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CCR2 imaging in human ST-segment elevation myocardial infarction

Nature Cardiovascular Research volume 2, pages 874–880 (2023)Cite this article

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Abstract

Among the diverse populations of myeloid cells that reside within the healthy and diseased heart, C-C chemokine receptor type 2 (CCR2) is specifically expressed on inflammatory populations of monocytes and macrophages that contribute to the development and progression of heart failure1,2,3,4. 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 individuals after 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.

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Fig. 1: CCR2 imaging in healthy controls and individuals after STEMI.

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All source data are provided in the supplementary materials; additional details are available from the authors upon reasonable request.

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No custom code was used in this manuscript.

References

  1. Epelman, S. et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40, 91–104 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lavine, K. J. et al. Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc. Natl Acad. Sci. USA 111, 16029–16034 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Epelman, S., Lavine, K. J. & Randolph, G. J. Origin and functions of tissue macrophages. Immunity 41, 21–35 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bajpai, G. et al. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat. Med. 24, 1234–1245 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Mann, D. L. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ. Res. 116, 1254–1268 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. van der Laan, A. M. et al. A proinflammatory monocyte response is associated with myocardial injury and impaired functional outcome in patients with ST-segment elevation myocardial infarction: monocytes and myocardial infarction. Am. Heart J. 163, 57–65 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Mariani, M. et al. Significance of total and differential leucocyte count in patients with acute myocardial infarction treated with primary coronary angioplasty. Eur. Heart J. 27, 2511–2515 (2006).

    Article  PubMed  Google Scholar 

  9. Rischpler, C. et al. Prospective evaluation of 18F-fluorodeoxyglucose uptake in postischemic myocardium by simultaneous positron emission tomography/magnetic resonance imaging as a prognostic marker of functional outcome. Circ. Cardiovasc. Imaging 9, e004316 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wollenweber, T. et al. Characterizing the inflammatory tissue response to acute myocardial infarction by clinical multimodality noninvasive imaging. Circ. Cardiovasc. Imaging 7, 811–818 (2014).

    Article  PubMed  Google Scholar 

  11. Thackeray, J. T. & Bengel, F. M. Molecular imaging of myocardial inflammation with positron emission tomography post-ischemia: a determinant of subsequent remodeling or recovery. JACC Cardiovasc. Imaging 11, 1340–1355 (2018).

    Article  PubMed  Google Scholar 

  12. Kunze, K. P. et al. Quantitative cardiovascular magnetic resonance: extracellular volume, native T1 and 18F-FDG PET/CMR imaging in patients after revascularized myocardial infarction and association with markers of myocardial damage and systemic inflammation. J. Cardiovasc. Magn. Reson. 20, 33 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Spieker, M. et al. T2 mapping cardiovascular magnetic resonance identifies the presence of myocardial inflammation in patients with dilated cardiomyopathy as compared to endomyocardial biopsy. Eur. Heart J. Cardiovasc. Imaging 19, 574–582 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Leuschner, F. et al. Silencing of CCR2 in myocarditis. Eur. Heart J. 36, 1478–1488 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Majmudar, M. D. et al. Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice. Circulation 127, 2038–2046 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chung, E. S. et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107, 3133–3140 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Parrillo, J. E. et al. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N. Engl. J. Med. 321, 1061–1068 (1989).

    Article  CAS  PubMed  Google Scholar 

  18. Giugliano, G. R., Giugliano, R. P., Gibson, C. M. & Kuntz, R. E. Meta-analysis of corticosteroid treatment in acute myocardial infarction. Am. J. Cardiol. 91, 1055–1059 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Han, K. H., Tangirala, R. K., Green, S. R. & Quehenberger, O. Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes. A regulatory role for plasma LDL. Arterioscler. Thromb. Vasc. Biol. 18, 1983–1991 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Auvynet, C. et al. ECL1i, d(LGTFLKC), a novel, small peptide that specifically inhibits CCL2-dependent migration. FASEB J. 30, 2370–2381 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Heo, G. S. et al. Molecular imaging visualizes recruitment of inflammatory monocytes and macrophages to the injured heart. Circ. Res. 124, 881–890 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Heo, G. S. et al. Targeted PET imaging of chemokine receptor 2-positive monocytes and macrophages in the injured heart. J. Nucl. Med. 62, 111–114 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, W. et al. Visualization of monocytic cells in regressing atherosclerotic plaques by intravital 2-photon and positron emission tomography-based imaging—brief report. Arterioscler. Thromb. Vasc. Biol. 38, 1030–1036 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hsiao, H.-M. et al. Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1β. J. Clin. Invest. 128, 2833–2847 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Brody, S. L. et al. Chemokine receptor 2-targeted molecular imaging in pulmonary fibrosis. A clinical trial. Am. J. Respir. Crit. Care Med. 203, 78–89 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Thackeray, J. T. et al. Molecular imaging of the chemokine receptor CXCR4 after acute myocardial infarction. JACC Cardiovasc. Imaging 8, 1417–1426 (2015).

