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Rationale: The use of extracorporeal membrane oxygenation (ECMO) in patients who are awake and spontaneously breathing may represent a novel bridging strategy toward lung transplantation (LuTx). Objectives: To evaluate the outcomes of patients treated with the 'awake ECMO' concept as bridge to transplantation. Methods: We performed a retrospective, single-center, intention-to-treat analysis of consecutive LuTx candidates with terminal respiratory or cardiopulmonary failure receiving awake ECMO support. The outcomes were compared with a historical control group of patients treated with conventional mechanical ventilation (MV group) as bridge to transplant. Measurements and Main Results: Twenty-six patients (58% female; median age, 44 yr; range, 23-62) were included in the awake ECMO group and 34 patients (59% female; median age, 36 yr; range, 18-59) in the MV group. The duration of ECMO support or MV, respectively, was comparable in both groups (awake ECMO: median, 9 d; range, 1-45. MV: median, 15 d; range, 1-71; P = 0.25). Six (23%) of 26 patients in the awake ECMO group and 10 (29%) of 34 patients in the MV group died before a donor organ was available (P = 0.20). Survival at 6 months after LuTx was 80% in the awake ECMO group versus 50% in the MV group (P = 0.02). Patients in the awake ECMO group required shorter postoperative MV (P = 0.04) and showed a trend toward a shorter postoperative hospital stay (P = 0.06). Conclusions: ECMO support in patients who are awake and nonintubated represents a promising bridging strategy, which should be further evaluated to determine its role in patients with end-stage lung disease awaiting LuTx. [ABSTRACT FROM AUTHOR]

Rationale: In addition to Kaposi's sarcoma, Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) has been associated with two other diseases: primary effusion lymphoma and the plasma cell variant of multicentric Castleman's disease. Recently, evidence of KSHV infection was reported in plexiform lesions of idiopathic pulmonary arterial hypertension (IPAH) as well as in adjacent parenchyma and bronchial epithelial cells.Objectives: To further investigate a possible association of KSHV and pulmonary arterial hypertension.Methods and Measurements: Twenty-six lungs explanted from German patients suffering from IPAH were tested for the presence of KSHV antigen and genomes by immunohistochemistry (IHC) and polymerase chain reaction (PCR).Main Results: When stained with a commercial monoclonal antibody directed against the latency-associated nuclear antigen of KSHV, LANA-1, a positive signal reminiscent of the 'speckled' nuclear pattern typical of latently KSHV-infected cells was found in 16 (61.5%) cases. Alveolar and bronchial epithelial cells in areas of unremarkable lung tissue, but not cells within the plexiform lesions, were the predominantly stained cell types. Different KSHV-PCR assays (based on orf26, orfK6, and orf72) performed on samples that had tested positively in IHC, however, could not confirm KSHV infection, indicating that the IHC signal was not due to KSHV infection. One IHC-negative patient tested positive by PCR. A PCR based on consensus degenerate hybrid oligonucleotide primers (CODEHOP) to detect yet unknown gamma-herpesviruses did not reveal any specific sequences. [ABSTRACT FROM AUTHOR]

Background: Pulse wave velocity (PWV) in the pulmonary arteries (PA) is a marker of vascular stiffening. Currently, only phase-contrast (PC) MRI-based options exist to measure PA-PWV., Purpose: To test feasibility, repeatability, and correlation to clinical data of Phase-Resolved Functional Lung (PREFUL) MRI-based calculation of PA-PWV., Study Type: Retrospective., Subjects: 79 (26 female) healthy subjects (age range 19-78), 58 (24 female) patients with chronic obstructive pulmonary disease (COPD, age range 40-77), 60 (33 female) patients with suspected pulmonary hypertension (PH, age range 28-85)., Sequence: 2D spoiled gradient echo, 1.5T., Assessment: PA-PWV was measured from PREFUL-derived cardiac cycles based on the determination of temporal and spatial distance between lung vasculature voxels using a simplified (sPWV) method and a more comprehensive (cPWV) method including more elaborate distance calculation. For 135 individuals, PC MRI-based PWV (PWV-QA) was measured., Statistical Tests: Intraclass-correlation-coefficient (ICC) and coefficient of variation (CoV) were used to test repeatability. Nonparametric tests were used to compare cohorts. Correlation of sPWV/cPWV, PWV-QA, forced expiratory volume in 1 sec (FEV 1 ) %predicted, residual volume (RV) %predicted, age, and right heart catheterization (RHC) data were tested. Significance level α = 0.05 was used., Results: sPWV and cPWV showed no significant differences between repeated measurements (P-range 0.10-0.92). CoV was generally lower than 15%. COPD and PH patients had significantly higher sPWV and cPWV than healthy subjects. Significant correlation was found between sPWV or cPWV and FEV 1 %pred. (R = -0.36 and R = -0.44), but not with RHC (P-range -0.11 - 0.91) or age (P-range 0.23-0.89). Correlation to RV%pred. was significant for cPWV (R = 0.42) but not for sPWV (R = 0.34, P = 0.055). For all cohorts, sPWV and cPWV were significantly correlated with PWV-QA (R = -0.41 and R = 0.48)., Data Conclusion: PREFUL-derived PWV is feasible and repeatable. PWV is increased in COPD and PH patients and correlates to airway obstruction and hyperinflation., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 2., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Risk stratification has gained an increasing role in predicting outcomes and guiding the treatment of patients with pulmonary arterial hypertension (PAH). The most predictive prognostic factors are three noninvasive parameters (World Health Organization functional class, 6-min walk distance and natriuretic