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Background: Imbalance between cell proliferation and apoptosis underlies the development of pulmonary arterial hypertension (PAH). Current vasodilator treatment of PAH does not target the uncontrolled proliferative process in pulmonary arteries. Proteins involved in the apoptosis pathway may play a role in PAH and their inhibition might represent a potential therapeutic target. Survivin is a member of the apoptosis inhibitor protein family involved in cell proliferation. Objectives: This study aimed to explore the potential role of survivin in the pathogenesis of PAH and the effects of its inhibition. Methods: In SU5416/hypoxia-induced PAH mice we assessed the expression of survivin by immunohistochemistry, western-blot analysis, and RT-PCR; the expression of proliferation-related genes (Bcl2 and Mki67); and the effects of the survivin inhibitor YM155. In explanted lungs from patients with PAH we assessed the expression of survivin, BCL2 and MKI67. Results: SU5416/hypoxia mice showed increased expression of survivin in pulmonary arteries and lung tissue extract, and upregulation of survivin, Bcl2 and Mki67 genes. Treatment with YM155 reduced right ventricle (RV) systolic pressure, RV thickness, pulmonary vascular remodeling, and the expression of survivin, Bcl2, and Mki67 to values similar to those in control animals. Lungs of patients with PAH also showed increased expression of survivin in pulmonary arteries and lung extract, and also that of BCL2 and MKI67 genes, compared with control lungs. Conclusion: We conclude that survivin might be involved in the pathogenesis of PAH and that its inhibition with YM155 might represent a novel therapeutic approach that warrants further evaluation.

Introduction : The mechanisms underlying the development of pulmonary hypertension (PH) and its severity in chronic lung diseases (CLD) are unknown. The study aimed to assess the protein expression profile in plasma in patients with chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD), according to the presence and severity of PH, and explore similarities with idiopathic pulmonary arterial hypertension (iPAH). Methods: We analysed 115 patients with CLD: 40 non-PH (19 COPD, 21 ILD), 41 with moderate PH (22 COPD, 19 ILD) and 34 with severe PH (21 COPD, 13 ILD); and 38 patients with iPAH. Plasma samples were analysed by liquid chromatography-mass spectrometry. Student t-tests were used to calculate each comparison and false discovery rates computed. Proteins with a fold change >|1.5|, p-value<0.05 and present in >80% cases of the cohort were selected. Results: CLD-PH had up-regulated proteins from the immunoglobulin superfamily (IgSF) compared with non-PH. Compared with CLD patients with moderate PH, those with severe PH had 6 IgSF proteins and lysozyme up-regulated; and keratin-1 down-regulated. Compared with iPAH, patients with CLD- severe PH had up-regulated 6 IgSF proteins, orosomucoid-1 and tenascin-C; and down-regulated IGF-binding protein-3 and tetranectin. Conclusions: Patients with CLD and PH show a distinct proteomic profile, particularly in IgSF expression, which is further amplified in severe PH. Patients with CLD- severe PH also differ from iPAH, specially in IgSF. Further studies are warranted to assess the functionality of IgSF proteins and their clinical implications in CLD-PH.

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P < 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 ± 5.2 mm vs 19.9 ± 6.7 mm, P < 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P < 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P < 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P < 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 ± 5.2 mm vs 19.9 ± 6.7 mm, P < 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P < 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P < 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment.

There are few published data on long-term treatment with sirolimus in lymphangioleiomyomatosis (LAM). The objective of this study was to describe the long-term effect of sirolimus in a series of LAM patients followed up in a referral centre, focusing on pulmonary function. We retrospectively reviewed a series of 48 patients with LAM diagnosed, followed up and treated with sirolimus in a single centre. Response to sirolimus was evaluated at 1 and 5 years. A negative sirolimus response was defined as an FEV decline greater than − 75 ml/year. A mixed-effects model was used to estimate the longitudinal changes in FEV (average slope), both as absolute (ml/year) and as predicted values (%predicted/year). From a total of 48 patients, 9 patients underwent lung transplantation and 4 died during the study. Mean (95% CI) FEV slope over 5 years was − 0.14 (− 26.13 to 25.85) ml/year in the whole LAM group, 42.55 (14.87 to 70.22) ml/year in the responder group, − 54.00 (− 71.60 to − 36.39) ml/year in the partial responder group and − 84.19 (− 113.5 to − 54.0) ml/year in the non-responder group. After 5 years of sirolimus treatment 59% had a positive response, 30% had a partial response and 11% had a negative response. Our study found that sirolimus treatment had a positive long-term effect on most LAM patients

