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1.  Expert review on coronary calcium 
While there is no doubt that high risk patients (those with >20% ten year risk of future cardiovascular event) need more aggressive preventive therapy, a majority of cardiovascular events occur in individuals at intermediate risk (10%–20% ten year risk). Accurate risk assessment may be helpful in decreasing cardiovascular events through more appropriate targeting of preventive measures. It has been suggested that traditional risk assessment may be refined with the selective use of coronary artery calcium (CAC) or other methods of subclinical atherosclerosis measurement. Coronary calcification is a marker of atherosclerosis that can be quantified with the use of cardiac CT and it is proportional to the extent and severity of atherosclerotic disease. The published studies demonstrate a high sensitivity of CAC for the presence of coronary artery disease but a lower specificity for obstructive CAD depending on the magnitude of the CAC. Several large clinical trials found clear, incremental predictive value of CAC over the Framingham risk score when used in asymptomatic patients. Based on multiple observational studies, patients with increased plaque burdens (increased CAC) are approximately ten times more likely to suffer a cardiac event over the next 3–5 years. Coronary calcium scores have outperformed conventional risk factors, highly sensitive C-reactive protein (CRP) and carotid intima media thickness (IMT) as a predictor of cardiovascular events. The relevant prognostic information obtained may be useful to initiate or intensify appropriate treatment strategies to slow the progression of atherosclerotic vascular disease. Current data suggests intermediate risk patients may benefit most from further risk stratification with cardiac CT, as CAC testing is effective at identifying increased risk and in motivating effective behavioral changes. This article reviews information pertaining to the clinical use of CAC for assessing coronary atherosclerosis as a useful predictor of coronary artery disease (CAD) in certain population of patients.
PMCID: PMC2496978  PMID: 18561507
computed tomography; electron beam; prognosis; review; coronary artery calcification; calcium score; atherosclerosis; multi-detector computed tomography
2.  Calcium Density of Coronary Artery Plaque and Risk of Incident Cardiovascular Events 
Coronary artery calcium (CAC), measured by computed tomography (CT), has strong predictive value for incident cardiovascular disease (CVD) events. The standard CAC score is the Agatston, which is weighted upward for greater calcium density. However, some data suggest increased plaque calcium density may be protective for CVD.
To determine the independent associations of CAC volume and CAC density with incident CVD events.
Design, Setting, and Participants
Multicenter, prospective observational MESA study (Multi-Ethnic Study of Atherosclerosis), conducted at 6 US field centers of 3398 men and women from 4 race/ethnicity groups; non-Hispanic white, African American, Hispanic, and Chinese. Participants were aged 45-84 years, free of known CVD at baseline, had CAC greater than 0 on their baseline CT, and were followed up through October 2010.
Main Outcomes and Measures
Incident coronary heart disease (CHD) and all CVD events
During a median of 7.6 years of follow-up, there were 175 CHD events and an additional 90 other CVD events for a total of 265 CVD events. With both lnCAC volume and CAC density scores in the same multivariable model, the lnCAC volume score showed an independent association with incident CHD, with a hazard ratio (HR) of 1.81 (95% CI, 1.47-2.23) per standard deviation (SD = 1.6) increase, absolute risk increase 6.1 per 1000 person-years, and for CVD an HR of 1.68 (95% CI, 1.42-1.98) per SD increase, absolute risk increase 7.9 per 1000 person-years. Conversely, the CAC density score showed an independent inverse association, with an HR of 0.73 (95% CI, 0.58-0.91) per SD (SD = 0.7) increase for CHD, absolute risk decrease 5.5 per 1000 person-years, and an HR of 0.71 (95% CI, 0.60-0.85) per SD increase for CVD, absolute risk decrease 8.2 per 1000 person years. Area under the receiver operating characteristic curve analyses showed significantly improved risk prediction with the addition of the density score to a model containing the volume score for both CHD and CVD. In the intermediate CVD risk group, the area under the curve for CVD increased from 0.53 (95% CI, 0.48-0.59) to 0.59 (95% CI, 0.54-0.64), P = .02.
Conclusions and Relevance
CAC volume was positively and independently associated with CHD and CVD risk. At any level of CAC volume, CAC density was inversely and significantly associated with CHD and CVD risk. The role of CAC density should be considered when evaluating current CAC scoring systems.
PMCID: PMC4091626  PMID: 24247483
3.  Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate Risk Individuals. The Multi-Ethnic Study of Atherosclerosis 
Risk markers including coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial Index (ABI), brachial flow-mediated dilation (FMD), high sensitivity C -reactive protein (hs-CRP) and family history (FH) of coronary heart disease (CHD) have been reported to improve on the Framingham risk score (FRS) for prediction of CHD. However, there are no direct comparisons of these markers for risk prediction in a single cohort.
We compared improvement in prediction of incident CHD/cardiovascular disease (CVD) of these 6 risk markers within intermediate risk participants (5 % < FRS < 20%) in the Multi-Ethnic Study of Atherosclerosis (MESA).
Design, Setting and Participants
Of 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2011. Probability- weighted Cox proportional hazard models were used to estimate hazard ratios (HR). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare incremental contributions of each marker when added to the FRS + race/ethnicity.
Main Outcome Measures
Incident CHD defined as MI, angina followed by revascularization, resuscitated cardiac arrest or CHD death. Incident CVD additionally included stroke or CVD death.
After median follow-up of 7.6 years (IQR 7.3 – 7.8 years), 94 CHD and 123 CVD events occurred. CAC, ABI, hs-CRP and FH were independently associated with incident CHD in multivariable analyses [HR (95%CI: 2.60(1.94-3.50), 0.79(0.66-0.95), 1.28(1.00-1.64) and 2.18(1.38-3.42) respectively]. CIMT and FMD were not associated with incident CHD in multivariable analyses [HR (95%CI) 1.17(0.95- 1.45) and 0.95(0.78 −1.14) respectively]. Although the addition of the markers individually to the FRS +race/ethnicity improved the AUC, CAC afforded the highest increment (0.623 vs. 0.784) while FMD afforded the least [0.623 vs. 0.639]. For incident CHD, the NRI with CAC was 0.659, FMD 0.024, ABI 0.036, CIMT 0.102, FH 0.160 and hs-CRP 0.079. Similar results were obtained for incident CVD.
