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PRECLINICAL STUDY: APO: A-I_MILANO

Rapid Change in Plaque Size, Composition, and Molecular Footprint After Recombinant Apolipoprotein A-I_Milano (ETC-216) Administration

Magnetic Resonance Imaging Study in an Experimental Model of Atherosclerosis

Borja Ibanez, MD^_*, Gemma Vilahur, DVM, PhD, Giovanni Cimmino, MD^_*, Walter S. Speidl, MD^_*, Antonio Pinero, MD^_*, Brian G. Choi, MD^_*, M. Urooj Zafar, MD^_*, Carlos G. Santos-Gallego, MD^_*, Brian Krause, PhD, Lina Badimon, PhD, Valentin Fuster, MD, PhD, FACC^_* and Juan J. Badimon, PhD, FACC^_*

^_* Cardiovascular Biology Research Laboratory, Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York
Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, UAB, Barcelona, Spain
Pfizer Research and Development, Groton, Connecticut.

Manuscript received July 3, 2007; revised manuscript received September 10, 2007, accepted September 17, 2007.

^_* Reprint requests and correspondence: Dr. Juan J. Badimon, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, New York 10029. (Email: juan.badimon{at}mssm.edu).

Objectives: This study sought to assess the effect of short-term apolipoprotein (apo) A-I_Milano administration on plaque size and on suspected markers of plaque vulnerability.

Background: Long-term lipid-lowering interventions can regress and stabilize atherosclerotic plaques. However, the majority of recurrent events occur early after the first episode. Interventions able to acutely induce plaque regression and stabilization are lacking. Regression of human coronary lesions after 5 weeks of treatment with apoA-I_Milano administration has been shown. However, there are no data regarding its effect on plaque vulnerability.

Methods: Advanced aortic lesions were induced in New Zealand White rabbits (n = 40). Plaque size was assessed by magnetic resonance imaging (MRI) at the end of atherosclerosis induction. Animals were randomized to placebo or apoA-I_Milano phospholipids (ETC-216), 2 infusions 4 days apart. After the last dose, another MRI study was performed and aortas were processed for cellular composition and gene protein expression of markers associated with plaque instability.

Results: Pre-treatment MRI showed similar plaque size in both groups, whereas post-treatment MRI showed 6% smaller plaques in apoA-I_Milano–treated animals compared with placebo (p = 0.026). The apoA-I_Milano treatment induced a 5% plaque regression (p = 0.003 vs. pre-treatment), whereas the placebo showed no significant effect. Plaque regression by apoA-I_Milano was associated with a reduction in plaque macrophage density and a significant down-regulation in gene and protein expression of tissue factor, monocyte chemoattractant protein-1, and cyclooxygenase-2, as well as marked decrease in gelatinolytic activity. Conversely, cyclooxygenase-1 was significantly up-regulated.

Conclusions: Acute plaque regression observed after short-term apoA-I_Milano administration was associated with a significant reduction in suspected makers of plaque vulnerability in an experimental model of atherosclerosis.

Abbreviations and Acronyms   apo = apolipoprotein   CETP = cholesteryl ester transfer protein   COX = cyclooxygenase   ETC-216 = recombinant apolipoprotein A-IMilano and 1-palmitoyl-2-oleoyl phosphatidylcholine complexes   HDL = high-density lipoprotein   MCP = monocyte chemoattractant protein   MMP = matrix metalloproteinase   MRI = magnetic resonance imaging   rApoA-IM = recombinant apolipoprotein A-IMilano   TF = tissue factor

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