Coronary Atherosclerotic Precursors of Acute Coronary Syndromes

Abstract

Background: The association of atherosclerotic features with first acute coronary syndromes (ACS) has not accounted for plaque burden.

Objectives: The purpose of this study was to identify atherosclerotic features associated with precursors of ACS.

Methods: We performed a nested case-control study within a cohort of 25,251 patients undergoing coronary computed tomographic angiography (CTA) with follow-up over 3.4 ± 2.1 years. Patients with ACS and nonevent patients with no prior coronary artery disease (CAD) were propensity matched 1:1 for risk factors and coronary CTA-evaluated obstructive (≥50%) CAD. Separate core laboratories performed blinded adjudication of ACS and culprit lesions and quantification of baseline coronary CTA for percent diameter stenosis (%DS), percent cross-sectional plaque burden (PB), plaque volumes (PVs) by composition (calcified, fibrous, fibrofatty, and necrotic core), and presence of high-risk plaques (HRPs).

Results: We identified 234 ACS and control pairs (age 62 years, 63% male). More than 65% of patients with ACS had nonobstructive CAD at baseline, and 52% had HRP. The %DS, cross-sectional PB, fibrofatty and necrotic core volume, and HRP increased the adjusted hazard ratio (HR) of ACS (1.010 per %DS, 95% confidence interval [CI]: 1.005 to 1.015; 1.008 per percent cross-sectional PB, 95% CI: 1.003 to 1.013; 1.002 per mm3 fibrofatty plaque, 95% CI: 1.000 to 1.003; 1.593 per mm3 necrotic core, 95% CI: 1.219 to 2.082; all p < 0.05). Of the 129 culprit lesion precursors identified by coronary CTA, three-fourths exhibited <50% stenosis and 31.0% exhibited HRP.

Conclusions: Although ACS increases with %DS, most precursors of ACS cases and culprit lesions are nonobstructive. Plaque evaluation, including HRP, PB, and plaque composition, identifies high-risk patients above and beyond stenosis severity and aggregate plaque burden.

Keywords: acute coronary syndrome; atherosclerosis; clinical outcome; coronary artery disease; coronary computed tomography angiography.

Conflict of interest statement

Disclosures/Conflicts: The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Dr. Chang receives funding from by Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (Grant No. 2012027176); Dr. Min receives funding from the National Institutes of Health (Grant Nos. R01 HL111141, R01 HL115150, R01 118019, and U01 HL 105907), the Qatar National Priorities Research Program (Grant No. 09-370-3-089), and GE Healthcare. Dr. Min served as a consultant to HeartFlow, serves on the scientific advisory board of Arineta, and has an equity interest in MDDX. Dr. Bax receives unrestricted research grants from Biotronik, Medtronic, Boston Scientific and Edwards Lifesciences. Dr. Leipsic serves as a consultant and has stock options in HeartFlow and Circle Cardiovascular Imaging, and receives speaking fees from GE Healthcare. Dr. Budoff receives grant support from the National Institutes of Health and General Electric. Dr. Samady receives grant support from Phillips/Volcano and St. Jude Abbott/Medtronic/Gilead. Dr. Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research and receives research support from CV Diagnostix and educational support from TeraRecon Inc. Dr. Pontone receives institutional research grants from GE Healthcare, HeartFlow, Medtronic, Bracco, and Bayer. Dr. Virmani has received institutional research support from 480 Biomedical, Abbott Vascular, ART, BioSensors International, Biotronik, Boston Scientific, Celonova, Claret Medical, Cook Medical, Cordis, Edwards Lifescience, Medtronic, MicroVention, OrbusNeich, ReCord, SINO Medical Technology, Spectranetics, Surmodics, Terumo Corporation, W.L. Gore and Xeltis. Dr. Virmani also receives honoraria from 480 Biomedical, Abbott Vascular, Boston Scientific, Cook Medical, Lutonix, Medtronic, Terumo Corporation, and W.L. Gore, and is a consultant for 480 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. All other authors have no conflicts of interest to disclose.

Published by Elsevier Inc.

Figures

Figure III-1

Propensity score distribution of candidate cases and controls prior to match

Figure III-2

Propensity score distribution of the 234 case:control pairs in the ICONIC study

Figure V-1. Society of Cardiovascular CT 18-segment Coronary Tree

The same model was applied to both ICA and CCTA in order align baseline CCTAs with follow-up culprit lesions by ICA.

Figure V-2. Determination of culprit lesion by ICA

Blinded adjudication determined the presence of a culprit lesion in the proximal left anterior descending (LAD) artery by the presence of a single significant stenosis on the ICA at the time of downstream ACS. Subsequently unblinded comparison was performed to align the culprit location to the culprit lesion precursor in the proximal LAD in the baseline CCTA.

Figure VI-1

Medis QAngio-CT measurement with center-plane reformat of coronary artery.

Figure 1. CONSORT Diagram for the ICONIC study

ACS, acute coronary syndrome; CAD, coronary artery disease; CDCC, The Clinical and Data Coordinating Center; CTA, coronary computed tomography angiography; MACE, major adverse cardiac event

Central Illustration. Precursors of ACS and controls as identified by CCTA

A. Adjudicated first ACS cases with CCTA measurements (n = 234) of a nested case-control cohort of 25,251 patients undergoing CCTA exhibit elevated fibro-fatty and necrotic core volumes (65.2 ± 95.4 mm3); 34.6% exhibit diameter stenosis ≥50% and 52.1% exhibit high-risk plaque. B. Non-event controls propensity matched by demographics, risk factors, and number of obstructive vessels by CCTA exhibit lesser fibro-fatty and necrotic core volumes (45.6 ± 68.8, multivariate adjusted p = 0.008) with no difference in calcified or total plaque volumes (p = NS for all); %DS and HRP are significantly decreased in control patients (p<0.05 for all). C. Culprit lesion precursors exhibit elevated fibro-fatty and necrotic core volumes (31.32 ± 55.5 mm3). D. Within-patient controls, using the non-culprit with the highest baseline %DS, exhibit lesser total plaque and necrotic core volumes (p<0.05 for both). E. Between-patient controls, using the lesion with the highest %DS in the control patient, exhibit lesser non-calcified plaque components (p = 0.04), but no decrease in calcified plaque volume (p = NS). ACS, acute coronary syndrome; CCTA, coronary computed tomographic angiography; %DS, percent diameter stenosis; HRP, high-risk plaque; NS, nonsignificant.