CAC, ABI, hs-CRP and FH are independent predictors of incident CHD/CVD in intermediate risk individuals. CAC provides superior discrimination and risk reclassification compared with other risk markers.
PMCID: PMC4141475  PMID: 22910756
4.  Coronary calcium predicts events better with absolute calcium scores than age-gender-race percentiles – The Multi-Ethnic Study of Atherosclerosis (MESA) 
The presence and extent of coronary artery calcium (CAC) correlates with the overall magnitude of coronary atherosclerotic plaque burden and with the development of subsequent coronary events. In this study we aim to establish whether age-gender specific percentiles of CAC predict cardiovascular outcomes better than the actual (absolute) CAC score.
MESA is a prospective cohort study of asymptomatic 6814 participants, followed for coronary heart disease (CHD) events including myocardial infarction, angina, resuscitated cardiac arrest, or CHD death. Time to incident CHD was modeled using Cox regression, and we compared models using percentiles based on age, gender and/or race/ethnicity to categories commonly used(0, 1-100, 101-400, 400+ Agatston units).
There were 163(2.4%) incident CHD events (median follow-up 3.75 years). Expressing CAC in terms of age and gender specific percentiles had significantly lower area under the ROC curve(AUC) than using absolute scores (women: AUC 0.73 versus 0.76,p=0.044; men: AUC 0.73 versus 0.77,p<0.001). Akaike’s information criterion (AIC) indicated better model fit using the overall score. Both methods robustly predicted events(>90th percentile associated with a hazard ratio(HR) of 16.4(95% c.i. 9.30,28.9), and score >400 associated with HR of 20.6(95% c.i. 11.8, 36.0). Within groups based on age/gender/race/ethnicity specific percentiles there remains a clear trend of increasing risk across levels of the absolute CAC groups. In contrast, once absolute CAC category is fixed, there is no increasing trend across levels of age/gender/race/ethnicity specific categories. Patients with low absolute scores are low risk, regardless of age-gender-ethnicity percentile rank. Persons with an absolute CAC score of >400 are high risk, regardless of percentile rank.
Using absolute CAC in standard groups performed better than age-gender-ethnicity percentiles in terms of model fit and discrimination. We recommend using cut-points based on the absolute CAC amount and the common CAC cutpoints of 100 and 400 appear to perform well.
PMCID: PMC2652569  PMID: 19161884
prognosis; atherosclerosis; cardiac CT; coronary calcium
5.  Interrelation of Coronary Calcification, Myocardial Ischemia, and Outcomes in Patients With Intermediate Likelihood of Coronary Artery Disease 
Circulation  2008;117(13):1693-1700.
Although the value of coronary artery calcium (CAC) for atherosclerosis screening is gaining acceptance, its efficacy in predicting flow-limiting coronary artery disease remains controversial, and its incremental prognostic value over myocardial perfusion is not well established.
Methods and Results
We evaluated 695 consecutive intermediate-risk patients undergoing combined rest-stress rubidium 82 positron emission tomography (PET) perfusion imaging and CAC scoring on a hybrid PET-computed tomography (CT) scanner. The frequency of abnormal scans among patients with a CAC score ≥400 was higher than that in patients with a CAC score of 1 to 399 (48.5% versus 21.7%, P<0.001). Multivariate logistic regression supported the concept of a threshold CAC score ≥400 governing this relationship (odds ratio 2.91, P<0.001); however, the frequency of ischemia among patients with no CAC was 16.0%, and its absence only afforded a negative predictive value of 84.0%. Risk-adjusted survival analysis demonstrated a stepwise increase in event rates (death and myocardial infarction) with increasing CAC scores in patients with and without ischemia on PET myocardial perfusion imaging. Among patients with normal PET myocardial perfusion imaging, the annualized event rate in patients with no CAC was lower than in those with a CAC score ≥1000 (2.6% versus 12.3%, respectively). Likewise, in patients with ischemia on PET myocardial perfusion imaging, the annualized event rate in those with no CAC was lower than among patients with a CAC score ≥1000 (8.2% versus 22.1%).
Although increasing CAC content is generally predictive of a higher likelihood of ischemia, its absence does not completely eliminate the possibility of flow-limiting coronary artery disease. Importantly, a stepwise increase occurs in the risk of adverse events with increasing CAC scores in patients with and without ischemia on PET myocardial perfusion imaging.
PMCID: PMC3955029  PMID: 18362235
calcium; ischemia; perfusion; imaging; prognosis
6.  Association between Red Blood Cell Distribution Width and Coronary Artery Calcification in Patients Undergoing 64-Multidetector Computed Tomography 
Korean Circulation Journal  2015;45(5):372-377.
Background and Objectives
The red blood cell distribution width (RDW) has been found to be associated with cardiovascular morbidity and mortality. The objective of this study was to determine whether the RDW measures are associated with the coronary artery calcification score (CACS) in patients who did not present with obvious coronary heart disease (CHD).
Subjects and Methods
A total of 527 consecutive patients with a low to intermediate risk for CHD but without obvious disease were enrolled in this study. The study subjects underwent coronary computerized tomography angiography and CACS was calculated. The patients were divided into two groups based on CACS: Group I (CACS≤100) and Group II (CACS>100). The two groups were compared in terms of classic CHD risk factors and haematological parameters, particularly the RDW.
Group I patients were younger than Group II patients. The Framingham risk score (FRS) in patients of Group II was significantly higher than that in patients of Group I. Group II patients had significantly elevated levels of haemoglobin, RDW, neutrophil count, and neutrophil/lymphocyte ratio compared with Group I patients. CACS was correlated with age, RDW, and ejection fraction. In the multivariate analysis, age, RDW, and FRS were independent predictors of CACS. Using the receiver-operating characteristic curve analysis, a RDW value of 13.05% was identified as the best cut-off for predicting the severity of CACS (>100) (area under the curve=0.706).
We found that the RDW is an independent predictor of the CACS, suggesting that it might be a useful marker for predicting CAD.
