By Sophie Bainbridge
ORLANDO, Fla -- March 31, 2009 -- Intensive lipid-lowering therapy significantly depletes carotid atherosclerotic plaque lipids with a time course of approximately 2 years, according to research presented here at the American College of Cardiology (ACC) 58th Annual Scientific Session.
It is well known that lipid-lowering therapy reduces cardiovascular events, said Xue Qiao Zhao, MD, University of Washington, Seattle, Washington. Twelve percent of all coronary lesions show angiographic evidence of regression during intensive lipid lowering.
It has been widely hypothesised that this regression reflects the depletion of the cholesterol esters from the lesions, but until the development of high-resolution magnetic resonance imaging (MRI), this hypothesis had been impossible to test in humans. The present study was undertaken to verify this hypothesis.
"While it is evident that lipid-lowering drugs lower plasma cholesterol, we also want to see how they deplete the fat content in the plaque or in the artery wall," Dr. Zhao noted at a presentation here on March 29. "Plaque lipid depletion has been shown in animal studies, which have demonstrated the selective depletion of cholesterol esters from the vulnerable subgroup of lipid, foam cell, and macrophage-rich lesions, reduction of inflammatory activity, and stabilisation of the mechanical strength of the plaque, and improvement of endothelial function."
"All these favourable changes by lipid-lowering therapy are thought to result in improved plaque stability and reduced cardiovascular events," Dr. Zhao added. "Now that we have state-of-the-art imaging techniques, we wanted to test this in humans and in vivo."
The investigators examined 180 subjects with coronary or carotid artery disease and levels of apolipoprotein B at 120 mg/dL or higher, who had not been treated with lipid-lowering therapy for 1 to 3 years. Subjects were randomised to 1 of 3 lipid-lowering regimens: (1) atorvastatin 10 to 80 mg/day; (2) atorvastatin plus extended-release niacin 2 g/day; or (3) atorvastatin plus extended-release niacin, plus colesevelam 3.8 g/day.
The patients in regimens 1 and 2 also took appropriate placebos. At 1 year, these intensive lipid therapies reduced average low-density lipoprotein cholesterol levels by 47%, 47%, and 57%, respectively. Triglyceride levels decreased by 25%, 33%, and 42%, respectively. High-density lipoprotein cholesterol levels were reduced by 12%, 25%, and 29%, respectively.
All subjects underwent high-resolution, multicontrast, bilateral carotid MRI scans at baseline and annually for 3 years. All images were analysed for quantifications of wall area and plaque composition by expert reviewers who were blinded to lipid-lowering therapy, laboratory results, and patients' clinical course.
Because the lipid-rich necrotic core (LRNC) is an important feature of vulnerable plaque, changes in LRNC volume and composition were selected as the study's primary endpoint.
All 3 lipid-lowering regimens significantly reduced the total LRNC volume at 3 years from a mean of 60.4 +- 59.5 to 37.4 +- 69.5 mm3 (P < .001) in the 33 subjects with measurable LRNC at baseline. Time-course changes over 3 years showed that the percentage of LRNC for areas with measurable LRNC at baseline decreased an average of 3.2% (P < .001) in the first year of treatment with all 3 regimens, by 3.0% in the second year of treatment (P = .005), and by 0.91% in the third year of treatment (P = .2). Changes in 2 other LRNC-related variables followed the same pattern.
"The plaque lipid content is one of plaque's unstable markers," commented Dr. Zhao. "Unstable plaque leads to heart attacks and stroke. Intensive lipid therapy depletes the lipid in the plaque and therefore stabilises the plaque and reduces clinical cardiovascular events. These results provide the vascular biological explanation as to why lipid therapy is beneficial," she said.
Most of the plaque depletion occurs during the first 2 years of treatment, Dr. Zhao added. "This explains why clinical benefits often begin at 1.5 to 2 years of lipid-lowering therapy in patients who have not been treated previously."
Dr. Zhao concluded that the present study did not determine which of the 3 drug regimens had the greatest impact on plaque lipid depletion. She and her colleagues are currently investigating this issue, and answers should be forthcoming in about 2 years, she said.
[Presentation title: Magnetic Resonance Imaging of Plaque Lipid Depletion During Lipid Therapy: A Prospective Assessment of Efficacy and Time-Course. Abstract 2905]
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