Atherosclerotic vascular disease is characterized by a chronic inflammatory process of the arterial wall at sites with disturbed laminar flow, such as arterial branches. It usually affects all arteries; while atherosclerosis in carotid and coronary arteries is a leading cause of mortality, peripheral arteries are more accessible for measurements, including risk assessment. Narrowing of arteries, usually due to atherosclerosis, is called cerebrovascular disease (CVD), when it affects the arteries that supply the brain, coronary artery disease (CAD), when it affects the heart, atherosclerotic renovascular disease (ARVD, ARAS) when the kidneys are affected, and peripheral arterial disease (PAD), when it affects other arteries. Peripheral vascular disease (PVD) includes PAD and chronic venous disease.
Atherosclerotic vascular disease results from the pathological deposition of lipids, such as cholesterol and triglycerides, within the walls of arterial blood vessels, leading to calcification, inflammation, and recruitment of macrophages and foam cells, and eventual thrombosis. Macrophages are not only recruited from circulation, but actively proliferating (Robbins et al., 2013). Expression of vascular adhesion molecule 1 (VCAM-1) and intracellular adhesion molecule 1 (ICAM-1) on vascular endothelial cells and production of chemotactic cytokines such as MCP-1 and TNF-α leads to adhesion of circulating leukocytes to the endothelium. Platelets are involved in the inflammation by releasing serotonin, P-selectin, and chemokines, attracting and guiding leukocytes. Platelets contain amyloid precursor protein (APP) which can be converted to amyloid β by macrophages. Platelet-derived SDF-1α mediates differentiation of endothelial progenitor cells into foam cells. Locally thickened arterial intima is called the plaque, or atheroma.
Atheroma is an accumulated mass (plaque) in the inner layer of arterial wall, consisting mostly of living and dead macrophages, lipids, MPO, calcium, and fibrous components of extracellular matrix. The plaque may narrow the artery, restricting the blood flow to the tissue that the artery is feeding. Ruptured plaques leak their contents, including cholesterol crystals, that cause inflammation and injury in other tissues.
Atherosclerosis occurs over a lifetime and is influenced by numerous factors, including excessive dietary fat, smoking, diabetes, sedentary lifestyle, and genetic factors. Atherosclerosis is found in practically all older people, and in most the development of atheromatous plaques is a silent and benign process. Accurate method for risk assessment and identifying the unstable plaques is of importance.
Low-density lipoprotein (LDL) metabolism is involved in the initiation and progression of atherosclerosis. The causal role of LDL cholesterol in the development of atherosclerotic disease is established by preclinical, clinical, and intervention studies. Lipid-lowering drugs, statins, inhibit the progression of the disease, and clinical benefit has been shown in individuals at risk of cardiovascular events (Piepoli et al., 2016; Grundy et al., 2019). Angioplasty benefits the patients in the late stages of atherosclerosis. Arterial walls and even plaques have active lymphatic drainage, and lymphatic vessels are the main return route of HDL and cholesterol from tissues to the blood. Lymphangiogenesis is studied as a potential way to reverse atherosclerosis.
Endothelial dysfunction and structural vessel wall alterations, such as the absence of a confluent luminal elastin layer and subsequent exposure of proteoglycans, permit sub-endothelial accumulation of LDL. LDL and other apolipoprotein B containing lipoproteins interact with the matrix proteoglycans, and accumulate in the intima. Aggregated and minimally oxidized LDL stimulates the overlaying endothelial cells to excrete pro-inflammatory factors which recruit monocytes and T lymphocytes, and inhibits the production of LDL. Monocytes/macrophages take up LDL and produce ROS and enzymes that further peroxidise lipids and modify LDL, escalating the inflammatory response. Degranulating neutrophils are particularly active in releasing ROS and myeloperoxidase (MPO) which oxidises LDL and modifies HDL already in the first steps of atherosclerosis (Nicholls & Hazen, 2005), and then MPO remains in the matured plaques. Scavenging of LDL by the macrophages transfers them to foam cells. Apoptosis of foam and other cells may lead to a necrotic core in the plaque. Hypoxic plaque core stimulates angiogenesis; immature micro-vessels are prone to intra-plaque haemorrhage (IPH). As part of the healing process, tiny calcium-containing deposits form in the plaque, weakening the fibrous cap (microcalcification); at later stage, the plaque and its necrotic core are largely calcified and inflammation is dampened (macrocalcification). Calcium scoring is feasible with CT, and the presence of obstructive and non-obstructive atherosclerosis can be assessed with MR and CT imaging. Low calcium score allows withholding statin therapy. Atherosclerotic plaque burden can be measured using ultrasound, CT, and MR.
