24 results on '"Peacock, Andrew"'
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2. Contributor contact details
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Hall, Matthew R., primary, Allinson, David, additional, Künzel, Hartwig M., additional, Karagiozis, Achilles, additional, Etheridge, David W., additional, Wu, Shenyi, additional, Parsons, Ken, additional, Brimblecombe, Peter, additional, Steele, Kristian, additional, Gellert, Roland, additional, Feldman, Dorel, additional, Zeitler, Ing. Martin, additional, Yarbrough, David W., additional, Yu, Chih-Hao, additional, Fu, Qijia J., additional, Edman Tsang, S.C., additional, Warwicker, Brian, additional, Farid, Mohammed M., additional, Sherrif, Adam, additional, Zhao, Xudong, additional, Mapston, Mike, additional, Westbrook, Charles, additional, Jones, James, additional, Clarke, Joe, additional, Johnstone, Cameron, additional, Watts, Bill, additional, Peacock, Andrew, additional, Chow, David H.C., additional, Davda, Prakash C.J., additional, Sex, Graham, additional, Broomfield, John, additional, Shao, L., additional, Gillott, Mark, additional, Spataru, Catalina, additional, and Gadi, Mohamed B., additional more...
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- 2010
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3. Short-term hemodynamic effects of apelin in patients with pulmonary arterial hypertension
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Brash, Lauren, Barnes, Gareth D., Brewis, Melanie J., Church, A. Colin, Gibbs, Simon J., Howard, Luke S.G.E., Jayasekera, Geeshath, Johnson, Martin K., McGlinchey, Neil, Onorato, Joelle, Simpson, Joanne, Stirrat, Colin, Thomson, Stephen, Watson, Geoffrey, Wilkins, Martin R., Xu, Carrie, Welsh, David J., Newby, David E., and Peacock, Andrew J. more...
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NO, nitric oxide ,CO, cardiac output ,PVR, pulmonary vascular resistance ,apelin ,SVR, systemic vascular resistance ,PAEC, pulmonary artery endothelial cells ,pulmonary arterial hypertension ,APJ ,human ,PAH, pulmonary arterial hypertension ,Cardiology and Cardiovascular Medicine ,FA, formic acid ,PDE5, phosphodiesterase-5 - Abstract
Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr1)apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr1)apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170) more...
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- 2018
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4. The REPAIR Study: Effects of Macitentan on RV Structure and Function in Pulmonary Arterial Hypertension.
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Vonk Noordegraaf A, Channick R, Cottreel E, Kiely DG, Marcus JT, Martin N, Moiseeva O, Peacock A, Swift AJ, Tawakol A, Torbicki A, Rosenkranz S, and Galiè N
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- Humans, Predictive Value of Tests, Pyrimidines adverse effects, Sulfonamides adverse effects, Ventricular Function, Right, Pulmonary Arterial Hypertension, Ventricular Dysfunction, Right
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Objectives: The REPAIR (Right vEntricular remodeling in Pulmonary ArterIal hypeRtension) study evaluated the effect of macitentan on right ventricular (RV) and hemodynamic outcomes in patients with pulmonary arterial hypertension (PAH), using cardiac magnetic resonance (CMR) and right heart catheterization (RHC)., Background: RV failure is the primary cause of death in PAH. CMR is regarded as the most accurate noninvasive method for assessing RV function and remodeling and CMR measures of RV function and structure are strongly prognostic for survival in patients with PAH. Despite this, CMR is not routinely used in PAH clinical trials., Methods: REPAIR was a 52-week, open-label, single-arm, multicenter, phase 4 study evaluating the effect of macitentan 10 mg, with or without phosphodiesterase type-5 inhibition, on RV remodeling and function and cardiopulmonary hemodynamics. Primary endpoints were change from baseline to week 26 in RV stroke volume, determined by CMR; and pulmonary vascular resistance, determined by RHC. Efficacy measures were assessed for all patients with baseline and week 26 data for both primary endpoints., Results: At a prespecified interim analysis in 42 patients, both primary endpoints were met, enrollment was stopped, and the study was declared positive. At final analysis (n = 71), RV stroke volume increased by 12 mL (96% confidence level: 8.4-15.6 mL; P < 0.0001) and pulmonary vascular resistance decreased by 38% (99% confidence level: 31%-44%; P < 0.0001) at week 26. Significant positive changes were also observed in secondary and exploratory CMR (RV and left ventricular), hemodynamic, and functional endpoints at week 26. Improvements in CMR RV and left ventricular variables and functional parameters were maintained at week 52. Safety (n = 87) was consistent with previous clinical trials., Conclusions: In the context of this study, macitentan treatment in patients with PAH resulted in significant and clinically-relevant improvements in RV function and structure and cardiopulmonary hemodynamics. At 52 weeks, improvements in RV function and structure were sustained. (REPAIR: Right vEntricular remodeling in Pulmonary ArterIal hypeRtension [REPAIR]; NCT02310672)., Competing Interests: Funding Support and Author Disclosures This study was funded by Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson. All statistical analyses were performed by the sponsor, in accordance with the prespecified statistical analysis plan. Dr Vonk Noordegraaf has received ongoing grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson, GlaxoSmithKline, and Merck Sharp & Dohme; and has received Speakers Bureau payments from Janssen Pharmaceutical Companies of Johnson & Johnson. Dr Channick has received consultancy fees from Arena Pharmaceuticals Ltd and Bayer; has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson and United Therapeutics; and is an advisory board member for Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer. Dr Cottreel is a former employee and patent holder with Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson. Dr Kiely has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, and GlaxoSmithKline; and has received other financial or material support from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, and Merck Sharp & Dohme. Dr Marcus has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson. Dr Martin is an employee of Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson; and currently holds shares in Johnson & Johnson. Dr Moiseeva has received lecture fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, and Pfizer. Dr Peacock has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, and GlaxoSmithKline, in addition to other financial or material support from Arena Pharmaceuticals Ltd and Merck Sharp & Dohme. Dr Swift has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson and General Electric Ltd; and has received grant support from GlaxoSmithKline. Dr Tawakol has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson and Esperion; and has received grant/research support from Genentech. Dr Torbicki has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Arena Pharmaceuticals Ltd, Bayer, Merck Sharp & Dohme, Pfizer, and United Therapeutics; has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson; has received Speakers Bureau fees from Janssen Pharmaceutical Companies of Johnson & Johnson, AOP, Bayer, Merck Sharp & Dohme, and Pfizer; and is an advisory board member for Janssen Pharmaceutical Companies of Johnson & Johnson. Dr Rosenkranz has received consultancy and/or lecture fees from Abbott, Acceleron, Arena Pharmaceuticals Ltd, Bayer, Bristol-Myers Squibb, Janssen Pharmaceutical Companies of Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, and United Therapeutics; and has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson, AstraZeneca, Bayer, and Novartis. Dr Galiè has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, and Pfizer; and has received Speakers Bureau fees from Merck Sharp & Dohme., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) more...
