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INNOVATIVE METHODOLOGY

Targeted imaging of hypoxia-induced integrin activation in myocardium early after infarction

¹Experimental Nuclear Cardiology Laboratory, Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; ²Department of Clinical Chemistry and Biochemistry, Medical University of Gdansk, Gdansk, Poland; and ³Departments of Pathology and ⁴Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut

Submitted 10 August 2007 ; accepted in final form 5 March 2008

The vβ3-integrin is expressed in angiogenic vessels in response to hypoxia and represents a potential novel target for imaging myocardial angiogenesis. This study evaluated the feasibility of noninvasively tracking hypoxia-induced vβ3-integrin activation within the myocardium as a marker of angiogenesis early after myocardial infarction. Acute myocardial infarction was produced by coronary artery occlusion in rodent and canine studies. A novel ¹¹¹In-labeled radiotracer targeted at the vβ3-integrin (¹¹¹In-RP748) was used to localize regions of hypoxia-induced angiogenesis early after infarction. In rodent studies, the specificity of ¹¹¹In-RP748 for vβ3-integrin was confirmed with a negative control compound (¹¹¹In-RP790), and regional uptake of these compounds correlated with ²⁰¹Tl perfusion and a ^99mTc-labeled nitroimidazole (BRU59-21), which was used as a quantitative marker of myocardial hypoxia. The ex vivo analysis demonstrated that only ¹¹¹In-RP748 was selectively retained in infarcted regions with reduced ²⁰¹Tl perfusion and correlated with uptake of BRU59-21. In canine studies, myocardial uptake of ¹¹¹In-RP748 was assessed using in vivo single-photon-emission computed tomography (SPECT), ex vivo planar imaging, and gamma well counting of myocardial tissue and correlated with ^99mTc-labeled 2-methoxy-2-methyl-propyl-isonitrile (^99mTc-sestamibi) perfusion. Dual-radiotracer in vivo SPECT imaging of ¹¹¹In-RP748 and ^99mTc-sestamibi provided visualization of ¹¹¹In-RP748 uptake within the infarct region, which was confirmed by ex vivo planar imaging of excised myocardial slices. Myocardial ¹¹¹In-RP748 retention was associated with histological evidence of vβ3-integrin expression/activation in the infarct region. ¹¹¹In-RP748 imaging provides a novel noninvasive approach for evaluation of hypoxia-induced vβ3-integrin activation in myocardium early after infarction and may prove useful for directing and evaluating angiogenic therapies in patients with ischemic heart disease.

angiogenesis; radiotracer imaging; myocardial infarction