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Rationale: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by pulmonary arterial muscularization due to excessive pulmonary vascular cell proliferation and migration, a phenotype dependent upon growth factors and activation of receptor tyrosine kinases (RTKs). p130(Cas) is an adaptor protein involved in several cellular signaling pathways that control cell migration, proliferation, and survival.Objectives: We hypothesized that in experimental and human PAH p130(Cas) signaling is overactivated, thereby facilitating the intracellular transmission of signal induced by fibroblast growth factor (FGF)2, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF).Measurements and Main Results: In patients with PAH, levels of p130(Cas) protein and/or activity are higher in the serum, in the walls of distal pulmonary arteries, in cultured smooth muscle cells (PA-SMCs), and in pulmonary endothelial cells (P-ECs) than in control subjects. These abnormalities in the p130(Cas) signaling were also found in the chronically hypoxic mice and monocrotaline-injected rats as models of human PAH. We obtained evidence for the convergence and amplification of the growth-stimulating effect of the EGF-, FGF2-, and PDGF-signaling pathways via the p130(Cas) signaling pathway. We found that daily treatment with the EGF-R inhibitor gefitinib, the FGF-R inhibitor dovitinib, and the PDGF-R inhibitor imatinib started 2 weeks after a subcutaneous monocrotaline injection substantially attenuated the abnormal increase in p130(Cas) and ERK1/2 activation and regressed established pulmonary hypertension.Conclusions: Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals. [ABSTRACT FROM AUTHOR]

Introduction: Pulmonary arterial hypertension (PAH) is a rare and severe disease for which most of the evidence about prognostic factors, evolution and treatment efficacy comes from cohorts, registries and clinical trials. We therefore aimed to develop and validate a new PAH identification algorithm that can be used in the French healthcare database "Système National des Données de Santé (SNDS)"., Methods: We developed and validated the algorithm using the Grenoble Alpes University Hospital medical charts. We first identified PAH patients following a previously validated algorithm, using in-hospital ICD-10 (10th revision of the International Statistical Classification of Diseases) codes, right heart catheterisation procedure and PAH-specific treatment dispensing. Then, we refined the latter with the exclusion of chronic thromboembolic pulmonary hypertension procedures and treatment, the main misclassification factor. Second, we validated this algorithm using a gold standard review of in-hospital medical charts and calculated sensitivity, specificity, positive and negative predictive value (PPV and NPV) and accuracy. Finally, we applied this algorithm in the French healthcare database and described the characteristics of the identified patients., Results: In the Grenoble University Hospital, we identified 252 unique patients meeting all the algorithm's criteria between 1 January 2010 and 30 June 2022, and reviewed all medical records. The sensitivity, specificity, PPV, NPV and accuracy were 91.0%, 74.3%, 67.9%, 93.3% and 80.6%, respectively. Application of this algorithm to the SNDS yielded the identification of 9931 patients with consistent characteristics compared to PAH registries., Conclusion: Overall, we propose a new PAH identification algorithm developed and adapted to the French specificities that can be used in future studies using the French healthcare database., Competing Interests: Conflict of interest: H. Bouvaist reports payment for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Merck, outside the submitted work. Conflict of interest: M. Humbert reports grants or contracts from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, outside the submitted work; consulting fees from 35 Pharma, Aerovate, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Keros, Merck, MorphogenIX, Shou Ti and United Therapeutics, outside the submitted work; payment for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen and Merck, outside the submitted work; and participation on a data safety monitoring or advisory board for Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work. Conflict of interest: D. Montani reports grants or contracts from Acceleron, Janssen and Merck MSD, outside the submitted work; consulting fees from Acceleron, Merck MSD, Janssen and Ferrer, outside the submitted work; payment or honoraria for speakers' bureaus from Bayer, Janssen, Boerhinger, Chiesi, GSK, Ferrer and Merck MSD, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Introduction: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are life-threatening conditions that can progress to death without treatment. Although strong medication adherence (MA) is known to enhance outcomes in chronic illnesses, its association with PAH and CTEPH was sporadically explored. This study aims to examine the MA of patients with PAH or CTEPH, identify factors associated with low adherence and explore the resulting outcomes., Methods: A systematic review was conducted by searching multiple databases (Medline, Embase, Cochrane Central, ClinicalTrials.gov, Scopus, Web of Science and Google Scholar) from 6 March 1998 to 6 July 2023. We included studies reporting MA as primary or secondary end-points. Study selection, data extraction and methodological quality assessment were performed in duplicate., Results: 20 studies involving 22 675 patients met the inclusion criteria. Heterogeneity was observed, particularly in the methods employed. MA means ranged from 0.62 to 0.96, with the proportion of patients exhibiting high MA varying from 40% (95% CI 35-45%) to 94% (95% CI 88-97%). Factors associated with low adherence included increased treatment frequency, time since diagnosis and co-payment. High MA seems to be associated with reduced hospitalisation rates, inpatient stays, outpatient visits and healthcare costs., Conclusions: This systematic review underscores the heterogeneity of MA across studies. Nevertheless, the findings suggest that high MA could improve patients' clinical outcomes and alleviate the economic burden. Identifying factors consistently associated with poor MA could strengthen educational efforts for these patients, ultimately contributing to improved outcomes., Competing Interests: Conflict of interest: A. Le Bozec, V. Korb-Savoldelli, C. Boiteau, M-C. Chaumais, C. Guignabert, A. Dechartres and S. Al Kahf have nothing to disclose. O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer and MSD, personal fees from Acceleron Pharmaceuticals, Gossamer Bio and Ferrer, and grants from GlaxoSmithKline. D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from GSK, Pfizer, MSD. X. Jaïs reports grants and personal fees from Actelion and MSD, and grants from Bayer, outside the submitted work. M. Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, United Therapeutics and Acceleron. L. Savale reports grants, personal fees and non-financial support from Actelion and GSK, and personal fees and non-financial support from MSD and Bayer., (Copyright ©The authors 2024.)