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- 2022
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5. Selonsertib in adults with pulmonary arterial hypertension (ARROW): a randomised, double-blind, placebo-controlled, phase 2 trial.
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Rosenkranz S, Feldman J, McLaughlin VV, Rischard F, Lange TJ, White RJ, Peacock AJ, Gerhardt F, Ebrahimi R, Brooks G, Satler C, and Frantz RP
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- Adolescent, Adult, Aged, Benzamides, Double-Blind Method, Humans, Imidazoles, Middle Aged, Pyridines, Treatment Outcome, Young Adult, Pulmonary Arterial Hypertension drug therapy
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Background: Data obtained in human lung tissue and preclinical models suggest that oxidative stress and increased apoptosis signal-regulating kinase 1 (ASK1) activity might have a prominent role in the pathobiology of pulmonary arterial hypertension (PAH). The purpose of this study was to determine the efficacy, safety, and tolerability of the ASK1 inhibitor selonsertib compared with placebo in patients with PAH., Methods: We did a randomised, double-blind, placebo-controlled, phase 2 trial at 46 centres located in Canada, France, Germany, Italy, the Netherlands, Spain, the UK, and the USA. Participants were aged 18-75 years and had an established diagnosis of idiopathic or hereditary PAH, or PAH associated with connective tissue disease, drugs or toxins, human immunodeficiency virus, or repaired congenital heart defects. Patients were stratified by PAH aetiology and background therapy, and randomly assigned (1:1:1:1) using an interactive voice-response or web-response system to placebo or selonsertib 2 mg, 6 mg, or 18 mg administered orally once daily. Both placebo and selonsertib were in tablet form. The primary efficacy endpoint was change in pulmonary vascular resistance, measured by right heart catheterisation, from baseline to week 24 in the full analysis set. Pair-wise comparisons between each of the selonsertib groups and the placebo group were made with a stratified Wilcoxon (van Elteren) rank sum test for participants without major protocol deviations who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02234141., Findings: Between Dec 3, 2014, and Nov 13, 2015, 151 patients were enrolled and randomly assigned. Of 150 participants who received selonsertib or placebo, 134 (89%) completed 24 weeks of the randomly assigned treatment; all were on background PAH therapy (138 [92%] on combination therapy). 90 (60%) patients were in functional class II and 60 (40%) in functional class III. Mean baseline pulmonary vascular resistance was 772 (SD 334) dyn·s/cm
5 . Change in pulmonary vascular resistance was 6·0 dyn·s/cm5 (SD 28·0; n=31) for placebo, and 35·0 (35·4) dyn·s/cm5 (n=35; p=0·21 vs placebo) for 2 mg selonsertib, -28·0 (30·2) dyn·s/cm5 (n=34; p=0·27 vs placebo) for 6 mg selonsertib, and -21·0 (37·9) dyn·s/cm5 (n=36; p=0·60 vs placebo) for 18 mg selonsertib. The most frequent adverse events were headache (17 [15%]), abnormal dreams (eight [7%]), nausea (seven [6%]), and diarrhoea (seven [6%]) in the selonsertib groups, and headache (six [16%]), nausea (five [14%]), and diarrhoea (two [5%]) in the placebo group. Serious adverse events occurred in 23 (20%) of 113 selonsertib-treated patients and seven (19%) of 37 patients who received placebo., Interpretation: Selonsertib once daily for 24 weeks did not lead to a significant reduction in pulmonary vascular resistance or to clinical improvement in patients with PAH, but appeared to be safe and well tolerated. Although these data do not support the clinical use of selonsertib in PAH, further study of the potential of targeting the ASK1-p38 pathway in PAH is warranted., Funding: Gilead Sciences., Competing Interests: Declaration of interests SR reports remuneration for lectures and consultancy from Abbott, Acceleron, Actelion, Arena, Bayer, Bristol-Myers Squibb, Ferrer, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, United Therapeutics, and Vifor; and grants to his institution from Actelion, AstraZeneca, Bayer, Novartis, and United Therapeutics. JF reports remuneration for lectures and consultancy from Actelion, Gilead, and United Therapeutics. VVM reports grant support from Acceleron, Actelion, Gilead, Reata, Sonovie, and United Therapeutics; and remuneration for scientific consulting from Acceleron, Actelion, Altavant, Caremark, CiVi Biopharma, Gossamer Bio, Liquidia, Limited Liability Company, and United Therapeutics. FR has received remuneration for consultancy and advisory roles, and research grants from Actelion, Bayer, Gilead, and United Therapeutics. TJL has received personal fees for lectures and consultancy from Acceleron Pharma, Actelion, Bayer, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, and United Therapeutics; and grants to his institution from Acceleron Pharma, Actelion, Bayer, Bellerophon, Gilead, Janssen-Cilag, Pfizer, and United Therapeutics. RJW has received research grants from Bayer, Gilead, Merck Sharp & Dohme, PhaseBio, and United Therapeutics; and reports personal fees for consultancy from Altavant, Bayer, Gilead, Merck Sharp & Dohme, and PhaseBio. AJP has received research grants assistance with travel and honoraria from Actelion, Bayer, Gilead, GlaxoSmithKline, and Merck Sharp & Dohme. FG reports remuneration for lectures from Actelion, Bayer, Janssen, and Merck Sharp & Dohme; and grants to his institution from Actelion, Bayer, and Janssen. RE is an employee of Gilead. GB and CS are former employees of Gilead. CS reports consulting fees from Respira. RPF has received reimbursement for travel to investigator meetings and advisory board meetings from Actelion, Gilead, and United Therapeutics; and consulting fees from Actelion and Liquidia., (Copyright © 2022 Elsevier Ltd. All rights reserved.) more...- Published
- 2022
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6. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.