peptides) that are included in all currently validated risk stratification tools. However, suffering from limitations mainly related to reduced specificity of PAH severity, these variables may not always be adequate in isolation for guiding individualised treatment decisions. Moreover, with effective combination treatment regimens and emerging PAH therapies, markers associated with pulmonary vascular remodelling are expected to become of increasing relevance in guiding the treatment of patients with PAH. While reaching a low mortality risk, assessed with a validated risk tool, remains an important treatment goal, preliminary data suggest that invasive haemodynamics and cardiac imaging may add incremental value in guiding treatment decisions., Competing Interests: Conflict of interest: F. Dardi reports consultancy fees from Janssen and Chiesi Farmaceutici, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen. A. Boucly reports grants from Acceleron, Janssen and MSD, payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen, Merck, AOP Orphan, Ferrer and AstraZeneca, and support for attending meetings from Janssen, MSD, Ferrer and AOP Orphan. R. Benza reports consultancy fees from Cereno, Gossamer and United Therapeutics, and participation on a data safety monitoring board or advisory board with Altavant. R. Frantz reports grants from NHLBI and Gossamer Bio, royalties or licences from UpToDate, consultancy fees from Gossamer Bio, Insmed, Merck and Liquidia, participation on a data safety monitoring board or advisory board with Aerovate Pharmaceuticals, leadership role with Pulmonary Hypertension Association Scientific Leadership Council, and stock (or stock options) with Merck. V. Mercurio reports consultancy fees from MSD, payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen, and support for attending meetings from Janssen and MSD. H. Olschewski reports consultancy fees from Actelion, AstraZeneca, Bayer, Boehringer, Janssen, MSD, Chiesi, GSK, Inventiva, Ferrer, Menarini and Sanofi, payment or honoraria for lectures, presentations, manuscript writing or educational events from Springer, Medupdate and Mondial, support for attending meetings from Boehringer, Menarini and MSD, participation on a data safety monitoring board or advisory board with Aerovate, Bayer, Pfizer and IQVIA, receipt of equipment, materials, drugs, medical writing, gifts or other services from Boehringer, and the following financial (or non-financial) interests: Deputy Director, Ludwig Boltzmann Institute for Lung Vascular Research, Graz. G. Rådegran reports grants from Nordic Infucare, payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen, MSD, Nodic Infucare and Orpha Care/AOP Health, and participation on a data safety monitoring board or advisory board with Janssen, MSD and Orpha Care/AOP Health. L.J. Rubin reports consultancy fees from Gossamer and SoniVie, payment for expert testimony from Sandoz, and is a member of the Organizing and Founders Committees, WSPH. M.M. Hoeper reports consultancy fees from Acceleron, Actelion, AOP Health, Bayer, Ferrer, Gossamer Bio, Janssen, Keros and MSD, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Actelion, AOP Health, Bayer, Ferrer, Janssen and MSD., (Copyright ©The authors 2024.)

Objectives: To investigate potential presence and resolution of longer-term pulmonary diffusion limitation and microvascular perfusion impairment in COVID-19 convalescents., Materials and Methods: This prospective, longitudinal study was carried out between May 2020 and April 2023. COVID-19 convalescents repeatedly and age/sex-matched healthy controls once underwent MRI including hyperpolarized 129 Xe MRI. Blood samples were obtained in COVID-19 convalescents for immunophenotyping. Ratios of 129 Xe in red blood cells (RBC), tissue/plasma (TP), and gas phase (GP) as well as lung surface-volume ratio were quantified and correlations with CD4 + /CD8 + T cell frequencies were assessed using Pearson's correlation coefficient. Signed-rank tests were used for longitudinal and U tests for group comparisons., Results: Thirty-five participants were recruited. Twenty-three COVID-19 convalescents (age 52.1 ± 19.4 years, 13 men) underwent baseline MRI 12.6 ± 4.2 weeks after symptom onset. Fourteen COVID-19 convalescents underwent follow-up MRI and 12 were included for longitudinal comparison (baseline MRI at 11.5 ± 2.7 weeks and follow-up 38.0 ± 5.5 weeks). Twelve matched controls were included for comparison. In COVID-19 convalescents, RBC-TP was increased at follow-up (p = 0.04). Baseline RBC-TP was lower in patients treated on intensive care unit (p = 0.03) and in patients with severe/critical disease (p = 0.006). RBC-TP correlated with CD4 + /CD8 + T cell frequencies (R = 0.61/ - 0.60) at baseline. RBC-TP was not significantly different compared to matched controls at follow-up (p = 0.25)., Conclusion: Impaired microvascular pulmonary perfusion and alveolar membrane function persisted 12 weeks after symptom onset and resolved within 38 weeks after COVID-19 symptom onset., Clinical Relevance Statement: 129 Xe MRI shows improvement of microvascular pulmonary perfusion and alveolar membrane function between 11.5 ± 2.7 weeks and 38.0 ± 5.5 weeks after symptom onset in patients after COVID-19, returning to normal in subjects without significant prior disease., Key Points: • The study aims to investigate long-term effects of COVID-19 on lung function, in particular gas uptake efficiency, and on the cardiovascular system. • In COVID-19 convalescents, the ratio of 129 Xe in red blood cells/tissue plasma increased longitudinally (p = 0.04), but was not different from matched controls at follow-up (p = 0.25). • Microvascular pulmonary perfusion and alveolar membrane function are impaired 11.5 weeks after symptom onset in patients after COVID-19, returning to normal in subjects without significant prior disease at 38.0 weeks., (© 2024. The Author(s).)

In Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) (NCT02891850), improvements in risk status were observed in patients with pulmonary arterial hypertension (PAH) at intermediate risk switching to riociguat versus continuing phosphodiesterase-5 inhibitors (PDE5i). This post hoc study applied the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2 and Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary (COMPERA) 2.0 risk-assessment tools to REPLACE to investigate the impact of baseline risk status on clinical improvement. The proportions of riociguat- and PDE5i-treated patients achieving the primary end-point at REVEAL Lite 2 low, intermediate, and high baseline risk reflected the overall population. Proportions of riociguat-treated patients achieving the primary end-point were comparable between the COMPERA 2.0 intermediate-low risk (39%) and intermediate-high risk (43%) groups. Our findings show that patients in REPLACE achieved clinical improvement by switching from PDE5i to riociguat across all COMPERA 2.0 and most REVEAL Lite 2 baseline risk strata., (Copyright © 2024. Published by Elsevier Inc.)

Background: MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation., Methods: The phase 2 INSIGNIA-PAH (NCT04732221) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg via dry powder inhalation for 12 weeks., Objectives: The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH., Results: 168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were -9.2% (95% CI -21.3%, 2.9%; p=0.068) with 32 µg, -22.0% (95% CI -33.7%, -10.3%; p<0.001) with 100 µg, and -19.9% (95% CI -33.4%, -6.4%; p=0.002) with 380 µg MK-5475. No treatment differences versus placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg)., Conclusions: In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect., Competing Interests: Conflict of interest: M. Humbert reports grants/contracts from Gossamer Bio and Merck & Co., Inc., Rahway, NJ, USA, consultancy for 35 Pharma, Aerovate Therapeutics, Inc., AOP Orphan Pharmaceuticals, Bayer, Chiesi Farmaceutici SpA, Ferrer Internacional SA, Gossamer Bio, Janssen Pharmaceuticals, Keros Therapeutics, Liquidia Corp., Merck & Co., Inc., Rahway, NJ, USA, Novartis, Respira Therapeutics, Roivant Sciences Ltd and United Therapeutics Corp., honoraria from Janssen Pharmaceuticals and Merck & Co., Inc., Rahway, NJ, USA, and participation on a data safety monitoring or advisory board for 35 Pharma, Aerovate Therapeutics, Inc., Janssen Pharmaceuticals, Keros Therapeutics, Merck & Co., Inc., Rahway, NJ, USA, Novartis and United Therapeutics Corp. P.M. Hassoun reports participation on a scientific steering committee for MSD and participation on a scientific advisory board for ARIA-CV. K.M. Chin reports fees for work on steering, advisory or adjudication committees from Gossamer Bio, Janssen, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics, and research support to institution for clinical studies overseen by her from Altavant, Gossamer Bio, Janssen, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics. G. Bortman reports consultancy for Biosidus Argentina, Tuteur SA, Aerovate Therapeutics Inc., Baliarda Argentina, Merck & Co, Inc., Glaxo Inc. and Tecnopharma/Raffo, Inc. M.J. Patel, C. La Rosa, W. Fu and M.J. Loureiro are current employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may hold stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. M.M. Hoeper reports consultancy for Acceleron Pharma, Inc., Actelion Pharmaceuticals, Aerovate, AOP Orphan Pharmaceuticals, Bayer HealthCare, Ferrer Internacional SA, Gossamer Bio, Janssen Global Services, LLC, Keros, Merck & Co., Inc., Rahway, NJ, USA, and Novartis., (Copyright ©The authors 2024.)

The clinical classification of pulmonary hypertension (PH) has guided diagnosis and treatment of patients with PH for several decades. Discoveries relating to underlying mechanisms, pathobiology and responses to treatments for PH have informed the evolution in this clinical classification to describe the heterogeneity in PH phenotypes. In more recent years, advances in imaging, computational science and multi-omic approaches have yielded new insights into potential phenotypes and sub-phenotypes within the existing clinical classification. Identification of novel phenotypes in pulmonary arterial hypertension (PAH) with unique molecular profiles, for example, could lead to new precision therapies. Recent phenotyping studies have also identified groups of patients with PAH that more closely resemble patients with left heart disease (group 2 PH) and lung disease (group 3 PH), which has important prognostic and therapeutic implications. Within group 2 and group 3 PH, novel phenotypes have emerged that reflect a persistent and severe pulmonary vasculopathy that is associated with worse prognosis but still distinct from PAH. In group 4 PH (chronic thromboembolic pulmonary disease) and sarcoidosis (group 5 PH), the current approach to patient phenotyping integrates clinical, haemodynamic and imaging characteristics to guide treatment but applications of multi-omic approaches to sub-phenotyping in these areas are sparse. The next iterations of the PH clinical classification are likely to reflect several emerging PH phenotypes and improve the next generation of prognostication tools and clinical trial design, and improve treatment selection in clinical