Although the traditional Agatston coronary artery calcium (CAC) score is a powerful predictor of mortality, it is unknown if the regional distribution of CAC further improves cardiovascular risk prediction. We retrospectively studied 23,058 patients referred for Agatston CAC scoring, of whom 61% had CAC (n = 14,084). CAC distribution was defined as the number of vessels with CAC (0 to 4, including left main). For multivessel CAC, “diffuse” CAC was defined by decreasing percentage of CAC in the single most affected vessel and by ≤75% total Agatston CAC score in the most calcified vessel. All-cause mortality was ascertained through the social security death index. The mean age was 55 ± 11 years, with 69% men. There were 584 deaths (2.5%) over 6.6 ± 1.7 years. Considerable heterogeneity existed between the Agatston CAC score group and the number of vessels with CAC. In each CAC group, increasing number of vessels with CAC was associated with an increased mortality rate. After adjusting for age, gender, Agatston CAC score, and cardiovascular risk factors, increasing number of vessels with CAC was associated with higher mortality risk compared with single-vessel CAC (2-vessel: HR 1.61 [95% CI 1.14 to 2.25], 3-vessel: 1.99 [1.44 to 2.77], and 4-vessel: 2.22 [1.53 to 3.23]). “Diffuse” CAC was associated with a higher mortality rate in the CAC 101 to 400 and >400 groups. Left main CAC was associated with increased mortality risk. In conclusion, increasing number of vessels with CAC and left main CAC predict increased all-cause mortality and improve the prognostic power of the traditional Agatston CAC score.
CAC scoring correlates with the overall burden of coronary atherosclerosis, inclusive of both noncalcified and fully calcified coronary atheromatous plaque. Although the Agatston CAC score is the most widely used method for CAC determination, it does not account for the regional distribution of CAC. Although a high Agatston CAC score may correlate with more diffuse coronary atherosclerosis, a single calcified coronary atherosclerotic lesion may account for most CAC seen in a given patient. A burgeoning body of evidence supports the finding that more diffuse coronary atherosclerosis is associated with a worse prognosis. Whether multivessel, diffuse CAC portends a worse prognosis compared with single-vessel CAC involvement in patients with similar overall CAC scores is unknown. We sought to describe the heterogeneity between the Agatston CAC score and simple measures of CAC distribution. We then sought to assess the added impact of CAC distribution in addition to the overall Agatston CAC score on the prediction of all-cause mortality in a large cohort of patients referred for CAC scoring based on cardiovascular risk factors.
Methods
The study cohort consisted of 23,058 asymptomatic adults referred for electron beam computed tomography (CT) for the assessment of subclinical atherosclerosis. This study incorporated data from 2 centers during the time period 1991 to2004 (Torrance, California [n = 14,657]; Columbus, Ohio [n = 8,401]), both of which used a common CAC scanning protocol. Methods of data collection were similar for both centers. Participants were referred by their primary physicians on the basis of established cardiovascular risk factors for atherosclerosis.
As an inclusion criterion, patients were determined to be free of known CAD based on previous assessment by the referring physician. All participants provided informed consent to undergo electron beam CT and for the use of their de-identified data for epidemiologic research. The study was conducted in accordance with the Declaration of Helsinki and received approval from the Humans Investigations Committee at each site. Separate Committee approval was also obtained for patient interviews and collection of baseline and follow-up data.
Participants completed a questionnaire for the collection of demographic and clinical characteristics, including baseline cardiovascular risk factors. Cigarette smoking was present if a subject was a smoker at the time of scanning. Dyslipidemia was defined by the presence of a history of high total cholesterol, high low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, hypertriglyceridemia, or current use of lipid-lowering therapy. Study subjects were considered to have diabetes mellitus if they reported using oral antidiabetes medications or insulin. Hypertension was defined as a self-reported history of hypertension or use of antihypertensive medication. Family history of premature CHD was determined solely by the presence of a first-degree relative with a history of CHD (men <55 years old/women <65 years old [Torrance, California]; <55 year old for both male and female relatives in 8,042 participants [Columbus, Ohio]).
All subjects underwent CAC scoring with either a C-100 or a C-150 Ultrafast CT scanner (GE-Imatron, South San Francisco, California). Using a tomographic slice thickness of 3 mm, a total of approximately 40 sections were obtained from the level of the carina to the diaphragm. Image acquisition was electrocardiographically triggered at 60% to 80% of the R-R interval, using a 100 ms/slice scanning time. A calcified lesion was defined as ≥3 contiguous pixels with a peak attenuation ≥130 Hounsfield units. Lesions were scored using the method developed by Agatston et al.
Participants’ overall Agatston CAC scores were categorized into 4 distinct CAC groups, representing increasing severity of CAC (CAC = 0, CAC 1 to 100, CAC 101 to 400, CAC >400). The number of vessels with CAC was described as an ordinal variable, accounting for the cumulative involvement of the left main, left anterior descending, left circumflex, and right coronary arteries (range 0 to 4). For patients with multivessel CAC (≥2 vessels involved), concentrated CAC was defined as the presence of >75% of the overall Agatston CAC score in the single most affected vessel, whereas diffuse CAC was defined as ≤75% overall Agatston CAC score in the most affected vessel.