Pulmonary arterial (PA) hypertension (PAH) is a severe cardiopulmonary disease that may be triggered by exposure to drugs such as dasatinib or facilitated by genetic predispositions. The incidence of dasatinib-associated PAH is estimated at 0.45%, suggesting individual predispositions. The mechanisms of dasatinib-associated PAH are still incomplete. We discovered a KCNK3 gene (Potassium channel subfamily K member 3; coding for outward K + channel) variant in a patient with dasatinib-associated PAH and investigated the impact of this variant on KCNK3 function. Additionally, we assessed the effects of dasatinib exposure on KCNK3 expression. In control human PA smooth muscle cells (hPASMCs) and human pulmonary endothelial cells (hPECs), we evaluated the consequences of KCNK3 knockdown on cell migration, mitochondrial membrane potential, ATP production, and in vitro tube formation. Using mass spectrometry, we determined the KCNK3 interactome. Patch-clamp experiments revealed that the KCNK3 variant represents a loss-of-function variant. Dasatinib contributed to PA constriction by decreasing KCNK3 function and expression. In control hPASMCs, KCNK3 knockdown promotes mitochondrial membrane depolarization and glycolytic shift. Dasatinib exposure or KCNK3 knockdown reduced the number of caveolae in hPECs. Moreover, KCNK3 knockdown in control hPECs reduced migration, proliferation, and in vitro tubulogenesis. Using proximity labeling and mass spectrometry, we identified the KCNK3 interactome, revealing that KCNK3 interacts with various proteins across different cellular compartments. We identified a novel pathogenic variant in KCNK3 and showed that dasatinib downregulates KCNK3, emphasizing the relationship between dasatinib-associated PAH and KCNK3 dysfunction. We demonstrated that a loss of KCNK3-dependent signaling contributes to endothelial dysfunction in PAH and glycolytic switch of hPASMCs.

Background: Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PIs). Our objective was to evaluate the association between PIs and PAH., Methods: Characteristics of incident PAH cases previously treated with carfilzomib or bortezomib were analysed from the French pulmonary hypertension registry and the VIGIAPATH programme from 2004 to 2023, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization (WHO) global database (VigiBase) and a meta-analysis of randomised controlled trials., Results: 11 incident cases of PI-associated PAH were identified (six with carfilzomib and five with bortezomib) with a female:male ratio of 2.7:1, a median age of 61 years, and a median delay between PI first exposure and PAH of 6 months. Four patients died (two from right heart failure, one from respiratory distress and one from an unknown cause). At diagnosis, six were in New York Heart Association Functional Class III/IV with severe haemodynamic impairment (median mean pulmonary arterial pressure 39 mmHg, cardiac index 2.45 L·min -1 ·m -2 and pulmonary vascular resistance 7.2 WU). In the WHO pharmacovigilance database, 169 cases of PH associated with PI were reported since 2013 with significant signals of disproportionate reporting (SDR) for carfilzomib, regardless of the definition of cases or control group. However, SDR for bortezomib were inconsistent. The systematic review identified 17 clinical trials, and carfilzomib was associated with a significantly higher risk of dyspnoea, severe dyspnoea and PH compared with bortezomib., Conclusion: PIs may induce PAH in patients undergoing treatment, with carfilzomib emitting a stronger signal than bortezomib, and these patients should be monitored closely., Competing Interests: Conflict of interest: X. Jaïs reports grants from Acceleron, Janssen, MSD and Bayer HealthCare, lecture honoraria from Janssen and MSD, and travel support from MSD, outside the submitted work. L. Savale reports grants from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, consulting fees from Acceleron, Bayer, Janssen and Merck, and lecture honoraria from Janssen and Merck, outside the submitted work. M. Jevnikar reports consulting fees from Janssen, and travel support from MSD and Janssen, outside the submitted work. A. Boucly reports grants from Acceleron, Janssen and MSD, and lecture honoraria and travel support from Janssen, Merck, AOP Orphan and Ferrer, outside the submitted work. G. Simonneau reports consulting fees and lecture honoraria from Actelion, Jansen, Bayer and MSD, travel support from Janssen, and advisory board participation with Acceleron, outside the submitted work. O. Sitbon reports grants from Acceleron (now MSD), AOP Orphan, Janssen (formerly Actelion) and MSD, consulting fees from Acceleron (now MSD), Altavant (now Enzyvant), AOP Orphan, Ferrer, Gossamer Bio, Janssen (formerly Actelion) and MSD, lecture honoraria from AOP Orphan, Janssen (formerly Actelion), Ferrer and MSD, and advisory board participation with Altavant (now Enzyvant), Gossamer Bio, Janssen (formerly Actelion) and MSD, outside the submitted work. M. Humbert reports grants from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, Morphogen-IX, Shou Ti and United Therapeutics, lecture honoraria from Janssen and Merck, and advisory board participation with Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work. D. Montani reports grants from Acceleron, Janssen and Merck MSD, consulting fees from Acceleron, Merck MSD, Janssen and Ferrer, and lecture honoraria from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck MSD, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Despite its known cardiac and lung toxicities, the chemotherapy drug gemcitabine has only rarely been associated with pulmonary hypertension (PH), and the underlying mechanism remains unclear. The objective of the present study was to assess the association between gemcitabine and PH., Methods: We identified incident cases of precapillary PH confirmed by right heart catheterisation in patients treated with gemcitabine from the French PH Registry between January 2007 and December 2022. The aetiology, clinical, functional, radiological and haemodynamic characteristics of PH were reviewed at baseline and during follow-up. A pharmacovigilance disproportionality analysis was conducted using the World Health Organization (WHO) pharmacovigilance database., Results: We identified nine cases of pulmonary arterial hypertension, either induced (in eight patients) or exacerbated (in one patient) by gemcitabine. Patients exhibited severe precapillary PH, with a median mean pulmonary arterial pressure of 40 (range 26-47) mmHg, a cardiac index of 2.4 (1.6-3.9) L·min -1 ·m -2 and a pulmonary vascular resistance of 6.3 (3.1-12.6) Wood units. The median time from the initiation of gemcitabine to the onset of PH was 7 (4-50) months, with patients receiving a median of 16 (6-24) gemcitabine injections. Six patients showed clinical improvement upon discontinuation of gemcitabine. In the WHO pharmacovigilance database, we identified a significant signal with 109 cases reporting at least one adverse event related to PH with gemcitabine., Conclusion: Both clinical cases and pharmacovigilance data substantiate a significant association between gemcitabine use and the onset or worsening of precapillary PH. The observed improvement following the discontinuation of treatment underscores the importance of PH screening in gemcitabine-exposed patients experiencing unexplained dyspnoea., Competing Interests: Conflict of interest: X. Jais reports grants or contracts from Acceleron, Janssen, MSD and Bayer HealthCare, outside the submitted work; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen and MSD, outside the submitted work. Conflict of interest: L. Savale reports grants or contracts from Bayer, Janssen and Merck, outside the submitted work; and speaker fees from Janssen, outside the submitted work. Conflict of interest: O. Sitbon reports grants or contracts from Acceleron, AOP Orphan, Janssen, GSK and MSD, outside the submitted work; consulting fees from Altavant, Gossamer Bio, Janssen and MSD, outside the submitted work; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events for AOP Orphan, Janssen, Ferrer and MSD, outside the submitted work; and participation on a Data Safety Monitoring Board or Advisory Board for Acceleron, Altavant, Gossamer Bio, Janssen, MSD and Ferrer, outside the submitted work. Conflict of interest: M. Humbert reports grants or contracts from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, outside the submitted work; consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti, Tiakis and United Therapeutics, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events for Janssen and Merck, outside the submitted work; and participation on a Data Safety Monitoring Board or Advisory Board for Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work. Conflict of interest: P. Bonniaud reports a research grant from AstraZeneca, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Sanofi and AstraZeneca, outside the submitted work; support for attending medical and research meetings from AstraZeneca, Novartis, Sanofi, Roche and Boehringer, outside the submitted work; and personal fees for advisory boards from AstraZeneca, Novartis, Sanofi, GSK, Roche and Boehringer, outside the submitted work. Conflict of interest: D. Montani reports grants or contracts from Acceleron, Janssen and Merck MSD, outside the submitted work; consulting fees from Acceleron, Merck MSD, Janssen and Ferrer, outside the submitted work; and speaker fees from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck MSD, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in the ABCC8 gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Conversely, activation of SUR1 and SUR2 leads to the relaxation of pulmonary arteries and reduces cell proliferation and migration. Diazoxide, a SUR1 activator, has been shown to alleviate experimental PH, suggesting its potential as a therapeutic option. However, there are paradoxical reports of diazoxide-induced PH in infants. This review explores the role of SUR1/2 in the pathophysiology of PH and the contradictory effects of diazoxide on the pulmonary vascular bed. Additionally, we conducted a comprehensive literature review of cases of diazoxide-associated PH and analysed data from the World Health Organization pharmacovigilance database (VigiBase). Significant disproportionality signals link diazoxide to PH, while no other SUR activators have been connected with pulmonary vascular disease. Diazoxide-associated PH seems to be dose-dependent and potentially related to acute effects on the pulmonary vascular bed. Further research is required to decipher the differing pulmonary vascular consequences of diazoxide in different age populations and experimental models., Competing Interests: Conflict of interest: D. Montani reports grants or contracts from Acceleron, Janssen and Merck MSD, outside the submitted work, consulting fees from Acceleron, Janssen, Merck MSD and Ferrer, outside the submitted work, and payment or honoraria for speakers’ bureaus from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck MSD, outside the submitted work. E-M. Jutant reports consulting fees from Chiesi, outside the submitted work, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GSK and Chiesi, outside the submitted work, and support for attending meetings and/or travel from Janssen, outside the submitted work. M. Humbert reports grants or contracts from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, outside the submitted work, consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti, Tiakis and United Therapeutics, outside the submitted work, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen and Merck, outside the submitted work, and participation on a data safety monitoring board or advisory board for Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2023.)

