Abstract 18088: Molecular Lipids Identify Cardiovascular Risk and Are Efficiently Lowered by Simvastatin and PCSK9 Deficiency
Recent clinical trial results have shown that lowering LDL-C or increasing HDL-C does not always lead to improved clinical outcomes despite favourable changes in plasma cholesterol levels. We wanted to investigate whether specific molecular lipid molecules would be better measures of the CVD outcomes. Thus, we performed a broad plasma lipidomic analysis of stable and unstable CAD patients. Importantly, we also evaluated the effect of different lipid lowering drugs on these lipid species.
Plasma samples obtained at baseline from CAD subjects (n=445) were analyzed with LC-MS/MS approach to identify lipid species that were differently expressed in patients (n=258) who died due to CVD reasons during the 3 year follow-up compared to survivors. Plasma samples from subjects (n=60) treated either with simvastatin (40mg), ezetimibe (10mg) or their combination were also analyzed. Furthermore, samples from loss-of-function mutation (R46L) carriers (n=22) of the PCSK9 gene were analyzed and compared with data obtained from major allele carriers (n=966).
Short chain ceramide and cerebroside species proved to associate very strongly with CVD death in male CAD patients. Strikingly, no significant difference was recorded in the LDL-C and HDL-C concentrations between these patient groups. Simvastatin lowered LDL-C by 41% and plasma sphingolipids, including the identified ceramide and cerebroside species by 25%. Ezetimibe resulted in 22% LDL-C reduction, but no change or even a slight increase in the short chain ceramides. Ezetimibe attenuated simvastatin driven ceramide lowering when given in combination despite -60% LDL-C reduction. PCSK9 deficiency associated with non-significantly (10%) lowered LDL-C levels, which was however, accompanied by a significant 20% reduction in plasma short chain ceramides.
These data suggest that the identified lipids are better read-outs of CVD risk than LDL-C. These data further show that these risk lipids respond in a specific fashion to various lipid lowering modalities. The loss-of-function PCSK9 mutation resulted in an efficient reduction of the risk lipids despite the modest LDL-C lowering effect, which may explain the good atheroprotective effect of this genetic variant observed in epidemiological studies.
- © 2012 by American Heart Association, Inc.