PMCID: PMC4580695  PMID: 26413104
Coronary artery calcification score; Coronary computerized tomography angiography; Red blood cell distribution width
7.  Computed Tomography-Derived Cardiovascular Risk Markers, Incident Cardiovascular Events, and All-Cause Mortality in Non- Diabetics. The Multi-Ethnic Study of Atherosclerosis 
We assess the improvement in discrimination afforded by the addition thoracic aorta calcium (TAC), aortic valve calcification (AVC), mitral annular calcification (MAC), pericardial adipose tissue volume (PAT) and liver attenuation (LA) to Framingham risk score(FRS) + coronary artery calcium (CAC) for incident CHD/CVD in a multi ethnic cohort.
Methods and Results
A total 5745(2710 were intermediate Framingham risk, 210 CVD and 155 CHD events) 251 had adjudicated CHD, 346 had CVD events, 321 died after 9 years of follow-up. Cox proportional hazard, receiver operator curve (ROC) and net reclassification improvement (NRI) analyses.
In the whole cohort and also when the analysis was restricted to only the intermediate risk participants: CAC, TAC, AVC and MAC were all significantly associated with incident CVD/CHD/ mortality; CAC had the strongest association. When added to the FRS, CAC had the highest area under the curve (AUC) for the prediction of incident CHD/CVD; LA had the least. The addition of TAC, AVC, MAC, PAT and LA to FRS + CAC all resulted in a significant reduction in AUC for incident CHD [0.712 vs. 0.646, 0.655, 0.652, 0.648 and 0.569; all p<0.01 respectively] in participants with intermediate FRS. The addition of CAC to FRS resulted in an NRI of 0.547 for incident CHD in the intermediate risk group. The NRI when TAC, AVC, MAC, PAT and LA were added to FRS + CAC were 0.024, 0.026, 0.019, 0.012 and 0.012 respectively, for incident CHD in the intermediate risk group. Similar results were obtained for incident CVD in the intermediate risk group and also when the whole cohort was used instead of the intermediate FRS group.
The addition of CAC to the FRS provides superior discrimination especially in intermediate risk individuals compared with the addition of TAC, AVC, MAC, PAT or LA for incident CHD/CVD. Compared with FRS + CAC, the addition of TAC, AVC, MAC, PAT or LA individually to FRS + CAC worsens the discrimination for incident CHD/CVD. These CT risk markers are unlikely to be useful for improving cardiovascular risk prediction.
PMCID: PMC4150859  PMID: 23689526
cardiac CT derived risk factors; coronary heart disease; cardiovascular events; risk prediction
8.  Carotid artery evaluation and coronary calcium score: which is better for the diagnosis and prevention of atherosclerotic cardiovascular disease? 
In recent clinical practice guidelines for risk assessment for a first atherosclerotic cardiovascular disease (ASCVD) event, it is not routinely recommended to measure carotid intima-media thickness (CIMT) or the coronary calcium score (CACS). The aim of this study was to elucidate the effect of combining carotid artery evaluation and CACS as surrogate markers or predictive values. A total of 938 patients (562 male (59.9%), mean age 61.5±11.6 years) with ASCVD (n=690) or without (n=248) were enrolled in this study. The diagnosis of ASCVD was established with CT angiography. These patients had undergone carotid scanning (HP Sonos-5500; Philips, Bothell, WA, USA) at St. Mary’s Hospital between September 2003 and March 2009. ASCVD outcomes were evaluated with a median follow-up of 1451 days. Thirty participants experienced initial ASCVD events during this study. Another 118 patients suffered secondary ASCVD events. After propensity score matching, multivariate analysis revealed that CACS was associated with ASCVD [Odds ratio 1.002, 95% confidence interval (CI) 1.002-1.003, P<0.001]. For primary prevention in patients without ASCVD, we found that carotid plaques [Hazard ratio (HR) 2.409, 95% CI 1.093-5.309, P=0.029] are also associated with ASCVD events. Carotid plaques are also associated with ASCVD events with regard to secondary prevention [HR 1.723, 95% CI 1.188-2.499, P=0.004] in patients with ASCVD. We propose that CACS assessment is useful in the diagnosis of, and as a surrogate marker of ASCVD in patients with risk factors. Our results also suggest that carotid artery evaluation may have a valuable predictive method in primary and secondary ASCVD prevention and risk assessment. Therefore, although there are no synergic effects of combining carotid artery evaluation and CACS, carotid ultrasound seems to be a better predictive method for assessing ASCVD events than CACS.
PMCID: PMC4694372  PMID: 26770472
Carotid plaque; coronary calcium score; atherosclerotic cardiovascular event; primary or secondary prevention
9.  Apolipoprotein B but not LDL Cholesterol Is Associated With Coronary Artery Calcification in Type 2 Diabetic Whites 
Diabetes  2009;58(8):1887-1892.
Evidence favors apolipoprotein B (apoB) over LDL cholesterol as a predictor of cardiovascular events, but data are lacking on coronary artery calcification (CAC), especially in type 2 diabetes, where LDL cholesterol may underestimate atherosclerotic burden. We investigated the hypothesis that apoB is a superior marker of CAC relative to LDL cholesterol.
We performed cross-sectional analyses of white subjects in two community-based studies: the Penn Diabetes Heart Study (N = 611 type 2 diabetic subjects, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (N = 803 nondiabetic subjects, 52.8% men) using multivariate analysis of apoB and LDL cholesterol stratified by diabetes status.
In type 2 diabetes, apoB was associated with CAC after adjusting for age, sex, and medications [Tobit regression ratio of increased CAC for 1-SD increase in apoB; 1.36 (95% CI 1.06–1.75), P = 0.016] whereas LDL cholesterol was not [1.09 (0.85–1.41)]. In nondiabetic subjects, both were associated with CAC [apoB 1.65 (1.38–1.96), P < 0.001; LDL cholesterol 1.56 (1.30–1.86), P < 0.001]. In combined analysis of diabetic and nondiabetic subjects, apoB provided value in predicting CAC scores beyond LDL cholesterol, total cholesterol, the total cholesterol/HDL cholesterol and triglyceride/HDL cholesterol ratios, and marginally beyond non-HDL cholesterol.
