Sanjay Rajagopalan

Ammar Hoori, Sadeer Al-Kindi, Tao Hu et al.

Background. Coronary artery calcium (CAC) is a powerful predictor of major adverse cardiovascular events (MACE). Traditional Agatston score simply sums the calcium, albeit in a non-linear way, leaving room for improved calcification assessments that will more fully capture the extent of disease. Objective. To determine if AI methods using detailed calcification features (i.e., calcium-omics) can improve MACE prediction. Methods. We investigated additional features of calcification including assessment of mass, volume, density, spatial distribution, territory, etc. We used a Cox model with elastic-net regularization on 2457 CT calcium score (CTCS) enriched for MACE events obtained from a large no-cost CLARIFY program (ClinicalTri-als.gov Identifier: NCT04075162). We employed sampling techniques to enhance model training. We also investigated Cox models with selected features to identify explainable high-risk characteristics. Results. Our proposed calcium-omics model with modified synthetic down sampling and up sampling gave C-index (80.5%/71.6%) and two-year AUC (82.4%/74.8%) for (80:20, training/testing), respectively (sampling was applied to the training set only). Results compared favorably to Agatston which gave C-index (71.3%/70.3%) and AUC (71.8%/68.8%), respectively. Among calcium-omics features, numbers of calcifications, LAD mass, and diffusivity (a measure of spatial distribution) were important determinants of increased risk, with dense calcification (>1000HU) associated with lower risk. The calcium-omics model reclassified 63% of MACE patients to the high risk group in a held-out test. The categorical net-reclassification index was NRI=0.153. Conclusions. AI analysis of coronary calcification can lead to improved results as compared to Agatston scoring. Our findings suggest the utility of calcium-omics in improved prediction of risk.

Hao Wu, Yingnan Song, Ammar Hoori et al.

Features of pericoronary adipose tissue (PCAT) assessed from coronary computed tomography angiography (CCTA) are associated with inflammation and cardiovascular risk. As PCAT is vascularly connected with coronary vasculature, the presence of iodine is a potential confounding factor on PCAT HU and textures that has not been adequately investigated. Use dynamic cardiac CT perfusion (CCTP) to inform contrast determinants of PCAT assessment. From CCTP, we analyzed HU dynamics of territory-specific PCAT, myocardium, and other adipose depots in patients with coronary artery disease. HU, blood flow, and radiomics were assessed over time. Changes from peak aorta time, Pa, chosen to model the time of CCTA, were obtained. HU in PCAT increased more than in other adipose depots. The estimated blood flow in PCAT was ~23% of that in the contiguous myocardium. Comparing PCAT distal and proximal to a significant stenosis, we found less enhancement and longer time-to-peak distally. Two-second offsets [before, after] Pa resulted in [ 4-HU, 3-HU] differences in PCAT. Due to changes in HU, the apparent PCAT volume reduced ~15% from the first scan (P1) to Pa using a conventional fat window. Comparing radiomic features over time, 78% of features changed >10% relative to P1. CCTP elucidates blood flow in PCAT and enables analysis of PCAT features over time. PCAT assessments (HU, apparent volume, and radiomics) are sensitive to acquisition timing and the presence of obstructive stenosis, which may confound the interpretation of PCAT in CCTA images. Data normalization may be in order.

Juhwan Lee, Sadeer Al-Kindi, Ammar Hoori et al.

Non-contrast computed tomography calcium scoring (CTCS) is widely recognized as an effective tool for cardiovascular risk stratification. This study aimed to develop a novel machine learning framework for predicting myocardial ischemia from routine non-contrast CTCS scans using quantitative coronary calcium assessment. This study analyzed 1,375 patients who underwent both non-contrast CTCS and regadenoson stress cardiac positron emission tomography myocardial perfusion imaging within one year at University Hospitals Cleveland Medical Center. A total of 74 variables, including clinical variables, Agatston score, and calcium-omics features, were evaluated. Relevant features were identified using XGBoost with Shapley Additive exPlanations (SHAP). Predictive models were trained and evaluated using 5-fold cross-validation. Among 987 patients, 89 (9%) were positive for myocardial ischemia. The final model incorporated the Agatston score, eight calcium-omics features, and age. The proposed model achieved a precision of 98.9+/-3.0%, sensitivity of 79.2+/-8.4, and F1 score of 87.7+/-5.3%. The addition of calcium-omics features significantly improved predictive performance compared with models using clinical variables alone or clinical variables with the Agatston score (p<0.05). Interestingly, the number of calcified arteries, despite being the lowest-ranked feature based on SHAP analysis, showed the strongest association with myocardial ischemia in logistic regression analysis (odds ratio: 3.63, 95% confidence interval: 2.80-4.77, p<0.00001). We developed a machine learning approach for predicting myocardial ischemia using routinely acquired non-contrast CTCS scans. Calcium-omics features provided incremental predictive value beyond conventional risk factors and Agatston scoring and may support more accessible cardiovascular risk stratification.

