PRE-CLINICAL IMAGING of ATHEROSCLEROSIS - first Meeting of the CV Study Group
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Optimal imaging protocols, tricks and pitfalls for MRI (#608)
M. R. Makowski1
1 Charité, Radiology, Berlin, Berlin, Germany
Optimal imaging protocols, tricks and pitfalls for MRI
This presentation will give an overview regarding optimal imaging protocols, tricks and pitfalls for magnetic resonance imaging with a specific focus on cardiovascular diseases. The first part of the presentation will focus on the technical aspects of imaging atherosclerotic plaque with MRI. The second part of the presentation will focus on the protocols and techniques needed for the visualization of molecular imaging probes. In the context of atherosclerosis, MRI allows the noninvasive characterization of the relative plaque composition, the integrity of the fibrous cap and the quantification of plaque burden. By multiparametric imaging protocols in combination with MR probes, contrast between plaque structures, such as the necrotic core and the fibrous cap, can be visualized. Most MRI probes are based on paramagnetic complexes, for instance paramagnetic gadolinium (Gd) based substances or iron-oxide nano-particles. Molecular Gd-based probes are a combination of a chelated Gd with a target specific component. Gd-based probes cause a positive signal effect, as a result of the shortening of the T1 relaxation time. Iron oxide based nanoparticles on the other hand cause a strong negative signal effect, as a result of the shortening of the T2/T2* relaxation time. The advantage of MRI is the detection and visualization of molecular probes with a high spatial and temporal resolution, compared to modalities such as positron emission tomography (PET) and single photon emission computed tomography (SPECT). MRI also allow the generation of anatomical images and enables the native characterization of atherosclerotic plaque components with a high soft tissue contrast based on local tissue properties. Additionally, MRI is a radiation free technique, therefore imaging can be repeated multiple times without associated risks. On the other hand, MRI is a relatively time-consuming technique, compared to e.g. CT and the sensitivity for the detection of molecular probes is lower compared to nuclear techniques like PET and SPECT.
A new picture of atherosclerosis – can Optical Imaging do more? (#576)
1 Westfälische Wilhelms Universität Münster, Translational Research Imaging Center, Münster, Germany
As atherosclerosis in generally perceived as an inflammatory disease, capturing immune and inflammation related biology is an important task for the molecular imaging community.
Optical Imaging has the advantage to cover a wide range of contrasts and synthesis of optical reporters targeting specific cellular or molecular aspects is chemically easier compared to the synthesis of Magnetic Resonance Agents or radiotracers. The limited penetration depth however remains the major hurdle of optical technologies. Diffuse attenuation and scattering of the light in complex tissue decreases signal intensity, spatial resolution and makes quantification of fluorescence cumbersome. Similarly, clinical translation of optical technologies for imaging cardiovascular disease is limited.
However, recent approaches such a hybridized optical imaging as well as photoacoustic imaging overcome several of the traditional drawbacks, improve spatial resolution and quantification and enable first attempts of clinical translation. Invasive optical technologies that bring the light source and detector close to the target via catheter devices are promising tools to move optical molecular imaging towards clinical applications.
Pre-clinical nuclear imaging of atherosclerosis. (#582)
1 Klinikum rechts der Isar-TUM, Nuclear medicine, Munich, Germany
Atherosclerosis is one of the most actively investigated fields in medical imaging. Nuclear imaging of plaque instability targets a wide range of pathophysiologic processes involved in atherosclerosis;
The accumulation of LDL or its oxidized derivatives is the first step of atherosclerosis which was adapted as target for imaging of atherosclerotic plaques in early studies (1, 2).
Endothelial activation is the sliding door for inflammation. The expression of VCAM-1 or selectins on the activated endothelium has been selected for plaque imaging and some radiotracers were utilized to this aim (3, 4).
Activated macrophages are the most extensively investigated imaging targets for assessing plaque vulnerability and [18F]-FDG is the most widely used imaging probe to this aim. The close correlation between [18F]-FDG uptake and macrophage accumulation has been reported both in animal models and human studies. However, high tracer uptake into myocytes of the heart in addition to lack of the specificity of [18F]-FDG to inflammatory cells limits its utility. Therefore, more specific tracers for detection of inflammatory activity in the vessel walls need to be pursued. Many surface receptors expressed on activated macrophages, including somatostatin receptor SSTR2, translocator protein TSPO, mannose receptor MR and chemokine receptor CXCR4, were utilized for plaque imaging (5, 6, 7, 8).
Several proteases released by macrophages, e.g. matrix metalloproteinase MMP, which are responsible to loosen the extracellular space so that inflammatory as well as smooth muscle cells can easily migrate through the space, were also targeted to image prone to rupture atherosclerotic plaques (9).
Increase of the plaque size as well as active and prolonged inflammation in vulnerable plaques leads to hypoxic conditions in the local tissue. [18F]-FMISO has been utilised to image hypoxia for plaque visualization (10).
Neoangiogenesis is another hallmark of vulnerable plaque. Radiotracers targeting integrin αvβ3 and VEGF receptors have been evaluated for plaque imaging (11, 12).
Apoptosis, which occurs in macrophages and other cell types as a result of inflammation, has also been adapted for atherosclerotic plaque imaging (13).
It has been proposed that by imaging calcification as a final process in inflammation we may be able to identify early calcific deposits and hence rupture-prone plagues (14).
In spite of acquired promising results, there are still considerable limitations in nuclear imaging of atherosclerosis. The main challenge to plaque imaging is that the accumulation of an imaging agent and hence signal is not enough in the target lesion because most of the lesions are very small and easily affected by the partial volume effect. Therefore, it may be necessary to employ a partial volume correction to improve the quantitative assessment of the plaque. Ex vivo confirmation of the tracer accumulation in the lesions is essential for tracer characterization. In addition, comparison studies to [18F]-FDG are likely required to determine the added value of the new radiotracer for plaque imaging.
