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Abstract Background Increased left ventricular (LV) torsion has been observed in patients with manifest familial hypertrophic cardiomyopathy (HCM), and is thought to be caused by subendocardial dysfunction. We hypothesize that increased LV torsion is already present in healthy mutation carriers with normal wall thickness. Methods Seventeen carriers with an LV wall thickness Results LV volumes, mass and circumferential strain were comparable between groups, whereas LV ejection fraction, torsion and TECS-ratio were increased in carriers compared to controls (63 ± 3% vs. 60 ± 3%, p = 0.04, 10.1 ± 2.5° vs. 7.7 ± 1.2°, p = 0.001, and 0.52 ± 0.14°/% vs. 0.42 ± 0.10°/%, p = 0.02, respectively). Conclusions Carriers with normal wall thickness display increased LV torsion and TECS-ratio with respect to controls, which might be due to subendocardial myocardial dysfunction. As similar abnormalities are observed in patients with manifest HCM, the changes in healthy carriers may be target for clinical intervention to delay or prevent the onset of hypertrophy.

Background: The longitudinal relation between coronary artery disease (CAD) polygenic risk score (PRS) and long-term plaque progression and high-risk plaque (HRP) features is unknown., Objectives: The goal of this study was to investigate the impact of CAD PRS on long-term coronary plaque progression and HRP., Methods: Patients underwent CAD PRS measurement and prospective serial coronary computed tomography angiography (CTA) imaging. Coronary CTA scans were analyzed with a previously validated artificial intelligence-based algorithm (atherosclerosis imaging-quantitative computed tomography imaging). The relationship between CAD PRS and change in percent atheroma volume (PAV), percent noncalcified plaque progression, and HRP prevalence was investigated in linear mixed-effect models adjusted for baseline plaque volume and conventional risk factors., Results: A total of 288 subjects (mean age 58 ± 7 years; 60% male) were included in this study with a median scan interval of 10.2 years. At baseline, patients with a high CAD PRS had a more than 5-fold higher PAV than those with a low CAD PRS (10.4% vs 1.9%; P < 0.001). Per 10 years of follow-up, a 1 SD increase in CAD PRS was associated with a 0.69% increase in PAV progression in the multivariable adjusted model. CAD PRS provided additional discriminatory benefit for above-median noncalcified plaque progression during follow-up when added to a model with conventional risk factors (AUC: 0.73 vs 0.69; P = 0.039). Patients with high CAD PRS had an OR of 2.85 (95% CI: 1.14-7.14; P = 0.026) and 6.16 (95% CI: 2.55-14.91; P < 0.001) for having HRP at baseline and follow-up compared with those with low CAD PRS., Conclusions: Polygenic risk is strongly associated with future long-term plaque progression and HRP in patients suspected of having CAD., Competing Interests: Funding Support and Author Disclosures Dr Nurmohamed is supported by grants from the Dutch Heart Foundation (Dekker grant number 03-007-2023-0068) and European Atherosclerosis Society (2023). Dr Fahed is supported by grants K08HL161448 and R01HL164629 from the National Heart, Lung, and Blood Institute. Dr Nurmohamed has received research funding/speaker fees from Cleerly, Daiichi Sankyo, and Novartis; and is co-founder of Lipid Tools. Dr Choi has received grant support from Cleerly Inc and GW Heart and Vascular Institute; has equity in Cleerly, Inc; and reports consulting with Siemens Healthineers. Dr Natarajan has received investigator-initiated grants from Allelica, Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; has received personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, GV, HeartFlow, Novartis, and Roche/Genentech; is a co-founder of TenSixteen Bio; is a scientific advisory board member of Esperion Therapeutics, Preciseli, and TenSixteen Bio; and reports spousal employment at Vertex Pharmaceuticals. Drs Earls and Min are employees of and hold equity in Cleerly Inc. Dr Stroes has received lecturing/advisory board fees from Amgen, Novartis, Esperion, Sanofi-Regeneron, and Akcea. Dr Knaapen has received research grants from HeartFlow, Inc and Cleerly Inc. Dr Reeskamp is cofounder of Lipid Tools; and has received speaker fees from Novartis, Daiichi Sankyo, and Ultragenyx. Dr Fahed is co-founder of Goodpath. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fractional flow reserve (FFR) or non-hyperaemic pressure ratios are recommended to assess functional relevance of intermediate coronary stenosis. Both diagnostic methods require the placement of a pressure wire in the coronary artery during invasive coronary angiography. Quantitative flow ratio (QFR) is an angiography-based computational method for the estimation of FFR that does not require the use of pressure wires. We aimed to investigate whether a QFR-based diagnostic strategy yields a non-inferior 12-month clinical outcome compared with an FFR-based strategy., Methods: FAVOR III Europe was a multicentre, randomised, open-label, non-inferiority trial comparing a QFR-based with an FFR-based diagnostic strategy for patients with intermediate coronary stenosis. Enrolment was performed in 34 centres across 11 European countries. Patients aged 18 years or older with either chronic coronary syndrome or stabilised acute coronary syndrome, and with at least one intermediate non-culprit stenosis (40-90% diameter stenosis by visual estimate; referred to here as a study lesion), were randomly assigned (1:1) to the QFR-guided or the FFR-guided group. Randomisation was done using a concealed web-based system and was stratified by diabetes and presence of a left anterior descending coronary artery study lesion. The primary endpoint was a composite of death, myocardial infarction, and unplanned revascularisation at 12 months. The predefined non-inferiority margin was 3·4% and the primary analysis was performed in the intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT03729739) and long-term follow-up is ongoing., Findings: Between Nov 6, 2018, and July 21, 2023, 2000 patients were enrolled and randomly assigned to the QFR-guided strategy (1008 patients) or the FFR-guided strategy (992 patients). The median age was 67·3 years (IQR 59·9-74·7); 1538 (76·9%) patients were male and 462 (23·1%) were female. Median follow-up time was 365 days (IQR 365-365). At 12 months, a primary endpoint event had occurred in 67 (6·7%) patients in the QFR group, and in 41 (4·2%) patients in the FFR group (hazard ratio 1·63 [95% CI 1·11-2·41]). The event proportion difference was 2·5% (90% two-sided CI 0·9-4·2). The upper limit of the 90% CI exceeded the prespecified non-inferiority margin of 3·4%. Therefore, QFR did not meet non-inferiority to FFR. A total of 18 (1·8%) patients in each group experienced an adverse procedural event, the most frequent being procedure-related myocardial infarction, which occurred in ten (1·0%) patients in the QFR group and seven (0·7%) in the FFR group. One patient in the QFR group died in relation to the index procedure., Interpretation: The results of the FAVOR III Europe trial do not support the use of QFR if FFR is available to guide revascularisation decisions in patients with intermediate coronary stenosis. This finding could have implications for current clinical guidelines recommending QFR for this purpose., Funding: Medis Medical Imaging Systems and Aarhus University., Competing Interests: Declaration of interests BKA reports an institutional research grant from Medis Medical Imaging and free licences for the QFR application from Medis Medical Imaging during the trial. GCam reports institutional research grants from SMT, Medis Medical Imaging, Abbott Vascular, GADA, Siemens, and GE Healthcare outside the present work. TR reports consultant and proctoring honoraria from Boston Scientific, EPS Vascular, and Cardirad. BES is supported by the H H Sheikh Khalifa bin Hamad Al-Thani Research Programme; has received research grants to the institution from Boston Scientific, the B Braun Foundation, the German Center for Cardiovascular Research (DZHK), the German Heart Research Foundation, Edwards Lifesciences, the Iten-Kohaut Foundation, and the OPO Foundation; has received consulting and speaker fees from Abbott Vascular, Abiomed, and Boston Scientific; and received free licences for the QFR application from Medis Medical Imaging during the trial. LDS reports consulting fees from Abbott Vascular, Boston Scientific, and Philips outside the submitted work. JE reports serving as a speaker or advisory board member for Abbott, Boston Scientific, Medis Medical Imaging, and Philips. RL-P received a free licence for the QFR software from Medis Medical Imaging during the trial. UL reports research grants to the institution from Abbott, Amgen, Bayer, and Novartis. RSD reports an institutional research grant from Medis Medical Imaging and free licences for the QFR application from Medis Medical Imaging during the trial. HM-R reports consultancy fees from Medis Medical Imaging and speaker fees from Philips and Abbott. LK received free licences for the QFR application from Medis Medical Imaging during the trial. JA reports teaching grants from Biotronik and Medis Medical Imaging. YSA reports consulting fees from Boston Scientific and Shockwave. TL served as a Medis technical and research support consultant in Haga Hospital (The Hague, Netherlands) and performed beta testing of software from Medis Medical Imaging, neither of which was study related, and received a free licence for the QFR application from Medis Medical Imaging during the trial. KL received free licences for the QFR application from Medis Medical Imaging during the trial; speaker fees and travel support from BMS and Boston Scientific; speaker fees from DGK; and served as an advisory board member for BMS. GCas received a free licence for the QFR application from Medis Medical Imaging during the trial. SB reports institutional research grants from Medis Medical Imaging, SMT, Abbott, Siemens, Insight Lifetech, and Amgen; free licences for the QFR application from Medis Medical Imaging during the trial; speaker's fee from SMT, Medis Medical Imaging, Abbott, and Siemens; and advisory board activities for Siemens. NTO reports institutional research grants from Abbott and from Shockwave. RS reports an institutional research grant from Abbott; institutional research contract with Medis Medical Imaging; and speaker and consultation fees from Abbott and Fondazione Menarini. EHC reports institutional research grants from Abbott, Biosensors, Meril, and Medis Medical Imaging; and speaker fees from Abbott and EPS. NRH reports Institutional research grants from Abbott, B Braun, Biosensors, Boston Scientific, and Medis Medical Imaging; and speaker fees from Abbott and EPS. