{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T05:37:05Z","timestamp":1776749825215,"version":"3.51.2"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T00:00:00Z","timestamp":1659225600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T00:00:00Z","timestamp":1659225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cardiovasc Disord"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Little is known about the association between bacterial DNA in human blood and the risk of cardiovascular disease (CVD) mortality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A case-cohort study was performed based on a 9 \u00bd year follow-up of the Oslo II study from 2000. Eligible for this analysis were men born in 1923 and from 1926 to 1932. The cases were men (n\u2009=\u2009227) who had died from CVD, and the controls were randomly selected participants from the same cohort (n\u2009=\u2009178). Analysis of the bacterial microbiome was performed on stored frozen blood samples for both cases and controls. Association analyses for CVD mortality were performed by Cox proportional hazard regression adapted to the case-cohort design. We used the Bonferroni correction due to the many bacterial genera that were identified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Bacterial DNA was identified in 372 (82%) of the blood samples and included 78 bacterial genera from six phyla. Three genera were significantly associated with CVD mortality. The genera<jats:italic>Kocuria<\/jats:italic>(adjusted hazard ratio (HR) 8.50, 95% confidence interval (CI) (4.05, 17.84)) and<jats:italic>Enhydrobacter<\/jats:italic>(HR 3.30 (2.01, 5.57)) indicate an association with CVD mortality with increasing levels. The genera<jats:italic>Paracoccus<\/jats:italic>(HR 0.29 (0.15, 0.57)) was inversely related. Significant predictors of CVD mortality were: the feeling of bad health; and the consumption of more than three cups of coffee per day. The following registered factors were borderline significant, namely: a history of heart failure; increased systolic blood pressure; and currently taking antihypertensive drugs now, versus previously.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The increasing levels of two bacterial genera<jats:italic>Kocuria<\/jats:italic>(skin and oral) and<jats:italic>Enhydrobacter<\/jats:italic>(skin) and low levels of<jats:italic>Paracoccus<\/jats:italic>(soil) were associated with CVD mortality independent of known risk factors for CVD.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12872-022-02791-7","type":"journal-article","created":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T07:03:27Z","timestamp":1659251007000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The blood microbiome and its association to cardiovascular disease mortality: case-cohort study"],"prefix":"10.1186","volume":"22","author":[{"given":"Graeme","family":"Lawrence","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingvild","family":"Midtervoll","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sven Ove","family":"Samuelsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne Karin","family":"Kristoffersen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morten","family":"Enersen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2012-6220","authenticated-orcid":false,"given":"Lise Lund","family":"H\u00e5heim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,7,31]]},"reference":[{"issue":"3","key":"2791_CR1","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1086\/514570","volume":"26","author":"KJ Mattila","year":"1998","unstructured":"Mattila KJ, Valtonen VV, Nieminen MS, Asikainen S. Role of infection as a risk factor for atherosclerosis, myocardial infarction, and stroke. Clin Infect Dis. 1998;26(3):719\u201334.","journal-title":"Clin Infect Dis"},{"key":"2791_CR2","doi-asserted-by":"publisher","first-page":"23408","DOI":"10.3402\/jom.v6.23408","volume":"6","author":"Z Armingohar","year":"2014","unstructured":"Armingohar Z, Jorgensen JJ, Kristoffersen AK, Abesha-Belay E, Olsen I. Bacteria and bacterial DNA in atherosclerotic plaque and aneurysmal wall biopsies from patients with and without periodontitis. J Oral Microbiol. 2014;6:23408.","journal-title":"J Oral Microbiol"},{"key":"2791_CR3","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/735378.I.K","author":"HL Lund","year":"2014","unstructured":"Lund HL. The infection hypothesis revisited: oral infections and cardiovascular diseases. Epidemiol Res Int. 2014. https:\/\/doi.org\/10.1155\/2014\/735378.I.K.","journal-title":"Epidemiol Res Int"},{"key":"2791_CR4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0120826","volume":"10","author":"C Damgaard","year":"2015","unstructured":"Damgaard C, Magnussen K, Enevold C. Viable bacteria associated with red blood cells and plasma in freshly drawn blood donations. PLoS ONE. 2015;10: e0120826.","journal-title":"PLoS ONE"},{"key":"2791_CR5","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1128\/JCM.39.5.1956-1959.2001","volume":"39","author":"S Nikkari","year":"2001","unstructured":"Nikkari S, McLaughlin IJ, Bi W, Dodge DE, Relman DA. Does blood of healthy subjects contain bacterial ribosomal DNA? J Clin Microbiol. 