differential treatment outcomes.

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.

Prognostic Significance and Determinants of the 6-Min Walk Test in Patients With Heart Failure and Preserved Ejection Fraction.

OBJECTIVES: This study sought to define the prognostic significance and clinical determinants of the 6-min walk distance (6-MWD) in affected patients. BACKGROUND: Symptoms of exertional fatigue and dyspnea, as well as a reduced exercise tolerance, are cardinal features of pulmonary hypertension associated with heart failure and preserved ejection fraction (PH-HFpEF). Mechanisms limiting exercise capacity in this specific entity remain incompletely understood. METHODS: Consecutive patients with PH-HFpEF, as confirmed by right heart catheter, were enrolled in our prospective registry. Hospitalization for HF and/or death for cardiac reasons were defined as primary outcome. Multiple regression models were constructed to establish determinants of the 6-MWD. For quantification of left ventricular (LV) extracellular matrix (ECM), myocardial biopsies were taken from 18 patients. RESULTS: Between December 2010 and July 2013, 142 PH-HFpEF patients were included in the study. After a mean follow-up of 14.0 ± 10.0 months, 43 patients (30.3%) reached the combined endpoint. The 6-MWD was found to be an independent predictor of outcome and was influenced by a variety of clinical, echocardiographic, hemodynamic, laboratory, and pulmonary parameters. There was a significant inverse correlation between the 6-MWD and the extent of ECM in the LV myocardium. CONCLUSIONS: Impaired exercise capacity in PH-HFpEF patients is explained by cardiac and noncardiac factors. The 6-MWD predicts outcome and may be a useful endpoint in clinical trials.

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.

Long-term treatment, tolerability, and survival with sub-cutaneous treprostinil for severe pulmonary hypertension.

BACKGROUND: Randomized controlled trials have resulted in improved outcomes in pulmonary arterial hypertension; however, they are biased by stringent inclusion criteria, pre-specified patient sub-sets, and study durations. In addition, common practice is to start oral therapies ahead of the more potent and titratable prostanoid therapies, despite advanced disease states at diagnosis. The objectives of our prospective registry were to evaluate long-term effects on functional class, 6-minute walking distance, hemodynamics, and survival, and also long-term tolerability of first-line sub-cutaneous treprostinil, a prostacyclin analog, in patients with severe pulmonary hypertension. METHODS: Data were collected from patients with functional class III/IV pre-capillary pulmonary hypertension (Dana Point groups 1 and 4; mean right arterial pressure ≥ 10 mmHg, and/or cardiac index ≤ 2.2 liters/min/m(2)). Treprostinil dose adjustments were driven by clinical symptoms and side effects. RESULTS: The study included 111 patients (1999 to 2010). Of these, 13 (12%) stopped treatment prematurely because of drug side effects, 11 (9.9%) underwent double lung transplantation, and 49 (44.1%) died of any cause (41 on treatment, 8 after early drug discontinuation). Overall survival rates at 1, 5, and 9 years were 84%, 53%, and 33%. In patients who were able to tolerate treatment > 6 months, survival rates were 57% at 9 years. CONCLUSION: First-line treatment of severe pre-capillary pulmonary hypertension with sub-cutaneous treprostinil is safe and efficacious over many years. If up-titration beyond 6 months is tolerated, effective doses are reached and outcomes are good.

Imaging in pulmonary hypertension.

Pulmonary hypertension is defined as an increase in mean pulmonary arterial pressure ≥25 mm Hg at rest and occurs in a majority of patients with heart failure. Diagnostic imaging targets the right ventricle and the pulmonary vasculature. Although echocardiography is cost-effective for screening and follow-up, right heart catheterization is still mandatory to differentiate pre- from post-capillary disease and to directly measure pressure and flow. An important goal is to rule out chronic thromboembolic pulmonary hypertension. This diagnostic step can be achieved by perfusion scintigraphy, whereas computed tomography and cardiac magnetic resonance have become indispensable ancillary methods for the diagnostic allocation to other World Health Organization subtypes of pulmonary hypertension.