Observational Study

. 2021 Jul 22;58(1):2004229.

doi: 10.1183/13993003.04229-2020. Print 2021 Jul.

Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation

David Montani^{1

2

3

4}, Barbara Girerd^{1

2

3

4}, Xavier Jaïs^{1

2

3}, Pierantonio Laveneziana^{5

6}, Edmund M T Lau⁷, Amir Bouchachi^{3

8}, Sébastien Hascoët^{3

9}, Sven Günther¹⁰, Laurent Godinas^{1

2

3}, Florence Parent^{1

2

3}, Christophe Guignabert^{1

3}, Antoine Beurnier^{3

11}, Denis Chemla^{3

11}, Philippe Hervé^{3

12}, Mélanie Eyries^{13

14}, Florent Soubrier^{13

14}, Gérald Simonneau^{1

2

3}, Olivier Sitbon^{1

2

3}, Laurent Savale^{1

2

3}, Marc Humbert^{15

2

3}

Affiliations

¹ School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
² Service de Pneumologie et Soins Intensifs Respiratoires, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
³ INSERM UMRS 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
⁴ These two authors contributed equally to this work.
⁵ INSERM UMRS 1158, Neurophysiologie Respiratoire Expérimentale et Clinique, Sorbonne Université, Paris, France.
⁶ Service des Explorations Fonctionnelles de la Respiration, de l'Exercice et de la Dyspnée, Département Médico-Universitaire "APPROCHES", Hôpitaux Universitaires Pitié-Salpêtrière, Tenon et Saint-Antoine, AP-HP, Sorbonne Université, Paris, France.
⁷ Dept of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, Australia.
⁸ Service de Cardiologie, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
⁹ Pôle de Cardiologie Pédiatrique et Congénitale, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
¹⁰ Service de Physiologie, AP-HP, Georges Pompidou European Hospital, Paris, France.
¹¹ Service de Physiologie, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
¹² Service de Chirurgie Thoracique, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
¹³ Département de Génétique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
¹⁴ INSERM UMRS 1166, Sorbonne Université and Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.
¹⁵ School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France marc.humbert@aphp.fr.

PMID: 33380512
PMCID: PMC8295506
DOI: 10.1183/13993003.04229-2020

Observational Study

Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation

David Montani et al. Eur Respir J. 2021.

. 2021 Jul 22;58(1):2004229.

doi: 10.1183/13993003.04229-2020. Print 2021 Jul.

Authors

Affiliations

¹ School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
² Service de Pneumologie et Soins Intensifs Respiratoires, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
³ INSERM UMRS 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
⁴ These two authors contributed equally to this work.
⁵ INSERM UMRS 1158, Neurophysiologie Respiratoire Expérimentale et Clinique, Sorbonne Université, Paris, France.
⁶ Service des Explorations Fonctionnelles de la Respiration, de l'Exercice et de la Dyspnée, Département Médico-Universitaire "APPROCHES", Hôpitaux Universitaires Pitié-Salpêtrière, Tenon et Saint-Antoine, AP-HP, Sorbonne Université, Paris, France.
⁷ Dept of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, Australia.
⁸ Service de Cardiologie, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
⁹ Pôle de Cardiologie Pédiatrique et Congénitale, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
¹⁰ Service de Physiologie, AP-HP, Georges Pompidou European Hospital, Paris, France.
¹¹ Service de Physiologie, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
¹² Service de Chirurgie Thoracique, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
¹³ Département de Génétique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
¹⁴ INSERM UMRS 1166, Sorbonne Université and Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.
¹⁵ School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France marc.humbert@aphp.fr.

PMID: 33380512
PMCID: PMC8295506
DOI: 10.1183/13993003.04229-2020

Abstract

Background: Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene. Based on expert consensus, guidelines recommend annual screening echocardiography in asymptomatic BMPR2 mutation carriers. The main objectives of this study were to evaluate the characteristics of asymptomatic BMPR2 mutation carriers, assess their risk of occurrence of PAH and detect PAH at an early stage in this high-risk population.

Methods: Asymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of 2 years (DELPHI-2 study; ClinicalTrials.gov: NCT01600898). Annual screening included clinical assessment, ECG, pulmonary function tests, 6-min walk distance, cardiopulmonary exercise testing, chest radiography, echocardiography and brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP level. Right heart catheterisation (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline.

Results: 55 subjects (26 males; median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT-proBNP levels. All subjects accepted RHC at inclusion, which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension (21.8%). At long-term follow-up (118.8 patient-years of follow-up), three additional cases were diagnosed, yielding a PAH incidence of 2.3% per year (0.99% per year in males and 3.5% per year in females). All PAH cases remained at low-risk status on oral therapy at last follow-up.

