{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T05:07:32Z","timestamp":1785820052180,"version":"3.56.0"},"reference-count":28,"publisher":"European Respiratory Society (ERS)","issue":"4","license":[{"start":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T00:00:00Z","timestamp":1720656000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014470","name":"Netherlands Heart Institute","doi-asserted-by":"publisher","award":["CVON-2017-10 Dolphin-Genesis"],"award-info":[{"award-number":["CVON-2017-10 Dolphin-Genesis"]}],"id":[{"id":"10.13039\/501100014470","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2024,6,19]]},"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Pathogenic variants in the gene encoding for<jats:italic>BMPR2<\/jats:italic>are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete penetrance, deep phenotyping of unaffected carriers of a pathogenic<jats:italic>BMPR2<\/jats:italic>variant through multimodality screening may aid in early diagnosis and identify susceptibility traits for future development of pulmonary arterial hypertension.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>28 unaffected carriers (44\u00b116\u2005years, 57% female) and 21 healthy controls (44\u00b118\u2005years, 48% female) underwent annual screening, including cardiac magnetic resonance imaging, transthoracic echocardiography, cardiopulmonary exercise testing and right heart catheterisation. Right ventricular pressure\u2013volume loops were constructed to assess load-independent contractility and compared with a healthy control group. A transgenic<jats:italic>Bmpr2<jats:sup>\u039471Ex1\/+<\/jats:sup><\/jats:italic>rat model was employed to validate findings from humans.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Unaffected carriers had lower indexed right ventricular end-diastolic (79.5\u00b117.6\u2005mL\u00b7m<jats:sup>\u22122<\/jats:sup><jats:italic>versus<\/jats:italic>62.7\u00b115.3\u2005mL\u00b7m<jats:sup>\u22122<\/jats:sup>; p=0.001), end-systolic (34.2\u00b110.5\u2005mL\u00b7m<jats:sup>\u22122<\/jats:sup><jats:italic>versus<\/jats:italic>27.1\u00b18.3\u2005mL\u00b7m<jats:sup>\u22122<\/jats:sup>; p=0.014) and left ventricular end-diastolic (68.9\u00b114.1\u2005mL\u00b7m<jats:sup>\u22122<\/jats:sup><jats:italic>versus<\/jats:italic>58.5\u00b110.7\u2005mL\u00b7m<jats:sup>\u22122<\/jats:sup>; p=0.007) volumes than control subjects.<jats:italic>Bmpr2<jats:sup>\u039471Ex1\/+<\/jats:sup><\/jats:italic>rats were also observed to have smaller cardiac volumes than wild-type rats. Pressure\u2013volume loop analysis showed that unaffected carriers had significantly higher afterload (arterial elastance 0.15\u00b10.06\u2005<jats:italic>versus<\/jats:italic>0.27\u00b10.08\u2005mmHg\u00b7mL<jats:sup>\u22121<\/jats:sup>; p&lt;0.001) and end-systolic elastance (0.28\u00b10.07\u2005<jats:italic>versus<\/jats:italic>0.35\u00b10.10\u2005mmHg\u00b7mL<jats:sup>\u22121<\/jats:sup>; p=0.047) in addition to lower right ventricular pulmonary artery coupling (end-systolic elastance\/arterial elastance 2.24\u00b11.03<jats:italic>versus<\/jats:italic>1.36\u00b10.37; p=0.006). During the 4-year follow-up period, two unaffected carriers developed pulmonary arterial hypertension, with normal N-terminal pro-brain natriuretic peptide and transthoracic echocardiography indices at diagnosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Unaffected<jats:italic>BMPR2<\/jats:italic>mutation carriers have an altered cardiac phenotype mimicked in<jats:italic>Bmpr2<jats:sup>\u039471Ex1\/+<\/jats:sup><\/jats:italic>transgenic rats. Future efforts to establish an effective screening protocol for individuals at risk for developing pulmonary arterial hypertension warrant longer follow-up periods.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.00442-2024","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T16:05:14Z","timestamp":1720713914000},"page":"2400442","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Deep phenotyping of unaffected carriers of pathogenic<i>BMPR2<\/i>variants screened for pulmonary arterial hypertension"],"prefix":"10.1183","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3259-9916","authenticated-orcid":false,"given":"Eszter N.","family":"T\u00f3th","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6727-7539","authenticated-orcid":false,"given":"Lucas R.","family":"Celant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6905-5368","authenticated-orcid":false,"given":"Marili","family":"Niglas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samara","family":"Jansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelco","family":"Tramper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoleta","family":"Baxan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Ashek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2401-7707","authenticated-orcid":false,"given":"Jeroen N.","family":"Wessels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Tim","family":"Marcus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7528-8307","authenticated-orcid":false,"given":"Lilian J.","family":"Meijboom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan C.","family":"Houweling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3854-4137","authenticated-orcid":false,"given":"Esther J.","family":"Nossent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6211-1791","authenticated-orcid":false,"given":"Jurjan","family":"Aman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5593-3383","authenticated-orcid":false,"given":"Julien","family":"Grynblat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Perros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-6922","authenticated-orcid":false,"given":"David","family":"Montani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4057-758X","authenticated-orcid":false,"given":"Anton","family":"Vonk Noordegraaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1177-5568","authenticated-orcid":false,"given":"Lan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances S.","family":"de Man","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harm Jan","family":"Bogaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2024,7,11]]},"reference":[{"key":"2024112623015124000_64.4.2400442.