Objectives: To better understand the role of pharmacists in patient education and counselling: describe the perception of knowledge exchange (KE) between asthma/pulmonary arterial hypertension patients and pharmacists (hospital/community) according to four dimensions (4C-typology): cure (C1), care (C2); coordination/supply chain (C3), characteristics of the pathophysiology/disease mechanisms (C4); factors correlated with KE., Methods: A mixed methods approach was used. Part A: data from semi-structured patient interviews were processed (thematic analysis), and a questionnaire developed. Part B: completed patient questionnaires were processed by correspondence factor analysis., Results: KE (4C-typology) was correlated with pathology, disease severity, disease duration, age, hospital/community pharmacist. Patients expected pharmacists to provide C2/C3 services. KE with pharmacists covered C1/C2/C3, and with physicians, C1/C2/C4. While patients perceived KE as a means of self-learning to improve self-care skills, the two-way nature meant it provided specific experiential information feedback to pharmacists., Conclusions: This 4C-typology provides a holistic framework for optimising the pharmacists' role in education and counselling of patients with chronic diseases., (Copyright © 2022 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Since the 1960s, several drugs have been linked to the onset or aggravation of pulmonary arterial hypertension (PAH): dasatinib, some amphetamine-like appetite suppressants (aminorex, fenfluramine, dexfenfluramine, benfluorex) and recreational drugs (methamphetamine). Moreover, in numerous cases, the implication of other drugs with PAH have been suggested, but the precise identification of iatrogenic aetiologies of PAH is challenging given the scarcity of this disease and the potential long latency period between drug intake and PAH onset. In this context, we used the World Health Organization's pharmacovigilance database, VigiBase, to generate new hypotheses about drug associated PAH., Methods: We used VigiBase, the largest pharmacovigilance database worldwide to generate disproportionality signals through the Bayesian neural network method. All disproportionality signals were further independently reviewed by experts in pulmonary arterial hypertension, pharmacovigilance and vascular pharmacology and their plausibility ranked according to World Health Organization causality categories., Results: We included 2184 idiopathic PAH cases, yielding a total of 93 disproportionality signals. Among them, 25 signals were considered very likely, 15 probable, 28 possible and 25 unlikely. Notably, we identified 4 new protein kinases inhibitors (lapatinib, lorlatinib, ponatinib and ruxolitinib), 1 angiogenesis inhibitor (bevacizumab), and several chemotherapeutics (etoposide, trastuzumab), antimetabolites (cytarabine, fludarabine, fluorouracil, gemcitabine) and immunosuppressants (leflunomide, thalidomide, ciclosporin)., Conclusion: Such signals represent plausible adverse drug reactions considering the knowledge of iatrogenic PAH, the drugs' biological and pharmacological activity and the characteristics of the reported case. Although confirmatory studies need to be performed, the signals identified may help clinicians envisage an iatrogenic aetiology when faced with a patient who develops PAH., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by the dysfunction of pulmonary endothelial cells (ECs) and obstructive vascular remodeling. cAbl (non-receptor tyrosine kinase c-Abelson) plays central roles in regulating cell-cycle arrest, apoptosis, and senescence after cellular stress. We hypothesized that cAbl is downactivated in experimental and human PAH, thus leading to reduced DNA integrity and angiogenic capacity of pulmonary ECs from patients with PAH (PAH-ECs). We found cAbl and phosphorylated cAbl concentrations to be lower in the endothelium of remodeled pulmonary vessels in the lungs of patients with PAH than in control subjects. Similar observations were obtained for the lungs of Sugen + hypoxia and monocrotaline rats with established pulmonary hypertension. These in situ abnormalities were also replicated in vitro , with cultured PAH-ECs displaying lower cAbl expression and activity and an altered DNA damage response and capacity of tube formation. Downregulation of cAbl by RNA interference in control ECs or its inhibition with dasatinib resulted in genomic instability and the failure to form tubes, whereas upregulation of cAbl with 5-(1,3-diaryl-1H-pyrazol-4-yl) hydantoin reduced DNA damage and apoptosis in PAH-ECs. Finally, we establish the existence of cross-talk between cAbl and bone morphogenetic protein receptor type II. This work identifies the loss of cAbl signaling as a novel contributor to pulmonary EC dysfunction associated with PAH.

