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Page 2 of 7 Kosmas et al. Vessel Plus 2019;3:2 I http://dx.doi.org/10.20517/2574-1209.2018.79

and cardiovascular risk, so that low HDL-C concentrations continue to exhibit a significant, independent
[2]
association with increased CVD risk despite statin therapy .

The cardioprotective effects of HDL are exerted mainly via its role in the reverse cholesterol transport
(RCT) pathway, by promoting the removal of cholesterol from peripheral cells and thus inhibiting foam
cell formation and preventing atherogenesis. Furthermore, HDL promotes endothelial repair, decreases the
expression of endothelial adhesion molecules and possess anti-inflammatory, antioxidant, antiaggregatory
and anticoagulant properties. Thus, it becomes evident that the cardioprotective effect of HDL goes beyond
[3,4]
RCT .

On the other hand, there is ample clinical evidence showing that HDL functionality, more than HDL-C
[5,6]
concentration per se, plays a crucial role in atheroprotection . HDL functionality is assessed by the
cholesterol efflux capacity (CEC), which determines the ability of HDL to accept cholesterol from
macrophages for excretion into the liver. CEC has been shown to be an excellent predictor of atherosclerotic
[7]
disease .

Furthermore, it is known that under certain conditions, such as the oxidative environment of the
acute-phase response, the HDL particles may lose their anti-inflammatory properties and become pro-
[8]
inflammatory .
In our review, we will present the clinical and scientific data pertaining to the factors and conditions that
impair HDL functionality and we will discuss the effects of dysfunctional HDL on atherogenesis.

HDL STRUCTURE AND HETEROGENEITY
HDL is synthesized in the intestine and the liver and consists of a heterogeneous group of particles,
[5,9]
which differ in density, size, electrophoretic mobility, and apolipoprotein content . Furthermore, the
HDL particles present marked structural, physiochemical, compositional and functional heterogeneity
and have significant differences in their biological properties [5,10,11] . The major apolipoproteins of HDL
are apolipoprotein A-I (ApoA-I), which constitutes approximately 70% of HDL protein and is present on
virtually all HDL particles, and ApoA-II, which constitutes approximately 20% of HDL protein and is
present on about two-thirds of HDL particles in humans [5,12] .

On the other hand, the structure of the HDL particles is very complex. Mass spectrometry studies have
shown that the HDL particles carry an array of proteins, which are engaged in lipid metabolism but also
affect complement regulation, acute-phase response and proteinase inhibition [5,13] . Moreover, lipidomic studies
have identified in excess of 200 molecular lipid species in normolipidemic HDL, including phospholipids,
sphingolipids, steroids, cholesteryl esters (CEs), triglycerides, diacylglycerides, monoacylglycerides and free
fatty acids [5,14] .

Given the above heterogeneity of HDL particles and their structural complexity, it becomes easily
understandable that any modifications of the components of the HDL particles may alter their functionality
and potentially render HDL dysfunctional.

FACTORS AFFECTING HDL FUNCTIONALITY
Certain genetic, environmental and pathophysiologic conditions can influence the HDL cardioprotective
effects by disrupting its protein components, lipid content, or by promoting modifications in the enzymes
responsible for HDL metabolism.