{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T03:26:34Z","timestamp":1783826794503,"version":"3.55.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100012264","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F30HL178232"],"award-info":[{"award-number":["F30HL178232"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL167199"],"award-info":[{"award-number":["R01HL167199"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL165218"],"award-info":[{"award-number":["R01HL165218"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R44HL156811"],"award-info":[{"award-number":["R44HL156811"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 GM152319"],"award-info":[{"award-number":["T32 GM152319"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>To develop assessments of low-density (\u2018sub-Agatston\u2019) coronary artery calcification (CAC) on non-contrast CT calcium score (CTCS) examinations to evaluate its association with the risk of atherosclerotic major adverse cardiac events (MACE) and with high-risk plaque (HRP) features from coronary CT angiography (CCTA).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We analysed 1837 asymptomatic individuals from the Community Benefit of No-charge Calcium Score Screening (CLARIFY) CTCS registry (NCT04075162) and 1075 patients presenting at chest-pain clinics from the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial (NCT01149590). MACE comprised death, myocardial infarction, stroke, or revascularization. We developed the vulnerable calcium index (VCI), which quantifies the proportional CAC mass increase after region-growing from 130 Hounsfield Units (HU) (Agatston) to 110 HU. Cox models were adjusted for age, sex, diabetes, hypertension, smoking, baseline statin use, and Agatston score. The association between VCI and CCTA-defined HRP (low-attenuation plaque, positive remodelling, spotty calcifications, mixed plaque, punctate calcification, napkin-ring sign) was assessed in patients with paired CTCS and CCTA in SCOT-HEART. Median follow-up was 4.8 years (CLARIFY) and 4.9 years (SCOT-HEART). VCI was independently associated with MACE in both cohorts: CLARIFY (adjusted hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.02\u20131.22, P = 0.02) per unit increase in VCI and SCOT-HEART (adjusted HR 1.16, 1.03\u20131.31, P = 0.02). Patients in the top quartile of adjusted model risk had markedly higher event rates compared with the lowest quartile (CLARIFY HR 25.0; SCOT-HEART HR 33.7 vs. Q1, P &amp;lt; 0.005 for both). Addition of VCI to Agatston significantly improved C-index (CLARIFY: 0.62 to 0.66, P &amp;lt; 0.001; SCOT-HEART: 0.72 to 0.75, P &amp;lt; 0.001) and net reclassification index (CLARIFY: 0.52 [0.40, 0.64], P &amp;lt; 0.005; SCOT-HEART: 0.72 [0.48, 0.94], P &amp;lt; 0.005). In SCOT-HEART, VCI was associated with all HRP features (odds ratio: 1.45\u20131.85, P &amp;lt; 0.001), adjusted for Agatston score.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>VCI captures sub-Agatston CAC linked to HRP and independently improves MACE prediction in both a primary-prevention and a mixed-risk symptomatic chest pain population. Incorporating VCI into CAC reporting may refine preventive risk stratification beyond the conventional Agatston score.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurjpc\/zwag285","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T11:44:28Z","timestamp":1780141468000},"source":"Crossref","is-referenced-by-count":2,"title":["Sub-Agatston coronary calcification on non-contrast cardiac CT and cardiovascular risk"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8429-5701","authenticated-orcid":false,"given":"Prerna","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, OH 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammar","family":"Hoori","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, OH 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juhwan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, OH 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle C","family":"Williams","sequence":"additional","affiliation":[{"name":"BHF Centre for Cardiovascular Science, University of Edinburgh , Edinburgh ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1122-7695","authenticated-orcid":false,"given":"Sadeer","family":"Al-Kindi","sequence":"additional","affiliation":[{"name":"DeBakey Heart and Vascular Center, Houston Methodist Hospital , Houston, TX ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E","family":"Newby","sequence":"additional","affiliation":[{"name":"BHF Centre for Cardiovascular Science, University of Edinburgh , Edinburgh ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Rajagopalan","sequence":"additional","affiliation":[{"name":"Harrington Heart and Vascular Institute,University Hospitals of Cleveland , Cleveland, OH ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9763-1463","authenticated-orcid":false,"given":"David L","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, OH 44106 ,","place":["USA"]},{"name":"Department of Radiology, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, OH 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"2026061107085092500_zwag285-B1","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/j.clinthera.2023.09.020","article-title":"Global trends in atherosclerotic cardiovascular disease","volume":"45","author":"Nedkoff","year":"2023","journal-title":"Clin Ther"},{"key":"2026061107085092500_zwag285-B2","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","article-title":"Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study","volume":"76","author":"Roth","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"2026061107085092500_zwag285-B3","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.jacc.2018.05.027","article-title":"Coronary