The Venous Valve and Primary Chronic Venous

Transcription

I S S U E
95
Medicographia
Vol 30, No. 2, 2008
ISSN 0243-3397
T he V enous V alve and
P rimary C hronic V enous D isease
J. BERGAN, USA
EDITORIAL
VENOUS VALVE INCOMPETENCE: THE FIRST CULPRIT
87
IN THE PATHOPHYSIOLOGY OF PRIMARY CHRONIC
VENOUS INSUFFICIENCY. INSUFFISANCE VALVULAIRE
VEINEUSE : PREMIER CHAÎNON DANS LA GÉNÈSE DE
LA MALADIE VEINEUSE CHRONIQUE PRIMAIRE
F. LURIE, USA
THE FUNCTIONING OF VENOUS VALVES IN NORMAL
95
AND PATHOLOGICAL CONDITIONS
A. CAGGIATI, ITALY
EMBRYOLOGY AND DISTRIBUTION OF LOWER LIMB
100
VENOUS VALVES IN HUMANS
M. SCHADECK, FRANCE
VENOUS VALVE INCOMPETENCE AND REFLUX IN
106
CHILDHOOD
L. TESSARI AND
M. CAPPELLI, ITALY
THE STUDY OF THE SAPHENOFEMORAL JUNCTION
112
TO UNDERSTAND THE DISTRIBUTION OF REFLUXES
IN CHRONIC VENOUS DISEASE
A journal of
medical information
and international
communication
from Servier
F. FERRARA AND
M. MIDIRI, ITALY
IMAGING OF VENOUS VALVES: B-FLOW
116
G. W. SCHMIDSCHÖNBEIN, USA
TRIGGERING MECHANISMS OF VENOUS VALVE
121
M. A. PISTORIUS,
FRANCE
VENOUS VALVE INCOMPETENCE: THE ROLE OF
A. JAWIEN, POLAND
TREATMENT OF VENOUS VALVE INCOMPETENCE: PAST,
CURRENT, AND FUTURE. A REFLECTION ON ITS EVOLU-
INCOMPETENCE
127
GENETIC FACTORS
131
TION IN COMPARISON WITH PEPTIC ULCER DISEASE
Contents continued overleaf...
Medicographia
Vol 30, No. 2, 2008
I S S U E
95
...Contents continued from cover page
T he V enous V alve and
P rimary C hronic V enous D isease
P. PAI, INDIA /
CONTROVERSIAL QUESTION
A. S. SABBOUR, EGYPT /
THE SAPHENOFEMORAL JUNCTION: TO LIGATE
A. MANSILHA, PORTUGAL / OR NOT TO LIGATE?
P. PITTALUGA AND
S. CHASTANET, FRANCE /
A. MASEGOSA, SPAIN /
A. OBERMAYER, AUSTRIA /
K. L. KATSENIS, GREECE /
L. VEVERKOVA, CZECH
REPUBLIC / A. K. BOZKURT,
TURKEY / C. E. VIRGINIMAGALHÃES, BRAZIL
F. PITSCH, FRANCE
DAFLON 500 MG
DAFLON 500 MG: PROTECTIVE AGAINST VENOUS
137
149
VALVE FAILURE
G. T. JONES,
NEW ZEALAND
INTERVIEW
ANIMAL MODELS IN CHRONIC VENOUS DISEASE
154
N. LABROPOULOS, USA
FOCUS
CUT POINT ON NORMAL AND PATHOLOGICAL VALUES
157
OF REFLUX
M. R. PERRIN,
FRANCE
C. RÉGNIER,
FRANCE
I. SPAAK, FRANCE
UPDATE
VENOUS VALVE DYSFUNCTION RESTORATION BY
163
SURGERY IN PRIMARY CHRONIC VENOUS DISEASE
A TOUCH OF FRANCE
THE SCIENCES UNDER LOUIS XVI. A KING TORN
169
BETWEEN ENLIGHTENMENT AND REVOLUTION
A TOUCH OF FRANCE
MARIE-ANTOINETTE, QUEEN OF FRANCE, QUEEN
OF STYLE
179
E
D I T O R I A L
Venous valve incompetence:
the first culprit in the pathophysiology
of primary chronic venous insufficiency
by J. Bergan, USA
C
John BERGAN, MD
The Vein Institute of La Jolla
Department of Surgery
UCSD School of Medicine
La Jolla, CA, USA
HRONIC VENOUS INSUFFICIENCY (CVI) IS MANIFESTED IN THE
lower extremities. Its most obvious sign is protuberant, saccular
varicose veins. These fail to fulfill their assigned function of transporting blood from the lower extremities to the heart. Instead, they
allow the weight of the column of blood from the right atrium as it is transmitted through the
valveless vena cava and iliac veins to be expressed in the thigh and leg. There, the venous hypertension initiates a cascade of inflammatory reactions that may progress to edema, venous eczema,
ankle skin hyperpigmentation, atrophie blanche, and other manifestations such as lipodermatosclerosis and venous leg ulcers.
Recently, considerable progress has been made in understanding the pathophysiological processes at the cellular and molecular level that cause these diverse manifestations. These may become targets for preventative pharmacologic intervention. If so, there will be a change in focus
from ablation to preservation. The goal of this editorial is to explain how the processes of venous
insufficiency begin because of initial venous valve failure and how they are perpetuated by that
valve failure.
Venous hypertension
In spite of the diversity of signs and symptoms associated with CVI, it is likely that they are all
related to venous hypertension. Venous hypertension involves reflux through incompetent
valves.1,2 Pressure in the veins of the leg is determined by two components, a hydrostatic component, described above, and a hydrodynamic component related to pressure generated by contraction of the skeletal muscles of the leg that is transmitted to the venular capillary network. Both
components are profoundly modified by the action of the venous valves. During standing without skeletal muscle activity, venous pressures in the leg are determined by the hydrostatic component and capillary flow. Skeletal muscle contractions, as during ambulation or exercise, increase pressure within the deep leg veins. Competent venous valves ensure that the resulting
blood flow is toward the heart, leading to emptying of the deep and superficial venous systems
and a fall in venous pressure. Even quite small leg movements can provide significant pumping
action. However, in the absence of competent valves, venous pressure fails to fall with leg movements, and the pressures generated by muscle contraction are transmitted to the skin microcirculation. Skin changes in CVI stem from venous pressures in the leg that reach higher than
normal levels and are elevated for abnormally prolonged periods of time.
Address for correspondence:
John Bergan, MD,
9850 Genesee, Suite 410,
La Jolla, CA 92037, USA
(e-mail: jbergan@ucsd.edu)
Medicographia.
2008;30:87-94.
Valvular incompetence
Venous valve incompetence is a central feature of venous hypertension that in turn underlies most
of the signs characteristic of chronic venous disease (CVD). Alterations and damage to valves have
been noted angioscopically. These include stretching, splitting, tearing, thinning, and adhesion
of valve leaflets.3 Reduction in the number of valves has been observed in segments of saphenous
veins from patients with CVI.4
Venous valve incompetence and primary chronic venous insufficiency – Bergan
MEDICOGRAPHIA, VOL 30, No. 2, 2008 87
EDITORIAL
These observations do not reveal the mechanism of valvular disappearance or how such remodeling fits into the pathophysiological sequence of events in CVD. However, an important step
forward came when we examined valves from great saphenous veins removed from patients with
CVD.5 Using a monoclonal antibody specific for monocytes and tissue macrophages, we found
infiltration of valve leaflets and the venous wall by monocytes and macrophages in all vein specimens from CVD patients and in none from controls with normal veins. Infiltration was greater
in the valve sinus and proximal venous wall than in the distal aspect of the valve leaflet and distal vein wall (Figure 1A). This suggested a link with elevated venous pressure. Further investigations have shown that inflammation and subsequent remodeling of the venous valves and wall
are the fundamental mechanisms underlying valve damage and the lesions seen angioscopically.6
Figure 1. A. A normal
venous valve is remarkably
adapted to its function of
allowing blood transport
proximally and halting
blood flow in a distal direction. Note the vein wall and
its enclosed valve sinus.
B. Venous hypertension is
responsible for initiating the
inflammatory reaction that
results in vein wall weakening, elongation, and dilation. Also, such hypertension triggers the inflammatory reaction that causes
valve damage and eventual
disappearance of the valve.
Molecular mechanisms
Hemodynamic forces, such as blood pressure changes
in the wall and sheer stress, as well as varying planes
of laminar and turbulent flow, induce activation of
the leukocytes and endothelial cells. Integrins appear
to act as intermediaries, and expression of adhesion
molecules has been observed. Breakdown of the extracellular matrix of the media and adventitia through
activation of matrix metalloproteases (MMPs) has
been observed. In particular, expression of MMP-1,
MMP-2, MMP-9, and tissue inhibitors of metalloproteinase (TIMP) have been studied. Telangiectasias,
reticular veins, and true varicose veins appear to be a
consequence of the changes induced by venous hypertension and sheer stress (Figure 1B). As described
A
B
above, when saphenous vein valves are observed angioscopically at the time of vein stripping, they show
severe deformities. The animal model of induced venous hypertension that we have worked
with demonstrates early venous valve changes that replicate those observed in humans.
This observation provides a link from venous hypertension to an induced inflammatory reaction that stimulates the valve damage. Thus the model has been useful for defining the fundamental mechanisms that cause venous valve failure and varicose veins. In the future it may
prove useful in pharmacologic testing to identify agents that will be useful to prevent or treat venous insufficiency.
Primary venous insufficiency
A dysfunctional venous system is caused for the main part by functional failure of venous valves.
The molecular mechanisms uncovered recently that enter into functional valve failure are mentioned above. Other factors are traditionally cited as contributing to venous valve failure; these
include female sex, pregnancy, obesity, a standing occupation in women,7 and heredity.8,9 An increase in vein diameter is one cause of valve dysfunction and reflux. Progesterone inhibits smooth
muscle contraction. This is useful in preventing uterine contraction and spontaneous abortion
in pregnancy. However, preventing vein wall smooth muscle contraction allows passive dilation
of veins and when a critical diameter is reached, a functioning venous valve becomes dysfunctional or incompetent. As half of a women’s adult lifetime is under the influence of progesterone,
and this is exacerbated markedly during pregnancy, it is no wonder that primary venous insufficiency is twice as common in women than in men.7
The effect of persistent valvular reflux is a chronic increase in distal venous pressure. This venous pressure increases as one proceeds from the inguinal ligament past the knee to the ankle.
The prolonged venous hypertension initiates a cascade of pathologic events. These manifest
themselves clinically as lower extremity edema, pain, itching, skin discoloration, and ulceration.10
The earliest signs of venous insufficiency are often varicose veins in the epidermis and dermis,
and these are called telangiectasias (Figure 2). Slightly deeper, are flat, blue-green veins of the
reticular (network) system. These may become varicose as well. Finally, deeper yet, are the varicose veins themselves. All of these abnormal veins and venules have one thing in common: they
are elongated, tortuous, and have dysfunctional venous valves.
Manifestations of telangiectasias, reticular varicosities, and varicose veins are grouped together under the term primary venous insufficiency.
88 MEDICOGRAPHIA, VOL 30, No. 2, 2008
EDITORIAL
Chronic venous insufficiency
Skin changes of hyperpigmentation, scarring from
previous ulceration, and active ulcerations are
Telangiectasia
grouped together under the term CVI. Numerous
theories have been postulated regarding the cause
Dermis
of CVI and that of venous ulceration.10,11
Reticular vein
Varicose
Some theories proposed in the last century
Perforating
tributary
vein
have shown remarkable prescience. An example
Superficial
is the theory of venous stasis first published in a
fascia
manuscript by John Homans of Harvard in 1917.12
Perforating
It was a treatise on diagnosis and management of
vein
patients with CVI, and in it, Dr Homans coined
Deep fascia
the term “postphlebitic syndrome” to describe the
Deep vein
skin changes of CVI. He stated that, “Overstretching of the vein walls and destruction of the
valves… interferes with the nutrition of the skin…
Figure 2. This diagram, drawn courtesy of George Somjen of
therefore, skin which is bathed under pressure Victoria, Australia, shows the intimate relationships of telangwith stagnant venous blood will form permanent iectasias, reticular veins, varicose tributary veins, and direct and
perforating veins. Note how venous hypertension in any
open sores or ulcers.” That he called attention to indirect
segment affects related segments. LSV, long saphenous vein.
destruction of valves was remarkable. However,
that statement, like many others that describe venous conditions and their treatments, is steeped
in dogma, and apart from the description of damaged valves, is short on observational fact. Actually, it is unlikely that Homans observed valve damage as we know it in primary venous insufficiency. He may have seen the ravages of the phlebitic valve destruction with adherence of
leaflets to one another and to the vein wall. The term stasis ulcer honors that misconception, as
do the terms venous stasis disease and stasis dermatitis.
Alfred Blalock, who later developed pericardiac surgery, disproved the theory of stagnant
blood by studying oxygen content from varicose veins and normal veins.13 He pointed out that
the oxygen content of the femoral vein in patients with severe CVI was greater than the oxygen
content of the contralateral nonaffected limb. Because oxygen content was higher, some investigators thought that arteriovenous fistulas caused venous stasis and varicose veins. That theory,
though disproved, has some basis in fact, since
the entire thermoregulatory apparatus in limbs
Nerve
depends on the opening and closing of arterial
Lymphatic
venous shunts (Figure 3). These shunts are important, as they explain some terrible accidents
Capillary
that happen during sclerotherapy when sclerosant
entering a vein is shunted into the arterial sysPrecapillary
tem and distributed in its normal arborization.14
sphincter
Microsphere investigations have failed to show
Arteriole
such shunting, and the theory of arteriovenous
communications has died despite the fact that
Venule
these shunts actually exist and do open and close
under the influence of venous hypertension and
ambient temperature.
Hypoxia and its part in causation of CVI were
Thermoregulatory
investigated throughout the last 25 years of the
A-V shunt
20th century. English investigators thought that
a fibrin cuff, observed histologically, blocked
transport of oxygen and was responsible for skin Figure 3. This diagram illustrates the close relationships between
changes in CVI at the ankles and distally.10 That arterioles, capillaries, venules, veins, and adjacent nerves.
A-V shunting is easy to imagine, as is the effect of dilated venous
theory has been abandoned.
varicosities on adjacent nerves.
There are two elements that interact to cause
all of the manifestations of lower extremity severe CVI. These are failure of the vein valves, the
first culprit, and subsequently the skin changes of hyperpigmentation, atrophie blanche, and
skin ulceration at the ankles. Both of these are related to venous hypertension. Our work suggests that venous hypertension causes a shear stress–dependent leukocyte-endothelial interaction, which has all of the manifestations of chronic inflammation.15 These are leukocyte rolling,
firm adhesion to endothelium, and subsequent migration of the cells through the endothelial
EDITORIAL
barrier into parenchyma of valves and vein walls.16 There, macrophages elaborate MMPs, which
destroy elastin and possibly collagen as well. Vein walls become stretched and elongated. Vein
valves become perforated, torn, and even scarred to the point of near total absence. These changes
are seen both macroscopically and angioscopically15 and have been produced experimentally by
constructing an arteriovenous fistula.
The second manifestation of CVI is expressed in the skin. There, leukocytes are also responsible for the observed changes. Skin biopsies showed that in liposclerotic eczematous skin,
macrophages and lymphocytes were predominant.17 Infiltration of leukocytes into the extracellular space has been documented by observing the localization of these leukocytes around
capillaries and postcapillary venules. Accompanying the leukocytes is a disorganized collagen
deposition. Clearly, CVI of the skin and its subcutaneous tissues is a disease of chronic inflammation, again, dependent upon venous hypertension. The injury involves extravasation of macromolecules and red blood cells into the dermal interstitium. Red blood cell degradation products
and interstitial protein extravasations are potent chemoattractants and represent the initial
chronic inflammatory signal responsible for leukocyte recruitment.18 As indicated, these follow
valve failure, the first culprit in primary and secondary venous insufficiency.
Conclusions
The processes of valve and vein wall damage and the advanced skin changes of CVI are the result
of sterile inflammatory reactions. Valve failure is triggered by venous hypertension and, in turn,
causes distal venous hypertension. Therefore, future therapy must be directed at preventing such
venous hypertension by preventing valve failure. REFERENCES
1. Labropoulos N. Hemodynamic changes according to the CEAP
classification. Phlebolymphology. 2003;40:130-136.
2. Kistner RL, Eklof B, Masuda EM. Diagnosis of chronic venous
disease of the lower extremities: “CEAP” classification. Mayo Clin
Proc. 1996;71:338-345.
3. Van Cleef JF, Hugentobler JP, Desvaux P, Griton P, Cloarec M.
Étude endoscopique des reflux valvulaires saphéniens. J Mal Vasc.
1992;17(suppl B):113-116.
4. Sales CM, Rosenthal D, Petrillo KA, et al. The valvular apparatus in venous insufficiency: a problem of quantity? Ann Vasc
Surg. 1998;12:153-155.
5. Ono T, Bergan JJ, Schmid-Schönbein GW, Takase S. Monocyte
infiltration into venous valves. J Vasc Surg. 1998;27:158-166.
6. Pascarella L, Schmid-Schonbein GW, Bergan J. An animal
model of venous hypertension: the role of inflammation in venous valve failure. J Vasc Surg. 2005;41:303-311.
7. Criqui M, Denenberg JO, Bergan JJ, Langer RD, Fronek A. Risk
factors for chronic venous disease: the San Diego population
study. J Vasc Surg. 2007;46:551-337.
8. Mellor RH, Brice G, Stanton AW, et al; Lymphoedema Research
Consortium. Mutations in FOXC2 are strongly associated with
primary valve failure in veins of the lower limb. Circulation. 2007;
115:1912-1920.
9. Saiki S, Sakai K, Saiki M, et al. Varicose veins associated with
CADASIL result from a novel mutation in the Notch3 gene. Neurology. 2006;67:337-339.
10. Browse NL, Burnand KG. The cause of venous ulceration.
Lancet. 1982;320:243-245.
11. Coleridge Smith PD. Treatment of microcirculation disorders
in venous leg ulcer. In: Messmer K, ed. Microcirculation in Chronic Venous Insufficiency. Basel, Switzerland: Karger Publishers;
2001:1-10.
12. Homans J. The aetiology and treatment of venous ulcers of
the leg. Surg Gynec Obst. 1917;24:300-311.
13. Blalock A. Oxygen content of blood in patients with varicose
veins. Arch Surg. 1929;19:898-904.
14. Bergan JJ, Weiss RA, Goldman MP. Extensive tissue necrosis
following high-concentration sclerotherapy for varicose veins.
Dermatol Surg. 2000;26:535-542.
15. Schmid-Schönbein GW, Takase S, Bergan JJ. New advances in
understanding the pathophysiology of chronic venous insufficiency. Angiology. 2001;52(suppl 1):S27-S34.
16. Takase S, Lerond L, Bergan JJ, Schmid-Schönbein GW. The
inflammatory reaction during venous hypertension in the rat.
Microcirculation. 2000;7:41-52.
17. Wilkerson LS, Bunker C, Edward JCW, Scurr JH, Coleridge
Smith PD. Leukocutes: their role in the etiopathogenesis of skin
damage in venous disease. J Vasc Surg. 1993;27:669-675.
18. Hoshino S, Satokawa H, Ono T, Igari T. Surgical treatment
for varicose veins of the legs using intraoperative angioscopy. In:
Raymond-Martimbeau P, Prescott R, Zummo M, eds. Phlebologie 92. Paris, France: John Libbey Eurotext; 1992:1083-1085.
Keywords: venous valve incompetence; venous hypertension; venous insufficiency; molecular
mechanisms; inflammation
ÉDITORIAL
Insuffisance valvulaire veineuse :
premier chaînon dans la
génèse de la maladie veineuse
chronique primaire
par J. Bergan, États-Unis
’
L
INSUFFISANCE VEINEUSE CHRONIQUE (IVC) SE MANIFESTE
dans les membres inférieurs. Son signe le plus évident est la présence de veines variqueuses saillantes et sacciformes. Ces veines
n’arrivent pas à remplir leur fonction, qui consiste à transporter
le sang des membres inférieurs vers le cœur. Au lieu de cela, elles permettent au poids de la colonne de sang provenant de l’oreillette droite par l’intermédiaire de la veine cave et des veines
iliaques sans valvules de se manifester dans la cuisse et la jambe. Là, l’hypertension veineuse
amorce une cascade de réactions inflammatoires susceptibles de progresser vers un œdème, un
eczéma veineux, une hyperpigmentation cutanée de la cheville, une atrophie blanche et d’autres
manifestations telles qu’une lipodermatosclérose et des ulcères veineux de jambes.
Ces derniers temps, des progrès considérables ont été faits dans la compréhension des processus physiopathologiques à l’origine de ces diverses manifestations aux niveaux cellulaire et
moléculaire. Ces processus sont susceptibles de devenir les cibles d’une intervention pharmacologique préventive faisant glisser le traitement de l’ablation à la conservation. L’objectif de
cet éditorial est d’expliquer comment l’insuffisance veineuse enclenche et entretient une insuffisance valvulaire veineuse initiale.
Hypertension veineuse
Il est probable que tous les signes et symptômes associés à l’IVC soient liés à l’hypertension veineuse. L’hypertension veineuse implique un reflux dû à une insuffisance valvulaire 1,2. La pression dans les veines de la jambe est déterminée par deux composantes, une composante hydrostatique, décrite ci-dessus, et une composante hydrodynamique en rapport avec la pression
générée par la contraction des muscles squelettiques de la jambe et transmise jusqu’au réseau
capillaire (formé de veinules). Ces deux composantes sont profondément modifiées par l’action
des valvules veineuses. En position debout sans activité des muscles squelettiques, les pressions
veineuses de la jambe sont déterminées par la composante hydrostatique et le débit capillaire.
Les contractions des muscles squelettiques, telles qu’elles existent pendant la marche ou l’exercice, augmentent la pression à l’intérieur des veines profondes de la jambe. L’étanchéité des valvules veineuses garantit que le flux sanguin qui en résulte est dirigé vers le cœur, ce qui conduit
à la vidange des systèmes veineux profond et superficiel et à une chute de la pression veineuse.
Même des mouvements de jambe relativement petits peuvent faire fonctionner la pompe de
façon significative.
Cependant, en l’absence de valvules étanches, la pression veineuse ne chute pas avec les
mouvements de la jambe et les pressions générées par la contraction musculaire sont transmises
à la microcirculation cutanée. Les changements cutanés de l’IVC sont dus aux pressions veineuses de la jambe, qui atteignent des niveaux supérieurs à la normale et restent élevés pendant
des durées anormalement prolongées.
Insuffisance valvulaire veineuse et maladie veineuse chronique primaire – Bergan
ÉDITORIAL
Insuffisance veineuse
L’insuffisance valvulaire veineuse est une caractéristique centrale de l’hypertension veineuse
qui, à son tour, est une cause sous-jacente de la plupart des signes caractéristiques de la maladie veineuse chronique (MVC). Des modifications et des lésions des valvules ont été observées par
angioscopie. Celles-ci incluent l’étirement, la rupture, la déchirure, l’amincissement et l’adhérence des valvules 3. Une réduction du nombre des valves a été observée dans des segments de
veines saphènes de patients présentant une insuffisance veineuse chronique 4.
Ces observations n’expliquent pas comment les valves disparaissent ni comment ce remodelage s’intègre dans l’enchaînement des événements qui aboutissent à la MVC. Cependant,
un pas important a été fait lorsque nous 5 avons examiné les valvules des grands veines saphènes retirées de patients atteints de MVC. En nous servant d’un anticorps monoclonal spécifique pour les monocytes et les macrophages tissulaires, nous avons trouvé une infiltration
des valves des valvules et de la paroi veineuse par des monocytes et des macrophages dans tous
les échantillons de veines provenant de patients atteints de MVC, alors qu’aucune n’a été retrouvée dans les échantillons des témoins avec des veines normales. L’infiltration était plus importante dans le sinus valvulaire et la paroi veineuse proximale que dans le côté distal de la valve
de la valvule et la paroi veineuse distale (Figure 1A). Cette découverte nous a fait envisager
l’existence d’un lien avec une pression veineuse élevée. D’autres recherches ont fait apparaître
l’inflammation et le remodelage ultérieur des valvules veineuses et de la paroi veineuse comme
les mécanismes fondamentaux sous-jacents à l’atteinte et aux lésions valvulaires observées
par angioscopie 6.
Figure 1. A. Une valvule du
sinus veineux normale est
remarquablement bien
adaptée à sa fonction, qui
consiste à permettre le
transport du sang à proximité et à arrêter le flux sanguin en direction distale.
Remarquez la paroi veineuse
et le sinus valvulaire qu’elle
entoure. B. L’hypertension
veineuse est responsable de
l’amorce de la réaction inflammatoire qui se traduit par un
affaiblissement, un allongement et une dilatation de la
paroi veineuse. En outre,
cette hypertension déclenche
la réaction inflammatoire à
l’origine de l’atteinte valv
laire et de la disparition
ultérieure de la valvule.
Mécanismes moléculaires
Des forces hémodynamiques, telles que des changements de la pression sanguine dans la paroi et la
contrainte de cisaillement, ainsi que des plans changeants d’écoulement laminaire et turbulent, induisent l’activation des leucocytes et des cellules endothéliales. Les intégrines semblent agir comme des
intermédiaires et l’expression de molécules d’adhésion a été observée. Une dégradation de la matrice
extracellulaire de la média et de l’adventice au travers de l’activation des métalloprotéases matricielles
(MMPs) a été observée. En particulier, les expressions
des MMP-1, MMP-2, MMP-9 et des inhibiteurs tissulaires des métalloprotéinases (TIMP) ont été étudiée.
Les télangiectasies, les veines réticulaires et les véA
B
ritables varices semblent être une conséquence des
changements induits par l’hypertension veineuse et
par la contrainte de cisaillement (Figure 1B). Comme indiqué ci-dessus, l’observation angioscopique des valvules des veines saphènes lors de l’éveinage des veines a fait apparaître les sévères
déformations décrites. Le modèle animal de l’hypertension veineuse induite sur lequel nous avons
travaillé démontre des changements précoces dans les valvules veineuses qui reproduisent ceux
observés chez les humains.
Cette observation lie l’hypertension veineuse et la réaction inflammatoire induite qui stimule l’atteinte valvulaire. Par conséquent, le modèle s’est révélé utile pour définir les mécanismes fondamentaux à l’origine de l’insuffisance valvulaire veineuse et des varices. À l’avenir,
il pourrait se révéler utile lors des essais pharmacologiques pour identifier les agents susceptibles d’être efficaces dans la prévention ou le traitement de l’insuffisance veineuse.
Insuffisance veineuse primaire
Le dysfonctionnement du système veineux est principalement provoqué par l’insuffisance fonctionnelle des valvules veineuses. Les mécanismes moléculaires, récemment découverts, qui entrent dans l’insuffisance valvulaire fonctionnelle sont mentionnés ci-dessus. Les autres facteurs
traditionnellement cités comme contribuant à l’insuffisance valvulaire veineuse incluent le sexe
féminin, la grossesse, l’obésité, un métier pratiqué en position debout chez les femmes 7 et l’hérédité 8,9. Une augmentation du diamètre de la veine représente une cause de dysfonction et de
reflux valvulaires. La progestérone inhibe la contraction des muscles lisses. Elle est utile dans
la prévention des contractions utérines et de l’avortement spontané au cours de la grossesse.
ÉDITORIAL
Toutefois, l’obstacle à la contraction des muscles
lisses de la paroi veineuse entraîne une dilatation
passive des veines et, lorsqu’un diamètre critique
Télangiectasie
est atteint, une valvule veineuse jusqu’alors fonctionnelle présente un dysfonctionnement ou une
Derme
insuffisance. Dans la mesure où la moitié de la vie
Veine réticulaire
Veine
collatérale
adulte des femmes est sous l’influence de la provariqueuse
Veine perforante
gestérone et où celle-ci est fortement exacerbée
Aponévrose
pendant la grossesse, on ne s’étonnera pas que
superficielle
l’insuffisance veineuse primaire soit deux fois plus
7
Veine
fréquente chez les femmes que chez les hommes .
