Breast arterial calcification as a cardiovascular risk biomarker: A multicenter analysis of Indian women

Breast arterial calcification (BAC) is an emerging marker of atherosclerotic cardiovascular disease (CVD) risk. However, most prior studies relied on traditional film mammography and on the dichotomy of presence/absence of BAC. Furthermore, race/ethnic differences in BAC are not well documented. The M ult i eth n ic Study of Br e ast A r terial Calcification and Cardio va scular Risk ( MINERVA ) study recruited 5,040 postmenopausal women after they underwent routine digital screening mammography at one of nine Northern California Kaiser Permanente Centers between 3/21/2013 and 9/1/2015. Study participants were free of CVD at baseline, and underwent an extensive clinic visit for ascertainment of CVD risk factors. Presence and gradation of BAC (calcium mass in mg) on raw images by dedicated software were ascertained by a novel densitometry method at the BAC Reading Center at UC Irvine. Data on BAC and demographics are presented here on the first 2,597 mammograms read. The mean age of the cohort was 66.5 ± 4.6 [range, 60-79 years old] and the ethnic breakdown was 67% white, 9% African-American, 10% Asian/Pacific Islander, 8% Latina and 6% mixed/other race. The overall prevalence of any BAC (calcium mass>0) was 30% (773/2,597) and increased with age: 26% in 60-69, 38% in 70-74 and 54% in 75-79 year old women. By race, BAC presence was higher in Latina (37%, 75/203), followed by African-American (30%, 66/222), white (29%, 514/1750), mixed/other (28%, 48/159), and Asian women (28%, 73/263). The age- and ethnic-specific gradation BAC data are summarized in the Table. Variation of BAC gradation was significant across age (Chi-square=142; p=0.0001) and nearly significant across race/ethnic groups (Chi-square=26; p=0.06). Overall, only 3% of women had a calcium mass between 11 and 25, with 3% over 25 mg. These percentages were higher among women over age 75 and in Latinas and African-Americans. These results document, for the first time, significant differences in BAC presence and gradation as a function of age and race/ethnicity.

Background: Breast arterial calcification (BAC) assessment on screening mammogram is a promising tool to improve cardiovascular disease (CVD) risk evaluation. Purpose: To evaluate the association between BAC and incident CVD in patients with and without CVD risk factors (RFs). Methods: This single-center retrospective study included women aged 40–90 years who underwent screening mammograms from 2006 to 2016. BAC was quantified using an automated platform (cmAngio, CureMetrix). Primary outcome was all-cause death. Secondary outcomes were acute myocardial infarction (MI), heart failure (HF), stroke, and time to CVD composite event (MI, HF, stroke, or CVD-death). Patients were stratified by presence/absence of BAC (BAC+, BAC-) and CVD RFs [hypertension (HTN), hyperlipidemia (HLD), diabetes, chronic kidney disease, smoking history, antiplatelet use, or anti-HLD or anti-HTN therapy] at time of mammogram. Results: Of 22,314 index mammograms included, mean age of participants was 55 ± 13 years. There were 780 CVD events (4.6%) in BAC- women and 765 (14.2%) in BAC+ women (p<0.001) over a median follow-up of 4.1 years [IQR 1.7, 6.5]. There were 486 deaths (2.9%) in BAC- women and 535 (9.9%) in BAC+ women (p<0.001) over a median follow-up of 5.8 years [IQR 3.3, 8.3]. Highest frequency of composite events and death occurred in the BAC+/RF+ group (18% and 12%, respectively). In multivariable analyses, BAC+/RF- women were not at increased risk of CVD event or death compared to BAC-/RF- women. However, among RF+ women, BAC+ was linked with higher CVD risk (aHR 1.50, p<0.001) and mortality (aHR 1.44, p<0.001) than BAC-. Among RF+ women on anti-HLD therapy, BAC+ was linked with higher CVD risk (aHR 1.42, p<0.001) and mortality (aHR 1.28, p<0.001) than BAC- counterparts. Among BAC+/RF+ women, no anti-HLD therapy was linked with higher CVD risk (aHR 1.44, p<0.001) and death (aHR 1.46, p<0.001) than use of anti-HLD therapy. Among RF+ women on anti-HTN therapy, BAC+ was linked with higher CVD risk (aHR 1.55, p<0.001) and death (aHR 1.42, p<0.001) than BAC- counterparts. Among BAC+/RF+ women, no anti-HTN therapy was linked with higher CVD risk (aHR 1.28, p<0.001) and death (aHR 1.28, p<0.001) than use of anti-HTN therapy. Conclusions: BAC is independently associated with increased death and CVD outcomes in women with CVD RFs, especially those not receiving anti-HTN or anti-HLD therapy. These findings suggest opportunities for using BAC to help guide clinical management of CVD risk.

