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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.)

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.)

Cardiac Magnetic Resonance (CMR) allows an accurate Right Ventricle (RV) assessment that could be of great relevance in diseases causing inflammation or fibrosis. The aim of this study was to evaluate the concomitant involvement of the RV in patients with delayed enhancement (DE) of the Left Ventricle (LV-DE) using CMR. We retrospectively enrolled 95 (male n. 66; age 55±18years; BMI 26±5kg/m2) consecutive patients with LV-DE who underwent a CMR (Achieva 1.5 T, Philips) for different indications: post-ischemic dilated cardiopathy (PDM), hypertrophic cardiomyopathy (HCM), myocardial infarction (MI), myocarditis/pericarditis (MP) and congenital heart disease (CD). We assessed the presence and extension of DE and functional parameters such as ventricular end-diastolic (EDV), end-systolic volumes (ESV) and ejection fraction (EF) of both LV and RV. Prevalence of RV-DE was 30.5% (29/95): 75% (3/4) for CD, 44% (4/9) for PDM, 36% (17/47) for MI, 27.8% (5/18) for MP and 0% (0/17) for HCM. LV-EF and RV-EF were 53±15mL and 51±13mL, respectively, for patients without RV-DE (RV-DE-), and 40±19 mL and 42±15 mL, respectively, for patients with RV-DE (RV-DE+) (p<0.05), while LV-EDV and LV-ESV were 80±28 mL and 40±26 mL, respectively, for RV-DE- and 100±45 mL and 65±49 mL, respectively, for RV-DE+ (p<0.05). The prevalence of RV-DE in patients with LV primary involvement is not negligible and it is found mainly in patients with CD and PDM and then in patients with MI and MP. It is more often associated with LV-EF and RV-EF reduction and increase in LV volumes.

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.)

Purpose: In this cohort study, 5-year data from the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry (ie, CONFIRM) were examined to identify associations of baseline aspirin and statin use with mortality, major adverse cardiovascular events (MACE), and myocardial infarction (MI) in individuals without substantial (≥50%) stenosis., Materials and Methods: In this prospective cohort study, all participants in the registry underwent coronary CT angiography and were classified as having no detectable coronary plaque or having nonobstructive coronary artery disease (CAD) (1%-49% stenosis). Participants with obstructive (≥50%) stenosis were excluded from analysis. The study commenced in June 2003 and was completed in March 2016. All unadjusted and risk-adjusted analyses utilized the Cox proportional hazard model with hospital sites modeled using shared frailty., Results: A total of 6386 participants with no detectable plaque or with nonobstructive CAD were included (mean age, 56.0 years ± 13.3 [SD], 52% men). The mean follow-up period was 5.66 years ± 1.10. Nonobstructive CAD ( n = 2815, 44% of all participants included in the study) was associated with a greater risk of all-cause mortality (10.6% [298 of 2815] vs 4.8% [170 of 3571], P < .001) compared to those without CAD ( n = 3571, 56%). Baseline aspirin and statin use was documented for 1415 and 1429 participants, respectively, with nonobstructive CAD, and for 1560 and 1565 participants without detectable plaque, respectively. In individuals with nonobstructive CAD, baseline aspirin use was not associated with a reduction in MACE (10.9% [102 of 936] vs 14.7% [52 of 355], P = .06), all-cause mortality (9.6% [95 of 991] vs 10.9% [46 of 424], P = .468), or MI (4.4% [41 of 936] vs 6.2% [22 of 355], P = .18). On multivariate risk-adjusted analysis, baseline statin use was associated with a lower rate of MACE (hazard ratio, 0.59; 95% CI: 0.40, 0.87; P = .007). Neither therapy improved clinical outcomes for participants with no detectable plaque., Conclusion: In participants with nonobstructive CAD, baseline use of statins, but not of aspirin, was associated with improved clinical outcomes. Neither therapy was associated with benefit in participants without plaque. Keywords: Aspirin, Statin, Coronary Artery Disease, CT Angiography, Nonobstructive Coronary Artery DiseaseClinical trial registration no. NCT01443637 Supplemental material is available for this article. © RSNA, 2022See also the commentary by Canan and Navar in this issue., Competing Interests: Disclosures of conflicts of interest: P.I. No relevant relationships. C.N. No relevant relationships. S.B.Z. No relevant relationships. H.G. No relevant relationships. P.B. Consulting fees from Edwards Lifesciences, Neovasc, and Boston Scientific. S.S. No relevant relationships. S.A. No relevant relationships. M.H.A. Grant/contract from Siemens; consulting fees from Philips. D.A. No relevant relationships. D.S.B. Software royalties from Cedars-Sinai Medical Center. M.J.B. No relevant relationships. F.C. No relevant relationships. T.Q.C. No relevant relationships. H.J.C. No relevant relationships. K.C. Executive Committee and Board of Directors, Society for Cardiovascular Computed Tomography (SCCT), unpaid. B.J.W.C. Saul and Edna Goldfarb Chair in Cardiac Imaging; research grants from TD Bank, AusculSciences, Artrya, and CV Diagnostix; board member of SCCT (ended in 2021); stock in GE (equity sold in 2021). R.C.C. Consults for Covera Health, GE Healthcare, and Cleerly (not related to the topic of this article). A.D. No relevant relationships. G.F. No relevant relationships. M.H. No relevant relationships. J.H. Grant/contract from Edwards Lifesciences, payment or honoraria from Abbott Vascular and Edwards Lifesciences, support for meetings and travel from Abbott Vascular and Edwards Lifesciences. P.A.K. University Hospital Zurich holds a research grant with GE Healthcare (unrelated to the present study), Advisory Board for GE Healthcare on the myocardial perfusion tracer Flurpiridaz (unrelated to present study), Vice Chair of the Swiss Society of Nuclear Medicine (unpaid). Y.J.K. No relevant relationships. E.M. No relevant relationships. H.M. No relevant relationships. P.d.A.G. No relevant relationships. G.P. No relevant relationships. G.L.R. No relevant relationships. R.R. Board member of SCCT. T.C.V. No relevant relationships. F.Y.L. Research grant from GE. L.J.S. No relevant relationships. J.N. No relevant relationships. J.J.B. The department of cardiology, Leiden University Medical Center has received unrestricted research grants from Abbott, Edwards Lifesciences, Bayer, Novartis, Boston Scientific, Medtronic, Biotronik, GE Healthcare; payment or honoraria from Speaker Bureau Abbott and Edwards Lifesciences. J.A.L. Unrestricted research grant from GE Healthcare, stock options and consulting fees from HeartFlow and Circle CVI, payment or honoraria from Philips, board of directors of SCCT, deputy editor for Radiology: Cardiothoracic Imaging., (© 2022 by the Radiological Society of North America, Inc.)

