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1. The six-minute walk test in sarcoidosis associated pulmonary hypertension: Results from an international registry

Author

Gupta, Rohit, Baughman, Robert P., Nathan, Steven D., Wells, Athol U., Kouranos, Vasilis, Alhamad, Esam H., Culver, Daniel A., Barney, Joseph, Carmona, Eva M., Cordova, Francis C., Huitema, Marloes, Scholand, Mary Beth, Wijsenbeek, Marlies, Ganesh, Sivagini, Birring, Surinder S., Price, Laura C., Wort, Stephen John, and Shlobin, Oksana A.

Published
2022
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2. Perioperative management of patients with pulmonary hypertension undergoing non-cardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement

Author

Price, Laura C., Martinez, Guillermo, Brame, Aimee, Pickworth, Thomas, Samaranayake, Chinthaka, Alexander, David, Garfield, Benjamin, Aw, Tuan-Chen, McCabe, Colm, Mukherjee, Bhashkar, Harries, Carl, Kempny, Aleksander, Gatzoulis, Michael, Marino, Philip, Kiely, David G., Condliffe, Robin, Howard, Luke, Davies, Rachel, Coghlan, Gerry, Schreiber, Benjamin E., Lordan, James, Taboada, Dolores, Gaine, Sean, Johnson, Martin, Church, Colin, Kemp, Samuel V., Wong, Davina, Curry, Andrew, Levett, Denny, Price, Susanna, Ledot, Stephane, Reed, Anna, Dimopoulos, Konstantinos, and Wort, Stephen John

Published
2021
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9. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Developed by the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG)

Author

Humbert, Marc, Kovacs, Gabor, Hoeper, Marius M., Badagliacca, Roberto, Berger, Rolf M. F., Brida, Margarita, Carlsen, Jorn, Coats, Andrew J. S., Escribano-Subias, Pilar, Ferrari, Pisana, Ferreira, Diogenes S., Ghofrani, Hossein Ardeschir, Giannakoulas, George, Kiely, David G., Mayer, Eckhard, Meszaros, Gergely, Nagavci, Blin, Olsson, Karen M., Pepke-Zaba, Joanna, Quint, Jennifer K., Radegran, Goran, Simonneau, Gerald, Sitbon, Olivier, Tonia, Thomy, Toshner, Mark, Vachiery, Jean-Luc, Noordegraaf, Anton Vonk, Delcroix, Marion, Rosenkranz, Stephan, Schwerzmann, Markus, Bush, Andy, Abdelhamid, Magdy, Aboyans, Victor, Arbustini, Eloisa, Asteggiano, Riccardo, Barbera, Joan-Albert, Beghetti, Maurice, Cikes, Maja, Condliffe, Robin, de Man, Frances, Falk, Volkmar, Fauchier, Laurent, Gaine, Sean, Galie, Nazzareno, Gin-Sing, Wendy, Granton, John, Grunig, Ekkehard, Hassoun, Paul M., Hellemons, Merel, Jaarsma, Tiny, Kjellstrom, Barbro, Klok, Frederikus A., Konradi, Aleksandra, Koskinas, Konstantinos C., Kotecha, Dipak, Lang, Irene, Lewis, Basil S., Linhart, Ales, Lip, Gregory Y. H., Lochen, Maja-Lisa, Mathioudakis, Alexander G., Mindham, Richard, Moledina, Shahin, Naeije, Robert, Nielsen, Jens Cosedis, Olschewski, Horst, Opitz, Isabelle, Petersen, Steffen E., Prescott, Eva, Rakisheva, Amina, Reis, Abilio, Ristic, Arsen D., Roche, Nicolas, Rodrigues, Rita, Selton-Suty, Christine, Souza, Rogerio, Swift, Andrew J., Touyz, Rhian M., Ulrich, Silvia, Wilkins, Martin R., Wort, Stephen John, Humbert, Marc, Kovacs, Gabor, Hoeper, Marius M., Badagliacca, Roberto, Berger, Rolf M. F., Brida, Margarita, Carlsen, Jorn, Coats, Andrew J. S., Escribano-Subias, Pilar, Ferrari, Pisana, Ferreira, Diogenes S., Ghofrani, Hossein Ardeschir, Giannakoulas, George, Kiely, David G., Mayer, Eckhard, Meszaros, Gergely, Nagavci, Blin, Olsson, Karen M., Pepke-Zaba, Joanna, Quint, Jennifer K., Radegran, Goran, Simonneau, Gerald, Sitbon, Olivier, Tonia, Thomy, Toshner, Mark, Vachiery, Jean-Luc, Noordegraaf, Anton Vonk, Delcroix, Marion, Rosenkranz, Stephan, Schwerzmann, Markus, Bush, Andy, Abdelhamid, Magdy, Aboyans, Victor, Arbustini, Eloisa, Asteggiano, Riccardo, Barbera, Joan-Albert, Beghetti, Maurice, Cikes, Maja, Condliffe, Robin, de Man, Frances, Falk, Volkmar, Fauchier, Laurent, Gaine, Sean, Galie, Nazzareno, Gin-Sing, Wendy, Granton, John, Grunig, Ekkehard, Hassoun, Paul M., Hellemons, Merel, Jaarsma, Tiny, Kjellstrom, Barbro, Klok, Frederikus A., Konradi, Aleksandra, Koskinas, Konstantinos C., Kotecha, Dipak, Lang, Irene, Lewis, Basil S., Linhart, Ales, Lip, Gregory Y. H., Lochen, Maja-Lisa, Mathioudakis, Alexander G., Mindham, Richard, Moledina, Shahin, Naeije, Robert, Nielsen, Jens Cosedis, Olschewski, Horst, Opitz, Isabelle, Petersen, Steffen E., Prescott, Eva, Rakisheva, Amina, Reis, Abilio, Ristic, Arsen D., Roche, Nicolas, Rodrigues, Rita, Selton-Suty, Christine, Souza, Rogerio, Swift, Andrew J., Touyz, Rhian M., Ulrich, Silvia, Wilkins, Martin R., and Wort, Stephen John

Published
2022

10. The CRASH report: emergency management dilemmas facing acute physicians in patients with pulmonary arterial hypertension

Author

Price, Laura C, Dimopoulos, Konstantinos, Marino, Philip, Alonso-Gonzalez, Rafael, McCabe, Colm, Kemnpy, Aleksander, Swan, Lorna, Boutsikou, Maria, Al Zahrani, Ahmed, Coghlan, Gerry J, Schreiber, Benjamin E, Howard, Luke S, Davies, Rachel, Toshner, Mark, Pepke-Zaba, Joanna, Church, Alistair C, Peacock, Andrew, Corris, Paul A, Lordan, James L, Gaine, Sean, Condliffe, Robin, Kiely, David G, and Wort, Stephen John

