Publications by authors named "Marc Humbert"

714 Publications

Preventing the Increase in Lysophosphatidic Acids: A New Therapeutic Target in Pulmonary Hypertension?

Metabolites 2021 Nov 17;11(11). Epub 2021 Nov 17.

UNIROUEN, INSERM U1096, CHU Rouen, Department of Pharmacology, Normandie University, F-76000 Rouen, France.

Cardiovascular diseases (CVD) are the leading cause of premature death and disability in humans that are closely related to lipid metabolism and signaling. This study aimed to assess whether circulating lysophospholipids (LPL), lysophosphatidic acids (LPA) and monoacylglycerols (MAG) may be considered as potential therapeutic targets in CVD. For this objective, plasma levels of 22 compounds (13 LPL, 6 LPA and 3 MAG) were monitored by liquid chromatography coupled with tandem mass spectrometry (HPLC/MS) in different rat models of CVD, i.e., angiotensin-II-induced hypertension (HTN), ischemic chronic heart failure (CHF) and sugen/hypoxia(SuHx)-induced pulmonary hypertension (PH). On one hand, there were modest changes on the monitored compounds in HTN (LPA 16:0, 18:1 and 20:4, LPC 16:1) and CHF (LPA 16:0, LPC 18:1 and LPE 16:0 and 18:0) models compared to control rats but these changes were no longer significant after multiple testing corrections. On the other hand, PH was associated with important changes in plasma LPA with a significant increase in LPA 16:0, 18:1, 18:2, 20:4 and 22:6 species. A deleterious impact of LPA was confirmed on cultured human pulmonary smooth muscle cells (PA-SMCs) with an increase in their proliferation. Finally, plasma level of LPA(16:0) was positively associated with the increase in pulmonary artery systolic pressure in patients with cardiac dysfunction. This study demonstrates that circulating LPA may contribute to the pathophysiology of PH. Additional experiments are needed to assess whether the modulation of LPA signaling in PH may be of interest.
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http://dx.doi.org/10.3390/metabo11110784DOI Listing
November 2021

Sex and gender in lung health and disease: more than just Xs and Ys.

Eur Respir Rev 2021 Dec 8;30(162). Epub 2021 Nov 8.

Faculty of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.

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http://dx.doi.org/10.1183/16000617.0217-2021DOI Listing
December 2021

Sex and gender in pulmonary arterial hypertension.

Eur Respir Rev 2021 Dec 8;30(162). Epub 2021 Nov 8.

School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France

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 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.
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http://dx.doi.org/10.1183/16000617.0330-2020DOI Listing
December 2021

[What's all that confusion about ? Delirium in the elderly].

Rev Med Suisse 2021 Nov;17(757):1871-1875

Service de gériatrie et de réadaptation gériatrique, CHUV, 1011 Lausanne.

Delirium is common in community-dwelling as well as in hospitalized older persons aged 75 years and older. Often underdiagnosed, delirium is associated with increased morbidity and mortality. Screening (with CAM and 3D-CAM) and identification of older people at increased risk for delirium is essential to enhance non-pharmacological preventative measures and monitor their evolution to allowing an early diagnosis. Screening instruments are currently available, such as the CAM and 3D-CAM. Pharmacological treatment is proposed only in situations where the patients endanger him-herself or other persons. In patients without previously known cognitive impairment, a cognitive assessment is mandated within the next 6 to 12 months period following the delirium episode.
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November 2021

External validation of a refined 4-strata risk assessment score from the French pulmonary hypertension Registry.

Eur Respir J 2021 Nov 4. Epub 2021 Nov 4.

Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France

Introduction: Contemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate, or high-risk. A minority of patients achieve low-risk status with most remaining intermediate-risk. Our aim was to validate a 4-strata risk assessment approach categorising patients as low, intermediate-low, intermediate-high, or high risk, as proposed by the COMPERA Registry investigators.

Methods: We evaluated incident patients from the French PAH Registry and applied a 4-strata risk method at baseline and at first reassessment. We applied refined cut-points for 3 variables: World Health Organization functional class, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide. We used Kaplan-Meier survival analyses and Cox proportional hazards regression to assess survival according to a 3-strata and 4-strata risk approach.

