{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:17:27Z","timestamp":1791580647953,"version":"4.3.4"},"reference-count":173,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH funding","award":["R21 AI178434"],"award-info":[{"award-number":["R21 AI178434"]}]},{"name":"NIH funding","award":["R21 AI66913"],"award-info":[{"award-number":["R21 AI66913"]}]},{"name":"NIH funding","award":["R01 GM111295"],"award-info":[{"award-number":["R01 GM111295"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sepsis is a life-threatening condition that occurs when the body is unable to effectively combat infection, leading to systemic inflammation and multi-organ failure. Interestingly, females exhibit lower sepsis incidence and improved clinical outcomes compared to males. However, the mechanisms underlying these sex-specific differences remain poorly understood. While sex hormones have been a primary focus, emerging evidence suggests that non-hormonal factors also play contributory roles. Despite sex differences in sepsis, clinical management is the same for both males and females, with treatment focused on combating infection using antibiotics and hemodynamic support through fluid therapy. However, even with these interventions, mortality remains high, highlighting the need for more effective and targeted therapeutic strategies. Sepsis-induced cardiomyopathy (SIC) is a key contributor to multi-organ failure and is characterized by left ventricular dilation and impaired cardiac contractility. In this review, we explore sex-specific differences in sepsis and SIC, with a particular focus on mitochondrial metabolism. Mitochondria generate the ATP required for cardiac function through fatty acid and glucose oxidation, and recent studies have revealed distinct metabolic profiles between males and females, which can further differ in the context of sepsis and SIC. Targeting these metabolic pathways could provide new avenues for sepsis treatment.<\/jats:p>","DOI":"10.3390\/ijms26094211","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T07:49:36Z","timestamp":1745912976000},"page":"4211","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Mitochondria at the Heart of Sepsis: Mechanisms, Metabolism, and Sex Differences"],"prefix":"10.3390","volume":"26","author":[{"given":"John Q.","family":"Yap","sequence":"first","affiliation":[{"name":"Department of Surgery, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"},{"name":"Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9810-6713","authenticated-orcid":false,"given":"Azadeh","family":"Nikouee","sequence":"additional","affiliation":[{"name":"Department of Surgery, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"},{"name":"Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie E.","family":"Lau","sequence":"additional","affiliation":[{"name":"Department of Surgery, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"},{"name":"Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8513-579X","authenticated-orcid":false,"given":"Gabriella","family":"Walsh","sequence":"additional","affiliation":[{"name":"Department of Surgery, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"},{"name":"Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6397-8896","authenticated-orcid":false,"given":"Qun Sophia","family":"Zang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"},{"name":"Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"},{"name":"Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"},{"name":"Cardiovascular Research Institute, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_2","unstructured":"Mahapatra, S., and Heffner, A.C. (2025). Septic Shock. StatPearls, StatPearls Publishing."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1001\/jama.2017.13836","article-title":"Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009\u20132014","volume":"318","author":"Rhee","year":"2017","journal-title":"JAMA"},{"key":"ref_4","unstructured":"Monegro, A.F., Muppidi, V., and Regunath, H. (2025). Hospital-Acquired Infections. StatPearls, StatPearls Publishing."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e206004","DOI":"10.1001\/jamanetworkopen.2020.6004","article-title":"Assessment of Health Care Exposures and Outcomes in Adult Patients With Sepsis and Septic Shock","volume":"3","author":"Fay","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.4161\/viru.27372","article-title":"Epidemiology of severe sepsis","volume":"5","author":"Mayr","year":"2014","journal-title":"Virulence"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1001\/jama.2009.1754","article-title":"International study of the prevalence and outcomes of infection in intensive care units","volume":"302","author":"Vincent","year":"2009","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e00355-19","DOI":"10.1128\/AAC.00355-19","article-title":"The Microbiology of Bloodstream Infection: 20-Year Trends from the SENTRY Antimicrobial Surveillance Program","volume":"63","author":"Diekema","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1016\/S0140-6736(22)02185-7","article-title":"Global mortality associated with 33 bacterial pathogens in 2019: A systematic analysis for the Global Burden of Disease Study 2019","volume":"400","author":"Collaborators","year":"2022","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100511","DOI":"10.1016\/j.lanepe.2022.100511","article-title":"One-year mortality and years of potential life lost following bloodstream infection among adults: A nation-wide population based study","volume":"23","author":"Schechner","year":"2022","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1056\/NEJMoa022139","article-title":"The epidemiology of sepsis in the United States from 1979 through 2000","volume":"348","author":"Martin","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1097\/SHK.0000000000001253","article-title":"Association of Sex With Clinical Outcome in Critically Ill Sepsis Patients: A Retrospective Analysis of the Large Clinical Database MIMIC-III","volume":"52","author":"Xu","year":"2019","journal-title":"Shock"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.1097\/CCM.0000000000002649","article-title":"Association