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Background: Carotid and femoral plaque burden is a recognized biomarker of cardiovascular disease risk. A new electronic-sweep 3-dimensional (3D)-matrix transducer method can improve the functionality and image quality of vascular ultrasound atherosclerosis imaging., Objectives: This study aimed to validate this method for plaque volume measurement in early and intermediate-advanced plaques in the carotid and femoral territories., Methods: Plaque volumes were measured ex vivo in pig carotid and femoral artery specimens by 3-dimensional vascular ultrasound (3DVUS) using a 3D-matrix (electronic-sweep) transducer and its associated 3D plaque quantification software, and were compared with gold-standard histology. To test the clinical feasibility and accuracy of the 3D-matrix transducer, an experiment was conducted in intermediate-high risk individuals with carotid and femoral atherosclerosis. The results were compared with those obtained using the previously validated mechanical-sweep 3D transducer and established 2-dimensional (2D)-based plaque quantification software., Results: In the ex vivo study, the authors assessed 19 atherosclerotic plaques (plaque volume, 0.76 µL-56.30 μL), finding strong agreement between measurements with the 3D-matrix transducer and the histological gold-standard (intraclass correlation coefficient [ICC]: 0.992; [95% CI: 0.978-0.997]). In the clinical analysis of 20 patients (mean age 74.6 ± 4.45 years; 40% men), the authors found 64 (36 carotid and 28 femoral) of 80 scanned territories with atherosclerosis (measured atherosclerotic volume, 10 μL-859 μL). There was strong agreement between measurements made from electronic-sweep and mechanical-sweep 3DVUS transducers (ICC: 0.997 [95% CI: 0.995-0.998]). Agreement was also high between plaque volumes estimated by the 2D and 3D plaque quantification software applications (ICC: 0.999 [95% CI: 0.998-0.999]). Analysis time was significantly shorter with the 3D plaque quantification software than with the 2D multislice approach with a mean time reduction of 46%., Conclusions: 3DVUS using new matrix transducer technology, together with improved 3D plaque quantification software, simplifies the accurate volume measurement of early (small) and intermediate-advanced plaques located in carotid and femoral arteries., Competing Interests: Funding Support and Author Disclosures This study was partially funded by grants from the Ministerio de Economia, Industria y Competividad (MEIC) with cofunding from the European Regional Development Fund (ERDF) (SAF2016-75580-R to Dr Bentzon) and (BES-2016-076633 to Dr Nogales). Research funding was also received from the Instituto de Salud Carlos III Spain (PIE16/00021 to Drs Bueno and Fuster). The CNIC is supported by the Ministerio de Ciencia, Innovacion y Universidades (MICINN) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (CEX2020-001041-S). This study forms part of a Master Research Agreement between the CNIC and Philips Healthcare. Drs Sánchez-González, Entrekin, and Collet-Billon are employees of Philips Healthcare. All other authors have reported that they have no relationships to disclose related to the contents of this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Atherosclerosis starts early in life and progresses silently for decades. Considering atherosclerosis as a "systemic disease" invites the use of noninvasive methodologies to detect disease in various regions before symptoms appear. The PESA-(Progression of Early Subclinical Atherosclerosis) CNIC-SANTANDER study is an ongoing prospective cohort study examining imaging, biological, and behavioral parameters associated with the presence and progression of early subclinical atherosclerosis. Between 2010 and 2014, PESA enrolled 4,184 asymptomatic middle-aged participants who undergo serial 3-yearly follow-up examinations including clinical interviews, lifestyle questionnaires, sampling, and noninvasive imaging assessment of multiterritorial subclinical atherosclerosis (carotids, iliofemorals, aorta, and coronaries). PESA tracks the trajectories of atherosclerosis and associated disorders from early stages to the transition to symptomatic phases. A joint venture between the CNIC and the Santander Bank, PESA is expected to run until at least 2029, and its significant contributions to date are presented in this review paper., Competing