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

Tarasov, Kirill; Ekroos, Kim; Suoniemi, Matti; Kauhanen, Dimple; Sylvänne, Tuulia; Hurme, Reini; Gouni-Berthold, Ioanna; Berthold, Heiner K; Kleber, Marcus E; Laaksonen, Reijo; März, Winfried

<bold>Context: </bold>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.<bold>Objective: </bold>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.<bold>Methods: </bold>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).<bold>Results: </bold>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.<bold>Conclusions: </bold>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.

Journal of Clinical Endocrinology & Metabolism, 2014, Vol 99, Issue 1, pE45

0021-972X

Academic Journal

10.1210/jc.2013-2559