Oral anticoagulant can have a significant risk of adverse events, particularly when it is initiated, modified or interrupted. Pharmaceutical care through medication reconciliation could improve the benefit-to-risk ratio of these drugs. A prospective and interventional single center study was conducted from March through August 2018 in medicine and surgical units. Patients with an oral anticoagulant prescribed and coming from outpatient sector were included. These patients received a medication reconciliation at admission and discharge. Frequency and type of discrepancies were studied. Their gravity rating was assessed using the Cornish et al. scale. This study included 162 patients. The medication reconciliation at the admission allowed the detection of 133 unintentional discrepancies which 16 of them represented a high risk for the patient included nine errors about oral anticoagulant prescribing. Concerning the reconciliation at discharge, 51 unintentional discrepancies had been detected: 12 of them represented a high risk for the patient included eight errors about oral anticoagulant prescription. The acceptance rate of the discrepancies was 86% and reflected discrepancies severity. This result reached 96.4% if we took into account discrepancies with a severe clinical impact. This study highlighted oral anticoagulant represented relevant prioritization criteria to the long-lasting implementation of pharmaceutical care. This secures the management of the patient since the admission until the hospital discharge. The last step of our approach would be to study the needs about data transmission to the community caregivers., (Copyright © 2021 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a rare disease characterised by pulmonary vascular remodelling and elevated pulmonary pressure, which eventually leads to right heart failure and death. Registries worldwide have noted a female predominance of the disease, spurring particular interest in hormonal involvement in the disease pathobiology. Several experimental models have shown both protective and deleterious effects of oestrogens, suggesting that complex mechanisms participate in PAH pathogenesis. In fact, oestrogen metabolites as well as receptors and enzymes implicated in oestrogen signalling pathways and associated conditions such as BMPR2 mutation contribute to PAH penetrance more specifically in women. Conversely, females have better right ventricular function, translating to a better prognosis. Along with right ventricular adaptation, women tend to respond to PAH treatment differently from men. As some young women suffer from PAH, contraception is of particular importance, considering that pregnancy in patients with PAH is strongly discouraged due to high risk of death. When contraception measures fail, pregnant women need a multidisciplinary team-based approach. This article aims to review epidemiology, mechanisms underlying the higher female predominance, but better prognosis and the intricacies in management of women affected by PAH., Competing Interests: Conflict of interest: C. Cheron has nothing to disclose. Conflict of interest: S.A. McBride has nothing to disclose. Conflict of interest: F Antigny has nothing to disclose. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: M. Chouchana has nothing to disclose. Conflict of interest: M-C. Chaumais has nothing to disclose. Conflict of interest: X. Jaïs reports grants, personal fees and non-financial support from Actelion/Janssen, personal fees and non-financial support from MSD, and grants from Bayer, outside the submitted work. Conflict of interest: L. Bertoletti reports grants, personal fees and non-financial support from Actelion, MSD, Bayer, BMS/Pfizer and Léo-Pharma, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion; personal fees from Acceleron, Ferrer and Gossamer Bio; grants and personal fees from Bayer and MSD; and grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc. and Actelion, personal fees and non-financial support from Bayer, and personal fees from Novartis, outside the submitted work. Conflict of interest: M. Humbert reports grants, personal fees and non-financial support from GlaxoSmithKline; personal fees from AstraZeneca, Novartis, Roche, Sanofi, Teva and Merck; grants and personal fees from Acceleron, Actelion and Bayer, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer; personal fees from GSK, Pfizer, Chiesi and Boerhinger; grants, personal fees and non-financial support from MSD; and non-financial support from Acceleron, outside the submitted work., (Copyright ©The authors 2021.)