To express the dispersion of CAC as a continuous variable, the maximal percentage of CAC in the most affected vessel was also determined. “CAC diffusivity” was defined by the following equation: (1 − maximal percentage of CAC in most affected vessel) and represented the relative dispersion of CAC within the coronary tree in patients with multivessel CAC. If CAC were highly concentrated in the single most affected vessel, this would result in a low “diffusivity” score. Conversely, if CAC were widely dispersed within the coronary tree leading to a low fraction of overall CAC in the single most affected vessel, the “diffusivity” score would be higher.
Patients were followed for a mean of 5.6 ± 2.6 years (range 1 to 13 years). The primary end point for the study cohort was all-cause mortality. Ascertainment of mortality was conducted using the Social Security Death Index and was verified by subjects blinded to baseline historical data and electron beam CT results. The US Social Security Death Index is a national registry of all deaths that occur within the United States and is a validated research tool for determining all-cause mortality. Follow-up, therefore, occurred by studying this database for the reporting of the deaths of patients enrolled in the study, allowing for mortality ascertainment in 100% of participants. Follow-up was not obtained by direct contact with patients, either by clinic visits or by telephone.
Chi-square testing was used to determine statistical significance between categorical variables, whereas analysis of variance was used to compare the means across continuous variables. Using standard survival statistics, the death rate/1,000 person-years was calculated per number of vessels with CAC, stratifying by CAC groups. A similar analysis was conducted for diffuse CAC. Multivariable Cox regression analysis was used to determine the hazard ratio of mortality for each measure of regional CAC distribution: number of vessels with CAC, concentrated versus diffuse CAC, CAC diffusivity, and the Agatston score in individual coronary arteries.
Adjustment included age, gender, Agatston CAC score (to adjust for residual confounding within each CAC group), hypertension, diabetes, hyperlipidemia, smoking, and a family history of premature CAD. As appropriate, the Agatston score was modeled as both the continuous score and by conventional CAC score groups. When modeling the number of vessels with CAC, single-vessel CAC was considered the reference group. CAC “diffusivity,” a measure of the extent of regional involvement of CAC, was modeled per 10% more diffuse distribution.
All statistical analyses were performed with STATA, version 13 (STATA Corp., College Station, Texas).
Results
The mean age of the study population was 58 ± 11 years old. The population was predominantly men (78%). CAC was present in 61% of the overall study cohort (14,084 of 23,058). The proportion of patients with hypertension, diabetes, hyperlipidemia, smoking, and a family history of premature CAD increased progressively with increasing number of vessels with CAC ( Table 1 ). Data on BMI were available for 6,839 patients, demonstrating a progressive increase in BMI with increasing coronary vessel involvement from 26.7 to 28.1 kg/m 2 (p <0.001, data not shown). Similarly, ethnicity data were available for 48% of the population, with these data showing more CAC with a more diffuse CAC distribution pattern in Caucasians compared with other races (p <0.001, Supplemental Figure 1 ).
| Variable | Total | CAC>0 | Number of Arteries With CAC | p-value across groups | ||||
|---|---|---|---|---|---|---|---|---|
| 0 ∗ | 1 | 2 | 3 | 4 | ||||
| Age: mean, years (SD) (n = 23,058) | 55 (11) | 58 (11) | 50 (9) | 54 (10) | 57 (10) | 61 (10) | 65 (10) | <0.001 |
| Male Gender (n=23,058) | 69% | 78% | 54% | 70% | 77% | 84% | 87% | <0.001 |
| Hypertension † | 30% | 36% | 20% | 26% | 35% | 43% | 49% | <0.001 |
| Diabetes mellitus † | 7% | 9% | 3% | 5% | 9% | 13% | 15% | <0.001 |
| Smoker † | 9% | 10% | 8% | 9% | 10% | 11% | 12% | <0.001 |
| Dyslipidemia † | 35% | 40% | 25% | 32% | 40% | 46% | 51% | <0.001 |
| Family History Premature CHD † | 44% | 46% | 42% | 44% | 45% | 47% | 50% | <0.001 |
Of the 14,084 patients with CAC, the median Agatston CAC score was 63 units (interquartile range 11 to 277, Table 2 ), whereas the mean number of vessels with CAC per patient was 2.2 ± 1.0. The majority of patients had CAC in the left anterior descending artery territory (84%), with a decreasing frequency in the right coronary (67%), circumflex (50%), and left main arteries (17%). Among patients with multivessel CAC (≥2 vessels), the mean maximal percentage of CAC in 1 vessel was 69%, whereas the proportion of patients with a diffuse CAC pattern was 62%.
| Coronary Artery Distribution | % With CAC | Mean CAC score (Standard Deviation) | Median CAC score (Inter-quartile Range) |
|---|---|---|---|
| Overall (N=14,084) | 100% | 285 (594) | 63 (11 -277) |
| Coronary Artery | |||
| Left Main | 17% | 8 (40) | 0 (0-0) |
| Left Anterior Descending | 84% | 134 (244) | 35 (3 –154) |
| Left Circumflex | 50% | 45 (140) | 0 (0 – 22) |
| Right | 67% | 98 (291) | 4 (0 – 53) |
In the CAC 1 to 100 group, 85% of patients had 1- or 2-vessel CAC, with a much smaller proportion of patients with 3- (14%) and 4-vessel CAC (2%). Conversely, for patients with CAC >400, there was a predominance of patients with 3- and 4-vessel CAC, with only 1% and 11% of patients having 1- or 2-vessel CAC, respectively. The intermediate CAC range (101 to 400) was far more heterogeneous, with a wider dispersion of the number of vessels involved ( Figure 1 ).
