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ObjectivesThe aim of this study was to describe the potential of 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) to identify graft vasculopathy and to investigate the influence of coronary artery bypass graft (CABG) surgery on native coronary artery disease activity and progression.BackgroundAs well as developing graft vasculopathy, CABGs have been proposed to accelerate native coronary atherosclerosis.MethodsPatients with established coronary artery disease underwent baseline 18F-NaF PET, coronary artery calcium scoring, coronary computed tomographic angiography, and 1-year repeat coronary artery calcium scoring. Whole-vessel coronary microcalcification activity (CMA) on 18F-NaF PET and change in calcium scores were quantified in patients with and without CABG surgery.ResultsAmong 293 participants (mean age 65 ± 9 years, 84% men), 48 (16%) underwent CABG surgery 2.7 years [IQR: 1.4-10.4 years] previously. Although all arterial and the majority (120 of 128 [94%]) of vein grafts showed no 18F-NaF uptake, 8 saphenous vein grafts in 7 subjects had detectable CMA. Bypassed native coronary arteries had 3 times higher CMA values (2.1 [IQR: 0.4-7.5] vs 0.6 [IQR: 0-2.7]; P < 0.001) and greater progression of 1-year calcium scores (118 Agatston unit [IQR: 48-194 Agatston unit] vs 69 [IQR: 21-142 Agatston unit]; P = 0.01) compared with patients who had not undergone CABG, an effect confined largely to native coronary plaques proximal to the graft anastomosis. In sensitivity analysis, bypassed native coronary arteries had higher CMA (2.0 [IQR: 0.4-7.5] vs 0.8 [IQR: 0.3-3.2]; P < 0.001) and faster disease progression (24% [IQR: 16%-43%] vs 8% [IQR: 0%-24%]; P = 0.002) than matched patients (n = 48) with comparable burdens of coronary artery disease and cardiovascular comorbidities in the absence of bypass grafting.ConclusionsNative coronary arteries that have been bypassed demonstrate increased disease activity and more rapid disease progression than nonbypassed arteries, an observation that appears independent of baseline atherosclerotic plaque burden. Microcalcification activity is not a dominant feature of graft vasculopathy.

ObjectivesThe aim of the current study was to explore the impact of plaque calcification in terms of absolute calcified plaque volume (CPV) and in the context of its percentage of the total plaque volume at a lesion and patient level on the progression of coronary artery disease.BackgroundCoronary artery calcification is an established marker of risk of future cardiovascular events. Despite this, plaque calcification is also considered a marker of plaque stability, and it increases in response to medical therapy.MethodsThis analysis included 925 patients with 2,568 lesions from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) registry, in which patients underwent clinically indicated serial coronary computed tomography angiography. Plaque calcification was examined by using CPV and percent CPV (PCPV), calculated as (CPV/plaque volume) × 100 at a per-plaque and per-patient level (summation of all individual plaques).ResultsCPV was strongly correlated with plaque volume (r = 0.780; p

ObjectivesThis study aimed to determine the rate and extent of plaque progression (PP), changes in plaque features, and clinical predictors of PP in patients with diabetes mellitus (DM).BackgroundThe natural history of coronary PP in patients with DM is not well established.MethodsA total of 1,602 patients (age 61.3 ± 9.0 years; 60.3% men; median scan interval 3.8 years) who underwent serial coronary computed tomography angiography over a period of at least 24 months were enrolled and analyzed from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) trial. Study endpoints were changes in plaque features in diabetics with PP and risk factors for PP by serial coronary computed tomography angiography between patients with and without DM. PP was defined if plaque volume at follow-up minus plaque volume at baseline was >0.ResultsDM was an independent risk factor for PP (84.6%; 276 of 326 patients with PP) in multivariate analysis (odds ratio [OR]: 1.526; 95% confidence interval [CI]: 1.100 to 2.118; p = 0.011). Independent risk factors for PP in patients with DM were male sex (OR: 1.485; 95% CI: 1.003 to 2.199; p = 0.048) and mean plaque burden at baseline ≥75% (OR: 3.121; 95% CI: 1.701 to 5.725; p ≤0.001). After propensity matching, percent changes in overall plaque volume (30.3 ± 36.9% in patients without DM and 36.0 ± 29.7% in those with DM; p = 0.032) and necrotic core volume (-7.0 ± 35.8% in patients without DM and 21.5 ± 90.5% in those with DM; p = 0.007) were significantly greater in those with DM. The frequency of spotty calcification, positive remodeling, and burden of low-attenuation plaque were significantly greater in patients with DM.ConclusionsPeople with DM experience greater PP, particularly significantly greater progression in adverse plaque, than those without DM. Male sex and mean plaque burden >75% at baseline were identified as independent risk factors for PP.