Published
2017
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11. Pathogenesis, clinical features, and phenotypes of pulmonary hypertension associated with interstitial lung disease: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative - Group 3 Pulmonary Hypertension

Author

Piccari, Lucilla, Allwood, Brian, Antoniou, Katerina, Chung, Jonathan H., Hassoun, Paul M., Nikkho, Sylvia M., Saggar, Rajan, Shlobin, Oksana A., Vitulo, Patrizio, Nathan, Steven D., and Wort, Stephen John

Subjects
IDIOPATHIC pulmonary fibrosis, INTERSTITIAL lung diseases, DRUG development, PULMONARY fibrosis, CONNECTIVE tissue diseases, PULMONARY emphysema, PULMONARY hypertension
Abstract

Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular and genetic pathways, with panvascular histopathologic changes, multiple pathophysiologic sequelae, and profound clinical ramifications. While there are some recognized clinical phenotypes such as combined pulmonary fibrosis and emphysema and some possible phenotypes such as connective tissue disease associated with ILD and PH, the identification of further phenotypes of PH in ILD has thus far proven elusive. This statement reviews the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect phenotypes of PH in ILD. Distinct phenotypes warrant recognition if they are characterized through either a distinct presentation, clinical course, or treatment response. Furthermore, we propose a set of recommendations for future studies that might enable the recognition of new phenotypes. [ABSTRACT FROM AUTHOR]

Published
2023
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13. Use of Pulmonary Arterial Hypertension Therapies in Patients with a Fontan Circulation: Current Practice Across the United Kingdom

Author

Constantine, Andrew, primary, Dimopoulos, Konstantinos, additional, Jenkins, Petra, additional, Tulloh, Robert M. R., additional, Condliffe, Robin, additional, Jansen, Katrijn, additional, Chung, Natali A. Y., additional, Oliver, James, additional, Parry, Helen, additional, Fitzsimmons, Samantha, additional, Walker, Niki, additional, Wort, Stephen John, additional, Papaioannou, Vasilios, additional, von Klemperer, Kate, additional, Clift, Paul, additional, Moledina, Shahin, additional, and Constantine, Andrew, additional

Published
2022
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14. Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Author

Zhu, Na, Swietlik, Emilia M., Welch, Carrie L., Pauciulo, Michael W., Hagen, Jacob J., Zhou, Xueya, Guo, Yicheng, Karten, Johannes, Pandya, Divya, Tilly, Tobias, Lutz, Katie A., Martin, Jennifer M., Treacy, Carmen M., Rosenzweig, Erika B., Krishnan, Usha, Coleman, Anna W., Gonzaga-Jauregui, Claudia, Lawrie, Allan, Trembath, Richard C., Wilkins, Martin R., Morrell, Nicholas W., Shen, Yufeng, Gräf, Stefan, Nichols, William C., Chung, Wendy K., Hirsch, Russel, White, R. James, Simon, Marc, Badesch, David, Rosenzweig, Erika, Burger, Charles, Chakinala, Murali, Thenappan, Thenappan, Elliott, Greg, Simms, Robert, Farber, Harrison, Frantz, Robert, Elwing, Jean, Hill, Nicholas, Ivy, Dunbar, Klinger, James, Nathan, Steven, Oudiz, Ronald, Robbins, Ivan, Schilz, Robert, Fortin, Terry, Wilt, Jeffrey, Yung, Delphine, Austin, Eric, Ahmad, Ferhaan, Bhatt, Nitin, Lahm, Tim, Frost, Adaani, Safdar, Zeenat, Rehman, Zia, Walter, Robert, Torres, Fernando, Bakshi, Sahil, Archer, Stephen, Argula, Rahul, Barnett, Christopher, Benza, Raymond, Desai, Ankit, Maddipati, Veeranna, Bogaard, Harm J., Church, Colin, Coghlin, Gerry, Condliffe, Robin, Eyries, Mélanie, Gall, Henning, Ghio, Stefano, Girerd, Barbara, Holden, Simon, Howard, Luke, Humbert, Marc, Kiely, David G., Kovacs, Gabor, Lordan, Jim, Machado, Rajiv D., MacKenzie Ross, Robert V., McCabe, Colm, Moledina, Shahin, Montani, David, Olschewski, Horst, Penkett, Christopher J., Pepke-Zaba, Joanna, Price, Laura, Rhodes, Christopher J., Seeger, Werner, Soubrier, Florent, Southgate, Laura, Suntharalingam, Jay, Swift, Andrew J., Toshner, Mark R., Noordegraaf, Anton Vonk, Wharton, John, Wild, Jim, Wort, Stephen John, and Apollo - University of Cambridge Repository

Subjects
Exome sequencing, Case-control association testing, Research, FOS: Biological sciences, Genetics, De novo variant analysis, Pulmonary arterial hypertension, Genome sequencing
Abstract

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods: To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results: Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions: Rare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.

Published
2021
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17. The Effect of Borderline Pulmonary Hypertension on Survival in Chronic Lung Disease.

Author

Piccari, Lucilla, Wort, Stephen John, Meloni, Federica, Rizzo, Monica, Price, Laura C., Martino, Lavinia, Salvaterra, Elena, Scelsi, Laura, López Meseguer, Manuel, Blanco, Isabel, Callari, Adriana, Pérez González, Virginia, Tuzzolino, Fabio, McCabe, Colm, Rodríguez Chiaradía, Diego Agustín, and Vitulo, Patrizio

Subjects
*BLOOD pressure, *CONFIDENCE intervals, *PULMONARY hypertension, *INTERSTITIAL lung diseases, *RETROSPECTIVE studies, *PULMONARY artery, *OBSTRUCTIVE lung diseases, *DESCRIPTIVE statistics, *DISEASE prevalence, *HEMODYNAMICS
Abstract

Background: The impact of the new "borderline" hemodynamic class for pulmonary hypertension (PH) (mean pulmonary artery pressure [mPAP], 21–24 mm Hg and pulmonary vascular resistance, [PVR], ≥3 wood units, [WU]) in chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) is unclear. Objectives: The aim of this study was to assess the effect of borderline PH (BLPH) on survival in COPD and ILD patients. Method: Survival was analyzed from retrospective data from 317 patients in 12 centers (Italy, Spain, UK) comparing four hemodynamic groups: the absence of PH (NoPH; mPAP <21 mm Hg or 21–24 mm Hg and PVR <3 WU), BLPH (mPAP 21–24 mm Hg and PVR ≥3 WU), mild-moderate PH (MPH; mPAP 25–35 mm Hg and cardiac index [CI] ≥2 L/min/m2), and severe PH (SPH; mPAP ≥35 mm Hg or mPAP ≥25 mm Hg and CI <2 L/min/m2). Results: BLPH affected 14% of patients; hemodynamic severity did not predict survival when COPD and ILD patients were analyzed together. However, survival in the ILD cohort for any PH level was worse than in NoPH (3-year survival: NoPH 58%, BLPH 32%, MPH 28%, SPH 33%, p = 0.002). In the COPD cohort, only SPH had reduced survival compared to the other groups (3-year survival: NoPH 82%, BLPH 86%, MPH 87%, SPH 57%, p = 0.005). The mortality risk correlated significantly with mPAP in ILD (hazard ratio [HR]: 2.776, 95% CI: 2.057–3.748, p < 0.001) and notably less in COPD patients (HR: 1.015, 95% CI: 1.003–1.027, p = 0.0146). Conclusions: In ILD, any level of PH portends worse survival, while in COPD, only SPH presents a worse outcome. [ABSTRACT FROM AUTHOR]

