Author + information
- Received April 16, 2015
- Revision received June 15, 2015
- Accepted June 18, 2015
- Published online February 1, 2016.
- Jan M. Hughes-Austin, PT, MPT, PhDa,b,
- Arturo Dominguez III, MDc,
- Matthew A. Allison, MD, MPHb,c,d,
- Christina L. Wassel, PhDe,
- Dena E. Rifkin, MD, MSb,c,d,
- Cindy G. Morgan, MSb,
- Michael R. Daniels, BSb,
- Umaira Ikram, MDb,
- Jessica B. Knox, MDb,
- C. Michael Wright, MDf,
- Michael H. Criqui, MD, MPHb and
- Joachim H. Ix, MD, MASb,c,d,∗ ()
- aDepartment of Orthopaedic Surgery, School of Medicine, University of California, San Diego, California
- bDepartment of Family Medicine and Public Health, School of Medicine, University of California, San Diego, California
- cDepartment of Medicine, School of Medicine, University of California, San Diego, California
- dVeterans Affairs San Diego Healthcare System, San Diego, California
- eDepartment of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
- fScripps Health, La Jolla, California
- ↵∗Reprint requests and correspondence:
Dr. Joachim H. Ix, Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, and San Diego Veterans Affairs Healthcare System, 3350 La Jolla Village Drive, Mail code 111-H. San Diego, California 92161.
Objectives The aim of this study was to determine the correlation between coronary artery calcium (CAC) scores on 3 mm electrocardiography (ECG)-gated computed tomography (CT) scans and standard 6 mm chest CT scans, and to compare relative strength of associations of CAC on each scan type with mortality risk.
Background Coronary artery calcification predicts cardiovascular disease (CVD) and all-cause mortality, and is typically measured on ECG-gated 3 mm CT scans. Patients undergo standard 6 mm chest CTs for various clinical indications much more frequently, but CAC is not usually quantified. To better understand the usefulness of standard chest CTs to quantify CAC, we conducted a case-control study among persons who had both scan types.
Methods Between 2000 and 2003, 4,544 community-living individuals self- or physician-referred for “whole-body” CT scans, had 3 mm ECG-gated CTs and standard 6 mm chest CTs, and were followed for mortality through 2009. In this nested case-control study, we identified 157 deaths and 494 controls frequency matched (1:3) on age and sex. The Agatston method quantified CAC on both scan types. Unconditional logistic regression determined associations with mortality, accounting for CVD risk factors.
Results Participants were 68 ± 11 years of age and 63% male. The Spearman correlation of CAC scores between the 2 scan types was 0.93 (p < 0.001); median CAC scores were lower on 6 mm CTs compared to 3 mm CTs (22 vs.104 Agatston units, p < 0.001). Adjusted for traditional CVD risk factors, each standard deviation higher CAC score on 6 mm CTs was associated with 50% higher odds of death (odds ratio: 1.5; 95% confidence interval: 1.2 to 1.9), similar to 50% higher odds on the 3 mm ECG-gated CTs (odds ratio: 1.5; 95% confidence interval: 1.1 to 1.9).
Conclusions CAC scores on standard 6 mm chest CTs are strongly correlated with 3 mm ECG-gated CTs and similarly predict mortality in community-living individuals. Chest CTs performed for other clinical indications may provide an untapped resource to garner CVD risk information without additional radiation exposure or expense.
Coronary artery disease (CAD) is the leading cause of mortality in the United States (1). Detection of coronary artery calcification (CAC) is a strong predictor of CAD, cardiovascular events, and all-cause mortality (2,3), above and beyond the Framingham risk score (2,4). CAC is usually quantified on dedicated 3 mm sliced computed tomography (CT) scans that are electrocardiography (ECG) gated, so as to minimize motion artifact from the beating heart and provide relatively fine cuts through the coronary arteries. These scans are done frequently in research settings, but uncommonly in clinical practice because most insurance providers do not cover the cost of the scan for preventive medicine and because the U.S. Preventive Task Force currently does not recommend preventive CAC screening in individuals without a history of CAD (5,6).
