Molecular Imaging of the Chemokine Receptor CXCR4 After Acute Myocardial Infarction.
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.
['Thackeray|James T|JT|', 'Derlin|Thorsten|T|', 'Haghikia|Arash|A|', 'Napp|L Christian|LC|', 'Wang|Yong|Y|', 'Ross|Tobias L|TL|', 'Schäfer|Andreas|A|', 'Tillmanns|Jochen|J|', 'Wester|Hans J|HJ|', 'Wollert|Kai C|KC|', 'Bauersachs|Johann|J|', 'Bengel|Frank M|FM|']
D000368:Aged D000818:Animals D015415:Biomarkers D004195:Disease Models, Animal D005500:Follow-Up Studies D006801:Humans D019028:Magnetic Resonance Imaging, Cine D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008875:Middle Aged D057054:Molecular Imaging D064847:Multimodal Imaging D009203:Myocardial Infarction D049268:Positron-Emission Tomography D019275:Radiopharmaceuticals D011897:Random Allocation D019718:Receptors, CXCR4 D012044:Regression Analysis D012494:Sampling Studies D015899:Tomography, Emission-Computed, Single-Photon D020257:Ventricular Remodeling
CXCR4 myocardial infarction positron emission tomography inflammation