Competing Interests: Funding Support and Author Disclosures Funding was received from St Paul's Foundation and the Providence Health Care Research Institute (PHCRI) Early Career Research Initiative. Dr Akodad has received research funding from Medtronic, Biotronik, MUSE Explore, and Federation Française de Cardiologie. Dr Sathananthan has received speaker fees from Edwards Lifesciences and NVT Medical; and has reported consulting for Edwards Lifesciences, Boston Scientific, and Medtronic. Dr Tzimas has reported support from the Fondation Vaudoise de Cardiologie. Dr Gulsin has reported support from a British Heart Foundation Travel Fellowship (FS/TF/21/33008). Dr Blanke has reported consulting for Edwards Lifesciences, Boston Scientific, and Neovasc; and has provided computed tomography core laboratory services for Edwards Lifesciences, Medtronic, Neovasc, Boston Scientific, and Abbott, for which no direct compensation was received. Dr Sondergaard has received consultant fees and/or institutional research grants from Abbott, Boston Scientific, Edwards Lifesciences, Medtronic, and SMT. Dr Wood has reported consulting for and has received research funding from Edwards Lifesciences and Abbott. Dr Webb has reported consulting for Edwards Lifesciences. Dr Leipsic has reported support from a Canadian Research Chair in Advanced Cardiopulmonary Imaging; has reported consulting for MVRX, HeartFlow, and Circle Cardiovascular Imaging; and has provided computed tomography core laboratory services for Edwards Lifesciences, Medtronic, Neovasc, Boston Scientific, and Abbott, for which no direct compensation is received. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Acute aortic syndrome is associated with aortic medial degeneration. 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography (PET) detects microscopic tissue calcification as a marker of disease activity., Objectives: In a proof-of-concept study, this investigation aimed to establish whether 18 F-NaF PET combined with computed tomography (CT) angiography could identify aortic medial disease activity in patients with acute aortic syndrome., Methods: Patients with aortic dissection or intramural hematomas and control subjects underwent 18 F-NaF PET/CT angiography of the aorta. Aortic 18 F-NaF uptake was measured at the most diseased segment, and the maximum value was corrected for background blood pool activity (maximum tissue-to-background ratio [TBR max ]). Radiotracer uptake was compared with change in aortic size and major adverse aortic events (aortic rupture, aorta-related death, or aortic repair) over 45 ± 13 months., Results: Aortic 18 F-NaF uptake co-localized with histologically defined regions of microcalcification and elastin disruption. Compared with control subjects, patients with acute aortic syndrome had increased 18 F-NaF uptake (TBR max : 1.36 ± 0.39 [n = 20] vs 2.02 ± 0.42 [n = 47] respectively; P < 0.001) with enhanced uptake at the site of intimal disruption (+27.5%; P < 0.001). 18 F-NaF uptake in the false lumen was associated with aortic growth (+7.1 mm/year; P = 0.011), and uptake in the outer aortic wall was associated with major adverse aortic events (HR: 8.5 [95% CI: 1.4-50.4]; P = 0.019)., Conclusions: In patients with acute aortic syndrome, 18 F-NaF uptake was enhanced at sites of disease activity and was associated with aortic growth and clinical events. 18 F-NaF PET/CT holds promise as a noninvasive marker of disease severity and future risk in patients with acute aortic syndrome. ( 18 F Sodium Fluoride PET/CT in Acute Aortic Syndrome [FAASt]; NCT03647566)., Competing Interests: Funding Support and Author Disclosure All funding support is from the United Kingdom. Mr Syed and Drs Fletcher, Dweck, Shah, and Tavares, Mr Kaczynki, and Dr Newby were supported by the British Heart Foundation (FS/18/31/33676, FS/19/15/34155, FS/11/014, FS/14/78/31020, CH/09/002, RG/16/10/32375, RE/18/5/34216). Dr Dweck has received the Sir Jules Thorn Award for Biomedical Research 2015 (15/JTA). Dr Newby has received a Wellcome Trust Senior Investigator Award (WT103782AIA). Dr van Beek has been supported by the Scottish Imaging Network—a Platform of Scientific Excellence (SINAPSE). Edinburgh Clinical Research Facility and Edinburgh Imaging Facility are supported by NHS Research Scotland. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