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Hoeper MM, Al-Hiti H, Benza RL, Chang SA, Corris PA, Gibbs JSR, Grünig E, Jansa P, Klinger JR, Langleben D, McLaughlin VV, Meyer GMB, Ota-Arakaki J, Peacock AJ, Pulido T, Rosenkranz S, Vizza CD, Vonk-Noordegraaf A, White RJ, Chang M, Kleinjung F, Meier C, Paraschin K, Ghofrani HA, and Simonneau G more...
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- Adult, Aged, Female, Humans, Male, Middle Aged, Prospective Studies, Young Adult, Phosphodiesterase 5 Inhibitors therapeutic use, Pulmonary Arterial Hypertension drug therapy, Pyrazoles therapeutic use, Pyrimidines therapeutic use
- Abstract
Background: Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality., Methods: Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18-75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology-European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20-40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N-terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov, NCT02891850., Findings: Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53-5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01-0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period., Interpretation: Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality., Funding: Bayer AG, Merck Sharp & Dohme., Competing Interests: Declaration of interests MMH has received fees for consultations and lectures from Acceleron, Actelion, Bayer, Janssen, Merck Sharpe & Dohme (MSD), and Pfizer. HA-H is an investigator of clinical studies with Actelion, Bayer AG, and Pfizer. RLB reports grants from Bellerophon, Bayer AG, Actelion, and EIGER. PAC reports grants and personal fees from Bayer AG, Actelion, and GlaxoSmithKline (GSK). JSRG reports grants and personal fees from Actelion, Bayer AG, United Therapeutics, and MSD, personal fees from Arena, Bellopheron, Acceleron, Complexa, and Pfizer, and grants from GSK and Amco. EG reports fees for lectures and consultations from Actelion, Bayer AG, GSK, MSD, United Therapeutics, and Pfizer. PJ reports personal fees from Actelion, Bayer AG, Reata Pharmaceuticals, AOP Orphan, and MSD, and is an investigator for Actelion, Bayer AG, and Reata Pharmaceuticals. JRK reports that his institution has received grant support for clinical trials and basic science research in pulmonary hypertension from Actelion, Bayer, Lung Biotechnology, and United Therapeutics. DL reports honoraria, consultation fees, research support, and travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, and United Therapeutics. VVM has received research support or grants from Acceleron Pharma, Actelion, Bayer AG, Reata Pharmaceuticals, SoniVie, and United Therapeutics, and has served as a consultant and on advisory committees for Acceleron, Actelion, Altavant, Bayer, Caremark, CiVi BioPharma, Gossamer, Liquidia, and United Therapeutics. GMBM reports lecture and consultation fees from Bayer AG, Eli Lilly, and GSK. ASP reports fees for research grants, support for travel to meetings, and honoraria from Actelion, Bayer AG, GSK, MSD, Pfizer, and United Therapeutics. TP reports grants and personal fees from Actelion–Janssen, grants from United Therapeutics, Reata Pharmaceuticals, and Bayer, and personal fees from Bayer and Pfizer. SR reports remunerations for lectures and consultancy from Abbott, Acceleron, Actelion, Arena, Bayer, Bristol-Myers Squibb, Ferrer, GSK, Janssen, MSD, Novartis, Pfizer, and United Therapeutics, and research support to his institution from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. AV-N is supported by the Netherlands CardioVascular Research Initiative (CVON-2012-08 PHAEDRA, CVON-2017-10 DOLPHIN-GENESIS) and the Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610, funding outside of the current study), has received speakers fees from Johnson & Johnson and Ferrer in the past 3 years, and served as a member of the scientific advisory board of Morphogen-XI. RJW reports grants and personal fees from Bayer AG and personal fees from MSD. MC, FK, CM, and KP are employees of Bayer AG. HAG reports personal fees and consultancy fees from Actelion, Bayer AG, GSK, Novartis, and Pfizer, consultancy fees from Bellerophon Pulse Technologies and MSD, and grants from Deutsche Forschungsgemeinschaft. GS reports personal fees and non-financial support from Actelion, Bayer, and MSD. S-AC, CDV, and JO-A declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.) more...
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- 2021
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7. I cannot live without air conditioning! The role of identity, values and situational factors on cooling consumption patterns in India.
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Osunmuyiwa OO, Payne SR, Vigneswara Ilavarasan P, Peacock AD, and Jenkins DP
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As the world continues to deal with climate-induced heat events, sustainable energy behaviours, or lifestyles combined with non-behavioural interventions have been identified as crucial pathways to curb the demand for air conditioners. Typically, ecological communities serve as a reference point for sustainable lifestyles as they have strong environmental self-identity and values and are more likely to further engage in pro-environmental and energy-saving actions. Yet, it is unknown if individuals within these communities will act as expected, especially when confronted with extreme climatic challenges like heatwaves. It is also unclear which factors will define individual responses to these challenges. Utilising environmental self-identity and Value-Belief-Norm theories, this paper examines factors underlying cooling consumption behaviours of households living in a Universal Community with strong environmental world views in India. Twenty in-depth qualitative interviews with residents, thematically analysed, found that while people expressed strong environmental self-identity, preferences for air conditioner use was often mediated by hedonic factors such as comfort and sleep. Moral norms played a positive role in how people operated their air conditioners. Yet, when faced with the choice of using energy-efficient air conditioners, biospheric concern was of limited importance while situational factors like cost and functionality were more pivotal. The above results raise interesting questions around the difficulties that might emerge in changing preferences around air conditioning behaviours in non-environmental communities, especially, if environmentally conscious communities which are expected to be "the locus of change for energy efficiency actions" are significantly influenced by hedonic values., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).) more...
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- 2020
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8. Patients with pulmonary arterial hypertension with and without cardiovascular risk factors: Results from the AMBITION trial.
