Enf. Venosa Crónica

8/11/2019 Enf. Venosa Crnica

1/11

review article

T h e n e w e n g l a n d j o u r n a l o f m ed i c i n e

n engl j med355;5 www.nejm.org august3,2006488

Mechanisms of Disease

Chronic Venous DiseaseJohn J. Bergan, M.D., Geert W. Schmid-Schnbein, Ph.D.,

Philip D. Coleridge Smith, D.M., Andrew N. Nicolaides, M.S.,Michel R. Boisseau, M.D., and Bo Eklof, M.D., Ph.D.

From the Departments of Surgery (J.J.B.)and Bioengineering (G.W.S.-S.), WhitakerInstitute of Biomedical Engineering, Uni-versity of California, San Diego, La Jolla;the Department of Vascular Surgery, RoyalFree and University College Medical School,Middlesex Hospital, London (P.D.C.S.); theDepartment of Surgery, Imperial College

London, University of Cyprus, and Vascu-lar Screening and Diagnostic Centre, Nic-osia, Cyprus (A.N.N.); the Department ofVascular Biology and Pharmacology, Uni-versity of Bordeaux 2, Bordeaux, France(M.R.B.); and the Department of Surgery,University of Lund, Lund, Sweden (B.E.).Address reprint requests to Dr. Berganat 9850 Genesee, Suite 410, La Jolla, CA92037, or at [email protected].

N Engl J Med 2006;355:488-98.Copyright 2006 Massachusetts Medical Society.

Chronic venous disease of the lower limbs is manifested by arange of signs, the most obvious of which are varicose veins and venous ul-cers. However, the signs also include edema, venous eczema, hyperpigmen-tation of skin of the ankle, atrophie blanche (white scar tissue), and lipodermato-sclerosis (induration caused by f ibrosis of the subcutaneous fat) (Fig. 1). Considerableprogress has been made in understanding the mechanisms that underlie these di-

verse manifestations, in particular the role of inf lammation. This article reviewsthese advances and places them in a clinical context.

Chronic venous disease can be graded according to the descriptive clinical,etiologic, anatomical, and pathophysiological (CEAP) classification, which providesan orderly framework for communication and decision making.1,2The clinical signsin the affected legs are categorized into seven classes designated C0to C6(Table 1).Leg symptoms associated with chronic venous disease include aching, heaviness,a sensation of swelling, and skin irritation; limbs categorized in any clinical classmay be symptomatic (S) or asymptomatic (A). Chronic venous disease encom-passes the full spectrum of signs and symptoms associated with classes C0,sto C6,whereas the term chronic venous insufficiency is generally restricted to diseaseof greater severity (i.e., classes C4to C6). Thus, varicose veins in the absence of skinchanges are not indicative of chronic venous insufficiency.

THE SCALE OF THE PROBLEM

Prevalence

Chronic venous disease is extremely common, although the prevalence estimatesvary. A cross-sectional study of a random sample of 1566 subjects 18 to 64 years ofage from the general population in Edinburgh, Scotland,3found that telangiectasesand reticular veins were each present in approximately 80 percent of men and 85percent of women. Varicose veins were present in 40 percent of men and 16 percentof women, whereas ankle edema was present in 7 percent of men and 16 percent ofwomen.3Active or healed venous leg ulcers occur in approximately 1 percent of thegeneral population.3,4

Although not restricted to the elderly, the prevalence of chronic venous disease,especially leg ulcers, increases with age.3-5Most studies have shown that chronicvenous disease is more prevalent among women, although in a recent study, thedifference between sexes was small.6In the Framingham Study, the annual inci-dence of varicose veins was 2.6 percent among women and 1.9 percent amongmen,7and in contrast to the Edinburgh Vein Study, the prevalence of varicose veinswas higher in men.3,8In the San Diego Population Study, chronic venous diseasewas more prevalent in populations of European origin than in blacks or Asians.9Risk factors for chronic venous disease include heredity, age, female sex, obesity

Downloaded from www.nejm.org on August 3, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved.


2/11

mechanisms of disease

n engl j med355;5 www.nejm.org august3,2006 489

A C

DB

Figure 1.Clinical Manifestations of Chronic Venous Disease.

Telangiectases (clinical, etiologic, anatomical, and pathophysiological [CEAP] class C1) are shown in Panel A, varicose

veins (CEAP class C2) in Panel B, pigmentation (CEAP class C4) in Panel C, and active ulceration (CEAP class C6) in

Panel D.



3/11



(especially in women), pregnancy, prolongedstanding, and greater height.4,8,10-12

Economic Impact

The high prevalence of varicose veins and thechronicity of leg ulcers mean that chronic venousdisease has a considerable impact on health careresources. In a population study in the UnitedKingdom, the median duration of ulceration wasnine months, 20 percent of ulcers had not healedwithin two years, and 66 percent of patients hadepisodes of ulceration lasting longer than fiveyears.13It has been estimated that venous ulcers

cause the loss of approximately 2 million workingdays and incur treatment costs of approximately$3 billion per year in the United States.14Overall,chronic venous disease has been estimated to ac-count for 1 to 3 percent of the total health carebudgets in countries with developed health caresystems.4,15,16

SYMPTOMS AND QUALITY OF LIFE

Symptoms traditionally ascribed to chronic ve-nous disease include aching, heaviness, a feelingof swelling, cramps, itching, tingling, and rest-less legs. The proportion of patients presentingwith any venous symptom increases with increas-ing CEAP class.17In an international study of 1422patients with chronic venous disease, the overallscore for symptom severity was significantly cor-related with the CEAP clinical class, after con-trolling for age, sex, body-mass index, coexisting

conditions, and the duration of chronic venous dis-ease.18

Chronic venous disease is associated with areduced quality of life, particularly in relation topain, physical function, and mobility. It is alsoassociated with depression and social isolation.19Venous leg ulcers, the most severe manifestationof chronic venous disease, are usually painful20and affect the quality of life.21A large-scale studyof 2404 patients using the generic Medical Out-comes Study 36-item Short-Form General HealthSurvey questionnaire found a significant associa-tion between the quality of life and the severity

of venous disease.22Similarly, a correlation be-tween the CEAP class and the quality of life hasbeen found with the use of a disease-specificquestionnaire.18The impairment associated withCEAP classes C5and C6has been likened to theimpairment associated with heart failure.23

