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Radiolabeled Arginine-Glycine-Aspartic Acid Peptides to Image Angiogenesis in Swine Model of Hibernating Myocardium

Lynne L. Johnson, MD, FACC^_*,_*, Lorraine Schofield, BS, Tammy Donahay, BS, Mark Bouchard, BS, Athena Poppas, MD, FACC, Roland Haubner, PhD^,

^_* Columbia University, New York, New York
Rhode Island Hospital, Providence, Rhode Island
Medizinische Universität Innsbruck, Innsbruck, Austria
Technische Universität München, Munich, Germany.

^_* Reprint requests and correspondence: Dr. Lynne L. Johnson, Columbia University Medical Center, PH 10-405, New York, New York 10032. (Email: lj2129{at}columbia.edu).

Objectives: Our aim was to image angiogenesis produced by endomyocardial injection of phVEGF₁₆₅ in a swine model of hibernating myocardium using [¹²³I]Gluco-arginine-glycine-aspartic acid (RGD) targeting the vβ3 integrins.

Background: A noninvasive test to monitor the efficacy of therapy inducing angiogenesis is needed. The interaction between extracellular matrix and endothelial cells in sprouting capillaries is effected primarily by vβ3 integrins that bind through RGD motifs.

Methods: At 21 ± 4 days, after left circumflex coronary artery ameroid constrictor placement, 8 swine received endomyocardial injection of 1.2 mg phVEGF₁₆₅ divided into 6 sites and 6 swine received saline (S) using nonfluoroscopic 3-dimensional endocardial mapping system (Noga)-guided delivery. After 20 ± 6 days, 13 animals were injected with 6.4 ± 1.7 mCi [¹²³I]Gluco-RGD, 1 VEGF (vascular endothelial growth factor)-injected animal with I-123–labeled peptide control, and all animals with 2.5 ± 0.4 mCi of Tl-201 and underwent single-photon emission computed tomography imaging. Blood flow and echocardiographic measurements were made at both time points and tissue analyzed for fibrosis and capillary density by lectin staining.

Results: Hibernating myocardium in the ameroid constrictor territory at time of injections was documented by reduced wall thickening compared with remote. Ratio of myocardial blood flow in left circumflex coronary artery/left anterior descending coronary artery territories increased by 15 ± 11% in the VEGF animals and fell 13 ± 12% in S-injected (p < 0.01). There was a small increase in wall thickening in constrictor territory after VEGF (8 ± 17%) while in S-injected animals wall thickening fell by 23 ± 31% (p = 0.01 vs. VEGF). Lectin staining as percent positive tissue staining for ameroid territory was higher in VEGF-injected compared with S-injected animals (2.5 ± 1.5% vs. 0.87 ± 0.52%, p = 0.01). Focal uptake of [¹²³I]Gluco-RGD corresponding to Tl-201 defects was seen in VEGF-injected but not in S-injected animals. [¹²³I]Gluco-RGD uptake in the ameroid territory as percent injected dose correlated with lectin staining (R² = 0.80, p = 0.002).

Conclusions: These data suggest that single-photon emission computed tomography imaging of radiolabeled RGD peptides may be a useful noninvasive method to monitor therapy that induces angiogenesis in the heart.

Key Words: angiogenesis • VEGF • integrins • cyclo-RGD peptides • myocardial hibernation

Abbreviations and Acronyms   HPLC = high pressure liquid chromatography   ID = injected dose   LV = left ventricle/ventricular   LVEF = left ventricular ejection fraction   PET = positron emission tomography   RGD = arginine-glycine-aspartic acid   SPECT = single-photon computed tomography   VEGF = vascular endothelial growth factor

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