Within both the CAC 1 to 100 and 101 to 400 groups, the annual mortality rate increased as the number of vessels with CAC increased ( Figure 2 ). The mortality rate for the CAC >400 group was uniformly elevated regardless of the number of vessels with CAC.
Diffuse CAC was associated with a higher annual mortality rate compared with concentrated CAC, both in the overall multivessel CAC subset and in patients with moderate and high CAC (101 to 400 and >400; Figure 2 ). In patients with mild CAC (1 to 100), there was no difference in mortality rate between patients with diffuse or concentrated CAC.
After adjusting for demographic variables, cardiovascular risk factors, and the Agatston CAC score, increasing number of vessels with CAC was associated with an incrementally increased risk of all-cause mortality compared with single-vessel CAC, regardless of whether the Agatston CAC score was adjusted for as a continuous variable or by CAC score groups ( Table 3 ). Patients with 3- and 4-vessel CAC were at an approximately twofold increased risk of death after adjusting for overall Agatston CAC score (3-vessel CAC: HR 1.99 [95% CI 1.44 to 2.77] and 4-vessel CAC: 2.22 [1.53 to 3.23]).
| Number of Coronary Arteries | Agatston Score by CAC Groups | Agatston CAC Score (continuous) | ||
|---|---|---|---|---|
| Model 1 | Model 2 | Model 1 | Model 2 | |
| 1 (N=4494) | 1 | 1 | 1 | 1 |
| 2 (N=4188) | 1.36 (1.00-1.86) | 1.45 (1.03 – 2.05) | 1.54 (1.14-2.09) | 1.61 (1.14 – 2.25) |
| 3 (N=3963) | 1.55 (1.11-2.15) | 1.62 (1.12 – 2.33) | 1.99 (1.49-2.67) | 1.99 (1.44 – 2.77) |
| 4 (N=1439) | 1.87 (1.28-2.74) | 1.91 (1.26 – 2.90) | 2.33 (1.67-3.25) | 2.22 (1.53 – 3.23) |
When mortality risk was stratified by individual CAC groups ( Table 4 ), there was a trend toward increased mortality risk in the mild-moderate CAC groups (CAC 1 to 400) with increasing number of vessels with CAC, which achieved borderline statistical significance (2-vessel CAC: HR 1.51 [95% CI 1.05 to 2.16], 3-vessel CAC: 2.72 [1.07 to 6.90], and 4-vessel CAC: 2.67 [0.94 to 7.63]). The addition of increasing number of vessels with CAC was not associated with an incremental increased mortality risk in the CAC >400 group.
| CAC Group | No Vessels | Model 1 ∗ Hazard Ratio | Model 1 ∗ P-value | Model 2 † Hazard Ratio | Model 2 † P-value |
|---|---|---|---|---|---|
| 1-100 | 1 | 1 | — | 1 | — |
| 2 | 1.23 (0.85-1.79) | 0.27 | 1.33 (0.88-2.02) | 0.18 | |
| 3 | 1.19 (0.73-1.96) | 0.49 | 1.20 (0.69-2.09) | 0.51 | |
| 4 | 1.89 (0.74-4.82) | 0.18 | 1.52 (0.53-4.39) | 0.43 | |
| 101-400 | 1 | 1 | — | 1 | — |
| 2 | 2.31 (0.90-5.89) | 0.08 | 2.14 (0.83-5.51) | 0.12 | |
| 3 | 2.99 (1.19-7.51) | 0.02 | 2.72 (1.07-6.90) | 0.04 | |
| 4 | 2.75 (0.98-7.72) | 0.05 | 2.67 (0.94-7.63) | 0.07 | |
| Intermediate CAC (1-400) | 1 | 1 | — | 1 | — |
| 2 | 1.37 (0.99-1.89) | 0.05 | 1.51 (1.05-2.16) | 0.03 | |
| 3 | 1.61 (1.12-2.30) | 0.01 | 1.67 (1.11-2.50) | 0.01 | |
| 4 | 1.63 (094-2.83) | 0.08 | 1.68 (0.92-3.04) | 0.09 | |
| >400 | 1 | 1 | — | 1 | — |
| 2 | 0.88 (0.12-6.6) | 0.91 | 0.83 (0.11-6.40) | 0.86 | |
| 3 | 0.81 (0.11-5.8) | 0.83 | 0.90 (0.12-6.49) | 0.92 | |
| 4 | 0.93 (0.13-6.7) | 0.94 | 0.99 (0.14-7.15) | 0.99 |
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