Servier – Phlebolymphology

Mieke FLOUR
MD, Dermatology Department, Univ. Hosp.
Leuven, Belgium.

This article will review the literature concerning the risk factors that identify C2, C3, C4 patients, according to the clinical, etiological, anatomical, pathophysiological (CEAP) classification, who are at risk for progression to C6.

Evidence concerning the risk factors for progression of chronic venous disease (CVD) is weak. There are no known hemodynamic methods to identify which patient with primary CVD and limbs with C-class 2 to 4 will develop leg ulcers. Duplex ultrasound scanning parameters of interest would be the anatomic extent and distribution of reflux and obstruction, and the quantification of reflux, measured at set time intervals in prospective longterm studies with a large sample size. History and physical examination should focus on the appearance of new signs during the interval period, but cannot reliably identify those patients in whom venous reflux changes develop over time. To detect clinical progression, these patients need to be followed up using clinical severity scores, which are more sensitive than the C-classification. Primary venous incompetence should be differentiated from secondary incompetence because the two conditions differ in pathophysiology, management, and prognosis.

Some clinical risk factors and clinical signs that warrant early intervention in patients with varicose veins have been detected, but it will probably be difficult to perform the required prospective longitudinal studies, crosscultural whenever possible, to evaluate the influence of such clinical factors on disease progression. Alternative ways need to be found.

There are gene polymorphisms and biomarkers that identify patients at high risk for progression to ulceration. In addition, genetic variations may differ across ethnic groups. Additional studies are needed to show if sex, age, ethnicity, and environment influence disease progression.

So far there are no available specific inflammatory mediators for CVD or reliable methods for assessment of endothelial function. Data regarding the deterioration of ankle mobility, calf muscle pump function, and patient activity need to be correlated with progression of the disease or with reversal under treatment, in order to use them to rate the progression of venous disease. If factors for disease progression in patients with primary CVD could be identified, a modification of these factors, if feasible, may prevent development of venous ulcer.

The natural history (progression) of CVD remains poorly understood: only a few longitudinal studies have been reported, and much of the available information is from cross-sectional studies.

Among patients awaiting surgery, nearly one third of those with venous reflux had progression in CEAP clinical stage and/or duplex ultrasound scanning. The great saphenous vein and tributaries were the anatomic sites most often affected by a change, either as extension of preexisting reflux (in antegrade and retrograde fashion) or as reflux in a new segment.¹

In a prospective 7-year follow-up of patients with both superficial and deep venous reflux, deterioration in clinical class was shown in most of the limbs at the end of the observation period. Limbs that underwent a superficial or deep venous procedure remained stable or improved over time; those that underwent elastic compression alone had worsening hemodynamic and clinical status.²

The Bochum study was a large cohort investigation in Germany exploring the natural history of preclinical (C0) and early stages (C1) of the development of varicosities and the behavior of venous calf pump function from childhood to adulthood in subjects with healthy veins. Telangiectasias and reticular veins were noted early on, independently of the presence of reflux. Large varicosities appeared in older subjects, often preceded by reflux in the saphenous veins.³

The Bonn Vein Study I, conducted in 2000, involved 3072 participants of the general population of the city of Bonn and two rural townships, aged 18 to 79 years (1350 men, 1722 women).⁴ In the follow-up study (Bonn Vein Study II) 6.6 years later, the same population was investigated again. The incidence of progress to chronic venous insufficiency (C3-C6) was approximately 2.0% per year. In a multivariate analysis, the main risk factors for developing severe stages (C4-C6) were age, hypertension, and obesity.

