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.
computed tomography; electron beam; prognosis; review; coronary artery calcification; calcium score; atherosclerosis; multi-detector computed tomography
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.
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.
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.
prognosis; atherosclerosis; cardiac CT; coronary calcium
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.
calcium; ischemia; perfusion; imaging; prognosis
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.
cardiac CT derived risk factors; coronary heart disease; cardiovascular events; risk prediction
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.
RESEARCH DESIGN AND METHODS
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.
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.
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.
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.
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.
coronary artery calcium; family history; risk factors
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.
coronary artery calcification; subclinical atherosclerosis; Multi-Ethnic Study of Atherosclerosis (MESA); Heinz Nixdorf Recall Study (HNR)
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.
Computed Tomography; Prognosis; Coronary Artery Calcification; Atherosclerosis; Coronary Calcium Score; Cardiac Events
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.
coronary disease; calcium; imaging; epidemiology
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.
Coronary calcification; ischemia; atherosclerosis; coronary artery disease
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.
coronary artery calcification; progression; type 1 diabetes mellitus; BMI
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.
Ankle Brachial Index; Coronary Artery Calcification; Physical Activity; Epidemiology; Prospective Cohort Study
We evaluated the hypothesis that plasma levels of adiponectin and leptin are independently but oppositely associated with coronary calcification (CAC), a measure of subclinical atherosclerosis. In addition, we assessed which biomarkers of adiposity and insulin resistance are the strongest predictors of CAC beyond traditional risk factors, the metabolic syndrome and plasma C-reactive protein (CRP).
Adipokines are fat-secreted biomolecules with pleiotropic actions that converge in diabetes and cardiovascular disease.
We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non-diabetic participants in the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA).
Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance and inflammation. Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjusting for age, gender, traditional risk factors and Framingham Risk Scores (FRS) [tobit regression ratio 2.42 (95% CI 1.48–3.95, p=0.002)] and further adjusting for metabolic syndrome and CRP [ratio 2.31 (95% CI 1.36–3.94, p=0.002)]. In contrast, adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, IL-6 and sol-TNFR2 as well as HOMA-IR predicted CAC scores but only leptin and HOMA-IR provided value beyond risk factors, the metabolic syndrome and CRP.
In SIRCA, while both leptin and adiponectin levels were associated with metabolic and inflammatory markers, only leptin was a significant independent predictor of CAC. Of several metabolic markers, leptin and the HOMA-IR index had the most robust, independent associations with CAC.
Adipokines are fat-secreted biomolecules with pleiotropic actions and represent novel markers for cardiovascular risk. We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non-diabetic Caucasians. Leptin was positively (top vs. bottom quartile) associated with higher CAC even after adjustment for age, gender, traditional risk factors, Framingham Risk Score, metabolic syndrome, and CRP [ratio 2.31 (95% CI 1.36–3.94, p=0.002)]. Adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, IL-6 and sol-TNFR2 as well as HOMA-IR predicted CAC scores, but only leptin and HOMA-IR provided value beyond risk factors, the metabolic syndrome and CRP.
Adiponectin; Leptin; Coronary Artery Calcification; Atherosclerosis; Inflammation
Many traditional and nontraditional risk factors contribute to vascular calcification among maintenance hemodialysis (MHD) patients. It is not clear whether coronary artery calcification (CAC) delineates a higher mortality risk independent of known risk factors. We examined 6-year (10/2001–9/2007) survival of 166 MHD patients, aged 53 ± 13 years, with baseline CAC scores. Patients were grouped into four CAC groups: 0, 1–100, 101–400, and 400+. The 101–400 and 400+ groups were associated with a significantly higher adjusted risk of death than CAC 0 with hazard ratios (HR) 8.5 (95% CI: 1.1–48.1, p = 0.02) and 13.3 (95% CI: 1.3–65.1, p = 0.01), respectively, independent of demographics, comorbidity, lipids and other cardiovascular risks, surrogates of bone disease, nutritional and inflammatory markers and dialysis dose. Total CAC [HR 6.7 (1.1–21.5, p = 0.03)] followed by the presence of CAC in the left main [4.6 (2.2–9.8, p = 0.001)] and left anterior descending artery [4.3 (2.1–14.2, p = 0.001)] were strong independent predictors of mortality even after adjusting for above covariates. Total and vessel-specific CAC predict mortality in MHD patients independent of traditional and nontraditional risk factors.
