Associations of coronary artery calcified plaque density with mortality in type 2 diabetes: the Diabetes Heart Study

Many studies have found computed tomography (CT)-based measures of calcified plaque in the coronary arteries (CAC) to be predictive of cardiovascular disease (CVD) events and mortality, independent from traditional CVD risk factors [1–5]. CAC is also a powerful independent risk factor for CVD and mortality in individuals with type 2 diabetes (T2D) [6–9], with elevated CAC burden in diabetic patients compared to non-diabetic individuals [10]. This is of particular interest due to the elevated CVD risk in individuals with T2D, with mortality risk from CVD increased two- to fourfold and approximately 68% of T2D-affected individuals age 65 or older succumbing to CVD [11].

Recent work from the Multi-Ethnic Study of Atherosclerosis (MESA) found that increased CAC density, in models adjusted for plaque volume, was associated with a decreased risk of coronary heart disease (CHD) events (HR of 0.73, 95% CI 0.58–0.91 per standard deviation increase) and all CVD events, with improved risk prediction for CHD and CVD events with the inclusion of density [12]. These results were contrary to the assumptions of using Agatston scores to assess CAC, as those scores are weighted for increased density [13, 14], and the results have been confirmed in re-analysis of the MESA dataset with additional events from 11 years median follow-up [15]. Further study of the role of calcified plaque density in CVD risk appears to be warranted. We evaluated the associations of CAC density measures with incident mortality in a high risk population with T2D, including participants of both European American (EA) and African American (AA) descent from the Diabetes Heart Study (DHS) and African American-Diabetes Heart Study (AA-DHS).

Demographic characteristics of AA and EA participants in the DHS and AA-DHS included in calcified plaque density analyses are summarized in Table 1. Mean diabetes duration was 10.6 ± 7.2 years [mean ± standard deviation (SD)] in EA participants and 10.7 ± 7.9 years in AA participants. 44.7% of EA participants and 35.7% of AA participants had a history of CVD, and mean BMI was > 30 kg/m² in both groups. While burden of subclinical CVD was extensive in both groups, EA participants had higher median calcified plaque volume (361) than AA participants (90), consistent with prior reports [16–18]. Using a 90 HU threshold, there were 901 EA participants with a non-zero Agatston score (median 365) and 551 AA participants with a non-zero score (median 82); as expected, fewer individuals had a non-zero Agatston score at the less sensitive but more specific 130 HU threshold, with 816 EA participants with a non-zero Agatston score (median 331) and 446 AA participants with a non-zero score (median 110). Incident all-cause mortality was greater for EA participants (31.7%) than AA participants (16.9%) as well, likely in part due to longer follow-up time in EA participants.

In both EA (Additional file 1: Table S1) and AA (Additional file 1: Table S2) participants, the CAC measures are highly correlated, with volume and Agatston score at the 90 HU and 130 HU threshold very highly correlated in both groups (r > 0.95). Volume and Agatston score measures were also significantly correlated with density in AA and in EA participants (r > 0.66).

As a supplementary analysis, we also analyzed associations of CAC measures with self-reported history of CVD and MI. In EA participants, all CAC measures, including density, were associated with higher odds of having a history of CVD and MI events (p ≤ 4.65 × 10⁻⁶), with similar results in AA participants (p ≤ 1.84 × 10⁻⁴) (Additional file 1: Table S3). With density and volume measures included in the same model, in EA participants both volume and density were associated with higher odds of prior CVD and MI (p ≤ 0.046); trends were similar but density was not significantly associated in AA participants (Additional file 1: Table S4).

Finally, to increase comparability of our results with the prior analysis of calcified plaque density in the MESA cohort [12], we repeated our analyses with an alternate measure of plaque density (Agatston score over area), which was derived in MESA as reliable mass measurements were unavailable. Results were broadly similar; higher density was associated with higher CVD mortality and higher odds of history of CVD and MI in EA and AA participants (p ≤ 0.014), as well as with higher all-cause mortality in EAs (p = 9.62 × 10⁻⁶) (Additional file 1: Table S5). Adjusting for volume, no significant associations with this alternate density measure remained (Additional file 1: Table S6).

The utility of CAC, usually assessed using Agatston or volume measures, in predicting CVD events and mortality is well-established in the general population [1–5] and in those with T2D [6–9]. Questions remain concerning whether CAC plaque density adds to the predictive power of CAC volume. This analysis from the DHS in both EA and AA participants with T2D assessed associations of multiple CAC measures, including plaque volume, Agatston scores, and density, with incident mortality. We found that all of these CAC measures, including density, were associated higher risk of all-cause and CVD mortality in EA participants. In models adjusted for volume, however, no independent associations with density measures remained. Results were broadly similar in AA participants, though no association of density unadjusted for volume with mortality risk was observed. These results do not suggest a consistent association of CAC density with mortality independent of volume in patients with T2D.

