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.
Methods and 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.