Busulfan is widely used to treat malignant diseases, particularly for therapeutic intensification prior to an autologous stem cell graft. Numerous side effects consecutive to busulfan are described, but few descriptions of pulmonary hypertension exist, while bronchiolitis obliterans remains a rare complication. We report the clinical observations of four patients from the French Pulmonary Hypertension Registry who experienced subacute pulmonary hypertension after receiving busulfan as preparation regimen before an autologous stem cell graft for malignancies (Hodgkin's disease, Ewing's sarcoma and primary large B cell lymphoma of the brain). Patients experienced severe pulmonary arterial hypertension 2 to 4.5 months after busulfan administration. Pulmonary hypertension improved after treatment with approved drugs for pulmonary arterial hypertension and/or corticosteroids. During the follow-up period, two patients developed chronic respiratory insufficiency due to interstitial lung disease, leading to double lung transplantation. The pathological assessment of explanted lungs revealed interstitial lung fibrosis with advanced bronchiolar lesions and severe pulmonary vascular damage. Three of the four patients were still alive after 36 to 80 months and the fourth died unexpectedly and suddenly after 5 months. In conclusion, PAH is a rare but severe complication associated with busulfan chemotherapy in adults. Histological examinations provide evidence for diffuse pulmonary vascular damage combined with interstitial lung injury in most cases., (© The Author(s) 2021.)

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.

Aims: Although right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), there is no treatment targeting directly the RV. We evaluate the efficacy of sacubitril/valsartan (LCZ 696) as add-on therapy to bosentan in rats with severe pulmonary hypertension (PH)., Methods and Results: Combination therapy of LCZ 696 and bosentan has additive vascular protective effects against the pulmonary vascular remodelling and PH in two preclinical models of severe PH. Compared with monotherapy, co-treatment of LCZ 696 (30 or 68 mg/kg/day for 2 weeks, per os) and bosentan (100 mg/kg/day for 2 weeks, per os) started 7 days after monocrotaline (MCT) injection substantially reduces pulmonary pressures, vascular remodelling, and RV hypertrophy and fibrosis in rats. Consistent with these observations, co-treatment of rats with established PH induced by sugen/hypoxia (SuHx) with LCZ 696 (30 mg/kg/day for 3 weeks, per os) and bosentan (100 mg/kg/day for 3 weeks, per os) started 5 weeks after Sugen injection partially attenuate total pulmonary vascular resistance and cardiovascular structures. We also obtained evidence showing that LCZ 696 has anti-proliferative effect on cultured human pulmonary artery smooth muscle cells derived from patients with idiopathic PAH, an effect that is more pronounced in presence of bosentan. Finally, we found that the plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) are higher in rats co-treated with LCZ 696 (30 mg/kg/day) and bosentan (100 mg/kg/day) than in MCT and SuHx rats treated with vehicle., Conclusion: Dual therapy with LCZ 696 plus bosentan proved significantly superior beneficial effect to LCZ 696 or bosentan alone on vascular remodelling and severity of experimental PH., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported., Research Question: What are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD?, Study Design and Methods: We report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum)., Results: From June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min × m 2 ), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (-4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively., Interpretation: PVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Viral respiratory infections are the main causes of asthma exacerbation. The susceptibility of patients with asthma to develop an exacerbation when they present with severe pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. The objective of this study was to investigate the characteristics and outcomes of asthmatic patients with coronavirus disease 2019 (COVID-19) pneumonia who required hospitalisation during the spring 2020 outbreak in Paris, France., Methods: A prospective cohort follow-up was carried out from 15 March to 15 April 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. These asthmatic patients were mainly female (70%) and nonsmokers (85%), with a median age of 54 years (interquartile range (IQR) 42-67 years). None of them presented with an asthma exacerbation. 22 (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 biological feature with a median count of 0 cells·mm -3 (IQR 0-0 cells·mm -3 ). 11 patients (30%) were admitted into the intensive care unit, with three deaths (8.1%) occurring in the context of comorbidities., Conclusion: Asthma patients were not overrepresented among those with severe pneumonia due to SARS-CoV-2 infection who required hospitalisation. The worst outcomes were observed mainly in patients with major comorbidities., Competing Interests: Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: M. Jevnikar has nothing to disclose. Conflict of interest: A. Boucly has nothing to disclose. Conflict of interest: J. Pichon has nothing to disclose. Conflict of interest: M. Preda has nothing to disclose. Conflict of interest: M. Frank has nothing to disclose. Conflict of interest: J. Laurent has nothing to disclose. Conflict of interest: C. Richard has nothing to disclose. Conflict of interest: X. Monnet has nothing to disclose. Conflict of interest: J. Duranteau has nothing to disclose. Conflict of interest: A. Harrois has nothing to disclose. Conflict of interest: M-C. Chaumais has nothing to disclose. Conflict of interest: M-F. Bellin has nothing to disclose. Conflict of interest: N. Noël has nothing to disclose. Conflict of interest: S. Bulifon has nothing to disclose. Conflict of interest: X. Jaïs has nothing to disclose. Conflict of interest: F. Parent has nothing to disclose. Conflict of interest: A. Seferian has nothing to disclose. Conflict of interest: L. Savale has nothing to disclose. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals and MSD, personal fees from Acceleron Pharmaceuticals, Gossamer Bio and Ferrer, grants and personal fees from Bayer, grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: D. Montani has nothing to disclose. Conflict of interest: M. Humbert reports grants, personal fees and non-financial support from GlaxoSmithKline, personal fees from AstraZeneca, Novartis, Roche, Sanofi and Teva, outside the submitted work., (Copyright ©ERS 2020.)

Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia., Competing Interests: Conflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc. and Actelion, personal fees and non-financial support from Bayer, personal fees from Novartis, grants from Alberta Lung Association, Canadian Vascular Network, European Respiratory Society and Canadian Thoracic Society, outside the submitted work. Conflict of interest: L. Bondeelle has nothing to disclose. Conflict of interest: M-C. Chaumais reports personal fees from Actelion, non-financial support from Bayer and Boehringer Ingelheim, outside the submitted work. Conflict of interest: C. Guignabert has nothing to disclose. Conflict of interest: L. Savale reports personal fees from Actelion, grants and personal fees from Bayer and GSK, outside the submitted work. Conflict of interest: X. Jaïs reports grants and personal fees from Actelion and MSD, grants from Bayer, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer HealthCare and MSD, personal fees and non-financial support from Acceleron Pharmaceuticals, personal fees from Ferrer, Gossamer Bio and United Therapeutics, grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: P. Rousselot reports grants and personal fees from Pfizer and Incyte, grants from Britol Myers Squibb, outside the submitted work. Conflict of interest: M. Humbert reports personal fees from Acceleron, Merck, Morphogen IX and United Therapeutics, grants and personal fees from Actelion, Bayer and GSK, outside the submitted work. Conflict of interest: A. Bergeron reports grants from SOS oxygene, personal fees from Shire, Pfizer, MSD and Gilead, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, personal fees from GSK, Pfizer, MSD and Chiesi, outside the submitted work., (Copyright ©ERS 2020.)

Background Pulmonary hypertension is a rare, chronic and life-threatening group of diseases. Recent advances in pulmonary hypertension management prolong survival and improve quality-of-life. However, highly complex drug therapy enhances the risk of drug-related problems. Objective To assess the impact of involving clinical pharmacists in the collaborative care of pulmonary hypertension patients. Setting Ten French University Hospital Pneumology departments, all members of the French Network for Pulmonary Hypertension. Methods This prospective multicenter randomized controlled trial included incident pulmonary hypertension patients who were followed-up for 18 months. Randomization using an adapted Zelen method allocated patients to collaborative care (n = 41) or usual care groups (n = 51). A collaborative care program involving clinical pharmacists was developed through a close partnership between with physicians, nurses and pharmacists. Besides usual care, the program includes regular one-to-one interviews between the pharmacist and the patient. These interviews had following objectives: to perform an exhaustive medication history review; to identify the patient' needs, knowledge and skills; to define educational objectives and to provide patients with relevant information when needed. Following each interview, a standardized report form containing the pharmacist's recommendations was provided to physicians and nurses and discussed collaboratively. An ancillary economic analysis was performed. Main outcome measure Number of drug-related problems and their outcomes. Results The number of drug-related problems was not significantly different between groups (1.6 ± 1.5 vs. 1.9 ± 2.4; p = 0.41). More problems were resolved in the collaborative care group than in the usual care group (86.5% vs. 66.7%, p = 0.01). Time to clinical worsening, therapeutic adherence, satisfaction or quality-of-life were not statistically different between groups. Collaborative care decreased costs of drug-related hospitalizations. Conclusion Including clinical pharmacists in the multidisciplinary care of hospitalized patients with pulmonary hypertension improved the outcome of drug-related problems and reduced the costs of related hospitalization. However, we observed no efficacy on medication errors, clinical outcomes or medication adherence. Clinical Trial Registration ClinicalTrials.gov Identifier NCT01038284.

Atrial fibrillation (AF) accounts for up to one third of strokes, one of the lead mortality causes worldwide. The European Society of Cardiology guidelines recommend opportunistic screening as a means to increase the odds of early detection and institution of appropriate treatment according to risk factors identified. However, in most countries there are various barriers to effective uptake of screening, including low awareness. The Atrial Fibrillation Association is a patient association engaged with raising awareness of AF. Establishing a partnership with the International Pharmacists for Anticoagulation Care Taskforce, we set as goals to test a model for raising awareness of AF involving pharmacists globally; and to identify barriers and enablers to its implementation. A cross-sectional study was conducted during the Arrhythmia Alliance World Heart Rhythm Week. Pharmacists from 10 countries invited individuals (≥ 40 years; without anticoagulation therapy of AF) to participate in the awareness campaign. Participants agreeing were engaged in the early detection of AF (EDAF) using pulse palpation. Individuals with rhythm discrepancies were referred and prospectively assessed to have information on the proportion of confirmed diagnosis, leading to estimate the detection rate. Interviews with country coordinators explored barriers and enablers to implementation. The study involved 4193 participants in the awareness campaign and 2762 in the EDAF event (mean age 65.3 ± 13.0), of whom 46.2% individuals were asymptomatic, recruited across 120 sites. Most common CHA 2 DS 2 -VASc risk factor was hypertension. Among 161 patients referred to physician, feedback was obtained for 32 cases, of whom 12 new arrhythmia diagnoses were confirmed (5 for AF, 2 for atrial flutter), all among elders (≥ 65 years). Qualitative evaluation suggested a local champion to enable pharmacists' success; technology enhanced engagement amongst patients and increased pharmacists' confidence in referring to physicians; interprofessional relationship was crucial in success. This study suggests pharmacists can contribute to greater outreach of awareness campaigns. Effective communication pathways for inter-professional collaboration were suggested enablers to gain full benefits of EDAF.

Background Oral anticoagulants are widely used for treatment and prevention of thromboembolic diseases. We set up a pharmaceutical counseling program for both direct oral anticoagulant and vitamin K antagonist drugs in our hospital in 2015. Objective Evaluate patient satisfaction and the evolution of their knowledge throughout the pharmaceutical counseling program on anticoagulants and identify knowledge variability factors. Setting Cardiology Inpatient Unit from the University Antoine Béclère Hospital, France. Methods Evaluation was based on data collection of patients surveyed between 2015 and 2018. Inpatients in the cardiology department on oral anticoagulants were eligible. The learning process was designed to enhance patient knowledge and understanding based on 10 cognitive or self-management skills, relating to the optimization of oral anticoagulant therapy management. It consisted in 2 face-to-face interviews during hospitalization and 2 additional phone interviews one and six months after discharge. The median patient score was evaluated at each step of the process as well as the mean score for each item from the global population. A sub-analysis was run on the less well-acquired skills in order to identify risk factors for limited knowledge. The association between those factors and the level of knowledge (score ≥ 7 or < 7) was assessed using Chi square test followed by multivariate analysis. Main outcome measure Patient knowledge of anticoagulation therapy depending on specific factors. Results Of the 880 patients eligible for pharmaceutical counseling, 319 entered the process and 102 completed it. Median knowledge scores were 8/10 and 9/10 after the first and the final interviews respectively with a significant improvement (p = 0.0003). The least well-acquired items at each step were surveillance and under-dosing management. The sub-analysis showed the use of vitamin K antagonist to be linked to an enhanced understanding related to treatment surveillance (p = 0.029). Patients suffering from atrial fibrillation were found to have a worse understanding of under-dosing management (p = 0.013). Finally, patients evaluated the process as helpful and suitable for their conditions. Conclusion Pharmaceutical counseling is appropriate for patients, improving and maintaining knowledge of oral anticoagulants. Our evaluation highlights the need to focus on patient-specific profiles to reach a satisfactory level of knowledge.

