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Background Mismatches between the severity of coronary stenosis and the presence of ischemia by invasive fractional flow reserve (FFR) are frequently reported. Purpose To investigate whether plaque characteristics as evaluated with coronary computed tomography angiography (CCTA) may explain this discordance in nonobstructive versus obstructive coronary artery disease (CAD). Methods From the CREDENCE trial, 612 patients with suspected CAD at 13 sites (64±10 years, 70% men) underwent CCTA with semi-automated whole heart quantification and invasive coronary angiography with 3-vessel FFR measurements. Obstructive CAD was visually defined as ≥50% stenosis. The primary endpoint of coronary vessel-specific ischemia was defined as FFR ≤0.80. Generalized estimating equations were calculated to evaluate the effect of plaque characteristics on coronary vessel-specific ischemia. Interactions were tested by obstructive CAD, adjusted for age. Results Among 1,686 vessels, ischemia was present in 436 (26%) vessels. In both nonobstructive and obstructive CAD, the majority of plaque characteristics were associated with coronary vessel-specific ischemia (p≤0.005, Figure 1). In nonobstructive CAD, odds for ischemia were significantly higher for total percent atheroma volume (PAV, p Conclusion Our findings reveal that ischemia by FFR is documented in the setting of both nonobstructive and obstructive CAD on CCTA. Detection of atherosclerotic plaque characteristics associated with ischemia can potentially improve diagnostic certainty and guide management of symptomatic patients with nonobstructive CAD. Figure 1. Odds ratios for ischemia. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health - National Heart, Lung, and Blood Institute

Background Evolving evidence suggests unique sex-specific mechanisms underlying coronary artery disease (CAD). However, it remains unknown if certain coronary atherosclerotic features confer a higher risk for ischemia in women versus men. Purpose To determine the association between coronary atherosclerotic features on coronary computed tomography angiography (CCTA) and ischemia by invasive fractional flow reserve (FFR) in women versus men. Methods Secondary analysis of the CREDENCE trial, including patients referred for nonemergent invasive coronary angiography (ICA). All patients underwent CCTA with semi-automatic quantification of coronary atherosclerosis, as well as ICA with FFR interrogation of all major epicardial arteries ≥2 mm. Generalized estimating equations were calculated to assess the association between coronary atherosclerotic features and invasive vessel-specific ischemia (FFR ≤0.80). Sex interactions were tested, adjusted for age. Results From 612 patients (mean age 64±10 years, 30% women) with 1,686 analyzed vessels, a total of 436 (26%) vessels were ischemic. Women were significantly older than men (p30% stenosis (p=0.030), noncalcified PAV Conclusion Our results support a prominent influence of coronary atherosclerotic features that uniquely impact ischemic risk among women more so than men. These data support the role of CCTA for providing valuable information to guide management of symptomatic women. Figure 1. Ischemic risk in women vs. men Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health - National Heart, Lung, and Blood Institute

Background Atherosclerotic plaques in the left circumflex artery (LCx) are associated with a lower risk of future events than plaques in the right coronary artery (RCA) and left anterior descending artery (LAD). High risk plaque subtypes including necrotic core and fibrofatty plaque can be evaluated on computed coronary tomography angiography (CCTA) by Hounsfield Unit (HU) density. To date, little is known regarding differences in high risk plaque composition between major epicardial vessels. Purpose The aim of this analysis was to compare plaque extent and composition between the three coronary arteries. Methods This is a secondary analysis of baseline scans from the PARADIGM study which enrolled consecutive patients with suspected coronary artery disease undergoing serial CCTA at a scan interval of ≥2 years. Plaque quantification by composition was performed in the three coronary arteries based on fixed HU thresholds: high risk subtypes consisting of necrotic core ( Results From 1,271 patients (mean age 60.3±9.3 years; 57% men; median ASCVD score 9.3%), 3,813 vessels were analyzed. The prevalence of any plaque was lowest in the LCx, as was the prevalence of high risk plaque (Figure; P Conclusion Prevalence of any plaque as well as high risk plaque subtypes was significantly higher in the LAD and RCA than in the LCx. Also, high risk plaque subtypes made up significantly the lowest proportion in the LCx, whereas calcified plaque made up the largest proportion in the LCx. These data support a different atherogenic milieu contributing to the variable risk patterns between the epicardial coronary arteries. Figure 1. Prevalence of (high risk) plaque Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (MSIT) (Grant no. 2012027176).

