Current and novel radiopharmaceuticals for imaging cardiovascular inflammation

Abstract

Cardiovascular disease (CVD) remains the leading cause of death worldwide despite advances in diagnostic technologies and treatment strategies. The underlying cause of most CVD is atherosclerosis, a chronic disease driven by inflammatory reactions. Atherosclerotic plaque rupture could cause arterial occlusion leading to ischemic tissue injuries such as myocardial infarction (MI) and stroke. Clinically, most imaging modalities are based on anatomy and provide limited information about the on-going molecular activities affecting the vulnerability of atherosclerotic lesion for risk stratification of patients. Thus, the ability to differentiate stable plaques from those that are vulnerable is an unmet clinical need. Of various imaging techniques, the radionuclide-based molecular imaging modalities including positron emission tomography and single-photon emission computerized tomography provide superior ability to noninvasively visualize molecular activities in vivo and may serve as a useful tool in tackling this challenge. Moreover, the well-established translational pathway of radiopharmaceuticals may also facilitate the translation of discoveries from benchtop to clinical investigation in contrast to other imaging modalities to fulfill the goal of precision medicine. The relationship between inflammation occurring within the plaque and its proneness to rupture has been well documented. Therefore, an active effort has been significantly devoted to develop radiopharmaceuticals specifically to measure CVD inflammatory status, and potentially elucidate those plaques which are prone to rupture. In the following review, molecular imaging of inflammatory biomarkers will be briefly discussed.

Figure 1.. Positron emission tomography (PET) of ⁶⁸Ga-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-ECL1i (extracellular loop 1 inverso) in a mouse model of closed-chest ischemia-reperfusion injury.

A, Representative ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT images obtained 5 d after 90 min of ischemia-reperfusion injury identifying the infarct region in mice that underwent ischemia-reperfusion injury (myocardial infarction [MI]) compared with sham controls. Transverse, coronal, and maximal-intensity projected (MIP) views are shown, and white arrows denote the infarct area. B, Representative ⁶⁸Ga-DOTA-ECL1i PET/CT images showing regional accumulation of ⁶⁸Ga-DOTA-ECL1i signal in the infarct and border zone 4 d after ischemia-reperfusion injury. Transverse, coronal, and MIP views are shown. Yellow arrow identifies tracer uptake in hearts that underwent ischemia-reperfusion injury compared with sham controls. White arrows denote the infarct area as determined by ¹⁸F-FDG imaging. C, Quantitative analysis of ⁶⁸Ga-DOTA-ECL1i accumulation in the hearts of naive, sham, MI, and CCR2 (C-C chemokine receptor type 2) KO (knockout) mice that underwent ischemia-reperfusion injury at the indicated time points. n=4 to 5 per experimental group. D, Regional accumulation of ⁶⁸Ga- DOTA-ECL1i uptake in the infarct and remote areas of sham and MI mice over the indicated time points. E, Biodistribution of ⁶⁸Ga activity 4 d after ischemia-reperfusion injury measured 1 h post-intravenous injection (tail vein) of ⁶⁸Ga-DOTA-ECL1i. n=5 per experimental group. F, Trichrome and hematoxylin and eosin (H&E) staining show the evolution of fibrosis (trichrome-blue, ×40 magnification) and cell infiltration (H&E, ×200 magnification) over time in the closed-chest ischemia-reperfusion injury model. Note the dense accumulation of cells within the infarct 4 d after ischemia-reperfusion injury. Representative images from 6 independent experiments. G, Flow cytometry analysis showing accumulation of CCR2+ monocytes (CCR2+MHCIIlow) and CCR2+ macrophages (CCR2+MHC-IIhigh) 4 d after ischemia-reperfusion injury and persistence of CCR2+ macrophages 7 d after ischemia reperfusion injury compared with sham controls. H, Immunostaining showing accumulation of CCR2+ cells (brown) in the infarct region peaking at day 4 after ischemia-reperfusion injury. I, Linear regression analyses showing the relationship between ⁶⁸Ga-DOTA-ECL1i heart uptake measured on day 4 after ischemia-reperfusion injury and echocardiographic assessment of LV ejection fraction and akinetic area measured on day 28 after ischemiareperfusion injury. *P<0.05, **P<0.01, ***P<0.005, ****P<0.001. MHC indicates major histocompatibility complex. Reprinted with permission from reference

Figure 2.. Comparison between ⁶⁸Ga-DOTATATE and ¹⁸F-FDG coronary PET inflammation imaging.

Images from a 57-year old man with acute coronary syndrome who presented with deep anterolateral T-wave inversion (arrow) on electrocardiogram (A) and serum troponin-I concentration elevated at 4,650 ng/l (NR: <17 ng/l). Culprit left anterior descending artery stenosis (dashed oval) was identified by X-ray angiography (B). After the patient underwent percutaneous coronary stenting (C), residual coronary plaque (*inset) with high-risk morphology (low attenuation and spotty calcification) is evident on CT angiography (D, E). Use of ⁶⁸Ga-DOTATATE PET (F, H, I) clearly detected intense inflammation in this high-risk atherosclerotic plaque/distal portion of the stented culprit lesion (arrow) and recently infarcted myocardium (*). In contrast, using ¹⁸F-FDG PET (G, J), myocardial spillover completely obscures the coronary arteries. CT = computed tomography; ¹⁸F-FDG = fluorine-18-labeled fluorodeoxyglucose; ⁶⁸Ga-DOTATATE = gallium-68-labeled DOTATATE; PET = positron emission tomography. Adapted with permission from reference

Figure 3.

Representative ¹⁸F-fluorocholine positron emission tomography-computed tomography (¹⁸F-FCH PET-CT) images and corresponding histology of a symptomatic and contralateral asymptomatic carotid plaque of a 67-year-old patient who experienced right-sided stroke 12 days before PET-CT imaging. A, Diagnostic contrast-enhanced CT shows a significant stenosis in the right internal carotid artery because of a soft plaque, whereas no atherosclerotic plaque can be seen on the contralateral internal carotid artery. Regions of interest (ROI, white outlining) drawn around the outer border of the vessel walls were placed along the right carotid stenosis and along the contralateral carotid artery, respectively. B, CT, inset on the symptomatic plaque. C, The fused PET-CT image denotes a focal area of high ¹⁸F-FCH uptake in the ROI drawn onto the right symptomatic carotid plaque, whereas there is no visible 18F-FCH uptake in the left asymptomatic carotid plaque. The activity recorded for both symptomatic and contralateral asymptomatic carotid arteries were corrected for venous blood background activity in the jugular veins, resulting in a maximum target-to-background ratio of 2.46 and 1.18, respectively. Corresponding immunohistochemistry sections indicating CD68+ (D), MHC-II+ (E), and HAM56+ (F) cells (all in brown). MHC-II indicates major histopathology complex class-II; HAM56, human alveolar macrophage marker-56. Reprinted with permission from reference

Figure 4.

¹⁸F-FLT and ¹⁸F-FDG positron emission tomography–computed tomography (PET-CT) in humans with atherosclerosis. A, Sagittal image revealing extensive calcification in the aorta and carotid artery (arrows). ¹⁸F-FDG (B) and ¹⁸F-FLT (C) images demonstrate uptake of the PET tracers in the vessel wall of the aortic arch (arrows). Adapted with permission from reference

Figure 5.. Applications of ¹⁸F-Macroflor.

PET imaging of aortic plaques in atherosclerotic mice (A) and rabbits (B). PET imaging of mice with acute myocardial infarction at day 6 post MI (C and D). White dotted line on PET/MRI outlines myocardium. Yellow dashed line on MRI outlines the infarct identified by gadolinium enhancement and wall motion abnormality in cine loops. Adapted with permission from reference