VENOUS HYPERTENSION

Despite the diversity of signs and symptoms as-sociated with chronic venous disease, it seemslikely that all are related to venous hypertension.In most cases, venous hypertension is caused byreflux through incompetent valves,6,24but othercauses include venous outflow obstruction andfailure of the calf-muscle pump owing to obesityor leg immobility. Reflux may occur in the super-ficial or deep venous system or in both. A reviewof 1153 cases of ulcerated legs with reflux foundsuperficial reflux alone in 45 percent, deep reflux

Table 1.Revised Clinical Classification of Chronic Venous Disease of the Leg.*

Class Definition Comments

C0 No visible or palpable signs of venous disease

C1 Telangiectases, reticular veins, malleolar flare Telangiectases defined by dilated intradermal venules3 mm in diameter

C3 Edema without skin changes

C4

C4a

C4b

Skin changes ascribed to venous disease

Pigmentation, venous eczema, or both

Lipodermatosclerosis, atrophie blanche, or both

C5 Skin changes with healed ulceration

C6 Skin changes with active ulceration

* Adapted from Porter and Moneta1and Eklof et al.2



4/11



alone in 12 percent, and both forms in 43 per-cent.25 An analysis of cases of chronic venousdisease indicated that primary valvular incompe-tence was present in 70 to 80 percent and a con-genital anomaly in 1 to 3 percent; valvular in-competence was due to trauma or deep-vein

thrombosis in 18 to 25 percent.6,24

Pressure in the veins of the leg is determinedby two components: a hydrostatic component re-lated to the weight of the column of blood fromthe right atrium to the foot and a hydrodynamiccomponent related to pressures generated by con-tractions of the skeletal muscles of the leg andthe pressure in the capillary network. Both com-ponents are profoundly influenced by the actionof the venous valves. During standing withoutskeletal-muscle activity, venous pressures in thelegs are determined by the hydrostatic compo-nent and capillary flow, and they may reach 80 to

90 mm Hg. Skeletal-muscle contractions, as dur-ing ambulation, transiently increase pressure with-in the deep leg veins. Competent venous valvesensure that venous blood flows toward the heart,thereby emptying the deep and superficial ve-nous systems and reducing venous pressure, usu-ally to less than 30 mm Hg (Fig. 2). Even verysmall leg movements can provide importantpumping action. In the absence of competentvalves, however, the decrease in venous pressurewith leg movements is attenuated. If valves inthe perforator veins are incompetent, the highpressures generated in the deep veins by calf-

muscle contraction can be transmitted to thesuperficial system and to the microcirculation inskin. It seems likely, therefore, that the clinicalsigns of chronic venous disease stem from venouspressures in the leg that reach higher-than-normallevels and remain elevated for prolonged periods.

VALVE AND VEIN-WALL CHANGES

IN CHRONIC VENOUS DISEASE

Changes in Venous Valves

Venous valve incompetence is central to the ve-nous hypertension that appears to underlie mostor all signs of chronic venous disease. Alterationsin and damage to valves have been noted on ex-amination with an angioscope, a fiberoptic cath-eter that allows clinicians to view the interior ofa blood vessel. These changes include stretching,splitting, tearing, thinning, and adhesion of valveleaflets.27A reduction in the number of valves

per unit length has been observed in segments ofsaphenous veins from patients with chronic ve-nous insufficiency.28An important step forwardcame when Ono et al.29found infiltration of valveleaflets and the venous wall by monocytes andmacrophages in all vein specimens from patientswith chronic venous disease and in no specimensfrom controls. Infiltration was associated withareas of endothelium that expressed intercellularadhesion molecule 1 (ICAM-1).30

Structural Changes in the Vein Wall

Histologic and ultrastructural studies of varicosesaphenous veins have found hypertrophy of thevein wall with increased collagen content,31to-gether with disruption of the orderly arrangementsof smooth-muscle cells and elastin fibers.32,33Cul-tures of smooth-muscle cells from varicose sa-phenous veins have disturbed collagen synthesis,resulting in overproduction of collagen type I andreduced synthesis of collagen type III.34Becausecollagen type I is thought to confer rigidity andcollagen type III to confer distensibility to tissues,such changes could contribute to the weaknessand reduced elasticity of varicose veins.

A complicating factor is the heterogeneity ofthe varicose-vein wall; hypertrophic segments canalternate with thinner atrophic segments withfewer smooth-muscle cells and reduced extracel-lular matrix. Degradation of extracellular matrix

Foot-VeinPressure(mmH

g)

80

90

70

60

40

30

10

50

20

00 10 20 30 40

Seconds

Limb with incompetent venous valves

Normal limb

100

WalkingStanding

Figure 2.Action of the Musculovenous Pump in Lowering Venous Pressurein the Leg.

After prolonged standing, venous pressure in the foot is approximately

90 mm Hg in both a patient with incompetent venous valves and a personwith a normal leg. During walking, the musculovenous pump rapidly lowers

the venous pressure in the normal leg but is ineffec tive in the leg with valvu-

lar incompetence. (Reproduced from Coleridge Smith26

with the permissionof the publisher.)