Reflux may develop at one or more locations, and can progress in a retrograde or antegrade manner, or in both directions. The progression of CVD is more rapid in postthrombotic limbs when compared with those with primary CVD. Poor prognostic factors for progression to advanced CVD include the combination of reflux and obstruction, ipsilateral recurrent deep venous thrombosis (DVT), and multisegmental involvement. People receiving no etiologic treatment are at greater risk for venous disease progression.⁵

There are no studies on how to identify patients with primary CVD who will develop more severe symptoms, complications, or recurrence following treatment. Kostas and co-workers evaluated the long-term (5 years) characteristics of CVD progression and its correlation with the modification of specific risk factors. The contralateral (normal) limb of 73 patients undergoing varicose vein surgery for unilateral varicosities was prospectively evaluated using physical and color duplex examination and classified by CEAP. In about half of patients, CVD (reflux development and clinical deterioration) developed in the contralateral, initially asymptomatic, limb in 5 years. In these patients, obesity, orthostatism, and noncompliance with the use of elastic stockings were independent risk factors for CVD progression, but estrogen therapy and multiparity were not.⁶

In secondary CVD, occurrence of postthrombotic syndrome after an episode of acute DVT is related to both failure of recanalization (with persistent venous obstruction), and the development of valvular incompetence. Progression from asymptomatic cosmetic varicose veins (C2) to symptomatic stages with pain, edema, skin changes, and ulceration has been shown to be more pathogenic than previously thought, and to have a high prevalence and a broad demographic spectrum in patients with CVD. Moreover, nonthrombotic iliac vein lesions are commonly found in the asymptomatic general population.⁷

It is important to correct the underlying disorder in patients with established venous ulcer disease in order to prevent recurrence. Residual iliofemoral vein obstruction, residual deep incompetence, particularly axial deep reflux, residual or recurrent superficial reflux, and persistent venous hypertension have been identified as risk factors for ulcer recurrence.^8,9

There are no known hemodynamic methods to identify which patients with primary CVD and limbs with C-class 2 to 4 will develop leg ulcers. Duplex ultrasound scanning parameters of interest would be the anatomic extent and distribution of reflux and obstruction, and the quantification of reflux, measured at set time intervals in prospective long-term studies with a large sample size. History and physical examination should focus on the appearance of new symptoms during the interval period, but cannot reliably identify those patients in whom venous reflux changes develop over time. To detect symptomatic progression, these patients need to be followed up using clinical severity scores, which are more sensitive than the C-classification. Primary venous incompetence should be differentiated from secondary postthrombotic venous incompetence because the two conditions differ in pathophysiology, management, and prognosis. Primary venous incompetence is recognized to be a slowly progressive disorder that may advance to C4-C6 manifestations over time in up to 20% or more of the older population.

If factors for disease progression in patients with primary CVD could be identified, a modification of these factors, if feasible, may prevent development of venous ulcer.¹⁰

Neglen pointed out that it is necessary first to develop a protocol for CVD investigation for clinical practice, and then introduce a more sophisticated protocol for longitudinal research in CVD. Additional methods of studying venous hemodynamics and the microcirculation should also be used in longitudinal studies. With regard to primary CVD, it is essential to identify measurements that predict progression from Cclass 2-4 to active leg ulcers.¹¹

Studies of risk factors for developing varicose veins have largely yielded inconsistent results. Much of the variation between studies is probably related to differences in definitions, in population sampling techniques (age, race, occupation, sex), and in assessment/measurement methods. References mention risk factors identified from several types of data sources: clinical investigations, especially in larger population samples, histological studies of the vein wall, and evaluation of treatment outcomes. The current belief is that both environmental and genetic factors are associated with the development of varicose veins.

Trunk varicose veins occur very commonly with increasing age.^4,12,13 Risk due to a positive family history has been investigated and confirmed by Cornu-Thénard and several others.^14,15

A genetic predisposition may be present, but evidence for this and for a mode of inheritance is lacking.¹⁶
Genetic twin studies in Germany^17,18 and England¹⁹ indicated a strong genetic influence on varicosities and on venous function, and the data strongly suggest that the FOXC2 gene on chromosome 16 is implicated in the development of varicose veins in the general population.

In women, obesity has been associated with the presence of varicose veins but it appears to be an aggravating factor rather than a primary cause; the evidence is inconsistent. Many studies consider body mass index to be more important in females than in males. However, obesity seems to play a more important role in the development of severe clinical signs of CVD, possibly due to functional more than to anatomical insuf fi – ciency.^12,13,20

Female sex is a universally cited risk factor, while large geographical differences suggest strong environmental influences. In most studies undertaken so far, CVD has been found to be more prevalent among women than among men, although the difference was small. A different timing of disease in the two sexes was observed by Fiebig¹⁸ in terms of the mean age at disease onset, with females showing first symptoms of CVD at 30.8 years of age, compared with 36.8 years for males.