of Gender With Outcome and Host Response in Critically Ill Sepsis Patients","volume":"45","author":"Scicluna","year":"2017","journal-title":"Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2960","DOI":"10.1097\/CCM.0b013e31825bc92f","article-title":"Patient and hospital characteristics associated with inpatient severe sepsis mortality in California, 2005\u20132010","volume":"40","author":"Banta","year":"2012","journal-title":"Crit. Care Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1089\/sur.2016.021","article-title":"Current Murine Models of Sepsis","volume":"17","author":"Lewis","year":"2016","journal-title":"Surg. Infect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0022-4804(80)90037-2","article-title":"Sepsis and septic shock--a review of laboratory models and a proposal","volume":"29","author":"Wichterman","year":"1980","journal-title":"J. Surg. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1056\/NEJM198806093182301","article-title":"Detection of circulating tumor necrosis factor after endotoxin administration","volume":"318","author":"Michie","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.1172\/JCI39421","article-title":"Animal models of sepsis and sepsis-induced kidney injury","volume":"119","author":"Doi","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"120","DOI":"10.5152\/eurasianjmed.2023.23364","article-title":"Experimental Sepsis Models: Advantages and Limitations","volume":"55","author":"Aydin","year":"2023","journal-title":"Eurasian J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1128\/CMR.00046-08","article-title":"Pathogen recognition and inflammatory signaling in innate immune defenses","volume":"22","author":"Mogensen","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e27","DOI":"10.4110\/in.2018.18.e27","article-title":"Damage-Associated Molecular Patterns in Inflammatory Diseases","volume":"18","author":"Roh","year":"2018","journal-title":"Immune Netw."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Guarino, M., Perna, B., Cesaro, A.E., Maritati, M., Spampinato, M.D., Contini, C., and De Giorgio, R. (2023). 2023 Update on Sepsis and Septic Shock in Adult Patients: Management in the Emergency Department. J. Clin. Med., 12.","DOI":"10.3390\/jcm12093188"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.jaci.2005.05.036","article-title":"Innate immune responses to infection","volume":"116","author":"Tosi","year":"2005","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s00441-017-2753-2","article-title":"Partners in crime: Neutrophils and monocytes\/macrophages in inflammation and disease","volume":"371","author":"Nicholls","year":"2018","journal-title":"Cell Tissue Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/s41392-024-01933-x","article-title":"Neutrophil extracellular traps in homeostasis and disease","volume":"9","author":"Wang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tecchio, C., Micheletti, A., and Cassatella, M.A. (2014). Neutrophil-derived cytokines: Facts beyond expression. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00508"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Arango Duque, G., and Descoteaux, A. (2014). Macrophage cytokines: Involvement in immunity and infectious diseases. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00491"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.imbio.2017.11.001","article-title":"Macrophages: Their role, activation and polarization in pulmonary diseases","volume":"223","author":"Arora","year":"2018","journal-title":"Immunobiology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"173090","DOI":"10.1016\/j.ejphar.2020.173090","article-title":"Macrophage M1\/M2 polarization","volume":"877","author":"Yunna","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1097\/CCM.0b013e31819da853","article-title":"Differences in immune response may explain lower survival among older men with pneumonia","volume":"37","author":"Reade","year":"2009","journal-title":"Crit. Care Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1177\/1753425917707026","article-title":"Sex differences in the pro-inflammatory cytokine response to endotoxin unfold in vivo but not ex vivo in healthy humans","volume":"23","author":"Wegner","year":"2017","journal-title":"Innate Immun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.1210\/en.2009-0098","article-title":"Estrogens augment cell surface TLR4 expression on murine macrophages and regulate sepsis susceptibility in vivo","volume":"150","author":"Rettew","year":"2009","journal-title":"Endocrinology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1095\/biolreprod.107.063545","article-title":"Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity","volume":"78","author":"Rettew","year":"2008","journal-title":"Biol. Reprod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"C1131","DOI":"10.1152\/ajpcell.2001.281.4.C1131","article-title":"17 beta-Estradiol normalizes immune responses in ovariectomized females after trauma-hemorrhage","volume":"281","author":"Knoferl","year":"2001","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1097\/00000658-200201000-00014","article-title":"Female sex hormones regulate macrophage function after trauma-hemorrhage and prevent increased death rate from subsequent sepsis","volume":"235","author":"Knoferl","year":"2002","journal-title":"Ann. Surg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1186\/s13054-016-1525-9","article-title":"Bioavailable estradiol concentrations are elevated and predict mortality in septic patients: A prospective cohort study","volume":"20","author":"Tsang","year":"2016","journal-title":"Crit. Care"},{"key":"ref_37","first-page":"580","article-title":"High levels of endogenous estrogens are associated with death in the critically injured adult","volume":"64","author":"Dossett","year":"2008","journal-title":"J. Trauma"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1097\/01.CCM.0000292015.16171.6D","article-title":"Estradiol is associated with mortality in critically ill trauma and surgical patients","volume":"36","author":"May","year":"2008","journal-title":"Crit. Care Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.jamcollsurg.2010.12.017","article-title":"Trends in estradiol during critical illness are associated with mortality independent of admission estradiol","volume":"212","author":"Kauffmann","year":"2011","journal-title":"J. Am. Coll. