Abstract 17773: Patients with Low Plasma High Density Lipoprotein-Cholesterol due to Mutations in the Gene Encoding for Lecithin: Cholesterol Acyl Transferase have Increased Atherosclerosis: A 3.0 Tesla MRI Study.
Background: The role of low plasma levels of high density lipoprotein-cholesterol (HDL-c) as a causal factor in atherogenesis has been questioned recently, particularly in view of the absent relation of variation in genes associated with low HDL-c with cardiovascular outcome. Lecithin:cholesterol acyl transferase (LCAT) is considered to be a rate-limiting enzyme in HDL metabolism as well as the reverse cholesterol transport pathway. To study the effect on atherogenesis of life-long low HDL-c due to partial dysfunction of LCAT, we assessed the atherosclerotic burden in carriers of LCAT gene mutations using 3-Tesla magnetic resonance imaging of the carotid arteries.
Methods and Results: MRI measurements were performed in 45 carriers of LCAT gene mutations and 45 controls, matched for age. Carriers had 31% lower LCAT activity levels compared to controls, which was accompanied by a 38% decrease in HDL-c levels (both p<0.001). Compared to controls, carriers presented with a 6% increase in normalized wall index (0.34±0.07 vs 0.32±0.05, p=0.05), a 19% increase in mean wall thickness (0.77±0.32mm vs 0.65±0.14mm, p=0.03) and a 13% increase in outer wall area (51.9±13.1mm2 vs 46.0±8.3mm2, p=0.01). These differences retained significance following adjustment for age, gender, body mass index, hypertension, low density lipoprotein-cholesterol, smoking status and family history for cardiovascular disease. In addition, the prevalence of atherosclerotic plaque components that relate to lipid rich tissue or calcification was higher in carriers than controls (20 vs 5, p=0.002).
Conclusion: The present study indicates that life-long low HDL-c caused by impaired LCAT function is associated with thickened carotid arteries, increased outward arterial remodelling and increased lipid rich tissue and calcifications in the vessel wall, all indicative of an increased risk for cardiovascular disease. The data lend support to the concept that low HDL-c is indeed causally related to atherogenesis and that raising LCAT activity is an attractive target to prevent cardiovascular disease.
- © 2010 by American Heart Association, Inc.