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The natural history of chronic venous disease (CVD) is poorly understood. There have been too few longitudinal studies. In Northern and Western Europe the prevalence of varicose veins without skin changes is 20% compared to 3%for advanced CVD. Only 10%of the many individuals with C2 varicose veins progress to ulceration. The risk factors for progression are currently believed to comprise the usual combination of the environmental and the genetic. More specifically, the Bonn Vein Study (2008) identified the main culprits as age, hypertension, and obesity, to which other studies have added previous deep vein thrombosis, absence of etiologic intervention, a positive family history, reduced ankle range of motion, and impaired calf muscle pump function. Both hemochromatosis and thrombophilia predispose to ulceration, while twin studies incriminate the FOXC2 gene on chromosome 16. Female gender barely qualifies. Yet despite an additional plethora of sophisticated studies featuring cytokine arrays and gene polymorphisms, there remains no test, or test battery, that identifies the individual patient with early CVD at risk of ulceration. The evidence suggests that best-practice prophylaxis comprises aggressive intervention early in the course of the disease combined where possible with a structured exercise program to improve ankle range of motion and calf muscle pump function.

How strong is the evidence for risk factors in the progression of chronic venous disease?

The natural history of chronic venous disease (CVD) remains poorly understood. Longitudinal studies are few. Most information comes from cross-sectional studies. One third of 116 limbs in 90 patients with venous reflux showed progression when re-examined a median 19 months later using the CEAP (Clinical- Etiological-Anatomical-Pathophysiological) classification and/or duplex ultrasound (DU).¹ A prospective study of superficial and deep venous reflux showed that most patients had clinically deteriorated after 7 years: limbs treated with a superficial or deep procedure improved or remained stable, while those treated with elastic compression deteriorated hemodynamically and clinically.²

The Bochum study explored the natural history of varicosities and calf pump function from childhood to adulthood. Telangiectasias and reticular veins occurred early on, independently of reflux. Large varicosities appeared in older subjects, often preceded by saphenous reflux. The Bonn Vein Studies I & II, conducted in 3072 women and men, found a 2.0% annual incidence of progression to C3-C6 disease (Table I). Age, hypertension, and obesity were the main risk factors for C4-C6 disease.³

Table I. CEAP clinical classification of chronic venous disease.

Factors for progression include the combination of reflux and obstruction, ipsilateral recurrent deep venous thrombosis (DVT), multisegmental involvement, and absence of etiologic CVD therapy. Prospective evaluation of the normal contralateral limb in 73 patients undergoing unilateral varicose vein (VV) surgery showed that half experienced clinical deterioration and reflux within 5 years. Independent risk factors were obesity, orthostatism, and noncompliance with the use of elastic stockings.⁴ However, we have no hemodynamic methods for identifying which patients with primary CVD and C2-C4 disease are likely to develop ulcers, despite the disease progressing to C4-C6 in up to 20% or more of the elderly.

Risk factors for ulcer recurrence include residual iliofemoral vein obstruction, residual deep incompetence (in particular axial deep reflux), residual or recurrent superficial reflux, and persistent venous hypertension. Correction of the underlying pathology reduces the risk of recurrence.

We need large, long-term prospective studies with DU scanning of the anatomic distribution of reflux and obstruction, and serial quantification of reflux. A more sophisticated protocol for longitudinal research is required, using studies of venous hemodynamics and the microcirculation. If we could identify the predictors of progression from C2-C4 to active ulceration, we could plan their modification where feasible.

What are the clinical risk factors warranting early intervention in stage C2 CVD?