Mammographic Breast arterial calcification (BAC) may be a novel subclinical cardiovascular disease (CVD) risk marker. Since subclinical and clinical CVD are associated with cognitive impairment, we set out to investigate whether there is a relation between BAC presence/severity and cognitive function (CF). We used data from the M ult I eth N ic study of br E ast a R terial calcium gradation and cardio VA scular disease (MINERVA), a multiethnic cohort of women aged 60-79 at baseline (10/2012 and 2/2015) who were free of symptomatic CVD, all recruited at Kaiser Permanente of Northern California. The sample available for analyses with complete data on BAC, cognitive function and covariates was 3,919 (mean ± SD age=67 ± 4, 52% white, 18% Asian, 15% African-American and 12% Latina). A BAC continuous mass score (mg) was obtained using a validated densitometry method. BAC presence was BAC score > 0 mg, and severe BAC was BAC score > 20 mg. CF was dichotomized as Montreal Cognitive Assessment (MoCA) score < 23 (first quartile) vs ≥ 23 (quartiles 2, 3 and 4). The unadjusted (Model 1) odds ratios (OR, 95% CI; p-value) of CF < 23 vs. ≥ 23 associated with BAC > 0 vs. BAC=0 was 1.15 (0.98-1.35; 0.08). However, adjustment for age, race and education (Model 2) abolished this association. Further adjustment for factors independently predicting CF (Model 3, with further inclusion of diabetes, HDL-C, CES depression score, breast feeding, multiple sclerosis and osteoarthitis) did not change the association. The unadjusted (Model 1) odds ratios (OR, 95% CI; p-value) of CF < 23 vs. ≥ 23 associated with BAC > 20 vs. BAC≤ 20 was 1.44 (1.02-2.01; 0.04). However, adjustment for age, race and education (Model 2) abolished this association and further adjustment for factors independently predicting CF did not alter the association. In conclusion, we found a statistically significant association between severe BAC and CF, but it was explained by covariation (confounding) by age, race and education, arguing that BAC may not play a role in cognitive impairment.

ObjectivesTo investigate the knowledge of radiologists on breast arterial calcifications (BAC) and attitude about BAC reporting, communication to women, and subsequent action.MethodsAn online survey was offered to EUSOBI members, with 17 questions focused on demographics, level of experience, clinical setting, awareness of BAC association with cardiovascular risk, mammographic reporting, modality of BAC assessment, and action habits. Descriptive statistics were used.ResultsAmong 1084 EUSOBI members, 378 (34.9%) responded to the survey, 361/378 (95.5%) radiologists, 263 females (69.6%), 112 males (29.6%), and 3 (0.8%) who did not specify their gender. Of 378 respondents, 305 (80.7%) declared to be aware of BAC meaning in terms of cardiovascular risk and 234 (61.9%) to routinely include BAC in mammogram reports, when detected. Excluding one inconsistent answer, simple annotation of BAC presence was declared by 151/233 (64.8%), distinction between low versus extensive BAC burden by 59/233 (25.3%), and usage of an ordinal scale by 22/233 (9.5%) and of a cardinal scale by 1/233 (0.4%). Among these 233 radiologists reporting BAC, 106 (45.5%) declared to orally inform the woman and, in case of severe BAC burden, 103 (44.2%) to investigate cardiovascular history, and 92 (39.5%) to refer the woman to a cardiologist.ConclusionAmong EUSOBI respondents, over 80% declared to be aware of BAC cardiovascular meaning and over 60% to include BAC in the report. Qualitative BAC assessment predominates. About 40% of respondents who report on BAC, in the case of severe BAC burden, investigate cardiovascular history and/or refer the woman to a cardiologist.Key Points• Of 1084 EUSOBI members, 378 (35%) participated: 81% of respondents are aware of breast arterial calcification (BAC) cardiovascular meaning and 62% include BAC in the mammogram report.• Of those reporting BAC, description of presence was declared by 65%, low versus extensive burden distinction by 25%, usage of an ordinal scale by 10%, and of a cardinal scale by 0.4%; 46% inform the woman and, in case of severe BAC burden, 44% examine cardiovascular history, and 40% refer her to a cardiologist.• European breast radiologists may be ready for large-scale studies to ascertain the role of BAC assessment in the comprehensive framework of female cardiovascular disease prevention.

