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

Background: Group 1 pulmonary arterial hypertension (PAH) is a progressive fatal condition characterized by right ventricular (RV) failure with worse outcomes in connective tissue disease (CTD). Obstructive sleep apnea and sleep-related hypoxia may contribute to RV dysfunction, though the relationship remains unclear., Objectives: The aim of this study was to prospectively evaluate the association of the apnea-hypopnea index (AHI) and sleep-related hypoxia with RV function and survival., Methods: Pulmonary Vascular Disease Phenomics (National Heart, Lung, and Blood Institute) cohort participants (patients with group 1 PAH, comparators, and healthy control participants) with sleep studies were included. Multimodal RV functional measures were examined in association with AHI and percentage of recording time with oxygen saturation <90% (T90) per 10-unit increment. Linear models, adjusted for demographics, oxygen, diffusing capacity of the lungs for carbon monoxide, pulmonary hypertension medications, assessed AHI and T90, and RV measures. Log-rank test/Cox proportional hazards models adjusted for demographics, oxygen, and positive airway pressure were constructed for transplantation-free survival analyses., Results: Analysis included 186 participants with group 1 PAH with a mean age of 52.6 ± 14.1 years; 71.5% were women, 80.8% were Caucasian, and there were 43 events (transplantation or death). AHI and T90 were associated with decreased RV ejection fraction (on magnetic resonance imaging), by 2.18% (-2.18; 95% CI: -4.00 to -0.36; P = 0.019) and 0.93% (-0.93; 95% CI: -1.47 to -0.40; P < 0.001), respectively. T90 was associated with increased RV systolic pressure (on echocardiography), by 2.52 mm Hg (2.52; 95% CI: 1.61 to 3.43; P < 0.001); increased mean pulmonary artery pressure (on right heart catheterization), by 0.27 mm Hg (0.27; 95% CI: 0.05 to 0.49; P = 0.019); and RV hypertrophy (on electrocardiography), 1.24 mm (1.24; 95% CI: 1.10 to 1.40; P < 0.001). T90, but not AHI, was associated with a 17% increased 5-year risk for transplantation or death (HR: 1.17; 95% CI: 1.07 to 1.28). In non-CTD-associated PAH, T90 was associated with a 21% increased risk for transplantation or death (HR: 1.21; 95% CI: 1.08 to 1.34). In CTD-associated PAH, T90 was associated with RV dysfunction, but not death or transplantation., Conclusions: Sleep-related hypoxia was more strongly associated than AHI with measures of RV dysfunction, death, or transplantation overall and in group 1 non-CTD-associated PAH but only with RV dysfunction in CTD-associated PAH. (Pulmonary Vascular Disease Phenomics Program [PVDOMICS]; NCT02980887)., Competing Interests: Funding Support and Author Disclosures This study was supported by grants U01 HL125218 (principal investigator, Dr Rosenzweig), U01 HL125205 (principal investigator, Dr Frantz), U01 HL125212 (principal investigator, Dr Hemnes), U01 HL125208 (principal investigator, Dr Rischard), U01 HL125175 (principal investigator, Dr Hassoun), U01 HL125215 (principal investigator, Dr Leopold), and U01 HL125177 (principal investigator, Dr Beck) and the Pulmonary Hypertension Association. Dr Hill is a scientific advisory board member for Aerovate and Insmed; is a consultant for Bellerophon; and is a data and safety monitoring board member for Merck. Dr Finet has served as a clinical practice advisor for Wolters Kluwer Health-Lexicomp (forfeited compensation); and is an Item-Writing Task Force member for the American Board of Internal Medicine. Dr Kwon has received funding from the National Heart, Lung, and Blood Institute (grant 1R01HL170090-01); and has a research agreement with Circle Cardiovascular Imaging. Dr Beck has received support from the Pulmonary Hypertension Association. Dr Frantz has consulting, steering committee, and advisory board relationships with Altavant Sciences, Bayer, Gossamer Bio, Janssen, Shouti, the France Foundation, IQVIA, Tenax, UpToDate, and United Therapeutics. Dr Hassoun serves on a scientific steering committee for Merck Sharpe & Dohme; and is a scientific adviser for ARIA-CV (unrelated to the present work). Dr Hemnes serves as a consultant for Bayer, United Therapeutics, Janssen, GossamerBio, and Tenax Therapeutics; holds stock in Tenax Therapeutics; and has received grants from the National Institutes of Health, the Cardiovascular Medical Research and Education Fund, and Imara. Dr Horn has conducted research studies with Acceleron/Merck, Cereno, and Insmed. Dr Leopold is a consultant for Abbott Vascular; is a speaker for United Therapeutics; has received research funding from Astellas to her institution; and has received support