{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:00:42Z","timestamp":1787803242945,"version":"build-2784847793"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"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><jats:title>Background<\/jats:title><jats:p>Cardiovascular disease (CVD) develops in men earlier in life but CVD women have a higher risk of cardiovascular mortality than CVD men. In addition, co-occurrence with type 2 diabetes mellitus (T2DM) increases CVD risk. We aimed to evaluate sex differences in endotoxemia and trimethylamine N-oxide (TMAO) plasma levels, in co-occurrence with T2DM in coronary heart disease (CHD) patients, and their potential sex-specific modulation by the consumption of healthy diets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study was carried out within the framework of the CORDIOPREV study, a clinical trial which included 1,002 (827 men and 175 women) with CHD, of whom 462 had no T2DM, 350 had T2DM, and 190 were newly diagnosed with T2DM at recruitment. Plasma lipopolysaccharide (LPS) was measured by LAL colorimetric assay and TMAO by HPLC. Intima-media thickness of both common carotid arteries (IMT-CC) and carotid plaques were assessed ultrasonically.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LPS and TMAO plasma levels were lower in CHD non-T2DM women than CHD non-T2DM men (both, <jats:italic>P<\/jats:italic>-value &amp;lt;0.05), whereas no sex differences were observed in CHD T2DM patients, or CHD newly-diagnosed T2DM patients. These sex differences were consistent with lower IMT-CC and a smaller number of plaques in CHD non-T2DM women than in CHD non-T2DM men, with no sex differences found in CHD T2DM patients, or CHD newly-diagnosed T2DM patients. In contrast, C-reactive protein plasma levels were higher in CHD T2DM women than CHD T2DM men (<jats:italic>P<\/jats:italic>\u2009=\u20090.012 and <jats:italic>P<\/jats:italic>\u2009=\u20090.001, respectively), with no sex differences found in CHD non-T2DM patients. Both, LF and Med diets reduced the LPS plasma levels in CHD men and women newly diagnosed with T2DM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results suggest that the sex differences in CHD patients are influenced by the presence of T2DM. Moreover, our results also suggest that the cardiovascular risk associated to T2DM, in co-occurrence with CVD, is higher in women than in men.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2025.1527406","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T05:37:29Z","timestamp":1761025049000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Sex-differences in endotoxemia and trimethylamine N-oxide according to the diet and type 2 diabetes status in coronary heart disease patients: from the CORDIOPREV study"],"prefix":"10.3389","volume":"12","author":[{"given":"Helena","family":"Garcia-Fernandez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Arenas-Montes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco M.","family":"Gutierrez-Mariscal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan F.","family":"Alcala-Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa","family":"Allais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio P.","family":"Arenas-de Larriva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Luque-Cordoba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose D.","family":"Torres-Pe\u00f1a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan L.","family":"Romero-Cabrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul M.","family":"Luque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feliciano","family":"Priego-Capote","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Delgado-Lista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Lopez-Miranda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Camargo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"100709","DOI":"10.1016\/j.ajpc.2024.100709","article-title":"Sex-related differences in the 20-year incidence of CVD and its risk factors: the ATTICA study (2002\u20132022)","volume":"19","author":"Sigala","year":"2024","journal-title":"Am J Prev Cardiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"101604","DOI":"10.1016\/j.cpcardiol.2023.101604","article-title":"Gender and CVD- does it really matters?","volume":"48","author":"Suman","year":"2023","journal-title":"Curr Probl Cardiol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2385","DOI":"10.1016\/S0140-6736(21)00684-X","article-title":"The lancet women and cardiovascular disease commission: reducing the global burden by 2030","volume":"397","author":"Vogel","year":"2021","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1001\/jamacardio.2020.0822","article-title":"Association of sex with severity of coronary artery disease, ischemia, and symptom burden in patients with moderate or severe ischemia: secondary analysis of the ISCHEMIA randomized clinical trial","volume":"5","author":"Reynolds","year":"2020","journal-title":"JAMA Cardiol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","article-title":"Global burden of cardiovascular diseases and risk factors, 1990\u20132019: update from the GBD 2019 study","volume":"76","author":"Roth","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"117279","DOI":"10.1016\/j.atherosclerosis.2023.117279","article-title":"Sex differences in the genetic and molecular mechanisms of coronary artery disease","volume":"384","author":"Sakkers","year":"2023","journal-title":"Atherosclerosis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1161\/CIRCRESAHA.120.315930","article-title":"Sex as a biological Variable in atherosclerosis","volume":"126","author":"Man","year":"2020","journal-title":"Circ Res"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e011612","DOI":"10.1161\/CIRCINTERVENTIONS.121.011612","article-title":"Sex differences in culprit plaque