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

Rationale: The relationship between the initial treatment strategy and survival in pulmonary arterial hypertension (PAH) remains uncertain. Objectives: To evaluate the long-term survival of patients with PAH categorized according to the initial treatment strategy. Methods: 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). Measurements and Main Results: 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) (P < 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 (n = 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 (n = 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; P = 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. Conclusions: 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.

Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation.

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.

Diffusion-weighted Imaging Voxelwise-matched Analyses of Lung Cancer at 3.0-T PET/MRI: Reverse Phase Encoding Approach for Echo-planar Imaging Distortion Correction.

Background PET/MRI has drawn increasing interest in thoracic oncology due to the simultaneous acquisition of PET and MRI data. Geometric distortions related to diffusion-weighted imaging (DWI) limit the evaluation of voxelwise multimodal analyses. Purpose To assess the effectiveness of reverse phase encoding in correcting DWI geometric distortion for multimodal PET/MRI voxelwise lung tumor analyses. Materials and Methods In this prospective study, reverse phase encoding method was implemented with 3.0-T PET/MRI to correct geometric distortions related to DWI. The method was validated in dedicated phantom and then applied to 12 consecutive patients (mean age, 66 years ± 13 [standard deviation]; 10 men) suspected of having lung cancer who underwent fluorodeoxyglucose PET/MRI between October 2018 and April 2019. The effects on DWI-related image matching and apparent diffusion coefficient (ADC) regional map computation were assessed. Consequences on multimodal PET/MRI voxelwise lung tumor analyses were evaluated. Spearman correlation coefficients (rs) between the standardized uptake value (SUV) and ADC data corrected for distortion were computed from optimal realigned DWI PET data, along with bootstrap confidence intervals. Results Phantom results showed that in highly distorted areas, correcting the distortion significantly reduced the mean error against the ground truth (-25% ± 10.6 to -18.4% ± 12.6; P < .001) and the number of voxels with more than 20% error (from 85.3% to 31.4%). In the 12 patients, the coregistration of multimodal PET/MRI tumor data was improved by using the reverse phase encoding method (0.4%-44%). In all tumors, voxelwise correlations (rs) between ADC and SUV revealed null or weak monotonic relationships (mean rs of 0.016 ± 0.24 with none above 0.5). Conclusion Reverse phase encoding is a simple-to-implement method for improved diffusion-weighted multimodal PET/MRI voxelwise-matched analyses in lung cancer. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Colletti in this issue.

Characteristics and outcomes of asthmatic patients with COVID-19 pneumonia who require hospitalisation.

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.

Prognostic Value of Follow-Up Hemodynamic Variables After Initial Management in Pulmonary Arterial Hypertension.

BACKGROUND: Hemodynamic variables such as cardiac index and right atrial pressure have consistently been associated with survival in pulmonary arterial hypertension (PAH) at the time of diagnosis. Recent studies have suggested that pulmonary arterial compliance may also predict prognosis in PAH. The prognostic importance of hemodynamic values achieved after treatment initiation is less well established. METHODS: Our objective was to evaluate the prognostic importance of clinical and hemodynamic variables during follow-up, including pulmonary arterial compliance, after initial management in PAH. We evaluated incident patients with idiopathic, drug- and toxin-induced, or heritable PAH enrolled in the French pulmonary hypertension registry between 2006 and 2016 who had a follow-up right-sided heart catheterization (RHC). The primary outcome was death or lung transplantation. We used stepwise Cox regression and the Kaplan-Meier method to assess variables obtained at baseline and at first follow-up RHC. RESULTS: Of 981 patients, a primary outcome occurred in 331 patients (33.7%) over a median follow-up duration of 2.8 years (interquartile range, 1.1-4.6 years). In a multivariable model considering only baseline variables, no hemodynamic variables independently predicted prognosis. Median time to first follow-up RHC was 4.6 months (interquartile range, 3.7-7.8 months). At first follow-up RHC (n=763), New York Heart Association functional class, 6-minute walk distance, stroke volume index (SVI), and right atrial pressure were independently associated with death or lung transplantation, adjusted for age, sex, and type of PAH. Pulmonary arterial compliance did not independently predict outcomes at baseline or during follow-up. The adjusted hazard ratio for SVI was 1.28 (95% confidence interval, 1.11-1.49; P<0.01) per 10-mL/m2 decrease and for right atrial pressure was 1.05 (95% confidence interval, 1.02-1.09; P<0.01) per 1-mm Hg increase. Among patients who had 2 (n=355) or 3 (n=193) low-risk prognostic features at follow-up, including a cardiac index ≥2.5 L·min-1·m-2, 6-minute walk distance >440 m, and New York Heart Association class I or II functional class, lower SVI was still associated with higher rates of death or lung transplantation (P<0.01). CONCLUSIONS: SVI and right atrial pressure were the hemodynamic variables that were independently associated with death or lung transplantation at first follow-up RHC after initial PAH treatment. These findings suggest that the SVI could be a more appropriate treatment target than cardiac index in PAH.

