BackgroundRecent randomized data suggest that calcium supplements may be associated with increased risk of cardiovascular disease (CVD) events. Using a longitudinal cohort study, we assessed the association between calcium intake, from both foods and supplements, and atherosclerosis, as measured by coronary artery calcification (CAC). Methods and ResultsWe studied 5448 adults free of clinically diagnosed CVD (52% female; aged 45–84 years) from the Multi‐Ethnic Study of Atherosclerosis. Baseline total calcium intake was assessed from diet (using a food frequency questionnaire) and calcium supplements (by a medication inventory) and categorized into quintiles. Baseline CAC was measured by computed tomography, and CAC measurements were repeated in 2742 participants ≈10 years later. At baseline, mean calcium intakes across quintiles were 313.3, 540.3, 783.0, 1168.9, and 2157.4 mg/day. Women had higher calcium intakes than men. After adjustment for potential confounders, among 1567 participants without baseline CAC, the relative risk (RR) of developing incident CAC over 10 years, by quintile 1 to 5 of calcium intake, were 1 (reference), 0.95 (0.79–1.14), 1.02 (0.85–1.23), 0.86 (0.69–1.05), and 0.73 (0.57–0.93). After accounting for total calcium intake, calcium supplement use was associated with increased risk for incident CAC (RR=1.22 [1.07–1.39]). No relation was found between baseline calcium intake and 10‐year changes in log‐transformed CAC among those participants with baseline CAC >0. ConclusionsHigh total calcium intake was associated with a decreased risk of incident atherosclerosis over long‐term follow‐up, particularly if achieved without supplement use. However, calcium supplement use may increase the risk for incident CAC.

The MESA (Multi-Ethnic Study of Atherosclerosis) was initiated to address unresolved questions about subclinical cardiovascular disease and its progression to clinically overt cardiovascular disease in a diverse population-based sample, incorporating emerging imaging technologies for better evaluation of subclinical disease and creating a population laboratory for future research. MESA's recruited (from 2000 to 2002) cohort comprised >6,000 adults from 4 racial/ethnic groups, ages 45 to 84 years, who were free of cardiovascular disease at baseline. Extensive cohort data have been collected over 5 exams (through 2011) with additional exam components added through extramurally funded ancillary study grants, and through regular phone follow-up contacts. Over 1,000 MESA papers have been published to date. Exam 6 will incorporate components that use novel wearable, imaging, and other technologies to address new research questions. MESA investigators have and continue to seek opportunities for collaboration with other researchers on a wide variety of topics to further expand the science of MESA.

Apolipoprotein L1 gene (APOL1) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans (AAs). Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin: creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2571 AAs from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary, or carotid artery revascularization) and CKD (eGFR under 60 ml/min per 1.73 m(2) and/or UACR over 30mg/g). AA SPRINT participants were 45.3% female with a mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100) mmHg, eGFR 76.3 (77.1) ml/min per 1.73 m(2), and UACR 49.9 (9.2) mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08-1.73) and log UACR estimated slope (beta) 0.33) and negatively associated with eGFR (beta - 3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82-1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not with prevalent CVD in AAs with a UACR under 1000 mg/g.

BACKGROUND Several studies have demonstrated the tremendous potential of using coronary artery calcium (CAC) in addition to traditional risk factors for coronary heart disease (CHD) risk prediction. However, to date, no risk score incorporating CAC has been developed.OBJECTIVES The goal of this study was to derive and validate a novel risk score to estimate 10-year CHD risk using CAC and traditional risk factors.METHODS Algorithm development was conducted in the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective community-based cohort study of 6,814 participants age 45 to 84 years, who were free of clinical heart disease at baseline and followed for 10 years. MESA is sex balanced and included 39% non-Hispanic whites, 12% Chinese Americans, 28% African Americans, and 22% Hispanic Americans. External validation was conducted in the HNR (Heinz Nixdorf Recall Study) and the DHS (Dallas Heart Study).RESULTS Inclusion of CAC in the MESA risk score offered significant improvements in risk prediction (C-statistic 0.80vs. 0.75; p < 0.0001). External validation in both the HNR and DHS studies provided evidence of very good discrimination and calibration. Harrell's C-statistic was 0.779 in HNR and 0.816 in DHS. Additionally, the difference in estimated 10-year risk between events and nonevents was approximately 8% to 9%, indicating excellent discrimination. Mean calibration, or calibration-in-the large, was excellent for both studies, with average predicted 10-year risk with in one-half of a percent of the observedevent rate.CONCLUSIONS An accurate estimate of 10-year CHD risk can be obtained using traditional risk factors and CAC. The MESA risk score, which is available online on the MESA web site for easy use, can be used to aid clinicians when communicating risk to patients and when determining risk-based treatment strategies. (C) 2015 by the American College of Cardiology Foundation.