practice., Competing Interests: Conflict of interest: J. Weatherald reports grants from Janssen, Bayer, Merck and AstraZeneca; consulting fees and lecture honoraria from Janssen and Merck; payment for expert testimony from Sprigings Intellectual Property Law; travel support from Janssen; advisory board participation with Janssen, Acceleron and Université Laval; and a leadership role on the medical advisory committee for Pulmonary Hypertension Association of Canada, outside the submitted work. A.R. Hemnes reports grants from NIH; consulting fees from Gossamer Bio, United Therapeutics, Bayer, Janssen, Merch and Tenax Therapeutics; advisory board participation with NIH/NHLBI; leadership roles with the Nashville Ballet and Pulmonary Vascular Research Institute; and stock or stock options with Tenax Therapeutics, outside the submitted work. B.A. Maron reports grants from NIH/NHLBI; consulting fees from Actelion and Tenax Therapeutics; and the following patents: PCT/US2019/059890, #9605047 and PCT/US2020/066886, outside the submitted work. L.M. Mielniczuk reports consulting fees from Bayer, Merck and Janssen; lecture honoraria from Janssen and Merck; and leadership roles as Chair of Pulmonary Hypertension Association of Canada and Vice President of Canadian Heart Failure Society, outside the submitted work. C. Gerges reports support for the present manuscript from OrphaCare; outside the submitted work, C. Gerges reports lecture honoraria from AOPHealth, AstraZeneca, Janssen and Ferrer; and travel support from AOPHealth, AstraZeneca, Cordis, Janssen and MSD. L.C. Price reports grants from Ferrer; lecture honoraria from Janssen, Ferrer and MSD; travel support from Janssen, Ferrer Pharmaceuticals and Altavant; and advisory board participation with Janssen, outside the submitted work. M.M. Hoeper reports consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Gossamer Bio, Janssen, Keros and MSD; lecture honoraria from Acceleron, Actelion, AOP Health, Bayer, Ferrer, Janssen and MSD; and US patent application #63466014 (Methods of improving lung diffusion capacity in a patients with pulmonary arterial hypertension, application filed by MSD), outside the submitted work. M. Humbert reports grants from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti; consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti and United Therapeutics; lecture honoraria from Janssen and Merck; and advisory board participation with Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: There is limited evidence to support treatment recommendations in patients with pulmonary arterial hypertension (PAH) and comorbidities. To investigate the impact of riociguat treatment in this patient population, we analyzed pooled data from randomized controlled trials of riociguat., Methods: This post hoc analysis included data from the PATENT-1, PATENT-2, PATENT PLUS, and REPLACE studies. Safety, efficacy (6-minute walk distance [6MWD], World Health Organization functional class [WHO-FC], and N-terminal probrain natriuretic peptide [NT-proBNP]), and COMPERA 2.0 risk status were assessed in patients with 0, 1 to 2, or 3 to 4 cardiometabolic comorbidities (obesity, systemic hypertension, diabetes mellitus, coronary artery disease) in the main phase of the studies. Safety was also assessed in the long-term extensions., Results: The analysis included 686 patients (riociguat, n = 440; placebo, n = 132; phosphodiesterase type 5 inhibitors [PDE5i], n = 114), of whom 55%, 39%, and 6% had 0, 1 to 2, and 3 to 4 comorbidities, respectively. In the main phase, rates and severity of adverse events (AEs) were similar in riociguat-treated patients across comorbidity subgroups. After 2 years, discontinuations of riociguat due to AEs were also similar across subgroups. Compared with placebo and PDE5i, riociguat improved 6MWD and NT-proBNP across comorbidity groups and improved WHO-FC and COMPERA 2.0 risk status in patients with 0 or 1 to 2 comorbidities., Conclusions: Riociguat had an acceptable safety profile in PAH patients with cardiometabolic comorbidities. Efficacy and risk assessment results suggest that riociguat can be beneficial for patients with PAH, irrespective of the presence of comorbidities., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mortality risk assessment informs clinical management of pulmonary arterial hypertension (PAH). The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2 is a simplified risk calculator discriminating 1-year mortality risk., Methods: This post-hoc analysis of the phase 3 GRIPHON study assessed changes in REVEAL Lite 2 risk score with selexipag versus placebo and whether changes were prognostic or predictive of time to first morbidity/mortality (M/M) event., Results: REVEAL Lite 2 risk category discriminated M/M risk (landmark concordance indices: 0.68-0.76, selexipag; 0.65-0.70, placebo). Across baseline risk categories, hazard ratios supported a lower risk of M/M events with selexipag versus placebo: low, 0.573 (95% confidence interval [CI] 0.361-0.908; p = 0.0178); intermediate, 0.423 (95% CI 0.274-0.655; p = 0.0001); and high, 0.711 (9% CI 0.520-0.972; p = 0.0326). Odds ratios for risk improvement were 2.0 (95% CI 1.50-2.65), 1.8 (95% CI 1.38-2.43), and 2.0 (95% CI 1.43-2.72) for selexipag versus placebo at 16, 26, and 52 weeks, respectively (all p < 0.001). REVEAL Lite 2 risk improvement at week 16 