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.
OBJECTIVE
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.
Ibanez
Borja
B
Cardiovascular Biology Research Laboratory, Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
Vilahur
Gemma
G
Cimmino
Giovanni
G
Speidl
Walter S
WS
Pinero
Antonio
A
Choi
Brian G
BG
Zafar
M Urooj
MU
Santos-Gallego
Carlos G
CG
Krause
Brian
B
Badimon
Lina
L
Fuster
Valentin
V
Badimon
Juan J
JJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage*; D001018:Aortic Diseases / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000008:administration & dosage*; D050197:Atherosclerosis / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D008297:Male; D010713:Phosphatidylcholines / Q000008:administration & dosage*; D011817:Rabbits; D011897:Random Allocation
D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; C474616:ETC216; D010713:Phosphatidylcholines