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McLaughlin VV, Vachiery JL, Oudiz RJ, Rosenkranz S, Galiè N, Barberà JA, Frost AE, Ghofrani HA, Peacock AJ, Simonneau G, Rubin LJ, Blair C, Langley J, and Hoeper MM
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- Adult, Aged, Cardiovascular Diseases epidemiology, Cardiovascular Diseases etiology, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Risk Factors, Antihypertensive Agents administration & dosage, Phenylpropionates administration & dosage, Pulmonary Arterial Hypertension complications, Pyridazines administration & dosage, Tadalafil administration & dosage, Vasodilator Agents administration & dosage, Ventricular Dysfunction, Left epidemiology, Ventricular Dysfunction, Left etiology
- Abstract
Background: The purpose of this study was to compare patients with pulmonary arterial hypertension enrolled in the AMBITION trial with (excluded from the primary analysis set [ex-primary analysis set]) and without (primary analysis set) multiple risk factors for left ventricular diastolic dysfunction., Methods: Treatment-naive patients with pulmonary arterial hypertension were randomized to once-daily ambrisentan and tadalafil combination therapy, ambrisentan monotherapy, or tadalafil monotherapy. The primary end point was time from randomization to first adjudicated clinical failure event., Results: Primary analysis set patients (n = 500), compared with ex-primary analysis set patients (n = 105), were younger (mean, 54.4 vs 62.1 years) with greater baseline 6-minute walk distance (median, 363.7 vs 330.5 meters) and fewer comorbidities (e.g., hypertension and diabetes). Treatment effects of initial combination therapy vs pooled monotherapy were directionally the same for both populations, albeit of a lower magnitude for ex-primary analysis set patients. Initial combination therapy reduced the risk of clinical failure compared with pooled monotherapy in primary analysis set patients (hazard ratio, 0.50; 95% confidence interval, 0.35-0.72), whereas the effect was less clear in ex-primary analysis set patients (hazard ratio, 0.70; 95% confidence interval, 0.35-1.37). Overall, primary analysis set patients had fewer clinical failure events (25% vs 33%), higher rates of satisfactory clinical response (34% vs 24%), and lower rates of permanent study drug withdrawal due to adverse events (16% vs 31%) than ex-primary analysis set patients., Conclusions: Efficacy of initial combination therapy vs pooled monotherapy was directionally similar for primary analysis set and ex-primary analysis set patients. However, ex-primary analysis set patients (with multiple risk factors for left ventricular diastolic dysfunction) experienced higher rates of clinical failure events and the response to combination therapy vs monotherapy was attenuated. Tolerability was better in primary analysis set than ex-primary analysis set patients., (Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2019
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9. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.
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Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L, Germain M, Pauciulo MW, Hadinnapola C, Aman J, Girerd B, Arora A, Knight J, Hanscombe KB, Karnes JH, Kaakinen M, Gall H, Ulrich A, Harbaum L, Cebola I, Ferrer J, Lutz K, Swietlik EM, Ahmad F, Amouyel P, Archer SL, Argula R, Austin ED, Badesch D, Bakshi S, Barnett C, Benza R, Bhatt N, Bogaard HJ, Burger CD, Chakinala M, Church C, Coghlan JG, Condliffe R, Corris PA, Danesino C, Debette S, Elliott CG, Elwing J, Eyries M, Fortin T, Franke A, Frantz RP, Frost A, Garcia JGN, Ghio S, Ghofrani HA, Gibbs JSR, Harley J, He H, Hill NS, Hirsch R, Houweling AC, Howard LS, Ivy D, Kiely DG, Klinger J, Kovacs G, Lahm T, Laudes M, Machado RD, MacKenzie Ross RV, Marsolo K, Martin LJ, Moledina S, Montani D, Nathan SD, Newnham M, Olschewski A, Olschewski H, Oudiz RJ, Ouwehand WH, Peacock AJ, Pepke-Zaba J, Rehman Z, Robbins I, Roden DM, Rosenzweig EB, Saydain G, Scelsi L, Schilz R, Seeger W, Shaffer CM, Simms RW, Simon M, Sitbon O, Suntharalingam J, Tang H, Tchourbanov AY, Thenappan T, Torres F, Toshner MR, Treacy CM, Vonk Noordegraaf A, Waisfisz Q, Walsworth AK, Walter RE, Wharton J, White RJ, Wilt J, Wort SJ, Yung D, Lawrie A, Humbert M, Soubrier F, Trégouët DA, Prokopenko I, Kittles R, Gräf S, Nichols WC, Trembath RC, Desai AA, Morrell NW, and Wilkins MR more...
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- Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques methods, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Signal Transduction genetics, Survival Analysis, HLA-DP alpha-Chains genetics, HLA-DP beta-Chains genetics, Pulmonary Arterial Hypertension diagnosis, Pulmonary Arterial Hypertension genetics, Pulmonary Arterial Hypertension metabolism, Pulmonary Arterial Hypertension mortality, SOXF Transcription Factors genetics
- Abstract
Background: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes., Methods: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses., Findings: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10
-15 ) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20 ) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12 ; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity., Interpretation: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials., Funding: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR., (Copyright © 2019 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.) more...- Published
- 2019
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10. Initial combination therapy with ambrisentan + tadalafil on pulmonary arterial hypertension‒related hospitalization in the AMBITION trial.
- Author
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Vachiéry JL, Galiè N, Barberá JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Blair C, Miller KL, Langley J, and Rubin LJ
- Subjects
- Aged, Antihypertensive Agents administration & dosage, Disease Progression, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Phosphodiesterase 5 Inhibitors administration & dosage, Pulmonary Arterial Hypertension physiopathology, Pulmonary Wedge Pressure drug effects, Pulmonary Wedge Pressure physiology, Treatment Outcome, Hospitalization trends, Phenylpropionates administration & dosage, Pulmonary Arterial Hypertension drug therapy, Pyridazines administration & dosage, Tadalafil administration & dosage
- Abstract
Background: In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization., Methods: The effect of initial combination therapy with ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication., Results: Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary)., Conclusions: Initial combination therapy with ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy., (Copyright © 2018. Published by Elsevier Inc.) more...
- Published
- 2019
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11. Survival in portopulmonary hypertension: Outcomes of the United Kingdom National Pulmonary Arterial Hypertension Registry.
- Author
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Sithamparanathan S, Nair A, Thirugnanasothy L, Coghlan JG, Condliffe R, Dimopoulos K, Elliot CA, Fisher AJ, Gaine S, Gibbs JSR, Gatzoulis MA, E Handler C, Howard LS, Johnson M, Kiely DG, Lordan JL, Peacock AJ, Pepke-Zaba J, Schreiber BE, Sheares KKK, Wort SJ, and Corris PA more...