5/11



proteins is caused by an array of proteolyticenzymes, including matrix metalloproteinases(MMPs) and serine proteinases, which are pro-duced by vascular cells and inflammatory cellssuch as macrophages.35MMPs are released as in-active proenzymes that are activated by other

proteinases, including those produced by mastcells,36,37 whereas tissue inhibitors of MMPs(TIMPs) reduce MMP activity. In varicose veins,ratios of TIMP-1 to MMP-2 and TIMP-2 to MMP-2have been found to be 3.6 times and 2.1 times,respectively, those in veins of control subjects.38These altered ratios could favor the accumulationof extracellular matrix material in varicose veins.

Elevated levels of the cytokines transforminggrowth factor 1(TGF-1) and fibroblast growthfactor (FGF-, also referred to as basic fibro-blast growth factor) have also been found in thewalls of varicose veins.39TGF-1stimulates col-

lagen and elastin synthesis and increases the ex-pression of TIMPs,40whereas FGF- is chemotac-tic and mitogenic for smooth-muscle cells.41Thesefindings of changes in proteolytic enzymes andtheir inhibitors and cytokines could signal thebeginning of an understanding of the mecha-nisms that cause hypertrophic changes in the veinwall.42Other changes have been found in vari-cose regions of saphenous veins, which containincreased numbers of mast cells.43Proteinasesfrom mast cells can activate MMPs, which de-grade extracellular matrix. With time, local differ-ences in the balance of opposing synthetic and

degradative processes could lead to hypertrophicand atrophic segments of the same vein.

Role of Pressure and Shear Stress

The Role of Elevated Pressure

The acute effects of increased venous pressurehave been studied in animal models. In rats, pro-duction of an arteriovenous fistula between thefemoral artery and vein abruptly increased thepressure in the femoral vein to approximately90 mm Hg.43-45Although the valves were stretchedimmediately by the increased pressure, reflux didnot occur until at least two days later and thenincreased with time. After three weeks, the num-bers of granulocytes, monocytes, macrophages,and lymphocytes were increased in the pressurizedvalves, and MMP-2 and MMP-9 levels were raised.Morphologic changes in the valves also occurred;there were reductions in leaflet height and width,

and some valves disappeared. These studies sug-gest that valves can tolerate high pressures forlimited periods, but when there is prolongedpressure-induced inflammation, valve remodel-ing and loss and reflux occur.

When a rat mesenteric venule was experimen-

tally occluded, the effects of increased pressurecould be separated from the effects of reducedflow by comparing regions on either side of theocclusion; flow was essentially zero at both sites,but only the upstream site had high pressure.46,47Leukocyte rolling, adhesion, and migration, aswell as microhemorrhage and parenchymal-celldeath, were all increased at the high-pressure site.

The Role of Shear Stress

Before considering the molecular mechanisms bywhich shear stress modulates endothelial and leu-kocyte behavior, we will summarize recent work

on blood flow through venous valves. Venousvalves are operated by pressure rather than byflow-driven devices, so that little or no reflux isneeded to bring about complete closure of thevalve.48 The recently introduced technique ofB-flow ultrasonography has allowed detailed in-vestigation of patterns of blood f low and valveoperation in situ.49Venous flow is normally pul-satile; venous valves open and close approximate-ly 20 times per minute while a person is standing.When the valve leaflets are fully open, they donot touch the sinus wall (Fig. 3). Flow throughthe valve separates into a proximally directed jet

and a vortical f low into the sinus pocket behindthe valve cusp; the vortical f low prevents stasis inthe pocket and ensures that all surfaces of thevalve are exposed to shear stress. Valve closureoccurs when the pressure caused by the vorticalflow exceeds the pressure on the luminal side ofthe valve leaflet because of the proximally directedjet. Interestingly, foot movements, which increasethe velocity of the jet, reduce the pressure on theluminal side of the valve leaf lets and cause closureof the valve. Thus, minimal reflux occurs andendothelial surfaces are not generally exposed toreverse blood flow.

Shear stress is transduced in endothelial cellsby several possible mechanisms and mediated bya complex network of signaling pathways50,51thatcan modify the expression of numerous genes.52An important theme of current research on theeffects of shear stress is that pulsatile, laminarshear stress can promote the release of factors



6/11


7/11



Chronic Inflammation

Current thinking about the basis of the skinchanges in chronic venous disease can be tracedback to the observation that the blood returningfrom feet that have been passively dependent for40 to 60 minutes is depleted of leukocytes, espe-cially in patients with chronic venous disease.68,69This finding suggests that leukocytes accumulatein the leg under conditions of high venous pres-sure. It is likely that the accumulation is largelydue to leukocyte adhesion to, as well as migrationthrough, the endothelium of small vessels, especial-ly postcapillary venules. Another observation isthat plasminogen activator is released into the con-gested vasculature, indicating that the accumulat-ed leukocytes become activated. All this suggeststhat an inf lammatory reaction is important in pro-voking skin changes in chronic venous disease.

Support for what has come to be known asthe microvascular leukocyte-trapping hypothesishas come from immunocytochemical and ultra-structural studies that showed elevated numbers

of macrophages, T lymphocytes, and mast cells inskin-biopsy specimens from lower limbs affectedby chronic venous disease.70,71In rat models ofboth acute72and chronic73venous hypertension,elevated levels of tissue leukocytes were found inskin samples from affected legs, but not in those

from sham-operated controls.

