By Michael H. Crawford, MD

Professor of Medicine, Associate Chief for Education, Division of Cardiology, University of California, San Francisco

Dr. Crawford reports no financial relationships relevant to this field of study.

SYNOPSIS: Researchers identified subjects with no known coronary artery disease drawn from a large international, multicenter registry of coronary CT angiography. The authors demonstrated those with a high density of calcium plaques experienced the fewest events, suggesting high-density calcium plaques are stable.

SOURCE: van Rosendael AR, et al. Association of high-density calcified 1K plaque with risk of acute coronary syndrome. JAMA Cardiol 2020; Jan 22. doi: 10.1001/jamacardio.2019.5315. [Epub ahead of print].

Coronary artery plaque characteristics are believed to be important for assessing the likelihood of plaque rupture, based largely on pathology studies. Although the presence of coronary artery calcium on CT scans identifies plaques, more does not necessarily predict subsequent coronary events.

Van Rosendael et al sought to determine the relationship between increasing density of calcified plaque and the risk of an acute coronary syndrome (ACS). They developed a case-controlled, nested study called ICONIC. Using information from the CONFIRM registry, van Rosendael et al identified subjects with no known coronary artery disease (CAD), who had undergone coronary CT angiography (CCTA), and who had been followed for four years. Patients who experienced an ACS event were matched with those who did not, which resulted in 189 pairs. The density of coronary plaques was expressed in Hounsfield units (HU). Plaques were categorized as necrotic core, fibro-fatty, fibrous, and calcified based on HU strata: < 30, 31-130, 131-350, and > 350, respectively. The authors focused on calcified plaques, and divided those into three groups: 351-700 HU, 701-1,000 HU, and > 1,000 HU. The latter group was termed 1K plaque. The mean age of the study population was 60 years, and 65% were men.

Total plaque volume was similar in the paired group. However, with each increasing calcium density stratum, calcium volume was lower in ACS subjects than in non-ACS subjects. The mean volume of 1K plaque in the ACS patients was 3.9 vs. 9.4 for the control subjects (P = 0.02). But for subjects > age 75 years, 1K plaque did not differ between patients and controls. Among the participants in the highest quartile of 1K plaque in both groups, there was more calcified plaque (48% vs. 25%; P < 0.001) and relatively less necrotic core plus fibro-fatty plaque (13% vs. 25%; P < 0.001) compared to the other three quartiles. The authors concluded that on a per patient basis, the measure of high-density (> 1,000 HU), calcified plaque was associated with a lower risk of subsequent ACS.


The Multi-Ethnic Study of Atherosclerosis (MESA) study included subjects without known CAD. Those authors, using non-contrast, older generation CT scanners, showed that coronary artery calcium (CAC) volume and density were more predictive of the risk of CAD events than the pooled atherosclerosis risk score. The MESA authors used the Agatston score to assess calcium volume, which is upwardly weighted for more density of calcium. The authors estimated calcium density from the Agatston score, which was associated with fewer CAD events. Here, van Rosendael et al used newer multislice CT scanners. These machines provide higher HU values because of the effect of contrast, which attenuates vascular structures. These authors demonstrated that higher calcium density reduces the risk of CAD events. This suggests more calcium density equates to plaque stabilization. Thus, the best risk prediction would factor in calcium volume (more risk) and calcium density (less risk). Notably, a high calcium density (> 1,000 HU) showed a significant association with fewer ACS events. Lower values did not, demonstrating the equipoise for CAD events between calcium volume and density at lower densities.

There were limitations to this study. The cohort was a subgroup derived from a larger registry study (CONFIRM), so there was selection bias and unmeasured confounders. In those > age 75 years, there was no association between calcium density and events, but this was a small group that was not as well matched. Also, subjects with total coronary artery occlusions were excluded, and the authors did not provide information on medication use. Thus, the study should be considered hypothesis-generating until a prospective, controlled study is completed.

However, this study does support the results of MESA, extending the observations of those authors using newer CT scanners with contrast images of the coronary arteries. Van Rosendael et al believe the features of atherosclerotic plaques are important for estimating prognosis in those with CAD, and that a high density of calcium represents plaque stability. Pathogenic studies have supported this concept because they have shown that ruptured plaques tend to be fibroatheromas with large necrotic cores and thin, inflamed fibrosis caps. The noninvasive detection of vulnerable plaques is the Holy Grail of coronary imaging.

How does this study of presumably stable high-density calcium plaques help clinicians? Based on the results of other studies, statins increase calcium volume and reduce the volume of the necrotic core in plaques. Presumably, many of the stable patients in the van Rosendael et al study were on statins. If not, would adding a statin to all those with calcium densities < 1,000 HU (but not to those > 1,000 HU) make sense? The former might, but I am not sure about the latter. This study adds support to the plaque stabilization by calcium theory and highlights the lack of value of serial CCTA imaging at this point in technologic development. Also, it emphasizes that the industry has moved on from the Agatston score and the need to use the advanced quantitative features of current CCTA imaging.