Macitentan seems to improve outcomes in patients with pulmonary arterial hypertension (PAH). Nevertheless, safety and efficacy in pediatric patients is still to be determined. Multi-center, observational study to assess safety and efficacy of oral macitentan in patients under 18 years-of-age from the Spanish Registry of Pediatric Pulmonary Hypertension with group 1 PAH. Outcome measures included changes in the World Health Organization Functional Class (WHO FC) from baseline to month 6, 6-min walking distance (6MWD), NT-proBNP levels, risk-stratification, echocardiographic and hemodynamic parameters, and Pediatric Quality of Life Inventory. Seventy-four patients (median age 9.6 years) with PAH were included in the study, of which thirty-one had idiopathic/heritable pulmonary arterial hypertension and 43 had PAH associated with congenital heart disease. Significant clinical improvement was observed after 6 months of treatment with macitentan: The percentage of patients on WHO FC III/IV decreased from 48 to 22% (p = 0.001); mean 6MWD (n = 42) increased significantly in around 45 m (p = 0.032); NT-proBNP decreased a mean of - 438.9 ± 175 pg/ml, (p = 0.015). There was a 17% increase in the number of patients meeting all three low-risk parameters of 17% (p = 0.002). Side effects were detected in four patients (5.4%). Macitentan was discontinued in one patient. Disease progression was observed in 6 patients despite macitentan therapy. This study provided evidence on the clinical benefits and good tolerance of macitentan in paediatric population with group I PAH treated in routine clinical practice.

Despite shared pathophysiological mechanisms, patients with idiopathic/heritable pulmonary arterial hypertension (IPAH/HPAH) have a poorer prognosis than those with PAH after congenital heart defect repair. Ventricular adaption remains unclear and could provide a basis for explaining differences in clinical outcomes. The aim of this prospective study was to assess clinical status, haemodynamic profile, and biventricular adaptation to PAH in children with various forms of PAH. Consecutive patients with IPAH/HPAH or post-operative PAH were prospectively recruited (n = 64). All patients underwent a comprehensive, protocolized assessment including functional assessment, measurement of brain natriuretic peptide (BNP) levels, invasive measurements, and a cardiac magnetic resonance (CMR) assessment. A cohort of age- and sex-matched healthy subjects served as controls. Patients with post-operative PAH had a better functional class (61.5 vs. 26.3% in Class I/II, P = 0.02) and a longer 6-min walk distance (320 ± 193 vs. 239 ± 156 m, P = 0.008) than IPAH/HPAH. While haemodynamic parameters were not significantly different between IPAH/HPAH and post-operative patients, post-operative patients with PAH presented with higher left ventricular volumes and better right ventricular function compared with patients with IPAH/HPAH (P < 0.05). On correlation analyses, left ventricular volumetric parameters were highly correlated with BNP and 6-min walk test distance in this population. Despite comparable haemodynamic profiles, patients with post-operative PAH had less functional limitation than their IPAH/HPAH counterparts. This is potentially related to the differential biventricular adaptation pattern evident on CMR with better myocardial contractility and higher left ventricular volumes in post-operative patients with PAH, highlighting the importance of ventriculo-ventricular interaction in the setting of PAH.

The adrenomedullin level increases in pulmonary arterial hypertension (PAH, and correlates with a high mortality rate. Its active form, bioactive adrenomedullin (bio-ADM), has been recently developed and has significant prognostic applications in acute clinical settings. Aside from idiopathic/hereditary PAH (I/H-PAH), atrial septal defects-associated pulmonary artery hypertension (ASD-PAH) is still prevalent in developing countries and associated with increased mortality. This study aimed to investigate the mortality-wise prognostic value of the plasma bio-ADM level by comparing subjects with ASD-PAH and I/H-PAH with ASD patients without pulmonary hypertension (PH) as a control group. This was a retrospective, observational cohort study. The subjects were Indonesian adult patients who were recruited from the Congenital Heart Disease and Pulmonary Hypertension (COHARD-PH) registry and divided into three groups: (1) ASD without PH (control group), (2) ASD-PAH and (3) I/H-PAH. During right-heart catheterization at the time of diagnosis, a plasma sample was taken and assayed for bio-ADM using a chemiluminescence immunoassay. Follow-up was performed as a part of the COHARD-PH registry protocol in order to evaluate the mortality rate. Among the 120 subjects enrolled: 20 turned out to have ASD without PH, 85 had ASD-PAH and 15 had I/H-PAH. Compared to the control group (5.15 (3.0-7.95 pg/mL)) and ASD-PAH group (7.30 (4.10-13.50 pg/mL)), bio-ADM levels were significantly higher in the I/H-PAH group (median (interquartile range (IQR)): 15.50 (7.50-24.10 pg/mL)). Moreover, plasma bio-ADM levels were significantly higher in subjects who died (n = 21, 17.5%) compared to those who survived (median (IQR): 11.70 (7.20-16.40 pg/mL) vs. 6.90 (4.10-10.20 pg/mL), p = 0.031). There was a tendency toward higher bio-ADM levels in those who died among the PAH subjects, in both ASD-PAH and I/H-PAH groups. In conclusion, the plasma bio-ADM level is elevated in subjects with PAH from both ASD-PAH and I/H-PAH origins, reaching the highest levels in subjects with the I/H-PAH form. A high bio-ADM level tended to be associated with a high mortality rate in all subjects with PAH, indicating a relevant prognostic value for this biomarker. In patients with I/H-PAH, monitoring bio-ADM could represent a valid tool for predicting outcomes, allowing more appropriate therapeutical choices.

