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Background: A lesion-level risk prediction for acute coronary syndrome (ACS) needs better characterization., Objectives: This study sought to investigate the additive value of artificial intelligence-enabled quantitative coronary plaque and hemodynamic analysis (AI-QCPHA)., Methods: Among ACS patients who underwent coronary computed tomography angiography (CTA) from 1 month to 3 years before the ACS event, culprit and nonculprit lesions on coronary CTA were adjudicated based on invasive coronary angiography. The primary endpoint was the predictability of the risk models for ACS culprit lesions. The reference model included the Coronary Artery Disease Reporting and Data System, a standardized classification for stenosis severity, and high-risk plaque, defined as lesions with ≥2 adverse plaque characteristics. The new prediction model was the reference model plus AI-QCPHA features, selected by hierarchical clustering and information gain in the derivation cohort. The model performance was assessed in the validation cohort., Results: Among 351 patients (age: 65.9 ± 11.7 years) with 2,088 nonculprit and 363 culprit lesions, the median interval from coronary CTA to ACS event was 375 days (Q1-Q3: 95-645 days), and 223 patients (63.5%) presented with myocardial infarction. In the derivation cohort (n = 243), the best AI-QCPHA features were fractional flow reserve across the lesion, plaque burden, total plaque volume, low-attenuation plaque volume, and averaged percent total myocardial blood flow. The addition of AI-QCPHA features showed higher predictability than the reference model in the validation cohort (n = 108) (AUC: 0.84 vs 0.78; P < 0.001). The additive value of AI-QCPHA features was consistent across different timepoints from coronary CTA., Conclusions: AI-enabled plaque and hemodynamic quantification enhanced the predictability for ACS culprit lesions over the conventional coronary CTA analysis. (Exploring the Mechanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary Computed Tomography Angiography and Computational Fluid Dynamics II [EMERALD-II]; NCT03591328)., Competing Interests: Funding Support and Author Disclosures This study received funding from HeartFlow Inc. The company performed the computational fluid dynamics, and artificial intelligence quantitative coronary plaque analysis but was not involved in the study design, collection, analysis, and interpretation of data; the writing of this paper; or the decision to submit it for publication. Dr Koo has received institutional research grants from Abbott, Philips, and HeartFlow Inc. Dr Nam has received institutional research grants from Abbott and Genoss. Dr Merkely has received direct personal payments for speaker fees or studies from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi Sankyo, DUKE Clinical Institute, Medtronic, and Novartis and institutional grants from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo, DUKE Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and VIFOR Pharma. Dr de Bruyne has received institutional unrestricted research grants from Abbott, Boston Scientific, and Biotronik; has received consulting fees from Abbott, Opsens, and Boston Scientific; and is a shareholder for Siemens, GE, Bayer, Philips, HeartFlow Inc, Edwards Life Sciences, Sanofi, and Omega Pharma. Dr Ko has equity in Artrya and has received honoraria from Medtronic, Abbott Vascular, and Canon Medical. Dr Leipsic is a consultant for and holds stock options in HeartFlow Inc and modest personal core lab fees from Arineta. Dr Shah has received honoraria as a speaker for HeartFlow Inc. Dr Bax has received unrestricted research grants from Abbott and Edwards Lifesciences to the Department of Cardiology, Leiden University Medical Center, the Netherlands. Dr Shaw has received honoraria from HeartFlow Inc and Elucid Imaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Backgrounds: The impact of quantitative assessment to differentiate total occlusions (TOs) from severe stenoses on coronary computed tomography angiography (CCTA) remains unknown., Objective: This study investigated whether quantitative characteristics assessed on CCTA could help differentiate a TO from a severe stenosis on invasive coronary angiography (ICA)., Methods: This study is a sub-analysis of the FASTTRACK CABG (NCT04142021) in which both CCTA and ICA were routinely performed. Quantitative analysis was performed with semi-automated CCTA plaque-analysis software. Blinded analysts compared TOs on CCTA, defined as a complete lack of contrast opacification within the coronary occlusion, with corresponding ICA., Results: Eighty-four TOs were seen on CCTA in 59 of the 114 patients enrolled in the trial. The concordance in diagnosing a TO between ICA and CCTA was 56.0% (n ​= ​47). Compared to severe stenoses, TOs had a significantly longer lesion length (25.1 ​± ​23.0 ​mm vs 9.4 ​± ​11.2 ​mm, P ​< ​0.001). The best cut-off value to differentiate a TO from severe stenosis was a lesion length of 5.5 ​mm (area under the curve 0.77, 95% CI: 0.66-0.87), with a 91.1% sensitivity and 61.1% specificity. Dense calcium percentage atheroma volume (PAV) was significantly higher in TOs compared to severe stenoses (18.7 ​± ​19.6% vs. 6.6 ​± ​13.0%, P ​< ​0.001), whilst the opposite was seen for fibro-fatty PAV (31.3 ​± ​14.2% vs. 19.5 ​± ​10.5%, P ​< ​0.001). On a multivariable logistic regression analysis, lesion length (>5.5 ​mm) was the only parameter associated with differentiating a TO from a severe stenosis., Conclusion: In quantitative CCTA analysis, a lesion length >5.5 ​mm was the only independent predictor differentiating a TO from a severe stenosis., Nct Registration Number: NCT04142021., Competing Interests: Declaration of competing interest Dr. Masuda received a grant from TERUMO corporation outside the submitted work. Dr. Miyashita received research grants from OrbusNeich Medical K.K., outside the submitted work. Dr. Tobe received a grant from the Fukuda foundation for medical technology. Dr. Scot received consultancy fees from Biosensors. Dr. P.W.S. reported consulting fees from SMT, Novartis, Meril Life, Philips, and Xeltis. All other authors have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We assessed whether combinations of cardiometabolic risk factors independently predict coronary plaque progression (PP) and major adverse cardiovascular events in patients with stable coronary artery disease., Methods: Patients with known or suspected stable coronary artery disease (60.9±9.3 years, 55.4% male) undergoing serial coronary computed tomography angiographies (≥2 years apart), with clinical characterization and follow-up (N=1200), were analyzed from the PARADIGM study (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging). Plaque volumes measured in coronary segments (≥2 mm in diameter) were summed to provide whole heart plaque volume (mm 3 ) and percent atheroma volume (plaque volume/vessel volume×100; %) per patient at baseline and follow-up. Rapid PP was defined as a percent atheroma volume increase of ≥1.0%/y. Major adverse cardiovascular events included nonfatal myocardial infarction, death, and unplanned coronary revascularization., Results: In an interscan period of 3.2 years (interquartile range, 1.9), rapid PP occurred in 341 patients (28%). At multivariable analysis, the combination of cardiometabolic risk factors defined as metabolic syndrome predicted rapid PP (odds ratio, 1.51 [95% CI, 1.12-2.03]; P =0.007) together with older age, smoking habits, and baseline percent atheroma volume. Among single cardiometabolic variables, high fasting plasma glucose (diabetes or fasting plasma glucose >100 mg/dL) and low HDL-C (high-density lipoprotein cholesterol; <40 mg/dL in males and <50 mg/dL in females) were independently associated with rapid PP, in particular when combined (odds ratio, 2.37 [95% CI, 1.56-3.61]; P <0.001). In a follow-up of 8.23 years (interquartile range, 5.92-9.53), major adverse cardiovascular events occurred in 201 patients (17%). At multivariable Cox analysis, the combination of high fasting plasma glucose with high systemic blood pressure (treated hypertension or systemic blood pressure >130/85 mm Hg) was an independent predictor of events (hazard ratio, 1.79 [95% CI, 1.10-2.90]; P =0.018) together with family history, baseline percent atheroma volume, and rapid PP., Conclusions: In patients with stable coronary artery disease, the combination of hyperglycemia with low HDL-C is associated with rapid PP independently of other risk factors, baseline plaque burden, and treatment. The combination of hyperglycemia with high systemic blood pressure independently predicts the worse outcome beyond PP., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02803411., Competing Interests: Dr Chang receives funding from the 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 GE Healthcare and serves on the scientific advisory board of Arineta and GE Healthcare. Dr Min also has an equity interest in and is an employee of Cleerly Inc. The other authors report no conflicts.

Background: Radiomics is expected to identify imaging features beyond the human eye. We investigated whether radiomics can identify coronary segments that will develop new atherosclerotic plaques on coronary computed tomography angiography (CCTA)., Methods: From a prospective multinational registry of patients with serial CCTA studies at ≥ 2-year intervals, segments without identifiable coronary plaque at baseline were selected and radiomic features were extracted. Cox models using clinical risk factors (Model 1), radiomic features (Model 2) and both clinical risk factors and radiomic features (Model 3) were constructed to predict the development of a coronary plaque, defined as total PV ​≥ ​1 ​mm 3 , at follow-up CCTA in each segment., Results: In total, 9583 normal coronary segments were identified from 1162 patients (60.3 ​± ​9.2 years, 55.7% male) and divided 8:2 into training and test sets. At follow-up CCTA, 9.8% of the segments developed new coronary plaque. The predictive power of Models 1 and 2 was not different in both the training and test sets (C-index [95% confidence interval (CI)] of Model 1 vs. Model 2: 0.701 [0.690-0.712] vs. 0.699 [0.0.688-0.710] and 0.696 [0.671-0.725] vs. 0.0.691 [0.667-0.715], respectively, all p ​> ​0.05). The addition of radiomic features to clinical risk factors improved the predictive power of the Cox model in both the training and test sets (C-index [95% CI] of Model 3: 0.772 [0.762-0.781] and 0.767 [0.751-0.787], respectively, all p ​< ​00.0001 compared to Models 1 and 2)., Conclusion: Radiomic features can improve the identification of segments that would develop new coronary atherosclerotic plaque., Clinical Trial Registration: ClinicalTrials.gov NCT0280341., Competing Interests: Declaration of competing interest Dr. Chang receives funding from 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). Dr. James K. Min receives funding from GE Healthcare and serves on the scientific advisory board of Arineta and GE Healthcare. Dr. Min also has an equity interest in and is an employee of Cleerly, Inc. The remaining authors have no relevant disclosures., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Objectives: No clear recommendations are endorsed by the different scientific societies on the clinical use of repeat coronary computed tomography angiography (CCTA) in patients with non-obstructive coronary artery disease (CAD). This study aimed to develop and validate a practical CCTA risk score to predict medium-term disease progression in patients at a low-to-intermediate probability of CAD., Methods: Patients were part of the Progression of AtheRosclerotic PlAque Determined by Computed Tomographic Angiography Imaging (PARADIGM) registry. Specifically, 370 (derivation cohort) and 219 (validation cohort) patients with two repeat, clinically indicated CCTA scans, non-obstructive CAD, and absence of high-risk plaque (≥ 2 high-risk features) at baseline CCTA were included. Disease progression was defined as the new occurrence of ≥ 50% stenosis and/or high-risk plaque at follow-up CCTA., Results: In the derivation cohort, 104 (28%) patients experienced disease progression. The median time interval between the two CCTAs was 3.3 years (2.7-4.8). Odds ratios for disease progression derived from multivariable logistic regression were as follows: 4.59 (95% confidence interval: 1.69-12.48) for the number of plaques with spotty calcification, 3.73 (1.46-9.52) for the number of plaques with low attenuation component, 2.71 (1.62-4.50) for 25-49% stenosis severity, 1.47 (1.17-1.84) for the number of bifurcation plaques, and 1.21 (1.02-1.42) for the time between the two CCTAs. The C-statistics of the model were 0.732 (0.676-0.788) and 0.668 (0.583-0.752) in the derivation and validation cohorts, respectively., Conclusions: The new CCTA-based risk score is a simple and practical tool that can predict mid-term CAD progression in patients with known non-obstructive CAD., Clinical Relevance Statement: The clinical implementation of this new CCTA-based risk score can help promote the management of patients with non-obstructive coronary disease in terms of timing of imaging follow-up and therapeutic strategies., Key Points: • No recommendations are available on the use of repeat CCTA in patients with non-obstructive CAD. • This new CCTA score predicts mid-term CAD progression in patients with non-obstructive stenosis at baseline. • This new CCTA score can help guide the clinical management of patients with non-obstructive CAD., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background