Advances in Clinical Imaging of Vascular Inflammation

Central Illustration

V ascular inflammation plays a critical role in the development and progression of various cardiovascular diseases, most importantly atherosclerotic coronary artery disease (CAD).Accurate noninvasive assessment of vascular inflammation has been a challenge for clinicians and researchers due to the limitations of traditional imaging modalities, with invasive assessment limited to surgical patients in highly controlled research settings.With the advent of more advanced imaging technologies such as multi-detector computed tomography (CT) scanners and molecular imaging using selective radiotracers in positron emission tomography (PET), it is now possible to directly assess vascular biology and inflammation, including in the coronary tree.Furthermore, the burgeoning field of CT radiomics has the potential to augment noninvasive inflammation detection for improvements in patient care.Concurrently, molecular imaging with PET has experienced tremendous growth in recent years, with numerous radiotracers and imaging technologies being developed for the detection of vascular inflammation.Intravascular ultrasound is also becoming increasingly available during invasive angiography, presenting a significant opportunity for the use of ultrasound-based methods for the indirect detection of the high-risk (and presumably inflamed) coronary plaque.
In the current state-of-the-art review, an overview is provided of the advances in all imaging technologies used for the detection of vascular inflammation, with a specific focus on coronary artery inflammation.
The review focuses on CT imaging techniques, which have seen huge interest in recent years, but it also includes dedicated discussion of magnetic resonance imaging (MRI), PET-CT and PET-MRI, and ultrasound.
Highlighted also is the recent progress in human translational applications of each imaging modality, evaluating their strengths and limitations in the assessment of vascular inflammation.

INTRODUCTION TO VASCULAR INFLAMMATION
Atherosclerosis is a chronic inflammatory condition of the vasculature.It is highly patterned in its pathophysiology, forming characteristic lesions within the arterial system all around the body.Broadly, atherosclerosis encompasses the stages of endothelial dysfunction, formation of fatty streak, plaque development (atheroma and fibroatheroma), and plaque disruption and thrombosis, including the pathophysiological processes that underpin these transitions.The spectrum of disease caused by atherosclerosis is vast, including myocardial infarction (MI), stroke, and peripheral arterial disease, which, among other related conditions, comprise cardiovascular disease, the leading cause of morbidity and mortality globally. 13][4] However, our understanding has flourished since Ross's canonical response-to-injury hypothesis, 5,6 which suggested that endothelial dysfunction (caused by genetics, vascular injury, elevated low-density lipoprotein The evolution of plaque then begins in the arterial intima, which contains a lipid-rich core from accumulation of LDL-C within macrophage foam cells underneath a fibrous cap formed from SMC migration and proliferation (Figure 1).This canonical view of the initiation of atherosclerosis has been updated to reveal a complex interrelated network of pathways involving not only the innate immune system but also adaptive immunity (T-and B-cell responses), thrombo-inflammation (platelet-triggered processes), and C-mediated processes, among others.The role of B cells in atherosclerosis is complex, 8 as some B-cell responses targeting oxidation-specific epitopes might be disease protective, whereas other downstream pathways may be pro-atherosclerotic.Furthermore, antibodyindependent roles include cytokine production and T-cell regulation that secondarily mediate atherosclerosis.B-cell depletion therapies have been investigated, but further isolation of the proatherosclerotic pathways may be even more useful in generating targeted therapies.A role for T helper 1 Imaging Vascular Inflammation cells is also being established. 9Platelets have been known to be critical in the early stages of atherosclerosis by releasing chemokine (C-C motif) ligand 5, a critical chemokine for promoting monocyte adhesion; increasingly complex roles are being elucidated. 10The role of these cell-mediated pathways and others (eg, protein kinase C) have been reviewed in detail elsewhere. 11e role of inflammation also extends to atherosclerotic disease progression. 7Activated macrophages that ingest lipid molecules subsequently secrete chemokines and cytokines and drive lipid accumulation. 12,13Notably, however, the role of macrophages in atherosclerosis is highly complex, with both pro-and anti-atherosclerotic functions.
One recent study suggests that mural cell-driven macrophage niches may be protective against chronic inflammation. 14Furthermore, as SMCs and macrophages apoptose and a necrotic core grows, senescent SMCs release pro-inflammatory cytokines and matrix metalloproteinases. 15Oxidized LDL-C also triggers the nuclear factor kB signaling pathway, promoting the transcription of the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome and pro-interleukin-1, triggering downstream pathways, which include the release of neutrophil extracellular traps.These traps further induce cytotoxicity by priming the NLRP3 inflammasome in macrophages and inducing platelet activation and the tissue factor pathway inhibitor. 7nally, inflammation is also a critical driver of vulnerable plaque rupture, which is a key pathogenic mechanism of acute coronary syndromes (ACS).
When the weakened cap breaks, procoagulant molecules in the blood are exposed to tissue factor within the lipid-rich core; platelet aggregation and thrombosis ensue.Superficial erosion is a second mechanism by which plaque progression occurs; depletion of neutrophils has been shown to prevent this process, further highlighting the role of inflammation. 16scular inflammation is therefore causally implicated in atherosclerosis from inception to complication.Clinical studies have concordantly confirmed the clinical relevance of inflammation in atherosclerotic cardiovascular disease.8][19] Inflammation also affects cardiovascular risk factors, possibly by decreasing nitric oxide bioavailability in the vascular endothelium. 20Vascular inflammation has furthermore been shown to affect serum lipid levels and lipoprotein function.It causes LDL-C to be more easily oxidized, 21 as the ability of HDL to prevent the oxidation of LDL-C is diminished.
It follows that lipid-modifying statins trigger clinically significant anti-inflammatory processes. 22erefore, targeting these complex pathways provides a promising route toward diagnosing and treating the disease.Our growing understanding of the complex interconnected pathways that give rise to the modern view of atherosclerosis serves as a potential avenue for precision medicine.Inflammation had been largely overlooked until recent years but has become a fast-growing target for innovation in diagnostics and treatment.In particular, the potential to further stratify CAD according to the presence of inflammation may be critical, as anti-inflammatory treatments for atherosclerosis are recommended in clinical guidelines. 23Its potential applications are also being investigated beyond ischemic heart disease to include cardiometabolic disease. 24ngina, and cardiovascular death) compared with placebo (rosuvastatin vs placebo 1.31 vs 0.77). 25wever, it was unclear whether it was an on-target

