Phenotype and Outcomes of Pulmonary Hypertension Associated with Neurofibromatosis Type 1.

Rationale: Pulmonary hypertension (PH) associated with neurofibromatosis type 1 (NF1) is a rare and largely unknown complication of NF1.Objectives: To describe characteristics and outcomes of PH-NF1.Methods: We reported the clinical, functional, radiologic, histologic, and hemodynamic characteristics, response to pulmonary arterial hypertension (PAH)-approved drugs, and transplant-free survival of patients with PH-NF1 from the French PH registry.Measurements and Main Results: We identified 49 PH-NF1 cases, characterized by a female/male ratio of 3.9 and a median (minimum-maximum) age at diagnosis of 62 (18-82) years. At diagnosis, 92% were in New York Heart Association functional class III or IV. The 6-minute-walk distance was 211 (0-460) m. Pulmonary function tests showed low DlCO (30% [12-79%]) and severe hypoxemia (PaO2 56 [38-99] mm Hg). Right heart catheterization showed severe precapillary PH with a mean pulmonary artery pressure of 45 (10) mm Hg and a pulmonary vascular resistance of 10.7 (4.2) Wood units. High-resolution computed tomography images revealed cysts (76%), ground-glass opacities (73%), emphysema (49%), and reticulations (39%). Forty patients received PAH-approved drugs with a significant improvement in functional class and hemodynamic parameters. Transplant-free survival at 1, 3, and 5 years was 87%, 54%, and 42%, respectively, and four patients were transplanted. Pathologic assessment showed nonspecific interstitial pneumonia and major pulmonary vascular remodeling.Conclusions: PH-NF1 is characterized by a female predominance, a low DlCO, and severe functional and hemodynamic impairment. Despite a potential benefit of PAH treatment, prognosis remains poor, and double-lung transplantation is an option for eligible patients.

Portopulmonary hypertension in the current era of pulmonary hypertension management.

BACKGROUND & AIMS: Long-term outcomes in portopulmonary hypertension (PoPH) are poorly studied in the current era of pulmonary hypertension management. We analysed the effect of pulmonary arterial hypertension (PAH)-targeted therapies, survival and predictors of death in a large contemporary cohort of patients with PoPH. METHODS: Data from patients with PoPH consecutively enrolled in the French Pulmonary Hypertension Registry between 2007 and 2017 were collected. The effect of initial treatment strategies on functional class, exercise capacity and cardiopulmonary haemodynamics were analysed. Survival and its association with PAH- and hepatic-related characteristics were also examined. RESULTS: Six hundred and thirty-seven patients (mean age 55 ± 10 years; 58% male) were included. Fifty-seven percent had mild cirrhosis, i.e. Child-Pugh stage A. The median model for end-stage liver disease (MELD) score was 11 (IQR 9-15). Most patients (n = 474; 74%) were initiated on monotherapy, either with a phosphodiesterase-5 inhibitor (n = 336) or with an endothelin-receptor antagonist (n = 128); 95 (15%) were initiated on double oral combination therapy and 5 (1%) on triple therapy. After a median treatment time of 4.5 months, there were significant improvements in functional class (p <0.001), 6-minute walk distance (6MWD) (p <0.0001) and pulmonary vascular resistance (p <0.0001). Overall survival rates were 84%, 69% and 51% at 1, 3 and 5 years, respectively. Baseline 6MWD, sex, age and MELD score or Child-Pugh stage were identified as independent prognostic factors. Survival from PoPH diagnosis was significantly better in the subgroup of patients who underwent liver transplantation (92%, 83% and 81% at 1, 3 and 5 years, respectively). CONCLUSION: Survival of patients with PoPH is strongly associated with the severity of liver disease. Patients who underwent liver transplantation had the best long-term outcomes. LAY SUMMARY: Portopulmonary hypertension is defined by the presence of pulmonary arterial hypertension in the context of chronic liver disease and is characterized by progressive shortness of breath and exercise limitation. The presence of severe pulmonary arterial hypertension in liver transplant candidates represents a contraindication for such a surgery; however, treatments targeting pulmonary arterial hypertension are efficacious, allowing for safe transplantation and conferring good survival outcomes in those who undergo liver transplantation.

Haemodynamics and serial risk assessment in systemic sclerosis associated pulmonary arterial hypertension.

The prognostic importance of follow-up haemodynamics and the validity of multidimensional risk assessment are not well established for systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH).We assessed incident SSc-PAH patients to determine the association between clinical and haemodynamic variables at baseline and first follow-up right heart catheterisation (RHC) with transplant-free survival. RHC variables included cardiac index, stroke volume index (SVI), pulmonary arterial compliance and pulmonary vascular resistance. Risk assessment was performed according to the number of low-risk criteria: 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-2Transplant-free survival from diagnosis (n=513) was 87%, 55% and 35% at 1, 3 and 5 years, respectively. At baseline, 6MWD was the only independent predictor. A follow-up RHC was available for 353 patients (median interval 4.6 months, interquartile range 3.9-6.4 months). The 6MWD, functional class, cardiac index, SVI, pulmonary arterial compliance and pulmonary vascular resistance were independently associated with transplant-free survival at follow-up, with SVI performing better than other haemodynamic variables. 1-year outcomes were better with increasing number of low-risk criteria at baseline (area under the curve (AUC) 0.63, 95% CI 0.56-0.69) and at first follow-up (AUC 0.71, 95% CI 0.64-0.78).Follow-up haemodynamics and multidimensional risk assessment had greater prognostic significance than at baseline in SSc-PAH.

Survival Improved in Patients Aged ≤ 70 Years With Systemic Sclerosis-Associated Pulmonary Arterial Hypertension During the Period 2006 to 2017 in France.

BACKGROUND: To date, nothing is known about the evolution of survival in systemic sclerosis-associated pulmonary arterial hypertension (PAH) over the last decade. METHODS: This study used a multivariate Cox regression model adjusted for clinically relevant baseline confounders to assess the association between the occurrence of death and date of PAH diagnosis comparing two periods of the same duration (2006-2011 vs 2012-2017). Interactions between the two diagnosis periods and baseline variables were tested. RESULTS: A total of 306 incident patients were included, 167 (54.6%) with a PAH diagnosis occurring in 2006 to 2011 and 139 (45.4%) in 2012 to 2017. No significant difference in survival was observed between patients diagnosed with PAH in 2012 to 2017 compared with those diagnosed in 2006 to 2011 (hazard ratio [HR], 0.76 [0.46-1.26]; P = .29). A significant interaction was observed between PAH diagnosis periods and age (P = .05). When stratifying according to age (based on the median age of 70 years), a significant increase was observed in survival in patients aged ≤ 70 years between the 2006 to 2011 period and the 2012 to 2017 period (HR, 0.40 [0.17-0.99]; P = .046) but not in older patients (HR, 1.29 [0.67-2.51]; P = .44). A significantly higher proportion of initial (ie, within the first 4 months) endothelin receptor antagonist/phosphodiesterase type 5 inhibitor combination therapy was observed in younger patients diagnosed from 2012 to 2017 vs those diagnosed from 2006 to 2011 (42.9% vs 19.5%; P = .002) but not in older patients. CONCLUSIONS: Over the period 2006 to 2017, survival in systemic sclerosis-associated PAH improved over time in patients aged ≤ 70 years but not in older patients. Further investigations are needed to confirm this relation, as general improvement in medical care and management may also be a possible explanation.