and Aims: Coronary hemodynamics impact coronary plaque progression and destabilization. The aim of the present study was to establish the association between focal vs. diffuse intracoronary pressure gradients and wall shear stress (WSS) patterns with atherosclerotic plaque composition., Methods: Prospective, international, single-arm study of patients with chronic coronary syndromes and hemodynamic significant lesions (fractional flow reserve [FFR] ≤ 0.80). Motorized FFR pullback pressure gradient (PPG), optical coherence tomography (OCT), and time-average WSS (TAWSS) and topological shear variation index (TSVI) derived from three-dimensional angiography were obtained., Results: One hundred five vessels (median FFR 0.70 [Interquartile range (IQR) 0.56-0.77]) had combined PPG and WSS analyses. TSVI was correlated with PPG (r = 0.47, [95% Confidence Interval (95% CI) 0.30-0.65], p < 0.001). Vessels with a focal CAD (PPG above the median value of 0.67) had significantly higher TAWSS (14.8 [IQR 8.6-24.3] vs. 7.03 [4.8-11.7] Pa, p < 0.001) and TSVI (163.9 [117.6-249.2] vs. 76.8 [23.1-140.9] m -1 , p < 0.001). In the 51 vessels with baseline OCT, TSVI was associated with plaque rupture (OR 1.01 [1.00-1.02], p = 0.024), PPG with the extension of lipids (OR 7.78 [6.19-9.77], p = 0.003), with the presence of thin-cap fibroatheroma (OR 2.85 [1.11-7.83], p = 0.024) and plaque rupture (OR 4.94 [1.82 to 13.47], p = 0.002)., Conclusions: Focal and diffuse coronary artery disease, defined using coronary physiology, are associated with differential WSS profiles. Pullback pressure gradients and WSS profiles are associated with atherosclerotic plaque phenotypes. Focal disease (as identified by high PPG) and high TSVI are associated with high-risk plaque features., Clinical Trial Registration: https://clinicaltrials,gov/ct2/show/NCT03782688., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: To identify anatomical and morphological plaque features predictors of PCI and create a multiparametric score to increase the predictive yield. Moreover, we assessed the incremental predictive value of FFR CT (Fractional Flow Reserve derived from CCTA) trans-lesion gradient (ΔFFR CT ) when integrated into the score., Methods: Observational cohort study including patients undergoing CCTA for suspected coronary artery disease, with FFR CT available, referred to invasive coronary angiogram and assessment of fractional flow reserve. Plaque analysis was performed using validated semi-automated software. Logistic regression was performed to identify anatomical and morphological plaque features predictive of PCI. Optimal thresholds were defined by area under the receiver-operating characteristics curve (AUC) analysis. A scoring system was developed in a derivation cohort (70 ​% of the study population) and tested in a validation cohort (30 ​% of patients)., Results: The overall study population included 340 patients (455 vessels), among which 238 patients (320 vessels) were included in the derivation cohort. At multivariate logistic regression analysis, absence of left main disease, diameter stenosis (DS), non-calcified plaque (NCP) volume, and percent atheroma volume (PAV) were independent predictors of PCI. Optimal thresholds were: DS ​≥ ​50 ​%, volume of NCP>113 ​mm 3 and PAV>17 ​%. A weighted score (CT-PCI Score) ranging from 0 to 11 was obtained. The AUC of the score was 0.80 (95%CI 0.74-0.86). The integration of ΔFFR CT in the CT-PCI score led to a mild albeit not significant increase in the AUC (0.82, 95%CI 0.77-0.87, p ​= ​0.328)., Conclusions: Plaque anatomy and morphology derived from CCTA could aid in identifying patients amenable to PCI., Competing Interests: Declaration of competing interest MB, PP, DTB, AL and MMV report research grants provided by Cardiopath Ph.D. program. NM has received speaker fees from Abbott. CC reports receiving research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, Cathworks, Boston Scientific, Siemens, HeartFlow Inc., and Abbott Vascular; and consultancy fees from Heart Flow Inc, Opsens, Abbott Vascular, and Philips Volcano. BDB reports receiving consultancy fees from Boston Scientific, and Abbott and receiving research grants from Coroventis Research, Pie Medical Imaging, Cathworks, Boston Scientific, Siemens, HeartFlow Inc., and Abbott Vascular. DA reports research grants from GE Healthcare and Bracco. The other authors have nothing to disclose., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: In the last 15 years, large registries and several randomized clinical trials have demonstrated the diagnostic and prognostic value of coronary computed tomography angiography (CCTA). Advances in CT scanner technology and developments of analytic tools now enable accurate quantification of coronary artery disease (CAD), including total coronary plaque volume and low attenuation plaque volume. The primary aim of CONFIRM2, (Quantitative COroNary CT Angiography Evaluation For Evaluation of Clinical Outcomes: An InteRnational, Multicenter Registry) is to perform comprehensive quantification of CCTA findings, including coronary, non-coronary cardiac, non-cardiac vascular, non-cardiac findings, and relate them to clinical variables and cardiovascular clinical outcomes., Design: CONFIRM2 is a multicenter, international observational cohort study designed to evaluate multidimensional associations between quantitative phenotype of cardiovascular disease and future adverse clinical outcomes in subjects undergoing clinically indicated CCTA. The targeted population is heterogenous and includes patients undergoing CCTA for atherosclerotic evaluation, valvular heart disease, congenital heart disease or pre-procedural evaluation. Automated software will be utilized for quantification of coronary plaque, stenosis, vascular morphology and cardiac structures for rapid and reproducible tissue characterization. Up to 30,000 patients will be included from up to 50 international multi-continental clinical CCTA sites and followed for 3-4 years., Summary: CONFIRM2 is one of the largest CCTA studies to establish the clinical value of a multiparametric approach to quantify the phenotype of cardiovascular disease by CCTA using automated imaging solutions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexander R. van Rosendael is a member, Cleerly Scientific Advisory Board. Tami Crabtree is an employee and equity holder, Cleerly, Inc. Gianluca Pontone has received honorarium as speaker/consultant and/or institutional research grant from GE Healthcare, Bracco, Medtronic, Novartis. Ronny R. Buechel reports receiving speaking honoraria from GE Healthcare, Pfizer, Gilead, and IBA. Christoph Gräni received funding from the Swiss National Science foundation, InnoSuisse, CAIM foundation, GAMBIT foundation, Novartis foundation for biomedical research, outside of the submitted work. Andrew D. Choi is a consultant for Siemens, holds equity in Cleerly, and receives grant support from the George Washing Heart and Vascular Institute.Carlos E. Rochitte reports receiving speaking honoraria for Pfizer, Edwards, GE, and Manole. David M. German reports no conflicts Himanshu Gupta reports no conflicts. Omar Khalique is a consultant for Edwards, Croivalve, Restore Medical, holds equity in Triflo, and has received honoraria for educational programs from Heartflow. Udo Hoffmann is an employee and equity holder, Cleerly, Inc., and has received honoraria from Stanford University, Clinical Cardiovascular Sciences, Rapid AI, MedTrace. James Earls is an employee and equity holder, Cleerly, Inc. James K. Min is an employee and equity holder, Cleerly, Inc. and a member of the Arineta Medical Advisory Board. Ibrahim Danad is a member, Cleerly Scientific Advisory Board. Hugo Marques is a consultant for Cleerly, Inc., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Non-obstructing small coronary plaques may not be well recognized by expert readers during coronary computed tomography angiography (CCTA) evaluation. Recent developments in atherosclerosis imaging quantitative computed tomography (AI-QCT) enabled by machine learning allow for whole-heart coronary phenotyping of atherosclerosis, but its diagnostic role for detection of small plaques on CCTA is unknown., Methods: We performed AI-QCT in patients who underwent serial CCTA in the multinational PARADIGM study. AI-QCT results were verified by a level III experienced reader, who was blinded to baseline and follow-up status of CCTA. This retrospective analysis aimed to characterize small plaques on baseline CCTA and evaluate their serial changes on follow-up imaging. Small plaques were defined as a total plaque volume <50 ​mm 3 ., Results: A total of 99 patients with 502 small plaques were included. The median total plaque volume was 6.8 ​mm 3 (IQR 3.5-13.9 ​mm 3 ), most of which was non-calcified (median 6.2 ​mm 3 ; 2.9-12.3 ​mm 3 ). The median age at the time of baseline CCTA was 61 years old and 63% were male. The mean interscan period was 3.8 ​± ​1.6 years. On follow-up CCTA, 437 (87%) plaques were present at the same location as small plaques on baseline CCTA; 72% were larger and 15% decreased in volume. The median total plaque volume and non-calcified plaque volume increased to 18.9 ​mm 3 (IQR 8.3-45.2 ​mm 3 ) and 13.8 ​mm 3 (IQR 5.7-33.4 ​mm 3 ), respectively, among plaques that persisted on follow-up CCTA. Small plaques no longer visualized on follow-up CCTA were significantly more likely to be of lower volume, shorter in length, non-calcified, and more distal in the coronary artery, as compared with plaques that persisted at follow-up., Conclusion: In this retrospective analysis from the PARADIGM study, small plaques (<50 ​mm 3 ) identified by AI-QCT persisted at the same location and were often larger on follow-up CCTA., (Copyright © 2023 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: The interplay between coronary hemodynamics and plaque characteristics remains poorly understood., Objectives: The aim of this study was to compare atherosclerotic plaque phenotypes between focal and diffuse coronary artery disease (CAD) defined by coronary hemodynamics., Methods: This multicenter, prospective, single-arm study was conducted in 5 countries. Patients with functionally significant lesions based on an invasive fractional flow reserve ≤0.80 were included. Plaque analysis was performed by using coronary computed tomography angiography and optical coherence tomography. CAD patterns were assessed using motorized fractional flow reserve pullbacks and quantified by pullback pressure gradient (PPG). Focal and diffuse CAD was defined according to the median PPG value., Results: A total of 117 patients (120 vessels) were included. The median PPG was 0.66 (IQR: 0.54-0.75). According to coronary computed tomography angiography analysis, plaque burden was higher in patients with focal CAD (87% ± 8% focal vs 82% ± 10% diffuse; P = 0.003). Calcifications were significantly more prevalent in patients with diffuse CAD (Agatston score per vessel: 51 [IQR: 11-204] focal vs 158 [IQR: 52-341] diffuse; P = 0.024). According to optical coherence tomography analysis, patients with focal CAD had a significantly higher prevalence of circumferential lipid-rich plaque (37% focal vs 4% diffuse; P = 0.001) and thin-cap fibroatheroma (TCFA) (47% focal vs 10% diffuse; P = 0.002). Focal disease defined by PPG predicted the presence of TCFA with an area under the curve of 0.73 (95% CI: 0.58-0.87)., Conclusions: Atherosclerotic plaque phenotypes associate with intracoronary hemodynamics. Focal CAD had a higher plaque burden and was predominantly lipid-rich with a high prevalence of TCFA, whereas calcifications were more prevalent in diffuse CAD. (Precise Percutaneous Coronary Intervention Plan [P3]; NCT03782688)., Competing Interests: Funding and Author Disclosures The study was sponsored by the Cardiac Research Institute Aalst with unrestricted grants from HeartFlow Inc. Dr Mizukami has received consulting fees from Zeon Medical and HeartFlow Inc; and speaker fees from Abbott Vascular. Dr Leipsic is a consultant and has holding stock options in Circle CVI and HeartFlow Inc; has received a research grant from GE; and modest speaker fees from GE and Philips. Drs Sonck and Munhoz have received research grants provided by the Cardiopath Ph.D. program. Dr Nørgaard has received unrestricted institutional research grants from Siemens and HeartFlow Inc. Dr Otake has received research grants from Abbott Vascular; and speaker fees from HeartFlow Inc and Abbott Vascular. Dr Ko has received consulting fees from Canon Medical, Abbott, and Medtronic. Dr Koo has received institutional research grants from HeartFlow Inc. Dr Maeng has received advisory board and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, and Novo Nordisk; and research grants from Bayer and Philips Healthcare. Dr Jensen has received unrestricted institutional research grants from Siemens and HeartFlow Inc. Dr Andreini has received research grants from GE Healthcare and Bracco. Dr Shinke has received research grants from Boston Scientific and Abbott Vascular. CT is an employee of HeartFlow Inc. Dr Barbato has received speaker fees from Boston Scientific, Abbott Vascular, and GE. Dr Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; significant institutional research support from St. Jude Medical (CONTRAST [Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?]; NCT02184117) and Philips/Volcano Corporation (DEFINE-FLOW [Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses]; NCT02328820) for studies using intracoronary pressure and flow sensors; has an institutional licensing agreement with Boston Scientific for the smart-minimum FFR algorithm commercialized under 510(k) K191008; and has pending patents on diagnostic methods for quantifying aortic stenosis and transcatheter aortic valve replacement physiology, as well as algorithms to correct pressure tracings from fluid-filled catheters. Dr De Bruyne has received consultancy fees from Boston Scientific and Abbott Vascular; research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow Inc, Edwards Life Sciences, Bayer, Sanofi, and Celyad. Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and consultancy fees from HeartFlow Inc, OpSens, Abbott Vascular, and Philips Volcano. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To investigate the impact of statins on plaque progression according to high-risk coronary atherosclerotic plaque (HRP) features and to identify predictive factors for rapid plaque progression in mild coronary artery disease (CAD) using serial coronary computed tomography angiography (CCTA)., Methods and Results: We analyzed mild stenosis (25-49%) CAD, totaling 1432 lesions from 613 patients (mean age, 62.2 years, 63.9% male) and who underwent serial CCTA at a ≥2 year inter-scan interval using the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging (NCT02803411) registry. The median inter-scan period was 3.5 ± 1.4 years; plaques were quantitatively assessed for annualized percent atheroma volume (PAV) and compositional plaque volume changes according to HRP features, and the rapid plaque progression was defined by the ≥90th percentile annual PAV. In mild stenotic lesions with ≥2 HRPs, statin therapy showed a 37% reduction in annual PAV (0.97 ± 2.02 vs. 1.55 ± 2.22, P = 0.038) with decreased necrotic core volume and increased dense calcium volume compared to non-statin recipient mild lesions. The key factors for rapid plaque progression were ≥2 HRPs [hazard ratio (HR), 1.89; 95% confidence interval (CI), 1.02-3.49; P = 0.042], current smoking (HR, 1.69; 95% CI 1.09-2.57; P = 0.017), and diabetes (HR, 1.55; 95% CI, 1.07-2.22; P = 0.020)., Conclusion: In mild CAD, statin treatment reduced plaque progression, particularly in lesions with a higher number of HRP features, which was also a strong predictor of rapid plaque progression. Therefore, aggressive statin therapy might be needed even in mild CAD with higher HRPs., Clinical Trial Registration: ClinicalTrials.gov NCT02803411., Competing Interests: Conflict of interest: Dr. Chang receives funding from by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number: 1711139017); 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. Chun receives funding from National Research Foundation (NRF) grant funded by the Korea government (Ministry of Education, Science and Technology; NRF-2015R1D1A1A01059717). Dr. Leipsic is a consultant and holds stock options in HeartFlow and Circle CVI. He receives modest speaking fees from Philips and GE Healthcare. Dr. Budoff receives grant support from the National Institutes of Health and GE Healthcare. Dr. Marques is a Consultant and holds stock options for Cleerly Inc. Dr. Samady is a co-founder and equity holder of Covanos, a consultant for Philips and Valo, and receives grant support from Phillips and St Jude Abbott/Medtronic. Dr. Andreini is on the Speakers Bureau for GE Healthcare and receives grant support from GE Healthcare and Bracco. Dr. Pontone receives institutional research grants from GE Healthcare, HeartFlow, Medtronic, Bracco, and Bayer. Dr. Berman receives software royalties from Cedars-Sinai. Dr. Virmani has received institutional research support from 480 Biomedical, Abbott Vascular, Arterial Remodeling Technologies, BioSensors International, Biotronik, Boston Scientific, Celonova, Claret Medical, Cook Medical, Cordis, Edwards Lifesciences, 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. Dr. Min is an employee and holds equity interest in Cleerly, Inc. He is also on the Medical Advisory Board at Arineta. The other authors report no conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

It is unknown whether gender influences the atherosclerotic plaque characteristics (APCs) of lesions of varying angiographic stenosis severity. This study evaluated the imaging data of 303 symptomatic patients from the derivation arm of the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia) trial, all of whom underwent coronary computed tomographic angiography and clinically indicated nonemergent invasive coronary angiography upon study enrollment. Index tests were interpreted by 2 blinded core laboratories, one of which performed quantitative coronary computed tomographic angiography using an artificial intelligence application to characterize and quantify APCs, including percent atheroma volume (PAV), low-density noncalcified plaque (LD-NCP), noncalcified plaque (NCP), calcified plaque (CP), lesion length, positive arterial remodeling, and high-risk plaque (a combination of LD-NCP and positive remodeling ≥1.10); the other classified lesions as obstructive (≥50% diameter stenosis) or nonobstructive (<50% diameter stenosis) based on quantitative invasive coronary angiography. The relation between APCs and angiographic stenosis was further examined by gender. The mean age of the study cohort was 64.4 ± 10.2 years (29.0% female). In patients with obstructive disease, men had more LD-NCP PAV (0.5 ± 0.4 vs 0.3 ± 0.8, p = 0.03) and women had more CP PAV (11.7 ± 1.6 vs 8.0 ± 0.8, p = 0.04). Obstructive lesions had more NCP PAV compared with their nonobstructive lesions in both genders, however, obstructive lesions in women also demonstrated greater LD-NCP PAV (0.4 ± 0.5 vs 1.0 ± 1.8, p = 0.03), and CP PAV (17.4 ± 16.5 vs 25.9 ± 18.7, p = 0.03) than nonobstructive lesions. Comparing the composition of obstructive lesions by gender, women had more CP PAV (26.3 ± 3.4 vs 15.8 ± 1.5, p = 0.005) whereas men had more NCP PAV (33.0 ± 1.6 vs 26.7 ± 2.5, p = 0.04). Men had more LD-NCP PAV in nonobstructive lesions compared with women (1.2 ± 0.2 vs 0.6 ± 0.2, p = 0.02). In conclusion, there are gender-specific differences in plaque composition based on stenosis severity., Competing Interests: Declaration of Competing Interest Crabtree, Jennings, Earls, Hoffmann, and Min are employees of Cleerly Inc.; Earls, Marques, Choi, and Min have equity in Cleerly Inc. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Inhibition of Renin-Angiotensin-Aldosterone-System (RAAS) has been hypothesized to improve endothelial function and reduce plaque inflammation, however, their impact on the progression of coronary atherosclerosis is unclear. We aim to study the effects of RAAS inhibitor on plaque progression and composition assessed by serial coronary CT angiography (CCTA)., Methods: We performed a prospective, multinational study consisting of a registry of patients without history of CAD, who underwent serial CCTAs. Patients using RAAS inhibitors were propensity matched to RAAS inhibitor naïve patients based on clinical and CCTA characteristics at baseline. Atherosclerotic plaques in CCTAs were quantitatively analyzed for percent atheroma volume (PAV) according to plaque composition. Interactions between RAAS inhibitor use and baseline PAV on plaque progression were assessed in the unmatched cohort using a multivariate linear regression model., Results: Of 1248 patients from the registry, 299 RAAS inhibitor taking patients were matched to 299 RAAS inhibitor naïve patients. Over a mean interval of 3.9 years, there was no significant difference in annual progression of total PAV between RAAS inhibitor naïve vs taking patients (0.75 vs 0.79%/year, p = 0.66). With interaction testing in the unmatched cohort, however, RAAS inhibitor use was significantly associated with lower non-calcified plaque progression (Beta coefficient -0.100, adjusted p = 0.038) with higher levels of baseline PAV., Conclusions: The use of RAAS inhibitors over a period of nearly 4 years did not significantly impact on total atherosclerotic plaque progression or various plaque components. However, interaction testing to assess the differential effect of RAAS inhibition based on baseline PAV suggested a significant decrease in progression of non-calcified plaque in patients with a higher burden of baseline atherosclerosis, which should be considered hypothesis generating., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Aims: The totality of atherosclerotic plaque derived from coronary computed tomography angiography (CCTA) emerges as a comprehensive measure to assess the intensity of medical treatment that patients need. This study examines the differences in age onset and prognostic significance of atherosclerotic plaque burden between sexes., Methods and Results: From a large multi-center CCTA registry the Leiden CCTA score was calculated in 24 950 individuals. A total of 11 678 women (58.5 ± 12.4 years) and 13 272 men (55.6 ± 12.5 years) were followed for 3.7 years for major adverse cardiovascular events (MACE) (death or myocardial infarction). The age where the median risk score was above zero was 12 years higher in women vs. men (64-68 years vs. 52-56 years, respectively, P < 0.001). The Leiden CCTA risk score was independently associated with MACE: score 6-20: HR 2.29 (1.69-3.10); score > 20: HR 6.71 (4.36-10.32) in women, and score 6-20: HR 1.64 (1.29-2.08); score > 20: HR 2.38 (1.73-3.29) in men. The risk was significantly higher for women within the highest score group (adjusted P-interaction = 0.003). In pre-menopausal women, the risk score was equally predictive and comparable with men. In post-menopausal women, the prognostic value was higher for women [score 6-20: HR 2.21 (1.57-3.11); score > 20: HR 6.11 (3.84-9.70) in women; score 6-20: HR 1.57 (1.19-2.09); score > 20: HR 2.25 (1.58-3.22) in men], with a significant interaction for the highest risk group (adjusted P-interaction = 0.004)., Conclusion: Women developed coronary atherosclerosis approximately 12 years later than men. Post-menopausal women within the highest atherosclerotic burden group were at significantly higher risk for MACE than their male counterparts, which may have implications for the medical treatment intensity., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Intravascular ultrasound (IVUS) studies have shown that biomechanical variables, particularly endothelial shear stress (ESS), add synergistic prognostic insight when combined with anatomic high-risk plaque features. Non-invasive risk assessment of coronary plaques with coronary computed tomography angiography (CCTA) would be helpful to enable broad population risk-screening., Aim: To compare the accuracy of ESS computation of local ESS metrics by CCTA vs IVUS imaging., Methods: We analyzed 59 patients from a registry of patients who underwent both IVUS and CCTA for suspected CAD. CCTA images were acquired using either a 64- or 256-slice scanner. Lumen, vessel, and plaque areas were segmented from both IVUS and CCTA (59 arteries, 686 3-mm segments). Images were co-registered and used to generate a 3-D arterial reconstruction, and local ESS distribution was assessed by computational fluid dynamics (CFD) and reported in consecutive 3-mm segments., Results: Anatomical plaque characteristics (vessel, lumen, plaque area and minimal luminal area [MLA] per artery) were correlated when measured with IVUS and CCTA: 12.7 ​± ​4.3 vs 10.7 ​± ​4.5 ​mm 2 , r ​= ​0.63; 6.8 ​± ​2.7 vs 5.6 ​± ​2.7 ​mm 2 , r ​= ​0.43; 5.9 ​± ​2.9 vs 5.1 ​± ​3.2 ​mm 2 , r ​= ​0.52; 4.5 ​± ​1.3 vs 4.1 ​± ​1.5 ​mm 2 , r ​= ​0.67 respectively. ESS metrics of local minimal, maximal, and average ESS were also moderately correlated when measured with IVUS and CCTA (2.0 ​± ​1.4 vs 2.5 ​± ​2.6 ​Pa , r ​= ​0.28; 3.3 ​± ​1.6 vs 4.2 ​± ​3.6 ​Pa, r ​= ​0.42; 2.6 ​± ​1.5 vs 3.3 ​± ​3.0 ​Pa, r ​= ​0.35, respectively). CCTA-based computation accurately identified the spatial localization of local ESS heterogeneity compared to IVUS, with Bland-Altman analyses indicating that the absolute ESS differences between the two CCTA methods were pathobiologically minor., Conclusion: Local ESS evaluation by CCTA is possible and similar to IVUS; and is useful for identifying local flow patterns that are relevant to plaque development, progression, and destabilization., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter H Stone reports financial support was provided by the National Institute of Health. Mona Ahmed reports financial support was provided by Swedish Heart and Lung Association. Mona Ahmed reports financial support was provided by Swedish Research Council. Peter H Stone reports financial support was provided by Schaubert Family.., (Copyright © 2023 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Coronary computed tomographic angiography (CCTA) is becoming the first-line investigation for establishing the presence of coronary artery disease and, with fractional flow reserve (FFR CT ), its haemodynamic significance. In patients without significant epicardial obstruction, its role is either to rule out atherosclerosis or to detect subclinical plaque that should be monitored for plaque progression/regression following prevention therapy and provide risk classification. Ischaemic non-obstructive coronary arteries are also expected to be assessed by non-invasive imaging, including CCTA. In patients with significant epicardial obstruction, CCTA can assist in planning revascularisation by determining the disease complexity, vessel size, lesion length and tissue composition of the atherosclerotic plaque, as well as the best fluoroscopic viewing angle; it may also help in selecting adjunctive percutaneous devices (e.g., rotational atherectomy) and in determining the best landing zone for stents or bypass grafts.