IMPORTANCEMyocardial scarring leads to cardiac dysfunction and poor prognosis. The prevalence of and factors associated with unrecognized myocardial infarction and scar have not been previously defined using contemporary methods in a multiethnic US population.OBJECTIVETo determine prevalence of and factors associated with myocardial scar in middle- and older-aged individuals in the United States.DESIGN, SETTING, AND PARTICIPANTSThe Multi-Ethnic Study of Atherosclerosis (MESA) study is a population-based cohort in the United States. Participants were aged 45 through 84 years and free of clinical cardiovascular disease (CVD) at baseline in 2000-2002. In the 10th year examination (2010-2012), 1840 participants underwent cardiac magnetic resonance (CMR) imaging with gadolinium to detect myocardial scar. Cardiovascular disease risk factors and coronary artery calcium (CAC) scores were measured at baseline and year 10. Logistic regression models were used to estimate adjusted odds ratios (ORs) for myocardial scar.EXPOSURESCardiovascular risk factors, CAC scores, left ventricle size and function, and carotid intima-media thickness.MAIN OUTCOMES AND MEASURESMyocardial scar detected by CMR imaging.RESULTSOf 1840 participants (mean [SD] age, 68 [9] years, 52% men), 146 (7.9%) had myocardial scars, of which 114 (78%) were undetected by electrocardiogram or by clinical adjudication. In adjusted models, age, male sex, body mass index, hypertension, and current smoking at baseline were associated with myocardial scar at year 10. The OR per 8.9-year increment was 1.61 (95% CI, 1.36-1.91; P < .001); for men vs women: OR, 5.76 (95% CI, 3.61-9.17; P < .001); per 4.8-SD body mass index: OR, 1.32 (95% CI, 1.09-1.61, P = .005); for hypertension: OR, 1.61 (95% CI, 1.12-2.30; P = .009); and for current vs never smokers: 2.00 (95% CI, 1.22-3.28; P = .006). Age-, sex-, and ethnicity-adjusted CAC scores at baseline were also associated with myocardial scar at year 10. Compared with a CAC score of 0, the OR for scores from 1 through 99 was 2.4 (95% CI, 1.5-3.9); from 100 through 399, 3.0 (95% CI, 1.7-5.1), and 400 or higher, 3.3 (95% CI, 1.7-6.1) (P ≤ .001). The CAC score significantly added to the association of myocardial scar with age, sex, race/ethnicity, and traditional CVD risk factors (C statistic, 0.81 with CAC vs 0.79 without CAC, P = .01).CONCLUSIONS AND RELEVANCEThe prevalence of myocardial scars in a US community-based multiethnic cohort was 7.9%, of which 78% were unrecognized by electrocardiography or clinical evaluation. Further studies are needed to understand the clinical consequences of these undetected scars.

Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results.

