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Rationale: MicroRNAs (miRNAs or miRs) are implicated in the pathogenesis of various cardiovascular diseases, including pulmonary arterial hypertension (PAH).Objectives: We sought to measure changes in plasma levels of miRNAs in patients with PAH and relate them to the severity of the disease.Methods: A microarray screen was performed on total plasma RNA from eight patients with PAH and eight healthy control subjects. Quantitative polymerase chain reaction confirmed reduced miR-150 concentrations and was then used to measure miR-150 levels in (1) two separate cohorts of patients with PAH, from London (n = 145) and Sheffield (n = 30), respectively; (2) circulating microvesicles and blood cells; and (3) lungs from a monocrotaline rat model.Measurements and Main Results: Fifty-eight miRNAs showed differences in plasma concentration and miR-150 the largest down-regulation in PAH. Receiver-operator-characteristic analysis showed both raw and normalized plasma miR-150 levels correlated with 2-year survival (P < 0.01) in patients with PAH. Cox regression analysis confirmed miR-150 levels as a significant predictor of survival. Age, baseline cardiac index, World Health Organization functional class, 6-minute walk distance, disease duration, and red cell distribution width also predicted survival. Entering these covariates in a multivariable model verified plasma miR-150 levels as an independent predictor of survival in PAH (hazard ratio, 0.533; P = 0.010). miR-150 levels also predicted survival in a second, independent PAH cohort. miR-150 levels were significantly reduced in circulating microvesicles from patients with PAH and the lungs of the monocrotaline rat.Conclusions: Reduced circulating miR-150 levels are associated with poor survival in PAH. [ABSTRACT FROM AUTHOR]

Rationale: Incident pulmonary arterial hypertension was underrepresented in most pulmonary hypertension registries and may have a different disease profile to prevalent disease. Objectives: To determine the characteristics and outcome of a purely incident, treatment-naive cohort of idiopathic, heritable, and anorexigen-associated pulmonary arterial hypertension and to determine the changes in presentations and survival over the past decade in the United Kingdom and Ireland. Methods: All consecutive newly diagnosed patients from 2001 to 2009 were identified prospectively. Measurements and Main Results: A total of 482 patients (93% idiopathic, 5% heritable, and 2% anorexigen-associated pulmonary arterial hypertension) were diagnosed, giving rise to an estimated incidence of 1.1 cases per million per year and prevalence of 6.6 cases per million in 2009. Younger patients (age ≤ 50 yrs) had shorter duration of symptoms, fewer comorbidities, better functional and exercise capacity, higher percent diffusing capacity of carbon monoxide, more severe hemodynamic impairment, but better survival compared with older patients. In comparison with the earlier cohorts, patients diagnosed in 2007-2009 were older, more obese, had lower percent diffusing capacity of carbon monoxide,(,) and more comorbidities, but better survival. Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) equation, REVEAL risk score, and Pulmonary Hypertension Connection Registry survival equation accurately predicted survival of our incident cohort at 1 year. Conclusions: This study highlights the influence of age on phenotypes of incident pulmonary arterial hypertension and has shown the changes in demographics and epidemiology over the past decade in a national setting. The results suggest that there may be two subtypes of patients: the younger subtype with more severe hemodynamic impairment but better survival, compared with the older subtype who has more comorbidities. [ABSTRACT FROM AUTHOR]

Rationale: Severe pulmonary arterial hypertension (PAH) is characterized by the formation of plexiform lesions and concentric intimal fibrosis in small pulmonary arteries. The origin of cells contributing to these vascular lesions is uncertain. Endogenous endothelial progenitor cells are potential contributors to this process.Objectives: To determine whether progenitors are involved in the pathobiology of PAH.Methods: We performed immunohistochemistry to determine the expression of progenitor cell markers (CD133 and c-Kit) and the major homing signal pathway stromal cell-derived factor-1 and its chemokine receptor (CXCR4) in lung tissue from patients with idiopathic PAH, familial PAH, and PAH associated with congenital heart disease. Two separate flow cytometric methods were employed to determine peripheral blood circulating numbers of angiogenic progenitors. Late-outgrowth progenitor cells were expanded ex vivo from the peripheral blood of patients with mutations in the gene encoding bone morphogenetic protein receptor type II (BMPRII), and functional assays of migration, proliferation, and angiogenesis were undertaken. measurements and main results: There was a striking up-regulation of progenitor cell markers in remodeled arteries from all patients with PAH, specifically in plexiform lesions. These lesions also displayed increased stromal cell-derived factor-1 expression. Circulating angiogenic progenitor numbers in patients with PAH were increased compared with control subjects and functional studies of late-outgrowth progenitor cells from patients with PAH with BMPRII mutations revealed a hyperproliferative phenotype with impaired ability to form vascular networks.Conclusions: These findings provide evidence of the involvement of progenitor cells in the vascular remodeling associated with PAH. Dysfunction of circulating progenitors in PAH may contribute to this process. [ABSTRACT FROM AUTHOR]