calcium score and cardiovascular risk","volume":"72","author":"Greenland","year":"2018","journal-title":"JACC"},{"key":"2026061107085092500_zwag285-B4","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/0735-1097(90)90282-T","article-title":"Quantification of coronary artery calcium using ultrafast computed tomography","volume":"15","author":"Agatston","year":"1990","journal-title":"J Am Coll Cardiol"},{"key":"2026061107085092500_zwag285-B5","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1001\/jamacardio.2019.5315","article-title":"Association of high-density calcified 1K plaque with risk of acute coronary syndrome","volume":"5","author":"van Rosendael","year":"2020","journal-title":"JAMA Cardiol"},{"key":"2026061107085092500_zwag285-B6","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.jcmg.2017.04.018","article-title":"Coronary artery calcium volume and density","volume":"10","author":"Criqui","year":"2017","journal-title":"JACC Cardiovasc Imaging"},{"key":"2026061107085092500_zwag285-B7","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.jcmg.2017.05.007","article-title":"Coronary artery calcium scoring","volume":"10","author":"Blaha","year":"2017","journal-title":"JACC Cardiovasc Imaging"},{"key":"2026061107085092500_zwag285-B8","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1016\/j.jcmg.2022.02.026","article-title":"Evolving role of calcium density in coronary artery calcium scoring and atherosclerotic cardiovascular disease risk","volume":"15","author":"Razavi","year":"2022","journal-title":"JACC Cardiovasc Imaging"},{"key":"2026061107085092500_zwag285-B9","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/HCO.0000000000001185","article-title":"Beyond the Agatston calcium score: role of calcium density and other calcified plaque markers for cardiovascular disease prediction","volume":"40","author":"Razavi","year":"2024","journal-title":"Curr Opin Cardiol"},{"key":"2026061107085092500_zwag285-B10","doi-asserted-by":"crossref","first-page":"10741","DOI":"10.1073\/pnas.1308814110","article-title":"Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries","volume":"110","author":"Kelly-Arnold","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026061107085092500_zwag285-B11","doi-asserted-by":"crossref","first-page":"H619","DOI":"10.1152\/ajpheart.00036.2012","article-title":"A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture","volume":"303","author":"Maldonado","year":"2012","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2026061107085092500_zwag285-B12","first-page":"460","article-title":"Spotty calcification and plaque vulnerability in vivo: frequency-domain optical coherence tomography analysis","volume":"4","author":"Kataoka","year":"2014","journal-title":"Cardiovasc Diagn Ther"},{"key":"2026061107085092500_zwag285-B13","doi-asserted-by":"crossref","first-page":"3424","DOI":"10.1161\/01.CIR.0000148131.41425.E9","article-title":"Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study","volume":"110","author":"Ehara","year":"2004","journal-title":"Circulation"},{"key":"2026061107085092500_zwag285-B14","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3390\/diagnostics9040125","article-title":"Coronary artery microcalcification: imaging and clinical implications","volume":"9","author":"Vancheri","year":"2019","journal-title":"Diagnostics"},{"key":"2026061107085092500_zwag285-B15","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.atherosclerosis.2020.05.017","article-title":"Calcium deposition within coronary atherosclerotic lesion: implications for plaque stability","volume":"306","author":"Jinnouchi","year":"2020","journal-title":"Atherosclerosis"},{"key":"2026061107085092500_zwag285-B16","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/S1388-1981(00)00146-3","article-title":"Cholesterol and phospholipid metabolism in macrophages","volume":"1529","author":"Tabas","year":"2000","journal-title":"Biochim Biophys Acta"},{"key":"2026061107085092500_zwag285-B17","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/S0002-9440(10)64641-X","article-title":"Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death","volume":"157","author":"Kolodgie","year":"2000","journal-title":"Am J Pathol"},{"key":"2026061107085092500_zwag285-B18","doi-asserted-by":"crossref","first-page":"H1608","DOI":"10.1152\/ajpheart.01081.2007","article-title":"Strain distribution over plaques in human coronary arteries relates to shear stress","volume":"295","author":"Gijsen","year":"2008","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2026061107085092500_zwag285-B19","doi-asserted-by":"crossref","first-page":"14678","DOI":"10.1073\/pnas.0606310103","article-title":"A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps","volume":"103","author":"Vengrenyuk","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026061107085092500_zwag285-B20","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0142335","article-title":"Intra-section analysis of human coronary arteries reveals a potential role for micro-calcifications in macrophage recruitment in the early stage of atherosclerosis","volume":"10","author":"Chatrou","year":"2015","journal-title":"PLoS One"},{"key":"2026061107085092500_zwag285-B21","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1161\/ATVBAHA.113.302642","article-title":"Has our understanding of calcification in human coronary atherosclerosis progressed?","volume":"34","author":"Otsuka","year":"2014","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026061107085092500_zwag285-B22","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1016\/j.jcin.2015.12.039","article-title":"CRT-200.07 spotty calcium location plays a key role in human plaque instability: insights from studies in vivo from cardiac arrest survivors and in vitro from autopsied sudden cardiac death