Objectives: In the modern era existing risk scores are not well calibrated, and may overestimate or underestimate risk in different populations. Several studies have demonstrated the added value of coronary artery calcium (CAC) over and above traditional risk factors for risk prediction. Our goal was to develop a risk score to estimate 10-year CHD risk using CAC and traditional risk factors. Methods: The MESA study is a cohort of 6814 participants aged 45-84 and free of clinical heart disease at baseline (2000-2002) in which CAC (Agatston score) was measured. Incident coronary heart disease (CHD) events included myocardial infarction, CHD death, and angina when accompanied by revascularization. Penalized Cox regression models (“shrinkage” models) were used to perform variable selection and estimate the risk score coefficients. Covariates which were considered for inclusion in the risk score model were: age, gender, race/ethnicity, HDL and total cholesterol, lipid lowering medication use, systolic blood pressure (SBP), anti-hypertensive medication use, body mass index (BMI), current smoking, family history of heart attack, diabetes, and CAC. Pre-specified interactions considered included: age, gender, race/ethnicity and CAC with all other predictors; anti-hypertensive medications-by-SBP; and lipid lowering medications-by- total cholesterol. Bootstrapping was used to establish the internal validity of the model to avoid over-optimism. Results: Participants were followed for a median of 10.2 years, and 393 CHD events were observed. With the exception of BMI and diastolic blood pressure, all the risk factors were included in the risk score. The risk score demonstrates good discrimination and calibration, with survival adapted area under the ROC curve (AUC) of 0.81 and discrimination slope of 0.91. The model exhibits improved performance compared to existing risk scores, even after recalibration of traditional risk scores to the MESA population, which have yield an AUC for Framingham risk score of 0.72, and an AUC for traditional risk factors fit to MESA of 0.76. The improvement reflects both the addition of CAC and a tuning of the parameter estimates for the traditional risk factors. The MESA 10-year CHD risk calculator will be available online to facilitate clinical use. Conclusions: An accurate estimate of 10-year CHD risk can be obtained using traditional cardiovascular risk factors and CAC.

Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this set of trials. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one participant. Conclusion Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.

Introduction: Cardiovascular magnetic resonance (CMR) can accurately assess myocardial damage resulting in scar/ fibrosis. The relationship of coronary artery calcium (CAC) score to subclinical myocardial damage is unknown. Hypothesis: Our aim was to determine the associations between CAC score, cardiovascular disease (CVD) risk factors and myocardial scar in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods: MESA study is a large population based cohort free of clinical CVD at baseline. In the 10th year of follow up, 1840 participants underwent CMR with gadolinium to evaluate myocardial scar. CVD risk factors including CAC score were measured both at baseline and follow up. Logistic regression models were used to estimate odds ratios (ORs) for scar. Results: Of 1840 participants (mean age 68±9 yrs, 52% male), 146 had myocardial scars (7.9%). Most myocardial scars (115/146, 79%) were unrecognized by electrocardiogram or clinical assessment. Age and concurrent CAC score were the main predictors of ...

OBJECTIVES:The study examined whether progression of coronary artery calcium (CAC) is a predictor of future coronary heart disease (CHD) events. BACKGROUND:CAC predicts CHD events and serial measurement of CAC has been proposed to evaluate atherosclerosis progression. METHODS:We studied 6,778 persons (52.8% female) aged 45 to 84 years from the MESA (Multi-Ethnic Study of Atherosclerosis) study. A total of 5,682 persons had baseline and follow-up CAC scans approximately 2.5 ± 0.8 years apart; multiple imputation was used to account for the remainder (n = 1,096) missing follow-up scans. Median follow-up duration from the baseline was 7.6 (max = 9.0) years. CAC change was assessed by absolute change between baseline and follow-up CAC. Cox proportional hazards regression providing hazard ratios (HRs) examined the relation of change in CAC with CHD events, adjusting for age, gender, ethnicity, baseline calcium score, and other risk factors. RESULTS:A total of 343 and 206 hard CHD events occurred. The annual change in CAC averaged 24.9 ± 65.3 Agatston units. Among persons without CAC at baseline (n = 3,396), a 5-unit annual change in CAC was associated with an adjusted HR (95% Confidence Interval) of 1.4 (1.0 to 1.9) for total and 1.5 (1.1 to 2.1) for hard CHD. Among those with CAC >0 at baseline, HRs (per 100 unit annual change) were 1.2 (1.1 to 1.4) and 1.3 (1.1 to 1.5), respectively. Among participants with baseline CAC, those with annual progression of ≥300 units had adjusted HRs of 3.8 (1.5 to 9.6) for total and 6.3 (1.9 to 21.5) for hard CHD compared to those without progression. CONCLUSIONS:Progression of CAC is associated with an increased risk for future hard and total CHD events.