While our results do not suggest an independent relationship of calcified plaque density with mortality, further study is needed to assess how the characteristics of calcified and non-calcified plaque may contribute to CVD risk. Our scans are done with non-contrast CT and we can comment on characteristics such as density for calcified plaque only, not the non-calcified portions; total coronary plaque area is generally ~ 5 times greater than calcified plaque area [27]. We did not assess more specific plaque characteristics such as the fibrous cap thickness or consider differential mortality risk based on characteristics such as lesion number and location in the coronary arteries [28]. Further understanding of plaque characteristics in multiple patient populations, including those with diabetes, may also help evaluate the usefulness of alternate calcified plaque scoring methods and density calculations [29–32], which may have advantages over the Agatston method in certain clinical and research settings (such as increased speed in CAC assessment [32, 33], or increased sensitivity for detecting very small plaques [29]). Plaque characteristics, as opposed to simply total plaque, may also modify observed associations with CVD events. In individuals with diabetes [34], as well as other patient populations [35, 36], some reports suggest that very high CAC scores, which may represent larger, denser plaques, are associated with increased risk of more stable CVD phenotypes (such as angina) versus sudden death or MI; however, in our population, previous work has shown very high mortality rates in individuals with T2D and CAC > 1000 [37], suggesting substantial CVD burden in this population. Further study is needed to determine what levels of CAC and CAC characteristics are associated with particular CVD events, particularly in individuals with T2D.

Results in the DHS differ from those previously observed in MESA, in which the largest existing multi-ethnic study of CAC plaque density was performed. Calcified plaque density unadjusted for volume was not predictive of CHD or CVD events in MESA, but, when models included both CAC volume and CAC density, increased plaque density was associated with a decreased risk of CHD and CVD events [12]. In the DHS, calcified plaque density unadjusted for volume was predictive of higher mortality risk (in EA participants); however, in models adjusted for volume, plaque density was not associated with mortality. There was a non-significant trend towards reduced risk of all-cause and CVD mortality with increased density in models adjusted for volume in African Americans, which would be concordant with the MESA results.

A number of differences exist between our analysis of the DHS and AA-DHS studies and the analysis in MESA. Most notably, our study was limited to participants with T2D, while MESA included only 17.9% T2D-affected participants. However, there was no significant interaction for diabetes in the most recent MESA analysis of density adjusted for volume [15]. The DHS is characterized by a high average burden of CAC, with a mean CAC Agatston score at the 130 HU threshold of 828 in EA participants and 446 in AA participants, compared to a mean CAC Agatston score of 293 for MESA participants, which recruited individuals free of clinical CVD at baseline. MESA had relatively low rates of statin use in those with non-zero CAC (20.1% of participants), likely due to lack of clinical CVD at baseline, while many EA and AA DHS participants reported a history of clinical CVD at baseline (> 35% in both groups), and statin use was higher (> 40%). Statin use may impact the differing relationships of CAC density and CVD in DHS and MESA, though both analyses did adjust for statin use; some studies indicate statins may increase CAC progression [38] and may impact CAC density, for example by reducing low attenuation plaque volume [39, 40]. A recent analysis from MESA suggested that statin use may attenuate the association between calcified plaque density and incident CVD in those with diabetes or metabolic syndrome [41]. We used a more intuitive mass over volume measure for density for our main analyses, though results were similar with an alternate density measure calculated as Agatston score over area (similar to that analyzed in MESA) in supplementary analyses. The Agatston score weighting of area is not based on a true measured density of each pixel, but instead incorporates a weighted measure from 1 to 4 based on the highest density pixel, limiting the interpretability of the Agatston/area estimate [13]. Other differences include smaller sample size, stratification by self-reported ethnicity (supported by significant interactions between self-reported ancestry and calcified plaque measures (p < 0.05) in joint models), higher correlation between density and volume (though no extreme collinearity problems (variance inflation factor > 4) were observed), and no data for incident events. We also acknowledge that inaccuracies in cause of death data from death certificates have been documented [42, 43]; under- or over-reporting by physicians may be a concern for our CVD mortality measure. It should be noted, however, that this ambiguity is not present when assessing all-cause mortality.

Analyses in MESA used the less sensitive but slightly more specific [30] 130 HU threshold for CAC assessment, as compared to use of a 90 HU threshold in the DHS cohorts, which may have contributed to different results between reports, as inclusion of more edge voxels at the 90 HU threshold can impact the measured area, volume, and density. As Agatston scores, but not volume and mass, were recorded in the DHS cohorts at both the 130 and 90 HU thresholds, we attempted to address this difference by limiting our analysis of density, Agatston score, and volume measures from the 90 HU threshold to only those with a non-zero Agatston score at the 130 HU threshold (n = 816 for EA participants, n = 446 for AA participants). Results were similar to the analysis in the full sample, with results displayed in Additional file 1: Tables S7 and S8. We ran similar models in European participants with all participants with an Agatston score less than 10 at the 130 HU threshold excluded. Again, results were similar, suggesting that small, potentially low density calcified plaques are not overly influencing our results.

In the T2D-affected DHS populations higher CAC plaque density was not consistently associated with risk of incident mortality in models adjusted for plaque volume. These results suggest that the role of CAC density may differ in the high CVD risk population of individuals affected by T2D; further study is needed to determine whether CAC density is independently predictive of CVD risk and its direction of effect in different patient populations. Longitudinal analyses of changes in CAC plaque density remain an important future goal.