Background It is unclear whether the annual progression of aortic valve calcification (AVC) is associated with the progression of coronary atherosclerosis. Purpose We explored the association between AVC and the total and compositional plaque volume (PV) progression. Methods We performed a prospective multinational registry of consecutive patients who underwent serial coronary computed tomography angiography (CTA) at ≥2-year intervals. AVC, and total and compositional PV at baseline and follow-up were quantitatively analyzed. Multivariate linear regression models were constructed. Results Overall, 594 patients (56% male, 61.5±9.7 years old) were included (mean coronary CTA interval, 3.9±1.5 years). At baseline, AVC was 30.9±117.3. Normalized total PV at baseline was 122.3±219.4mm3, encompassing 41.9±116.8mm3 of calcified PV and 80.4±131.5mm3 of non-calcified PV. After adjustment of age, sex, clinical risk factors, and drug use, AVC at baseline was independently associated with total and all compositional PVs (all p0.05) (Table, Figure). Conclusion The overall burden of coronary atherosclerosis is associated with AVC at baseline. However, the progression of AVC is associated only with the progression of calcified PV but not with that of total and non-calcified PV. Representative case Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (MSIT)

Background It is still debatable whether the so-called high-risk plaque (HRP) simply represents a certain phase during the natural history of coronary atherosclerotic plaques or the disease progression would differ according to the presence of HRP. Purpose We determined whether the pattern of non-obstructive lesion progression into obstructive lesions would differ according to the presence of HRP. Methods Patients with non-obstructive coronary artery disease, defined as % diameter stenosis (%DS) ≥50%, were enrolled from a prospective, multinational registry of consecutive patients who underwent serial coronary computed tomography angiography at an inter-scan interval of ≥2 years. HRP was defined as lesions with ≥2 of positive remodelling, spotty calcification, and low-attenuation plaque. The total and compositional percent atheroma volume (PAV) at baseline and annualized PAV change were compared between non-HRP and HRP lesions. Results A total of 1,115 non-obstructive lesions were identified from 327 patients (61.1±8.9 years old, 66.0% male). There were 690 non-HRP and 425 HRP lesions. HRP lesions possessed greater PAV and %DS at baseline compared to non-HRP lesions. However, the annualized total and non-calcified PAV change were greater in non-HRP lesions than in HRP lesions. On multivariate analysis, addition of baseline PAV and %DS to clinical risk factors improved the predictive power of the model (Table). When clinical risk factors, PAV, %DS, and HRP were all adjusted on Model 3, only baseline PAV and %DS independently predicted the development of obstructive lesions (hazard ratio (HR) 1.046 [95% confidence interval (CI): 1.026–1.066] and HR 1.087 [95% CI: 1.055–1.119], respectively, all p0.05). Comparison of C-statistics of per-lesion analysis to predict progression to obstructive lesion C-statistics (95% CI) P Model 1: Baseline PAV 0.880 (0.879–0.884) – Model 2: Model 1 + baseline %DS 0.938 (0.937–0.939) vs. Model 1: Conclusion The pattern of individual coronary atherosclerotic plaque progression differed according to the presence of HRP. Baseline PAV was the most important predictor for lesions developing into obstructive lesions rather than the presence of HRP features at baseline. Acknowledgement/Funding This work was supported by the National Research Foundation of Korea funded by the Ministry of Science and ICT (Grant No. 2012027176).

