Olivier Sitbon

The study of risk in pulmonary arterial hypertension

A growing body of published evidence exists on the risk factors for disease progression in pulmonary arterial hypertension (PAH). The Scientific Steering Committee for the Study of Risk in PAH was established to bring together leading clinical and statistical experts in PAH and risk modelling, for the purpose of advancing the understanding of the risk of development and progression of PAH. Herein, we discuss the impact of this information on three key areas: 1) clinical decision-making; 2) policy and reimbursement; and 3) future trials and research.

Pulmonary Arterial Hypertension Associated With Systemic Lupus Erythematosus: Results From the French Pulmonary Hypertension Registry

Background Pulmonary arterial hypertension (PAH) is a rare complication of systemic lupus erythematosus (SLE). Methods We identified all patients with SLE and PAH (SLE‐PAH) who were enrolled in the French Pulmonary Hypertension Registry with a diagnosis confirmed by right heart catheterization (RHC). A control group of 101 patients with SLE without known PAH was selected from SLE expert centers participating in the Pulmonary Hypertension Registry. Survival was estimated by the Kaplan‐Meier method. Hazard ratios associated with potential predictors of death were estimated using Cox proportional hazard models. Results Of the 69 patients with SLE‐PAH identified in the French Pulmonary Hypertension Registry, 51 were included in the study. They did not differ from the control group regarding age, sex, or duration of SLE at the time of the analysis but had a higher frequency of anti‐SSA and anti‐SSB antibodies. The delay between SLE diagnosis and PAH diagnosis was 4.9 years (range, 2.8‐12.9) years. The 3‐ and 5‐year overall survival rates were 89.4% (95% CI, 76.2%‐96.5%) and 83.9% (95% CI, 68.8%‐92.1%), respectively. The survival rate was significantly better in patients with anti‐U1‐RNP antibodies (P = .04). Conclusions Patients with SLE‐PAH have an overall 5‐year survival rate of 83.9% after the PAH diagnosis. Anti‐SSA/SSB antibodies may be a risk factor for PAH, and the presence of anti‐U1‐RNP antibodies appears to be a protective factor regarding survival.

Long-term outcomes of pulmonary arterial hypertension under specific drug therapy in Eisenmenger syndrome

BACKGROUND The long-term effectiveness of pulmonary arterial hypertension-specific drug therapy (PAH-SDT) in Eisenmenger syndrome is controversial. We investigated short-term and long-term hemodynamic changes under PAH-SDT and their associations with outcomes in a bicentric cohort. METHODS Over 20 years, we included 69 patients with congenital heart disease, an indexed pulmonary vascular resistance (PVRi) >8 WU·m2, and 292 standardized catheterizations at baseline and after PAH-SDT initiation or intensification. Oxygen consumption was measured and the Fick principle applied to calculate indexed pulmonary output (Qpi) and PVRi. RESULTS After PAH-SDT initiation or intensification, median (interquartile range) PVRi decrease was 5.1 WU·m2 (-1.4, -12.6) (p < 0.0001). Median Qpi and 6-minute walk test increases were +0.4 liter/min/m2 (0.0, +0.9) (p < 0.0001) and +49 m (+15, +93) (p = 0.0003), respectively. Hemodynamic response combining increased Qpi with decreases in transpulmonary gradient and PVRi occurred in 68.0% of patients. After a median of 4.9 years, PVRi and Qpi changes were no longer significant. Over a median of 7.2 years, 23 (33.3%) patients met a composite criterion (death, n = 8; heart-lung transplantation or listing for transplantation, n = 15). The 15-year cumulative event rate was 49.2%. By multivariate analysis, independent predictors of events were superior vena cava oxygen saturation and hemodynamic response (p = 0.048 and p < 0.0001). CONCLUSIONS In Eisenmenger syndrome, PAH-SDT induces early hemodynamic improvements, which decline over time. Hemodynamic changes under PAH-SDT vary across patients. Hemodynamic parameters at baseline and under PAH-SDT are associated with events. PAH-SDT may need to be individualized based on hemodynamic changes.

Ambrisentan use for pulmonary arterial hypertension in a post-authorization drug registry: The VOLibris Tracking Study

BACKGROUND The VOLibris Tracking (VOLT) Study was an open-label, prospective, observational, multicenter, post-marketing registry program designed to more fully characterize the safety profile of ambrisentan for the treatment of pulmonary arterial hypertension (PAH). The key outcome was the incidence of aminotransferase elevations >3× the upper limit of normal (ULN). METHODS In total, 999 patients from 115 centers in 15 countries, who were prescribed ambrisentan for the treatment of PAH (Functional Class II and III) between 30 June 2008 and 13 May 2011, were enrolled. Of these, 238 had PAH associated with connective tissue disease (PAH-CTD) and 220 had no prior PAH-specific therapy. Routine clinical monitoring data were collected by physicians. RESULTS The incidence of both alanine and aspartate aminotransferase events (>3× ULN) was 0.02 per patient-year (95% confidence interval 0.015 to 0.027). Similar results were reported for the PAH-CTD and PAH-specific-therapy-naive subgroups. Overall, 514 (52%) patients reported treatment-emergent adverse events of special interest, most commonly edema/fluid retention (249, or 25%) and anemia (143, or 14%). CONCLUSIONS Data from the VOLT study indicate no new ambrisentan-related safety signals. Ambrisentan was not associated with increases in liver function test abnormalities above the assumed background incidence of 1.5% per year, and the observed safety profile of ambrisentan was consistent with previously published data.

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

BackgroundThe 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 ResultsFifty-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.ConclusionsThe 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).

Pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 (GCN2) in pulmonary veno-occlusive disease

BACKGROUND Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene, leading to a loss of general control nonderepressible 2 (GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD. METHODS Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [BMPR2] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models. RESULTS PVOD patients showed a significant decrease of pulmonary arterial patency (p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001), less severe medial hypertrophy (p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins (p = 0.002). GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03) as well as in heritable (p = 0.002) and idiopathic PAH (p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model (p < 0.0001 for all models). CONCLUSIONS Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities.

Pharmacovigilance in a rare disease: example of the VIGIAPATH program in pulmonary arterial hypertension

Spontaneous reporting is the primary method used in pharmacovigilance (PV) to detect drug safety signal. Specific criteria used in pharmacovigilance to prove accountability of a drug are rarely present in rare disease. The low number of alerts also makes it challenging. The aim of this commentary is to raise awareness among pharmacists on issues and opportunities for pharmacovigilance in rare diseases, taking pulmonary arterial hypertension (PAH) as example, from which a subset of cases are drug-induced. It is demonstrated how a dedicated program named VIGIAPATH created to reinforce pharmacovigilance of drug-induced pulmonary arterial hypertension at a national level, led to increase self-reporting and confirm safety signals. Thanks to a specific program such as VIGIAPATH, pharmacists can play an important role in communication with clinicians, patients and regulatory agencies, facilitating the detection of potential safety signals at an early stage in rare disease.

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).

Portopulmonary Hypertension and Hepatopulmonary Syndrome

Liver disease and/or portal hypertension may have major consequences on pulmonary vasculature. Two distinct vascular disorders associated with this condition are described: hepatopulmonary syndrome (H