Meoli, D. F. et al. Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction. J. Clin. Invest. 113, 1684-1691

Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8017, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 07/2004; 113(12):1684-91. DOI: 10.1172/JCI20352
Source: PubMed


Noninvasive imaging strategies will be critical for defining the temporal characteristics of angiogenesis and assessing efficacy of angiogenic therapies. The alphavbeta3 integrin is expressed in angiogenic vessels and represents a potential novel target for imaging myocardial angiogenesis. We demonstrated the localization of an indium-111-labeled ((111)In-labeled) alphavbeta3-targeted agent in the region of injury-induced angiogenesis in a chronic rat model of infarction. The specificity of the targeted alphavbeta3-imaging agent for angiogenesis was established using a nonspecific control agent. The potential of this radiolabeled alphavbeta3-targeted agent for in vivo imaging was then confirmed in a canine model of postinfarction angiogenesis. Serial in vivo dual-isotope single-photon emission-computed tomographic (SPECT) imaging with the (111)In-labeled alphavbeta3-targeted agent demonstrated focal radiotracer uptake in hypoperfused regions where angiogenesis was stimulated. There was a fourfold increase in myocardial radiotracer uptake in the infarct region associated with histological evidence of angiogenesis and increased expression of the alphavbeta3 integrin. Thus, angiogenesis in the heart can be imaged noninvasively with an (111)In-labeled alphavbeta3-targeted agent. The noninvasive evaluation of angiogenesis may have important implications for risk stratification of patients following myocardial infarction. This approach may also have significant clinical utility for noninvasively tracking therapeutic myocardial angiogenesis.