Introduction: Mammographically detected breast arterial calcification (BAC) is purported as a surrogate marker for cardiovascular disease (CVD). We conducted a systematic review and meta-analysis to determine the prevalence of BAC and its association with CVD risk and disease. Methods: Online databases were searched until March 2021 for studies reporting BAC. Four endpoints were evaluated: (1) BAC prevalence, (2) association with CVD risk factors, (3) prevalent and incident vascular disease and (4) BAC prevalence based on estimated CVD risk. Random-effects models were used. Data was analysed as odds ratio (OR), hazard ratio (HR) or effect size (ES) obtained through data transformation for differentially reported data. A CVD-specific risk metric was calculated as the product of CVD risk factor proportion and HR risk estimate from the CAD Consortium Risk Calculator and summed for all risk factors. Meta-regression modelling with predicted BAC prevalence stratified by age was performed. Results: There were 77 studies (104,710 patients) included. Pooled BAC prevalence was 22% (95%CI: 19-25%) with cumulatively increasing prevalence annually. Significant BAC predictors were age, hypertension, diabetes, hypercholesterolemia (p<0.01). BAC was associated with CAD (OR 2.65, 95%CI: 2.17-3.23, p<0.01) and non-coronary vascular disease (ES 0.80, 95%CI: 0.51-1.09, p<0.01). BAC associated with incident cardiovascular events (HR 1.61, 95%CI: 1.11-2.32, p=0.001). Predicted BAC prevalence associated significantly with increasing CVD risk regardless of age (Figure). Conclusions: BAC is significantly associated with prevalent and incident vascular disease affecting intimal and medial arterial beds. BAC is highly prevalent and associated with CVD risk factors individually and cumulatively. Routine assessment of BAC should be considered in screening mammography to potentially trigger CVD risk consultation.

Objective:Breast arterial calcification (BAC), medial calcific sclerosis of small to medium-sized muscular arteries, is a benign finding of mammographic evaluation. Previous studies have shown the relationships between BAC and systemic disorders such as cardiovascular disease, diabetes mellitus and hypertension. The aim of this study was to determine the association between reduced bone mineral density and BAC.Methods:The study population consisted of 567 women who had both mammography and bone mineral density evaluation. BAC (+) and BAC (-) women were compared for age, body mass index, postmenopausal duration, number of deliveries, breastfeeding duration, DM, HT, lipid treatment, osteopenia, and osteoporosis.Results:BAC was seen in mammographic evaluation of 179 women and 388 subjects without BAC accepted as the control group. There was a statistically significant relationship between age, postmenopausal duration, number of deliveries, history of DM, HT, lipid treatment and BAC. While the prevalence of osteopenia was higher in control group (52.8%), the rate of osteoporosis (48.7%) was higher in group with BAC.Conclusion:There was statistically significant relationship between BAC and osteoporosis in postmenopausal women. Determination of BAC in routine screening mammography might be helpful in both identifying women with risk of cardiovascular disease and osteoporosis.