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Hypertension, Portal etiology, Hypertension, Portal therapy, Hypertension, Pulmonary etiology, Hypertension, Pulmonary therapy, Male, Middle Aged, Retrospective Studies, Survival Rate, United Kingdom epidemiology, Young Adult, Hypertension, Portal mortality, Hypertension, Pulmonary mortality, Registries
- Abstract
Background: Portopulmonary hypertension (PoPH) is a rare condition associated with poor survival, and the effect of modern therapies that target pulmonary arterial hypertension (PAH) on long-term outcome is unknown. This study investigated the baseline characteristics and survival in the cohort of patients diagnosed with PoPH in the United Kingdom National Pulmonary Hypertension Service., Methods: A retrospective review was conducted of all incident treatment-naïve patients with PoPH within the United Kingdom national registry diagnosed between January 2001 and December 2010., Results: Patients with PoPH (n = 110) had survival rates of 85%, 60%, and 35% at 1, 3, and 5 years. The prevalence of PoPH was 0.85 cases/1 million. Mean age at diagnosis was 53 ± 12 years, with a balanced distribution in gender. Alcohol (n = 57) and hepatitis C (n = 10) were the most common causes of portal hypertension. Phosphodiesterase V inhibitors were the most frequently used targeted therapy, in 63.6% (n = 70) of patients, endothelin receptor antagonists were used in 10% (n = 11) and prostacyclin analogs in 12.7% (n = 14). Univariate and multivariate analysis of baseline characteristics did not demonstrate a significant influence of severity of portal hypertension or liver cirrhosis, World Health Organization Functional Class, cardiopulmonary hemodynamics, or year of diagnosis on survival., Conclusions: Survival of patients with PoPH remains poor despite targeted therapy and worse than patients with idiopathic PAH. The benefit of PAH therapies in PoPH on long-term morbidity and mortality outcomes needs further consideration and study., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2017
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12. Ambrisentan use for pulmonary arterial hypertension in a post-authorization drug registry: The VOLibris Tracking Study.
- Author
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Vachiéry JL, Hoeper MM, Peacock AJ, Sitbon O, Cheli M, Church C, Olsson KM, Palazzini M, Waterhouse B, Langley J, and Galié N
- Subjects
- Adult, Aged, Female, Hospitalization, Humans, Hypertension, Pulmonary enzymology, Male, Middle Aged, Prospective Studies, Transaminases blood, Treatment Outcome, Antihypertensive Agents therapeutic use, Hypertension, Pulmonary drug therapy, Phenylpropionates therapeutic use, Product Surveillance, Postmarketing, Pyridazines therapeutic use, Registries
- Abstract
Background: The VOLibris Tracking (VOLT) Study was an open-label, prospective, observational, multicenter, post-marketing registry program designed to more fully characterize the safety profile of ambrisentan for the treatment of pulmonary arterial hypertension (PAH). The key outcome was the incidence of aminotransferase elevations >3× the upper limit of normal (ULN)., Methods: In total, 999 patients from 115 centers in 15 countries, who were prescribed ambrisentan for the treatment of PAH (Functional Class II and III) between 30 June 2008 and 13 May 2011, were enrolled. Of these, 238 had PAH associated with connective tissue disease (PAH-CTD) and 220 had no prior PAH-specific therapy. Routine clinical monitoring data were collected by physicians., Results: The incidence of both alanine and aspartate aminotransferase events (>3× ULN) was 0.02 per patient-year (95% confidence interval 0.015 to 0.027). Similar results were reported for the PAH-CTD and PAH-specific-therapy-naive subgroups. Overall, 514 (52%) patients reported treatment-emergent adverse events of special interest, most commonly edema/fluid retention (249, or 25%) and anemia (143, or 14%)., Conclusions: Data from the VOLT study indicate no new ambrisentan-related safety signals. Ambrisentan was not associated with increases in liver function test abnormalities above the assumed background incidence of 1.5% per year, and the observed safety profile of ambrisentan was consistent with previously published data., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2017
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13. Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study.
- Author
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Hoeper MM, McLaughlin VV, Barberá JA, Frost AE, Ghofrani HA, Peacock AJ, Simonneau G, Rosenkranz S, Oudiz RJ, White RJ, Miller KL, Langley J, Harris JHN, Blair C, Rubin LJ, and Vachiery JL
- Subjects
- Adult, Aged, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Intention to Treat Analysis, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Pulmonary Artery, Treatment Outcome, Antihypertensive Agents administration & dosage, Hypertension, Pulmonary drug therapy, Hypertension, Pulmonary mortality, Phenylpropionates administration & dosage, Pyridazines administration & dosage, Tadalafil administration & dosage
- Abstract
Background: In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival., Methods: We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial. AMBITION was a multicentre, randomised, double-blind study, in which treatment-naive patients with pulmonary arterial hypertension were randomly assigned in a 2:1:1 ratio and received combination therapy with ambrisentan and tadalafil, ambrisentan and placebo, or tadalafil and placebo. We did a prespecified analysis of all mortality events from randomisation to the end of the study, including patients who discontinued their assigned treatment. In a post-hoc analysis, we analysed survival at 7 days after the termination of each individual patient's randomised treatment. We used Cox proportional hazard regression, Kaplan-Meier survival estimates, and the stratified log-rank test to compare the survival of patients receiving initial combination therapy or initial monotherapy., Findings: The study population consisted of 605 patients with pulmonary arterial hypertension who were randomly assigned and received combination therapy (n=302) or monotherapy (n=303; 152 patients assigned to ambrisentan monotherapy and 151 patients to tadalafil monotherapy). At the end of the study, 29 (10%) of 302 patients in the combination therapy group had died compared with 41 (14%) of 303 patients in the monotherapy group (hazard ratio 0·67, 95% CI 0·42-1·08; stratified log-rank p=0·10). At 7 days after the end of randomised treatment, fewer patients had died in the combination therapy group (3 [1%] of 302 patients) compared with the monotherapy group (13 [4%] of 303 patients; hazard ratio 0·21, 95% CI 0·06-0·73)., Interpretation: These data indicate that initial combination therapy might be associated with a survival advantage compared with initial monotherapy in patients with newly diagnosed pulmonary arterial hypertension. This hypothesis needs to be addressed in future studies., Funding: Gilead, GlaxoSmithKline., (Copyright © 2016 Elsevier Ltd. All rights reserved.) more...
- Published
- 2016
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14. Imaging right ventricular function to predict outcome in pulmonary arterial hypertension.