Juhwan Lee, Ammar Hoori, Tao Hu et al.

Non-contrast computed tomography calcium scoring (CTCS) is a cost-effective imaging modality widely used to detect coronary artery calcifications. This study aimed to develop an advanced machine learning framework that utilizes quantitative analyses of coronary calcium and epicardial fat from CTCS images to predict obstructive coronary artery disease (CAD). The study population consisted of 1,324 patients from the SCOT-HEART clinical trial who underwent both CTCS and coronary CT angiography. We extracted and analyzed a broad range of features, including 24 clinical variables, 189 calcium-omics, and 211 epicardial fat-omics features from the CTCS images. Feature selection was conducted using the CatBoost algorithm combined with SHapley Additive exPlanation (SHAP) values. Predictive modeling utilized the CatBoost gradient boosting method, focusing on the most informative features. From an initial set of 424 candidate features, 14 were identified as most predictive through the CatBoost-SHAP method. The top two predictive features originated from fat-omics, with the remaining 12 features derived from calcium-omics. The optimized model achieved robust predictive capabilities, demonstrating a sensitivity of 83.1+/-4.6%, specificity of 93.8+/-1.7%, accuracy of 85.3+/-2.0%, and an F1 score of 73.9+/-3.3%. Inclusion of calcium-omics and fat-omics data significantly improved predictive performance. Notably, the model also showed reliable predictive accuracy in patients with diverse coronary calcium scores, including cases with obstructive CAD despite a zero-calcium score. This innovative approach holds promise for improving clinical decision-making and potentially reducing dependence on contrast-enhanced or invasive diagnostic procedures, particularly within low-to intermediate-risk patient groups.

Tao Hu, Joshua Freeze, Prerna Singh et al.

Background: Recent studies have used basic epicardial adipose tissue (EAT) assessments (e.g., volume and mean HU) to predict risk of atherosclerosis-related, major adverse cardiovascular events (MACE). Objectives: Create novel, hand-crafted EAT features, 'fat-omics', to capture the pathophysiology of EAT and improve MACE prediction. Methods: We segmented EAT using a previously-validated deep learning method with optional manual correction. We extracted 148 radiomic features (morphological, spatial, and intensity) and used Cox elastic-net for feature reduction and prediction of MACE. Results: Traditional fat features gave marginal prediction (EAT-volume/EAT-mean-HU/ BMI gave C-index 0.53/0.55/0.57, respectively). Significant improvement was obtained with 15 fat-omics features (C-index=0.69, test set). High-risk features included volume-of-voxels-having-elevated-HU-[-50, -30-HU] and HU-negative-skewness, both of which assess high HU, which as been implicated in fat inflammation. Other high-risk features include kurtosis-of-EAT-thickness, reflecting the heterogeneity of thicknesses, and EAT-volume-in-the-top-25%-of-the-heart, emphasizing adipose near the proximal coronary arteries. Kaplan-Meyer plots of Cox-identified, high- and low-risk patients were well separated with the median of the fat-omics risk, while high-risk group having HR 2.4 times that of the low-risk group (P<0.001). Conclusion: Preliminary findings indicate an opportunity to use more finely tuned, explainable assessments on EAT for improved cardiovascular risk prediction.

Yingnan Song, Hao Wu, Juhwan Lee et al.

We investigated the feasibility and advantages of using non-contrast CT calcium score (CTCS) images to assess pericoronary adipose tissue (PCAT) and its association with major adverse cardiovascular events (MACE). PCAT features from coronary CTA (CCTA) have been shown to be associated with cardiovascular risk but are potentially confounded by iodine. If PCAT in CTCS images can be similarly analyzed, it would avoid this issue and enable its inclusion in formal risk assessment from readily available, low-cost CTCS images. To identify coronaries in CTCS images that have subtle visual evidence of vessels, we registered CTCS with paired CCTA images having coronary labels. We developed a novel axial-disk method giving regions for analyzing PCAT features in three main coronary arteries. We analyzed novel hand-crafted and radiomic features using univariate and multivariate logistic regression prediction of MACE and compared results against those from CCTA. Registration accuracy was sufficient to enable the identification of PCAT regions in CTCS images. Motion or beam hardening artifacts were often present in high-contrast CCTA but not CTCS. Mean HU and volume were increased in both CTCS and CCTA for MACE group. There were significant positive correlations between some CTCS and CCTA features, suggesting that similar characteristics were obtained. Using hand-crafted/radiomics from CTCS and CCTA, AUCs were 0.82/0.79 and 0.83/0.77 respectively, while Agatston gave AUC=0.73. Preliminarily, PCAT features can be assessed from three main coronary arteries in non-contrast CTCS images with performance characteristics that are at the very least comparable to CCTA.