Parietal and valvular venous insufficiency: the influence of heredity

by V. Crébassa, France

Médecin Vasculaire et
Phlébologue à la Clinique du
Millénaire, Montpellier
Lecturer at Pierre and Marie
Curie University Paris VI

A recent cross-sectional study on heredity and venous disorders has provided us with a vast amount of data concerning chronic venous disorders (CVDs) across a wide range of clinical stages of CVD and ages. These data have deeply modified our knowledge of CVD. Indeed, it has shown that the evolution of this disease in patients with no direct inherited condition and in those with inherited CVD is different. Differences between paternal and maternal transmission have been identified as well. With inherited CVD, the impact of the disease is aggravated at all ages. The hereditary weakening of the venous system is almost certainly linked to deregulation of parietal and valvular renewal, even though the genetic factor has not yet been formally identified. This matrix metalloproteinase–induced impairment of the renewal mechanism explains the premature weakening of the veins of our patients, who eventually suffer from venous hypertension, in this case “secondary” and linked to venous stasis and inflammation. The roles of flavonoids in regulating matrix metalloproteinase levels and activity help explain their beneficial effect in reducing pathophysiological mechanisms. The hereditary factor is a major criterion in daily practice and can help define the risk profile of each of our patients. These new data have profoundly challenged our assumptions about the therapeutic management of CVD, the advice we give patients, and the way we follow up the disease.

Medicographia. 2016;38:155-161 (see French abstract on page 161)


The influence of heredity in venous disease

Although the influence of heredity has been considered clinically obvious in venous diseases for a long time, it has only been scientifically documented since the beginning of the 1990s, thanks in particular to the work of Cornu- Thenard et al.1 However, despite the carrying out of other epidemiological2,3 and genomic studies4-6 since, the mode of transmission of the disease remains relatively poorly researched and incompletely determined.

In 2010, an international study—the Vein Consult Program7—was carried out to evaluate the prevalence of venous disease in all patients over 18 years of age who consulted their general practitioner. As part of this study, over a 2-day period 1040 French general practitioners described the clinical condition of their patients’ venous circulation according to the CEAP (Clinical–Etiological–Anatomical–Pathophysiological) classification system and recorded, among other things, their patients’ direct parental venous background irrespective of sex or reason for the consultation.8 Data in the 21 319 completed medical files (25.9% male, 74.1% female) thus included a hereditary perspective of venous disease. The prevalence of venous disease was 58.8% in the entire population; 38.2% in those with no direct parental background, 67.0% in those with a unilateral paternal background, 71.3% in those with a unilateral maternal background, and 79.2% in those with a bilateral background (P<0.0001). In men, the prevalence of venous disease was 38.9%; 22.5% in men without parental background, 58.1% in men with a unilateral paternal background, 52.6% in men with a unilateral maternal background, and 71.5% in men with a bilateral background (P<0.0001). Venous disease was more prevalent in women; it was present in 46.8% of those without a parental background of venous disease, 70.8% in women with a unilateral paternal background, 75.1% in women with a unilateral maternal background, and 81.5% in women with a bilateral background (P<0.0001).

Figure 1. Comparison according to the source of heredity of venous
disease of odds ratios for the occurrence of venous disease
(versus patients with no family history of venous disease) in men
and women.
Modified from reference 8: Crébassa et al. Phlébologie. 2014;67(3):13-21.
© 2014, Éditions Phlébologiques Françaises.

Nearly half of men (46.0%) had a parental history of venous disease: a quarter of men (26.8%) had a unilateral history of maternal venous disease, 10.7% a bilateral history, and 8.5% a unilateral paternal history. Nearly two thirds of women (63.5%) had a parental history of venous disease: nearly half (45.8%) had a unilateral maternal history, 10.7% a bilateral parental history, and 7.0% a unilateral paternal history.

The risk of venous disease increased significantly with a family history of venous disease: in patients with unilateral paternal heredity (odds ratio [OR], 3.2; 95% CI, 2.8-3.6), those with unilateral maternal heredity (OR, 3.4; 95% CI, 3.2-3.7), and those with bilateral heredity (OR, 5.6; 95% CI, 5.0-6.2), compared with patients with no familial history of venous disease. In comparison to men without a family history of venous disease, the OR of paternal heredity in men was 4.8 (95% CI, 3.9-5.8; P<0.0001), the OR of maternal heredity in men was 3.8 (95% CI, 3.3-4.4; P<0.0001), and the OR of bilateral heredity in men was 8.6 (7.1-10.5; P<0.0001), all in favor of the occurrence of venous disease (Figure 1).8 The same comparisons in women also found significant ratios in favor of heredity of venous disease: the OR in women with paternal heredity was 2.8 (95% CI, 2.4-3.2), the OR in women with maternal heredity was 3.4 (95% CI, 3.2-3.7), and the OR in women with bilateral heredity was 5.0 (95% CI, 4.4-5.7). The influence of heredity on venous disease appears to be stronger in men than in women, regardless of the source of heredity, ie, maternal, paternal, or both (Figure 1).8