Background: Statins reduce the incidence of major cardiovascular events, but residual risk remains. The study examined the determinants of atherosclerotic statin nonresponse., Objectives: This study aimed to investigate factors associated with statin nonresponse-defined atherosclerosis progression in patients treated with statins., Methods: The multicenter PARADIGM (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging) registry included patients who underwent serial coronary computed tomography angiography ≥2 years apart, with whole-heart coronary tree quantification of vessel, lumen, and plaque, and matching of baseline and follow-up coronary segments and lesions. Patients with statin use at baseline and follow-up coronary computed tomography angiography were included. Atherosclerotic statin nonresponse was defined as an absolute increase in percent atheroma volume (PAV) of 1.0% or more per year. Furthermore, a secondary endpoint was defined by the additional requirement of progression of low-attenuation plaque or fibro-fatty plaque., Results: The authors included 649 patients (age 62.0 ± 9.0 years, 63.5% male) on statin therapy and 205 (31.5%) experienced atherosclerotic statin nonresponse. Age, diabetes, hypertension, and all atherosclerotic plaque features measured at baseline scan (high-risk plaque [HRP] features, calcified and noncalcified PAV, and lumen volume) were significantly different between patients with and without atherosclerotic statin nonresponse, whereas only diabetes, number of HRP features, and noncalcified and calcified PAV were independently associated with atherosclerotic statin nonresponse (odds ratio [OR]: 1.41 [95% CI: 0.95-2.11], OR: 1.15 [95% CI: 1.09-1.21], OR: 1.06 [95% CI: 1.02-1.10], OR: 1.07 [95% CI: 1.03-1.12], respectively). For the secondary endpoint (N = 125, 19.2%), only noncalcified PAV and number of HRP features were the independent determinants (OR: 1.08 [95% CI: 1.03-1.13] and OR: 1.21 [95% CI: 1.06-1.21], respectively)., Conclusions: In patients treated with statins, baseline plaque characterization by plaque burden and HRP is associated with atherosclerotic statin nonresponse. Patients with the highest plaque burden including HRP were at highest risk for plaque progression, despite statin therapy. These patients may need additional therapies for further risk reduction., Competing Interests: Funding Support and Author Disclosures 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). The study was also funded in part by a generous gift from the Dalio Institute of Cardiovascular Imaging (New York, New York, USA) and the Michael Wolk Foundation (New York, New York, USA). Dr Min is an employee of Cleerly Inc. Dr Leipsic is a consultant to and holds stock options in Circle CVI and HeartFlow; and has received modest speaking fees from Philips and GE Healthcare. Dr Chinnaiyan is a noncompensated medical advisory board member of Heartflow Inc. Dr Samady serves on the scientific advisory board of Philips; has equity interest in Covanos Inc; and has a research grant from Medtronic, Abbott Vascular, and Philips. Dr Virmani is a consultant of Abbott Vascular, Boston Scientific, Celonova, OrbusNeich Medical, Terumo Corporation, W.L. Gore, Edwards Lifesciences, Cook Medical, CSI, ReCor Medical, SinoMedical Sciences Technology, Surmodics, and Bard BD; and is a scientific Advisory Board Member of Medtronic and Xeltis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

There is increasing evidence that in patients with atherosclerotic cardiovascular disease (ASCVD) under optimal medical therapy, a persisting dysregulation of the lipid and glucose metabolism, associated with adipose tissue dysfunction and inflammation, predicts a substantial residual risk of disease progression and cardiovascular events. Despite the inflammatory nature of ASCVD, circulating biomarkers such as high-sensitivity C-reactive protein and interleukins may lack specificity for vascular inflammation. As known, dysfunctional epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT) produce pro-inflammatory mediators and promote cellular tissue infiltration triggering further pro-inflammatory mechanisms. The consequent tissue modifications determine the attenuation of PCAT as assessed and measured by coronary computed tomography angiography (CCTA). Recently, relevant studies have demonstrated a correlation between EAT and PCAT and obstructive coronary artery disease, inflammatory plaque status and coronary flow reserve (CFR). In parallel, CFR is well recognized as a marker of coronary vasomotor function that incorporates the haemodynamic effects of epicardial, diffuse and small-vessel disease on myocardial tissue perfusion. An inverse relationship between EAT volume and coronary vascular function and the association of PCAT attenuation and impaired CFR have already been reported. Moreover, many studies demonstrated that 18F-FDG PET is able to detect PCAT inflammation in patients with coronary atherosclerosis. Importantly, the perivascular FAI (fat attenuation index) showed incremental value for the prediction of adverse clinical events beyond traditional risk factors and CCTA indices by providing a quantitative measure of coronary inflammation. As an indicator of increased cardiac mortality, it could guide early targeted primary prevention in a wide spectrum of patients. In this review, we summarize the current evidence regarding the clinical applications and perspectives of EAT and PCAT assessment performed by CCTA and the prognostic information derived by nuclear medicine., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Objective: This study evaluates the relationship between atherosclerotic plaque characteristics (APCs) and angiographic stenosis severity in patients with and without diabetes. Whether APCs differ based on lesion severity and diabetes status is unknown., Research Design and Methods: We retrospectively evaluated 303 subjects from the Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia (CREDENCE) trial referred for invasive coronary angiography with coronary computed tomographic angiography (CCTA) and classified lesions as obstructive (≥50% stenosed) or nonobstructive using blinded core laboratory analysis of quantitative coronary angiography. CCTA quantified APCs, including plaque volume (PV), calcified plaque (CP), noncalcified plaque (NCP), low-density NCP (LD-NCP), lesion length, positive remodeling (PR), high-risk plaque (HRP), and percentage of atheroma volume (PAV; PV normalized for vessel volume). The relationship between APCs, stenosis severity, and diabetes status was assessed., Results: Among the 303 patients, 95 (31.4%) had diabetes. There were 117 lesions in the cohort with diabetes, 58.1% of which were obstructive. Patients with diabetes had greater plaque burden (P = 0.004). Patients with diabetes and nonobstructive disease had greater PV (P = 0.02), PAV (P = 0.02), NCP (P = 0.03), PAV NCP (P = 0.02), diseased vessels (P = 0.03), and maximum stenosis (P = 0.02) than patients without diabetes with nonobstructive disease. APCs were similar between patients with diabetes with nonobstructive disease and patients without diabetes with obstructive disease. Diabetes status did not affect HRP or PR. Patients with diabetes had similar APCs in obstructive and nonobstructive lesions., Conclusions: Patients with diabetes and nonobstructive stenosis had an association to similar APCs as patients without diabetes who had obstructive stenosis. Among patients with nonobstructive disease, patients with diabetes had more total PV and NCP., (© 2023 by the American Diabetes Association.)

Background: HDL is endowed with several metabolic, vascular, and immunoinflammatory protective functions. Among them, a key property is to promote reverse cholesterol transport from cells back to the liver. The aim of this study was to estimate the association of scavenger receptor class B type I (SR-BI)- and ATP binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux (the two major routes for cholesterol efflux to HDL) with the presence, extent, and severity of coronary artery disease (CAD), vascular wall remodelling processes, coronary plaque characteristics, and the incidence of myocardial infarction in the different subgroups of patients from the CAPIRE study., Methods: Patients ( n  = 525) from the CAPIRE study were divided into two groups: low-risk factors (RF), with 0-1 RF ( n  = 263), and multiple-RF, with ≥2 RFs; within each group, subjects were classified as no-CAD or CAD based on the segment involvement score (SIS) evaluated by coronary computed tomography angiography (SIS = 0 and SIS > 5, respectively). SR-BI- and ABCA1-mediated cholesterol efflux were measured using the plasma of all patients., Results: SR-BI-mediated cholesterol efflux was significantly reduced in patients with CAD in both the low-RF and multiple-RF groups, whereas ABCA1-mediated cholesterol efflux was similar among all groups. In CAD patients, multivariable analysis showed that SR-BI-mediated cholesterol efflux <25 th percentile predicted cardiovascular outcome (odds ratio 4.1; 95% CI: 1.3-13.7; p  = .019), whereas ABCA-1-mediated cholesterol efflux and HDL-C levels significantly did not. Despite this finding, reduced SR-BI-mediated cholesterol efflux was not associated with changes in high-risk plaque features or changes in the prevalence of elevated total, non-calcified, and low-attenuation plaque volume., Conclusion: SR-BI-mediated cholesterol efflux capacity is lower in patients with diffuse coronary atherosclerosis. In addition, a lower SR-BI-mediated cholesterol efflux capacity is associated with the worst clinical outcomes in patients with CAD, independently of atherosclerotic plaque features. Key MessagesIncreased cholesterol efflux capacity, an estimate of HDL function, is associated with a reduced CVD risk, regardless of HDL-C levels.HDL-C levels are significantly lower in patients with CAD.Lower SR-BI-mediated cholesterol efflux capacity is observed in patients with diffuse coronary atherosclerosis and is associated with the worst clinical outcomes in patients with CAD, independently of atherosclerotic plaque features.

Background: The baseline coronary plaque burden is the most important factor for rapid plaque progression (RPP) in the coronary artery. However, data on the independent predictors of RPP in the absence of a baseline coronary plaque burden are limited. Thus, this study aimed to investigate the predictors for RPP in patients without coronary plaques on baseline coronary computed tomography angiography (CCTA) images., Methods: A total of 402 patients (mean age: 57.6 ± 10.0 years, 49.3% men) without coronary plaques at baseline who underwent serial coronary CCTA were identified from the Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging (PARADIGM) registry and included in this retrospective study. RPP was defined as an annual change of ≥ 1.0%/year in the percentage atheroma volume (PAV)., Results: During a median inter-scan period of 3.6 years (interquartile range: 2.7-5.0 years), newly developed coronary plaques and RPP were observed in 35.6% and 4.2% of the patients, respectively. The baseline traditional risk factors, i.e., advanced age (≥ 60 years), male sex, hypertension, diabetes mellitus, hyperlipidemia, obesity, and current smoking status, were not significantly associated with the risk of RPP. Multivariate linear regression analysis showed that the serum hemoglobin A1c level (per 1% increase) measured at follow-up CCTA was independently associated with the annual change in the PAV (β: 0.098, 95% confidence interval [CI]: 0.048-0.149; P < 0.001). The multiple logistic regression models showed that the serum hemoglobin A1c level had an independent and positive association with the risk of RPP. The optimal predictive cut-off value of the hemoglobin A1c level for RPP was 7.05% (sensitivity: 80.0%, specificity: 86.7%; area under curve: 0.816 [95% CI: 0.574-0.999]; P = 0.017)., Conclusion: In this retrospective case-control study, the glycemic control status was strongly associated with the risk of RPP in patients without a baseline coronary plaque burden. This suggests that regular monitoring of the glycemic control status might be helpful for preventing the rapid progression of coronary atherosclerosis irrespective of the baseline risk factors. Further randomized investigations are necessary to confirm the results of our study., Trial Registration: ClinicalTrials.gov NCT02803411., (© 2022. The Author(s).)

Background: We examined age differences in whole-heart volumes of non-calcified and calcified atherosclerosis by coronary computed tomography angiography (CCTA) of patients with future ACS., Methods: A total of 234 patients with core-lab adjudicated ACS after baseline CCTA were enrolled. Atherosclerotic plaque was quantified and characterized from the main epicardial vessels and side branches on a 0.5 ​mm cross-sectional basis. Calcified plaque and non-calcified plaque were defined by above or below 350 Hounsfield units. Patients were categorized according to their age by deciles. Also, coronary artery calcium scores (CACS) were evaluated when available., Results: Patients were on average 62.2 ​± ​11.5 years old. On the pre-ACS CCTA, patients showed diffuse, multi-site, predominantly non-obstructive atherosclerosis across all age categories, with plaque being detected in 93.5% of all ACS cases. The proportion calcified plaque from the total plaque burden increased significantly with older presentation (10% calcification in those <50 years, and 50% calcification in those >80 years old). Patients with ACS <50 years had remarkably lower atherosclerotic burden compared with older patients, but a high proportion of high risk markers such as low-attenuation plaque. CACS was >0 in 85% of the patients older than 50 years, and in 57% of patients younger than 50 years., Conclusion: The proportion of calcified plaque varied depending on patient age at the time of ACS. Only a small proportion of plaque was calcified when ACS occurred at <50 years old, while this increased gradually with older age. Purely non-calcified atherosclerotic plaque was not uncommon in patients <50 years., Competing Interests: Declaration of competing interest Dr. Chinnaiyan is a non-compensated medical advisory board member of Heartflow Inc. Dr. Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research, receives support from CV Diagnostix and Ausculsciences, receives educational support from TeraRecon Inc., and has equity interest in General Electric. Dr. Min is an employee of Cleerly, Inc. Dr. Samady serves on the scientific advisory board of Philips, has equity interest in Covanos Inc., and has a research grant from Medtronic, Abbott Vascular, and Philips. Dr. Shaw is on the scientific advisory board for Covanos, Inc. The remaining authors have no relevant conflicts to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Aims: Atherosclerosis develops progressively and worsens over time, yet event risk patterns vary in the left circumflex (LCx), right coronary artery (RCA) and left anterior descending (LAD). The aim of this analysis was to examine varying progressive disease alterations between the three major coronary arteries., Methods and Results: Patients were included from a prospective, international registry of consecutive patients who underwent serial CCTA at a median interval of 3.3 years. Annual progression of quantitative total and compositional plaque volume were compared between the three coronary arteries (LCx, LAD, and RCA). Other analyses compared stenosis ≥50% and new high-risk plaque (HRP; ≥2 of the following: spotty calcification, positive remodelling, napkin-ring sign, and low-attenuation plaque) on follow-up. Generalized estimating equations and marginal Cox regression models were used to compare progression, with covariate adjustment by the baseline atherosclerotic cardiovascular disease risk score, statin use, and plaque burden. Quantitative plaque measurements were calculated in 1344 patients (age 60 ± 9 years, 57% men). Plaque progression occurred less often in the LCx (41.0%) as compared to the RCA (52.7%) and LAD (77.4%, P &lt; 0.001). Odds for annual plaque burden increase ≥population mean were 1.98- and 1.43-fold as high in the LAD (P &lt; 0.001) and RCA (P &lt; 0.001) as compared to the LCx. Similarly, the LAD was associated with a 2.45 higher risk of progression to obstructive CAD (P &lt; 0.001), as compared to the LCx; with no differences between the RCA and LCx (P = 0.13). New HRP lesions formed least often in the LCx (3.4%), followed by the RCA (8.1%) and most often in the LAD (10.1%; P &lt; 0.001)., Conclusions: Our findings reveal novel insights into varied patterns of atherosclerotic plaque progression within the LCx as compared to the other epicardial coronary arteries. These varied patterns reflect differing stages in the disease process or differing pathogenic milieu across the coronary arteries., Competing Interests: Conflict of