Mechanisms of Inflammation

Circulating leukocytes and vascular endothelialcells express several types of membrane adhesionmolecules. The transient binding of L-selectin onthe leukocyte surface to E-selectin on endothelialcells underlies leukocyte rolling along the endo-thelial surface. When leukocytes are activated,they shed L-selectin into the plasma and expressmembers of the integrin family, including CD11b,which binds to ICAM-1. Integrin binding promotesfirm adhesion of leukocytes, the starting point

for their migration out of the vasculature and de-granulation.74

After venous hypertension was induced in pa-tients with chronic venous disease by their stand-ing for 30 minutes, levels of L-selectin and theintegrin CD11b on circulating neutrophils andmonocytes decreased, ref lecting the trapping ofthese cells in the microcirculation. Simultaneous-ly, plasma levels of soluble L-selectin increased,reflecting the shedding of these molecules fromleukocyte surfaces during leukocyteendothelialadhesion.75Basal plasma levels of the adhesionmolecules ICAM-1, endothelial leukocyte-adhesion

molecule 1, and vascular-cell adhesion molecule 1were higher in patients with chronic venous dis-ease than in control subjects, and increased sig-nificantly in response to venous hypertension pro-voked by standing.76

In addition to having local factors operatingin relation to venous hypertension, patients withchronic venous disease tend to have a systemicincrease in leukocyte adhesion. For example, plas-ma from patients with chronic venous disease in-duces more activation of normal, quiescent leuko-cytes (assessed by oxygen free radical productionand pseudopod formation) than does plasma fromcontrol subjects.77The plasma factor responsiblefor this effect is unknown.

The Link between Inflammation

and Skin Changes

The chronic inflammatory state in patients withchronic venous disease is related to the skin chang-es that are typical of the condition. Increased ex-

Steady laminar blood flow

Shear stress

Low mean shear stress

Antithrombotic agents

NOProstacyclinTissue plasminogenactivatorThrombomodulin

Growth-inhibiting

agents

Growth-promoting

agents

Vein-wall damage

NOTGF-b

Angiotensin IIEndothelin-1Platelet-derived growth factor

NO

Antimigration agents

Prosurvival

Prothrombotic agents

MCP-1VCAM-1

Promotionof migration Promotion

of apoptosis

A

Flow reversalB

Tunica externa

Tunica media

Tunica intima

Smooth-muscle cells

Endothelium

Figure 4.Contrasting Effects of Steady, Laminar Shear Stress (Panel A)and Turbulent or Reversing Shear Stress (Panel B) on Vessel Walls.

NO denotes nitric oxide, MCP-1 monocyte chemoattractant protein 1,and VCAM-1 vascular-cell adhesion molecule. (Reproduced from Traub

and Berk50with the permission of the publisher.)



8/11



pression and activity of MMP (especially MMP-2)have been reported in lipodermatosclerosis,78invenous leg ulcers,79 and in wound fluid fromnonhealing venous ulcers.80In addition, levels ofTIMP-2 are lower in lipodermatosclerotic skin andulcers.78,80Unrestrained MMP activity may con-

tribute to the breakdown of the extracellular ma-trix, which promotes the formation of ulcers andimpairs healing.

In lipodermatosclerosis, the skin capillariesare elongated and tortuous,81and they may takeon a glomerular appearance, with proliferationof the capillary endothelium in more advancedcases.82Vascular endothelial growth factor (VEGF),which is likely to be involved in these changes,has been shown to increase microvascular per-meability.83Plasma levels of VEGF increased dur-ing the venous hypertension that was induced by30 minutes of standing in control subjects and

in patients with chronic venous disease, and thelevels were higher in patients than in control sub-jects.84Furthermore, plasma VEGF levels werehigher in patients with chronic venous diseasewith skin changes than in such patients withnormal skin.85

Another feature of the skin changes associatedwith chronic venous disease is dermal t issue fi-brosis. TGF-1is a fibrogenic cytokine. In onestudy, skin from the lower calf of patients withchronic venous disease contained significantlyelevated levels of active TGF-1as compared withnormal skin or skin from the thigh region of the

same patients.86The TGF-1was located in leu-kocytes and fibroblasts and on collagen fibrils.Pappas et al.86have proposed that activated leuko-cytes migrate out of the vasculature and releaseTGF-1, stimulating collagen production by der-mal fibroblasts, which culminates in dermal fi-brosis. Altered collagen synthesis by dermal fibro-blasts in apparently healthy areas of skin inpatients with varicose veins has also been re-ported.87

The hyperpigmentation of skin in lipodermato-sclerosis may not be just an innocent by-productof capillary hyperpermeability. The extravasationof red cells leads to elevated levels of ferritin andferric iron in affected skin.88,89These increasesmay cause oxidative stress, MMP activation, andthe development of a microenvironment that ex-acerbates tissue damage and delays healing.90Consistent with this view, the hemochromatosisC282Y mutation (a common genetic defect of ironmetabolism) is associated with an increase in

the risk of ulceration by a factor of nearly sevenin patients with chronic venous disease.91

IMPLICATIONS FOR TREATMENT

Although the causal and temporal sequences ofevents that occur during the development andprogression of chronic venous disease have notbeen ascertained, the emerging twin themes ofdisturbed venous-flow patterns and chronic in-flammation may underlie all the clinical manifes-tations of the disease (Fig. 5). Early treatmentaimed at preventing venous hypertension, reflux,and inflammation could alleviate symptoms ofchronic venous disease and reduce the risk of ul-cers, both of which reduce the quality of life andare expensive to treat. Compression stockings im-prove venous hemodynamics,92reduce edema andskin discoloration,93and improve the quality of

Risk factors for chronic venous diseaseGenetic factorsFemale sex (progesterone)PregnancyAgeGreater heightProlonged standing

Obesity

Venous dilation

Inflammation

Valve distortion,leakage

Altered shearstress

Valve and vein-wall changes

Capillary

hypertension Capillary leakage

Inflammation

Edema

Venoushypertension

Chronicreflux

Venous ulcer Skin changes

Figure 5.Venous Hypertension as the Hypothetical Cause of the ClinicalManifestations of Chronic Venous Disease, Emphasizing the Importance

of Inflammation.

Some steps are speculative, and to enhance clarity, not all possible inter-

connections are shown.



