Molecular lipids identify cardiovascular risk and are efficiently lowered by simvastatin and PCSK9 deficiency.
BACKGROUND
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.
Zora 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.
Kirill
K
Tarasov
Kim
K
Ekroos
Matti
M
Suoniemi
Dimple
D
Kauhanen
Tuulia
T
Sylvänne
Reini
R
Hurme
Ioanna
I
Gouni-Berthold
Heiner K
HK
Berthold
Marcus E
ME
Kleber
Reijo
R
Laaksonen
Winfried
W
März
D000368:Aged; D001384:Azetidines / Q000627:therapeutic use; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology*; D000069438:Ezetimibe; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood*; D046911:Macromolecular Substances / Q000097:blood; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000172:deficiency / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics*; D019821:Simvastatin / Q000627:therapeutic use*
D001384:Azetidines; D000960:Hypolipidemic Agents; D008055:Lipids; D046911:Macromolecular Substances; D019821:Simvastatin; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000069438:Ezetimibe