Abstract
High-density lipoproteins (HDLs) have multiple pleiotropic effects against arteriosclerosis.
Most are independent of the cholesterol mass within HDL particles. Yet, HDL cholesterol
(HDL-C) remains a biomarker to assess cardiovascular risk. Whereas the epidemiological
association between HDL-C and cardiovascular risk is strong, graded and coherent across
populations, Mendelian randomization studies cast doubt on whether HDL-C is causally
related to atherosclerotic cardiovascular disease. The apparent failure of HDL-C-raising
therapies (fibrates, niacin, and cholesteryl ester transfer protein inhibitors) raises
questions about the HDL-C hypothesis. HDL particles are heterogeneous in lipid and
protein composition, and thus in size and function. Multiple factors related to oxidation
and inflammation might render HDL particles malfunctional or proatherogenic. HDL functionality
might be a preferred biomarker and therapeutic target. However, most of the beneficial
events of HDL particles occur in the subendothelial layer of arteries and not in plasma.
In this report, we review the complexity and controversies surrounding HDL and atherosclerotic
cardiovascular disease. Importantly, intimal HDL biogenesis, function, and egress
from the arterial wall might hold the key to unlocking the therapeutic potential of
HDL.
Résumé
Les lipoprotéines de haute densité (HDL) ont de multiples effets pléiotropiques contre
l’artériosclérose. La plupart sont indépendants de la masse de cholestérol des particules
HDL. Toutefois, le cholestérol HDL demeure un biomarqueur pour évaluer les risques
cardiovasculaires. Alors qu’il existe un lien épidémiologique fort, marqué et cohérent
entre le cholestérol HDL et les risques cardiovasculaires dans l’ensemble des populations,
les études à répartition aléatoire mendélienne remettent en question le lien causal
entre le cholestérol HDL et la maladie cardiovasculaire athérosclérotique. L’échec
apparent des traitements qui augmentent le cholestérol HDL (fibrates, niacine et inhibiteurs
de la protéine de transfert des esters de cholestérol) soulève des questions sur l’hypothèse
du cholestérol HDL. Les particules HDL sont hétérogènes quant à leur composition lipidique
et protéique et par conséquent, quant à leur taille et leur fonctionnement. De multiples
facteurs liés à l’oxydation et à l’inflammation pourraient entraîner un dysfonctionnement
des particules HDL ou les rendre pro-athérogènes. La fonctionnalité des HDL pourrait
constituer un biomarqueur et une cible thérapeutique privilégiés. Toutefois, la plupart
des manifestations bénéfiques des particules HDL se produisent dans la couche sous-endothéliale
des artères, et non dans le plasma. Dans le présent article, nous passons en revue
la complexité et les controverses qui entourent les HDL et la maladie cardiovasculaire
athérosclérotique. Notamment, la biogenèse intimale des HDL, leur fonctionnement et
leur évacuation de la paroi artérielle pourraient se révéler la clé de l’exploitation
du potentiel thérapeutique des HDL.
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Article info
Publication history
Published online: October 20, 2016
Accepted:
September 19,
2016
Received:
August 7,
2016
Footnotes
See page 332 for disclosure information.
Identification
Copyright
© 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
