Published Online
on November 10, 2003

A more recent version of this article appeared on December 2, 2003

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Submitted on April 17, 2003
Revised on July 31, 2003
Accepted on August 1, 2003

Liposomal Alendronate Inhibits Systemic Innate Immunity and Reduces In-Stent Neointimal Hyperplasia in Rabbits

Haim D. Danenberg MD^*, Gershon Golomb PhD, Adam Groothuis MS, Jianchuan Gao MD, Hila Epstein MSc, Rajesh V. Swaminathan BSc, Philip Seifert MS, and Elazer R. Edelman MD, PhD

From the Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Mass (H.D.D., A.G., R.V.S., P.S., E.R.E.); and the Department of Cardiology, Hadassah University Hospital (H.D.D.), and School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem (G.G., J.G., H.E.), Jerusalem, Israel.

^* To whom correspondence should be addressed. E-mail: danen{at}mit.edu.

Background--Innate immunity is of major importance in vascular repair. The present study evaluated whether systemic and transient depletion of monocytes and macrophages with liposome-encapsulated bisphosphonates inhibits experimental in-stent neointimal formation.

Methods and Results--Rabbits fed on a hypercholesterolemic diet underwent bilateral iliac artery balloon denudation and stent deployment. Liposomal alendronate (3 or 6 mg/kg) was given concurrently with stenting. Monocyte counts were reduced by >90% 24 to 48 hours after a single injection of liposomal alendronate, returning to basal levels at 6 days. This treatment significantly reduced intimal area at 28 days, from 3.88±0.93 to 2.08±0.58 and 2.16±0.62 mm². Lumen area was increased from 2.87±0.44 to 3.57±0.65 and 3.45±0.58 mm², and arterial stenosis was reduced from 58±11% to 37±8% and 38±7% in controls, rabbits treated with 3 mg/kg, and rabbits treated with 6 mg/kg, respectively (mean±SD, n=8 rabbits/group, P<0.01 for all 3 parameters). No drug-related adverse effects were observed. Reduction in neointimal formation was associated with reduced arterial macrophage infiltration and proliferation at 6 days and with an equal reduction in intimal macrophage and smooth muscle cell content at 28 days after injury. Conversely, drug regimens ineffective in reducing monocyte levels did not inhibit neointimal formation.

Conclusions--Systemic transient depletion of monocytes and macrophages, by a single liposomal bisphosphonates injection concurrent with injury, reduces in-stent neointimal formation and arterial stenosis in hypercholesterolemic rabbits.

Key words: angioplasty • stents • restenosis • leukocytes • inflammation

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