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BACKGROUND Risk assessment is essential in pulmonary arterial hypertension (PAH) management. We investigated the effect of riociguat on REVEAL Lite 2 score, an abridged version of the REVEAL risk score, and its association with long-term outcomes in PATENT. METHODS PATENT-1 was a randomized, double-blind study of riociguat vs placebo in patients with PAH. In the PATENT-2 open-label extension, all patients received riociguat up to 2.5 mg three times daily (n = 396). REVEAL Lite 2 scores were calculated at baseline, PATENT-1 Week 12, and PATENT-2 Week 12, with patients stratified as low- (1-5), intermediate- (6-7), or high-risk (≥8). Kaplan-Meier and Cox proportional hazards analyses assessed association of riociguat with survival and clinical worsening-free survival (CWFS). RESULTS REVEAL Lite 2 score improved with riociguat 2.5 mg at PATENT-1 Week 12 (least-squares mean difference vs placebo: -0.8; p = 0.0004). More patients receiving riociguat 2.5 mg stabilized or improved risk stratum at PATENT-1 Week 12 vs placebo (p = 0.0005) and achieved low-risk status. REVEAL Lite 2 score at baseline and PATENT-1 Week 12 were associated with survival and CWFS (all p < 0.0001), as was change in score from baseline to Week 12 (p = 0.0002 and p < 0.0001, respectively). Survival and CWFS differed between risk strata at baseline (p < 0.0001) and PATENT-1 Week 12 (p < 0.0001). CONCLUSIONS This analysis confirms the risk-reduction benefits of riociguat in patients with PAH and further contributes to the validation of REVEAL Lite 2 in facilitating PAH risk assessment.

International audience; Rationale: The relationship between the initial treatment strategy and survival in pulmonary arterial hypertension (PAH) remains uncertain. Objectives: To evaluate the long-term survival of patients with PAH categorized according to the initial treatment strategy. Methods: A retrospective analysis of incident patients with idiopathic, heritable, or anorexigen-induced PAH enrolled in the French Pulmonary Hypertension Registry (January 2006 to December 2018) was conducted. Survival was assessed according to the initial strategy: monotherapy, dual therapy, or triple-combination therapy (two oral medications and a parenteral prostacyclin). Measurements and Main Results: Among 1,611 enrolled patients, 984 were initiated on monotherapy, 551 were initiated on dual therapy, and 76 were initiated on triple therapy. The triple-combination group was younger and had fewer comorbidities but had a higher mortality risk. The survival rate was higher with the use of triple therapy (91% at 5 yr) as compared with dual therapy or monotherapy (both 61% at 5 yr) (P < 0.001). Propensity score matching of age, sex, and pulmonary vascular resistance also showed significant differences between triple therapy and dual therapy (10-yr survival, 85% vs. 65%). In high-risk patients (n = 243), the survival rate was higher with triple therapy than with monotherapy or dual therapy, whereas there was no difference between monotherapy and double therapy. In intermediate-risk patients (n = 1,134), survival improved with an increasing number of therapies. In multivariable Cox regression, triple therapy was independently associated with a lower risk of death (hazard ratio, 0.29; 95% confidence interval, 0.11-0.80; P = 0.017). Among the 148 patients initiated on a parenteral prostacyclin, those on triple therapy had a higher survival rate than those on monotherapy or dual therapy. Conclusions: Initial triple-combination therapy that includes parenteral prostacyclin seems to be associated with a higher survival rate in PAH, particularly in the youngest high-risk patients.

Common variable immunodeficiency (CVID) is known to cause infectious, inflammatory, and autoimmune manifestations. Pulmonary hypertension (PH) is an unusual complication of CVID with largely unknown characteristics and mechanisms. We report the clinical, functional, hemodynamics, radiologic and histologic characteristics, and outcomes of CVID-associated PH patients from the French PH Network. Ten patients were identified. The median (range) age at CVID diagnosis was 36.5 (4–49) years and the median delay between CVID and PH diagnosis was 12 (0–30) years. CVID-associated PH affected predominantly women (female-to-male ratio 9:1). Most patients were New York Heart Association functional class III with a severe hemodynamic profile and frequent portal hypertension (n = 6). Pulmonary function tests were almost normal in 70% of patients and showed a mild restrictive syndrome in 30% of patients while the diffusing capacity for carbon monoxide was decreased in all but one patient. High-resolution computed tomography found enlarged mediastinal nodes, mild interstitial infiltration with reticulations and nodules. Two patients had a CIVD-interstitial lung disease, and one presented with bronchiectasis. Pathologic assessment of lymph nodes performed in 5 patients revealed the presence of granulomas (n = 5) and follicular lymphoid hyperplasia (n = 3). At last follow-up (median 24.5 months), 9 patients were alive, and one patient died of Hodgkin disease. PH is a possible complication of CVID whose pathophysiological mechanisms, while still unclear, would be due to the inflammatory nature of CVID. CVID-associated PH presents as precapillary PH with multiple possible causes, acting in concert in some patients: a portal hypertension, a pulmonary vascular remodeling, sometimes a pulmonary parenchymal involvement and occasionally an extrinsic compression by mediastinal lymphadenopathies, which would be consistent with its classification in group 5 of the current PH classification.