Introduction Little is known regarding the impact of serum hemoglobin level changes (Δ hemoglobin) on coronary plaque volume. This study evaluated the association between Δ hemoglobin and coronary plaque volume change (PVC) using serial coronary computed tomographic angiography (CCTA). Methods A total of 830 subjects (61±10 years, 51.9% male) who underwent serial CCTA with available hemoglobin levels were analyzed from the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry. The median inter-scan period was 3.2 (2.5 to 4.4) years. Quantitative assessment of coronary plaques was performed at both scans. All participants were stratified into four groups based on the quartile of baseline hemoglobin levels. Annualized PVC was defined as total PVC divided by inter-scan period. Plaque progression (PP) was defined as plaque volume at follow-up minus plaque volume at index >0. Results Baseline total plaque volume (mm3) was not different among all groups (group I [lowest]: 34.1 (0.0–127.4) vs. group II: 28.8 (0.0–123.0) vs. group III: 49.9 (5.6–135.0) vs. group IV [highest]: 34.3 (0.0–130.7); p=0.235). During follow-up, Δ hemoglobin was related to annualized PVC (β:−0.114; p=0.001) and PP (odds ratio: 0.868; 95% confidence interval: 0.770–0.978; p=0.020). Multiple linear regression models showed that Δ hemoglobin significantly impacted on annualized PVC in only the composite of I and II groups. Conclusion Based on serial CCTA findings, Δ hemoglobin independently impacted on coronary PVC in individuals with low to normal baseline hemoglobin level.

Background Epicardial adipose tissue (EAT), a metabolically active visceral fat depot surrounding the coronary arteries, has been shown to promote the development of atherosclerosis in underlying coronary vasculature. Purpose We evaluate the performance of deep learning (DL), a sub-group of machine learning algorithms, for robust and fully automated quantification of EAT on multi-center cardiac CT data. Methods In this study, 850 non-contrast calcium scoring CT scans, from multiple cohorts, scanners and protocols, with manual measurements of EAT from 3 different readers were considered. The DL method was based on a convolutional neural network trained to reproduce the expert measurement. DL global performance was first assessed using all the scans, and then compared to inter-observer variability on a subset of 141 scans. Finally, automated EAT progression was compared to manual measurement using baseline and follow-up serial scans available for 70 subjects. The proposed model was validated using 10-fold cross validation. Results Automated quantification was performed in 1.57±0.49 seconds compared to 15 minutes for manual measurement. DL provided high agreement with expert manual quantification for all scans (R=0.974, p Automated vs. manual EAT volume Conclusion Deep learning allows rapid, robust and fully automated quantification of EAT from calcium scoring CT. It performs as an expert reader and can be implemented for routine cardiovascular risk assessment. Acknowledgement/Funding 1R01HL133616/01EX1012B/Adelson Medical Research Foundation

Background Conventional protocol contrast MRI (cMRI) for evaluating carotid artery atherosclerosis is clinically under-utilized due to complex scanning procedures and long scan time. Recently, the Quantitative Multi-contrast Atherosclerosis Characterization (qMATCH) has been proposed, which allows comprehensive and quantitative assessment of atherosclerosis including MRA, dark-blood vessel wall morphology, and T1/T2 mapping with an 8-minute single scan (Figure1). However, the diagnostic accuracy and feasibility of qMATCH has not been validated in clinical circumstances. Purpose To evaluate the diagnostic accuracy of quantitative plaque analysis of qMATCH compared with cMRI Method We prospectively enrolled 43 patients who have carotid plaques diagnosed by carotid ultrasound. cMRI was performed along with qMATCH scan. All imaging data were acquired with a clinical 3T scanner using a 64-channel head & neck coil. In the current analysis, we evaluated the diagnostic accuracy of qMATCH in the quantitative assessment of carotid plaque. Plaque area measurements using dark-blood wall images with qMATCH were compared with corresponding cross-sectional T1/T2-weighted images with cMRI as references values (Figure 2). These inter-technique comparisons included linear regression with Pearson correlation and Bland-Altman analyses to assess the mean inter-technique differences (biases) and limits of agreements. Result Among 90 segments, mean plaque areas measured by cMRI and qMATCH were 43.83±21.21 mm2 and 42.47±19.23mm2, respectively (mean differences, −1.36±8.12mm2; p for a paired t-test, 0.073). Correlation coefficient showed excellent correlation between plaque areas measured by cMRI and qMATCH (r=0.943, p Conclusion Quantitative carotid plaque burden analysis by a novel sequence with qMATCH is feasible and accurate compared with conventional MRI. Given that qMATCH can reduce scan time and allow quantitative relaxometry mapping, fast and accurate carotid plaque analysis would be feasible. Further studies to evaluate the accuracy of qualitative plaque analysis should be performed to confirm the “all-in-one” assessment of carotid atherosclerosis using qMATCH.

