{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T04:48:28Z","timestamp":1773204508992,"version":"3.50.1"},"reference-count":55,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislaufforschung","doi-asserted-by":"publisher","award":["81Z0600207"],"award-info":[{"award-number":["81Z0600207"]}],"id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003061","name":"Erasmus Medisch Centrum","doi-asserted-by":"publisher","award":["2016\u201015"],"award-info":[{"award-number":["2016\u201015"]}],"id":[{"id":"10.13039\/501100003061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Prematurely born young adults who experienced neonatal oxidative injury (NOI) of the lungs have increased incidence of cardiovascular disease. Here, we investigated the long\u2010term effects of NOI on cardiopulmonary function in piglets at the age of 10\u201312\u00a0weeks. To induce NOI, term\u2010born piglets (1.81\u00a0\u00b1\u00a00.06\u00a0kg) were exposed to hypoxia (10\u201312% ), within 2\u00a0days after birth, and maintained for 4\u00a0weeks or until symptoms of heart failure developed (range 16\u201328\u00a0days), while SHAM piglets were normoxia raised. Following recovery (&gt;5\u00a0weeks), NOI piglets were surgically instrumented to measure haemodynamics during hypoxic challenge testing (HCT) and exercise with modulation of the nitric\u2010oxide system. During exercise, NOI piglets showed a normal increase in cardiac index, but an exaggerated increase in pulmonary artery pressure and a blunted increase in left atrial pressure \u2013 suggesting left atrial under\u2010filling \u2013 consistent with an elevated pulmonary vascular resistance (PVR), which correlated with the duration of hypoxia exposure. Moreover, hypoxia duration correlated inversely with stroke volume (SV) during exercise. Nitric oxide synthase inhibition and HCT resulted in an exaggerated increase in PVR, while the PVR reduction by phosphodiesterase\u20105 inhibition was enhanced in NOI compared to SHAM piglets. Finally, within the NOI piglet group, prolonged duration of hypoxia was associated with a better maintenance of SV during HCT, likely due to the increase in RV mass. In conclusion, duration of neonatal hypoxia appears an important determinant of alterations in cardiopulmonary function that persist further into life. These changes encompass both pulmonary vascular and cardiac responses to hypoxia and exercise.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15203-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Children who suffered from neonatal oxidative injury, such as very preterm born infants, have increased risk of cardiopulmonary disease later in life.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Risk stratification requires knowledge of the mechanistic underpinning and the time course of progression into cardiopulmonary disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Exercise and hypoxic challenge testing showed that 10\u2010 to 12\u2010week\u2010old swine that previously experienced neonatal oxidative injury had increased pulmonary vascular resistance and nitric oxide dependency.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Duration of neonatal oxidative injury was a determinant of structural and functional cardiopulmonary remodelling later in life.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Remodelling of the right ventricle, as a result of prolonged neonatal oxidative injury, resulted in worse performance during exercise, but enabled better performance during the hypoxic challenge test.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Increased nitric oxide dependency together with age\u2010 or comorbidity\u2010related endothelial dysfunction may contribute to predisposition to pulmonary hypertension later in life.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp282906","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T17:23:00Z","timestamp":1658424180000},"page":"3931-3950","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Exercise and hypoxia unmask pulmonary vascular disease and right ventricular dysfunction in a 10\u2010 to 12\u2010week\u2010old swine model of neonatal oxidative injury"],"prefix":"10.1113","volume":"600","author":[{"given":"Jarno J.","family":"Steenhorst","sequence":"first","affiliation":[{"name":"Division of Experimental Cardiology Department of Cardiology Erasmus MC University Medical Center Rotterdam  Rotterdam the Netherlands"},{"name":"Department of Radiology and Nuclear Medicine Erasmus MC University Medical Center Rotterdam  Rotterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology Department of Cardiology Erasmus MC University Medical Center Rotterdam  Rotterdam the Netherlands"},{"name":"Department of Radiology and Nuclear Medicine Erasmus MC University Medical Center Rotterdam  Rotterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annemarie","family":"Verzijl","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology Department of Cardiology Erasmus MC University Medical Center Rotterdam  Rotterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piotr","family":"Wielopolski","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Erasmus MC University Medical Center Rotterdam  Rotterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daphne","family":"de Wijs\u2010Meijler","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology Department of Cardiology Erasmus MC University Medical Center Rotterdam  Rotterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2836-2241","authenticated-orcid":false,"given":"Dirk J.","family":"Duncker","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology Department of Cardiology Erasmus MC University Medical Center Rotterdam  Rotterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irwin K. 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