Introduction: Breast arterial calcification (BAC) is gaining acceptance as a CVD risk factor (RF), though overlap with traditional RFs remains unclear. We tested the hypothesis that BAC, assessed via the Bradley score, is associated with CVD RFs. Methods: We analyzed baseline cross-sectional data from 16,217 women who underwent screening digital mammography between 2008-2016 at a single center. BAC was quantified using an algorithm from a trained, deep neural network (CureMetrix), resulting in an automated and continuous Bradley score; >10 was considered BAC positive. CVD RFs were obtained via medical records. We calculated odds ratios (OR) for RFs per Bradley score quartile and created distribution plots. Results: At baseline (mean age 55 ± 11 yrs; 70% White, 45% Black, 25% other), 8% had diabetes, 30% hypertension, 30% hyperlipidemia, and 5% smoked; 22% and 6% took lipid-lowering and anticoagulant medication, respectively. There were 1,904 women (13%) with BAC (median Bradley score 42). BAC prevalence increased with age, and those in the highest quartile of the Bradley score, compared to lowest, were significantly more likely to have hypertension (OR 4.1, 95% CI 3.3-5.0; p<0.001), diabetes (OR 2.8, 95% CI 2.2-3.6; p<0.001), and hyperlipidemia (OR 2.4, 95% CI 2.0-3.0; p<0.001) ( Figure). Additionally, 492 women (7%) with zero traditional RFs had BAC ( Table ). Conclusions: BAC prevalence on mammography is robustly associated with traditional CVD RFs, however BAC was present in 7% of women without RFs. Future studies are needed to determine the significance of BAC among women without RFs, as it may provide insight and opportunity for prevention before traditional CVD RFs develop.

Breast arterial calcification (BAC) detected in mammograms is an emerging risk-enhancing factor for atherosclerotic cardiovascular disease (ASCVD). The predictive value of coronary artery calcification (CAC) for risk of ASCVD above and beyond traditional risk factors is well-established in women. However, there are few studies that have simultaneously evaluated BAC and CAC. The Multiethnic study of breast arterial calcium gradation and cardiovascular disease (MINERVA) cohort, a large, racially and ethnically diverse cohort of postmenopausal women aged 60-69 (n=5,059) was recruited in 2012-15 at Kaiser Permanente of Northern California (KPNC). BAC was assessed using a densitometry method, and presence of BAC was defined as a calcium mass score>0 mg. Searching the electronic health record up to 5 years after baseline, we identified 33 women (39% non-white) who underwent cardiac computed tomography (CT) because of medical indication. BAC was present in 33% (11/33) whereas CAC (Agastston score >0) was present in 61% (20/33). Nine (27%) were BAC and CAC -; 7 (21%) were BAC and CAC+; 4 (12%) were BAC+ and CAC -; and 13 (39%) were BAC - and CAC+. The correlation between log (BAC+1) and log (CAC+1) was 0.45 (p=0.02) in the entire sample (n=33) and was 0.68 (p=0.09) in the 7 women who were BAC and CAC+. The concordance, sensitivity, specificity, PPV, NPV for BAC considering CAC as the gold standard were 0.48, 0.35, 0.69, 0.63 and 0.41, respectively. The unadjusted odds ratio for log (CAC+1)>0 as a function of Log (BAC+1) was 1.21 (95% CI, 0.27-5.38; p=0.80). Although our sample was small, the findings reflect real-world evidence and suggest that BAC and CAC are not entirely overlapping and thus may convey independent predictive information for ASCVD.