Interests: Funding Support and Author Disclosures The PESA study is funded by the CNIC and Santander Bank. The study has also received funding from the Carlos III Institute of Health (ISCIII, PI15/02019, PI17/00590, and PI20/00819) and the European Regional Development Fund. The CNIC is supported by the ISCIII, the MICIN, and the Pro CNIC Foundation. Dr Ibanez is the recipient of a European Research Council grant MATRIX (ERC-COG-2018-ID: 819775). Dr Andrés is supported by grant PID2019-108489RB-I00 from the Spanish Ministerio de Ciencia e Innovación (MICIN), with cofunding from the European Regional Development Fund/Fondo Europeo de Desarrollo Regional (ERDF/FEDER, “A way to build Europe”). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Background: The mechanisms underlying early atherosclerotic plaque formation are not completely understood. Moreover, plasma biomarkers of subclinical atherosclerosis are lacking., Objectives: The purpose of this study was to analyze the temporal and topologically resolved protein changes taking place in human aortas with early atherosclerosis to find new potential diagnostic and/or therapeutic targets., Methods: The protein composition of healthy aortas (media layer) or with early atheroma (fatty streak and fibrolipidic, media and intima layers) was analyzed by deep quantitative multiplexed proteomics. Further analysis was performed by Western blot, immunohistochemistry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. Plasma levels of complement C5 were analyzed in relation to the presence of generalized (>2 plaques) or incipient (0 to 2 plaques) subclinical atherosclerosis in 2 independent clinical cohorts (PESA [Progression of Early Subclinical Atherosclerosis] [n = 360] and NEFRONA [National Observatory of Atherosclerosis in Nephrology] [n = 394])., Results: Proteins involved in lipid transport, complement system, immunoglobulin superfamily, and hemostasis are increased in early plaques. Components from the complement activation pathway were predominantly increased in the intima of fibrolipidic plaques. Among them, increased C5 protein levels were further confirmed by Western blot, enzyme-linked immunosorbent assay and immunohistochemistry, and associated with in situ complement activation. Plasma C5 was significantly increased in individuals with generalized subclinical atherosclerosis in both PESA and NEFRONA cohorts, independently of risk factors. Moreover, in the PESA study, C5 plasma levels positively correlated with global plaque volume and coronary calcification., Conclusions: Activation of the complement system is a major alteration in early atherosclerotic plaques and is reflected by increased C5 plasma levels, which have promising value as a novel circulating biomarker of subclinical atherosclerosis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atherosclerosis is a chronic inflammatory disease, but data on arterial inflammation at early stages is limited., Objectives: The purpose of this study was to characterize vascular inflammation by hybrid 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI)., Methods: Carotid, aortic, and ilio-femoral 18 F-FDG PET/MRI was performed in 755 individuals (age 40 to 54 years; 83.7% men) with known plaques detected by 2-/3-dimensional vascular ultrasound and/or coronary calcification in the PESA (Progression of Early Subclinical Atherosclerosis) study. The authors evaluated the presence, distribution, and number of arterial inflammatory foci (increased 18 F-FDG uptake) and plaques with or without inflammation (coincident 18 F-FDG uptake)., Results: Arterial inflammation was present in 48.2% of individuals (24.4% femorals, 19.3% aorta, 15.8% carotids, and 9.3% iliacs) and plaques in 90.1% (73.9% femorals, 55.8% iliacs, and 53.1% carotids). 