2001;39:1956\u20139.","journal-title":"J Clin Microbiol"},{"key":"2791_CR6","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1111\/j.1348-0421.2008.00048.x","volume":"52","author":"K Moriyama","year":"2008","unstructured":"Moriyama K, Ando C, Tashiro K, Kuhara S, Okamura S, Nakano S, Takagi Y, Miki T, Nakashima Y, Hirakawa H. Polymerase chain reaction detection of bacterial 16S rRNA gene in human blood. Microbiol Immunol. 2008;52:375\u201382.","journal-title":"Microbiol Immunol"},{"key":"2791_CR7","doi-asserted-by":"publisher","first-page":"148","DOI":"10.3389\/fcimb.2019.00148","volume":"9","author":"DJ Castillo","year":"2019","unstructured":"Castillo DJ, Rifkin RF, Cowan DA, Potgieter M. The healthy human blood microbiome: fact or fiction? Front Cell Infect Microbiol. 2019;9:148.","journal-title":"Front Cell Infect Microbiol"},{"key":"2791_CR8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0105221","volume":"9","author":"V Dinakaran","year":"2014","unstructured":"Dinakaran V, Rathinavel A, Pushpanathan M, Sivakumar R, Gunasekaran P, Rajendhran J. Elevated levels of circulating DNA in cardiovascular disease patients: metagenomic profiling of microbiome in the circulation. PLoS ONE. 2014;9: e105221.","journal-title":"PLoS ONE"},{"key":"2791_CR9","doi-asserted-by":"publisher","first-page":"e54461","DOI":"10.1371\/journal.pone.0054461","volume":"8","author":"J Amar","year":"2013","unstructured":"Amar J, Lange C, Payros G, Garret C, Chabo C, Lantieri O, Courtney M, Marre M, Charles MA, Balkau B, et al. Blood microbiota dysbiosis is associated with the onset of cardiovascular events in a large general population: the D.E.S.I.R. study. PLoS ONE. 2013;8:e54461.","journal-title":"PLoS ONE"},{"issue":"Suppl 1","key":"2791_CR10","doi-asserted-by":"publisher","first-page":"4592","DOI":"10.1073\/pnas.1011383107","volume":"108","author":"O Koren","year":"2011","unstructured":"Koren O, Spor A, Felin J, F\u00e5k F, Stombaug J, Tremaroli V, Behre CJ, Knight R, Fagerberg B, Ley R, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4592\u20138.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2791_CR11","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.immuni.2017.09.008","volume":"47","author":"I Tabas","year":"2017","unstructured":"Tabas I, Lichtman AH. Monocyte-macrophages and T cells in atherosclerosis. Immunity. 2017;47:621\u201334.","journal-title":"Immunity"},{"key":"2791_CR12","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.3389\/fphys.2017.01075","volume":"8","author":"D An","year":"2017","unstructured":"An D, Hao F, Hu C, et al. JNK1 mediates lipopolysaccharide-induced CD14 and SR-AI expression and macrophage foam cell formation. Front Physiol. 2017;8:1075.","journal-title":"Front Physiol"},{"key":"2791_CR13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0052606","volume":"7","author":"PH Rodrigues","year":"2012","unstructured":"Rodrigues PH, Reyes L, Chadda AS, Belanger M, Wallet SM, Akin D, Dunn W Jr, Progulske-Fox A. Porphyromonas gingivalis strain specific interactions with human coronary artery endothelial cells: a comparative study. PLoS ONE. 2012;7: e52606.","journal-title":"PLoS ONE"},{"key":"2791_CR14","doi-asserted-by":"publisher","first-page":"123","DOI":"10.2217\/fca.11.75","volume":"8","author":"E Kozarov","year":"2012","unstructured":"Kozarov E. Bacterial invasion of vascular cell types: vascular infectology and atherogenesis. Future Cardiol. 2012;8:123\u201338. https:\/\/doi.org\/10.2217\/fca.11.75.","journal-title":"Future Cardiol"},{"key":"2791_CR15","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1093\/femsre\/fuv013","volume":"39","author":"M Potgieter","year":"2015","unstructured":"Potgieter M, Bester J, Kell DB, Pretorius E. The dormant blood microbiome in chronic, inflammatory diseases. FEMS Microbiol Rev. 2015;39:567\u201391.","journal-title":"FEMS Microbiol Rev"},{"key":"2791_CR16","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/nrendo.2011.126","volume":"7","author":"NM Delzenne","year":"2011","unstructured":"Delzenne NM, Neyrinck AM, B\u00e4ckhed F, Cani PD. Targeting gut microbiota in obesity: effects of prebiotics and probiotics. Nat Rev Endocrinol. 2011;7:639\u201346.","journal-title":"Nat Rev Endocrinol"},{"key":"2791_CR17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004923","volume":"11","author":"RP Dickson","year":"2015","unstructured":"Dickson RP, Huffnagle GB. The lung microbiome: new principles for respiratory bacteriology in health and disease. PLoS Pathog. 