Evidence for lower variability of coronary artery calcium mineral mass measurements by multi-detector computed tomography in a community-based cohort—Consequences for progression studies

Abstract

Purpose

To compare the measurement variability for coronary artery calcium (CAC) measurements using mineral mass compared with a modified Agatston score (AS) or volume score (VS) with multi-detector CT (MDCT) scanning, and to estimate the potential impact of these methods on the design of CAC progression studies.

Materials and methods

We studied 162 consecutive subjects (83 women, 79 men, mean age 51 ± 11 years) from a general Caucasian community-based cohort (Framingham Heart Study) with duplicate runs of prospective electrocardiographically-triggered MDCT scanning. Each scan was independently evaluated for the presence of CAC by four experienced observers who determined a “modified” AS, VS and mineral mass.

Results

Of the 162 subjects, CAC was detected in both scans in 69 (42%) and no CAC was detected in either scan in 72 (45%). Calcium scores were low in the 21/162 subjects (12%) for whom CAC was present in one but not the other scan (modified AS <20 in 20/21 subjects, mean AS 4.6 ± 1.9). For all three quantification algorithms, the inter- and intraobserver correlation were excellent (r > 0.96). However, the mean interscan variability was significantly different between mineral mass, modified AS, and VS (coefficient of variation 26 ± 19%, 41 ± 28% and 34 ± 25%, respectively; p < 0.04), with significantly smaller mean differences in pair-wise comparisons for mineral mass compared with modified AS (p < 0.002) or with VS (p < 0.03). The amount of CAC but not heart rate was an independent predictor of interscan variability (r = −0.638, −0.614 and −0.577 for AS, VS, and mineral mass, respectively; all p < 0.0001). The decreased interscan variability of mineral mass would allow a sample size reduction of 5.5% compared with modified AS for observational studies of CAC progression and for randomized clinical trials.

Conclusion

There is significantly reduced interscan variability of CAC measurements with mineral mass compared with the modified AS or VS. However, the measurement variability of all quantification methods is predicted by the amount of CAC and is inversely correlated to the extent of partial volume artifacts. Moreover, the improvement of measurement reproducibility leads to a modest reduction in sample size for observational epidemiological studies or randomized clinical trials to assess the progression of CAC.

Introduction

Coronary artery calcium (CAC) can be detected by electron beam computed tomography (CT) and multi-detector computed tomography (MDCT). While CAC measurements may be potentially helpful to identify asymptomatic individuals at increased risk for cardiovascular events [1], [2], [3], [4], it has been proposed that CT-based measurements of CAC may be valuable for predicting risks for coronary events or for monitoring the natural progression of coronary artery disease or the response to therapeutic interventions such as lipid-lowering therapy [5], [6], [7].

Three algorithms have been generally used to determine the amount of CAC. The Agatston score (AS) method was developed for electron beam CT, but it has been used with minor modifications for MDCT. The interscan reproducibility of the AS method is moderate, ranging from 15 to 21% [8], [9], [10], [11]. The volume score (VS) has improved reproducibility as compared with the AS (from 9 to 16%) [9], [11]. However, the VS is susceptible to partial volume artifacts and may not be adequate to compare CAC measurements obtained using different CT protocols (slice thickness, tube energy) and scanners [12].

A third algorithm, the calculation of mineral mass, provides an actual quantitative measurement of CAC and, as such, has been proposed to be a superior measurement method that could replace the AS or VS methods [11], [13], [14]. Mineral mass measurements require calculation of calcium concentration (CC) within calcified plaques based upon the calibration of the CT attenuation using a reference calcium hydroxyapatite phantom [15], [16]. Ex vivo studies on phantoms [17], [18] and excised arterial specimens [12] have demonstrated that calibrated mineral mass accurately measures the mineral content of calcified atherosclerotic plaques. Mineral mass measurements may allow for better correction for variation of CAC measurements due to individual scanner type, scan parameter (tube energy, image noise) and patient-dependent factors [12], [13], [15], [19], [20]. It is also possible that there is significantly reduced interscan variability of CAC measurements determined by the mineral mass method [11], [12].

One potential advantage of mineral mass would be for accurate quantification of plaque progression. CAC appears to consistently progress with increasing age [21], [22]. Electron beam CT studies have demonstrated that the relative natural progression over time is a function of the presence and amount of baseline CAC [6], [7], [23], [24]. In addition, some studies in small selected patient cohorts report a significantly slower progression of CAC measured by electron beam CT in subjects receiving lipid-lowering therapy as compared to untreated subjects (17–60% for VS) [5], [6], [25], [26]. An association between a reduction in low-density lipoprotein levels and a reduction of CAC progression in the treated groups has been suggested [5], [6], [7], [23]. However, other studies failed to demonstrate an association between changes in low-density lipoprotein and CAC progression or differences in CAC progression between treated and untreated subjects [7], [27]. It is possible that the discordant results of these studies were due to either patient selection or measurement variability of CAC. A CAC measurement with improved interscan reproducibility would facilitate research on CAC progression and the effect of therapeutic interventions.

The goal of this study was to determine the reproducibility of CAC measurements by mineral mass compared with modified AS and VS in a general community-based cohort, and to estimate the effect of improved reproducibility of CAC measurements on observational studies and randomized clinical trials on the progression of CAC.