The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease.
OBJECTIVE
The aim of this study was to evaluate the effects of low-dose (10 mg) and high-dose (80 mg) atorvastatin on carotid plaque inflammation as determined by ultrasmall superparamagnetic iron oxide (USPIO)-enhanced carotid magnetic resonance imaging (MRI). The hypothesis was that treatment with 80 mg atorvastatin would demonstrate quantifiable changes in USPIO-enhanced MRI-defined inflammation within the first 3 months of therapy.


BACKGROUND
Preliminary studies indicate that USPIO-enhanced MRI can identify macrophage infiltration in human carotid atheroma in vivo and hence may be a surrogate marker of plaque inflammation.


METHODS
Forty-seven patients with carotid stenosis >40% on duplex ultrasonography and who demonstrated intraplaque accumulation of USPIO on MRI at baseline were randomly assigned in a balanced, double-blind manner to either 10 or 80 mg atorvastatin daily for 12 weeks. Baseline statin therapy was equivalent to 10 mg of atorvastatin or less. The primary end point was change from baseline in signal intensity (DeltaSI) on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks.


RESULTS
Twenty patients completed 12 weeks of treatment in each group. A significant reduction from baseline in USPIO-defined inflammation was observed in the 80-mg group at both 6 weeks (DeltaSI 0.13; p = 0.0003) and at 12 weeks (DeltaSI 0.20; p < 0.0001). No difference was observed with the low-dose regimen. The 80-mg atorvastatin dose significantly reduced total cholesterol by 15% (p = 0.0003) and low-density lipoprotein cholesterol by 29% (p = 0.0001) at 12 weeks.


CONCLUSIONS
Aggressive lipid-lowering therapy over a 3-month period is associated with significant reduction in USPIO-defined inflammation. USPIO-enhanced MRI methodology may be a useful imaging biomarker for the screening and assessment of therapeutic response to "anti-inflammatory" interventions in patients with atherosclerotic lesions. (Effects of Atorvastatin on Macrophage Activity and Plaque Inflammation Using Magnetic Resonance Imaging [ATHEROMA]; NCT00368589).
Tang
Tjun Y
TY
University Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Howarth
Simon P S
SP
Miller
Sam R
SR
Graves
Martin J
MJ
Patterson
Andrew J
AJ
U-King-Im
Jean-Marie
JM
Li
Zhi Y
ZY
Walsh
Stewart R
SR
Brown
Andrew P
AP
Kirkpatrick
Peter J
PJ
Warburton
Elizabeth A
EA
Hayes
Paul D
PD
Varty
Kevin
K
Boyle
Jonathan R
JR
Gaunt
Michael E
ME
Zalewski
Andrew
A
Gillard
Jonathan H
JH
D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000069059:Atorvastatin; D015415:Biomarkers; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology; D016893:Carotid Stenosis / Q000175:diagnosis* / Q000188:drug therapy / Q000473:pathology; D003287:Contrast Media; D003911:Dextrans; D004311:Double-Blind Method; D005260:Female; D052203:Ferrosoferric Oxide; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology; D007501:Iron; D008264:Macrophages / Q000187:drug effects*; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods; D058185:Magnetite Nanoparticles; D008297:Male; D008875:Middle Aged; D053758:Nanoparticles; D010087:Oxides; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D015415:Biomarkers; D003287:Contrast Media; D003911:Dextrans; D006538:Heptanoic Acids; D058185:Magnetite Nanoparticles; D010087:Oxides; D011758:Pyrroles; C097921:ferumoxtran-10; D000069059:Atorvastatin; D007501:Iron; D052203:Ferrosoferric Oxide