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Aims: The objective of this study is to conduct a meta-analysis to assess the diagnostic performance of Coronary Computed Tomography Angiography (CCTA) and a hybrid approach that incorporates Computed Tomography Perfusion (CTP) in addition to CCTA (CCTA ​+ ​CTP) for the detection of in-stent restenosis (ISR), as defined by angiography., Methods: A comprehensive search of articles identified 18,513 studies. After removing duplicates, title/abstract screening, and full-text review, 17 CCTA and 3 CCTA ​+ ​CTP studies were included. Only studies using ≥64-slices multidetector computed tomography (CT) were considered eligible., Results: The per-patient ISR prevalence was 43 ​%, with 92 ​% of stents fully interpretable with CCTA. Meta-analysis exhibited a per-stent CCTA (n ​= ​2674) sensitivity of 90 ​% (95 ​% CI; 84-94 ​%), specificity of 89 ​% (95 ​% CI; 86-92 ​%), positive likelihood ratio of 7.17 (95 ​% CI; 5.24-9.61), negative likelihood ratio of 0.17 (95 ​% CI; 0.10-0.25), and diagnostic odds ratio of 45.7 (95 ​% CI; 22.71-82.43). Additional sensitivity analyses revealed no influence of stent diameter or strut thickness on the diagnostic yield of CCTA. The per-stent diagnostic performance of CCTA ​+ ​CTP (n ​= ​752) did not show differences compared to CCTA., Conclusions: With currently utilized scanners, CCTA and CCTA ​+ ​CTP demonstrated high diagnostic performance for in-stent restenosis evaluation. Consequently, a history of previous stent implantation should not be an argument to preclude using these methods in clinically suspected patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: We sought to investigate the impact of sex on myocardial perfusion changes following chronic total coronary occlusion (CTO) percutaneous coronary intervention (PCI) as measured by [ 15 O]H 2 O positron-emission tomography (PET) perfusion imaging., Background: CTO PCI has been associated with an increase in myocardial perfusion, yet females are less likely to undergo revascularization. As such, data on the impact of sex on myocardial perfusion following CTO PCI is scarce., Methods: A total of 212 patients were prospectively enrolled and underwent CTO PCI combined with [ 15 O]H 2 O PET perfusion imaging prior to and 3 months after PCI. Hyperemic myocardial blood flow (hMBF, mL·min -1 ·g -1 ) and coronary flow reserve (CFR) allocated to the CTO territory were quantitatively assessed., Results: This study comprised 34 (16 %) females and 178 (84 %) males. HMBF at baseline did not differ between sexes. Females showed a higher increase in hMBF than males (Δ1.34 ± 0.67 vs. Δ1.06 ± 0.74, p = 0.044), whereas post-PCI hMBF was comparable (2.59 ± 0.85 in females vs. 2.28 ± 0.84 in males, p = 0.052). Female sex was independently associated with a higher increase in hMBF after correction for clinical covariates. CFR increase after revascularization was similar in females and males (Δ1.47 ± 0.99 vs. Δ1.30 ± 1.14, p = 0.711)., Conclusions: The present study demonstrates a greater recovery of stress perfusion in females compared to males as measured by serial [ 15 O]H 2 O PET imaging. In addition, a comparable increase in CFR was found in females and males. These results emphasize the benefit of performing CTO PCI in both sexes., Clinical Perspective: What is new? What are the clinical implications?, Competing Interests: Declaration of competing interest Nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Noninvasive stress testing is commonly used for detection of coronary ischemia but possesses variable accuracy and may result in excessive health care costs., Objectives: This study aimed to derive and validate an artificial intelligence-guided quantitative coronary computed tomography angiography (AI-QCT) model for the diagnosis of coronary ischemia that integrates atherosclerosis and vascular morphology measures (AI-QCT ISCHEMIA ) and to evaluate its prognostic utility for major adverse cardiovascular events (MACE)., Methods: A post hoc analysis of the CREDENCE (Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia) and PACIFIC-1 (Comparison of Coronary Computed Tomography Angiography, Single Photon Emission Computed Tomography [SPECT], Positron Emission Tomography [PET], and Hybrid Imaging for Diagnosis of Ischemic Heart Disease Determined by Fractional Flow Reserve) studies was performed. In both studies, symptomatic patients with suspected stable coronary artery disease had prospectively undergone coronary computed tomography angiography (CTA), myocardial perfusion imaging (MPI), SPECT, or PET, fractional flow reserve by CT (FFR CT ), and invasive coronary angiography in conjunction with invasive FFR measurements. The AI-QCT ISCHEMIA model was developed in the derivation cohort of the CREDENCE study, and its diagnostic performance for coronary ischemia (FFR ≤0.80) was evaluated in the CREDENCE validation cohort and PACIFIC-1. Its prognostic value was investigated in PACIFIC-1., Results: In CREDENCE validation (n = 305, age 64.4 ± 9.8 years, 210 [69%] male), the diagnostic performance by area under the receiver-operating characteristics curve (AUC) on per-patient level was 0.80 (95% CI: 0.75-0.85) for AI-QCT ISCHEMIA , 0.69 (95% CI: 0.63-0.74; P < 0.001) for FFR CT , and 0.65 (95% CI: 0.59-0.71; P < 0.001) for MPI. In PACIFIC-1 (n = 208, age 58.1 ± 8.7 years, 132 [63%] male), the AUCs were 0.85 (95% CI: 0.79-0.91) for AI-QCT ISCHEMIA , 0.78 (95% CI: 0.72-0.84; P = 0.037) for FFR CT , 0.89 (95% CI: 0.84-0.93; P = 0.262) for PET, and 0.72 (95% CI: 0.67-0.78; P < 0.001) for SPECT. Adjusted for clinical risk factors and coronary CTA-determined obstructive stenosis, a positive AI-QCT ISCHEMIA test was associated with aHR: 7.6 (95% CI: 1.2-47.0; P = 0.030) for MACE., Conclusions: This newly developed coronary CTA-based ischemia model using coronary atherosclerosis and vascular morphology characteristics accurately diagnoses coronary ischemia by invasive FFR and provides robust prognostic utility for MACE beyond presence of stenosis., Competing Interests: Funding Support and Author Disclosures This project has been supported by the Foundation “De Drie Lichten” in the Netherlands. Dr Nurmohamed has received grants from the Dutch Heart Foundation (Dekker 03-007-2023-0068) and grants from the European Atherosclerosis Society (2023); and is co-founder of Lipid Tools. Mr Wang, Dr Chan, Ms Crabtree, Ms Aquino, Dr Min, and Dr Earls are employees of Cleerly Inc. Dr Choi has received grant support from GW Heart and Vascular Institute; equity in Cleerly, Inc; and has received consulting fees from Siemens Healthineers. Dr Knaapen has received research grants from HeartFlow, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Microvascular Resistance Reserve (MRR) has recently been introduced as a microvasculature-specific index and hypothesized to be independent of coronary stenosis. The aim of this study was to investigate the change of MRR after percutaneous coronary intervention (PCI)., Methods: In this post-hoc analysis from the PACIFC trials, symptomatic patients underwent [ 15 O]H 2 O positron emission tomography (PET) and invasive fractional flow reserve (FFR) before and after revascularization. Coronary flow reserve (CFR) from PET and invasive FFR were used to calculate MRR., Results: Among 52 patients (87 % male, age 59.4 ± 9.4 years), 61 vessels with a median FFR of 0.71 (95 % confidence interval: 0.55 to 0.74) and a mean MRR of 3.80 ± 1.23 were included. Following PCI, FFR, hyperemic myocardial blood flow (hMBF) and CFR increased significantly (all p-values ≤0.001). MRR remained unchanged after PCI (3.80 ± 1.23 before PCI versus 3.60 ± 0.97 after PCI; p=0.23). In vessels with a pre-PCI, FFR ≤0.70 pre- and post-PCI MRR were 3.90 ± 1.30 and 3.73 ± 1.14 (p=0.56), respectively. Similar findings were observed for vessels with a FFR between 0.71 and 0.80 (pre-PCI MRR 3.70 ± 1.17 vs. post PCI MRR 3.48 ± 0.76, p=0.19)., Conclusions: Our study indicates that MRR, assessed using a hybrid approach of PET and invasive FFR, is independent of the severity of epicardial stenosis. These findings suggest that MRR is a microvasculature-specific parameter., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The microvascular resistance reserve (MRR) is an innovative index to assess the vasodilatory capacity of the coronary circulation while accounting for the presence of concomitant epicardial disease. The MRR has shown to be a valuable diagnostic and prognostic tool in the general coronary artery disease (CAD) population. However, considering the fundamental aspects of its assessment and the unique hemodynamic characteristics of women, it is crucial to provide additional considerations for evaluating the MRR specifically in women., Aim: The aim of this study was to assess the diagnostic and prognostic applicability of the MRR in women and assess the potential differences across different sexes., Methods: From the ILIAS Registry, we enrolled all patients with a stable indication for invasive coronary angiography, ensuring complete physiological and follow-up data. We analyzed the diagnostic value by comparing differences between sexes and evaluated the prognostic value of the MRR specifically in women, comparing it to that in men., Results: A total of 1494 patients were included of which 26% were women. The correlation between MRR and CFR was good and similar between women (r = 0.80, p < 0.005) and men (r = 0.81, p < 0.005). The MRR was an independent and important predictor of MACE in both women (HR 0.67, 0.47-0.96, p = 0.027) and men (HR 0.84, 0.74-0.95, p = 0.007). The optimal cut-off value for MRR in women was 2.8 and 3.2 in men. An abnormal MRR similarly predicted MACE at 5-year follow-up in both women and men., Conclusion: The MRR seems to be equally applicable in both women and men with stable coronary artery disease., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The recent development of artificial intelligence-guided quantitative coronary computed tomography angiography analysis (AI-QCT) has enabled rapid analysis of atherosclerotic plaque burden and characteristics., Objectives: This study set out to investigate the 10-year prognostic value of atherosclerotic burden derived from AI-QCT and to compare the spectrum of plaque to manually assessed coronary computed tomography angiography (CCTA), coronary artery calcium scoring (CACS), and clinical risk characteristics., Methods: This was a long-term follow-up study of 536 patients referred for suspected coronary artery disease. CCTA scans were analyzed with AI-QCT and plaque burden was classified with a plaque staging system (stage 0: 0% percentage atheroma volume [PAV]; stage 1: >0%-5% PAV; stage 2: >5%-15% PAV; stage 3: >15% PAV). The primary major adverse cardiac event (MACE) outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and all-cause mortality., Results: The mean age at baseline was 58.6 years and 297 patients (55%) were male. During a median follow-up of 10.3 years (IQR: 8.6-11.5 years), 114 patients (21%) experienced the primary outcome. Compared to stages 0 and 1, patients with stage 3 PAV and percentage of noncalcified plaque volume of >7.5% had a more than 3-fold (adjusted HR: 3.57; 95% CI 2.12-6.00; P < 0.001) and 4-fold (adjusted HR: 4.37; 95% CI: 2.51-7.62; P < 0.001) increased risk of MACE, respectively. Addition of AI-QCT improved a model with clinical risk factors and CACS at different time points during follow-up (10-year AUC: 0.82 [95% CI: 0.78-0.87] vs 0.73 [95% CI: 0.68-0.79]; P < 0.001; net reclassification improvement: 0.21 [95% CI: 0.09-0.38]). Furthermore, AI-QCT achieved an improved area under the curve compared to Coronary Artery Disease Reporting and Data System 2.0 (10-year AUC: 0.78; 95% CI: 0.73-0.83; P = 0.023) and manual QCT (10-year AUC: 0.78; 95% CI: 0.73-0.83; P = 0.040), although net reclassification improvement was modest (0.09 [95% CI: -0.02 to 0.29] and 0.04 [95% CI: -0.05 to 0.27], respectively)., Conclusions: Through 10-year follow-up, AI-QCT plaque staging showed important prognostic value for MACE and showed additional discriminatory value over clinical risk factors, CACS, and manual guideline-recommended CCTA assessment., Competing Interests: Funding Support and Author Disclosures Dr Nurmohamed is co-founder of Lipid Tools. Dr Stroes has received lecturing/advisory board fees from Amgen, Novartis, Esperion, Sanofi-Regeneron, and Akcea. Drs Min and Earls are employees of and hold equity in Cleerly Inc. Dr Choi has received grant support from GW Heart and Vascular Institute; holds equity in Cleerly, Inc; and has provided consulting services to Siemens Healthineers. Dr Knaapen has received research grants from HeartFlow, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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