Chronic kidney disease; Coronary artery calcium; Dialysis; Inflammation; Phosphorus binder; Sevelamer; Death risk
The presence and extent of coronary artery calcium (CAC) is an independent predictor of coronary heart disease (CHD) morbidity and mortality. Few studies have evaluated interactions or independent incremental risk for coronary and thoracic aortic calcification (TAC). The independent predictive value of TAC for CHD events is not well-established.
This study used risk factor and computed tomography scan data from 6,807 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Using the same images for each participant, TAC and CAC were each computed using the Agatston method. The study subjects were free of incident CHD at entry into the study.
The mean age of the study population (n=6807) was 62±10 years (47% males). At baseline, the prevalence of TAC and CAC was 28 % (1,904/6,809) and 50% (3393/6809), respectively. Over 4.5±0.9 years, a total of 232 participants (3.41%) had CHD events, of which 132 (1.94%) had a hard event (myocardial infarction, resuscitated cardiac arrest, or CHD death). There was a significant interaction between gender and TAC for CHD events (p<0.05). Specifically, in women, the risk of all CHD event was nearly 3-fold greater among those with any TAC (hazard ratio: 3.04, 95% CI; 1.60–5.76). After further adjustment for increasing CAC score, this risk was attenuated but remained robust (HR: 2.15, 95% CI: 1.10–4.17). Conversely, there was no significant association between TAC and incident CHD in men. In women, the likelihood ratio chi square statistics indicate that the addition of TAC contributed significantly to predicting incident CHD event above that provided by traditional risk factors alone (chi square= 12.44, p=0.0004) as well as risk factors + CAC scores (chi square= 5.33, p=0.02) . On the other hand, addition of TAC only contributed in the prediction of hard CHD events to traditional risk factors (chi-square=4.33, p=0.04) in women, without contributing to the model containing both risk factors and CAC scores (chi square=1.55, p=0.21).
Our study indicates that TAC is a significant predictor of future coronary events only in women, independent of CAC. On studies obtained for either cardiac or lung applications, determination of TAC may provide modest supplementary prognostic information in women with no extra cost or radiation.
atherosclerosis; cardiac CT; coronary calcium; multi-detector CT; prognosis; thoracic atherosclerosis
This study sought to evaluate the relationship between microalbuminuria (MA) and the development and progression of atherosclerosis, as assessed by incident and progression of coronary artery calcification (CAC).
MA is associated with an increased risk of cardiovascular disease, but the mechanism by which MA imparts this increased risk is not known.
The MESA (Multi-Ethnic Study of Atherosclerosis) study is a prospective cohort study of 6,814 self-identified White, African-American, Hispanic, or Chinese participants free of clinical cardiovascular disease at entry. Of the 6,775 individuals with available urine albumin data, we excluded 97 subjects with macroalbuminuria and 1,023 with missing follow-up CAC data. The final study population consists of 5,666 subjects.
At baseline, individuals with MA were more likely to have CAC >0 compared with those without MA (62% vs. 48%, p < 0.0001). During a mean follow-up of 2.4 ± 0.8 years, those with MA and no CAC at baseline were more likely to develop CAC (relative risk [RR]: 2.05, 95% confidence interval [CI]: 1.41 to 3.02, p < 0.0001) as compared with those without MA in demographic-adjusted analyses. After multivariant adjustment, the relationship was attenuated but remained statistically significant (RR: 1.76, 95% CI: 1.19 to 2.61, p = 0.005). Among those with CAC at baseline, those with versus those without MA had a 15 (95% CI: 8 to 22, p < 0.0001) volume units higher median increase in CAC in demographic-adjusted analyses. After multivariant adjustment, MA remained associated with incident CAC (RR: 1.76, 95% CI: 1.19 to 2.61, p = 0.005) and with progression of CAC (median increase in CAC volume score of 9 [95% CI: 2 to 16, p = 0.009]), relative to those without MA.
