Screening of Pulmonary Arterial Hypertension in BMPR2 Mutation Carriers (DELPHI-2)

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.