9/11



life94 in patients with chronic venous disease.Evidence is accumulating that surgery aimed atpreventing venous reflux can aid healing andprevent the recurrence of ulcers95,96; it thereforeseems reasonable to speculate that such treat-ment could reduce the risk of ulcers if performed

early in the course of chronic venous disease.Treatment to inhibit inflammation may offer thegreatest opportunity to prevent disease-relatedcomplications. Currently available drugs can at-tenuate various elements of the inflammatory cas-cade,97,98particularly the leukocyteendotheliuminteractions that are important in many aspectsof the disease.46,99,100These agents deserve de-

tailed study. Overall, a determined and proactiveapproach to the treatment of the early stages ofchronic venous disease could reduce the numberof patients needing treatment for intractable ul-cers. In the long term, improved understanding ofthe cellular and molecular mechanisms involved

may allow the identification of additional targetsfor pharmacologic intervention.Dr. Bergan reports having served as a consultant to VNUS

Technologies. Dr. Schmid-Schnbein reports being a member ofthe editorial board of Phlebolymphology,a journal sponsored byServier. Dr. Coleridge Smith reports having received consultingfees from Servier and lecture fees from Medi Stockings, Servier,and Saltzmann. No other potential conflict of interest relevantto this article was reported.

References

Porter JM, Moneta GL. Reporting stan-dards in venous disease: an update. J VascSurg 1995;21:635-45.

Eklof B, Rutherford RB, Bergan JJ, et

al. Revision of the CEAP classification forchronic venous disorders: consensus state-ment. J Vasc Surg 2004;40:1248-52.

Evans CJ, Fowkes FGR, Ruckley CV,Lee AJ. Prevalence of varicose veins andchronic venous insufficiency in men and

women in the general population: Edin-burgh Vein Study. J Epidemiol CommunityHealth 1999;53:149-53.

Kurz X, Kahn SR, Abenhaim L, et al.Chronic venous disorders of the leg: epi-demiology, outcomes, diagnosis and man-agement: summary of an evidence-basedreport of the VEINES task force. Int Angiol1999;18:83-102.

Moffatt CJ, Franks PJ, Doherty DC,Martin R, Blewett R, Ross F. Prevalence

of leg ulceration in a London population.QJM 2004;97:431-7.

Labropoulos N. Hemodynamic chang-es according to the CEAP classification.Phlebolymphology 2003;40:130-6.

Brand FN, Dannenberg AL, Abbott RD,Kannel WB. The epidemiology of varicose

veins: the Framingham Study. Am J PrevMed 1988;4:96-101.

Lee AJ, Evans CJ, Allan PL, Ruckley CV,Fowkes FG. Lifestyle factors and the riskof varicose veins: Edinburgh Vein Study.

J Clin Epidemiol 2003;56:171-9.Criqui MH, Jamosmos M, Fronek A, et

al. Chronic venous disease in an ethnicallydiverse population: the San Diego Popula-tion Study. Am J Epidemiol 2003;158:448-

56.Fowkes FG, Lee AJ, Evans CJ, Allan PL,

Bradbury AW, Ruckley CV. Lifestyle riskfactors for lower limb venous reflux in thegeneral population: Edinburgh Vein Study.Int J Epidemiol 2001;30:846-52.

Laurikka JO, Sisto T, Tarkka MR,Auvinen O, Hakama M. Risk indicatorsfor varicose veins in forty- to sixty-year-

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

olds in the Tampere varicose vein study.World J Surg 2002;26:648-51.

Chiesa R, Marone EM, Limoni C,Volonte M, Schaefer E, Petrini O. Demo-

graphic factors and their relationship withthe presence of CVI signs in Ita ly: the 24-cities cohort study. Eur J Vasc EndovascSurg 2005;30:674-80.

Callam MJ, Harper DR, Dale J J, Ruck-ley CV. Chronic ulcer of the leg: clinicalhistory. Br Med J (Clin Res Ed) 1987;294:1389-91.

McGuckin M, Waterman R, Brooks J,et al. Validation of venous leg ulcer guide-lines in the United States and UnitedKingdom. Am J Surg 2002;183:132-7.

Ruckley CV. Socioeconomic impact ofchronic venous insufficiency and leg ulcers.Angiology 1997;48:67-9.

Van den Oever R, Hepp B, Debbaut B,Simon I. Socio-economic impact of chron-

ic venous insufficiency: an underestimat-ed public health problem. Int Angiol 1998;17:161-7.

Carpentier PH, Cornu-Thnard A, UhlJ-F, Partsch H, Antignani PL. Appraisal ofthe information content of the C classesof CEAP clinical classification of chronic

venous disorders: a multicenter evaluationof 872 patients. J Vasc Surg 2003;37:827-33.

Kahn SR, Mlan CE, Lamping DL,Kurz X, Brard A, Abenhaim LA. Relation-ship between clinical classification ofchronic venous disease and patient-report-ed quality of life: results from an interna-tional cohort study. J Vasc Surg 2004;39:823-8.

van Korlaar I, Vossen C, Rosendaal F,Cameron L, Bovill E, Kaptein A. Quality oflife in venous disease. Thromb Haemost2003;90:27-35.

Nemeth KA, Harrison MB, GrahamID, Burke S. Understanding venous legulcer pain: results of a longitudinal study.Ostomy Wound Manage 2004;50:34-46.

Franks PJ, Moffatt CJ. Health related

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

quality of life in patients with venous ul-ceration: use of the Nottingham healthprofile. Qual Life Res 2001;10:693-700.

Kaplan RM, Criqui MH, Denenberg JO,

Bergan J, Fronek A. Quality of life in pa-tients with chronic venous disease: SanDiego Population Study. J Vasc Surg 2003;37:1047-53.