- Author
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Brewis MJ, Bellofiore A, Vanderpool RR, Chesler NC, Johnson MK, Naeije R, and Peacock AJ
- Subjects
- Adult, Aged, Female, Humans, Hypertension, Pulmonary physiopathology, Male, Middle Aged, Multivariate Analysis, Predictive Value of Tests, Ventricular Function, Right, Heart Ventricles physiopathology, Hypertension, Pulmonary mortality, Pulmonary Artery physiopathology
- Abstract
Background: Right ventricular (RV) function is a major determinant of outcome in pulmonary arterial hypertension (PAH). However, uncertainty persists about the optimal method of evaluation., Methods: We measured RV end-systolic and end-diastolic volumes (ESV and EDV) using cardiac magnetic resonance imaging and RV pressures during right heart catheterization in 140 incident PAH patients and 22 controls. A maximum RV pressure (Pmax) was calculated from the nonlinear extrapolations of early and late systolic portions of the RV pressure curve. The gold standard measure of RV function adaptation to afterload, or RV-arterial coupling (Ees/Ea) was estimated by the stroke volume (SV)/ESV ratio (volume method) or as Pmax/mean pulmonary artery pressure (mPAP) minus 1 (pressure method) (n=84). RV function was also assessed by ejection fraction (EF), right atrial pressure (RAP) and SV., Results: Higher Ea and RAP, and lower compliance, SV and EF predicted outcome at univariate analysis. Ees/Ea estimated by the pressure method did not predict outcome but Ees/Ea estimated by the volume method (SV/ESV) did. At multivariate analysis, only SV/ESV and EF were independent predictors of outcome. Survival was poorer in patients with a fall in EF or SV/ESV during follow-up (n=44, p=0.008)., Conclusion: RV function to predict outcome in PAH is best evaluated by imaging derived SV/ESV or EF. In this study, there was no added value of invasive measurements or simplified pressure-derived estimates of RV-arterial coupling., Competing Interests: Dr Bellofiore, Dr Vanderpool, Dr Chesler and Professor Naeije report no relationships that could be construed as a conflict of interest., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.) more...
- Published
- 2016
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15. Long-term safety and efficacy of imatinib in pulmonary arterial hypertension.
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Frost AE, Barst RJ, Hoeper MM, Chang HJ, Frantz RP, Fukumoto Y, Galié N, Hassoun PM, Klose H, Matsubara H, Morrell NW, Peacock AJ, Pfeifer M, Simonneau G, Tapson VF, Torres F, Dario Vizza C, Lawrence D, Yang W, Felser JM, Quinn DA, and Ghofrani HA more...
- Subjects
- Adolescent, Adult, Aged, Dose-Response Relationship, Drug, Double-Blind Method, Exercise Tolerance physiology, Female, Follow-Up Studies, Humans, Hypertension, Pulmonary physiopathology, Male, Middle Aged, Protein Kinase Inhibitors administration & dosage, Retrospective Studies, Time Factors, Treatment Outcome, Young Adult, Hemodynamics drug effects, Hypertension, Pulmonary drug therapy, Imatinib Mesylate administration & dosage
- Abstract
Background: Imatinib is an oral inhibitor of several protein kinases implicated in the pathophysiology of pulmonary hypertension. Treatment with imatinib resulted in improved hemodynamics and exercise capacity in a controlled trial (Imatinib [QTI571] in Pulmonary Arterial Hypertension, a Randomized Efficacy Study [IMPRES]), among pulmonary arterial hypertension (PAH) patients inadequately responsive to 2 to 3 PAH-specific therapies., Methods: The long-term (up to 204 weeks) safety and efficacy of imatinib in this open-label extension study were reviewed until early study termination on April 16, 2014. Of 202 IMPRES-enrolled patients, 66 imatinib and 78 placebo recipients entered the extension., Results: Overall, 93.8% (135 of 144) of patients discontinued the extension study; administrative issues (i.e., sponsor termination; 32.6%) and adverse events (31.3%) were the primary reasons for discontinuation. Nine patients completed the extension study before it was terminated. Serious and unexpected adverse events were frequent. These included 6 subdural hematomas in the extension study and 17 deaths during or within 30 days of study end. Although the patients who tolerated imatinib and remained in the extension for a longer duration did experience an improvement in functional class and walk distance, most discontinued the drug and the study., Conclusions: Severe adverse events, significant side effects, and a high discontinuation rate limit the utility of imatinib in the treatment of PAH. These risks outweigh any possible improvements in hemodynamics and walk distance seen in those patients able to remain on drug. The off-label use of this compound in PAH is discouraged., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2015
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16. Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension.
- Author
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Shao D, Perros F, Caramori G, Meng C, Dormuller P, Chou PC, Church C, Papi A, Casolari P, Welsh D, Peacock A, Humbert M, Adcock IM, and Wort SJ
- Subjects
- Base Sequence, Binding Sites, Case-Control Studies, Cells, Cultured, Endothelial Cells metabolism, Endothelium, Vascular cytology, Endothelium, Vascular metabolism, Familial Primary Pulmonary Hypertension pathology, Gene Expression Regulation, Humans, Inflammation Mediators metabolism, Interleukin-1 Receptor-Like 1 Protein, Interleukin-33, Interleukin-6 genetics, Interleukins blood, Interleukins genetics, Lung metabolism, Molecular Sequence Data, Promoter Regions, Genetic, Receptors, Cell Surface blood, Receptors, Cell Surface genetics, Signal Transduction, Familial Primary Pulmonary Hypertension metabolism, Interleukin-6 metabolism, Interleukins metabolism, Receptors, Cell Surface metabolism
- Abstract
Idiopathic pulmonary arterial hypertension (IPAH) is an incurable condition leading to right ventricular failure and death and inflammation is postulated to be associated with vascular remodelling. Interleukin (IL)-33, a member of the "alarmin" family can either act on the membrane ST2 receptor or as a nuclear repressor, to regulate inflammation. We show, using immunohistochemistry, that IL-33 expression is nuclear in the vessels of healthy subjects whereas nuclear IL-33 is markedly diminished in the vessels of IPAH patients. This correlates with reduced IL-33 mRNA expression in their lung. In contrast, serum levels of IL-33 are unchanged in IPAH. However, the expression of the soluble form of ST2, sST2, is enhanced in the serum of IPAH patients. Knock-down of IL-33 in human endothelial cells (ECs) using siRNA is associated with selective modulation of inflammatory genes involved in vascular remodelling including IL-6. Additionally, IL-33 knock-down significantly increased sST2 release from ECs. Chromatin immunoprecipitation demonstrated that IL-33 bound multiple putative homeodomain protein binding motifs in the proximal and distal promoters of ST2 genes. IL-33 formed a complex with the histone methyltransferase SUV39H1, a transcriptional repressor. In conclusion, IL-33 regulates the expression of IL-6 and sST2, an endogenous IL-33 inhibitor, in primary human ECs and may play an important role in the pathogenesis of PAH through recruitment of transcriptional repressor proteins., (Copyright © 2014 Elsevier Inc. All rights reserved.) more...