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

Background: Bioprosthetic valve thrombosis may have implications for valve function and durability., Objectives: Using a novel glycoprotein IIb/IIIa receptor radiotracer 18F-GP1, we investigated whether positron emission tomography (PET)-computed tomography (CT) could detect thrombus formation on bioprosthetic aortic valves., Methods: Ex vivo experiments were performed on human platelets and explanted bioprosthetic aortic valves. In a prospective cross-sectional study, patients with either bioprosthetic or normal native aortic valves underwent echocardiography, CT angiography, and 18F-GP1 PET-CT., Results: Flow cytometric analysis, histology, immunohistochemistry, and autoradiography demonstrated selective binding of 18F-GP1 to activated platelet glycoprotein IIb/IIIa receptors and thrombus adherent to prosthetic valves. In total, 75 participants were recruited: 53 with bioprosthetic valves (median time from implantation 37 months [IQR: 12-80 months]) and 22 with normal native aortic valves. Three participants had obstructive valve thrombosis, and a further 3 participants had asymptomatic hypoattenuated leaflet thickening on CT angiography. All bioprosthetic valves, but none of the native aortic valves, demonstrated focal 18F-GP1 uptake on the valve leaflets: median maximum target-to-background ratio 2.81 (IQR: 2.29-3.48) vs 1.43 (IQR: 1.28-1.53) (P < 0.001). Higher 18F-GP1 uptake was independently associated with duration of valve implantation and hypoattenuated leaflet thickening. All 3 participants with obstructive valve thrombosis were anticoagulated for 3 months, leading to resolution of their symptoms, improvement in mean valve gradients, and a reduction in 18F-GP1 uptake., Conclusions: Adherence of activated platelets is a common and sustained finding on bioprosthetic aortic valves. 18F-GP1 uptake is higher in the presence of thrombus, regresses with anticoagulation, and has potential use as an adjunctive clinical tool. (18F-GP1 PET-CT to Detect Bioprosthetic Aortic Valve Thrombosis; NCT04073875)., Competing Interests: Funding Support and Author Disclosures This work was funded by the British Heart Foundation, London, United Kingdom (RG/16/10/32375 and PG/19/40/34422). The Edinburgh Clinical Research Facilities and Edinburgh Imaging facility is supported by the National Health Service Research Scotland (NRS) through National Health Service Lothian Health Board. This work and Drs Bing, Tzolos, Williams, Dweck, and Newby are supported by the British Heart Foundation (PG/19/40/34422, FS/ICRF/20/26002, FS/CRTF/20/24086, FS/14/78/31020, CH/09/002, RG/16/10/32375, RE/18/5/34216, FS/SCRF/21/32010). Dr van Beek is supported by the Scottish Imaging Network. Dr Sellers is supported by fellowships from the Michael Smith Foundation for Health Research and the Canadian Institutes of Health Research. Drs Koglin and Stephens are employees of Life Molecular Imaging GmbH, who provided reagents for radiotracer production. Dr Leipsic is supported by a Canadian Research Chair in Advanced CardioPulmonary Imaging and the Jon DeHaan Award for Innovation in Cardiology; is a consultant for Edward Lifesciences; and provides computed tomography core laboratory services to Edwards Lifesciences, Medtronic, Neovasc, Aegis, and Tendyne, for which no direct compensation is received. Dr Williams is supported by The Chief Scientist Office of the Scottish Government Health and Social Care Directorates (PCL/17/04). Dr Newby is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). 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: This study investigated processes causing leaflet thickening and structural valve degeneration (SVD)., Background: Although transcatheter aortic valve replacement (TAVR) has changed the treatment of aortic stenosis, concerns remain regarding SVD, potentially related to valve thrombosis and thickening, based on studies using computed tomography (CT). Detailed histological analyses are provided to help attain insights into these processes., Methods: Explanted transcatheter heart valves (THVs) were evaluated for thrombosis, fibrosis, and calcification for quantification of leaflet thickness. Immunohistochemical and microscopy approaches were used to investigate SVD-associated mechanisms., Results: THVs (n = 23) were obtained from 22 patients (median 81 years of age; 50% male) from 0 to 2,583 days post TAVR. Maximal leaflet thickness increased relative to implant duration (ρ = 0.427; p = 0.027). THVs explanted after >2 years were thicker than those explanted after <2 years (p = 0.007). All THVs had adherent thrombus on both aortic and ventricular sides, which beyond 60 days was seen in combination with fibrosis and beyond 4 years had calcification. Early thrombus formation (<60 days) occurred despite rapid endothelialization with an abnormal hyperplastic phenotype. Fibrosis was observed in 6 patients on both the aortic and the ventricular THV surfaces, remodeled over time, and was associated with matrix metalloproteinase-1 expression. Five THVs showed overt calcification associated with adherent thrombus and fibrosis., Conclusions: There is a time-dependent degeneration of THVs consisting of thrombus formation, endothelial hyperplasia, fibrosis, tissue remodeling, proteinase expression, and calcification. Future investigation is needed to further understand these mechanisms contributing to leaflet thickening and SVD., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)