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Rationale: Precapillary pulmonary hypertension (PH) is a devastating complication of sickle cell disease (SCD). Little is known about the influence of the SCD genotype on PH characteristics., Objectives: To describe clinical phenotypes and outcomes of precapillary PH due to SCD according to disease genotype., Methods: A nationwide multicentre retrospective study including all patients with SCD-related precapillary PH from the French PH Registry was conducted. Clinical characteristics and outcomes according to SCD genotype were analysed., Results: 58 consecutive SCD patients with precapillary PH were identified, of whom 41 had homozygous for haemoglobin S (SS) SCD, three had S-β 0 thalassaemia (S-β 0 thal) and 14 had haemoglobin SC disease (SC). Compared to SC patients, SS/S-β 0 thal patients were characterised by lower 6-min walk distance (p=0.01) and lower pulmonary vascular resistance (p=0.04). Mismatched segmental perfusion defects on lung scintigraphy were detected in 85% of SC patients and 9% of SS/S-β 0 thal patients, respectively, and 50% of SS/S-β 0 thal patients had heterogeneous lung perfusion without segmental defects. After PH diagnosis, 31 patients (53%) received medical therapies approved for pulmonary arterial hypertension, and chronic red blood cell exchange was initiated in 23 patients (40%). Four patients were managed for chronic thromboembolic PH by pulmonary endarterectomy (n=1) or balloon pulmonary angioplasty (n=3). Overall survival was 91%, 80% and 60% at 1, 3 and 5 years, respectively, without influence of genotype on prognosis., Conclusions: Patients with precapillary PH related to SCD have a poor prognosis. Thrombotic lesions appear as a major component of PH related to SCD, more frequently in SC patients., Competing Interests: Conflict of interest: L. Savale reports grants, personal fees and non-financial support from Actelion, MSD, GSK and Bayer, outside the submitted work. Conflict of interest: A. Habibi has nothing to disclose. Conflict of interest: F. Lionnet has nothing to disclose. Conflict of interest: B. Maitre has nothing to disclose. Conflict of interest: V. Cottin reports personal fees for consultancy and lectures, and non-financial support for travel to meetings from Actelion, grants, personal fees for consultancy and lectures, and non-financial support for travel to meetings from Boehringer Ingelheim and Roche, personal fees for consultancy from Bayer/MSD and Galapagos, personal fees for adjudication committee work from Gilead, personal fees for consultancy and lectures from Novartis and Astra Zeneca, grants from Sanofi, and personal fees for data monitoring committee work from Promedior and Celgene, outside the submitted work. Conflict of interest: X. Jais reports grants, personal fees and non-financial support from Actelion, MSD, GSK and Bayer, outside the submitted work. Conflict of interest: A. Chaouat has nothing to disclose. Conflict of interest: E. Artaud-Macari has nothing to disclose. Conflict of interest: M. Canuet reports personal fees for advisory board work from Actelion, non-financial support for travel to meetings from France Oxygene, outside the submitted work. Conflict of interest: G. Prevot has nothing to disclose. Conflict of interest: C. Chantalat-Auger has nothing to disclose. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, personal fees from GSK, MSD and Pfizer, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals and GlaxoSmithKline, grants and personal fees from Bayer HealthCare, grants and non-financial support from Merck, personal fees from Arena Pharmaceuticals, outside the submitted work. Conflict of interest: F. Galacteros has nothing to disclose. Conflict of interest: G. Simonneau reports grants, personal fees and non-financial support from Actelion Pharmaceuticals and GlaxoSmithKline, grants and personal fees from Bayer HealthCare, grants and non-financial support from Merck, personal fees from Arena Pharmaceuticals, outside the submitted work. Conflict of interest: F. Parent has nothing to disclose. Conflict of interest: P. Bartolucci has nothing to disclose. Conflict of interest: M. Humbert has relationships with drug companies including Actelion, Bayer, GSK, Novartis, Pfizer and United Therapeutics. In addition to being investigator in trials involving these companies, relationships include consultancy service and membership of scientific advisory boards., (Copyright ©ERS 2019.)