A logistic regression model adjusted for age and sex showed that heredity was an independent predictor of venous disease. Similar analyses were also carried out in men and women, separately; in women, by introducing sex-specific risk factors into the model, ie, number of children, oral contraception, menopause, and hormone replacement therapy. These analyses confirmed the finding that heredity was an independent predictor of venous disease. For women, having children increases the risk of venous disease.

Figure 2. Age-stratified comparison of the prevalence
of venous disease in patients whose parents
both had venous disease versus patients
whose parents did not have venous disease,
which clearly shows the impact of heredity on
venous disease. After data from reference 8.

Figure 3. Impact of heredity on the prevalence of chronic venous disease by
clinical stage of venous disease.

The risk of venous disease increases with age. In fact, age based analyses showed that the prevalence of venous disease increased with age, irrespective of family history of venous disease (P<0.0001) (Figure 2).8 Whatever the age group, venous disease was significantly more prevalent in patients with either a unilateral or a bilateral family background of venous disease compared with patients with no family history of venous disease (P<0.0001). Regardless of the grade of severity of chronic venous disease, the prevalence of chronic venous disorders (CVDs) has been shown to be higher in patients with a family history of venous disease than in those without (Figure 3). The impact of heredity is further enhanced if it is bilateral in nature and if the patient develops CVD when young.

Among recent studies that take age, sex, and information on heredity into account, reference must be made to the study by Laurikka et al3 in 6874 patients with or without mild venous disease (varicose veins). The risk of varicose veins increased in those with a family background of varicose veins (OR, 4.9). The study was, however, limited by its specific focus on varicose veins (C2) rather than the whole spectrum of venous insufficiency. Nevertheless, the OR identified was globally of the same order as that observed in a recent cross-sectional study on heredity and venous disorders.8 Further confirmation of the role of heredity in venous disease comes from the San Diego Population Study, in which a family history of venous disease was found to be a sex-independent risk factor for moderate or severe venous disease.2 We can conclude by saying the following: (i) the hereditary transmission of CVDs is as much paternal as maternal; and (ii) in patients with a family history of venous disease, CVD is much more frequent at all ages, CVD occurs earlier (with its prevalence practically tripling in those 20 to 25 years of age), and at any given age the severity of CVD is likely to be greater than in patients with no family history of venous disease.

Venous degeneration and its consequences

Just like bone, whose turnover depends on the equilibrium between destruction by osteoclasts and reconstruction by osteoblasts, the integrity of vein walls and venous valves depends on the renewal of elastin (type III collagen). This elastin, produced continually by smooth muscle cells, is essential to venous parietal and valvular architecture and function.9-11 If the deterioration of elastin is quicker than its renewal, the architecture of the vein wall changes and the vein loses its elasticity, the capacity of a vein to return to its original form. The vein dilates and consequent stasis, excessive venous pressure, and inflammation contribute to further deterioration of the vein.

Figure 4. Mechanism of imbalanced production of collagens I and
III by the muscular cell of the varicose wall.
Abbreviation: MMP, matrix metalloproteinase.

Deterioration of elastin by type 3 metalloproteinase
These modifications are due to an increase in the precursor of matrix metalloproteinase 3, type 3 pro–matrix metalloproteinase (pro-MMP-3), which is produced in excess quantities by smooth muscle cells in patients with varicose veins. This deregulation has also been found in the dermis of patients suffering from CVDs.12,13 An increase in pro-MMP-3 leads to a decrease in the production of elastin and an increase in that of type I collagen, via a decrease in the negative retrocontrol that elastin exerts on the production of type I collagen (Figure 4).

As a result of these changes in composition, the integrity of the venous system alters rapidly and prematurely due to imperfect renewal of elastin fibers within the valves and venous walls of patients suffering from CVDs. The structure of vessels deteriorates before varicose veins appear, which may explain why C0 patients feel pain—caused by the stimulation of C fibers due to inflammation—even though neither varicose veins nor telangiectasias are visible.14

This impaired renewal, caused by the overproduction of pro-MMP-3, may be triggered more easily in prevaricose veins, under the influence of activators, than in ordinary veins.13 Therefore, this hereditary architectural defect reveals itself more quickly under the influence of aggravating and triggering factors, causing CVDs to occur earlier and develop more quickly.