Background: Microvascular resistance (MR) has prognostic value in acute and chronic coronary syndromes following percutaneous coronary intervention (PCI), however anatomic and physiologic determinants of the relative changes of MR and its association to target vessel failure (TVF) has not been investigated previously. This study aims to evaluate the association between changes in MR and TVF., Methods: This is a sub-study of the Inclusive Invasive Physiological Assessment in Angina Syndromes (ILIAS) registry which is a global multi-centre initiative pooling lesion-level coronary pressure and flow data., Results: Paired pre-post PCI haemodynamic data were available in n = 295 vessels out of n = 828 PCI treated patients and of these paired data on MR was present in n = 155 vessels. Vessels were divided according to increase vs. decrease % in microvascular resistance following PCI (ΔMR % ≤ 0 vs. ΔMR > 0%). Decreased microvascular resistance ΔMR % ≤ 0 occurred in vessels with lower pre-PCI fractional flow reserve (0.67 ± 0.15 vs. 0.72 ± 0.09 p = 0.051), coronary flow reserve (1.9 ± 0.8 vs. 2.6 ± 1.8 p < 0.0001) and higher hyperemic microvascular resistance (2.76 ± 1.3 vs. 1.62 ± 0.74 p = 0.001) and index of microvascular resistance (24.4 IQ (13.8) vs. 15. 8 IQ (13.2) p = 0.004). There was no difference in angiographic parameters between ΔMR % ≤ 0 vs. ΔMR > 0%. In a cox regression model ΔMR % > 0 was associated with increased rate of TVF (hazard ratio 95% CI 3.6 [1.2; 10.3] p = 0.018)., Conclusion: Increased MR post-PCI was associated with lesions of less severe hemodynamic influence at baseline and higher rates of TVF at follow-up., Competing Interests: Declaration of Competing Interest There are no conflicts of interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: The management of chronic coronary syndrome (CCS) is informed by studies predominantly including men. This study investigated the relationship between patients sex and different endotypes of CCS, including sex-specific clinical outcomes., Methods: In patients with CCS undergoing coronary angiography, invasive Fractional Flow Reserve (FFR) and Coronary Flow Reserve (CFR) were measured. Patients were stratified into groups: 1) obstructive coronary artery disease (oCAD) (FFR≤0.80, no revascularization), 2) undergoing revascularization, 3) non-obstructive coronary artery disease with coronary microvascular dysfunction (CMD) (FFR>0.80, CFR≤2.5), and 4) non-obstructive coronary artery disease without CMD (FFR>0.80 and CFR>2.5)., Results: 1836 patients (2335 vessels) were included, comprising 1359 (74.0%) men and 477 (26.0%) women. oCAD was present in 14.1% and was significantly less prevalent in women than in men (10.3% vs 15.5%, respectively p < 0.01). Revascularization was present in 30.9% and was similarly prevalent in women and men (28.2% vs. 31.9%, respectively p = 0.13). CMD was present in 24.2% and was significantly more prevalent in women than men (28.6% vs 22.6%, respectively p < 0.01). Normal invasive measurements were found in 564 patients (33.0% women vs 30.0% men, p = 0.23). Male sex was associated with an increased risk of target vessel failure compared to women (HR.1.89, 95% CI 1.12-3.18, p = 0.018), regardless of CCS-endotype., Conclusions: Sex differences exist in the prevalence and outcomes of different endotypes of CCS in symptomatic patients undergoing invasive coronary angiography. In particular, oCAD (and subsequent revascularization) were more prevalent in men. Conversely, CMD was more prevalent in women. Overall, men experienced a worse cardiovascular outcome compared to women, independent of any specific CCS endotype., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Myocardial perfusion imaging (MPI) and anatomical imaging with coronary computed tomography angiography (CCTA) can play an important role in the preprocedural planning of a chronic total occlusion (CTO) percutaneous coronary intervention (PCI). We aimed to establish the feasibility of a novel dynamic computed tomography perfusion (CTP) analysis for the assessment of myocardial perfusion before and after a successful recanalization of CTO in patients undergoing CCTA as part of a standard preprocedural workup., Methods: In a prospective observational study symptomatic patients underwent dynamic CTP on a dual-source CT scanner both before and 3 months after successful CTO PCI., Results: Twenty-seven patients completed the study (63 ± 8 years old, 78% male). Following successful CTO PCI, there was a significant reduction in the ischemic burden (5 [5-7] versus 1 [0-2] segments, p < 0.001), and improvement in myocardial blood flow (85.3 [71.7-94.1] versus 134.6 [123.8-156.9] mL/min, p < 0.001) resulting in an increase in the relative flow reserve (0.49 [0.41-0.57] versus 0.88 [0.74-0.95], p < 0.001)., Conclusions: CTP emerges as a robust and safe method for MPI in CTO patients. The single imaging session assessment of both coronary anatomy and perfusion with CT lends itself to precise disease phenotyping in the challenging population of CTO patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is associated with a considerable risk of complications, and risk stratification is of utmost importance., Aims: To assess the clinical usefulness of the recently developed PROGRESS-CTO (NCT02061436) complication risk scores in an independent cohort., Methods: Individual patient data pooled analysis of 3 registries was performed., Results: Of the 4569 patients who underwent CTO PCI, 102 (2.2%) had major adverse cardiovascular events (MACE). Patients with MACE were older (69 ± 11 vs. 65 ± 10, p < 0.001), more likely to have a history of prior coronary artery bypass graft surgery, and unfavorable angiographic characteristics J-CTO score (2.4 ± 1.2 vs. 2.1 ± 1.3, p = 0.007), including blunt stump (59% vs. 49%, p = 0.047). Technical success was lower in patients with MACE (59% vs. 86%, p < 0.001). The area under the receiver operating characteristic curve of the PROGRESS-CTO complication risk models were as follows: MACE 0.72 (95% confidence interval [CI], 0.67-0.76), mortality 0.73 (95% CI, 0.61-0.85), and pericardiocentesis 0.69 (95% CI, 0.62-0.77) in the validation dataset. The observed complication rates increased with higher PROGRESS-CTO complication scores. The PROGRESS-CTO MACE score showed good calibration in this external cohort, with MACE rates similar to the original study: 0.7% (score 0-1), 1.5% (score 2), 2.2% (score 3), 3.8% (score 4), 4.9% (score 5), 5.8% (score 6-7)., Conclusion: Given the good discriminative performance, calibration, and ease of calculation, the PROGRESS-CTO complication scores could help assess the risk of complications in patients undergoing CTO PCI., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Distinct sex-related differences exist in coronary artery plaque burden and distribution. We aimed to explore sex differences in quantitative plaque burden by coronary CT angiography (CCTA) in relation to ischemia by invasive fractional flow reserve (FFR)., Methods: This post-hoc analysis of the PACIFIC trial included 581 vessels in 203 patients (mean age 58.1 ​± ​8.7 years, 63.5% male) who underwent CCTA and per-vessel invasive FFR. Quantitative assessment of total, calcified, non-calcified, and low-density non-calcified plaque burden were performed using semiautomated software. Significant ischemia was defined as invasive FFR ≤0.8., Results: The per-vessel frequency of ischemia was higher in men than women (33.5% vs. 7.5%, p ​< ​0.001). Women had a smaller burden of all plaque subtypes (all p ​< ​0.01). There was no sex difference on total, calcified, or non-calcified plaque burdens in vessels with ischemia; only low-density non-calcified plaque burden was significantly lower in women (beta: -0.183, p ​= ​0.035). The burdens of all plaque subtypes were independently associated with ischemia in both men and women (For total plaque burden (5% increase): Men, OR: 1.15, 95%CI: 1.06-1.24, p ​= ​0.001; Women, OR: 1.96, 95%CI: 1.11-3.46, p ​= ​0.02). No significant interaction existed between sex and total plaque burden for predicting ischemia (interaction p ​= ​0.108). The addition of quantitative plaque burdens to stenosis severity and adverse plaque characteristics improved the discrimination of ischemia in both men and women., Conclusions: In symptomatic patients with suspected CAD, women have a lower CCTA-derived burden of all plaque subtypes compared to men. Quantitative plaque burden provides independent and incremental predictive value for ischemia, irrespective of sex., Competing Interests: Declaration of Competing Interest Outside of the current work, S.C., P.S., and D.D. received software royalties from Cedars-Sinai Medical Center. D.B, P.S., and D.D. hold a patent (US8885905B2 in USA and WO patent WO2011069120A1, Method and System for Plaque Characterization)., (Copyright © 2022 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Clinical reads of coronary computed tomography angiography (CTA), especially by less experienced readers, may result in overestimation of coronary artery disease stenosis severity compared with expert interpretation. Artificial intelligence (AI)-based solutions applied to coronary CTA may overcome these limitations., Objectives: This study compared the performance for detection and grading of coronary stenoses using artificial intelligence-enabled quantitative coronary computed tomography (AI-QCT) angiography analyses to core lab-interpreted coronary CTA, core lab quantitative coronary angiography (QCA), and invasive fractional flow reserve (FFR)., Methods: Coronary CTA, FFR, and QCA data from 303 stable patients (64 ± 10 years of age, 71% male) from the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic DEtermiNants of Myocardial IsChEmia) trial were retrospectively analyzed using an Food and Drug Administration-cleared cloud-based software that performs AI-enabled coronary segmentation, lumen and vessel wall determination, plaque quantification and characterization, and stenosis determination., Results: Disease prevalence was high, with 32.0%, 35.0%, 21.0%, and 13.0% demonstrating ≥50% stenosis in 0, 1, 2, and 3 coronary vessel territories, respectively. Average AI-QCT analysis time was 10.3 ± 2.7 minutes. AI-QCT evaluation demonstrated per-patient sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 94%, 68%, 81%, 90%, and 84%, respectively, for ≥50% stenosis, and of 94%, 82%, 69%, 97%, and 86%, respectively, for detection of ≥70% stenosis. There was high correlation between stenosis detected on AI-QCT evaluation vs QCA on a per-vessel and per-patient basis (intraclass correlation coefficient = 0.73 and 0.73, respectively; P < 0.001 for both). False positive AI-QCT findings were noted in in 62 of 848 (7.3%) vessels (stenosis of ≥70% by AI-QCT and QCA of <70%); however, 41 (66.1%) of these had an FFR of <0.8., Conclusions: A novel