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/ni.3398","article-title":"Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis","volume":"17","author":"Cheng","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.cell.2016.08.064","article-title":"Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages","volume":"167","author":"Mills","year":"2016","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature11986","article-title":"Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha","volume":"496","author":"Tannahill","year":"2013","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e99292","DOI":"10.1172\/jci.insight.99292","article-title":"Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival","volume":"3","author":"McCall","year":"2018","journal-title":"JCI Insight"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Liu, Z., Ting, Y., Li, M., Li, Y., Tan, Y., and Long, Y. (2024). From immune dysregulation to organ dysfunction: Understanding the enigma of Sepsis. Front. Microbiol., 15.","DOI":"10.3389\/fmicb.2024.1415274"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ccr.2004.11.022","article-title":"Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase","volume":"7","author":"Selak","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.cmet.2020.08.002","article-title":"The Role of HIF in Immunity and Inflammation","volume":"32","author":"McGettrick","year":"2020","journal-title":"Cell Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41419-023-05656-9","article-title":"Epigenetic mechanisms of Immune remodeling in sepsis: Targeting histone modification","volume":"14","author":"Wu","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"110660","DOI":"10.1016\/j.celrep.2022.110660","article-title":"SENP1-Sirt3 signaling promotes alpha-ketoglutarate production during M2 macrophage polarization","volume":"39","author":"Zhou","year":"2022","journal-title":"Cell Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"25758","DOI":"10.1074\/jbc.M112.362343","article-title":"NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response","volume":"287","author":"Liu","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1002\/JLB.3A1119-236R","article-title":"Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes","volume":"107","author":"Zhu","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_51","unstructured":"Alabduladhem, T.O., and Bordoni, B. (2025). Physiology, Krebs Cycle. StatPearls, StatPearls Publishing."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6082","DOI":"10.4049\/jimmunol.1402469","article-title":"Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism","volume":"194","author":"Tan","year":"2015","journal-title":"J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6815","DOI":"10.2147\/JIR.S477495","article-title":"The Values of PDK1 and LDH Levels in Patients with Sepsis and Septic Shock: A Prospective Observational Study","volume":"17","author":"Liu","year":"2024","journal-title":"J. Inflamm. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1002\/eji.202149410","article-title":"Innate immune signaling and immunothrombosis: New insights and therapeutic opportunities","volume":"52","author":"Ryan","year":"2022","journal-title":"Eur. J. Immunol."},{"key":"ref_55","unstructured":"Chaudhry, R., Usama, S.M., and Babiker, H.M. (2025). Physiology, Coagulation Pathways. StatPearls, StatPearls Publishing."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1084\/jem.174.6.1517","article-title":"Lipopolysaccharide-mediated transcriptional activation of the human tissue factor gene in THP-1 monocytic cells requires both activator protein 1 and nuclear factor kappa B binding sites","volume":"174","author":"Mackman","year":"1991","journal-title":"J. Exp. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1182\/blood-2009-02-205914","article-title":"Activation of endothelial intrinsic NF-kappaB pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice","volume":"114","author":"Song","year":"2009","journal-title":"Blood"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Mussbacher, M., Salzmann, M., Brostjan, C., Hoesel, B., Schoergenhofer, C., Datler, H., Hohensinner, P., Basilio, J., Petzelbauer, P., and Assinger, A. (2019). Cell Type-Specific Roles of NF-kappaB Linking Inflammation and Thrombosis. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00085"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/j.immuni.2019.04.003","article-title":"Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis","volume":"50","author":"Wu","year":"2019","journal-title":"Immunity"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1213\/ANE.0000000000006888","article-title":"Sepsis-Induced Coagulopathy: A Comprehensive Narrative Review of Pathophysiology, Clinical Presentation, Diagnosis, and Management Strategies","volume":"138","author":"Williams","year":"2024","journal-title":"Anesth. Analg."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/s12967-015-0518-9","article-title":"Diagnostic and prognostic utility of tissue factor for severe sepsis and sepsis-induced acute lung injury","volume":"13","author":"Xue","year":"2015","journal-title":"J. Transl. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13613-019-0499-6","article-title":"Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: Results of an observational pilot study","volume":"9","author":"Schmitt","year":"2019","journal-title":"Ann. Intensive Care"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"10760296221101386","DOI":"10.1177\/10760296221101386","article-title":"Decreasing Plasma Fibrinogen Levels in the Intensive Care Unit Are Associated with High Mortality Rates In Patients With Sepsis-Induced Coagulopathy","volume":"28","author":"Mori","year":"2022","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1182\/blood-2002-05-1300","article-title":"Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells","volume":"101","author":"Fiuza","year":"2003","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1532\/IJH97.05190","article-title":"Plasminogen activator inhibitor 1 promotes a poor prognosis in sepsis-induced disseminated intravascular coagulation","volume":"84","author":"Madoiwa","year":"2006","journal-title":"Int. J. Hematol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1097\/SHK.0000000000001847","article-title":"Which Septic Shock Patients With Non-Overt DIC Progress to DIC After Admission? Point-of-Care Thromboelastography Testing","volume":"57","author":"Kim","year":"2022","journal-title":"Shock"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s00424-007-0212-8","article-title":"The endothelial glycocalyx: Composition, functions, and visualization","volume":"454","author":"Reitsma","year":"2007","journal-title":"Pflug. Arch."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.matbio.2011.10.001","article-title":"Molecular functions of syndecan-1 in disease","volume":"31","author":"Teng","year":"2012","journal-title":"Matrix Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.jamcollsurg.2018.09.003","article-title":"Elevated Syndecan-1 after Trauma and Risk of Sepsis: A Secondary Analysis of Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial","volume":"227","author":"Wei","year":"2018","journal-title":"J. Am. Coll. Surg."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1186\/s13054-015-0918-5","article-title":"Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: A prospective study","volume":"19","author":"Ostrowski","year":"2015","journal-title":"Crit. Care"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jcrc.2016.06.027","article-title":"Plasma syndecan-1 levels identify a cohort of patients with severe sepsis at high risk for intubation after large-volume intravenous fluid resuscitation","volume":"36","author":"Puskarich","year":"2016","journal-title":"J. Crit. Care"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jcrc.2014.10.006","article-title":"Sympathoadrenal activation and endothelial damage in patients with varying degrees of acute infectious disease: An observational study","volume":"30","author":"Ostrowski","year":"2015","journal-title":"J. Crit. Care"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/j.clinbiochem.2016.02.014","article-title":"Evolution of serum hyaluronan and syndecan levels in prognosis of sepsis patients","volume":"49","author":"Anand","year":"2016","journal-title":"Clin. Biochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"H647","DOI":"10.1152\/ajpheart.00090.2018","article-title":"Role of matrix metalloproteinases and histone deacetylase in oxidative stress-induced degradation of the endothelial glycocalyx","volume":"316","author":"Ali","year":"2019","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.brainres.2011.01.076","article-title":"Differential roles of ERK, JNK and p38 MAPK in pain-related spatial and temporal enhancement of synaptic responses in the hippocampal formation of rats: Multi-electrode array recordings","volume":"1382","author":"Liu","year":"2011","journal-title":"Brain Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1002\/cyto.a.20952","article-title":"Proinflammatory activation pattern of human umbilical vein endothelial cells induced by IL-1beta, TNF-alpha, and LPS","volume":"77","author":"Mako","year":"2010","journal-title":"Cytom. A"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Feng, Y., Zhou, S., Gao, S., Xiong, B., Gao, X., Song, Y., Liu, L., Wang, C., and Yang, Y. (2024). Establishment of a model of LPS-induced inflammatory injury in human aortic endothelial cells. Biomed. Pharmacother., 174.","DOI":"10.1016\/j.biopha.2024.116576"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/j.intimp.2008.05.004","article-title":"Expression of NADPH oxidases and enhanced H(2)O(2)-generating activity in human coronary artery endothelial cells upon induction with tumor necrosis factor-alpha","volume":"8","author":"Yoshida","year":"2008","journal-title":"Int. Immunopharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"6209","DOI":"10.1128\/IAI.68.11.6209-6214.2000","article-title":"Augmentation of nitric oxide production by gamma interferon in a mouse vascular endothelial cell line and its modulation by tumor necrosis factor alpha and lipopolysaccharide","volume":"68","author":"Morikawa","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1006\/bbrc.1994.1949","article-title":"Differential regulation of constitutive and inducible nitric oxide production by inflammatory stimuli in murine endothelial cells","volume":"202","author":"Walter","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3356","DOI":"10.1210\/en.2006-1441","article-title":"Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway","volume":"148","author":"Li","year":"2007","journal-title":"Endocrinology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/01.CCM.0000105118.66983.19","article-title":"Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: Results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002)","volume":"32","author":"Bakker","year":"2004","journal-title":"Crit. Care Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/CCM.0000000000000554","article-title":"Multicenter, randomized, placebo-controlled phase III study of pyridoxalated hemoglobin polyoxyethylene in distributive shock (PHOENIX)","volume":"43","author":"Vincent","year":"2015","journal-title":"Crit. Care Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1097\/01.CCM.0000105581.01815.C6","article-title":"Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock","volume":"32","author":"Lopez","year":"2004","journal-title":"Crit. Care Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.freeradbiomed.2020.09.025","article-title":"Control of systemic inflammation through early nitric oxide supplementation with nitric oxide releasing