Plasma apoB, but not LDL cholesterol, levels were associated with CAC scores in type 2 diabetic whites. ApoB levels may be particularly useful in assessing atherosclerotic burden and cardiovascular risk in type 2 diabetes.
PMCID: PMC2712798  PMID: 19491209
10.  Arterial Age as a Function of Coronary Artery Calcium (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
It has been proposed that coronary artery calcium (CAC) can be used to estimate an arterial age in adults. Supporting this concept is that chronologic age, as used in cardiovascular risk assessment, is a surrogate for atherosclerotic burden. This measure can provide the patient with a more understandable version of their CAC score (e.g. you are 55 years old, but your arteries are more consistent with an arterial age of 65). We describe a method of estimating arterial age by equating estimated coronary heart disease (CHD) risk for observed age and coronary artery calcium (CAC). Arterial age is then the risk-equivalent of coronary artery calcium. We use data from the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 participants free of clinical cardiovascular disease, followed for an average of 4 years. Estimated arterial age is obtained as a simple linear function of log-transformed CAC. In a model for incident CHD risk controlling for both age and arterial age, only arterial age was significant, indicating that observed age does not provide additional information after controlling for arterial age. Framingham risk calculated using this arterial age is more predictive of short-term incident coronary events than Framingham risk based on observed age (area under the ROC curve 0.75 for Framingham risk based on observed age, 0.79 using arterial age, p=0.006). In conclusion, arterial age provides a convenient transformation of CAC from Agatston units to a scale more easily appreciated by both patients and treating physicians.
PMCID: PMC2621006  PMID: 19101230
11.  Coronary Artery Calcium and Incident Cerebrovascular Events in an Asymptomatic Multi Ethnic Cohort. MESA 
JACC. Cardiovascular imaging  2014;7(11):1108-1115.
We assessed the predictive value of coronary artery calcium (CAC) score for CVA events in an asymptomatic multi-ethnic cohort.
The coronary artery calcium (CAC) score, a measure of atherosclerotic burden, has been shown to improve prediction of coronary heart disease events. However, the predictive value of CAC for cerebrovascular (CVA) events is unclear.
CAC was measured at baseline exam of participants (N=6779) of the Multi Ethnic Study of atherosclerosis (MESA) and then followed for an average of 9.5(2.4) years for the diagnosis of incident CVA defined as all strokes or TIAs.
During the follow up 234(3.5%) adjudicated CVA events occurred. In Kaplan Meier analysis the presence of CAC was associated with a lower CVA event - free survival versus CAC absent (Log rank χ2 = 59.8, p<0.0001). Log transformed CAC was associated with increased risk for CVA after adjusting for age, gender, race/ethnicity, BMI, systolic and diastolic blood pressure, total cholesterol, HDL-C, cigarette smoking status, blood pressure medication use, statin use and interim atrial fibrillation[hazard ratio(95% CI): 1.13(1.07 – 1.20),p<0.0001]. The ACC/AHA recommended CAC cut off was also an independent predictor of CVA and strokes [HR (95%CI): 1.70(1.24–2.35),p=0.001 and 1.59(1.11–2.27), p=0.01 respectively]. CAC was an independent predictor of CVA when analysis was stratified by gender or race/ethnicity, and improved discrimination for CVA when added to the full model (c statistic: 0.744 vs. 0.755). CAC also improved the discriminative ability of the Framingham stroke risk score for CVA.
CAC is an independent predictor of CVA events, and improves the discrimination afforded by current stroke risk factors or the Framingham stroke risk score for incident CVA in an initially asymptomatic multi-ethnic adult cohort.
PMCID: PMC4254694  PMID: 25459592
Coronary artery calcium score; cerebrovascular disease; risk prediction; prevention
12.  Computed Tomographic Coronary Artery Calcium Assessment for Evaluating Chest Pain in the Emergency Department: Long-term Outcome of a Prospective Blind Study 
Mayo Clinic Proceedings  2010;85(4):314-322.
OBJECTIVE: To determine the long-term outcome of computed tomographic (CT) quantification of coronary artery calcium (CAC) used as a triage tool for patients presenting with chest pain to an emergency department (ED).
PATIENTS AND METHODS: Patients (men aged 30-62 years and women aged 30-65 years) with chest pain and low-to-moderate probability of coronary artery disease underwent both conventional ED chest pain evaluation and CT CAC assessment prospectively. Patients' physicians were blinded to the CAC results. The results of the conventional evaluation were compared with CAC findings on CT, and the long-term outcome in patients undergoing CT CAC assessment was established. Primary end points (acute coronary syndrome, death, fatal or nonfatal non–ST-segment elevation myocardial infarction, fatal or nonfatal ST-segment elevation myocardial infarction) and secondary outcomes (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, coronary stenting, or a combination thereof) were obtained when the patient was dismissed from the ED or hospital and then at 30 days, 1 year, and 5 years.
RESULTS: Of the 263 study patients, 133 (51%) had a CAC score of zero. This absence of CAC correlated strongly with the likelihood of noncardiac chest pain. Among 133 patients with a CAC score of zero, only 1 (<1%) had cardiac chest pain. Conversely, of the 31 patients shown to have cardiac chest pain, 30 (97%) had evidence of CAC on CT. When a CAC cutoff score of 36 was used, as suggested by receiver operating characteristic analysis, sensitivity was 90%; specificity, 85%; positive predictive value, 44%; and negative predictive value, 99%. During long-term follow-up, patients without CAC experienced no cardiac events at 30 days, 1 year, and 5 years.
CONCLUSION: Findings suggest that CT CAC assessment is a powerful adjunct in chest pain evaluation for the population at low-to-intermediate risk. Absent or minimal CAC in this population makes cardiac chest pain extremely unlikely. The absence of CAC suggests an excellent long-term (5-year) prognosis, with no primary or secondary cardiac outcomes ocurring in study patients at 5-year follow-up.