Results: At baseline (n=2879), the 4-strata approach identified 4 distinct risk groups and performed better than a 3-strata method for predicting mortality. The 4-strata model discrimination was higher than the 3-strata method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease, and portopulmonary hypertension. Using the 4-strata approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the 3-strata approach. Those who achieved or maintained a low-risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high.

Conclusions: The 4-strata risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the 3-strata approach.
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http://dx.doi.org/10.1183/13993003.02419-2021DOI Listing
November 2021

Double-lung transplantation followed by delayed percutaneous repair for atrial septal defect-associated pulmonary arterial hypertension.

Eur Respir J 2021 Nov 4. Epub 2021 Nov 4.

Service de Chirurgie Thoracique, Vasculaire et Transplantation Cardio-pulmonaire, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France

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http://dx.doi.org/10.1183/13993003.02388-2021DOI Listing
November 2021

Reply to: Jin et al. and Sun et al.

Am J Respir Crit Care Med 2021 Oct 21. Epub 2021 Oct 21.

CHU de Bicetre, Service de Pneumologie, Le Kremlin Bicetre, France;

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http://dx.doi.org/10.1164/rccm.202107-1725LEDOI Listing
October 2021

[Targeting activin receptor IIA ligands for the treatment of pulmonary arterial hypertension].

Med Sci (Paris) 2021 Oct 14;37(10):839-843. Epub 2021 Oct 14.

Université Paris-Saclay, Faculté de médecine, 94270 Le Kremlin-Bicêtre, France - Inserm UMR-S 999, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France.

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http://dx.doi.org/10.1051/medsci/2021131DOI Listing
October 2021

Pulmonary hypertension associated with busulfan.

Pulm Circ 2021 Oct-Dec;11(4):20458940211030170. Epub 2021 Sep 30.

Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

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.
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http://dx.doi.org/10.1177/20458940211030170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488760PMC
September 2021

Pulmonary hypertension: A rare but severe complication of common variable immunodeficiency.

Ann Allergy Asthma Immunol 2021 10;127(4):512-513

Assistance Publique-Hôpitaux de Paris (AP-HP), Centre de Référence National de l'Hypertension Pulmonaire, Département de Médecine Respiratoire et Soins Intensifs Respiratoires, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Hypertension Arterielle Pulmonaire: Physiopathologie Et Nouvelles Thérapies, Le Plessis-Robinson, France. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2021.06.016DOI Listing
October 2021

Omalizumab Effectiveness in Severe Allergic Asthma with Multiple Allergic Comorbidities: A Post-Hoc Analysis of the STELLAIR Study.

J Asthma Allergy 2021 23;14:1129-1138. Epub 2021 Sep 23.

Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France.

Background: Immunoglobulin (Ig) E-mediated pathophysiological mechanisms are common in allergic diseases including severe allergic asthma (SAA). The anti-IgE monoclonal antibody omalizumab may be particularly beneficial for patients with SAA and multiple allergic comorbidities (AC) including perennial/seasonal rhinitis, conjunctivitis, atopic dermatitis (AD), and food allergy.

Methods: We conducted a post-hoc analysis of the patients from the STELLAIR study (n=872, 149 minors and 723 adults). The patients were classified based on the presence of multiple AC (≥3 AC or <3 AC) or AD as assessed by questionnaire. Response to omalizumab was assessed after 4-6 months (T) and after 12 months (T). Asthma response at T was based on global evaluation of treatment effectiveness, reduction of ≥40% in annual exacerbation rate, and a combination of both. Asthma response at T was based on change in yearly exacerbation and hospitalization rates. AC improvement at T was based on patient perception.

Results: Patients with ≥3 AC demonstrated a higher combined response to omalizumab (74.7% vs 58.3%) at T and had reduced yearly exacerbation and hospitalization rates (88.9% vs 77.4% and -94.0% vs -70.5%, respectively). Patients with ≥3 AC were more likely to show an improvement in their AC (85.3% vs 51.9%) at T. Results were similar in minors and adults. The presence of AD was associated with greater omalizumab effectiveness at T and a greater AC improvement at T. Improvement of AD and food allergies at T were 73.2% and 38.7%, respectively, in the population overall.