Background: Despite a potential role of hemoglobin in atherosclerosis, data on coronary plaque volume changes (PVC) related to serum hemoglobin levels are limited., Objectives: The authors sought to evaluate coronary atherosclerotic plaque burden changes related to serum hemoglobin levels using serial coronary computed tomographic angiography (CCTA)., Methods: A total of 830 subjects (age 61 ± 10 years, 51.9% male) who underwent serial CCTA were analyzed. The median interscan period was 3.2 (IQR: 2.5-4.4) years. Quantitative assessment of coronary plaques was performed at both scans. All participants were stratified into 4 groups based on the quartile of baseline hemoglobin levels. Annualized total PVC (mm 3 /year) was defined as total PVC divided by the interscan period., Results: Baseline total plaque volume (mm 3 ) was not different among all groups (group I [lowest]: 34.1 [IQR: 0.0-127.4] vs group II: 28.8 [IQR: 0.0-123.0] vs group III: 49.9 [IQR: 5.6-135.0] vs group IV [highest]: 34.3 [IQR: 0.0-130.7]; P  = 0.235). During follow-up, serum hemoglobin level changes (Δ hemoglobin; per 1 g/dL) was related to annualized total PVC (β = -0.114) in overall participants ( P  < 0.05). After adjusting for age, sex, traditional risk factors, baseline hemoglobin and creatinine levels, baseline total plaque volume, and the use of aspirin, beta-blocker, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and statin, Δ hemoglobin significantly affected annualized total PVC in only the composite of groups I and II (β = -2.401; P  = 0.004)., Conclusions: Serial CCTA findings suggest that Δ hemoglobin has an independent effect on coronary atherosclerosis. This effect might be influenced by baseline hemoglobin levels. (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging [PARADIGM]; NCT02803411)., Competing Interests: 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 & Welfare, the Ministry of Food and Drug Safety) (Project Number: 1711139017). Dr. Leipsic has served as a consultant for and has stock options in HeartFlow and Circle Cardiovascular Imaging; has received grant support from GE Healthcare; and has received speaker fees from Philips. Dr. Samady has equity interest in Covanos. Dr. Berman receives software royalties from Cedars-Sinai Medical Center. Dr. Min has received funding from the Dalio Foundation, National Institutes of Health, and GE Healthcare. Dr. Min has served on scientific advisory boards for Arineta and GE Healthcare; and has an equity interest in Cleerly. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

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.

Bacterial populations are ubiquitously threatened by viral predation. In this issue, Tzipilevich and colleagues show that bacteria killed by viruses release a danger signal that warns neighboring cells to ramp up their defenses. This "message from the dead" thereby induces phenotypic tolerance to infections and slows down viral spread in the population., (© 2021 The Authors.)

Aims: The relationship between dyspnoea, coronary artery disease (CAD), and major cardiovascular events (MACE) is poorly understood. This study evaluated (i) the association of dyspnoea with the severity of anatomical CAD by coronary computed tomography angiography (CCTA) and (ii) to which extent CAD explains MACE in patients with dyspnoea., Methods and Results: From the international COronary CT Angiography EvaluatioN for Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry, 4425 patients (750 with dyspnoea) with suspected but without known CAD were included and prospectively followed for ≥5 years. First, the association of dyspnoea with CAD severity was assessed using logistic regression analysis. Second, the prognostic value of dyspnoea for MACE (myocardial infarction and death), and specifically, the interaction between dyspnoea and CAD severity was investigated using Cox proportional-hazard analysis. Mean patient age was 60.3 ± 11.9 years, 63% of patients were male and 592 MACE events occurred during a median follow-up duration of 5.4 (IQR 5.1-6.0) years. On uni- and multivariable analysis (adjusting for age, sex, body mass index, chest pain typicality, and risk factors), dyspnoea was associated with two- and three-vessel/left main (LM) obstructive CAD. The presence of dyspnoea increased the risk for MACE [hazard ratio (HR) 1.57, 95% confidence interval (CI): 1.29-1.90], which was modified after adjusting for clinical predictors and CAD severity (HR 1.26, 95% CI: 1.02-1.55). Conversely, when stratified by CAD severity, dyspnoea did not provide incremental prognostic value in one-, two-, or three-vessel/LM obstructive CAD, but dyspnoea did provide incremental prognostic value in non-obstructive CAD., Conclusion: In patients with suspected CAD, dyspnoea was independently associated with severe obstructive CAD on CCTA. The severity of obstructive CAD explained the elevated MACE rates in patients presenting with dyspnoea, but in patients with non-obstructive CAD, dyspnoea portended additional risk., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

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.)