Standard chest CT scans are used for numerous clinical indications including lung cancer screenings, evaluation for pulmonary embolism, adenopathy, pleural diseases, and pneumonia, among others. Calcium within the coronary arteries can be easily recognized on these scans (7), and prior studies have evaluated CAC on lung CTs for CAD screening in smokers at high risk for lung cancer (8,9). However, CAC screening may be most useful in persons at intermediate risk for CAD (2), where presence and severity of CAC may modify the approach to preventive strategies such as use of statins and other interventions. In comparison with the approximate 600,000 3 mm ECG-gated CT scans done in the United States annually, it is estimated that over 7.1 million 6 mm lung CT scans are done annually for other clinical indications (10). While several studies have demonstrated agreement between 3 mm ECG-gated CTs and standard chest CTs in their measurement of CAC (7,9,11), whether standard chest CTs can predict outcomes in the general population, and whether results are similar to 3 mm electron beam CT scan data, despite the wider cuts and absence of ECG gating, is unknown.
To better understand the usefulness of standard chest CTs for this purpose, we conducted a case-control study among persons who had both scan types when they were seen in 2000 to 2003 and who were followed for mortality for approximately 8 years thereafter.
Study population and study design
Study participants were recruited through a San Diego cardiovascular imaging clinic between 2000 and 2003, where 4,544 community-living individuals who were mostly asymptomatic were self-referred or referred by primary care physicians for “whole-body” CT scans. Participants were followed for mortality through 2009, during which 173 participants died. Using a nested case-control study design, each death (case) was frequency matched on sex and age within 1 year with 3 surviving controls, resulting in 518 controls, and totaling 691 participants (12). Following the selection of cases and matching controls, we further excluded any participant who had undergone any angioplasty, stent, or bypass revascularization procedure (n = 41), which resulted in a total of 651 participants—157 deaths and 494 controls. Five of the oldest cases did not have age matches within 1 year. Thus, controls for these 5 cases were within 3 to 5 years of the ages of these 5 cases. A 3 mm ECG-gated CT was obtained and scored for CAC at the time of the initial visit. A 6 mm standard chest CT was also obtained and read for general lung pathology, but was not scored for CAC at the time of the baseline visit. Our case-control design, nested within a prospective cohort study, allowed us a targeted approach to retrieve chest CTs and reread them for CAC without significant loss of statistical power. All participants provided informed consent and the study was approved by the University of California, San Diego, Human Research Protections Program.
Coronary artery calcification imaging and scoring
CT scans were performed using an Imatron C-150 scanner (San Francisco, California), which is an electron beam CT scanner with a high-resolution detector system. We used the standard single-section mode, which involves an image acquisition time of 100 ms and 3 mm section thickness. The 3 mm ECG-gated CT scans were electrocardiographically triggered at 40% or 65% of the R-R interval, depending on the participant’s heart rate, and resulted in 1.0 and 1.3 mSv of radiation for women and men, respectively (13). For the 6 mm chest CT scans, subjects were scanned from the sternal notch to base of the diaphragm without ECG gating. Radiation exposure for this type of scan, as presented in lung cancer screening literature for low-dose CT scan screening is approximately 1.5 mSv (14). Methods for scoring CAC follow those described by Agatston et al. (15) on both scan types. The 3 mm ECG-gated scans were read at the time of scan acquisition, while the 6 mm chest CT scans were read for CAC in 2012. Readers were blinded to participant clinical data and to their 3 mm CT CAC score.
In 2009, we linked the data with the Social Security Death Index to identify individuals who had died in the intervening period. Potential deaths identified by the Social Security Death Index were cross referenced with their patient clinical records to confirm identity.