nanoparticles","volume":"161","author":"Williams","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1186\/s13054-022-04075-0","article-title":"A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach","volume":"26","author":"Singh","year":"2022","journal-title":"Crit. Care"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1097\/SHK.0000000000000649","article-title":"High Levels of Methylarginines Were Associated With Increased Mortality in Patients With Severe Sepsis","volume":"46","author":"Mortensen","year":"2016","journal-title":"Shock"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1186\/s13054-018-2090-1","article-title":"Symmetrical (SDMA) and asymmetrical dimethylarginine (ADMA) in sepsis: High plasma levels as combined risk markers for sepsis survival","volume":"22","author":"Winkler","year":"2018","journal-title":"Crit. Care"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s10753-017-0660-z","article-title":"Time-Dependent Production of Endothelium-Related Biomarkers is Affected Differently in Hemorrhagic and Septic Shocks","volume":"41","author":"Coskun","year":"2018","journal-title":"Inflammation"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1165\/rcmb.2013-0193OC","article-title":"Dimethylarginine dimethylaminohydrolase II overexpression attenuates LPS-mediated lung leak in acute lung injury","volume":"50","author":"Aggarwal","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1016\/S0140-6736(02)11393-6","article-title":"Nitroglycerin in septic shock after intravascular volume resuscitation","volume":"360","author":"Spronk","year":"2002","journal-title":"Lancet"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1097\/CCM.0b013e3181b02fc1","article-title":"Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis\/septic shock after a strict resuscitation protocol: A double-blind randomized placebo controlled trial","volume":"38","author":"Boerma","year":"2010","journal-title":"Crit. Care Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1128\/IAI.66.4.1400-1407.1998","article-title":"Endotoxin-neutralizing protein protects against endotoxin-induced endothelial barrier dysfunction","volume":"66","author":"Bannerman","year":"1998","journal-title":"Infect. Immun."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"35371","DOI":"10.1074\/jbc.273.52.35371","article-title":"Bacterial lipopolysaccharide disrupts endothelial monolayer integrity and survival signaling events through caspase cleavage of adherens junction proteins","volume":"273","author":"Bannerman","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_95","first-page":"H286","article-title":"Cytoskeletal rearrangement mediates human microvascular endothelial tight junction modulation by cytokines","volume":"273","author":"Blum","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"He, R.R., Yue, G.L., Dong, M.L., Wang, J.Q., and Cheng, C. (2024). Sepsis Biomarkers: Advancements and Clinical Applications-A Narrative Review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25169010"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1001\/jama.2016.20328","article-title":"Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit","volume":"317","author":"Raith","year":"2017","journal-title":"JAMA"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1097\/CCM.0000000000004842","article-title":"Sepsis Subclasses: A Framework for Development and Interpretation","volume":"49","author":"DeMerle","year":"2021","journal-title":"Crit. Care Med."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Baghela, A., Pena, O.M., Lee, A.H., Baquir, B., Falsafi, R., An, A., Farmer, S.W., Hurlburt, A., Mondragon-Cardona, A., and Rivera, J.D. (2022). Predicting sepsis severity at first clinical presentation: The role of endotypes and mechanistic signatures. eBioMedicine, 75.","DOI":"10.1016\/j.ebiom.2021.103776"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Bodinier, M., Peronnet, E., Brengel-Pesce, K., Conti, F., Rimmele, T., Textoris, J., Vedrine, C., Quemeneur, L., Griffiths, A.D., and Tan, L.K. (2021). Monocyte Trajectories Endotypes Are Associated With Worsening in Septic Patients. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.795052"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s11886-020-01277-2","article-title":"Sepsis-Induced Cardiomyopathy: A Comprehensive Review","volume":"22","author":"Sternberg","year":"2020","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"132","DOI":"10.31083\/j.rcm2504132","article-title":"Sex Differences in the Epidemiology, Risk Factors, and Prognosis of Malignant Ventricular Arrhythmias in Sepsis Patients","volume":"25","author":"Li","year":"2024","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e5031","DOI":"10.1097\/MD.0000000000005031","article-title":"Prevalence and risk factors of sepsis-induced cardiomyopathy: A retrospective cohort study","volume":"95","author":"Sato","year":"2016","journal-title":"Medicine"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Liu, Y.W., Wang, Y.F., Chen, Y., Dong, R., Li, S., Peng, J.M., Liufu, R., Weng, L., Xu, Y., and Du, B. (2024). A nationwide study on new onset atrial fibrillation risk factors and its association with hospital mortality in sepsis patients. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-62630-x"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Solaro, R.J. (2011). Regulation of Cardiac Contractility, Morgan & Claypool Publishers.","DOI":"10.4199\/C00030ED1V01Y201104ISP018"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12967-022-03842-5","article-title":"Angiotensin-(1-7) ameliorates sepsis-induced cardiomyopathy by alleviating inflammatory response and mitochondrial damage through the NF-kappaB and MAPK pathways","volume":"21","author":"Chen","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"106473","DOI":"10.1016\/j.phrs.2022.106473","article-title":"Losartan attenuates sepsis-induced cardiomyopathy by regulating macrophage polarization via TLR4-mediated NF-kappaB and MAPK signaling","volume":"185","author":"Chen","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"20","DOI":"10.3892\/ijmm.2021.4853","article-title":"Inhibition of miR-101-3p protects against sepsis-induced myocardial injury by inhibiting MAPK and NF-kappaB pathway activation via the upregulation of DUSP1","volume":"47","author":"Xin","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Ruan, W., Ji, X., Qin, Y., Zhang, X., Wan, X., Zhu, C., Lv, C., Hu, C., Zhou, J., and Lu, L. (2021). Harmine Alleviated Sepsis-Induced Cardiac Dysfunction by Modulating Macrophage Polarization via the STAT\/MAPK\/NF-kappaB Pathway. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.792257"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1161\/CIRCULATIONAHA.104.490979","article-title":"Ventricular myocyte caspases are directly responsible for endotoxin-induced cardiac dysfunction","volume":"111","author":"Lancel","year":"2005","journal-title":"Circulation"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jacc.2006.02.069","article-title":"Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality","volume":"48","author":"Larche","year":"2006","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1161\/CIRCULATIONAHA.117.032821","article-title":"Beclin-1-Dependent Autophagy Protects the Heart During Sepsis","volume":"138","author":"Sun","year":"2018","journal-title":"Circulation"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Nikouee, A., Yap, J.Q., Rademacher, D.J., Kim, M., and Zang, Q.S. (2024). An optimized Langendorff-free method for isolation and characterization of primary adult cardiomyocytes. BMC Cardiovasc. Disord., 24.","DOI":"10.1186\/s12872-024-04256-5"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Kim, M., Nikouee, A., Sun, Y., Zhang, Q.J., Liu, Z.P., and Zang, Q.S. (2022). Evaluation of Parkin in the Regulation of Myocardial Mitochondria-Associated Membranes and Cardiomyopathy During Endotoxemia. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.796061"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1161\/CIRCHEARTFAILURE.112.000177","article-title":"Peroxisome proliferator-activated receptor-gamma activation prevents sepsis-related cardiac dysfunction and mortality in mice","volume":"6","author":"Drosatos","year":"2013","journal-title":"Circ. Heart Fail."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"H283","DOI":"10.1152\/ajpheart.00108.2019","article-title":"beta(3)-Adrenergic receptor blockade reduces mortality in endotoxin-induced heart failure by suppressing induced nitric oxide synthase and saving cardiac metabolism","volume":"318","author":"Kawaguchi","year":"2020","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e131571","DOI":"10.1172\/jci.insight.131571","article-title":"Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial sepsis","volume":"5","author":"Zechendorf","year":"2020","journal-title":"JCI Insight"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13054-015-0820-1","article-title":"beta(1)-adrenoceptor stimulation promotes LPS-induced cardiomyocyte apoptosis through activating PKA and enhancing CaMKII and IkappaBalpha phosphorylation","volume":"19","author":"Wang","year":"2015","journal-title":"Crit. Care"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1006\/jmcc.2001.1385","article-title":"Effect of NF-kappa B Inhibition on TNF-alpha-induced apoptosis and downstream pathways in cardiomyocytes","volume":"33","author":"Bergmann","year":"2001","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"H1608","DOI":"10.1152\/ajpheart.2001.280.4.H1608","article-title":"Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis","volume":"280","author":"Fauvel","year":"2001","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1164\/ajrccm.163.1.2003109","article-title":"Caspase inhibition prevents cardiac dysfunction and heart apoptosis in a rat model of sepsis","volume":"163","author":"Neviere","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1161\/HYPERTENSIONAHA.119.13197","article-title":"Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Short-Term Mortality After Sepsis: A Population-Based Cohort Study","volume":"75","author":"Hsu","year":"2020","journal-title":"Hypertension"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1074\/jbc.M117.812289","article-title":"Toll-like receptor 4-induced ryanodine receptor 2 oxidation and sarcoplasmic reticulum Ca(2+) leakage promote cardiac contractile dysfunction in sepsis","volume":"293","author":"Yang","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"e94248","DOI":"10.1172\/jci.insight.94248","article-title":"Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function","volume":"2","author":"Joseph","year":"2017","journal-title":"JCI Insight"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"R1095","DOI":"10.1152\/ajpregu.90902.2008","article-title":"MitoQ administration prevents endotoxin-induced cardiac dysfunction","volume":"297","author":"Supinski","year":"2009","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"H1189","DOI":"10.1152\/ajpheart.00392.2012","article-title":"SERCA Cys674 sulphonylation and inhibition of L-type Ca2+ influx contribute to cardiac dysfunction in endotoxemic mice, independent of cGMP synthesis","volume":"305","author":"Hobai","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1164\/ajrccm.165.4.2105084","article-title":"Protective effects of cyclosporin A from endotoxin-induced myocardial dysfunction and apoptosis in rats","volume":"165","author":"Fauvel","year":"2002","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_128","first-page":"6937","article-title":"High-dose Vitamin C injection ameliorates against sepsis-induced myocardial injury by anti-apoptosis, anti-inflammatory and pro-autophagy through regulating MAPK, NF-kappaB and PI3K\/AKT\/mTOR signaling pathways in rats","volume":"16","author":"Cui","year":"2024","journal-title":"Aging"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.chest.2016.11.036","article-title":"Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study","volume":"151","author":"Marik","year":"2017","journal-title":"Chest"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"94","DOI":"10.4103\/2279-042X.179569","article-title":"Effect of high-dose Ascorbic acid on vasopressor\u2019s requirement in septic shock","volume":"5","author":"Zabet","year":"2016","journal-title":"J. Res. Pharm. Pract."