    Article  PubMed  Google Scholar 

  27. Gibb, A. A., Lazaropoulos, M. P. & Elrod, J. W. Myofibroblasts and fibrosis: mitochondrial and metabolic control of cellular differentiation. Circ. Res. 127, 427–447 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lombardi, A. A. et al. Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation. Nat. Commun. 10, 4509 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Tavakoli, S. et al. Differential regulation of macrophage glucose metabolism by macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: implications for 18F FDG PET imaging of vessel wall inflammation. Radiology 283, 87–97 (2017).

    Article  PubMed  Google Scholar 

  30. Koenig, A. L. et al. Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure. Nat. Cardiovasc. Res. 1, 263–280 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Sicklinger, F. et al. Basophils balance healing after myocardial infarction via IL-4/IL-13. J. Clin. Invest. 131, e136778 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sager, H. B. et al. Proliferation and recruitment contribute to myocardial macrophage expansion in chronic heart failure. Circ. Res. 119, 853–864 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dorbala, S. et al. Single photon emission computed tomography (SPECT) myocardial perfusion imaging guidelines: instrumentation, acquisition, processing, and interpretation. J. Nucl. Cardiol. 25, 1784–1846 (2018).

    Article  PubMed  Google Scholar 

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Acknowledgements

K.J.L. is supported by grants from the National Institutes of Health (NIH) (nos. HL161185, HL150891 and HL151078), the Children’s Discovery Institute (no. PM-LI-2019-829), Burroughs Welcome Fund (no. 1014782), Leducq Foundation (no. 20CVD02) and generous gifts through Washington University and Barnes-Jewish Hospital. S.L.B. is supported for these studies by the NIH (no. HL151685) and the Barnes-Jewish Hospital Foundation. Y.L. is supported by grants from the NIH (nos. HL145212, HL150891, HL153436, HL151685 and EB025815).

Author information

Author notes

  1. These authors jointly supervised this work: Kory J. Lavine, Yongjian Liu.

Authors and Affiliations

  1. Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Kory J. Lavine, Steven L. Brody & Robert J. Gropler

  2. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA

    Kory J. Lavine

  3. Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, MO, USA

    Kory J. Lavine & Daniel Kreisel

  4. Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA

    Deborah Sultan, Hannah Luehmann, Lisa Detering, Xiaohui Zhang, Gyu Seong Heo, Xiuli Zhang, Michelle Hoelscher, Kitty Harrison, Richard Laforest, Pamela K. Woodard, Steven L. Brody, Robert J. Gropler & Yongjian Liu

  5. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Centre d’Immunologie et des Maladies Infectieuses, Paris, France

    Christophe Combadière

  6. Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA

    Daniel Kreisel

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  1. Kory J. Lavine
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Contributions

K.J.L., Y.L. and R.J.G. conceived and designed the study and wrote the paper. Y.L., D.S., H.L., L.D., Xiaohui Zhang., G.S.H. and Xiuli Zhang were responsible for the radiotracer synthesis. M.H., K.H. and R.J.G. were responsible for regulatory compliance and patient enrollment. R.L., P.K.W. and R.J.G. were responsible for image analysis and interpretation. C.C. provided the ECL1i peptide. S.L.B., D.K. and R.J.G. assisted with writing the paper and interpreting the data.

Corresponding authors

Correspondence to Kory J. Lavine or Yongjian Liu.

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Competing interests

K.J.L. serves as a consultant for Implicit Bioscience 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. are inventors on a pending patent entitled ‘Methods for detecting CCR2 receptors’ (application no. US17/001,857). This patent was submitted by Washington University School of Medicine and pertains to the CCR2 imaging tracer used in the manuscript. The other authors declare no competing interests.

Peer review

Peer review information

Nature Cardiovascular Research thanks R.H.J.A. Slart, C. Schulz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: E. Martini, in collaboration with the Nature Cardiovascular Research team.

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Extended data

Extended Data Fig. 1 In vitro cell binding assays of 64Cu-DOTA-ECL1i in THP-1 cells and 293 T 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.

Source data

Extended Data Fig. 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.

Source data

Extended Data Fig. 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 Fig. 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 Fig. 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 Fig. 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.

Extended Data Table 1 Imaging tracer activities
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Supplementary information

Source data

Source Data Fig. 1

Source data for Fig. 1.

Source Data Extended Data Fig. 1

Source data for Extended Data Fig. 1.

Source Data Extended Data Fig. 2

Source data for Extended Data Fig. 2.

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Lavine, K.J., Sultan, D., Luehmann, H. et al. CCR2 imaging in human ST-segment elevation myocardial infarction. Nat Cardiovasc Res 2, 874–880 (2023). https://doi.org/10.1038/s44161-023-00335-6

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