- Published
- 2014
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17. LA volume by CMR distinguishes idiopathic from pulmonary hypertension due to HFpEF.
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Crawley SF, Johnson MK, Dargie HJ, and Peacock AJ
- Subjects
- Cardiac Catheterization, Diagnosis, Differential, Humans, Hypertension, Pulmonary etiology, Hypertension, Pulmonary pathology, Hypertension, Pulmonary physiopathology, Predictive Value of Tests, Prospective Studies, Heart Atria pathology, Heart Failure complications, Hypertension, Pulmonary diagnosis, Magnetic Resonance Imaging, Stroke Volume, Ventricular Function, Left
- Published
- 2013
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18. Survival in pulmonary hypertension registries: the importance of incident cases.
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Condliffe R, Kiely DG, Coghlan JG, Gibbs JSR, Wort SJ, Corris PA, Peacock AJ, and Pepke-Zaba J
- Subjects
- Humans, Incidence, Prevalence, Reproducibility of Results, Hypertension, Pulmonary diagnosis, Hypertension, Pulmonary epidemiology, Registries
- Published
- 2011
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19. Effects of frozen storage and sample temperature on water compartmentation and multiexponential transverse relaxation in cartilage.
- Author
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Reiter DA, Peacock A, and Spencer RG
- Subjects
- Animals, Cattle, Computer Simulation, Freezing, Nasal Cartilages pathology, Reproducibility of Results, Specimen Handling, Temperature, Cartilage pathology, Magnetic Resonance Spectroscopy methods, Water chemistry
- Abstract
Multiexponential transverse relaxation in tissue has been interpreted as a marker of water compartmentation. Articular cartilage has been reported to exhibit such relaxation in several studies, with the relative contributions of tissue heterogeneity and tissue microstructure remaining unspecified. In bovine nasal cartilage, conflicting data regarding the existence of multiexponential relaxation have been reported. Imaging and analysis artifacts as well as rapid chemical exchange between tissue compartments have been identified as potential causes for this discrepancy. Here, we find that disruption of cartilage microstructure by freeze-thawing can greatly alter the character of transverse relaxation in this tissue. We conclude that fresh cartilage exhibits multiexponential relaxation based upon its microstructural water compartments, but that multiexponentiality can be lost or rendered undetectable by freeze-thawing. In addition, we find that increasing chemical exchange by raising sample temperature from 4°C to 37°C does not substantially limit the ability to detect multiexponential relaxation., (Published by Elsevier Inc.) more...
- Published
- 2011
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20. The relationship between the components of pulmonary artery pressure remains constant under all conditions in both health and disease.
- Author
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Syyed R, Reeves JT, Welsh D, Raeside D, Johnson MK, and Peacock AJ
- Subjects
- Adult, Aged, Aged, 80 and over, Blood Pressure Determination methods, Cardiac Catheterization, Female, Follow-Up Studies, Humans, Hypertension, Pulmonary diagnosis, Male, Middle Aged, Rest physiology, Retrospective Studies, Supine Position physiology, Hypertension, Pulmonary physiopathology, Pulmonary Wedge Pressure physiology
- Abstract
Background: The relationships among systolic pulmonary artery pressure (SPAP), diastolic pulmonary artery pressure (DPAP), and mean pulmonary artery pressure (MPAP) have been found to be constant in humans breathing air, at rest, while supine. It would be important for those studying the pulmonary circulation if this relationship were maintained under other circumstances, such as change in posture, during exercise, or after pharmacologic manipulation. In particular, it would be useful if the relationship were maintained when treating pulmonary hypertension because this would allow different methods of measurement to be compared, such as SPAP from echocardiography and MPAP from right heart catheterization., Methods: Data were reviewed from both healthy subjects and those with pulmonary hypertension (n = 65) who had a micromanometer-tipped, high-fidelity pulmonary artery catheter inserted for between 6 and 36 h in the Scottish Pulmonary Vascular Unit between 1997 and 2003. The 5-min averages, while the patient was supine at rest, were analyzed by linear regression to compare the response of SPAP and DPAP with MPAP., Results: There were linear relationships (measured in millimeters of mercury) of SPAP with MPAP (SPAP = 1.50 MPAP + 0.46), and DPAP with MPAP (DPAP = 0.71 MPAP - 0.66). These were maintained with a high degree of accuracy following changes in posture and activity., Conclusions: SPAP, MPAP, and DPAP were strongly related, and these relationships were maintained under varying conditions. This finding will allow comparison between invasive and noninvasive descriptions of pulmonary hemodynamics found in the literature. more...
- Published
- 2008
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21. Prognostic impact of pulmonary arterial hypertension: a population-based analysis.