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1479-5876-12-32","article-title":"Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis","volume":"12","author":"Fowler","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s40635-022-00454-7","article-title":"Sex-specific differences in cardiac function, inflammation and injury during early polymicrobial sepsis","volume":"10","author":"Walker","year":"2022","journal-title":"Intensive Care Med. Exp."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"155934","DOI":"10.1016\/j.metabol.2024.155934","article-title":"Estradiol contributes to sex differences in resilience to sepsis-induced metabolic dysregulation and dysfunction in the heart via GPER-1-mediated PPARdelta\/NLRP3 signaling","volume":"156","author":"Adekunle","year":"2024","journal-title":"Metabolism"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.yjmcc.2009.05.002","article-title":"Rac1 mediates sex difference in cardiac tumor necrosis factor-alpha expression via NADPH oxidase-ERK1\/2\/p38 MAPK pathway in endotoxemia","volume":"47","author":"Zhu","year":"2009","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1097\/01.sla.0000254417.15591.88","article-title":"The PI3K\/Akt pathway mediates the nongenomic cardioprotective effects of estrogen following trauma-hemorrhage","volume":"245","author":"Yu","year":"2007","journal-title":"Ann. Surg."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.mvr.2012.10.002","article-title":"Estradiol receptors agonists induced effects in rat intestinal microcirculation during sepsis","volume":"85","author":"Sharawy","year":"2013","journal-title":"Microvasc. Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1161\/01.CIR.75.3.533","article-title":"Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock","volume":"75","author":"Dhainaut","year":"1987","journal-title":"Circulation"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1161\/01.CIR.73.4.637","article-title":"The coronary circulation in human septic shock","volume":"73","author":"Cunnion","year":"1986","journal-title":"Circulation"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/j.bbalip.2016.03.014","article-title":"Fuel availability and fate in cardiac metabolism: A tale of two substrates","volume":"1861","author":"Pascual","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Jia, X., Peng, Y., Ma, X., Liu, X., Yu, K., and Wang, C. (2022). Analysis of metabolic disturbances attributable to sepsis-induced myocardial dysfunction using metabolomics and transcriptomics techniques. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.967397"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s00395-007-0666-z","article-title":"Excitation-contraction coupling and mitochondrial energetics","volume":"102","author":"Maack","year":"2007","journal-title":"Basic. Res. Cardiol."},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Shi, X., and Qiu, H. (2022). New Insights Into Energy Substrate Utilization and Metabolic Remodeling in Cardiac Physiological Adaption. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.831829"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"8162","DOI":"10.1016\/S0021-9258(18)92956-X","article-title":"Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts","volume":"266","author":"Saddik","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.nuclcard.2007.03.001","article-title":"Sex differences in myocardial oxygen and glucose metabolism","volume":"14","author":"Peterson","year":"2007","journal-title":"J. Nucl. Cardiol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.jcmg.2008.05.004","article-title":"Impact of gender on the myocardial metabolic response to obesity","volume":"1","author":"Peterson","year":"2008","journal-title":"JACC Cardiovasc. Imaging"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"36331","DOI":"10.1074\/jbc.M111.272146","article-title":"Inhibition of c-Jun-N-terminal kinase increases cardiac peroxisome proliferator-activated receptor alpha expression and fatty acid oxidation and prevents lipopolysaccharide-induced heart dysfunction","volume":"286","author":"Drosatos","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Guo, X., Hong, T., Zhang, S., Wei, Y., Jin, H., Miao, Q., Wang, K., Zhou, M., Wang, C., and He, B. (2021). IL-13 Alleviates Cardiomyocyte Apoptosis by Improving Fatty Acid Oxidation in Mitochondria. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.736603"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1161\/CIRCHEARTFAILURE.110.959833","article-title":"Toll-like receptor-mediated inflammatory signaling reprograms cardiac energy metabolism by repressing peroxisome proliferator-activated receptor gamma coactivator-1 signaling","volume":"4","author":"Schilling","year":"2011","journal-title":"Circ. Heart Fail."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1097\/SHK.0000000000001858","article-title":"Pyruvate-Driven Oxidative Phosphorylation is Downregulated in Sepsis-Induced Cardiomyopathy: A Study of Mitochondrial Proteome","volume":"57","author":"Shimada","year":"2022","journal-title":"Shock"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1093\/cvr\/cvv105","article-title":"Good and bad consequences of altered fatty acid metabolism in heart failure: Evidence from mouse models","volume":"106","author":"Abdurrachim","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1093\/infdis\/jiad365","article-title":"Inhibition of Pyruvate Dehydrogenase Kinase 4 Attenuates Myocardial and Mitochondrial Injury in Sepsis-Induced Cardiomyopathy","volume":"229","author":"Chen","year":"2024","journal-title":"J. Infect. Dis."