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J Clin Endocrinol Metab. 2014 Jan;99(1):E45-52. doi: 10.1210/jc.2013-2559. Epub 2013 Dec 20.

Molecular lipids identify cardiovascular risk and are efficiently lowered by simvastatin and PCSK9 deficiency.

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  • 1Zora Biosciences (K.T., K.E., M.S., D.K., T.S., R.H., R.L.), Biologinkuja 1, FI-02150 Espoo, Finland; University Hospital (R.L.), FI-33521 Tampere, Finland; Department of Clinical Pharmacology (K.T., R.L.), University of Helsinki, FI-00290 Helsinki, Finland; Center for Endocrinology, Diabetes, and Preventive Medicine (I.G.-B.), University of Cologne, D-50937 Cologne, Germany; Evangelical Geriatrics Center Berlin (H.K.B.), Charité University Medicine Berlin, D-13347, Berlin, Germany; Medical Clinic V, (M.E.K., W.M.), Medical Faculty Mannheim, University of Heidelberg, 69115 Heidelberg; Synlab Academy (W.M.), Synlab Services GmbH, D-68165 Mannheim, Germany; and Clinical Institute of Medical and Clinical Laboratory Diagnostics (W.M.), Medical University of Graz, 8036 Graz, Austria.

Abstract

CONTEXT:

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.

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