Andreozzi GM, Cordova RM, Scom-parin A, Martini R, DEri A, Andreozzi F.Quality of life in chronic venous insuffi-ciency: an Italian pilot study of the Tri-

veneto Region. Int Angiol 2005;24:272-7.Kistner RL, Eklof B, Masuda EM. Di-

agnosis of chronic venous disease of thelower extremities: the CEAP classifica-tion. Mayo Clin Proc 1996;71:338-45.

Tassiopoulos AK, Golts E, Oh DS, Lab-ropoulos N. Current concepts in chronic

venous ulceration. Eur J Vasc EndovascSurg 2000;20:227-32.

Coleridge Smith PD. The microcircu-lation in venous hypertension. Vasc Med1997;2:203-13.

Van Cleef JF, Hugentobler JP, DesvauxP, Griton P, Cloarec M. tude endosco-pique des reflux valvulaires saphniens.

J Mal Vasc 1992;17:Suppl B:113-6.Sales CM, Rosenthal D, Petrillo KA, et

al. The valvular apparatus in venous in-sufficiency: a problem of quantity? AnnVasc Surg 1998;12:153-5.

Ono T, Bergan JJ, Schmid-SchnbeinGW, Takase S. Monocyte infiltration into

venous valves. J Vasc Surg 1998;27:158-66.Takase S, Bergan JJ, Schmid-Schn-

bein GW. Expression of adhesion mole-cules and cytokines on saphenous veins

in chronic venous insuff iciency. Ann VascSurg 2000;14:427-35.

Travers JP, Brookes CE, Evans J, et al.Assessment of wall structure and compo-sition of varicose veins with reference tocollagen, elastin and smooth muscle con-tent. Eur J Vasc Endovasc Surg 1996;11:230-7.

Porto LC, Ferreira MA, Costa AM, da

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.



10/11



Silveira PR. Immunolabeling of type IVcollagen, laminin, and alpha-smooth mus-cle actin cells in the intima of normal and

varicose saphenous veins. Angiology 1998;49:391-8.

Wali MA, Eid RA. Changes of elasticand collagen fibers in varicose veins. IntAngiol 2002;21:337-43.

Sansilvestri-Morel P, Rupin A, Badier-Commander C, et al. Imbalance in thesynthesis of collagen type I and collagentype III in smooth muscle cells derivedfrom human varicose veins. J Vasc Res2001;38:560-8.

Jacob MP, Badier-Commander C, Fon-taine V, Benazzoug Y, Feldman L, Michel

JB. Extracellular matrix remodeling in thevascular wall. Pathol Biol (Paris) 2001;49:326-32.

Lees M, Taylor DJ, Woolley DE. Mastcell proteinases activate precursor formsof collagenase and stromelysin, but not ofgelatinases A and B. Eur J Biochem 1994;223:171-7.

Johnson JL, Jackson CL, Angelini GD,George SJ. Activation of matrix-degradingmetalloproteinases by mast cell proteasesin atherosclerotic plaques. ArteriosclerThromb Vasc Biol 1998;18:1707-15.

Badier-Commander C, Verbeuren T,Lebard C, Michel J-B, Jacob M-P. IncreasedTIMP/MMP ratio in varicose veins: a pos-sible explanation for extracellular matrixaccumulation. J Pathol 2000;192:105-12.

Badier-Commander C, Couvelard A,Henin D, Verbeuren T, Michel J-B, JacobM-P. Smooth muscle cell modulat ion andcytokine overproduction in varicose veins:an in situstudy. J Pathol 2001;193:398-407.

Overall CM, Wrana JL , Sodek J. Tran-scriptional and post-transcriptional regu-lation of 72-kD gelatinase/t ype IV collage-nase by transforming growth factor-1 inhuman f ibroblasts: comparisons with col-lagenase and tissue inhibitor of matrixmetalloproteinase gene expression. J BiolChem 1991;266:14064-71.

Lindner V, Reidy MA. Proliferation ofsmooth muscle cells after vascular injuryis inhibited by an antibody against basicfibroblast growth factor. Proc Natl AcadSci U S A 1991;88:3739-43.

Morozov KM, Abalmasov KG, SerovRA, Krylova RG. Morphological changesin femoral vein wall structure in presenceof persistent vertical reflux. Vestn RossAkad Med Nauk 2005;4:81-5. (In Russian.)

Takase S, Pascarella L, Bergan JJ,Schmid-Schnbein GW. Hypertension-induced venous valve remodeling. J VascSurg 2004;39:1329-34.

Takase S, Pascarella L, Lerond L, Ber-gan JJ, Schmid-Schnbein GW. Venoushypertension, inflammation and valve re-modeling. Eur J Vasc Endovasc Surg 2004;28:484-93.

Pascarella L, Schmid-Schnbein GW,Bergan J. An animal model of venous hy-pertension: the role of inflammation in

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

venous valve failure. J Vasc Surg 2005;41:303-11.

Takase S, Lerond L, Bergan J J, Schmid-Schnbein GW. The inflammatory reac-tion during venous hypertension in therat. Microcirculation 2000;7:41-52.

Idem. Enhancement of reperfusion in-jury by elevation of microvascular pres-sures. Am J Physiol Heart Circ Physiol2002;282:H1387-H1394.

Qui Y, Quijano RC, Wang SK, HwangNH. Fluid dynamics of venous valve clo-sure. Ann Biomed Eng 1995;23:750-9.

Lurie F, Kistner RL, Eklof B, Kessler D.Mechanism of venous valve closure androle of the valve in circulation: a new con-cept. J Vasc Surg 2003;38:955-61.

Traub O, Berk BC. Laminar shearstress: mechanisms by which endothelialcells transduce an atheroprotective force.Arterioscler Thromb Vasc Biol 1998;18:677-85.

Yoshizumi M, Abe J, Tsuchiya K, BerkBC, Tamaki T. Stress and vascular respons-es: atheroprotective effect of laminar f luidshear stress in endothelial cells: possiblerole of mitogen-activated protein kinases.

