{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T07:12:36Z","timestamp":1784099556020,"version":"3.55.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Biomarkers for predicting preeclampsia are not routinely available. Currently, preeclampsia is diagnosed with the development of clinical manifestations and proteinuria when widespread endothelial dysfunction and end-organ dysfunction have occurred.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study aimed to (1) compare the serial changes in circulating mitochondrial cell-free DNA (ccf-mtDNA) levels between pregnant women who developed preeclampsia and healthy pregnant controls and (2) to determine if circulating microRNAs (miRNAs) previously linked to placenta development and\/or preeclampsia could be detected.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This single-center, nested case\u2013control study involved singleton pregnancies less than 16 weeks of gestation at increased risk for preeclampsia, with at least one high-risk factor or two moderate-risk factors, and healthy pregnant controls. Patients were followed throughout their pregnancy, with blood collected at three time points to quantify plasma levels of ccf-mtDNA and five microRNAs (miRNAs). All patients received 81\u2005mg aspirin daily initiated before 16 weeks of gestation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The mean and standard deviation (SD) of age in years was 31.1\u2009\u00b1\u20097.5 for the preeclampsia group and 31.9\u2009\u00b1\u20095.7 for the control group. Gestational age at delivery in weeks was 36.3\u2009\u00b1\u20093.2 for the preeclampsia group and 36.9\u2009\u00b1\u20094.3 for the healthy control group. The gestational age at diagnosis of preeclampsia was 34.8\u2009\u00b1\u20093.4 weeks. Participants who developed preeclampsia had a significantly reduced amount of ccf-mtDNA in the maternal circulation compared to that in healthy pregnant controls. The reduction in ccf-mtDNA reached significance at Visit 1 (1.688\u2009\u00b1\u20091.254 copies for the preeclampsia group versus 4.014\u2009\u00b1\u20092.381 copies for 1\u2005\u00b5L of plasma for the healthy control group), corresponding to the second trimester. ccf-mtDNA levels in the exosomal fraction remained unchanged throughout pregnancy. The plasma levels of miRNA-137 were significantly decreased in patients with preeclampsia compared to healthy pregnant controls at all time points.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Plasma levels of miRNA-137 and ccf-mtDNA are decreased as early as the first and second trimester, respectively before the clinical diagnosis of preeclampsia in the third trimester. Early detection of changes in plasma levels of miRNAs and ccf-mtDNA could be used for early prediction of preeclampsia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1778221","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T04:34:46Z","timestamp":1775018086000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Cell-free mitochondrial DNA and microRNA-137 for early diagnosis of preeclampsia"],"prefix":"10.3389","volume":"13","author":[{"given":"Stefanie","family":"Marek-Iannucci","sequence":"first","affiliation":[{"name":"Advanced Heart Failure and Transplantation, Thomas Jefferson University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Tigano","sequence":"additional","affiliation":[{"name":"Department of Pathology & Genomic Medicine, Thomas Jefferson University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlyn","family":"Cardetti","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Thomas Jefferson University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shey-Shing","family":"Sheu","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Thomas Jefferson University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gamero Huaman","sequence":"additional","affiliation":[{"name":"Advanced Heart Failure and Transplantation, Thomas Jefferson University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene J.","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Advanced Heart Failure and Transplantation, Thomas Jefferson University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Rame","sequence":"additional","affiliation":[{"name":"Advanced Heart Failure and Transplantation, Thomas Jefferson University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupsa C.","family":"Boelig","sequence":"additional","affiliation":[{"name":"Department of Maternal Fetal Medicine, Thomas Jefferson University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indranee N.","family":"Rajapreyar","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Tufts Medical Center","place":["Boston, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1690","DOI":"10.1016\/j.jacc.2020.08.014","article-title":"Preeclampsia-pathophysiology and clinical presentations: JJACC State-of-the-Art Review","volume":"76","author":"Ives","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1161\/CIRCRESAHA.118.313276","article-title":"Preeclampsia: pathophysiology, challenges, and perspectives","volume":"124","author":"Rana","year":"2019","journal-title":"Circ Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"S1019","DOI":"10.1016\/j.ajog.2020.10.022","article-title":"Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders","volume":"226","author":"Rana","year":"2022","journal-title":"Am J Obstet Gynecol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"5581570","DOI":"10.1155\/2021\/5581570","article-title":"The role of oxidative stress in hypertensive disorders of pregnancy (preeclampsia, gestational hypertension) and metabolic disorder of pregnancy (gestational diabetes mellitus)","volume":"2021","author":"Phoswa","year":"2021","journal-title":". Oxid Med Cell Longev"},{"key":"B5","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/s41388-023-02907-z","article-title":"ROS