Author(s): Liu, Songtao; Liu, Chia-Ying; Han, Jing; Turkbey, Evrim B; Liu, Yuan; Bild, Diane; Arai, Andrew E; McClelland, Robyn; Hundley, W; Gomes, Antoinette S; Tracy, Russell; Kronmal, Richard; Lima, Joao A; Bluemke, David A

Coronary heart disease (CHD) incidence has declined significantly in the US, as have levels of major coronary risk factors, including LDL-cholesterol, hypertension and smoking, but whether trends in subclinical atherosclerosis mirror these trends is not known.To describe recent secular trends in subclinical atherosclerosis as measured by serial evaluations of coronary artery calcification (CAC) prevalence in a population over 10 years, we measured CAC using computed tomography (CT) and CHD risk factors in five serial cross-sectional samples of men and women from four race/ethnic groups, aged 55-84 and without clinical cardiovascular disease, who were members of Multi-Ethnic Study of Atherosclerosis (MESA) cohort from 2000 to 2012. Sample sizes ranged from 1062 to 4837. After adjusting for age, gender, and CT scanner, the prevalence of CAC increased across exams among African Americans, whose prevalence of CAC was 52.4% in 2000-02, 50.4% in 2003-04, 60.0% is 2005-06, 57.4% in 2007-08, and 61.3% in 2010-12 (p for trend <0.001). The trend was strongest among African Americans aged 55-64 [prevalence ratio for 2010-12 vs. 2000-02, 1.59 (95% confidence interval 1.06, 2.39); p = 0.005 for trend across exams]. There were no consistent trends in any other ethnic group. Risk factors generally improved in the cohort, and adjustment for risk factors did not change trends in CAC prevalence.There was a significant secular trend towards increased prevalence of CAC over 10 years among African Americans and no change in three other ethnic groups. Trends did not reflect concurrent general improvement in risk factors. The trend towards a higher prevalence of CAC in African Americans suggests that CHD risk in this population is not improving relative to other groups.

Introduction: Some reports indicate that calcium supplements are associated with adverse cardiovascular (CVD) events in post-menopausal women. We investigated the association between calcium supplements and CVD events in a multi-ethnic cohort. Methods: We studied 6,237 participants (2472 Caucasian, 790 Chinese, 1615 African-American, and 1360 Hispanic) in the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort study of adults, ages 45-84, free of clinical CVD who had data on dietary calcium intake, calcium supplements and covariates. Cox proportional hazard models were used to study the association between daily calcium supplements (none [reference], 1-500 mg, 500-1000 mg, and >1000 mg) and 6.1 year incident CVD events after adjusting for age, race, sex, education level, household income, site, total and HDL cholesterol, dietary calcium intake, lipid medication use, systolic blood pressure, anti-hypertensive medications, diabetes status, body mass index (BMI), estimated glomerular filtration rate (eGFR), physical activity, and smoking. Results: Calcium supplements were taken by 2,870 MESA participants. There were 357 CVD events over 6.1 years of follow up. The cumulative 6.1 year CVD event rate for calcium supplement was 5.5% versus 6.4% for non-users. Adjusted hazard ratio (HR, 95% CI) for incident CVD for any calcium supplementation versus none was 0.92 (0.74-1.14). HR's (95%CI) were: Calcium 1-500: 0.84 (0.64-1.08); Calcium 500-1000: 0.89 (0.58-1.32); and Calcium 1000 mg: 1.21 (0.84-1.70). In a similar separate analysis of postmenopausal women (n=2,703), calcium supplement, as in above-mentioned categories, was not associated with incident CVD events. Additionally, no significant interaction was noted between calcium supplements and incident CVD events by race or chronic kidney disease (CKD=eGFR ≤ 60 ml/min/1.73 m 2 ), (calcium x race, p=0.3; calcium x CKD, p=0.9). Conclusion: In this multi-ethnic observational cohort calcium supplementation was not associated with incident CVD events in either men or women including postmenopausal women.