Aponévrose
perforante
Le reflux valvulaire persistant entraîne une
profonde
augmentation chronique de la pression veineuse
Veine profonde
distale. Cette pression veineuse augmente à mesure que l’on passe du pilier du canal inguinal à
la cheville, en passant par le genou. L’hyperten2. Ce schéma, dessiné par George Somjen de Victoria
sion veineuse prolongée amorce une cascade Figure
(Australie), montre les relations étroites entre les télangiectasies,
d’événements pathologiques. Ces événements se les veines réticulaires, les veines collatérales variqueuses et les
manifestent cliniquement sous forme d’œdèmes, veines perforantes directes et indirectes. Remarquez comment
veineuse de n’importe quel segment touche les
de douleurs, de démangeaisons, de décoloration l’hypertension
segments
en
rapport.
cutanée et d’ulcération des membres inférieurs. 10
Les premiers signes de l’insuffisance veineuse sont souvent l’apparition de varices dans l’épiderme et le derme, ces dernières étant appelées télangiectasies (Figure 2). Un peu plus profondément, on trouve les veines bleu-vert plates du système (réseau) réticulaire. Ces veines sont également susceptibles de devenir variqueuses. Enfin, encore plus profond, on trouve les varices
elles-mêmes. Toutes ces veines et veinules anormales ont un point commun : elles sont allongées, sinueuses et présentent un dysfonctionnement des valvules veineuses.
Les manifestations des télangiectasies, les varicosités réticulaires et les varices sont regroupées sous le même terme d’insuffisance veineuse primaire.
Insuffisance veineuse chronique
Les changements cutanés liés à l’hyperpigmentation, les cicatrices dues à une ulcération antérieure et les ulcérations actives sont regroupés sous le même terme d’insuffisance veineuse
chronique (IVC). De nombreuses théories ont été avancées sur la cause de l’insuffisance veineuse
chronique et des ulcères veineux 10,11.
Certaines des théories proposées au siècle dernier ont fait preuve d’une remarquable prescience. À titre d’exemple, la théorie de la stase veineuse, publiée pour la première fois dans un
manuscrit de John Homans, de Harvard, en 1917 12. Il s’agissait d’un traité portant sur le diagnostic et la prise en charge de patients présentant une insuffisance veineuse chronique, dans
lequel le Dr Homans a inventé le terme de « syndrome post-phlébitique » pour décrire les
changements cutanés de l’IVC. Il affirmait alors que « L’étirement excessif des parois veineuses
et la destruction des valvules… interfèrent avec la nutrition de la peau… par conséquent, la
peau soumise à un bain sous pression avec du sang veineux stagnant forme des plaies ouvertes
permanentes ou des ulcères ». Le fait d’avoir attiré l’attention sur la destruction des valvules
était remarquable. Cependant, cette affirmation, comme de nombreuses autres qui décrivent
les pathologies veineuses et leurs traitements, relève du dogme et, à l’exception de la description de l’atteinte des valvules, manque de faits d’observation. En fait, il est peu probable que
Homans ait observé les atteintes valvulaires telles que nous les connaissons dans l’insuffisance
veineuse primaire. Il est possible qu’il ait vu les ravages de la destruction valvulaire phlébitique avec adhérence des valves l’une sur l’autre et sur la paroi veineuse. Le terme d’ulcère de
stase fait honneur à cette idée fausse, tout comme les termes de maladie de stase veineuse et de
dermite de stase.
Alfred Blalock, qui, plus tard, a développé la chirurgie péricardiaque, a contesté la théorie
du sang stagnant en étudiant la teneur en oxygène des varices et des veines normales 13. Il a
notamment fait remarquer que la teneur en oxygène de la veine fémorale des patients présentant une insuffisance veineuse chronique sévère était supérieure à la teneur en oxygène du
membre opposé non atteint. La teneur en oxygène étant plus élevée, certains investigateurs ont
pensé que les fistules artérioveineuses pouvaient être à l’origine de la stase veineuse et des varices. Cette théorie, bien que réfutée, n’est pas dénuée de fondement, dans la mesure où l’intéInsuffisance valvulaire veineuse et maladie veineuse chronique primaire – Bergan
ÉDITORIAL
gralité de l’appareil thermorégulateur des membres dépend de l’ouverture et de la fermeture
de shunts artérioveineux (Figure 3). Ces shunts sont importants, dans la mesure où ils expliquent certains accidents terribles qui se produisent pendant les injections sclérosantes lorsque
le produit sclérosant qui pénètre dans une veine est dérivé dans le système artériel et distribué
dans sa ramification normale 14. Des études sur microsphères n’ont pas permis de mettre en
évidence une telle dérivation et la théorie des communications artérioveineuses a été abandonnée bien que ces shunts existent réellement et
qu’ils s’ouvrent et se ferment sous l’influence de l’hyNerf
pertension veineuse et de la température ambiante.
Lymphatique
L’hypoxie et le rôle qu’elle joue dans la causalité
de l’insuffisance veineuse chronique ont été étudiés
Capillaire
pendant les 25 dernières années du XX e siècle. Des
chercheurs anglais ont pensé qu’un manchon de fiSphincter
brine, observé histologiquement, bloquait le transprécapillaire
port de l’oxygène et était responsable des changeArtériole
ments cutanés de l’IVC aux chevilles et à distance 10.
Cette théorie a été abandonnée.
Veinule
Toutes les manifestations de l’IVC sévère des
membres inférieurs sont provoquées par l’interaction
de deux éléments. Ces éléments sont l’insuffisance
des valvules veineuses, le principal coupable, et plus
Shunt A-V
tard, les changements cutanés entraînés par l’hyperthermorégulateur
pigmentation, l’atrophie blanche et l’ulcération cutanée des chevilles. Tous deux sont liés à l’hypertension veineuse. Notre travail nous autorise à penser
Figure 3. Ce schéma illustre les relations étroites entre les artérioles, les capillaires, les veinules, les veines et les nerfs adjacents.
que l’hypertension veineuse cause une contrainte
Le shunt A-V est facile à imaginer, tout comme l’est l’effet des
de cisaillement dépendante de l’interaction leucovaricosités veineuses dilatées sur les nerfs adjacents.
cytes - cellules endothéliales, qui comporte toutes les
manifestations d’une inflammation chronique 15. Ces manifestations sont le roulement des leucocytes, une solide adhérence à l’endothélium et la migration ultérieure des cellules à travers
la barrière endothéliale jusqu’au parenchyme des parois des valvules et des veines 16. Là, les macrophages élaborent les métalloprotéases matricielles, qui détruisent l’élastine et peut-être
également le collagène. Les parois veineuses subissent un étirement et un allongement. Les valvules du sinus veineux présentent des perforations, des déchirures et même des cicatrices si importantes que les valvules disparaissent quasi-totalement. Ces changements s’observent aux
niveaux macroscopique et angioscopique 15 et ont été produits de façon expérimentale par la
constitution d’une fistule artérioveineuse.
La seconde manifestation de l’insuffisance veineuse chronique s’exprime dans la peau. Là,
les leucocytes sont également responsables des changements observés. Des biopsies cutanées ont
montré qu’il y avait une prédominance de macrophages et de lymphocytes dans une peau liposclérosée et eczémateuse 17. Une infiltration de leucocytes dans l’espace extracellulaire a été
établie en observant la localisation de ces leucocytes autour des veinules capillaires et post-capillaires. Les leucocytes sont accompagnés d’un dépôt de collagène désorganisé. À l’évidence,
l’insuffisance veineuse chronique de la peau et de ses tissus sous-cutanés est une pathologie inflammatoire chronique qui, rappelons-le, dépend de l’hypertension veineuse. Elle se traduit par
un épanchement de macromolécules et de globules rouges dans l’interstitium dermique. Les
produits de dégradation des globules rouges et les épanchements des protéines interstitielles sont
de puissants chimioattractifs et représentent le signal inflammatoire chronique initial responsable du recrutement des leucocytes 18. Comme indiqué, ceux-ci font suite à une insuffisance valvulaire, coupable initiale de l’insuffisance veineuse primaire et secondaire.
Conclusions
Les processus d’atteinte des parois des valvules et des veines, ainsi que les changements cutanés
avancés de l’IVC, sont la conséquence de réactions inflammatoires stériles. L’insuffisance valvulaire est déclenchée par une hypertension veineuse et, à son tour, provoque une hypertension
veineuse à distance. Par conséquent, les traitements futurs devront s’orienter vers la prévention
d’une telle hypertension veineuse, en empêchant l’insuffisance valvulaire. 94 MEDICOGRAPHIA, VOL 30, No. 2, 2008
THE VENOUS VALVE
AND
PRIMARY CHRONIC VENOUS DISEASE
Fedor LURIE, MD, PhD
John A. Burns School of Medicine
University of Hawaii
Hawaii, USA
The functioning of
venous valves in normal
and pathological conditions
b y F. L u r i e , U S A
ncreasing awareness of chronic venous disease
as a growing public health problem in an aging
population has uncovered significant gaps in our
understanding of the physiology and pathophysiology of the venous system. Among the many features
distinguishing the venous system from other vasculature, is the unique and most intriguing delicate
structure of the venous valve.
The apparent simplicity of this apparatus leaves
very little room for speculation regarding its function. Long before Harvey, the venous valve was
viewed as a passive membrane that opened and
closed the vessel’s lumen.1 An elegant and convincing demonstration of unidirectional venous flow,
first formulated in Excercitarto Anatomicae de
Motu Cordis et Sangunis in Animalibus, was an essential part of the modern understanding of the
cardiovascular system.2
I
ased on recent observations, a new concept of the mechanism of venous
valve closure and the role of valves in the circulation has been proposed.
In healthy individuals, valve geometry and pulsatile venous flow determine the mechanical forces that act on the valve’s cusps, causing their movements. Under physiological conditions, the venous valve creates a complex local flow pattern that facilitates forward movement of blood, increases the supply
of oxygenated blood to valve pockets, and causes the cyclic closure of the valve
itself, securing the pulsatile nature of venous flow. In rare circumstances of
reverse flow, valves close, securing unidirectional flow. Dysfunction of the
valve can lead to disruption of a normal flow pattern. This changes the oxygenation of valve pockets, potentially leading to thrombi formation, or causes
asymmetrical jets of reverse flow through an incompetent valve, producing shear
stress–mediated pro-inflammatory and pro-thrombotic endothelial transformations.
B
Medicographia. 2008;30:95-99.
(see French abstract on page 99)
Keywords: venous valve function; physiology; reverse flow; pathology
Address for correspondence: Prof Fedor Lurie, Clinical Professor of Surgery,
John A. Burns School of Medicine, University of Hawaii, Hawaii, USA
(e-mail: tedlurie@yahoo.com)
The functioning of venous valves in normal and pathological conditions – Lurie
The challenge to this concept came centuries later, when direct observation of valve movements and
in vivo measurement of blood flow velocity revealed
some intriguing phenomena. In 1926, E. B. Carrier
described an intricate blood flow pattern around
the venous valve leaflets, by direct observation of red
blood cell movement in the wing of the bat.3 This
was exactly the same pattern as predicted by Leonardo da Vinci, and confirmed by K. D. Kele for a
geometrically similar aortic valve.4 While the role
of this flow phenomenon in the functioning of the
aortic valve was understood, in the case of the venous valve, it was simply ignored. Carrier’s observations that venous valve leaflets do not open all the
way out to touch the sinus wall were confirmed by
in vitro experimentation with human saphenous
valves.5 These findings demonstrated the complexity of the hemodynamics around the valve that far
exceeded the simple sequence of forward and backward flow, and challenged the simplicity of the then
current concept of the physics behind the closing
of the venous valve.
Development of modern diagnostic ultrasound
techniques opened up the opportunity to detect
valvular incompetence in patients with chronic venous diseases.6 At the time of the original work in
this area, ultrasound equipment did not allow reliable visualization of the valve itself. Instead, Doppler-based registration of reverse blood flow in the
venous segment in response to Valsalva or rapid
compression-decompression maneuvers was used
to define valvular insufficiency. This approach advanced venous diagnosis by providing a reliable tool
for reflux detection that is used to this day. Unfortunately, the indirect approach also created confusion between the presence of reverse flow in the
vein and the function of the valve itself. The terms
“reflux time” and “valve closure time” were incorrectly used interchangeably. As a consequence, the
view that reverse flow through the valve is necessary for valve closure was promulgated.7
MEDICOGRAPHIA, VOL 30, No. 2, 2008
95
THE VENOUS VALVE
AND
A new generation of ultrasound equipment, particularly the introduction of B-flow modality, has
made it possible to observe venous valves and blood
flow in the area of the valve in undisturbed physiologic conditions. Artificial maneuvers to force the
blood backward to check the competency of the
valve are no longer needed for normal valve observations. One can simultaneously observe the motions of valve leaflets, changes in venous sinus shape
and size, and blood flow through the valve during
a normal respiratory cycle, in different positions of
the body and during exercises such as dorsal and
plantar flexion of the foot.
Function of the normal valve
Valve closure by reverse flow
The ability of the venous valve to close in reaction
to reverse flow or a distally directed pressure gradient has been used for the diagnosis of venous insufficiency ever since Brodie and Trendelenburg developed their simple and useful clinical test.8,9 20s
century plethysmographic techniques involved
changing the patient’s position from horizontal to
vertical to measure the refill time as an indicator
Opening phase
Closed phase
Equilibrium phase
Valve cycle
Closing phase
Figure 1.
The four phases
of the valve cycle.
96
of valvular competency. A more physiologic method
of emptying the calf veins using exercise was added
later. These techniques were not convenient for ultrasound-based investigations, however, and were
replaced by the Valsalva maneuver, compression of
the extremity proximal to the segment of interest,
or compression of the extremity distally, followed
by rapid decompression.10
Widespread use of ultrasound-based diagnostics
exposed the existence of retrograde flow in clinically healthy extremities under test conditions. To
resolve this issue, cut-off values were proposed to
differentiate pathologic reflux from physiologically
normal reverse flow.11 Surprisingly, very little attention had been paid to such an interesting phenomenon as the existence of reverse flow in veins.
The exception is a single report postulating that
unless a certain “critical” velocity of reverse flow is
reached, the valve remains open.7 Both the apparent
disagreement between these findings and the con-
cept of unidirectional flow in veins, in addition to
the alternative interpretations of Doppler-based flow
measurements were never seriously studied.
The engineering of artificial valves revived the
interest in the study of the mechanism of valve
closure. Experimental and computational models
showed that the geometry of the valve plays an important role in its function. The depth of valve pockets, for example, determines the valve competency:
deeper sinuses provide better reaction to reverse
flow. At the same time, deep sinuses increase the
chances of blood stagnation.12 A compromise is hard
to reach when artificial valves are designed, but the
variety of configurations in natural valves demonstrates that not all of them are optimized to react
to reverse flow. Interestingly, the depth of the valve
pockets has little effect on antegrade flow.
Valve closure by antegrade flow:
the valve cycle
By observing valves in femoral and great saphenous veins of healthy volunteers, we identified a
consistent pattern of flow events as the blood passes
through a valve station during rhythmic opening
and closing of the valve cusps. The flow and the
movements of the valve appear to be two parts of the
same physiologic process of the “valve cycle”— the
time period between two consecutive closures of
the valve, which we arbitrarily divided into four
phases (Figure 1).13
Opening phase
During the opening phase, the cusps move from
the closed position toward the sinus wall. This phase
lasts on average for 0.3 seconds when the patient is
in the horizontal position.
Equilibrium phase
After reaching a certain point in this phase, the
valves cease opening and enter the equilibrium
phase. During this phase, the leading edges remain
suspended in the flowing stream and undergo oscillations that resemble the flutter of flags in the wind.
The valve is maximally open during this phase. Still
cusps maintain their position at some distance from
the wall, creating a funnel-like narrowing of the lumen. The cross-sectional area between the leaflets
is about two thirds of the cross-sectional area of the
vein distal to the valve. The flow accelerates in this
stenotic area, forming a proximally-directed jet.
Upon impact of the jet against a layer of much slower-moving blood proximal to the valve, reflection of
flow occurs in the mural parts of the stream. While
the larger stream located in the center of the vessel
is directed proximally along the axis of the vein, the
smaller part of the flow turns into the sinus pocket
behind the valve cusp. This part of the stream forms
a vortex along the sinus wall and the mural side of
the valve cusp before re-emerging into the main
stream in the vein.
As vortical flow persists, it applies pressure upon
the mural surface of the valve cusps. When the pressure on the mural side of the cusp and the pressure
on the luminal side of the cusp are in equilibrium,
the valve remains open and the cusps float in the
stream. This dynamic equilibrium is sustained by an
equilibrium in the velocities of the two streams—
THE VENOUS VALVE
Figure 2. Forces acting on the
valve leaflets. Axial flow (Vaxial)
produces pressure directed toward
the sinus wall (P0), while vortex
flow inside the pocket (Vvortex)
generates pressure directed inside
the lumen (Pi). An increase in Vaxial
causes a decrease in P0, while Pi
remains unchanged. The resulting
pressure gradient moves the leaflet
toward the axis of the vein, closing
the valve.
Vvortex
Po
Pi
Vaxial
vortex on the mural side, and axial flow on the luminal side of the valve cusps. Changes in either of
these streams can lead to the closure of the valve.
Self-excited oscillations of the leading edges of the
leaflets that occur during this equilibrium phase
make this balance unstable and very sensitive to
small changes in flow.
Closing phase and closed phase
When the venous flow rate increases distal to the
valve, as occurs during foot movements, the velocity of the flow between the valve cusps rapidly increases. This causes a fall in the pressure on the luminal side of the cusp, and the cusps start moving
toward the axis of the vessel, further constricting
the lumen (Figure 2). With rising pressures on the
mural side and falling pressures on the luminal side
of the cusps, valve closure is favored. The closing
phase ensues. The leaflets move synchronously toward the center. The cusps of the valve assume a
symmetrical position at an equal distance from the
walls on both sides of the sinus. This phase lasts 0.4
seconds when the subject is at rest, and is shorter
when foot movements are performed. The last phase
is the closed phase, during which, the cusps remain
closed.
The duration of the valve cycle and each of its four
phases depends upon the position of the body. In the
standing position, we found that the duration of the
cycle was from 2.9 seconds to 3.2 seconds (95% confidence interval [CI]), which corresponds to a frequency of 18.8 to 20.4 cycles per minute (similar to
respiration frequency). In a horizontal position, the
duration of the cycle was from 1.7 seconds to 1.8
seconds (95% CI). This rhythm (34.2 to 36.1 cycles
per minute) is most likely influenced by both respiratory and cardiac cycles. Muscle activity (dorsal
and plantar flexions of the foot) causes shortening
of the closing phase. As we observed, every single
foot movement causes a significant increase in velocity and closure of the valve.
Based on our observations, we proposed a new
concept of the mechanism of venous valve closure
and the role of the valve in circulation. In the absence of forced reverse flow, the valve cusps consistently undergo the four phases constituting the
valve cycle. The local hemodynamic events, such as
vortical flow in the sinus pocket, play important
roles in the valve operation. These hemodynamic
events are predetermined by the shape and mechanical properties of the sinus and the valve cusps,
and they constitute a self-sustained mechanism for
competent valve operation.
AND
Valve functions other than prevention of reflux
The blood flow in peripheral veins is much more
complex than that in arteries and capillaries. At any
given time, it can be continuous, pulsatile, or absent. The transitions from one state to another produce even more complex fluid dynamic phenomena. The presence of valves complicates this even
further, as valves are not only moved by the flow,
but participate in flow changes. In this sense, we
can postulate that the venous valve has physiologic
functions other than securing unidirectional flow,
broadly characterized as flow modulation. Responsibility for the central role in providing this function belongs to the geometry of the valve and to the
distinct mechanical properties of leaflets, walls of
the sinus, and walls of adjoining segments.
During the opening and equilibrium phases of
the valve cycle, a proximally-directed jet forms in
the valve orifice. The shape of this orifice with fused
leaflets on both sides and gradual widening toward
the center significantly differs from a circular crosssection of adjoining venous segments. As blood
passes through the valve orifice, its velocity profile
flattens. This makes possible the formation of organized flow patterns, for example spiral flow in the
great saphenous vein where valves are positioned at
a small angle to one another, thus rotating the flow
as it passes proximally. This is more likely to happen
in segments with several closely located valves, such
as crural veins. The existence of such organized flow
patterns may conserve a significant amount of energy, facilitating venous return. As of now, this remains a theoretical construct awaiting experimental confirmation.
The flow inside the valve pocket deserves special
attention. It is essential for keeping valve leaflets
away from the venous wall, and for closing the valve.
It also provides “flushing” of the valve pocket during each valve cycle. Experiments have shown that
when this flushing does not happen regularly, the
oxygen content of the blood inside the valve pockets drops. This occurs during a period of continuous
flow. With pulsatile flow, the flushing happens regularly, and the oxygen content in valve pockets is
not different from the rest of the venous blood.14
Avascularity of the valve leaflets predisposes them
to ischemic damage, thus, prolonged time periods
of continuous flow followed by reperfusion of valve
pockets may play an important role in the formation of venous thrombi.15 This is one of the likely
explanations for the established fact that valve pockets are often the site of initial thrombus develop-
97
THE VENOUS VALVE
AND
Figure 4.
B-flow
image of
reflux jet in
a saphenous
aneurysm.
Figure 3.
B-flow image
of reflux jet
directed toward
the venous wall.
ment.16 By closing in reaction to increasing flow
velocity, venous valves interrupt continuous flow
converting it into pulsatile flow, which secures adequate oxygenation of valve pockets and prevents
formation of thrombi.
The predominant concept of venous valve physiology holds that the venous valve reacts to reverse flow
by closing, ensuring unidirectional flow in veins.
Not surprisingly, the role of the venous valve in the
development of chronic venous disease is viewed as
a simple failure to close, leading to recirculation,
venous hypertension, or both. Ceaseless discussion
of whether changes in the venous wall lead to valvular incompetence or whether valves undergo independent pathological changes, rarely, if ever, concentrates on the third possible scenario—namely,
that valvular incompetence causes changes in the
venous wall. This is despite existing evidence that
in superficial veins, varices and dilations are located distally to valves, and not proximally, as one would
expect if the hydrostatic pressure induced primary changes.17 Dilation of deep veins is much less
common, but the severity of changes in the valves
is similar.18,19
Observation of incompetent valves with B-flow
ultrasound convinced us that with the exception of
advanced valvular degeneration, the reflux is asymmetrical. Retrograde flow through incompetent
valves occurs as a jet directed toward the venous
wall. One of the two cusps remains in the normal
position, while the other cusp prolapses, directing
reflux along the lumenal surface of the “normal”
cusp (Figure 3).
This is strikingly similar to the flow pattern in
venous dilations (Figure 4), allowing the hypothesis that valvular incompetence and the resulting
retrograde jet cause changes in the distal venous
segment. The biological plausibility of this hypothesis was recently demonstrated experimentally. It
has been shown that disturbed flow, and especially
flow in the reverse direction or oscillatory flow, has
a pro-inflammatory action via its promotion of an
inflammatory endothelial phenotype. By contrast,
unidirectional flow — either continuous or pulsatile—produces shear stress that is transduced by
endothelial cells, and thus has an anti-inflammatory action.20
The role of inflammation in the development of
pathological changes in the venous wall and valve
has been known for a long time. Saphire demonstrated inflammation and leukocyte infiltration in
the venous valve, even suggesting the term “valvulitis” to describe these changes.21 A similar process at
the microcirculatory level demonstrated a relationship between abnormal flow and the development
of skin changes in chronic venous disease.22 However, the exact mechanisms of flow-mediated inflammation in veins remain unclear. Recent experimental work utilizing an animal model of increased
venous flow rate and pressure provided promising
direction in the discovery of such mechanisms. It
demonstrated that shear stress–mediated changes
in the venous wall and valves in such a model are
remarkably similar to those in humans with chronic venous disease.23
It is now becoming evident that the role of valves
in venous circulation exceeds that of a simple reaction to reverse flow. The valve’s geometry and the
mechanical properties of its components determine
a series of hemodynamic events in, and possibly
beyond, the valve’s vicinity. In disease, valvular
incompetence not only leads to recirculation and
inefficiency of the muscular pump, but promotes
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THE VENOUS VALVE
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valve closure and role of the valve in circulation: a new concept.
J Vasc Surg. 2003;38:955-961.
14. Hamer JD, Malone PC, Silver IA. The PO2 in venous valve
pockets: its possible bearing on thrombogenesis. Br J Surg. 1981;
68:166-170.
AND
15. Malone PC, Agutter PS. The aetiology of deep venous thrombosis. QJM. 2006;99:581-593.
16. Sevitt S. The structure and growth of valve-pocket thrombi in femoral veins. J Clin Pathol. 1974;27:517-528.
17. Porto LC, da Silveira PR, de Carvalho JJ, Panico MD. Connective tissue accumulation in the muscle layer in normal and
varicose saphenous veins. Angiology. 1995;46:243-249.
18. Perrin M. Reconstructive surgery for deep venous reflux: a
report on 144 cases. Cardiovasc Surg. 2000;8:246-255.
19. Hoshino S, Satakawa H, Iwaya F, Igari T, Ono T, Takase S.
External valvuloplasty under preoperative angioscopic control.
Phlebologie. 1993;46:521-529.
20. Bergan JJ, Schmid-Schônbein G, Coleridge-Smith P, Nicolaides A, Boisseau M, Eklof B. Chronic venous disease. N Engl J
Med. 2006;355:488-498.
21. Saphir O, Lev M. Venous valvulitis. AMA Arch Pathol.1952;
53:456-469.
22. Coleridge Smith PD. Deleterious effects of white cells in the
course of skin damage in CVI. Int Angiol. 2002;21(suppl 1):2632.
23. Takase S, Pascarella L, Lerond L, Bergan JJ, Schmid-Schonbein GW. Venous hypertension, inflammation and valve remodeling. Eur J Vasc Endovasc Surg. 2004;28:484-493.
LE FONCTIONNEMENT DES VALVULES
EN CONDITIONS NORMALES ET PATHOLOGIQUES
U
n nouveau concept du mécanisme de fermeture des valvules et de leur
rôle dans la circulation, fondé sur des observations récentes, a été proposé. Chez les personnes en bonne santé, la géométrie valvulaire et le
débit veineux pulsatile déterminent les forces mécaniques qui interviennent
sur les valves des valvules, provoquant leurs mouvements. En conditions physiologiques, les valvules créent un débit local complexe qui favorise un mouvement sanguin vers l’avant, augmente l’apport de sang oxygéné aux cavités valvulaires et provoque la fermeture cyclique des valvules elles-mêmes, préservant
la nature pulsatile du débit veineux. En cas de reflux, les valvules se ferment,
garantissant un débit unidirectionnel. Le dysfonctionnement d’une valvule
peut conduire à la perturbation du débit normal. Ceci modifie l’oxygénation
des cavités valvulaires, pouvant conduire à la formation de thrombi, ou provoque des jets asymétriques de reflux inverse dans une valvule incontinente,
produisant des transformations endothéliales prothrombotiques et pro-inflammatoires médiées par des contraintes de cisaillement.
99
THE VENOUS VALVE
AND
Alberto CAGGIATI, MD, PhD
Department of Anatomy
La Sapienza University
Rome, ITALY
Embryology and distribution
of lower limb venous valves
in humans
by A. Caggiati, Italy
Historical background
enous valves (VVs) were first mentioned in
1544 by the Spanish anatomist Ludovicus
Vassaeus in his De Anatomen Corporis Humani tabulae quator.1 Sylvius Ambianus (14781555) is quoted as being the first to describe the
presence of valves in the veins of the lower limbs.