J Pharmacol Sci 2003;91:172-6.Ohura N, Yamamoto K, Ichioka S, et al.

Global analysis of shear stress-responsivegenes in vascular endothelial cells. J Ath-eroscler Thromb 2003;10:304-13.

Berk BC, Abe JI, Min W, SurapisitchatJ, Yan C. Endothelial atheroprotective andanti-inflammatory mechanisms. Ann N YAcad Sci 2001;947:93-109.

Passerini AG, Milsted A, Rittgers SE.Shear stress magnitude and directionalitymodulate growth factor gene expressionin preconditioned vascular endothelial cells.

J Vasc Surg 2003;37:182-90.Sorescu GP, Sykes M, Weiss D, et al.

Bone morphogenic protein 4 produced inendothelial cells by oscillatory shear stressstimulates an inflammatory response.

J Biol Chem 2003;278:31128-35.Asakura T, Karino T. Flow patterns

and spatial distribution of atheroscleroticlesions in human coronary arteries. CircRes 1990;66:1045-66.

Moore JE Jr, Xu C, Glagov S, ZarinsCK, Ku DN. Fluid wall shear stress mea-surements in a model of the human ab-dominal aorta: oscillatory behavior andrelationship to atherosclerosis. Atheroscle-rosis 1994;110:225-40.

Moazzam F, DeLano FA, Zweifach BW,Schmid-Schnbein GW. The leukocyte re-sponse to fluid stress. Proc Natl Acad SciU S A 1997;94:5338-43.

Fukuda S, Schmid-Schnbein GW.Regulation of CD18 expression on neutro-phils in response to fluid shear stress.Proc Natl Acad Sci U S A 2003;100:13152-7.

Fukuda S, Yasu T, Predescu DN,Schmid-Schnbein GW. Mechanisms forregulation of fluid shear stress responsein circulating leukocytes. Circ Res 2000;86:E13-E18.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

Secomb TW, Hsu R, Pries AR. Effectof the endothelial surface layer on trans-mission of fluid shear stress to endothe-lial cells. Biorheology 2001;38:143-50.

Zhao Y, Chien S, Weinbaum S. Dynam-ic contact forces on leukocyte microvilliand their penetration of the endothelialglycocalyx. Biophys J 2001;80:1124-40.

Mulivor AW, Lipowsky HH. Role ofthe glycocalyx in leukocyte-endothelial celladhesion. Am J Physiol Heart Circ Physiol2002;283:H1282-H1291.

Idem. Inflammation- and ischemia-induced shedding of venular glycocalyx.Am J Physiol Heart Circ Physiol 2004;286:H1672-H1680.

Payne SP, London NJ, Newland CJ,Thrush AJ, Barrie WW, Bell PR. Ambula-tory venous pressure: correlation with skincondition and role in identifying surgi-cally correct ible disease. Eur J Vasc Endo-

vasc Surg 1996;11:195-200.Nicolaides AN, Hussein MK, Szendro

G, Christopoulos D, Vasdekis S, Clarke H.The relation of venous ulceration with am-bulatory venous pressure measurements.

J Vasc Surg 1993;17:414-9.Burnand KG, Whimster I, Naidoo A,

Browse NL. Pericapillary fibrin in the ulcer-bearing skin of the leg: the cause of lipo-dermatosclerosis and venous ulceration.Br Med J (Clin Res Ed) 1982;285:1071-2.

Moyses C, Cederholm-Williams SA,Michel CC. Haemoconcentration and ac-cumulation of white cells in the feet dur-ing venous stasis. Int J Microcirc Clin Exp1987;5:311-20.

Thomas PR, Nash GB, Dormandy JA.White cell accumulation in dependent legsof patients with venous hyper tension: apossible mechanism for trophic changesin the skin. Br Med J (Clin Res Ed) 1988;296: 1693-5.

Wilkinson LS, Bunker C, Edwards JC,Scurr JH, Smith PD. Leukocytes: their rolein the etiopathogenesis of skin damage in

venous disease. J Vasc Surg 1993;17:669-75.Pappas PJ, DeFouw DO, Venezio LM,

et al. Morphometric assessment of thedermal microcirculation in patients withchronic venous insufficiency. J Vasc Surg1997;26:784-95.

Lalka SG, Unthank JL, Nixon JC. Ele-vated cutaneous leukocyte concentrationin a rodent model of acute venous hyper-tension. J Surg Res 1998;74:59-63.

Hahn TL, Unthank JL, Lalka SG. In-creased hindlimb leukocyte concentrationin a chronic rodent model of venous hyper-tension. J Surg Res 1999;81:38-41.

Yong K, Khwaja A. Leukocyte cellularadhesion molecules. Blood Rev 1990;4:211-25.

Saharay M, Shields DA, Porter JB,Scurr JH, Coleridge Smith PD. Leukocyteactivity in the microcirculation of the legin patients with chronic venous disease.

J Vasc Surg 1997;26:265-73.Saharay M, Shields DA, Georgiannos

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.



11/11



SN, Porter JB, Scurr JH, Coleridge SmithPD. Endothelial activation in patients withchronic venous disease. Eur J Vasc Endo-

vasc Surg 1998;15:342-9.Takase S, Schmid-Schnbein G, Ber-

gan JJ. Leukocyte activation in patientswith venous insuf ficiency. J Vasc Surg1999;30:148-56.

Herouy Y, May AE, Pornschlegel G, etal. Lipodermatosclerosis is characterizedby elevated expression and activation ofmatrix metalloproteinases: implicationsfor venous ulcer formation. J Invest Der-matol 1998;111:822-7.

Norgauer J, Hildenbrand T, Idzko M,et al. Elevated expression of extracellularmatrix metalloproteinase inducer (CD147)and membrane-type matrix metallopro-teinases in venous leg ulcers. Br J Derma-tol 2002;147:1180-6.