18 F-FDG arterial uptakes and plaques significantly increased with cardiovascular risk factors (p < 0.01). Coincident 18 F-FDG uptakes were present in 287 of 2,605 (11%) plaques, and most uptakes were detected in plaque-free arterial segments (459 of 746; 61.5%). Plaque burden, defined by plaque presence, number, and volume, was significantly higher in individuals with arterial inflammation than in those without (p < 0.01). The number of plaques and 18 F-FDG uptakes showed a positive albeit weak correlation (r = 0.25; p < 0.001)., Conclusions: Arterial inflammation is highly prevalent in middle-aged individuals with known subclinical atherosclerosis. Large-scale multiterritorial PET/MRI allows characterization of atherosclerosis-related arterial inflammation and demonstrates 18 F-FDG uptake in plaque-free arterial segments and, less frequently, within plaques. These findings suggest an arterial inflammatory state at early stages of atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Detection of subclinical atherosclerosis improves risk prediction beyond cardiovascular risk factors (CVRFs) and risk scores, but quantification of plaque burden may improve it further. Novel 3-dimensional vascular ultrasound (3DVUS) provides accurate volumetric quantification of plaque burden., Objectives: The authors evaluated associations between 3DVUS-based plaque burden and CVRFs and explored potential added value over simple plaque detection., Methods: The authors included 3,860 (92.2%) PESA (Progression of Early Subclinical Atherosclerosis) study participants (age 45.8 ± 4.3 years; 63% men). Bilateral carotid and femoral territories were explored by 3DVUS to determine the number of plaques and territories affected, and to quantify global plaque burden defined as the sum of all plaque volumes. Linear regression and proportional odds models were used to evaluate associations of plaque burden with CVRFs and estimated 10-year cardiovascular risk., Results: Plaque burden was higher in men (63.4 mm 3 [interquartile range (IQR): 23.8 to 144.8 mm 3 ] vs. 25.7 mm 3 [IQR: 11.5 to 61.6 mm 3 ] in women; p < 0.001), in the femoral territory (64 mm 3 [IQR: 27.6 to 140.5 mm 3 ] vs. 23.1 mm 3 [IQR: 9.9 to 48.7 mm 3 ] in the carotid territory; p < 0.001), and with increasing age (p < 0.001). Age, sex, smoking, and dyslipidemia were more strongly associated with femoral than with carotid disease burden, whereas hypertension and diabetes showed no territorial differences. Plaque burden was directly associated with estimated cardiovascular risk independently of the number of plaques or territories affected (p < 0.01)., Conclusions: 3DVUS quantifies higher plaque burden in men, in the femoral territory, and with increasing age during midlife. Plaque burden correlates strongly with CVRFs, especially at the femoral level, and reflects estimated cardiovascular risk more closely than plaque detection alone. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The goal of this study was to develop and validate a noninvasive imaging tool to visualize the in vivo behavior of high-density lipoprotein (HDL) by using positron emission tomography (PET), with an emphasis on its plaque-targeting abilities., Background: HDL is a natural nanoparticle that interacts with atherosclerotic plaque macrophages to facilitate reverse cholesterol transport. HDL-cholesterol concentration in blood is inversely associated with risk of coronary heart disease and remains one of the strongest independent predictors of incident cardiovascular events., Methods: Discoidal HDL nanoparticles were prepared by reconstitution of its components apolipoprotein A-I (apo A-I) and the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine. For radiolabeling with zirconium-89 ((89)Zr), the chelator deferoxamine B was introduced by conjugation to apo A-I or as a phospholipid-chelator (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-deferoxamine B). Biodistribution and plaque targeting of radiolabeled HDL were studied in established murine, rabbit, and porcine atherosclerosis models by using PET combined with computed tomography (PET/CT) imaging or PET combined with magnetic resonance imaging. Ex vivo validation was conducted by radioactivity counting, autoradiography, and near-infrared fluorescence imaging. Flow cytometric assessment of cellular specificity in different tissues was performed in the murine model., Results: We observed distinct pharmacokinetic profiles for the two (89)Zr-HDL nanoparticles. Both apo A-I- and phospholipid-labeled HDL mainly accumulated in the kidneys, liver, and spleen, with some marked quantitative differences in radioactivity uptake values. Radioactivity concentrations in rabbit atherosclerotic aortas were 3- to 4-fold higher than in control animals at 5 days' post-injection for both (89)Zr-HDL nanoparticles. In the porcine model, increased accumulation of radioactivity was observed in lesions by using in vivo PET imaging. Irrespective of the radiolabel's location, HDL nanoparticles were able to preferentially target plaque