Targeted imaging of hypoxia-induced integrin activation in myocardium early after infarction.
The alphavbeta3-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 alphavbeta3-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 (111)In-labeled radiotracer targeted at the alphavbeta3-integrin ((111)In-RP748) was used to localize regions of hypoxia-induced angiogenesis early after infarction. In rodent studies, the specificity of (111)In-RP748 for alphavbeta3-integrin was confirmed with a negative control compound ((111)In-RP790), and regional uptake of these compounds correlated with (201)Tl perfusion and a (99m)Tc-labeled nitroimidazole (BRU59-21), which was used as a quantitative marker of myocardial hypoxia. The ex vivo analysis demonstrated that only (111)In-RP748 was selectively retained in infarcted regions with reduced (201)Tl perfusion and correlated with uptake of BRU59-21. In canine studies, myocardial uptake of (111)In-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 (99m)Tc-labeled 2-methoxy-2-methyl-propyl-isonitrile ((99m)Tc-sestamibi) perfusion. Dual-radiotracer in vivo SPECT imaging of (111)In-RP748 and (99m)Tc-sestamibi provided visualization of (111)In-RP748 uptake within the infarct region, which was confirmed by ex vivo planar imaging of excised myocardial slices. Myocardial (111)In-RP748 retention was associated with histological evidence of alphavbeta3-integrin expression/activation in the infarct region. (111)In-RP748 imaging provides a novel noninvasive approach for evaluation of hypoxia-induced alphavbeta3-integrin activation in myocardium early after infarction and may prove useful for directing and evaluating angiogenic therapies in patients with ischemic heart disease.
Kalinowski
Leszek
L
Experimental Nuclear Cardiology Laboratory, Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8017, USA.
Dobrucki
Lawrence W
LW
Meoli
David F
DF
Dione
Donald P
DP
Sadeghi
Mehran M
MM
Madri
Joseph A
JA
Sinusas
Albert J
AJ
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015415:Biomarkers; D001711:Biotransformation / Q000502:physiology; D004285:Dogs; D006573:Heterocyclic Compounds, 1-Ring; D000860:Hypoxia / Q000378:metabolism*; D007093:Imidazoles; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis / Q000235:genetics; D016023:Integrins / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D017202:Myocardial Ischemia / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D009942:Organometallic Compounds; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D017256:Technetium Tc 99m Sestamibi; D015899:Tomography, Emission-Computed, Single-Photon
D000199:Actins; C403973:BRU 59-21; D015415:Biomarkers; D006573:Heterocyclic Compounds, 1-Ring; D007093:Imidazoles; D039302:Integrin alphaVbeta3; D016023:Integrins; D009942:Organometallic Compounds; D015609:Organotechnetium Compounds; C494048:RP 748; D019275:Radiopharmaceuticals; D017256:Technetium Tc 99m Sestamibi