Finally, epigenetic triggers and sensitizing factors that are present in women and nonexistent in men, eg, female hormones (?), may have a role in the manifestation of CVD, as paternal transmission of CVD is more significant than maternal transmission yet the disease is more present in women than men.15 Clinically, this fundamental research shows that we should be targeting both hereditary factors and aggravating factors in order to break the vicious circle of venous wall and valve degradation, which leads to venous hypertension, stasis, and inflammation (Figure 5).

The harmfulness of excess MMP-3 can be effectively decreased by using flavonoids.16-23 Like nano-oligosaccharide factor, which is applied on bandages in the treatment of ulcers, flavonoids block the action of metalloproteinase. We can decrease the pressure of a varicose vein through the vein wall not only by exerting counterpressure using compression devices, but also by restoring the tonicity of the vein by direct action on parietal muscle cells. These two therapeutic targets explain the results of one study24 that showed a synergetic pain relief by associating compression with venotonics.

The Satisfy survey demonstrated a clear reduction in microsclerotic skin complications (OR 2.5) in patients treated with flavonoids, without doubt by this same mechanism: restoration of vein tonicity.25 Of course, many other insights exist and have been summarized.26

Daily consequences of venous disease in medical practice

Venous disease involves structural pathology of the vein walls and the valves. Its occurrence is the result of heredity,6 whose predominantly maternal roots8 are now being questioned, and of risk factors favoring its appearance. Some of these risk factors cannot be modified, such as sex and hormones, but others, such as obesity, inactivity, exposure to heat, and prolonged standing or sitting, can.27-31 Besides acting on these modifiable risk factors, which doctors and pharmacists should advise patients to do in order to prevent venous disease, more attention should be paid to ensuring early management of venous disease.32-35 Too often, and this is particularly true inmen,33 patients fail to seek advice or consult their doctor before the development of venous disease is already relatively advanced.

Figure 5. A vicious cycle initiated by MMP-3, the source of the valvular and
parietal degradation whose consequences are venous hypertension, venous
stasis, and secondary parietal inflammation.
Abbreviations: C, clinical [stage]; CEAP, Clinical–Etiological–Anatomical–Pathophysiological
[classification system for chronic venous disorders]; MMP, matrix metalloproteinase.

We need to define a risk profile for each of our patients before considering any therapeutic treatment because we know that venous disease encompasses several types of risk: evolving risk (from diverse trophic disorders to ulcers); inherent risks linked to acute complications (from varicose hemorrhages to thrombosis); and risks of chronic complications (postthrombotic syndrome). However, the treatment of varicose veins also carries risks. Apart from the inherent risks of each treatment, we must, as doctors, protect the integrity of the venous system of our patients by preserving the venous axes, sometimes even those that are flowing back.

We thus wanted to establish a scalability score for venous disease, based on sex, risk factors, and clinical condition, that determined the probability of aggravation of CVD for a patient in future decades. Following on from the evaluation of venous age with VeinScore,35,36 VeinRisk aimed to raise awareness among patients about their CVD and to emphasize the necessity of managing modifiable risk factors to prevent aggravation. Another aim was to help establish therapeutic strategies especially adapted to the risk profile of each patient.

This calculation was based on the analysis of an international database of 124 335 people carried out in the same manner as the Vein Consult Program quoted at the beginning of this article, but in 24 countries with the help of more than 6000 practitioners who recorded not only established or suspected risk factors, but also the symptoms of each patient. Statistical analysis using sex and risk factor data determined the evolution of CVD on the basis of CEAP classification in different 10-year age categories: 30 to 40 years, 40 to 50 years, 50 to 60 years, and over 60 years.

It is essential to signal that we worked on the different clinical components of the CEAP classification system in order to be able to describe the frequency of the different signs presented (varicosities, varicose veins, edemas, trophic disorders, and healed or open ulcers) rather than the global CEAP classification, as the latter, for example, does not take into account the presence or absence of edema and varicose veins when the patient is C4. For this reason, the sum of the different percentages can exceed 100%.

Of the risk factors presented by patients, 57% had a family background of venous disease. A fifth (20%) were obese and over half (61.5%) were physically inactive (seated or upright for more than 8 hours per day). Each patient had on average 2±1.5 children. More than three quarters (77.4%) felt at least one symptom that may have been related to venous insufficiency: heavy legs, night cramps, leg pain, itching, feeling of swelling, or tingling and burning sensations. Clinical examination of the legs showed that 40.6% had telangiectasia (C1), 34.8% had varicose veins (C2), 24.9% had edema (C3), 14.0% had trophic disorders (pigmentation, eczema, white atrophy) (C4), 7.3% had a healed venous ulcer (C5), and 4.3% had an open venous ulcer (C6).