Bacteriophages, the viruses infecting bacteria, hold great potential for the treatment of multidrug-resistant bacterial infections and other applications due to their unparalleled diversity and recent breakthroughs in their genetic engineering. However, fundamental knowledge of the molecular mechanisms underlying phage-host interactions is mostly confined to a few traditional model systems and did not keep pace with the recent massive expansion of the field. The true potential of molecular biology encoded by these viruses has therefore remained largely untapped, and phages for therapy or other applications are often still selected empirically. We therefore sought to promote a systematic exploration of phage-host interactions by composing a well-assorted library of 68 newly isolated phages infecting the model organism Escherichia coli that we share with the community as the BASEL (BActeriophage SElection for your Laboratory) collection. This collection is largely representative of natural E. coli phage diversity and was intensively characterized phenotypically and genomically alongside 10 well-studied traditional model phages. We experimentally determined essential host receptors of all phages, quantified their sensitivity to 11 defense systems across different layers of bacterial immunity, and matched these results to the phages' host range across a panel of pathogenic enterobacterial strains. Clear patterns in the distribution of phage phenotypes and genomic features highlighted systematic differences in the potency of different immunity systems and suggested the molecular basis of receptor specificity in several phage groups. Our results also indicate strong trade-offs between fitness traits like broad host recognition and resistance to bacterial immunity that might drive the divergent adaptation of different phage groups to specific ecological niches. We envision that the BASEL collection will inspire future work exploring the biology of bacteriophages and their hosts by facilitating the discovery of underlying molecular mechanisms as the basis for an effective translation into biotechnology or therapeutic applications., Competing Interests: The authors have declared that no competing interests exist.

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.

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.)

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.)

Objectives: This study sought to identify distinct patient groups and their association with outcome based on the patient similarity network using quantitative coronary plaque characteristics from coronary computed tomography angiography (CTA)., Background: Coronary CTA can noninvasively assess coronary plaques quantitatively., Methods: Patients who underwent 2 coronary CTAs at a minimum of 24 months' interval were analyzed (n = 1,264). A similarity Mapper network of patients was built by topological data analysis (TDA) based on the whole-heart quantitative coronary plaque analysis on coronary CTA to identify distinct patient groups and their association with outcome., Results: Three distinct patient groups were identified by TDA, and the patient similarity network by TDA showed a closed loop, demonstrating a continuous trend of coronary plaque progression. Group A had the least coronary plaque amount (median 12.4 mm 3 [interquartile range (IQR): 0.0 to 39.6 mm 3 ]) in the entire coronary tree. Group B had a moderate coronary plaque amount (31.7 mm 3 [IQR: 0.0 to 127.4 mm 3 ]) with relative enrichment of fibrofatty and necrotic core (32.6% [IQR: 16.7% to 46.2%] and 2.7% [IQR: 0.1% to 6.9%] of the total plaque, respectively) components. Group C had the largest coronary plaque amount (187.0 mm 3 [IQR: 96.7 to 306.4 mm 3 ]) and was enriched for dense calcium component (46.8% [IQR: 32.0% to 63.7%] of the total plaque). At follow-up, total plaque volume, fibrous, and dense calcium volumes increased in all groups, but the proportion of fibrofatty component decreased in groups B and C, whereas the necrotic core portion decreased in only group B (all p < 0.05). Group B showed a higher acute coronary syndrome incidence than other groups (0.3% vs. 2.6% vs. 0.6%; p = 0.009) but both group B and C had a higher revascularization incidence than group A (3.1% vs. 15.5% vs. 17.8%; p < 0.001). Incorporating group information from TDA demonstrated increase of model fitness for predicting acute coronary syndrome or revascularization compared with that incorporating clinical risk factors, percentage diameter stenosis, and high-risk plaque features., Conclusions: The TDA of quantitative whole-heart coronary plaque characteristics on coronary CTA identified distinct patient groups with different plaque dynamics and clinical outcomes. (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging [PARADIGM]; NCT02803411)., Competing Interests: Funding Support And Author Disclosures This work was supported by a grant from Seoul National University Hospital research fund (Grant No. 0320200430), 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) (to Dr. Chang), and the National Research Foundation of Korea funded by the Ministry of Science and ICT (Grant No. 2017R1E1A1A03070779, 2018R1A2A3075511, 2019R1A2C2084099, and 2020R1A2C1A01011543). The study was also funded in part by a generous gift from the Dalio Institute of Cardiovascular Imaging and the Michael Wolk Foundation. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Dr. Koo has received institutional research grant support from St. Jude Medical (Abbott Vascular) and Philips Volcano. Dr. Samady has served on the scientific advisory board of Philips; has an equity interest in Covanos Inc.; and has received research grant support from Medtronic. Dr. Min has received funding from the Dalio Foundation, the National Institutes of Health, and GE Healthcare; has served on the scientific advisory board of Arineta and GE Healthcare; and has an equity interest in Cleerly. 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.)

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.