Care of pulmonary hypertension (PH) patients in special situations requires insightful knowledge of the pathophysiology of the cardiopulmonary system and close interaction with different specialists, depending on the situation. The role of this task force was to gather knowledge about five conditions that PH patients may be faced with. These conditions are 1) perioperative care; 2) management of pregnancy; 3) medication adherence; 4) palliative care; and 5) the influence of climate on PH. Many of these aspects have not been covered by previous World Symposia on Pulmonary Hypertension. All of the above conditions are highly affected by psychological, geographical and socioeconomic factors, and share the need for adequate healthcare provision. The task force identified significant gaps in information and research in these areas. The current recommendations are based on detailed literature search and expert opinion. The task force calls for further studies and research to better understand and address the special circumstances that PH patients may encounter., Competing Interests: Conflict of interest: I.R. Preston reports grants from Janssen, Merck, United Therapeutics and Respira, consultancy fees from Janssen, Merck, United Therapeutics, Liquidia, Gossamer and Aerovate, payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen and United Therapeutics, and support for attending meetings from Janssen and United Therapeutics. L.S. Howard reports grants from MSD, consultancy fees from Ferrer, Janssen and Morphic, payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen, MSD, Aerovate and Ferrer, payment for expert testimony from Janssen, support for attending meetings from Janssen and Gossamer Bio, participation on a data safety monitoring board or advisory board with MSD, Janssen, Gossamer Bio, Apollo Therapeutics and Altavant, and stock (or stock options) with Circular, ATXA Therapeutics, iOWNA, Calibre Biometrics and OneWelbeck Clinic. D. Langleben reports grants from Acceleron/Merck, Aerovate and Janssen, consultancy fees from Merck, Janssen, Actelion, Enzyvant, PhaseBio, Gossamer Bio and Bayer, payment or honoraria for lectures, presentations, manuscript writing or educational events from Merck, Janssen and Bayer, support for attending meetings from Acceleron/Merck, Janssen, Enzyvant and Gossamer Bio, and participation on a data safety monitoring board or advisory board with Phase Bio, Merck, Janssen, Actelion, Enzyvant and Gossamer Bio. M. Lichtblau reports payment or honoraria for lectures, presentations, manuscript writing or educational events from, and participation on a data safety monitoring board or advisory board with MSD, and support for attending meetings from MSD and Janssen. T. Pulido reports grants from Aerovate, Bayer, Janssen, MSD, Pfizer and United Therapeutics, consultancy fees from Bayer, MSD, Gossamer Bio, Aerovate and Ferrer, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Janssen, MSN Labs, Tuteur and Ferrer, support for attending meetings from Bayer, Janssen and Ferrer, participation on a data safety monitoring board or advisory board with Janssen, MSD, Bayer and Gossamer Bio, and is consultant and part of the advisory board for the Mexican Society of Pulmonary Arterial Hypertension. R. Souza reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer and Janssen, and participation on a data safety monitoring board or advisory board with Janssen, Bayer and MSD. K.M. Olsson reports grants from Acceleron, MSD and Janssen, consultancy fees from Acceleron, Actelion, Janssen, Ferrer, Merck, AOP Health, Gossamer and Bayer, payment or honoraria for lectures, presentations, manuscript writing or educational events from Acceleron, Actelion, AOP Health, Janssen, Bayer, MSD, Ferrer and Gossamer, and support for attending meetings from Acceleron/MSD and Janssen/Actelion., (Copyright ©The authors 2024.)

Background: Pulmonary embolism (PE) is a well-recognised complication of coronavirus disease 2019 (COVID-19) infection, and chronic thromboembolic pulmonary disease with and without pulmonary hypertension (CTEPD/CTEPH) are potential life-limiting consequences. At present the burden of CTEPD/CTEPH is unclear and optimal and cost-effective screening strategies yet to be established., Methods: We evaluated the CTEPD/CTEPH referral rate to the UK national multidisciplinary team (MDT) during the 2017-2022 period to establish the national incidence of CTEPD/CTEPH potentially attributable to COVID-19-associated PE with historical comparator years. All individual cases of suspected CTEPH were reviewed by the MDT for evidence of associated COVID-19. In a separate multicentre cohort, the risk of developing CTEPH following hospitalisation with COVID-19 was calculated using simple clinical parameters at a median of 5 months post-hospital discharge according to existing risk scores using symptoms, ECG and N-terminal pro-brain natriuretic peptide., Results: By the second year of the pandemic, CTEPH diagnoses had returned to the pre-pandemic baseline (23.1 versus 27.8 cases per month; p=0.252). Of 334 confirmed CTEPD/CTEPH cases, four (1.2%) patients were identified to have CTEPH potentially associated with COVID-19 PE, and a further three (0.9%) CTEPD without PH. Of 1094 patients (mean age 58 years, 60.4% male) hospitalised with COVID-19 screened across the UK, 11 (1.0%) were at high risk of CTEPH at follow-up, none of whom had a diagnosis of CTEPH made at the national MDT., Conclusion: A priori risk of developing CTEPH following COVID-19-related hospitalisation is low. Simple risk scoring is a potentially effective way of screening patients for further investigation., Competing Interests: Conflict of interest: J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell; received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon; and is Chief Editor of the European Respiratory Journal. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: The incidence of Pulmonary Hypertension (PH) and Pulmonary Arterial Hypertension (PAH) is believed to be on the rise and is associated with poor outcomes., Methods: We extracted age-standardized mortality rates (ASMRs) for decedents ≥ 18 years of age from the World Health Organization Mortality Database, using International Classification of Diseases 10th edition codes for PH and PAH, covering the period from 2001 to 2019. The UK and European Union countries with at least 1,000,000 inhabitants and at least 75% of available data points over the study period were included., Results: Between 2001 and 2019, in countries with available data, the median ASMR for PH increased by + 1.19 per 1,000,000 (+ 22.51%) in females and + 0.36 per 1,000,000 (+ 6.06%) in males. Out of 19 countries, 13 demonstrate an increase in female PH ASMR, and 12 reported an increase in male PH ASMR. In contrast, median PAH ASMR decreased by -0.29 per 1,000,000 (-28.74%) in females and remained relatively unchanged in males, with a minor increase of + 0.01 per 1,000,000 (+ 1.07%). Notably, there was significant inter-country heterogeneity, with countries such as Hungary, Romania, and Poland displaying results incongruous with the rest of Europe., Conclusions: While publicly available mortality statistics for PH may be unreliable, these data suggest an overall increase in mortality across Europe from 2001 to 2019. However, mortality from PAH has shown a decrease in females and a modest increase in males. This underscores the urgent need for robust and high-quality mortality reporting, including international registries, for both PH and PAH., (© 2024. The Author(s).)