Mwaura B, Mahendran B, Hynes N, etal. The impact of differentia l expression ofextracellular matrix metalloproteinase in-ducer, matrix metalloproteinase-2, tissueinhibitor of matrix metalloproteinase-2and PDGF-AA on the chronicity of venousleg ulcers. Eur J Vasc Endovasc Surg 2006;31:306-10.

Burnand KG, Whimster I, ClemensonG, Thomas ML, Browse NL. The relat ion-ship between the number of capillaries inthe skin of the venous ulcer-bearing areaof the lower leg and the fall in foot veinpressure during exercise. Br J Surg 1981;68:297-300.

Junger M, Hahn U, Bort S, Klyscz T,Hahn M, Rassner G. Signif icance of cuta-neous microangiopathy for the pathogen-esis of dermatitis in venous congestion dueto chronic venous insuff iciency. Wien MedWochenschr 1994;144:206-10. (In German.)

Bates DO, Curry FE. Vascular endothe-lial growth factor increases hydraulic con-ductivity of isolated perfused microvessels.Am J Physiol 1996;271:H2520-H2528.

77.

78.

79.

80.

81.

82.

83.

Shoab SS, Scurr JH, Coleridge-SmithPD. Increased plasma vascular endothelialgrowth factor among patients with chron-ic venous disease. J Vasc Surg 1998;28:535-40.

Idem. Plasma VEGF as a marker oftherapy in patients with chronic venousdisease treated with oral micronised fla-

vonoid fraction a pilot study. Eur J VascEndovasc Surg 1999;18:334-8.

Pappas PJ, You R, Rameshwar P, et al.Dermal tissue fibrosis in patients withchronic venous insufficiency is associated

with increased transforming growth fac-tor-

1 gene expression and protein pro-

duction. J Vasc Surg 1999;30:1129-45.Sansilvestri-Morel P, Rupin A, Jaisson

S, Fabiani J-N, Verbeuren TJ, Vanhoutte PM.Synthesis of collagen is dysregulated incultured fibroblasts derived from skin ofsubjects with varicose veins as it is in ve-nous smooth muscle cells. Circulation2002;106:479-83.

Ackerman Z, Seidenbaum M, Loewen-thal E, Rubinow A. Overload of iron in theskin of patients with varicose ulcers: pos-sible contributing role of iron accumula-tion in progression of the disease. ArchDermatol 1988;124:1376-8.

Yeoh-Ellerton S, Stacey MC. Iron and8-isoprostane levels in acute and chronic

wounds. J Invest Dermatol 2003;121:918-25.

Wenk J, Foitzik A, Achterberg V, et al.Selective pick-up of increased iron by defe-roxamine-coupled cellulose abrogates theiron-driven induction of matrix-degrad-ing metalloproteinase-1 and lipid peroxi-dation in human dermal fibroblasts in

vitro: a new dressing concept. J InvestDermatol 2001;116:833-9.

Zamboni P, Tognazzo S, Izzo M, et a l.Hemochromatosis C282Y gene mutationincreases the risk of venous leg ulceration.

J Vasc Surg 2005;42:309-14.

84.

85.

86.

87.

88.

89.

90.

91.

Ibegbuna V, Delis KT, Nicolaides AN,Aina O. Effect of elast ic compression stock-ings on venous hemodynamics during

walking. J Vasc Surg 2003;37:420-5.Motykie GD, Caprini JA, Arcelus JI,

Reyna JJ, Overom E, Mokhtee D. Evalua-tion of therapeutic compression stock-ings in the treatment of chronic venousinsufficiency. Dermatol Surg 1999;25:116-20.

Andreozzi GM, Cordova R, ScomparinMA, Martini R, DEri A, Andreozzi F. Ef-fects of elastic stocking on quality of lifeof patients with chronic venous insuffi-ciency: an Italian pilot study on TrivenetoRegion. Int Angiol 2005;24:325-9.

Barwell JR, Davies CE, Deacon J, et al.Comparison of surgery and compression

with compression alone in chronic venousulceration (ESCHAR study): randomisedcontrolled trial. Lancet 2004;363:1854-9.

Tenbrook JA Jr, Iafrati MD, ODonnellTF Jr, et al. Systematic review of outcomesafter surgical management of venous dis-ease incorporating subfascial endoscopicperforator surgery. J Vasc Surg 2004;39:583-9.

Boisseau MR. Pharmacologie des mdi-caments veinotoniques: donnes actuellessur leur mode daction et les cibles thra-peutiques. Angeiologie 2000;52:71-7.

Eberhardt RT, Raffetto JD. Chronic ve-nous insufficiency. Circulation 2005;111:2398-409.

Takase S, Delano FA, Lerond L, BerganJJ, Schmid-Schnbein GW. Inf lammationin chronic venous insufficiency: is theproblem insurmountable? J Vasc Res 1999;36:Suppl 1:3-10.

Nicolaides AN. From symptoms to legedema: efficacy of Daflon 500 mg. Angi-ology 2003;54:Suppl 1:S33-S44.Copyright 2006 Massachusetts Medical Society.

92.

93.

94.

95.

96.

97.

98.

99.

100.

CLINICALTRIALREGISTRATION

TheJournalencourages investigators to register their clinical trialsin a public trials registry. The members of the International Committeeof Medical Journal Editors plan to consider clinical trials for publicationonly if they have been registered (see N Engl J Med 2004;351:1250-1).

The National Library of Medicines www.clinicaltrials.gov is a free registry,open to all investigators, that meets the committees requirements.

Downloaded from www nejm org on August 3 2006 Copyright 2006 Massachusetts Medical Society All rights reserved

Enf. Venosa Crónica

Documents

Transcript of Enf. Venosa Crónica