Conclusion: This post-hoc analysis of the STELLAIR study shows that omalizumab is beneficial for all SAA patients and especially for patients with multiple AC or AD. In patients with ≥3 AC, omalizumab also improved AC outcomes.
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http://dx.doi.org/10.2147/JAA.S310888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475967PMC
September 2021

Investigating the association between ALK Receptor Tyrosine Kinase inhibitors and pulmonary arterial hypertension: a disproportionality analysis from the WHO pharmacovigilance database.

Eur Respir J 2021 Sep 29. Epub 2021 Sep 29.

INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis Robinson, France.

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http://dx.doi.org/10.1183/13993003.01576-2021DOI Listing
September 2021

Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH.

Eur Respir J 2021 Sep 29. Epub 2021 Sep 29.

Genetics and Molecular Medicine, King's College, London, UK.

Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension. Compelling preclinical data supports the therapeutic blockade of interleukin-6 signalling.We conducted an open-label phase-II study of intravenous tocilizumab (8 mg·kg) over 6 months in group 1 pulmonary arterial hypertension. Co-primary endpoints were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a Mendelian randomisation study was undertaken on 11,744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL6R variant (rs7529229), known to associate with circulating IL6R levels.Twenty-nine patients (M/F 10/19; mean age 54.9[SD11.4]) were recruited. Nineteen had heritable/idiopathic and ten connective tissue disease associated pulmonary arterial hypertension. Six were withdrawn prior to drug administration. Twenty-three patients received at least one dose of tocilizumab. Tocilizumab was discontinued in 4 patients due to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma interleukin-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead variant on risk of pulmonary arterial hypertension (OR 0.99, p=0.88).Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
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http://dx.doi.org/10.1183/13993003.02463-2020DOI Listing
September 2021

An Updated Definition and Severity Classification of COPD Exacerbations: The Rome Proposal.

Am J Respir Crit Care Med 2021 Sep 27. Epub 2021 Sep 27.

Imperial College London, National Heart and Lung Institute, London, United Kingdom of Great Britain and Northern Ireland.

The current definition of a chronic obstructive pulmonary disease (COPD) exacerbation (ECOPD) is based solely on worsening respiratory symptoms, with severity classified post hoc by the healthcare resource used to treat the event, which may vary among practitioners and healthcare systems. These shortcomings support a need to revise the ECOPD definition and severity classification to one that is useful at time of patient contact. To achieve this, an expert panel used a modified Delphi method of five rounds of questions generated by a thorough review of the literature, supplemented by virtual discussions. For the 80 identified questions, the agreement level was rated using a Likert scale from 0 (strongly disagree) to 9 (strongly agree). Consensus was defined a priori as a median score ≥7 (strong agreement). The proposed definition states: "In a patient with COPD, an exacerbation is an event characterized by dyspnea and/or cough and sputum that worsens over ≤14 days, that may be accompanied by tachypnea and/or tachycardia, often associated with increased local and systemic inflammation caused by airway infection, pollution, or other insult to the airways." Three severity categories (mild, moderate, or severe) were defined using integration of six clinically measurable variables: intensity of dyspnea, oxygen saturation, respiratory rate, heart rate, C-reactive protein, and, if indicated, arterial blood gases. In conclusion, by incorporating measurable clinical and laboratory variables at the time of exacerbation, the Rome proposal for an updated definition of ECOPD could help standardize care and outcomes for clinicians and researchers alike. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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http://dx.doi.org/10.1164/rccm.202108-1819PPDOI Listing
September 2021

Pulmonary Endarterectomy in Patients With Myeloproliferative Neoplasms.

Chest 2021 Sep 17. Epub 2021 Sep 17.

Cardiothoracic Intensive Care Unit, Hôpital Marie Lannelongue, Le Plessis-Robinson, France; University Paris-Saclay, Faculty of Medicine, Le Plessis-Robinson, France; INSERM U999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension Reference Center of Hôpital Bicêtre, Kremlin-Bicêtre, France. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2021.09.007DOI Listing
September 2021

Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension.

Int J Mol Sci 2021 Aug 24;22(17). Epub 2021 Aug 24.

Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Pulmonary arterial hypertension (PAH) is a devastating lung disease characterized by the progressive obstruction of the distal pulmonary arteries (PA). Structural and functional alteration of pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) contributes to PA wall remodeling and vascular resistance, which may lead to maladaptive right ventricular (RV) failure and, ultimately, death. Here, we found that decreased expression of sarcoplasmic/endoplasmic reticulum Ca ATPase 2a (SERCA2a) in the lung samples of PAH patients was associated with the down-regulation of bone morphogenetic protein receptor type 2 (BMPR2) and the activation of signal transducer and activator of transcription 3 (STAT3). Our results showed that the antiproliferative properties of SERCA2a are mediated through the STAT3/BMPR2 pathway. At the molecular level, transcriptome analysis of PASMCs co-overexpressing SERCA2a and BMPR2 identified STAT3 amongst the most highly regulated transcription factors. Using a specific siRNA and a potent pharmacological STAT3 inhibitor (STAT3i, HJC0152), we found that SERCA2a potentiated BMPR2 expression by repressing STAT3 activity in PASMCs and PAECs. In vivo, we used a validated and efficient model of severe PAH induced by unilateral left pneumonectomy combined with monocrotaline (PNT/MCT) to further evaluate the therapeutic potential of single and combination therapies using adeno-associated virus (AAV) technology and a STAT3i. We found that intratracheal delivery of AAV1 encoding SERCA2 or BMPR2 alone or STAT3i was sufficient to reduce the mean PA pressure and vascular remodeling while improving RV systolic pressures, RV ejection fraction, and cardiac remodeling. Interestingly, we found that combined therapy of AAV1.hSERCA2a with AAV1.hBMPR2 or STAT3i enhanced the beneficial effects of SERCA2a. Finally, we used cardiac magnetic resonance imaging to measure RV function and found that therapies using AAV1.hSERCA2a alone or combined with STAT3i significantly inhibited RV structural and functional changes in PNT/MCT-induced PAH. In conclusion, our study demonstrated that combination therapies using SERCA2a gene transfer with a STAT3 inhibitor could represent a new promising therapeutic alternative to inhibit PAH and to restore BMPR2 expression by limiting STAT3 activity.
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http://dx.doi.org/10.3390/ijms22179105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431626PMC
August 2021

A CELSR1 variant in a patient with pulmonary arterial hypertension.

Clin Genet 2021 12 25;100(6):771-772. Epub 2021 Aug 25.

Department of Respiratory and Intensive Care Medicine, Université Paris-Saclay, AP-HP, INSERM UMR_S 999, Pulmonary Hypertension National Referral Centre, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

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http://dx.doi.org/10.1111/cge.14046DOI Listing
December 2021

Response to: Life-threatening PPHN refractory to NO: therapeutic algorithm.

Eur J Pediatr 2021 Aug 26. Epub 2021 Aug 26.

Division of Pediatrics and Neonatal Critical Care, "A.Béclère" Medical Center, Paris Saclay University Hospitals, APHP, Paris, France.

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http://dx.doi.org/10.1007/s00431-021-04228-3DOI Listing
August 2021

Comment on: Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype.

Eur Respir J 2021 08 19;58(2). Epub 2021 Aug 19.

Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France.

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http://dx.doi.org/10.1183/13993003.01365-2021DOI Listing
August 2021

Phenotypic Diversity of Vascular Smooth Muscle Cells in Pulmonary Arterial Hypertension: Implications for Therapy.

Chest 2021 Aug 12. Epub 2021 Aug 12.

School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France; INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France. Electronic address:

Pulmonary arterial hypertension (PAH) is a progressive incurable condition that is characterized by extensive remodeling of the pulmonary circulation, leading to severe right-sided heart failure and death. Similar to other vascular contractile cells, pulmonary arterial smooth muscle cells play central roles in physiological and pathologic vascular remodeling because of their remarkable ability to dynamically modulate their phenotype to ensure contractile and synthetic functions. The dysfunction and molecular mechanisms underlying their contribution to the various pulmonary vascular lesions associated with PAH have been a major focus of research. The aim of this review is to describe the medial and nonmedial origins of contractile cells in the pulmonary vascular wall and present evidence of how they contribute to the onset and progression of PAH. We also highlight specific potential target molecules and discuss future directions that are being explored to widen the therapeutic options for the treatment of PAH.
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http://dx.doi.org/10.1016/j.chest.2021.08.040DOI Listing
August 2021

Looking forward: key initiatives to improve the care of rare diseases and streamline the delivery of medicines and vaccines in Europe.