explained 19.1% of the treatment effect in all patients and 47.0% in patients with REVEAL Lite 2 baseline risk score of ≥7., Conclusions: REVEAL Lite 2 can monitor PAH M/M risk and facilitate treatment optimization. Baseline REVEAL Lite 2 risk score was prognostic of M/M risk in patients with PAH and mediates treatment effect up to 47% for those at higher risk. Lower M/M risk with selexipag versus placebo occurred irrespective of baseline risk category (ClinicalTrials.gov identifier: NCT01106014)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension., Methods: In the double-blind PASSION study (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension), patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension were randomized 1:1 to receive tadalafil at a target dose of 40 mg or placebo. The primary end point was the time to the first composite event of adjudicated heart failure hospitalization or all-cause death. Secondary end points included all-cause mortality and improvements in New York Heart Association functional class or ≥10% improvement in 6-minute walking distance from baseline., Results: Initially targeting 372 patients, the study was terminated early because of disruption in study medication supply. At that point, 125 patients had been randomized (placebo: 63; tadalafil: 62,). Combined primary end-point events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil (hazard ratio, 1.02 [95% CI, 0.52-2.01]; P =0.95). There was a possible signal of higher all-cause mortality in the tadalafil group (hazard ratio, 5.10 [95% CI, 1.10-23.69]; P =0.04). No significant between-group differences were observed in other secondary end points. Serious adverse events occurred in 29 participants (48%) in the tadalafil group and 35 (56%) in the placebo group., Conclusions: The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, with potential safety concerns and no observed benefits in primary and secondary end points., Registration: URL: https://www.clinicaltrialsregister.eu/; Unique identifier: 2017-003688-37. URL: https://drks.de; Unique identifier: DRKS -DRKS00014595., Competing Interests: Dr Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, AOP Health, Bayer, Ferrer, GossamerBio, Janssen, Keros, and MSD. Max Wissmüller has received lecture fees from Janssen. Hanno Leuchte has received fees for consultations and/or lectures from Acceleron, Jansse-Cilag, Bayer, Boehringer-Ingelheim, Ferrer, MSD, and Pfizer. Michael Halank has received fees for lectures and/or consultations from AstraZeneca, Janssen-Cilag, and MSD. In addition, he has received support for attending meetings and/or travel from AOP Health and Janssen-Cilag. Hans-Jürgen Seyfarth has received fees for lectures and/or consultations from Janssen-Cilag and MSD. Stephan Baldus has received fees for lectures and/or consultations from Abbott, Edwards, Jenavalve, AstraZeneca, Bayer, Daiicho Sankyo, and Amgen, as well as research grants from Abbott, AstraZeneca, and Daiichi Sankyo. Johann Bauersachs has received fees for lectures and/or consultations from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cardior, Corvia, CVRx, Edwards, Norgine, Novartis, Pfizer, Roche and Vifor. In addition, institutional grants have been provided by Abiomed, CVRx, Norgine, Roche, and Zoll. He holds patents for microRNA and downstream targets for diagnostics and therapeutic purposes (PCT/EP2007/008772 and PCT/EP2009/051986). Michael Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project No. 322900939) and reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, ReCor, Servier and Vifor. Hossein-Ardeschir Ghofrani has received honoraria for consultations and/or speaking at conferences from Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Lilly, and Novartis. He is member of the Advisory Board for Acceleron, Bayer HealthCare AG, Pfizer, GSK, Actelion, Lilly, Merck, Encysive, and Ergonex. He has also received governmental grants from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, State Government of Hessen, and the German Ministry for Education and Research. Stavros Konstantinides reports personal lecture/advisory fees and research grants to his institution from Bayer AG, Boston Scientific, Daiichi-Sankyo, LumiraDx, and Penumbra, as well as personal lecture/advisory fees from MSD and Pfizer–Bristol-Myers Squibb. Karen M. Olsson has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, Ferrer, GSK, Janssen, MSD, Pfizer, and United Therapeutics. Rolf Wachter has received fees for lectures and/or consultation from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Medtronic, Novartis, Pfizer, Pharmacosmo, Sciarc, Servier, and Vifor. His institution has received research grants from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Union, and Medtronic. Carolyn S.P. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from NovoNordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corp, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and non–executive director of Us2.ai. Stephan Rosenkranz has received fees for lectures and/or consultations from Abbott, Acceleron, Actelion, Aerovate, AOP, AstraZeneca, Bayer, Boehringer-Ingelheim, Edwards, Ferrer, Gossamer, Janssen, MSD, and United Therapeutics. His institution has received research grants from Actelion, AstraZeneca, Bayer, Janssen, and Lempo. The other authors report no conflicts.

