Molecular Lipids Identify Cardiovascular Risk and Are Efficiently Lowered by Simvastatin and PCSK9 Deficiency

• Published in: The journal of clinical endocrinology and metabolism Vol. 99; no. 1; pp. E45 - E52
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.01.2014; Copyright by The Endocrine Society; Endocrine Society
• Subjects: Aged; Azetidines - therapeutic use; Cardiovascular disease; Cardiovascular diseases; Case-Control Studies; Ceramide; Cholesterol; Coronary artery disease; Coronary Artery Disease - blood; Coronary Artery Disease - drug therapy; Coronary Artery Disease - epidemiology; Drug development; Ezetimibe; Female; Follow-Up Studies; Genetic Association Studies; Genetic Predisposition to Disease; Heart diseases; Hot Topics in Translational Endocrinology; Humans; Hypolipidemic Agents - therapeutic use; Lipids; Lipids - blood; Macromolecular Substances - blood; Male; Middle Aged; Morbidity; Proprotein Convertase 9; Proprotein Convertases - deficiency; Proprotein Convertases - genetics; Randomized Controlled Trials as Topic; Risk Factors; Serine Endopeptidases - deficiency; Serine Endopeptidases - genetics; Simvastatin; Simvastatin - therapeutic use
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2013-2559

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.