Right ventricular failure (RVF) is a common cause of admission to the intensive care unit and its presence is a major prognostic factor in acute pulmonary embolism (PE) and chronic pulmonary hypertension (PH). RVF results from an incapacity of the RV to adapt to an increase in afterload so it can become critical in acute PE and chronic PH. The presence of RVF in cases of acute PE with haemodynamic instability is an indication for thrombolytic therapy. RVF represents the most common cause of death in chronic PH. Factors triggering RV failure in PH, such as infection, PE, arrhythmias, or unplanned withdrawal of pulmonary arterial hypertension (PAH)-targeted therapy, have to be considered and treated if identified. However, RVF may also represent progression to end-stage disease. The management of RVF in patients with PH requires expertise and consists of optimization of fluid balance (with diuretics), cardiac output (with inotropic support such as dobutamine), perfusion pressure (with norepinephrine), and reduction of RV afterload with PAH-targeted therapies. Extracorporeal life support, lung transplantation or heart-lung transplantation should be considered in cases of refractory RVF in eligible patients.

Background Although preserved right ventricular (RV) function is consistently associated with better survival in pulmonary arterial hypertension (PAH), the French risk assessment method has not yet considered echocardiographic criteria of RV function. Purpose In the present study, we tested the value of tricuspid annular plane systolic excursion (TAPSE) measured by echocardiography for non-invasive PAH risk assessment. Methods We retrospectively studied a cohort of 306 incident PAH patients treated in two French expert centers who underwent follow-up TAPSE measurement from echocardiographic apical 4-chamber view in addition to previously validated invasive and non-invasive risk stratification variables. The primary composite outcome was 3-year lung transplantation free survival after follow-up assessment. Results At re-evaluation, 66% of patients were in NYHA functional class I-II and mean pulmonary arterial pressure, cardiac index, N-Terminal pro brain natriuretic peptide (NTproBNP), and 6-minute walk distance (6MWD) were 40±16 mmHg, 3.5±1.1 L/min/m2, 270 [interquartile range (IQR) 896] ng/L and 401 (IQR 213) meters, respectively. The primary outcome occurred in 58 (19%) patients. In multivariable Cox regression analysis, NYHA functional class I-II (p=0.02), NTproBNP 440m (p=0.049) and TAPSE≥17 mm (p=0.02) were associated with lung transplantation free survival. TAPSE provided similar information over 6MWD when both were used alternatively to stratify PAH patients at low risk (log-rank Conclusion Three dichotomized low-risk criteria (TAPSE, 6MWD and NTproBNP or BNP plasma levels) allow non-invasive risk assessment in PAH. Funding Acknowledgement Type of funding sources: None. 3-years transplant-free survival

Introduction: Whipple’s disease (WD) is a rare multivisceral disorder with few descriptions of pulmonary hypertension (PH) Aims and objectives: To describe the association between PH and WD (PH-WD). Methods: We report the characteristics and outcomes of two patients with PH-WD hospitalized in the French PH reference center. Results: PH-WD was diagnosed in two men (54 and 59-yo) hospitalized for right heart failure. Both reported a deterioration in general state over the previous year, associated with diarrhea and mood change (patient 1) and a seronegative polyarthritis and purpura (patient 2). Initial right heart catheterization (RHC) confirmed severe precapillary PH in patient 1: mean pulmonary artery pressure 40 mmHg, cardiac index 2 L/min/m2, pulmonary artery wedge pressure13 mmHg, pulmonary vascular resistance 8 WU. The second patient presented with advanced right heart failure, high echocardiographic probability of PH and no evidence of left heart disease. Both patients were treated with intravenous dobutamine and large spectrum antibiotics. The diagnosis of WD was established by duodenal biopsies and positive T. whipplei PCR in the saliva (patient 1) and in the blood and stools (patient 2). The first patient rapidly improved and experienced complete recovery after one year of treatment associating bosentan, tadalafil, doxycycline and hydroxychloroquine. The second patient rapidly deteriorated and died 24h after his admission because of end-stage right heart failure. Conclusions: WD is a rare cause of severe but potentially reversible PH. Due to poor awareness, delayed diagnosis may lead to death due to end-stage right heart failure.

International audience; Rationale: Pulmonary hypertension (PH) has been described in patients treated with leflunomide. Objectives: To assess the association between leflunomide and PH. Methods: We identified incident cases of PH in patients treated with leflunomide from the French PH Registry and through the pharmacoVIGIlAnce in Pulmonary ArTerial Hypertension (VIGIAPATH) program between September 1999 to December 2019. PH etiology, clinical, functional, radiologic, and hemodynamic characteristics were reviewed at baseline and follow-up. A pharmacovigilance disproportionality analysis using the World Health Organization's global database was conducted. We then investigated the effect of leflunomide on human pulmonary endothelial cells. Data are expressed as median (min-max). Results: Twenty-eight patients treated with leflunomide before PH diagnosis was identified. A total of 21 (75%) had another risk factor for PH and 2 had two risk factors. The median time between leflunomide initiation and PH diagnosis was 32 months (1-120). Right heart catheterization confirmed precapillary PH with a cardiac index of 2.37 L⋅min-1 ⋅m-2 (1.19-3.1) and elevated pulmonary vascular resistance at 9.63 Wood Units (3.6-22.1) without nitric oxide reversibility. Five patients (17.9%) had no other risk factor for PH besides exposure to leflunomide. No significant hemodynamic improvement was observed after leflunomide withdrawal. The pharmacovigilance disproportionality analysis using the World Health Organization's database revealed a significant overrepresentation of leflunomide among reported pulmonary arterial hypertension-adverse drug reactions. In vitro studies showed the dose-dependent toxicity of leflunomide on human pulmonary endothelial cells. Conclusions: PH associated with leflunomide is rare and usually associated with other risk factors. The pharmacovigilance analysis suggests an association reinforced by experimental data.

