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Molecular lipids identify cardiovascular risk and are efficiently lowered by simvastatin and PCSK9 deficiency Tarasov K; Ekroos K; Suoniemi M; Kauhanen D; Sylvanne T; Hurme R; Gouni-Berthold I; Berthold HK; Kleber ME; Laaksonen R; Marz WJ Clin Endocrinol Metab 2014[Jan]; 99 (1): E45-52CONTEXT: Coronary artery disease (CAD) is among the leading causes of mortality and morbidity worldwide. Traditional risk markers explain only a proportion of total cardiovascular risk. Thus, development and improvement of early diagnostic strategies and targeted initiation of preventive measures would be of great benefit. OBJECTIVE: We aimed to identify molecular lipids that are associated with fatal outcome of CAD patients. Furthermore, the effect of different lipid-lowering drugs on novel risk lipids was evaluated. METHODS: Serum samples of 445 CAD subjects participating in a long-term follow-up of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study were analyzed. In addition, samples obtained from a separate randomized parallel three-group study of subjects treated with simvastatin (n=24), ezetimibe (n=24), or their combination (n=24) were studied. Furthermore, samples from the LURIC participants with a loss-of-function mutation (R46L) in the PCSK9 gene (n=19) were analyzed and compared with major allele carriers (n=868). RESULTS: Distinct ceramide species were significantly associated with the fatal outcome of CAD patients. Simvastatin lowered plasma ceramides broadly by about 25%, but no changes in ceramides were observed in the ezetimibe group. PCSK9 deficiency was significantly associated (-13%) with lowered low-density lipoprotein cholesterol accompanied by a significant 20% reduction in CAD outcome risk-related ceramides. CONCLUSIONS: These data suggest that distinct ceramides associate significantly with CAD outcome independently of traditional risk factors and that the mechanism of lipid lowering is important.|Aged[MESH]|Azetidines/therapeutic use[MESH]|Case-Control Studies[MESH]|Coronary Artery Disease/blood/*drug therapy/*epidemiology[MESH]|Ezetimibe[MESH]|Female[MESH]|Follow-Up Studies[MESH]|Genetic Association Studies[MESH]|Genetic Predisposition to Disease[MESH]|Humans[MESH]|Hypolipidemic Agents/*therapeutic use[MESH]|Lipids/*blood[MESH]|Macromolecular Substances/blood[MESH]|Male[MESH]|Middle Aged[MESH]|Proprotein Convertase 9[MESH]|Proprotein Convertases/deficiency/*genetics[MESH]|Randomized Controlled Trials as Topic[MESH]|Risk Factors[MESH]|Serine Endopeptidases/deficiency/*genetics[MESH]|Simvastatin/*therapeutic use[MESH] |
