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(Circulation. 2001;104:I-218.)
© 2001 American Heart Association, Inc.

Thoracic Transplantation and Ventricular Assist Devices

Enhanced Myocardial Angiogenesis by Gene Transfer With Transplanted Cells

Terrence M. Yau, MD, MSc; Karen Fung, BSc; Richard D. Weisel, MD; Takeshiro Fujii, MD; Donald A.G. Mickle, MD; Ren-Ke Li, MD, PhD

Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

Correspondence to Terrence M. Yau, MD, MSc, 13EN-239, The Toronto Hospital, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada. E-mail terry.yau{at}utoronto.ca

Background— The combination of myocardial cell transplantation and angiogenic gene transfer may improve postinfarction left ventricular (LV) perfusion. We evaluated the angiogenic effect of heart cells transfected with vascular endothelial growth factor (VEGF) and transplanted into a myocardial scar.

Methods and Results— Donor rat heart cells were transfected with plasmids encoding VEGF₁₆₅ and green fluorescence protein. Syngeneic adult rats underwent LV cryoinjury to create a transmural scar. Three weeks later, 4x10⁶ transfected heart cells (n=14), untransfected heart cells (n=13), or culture medium (n=16) were transplanted into the center of the scar. After 5 weeks, LV function, quantitative histology, and regional blood flow were evaluated. Plates of heart cells transfected with VEGF₁₆₅ produced 6.1 times more intracellular VEGF than nontransfected cells. Capillary density (mean±SEM) per high-power field in the center of the myocardial scar was 1.1±0.02 in control rats, 3.9±0.11 in untransfected rats, and 6.3±0.11 in transfected rats (P=0.0002). Capillary density in the border zone around the scar was 1.9±0.03 in control rats, 6.4±0.10 in untransfected rats, and 8.7±0.16 in transfected rats (P=0.004). Regional blood flow within the scar was 8.8±0.8% of normalized flow in control hearts, 10.4±0.7% in hearts transplanted with untransfected cells, but 17.6±1.2% in hearts transplanted with transfected cells (P=0.03 versus control, P=0.07 versus nontransfected). There was no difference in LV function attributable to transplantation with transfected cells at the time point studied.

Conclusions— Transplantation of heart cells transfected with VEGF induced greater angiogenesis than transplantation of unmodified cells. Combined gene transfer and cell transplantation strategies may improve postinfarction LV perfusion and function.

Key Words: gene therapy • cells • transplantation • angiogenesis