Background: Breast arterial calcifications (BAC) are incidentally observed on screening mammography. BAC has been shown to be associated with the presence of coronary artery calcification (CAC) and increased risk of coronary artery disease (CAD). Given that population-based mammography is currently recommended to women, the evaluation of BAC may be important in identifying high-risk women without additional cost or radiation exposure. Aims: We sought to identify reproductive and cardiovascular risk factors associated with the presence of detectable BAC and CAC in women participated to mammography screening. Also, we aimed to determine the association between BAC and presence of CAC. Further, we investigated presence of BAC, CAC and estimated 10-year risk of atherosclerotic cardiovascular disease (ASCVD). Methods: In this cross-sectional study, reproductive history and CVD risk factors were obtained in 215 women ≥ 18 years of age that underwent mammography and cardiac computed tomographic angiography (CCTA) within 2 years of each other between January 2007 and September 2017 at Weill Cornell Medicine/ New York Presbyterian hospital (WCM/NYP). BAC was recorded in two ways: a binary scale (presence/absence) and a semi-quantitative scale (mild, moderate, severe). CAC was calculated using the Agatston method and was recorded as a binary variable (presence/absence). Information regarding reproductive history and CVD risk factors, medical history, and relevant demographics were obtained by chart review. Odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for age at study entry as a potential confounder, were estimated. The 10-year risk of atherosclerotic cardiovascular disease (ASCVD) was calculated using the Pooled Cohort Risk Equations. Results: The odds of presence of BAC increased with increasing age . Women age ≥60 had a near 6-fold higher odds of BAC (OR = 5.77; 95% CI = 2.45 to 16.00) compared with women <60 years old. Other factors associated with presence of BAC after controlling for age were diastolic blood pressure ≥80 ( P = 0.0008), systolic blood pressure ≥140 ( P = 0.0009), number of children (P = 0.01). Younger age at first birth (≤28 years) was associated with 3-fold higher odds of BAC compared with women with age at first birth >28 years. Except for age at study entry, the only factor associated with presence of CAC was hyperlipidemia ( P = 0.002). We found no association between presence of BAC with CAC. We observed women with presence of both BAC and CAC had the highest estimated 10-year risk of ASCVD: 18.54%, followed by presence of BAC but absence of CAC 11.65%, absence of BAC and presence of CAC 6.01%, and women with no BAC and no CAC presence had a mean 10-year risk of ASCVD of 5.25%. Conclusions: These findings support the value of BAC in identifying women at potentially increased risk of future cardiovascular disease without additional cost and radiation exposure.

Background: Breast arterial calcifications (BAC) on mammography has been historically overlooked and underreported as an “incidental finding”. Due to the success of mammography as a screening platform and known gaps in cardiac screening for women, BAC presence and extent can potentially identify women that may benefit from enhanced cardiac screening and medical optimization.Methods: A set of 3558 Hologic Digital Breast Tomosynthesis (DBT) screening mammograms, including 394 cancer cases and 3164 noncancer cases from October 7, 2014 to April 16, 2021 across 3 healthcare systems were analyzed using a deep learning AI algorithm trained to detect BAC on 2D images from combo DBT or 2D synthetic images from DBT. Patients ranged from 35 to 94 years of age. The dataset was weighted relative to a screening population based on Breast Cancer Surveillance Consortium based on specific clinical characteristics, namely age, race, and mammographic density with a cancer incidence of 6/1000. The study assessed overall prevalence of BAC as well as distribution among women with cancer and without cancer and by race and age.The AI model was trained using an internal dataset of 2D/synthetic mammograms to detect BAC based on expert annotation and provides a BAC of present or absent. The accuracy of the AI model was validated on a data set of 2D mammograms from 8,881 women. Ther was no overlap in the training, validation and the 3558 women prospective study data sets.Results: The unweighted overall prevalence of BAC in this cancer enriched dataset of screening exams is 17.7%. When normalized by standard age, mammographic density, and racial demographic data with a cancer incidence of 6/1000, the (weighted) prevalence of BAC changed to 15.0%, which was used for subsequent analyses. BAC is present in mammogram exams in 33.9% of women with cancer and 14.8% of women without cancer. BAC prevalence per race in the screening adjusted dataset is 14.6% White, 17.7% Black, 13.9% Asian and 17.4% in other races. BAC prevalence per age group in the screening adjusted dataset is 3.7% in women <50 years old, 8.6% in 50-59, 17.3% in 60-69 and 37.4% in women 70 and older. When the age deciles were consolidated into two groups above and below age 60, the weighted BAC prevalence was 25% in patients age 60 or above and 6.5% below the age of 60.Conclusion: The weighted prevalence and distribution of BAC increases with age as expected in a screening population. Interestingly, BAC prevalence did not vary by race suggesting it could serve as an effective cardiovascular biomarker across racial groups. AI based BAC detection on mammography demonstrates high prevalence of BAC in women with mammographically detected breast cancer. Women with increased BAC and breast cancer may benefit from cardiovascular assessment in addition to undergoing oncological treatment. In that sense, a conventional mammogram can identify cardiac needs of patients prior to or at the time of breast cancer diagnosis. Citation Format: Chirag Parghi, Jennifer Pantleo, Jeff Hoffmeister, Julie Shisler, Wei Zhang, Avi Sharma, Zi Zhang. Use of an AI Algorithm to Determine the Prevalence of Breast Arterial Calcifications in Women Undergoing Screening Mammograms Based on Race, Age and Cancer Status [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-06-20.