CAUSAL
West et al  28 An ancillary study found that impaired coronary flow reserve was independently associated with increased inflammation and myocardial strain, which may have implications in heart failure. 24The contrasting results of the CIRT and CANTOS trials show that anti-inflammatory therapies effective against atherosclerosis must be biochemically targeted to the specific inflammatory  We provide a review of the major noninvasive imaging modalities available to researchers and clinicians to visualize vascular inflammation in vivo with a focus on both the molecular mechanisms that these imaging modalities rely upon and their clinical applications.Invasive modalities such as intravascular imaging techniques are not included in this review.
The noninvasive imaging modalities for the detection of vascular inflammation discussed here are summarized in the Central Illustration along with their strengths and weaknesses.
West et al One of the key advances that has facilitated CT imaging to becoming a "one-stop-shop" 41 for imaging of the vasculature, particularly the coronary arteries, is the fundamental but often overlooked fact that three-dimensional medical images, like all images, are data sets.

Imaging Vascular Inflammation
The first major imaging technology that utilizes coronary CTA for the detection of vascular inflammation is the perivascular fat attenuation index (FAI).This noninvasive, CT imaging-derived biomarker relies on attenuation mapping of pericoronary adipose tissue (PCAT) composition to extract information about the inflammatory status of the adjacent coronary artery. 42,43The premise of this work emerges from the understanding that adipose tissue is a key regulator of cardiometabolic health. 44,45PVAT is the adipose tissue that forms a contiguous entity with the arterial adventitia and plays a key role in vascular homeostasis and atherogenesis by regulating the local microenvironment through the release of bioactive adipokines, 46,47 as well as gaseous and other lipid messengers. 42,44udies that used 18 F-fluorodeoxyglucose ( 18 F-FDG) PET-CT imaging to visualize inflammation in PVAT (as outlined later in this review) have highlighted significant relationships between this inflammation and a range of clinically significant cardiovascular disease endpoints. 48Importantly, our group showed that the paracrine interactions between the arterial wall and the PVAT are bidirectional. 43,46,47,49We found that in the presence of increased vascular oxidative stress, lipid peroxidation products such as 4-hydroxynonenal are increasingly produced and diffuse from the vascular wall to the PVAT. 50These substances activate HU). 43,53The perivascular FAI utilizes coronary CTA to track spatial changes in PVAT composition that are induced by inflamed coronary vessels as outlined earlier. 43The FAI relies on the concept that the inflammation-induced changes in adipocyte size are associated with a detectable shift in CT attenuation toward a less negative HU range (toward -30 HU).The perivascular FAI (calculated by using the CaRi-HEART medical device; Caristo Diagnostics 54 ) captures and interprets these attenuation gradients in the perivascular space, with high perivascular FAI linked to a higher inflammatory burden 43,55 (Figures 2A to 2E).
Importantly, there is strong evidence that CAD is associated with a higher perivascular FAI compared with healthy individuals. 43   prognostic models. 68The goal is to provide clinically meaningful information in primary and secondary prevention of atherosclerotic heart disease, which offers the best high-level guidance for clinicians yet.
A relevant meta-analysis recently tested all current clinically available approaches to vascular inflammation detection and assessed their prognostic value. 69e measurement of vascular inflammation in addition to clinical risk factors was found to significantly enhance risk discrimination for cardiovascular events (Figure 5).burden as determined by the perivascular FAI and observed rates of cardiac mortality within each group.The combination of HRP and high FAI could be used to identify vulnerable patients at the highest risk who are eligible for aggressive prevention strategies; derived from post hoc data analysis of CRISP-CT data in the Oxford Academic Cardiovascular Computed Tomography Core Laboratory.Reproduced with permission from Antoniades et al. 111 AUC ¼ area under the curve; other abbreviations as in Figure 2. Imaging Vascular Inflammation to compute many hundreds of shape-, attenuation-, and texture-related features for a given anatomical volume or segmentation. 70Many radiomic features used together can be employed for disease diagnosis or prognostication.The field of radiomics was developed for the large-scale analysis of geospatial satellite imagery and first applied to health care in the field of cancer imaging. 71     of anti-interleukin-1b therapy. 84Ultrasound therefore has the potential to evaluate the effects of Recently, however, superb microvascular imaging, a noninvasive technique that removes noise while preserving low-velocity flow signal, has been shown to accurately detect intraplaque neovascularization. 85prospective cohort study comparing superb microvascular imaging against existing validated methods for detecting carotid plaque instability (eg, contrastenhanced ultrasound, carotid-MRI and PET-18 F-FDG, histology) is currently being conducted; the results have significant potential implications for detection of carotid inflammation and risk prediction of carotid ischemic events beyond extent of stenosis. 86erall, although the results to date suggest that any ultrasound-based method of inflammation detection can be expected to have limited sensitivity relative to other imaging modalities, this is an area that could yield promising results in the future.This is especially true given that intravascular ultrasound