Pregnancy (multiparity) is an established risk factor or aggravating factor for the development of varicose veins. The use of hormones, eg, birth control pills, is not universally accepted as a risk factor. Smoking affects the vascular wall and has an impact on endothelial cell function and behavior. As for several other cultural and behavioral habits, their role as risk factors for the development of varicose veins is difficult to prove.^13,20

Compared with women without clinical signs in the Framingham Study, women with varicose veins were more often obese, had lower levels of physical activity, higher systolic blood pressure, and were older at menopause. For men, varicose veins coexisted with lower levels of physical activity and higher smoking rates. These results suggest that increased physical activity and weight control may help prevent varicose veins among adults at high risk, and reduce the overall risk of atherosclerotic cardiovascular disease as well.¹³

Prolonged standing has been cited as a risk factor, but the data should be interpreted with caution given the difficulty in measuring levels of posture and because of potential bias in selection of the study population.

In the Bonn Vein Study II, “sensation of swelling” significantly increased the risk for the development of chronic venous insufficiency (CVI).⁴ Clinical signs (eg, corona phlebectatica and other skin changes) may warrant early intervention to prevent later ulcer formation. The risk of ulceration is related to the severity of varicosities and venous insufficiency, and is increased following deep vein thrombosis (incompetence). However, the risks may also be increased in those who smoke, are obese, and have restricted ankle movement and reduced calf muscle pump power.²⁰

There are studies showing that mechanical dysfunction of the calf muscle pump may enhance the development of leg ulceration.²¹ It will therefore be important to investigate ankle range of motion, calf muscle pump function, and patient activity in relation to progression of disease. The data that are presently available need to be correlated with progression of the disease.^13,20,22

Clinically observed thickening of the vessel wall appears to be associated with an increase of thick and disorganized collagen bundles and fragmentation of elastic fibers. Similar alterations of extracellular matrix are found in the vein wall and skin of C2 patients.²³

Follow-up duplex scanning after aggressive treatment of superficial venous disease showed improvement or complete reversal of deep venous insufficiency in the majority of patients as reported by Ahmad. Only 28% of patients receiving less aggressive treatment showed improvement in their reflux valve closure time; the remaining 72% were unchanged or showed deterioration.²⁴

It will probably be difficult to perform the needed prospective longitudinal studies, cross-cultural whenever possible, to evaluate the influence of these clinical factors on disease progression. An alternative way is to find unique features in limbs with already established ulcers (C6) as compared with limbs with lower severity venous disease (C2 to C4).¹¹

Varicose veins without skin changes have a prevalence of approximately 20% in Northern and Western Europe, while advanced CVI affects about 3% of the population. Among the many who have varicose veins (C2), only 10% will develop a venous ulcer. Genetic risk factors are thought to play an important role in the etiology of both varicose veins without skin changes and of venous ulcer. Clinical as well as hemodynamic parameters (including duplex scanning, plethysmography, or both) fail to predict ulcer appearance.
1) Genetic factors may play a role in the etiology and progression to advanced CVD (see above), but there is a need to establish biobanks and blood banks for subsequent analysis in longitudinal studies.¹¹
2) Some data are available on gene polymorphisms and biomarkers that may identify patients at high risk for progression to ulceration.