Risk factor studies have given inconsistent results due to multiple methodological differences. Risk factors are currently thought to combine the environmental with the genetic. Age, a major risk factor, is compounded by a positive family history, although evidence for a mode of inheritance is lacking. Twin studies in Germany point to the FOXC2 gene on chromosome 16.⁵

Obesity has been incriminated in women, but appears to be aggravating rather than causal. It precipitates severe CVD, perhaps from functional rather than anatomical insufficiency. Female gender is universally cited, but CVD is barely more prevalent in women. Onset is earlier in women, at 30.8 years (36.8 years in men). Pregnancy (multiparity) is a universally recognized risk or aggravating factor, but not oral contraception. Major geographic differences suggest strong environmental influences. Although smoking affects the vascular wall and impairs endothelial function and behavior, its status as a risk factor is inconclusive. In the Framingham Study, women with VVs were more often obese, sedentary, older at menopause, and had higher systolic blood pressure; in men, VVs coexisted with sedentary lifestyle and higher smoking rates, suggesting that increased physical activity and weight control may prevent VVs in high-risk adults.

The Bonn Vein Study II reported the “sensation of swelling” as symptomatic of impending CVD.³ Signs such as corona phlebectatica and other skin changes may warrant early intervention to prevent ulcer formation. Risk relates to the severity of varicosity and increases after DVT. But it may also be increased in smokers, the obese, and those with reduced ankle range of motion (ROM) and calf pump power.

Clinical hardening of the vessel wall is associated with an increase in thick disorganized collagen bundles and elastic fiber fragmentation. Similar changes in the extracellular matrix are found in the vein wall and skin of C2 patients. Follow-up DU after aggressive treatment of superficial CVD supports the case for early recognition and intervention by showing improvement or complete reversal of deep venous insufficiency in most patients. Less aggressive treatment improved reflux valve closure time in only 28%.⁶

It will be difficult to perform the prospective longitudinal and cross-cultural studies that we need in order to measure the impact of these clinical factors on disease progression. An alternative is to identify features unique to limbs with established ulcers (C6) and compare them to limbs with C2-C4 disease.

Do any gene polymorphisms or biomarkers identify patients at high risk of ulceration?

In Northern andWestern Europe the prevalence of VVs without skin changes is 20% compared to 3% for advanced CVD. Only 10%of themany individuals with C2 VVs proceed to ulceration. Genetic factors may play an important causal role in both mild and severe disease, but we need to establish biobanks and bloodbanks for longitudinal analysis.

Gene polymorphism and biomarker data may identify patients at high risk of ulceration:
_ Tumor necrosis factor α(TNF-α) gene polymorphism has been associated with increased susceptibility to ulceration. However, others dispute that the A allele of the 308 G/A single nucleotide polymorphism (SNP) located in the promoter region of the TNFA gene is a potential factor for ulcer susceptibility, arguing that this association is secondary and that the primary association is probably with obesity.
_ Estrogen receptor-beta polymorphism, associated with impaired healing in the elderly, predisposes to venous ulceration.
_ SNPs of the fibroblast growth factor receptor 2 gene are significantly more frequent in CVD patients with chronic nonhealing wounds.
_ Hemochromatosis studies suggest a role for iron deposition, iron trafficking genes, transglutaminases, and C282Y polymorphism of the hemochromatosis gene in ulceration. A simple C282Y blood test was highly specific in predicting ulcer development (98%), while ulcer onset was almost 10 years earlier in patients carrying the H63D variant.⁷
_ Thrombophilia: venous ulceration was 2 to 30 times more prevalent in thrombophilia patients, even with no history or DU evidence of DVT, than in the general population.⁸
_ Cytokine gene polymorphisms do not significantly influence venous thrombosis risk, despite the close relationship between venous thrombosis and inflammation.

Ongoing studies, including those using the genome-wide association approach, are looking to identify relevant patterns of SNPs to predict disease states and evaluate gene patterns that relate to multiple phenotypes of complex diseases. Gender, age, ethnicity, and environment appear strong determinants of disease penetrance. We need systematic population- based searches for CVD susceptibility genes.

Are there differences in skin type, metabolism, or race that increase the risk of ulceration?

Sociodemographic factors may influence CVD progression. A West London study collected age, sex, and ethnicity data on all leg ulcer patients over one year. Ulceration was more frequent in whites than in South Asians (odds ratio, 4.43; P=0.0004), suggesting either a real difference in prevalence or a South Asian reluctance to seek treatment.

The San Diego multiethnic cross-sectional study in 2211 subjects found superficial functional disease to be more common in women, while deep functional disease was more common in men. CVD was more common in non-Hispanic whites than in Hispanics, African Americans, or East Asians.