West et al
has not yet been tested with the techniques discussed herein but could provide an exciting avenue for further research with greater resolution of the relevant tissues in real time.reviewed elsewhere. 91The most common intravenous tracer agent used in PET is 18 F-FDG.This agent can noninvasively assess arterial inflammation as well as other inflammatory processes throughout the body. 18F-FDG uptake reflects glucose metabolism, which is particularly increased in inflamed atherosclerotic disease exhibiting the retention of macrophages and hypoxic stress. 18F-FDG has been used to assess the activity of metabolically active inflammatory cells and has shown a preference for inflamed coronary plaque in patients who have undergone proper preparation (low-carbohydrate, high-fat diet to suppress myocardial uptake of the tracer). 92Currently, 18 F-FDG PET-CT imaging is used in the clinic to assess myocardial viability and blood flow, as well as to detect and monitor noncoronary conditions such as sarcoidosis and myocarditis.It is also well validated for the identification of carotid plaque instability. 85other radiotracer, gallium-68-labeled DOTA-TATE ( 68 Ga-DOTATATE), can also provide clinically useful images of vascular inflammation.This tracer is widely used in imaging neuroendocrine tumors and binds to the somatostatin receptor subtype 2 (SST 2 ), which is expressed by M1 pro-inflammatory macrophages.PET-CT images using 68 Ga-DOTATATE have been found to produce better image quality than 18 F-FDG and can be used to identify inflamed coronary lesions 93 and residual inflammation in myocardial tissue after an acute MI. 94 Figure 7 illustrates the use of 68 Ga-DOTATATE for detection of coronary artery vascular inflammation compared with 18 F-FDG.
Several other radiotracers have also shown promise in imaging inflammation within the coronary wall.
For instance, 18 F-NaF, which has a strong affinity for the vascular wall, has been shown to incorporate into hydroxyapatite in areas of arterial wall microcalcification.Imaging with 18 F-NaF has shown promising accuracy in detecting the culprit coronary lesions and abdominal aortic aneurysms, 95 with 18 F-NaF PET-CT imaging being the first noninvasive imaging method to identify and localize ruptured and high-risk coronary plaque. 96 18F-NaF has been used to investigate developing microcalcification in the vasculature.Work from Dweck et al 97 showed that coronary uptake was associated with cardiovascular risk, describing significant associations between coronary arterial NaF uptake and prior coronary events, angina status, and Framingham risk scores.Recent work from the same group has shown that in a small cohort of patients with established CAD pooled from a prospective observational study, 18 F-NaF PET provides powerful independent prediction of fatal or nonfatal MI. 98 18 F-fluciclatide, a PET tracer that binds to a v b 3 integrin, is also considered a promising tool for identifying high-risk coronary plaque. 99Indeed, small studies in humans have shown that the quantification of a v b 3 integrin expression with 18 F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in aortic atherosclerosis. 100ere is early evidence to suggest that the 18 kDa translocator protein could be used as a target for imaging inflammation using a specific PET-CT tracer.
For example, 11 C-PK11195 has been used to this end, although primarily in carotid disease cases.PET-CT imaging using 11 C-PK11195 has been found to distinguish between recently symptomatic and asymptomatic plaque in carotid disease populations. 101,102her experimental techniques have also been explored to visualize coronary artery inflammation using PET-CT imaging, such as visualizing chemokine receptors, which are up-regulated in pro-inflammatory macrophages, in experimental nanoplatforms, 103 or visualizing endothelial activation and inflammation using 18 F-labeled small VCAM-1 affinity ligands. 104gnetic resonance and optical detection technologies can be combined with PET to visualize inflammation by using 64 Cu-labeled 20 nm magnetofluorescent polysaccharide-containing nanoparticles, 105 which have been found to accumulate in macrophages in atherosclerotic lesions in apolipoprotein E knock-out mice.
Single-photon emission CT imaging/CT imaging that uses 111 In-and 123 I-radiolabeled compounds is another experimental approach to noninvasively visualize coronary artery inflammation.These compounds target activated matrix metallopeptidases and allow the detection and tracking of plaque composition in response to treatment. 106though 18 F-FDG PET-CT imaging and increasingly 18  PET-MRI was found to be consistent with 18

[
LDL-C] levels, free radicals from cigarette smoking, and hypertension, among others) causes collagen exposure and platelet adhesion, aggregation, and degranulation to initiate atherosclerosis.Adhesion markers (intercellular adhesion molecule-1, vascular cell adhesion molecule [VCAM-1]), in conjunction with chemotactic agents (chemokine [C-C motif] ligand 5) secreted by platelet degranulation, then act to stimulate neutrophil and macrophage migration and subendothelial accumulation of monocytes and LDL-C, initiating the inflammatory process. 7Other cytokines such as chemokine (C-C motif) ligand 2 are also released by neutrophils and smooth muscle cells (SMCs) and stimulate further leukocyte chemotaxis.

