Advances in Clinical Imaging of Vascular Inflammation

Figures

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  Figure 1. Simplified Schematic of Vascular Inflammation Driving Atherosclerosis Endothelial dysfunction results in collagen exposure and adhesion of circulating immune cells to the vascular wall at sites of up-regulation of adhesion markers such as intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule. The immune cells that migrate into the arterial wall along with circulating low-density lipoprotein cholesterol (LDL-C) initiate inflammatory responses in the subendothelial space. This mechanism drives the creation of foam cells and the organization of healing processes such as fibrotic change within the intima and the migration of smooth muscle cells into the atherosclerotic site. The influence of this process extends beyond the arterial intima and affects the arterial media and adventitia, including perivascular adipose tissue. eNOS = endothelial nitric oxide synthase; NADPH = nicotinamide adenine dinucleotide phosphate; NO = nitric oxide; O2 = oxygen; PPARγ = peroxisome proliferator-activated receptor-γ; VCAM-1 = vascular cell adhesion protein-1; VSMC = vascular smooth muscle cell.

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  Central Illustration. Imaging Modalities to Detect Vascular Inflammation Summary of the clinical imaging modalities in use or under development for the noninvasive detection of vascular inflammation. CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography.

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  Figure 2. Schematic Representation of the Biology Underlying the Detection of Coronary Inflammation by Imaging PVAT (A) Exposure of adipose tissue to exogenous inflammation leads to smaller adipocytes and low levels of intracellular lipids. (B) Illustration of inflamed adipose tissue containing small adipocytes, with low intracellular fat levels and high macrophage infiltration. (C) Morphologic appearance of perivascular adipose tissue (PVAT) surrounding inflamed coronary arteries. Vascular inflammation leads to a gradient in the adipocyte size (D) and the lipid:aqueous phase in perivascular adipose tissue (E), which can be detected by coronary computed tomography angiography. (F) Standard-of-care routine coronary computed tomography angiography data sets can be used for fat attenuation index (FAI) measurements. Perivascular FAI mapping can discriminate unstable (ruptured) from stable atherosclerotic plaques (G) and is increased in patients with atherosclerosis (H). Reproduced with permission from Antoniades et al.111

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  Figure 3. Prognostic Value of Perivascular FAI 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…

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  Figure 4. Concepts for Implementing Coronary Artery Plaque and Inflammation-Guided Management via CT Imaging in Clinical Practice (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 = coronary computed tomography angiography; ORFAN = Oxford Risk Factors and Non Invasive Imaging Study; RCA = right coronary artery; other abbreviations as in Figures 2 and 3.

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  Figure 5. The Prognostic Performance (C-Index) of Inflammation Biomarkers for the Composite Endpoint of Major Adverse Clinical Outcomes and All-Cause Mortality Each “bubble” on the graph represents a study with its size being proportional to the sample size. Boxplots of the added prognostic value (Δ[c-index]) provided by each biomarker (calculated as the difference in C-index of the best clinical model in each study with the addition of the biomarker of interest; lower part of the panel). The added prognostic value of CCTA-HRP is reported in addition to coronary atherosclerosis extent, whereas that of CCTA-PVAT is reported in addition to coronary atherosclerosis extent and HRP. Reproduced with permission from Antonopoulos et al.6918FFDG = 18F-fluorodeoxyglucose; CRP = C-reactive protein; IL = interleukin; PET = arterial positron emission tomography; TNF = tumor necrosis factor; other abbreviations as in Figures 2, 3, and 4.

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  Figure 6. Radiotranscriptomic Detection of COVID-19 Severity Risk Using CT Detection of Perivascular Inflammation (A) Example workflow for the construction of CT radiotranscriptomoc biomarkers of vascular disease, with the merging of tissue markers such as RNA sequencing data with imaging detection of that disease processes via CT radiomics. (B) Illustration of perivascular adipose tissue mapping in CCTA in a patient 3 years before and during SARS-CoV-2 infection. (C) Kaplan-Meier curve and adjusted HR for in-hospital death for high vs low C19-RS groups in the SARS-CoV-2–positive study population (n = 254 [n = 139 from the first wave and n = 115 from the second wave]) with 39 deaths. HR adjusted for age >65 years, sex, cardiovascular risk factors (hypertension, hyperlipidemia, diabetes, body mass index, and presence of coronary artery disease), C-reactive protein plasma concentrations, white blood cell count, plasma troponin, history of chronic obstructive pulmonary disease, tube voltage, and dexamethasone treatment. (D) Kaplan-Meier curve and adjusted HR for in-hospital death for high vs low C19-RS groups in the SARS-CoV-2–positive study arm population who did not receive dexamethasone…

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  Figure 7. Coronary Artery PET Inflammation Imaging With 68Ga-DOTATATE Radiograph (A) and CT coronary angiograms (D) of a 67-year-old man with stable angina, showing minor left circumflex atheroma (hatched oval) with spotty calcification ([inset] ∗calcium scan) and calcified plaque in the left anterior descending artery. Although gallium-68-labeled DOTATATE (68Ga-DOTATATE) positron emission tomography (PET) (B, E) allows unimpeded interpretation of inflammation in the left circumflex artery lesion (B, arrow), and lack of signal in the left anterior descending artery, coronary 18F-fluorodeoxyglucose imaging is obscured by patchy myocardial tracer uptake (C). Adapted with permission from Tarkin et al.93