Previous studies have suggested an association between uric acid (UA) and the severity of pulmonary arterial hypertension (PAH), but it is unknown whether UA contributes to disease pathogenesis.The aim of this study was to determine the prognostic value of circulating UA in the era of current management of PAH and to investigate the role of UA in pulmonary vascular remodelling.Serum UA levels were determined in idiopathic, heritable or anorexigen PAH at baseline and first re-evaluation in the French Pulmonary Hypertension Network. We studied protein levels of xanthine oxidase (XO) and the voltage-driven urate transporter 1 (URATv1) in lungs of control and PAH patients and of monocrotaline (MCT) and Sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH).High serum UA levels at first follow-up, but not at baseline, were associated with a poor prognosis. Both the generating enzyme XO and URATv1 were upregulated in the wall of remodelled pulmonary arteries in idiopathic PAH patients and MCT and SuHx rats. High UA concentrations promoted a mild increase in cell growth in idiopathic PAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, oxonic acid-induced hyperuricaemia did not aggravate MCT-induced PH in rats. Finally, chronic treatment of MCT and SuHx rats with benzbromarone mildly attenuated pulmonary vascular remodelling.UA levels in idiopathic PAH patients were associated with an impaired clinical and haemodynamic profile and might be used as a non-invasive indicator of clinical prognosis during follow-up. Our findings also indicate that UA metabolism is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH.

Background and Objective Ventilatory inefficiency (high V′E/V′CO2) and resting hypocapnia are common in pulmonary vascular disease and are associated with poor prognosis. Low resting PaCO2 suggests increased chemosensitivity or an altered PaCO2 set-point. We aimed to determine the relationships between exercise gas exchange variables reflecting the PaCO2 set-point, exercise capacity, hemodynamics and V′E/V′CO2. Methods Pulmonary arterial hypertension (n = 34), chronic thromboembolic pulmonary hypertension (CTEPH, n = 19) and pulmonary veno-occlusive disease (PVOD, n = 6) patients underwent rest and peak exercise arterial blood gas measurements during cardiopulmonary exercise testing. Patients were grouped according to resting PaCO2: hypocapnic (PaCO2 ≤34 mmHg) or normocapnic (PaCO2 35–45 mmHg). The PaCO2 set-point was estimated by the maximal value of end-tidal PCO2 (maximal PETCO2) between the anaerobic threshold and respiratory compensation point. Results The hypocapnic group (n = 39) had lower resting cardiac index (3.1 ±0.8 vs. 3.7 ±0.7 L/min/m2, p Conclusions Resting hypocapnia is associated with worse cardiac function, more ventilatory inefficiency and reduced exercise capacity. This could be explained by elevated chemosensitivity and lower PaCO2 set-point. Maximal PETCO2 may be a useful non-invasive marker of PaCO2 setpoint and disease severity even with submaximal effort.

Background Viral respiratory infections are the main causes of asthma exacerbation. The susceptibility of asthmatics to develop an exacerbation when they present with severe pneumonia due to SARS-CoV-2 infection is unknown. The objective of this study was to investigate the characteristics and outcomes of asthmatic patients with COVID-19 pneumonia who required hospitalisation during the spring 2020 outbreak in Paris, France. Methods A prospective cohort follow-up was carried out from March 15 to April 15, 2020 in Bicêtre Hospital, University Paris-Saclay, France. All hospitalised patients with a SARS-CoV-2 infection who reported a history of asthma were included. Results Among 768 hospitalised patients, 37 (4.8%) reported a history of asthma, which had been previously confirmed by a pulmonologist in 85% of cases. Patients were mainly female (70%), non-smokers (85%), with a median age of 54 years (interquartile range, IQR 42–67). None of them presented with an asthma exacerbation. Twenty-two (59%) had major comorbidities and 31 (84%) had a body mass index ≥25 kg·m−2. The most common comorbidities were obesity (36%), hypertension (27%) and diabetes (19%). All patients had a confirmed diagnosis of COVID-19 pneumonia on computed tomography of the chest. Eosinopenia was a typical biologic feature with a median count of 0/mm3 (IQR 0–0). Eleven patients (30%) were admitted in intensive care unit with three death (8.1%) occurring in the context of comorbidities. Conclusion Asthmatics were not overrepresented among patients with severe pneumonia due to SARS-CoV-2 infection who required hospitalisation. Worst outcomes were observed mainly in patients with major comorbidities., Asthmatics were not overrepresented among patients with severe pneumonia due to SARS-CoV-2 infection who require hospitalisation. None of them presented with an asthma exacerbation. Worst outcomes were observed mainly in patients with major comorbidities.

Pre-capillary pulmonary hypertension is a rare and heterogenous complication in sarcoidosis. 6-min walking distance is a robust and consistent prognostic factor, but the role of pulmonary arterial hypertension-targeted treatments remains controversial.http://bit.ly/2J27Yps

Background:Hemodynamic variables such as cardiac index and right atrial pressure have consistently been associated with survival in pulmonary arterial hypertension (PAH) at the time of diagnosis. Recent studies have suggested that pulmonary arterial compliance may also predict prognosis in PAH. The prognostic importance of hemodynamic values achieved after treatment initiation is less well established.Methods:Our objective was to evaluate the prognostic importance of clinical and hemodynamic variables during follow-up, including pulmonary arterial compliance, after initial management in PAH. We evaluated incident patients with idiopathic, drug- and toxin-induced, or heritable PAH enrolled in the French pulmonary hypertension registry between 2006 and 2016 who had a follow-up right-sided heart catheterization (RHC). The primary outcome was death or lung transplantation. We used stepwise Cox regression and the Kaplan-Meier method to assess variables obtained at baseline and at first follow-up RHC.Results:Of 981 patients, a primary outcome occurred in 331 patients (33.7%) over a median follow-up duration of 2.8 years (interquartile range, 1.1–4.6 years). In a multivariable model considering only baseline variables, no hemodynamic variables independently predicted prognosis. Median time to first follow-up RHC was 4.6 months (interquartile range, 3.7–7.8 months). At first follow-up RHC (n=763), New York Heart Association functional class, 6-minute walk distance, stroke volume index (SVI), and right atrial pressure were independently associated with death or lung transplantation, adjusted for age, sex, and type of PAH. Pulmonary arterial compliance did not independently predict outcomes at baseline or during follow-up. The adjusted hazard ratio for SVI was 1.28 (95% confidence interval, 1.11–1.49;P2decrease and for right atrial pressure was 1.05 (95% confidence interval, 1.02–1.09;P−1·m−2, 6-minute walk distance >440 m, and New York Heart Association class I or II functional class, lower SVI was still associated with higher rates of death or lung transplantation (PConclusions:SVI and right atrial pressure were the hemodynamic variables that were independently associated with death or lung transplantation at first follow-up RHC after initial PAH treatment. These findings suggest that the SVI could be a more appropriate treatment target than cardiac index in PAH.

IntroductionContemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators.MethodsWe evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan–Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches.ResultsAt baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk.ConclusionsThe four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach.

Background: Some previous reports suggested that “persistent PH” leads to poor surgical outcome after endarterectomy in patients with CTEPH. Dilatated BAs in patients with CTEPH would be decreased after endarterectomy, however some cases would not be changed. It might reflect the development of small-vessel remodeling and lead to “persistent PH”. Aim: To clarify that the BA total cross-sectional area(CSA) predicts the extent of persistent PH after endarterectomy. Method and Result: We retrospectively reviewed 81 CTEPH patients from the French PH Registry that underwent PEA from 2014 to 2018 (age: 59.2±13.6[SEM] years, male39/ female42). Pre- and post-operative total CSA of BAs was measured by computed tomography, and its correlation with surgical outcome was assessed. After endarterectomy, the total CSA of BAs was significantly reduced (pre-operative 12.22±4.3 [SEM] mm2 vs post-operative 7.4±3.0 [SEM] mm2, p Conclusion: After PEA, the total CSA of the BAs significantly decreased in patients with CTEPH. There is a significant correlation between pre-operative total CSA of the BAs and pre-operative hemodynamic data. Furthermore, accumulations of numbers are needed to better understand that total CSA of the BAs and its changes with predict of surgical outcomes in CTEPH.

Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) have recently evolved with the availability of balloon pulmonary angioplasty (BPA) and pulmonary vasodilators. Our aim was to analyze the prognostic variables associated with long-term outcome in a cohort of patients with not-operated CTEPH.From January 2006 to December 2016, 343 newly diagnosed consecutive patients with not-operated CTEPH were diagnosed and followed up in the French Reference Center for Pulmonary Hypertension. Overall long-term survival and prognostic factors according to the diagnosis period (early period, 2006-2012, vs recent period, since 2013, i.e., one year before availability of BPA) were analyzed.In the overall population, baseline New York Heart Association functional class, right atrial pressure, 6-minute walk distance (6MWD), and diagnosis period were independent predictors of survival. The 1- and 3-year survival rates of patients diagnosed in the recent period (n = 170) were 91.6% and 85.0%, compared with 89.0% and 74.3% in patients diagnosed in the early period (n = 173), respectively (p = 0.030). Multivariate analysis from patients diagnosed in the recent period found that baseline 6MWD (per 20 m increase in distance) (hazard ratio [HR], 0.879; 95% confidence interval [CI], 0.832-0.928, p0.001) and BPA (HR, 0.307; 95% CI, 0.099-0.957; p = 0.042) were independently associated with survival.Survival of not-operated patients with CTEPH has significantly improved in the recent management era. New treatment options, including BPA, might have the potential to improve the prognosis of patients with inoperable CTEPH.

Background To date, nothing is known about the evolution of survival in systemic sclerosis-associated pulmonary arterial hypertension (PAH) over the last decade. Methods This study used a multivariate Cox regression model adjusted for clinically relevant baseline confounders to assess the association between the occurrence of death and date of PAH diagnosis comparing two periods of the same duration (2006-2011 vs 2012-2017). Interactions between the two diagnosis periods and baseline variables were tested. Results A total of 306 incident patients were included, 167 (54.6%) with a PAH diagnosis occurring in 2006 to 2011 and 139 (45.4%) in 2012 to 2017. No significant difference in survival was observed between patients diagnosed with PAH in 2012 to 2017 compared with those diagnosed in 2006 to 2011 (hazard ratio [HR], 0.76 [0.46-1.26]; P = .29). A significant interaction was observed between PAH diagnosis periods and age (P = .05). When stratifying according to age (based on the median age of 70 years), a significant increase was observed in survival in patients aged ≤ 70 years between the 2006 to 2011 period and the 2012 to 2017 period (HR, 0.40 [0.17-0.99]; P = .046) but not in older patients (HR, 1.29 [0.67-2.51]; P = .44). A significantly higher proportion of initial (ie, within the first 4 months) endothelin receptor antagonist/phosphodiesterase type 5 inhibitor combination therapy was observed in younger patients diagnosed from 2012 to 2017 vs those diagnosed from 2006 to 2011 (42.9% vs 19.5%; P = .002) but not in older patients. Conclusions Over the period 2006 to 2017, survival in systemic sclerosis-associated PAH improved over time in patients aged ≤ 70 years but not in older patients. Further investigations are needed to confirm this relation, as general improvement in medical care and management may also be a possible explanation.