2015;11: e1004923.","journal-title":"PLoS Pathog"},{"key":"2791_CR18","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.3390\/jcm8081135","volume":"8","author":"E Kononen","year":"2019","unstructured":"Kononen E, Gursoy M, Gursoy UK. Periodontitis: a multifaceted disease of tooth-supporting tissues. J Clin Med. 2019;8:1135.","journal-title":"J Clin Med"},{"key":"2791_CR19","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2020.109575","volume":"138","author":"L Lund H\u00e5heim","year":"2020","unstructured":"Lund H\u00e5heim L, Schwarze PE, Thelle DS, Nafstad P, R\u00f8nningen KS, Olsen I. Low levels of antibodies for the oral bacterium Tannerella forsythia predict cardiovascular disease mortality in men with myocardial infarction: a prospective cohort study. Med Hypotheses. 2020;138: 109575. https:\/\/doi.org\/10.1016\/j.mehy.2020.109575.","journal-title":"Med Hypotheses"},{"key":"2791_CR20","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1016\/j.ahj.2005.06.018","volume":"151","author":"F D'Aiuto","year":"2006","unstructured":"D\u2019Aiuto F, Parkar M, Nibali L, Suvan J, Lessem J, Tonetti MS. Periodontal infections cause changes in traditional and novel cardiovascular risk factors: results from a randomized controlled clinical trial. Am Heart J. 2006;151:977\u201384.","journal-title":"Am Heart J"},{"key":"2791_CR21","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1177\/1403494819879351","volume":"48","author":"LL H\u00e5heim","year":"2020","unstructured":"H\u00e5heim LL, Nafstad P, Schwarze PE, Olsen I, R\u00f8nningen KS, Thelle DS. Oral health and cardiovascular disease risk factors and mortality of cerebral haemorrhage, cerebral infarction and unspecified stroke in elderly men: a prospective cohort study. Scand J Public Health. 2020;48:762\u20139. https:\/\/doi.org\/10.1177\/1403494819879351.","journal-title":"Scand J Public Health"},{"key":"2791_CR22","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1111\/1467-9868.00313","volume":"63","author":"KN Chen","year":"2001","unstructured":"Chen KN. Generalized case-cohort sampling. J Roy Statist Soc Ser B. 2001;63:791\u2013809.","journal-title":"J Roy Statist Soc Ser B"},{"key":"2791_CR23","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1111\/j.1467-9469.2006.00552.x","volume":"34","author":"SO Samuelsen","year":"2007","unstructured":"Samuelsen SO, \u00c5nestad H, Skrondal A. Stratified case-cohort analysis of general cohort sampling designs. Scand J Statist. 2007;34:103\u201319.","journal-title":"Scand J Statist"},{"key":"2791_CR24","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.oooo.2016.11.011","volume":"123","author":"F Hallmer","year":"2017","unstructured":"Hallmer F, Bjornland T, Andersson G, Becktor JP, Kristoffersen AK, Enersen M. Bacterial diversity in medication-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;123:436\u201344.","journal-title":"Oral Surg Oral Med Oral Pathol Oral Radiol"},{"key":"2791_CR25","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.2517-6161.1972.tb00899.x","volume":"34","author":"DR Cox","year":"1972","unstructured":"Cox DR. Regression models and life-tables. J Roy Stat Soc Ser B (Methodol). 1972;34:187\u2013220.","journal-title":"J Roy Stat Soc Ser B (Methodol)"},{"key":"2791_CR26","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1023\/A:1009661900674","volume":"6","author":"\u00d8 Borgan","year":"2000","unstructured":"Borgan \u00d8, Langholz B, Samuelsen SO, Goldstein L, Pogoda J. Exposure stratified case-cohort designs. Lifetime Data Anal. 2000;6:39\u201358.","journal-title":"Lifetime Data Anal"},{"key":"2791_CR27","doi-asserted-by":"publisher","first-page":"3737","DOI":"10.1016\/j.csda.2006.12.028","volume":"51","author":"B Langholz","year":"2007","unstructured":"Langholz B, Jiao J. Computational methods for case-cohort studies. Comput Stat Data Anal. 2007;51:3737\u201348.","journal-title":"Comput Stat Data Anal"},{"key":"2791_CR28","unstructured":"Team RC. R: A language and environment for statistical computing. R Foundation for Statistical Computing. 2015."},{"key":"2791_CR29","unstructured":"Lawrence G. Bacteraemia and Cardiovascular disease. A case-cohort study of the Oslo II dataset. Master\u2019s Thesis, 2020, Department of Mathematics, Faculty of Mathematics and Natural Sciences, University of Oslo, Norway."},{"key":"2791_CR30","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s40168-018-0412-9","volume":"6","author":"MHY Leung","year":"2018","unstructured":"Leung MHY, Tong X, Wilkins D, Cheung HHL, Lee PKH. Individual and household attributes influence the dynamics of the personal skin microbiota and its association network. Microbiome. 