Am J Physiol Lung Cell Mol Physiol 2021 09 28;321(3):L616-L618. Epub 2021 Jul 28.

Respiratory & Sleep Medicine, Royal Brompton & Harefield Hospital, London, United Kingdom.

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http://dx.doi.org/10.1152/ajplung.00317.2021DOI Listing
September 2021

Pulmonary hypertension associated with neurofibromatosis type 2.

Pulm Circ 2021 Jul-Sep;11(3):20458940211029550. Epub 2021 Jul 5.

Department of Cardiology, International University of Health and Welfare Mita Hospital, Tokyo, Japan.

Although precapillary pulmonary hypertension is a rare but severe complication of patients with neurofibromatosis type 1 (NF1), its association with NF2 remains unknown. Herein, we report a case of a 44-year-old woman who was initially diagnosed with idiopathic pulmonary arterial hypertension and treated with pulmonary arterial hypertension-specific combination therapy. However, a careful assessment for a relevant family history of the disease and genetic testing reveal that this patient had a mutation in the gene. Using immunofluorescence and Western blotting, we demonstrated a decrease in endothelial NF2 protein in lungs from idiopathic pulmonary arterial hypertension patients compared to control lungs, suggesting a potential role of NF2 in pulmonary arterial hypertension development. To our knowledge, this is the first time that precapillary pulmonary hypertension has been described in a patient with NF2. The altered endothelial NF2 expression pattern in pulmonary arterial hypertension lungs should stimulate work to better understand how NF2 is contributing to the pulmonary vascular remodelling associated to these severe life-threatening conditions.
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http://dx.doi.org/10.1177/20458940211029550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264739PMC
July 2021

Severe pulmonary hypertension associated with chronic obstructive pulmonary disease: A prospective French multicenter cohort.

J Heart Lung Transplant 2021 09 11;40(9):1009-1018. Epub 2021 May 11.

Service de pneumologie B, hôpital Bichat, Paris, France, Université Paris 7, Inserm UMR1152. Electronic address:

Background: A small proportion of patients with chronic obstructive pulmonary disease (COPD) patients present severe pulmonary hypertension (PH), defined by mean pulmonary artery pressure (mPAP) ≥35 mm Hg measured by right heart catheterization. Little is known about the characteristics of severe PH-COPD. The aim of the study based on a national registry was to describe this phenotype.

Methods: We prospectively included and followed patients with incident PH-COPD. Clinical, functional, hemodynamic data at inclusion and follow-up were retrieved. Survival assessed by Kaplan-Meier analysis was the primary end-point.

Results: From 2012 to 2016, 99 patients from 13 French centers were included in the study (82 males; median age 66.0 years [interquartile range 62.0-72.0]). At inclusion, most patients had marked dyspnea (55.6% and 22.2% New York Heart Association class III and IV, respectively). During 12 months before inclusion, 42.9% had an exacerbation requiring a hospitalization. Pulmonary function tests showed a moderate obstructive pattern with median (interquartile range) FEV 50.0 [35.0-63.0] % predicted and low diffusing capacity for carbon monoxide, median 20.0 [16.5-30.6] % predicted. The median values for PaO and PaCO on room air were 50.0 [44.8-62.0] and 36.0 [31.1-43.0] mm Hg. Median values of mPAP, pulmonary artery occlusion pressure, cardiac index and pulmonary vascular resistance were 42.0 [37.0-48.0] mm Hg, 11.0 [9.0-14.0] mm Hg, 3.0 [2.4-3.6] L/min/m, and 6.3 [4.2-7.9] WU, respectively. Mean restricted survival was 15.0 [13.9-16.0] months.

Conclusions: Severe PH-COPD is characterized by moderate airway obstruction but marked dyspnea and marked hypoxemia, low DLCO and high mPAP. This phenotype is associated with poor prognosis.
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http://dx.doi.org/10.1016/j.healun.2021.04.021DOI Listing
September 2021

Right Ventricle Remodeling Metabolic Signature in Experimental Pulmonary Hypertension Models of Chronic Hypoxia and Monocrotaline Exposure.