Background: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy., Methods: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm 5 and ≥800 dyne·s/cm 5 ). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm 5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed., Findings: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm 5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm 5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm 5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group., Interpretation: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH., Funding: Gossamer Bio., Competing Interests: Declaration of interests ARH reports having received consulting fees from United Therapeutics, Tenax Therapeutics, Merck, and Janssen; having served as an advisory committee member for Gossamer Bio; and having held stock from Tenax Therapeutics. CT, DM, EE, EP, J-MB, LSZ, MC, RA, RFR, and RO report stocks or stock options from Gossamer Bio; and employment at Gossamer Bio. LSZ also reported patents related to seralutinib (assigned to Gossamer Bio or Pulmokine); stocks or stock options from Pulmokine. RFR also reported previous consulting fees from Gossamer Bio. H-AG reports having received consulting fees from Gossamer Bio, Aerovate, Altavant, Bayer AG, Attgeno, Janssen and Actelion, MSD and Acceleron, and Pfizer; payment or honoraria for lectures, presentations, speaker bureaus, or educational events from Bayer AG, Janssen and Actelion, and MSD and Acceleron; participated as an advisory committee member for Aerovate, Altavant, Bayer AG, Attgeno, Janssen and Actelion, MSD and Acceleron, and Pfizer; and as a member of a data and safety monitoring board for Insmed. J-LV reports having received consulting fees from Gossamer Bio, ShouTi, Janssen, Enzyvant, Bayer HealthCare, Merck, Liquidia, Aerami, and Insmed; received payment or honoraria (payment to their institution) for lectures, presentations, or educational events from Janssen, Merck, Novartis, and Boehringer Ingelheim; received payment for expert testimony from Actelion Pharmaceuticals; received either support for attending meetings or travel (payment to their institution) from Merck; participated on a data safety monitoring board (payment to their institution) from Janssen, GSK, and Moderna; membership on steering committees for Gossamer Bio, Insmed, Merck, and United Therapeutics. KMC reports having received grants or contracts (payment made to their institution) for clinical studies overseen by her from Gossamer Bio, Janssen, United Therapeutics, Merck, Acceleron, and Altavant; received consulting fees from Acceleron; received fees for participating on an advisory board for Merck; received fees for work as an advisory committee member for Gossamer Bio; received fees for work as a steering committee member for Janssen; received fees for work on an adjudication committee for Arena and United Therapeutics; and received fees for an editorial role with the American Heart Association. LSH reported having received payment or honoraria for speaker bureau membership from Janssen; participated as an advisory board member for Janssen, MSD, Altavant, and United Therapeutics, and as an advisory committee member for Gossamer Bio; and having stock or stock options at ATXA Therapeutics, iOWNA, and Circular. OS reports having received grants or contracts for research (payment made to their institution) from Janssen, MSD, and AOP Orphan; payment or honoraria for lectures or an educational event from AOP Orphan, Ferrer, Janssen, and MSD; support for attending meetings or travel from MSD and Janssen; and participated on an advisory committee for Gossamer Bio, AOP Orphan, Enzyvant, Ferrer, Janssen, and MSD. PES reports having received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, MSD, Ferrer, and AOT; support for either attending meetings or travel from Janssen and MSD; participated in a data safety monitoring board or advisory board for Janssen, MSD, Ferrer, Gossamer Bio, and AOT; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Gossamer Bio. RLB reports having received consulting fees from Merck, United Therapeutics, KEROS, Aerovate, Insmed, and Cereno; served as an advisory committee member for Gossamer Bio; served as an advisory board member for Altavant, Merck, Janssen, and Insmed; served on a data safety monitoring board for Janssen; and served on a scientific advisory board for Cereno. RLZ reports having received consulting fees from Johnson & Johnson, United Therapeutics, Bayer, and Alnylam. RNC reports having received consulting fees from Gossamer Bio, Janssen, Bayer, United Therapeutics, and Third Pole; payment or honoraria for lectures from Janssen and Bayer; and participated on an advisory committee for Gossamer Bio, Janssen, and Bayer. RPF reports having royalties or licenses from UpToDate; receiving consulting fees from Janssen and Liquidia; participated on a data safety monitoring board or advisory board from Gossamer Bio (as an advisory committee member); participated on an advisory board for Janssen, Liquidia, Tenax Therapeutics, ShouTi, Insmed, and Merck; and participated on a data safety monitoring board for Aerovate. RTZ reports having received grants or contracts for industry-supported research from United Therapeutics, Janssen, Tenax Therapeutics, and Gossamer Bio; consulting fees from Janssen, Vivus, Morphogen-IX, Merck, and Gossamer Bio; and stock or stock options from Selten. SS reports having received a research grant from United Therapeutics; speaker honoraria (received by his institute) from Janssen and United Therapeutics; served as an advisor to Janssen, Bayer, United Therapeutics, Gossamer Bio, Altavant Sciences, and Merck; served as a steering committee member for Bayer, Keros, and Liquidia Technologies; and served as a data safety monitoring board committee member for the National Institutes of Health K23 grant. VVM reports having received grant support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovie; consulting fees from Aerami, Aerovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex; and participated as an advisory committee member for Gossamer Bio. All authors report receiving medical writing and editorial support for the present manuscript funded by Gossamer Bio., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar., Methods: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm 5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292., Findings: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 71·5% of baseline in the macitentan group and to 87·6% in the placebo group (geometric means ratio 0·81, 95% CI 0·70-0·95, p=0·0098). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%])., Interpretation: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated., Funding: Actelion Pharmaceuticals Ltd., Competing Interests: Declaration of interests H-AG has received fees for serving as a board member for AbbVie, Bellerophon Pulse Technologies, Medscape, OMT, UCB Celltech, and Web MD Global; consultancy fees and fees for serving on a steering committee for Actelion Pharmaceuticals, Bayer, Gilead Sciences, GlaxoSmithKline, Merck, Novartis, and Pfizer; lecture fees from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Merck, Novartis, and Pfizer; and grant support from Actelion Pharmaceuticals, Bayer, Novartis, and Pfizer. GS has received consultancy fees, lecture fees and travel support from Actelion Pharmaceuticals, Bayer, Merck, GlaxoSmithKline, and Pfizer; and grant support and fees for serving on a steering committee from Actelion Pharmaceuticals and Bayer. AMD’A has received fees for organising Masters-level courses, lecture fees and writing assistance from Bayer and Merck; and fees for serving on steering committees from Actelion Pharmaceuticals. PF has received fees for serving on an adjudication committee for Actelion Pharmaceuticals. LSH has received consultancy fees from Endotronix; fees for serving on steering committees from Actelion Pharmaceuticals, Bristol-Myers Squibb, and BTG plc; lecture fees, fees for serving on advisory boards, and travel support from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, and Merck; grant support from Bayer; and departmental funding from Actelion Pharmaceuticals. XJ has received fees for serving on an adjudication committee for Actelion Pharmaceuticals; grant support from Actelion Pharmaceuticals and GlaxoSmithKline; and personal fees from Actelion Pharmaceuticals, GlaxoSmithKline, and Merck. DPJ has received fees for serving on a steering committee for Actelion Pharmaceuticals and lecture fees from Bayer. Z-CJ has received consultancy fees, lecture fees and fees for serving on a steering committee from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Lee's Pharmaceuticals, and Pfizer; fees for serving on an adjudication committee from Actelion Pharmaceuticals; and grant support from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Pfizer, The National Science Fund for Distinguished Young Scholars (81425002), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002), and The National Key Research and Development Program of China (No. 2016YFC0901502). MMM has received fees for serving on an adjudication committee for Actelion Pharmaceuticals and consultancy fees from Bayer. NM is an employee of Actelion Pharmaceuticals. EM has received consultancy fees from Actelion Pharmaceuticals, Bayer, Merck, and GlaxoSmithKline; lecture fees from Actelion Pharmaceuticals, Bayer, Merck, Pfizer, and GlaxoSmithKline; and fees for serving on a steering committee for Actelion Pharmaceuticals. KP and DR are employees of and hold stock in Actelion Pharmaceuticals. NHK has received consultancy fees from Actelion Pharmaceuticals, Arena, Bayer, Merck, and SteadyMed; lecture fees from Actelion Pharmaceuticals and Bayer; fees for serving on a steering committee for Actelion Pharmaceuticals; and grant support from Bellerophon, Eiger, Gilead, Lung Biotechnology, and Sonivie., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood 1 . Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials., (© 2024. The Author(s).)

Background: Long-term changes in exercise capacity and cardiopulmonary hemodynamics after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) have been poorly described., Methods: We analyzed the data from 2 prospective surgical CTEPH cohorts in Hammersmith Hospital, London, and Amsterdam UMC. A structured multimodal follow-up was adopted, consisting of right heart catheterization, cardiac magnetic resonance imaging, and cardiopulmonary exercise testing before and after PEA. Preoperative predictors of residual pulmonary hypertension (PH; mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance ≥2 WU) and long-term exercise intolerance (VO 2 max <80%) at 18 months were analyzed., Results: A total of 118 patients (61 from London and 57 from Amsterdam) were included in the analysis. Both cohorts displayed a significant improvement of pulmonary hemodynamics, right ventricular (RV) function, and exercise capacity 6 months after PEA. Between 6 and 18 months after PEA, there were no further improvements in hemodynamics and RV function, but the proportion of patients with impaired exercise capacity was high and slightly increased over time (52%-59% from 6 to 18 months). Long-term exercise intolerance was common and associated with preoperative diffusion capacity for carbon monoxide (DLCO), preoperative mixed venous oxygen saturation, and postoperative PH and right ventricular ejection fraction (RVEF). Clinically significant RV deterioration (RVEF decline >3%; 5 [9%] of 57 patients) and recurrent PH (5 [14%] of 36 patients) rarely occurred beyond 6 months after PEA. Age and preoperative DLCO were predictors of residual PH post-PEA., Conclusions: Restoration in exercise tolerance, cardiopulmonary hemodynamics, and RV function occurs within 6 months. No substantial changes occurred between 6 and 18 months after PEA in the Amsterdam cohort. Nevertheless, long-term exercise intolerance is common and associated with postoperative RV function., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls. Three loci, at Cathepsin Z (CTSZ, cg04917472), Conserved oligomeric Golgi complex 6 (COG6, cg27396197), and Zinc Finger Protein 678 (ZNF678, cg03144189), reached epigenome-wide significance (p < 10 -7 ) and are hypermethylated in PAH, including in individuals with PAH at 1-year follow-up. Of 16 established PAH genes, only cg10976975 in BMP10 shows hypermethylation in PAH. Hypermethylation at CTSZ is associated with decreased blood cathepsin Z mRNA levels. Knockdown of CTSZ expression in human pulmonary artery endothelial cells increases caspase-3/7 activity (p < 10 -4 ). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ, encoding protease cathepsin Z., (© 2024. The Author(s).)

Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea., Methods: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2-7 months after hospital discharge and a later time point 10-14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107)., Findings: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4-6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5-8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (-19%; 95% CI -20 to -16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18-39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27-41% of this effect., Interpretation: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition., Funding: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council., Competing Interests: Declaration of interests IDS declares a statistical editor honoraria role with Thorax. TP declares support from the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (BRC) to complete the work. ALH declares an editor-in-chief role for Computer Physics Communications. RA declares speaker fees and travel support from Boehringer Ingelheim. CEB declares their institute was awarded a grant from the UK Research and Innovation (UKRI)/NIHR and institutional support from NIHR Nottingham BRC to complete this work; the author reports grants from Nottingham Hospitals Charity and Nottingham University Hospitals Research and Innovation Department. TC declares support from the NIHR South London and Maudsley NHS Foundation Trust, King's College London BRC to complete the work; the author reports grants from Guy's and St Thomas' Charity, NIHR, and UKRI; the author has published self-help books on chronic fatigue for which she receives royalties; the author has received ad-hoc payments for workshops carried out in long-term conditions; the author declares travel and accommodation support; the author is part of the scientific committee of the British Association for Behavioural and Cognitive Psychotherapies (BABCP) and she is on the expert advisory panel for COVID-19 Rapid Guidelines. JDC declares grants from AstraZeneca, Novartis, Boehringer Ingelheim, Genentech, Gilead Sciences, Insmed, GlaxoSmithKline, and Grifols; the author reports consulting fees from AstraZeneca, Insmed, Boehringer Ingelheim, Janssen, Antabio, Chiesi, Novartis, Pfizer, Zambon, GlaxoSmithKline, and Grifols. GD declares support from the NIHR Imperial BRC, Royal Brompton and Harefield NGS Foundation Trust, Royal Brompton & Harefield Hospitals Charity, Imperial College Healthcare NHS Trust, and the Medical Research Council (MRC) to complete this work; the author reports grants from Genentech, AstraZeneca, British Lung Foundation (BLF) Early Cohort, GlaxoSmithKline, Novartis, Chiesi, and Boehringer Ingelheim; the author has a published chapter in a textbook for which he receives payment; the author declares a role in the advisory boards for AstraZeneca and Novartis and as honorarium as deputy editor of the American Journal of Respiratory and Critical Care Medicine (AJRCCM). L-PH declares grants from NIHR Oxford BRC. MGJ declares grants from the Royal Society, MRC, BLF, Boehringer Ingelheim, and the Asthma, Allergy and Inflammatory Research Charity. BR declares support from the British Heart Foundation (BHF) Oxford Centre of Research Excellence (CRE) to complete this work. SLR-J declares support for her institute from UKRI to complete the work; the author reports grants from UKRI, The European and Developing Countries Clinical Trials Partnership (EDCTP), MRC, Rosetrees Trust, and the Global Challenges Research Fund (GCRF); the author reports an honorarium for chapter contribution from the Federation of European Academies of Medicine; the author is Data and Safety Monitoring Board (DSMB) Chair for a Bexsero trial funded by Wellcome Trust; the author declares an editor role for AIDS journal. AVR declares support from NIHR Leicester BRC to complete the work. MS declares support for his institute from MRC/Department of Health and Social Care (DHSC) to complete the work. ASi declares support for her institute from UKRI/NIHR to complete the work. DGW declares an advanced Fellowship grant from NIHR; the author receives an honorarium from bioMérieux to present. TY declares support from the NIHR Leicester BRC to complete the work. RGJ declares grants from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, Nordic Biosciences, RedX, Pliant; the author received consulting fees from AstraZeneca, Brainomix, Bristol Myers Squibb, Chiesi, Cohbar, Daewoong, GlaxoSmithKline, Veracyte, Resolution Therapeutics, and Pliant; the author has received payments from Boehringer Ingelheim, Chiesi, Roche, patientMpower, and AstraZeneca; the author was paid for expert testimony by Pinsent Masons LLP; the author has participated on a DSMB for Boehringer Ingelheim, Galapagos, and Vicore; the author has held a leadership role at NuMedii and is President of Action for Pulmonary Fibrosis. SJS declares grants from NIHR, Wellcome Doctoral Training Programme (DTP), the Human Tissue Authority, NIHR DHSC/UKRI COVID-19 Rapid Response Initiative, NIHR Global Research Group, Actegy Limited, and as an NIHR Senior Investigator; the author has presented for GlaxoSmithKline, Ministry of Justice, CIPLA, and Sherbourne Gibbs; the author is on the National Institute for Health and Care Excellence (NICE) Expert Advisor Panel for Long COVID and was on the Wales Long COVID Advisory Board; the author is the American Thoracic Society (ATS) Pulmonary Rehabilitation Assembly Chair, Clinical Lead Royal Society of Physicians (RSP) Pulmonary Rehabilitation Accreditation Scheme, and Clinical Lead Nation Asthma and COPD Audit Programme (NACAP) for Pulmonary Rehabilitation. WD-CM declares grants for his institution from NIHR, National Health Service (NHS) Accelerated Access Collaborative, and BLF; the author is the honorary President of the Association for Respiratory Technology and Physiology but receives no payment. CEBr declares support from UKRI/DHSC and NIHR Leicester BRC to complete the work; the author reports grants from GlaxoSmithKline, AstraZeneca, Sanofi, CI, Chiesi, Novartis, Roche, Genentech, Mologic, and 