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.10.047"},{"key":"2024112623015124000_64.4.2400442.2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S2213-2600(15)00544-5","article-title":"BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis","volume":"4","author":"Evans","year":"2016","journal-title":"Lancet Respir Med"},{"key":"2024112623015124000_64.4.2400442.3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201205-0886OC"},{"key":"2024112623015124000_64.4.2400442.4","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00879-2022"},{"key":"2024112623015124000_64.4.2400442.5","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01471-2022"},{"key":"2024112623015124000_64.4.2400442.6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.recesp.2016.01.002","article-title":"2015 ESC\/ERS guidelines for the diagnosis and treatment of pulmonary hypertension","volume":"69","author":"Galie","year":"2016","journal-title":"Rev Esp Cardiol (Engl Ed)"},{"key":"2024112623015124000_64.4.2400442.7","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.04229-2020"},{"key":"2024112623015124000_64.4.2400442.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.08.019"},{"key":"2024112623015124000_64.4.2400442.9","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1161\/CIRCULATIONAHA.118.033744","article-title":"Bmpr2 mutant rats develop pulmonary and cardiac characteristics of pulmonary arterial hypertension","volume":"139","author":"Hautefort","year":"2019","journal-title":"Circulation"},{"key":"2024112623015124000_64.4.2400442.10","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2024112623015124000_64.4.2400442.11","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00145608"},{"key":"2024112623015124000_64.4.2400442.12","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCIMAGING.108.780247"},{"key":"2024112623015124000_64.4.2400442.13","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s10554-014-0580-z","article-title":"Pulmonary vascular remodeling before and after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension: a cardiac magnetic resonance study","volume":"31","author":"Rolf","year":"2015","journal-title":"Int J Cardiovasc Imaging"},{"key":"2024112623015124000_64.4.2400442.14","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.020696"},{"key":"2024112623015124000_64.4.2400442.15","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201306-1086OC"},{"key":"2024112623015124000_64.4.2400442.16","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.019351"},{"key":"2024112623015124000_64.4.2400442.17","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201507-1444OC"},{"key":"2024112623015124000_64.4.2400442.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.10.027"},{"key":"2024112623015124000_64.4.2400442.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.06.068"},{"key":"2024112623015124000_64.4.2400442.20","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(00)01102-5"},{"key":"2024112623015124000_64.4.2400442.21","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.898122"},{"key":"2024112623015124000_64.4.2400442.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.12.076"},{"key":"2024112623015124000_64.4.2400442.23","first-page":"402","article-title":"Muscle fiber orientation in the development and regression of right ventricular hypertrophy in pigs","volume":"40","author":"Tezuka","year":"1990","journal-title":"Acta Pathol Jpn"},{"key":"2024112623015124000_64.4.2400442.24","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3390\/biomedicines9010057","article-title":"Endothelial dysfunction in pulmonary hypertension: cause or consequence?","volume":"9","author":"Kurakula","year":"2021","journal-title":"Biomedicines"},{"key":"2024112623015124000_64.4.2400442.25","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000012754.72951.3D"},{"key":"2024112623015124000_64.4.2400442.26","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.800938"},{"key":"2024112623015124000_64.4.2400442.27","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.healun.2016.06.018","article-title":"Right ventricular and pulmonary vascular reserve in asymptomatic BMPR2 mutation carriers","volume":"36","author":"Claessen","year":"2017","journal-title":"J Heart Lung Transplant"},{"key":"2024112623015124000_64.4.2400442.28","doi-asserted-by":"crossref","first-page":"e91374","DOI":"10.1371\/journal.pone.0091374","article-title":"Identification of a new intronic BMPR2-mutation and early diagnosis of heritable pulmonary arterial hypertension in a large family with mean clinical follow-up of 12\u2005years","volume":"9","author":"Hinderhofer","year":"2014","journal-title":"PLoS One"}],"container-title":["European Respiratory Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/13993003.00442-2024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T07:21:31Z","timestamp":1740381691000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/13993003.00442-2024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,11]]},"references-count":28,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,10,3]]},"published-print":{"date-parts":[[2024,10]]}},"alternative-id":["10.1183\/13993003.00442-2024"],"URL":"https:\/\/doi.org\/10.1183\/13993003.00442-2024","relation":{},"ISSN":["0903-1936","1399-3003"],"issn-type":[{"value":"0903-1936","type":"print"},{"value":"1399-3003","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,11]]}}}