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Background: Health-related quality of life (HRQOL) is frequently impaired in pulmonary arterial hypertension. However, little is known about HRQOL in other forms of pulmonary hypertension (PH)., Research Question: Does HRQOL vary across groups of the World Symposium on Pulmonary Hypertension (WSPH) classification system?, Study Design and Methods: This cross-sectional study included patients with PH from the Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort study. HRQOL was assessed by using emPHasis-10 (e-10), the 36-item Medical Outcomes Study Short Form survey (physical component score [PCS] and mental component score), and the Minnesota Living with Heart Failure Questionnaire. Pearson correlations between HRQOL and demographic, physiologic, and imaging characteristics within each WSPH group were tested. Multivariable linear regressions compared HRQOL across WSPH groups, adjusting for demographic characteristics, disease prevalence, functional class, and hemodynamics. Cox proportional hazards models were used to assess associations between HRQOL and survival across WSPH groups., Results: Among 691 patients with PH, HRQOL correlated with functional class and 6-min walk distance but not hemodynamics. HRQOL was severely depressed across WSPH groups for all measures except the 36-item Medical Outcomes Study Short Form survey mental component score. Compared with Group 1 participants, Group 2 participants had significantly worse HRQOL (e-10 score, 29 vs 24 [P = .001]; PCS, 32.9 ± 8 vs 38.4 ± 10 [P < .0001]; and Minnesota Living with Heart Failure Questionnaire score, 50 vs 38 [P = .003]). Group 3 participants similarly had a worse e-10 score (31 vs 24; P < .0001) and PCS (33.3 ± 9 vs 38.4 ± 10; P < .0001) compared with Group 1 participants, which persisted in multivariable models (P < .05). HRQOL was associated in adjusted models with survival across Groups 1, 2, and 3., Interpretation: HRQOL was depressed in PH and particularly in Groups 2 and 3 despite less severe hemodynamics. HRQOL is associated with functional capacity, but the severity of hemodynamic disease poorly estimates the impact of PH on patients' lives. Further studies are needed to better identify predictors and treatments to improve HRQOL across the spectrum of PH., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: H. M. D. has received grant funding from Bayer Pharmaceuticals, has served on advisory boards for Janssen Pharmaceuticals and has received consulting fees from Janssen Pharmaceuticals. N. S. H. serves on a clinical trial steering committee for Aerovate, advisory board for Gossamer, DSMB for Merch, and consultant for Liquidia and United Therapeutics. R.M. has received an honorarium from the American Academy of Sleep Medicine; funds for service on the American Board of Internal Medicine and as associate editor of the American Journal of Respiratory and Critical Care Medicine; has received National Institutes of Health funding; and has received royalties from UpToDate. A. R. H. has served as a consultant for Bayer, GossamerBio, Janssen, Merck, Tenax, and United Therapeutics. She owns stock in Tenax. P. M. H. has served on a steering committee for Merck and as consultant ARIA-CVS. S. C. M. has served as a consultant for Acceleron, Janssen, Merck, and United Therapeutics. None declared (A. B., A. B. L., E. M. H., M. S. J., J. A. L., M. K. R., S. C. E., E. B. R., R. P. F., F. P. R., G. J. B.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: This study aims to assess the impact of sotatercept on exercise tolerance, exercise capacity, and right ventricular function in pulmonary arterial hypertension., Methods: SPECTRA (Sotatercept Phase 2 Exploratory Clinical Trial in PAH) was a phase 2a, single-arm, open-label, multicenter exploratory study that evaluated the effects of sotatercept by invasive cardiopulmonary exercise testing in participants with pulmonary arterial hypertension and World Health Organization functional class III on combination background therapy. The primary end point was the change in peak oxygen uptake from baseline to week 24. Cardiac magnetic resonance imaging was performed to assess right ventricular function., Results: Among the 21 participants completing 24 weeks of treatment, there was a significant improvement from baseline in peak oxygen uptake, with a mean change of 102.74 mL/min ([95% CIs, 27.72-177.76]; P =0.0097). Sotatercept demonstrated improvements in secondary end points, including resting and peak exercise hemodynamics, and 6-minute walk distance versus baseline measures. Cardiac magnetic resonance imaging showed improvements from baseline at week 24 in right ventricular function., Conclusions: The clinical efficacy and safety of sotatercept demonstrated in the SPECTRA study emphasize the potential of this therapy as a new treatment option for patients with pulmonary arterial hypertension. Improvements in right ventricular structure and function underscore the potential for sotatercept as a disease-modifying agent with reverse-remodeling capabilities., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03738150., Competing Interests: Disclosures Dr Waxman is a Steering Committee member for Acceleron Pharma, a wholly owned subsidiary of Merck & Co Inc (Rahway, NJ) and United Therapeutics; and is an investigator and principal investigator for Acceleron Pharma, Aria CV, OrphAI, and United Therapeutics. Dr Manimaran is an employee of Acceleron Pharma. Dr de Oliveira Pena is an employee of Oorja Bio Inc and a former employee of Acceleron Pharma. Dr Lu is an employee of SalioGen Therapeutics and a former employee of Acceleron Pharma. F. P. Rischard has been a consultant for Acceleron Pharma and United Therapeutics. He has received research support from Acceleron Pharma, Bayer, ISMed, Janssen, the National Heart, Lung, and Blood Institute, the National Institutes of Health, and United Therapeutics. The other author reports no conflicts.