Background It is unclear whether sex impacts the plaque volume (PV) progression in patients with stable coronary artery disease (CAD). Purpose To explore whether the total and compositional PV progression rate differ according to sex. Methods We performed a prospective multinational registry of consecutive patients who underwent serial CCTA at ≥2-year interval. Total and compositional PV at baseline and follow-up were quantitatively analysed and normalized using the analysed total vessel length. Multivariate linear regression models were constructed for each women and men. Results Of the 1,255 patients included (median CT interval 3.8 years), 543 were women and 712 were men. Women were older (62±9 years vs. 59±9 years, p0.05). At baseline, men possessed greater total PV (131.5±230.5mm3 vs. 97.7±193.6mm3, p=0.005) and a higher prevalence of high-risk plaques (HRP) than women (31% vs. 20%, p In multivariate analysis (TABLE), although total PV progression rate was not different, women were associated with greater calcified PV progression (β=2.83, p=0.004) but slower non-calcified PV progression (β=-3.39, p=0.008) and less development of HRP (β=-0.18, p=0.049) than men. CCTA findings according to sex Univariate analysis Female Sex in Multivariable Analysis Women (n=543) Men (n=712) P β SE P Agatston CACS, /year 0.44±0.7 0.4±0.7 0.332 0.106 0.04 0.006 Total PVnormalized, mm3/year 14.7±23.4 17.8±26.2 0.026 -0.56 1.33 0.677 Calcified PVnormalized, mm3/year 10.5±21.5 10.0±19.1 0.670 2.83 0.98 0.004 Non-calcified PVnormalized, mm3/year 4.2±17.3 7.8±21.2 0.001 -3.39 1.28 0.008 Development of high-risk plaque*, n (%) 86 (15.8) 139 (19.5) 0.092 -0.18 0.09 0.049 In linear multivariate regression analysis adjusted with age, race, HTN, DM, family history, smoking, LDL, statin, anti-platelets, beta-blockers, and PV at baseline, women were associated with greater calcified PV progression and slower non-calcified PV progression. (High-risk plaque was defined as ≥2 of low-attenuation plaque, spotty calcification, and positive remodelling.) Conclusion In this large CCTA cohort, we found that the compositional PV progression differs according to sex. These findings, which are hypothesis generating, suggest that comprehensive plaque evaluation may contribute to further refine risk stratification according to sex. Acknowledgement/Funding This work was supported by the National Research Foundation of Korea funded by the Ministry of Science and ICT (Grant No. 2012027176).

Aims We evaluated coronary artery disease (CAD) extent, severity, and major adverse cardiac events (MACEs) in never, past, and current smokers undergoing coronary CT angiography (CCTA). Methods and results We evaluated 9456 patients (57.1 +/- 12.3 years, 55.5% male) without known CAD (1588 current smokers; 2183 past smokers who quit >= 3 months before CCTA; and 5685 never smokers). By risk-adjusted Cox proportional-hazards models, we related smoking status to MACE (all-cause death or non-fatal myocardial infarction). We further performed 1: 1: 1 propensity matching for 1000 in each group evaluate event risk among individuals with similar age, gender, CAD risk factors, and symptom presentation. During a mean follow-up of 2.8 +/- 1.9 years, 297 MACE occurred. Compared with never smokers, current and past smokers had greater atherosclerotic burden including extent of plaque defined as segments with any plaque (2.1 +/- 2.8 vs. 2.6 +/- 3.2 vs. 3.1 +/- 3.3, P < 0.0001) and prevalence of obstructive CAD [1-vessel disease (VD): 10.6% vs. 14.9% vs. 15.2%, P < 0.001; 2-VD: 4.4% vs. 6.1% vs. 6.2%, P = 0.001; 3-VD: 3.1% vs. 5.2% vs. 4.3%, P < 0.001]. Compared with never smokers, current smokers experienced higher MACE risk [ hazard ratio (HR) 1.9, 95% confidence interval (CI) 1.4-2.6, P < 0.001], while past smokers did not (HR 1.2, 95% CI 0.8-1.6, P = 0.35). Among matched individuals, current smokers had higher MACE risk (HR 2.6, 95% CI 1.6-4.2, P < 0.001), while past smokers did not (HR 1.3, 95% CI 0.7-2.4, P = 0.39). Similar findings were observed for risk of all-cause death. Conclusion Among patients without known CAD undergoing CCTA, current and past smokers had increased burden of atherosclerosis compared with never smokers; however, risk of MACE was heightened only in current smokers.