The function of VVs was clearly identified in 1559 by
Andrea Cesalpino in his De Re Anatomica: “...certain membranes placed at the openings of the vessels prevent the blood from returning.” The German Salomon Alberti published the first drawings
of a VV in 1585. In 1603, Hyeronimus Fabricius ab
Aquapendente (1533-1619) published the first treatise on VVs entitled De Venarum Ostiolis. Fabricius
V
enous valves appear in the embryo after the heart begins to beat and the
primordial muscles begin to move the limb buds. The pressure gradient
along the vein triggers a five-step process of valve development. Prenatal and perinatal morphological and numerical rearrangements have been described, but they have still to be clearly demonstrated. The cusps of the venous
valves consist of thin collagen half moon–shaped folds covered by endothelium,
which spring from the wall of the vein very close to each other. The vein wall is
thicker at the base of the valve cusps, due to larger quantities of smooth muscle
cells of the media. With increasing age, the loose areolar collagen stroma of the
cusp is gradually replaced by thick and fibrous tissue. Data from different authors regarding the distribution of valves in the deep, superficial, and perforating veins of the lower limbs are summarized. Finally, valves located in the
microveins of the skin of the lower limbs are described.
V
Keywords: embryology; human venous valve; morphology; aging; microvein;
varicose disease
Address for correspondence: Alberto Caggiati, Department of Anatomy,
La Sapienza University, Rome, Italy
(e-mail: alberto.caggiati@uniroma1.it)
meticulously described VV anatomy and topography in the whole venous system. More importantly,
Fabricius described a test to evaluate VV competence (Figure 1) that led his student William Harvey
(De Motu Cordis, 1628) to discover the circulation
of the blood.2
Embryology of venous valves
Very few studies have investigated the development
of VVs in the human embryo. According to Kampmeier and Birch (1926), VVs arise from the media
of the primordial tube.3 By contrast, CzarniawskaGrzesinska and Bruska stated in 2002 that VVs originate as a “condensation” of the endothelium.4 Due
to the presence of endothelium, elastic laminae,
connective tissue, and smooth muscle cells within
the cusps, VVs actually appear to arise via differentiation of the whole intima.
In 1926, Jaeger stated that “a certain pressure
gradient along the vein” is necessary for VV development.5 This is why the development of VVs occurs
only after the heart begins to beat and the primordial muscles begin to move the limb buds. In humans, VVs arise in the peripheral veins after approximately 3 to 4 months of prenatal development.3
Kampmeier and Birch state that the earliest valves
of the lower extremity appear in the deep veins of
the femoral trigone and popliteal fossa, and in the
upper end of the great saphenous vein (GSV).3
SELECTED
ABBREVIATIONS
GSV
great saphenous vein
MVV
microscopic venous valve
PTV
preterminal valve
SFJ
saphenofemoral junction
VV
venous valve
Embryology and distribution of lower limb venous valves in humans – Caggiati
THE VENOUS VALVE
According to Kampmeier and Birch, the pressure
gradient along the vein triggers a five-step process
of valve development (Figure 2): 3 (i) thickening
of the endothelium, which forms a pair of ridges
placed transverse to the axis of the vessel; (ii)
growth of the endothelial ridges due to their invasion by the underlying mesenchyma, which bulges
out of the valvular anlage; (iii) the evolving valve
directs itself toward the heart; (iv) the valvular cusps
widen into a nodular shape, while the valvular sac
gains in capacity; and (v) the venous wall thins
down considerably in the region of the valvular sinus, mainly due to thickening of the media.
VVs increase in number during prenatal life. Differences with regard to their distribution and characteristics in different areas of the human body start
immediately after birth. In 1981, Maros pointed out
that “Certain findings suggest a reorganization after birth of the venous valves which are frequently
met in fetus. The close relation between hemodynamic mechanisms and the blood guiding structures may explain the changes (disappearance or
persistence) of venous valves in some areas after
birth.” 6
AND
tinuation of the internal elastic lamina. The parietalis is lined by a layer of endothelial cells, which
are elongated transversely. The remainder of the
parietalis consists of loose connective tissue. At the
base of the cusp, the parietalis contains scattered
smooth muscle cells extended from the longitudinal muscular bundles of the vein intima. The luminalis and the parietalis join or fuse at the distal
end of the cusp, which is thinner than the rest of the
cusp; elastic and connective fibers are thinner here
too. No blood vessels are found within the cusps.
Morphology of the venous valves
“The shape of valves is such that they resemble
the nail of the index or other three fingers.”
Hyeronimus Fabricius ab Aquapendente, 1603.
According to Saphir and Lev (1952), the cusps of
the VV consist of thin collagen half moon–shaped
folds covered by endothelium, which spring from
the wall of the vein very close to each other.7 Their
free margins diverge to become attached again at
the opposite section of the vein wall. The space between the attachment of the free margins of the
cusps is called the commissure (Figure 3, page 102).
The commissure itself is slightly raised because of
a thickening of the vein wall in that area. The cusps
are thicker at their bases, where they join the wall
of the vein. This thickened attachment of the cusp
framework was named “agger” by Franklin,8 and
“limbus” or “tuberculum” by others. It is shaped like
a double horseshoe, with the convex sides arranged
distally, and contains smooth muscle cells. The continuations of the free border of the cusp where it
meets the vein wall are named “cornua.” The valvular sinus (or pocket) is the space between the cusps
and venous wall, which at that level is particularly
thin (Figure 4, page 102). According to Franklin,8
the vertical length of the cusps will often be twice
the diameter of the vessel (Figures 3 and 4).
The cusps can be designated into two faces: luminalis, that part of the cusp close to the lumen of
the vein and facing the circulating blood stream,
and parietalis, that part of the cusp facing the vein
wall of the sinus. The luminalis is lined by one layer of endothelial cells, which is elongated along
the major axis of the vessel. Beneath this layer of
endothelial cells is a small amount of connective
tissue that is especially noticeable in childhood.
Immediately beneath the tissue, there are moderately thick, slightly wavy elastic lamellae, the con-
Figure 1. Plate 2 of Fabricius’ De venarum ostiolis was modified by
William Harvey (insert) to demonstrate the direction of flow into
the veins.
Figure 2. The five steps of venous valve development.
Modified from reference 3: Kampmeier OF, Birch LF. The origin and development
of the venous valves, with particular reference to the saphenous district. Am J
Anat. 1927;38:451-499. Copyright © 1927, Wiley-Liss, Inc.
The vein wall is thicker at the base of the valve
cusps, due to an increase in smooth muscle cells of
the media (Figure 4). Some of these cells run circumferentially in bundles and some run longitudinally and seem to split off from the inner portion
of the media to extend into the cusp for a variable
extension. Above the agger, the muscular tissue of
the vein wall decreases. Elastic fibers from the internal elastic lamina of the vein extend along the
cusp close to the basement membrane of the endothelium. In addition, elastic bundles reinforce the
base of the cusps. Due to its thickness and muscular content, the valvular agger is credited as preventing venous dilation, as firstly stated in 1603 by
THE VENOUS VALVE
AND
F
Sinus
wall
Agger
Figure 4. Scanning electron microscopy demonstrating the difference in
wall thickness between
the agger and the sinus.
A
A
B
C
Figure 3. The nomenclature of venous valves (Panels A and B), showing the sinus (A), free (B), and attached (C)
borders. D indicates the cornua, E indicates the valve cusps, and F indicates the agger. Panel C shows that the
length of the cusps is about twice the diameter of the vessel. Courtesy of Alessandro Pieri.
Hyeronimus Fabricius ab Acquapendente: “Quoque
venarum distensionem fuisse ostiola a Summo Opifice fabrefacta” (“The Supreme Artificer made valves
to prevent venous distension”). Moreover, the tissue organization of the valve sites suggests that the
action of valves is not merely that of passive flaps,
but that they can also actively regulate the flow, especially in conditions of low velocity. According to
Fegan:9
Contraction of the circular bundles at the base of
the cusps reduces the diameter of the vein. Contraction of the longitudinal muscular fibers of
the cusps reduces their length and increases their
thickness. In addition, the cusps are drawn down
towards their roots, and away from each other,
but the sphincteric action of the circular bundles
compensates for this. The upper free parts of the
cusps press against the vein wall at the lateral
attachments of the valve, and thus, with the intimal cushions, help to seal the potential leaks.
Age-related structural changes of venous valves
Age-related morphological changes in VV leaflets
were comprehensively described by Saphir and Lev:7
Starting after the age of 30, the loose areolar collagen stroma of the cusp is gradually replaced
by thick and fibrous tissue. After 40, an increase
in elastic tissue starts at the base of the cusp, to
gradually spar the free margin. In the parietal
portion of the leaflet, accumulation of densecollagenous fibers. In the luminal, deposition of
collagen between endothelium and elastic membrane.
These changes are similar to those described in
the superficial veins of aged individuals.10 They
can be attributed to the physiologic hemodynamic
stress related to standing and muscular contractions. However, changes related to senility do not
imply VV dysfunction with significant reflux.
Distribution of venous valves
in the lower limbs
Kampmeier and Birch correctly stated that, as a
general rule, “Valves are present in those vessels
which are subject to pressure from without and
in those in the immediate sphere of muscular per102 MEDICOGRAPHIA, VOL 30, No. 2, 2008
formance, such as in the veins of the extremities
and stomach.” 3 Many studies have dealt with the
number and location of VVs in the inferior vena
cava region.11-18 Data provided by different authors
regarding the distribution of valves in the veins of
the lower limbs are summarized in the following
paragraphs. Unfortunately, these data are difficult to
compare, mainly due to the different topographic
designation of the veins.
Addomino-pelvic region
The inferior vena cava is without VVs. Sporadic
monocuspid valves have been exceptionally reported.8 Occasionally, one sporadic and mostly incomplete valve, similar to a spur, is reported in the
common iliac vein (in 1% to 7% of limbs).15,16 One
VV is located in the external iliac vein of about a
quarter of white subjects. Friederich noted in 1882
that one VV is located in about 35% of external iliac
veins, “but often mainly decadent.”17 La Page and
colleagues reported one well-developed VV located
within 2 cm distal to the entrance of the internal
iliac vein in 26% of legs.18 The right external iliac
vein has almost three times as many valves as the
left (39.6% vs 14.6%). According to Kampmeier and
Birch, the internal iliac vein is avalvular, whereas
its main tributaries (gluteal, sacral, and obturator
veins) are valvular.3 By contrast, more recently La
Page and colleagues18 stated that in 7.6% of individuals, a well-developed ostial valve is present, and
parietal valves are found in only 2.2%. Finally, its
tributaries will be valvular in only 10% of cases.
Deep veins
The common femoral vein shows one VV above
the saphenofemoral junction (SFJ), known as the
“supra-saphenic valve.” It protects the saphenous
axis against rises in intra-abdominal venous pressure.19 According to Basmajan, two VVs are located
in the same tract in about 5% of normal limbs.11
The femoral vein shows about three valves. The
most constant valve (found in about 90%-100% of
cases, according to Banjo16), is located just below
the conjunction of the deep femoral vein.16 No data
are available with regard to the lateral and medial
circumflex veins. The deep femoral vein and the
deep femoral perforators are valvular.20 The popliteal vein displays one to three VVs. Finally, the deep
THE VENOUS VALVE
A
AND
B
C
Figure 5. The valves of the inguinal area, as depicted by Fabricius in 1603 (Panel A), and in a schematic drawing
(Panel B). The confluence of junctional tributaries is between the two last valves of the great saphenous vein.
Panel C: incompetence of the preterminal valve explains a varicose great saphenous vein with a normal terminal valve.
Abbreviations: ptv, preterminal valve; ssv, supra-safenic valve; tv, terminal valve.
veins of the leg are richly valvular. According to
Gottlob and May, 8 to 19 VVs are located in each of
the posterior tibial veins, and 8 to 11 VVs in both
the anterior tibial and peroneal veins.20
Superficial veins
Cotton calculated that 7.2 ±2.3 valves are located
along the entire length of the GSV.21 According to
Raivio, between 1 and 7 valves are located along the
thigh portion of the GSV (mean number, 3.5), 2 to
6 valves are located along the leg (mean number,
4), and finally 1 to 4 valves are located at the foot
(along the marginal veins).22 The valves of the SFJ
are of particular clinical relevance. In 1603, Fabricius stated that the terminal portion of the GSV has
a bicuspid valve at the orifice, then at two fingers’
distance, a further set of twin valves (Figure 5). The
first is the well-known terminal valve situated at
the termination of the GSV to prevent reflux from
the femoral vein. The more distal one is the preterminal valve (PTV), which lies just below the openings of the SFJ tributaries. The PTV prevents venous
reflux from the tributaries of the SFJ into the GSV
trunk while the terminal valve is closed. Incompetence of the PTV is the reason for reflux into the
GSV in cases in which the terminal valve is still
competent.19 The terminal valve is present in 98%
to 99% of normal legs, whereas the PTV is present
in only about 70% to 85%. Finally, in about 2% of
limbs, no valves are present in the last portion of
the GSV.23
According to Raivio, the global number of VVs
along the small saphenous vein is an average of
8.2.22 The terminal valve is located in all legs with
a saphenopopliteal junction. No data are available
on the presence of VVs along the thigh extension
of the small saphenous vein, which shows, in normal conditions, an antegrade flow directed toward
the GSV or toward tributaries of the internal iliac
vein (inferior gluteal or ischiatic veins).
their course, and at the point of entry of a smaller vein.24 Avalvular superficial veins connect main
valvular superficial veins (oscillating veins).25
Perforating veins
It is well known that perforating veins are furnished
with valves. The number of VVs in perforating veins
ranges between 1 and 5 (the mean is 2). In 1978,
Pirner affirmed that “all valves were found in the
subfascial part of the perforating veins.” 26 In the
same year, Van Limborgh and Hage noted that “the
number of valves in the epifascial part of the perforators was significantly less in those (perforating)
veins which frequently become incompetent.” 27
However, Raivio reported that only 75% of the
perforating veins are valvular.22 Avalvular perforating veins are found mainly in the foot, hand, and
forearm. However, avalvular perforating veins are
reported elsewhere in the human body, and work
like oscillating veins connecting deep and superficial districts. This was confirmed by duplex investigations that demonstrated bidirectional flow
in perforating veins of people without any sign of
venous disease.28-30
Number of venous valves
and varicose desease
While valvular agenesis is a known, but rare cause
of venous insufficiency, the relationship between
the number of VVs and varicose disease has been
poorly investigated. Sales and colleagues demonstrated that the mean number of valves in varicose
saphenous veins differed from that of nonvaricose
ones (2.3 ±0.83 vs 4.8 ±2.01, respectively).31 Banjo
comparatively evaluated the presence of VVs in
whites and black Africans, and demonstrated that
the number of valves is higher in the latter.16 This
may account for the high prevalence of varicose
veins (between 10% and 18%) in whites, and the low
prevalence (1% to 2%) of the condition in Africans.
Saphenous accessories and other
superficial veins
Fabricius affirmed that smaller superficial veins
(saphenous tributaries, communicating veins, and
reticular veins) are avalvular. By contrast, Bouchet
affirmed that they are valvular at their end, along
Age-related changes in the
number of venous valves
A reduction in the number of VVs as a function of
aging is a debated topic. The theory proposed by
THE VENOUS VALVE
AND
Bardeleben in 188032 and reconsidered by Powell
and Linn in 1951,33 which proposed a lifelong and
progressive reduction in the number of VVs due
to involutive noninflammatory phenomena, was
strongly denied by Leu and colleagues in 1979,34 and
has been definitively abandoned. Leu and colleagues
confirmed what Klotz demonstrated in 1887; ie, the
number of VVs does not decrease with age, but the
number of incompetent VVs increases with age.35
Author (year discovered)
Area of the body
Popoff (1934)
Digital skin
Pirro (1950)
Calf muscles
Valves in microveins
According to Gottlob and May, “venous valves
cannot disappear but pathological processes may
cause them to become incompetent.”20 This can
be a result of the well-known effects of a massive
thrombosis, but also because of subclinical localized thrombosis of the valvular sinus, as described
by Sevitt in 1974,36 dilation of the valvular anlage
(as in varicose veins), and other regressive phenomena currently not well defined.
Senile involution of VVs was investigated in depth
by Marinov in 1973.37 He established that in parallel
with aging, the number of fully developed valves
reduces, while that of “partial” valves increases, with
the highest intensity of the process being recorded
during the period between 25 and 60 years of age.37
In subjects older than 60 years, the number of partial valves represents between one fifth and one
Anatomists, physiologists, and clinicians consider
the venous bed to be “valveless” from the venular
level up to 2 mm large veins. On the contrary, microscopic venous valves (MVVs) have been described
in the microvascular bed (postcapillary venules and
venulae efferents of arteriovenous anastomoses), in
collecting venules, and in small caliber veins (with
diameters up to 800 to 1000 μM).38 MVVs have been
found in the subcutaneous layer and in muscles
of various areas of the human body (Table I).
Generally, MVVs are described as bicuspid. MVVs
are arranged in series along a vein or are situated
at the merging point of two veins. The valves always point in the direction of the larger vessel, as
in the collecting veins. Two layers of endothelial
cells surround a core of basement membrane material, in which bundles of collagen fibrils are embedded.
MVVs are identical in structure, location, and orientation to the VVs of the leg macroscopic veins.
This has led to the hypothesis that their role is to
resist blood reflux in small sized veins and collecting venulae, and to prevent reflux from postcapillary venulae to the capillary bed and arteriovenous
anastomosis.38 This hypothesis is corroborated by
two pieces of evidence: (i) the absence of MVVs in
regions with a favorable venous return; and (ii) the
abundance of MVVs in regions subject to gravitational backflow and where blood flow is irregular
or altered by muscular contraction, as with VVs.
The absence of MVVs, as well as their incompetence,
could explain clinical syndromes characterized by
signs and symptoms of chronic venous insufficiency in limbs with competent VVs in large veins.38 REFERENCES
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1317.
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venous valves, with particular reference to the saphenous district.
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Miani and Ruberti (1958)
Foot sole skin
Braverman, et al. (1983)
Abdominal wall
Curri, et al. (1987)
Vastus lateralis, Gastrocnemius
Caggiati, et al. (1987)
Vastus lateralis
Miyake, et al. (1996)
Human maxillo face
Aharinejad, et al. (1997)
Exocrine pancreas
Human dorsal thoracic fascia
Skin of the scapular area
Skin of the inferior limb
Shangkuan, et al. (2001)
Tongue
Phillips, et al. (2004)
Skin of the inferior limb
Table I. Areas of the
human body found to
contain microscopic
venous valves.
tenth of their total quantity of VVs; in the superficial veins, the amount is 1.5 to 2 times higher than
in the deep veins.37 These regressive phenomena
are subject to regional differences. According to
Gottlob and May, “venous systems, in which unidirectional flow conditions are prevalent, tend to lose
their ‘superfluous’ valves more readily, whereas
systems, in which heavier strain is exerted on the
valves due to hydrostatic stress or reversed flow,
preserve their valves throughout life.”20
THE VENOUS VALVE
17. Friederick N. Ueber das verhalten der klappen in den cruralvenen. Morph Jahrbuch. 1882;7:323-325.
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H. Nomenclature of the veins of the lower limbs: extensions,
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26. Pirner F. On the valves of the perforating veins. In: May R,
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27. Van Limborgh J, Hage RW. Anatomical features of those perforating veins of the leg which frequently or infrequently become
incompetent. In. May R, Partsch H, Staubesand J, eds. Perforating
Veins. Munich, Germany: Urban & Schwarzenberg; 1979:49-59.
28. Sarin S, Scurr JH, Smith PD. Medial calf perforators in ve-
AND
nous disease: the significance of outward flow. J Vasc Surg.1992;
16:40-46.
29. Stuart WP, Adam DJ, Allan PL, Ruckley CV, Bradbury AW. The
relationship between the number, competence, and diameter of
medial calf perforating veins and the clinical status in healthy
subjects and patients with lower-limb venous disease. J Vasc Surg.
2000;32:138-143.
30. van Neer PA, Veraart JC, Neumann HC. Venae perforantes: a
clinical review. Dermatol Surg. 2003;9:931-942.
31. Sales CM, Rosenthal D, Petrillo KA, et al. The valvular apparatus in venous insufficiency: a problem of quantity? Ann Vasc
Surg. 1998;12:153-155.
32. Bardeleben K. Das Klappen-Distanz-Gesetz. Jenaische Ztschr.
Naturwisse. 1880;12:467-529.
33. Powell T, Lynn RB. The valves of the external iliac, femoral
and upper third of the popliteal veins. Surg Gynecol Obstet.1951;
92:453-455.
34. Leu HJ, Vogt M, Pfrundes H. Morphological alterations of nonvaricose and varicose veins. Basic Res Cardiol. 1979;74:435-443.
35. Klotz K. Unteresuchungen uber die Vena Saphena Magna
bein Menschen. Arch Anat Physiol Anat Abt.1887;159:174-178.
36. Sevitt S. Organization of valve pocket thrombi and the anomalies of double thrombi and valve cusp involvement. Br J Surg.
1974;61:641-649.
37. Marinov G. Changes with age in the valvular apparatus of the
superficial and deep veins of the leg. Eksp Med Morfol.1973;12:
86-91.
38. Caggiati A, Phillips M, Lametschwandtner A, Allegra C. Valves
in small veins and venules. Eur J Vasc Endovasc Surg. 2006;32:
447-452.
EMBRYOLOGIE
ET RÉPARTITION DES VALVULES VEINEUSES
DU MEMBRE INFÉRIEUR CHEZ L’HOMME
E
n embryologie, les valvules veineuses apparaissent après les premiers
battements cardiaques et les premiers mouvements des bourgeons des
membres commandés par les principaux muscles. Le gradient de pression le long de la veine déclenche le développement de la valvule en cinq étapes.
Les réarrangements morphologiques et numériques prénataux et périnataux,
déjà décrits, demandent à être démontrés. Les valvules veineuses sont constituées de fins replis de collagène, en demi-lune, recouverts d’endothélium, qui
surgissent de la paroi veineuse, très proches l’un de l’autre. La paroi veineuse
est plus fine à la base des valvules en raison du plus grand nombre de cellules
musculaires lisses de la média. Avec l’âge, le stroma collagène aréolaire de la
valvule disparaît progressivement au profit d’un tissu épais et fibreux. Sont résumées ici les données de différents auteurs sur la répartition des valvules dans
les veines profondes, superficielles et perforantes des membres inférieurs. Enfin,
les valvules des microveines cutanées des membres inférieurs sont décrites.
THE VENOUS VALVE
AND
his literature review, which includes some of
our own work, sets out to show that chronic
venous insufficiency (CVI) can begin very early in childhood and adolescence and that reflux is
an excellent indicator of its progression. Although
hemodynamics is our main concern, we shall also
discuss epidemiology and heredity, before advocating the grading of CVI based on hemodynamic and
clinical characteristics.
T
Michel SCHADECK, MD, FACPh
Past President of the French
Society of Phlebology
Paris, FRANCE
Epidemiology
Venous valve
incompetence and
reflux in childhood
by M. Schadeck, France
hronic venous insufficiency (CVI) is common in children and adolescents, often beginning very early. Reflux is a major item in the initial
assessment and follow-up. This article proposes an investigation and
management plan. Continuous-wave Doppler ultrasound has been used in a
small number of epidemiological studies to determine the prevalence of great
saphenous vein reflux in children and adolescents and its progression with age,
which has been confirmed using the Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification. Duplex scanning, although unable to truly quantify
reflux, has since helped to classify it by type, height, outcome, topography, and
the relationship between subject age and topography. These parameters are
combined with clinical examination to score the severity at presentation and
monitor the disease course. The results show that the frequency of CVI in the
young depends on the study population and ranges from 3% to 10%, depending on age; it may exceed 50% in those with one or two varicose parents. Reflux generally begins around the knee and progresses proximally with age. It
may appear before or after puberty. Despite the substantial advance in characterization of CVI and reflux in the young, a consensus has yet to be reached as
to treatment indications and modalities.
C
Keywords: childhood; chronic venous disease; saphenous reflux; varicose
veins; venous valve incompetence
Venous angiodysplasia and deep vein thrombosis
dominate the venous disease literature.1,2 Few even
recent studies have specifically addressed CVI in
children and adolescents. Most cohorts range in
age from 18 years to over 90 years, as if CVI only
starts after adolescence.3-8 A few large-scale studies
have included subjects from the ages of 12 or 15
years upward, but without drawing any conclusions
specific to this age group.9,10 However, clinical signs
such as small varices, and even hyperplasia of the
great saphenous vein (GSV), began to be recognized
as heralding CVI11 when continuous-wave Doppler
entered standard practice.
A key epidemiological study in the young was that
of Heede in 1989, carried out in 8- to 18-year-olds.12
Clinical examination revealed varices or telangiectases from the foot to the groin, with 52% in the
popliteal region, confirming results of a 1978 Prague
study.13 The overall prevalence of varicose veins was
14% and appeared to increase with age: 2.3% of the
overall population showed reflux at the saphenofemoral junction (SFJ) versus 3.2% in the 14- to
18-year-old subgroup, consistent with the 1981
study by Fischer.14
The prospective Bochum Study15 monitored 740
pupils aged 10 to 12 years from 11 secondary schools
for 9 years from 1982. It combined clinical examination with photoplethysmography and continuous-wave Doppler assessment of reflux. Results
were identical to those of Heede, with GSV reflux
being observed in 2.9% of the youngest subjects
in Bochum Study I. Four years later, in Bochum
Study II, reflux had risen to 10.4%, with primary
valve failure being diagnosed in 1% to 2%. The authors considered reflux to be the first sign of truncal varicosis, while the mainly popliteal reticular
varices were earlier in onset but not directly related to the reflux observed later. Another 1989 study,
in 741 6- to 14-year-olds, found truncal or perforator incompetence in 13.9%, but failed to detail the
methods used.16 In 2006, we published a clinical and
duplex ultrasound study of 142 young subjects,
SELECTED
ABBREVIATIONS AND ACRONYMS
CEAP Clinical-Etiology-Anatomy-Pathophysiology
(classification)
Address for correspondence: Michel Schadeck, 5 rue Michel Chasles, F-75012 Paris, France
(e-mail: flbskool@easynet.fr)
CVI
chronic venous insufficiency
GSV
IMT
intima-media thickness
SFJ
Venous valve incompetence and reflux in childhood – Schadeck
THE VENOUS VALVE
Heredity
Heredity has been considered to play a major role
in CVI, with well-established evidence of transmission, although acquired factors have remained paramount for some authors. In 1937, Troisier and
Le Bayon (cited by Merlen et al18) postulated sex-
Investigations
Prospective randomized controlled trials are not
feasible in children. We were initially confined to
hemodynamic observations that were empirical
A
B
60%
Group 1
Group 2
58.7%
Group 1
Group 2
P<0.05
56.3%
P<0.0001
50%
100
92.9%
87.1%
90
40%
30%
20%
10%
C
0.0%
C0s
C1a
C1s
Anat.
100
P<0.01
C2a
92.9%
90
1.7±0.8
1.5±0.6
50
40
1.1±0.3
20
10
50
42.4%
40
30
7.1%
16-18 years
0
8-13
12.9%
12.9%
7.1%
8-13
Clin.0
Clin.1
P<0.01
57.6%
60
10
14-15
0
70
20
8 -13
87.1%
30.3%
30
C2s
80
Clinical score (%)
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
60
2.7%
C0a
69.7%
70
100
16 -18 years
92.9%
16-18
87.1%
80
Years
Disab.0
Disab.1
P<0.001
70
60
54.6%
45.4%
50
40
30
20
10
14 -15
14-15
90
Disability score (%)
0%
80
Affected subjects (%)
Affected subjects (%)
linked inheritance with female predominance, although most authors at that time believed that what
was inherited was a susceptibility syndrome rather
than CVI itself. However, the epidemiological data
on which inheritance hypotheses were based were
obtained largely by interview, not examination. In
1994, a French case-control study provided a clear
answer to the inheritance issue by examining 402
subjects from 134 families.19 It included the nonvaricose spouses of affected cases in an attempt to
control for confounders such as diet and lifestyle.