2018;6:26.","journal-title":"Microbiome"},{"key":"2791_CR31","doi-asserted-by":"publisher","first-page":"135","DOI":"10.4103\/jpgm.JPGM_441_16","volume":"63","author":"P Gunaseelan","year":"2017","unstructured":"Gunaseelan P, Suresh G, Raghavan V, Varadarajan S. Native valve endocarditis caused by Kocuria rosea complicated by peripheral mycotic aneurysm in an elderly host. J Postgrad Med. 2017;63:135\u20137.","journal-title":"J Postgrad Med"},{"key":"2791_CR32","doi-asserted-by":"publisher","first-page":"2553","DOI":"10.3389\/fmicb.2018.02553","volume":"9","author":"R Lasek","year":"2018","unstructured":"Lasek R, Szuplewska M, Mitura M, Decewicz P, Chmielowska C, Pawlot A, Sentkowska D, Czarnecki J, Bartosik D. Genome structure of the opportunistic pathogen Paracoccus yeei (Alphaproteobacteria) and Identification of putative virulence factors. Front Microbiol. 2018;9:2553.","journal-title":"Front Microbiol"},{"key":"2791_CR33","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1038\/s41598-022-05337-1","volume":"12","author":"Z Corredor","year":"2022","unstructured":"Corredor Z, Suarez-Molina A, Fong C, Cifuentes CL, Guauque-Olarte S. Presence of periodontal pathogenic bacteria in blood of patients with coronary artery disease. Sci Rep. 2022;12:1241.","journal-title":"Sci Rep"},{"key":"2791_CR34","doi-asserted-by":"publisher","first-page":"1281562","DOI":"10.1080\/20002297.2017.1281562","volume":"9","author":"J-LC Mougeot","year":"2017","unstructured":"Mougeot J-LC, Stevens CB, Paster BJ, Brennan MT, Lockhart PB, Mougeot FKB. Porphyromonas gingivalis is the most abundant species detected in coronary and femoral arteries. J Oral Microbiol. 2017;9:1281562.","journal-title":"J Oral Microbiol"},{"key":"2791_CR35","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1111\/j.1600-051x.1998.tb02419.x","volume":"25","author":"SS Socransky","year":"1998","unstructured":"Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL Jr. Microbial complexes in subgingival plaque. J Clin Periodontol. 1998;25:134\u201344. https:\/\/doi.org\/10.1111\/j.1600-051x.1998.tb02419.x.","journal-title":"J Clin Periodontol"},{"key":"2791_CR36","first-page":"350","volume-title":"Oral microbiology and immunology","author":"G Dahl\u00e9n","year":"2012","unstructured":"Dahl\u00e9n G, Fiehn N-E, Olsen I, Dahlgren U. Oral microbiology and immunology. Munksgaard: K\u00f8benhavn; 2012. p. 350."},{"key":"2791_CR37","volume-title":"Oral infections and cardiovascular disease","year":"2011","unstructured":"Lund H\u00e5heim L, editor. Oral infections and cardiovascular disease. New York: Bentham Science Publishers Ltd; 2011."},{"key":"2791_CR38","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.856118","volume":"10","author":"Z Xuanzhi","year":"2022","unstructured":"Xuanzhi Z, Hanyao H, Lei Z. PAMPs and DAMPs as the bridge between periodontitis and atherosclerosis: the potential therapeutic targets. Front Cell Dev Biol. 2022;10: 856118. https:\/\/doi.org\/10.3389\/fcell.2022.856118.","journal-title":"Front Cell Dev Biol"}],"container-title":["BMC Cardiovascular Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12872-022-02791-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12872-022-02791-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12872-022-02791-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T08:32:26Z","timestamp":1727685146000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmccardiovascdisord.biomedcentral.com\/articles\/10.1186\/s12872-022-02791-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,31]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["2791"],"URL":"https:\/\/doi.org\/10.1186\/s12872-022-02791-7","relation":{},"ISSN":["1471-2261"],"issn-type":[{"value":"1471-2261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,31]]},"assertion":[{"value":"6 December 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 July 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The Data Inspectorate and The Regional Ethical Review Board for Medical Research, Eastern Norway, had approved the study. The Oslo II study followed the ethical principles of the Declaration of\u00a0Helsinki for Medical Research involving persons. All participants gave their written informed consent to the use of the data and biological material on the condition that The Data Inspectorate and The Regional Ethical Review Board for Medical Research, Eastern Norway, had granted the permission.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and informed consent to participate"}},{"value":"Consent to publish by the participants was not found to be applicable as the results presented do not identify individuals.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"No competing interests nor conflict of interests was reported by the authors with respect to the research, authorship, and\/or publication of this article.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"344"}}