Nitric oxide (NO) donors may be useful for treating pulmonary hypertension (PH) complicating sickle cell disease (SCD), as endogenous NO is inactivated by hemoglobin released by intravascular hemolysis. Here, we investigated the effects of the new NO donor NCX1443 on PH in transgenic SAD mice, which exhibit mild SCD without severe hemolytic anemia. In SAD and wild-type (WT) mice, the pulmonary pressure response to acute hypoxia was similar and was abolished by 100 mg/kg NCX1443. The level of PH was also similar in SAD and WT mice exposed to chronic hypoxia (9% O2) alone or with SU5416 and was similarly reduced by daily NCX1443 gavage. Compared with WT mice, SAD mice exhibited higher levels of HO-1, endothelial NO synthase, and PDE5 but similar levels of lung cyclic guanosine monophosphate. Cultured pulmonary artery smooth muscle cells from SAD mice grew faster than those from WT mice and had higher PDE5 protein levels. Combining NCX1443 and a PDE5 inhibitor suppressed the growth rate difference between SAD and WT cells and induced a larger reduction in hypoxic PH severity in SAD than in WT mice. By amplifying endogenous protective mechanisms, NCX1443 in combination with PDE5 inhibition may prove useful for treating PH complicating SCD.

Recent hemodynamic studies performed in large cohorts of adult patients with sickle cell disease have established the prevalence of pulmonary hypertension in this disease about 6 to 10%. Over half of these correspond to postcapillary pulmonary hypertension. Precapilliary arterial pulmonary hypertension seems to be a relatively infrequent complication of the disease. It is characterized by a different hemodynamic profile of idiopathic PAH with lower levels of pulmonary pressures and pulmonary vascular resistance. However, pulmonary vascular disease appears to have a significant impact on the functional status and vital prognosis of patients with sickle cell disease. The predictive value of echocardiography to detect pulmonary hypertension in this population is low (25-32%) when the threshold of tricuspid regurgitation velocity of 2.5m/s is used. At present, no specific treatments for pulmonary arterial hypertension is currently approved for the treatment of PAH associated with sickle cell disease due to lack of data in this specific population., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Background: The prevalence and characteristics of pulmonary hypertension in adults with sickle cell disease have not been clearly established., Methods: In this prospective study, we evaluated 398 outpatients with sickle cell disease (mean age, 34 years) at referral centers in France. All patients underwent Doppler echocardiography, with measurement of tricuspid-valve regurgitant jet velocity. Right heart catheterization was performed in 96 patients in whom pulmonary hypertension was suspected on the basis of a tricuspid regurgitant jet velocity of at least 2.5 m per second. Pulmonary hypertension was defined as a mean pulmonary arterial pressure of at least 25 mm Hg., Results: The prevalence of a tricuspid regurgitant jet velocity of at least 2.5 m per second was 27%. In contrast, the prevalence of pulmonary hypertension as confirmed on catheterization was 6%. The positive predictive value of echocardiography for the detection of pulmonary hypertension was 25%. Among the 24 patients with confirmed pulmonary hypertension, the pulmonary-capillary wedge pressure was 15 mm Hg or less (indicating precapillary pulmonary hypertension) in 11 patients. Patients with confirmed pulmonary hypertension were older and had poorer functional capacity and higher levels of N-terminal pro-brain natriuretic peptide than other patients. In contrast, patients who had a tricuspid regurgitant jet velocity of at least 2.5 m per second without pulmonary hypertension and patients with a tricuspid regurgitant jet velocity of less than 2.5 m per second had similar clinical characteristics., Conclusions: In this study of adults with sickle cell disease, the prevalence of pulmonary hypertension as confirmed on right heart catheterization was 6%. Echocardiographic evaluation alone had a low positive predictive value for pulmonary hypertension. (Funded by the French Ministry of Health and Assistance Publique-Hôpitaux de Paris; ClinicalTrials.gov number, NCT00434902.).

Background: The association between chronic kidney involvement and sickle cell disease (SCD) has been well characterized, but our knowledge on acute kidney injury (AKI) in relation to SCD remains limited., Methods: We retrospectively assessed 254 episodes of vaso-occlusive complication in 161 SCD patients who were admitted to our hospital: these included 174 episodes of painful crisis (PC), 58 episodes of moderate acute chest syndrome (ACS) and 22 episodes of severe ACS., Results: The overall incidence of AKI [defined according to Acute Kidney Injury Network (AKIN) criteria] during vaso-occlusive complications was low (4.3%) but seemed to be related to its severity: 2.3% for PC vs 6.9% for moderate ACS and 13.6% for severe ACS (P = 0.03). This finding led us prospectively to look at specific risk factors for AKI occurrence in SCD patients admitted to our intensive care unit for severe ACS and, in particular, the possible link between AKI and haemodynamic status (transthoracic echocardiography). Among patients with severe ACS, those with AKI displayed significantly greater aminotransferases, bilirubin and lactate dehydrogenase levels than patients without AKI. Echocardiography identified higher systolic pulmonary artery pressure in patients with AKI than in those without, whereas the cardiac index was similar between groups., Conclusions: AKI incidence during vaso-occlusive complications of SCD is relatively low (<5%) and appears to be confined to patients with ACS and pulmonary hypertension. These findings suggest a pathophysiological process involving right ventricular dysfunction and venous congestion.

