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Imaging inflammation in atherosclerosis: Exploring all avenues

Despite remarkable advances in preventive and therapeutic strategies, cardiovascular disease (CVD) remains the primary source of death and disability worldwide.1 Further, the demographic shift towards an older population will result in increasing numbers of patients, among whom heart disease is the leading cause of death. In view of this global burden, personalized risk-stratification tools and a cost-effective management of CVD are urgently needed. Although rapid innovations in atherosclerosis imaging have widened its applications from anatomical plaque detection to physiological assessment and complex evaluation of vascular biology, non-invasive imaging tools that flag the ‘vulnerable’ patient are still lacking. Indeed, although the presence of coronary artery stenosis is associated with subsequent events, most myocardial infarctions occur in segments with non-obstructive rather than obstructive disease.2 As recent landmark trials have further highlighted the fundamental role of inflammation during all stages of atherosclerosis, the assessment of ‘residual inflammatory risk’ has been proposed as a promising strategy for improving CVD risk prediction and providing guidance for novel precision treatments.3,4

Several molecular imaging modalities including 99mTc-based single-photon emission computed tomography (SPECT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) have been developed for the non-invasive detection of vascular inflammatory activities5,6 (Figure 1). 18F-FDG-PET has been used to detect macrophage-rich atherosclerotic lesions and as a surrogate endpoint for vascular interventional drug trials.7 However, it is limited by its moderate reproducibility and sensitivity for the detection of coronary atherosclerotic changes. In addition, 18F-FDG-PET has logistical and technical constraints including the need to suppress myocardial and peripheral muscle FDG uptake for the analysis as well as the high FDG uptake in structures close to the vessel wall. Hence, given the small size of the atherosclerotic lesion and the continuous cardiac and respiratory movements during PET acquisition, nuclear imaging of atherosclerosis remains challenging. Therefore, high-sensitivity PET and SPECT imaging probes that specifically target inflammatory cells in the vessel wall would greatly facilitate the non-invasive evaluation of the vulnerable plaque.

Figure 1
figure1

Molecular targets and selected probes for atherosclerosis imaging by positron emission tomography (PET) and single-photon emission computed tomography (SPECT). (1) 68Ga-DOTA-(Tyr3)-octreotate (68Ga-DOTATATE),111In-DOTA-JR11. (2) 11C-choline. (3) 99mTc-RP805, 111In-RP702. (4) 11C-PK11195, 18F-GE180. (5) 18F-fluorodeoxyglucose (18F-FDG). (6) 99mTc-cAbVCAM1-5. (7) 124I-hypericin. (8) 18F-fluoromisonidazole (18F-FMISO). (9) 18F-sodium fluoride (18F-NaF). (10) 18F-Galacto-RGD, 68Ga-NOTA-RGD. GLUT, glucose transporter; MMPs, matrix metalloproteinases; SST2 somatostatin receptor 2; TSPO, translocator protein

In this issue of the Journal of Nuclear Cardiology, Meester et al.8 analyzed the diagnostic potential of DOTA-JR11, labeled with 111indium (111In), in a mouse model of atherosclerosis as well as in human carotid endarterectomy tissue. 111In-DOTA-JR11 targets the up-regulated somatostatin receptor subtype 2 (SST2) on activated macrophages and might thus provide functional information about plaque activity and stability. The authors report that aortic plaques were detectable in all atherosclerotic mice, providing a proof-of-concept for the utility of 111In-DOTA-JR11 in preclinical atherosclerosis imaging. Further, 111In-DOTA-JR11 co-localized with CD68- and SST2-expressing cells on human carotid tissue sections indicating that the tracer is suitable to detect inflammatory activities in human atherosclerotic plaques. Their data are consistent with previous reports unveiling a close relationship between CVD risk factors, coronary calcium burden, and arterial uptake of 68Ga-DOTA-(Tyr3)-octreotate (68Ga-DOTATATE)—the most extensively validated SST2-targeted tracer.9 Indeed, in a prospective clinical investigation, Tarkin et al. recently demonstrated that 68Ga-DOTATATE can be used to differentiate between high-risk vs. low-risk carotid and coronary atherosclerotic lesions.10 Further, 68Ga-DOTATATE was superior to 18F-FDG-PET in discriminating between high-risk vs. low-risk human atherosclerotic plaques, underlining the capability of SST2-targeted tracers in capturing vulnerable plaque features.11

In contrast to DOTATATE, DOTA-JR11 belongs to the new generation of SST2 ligands that are based on antagonistic structures and exhibit more favorable receptor binding, pharmacokinetics, and biodistribution properties.12 It should be noted, however, that SST2-directed probes have originally been developed and approved for the detection of SST2 overexpression on neuroendocrine tumors.13 As such, DOTA-JR11 has recently shown promise in exhibiting a several-fold higher tumor uptake than DOTATATE,14 thereby highlighting its potential for a broad clinical applicability. Meester et al. now extend previous findings by demonstrating that DOTA-JR11, when labeled with indium-111, is sensitive to atherosclerotic plaque detection. Although this is an important finding, the authors did not perform a direct comparison between 111In-DOTA-JR11 SPECT and 68Ga-DOTATATE PET. Thus, whether second-generation SST2-based probes will outperform 68Ga-DOTATATE in atherosclerosis imaging will have to be tested in future studies. Further, N-terminal radiometal modifications may substantially affect the performance characteristics of DOTA-JR11.15 Given that gallium-68 labeled DOTA-JR11 (68Ga-DOTA-JR11) has not yet been evaluated for the imaging of coronary vascular inflammation, it is unclear how radiometal exchange between 111In and 68Ga will affect tracer performance. Nonetheless, a recent first-in-man study with 68Ga-DOTA-JR11 demonstrated pharmacokinetics and dosimetric data that compared favorably with 68Ga-DOTATATE,16 thus, paving the way for a head-to-head comparison between 68Ga-DOTA-JR11 and 68Ga-DOTATATE PET in atherosclerosis imaging.

Meester et al. conclude their discussion by stressing the need for future trials demonstrating the clinical utility of DOTA-JR11-based probes in plaque phenotyping. Indeed, provided that an increase in DOTA-JR11 signal is associated with the progression of atherosclerosis and the risk of cardiovascular events, high specific uptake of DOTA-JR11 might not only identify patients with high-risk plaques, but also individuals who could benefit from novel anti-inflammatory treatments. However, pertaining to a wider clinical use of SST2 imaging, it will be indispensable to consider the influence of sex on the complexity of atherosclerotic plaque morphology and activity. The study by Meester et al. did not address this important issue; nonetheless, sexual dimorphism in the association between inflammation and coronary artery disease has recently been demonstrated.17,18 Further, recent advances in coronary computed tomography angiography (CCTA) technology allow to detect coronary inflammation by capturing perivascular fat attenuation.19 Given the widespread use of CCTA as well as novel CCTA acquisition techniques ranging in a sub-millisievert fraction of effective radiation dose,20 the prognostic performance of SST2-targeted probes will have to be validated against novel imaging biomarkers derived from CCTA before they may advance from research tools to clinical applications. Future studies should also address potential synergistic applications of nuclear imaging techniques and CCTA, with the ultimate goal to identify the vulnerable plaque, the vulnerable artery, and, most importantly, the vulnerable patient.

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Disclosure

All authors have the following to disclose: The University Hospital of Zurich holds a research contract with GE Healthcare. CG has received research grants from the Novartis Foundation, Switzerland.

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Correspondence to Catherine Gebhard MD, PhD.

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CG was supported by grants from the Swiss National Science Foundation (SNSF), the Olga Mayenfisch Foundation, Switzerland, the OPO Foundation, Switzerland, the Novartis Foundation, Switzerland, the Swiss Heart Foundation, the Helmut Horten Foundation, Switzerland, the EMDO Foundation, Switzerland, and the Iten-Kohaut Foundation, Switzerland. SB and AH were supported by the University of Zurich (UZH) Foundation. SB was supported by the Swiss Heart Foundation, Switzerland.

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Haider, A., Bengs, S. & Gebhard, C. Imaging inflammation in atherosclerosis: Exploring all avenues. J. Nucl. Cardiol. (2020). https://doi.org/10.1007/s12350-020-02103-6

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