The small bowel angiodysplasia is a rare cause of intestinal bleeding. Usually, the diagnosis is performed with selective conventional angiography. We report a case of 73-year-old man, who was hospitalized after recurrent episodes of melena and anaemia. MDCT-enterography performed before and after intravenous administration of contrast medium, detected an increased density area which was confirmed to be a jejunal angiodysplasia.

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: This study aims to investigate whether HS-when associated with an excessive amount of epicardial adipose tissue-correlates with CAD in subjects with symptoms suggestive of CVD., Methods and Results: CCTA images, demographic and clinical variables of 1.182 individuals were retrieved: semi-automated measurements for EFV, CAC, and MLD were obtained. Individuals were grouped into three categories according to the presence of CAD, resulting in absent (CAD 0 ), non-obstructive (CAD 1 ) or obstructive (CAD 2 ) disease-groups, and into two categories based on the presence of HS (with no HS, named HS - , and with HS, named HS + ). EFV was significantly higher in HS + than in HS - group (p < 0.001), whereas MLD was lower in CAD + than in CAD - subjects (p < 0.001). Two predictive models for CAD were tested: the former included clinical risk factors for CAD along with age, gender, EFV and MLD, whereas the latter did not include clinical variables. The logistic regression analysis of the second proposed model reliably discriminated CAD 0 from CAD 1 and CAD 2 (AUC of 0.712, range 0.682-0.742)., Conclusion: Lower MLD was associated with increased EFV, and MLD-as a marker of HS-discriminate symptomatic patients with CAD from whom without.

Introduction: The introduction of Cardiac Computed Tomography (CCT) has changed the paradigm in the field of diagnostic cardiovascular medicine. CCT is the primary tool in the assessment of suspected Coronary Artery Disease (CAD) and should be followed by functional assessment when needed to stratify disease and to plan potential interventional or surgical therapy., Areas Covered: We provided the current state of the knowledge on the main aspects of technique of examination, image interpretation and clinical indications. We have focused our attention on the basic routine applications and activities., Expert Opinion: The primary role of CCT in suspected CAD will progressively become the standard approach. In general, any situation in which anatomy of the heart and thoracic vessels/structures is mandatory must be approached using CT first, whenever possible. The quantity and quality of information that can be provided by CCT is big and the operators should learn how to deal with this information. On the other hand, CCT is only apparently a straightforward and simple examination. It is actually the most complex diagnostic procedure that can be performed on CT and requires highly skilled operators and state-of-art-technology.

Since 1974, when Wortzman et al were the first to describe a case of idiopathic spinal cord herniation (ISCH), the number of reported cases has increased owing to magnetic resonance imaging (MRI) now is routinely available for patients with myelopathy and spinal surgeons are becoming more familiar with this clinical entity. This extremely rare herniation occurs exclusively in the thoracic spine, causing slowly progressive myelopathy. Diagnosis is based on ventral displacement of the spinal cord in the thoracic spine. MRI is the technique of choice to exclude a posterior arachnoid cyst, the most common mistaken diagnosis, and to recognize a spinal cord herniation when an anterior dural defect is present. A case of ISCH is reported and a Literature review of this clinical entity often mis-diagnosed has been obtained.

We describe a case of a 52 year-old-woman with aortic coarctation demonstrated by means of 40-slice MSCT angiography. Based on the information extracted from MSCT it was possible to display the anatomical configuration of the disease, the thoraco-abdominal collateral pathways. The best therapeutic approach was established on the basis of MSCT findings. MSCT is a reliable and comprehensive tool for the assessment of adult patients with aortic coarctation.

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.)

The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we used in vitro evolution and analyzed the inpatient microevolution of Pseudomonas aeruginosa , an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistance in vitro , and we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections, P. aeruginosa first acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multidrug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections. IMPORTANCE Over the past decades, pan-resistant strains of major bacterial pathogens have emerged and have rendered clinically available antibiotics ineffective, putting at risk many of the major achievements of modern medicine, including surgery, cancer therapy, and organ transplantation. A thorough understanding of processes leading to the development of antibiotic resistance in human patients is thus urgently needed. We show that drug tolerance, the ability of bacteria to survive prolonged exposure to bactericidal antibiotics, rapidly evolves in the opportunistic human pathogen Pseudomonas aeruginosa upon recurrent exposures to antibiotics. Our studies show that tolerance protects P. aeruginosa against different classes of antibiotics and that it generally precedes and promotes resistance development. The rapid evolution of tolerance during treatment regimens may thus act as a strong driving force to accelerate antibiotic resistance development. To successfully counter resistance, diagnostic measures and novel treatment strategies will need to incorporate the important role of antibiotic tolerance., (Copyright © 2021 Santi et al.)

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.)

