{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:04:42Z","timestamp":1788930282902,"version":"build-2803163510"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,9]],"date-time":"2023-12-09T00:00:00Z","timestamp":1702080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bundesministerium f\u00fcr Bildung und Forschung"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Lipids are important modifiers of protein function, particularly as parts of lipoproteins, which transport lipophilic substances and mediate cellular uptake of circulating lipids. As such, lipids are of particular interest as blood biological markers for cardiovascular disease (CVD) as well as for conditions linked to CVD such as atherosclerosis, diabetes mellitus, obesity and dietary states. Notably, lipid research is particularly well developed in the context of CVD because of the relevance and multiple causes and risk factors of CVD. The advent of methods for high-throughput screening of biological molecules has recently resulted in the generation of lipidomic profiles that allow monitoring of lipid compositions in biological samples in an untargeted manner. These and other earlier advances in biomedical research have shaped the knowledge we have about lipids in CVD. To evaluate the knowledge acquired on the multiple biological functions of lipids in CVD and the trends in their research, we collected a dataset of references from the PubMed database of biomedical literature focused on plasma lipids and CVD in human and mouse. Using annotations from these records, we were able to categorize significant associations between lipids and particular types of research approaches, distinguish non-biological lipids used as markers, identify differential research between human and mouse models, and detect the increasingly mechanistic nature of the results in this field. Using known associations between lipids and proteins that metabolize or transport them, we constructed a comprehensive lipid\u2013protein network, which we used to highlight proteins strongly connected to lipids found in the CVD-lipid literature. Our approach points to a series of proteins for which lipid-focused research would bring insights into CVD, including Prostaglandin G\/H synthase 2 (PTGS2, a.k.a. COX2) and Acylglycerol kinase (AGK). In this review, we summarize our findings, putting them in a historical perspective of the evolution of lipid research in CVD.<\/jats:p>","DOI":"10.3390\/cimb45120618","type":"journal-article","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T14:12:51Z","timestamp":1702303971000},"page":"9904-9916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Systematic Review of Lipid-Focused Cardiovascular Disease Research: Trends and Opportunities"],"prefix":"10.3390","volume":"45","author":[{"given":"Uchenna Alex","family":"Anyaegbunam","sequence":"first","affiliation":[{"name":"Computational Biology and Data Mining Group (CBDM), Institute of Organismic and Molecular Evolution (iOME), Johannes Gutenberg University, 55122 Mainz, 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent ten","family":"Cate","sequence":"additional","affiliation":[{"name":"Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"},{"name":"Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis (CTH), University Medical Center, 55131 Mainz, Germany"},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Bauer","sequence":"additional","affiliation":[{"name":"Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"},{"name":"Computational Systems Medicine, Center for Thrombosis and Hemostasis (CTH), 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8031-6384","authenticated-orcid":false,"given":"Ute","family":"Distler","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"},{"name":"Research Centre for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Araldi","sequence":"additional","affiliation":[{"name":"Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"},{"name":"Computational Systems Medicine, Center for Thrombosis and Hemostasis (CTH), 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5538-2008","authenticated-orcid":false,"given":"Laura","family":"Bindila","sequence":"additional","affiliation":[{"name":"Institute of Physiological Chemistry, University Medical Center, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4413-9752","authenticated-orcid":false,"given":"Philipp","family":"Wild","sequence":"additional","affiliation":[{"name":"Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"},{"name":"Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis (CTH), University Medical Center, 55131 Mainz, Germany"},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6650-1711","authenticated-orcid":false,"given":"Miguel A.","family":"Andrade-Navarro","sequence":"additional","affiliation":[{"name":"Computational Biology and Data Mining Group (CBDM), Institute of Organismic and Molecular Evolution (iOME), Johannes Gutenberg University, 55122 Mainz, 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Markers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1161\/CIRCRESAHA.117.306458","article-title":"Environmental Determinants of Cardiovascular Disease","volume":"121","author":"Bhatnagar","year":"2017","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1161\/CIRCULATIONAHA.106.637793","article-title":"Triglycerides and the Risk of Coronary Heart Disease: 10,158 Incident Cases among 262,525 Participants in 29 Western Prospective Studies","volume":"115","author":"Sarwar","year":"2007","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1365-2796.2006.01643.x","article-title":"The ApoB\/ApoA-I Ratio: A Strong, New Risk Factor for Cardiovascular Disease and a Target for Lipid-Lowering Therapy\u2014A Review of the Evidence","volume":"259","author":"Walldius","year":"2006","journal-title":"J. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1194\/jlr.P900033-JLR200","article-title":"Genetic and environmental influences on factors associated with cardiovascular disease and the metabolic syndrome","volume":"50","author":"Elder","year":"2009","journal-title":"J. Lipid. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1056\/NEJM197709222971206","article-title":"Diet-Heart: End of an era","volume":"297","author":"Mann","year":"1977","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Soliman, G.A. (2018). Dietary Cholesterol and the Lack of Evidence in Cardiovascular Disease. Nutrients, 10.","DOI":"10.3390\/nu10060780"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8408","DOI":"10.1016\/S0021-9258(19)43148-7","article-title":"Inhibition of sterol synthesis in cultured mouse cells by 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol, and 7-ketocholesterol","volume":"248","author":"Kandutsch","year":"1973","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1080\/14017430801983082","article-title":"The fallacies of the lipid hypothesis","volume":"42","author":"Ravnskov","year":"2008","journal-title":"Scand. Cardiovasc. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2880","DOI":"10.1093\/cvr\/cvab316","article-title":"Environmental risk factors and cardiovascular diseases: A comprehensive expert review","volume":"118","author":"Hahad","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1194\/jlr.R300004-JLR200","article-title":"Global analyses of cellular lipidomes directly from crude extracts of biological samples by ESI mass spectrometry: A bridge to lipidomics","volume":"44","author":"Han","year":"2003","journal-title":"J. Lipid. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"D10","DOI":"10.1093\/nar\/gkaa892","article-title":"Database resources of the National Center for Biotechnology Information","volume":"49","author":"Sayers","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_13","first-page":"114","article-title":"Medical subject headings","volume":"51","author":"Rogers","year":"1963","journal-title":"Bull. Med. Libr. Assoc."},{"key":"ref_14","first-page":"88","article-title":"Evolving research trends in bioinformatics","volume":"8","author":"Wren","year":"2007","journal-title":"Brief. Bioinform."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1007\/s11192-022-04292-y","article-title":"How to catch trends using MeSH terms analysis?","volume":"127","author":"Ilgisonis","year":"2022","journal-title":"Scientometrics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3981","DOI":"10.1093\/bioinformatics\/btab559","article-title":"LipiDisease: Associate lipids to diseases using literature mining","volume":"37","author":"More","year":"2021","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1194\/jlr.R800095-JLR200","article-title":"Update of the LIPID MAPS comprehensive classification system for lipids","volume":"50","author":"Fahy","year":"2009","journal-title":"J. Lipid. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/s41467-023-36520-1","article-title":"Four-dimensional trapped ion mobility spectrometry lipidomics for high throughput clinical profiling of human blood samples","volume":"14","author":"Lerner","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2860","DOI":"10.1093\/bioinformatics\/btv285","article-title":"The SwissLipids knowledgebase for lipid biology","volume":"31","author":"Aimo","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_20","first-page":"H2147","article-title":"Myocardial ischemia and reperfusion: A murine model","volume":"269","author":"Michael","year":"1995","journal-title":"Am. J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1161\/01.CIR.94.5.1109","article-title":"Transthoracic echocardiography in models of cardiac disease in the mouse","volume":"94","author":"Tanaka","year":"1996","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1042\/CS20090488","article-title":"Inflammatory cell recruitment in cardiovascular disease: Murine models and potential clinical applications","volume":"118","author":"McNeill","year":"2010","journal-title":"Clin. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hu, N., Han, X., Lane, E.K., Gao, F., Zhang, Y., and Ren, J. (2013). Cardiac-specific overexpression of metallothionein rescues against cigarette smoking exposure-induced myocardial contractile and mitochondrial damage. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057151"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.arr.2016.10.006","article-title":"The senescence accelerated mouse prone 8 (SAMP8): A novel murine model for cardiac aging","volume":"35","author":"Karuppagounder","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"W455","DOI":"10.1093\/nar\/gkr246","article-title":"Genie: Literature-based gene prioritization at multi genomic scale","volume":"39","author":"Fontaine","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Fontaine, J.F., and Andrade-Navarro, M.A. (2016). Gene set to Diseases (GS2D): Disease enrichment analysis on human gene sets with literature data. Genom. Comput. Biol., 2.","DOI":"10.18547\/gcb.2016.vol2.iss1.e33"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.freeradbiomed.2021.05.009","article-title":"Verification of ferroptosis and pyroptosis and identification of PTGS2 as the hub gene in human coronary artery atherosclerosis","volume":"171","author":"Zhou","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1007\/s11427-020-1792-5","article-title":"Congestive heart failure in COX2 deficient rats","volume":"64","author":"Wan","year":"2021","journal-title":"Sci. China Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1111\/bph.14167","article-title":"Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system","volume":"176","author":"Mitchell","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s10020-021-00358-4","article-title":"New horizons in the roles and associations of COX-2 and novel natural inhibitors in cardiovascular diseases","volume":"27","author":"Chen","year":"2021","journal-title":"Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s13023-014-0119-3","article-title":"Sengers syndrome: Six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients","volume":"9","author":"Haghighi","year":"2014","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Barbosa-Gouveia, S., V\u00e1zquez-Mosquera, M.E., Gonzalez-Vioque, E., Hermida-Ameijeiras, \u00c1., Valverde, L.L., Armstrong-Moron, J., Fons-Estupi\u00f1a, M.d.C., Wintjes, L.T., Kappen, A., and Rodenburg, R.J. (2021). Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413484"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/s41390-023-02515-3","article-title":"A novel AGK splicing mutation in a patient with Sengers syndrome and left ventricular non-compaction cardiomyopathy","volume":"94","author":"Fan","year":"2023","journal-title":"Pediatr. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ymgme.2012.11.282","article-title":"Mitochondrial citrate synthase crystals: Novel finding in Sengers syndrome caused by acylglycerol kinase (AGK) mutations","volume":"108","author":"Siriwardena","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1007\/s12031-022-02014-w","article-title":"Lipidomics Analysis Reveals a Protective Effect of Myriocin on Cerebral Ischemia\/Reperfusion Model Rats","volume":"72","author":"Wang","year":"2022","journal-title":"J. Mol. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Parveen, F., Bender, D., Law, S.-H., Mishra, V.K., Chen, C.-C., and Ke, L.-Y. (2019). Role of Ceramidases in Sphingolipid Metabolism and Human Diseases. Cells, 8.","DOI":"10.3390\/cells8121573"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Casares-Marfil, D., Kerick, M., Andr\u00e9s-Le\u00f3n, E., Bosch-Nicolau, P., Molina, I., Martin, J., Acosta-Herrera, M., and Network, C.G.C. (2021). GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels. PLoS Negl. Trop. Dis., 15.","DOI":"10.1371\/journal.pntd.0009874"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1177\/1358863X20947467","article-title":"Skeletal muscle expression of adipose-specific phospholipase in peripheral artery disease","volume":"25","author":"Parmer","year":"2020","journal-title":"Vasc. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1161\/01.CIR.0000130070.96758.7b","article-title":"The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease","volume":"109","author":"Ledmyr","year":"2004","journal-title":"Circulation"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1161\/CIRCRESAHA.116.307473","article-title":"Dietary Interventions, Cardiovascular Aging, and Disease: Animal Models and Human Studies","volume":"118","author":"Mirzaei","year":"2016","journal-title":"Circ. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"D1259","DOI":"10.1093\/nar\/gkaa1067","article-title":"MarkerDB: An online database of molecular biomarkers","volume":"49","author":"Wishart","year":"2021","journal-title":"Nucleic Acids Res."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/12\/618\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:36:04Z","timestamp":1760132164000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/12\/618"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,9]]},"references-count":41,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["cimb45120618"],"URL":"https:\/\/doi.org\/10.3390\/cimb45120618","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,9]]}}}