production by mitochondria: function or dysfunction?","volume":"43","author":"Palma","year":"2024","journal-title":"Oncogene"},{"key":"B6","doi-asserted-by":"publisher","first-page":"0","DOI":"10.1152\/physiol.00037.2021","article-title":"Circulating cell-free mitochondrial DNA in pregnancy","volume":"37","author":"Bradshaw","year":"2022","journal-title":"Physiology (Bethesda)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/s11906-022-01184-7","article-title":"Mitochondrial dysfunction in the pathogenesis of preeclampsia","volume":"24","author":"Hu","year":"2022","journal-title":"Curr Hypertens Rep"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e021726","DOI":"10.1161\/JAHA.121.021726","article-title":"Reduced maternal circulating cell-free mitochondrial DNA is associated with the development of preeclampsia","volume":"11","author":"Cushen","year":"2022","journal-title":"J Am Heart Assoc"},{"key":"B9","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1038\/s41440-020-0423-3","article-title":"MitomiRs: new emerging microRNAs in mitochondrial dysfunction and cardiovascular disease","volume":"43","author":"Paramasivam","year":"2020","journal-title":"Hypertens Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"970265","DOI":"10.1155\/2013\/970265","article-title":"Maternal plasma miRNAs expression in preeclamptic pregnancies","volume":"2013","author":"Li","year":"2013","journal-title":"Biomed Res Int"},{"key":"B11","doi-asserted-by":"publisher","first-page":"553.e1","DOI":"10.1016\/j.ajog.2023.05.015","article-title":"Noninvasive preeclampsia prediction using plasma cell-free RNA signatures","volume":"229","author":"Zhou","year":"2023","journal-title":"Am J Obstet Gynecol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1001\/jama.2017.3439","article-title":"Screening for preeclampsia: US Preventive Services Task Force recommendation statement","volume":"317","author":"Bibbins-Domingo","year":"2017","journal-title":"JAMA"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e237","DOI":"10.1097\/AOG.0000000000003891","article-title":"Gestational hypertension and preeclampsia: ACOG practice bulletin. Number:222","volume":"135","year":"2020","journal-title":"Obstet Gynecol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1038\/s12276-023-00965-7","article-title":"Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway","volume":"55","author":"Kim","year":"2023","journal-title":"Exp Mol Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1038\/s41467-021-21984-w","article-title":"Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs","volume":"12","author":"Todkar","year":"2021","journal-title":"Nat Commun"},{"key":"B16","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1083\/jcb.201211138","article-title":"Extracellular vesicles: exosomes, microvesicles, and friends","volume":"200","author":"Raposo","year":"2013","journal-title":"J Cell Biol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.preghy.2018.10.003","article-title":"Maternal serum mitochondrial DNA (mtDNA) levels are elevated in preeclampsia\u2014a matched case-control study","volume":"14","author":"Marschalek","year":"2018","journal-title":"Pregnancy Hypertens"},{"key":"B18","doi-asserted-by":"publisher","first-page":"R445","DOI":"10.1152\/ajpregu.00324.2019","article-title":"Cell-free mitochondrial DNA increases in maternal circulation during healthy pregnancy: a prospective, longitudinal study","volume":"318","author":"Cushen","year":"2020","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.preghy.2018.06.012","article-title":"Exploring the role of mitochondrial dysfunction in the pathophysiology of pre-eclampsia","volume":"13","author":"Williamson","year":"2018","journal-title":"Pregnancy Hypertens"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.preghy.2020.10.002","article-title":"Mitochondrial DNA copy number variation\u2014a potential biomarker for early onset preeclampsia","volume":"23","author":"Pandey","year":"2021","journal-title":"Pregnancy Hypertens"},{"key":"B21","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.jare.2023.12.014","article-title":"Advances in the study of exosomes in cardiovascular diseases","volume":"66","author":"Zhang","year":"2023","journal-title":"J Adv Res"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e24029","DOI":"10.1016\/j.heliyon.2024.e24029","article-title":"Advances in crosstalk among innate immune pathways activated by mitochondrial DNA","volume":"10","author":"Tao","year":"2024","journal-title":"Heliyon"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2378189","DOI":"10.1016\/j.heliyon.2024.e24029","article-title":"Impact of obesity and hyperglycemia on placental mitochondria","volume":"2018","author":"Mando","year":"2018","journal-title":"Oxid Med Cell Longev"},{"key":"B24","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1155\/2018\/2378189","article-title":"Placental origins of adverse pregnancy outcomes: potential molecular targets: an executive workshop summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development","volume":"215","author":"Ilekis","year":"2016","journal-title":"Am J Obstet Gynecol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2395","DOI":"10.1016\/j.ajog.2016.03.001","article-title":"A new framework for the diagnosis, staging and management of obesity in adults","volume":"30","author":"Busetto","year":"2024","journal-title":"Nat Med"},{"key":"B26","doi-asserted-by":"publisher","first-page":"107245","DOI":"10.1038\/s41591-024-03095-3","article-title":"Inflammatory signalling during the perinatal period: implications for short- and long-term disease risk","volume":"172","author":"Garcia de Leon","year":"2025","journal-title":"Psychoneuroendocrinology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.psyneuen.2024.107245","article-title":"The role of inflammation in diabetes: current concepts and future