AI-based evaluation of coronary CTA enables rapid and accurate identification and exclusion of high-grade stenosis and with close agreement to blinded, core lab-interpreted quantitative coronary angiography. (Computed TomogRaphic Evaluation of Atherosclerotic DEtermiNants of Myocardial IsChEmia [CREDENCE]; NCT02173275)., Competing Interests: Funding Support and Author Disclosures Drs Choi and Marques have equity interest in Cleerly Inc. Dr Earls has equity interest in and as of April 1, 2021, is an employee of Cleerly Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study is to evaluate the diagnostic and prognostic value of non-hyperaemic Pd/Pa and to determine its additional value when combined with the gold standard hyperaemic pressure ratio (FFR) to guide revascularization., Methods: In a large, multi-center, retrospective registry, we included a total of 2141 patients with a clinical indication for coronary angiography providing physiological data in 2726 vessels. A classification was made based on the FFR (cut-off value: 0.80) and non-hyperaemic Pd/Pa (cut-off value: 0.92) values and the primary outcome was target-vessel failure (TVF) at 5-year follow-up., Results: Mean age was 63 ± 10.0 and 75% of the study population were men. Regression analysis showed an overall good correlation between FFR and non-hyperaemic Pd/Pa (r = 0.73, p < 0.005) and discordance was present in 17% of the vessels. Resting Pd/Pa was independently associated with TVF at 5-year follow-up (HR 0.08, 95%CI: 0.02-0.27; p < 0.005). The risk for TVF was the lowest in vessles with concordant normal pressure ratio's, with the highest risk in vessels with any abnormal pressure ratio in which revascularization was deferred. In these vessels, there was no difference in risk for TVF between the discordant and concordant abnormal values., Conclusion: Abnormal pressure ratios in both non-hyperemic and hyperemic conditions portend important prognostic value. Combined application of FFR and non-hyperemic Pd/Pa efficiently identifies those vessels with concordant normal resting and hyperemic pressure ratios of which long-term clinical outcomes are excellent. These data lead to hypothesize that the decision to defer revascularization should potentially be based on combined non-hyperemic and hyperemic pressure ratios., Clinical Trial Registration: Inclusive Invasive Physiological Assessment in Angina Syndromes Registry (ILIAS Registry), NCT04485234., Competing Interests: Conflict of Interest Tvdh has received speaker fees and institutional research grants from Abbott and Philips. JML received research grants from Abbott and Philips. MEP has received speaker fees from Abbott and Philips. BKK has received institutional research grants from Abbott Vascular and Philips Volcano. JJP has received support as consultant for Philips/Volcano, and has received institutional research grants from Philips. The other authors report no relationship with industry related to this work., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Coronary CT angiography (CCTA) demonstrated high diagnostic accuracy for detecting coronary artery disease (CAD) and a key role in the management of patients with low-to-intermediate pretest likelihood of CAD. However, the clinical information provided by this noninvasive method is still regarded insufficient in patients with diffuse and complex CAD and for planning percutaneous coronary intervention (PCI) and surgical revascularization procedures. On the other hand, technology advancements have recently shown to improve CCTA diagnostic accuracy in patients with diffuse and calcific stenoses. Moreover, stress CT myocardial perfusion imaging (CT-MPI) and fractional flow reserve derived from CCTA (CT-FFR) have been introduced in clinical practice as new tools for evaluating the functional relevance of coronary stenoses, with the possibility to overcome the main CCTA drawback, i.e. anatomical assessment only. The potential value of CCTA to plan and guide interventional procedures lies in the wide range of information it can provide: a) detailed evaluation of plaque extension, volume and composition; b) prediction of procedural success of CTO PCI using scores derived from CCTA; c) identification of coronary lesions requiring additional techniques (e.g., atherectomy and lithotripsy) to improve stent implantation success by assessing calcium score and calcific plaque distribution; d) assessment of CCTA-derived Syntax Score and Syntax Score II, which allows to select the mode of revascularization (PCI or CABG) in patients with complex and multivessel CAD. The aim of this Consensus Document is to review and discuss the available data supporting the role of CCTA, CT-FFR and stress CT-MPI in the preprocedural and possibly intraprocedural planning and guidance of myocardial revascularization interventions., Competing Interests: Declaration of competing interest Carlos Collet reports receiving Consultant/Honoraria: Abbott Vascular, HeartFlow, Siemens and Grants/research support: Abbott Vascular, HeartFlow, Siemens. Patrick Serruys reports consultancy fees from Abbott, Biosensors, Medtronic, Micell, Qualimed, Sinomedical Sciences, St. Jude Medical, Stentys, Svelte Medical Systems, Philips/Volcano, Xeltis, StentIt and HeartFlow. Koen Nieman reports unrestricted institutional research support from Siemens Healthineers, HeartFlow Inc, Bayer. Marcio Bittencourt reports Consultant/Honoraria: Bayer, Research funding: Sanofi and Speaker's bureau: NovoNordisk, EMS, Novartis, GE Healthcare. Jonathon Leipsic reports Consultant/Honoraria: Circle CVI, HeartFlow, MVRX; Grants/Research Support: Abbott, Boston Scientific, GE Healthcare, Edwards, Medtronic; Speaker's Bureau: Philips; Stock and stock options: HeartFlow, Circle CVI. Giulio Stefanini reports research grant (to the Institution) from Boston Scientific, and speaker fees Abbott Vascular and Boston Scientific. Brian Ghoshhajra reports Grants and research support: Siemens Healthineers. The other authors report no conflict of interest., (Copyright © 2022 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

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

Objectives: The authors sought to evaluate comparative prognosis between deferred versus performed percutaneous coronary intervention (PCI) according to coronary flow reserve (CFR) values of patients with intermediate fractional flow reserve (FFR)., Background: For coronary stenosis with intermediate FFR, the prognostic value of PCI remains controversial. The prognostic impact of PCI may be different according to CFR in patients with intermediate FFR., Methods: From the ILIAS Registry (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry, N = 2,322), 400 patients (412 vessels) with intermediate FFR (0.75-0.80) were selected. Patients were stratified into preserved CFR (>2.0, n = 253) and depressed CFR (≤2.0, n = 147) cohorts. Per-vessel clinical outcomes during 5 years of follow-up were compared between deferred versus performed PCI groups in both cohorts. The primary outcome was target vessel failure (TVF), a composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization., Results: Among the study population, PCI was deferred for 210 patients (219 vessels, 53.2%) (deferred group) and performed for 190 patients (193 vessels, 46.8%) (performed group). The risk of TVF was comparable between the deferred and performed groups (12.8% vs 14.2%; adjusted HR: 1.403; 95% CI: 0.584-3.369; P = 0.448). When stratified by CFR, PCI was performed in 39.1% (100/261 vessels) of the preserved CFR cohort and 61.9% (93/151 vessels) of the depressed CFR cohort. Within the preserved CFR cohort, the risk of TVF did not differ significantly between the deferred and performed groups (11.0% vs 13.9%; adjusted HR: 0.770; 95% CI: 0.262-2.266; P = 0.635). However, in the depressed CFR cohort, the deferred group had a significantly higher risk of TVF than the performed group (17.2% vs 14.2%; adjusted HR: 4.932; 95% CI: 1.312-18.53; P = 0.018). A significant interaction was observed between CFR and the treatment decision (interaction P = 0.049). Results were consistent after inverse probability weighting adjustment., Conclusions: In patients with intermediate FFR of 0.75 to 0.80, the prognostic value of PCI differed according to CFR, with a significant interaction. PCI was associated with a lower risk of TVF compared with the deferral strategy when CFR was depressed (≤2.0), but there was no difference when CFR was preserved (>2.0). CFR could be used as an additional risk stratification tool to determine treatment strategies in patients with intermediate FFR. (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry [ILIAS Registry]; NCT04485234)., Competing Interests: Funding Support and Author Disclosures Dr Joo Myung Lee has received research grants from Abbott and Philips. Dr Mejia-Renteria has received speaker fees from Philips, Abbott, and Medis. Dr Echavarria-Pinto has received speaker fees from Abbott and Philips. Dr van de Hoef has received speaker fees and institutional research grants from Abbott and Philips. Dr van Royen has received speaker fees and institutional research grants from Abbott and Philips. Dr Koo has received institutional research grants from Abbott Vascular and Philips Volcano. Dr Piek has received support as a consultant for Philips/Volcano; and has received institutional research grants from Philips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to compare Doppler flow velocity and thermodilution-derived indexes and to determine the optimal thermodilution-based diagnostic thresholds for coronary flow reserve (CFR)., Background: The majority of clinical data and diagnostic thresholds for flow-based indexes are derived from Doppler measurements, and correspondence with thermodilution-derived indices remain unclear., Methods: An international multicenter registry was conducted among patients who had coronary flow measurements using both Doppler and thermodilution techniques in the same vessel and during the same procedure., Results: Physiological data from 250 vessels (in 149 patients) were included in the study. A modest correlation was found between thermodilution-derived CFR (CFR thermo ) and Doppler-derived CFR (CFR Doppler ) (r 2  = 0.36; P < 0.0001). CFR thermo overestimated CFR Doppler (mean 2.59 ± 1.46 vs 2.05 ± 0.89; P < 0.0001; mean bias 0.59 ± 1.24 by Bland-Altman analysis), the relationship being described by the equation CFR thermo  = 1.04 × CFR Doppler  + 0.50. The commonly used dichotomous CFR thermo threshold of 2.0 had poor sensitivity at predicting a CFR Doppler value <2.5. The optimal CFR thermo threshold was 2.5 (sensitivity 75.54%, specificity 81.25%). There was only a weak correlation between hyperemic microvascular resistance and index of microvascular resistance (r 2  = 0.19; P < 0.0001), due largely to variation in the measurement of flow by each modality. Forty-four percent of patients were discordantly classified as having abnormal microvascular resistance by hyperemic microvascular resistance (≥2.5 mm Hg · cm -1 · s) and index of microvascular resistance (≥25)., Conclusions: CFR calculated by thermodilution overestimates Doppler-derived CFR, while both parameters show modest correlation. The commonly used CFR thermo threshold of 2.0 has poor sensitivity for identifying vessels with diminished CFR, but using the same binary diagnostic threshold as for Doppler (<2.5) yields reasonable diagnostic accuracy. There was only a weak correlation between microvascular resistance indexes assessed by the 2 modalities., Competing Interests: Funding Support and Author Disclosures This work was supported by the British Heart Foundation (PG/19/9/34228), the National Institute for Health Research via the Biomedical Research Centre award to Guy’s and St Thomas’ Hospital and King’s College London, and the National Institute for Health Research Oxford Biomedical Research Centre. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to demonstrate the clinical implications of combined assessment of fractional flow reserve (FFR) and coronary flow reserve (CFR)., Background: Combined assessment of FFR and CFR allows detailed characterization of pathophysiology in chronic coronary syndromes. Data on the clinical implications of distinct FFR and CFR patterns are limited, leading to uncertainty regarding their relevance., Methods: Patients with chronic coronary syndromes and obstructive coronary artery disease were selected from the multicenter ILIAS (Inclusive Invasive Physiological Assessment in Angina Syndromes) registry. Patients were classified into 4 groups on the basis of FFR ≤0.80 and CFR <2.0. The endpoint was the 5-year target vessel failure (TVF) rate., Results: A total of 2,143 patients with 2,725 lesions were included. Compared with normal FFR/normal CFR, low FFR/low CFR carried the highest risk for TVF (HR: 5.4; 95% CI: 3.2-9.3; P < 0.001), significantly higher than in revascularized vessels (P = 0.007). Discordance, with either low FFR/normal CFR or normal FFR/low CFR, was associated with increased TVF rates compared with normal FFR/normal CFR (low FFR/normal CFR: HR: 3.5 [95% CI: 2.2-5.4; P < 0.001]; normal FFR/low CFR: HR: 3.0 [95% CI: 1.9-4.7; P < 0.001]). No difference in 5-year TVF was observed between the 2 discordant groups (P = 0.57) or between the discordant groups and the revascularized group (P = 0.26 vs low FFR/normal CFR; P = 0.60 vs normal FFR/low CFR)., Conclusions: Impaired coronary hemodynamics are uniformly associated with increased 5-year TVF rates. Nonrevascularized vessels with discordant FFR and CFR are associated with 5-year event rates that are equivalent to those of vessels that undergo revascularization, whereas vessels with combined low FFR and CFR exhibit event rates that are significantly higher than after revascularization. (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry [ILIAS Registry]; NCT04485234)., Competing Interests: Funding Support and Author Disclosures Dr van de Hoef has received speaker fees and institutional research grants from Abbott and Philips. Dr J.M. Lee has received research grants from Abbott and Philips. Dr Echavarria-Pinto has received speaker fees from Abbott and Philips. Dr van Royen has received speaker fees and institutional research grants from Abbott and Philips. Dr Escaned is a speaker and consultant for Abbott, Boston Scientific, and Philips; and has received personal fees from Philips, Boston Scientific, and Abbott/St. Jude Medical outside the submitted work. Dr Koo has received institutional research grants from Abbott Vascular and Philips Volcano. Dr Piek has received support as a consultant for Philips/Volcano; and has received institutional research grants from Philips. 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.)

Background and Aims: In this study, we investigated whether increased renin angiotensin aldosterone system (RAAS) activation and endothelin-1 levels are related to coronary artery calcium (CAC) score, total plaque volume (TPV), high risk plaque, hyperemic myocardial blood flow (MBF) and coronary microvascular dysfunction (CMD)., Methods: In a prospective, observational, cross-sectional cohort, renin as a marker for RAAS activation and endothelin-1 were measured in peripheral venous blood of 205 patients (64% men; age 58 ± 8.7 years) with suspected coronary artery disease (CAD) who underwent coronary computed tomography angiography (CCTA), [ 15 O]H 2 O positron emission tomography (PET) perfusion imaging and invasive fractional flow reserve (FFR) measurements. Patients were categorized into three groups based on FFR (≤0.80) and hyperemic MBF <2.3 ml/min/g: [1] obstructive CAD (n = 92), [2] CMD (n = 26) or [3] no or non-obstructive CAD (n = 85)., Results: After correction for baseline characteristics, including RAAS inhibiting therapy, renin associated positively with CAC score and TPV, but not with hyperemic MBF (p < 0.01; p = 0.02 and p = 0.23). Patients with high risk plaque displayed higher levels of renin (mean logarithmic renin 1.25 ± 0.43 vs. 1.12 ± 0.35 pg/ml; p = 0.04), but not endothelin-1. Compared to no or non-obstructive CAD patients, renin was significantly elevated in obstructive CAD patients but not in CMD patients (mean logarithmic renin 1.06 ± 0.34 vs. 1.23 ± 0.36; p < 0.01 and 1.06 ± 0.34 vs. 1.16 ± 0.41 pg/ml; p = 0.65). Endothelin-1 did not differ between the three patient groups., Conclusions: Our report provides evidence that RAAS activity measured by renin concentration is elevated in patients with coronary atherosclerosis and high risk plaque but not in patients with CMD, whereas endothelin-1 is not related to either., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To determine whether coronary computed tomography angiography (CCTA) scanning, scan preparation, contrast, and patient based parameters influence the diagnostic performance of an artificial intelligence (AI) based analysis software for identifying coronary lesions with ≥50% stenosis., Background: CCTA is a noninvasive imaging modality that provides diagnostic and prognostic benefit to patients with coronary artery disease (CAD). The use of AI enabled quantitative CCTA (AI-QCT) analysis software enhances our diagnostic and prognostic ability, however, it is currently unclear whether software performance is influenced by CCTA scanning parameters., Methods: CCTA and quantitative coronary CT (QCT) data from 303 stable patients (64 ± 10 years, 71% male) from the derivation arm of the CREDENCE Trial were retrospectively analyzed using an FDA-cleared cloud-based software that performs AI-enabled coronary segmentation, lumen and vessel wall determination, plaque quantification and characterization, and stenosis determination. The algorithm's diagnostic performance measures (sensitivity, specificity, and accuracy) for detecting coronary lesions of ≥50% stenosis were determined based on concordance with QCA measurements and subsequently compared across scanning parameters (including scanner vendor, model, single vs dual source, tube voltage, dose length product, gating technique, timing method), scan preparation technique (use of beta blocker, use and dose of nitroglycerin), contrast administration parameters (contrast type, infusion rate, iodine concentration, contrast volume) and patient parameters (heart rate and BMI)., Results: Within the patient cohort, 13% demonstrated ≥50% stenosis in 3 vessel territories, 21% in 2 vessel territories, 35% in 1 vessel territory while 32% had <50% stenosis in all vessel territories evaluated by QCA. Average AI analysis time was 10.3 ± 2.7 min. On a per vessel basis, there were significant differences only in sensitivity for ≥50% stenosis based on contrast type (iso-osmolar 70.0% vs non isoosmolar 92.1% p = 0.0345) and iodine concentration (<350 mg/ml 70.0%, 350-369 mg/ml 90.0%, 370-400 mg/ml 90.0%, >400 mg/ml 95.2%; p = 0.0287) in the context of low injection flow rates. On a per patient basis there were no significant differences in AI diagnostic performance measures across all measured scanner, scan technique, patient preparation, contrast, and individual patient parameters., Conclusion: The diagnostic performance of AI-QCT analysis software for detecting moderate to high grade stenosis are unaffected by commonly used CCTA scanning parameters and across a range of common scanning, scanner, contrast and patient variables., Condensed Abstract: An AI-enabled quantitative CCTA (AI-QCT) analysis software has been validated as an effective tool for the identification, quantification and characterization of coronary plaque and stenosis through comparison to blinded expert readers and quantitative coronary angiography. However, it is unclear whether CCTA screening parameters related to scanner parameters, scan technique, contrast volume and rate, radiation dose, or a patient's BMI or heart rate at time of scan affect the software's diagnostic measures for detection of moderate to high grade stenosis. AI performance measures were unaffected across a broad range of commonly encountered scanner, patient preparation, scan technique, intravenous contrast and patient parameters., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study was designed to assess the prognostic value of pericoronary adipose tissue computed tomography attenuation (PCATa) beyond quantitative coronary computed tomography angiography (CCTA)-derived plaque volume and positron emission tomography (PET) determined ischemia., Background: Inflammation plays a crucial role in atherosclerosis. PCATa has been shown to assess coronary-specific inflammation and is of prognostic value in patients with suspected coronary artery disease (CAD)., Methods: A total of 539 patients who underwent CCTA and [ 15 O]H 2 O PET perfusion imaging because of suspected CAD were included. Imaging assessment included coronary artery calcium score (CACS), presence of obstructive CAD (≥50% stenosis) and high-risk plaques (HRPs), total plaque volume (TPV), calcified/noncalcified plaque volume (CPV/NCPV), PCATa, and myocardial ischemia. The endpoint was a composite of death and nonfatal myocardial infarction. Prognostic thresholds were determined for quantitative CCTA variables., Results: During a median follow-up of 5.0 (interquartile range: 4.7 to 5.0) years, 33 events occurred. CACS >59 Agatston units, obstructive CAD, HRPs, TPV >220 mm 3 , CPV >110 mm 3 , NCPV >85 mm 3 , and myocardial ischemia were associated with shorter time to the endpoint with unadjusted hazard ratios (HRs) of 4.17 (95% confidence interval [CI]: 1.80 to 9.64), 4.88 (95% CI: 1.88 to 12.65), 3.41 (95% CI: 1.72 to 6.75), 7.91 (95% CI: 3.05 to 20.49), 5.82 (95% CI: 2.40 to 14.10), 8.07 (95% CI: 3.33 to 19.55), and 4.25 (95% CI: 1.84 to 9.78), respectively (p < 0.05 for all). Right coronary artery (RCA) PCATa above scanner specific thresholds was associated with worse prognosis (unadjusted HR: 2.84; 95% CI: 1.44 to 5.63; p = 0.003), whereas left anterior descending artery and circumflex artery PCATa were not related to outcome. RCA PCATa above scanner specific thresholds retained is prognostic value adjusted for imaging variables and clinical characteristics associated with the endpoint (adjusted HR: 2.45; 95% CI: 1.23 to 4.93; p = 0.011)., Conclusions: Parameters associated with atherosclerotic burden and ischemia were more strongly associated with outcome than RCA PCATa. Nonetheless, RCA PCATa was of prognostic value beyond clinical characteristics, CACS, obstructive CAD, HRPs, TPV, CPV, NCPV, and ischemia., Competing Interests: Funding Support and Author Disclosures Dr. Knaapen has received research grants from HeartFlow Inc. Dr. Min is employee and has an equity interest in Cleerly, Inc.; and serves on the advisory board of Arineta. Dr. Leipsic has received research grants from GE Healthcare and Edwards Lifesciences; and serves as consultant for HeartFlow Inc. and Circle CVI. Drs. Freiman, Goshen, Heitel, and Langzam are employees of Philips Healthcare. 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.)