It has been suggested that tumor necrosis factor-alpha (TNFα) gene polymorphism is associated with increased susceptibility to venous leg ulceration,25 but some authors refute a direct link between these two findings since the A allele of the -308 G/A single nucleotide polymorphism (SNP) in the promoter region of the TNF-α gene might be a factor for venous leg ulcer susceptibility. However, their data suggest that this association is secondary and that the primary association is probably with obesity.²⁶ Estrogen receptor beta (ER-β) polymorphism is associated with impaired healing in the elderly, reportedly predisposing individuals to venous ulceration.²⁷

Studies on single nucleotide polymorphisms of the fibroblast growth factor receptor 2 (FGFR-2) gene indicate a genetic alteration in the FGFR-2 gene which is present significantly more often in CVI patients with chronic nonhealing wounds.²⁸

Studies on hemochromatosis suggest that there could be a pathophysiological role of iron deposition, iron trafficking genes, and transglutaminases in venous leg ulcer, resulting in a strong genetic component in ulcer pathogenesis. A relationship has been described between the C282Y polymorphism in the hemochromatosis (HFE) gene and venous ulceration. In such cases, a simple C282Y blood genetic test demonstrated a more than 6-fold increase in specificity in predicting ulcer development (98%; CI 95%, 92.8–99.7), while ulcer onset occurs almost 10 years earlier in patients carrying the H63D variant.²⁹

Studies on thrombophilia: In patients with chronic venous leg ulceration, MacKenzie defined the prevalence of thrombophilia, and determined whether this is associated with medical history or with duplex scan evidence of DVT. Despite no previous DVT (duplex/ history), patients with ulcers have a 2 to 30 times higher prevalence of thrombophilia (41%) compared with the general population. Certain thrombophilias (antithrombin deficiency) may be a risk factor for ulcer development. But in this study, in patients with chronic venous leg ulceration, there was no difference in DVT rates between those with and without thrombophilia.³⁰

Venous thrombosis and inflammation are closely related. In an assessment of whether there is a relation between genetic modifiers of the inflammatory response and the risk of venous thrombosis, Pieroni et al concluded that cytokine gene polymorphisms did not significantly influence venous thrombotic risk.³¹

3) Some studies are in progress, like the genome-wide association studies approach that identify relevant patterns of numerous SNPs to predict future disease states and evaluate gene patterns that relate to multiple phenotypes of complex diseases. Sex, age, ethnicity, and environment seem to influence strongly the penetrance of disease.²⁹

4) There is a need for additional large cross-sectional and longitudinal studies on the natural history of primary CVD including systematic population-based searches for CVD susceptibility genes and factors that could be regarded as prognostic markers in CVD progression to ulcer formation.¹¹

Some publications indicate sociodemographic differences in the risk of progression of CVI.
A study in West London collected details on age, sex, and ethnic background of all patients who attended for treatment of leg ulceration over a one-year period.³² While the overall estimate of ulcer prevalence was 1.02 per 1000 population, there was a significantly higher proportion of whites suffering from leg ulceration compared with South Asians (Indian subcontinent background): odds ratio of 4.43 (95%; CI, 1.94-10.13; P=0.0004). Because of selection bias, the authors conclude that either there is a real difference in prevalence or South Asians do not attend the clinic for treatment.

In the San Diego cross-sectional study of a multiethnic sample of more than 2000 men and women between 1994 and 1998, the authors report that women had more superficial functional disease, whereas men had more deep functional disease. CVD increased with age, and non-Hispanic Whites had more venous insufficiency than did Hispanics, African Americans, or Asians.³³

Humoral or genetic factors responsible for disease progression to ulcer formation are related to thrombosis and to inflammation. Hyperhomocysteinemia is recognized as one of many risk factors for venous thrombosis, and for the development and progression of CVI, and is present in about 65% of patients with CVI. In the publication of Sam et al, a strong relationship was observed between mild to moderately elevated plasma homocysteine concentration and increasing severity of venous disease (C6> C5 > C4). The authors suggest that these data confirm the ‘multihit’ hypothesis suggesting that various inherited and acquired factors act in concert to raise individuals above the thrombotic threshold. Prevalence of the C677T MTHFR mutation (methylene tetrahydrofolate reductase) was higher in complicated C4-C6 disease (20%) than in uncomplicated C2-C3 disease (10%), and overall more patients (15%) were homozygous, compared with an estimated 5% of the healthy white population.³⁴

Genetic variations that affect chronic inflammation may differ across ethnic groups. SNPs in cytokine genes affect cytokine levels and the degree of inflammation. Genetic variants, specifically SNPs in cytokine genes can affect cytokine production and, therefore, may in part modulate the inflammatory response.³⁵

It is generally agreed that universal markers such as IL- 6 are elevated, but it is uncertain whether or not they indicate progression of the disease. It would be of value to identify biomarkers signaling an increased risk of ulcer formation.