The pathophysiology of pulmonary arterial hypertension (PAH) induced by protein kinase inhibitors (PKIs) remains unclear. To gain knowledge into this rare and severe pathology we performed a study combining a pharmacovigilance approach and the pharmacodynamic properties of PKIs.A disproportionality analysis on the World Health Organization pharmacovigilance database VigiBase using the reporting odds ratio (ROR) and 95% confidence interval was first performed. Then, we identified the most relevant cellular targets of interest through a systematic literature review and correlated the pharmacovigilance signals with the affinity for the different PKIs. We further performed a hierarchical cluster analysis to assess patterns of binding affinity.A positive disproportionality signal was found for dasatinib, bosutinib, ponatinib, ruxolitinib and nilotinib. Five non-receptor protein kinases significantly correlate with disproportionality signals: c-Src (r=0.79, p=0.00027), c-Yes (r=0.82, p=0.00015), Lck (r=0.81, p=0.00046) and Lyn (r=0.80, p=0.00036), all belonging to the Src protein kinase family, and TEC (r=0.85, p=0.00006). Kinases of the bone morphogenetic protein signalling pathway also seem to play a role in the pathophysiology of PKI-induced PAH. Interestingly, the dasatinib affinity profile seems to be different from that of other PKIs in the cluster analysis.The study highlights the potential role of the Src protein kinase family and TEC in PAH induced by PKIs. This approach combining pharmacovigilance and pharmacodynamics data allowed us to generate some hypotheses about the pathophysiology of the disease; however, the results have to be confirmed by further studies., Competing Interests: Conflict of interest: L. Cornet has nothing to disclose. Conflict of interest: C. Khouri has nothing to disclose. Conflict of interest: M. Roustit reports grants from United Therapeutics outside the submitted work. Conflict of interest: C. Guignabert has nothing to disclose. Conflict of interest: M-C. Chaumais reports nonfinancial support from Bayer and personal fees from Actelion, outside the submitted work. Conflict of interest: M. Humbert reports personal fees from Actelion, Bayer, GSK, Merck and United Therapeutics, during the conduct of the study. Conflict of interest: B. Revol has nothing to disclose. Conflict of interest: F. Despas has nothing to disclose. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from BMS, GSK, MSD and Pfizer, outside the submitted work. Conflict of interest: J-L. Cracowski reports grants from Bioprojet and Topadur, outside the submitted work., (Copyright ©ERS 2019.)

Spontaneous reporting is the primary method used in pharmacovigilance (PV) to detect drug safety signal. Specific criteria used in pharmacovigilance to prove accountability of a drug are rarely present in rare disease. The low number of alerts also makes it challenging. The aim of this commentary is to raise awareness among pharmacists on issues and opportunities for pharmacovigilance in rare diseases, taking pulmonary arterial hypertension (PAH) as example, from which a subset of cases are drug-induced. It is demonstrated how a dedicated program named VIGIAPATH created to reinforce pharmacovigilance of drug-induced pulmonary arterial hypertension at a national level, led to increase self-reporting and confirm safety signals. Thanks to a specific program such as VIGIAPATH, pharmacists can play an important role in communication with clinicians, patients and regulatory agencies, facilitating the detection of potential safety signals at an early stage in rare disease.

We report here the first cases, to our knowledge, of pulmonary arterial hypertension induced by lorlatinib. It s the first time that a tyrosine kinase inhibitor for lung cancer is associated with pulmonary arteriel hypertension., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose of Review: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of several neoplastic conditions; however, pulmonary arterial hypertension (PAH) has been reported as a complication of TKIs, predominantly with dasatinib. Recent studies have elucidated the potential mechanisms of TKI-induced PAH and have better clarified the long-term outcomes., Recent Findings: In addition to the known association between dasatinib and PAH, several other TKIs have recently been reported to cause PAH, including ponatinib, bosutinib and lapatinib. Dasatinib causes direct pulmonary artery endothelial cell toxicity through the production of mitochondrial reactive oxygen species, but likely requires the presence of a second risk factor to cause PAH. Symptoms and haemodynamic abnormalities frequently resolve after discontinuation of the TKI, but PAH persists in over a third of patients and can reoccur when other TKIs are used, which warrants close follow-up. Rare fatal cases have occurred; therefore, treatment with PAH-specific therapy is recommended for patients with right heart failure or persistent PAH after discontinuation of the TKI., Summary: PAH is a rare but important complication of several TKIs. Management includes discontinuation of the TKI, close follow-up and PAH-specific therapy in severe cases.

