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Low Levels of Low-Density Lipoprotein-C Associated With Proprotein Convertase Subtilisin Kexin 9 Inhibition Do Not Increase the Risk of Hemorrhagic Transformation.
MedLine Citation:
PMID:  25123222     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Low levels of low-density lipoprotein-cholesterol (LDL-C) are suspected to be associated with a risk of hemorrhagic transformation after ischemic stroke. We assessed the risk of hemorrhagic transformation after cerebral ischemia/reperfusion in mice with low levels of LDL-C resulting from proprotein convertase subtilisin kexin 9 (PCSK9) deficiency.
METHODS: PCSK9(-/-) and PCSK9(+/+) mice were fed with a high-fat/high-cholesterol (21%/0.15%) diet for 1 month. Plasma lipids were measured using colorimetric assays. PCSK9(-/-) and PCSK9(+/+) mice (n=15 per group) were subjected to a 4-hour intraluminal occlusion of the middle cerebral artery followed by 20 hours of reperfusion. Spontaneous hemorrhagic transformation was assessed by quantification of hemoglobin in ischemic tissue. In vitro, a cell model of blood-brain barrier was used to test endothelial barrier integrity in response to decreasing concentrations of LDL-C from 1 to 0.25g/L in ischemia/reperfusion conditions.
RESULTS: PCSK9(-/-) mice had lower LDL-C, high-density lipoprotein-cholesterol, and total cholesterol levels than PCSK9(+/+) mice before and after 1 month on the high-fat/high-cholesterol diet. Hemoglobin concentration in ischemic cerebral tissue was not different between PCSK9(-/-) and PCSK9(+/+) mice (31.5 [18.9-60.1] and 32.8 [14.7-69.9] ng/mg protein, respectively; P=0.81). Infarct volume was also similar in both groups (P=0.66). Incubation of human cerebral endothelial cells with decreasing concentrations of LDL-C under ischemia/reperfusion conditions did not alter blood-brain barrier permeability.
CONCLUSIONS: Low levels of LDL-C did not increase the risk of hemorrhagic transformation after cerebral ischemia/reperfusion in mice. Our observations suggest that PCSK9 inhibition, leading to LDL-C lowering, should not increase hemorrhagic complications after acute ischemic stroke.
Authors:
Alexy Tran-Dinh; Angélique Levoye; Gilles Lambert; Liliane Louedec; Clément Journé; Olivier Meilhac; Pierre Amarenco
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-8-14
Journal Detail:
Title:  Stroke; a journal of cerebral circulation     Volume:  -     ISSN:  1524-4628     ISO Abbreviation:  Stroke     Publication Date:  2014 Aug 
Date Detail:
Created Date:  2014-8-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0235266     Medline TA:  Stroke     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2014 American Heart Association, Inc.
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