Published
2022
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18. Right ventricular dysfunction in critically ill COVID-19 ARDS

Author

Bleakley, Caroline, primary, Singh, Suveer, additional, Garfield, Benjamin, additional, Morosin, Marco, additional, Surkova, Elena, additional, Mandalia, Ms Sundhiya, additional, Dias, Bernardo, additional, Androulakis, Emmanouil, additional, Price, Laura C., additional, McCabe, Colm, additional, Wort, Stephen John, additional, West, Cathy, additional, Li, Wei, additional, Khattar, Rajdeep, additional, Senior, Roxy, additional, Patel, Brijesh V., additional, and Price, Susanna, additional

Published
2021
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19. Reduced transfer coefficient of carbon monoxide in pulmonary arterial hypertension implicates rare protein-truncating variants in KDR

Author

Swietlik, Emilia M., Greene, Daniel, Zhu, Na, Megy, Karyn, Cogliano, Marcella, Rajaram, Smitha, Pandya, Divya, Tilly, Tobias, Lutz, Katie A., Welch, Carrie C. L., Pauciulo, Michael W., Southgate, Laura, Martin, Jennifer M., Treacy, Carmen M., Bogaard, Harm J., Church, Colin, Coghlan, Gerry, Coleman, Anna W., Condliffe, Robin, Eyries, Mélanie, Gall, Henning, Ghio, Stefano, Girerd, Barbara, Holden, Simon, Howard, Luke, Humbert, Marc, Kiely, David G., Kovacs, Gabor, Lordan, Jim, Machado, Rajiv D., MacKenzie Ross, Robert V., Moledina, Shahin, Montani, David, Olschewski, Horst, Pepke-Zaba, Joanna, Rhodes, Christopher J., Seeger, Werner, Soubrier, Florent, Suntharalingam, Jay, Toshner, Mark R., Noordegraaf, Anton Vonk, Wharton, John, Wild, Jim, Wort, Stephen John, Lawrie, Allan, Wilkins, Martin R., Trembath, Richard C., Shen, Yufeng, Chung, Wendy K., Swift, Andrew J., Nichols, William C., Morrell, Nicholas W., and Gräf, Stefan

Abstract

Background To date, approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbour rare mutations in disease-causing genes. Given the small number of patients affected by mutations in most PAH genes, the identification of the missing heritability in PAH is challenging. We hypothesised that integrating deep phenotyping data with whole-genome sequencing data will reveal additional disease variants that are extremely rare and/or have a unique phenotypic signature. Methods We analysed whole-genome sequencing data from 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NIHRBR-RD) study, of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. We defined the groups for comparison by assigning labels (‘tags’) inferred from the current diagnostic classification of PAH, stratification by age at diagnosis and transfer coefficient of carbon monoxide (KCO). Results Protein truncating variants (PTV) in KDR were strongly associated with the lower KCO tertile (posterior probability (PP)=0.989) and the higher age tertile (PP=0.912) groups. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the patients harbouring PTV in KDR . KCO stratification also highlighted an association between Isocitrate Dehydrogenase (NAD(+)) 3 Non-Catalytic Subunit Gamma ( IDH3G ) and moderately reduced KCO in patients with pulmonary hypertension (PP=0.920). The US PAH Biobank was used to independently validate these findings and identified four additional PAH cases with PTV in KDR and two in IDH3G . We confirmed associations between previously established genes and PAH. Conclusions PTVs in KDR , the gene encoding vascular endothelial growth factor receptor 2 (VEGFR2), are significantly associated with two specific phenotypes of PAH, reduced KCO and later age of onset, highlighting a role for VEGF signalling in the pathogenesis of human PAH. We also report IDH3G as a new PAH risk gene. Moreover, we demonstrate that the use of deep clinical phenotyping data advances the identification of novel causative rare variants.

Published
2019
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20. Bayesian Inference Associates Rare KDR Variants With Specific Phenotypes in Pulmonary Arterial Hypertension