from the American Heart Association (grant AIM 19AIML34980000; National Heart, Lung, and Blood Institute grant U01 HL125215). Dr Rischard has consulting relationships with Acceleron and United Therapeutics; is a steering committee member for Acceleron; and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Janssen, and Aadi Bioscience. Dr Mehra has received an honorarium from the American Academy of Sleep Medicine; has received funds for service on the American Board of Internal Medicine and as associate editor of the American Journal of Respiratory and Critical Care Medicine; has received National Institutes of Health funding; has received investigator-initiated research funds to her institution from Resmed, Inspire, and Sommetrics; and has received royalties from UpToDate. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background Pulmonary vascular distensibility associates with right ventricular function and clinical outcomes in patients with unexplained dyspnea and pulmonary hypertension. Alpha distensibility coefficient is determined from a nonlinear fit to multipoint pressure-flow plots. Study aims were to (1) create and test a user-friendly tool to standardize analysis of exercise hemodynamics including distensibility, and (2) investigate changes in distensibility following treatment in patients with pulmonary arterial hypertension. Methods and Results Participants with an exercise right heart catherization were retrospectively identified from the University of Arizona Pulmonary Hypertension (UA PH) registry and split into a pulmonary arterial hypertension group, a comparator group, and a control group. Right ventricular function was quantified using the coupling ratio and diastolic stiffness. Prototypes of the invasive cardiopulmonary exercise testing (iCPET) calculator were developed using Matlab, Python, and RShiny to analyze exercise hemodynamics and alpha distensibility coefficient, α (%/mm Hg) from multipoint pressure flow plots. Interclass correlation coefficients were calculated for interplatform and interobserver variability in alpha. No significant bias in the intraplatform (Matlab versus RShiny; intraclass correlation coefficient: 0.996) or interobserver (intraclass correlation coefficient: 0.982) comparison of alpha values. Afterload significantly decreased ( P <0.05) with no change in alpha distensibility in the pulmonary arterial hypertension group at follow-up. The comparator group had no change in pressure, resistance or alpha distensibility. There were no significant changes in RV diastolic stiffness at follow-up. Conclusions The interactive user interface in the iCPET calculator allows exploration of alpha distensibility using standardized methods. No significant change in alpha distensibility at follow-up suggests that alpha may be less modifiable in patients with long-standing pulmonary arterial hypertension.

Background: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition., Methods: We evaluated 63 incident patients with pulmonary arterial hypertension by right heart catheterization and cardiac magnetic resonance imaging at diagnosis and cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing following treatment (≈11 months). Sex, age, ethnicity matched healthy control subjects (n=62) with 1-time cardiac magnetic resonance imaging and noninvasive cardiopulmonary exercise testing were recruited from the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) project. We examined therapeutic cardiac magnetic resonance imaging changes relative to the evidence-based peak oxygen consumption (VO 2peak )>15 mL/(kg·min) to define RVFnRec by receiver operating curve analysis. Afterload was measured as mean pulmonary artery pressure, resistance, compliance, and elastance., Results: A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (area under the curve, 0.87; P =0.0001) and neared upper 95% CI RV end-diastolic volume of controls. This cutoff was met by 22 out of 63 (35%) patients which was reinforced by freedom from clinical worsening, RVFnRec 1 out of 21 (5%) versus no RVFnRec 17 out of 42, 40% (log-rank P =0.006). A therapy-associated increase of 0.8 mL/mm Hg in compliance had the best predictive value of RVFnRec (area under the curve, 0.76; [95% CI, 0.64-0.88]; P =0.001). RVFnRec patients had greater increases in stroke volume, and cardiac output at exercise., Conclusions: RVFnRec defined by RV end-diastolic volume therapeutic decrease of -15 mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise., Competing Interests: Disclosures Dr Rischard has consulting relationships with Bayer and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Merck, and Janssen. Dr Naeije reports