Combined mammographic breast density and breast arterial calcification is incrementally predictive of coronary artery disease beyond traditional risk factors

Presence of breast arterial calcification (BAC) has been shown to be independently associated with increased risk of subclinical cardiovascular disease (CVD), angiographically-defined coronary disease and with incident coronary heart disease, stroke and heart failure. However, a relationship between BAC and peripheral vascular disease has not been established. The ankle brachial index (ABI) is an indicator of the severity of peripheral arterial disease (PAD) that predicts future CVD risk. We utilized cross-sectional data collected at the baseline examination (2012-15) of the MultIethNic Study of BrEast ARterial Calcium Gradation and CardioVAscular Disease (MINERVA Study), a cohort study of 5,145 post-menopausal women who were members of the Kaiser Permanente Medical Care Program of Northern California (KPNC) who were free of clinical CVD at baseline. Presence and gradation (in mg of calcium mass) of BAC in digital mammograms was ascertained with a validated densitometry method. ABI, the average of two ankle systolic pressure readings divided by the average of two brachial systolic pressure readings, was measured by trained and certified personnel after a ten-minute rest. A total of 3,693 women had complete data on all variables of interest; their mean (SD) age was 66 (4) years and 64% were white, 12% African-American, 14% Asian, 9% Latina and 1% mixed or other. While 28.2% presented with any detectable BAC (i.e., BAC mass > 0 mg), 5.4% had an ABI < 0.90. Three women had ABI>1.40 and were excluded from analyses (none had BAC>0). Prevalence of ABI < 0.90 was 4.8% (27/2,653) in women with BAC=0 and 6.9% (72/1,040) in women with any detectable BAC. The Odds Ratio of ABI<0.90 associated with any BAC was 1.39 (95% CI, 1.03-1.89) in a model adjusting for age and race/ethnicity, and was 1.38 (95% CI, 1.02-1.88) in a model with further adjustment for BMI, smoking status, diabetes, hypertension, LDL cholesterol, HDL cholesterol and hs-CRP. However, among women with any detectable BAC, standardized log_BAC mass (mg) was not significantly associated in bivariate linear regression analysis with ABI (slope=-0.0030 [SE=0.0031]; p=0.32). Our study demonstrates (for the first time) an independent association between presence of BAC and ABI indicative of PAD, with no apparent linear dose-response relationship.

Purpose: Mammographically detected breast arterial calcification (BAC) has been reported as a surrogate marker for coronary vascular disease (CVD). BAC is often not reported, reducing the power of this risk marker. Here we assess a deep-learning algorithm for BAC quantification, and in cases where the software identified BAC but the readers did not, assess correlation with clinical CVD. Methods: Screening digital mammograms (n=285, 1232 images) were selected from a tertiary Australian hospital from a sample of patients who underwent CVD screening (137 confirmed CVD). Two readers identified binary presence/absence of BAC. A deep learning software (cmAngio™ , CureMetrix, USA) quantified BAC score (scale 0-100). Reader-software discordance was adjudicated by a third observer. Area under the curve (AUC) was used to assess performance with 95% confidence intervals (CI) presented. Interobserver agreement was assessed by Cohen’s kappa (k). Results: Interobserver agreement for visual BAC was good (k=0.78, CI:0.71-0.85, p<0.01). BAC scores ranged from 0-100, with 12% scoring 0. The algorithm had high performance, AUC 0.92 (CI:0.88-0.96, p<0.001) vs initial reader assessment, increasing to AUC 0.98 (CI:0.97-0.99, p<0.001) after adjudicated assessment. At an empirical threshold of BAC score ≥5 to denote BAC presence, BAC prevalence was 38% (109/285) by software, and 31% (87/285) visually. In cases where only the software identified BAC (n=35), BAC scores were all <25, with 37% (n=13) having confirmed CVD and 9% (n=3) myocardial infarction. Conclusion: cmAngio demonstrates excellent performance for detecting BAC on screening mammograms. Faint BAC may be missed by human readers, is better identified by the software, and in these cases there is a high rate of CVD suggesting use in a screening population may improve risk prediction for CVD.