Author

Swietlik, Emilia M., primary, Greene, Daniel, additional, Zhu, Na, additional, Megy, Karyn, additional, Cogliano, Marcella, additional, Rajaram, Smitha, additional, Pandya, Divya, additional, Tilly, Tobias, additional, Lutz, Katie A., additional, Welch, Carrie C.L., additional, Pauciulo, Michael W., additional, Southgate, Laura, additional, Martin, Jennifer M., additional, Treacy, Carmen M., additional, Penkett, Christopher J., additional, Stephens, Jonathan C., additional, Bogaard, Harm J., additional, Church, Colin, additional, Coghlan, Gerry, additional, Coleman, Anna W., additional, Condliffe, Robin, additional, Eichstaedt, Christina A., additional, Eyries, Mélanie, additional, Gall, Henning, additional, Ghio, Stefano, additional, Girerd, Barbara, additional, Grünig, Ekkehard, additional, Holden, Simon, additional, Howard, Luke, additional, Humbert, Marc, additional, Kiely, David G., additional, Kovacs, Gabor, additional, Lordan, Jim, additional, Machado, Rajiv D., additional, MacKenzie Ross, Robert V., additional, McCabe, Colm, additional, Moledina, Shahin, additional, Montani, David, additional, Olschewski, Horst, additional, Pepke-Zaba, Joanna, additional, Price, Laura, additional, Rhodes, Christopher J., additional, Seeger, Werner, additional, Soubrier, Florent, additional, Suntharalingam, Jay, additional, Toshner, Mark R., additional, Vonk Noordegraaf, Anton, additional, Wharton, John, additional, Wild, James M., additional, Wort, Stephen John, additional, Lawrie, Allan, additional, Wilkins, Martin R., additional, Trembath, Richard C., additional, Shen, Yufeng, additional, Chung, Wendy K., additional, Swift, Andrew J., additional, Nichols, William C., additional, Morrell, Nicholas W., additional, Gräf, Stefan, additional, Abbs, Stephen, additional, Abulhoul, Lara, additional, Adlard, Julian, additional, Ahmed, Munaza, additional, Aitman, Timothy J., additional, Alachkar, Hana, additional, Allsup, David J., additional, Ancliff, Philip, additional, Antrobus, Richard, additional, Armstrong, Ruth, additional, Arno, Gavin, additional, Ashford, Sofie, additional, Astle, William J., additional, Attwood, Anthony, additional, Aurora, Paul, additional, Babbs, Christian, additional, Bacchelli, Chiara, additional, Bakchoul, Tamam, additional, Banka, Siddharth, additional, Bariana, Tadbir, additional, Barwell, Julian, additional, Batista, Joana, additional, Baxendale, Helen E., additional, Beales, Phil L., additional, Bennett, David L., additional, Bierzynska, Agnieszka, additional, Biss, Tina, additional, Bitner-Glindzicz, Maria A.K., additional, Black, Graeme C., additional, Bleda, Marta, additional, Blesneac, Iulia, additional, Bockenhauer, Detlef, additional, Boyce, Sara, additional, Bradley, John R., additional, Breen, Gerome, additional, Brennan, Paul, additional, Brewer, Carole, additional, Brown, Matthew, additional, Browning, Andrew C., additional, Browning, Michael J., additional, Buchan, Rachel J., additional, Buckland, Matthew S., additional, Bueser, Teofila, additional, Diz, Carmen Bugarin, additional, Burn, John, additional, Burns, Siobhan O., additional, Burren, Oliver S., additional, Burrows, Nigel, additional, Campbell, Carolyn, additional, Carr-White, Gerald, additional, Carss, Keren, additional, Casey, Ruth, additional, Caulfield, Mark J., additional, Chambers, Jenny, additional, Chambers, John, additional, Chan, Melanie M.Y., additional, Cheng, Floria, additional, Chinnery, Patrick F., additional, Chitre, Manali, additional, Christian, Martin T., additional, Clayton-Smith, Jill, additional, Cleary, Maureen, additional, Brod, Naomi Clements, additional, Colby, Elizabeth, additional, Cole, Trevor R.P., additional, Collins, Janine, additional, Collins, Peter W., additional, Compton, Cecilia J., additional, Cook, H. Terence, additional, Cook, Stuart, additional, Cooper, Nichola, additional, Corris, Paul A., additional, Curry, Nicola S., additional, Daniels, Matthew J., additional, Dattani, Mehul, additional, Daugherty, Louise C., additional, Davis, John, additional, De Soyza, Anthony, additional, Deevi, Sri V.V., additional, Dent, Timothy, additional, Deshpande, Charu, additional, Dewhurst, Eleanor F., additional, Dixon, Peter H., additional, Douzgou, Sofia, additional, Downes, Kate, additional, Drazyk, Anna M., additional, Drewe, Elizabeth, additional, Duarte, Daniel, additional, Dutt, Tina, additional, Edgar, J. David M., additional, Edwards, Karen, additional, Egner, William, additional, Ekani, Melanie N., additional, Elliott, Perry, additional, Erber, Wendy N., additional, Erwood, Marie, additional, Estiu, Maria C., additional, Evans, Dafydd Gareth, additional, Evans, Gillian, additional, Everington, Tamara, additional, Fassihi, Hiva, additional, Favier, Remi, additional, Fletcher, Debra, additional, Flinter, Frances A., additional, Floto, R. Andres, additional, Fowler, Tom, additional, Fox, James, additional, Frary, Amy J., additional, French, Courtney E., additional, Freson, Kathleen, additional, Frontini, Mattia, additional, Furnell, Abigail, additional, Gale, Daniel P., additional, Ganesan, Vijeya, additional, Gattens, Michael, additional, Ghofrani, Hossein-Ardeschir, additional, Gibbs, J. Simon R., additional, Gibson, Kate, additional, Gilmour, Kimberly C., additional, Gleadall, Nicholas S., additional, Goddard, Sarah, additional, Gomez, Keith, additional, Gordins, Pavels, additional, Gosal, David, additional, Graham, Jodie, additional, Grassi, Luigi, additional, Greenhalgh, Lynn, additional, Greinacher, Andreas, additional, Gresele, Paolo, additional, Griffiths, Philip, additional, Grigoriadou, Sofia, additional, Grozeva, Detelina, additional, Gurnell, Mark, additional, Hackett, Scott, additional, Hadinnapola, Charaka, additional, Hague, Rosie, additional, Hague, William M., additional, Haimel, Matthias, additional, Hall, Matthew, additional, Hanson, Helen L., additional, Haque, Eshika, additional, Harkness, Kirsty, additional, Harper, Andrew R., additional, Harris, Claire L., additional, Hart, Daniel, additional, Hassan, Ahamad, additional, Hayman, Grant, additional, Henderson, Alex, additional, Herwadkar, Archana, additional, Hoffman, Jonathan, additional, Horvath, Rita, additional, Houlden, Henry, additional, Houweling, Arjan C., additional, Hu, Fengyuan, additional, Hudson, Gavin, additional, Huissoon, Aarnoud P., additional, Hurles, Matthew, additional, Irving, Melita, additional, Izatt, Louise, additional, James, Roger, additional, Johnson, Sally A., additional, Jolles, Stephen, additional, Jolley, Jennifer, additional, Josifova, Dragana, additional, Jurkute, Neringa, additional, Kasanicki, Mary A., additional, Kazkaz, Hanadi, additional, Kazmi, Rashid, additional, Kelleher, Peter, additional, Kelly, Anne M, additional, Kelsall, Wilf, additional, Kempster, Carly, additional, Kingston, Nathalie, additional, Koelling, Nils, additional, Kostadima, Myrto, additional, Koziell, Ania, additional, Kreuzhuber, Roman, additional, Kuijpers, Taco