Height and weight were measured at clinic visits, and body mass index (BMI) was calculated (in kg/m2). Age and sex were obtained through self-report, and a questionnaire was used to obtain a participant’s medical history including smoking status (never, former, or current), prevalent hypertension, and cholesterol medication use. Nonfasting serum lipid and glucose levels were obtained via finger-stick using the Cholestech LDX system (Hayward, California). Diabetes was defined as serum glucose >200 mg/dl, or the use of glucose-lowering medications. Dyslipidemia was defined as total to high-density lipoprotein cholesterol ratio >5, or the use of cholesterol-lowering medication. Systolic and diastolic blood pressures were obtained from a trained technician after the participant rested for 5 min. Hypertension was defined as systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg, or the use of antihypertensive medications.
We evaluated differences in demographics and traditional cardiovascular disease (CVD) risk factors in cases and controls using Student t tests or Wilcoxon rank sum tests for continuous variables and chi-square tests or Fisher exact tests for categorical variables. We evaluated the correlation of CAC scores on the 2 scan types using Spearman correlations for continuous CAC scores, given skewed distributions, and Kappa statistics for categorical CAC scores. We also performed a Bland-Altman analysis to determine the bias and limits of agreement between the 3 mm ECG-gated CT and the 6 mm standard chest CT scans (16). Next, we used unconditional logistic regression to examine associations of each scan type with mortality. Initial models were unadjusted. Subsequent models adjusted for demographics and traditional CVD risk factors (age, sex, diabetes, hypertension, dyslipidemia, BMI, smoking, and family history of CVD). We evaluated each CAC score as both a continuous and categorical variable. For analysis using a continuous CAC score, we added 1 to each CAC score (such that zero scores were not excluded from the analysis) and natural log transformed the distribution (Ln[CAC +1]) to approximate a normal distribution of CAC scores. We used standardized coefficients to compare strength of association per standard deviation of LnCAC+1 across the 2 scan types. For analysis using a categorical CAC score, we categorized patients into 4 groups according to standard 3 mm Agatston CAC score cutpoints, which facilitated comparisons across scan types (17).
In evaluating the 6 mm chest CT scan Agatston CAC scores, 34% had Agatston scores of 0, whereas 24% had scores of 0 using the 3 mm ECG-gated CT scans. Using standard cutpoints proposed by Detrano et al. (17), we defined 4 categories of CAC for both 3 mm ECG-gated and 6 mm chest CT scans: CAC = 0, CAC = 1 to 100, CAC = 101 to 300, and CAC >300. All analyses were conducted using Stata version 11.0SE (Stata Corp., College Station, Texas) and SAS version 9.4 (SAS Institute, Cary, North Carolina), and p values <0.05 were considered statistically significant.
The 651 participants in this study had a mean age of 68 years, and 63% were male. Cases and controls had similar BMI, total cholesterol, high-density lipoprotein cholesterol, and use of lipid-lowering medications. However, a greater proportion of cases had diabetes and hypertension, were former or current smokers, and had a family history of CVD. Cases also had higher median CAC scores on both the 3 and 6 mm CT scans compared to controls at baseline (Table 1). Race/ethnicity was not required to obtain a CT scan, thus it was provided by 199 individuals in this study. Of these 199 individuals with reported ethnicity, 100% (43) of deaths occurred in Caucasians. This subsample of 199 included 0.6% Asian, 12% Hispanic, and 2% other—the remaining 85% were Caucasian.
