title: Molecular Imaging of the Chemokine Receptor CXCR4 After Acute Myocardial Infarction.
abstract: OBJECTIVE
  An assay for molecular imaging of myocardial CXCR4 expression was evaluated, in order to obtain mechanistic insights noninvasively based on quantitative positron emission tomography (PET).
  
  
  BACKGROUND
  The chemokine receptor CXCR4 has emerged as a therapeutic target after acute myocardial infarction (AMI), because of its role in inflammatory and progenitor cell recruitment.
  
  
  METHODS
  PET with the specific CXCR4 ligand, gallium-68 ((68)Ga)-pentixafor, was performed in mice (n = 53) and compared with ex vivo autoradiography, immunohistochemistry, and left ventricular flow cytometry. In addition, 12 patients were imaged at 2 to 8 days after AMI.
  
  
  RESULTS
  In mice, (68)Ga-pentixafor identified regional CXCR4 upregulation in the infarct region, peaking at 3 days (infarct/remote [I/R] ratio 1.5 ± 0.2 at 3 days vs. 1.2 ± 0.3 at 7 days; p = 0.03), corresponding to a flow cytometry-based peak of CD45+ leukocytes and immunohistochemical detection of CD68+ macrophages and Ly6G+ granulocytes. Blockade with the CXCR4 antagonist AMD3100 abolished the signal. No specific uptake was found in sham-operated or control animals. Long-term treatment with oral enalapril attenuated the CXCR4 signal (I/R 1.2 ± 0.2 at 3 days and 1.0 ± 0.0.1 at 7 days; p = 0.01 vs. untreated). Patients showed variable degrees of CXCR4 upregulation in the infarct region. No single clinical parameter allowed for prediction of CXCR4 signal strength. At multivariate analysis, a combination of infarct size and time after reperfusion predicted the CXCR4 infarct signal (rmultiple = 0.73; p = 0.03). Infarct signal in the myocardium was paralleled by elevated pentixafor uptake in bone marrow (r = 0.61; p = 0.04), which highlighted systemic interactions.
  
  
  CONCLUSIONS
  Targeted PET imaging with (68)Ga-pentixafor identifies the global and regional CXCR4 expression pattern in myocardium and systemic organs. CXCR4 upregulation after AMI coincides with inflammatory cell infiltration, but shows interindividual variability in patients. This may have implications for the response to CXCR4- or other inflammation-targeted therapy, and for subsequent ventricular remodeling.
authors.affiliation: Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: James T
authors.initials: JT
authors.lastname: Thackeray
authors.affiliation: Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Derlin
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Arash
authors.initials: A
authors.lastname: Haghikia
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: L Christian
authors.initials: LC
authors.lastname: Napp
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Tobias L
authors.initials: TL
authors.lastname: Ross
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäfer
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Tillmanns
authors.affiliation: Pharmaceutical Radiochemistry, Technical University of Munich, Munich, Germany.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Wester
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.affiliation: Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany. Electronic address: bengel.frank@mh-hannover.de.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Bengel
mesh_terms: D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods*; D064847:Multimodal Imaging / Q000379:methods*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging* / Q000473:pathology*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D011897:Random Allocation; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012044:Regression Analysis; D012494:Sampling Studies; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D015415:Biomarkers; D019275:Radiopharmaceuticals; D019718:Receptors, CXCR4
keywords: CXCR4; inflammation; myocardial infarction; positron emission tomography