Objectives: The aim of the current study was to explore the impact of plaque calcification in terms of absolute calcified plaque volume (CPV) and in the context of its percentage of the total plaque volume at a lesion and patient level on the progression of coronary artery disease., Background: Coronary artery calcification is an established marker of risk of future cardiovascular events. Despite this, plaque calcification is also considered a marker of plaque stability, and it increases in response to medical therapy., Methods: This analysis included 925 patients with 2,568 lesions from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) registry, in which patients underwent clinically indicated serial coronary computed tomography angiography. Plaque calcification was examined by using CPV and percent CPV (PCPV), calculated as (CPV/plaque volume) × 100 at a per-plaque and per-patient level (summation of all individual plaques)., Results: CPV was strongly correlated with plaque volume (r = 0.780; p < 0.001) at baseline and with plaque progression (r = 0.297; p < 0.001); however, this association was reversed after accounting for plaque volume at baseline (r = -0.146; p < 0.001). In contrast, PCPV was an independent predictor of a reduction in plaque volume (r = -0.11; p < 0.001) in univariable and multivariable linear regression analyses. Patient-level analysis showed that high CPV was associated with incident major adverse cardiac events (hazard ratio: 3.01: 95% confidence interval: 1.58 to 5.72), whereas high PCPV was inversely associated with major adverse cardiac events (hazard ratio: 0.529; 95% confidence interval: 0.229 to 0.968) in multivariable analysis., Conclusions: Calcified plaque is a marker for risk of adverse events and disease progression due to its strong association with the total plaque burden. When considered as a percentage of the total plaque volume, increasing PCPV is a marker of plaque stability and reduced risk at both a lesion and patient level. (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging [PARADIGM]; NCT02803411)., Competing Interests: Author Disclosures This study was supported by 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) and funded in part by a generous gift from the Dalio Institute of Cardiovascular Imaging and the Michael Wolk Foundation. This work was supported by a grant from Research year of Inje University in 20170038. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. 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). Dr. Min has received funding from the National Institutes of Health (grants R01 HL111141, R01 HL115150, R01 118019, and U01 HL 105907), the Qatar National Priorities Research Program (grant 09-370-3-089), and GE Healthcare; has served as a consultant to HeartFlow; serves on the scientific advisory board of Arineta; and has an equity interest in MDDX. Dr. Bax has received unrestricted research grants from Biotronik, Medtronic, Boston Scientific, and Edwards Lifesciences. Dr. Chun has received funding from a National Research Foundation grant funded by the South Korea government (MEST) (NRF-2015R1D1A1A01059717). Dr. Leipsic serves as a consultant and has stock options in HeartFlow and Circle Cardiovascular Imaging; and receives speaking fees from GE Healthcare. Dr. Budoff has received grant support from the National Institutes of Health and GE Healthcare. Dr. Samady has received grant support from Phillips/Volcano and St. Jude Abbott/Medtronic/Gilead. Dr. Andreini is on the Speakers Bureau for GE Healthcare; and receives grant support from GE Healthcare and Bracco. Dr. Pontone has received institutional research grants from GE Healthcare, HeartFlow, Medtronic, Bracco, and Bayer. Dr. Berman has received software royalties from Cedars-Sinai. 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. 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.)

Bacterial persisters are difficult to eradicate because of their ability to survive prolonged exposure to a range of different antibiotics. Because they often represent small subpopulations of otherwise drug-sensitive bacterial populations, studying their physiological state and antibiotic stress response remains challenging. Sorting and enrichment procedures of persister fractions introduce experimental biases limiting the significance of follow-up molecular analyses. In contrast, proteome analysis of entire bacterial populations is highly sensitive and reproducible and can be employed to explore the persistence potential of a given strain or isolate. Here, we summarize methodology to generate proteomic signatures of persistent Pseudomonas aeruginosa isolates with variable fractions of persisters. This includes proteome sample preparation, mass spectrometry analysis, and an adaptable machine learning regression pipeline. We show that this generic method can determine a common proteomic signature of persistence among different P. aeruginosa hyper-persister mutants. We propose that this approach can be used as diagnostic tool to gauge antimicrobial persistence of clinical isolates., (© 2021. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Antibiotic tolerance and persistence allow bacteria to survive lethal doses of antibiotic drugs in the absence of genetic resistance. Despite the urgent need to address these phenomena as a cause of clinical antibiotic treatment failure, studies on antibiotic tolerance and persistence are notorious for contradictory and inconsistent findings. Many of these problems are likely caused by differences in the methodology used to study antibiotic tolerance and persistence in the laboratory. Standardized experimental procedures would therefore greatly promote research in this field by facilitating the integrated analysis of results obtained by different research groups. Here, we present a robust and adaptable methodology to study antibiotic tolerance/persistence in broth cultures of Escherichia coli and Pseudomonas aeruginosa . The hallmark of this methodology is that the formation and disappearance of antibiotic-tolerant cells is recorded throughout all bacterial growth phases from lag after inoculation over exponential growth into early and then late stationary phase. In addition, all relevant experimental conditions are rigorously controlled to obtain highly reproducible results. We anticipate that this methodology will promote research on antibiotic tolerance and persistence by enabling a deeper view at the growth-dependent dynamics of this phenomenon and by contributing to the standardization or at least comparability of experimental procedures used in the field., (© 2021. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Cardiac or left ventricular perfusion performed with cardiac computed tomography (CCT) is a developing method that may have the potential to complete in a very straight forward way the assessment of ischemic heart disease by means of CT. Myocardial CT perfusion (CTP) can be achieved with a single static scan during the first-pass of the iodinate contrast agent, with the monoenergetic or dual-energy acquisition, or as a dynamic, time-resolved scan during stress by using coronary vasodilator agents. Several methods can be performed, and we focused on static perfusion. CTP may serve as a useful adjunct to coronary CT angiography (CTA) to improve specificity of detecting myocardial ischemia. Technological advances will reduce the radiation dose of myocardial CTP, such as low tube voltage imaging or new reconstruction algorithms, making it a more viable clinical option. The advantages of static first-pass non-stress perfusion are several; the main one is that it can be done to each and every patient who undergoes CCT for the assessment of coronary artery tree. Future advances in CTP will likely improve the diagnostic accuracy of CTP + CTA, and will better estimate the severity of ischemia Therefore, it is simple and comprehensive. However, it has several limitations. In this review we will discuss the technique with its advantages and limitations., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-552). The series “Clinical Impact of Cardiac CT in Clinical Practice” was commissioned by the editorial office without any funding or sponsorship. FC served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from Jul 2019 to Jun 2021. LS serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from Jul 2019 to Jun 2021. The other authors have no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