IL-6 occupies a central place in the inflammatory response. It is produced and released into the systemic circulation from many different cells in the body, including endothelial cells, fibroblasts, subcutaneous adipose tissue, as well as from cells of the immune system. The levels correlate with body mass index and percent body fat. It is the only cytokine that can stimulate the synthesis of all the acute phase proteins involved in the inflammatory response. As a universal marker IL-6 is not specific to, or diagnostic in, progression of venous disease.

Genetic polymorphism influences the plasma levels of IL-6 (GG allele carriers have IL-6 levels twice those of individuals with the CC allele).

In a prospective cohort study of representative community residents aged 71 years and older, Purser reported that geographical segregation could influence the level of IL-6.³⁶ Results showed that socially disadvantaged environments may influence IL-6, a biomarker of age-associated inflammation: being older, African American, taking more prescription drugs, having a body mass index greater than 30, consuming greater levels of alcohol, and being a current smoker were all strong and important individual level predictors of elevated IL-6.

Several biomarkers reflect functional activation of monocyte-macrophages and damage to the endothelial structure related to venous stasis and venous hypertension.

The elevated plasma levels of several inflammatory mediators (TNF-α, IL-1β, IL-6, IL-10, IL-8, IL-12p70) are also risk determinants for venous thrombotic disease.³⁷

Many studies have investigated the relation between venous stasis, functions of the vascular and perivascular anatomic structure, venous endothelium, and circulating leukocytes. Their results revealed elevated baseline production of inflammatory markers in patients with varicose veins, and that induced venous occlusion (cuff inflation) further augmented the levels of all cytokines in the study series, especially in patients with varicose veins. The authors believe that the study shows functional activation of monocyte-macrophages related to venous stasis as a consequence of venous hypertension. Cell response damages the endothelial structure and may represent an important element in the pathophysiology of CVI.³⁸

Fox published a systematic review of clinical studies that have examined the association between inflammation and venous thrombosis, specifically: the value of inflammatory markers in predicting the future development of venous thrombosis; test characteristics of markers of inflammation in the diagnosis of acute venous thrombosis; and the effect of venous thrombosis on blood levels of inflammatory markers. Results show that plasma C-reactive protein levels do not appear to predict risk of future venous thrombosis.³⁹

Christiansen confirmed that IL-6 is not a marker for disease progression. Between August 1995 and June 1997, blood was collected from 66 140 people in the second Norwegian Health (cohort) Study of Nord- Trondelag (HUNT2). A total of 506 cases were registered with a first venous thrombosis. Levels of IL-1β, IL-6, -8, -10, -12p70 and TNF-α were measured in the baseline sample. Authors did not find evidence for a relationship between venous thrombosis and an altered inflammatory profile. The results from this population sample suggest that an altered inflammatory profile is more likely to be a result rather than a cause of venous thrombosis, although short-term effects of transiently elevated levels cannot be ruled out.⁴⁰

As for wound healing, although a large number of parameters have been shown to be differentially expressed between healing and nonhealing wounds, no single or combination of biomarkers has been demonstrated to accurately reflect wound progression on a single patient basis.⁴¹

Although the etiology of varicose veins remains partly unknown, recent studies have focused on endothelial cell integrity and function. Current evidence suggests the multifactorial origin of primary CVD, leading to tissue remodeling of the venous wall with changes in the microcirculation and dermis.

Markers of endothelial cell dysfunction have been shown to be of prognostic significance in predicting vascular events. They are linked to (can result from and/or contribute to) many disorders characterized by micro- or macrovascular pathology, they are an early marker of the development of vascular changes, and can pre-date clinically obvious vascular pathology by many months or years. In this context, elevated markers of endothelial cell dysfunction are found in association with aging, venous disorders (spontaneous venous thromboembolism, venous hypertension, reduction of shear stress, and varicosis), but also with many other disease entities, including endocrinopathies (diabetes type 1, type 2 and their complications, thyroid disease, obesity, metabolic syndrome, and sleep apnea syndrome), and in arterial pathology (hypertension, hyper cholesterolemia and atherosclerosis, plaque rupture, infarction or heart failure, recurrent stroke), in connective tissue diseases, and smoking or exposure to air pollution.