interest: K.C. is a non-compensated medical advisor for Heartflow Inc. L.J.S. is on the scientific advisory board for Covanos Inc. J.A.L. is a consultant to and hold stock options in Circle CVI and HeartFlow and receives research support from GE Healthcare and serves on the speakers’ bureau for Philips and GE Healthcare. G.S. has received speaker or other honoraria from Cook, Terumo, QOOL Therapeutics, and Orchestra Biomed; has served as a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, Cardiomech; and has equity/options from Ancora, Qool Therapeutics, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds, and Valfix., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Background: The association between the change in vessel inflammation, as quantified by perivascular adipose tissue (PVAT) density, and the progression of coronary atherosclerosis remains to be determined., Objectives: The purpose of this study was to explore the association between the change in PVAT density and the progression of total and compositional plaque volume (PV)., Methods: Patients were selected from a prospective multinational registry. Patients who underwent serial coronary computed tomography angiography studies with ≥2-year intervals and were scanned with the same tube voltage at baseline and follow-up were included. Total and compositional PV and PVAT density at baseline and follow-up were quantitatively analyzed for every lesion. Multivariate linear regression models using cluster analyses were constructed., Results: A total of 1,476 lesions were identified from 474 enrolled patients (mean age 61.2 ± 9.3 years; 65.0% men). The mean PVAT density was -74.1 ± 11.5 HU, and total PV was 48.1 ± 83.5 mm 3 (19.2 ± 44.8 mm 3 of calcified PV and 28.9 ± 51.0 mm 3 of noncalcified PV). On multivariate analysis (adjusted for clinical risk factors, medication use, change in lipid levels, total PV at baseline, luminal HU attenuation, location of lesions, and tube voltage), the increase in PVAT density was positively associated with the progression of total PV (estimate = 0.275 [95% CI: 0.004-0.545]; P = 0.047), driven by the association with fibrous PV (estimate = 0.245 [95% CI: 0.070-0.420]; P = 0.006). Calcified PV progression was not associated with the increase in PVAT density (P > 0.050)., Conclusions: Increase in vessel inflammation represented by PVAT density is independently associated with the progression of the lipid component of coronary atherosclerotic plaques. (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging [PARADIGM]; NCT02803411)., Competing Interests: Funding Support and Author Disclosures This work was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT; the Ministry of Trade, Industry and Energy; the Ministry of Health and Welfare, Republic of Korea, the Ministry of Food and Drug Safety) (Project Number: 202016B02). The study was also funded in part by a grant from the Dalio Foundation. Dr Leipsic has served as a consultant for and holds stock options in HeartFlow and Circle CVI. Drs Kitslaar and Reiber are employees of Medis Medical Imaging. Dr Samady has served on the scientific advisory board of Philips; has equity interest in Covanos Inc; and has received a research grant from Medtronic. Dr Lin has received grant support from GE Healthcare. Dr Min has received funding from GE Healthcare; has served on the scientific advisory board of Arineta and GE Healthcare; and has an equity interest in and is an employee of Cleerly, Inc. Dr Chang has received funding from 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). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The temporal instability of coronary atherosclerotic plaque preceding an incident acute coronary syndrome (ACS) is not well defined. We sought to examine differences in the volume and composition of coronary atherosclerosis between patients experiencing an early (≤90 days) versus late ACS (>90 days) after baseline coronary computed tomography angiography (CCTA)., Methods and Results: From a multicenter study, we enrolled patients who underwent a clinically indicated baseline CCTA and experienced ACS during follow-up. Separate core laboratories performed blinded adjudication of ACS events and quantification of CCTA including compositional plaque volumes by Hounsfield units (HU): calcified plaque >350 HU, fibrous plaque 131-350 HU, fibrofatty plaque 31-130 HU and necrotic core <30 HU. In 234 patients (mean age 62 ± 12 years, 36% women), early and late ACS occurred in 129 and 105 patients after a mean of 395 ± 622 days, respectively. Patients with early ACS had a greater maximal diameter stenosis and maximal cross-sectional plaque burden as compared to patients with late ACS (P < 0.05). Larger total, fibrous, fibrofatty, and necrotic core volumes were observed in the early ACS group (P < 0.05). Findings for total, fibrous, fibrofatty, and necrotic core volumes were reproduced in an external validation cohort (P < 0.05)., Conclusions: Volumetric differences in composition of coronary atherosclerosis exist between ACS patients according to their timing antecedent to the acute event. These data support that a large burden of non-calcified plaque on CCTA is strongly associated with near-term plaque instability and ACS risk., Competing Interests: Conflict of interest: Dr Chow receives support from CV Diagnostix and Ausculsciences, educational support from TeraRecon Inc., and has equity interest in General Electric. Dr Leipsic is a consultant and has stock options in Circle CVI and HeartFlow and receives research support from GE Healthcare. Dr Min is an employee of Cleerly, Inc. Dr Shaw serves on the scientific advisory board for Covanos, Inc. Dr Samady serves on the scientific advisory board of Philips, has equity interest in Covanos Inc., and has a research grant from Medtronic, Abbott Vascular, and Philips. The remaining authors have no relevant conflicts to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: The magnitude of alterations in which coronary arteries remodel and narrow over time is not well understood. We aimed to examine changes in coronary arterial remodelling and luminal narrowing by three-dimensional (3D) metrics from serial coronary computed tomography angiography (CCTA)., Methods and Results: From a multicentre registry of patients with suspected coronary artery disease who underwent clinically indicated serial CCTA (median interscan interval = 3.3 years), we quantitatively measured coronary plaque, vessel, and lumen volumes on both scans. Primary outcome was the per-segment change in coronary vessel and lumen volume from a change in plaque volume, focusing on arterial remodelling. Multivariate generalized estimating equations including statins were calculated comparing associations between groups of baseline percent atheroma volume (PAV) and location within the coronary artery tree. From 1245 patients (mean age 61 ± 9 years, 39% women), a total of 5721 segments were analysed. For each 1.00 mm3 increase in plaque volume, the vessel volume increased by 0.71 mm3 [95% confidence interval (CI) 0.63 to 0.79 mm3, P < 0.001] with a corresponding reduction in lumen volume by 0.29 mm3 (95% CI -0.37 to -0.21 mm3, P < 0.001). Serial 3D arterial remodelling and luminal narrowing was similar in segments with low and high baseline PAV (P ≥ 0.496). No differences were observed between left main and non-left main segments, proximal and distal segments and side branch and non-side branch segments (P ≥ 0.281)., Conclusions: Over time, atherosclerotic coronary plaque reveals prominent outward arterial remodelling that co-occurs with modest luminal narrowing. These findings provide additional insight into the compensatory mechanisms involved in the progression of coronary atherosclerosis., Competing Interests: Conflict of interest: J.K.M. has an equity interest in Cleerly. K.C. is a non-compensated medical advisory board member of Heartflow Inc. H.S. serves on the scientific advisory board of Philips, has equity interest in Covanos Inc., and has a research grant from Medtronic, Abbott Vascular and Philips. L.J.S. serves on the scientific advisory board for Covanos, Inc. The remaining authors have no relevant disclosures., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Atherosclerotic plaque characterization by coronary computed tomography angiography (CCTA) enables quantification of coronary artery disease (CAD) burden and type, which has been demonstrated as the strongest discriminant of future risk of major adverse cardiac events (MACE). To date, there are no clinically useful thresholds to assist with understanding a patient's disease burden and guide diagnosis and management, as there exists with coronary artery calcium (CAC) scoring. The purpose of this manuscript is to establish clinically relevant plaque stages and thresholds based on evidence from invasive angiographic stenosis (ICA) and fractional flow reserve (FFR) data., Methods: 303 patients underwent CCTA prior to ICA and FFR for an AHA/ACC clinical indication. Quantitative computed tomography (QCT) was performed for total plaque volume (TPV, mm 3 ) and percent atheroma volume (PAV, %). We segmented atherosclerosis by composition for low-density non-calcified plaque (LD-NCP), non-calcified plaque (NCP), and calcified plaque (CP). ICAs were evaluated by quantitative coronary angiography (QCA) for all coronary segments for % diameter stenosis. The relationship of atherosclerotic plaque burden and composition by QCT to ICA stenosis extent and severity by QCA and presence of ischemia by FFR was assessed to develop 4 distinct disease stages., Results: The mean age of the patients was 64.4 ​± ​10.2 years; 71% male. At the 50% QCA stenosis threshold, QCT revealed a mean PAV of 9.7 (±8.2)% and TPV of 436 (±444.9)mm 3 for those with non-obstructive CAD; PAV of 11.7 (±8.0)% and TPV of 549.3 (±408.3) mm 3 for 1 vessel disease (1VD), PAV of 17.8 (±9.8)% and TPV of 838.9 (±550.7) mm 3 for 2VD, and PAV of 19.2 (±8.2)% and TPV of 799.9 (±357.4) mm 3 for 3VD/left main disease (LMD). Non-ischemic patients (FFR >0.8) had a mean PAV of 9.2 (±7.3) % and TPV of 422.9 (±387.9 ​mm 3 ) while patients with at least one vessel ischemia (FFR ≤0.8) had a PAV of 15.2 (±9.5)% and TPV of 694.6 (±485.1). Definition of plaque stage thresholds of 0, 250, 750 ​mm 3 and 0, 5, and 15% PAV resulted in 4 clinically distinct stages in which patients with no, nonobstructive, single VD and multi-vessel disease were optimally distributed., Conclusion: Atherosclerotic plaque burden by QCT is related to stenosis severity and extent as well as ischemia. We propose staging of CAD atherosclerotic plaque burden using the following definitions: Stage 0 (Normal, 0% PAV, 0 ​mm 3 TPV), Stage 1 (Mild, >0-5% PAV or >0-250 ​mm 3 TPV), Stage 2 (Moderate, >5-15% PAV or >250-750 ​mm 3 TPV) and Stage 3 (Severe, >15% PAV or >750 mm3 TPV)., Competing Interests: Declaration of competing interest JKM, TC, JPE are employees and retain equity interest in Cleerly., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Obstructive coronary artery disease (CAD) in proximal coronary segments is associated with a poor prognosis. However, the relative importance of plaque location regarding the risk for major adverse cardiovascular events (MACE) in patients with non-obstructive CAD has not been well defined., Methods and Results: From the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry, 4644 patients without obstructive CAD were included in this study. The degree of stenosis was classified as 0 (no) and 1-49% (non-obstructive). Proximal involvement was defined as any plaque present in the left main or the proximal segment of the left anterior descending artery, left circumflex artery, and right coronary artery. Extensive CAD was defined as segment involvement score of >4. During a median follow-up of 5.2 years (interquartile range 4.1-6.0), 340 (7.3%) MACE occurred. Within the non-obstructive CAD group (n = 2065), proximal involvement was observed in 1767 (85.6%) cases. When compared to non-obstructive CAD patients without proximal involvement, those with proximal involvement had an increased MACE risk (log-rank P = 0.033). Multivariate Cox analysis showed when compared to patients with no CAD, proximal non-obstructive CAD was associated with increased MACE risk [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.47-2.45, P < 0.001] after adjusting for extensive CAD and conventional cardiovascular risk factors; however, non-proximal non-obstructive CAD did not increase MACE risk (HR 1.26, 95% CI 0.79-2.01, P = 0.339)., Conclusions: Independent of plaque extent, proximal coronary involvement was associated with increased MACE risk in patients with non-obstructive CAD. The plaque location information by coronary computed tomography angiography may provide additional risk prediction over CAD extent in patients with non-obstructive CAD., Competing Interests: Conflict of interest: J.K.M. receives funding from the Dalio Foundation, National Institutes of Health, and GE Healthcare; has serves on the scientific advisory board of Arineta and GE Healthcare; and has an equity interest in Cleerly. B.J.W.C. receives research grant support from TD Bank, Artrya, Siemens, and AusculSciences and has an equity interest in GE healthcare. P.A.K.’s nuclear department at the University Hospital Zurich holds research agreement with GE Healthcare. G.P. receives honorarium as speaker and research institutional grant from GE, Bracco, Boehringer, and HeartFlow. All other authors declared no conflict of interest., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: The relationship between AtheroSclerotic CardioVascular Disease (ASCVD) risk and vessel-specific plaque evaluation using coronary computed tomography angiography (CCTA), focusing on plaque extent and composition, has not been examined. To evaluate differences in quantified plaque characteristics (using CCTA) between the three major coronary arteries [left anterior descending (LAD), right coronary (RCA), and left circumflex (LCx)] among subgroups of patients with varying ASCVD risk., Methods and Results: Patients were included from a prospective, international registry of consecutive patients who underwent CCTA for evaluation of coronary artery disease. ASCVD risk groups were <7.5% (low), 7.5-20% (intermediate), and ≥20% (high). Among the ASCVD risk groups, the three coronary arteries were compared regarding quantified plaque volume and composition. Whole-heart plaque quantification was performed in 1340 patients (age 60 ± 9 years, 58% men). Across low, intermediate, and high ASCVD risk patients, the volume of plaque increased proportionally but was least in the LCx (7.4, 9.0, and 25.3 mm3, respectively) as compared with the RCA (19.3, 32.6, and 67.0 mm3, respectively, all P ≤ 0.006) and LAD (39.9, 60.8, and 93.3 mm3, respectively, all P < 0.001). In each ASCVD risk group, the composition of plaque in the LCx exhibited the least necrotic core and fibrofatty plaque (P < 0.05 vs. LAD and RCA)., Conclusion: Among patients with varying risk of ASCVD, plaque in the LCx is decidedly less and is comprised of less non-calcified plaque supporting prior evidence of the lower rates of acute coronary events in this vessel., Competing Interests: Conflict of interest: K.C. is a non-compensated medical advisor for Heartflow, Inc. L.J.S. is on the scientific advisory board for Covanos, Inc. J.A.L. is a consultant to and has stock options in Circle CVI and HeartFlow, receives research support from GE Healthcare and serves on the speakers’ bureau for Philips and GE Healthcare. All other authors have no conflicts of interest to report., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Background: Atherosclerosis-related adverse events are commonly observed even in conditions with low cardiovascular (CV) risk. Longitudinal data regarding the association of normal systolic blood pressure maintenance (SBP maintain ) with coronary plaque volume changes (PVC) has been limited in adults without traditional CV disease., Hypothesis: Normal SBP maintain is important to attenuate coronary atherosclerosis progression in adults without baseline CV disease., Methods: We analyzed 95 adults (56.7 ± 8.5 years; 40.0% men) without baseline CV disease who underwent serial coronary computed tomographic angiography with mean 3.5 years of follow-up. All participants were divided into two groups of normal SBP maintain (follow-up SBP < 120 mm Hg) and ≥elevated SBP maintain (follow-up SBP ≥ 120 mm Hg). Annualized PVC was defined as PVC divided by the interscan period., Results: Compared to participants with normal SBP maintain , those with ≥elevated SBP maintain had higher annualized total PVC (mm 3 /year) (0.0 [0.0-2.2] vs. 4.1 [0.0-13.0]; p < .001). Baseline total plaque volume (β = .10) and the levels of SBP maintain (β = .23) and follow-up high-density lipoprotein cholesterol (β = -0.28) were associated with annualized total PVC (all p < .05). The optimal cutoff of SBP maintain for predicting plaque