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Page 8 of 14 Orekhov et al. Vessel Plus 2019;3:3 I http://dx.doi.org/10.20517/2574-1209.2018.80

murine plaques. It was established that lipid droplet proteins can promote atherogenesis being critical to
[29]
the foam cell formation and lipid deposition . Lysophosphatidic acid (LPA) is a bioactive phospholipid
produced by activated platelets that is formed during the oxidation of LDL. The formation of foam cells is
[30]
significantly enhanced by LPA alone through upsetting the imbalance between lipid uptake and efflux .
CLINICAL APPLICATIONS
The results obtained in clinical studies did not always correspond to the theoretical understanding of the
role of LDL in atherogenesis. As follows from the concept of evidence-based medicine, the mechanistic role
[31]
of biomarkers should be confirmed by clinical studies (trials and surveys) . In other words, the modulation
of the biomarker should affect the established endpoints. In the case of atherosclerotic diseases, such
endpoints are: fatal and non-fatal cardiovascular events, angina pectoris, revascularization, fatal and non-
fatal myocardial infarction, stroke, etc. When talking about the direct relationship with atherosclerosis,
endpoints often use surrogate instrumental methods, namely angiography of coronary arteries, ultrasound
imaging of the carotid intima-media thickness and, less commonly, calcification of the coronary arteries.

Diagnostics
Unfortunately, modified LDL is not used in American and European recommendations and guidelines
for reducing the risk of developing atherosclerotic cardiovascular diseases [32-34] . This is the result of the
fact that the available data from clinical studies do not allow us to justify the use of modified LDL and
HDL as mechanistic biomarkers of atherosclerotic disease. Apparently, the results of such studies would
be more encouraging if atherogenic multiply modified LDL and dysfunctional HDL were considered as
pharmacological targets and biomarkers.

The difficulties in verifying new biomarkers are related to the complexity of interaction of different markers
and risk factors. In addition, against the background of usual risk factors, new biomarkers are often not
supported by evidence of their ability to contribute to the assessment of atherosclerotic risk and possess no
significant diagnostic or prognostic role [35-38] . Currently, numerous traditional and experimental biomarkers
are considered to assess atherosclerotic risk. Along with lipid markers, which include modified LDL,
dysfunctional HDL and apolipoproteins, non-lipid markers are considered. Non-lipid biomarkers include
inflammatory molecules, namely fibrinogen and a highly sensitive C-reactive protein. Lipoprotein-associated
phospholipase A2 and homocysteine are considered as thrombotic markers. Other indexes are glucose
metabolism markers and organ-specific markers.

Clinical studies of modified LDL as a biomarker of atherosclerosis have certain limitations. In particular,
the use of the term “oxidized LDL” causes confusion. To measure the allegedly “oxidized” LDL in clinical
trials, antibodies against MDA-LDL are used. Such an indicator cannot be called oxidized LDL. It is clear
that in this case it is possible to evaluate the clinical significance of some indicator whose physical meaning
is difficult to interpret. Autoantibodies against LDL found in the blood of atherosclerotic patients cross-react
[39]
with MDA-LDL, multitude modified LDL and desialylated LDL . Moreover, these autoantibodies possess
2+
the highest affinity with desialylated LDL while they did not distinguish between native and Cu -oxidized
LDL. Therefore, MDA-LDL to some extent evaluate the desialylated and not oxidized LDL.

Since it was impossible to directly demonstrate the presence of oxidized LDL in the bloodstream, the term
“minimally oxidized LDL” has been introduced. This should imply some hypothetical particle that cannot
be isolated or characterized by existing methods, but which actually exists penetrating the artery wall,
[40]
undergoing further modification, and triggering atherosclerosis . Unfortunately, such “pure faith” is
widespread and is not subject to revision.

As a result of experimental or clinical studies of oxidized LDL, both indirect and direct oxidation indices
can be obtained. Indirect indices are based on the measurements using anti-MDA-LDL or anti-copper-