Long-term outcomes and prognostic factors in PoPH remain controversial in the era of modern PAH-targeted therapies. The aim of our study was to determine long-term survival and prognostic factors in a large cohort of incident patients with PoPH in the era of modern PAH-targeted therapy (2007-2017). Among the 209 patients analysed (60% male, age 55±11 years), 128 (61%) had mild cirrhosis, i.e. Child-Pugh (CP) stage A. The mean MELD score was 13±6. Baseline NYHA functional class (FC) distribution was I-II (30%), III (60%), IV (10%). Baseline 6-min walk distance (6MWD) was 350±134 m, mean PAP 46±13 mmHg, cardiac index 3.0±1.0 L/min/m2 and pulmonary vascular resistance (PVR) 7.5±4.4 WU. The majority of patients have been initiated with monotherapy (PDE-5 inhibitor, n=93, or endothelin-receptor antagonist, n=34), 40 (19%) with dual oral combination therapy and 7 (3%) with a PGI2 analogue. After a median follow-up of 4 months, there were significant improvements from baseline in FC (p Survival of patients with PoPH is mainly determined by the severity of the underlying liver disease. Combination of PAH-targeted therapy and LT is associated with a better survival.

Background: Initial dual combination therapy is superior to monotherapy for lowering the risk of clinical-failure events in patients with PAH. However, the impact of initial treatment strategy on long-term survival is still unknown. Objective: To analyse the effect of initial monotherapy, dual or triple (with IV/SC prostacyclin) combination therapy on survival in newly diagnosed PAH patients. Methods: We analysed 1295 consecutive incident patients with functional class (FC) II-IV idiopathic, heritable, or drug-induced PAH diagnosed between 2006 and 2016 and initiated with PAH-targeted therapy: monotherapy (n=824, 64%), dual combination (n=400, 31%) or triple therapy (n=71, 5%). Survival in each treatment group (mono, dual, triple combination) was compared to predicted survival from the French registry equation (Humbert, et al. Eur Respir J 2010). Uni- and multivariate Cox regression was performed to assess survival according to treatment group. Results: Patients initiated with triple therapy were younger with more severe hemodynamics (PVR 18.6±7.5 vs dual therapy 12.1±5.8 and monotherapy 8.9±4.6 WU). Actual three-year survival was better than predicted in all treatment groups: monotherapy 73% vs 63%, dual therapy 72% vs 57%, triple therapy 90% vs 46%. Adjusting for age, gender, FC, 6-min walk distance, right atrial pressure, and cardiac index, the use of initial triple therapy reduced the risk of death compared to mono or dual therapy (HR 0.35, 95% CI 0.17-0.71, p=0.003). Conclusion: Initial triple therapy with IV/SC prostacyclin may reduce the risk of death in incident patients with PAH. This supports the notion of an aggressive early treatment strategy for newly diagnosed patients.

Background: Treatment options for non-operable CTEPH have recently changed with the availability of balloon pulmonary angioplasty (BPA). The aim was to analyse survival and prognostic factors of patients with not-operated CTEPH in the modern management era. Methods: We retrospectively reviewed data from 343 consecutive not-operated CTEPH diagnosed from 01/2006 to 12/2016. Clinical and hemodynamic data at diagnosis and during follow-up were collected. Overall survival and prognostic factors according to diagnostic period (2006-2012 vs since 2013, i.e. one year before availability of BPA) were analysed. Results: Baseline NYHA functional class III/IV, right atrial pressure, 6-min walk distance (6MWD) and diagnostic period were associated with survival in multivariate analysis. Survival of recently diagnosed patients (since 2013; n=170) was better than that of patients diagnosed from 2006 to 2012 (n=173) (Figure, p=0.017, log-rank test). Multivariate analysis in recently diagnosed patients showed that baseline 6MWD (HR 0.994, 95% CI 0.991-0.997, p Conclusion: Survival of not-operated CTEPH patients has significantly improved recently with the availability of BPA. BPA might have the potential to improve outcome of non-operable CTEPH patients.

Data on efficacy and safety of tadalafil in portopulmonary hypertension (PoPH) are lacking. The aim of our study was to analyze short- and long-term efficacy and safety of an initial monotherapy with tadalafil in patients with PoPH. All consecutive patients with PoPH initiated with tadalafil were retrospectively analyzed. Clinical and haemodynamic characteristics were assessed at the time of diagnosis (baseline) and during follow-up. Overall survival was analyzed. Thirty-eight patients were analyzed (71% males, mean age 54±11 years). Fourteen patients (37%) were in Child-Pugh (CP) stage A and twenty-four (63%) in CP stage B or C. The mean MELD score was 14±5. Baseline NYHA functional class (FC) distribution was I-II (34%), III (58%) and IV (8%). Baseline 6-min walk distance (6MWD) was 380±120 m, mean pulmonary artery pressure (mPAP) 44±8 mmHg, cardiac index (CI) 3.1±0.9 L/min/m2 and pulmonary vascular resistance (PVR) 6.6±2.8 WU. After a median follow-up of 4 months, 33 patients have been reevaluated. There were significant improvements from baseline in FC (p Conclusion: Tadalafil was well tolerated and significantly improved FC and hemodynamics in PoPH. Change in PVR was similar irrespective of cirrhosis severity.