Humoral or genetic factors responsible for progression to ulcer formation are related to thrombosis and inflammation. Hyperhomocysteinemia, a risk factor for venous thrombosis and CVD development and progression, is present in about 65% of patients with CVD. Mild to moderately elevated plasma homocysteine was closely associated with increasing CVD severity, confirming that various inherited and acquired factors act in concert to raise individuals above the thrombotic threshold. Prevalence of the C677T methylene tetrahydrofolate reductase mutation was higher in complicated C4-C6 disease (20%) than in uncomplicated C2-C3 disease (10%), and more patients overall (15%) were homozygous compared with an estimated 5% of the healthy white population.⁹

Genetic variations that affect chronic inflammation may differ across ethnic groups. Cytokine SNPs affect cytokine levels and hence the inflammatory response.

Elevation of interleukin 6 is a well-documented inflammatory marker, but does it predict CVD progression?

Most people agree that markers such as interleukin 6 (IL-6) are elevated in CVD. IL-6 is produced and released into the systemic circulation from many different cells. It is the only cytokine to stimulate synthesis of all the acute-phase proteins involved in the inflammatory response. It is a universal marker, hence not specific to nor diagnostic of CVD progression. We need a specific biomarker for increased ulcer risk.

A prospective cohort study of elderly community residents showed an association between sociogeographic segregation and IL-6 levels. Ingredients of social disadvantage (age, African American ethnicity, high prescription drug consumption, body mass index >30, high alcohol consumption, and smoking) were all strong predictors of IL-6 elevation.

Elevated plasma inflammatory mediator levels are also risk factors for venous thrombosis. Several biomarkers reflect functional monocyte-macrophage activation and structural endothelial lesions related to venous stasis and venous hypertension that predispose to CVD. Baseline production of inflammatory markers is duly elevated in VV patients, and all cytokine levels sharply increase in response to venous occlusion produced by cuff inflation. However, a systematic review of studies of the association between inflammatory markers and venous thrombosis concluded that plasma C reactive protein levels do not predict venous thrombosis.¹⁰

Between August 1995 and June 1997, blood was collected from 66 140 people in the second Norwegian Health (cohort) Study of Nord-Trondelag (HUNT2); 506 cases were registered with a first venous thrombosis. Levels of IL-1β, IL-6, IL-8, IL-10, IL-12p70, and TNF-α, measured at baseline, showed no relationship between an altered inflammatory profile and venous thrombosis. These results suggest that an altered inflammatory profile is more likely to be a result than a cause of venous thrombosis, although a short-termimpact with transiently elevated levels cannot be excluded.¹¹

No biomarker that accurately reflects wound healing status in individual patients, singly or in combination, has been identified.

What information would a test of endothelial dysfunction provide, and what are the prospects of one being developed in the near future?

Recent studies of CVD etiology have focused on endothelial cell integrity and function. Current evidence favors a multifactorial origin involving vein wall remodeling and changes in the microcirculation and dermis. Venous endothelial dysfunction is almost certainly implicated in the wall dilatation and valve incompetence seen in primary CVD. Markers of endothelial cell dysfunction are predictive of vascular events. They reflect multiple micro- or macrovascular disorders and early vascular changes, predating clinical pathology by many months or even years. Elevation is associated with aging, endocrinopathy, arterial disease, connective tissue disease, smoking, and exposure to air pollution, in addition to venous disease. Endothelial function testing has great potential in cardiovascular screening, but is not yet feasible in routine assessment: no test is sufficiently sensitive and specific for clinical use. Most studies are observational. We still don’t know how best to investigate the multifaceted aspects of endothelial dysfunction.

Three types of test are available: vascular reactivity, systemic plasma markers, and histological immunostaining.

_ Vascular reactivity tests
Vascular reactivity tests are the most widely used: they are noninvasive, and they evaluate the peripheral macrocirculation (conduit arteries) or microcirculation (resistance arteries and arterioles).