Aims: According to current guidelines, initial monotherapy should be considered for pulmonary arterial hypertension (PAH) patients with cardiopulmonary comorbidities. This analysis of combined data from the TRITON and REPAIR clinical trials, assesses efficacy and safety of initial double combination therapy in patients without vs. with 1-2 cardiac comorbidities., Methods and Results: Data were combined for patients from TRITON (NCT02558231) and REPAIR (NCT02310672) on initial macitentan and tadalafil double combination therapy (overall set, n = 148) and two subgroups defined as patients without cardiac comorbidities (n = 62) and those with 1-2 cardiac comorbidities (n = 78). Patients with ≥3 comorbidities were excluded from these studies. For the overall set, the median (Q1-Q3) duration of combined macitentan and tadalafil exposure was 513.0 (364.0-778.0) days, and was similar between subgroups. Change from baseline to Week 26 for pulmonary vascular resistance was -55% and -50% for patients without and with 1-2 cardiac comorbidities, respectively; marked improvements in other hemodynamic and functional parameters were also observed, although functional parameters improved to a lesser extent in patients with comorbidities. At Week 26, the majority of patients had improved PAH risk status, according to the non-invasive four-strata and REVEAL Lite 2.0 methods. The safety profile of initial macitentan plus tadalafil combination therapy was consistent with the known profiles of the two drugs, and similar between the subgroups., Conclusions: Initial double combination therapy with macitentan plus tadalafil is efficacious in patients with PAH with 1-2 cardiac comorbidities and those without, with similar safety and tolerability profiles between the two groups., (© 2024 Actelion Pharmaceuticals Ltd. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH., Methods: This randomized, double-blind study compared sildenafil at doses of 5, 20, or 80 mg TID in adults with PAH. The primary objective was noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. Secondary end points included time to clinical worsening and change in 6-minute walk distance at 6 months. Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population., Results: The study was halted after the first interim analysis, demonstrating noninferiority for 80 mg of sildenafil versus 5 mg. Of 385 patients enrolled across all dose groups, 78 died. The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; P <0.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg. Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; P <0.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; P =0.0201). No significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance. Adverse event-related drug discontinuations were numerically higher with 80 mg of sildenafil., Conclusions: Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg. On the basis of these findings, the Food and Drug Administration recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID as the recommended dose, and now allows dose titration up to 80 mg TID, if needed., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487., Competing Interests: Disclosures M.M.H. is a paid consultant and speaker of pharmaceutical companies including Actelion, Acceleron, AOP Health, Bayer, Ferrer, Gossamer, Janssen, Keros, and MSD. R.E. is a paid consultant for advisory boards and scientific lectures from Janssen, Boehringer Ingelheim, AOP, United Therapeutic, Novartis, AstraZeneca, and OMT. P.J. is a paid consultant and speaker for numerous pharmaceutical companies and has received financial grant for Janssen Pharmaceutical Companies of Johnson & Johnson, AOP Orphan, Bayer Healthcare, MSD, and Arena Pharmaceuticals Inc. Y.S. is an employee of NSC MD Strazhesko Institute of Cardiology, Clinical and Regenerative Medicine of the National AMS of Ukraine. A.S. is a paid consultant of pharmaceutical companies including Gossamer Bio, AOP Orphan, and Medison Pharma, and is paid as a speaker for KRKA, Altavant Sciences. C.B. is currently employee of Pfizer and hold stocks in Pfizer and Viatris. S. Hackley is a former employee of Pfizer and current employee of Viatris and hold stocks in Viatris. S.V. is an employee of MEDA Pharma GmbH & Co KG (A Viatris Company). P.A. hold shares of Pfizer. S. Haughie hold stocks in Viatris. T.H. is currently employee of Viatris and hold stocks of Viatris. R.J.O. is a principal investigator in studies and attends ad hoc advisory boards sponsored by Aerovate, Gossamer Bio, Janssen, Keros, Merck, and United Therapeutics. He is a paid speaker for Janssen and United Therapeutics.

Background: Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes., Methods: Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured., Results: Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival., Conclusions: Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response., Competing Interests: Disclosures Dr Gerhardt reports remuneration for lectures from Actelion, Bayer, Janssen, and MSD, and grants to the institution from Actelion, Bayer, and Janssen. E. Fiessler reports no disclosures. Dr Olsson reports fees for lectures or consultations from Acceleron, Actelion, Bayer, Janssen, United Therapeutics, MSD, GSK, and Pfizer. Dr Kayser reports no disclosures. Dr Kovacs reports personal fees for lectures or consultancy from Actelion, Bayer, GSK, MSD, Novartis, Pfizer, Chiesi, and Boehringer-Ingelheim. Dr Gall reports fees for lectures or consultancy from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Ghofrani reports personal fees and consultancy fees from Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer; other from Bellerophon Pulse Technologies; and consultancy fees from MSD. Dr Eslam reports no disclosures. Dr Lang reports remuneration for lectures or consultancy from Actelion, AOP Orphan, AstraZeneca, Bayer-Schering, Cordis, Daiichi-Sankyo, Ferrer, Neutrolis, Janssen, and United Therapeutics. N. Benjamin reports fees for lectures from Actelion, Bayer, MSD, and Janssen. Dr Grünig reports fees for lectures or consultations from Actelion, Bayer, GSK, Janssen, MSD, Pfizer, and United Therapeutics. Dr Halank reports remuneration for consultancy or lectures from Acceleron, Actelion, AstraZeneca, Bayer, BerlinChemie, GSK, Janssen, MSD, and Novartis. Dr Lange reports personal fees for lectures or consultancy from Acceleron Pharma, Actelion, Bayer, GSK, Janssen-Cilag, MSD, Pfizer, and United Therapeutics; and grants to the institution from Acceleron Pharma, Actelion, Bayer, Bellerophon, Gilead, Janssen-Cilag, Pfizer, and United Therapeutics. Dr Ulrich reports grants from Swiss National Science Foundation, Zurich Lung, Swiss Lung, and Orpha Swiss; and grants and personal fees from Actelion, Johnson & Johnson, and MSD. Dr Leuchte reports fees for lectures or consultancy from Actelion, Bayer, GSK, Merck, and Pfizer. Dr Held reports personal fees for lectures or consultancy from Actelion, AstraZeneca, Bayer, Berlin Chemie, Boehringer, GSK, Janssen, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Klose reports speaker or consultancy fees from Actelion, Bayer, Berlin Chemie, GSK, MSD, Novartis, Pfizer, and United Therapeutics. Dr Ewert reports lecture fees from Actelion, AstraZeneca, Bayer, and OMT; and industry-sponsored grants from Actelion and OMT. Dr Wilkens reports personal fees from Actelion, Bayer, Biotest, Boehringer, GSK, Pfizer, and Roche. Dr Pizarro reports honoraria for lectures from Actelion and Janssen. Dr Skowasch reports honoraria for lectures and consultancy from Actelion and Janssen. Dr Wissmüller reports remunerations for lectures from Janssen. Dr Hellmich reports no disclosures. Dr Olschewski reports remuneration for lectures or consultancy or grants to the institution from Actelion, Bayer, Belerophon, Boehringer, GSK, Inventiva, Janssen, Menarini, MSD, Novartis, Pfizer, and Roche. Dr Hoeper reports fees for consultations or lectures from Acceleron, Actelion, Bayer, Janssen, MSD, and Pfizer. Dr Rosenkranz reports remuneration for lectures or consultancy from Abbott, Acceleron, Actelion, Aerovate, Altavant, AOP, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Edwards, Ferrer, Gossamer, Janssen, MSD, OMT, Pfizer, United Therapeutics, and Vifor; and grants to the institution from Actelion, AstraZeneca, Bayer, and Janssen.