There is no data on initial dual oral combination therapy in patients with inoperable CTEPH. The aim of our study was to evaluate the efficacy and safety of different regimen of dual combination of oral PAH drugs initiated in this population. A retrospective analysis was carried out between 2007 and 2017 in 139 consecutive patients with inoperable CTEPH initiated with a combination of endothelin-receptor antagonists (ERAs) with riociguat (RIO) or PDE-5 inhibitor. Results: Mean age was 63±13 years (48% males). ERAs were combined with sildenafil (SIL, n=72), tadalafil (TAD, n=40) or RIO (n=27). In the 117 patients re-evaluated after 4 months (median), there were significant improvements in functional class (class I-II 17% to 39%, p

An obesity paradox, wherein patients who are obese have lower mortality, has been described in cardiopulmonary diseases, including pulmonary arterial hypertension (PAH). Our objective was to determine whether obesity and BMI are associated with mortality in patients with PAH.We assessed incident patients with idiopathic, drug-induced, and heritable PAH from the French Pulmonary Hypertension Network registry. Cox regression and Kaplan-Meier analysis were used to assess the association between BMI and obesity with all-cause mortality.Of 1,255 patients included, 30% were obese. A higher proportion of women (65.1% vs 53.4%, P .01), drug-induced PAH (28.9% vs 9.2%, P .01), systemic hypertension, diabetes, and hypothyroidism were present in the obese group. More obese patients were in New York Heart Association class III (66.4% vs 57.1%), fewer were class IV (11.8% vs 16.9%, P .01), and 6-min walk distance was lower (276 ± 121 vs 324 ± 146, P .01). Right atrial pressure, pulmonary wedge pressure, and cardiac index were higher, whereas pulmonary vascular resistance was lower in patients who were obese. Neither BMI (hazard ratio [HR], 0.99; 95% CI, 0.97-1.01; P = .41) nor obesity (HR, 1.0; 95% CI, 0.99-1.01; P = .46) were associated with mortality in multivariable analyses. There was a significant interaction between age and obesity such that mortality increased among patients 65 years of age who were morbidly obese (HR, 3.01; 95% CI, 1.56-5.79; P = .001).Obesity was not associated with mortality in the overall population, but there was an age-obesity interaction with increased mortality among young patients who were morbidly obese. These results have implications for active weight management in younger patients who are morbidly obese who are otherwise candidates for lung transplantation.

Background The role of decreased pulmonary arterial (PA) compliance (C), equivalent to increased PA stiffness (1/C), as a critical determinant of right ventricular dysfunction and prognosis has been emphasized in pulmonary arterial hypertension (PAH). Methods This study retrospectively reviewed all incident patients diagnosed with idiopathic PAH according to right heart catheterization who were enrolled in the French Pulmonary Arterial Hypertension Network registry between 2006 and 2016 and who had complete baseline data allowing calculation of stiffness (PA pulse pressure/stroke volume index). Results In the 719 patients included (median age: 66 years; 53.7% female), PA stiffness was 1.49 mm Hg × m2/mL (interquartile ratio: 1.08-2.04 mm Hg × m2/mL). Stiffness was related to mean pulmonary artery pressure (mPAP) (r2 = 0.33) and heart rate (r2 = 0.15) but not to age or sex. Higher PA stiffness and higher pulmonary vascular resistance (PVR) were documented in high-risk vs low-risk patients, as defined according to the European Society of Cardiology/European Respiratory Society guidelines. The dispersion of the PVR × C product was as variable as patient age and mPAP, and C could not be estimated on the basis of PVR alone (95% limits of agreement of the bias: –50% to 54%). Although transplant-free survival differed across PA stiffness quartiles (P = .04), stiffness was not an independent predictor of long-term outcome (median follow-up duration: 2.43 years). Conclusions In incident idiopathic PAH, PA stiffness was related to mPAP and heart rate, and this finding outperformed the potential influences of age and sex. Baseline PA stiffness did not independently predict outcome. The great dispersion of the PVR × C product implied that PVR and PA stiffness were differently affected by the disease process.

Acute right heart failure in chronic precapillary pulmonary hypertension is characterised by a rapidly progressive syndrome with systemic congestion resulting from impaired right ventricular filling and/or reduced right ventricular flow output. This clinical picture results from an imbalance between the afterload imposed on the right ventricle and its adaptation capacity. Acute decompensated pulmonary hypertension is associated with a very poor prognosis in the short term. Despite its major impact on survival, its optimal management remains very challenging for specialised centres, without specific recommendations. Identification of trigger factors, optimisation of fluid volume and pharmacological support to improve right ventricular function and perfusion pressure are the main therapeutic areas to consider in order to improve clinical condition. At the same time, specific management of pulmonary hypertension according to the aetiology is mandatory to reduce right ventricular afterload. Over the past decade, the development of extracorporeal life support in refractory right heart failure combined with urgent transplantation has probably contributed to a significant improvement in survival for selected patients. However, there remains a considerable need for further research in this field.

Studies reporting the effects of modern strategies with pulmonary arterial hypertension (PAH)-targeted therapies in sarcoidosis-associated pulmonary hypertension (S-APH) are limited.Clinical and haemodynamic data from newly diagnosed patients with severe S-APH (mean pulmonary artery pressure (mPAP) >35 mmHg or mPAP 25–35 mmHg with cardiac index −1·m−2) were collected from the French Pulmonary Hypertension Registry between 2004 and 2015.Data from 126 patients with severe S-APH were analysed (mean±sd age 57.5±11.6 years, 74% radiological stage IV). 97 patients (77%) received PAH-targeted therapy and immunosuppressive therapy was initiated or escalated in 33 patients at the time of pulmonary hypertension diagnosis. Four months after PAH-targeted therapy initiation, mean±sd pulmonary vascular resistance decreased from 9.7±4.4 to 6.9±3.0 Wood units (pPAH-targeted therapy improved short-term pulmonary haemodynamics in severe S-APH without change in exercise capacity. Immunosuppressive therapy improved haemodynamics in selected patients. Pulmonary hypertension in sarcoidosis remains associated with a poor prognosis.