This large multiethnic, population-based study of asymptomatic individuals demonstrates an increased risk of incident CAC as well as greater CAC progression among those with MA. Further study is needed to determine the degree to which MA precedes and predicts progression of atherosclerosis and how this information can be used to reduce cardiovascular events.
coronary artery calcium; microalbuminuria; risk prediction; coronary heart disease; Multi-Ethnic Study of Atherosclerosis
This study sought to evaluate the interrelation of atherosclerotic burden, as assessed by coronary artery calcium (CAC) score and coronary vascular function, as assessed by quantitative estimates of coronary flow reserve (CFR), with respect to prediction of clinical outcomes.
The contribution of coronary vascular dysfunction, atherosclerotic burden, and the 2 combined to cardiac events is unknown.
A total of 901 consecutive patients underwent 82Rubidium myocardial perfusion imaging (MPI) positron emission tomography (PET) and CAC scan. All patients had normal MPI. The primary endpoint was a composite of major adverse cardiac events (MACE) including cardiac death, nonfatal myocardial infarction, late revascularization, and admission for heart failure.
At baseline, CFR decreased (2.15 ± 0.72, 2.02 ± 0.65, and 1.88 ± 0.64, p < 0.0001) with increasing levels of CAC (0, 1 to 399, and ≥400). Over a median of 1.53 years (interquartile range: 0.77 to 2.44), there were 57 MACE. Annual risk-adjusted MACE rates were higher for patients with CFR <2.0 compared with ≥2.0 (1.9 vs. 5.5%/year, p = 0.0007) but were only borderline associated with CAC (3.1%, 3.4%, and 6.2%/year for CAC of 0, 1 to 399, and ≥400, respectively; p = 0.09). Annualized adjusted MACE was increased in the presence of impaired CFR even among patients with CAC = 0 (1.4% vs. 5.2%, p = 0.03). Cox proportional hazards analysis revealed that CFR improved model fit, risk discrimination, and risk reclassification over clinical risk, whereas CAC only modestly improved model fit without improving risk discrimination or reclassification.
In symptomatic patients with normal MPI, global CFR but not CAC provides significant incremental risk stratification over clinical risk score for prediction of major adverse cardiac events.
atherosclerotic burden; coronary artery calcium; coronary flow reserve; hybrid PET/CET; prognosis
The incremental value of CAC over traditional risk factors to predict coronary vasodilator dysfunction and inherent myocardial blood flow (MBF) impairment is only scarcely documented (MBF). The aim of this study was therefore to evaluate the relationship between CAC content, hyperemic MBF, and coronary flow reserve (CFR) in patients undergoing hybrid 15O-water PET/CT imaging.
We evaluated 173 (mean age 56 ± 10, 78 men) patients with a low to intermediate likelihood for coronary artery disease (CAD), without a documented history of CAD, undergoing vasodilator stress 15O-water PET/CT and CAC scoring. Obstructive coronary artery disease was excluded by means of invasive (n = 44) or CT-based coronary angiography (n = 129).
91 of 173 patients (52%) had a CAC score of zero. Of those with CAC, the CAC score was 0.1-99.9, 100-399.9, and ≥400 in 31%, 12%, and 5% of patients, respectively. Global CAC score showed significant inverse correlation with hyperemic MBF (r = −0.32, P < .001). With increasing CAC score, there was a decline in hyperemic MBF on a per-patient basis [3.70, 3.30, 2.68, and 2.53 mL · min−1 · g−1, with total CAC score of 0, 0.1-99.9, 100-399.9, and ≥400, respectively (P < .001)]. CFR showed a stepwise decline with increasing levels of CAC (3.70, 3.32, 2.94, and 2.93, P < .05). Multivariate analysis, including age, BMI, and CAD risk factors, revealed that only age, male gender, BMI, and hypercholesterolemia were associated with reduced stress perfusion. Furthermore, only diabetes and age were independently associated with CFR.