Altogether, the range of targets reflects the complexity of the disease process, and definition of the optimal target for identification of vulnerability remains unclear.
1. Shaw PX, Hörkkö S, Tsimikas S, Chang MK, Palinski W, Silverman GJ, et al. Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler Thromb Vasc Biol. 2001;21:1333–1339.
2. Tekabe Y, Li Q, Rosario R, Sedlar M, Majewski S, Hudson BI, et al. Development of receptor for advanced glycation end products-directed imaging of atherosclerotic plaque in a murine model of spontaneous atherosclerosis. Circ Cardiovasc Imaging. 2008;1:212–219.
3. Nahrendorf M, Keliher E, Panizzi P, Zhang H, Hembrador S, Figueiredo JL, et al. 18F-4V for PET-CT imaging of VCAM-1 expression in atherosclerosis. JACC Cardiovasc Imaging. 2009;2:1213–1222.
4. Li X, Bauer W, Israel I, Kreissl MC, Weirather J, Richter D, et al. Targeting P-selectin by gallium-68-labeled fucoidan positron emission tomography for noninvasive characterization of vulnerable plaques: correlation with in vivo 17.6T MRI. Arterioscler Thromb Vasc Biol. 2014;34:1661–1667.
5. Rinne P, Hellberg S, Kiugel M, Virta J, Li XG, Kakela M, et al. Comparison of Somatostatin Receptor 2-Targeting PET Tracers in the Detection of Mouse Atherosclerotic Plaques. Mol Imaging Biol. 2016;18(1):99-108.
6. Hellberg S, Silvola JMU, Kiugel M, Liljenback H, Savisto N, Li XG, et al. 18-kDa translocator protein ligand 18F-FEMPA: Biodistribution and uptake into atherosclerotic plaques in mice. J Nucl Cardiol. 2017;24(3):862-71.
7. Tahara N, Mukherjee J, de Haas HJ, Petrov AD, Tawakol A, Haider N, et al. 2-deoxy-2-[18F]fluoro-D-mannose positron emission tomography imaging in atherosclerosis. Nat Med. 2014;20(2):215-9.
8. Hyafil F, Pelisek J, Laitinen I, Schottelius M, Mohring M, Doring Y, et al. Imaging the Cytokine Receptor CXCR4 in Atherosclerotic Plaques with the Radiotracer (68)Ga-Pentixafor for PET. J Nucl Med. 2017;58(3):499-506.
9. Schäfers M, Riemann B, Kopka K, Breyholz HJ, Wagner S, Schäfers KP, et al. Scintigraphic imaging of matrix metalloproteinase activity in the arterial wall in vivo. Circulation. 2004;109:2554–2559.
10. Mateo J, Izquierdo-Garcia D, Badimon JJ, Fayad ZA, Fuster V. Noninvasive assessment of hypoxia in rabbit advanced atherosclerosis using (1)(8)F-fluoromisonidazole positron emission tomographic imaging. Circ Cardiovasc Imaging. 2014;7(2):312-20.
11. Golestani R, Zeebregts CJ, Terwisscha van Scheltinga AG, Lub-de Hooge MN, van Dam GM, Glaudemans AW, et al. Feasibility of vascular endothelial growth factor imaging in human atherosclerotic plaque using (89)Zr-bevacizumab positron emission tomography. Mol Imaging. 2013;12(4):235-43.
12. Laitinen I, Saraste A, Weidl E, Poethko T, Weber AW, Nekolla SG, et al. Evaluation of alphavbeta3 integrin-targeted positron emission tomography tracer 18F-galacto-RGD for imaging of vascular inflammation in atherosclerotic mice. Circ Cardiovasc Imaging. 2009;2(4):331-8.
13. Johnson LL, Schofield L, Donahay T, Narula N, Narula J. 99mTc-annexin V imaging for in vivo detection of atherosclerotic lesions in porcine coronary arteries. J Nucl Med. 2005;46:1186–1193.
14. Irkle A, Vesey AT, Lewis DY, Skepper JN, Bird JL, Dweck MR, et al. Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography. Nat Commun. 2015;6:7495.
Keywords: Nuclear imaging, Pre-clinical imaging, Atherosclerosis
The immune system as a target for treating complex cardiovascular disease (#613)
W. Mulder1, 2
1 Icahn School of Medicine at Mount Sinai, Department of Radiology, New York, United States of America
Thrombotic events in atherosclerosis are the ultimate consequence of chronic, maladaptive lipid-driven vessel wall inflammation. As atherosclerotic disease progresses, plaque monocyte-derived macrophages destabilize the vessel wall by secreting inflammatory cytokines and proteases that digest extracellular matrix, thereby weakening the protective fibrous cap and promoting thrombosis. Immunological studies have elucidated that macrophage dynamics in atherosclerosis is a complex systemic process which, after initial production of monocytes in the bone marrow, involves monocyte egress from the bone marrow and spleen, and subsequent plaque monocyte recruitment, resulting in increased macrophage accumulation. To add to the complexity, recent preclinical and clinical data describe a direct causal link between clinical cardiovascular events and the aggravation of inflammatory atherosclerosis.
In this presentation, macrophage dynamics in atherosclerosis and the role of imaging to noninvasively quantify this process systemically are elucidated. Lessons learned from the first trial focusing on inflammation (CANTOS) have redefined the cardiovascular therapeutic landscape, generating new opportunities for nanoimmunotherapy, one such — we recently developed — will be highlighted.
Open Discussion on future directions, group activities, and review article.