{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T21:20:23Z","timestamp":1792185623894,"version":"4.4.0"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T00:00:00Z","timestamp":1745539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"School of Medicine, University of St Andrews","award":["NIHR202632"],"award-info":[{"award-number":["NIHR202632"]}]},{"DOI":"10.13039\/501100000272","name":"Health Informatics Centre at the University of Dundee","doi-asserted-by":"publisher","award":["NIHR202632"],"award-info":[{"award-number":["NIHR202632"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Cardiovascular diseases (CVDs) are the leading cause of global mortality. Major adverse cardiovascular events (MACEs)\u2014such as acute myocardial infarction, stroke, and heart failure\u2014are critical endpoints in the clinical research. The existing research has shown metal ions are important regulators of cardiovascular functioning, and defective metal handling may be associated with an increased risk of CVD. This study examines the association of the plasma\/serum levels of magnesium, copper, and zinc with MACE incidence and the prevalence of circulatory system diseases, by using electronic health records from a subset of the Scottish population. Methods: We categorised individuals by high, low, or normal plasma\/serum metal levels, and calculated the percentage of those who subsequently developed a MACE, identified using related International Classification of Diseases, 10th Revision codes from hospital admission records. Logistic regression was employed to analyse the association between pre-event metal ion levels and the development of specific circulatory system disease subgroups. Results: This study found abnormal magnesium, high copper, and low zinc were associated with a higher risk of developing MACEs. Low magnesium, high copper, or low zinc were associated with increased risks of various circulatory diseases, with specific variations, like low copper increasing venous and lymphatic disease risk. Conclusions: Our findings suggest abnormal plasma metal profiles are associated with the development of MACEs and circulatory disease events, underscoring the importance of monitoring plasma metal levels for cardiovascular risk management and prevention.<\/jats:p>","DOI":"10.3390\/nu17091447","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T08:02:57Z","timestamp":1745568177000},"page":"1447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Abnormal Plasma\/Serum Magnesium, Copper, and Zinc Concentrations Associate with the Future Development of Cardiovascular Diseases"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8675-4730","authenticated-orcid":false,"given":"Boyang","family":"Lin","sequence":"first","affiliation":[{"name":"School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Alexander","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3457-8364","authenticated-orcid":false,"given":"Remi","family":"Fritzen","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Mills","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4580-1840","authenticated-orcid":false,"given":"Alan","family":"Stewart","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9466-833X","authenticated-orcid":false,"given":"Colin","family":"McCowan","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"ref_1","unstructured":"WHO (2025, March 07). Cardiovascular Diseases. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/cardiovascular-diseases-(cvds)."},{"key":"ref_2","unstructured":"GBD (2024). Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990\u20132021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet, 403, 2133\u20132161."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"rbad103","DOI":"10.1093\/rb\/rbad103","article-title":"Exogeneous metal ions as therapeutic agents in cardiovascular disease and their delivery strategies","volume":"11","author":"Hong","year":"2023","journal-title":"Regen. Biomater."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e000775","DOI":"10.1136\/openhrt-2018-000775","article-title":"Magnesium for the prevention and treatment of cardiovascular disease","volume":"5","author":"DiNicolantonio","year":"2018","journal-title":"Open Heart"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Fritzen, R., Davies, A., Veenhuizen, M., Campbell, M., Pitt, S.J., Ajjan, R.A., and Stewart, A.J. (2023). Magnesium deficiency and cardiometabolic disease. Nutrients, 15.","DOI":"10.3390\/nu15102355"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Nielsen, F.H. (2024). The role of dietary magnesium in cardiovascular disease. Nutrients, 16.","DOI":"10.3390\/nu16234223"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"489S","DOI":"10.1093\/jn\/130.2.489S","article-title":"Cardiovascular disease from copper deficiency\u2014A history","volume":"130","author":"Klevay","year":"2000","journal-title":"J. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/s41392-022-01229-y","article-title":"Copper homeostasis and cuproptosis in health and disease","volume":"7","author":"Chen","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/s41419-023-05639-w","article-title":"Copper homeostasis and copper-induced cell death in the pathogenesis of cardiovascular disease and therapeutic strategies","volume":"14","author":"Chen","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1160\/TH12-07-0465","article-title":"Zinc: An important cofactor in haemostasis and thrombosis","volume":"109","author":"Vu","year":"2013","journal-title":"Thromb. Haemost."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.abb.2014.07.014","article-title":"Disrupted calcium homeostasis is involved in elevated zinc ion-induced photoreceptor cell death","volume":"560","author":"Guo","year":"2014","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1038\/aps.2018.25","article-title":"Zinc deficiency and cellular oxidative stress: Prognostic implications in cardiovascular diseases","volume":"39","author":"Choi","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1161\/CIRCULATIONAHA.119.041022","article-title":"Impact of regulatory guidance on evaluating cardiovascular risk of new Glucose-Lowering therapies to treat Type 2 diabetes mellitus","volume":"141","author":"Sharma","year":"2020","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.2337\/dc17-0068","article-title":"Composite primary end points in cardiovascular outcomes trials involving Type 2 diabetes patients: Should unstable angina be included in the primary end point?","volume":"40","author":"Marx","year":"2017","journal-title":"Diabetes Care"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Bosco, E., Hsueh, L., McConeghy, K.W., Gravenstein, S., and Saade, E. (2021). Major adverse cardiovascular event definitions used in observational analysis of administrative databases: A systematic review. BMC Med. Res. Methodol., 21.","DOI":"10.1186\/s12874-021-01440-5"},{"key":"ref_16","unstructured":"HIC (2025, March 07). Data service at HIC. University of Dundee, UK. Available online: https:\/\/www.dundee.ac.uk\/hic\/data-service."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e038829","DOI":"10.1136\/bmjopen-2020-038829","article-title":"Patterns of multimorbidity and their effects on adverse outcomes in rheumatoid arthritis: A study of 5658 UK Biobank participants","volume":"10","author":"McQueenie","year":"2020","journal-title":"BMJ Open"},{"key":"ref_18","unstructured":"WHO (2025, March 07). International Statistical Classification of Diseases and Related Health Problems, 10th Revision, 2019 Edition. Available online: https:\/\/icd.who.int\/browse10\/2019\/en."},{"key":"ref_19","unstructured":"Public Health England (2025, April 09). National Diet and Nutrition Survey: Results from Years 9 to 11 (2016\/2017 to 2018\/2019), Available online: https:\/\/www.gov.uk\/government\/statistics\/ndns-results-from-years-9-to-11-2016-to-2017-and-2018-to-2019."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.3168\/jds.2017-13112","article-title":"Invited review: Mineral absorption mechanisms, mineral interactions that affect acid\u2013base and antioxidant status, and diet considerations to improve mineral status","volume":"101","author":"Goff","year":"2018","journal-title":"J. Dairy Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yin, X.-C., Wang, W.-F., Li, Z.-M., Duan, Y.-J., Chen, M., Wu, Y.-N., and Hu, Y.-M. (2023). The Relationship between Dietary Patterns and Blood Mineral Concentration among Children in Hunan Province of China. BMC Public Health, 23.","DOI":"10.1186\/s12889-023-16429-6"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41591-020-01183-8","article-title":"Microbiome Connections with Host Metabolism and Habitual Diet from 1,098 Deeply Phenotyped Individuals","volume":"27","author":"Asnicar","year":"2021","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhu, Q., Chen, B., Zhang, F., Zhang, B., Guo, Y., Pang, M., Huang, L., and Wang, T. (2024). Toxic and Essential Metals: Metabolic Interactions with the Gut Microbiota and Health Implications. Front. Nutr., 11.","DOI":"10.3389\/fnut.2024.1448388"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.aninu.2021.03.005","article-title":"Trace Metals and Animal Health: Interplay of the Gut Microbiota with Iron, Manganese, Zinc, and Copper","volume":"7","author":"Pajarillo","year":"2021","journal-title":"Anim. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Del Chierico, F., Trapani, V., Petito, V., Reddel, S., Pietropaolo, G., Graziani, C., Masi, L., Gasbarrini, A., Putignani, L., and Scaldaferri, F. (2021). Dietary Magnesium Alleviates Experimental Murine Colitis through Modulation of Gut Microbiota. Nutrients, 13.","DOI":"10.3390\/nu13124188"},{"key":"ref_26","first-page":"555","article-title":"Nutraceuticals and Gut Microbiota: Understanding the Connection for Improved Health","volume":"102","author":"Kumar","year":"2020","journal-title":"Trends Food Sci. Technol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4418","DOI":"10.1007\/s12011-023-04034-y","article-title":"The association between magnesium depletion score and hypertension in US adults: Evidence from the national Health and nutrition examination survey (2007\u20132018)","volume":"202","author":"Tan","year":"2023","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhao, B., Hu, L., Dong, Y., Xu, J., Wei, Y., Yu, D., Xu, J., and Zhang, W. (2019). The effect of magnesium intake on stroke incidence: A systematic review and meta-analysis with trial sequential analysis. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00852"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e000668","DOI":"10.1136\/openhrt-2017-000668","article-title":"Subclinical magnesium deficiency: A principal driver of cardiovascular disease and a public health crisis","volume":"5","author":"DiNicolantonio","year":"2018","journal-title":"Open Heart"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.neures.2015.12.005","article-title":"Mechanisms of magnesium-induced vasodilation in cerebral penetrating arterioles","volume":"107","author":"Murata","year":"2015","journal-title":"Neurosci. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3406","DOI":"10.1038\/s41598-018-21783-2","article-title":"Magnesium enhances the chondrogenic differentiation of mesenchymal stem cells by inhibiting activated macrophage-induced inflammation","volume":"8","author":"Hu","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e14597","DOI":"10.1111\/cns.14597","article-title":"Research hotpots and frontier trends of neuroprotective effects of magnesium from 1999 to 2023: A bibliometric analysis","volume":"30","author":"Song","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"122711","DOI":"10.1016\/j.envpol.2023.122711","article-title":"Circulating copper levels and the risk of cardio-cerebrovascular diseases and cardiovascular and all-cause mortality: A systematic review and meta-analysis of longitudinal studies","volume":"340","author":"Zhao","year":"2023","journal-title":"Environ. Pollut."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1093\/jn\/127.12.2274","article-title":"Dietary copper in the physiology of the microcirculation","volume":"127","author":"Schuschke","year":"1997","journal-title":"J. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Cheng, F., Peng, G., Lu, Y., Wang, K., Ju, Q., Ju, Y., and Ouyang, M. (2022). Relationship between copper and immunity: The potential role of copper in tumor immunity. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1019153"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"410","DOI":"10.3181\/00379727-188-42753","article-title":"Effect of copper deficiency on the lymphatic absorption of cholesterol, plasma chylomicron clearance, and postheparin lipase activities","volume":"188","author":"Koo","year":"1988","journal-title":"Exp. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e000784","DOI":"10.1136\/openhrt-2018-000784","article-title":"Copper deficiency may be a leading cause of ischaemic heart disease","volume":"5","author":"DiNicolantonio","year":"2018","journal-title":"Open Heart"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"C404","DOI":"10.1152\/ajpcell.00279.2017","article-title":"Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR\/GPR39","volume":"314","author":"Zhu","year":"2017","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3296","DOI":"10.1038\/s41467-021-23198-6","article-title":"Zinc drives vasorelaxation by acting in sensory nerves, endothelium and smooth muscle","volume":"12","author":"Betrie","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2018\/6057348","article-title":"The relationship between serum zinc level and heart failure: A meta-analysis","volume":"2018","author":"Yu","year":"2018","journal-title":"BioMed. Res. Int."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tanita, A., Namiuchi, S., Onodera, K., Sunamura, S., Ogata, T., Noda, K., and Takii, T. (2024). Serum zinc concentration in patients with myocardial infarction: A retrospective study. BMC Cardiovasc. Disord., 24.","DOI":"10.1186\/s12872-024-03776-4"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"14714","DOI":"10.1038\/s41598-022-18872-8","article-title":"Effect of oral zinc regimens on human hepatic copper content: A randomized intervention study","volume":"12","author":"Munk","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1155\/2018\/9156285","article-title":"Critical role of zinc as either an antioxidant or a prooxidant in cellular systems","volume":"2018","author":"Lee","year":"2018","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/BF02685996","article-title":"Correlations between serum zinc concentrations and oxygen balance parameters in patients with primary arterial hypertension","volume":"115","author":"Tubek","year":"2007","journal-title":"Biol. Trace Elem. Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1447\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:21:28Z","timestamp":1760030488000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1447"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,25]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["nu17091447"],"URL":"https:\/\/doi.org\/10.3390\/nu17091447","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,25]]}}}