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Abstract Selexipag is indicated for the treatment of pulmonary arterial hypertension (PAH), including PAH associated with connective tissue disease (CTD), and further insights into the management of selexipag‐treated PAH‐CTD patients in clinical settings are needed. These analyses of the ongoing, multicenter, prospective EXPOSURE (EUPAS19085) study describe characteristics, treatment patterns, tolerability, and outcomes of PAH‐CTD patients initiating selexipag in Europe/Canada. All analyses were descriptive, with idiopathic PAH patients who typically display better prognosis included for context. Six hundred ninety‐eight selexipag‐treated patients had follow‐up information; 178 (26%) had PAH‐CTD. The median age was 68 years, patients were predominantly female (88%), and with WHO functional class III symptoms (63%); the median time since diagnosis was 1.7 years. There were 5% patients at low, 25% intermediate‐low, 40% intermediate‐high, and 30% high risk of 1‐year mortality, according to the ESC/ERS 4‐strata risk score. Most (80%) initiated selexipag as a triple oral therapy, and most of these (62%) remained on triple therapy 6 months post‐baseline. Over a median (Q1−Q3) selexipag exposure period of 8.6 (2.5−17.2) months, 79 (44%) patients discontinued selexipag; 36 (20%) due to tolerability/adverse events. Sixty (34%) patients were hospitalized at least once; 120 hospitalizations occurred, with 49 (48%) deemed PAH‐related. Survival at 1 year was 85%, and at 2 years was 71%; 29 (16%) patients died. These results describe the use of combination therapy with selexipag for patients with PAH‐CTD. These findings suggest an opportunity to optimize the benefits of selexipag among patients with PAH‐CTD by moving from escalating after years in response to clinical deterioration to escalating sooner to prevent clinical deterioration.

Abstract A simplified 4‐strata risk stratification approach based on three variables is widespread in pulmonary arterial hypertension (PAH) at follow‐up. This study aimed to assess the impact of replacing the 6‐min walk test (6MWT) with the peak 02 uptake evaluated by the cardiopulmonary exercise test (CPET) on risk stratification by this scale. We included 180 prevalent patients with PAH from two reference hospitals in Spain, followed up between 2006 and 2022. Patients were included if all the variables of interest were available within a 3‐month period on the Spanish Registry of Pulmonary Arterial Hypertension (REHAP): functional class (FC); NT‐proBNP; 6MWT; and CPET. The original 4‐strata model (NT‐proBNP, 6MWT, FC) identified most patients at low or intermediate‐low risk (36.7% and 51.1%, respectively). Notably, the modified scale (NT‐proBNP, CPET, FC) improved the identification of patients at intermediate‐high risk up to 18.9%, and at high risk up to 1.1% in comparison with the previous 12.2% and 0.0% in the original scale. This new model increased the number of patients correctly classified into higher‐risk strata (positive NRI of 0.06), as well as classified more patients without events in lower‐risk strata (negative NRI of 0.04). The proposed score showed a slightly superior prognostic capacity compared with the original model (Harrel's C‐index 0.717 vs. 0.709). Using O2 uptake instead of distance walked in the 6MWT improves the identification of high‐risk patients using the 4‐strata scale. This change could have relevant prognostic implications and lead to changes in the specific treatment of PAH.

Abstract The coronavirus 2019 disease (COVID‐19) pandemic threatened the Spanish health‐care system. Patients with demanding conditions such as precapillary pulmonary hypertension (PH) faced a potentially severe infection, while their usual access to medical care was restricted. This prospective, unicentric study assessed the impact of COVID‐19 on PH patients' outcomes and the operational changes in the PH network. Sixty‐three PH patients (41 pulmonary arterial hypertension [PAH]; 22 chronic thromboembolic pulmonary hypertension [CTEPH]) experienced COVID‐19. Overall mortality was 9.5% without differences when stratifying by hemodynamics or PAH‐risk score. Patients who died were older (73.6 ± 5 vs. 52.2 ± 15.4; p = 0.001), with more comorbidities (higher Charlson index: 4.17 ± 2.48 vs. 1.14 ± 1.67; p = 0.0002). Referrals to the PH expert center decreased compared to the previous 3 years (123 vs. 160; p = 0.002). The outpatient activity shifted toward greater use of telemedicine. Balloon pulmonary angioplasty activity could be maintained after the first pandemic wave and lockdown while pulmonary thromboendarterectomy procedures decreased (19 vs. 36; p = 0.017). Pulmonary transplantation activity remained similar. The COVID‐19 mortality in PAH/CTEPH patients was not related to hemodynamic severity or risk stratification, but to comorbidities. The pandemic imposed structural changes but a planned organization and resource reallocation made it possible to maintain PH patients' care.