A 2 VCAM- 1
B B R E V I A T I O N S A N D A C R O N Y M S 18 F-FDG = 18 Ffluorodeoxyglucose 18 F-NaF = 18 F-sodium fluoride 68 Ga-DOTATATE = gallium-68-labeled DOTATATE ACS = acute coronary syndromes AI = artificial intelligence CAD = coronary artery disease CTA = computed tomography angiography CMR = cardiac magnetic resonance FAI = fat attenuation index FRP = fat radiomic profile HRP = high-risk plaque LDL-C = low-density lipoprotein MACE = major adverse cardiovascular events MI = myocardial infarction MRI = magnetic resonance imaging NLRP3 = NOD-, LRR-, and pyrin domain-containing 3 PCAT = pericoronary adipose tissue PET = positron emission tomography PVAT = perivascular adipose tissue SMC = smooth muscle cell SST2 = somatostatin receptor subtype = vascular cell adhesion molecule type 1 J A C C : B A S I C T O T R A N S L A T I O N A L SCIENCE VOL. 9, NO. 5, 2024 West et al M A Y 2 0 2 4 : 7 1 0 -7 3 2 RELATIONSHIPS BETWEEN INFLAMMATION AND CARDIOVASCULAR EVENTS: INSIGHTS FROM RANDOMIZED CLINICAL TRIALS The advance in understanding of the cellular mechanisms of the chronic inflammatory process underlying atherosclerosis is increasingly being translated into actionable clinical discoveries.Phase 3, doubleblind, randomized controlled clinical trials have now shown that targeting specific inflammatory pathways can improve clinical outcomes and reduce cardiovascular events in select populations.Importantly, different anti-inflammatory strategies may have varying agent-related effectiveness due to diversity in underlying mechanisms, specifically whether they prevent early disease progression, lessen plaque formation, or reduce late-stage plaque rupture to prevent acute cardiac events.This scenario highlights a major challenge in clinical trials for antiinflammatory agents: what is the population of relevance for the specific agent, and what is the relevant outcome that the agent may modify?The first trial to test a clinical treatment strategy based on inflammatory markers was JUPITER (Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin).In 17,802 patients selected per LDL-C level <130 mg/dL and high-sensitivity C-reactive protein level $2 mg/L, rosuvastatin 20 mg was associated with a reduction in the rate of primary endpoint (MI, stroke, arterial revascularization, hospitalization for unstable

FIGURE 1
FIGURE 1 Simplified Schematic of Vascular Inflammation Driving Atherosclerosis