Clinical examination in children and parents was
complemented in many cases by Doppler ultrasound
(although these results were not an inclusion criterion). Statistical analysis showed that the risk of
CVI in children, depending on the presence or absence of parental disease, was 20% if neither parent
was affected, 25% in boys and 62% in girls (mean
45%) if one parent was affected, and 90% if both
parents were affected. Inheritance is therefore a significant factor (P<0.001), and an indication for the
monitoring of children with a strong family history.
with significant GSV reflux (>0.5 seconds) in 92
cases, and none in the remaining 50 cases.17 The affected population comprised 77 girls (83.7%) and
15 boys (16.3%) aged 14±2 (8-18) years. We divided
the leg into seven segments: reflux was found to extend over more than two segments of the thigh or
leg in 16 patients (Group 1), and it was confined to
one segment (short reflux) in 76 patients (Group 2).
All patients were classified by age and ClinicalEtiology-Anatomy-Pathophysiology (CEAP) score,
ranging from asymptomatic C0 (C0a) to symptomatic C2 (C2s). Scores differed significantly between the groups, with 0.0% C0a in Group 1 versus
58.7% in Group 2 (P<0.0001), and 56.3% C2s in
Group 1 versus 2.7% in Group 2 (P<0.0001) (Figure 1A). Division into three age groups (8-13 years
old, 14-15 years old, and 16-18 years old) showed a
correlation between age and CVI severity (P<0.01)
(Figure 1B), confirmed by the anatomical, clinical,
and disability scores (Figure 1C).
Anatomical score
AND
0
7.1%
8 -13
12.9%
14 -15
16 -18 years
Figure 1. Relationship between reflux severity and Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification, age distribution, and
other scores in the 92 subjects (77 girls [83.7%] and 15 boys [16.3%] aged 14±2 [8-18] years) with significant great saphenous vein (GSV)
reflux (>0.5 seconds) in a population of 142 children/adolescents. Affected subjects were divided into 2 groups: those with reflux extending
over more than two segments of the thigh or leg (Group 1; n=16), and those in whom reflux was confined to one segment (Group 2; n=76).
A, CEAP classification and reflux severity, ranging from asymptomatic C0 (C0a) to symptomatic C2 (C2s); B, age and reflux severity; C, other
scores and reflux severity.
After reference 17: Schadeck M, Allaert FA. CEAP classification applied to children and teenagers. Phlebologie. 2006;35:A41. Copyright © 2006, Schattauer.
THE VENOUS VALVE
AND
rather than strictly scientific. Clinical examination
was the cornerstone procedure, as it is now. Over
the years, it has been complemented by three types
of investigation.
Photoplethysmography
This technique failed to improve understanding of
CVI in the young. Even in combination with Doppler
ultrasound, it could not differentiate between normal results and various forms of incipient CVI.20 The
consensus is that muscle immaturity in the young
makes it impossible to use the data collected.14,20-22
Ultrasound
Ultrasound soon replaced radiology as the standard
structural investigation.23 It maps the anatomy of
the diseased superficial venous system and identifies the defective valves. It provides an initial score,
which can be supplemented by vessel diameter values. Intima-media thickness (IMT) provides a measure of the vein wall changes induced by the disease,
and is significantly increased in affected young subjects compared with normal adults.24
Figure 2. Continuous-wave Doppler recording made in 1988 of reflux at
the saphenofemoral junction in an 11-year-old girl showing a saphenous
vein diameter of 6 mm.
Doppler ultrasound
Ever since its introduction, Doppler ultrasound has
been the essential hemodynamic investigation for
confirming the diagnosis of CVI. From 1985 to 1990,
it was used in continuous-wave mode,25 but according to no standard technique or specific recommendations (Figure 2). The patient’s position during the examination and the maneuvers employed
were not clearly specified. Only the Valsalva maneuver was regularly mentioned. This explains why patients were generally examined for reflux at the SFJ
or saphenopopliteal junction. The duration of significant reflux was not considered an important
parameter. Nevertheless, it was the hemodynamic
studies using continuous-wave Doppler that yielded the epidemiological results cited above.
Today, not only do we have color duplex scanning,
we also have a consensus document, Duplex ultrasound investigation of the veins in chronic venous
disease of the lower limbs,23 which lays down clear
and detailed instructions for examining venous regions of interest. It defines significant pathological
reflux in the great or small saphenous vein as being
retrograde flow in the anti-physiological direction
lasting for more than 0.5 seconds.26 This is the only
information on reflux in the consensus document.
However, retrograde reflux does not necessarily imply true reflux, still less valve incompetence. It is
also important to know whether the superficial venous reflux is spontaneous or induced, transient
or permanent, and where it occurs.27 These are all
hemodynamic parameters that we need to consider if we are to make as comprehensive an analysis
as possible. They are as applicable to young subjects
as to adults.
Reflux
Spontaneous and induced reflux
Color Doppler scanning may reveal spontaneous reflux when the subject is mobilized. It can be confirmed and assessed using compression-decompression maneuvers. Reflux in young people is often
found below the knee along the GSV trajectory.
Compression of the muscle compartments drained
by the GSV will demonstrate its actual origin. However, this may require displacing a substantial volume of blood, which should not be repeated too
forcefully in somewhat timid young subjects, for
fear of triggering a vasovagal reaction.
Intervalvular and commissural reflux
Intervalvular reflux is associated with incompetent
valve leaflets that are damaged and no longer functional. Reflux is always pathological if it lasts more
than 0.5 seconds.
Commissural reflux 28,29 through one or both spaces
between the valve leaflets can often be demonstrated in the standing position in the lower third of the
thigh. This high-intensity reflux shows as frequency
saturation in pulsed Doppler mode and as a brightly colored stream on one or both sides of the valve
in color Doppler mode (Figure 3). Endoscopy can
corroborate commissural reflux.30 Although it mimics pathological reflux hemodynamically in that its
duration greatly exceeds 0.5 seconds, it remains localized to the valve, with no distal extension, making it difficult to interpret. It could be that it reflects no more than slow closure of the commissural
space, in no way heralding the development of CVI.
It is therefore essential to recognize it for what it
is and not mistake it for pathology.
Transient and permanent reflux
It is important to differentiate between transient
and permanent reflux in the young, as one is a harmless sign, while the other marks the onset of irreversible CVI.
Reversible transient reflux always exceeds 1 second but is not consistently reproducible. It can occur after prolonged standing, and may be present
one day and absent the next. It fully meets the definition of reflux through a healthy valve demonstrated in the GSV terminal segment.31 It reflects no
more than functional dilatation of the perivalvu-
THE VENOUS VALVE
AND
Figure 3. Color Doppler
recording of commissural
reflux in the saphenous
trunk.
lar wall ring with no valve lesion. Such reflux is
readily identified using continuous-wave Doppler,
but is more difficult in pulsed Doppler mode.
Permanent and irreversible reflux reflects a structural valve lesion, and is therefore present at every
examination.
Reflux topography
Superficial venous reflux arises from various sources,
including the saphenous veins, accessory saphenous
veins, perforators, pelvic veins, and nonsaphenous
veins.27,32 In children, it can also originate from collateral branches mainly below the knee.29
Reflux often begins at the knee or anywhere
along the course of the GSV and its branches. In a
prospective clinical and Doppler study in 81 5- to
18-year-olds (89% girls) with a positive family history, we identified the site of reflux by compression-decompression of the thigh or calf.29 Reflux was
significant in 38% of cases, and was distributed
along the entire GSV. In 55.5% of cases, it occurred
on either side of the knee, where it was slow and
confined to a single intervalvular interval. The very
low incidence of SFJ reflux (5.7%) would seem to
eliminate femoral reflux as a cause of saphenous
reflux. A fuller study 6 years later in 161 subjects
amply confirmed these results, with reflux around
the knee in 75.3% of cases, and proximal reflux up
to the SFJ in the remainder.33
Detailed hemodynamic analysis at the SFJ is relatively recent.34-36 There have been no specific studies of terminal and/or subterminal valve lesions in
young patients, although we have observed several cases of terminal valve incompetence. Saphenous
reflux in youths may also be associated with a varicocele.37
Height of reflux
By dividing the limb into seven segments, three
above and three below the knee, and one for the
ankle and below, reflux height can be used to compare two successive investigations and plot the disease course.33 Height reflects severity. An ultrasound study used height to define three types of
reflux in young subjects: 38 type 0, no reflux; type 1,
reflux limited to one limb segment; type 2, reflux
stretching over more than one segment. The authors combined these data with other anatomical
or structural parameters into a composite disease
score that can be used in monitoring and, above
all, in detecting CVI as early as possible. We have
also included height as an indication for ultrasound-guided sclerotherapy when reflux reaches or
exceeds two limb segments.33
Age and reflux topography
Longitudinal monitoring is difficult in practice, but
we have monitored pathological reflux in several
young patients at yearly intervals. The reflux underwent progressively proximal ascent to the SFJ,29,34,38
confirmed statistically by the correlation between
subject age and ascending reflux topography. Children with reflux in the terminal GSV segment were
older than those with reflux either side of the knee
(14.4 years versus 13.2 years). The mean age of our
general population, including normal and pathological subjects, was 13.7 years; this compared with
14.4 years for those with reflux, and 16.2 years for
those with reflux involving two limb segments.
These results are consistent with those showing a
correlation between SFJ reflux and higher age in
adults.39 Puberty, which was long assumed to be an
important determinant of reflux, has an inconclusive role: in 156 adolescent girls, 77 had significant
reflux, of whom 53.3% were prepubertal and 59.5%
postpubertal.16
Management
Based on the epidemiological and genetic data, and
the current structural and hemodynamic studies
of early-onset CVI, we propose the following management guidelines:
Mandatory screening for all girls with one CVIpositive parent and all children with two affected
parents.19
Diagnostic structural and hemodynamic studies to confirm reflux and determine its topography,
height, origin, and score severity in conjunction
with the CEAP classification as a basis for a rational
management strategy.38
Follow-up at 6 or 12 months to confirm initial
findings and check for progression.
Curative treatment for adolescents with documented GSV incompetence,33,40,41 in the absence of
other consensus as to treatment indications and
modalities. Ultrasound-guided sclerotherapy was
successful in 15 out of 16 of our patients with reflux
exceeding two limb segments; the remaining patient required surgery.17 This approach remains relMEDICOGRAPHIA, VOL 30, No. 2, 2008 109
THE VENOUS VALVE
AND
atively rare but is increasing. When we reported our
ongoing study of 4311 cases treated by ultrasoundguided sclerotherapy, only 0.7% were under 24
years of age, with adolescents accounting for 0.2%.42
Today, however, children and adolescents make up
0.5% of my patients treated by echosclerosis, whose
number now exceeds 5000.
Discussion
The epidemiological data, reinforced by studies applying the CEAP classification, show that CVI can
begin in early childhood and that it progresses with
age. Clinical evidence from before the ultrasound
era12,14 indicated that varicose disease did not originate at the SFJ, but tended to be distributed in the
popliteal region, where reticular varices were predictive of CVI. Doppler ultrasound then confirmed
the marked predominance (75%) of GSV reflux either side of the knee on presentation in children.
Reflux that has reached the SFJ is evidence of already advanced disease and is characteristic of older
children and adolescents.
Commissural reflux needs to be differentiated
from pathological reflux, since follow-up in many
of our young patients shows that it disappears after
1 to 2 years. Height is a marker of reflux severity
and a useful monitoring tool. Pathological reflux
may occur from earliest childhood onward, with
no direct relationship to puberty.
This confirms Heede’s 1989 study showing no
evidence for significant hormonal influence.11 However, puberty may be an aggravating factor in incipient or established pathological reflux. In any event,
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Doppler ultrasound has transformed our understanding of CVI in children and adolescents in recent years, although the topic remains generally
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26. Van Bemmelen PS, Bedford G, Beach K, Strandness DE.
Quantitative segmental evaluation of venous valvular reflux with
ultrasound scanning. J Vasc Surg. 1989;10:425-431.
27. Guias B, Schadeck M, Bressolette L. Reflux veineux superficiel et explorations ultrasonores. Revue de la littérature [Superficial venous reflux and ultrasound investigations. A review of
the literature]. Phlébologie. 1998;51:147-154.
28. Schadeck M. Hemodynamic aspects. In: Duplex and Phlebology. Naples, Italy: Gnocchi; 1994:53-55.
29. Schadeck M. Etude par le duplex des grandes saphènes de l’enfant: calibres, reflux et conséquences thérapeutiques [Duplex
scanning study of great saphenous veins in children: diameter,
reflux and influence on therapy]. Phlébologie.1996;49:413-418.
30. Van Cleef JF, Hugentobler JP, Desvaux P, Griton P, Cloarec M.
Etude endoscopique des reflux valvulaires saphèniens [Endoscopic study of reflux of the saphenous valve]. J Mal Vasc. 1992;17:
113-116.
31. Schadeck M. Le reflux sur valvules saines en grande saphène
[Reflux in healthy valves of the great saphenous vein]. Phlébologie. 1991;44:603-613.
32. Labropoulos N, Tiongson J, Pryor L, et al. Nonsaphenous superficial vein reflux. J Vasc Surg. 2001;34:872-877.
33. Schadeck M. Indications de la sclérothérapie chez l’enfant et
l’adolescent [Indications of sclerotherapy in children and teenagers]. Phlébologie. 2002;55:33-39.
AND
34. Vin F, Lemasle P, Lefèbrve-Vilardebo M, Uhl JF. Niveau de reflux de la grande veine saphène : indications thérapeutiques [Level of incompetence in the great saphenous vein: therapeutic consequences]. Phlébologie. 2004;57:255-259.
35. Capelli M, Molino Lova R, Ermini S, Giangrandi F, Giannelli F, Zamboni P. Hemodynamics of the saphenofemoral complex: an operational diagnosis of proximal femoral valve function.
Int Angiol. 2006;25:356-360.
36. Pieri A, Vannuzzi A, Moretti R, Gatti R, Caillard P, Vin F. Aspects échographiques de la jonction saphéno-fémorale et de la
jonction saphéno-poplitée. Valvule et rapports avec les collatérales
accessoires [Color duplex investigation of saphenofemoral and
saphenopopliteal junctions. Venous valves and collateral veins].
Phlébologie. 2002;55:317-328.
37. Karadeniz-Bilgili MY, Basar H, Simsir I, Unal B, Batislam E.
Assessment of saphenofemoral junction continence in patients
with primary adolescent varicocoele. Pediatr Radiol. 2003;33:
603-606.
38. Ricci S, Casoni P. Étude ultrasonique du système veineux superficiel des membres inférieurs en période pré-pubértaire. Recherche de possibles critères de prévision de la maladie variqueuse [Ultrasound study of the superficial venous system of the
lower limbs in the prepubertal period to identify possible predictors of varicose disease]. Phlébologie. 2007;60:335-343.
39. Pittaluga P, Chastanet S, Rea B, Barber R, Guex JJ, Locret T.
Corrélation entre l’âge, les signes et symptômes de l’insuffisance
veineuse superficielle et les résultats de l’exploration écho-doppler
[Duplex ultrasonography scanning for superficial venous insufficiency: Correlation of mapping with age, symptoms and signs].
Phlébologie. 2006;59:149-156.
40. Schadeck M. Indications: sclérothérapie chez l’enfant et l’adolescent [Indications: sclerotherapy in children and adolescents].
In: Gobin JP, Benigni JP, eds. Sclérothérapie et Maladie Veineuse
Chronique Superficielle [Sclerotherapy and Superficial Chronic
Venous Insufficiency]. Eska Ed; 2007:161-165.
41. Schadeck M, Allaert FA. Prise en charge de la MVCS chez l’enfant et l’adolescente [Management of superficial chronic venous
insufficiency in children and adolescents]. In : Abstracts of the
French Phlebology Society meeting. Venous Pathology in Gynecology and Obstetrics; June 3, 2006; Lyon, France; Abstract P19.
42. Schadeck M. Evolution de la pathologie veineuse chez la
femme depuis 1985 [Evolution of venous disease in women since
1985]. Phlébologie. 2007;60:149-154.
L’INCONTINENCE
VALVULAIRE VEINEUSE
ET LE REFLUX CHEZ L’ENFANT
L
a maladie veineuse chronique de l’enfant et de l’adolescent (MVC) est une
pathologie qui commence très tôt, et le reflux représente un élément majeur dans l’évaluation initiale et sa surveillance. Dans cet article, nous
proposons une méthodologie d’examen et une conduite à tenir. Comme le montrent de rares études épidémiologiques, le Doppler continu permet d’évaluer le
pourcentage de jeunes présentant un reflux au niveau des grandes saphènes et
de montrer que cette pathologie progresse avec l’âge. La classification CEAP
(Clinique; Étiologique; Anatomique; Physiopathologique) confirme cette évolution. Malgré l’absence d’une véritable quantification du reflux, l’écho-Doppler
peut définir son type, sa nature, sa topographie, son évolution, son« âge ». Associés à l’examen morphologique, ces différents paramètres permettent d’établir un score initial de sévérité et d’observer ainsi l’évolution de la MVC. Il apparaît ainsi que la fréquence de cette pathologie chez le jeune dépend de la
population étudiée et varie de 3 à 10% en fonction de l’âge du patient. Chez les
jeunes dont un ou deux parents sont variqueux, cette fréquence peut dépasser
50%. Le reflux débute généralement au niveau du genou. Sa progression est en
rapport avec l’âge, tout en sachant qu’il peut apparaître avant la puberté. Au
total, la MVC débute très tôt chez le jeune et évolue avec l’âge. L’analyse du
reflux associée à l’étude morphologique permet d’établir un score de sévérité
de la pathologie. Toutefois, il n’existe à ce jour aucun consensus sur l’attitude
thérapeutique.
THE VENOUS VALVE
AND
Lorenzo TESSARI, MD
Fondazione Glauco Bassi
Trieste, ITALY
The study of the saphenofemoral junction to understand
the distribution of refluxes in
chronic venous disease
Massimo CAPPELLI, MD
Studio Flebologico
Florence, ITALY
b y L . Te s s a r i a n d M . C a p p e l l i , I t a l y
ome of the techniques currently in use for the
treatment of the varices of the lower extremities were introduced at the beginning of the
20th century: the Narath technique in 1904 (multiple stab incisions phlebectomy), the Keller technique in 1905 (invaginated stripping on thread),
the Mayo technique in 1906 (external stripping),
and the Babcock technique in 1907 (internal stripping).1
S
efore any decision can be made regarding the appropriate therapeutic
technique for a varicose patient, it is necessary to define how a specific
area (for instance, the saphenofemoral complex) should be assessed in
the patient. We are going to consider two different aspects: first, how to study
an incontinent segment, and second, how to study the saphenofemoral complex (on the basis of the general criteria described for an incontinent segment).
Valvular continence must be studied in the orthostatic position so as to develop a transvalvular retrograde gradient (opposite to the orientation of valvular
planes). Retrograde gradients are studied in two different ways: (i) a high pressure test, such as the Valsalva test; and (ii) a gravitational test, which exploits
the weight of the hematic column once it has been mobilized. Analysis of 1294
patients with incontinent great saphenous vein crosses (saphenofemoral complexes) revealed complete incontinence of the saphenofemoral junction in only
55% of cases. In 6% of cases, a dissociation pattern was noted. Using the same
criteria, the proximal femoral valve (ie, the valve in the common femoral vein
located above the saphenofemoral junction) was also studied. This turned out
to be continent in the saphenofemoral junction and in the saphenous vein arch
in 58.4% of complete incontinence cases. In cases of continence of the upper
femoral valve, the saphenous trunks (measured at the mid thigh area) mostly
exhibit a diameter that is less than 7 mm.
B
Keywords: assessment; saphenofemoral complex; reflux; valvular continence;
Valsalva maneuver; gravitational test
Address for correspondence: Lorenzo Tessari, Localité Broglie 8 F,
37019 Peschiera du Garda (VR), Italy
(e-mail: lorenzo.tessari@libero.it)
In the first years of the 21st century, several new
techniques for varicose vein treatment have also
been developed, both in the surgical field (hemodynamic conservative surgery according to the
Conservative Hemodynamic treatment of Incompetent Varicose veins in Ambulatory patients [CHIVA]
strategy) and in the sclerotherapy area. The latter
has recently been gaining great success, thanks to
echographic techniques and the use of foam.
At present, the most commonly used techniques
for treatment of the saphenous varices are those involving endovascular obliteration (laser, radiofrequency, and sclerosant foam with either a long or
short catheter). These techniques have in common
the inability to completely occlude the saphenous
junction properly, and they therefore expose the patient to a risk of possible relapse, traditional sclerotherapy with liquid being a notable example. This
is what happens whenever the surgical disconnection of the saphenofemoral junction is not performed completely flush on the femoral vein. The
remaining stump can be the cause of a possible evolution of the varicose disease. On the other hand, it
must be pointed out that many surgical procedures
involving the saphenofemoral junction do not show
any evolution signs, even if they have not been correctly performed.
These differences can be explained by the fact that
endovascular procedures as well as surgery are frequently performed without any preventive hemodynamic analysis, so the same therapeutic plan is
SELECTED
CHIVA
Conservative Hemodynamic treatment
of Incompetent Varicose veins in Ambulatory patients (French acronym)
C/R (test) compression release (test)
Study of the saphenofemoral junction to understand reflux distribution in CVD – Tessari and Cappelli
THE VENOUS VALVE
applied in different hemodynamic conditions, resulting in different long-term outcomes. The often
animated discussion regarding how to determine
the best therapeutic technique has resulted in a series of publications about personalized technological approaches.
Unfortunately, these studies have often not been
supported by accurate color-duplex ultrasound research of valvular functions and reflux dynamics,
which could have otherwise helped to plan a more
conservative and personalized therapeutic strategy. A personalized therapy should be based on an
accurate color-duplex ultrasound analysis of the patient’s varicose situation; this assessment leads to
a morphological and, in particular, hemodynamic
map, which represents the basic element for defining the therapeutic plan.
Before any decision can be made regarding the
appropriate therapeutic technique to use, it is necessary to define how a specific area (eg, the saphenofemoral complex) should be studied in a varicose
patient. We are going to consider two different aspects: (i) how to study an incontinent segment; and
(ii) how to study the saphenofemoral complex according to the general criteria listed in point (i).
Study of an incontinent segment
Valvular continence must be studied with the subject in the orthostatic position, to develop a transvalvular retrograde gradient (opposite to the orientation of valvular planes). Retrograde gradients are
of two different types; either that with a high pressure test, such as the Valsalva test, or that with a
gravitational test, which exploits the weight of the
hematic column once it has been mobilized. The
mobilization of the column may occur in a static
way through the compression/release (C/R) test
(static test) or in a dynamic manner through activation of the muscular pump using any of the following: (i) Parana test; (ii) Oscillation test; (iii) Lifting on Tiptoes test; and (iv) Toes Dorsiflexion test.
High pressure gradient (Valsalva maneuver)
The high pressure charge developed during the Valsalva maneuver is transmitted in a distal way independent of the continence of the proximal valvular
planes. This is possible thanks to the closure inertia of valvular planes themselves, which permits the
passage of the pressure wave. Its propagation speed
is definitively superior to the speed of the hematic
flux, as is clearly shown in the arterial system. We
can see that the Valsalva test always determines distal transmission of the pressure wave. When valvular incontinence among different compartments is
present (eg, between the deep and the superficial
nets), the pressure wave is associated with the appearance of transcompartmental reflux. The passages among compartments (between the deep and
superficial nets and between the saphenous system
and its secondary ramifications), which are incontinent with the Valsalva test, are called points of reflux.
The evaluation of the correct execution of the
Valsalva test is shown by the appearance of an anterograde flux, that is, the restarting of the flux as
AND
soon as the maneuver is completed. This shows that
the hypertensive charge (ie, the blocking of anterograde physiologic flux) has been properly performed.
It is essential to highlight here that transcompartmental reflux assessment can only be performed
if at the moment of application of a retrograde gradient, a re-entry system toward a compartment with
lower pressure is present (which could be the deep
venous system too), and the lower pressure in the
“recipient” system is possible thanks to the closure
of its valvular planes (dynamic subdivision of the
pressure column).
The above statement can be tested in every patient. Closure through digital compression of the
reflux re-entry, eg, the saphenous trunk, brings
about the disappearance of the reflux in many tests,
mostly the gravitational ones.2
Gravitational gradient
It must be underlined that dynamic tests, through
the activation of muscle-joint pumps, will mobilize
much more blood at a deeper level than the C/R
test, particularly in big dimension calves. We will
therefore have a larger subdivision of the deep hydrostatic column through the closure of the valvular planes, with a consequent decrease in pressure,
and consequently there will be the development of
a much higher re-entry gradient (in the case of incontinence of the superficial net) than the one developed in the C/R test. Hence, in order to detect
reflux, the dynamic tests will be much more effective than the C/R test.3
Gravitational tests will point out valvular incontinence in a zone distal to the position of the Doppler
sample. They will not give any information on the
functioning of the proximal valvular plane. Thus
one must position the Doppler sample on the proximal side of the valve that is to be studied (eg, on
the femoral side if we are going to analyze the functioning of the terminal saphenous valve).4
We can therefore state that the gravitational tests
point out valvular incontinence in general, while a
positive Valsalva test shows how this incontinence
is mostly associated with points of reflux, which are
in fact the incontinent compartment passages. Furthermore, it should be remembered that the incontinence of the venous axes is not always associated with points of reflux, in which case there will be
negative Valsalva refluxes. As a consequence of these
findings, it is argued that the multiple tests we currently use aimed at the elicitation of the reflux cannot be used indifferently in order to establish a diagnosis of valvular incontinence. Some valves show
either commissural or complete incontinence during the Valsalva maneuver, but they turn out to be
continent if exposed to a transvalvular gradient of
the gravitational type.
The observation of this different valvular behavior during the execution of different tests can indicate a partial incontinence of valvular planes. These
valves may as a result be continent to normal gravitational gradients caused by movement, while they
“leak” under the high-pressure gradients developed
with the Valsalva maneuver. These valves are thus
not completely incontinent, and they have a high
THE VENOUS VALVE
AND
probability of recovery with reduction of the diameter of the venous axis through targeted surgical
interventions on saphenous collaterals.5
Study of the saphenofemoral complex
It must be pointed out that the saphenofemoral
junction is just a part of the so-called “saphenofemoral complex.” The hemodynamics of this region are both physiologically and pathologically influenced by other structures. By saphenofemoral
complex we mean:
The saphenous arch (saphenofemoral cross with
its two valves— the terminal valve and the preterminal valve, differently positioned). The saphenofemoral junction is part of the cross. It represents
the passage between the great saphenous vein and
the common femoral vein.
The femoral valve proximal to (above) the saphenofemoral junction. This valve may not be present
in 20% to 24% of patients.6,7
The femoral valve distal to (under) the saphenofemoral junction.
The upper tributaries of the saphenous arch,
which in a variable way drain the superficial blood
from the lower half of the abdomen. In fact, physiologically, a descending flow toward the arch can
be observed. The physiological direction of flux is
stated by the orientation of valvular planes.8
The hemodynamic study of the saphenofemoral
complex consists in the positioning of the Doppler
sample above and below the valve to be studied and
in the application of all the aforementioned investigative methods. All these tests should point out
valvular incontinence in the various parts of the
complex. In this way, the hemodynamics of the region can be exactly described. The purpose of these
tests is to determine a targeted therapeutic approach, which may help to avoid either incomplete
or useless radical surgery, which can in fact accelerate the evolution of the varicose disease, commonly called “relapse.” The study of the hemodynamics
of the saphenofemoral complex must determine:
The presence of points of reflux represented not
only by the incontinence of the saphenofemoral
junction but also by the connection that some
pelvic points of reflux have with the great saphenous vein through the arch tributaries. In such cases, we will find arch tributaries that show a Valsalva
positive reflux. The exact position of pelvic shunts
must also be pointed out on the map of the leg.
The incontinence/continence state of the terminal valve—that is, the valve situated in the area
of the saphenofemoral junction. This can vary; we
may have: (i) complete continence both in the Valsalva and dynamic tests performed with the Doppler
sample positioned on the femoral side of the valve.