The correlation between CAC scores on the 3 mm ECG-gated CT and the 6 mm standard chest CT was 0.93 (p < 0.001) (Figure 1). However, the median CAC scores were significantly lower on the 6 mm CT scan than on the 3 mm ECG-gated scan (22 vs. 104 Agatston units, respectively, p < 0.001). The Kappa statistic for agreement between CAC score categories on the 3 mm ECG-gated CT compared to the 6 mm standard chest CT was 0.41, and the weighted Kappa statistic was 0.62, indicating moderate to substantial agreement between the 2 scans using standard clinical cutpoints (CAC = 0, 1 to 100, 101 to 300, and >300). Bland-Altman analysis showed a mean bias of 3.23, with limits of agreement between 0.6 and 17.3, as shown in Figure 2, suggesting that Agatston scores on 3 mm ECG-gated CT scans were, on average, approximately 323% higher than Agatston scores on the 6 mm standard chest CT scan (16). As illustrative examples of the difference in sensitivity, Figure 3 presents CAC measured on 3 mm ECG-gated CT (CAC = 372) and 6 mm chest CT (CAC = 117) at approximately the same location within an individual. In a participant with more advanced CAC, Figure 4 presents 2 consecutive slices within the same individual where CAC measured on 3 mm ECG-gated CT totaled to 3,213 and CAC measured on 6 mm chest CT totaled to 1,044. These examples demonstrate that, while CAC is present and quantifiable on both the 3 and 6 mm scans, the clarity and amount of CAC is higher on average using a 3 mm ECG-gated CT scan.
Table 2 shows the associations of CAC scores on the 2 scan types with mortality. When evaluating CAC on the 6 mm chest CT scans, compared to the CAC = 0 reference category, there was a graded relationship of higher CAC score with higher odds of mortality such that those with CAC scores between 1 and 100 had 1.9-fold higher odds of mortality, between 101 and 300 had 2.3-fold higher odds of mortality, and those with CAC greater than 300 had 2.6-fold higher odds for mortality in models adjusted for demographics and traditional CVD risk factors. In comparison, with the 3 mm ECG-gated scans, compared to the CAC = 0 reference category, participants with CAC scores between 1 and 100 had 2.1-fold higher odds of mortality, between 101 and 300 had 2.9-fold higher odds of mortality, and those greater than 300 had 3.2-fold higher odds of mortality in adjusted models. These associations have been plotted in Figure 5. When CAC scores were evaluated as a continuous variable, each SD higher CAC score on the 6 mm chest CTs was associated with 1.5-fold higher odds of mortality. Similarly, each SD higher score on the 3 mm ECG-gated scans was associated with 1.5-fold higher odds of mortality. All of these results were statistically significant.
In this population of community-living individuals who self-referred or were referred by their primary care physicians for “whole-body” CT scans, CAC scores on standard 6 mm chest CTs were strongly correlated to those on the 3 mm ECG-gated CT scans specifically designed for CAC measurement. Scores on either scan type were strongly associated with all-cause mortality, and the relative strength of association was similar irrespective of the scan type.
CAC screening has been considered useful for prevention of CVD because it can further risk stratify persons who are considered intermediate risk for incident CVD events by the Framingham risk score. Several investigators have reported that standard chest CT scans used for lung cancer screening can also detect and quantify CAC (3,4,9,11,18,19). Our study confirms these results, and extends them to a community-living population for the first time. Moreover, to our knowledge, this is the first study to compare the correlation and relative strengths of association of CAC on the standard chest CT and the 3 mm ECG-gated CT with mortality.
Our results may have important implications for preventive cardiology clinical practice. In 2007, approximately 7.1 million chest CT scans were performed in the United States, compared to 600,000 CT scans for calcium scoring, presumably using 3 mm ECG-gated CTs (10). There is concern that radiation exposure from CT scans may increase cancer risk (20,21). In addition, many health insurance plans do not cover the expense of CT scanning for CAC measurement for preventive care purposes. Given that chest CTs are done frequently for numerous other clinical indications, many individuals may already have scans that can be scored for CAC, which may guide preventive cardiology care. Thus, if our results are confirmed, health care providers may consider utilizing previously obtained CT scans to assess CAC while avoiding the potential risks and expense of repeat CT scans designed specifically for CAC measurement.
Currently, CAC observed on standard chest CT scans is not routinely reported by radiologists, and use of the Agatston method is even less common. For example, Williams et al. (22) reported that CAC on chest CTs was recorded in the final radiology report in only 44% of patients with known CAC. Jacobs et al. (23) demonstrated that, by using simple visual grading to measure CAC on standard chest CT, CAC was strongly associated with future CVD events. Thus, by simple visual grading system evaluated by others (23,24), or by the Agatston method used here, the detection of CAC on standard chest CT has prognostic implications. As it has important implications for preventive care, we believe it should be systematically reported.