M A Y 2 0 2 4 : 7 1 0 -7 3 2 CT
IMAGING.The use of CT imaging to visualize the heart and vascular structures has increased dramatically in recent decades owing to improved imaging technology and widespread utility of CT scanners across a broad range of clinical indications.Coronary computed tomography angiography (CTA) has become the noninvasive imaging modality of choice for the noninvasive examination of the coronary arteries.The currently accepted broad indications for coronary CTA in clinical practice that are relevant to inflammatory vascular disease include: 1) suspected or known CAD (to evaluate the severity and extent of CAD, particularly in patients with symptoms such as stable chest pain, shortness of breath, and exercise intolerance); 2) assessing the anatomy of the coronary arteries before revascularization procedures such as coronary artery bypass surgery or percutaneous coronary intervention; 3) preoperative evaluation for noncardiac surgery to assess the presence and severity of CAD in patients scheduled for noncardiac surgery; and 4) monitoring the progression of CAD or assessing the effectiveness of treatment, including lifestyle changes, medication, or revascularization procedures.It is important to note that coronary CTA is not always the first-line imaging modality for all these broad indications in all settings.The choice of imaging test often depends on an individual patient's disposition.Beyond the indications listed here, the role of CT imaging has recently expanded to include the direct noninvasive imaging of vascular inflammation.CT imaging offers unparalleled potential for widespread clinical uptake of vascular inflammation assessment, upheld by the existing reliance on CT scans in clinical guidelines for the investigation of chest pain worldwide. 37,38Advances that allow these scans to be further utilized for the visualization of coronary inflammation would improve and streamline clinical practice and add immense value for patients and clinicians.Currently, when plaque is visualized with coronary CTA, plaque risk is stratified to assess plaque stability and therefore risk of cardiac events.High-risk plaque (HRP) features include low attenuation, positive CENTRAL ILLUSTRATION Imaging Modalities to Detect Vascular Inflammation West HW, et al.J Am Coll Cardiol Basic Trans Science.2024;9(5):710-732.Summary of the clinical imaging modalities in use or under development for the noninvasive detection of vascular inflammation.CT ¼ computed tomography; MRI ¼ magnetic resonance imaging; PET ¼ positron emission tomography.remodeling, spotty calcification, and the napkin ring sign (ringlike peripheral higher attenuation with central low attenuation), among others.On the other hand, calcification signifies stability and low inflammation.However, HRP features are not reliable in assessing plaque inflammation.The absence of these features does not necessarily correlate with lack of inflammation because by the time plaque appears, vascular inflammation has been ongoing for some time.Indeed, recent studies show that the traditional stenosis-based approach has failed to identify at-risk patients (Coronary Artery Disease Reporting and Data System 2.0 [CAD-RADS 2.0]) 39 and furthermore failed to improve clinical outcomes beyond symptom improvement in patients with stable CAD (ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches]). 40Therefore, to maximize prevention of cardiac events, imaging biomarkers specific to vascular inflammation are needed to detect coronary inflammation before plaque formation is detectable.Perivascular adipose tissue (PVAT) can detect signals of disease emanating from the vascular wall.In brief, in conditions of cardiovascular disease, the arterial wall releases various mediators such as oxidation products (eg, 4-hydroxynonenal), which diffuse to PVAT, inducing the transformation of adipocytes from quiescent lipid-storage cells to active biosynthetic cells that secrete antioxidant adipokines such as adiponectin.These adipokines are then transported back to the vascular wall, acting as a defense mechanism against vascular oxidative damage.Inflammatory