Computed tomographic coronary artery calcium assessment is a powerful adjunct in evaluation of chest pain for the population at low-to-intermediate risk; the absence of coronary artery calcium in this population makes cardiac chest pain extremely unlikely and suggests an excellent 5-year prognosis.
PMCID: PMC2848419  PMID: 20360291
13.  Relationship between Coronary Artery and Descending Thoracic Aortic Calcification as Detected by Computed Tomography: the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;204(2):440-446.
Cardiac computed tomography (CT) is a well-established tool for the detection of cardiovascular calcium. Coronary artery calcification (CAC) is highly sensitive for the detection of coronary artery disease (CAD) as well as predictive of future cardiovascular (CV) events. Descending thoracic aortic calcification (DTAC) is common in the elderly and its presence is also associated with increased risk of CV events. Previous studies demonstrate that DTAC is associated with obstructive CAD and coronary risk factors. However, no prior studies have examined the association of CAC and DTAC as detected by cardiac CT in a large population-based cohort.
In the Multi-Ethnic Study of Atherosclerosis, the study population included a population based sample of four ethnic groups (Chinese, White, Hispanic and African-American) of 6814 women and men ages 45−84 years old. Participants underwent non-enhanced cardiac CT and both CAC and DTAC were quantified. DTAC was measured from the lower edge of the pulmonary artery bifurcation to the cardiac apex. Multivariable relative risk regression was used to evaluate relationships between CAC, DTAC and measured cardiovascular risk factors.
Overall 3030 (44%) did not demonstrate any detectable CAC or DTAC. A total of 1930 (28%) had only CAC, 386 (6%) had isolated DTAC, and 1464 (22%) participants were found to have both CAC and DTAC. CAC had a higher prevalence than DTAC in men (58% vs. 45%). Participants with DTAC were older than those with CAC (mean age was 71 and 66 years old, respectively). Participants with DTAC had increased risk for the presence of CAC independent of cardiovascular risk factors (prevalence ratio [PR]; 1.17 95% CI 1.07−1.28). Severity of DTAC was a stronger predictor of the presence of CAC in women as compared to men (PR; 1.04 95% CI 1.02 −1.06, and PR; 0.99 95% CI 0.98− 1.01, respectively).
DTAC was found to be a strong predictor of CAC independent of CV risk factors. Ongoing follow-up of this cohort will evaluate whether DTAC is an independent marker of risk for CV events.
PMCID: PMC2732017  PMID: 19027115
14.  The General Cardiovascular Risk Profile Identifies Advanced Coronary Artery Calcium and is Improved by Family History. The Multi-Ethnic Study of Atherosclerosis 
The General Cardiovascular Risk Profile (GCRP) is a multivariable model that predicts global cardiovascular disease risk. Our goal was to assess the ability of the GCRP to identify individuals with advanced coronary artery calcification (CAC), and determine whether identification is improved with family history.
Methods and Results
Using data from the Multi-Ethnic Study of Atherosclerosis, three sex-specific models were developed with ordinal logistic regressions to relate risk factors to CAC scores. Model 1 included covariates in the GCRP. Then family history was added, defined as having at least one first-degree relative with premature coronary heart disease (CHD) (Model 2), or as a weak, moderate or strong family history based on number of relatives with CHD, age at onset, and presence of stroke or diabetes in the family (Model 3). For each model, we estimated mathematical CAC risk functions, derived CAC score sheets, evaluated the ability to discriminate persons having positive CAC scores, and assessed reclassification of individuals with low, intermediate, or high probability of CAC >300. Model 1 worked well to identify women and men with positive CAC scores; c-statistics were 0.752 and 0.718 and X2 values were 821.2 (p<0.0001) and 730.6 (p<0.0001), respectively. Addition of family history improved discrimination and fit of Model 1. However, reclassification of participants with advanced CAC was significantly improved with Model 3 only.
The GCRP identifies advanced CAC, an emerging indication for aggressive risk factor modification. Incorporation of family history, especially comprehensive familial risk stratification, provides incremental prognostic value.
PMCID: PMC2932659  PMID: 20160201
coronary artery calcium; family history; risk factors
15.  Cost-Effectiveness of Coronary Artery Calcium Testing for Coronary Heart and Cardiovascular Disease Risk Prediction to Guide Statin Allocation: The Multi-Ethnic Study of Atherosclerosis (MESA) 
PLoS ONE  2015;10(3):e0116377.
The Multi-Ethnic Study of Atherosclerosis (MESA) showed that the addition of coronary artery calcium (CAC) to traditional risk factors improves risk classification, particularly in intermediate risk asymptomatic patients with LDL cholesterol levels <160 mg/dL. However, the cost-effectiveness of incorporating CAC into treatment decision rules has yet to be clearly delineated.
To model the cost-effectiveness of CAC for cardiovascular risk stratification in asymptomatic, intermediate risk patients not taking a statin. Treatment based on CAC was compared to (1) treatment of all intermediate-risk patients, and (2) treatment on the basis of United States guidelines.
We developed a Markov model of first coronary heart disease (CHD) and cardiovascular disease (CVD) events. We modeled statin treatment in intermediate risk patients with CAC≥1 and CAC≥100, with different intensities of statins based on the CAC score. We compared these CAC-based treatment strategies to a “treat all” strategy and to treatment according to the Adult Treatment Panel III (ATP III) guidelines. Clinical and economic outcomes were modeled over both five- and ten-year time horizons. Outcomes consisted of CHD and CVD events and Quality-Adjusted Life Years (QALYs). Sensitivity analyses considered the effect of higher event rates, different CAC and statin costs, indirect costs, and re-scanning patients with incidentalomas.
We project that it is both cost-saving and more effective to scan intermediate-risk patients for CAC and to treat those with CAC≥1, compared to treatment based on established risk-assessment guidelines. Treating patients with CAC≥100 is also preferred to existing guidelines when we account for statin side effects and the disutility of statin use.
Compared to the alternatives we assessed, CAC testing is both effective and cost saving as a risk-stratification tool, particularly if there are adverse effects of long-term statin use. CAC may enable providers to better tailor preventive therapy to patients' risks of CVD.