Endothelial function testing may have great potential prognostic value for the detection of cardiovascular disease, but the available tests are not to be used in routine clinical assessment: no available test to assess endothelial cell dysfunction has sufficient sensitivity and specificity to be used in clinical practice. Most of the studies are observational. The optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate.

Three types of testing for endothelial dysfunction are used: vascular reactivity tests, systemic plasma markers, and immunostaining of histological specimens. Most authors would agree that wall dilation and valve incompetence in primary CVD are related to venous endothelial dysfunction. Varicose vein patients demonstrate imbalances in the humoral mediators of vasoconstriction and venous dilatation.

1) Vascular reactivity tests are the most widely used methods in the clinical assessment of endothelial function: they are noninvasive and evaluate the peripheral macrocirculation (conduit arteries) or microcirculation (resistance arteries and arterioles).⁴²

2) Systemic plasma markers of endothelial damage and repair (endothelial cell injury, endothelial cell activation) have only a very limited role in the assessment of individual patients (as a result of biological availability or assay variability).

– Measurements of nitric oxide biology: Plasma levels of nitric oxide, a potent mediator of vascular relaxation, may be modulated in venous disease.

– Humoral mediators of vasoconstriction and venous dilatation: Varicose vein patients show imbalances in the humoral mediators of vasoconstriction and venous dilatation. Plasma levels of endothelin-1 are increased in those with varicose veins and rise disproportionately in response to venous stasis with low vessel tone.

– Pro- and anti-inflammatory cytokines: Chronic venous hypertension leading to endothelial cellular injury and activation can be associated with an inflammatory reaction and leukocyte recruitment in venous valves, a process that may lead to their dysfunction, reflux, and upstream elevation of venous pressure.

– Adhesion molecules (ICAM-1, VCAM-1, E-selectin, vWF, soluble P-selectin, CD40 ligand) reflect early stages of leukocyte-endothelium interactions. Although these are generally considered pathogenetic in venous disease, Ghaderian found no major differences in ICAM-1 or E-selectin expression in varicose vein specimens compared with controls.⁴³

– Leukocyte recruitment and endothelium interaction (monocytes and macrophages) for which one of the markers, HIF-1α (the transcription factor hypoxiainducible factor-1α), is elevated in some cases with varicosis. Some authors suggest that this supports the hypothesis of hypoxia in varicose veins. The factor is increased by prolonged mechanical stretch or by increases in vein wall tension.⁴⁴

– Soluble markers are in fact mixtures of true soluble molecules with membrane-bound forms such as endothelial microparticles, which are heterogeneous and distinctive in phenotypic markers and procoagulant properties: phenotype analysis can distinguish endothelial cell activation from apoptosis. Endothelial microparticle-monocytes conjugates were found to enhance transendothelial migration of leukocytes in vitro and to be a marker of several inflammatory diseases. Elevated endothelial microparticles are not diagnostic of venous disease progression or inflammation.⁴⁵

– Enzymatic activity: MMP-1, -2, -8, and -9 and TIMP-1, -2, and -3 are increased in both high and low venous pressure regions. The degree of extracellular matrix remodeling of the venous wall and valve leaflets correlates with the morphologic findings of macroscopic lesions with changes in the microcirculation and in the dermis. MMP-2 is said to induce venous relaxation / to inhibit contraction of the inferior vena cava.⁴⁶

– Plasma thrombomodulin (TM) is considered to be a marker of endothelial injury. The relationship of soluble TM with thrombosis is complex: there is no difference in the prevalence of the 3 TM genotypes between thrombosis cases and controls (in 2 cohort studies). There was no difference in age-adjusted mean values of sTM by genotype, no associations of ageadjusted sTM or TMA455V genotype with overall venous thromboembolism or with thrombosis (any subtype).⁴⁷

3) Histopathology: immunostaining and RT-PCR reveal alterations of the intima, like focal intimal discontinuity and denudation of endothelium in varicose veins.⁴³ Recent evidence suggests that changes in the vein wall may precede valvular dysfunction. Areas of intimal hyperplasia and smooth muscle cell proliferation are often noted in varicose veins, although regions of atrophy are also present. The total elastin content in varicose as opposed to nonvaricose veins is reduced; changes in overall collagen content are uncertain.⁴⁴

More studies to identify markers of endothelial dysfunction of prognostic value are necessary.