Conclusions: Asymptomatic BMPR2 mutation carriers have a significant risk of developing incident PAH. International multicentre studies are needed to confirm that refined multimodal screening programmes with regular follow-up allow early detection of PAH.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, personal fees from GlaxoSmithKline, Pfizer, Chiesi, Boehringer and Incyte Biosciences France, grants, personal fees and nonfinancial support from MSD, nonfinancial support from Acceleron, outside the submitted work. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: X. Jaïs reports grants from Bayer, grants and personal fees from MSD, grants, personal fees and nonfinancial support from Actelion/Janssen, outside the submitted work. Conflict of interest: P. Laveneziana reports personal fees from Novartis France and Chiesi France, outside the submitted work. Conflict of interest: E.M.T. Lau reports grants and personal fees from Actelion and GlaxoSmithKline, outside the submitted work. Conflict of interest: A. Bouchachi has nothing to disclose. Conflict of interest: S. Hascoët reports grants and personal fees from Abbott, outside the submitted work. Conflict of interest: S. Gunther has nothing to disclose. Conflict of interest: L. Godinas has nothing to disclose. Conflict of interest: F. Parent has nothing to disclose. Conflict of interest: C. Guignabert has nothing to disclose. Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: D. Chemla has nothing to disclose. Conflict of interest: P. Hervé has nothing to disclose. Conflict of interest: M. Eyries has nothing to disclose. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: G. Simonneau reports personal fees from Bayer and Acceleron, personal fees and nonfinancial support from MSD, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and nonfinancial support from Actelion Pharmaceuticals, personal fees from Acceleron Pharmaceuticals, AOP Orphan, Ferrer and Gossamer Bio, grants and personal fees from Bayer HealthCare and MSD, grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: L. Savale reports personal fees and nonfinancial support from Actelion and Bayer, grants, personal fees and nonfinancial support from GlaxoSmithKline, nonfinancial support from MSD, outside the submitted work. Conflict of interest: M. Humbert reports grants, personal fees and nonfinancial 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.

Figures

**FIGURE 1**
Flowchart of DELPHI-2. PAH: pulmonary arterial hypertension; PH: pulmonary hypertension.

**FIGURE 2**
Baseline evaluation and follow-up of the 55 asymptomatic *BMPR2* mutation carriers. PAH: pulmonary arterial hypertension; RHC: right heart catheterisation; PH: pulmonary hypertension. ^#: defined as mean pulmonary arterial pressure >30 mmHg and total pulmonary resistance >3 WU.

**FIGURE 3**
Distribution of haemodynamics at baseline among 55 asymptomatic *BMPR2* mutation carriers: a) mean pulmonary arterial pressure (mPAP) (dark red: patients with mPAP ≥25 mmHg; light red: mPAP 21–24 mmHg; blue: mPAP ≤20 mmHg) and b) pulmonary vascular resistance (PVR) (dark red: patients with PVR >3 WU; blue: PVR ≤3 WU).

**FIGURE 4**
Family trees of *BMPR2* mutation carriers who developed pulmonary arterial hypertension (PAH) during DELPHI-2. Arrows indicate the index case in each family. Patient 1 belongs to family 1 (III2), patient 2 belongs to family 2 (II7), patient 3 belongs to family 3 (III11), and patients 4 and 5 belong to family 4 (II3 and III11, respectively).

**FIGURE 5**
Time to death or lung transplantation in index cases of the 31 families of subjects included in DELPHI-2.

See this image and copyright information in PMC

Comment in

Screening asymptomatic BMPR2 mutation carriers: a new frontier for pulmonary hypertension physicians?
Morrell NW. Morrell NW. Eur Respir J. 2021 Jul 22;58(1):2100286. doi: 10.1183/13993003.00286-2021. Print 2021 Jul. Eur Respir J. 2021. PMID: 34301716 No abstract available.

References

1. Simonneau G, Montani D, Celermajer DS, et al. . Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019; 53: 1801913. doi:10.1183/13993003.01913-2018 - DOI - PMC - PubMed
1. Galiè N, Humbert M, Vachiery J-L, et al. . 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Respir J 2015; 46: 903–975. doi:10.1183/13993003.01032-2015 - DOI - PubMed
1. Humbert M, Guignabert C, Bonnet S, et al. . Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J 2019; 53: 1801887. doi:10.1183/13993003.01887-2018 - DOI - PMC - PubMed
1. Galié N, Humbert M, Vachiery J-L, et al. . 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension – web addenda. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and of the European Respiratory Society (ERS). Eur Heart J 2016; 37: 67–119. doi:10.1093/eurheartj/ehv317 - DOI - PubMed
1. Larkin EK, Newman JH, Austin ED, et al. . Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186: 892–896. doi:10.1164/rccm.201205-0886OC - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

LinkOut - more resources

Full Text Sources
Medical
- ClinicalTrials.gov
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation

Affiliations

Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous