Imaging Immunometabolism in Atherosclerosis

Philip Z. Mannes; Sina Tavakoli

doi:10.2967/jnumed.120.245407

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FIGURE 1.
(A) Overlapping and stimulus-specific metabolic reprogramming of macrophages polarized into proinflammatory (M1) and inflammation-resolving (M2) states. Metabolic changes in response to lipopolysaccharide with or without IFN-γ and GM-CSF, as examples of M1-polarizing stimuli, vs. IL-4 and M-CSF, as examples of M2-polarizing stimuli, are summarized. Immunometabolic profiles of macrophages within plaque microenvironment are far more complex and cannot be accurately extrapolated from M1/M2 polarization scheme. (B) Major metabolic pathways targeted by PET imaging and examples of available radiotracers. ⁶⁴Cu-ATSM = ⁶⁴Cu-copper(II)diacetyl-di(N4-methylthiosemicarbazone); CoA = coenzyme A; FADH2 = reduced flavin adenine dinucleotide; FAO = fatty acid oxidation; FAS = fatty acid synthesis; ¹⁸F-FEC = ¹⁸F-fluoroethylcholine; ¹⁸F-FGln = ¹⁸F-(2S,4R)-4-fluoro-L-glutamine; ¹⁸F-FMC = ¹⁸F-fluoromethylcholine; ¹⁸F-FTHA = ¹⁸F-fluoro-6-thia-heptadecanoic acid; ¹⁸F-FTP = ¹⁸F-fluoro-4-thia-palmitate; ¹¹C-Gln = l-5-¹¹C-glutamine; LPS = lipopolysaccharide; NADH = reduced nicotinamide adenine dinucleotide; OxPhos = oxidative phosphorylation.
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FIGURE 2.
PET metabolic imaging of atherosclerosis. (A) Examples of ¹⁸F-FMISO and ¹⁸F-FDG PET/CT in patient with carotid artery atherosclerosis demonstrate uptake of both tracers in left carotid artery plaque (arrows). Graph shows that ¹⁸F-FMISO uptake correlates with ¹⁸F-FDG uptake. (B) Examples of ¹¹C-acetate PET/CT of aorta in patients receiving whole-body scans for oncologic indications. Images from patient 1 indicate ¹¹C-acetate uptake in aortic region without calcified plaques, whereas images from patient 2 demonstrate colocalization of ¹¹C-acetate uptake with aortic calcifications (arrows point to areas of arterial ¹¹C-acetate uptake). (C) Examples of ¹¹C-choline PET/CT of aortic arch in men receiving whole-body scans for assessment of prostate cancer. Colocalization of ¹¹C-choline uptake with aortic calcifications is observed in patient 2 but not in patient 1 (arrows indicate areas of aortic arch calcification). MaxTBR = maximum target-to-background ratio. (Reprinted with permission of (27,30,37).)

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TABLE 1

Summary of Metabolic Radiotracers Used for PET/CT Imaging of Atherosclerosis

Tracer	Metabolic targets	Advantages and key findings	Limitations	Study
¹⁸F-FDG	Glucose transport and phosphorylation	Tracer is readily available and the most extensively validated in preclinical and clinical studies; uptake correlates with overall inflammatory burden of plaques, for example, macrophage content; early detection of response to statins is possible	Tracer targets nearly ubiquitous metabolic process, with limited specificity for individual cell type or phenotype	(12–15)
¹⁸F-FMISO	Cellular hypoxia	Uptake is higher in symptomatic carotid plaques; positive correlation exists between ¹⁸F-FMISO and ¹⁸F-FDG uptake	Diffusion barrier limits uptake; cell specificity is lacking	(27)
¹⁸F-HX4	Cellular hypoxia	Positive correlation exists between ¹⁸F-HX4 and ¹⁸F-FDG uptake	Diffusion barrier limits uptake; cell specificity is lacking	(26)
⁶⁴Cu-ATSM	Cellular hypoxia	Uptake correlates with plaque hypoxia and macrophage content; hypoxic cell uptake is higher than for ¹⁸F-FMISO, and washout from normoxic tissues is faster	Diffusion barrier limits uptake; cell specificity is lacking	(28)
¹¹C-acetate	TCA, FAO, FAS, OxPhos	Focal uptake occurs in calcified plaques and arterial segments without calcifications	Half-life is short, limiting availability	(30)
¹¹C-choline	FAS, biosynthesis	Uptake is mostly in arterial segments with thickening and increased lipid content; cardiac uptake is lower than that of ¹⁸F-FDG	Half-life is short, limiting availability	(37)
¹⁸F-FMC	FAS, biosynthesis	Uptake is mostly in arterial segments with thickening and increased lipid content	Tracer may be substrate for distinct set of transporters from those used to transport choline	(36)
¹⁸F-FEC	FAS, biosynthesis	Uptake correlates with cardiovascular risk factors; no association exists between uptake and prior cerebrovascular or cardiovascular events	Tracer may be substrate for distinct set of transporters from those used to transport choline	(38)

ATSM = diacetyl-bis(N4-methylthiosemicarbazone); FAO = fatty acid oxidation; FAS = fatty acid synthesis; FMC = fluoromethylcholine; FEC = fluoroethylcholine.