Regional hypoxia correlates with the uptake of a radiolabeled targeted marker of angiogenesis in rat model of myocardial hypertrophy and ischemic injury.
BACKGROUND
Non-invasive imaging strategies play a critical role for assessment of the efficacy of angiogenesis therapies. Hypoxia resulting from deficient blood flow is a potent stimulator of angiogenesis which is marked by upregulated alphavbeta3 integrin receptor.


RESULTS
The use of dual-isotope radiotracers targeted at alphavbeta3 and myocardial hypoxia has been demonstrated to non-invasively track hypoxia-induced angiogenesis in ischemic rat model of myocardial hypertrophy, which was induced by non-occlusive abdominal aortic banding followed by myocardial infarction at 6 weeks after the banding procedure. The pressure overload-induced myocardial hypertrophy was confirmed by 2D echocardiography. Two radiotracers; 111In-labeled agent targeted at the alphavbeta3 (RP748) and 99mTc-labeled nitroimidazole retained in hypoxic myocardium (BRU-5921) have been used. Gamma well counting analysis demonstrated an inverse linear relationship (R2=0.5) between BRU-5921 myocardial uptake and the degree of hypoperfusion assessed by 201Tl chloride. 111In-RP748 was found to be preferentially retained in hypoxic myocardium identified by increased BRU-5921 uptake and localized to anterior-lateral wall as assessed by dual-isotope microautoradiography. There was a significant (P<0.01) almost four-fold increase in RP748 uptake in myocardial segments with highest relative BRU-5921 retention (200-600% non-ischemic). Immunohistochemical staining confirmed that increased RP748 uptake is associated with an augmented alphav and beta3 integrin expression within infarcted myocardium.


CONCLUSIONS
Angiogenesis in the rodent model of combined myocardial hypertrophy and infarction was successfully assessed with alphavbeta3-targeted agent in relation to tissue hypoxia measured with 99mTc -labeled nitroimidazole retained in hypoxic myocardium. Regional retention of RP748 correlated well with BRU-5921 retention, supporting the role of RP748 as a targeted marker of hypoxia-stimulated angiogenesis with a potential clinical use to track naturally occurring and therapeutic angiogenesis and to predict the left ventricular remodeling in patients following myocardial infarction.
Dobrucki
L W
LW
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8017, USA.
Meoli
D F
DF
Hu
J
J
Sadeghi
M M
MM
Sinusas
A J
AJ
D000818:Animals; D001345:Autoradiography; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000378:metabolism*; D006321:Heart / Q000000981:diagnostic imaging; D006573:Heterocyclic Compounds, 1-Ring; D000860:Hypoxia / Q000000981:diagnostic imaging / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000378:metabolism*; D009942:Organometallic Compounds; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D014463:Ultrasonography
D006573:Heterocyclic Compounds, 1-Ring; D009942:Organometallic Compounds; C494048:RP 748; D019275:Radiopharmaceuticals