ACS patients show less dense, calcified plaque than ACS-free controls on clinically indicated CCTA

Association of High-Density Calcified 1K Plaque With Risk of Acute Coronary Syndrome

Literature - Van Rosendael AR, Narula J, Lin FY et al., - JAMA Cardiol. 2020. doi:10.1001/jamacardio.2019.5315

Introduction and methods

Coronary atherosclerotic plaque can be quantified by coronary computed tomography angiography (CCTA). Overall plaque burden is related to future major CV events. Lesions of acute coronary syndrome (ACS) or sudden coronary death often show necrotic lipid-laden cores, positive remodeling, spotty calcification, high cross-sectional plaque burden, high stenosis severity and thin-cap fibroatheroma [1,2]. Evolution of fibroatheromas, the development of sheets of calcification and reduction in necrotic core size are considered stabilizing factors [3].

Little is known about the evolution of calcified coronary plaques, but it has been postulated that increasing Hounsfield unit (HU) density (or brightness) as seen on CCTA may reflect a stabilizing process. The MESA study has previously described an association between higher overall calcium density score and lower risk for major CV events after adjusting for overall calcium volume [4].

This case-control cohort study aimed to ascertain the association between increasing density of calcified plaque and risk of future ACS, by using data of the Incident Coronary Syndromes Identified by Computed Tomography (ICONIC) study [2]. The ICONIC study included patients with no known CAD from the CONFIRM registry, which prospectively collected baseline demographic and clinical data of patients who underwent clinically indicated CCTA for suspected CAD and then followed them for the occurrence of MACE [5].

Patients with site-adjudicated ACS were matched 1:1 to within-site controls who did not experience ACS during the mean follow-up period of 3.9 (2.5) years. Matching was based on CV risk factors and angiographic coronary artery disease (CAD) severity. Total plaque volume did not differ between groups. 189 Participants (<75 years) experiencing core laboratory verified ACS and 189 matched controls were studied (mean age: 59.9, SD: 9.8, 65.3% male).

Main results

  • Patients and controls did not show a different total mean (SD) calcified plaque volume (>350 HU): 76.4 (101.6) mm³ vs. 99.0 (156.1) mm³ (P=0.32).
  • The mean (SD) volume of 1K plaque (>1000 HU) differed significantly (P=0.02) between groups, with 3.9 (8.3) mm³ in patients and 9.4 (23.2) mm³ in controls.
  • When limiting the analysis to patients who experienced myocardial infarction (MI), the result was similar: mean (SD) volume of 1K plaque in patients was 3.6 (7.2) mm³ vs. 10.0 (23.6) mm³ in controls (P=0.01).
  • Patients in the highest quartile of volume of 1K plaque showed a higher overall mean (SD) plaque volume than patients in the other 3 quartiles (539.6 [339.7] mm³ vs. 206 [196.6] mm³, P<0.001), as well as more calcified plaque (48.3% [17.3%] vs. 24.9% [21.0%], P<0.001), and relatively less necrotic core plus fibro-fatty plaque (12.6 [10.4]% vs. 24.9% [20.6], P<0.001).
  • In 93 patients (49.2%) a CCTA precursor lesion for future ACS culprit lesion could be identified with invasive angiography. These culprit precursor lesions had lower mean (SD) volume of 1K plaque (2.6 [7.2] mm³ vs. 7.6 [20.3] mm³, P=0.01) than lesions associated with the greatest stenosis in controls.


Patients who experienced ACS after a clinically indicated baseline CCTA showed a lower per-patient volume of 1K plaque than control individuals who did not experience ACS. The precursor culprit lesions associated with future ACS also showed lower 1K plaque volume than the most severe stenotic lesion in controls. These findings support the hypothesis that higher-density, thus higher calcium content plaque indicates stability and lower risk of ACS.

Editorial comment

In their editorial comment, Criqui et al note that the protective association that has been described previously between higher coronary artery calcium (CAC) density and a lower coronary event risk, was only found after adjustment for CAC volume. This implies that there is an inherent risk of the presence and extent of calcified atherosclerosis, which is partly mitigated by highly dense calcium. The current study adds to the evidence by demonstrating the protective association in persons with image-documented CAD at baseline.

The combined measures of CAC volume and CAC density have been found to be more strongly associated with risk than the combination of standard ASCVD risk factors. Criqui and colleagues agree with the conclusion of the authors that measurement of 1K plaque may improve risk stratification beyond plaque burden. However, they wonder about the therapeutic implication, as ‘Patients with known CAD should receive maximal preventive therapy in any case.’ They acknowledge, however, that new attention to the associations of plaque density may be useful, for instance in light of the available evidence that statins increase calcification and reduce necrotic core volume. Moreover, it is relevant to note that lower levels of CAC volume and higher levels of CAC density have been described for ethnic minorities, compared with non-Hispanic white individuals.


1. Motoyama S, Ito H, Sarai M, et al. Plaque characterization by coronary computed tomography angiography and the likelihood of acute coronary events in mid-term follow-up. J Am Coll Cardiol. 2015;66(4):337-346. doi:10.1016/j.jacc.2015.05.069

2. Chang HJ, Lin FY, Lee SE, et al. Coronary atherosclerotic precursors of acute coronary syndromes. J AmColl Cardiol. 2018;71(22):2511-2522. doi:10.1016/j.jacc.2018.02.079

3. Mori H, Torii S, Kutyna M et al. Coronary artery calcification and its progression: what does it really mean? JACC Cardiovasc Imaging. 2018;11(1):127-142. doi:10.1016/j.jcmg.2017.10.012

4. Criqui MH, Denenberg JO, Ix JH, et al. Calcium density of coronary artery plaque and risk of incident cardiovascular events. JAMA. 2014;311(3): 271-278. doi:10.1001/jama.2013.282535

5. Min JK, Dunning A, Lin FY, et al. Rationale and design of the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) Registry. J Cardiovasc Comput Tomogr. 2011;5(2):84-92. doi:10.1016/j.jcct.2011.01.007

6. Criqui MH, Forbang NI, Thomas IC. The Importance of Coronary Artery Calcium Density. JAMA Cardiol. doi:10.1001/jamacardio.2019.5745

Find this article online at JAMA Cardiol

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