W., additional, Kumar, Ajith, additional, Kumararatne, Dinakantha, additional, Kurian, Manju A., additional, Laffan, Michael A., additional, Lalloo, Fiona, additional, Lambert, Michele, additional, Allen, Hana Lango, additional, Layton, D. Mark, additional, Lentaigne, Claire, additional, Lester, Tracy, additional, Levine, Adam P., additional, Linger, Rachel, additional, Longhurst, Hilary, additional, Lorenzo, Lorena E., additional, Louka, Eleni, additional, Lyons, Paul A., additional, Madan, Bella, additional, Maher, Eamonn R., additional, Maimaris, Jesmeen, additional, Malka, Samantha, additional, Mangles, Sarah, additional, Mapeta, Rutendo, additional, Marchbank, Kevin J., additional, Marks, Stephen, additional, Markus, Hugh S., additional, Marschall, Hanns-Ulrich, additional, Marshall, Andrew, additional, Mathias, Mary, additional, Matthews, Emma, additional, Maxwell, Heather, additional, McAlinden, Paul, additional, McCarthy, Mark I., additional, McKinney, Harriet, additional, Meacham, Stuart, additional, Mead, Adam J., additional, Mehta, Sarju G., additional, Michaelides, Michel, additional, Millar, Carolyn, additional, Mohammed, Shehla N., additional, Moore, Anthony T., additional, Mozere, Monika, additional, Muir, Keith W., additional, Mumford, Andrew D., additional, Nemeth, Andrea H., additional, Newman, William G., additional, Newnham, Michael, additional, Noorani, Sadia, additional, Nurden, Paquita, additional, O’Sullivan, Jennifer, additional, Obaji, Samya, additional, Odhams, Chris, additional, Okoli, Steven, additional, Olschewski, Andrea, additional, Ong, Kai Ren, additional, Oram, S. Helen, additional, Ormondroyd, Elizabeth, additional, Ouwehand, Willem H., additional, Palles, Claire, additional, Papadia, Sofia, additional, Park, Soo-Mi, additional, Parry, David, additional, Patel, Smita, additional, Paterson, Joan, additional, Peacock, Andrew, additional, Pearce, Simon H., additional, Peerlinck, Kathelijne, additional, Petersen, Romina, additional, Pilkington, Clarissa, additional, Poole, Kenneth E.S., additional, Psaila, Bethan, additional, Pyle, Angela, additional, Quinton, Richard, additional, Rahman, Shamima, additional, Rao, Anupama, additional, Raymond, F. Lucy, additional, Rayner-Matthews, Paula J., additional, Rendon, Augusto, additional, Renton, Tara, additional, Rice, Andrew S.C., additional, Richter, Alex, additional, Robert, Leema, additional, Roberts, Irene, additional, Rose, Sarah J., additional, Ross-Russell, Robert, additional, Roughley, Catherine, additional, Roy, Noemi B.A., additional, Ruddy, Deborah M., additional, Sadeghi-Alavijeh, Omid, additional, Saleem, Moin A., additional, Samani, Nilesh, additional, Samarghitean, Crina, additional, Sanchis-Juan, Alba, additional, Sargur, Ravishankar B., additional, Sarkany, Robert N., additional, Satchell, Simon, additional, Savic, Sinisa, additional, Sayer, Genevieve, additional, Sayer, John A., additional, Scelsi, Laura, additional, Schaefer, Andrew M., additional, Schulman, Sol, additional, Scott, Richard, additional, Scully, Marie, additional, Searle, Claire, additional, Sen, Arjune, additional, Sewell, W.A. Carrock, additional, Seyres, Denis, additional, Shah, Neil, additional, Shamardina, Olga, additional, Shapiro, Susan E., additional, Shaw, Adam C., additional, Sibson, Keith, additional, Side, Lucy, additional, Simeoni, Ilenia, additional, Simpson, Michael A., additional, Sims, Matthew C., additional, Sivapalaratnam, Suthesh, additional, Smedley, Damian, additional, Smith, Katherine R., additional, Smith, Kenneth G.C., additional, Snape, Katie, additional, Soranzo, Nicole, additional, Spasic-Boskovic, Olivera, additional, Staines, Simon, additional, Staples, Emily, additional, Stark, Hannah, additional, Stirrups, Kathleen E., additional, Stuckey, Alex, additional, Syrris, Petros, additional, Tait, R. Campbell, additional, Talks, Kate, additional, Tan, Rhea Y.Y., additional, Taylor, Jenny C., additional, Taylor, John M., additional, Thaventhiran, James E., additional, Themistocleous, Andreas C., additional, Thomas, David, additional, Thomas, Ellen, additional, Thomas, Moira J., additional, Thomas, Patrick, additional, Thomson, Kate, additional, Thrasher, Adrian J., additional, Thys, Chantal, additional, Tischkowitz, Marc, additional, Titterton, Catherine, additional, Toh, Cheng-Hock, additional, Tomlinson, Ian P., additional, Traylor, Matthew, additional, Treadaway, Paul, additional, Tuna, Salih, additional, Turro, Ernest, additional, Twiss, Philip, additional, Vale, Tom, additional, Van Geet, Chris, additional, van Zuydam, Natalie, additional, Vandersteen, Anthony M, additional, Vazquez-Lopez, Marta, additional, von Ziegenweidt, Julie, additional, Wagner, Annette, additional, Waisfisz, Quinten, additional, Walker, Neil, additional, Walker, Suellen M., additional, Ware, James S., additional, Watkins, Hugh, additional, Watt, Christopher, additional, Webster, Andrew R., additional, Wedderburn, Lucy, additional, Wei, Wei, additional, Welch, Steven B., additional, Wessels, Julie, additional, Westbury, Sarah K., additional, Westwood, John-Paul, additional, Whitehorn, Deborah, additional, Whitworth, James, additional, Wilkie, Andrew O.M., additional, Williamson, Catherine, additional, Wilson, Brian T., additional, Wong, Edwin K.S., additional, Wood, Nicholas, additional, Wood, Yvette, additional, Woods, Christopher Geoffrey, additional, Woodward, Emma R., additional, Worth, Austen, additional, Wright, Michael, additional, Yates, Katherine, additional, Yong, Patrick F.K., additional, Young, Timothy, additional, Yu, Ping, additional, Yu-Wai-Man, Patrick, additional, Zlamalova, Eliska, additional, Hirsch, Russel, additional, White, R. James, additional, Simon, Marc, additional, Badesch, David, additional, Rosenzweig, Erika, additional, Burger, Charles, additional, Chakinala, Murali, additional, Thenappan, Thenappan, additional, Elliott, Greg, additional, Simms, Robert, additional, Farber, Harrison, additional, Frantz, Robert, additional, Elwing, Jean, additional, Hill, Nicholas, additional, Ivy, Dunbar, additional, Klinger, James, additional, Nathan, Steven, additional, Oudiz, Ronald, additional, Robbins, Ivan, additional, Schilz, Robert, additional, Fortin, Terry, additional, Wilt, Jeffrey, additional, Yung, Delphine, additional, Austin, Eric, additional, Ahmad, Ferhaan, additional, Bhatt, Nitin, additional, Lahm, Tim, additional, Frost, Adaani, additional, Safdar, Zeenat, additional, Rehman, Zia, additional, Walter, Robert, additional, Torres, Fernando, additional, Bakshi, Sahil, additional, Archer, Stephen, additional, Argula, Rahul, additional, Barnett, Christopher, additional, Benza, Raymond, additional, Desai, Ankit, additional, and Maddipati, Veeranna, additional