victims","volume":"9","author":"Pu","year":"2016","journal-title":"JACC Cardiovasc Interv"},{"key":"2026061107085092500_zwag285-B23","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/PL00002026","article-title":"Pathophysiology of calcium deposition in coronary arteries","volume":"26","author":"Burke","year":"2001","journal-title":"Herz"},{"key":"2026061107085092500_zwag285-B24","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.jacc.2007.03.044","article-title":"Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes","volume":"50","author":"Motoyama","year":"2007","journal-title":"J Am Coll Cardiol"},{"key":"2026061107085092500_zwag285-B25","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.jcct.2021.10.004","article-title":"Detection of small coronary calcifications in patients with Agatston coronary artery calcium score of zero","volume":"16","author":"Tzolos","year":"2022","journal-title":"J Cardiovasc Comput Tomogr"},{"key":"2026061107085092500_zwag285-B26","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1007\/s10554-011-9914-2","article-title":"Very small calcifications are detected and scored in the coronary arteries from small voxel MDCT images using a new automated\/calibrated scoring method with statistical and patient specific plaque definitions","volume":"28","author":"Arnold","year":"2012","journal-title":"Int J Cardiovasc Imaging"},{"key":"2026061107085092500_zwag285-B27","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1007\/s00330-004-2479-x","article-title":"Influence of scoring parameter settings on Agatston and volume scores for coronary calcification","volume":"15","author":"van Ooijen","year":"2005","journal-title":"Eur Radiol"},{"key":"2026061107085092500_zwag285-B28","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.amjcard.2022.03.019","article-title":"Effect of No-charge coronary artery calcium scoring on cardiovascular prevention","volume":"174","author":"Al-Kindi","year":"2022","journal-title":"Am J Cardiol"},{"key":"2026061107085092500_zwag285-B29","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1016\/j.jacc.2016.02.026","article-title":"Use of coronary computed tomographic angiography to guide management of patients with coronary disease","volume":"67","author":"Williams","year":"2016","journal-title":"J Am Coll Cardiol"},{"key":"2026061107085092500_zwag285-B30","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.jacc.2018.10.066","article-title":"Coronary artery plaque characteristics associated with adverse outcomes in the SCOT-HEART study","volume":"73","author":"Williams","year":"2019","journal-title":"J Am Coll Cardiol"},{"key":"2026061107085092500_zwag285-B31","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1016\/S0140-6736(15)60291-4","article-title":"CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial","volume":"385","author":"Investigators SCOT-HEART","year":"2015","journal-title":"Lancet"},{"key":"2026061107085092500_zwag285-B32","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1056\/NEJMoa1805971","article-title":"Coronary CT angiography and 5-year risk of myocardial infarction","volume":"379","author":"Investigators SCOT-HEART","year":"2018","journal-title":"N Engl J Med"},{"key":"2026061107085092500_zwag285-B33","article-title":"Improved bias and reproducibility of coronary artery calcification features using deconvolution","volume":"10","author":"Song","year":"2023","journal-title":"JMI"},{"key":"2026061107085092500_zwag285-B34","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.jcmg.2012.09.016","article-title":"Napkin-ring sign on coronary CT angiography for the prediction of acute coronary syndrome","volume":"6","author":"Otsuka","year":"2013","journal-title":"JACC Cardiovasc Imaging"},{"key":"2026061107085092500_zwag285-B35","doi-asserted-by":"crossref","first-page":"11134","DOI":"10.1038\/s41598-024-60584-8","article-title":"Enhancing cardiovascular risk prediction through AI-enabled calcium-omics","volume":"14","author":"Hoori","year":"2024","journal-title":"Sci Rep"},{"key":"2026061107085092500_zwag285-B36","doi-asserted-by":"crossref","first-page":"26898","DOI":"10.1038\/s41598-024-77269-x","article-title":"Leveraging calcium score CT radiomics for heart failure risk prediction","volume":"14","author":"Singh","year":"2024","journal-title":"Sci Rep"},{"key":"2026061107085092500_zwag285-B37","doi-asserted-by":"crossref","DOI":"10.1161\/CIRCIMAGING.120.011981","article-title":"Spatially weighted coronary artery calcium score and coronary heart disease events in the multi-ethnic study of atherosclerosis","volume":"14","author":"Shea","year":"2021","journal-title":"Circ Cardiovasc Imaging"},{"key":"2026061107085092500_zwag285-B38","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1471-2342-12-14","article-title":"An alternative method for quantifying coronary artery calcification: the multi-ethnic study of atherosclerosis (MESA)","volume":"12","author":"Liang","year":"2012","journal-title":"BMC Med Imaging"}],"container-title":["European Journal of Preventive Cardiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/eurjpc\/advance-article-pdf\/doi\/10.1093\/eurjpc\/zwag285\/68445098\/zwag285.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eurjpc\/advance-article-pdf\/doi\/10.1093\/eurjpc\/zwag285\/68445098\/zwag285.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T11:09:05Z","timestamp":1781176145000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eurjpc\/advance-article\/doi\/10.1093\/eurjpc\/zwag285\/8699479"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,1]]},"references-count":38,"URL":"https:\/\/doi.org\/10.1093\/eurjpc\/zwag285","relation":{},"ISSN":["2047-4873","2047-4881"],"issn-type":[{"value":"2047-4873","type":"print"},{"value":"2047-4881","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,1]]},"article-number":"zwag285"}}