Objectives: Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH., Methods: We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes., Results: This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n = 390) were 85%, 59% and 42%; for SLE-PAH (n = 34) they were 97%, 77% and 61%; for MCTD-PAH (n = 33) they were 97%, 70% and 59%; for UCTD-PAH (n = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P = 0.001). In these patients, the survival estimates were significantly better with initial ERA-PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P = 0.016 and P = 0.012, respectively)., Conclusions: Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA-PDE5i combination therapy compared with initial monotherapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Purpose: Post-acute sequelae of COVID-19 (PASC) affect approximately 10% of convalescent patients. The spectrum of symptoms is broad and heterogeneous with fatigue being the most often reported sequela. Easily accessible blood biomarkers to determine PASC severity are lacking. Thus, our study aimed to correlate immune phenotypes with PASC across the severity spectrum of COVID-19., Methods: A total of 176 originally immunonaïve, convalescent COVID-19 patients from a prospective cohort during the first pandemic phase were stratified by initial disease severity and underwent clinical, psychosocial, and immune phenotyping around 10 weeks after first COVID-19 symptoms. COVID-19-associated fatigue dynamics were assessed and related to clinical and immune phenotypes., Results: Fatigue and severe fatigue were commonly reported irrespective of initial COVID-19 severity or organ-specific PASC. A clinically relevant increase in fatigue severity after COVID-19 was detected in all groups. Neutralizing antibody titers were higher in patients with severe acute disease, but no association was found between antibody titers and PASC. While absolute peripheral blood immune cell counts in originally immunonaïve PASC patients did not differ from unexposed controls, peripheral CD3 + CD4 + T cell counts were independently correlated with fatigue severity across all strata in multivariable analysis., Conclusions: Patients were at similar risk of self-reported PASC irrespective of initial disease severity. The independent correlation between fatigue severity and blood T cell phenotypes indicates a possible role of CD4 + T cells in the pathogenesis of post-COVID-19 fatigue, which might serve as a blood biomarker., (© 2023. The Author(s).)

AV-101 (imatinib) powder for inhalation, an investigational dry powder inhaled formulation of imatinib designed to target the underlying pathobiology of pulmonary arterial hypertension, was generally well tolerated in healthy adults in a phase 1 single and multiple ascending dose study. I nhaled I m atinib P ulmonary A rterial H ypertension C linical T rial (IMPAHCT; NCT05036135) is a phase 2b/3, randomized, double-blind, placebo-controlled, dose-ranging, and confirmatory study. IMPAHCT is designed to identify an optimal AV-101 dose (phase 2b primary endpoint: pulmonary vascular resistance) and assess the efficacy (phase 3 primary endpoint: 6-min walk distance), safety, and tolerability of AV-101 dose levels in subjects with pulmonary arterial hypertension using background therapies. The study has an operationally seamless, adaptive design allowing for continuous recruitment. It includes three parts; subjects enrolled in Part 1 (phase 2b dose-response portion) or Part 2 (phase 3 intermediate portion) will be randomized 1:1:1:1 to 10, 35, 70 mg AV-101, or placebo (twice daily), respectively. Subjects enrolled in Part 3 (phase 3 optimal dose portion) will be randomized 1:1 to the optimal dose of AV-101 and placebo (twice daily), respectively. All study parts include a screening period, a 24-week treatment period, and a 30-day safety follow-up period; the total duration is ∼32 weeks. Participation is possible in only one study part. IMPAHCT has the potential to advance therapies for patients with pulmonary arterial hypertension by assessing the efficacy and safety of a novel investigational drug-device combination (AV-101) using an improved study design that has the potential to save 6-12 months of development time. ClinicalTrials.gov Identifier: NCT05036135., Competing Interests: Hunter Gillies, Benjamin T. Dake, Jonathan Langley, Ralph W. Niven, and Xiaosha Zhang are employees of Aerovate Therapeutics Inc. Murali M. Chakinala received research grants/funding from Acceleron Pharma, Actelion, Gossamer Bio, Medtronic, Respira Therapeutics, and United Therapeutics Corporation; and served as a consultant for Actelion, Altavant Sciences Inc., Express Scripts Holding Company, Liquidia Technologies Inc., PhaseBio Pharmaceuticals, United Therapeutics Corporation, and WebMD LLC (Medscape). Jeremy P. Feldman received honoraria from Acceleron Pharma, Altavant Sciences, Bayer, Gilead Sciences, and United Therapeutics Corporation. Marius M. Hoeper received fees for lectures/consultations from Acceleron, Actelion, AOP Health, Bayer, Ferrer, Gossamer Bio, Janssen, Merck, and Pfizer. Marc Humbert received research grants/funding from Acceleron Pharma, Aerovate Therapeutics Inc., Altavant Sciences Inc., Bayer, Janssen Pharmaceuticals, Merck, Morphogen‐IX Limited, and United Therapeutics Corporation; and received honoraria from Acceleron Pharma, Actelion, Bayer, GSK, Merck, and United Therapeutics Corporation. Vallerie