progression was 118.5 mm Hg (sensitivity: 78.2%, specificity: 62.5%; area under curve: 0.700; 95% confidence interval [CI]: 0.59-0.81; p < .05). SBP maintain  ≥ 118.5 mm Hg (odds ratio [OR]: 4.03; 95% CI: 1.51-10.75) and baseline total plaque volume (OR: 1.03; 95% CI: 1.01-1.06) independently influenced coronary plaque progression (all p < .05)., Conclusion: Normal SBP maintain is substantial to attenuate coronary atherosclerosis progression in conditions without established CV disease., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Background: Among symptomatic patients, it remains unclear whether a coronary artery calcium (CAC) score alone is sufficient or misses a sizeable burden and progressive risk associated with obstructive and nonobstructive atherosclerotic plaque., Objectives: Among patients with low to high CAC scores, our aims were to quantify co-occurring obstructive and nonobstructive noncalcified plaque and serial progression of atherosclerotic plaque volume., Methods: A total of 698 symptomatic patients with suspected coronary artery disease (CAD) underwent serial coronary computed tomographic angiography (CTA) performed 3.5 to 4.0 years apart. Atherosclerotic plaque was quantified, including by compositional subgroups. Obstructive CAD was defined as ≥50% stenosis. Multivariate linear regression models were used to measure atherosclerotic plaque progression by CAC scores. Cox proportional hazard models estimated CAD event risk (median of 10.7 years of follow-up)., Results: Across baseline CAC scores from 0 to ≥400, total plaque volume ranged from 30.4 to 522.4 mm 3 (P < 0.001) and the prevalence of obstructive CAD increased from 1.4% to 49.1% (P < 0.001). Of those with a 0 CAC score, 97.9% of total plaque was noncalcified. Among patients with baseline CAC <100, nonobstructive CAD was prevalent (40% and 89% in CAC scores of 0 and 1-99), with plaque largely being noncalcified. On the follow-up coronary CTA, volumetric plaque growth (P < 0.001) and the development of new or worsening stenosis (P < 0.001) occurred more among patients with baseline CAC ≥100. Progression varied compositionally by baseline CAC scores. Patients with no CAC had disproportionate growth in noncalcified plaque, and for every 1 mm 3 increase in calcified plaque, there was a 5.5 mm 3 increase in noncalcified plaque volume. By comparison, patients with CAC scores of ≥400 exhibited disproportionate growth in calcified plaque with a volumetric increase 15.7-fold that of noncalcified plaque. There was a graded increase in CAD event risk by the CAC with rates from 3.3% for no CAC to 21.9% for CAC ≥400 (P < 0.001)., Conclusions: CAC imperfectly characterizes atherosclerotic disease burden, but its subgroups exhibit pathogenic patterns of early to advanced disease progression and stratify long-term prognostic risk., Competing Interests: Funding Support and Author Disclosures Partial funding was provided by a gift from the Dalio Foundation (New York, New York) and supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation funded by the Ministry of Science and Information and Communications Technology of Korea (Grant number 2012027176). Dr Chinnaiyan is a medical advisor (unpaid) for Heartflow, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate potential differences in plaque progression (PP) between in East Asians and Caucasians as well as to determine clinical predictors of PP in East Asians., Background: Studies have demonstrated differences in cardiovascular risk factors as well as plaque burden and progression across different ethnic groups., Methods: The study comprised 955 East Asians (age 60.4 ​± ​9.3 years, 50.9% males) and 279 Caucasians (age 60.4 ​± ​8.6 years, 74.5% males) who underwent two serial coronary computed tomography angiography (CCTA) studies over a period of at least 24 months. Patients were enrolled and analyzed from the PARADIGM (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging) registry. After propensity-score matching, plaque composition and progression were compared between East Asian and Caucasian patients. Within East Asians, the plaque progression group (defined as plaque volume at follow-up CCTA minus plaque volume at baseline CCTA> 0) was compared to the no PP group to determine clinical predictors for PP in East Asians., Results: In the matched cohort, baseline volumes of total plaque as well as all plaque subtypes were comparable. There was a trend towards increased annualized plaque progression among East Asians compared to Caucasians (18.3 ​± ​24.7 ​mm 3 /year vs 16.6 ​mm 3 /year, p ​= ​0.054). Among East Asians, 736 (77%) had PP. East Asians with PP had more clinical risk factors and higher plaque burden at baseline (normalized total plaque volume of144.9 ​± ​233.3 ​mm 3 vs 36.6 ​± ​84.2 ​mm 3 for PP and no PP, respectively, p ​< ​0.001). Multivariate logistic regression analysis showed that baseline normalized plaque volume (OR: 1.10, CI: 1.10-1.30, p ​< ​0.001), age (OR: 1.02, CI: 1.00-1.04, p ​= ​0.023) and body mass index (OR: 2.24, CI: 1.01-1.13, p ​= ​0.024) were all predictors of PP in East Asians. Clinical events, driven mainly by percutaneous coronary intervention, were higher among the PP group with a total of 124 (16.8%) events compared to 22 (10.0%) in the no PP group (p ​= ​0.014)., Conclusion: East Asians and Caucasians had comparable plaque composition and progression. Among East Asians, the PP group had a higher baseline plaque burden which was associated with greater PP and increased clinical events., (Copyright © 2022. Published by Elsevier Inc.)

Background and Aims: The aim of the present study is to evaluate whether advanced coronary atherosclerosis analysis by CCTA may improve prognostic stratification among diabetic patients at high cardiovascular risk (CV risk)., Methods and Results: The study population consisted of 265 consecutive diabetic patients at high CV risk who underwent CCTA for suspected CAD between January 2011 and December 2016. For every patients both traditional and advanced, qualitative and quantitative coronary plaque analysis were performed. The occurrence of cardiac death, ACS, and non-urgent revascularization were recorded at follow-up. Among the 265 patients enrolled, 21 were lost to follow-up, whereas 244 (92%) had a complete follow-up (mean 45 ± 22 months) and were classified at high (n = 67) or very high cardiovascular risk (n = 177), according to ESC Guidelines. A total of 63 events were recorded (3 Cardiac Death, 3 NSTEMI, 8 unstable angina, 36 late non-urgent revascularization and 13 non-cardiac death) in 57 different patients. Elevated fibro-fatty plaque volume was the only predictor of events over age, gender and traditional risk factor when ACS and MACE were considered as end-points [HR (95% CI) 6.01 (1.65-21.87), p = 0.006 and 3.46 (2.00-5.97); p < 0.001]., Conclusion: The present study confirms the prognostic role of advance coronary atherosclerosis evaluation beyond risk factors and stenosis severity, even in diabetics. Despite the very high cardiovascular risk of study population, a not negligible portion (23%) of patients exhibited totally normal coronaries., Competing Interests: Declaration of competing interest None declared., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Importance: Distinct plaque locations and vessel geometric features predispose to altered coronary flow hemodynamics. The association between these lesion-level characteristics assessed by coronary computed tomographic angiography (CCTA) and risk of future acute coronary syndrome (ACS) is unknown., Objective: To examine whether CCTA-derived adverse geometric characteristics (AGCs) of coronary lesions describing location and vessel geometry add to plaque morphology and burden for identifying culprit lesion precursors associated with future ACS., Design, Setting, and Participants: This substudy of ICONIC (Incident Coronary Syndromes Identified by Computed Tomography), a multicenter nested case-control cohort study, included patients with ACS and a culprit lesion precursor identified on baseline CCTA (n = 116) and propensity score-matched non-ACS controls (n = 116). Data were collected from July 20, 2012, to April 30, 2017, and analyzed from October 1, 2020, to October 31, 2021., Exposures: Coronary lesions were evaluated for the following 3 AGCs: (1) distance from the coronary ostium to lesion; (2) location at vessel bifurcations; and (3) vessel tortuosity, defined as the presence of 1 bend of greater than 90° or 3 curves of 45° to 90° using a 3-point angle within the lesion., Main Outcomes and Measures: Association between lesion-level AGCs and risk of future ACS-causing culprit lesions., Results: Of 548 lesions, 116 culprit lesion precursors were identified in 116 patients (80 [69.0%] men; mean [SD], age 62.7 [11.5] years). Compared with nonculprit lesions, culprit lesion precursors had a shorter distance from the ostium (median, 35.1 [IQR, 23.6-48.4] mm vs 44.5 [IQR, 28.2-70.8] mm), more frequently localized to bifurcations (85 [73.3%] vs 168 [38.9%]), and had more tortuous vessel segments (5 [4.3%] vs 6 [1.4%]; all P < .05). In multivariable Cox regression analysis, an increasing number of AGCs was associated with a greater risk of future culprit lesions (hazard ratio [HR] for 1 AGC, 2.90 [95% CI, 1.38-6.08]; P = .005; HR for ≥2 AGCs, 6.84 [95% CI, 3.33-14.04]; P < .001). Adverse geometric characteristics provided incremental discriminatory value for culprit lesion precursors when added to a model containing stenosis severity, adverse morphological plaque characteristics, and quantitative plaque characteristics (area under the curve, 0.766 [95% CI, 0.718-0.814] vs 0.733 [95% CI, 0.685-0.782]). In per-patient comparison, patients with ACS had a higher frequency of lesions with adverse plaque characteristics, AGCs, or both compared with control patients (≥2 adverse plaque characteristics, 70 [60.3%] vs 50 [43.1%]; ≥2 AGCs, 92 [79.3%] vs 60 [51.7%]; ≥2 of both, 37 [31.9%] vs 20 [17.2%]; all P < .05)., Conclusions and Relevance: These findings support the concept that CCTA-derived AGCs capturing lesion location and vessel geometry are associated with risk of future ACS-causing culprit lesions. Adverse geometric characteristics may provide additive prognostic information beyond plaque assessment in CCTA.

Objectives: This study sought to investigate the impact of low tube voltage scanning heterogeneity of coronary luminal attenuation on plaque quantification and characterization with coronary computed tomography angiography (CCTA)., Background: The impact of low tube voltage and coronary luminal attenuation on quantitative coronary plaque remains uncertain., Methods: A total of 1,236 consecutive patients (age: 60 ± 9 years; 41% female) who underwent serial CCTA at an interval of ≥2 years were included from an international registry. Patients with prior revascularization or nonanalyzable coronary CTAs were excluded. Total coronary plaque volume was assessed and subclassified based on specific Hounsfield unit (HU) threshold: necrotic core, fibrofatty plaque, and fibrous plaque and dense calcium. Luminal attenuation was measured in the aorta., Results: With increasing luminal HU (<350, 350-500, and >500 HU), percent calcified plaque was increased (16%, 27%, and 40% in the median; P < 0.001), and fibrofatty plaque (26%, 13%, and 4%; P < 0.001) and necrotic core (1.6%, 0.3%, and 0.0%; P < 0.001) were decreased. Higher tube voltage scanning (80, 100, and 120 kV) resulted in decreasing luminal attenuation (689 ± 135, 497 ± 89, and 391 ± 73 HU; P < 0.001) and calcified plaque volume (59%, 34%, and 23%; P < 0.001) and increased fibrofatty plaque (3%, 9%, and 18%; P < 0.001) and necrotic core (0.2%, 0.1%, and 0.6%; P < 0.001). Mediation analysis showed that the impact of 100 kV on plaque composition, compared with 120 kV, was primarily caused by an indirect effect through blood pool attenuation. Tube voltage scanning of 80 kV maintained a direct effect on fibrofatty plaque and necrotic core in addition to an indirect effect through the luminal attenuation., Conclusions: Low tube voltage usage affected plaque morphology, mainly through an increase in luminal HU with a resultant increase in calcified plaque and a reduction in fibrofatty and necrotic core. These findings should be considered as CCTA-based plaque measures are being used to guide medical management and, in particular, when being used as a measure of treatment response. (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging [PARADIGM]; NCT02803411)., Competing Interests: Funding Support and Author Disclosures This work was supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (MSIT) (grant number 2012027176). The study was also funded in part by a grant from the Dalio Foundation (New York, New York). Dr Leipsic receives institutional grants to provide core lab services to Edwards Life Sciences, Abbott, Boston Scientific, and Medtronic and is a consultant to and has stock options in Circle CVI and HeartFlow. Dr Andreini is on the Speakers Bureau for GE Healthcare and receives grant support from GE Healthcare and Bracco. Dr Budoff has received grant support from the National Institutes of Health and GE Healthcare. Dr Chun has received funding from a National Research Foundation grant funded by the South Korea government (MEST) (NRF- 2015R1D1A1A01059717). Dr Pontone has received 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 Lifesciences, Medtronic, MicroVention, OrbusNeich, ReCord, SINO Medical Technology, Spectranetics, Surmodics, Terumo Corporation, W.L. Gore, and Xeltis; has received 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. Dr Samady has received grant support from Phillips/Volcano and St. Jude Abbott/Medtronic/Gilead. Dr Berman has received software royalties from Cedars-Sinai. Dr Bax has received unrestricted research grants from Biotronik, Medtronic, Boston Scientific, and Edwards Lifesciences. Dr Chang has received funding from the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT, and Future Planning (grant 2012027176). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: The density of atherosclerotic plaque forms the basis for categorizing calcified and noncalcified morphology of plaques., Objective: To assess whether alterations in plaque across a range of density measurements provide a more detailed understanding of atherosclerotic disease progression., Design, Setting, and Participants: This cohort study enrolled 857 patients who underwent serial coronary computed tomography angiography 2 or more years apart and had quantitative measurements of coronary plaques throughout the entire coronary artery tree. The study was conducted from 2013 to 2016 at 13 sites in 7 countries., Main Outcomes and Measures: The main outcome was progression of plaque composition of individual coronary plaques. Six plaque composition types were defined on a voxel-level basis according to the plaque attenuation (expressed in Hounsfield units [HU]): low attenuation (-30 to 75 HU), fibro-fatty (76-130 HU), fibrous (131-350 HU), low-density calcium (351-700 HU), high-density calcium (701-1000 HU), and 1K (>1000 HU). The progression rates of these 6 compositional plaque types were evaluated according to the interaction between statin use and baseline plaque volume, adjusted for risk factors and time interval between scans. Plaque progression was also examined based on baseline calcium density. Analysis was performed among lesions matched at baseline and follow-up. Data analyses were conducted from August 2019 through March 2020., Results: In total, 2458 coronary lesions in 857 patients (mean [SD] age, 62.1 [8.7] years; 540 [63.0%] men; 548 [63.9%] received statin therapy) were included. Untreated coronary lesions increased in volume over time for all 6 compositional types. Statin therapy was associated with volume decreases in low-attenuation plaque (β, -0.02; 95% CI, -0.03 to -0.01; P = .001) and fibro-fatty plaque (β, -0.03; 95% CI, -0.04 to -0.02; P < .001) and greater progression of high-density calcium plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001) and 1K plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001). When analyses were restricted to lesions without low-attenuation plaque or fibro-fatty plaque at baseline, statin therapy was not associated with a change in overall calcified plaque volume (β, -0.03; 95% CI, -0.08 to 0.02; P = .24) but was associated with a transformation toward more dense calcium. Interaction analysis between baseline plaque volume and calcium density showed that more dense coronary calcium was associated with less plaque progression., Conclusions and Relevance: The results suggest an association of statin use with greater rates of transformation of coronary atherosclerosis toward high-density calcium. A pattern of slower overall plaque progression was observed with increasing density. All findings support the concept of reduced atherosclerotic risk with increased densification of calcium.

