{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T02:10:59Z","timestamp":1789006259977,"version":"build-2803163510"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Single ventricle congenital heart disease like hypoplastic left heart syndrome with a Fontan circulation constitutes, the largest group of children hospitalized with circulation failure, experiencing an in-hospital mortality rate of 20% to 50%. We investigated the mechanisms leading to Fontan failure to identify novel therapeutic targets.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Blood was collected from patients with hypoplastic left heart syndrome post-Fontan and controls (n=6\/group). Plasma microvesicles were isolated, and proteomics assessed using data-independent acquisition mass spectroscopy. Dysregulated proteins with a fold change &gt;1.5 or \u22641.5,\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.05, were evaluated using the Database for Annotation, Visualization, and Integrated Discovery and Ingenuity pathway analysis. Correlation of highly dysregulated proteins was assessed with New York Heart Association class, right ventricular fractional area change, oxygen saturation, and hemoglobin.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              The age of Fontan patients versus controls was 16.0\u00b12.1 versus 15.3\u00b12.2. Three of 6 Fontan patients were in New York Heart Association class II, and 3 of 6 were in New York Heart Association III\/IV; 4 of 6 had Fontan-associated liver disease. Overall, 72 proteins were upregulated, and 187 proteins were downregulated in Fontan failure. Proteins upregulated in Fontan failure predicted cell death pathways (Solute carrier family 2, Angiotensinogen, CD14) and mitochondrial reactive oxygen species signaling (ATP5F1A, S100A8); downregulated proteins predicted impaired cell survival (tyrosine-protein kinase, endothelial growth factors) and mitochondrial antioxidant enzymes (GPX1, PRDX5) Increasing expression of the following proteins was associated with worsening New York Heart Association class, ventricular function and cyanosis: complement system (C1QA,\n              <jats:italic toggle=\"yes\">r<\/jats:italic>\n              =0.91), mitochondrial reactive oxygen species generation (HSPD1,\n              <jats:italic toggle=\"yes\">r<\/jats:italic>\n              =0.81; ATP5F1A,\n              <jats:italic toggle=\"yes\">r<\/jats:italic>\n              =0.75), and cytoskeletal proteins (ANK1,\n              <jats:italic toggle=\"yes\">r<\/jats:italic>\n              =0.63; ACTN1,\n              <jats:italic toggle=\"yes\">r<\/jats:italic>\n              =0.76).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Proteins from circulating microvesicles from patients with hypoplastic left heart syndrome post-Fontan are mostly from the liver. While this pilot study is limited by its sample size and may not represent the broader Fontan population, the proteomic changes were associated with worsening heart failure and cyanosis, suggesting their potential utility as biomarkers.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circheartfailure.124.012136","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T09:00:20Z","timestamp":1744794020000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Plasma Proteomics of the Fontan Circulation Reveal Signatures of Oxidative Stress and Cell Death"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9896-3590","authenticated-orcid":true,"given":"Joiliana","family":"Lecointe","sequence":"first","affiliation":[{"name":"School of Medicine, Meharry Medical College, Nashville, TN (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0221-9925","authenticated-orcid":true,"given":"Sushrima","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Cardiology) and Cardiovascular Institute (S.G., S.I., A.K., S.R.), Stanford University, Palo Alto, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7296-6654","authenticated-orcid":true,"given":"Dipti","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Department of Surgery (D.T.), Stanford University, Palo Alto, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0773-3045","authenticated-orcid":true,"given":"Shoko","family":"Ichimura","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Cardiology) and Cardiovascular Institute (S.G., S.I., A.K., S.R.), Stanford University, Palo Alto, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1877-2557","authenticated-orcid":true,"given":"Katie L.","family":"Clouthier","sequence":"additional","affiliation":[{"name":"Department of Anesthesia Critical Care Medicine, Children\u2019s Hospital Los Angeles, CA (K.L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9458-5813","authenticated-orcid":true,"given":"Ankit","family":"Kushwaha","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Cardiology) and Cardiovascular Institute (S.G., S.I., A.K., S.R.), Stanford University, Palo Alto, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2170-5942","authenticated-orcid":true,"given":"Laura","family":"Mercer-Rosa","sequence":"additional","affiliation":[{"name":"Cardiac Centre, Children\u2019s Hospital of Philadelphia, PA (L.M.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3530-8630","authenticated-orcid":true,"given":"Sushma","family":"Reddy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Cardiology) and Cardiovascular Institute (S.G., S.I., A.K., S.R.), Stanford University, Palo Alto, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.007764"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2016.05.035"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2018.11.010"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.12.053"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.12.054"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.011728"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.118.009145"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.21037\/acs.2018.01.16"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.015871"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3870"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.3390\/children4080071"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2012.11.031"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2013.02.036"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/chd.12692"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-65852-x"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2009.06.046"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-021-01846-8"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0183624"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.3791\/55057"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2016.0530"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth1019"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.91625"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijsu.2014.07.013"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260419"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.08.002"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0735-1097(02)01718-7"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2023.1100514"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehq386"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00614.2005"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.121.053575"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.120.017835"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vesic.2022.100013"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.039262"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1080\/14737159.2017.1356230"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2000.tb03119.x"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2020.00103"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.618173"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.6064\/2012\/402783"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06802-1"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107038"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1911303"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.02.092"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.123.029427"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-016-1087-2"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.3390\/medicina60020268"},{"key":"e_1_3_3_47_2","first-page":"31","article-title":"Measurement of von Willebrand factor as the marker of endothelial dysfunction in vascular diseases.","volume":"9","author":"Horvath B","year":"2004","unstructured":"Horvath B, Hegedus D, Szapary L, Marton Z, Alexy T, Koltai K, Czopf L, Wittmann I, Juricskay I, Toth K, et al. Measurement of von Willebrand factor as the marker of endothelial dysfunction in vascular diseases. Exp Clin Cardiol. 2004;9:31\u201334.","journal-title":"Exp Clin Cardiol"}],"container-title":["Circulation: Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCHEARTFAILURE.124.012136","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T18:00:23Z","timestamp":1747764023000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCHEARTFAILURE.124.012136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1161\/CIRCHEARTFAILURE.124.012136"],"URL":"https:\/\/doi.org\/10.1161\/circheartfailure.124.012136","relation":{},"ISSN":["1941-3289","1941-3297"],"issn-type":[{"value":"1941-3289","type":"print"},{"value":"1941-3297","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5]]},"assertion":[{"value":"2024-06-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}