PMCID: PMC4364761  PMID: 25786208
16.  A comparison of outcomes with coronary artery calcium scanning in Unselected Populations - The Multi-Ethnic Study of Atherosclerosis (MESA) and Heinz Nixdorf Recall Study (HNR) 
The Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR)) differed in regards to informing physicians and patients of the results of their subclinical atherosclerosis.
This study investigates whether the association of coronary artery calcium (CAC) with incident non-fatal and fatal cardiovascular (CVD) events is different among these two large, population-based observational studies.
All Caucasian subjects aged 45–75 years, free of baseline cardiovascular disease were included (n=2232 in MESA, n=3119 HNR participants). We studied the association between CAC and event rates at 5 years, including hard cardiac events (MI, cardiac death, resuscitated cardiac arrest), and separately added revascularizations, and strokes (fatal and non-fatal) to determine adjusted hazard ratios (HR).
Both cohorts demonstrated very low CHD (including revascularization) rates with zero calcium (1.13 and 1.16% over 5 years in MESA and HNR respectively) and increasing significantly in both groups with CAC 100–399 (6.71 and 4.52% in MESA and HNR) and CAC >400 (12.5 and 13.54% in MESA and HNR respectively) and demonstrating strong independent predictive values for scores of 100–399 and >400, despite multivariable adjustment for risk factors. Risk factor adjusted five year revascularization rates were nearly identical for HNR and MESA, and generally low for both studies (1.4% [45/3119] for HNR and 1.9% [43/2232] for MESA) over 5 years.
Across two culturally diverse populations, CAC >400 is a strong predictor of events. High CAC did not determininistically result in revascularization and knowledge of CAC did not increase revascularizations.
PMCID: PMC3732186  PMID: 23849491
coronary artery calcification; subclinical atherosclerosis; Multi-Ethnic Study of Atherosclerosis (MESA); Heinz Nixdorf Recall Study (HNR)
17.  Using the Coronary Artery Calcium Score to Guide Statin Therapy 
The coronary artery calcium score (CAC) predicts future coronary heart disease (CHD) events and could be used to guide primary prevention interventions, but CAC measurement has costs and exposes patients to low-dose radiation.
Methods and Results
We estimated the cost-effectiveness of measuring CAC and prescribing statin therapy based on the resulting score under a range of assumptions using an established model enhanced with CAC distribution and risk estimates from the Multi-Ethnic Study of Atherosclerosis (MESA). Ten years of statin treatment for 10,000 55-year-old women with high cholesterol (10-year CHD risk=7.5%) was projected to prevent 32 myocardial infarctions, cause 70 cases of statin-induced myopathy, and add 1,108 years to total life-expectancy. Measuring CAC and targeting statin treatment to the 2,500 women with CAC>0 would provide 45% of the benefit (+501 life-years), but CAC measurement would cost $2.25 million and cause 9 radiation-induced cancers. Treat All was preferable to CAC screening in this scenario and across a broad range of other scenarios (CHD risk=2.5-15%) when statin assumptions were favorable ($0.13/pill and no quality of life penalty). When statin assumptions were less favorable ($1.00/pill and disutility=0.00384), CAC screening with statin treatment for persons with CAC>0 was cost-effective (<$50,000/quality-adjusted life-year) in this scenario, in 55-year old men with CHD risk=7.5%, and in other intermediate risk scenarios (CHD risk=5-10%). Our results were critically sensitive to statin cost and disutility, and relatively robust to other assumptions. Alternate CAC treatment thresholds (>100 or >300) were generally not cost-effective.
CAC testing in intermediate risk patients can be cost-effective, but only if statins are costly or significantly impact quality of life.
PMCID: PMC4156513  PMID: 24619318
coronary; atherosclerosis; economics; calcium; statins
18.  CT Attenuation Features of Individual Calcified Coronary Plaque: Differences among Asymptomatic, Stable Angina Pectoris, and Acute Coronary Syndrome Groups 
PLoS ONE  2015;10(6):e0131254.
Coronary artery calcium (CAC) assessed by non-contrast cardiac CT has been shown to be an independent factor from the Framingham risk factors in predicting cardiovascular events. However, many patients with acute coronary syndrome (ACS) have low CAC score. A recent study that re-analyzed the previous CAC CT scan of MESA cohort showed that in subjects with global lower density, CAC was associated with higher risk of ACS. We aimed to further evaluate the characteristics of CAC attenuation features in ACS subjects, in comparison to asymptomatic and stable angina pectoris (SAP) groups.
In a period of 18 months, 524 consecutive subjects received standard CAC CT scans in our department; 278 of 524 subjects with presence of CAC (225 men, age = 60.6±9.5 years; ACS = 41, SAP = 78, asymptomatic = 159) were enrolled. Agatston score, number of plaques (NP) per subject and mean (HMEAN) and standard deviation (HSD) of attenuation of each calcified plaque were measured. Three regression models to distinguish the groups were built: model 1, conventional risk factors only; model 2, Agatston score plus model 1; model 3, plaque attenuation features plus model 2.
Agatston score in ACS group (median = 112.9) was higher than in the asymptomatic group (median = 54.4, P = 0.028) and similar to the SAP group (median = 237.8, P = 0.428). Calcified plaques in the ACS group showed lower (HMEAN = 180.5) and more homogenous (HSD = 31.2) attenuation than those of the asymptomatic group (HMEAN = 205.9, P = 0.002; HSD = 52.4, P = 0.006) and the SAP group (HMEAN = 204.1, P = 0.016; HSD = 54.4, P = 0.011). Model 3 significantly improved the distinction between ACS and asymptomatic groups (area under curve [AUC] = 0.93) as compared to model 2 (AUC = 0.83, P = 0.003) and model 1 (AUC = 0.79, P = 0.001).
Calcified plaques in the ACS group were characteristically of low and homogenous CT attenuation. With validation in a large cohort, analysis of CT attenuation features may improve risk stratification of ACS using CAC CT scan.
PMCID: PMC4481104  PMID: 26106881
19.  Cardiovascular events with absent or minimal coronary calcification: the Multi-Ethnic Study of Atherosclerosis (MESA) 
American heart journal  2009;158(4):554-561.