The change of paradigm determined by the introduction of cardiac computed tomography (CCT) in the field of cardiovascular medicine has allowed new evidence to emerge. These evidences point towards a major role, probably the most important one in terms of prognostic impact, in the detection, characterization and quantification of atherosclerosis as the main driver and endpoint for the management of coronary artery disease (CAD). Extensive literature has been published in the last decade with large numbers and patients' populations, investigating several aspects and correlations between atherosclerotic plaque features and risk factors; also, the relationship between plaque features, both with qualitative and quantitative approaches, and cardiovascular events has been investigated. More recent studies have also pointed out the relationship between the knowledge and classification of sub-clinical atherosclerosis and the induced modification of medical therapy (both aggressiveness and compliance) that is most likely able to increase the effect of anti-atherosclerotic drugs, hence significantly improving prognosis. Non-invasive assessment of CAD by means of CCT is becoming the primary tool for management and also the most important parameter for the comprehension of natural history of CAD and how the therapies we adopt are affecting plaque burden as a whole. In this review we will address the modern concepts of CAD driven understanding and management of cardiovascular disease., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-525). The series “Clinical Impact of Cardiac CT in Clinical Practice” was commissioned by the editorial office without any funding or sponsorship. FC served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from Jul 2019 to Jun 2021. LS serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from Jul 2019 to Jun 2021. The authors have no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Cardiovascular diseases are the first cause of death globally; early detection of coronary artery disease (CAD) is a challenge for clinicians and radiologists. Over the past 2 decades there have been several improvements in the methods for the assessment of diagnosis and prognosis in patients with suspected CAD; most of these methods are imaging methods and they operate with high-end technologies. Cardiac computed tomography (CCT) as we know it today was introduced in 1998 and has ever progressed with constant pace. The first decade was the technical validation phase of the method while the second decade was the clinical validation phase. CCT has developed an excellent diagnostic and prognostic value; technological development together with radiation dose reduction, contributed to the widening of its clinical indications. The diagnostic value of CCT is particularly important as a first line in symptomatic patients with suspected obstructive CAD and low-to-intermediate cardiovascular risk. It is a test that should come, whenever possible, in front of functional evaluation because of its very high sensitivity and negative predictive value. The prognostic value of CCt is still investigational, even though it is becoming quite evident that the atherosclerotic phenotype plays a major role in the determination of prognosis, and as consequence, in the individualization of optimal pharmacological therapy, especially in the cohort without significant obstructive CAD. Recently, scientific and practical guidelines have been updated taking into account the role of CCT, which is able to provide a reliable and fast diagnosis with an additional resources optimization. Multiple registries and trials have been developed and will be summarized in this review. Recent guidelines highlighted the role of CCT in diagnosing suspected CAD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-526). The series “Impact of Cardiac CT in Clinical Practice” was commissioned by the editorial office without any funding or sponsorship. FC served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from Jul 2019 to Jun 2021. The authors have no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Non-invasive depiction of coronary arteries has been a great challenge for imaging specialists since the introduction of computed tomography (CT). Technological development together with improvements in spatial, temporal, and contrast resolution, progressively allowed implementation of the current clinical role of the CT assessment of coronary arteries. Several technological evolutions including hardware and software solutions of CT scanners have been developed to improve spatial and temporal resolution. The main challenges of cardiac computed tomography (CCT) are currently plaque characterization, functional assessment of stenosis and radiation dose reduction. In this review, we will discuss current standards and future improvements in CCT., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-527). The series “Impact of Cardiac CT in Clinical Practice” was commissioned by the editorial office without any funding or sponsorship. FC served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from Jul 2019 to Jun 2021. The authors have no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

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.