characteristics among different age groups in patients with acute coronary syndromes","volume":"15","author":"Seegers","year":"2022","journal-title":"Circ Cardiovasc Interv"},{"key":"B9","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1093\/eurheartj\/ehad720","article-title":"Platelet biology and function: plaque erosion vs. rupture","volume":"45","author":"Baaten","year":"2024","journal-title":"Eur Heart J"},{"key":"B10","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/nrendo.2013.122","article-title":"Testosterone and insulin resistance in the metabolic syndrome and T2DM in men","volume":"9","author":"Rao","year":"2013","journal-title":"Nat Rev Endocrinol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1007\/164_2023_683","article-title":"Sex-gender-based differences in metabolic diseases","volume":"282","author":"Campesi","year":"2023","journal-title":"Handb Exp Pharmacol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"704145","DOI":"10.3389\/fcvm.2021.704145","article-title":"Impact of metabolic syndrome and it\u2019s components on prognosis in patients with cardiovascular diseases: a meta-analysis","volume":"8","author":"Li","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1373\/clinchem.2013.202549","article-title":"Sex differences in the metabolic syndrome: implications for cardiovascular health in women","volume":"60","author":"Pradhan","year":"2014","journal-title":"Clin Chem"},{"key":"B14","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.ejim.2023.10.006","article-title":"Role of sex and gender-related variables in development of metabolic syndrome: a prospective cohort study","volume":"121","author":"Alipour","year":"2024","journal-title":"Eur J Intern Med"},{"key":"B15","first-page":"1","article-title":"Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003\u20132006","volume":"13","author":"Ervin","year":"2009","journal-title":"Natl Health Stat Rep"},{"key":"B16","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1111\/joim.12804","article-title":"Cardiovascular disease in diabetes type 2: current concepts","volume":"284","author":"Rosengren","year":"2018","journal-title":"J Intern Med"},{"key":"B17","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/nrcardio.2016.183","article-title":"Role of gut microbiota in atherosclerosis","volume":"14","author":"Jonsson","year":"2017","journal-title":"Nat Rev Cardiol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.metabol.2016.12.009","article-title":"Metabolic endotoxemia and diabetes mellitus: a systematic review","volume":"68","author":"Gomes","year":"2017","journal-title":"Metab Clin Exp"},{"key":"B19","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.cmet.2012.12.011","article-title":"Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation","volume":"17","author":"Bennett","year":"2013","journal-title":"Cell Metab"},{"key":"B20","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13293-019-0240-z","article-title":"Sex, gut microbiome, and cardiovascular disease risk","volume":"10","author":"Razavi","year":"2019","journal-title":"Biol Sex Differ"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.1007\/s00125-010-1684-1","article-title":"Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard lecture 2009","volume":"53","author":"Defronzo","year":"2010","journal-title":"Diabetologia"},{"key":"B22","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s12933-022-01516-6","article-title":"Cardiovascular disease in type 2 diabetes mellitus: progress toward personalized management","volume":"21","author":"Ma","year":"2022","journal-title":"Cardiovasc Diabetol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1876","DOI":"10.1016\/S0140-6736(22)00122-2","article-title":"Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial","volume":"399","author":"Delgado-Lista","year":"2022","journal-title":"Lancet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"S62","DOI":"10.2337\/dc11-S062","article-title":"Diagnosis and classification of diabetes mellitus","volume":"34","year":"2011","journal-title":"Diabetes Care"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2486","DOI":"10.1001\/jama.285.19.2486","article-title":"Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III)","volume":"285","year":"2001","journal-title":"JAMA"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e34","DOI":"10.1056\/NEJMoa1800389","article-title":"Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts","volume":"378","author":"Estruch","year":"2018","journal-title":"N Engl J Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e0154090","DOI":"10.1371\/journal.pone.0154090","article-title":"Intestinal microbiota is influenced by gender and body mass index","volume":"11","author":"Haro","year":"2016","journal-title":"PLoS One"},{"key":"B28","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1093\/clinchem\/20.4.470","article-title":"Enzymatic determination of total serum cholesterol","volume":"20","author":"Allain","year":"1974","journal-title":"Clin Chem"},{"key":"B29","doi-asserted-by":"publisher","first-page":"2730","DOI":"10.1093\/jn\/126.11.2730","article-title":"Temporal-regulation of serum lipids and stearoyl CoA desaturase and lipoprotein lipase mRNA in BALB\/cHnn mice","volume":"126","author":"Paisley","year":"1996","journal-title":"J Nutr"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1093\/clinchem\/28.6.1379","article-title":"Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol","volume":"28","author":"Warnick","year":"1982","journal-title":"Clin Chem"},{"key":"B31","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.clnu.2018.03.016","article-title":"Postprandial endotoxemia may influence the development of type 2 diabetes mellitus: from the CORDIOPREV study","volume":"38","author":"Camargo","year":"2019","journal-title":"Clin