Even though pulmonary arterial hypertension (PAH) remains an incurable disease, the combination of PAH-specific therapies allowed evolving from symptom-based strategies to others aiming to move patients to low-risk conditions. Endothelin-1 (ET-1) receptor antagonists emerged as specific-PAH drugs that can be used in combination with other specific therapies. This work aimed to perform a prospective clinical assessment of patients with PAH that switched from bosentan to macitentan (POTENT), due to inadequate response. POTENT is a prospective, open-label, single-arm, uncontrolled study including PAH patients from our ongoing SAUDIPH registry. It enrolled 50 PAH patients divided as follows: idiopathic/heritable pulmonary arterial hypertension (I/HPAH); n = 24; PAH associated with congenital heart disease, n = 19; PAH associated with connective tissue diseases, n = 5; and pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH), n = 2. At baseline, most patients were in World Health Organization Functional Class (WHO FC) II/III (52.0%). After switching to macitentan, patients were more likely to be in WHO FC I/II (78%) and 22% of the overall cohort moved to a lower risk condition, with three low risk stratification parameters. Mean 6-min walking distance increased about 34 m after 12 months, with a significant mean change over time (12.63 ± 11.69 at month 3 vs. 40.75 ± 12.57 at month 12, p = 0.002). Most haemodynamic parameters decreased over time, with corresponding negative mean changes (p < 0.001). The safety of macitentan was confirmed by the absence of anaemia and liver injury; clinical worsening was observed only in a small group of patients. In general, macitentan might be a valid alternative to bosentan in PAH stable patients on combination therapy with insufficient clinical response, and presenting intermediate and high-risk parameters. We anticipate that studying this strategy in PAH subgroups would further clarify its potential and limitations.

Trimethylamine N-oxide (TMAO), the gut microbiota-dependent metabolite, is a potential biomarker in several cardiovascular diseases. However, no study has investigated its value in pulmonary hypertension (PH). Therefore, this study aimed to explore the association between plasma TMAO levels and prognosis in patients with PH. Inpatients with idiopathic/heritable pulmonary arterial hypertension (IPAH/HPAH), PAH associated with congenital heart disease (CHD-PAH), and chronic thromboembolic pulmonary hypertension (CTEPH) at Fuwai Hospital were enrolled after excluding those with relative comorbidities. The endpoint was defined as a composite outcome including death, rehospitalisation due to heart failure, and at least 15% decreased 6-min walk distance from the baseline. Fasting blood samples were collected to measure plasma levels of TMAO and other clinical indicators. The associations between TMAO levels with disease severity and patients' prognosis were investigated. In total, 163 patients with PH were included, with a mean follow-up duration of 1.3 years. After adjusting for confounding factors, elevated TMAO levels were still associated with severe disease conditions. TMAO levels dynamically decreased in stable and improved patients after treatment [ΔTMAO = - 0.2 (- 1.6, 0.7) μmol/L, P = 0.006]. Moreover, high plasma TMAO levels predicted a poor prognosis in the PH cohort (P < 0.001), and the association remained significant after adjusting the confounders, including treatment, risk stratification, and PH subtypes. Elevated plasma TMAO levels were associated with severe disease conditions and poor prognosis in patients with PH, indicating its potential biomarker role in PH.