Background: Pulmonary artery remodeling triggered by alveolar hypoxia is considered the main mechanism of pulmonary hypertension (PH) in COPD patients. We hypothesized that the risk for PH in COPD is increased by an elevation in the proinflammatory cytokines interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and IL-1beta, as well as by specific genetic polymorphisms of these cytokines., Methods: We assessed cytokine plasma levels and the polymorphisms G(-174)C IL-6, C(-511)T IL-1beta, and A(-2518)G MCP-1 in 148 COPD patients (recruited at two centers) with right heart catheterization data and 180 control subjects including smokers and nonsmokers. Human pulmonary artery smooth muscle cells (PA-SMCs) were cultured for IL-6 messenger RNA assays under normoxic and hypoxic conditions., Results: Patients with PH (mean pulmonary artery pressure [PAP], >or= 25 mm Hg) had lower Pao(2) and higher plasma IL-6 values than those without PH; there were no differences in terms of pulmonary function test results or CT scan emphysema scores. Plasma IL-6 correlated with mean PAP (r = 0.39; p < 0.001) and was included in a multiple stepwise regression analysis, with mean PAP as the dependent variable. In patients with the IL-6 GG genotype, the mean PAP value was significantly higher and PH was more common than in CG or CC patients (adjusted odds ratio, 4.32; 95% confidence interval, 1.96 to 9.54). Exposure to 4 h of hypoxia led to an about twofold increase in IL-6 messenger RNA in cultured human PA-SMCs., Conclusions: Inflammation, most likely involving IL-6, may contribute substantially to PH complicating COPD.

Pulmonary hypertension (PH) is a progressive, lethal lung disease characterized by pulmonary artery SMC (PA-SMC) hyperplasia leading to right-sided heart failure. Molecular events originating in pulmonary ECs (P-ECs) may contribute to the PA-SMC hyperplasia in PH. Thus, we exposed cultured human PA-SMC to medium conditioned by P-EC from patients with idiopathic PH (IPH) or controls and found that IPH P-EC-conditioned medium increased PA-SMC proliferation more than control P-EC medium. Levels of FGF2 were increased in the medium of IPH P-ECs over controls, while there was no detectable difference in TGF-beta1, PDGF-BB, or EGF levels. No difference in FGF2-induced proliferation or FGF receptor type 1 (FGFR1) mRNA levels was detected between IPH and control PA-SMCs. Knockdown of FGF2 in P-EC using siRNA reduced the PA-SMC growth-stimulating effects of IPH P-EC medium by 60% and control P-EC medium by 10%. In situ hybridization showed FGF2 overproduction predominantly in the remodeled vascular endothelium of lungs from patients with IPH. Repeated intravenous FGF2-siRNA administration abolished lung FGF2 production, both preventing and nearly reversing a rat model of PH. Similarly, pharmacological FGFR1 inhibition with SU5402 reversed established PH in the same model. Thus, endothelial FGF2 is overproduced in IPH and contributes to SMC hyperplasia in IPH, identifying FGF2 as a promising target for new treatments against PH.

Background: Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH). Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6)., Methods: To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/-) and wild-type (IL-6+/+) mice exposed to hypoxia for 2 weeks., Results: Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer) mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs) and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines., Conclusion: These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice.