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    • "Radiolabelled antagonists containing the αvβ3-specific cyclic RGD peptide can be used for molecular imaging of αvβ3 integrin expression after MI [5-7]. Uptake is the highest at 1 week after infarct corresponding to the peak time of neovessel formation [5]. Our recent study shows that the uptake of 18F-galacto-cyclo(RGDfK) (18F-galacto-RGD) in the infarct area at 1 week after MI predicts improved healing in the form of less LV remodelling seen 12 weeks after the injury [8]. "
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    ABSTRACT: Background Expression of αvβ3 integrin is increased after myocardial infarction as part of the repair process. Increased expression of αvβ3 has been shown by molecular imaging with 18F-galacto-RGD in a rat model. The 68Ga-labelled RGD compounds 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 have high specificity and affinity, and may therefore serve as alternatives of 18F-galacto-RGD for integrin imaging. Methods Left coronary artery ligation was performed in rats. After 1 week, rats were imaged with [13N]NH3, followed by 18F-galacto-RGD, 68Ga-NODAGA-RGD or 68Ga-TRAP(RGD)3 using a dedicated animal PET/CT device. Rats were killed, and the activity in tissues was measured by gamma counting. The heart was sectioned for autoradiography and histology. Immunohistochemistry was performed on consecutive sections using CD31 for the endothelial cells and CD61 for β3 expression (as part of the αvβ3 receptor). Results In vivo imaging showed focal RGD uptake in the hypoperfused area of infarcted myocardium as defined with [13N]NH3 scan. In autoradiography images, augmented uptake of all RGD tracers was observed within the infarct area as verified by the HE staining. The tracer uptake ratios (infarct vs. remote) were 4.7 ± 0.8 for 18F-galacto-RGD, 5.2 ± 0.8 for 68Ga-NODAGA-RGD, and 4.1 ± 0.7 for 68Ga-TRAP(RGD)3. The 68Ga-NODAGA-RGD ratio was higher compared to 68Ga-TRAP(RGD)3 (p = 0.04), but neither of the 68Ga tracers differed from 18F-galacto-RGD (p > 0.05). The area of augmented 68Ga-RGD uptake was associated with β3 integrin expression (CD61). Conclusion 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 uptake was equally increased in the infarct area at 1 week post infarction as 18F-galacto-RGD. These results show the potential of 68Ga-labelled RGD peptides to monitor integrin expression as a part of myocardial repair and angiogenesis after ischaemic injury in vivo.
    EJNMMI Research 05/2013; 3(1):38. DOI:10.1186/2191-219X-3-38
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    • "Additionally, ischemic damage triggers inflammation and extracellular matrix activation, which in turn support cell migration and angiogenesis [13]. Of note, many of these activated pathways can now be imaged noninvasively using molecular imaging techniques [7, 8, 12, 15, 25]. Future studies may thus focus on a direct, integrated assessment of the role of these molecular pathways, which are activated after myocardial infarction, on cell engraftment [18, 30]. "
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    ABSTRACT: Therapeutic cell retention and engraftment are critical for myocardial regeneration. Underlying mechanisms, including the role of tissue perfusion, are not well understood. In Wistar Kyoto rats, syngeneic cardiosphere-derived cells (CDCs) were injected intramyocardially, after experimental myocardial infarction. CDCs were labeled with [(18)F]-FDG (n = 7), for quantification of 1-h retention, or with sodium-iodide-symporter gene (NIS; n = 8), for detection of 24-h engraftment by reporter imaging. Perfusion was imaged simultaneously. Infarct size was 37 ± 9 and 38 ± 9% of LV in FDG and NIS groups. Cell signal was located in the infarct border zone in all animals. No significant relationship was observed between infarct size and 1-h CDC retention (r = -0.65; P = 0.11). However, infarct size correlated significantly with 24-h engraftment (r = 0.75; P = 0.03). Residual perfusion at the injection site was not related to cell retention/engraftment. Larger infarcts are associated with improved CDC engraftment. This observation encourages further investigation of microenvironmental conditions after ischemic damage and their role in therapeutic cell survival.
    Archiv für Kreislaufforschung 06/2011; 106(6):1379-86. DOI:10.1007/s00395-011-0197-5 · 5.41 Impact Factor
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    • "Using an RGD mimetic peptide (99mTc-NC100692), Hua and colleagues imaged αvβ3 expression in a murine limb ischemia model [21]. Integrin expression has also been targeted for in vivo nuclear imaging in myocardial infarction and remodeling and in response to VEGF therapy in chronic low flow dysfunctional myocardium [22,23]. Our study extends these reports to document the value of this imaging approach to molecular pathways involved in diabetes. "
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    ABSTRACT: Receptor for advanced glycation endproducts (RAGE) expression contributes to the impaired angiogenic response to limb ischemia in diabetes. The aim of this study was to detect the effect of increased expression of RAGE on the angiogenic response to limb ischemia in diabetes by targeting αvβ3 integrin with 99mTc-labeled Arg-Gly-Asp (RGD). Male wild-type (WT) C57BL/6 mice were either made diabetic or left as control for 2 months when they underwent femoral artery ligation. Four groups were studied at days 3 to 7 after ligation: WT without diabetes (NDM) (n = 14), WT with diabetes (DM) (n = 14), RAGE-/- NDM (n = 16), and RAGE-/- DM (n = 14). Mice were injected with 99mTc-HYNIC-RGD and imaged. Count ratios for ischemic/non-ischemic limbs were measured. Muscle was stained for RAGE, αvβ3, and lectins. There was no difference in count ratio between RAGE-/- and WT NDM groups. Mean count ratio was lower for WT DM (1.38 ± 0.26) vs. WT NDM (1.91 ± 0.34) (P<0.001). Mean count ratio was lower for the RAGE-/- DM group than for RAGE-/- NDM group (1.75 ± 0.22 vs. 2.02 ± 0.29) (P<0.001) and higher than for the WT DM group (P<0.001). Immunohistopathology supported the scan findings. In vivo imaging of αvβ3 integrin can detect the effect of RAGE on the angiogenic response to limb ischemia in diabetes.
    EJNMMI Research 06/2011; 1(1):3. DOI:10.1186/2191-219X-1-3
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