molecules originating from the vascular wall also diffuse into adjacent adipose tissue, preventing pre-adipocyte differentiation into mature adipocytes within PVAT.In addition, these inflammatory molecules stimulate perivascular lipolysis, generating a gradient of adipocyte size surrounding the inflamed artery.The adipocyte size gradient in PVAT close to the inflamed artery results in a higher lipid/water ratio in the layers of PVAT adjacent to the inflamed vascular wall.The gradient changes in PVAT's structure and composition around inflamed arteries could act as an internal "thermometer" of vascular inflammation if it can be visualized and quantified noninvasively.
peroxisome proliferator-activated receptor-g signaling in PVAT adipocytes, which results in an upregulation and increased secretion of the antioxidant adiponectin from the perivascular adipocytes. 51Adiponectin can then diffuse back to the vascular wall and proximal myocardial tissue and reduce superoxide production by suppressing the activity of nicotinamide adenine dinucleotide phosphate oxidases, as well as by improving the coupling of endothelial nitric oxide synthase in the vascular endothelium. 46,47,52During the process of shifting the phenotype of PVAT adipocytes from energy storing to active secretory cells, their dimensions, shape, and content change, becoming smaller in size and with reduced intracellular lipid content.The ability to evolve in response to signals from the cardiovascular system is also shown by the ability of adipocytes to activate lipolysis and reduce adipogenesis in the presence of exogenous inflammation and circulating molecules such as brain natriuretic peptide. 49Importantly, we have also shown that if vascular inflammation is present, the release of proinflammatory mediators such as tumor necrosis factor-a, interleukin-6, and interferon gamma blocks the ability of perivascular pre-adipocytes to differentiate into mature lipid-laden adipocytes. 43Indeed, per results of paired PVAT biopsies from a site attached to the right coronary artery, perivascular adipocytes were significantly smaller and less well differentiated compared with adipocytes from epicardial adipose tissue biopsies obtained >2 cm away from any coronary artery (non-PVAT); this was evidenced by a lower relative expression of the adipocyte differentiation markers peroxisome proliferator-activated receptor-g and fatty acid binding protein-4.This gradient in PVAT composition reflects the inflammatory burden of a given coronary segment and has highlighted PVAT as a biological sensor of coronary artery inflammation.If these gradients of PVAT composition around the coronary arteries is visualized and quantified using noninvasive imaging, we would be able to detect or even quantify coronary artery inflammation noninvasively, leading to a new generation of diagnostic and prognostic biomarkers of cardiovascular events.These laboratory findings have been translated to coronary CTA through the segmentation and analysis of PVAT along the coronary vessels using predefined validated Hounsfield unit (HU) cutoffs (-190 to -30

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A C C : B A S I C T O T R A N S L A T I O N A L SCIENCE VOL. 9, NO. 5, 2024 higher perivascular fat radiodensity has been shownto strongly correlate with both increased plaque inflammation as assessed by18 F-sodium fluoride ( 18 F-NaF) uptake on PET-CT imaging 63 and the progression of total and noncalcified atherosclerotic plaque burden in the adjacent vessel.64It is noteworthy that in symptomatic patients undergoing cardiac CT imaging, the information captured by perivascular FAI is independent of coronary calcification42,43 or systemic markers of inflammation such as high-sensitivity C-reactive protein.42Measuring perivascular attenuation in clinical practice is problematic, however, as it is affected by factors such as technical scan acquisition settings, image postprocessing, and local anatomical and biological factors.65This has led to the development of a fully corrected metric of coronary inflammation, the FAI Score, which allows us to individualize the

