{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T02:03:59Z","timestamp":1779674639300,"version":"3.53.1"},"reference-count":21,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T00:00:00Z","timestamp":1779580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Coronavirus disease 2019 (COVID-19) has been associated with an increased long-term cardiovascular risk, potentially mediated by magnitude of the acute inflammatory response inflammation. Interleukin-6 (IL-6) and serum amyloid A (SAA) are key components of the inflammatory cascade and may serve as biomarkers of post-COVID cardiovascular vulnerability. This longitudinal observational study investigated the association between post- COVID-19 infection IL-6 and SAA levels and major cardiovascular events over a six-year follow-up period. A total of 97 individuals with documented prior SARS-CoV-2 infection were included. Circulating IL-6 and SAA concentrations were measured in the acute phase. The composite endpoint included incident arrhythmia, myocardial infarction, and all-cause mortality. Biomarker distributions were right-skewed and were therefore analyzed using non-parametric methods and penalized logistic regression models. During follow-up, 14.4% of participants experienced the composite endpoint. Individuals with adverse outcomes had significantly higher IL-6 and SAA levels compared with event-free participants. IL-6 demonstrated the strongest association with mortality, whereas SAA showed particularly robust associations with the composite endpoint, and with myocardial infarction. Both biomarkers independently predicted long-term adverse events. Circulating IL-6 and SAA concentrations measured during the acute phase of SARS-CoV-2 infection were analyzed in relation to long-term cardiovascular outcomes. These findings support the hypothesis that the magnitude of the acute inflammatory response during SARS-CoV-2 infection may be associated with long-term cardiovascular outcomes and suggest that combined assessment of IL-6 and SAA may have potential utility for hypothesis-generating prognostic signal requiring validation, pending validation in larger studies.<\/jats:p>","DOI":"10.3390\/ijms27114721","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T01:45:08Z","timestamp":1779673508000},"page":"4721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of Acute-Phase IL-6 and SAA with Cardiovascular Events and Mortality Six Years After COVID-19 Infection: An Observational Cohort Study"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1174-3128","authenticated-orcid":false,"given":"Rumen","family":"Filev","sequence":"first","affiliation":[{"name":"Department of Nephrology, Internal Disease Clinic, University Hospital \u201cSaint Anna\u201d, 1750 Sofia, Bulgaria"},{"name":"Faculty of Medicine, Medical University Sofia, 1504 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4578-6265","authenticated-orcid":false,"given":"Boris","family":"Bogov","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Internal Disease Clinic, University Hospital \u201cSaint Anna\u201d, 1750 Sofia, Bulgaria"},{"name":"Faculty of Medicine, Medical University Sofia, 1504 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralica","family":"Hadjieva","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Internal Disease Clinic, University Hospital \u201cSaint Anna\u201d, 1750 Sofia, Bulgaria"},{"name":"Faculty of Medicine, Medical University Sofia, 1504 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7652-3463","authenticated-orcid":false,"given":"Krassimir","family":"Kalinov","sequence":"additional","affiliation":[{"name":"Head Biometrics Group, Comac-Medical Ltd., 1404 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9915-3282","authenticated-orcid":false,"given":"Julieta","family":"Hristova","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical University Sofia, 1504 Sofia, Bulgaria"},{"name":"Department of Clinical Laboratory, University Hospital \u201cAlexandrovska\u201d, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dobrin","family":"Svinarov","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical University Sofia, 1504 Sofia, Bulgaria"},{"name":"Department of Clinical Laboratory, University Hospital \u201cAlexandrovska\u201d, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5130-7286","authenticated-orcid":false,"given":"Lionel","family":"Rostaing","sequence":"additional","affiliation":[{"name":"Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, Grenoble University Hospital, 38043 Grenoble, France"},{"name":"Internal Disease Department, Grenoble Alpes University, 38043 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,24]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2023). WHO Coronavirus (COVID-19) Dashboard, WHO. Available online: https:\/\/data.who.int\/dashboards\/covid19\/cases."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1126\/science.abb8925","article-title":"Cytokine release syndrome in severe COVID-19","volume":"368","author":"Moore","year":"2020","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"a016295","DOI":"10.1101\/cshperspect.a016295","article-title":"IL-6 in inflammation, immunity, and disease","volume":"6","author":"Tanaka","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1161\/01.CIR.101.15.1767","article-title":"Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men","volume":"101","author":"Ridker","year":"2000","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1016\/j.jacc.2009.09.009","article-title":"Inflammation in atherosclerosis: From pathophysiology to practice","volume":"54","author":"Libby","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1046\/j.1432-1327.1999.00657.x","article-title":"Serum amyloid A, the major vertebrate acute-phase reactant","volume":"265","author":"Uhlar","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.jinf.2020.03.035","article-title":"Serum Amyloid A is a biomarker of severe Coronavirus Disease and poor prognosis","volume":"80","author":"Li","year":"2020","journal-title":"J. Infect."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41591-022-01689-3","article-title":"Long-term cardiovascular outcomes of COVID-19","volume":"28","author":"Xie","year":"2022","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1001\/jamacardio.2020.3557","article-title":"Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered from Coronavirus Disease 2019 (COVID-19)","volume":"5","author":"Puntmann","year":"2020","journal-title":"JAMA Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","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":"ref_13","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0140-6736(17)32814-3","article-title":"Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: A secondary analysis from the CANTOS randomised controlled trial","volume":"391","author":"Ridker","year":"2018","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/S0140-6736(20)30937-5","article-title":"Endothelial cell infection and endotheliitis in COVID-19","volume":"395","author":"Varga","year":"2020","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1161\/CIRCULATIONAHA.120.047293","article-title":"COVID-19, Arrhythmic Risk, and Inflammation: Mind the Gap!","volume":"142","author":"Lazzerini","year":"2020","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2000045","DOI":"10.2807\/1560-7917.ES.2020.25.3.2000045","article-title":"Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR","volume":"25","author":"Corman","year":"2020","journal-title":"Euro Surveill."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"World Medical Association (2013). World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA, 310, 2191\u20132194.","DOI":"10.1001\/jama.2013.281053"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Filev, R., Rostaing, L., Lyubomirova, M., Bogov, B., Kalinov, K., and Svinarov, D. (2022). COVID-19 Infection in Chronic Kidney Disease Patients in Bulgaria: Risk Factors for Death and Acute Kidney Injury. J. Pers. Med., 12.","DOI":"10.3390\/jpm12101676"},{"key":"ref_19","first-page":"e596","article-title":"2019 ACC\/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines","volume":"140","author":"Arnett","year":"2019","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Filev, R., Lyubomirova, M., Bogov, B., Kalinov, K., Hristova, J., Svinarov, D., and Rostaing, L. (2024). IL-6 and SAA\u2014Strong Predictors for the Outcome in COVID-19 CKD Patients. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010311"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e618","DOI":"10.1161\/CIR.0000000000000617","article-title":"Fourth Universal Definition of Myocardial Infarction (2018)","volume":"138","author":"Thygesen","year":"2018","journal-title":"Circulation"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4721\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T01:50:52Z","timestamp":1779673852000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4721"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,24]]},"references-count":21,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27114721"],"URL":"https:\/\/doi.org\/10.3390\/ijms27114721","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,24]]}}}