macrophages and monocytes., Conclusions: (89)Zr labeling of HDL allows study of its in vivo behavior by using noninvasive PET imaging, including visualization of its accumulation in advanced atherosclerotic lesions. The different labeling strategies provide insight on the pharmacokinetics and biodistribution of HDL's main components (i.e., phospholipids, apo A-I)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Direct quantification of atherosclerotic plaque volume by three-dimensional vascular ultrasound (3DVUS) is more reproducible than 2DUS-based three-dimensional (2D/3D) techniques that generate pseudo-3D volumes from summed 2D plaque areas; however, its accuracy has not been reported. We aimed to determine 3DVUS accuracy for plaque volume measurement with special emphasis on small plaques (a hallmark of early atherosclerosis)., Methods: The in vitro study consisted of nine phantoms of different volumes (small and medium-large) embedded at variable distances from the surface (superficial vs. >5 cm-depth) and comparison of 3DVUS data generated using a novel volumetric-linear array method with the real phantom volumes. The in vivo study was undertaken in a rabbit model of atherosclerosis in which 3DVUS and 2D/3D volume measurements were correlated against gold-standard histological measurements., Results: In the in vitro setting, there was a strong correlation between 3DVUS measures and real phantom volume both for small (3.0-64.5 mm(3) size) and medium-large (91.1-965.5 mm(3) size) phantoms embedded superficially, with intraclass correlation coefficients (ICC) of 0.99 and 0.98, respectively; conversely, when phantoms were placed at >5 cm, the correlation was only moderate (ICC = 0.67). In the in vivo setting there was strong correlation between 3DVUS-measured plaque volumes and the histological gold-standard (ICC = 0.99 [4.02-92.5 mm(3) size]). Conversely, the correlation between 2D/3D values and the histological gold standard (sum of plaque areas) was weaker (ICC = 0.87 [49-520 mm(2) size]), with large dispersion of the differences between measurements in Bland-Altman plots (mean error, 79.2 mm(2))., Conclusions: 3DVUS using the volumetric-linear array method accurately measures plaque volumes, including those of small plaques. Measurements are more accurate for superficial arterial territories than for deep territories., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Plaque development has been extensively studied using magnetic resonance imaging (MRI) in animal models of rapidly progressing atherosclerosis, such as apolipoprotein E-knockout (apoE-KO) mice. Preclinical MRI plays a significant role in the study of experimental atherosclerosis. Currently, MRI is capable of detecting luminal narrowing, plaque size, and morphology with high accuracy and reproducibility, providing reliable measurements of plaque burden. Therefore, MRI offers a noninvasive approach to serially monitor the progression of the disease. Compared with other imaging modalities, MRI appears to have the greatest potential for plaque characterization, through the use of multiple contrast weightings (e.g., T1, T2, and proton density). Here, we illustrate a standard procedure to image the aorta of atherosclerotic mice using noninvasive MRI.

Imaging subclinical atherosclerosis holds the promise of individualized cardiovascular (CV) risk assessment. The large arsenal of noninvasive imaging techniques available today is playing an increasingly important role in the diagnosis and monitoring of subclinical atherosclerosis. However, there is a debate about the advisability of clinical screens for subclinical atherosclerosis and which modality is the most appropriate for monitoring risk and atherosclerosis progression. This article offers an overview of the traditional and emerging noninvasive imaging modalities used to detect early atherosclerosis, surveys population studies addressing the value of subclinical atherosclerosis detection, and also examines guideline recommendations for their clinical implementation. The clinical relevance of this manuscript lies in the potential of current imaging technology to improve CV risk prediction based on traditional risk factors and the present recommendations for subclinical atherosclerosis assessment. Noninvasive imaging will also help to identify individuals at high CV who would benefit from intensive prevention or therapeutic interventions.