Nutr"},{"key":"B32","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.atherosclerosis.2015.02.025","article-title":"Age and sex differences in the effect of parental stroke on the progression of carotid intima-media thickness","volume":"241","author":"Lin","year":"2015","journal-title":"Atherosclerosis"},{"key":"B33","doi-asserted-by":"publisher","first-page":"249","DOI":"10.5534\/wjmh.230366","article-title":"TMA Oxidation into the pro-atherogenic TMAO is higher in coronary heart disease men: from the CORDIOPREV study","volume":"43","author":"Garcia-Fernandez","year":"2025","journal-title":"World J Men Health"},{"key":"B34","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1111\/j.1365-2796.2010.02270.x","article-title":"Effects of gut microbiota on obesity and atherosclerosis via modulation of inflammation and lipid metabolism","volume":"268","author":"Caesar","year":"2010","journal-title":"J Intern Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1152\/physiol.00041.2015","article-title":"Linking gut microbiota and inflammation to obesity and insulin resistance","volume":"31","author":"Saad","year":"2016","journal-title":"Physiology (Bethesda)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"15295","DOI":"10.1038\/s41598-020-72247-5","article-title":"Elevated acute phase proteins reflect peripheral inflammation and disease severity in patients with amyotrophic lateral sclerosis","volume":"10","author":"Beers","year":"2020","journal-title":"Sci Rep"},{"key":"B37","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3390\/idr17010010","article-title":"Plasma lipopolysaccharide-binding protein (LBP) is induced in critically ill females with gram-negative infections-preliminary study","volume":"17","author":"Utrata","year":"2025","journal-title":"Infect Dis Rep"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1056\/NEJMoa1707914","article-title":"Antiinflammatory therapy with canakinumab for atherosclerotic disease","volume":"377","author":"Ridker","year":"2017","journal-title":"N Engl J Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"85","DOI":"10.3949\/ccjm.90a.22048","article-title":"The constellation of vitamin D, the acute-phase response, and inflammation","volume":"90","author":"Antonelli","year":"2023","journal-title":"Cleve Clin J Med"},{"key":"B40","doi-asserted-by":"publisher","first-page":"166","DOI":"10.2337\/dc12-0702","article-title":"Inflammatory markers and risk of type 2 diabetes: a systematic review and meta-analysis","volume":"36","author":"Wang","year":"2013","journal-title":"Diabetes Care"},{"key":"B41","doi-asserted-by":"publisher","first-page":"4573","DOI":"10.1038\/s41598-019-40987-8","article-title":"Association of C-reactive protein with risk of developing type 2 diabetes mellitus, and role of obesity and hypertension: a large population-based Korean cohort study","volume":"9","author":"Kanmani","year":"2019","journal-title":"Sci Rep"},{"key":"B42","doi-asserted-by":"publisher","first-page":"9129","DOI":"10.3390\/ijms24119129","article-title":"C-reactive protein levels and risk of cardiovascular diseases: a two-sample bidirectional Mendelian randomization study","volume":"24","author":"Kuppa","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B43","doi-asserted-by":"publisher","first-page":"3251","DOI":"10.1210\/jc.2008-2406","article-title":"Sex differences in the relationship between C-reactive protein and body fat","volume":"94","author":"Khera","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"B44","doi-asserted-by":"publisher","first-page":"111804","DOI":"10.1016\/j.mad.2023.111804","article-title":"Sex and age differences in the association between high sensitivity C-reactive protein and all-cause mortality: a 12-year prospective cohort study","volume":"211","author":"Bafei","year":"2023","journal-title":"Mech Ageing Dev"},{"key":"B45","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1146\/annurev-nutr-071816-064732","article-title":"Trimethylamine N-oxide, the microbiome, and heart and kidney disease","volume":"37","author":"Zeisel","year":"2017","journal-title":"Annu Rev Nutr"},{"key":"B46","doi-asserted-by":"publisher","first-page":"10397","DOI":"10.3390\/ijms251910397","article-title":"Low-molecular-weight compounds produced by the intestinal Microbiota and cardiovascular disease","volume":"25","author":"Cuervo","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B47","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.atherosclerosis.2020.09.015","article-title":"Carotid intima-media thickness should not be referred to as subclinical atherosclerosis: a recommended update to the editorial policy at atherosclerosis","volume":"312","author":"Raggi","year":"2020","journal-title":"Atherosclerosis"},{"key":"B48","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.atherosclerosis.2020.09.016","article-title":"IMT is not atherosclerosis","volume":"312","author":"Spence","year":"2020","journal-title":"Atherosclerosis"},{"key":"B49","doi-asserted-by":"publisher","first-page":"S58","DOI":"10.1067\/mhj.2001.109946","article-title":"Effect of menopause on plaque morphologic characteristics in coronary atherosclerosis","volume":"141","author":"Burke","year":"2001","journal-title":"Am Heart J"},{"key":"B50","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/s41572-024-00563-5","article-title":"Metabolic syndrome","volume":"10","author":"Neeland","year":"2024","journal-title":"Nat Rev Dis Primers"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2025.1527406\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T05:37:31Z","timestamp":1761025051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2025.1527406\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,21]]},"references-count":50,"alternative-id":["10.3389\/fcvm.2025.1527406"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2025.1527406","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,21]]},"article-number":"1527406"}}