4DPharma; the author received consulting fees paid to his institution from GlaxoSmithKline, AstraZeneca, Sanofi, BI, Chiesi, Novartis, Roche, Genentech, Mologic, 4DPharma, and TEVA. LVW declares support from UKRI, GlaxoSmithKline/Asthma + Lung UK, and NIHR to complete this work; the author receives grants from Orion Pharma, GlaxoSmithKline, Genentech, and AstraZeneca; the author received consulting fees paid to her institution from Galapagos and Boehringer Ingelheim; the author received support for attending a meeting from Genentech. JCP received consulting fees from Istesso and The Limbic; the author participated on a DSMB for Vicore. AART declares a fellowship grant from BHF and a grant from NIHR to his institution; the author received an honorarium for lectures from Janssen-Cilag Ltd; the author received support for attending meetings from Janssen-Cilag Ltd. AH declares support from UKRI, NIHR, and NIHR Manchester BRC to complete the work; the author is Chair NIHR Translational Research Collaboration (unpaid). PLM declares a grant for his institution from AstraZeneca; the author received consulting fees from Hoffmann-La Roche, Boehringer Ingelheim, AstraZeneca, Trevi, and Qureight; the author received speaker fees from Boehringer Ingelheim and Hoffmann-La Roche. RAE declares support from UKRI/MRC to complete the work; the author reports a grant from NIHR/Wolfson Foundation; the author received consulting fees from AstraZeneca for Long COVID; the author received a speaker fee from Boehringer Ingelheim for a lecture on Long COVID; the author received support to attend BTS conference virtually from Chiesi; the author is the European Respiratory Society Group 01.02 Pulmonary Rehabilitation Secretary (unpaid). JFB declares support to his institute from an MRC Transition Fellowship, Asthma + Lung UK, NIHR Manchester BRC, and UKRI; the author reports grants paid to his institution from the Small Business Research Initiative Home Spirometer and the National Institute of Academic Anaesthesia; the author has received support for attending meetings from TEVA and Therakos; the author is a committee member of the Royal Society of Medicine (RSM). All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Data on right ventricular (RV) exercise adaptation following acute intermediate and high-risk pulmonary embolism (PE) remain limited. This study aimed to evaluate the symptom burden, RV functional recovery during exercise and cardiopulmonary exercise parameters in survivors of intermediate and high-risk acute PE., Methods: We prospectively recruited patients following acute intermediate and high-risk PE at four sites in Australia and UK. Study assessments included stress echocardiography, cardiopulmonary exercise testing (CPET) and ventilation-perfusion (VQ) scan at 3 months follow-up., Results: Thirty patients were recruited and 24 (median age: 55 years, IQR: 22) completed follow-up. Reduced peak oxygen consumption (VO 2 ) and workload was seen in 75.0% (n=18), with a persistent high symptom burden (mean PEmb-QoL Questionnaire 48.4±21.5 and emPHasis-10 score 22.4±8.8) reported at follow-up. All had improvement in RV-focused resting echocardiographic parameters. RV systolic dysfunction and RV to pulmonary artery (PA) uncoupling assessed by stress echocardiography was seen in 29.2% (n=7) patients and associated with increased ventilatory inefficiency (V̇E/V̇CO 2 slope 47.6 vs 32.4, p=0.03), peak exercise oxygen desaturation (93.2% vs 98.4%, p=0.01) and reduced peak oxygen pulse (p=0.036) compared with controls. Five out of seven patients with RV-PA uncoupling demonstrated persistent bilateral perfusion defects on VQ scintigraphy consistent with chronic thromboembolic pulmonary vascular disease., Conclusion: In our cohort, impaired RV adaptation on exercise was seen in almost one-third of patients. Combined stress echocardiography and CPET may enable more accurate phenotyping of patients with persistent symptoms following acute PE to allow timely detection of long-term complications., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers., Methods: Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues., Results: Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50-81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000-1.001]; P =0.037 and 1.263 [95% CI, 1.049-1.520]; P =0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001-1.005]; P =0.001 and 1.365 [95% CI, 1.185-1.573]; P <0.001, respectively) serum levels of activin A and FSTL3 were associated with transplant-free survival in a model adjusted for age and sex. Thresholds determined by receiver operating characteristic analyses were 393 pg/mL for activin A and 16.6 ng/mL for FSTL3. When adjusted with New York Heart Association functional class, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, the hazard ratios for transplant-free survival for baseline activin A <393 pg/mL and FSTL3 <16.6 ng/mL were, respectively, 0.14 (95% CI, 0.03-0.61; P =0.009) and 0.17 (95% CI, 0.06-0.45; P <0.001), and for follow-up measures, 0.23 (95% CI, 0.07-0.78; P =0.019) and 0.27 (95% CI, 0.09-0.78, P =0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin., Conclusions: These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH., Competing Interests: Disclosures An academic patent application for these biomarkers has been filed. During the past 3 years, Dr Humbert reports grants and personal fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX and United Therapeutics, outside the submitted work. Dr Guignabert reports grants from Acceleron, Corteria, Structure therapeutics (ex ShouTi), and Janssen and grants and personal fees from Merck, outside the submitted work. Dr Howard reports honoraria for scientific advisory board from Acceleron (not related to the work). Dr Sitbon reports honoraria for speaking, steering committees, scientific advisory boards from Janssen, Bayer, Merck, Gossamer Bio, Ferrer, United Therapeutics. Dr Savale reports personal fees from Actelion, personal fees from MSD, grants and personal fees from GSK, outside the submitted work.