Background: Quantifying right ventricular (RV) function is important to describe the pathophysiology of in pulmonary hypertension (PH). Current phenotyping strategies in PH rely on few invasive hemodynamic parameters to quantify RV dysfunction severity. The aim of this study was to identify novel RV phenotypes using unsupervised clustering methods on advanced hemodynamic features of RV function., Methods: Participants were identified from the University of Arizona Pulmonary Hypertension Registry (n = 190). RV-pulmonary artery coupling (Ees/Ea), RV systolic (Ees), and diastolic function (Eed) were quantified from stored RV pressure waveforms. Consensus clustering analysis with bootstrapping was used to identify the optimal clustering method. Pearson correlation analysis was used to reduce collinearity between variables. RV cluster subphenotypes were characterized using clinical data and compared to pulmonary vascular resistance (PVR) quintiles., Results: Five distinct RV clusters (C1-C5) with distinct RV subphenotypes were identified using k-medoids with a Pearson distance matrix. Clusters 1 and 2 both have low diastolic stiffness (Eed) and afterload (Ea) but RV-PA coupling (Ees/Ea) is decreased in C2. Intermediate cluster (C3) has a similar Ees/Ea as C2 but with higher PA pressure and afterload. Clusters C4 and C5 have increased Eed and Ea but C5 has a significant decrease in Ees/Ea. Cardiac output was high in C3 distinct from the other clusters. In the PVR quintiles, contractility increased and stroke volume decreased as a function of increased afterload. World Symposium PH classifications were distributed across clusters and PVR quintiles., Conclusions: RV-centric phenotyping offers an opportunity for a more precise-medicine-based management approach., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Inhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD exacerbations from the 16-week INCREASE study and change in 6-minute walking distance (6MWD) in the INCREASE open-label extension (OLE) in patients with less severe haemodynamics., Methods: Patients were stratified by baseline pulmonary vascular resistance (PVR) of <4 Wood units (WU) versus ≥4 WU and <5 WU versus ≥5 WU. Exacerbations of underlying lung disease, clinical worsening and change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in INCREASE were evaluated. For the OLE, patients previously assigned to placebo were considered to have a 16-week treatment delay. 6MWD and clinical events in the OLE were evaluated by PVR subgroup., Results: Of the 326 patients enrolled in INCREASE, patients with less severe haemodynamics receiving iTre had fewer exacerbations of underlying lung disease and clinical worsening events. This was supported by the Bayesian analysis of the risk of disease progression (HR<1), and significant decreases in NT-proBNP levels. In the OLE, patients without a treatment delay had improved exercise capacity after 1-year compared with those with a 16-week treatment delay (22.1 m vs -10.3 m). Patients with a PVR of ≤5 WU without a treatment delay had a change of 5.5 m compared with -8.2 m for those with a treatment delay. Patients without a treatment delay had a prolonged time to hospitalisation, lung disease exacerbation and death., Conclusion: Treatment with iTre led to consistent benefits in clinical outcomes in patients with PH-ILD and less severe haemodynamics. Earlier treatment in less severe PH-ILD may lead to better exercise capacity long-term, however, the subgroup analyses in this post hoc study were underpowered and confirmation of these findings is needed., Competing Interests: Competing interests: ABW has received grant support or consulting fees from AI Therapeutics, ARIA-CV, Acceleron/Merck, Janssen Pharmaceuticals, and has participated on a data and safety monitoring board for Insmed. SDN has received consulting fees or payment or honoraria, from United Therapeutics, Boehringer-Ingelheim, Roche, Bellerophon Therapeutics, Altavant Sciences, and Merck. JW has received grants or contracts to his institution from AstraZeneca, Bayer, Janssen and Merck; consulting fees from Janssen and Merck; honoraria from Janssen and Merck; payment for expert testimony from Sprigings Intellectual Property Law; travel support from Janssen; participation on Data Safety and Monitoring Board or advisory board from Janssen, Acceleron, and the Université de Laval; and has unpaid leadership role at the Pulmonary Hypertension Association of Canada. CQD, ES and MD are employees of and may have received stock or stock options from United Therapeutics. RGA has participated in advisory boards, disease state-specific speaking engagements and clinical trials sponsored by United Therapeutics. VFT reports research grants paid to institution from Boston Scientific Corporation, Bristol Myers Squibb and Genentech, speaker and consulting fees from Janssen, fees from Boston Scientific Corporation for participating in an executive committee for a clinical trial, that he serves as President for PE Response Team Consortium (unpaid), owns stock in Thrombolex and Inari Medical, and that he is employed as VP of Medical Affairs at Inari Medical. HMD is a consultant for Janssen Pharmaceuticals, has received grant funding from Bayer and has served on advisory boards for United Therapeutics and Janssen Pharmaceuticals. FR is a consultant for Acceleron and United Therapeutics and is on a steering committee for Acceleron, Ismed, United Therapeutics, Bayer, Acceleron, Janssen and AADI. SJC is a consultant for Iota Biosciences, Inc. KE-K is a consultant for Acceleron, Merck, United Therapeutics, J&J Actelion and served on advisory boards for J&J Actelion, Merck and United Therapeutics, received institutional research funding from J&J Actelion and United Therapeutics and participated in United Therapeutics speaker bureau, steering committee and clinical studies. JT has received consulting fees or payment or honoraria from United Therapeutics and Medtronic, Inc., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)