FIGURE 2 FIGURE 3 2
FIGURE 2 Schematic Representation of the Biology Underlying the Detection of Coronary Inflammation by Imaging PVAT PVAT assessment with CT imaging yielded the highest C-index values of all means assessed.Thus, coronary CTA biomarkers such as HRP features and pericoronary fat imaging through the FAI (alone or in combination) enhance cardiovascular risk discrimination beyond circulating biomarkers of inflammation.CT RADIOTRANSCRIPTOMICS FOR THE DETECTION OF VASCULAR INFLAMMATION.Handling CT scans as data sets for analysis rather than as images to examine with the human eye is the focus of the field of radiomics.Radiomics uses mathematical formulae

FIGURE 3 Continued
FIGURE 3 Continued Prognostic value of perivascular FAI.(A, B) In the CRISP-CT (Cardiovascular Risk Prediction Using Computed Tomography) study, which evaluated 2 prospective clinical cohorts of 3,912 patients undergoing diagnostic coronary computed tomography angiography for clinical indications, perivascular FAI was predictive of cardiac mortality in both the derivation cohort and the validation cohort.(C, D) The FAI provided incremental prognostic value for cardiac mortality on top of traditional clinical risk factors, the Duke CAD Index, and number of high-risk plaque (HRP) features on coronary computed tomography angiography.Reproduced with permission from Oikonomou EK, Marwan M, Desai MY, et al.Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data.Lancet.2018;392:929-939.(E) HRP features on coronary computed tomography angiography are defined as the napkin-ring sign (NRS), low attenuation plaque (LAP), spotty calcification (SC), and positive remodeling (PR).(F, G) Stratification of the pooled population of CRISP-CT based on the presence of HRP and high coronary inflammatory

FIGURE 4
FIGURE 4 Concepts for Implementing Coronary Artery Plaque and Inflammation-Guided Management via CT Imaging in Clinical Practice

FIGURE 4
FIGURE 4 Continued (A) Example of workflow for artificial intelligence (Ai)-assisted computed tomography (CT) interpretation for the assessment of coronary artery disease, which includes automated prediction of a patient's risk of major adverse cardiovascular events and suggested medical management.(B) Schematic representation of the biology underlying the detection of coronary inflammation by imaging PVAT.Health coronary artery shown on bottom and high inflammation at top, with corresponding low and high FAI Scores, respectively.At right is an example of a single patient with a high FAI Score at baseline with reduced vascular inflammation after 1 year of treatment with atorvastatin 40 mg once daily.A is reproduced with permission from Antoniades et al. 67 B is reproduced with permission from Antoniades C et al. 111 CCTA ¼ coronary computed tomography angiography; ORFAN ¼ Oxford Risk Factors and Non Invasive Imaging Study; RCA ¼ right coronary artery; other abbreviations as in Figures 2 and 3.

FIGURE 5
FIGURE 5 The Prognostic Performance (C-Index) of Inflammation Biomarkers for the Composite Endpoint of Major Adverse Clinical Outcomes and All-Cause Mortality

FIGURE 6
FIGURE 6 Radiotranscriptomic Detection of COVID-19 Severity Risk Using CT Detection of Perivascular Inflammation

