OBJECTIVES: 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.
OBJECTIVES: 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 CXCR4infarct 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: Andrew J Einstein; Steven G Lloyd; Farooq A Chaudhry; Wael A AlJaroudi; Fadi G Hage Journal: J Nucl Cardiol Date: 2016-01-27 Impact factor: 5.952
Authors: Matthias Nahrendorf; Friedrich Felix Hoyer; Anu E Meerwaldt; Mandy M T van Leent; Max L Senders; Claudia Calcagno; Philip M Robson; George Soultanidis; Carlos Pérez-Medina; Abraham J P Teunissen; Yohana C Toner; Kiyotake Ishikawa; Kenneth Fish; Ken Sakurai; Esther M van Leeuwen; Emma D Klein; Alexandros Marios Sofias; Thomas Reiner; David Rohde; Aaron D Aguirre; Gregory Wojtkiewicz; Stephen Schmidt; Yoshiko Iwamoto; David Izquierdo-Garcia; Peter Caravan; Filip K Swirski; Ralph Weissleder; Willem J M Mulder Journal: Circ Cardiovasc Imaging Date: 2020-10-20 Impact factor: 7.792
Authors: Rudolf A Werner; Matthias Kroiss; Masatoyo Nakajo; Dirk O Mügge; Stefanie Hahner; Martin Fassnacht; Andreas Schirbel; Christina Bluemel; Takahiro Higuchi; Laszló Papp; Norbert Zsótér; Andreas K Buck; Ralph A Bundschuh; Constantin Lapa Journal: Endocrine Date: 2016-05-02 Impact factor: 3.633