Objectives: The authors sought to evaluate the impact of ischemic burden reduction after chronic total occlusion (CTO) percutaneous coronary intervention (PCI) on long-term prognosis and cardiac symptom relief., Background: The clinical benefit of CTO PCI is questioned., Methods: In a high-volume CTO PCI center, 212 patients prospectively underwent quantitative [ 15 O]H 2 O positron emission tomography perfusion imaging before and three months after successful CTO PCI between 2013-2019. Perfusion defects (PD) (in segments) and hyperemic myocardial blood flow (hMBF) (in ml · min -1 · g -1 ) allocated to CTO areas were related to prognostic outcomes using unadjusted (Kaplan-Meier curves, log-rank test) and risk-adjusted (multivariable Cox regression) analyses. The prognostic endpoint was a composite of all-cause death and nonfatal myocardial infarction., Results: After a median [interquartile range] of 2.8 years [1.8 to 4.3 years], event-free survival was superior in patients with ≥3 versus <3 segment PD reduction (p < 0.01; risk-adjusted p = 0.04; hazard ratio [HR]: 0.34 [95% confidence interval (CI): 0.13 to 0.93]) and with hMBF increase above (Δ≥1.11 ml · min -1 · g -1 ) versus below the population median (p < 0.01; risk-adjusted p < 0.01; HR: 0.16 [95% CI: 0.05 to 0.54]) after CTO PCI. Furthermore, event-free survival was superior in patients without versus any residual PD (p < 0.01; risk-adjusted p = 0.02; HR: 0.22 [95% CI: 0.06 to 0.76]) or with a residual hMBF level >2.3 versus ≤2.3 ml · min -1 · g -1 (p < 0.01; risk-adjusted p = 0.03; HR: 0.25 [95% CI: 0.07 to 0.91]) at follow-up positron emission tomography. Patients with residual hMBF >2.3 ml · min -1 · g -1 were more frequently free of angina and dyspnea on exertion at long-term follow-up (p = 0.04)., Conclusions: Patients with extensive ischemic burden reduction and no residual ischemia after CTO PCI had lower rates of all-cause death and nonfatal myocardial infarction. Long-term cardiac symptom relief was associated with normalization of hMBF levels after CTO PCI., Competing Interests: Funding Support and Author Disclosures The 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.)

Objectives: The aim of this study was to investigate whether transradial (TR) percutaneous coronary intervention (PCI) is superior to transfemoral (TF) PCI in complex coronary lesions with large-bore guiding catheters with respect to clinically relevant access site-related bleeding or vascular complications., Background: The femoral artery is currently the most applied access site for PCI of complex coronary lesions, especially when large-bore guiding catheters are required. With downsizing of TR equipment, TR PCI may be increasingly applied in these patients and might be a safer alternative compared with the TF approach., Methods: An international prospective multicenter trial was conducted, randomizing 388 patients with planned PCI for complex coronary lesions, including chronic total occlusion, left main, heavy calcification, or complex bifurcation, to either 7-F TR access (TRA) or 7-F TF access (TFA). The primary endpoint was defined as access site-related clinically significant bleeding or vascular complications requiring intervention at discharge. The secondary endpoint was procedural success., Results: The primary endpoint event rate was 3.6% for TRA and 19.1% for TFA (p < 0.001). The crossover rate from radial to femoral access was 3.6% and from femoral to radial access was 2.6% (p = 0.558). The procedural success rate was 89.2% for TFA and 86.0% for TRA (p = 0.285). There was no difference between TFA and TRA with regard to procedural duration, contrast volume, or radiation dose., Conclusions: In patients undergoing PCI of complex coronary lesions with large-bore access, radial compared with femoral access is associated with a significant reduction in clinically relevant access-site bleeding or vascular complications, without affecting procedural success. (Complex Large-Bore Radial Percutaneous Coronary Intervention [PCI] Trial [Color]; NCT03846752)., Competing Interests: Funding Support and Author Disclosures Terumo EMEA supported this investigator-initiated study with an unrestricted grant. Drs. van Leeuwen, Aminian, Dens, and Iglesias are consultants for Terumo. Drs. Iglesias and Schmitz have received honoraria and speaker fees from Terumo. 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.)

Objectives: The authors sought to examine the outcomes of percutaneous coronary intervention (PCI) for in-stent restenosis (ISR) chronic total occlusions (CTOs)., Background: The outcomes of PCI for ISR CTOs have received limited study., Methods: The authors examined the clinical and angiographic characteristics and procedural outcomes of 11,961 CTO PCIs performed in 11,728 patients at 107 centers in Europe, North America, Latin America, and Asia between 2012 and 2020, pooling patient-level data from 4 multicenter registries. In-hospital major adverse cardiovascular events (MACE) included death, myocardial infarction, stroke, and tamponade. Long-term MACE were defined as the composite of all-cause death, myocardial infarction, and target vessel revascularization., Results: ISR represented 15% of the CTOs (n = 1,755). Patients with ISR CTOs had higher prevalence of diabetes (44% vs. 38%; p < 0.0001) and prior coronary artery bypass graft surgery (27% vs. 24%; p = 0.03). Mean J-CTO (Multicenter CTO Registry in Japan) score was 2.32 ± 1.27 in the ISR group and 2.22 ± 1.27 in the de novo group (p = 0.01). Technical (85% vs. 85%; p = 0.75) and procedural (84% vs. 84%; p = 0.82) success was similar for ISR and de novo CTOs, as was the incidence of in-hospital MACE (1.7% vs. 2.2%; p = 0.25). Antegrade wiring was the most common successful strategy, in 70% of ISR and 60% of de novo CTOs, followed by retrograde crossing (16% vs. 23%) and antegrade dissection and re-entry (15% vs. 16%; p < 0.0001). At 12 months, patients with ISR CTOs had a higher incidence of MACE (hazard ratio: 1.31; 95% confidence interval: 1.01 to 1.70; p = 0.04)., Conclusions: ISR CTOs represent 15% of all CTO PCIs and can be recanalized with similar success and in-hospital MACE as de novo CTOs., Competing Interests: Funding Support and Author Disclosures This work was supported by an Abbott Northwestern Hospital Foundation Innovation Grant and a gift from the Joseph F. and Mary M. Fleischhacker Foundation. Dr. Rafeh is a proctor for and has received speaker honoraria from Boston Scientific and Abbott Vascular. Dr. Alaswad has received consulting fees from Terumo and Boston Scientific; and is a consultant (no financial compensation) for Abbott Laboratories. Dr. Avran has received proctoring income from Boston Scientific, Abbott Vascular, Terumo, Biotronik, and Biosensors. Dr. El-Guindy has received consulting, speaker, and proctoring honoraria from Medtronic, Boston Scientific, Asahi Intecc, Terumo, and Abbott Vascular. Dr. Jaffer is a consultant for Abbott Vascular, Boston Scientific, and Siemens; and has received research grants from Canon, Siemens, and the National Institutes of Health. Dr. Karmpaliotis has received speaker honoraria from Abbott Vascular, Boston Scientific, Medtronic, and Vascular Solutions. Dr. Khatri has received honoraria from Asahi Intecc; and is a speaker and proctor for Abbott Vascular. Dr. Knaapen has received grant support from HeartFlow. Dr. Rinfret has received consulting honoraria from Boston Scientific, Teleflex, Abbott Vascular, Abiomed, and SoundBite Medical. Dr. Walsh is a consultant to Abbott, Boston, Medtronic, and Teleflex. Dr. Brilakis has received consulting and speaker honoraria from Abbott Vascular, the American Heart Association (associate editor, Circulation), Amgen, Biotronik, Boston Scientific, the Cardiovascular Innovations Foundation (board of directors), ControlRad, CSI, Ebix, Elsevier, GE Healthcare, InfraRedx, Medtronic, Siemens, and Teleflex; has received research support from Regeneron and Siemens; is an owner of Hippocrates; and is a shareholder in MHI Ventures. Dr. Azzalini has received honoraria from Abbott Vascular, Guerbet, Terumo, and Sahajanand Medical Technologies; and has received research support from ACIST Medical Systems, Guerbet, and Terumo. 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 and Aims: Both plasma low-density lipoprotein (LDL) cholesterol levels and risk for premature cardiovascular disease are extremely elevated in patients with homozygous familial hypercholesterolemia (HoFH), despite the use of multiple cholesterol lowering treatments. Given its inborn nature, atherosclerotic plaques are commonly observed in young HoFH patients. Whether intensive lipid lowering strategies result in plaque regression in adolescent patients is unknown., Methods: Two HoFH patients with null/null LDLR variants, who participated in the R1500-CL-1629 randomized clinical trial (NCT03399786) evaluating the LDL cholesterol lowering effect of evinacumab (a human antibody directed against ANGPTL3; 15 mg/kg intravenously once monthly), were included in this study. Patients underwent coronary computed tomography angiography (CCTA) before randomization and after 6 months of treatment., Results: Both patient A (aged 12) and B (aged 16) were treated with a statin, ezetimibe and weekly apheresis. Evinacumab decreased mean pre-apheresis LDL cholesterol levels from 5.51 ± 0.75 and 5.07 ± 1.45 mmol/l to 2.48 ± 0.31 and 2.20 ± 0.13 mmol/l and post-apheresis LDL levels from 1.45 ± 0.26 and 1.37 ± 39 mmol/l to 0.80 ± 0.16 and 0.78 ± 0.13 mmol/l in patient A and B, respectively. Total plaque volumes were reduced by 76% and 85% after 6 months of evinacumab treatment in patient A and B, respectively., Conclusions: We describe two severely affected young HoFH patients in whom profound plaque reduction was observed with CCTA after intensive lipid lowering therapy with statins, ezetimibe, LDL apheresis, and evinacumab. This shows that atherosclerotic plaques possess the ability to regress at young age, even in HoFH patients., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: This study aimed to investigate the diagnostic value of comprehensive on-site coronary computed tomography angiography (CCTA) using stenosis and plaque measures and subtended myocardial mass (V sub ) for fractional flow reserve (FFR) defined hemodynamically obstructive coronary artery disease (CAD). Additionally, the incremental diagnostic value of off-site CT-derived FFR (FFR CT ) was assessed., Methods: Prospectively enrolled patients underwent CCTA followed by invasive FFR interrogation of all major coronary arteries. Vessels with ≥30% stenosis were included for analysis. On-site CCTA assessment included qualitative and quantitative stenosis (visual grading and minimal lumen area, MLA) and plaque measures (characteristics and volumes), and V sub . Diagnostic value of comprehensive on-site CCTA assessment was tested by comparing area under the curves (AUC). In vessels with available FFR CT , the incremental value of off-site FFR CT was tested., Results: In 236 vessels (132 patients), MLA, positive remodeling, non-calcified plaque volume, and V sub were independent on-site CCTA predictors for hemodynamically obstructive CAD (p < 0.05 for all). V sub /MLA 2 outperformed all these on-site CCTA parameters (AUC = 0.85) and V sub was incremental to all other CCTA predictors (p = 0.02). In subgroup analysis (n = 194 vessels), diagnostic performance of FFR CT and V sub /MLA 2 was similar (AUC 0.89 and 0.85 respectively, p = 0.25). Furthermore, diagnostic performance significantly albeit minimally increased when FFR CT was added to on-site CCTA assessment (ΔAUC = 0.03, p = 0.02)., Conclusions: In comprehensive on-site CCTA assessment, V sub /MLA2 demonstrated greatest diagnostic value for hemodynamically obstructive CAD and V sub was incremental to all evaluated CCTA indices. Additionally, adding FFR CT only minimally increased diagnostic performance, demonstrating that on-site CCTA assessment is a reasonable alternative to FFR CT ., Competing Interests: Declaration of competing interest Dr. Min serves as a consultant to Abbott Vascular, serves on the scientific advisory board of Arineta, and has an equity interest in MDDX. Dr. Leipsic has received research grants from GE Healthcare; and serves as a consultant and holds stock options in Circle CVI and HeartFlow. Dr. Taylor has an equity interest in and is an employee of HeartFlow. Dr. Knaapen has received unrestricted research grants from HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 [The Author/The Authors]. Published by Elsevier Inc. All rights reserved.)