relationships including consultancies, speakers fees, and membership of advisory boards with AOP Orphan Pharmaceuticals, Johnson & Johnson, Lung Biotechnology Corporation, and United Therapeutics. Dr Garcia is Chief Executive Officer and founder of Aqualung Therapeutics Corporation. Dr Frantz has consulting, steering committee, and advisory board relationships with Altavant Sciences, Bayer, Gossamer Bio, Janssen, Shouti, France Foundation, IQVIA, Tenax, UpToDate, and United Therapeutics. Dr Hassoun has served as consultant for Merck. Dr Hemnes has consulting relationships with Janssen, Merck, Gossamer, Bio, United Therapeutics, Bayer, Tenax. She owns stock in Tenax therapeutics and she has received research support from National Heart, Lung, and Blood Institute and Cardiovascular Medical Research and Education Fund. Dr Hill is the chair for an Aerovate steering committee. He is a consultant for Bellerophon and Liquidia and Merck. Dr Horn has consulting relationships with Biotronik and AADI biosciences. She serves on the DSMB for SoniVie and V-waves Ltd. She receives research support from Merck and Cereno. Dr Leopold Abbott has served as a consultant for Aria. She has research support from Astellas Pharma and United Therapeutics. Dr Rosenzweig has received consulting fees from Acceleron for a scientific advisory board meeting; and her institution receives grant support from Bayer, United Therapeutics, Janssen, and SonVie. Dr Tang served as consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Renovacor, WhiteSwell, Kiniksa, Boston Scientific, and CardiaTec Biosciences and has received honorarium from Springer Nature and American Board of Internal Medicine. The other authors report no conflicts.

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis., Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms., Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options., Registration: NCT05172024., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Helen Chu reported consulting for Merck, GSK, Pfizer, Ellume, Janssen, Vindico CME, and the Bill and Melinda Gates Foundation, and receiving research support from Gates Ventures, Ellume, and Sanofi Pasteur. She also serves as a co-investigator on studies funded by Pfizer, Novavax, and GSK. Maged Costantine reported receiving grant support for work not related to RECOVER work/publications from Baxter International and Siemens Healthcare and personal consulting fees not related to this paper from Progenity, Quidel Ortho, and Siemens Healthcare. Kristine Erlandson reported research funding from Gilead Sciences and consulting payments from Gilead Sciences, Merck, and ViiV Pharmaceuticals, all paid to the University of Colorado. Emily Gallagher reported consulting for Novartis, Flare Therapeutics and Seagen. Edward Gardner reported research support (clinical trials) from Gilead Sciences, ViiV Healthcare, and Cepheid. Jason Goldman reported research support from Gilead, Eli Lilly and Regeneron; grants from Gilead, Merck (BARDA); personal fees for consulting from Gilead, Eli Lilly; and non-financial support from Adaptive Biotechnologies and Labcorp/Monogram Biosciences outside the submitted work. Timothy Heinrich reported grant support from Merck Inc. and consulting fees from Roche. Rachel Hess reported serving as Data Safety Monitoring Board member for Astellas Pharmaceuticals unrelated to the current work. Leora Horwitz reported being a member of the National Academy of Medicine Committee on the Long-Term Health Effects Stemming from COVID-19 and Implications for the Social Security Administration. Priscilla Hsue reported receiving honoraria from Gilead and Merck unrelated to study topic, receiving study drug from Regeneron unrelated to study topic, and receiving a research grant from Novartis. Judith James reported OMRF has licensed her IP to Progentec Biosciences, has received grant support from Progentec Biosciences, and serves on Advisory Committees to Glaxo Smith Klein, Merck and Novartis. Arthur Kim reports providing educational materials to Clinical Care Options and UpToDate and serving on a Data Safety Monitoring board for Kintor Pharmaceuticals, Ltd. Bruce Levy reported serving as a consultant for AstraZeneca, Entrinsic Biosciences, Gossamer Bio and Nocion Therapeutics and receiving research support from Amgen, Genentech, GlaxoSmithKline, Pieris Pharmaceuticals, SRA and Sanofi unrelated to the current work. Vincent Marconi reported receiving grants from NIH during the conduct of the study and grants from NIH, Veteran Affairs, and Centers for Disease Control and Prevention; grants, personal fees, nonfinancial support, and other from Lilly and Gilead; grants and personal fees from