The aim of this study was to elucidate whether long-term LT survivors with normal spirometry achieve normal exercise capacity, and to identify predictive factors of exercise capacity. This was a cross-sectional multicentre study, where bilateral LT recipients who survived at least 10 years after LT, with normal spirometry, no diagnosis of CLAD and modified Medical Research Council dyspnoea degree ≤2 underwent cardiopulmonary exercise testing (CPET). 28 LT recipients were included with a mean± age of 48.7±13.6 years. Oxygen uptake (V' ) had a mean± value of 21.49±6.68 mL·kg −1 ·min −1 (75.24±15.6%) and the anaerobic threshold was reached at 48.6±10.1% of the V' predicted. The mean± heart rate reserve at peak exercise was 17.56±13.6%. The oxygen pulse increased during exercise and was within normal values at 90.5±19.4%. The respiratory exchange ratio exceeded 1.19 at maximum exercise. The median (25-75 th percentile) EuroQol-5D score was 1 (0.95-1), indicating a good quality of life. The median (25-75 th percentile) International Physical Activity Questionnaire score was 5497 (4007-9832) MET-min·week −1 with 89% of patients reporting more than 1500 MET-min·week −1. In the multivariate regression models, age, sex and diffusing capacity of the lung for carbon monoxide remained significantly associated with V' (mL·kg −1 ·min −1); haemoglobin and forced expiratory volume in 1 s were significantly associated with maximum work rate (watts), after adjusting for confounders. We report for the first time near-normal peak V' values during CPET and normal exercise capacity in long-term LT recipients without CLAD. This is a multicentre study reporting, for the first time, near-normal peak V ' values during cardiopulmonary exercise testing and normal exercise capacity in long-term lung transplant recipients without CLAD

[Introduction] REHAP is a voluntary, observational Spanish registry of patients with pulmonary arterial hypertension. We analyzed the experience (use and effectiveness) with inhaled iloprost (inh-ILO) in real-life conditions during a 3-year period., [Methods] Patients included were those with PAH ≥14 years recruited during 1998–2016 who had received inh-ILO. Variables were collected at the beginning of treatment (0 ± 3 months) and 12 ± 3/36 ± 6 months follow-up. Effectiveness was assessed in the intent-to-treat population as changes in functional class and/or physical performance and transplant-free survival from the beginning of treatment. Stopping inh-ILO-related survival was also assessed. Subanalyses included treatment strategy (first-line therapy –monotherapy or upfront combination- or sequential therapy) and risk of clinical worsening/death., [Results] Inh-ILO was the most frequently used prostanoid in Spain, rendering 267 patients eligible for analysis. Median age was 54 years; 61% were WHO FC III. Sixty (23%) patients started inh-ILO as monotherapy, 27 (10%) as upfront combination and 180 (67%) sequentially. At 3-year follow-up significant clinical improvements were observed; however, transplant-free survival rate was 54%, being poorer in patients at high risk (63% vs. 85% in low risk patients; P < 0.001) and similar in the three treatment strategies. Only 25% patients remained on inh-ILO. Three-year after stopping inh-ILO-related survival rate was 24.7%., [Conclusion] Data from the REHAP collected during 3 years shows that inh-ILO has low effectiveness independently of the treatment strategy used, with a 3-year survival rate of 54% despite significant clinical improvements, probably due to the use in high-risk patients. Discontinuation rate was as high as 75%.