Objective: The study evaluates the relationship of coronary stenosis, atherosclerotic plaque characteristics (APCs) and age using artificial intelligence enabled quantitative coronary computed tomographic angiography (AI-QCT)., Methods: This is a post-hoc analysis of data from 303 subjects enrolled in the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia) trial who were referred for invasive coronary angiography and subsequently underwent coronary computed tomographic angiography (CCTA). In this study, a blinded core laboratory analysing quantitative coronary angiography images classified lesions as obstructive (≥50%) or non-obstructive (<50%) while AI software quantified APCs including plaque volume (PV), low-density non-calcified plaque (LD-NCP), non-calcified plaque (NCP), calcified plaque (CP), lesion length on a per-patient and per-lesion basis based on CCTA imaging. Plaque measurements were normalised for vessel volume and reported as % percent atheroma volume (%PAV) for all relevant plaque components. Data were subsequently stratified by age <65 and ≥65 years., Results: The cohort was 64.4±10.2 years and 29% women. Overall, patients >65 had more PV and CP than patients <65. On a lesion level, patients >65 had more CP than younger patients in both obstructive (29.2 mm 3 vs 48.2 mm 3 ; p<0.04) and non-obstructive lesions (22.1 mm 3 vs 49.4 mm 3 ; p<0.004) while younger patients had more %PAV (LD-NCP) (1.5% vs 0.7%; p<0.038). Younger patients had more PV, LD-NCP, NCP and lesion lengths in obstructive compared with non-obstructive lesions. There were no differences observed between lesion types in older patients., Conclusion: AI-QCT identifies a unique APC signature that differs by age and degree of stenosis and provides a foundation for AI-guided age-based approaches to atherosclerosis identification, prevention and treatment., Competing Interests: Competing interests: Equity Interest Cleerly, JE, HM, ADC, Employees of Cleerly – RJe, TRC, JKM, JE., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Although acute coronary syndrome culprit lesions occur more frequently in the proximal coronary artery, whether the proximal clustering of high-risk plaque is reflected in earlier-stage atherosclerosis remains unclarified. We evaluated the longitudinal distribution of stable atherosclerotic lesions on coronary computed tomography angiography (CCTA) in 1,478 patients (mean age, 61 years; men, 58%) enrolled from a prospective multinational registry of consecutive patients undergoing serial CCTA. Of 3,202 coronary artery lesions identified, 2,140 left lesions were classified (based on the minimal lumen diameter location) into left main (LM, n = 128), proximal (n = 739), and other (n = 1,273), and 1,062 right lesions were classified into proximal (n = 355) and other (n = 707). Plaque volume (PV) was the highest in proximal lesions (median, 26.1 mm 3 ), followed by LM (20.6 mm 3 ) and other lesions (15.0 mm 3 , p <0.001), for left lesions, and was lager in proximal (25.8 mm 3 ) than in other lesions (15.2 mm 3 , p <0.001) for right lesions. On both sides, proximally located lesions tended to have greater necrotic core and fibrofatty components than other lesions (left: LM, 10.6%; proximal, 5.8%; other, 3.4% of the total PV, p <0.001; right: proximal, 8.4%; other 3.1%, p <0.001), with less calcified plaque component (left: LM, 18.3%; proximal, 30.3%; other, 37.7%, p <0.001; right: proximal, 23.3%, other, 36.6%, p <0.001), and tended to progress rapidly (adjusted odds ratios: left: LM, reference; proximal, 0.95, p = 0.803; other, 0.64, p = 0.017; right: proximal, reference; other, 0.52, p <0.001). Proximally located plaques were larger, with more risky composition, and progressed more rapidly., Competing Interests: Disclosures The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose of Review: Multicenter studies showed that the characterization of coronary atherosclerosis by coronary computed tomography (CT) angiography (CCTA) provides independent and incremental prognostic value above and beyond traditional measures of coronary artery disease (CAD) and is able to identify patients at risk of future event. Aim of the present review is to expound the major imaging plaque features associated with increased risk of coronary event and to review the data supporting the usefulness of CCTA as tool for plaque assessment and for monitoring the changes in atherosclerotic burden., Recent Findings: The evaluation of coronary atherosclerosis, including the measurement of imaging risk scores (e.g. CT-adapted Leaman score) was demonstrated as independent long-term predictor of acute coronary events. In particular, qualitative (remodelling index, low-attenuation plaque, napkin-ring sign, small spotty calcifications) and quantitative (plaque burden, total-, noncalcific- and fibrofatty plaque volume) plaque features were associated with increased risk. CCTA was also demonstrated to accurately quantify plaque volume vs. intravascular ultrasound and findings from PARADIGM and EVAPORATE studies supported the use of CCTA as noninvasive tool to follow the effect of medication on plaque progression/regression. Finally, interesting relationship between plaque features, coronary physiology and biomarkers have been described., Summary: Latest guidelines on the management of patients with stable CAD recommended CCTA in Class I of evidence, particularly when 'information on atherosclerosis are desired', underlining the usefulness of CCTA to characterize and quantify the atherosclerotic burden., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Patient-specific phenotyping of coronary atherosclerosis would facilitate personalized risk assessment and preventive treatment. We explored whether unsupervised cluster analysis can categorize patients with coronary atherosclerosis according to their plaque composition, and determined how these differing plaque composition profiles impact plaque progression. Patients with coronary atherosclerotic plaque (n = 947; median age, 62 years; 59% male) were enrolled from a prospective multi-national registry of consecutive patients who underwent serial coronary computed tomography angiography (median inter-scan duration, 3.3 years). K-means clustering applied to the percent volume of each plaque component and identified 4 clusters of patients with distinct plaque composition. Cluster 1 (n = 52), which comprised mainly fibro-fatty plaque with a significant necrotic core (median, 55.7% and 16.0% of the total plaque volume, respectively), showed the least total plaque volume (PV) progression (+ 23.3 mm 3 ), with necrotic core and fibro-fatty PV regression (- 5.7 mm 3 and - 5.6 mm 3 , respectively). Cluster 2 (n = 219), which contained largely fibro-fatty (39.2%) and fibrous plaque (46.8%), showed fibro-fatty PV regression (- 2.4 mm 3 ). Cluster 3 (n = 376), which comprised mostly fibrous (62.7%) and calcified plaque (23.6%), showed increasingly prominent calcified PV progression (+ 21.4 mm 3 ). Cluster 4 (n = 300), which comprised mostly calcified plaque (58.7%), demonstrated the greatest total PV increase (+ 50.7mm 3 ), predominantly increasing in calcified PV (+ 35.9 mm 3 ). Multivariable analysis showed higher risk for plaque progression in Clusters 3 and 4, and higher risk for adverse cardiac events in Clusters 2, 3, and 4 compared to that in Cluster 1. Unsupervised clustering algorithms may uniquely characterize patient phenotypes with varied atherosclerotic plaque profiles, yielding distinct patterns of progressive disease and outcome., (© 2021. The Author(s).)

Aims: To investigate the change in atherosclerotic plaque volume in patients with chronic kidney disease (CKD) and declining renal function, using coronary computed tomography angiography (CCTA)., Methods and Results: In total, 891 participants with analysable serial CCTA and available glomerular filtration rate (GFR, derived using Cockcroft-Gault formulae) at baseline (CCTA 1) and follow-up (CCTA 2) were included. CKD was defined as GFR <60 mL/min/1.73 m2. Declining renal function was defined as ≥10% drop in GFR from the baseline. Quantitative assessment of plaque volume and composition were performed on both scans. There were 203 participants with CKD and 688 without CKD. CKD was associated with higher baseline total plaque volume, but similar plaque progression, measured by crude (57.5 ± 3.4 vs. 65.9 ± 7.7 mm3/year, P = 0.28) or annualized (17.3 ± 1.0 vs. 19.9 ± 2.0 mm3/year, P = 0.25) change in total plaque volume. There were 709 participants with stable GFR and 182 with declining GFR. Declining renal function was independently associated with plaque progression, with higher crude (54.1 ± 3.2 vs. 80.2 ± 9.0 mm3/year, P < 0.01) or annualized (16.4 ± 0.9 vs. 23.9 ± 2.6 mm3/year, P < 0.01) increase in total plaque volume. In CKD, plaque progression was driven by calcified plaques whereas in patients with declining renal function, it was driven by non-calcified plaques., Conclusion: Decline in renal function was associated with more rapid plaque progression, whereas the presence of CKD was not., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: The current study aimed to examine the independent prognostic value of whole-heart atherosclerosis progression by serial coronary computed tomography angiography (CCTA) for major adverse cardiovascular events (MACE)., Methods: The multi-center PARADIGM study includes patients undergoing serial CCTA for symptomatic reasons, ≥2 years apart. Whole-heart atherosclerosis was characterized on a segmental level, with co-registration of baseline and follow-up CCTA, and summed to per-patient level. The independent prognostic significance of atherosclerosis progression for MACE (non-fatal myocardial infarction [MI], death, unplanned coronary revascularization) was examined. Patients experiencing interval MACE were not omitted., Results: The study population comprised 1166 patients (age 60.5 ​± ​9.5 years, 54.7% male) who experienced 139 MACE events during 8.2 (IQR 6.2, 9.5) years of follow up (15 death, 5 non-fatal MI, 119 unplanned revascularizations). Whole-heart percent atheroma volume (PAV) increased from 2.32% at baseline to 4.04% at follow-up. Adjusted for baseline PAV, the annualized increase in PAV was independently associated with MACE: OR 1.23 (95% CI 1.08, 1.39) per 1 standard deviation increase, which was consistent in multiple subpopulations. When categorized by composition, only non-calcified plaque progression associated independently with MACE, while calcified plaque did not. Restricting to patients without events before follow-up CCTA, those with future MACE showed an annualized increase in PAV of 0.93% (IQR 0.34, 1.96) vs 0.32% (IQR 0.02, 0.90), P ​< ​0.001., Conclusions: Whole-heart atherosclerosis progression examined by serial CCTA is independently associated with MACE, with a prognostic threshold of 1.0% increase in PAV per year., Competing Interests: Declaration of competing interest Dr. James K. Min receives funding from the Dalio Foundation, National Institutes of Health, and GE Healthcare. Dr. Min serves on the scientific advisory board of Arineta and GE Healthcare, and has an equity interest in Cleerly. Dr. Habib Samady serves on the medical advisory board of Philips and has equity holding in Covanos. The remaining authors have no relevant disclosures., (Copyright © 2020 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background Aortic valve calcification (AVC) is a key feature of aortic stenosis, and patients with aortic stenosis often have coronary -artery disease. Therefore, proving the association between the progression of AVC and coronary atherosclerosis could improve follow-up and treatment strategies. Purpose To explore the association between the progression of AVC and the progression of total and plaque volume composition from a large multicenter registry of serial coronary CT angiographic examinations. Materials and Methods A prospective multinational registry (PARADIGM) of consecutive participants who underwent serial coronary CT angiography at intervals of every 2 years or more was performed (January 2003-December 2015). AVC and the total and plaque volume composition at baseline and follow-up angiography were quantitatively analyzed. Plaque volumes were normalized by using the mean total analyzed vessel length of the study population. Multivariable linear mixed-effects models were constructed. Results Overall, 594 participants (mean age ± standard deviation, 62 years ± 10; 330 men) were included (mean interval between baseline and follow-up angiography, 3.9 years ± 1.5). At baseline, the AVC score was 31 Agatston units ± 117, and the normalized total plaque volume at baseline was 122 mm 3 ± 219. After adjustment for age, sex, clinical risk factors, and medication use, AVC was independently associated with total plaque volume (standardized β = 0.24; 95% CI: 0.16, 0.32; P < .001) and both calcified (β = 0.26; 95% CI: 0.18, 0.34; P < .001) and noncalcified (β = 0.17; 95% CI: 0.08, 0.25; P < .001) plaque volumes at baseline. The progression of AVC was associated with the progression of total plaque volume (β = 0.13; 95% CI: 0.03, 0.22; P = .01), driven solely by calcified plaque volume (β = 0.24; 95% CI: 0.14, 0.34; P < .001) but not noncalcified plaque volumes (β = -0.06; 95% CI: -0.14, 0.03; P = .17). Conclusion The overall burden of coronary atherosclerosis was associated with aortic valve calcification at baseline. However, the progression of aortic valve calcification was associated with only the progression of calcified plaque volume but not with the -progression of noncalcified plaque volume. Clinical trial registration no. NCT02803411 © RSNA, 2021 See also the editorial by Sinitsyn in this issue.