In this case, both tests will be negative; (ii) complete incontinence, when both tests are positive; or
(iii) dissociated findings with a leaking terminal
valve under a high pressure charge, but a resisting
terminal valve when gravitational gradients are applied. In this case, we have a positive Valsalva test
and a negative gravitational test, particularly when
a dynamic test is applied.
The extension of the incontinence, ie, whether
the reflux is limited to the preterminal, terminal or
femoral valve. The study of either the continence or
the incontinence/absence of the proximal femoral
valve is performed by positioning the Doppler sample under the inguinal ligament. The probe must
be directed from the groin upward in order to be
in a proximal position with respect to the femoral
valve and for subsequent application of a combination of the two maneuvers: the Valsalva and dynamic tests.9 The incontinence extension will condition
different pressure columns, with a consequent difference in the reflux hydrodynamic energy; indeed
pressure is one of the energy components, together with the retrograde volume (energy = pressure volume). The hydrodynamic energy, together with
parietal factors, determines the vessel diameter. In
fact there is a correlation between the incontinence
extension and the saphenous vein diameter.9
The level at which the upper arch tributaries
drain toward the saphenofemoral junction. This
level has been defined as the “geometrical discharge
height of the upper arch tributaries.” The disconnection of tributaries at a high geometrical height
could cause the formation of a collateral circle that
is vicarious because of the obstruction (iatrogenicsurgical), and this could be the source of retrograde
flow either after crossectomy or after strippingcrossectomy. In such cases, the reflux is not associated with points of reflux, as is often shown in
maps referring to patients operated on with excessively ablative methods. In fact, in these tributaries,
the pressure components are represented not only
by the residual venular pressure, but also by a high
hydrostatic column. By contrast, the hydrostatic
column is very low in the tributaries that are located at low geometrical height. The evolution of these
collateral circles can cause cavernomas (“neovascularization”), which represent the re-entry of the relapse itself. These are negative Valsalva cavernomas.
In subsequent years, these areas can become reflux
points from the common femoral vein, and they can
therefore become Valsalva positive reflux points.
Valsalva positive reflux points can also be those cavernomas that originate from tributary disconnection from a pelvic shunt.
As a consequence of the aforementioned speculations and findings, it could be argued that the
study of inflow level of the tributaries may condition the choice between tie/no tie of these arch
tributaries and, in the case of their conservation, it
will be of importance to decide where to let them
drain — either in the common femoral vein or in
the saphenous vein.
In an analysis of 1294 patients with incontinent
great saphenous vein crosses (saphenofemoral complexes), complete incontinence of the saphenofemoral junction was noticed in only 55% of cases.9
In 6% of cases, a dissociation pattern (see above)
was noted. Using the same criteria, the proximal
femoral valve (ie, the valve in the common femoral
vein located above the saphenofemoral junction)
was also studied. In 58.4% of complete incontinence
cases, it was found to be continent in the saphenofemoral junction and the saphenous vein arch. In
THE VENOUS VALVE
AND
most cases of continence of the upper femoral valve,
the saphenous trunks (measured at the mid thigh
area) exhibit a diameter that is lower than 7 mm.9
These observations outline some important considerations: first, 42% of incontinence in the great
saphenous vein with incontinence of the saphenofemoral junction is associated with the absence of
incontinence of the femoral valve located above the
saphenofemoral junction. In such cases, the hydrostatic column is of relevance, and a saphenofemoral
surgical disconnection (eg, crossectomy or crossotomy) would be appropriate. Second, 58% of incontinence of the great saphenous vein with incontinence of the saphenofemoral junction is associated
with continence of the proximal femoral valve. In
these cases, where the hydrostatic femoral column
is low, any of the endovenous procedures can be
recommended when a “demolishing” operation is
preferred (chosen?). Last, 45% of the generically
termed “cross incontinence” in the great saphenous vein is in reality associated with continence
of the terminal saphenous valve. In these cases, the
therapeutic gold standard is treatment of pelvic reflux and/or suppression of incontinent peripheral
tributaries (first time CHIVA 2), and surgical treatment of the cross would not be recommended. Endovenous ablative treatments could be indicated in
cases where the terminal valve of the great saphenous vein is continent, although we would like to
highlight the ethical problem regarding the possible demolition of these saphenous veins, which
have a diameter that is normally less than 6 mm.
Hence, either disconnection or sclerotherapy procedures on the incontinent tributaries can be performed, without any treatment of the saphenous
trunk.10 REFERENCES
1. Tessari L. Histoire des éveinages: des origines au début du
XX e siècle. Phlébologie. 2000;2:259-265.
2. Cappelli M, Molino Lova R, Ermini S, et al. Ambulatory conservative hemodynamic management of varicose veins: critical
analysis of results at 3 years. Ann Vasc Surg. 2000;14:376-384.
3. Cappelli M, Molino Lova R, Ermini S, Zamboni P. Hemodynamics of the saphenous-femoral junction. Patterns of reflux and
their clinical implications. Int Angiol. 2004;23:25-28.
4. Escribano JM, Juan J, Bofill R, Maeso J, Rodriguez-Mori A,
Matas M. Durability of reflux elimination by a minimal invasive
CHIVA procedure on patients with varicose veins. A 3-year
prospective case study. Eur J Vasc Endovasc Surg. 2003;25:159163.
5. Criado E, Juan J, Fontcuberta J, Escribano JM. Haemodynamic surgery for varicose veins: Rationale and anatomic and haemodynamic basis. Phlebology. 2003;18:158-166.
6. Cappelli M, Molino Lova R, Ermini S, Zamboni P. Relationship
between the caliber of the greater saphenous vein and the com-
petence, or absence/incompetence of femoral valve in subject
with incompetence of the sapheno-femoral junction. 5th meeting of the European Venous Forum. June 25-June 27, 2004;
Warsaw, Poland. Abstract.
7. Reagan B, Folse R. Lower limb venous dynamics in normal
persons and children of patients with varicose veins. Surg Gynecol
Obstet. 1971;132:15-18.
8. Genovese G. Chirurgia delle Vene e dei Linfatici. Masson Edit;
2005.
9. Cappelli M, Molino Lova R, Ermini S, Giangrandi I, Giannelli
F, Zamboni P. Hemodynamics of the sapheno-femoral complex:
an operational diagnosis of femoral valve function. Int Angiol.
2006;25:356-360.
10. Tessari L. Empleo de esclerosantes en forma de microespumas
en la terapéutica de los grandes ejes venosos superficiales. Magistral lecture at the 2nd International Course on Subdiaphragmatic Chronic Venous Insufficiency: Abdominopelvic and Lower
Limbs. October, 2004; Madrid, Spain.
ÉTUDE DE LA JONCTION SAPHÉNOFÉMORALE
POUR COMPRENDRE LA DISTRIBUTION DES REFLUX
DANS LA MALADIE VEINEUSE CHRONIQUE
A
vant de prendre une décision concernant le traitement adéquat pour
un patient variqueux, il est nécessaire de définir comment une aire spécifique (par exemple le complexe saphénofémoral) peut être évaluée
chez le patient. Nous allons envisager deux aspects différents : d’abord, comment étudier un segment incontinent, ensuite, comment observer le complexe
saphénofémoral, en se fondant sur les critères généraux décrits pour un segment incontinent. La continence valvulaire doit être étudiée en orthostatisme
de façon à développer un gradient transvalvulaire rétrograde (opposé à l’orientation du plan valvulaire). Le gradient rétrograde est étudié de deux façons
différentes : 1) un test de haute pression, tel que le test de Valsalva ; et 2) un test
de gravitation, qui exploite le poids de la colonne sanguine une fois qu’elle a été
mobilisée. L’analyse de 1294 patients ayant une incontinence de la crosse de
la grande veine saphène (complexe saphénofémoral) n’a révélé l’incontinence
complète de la jonction saphénofémorale que dans seulement 55 % des cas. Une
dissociation n’était notée que dans 6 % des cas. La valvule fémorale proximale
a aussi été étudiée en utilisant les mêmes critères (par ex. la valvule de la veine
fémorale commune située au-dessus de la jonction saphénofémorale). Elle s’est
avérée être continente à la jonction saphénofémorale et au niveau de la voûte
de la veine saphène dans 58,4 % des cas d’incontinence complète. Lorsque la
valvule fémorale supérieure est continente, les troncs saphènes (mesurés au milieu de la cuisse) présentent un diamètre inférieur à 7 mm.
THE VENOUS VALVE
AND
he different pathological conditions affecting the venous system of the lower limbs can
be complicated to diagnose because of the
anatomical and physiological characteristics of this
area.
The superficial venous system of the lower limbs,
which statistically is more affected by parietal and
valvular alterations than other venous regions of
the body, is made up of two main veins, the great
and the small saphenous veins, and various collateral veins. It is linked to the deep venous system by
the perforating system, which although we cannot
define as a superficial venous system, is often involved in the pathological processes of this system.
Moreover, 6% of individuals are carriers of anomalies of the internal saphena, such as the double
saphena or triple saphena, or irregularities of calibre or position.1 Similar considerations can be made
with regard to the external saphena in terms of anomalies or the number of collaterals2; these anomalies are often more complex than those of the internal saphena. Absence of the saphenopopliteal
junction, with an implantation of the external
saphena in other veins (perforations of the leg or internal saphena)3 or anastomosis with the popliteal
vein at a different level from normal, represent some
of the challenges in diagnostics and in surgical
therapy.4
To these anatomical observations we need to add
others regarding physiological aspects. The first
consideration is regarding the force of gravity,
which obstructs the venous return to the right atrium. The return of venous blood to the right atrium
is a result of the equilibrium between the centrifugal and the centripetal forces, the first being represented most importantly and constantly by the
force of gravity, but also by accidental forces, such
as coughing or certain movements such as jumping to one’s feet or going up or down the stairs. The
centripetal force is represented by the “vis a tergo”
and the “vis a fronte:” plantar pressure reduction
during walking,5 the calf muscle pump,6-9 venous
tone, and the pulse of the contiguous arteries.10 The
return of venous blood to the right atrium is also
helped by the venous valves. These valves are bicuspid plicae of endothelium and they serve to block
the centrifugal forces and to ensure the one-way
flow of blood.
Venous circulation is regulated by the Poiseuille
law, which organizes liquid flow in the vessels; its
application is more complicated than in the arterial system, because of the anatomical and physiological considerations described above. In the 1930s,
engineering and medical research focused its attention on diagnostic systems that would be able to
detect anatomical and hemodynamic alterations to
the venous system.
T
Filippo FERRARA, MD
Department of Internal Medicine
Cardiovascular disease and Nephro-urology
Massimo MIDIRI, MD
Department of Radiological Science
University of Palermo, ITALY
Imaging of venous
valves: B-Flow
b y F. F e r r a r a a n d M . M i d i r i ,
Italy
iagnosis of the different pathological conditions of the lower limb venous system is complicated, because of the anatomical and physiological characteristics of this region. A total of 6% of individuals have an
anatomical anomaly of the internal or external saphena (ie, double or triple
saphena, irregularities of calibre or position), and in addition, there are physiological aspects that need to be considered regarding the return of blood to
the right atrium, which is important for the equilibrium between the centrifugal and centripetal forces. In the 1930s, engineering and medical research was
based on diagnostic systems that detected anatomical and hemodynamic alterations. The introduction of the echo-color Doppler systems represented an
important evolution. Nevertheless, conventional B-mode and color flow imaging have inherent limitations that degrade their utility: B-mode and color flow
involve compromises in either axial resolution or penetration; in addition, acoustic noise artifacts may mask out the extremely weak echoes from red blood
cells. This is an important limitation, especially in the evaluation of the venous
system. B-Flow imaging is a new technique that uses digitally encoded sonographic technology to provide direct visualization of blood echoes in grayscale.
This technique allows simultaneous imaging of blood flow, vessel walls, and
neighboring tissues. Compared with color Doppler sonography, B-Flow sonography has a higher frame rate and better spatial resolution. Major limitations
of color Doppler sonography, such as aliasing, signal dropout at high Doppler
angles, color flash, and perivascular color artifacts, are eliminated with this
technique.
D
Keywords: venous valve; blood echo; color flow Doppler; B-Flow imaging;
spatial resolution
Doppler evaluation of the
venous system
Address for correspondence: Prof Filippo Ferrara, Via Autonomia Siciliana 94, 90143 Palermo, Italy
(e-mail: f_ferrara@virgilio.it)
Continuous wave Doppler
In the 1970s, the first applications of continuous
wave Doppler were described in venous diagnostics;
this method demonstrated important limitations,
Imaging of venous valves: B-Flow – Ferrara and Midiri
THE VENOUS VALVE
however. It was not able to demonstrate the morphological alterations of the vein walls, and it could
not identify all of the low-velocity flow.
AND
Less energy:
poor penetration
More energy:
good penetration
Wideband:
good axial resolution
Narrowband:
poor axial resolution
B-mode and color flow Doppler
In subsequent years, the introduction of the echocolor Doppler systems represented an important
evolution, especially when new tools were used with
color module and pulsed wave Doppler. These tools
can directly and immediately identify alterations in
the morphology of the vein wall and valves, and can
study the venous flow, even with the Valsalva test
or A-sound and S-sound squashing applications.
Nevertheless, despite many improvements over the
past two decades, conventional B-mode and color
flow Doppler imaging have a number of inherent
limitations that degrade their utility for assessing
hemodynamics in major blood vessels.
Limitations
First, both B-mode and color flow imaging involve
compromises in either axial resolution or penetration. This fundamental trade-off is illustrated in Figure 1. In general, the shorter the transmit pulse,
the better the axial resolution (ability to resolve two
closely spaced objects). On the other hand, in order to improve penetration, more signal energy is
needed. The problem is that the pulse amplitude
(instantaneous sound pressure) must be kept within some maximum allowable limit in accordance
with regulatory requirements. This means that the
only way to increase the energy of the pulse is to
transmit a longer pulse. As a result, improved penetration invariably compromises axial resolution.
In addition, in B-mode, acoustic noise artifacts
may mask out the extremely weak echoes from red
blood cells—echoes that are typically 1/1000th the
strength of signals from the vessel wall and surrounding tissue. This is an important limitation in
the evaluation of the venous system.
By using large “packets” of longer transmit pulses, along with special filtering and signal processing, color flow imaging is able to offer far better visualization of weak blood echoes. However, there
are drawbacks to this improvement in flow sensitivity: the large packets limit frame rate, and the
longer transmit pulses degrade spatial resolution.
So while color flow imaging may be very sensitive
to flow signals, thereby yielding valuable quantita-
Figure 1. With conventional B-mode and color flow Doppler, users
must choose between good axial resolution and good penetration.
With less energy there is poorer penetration, and with more energy,
there is better penetration. With wideband, there is good axial resolution, with narrowband, there is poor axial resolution.
tive velocity and power information, its temporal
and spatial resolution is very limited. In an attempt
to combine the better aspects of each mode, the conventional approach is to acquire and overlay color
flow data on B-mode data. But this approach also
poses significant snags. Alternating between these
two modes inevitably compromises the scanner’s
frame rate. In addition, any large tissue motion in
the color flow overlay may be displayed as a “color
flash artifact,” overshadowing the true flow data.
Finally, because color flow has lower resolution, filling in the vessels with color will almost always result in some overwriting of the vessel walls in the
B-mode image, which can conceal subtle lesions in
the vessel being studied.
B-Flow imaging
B-Flow imaging11 is a relatively new technique that
uses digitally encoded sonographic technology to
provide direct visualization of blood echoes in grayscale. This technique allows simultaneous imaging
of blood flow, vessel walls, and neighboring tissues.
When compared with color Doppler sonography,
B-Flow sonography has a higher frame rate and
better spatial resolution. Major limitations of color
Doppler sonography, such as aliasing, signal dropout at high Doppler angles, color flash, and perivascular color artifacts, are eliminated with this technique.12
With B-Flow imaging, we enhance weak signals
and suppress unwanted echoes. As illustrated in
Figure 2, the digitally encoded ultrasound beam-
Receive decoder
Transmit
encoder
Sensitivity
increase
Equalize
tissue-blood
B-mode
processing
Display
monitor
Figure 2.
The B-Flow image
formation process.
Electronic focusing
Probe
Flow vessel
After reference 13:
GE Ultrasound Europe.
B-Flow: A New Way of
Visualizing Blood Flow:
Ultrasound Technology
Update. Solinger, Germany: GE Ultrasound
Europe; 1999. Copyright
© 1999, GE Ultrasound
Europe.
THE VENOUS VALVE
AND
Transmit
Figure 3. Illustration
of the mechanism
behind coded excitation
encoding and decoding.
After reference 13: GE Ultrasound
Europe. B-Flow: A New Way of
Visualizing Blood Flow: Ultrasound Technology Update.
Solinger, Germany: GE Ultrasound Europe; 1999. Copyright ©
1999, GE Ultrasound Europe.
Receive
1
1
1
0
1
0
1 1
Digital
encoder
Sensitivity
increase
Coded sequence of 8 pulses
Wideband
pulse
former consists of a transmit encoder and a receive decoder in addition to the array focusing
electronics. Sending coded pulse sequences into
the body, the system decodes the returning signals
to enhance sensitivity to weak signals, and to suppress nonmoving tissue signals. The rest of the data
processing is essentially the same as with conventional B-mode. To form a two-dimensional B-Flow
image, the B-mode processor accumulates the decoded and processed signals from the transducer
array, reformats them into a pixel display—a process
known as scan conversion—and produces an intensity mapping of the resultant data using B-mode’s
finely graded grayscale.
For each scan line in the image, the scanner
transmits not one, but a coded sequence of wideband pulses that are amplitude-modulated according to a special digital code (saw-tooth pattern in
bold line, Figure 3). Clearly, the coded pulse sequence carries much more energy than a single
pulse, which translates directly into better signalto-noise ratio or sensitivity.
Now imagine the coded pulse sequence bouncing
back from a single perfect reflector. The receive
decoder recognizes the code, disassembles the pulse
sequence into individual amplitude-modulated pulse
units, and effectively stacks them up to form a single pulse of amplitude given by the sum of the individual code units. Notice that the higher amplitude
pulse has the same temporal length as the original
wideband pulse. Therefore, after decoding, one sees
an imaging pulse of increased energy while maintaining wideband resolution.
By itself, the aforementioned operation would
increase both tissue and blood flow echoes by the
same amount, which could make the large tissue
signals look saturated in the display. Thus, for each
scan line, the decoder further preferentially suppresses the signal samples that show a high degree
of similarity between successive pulse sequences,
which are indicative of nonmoving tissue. The degree of tissue suppression is adjustable. The preferred mode is to reduce nonmoving tissue signals
to a level comparable with that of flow signals, but
as an option, the decoder can also completely remove all background tissue, resulting in an angiogram-like display.
B-Flow provides direct visualization of blood
echoes in a display just like that of B-mode. Because
it images blood flow and its surrounding anatomy
simultaneously and eliminates the need for overlays, the resulting images provide a clear, unob118 MEDICOGRAPHIA, VOL 30, No. 2, 2008
Enhanced
wideband pulse
structed view of the vessel lumen. The grayscale
presentation of the flow data is also very intuitive,
requiring no mental translation of the pixel data
into velocity or power information.
B-Flow pixel brightness
Two primary factors determine the pixel brightness
in B-Flow images: the strength of echoes from the
blood, and the velocity of blood. In arterial flow, the
blood echo in each pixel represents the summed
effect of backscattered sound waves from tens of
A
B
C
Figure 4. Superiority of B-Flow (B and C) over color
Doppler imaging (A) in the visualization of venous
flow and the venous wall.
THE VENOUS VALVE
A
C
thousands of red blood cells. The fine-grained appearance of the blood echoes is therefore similar
to the “speckle” texture one sees in conventional
B-mode images of soft tissue.
In general, blood echogenicity varies with a number of interrelated blood conditions, including
hematocrit, the degree of red blood cell aggregation14 (rouleaux formation), and flow state (laminar
or turbulent).15 For example, the extensive red blood
cell aggregations that occur in low shear venous
flow can significantly enhance blood echoes.
The velocity of blood relative to the ultrasound
beam determines the degree of similarity between
echoes from successive coded sequences. As the
blood velocity increases, the red blood cells will
move in and out of each resolution volume of the ultrasound beam faster. As a result, the echoes from
the resolution volume will change by a greater
amount from one coded sequence to the next. Since
the change in echo information is used by the decoder to achieve tissue-blood equalization, the BFlow pixel brightness generally varies with both the
speed and direction of blood flow relative to the ultrasound beam. In general, as flow velocity increases, the B-Flow signal tends to increase. As the velocity becomes so high that the signal samples from
successive firings are uncorrelated, the corresponding B-Flow pixel brightness approaches a maximum.
Finally, extra care should be exercised in interpreting B-Flow images of disturbed or diseased flow
states. For example, rouleaux formation may be
promoted in the stagnant flow regions around a major blockage, which can enhance the B-Flow signal.
Flow turbulence that occurs distal to a significant
occlusion can, in theory, also enhance blood echogenicity. B-Flow interpretation is clearly more chal-
AND
B
Figure 5. Ability of B-Flow
imaging to highlight slow
venous flow. Panels A and B
show color Doppler images
with A-sound and S-sound
maneuvering, while panels C
and D show B-Flow images.
D
lenging in these situations, but it may also reveal
hemodynamics that have yet to be understood and
used for diagnosis. B-Flow offers a number of advantages over conventional imaging techniques.
Compared with conventional color techniques, BFlow delivers superior spatial resolution and frame
rate, allowing far better appreciation of the venous
hemodynamics. B-Flow is much less dependent on
the user or scanning angle.16 There is no need to
manipulate complex color control parameters such
as packet size, wall filters, and color write-priority
threshold—in fact, the vessel-wall overwriting problem is completely eliminated, as B-Flow is not an
overlay technique.
Although Doppler processing can clearly provide
valuable diagnostic information in terms of detecting blood flow, it is susceptible to such limitations
as aliasing, signal dropout at orthogonal detection
angles, and wall-filter limitations. As a B-mode
imaging technique, B-Flow provides direct visualization of blood echoes without these limitations.17
Clinical applications
B-Flow has especially been used to demonstrate ulcerated plaque and vessel-wall irregularities, as well
as being used to measure stenoses.18,19 It should
permit clinicians to measure the progression of
stenoses with greater precision, which will help to
better determine the appropriate follow-up intervals. B-Flow also has the potential to minimize the
need for angiography as well as its inherent costs
and risks.20,21
B-Flow’s ability to scan at high frame rates is important for visualizing not only vascular hemodynamics, but also the interaction of blood flow with
THE VENOUS VALVE
AND
anatomical structures inside the vessel such as venous valve cusps and thrombi. These fine structures
are usually masked by the color overlay in color flow
imaging.22
In Figure 4A (page 118), color-Doppler evaluation
shows a flow signal that is not contained within the
venous walls, thus hampering the visualization of
the vessel’s borders. B-flow technique improves
imaging quality, and can depict venous flow and the
vessel wall without the presence of “overwriting”
artifacts. Figure 4B illustrates B-flow evaluation before the Valsalva maneuver, and Figure 4C illustrates B-flow evaluation after the Valsalva maneuver: in addition to the reflux, the venous valve can
be seen as a slightly hypoechoic linear image (white
arrow).
Another advantage of B-Flow is that it can highlight slow venous flow (Figures 5C and D, page 119),
REFERENCES
1. Bouchet A. Anatomie normale et variations du système veineux
des membres inférieurs. I Artères et Veines. 1988;3:246-261.
2. De Simone J. Anatomie des veines musculaires du mollet. Phlébologie. 1996;49:299-308.
3. Dortu JA, Dortu J. Anatomie clinique du complexe saphénien
a la cuisse. Phlébologie. 1993;46:91-100.
4. Pfeifer JR. The anatomy and physiology of the venous system
of the lower extremities. Phlébologie. 1992;45:12-19.
5. Van Cleef JF. Modele dynamique de la pompe musculaire de
mollet dans l’insuffisance veineuse profunde. Phlébologie. 1992;
45:259-263.
6. Clayes R. Activitès de la musculature jambière dans la vie courante. Phlébologie. 1990;42:55-62.
7. Yang D, Vandongen YK, Stacey MC. Effect of exercise on calf
muscle pump function in patients with chronic venous disease.
Br J Surg. 1999;86:338-341.
8. Padberg FT Jr, Johnston MV, Sisto SA. Structured exercise improves calf muscle pump function in chronic venous insufficiency: a randomized trial. J Vasc Surg. 2004;39:79-87.
9. Labropoulos N, Giannoukas AD, Nicolaides AN, Veller M, Leon
M, Volteas N. The role of venous reflux and calf muscle pump
function in nonthrombotic chronic venous insufficiency. Correlation with severity of signs and symptoms. Arch Surg.1996;131:
403-406.
10. Van der Stricht J, Staelens I. Veines musculaires du mollet.
Phlébologie. 1994;47:135-142.
11. Chiao R, Mo L, Hall A, et al. “B-mode Blood Flow Imaging,”
AIUM Annual Convention, San Francisco, 2000 April 2-5. Abstract.
12. Clevert DA, Rupp N, Reiser M, Jung EM. Improved diagnosis
of vascular dissection by ultrasound B flow: a comparison with
color-coded Doppler and power Doppler sonography. Eur Radiol.
2005;15:342-347.
13. GE Ultrasound Europe. B-Flow: A New Way of Visualizing
Blood Flow: Ultrasound Technology Update. Solinger, Germany:
GE Ultrasound Europe; 1999.
14. Yuan YW and Shung KK. Ultrasonic backscatter from flowing whole blood. I: dependence on shear rate and hematocrit.
J Acoust Soc Am. 1988,84:52-58.
15. Sigel B, Machi J, Beitler JC, Justin JR, Coelho JCU. Variable
ultrasound echogenicity in flowing blood. Science. 1982;218:
1321-1323.
16. Whittinghan TA. Medical diagnostic applications and sources.
Prog Biophys Mol Biol. 2007;93:84-110.
17. Yucel C, Oktar SO, Erten Y, et al. B-flow sonographic evaluation of hemodialysis fistulas: a comparison with low- and highpulse repetition frequency color and power Doppler sonography.
J Ultrasound Med. 2005;24:1503-1508.
which cannot be visualized by color Doppler without the aid of A-sound and S-sound maneuvering
(Figures 5A and B). This permits an anatomical and
functional study of the valvular apparatus and venous hemodynamics in the functional conditions in
which the apparatus is to be found at the moment
of observation, and avoids the need to resort to the
aforementioned accelerations in flow that can result
in an overestimation of the extent of valvular insufficiency.
The usefulness of B-Flow will continue to evolve
as sonographers and physicians evaluate its utility
in new clinical situations. Its unique advantages
promise to make it an invaluable complement to
color flow imaging techniques in peripheral vascular applications. Its continued development also indicates that it might hold potential for other clinical applications and for contrast agent imaging. 18. Clevert DA, Johnson T, Jung EM, et al. Color Doppler, power
Doppler and B-flow ultrasound in the assessment of ICA stenosis:
comparison with 64-MD-CT angiography. Eur Radiol. 2007;17:
2149-2159.
19. Jung EM, Kubale R, Ritter G, et al. Diagnostics and characterization of preocclusive stenoses and occlusions of the internal
carotid artery with B-flow. Eur Radiol. 2007;17:439-447.
20. Yurdakul M, Tola M, Cumhur T. B-flow imaging of internal
carotid artery stenosis: comparison with power Doppler imaging
and digital subtraction angiography. J Clin Ultrasound. 2004;32:
243-248.
21. Wachsberg RH. B-flow, a non-Doppler technology for flow
mapping: early experience in the abdomen. Ultrasound Q. 2003;
19:114-122.
22. Graiche JA, Lane RJ, Cuzzilla MI, Coroneos JC, Berney CR.
Incompetent venous valves: ultrasound imaging and exo-stent
repair. Phlébologie. 2004;57:237-252.