Myeloperoxidase can be targeted in MR imaging: MPO-Gd contains two serotonin moieties attached to gadolinium. Extracellular MPO oxidises MPO-Gd, leading to formation of oligomers which can be observed with T1-weighted MRI (Ali et al., 2014).
Vascular calcification can be assessed using [18F]NaF PET (Derlin et al., 2011; Dweck et al., 2014; Irkle et al., 2015; Li et al., 2017). Fluoride PET may also be useful in identifying ruptured and vulnerable plaques (Joshi et al., 2014). Blood activity decreases with time, and therefore PET scan should be performed at least 1 h after [18F]NaF administration (Kwiecinski et al., 2019).
Incretin hormone GLP-1 receptor (GLP-1R) agonists reduce systemic inflammation and attenuate atherosclerotic lesion development. GLP-1R is primarily localized in M2 macrophages, and can be assessed with PET imaging (Ståhle et al., 2021).
Plaques are covered by fibrous collagen cap, produced by intimal fibromyoblast-like smooth muscle cells. In vulnerable plaques the collagen cap is thinned down, and thus vulnerable to rupture; thinning is caused by reduced production of ECM proteins because smooth muscle cell numbers are reduced or going through apoptosis, and increased degradation as macrophages produce matrix metalloproteinases (MMPs).
Rupture of atherosclerotic plaque is responsible for myocardial infarction and stroke. An injury to the plaque cap exposes plaque contents to the blood, causing acute thrombus formation and possibly occlusion of the vessel lumen; yet, most of the ruptures do not cause infarction, but just growth of the plaque.
Imaging methods are being developed for separating the unstable and stable plaques, based on their inherently different properties: plaques vulnerable for rupture have thin cap, large hypoxic and apoptotic or necrotic core, active inflammation, haemorrhage, and microcalcification; stable plaques have thick fibrous cap and macrocalcification (Langer et al., 2008; Sadeghi et al., 2010; Vancraeynest et al., 2011; Pedersen et al., 2014; Teague et al., 2017; Andrews et al., 2018). Contrast coronary CT angiography (CCTA) can identify calcified and non-calcified plaques, and some characteristics of unstable plaques. T1 weighted MR can identify intra-plaque haemorrhage and intraluminal thrombosis in coronary and carotid arteries. With suitable radioligands, PET/CT could be used to assess the activity of the atherosclerotic disease.
[18F]FDG uptake is increased in the inflamed macrophage-rich, possibly hypoxic, plaques, and is suitable for imaging large arteries. Treatment response to delcetrapid and and statins have been assessed using [18F]FDG (Fayad et al., 2011; Tawakol et al., 2013). However, [18F]FDG has limited utility in imaging coronary arteries because of the high [18F]FDG uptake in the myocardial muscle (Andrews et al., 2018). [18F]F- could be better for imaging coronary plaques than [18F]FDG (Adamson et al., 2015). Patient movement is common during coronary [18F]fluoride scan; gating and movement correction improves the reproducibility of coronary PET (Lassen et al., 2019a and 2019b).
[1-14C]acetate uptake is increased in animal model of atherosclerosis (Yamasaki et al., 2018). [1-11C]acetate PET could be used for assessing fatty acid synthesis in atherosclerotic arterial walls (Derlin et al., 2011).
Choline uptake is increased in activated macrophages. 18F- and 11C-labelled choline may be useful in imaging atherosclerosis, based on animal models (Laitinen et al., 2010; Hellberg et al., 2016) and human studies (Bucerius et al., 2008; Kato et al., 2009; Förster et al., 2010).
Macrophages express somatostatin receptor SSTR2, and [68Ga]DOTATOC, [68Ga]DOTATATE, and some other somatostatin receptor tracers are useful in imaging inflammation, including active plaques Li et al., 2013). Uptake in thoracic aorta correlates with cardiovascular risk factors (Lee et al., 2018). In atherosclerosis patients, [68Ga]DOTATATE discriminates high-risk versus low-risk coronary lesions better than [18F]FDG, and offers good image quality (Tarkin et al., 2017).
Integrin αvβ3 targeting RGD-based PET radiopharmaceuticals have been tested for imaging angiogenesis and inflammation in atherosclerotic plaques (Laitinen et al., 2009 Beer et al., 2014; Dietz et al., 2021).