Finally, C19 -
RS was strongly associated (R ¼ 0.61; P ¼ 0.00031) with a whole blood transcriptional module representing dysregulation of coagulation and platelet aggregation pathways.This radiotranscriptomic signature for in-hospital mortality in acute COVID-19 worked even when applied in nongated CT angiograms of the pulmonary arteries.Texture radiotranscriptomics can also be used to capture and quantify microcirculation in the perivascular space, in addition to lipolysis/adipogenesis, fibrosis, and edema, offering additional prognostic value over the perivascular FAI Score for cardiac events.Machine learning/radiotranscriptomic approaches are anticipated to revolutionize the utilization of adipose tissue as a tool for exploring vascular biology.COMPETING TECHNOLOGIES ULTRASOUND.Contrast-enhanced ultrasound has been investigated for visualization of inflammation in vessels affected by atherosclerosis.Although the techniques that have been developed have been useful in researching vascular inflammation, their clinical utility has not been fully realized.The potential future applications of ultrasound are particularly of interest as it could serve as a low-cost noninvasive modality for vascular inflammation detection.The initial utility of ultrasound was in detection of early inflammation in the murine aorta, a classic animal model for cardiovascular disease.More recently, microbubbles targeted at VCAM type 1 (VCAM-1), a chemokine expressed by activated endothelial cells in atherosclerosis, 77 have facilitated use of ultrasound scans to evaluate arterial inflammation initially in vitro. 78Noninvasive ultrasound has since been shown to detect VCAM-1 on human carotid arterial tissue using specialized microbubbles with a maleimide-thiol conjugation of an anti-VCAM-1 nanobody. 79,80Further in vitro research using contrast-enhanced ultrasound and von Willebrand factor A1-bearing microbubbles has been shown to detect activated platelets on vascular endothelium and indicate lesion severity in a rodent model of atherosclerosis. 81The use of microbubbles has not yet been validated in vivo in humans.A recent translational study by Punjabi et al 82 described the ability of VCAM-1-targeted microbubbles to detect treatment response to the glucagonlike peptide-1 agonist liraglutide by monitoring the VCAM-1 signal.This work shows the power of using biochemically targeted ultrasound imaging to prove molecular involvement in vivo.Intercellular adhesion molecule 1-targeted nano-ultrasonic contrast also has potential for future technological innovation to further our bottom-up understanding of atherosclerosis. 83Furthermore, echocardiographic molecular imaging of vascular endothelium has recently been shown to detect reductions in pro-inflammatory signals (eg, P-selectin, VCAM-1, von Willebrand factor) as a result

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A C C : B A S I C T O T R A N S L A T I O N A L SCIENCE VOL. 9, NO.marker of carotid instability, a known precursor to embolic stroke, but is not detectable with Doppler ultrasound; contrastenhanced ultrasound can detect it only invasively.

MAGNETIC
RESONANCE IMAGING.Along with echocardiography and PET, CMR imaging is widely considered a key tool for the diagnosis of inflammatory myocardial disease, with a Class I recommendation for the assessment of myocarditis and storage diseases in the current European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure. 87Despite CMR being

FIGURE 7
FIGURE 7 Coronary Artery PET Inflammation Imaging With 68Ga-DOTATATE F-FDG PET-CT imaging in patients with large vessel vasculitis.Resolution of the PET-MRI clinical images was found to be suitable for coronary and intracranial arteries.Other experimental PET-MRI probes are currently in development for inflammatory purposes.These include 18 fluorine-fluoromethylcholine, which has shown better identification of atherosclerotic plaque and lower myocardial uptake compared with 18 F-FDG in murine models.Current trials of this probe include a PET-MRI study recruiting those with ACS who will undergo optical coherence tomography to investigate if intravascular findings of high-risk plaque correlate with 18 fluorine-fluoromethylcholine uptake on PET-MRI (NCT03252990).There are also a number of small clinical studies investigating the use of cell adhesion motifs for inflammatory imaging in atherosclerosis.One of the most advanced is tripeptide Arg-Gly-Asp (RGD), which was originally identified as the sequence within fibronectin that mediates cell attachment.The RGD motif has now been found in numerous other proteins and has been identified as a key molecule that supports cell adhesion within atherosclerotic plaque.An ongoing 18 F-FPPRGD2 study is exploring the use of these probes in both PET-MRI and PET-CT imaging in a cohort of carotid endarterectomy patients (NCT02995642).CONCLUSIONS The field of noninvasive clinical imaging of vascular inflammation has undergone significant advancements in recent years (Table 1).The integration of various imaging modalities into clinical practice such as CT and molecular imaging with PET-CT imaging has allowed for a more comprehensive and accurate assessment of the presence and extent of vascular inflammation, particularly in the coronary arteries.The application of image analysis techniques on imaging data sets (eg, perivascular FAI Score and radiotranscriptomic phenotyping from routine coronary CTA) have shown very promising results in the use of vascular inflammation as part of CAD risk stratification.Ongoing studies are expected to validate their clinical utility, economic feasibility, and overall impact on clinical management in primary and secondary prevention.