- Author
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Carrington M, Murphy NF, Strange G, Peacock A, McMurray JJ, and Stewart S
- Subjects
- Adolescent, Adult, Age Distribution, Aged, Confidence Intervals, Female, Humans, Hypertension, Pulmonary therapy, Incidence, Logistic Models, Male, Middle Aged, Odds Ratio, Probability, Prognosis, Scotland epidemiology, Severity of Illness Index, Sex Distribution, Survival Analysis, Cause of Death, Hypertension, Pulmonary diagnosis, Hypertension, Pulmonary mortality
- Abstract
Background: Although pulmonary arterial hypertension (PAH) is widely accepted as deadly, if not a rare disease, its prognostic impact beyond reports from specialist centres is unknown., Methods: Using the unique Scottish Morbidity Record Scheme and linked survival data, we tracked the survival of all Scottish adults aged < or =65 years admitted for the first time during the period of 1986 to 2001 with a probable diagnosis of Idiopathic PAH and a PAH related to connective tissue disorders (Connective PAH) and congenital abnormalities (Congenital PAH) - the three most common forms of PAH., Results: Overall, 374 Scottish men and women were discharged from the hospital with incident PAH during the period 1986 to 2001. On an unadjusted basis, Congenital PAH (40-45%) was associated with the lowest case fatality at 5 years in both men and women. In both sexes, Idiopathic PAH and Connective PAH were associated with high initial one-year case fatality (20-30%) with a steady accumulation of fatal events in the four years thereafter (60-75% case fatality at 5 years). Overall, the adjusted risk of dying within one year in the period 1986 to 1989 was 2.22-fold greater (OR 95% CI, 1.27 to 3.85) than in 1998 to 2001 (P<0.001). The greatest falls in one year case fatality were seen in those with Connective PAH (18-fold increased risk of dying in 1986 to 1989 versus 1998 to 2001: P=0.013). Similarly, women (adjusted OR 1.38, 95% CI 1.16 to 1.63: P<0.001) and the most deprived individuals (OR 2.38, 95% CI 1.17 to 4.82: P<0.05) were at greater risk of dying within 5 years. Alternatively, those patients discharged in 1997 were less likely to die during this period compared to their 1986 counterparts, although this difference did not quite reach statistical significance (OR 0.45, 95% CI 0.22 to 1.06: P=0.056)., Conclusion: This population-based study has confirmed the deadly impact of the three most common forms of PAH. Overall, there are encouraging trends in relation to one and five year adjusted survival rates; particularly in relation to PAH related to connective tissue disorders. more...
- Published
- 2008
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22. Pulmonary arterial pulse pressure and mortality in pulmonary arterial hypertension.
- Author
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Blyth KG, Syyed R, Chalmers J, Foster JE, Saba T, Naeije R, Melot C, and Peacock AJ
- Subjects
- Aged, Blood Pressure, Diastole, Female, Humans, Hypertension, Pulmonary mortality, Male, Middle Aged, Prognosis, Proportional Hazards Models, Regression Analysis, Retrospective Studies, Survival Rate, Systole, Vascular Resistance, Ventricular Dysfunction, Right physiopathology, Hypertension, Pulmonary physiopathology, Pulmonary Artery physiopathology
- Abstract
In the Framingham studies, systemic arterial pulse pressure correlated linearly with morbidity and mortality. Right ventricular (RV) systolic dysfunction and pulmonary circulation stiffening result in abnormalities of pulmonary arterial (PA) pulse pressure in PA hypertension (PAH). We investigated the prognostic potential of PA pulse pressure in 67 patients with PAH diagnosed between January 1996 and March 2004 (33 idiopathic PAH, 34 PAH-connective tissue disease). The population was arbitrarily divided into tertiles of PA pulse pressure (= systolic-diastolic PA pressure) and 5-year mortality was assessed using the Kaplan-Meier method. The extent of RV systolic dysfunction and pulmonary circulation stiffening within each tertile was assessed by comparing the mean cardiac index and alpha (a recently described measure of pulmonary circulation distensibility) in each. Independent predictors of mortality were identified by Cox regression. Five-year mortality rates in patients with low, intermediate and high pulse pressures were 40%, 91% and 54%, respectively. Pulse pressure did not independently predict mortality, but cardiac index, 6-min walk test distance and mixed venous oxygen saturation did. Pulse pressure correlated with circulation stiffening (alpha) but did not correlate with cardiac index which tended to be lower in patients with intermediate pulse pressure and high mortality. PA pulse pressure correlated with pulmonary circulation stiffening but did not predict mortality in this study. RV dysfunction provided better prognostic information and probably explains the higher mortality seen in patients with intermediate pulse pressure. more...
- Published
- 2007
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23. Pulmonary artery pressure in healthy subjects at 4250 m measured by Doppler echocardiography.
- Author
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Dubowitz G and Peacock AJ
- Subjects
- Cross-Sectional Studies, Female, Humans, Male, Mountaineering, Altitude, Altitude Sickness diagnostic imaging, Echocardiography, Doppler, Color methods, Hypoxia diagnostic imaging, Pulmonary Wedge Pressure physiology
- Abstract
Objective: Acute hypoxia causes vasoconstriction in the pulmonary arteries. This hypoxic pulmonary vasoconstriction (HPV) has been reported to be common in subjects exposed to high altitude. In the past, it has been difficult to directly measure this HPV because of the invasive nature of tests, but the recent availability of portable color flow Doppler ultrasound has enabled measurements of pulmonary artery systolic pressure (PASP) in the field. We set out to study the feasibility of this method to detect changes related to HPV at 4250 m. We hypothesized that significant changes in the cardiopulmonary circulation are seen at high altitude and are detectable with Doppler echocardiography. In addition, we hypothesized that detected changes are related to the syndrome of acute mountain sickness (AMS) and could be reversed using 100% oxygen., Methods: Over a 10-week period in the spring of 1998, 56 healthy lowlanders not normally residing at altitude were studied while visiting 4250 m in Nepal having walked from 2774 m. This was a cross-sectional observational study conducted by a single experienced observer at high altitude, using transthoracic color flow continuous wave Doppler echocardiography. Subjects were initially assessed for significant tricuspid regurgitation (TR) to measure PASP. After estimating PASP under ambient conditions at altitude, oxygen was delivered and PASP remeasured., Results: Of 56 subjects, 36 had Doppler signals appropriate for estimation of pulmonary artery systolic pressure. In these 36, a wide range of PASP was observed (mean 25 mm Hg, range 18-36 mm Hg), but none fell outside of the normal range. After oxygen administration, PASP was reduced (from mean 25 mm Hg to mean 18 mm Hg, P<.0001) suggesting that a degree of hypoxic pulmonary vasoconstriction was present. No subjects in the study group reported clinical AMS., Conclusions: We found PASP at 4250 m to be within the normal range but higher than would be expected at sea level; however, unlike previous reports, we found such increases to be mild and reversible with oxygen. In addition, the observed incidence of AMS was low when compared with earlier studies, perhaps related to adequate acclimatization. more...
- Published
- 2007
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24. The role of p38 mitogen-activated protein kinase in hypoxia-induced vascular cell proliferation: an interspecies comparison.
- Author
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Welsh D, Mortimer H, Kirk A, and Peacock A
- Subjects
- Animals, Cattle, Extracellular Signal-Regulated MAP Kinases physiology, Humans, JNK Mitogen-Activated Protein Kinases physiology, Rats, Species Specificity, Hypoxia pathology, Pulmonary Artery pathology, p38 Mitogen-Activated Protein Kinases physiology
- Published
- 2005
- Full Text
- View/download PDF
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