Objectives: This study compared the performance of the quantitative flow ratio (QFR) with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) myocardial perfusion imaging (MPI) for the diagnosis of fractional flow reserve (FFR)-defined coronary artery disease (CAD)., Background: QFR estimates FFR solely based on cine contrast images acquired during invasive coronary angiography (ICA). Head-to-head studies comparing QFR with noninvasive MPI are lacking., Methods: A total of 208 (624 vessels) patients underwent technetium- 99 m tetrofosmin SPECT and [ 15 O]H 2 O PET imaging before ICA in conjunction with FFR measurements. ICA was obtained without using a dedicated QFR acquisition protocol, and QFR computation was attempted in all vessels interrogated by FFR (552 vessels)., Results: QFR computation succeeded in 286 (52%) vessels. QFR correlated well with invasive FFR overall (R = 0.79; p < 0.001) and in the subset of vessels with an intermediate (30% to 90%) diameter stenosis (R = 0.76; p < 0.001). Overall, per-vessel analysis demonstrated QFR to exhibit a superior sensitivity (70%) in comparison with SPECT (29%; p < 0.001), whereas it was similar to PET (75%; p = 1.000). Specificity of QFR (93%) was higher than PET (79%; p < 0.001) and not different from SPECT (96%; p = 1.000). As such, the accuracy of QFR (88%) was superior to both SPECT (82%; p = 0.010) and PET (78%; p = 0.004). Lastly, the area under the receiver operating characteristics curve of QFR, in the overall sample (0.94) and among vessels with an intermediate lesion (0.90) was higher than SPECT (0.63 and 0.61; p < 0.001 for both) and PET (0.82; p < 0.001 and 0.77; p = 0.002), respectively., Conclusions: In this head-to-head comparative study, QFR exhibited a higher diagnostic value for detecting FFR-defined significant CAD compared with perfusion imaging by SPECT or PET., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study presents a head-to-head comparison of the value of cardiac magnetic resonance (CMR)-derived left-ventricular (LV) function and scar burden and positron emission tomography (PET)-derived perfusion and innervation in predicting ventricular arrhythmias (VAs)., Background: Improved risk stratification of VA is important to identify patients who should benefit of prophylactic implantable cardioverter-defibrillator (ICD) implantation. Perfusion abnormalities, sympathetic denervation, and scar burden have all been linked to VA, although comparative studies are lacking., Methods: Seventy-four patients with ischemic cardiomyopathy and left-ventricular ejection fraction (LVEF) ≤35%, referred for primary prevention ICD placement were enrolled prospectively. Late gadolinium-enhanced (LGE) CMR was performed to assess LV function and scar characteristics. [ 15 O]H 2 O and [ 11 C]hydroxyephedrine positron emission tomography (PET) were performed to quantify resting and hyperemic myocardial blood flow (MBF), coronary flow reserve (CFR), and sympathetic innervation. During follow-up of 5.4 ± 1.9 years, the occurrence of sustained VA, appropriate ICD therapy, and mortality were evaluated., Results: In total, 20 (26%) patients experienced VA. CMR and PET parameters showed considerable overlap between patients with VA and patients without VA, caused by substantial heterogeneity within groups. Univariable analyses showed that lower LVEF (hazard ratio [HR]: 0.92; p = 0.03), higher left-ventricular end-diastolic volume index (LVEDVi) (HR 1.02; p < 0.01), and larger scar border zone (HR 1.11; p = 0.03) were related to VA. Scar core size, resting MBF, hyperemic MBF, perfusion defect size, innervation defect size, and the innervation-perfusion mismatch were not found to be associated with VA., Conclusions: In patients with ischemic cardiomyopathy, lower LVEF, higher LVEDVi, and larger scar border zone were related to VA. PET-derived perfusion and sympathetic innervation, as well as CMR-derived scar core size were not associated with VA. These results suggest that improved prediction of VA by advanced imaging remains challenging for the individual patient., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Visually estimated angiographic V-RESOLVE score was developed as a simple and accurate prediction tool for side branch (SB) occlusion in patients undergoing coronary bifurcation intervention. Data on the use of coronary computed tomography angiography (coronary CTA) for guiding percutaneous coronary intervention in bifurcation lesions is scarce., Objectives: We aimed to validate the ability of quantitative CTA-derived RESOLVE score for predicting SB occlusion in coronary bifurcation intervention and to compare its predictive value with that of the angiography-based V-RESOLVE score., Methods: We included 363 patients with 400 bifurcation lesions. Angiographic V-RESOLVE score and CTA-derived RESOLVE score were calculated utilizing the weights from the QCA-based RESOLVE score. The scoring systems were divided into quartiles, and classified as the non-high-risk group and the high-risk group. Accuracy was assessed using areas under the receiver-operator characteristic curve (AUC). SB occlusion was defined as any decrease in Thrombolysis in Myocardial Infarction flow grade (including the absence of flow) in the SB after main vessel stenting., Results: In total, 28 SB occlusions (7%) occurred. CTA-derived RESOLVE and V-RESOLVE scores achieved comparable predictive accuracy (0.709 vs. 0.752, respectively, p = 0.531) for predicting SB occlusion, and the analysis of AUC for each constituent element of the scores did not show any significant difference between CTA and visual angiography. The total net reclassification index was -18.6% (p = 0.194), and there were no significant differences in the rates of SB occlusion in the non-high-risk group (4.9% vs. 3.8%, p = 0.510) and the high-risk group (13.8% vs. 18.6%, p = 0.384) between CTA-derived RESOLVE and V-RESOLVE scores., Conclusions: The quantitative CTA-derived RESOLVE score is an accurate and reliable alternative to the visually estimated angiographic V-RESOLVE score for prediction of SB occlusion in coronary bifurcation intervention., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03709836., Competing Interests: Declaration of competing interest Authors have no conflict of interest to declare., (Copyright © 2020 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Objectives: This study designed and evaluated an end-to-end deep learning solution for cardiac segmentation and quantification., Background: Segmentation of cardiac structures from coronary computed tomography angiography (CCTA) images is laborious. We designed an end-to-end deep-learning solution., Methods: Scans were obtained from multicenter registries of 166 patients who underwent clinically indicated CCTA. Left ventricular volume (LVV) and right ventricular volume (RVV), left atrial volume (LAV) and right atrial volume (RAV), and left ventricular myocardial mass (LVM) were manually annotated as ground truth. A U-Net-inspired, deep-learning model was trained, validated, and tested in a 70:20:10 split., Results: Mean age was 61.1 ± 8.4 years, and 49% were women. A combined overall median Dice score of 0.9246 (interquartile range: 0.8870 to 0.9475) was achieved. The median Dice scores for LVV, RVV, LAV, RAV, and LVM were 0.938 (interquartile range: 0.887 to 0.958), 0.927 (interquartile range: 0.916 to 0.946), 0.934 (interquartile range: 0.899 to 0.950), 0.915 (interquartile range: 0.890 to 0.920), and 0.920 (interquartile range: 0.811 to 0.944), respectively. Model prediction correlated and agreed well with manual annotation for LVV (r = 0.98), RVV (r = 0.97), LAV (r = 0.78), RAV (r = 0.97), and LVM (r = 0.94) (p < 0.05 for all). Mean difference and limits of agreement for LVV, RVV, LAV, RAV, and LVM were 1.20 ml (95% CI: -7.12 to 9.51), -0.78 ml (95% CI: -10.08 to 8.52), -3.75 ml (95% CI: -21.53 to 14.03), 0.97 ml (95% CI: -6.14 to 8.09), and 6.41 g (95% CI: -8.71 to 21.52), respectively., Conclusions: A deep-learning model rapidly segmented and quantified cardiac structures. This was done with high accuracy on a pixel level, with good agreement with manual annotation, facilitating its expansion into areas of research and clinical import., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Left atrial (LA) sphericity has been proposed as a more sensitive marker of atrial fibrillation (AF)-associated atrial remodeling compared to traditional markers such as LA size. However, mechanisms that underlie changes in LA sphericity are not fully understood and studies investigating the predictive value of LA sphericity for AF ablation outcome have yielded conflicting results. The present study aimed to assess correlates of LA sphericity and to compare LA sphericity in subjects with and without AF., Methods: Measures of LA size (LA diameter, LA volume, LA volume index), LA sphericity and thoracic anteroposterior diameter (APd) at the level of the LA were determined using computed tomography (CT) imaging data in 293 AF patients (62% paroxysmal AF) and 110 controls., Results: LA diameter (40.1 ± 6.8 mm vs. 35.2 ± 5.1 mm; p < 0.001), LA volume (116.0 ± 33.0 ml vs. 80.3 ± 22.6 ml; p < 0.001) and LA volume index (56.1 ± 15.3 ml/m 2 vs. 41.6 ± 11.1 ml/m 2 ; p < 0.001) were significantly larger in AF patients compared to controls, also after adjustment for covariates. LA sphericity did not differ between AF patients and controls (83.7 ± 2.9 vs. 83.9 ± 2.4; p = 0.642). Multivariable linear regression analysis demonstrated that LA diameter, LA volume, female sex, body length and thoracic APd were independently associated with LA sphericity., Conclusions: The present study suggests that thoracic constraints rather than the presence of AF determine LA sphericity, implying LA sphericity to be unsuitable as a marker of AF-related atrial remodeling., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The current substudy of the PACIFIC (Prospective Comparison of Cardiac PET/CT, SPECT/CT Perfusion Imaging and CT Coronary Angiography With Invasive Coronary Angiography) trial explores the impact of computed tomography (CT)-derived unfavorable plaque features on both hyperemic and non-hyperemic flow indices., Background: Next to lesion severity, plaque