Abstract Preclinical and early clinical studies suggest that angiotensin‐converting enzyme type 2 activity may be impaired in patients with pulmonary arterial hypertension (PAH); therefore, administration of exogenous angiotensin‐converting enzyme type 2 (ACE2) may be beneficial. This Phase IIa, multi‐center, open‐label, exploratory, single‐dose, dose‐escalation study (NCT03177603) assessed the potential vasodilatory effects of single doses of GSK2586881 (a recombinant human ACE2) on acute cardiopulmonary hemodynamics in hemodynamically stable adults with documented PAH who were receiving background PAH therapy. Successive cohorts of participants were administered a single intravenous dose of GSK2586881 of 0.1, 0.2, 0.4, or 0.8 mg/kg. Dose escalation occurred after four or more participants per cohort were dosed and a review of safety, tolerability, pharmacokinetics, and hemodynamic data up to 24 h postdose was undertaken. The primary endpoint was a change in cardiopulmonary hemodynamics (pulmonary vascular resistance, cardiac index, and mean pulmonary artery pressure) from baseline. Secondary/exploratory objectives included safety and tolerability, effect on renin‐angiotensin system peptides, and pharmacokinetics. GSK2586881 demonstrated no consistent or sustained effect on acute cardiopulmonary hemodynamics in participants with PAH receiving background PAH therapy (N = 23). All doses of GSK2586881 were well tolerated. GSK2586881 was quantifiable in plasma for up to 4 h poststart of infusion in all participants and caused a consistent and sustained reduction in angiotensin II and a corresponding increase in angiotensin (1–7) and angiotensin (1–5). While there does not appear to be a consistent acute vasodilatory response to single doses of GSK2586881 in participants with PAH, the potential benefits in terms of chronic vascular remodeling remain to be determined.

Background The determinants and consequences of pulmonary hypertension after successfully corrected valvular heart disease remain poorly understood. We aim to clarify the hemodynamic bases and risk factors for mortality in patients with this condition. Methods and Results We analyzed long‐term follow‐up data of 222 patients with pulmonary hypertension and valvular heart disease successfully corrected at least 1 year before enrollment who had undergone comprehensive hemodynamic and imaging characterization as per the SIOVAC (Sildenafil for Improving Outcomes After Valvular Correction) clinical trial. Median (interquartile range) mean pulmonary pressure was 37 mm Hg (32–44 mm Hg) and pulmonary artery wedge pressure was 23 mm Hg (18–26 mm Hg). Most patients were classified either as having combined precapillary and postcapillary or isolated postcapillary pulmonary hypertension. After a median follow‐up of 4.5 years, 91 deaths accounted for 4.21 higher‐than‐expected mortality in the age‐matched population. Risk factors for mortality were male sex, older age, diabetes mellitus, World Health Organization functional class III and higher pulmonary vascular resistance—either measured by catheterization or approximated from ultrasound data. Higher pulmonary vascular resistance was related to diabetes mellitus and smaller residual aortic and mitral valve areas. In turn, the latter correlated with prosthetic nominal size. Six‐month changes in the composite clinical score and in the 6‐minute walk test distance were related to survival. Conclusions Persistent valvular heart disease–pulmonary hypertension is an ominous disease that is almost universally associated with elevated pulmonary artery wedge pressure. Pulmonary vascular resistance is a major determinant of mortality in this condition and is related to diabetes mellitus and the residual effective area of the corrected valve. These findings have important implications for individualizing valve correction procedures. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00862043.

This multicenter, randomized, double-blind, placebo-controlled study assessed ambrisentan or placebo in patients with inoperable chronic thromboembolic pulmonary hypertension. Futility of enrollment led to early termination. Trends of improvement in favor of ambrisentan versus placebo in the primary and some secondary endpoints were observed; adverse event profiles were similar between groups.