perspectives","volume":"14","author":"Tsalamandris","year":"2019","journal-title":"Eur Cardiol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1186\/s12884-019-2383-7","article-title":"Hypertensive disorders of pregnancy are associated with an inflammatory state: evidence from hematological findings and cytokine levels","volume":"19","author":"Mtali","year":"2019","journal-title":"BMC Pregnancy Childbirth"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1872","DOI":"10.1016\/j.cmet.2023.10.011","article-title":"Mitohormesis","volume":"35","author":"Cheng","year":"2023","journal-title":"Cell Metab"},{"key":"B30","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1186\/s12964-025-02042-0","article-title":"Mitochondrial DNA signals driving immune responses: why, how, where?","volume":"23","author":"Giordano","year":"2025","journal-title":"Cell Commun Signal"},{"key":"B31","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.mito.2021.08.008","article-title":"MicroRNA-128 inhibits mitochondrial biogenesis and function via targeting PGC1\u03b1 and NDUFS4","volume":"60","author":"Sharma","year":"2021","journal-title":"Mitochondrion"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1279548","DOI":"10.3389\/fphys.2023.1279548","article-title":"Mitochondrial-related microRNAs and their roles in cellular senescence","volume":"14","author":"Luo","year":"2023","journal-title":"Front Physiol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"537","DOI":"10.2174\/138920210793175895","article-title":"MicroRNA: biogenesis, function and role in cancer","volume":"11","author":"Macfarlane","year":"2010","journal-title":"Curr Genomics"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2463","DOI":"10.3390\/cells10092463","article-title":"Mitochondrial biogenesis, mitochondrial dynamics, and mitophagy in the maturation of cardiomyocytes","volume":"10","author":"Ding","year":"2021","journal-title":"Cells"},{"key":"B35","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1186\/s13024-016-0121-4","article-title":"miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1)","volume":"11","author":"Kim","year":"2016","journal-title":"Mol Neurodegener"},{"key":"B36","doi-asserted-by":"publisher","first-page":"10691","DOI":"10.1074\/jbc.M113.537050","article-title":"MicroRNA-137 is a novel hypoxia-responsive microRNA that inhibits mitophagy via regulation of two mitophagy receptors FUNDC1 and NIX","volume":"289","author":"Li","year":"2014","journal-title":"J Biol Chem"},{"key":"B37","doi-asserted-by":"publisher","first-page":"42274","DOI":"10.18632\/oncotarget.9786","article-title":"MicroRNA-181a suppresses parkin-mediated mitophagy and sensitizes neuroblastoma cells to mitochondrial uncoupler-induced apoptosis","volume":"7","author":"Cheng","year":"2016","journal-title":"Oncotarget"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e8734","DOI":"10.15252\/emmm.201708734","article-title":"miR-181a\/b downregulation exerts a protective action on mitochondrial disease models","volume":"11","author":"Indrieri","year":"2019","journal-title":"EMBO Mol Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2262","DOI":"10.3892\/etm.2020.8924","article-title":"MicroRNA-27a inhibits trophoblast cell migration and invasion by targeting SMAD2: potential role in preeclampsia","volume":"20","author":"Zheng","year":"2020","journal-title":"Exp Ther Med"},{"key":"B40","doi-asserted-by":"publisher","first-page":"10873","DOI":"10.18632\/aging.103301","article-title":"miR-137 prevents inflammatory response, oxidative stress, neuronal injury and cognitive impairment via blockade of Src-mediated MAPK signaling pathway in ischemic stroke","volume":"12","author":"Tian","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"165354","DOI":"10.1016\/j.bbadis.2018.12.005","article-title":"Oxidative stress: normal pregnancy versus preeclampsia","volume":"1866","author":"Chiarello","year":"2020","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B42","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1093\/clinchem\/hvaa103","article-title":"Plasma or serum: which is preferable for mutation detection in liquid biopsy?","volume":"66","author":"Pittella-Silva","year":"2020","journal-title":"Clin Chem"},{"key":"B43","doi-asserted-by":"publisher","first-page":"319","DOI":"10.3892\/mmr.2021.11958","article-title":"Serum from patients with hypertension promotes endothelial dysfunction to induce trophoblast invasion through the miR-27b-3p\/ATPase plasma membrane Ca(2+) transporting 1 axis","volume":"23","author":"Zhu","year":"2021","journal-title":"Mol Med Rep"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.3892\/mmr.2021.11958","article-title":"Elevated microRNA-181a-5p contributes to trophoblast dysfunction and preeclampsia","volume":"26","author":"Huang","year":"2019","journal-title":"Reprod Sci"},{"key":"B45","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.1016\/j.ymthe.2018.07.009","article-title":"MicroRNA-218-5p promotes endovascular trophoblast differentiation and spiral artery remodeling","volume":"26","author":"Brki\u0107","year":"2018","journal-title":"Mol Ther"},{"key":"B46","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1177\/1933719116650754","article-title":"MicroRNA-137 affects proliferation and migration of placenta trophoblast cells in preeclampsia by targeting ERR\u03b1","volume":"24","author":"Lu","year":"2017","journal-title":"Reprod Sci"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1778221\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T04:34:51Z","timestamp":1775018091000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1778221\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":46,"alternative-id":["10.3389\/fcvm.2026.1778221"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2026.1778221","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,1]]},"article-number":"1778221"}}