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Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16 Page 5 of 30

instance, the Framingham Study showed a greater annual incidence of VVs in women (2.6%) than in men
[13]
(1.9%) . Also, the Edinburgh Vein Study screened for CVD in 1566 subjects 18-64 years old at 12 general
[14]
practices and showed that females reported more leg symptoms . However, a follow-up study found that
the age-adjusted prevalence of truncal VVs was ~40% in males and ~32% in females, and VVs and CVD
prevalence increased with age in both sexes . Also, studies using Duplex ultrasound to evaluate venous
[15]
reflux reported CVD in ~9.4% of males and ~6.6% of females, and an increase in the incidence with age to
~21.2% in males older than 50, and to ~12.0% in females older than 50 . Interestingly, we have shown that
[16]
2+
α-adrenergic-, angiotensin II (AngII)-, depolarization-induced, and [Ca ]-dependent venous tissue
contraction are less in female than in male rat inferior vena cava (IVC), likely because of increased
expression and activity of estrogen receptors and increased endothelium-dependent venous relaxation
pathways in female compared with male rats. These observations suggested gender differences in venous
function, enhanced estrogen-induced venous relaxation pathways and decreased mechanisms of VSM
contraction, leading to more distention of the venous wall in females .
[24]

Overweight and obesity in women increase the risk of developing VVs . Compared with lean women,
[25]
2
women with moderate overweight (BMI = 25.0-29.9 kg/m ) were more likely to present with VVs, and obese
women (BMI ≥ 30 kg/m ) were 3 times more likely to present with VVs. On the other hand, a positive
2
relation between BMI and CVD was not observed among men . Of note, the plasma levels of total and
[26]
bioavailable estrogens are greater in overweight and obese women compared with lean women particularly
[27]
in the postmenopausal period , further highlighting the positive association between plasma estrogen
levels and the incidence of VVs.
Pregnancy involves important physiological changes that could promote venous dilation and VVs
formation. Plasma levels of estrogen and progesterone are elevated during pregnancy . Also, increased
[28]
blood volume and plasma volume expansion occur during early pregnancy . The progressive fetal growth
[29]
and weight gain during pregnancy also cause increases in intra-abdominal pressure and central venous
return [30,31] , which could cause venous valve incompetence and further progression of VVs.

Behavioral factors including prolonged sitting or standing and sedentary lifestyle could represent a risk for
CVD [25,32,33] . Also, the physical activity and ergonomics of an occupation and a work place may influence
VVs epidemiology. In a community-based study on males and females of 20 to 64 years old in Jerusalem,
the VVs prevalence was higher in individuals spending most of their workday in a standing position. Also,
reporting of occupations requiring prolonged standing was higher in females (31.4%) compared with males
(13.6%), although the ratio of standing vs. sitting workplace posture was higher in men (1.88) than in
women (1.53) .
[34]
Predisposing hereditary and genetic factors in CVD
Family history, hereditary and genetic factors could increase the risk for VVs [Table 1] [35,36] . The lower
extremity venous hemodynamics and elasticity of the vein wall are decreased in the children of patients with
VVs . Of note, the VVs pathology may not be restricted to the lower limb veins, and patients with VVs
[37]
may show abnormal increase in distensibility of the arm veins, which suggests a more generalized and
[12]
systemic disorder of the vein wall . There is also an increasing evidence of a genetic component in VVs.
Microarray analysis of 3063 cDNAs from patients with VVs demonstrated an upregulation of 82 genes,
[35]
especially those involved in the regulation of myofibroblasts, cytoskeletal proteins and ECM . An elegant
study of nearly half a million subjects (control and cases), utilizing machine learning for risk factors as well
as genome-wide association study (GWAS), implicated advanced age, female sex, obesity, pregnancy, DVT,
increased height, and leg bioimpedance as risk factors for VVs. The GWAS found 30 novel genome loci that