Clinical phenotypes and outcomes of precapillary pulmonary hypertension of sickle cell disease.

RATIONALE: Precapillary pulmonary hypertension (PH) is a devastating complication of sickle cell disease (SCD). Little is known about the influence of the SCD genotype on PH characteristics. OBJECTIVES: To describe clinical phenotypes and outcomes of precapillary PH due to SCD according to disease genotype. METHODS: A nationwide multicentre retrospective study including all patients with SCD-related precapillary PH from the French PH Registry was conducted. Clinical characteristics and outcomes according to SCD genotype were analysed. RESULTS: 58 consecutive SCD patients with precapillary PH were identified, of whom 41 had homozygous for haemoglobin S (SS) SCD, three had S-ß0 thalassaemia (S-ß0 thal) and 14 had haemoglobin SC disease (SC). Compared to SC patients, SS/S-ß0 thal patients were characterised by lower 6-min walk distance (p=0.01) and lower pulmonary vascular resistance (p=0.04). Mismatched segmental perfusion defects on lung scintigraphy were detected in 85% of SC patients and 9% of SS/S-ß0 thal patients, respectively, and 50% of SS/S-ß0 thal patients had heterogeneous lung perfusion without segmental defects. After PH diagnosis, 31 patients (53%) received medical therapies approved for pulmonary arterial hypertension, and chronic red blood cell exchange was initiated in 23 patients (40%). Four patients were managed for chronic thromboembolic PH by pulmonary endarterectomy (n=1) or balloon pulmonary angioplasty (n=3). Overall survival was 91%, 80% and 60% at 1, 3 and 5 years, respectively, without influence of genotype on prognosis. CONCLUSIONS: Patients with precapillary PH related to SCD have a poor prognosis. Thrombotic lesions appear as a major component of PH related to SCD, more frequently in SC patients.

French experience of balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.

AIMS: To evaluate safety and efficacy of balloon pulmonary angioplasty (BPA) in a large cohort of patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: From 2014 to 2017, 184 inoperable CTEPH patients underwent 1006 BPA sessions. Safety and efficacy during the first 21 months (initial period) were compared with those of the last 21 months (recent period). A total of 154 patients had a full evaluation after a median duration of 6.1 months. RESULTS: Overall, there was a significant improvement in New York Heart Association functional class, 6-min walk distance (mean change +45 m), and a significant decrease in mean pulmonary artery pressure (PAP) and in pulmonary vascular resistance (PVR) by 26% and 43%, respectively. The percentage decreases of mean PAP and PVR were 22% and 37% in the initial period versus 30% and 49% in the recent period, respectively (p<0.05). The main complications included lung injury, which occurred in 9.1% of 1006 sessions (13.3% in the initial period versus 5.9% in the recent period; p<0.001). Per-patient multivariate analysis revealed that baseline mean PAP and the period during which BPA procedure was performed (recent versus initial period) were the strongest factors related to the occurrence of lung injury. 3-year survival was 95.1%. CONCLUSION: This study confirms that a refined BPA strategy improves short-term symptoms, exercise capacity and haemodynamics in inoperable CTEPH patients with an acceptable risk-benefit ratio. Safety and efficacy improve over time, underscoring the unavoidable learning curve for this procedure.