IMAGERIE
DES VALVULES VEINEUSES
:
LE MODE
B
L
e diagnostic des différentes pathologies du système veineux du membre
inférieur est compliqué en raison des caractéristiques anatomiques et
physiologiques de cette région. Six pour cent d’individus au total présentent des anomalies anatomiques des saphènes interne ou externe (par exemple,
saphène triple ou double, des irrégularités de calibre ou de situation) et en plus,
certains aspects physiologiques doivent être pris en compte en ce qui concerne
le retour veineux dans l’oreillette droite, important pour l’équilibre entre les
forces centrifuge et centripète. Dans les années 30, la recherche industrielle et
médicale était basée sur des systèmes de diagnostic qui détectaient les altérations anatomiques et hémodynamiques. L’introduction de l’écho-Doppler
couleur est une évolution importante. Les limites inhérentes à l’imagerie en
mode B conventionnel et en couleur diminuent néanmoins leur utilité : le Doppler couleur et en mode B font un compromis entre la résolution axiale ou la
pénétration ; de plus, les artéfacts acoustiques sonores peuvent masquer les
échos extrêmement faibles venant des globules rouges. Cette limite est importante surtout dans l’évaluation du système veineux. L’imagerie en mode B est
une nouvelle technique qui utilise une technologie échographique numérisée
qui permet de visualiser directement les échos sanguins en échelle de gris. Elle
permet d’obtenir simultanément des images du flux sanguin, de la paroi des
vaisseaux et des tissus environnants. Comparée à l’écho-Doppler couleur, l’écho
en mode B a une vitesse de lecture d’images supérieure et une meilleure résolution spatiale. Elle élimine les principales limites de l’écho-Doppler couleur,
tels le repliement spectral, la disparition du signal aux angles Doppler élevés,
le flash couleur et les artéfacts de couleur périvasculaires.
THE VENOUS VALVE
AND
obust evidence has now been gathered to indicate that chronic venous disease (CVD) of
the lower limb is a noninfectious inflammatory disease.1 This picture has opened the door to
further investigation that may lead to an understanding of the trigger mechanisms of inflammation in CVD— the cause of its earliest manifestations—to form a basis for prevention and design of
new interventions. Markers of inflammation accompany every stage of the disease — from telangiectasia, venous eczema, ankle skin hyperpigmentation, atrophie blanche, and lipodermatosclerosis, to
the most severe forms involving varicose veins and
venous leg ulcers. This picture facilitates our understanding of the pathophysiological processes
that underlie these diverse manifestations, particularly at the cellular and molecular levels.
R
Geert W. SCHMID-SCHÖNBEIN, PhD
The Whitaker Institute of
Biomedical Engineering
University of California San Diego
La Jolla, CA, USA
Triggering mechanisms
of venous valve
incompetence
b y G . W. S c h m i d - S c h ö n b e i n , U S A
enetic risk factors, hormonal impregnation, prolonged hydrostatic pressure, and abnormal fluid shear stress in chronic venous insufficiency
may all serve as mechanisms that lead to the cascade of events associated with aseptic inflammation. The inflammation is manifest in the form of
activated endothelium, leukocyte adhesion to the endothelium and migration
into the tissue, mast cell degranulation, and T-lymphocyte and monocyte infiltration with macrophage transformation. Fibroblasts target the extracellular
matrix as well as parenchymal cells, and produce a spectrum of inflammatory
mediators and metabolites, cell membrane adhesion molecules, prothrombotic receptors, growth factors, and chemotactic agents. The inflammatory cascade serves fundamentally as a tissue repair mechanism. However, in chronic
venous insufficiency with development of valvular incompetence, the inflammation does not resolve, and instead leads to clinical manifestations that range
from varicosities to the eventual occurrence of ulcers. The factors that trigger
the inflammation in chronic venous insufficiency are still uncertain.
G
Keywords: inflammation; endothelium; growth factor; leukocyte; adhesion
molecule; proteinase; fluid shear stress; venous wall stretch
Address for correspondence: Geert W. Schmid-Schönbein, Department of Bioengineering,
Whitaker Institute of Biomedical Engineering, University of California San Diego,
La Jolla, CA 92093-0412, USA
(e-mail: gwss@bioeng.ucsd.edu)
Triggering mechanisms of venous valve incompetence – Schmid-Schönbein
The inflammatory process is
a repair mechanism
As a background to the following discussion, it is
important to remember that the inflammatory cascade, with its stereotypic steps, is designed to achieve
the initial removal of damaged tissue and the eventual generation and deposition of new tissue in the
“resolution of the inflammation.” As such, it serves
as the main biological repair mechanism in living
organisms. Every tissue can mount an inflammatory cascade and it is the only repair mechanism
present in mammalian tissue; it is used over and
again, from birth and through all the injuries sustained over a lifetime. Many individual steps in the
inflammatory cascade are required to achieve resolution of the inflammation. For example, the generation of new proteins, such as acute phase proteins,
cytokines, chemokines, or growth factors, forms
part of the repair aspect of the inflammatory cascade. If markers of inflammation persist over time,
and CVD is a prime example in this regard as it may
last for many years, we have to ask the question as
to what mechanisms exist to prevent resolution of
the inflammation and instead continue to cause
injury. It is not until we understand the initial injury mechanisms that we will be able to find the
most effective intervention. Otherwise, we are relegated to treatment of the disease symptoms only.
Early microvascular
manifestations of inflammation
One of the early signs of CVD at the microvascular level is elevated endothelial permeability, a state
that tends to be caused by the opening of interendothelial tight junctions as well as endothelial pore
formation. This can be readily observed in acute
SELECTED
CVD
ICAM-1
MMP
TGFβ1
VEGF
intercellular adhesion molecule–1
matrix metalloproteinase
transforming growth factor β-1
vascular endothelial growth factor
THE VENOUS VALVE
AND
models of venous hypertension. There are a large
number of mediators (histamine, complement protein, platelet activating factor, vascular endothelial growth factor [VEGF], cytokines) with the ability to elevate endothelial permeability; most of them
when applied to a venule, act transiently via nitric
oxide,2 actin polymerization, and selected small
GTPases.3,4 These early events in CVD may already
be driven by mechanisms that have the ability to
produce chronic inflammation. Elevation of endothelial permeability, with the opening of leakage
sites between endothelial cells, depends on the interendothelial adhesion molecule VE-cadherin,5 an
endothelial glycocalyx layer that is sensitive to enzyme degradation,6 the specific venular genotypes,7
and on exercise training.8 Thus, the reduction of endothelial permeability may be a target opportunity
for early intervention in CVD.
Angiogenesis and microvascular restructuring
A rich record exists of the relatively early event in
the inflammatory process in CVD that involves liposclerotic skin formed via capillary angiogenesis
and apoptosis in superficial layers of the skin. Areas
of white atrophy, known as atrophie blanche, may
show a loss of capillaries, while in other areas, the
capillaries become dilated, elongated, coiled, and
tortuous.9 This goes hand in hand with the occurrence of lesions in endothelial cells, with irregular
cell shapes and distortion of the luminal surface, increased intracytoplasmic vesicles, and intracellular
edema. Basement membranes fuse with the surrounding tissue. Pericapillary spaces are filled with
a fluid that can contain cellular fragments and proteins. Fibrinogen deposits known as fibrin cuffs can
be observed in the pericapillary spaces and around
capillaries.10
In lipodermatosclerosis, the skin capillaries are
elongated and tortuous, and even have a glomerular
appearance with proliferation of the capillary endothelium. VEGF is an obvious candidate for involvement in these changes, a factor that has also been
shown to increase microvascular permeability.
Plasma levels of VEGF increase during acute venous
hypertension11 and are higher in CVD patients with
skin changes than in CVD patients with normal
skin. Both VEGF expression and expression of its
receptor, Flk-1, are influenced by blood shear stress
and an inflammatory reaction. VEGF levels increase
with the severity of the disease and the CEAP score
(Clinical condition, Etiology, Anatomic location and
Pathophysiology).
It should be mentioned that in CVD, the skin is
associated with dermal tissue fibrosis. Immunocytochemical analysis of punch biopsy specimens
has shown that skin from the lower calf of CVD patients has significantly elevated active transforming
growth factor β–1 (TGFβ1) levels compared with
normal skin or skin taken from the thigh region of
the same patients. The TGFβ1 is located in leukocytes and fibroblasts, and on collagen fibrils. Activated leukocytes migrate out of the vasculature (see
next section) and release TGFβ1, stimulating increased collagen production by dermal fibroblasts,
leading to dermal fibrosis.12
Circulating cell entrapment and membrane
adhesion
The structural changes in the capillary network are
also accompanied by erythrocyte packing in the
lumen of capillaries, leukocyte entrapment within
capillaries and adhesion to the venular endothelium and valve leaflets, and even white cell/platelet
aggregate formation that can fill the lumen of microvessels. Leukocytes may be found in pericapillary
tissue in patients with CVD.13 Skin biopsies from
CVD limbs show elevated numbers of macrophages,
T-lymphocytes, and mast cells.14 The same pattern
has been observed in both acute15 and chronic16 experimental rat models of venous hypertension that
depend predominantly on pressure and fluid shear,
with elevated levels of tissue leukocytes in skin samples from affected limbs, but not from sham-operated controls.
The leukocyte entrapment within capillaries is
a result of the stiff cytoplasmic properties of the
leukocytes and their ability to express membrane
adhesion molecules. As a consequence, leukocytes
(eg, neutrophils, monocytes, T-lymphocytes) accumulate in the lower extremities under conditions of
high venous pressure. Their accumulation in microvessels is enhanced by the fact that the cells may
already be activated in the central circulation in patients with CVD,17 a process that further enhances
the stiffness of the cytoplasm as well as the membrane adhesion.18 At the microvascular level, there
are important details to consider regarding microvascular entrapment in the skin. Leukocyte entrapment in the narrow, single file capillaries can be
caused by a simple stiffening of the cytoplasm or by
projection of cytoplasmic pseudopods.19 No membrane adhesion is required. Since entrapment of
leukocytes by cytoplasmic stiffening is limited to
capillaries, the cytotoxic properties of leukocytes
have a bearing on the tissue parenchyma that surrounds the capillary network.
By contrast, attachment of leukocytes to postcapillary venules in the skin microcirculation requires
membrane adhesion to the endothelium via L-selectin on the leukocyte membrane and E-selectin
on endothelial cells. In this case, the venules are
the major site for the cytotoxic activity of leukocytes. The initial transient membrane attachment
is followed by firm adhesion via integrins, the starting point for leukocyte migration out of the vasculature and degranulation. In CVD, the evidence suggests that a variety of membrane adhesion molecules
on endothelial cells and leukocytes (intercellular
adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], lymphocyte function–
associated antigen–1 [LFA-1], very late antigen–4
[VLA-4], Mac 1, and others) appear to facilitate the
adhesion and stimulate the projection of pseudopodia as a requirement for transmigration of the
leukocyte into the venous wall. Basal plasma levels of the adhesion molecules ICAM-1, endothelial leukocyte adhesion molecule–1 (ELAM-1) and
VCAM-1 are higher in CVD patients than in controls, and are increased significantly in response to
venous hypertension provoked by standing.20 Any
combination of leukocyte cytoplasmic stiffening
THE VENOUS VALVE
and pseudopod formation together with enhanced
membrane adhesion molecule expression serves to
further enhance leukocyte trapping both in capillaries and in venules.
Little is currently known about the adhesion
molecules expressed on venous valve leaflets, although it is known that the valves require specific
transcription factors to be formed and that the endothelium on valve leaflets may have a different
phenotype to that of the endothelium on adjacent
blood vessels.21
Leukocyte activation
Leukocytes that accumulate in the microcirculation
become activated and are key players in the inflammatory reaction, provoking skin changes in CVD.
Although cytokines are part of the inflammatory reaction in CVD,22 no clear picture exists about their
exact role. For example, treatment with granulocyte/monocyte colony stimulating factor (GM-CSF)
to heal ulcers leads to mixed results. Tumor necrosis factor–α (TNFα), whose expression is enhanced
in many inflammatory reactions, stimulates the expression of inflammatory adhesion molecules, the
synthesis and release of other cytokines, and the
chemotaxis of neutrophils and macrophages. The
expression of TNFα appears to be upregulated in
patients with venous ulcers, and healing of the ulcer may reduce the level of TNFα.23 It is important
to remember that cytokine expression forms part of
the repair aspect of the inflammatory cascade, and
therefore no clear correlation with the degree of the
disease may exist.
Treatment of CVD patients by compression bandage wrapped around the diseased leg has a distinct anti-inflammatory effect.24 Although the exact
mechanism by which compression therapy operates
is unknown, the evidence indicates that we need to
consider mechanical stress as a mechanism for inflammation. Indeed, the transition from a normal
inactivated state to an activated state may not only
be facilitated by inflammatory mediators released
from the endothelium or from adjacent tissue (eg,
release of platelet activating factor, TNFα, and others) but also be caused by mechanical fluid shear
stress25 in the absence of chemical mediators.
Fluid shear stress is a tangential force (per unit
area), and it is present in all parts of a venule; on the
endothelium, in the wall of the venule, in the valve
leaflets, and elsewhere. Among the many mechanisms responsible, it can be produced by the movement of blood acting on the endothelial surface, in
which case it is a function of the velocity gradient of
blood near the endothelial surface and the blood
viscosity. This particular fluid shear stress is relatively low, ie, of the order of 10 dyn/cm2, a quantity
that is ~1/100th of the stress caused by the weight
of 1 cm H2O! Yet the lack of such low, but still physiologically relevant, levels of fluid shear stress can
lead to leukocyte activation even in the absence of
biochemical inflammatory mediators.26 The ability
of leukocytes and other cardiovascular cells to respond either to chemical or physical stimulation
has led to a significant deviation from past thinking
regarding trigger mechanisms for inflammation.
AND
The sensing mechanisms that allow cells to respond
to such small fluid mechanical forces involve Gprotein–coupled receptors.27 The phenomenon may
be quite relevant with respect to CVD, because of
the strong hemodynamic components of the disease. In the presence of a biophysical response to
fluid shear stress, a mere shift in the blood flow
field in venules may itself be a proinflammatory
stimulus.
There is now a large body of evidence to suggest
that virtually all functions of endothelial cells are
controlled by fluid shear stress.28,29 Steady shear
stress within a normal physiological range of about
10 dyn/cm2 is largely anti-inflammatory. In contrast,
low flow or flow disturbances, especially if they involve instances of reversed flow direction with forward and backward shear, cause a loss of this phenotype. Instead, the endothelial cell becomes more
susceptible to inflammatory mediators. Stretch of
endothelial cells and smooth muscle cells also has
a direct effect on many aspects of their biology,30 including synthesis and release of inflammatory molecules such as leukotrienes, prostaglandin, bradykinin, free oxygen radicals, and cytokines.
Finally, we should note that in addition to local
biochemical or biophysical factors operating during venous hypertension, CVD patients have a tendency toward systemically elevated leukocyte adhesion outside the veins in the affected leg. Central
venous plasma obtained from CVD patients has been
shown to induce higher degrees of activation (assessed by oxygen-free radical production and pseudopod formation) in healthy, naive granulocytes
than did plasma taken from normal subjects.17 The
nature of the plasma factor(s) responsible for the
activation is currently unknown.
Valve failure
A key event in CVD is the loss of the ability to properly close venous valves. Failure of valves may be
brought about by dilation of the venous wall and
the valvular annulus with remodeling of the valve
leaflets, bulging and stretching of valve leaflets,
commissural dilation, shortening, tearing and perforation of leaflets and, finally, complete destruction of the valve.31,32 Furthermore, ultrastructural
and immunohistochemical studies of valves and the
venous wall have revealed the presence of leukocytes adhering and transmigrating into the venous
wall.17,33 The leukocyte infiltration of the venous
parenchyma is accompanied by remodeling of the
extracellular matrix, a process that may in part be
responsible for the destruction of venous valves.
Tissue proteolytic activity
Chronic dermal ulcers involve proteolytic activity
that degrades extracellular matrix proteins. Proteases are also of major interest in this context, because
of their involvement in both the inflammatory reaction and the remodeling of cutaneous tissue.34,35
The overexpression of Ca/Zn-dependent endoproteinases (matrix metalloproteinases, MMPs), MMP-3
(stromelysin-1), and MMP-13 (collagenase-3) is as-
THE VENOUS VALVE
AND
A
Figure 1. A schematic
diagram illustrating selected
mechanisms that may control
inflammation of the vein wall
and valve leaflet. Normal vein
and valve leaflets (A). Valve
leaflets may be subject to
inflammatory damage by
alteration in magnitude and
direction of fluid shear stress
on the endothelium (B).
Venous valves may become
unable to close their leaflets
due to vein wall distension by
(C) elevated venous pressure
or by (D) weakening of the
vein wall due to proteolytic
degradation of its extracellular matrix. MMP, matrix
metalloproteinase.
Vein wall
Valve leaflet destruction
Altered fluid shear
stress on endothelium
Vein valve
C
Vein wall distension by pressure
Venous pressure
elevation by
• Orthostatic pressure
• Proximal venous obstruction
D
Vein wall distension by
proteolytic tissue weakening
Mechanisms for MMP
• Progesterone
• Genetic and environmental
• Leukocyte adhesion
sociated with nonhealing wounds.36 There is increased expression of MMP-2 and tissue inhibitor
of metalloproteinase (TIMP)–1 in liposclerotic skin,
venous leg ulcers, and wound fluid from nonhealing venous ulcers.37 An upregulation of the expression of MMP-9 has been observed on the edges of
venous ulcers, and the plasma of patients with severe CVD has an increased rate of MMP-9 activation.
Levels of TIMP-2 are lower in lipodermatosclerotic
skin and ulcers.37 Uncontrolled MMP activity may
contribute to extracellular matrix protein breakdown, which impairs healing.
MMPs are positioned on extracellular matrix proteins, and may be released from preexisting pools
or may be newly synthesized. The inactive pro-enzymes are activated by other proteinases, including
those produced by mast cells.38 Neutrophils have
gelatinolytic activity discharged by MMP-9, MMP-8
(a neutrophil collagenase), and leukolysin (a membrane-type MMP). Knockout experiments suggest
that MMP-9 acts upstream of neutrophil elastase by
proteolytically inactivating neutrophil elastase inhibitor A1PI,39 and that it can activate other MMPs.40
Extracellular MMP inducer (EMMPRIN; CD147) has
been observed to increase MMP expression, and
membrane type 1 MMP (MT1-MMP) was implicated
in the activation of MMPs. Venous leg ulcers have
elevated expression of EMMPRIN, MMP-2, MT1MMP, and MT2-MMP.41
An important issue is the activation of inactive
proenzymes in CVD. As discussed above, leukocyte
activation in patients with chronic venous insufficiency manifests itself in the form of degranulation,
with an increase in neutrophil elastase and lactoferrin release.42 The enzymes have been proposed to be
effective activators of other proenzymes, such as
MMPs.43 Other mechanisms by which MMPs are activated may involve serine proteases, such as trypsin,44 MMP-3, and MMP-13.45 Plasmin stimulates
pro-MMP enzyme conversion to the active form.46
Plasmin hyperactivity caused by decreased plasminogen activator inhibitor–1 (PAI-1) may thus
cause uncontrolled MMP activity. Elevated venous
pressure in CVD causes stretch not only of the veins
B
and venules, but also of the capillary network feeding the venules. An issue quite relevant, therefore,
is the fact that the expression levels of MMPs can be
controlled by mechanical stretch of cells in a way
that depends on the time course of the strain. This
has been studied in vitro in smooth muscle cells subjected to oscillatory and constant strain. Stationary
strain significantly increases MMP-2 mRNA levels
at all time points, whereas cyclic strain decreases it
after 48 hours. Both secreted and cell-associated
pro-MMP-2 levels are increased by stationary strain
at all time points, whereas cyclic strain decreases
secreted levels after 48 hours. MMP-9 mRNA levels
and pro-MMP-9 protein are increased after 48 hours
of stationary strain compared with no strain and
cyclic strain.47 Endothelial cells also respond to
stretch by restructuring the cell cytoplasm.48
Trigger mechanisms for inflammation
in chronic venous disease
Inflammation in CVD may continue without resolution for months and years. Our understanding of
the mechanisms that serve to maintain such an inflammatory state needs to be improved. The discussion above suggests that elevation of venous pressure per se, eg, after the loss of venous valves, with
stretching of endothelial cells and development of
an abnormal fluid shear stress pattern, may itself be
an injurious inflammatory stimulus. The available
evidence is compatible with this proposal, but detailed analysis with realistic models of the mechanical pattern of fluid in human veins is not currently available.
But one is compelled to ask the question “What
mechanisms may lead to destruction of a venous
valve in the first place?” (Figure 1). There is the possibility of venous wall distension by blood pressure
elevation, caused by posture or inadequate lower
limb activity (prolonged standing with lack of venous compression by muscle contraction). Some
patients may have obstructed proximal venous
pathways (eg, due to obesity) that cause chronically elevated pressure in veins of the lower limbs, and
THE VENOUS VALVE
may thus be candidates for venous stents. Longterm measurements in real-life environments are
required to fully understand the role of such factors in the disease. The venous wall may also be
distended because its mechanical properties are
weakened or because its smooth muscle is dilated.
The underlying mechanisms may be derived from
a genetic defect49 or the presence of a hormonal
load during early pregnancy (eg, progesterone50).
The distension of veins after pregnancy may remain without recovery if during pregnancy the exREFERENCES
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tracellular matrix was restructured. Over the period
of time required to develop manifestations of CVD,
it is likely that more than one mechanism may be
responsible for the injury and inflammation in veins.
The challenge is to identify the prevailing mechanism underlying CVD in each individual. Acknowledgement: I would like to thank my colleagues,
Drs John J. Bergan, Luigi Pascarella, Shinya Takase,
Takeshi Ono, Thomas Alsaigh, and Alexander Penn who
carried out the experimental studies summarized in
this report.
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in patients undergoing compression therapy. Eur J Vasc Endovasc
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Mechanisms for regulation of fluid shear stress response in circulating leukocytes. Circulation Research. 2000;86:E13-E18.
27. Makino A, Prossnitz ER, Bunemann M, Wang JM, Yao W,
Schmid-Schönbein GW. G protein-coupled receptors serve as
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28. Kakisis JD, Liapis CD, Sumpio BE. Effects of cyclic strain on
vascular cells. Endothelium. 2004;11:17-28.
29. Resnick N, Yahav H, Shay-Salit A, et al. Fluid shear stress and
the vascular endothelium: for better and for worse. Prog Biophys
Mol Biol. 2003;81:177-199.
30. Sasamoto A, Nagino M, Kobayashi S, Naruse K, Nimura Y,
Sokabe M. Mechanotransduction by integrin is essential for IL-6
secretion from endothelial cells in response to uniaxial continuous stretch. Am J Physiol Cell Physiol. 2005;288:C1012-C1022.
31. Van Cleef JF, Desvaux P, Hugentobler JP, et al. Étude endoscopique des reflux valvulaires sapheniens. J Mal Vasc. 1992;17:
113-116.
32. Blanchemaison P. Interet de L’endoscopie veineuse dans l’exploration et le traitement de l’insuffisance veineuse des membres
inferieurs. [Significance of venous endoscopy in the exploration
and the treatment of venous insufficiency of the legs]. J Mal Vasc.
1992;17(suppl B):109-112.
33. Ono T, Bergan JJ, Schmid-Schönbein GW, Takase S. Monocyte
infiltration into venous valves. J Vasc Surg. 1998;27:158-166.
34. Woodside KJ, Hu M, Burke A, et al. Morphologic characteristics of varicose veins: possible role of metalloproteinases. J Vasc
Surg. 2003;38:162-169.
35. Saito S, Trovato MJ, You R, et al. Role of matrix metalloproteinases 1, 2, and 9 and tissue inhibitor of matrix metalloproteinase-1 in chronic venous insufficiency. J Vasc Surg. 2001;34:
930-938.
36. Fray MJ, Dickinson RP, Huggins JP, Occleston NL. A potent,
selective inhibitor of matrix metalloproteinase-3 for the topical
treatment of chronic dermal ulcers. J Med Chem. 2003;46:35143525.
37. Mwaura B, Mahendran B, Hynes N, et al. The impact of differential expression of extracellular matrix metalloproteinase inducer, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-2 and PDGF-AA on the chronicity of venous leg
ulcers. Eur J Vasc Endovasc Surg. 2006;31:306-310.
38. Lees M, Taylor DJ, Woolley DE. Mast cell proteinases activate
precursor forms of collagenase and stromelysin, but not of gelatinases A and B. Eur J Biochem. 1994;223:171-177.
39. Liu Z, Zhou X, Shapiro SD, et al. The serpin alpha1-proteinase
inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo.
Cell. 2000;102:647-655.
40. Velasco G, Cal S, Merlos-Suarez A, et al. Human MT6-matrix
metalloproteinase: identification, progelatinase A activation, and
expression in brain tumors. Cancer Res. 2000;60:877-882.
41. Norgauer J, Hildenbrand T, Idzko M, et al. Elevated expression of extracellular matrix metalloproteinase inducer (CD147)
and membrane-type matrix metalloproteinases in venous leg ulcers. Br J Dermatol. 2002;147:1180-1186.
42. Shields DA, Andaz SK, Abeysinghe RD, Porter JB, Scurr JH,
Coleridge-Smith PD. Plasma lactoferrin as a marker of white cell
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AND
degranulation in venous disease. Phlebology. 1994;9:55-58.
43. Sansilvestri-Morel P, Rupin A, Jullien ND, et al. Decreased
production of collagen Type III in cultured smooth muscle cells
from varicose vein patients is due to a degradation by MMPs: possible implication of MMP-3. J Vasc Res. 2005;42:388-398.
44. Rosario HS, Waldo SW, Becker SA, Schmid-Schönbein GW.
Pancreatic trypsin increases matrix metalloproteinase-9 accumulation and activation during acute intestinal ischemia-reperfusion in the rat. Am J Pathol. 2004;164:1707-1716.
45. Vaalamo M, Mattila L, Johansson N, et al. Distinct populations
of stromal cells express collagenase-3 (MMP-13) and collagenase-1
(MMP-1) in chronic ulcers but not in normally healing wounds.
J Invest Dermatol. 1997;109:96-101.
46. Ercan E, Tengiz I, Duman C, et al. Decreased plasminogen
activator inhibitor-1 levels in coronary artery aneurysmatic pa-
tients. J Thromb Thrombolysis. 2004;17:207-211.
47. Asanuma K, Magid R, Johnson C, Nerem RM, Galis ZS. Uniaxial strain upregulates matrix-degrading enzymes produced by
human vascular smooth muscle cells. Am J Physiol Heart Circ
Physiol. 2003;284:H1778-H1784.
48. Kaunas R, Nguyen P, Usami S, Chien S. Cooperative effects of
Rho and mechanical stretch on stress fiber organization. Proc
Natl Acad Sci U S A. 2005;102:15895-15900.
49. Sansilvestri-Morel P, Rupin A, Badier-Commander C, et al.
Imbalance in the synthesis of collagen type I and collagen type III
in smooth muscle cells derived from human varicose veins. J Vasc
Res. 2001;38:560-568.
50. Miller AP, Feng W, Xing D, et al. Estrogen modulates inflammatory mediator expression and neutrophil chemotaxis in injured
arteries. Circulation. 2004;110:1664-1669.