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1007\/s10753-024-01981-z","article-title":"Inhibition of Pyruvate Dehydrogenase Kinase 4 Protects Cardiomyocytes from lipopolysaccharide-Induced Mitochondrial Damage by Reducing Lactate Accumulation","volume":"47","author":"Chen","year":"2024","journal-title":"Inflammation"},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"Wang, X., Shen, X., Yan, Y., and Li, H. (2021). Pyruvate dehydrogenase kinases (PDKs): An overview toward clinical applications. Biosci. Rep., 41.","DOI":"10.1042\/BSR20204402"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"6915","DOI":"10.1074\/jbc.RA117.000268","article-title":"Coenzyme A-mediated degradation of pyruvate dehydrogenase kinase 4 promotes cardiac metabolic flexibility after high-fat feeding in mice","volume":"293","author":"Schafer","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1074\/jbc.M116.754127","article-title":"Regulation of Pyruvate Dehydrogenase Kinase 4 in the Heart through Degradation by the Lon Protease in Response to Mitochondrial Substrate Availability","volume":"292","author":"Crewe","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1210\/en.2009-1072","article-title":"The increase in cardiac pyruvate dehydrogenase kinase-4 after short-term dexamethasone is controlled by an Akt-p38-forkhead box other factor-1 signaling axis","volume":"151","author":"Puthanveetil","year":"2010","journal-title":"Endocrinology"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1172\/JCI60329","article-title":"Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice","volume":"122","author":"Battiprolu","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"108935","DOI":"10.1016\/j.celrep.2021.108935","article-title":"FoxO1 inhibition alleviates type 2 diabetes-related diastolic dysfunction by increasing myocardial pyruvate dehydrogenase activity","volume":"35","author":"Gopal","year":"2021","journal-title":"Cell Rep."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"e2120157119","DOI":"10.1073\/pnas.2120157119","article-title":"Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status","volume":"119","author":"Thoudam","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1007\/s00432-024-05748-9","article-title":"Abrogating PDK4 activates autophagy-dependent ferroptosis in breast cancer via ASK1\/JNK pathway","volume":"150","author":"Shi","year":"2024","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Khandia, R., Dadar, M., Munjal, A., Dhama, K., Karthik, K., Tiwari, R., Yatoo, M.I., Iqbal, H.M.N., Singh, K.P., and Joshi, S.K. (2019). A Comprehensive Review of Autophagy and Its Various Roles in Infectious, Non-Infectious, and Lifestyle Diseases: Current Knowledge and Prospects for Disease Prevention, Novel Drug Design, and Therapy. Cells, 8.","DOI":"10.3390\/cells8070674"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/s41392-023-01503-7","article-title":"The mitophagy pathway and its implications in human diseases","volume":"8","author":"Wang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1161\/CIRCRESAHA.111.244707","article-title":"Autophagy and p62 in cardiac proteinopathy","volume":"109","author":"Zheng","year":"2011","journal-title":"Circ. Res."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Yoshii, S.R., and Mizushima, N. (2017). Monitoring and Measuring Autophagy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091865"},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Zou, H.X., Qiu, B.Q., Zhang, Z.Y., Hu, T., Wan, L., Liu, J.C., Huang, H., and Lai, S.Q. (2022). Dysregulated autophagy-related genes in septic cardiomyopathy: Comprehensive bioinformatics analysis based on the human transcriptomes and experimental validation. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.923066"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"e70397","DOI":"10.1096\/fj.202402599RR","article-title":"TMBIM1 ameliorates sepsis-induced cardiac dysfunction by promoting Parkin-mediated mitophagy","volume":"39","author":"Huang","year":"2025","journal-title":"FASEB J."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1177\/0300060519837103","article-title":"Levosimendan as a new force in the treatment of sepsis-induced cardiomyopathy: Mechanism and clinical application","volume":"47","author":"Yang","year":"2019","journal-title":"J. Int. Med. Res."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.ijcard.2016.07.202","article-title":"Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper","volume":"222","author":"Farmakis","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"212","DOI":"10.21037\/atm-22-483","article-title":"Levosimendan protects from sepsis-inducing cardiac dysfunction by suppressing inflammation, oxidative stress and regulating cardiac mitophagy via the PINK-1-Parkin pathway in mice","volume":"10","author":"Shi","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_170","doi-asserted-by":"crossref","unstructured":"Tan, R., Guo, H., Yang, Z., Yang, H., Li, Q., Zhu, Q., and Du, Q. (2024). Efficacy and safety of levosimendan in patients with sepsis: A systematic review and network meta-analysis. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1358735"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"329","DOI":"10.2131\/jts.43.329","article-title":"Protective effects of rutin on lipopolysaccharide-induced heart injury in mice","volume":"43","author":"Xianchu","year":"2018","journal-title":"J. Toxicol. Sci."},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Lew, W.Y., Bayna, E., Dalle Molle, E., Contu, R., Condorelli, G., and Tang, T. (2014). Myocardial fibrosis induced by exposure to subclinical lipopolysaccharide is associated with decreased miR-29c and enhanced NOX2 expression in mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107556"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"7143","DOI":"10.1016\/j.cell.2024.09.034","article-title":"Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target","volume":"187","author":"Zhang","year":"2024","journal-title":"Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4211\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:23:50Z","timestamp":1760030630000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4211"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,29]]},"references-count":173,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094211"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094211","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,29]]}}}