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Smooth Muscle Cell Proliferation Index Correlates with ¹¹¹In-Labeled Antibody Z2D3 Uptake in a Transplant Vasculopathy Swine Model

¹ Division of Cardiology, Rhode Island Hospital, Brown University, Providence, Rhode Island
² Northeastern University, Boston, Massachusetts

Transplant vasculopathy is a major cause of morbidity and mortality in heart transplantation. The proliferation of coronary vascular smooth muscle cells is a hallmark of transplant vasculopathy. The goal of this study was to detect coronary vascular smooth muscle cell proliferation in a swine model by imaging regions of uptake of a monoclonal antibody (Z2D3) labeled with ¹¹¹In. Methods: Coronary-to-right carotid artery transplantation was performed in 10 Yucatan minipigs with coronary arteries from farm pigs as donors. In 5 of these experiments, the right carotid artery was also grafted to the left carotid artery as a homograft. In 1 farm pig, the left and right carotid arteries were switched. After 44 ± 22 days (mean ± SE), animals were injected with 5-bromo-2-deoxyuridine (BrDU) and ¹¹¹In-Z2D3 F(ab')₂. Approximately 24 h later, the pigs underwent planar and SPECT imaging. After the imaging session, the pigs were sacrificed and the vessels were removed. Ex vivo autoradiography of all grafts was performed. Next, the tissues were immersion fixed, paraffin embedded, sectioned, and stained for histologic or immunohistologic examination. Quantitative morphometry was performed. A smooth muscle cell proliferation index, calculated as (BrDU- and actin-stained cells/actin-stained cells) x 100, was correlated with in vivo and ex vivo radiotracer uptake. Results: Patency or neovascularization was demonstrated in 10 of 10 allografts and 5 of 6 homografts. Ten of the scans were positive for focal tracer uptake in the neck in the area corresponding to the graft site, and 6 were negative. Actin- and BrDU-stained cells were seen in the media of allografts and in the recanalized lumen of occluded homografts. A smooth muscle cell proliferation index of 30 was used as a cutoff for scan positivity, on the basis of previous work. Analysis by the ² test indicated significant concordance (P < 0.01). Ex vivo vessel count ratios were significantly correlated with the smooth muscle cell proliferation index (r² = 0.528, P < 0.01). Conclusion: The use of monoclonal antibody Z2D3 tagged with ¹¹¹In allows the detection of proliferating smooth muscle cells and correlates with the intensity of cell proliferation. This diagnostic method could allow early noninvasive detection of transplant vasculopathy.

Key Words: monoclonal antibodies • transplant vasculopathy • swine