The median CAC scores on the 6 mm chest CT scans were substantially lower on average than on the 3 mm ECG-gated CT scans. This may be because there are fewer slices to evaluate and score on the 6 mm scan. With fewer slices, there may also be volume averaging in plaque based on interpolation algorithms from slice to slice. Also, small plaques may be missed between 6 mm cuts. Therefore, 6 mm chest CT scans may be less sensitive for low levels of CAC, and the good prognosis provided by a 3 mm ECG-gated scan showing zero CAC may not be as robust for a 6 mm chest CT with zero CAC. Absence of any CAC on an ECG-gated 3 mm scan has been associated with low risk for incident CVD, and relatively standard CAC cutpoints (e.g., 0 to 100, 101 to 300, >300) have been used frequently in prior studies. In this study, we have extended these cutpoints to 6 mm standard chest CT scans, which were similarly associated with mortality risk, but the implication of a specific CAC score may differ across scan types. For example the median 6 mm standard chest CT scan CAC scores were 3, 46, and 286 in individuals in the 3 mm CT scan CAC categories of 1 to 100, 101 to 300, and >300, respectively. Establishing applicable cutpoints for Agatston CAC scores on 6 mm standard chest CT scans warrant further development. However, our data suggest that CAC scores on 6 mm chest CT scans may underestimate the CAC burden compared to 3 mm ECG-gated CT scores.
Our study population was mostly older non-Hispanic white adults, many of whom self-referred for “whole-body” CT scans for preventive care. Such individuals may be particularly motivated to prevent chronic diseases. Future studies in other settings are required to confirm these findings. As discussed previously, although the associations of either scan type with mortality were similar, there are absolute differences in the CAC scores across scan types, which may impact sensitivity to detect low level CAC using 6 mm chest CT scans and will influence specific cutpoints. Thus, specific CAC values should be interpreted with knowledge about the scan type.
Despite the absence of ECG gating and wider slice thickness, CAC scores on standard 6 mm chest CTs are highly correlated with those on 3 mm ECG-gated CT scans, and are similarly associated with mortality risk in community-living individuals. Most insurance providers do not routinely cover the expense of 3 mm ECG-gated scans for CAC scoring, and conversely approximately 7 million chest CT scans are done annually in the United States for other clinical indications (10). Persons who have chest CTs for other clinical indications may benefit from systematic reading of CAC to garner additional information on CVD risk without the added expense and radiation exposure required for dedicated 3 mm ECG-gated scans.
COMPETENCY IN MEDICAL KNOWLEDGE: Standard chest CT scans are often not read for CAC severity by radiologists when reading scans obtained for other clinical indications. We show that detection of CAC on standard chest CT scans is closely correlated with CAC on the ECG-gated CT scans, and similarly predicts mortality. Therefore, chest CT scans obtained for various clinical indications can also inform CVD risk through measurement of CAC.
TRANSLATIONAL OUTLOOK: While similarly predictive of events, a CAC score on a standard chest CT was lower than on an ECG-gated CT on the same individual. Future studies are required to determine applicable cutpoints for CAC scores on standard CT scans relative to the ECG-gated CT.
The authors thank the participants of this study, the clinic staff who received and examined these participants, and Julie Denenberg for her assistance and organization.
Funding for this project comes from the National Institutes of Health, National Heart, Lung, and Blood Institute R01HL116395, American Heart Association Established Investigator Award EIA18560026, American Heart Association Fellow to Faculty Award 0475029N, and K23DK091521. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- body mass index
- coronary artery calcium
- coronary artery disease
- computed tomography
- cardiovascular disease
- electrocardiogram / electrocardiography
- Received April 16, 2015.
- Revision received June 15, 2015.
- Accepted June 18, 2015.
- American College of Cardiology Foundation
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