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Orekhov et al. Vessel Plus 2019;3:3 I http://dx.doi.org/10.20517/2574-1209.2018.80 Page 9 of 14

oxidized LDL-antibodies. The limitations of these approaches were discussed above. Direct markers of
oxidation are based on evaluating oxidized lipids including phospholipids. A non-pathological retard in
LDL catabolism which is reflected in the appearance of senescent LDL in the blood may be a limitation of
this approach. It should be noted that the clinical studies did not examine the mechanistic significance of
the modified LDL in atherogenesis but tried to position it as a biomarker. Admittedly, these attempts were
unsuccessful and did not lead to definitive conclusions about the sensitivity and specificity of modified LDL.

[41]
LDL(-) as a diagnostic parameter attracts the attention of several groups . There are certain successes in the
[42]
implementation of this indicator in clinical practice .

The ability of atherogenic modified LDL to cause the accumulation of cholesterol in cultured cells could
be used to create a diagnostic test system for assessing the atherogenicity of lipoproteins. However, the
cellular test is not a useful biomarker for implementation in clinical practice. A search for more adequate
tests was conducted. It was found that the LDL level in the CIC very closely correlates with the value of
LDL atherogenicity estimated in the cellular test [43-45] . The most successful were attempts to introduce
into the clinic such a parameter as the content of LDL in the CIC. The association between progression
of cardiovascular diseases and high levels of cholesterol in precipitated CIC has been found [46,47] . The high
diagnostic and prognostic significance of this parameter was also demonstrated for carotid and coronary
atherosclerosis [43-45,48,49] .

Therapy
The mechanistic role of oxidized LDL as an effector of atherosclerosis could be confirmed by clinical trials
using antioxidants. To the complete disappointment of supporters of the oxidative theory, randomized
trials have shown a lack of risk reduction or even an increased risk of atherosclerosis in patients receiving
[50]
antioxidants . Despite attempts to explain the negative results, the topic of oxidized LDL in atherosclerosis
was closed. Unfortunately, along with this, the interest to general problems of modified LDL was lost at
all. As a result, the American Heart Association did not recommend antioxidants for the prevention of
[51]
atherosclerotic diseases although the question on modified LDL as a mechanistic factor or biomarker of
atherosclerosis remains open.

Over the past two decades, data demonstrating the non-linear dependence of the reduction in the risk of
atherosclerosis from the therapeutic reduction in total LDL level are widely discussed [52-61] . Figure 2 clearly
shows that the clinical manifestations of atherosclerosis are due not only to the total level of LDL in the
blood. It is necessary to conduct similar studies with measuring the level of modified LDL in order to
evaluate its value as a mechanistic effector.

In contrast to the outdated concepts of the total level of circulating LDL as a cause for the formation of
atherosclerotic lesion, it seems more reasonable the idea that the key initiating event in atherogenesis is
the retention, or trapping, of LDL within the arterial wall [62,63] . The paradigm of the key role of LDL and
foam cells in atherogenesis gave rise to the concept of cellular cholesterol retention [64,65] . Cell models have
been developed to evaluate the effect of various agents on the retention of cellular cholesterol caused by
[66]
atherogenic modified LDL .
In the in vitro model, primary cultures of human aortic cells or human monocyte-derived macrophages
are used for the screening of potential drugs, the investigation of their mechanisms of action, and the
optimization of anti-atherosclerotic drug therapy. Cells of the subendothelial intima isolated from
atherosclerotic lesions retain all major characteristics of atherosclerotic cells when cultured. Many cells
cultured from atherosclerotic lesions are so-called foam cells, which contain numerous inclusions, likely
[67]
lipid droplets, that fill the entirety of the cytoplasm . The bulk of excess lipids in foam cells consists of free