Objectives: This study sought to explore sex-based differences in total and compositional plaque volume (PV) progression., Background: It is unclear whether sex has an impact on PV progression in patients with coronary artery disease (CAD)., Methods: The study analyzed a prospective multinational registry of consecutive patients with suspected CAD who underwent 2 or more clinically indicated coronary computed tomography angiography (CTA) at ≥2-year intervals. Total and compositional PV at baseline and follow-up were quantitatively analyzed and normalized using the analyzed total vessel length. Multivariate linear regression models were constructed., Results: Of the 1,255 patients included (median coronary CTA interval 3.8 years), 543 were women and 712 were men. Women were older (62 ± 9 years of age vs. 59 ± 9 years of age; p < 0.001) and had higher total cholesterol levels (195 ± 41 mg/dl vs. 187 ± 39 mg/dl; p = 0.002). Prevalence of hypertension, diabetes, and family history of CAD were not different (all p > 0.05). At baseline, men possessed greater total PV (31.3 mm 3 [interquartile range (IQR): 0 to 121.8 mm 3 ] vs. 56.7 mm 3 [IQR: 6.8 to 152.1 mm 3 ] p = 0.005), and there was an approximately 9-year delay in women in developing total PV than in men. The prevalence of high-risk plaques was greater in men than women (31% vs. 20%; p < 0.001). In multivariate analysis, after adjusting for age, clinical risk factors, medication use, and total PV at baseline, despite similar total PV progression rates, female sex was associated with greater calcified PV progression (β = 2.83; p = 0.004) but slower noncalcified PV progression (β = -3.39; p = 0.008) and less development of high-risk plaques (β = -0.18; p = 0.049) than in men., Conclusions: The compositional PV progression differed according to sex, suggesting that comprehensive plaque evaluation may contribute to further refining of risk stratification according to sex. (NCT02803411)., Competing Interests: Author Relationship With Industry 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 (Grant No. 2012027176) (to Dr. Chang). The study was also funded in part by a generous gift from the Dalio Institute of Cardiovascular Imaging and the Michael Wolk Foundation. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Dr. Min has received funding from the Dalio Foundation, National Institutes of Health, and GE Healthcare; has served on the scientific advisory board of Arineta and GE Healthcare; and owns equity interest in Cleerly. Dr. Samady has served on the scientific advisory board of Philips; owns equity interest in Covanos Inc.; and has received research grant support from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In the past decades, coronary computed tomography angiography (CCTA) has become a powerful tool in the management of coronary artery disease. The diagnostic and prognostic value of CCTA has been extensively demonstrated in both large observational studies and clinical trials among stable chest pain patients. The quantification of coronary artery calcium score (CACS) is a well-established predictor of cardiovascular morbidity and mortality in asymptomatic subjects. Besides CACS, the main strength of CCTA is the accurate assessment of the individual total atherosclerotic plaque burden, which holds important prognostic information. In addition, CCTA, by providing detailed information on coronary plaque morphology and composition with identification of specific high-risk plaque features, may further improve the risk stratification beyond the assessment of coronary stenosis. The development of new CCTA applications, such as stress myocardial CT perfusion and computational fluids dynamic applied to standard CCTA to derive CT-based fractional flow reserve (FFR) values have shown promising results to guide revascularization, potentially improving clinical outcomes in stable chest pain patients. In this review, starting from the role of CACS and moving beyond coronary stenosis, we evaluate the existing evidence of the prognostic effectiveness of the CCTA strategy in real-world clinical practice.

Aortic valve stenosis (AS) is a common valvular heart disease. Recently, transcatheter aortic valve implantation (TAVI) has changed the treatment of severe AS in elderly patients with contraindications to traditional surgical replacement. Echocardiography is conventionally used as the first imaging modality to assess the presence and severity of AS and to provide anatomical and functional information. Nowadays, imaging techniques play a crucial role in the planning of TAVI to define suitable candidates. Computed tomography (CT) is essential to display the anatomy of the aortic valve complex (including aortic annulus, Valsalva sinuses, coronary arteries ostia, sinotubular junction), thoracoabdominal aorta, and vascular access. Cardiac CT may also provide the evaluation of coronary arteries in alternative to conventional coronary angiography. Magnetic resonance imaging may be alternative or supplementary in selected cases, providing detailed information of cardiac function and myocardial wall characteristics. More recently, advanced computer modeling image-based techniques can be used to support the evaluation of the feasibility and safety of TAVI procedures.

Objectives: This study sought to identify culprit lesion (CL) precursors among acute coronary syndrome (ACS) patients based on qualitative and quantitative computed tomography-based plaque characteristics., Background: Coronary computed tomography angiography (CTA) has been validated for patient-level prediction of ACS. However, the applicability of coronary CTA to CL assessment is not known., Methods: Utilizing the ICONIC (Incident COroNary Syndromes Identified by Computed Tomography) study, a nested case-control study of 468 patients with baseline coronary CTA, the study included ACS patients with invasive coronary angiography-adjudicated CLs that could be aligned to CL precursors on baseline coronary CTA. Separate blinded core laboratories adjudicated CLs and performed atherosclerotic plaque evaluation. Thereafter, the study used a boosted ensemble algorithm (XGBoost) to develop a predictive model of CLs. Data were randomly split into a training set (80%) and a test set (20%). The area under the receiver-operating characteristic curve of this model was compared with that of diameter stenosis (model 1), high-risk plaque features (model 2), and lesion-level features of CL precursors from the ICONIC study (model 3). Thereafter, the machine learning (ML) model was applied to 234 non-ACS patients with 864 lesions to determine model performance for CL exclusion., Results: CL precursors were identified by both coronary angiography and baseline coronary CTA in 124 of 234 (53.0%) patients, with a total of 582 lesions (containing 124 CLs) included in the analysis. The ML model demonstrated significantly higher area under the receiver-operating characteristic curve for discriminating CL precursors (0.774; 95% confidence interval [CI]: 0.758 to 0.790) compared with model 1 (0.599; 95% CI: 0.599 to 0.599; p < 0.01), model 2 (0.532; 95% CI: 0.501 to 0.563; p < 0.01), and model 3 (0.672; 95% CI: 0.662 to 0.682; p < 0.01). When applied to the non-ACS cohort, the ML model had a specificity of 89.3% for excluding CLs., Conclusions: In a high-risk cohort, a boosted ensemble algorithm can be used to predict CL from non-CL precursors on coronary CTA., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Different methodologies to report whole-heart atherosclerotic plaque on coronary computed tomography angiography (CCTA) have been utilized. We examined which of the three commonly used plaque burden definitions was least affected by differences in body surface area (BSA) and sex., Methods: The PARADIGM study includes symptomatic patients with suspected coronary atherosclerosis who underwent serial CCTA >2 years apart. Coronary lumen, vessel, and plaque were quantified from the coronary tree on a 0.5 mm cross-sectional basis by a core-lab, and summed to per-patient. Three quantitative methods of plaque burden were employed: (1) total plaque volume (PV) in mm 3 , (2) percent atheroma volume (PAV) in % [which equaled: PV/vessel volume * 100%], and (3) normalized total atheroma volume (TAV norm ) in mm 3 [which equaled: PV/vessel length * mean population vessel length]. Only data from the baseline CCTA were used. PV, PAV, and TAV norm were compared between patients in the top quartile of BSA vs the remaining, and between sexes. Associations between vessel volume, BSA, and the three plaque burden methodologies were assessed., Results: The study population comprised 1479 patients (age 60.7 ± 9.3 years, 58.4% male) who underwent CCTA. A total of 17,649 coronary artery segments were evaluated with a median of 12 (IQR 11-13) segments per-patient (from a 16-segment coronary tree). Patients with a large BSA (top quartile), compared with the remaining patients, had a larger PV and TAV norm , but similar PAV. The relation between larger BSA and larger absolute plaque volume (PV and TAV norm ) was mediated by the coronary vessel volume. Independent from the atherosclerotic cardiovascular disease risk (ASCVD) score, vessel volume correlated with PV (P < 0.001), and TAV norm (P = 0.003), but not with PAV (P = 0.201). The three plaque burden methods were equally affected by sex., Conclusions: PAV was less affected by patient's body surface area then PV and TAV norm and may be the preferred method to report coronary atherosclerotic burden., 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 scientific advisory board of Philips, has equity interest in Covanos Inc., and has a research grant from Medtronic. Dr. Kavitha Chinnaiyan is a non-compensated medical advisory board member of Heartflow Inc. The remaining authors have no relevant disclosures., (Copyright © 2020. Published by Elsevier Inc.)