Over the past 60 years, revolutionary discoveries made by epidemiologists have contributed to marked declines in cardiovascular disease morbidity and mortality. Now, in an era of increasingly constrained resources, researchers in cardiovascular epidemiology face a number of challenges that call for novel, paradigm-shifting approaches. In this paper, the authors pose to the community 4 critical questions: 1) How can we avoid wasting resources on studies that provide little incremental knowledge? 2) How can we assure that we direct our resources as economically as possible towards innovative science? 3) How can we be nimble, responding quickly to new opportunities? 4) How can we identify prospectively the most meritorious research questions? Senior program staff at the National Heart, Lung, and Blood Institute invite the epidemiology community to join them in an ongoing Web-based blog conversation so that together we might develop novel approaches that will facilitate the next generation of high-impact discoveries.

Background—Coronary artery calcium (CAC), carotid intima-media thickness, and left ventricular (LV) mass and geometry offer the potential to characterize incident cardiovascular disease (CVD) risk in clinically asymptomatic individuals. The objective of the study was to compare these cardiovascular imaging measures for their overall and sex-specific ability to predict CVD. Methods and Results—The study sample consisted of 4965 Multi-Ethnic Study of Atherosclerosis participants (48% men; mean age, 62 10 years). They were free of CVD at baseline and were followed for a median of 5.8 years. There were 297 CVD events, including 187 coronary heart disease (CHD) events, 65 strokes, and 91 heart failure (HF) events. CAC was most strongly associated with CHD (hazard ratio [HR], 2.3 per 1 SD; 95% CI, 1.9 to 2.8) and all CVD events (HR, 1.7; 95% CI, 1.5 to 1.9). Most strongly associated with stroke were LV mass (HR, 1.3; 95% CI, 1.1 to 1.7) and LV mass/volume ratio (HR, 1.3; 95% CI, 1.1 to 1.6). LV mass showed the strongest association with HF (HR, 1.8; 95% CI, 1.6 to 2.1). There were no significant interactions for imaging measures with sex and ethnicity for any CVD outcome. Compared with traditional risk factors alone, overall risk prediction (C statistic) for future CHD, HF, and all CVD was significantly improved by adding CAC, LV mass, and CAC, respectively (all P 0.05). Conclusions—There was no evidence that imaging measures differed in association with incident CVD by sex. CAC was most strongly associated with CHD and CVD; LV mass and LV concentric remodeling best predicted stroke; and LV mass best predicted HF. (Circ Cardiovasc Imaging. 2011;4:8-15.)

Objectives By examining the distribution of coronary artery calcium (CAC) levels across Framingham risk score (FRS) strata in a large, multiethnic, community-based sample of men and women, we sought to determine if lower-risk persons could benefit from CAC screening.Background The 10-year FRS and CAC levels are predictors of coronary heart disease. A CAC level of 300 or more is associated with the highest risk for coronary heart disease even in low-risk persons (FRS, <10%); however, expert groups have suggested CAC screening only in intermediate-risk groups (FRS, 10% to 20%).Methods We included 5,660 Multi-Ethnic Study of Atherosclerosis participants. The number needed to screen (number of people that need to be screened to detect 1 person with CAC level above the specified cutoff point) was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using chi-square tests.Results CAC levels of more than 0, of 100 or more, and of 300 or more were present in 46.4%, 20.6%, and 10.1% of participants, respectively. The prevalence and amount of CAC increased with higher FRS. A CAC level of 300 or more was observed in 1.7% and 4.4% of those with FRS of 0% to 2.5% and of 2.6% to 5%, respectively (number needed to screen, 59.7 and 22.7, respectively). Likewise, a CAC level of 300 or more was observed in 24% and 30% of those with FRS of 15.1% to 20% and more than 20%, respectively (number needed to screen, 4.2 and 3.3, respectively). Trends were similar when stratified by age, sex, and race or ethnicity.Conclusions Our study suggests that in very low-risk individuals (FRS <= 5%), the yield of screening and probability of identifying persons with clinically significant levels of CAC is low, but becomes greater in low-and intermediate-risk persons (FRS 5.1% to 20%). (J Am Coll Cardiol 2011; 57: 1838-45) (C) 2011 by the American College of Cardiology Foundation