Introduction: Acute right heart failure (RHF) remains the leading cause of death in patients with precapillary pulmonary hypertension (PH). The impact of extracorporeal life support (ECLS) and urgent transplantation on the outcome of this life threatening condition is unknown. Aims and objectives: to determine the characteristics and survival of patients suffering from pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH) admitted to intensive care unit (ICU) for acute RHF in the modern management era. Methods: characteristics and outcomes of 83 patients admitted for acute RHF in an ICU from March 2015 to April 2016 were prospectively analyzed in an observational, single-centre study. Results: Mean age was 59 years. Catecholamines were initiated in 57 (68.5%). Urgent lung transplantation was performed in 10 patients. ECLS was used as a bridge to transplantation in 4 of them. Urgent endarterectomy was performed in 9 patients with CTEPH. Mortality rates in ICU, at 1 month and 3 month were 18, 20 and 28%, respectively. Mortality rates at 3 months in patients 65 years and treated with catecholamines was 7, 36 and 52%, respectively. Already known PH (HR 4; p=0.05), catecholamine initiation (HR 5; p=0.03), identification of a triggering factor (HR 2.8; p=0.04), average blood pressure at third day (HR 0.9; p=0.001) and creatinine level (HR 1; p=0,05) were identified as risk factors for mortality at one month. Conclusion: Mortality from acute RHF remains high. However, recent progress in lung graft allocation rules and management of acute RHF dramatically improved outcomes in younger patients.

Background: Current European (ERS/ESC) PH guidelines recommend risk assessment in patients with pulmonary arterial hypertension (PAH). The aim of our study were to analyze the association between the number of determinants of low-risk criteria achieved and long-term outcome. Methods: All patients with idiopathic, heritable and drug-induced PAH entered into the French Registry from 2006 and reassessed within a year were analyzed. The Cox model was used to determine the weight of 4 low-risk criteria achieved at first follow-up visit: NYHA FC, 6MWD, right atrial pressure (RAP) and cardiac index (CI). Results: 1017 patients were analyzed (mean age 57 yrs, 59% female, 75% iPAH). After a median follow-up of 34 months, 23% had died. In univariate analysis, HR (95%CI) for NYHA FC I-II, 6MWD>440 m, RAP Conclusion: These results support the relevance of ESC/ERS guidelines risk stratification to define treatment goals in patients with PAH.

Background: Despite the deleterious health effects of obesity, an obesity paradox has been described in many diseases, including in heterogeneous populations with pulmonary hypertension. Whether obesity is associated with better outcomes in idiopathic (IPAH), drug and toxin-induced (DPAH) or heritable pulmonary arterial hypertension (HPAH) is not known. Methods: We assessed 1363 incident patients with IPAH, DPAH, and HPAH from the French Pulmonary Hypertension Registry. Cox proportional hazards regression was used to assess the effect of obesity on the risk of death or lung transplantation. Obesity was defined as body mass index (BMI)>30 kg/m2. Results: The prevalence of obesity was 30.7%. There was a higher proportion of females (66.6% vs 53.4%, p Conclusions: We found no association between obesity and survival in a large cohort of incident IPAH, DPAH and HPAH patients. Previous evidence of an obesity paradox in pulmonary hypertension may be related to other confounding factors.

Background: The prognostic value of hemodynamic variables after treatment initiation in pulmonary arterial hypertension (PAH) is not well established. Methods: We evaluated incident patients between 2006-2016 with idiopathic, drug and toxin-induced or heritable PAH who had a follow-up right heart catheterization (RHC). The primary outcome was death or lung transplantation. We used stepwise Cox regression and receiver operating characteristic (ROC) analysis to assess variables at first follow-up RHC Results: Of 763 patients, death or transplantation occurred in 211 (27.7%) over a median follow-up time of 3.2 years (IQR25-75% 1.61-5.13). Median time to first follow-up RHC was 4.6 months (IQR 3.7-7.8). Multivariate predictors at first follow-up RHC were: age, male gender, idiopathic PAH, New York Heart Association functional class, 6-minute walk distance, stroke volume index (SVI), and right atrial pressure (RAP). Adjusted hazard ratios for hemodynamic variables were: SVI 0.975 (95%CI 0.961-0.989, p Conclusions: Stroke volume index and right atrial pressure at first follow-up catheterization were the best hemodynamic predictors of death or transplantation. These variables should be further validated as treatment targets in a prospective study.

Current European guidelines recommend periodic risk assessment for patients with pulmonary arterial hypertension (PAH). The aim of our study was to determine the association between the number of low-risk criteria achieved within 1 year of diagnosis and long-term prognosis. Incident patients with idiopathic, heritable and drug-induced PAH between 2006 and 2016 were analysed. The number of low-risk criteria present at diagnosis and at first re-evaluation were assessed: World Health Organization (WHO)/New York Heart Association (NYHA) functional class I or II, 6-min walking distance (6MWD) >440 m, right atrial pressure, Simplified risk assessment using the number of low-risk criteria predicts prognosis at baseline and follow-up in PAH http://ow.ly/KMsj30cPNbm

No advantage to using indexed total pulmonary resistance in the definition of exercise pulmonary hypertension http://ow.ly/tmgi30dMN5T

