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Page 8 of 13 Smetanina et al. Vessel Plus 2021;5:19 https://dx.doi.org/10.20517/2574-1209.2021.17

[41]
PLG) . Bioflavonoids found in citrus bioflavonoid extract, grape seed extract, pine bark extract and green
tea extract participate in the regulation of human aortic smooth muscle cell-mediated contraction and have
a strong potential for counteracting pathophysiological effects of angiotensin II-the leading mediator of
[42]
clinical systemic hypertension . Anti-hypertensive effects of diosmin (namely, compromised NO-synthase
inhibitor induced cardiac infarcts, hyaline arteriopathy and fibrinoid necrosis), presumably because of its
[43]
activity in elimination of superoxide anions, were demonstrated in a rat model . Peripheral arterial disease
may also be treated with Sulodexide, which prevents cardiovascular events after myocardial infarction and
[44]
exerts the relief of intermittent claudication .
In 2020, a Russian group of scientists performed a scrutinizing review based on the literature data and their
own works and postulated that: (a) primary varicose transformation of superficial veins develops as a result
of remodeling of their walls; (b) vein wall remodeling is based on a complex of molecular processes
determined by genetic predisposition; (c) vein wall remodeling is reversible, i.e., the dilated and altered vein
can return to its original (“healthy”) state; and (d) varicose veins can probably be successfully cured
pharmacologically with no surgical interventions needed . Table 1, compiled on the basis of data from
[45]
Kharkevich (2004) , Maggioli (2016), Ramelet et al. (2017) and Mansilha and Sousa (2018), as well
[47]
[48]
[46]
[39]
as other sources, is a kind of generalization of the treatment options for patients suffering from chronic
venous diseases.
Apparently, not all the works devoted to the investigation of phlebotonics’ efficacy are cited in this table.
[72]
Martinez-Zapata et al. performed a very thorough (237 pages) review “Phlebotonics for venous
insufficiency” on randomized, double-blind, placebo-controlled trials where the efficacy of phlebotonics
(rutosides, diosmine, hidrosmine, calcium dobesilate, aminaftone, disodium flavodate, chromocarbe,
Centella asiatica, French maritime pine bark extract and grape seed extract) was assessed. The authors
concluded that there was “moderate-certainty evidence that phlebotonics probably reduce (o)edema
slightly, compared to placebo; moderate-certainty evidence of little or no difference in quality of life; and
low-certainty evidence that these drugs do not influence ulcer healing; moderate-certainty evidence suggests
[72]
that phlebotonics are probably associated with a higher risk of adverse events than placebo” . One possible
reason that the desired efficacies were not observed in many clinical trials could be because, in order to have
an effect, many flavonoids should be metabolized due to the intestine microflora [46,43] . What if the patient’s
microflora is impaired? Does that mean all those efforts might be in vain? It is known that one of the most
popular drugs in phlebological practice - micronized purified flavonoid fraction - is more effective as a
complex substance rather than its components applied separately . Nowadays, new possible venoactive
[73]
drugs are being investigated. Recently, using a mouse model, Lust et al. showed that diclofenac (COX-2,
[74]
or cyclooxygenase, inhibitor) is capable of attenuating venous remodeling in vivo . We are likely entering
[74]
the era of research on new potential substances targeting the main drivers of pathological processes in
varicose vein disease.

CONCLUSION
In recent decades, the studies on varicose veins have paid much attention to its genetic constituent. In this
perspective, we provide a critical overview and literature analysis on the heredity of varicose veins, genetic
association studies, gene expression and epigenetic studies and point out the gaps existing in the field. We
hope that the generalized information given will be useful not only for fundamental scientific researchers,
but also for clinicians, and will be further used in phlebological practice. Revealing the genetic basis of
venous diseases can help to clarify the mechanisms of pathogenesis, and their understanding, in turn, can
help to develop new methods of prevention and treatment of varicose veins. Of note, for disease risk
assessment, epigenetic factors and their heritability should be considered as well. Perhaps in our century