ViiV; and nonfinancial support from Bayer outside the submitted work. Grace McComsey reported serving as consultant for Merck, Gilead, ViiV, Janssen and have received research support from Pfizer, Vanda, Genentech, Roche, Redhill and Cognivue. Torri Metz reported being a site PI and a participant in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She also reported being a site PI for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Janet Mullington reported support for investigator-initiated research by "Open Medicine Foundation and the Patient-Led Research Collaborative" Princess Ogbogu reported research support from Astrazeneca, GSK, Blueprint medical; advisory board for Astrazeneca, GSK, Sanofi, Kalvista; and consulting for Astrazeneca, GSK Sairam Parthasarathy reported research funding to Institution from Sergey Brin foundation of COVID and Long-COVID research. Michael Peluso reported consulting fees from Gilead Sciences and AstraZeneca, and service on data safety monitoring board for American Gene Technologies. Sean Quigley reported service on speaker Board for Servier, Alnylam, Agios; service on advisory board for Recordati, Alexion. Franz Rischard reported research support from NIH/NHLBI, United Therapeutics, Acceleron/Merck, Janssen, Insmed, Aerovate, and Bayer; and consulting/advisory compensation from Acceleron and Bayer. Nadine Rouphael reported being a consultant for ICON and EMMES as a safety consultant for clinical trials; service on the advisory boards for Moderna; funds to institution from Sanofi, Lilly, Merck, Quidel and Pfizer. PJ Utz reported stock ownership of Gilead and PI of biomarker studies for Pfizer STOP-PASC paxlovid trial Juan Wisnivesky received receiving consulting honorarium from Sanofi, Banook, Prospero, PPD and Atea and research grants from Sanofi, Regeneron, Axella, and Arnold Consultants., (Copyright: © 2023 Horwitz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear., Methods and Results: Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P > 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) <21% did. Compared to those with TSAT ≥21%, patients with TSAT <21% demonstrated lower peakVO2 [absolute difference: -1.89 (-2.73 to -1.04) mL/kg/min], 6-min walk test distance [absolute difference: -34 (-51 to -17) m], and SF-36 physical component score [absolute difference: -2.5 (-1.3 to -3.8)] after adjusting for age, sex, and hemoglobin (all P < 0.001). Patients with a TSAT <21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation <21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13-2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide., Conclusion: The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT <21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes., Competing Interests: Conflict of interest P.M. has received consultancy fees from AstraZeneca, Abbott, Bayer, Boehringer-Ingelheim, Daiichi Sankyo, Novartis, Novo Nordisk, and Vifor Pharma. B.A.B. receives research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics, has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer-Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations, and is named inventor (US Patent no. 10307179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. A.R.H. has served as a consultant for GossamerBio, Tenax Therapeutics, United Therapeutics, Merck, and Janssen. She is a stock holder in Tenax Therapeutics. W.H.W.T. is a consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Renovacor, Kiniksa, WhiteSwell, Boston Scientific, and CardiaTec Biosciences and has received honorarium from Springer Nature and American Board of Internal Medicine. All other authors reported no relevant relationships to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is believed to involve both vascular obstruction and vasoconstriction; hence, pulmonary vasodilators such as riociguat may be beneficial. Acute vasoreactivity testing (AVT) is seldom performed routinely in CTEPH patients, so there is limited understanding of the frequency and significance of an acute vasodilator response. Systematic vasodilator testing with oxygen (O 2 ) and oxygen plus inhaled nitric oxide (O 2  + iNO) was performed as part of the Pulmonary Vascular Disease Omics (PVDOMICS) NHLBI project, providing an opportunity to examine AVT responses in CTEPH. Patients with CTEPH enrolled in PVDOMICS ( n  = 49, 40 with prevalent CTEPH [82%]) underwent right heart catheterization including AVT with O 2 and O 2  + iNO. Hemodynamics were obtained at baseline and with each challenge. Fourteen of 49 patients (29%) had >20% drop in pulmonary vascular resistance (PVR) with O 2 . With O 2  + iNO, 30/49 (61%) had >20% drop in PVR, 