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Sobenin et al. Vessel Plus 2019;3:15 I http://dx.doi.org/10.20517/2574-1209.2019.09 Page 7 of 9

genetic factors evolved from variation of nuclear genome can be attributed approximately to 5% variability of
[13]
atherosclerotic diseas . On the opposite, the latest findings on the role of mitochondrial DNA variation in
individual predisposition to atherosclerosis provide a growing body of evidence and the expectation of the
breakthrough in understanding of molecular mechanisms and pathways of atherogenesis [14,15] . Heteroplasmic
mtDNA mutations represent a promising molecular biomarker of genetic susceptibility to atherosclerosis
and related pathologies [16-19] . In our study, we have demonstrated that several atherosclerosis-associated
mutations of mitochondrial DNA taken together as a mutation burden of mitochondrial genome possess
their own explanatory power and give a significant increase atop of assessment of conventional risk factors.

Undoubtedly, this study has certain limitations. First, the study was performed on a limited and fairly
specific contingent (Muscovites, the elderly persons, mostly with higher education, focused on maintaining
a healthy lifestyle, but with high level of convenient cardiovascular risk factors). Data from IMPROVE Study
show that the cIMT varies significantly even between populations that are geographically close to each
other. It is clear that in Russia in the areas differing not only geographically, but also in socio-economic,
environmental and ethnic aspects, the variability of cIMT, as well as cardiovascular mortality, can differ
significantly. The only possible resolution of this restriction may be the performance of similarly designed
cross-sectional studies in various regions of Russia.

The second limitation is that the study did not assess socio-economic and ethnic variables. These
unaccounted factors may also play a role in the formation of susceptibility to atherosclerosis and,
undoubtedly, should be studied in further population-based studies.

The third limitation comes from the inability to quantitatively explore the interaction of mitochondrial DNA
variants with conventional cardiovascular risk factors and environmental ones; therefore, the hypothesis
on their interplay in the development of atherosclerosis remains the plausible idea, which needs further
investigations. Besides, the fundamental problem still exists, since the molecular mechanisms whereby
mitochondrial genome mutations may promote atherogenesis remain obscure. The most intriguing solution
of this problem may be related to generation of cellular lines with edited mtDNA, which should reproduce
pathologic phenotype and serve as the model for studying the effects of certain mtDNA mutations on cell
functionality and mitochondrial dysfunction.

Finally, of all possible environmental factors theoretically capable of influencing the formation of phenotypic
susceptibility to atherosclerosis (namely, diffuse intimal thickening, diagnosed ultrasonographically as
an increased cIMT), only the integral indicator of atmospheric pollution was evaluated in our study. This
indicator is neither standardized nor generally accepted. There is still no single worldwide database on air
pollution. Each country uses its own standards, maximum permissible levels for the content of pollutants in
the atmosphere, and methods for their determination. One of the adverse environmental factors is the dust
load, which is not regulated and is not evaluated in the vast majority of countries around the world. In our
study, the association of the cIMT with the content of dust particles in the atmosphere was not evaluated,
mainly due to the lack of valid data. Therefore, the data on correlation between cIMT and air pollution
index should be verified in a specially designed multicenter study; otherwise, these findings lead to rather
speculative conclusions. However, a recent study in Germany showed that the content of solid dust particles
of exhaust gases in atmospheric air is related to the degree of subclinical atherosclerosis, the prevalence of
[20]
coronary heart disease and the incidence of myocardial infarction .
Despite the above limitations, the results of our study suggest that environmental and genetic factors are
involved in the formation of susceptibility to atherosclerosis and should be considered as plausible risk
factors for cardiovascular diseases. However, the question on the plausibility of findings in routine clinical
[21]
practice and preventive medicine remains disputable . It is likely that early awareness on individual genetic
predisposition to atherosclerosis may be the motivating factor for higher personal compliance to healthy