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PRECLINICAL INTERVENTIONAL RESEARCH

PhotoPoint Photodynamic Therapy Promotes Stabilization of Atherosclerotic Plaques and Inhibits Plaque Progression

Ron Waksman, MD^_*,_*, Pauline E. McEwan, PhD, Travis I. Moore, BS, Rajbabu Pakala, PhD^_*, Frank D. Kolodgie, PhD, David G. Hellinga, MSc^_*, Rufus C. Seabron^_*, Steven J. Rychnovsky, PhD, Jeffrey Vasek, BEng, Robert W. Scott, MD and Renu Virmani, MD

^_* Cardiovascular Research Institute, Washington Hospital Center, Washington, DC
Miravant Medical Technologies Inc., Santa Barbara, California
CV Path, International Registry of Pathology, Gaithersburg, Maryland

Manuscript received March 27, 2008; revised manuscript received June 4, 2008, accepted June 6, 2008.

^_* Reprint requests and correspondence: Dr. Ron Waksman, Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010 (Email: ron.waksman{at}medstar.net).

Objectives: The purpose of this study was to determine how photodynamic therapy (PDT) promotes stabilization and reduction of regional atherosclerosis.

Background: Photodynamic therapy, a combination of photosensitizer and targeted light to promote cell apoptosis, has been shown to reduce atherosclerotic plaque inflammation.

Methods: Forty New Zealand White rabbits were fed with cholesterol. The iliac arteries were balloon denuded and randomized to receive either PhotoPoint PDT treatment (photosensitizer and light) (Miravant Medical Technologies, Santa Barbara, California), photosensitizer (MV0611) alone, or light alone and were then compared at 7 and 28 days. Arteries were examined for evidence of plaque volume, cell number, macrophage and smooth muscle cell (SMC) content, and plaque cell proliferation.

Results: Compared with contralateral iliac artery controls at 7 days, plaque progression was reduced by approximately 35% (p < 0.01); plaque progression was further reduced to approximately 53% (p < 0.01) by 28 days, leading to an increase in lumen patency (p < 0.05). At 7 days after PDT, percent plaque area occupied by macrophages decreased by approximately 98% (p < 0.001) and SMCs by approximately 72% (p < 0.05). At 28 days after PDT, removal of macrophages was sustained (approximately 92% decrease, p < 0.001) and plaques were repopulated with non-proliferating SMCs (approximately 220% increase, p < 0.001). There was no evidence of negative or expansive arterial remodeling, thrombosis, or aneurysm formation.

Conclusions: Photodynamic therapy simultaneously reduces plaque inflammation and promotes repopulation of plaques with a SMC-rich stable plaque cell phenotype while reducing disease progression. These early healing responses suggest that PDT is a promising therapy for the treatment of acute coronary syndromes.

Key Words: atherosclerosis • macrophages • photodynamic therapy • plaque stabilization

Abbreviations and Acronyms   AMI = acute myocardial infarction   ATM = atmospheres   EEL = external elastic lamina   IEL = internal elastic lamina   MV0611 = Miravant photosensitizer compound   NZW = New Zealand White   PDT = photodynamic therapy   SMC = smooth muscle cell

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