_ Systemic plasma markers
Systemic plasma markers of endothelial damage and repair play a minor role in individual patient assessment:
_ Nitric oxide: plasma levels of this potent mediator of vascular relaxation may be modulated in CVD.
_ Humoral mediators of vasoconstriction and venous dilatation: endothelin 1 levels increase and rise disproportionately in response to venous stasis.
_ Pro- and anti-inflammatory cytokines: chronic venous hypertension leading to endothelial cellular injury and activation promotes inflammatory reaction and leukocyte recruitment in venous valves, causing dysfunction, reflux, and upstream venous hypertension.
_ Adhesion molecules: despite reflecting early leukocyte-endothelium interaction, intercellular adhesion molecule 1 and E-selectin expression did not differ significantly between VV patients and controls.
_ Hypoxia inducible factor 1α: Elevation of this marker of leukocyte-endothelium interaction results from prolonged mechanical stretching and increased vein wall tension, supporting the hypothesis of VV hypoxia.
_ Soluble markers are mixtures of truly soluble molecules with membrane-bound forms, eg, endothelial microparticles (EMP). EMP-monocyte conjugates enhance transendothelial leukocyte migration in vitro and reflect several inflammatory diseases. But EMP elevation is not diagnostic for CVD progression or inflammation.
_ Enzyme activity (matrix metalloproteinases [MMPs] and their inhibitors) increases in both high and low venous pressure regions. The degree of extracellular matrix remodeling of the venous wall and valve leaflets correlates with macroscopic lesion morphology and changes in the microcirculation and dermis. MMP-2 may induce venous relaxation or inhibit venous contraction.
_ Plasma thrombomodulin (TM) is a marker of endothelial injury. Two cohort studies found no difference in the prevalence of the three TM genotypes between thrombosis cases and controls. There was no difference in age-adjusted mean soluble TM values by genotype, nor any association between age-adjusted soluble TM or the TMA455V genotype and overall venous thromboembolism or thrombosis.

_ Histological immunostaining
Immunostaining and real-time polymerase chain reaction (RTPCR) analysis reveal VV intimal changes, such as focal intimal discontinuity and endothelial denudation. Vein wall changes may precede valvular dysfunction. Total elastin content is lower in VVs than in healthy veins.

We need more longitudinal studies to identify prognostic markers of endothelial dysfunction. We must also identify the genetic and humoral mediators of endothelial dysfunction in limbs with primary CVD and disease progression.

How reliable are ankle mobility, calf muscle pump function, and patient activity in rating CVD progression?

Both photoplethysmography and air plethysmography show end-of-day deterioration in calf pump function, suggesting that venous return deteriorates with prolonged standing. Musculoskeletal changes affect calf pump hemodynamics, complicating differentiation between cause and effect.

Goniometry shows significantly reduced ankle ROM across all grades of CVD.¹² ROM decreases with increasing clinical severity, impairing calf pump function, and sustaining ambulatory venous hypertension. Gastrocnemius biopsies reveal morphologic changes suggesting that disuse, denervation, and ischemia lead to muscle dysfunction. The resultant impact on gait and ambulation predisposes to venous ulceration. Over two-thirds of ulcer patients have an impaired calf pump. Use of air plethysmography and color Doppler to study the relationship between degree of venous insufficiency, calf pump dysfunction, and venous ulceration showed significantly poorer pump function in legs with active ulcers than in those with healed ulcers or no history of ulceration. CVD is a necessary but limited cause of ulceration; calf pump dysfunction is a significant contributor to the severity of venous ulceration.¹³ In addition to known risk factors (longer ulcer duration, large surface area, ankle brachial pressure index <0.85), calf pump dysfunction correlates with delayed ulcer healing even with adequate compression. A study in 189 patients identified that calf/ankle circumference ratio <1.3, a fixed ankle joint, and reduced ankle ROM were the only independent parameters associated with nonhealing.¹⁴ Prospective controlled studies show that supervised exercise programs to improve calf pump function, muscle strength, and endurance improve healing rates and decrease recurrence in C6 disease, with benefit being maintained for at least 3 months.¹⁵ _

References
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Keywords: risk factors; identification; chronic venous disease