{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T20:16:34Z","timestamp":1776370594049,"version":"3.51.2"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Despite a phenylalanine (Phe) restrictive diet, most adult patients with \u2018classical\u2019 phenylketonuria (PKU) maintain life\u2010long Phe concentrations above the normal range and receive tyrosine (Tyr) and protein\u2010enriched diets to maintain acceptable concentrations and ensure normal development. While these interventions are highly successful in preventing adverse neuropsychiatric complications, their long\u2010 term consequences are incompletely explored. We observed early cardiomyopathic characteristics and associated hemodynamic changes in adult PKU patients and present here the results of a longitudinal evaluation of cardiac phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Fifteen adult patients with PKU (age: 39.8\u2009\u00b1\u20098.1\u2009years, 9 males and 6 females) underwent a comprehensive follow\u2010up cardiac magnetic resonance (CMR) imaging assessment after a mean follow\u2010up interval of 8.3\u2009\u00b1\u20090.3\u2009years from the initial baseline visit. The CMR protocol included left (LV) and right (RV) ventricular and left atrial (LA) volumetric assessment, LV parametric mapping (precontrast and postcontrast T1 and T2 maps, extracellular volume [ECV]), multilayer LV myocardial strain, systolic and diastolic hemodynamic forces and RV and LA strain and aortic distensibility evaluation. Plasma concentrations of Phe, tyrosine (Tyr) and other biochemical markers of disease were retrospectively collected. For comparison, a group of 20 matched control subjects undergoing an identical CMR protocol was included.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      On average, the LV end\u2010diastolic volume (EDV) (158\u2009\u00b1\u200929 vs. 143\u2009\u00b1\u200929\u2009mL,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.013) and end\u2010systolic volume (ESV) (68\u2009\u00b1\u200918 vs. 62\u2009\u00b1\u200918\u2009mL,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.011) were lower at follow\u2010up. In contrast, LV mass (LVM) (72\u2009\u00b1\u200925 vs. 82\u2009\u00b1\u200929\u2009g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and the ratio LVM\/EDV (0.46\u2009\u00b1\u20090.12 vs. 0.58\u2009\u00b1\u20090.23\u2009g\/mL,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.005) were increased, and T1 times were longer (940\u2009\u00b1\u200942 vs. 1010\u2009\u00b1\u200935\u2009ms,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). LV EF (57\u2009\u00b1\u20096 vs. 57\u2009\u00b1\u20097%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.90), longitudinal (GLS) and circumferential (GCS) systolic strain remained unchanged, but early diastolic hemodynamic (HD) forces were more markedly negative (\u221219.4\u2009\u00b1\u20097.0 vs. \u221226.5\u2009\u00b1\u200912.2%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.012), while LA strain 43.8\u2009\u00b1\u200911.3 vs. 37.3\u2009\u00b1\u20099.6%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.031) and aortic distensibility (6.38\u2009\u00b1\u20091.75 vs. 5.21\u2009\u00b1\u20091.17 10\n                      <jats:sup>\u22123<\/jats:sup>\n                      \u2009mmHg\n                      <jats:sup>\u22121<\/jats:sup>\n                      ,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.008) decreased at follow\u2010up. Compared with controls, PKU patients maintain reduced systolic function with lower LV EF and impaired GCS and have more markedly negative early diastolic HD pressures. A higher decrease in Phe concentration (\u0394Phe) was associated with longer T1 times, \u0394T1 (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u2009\u22120.78,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), increased ECV, \u0394ECV (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u2009\u22120.61,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.016) and a decrease in systolic function, \u0394EF (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u20090.61,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.017). In contrast, variations in Tyr concentrations did not affect the cardiac phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>At long\u2010term follow\u2010up, a marked drop in Phe plasma concentration was associated with detrimental cardiac remodelling consisting of decreased LV systolic function and increased diffuse fibrosis, in PKU patients. These new data prompt further investigation into the effects of large Phe variability over time and underline the usefulness of periodic cardiovascular assessment in adults with PKU.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13667","type":"journal-article","created":{"date-parts":[[2025,1,11]],"date-time":"2025-01-11T02:37:38Z","timestamp":1736563058000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Large Variations in Phenylalanine Concentrations Associate Adverse Cardiac Remodelling in Adult Patients With Phenylketonuria\u2014A Long\u2010Term CMR Study"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2193-9813","authenticated-orcid":false,"given":"Radu","family":"Tanacli","sequence":"first","affiliation":[{"name":"Department of Cardiology Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9  Berlin Germany"},{"name":"Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t Zu Berlin  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Doeblin","sequence":"additional","affiliation":[{"name":"Department of Cardiology Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Faragli","sequence":"additional","affiliation":[{"name":"Department of Cardiology Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan\u2010Hendrik","family":"Hassel","sequence":"additional","affiliation":[{"name":"Department of Cardiology Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Stehning","sequence":"additional","affiliation":[{"name":"Philips Clinical Science  Hamburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ursula","family":"Pl\u00f6ckinger","sequence":"additional","affiliation":[{"name":"Interdisziplin\u00e4res Stoffwechsel\u2010Centrum Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Campus Virchow Klinikum  Berlin Germany"},{"name":"Department of Endocrinology, Diabetes, and Nutrition Charit\u00e9 University Medicine Berlin  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Athanasia","family":"Ziagaki","sequence":"additional","affiliation":[{"name":"Interdisziplin\u00e4res Stoffwechsel\u2010Centrum Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Campus Virchow Klinikum  Berlin Germany"},{"name":"Department of Endocrinology, Diabetes, and Nutrition Charit\u00e9 University Medicine Berlin  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Kelle","sequence":"additional","affiliation":[{"name":"Department of Cardiology Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9  Berlin Germany"},{"name":"Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t Zu Berlin  Berlin Germany"},{"name":"German Centre for Cardiovascular Research DZHK, Partner Site Berlin  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,1,10]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00267-0"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-020-01391-y"},{"key":"e_1_2_10_4_1","first-page":"1430","article-title":"National Institutes of H. 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