vulnerability as assessed using coronary CT angiography affects fractional flow reserve (FFR), which is associated with imminent acute coronary syndromes. Instantaneous wave-free ratio (iFR) has recently emerged as an alternative for FFR to interrogate coronary lesions for ischemia. It is, however, unknown whether vasodilator-free assessment with iFR is associated with plaque stability similarly as FFR., Methods: Of 120 patients (62% men, age 58.3 ± 8.6 years) with suspected coronary artery disease, 257 vessels were prospectively evaluated. Each patient underwent 256-slice coronary CT angiography to assess stenosis severity and plaque features (positive remodeling [PR], low attenuation plaque [LAP], spotty calcification [SC], and napkin ring sign [NRS]), as well as intracoronary pressure measurements (FFR, iFR, Pd/Pa, and pressure ratio during adenosine within the wave-free period [iFRa]). CT-derived plaque characteristics were related to these invasive pressure measurements., Results: Atherosclerotic plaques were present in 170 (66%) coronary arteries. On a per-vessel basis, luminal stenosis severity was significantly associated with impaired FFR, iFR, Pd/Pa, and iFRa. Multivariable analysis revealed that FFR and iFR were independently related to ≥70% stenosis (-0.10, p < 0.001 and -0.09, p = 0.003, respectively) and plaque volume (-0.02, p = 0.020 and -0.02, p = 0.030, respectively). Additionally, PR and SC were also independent predictors of an impaired FFR (-0.10, p < 0.001 and -0.07, p = 0.021, respectively), but adverse plaque characteristics were not independently related to the vasodilator-free iFR., Conclusions: CT-derived vulnerable plaque characteristics are independently associated with hyperemic flow indices as assessed with FFR and iFRa, but not with non-hyperemic indices such as iFR and Pd/Pa. These findings suggest that the effects of hyperemia on pressure-derived indices might depend not only on hemodynamic stenosis severity but also on plaque characteristics., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of the present study was to determine the effect of a delayed versus an immediate invasive approach on final infarct size and clinical outcome up to 1 year., Background: Up to 24% of patients with acute coronary syndromes present with ST-segment elevation myocardial infarction (STEMI) but show complete resolution of ST-segment elevation and symptoms before revascularization. Current guidelines do not clearly state whether these patients with transient STEMI should be treated with a STEMI-like or non-ST-segment elevation acute coronary syndrome-like intervention strategy., Methods: In this multicenter trial, 142 patients with transient STEMI were randomized 1:1 to either delayed or immediate coronary intervention. Cardiac magnetic resonance imaging was performed at 4 days and at 4-month follow-up to assess infarct size and myocardial function. Clinical follow-up was performed at 4 and 12 months., Results: In the delayed (22.7 h) and the immediate (0.4 h) invasive groups, final infarct size as a percentage of the left ventricle was very small (0.4% [interquartile range: 0.0% to 2.5%] vs. 0.4% [interquartile range: 0.0% to 3.5%]; p = 0.79), and left ventricular function was good (mean ejection fraction 59.3 ± 6.5% vs. 59.9 ± 5.4%; p = 0.63). In addition, the overall occurrence of major adverse cardiac events, consisting of death, recurrent infarction, and target lesion revascularization, up to 1 year was low and not different between both groups (5.7% vs. 4.4%, respectively; p = 1.00)., Conclusions: At follow-up, patients with transient STEMI have limited infarction and well-preserved myocardial function in general, and delayed or immediate revascularization has no effect on functional outcome and clinical events up to 1 year., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to assess the presence and morphological features of coronary plaques on optical coherence tomography (OCT) as the causes of myocardial infarction with nonobstructive coronary arteries (MINOCA)., Background: Although coronary atherosclerosis has been postulated as a potential mechanism of MINOCA, the interaction between disrupted coronary plaques and myocardial injury remains unknown., Methods: In a prospective study, consecutive patients with MI but without significant coronary stenosis (≥50%) at angiography underwent OCT and cardiac magnetic resonance (CMR) with late gadolinium-enhancement (LGE). The infarct-related artery (IRA) was identified by localization of ischemic-type LGE., Results: Thirty-eight MINOCA patients (mean age 62 ± 13 years, 55% female, 39% with ST-segment elevation) were enrolled. Maximal diameter stenosis was 35% by angiography, and 5 patients (13%) had normal angiogram results. Plaque disruption and coronary thrombus were observed in 9 patients (24%) and 7 patients (18%), respectively. Sixteen of 31 patients (52%) undergoing CMR showed LGE. Ischemic-type LGE was present in 7 patients (23%) and was more common in patients with than without plaque disruption (50% vs. 13%, respectively; p = 0.053) and coronary thrombus (67% vs. 12%, respectively; p = 0.014). In the per-lesion analysis, the IRA showed significantly more plaque disruption (40% vs. 6%; p = 0.02), thrombus (50% vs. 4%; p = 0.014), and thin-cap fibroatheroma (70% vs. 30%; p = 0.03) than the non-IRA., Conclusions: Plaque disruption and thrombus are not uncommon in MI without obstructive coronary stenoses at angiography and may be associated with the presence and location of ischemic-type myocardial injury on CMR. OCT may be valuable in identifying atherosclerotic etiology in individuals with MINOCA. (Optical Coherence Tomography in Patients With Acute Myocardial Infarction and Nonobstructive Coronary Artery Disease [SOFT-MI]; NCT02783963)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study developed a neural network to perform automated pressure waveform analysis and allow real-time accurate identification of damping., Background: Damping of aortic pressure during coronary angiography must be identified to avoid serious complications and make accurate coronary physiology measurements. There are currently no automated methods to do this, and so identification of damping requires constant monitoring, which is prone to human error., Methods: The neural network was trained and tested versus core laboratory expert opinions derived from 2 separate datasets. A total of 5,709 aortic pressure waveforms of individual heart beats were extracted and classified. The study developed a recurrent convolutional neural network to classify beats as either normal, showing damping, or artifactual. Accuracies were reported using the opinions of 2 independent core laboratories., Results: The neural network was 99.4% accurate (95% confidence interval: 98.8% to 99.6%) at classifying beats from the testing dataset when judged against the opinions of the internal core laboratory. It was 98.7% accurate (95% confidence interval: 98.0% to 99.2%) when judged against the opinions of an external core laboratory not involved in neural network training. The neural network was 100% sensitive, with no beats classified as damped misclassified, with a specificity of 99.8%. The positive predictive and negative predictive values were 98.1% and 99.5%. The 2 core laboratories agreed more closely with the neural network than with each other., Conclusions: Arterial waveform analysis using neural networks allows rapid and accurate identification of damping. This demonstrates how machine learning can assist with patient safety and the quality control of procedures., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess the 2-year clinical outcomes of the Firehawk stent (Shanghai MicroPort Medical Group, Shanghai, China), a novel abluminal groove-filled biodegradable-polymer sirolimus-eluting coronary stent, compared with XIENCE (Abbott Vascular, Santa Clara, California), a durable-polymer everolimus-eluting coronary stent., Background: The long-term outcomes of the Firehawk stent have not been evaluated beyond 1 year in a randomized all-comers clinical trial., Methods: The TARGET All Comers study is a prospective, multicenter, all-comers, randomized, noninferiority trial conducted in Europe. A total of 1,653 patients were randomly assigned to undergo implantation of either the Firehawk or the XIENCE stent. The primary endpoint was target lesion failure, a composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization., Results: At 2-year follow-up, the incidence of target lesion failure was 8.7% in the Firehawk group versus 8.6% in the XIENCE group (p = 0.92). The event rates of individual components of the primary endpoint were comparable for the 2 groups. Landmark analyses between 1- and 2-year follow-up revealed no statistically significant difference of TLF for the Firehawk versus the XIENCE stent. Beyond 1 year, very late definite or probable stent thrombosis occurred in 3 patients (0.4%) in the Firehawk group and in 7 patients (0.9%) in the XIENCE group (p = 0.34)., Conclusions: The 2-year follow-up of the TARGET All Comers study confirms comparable safety and efficacy profiles of the Firehawk and XIENCE stents., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Despite decades of research and major innovations in technology, cardiovascular disease remains the leading cause of death globally. Our understanding of major cardiovascular events and their prevention is centred around the atherosclerotic plaque and the processes that ultimately lead to acute plaque rupture. Recent advances in hybrid imaging technology allow the combination of high spatial resolution and anatomical detail with molecular assessments of disease activity. This provides the ability to identify vulnerable plaque characteristics and differentiate active and quiescent disease, with the potential to improve patient risk stratification. Combined positron emission tomography and computed tomography is the prototypical non-invasive hybrid imaging technique for coronary artery plaque assessment. In this review we discuss the current state of play in the field of hybrid coronary atherosclerosis imaging., (Copyright © 2019 [The Author/The Authors]. Published by Elsevier Inc. All rights reserved.)