Elevated coronary artery calcium (CAC) is a marker for increase risk of coronary heart disease (CHD). While the majority of CHD events occur among individuals with advanced CAC, CHD can also occur in individuals with little or no calcified plaque. In this study, we sought to evaluate the characteristics associated with incident CHD events in the setting of minimal (score ≤10) or absent CAC (score of zero).
Asymptomatic participants in the Multi-Ethnic Study of Atherosclerosis (MESA) (N=6,809), were followed for occurrence of all CHD events (including myocardial infarction(MI), angina, resuscitated cardiac arrest, or CHD death) and hard CHD events (MI or CHD death). Time to incident CHD was modeled using age-and gender-adjusted Cox regression.
The final study population consisted of 3,923 MESA asymptomatic participants (mean age: 58±9years,39% males) had with CAC scores of 0-10. Overall no detectable CAC was seen in 3415 individuals, whereas 508 had CAC scores of 1-10. During follow up (median 4.1 years) there were 16 incident hard events, and 28 all CHD events in individuals with absent or minimal CAC. In age, gender, race and CHD risk factors adjusted analysis, minimal CAC (1-10) was associated with an estimated 3-fold greater risk of a hard CHD event (HR: 3.23, 95% CI: 1.17-8.95), or of all CHD event (HR: 3.66, 95% CI 1.71-7.85) compared to those with CAC=0. Former smoking (HR=3.57; 1.08-11.77), current smoking (HR=4.93; 1.20-20.30), and diabetes (HR=3.09; 1.07-8.93) were significant risk factors for events in those with CAC=0.
Asymptomatic persons with absent or minimal CAC are at very low risk of future cardiovascular events. Individuals with minimal CAC (1-10) were significantly increased to three fold increased risk for incident CHD events relative to those with CAC scores of zero.
PMCID: PMC2766514  PMID: 19781414
Computed Tomography; Prognosis; Coronary Artery Calcification; Atherosclerosis; Coronary Calcium Score; Cardiac Events
20.  Interpretation of the Coronary Artery Calcium Score in Combination with Conventional Cardiovascular Risk Factors: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Circulation  2013;128(10):10.1161/CIRCULATIONAHA.113.002598.
The coronary artery calcium (CAC) score predicts coronary heart disease (CHD) events, but methods for interpreting the score in combination with conventional CHD risk factors have not been established.
Methods and Results
We analyzed CAC scores and CHD risk factor measurements from 6757 Black, Chinese, Hispanic and white men and women aged 45–84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). CAC was associated with age, sex, race-ethnicity, and all conventional CHD risk factors. Multivariable models using these factors predicted the presence of CAC (C-statistic = 0.789) and degree of elevation (16% of variation explained), and can be used to update a “pre-test” CHD risk estimate, such as the 10-year Framingham Risk Score, that is based on an individual’s conventional risk factors. In scenarios where a high CAC score is expected, a moderately elevated CAC score of 50 is reassuring (e.g., reducing risk from 10% to 6% in a healthy older white man); but when a low/zero CAC score is expected, even with identical pre-test CHD risk, the same CAC score of 50 may be alarmingly high (e.g., increasing risk from 10% to 20% in a middle-aged black woman with multiple risk factors). Both the magnitude and direction of the shift in risk varied markedly with pre-test CHD risk and with the pattern of risk factors.
Knowing what CAC score to expect for an individual patient, based on their conventional risk factors, may help clinicians decide when to order a CAC test and how to interpret the results.
PMCID: PMC3840900  PMID: 23884352
coronary disease; calcium; imaging; epidemiology
21.  Reassessing the Usefulness of Coronary Artery Calcium Score among Varying Racial and Ethnic Groups by Geographic Locations: Relevance of the Korea Initiatives on Coronary Artery Calcification Registry 
There is some disparity in the morbidity and mortality rates of cardiovascular disease (CVD) according to race, ethnicity, and geographic regions. Although prediction algorithms that evaluate risk of cardiovascular events have been established using traditional risk factors, they have also demonstrated a number of differences along with race and ethnicity. Of various risk assessment modalities, coronary artery calcium (CAC) score is a sensitive marker of calcific atherosclerosis and correlates well with atherosclerotic plaque burden. Although CAC score is now utilized as a useful tool for early detection of coronary artery disease, prior studies have suggested some variability in the presence and severity of coronary calcification according to race, ethnicity, and/or geographic regions. Among Asian populations, it would appear necessary to reappraise the utility of CAC score and whether it remains superior over and above established clinical risk prediction algorithms. To this end, the Korea initiatives on coronary artery calcification (KOICA) registry has been designed to identify the effectiveness of CAC score for primary prevention of CVD in asymptomatic Korean adults. This review discusses the important role of CAC score for prognostication, while also describing the design and rationale of the KOICA registry.
PMCID: PMC4707303  PMID: 26755926
Cardiovascular disease; Coronary artery calcium score; Coronary artery disease; Risk prediction algorithm; Ethnicity
22.  Progression of Coronary Artery Calcium in Type 1 Diabetes Mellitus 
The American journal of cardiology  2007;100(10):1543-1547.
Coronary artery calcium (CAC) has been previously associated with atherosclerotic plaque disease and coronary events. Thus, identifying predictors of CAC progression may provide new insights on early risk factor intervention and subsequent reduction of more severe atherosclerotic disease. We aimed to identify risk factors of CAC progression and evaluate whether risk factor change relates to CAC progression in a cohort of type 1 diabetes mellitus (DM). Participants of the Pittsburgh Epidemiology of Diabetes Complications study, a prospective investigation of childhood-onset type 1 DM, who received 2 electron beam computed tomography screenings 4 years apart were selected for study (n=222). CAC was calculated by the Agatston method of scoring and progression was defined as an increase >2.5 in the square root-transformed CAC score. Adjusting for diabetes duration and initial CAC score, body mass index (BMI, OR=1.13 95% CI=1.01-1.26), non-high density lipoprotein cholesterol (OR=1.01, 95% CI=1.003-1.03), and albumin excretion rate (OR=1.30, 95% CI=1.03-1.63) were associated with CAC progression. When considering change in risk factors, an increase in BMI (OR=1.38, 95% CI=1.10-1.72) was also associated with CAC progression after adjustment. In conclusion, in this cohort of type 1 DM, in addition to baseline BMI, non-high density lipoprotein cholesterol and albumin excretion rate, all known coronary artery disease risk factors, weight gain further added to the prediction of CAC progression. Thus, weight control, in addition to lipid and renal management may help retard atherosclerosis progression in type 1 DM.