V. McLaughlin received research grants/funding from Aerovate Therapeutics Inc., Altavant Sciences, Gossamer Bio, Janssen Pharmaceuticals, Merck, and SoniVie; and served as a consultant for Aerami Therapeutics, Aerovate Therapeutics Inc., Altavant Sciences, Bayer, Caremark LLC, CorVista, Gossamer Bio, Janssen Pharmaceuticals, Merck, and United Therapeutics Corporation. Stephan Rosenkranz received fees for lectures/consultations from Abbott, Actelion, Acceleron, AstraZeneca, AOP, Bayer, Boehringer Ingelheim, Ferrer, Gossamer, Janssen Pharmaceuticals, MSD, UT, and Vifor; and received institutional research grants from AstraZeneca, Bayer, and Janssen Pharmaceuticals. Nicholas S. Hill served as a consultant for Acceleron/Merck, Aerovate Therapeutics Inc., Altavant Sciences, Gossamer Bio, Insmed, and United Therapeutics Corporation. Zhi‐Cheng Jing declares no conflict of interest., (© 2024 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

A minimal diffusion barrier is key to the pulmonary gas exchange. In alveolar capillary dysplasia (ACD), a rare genetically driven disease of early infancy, this crucial fibrovascular interface is compromised while the underlying pathophysiology is insufficiently understood. Recent in-depth analyses of vascular alterations in adult lung disease encouraged researchers to extend these studies to ACD and compare the changes of the microvasculature. Lung tissue samples of children with ACD (n = 12), adults with non-specific interstitial pneumonia (n = 12), and controls (n = 20) were studied using transmission electron microscopy, single-gene sequencing, immunostaining, exome sequencing, and broad transcriptome profiling. In ACD, pulmonary capillary basement membranes were hypertrophied, thickened, and multilamellated. Transcriptome profiling revealed increased CDH5, COL4A1, COL15A1, PTK2B, and FN1 and decreased VIT expression, confirmed by immunohistochemistry. In contrast, non-specific interstitial pneumonia samples showed a regular basement membrane architecture with preserved VIT expression but also increased COL15A1 + vessels. This study provides insight into the ultrastructure and pathophysiology of ACD. The lack of normally developed lung capillaries appeared to cause a replacement by COL15A1 + vessels, a mechanism recently described in interstitial lung disease. The VIT loss and FN1 overexpression might contribute to the unique appearance of basement membranes in ACD. Future studies are needed to explore the therapeutic potential of down-regulating the expression of FN1 and balancing VIT deficiency., Competing Interests: Disclosure Statement J.C.S. received fees for lectures from Boehringer Ingelheim and Kinevant, all outside the present study. T.W. declares funding by the German Ministry of Research and Education. M.M.H. received fees for lectures and consultations from Acceleron, Actelion, AOP, Bayer, Janssen, MSD, and Pfizer, all outside the present study. J.F. received personal fees/speaker honoraria from AstraZeneca, outside the submitted work. M.G. received fees for lectures from Boehringer Ingelheim, participates in an adjudication board in a nintedanib clinical trial, and received a research grant from Boehringer Ingelheim. D.D.J. received fees for lectures from Boehringer Ingelheim and declares a research contract with Boehringer Ingelheim (contract number 43099358). All other authors declare no existing conflicts of interest., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Pulmonary arterial hypertension (PAH) is a rare, progressive disease associated with significant morbidity and mortality. The phase 3 STELLAR trial tested sotatercept plus background therapy (BGT) versus placebo plus BGT. BGT was comprised of mono-, double-, or triple-PAH targeted therapy. Building on STELLAR findings, we employed a population health model to assess the potential long-term clinical impact of sotatercept., Methods: Based on the well-established ESC/ERS 4-strata risk assessment approach, we developed a six-state Markov-type model (low risk, intermediate-low risk, intermediate-high risk, high risk, lung/heart-lung transplant, and death) to compare the clinical outcomes of sotatercept plus BGT versus BGT alone over a lifetime horizon. State-transition probabilities were obtained from STELLAR. Risk stratum-adjusted mortality and lung/heart-lung transplant probabilities were based on COMPERA PAH registry data, and the post-transplant mortality probability was obtained from existing literature. Model outcomes were discounted at 3% annually. Sensitivity analyses were conducted to examine model robustness., Results: In the base case, sotatercept plus BGT was associated with longer life expectancy from model baseline (16.5 vs 5.1 years) versus BGT alone, leading to 11.5 years gained per patient. Compared with BGT alone, sotatercept plus BGT was further associated with a gain in infused prostacyclin-free life years per patient, along with 683 PAH hospitalizations and 4 lung/heart-lung transplant avoided per 1000 patients., Conclusions: According to this model, adding sotatercept to BGT increased life expectancy by roughly threefold among patients with PAH while reducing utilization of infused prostacyclin, PAH hospitalizations, and lung/heart-lung transplants. Real-world data are needed to confirm these findings., Trial Registration: ClinicalTrials.gov identifier, NCT04576988 (STELLAR)., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates.)