Aim Prior evidence observed no predictive utility of coronary CT angiography (CCTA) over the coronary artery calcium score (CACS) and the Framingham risk score (FRS), among asymptomatic individuals. Whether the prognostic value of CCTA differs for asymptomatic patients, when stratified by CACS severity, remains unknown. Methods and results From a 12-centre, 6-country observational registry, 3217 asymptomatic individuals without known coronary artery disease (CAD) underwent CACS and CCTA. Individuals were categorized by CACS as: 0-10, 11-100, 101-400, 401-1000 >1000. For CCTA analysis, the number of obstructive vessels-as defined by the per-patient presence of a >= 50% luminal stenosis-was used to grade the extent and severity of CAD. The incremental prognostic value of CCTA over and above FRS was measured by the likelihood ratio (LR) chi(2), C-statistic, and continuous net reclassification improvement (NRI) for prediction, discrimination, and reclassification of all-cause mortality and non-fatal myocardial infarction. During a median follow-up of 24 months (25th-75th percentile, 17-30 months), there were 58 composite end-points. The incremental value of CCTA over FRS was demonstrated in individuals with CACS>100 (LR chi(2), 25.34; increment in C-statistic, 0.24; NRI, 0.62, all P < 0.001), but not among those with CACS 0.05). For subgroups with CACS > 100, the utility of CCTA for predicting the study end-point was evident among individuals whose CACS ranged from 101 to 400; the observed predictive benefit attenuated with increasing CACS. Conclusion Coronary CT angiography provides incremental prognostic utility for prediction of mortality and non-fatal myocardial infarction for asymptomatic individuals with moderately high CACS, but not for lower or higher CACS.

Aims High calcium (Ca), phosphate (P), and Ca–P product (CPP) are associated with cardiovascular disease in patients with chronic kidney disease. Whether this relationship persists in individuals with normal kidney function is not yet elucidated. We explored the relationship of serum Ca, P, and CPP to coronary atherosclerosis assessed by cardiac computed tomography angiography (cCTA) in participants with normal kidney function. Methods and results This study included 7553 participants (52 ± 10 years, male 57%) with near-normal kidney function (estimated glomerular filtration rate > 60 mL/min/1.73 m2) who underwent cCTA. The relationship of Ca, P, and CPP to coronary atherosclerosis [coronary artery Ca score (CACS) >100 and the presence of coronary artery disease (CAD)] was evaluated. Higher Ca, P, and CPP were significantly associated with CACS > 100 continuously [adjusted odds ratio (OR) per mg/dL: Ca 1.21, P = 0.026; P 1.29, P < 0.001; CPP 1.03, P < 0.001]. However, they correlate only weakly with the presence of CAD (OR: Ca 1.17, P = 0.001; P 1.05, P = 0.173; CPP 1.01, P = 0.034). This discrepancy was because calcified or mixed plaque and non-calcified plaque (NCP) were included in CAD. A significant relationship was demonstrated between calcified or mixed plaque and Ca, P, and CPP (OR: Ca 1.20, P = 0.001; P 1.13, P = 0.003; CPP 1.02, P = 0.001), but not NCP. Conclusion Elevated serum levels of Ca, P, and CPP are significantly associated with the presence of calcified coronary atherosclerotic plaque. It is unclear if there is a causal relationship. This relationship is thought to contribute to vascular calcification, but is less closely associated with NCP. The originally published version of this paper was incorrect. The author affiliations have been amended.