Background: Persistence of respiratory symptoms, particularly breathlessness, after acute coronavirus disease 2019 (COVID-19) infection has emerged as a significant clinical problem. We aimed to characterise and identify risk factors for patients with persistent breathlessness following COVID-19 hospitalisation., Methods: PHOSP-COVID is a multicentre prospective cohort study of UK adults hospitalised for COVID-19. Clinical data were collected during hospitalisation and at a follow-up visit. Breathlessness was measured by a numeric rating scale of 0-10. We defined post-COVID-19 breathlessness as an increase in score of ≥1 compared to the pre-COVID-19 level. Multivariable logistic regression was used to identify risk factors and to develop a prediction model for post-COVID-19 breathlessness., Results: We included 1226 participants (37% female, median age 59 years, 22% mechanically ventilated). At a median 5 months after discharge, 50% reported post-COVID-19 breathlessness. Risk factors for post-COVID-19 breathlessness were socioeconomic deprivation (adjusted OR 1.67, 95% CI 1.14-2.44), pre-existing depression/anxiety (adjusted OR 1.58, 95% CI 1.06-2.35), female sex (adjusted OR 1.56, 95% CI 1.21-2.00) and admission duration (adjusted OR 1.01, 95% CI 1.00-1.02). Black ethnicity (adjusted OR 0.56, 95% CI 0.35-0.89) and older age groups (adjusted OR 0.31, 95% CI 0.14-0.66) were less likely to report post-COVID-19 breathlessness. Post-COVID-19 breathlessness was associated with worse performance on the shuttle walk test and forced vital capacity, but not with obstructive airflow limitation. The prediction model had fair discrimination (concordance statistic 0.66, 95% CI 0.63-0.69) and good calibration (calibration slope 1.00, 95% CI 0.80-1.21)., Conclusions: Post-COVID-19 breathlessness was commonly reported in this national cohort of patients hospitalised for COVID-19 and is likely to be a multifactorial problem with physical and emotional components., Competing Interests: Conflict of interest: C.E. Brightling, A. Shikotra and M. Sereno report grants from UKRI–MRC/DHSC–NIHR during the conduct of the study. J.D. Chalmers reports grants and personal fees from AstraZeneca and BI, personal fees from Chiesi, grants from Gilead Sciences, grants and personal fees from GSK and Insmed, personal fees from Janssen, grants and personal fees from Novartis, and personal fees from Zambon outside the submitted work, and is an associate editor of this journal. A. De Soyza reports grants, personal fees and other support from AstraZeneca, Bayer, BI, Chiesi, Forest Labs, GSK, Grifols, Insmed, MedImmune, Novartis, Pfizer and 30T outside the submitted work. R.A. Evans reports grants from UKRI/MRC/NIHR during the conduct of the study and speaker fees from BI. A. Horsley reports funding from NIHR Manchester Biomedical Research Centre, grants from the Cystic Fibrosis Foundation, JP Moulton Trust and NIHR, and personal fees from Vertex Pharmaceuticals and Mylan Healthcare, all outside the submitted work. L.G. Heaney reports support from AstraZeneca, BI, Chiesi, GSK and Napp Pharmaceuticals, personal fees from Novartis, Hoffman la Roche/Genentech Inc., Sanofi, Evelo Biosciences, GSK, AstraZeneca, Teva, Theravance and Circassia, grants from Medimmune, Novartis UK, Roche/Genetech Inc and GSK, Amgen, Genetech/Hoffman la Roche, AZ, Medimmune, GSK, Aerocrine and Vitalograph, outside the submitted work. J.R. Hurst reports grants, personal fees and nonfinancial support from pharmaceutical companies that make medicines to treat respiratory disease, outside the submitted work. G. Jenkins reports grants from GSK, grants and personal fees from Pliant Therapeutics, and grants from Biogen, during the conduct of the study; personal fees from Galapagos, other support from Galecto, personal fees and other support from GSK and AstraZeneca, personal fees from Boehringer Ingelheim, Pliant, Bristol Myers Squibb, Chiesi and Roche/Promedior, personal fees and other support from RedX, other support from NuMedii and Nordic Biosciences, personal fees from Veracyte, PatientMPower, Resolution Therapeutics and Vicore, outside the submitted work; and is supported by a National Institute of Health Research Professorship (NIHR ref. RP-2017-08-ST2-014) and is trustee for Action for Pulmonary Fibrosis. P. Pfeffer reports grants from NIHR outside the submitted work. J.K. Quint reports grants and personal fees from AstraZeneca, grants from Bayer, grants and personal fees from BI, Chiesi and GSK, grants from MRC, The Health Foundation and AUK/BLF, outside the submitted work. B. Raman is supported by the British Heart Foundation Oxford Centre of Research Excellence (RE/18/3/34214). A. Sheikh reports grants from HDRUK, NIHR, MRC and ICSF, during the conduct of the study; and is a Member of the Scottish Government's CMO COVID-19 Advisory Group and Standing Committee on Pandemics. A. Singapuri reports grants from MRC during the conduct of the study. S. Siddiqui reports grants from NIHR Leicester Biomedical Research Centre and NIHR PHOSP COVID, personal fees from AstraZeneca, GSK, CSL Behring, Knopp Biosciences, Owlstone Medical and Chiesi, outside the submitted work; and has a patent pending for volatile breath biomarkers of breathlessness. M. Toshner reports personal fees from Actelion/J&J and GSK, and other support from Morphogen-IX, outside the submitted work. L.V. Wain reports grants from GSK and Orion, outside the submitted work. All other authors declare no competing interests., (Copyright ©The authors 2023.)