20% had >20% drop in mean pulmonary artery pressure (mPAP) and PVR, and 8% had >10 mmHg decline in mPAP to mPAP < 40 with normal cardiac output. Patients on riociguat had less response to O 2  + iNO than patients on phosphodiesterase-5 inhibitors. Our findings shed light on the significant variability in vascular tone that is present in CTEPH, confirming that CTEPH represents a combination of mechanical obstruction and vasoconstriction that appears similar to that observed with Group 1 PAH. Additional study regarding whether results of acute vasodilator testing predict response to therapy and relate to prognosis is warranted., Competing Interests: Anna R. Hemnes has served as a consultant for Bayer, United Therapeutics, Janssen, GossamerBio, and Tenax Therapeutics; holds stock in Tenax Therapeutics; and has received grants from the National Institutes of Health, CMREF, and Imara. Erika B. Rosenzweig has received consulting fees from Acceleron for a scientific advisory board meeting; and her institution receives grant support from Bayer, United Therapeutics, Janssen, and SonVie. Robert P. Frantz has consulting, steering committee, and advisory board relationships with Altavant Sciences, Bayer, Gossamer Bio, Janssen, Shouti, France Foundation, IQVIA, Tenax Therapeutics, UpToDate, and United Therapeutics. Paul M. Hassoun has served as scientific advisor for Merck Sharp & Dohme, an activity unrelated to the current work. Nicholas S. Hill has received research grants for Acceleron, Aerovate. Altavant, Gossamer. Liquidia, Merck, and United Therapeutics; and has served on advisory boards for Acceleron, Aerovate, Altavant, Gossamer, and Liquidia. Actelion Sciences, and Tenax Therapeutics; and has U.S. Patent#9,605,047, Patent pending PCT/US2019/059890, Patent application 2021/133937. Stephen C. Mathai has served as a consultant for Acceleron, Actelion Sciences, Bayer, and United Therapeutics.  Margaret M. Park has served on the Speakers Bureau of Lantheus Medical Imaging (Definity contrast). Franz P. Rischard has consulting relationships with Acceleron and United Therapeutics; is on a Steering Committee for Acceleron; and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Janssen, and AADI. Evelyn M. Horn has served on the Data and Safety Monitoring Board of AADi Biosciences and SoniVie; has served on the Clinical Events Committee for V‐wave; and has served as a consultant for Biotronik. The remaining authors declare no conflicts of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification., Objectives: The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort., Methods: Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death., Results: A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH., Conclusions: PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification. (Pulmonary Vascular Disease Phenomics Program PVDOMICS [PVDOMICS]; NCT02980887)., Competing Interests: Funding Support and Author Disclosures The study received grants U01 HL125218 (Principal Investigator: Dr Rosenzweig), U01 HL125205 (Principal Investigator: Dr Frantz), U01 HL125212 (Principal Investigator: Dr Hemnes), U01 HL125208 (Principal Investigator: Dr Rischard), U01 HL125175 (Principal Investigator: Dr Hassoun), U01 HL125215 (Principal Investigator: Dr Leopold), and U01 HL125177 (Principal Investigator: Dr Beck) and was supported by the Pulmonary Hypertension Association. Dr Hemnes has served as a consultant for Bayer, United Therapeutics, Janssen, GossamerBio, and Tenax Therapeutics; holds stock in Tenax Therapeutics; and has received grants from the National Institutes of Health, CMREF, and Imara. Dr Leopold is supported by the National Institutes of Health grant U01 125215 and the American Heart Association 19AIML34980000; receives salary support from the Massachusetts Medical Society; has received research funding (to her institution) from Astellas; has served as a consultant for Abbott Vascular and United Therapeutics; and has served as a site principal investigator for a study sponsored by Aria CV. Dr Abidov is supported by research grants from Astellas Pharma, Boehringer Ingelheim, and Kiniksa outside of the submitted work. Dr Rosenzweig has received consulting fees from Acceleron for a scientific advisory board meeting; and her institution receives grant support from Bayer, United Therapeutics, Janssen, and SonVie. Dr Borlaug has received research grants from National Institutes of Health/NHLBI, AstraZeneca, Medtronic, GlaxoSmithKline, Mesoblast, Novartis, and Tenax Therapeutics; and has received consulting fees from Actelion, Amgen, Aria, Axon Therapies, Boehringer Ingelheim, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, and