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. 2023 Oct;2(10):874-880.
Epub 2023 Sep 21.

CCR2 Imaging in Human ST-Segment Elevation Myocardial Infarction

Kory J Lavine  1   2   3 , Deborah Sultan  4 , Hannah Luehmann  4 , Lisa Detering  4 , Xiaohui Zhang  4 , Gyu Seong Heo  4 , Xiuli Zhang  4 , Michelle Hoelscher  4 , Kitty Harrison  4 , Christophe Combadière  5 , Richard Laforest  4 , Daniel Kreisel  3   6 , Pamela K Woodard  4 , Steven L Brody  1   4 , Robert J Gropler  1   4 , Yongjian Liu  4
Affiliations

CCR2 Imaging in Human ST-Segment Elevation Myocardial Infarction

Kory J Lavine et al. Nat Cardiovasc Res. 2023 Oct.

Abstract

Among the diverse populations of myeloid cells that reside within the healthy and diseased heart, C-C chemokine receptor 2 (CCR2) is specifically expressed on inflammatory populations of monocytes and macrophages that contribute to the development and progression of heart failure1-4. Here, we evaluated a peptide-based imaging probe (64Cu-DOTA-ECL1i) that specifically recognizes CCR2+ monocytes and macrophages for human cardiac imaging. Compared to healthy controls, 64Cu-DOTA-ECL1i heart uptake was increased in subjects following acute myocardial infarction, predominately localized within the infarct area, and was associated with impaired myocardial wall motion. These findings establish the feasibility of molecular imaging of CCR2 expression to visualize inflammatory monocytes and macrophages in the injured human heart.

Keywords: CC Chemokine Receptor 2 (CCR2); Macrophage; Molecular Imaging; Monocyte; Myocardial Infarction; Positron emission tomography.

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Conflict of interest statement

Competing interests K.J.L. serves as a consultant for Implicit Biosciences and Medtronic and is the recipient of sponsored research agreements with Amgen and Novartis. K.J.L., D.K., S.L.B., R.J.G., and Y.L. have a pending patent entitled “Methods for detecting CCR2 receptors” (application number: US17/001,857). The remaining authors declare no competing interests

Figures

Extended data Figure 1.
Extended data Figure 1.. In vitro cell binding assays of 64Cu-DOTA-ECL1i in THP-1 cells and 293T cells.
Data are representative of at least three independent experiments from THP cells (left, express CCR2) and HEK293T cells (right, do not express CCR2). Cells (2 × 106) were incubated with approximately 37 KBq of 64Cu-DOTA-ECL1i with the indicated concentrations of cold DOTA-ECL1i at room temperature for 1 h. n=3 technical replicates. Error bars are standard deviation.
Extended data Figure 2.
Extended data Figure 2.. In vitro cell binding assays of 64Cu-DOTA-ECL1i in human immune cells.
Data are representative of at least three independent experiments from 2 donors. *** p<0.001, **** p<0.0001. 1-way ANOVA. CPM: counts per minute. n=3 technical replicates. Error bars are standard deviation.
Extended data Figure 3.
Extended data Figure 3.. CCR2 imaging in the other control subjects.
99mTc-Tetrofosmin (99mTc) SPECT/CT and differential 64Cu-DOTA-ECL1i (CCR2) PET/CT fused images as described in Figure 1. SPECT/CT perfusion and CCR2 PET/CT images are co-registered and comparative anatomic slices displayed. Differential 64Cu-DOTA-ECL1i images are corrected for blood activity. Color scale indicates normalized relative tracer uptake.
Extended data Figure 4.
Extended data Figure 4.. CCR2 imaging in the STEMI patients.
99mTc-Tetrofosmin (99mTc) SPECT/CT and differential 64Cu-DOTA-ECL1i (CCR2) PET/CT fused images as described in Figure 1. SPECT/CT perfusion and CCR2 PET/CT images are co-registered and comparative anatomic slices displayed. Differential 64Cu-DOTA-ECL1i images are corrected for blood activity. Green and red arrows denote the infarct region. Color scale indicates normalized relative tracer uptake.
Figure 1.
Figure 1.. CCR2 imaging in healthy controls and subjects following STEMI.
A, Representative 99mTc-tetrofosmin (99mTc) SPECT/CT and differential 64Cu-DOTA-ECL1i (CCR2) PET/CT fused images of healthy controls and STEMI patients. SPECT/CT perfusion and CCR2 PET/CT images are co-registered and comparative anatomic slices displayed. Differential 64Cu-DOTA-ECL1i images are corrected for blood activity. Green and red arrows denote the infarct region. Color scale bar indicates normalized relative tracer uptake. B, 64Cu-DOTA-ECL1i myocardial signal. For STEMI subjects, differential mean standardized uptake value (SUVmean) was calculated in the infarct and remote regions. Statistical significance was determined using 1-way ANOVA. Control n=6, STEMI n=7. C, 64Cu-DOTA-ECL1i skeletal muscle signal. Statistical significance was determined using Mann-Whitney test (2-sided). Control n=6, STEMI n=7. D, 64Cu-DOTA-ECL1i myocardial signal as a function of time following STEMI. Each data point represents an individual patient. The mean value for controls with standard deviation is displayed as line with grey zones. STEMI n=7. E, Corresponding 17-segment model polar maps of SPECT/CT perfusion and myocardial wall motion and CCR2 PET/CT from a representative subject. 99mTc-tetrofosmin SPECT/CT and wall motion polar maps are displayed as % of maximal value (100%). The CCR2 PET/CT polar map represents SUVmean values. F, Linear regression analysis examining the association between CCR2 tracer uptake and wall motion score. p<0.05 and r2=0.4. n=7. Each data point represents an individual patient. Error bars represent standard deviation.
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