Rationale: Steady-state mild pulmonary hypertension is a risk factor for death in adults with sickle cell disease. Acute pulmonary hypertension has been reported during exercise and vasoocclusive pain crisis in these patients., Objectives: The aim of the present study was to evaluate changes in pulmonary pressures and cardiac biomarkers during severe acute chest syndrome and their associations with mortality., Methods: We prospectively evaluated 70 consecutive adults who received standardized treatment in our intensive care unit for a total of 84 episodes. At admission, cardiac biomarkers were measured. Transthoracic echocardiography was performed for pulmonary hypertension assessment via measurement of tricuspid regurgitant jet velocity and was repeated when possible after resolution., Measurements and Main Results: Tricuspid jet velocity was less than 2.5 m/second in 34 (40%) of the 84 episodes, 2.5 to 2.9 m/second in 19 (23%), and 3 m/second or greater in 31 episodes (37%). Cor pulmonale occurred in 11 (13%) episodes. Tricuspid jet velocity showed significant positive correlations with B-type natriuretic peptide (rho = 0.54, P < 0.01) and cardiac troponin I (rho = 0.42, P < 0.01). Pulmonary pressures increased compared with steady state then decreased after resolution. All five patients who required invasive ventilation and all four patients who died during the immediate hospital course had jet velocity values of 3 m/second or greater. Overall mortality was 12.9% (9 patients) and survival was significantly lower in patients whose jet velocity was 3 m/second or greater during at least one episode, compared with the other patients (P < 0.01)., Conclusions: Pulmonary pressures increase during severe acute chest syndrome, and pulmonary hypertension is associated with cardiac biomarker elevation and a higher risk of death.

Background: Bone marrow -derived cells (BMDCs) can either limit or contribute to the process of pulmonary vascular remodeling. Whether the difference in their effects depends on the mechanism of pulmonary hypertension (PH) remains unknown., Objectives: We investigated the effect of BMDCs on PH induced in mice by either monocrotaline or exposure to chronic hypoxia., Methods: Intravenous administration of the active monocrotaline metabolite (monocrotaline pyrrole, MCTp) to C57BL/6 mice induced PH within 15 days, due to remodeling of small distal vessels. Three days after the MCTp injection, the mice were injected with BMDCs harvested from femurs and tibias of donor mice treated with 5-fluorouracil (3.5 mg IP/animal) to deplete mature cells and to allow proliferation of progenitor cells., Results: BMDCs significantly attenuated PH as assessed by reductions in right ventricular systolic pressure (20 +/- 1 mmHg vs. 27 +/- 1 mmHg, P < or = 0.01), right ventricle weight/left ventricle+septum weight ratio (0.29 +/- 0.02 vs. 0.36 +/- 0.01, P < or = 0.03), and percentage of muscularized vessels (26.4% vs. 33.5%, P < or = 0.05), compared to control animals treated with irradiated BMDCs. Tracking cells from constitutive GFP-expressing male donor mice with anti-GFP antibodies or chromosome Y level measurement by quantitative real-time PCR showed BMDCs in the lung. In contrast, chronically hypoxic mice subjected to the same procedure failed to show improvement in PH., Conclusion: These results show that BMDCs limit pulmonary vascular remodeling induced by vascular injury but not by hypoxia.

Rationale: Angiopoietins are involved in blood vessel maturation and remodeling., Objectives: One consequence of endothelium-specific tyrosine kinase-2 (Tie2) receptor activation by angiopoietin-1 (Ang1) is the release of endothelium-derived growth factors that recruit vascular wall cells. We investigated this process in idiopathic pulmonary arterial hypertension (iPAH)., Methods: Ang1, Ang2, and total and phosphorylated Tie2 expression (mRNA and protein) was evaluated in human lung specimens and in cultured pulmonary artery smooth muscle cells (PA-SMCs) and pulmonary endothelial cells (P-ECs) isolated from patients with iPAH and control subjects. Media collected from Ang1-treated P-ECs were assessed for their PA-SMC growth-promoting effect., Measurements and Main Results: Tie2 receptor was fourfold higher in lungs and P-ECs from patients with iPAH than in those from control subjects, with a parallel increase in phosphorylated lung Tie2 receptor. In contrast, Ang1 and Ang2 expression in lungs, P-ECs, and PA-SMCs did not differ. Incubation of PA-SMCs with medium collected from P-EC cultures induced marked proliferation, and this effect was stronger when using P-ECs from patients with iPAH than from control subjects. Ang1 pretreatment of P-ECs from either patients or control subjects induced a further increase in PA-SMC proliferation. Fluoxetine, an inhibitor of the mitogenic action of serotonin, reduced the growth-promoting effect of P-EC media. Ang1 added to P-ECs from patients with iPAH increased the production of endothelin-1 (ET-1) and serotonin, but not of platelet-derived growth factor-BB or epidermal growth factor, and increased the amount of mRNA encoding tryptophan hydroxylase-1 (the rate-limiting enzyme of serotonin synthesis), preproET-1, and ET-1-converting enzyme., Conclusions: The Ang1/Tie2 pathway is potentiated in iPAH, contributing to PA-SMC hyperplasia via increased stimulation of endothelium-derived growth factors synthesis by P-ECs.