In the last few years there has been a large discussion on the properties of high density lipoprotein cholesterol (HDL-C).
The main part of this debate concerns the role of HDL-C in predicting cardiovascular (CV) events and mortality, and in consequence,
in reducing the residual risk . It is connected to the fact that all large randomized controlled trials (RCTs) which
were dedicated to investigate this role of HDL-C gave negative results .
HDL particles can be divided into different subpopulations/subfractions, according to their size, density, electrophoretic
mobility, and apolipoprotein (Apo) composition. They are composed of the highest proportion of apolipoprotein A-I (apoA-I;
60% of the protein content), apoA-II (20% of the protein content), with small amounts of apoC, E, A-IV, D and J . Their
properties are also associated with the fact that HDL particles carry important anti-oxidant enzymes: paraoxonase-1 (PON1),
platelet-activating factor acetyl hydrolase (PAF-AH), glutathione selenoperoxidase (GSPx), lecithin-cholesterol acyltransferase
(LCAT) and phospholipid transfer protein (PLTP) [4-6]. The qualitative and quantitative content of lipids and Apos,
as well as enzymes vary resulting in different HDL subclasses, which can be distinguished using different methods [4-7]. As for
example, activities of HDL-associated enzymes such as LCAT, PON1and PAF-AH are much elevated in small, dense HDL-3c
and these particles also have a predominance of apoJ, apoL-1 and apoF proteins and PLTP as well; in contrast, apoE, apoC-I, -
II and -III occur predominantly in large, less dense HDL-2 particles [7-10]. Continuous intravascular remodeling of HDL particles
during reverse cholesterol transport (RCT) also contributes to their heterogeneity – the nascent discoidal HDL particles are
progressively lapidated to form, in succession, small, dense HDL-3 and then large HDL-2 particles by LCAT [8-10].
Despite our intensive knowledge on the structure of HDL particles, as well as HDL subfractions/subpopulations, we have
still had very limitted, and often exclusive data on their properties and role in CV risk prediction . As for instance, in some
available studies it was shown that small HDL subfractions might significantly increase the risk of CVD (similarly to small
dense low density lipoprotein cholesterol [LDL-C]). In others they were observed as being highly protective . There are at
least few explanations for that. The most important one is connected to the fact that there are many different methods of HDL
subfractions/subpopulations analysis, which have been used in available studies. On the other hand, the CV risk of investigated
patients in these studies was very different from primary prevention patients with concomitant CV risk factors, through subjects
after acute coronary event/stroke, finishing with individuals with CVD and chronic kidney disease [11,12]. In all these subjects
the role of HDL particles might be completely different, because their properties on a large degree depend on inflammation (as
well as oxidative stress) intensity [1, 13]. The bigger the intensity of inflammation, the more the HDL particles with impaired
functionality. Therefore, it might be that the size of HDL particles is not so important, and, according to our hypothesis, the
more important question might be when, and at what stage of HDL metabolism these particles are the most prone to functional
It needs to be also emphasized that most of the epidemiological studies and RCTs evaluated only the quantity of circulating
HDL-C, but not the quality and functionality of its subclasses, and nowadays it seems to be commonly accepted that the functionality
of HDL subclasses defines the anti-atherogenic quality of HDL [1,7,13,14]. In this respect, the new concept of "dysfunctional
HDL", "pro-inflammatory HDL" or "pro-atherogenic HDL" is currently under very active investigation [1,7,13,15].
The current special issue of Current Medicinal Chemistry on “Current research, knowledge and controversies on high density
lipoprotein (HDL)” has been completely dedicated to the most recent knowledge, and the current status of the mentioned
above debate on the position of HDL-C as a cardiovascular biomarker. The Readers can, therefore, find papers on genetic determinants
of HDL metabolism by Dr. Calabresi and her team , as well as on HDL metabolism regulation by Dr. Kardasis
et al. . The issue also includes a very important paper presenting the current expert opinions on subfraction and subpopulations
of HDL cholesterol (by Dr. Rizzo et al.)  with the detailed information on the methods on analysis and reasons why
there are still doubts on its role. Dr. Oravec et al.  present a paper on new hypothetical phenomena called atherogenic normolipidemia
and non-atherogenic hyperlipidemia indicating that sometimes it might be necessary to widen the diagnostics and
analyse the HDL and LDLsubfractions/subpopulations . It also presents the current role of HDL cholesterol, both on endothelium
and in CVD (by Dr. Madahian et al.) , in CHD patients (by Dr. Rysz et al.) , as well as in subjects with infection
and cancer (by Dr. Katsiki et al.) . Finally, Dr. Dragan and her colleagues present the scientifically confirmed methods
to influence HDL functionality [24,25], and Drs. Duong and Nicholls describe the current state of research on new drugs for
HDL disorders [26,27].
I do hope that that this special issue of Current Medicinal Chemistry will contribute to a better understanding of the properties
and the role of HDL particles. Enjoy reading this issue!