Cells 2021 06 21;10(6). Epub 2021 Jun 21.

Faculté de Médecine, Université Paris-Saclay, 91191 Gif-sur-Yvette, France.

Introduction: Over time and despite optimal medical management of patients with pulmonary hypertension (PH), the right ventricle (RV) function deteriorates from an adaptive to maladaptive phenotype, leading to RV failure (RVF). Although RV function is well recognized as a prognostic factor of PH, no predictive factor of RVF episodes has been elucidated so far. We hypothesized that determining RV metabolic alterations could help to understand the mechanism link to the deterioration of RV function as well as help to identify new biomarkers of RV failure.

Methods: In the current study, we aimed to characterize the metabolic reprogramming associated with the RV remodeling phenotype during experimental PH induced by chronic-hypoxia-(CH) exposure or monocrotaline-(MCT) exposure in rats. Three weeks after PH initiation, we hemodynamically characterized PH (echocardiography and RV catheterization), and then we used an untargeted metabolomics approach based on liquid chromatography coupled to high-resolution mass spectrometry to analyze RV and LV tissues in addition to plasma samples from MCT-PH and CH-PH rat models.

Results: CH exposure induced adaptive RV phenotype as opposed to MCT exposure which induced maladaptive RV phenotype. We found that predominant alterations of arginine, pyrimidine, purine, and tryptophan metabolic pathways were detected on the heart (LV+RV) and plasma samples regardless of the PH model. Acetylspermidine, putrescine, guanidinoacetate RV biopsy levels, and cytosine, deoxycytidine, deoxyuridine, and plasmatic thymidine levels were correlated to RV function in the CH-PH model. It was less likely correlated in the MCT model. These pathways are well described to regulate cell proliferation, cell hypertrophy, and cardioprotection. These findings open novel research perspectives to find biomarkers for early detection of RV failure in PH.
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http://dx.doi.org/10.3390/cells10061559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235667PMC
June 2021

Association between Initial Treatment Strategy and Long-Term Survival in Pulmonary Arterial Hypertension.

Am J Respir Crit Care Med 2021 10;204(7):842-854

Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.

The relationship between the initial treatment strategy and survival in pulmonary arterial hypertension (PAH) remains uncertain. To evaluate the long-term survival of patients with PAH categorized according to the initial treatment strategy. A retrospective analysis of incident patients with idiopathic, heritable, or anorexigen-induced PAH enrolled in the French Pulmonary Hypertension Registry (January 2006 to December 2018) was conducted. Survival was assessed according to the initial strategy: monotherapy, dual therapy, or triple-combination therapy (two oral medications and a parenteral prostacyclin). Among 1,611 enrolled patients, 984 were initiated on monotherapy, 551 were initiated on dual therapy, and 76 were initiated on triple therapy. The triple-combination group was younger and had fewer comorbidities but had a higher mortality risk. The survival rate was higher with the use of triple therapy (91% at 5 yr) as compared with dual therapy or monotherapy (both 61% at 5 yr) ( < 0.001). Propensity score matching of age, sex, and pulmonary vascular resistance also showed significant differences between triple therapy and dual therapy (10-yr survival, 85% vs. 65%). In high-risk patients ( = 243), the survival rate was higher with triple therapy than with monotherapy or dual therapy, whereas there was no difference between monotherapy and double therapy. In intermediate-risk patients ( = 1,134), survival improved with an increasing number of therapies. In multivariable Cox regression, triple therapy was independently associated with a lower risk of death (hazard ratio, 0.29; 95% confidence interval, 0.11-0.80;  = 0.017). Among the 148 patients initiated on a parenteral prostacyclin, those on triple therapy had a higher survival rate than those on monotherapy or dual therapy. Initial triple-combination therapy that includes parenteral prostacyclin seems to be associated with a higher survival rate in PAH, particularly in the youngest high-risk patients.
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http://dx.doi.org/10.1164/rccm.202009-3698OCDOI Listing
October 2021

Stopping continuing long-term mepolizumab treatment in severe eosinophilic asthma (COMET study).

Eur Respir J 2021 Jul 15. Epub 2021 Jul 15.

Divisions of Allergy and Clinical Immunology, Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA.

The long-term efficacy and safety of mepolizumab for treatment of severe eosinophilic asthma are well established. Here, we examine the clinical impact of stopping mepolizumab after long-term use.COMET (NCT02555371) was a randomised, double-blind, placebo-controlled, parallel-group, multicenter study. Patients who had completed COLUMBA (NCT01691859) or COSMEX (NCT02135692) and received continuous mepolizumab treatment for ≥3 years were randomised 1:1 to stop (switch to placebo) or continue subcutaneous mepolizumab 100 mg every 4 weeks for 52 weeks. Primary endpoint: time to first clinically significant exacerbation; secondary endpoints: time to first exacerbation requiring hospitalisation/emergency department visit, time to decrease in asthma control (≥0.5-point increase in Asthma Control Questionnaire-5 score from COMET baseline), and blood eosinophil count ratio to COMET baseline. Safety was assessed.Patients stopping (n=151) continuing (n=144) mepolizumab had significantly shorter times to first clinically significant exacerbation (hazard ratio: 1.61 [95% confidence interval: 1.17,2.22]; p=0.004) and decrease in asthma control (hazard ratio: 1.52 [1.13,2.02]; p=0.005), and higher blood eosinophil counts at Week 52 (270 40 cells·µL; ratio [stopping continuing]: 6.19 [4.89, 7.83]; p<0.001). Differences in efficacy outcomes between groups were observed when assessed from Week 12 (16 weeks after last mepolizumab dose). Exacerbations requiring hospitalisation/emergency department visit were rare. Adverse events in patients continuing mepolizumab were consistent with previous studies. For patients who stopped mepolizumab, the safety profile was consistent with other eosinophilic asthma populations.Patients who stopped mepolizumab had an increase in exacerbations and reduced asthma control those who continued.
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http://dx.doi.org/10.1183/13993003.00396-2021DOI Listing
July 2021

Association between sex and SARS-CoV-2 infection and hospitalisation as a result of COVID-19.

Lancet Respir Med 2021 08 18;9(8):e75-e76. Epub 2021 Jun 18.

Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Centre, Haifa, Israel.

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http://dx.doi.org/10.1016/S2213-2600(21)00239-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213357PMC
August 2021

COVID-19 risk and outcomes in adult asthmatic patients treated with biologics or systemic corticosteroids: Nationwide real-world evidence.

J Allergy Clin Immunol 2021 08 15;148(2):361-367.e13. Epub 2021 Jun 15.

Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.

Background: Managing severe asthma during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is challenging, particularly due to safety concerns regarding the use of systemic corticosteroids and biologics.

Objectives: We sought to determine the association between biologics or systemic corticosteroids use and PCR positivity for SARS-CoV-2 and coronavirus disease 2019 (COVID-19) outcomes among asthmatic patients.

Methods: We used the computerized database of Clalit Health Services, the largest health care provider in Israel, to identify all asthmatic adult patients who underwent PCR testing for SARS-CoV-2, between March 1, 2020, and December 7, 2020. A cohort approach was used to assess the association between biologics use and steroids treatment and COVID-19 severity and 90-day mortality.

Results: Overall, 8,242 of 80,602 tested asthmatic patients had positive PCR testing result for SARS-CoV-2. Both biologics and systemic corticosteroids were not associated with increased risk of SARS-CoV-2 infection. Multivariate analyses revealed that biologics were not associated with a significantly increased risk of moderate to severe COVID-19, nor with the composite end point of moderate to severe COVID-19 or all-cause mortality within 90 days. Chronic systemic corticosteroid use was associated with significantly increased risk of all tested outcome. Recent (within the previous 120 days) systemic corticosteroid use, but not former use, was significantly associated with increased risk of both moderate to severe COVID-19 and the composite of moderate to severe COVID-19 or all-cause mortality.

Conclusions: Biologics approved for asthma and systemic corticosteroids are not associated with increased risk of SARS-CoV-2 infection. In contrast, systemic corticosteroids are an independent risk factor for worst COVID-19 severity and all-cause mortality. Our findings underscore the risk of recent or current exposure to systemic corticosteroids in asthmatic patients infected with SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jaci.2021.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205279PMC
August 2021
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