Published
2021
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23. Growth/differentiation factor 15 causes TGFβ-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension

Author

Garfield, Benjamin E, primary, Crosby, Alexi, additional, Shao, Dongmin, additional, Yang, Peiran, additional, Read, Cai, additional, Sawiak, Steven, additional, Moore, Stephen, additional, Parfitt, Lisa, additional, Harries, Carl, additional, Rice, Martin, additional, Paul, Richard, additional, Ormiston, Mark L, additional, Morrell, Nicholas W, additional, Polkey, Michael I, additional, Wort, Stephen John, additional, and Kemp, Paul R, additional

Published
2018
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25. A stepwise composite echocardiographic score predicts severe pulmonary hypertension in patients with interstitial lung disease

Author

Bax, Simon, primary, Bredy, Charlene, additional, Kempny, Aleksander, additional, Dimopoulos, Konstantinos, additional, Devaraj, Anand, additional, Walsh, Simon, additional, Jacob, Joseph, additional, Nair, Arjun, additional, Kokosi, Maria, additional, Keir, Gregory, additional, Kouranos, Vasileios, additional, George, Peter M., additional, McCabe, Colm, additional, Wilde, Michael, additional, Wells, Athol, additional, Li, Wei, additional, Wort, Stephen John, additional, and Price, Laura C., additional

Published
2018
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26. Pulmonary hypertension in interstitial lung disease: non-invasive techniques for screening and diagnosis

Author

Macdonald, Peter, Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW, Wells, Athol, Royal Brompton Hospital, London, UK, Wort, Stephen John, Royal Brompton Hospital, London, UK, Keir, Gregory, Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW, Macdonald, Peter, Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW, Wells, Athol, Royal Brompton Hospital, London, UK, Wort, Stephen John, Royal Brompton Hospital, London, UK, and Keir, Gregory, Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW

Abstract

Background: Pulmonary hypertension (PH) complicating interstitial lung disease (ILD) may be associated with significant morbidity and mortality. Transthoracic echocardiography (TTE), the most widely used screening test for PH, may be inaccurate in up to 50% of ILD patients. We evaluate the utility of TTE, in isolation and in combination with several non-invasive screening tests, for predicting the presence and severity of ILD-PH. Novel techniques, including non-invasive assessment of pulmonary blood flow and dual energy CT pulmonary angiography (DE-CTPA), were also evaluated for identifying pulmonary vasospasm in systemic sclerosis (SSc).Methods: In 265 consecutive patients with ILD and suspected PH, the predictive utility of the updated European Society of Cardiology/European Respiratory Society (ESC/ERS) TTE PH screening recommendations was evaluated against RHC testing. In a subgroup of 114 patients, combined non-invasive investigations (including TTE, respiratory function tests, brain natriuretic peptide (BNP), vascular dimensions on CT, and 6 minute walk test) was assessed for predicting PH. Equations predicting the presence and severity of PH were then tested prospectively in a validation cohort. Results: In patients classified as ‘high probability’ of PH by ESC/ERS TTE criteria, PH was confirmed on RHC in 86%. However, 40% of patients were misclassified as ‘low probability’ of PH (tricuspid regurgitation velocity <2.8 m/s), when PH was confirmed on subsequent RHC. At regression analysis, TTE derived right ventricular systolic pressure (RVSP) (R2=0.37; p<0.01), BNP (R2=0.25; p<0.01), and main pulmonary artery diameter (mPA) on CT scan (R2=0.23; p<0.01) correlated most strongly with RHC measured mean pulmonary artery pressure (mPAP), and a ‘best fit’ equation for predicting mPAP (tested in the validation cohort) was more strongly predictive of PH (with a receiver operating characteristic AUC of 0.93) than any single non-invasive test in isolation.Conclusion: Cu

Published
2017

27. Growth/differentiation factor 15 causes TGFβ-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension.

Author

Garfield, Benjamin E., Crosby, Alexi, Shao, Dongmin, Yang, Peiran, Read, Cai, Sawiak, Steven, Moore, Stephen, Parfitt, Lisa, Harries, Carl, Rice, Martin, Paul, Richard, Ormiston, Mark L., Morrell, Nicholas W., Polkey, Michael I., Wort, Stephen John, and Kemp, Paul R.

Subjects
PULMONARY hypertension, TIBIALIS anterior, ANIMALS, MUSCLES, MUSCLE strength, ANIMAL experimentation, CELLULAR signal transduction, COMPARATIVE studies, CYTOKINES, ENZYME-linked immunosorbent assay, GROWTH factors, IMMUNOHISTOCHEMISTRY, RESEARCH methodology, MEDICAL cooperation, MICE, MUSCULAR atrophy, POLYMERASE chain reaction, RATS, RESEARCH, RESEARCH funding, TRANSFERASES, WESTERN immunoblotting, EVALUATION research, SKELETAL muscle, DISEASE complications
Abstract

Introduction: Skeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other conditions. We aimed to define the associations of GDF-15 and muscle wasting in PAH, to assess its utility as a biomarker of muscle loss and to investigate its downstream signalling pathway as a therapeutic target.Methods: GDF-15 levels and measures of muscle size and strength were analysed in the monocrotaline (MCT) rat, Sugen/hypoxia mouse and in 30 patients with PAH. In C2C12 myotubes the downstream targets of GDF-15 were identified. The pathway elucidated was then antagonised in vivo.Results: Circulating GDF-15 levels correlated with tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=-0.61, p=0.003). In patients with PAH, plasma GDF-15 levels of <564 pg/L predicted those with preserved muscle strength with a sensitivity and specificity of ≥80%. In vitro GDF-15 stimulated an increase in phosphorylation of TGFβ-activated kinase 1 (TAK1). Antagonising TAK1, with 5(Z)-7-oxozeaenol, in vitro and in vivo led to an increase in fibre diameter and a reduction in mRNA expression of atrogin-1 in both C2C12 cells and in the TA of animals who continued to grow. Circulating GDF-15 levels were also reduced in those animals which responded to treatment.Conclusions: Circulating GDF-15 is a biomarker of muscle loss in PAH that is responsive to treatment. TAK1 inhibition shows promise as a method by which muscle atrophy may be directly prevented in PAH.Trial Registration Number: NCT01847716; Results. [ABSTRACT FROM AUTHOR]

Published
2019
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28. The clinical relevance of non-invasive and invasive markers of pulmonary vascular dysfunction in interstitial lung disease

Author

Macdonald, Peter, Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW, Wells, Athol, Royal Brompton Hospital, and Imperial College, London, UK, Wort, Stephen John, Royal Brompton Hospital, and Imperial College, London, UK, Corte, Tamera Jo, Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW, Macdonald, Peter, Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW, Wells, Athol, Royal Brompton Hospital, and Imperial College, London, UK, Wort, Stephen John, Royal Brompton Hospital, and Imperial College, London, UK, and Corte, Tamera Jo, Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW

Abstract

Background and Goals: Pulmonary hypertension (PH) is common in patients with interstitial lung disease (ILD), and is associated with increased short-term mortality. We hypothesise that in advanced ILD, short-term mortality is related to the severity of pulmonary vascular disease, rather than the severity of pulmonary fibrosis, or the underlying ILD diagnosis. We suggest that markers of established pulmonary vascular disease are associated with short-term mortality, whereas markers of early pulmonary vascular disease are linked to longer-term mortality. This thesis is concerned with the relationship between markers of pulmonary vascular disease to early and overall mortality across the ILD population. A secondary goal of this thesis is to explore the relationship between invasive and non-invasive markers of pulmonary vascular disease.Results: Early mortality was strongly associated with increased pulmonary vascular resistance (PVR), as measured on right heart catheter, independent of the ILD severity, or specific ILD diagnosis. Early mortality was also linked to non-invasive markers including: right ventricular (RV) dilatation, six-month decline in KCO, six-minute walk test (6MWT) oxygen desaturation, and impaired cardiac index (CI, InnocorTM). Longer-term mortality was strongly linked to elevated brain natriuretic peptide (BNP) levels, maximal exercise dead space/tidal volume ratio (VD/VT), nocturnal desaturation index (DI), and maximal exercise oxygen desaturation, and moderate-severe PH on echocardiography. Longer-term mortality was also associated with increased PVR, RV dilatation, six-month decline in KCO and the diagnosis of idiopathic pulmonary fibrosis. PH on echocardiography was associated with: increased BNP levels, maximal exercise VD/VT, maximal exercise and 6MWT oxygen desaturation and increased nocturnal DI. Six-month decline in KCO strongly predicted the development of PH at follow-up. However, no non-invasive variable was able to identify PH at RHCCon

Published
2010

32. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Author

Swietlik, Emilia M, Greene, Daniel, Zhu, Na, Megy, Karyn, Cogliano, Marcella, Rajaram, Smitha, Pandya, Divya, Tilly, Tobias, Lutz, Katie A, Welch, Carrie CL, Pauciulo, Michael W, Southgate, Laura, Martin, Jennifer M, Treacy, Carmen M, Penkett, Christopher J, Stephens, Jonathan C, Bogaard, Harm J, Church, Colin, Coghlan, Gerry, Coleman, Anna W, Condliffe, Robin, Eichstaedt, Christina A, Eyries, Mélanie, Gall, Henning, Ghio, Stefano, Girerd, Barbara, Grünig, Ekkehard, Holden, Simon, Howard, Luke, Humbert, Marc, Kiely, David G, Kovacs, Gabor, Lordan, Jim, Machado, Rajiv D, Mackenzie Ross, Robert V, McCabe, Colm, Moledina, Shahin, Montani, David, Olschewski, Horst, Pepke-Zaba, Joanna, Price, Laura, Rhodes, Christopher J, Seeger, Werner, Soubrier, Florent, Suntharalingam, Jay, Toshner, Mark R, Vonk Noordegraaf, Anton, Wharton, John, Wild, James M, Wort, Stephen John, Lawrie, Allan, Wilkins, Martin R, Trembath, Richard C, Shen, Yufeng, Chung, Wendy K, Swift, Andrew J, Nichols, William C, Morrell, Nicholas W, and Gräf, Stefan

Subjects
computed tomography, 3. Good health
Abstract

Background - Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. Results - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions - The Bayesian inference approach allowed us to independently validate KDR, which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

33. Prediction and prognostication in interstitial lung disease associated pulmonary hypertension using baseline and longitudinal trends in non-invasive variables

Author

Bax, Simon and Wort, Stephen John

Subjects
616.2
Abstract

Pulmonary hypertension (PH) commonly occurs in patients with interstitial lung disease (ILD) and is associated with worsening of symptoms and an adverse prognosis. The onset of PH is extremely difficult to predict due to the very similar symptomology of the two conditions and confounding of common screening tests for PH in patients with ILD. It is not clear what invasive and non-invasive variables predict mortality in ILD-PH patients, or whether existing mortality prediction tools used in ILD patients are valid in ILD-PH. I hypothesised that the prediction of PH occurring in ILD patients was possible using non invasive screening tests, and that baseline and longitudinal change in non-invasive variables would predict mortality in ILD-PH patients. The integration of echocardiographic, brain natriuretic peptide (BNP), pulmonary function tests and CT variables showed that prediction of PH occurring in ILD patients was possible, although false positives were common. Echocardiographic variables best correlated with invasive right heart catheter (RHC) pressures. A score was developed to predict severe PH using echocardiographic variables, and was effective even when blinding the most powerful predictor which is commonly unavailable in patients with ILD-PH. CT is commonly employed in suspected ILD-PH patients to exclude co-existent pulmonary emboli and assess parenchymal disease progression. The right ventricle to left ventricle measured at CT pulmonary angiography was superior to both echocardiographic and RHC derived variables at predicting mortality. The presence of PH confounds commonly used mortality prediction tools in ILD. A multi modality mortality prediction model was developed to predict mortality using baseline demographics, lung function and ILD diagnosis. Longitudinal change in pulmonary function tests and BNP were shown to predict mortality. A longitudinal model using demographics and change in gas transfer was developed. External validation of the mortality prediction tools is necessary before its utility is demonstrated.

Published
2020
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34. Eisenmenger syndrome physiology : mechanisms of disease, response to novel therapies and mortality risk stratification

Author

Kempny, Aleksander, Wort, Stephen John, Gatzoulis, Michael A., and Dimopoulos, Konstantinos

Subjects
616.1
Abstract

Eisenmenger syndrome (ES) represents the extreme manifestation of pulmonary arterial hypertension in patients with congenital heart disease and is associated with significant morbidity and mortality. Yet, survival prospects and exercise performance vary significantly among ES patients. Those at higher risk of death may benefit from closer follow-up, more intense conservative management and may be considered for heart and lung or, occasionally, lung-only transplantation. Yet, mortality risk assessment is challenging and there were in 2013 no established mortality risk stratification methods. I explore in this thesis the pathophysiology of ES and the prognostic significance of commonly used clinical markers of disease progression. Chapters III - VI present analyses performed on a large cohort of patients with ES at the Royal Brompton Hospital in London while Chapter VII presents results of the largest multicentre study on mortality risk stratification in ES. Chapter III explores the exercise physiology and methods for assessment of exercise performance in ES. I demonstrate that six-minute walk test (6MWT) distance and arterial oxygen saturation (SO2) at rest significantly contribute to mortality risk stratification. Chapter IV and V discuss the role of inflammation and dysproteinaemia in ES and demonstrate that assessment of serum C-reactive protein and albumin levels may contribute to prognostication. Chapter VI discusses the challenges associated with multivariable mortality risk stratification in ES and the pathophysiologic rationale for collection of selected parameters in the multicentre study. Chapter VII presents the results of a multicentre study for assessment of mortality and predictors of death in contemporary ES patients. I demonstrate that five simple, non-invasive predictors of death, including age, SO2, type of shunt, 6MWT distance and presence or absence of pericardial effusion on echocardiography, enable accurate mortality risk stratification. These predictors identify a high-risk subgroup which may benefit from optimization of therapy or transplantation.