VADovations. Dr Dubrock has received consulting fees from Janssen Pharmaceuticals; and has served on advisory boards for Janssen Pharmaceuticals and United Therapeutics. Dr Finet is a consultant to Wolters Kluwer Health, Clinical Drug Information Ad Honorem. Dr Frantz has consulting, steering committee, and advisory board relationships with Altavant Sciences, Bayer, Gossamer Bio, Janssen, Shouti, France Foundation, IQVIA, Tenax, UpToDate, and United Therapeutics. Dr Garcia is CEO and founder of Aqualing Therapeutics. Dr Hassoun has served as scientific advisor for Merck Sharp & Dohme, an activity unrelated to the current work. Dr Highland has grants/contracts with Acceleron Pharmaceuticals, Actelion Pharmaceuticals (Janssen), Bayer Healthcare, Boehringer Ingelheim, Eiger Pharmaceuticals, Eli Lilly, Gossamer Bio, United Therapeutics, and Viela Bio (Horizon); has served as a consultant and/or member of a steering or advisory committee with Acceleron Pharmaceuticals, Actelion Pharmaceuticals (Janssen), Boehringer Ingelheim, Forsee, Genentech, Gossamer Bio, and United Therapeutics; and has served on the Speakers Bureau for Actelion Pharmaceuticals (Janssen), Bayer Healthcare, Boehringer Ingelheim, and United Therapeutics. Dr Hill has received research grants for Acceleron, Aerovate. Altavant, Gossamer. Liquidia, Merck, and United Therapeutics; and has served on advisory boards for Acceleron, Aerovate, Altavant, Gossamer, and Liquidia. Dr Maron has relationships with Deerfield Corporation, Actelion Sciences, and Tenax Therapeutics; and has U.S. Patent #9,605,047, Patent pending PCT/US2019/059890, Patent application 2021/133937. Dr Mathai has served as a consultant for Acceleron, Actelion, Bayer, and United Therapeutics. Dr Mehra is supported by National Institutes of Health grants U01HL125177 and UH3HL140144 and the American Heart Association AHA 18SFRN34170013; has received royalties from Up to Date; has received compensation from the American Board of Internal Medicine; and has received an honorarium from the American Academy of Sleep Medicine. M.M. Park has served on the Speakers Bureau of Lantheus Medical Imaging (Definity contrast). Dr Rischard has consulting relationships with Acceleron and United Therapeutics; is on a Steering Committee for Acceleron; and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Janssen, and AADI. Dr Thomas has served as a consultant for GE, Abbott, egnite, EchoIQ, and Caption Health; as well as spouse employment for Caption Health. Dr Horn has served on the Data and Safety Monitoring Board of AADi Biosciences and SoniVie; has served on the Clinical Events Committee for V-wave; and has served as a consultant for Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension., Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise., Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02980887.

Despite the increasing trends, reports on long-term follow-up are limited on transitioning from parenteral to oral treprostinil therapy in patients with pulmonary arterial hypertension (PAH). We investigated both the effectiveness of parenteral to oral treprostinil transition and the characteristics associated with transition failure over a duration of two years. The study included 37 Group I functional class I and II patients with PAH on combination therapy. Patients were excluded if cardiac index ≤2.2 L/min/m 2 , right atrial pressure ≥11 mmHg, or 6-min walk distance ≤250 m. Patients were categorized as successful ( S Transition) or unsuccessful ( U Transition) transition based on clinical stability, or a parenteral comparator ( C Parenteral) if they remained on parenteral therapy (no transition). All patients underwent two right heart catheterizations, one at enrollment and a second post transition. Of 24 total transition patients, 46% were classified as U Transition. U Transition occurred on average 577 days post transition. Both U Transition and S Transition had similar hemodynamics at diagnosis and treprostinil dose before and after transition. Before transition, the pulmonary vascular resistance (PVR) was significantly higher in the U Transition (6.7 ± 2 WU) vs. S Transition group (3.5 ± 1.5 WU). At follow-up catheterization, the U Transition group demonstrated further increases in PVR, greater than the C Parenteral group, without recovery despite "rescue" therapy in the U Transition group. A pre-transition PVR of 4.16 WU discriminated the U Transition from the S Transition group. While a subset of PAH patients on combination therapy may be safely transitioned from parenteral to oral treprostinil, caution should be exercised in patients with elevated baseline PVR to avoid irreversible destabilization.