PMCID: PMC2206537  PMID: 17996516
coronary artery calcification; progression; type 1 diabetes mellitus; BMI
23.  Comparison of the atherosclerotic burden among asymptomatic patients vs matched volunteers 
Journal of Nuclear Cardiology  2010;18(2):291-298.
While asymptomatic patients should have a lower risk of cardiac events compared to symptomatic patients referred for cardiac stress testing, comparable event rates have been noted in some prior prognostic studies. To test if a high burden of undetected atherosclerosis among asymptomatic patients helps explain such findings, we compared atherosclerotic burden, as measured by coronary artery calcium (CAC) scanning, in propensity-matched groups of volunteers and asymptomatic patients.
CAC scans were performed on a research basis in 136 asymptomatic patients referred for exercise myocardial perfusion SPECT and in 1,398 volunteers. We performed matching by propensity scores to compare volunteers with the same CAD risk factor profile as our asymptomatic patients.
Among our matched groups, asymptomatic patients had significantly greater mean CAC scores than volunteers (394 ± 805 vs 151 ± 349, P = .001), primarily due to a higher frequency of CAC scores >1,000 (15.4% vs 2.5%, P < .001). Inducible myocardial ischemia by SPECT was present in 7% of patients, but was selectively concentrated among those with CAC scores >1,000, occurring in 27.0% of such patients vs only 1.9% among patients with CAC scores <1,000 (P < .0001).
In contrast to asymptomatic volunteers, asymptomatic patients referred for cardiac stress testing possess more extensive atherosclerosis as measured by CAC. Among asymptomatic patients with high CAC scores, the frequency of concomitant inducible myocardial ischemia is high. These results help explain prior prognostic studies concerning asymptomatic patients and indicate the importance of making a clinical distinction between healthy subjects and asymptomatic patients with respect to atherosclerotic risk.
PMCID: PMC3069310  PMID: 21184209
Coronary calcification; ischemia; atherosclerosis; coronary artery disease
24.  The ability of the 2013 ACC/AHA cardiovascular risk score to identify rheumatoid arthritis patients with high coronary artery calcification scores 
Patients with rheumatoid arthritis (RA) have increased risk of atherosclerotic cardiovascular disease (ASCVD) that is underestimated by the Framingham risk score (FRS). We hypothesized that the 2013 ACC/AHA 10-year risk score would perform better than the FRS and the Reynolds risk score (RRS) in identifying RA patients known to have elevated cardiovascular risk based on high coronary artery calcification (CAC) scores.
Among 98 RA patients eligible for risk stratification using the ACC/AHA score we identified 34 patients with high CAC (≥ 300 Agatston units or ≥75th percentile) and compared the ability of the 10-year FRS, RRS and the ACC/AHA risk scores to correctly assign these patients to an elevated risk category.
All three risk scores were higher in patients with high CAC (P values <0.05). The percentage of patients with high CAC correctly assigned to the elevated risk category was similar among the three scores (FRS 32%, RRS 32%, ACC/AHA 41%) (P=0.233). The c-statistics for the FRS, RRS and ACC/AHA risk scores predicting the presence of high CAC were 0.65, 0.66, and 0.65, respectively.
The ACC/AHA 10-year risk score does not offer any advantage compared to the traditional FRS and RRS in the identification of RA patients with elevated risk as determined by high CAC. The ACC/AHA risk score assigned almost 60% of patients with high CAC into a low risk category. Risk scores and standard risk prediction models used in the general population do not adequately identify many RA patients with elevated cardiovascular risk.
PMCID: PMC4369184  PMID: 25371313
RA; cardiovascular risk; atherosclerosis
25.  The Association Between Physical Activity and Both Incident Coronary Artery Calcification and Ankle Brachial Index Progression: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2013;230(2):278-283.
Both coronary artery calcification (CAC) and the ankle brachial index (ABI) are measures of subclinical atherosclerotic disease. The influence of physical activity on the longitudinal change in these measures remains unclear. To assess this we examined the association between these measures and self-reported physical activity in the Multi-Ethnic Study of Atherosclerosis (MESA).
At baseline, the MESA participants were free of clinically evident cardiovascular disease. We included all participants with an ABI between 0.90 and 1.40 (n=5656). Predictor variables were based on self-reported measures with physical activity being assessed using the Typical Week Physical Activity Survey from which metabolic equivalent-minutes/week of activity were calculated. We focused on physical activity intensity, intentional exercise, sedentary behavior, and conditioning. Incident peripheral artery disease (PAD) was defined as the progression of ABI to values below 0.90 (given the baseline range of 0.90 to 1.40). Incident CAC was defined as a CAC score >0 Agatston units upon follow up with a baseline score of 0 Agatston units.
Mean age was 61 years, 53% were female, and mean body mass index was 28 kg/m2. After adjusting for traditional cardiovascular risk factors and socioeconomic factors, intentional exercise was protective for incident peripheral artery disease (Relative Risk (RR)= 0.85, 95% Confidence Interval (CI): 0.74 to 0.98). After adjusting for traditional cardiovascular risk factors and socioeconomic factors, there was a significant association between vigorous PA and incident CAC (RR=0.97, 95% CI: 0.94 to 1.00). There was also a significant association between sedentary behavior and increased amount of CAC among participants with CAC at baseline (Δlog(Agatston Units +25)=0.027, 95% CI 0.002, 0.052).
These data suggest that there is an association between physical activity/sedentary behavior and the progression of two different measures of subclinical atherosclerotic disease.
PMCID: PMC4085097  PMID: 24075757
Ankle Brachial Index; Coronary Artery Calcification; Physical Activity; Epidemiology; Prospective Cohort Study

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