In patients without significant obstructive CAD, a greater CAC burden is associated with a decreased hyperemic MBF and CFR. However, this association disappeared after adjustment for traditional CAD risk factors. These results suggest that CAC does not add incremental value regarding hyperemic MBF and CFR over established CAD risk factors in patients without obstructive CAD.
Coronary artery calcium; hyperemic myocardial blood flow; coronary risk factors
Coronary artery calcium (CAC) and carotid intima-media thickness (IMT) are noninvasive measures of atherosclerosis that consensus panels have recommended as possible additions to risk factor assessment for predicting the probability of cardiovascular disease (CVD) occurrence.
To assess whether maximum carotid IMT or CAC (Agatston Score) is the better predictor of incident CVD.
Design, Setting, Patients
Prospective cohort study of 45–84 year-olds initially free of CVD (n = 6,698) in four ethnic groups, with standardized carotid IMT and CAC measures at baseline, in six field centers of the Multi-Ethnic Study of Atherosclerosis (MESA).
Main Outcome Measure(s)
Incident CVD events (coronary heart disease, stroke, and fatal CVD) over a maximum of 5.3 years of follow-up.
There were 222 CVD events during follow-up. CAC was associated more strongly than carotid IMT with risk of incident CVD. After adjustment for each other and traditional CVD risk factors, the hazard of CVD increased 2.1-fold (95% CI 1.8–2.5) for each standard deviation greater level of log-transformed CAC, versus 1.3-fold (95% CI 1.1–1.4) for each standard deviation greater maximum IMT. For coronary heart disease, the hazard ratios per standard deviation increment were 2.5-fold (95% CI 2.1–3.1) for CAC and 1.2-fold (95% CI 1.0–1.4) for IMT. An ROC analysis also suggested that CAC predicted incident CVD better than IMT did.
Although whether and how to clinically use bio-imaging tests of subclinical atherosclerosis remains a topic of debate, this study found that CAC predicts subsequent CVD events better than does carotid IMT.
Elevated plasma levels of lipoprotein(a) (Lp(a)) and a higher degree of coronary artery calcification (CAC) are both considered to be risk factors for atherosclerosis. However, previous studies have demonstrated that the relationship between Lp(a) levels and the degree of CAC indicates significant heterogeneity that may be due to varying ethnicities. The purpose of this study was to examine the predictive power of Lp(a) for CAC as measured by multidetector computed tomography (MDCT) in the Han ethnic group of China.
A total of 1082 subjects were recruited in this study. The patients were divided into four groups: patients without hypertension or diabetes were group 1, patients with hypertension were group 2, patients with diabetes were group 3 and patients with both hypertension and diabetes were group 4. CAC score (CACs), lipid profiles (Lp(a), LDL, HDL, TG, TC), HbA1C, glucose, personal health history and body morphology were measured in all participants. The predictive power of Lp(a) for calcified atherosclerotic plaque was determined by correlations and ordinal logistic regression.
There was no significant difference in the CACs between group 2 and group 3 (z = 1.790, p = 0.736), and there were significant differences among the other groups. However, there was no significant difference in the total Lp(a) among the 4 groups (χ2 = 0.649, p = 0.885). Only In group 1, Lp(a) was a statistically significant predictor of the presence of calcified coronary plaque using ordinal logistic regression.
Levels of Lp(a) positively correlate with CACs among Chinese Han people who are without diabetes and hypertension, suggesting that Lp(a) may be an important risk factor for the presence of calcified atheromas.