Background: Reduced daily life physical activity (DLPA) in pulmonary arterial hypertension (PAH) contributes to a poor quality of life., Research Question: Can actigraphy be used to assess changes in DLPA in patients with PAH receiving selexipag or placebo?, Study Design and Methods: Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension (TRACE) was a prospective, multicenter, randomized, placebo-controlled, double-blind, exploratory phase 4 study enrolling patients with PAH in World Health Organization functional class II/III, receiving stable endothelin receptor antagonist with/without phosphodiesterase type 5 inhibitor background therapy. Primary end points were change from baseline to Week 24 in actigraphy-assessed DLPA (recorded by using an accelerometer), including daily time spent in nonsedentary physical activity (NSPA), daily time spent in moderate to vigorous physical activity (MVPA), daily volume of activity, and daily number of steps., Results: At baseline, patients (N = 108) were prevalent, on stable background PAH therapy, and at low risk of disease progression. Patients showed high compliance with wear of the accelerometer throughout the study. From baseline to Week 24, mean daily time spent in NSPA increased by 1.1 min and decreased by 16.7 min in the selexipag and placebo groups (treatment difference [95% CI], 17.8 [-6.0, 41.6] min); mean time spent in MVPA increased by 0.3 min and was reduced by 2.0 min in the selexipag and placebo groups (treatment difference [95% CI], 2.3 [-10.8, 15.4] min); and mean number of daily steps decreased by 0.3 and 201.9 in the selexipag and placebo groups (treatment difference [95% CI], 201.6 [-243.0, 646.2])., Interpretation: TRACE enrolled a prevalent population on background therapy and at low risk of disease progression. Changes in DLPA were small and highly variable, with no statistically significant differences between treatment groups. This patient-centric study was the first randomized trial in PAH to capture high-quality actigraphy data and to describe DLPA in terms of mean/median and variability, which may inform the design of future studies., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03078907; URL: www., Clinicaltrials: gov., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A 2 receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4 , a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction., Methods: The effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42 , was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM)., Results: In the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM., Conclusion: This study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4 , and its potential to be a disease-modifying therapy in PAH and other cardiac conditions., Competing Interests: EM, FR, LB, VS, HR, and BK were employees of ATXA Therapeutics Limited at the time of conducting the work reported in this manuscript. BK was also the founder and a member of the board of directors of ATXA Therapeutics Limited. Studies performed at the University of Porto or at IPS Therapeutique Inc./ToxiPharm Laboratories Inc. were sponsored by ATXA Therapeutics Ltd. LH reported grants from Janssen, honoraria for speaking from Janssen and MSD, supported for attending congresses from Janssen, and participates on the advisory board or steering committee for Janssen, Gossamer Bio, MSD, and Acceleron. DM reported grants from Acceleron, Janssen, and Merck, consulting fees from Acceleron and speakers’ honoraria from Bayer, Janssen, and Merck. MH reported grants from Acceleron, AOP Orphan, Janssen, Merck, and Shou Ti, consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, and United Therapeutics, speakers’ honoraria from Janssen and Merck, and participates on the advisory board for Janssen, Altavant, Merck, United Therapeutics, and Acceleron. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mulvaney, Renzo, Adão, Dupre, Bialesova, Salvatore, Reid, Conceição, Grynblat, Llucià-Valldeperas, Michel, Brás-Silva, Laurent, Howard, Montani, Humbert, Vonk Noordegraaf, Perros, Mendes-Ferreira and Kinsella.)

COVID-19 infection primarily targets the lungs, which in severe cases progresses to cytokine storm, acute respiratory distress syndrome, multiorgan dysfunction, and shock. Survivors are now presenting evidence of cardiopulmonary sequelae such as persistent right ventricular dysfunction, chronic thrombosis, lung fibrosis, and pulmonary hypertension. This review will summarize the current knowledge on long-term cardiopulmonary sequelae of COVID-19 and provide a framework for approaching the diagnosis and management of these entities. We will also identify research priorities to address areas of uncertainty and improve the quality of care provided to these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Oliveira, Nyasulu, Iqbal, Hamdan Gul, Ferreira, Leclair, Htun, Howard, Mocumbi, Bryant, Tamuzi, Avdeev, Petrosillo, Hassan, Butrous and de Jesus Perez.)

Pulmonary arterial hypertension (PAH) is an unmet clinical need. The lack of models of human disease is a key obstacle to drug development. We present a biomimetic model of pulmonary arterial endothelial-smooth muscle cell interactions in PAH, combining natural and induced bone morphogenetic protein receptor 2 (BMPR2) dysfunction with hypoxia to induce smooth muscle activation and proliferation, which is responsive to drug treatment. BMPR2- and oxygenation-specific changes in endothelial and smooth muscle gene expression, consistent with observations made in genomic and biochemical studies of PAH, enable insights into underlying disease pathways and mechanisms of drug response. The model captures key changes in the pulmonary endothelial phenotype that are essential for the induction of SMC remodelling, including a BMPR2-SOX17-prostacyclin signalling axis and offers an easily accessible approach for researchers to study pulmonary vascular remodelling and advance drug development in PAH., (© 2022. The Author(s).)

Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis -pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH.

Competing Interests: Competing interests: None declared.