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By design, this is a hypothesis-free unbiased discovery study collecting a large number of biologically related factors to examine biological associations between genomic, proteomic, metabolomic, lipidomic, and phenotypic factors of atherosclerosis. The Genetic Loci and the Burden of Atherosclerotic Lesions study (NCT01738828) is a prospective, multicenter, international observational study of atherosclerotic coronary artery disease. Approximately 7500 patients are enrolled and undergo non-contrast-enhanced coronary calcium scanning by CT for the detection and quantification of coronary artery calcium, as well as coronary artery CT angiography for the detection and quantification of plaque, stenosis, and overall coronary artery disease burden. In addition, patients undergo whole genome sequencing, DNA methylation, whole blood-based transcriptome sequencing, unbiased proteomics based on mass spectrometry, as well as metabolomics and lipidomics on a mass spectrometry platform. The study is analyzed in 3 subsequent phases, and each phase consists of a discovery cohort and an independent validation cohort. For the primary analysis, the primary phenotype will be the presence of any atherosclerotic plaque, as detected by cardiac CT. Additional phenotypic analyses will include per patient maximal luminal stenosis defined as 50% and 70% diameter stenosis. Single-omic and multi-omic associations will be examined for each phenotype; putative biomarkers will be assessed for association, calibration, discrimination, and reclassification.

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Computed tomography coronary angiography (CTA) is a novel, non-invasive method for coronary plaque detection and quantification. We hypothesized that CTA can detect early vessel wall thickening with preserved luminal size in patients without known coronary artery disease and intermediate/high Framingham Risk Score (FRS) compared to those with low FRS. Vessel-wall and plaque geometrical and compositional parameters were measured on CTA in 375 coronary segments with a highly standardized method. These parameters were then compared in patients with low versus intermediate/high FRS. The relationship between coronary artery calcium by non-contrast CT scanning (Agatston score) and percent atheroma volume (PAV) was determined by linear regression. P value <0.05 was considered significant. PAV and remodeling index were significantly higher in patients with intermediate/high FRS compared to those with low FRS (45.9 ± 6.8 vs. 42.3 ± 6.7; P = 0.004) and (0.97 ± 0.15 vs. 0.92 ± 0.13; P = 0.04), while minimal luminal diameter and minimal luminal area were similar. There was significant correlation between Agatston score and PAV (r(2) = 0.42, P = 0.0036). However, Agatston score and plaque compositional parameters were similar between the groups. In conclusion, we demonstrated that CTA can detect early vessel-wall thickening with preserved luminal size in patients with intermediate/high versus low FRS.

Abstract. Conventional whole-heart CAC quantification has been demonstrated to be insufficient in predicting coronary events, especially in accurately predicting near-term coronary events in high-risk adults [1]. In this paper, we propose a lesion-specific CAC quantification framework to improve CAC's near term predictive value in intermediate to high-risk populations with a novel multiple instance support vector machines (MISVM) approach. Our method works on data sets acquired with clinical imaging protocols on conventional CT scanners without modifying the CT hardware or updating the imaging protocol. The calcific lesions are quantified by geometric information, density, and some clinical measurements. A MISVM model is built to predict cardiac events, and moreover, to give a better insight of the characterization of vulnerable or culprit lesions in CAC. Experimental results on 31 patients showed significant improvement of the predictive value with the ROC analysis, the net reclassification improvement evaluation, and the leave-one-out validation against the conventional methods.