Background: The association of age with coronary plaque dynamics is not well characterized by coronary computed tomography angiography (CCTA)., Methods: From a multinational registry of patients who underwent serial CCTA, 1153 subjects (61 ± 5 years old, 61.1% male) were analyzed. Annualized volume changes of total, fibrous, fibrofatty, necrotic core, and dense calcification plaque components of the whole heart were compared by age quartile groups. Clinical events, a composite of all-cause death, acute coronary syndrome, and any revascularization after 30 days of the initial CCTA, were also analyzed. Random forest analysis was used to define the relative importance of age on plaque progression., Results: With a 3.3-years' median interval between the two CCTA, the median annual volume changes of total plaque in each age quartile group was 7.8, 10.5, 10.8, and 12.1 mm 3 /year and for dense calcification, 2.5, 4.6, 5.4, and 7.1 mm 3 /year, both of which demonstrated a tendency to increase by age (p-for-trend = 0.001 and < 0.001, respectively). However, this tendency was not observed in any other plaque components. The annual volume changes of total plaque and dense calcification were also significantly different in the propensity score-matched lowest age quartile group versus the other age groups as was the composite clinical event (log-rank p = 0.003). In random forest analysis, age had comparable importance in the total plaque volume progression as other traditional factors., Conclusions: The rate of whole-heart plaque progression and dense calcification increases depending on age. Age is a significant factor in plaque growth, the importance of which is comparable to other traditional risk factors., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02803411., Competing Interests: Declaration of competing interest Dr. Min receives funding from the Dalio Foundation, National Institutes of Health, and GE Healthcare and serves on the scientific advisory board of Arineta and GE Healthcare, and has an equity interest in Clearly. Dr. Samady serves on the scientific advisory board of Philips, has equity interest in Covanos Inc., and has a research grant from Medtronic. The remaining authors have no relevant disclosures., (Copyright © 2020 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The atherogenic index of plasma (AIP) has been suggested as a marker of plasma atherogenicity. This study aimed to assess the association between AIP and the rapid progression of coronary atherosclerosis using serial coronary computed tomography angiography (CCTA)., Methods: A total of 1488 adults (60.9 ± 9.2 years, 58.9% male) who underwent serial CCTA with a median inter-scan period of 3.4 years were included. AIP was defined as the base 10 logarithm of the ratio of the concentrations of triglyceride to high-density lipoprotein cholesterol. Rapid plaque progression (RPP) was defined as the change of percentage atheroma volume (PAV) ≥1.0%/year. All participants were divided into three groups based on AIP tertiles., Results: Baseline total PAV (median [interquartile range (IQR)]) (%) (group I [lowest]: 1.91 [0.00, 6.21] vs. group II: 2.82 [0.27, 8.83] vs. group III [highest]: 2.70 [0.41, 7.50]), the annual change of total PAV (median [IQR]) (%/year) (group I: 0.27 [0.00, 0.81] vs. group II: 0.37 [0.04, 1.11] vs. group III: 0.45 [0.06, 1.25]), and the incidence of RPP (group I: 19.7% vs. group II: 27.3% vs. group III: 31.4%) were significantly different among AIP tertiles (all p < 0.05). In multiple logistic regression analysis, the risk of RPP was increased in group III (odds ratio: 1.52, 95% confidence interval: 1.02-2.26; p = 0.042) compared to group I after adjusting for clinical factors and baseline total PAV., Conclusions: Based on serial CCTA findings, AIP is an independent predictive marker for RPP beyond traditional risk factors., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Anatomic series commonly report the extent and severity of coronary artery disease (CAD), regardless of location. The aim of this study was to evaluate differences in atherosclerotic plaque burden and composition across the major epicardial coronary arteries., Methods and Results: A total of 1271 patients (age 60 ± 9 years; 57% men) with suspected CAD prospectively underwent coronary computed tomography angiography (CCTA). Atherosclerotic plaque volume was quantified with categorization by composition (necrotic core, fibrofatty, fibrous, and calcified) based on Hounsfield Unit density. Per-vessel measures were compared using generalized estimating equation models. On CCTA, total plaque volume was lowest in the LCx (10.0 ± 29.4 mm3), followed by the RCA (32.8 ± 82.7 mm3; P < 0.001), and LAD (58.6 ± 83.3 mm3; P < 0.001), even when correcting for vessel length or volume. The prevalence of ≥2 high-risk plaque features, such as positive remodelling or spotty calcification, occurred less in the LCx (3.8%) when compared with the LAD (21.4%) or RCA (10.9%, P < 0.001). In the LCx, the most stenotic lesion was categorized as largely calcified more often than in the RCA and LAD (55.3% vs. 39.4% vs. 32.7%; P < 0.001). Median diameter stenosis was also lowest in the LCx (16.2%) and highest in the LAD (21.3%; P < 0.001) and located more distal along the LCx when compared with the RCA and LAD (P < 0.001)., Conclusion: Atherosclerotic plaque, irrespective of vessel volume, varied across the epicardial coronary arteries; with a significantly lower burden and different compositions in the LCx when compared with the LAD and RCA. These volumetric and compositional findings support a diverse milieu for atherosclerotic plaque development and may contribute to a varied acute coronary risk between the major epicardial coronary arteries., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Plaque rupture followed by intracoronary thrombus formation is recognized as the most common pathophysiological mechanism in acute coronary syndromes (ACS). The second most common underlying substrate for ACS is plaque erosion whose hallmark is thrombus formation without cap disruption. Invasive and non-invasive methods have emerged as a promising tool for evaluation of plaque features that either predict or detect plaque erosion. Optical coherence tomography (OCT), high-definition intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and near-infrared autofluorescence (NIRF) have been used to study plaque erosion. The detection of plaque erosion in the clinical setting, mainly facilitated by OCT, has shed light upon the complex pathophysiology underlying ACS not related to plaque rupture. Coronary computed tomography angiography (CCTA), which is to date the most commonly used non-invasive technique for coronary plaque evaluation, may also have a role in the evaluation of patients predisposed to erosion. Also, computational models enabling quantification of endothelial shear stress may pave the way to new research in coronary plaque pathophysiology. This review focuses on the recent imaging techniques for the evaluation of plaque erosion including invasive and non-invasive assessment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Although there is increasing evidence supporting coronary atherosclerosis evaluation by coronary computed tomography angiography (CCTA), no data are available on age and sex differences for quantitative plaque features. The aim of this study was to investigate sex and age differences in both qualitative and quantitative atherosclerotic features from CCTA prior to acute coronary syndrome (ACS)., Methods and Results: Within the ICONIC study, in which 234 patients with subsequent ACS were propensity matched 1:1 with 234 non-event controls, our current subanalysis included only the ACS cases. Both qualitative and quantitative advance plaque analysis by CCTA were performed by a core laboratory. In 129 cases, culprit lesions identified by invasive coronary angiography at the time of ACS were co-registered to baseline CCTA precursor lesions. The study population was then divided into subgroups according to sex and age (<65 vs. ≥ 65 years old) for analysis. Older patients had higher total plaque volume than younger patients. Within specific subtypes of plaque volume, however, only calcified plaque volume was higher in older patients (135.9 ± 163.7 vs. 63.8 ± 94.2 mm3, P < 0.0001, respectively). Although no sex-related differences were recorded for calcified plaque volume, females had lower fibrous and fibrofatty plaque volume than males (Fibrofatty volume 29.6 ± 44.1 vs. 75.3 ± 98.6 mm3, P = 0.0001, respectively). No sex-related differences in the prevalence of qualitative high-risk plaque features were found, even after separate analyses considering age were performed., Conclusion: Our data underline the importance of age- and sex-related differences in coronary atherosclerosis presentation, which should be considered during CCTA-based atherosclerosis quantification., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Importance: Stress imaging has been the standard for diagnosing functionally significant coronary artery disease. It is unknown whether novel, atherosclerotic plaque measures improve accuracy beyond coronary stenosis for diagnosing invasive fractional flow reserve (FFR) measurement., Objective: To compare the diagnostic accuracy of comprehensive anatomic (obstructive and nonobstructive atherosclerotic plaque) vs functional imaging measures for estimating vessel-specific FFR., Design, Setting, and Participants: Controlled clinical trial of diagnostic accuracy with a multicenter derivation-validation cohort of patients referred for nonemergent invasive coronary angiography. A total of 612 patients (64 [10] years; 30% women) with signs and symptoms suggestive of myocardial ischemia from 23 sites were included. Patients were recruited from 2014 to 2017. Data analysis began in August 2018., Interventions: Patients underwent invasive coronary angiography with measurement of invasive FFR, coronary computed tomographic angiography (CCTA) quantification of atherosclerotic plaque and FFR by CT (FFR-CT), and semiquantitative scoring of rest/stress myocardial perfusion imaging (by magnetic resonance, positron emission tomography, or single photon emission CT). Multivariable generalized linear mixed models were derived and validated calculating the area under the receiver operating characteristics curve., Main Outcomes and Measures: The primary end point was invasive FFR of 0.80 or less., Results: Of the 612 patients, the mean (SD) age was 64 (10) years, and 426 (69.9%) were men. An invasive FFR of 0.80 or less was measured in 26.5% of 1727 vessels. In the derivation cohort, CCTA vessel-specific factors associated with FFR 0.80 or less were stenosis severity, percentage of noncalcified atheroma volume, lumen volume, the number of lesions with high-risk plaque (≥2 of low attenuation plaque, positive remodeling, napkin ring sign, or spotty calcification), and the number of lesions with stenosis greater than 30%. Fractional flow reserve-CT was not additive to this model including stenosis and atherosclerotic plaque. Significant myocardial perfusion imaging predictors were the summed rest and difference scores. In the validation cohort, the areas under the receiver operating characteristic curve were 0.81 for CCTA vs 0.67 for myocardial perfusion imaging (P < .001)., Conclusions and Relevance: A comprehensive anatomic interpretation with CCTA, including quantification of obstructive and nonobstructive atherosclerotic plaque, was superior to functional imaging in the diagnosis of invasive FFR. Comprehensive CCTA measures improve prediction of vessel-specific coronary physiology more so than stress-induced alterations in myocardial perfusion., Trial Registration: ClinicalTrials.gov Identifier: NCT02173275.

To determine whether the assessment of individual plaques is superior in predicting the progression to obstructive coronary artery disease (CAD) on serial coronary computed tomography angiography (CCTA) than per-patient assessment. From a multinational registry of 2252 patients who underwent serial CCTA at a ≥ 2-year inter-scan interval, patients with only non-obstructive lesions at baseline were enrolled. CCTA was quantitatively analyzed at both the per-patient and per-lesion level. Models predicting the development of an obstructive lesion at follow up using either the per-patient or per-lesion level CCTA measures were constructed and compared. From 1297 patients (mean age 60 ± 9 years, 43% men) enrolled, a total of 3218 non-obstructive lesions were identified at baseline. At follow-up (inter-scan interval: 3.8 ± 1.6 years), 76 lesions (2.4%, 60 patients) became obstructive, defined as > 50% diameter stenosis. The C-statistics of Model 1, adjusted only by clinical risk factors, was 0.684. The addition of per-patient level total plaque volume (PV) and the presence of high-risk plaque (HRP) features to Model 1 improved the C-statistics to 0.825 [95% confidence interval (CI) 0.823-0.827]. When per-lesion level PV and the presence of HRP were added to Model 1, the predictive value of the model improved the C-statistics to 0.895 [95% CI 0.893-0.897]. The model utilizing per-lesion level CCTA measures was superior to the model utilizing per-patient level CCTA measures in predicting the development of an obstructive lesion (p < 0.001). Lesion-level analysis of coronary atherosclerotic plaques with CCTA yielded better predictive power for the development of obstructive CAD than the simple quantification of total coronary atherosclerotic burden at a per-patient level.Clinical Trial Registration: ClinicalTrials.gov NCT0280341.