This study aimed to describe the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib.21 incident, right heart catheterisation-confirmed cases of dasatinib-induced PAH were identified from the French Pulmonary Hypertension Registry. Clinical and haemodynamic variables were compared from baseline to last follow-up (median (range) 24 (1-81) months).Median age was 52 years and 15 patients were female (71%). 19 patients received dasatinib for chronic myelogenous leukaemia for a median (range) duration of 42 (8-74) months before PAH diagnosis. No bone morphogenic protein receptor-2 ( BMPR2 ) mutations were found in the 10 patients tested. Dasatinib was uniformly discontinued and 11 patients received PAH medications. Four patients died during follow-up. New York Heart Association functional class improved from 76% in class III/IV to 90% in class I/II (p<0.01). Median (range) 6-min walk distance improved from 306 (0-660) to 430 (165-635) m (p<0.01). Median (range) mean pulmonary arterial pressure improved from 45 (30-70) to 26 (17-50) mmHg (p<0.01) and pulmonary vascular resistance from 6.1 (3.2-27.3) to 2.6 (1.2-5.9) Wood units (p<0.01). Patients treated with PAH medications had worse baseline haemodynamics but similar long-term outcomes to untreated patients. PAH persisted in 37% of patients.Dasatinib-induced PAH frequently improves after discontinuation but persisted in over one-third of patients, therefore systematic follow-up is essential., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Purpose of Review: Pulmonary adverse effects of interferon (IFN) therapies are rare but can be life threatening. This article proposes to review clinical and experimental data suggesting a causal link between interferon exposure and pulmonary arterial hypertension (PAH)., Recent Findings: Interferon has recently been added to the list of possible risk factors for PAH. This was justified by the reporting of many cases of pulmonary hypertension potentially associated with IFN-α or IFN-β exposure. Some of them were reversible after cessation of interferon exposure, especially in patients without concomitant risk factors for pulmonary hypertension. In contrast, it remains a challenge to definitively confirm the causal role of IFN-α in patients treated for hepatitis C viral infection because of frequent concomitant PAH risk factors such as portal hypertension and/or HIV infection. In these patients, temporal and clinical arguments suggest that interferon may potentially act as an additional trigger for PAH. Moreover, the information obtained from clinical experience with interferon therapy has been enriched by basic science research on this topic suggesting that interferon is involved in both human and experimental pulmonary hypertension., Summary: Many clinical and experimental data corroborate the link between interferon exposure and the risk to develop PAH.

Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.

Prostacyclin (PGI2) is a prostaglandin derived from arachidonic acid in the endothelium and smooth muscle which causes vasodilation, inhibits platelet aggregation, and has anti-inflammatory, anti-thrombotic and anti-proliferative effects. In pulmonary arterial hypertension (PAH), PGI2 levels and PGI2 synthase expression are reduced, contributing to the vasoconstriction and vascular smooth muscle cell proliferation seen in the disease. Based on these findings, PGI2 analogues were developed to target this pathway. Epoprostenol was the first targeted therapy available for treating PAH. Due to the short half-life of this drug, it requires administration via a continuous intravenous infusion, and therefore it carries the risks of central line infections and thrombosis. However, it remains the treatment of choice in patients with severe PAH as it has a proven survival benefit as well as improved functional class and exercise capacity. Subsequently, several other PGI2 analogues have been developed with differing modes of administration and varying degrees of efficacy. Beraprost is an oral PGI2 analogue for which a sustained efficacy has not been demonstrated. Iloprost is a nebulised PGI2 analogue that requires administration six to nine times a day and leads to improved functional class, exercise capacity and haemodynamics. There are inhaled, oral, subcutaneous and intravenous forms of treprostinil. Subcutaneous treprostinil avoids the risks of a continuous intravenous administration; however, this drug can cause intractable pain at the injection site. Selexipag is the new oral non-prostanoid IP prostacyclin receptor agonist that has shown improved haemodynamics and good tolerance in a phase II study. Initial results of the phase III trial are promising. Comparison of the different PGI2 agents is limited by a lack of head-to-head clinical trials. However, the development of PGI2 analogues has improved survival in patients with PAH and remains the main treatment option in advanced disease. While PGI2 analogues have good efficacy in PAH, they are not interchangeable, and their delivery systems have many limitations; in particular, they are associated with significant deleterious consequences. In the future, it is hoped that the elusive goal of developing an effective oral PGI2 analogue will be achieved. This would increase the number of people who could benefit from the treatment while reducing the associated adverse events, and as a result improve the survival and quality of life for these patients.

Sofosbuvir and daclatasvir are direct-acting antiviral drugs used to treat chronic hepatitis C virus infection. In 2015, the Food and Drug Administration and European Medical Agency warned that bradycardia could occur when amiodarone was administered in combination with sofosbuvir, but no case reports had been published. We report extreme bradycardia within 2 hrs after intake of sofosbuvir and daclatasvir by 2 patients receiving amiodarone. The first patient had a cardiac asystole 30 min after receiving sofosbuvir and daclatasvir. Amiodarone, sofosbuvir, and daclatasvir treatment were stopped; after 10 days, the cardiac evaluation was normal and patient was discharged. The second patient was taking amiodarone and propranolol; 2 hrs after receiving sofosbuvir and daclatasvir, he had an extreme sinus node dysfunction (heart rate of 27beats/min). Amiodarone and propranolol were stopped, but the patient continued receiving sofosbuvir and daclatasvir for 3 days and sinus bradycardia was recorded each day, 2 hrs after intake of these drugs. When he stopped taking the drugs, no bradycardia was observed. Administration of sofosbuvir and daclatasvir on day 13 induced bradycardia 2 hrs after intake. However, no bradycardia occurred following a rechallenge 8 weeks after the patient stopped taking amiodarone. These observations indicate that patients treated with amiodarone should be continuously monitored within the first 48 hrs following the initiation of sofosbuvir and daclatasvir., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD., Methods and Results: We reported on the clinical, functional, and hemodynamic characteristics and outcomes of 7 cases of PVOD induced by mitomycin-C (MMC) therapy from the French Pulmonary Hypertension Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9 of 1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million per year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21 to 35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented the development of MMC-induced PVOD in rats., Conclusions: MMC therapy is a potent inducer of PVOD in humans and rats. Amifostine prevents MMC-induced PVOD in rats and should be tested as a preventive therapy for MMC-induced PVOD in humans. MMC-induced PVOD in rats represents a unique model to test novel therapies in this devastating orphan disease., (© 2015 American Heart Association, Inc.)

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)