Longitudinal studies will be necessary to evaluate the factors responsible for disease progression. In addition the genetic and humoral mediators of endothelial dysfunction present in limbs with primary CVD and disease progression should be identified.¹¹

Physiologic deterioration of calf muscle pump function at the end of the day was reported using both photoplethysmography and air plethysmography. Although the variance was relatively limited, these findings suggest that venous return from the limb deteriorates with prolonged upright activity.⁴⁸ Musculoskeletal changes impact on the hemodynamics of the calf muscle pump and it is not always easy to distinguish between cause and effect.⁴⁹

When measuring ankle range of motion using goniometry, there was an association with significantly reduced range in all grades of venous insufficiency (C2- C6).²² Limbs with CVI have a limited ankle range of motion that decreases with increasing severity of clinical symptoms; this decreased range of motion is associated with, and may contribute to, poor calf pump function.⁵⁰

With increased severity of CVI this mechanical dysfunction of the calf muscle pump results in sustained ambulatory venous hypertension.⁵¹

Changes in nerve and muscle function and range of motion may affect gait and ambulation: either causal in disease formation, or leading to a worsening or progression of disease symptomatology.²¹

In CVI and venous hypertension, muscle changes have been observed on biopsy specimens of the gastrocnemius muscle,⁵² but these are not correlated with progression of disease: histopathology study revealed morphologic changes suggesting that disuse, denervation, and ischemia may contribute to changes in muscle function.

NB. Several cofactors may contribute to, or worsen, CVD: Local tissue destruction in CVI develops in conjunction with damage to peripheral nerves, which has been demonstrated in both clinical and immunohistochemical studies. Nerve involvement may result in neuropathic pain and muscle dysfunction, alterations in mobility may lead to gait alterations and decrease in range of motion, all affecting calf muscle pump function, and so contribute to the pathogenesis of venous ulcers.²¹

More than two-thirds of leg ulcer patients have an impaired calf muscle pump, which is regarded as causal to the development of the ulceration.⁵³ Air plethysmography, by assessing muscle pump function, has been shown to reliably predict prognosis of venous ulcers. Patients with clinically evident CVI were evaluated to relate the degree of insufficiency (measured by air plethysmography, color duplex) and calf muscle pump dysfunction to venous ulceration. Legs with active venous ulcers had significantly poorer calf muscle pump function than those with healed ulcers or with no history of ulceration. Thus, CVI is a necessary but not sufficient cause of ulceration, and a deficiency of the calf muscle pump is significantly related to the severity of venous ulceration.⁵³

Apart from known risk factors (as longer ulcer duration, large surface area, ankle brachial pressure index <0.85), dysfunction of calf muscle pump has been correlated with delayed healing or nonhealing of leg ulceration despite adequate compression treatment. In this study a calf/ankle circumference ratio of less than 1.3, a fixed ankle joint, and reduced ankle range of motion were the only independent parameters associated with nonhealing.⁵⁴

The data that are presently available need to be correlated with progression of the disease or with reversal under treatment. Prospective controlled studies have assessed improvement of venous hemodynamics or ulcer healing following supervised exercise programs directed to improve calf pump function, muscle strength, and endurance. This confirms positive results obtained after a few months in terms of hemodynamic parameters, calf muscle pump, and concomitant osteoarthritis. Physical rehabilitation and gait training can potentially improve healing rates, or help decrease recurrences in patients affected by stage C6. The benefits of this conditioning were maintained for at least 3 months.^22,51,55,56

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