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Page 4 of 7 Kosmas et al. Vessel Plus 2019;3:2 I http://dx.doi.org/10.20517/2574-1209.2018.79

In a post hoc analysis of two large prospective studies, the IDEAL (Incremental Decrease in End Points
through Aggressive Lipid Lowering) trial and the EPIC (European Prospective Investigation into Cancer and
Nutrition)-Norfolk case-control study, it was shown that very high plasma HDL-C levels (≥ 70 mg/dL) and
very large HDL particles (> 9.53 nm) conferred an increased risk for coronary artery disease (CAD) when
[33]
levels of ApoA-I and ApoB were kept constant . This observation may be explained by the hypothesis that
very large, cholesterol-enriched HDL particles, may at some point become cholesterol donors rather than
[33]
acceptors and thus become pro-atherogenic . This hypothesis was supported in another community-based
cohort study, in which it was clearly shown that cholesterol-overloaded HDL particles were independently
associated with progression of carotid atherosclerosis in a population free of CVD. More specifically,
participants with the highest estimated number of cholesterol molecules per HDL particle (≥ 53.0) had 1.56-
fold increased progression of carotid atherosclerosis, as compared with those with the lowest estimated
number of cholesterol molecules per HDL particle (< 41.0) [5,34] . Furthermore, in a very recent study of two
large population-based cohorts in Denmark (52,268 men and 64,240 women), it was clearly shown that in
men and women in the general population extremely high HDL-C levels were paradoxically associated with
[35]
high all-cause mortality risk . In addition, in a large-scale pooled analysis of 9 Japanese cohorts, which
included 43,407 participants, it was again shown that extremely high HDL-C levels led to an increase of
[36]
atherosclerotic CVD mortality .
As it was mentioned earlier in this review, CEC from macrophages is currently considered an important
metric of HDL function. In this regard, multiple studies have shown an inverse relationship between
CEC and the incidence of cardiovascular events, independent to HDL-C levels [7,37,38] . In the Dallas heart
study, a multiethnic, population-based, cohort study, in which the HDL cholesterol level, HDL particle
concentration, and CEC were measured at baseline in 2,924 adults free from CVD over a mean follow-up
period of 9.4 years, there was a 67% reduction in the risk for cardiovascular events in the highest quartile of
[7]
CEC, as compared to the lowest quartile . This again proves that dysfunctional HDL with low CEC may be
an important factor in atherogenesis.

In addition, it has been shown that HDL and ApoA-I recovered from human atheroma are dysfunctional and
are extensively oxidized by MPO. More specifically, while the amount of circulating ApoA-I that contains
a 2-OH-Trp72 group (oxTrp72-ApoA-I) is minimal under normal conditions, it accounts for 20% of the
ApoA-I in atherosclerotic arteries. Increased levels of oxTrp72-ApoA-I have been linked to an increased risk
[39]
for CVD . Most importantly, there is evidence showing that dysfunctional HDLs with diminished anti-
inflammatory activity are present in patients with CAD and they are actually found in higher abundance in
[40]
patients with acute coronary syndrome (ACS) than in patients with stable angina .

Furthermore, as it was alluded to earlier, HDL isolated from patients with CAD (but not HDL from healthy
subjects) exhibits a pro-inflammatory rather than an anti-inflammatory effect when exposed to endothelial
cells. In addition, HDL from patients with CAD (in contrast to HDL from healthy subjects) did not
stimulate endothelial cell NO production, due to inhibition of the activation of endothelial NO synthase,
leading to the loss of the endothelial anti-inflammatory and repair-stimulating effects of HDL in patients
with CAD [41,42] .

The above were also corroborated in a large clinical study, which included 1,548 patients with CAD
undergoing coronary artery bypass grafting. This study clearly demonstrated that higher pre-operative
HDL-C levels were not associated with a reduction but rather with a clear tendency for an increase in the
[43]
occurrence of major adverse cardiovascular events . This was attributed to the presence of dysfunctional
HDL in patients with CAD, as it was clearly alluded above.

CONCLUSION
From the above review of the scientific and clinical data, it becomes evident that the HDL particles possess
potent cardioprotective biological functions. In addition to their effect in the facilitation of RCT, the HDL