Rapid Contour-based Segmentation for 18F-FDG PET Imaging of Lung Tumors by Using ITK-SNAP: Comparison to Expert-based Segmentation.

Purpose To assess the performance of the ITK-SNAP software for fluorodeoxyglucose (FDG) positron emission tomography (PET) segmentation of complex-shaped lung tumors compared with an optimized, expert-based manual reference standard. Materials and Methods Seventy-six FDG PET images of thoracic lesions were retrospectively segmented by using ITK-SNAP software. Each tumor was manually segmented by six raters to generate an optimized reference standard by using the simultaneous truth and performance level estimate algorithm. Four raters segmented 76 FDG PET images of lung tumors twice by using ITK-SNAP active contour algorithm. Accuracy of ITK-SNAP procedure was assessed by using Dice coefficient and Hausdorff metric. Interrater and intrarater reliability were estimated by using intraclass correlation coefficients of output volumes. Finally, the ITK-SNAP procedure was compared with currently recommended PET tumor delineation methods on the basis of thresholding at 41% volume of interest (VOI; VOI41) and 50% VOI (VOI50) of the tumor's maximal metabolism intensity. Results Accuracy estimates for the ITK-SNAP procedure indicated a Dice coefficient of 0.83 (95% confidence interval: 0.77, 0.89) and a Hausdorff distance of 12.6 mm (95% confidence interval: 9.82, 15.32). Interrater reliability was an intraclass correlation coefficient of 0.94 (95% confidence interval: 0.91, 0.96). The intrarater reliabilities were intraclass correlation coefficients above 0.97. Finally, VOI41 and VOI50 accuracy metrics were as follows: Dice coefficient, 0.48 (95% confidence interval: 0.44, 0.51) and 0.34 (95% confidence interval: 0.30, 0.38), respectively, and Hausdorff distance, 25.6 mm (95% confidence interval: 21.7, 31.4) and 31.3 mm (95% confidence interval: 26.8, 38.4), respectively. Conclusion ITK-SNAP is accurate and reliable for active-contour-based segmentation of heterogeneous thoracic PET tumors. ITK-SNAP surpassed the recommended PET methods compared with ground truth manual segmentation.

Chronic blood exchange transfusions in the management of pre-capillary pulmonary hypertension complicating sickle cell disease.

The long-term effects of chronic blood exchange transfusions (BETs) on pre-capillary pulmonary hypertension complicating sickle cell disease (SCD) are unknown.13 homozygous SS SCD patients suffering from pre-capillary pulmonary hypertension and treated by chronic BETs were evaluated retrospectively. Assessments included haemodynamics, New York Heart Association Functional Class (NYHA FC), 6-min walk distance (6MWD) and blood tests.Before initiating BETs, all patients were NYHA FC III or IV, median (range) 6MWD was 223 (0-501) m and median (range) pulmonary vascular resistance (PVR) was 3.7 (2-12.5) Wood Units. After a median number of 4 BET sessions, all patients had improved to NYHA FC II or III. Significant improvements in haemodynamics were observed, including a decrease in PVR (p=0.01). There was a trend to higher 6MWD (p=0.09). Median (range) follow-up time after initiation of BETs was 25 (6-53) months. During this period, two patients decided to stop BETs. One of them died from acute right heart failure and the other experienced worsening pulmonary hypertension. Two other patients died during follow-up at 25 and 54 months after BET initiation.Chronic BETs may be a potential therapeutic option in pre-capillary pulmonary hypertension complicating SCD, leading to significant clinical and haemodynamic improvements. These data must be confirmed in a prospective study.

Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial.

