Unraveling Vascular Inflammation: From Immunology to Imaging

Abstract

Inflammation is a critical factor in early atherosclerosis and its progression to myocardial infarction. The search for valid surrogate markers of arterial vascular inflammation led to the increasing use of positron emission tomography/computed tomography. Indeed, vascular inflammation is associated with future risk for myocardial infarction and can be modulated with short-term therapies, such as statins, that mitigate cardiovascular risk. However, to better understand vascular inflammation and its mechanisms, a panel was recently convened of world experts in immunology, human translational research, and positron emission tomographic vascular imaging. This contemporary review first strives to understand the diverse roles of immune cells implicated in atherogenesis. Next, the authors describe human chronic inflammatory disease models that can help elucidate the pathophysiology of vascular inflammation. Finally, the authors review positron emission tomography-based imaging techniques to characterize the vessel wall in vivo.

Keywords: T cells; cardiovascular imaging; monocytes; neutrophils.

Figure 1. NETosis Induces Vascular Damage

Neutrophil extracellular traps (NETs) in the time line of deep vein thrombosis (DVT): a model. (A) DVT is initiated by local hypoxia and activation of endothelial cells (ECs) as a result of flow restriction/disturbances. Activated endothelium releases ultralarge von Willebrand factor (ULVWF) and P-selectin from Weibel-Palade bodies (WPB), which mediate platelet and neutrophil adhesion. Activated platelets recruit tissue factor (TF)–containing microparticles that enhance thrombin generation in the growing thrombus. (B) Activated platelets and endothelium or other stimulus induce NET formation in adherent neutrophils. NETs provide an additional scaffold for platelet and red blood cell (RBC) adhesion, promote fibrin formation, and exacerbate platelet and endothelial activation. (C) Plasmin, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), and deoxyribonuclease (DNase) mediate thrombolysis by degrading fibrin, ULVWF, and DNA, respectively. Monocytes/macrophages (Mø) release an additional source of DNase and generate plasmin and promote restoration of blood flow (10).

Figure 2. Vascular Images of Chronically Inflamed Human Models

Representative ¹⁸F-FDG-PET/CT imaging of the aorta in a healthy volunteer (A), compared with the aortas of patients with human immunodeficiency virus (B), psoriasis (C), and systemic lupus erythematosus (D). CT = computed tomography; FDG = fluorodeoxyglucose; PET = positron emission tomography.

Figure 3. NaF Uptake in the Coronary Arteries

A discrete focus of fluorine 18 sodium fluoride (¹⁸F-NaF) uptake overlying an otherwise heavily calcified left anterior descending artery, suggesting a locus of active calcification with potentially increased vulnerability for rupture.

Central Illustration. Progression of Vascular Inflammation in Human Inflammatory Models

A gross illustration of the aortic arch has been taken in cross-section to magnify the vessel wall. Neutrophil activation due to systemic inflammation leads to NETosis and may initiate damage to the endothelium. Monocytes and T cells then infiltrate the lesion. Monocytes differentiate into macrophages, where they proliferate to sustain their population. Macrophages within the vessel wall have high glycolytic rates and take up the ¹⁸F-fluorodeoxyglucose (FDG) tracer, which is detectable by FDG positron emission tomography in human models of inflammation. NETosis = neutrophil extracellular trap activation and release. IFN = interferon; IL = interleukin