Introduction: Breast arterial calcifications (BAC) are a type of medial arterial calcification observed at mammography. They are more prevalent among diabetes patients and thought to be associated with increased cardiovascular risk, but high quality longitudinal studies are scarce. We aimed to investigate the association of BAC with risk of different types of cardiovascular outcomes. Methods: We performed a series of case-cohort studies nested within the PROSPECT-EPIC cohort, including a random subcohort (n = 1672), and incident cases of coronary heart disease (n=1050), stroke (n=399) peripheral artery disease (n=257), cardiovascular mortality (n=250), and type 2 diabetes (n=526). At baseline BAC was scored as absent, mild, moderate or severe by experienced radiologists. The average follow-up time was 12.0(±1.9) years. We calculated hazard ratios(HRs) using Cox proportional hazards models, adapted to the case-cohort design through Prentice-weighting and adjusting for traditional cardiovascular risk factors. Results: Of the women in the sub cohort with mammograms available (n=1540), 133 women (8.6%) had BAC in at least one breast. Grade was scored as mild in 75 women (4.9%), moderate in 39 women (2.5%) and severe in 19 women (1.2%). BAC presence was borderline significantly (0.05<p<0.10) associated with risk of coronary heart disease, stroke and cardiovascular mortality, with adjusted HR estimates ranging from 1.42 to 1.58. Much larger effect sizes were found for women with the most severe grade of BAC, as they had a HR of 3.43 (95% CI 1.85-6.37) for coronary heart disease, a HR of 3.19 (95% CI 1.52-6.72) for stroke, a HR of 2.92 (95%CI 1.02-8.35) for peripheral artery disease and a HR of 3.55 (95%CI 1.48-8.52) for cardiovascular mortality compared to women without BAC. Conclusions: BAC presence is modestly associated with cardiovascular disease, with an approximately 3-fold increased risk for the severest grade of BAC, independent of traditional risk factors. This indicates a possible contribution of a medial, non-atherosclerotic pathway to cardiovascular disease events. Whether BAC is a marker of medial arterial calcification in different vascular beds needs to be further investigated.

Breast arterial calcification (BAC), a common incidental finding in mammography, has been shown to be associated with angiographic coronary artery disease and cardiovascular disease (CVD) outcomes. We aimed to (1) examine the association of BAC presence and quantity with hard atherosclerotic CVD (ASCVD) and global CVD; (2) ascertain model calibration, discrimination and reclassification of ASCVD risk; (3) assess the joint effect of BAC presence and 10-year pooled cohorts equations risk on ASCVD. A cohort study of 5059 women aged 60-79 years recruited after attending mammography screening between October 2012 and February 2015 was conducted in a large health plan in Northern California, United States. BAC status (presence versus absence) and quantity (calcium mass mg) was determined using digital mammograms. Prespecified end points were incident hard ASCVD and a composite of global CVD. Twenty-six percent of women had BAC >0 mg. After a mean (SD) follow-up of 6.5 (1.6) years, we ascertained 155 (3.0%) ASCVD events and 427 (8.4%) global CVD events. In Cox regression adjusted for traditional CVD risk factors, BAC presence was associated with a 1.51 (95% CI, 1.08-2.11; P=0.02) increased hazard of ASCVD and a 1.23 (95% CI, 1.002-1.52; P=0.04) increased hazard of global CVD. While there was no evidence of dose-response association with ASCVD, a threshold effect was found for global CVD at very high BAC burden (95th percentile when BAC present). BAC status provided additional risk stratification of the pooled cohorts equations risk. We noted improvements in model calibration and reclassification of ASCVD: the overall net reclassification improvement was 0.12 (95% CI, 0.03-0.14; P=0.01) and the bias-corrected clinical-net reclassification improvement was 0.11 (95% CI, 0.01-0.22; P=0.04) after adding BAC status. Our results indicate that BAC has potential utility for primary CVD prevention and, therefore, support the notion that BAC ought to be considered a risk-enhancing factor for ASCVD among postmenopausal women.