Uncovering atherosclerotic cardiovascular disease by PET imaging

Abstract

Assessing atherosclerosis severity is essential for precise patient stratification. Specifically, there is a need to identify patients with residual inflammation because these patients remain at high risk of cardiovascular events despite optimal management of cardiovascular risk factors. Molecular imaging techniques, such as PET, can have an essential role in this context. PET imaging can indicate tissue-based disease status, detect early molecular changes and provide whole-body information. Advances in molecular biology and bioinformatics continue to help to decipher the complex pathogenesis of atherosclerosis and inform the development of imaging tracers. Concomitant advances in tracer synthesis methods and PET imaging technology provide future possibilities for atherosclerosis imaging. In this Review, we summarize the latest developments in PET imaging techniques and technologies for assessment of atherosclerotic cardiovascular disease and discuss the relationship between imaging readouts and transcriptomics-based plaque phenotyping.

Fig. 1 |. Representative PET images of atherosclerosis.

a, [¹⁸F]Fluorodeoxyglucose ([¹⁸F]FDG) PET–CT image of the ascending aorta in a patient with acute coronary syndrome. b, Coronary artery sodium [¹⁸F]fluoride ([¹⁸F]NaF) PET–CT images of a patient who later presented with an inferior myocardial infarction. c, ⁶⁸Ga-DOTATATE PET–CT images showing uptake in a coronary artery (left image, arrow) and the carotid arteries (right image, inset). d, ⁶⁸Ga-pentixafor PET–CT image showing focal tracer accumulation in a coronary artery (arrow). LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; RCA, right coronary artery; SUV, standardized uptake value. Panel a adapted with permission from ref. , Elsevier; panel b adapted with permission from ref. , Elsevier; panel c adapted from ref. , CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/); panel d adapted from ref. , CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).

Fig. 2 |. Imaging the systemic inflammatory effects that aggravate atherosclerosis.

a, Factors that influence the immune system and contribute to atherosclerosis progression or regression include acute cardiovascular events, cardiovascular risk factors, inflammatory conditions, lifestyle factors and medication. These factors influence the immune system in different ways and with varying intensity. The effects on the immune system include, but are not limited to, stimulation of haematopoietic stem and progenitor cell (HSPC) and mature immune cell proliferation, immune cell egress from haematopoietic organs and recruitment to the atherosclerotic plaque, and the induction of trained immunity. b, Representative PET–CT images from an individual with acute coronary syndrome (ACS), showing increased [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) uptake in the aorta, bone marrow (BM) and spleen, as compared with PET–CT images from a control individual. c, Representative images of differences in [¹⁸F]FDG uptake (visualized in blue) in the BM in patients with subclinical atherosclerosis. The L3 and L4 vertebrae (white arrows) show high uptake. High [¹⁸F]FDG uptake was associated with metabolic syndrome. The asterisk indicates the bladder (visualized in red). d, Representative [¹⁸F]FDG PET images of differences in metabolic activity in the amygdala, aortic atherosclerotic plaque and BM in an individual with a subsequent cardiovascular event compared with a control individual. The values shown on the white arrows in the top and middle panels are the target-to-background ratios, the values shown in the bottom panels are the standardized uptake values. CVD, cardiovascular disease. Panel b adapted with permission from ref. , Elsevier; panel c adapted with permission from ref. , OUP; panel d adapted with permission from ref. , Elsevier.

Fig. 3 |. Technological advances to overcome limitations in PET imaging of atherosclerosis.

Several technological advances (blue) might contribute to achieve the goals for atherosclerosis PET imaging (grey). LAFOV, long axial field of view.

Fig. 4 |. PET tracer development and in vivo tracer labelling techniques.

a, Schematic representation of human antibody (and fragments) and camelid antibody (and fragments) used for PET imaging. The approximate molecular weights are indicated. b, In vivo pre-targeting. First, specific antibodies are injected intravenously and allowed to bind to their cellular target. After a few days, the radioisotope is injected and binds to the antibody in vivo. The antibody (blue) has a long circulation half-life, whereas the radioisotope (yellow) clears quickly from the body, resulting in low radiation exposure. CH, constant heavy; VH, variable heavy; CL, constant light; VL, variable light; V_HH, variable heavy of heavy-chain-only antibodies.

Fig. 5 |. Advances in PET imaging technologies.

a, Extending the field of view (FOV) from ~20 cm (conventional systems) to ~60 cm (long axial FOV) or even ~200 cm (total body) can enable detection of more photons and increase sensitivity. b, Schematic representation of dynamic imaging through a multipass protocol. c, Simultaneous quantitative imaging of two PET tracers can be achieved by using tracers with different isotope properties. List-mode reconstruction data can be used to separate isotopes emitting a prompt γ-ray (red) from pure positron emitters (blue). d, Positronium imaging assesses the lifetime of a positronium (the positron–electron bound state; yellow box) by measuring the time between positron emission and annihilation photon detection. The decay rate of the positronium depends on its environment. For example, positronium lifetime is longer when oxygen levels are low (bottom graph).