We aimed to identify risk factors for recurrent venous thromboembolism (VTE) after unprovoked pulmonary embolism.Analyses were based on the double-blind randomised PADIS-PE trial, which included 371 patients with a first unprovoked pulmonary embolism initially treated during 6 months who were randomised to receive an additional 18 months of warfarin or placebo and followed up for 2 years after study treatment discontinuation. All patients had ventilation/perfusion lung scan at inclusion (i.e. at 6 months of anticoagulation).During a median follow-up of 41 months, recurrent VTE occurred in 67 out of 371 patients (6.8 events per 100 person-years). In main multivariate analysis, the hazard ratio for recurrence was 3.65 (95% CI 1.33-9.99) for age 50-65 years, 4.70 (95% CI 1.78-12.40) for age >65 years, 2.06 (95% CI 1.14-3.72) for patients with pulmonary vascular obstruction index (PVOI) ≥5% at 6 months and 2.38 (95% CI 1.15-4.89) for patients with antiphospholipid antibodies. When considering that PVOI at 6 months would not be available in practice, PVOI ≥40% at pulmonary embolism diagnosis (present in 40% of patients) was also associated with a 2-fold increased risk of recurrence.After a first unprovoked pulmonary embolism, age, PVOI at pulmonary embolism diagnosis or after 6 months of anticoagulation and antiphospholipid antibodies were found to be independent predictors for recurrence.

Long-term outcome in liver transplantation candidates with portopulmonary hypertension.

Portopulmonary hypertension (PoPH) is diagnosed in 2-6% of liver transplantation (LT) candidates. We studied outcomes of candidates for LT suffering from PoPH. Data were collected retrospectively from a prospective registry. Pulmonary hemodynamic variables were collected at the time of PoPH diagnosis, at last evaluation before LT, and within 6 months and beyond 6 months after LT. Forty-nine patients (35 males, 48 ± 8 years) were analyzed (median Model for End-Stage Liver Disease score 20). At baseline, mean pulmonary artery pressure (mPAP) was 44 ± 10 mm Hg (range 26-73 mm Hg), cardiac index was 3.5 ± 0.9 L/min/m2 , and pulmonary vascular resistance was 5.6 ± 2.8 Wood units. Hemodynamic reassessment performed in 35 patients who were treated with pulmonary arterial hypertension-targeted therapies before LT resulted in significant decreases in both mPAP (36 ± 7 versus 47 ± 10 mm Hg, P < 0.0001) and pulmonary vascular resistance (3.0 ± 1.4 versus 6.1 ± 3.1 Wood units, P < 0.0001). Fourteen patients (29%) died without having had access to LT. Thirty-five patients underwent LT and were followed up for a median of 38 months. Eight patients (23%) died after LT including 5 due to PoPH (after 1 day to 6 months). Among survivors (n = 27), all patients treated with intravenous epoprostenol were weaned off post-LT, and endothelin receptor antagonist or phosphodiesterase type 5 inhibitors were continued in 15/27 patients (55%). At last evaluation, 20/27 patients (74%) had mPAP <35 mm Hg and 8 of them (30%) had mPAP <25 mm Hg. Overall survival estimates after LT were 80%, 77%, and 77% at 6 months, 1 year, and 3 years, respectively. CONCLUSION: Stabilization or reversibility of PoPH seems to be an attainable goal using the combination of pulmonary arterial hypertension-targeted therapies and LT in patients who are transplantation candidates. (Hepatology 2017;65:1683-1692).

RV Fractional Area Change and TAPSE as Predictors of Severe Right Ventricular Dysfunction in Pulmonary Hypertension: A CMR Study.

BACKGROUND: The right ventricular ejection fraction (RVEF) is a surrogate marker of right ventricular function in pulmonary hypertension (PH), but its measurement is complicated and time consuming. The tricuspid annular plane systolic excursion (TAPSE) measures only the longitudinal component of RV contraction while the right ventricular fractional area change (RVFAC) takes into account both the longitudinal and the transversal components. The aim of our study was to evaluate the relationship between RVEF, RVFAC, and TAPSE according to hemodynamic severity in two groups of patients with PH: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: Fifty-four patients with PAH (n = 15) and CTEPH (n = 39) underwent right heart catheterization and cardiac magnetic resonance (CMR). The ventricular volumes and areas, TAPSE, and eccentricity index were measured. The RVFAC was more strongly correlated with the RVEF (r = 0.81, p < 0.0001) than the TAPSE (r = 0.63, p < 0.0001). RVEF < 35% was better predicted by the RVFAC than the TAPSE (TAPSE: AUC = 0.77 and RVFAC: AUC = 0.91; p = 0.042). In the group with the worse hemodynamic status, the RVFAC correlated much better with the RVEF than the TAPSE. There were no significant differences in the CMR data analyzed between the groups of PAH and CETPH patients. CONCLUSIONS: The RVFAC is a good index to estimate RVEF in PH patients; even better than the TAPSE in patients with more severe hemodynamic profile, possibly for including the transversal component of right ventricular function in its measurement. Furthermore, RVFAC performance was similar in the two PH groups (PAH and CTEPH).

Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension.

Current European guidelines recommend periodic risk assessment for patients with pulmonary arterial hypertension (PAH). The aim of our study was to determine the association between the number of low-risk criteria achieved within 1 year of diagnosis and long-term prognosis.Incident patients with idiopathic, heritable and drug-induced PAH between 2006 and 2016 were analysed. The number of low-risk criteria present at diagnosis and at first re-evaluation were assessed: World Health Organization (WHO)/New York Heart Association (NYHA) functional class I or II, 6-min walking distance (6MWD) >440 m, right atrial pressure <8 mmHg and cardiac index ≥2.5 L·min-1·m-21017 patients were included (mean age 57 years, 59% female, 75% idiopathic PAH). After a median follow-up of 34 months, 238 (23%) patients had died. Each of the four low-risk criteria independently predicted transplant-free survival at first re-evaluation. The number of low-risk criteria present at diagnosis (p<0.001) and at first re-evaluation (p<0.001) discriminated the risk of death or lung transplantation. In addition, in a subgroup of 603 patients with brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements, the number of three noninvasive criteria (WHO/NYHA functional class, 6MWD and BNP/NT-proBNP) present at first re-evaluation discriminated prognostic groups (p<0.001).A simplified risk assessment tool that quantifies the number of low-risk criteria present accurately predicted transplant-free survival in PAH.

Pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH) characterised by preferential remodelling of the pulmonary venules. In the current PH classification, PVOD and pulmonary capillary haemangiomatosis (PCH) are considered to be a common entity and represent varied expressions of the same disease. The recent discovery of biallelic mutations in the EIF2AK4 gene as the cause of heritable PVOD/PCH represents a major milestone in our understanding of the molecular pathogenesis of PVOD. Although PVOD and pulmonary arterial hypertension (PAH) share a similar clinical presentation, with features of severe precapillary PH, it is important to differentiate these two conditions as PVOD carries a worse prognosis and life-threatening pulmonary oedema may occur following the initiation of PAH therapy. An accurate diagnosis of PVOD based on noninvasive investigations is possible utilising oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest. No evidence-based medical therapy exists for PVOD at present and lung transplantation remains the preferred definitive therapy for eligible patients.

Genetic counselling in a national referral centre for pulmonary hypertension.

Genetic causes of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD) have been identified, leading to a growing need for genetic counselling.Between 2003 and 2014, genetic counselling was offered to 529 PAH and 100 PVOD patients at the French Referral Centre for Pulmonary Hypertension.Mutations in PAH-predisposing genes were identified in 72 patients presenting as sporadic PAH (17% of cases; 62 mutations in BMPR2, nine in ACVRL1 (ALK1) and one in ENG) and in 94 patients with a PAH family history (89% of cases; 89 mutations in BMPR2, three in ACVRL1 (ALK1) and two in KCNK3). Bi-allelic mutations in EIF2AK4 were identified in all patients with a family history of PVOD (n=19) and in seven patients (8.6%) presenting as sporadic PVOD. Pre-symptomatic genetic diagnosis was offered to 272 relatives of heritable PAH patients, identifying mutations in 36.4% of them. A screening programme is now offered to asymptomatic mutation carriers to detect PAH in an early phase and to identify predictors of outcomes in asymptomatic BMPR2 mutation carriers. BMPR2 screening allowed us to offer pre-implantation diagnosis to two couples with a BMPR2 mutation.Genetic counselling can be implemented in pulmonary hypertension centres.