MÉCANISMES DÉCLENCHANT
L’INCONTINENCE VALVULAIRE VEINEUSE
L
es mécanismes conduisant à la cascade d’événements associés à l’inflammation aseptique au cours de l’insuffisance veineuse chronique sont
les facteurs de risque génétiques, l’imprégnation hormonale, la pression
hydrostatique prolongée et la contrainte liquide de cisaillement anormale. L’inflammation se manifeste par l’activation endothéliale, l’adhésion leucocytaire
à l’endothélium et la migration dans les tissus, la dégranulation des mastocytes
et l’infiltration des monocytes et des T-lymphocytes avec transformation des
macrophages. Les fibroblastes ciblent la matrice extracellulaire ainsi que les
cellules parenchymateuses, et produisent un ensemble de métabolites et de médiateurs inflammatoires, de molécules d’adhésion des membranes cellulaires,
de récepteurs prothrombotiques, de facteurs de croissance et d’agents chimiotactiques. La cascade inflammatoire sert de façon fondamentale comme mécanisme de réparation tissulaire. Cependant, en cas d’insuffisance veineuse
chronique associée au développement d’une incontinence valvulaire, l’inflammation ne résoud pas et au contraire conduit à des manifestations cliniques
pouvant aller de la présence de varicosités à d’éventuels ulcères. Les facteurs
déclenchant l’inflammation dans l’insuffisance veineuse chronique restent encore incertains.
THE VENOUS VALVE
AND
Types of inheritance: the hypotheses
redisposing factors play a currently well-recognized role in varicose veins. The clinical
consensus is that primary varicose disease is
probably genetic in origin. As early as 1851, Rudolf
Virchow (1821-1902) observed an excess of family
cases, and in 1868, the pedigrees of two affected
families were reported. However, nongenetic factors probably play an important modulating role,
compounding the task of analysis. Late onset is entirely compatible with a genetic origin, as has been
shown in other common diseases (eg, familial atrioventricular block).1 The few twin studies provide
additional information: what data are available show
markedly higher concordance rates in monozygotic twins (75%) than in dizygotic twins (52%), although the difference is not statistically significant
given the small sample size.2 Impedance plethysmography of venous distensibility in twins has also
revealed that heredity plays an important role.3
The genetic factor thus appears to weigh heavily,
but its nature remains unelucidated. What is the
mode of transmission? Clues from family tree studies point to different types of inheritance: some early investigators suggested an autosomal dominant
mode of transmission,4-6 whereas others reported
findings more consistent with recessive transmission.7-9 It may therefore be that mode of transmission differs between families. Indeed, in 1969, Hauge
and Gundersen10 proposed a polygenic inheritance
hypothesis, based on cooperation between a number of independent genes each having minor pathogenic effect, but which collectively, when present
in sufficient numbers, resulted in varicose vein disease, just as in other common diseases in which inheritance plays a major role. The literature on varicose vein inheritance allows little in the way of
robust conclusions, given the numerous forms of
bias in data collection depending on the diagnostic
criteria used, the population selected, and whether
data about previous family members have been obtained by questioning the patient or by examining
the relative concerned. The reference study by Cornu-Thénard et al was based on 134 families whose
members were examined.11 Even if the multifactorial hypothesis readily accounts for a large number of family patterns, this does not mean that this
is the actual mode of transmission. In 1998, a Chinese study attempted a conclusive breakdown of
modes of varicose disease transmission:12 nuclear
family analysis was consistent with dominant autosomal transmission with 70% to 92% penetrance;
other pedigrees were consistent with autosomal recessive transmission, and 37% of cases were sporadic. These family transmission studies are fundamental because they inform molecular genetic
strategy, which can be either direct or indirect.
P
Marc A. PISTORIUS, MD
Department of Vascular Medicine
Centre Hospitalier Universitaire
de Nantes Hôtel-Dieu
Nantes, FRANCE
Venous valve
incompetence: the role
of genetic factors
by M. A. Pistorius, France
he role of inheritance in primary varicose veins is now well recognized,
although uncertainty persists as to the type of inheritance involved. Clear
understanding of the mode of transmission is essential in informing genetic research strategy. When the disease mechanism is known, direct methods can be used, but this does not apply to varicose veins; indirect methods must
be used instead. As in other common diseases, several types of inheritance may
be involved. In some families, transmission is dominant, strongly expressed,
and with a homogeneous phenotype. In such cases, a reverse genetic technique
can be applied known as linkage analysis, based on the study of large families.
We have used this to identify several loci potentially related to varicose veins,
but despite the presence of candidate genes within these regions of interest,
we have not yet identified a mutation within these families. At the same time,
other methods of investigation (transcription products of tissue samples, differential expression studies using deoxyribonucleic acid chips) may help to identify
new candidate genes. However, in most cases, the mode of segregation appears
nonMendelian, and associated with the environmental factors traditionally
described. This suggests polygenic or multifactorial inheritance. The molecular genetic techniques that can be used to identify one or more susceptibility
genes are more complex (sib-pair and association methods) and require a large
number of samples.
T
Keywords: extracellular matrix; genetics; inheritance; smooth muscle cell;
transmission; varicose vein disease
Address for correspondence: Prof Marc Pistorius, Médecine Vasculaire,
CHU Hôtel-Dieu, F-44000 Nantes, France
(e-mail: marc.pistorius@chu-nantes.fr)
Venous valve incompetence: the role of genetic factors – Pistorius
SELECTED
ECM
MMP
SMC
extracellular matrix
matrix metalloproteinase
smooth muscle cell
THE VENOUS VALVE
AND
Molecular genetic strategy
Direct methods
Direct methods can be used if the pathophysiology
of a particular disease has been elucidated, as when
an abnormal protein is shown to have a direct pathological role, and gene sequencing identifies a mutation (eg, hereditary hemoglobinopathy). Such
methods do not extrapolate to varicose veins, because the molecular mechanism is complex and remains unelucidated. Numerous pathophysiological
mechanisms have been described. Some investigators have differentiated primary changes that begin
in the vessel wall from those that begin in the valves.
Such an approach appears oversimplistic, since the
situation is rarely unambiguous. Even if valve lesions are recognized to be early and crucial events
in varicose disease, more widespread changes have
been identified in varicose patients, involving valve
insertions in the vein wall, changes in the vein wall
itself, and even the skin.13 Varicose disease is a pathological entity in its own right.14 It is not secondary
to physiological aging, but an instance of genuine
vascular dysplasia, comprising disorganization of
the vessel wall and a specific ratio of fibrillar to
basement membrane collagen that remains stable
over time.15
The first and most visible changes to have been
identified were abnormalities in extracellular matrix (ECM) metabolism, notably with a well-documented imbalance between types I and III collagen.16
This dysregulation in connective tissue synthesis
concerns abnormalities in ECM remodeling, mainly dependent on matrix metalloproteinases (MMPs)
and tissue inhibitors of metalloproteinases (TIMP).17
Abnormalities of MMP expression have been identified in varicose compared with control vessel wall:
increased expression of MMP1, and decreased expression of MMP9, each unevenly distributed within
the wall and varying between varicose segments.18,19
MMP imbalance within the ECM (in particular with
an accumulation of type I collagen and a decrease
in type III collagen) is found in the varicose wall
(myocytes), but also in the skin (fibroblasts),13,20 indicating a more general disorder of connective tissue synthesis in varicose patients.
After the ECM, the next most obvious abnormalities involve the smooth muscle cell (SMC) itself,
given its major role in ECM metabolism. Many
changes, both morphological21 and functional,22-24
have been demonstrated in varicose SMC. In addition, specific mutations may affect the complex, twoway, integrin pathway relationships between SMC
and ECM, with major potential impact on remodeling of the ECM and reorganization of the SMC cytoskeleton.25 More recently, the importance has been
emphasized of cell infiltration of the varicose wall,
in particular by monocytes and macrophages.26-28
The detailed role of this inflammatory infiltrate in
varicose vein remodeling has been elucidated: venous hypertension induces a leukocytic and endothelial inflammatory cascade via a mechanism that
combines valvular and vein wall hypoxia and slowing of blood flow (decreased shear stress).29,30 This
induces the expression of leukocyte adhesion mole-
cules,31 leading to valvular and vein wall infiltration by mononuclear cells (monocytes and mast
cells), which in turn are responsible for the production of growth factors, including transforming
growth factor β1 (TGFβ1).32,33 TGFβ1 is an important modulator of MMP/TIMP balance and is actually involved in the regulation of cellular apoptosis
and proliferation, a pivotal element in vascular remodeling. Several studies have in fact documented
inhibition of apoptosis in varicose wall myocytes.34,35
Many variations have been described in the expression of various proteins in varicose vein disease,
but differential gene expression has been less studied. Nevertheless, certain recently targeted abnormalities deserve our attention: what is the impact
of variations in the repeated nucleotide sequences
modulating the expression of structural genes (eg,
for connective tissue and elastic tissue) in the development of primary varicose veins?36 What is the
role of the transcriptional changes in vascular endothelial growth factor (VEGF) and its receptors,37
or of the mutations recently identified in the gene
coding for forkhead box C2 (FOXC2), a transcription factor specifically involved in valve development and maintenance?38 Other mutations or polymorphisms of candidate genes have been described
in the literature: MMP3 (stromelysin-1) polymorphism,39 the spondin 1 gene,40 or the thrombomodulin gene promoter,41 although with no conclusively identified pathophysiological implications. Each
of these molecular targets represents a potential
line of research, such as in functional SMC studies
(messenger ribonucleic acid, proteins), or comparative studies between varicose and healthy veins,
whether of differential ECM and SMC gene expression or of the signaling pathways involved. Direct
study of the molecular mechanism(s) leading to
varicose veins thus offers multiple interesting leads
but has limitations: what is the primary abnormality? Is it single or multiple? Are we not too focused
on disruption of a secondary control system?
Reverse genetics
When the pathophysiological mechanism behind a
condition is unknown, we can use a reverse genetic approach that identifies a potential culprit gene
by studying patients; once a gene is identified, we
can then elucidate the molecular mechanism behind the disease concerned. The multifactorial hypothesis accounts for a number of situations but,
as in other common diseases, there also appear to
be other modes of transmission. Several molecular
biology strategies are complementary and therefore
need to be conducted in parallel.
Bearing in mind the genetic heterogeneity seen
in other common conditions, we cannot rule out
the involvement in certain families of a single or
major gene with dominant effect, whose expression
is modulated by age and sex. Such families show
a clearly dominant and strongly expressed mode of
transmission, with a strikingly homogeneous phenotype.42 The reverse genetic technique of linkage
analysis can then be used.43 It is based on the study
of large data-rich families, with plenty of affected individuals and healthy controls, stretching over sev-
THE VENOUS VALVE
eral generations. Linkage analysis is an indirect
statistical method based on two fundamental biological phenomena: meiotic recombination (ie, the intense exchange of chromosome segments at meiosis), and the presence of polymorphic markers
throughout the genome (these are repeat sequences
that vary in length between individuals and are
found at regular intervals throughout the genome).44
The analysis searches for a statistical relationship
between one of these markers and the culprit gene,
reflected in the family tree by an affected phenotype. The result, expressed as the logarithm of the
odds (LOD) score, reflects the probability of a statistical linkage for each marker. The next step, which
is essential in pursuing the search for candidate
genes, consists of recruiting new families in order to
narrow these broad regions of interest by determining the shortest linkage interval shared by the different families. Once narrowed to a minimum, these
regions of interest can be searched for candidate
genes using computerized databases, using sequencing to detect a mutation in one of them.
From theory to practice:
our experience
In 2000, we began our study of six extended families in whom varicose disease segregated according
to a strongly expressed autosomal dominant mode
of transmission, with a particularly homogeneous
phenotype and high penetrance.42 We have managed to identify several loci potentially associated
with varicose disease, based on the phenocopy hypothesis (subjects with the same phenotype based
on a different genetic abnormality—a plausible hypothesis given the high frequency of the disease in
the general population) and the assumption of nonpenetrance in some subjects (ie, carriers of the mutant gene who do not express the disease). However,
despite the presence of candidate genes within these
regions of interest (genes involved in ECM metabolism, such as those coding for TIMP2, spondin-1,
elastases, integrins, and different types of collagen),
we have not yet identified a mutation in our families. Nor have our families shown the mutations
previously cited in the literature.39-41 Alternatively,
new candidate genes can be identified using parallel and complementary techniques, such as studies
of tissue sample transcription products36 or of differential expression using deoxyribonucleic acid
chips.45 Varicose vein disease also appears to be heterogeneous, both clinically and genetically. Like
others, we consider it to be a highly heterogeneous
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greater quantities of MMP-1 than normal veins and demonstrate
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233-238.
19. Woodside KJ, Hu M, Burke A, et al. Morphologic characteristics of varicose veins: possible role of metalloproteinases. J Vasc
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PD. Leukocyte activity in the microcirculation of the leg in patients with chronic venous disease. J Vasc Surg.1997;26:265-273.
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45. Lee S, Lee W, Choe Y, et al. Gene expression profiles in varicose veins using complementary DNA microarray. Dermatol
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439-454.
L’INCONTINENCE
VALVULAIRE VEINEUSE
LE RÔLE DES FACTEURS GÉNÉTIQUES
:
L’
importance de l’hérédité dans l’origine des varices primitives est actuellement admise. Des incertitudes persistent cependant concernant le type
d’hérédité en cause. Une bonne connaissance du mode de transmission
est cependant indispensable car cette étape guide la stratégie de recherche génétique. Les méthodes directes peuvent être appliquées lorsque le mécanisme
d’une maladie est connu, ce qui n’est pas le cas de la maladie variqueuse. Le recours aux méthodes indirectes s’impose. Comme dans d’autres maladies communes, plusieurs modes d’hérédité semblent exister. On observe en effet dans
certaines familles une transmission de type dominant, avec une expression
forte et un phénotype homogène. On peut alors appliquer une technique de
génétique inverse appelée « analyse de liaison », menée à partir de l’étude de
grandes familles. Elle a permis d’identifier plusieurs locus potentiellement liés
à la maladie variqueuse ; cependant, malgré la présence de gènes candidats au
sein de ces régions d’intérêt, aucune mutation n’a été identifiée pour l’instant
au sein de ces familles. Parallèlement, d’autres méthodes d’investigation (produits de transcription à partir de prélèvements tissulaires, étude de l’expression
différentielle sur puces à DNA), sont actuellement en cours et peuvent contribuer à identifier de nouveaux gènes candidats. Cependant, dans la majorité des
cas, le mode de ségrégation semble non mendélien, associé aux facteurs environnementaux classiquement décrits. Ceci fait appel aux notion d’hérédité
polygénique ou multifactorielle. Les méthodes de génétique moléculaire que
l’on peut mettre en œuvre pour identifier un ou plusieurs gènes de prédisposition sont plus complexes (méthode des « sib-pairs », méthode d’association) et
nécessitent un grand nombre d’échantillons.
THE VENOUS VALVE
AND
Arkadiusz JAWIEN, MD
Klinika Chirurgii Ogolnej
Bydgoszcz, POLAND
Treatment of
venous valve incompetence:
past, current, and future
A reflection on its evolution in
comparison with peptic ulcer disease
by A. Jawien, Poland
mproving the management of chronic venous
disorders is a timely topic, and our knowledge of
the disease remains incomplete. This is acknowledged by many experts in venous disease worldwide.1 With this in mind, I will attempt to establish
a parallel in this paper between research and advances in peptic ulcer disease and those in chronic
venous disease. The idea is to demonstrate that today, we have become “reflux hunters,” but the causes of diseased veins most probably lie elsewhere, and
might be approached via genetics, molecular biolo-
I
he aim of this article is to establish a parallel between the
dramatic evolution of treatment for peptic ulcer disease and
that of refluxing veins. Treatment of acid peptic disease has
involved a series of attempts to control gastric acid secretion in
order to heal and prevent recurrence of duodenal ulcers. Likewise,
it is believed that repair of refluxing valves and even more prevention of valve damage are the future of chronic venous disease
treatment. To come back to acid peptic disease, surgeons like
Pean, Rydygier, and Billroth began performing gastric resections
in the second half of the 19th century. In 1943, the first truncal
vagotomy was performed to limit cholinergic stimulation of gastric acid secretion. This led to surgery that combined gastric resections with vagotomy. In 1970, the first microsurgical technique
was performed, consisting of parietal cell vagotomy. This was able
to limit vagal initiation of acid secretion, while minimizing the
impact on other gastrointestinal functions. By the 1960s, pharmacological intervention included antacids to neutralize acid,
and anticholinergics to reduce the amount of acid produced. In
1976, treatment of acid peptic disease began a new phase, with
the introduction of the first H2 receptor antagonist. Since 1982,
the discovery of Helicobacter pylori has dramatically altered the
role of surgery in the management of peptic ulcer disease. In most
cases, medical treatment is undertaken with the use of specific
drugs aimed at managing Helicobacter pylori and acid secretion,
and interventional methods are mostly reserved for the treatment
of ulcer perforation. Today, surgeons are left only with surgical
T
gy, or pharmacogenotherapy. This is clearly the future, yet today, state-of-the-art treatment in venous
disease mirrors that of gastric surgery 25 years ago,
when gastric resection was the method of choice
for all patients with a peptic ulcer. I do not know if
our achievement in the next 25 years within the venous field will be comparable to that achieved in
gastric and duodenal ulcer therapy, but certainly
our patients will expect us to make much bigger
progress in the avoidance of surgery and the improvement of varicose vein treatment to make it
treatment of gastric ulcer complications (eg, perforations, bleeding, or neoplasmatic transformation of gastric ulcers). With regard to management of venous disease, a similar evolution over
time has been seen. For years, the method used for the elimination of superficial refluxes has been the stripping of the veins in
which the diseased valves were located. The high recurrence rate
after great saphenous vein surgery, together with the dramatic
improvement in the imaging of venous valves by means of sophisticated duplex scanning methods, has made it possible to reconstruct the diseased valve rather than remove it. The future remains to be determined in the field of venous disease management.
Strategies focused on the prevention of valve damage rather than
its reparation or resection might be envisaged. Similar to peptic
ulcer disease management, it is possible to contemplate that specific drugs aimed at correcting genetic defects, reinforcing venous
tone or preventing the inflammatory events that cause damage
to the valves could replace current treatment methods.
Keywords: acid peptic disease; venous valve incompetence;
reflux; pharmacological intervention; proton pump inhibitor;
progress
Address for correspondence: Prof Arkadiusz Jawien, Szpital Wojewodzki, SP ZOZ,
Klinika Chirurgii Ogolnej, ul. Ujejskiego 75, 85-168 Bydgoszcz, Poland
(e-mail: ajawien@ceti.com.pl)
Evolution of treatment of venous valve incompetence compared with peptic ulcer disease – Jawien
THE VENOUS VALVE
AND
Figure 1. X-ray image
of a gastric ulcer.
Copyright © Wellcome
Photo Library, Wellcome
Images, The Wellcome Trust.
more pleasant and effective, and with less recurrence. This raises the questions: what do we know,
what do we not know, what should we know to
progress in the management of venous disease, and
what can be contemplated in the near future to improve the management of our patients?
dor Billroth, performed a similar operation and later introduced another type of gastric resection consisting of a gastroenterostomy with oversewing of
the duodenal stump (known today as a Billroth II
gastric resection). Following the observation that
only partial gastrectomy made a hyperacid stomach
permanently anacid, by the 1930s, the removal of
66% to 75% of the distal stomach became the standard operation for peptic ulcer disease.2
In addition to many other people, Dragstedt knew
that peptic ulcers were caused by excess acid in the
stomach. Because of the known action of the vagus
nerves on gastric secretion, in 1943, he performed
the first truncal vagotomy to limit cholinergic stimulation of gastric acid secretion. This operation reduced 12-hour overnight gastric secretion by 50%
to 60% in all patients. After Dragstedt’s introduction of the vagotomy, it was simply a matter of time
before it was combined with gastric resections.2
In the early 1900s, Edkins reported that an antral
hormone, which he named gastrin, caused gastric
resection. Further experiments in dogs showed that
The history of peptic ulcer therapy
The history of the treatment of acid peptic disease
has involved a series of attempts to control gastric
acid secretion in order to heal gastric and duodenal ulcers and prevent their recurrence (Figure 1).
Gastric secretion is mediated by way of the vagus
nerves, gastrin, and protein derivatives of the digestion process.
Early treatment
Early treatment attempted to heal the disease by
neutralizing gastric acid with diet modification—
the Sippy diet, and Doll’s milk drip. Just before the
turn of the century, surgeons began performing gastric resections.
Resection procedures
Blalock gave a very good review of the history of
peptic ulcer surgery.2 On November 21, 1881, the
Polish surgeon, Ludwik Rydygier (Figure 2), became the first to excise the pylorus of a 30-year-old
woman with a gastric ulcer and successfully anastomose the stomach with the duodenum. This was
the first successful gastric resection ever performed
for a gastric ulcer, and the patient lived for the next
17 years without any clinical symptoms or signs. At
almost the same time, an Austrian surgeon, TheoSELECTED
CHIVA
DVR
deep venous reflux
GSV
PPI
proton pump inhibitor
Figure 2. Professor Ludwik Rydygier, the pioneer of
stomach surgery, who performed the first successful gastric resection for a gastric ulcer in 1881. Oil on canvas,
by the Polish painter Leon Wyczolkowski (1852-1936).
antrectomy caused a marked reduction in gastric
secretion. In 1976, Herrington published the results
of a large series of vagotomies and antrectomies,
following which, a more conservative vagotomy was
performed to prevent the nerves of the antrum and
pylorus from being injured. In 1970, the first parietal cell vagotomy was performed. This microsurgical technique limited vagal initiation of acid secretion, while minimizing the impact on other
gastrointestinal functions.2
Today, surgery for intractable or chronic ulcer
disease is rarely necessary; as a consequence, such
complex procedures as vagotomy with antrectomy
or highly selective vagotomy are virtually nonexistent. Surgery is now reserved for the treatment of
THE VENOUS VALVE
complications of the acute ulcer (eg, bleeding, perforation, and obstruction).3 Regarding duodenal ulcer perforation, the most common operative treatment is an omental (Graham) patch. More definitive
management is rarely necessary.
Pharmacological intervention
Progress in gastroenterological research over the
past century started as a consequence of the discoveries by Prout in the early 18th century of the presence of inorganic hydrochloric acid in the stomach
and Pavlov at the end of the 19th century of the neuroreflex stimulation of its secretion, for which he
was awarded the Nobel prize in 1904. The discovery
of H2 receptor antagonists by Black (Figure 3) and
their usefulness in the control of gastric secretion
and ulcer healing, was a real breakthrough both for
the elucidation of gastric secretory mechanisms and
for ulcer therapy. He was awarded the Nobel Prize
for this discovery, which opened the path to pharmacological intervention for gastric ulcers.
By the 1960s, pharmacological intervention included antacids to neutralize acid and anticholinergics to reduce the amount of acid produced. These
treatments varied in their effectiveness, and some of
them caused significant side effects. In 1976, treatment of acid peptic disease began a new phase, with
the introduction of the first H2 receptor antagonist,
cimetidine, which partially suppresses basal and
meal-stimulated acid secretion. Ranitidine, the second H2 receptor antagonist, produced greater acid
suppression capable of inducing an intragastric pH
level greater than 3, lasting for approximately 10
hours per day when given twice daily at recommended doses. This level of acid suppression can
facilitate the healing of duodenal ulcers, but has
limited efficacy for other indications (eg, gastrointestinal bleeding). The knowledge that there is a circadian pattern in acid production, with higher levels between 10 PM and 2 AM, further resulted in the
development and use of a single evening dose of
ranitidine.4
Research continued to be carried out to investigate the effects of dose timing and the influence
of more potent acid-suppressing agents. In the
late 1980s, a more potent class of acid-suppressing
agents was developed, the proton pump inhibitors
(PPIs). PPIs can induce an intragastric pH above 3
that lasts for approximately 17 hours per day, and
an intragastric pH above 5 that lasts for approximately 9 hours per day after once-daily oral administration of recommended doses. It is possible to attain even higher target pH values with large doses
and with continuous intravenous infusion. Thus,
PPIs are the agents of choice for the treatment of
many acid-related disorders, including peptic ulcer
disease and moderate-to-severe gastroesophageal
reflux disease, and for prevention of rebleeding in
patients with upper gastrointestinal bleeding. Availability of an intravenous formulation, pantoprazole,
enables hospitalized patients for whom oral administration is not feasible to benefit from the superior
potency of PPIs. It was suggested that intravenous
PPIs may be more effective than H2 receptor antagonist prophylaxis against stress-related ulcer
AND
bleeding for intensive care patients, and should facilitate healing in those with bleeding ulcers of the
upper gastrointestinal tract.5 A great step forward
was made when two Australian clinical researchers,
Warren and Marshall, discovered spiral bacteria in
the stomach, named Helicobacter pylori (H. pylori)
(Figure 4). They received the third Nobel prize in
the field of gastrology in the past century for the
finding that this bacterium is related to the pathogenesis of gastritis and peptic ulcer.6 They documented that the eradication of H. pylori from the
stomach, using antibiotics and potent gastric inhibitors, not only accelerates healing of the ulcer
but also prevents its recurrence, a finding considered to be the greatest practical discovery in gastrology during the last century. Thus, the outstanding achievements in gastroenterology during the
last century have resulted in three Nobel prizes and
have been appreciated by millions of ulcer patients
all over the world. Infection with H. pylori causes most duodenal ulcers (95%) and gastric ulcers
(70%). It is also likely to cause around 9% of dyspepsia cases in which no ulcers are detected.7
Figure 3. Sir James W.
Black, who developed the
first clinically useful H2
receptor antagonist,
cimetidine, for the treatment of gastric ulcer.
Copyright © The Nobel
Foundation.
Figure 4. Helicobacter pylori, discovered in the early
1980s by Robin Warren and Barrie Marshall to be the
cause of the majority of gastric and duodenal ulcers via
infection of the lower stomach and upper duodenum.
Copyright © 2006, Australian Academy of Science.
The dramatic success of pharmacological acid
suppression in the healing of peptic ulcers and the
management of patients with gastroesophageal reflux disease has been reflected in the virtual abolition of elective surgery for ulcer disease, a reduction
in nonsteroidal anti-inflammatory drug–associated
gastropathy, and the decision by most patients with
reflux symptoms to continue medical therapy rather
than undergo surgical intervention.8 The latter is
currently reserved only for gastric ulcer complications, namely perforation, bleeding, and neoplasmatic transformation of a gastric ulcer.
A number of challenges remain in the management of acid-related disorders, however, and a number of new drugs are currently being investigated
to provide a significant advance on current treatments. Some of them (namely, potassium-competitive acid blockers and cholecystokinin 2 [CCK2]–
THE VENOUS VALVE
AND
receptor antagonists) have already reached the
clinical testing stage, while others (for instance, the
antigastrin vaccine, H3-receptor ligands, and gastrin-releasing peptide receptor antagonists) are still
in preclinical development, requiring proof-of-concept in human beings. Of the current approaches
to acid secretion reduction, potassium-competitive
acid blockers and CCK2-receptor antagonists certainly hold the greatest promise, with several compounds already in clinical trials.
A parallel with the treatment of
superficial venous valve incompetence
The aim of treatment in chronic venous disease is
to eliminate sources of venous hypertension.9
Resection of the diseased superficial vein
In superficial venous insufficiency, the aim of treatment is to suppress reflux in the superficial diseased
veins (varicose veins).10 Reflux in superficial veins is
mostly responsible for venous hypertension. Until
10 years ago, the usual way to suppress reflux in diseased superficial veins was the following: first, suppress leakage points in the deep venous network
Figure 5. Incision in the
groin crease with exposure
of the great saphenous vein
(ligature surrounds it)
at the saphenofemoral
junction.
Reproduced from reference 12:
Goldman MP, Bergan JJ, Guex JJ,
eds. Role of surgery in treatment of
varicose veins. In: Sclerotherapy
Treatment of Varicose and
Telangiectatic Leg Veins, 4th ed.
Philadelphia, Pa: Mosby Elsevier;
2007:285-306. Copyright
© 2007, Elsevier Inc.
that could be responsible for reflux in the superficial system; next, strip pathologic superficial veins,
either by stripping the great saphenous vein (GSV)
of the thigh or at the other end of the spectrum,
stripping the entire saphenous vein from the ankle
to the groin, along with stab avulsion of varices. In
France, the two most performed procedures in 2001
were high ligation plus saphenous trunk stripping
and tributary stab avulsion (71.9%), and high ligation plus saphenous trunk stripping (17.3%).11 By
contrast, in the USA, high ligation alone at the
saphenofemoral junction has been widely practiced.9
Thus, type of procedures varied greatly depending
on countries and the dominant thinking among
phlebologists and surgeons. For a long time and
until recently, saphenofemoral ligation (Figure 5)
associated with stripping of the GSV was considered
the best procedure to achieve the goal of suppressing reflux in the superficial system.
