Screening of Pulmonary Arterial Hypertension in BMPR2 Mutation Carriers
Screening of Pulmonary Arterial Hypertension in BMPR2 Mutation Carriers
In this prospective study, the investigators will implement a systematic screening program
 and 3-year follow-up in a cohort of asymptomatic BMPR2 mutation carriers. This study is
 designed to:

 -  determine predictive factors (biological, functional, radiological and hemodynamic) of
 development of PAH

 -  monitor these subjects' clinical, functional, biological, echocardiographic and
 hemodynamic characteristics

 -  assess the risk of occurrence of PAH

 -  screen patients with PAH at an early stage of disease and offer them an early management

 -  constitute a collection of biological samples (0, 12, 24 months follow-up) of
 asymptomatic BMPR2 mutation carriers.
Introduction:

 Pulmonary arterial hypertension is characterized by remodeling of small pulmonary arteries
 leading to a progressive increase in pulmonary vascular resistance resulting to right heart
 failure and ultimately death. The disease is diagnosed when symptomatic, demonstrating the
 existence of an already advanced form of the disease. Indeed, there is no simple tool
 allowing an early diagnosis of PAH and the disease is usually diagnosed in advanced stages.
 Diagnostic confirmation of PAH is based on the elevation of mean pulmonary arterial pressures
 measured during right heart catheterization. Despite the development of specific treatment in
 recent years, PAH remains a disease with poor prognosis, for which no cure is possible, apart
 from lung transplantation in selected cases. However recent studies have shown that specific
 drug therapy in early disease stages could improve the prognosis of this life threatening
 disease. This is why it seems important to establish early diagnosis of PAH, especially in
 high-risk populations such as asymptomatic carriers of BMPR2 (Bone Morphogenetic Protein
 Receptor 2) mutations. PAH due to BMPR2 mutations is an autosomal dominant disease with
 incomplete penetrance. Even if there are no accurate data in the literature, it is estimated
 that 20% of patients with BMPR2 mutations develop PAH in the course of their life. The
 implementation of a genetic counseling in the National Reference Center for Severe Pulmonary
 Hypertension (BICETRE Hospital) allowed us to propose systematic assessment of BMPR2
 mutations in patients with idiopathic or familial PAH. In 2012 we identified 130 PAH patients
 carriers of a BMPR2 mutation. This approach has enabled the detection of families at risk for
 PAH and to offer genetic counseling to the asymptomatic relatives with BMPR2 mutation.
 However, data on the evolution of asymptomatic carriers of BMPR2 mutation are lacking.
 Furthermore, there is no available consensus or guideline on how to follow this population.
 To date, it is not possible to differentiate asymptomatic subjects carrying BMPR2 mutations
 that will develop PAH from those who will never develop this disease. However, given the high
 risk of these subjects to develop PAH (risk of 20% against 25/million in the general
 population), and the limited knowledge of characteristics of this population, it seems
 essential to offer a prospective follow-up to this population at risk.

 Aim and objective:

 The main objective of this study to is follow prospectively for 3 years a cohort of
 asymptomatic carriers of BMPR2 mutation to:

 -  determine predictive factors (biological, functional, radiological and hemodynamic) of
 development of PAH

 -  monitor these subjects' clinical, functional, biological, echocardiographic and
 hemodynamic characteristics

 -  assess the risk of occurrence of PAH

 -  screen patients with PAH at an early stage of disease and offer them an early management

 -  constitute a collection of biological samples (0, 12, 24 months follow-up) of
 asymptomatic BMPR2 mutation carriers.

 Methodology :

 Evaluation of subjects at inclusion after informed consent (Ethics Committee approval
 obtained since 2011):

 -  Clinical evaluation: dyspnea assessed by NYHA functional class (I-IV), signs of right
 heart failure

 -  Chest radiograph, electrocardiogram

 -  Right heart catheterization (in a subset of volunteers): measurement of mean pulmonary
 artery pressure, pulmonary artery occlusion pressure (PAOP) and cardiac output (CO) at
 rest and during exercise

 -  Echocardiography: measurement of the velocity of tricuspid regurgitation (VIT),
 measurement of TAPSE and Tei index, pericardial effusion, dilatation and hypertrophy of
 the right ventricle

 -  Stress Test: VO2 peak and VO2 specific, VE minute ventilation, VD / VT dead space,
 ventilatory reserve, alveolar-arterial gradient, pulse oxygen, PaO2

 -  Lung function tests: measurement of DLCO and DLNO

 -  Magnetic resonance imaging (MRI) measuring end systolic diastolic volumes of the right
 ventricle, right ventricular mass, septal curvature, diameter of the pulmonary arteries,
 surface of the right atrium

 -  Biology: Determination of plasma NT-proBNP, uric acid, serum sodium, creatinine, PDGF,
 ET-1, ET-3, CRPus, IL-6, soluble c-kit, CXCL12, progenitors and circulating fibrocytes

 Subjects will be evaluated as outpatients scheduled to the National Reference Center for
 Severe Pulmonary Hypertension 12, 24 and 36 months after inclusion or if symptoms appear
 (dyspnoea, right heart failure, malaise or syncope).

 During these consultations, the assessment will include: clinical evaluation, chest
 radiograph, electrocardiogram, echocardiogram, stress testing, pulmonary function tests,
 magnetic resonance imaging, and biology.

 To confirm the suspicion of PAH and assess their severity, right heart catheterization at
 rest and during exercise will be offered according to a decision algorithm.

 Right heart catheterization will be performed if one of the following abnormalities is found:

 -  Dyspnea, malaise or unexplained syncope

 -  Tricuspid regurgitation velocity ≥ 2.8 m / s

 -  Decrease of the specific peak VO2 ≥ 20% as compared to the gold standard

 If diagnosis of PAH is confirmed, patients will be treated according to the recently updated
 recommendations of the European Respiratory Society and European Society of Cardiology.
Inclusion Criteria:

 -  men and women over 18 years old,

 -  carriers of a BMPR2 mutation without known PAH,

 -  having given his informed consent

 Exclusion Criteria:

 -  men and women under 18 years old,

 -  patients with a known PAH,

 -  pregnant women,

 -  adults protected,

 -  detainees,

 -  people in emergencies,

 -  people refusing or unable to give informed consent,

 -  no affiliation to a regime of social security.