Dynamic hyperinflation is observed during exercise in 60% of patients with clinically stable pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), intensifying exertional dyspnoea. The impact of dynamic changes in respiratory mechanics during exercise on qualitative dimensions of dyspnoea in these patients has not been evaluated.26 patients (PAH n=17; CTEPH n=9) performed an incremental symptom-limited cycle exercise test. Minute ventilation (V′E), breathing pattern, operating lung volumes and dyspnoea intensity were assessed throughout exercise. Dyspnoea quality was serially assessed during exercise using a three-item questionnaire (dyspnoea descriptors). The inflection point of tidal volume (VT) relative to V′E was determined for each incremental test. Changes in inspiratory capacity during exercise defined two groups of patients: hyperinflators (65%) and non-hyperinflators (35%). Multidimensional characterisation of dyspnoea was performed after exercise using the Multidimensional Dyspnea Profile.In hyperinflators, inspiratory capacity decreased progressively throughout exercise by 0.36 L, while remaining stable in non-hyperinflators. The “work/effort” descriptor was most frequently selected throughout exercise in both types of patients (65% of all responses). At the VT/V′E inflection, work/effort plateaued while “unsatisfied inspiration” descriptors became selected predominantly only in hyperinflators (77% of all responses). In the affective domain, the emotion most frequently associated with dyspnoea was anxiety.In pulmonary hypertension patients who develop hyperinflation during exercise, dyspnoea descriptors referring to unsatisfied inspiration become predominant following the VT/V′E inflection. As these descriptors are generally associated with more negative emotional experiences, delaying or preventing the VT/V′E inflection may have important implications for symptom management in patients with pulmonary hypertension.

Extraction and purification of an acid β-glucosidase from human placenta (alglucerase) for the treatment of Gaucher disease, replaced a few years later by a recombinant enzyme (imiglucerase, Cerezyme(®)), has paved the way to the development of enzyme replacement therapies (ERT) for the treatment of lysosomal storage diseases (LSD) among which Fabry disease for which the long-term efficacy of the two currently available preparations (agalsidase alfa, Replagal(®) and Fabrazyme(®)) is still being investigated. Mucopolysaccharidosis (MPS) type I (Hurler and Scheie diseases), II (Hunter syndrome) and VI (Maroteaux-Lamy disease) also benefit from ERT using laronidase (Aldurazyme(®)), idursulfase (Elaprase(®)) and galsulfase (Naglazyme(®)), respectively. ERT reduces the hepatosplenomegaly and improves the physical and respiratory capacities of MPS patients with a globally acceptable safety profile although the possibility of infusion-associated should always be kept in mind. Alglucosidase alpha (Myozyme(®)) improves the cardiomyopathy and life expectancy of infants suffering from Pompe disease and is under evaluation for the treatment of the juvenile and adult forms of the disease. CNS involvement remains a major challenge for many LSD and innovative research and approaches are needed to address the fact that recombinant enzymes do not cross the blood-brain barrier and therefore are not expected to lead to any improvement in CNS damages, except if alternative routes such as intrathecal administration would be developed. Molecular chaperones (e.g. migalastat for Fabry disease) and inhibitors of glucosylceramide synthesis (e.g. eliglustat tartrate for Gaucher disease) are currently under investigation in various clinical trials.

Objective: To determine whether septic shock patients have an abnormal reponse to increasing osmolarity. Design: Prospective interventional study. Setting: Intensive care unit at Raymond Poincare and Etampes Hospitals. Patients: Normonatremic patients at >72 hrs from septic shock onset. Intervention: Osmotic challenge consisting of infusing 500 mL of hypertonic saline solution (with cumulative amount of sodium not exceeding 24 g) over 120 mins. Measurements and Main Results: Plasma arginine vasopressin levels were measured 15 mins before the test and then four times every 30 mins. A slope of the relation between arginine vasopressin and plasma sodium levels of

The prognostic importance of follow-up haemodynamics and the validity of multidimensional risk assessment are not well established for systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH).We assessed incident SSc-PAH patients to determine the association between clinical and haemodynamic variables at baseline and first follow-up right heart catheterisation (RHC) with transplant-free survival. RHC variables included cardiac index, stroke volume index (SVI), pulmonary arterial compliance and pulmonary vascular resistance. Risk assessment was performed according to the number of low-risk criteria: functional class I or II, 6-min walking distance (6MWD) >440 m, right atrial pressure −1·m−2.Transplant-free survival from diagnosis (n=513) was 87%, 55% and 35% at 1, 3 and 5 years, respectively. At baseline, 6MWD was the only independent predictor. A follow-up RHC was available for 353 patients (median interval 4.6 months, interquartile range 3.9–6.4 months). The 6MWD, functional class, cardiac index, SVI, pulmonary arterial compliance and pulmonary vascular resistance were independently associated with transplant-free survival at follow-up, with SVI performing better than other haemodynamic variables. 1-year outcomes were better with increasing number of low-risk criteria at baseline (area under the curve (AUC) 0.63, 95% CI 0.56–0.69) and at first follow-up (AUC 0.71, 95% CI 0.64–0.78).Follow-up haemodynamics and multidimensional risk assessment had greater prognostic significance than at baseline in SSc-PAH.

Older patients with IPAH often present with distinct phenotypes and show less improvements with targeted therapy than younger patientshttp://ow.ly/vsCb30jqOB3

Background: Pulmonary hypertension (PH) is a frequent complication of sarcoidosis. Its mechanisms are multiple and unclear. Few studies reported the effects of pulmonary arterial hypertension-targeted therapies (PAH-TT) in sarcoidosis-associated PH (S-APH). Methods: Clinical and hemodynamic data from newly diagnosed patients with S-APH were collected from the French prospective PH registry (2004-2014). Results: All 121 consecutive patients with S-APH were analyzed (57±11 years; 67 females). Mean FVC was 64%±20 and 78% had radiologic stage IV at time of PH diagnosis. Sixty two percent of patients had out of proportion severe PH, 27% PH related to pulmonary fibrosis and 11% extrinsic pulmonary vessels compression. Eighty nine patients (73%) received PAH-TT (70% ERA, 13% PDE-5 inhibitors, 2% prostanoid, 15% oral combination therapy). Immunosuppressive therapy was initiated or reinforced in 19 patients after PH diagnosis. At 3-6 months after PAH-TT initiation, mean PAP decrease from 46±9 to 42±11 (p