Background: To determine if an increased epicardial fat volume (EFV) is associated with coronary artery disease (CAD) in individuals with symptoms of cardiovascular (CV) disease., Methods: Coronary Computed Tomographic Angiography (CCTA), demographic and clinical variables of 1344 individuals were retrieved: semi-automated measurements for EFV and coronary artery calcifications (CAC) were obtained. Individuals were grouped into three categories according to the presence of CAD, resulting in absent (CAD 0 ), non-obstructive (CAD 1 ) or obstructive (CAD 2 ) disease-groups. Relation of EFV with CAD was assessed with two approaches: 1) presence of any CAD; 2) each individual CAD category., Results: Median EFV was 90.52 ml (range 11.27-442.21 ml); median CAC was 56.5 (range 0-10,144); 848 individuals (63.1%) were categorized as CAD 0 , 326 (24.3%) as CAD 1 , 170 (12.6%) as CAD 2 . EFV was lower in subjects without CAC (EFV median  = 66.5 ml), as compared to those with CAC 0.1-100 (EFV median  = 91.47), CAC 100.1-400 (EFV median  = 97.46) and CAC >400 (EFV median  = 109.48) (p < 0.001). EFV was lower in CAD 0 (EFV median  = 87.21 ml), as compared to CAD 1 (EFV median  = 93.89 ml) and CAD 2 (EFV median  = 102.98 ml) individuals (p < 0.001). A logistic regression model built by including demographic and clinical variables showed inconsistent predictive value of EFV for either CAD 1 or CAD 2 (p > 0.05)., Conclusions: In the setting of symptomatic individuals, an increased amount of epicardial fat was associated with larger amount of coronary artery calcifications and was observed in individuals with obstructive CAD, however without predictive value to confidently determine CAD presence and severity., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: High-risk plaque (HRP) and non-obstructive coronary artery disease independently predict adverse events, but their importance to future culprit lesions has not been resolved. We sought to determine in patients prior to confirmed acute coronary syndrome (ACS) the association between lesion percent diameter stenosis (%DS), and the absolute number and prevalence of HRP. The secondary objective was to examine the relative importance of non-obstructive HRP in future culprit lesions., Methods and Results: Within the ICONIC study, a nested case-control study of patients undergoing coronary computed tomographic angiography (coronary CT), we included ACS cases with culprit lesions confirmed by invasive coronary angiography and coregistered to baseline coronary CT. Quantitative CT was used to evaluate obstructive (≥50%) and non-obstructive (<50%) diameter stenosis, with HRP defined as ≥2 features of spotty calcification, positive remodelling, or low-attenuation plaque at baseline. A total of 234 patients with downstream ACS over 54 (interquartile range 5-525.5) days exhibited 198/898 plaques with HRP on coronary CT. While HRP was less prevalent in non-obstructive (19.7%, 161/819) than obstructive lesions (46.8%, 37/79, P < 0.001), non-obstructive plaque comprised 81.3% (161/198) of HRP lesions overall. Among the 128 patients with identifiable culprit lesion precursors, the adjusted hazard ratio (HR) was 1.85 [95% confidence interval (CI) 1.26-2.72] for HRP, with no interaction between %DS and HRP (P = 0.82). Compared to non-obstructive HRP lesions, obstructive lesions without HRP exhibited a non-significant HR of 1.41 (95% CI 0.61-3.25, P = 0.42)., Conclusions: While HRP is more prevalent among obstructive lesions, non-obstructive HRP lesions outnumber those that are obstructive and confer risk clinically approaching that of obstructive lesions without HRP., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)