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(Circulation. 2000;102:III-275.)
© 2000 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Reduction of Vein Graft Disease Using Photodynamic Therapy with Motexafin Lutetium in a Rodent Isograft Model

Atsushi Yamaguchi, MD, PhD; Kathryn W. Woodburn, PhD; Motoya Hayase, MD; Robert C. Robbins, MD

From the Departments of Cardiothoracic Surgery and Cardiovascular Medicine, Stanford University (A.Y., M.H., R.C.R.), Stanford, Calif, and Pharmacyclics, Inc (K.W.W.), Sunnyvale, Calif.

Correspondence to Dr Robbins, Department of Cardiothoracic Surgery, Falk Research Center, Stanford, CA 94305. E-mail robbins{at}leland.stanford.edu

Background—Motexafin lutetium (Lu-Tex) is a photosensitizer that targets atheromatous plaque. Subsequent photoactivation (photodynamic therapy [PDT]) induces local cytotoxic effects. The aim of the present study was to investigate whether Lu-Tex targets vein graft intimal hyperplasia and whether subsequent photoactivation attenuates the disease process.

Methods and Results—The subcellular localization of Lu-Tex and postillumination viability were studied in cultured human vein graft smooth muscle cells. Inferior vena cava–grafted rats were injected with Lu-Tex (10 mg/kg) 4 or 12 weeks after grafting. Biodistribution was assessed in a subgroup 24 hours after administration. Light therapy (742 nm) was performed 24 hours after Lu-Tex injection by illuminating intraperitoneally placed isografts using a laparotomy. Animals were divided into the following 4 groups: PDT (n=15), Lu-Tex injection and laparotomy (n=13), light treatment (n=14), and laparotomy only (n=13). Grafts were harvested 14 days after treatment for histochemical analysis. Lu-Tex localized within subcellular organelles of smooth muscle cells, and subsequent photoactivation induced cell death via apoptosis. The Lu-Tex concentrations present in the vein grafts were 9.3 times higher than those in the normal inferior vena cava. Postoperative PDT at 4 weeks after surgery significantly reduced the intima/media ratio, whereas treatment at 12 weeks did not reduce the intima/media ratio. Activated macrophages were observed 4 weeks after grafting; however, a significant reduction occurred in these cells by 12 weeks. The mechanism by which PDT works may be related to the presence of activated macrophages.

Conclusions—PDT significantly reduces the intima/media ratio in the early phase of vein graft disease. Lu-Tex–mediated PDT may be a viable method for the attenuation of atherosclerotic disease in vein grafts.

Key Words: angioplasty • bypass • grafting • coronary disease • lasers