Statistical analyses showed that the risk factors that played a major role in the evolution of the disease were: a family background of chronic venous diseases; and pregnancy (OR of 1.42 for the first birth, 1.37 for the second, and 1.72 for the third).2 Other risk factors included: obesity; and physical inactivity, in a broad sense (standing and/or remaining seated for long periods of time).

For instance, according to VeinRisk calculations, an obese female patient between 40 and 50 years of age has a 23% risk of having varicose veins (C2), which rises to 29% if she is also inactive and to 32% risk if she has had more than one child. An obese male patient between 40 and 50 years of age has a 13% risk of having varicose veins (C2); with increasing age, this rises to 21% between 50 and 60 years and to 30% after 60 years. If this male patient is also inactive, the corresponding values increase to 18%, 27%, and 35%. The important impact of heredity on the risks of venous disorders in both women and men should also be noted. If heredity is a factor, the risk of varicose veins in a man over 60 years of age who is obese and inactive increases to 54%, while in a woman with the equivalent characteristics, the risk of varicose veins is 66%. Consequently, in patients for whom heredity is a risk factor, we must be more attentive, manage their disease earlier, and correct different modifiable risk factors to reduce aggravating effects and halt the development of CVD.

It is, of course, in these preventive situations that people have the greatest difficulties in adhering to treatment. The use of VeinScore to determine venous age and now VeinRisk can help persuade patients to use these treatments by showing them their “venous futures” if they don’t take the appropriate steps required to reduce the risks. For instance, an application for smartphones that calculates the daily time spent seated or standing (Happlivein) can help patients reduce sedentarity by proposing intermittent physical activity (walking or sport) throughout the day.

Of course, advice concerning how to reduce modifiable risks is welcome, but the hereditary fragility of vein wall and valves is unmodifiable. As such, there is little logic in making patients feel guilty about relapses or the development of venous disease. It would be preferable to explain hereditary chronic fragility and to give advice about avoiding triggers or aggravating elements, such as gaining weight during pregnancy.

The preeminent role of heredity as a risk factor relativizes all healthy living advice. Indeed, heredity is a major risk factor not only in terms of prevalence of the disease (and this for all the age groups studied), but also in terms of early development (2.6 times more CVD between 20 and 35 years of age) or seriousness (at all stages of CVD in the same age group with heredity, the frequency of CVD increases).

VeinRisk is already an important decision-making tool. For example, using VeinRisk we would not treat in the same way a 37-year-old female patient with a 6 mm preterminal saphenous incontinence, who is overweight, has a sedentary lifestyle, and paternal and maternal heredity as the same patient without either the hereditary or coronary risk factors; the speed of treatment and follow-up would be different. We hope that VeinRisk will also become a practical, awareness-raising tool that will promote communication between doctors, pharmacists, and patients. Our therapeutic reflections must, from now on, be enriched and guided by the additional information about benefit-risk that VeinRisk and its scalable probabilities provides.

In the same way, the follow-up for patients at high risk of CVD should be at shorter intervals than for other patients, be it only to refresh advice about diet or to monitor clinical signs that patients get so used to. There is a 7-year delay in managing medical treatment for venous disorders in France, and over two thirds (70%) of patients suffering from a chronic venous disease in France are not treated.7

Physicians should take care not to oversimplify the impact of heredity in CVD. Though important, treating varicose veins, stage C2 of the 7 clinical stages of the CEAP classification, cannot adequately summarize the management of a chronic hereditary venous disease. Furthermore, the end stage of this disease is not systematically an ulcer or a thrombosis.

Each patient’s risk profile and the evolution of the disease according to the risk factors are different and should be included in our decisional arguments at the same time as the clinical, anatomic, and hemodynamic evaluation. This will allow us to better link a patient’s risk profile with his clinical condition, which in turn may allow us to consider an alternative approach that leads to the conservation of a vein despite certain refluxes said to be pathological.


The determination of venous age can make patients aware of their CVD and allows early medical care, if necessary. The evolving risk factors of patients must be weighed against the risks inherent to CVD (its development and complications) and therapy and other risks (autologous bypass, occupational traumatic risks, etc). Knowledge of direct parental hereditary background of venous disease is fundamentally important for setting up a more active CVD prevention plan featuring earlier treatment initiation and shorter follow-up intervals to limit complications. Fundamental research on hereditary factors in CVD will undoubtedly bring us answers. These answers will most probably be genetic in nature, but there will be epigenetic ones, too, that will elucidate the triggering and aggravating factors of CVD.


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Keywords: cardiovascular disease; genetic; heredity; matrix metalloproteinase; risk factors