Published
2018
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35. Prediction and prognostication in interstitial lung disease associated pulmonary hypertension using baseline and longitudinal trends in non-invasive variables

Author

Bax, Simon, Wort, Stephen John, and Imperial College London

Subjects
respiratory system, behavioral disciplines and activities, respiratory tract diseases
Abstract

Pulmonary hypertension (PH) commonly occurs in patients with interstitial lung disease (ILD) and is associated with worsening of symptoms and an adverse prognosis. The onset of PH is extremely difficult to predict due to the very similar symptomology of the two conditions and confounding of common screening tests for PH in patients with ILD. It is not clear what invasive and non-invasive variables predict mortality in ILD-PH patients, or whether existing mortality prediction tools used in ILD patients are valid in ILD-PH. I hypothesised that the prediction of PH occurring in ILD patients was possible using non invasive screening tests, and that baseline and longitudinal change in non-invasive variables would predict mortality in ILD-PH patients. The integration of echocardiographic, brain natriuretic peptide (BNP), pulmonary function tests and CT variables showed that prediction of PH occurring in ILD patients was possible, although false positives were common. Echocardiographic variables best correlated with invasive right heart catheter (RHC) pressures. A score was developed to predict severe PH using echocardiographic variables, and was effective even when blinding the most powerful predictor which is commonly unavailable in patients with ILD-PH. CT is commonly employed in suspected ILD-PH patients to exclude co-existent pulmonary emboli and assess parenchymal disease progression. The right ventricle to left ventricle measured at CT pulmonary angiography was superior to both echocardiographic and RHC derived variables at predicting mortality. The presence of PH confounds commonly used mortality prediction tools in ILD. A multi modality mortality prediction model was developed to predict mortality using baseline demographics, lung function and ILD diagnosis. Longitudinal change in pulmonary function tests and BNP were shown to predict mortality. A longitudinal model using demographics and change in gas transfer was developed. External validation of the mortality prediction tools is necessary before its utility is demonstrated. Open Access

Published
2019

36. Eisenmenger syndrome physiology. mechanisms of disease, response to novel therapies and mortality risk stratification

Author

Kempny, Aleksander, Wort, Stephen John, Gatzoulis, Michael A, and Dimopoulos, Konstantinos

Abstract

Eisenmenger syndrome (ES) represents the extreme manifestation of pulmonary arterial hypertension in patients with congenital heart disease and is associated with significant morbidity and mortality. Yet, survival prospects and exercise performance vary significantly among ES patients. Those at higher risk of death may benefit from closer follow-up, more intense conservative management and may be considered for heart and lung or, occasionally, lung-only transplantation. Yet, mortality risk assessment is challenging and there were in 2013 no established mortality risk stratification methods. I explore in this thesis the pathophysiology of ES and the prognostic significance of commonly used clinical markers of disease progression. Chapters III – VI present analyses performed on a large cohort of patients with ES at the Royal Brompton Hospital in London while Chapter VII presents results of the largest multicentre study on mortality risk stratification in ES. Chapter III explores the exercise physiology and methods for assessment of exercise performance in ES. I demonstrate that six-minute walk test (6MWT) distance and arterial oxygen saturation (SO2) at rest significantly contribute to mortality risk stratification. Chapter IV and V discuss the role of inflammation and dysproteinaemia in ES and demonstrate that assessment of serum C-reactive protein and albumin levels may contribute to prognostication. Chapter VI discusses the challenges associated with multivariable mortality risk stratification in ES and the pathophysiologic rationale for collection of selected parameters in the multicentre study. Chapter VII presents the results of a multicentre study for assessment of mortality and predictors of death in contemporary ES patients. I demonstrate that five simple, non-invasive predictors of death, including age, SO2, type of shunt, 6MWT distance and presence or absence of pericardial effusion on echocardiography, enable accurate mortality risk stratification. These predictors identify a high-risk subgroup which may benefit from optimization of therapy or transplantation. Open Access

Published
2017

37. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension.

Author

Swietlik EM, Greene D, Zhu N, Megy K, Cogliano M, Rajaram S, Pandya D, Tilly T, Lutz KA, Welch CCL, Pauciulo MW, Southgate L, Martin JM, Treacy CM, Penkett CJ, Stephens JC, Bogaard HJ, Church C, Coghlan G, Coleman AW, Condliffe R, Eichstaedt CA, Eyries M, Gall H, Ghio S, Girerd B, Grünig E, Holden S, Howard L, Humbert M, Kiely DG, Kovacs G, Lordan J, Machado RD, Mackenzie Ross RV, McCabe C, Moledina S, Montani D, Olschewski H, Pepke-Zaba J, Price L, Rhodes CJ, Seeger W, Soubrier F, Suntharalingam J, Toshner MR, Vonk Noordegraaf A, Wharton J, Wild JM, Wort SJ, Lawrie A, Wilkins MR, Trembath RC, Shen Y, Chung WK, Swift AJ, Nichols WC, Morrell NW, and Gräf S

Abstract

Background - Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. Results - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor ( KDR ) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR . Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions - The Bayesian inference approach allowed us to independently validate KDR , which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Published
2020
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38. Pathophysiology of pulmonary hypertension in acute lung injury.

Author

Price LC, McAuley DF, Marino PS, Finney SJ, Griffiths MJ, and Wort SJ

Subjects
Acute Lung Injury blood, Acute Lung Injury complications, Acute Lung Injury pathology, Animals, Blood Cells pathology, Blood Cells physiology, Blood Physiological Phenomena, Endothelium physiopathology, Humans, Hypertension, Pulmonary blood, Hypertension, Pulmonary etiology, Hypertension, Pulmonary pathology, Lung blood supply, Lung pathology, Lung physiopathology, Microvessels pathology, Microvessels physiopathology, Acute Lung Injury physiopathology, Hypertension, Pulmonary physiopathology
Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome are characterized by protein rich alveolar edema, reduced lung compliance, and acute severe hypoxemia. A degree of pulmonary hypertension (PH) is also characteristic, higher levels of which are associated with increased morbidity and mortality. The increase in right ventricular (RV) afterload causes RV dysfunction and failure in some patients, with associated adverse effects on oxygen delivery. Although the introduction of lung protective ventilation strategies has probably reduced the severity of PH in ALI, a recent invasive hemodynamic analysis suggests that even in the modern era, its presence remains clinically important. We therefore sought to summarize current knowledge of the pathophysiology of PH in ALI.

Published
2012
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