TSPO is highly expressed in active macrophages and steroid producing tissues. Many TSPO-binding radioligands have been developed, mainly for detecting neuroinflammation, but imaging of vascular inflammation and atherosclerotic plaques is also possible (Laitinen et al., 2009; Pugliese et al., 2010; Gaemperli et al., 2012; Hellberg et al., 2018).
Intra-plaque haemorrhage is typical for plaques prone to rupture. Platelet APP can be converted to amyloid β by activated macrophages, which can be detected with amyloid β tracer [18F]flutemetamol (Hellberg et al., 2019).
Mannose receptor (CD206) is expressed on the surface of macrophages. Li et al (2016) developed 18F-labeled mannan, and found high uptake in atherosclerotic lesions in mice, as well as in macrophage-rich organs in healthy rats.
Peripheral artery disease affects most commonly the legs, which causes claudication, a walking-induced pain, leading to sedentary lifestyle, and can lead to critical limb ischemia (CLI) with rest pain, non-healing ulcers and infection, and high risk of limb amputation. Revascularization therapy is not effective in all CLI patients, possibly due to microvascular dysfunction. Exercise training can improve muscle blood flow and oxygenation PAD patients during physical activity (Baker et al., 2017).
An early study conducted with labelled microspheres suggested that PAD patients and healthy subjects cannot be separated by muscle perfusion at rest (Rhodes et al., 1973). Using PET and [15O]O2 and [15O]CO2 inhalation techniques, Clyne et al. (1979) reported that perfusion was reduced and oxygen extraction increased in the limb with claudication, and normalized after iliac endarterectomy. Depairon et al (1988a and 1988b) noticed small differences in PAD patients and normal subjects, mainly in the distribution of [15O]CO2 and [15O]O2 uptake. After exercise, perfusion and oxygen consumption stays higher in PAD leg (Depairon et al., 1988c; Depairon & Zicot, 1996). In subjects with neurogenic claudication (possibly with also PAD) Keenan et al (1995) did not find any difference in mid-thigh and mid-calf muscle perfusion between symptomatic and asymptomatic leg with [15O]H2O PET. Burchert et al (1997) found no difference in perfusion between patient and control groups at rest. Scremin et al. (2010) reported that perfusion during exercise was lower in the ischemia subjects and could be used when deciding the level of amputation. T2*-weighted MR signal changes during exercise may also separate PAD and control group (Li et al., 2017).
Drugs promoting angiogenesis have been studied in treatment of PAD, and PET radioligands targeting angiogenic system have been used in animal models.
- Metabolic syndrome
- Circulatory system
- Inflammation and infection
- Atherosclerotic renovascular disease
Dieter RS, Dieter RA Jr, Dieter RA III (eds.): Peripheral Arterial Disease. McGraw-Hill, 2009. ISBN: 978-0-07-164120-3.
Dieter R, Dieter RA Jr, Dieter RA III, Nanjundappa A (eds.): Critical Limb Ischemia - Acute and Chronic. Springer, 2017. doi: 10.1007/978-3-319-31991-9.
Grundy SM (ed.): Atlas of Atherosclerosis and Metabolic Syndrome, 5th ed., Springer, 2011. doi: 10.1007/978-1-4419-5839-6.
Kramer CM (ed.): Imaging in Peripheral Arterial Disease - Clinical and Research Applications. Springer, 2020. doi: 10.1007/978-3-030-24596-2.
Nicholls SJ, Crowe T (eds.): Imaging Coronary Atherosclerosis. Humana Press, Springer, 2014. doi: 10.1007/978-1-4939-0572-0.
Orbay H, Hong H, Zhang Y, Cai W. Positron emission tomography imaging of atherosclerosis. Theranostics 2013; 3(11): 894-902. doi: 10.7150/thno.5506.
Saba L, Sanches JM, Pedro LM, Suri JS (eds.): Multi-Modality Atherosclerosis Imaging and Diagnosis. Springer, 2014. doi: 10.1007/978-1-4614-7425-8.
Taylor AJ, Villines TC (eds.): Atherosclerosis: Clinical Perspectives Through Imaging. Springer, 2013. 10.1007/978-1-4471-4288-1.
Trivedi R, Saba L, Suri JS (eds.): 3D Imaging Technologies in Atherosclerosis. Springer, 2015. doi: 10.1007/978-1-4899-7618-5.
Wang H, Patterson C (eds.): Atherosclerosis - Risks, Mechanisms, and Therapies. Wiley, 2015. ISBN 978-1-118-28591-6.
Updated at: 2022-01-22
Created at: 2018-09-19
Written by: Vesa Oikonen