Published Online
on September 27, 2004

A more recent version of this article appeared on October 5, 2004

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Submitted on May 7, 2004
Revised on July 22, 2004
Accepted on August 2, 2004

Angiotensin Receptor Blockade With Candesartan Attenuates Atherosclerosis, Plaque Disruption, and Macrophage Accumulation Within the Plaque in a Rabbit Model

Michael T. Johnstone MD^*, Alexandra S. Perez BS, Imad Nasser MD, Robert Stewart MD, Anand Vaidya BS, Fawaz Al Ammary MD, Ben Schmidt AB, Gary Horowitz MD, Jennifer Dolgoff BS, James Hamilton PhD, and William C. Quist MD, PhD

From the Departments of Medicine (Cardiovascular Division: M.T.J., A.S.P., A.V., F.A., B.S., J.D.), Surgery (R.S.), and Pathology (I.N., G.H., W.C.Q.), Beth Israel Deaconess Medical Center and Harvard Medical School, and the Department of Biophysics and Physiology (J.H.), Boston University School of Medicine, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: mjohnst1{at}bidmc.harvard.edu.

Background--Little is known about whether direct angiotensin receptor blockade can reduce atherosclerosis and plaque disruption. This study evaluated the effect of angiotensin receptor blockade on both the development of atherosclerosis and the disruption of plaque in a modified Constantinides animal model.

Methods and Results--Twenty-eight New Zealand White rabbits underwent aortic balloon injury followed by a 1% cholesterol diet for 8 weeks. Thirteen rabbits received candesartan at 0.5 mg · kg^-1 · d^-1 beginning 2 days before aortic balloon injury and continued for the total 8 weeks of the cholesterol diet. The rabbits were then pharmacologically triggered and humanely killed, and their aortas were analyzed. The degree of atherosclerosis was determined by intima-media ratio of the infrarenal portion of the aorta. The frequency of intra-aortic thrombosis, a measure of plaque disruption, and the percentages of macrophage area and collagen-staining area of the plaque were determined. Candesartan-treated rabbits had less atherosclerosis (intima-media infrarenal aorta ratio of 1.18±0.08 versus 1.57±0.08 [mean±SEM] for the placebo group, P<0.001); fewer thrombi (3 of 13 versus 11 of 15; P<0.05); lower percentage area of macrophages to total plaque (18.8±2.7% versus 27±2.5%, P<0.05); and higher collagen to total plaque area (45±3% versus 35±2%, P<0.01).

Conclusions--These results demonstrate that angiotensin receptor blockade attenuates the degree of atherosclerosis and reduces both plaque disruption and macrophage accumulation while increasing collagen deposition in the aortas of this animal model.

Key words: atherosclerosis • plaque • thrombosis • angiotensin

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