Recurrent varicose veins after surgery are acknowledged to be a major problem for patients and
society. In an attempt to perform less bloody surgery
procedures, endovenous ablation was developed in
the 1990s. This procedure was found to be safe and
effective in eliminating the GSV from the venous
circulation. The two currently available methods
used to achieve ablation of the GSV are the Closure®
procedure using a radiofrequency catheter and generator, and endovenous laser ablation using a laser
fiber and generator (Figure 6). Both systems use
electromagnetic energy to destroy the GSV in situ.
We are presently lacking follow-up data to verify
whether these endovenous procedures lead to less
neovascularization than open surgery, but patient
acceptance of these minimally invasive procedures
is overwhelmingly better than with stripping. In
this regard, one can say that a step forward has been
made in the treatment of venous insufficiency, with
less invasive methods that are more comfortable
for patients.
Valve repair in superficial and deep venous
insufficiency
Specialists in venous disease dreamt of a valve repair or valve restoration process that could spare the
vein itself, much like the patches that were developed for perforation of duodenal ulcers. Direct and
indirect restoration of valve function was eventually performed.
Methods for indirect valve function restoration
all have in common the fact that they preserve the
saphenous trunk and restore its valve function via
modification of the hemodynamics. Conservative
Hemodynamic treatment of Incompetent Varicose
veins in Ambulatory patients (CHIVA) is a technique
that seeks to normalize venous pressure by ligation
of points of venous reflux at re-entry perforators.9
High ligation plus tributary phlebectomy plus/minus a perforator ablation procedure was first reported by Hammarsten, and was only used for treating
GSV insufficiency. The CHIVA procedure was later
further developed and popularized by Franchesci,
Zamboni, and Cappelli (see article by Perrin in the
current issue). Another vein-sparing technique is
external banding, which aims to restore proximal
valvular competence of the GSV. These procedures
are not widely practiced, however.
For deep venous insufficiency, the goal is to correct the deep venous reflux (DVR) at the subinguinal level. This reflux leads to a permanent increase in venous pressure, unaffected by the activity
of the calf venomuscular pump. But it must be kept
in mind that DVR is frequently combined with superficial and perforator reflux, consequently all
these mechanisms have to be corrected in order to
reduce the permanent increased venous pressure.
Several methods are used: internal valvuloplasty,
venous segment transfer, vein valve transplantation,
neo valve, and allograft. All these methods are associated with phlebectomy, while valvuloplasty and
percutaneous placed devices do not need associated phlebectomy.
Chemical interventions: sclerotherapy
Until now, chemical intervention has been limited
to liquid and foam sclerotherapy. Liquid sclerotherapy is mostly used in the treatment of telangiec-
THE VENOUS VALVE
Saphenous
femoral
junction
Saphenous femoral
junction
AND
n
essio
mpr
o
c
l
ta
Digi
Aiming
beam
Withdraw
fiber and
sheath
Great
saphenous
vein
Femoral
vein
Femoral
vein
A
B
Figure 6. Endovenous laser treatment. A. Fiber optic starting position, before applying laser energy and withdrawing, in the great saphenous vein. B. Catheter and fiber withdrawal in pulsed mode.
Reproduced from reference 13: Goldman MP, Bergan JJ, Guex JJ, eds. Intravascular approaches to the treatment of varicose veins: radiofrequency and lasers. In: Sclerotherapy Treatment of Varicose and Telangiectatic Leg Veins, 4th ed. Philadelphia, Pa: Mosby Elsevier; 2007:
307-316. Copyright © 2007, Elsevier Inc.
tases. The results of such treatment for saphenous
vein insufficiency have been disappointing and
long-term results are missing. Ultrasound-guided
sclerotherapy with foam can be considered as a new
treatment for varicose veins.9 The principle of sclerosing agents is that they produce a lesion of the
venous wall, predominantly of the endothelium.
Venous spasm is observed within minutes, and is associated with endothelial cell destruction. The early
results seem to be very promising, but again, there
are few studies assessing the long-time results. Nevertheless, at least in Europe, the ultrasound-guided
sclerotherapy with foam has dramatically reduced
the number of varicose vein surgical operations and
has opened the door to minimally invasive, highly
effective treatment that can replace saphenectomy and eliminate reflux in the superficial venous
system.
Conclusion
If dramatic progress has been made over the last
decade in the treatment of venous insufficiency,
moving from open surgery to minimally invasive
interventions, a great step remains if we are to accomplish an advance that is comparable with that
achieved in the treatment of peptic ulcers. This is in
large part due to a lack of research into the fundamental mechanisms of chronic venous disease progression. As says Professor John Bergan, the first
author of an outstanding review on chronic venous
disease:14
It is an unfortunate fact that research interest
and funding attracted by chronic venous disease
has been in inverse proportion to its prevalence
and socioeconomic burden. It has enormous capacity to impair the quality of patients’ lives, mildly in most cases, moderately in many, and severely in the cases of the significant number with leg
ulceration. This state of affairs is unwarranted,
not simply for humanitarian reasons, but also in
terms of fundamental research. Recent studies in
chronic venous disease have illuminated our understanding of the underlying mechanisms responsible for the progression of such disease to
the extent that it was useful for us to review current knowledge, with particular regard to the roles
of the key players namely the leukocyte, its inflammatory products, and biomechanical factors.
It appears that inflammatory processes involving
leukocyte/endothelial interactions, triggered largely in response to abnormal venous flow, are important in causing the adverse changes in venous
valves and vein walls. Elevated venous pressure and
changes in shear stress are involved in the control
of inflammatory reactions in endothelial cells and
circulating leukocytes. Decreased shear stress modifies gene expression at the endothelial surface,
promoting an inflammatory endothelial phenotype.
Normal shear stress prevents leukocyte adhesion to
valves, while inflammatory mediators suppress the
response of leukocytes to shear stress. Thus the interaction between leukocytes and valve endothelium is facilitated. Inflammation unmasks cell adhesion molecules at the surface of the endothelium,
promoting leukocyte adhesion to the endothelium.
In addition, chronic venous disease patients have a
tendency for systematically elevated leukocyte adhesion.14
The practical purpose of elucidating the molecular steps involved in the development of valve lesions is to intervene with a targeted treatment. The
sequence of leukocyte adhesion, endothelial interaction, activation, and migration, and its association with valvular damage, has focused attention on
available molecules with known activity to modify
this chain of events. It is high time we stopped our
role as venous reflux hunters and became wise, modern pharmacogeno-healers, armed with new molecular biology and nanotechnology tools. Let us hope
that this will be realized in the coming years. Evolution of treatment of venous valve incompetence compared with peptic ulcer disease – Jawien
THE VENOUS VALVE
AND
REFERENCES
1. Padberg FT. Improving the management of chronic venous
disorders: exploration, description, and understanding. Parallels
in the worlds of the Renaissance and the American Venous Forum. J Vasc Surg. 2005;41:355-365.
2. Blalock J. History and evolution of peptic ulcer surgery. Am
J Surg. 1981;141:317-322.
3. Ramsay Camp E, Hochwald SN. Gastroduodenal procedures.
Available at: http://www.medscape.com. Accessed September 17,
2007.
4. Warner CW, McIsaac RL. The evolution of peptic ulcer therapy. A role for temporal control of drug delivery. Ann N Y Acad Sci.
1991;618:504-516.
5. Garnett WR. History of acid suppression: focus on the hospital
setting. Pharmacotherapy. 2003;23:56S-60S.
6. Konturek SJ, Konturek PC, Brzozowski T, Konturek JW, Pawlik WW. From nerves and hormones to bacteria in the stomach;
Nobel prize for achievements in gastrology during last century.
J Physiol Pharmacol. 2005;56:507-530.
7. Shah R. Dyspepsia and helicobacter pylori. BMJ. 2007;334:
41-43.
8. Scarpignato C, Pelosini I, Di Mario F. Acid suppression therapy: where do we go from here? Dig Dis. 2006;24:11-46.
9. Zimmet SE. Principles of treatment of varicose veins by sclerotherapy and surgery. In: Bergan JJ, ed. The Vein Book.London,
England: Elsevier; 2007:227-230.
10. Perrin M. Cure chirurgicale des varices des membres inférieurs par stripping des veines saphènes. Ann Chir.1997;7:735-744.
11. Bergan JJ. Inversion stripping of the saphenous vein. In:
Bergan JJ, ed. The Vein Book. London, England: Elsevier; 2007:
231-237.
12. Goldman MP, Bergan JJ, Guex JJ, eds. Role of surgery in treatment of varicose veins. In: Sclerotherapy Treatment of Varicose
and Telangiectatic Leg Veins, 4th ed. Philadelphia, Pa: Mosby Elsevier; 2007;285-306.
13. Goldman MP, Bergan JJ, Guex JJ, eds. Intravascular approaches to the treatment of varicose veins: radiofrequency and lasers.
In: Sclerotherapy Treatment of Varicose and Telangiectatic Leg
Veins, 4th ed. Philadelphia, Pa: Mosby Elsevier; 2007;307-316.
14. Bergan JJ, Schmid-Schônbein G, Coleridge-Smith P, Nicolaides A, Boisseau M, Eklof B. Chronic venous disease. N Engl
J Med. 2006;355:488-498.
TRAITEMENT DE L’INSUFFISANCE VALVULAIRE VEINEUSE : PASSÉ, PRÉSENT ET FUTUR
UNE RÉFLEXION SUR SON ÉVOLUTION COMPARÉE À L’ULCÈRE GASTRODUODÉNAL
et article veut établir un parallèle entre l’évolution remarquable du traitement de l’ulcère gastroduodénal et celui
des veines refluantes. Pour traiter la maladie acido-peptique, on a tenté de contrôler la sécrétion gastrique acide afin de
guérir et prévenir la récidive d’ulcères duodénaux. De même, la
réparation de valvules refluantes et même plus, la prévention des
lésions valvulaires sont présentées comme l’avenir du traitement
de la maladie veineuse chronique. Pour revenir à la maladie acido-peptique, des chirurgiens comme Pean, Rydygier et Billroth
ont réalisé leurs premières résections gastriques dans la deuxième
moitié du XIXe siècle. En 1943, la première vagotomie tronculaire a été effectuée pour limiter la stimulation cholinergique de
la sécrétion gastrique acide. Ceci a mené à une chirurgie qui a associé résections gastriques et vagotomie. En 1970, la première
technique microchirurgicale est apparue sous la forme d’une vagotomie cellulaire pariétale. Elle permettait de limiter la composante vagale de départ de la sécrétion acide en minimisant l’impact sur les autres fonctions gastro-intestinales. Dans les années
60, les antiacides pour neutraliser l’acide et les anticholinergiques
pour diminuer la quantité d’acide produite ont fait partie des traitements pharmacologiques. En 1976, une nouvelle phase du traitement de la maladie acido-peptique voit le jour avec l’introduction du premier antagoniste des récepteurs H2 . Depuis 1982, la
découverte d’Helicobacter pylori a complètement bouleversé le
C
rôle de la chirurgie dans la prise en charge de l’ulcère gastroduodénal. Dans la plupart des cas, le traitement médical est entrepris
avec des molécules spécifiques destinées à Helicobacter pylori et
la sécrétion acide et les méthodes interventionnelles sont principalement réservées au traitement de l’ulcère perforé. De nos jours,
les chirurgiens ne s’occupent que du traitement chirurgical des
complications de l’ulcère gastrique (par exemple, perforations,
saignement ou transformation maligne des ulcères gastriques).
La même évolution au cours du temps a eu lieu en ce qui concerne
la prise en charge de la maladie veineuse. Depuis des années, le
stripping des veines abritant des valvules pathologiques a été la
méthode utilisée pour l’élimination des reflux superficiels. Le taux
élevé de récidive après chirurgie de la grande veine saphène associé à l’amélioration très importante de l’imagerie des valvules
veineuses grâce à des méthodes sophistiquées d’écho-Doppler pulsé, ont permis d’envisager la reconstruction de la valve malade
plutôt que sa résection. Les perspectives dans le cadre de la prise
en charge de la maladie veineuse restent à préciser et il faudrait
créer des stragégies de prévention des lésions valvulaires plutôt
que la résection ou la réparation. Comme pour l’ulcère gastroduodénal, il est possible de considérer que les médicaments spécifiques destinés à corriger les défauts génétiques, renforcer le tonus
veineux ou prévenir l’inflammation qui endommage les valvules,
pourraient remplacer les méthodes de traitement actuelles.
C
O N T R O V E R S I A L
Q
U E S T I O N
The saphenofemoral junction:
to ligate or not to ligate?
1
P. Pai, India
igation of the saphenofemoral junction
(SFJ) was first proposed by Trendelenburg
in 1890 and modified to its current form
by Moore and Thomas in 1896.1 Extended flush
high ligation (HL), taking care to cauterize or tie
all the tributaries right up to the first or second
level, is the current recommended technique.2 HL
with removal of the great saphenous vein (GSV)
has been the universally accepted surgical treatment of axial venous reflux for almost a century.
HL alone aimed at preserving the GSV for future
use is associated with poor results, because reflux
persists,3 resulting in recurrent varicose veins.4-7
HL with stripping of the thigh GSV gives better
results than HL with sclerotherapy or stab avulsions.8 These results suggest that removal of the
thigh portion of the GSV with detachment of its
perforator tributaries is more important than HL
itself and it remains a crucial step in the treatment of axial reflux.2 Two issues now threaten this
procedure after almost 100 years. First, there is
the need among surgeons who treat venous reflux to use minimally invasive methods, ablating
only the GSV and leaving the SFJ untouched.
The second is the duplex ultrasonography (DUS)based observation that significant varicose vein
recurrence 9 is due to neovascularization, even after technically correct HL. Several aspects need to
be answered in deciding for or against HL: (i) what
are the causes of recurrence after SFJ ligation?
(ii) is the risk of neovascularization sufficient to
abandon the procedure? (iii) does neovascularization also occur if the SFJ is left untouched? and
(iv) what are the alternative procedures available?
Most recurrence is due to technical failure. Viani
et al 10 reported that in 61 patients with recurrence, 50.8% had an intact SFJ, 44.2% had intact
tributaries coming from the SFJ, and only 3.2%
showed neovascularization. Bradbury et al 11 found
that of 71 patients undergoing repeat groin dissection, only 20 (28%) had a ligated SFJ, 31 (44%)
had intact major tributaries, and 52 (73%) had
an intact GSV in the thigh. Neovascularization is
considered to be the cause of recurrence when
HL is technically perfect.9,12 However, Egan et al 13
found that DUS identified neovascularization in
only 8.2% limbs with recurrence. Surgical exploration revealed a residual GSV stump with one
or more significant tributaries in 27 out of 41 recurrent limbs. Each of the remaining 14 limbs had
a residual incompetent thigh GSV. Two prospective studies by De Maeseneer et al suggested that
the incidence of neovascularization after SFJ
ligation is much higher in both the short term 12
(14% of cases at 1 year) and long term 14 (68% of
cases at 5 years). Neovascularization is also seen
after radiofrequency ablation of the GSV and,
surprisingly, is more common when the SFJ is
not ligated (67% vs 34% when ligated).15 Neovascularization after HL may be reduced by using
barrier techniques such as polytetrafluoroethylene
(PTFE),16 silicon17 patches, and endoablation of
the intima of the ligated SFJ stump by under-running the mouth with prolene sutures.18 In summary, at this stage, it may be premature to condemn HL as a cause of neovascularization and/or
recurrence. Technical modifications with better
preoperative assessment to identify other factors
responsible for high hydrostatic and hemodynamic forces will probably give better recurrence-free
results after HL. More prospective randomized
trials with periodic and regular DUS follow-up
are needed before the concept of sparing the SFJ
can be proved to be effective and acceptable. REFERENCES
1. Caggiati A, Allegra C. Historical introduction. In: Bergan
JJ ed. The vein book. Oxford, UK: Elsevier Academic Press;
2007:1-14.
2. Bergan JJ, Kumins NH, Owens EL, Sparks SR. Surgical
and endovascular treatment of lower extremity venous insufficiency. J Vasc Interv Radiol. 2002;13:563-568.
3. Fligelston L, Carolan G, Pugh N, Minst P, Shandall A, Lane I.
An assessment of the long saphenous vein for potential use
as a vascular conduit after varicose vein surgery. J Vasc Surg.
1993;18:836-840.
4. McMullin GM, Coleridge-Smith PD, Scurr JH. Objective
assessment of high ligation without stripping the long saphenous vein. Br J Surg. 1991;78:1139-1142.
5. Jones L, Braithwaithe BD, Selwyn D, Cooke S, Earnshaw JJ.
Neovascularisation is the principal cause of varicose vein recurrence. Results of a randomised trial of stripping of the long
saphenous vein. Eur J Vasc Endovasc Surg. 1996;12:442-445.
6. Dwerryhouse S, Davies B, Harradine K, Earnshaw JJ.
Stripping the long saphenous vein reduces the rate of re-operation for recurrent varicose veins: Five-year results of a
randomised trial. J Vasc Surg. 1999;29:589-592.
7. Winterborn RJ, Foy C, Earnshaw JJ. Causes of varicose vein
recurrence: Late results of a randomised trial of stripping of
the long saphenous vein. J Vasc Surg. 2004;40:634-639.
8. Rutgers PH, Kitslaar PJ. Randomized trial of stripping versus
high ligation combined with sclerotherapy in the treatment
of the incompetent greater saphenous vein. Am J Surg. 1994;
168:311-315.
9. De Maeseneer M. Neovascularisation: an adverse response
to proper groin dissection. In: Bergan JJ, ed. The vein book.
Oxford, UK: Elsevier Academic Press; 2007:239-246.
10. Viani MP, Poggi RV, Pinto A, Andreani SM, Spagnoli C,
Maruotti RA. Re-exploration of the sapheno-femoral junction
in the treatment of recurrent varicose veins. Int Surg.
1996;81:382-384.
11. Bradbury AW, Stonebridge PA, Ruckley CV, Beggs I. Re-
L
Paresh PAI, MS
The Vascular Clinic
15 Dar-Ul-Muluk
26 Pandita Ramabai Road
Mumbai 400 007, INDIA
(e-mail:
drpareshpai@mtnl.net.in)
The saphenofemoral junction: to ligate or not to ligate?
current varicose veins: correlation between preoperative clinical and hand-held Doppler ultrasonographic examination,
and anatomical findings at surgery. Br J Surg. 1993;80:
849-851.
12. De Maeseneer MG, Ongena KP, van den Brande F, Van
Schil PE, De Hert SG, Eyskens EJ. Duplex ultrasound assessment of neovascularisation after sapheno-femoral or sapheno-popliteal junction ligation. Phlebology. 1997;12:64-68.
13. Egan B, Donnelly M, Bresnihan M, Tierney S, Feeley M.
Neovascularization: an “innocent bystander” in recurrent
varicose veins. J Vasc Surg. 2006;44:1279-1284.
14. De Maeseneer MG, Tielliu IF, Van Schil PE, De Hert SG,
Eyskens EJ. Clinical relevance of neovascularisation on duplex
ultrasound in the long-term follow-up after varicose vein operation. Phlebology. 1999;14:118-122.
2
15. Salles-Cunha SX, Comerota AJ, Tzilinis A, et al. Ultrasound
findings after radiofrequency ablation of the great saphenous
vein: Descriptive analysis. J Vasc Surg. 2004;40:1166-1173.
16. Earnshaw JJ, Davies B, Harradine K, Heather BP. Preliminary results of PTFE patch saphenoplasty to prevent neovascularisation leading to recurrent varicose veins. Phlebology.
1998;13:10-13.
17. De Maeseneer MG, Vandenbroeck CP, Van Schil PE. Silicon
patch saphenoplasty to prevent repeat recurrence after surgery
to treat saphenofemoral incompetence. Long-term follow-up
study. J Vasc Surg. 2004;40:98-105.
18. Frings N, Nelle A, Tran P, Fischer R, Krug W. Reduction of
neoreflux after correctly performed ligation of the saphenofemoral junction. A randomized trial. Eur J Vasc Endovasc
Surg. 2004;28:246-252.
A. S. Sabbour, Egypt
main aim of venous surgery is to eliminate venous reflux. However, with all
treatment modalities, long-term recurrence remains a challenging problem, and one
with a relatively high incidence, for reasons that
have attracted many explanations,1 in particular
poor surgical technique and neovascularization.
During my surgical residency 25 years ago, “To
ligate or not to ligate” was not a question that
would ever have been proposed. Saphenofemoral
flush ligation, with meticulous ligation of all
tributaries at that level, was combined with great
saphenous vein (GSV) stripping as the standard
surgical technique. The growing trend toward less
invasive low-morbidity intervention, day surgery,
and outpatient procedures has combined with
the refinement of endoluminal vascular instruments to favor the introduction and increased
use of endoluminal ablation for GSV reflux. It
was these emerging techniques that prompted
the question “To ligate or not to ligate” since it
became impossible to ligate the saphenofemoral
junction (SFJ) and we therefore ignored the numerous venous tributaries around it. Research
sought to determine the effect of ligation and nonligation on the incidence of recurrence, and was
pushed a step forward to postulate that if recurrence was caused by neovascularization, then the
solution was to avoid surgical groin hematoma.
In the case of conventional surgery, we have longterm studies of patients’ groins up to 14 years
postoperatively.2 The consensus is that neovascu-
larization is the cause of recurrence in such cases,
in the absence of surgical error. By contrast, only
short-term follow-up is available for patients
treated with radiofrequency ablation,3 and very
few studies after endolaser ablation. Compared
with stripping and SFJ ligation, radiofrequency
ablation leaves physiologic tributary flow relatively undisturbed. Two year follow-up showed no
evidence of inguinal neovascularization.3 We
would do well to ask whether longer follow-up
would produce the same results. Descriptive analysis of ultrasound findings after radiofrequency
ablation showed small-vessel networks adjacent
or connected to the ablated GSV in most cases.
SFJ ligation, on the other hand, was associated
with fewer small-vessel networks and proximal
GSV recanalization when examined after a similar follow-up period.4 Whether these small networks will develop into large-caliber refluxing
veins needs long-term follow-up. At present, the
trend not to ligate the SFJ and its tributaries is
strongly supported by the growing endoluminal
ablation market. The technique is definitely less
invasive and gives results comparable to conventional surgery in terms of venous reflux elimination and patient satisfaction.5 Only time will
tell its effect on late recurrence. As the pendulum
swings between different emerging techniques,
it is clear that the ideal treatment for varicose
veins, based on a proper understanding of the
underlying pathology and hemodynamics, continues to elude us. REFERENCES
1. Perrin M, Gobin JP, Nicolini P. Recurrent varicose veins in
the groin after surgery. J Mal Vasc. 1997;22:303-312.
2. Hartmann K, Klode J, Pfister R, et al. Recurrent varicose
veins: sonography-based re-examination of 210 patients 14
years after ligation and saphenous vein stripping. Vasa. 2006;
35:21-26.
3. Pichot O, Kabnick LS, Creton D, et al. Duplex ultrasound
scan findings two years after great saphenous vein radiofre-
quency endovenous obliteration. J Vasc Surg. 2004;39:189-195.
4. Salles-Cunha SX, Comerota AJ, Tzilinis A, et al. Ultrasound findings after radiofrequency ablation of the great
saphenous vein: descriptive analysis. J Vasc Surg. 2004;40:
1166-1173.
5. Pannier F, Rabe E. Endovenous laser therapy and radiofrequency ablation of saphenous varicose veins. J Cardiovasc
Surg. 2006;47:3-8.
A
Ali S. SABBOUR, MD
Professor of Vascular Surgery
Ain Shams University
Cairo, EGYPT
(e-mail: alisabbour@link.net)
3
A. Mansilha, Portugal
arious interventions have been described
to correct the underlying pathophysiological abnormalities that lead to varicose
veins. Appropriate patient selection is crucial for
success. Treatment planning should be directed
by the presence/absence and location of axial
reflux, and the extent and location of the superficial venous pathology. Duplex ultrasonography
(DUS) has become the gold standard for this purpose and in most patients is the only diagnostic
investigation necessary in selecting the most
appropriate intervention. The parameters evaluated by DUS comprise: patency of the deep venous
system, evidence of prior deep vein thrombosis
or deep venous system reflux, great saphenous
vein (GSV) reflux and anatomy (eg, double GSV),
GSV diameter and distance from skin, small
saphenous vein reflux, anatomy of the saphenopopliteal junction, and perforator incompetence
and location. Treatment options include (i) for
GSV reflux: ligation and stripping, radiofrequency
or laser endovenous thermal ablation, and endovenous chemical ablation with a foam detergent;
(ii) for perforator incompetence: minimally invasive ligation, subfascial endoscopic perforator
surgery, sclerotherapy or even the Linton procedure; and (iii) for superficial varicosities and
varicose veins: stab avulsion phlebectomy, sclerotherapy and/or laser therapy. Management of GSV
incompetence has historically been treated with
high ligation of the GSV at the saphenofemoral
junction, ligation of all tributaries, and grointo-ankle stripping of the saphenous vein.1 This
surgery was highly invasive and associated with
severe pain and bruising, swelling, and disfiguring
scars. However, modern stripping techniques have
greatly reduced the associated trauma and morbidity. Stripping can now be performed as an
outpatient procedure in the above-knee segment
of the GSV without a distal incision for a better
cosmetic result. Early ambulation with elastic
stockings is encouraged. Endoluminal laser or
radiofrequency thermal ablation requires percutaneous access to the vein lumen. Initially, in
these ambulatory procedures, there was a concern
to use limited energy to restore competence to
the saphenofemoral valve, but this did not prove
effective in the long term.2 Intraoperative and
postoperative complications are infrequent, generally well tolerated, and include difficult device
access or advancement, transient heat, bruising,
pain, paresthesia, thermal skin damage, superficial thrombophlebitis, lymphedema, and deep
vein thrombosis. Some randomized trials have
concluded that endoluminal thermal vein ablation is as effective as conventional stripping.3,4
Some enthusiasts of ultrasound guidance and
intravenous foam injection have expanded the
indications for conventional sclerotherapy to include treatment of an incompetent GSV. They
argue that saphenofemoral occlusion using external compression or a balloon-tipped catheter
permits retention of foam sclerosant in the vein
long enough to produce sufficient damage to
cause sclerosis. Side effects are infrequent, usually
resolve spontaneously, and can include chest discomfort, nausea, dry cough, headache, dizziness,
visual disturbance, and psychogenic reactions.
Recently some authors have shown that ultrasound-guided foam sclerotherapy can be effective
even if GSV diameter at the saphenofemoral junction exceeds 10 mm, to a maximum of 16 mm,5
but further information is needed regarding bubble emboli and long-term follow-up. Procedure
costs appear highest for radiofrequency ablation,
somewhat lower for laser ablation, and significantly lower for chemical ablation. The answer
to the question “To ligate or not to ligate?” hangs
on the definition of neovascularization or recurrence. Some authors agree that neovascularization is secondary to “frustrated” venous drainage
from the abdominal wall and perineum, while
others believe that recurrence is the issue, due to
the enlargement of previously existing veins that
were ineffectively ligated and consequently cause
recurrent reflux in the thigh. The literature contains various reports of neovascularization or
recurrence after ligation and stripping 6 and also
after radiofrequency/laser procedures.7 In my view
the answer also depends on the definition of successful treatment, including the entire procedure,
the method of screening for treatment failure,
and the reporting of results. Recent advances in
ultrasound technology allow more critical evaluation of clinical results than in the past. We
need more high-quality randomized multicenter
studies, and long-term follow-up of endoluminal
ablation, both thermal and chemical, before we
can define their role and costs compared with
modern minimally-invasive GSV stripping. REFERENCES
1. Sarin S, Scurr JH, Coleridge-Smith PD. Stripping of the
long saphenous vein in the treatment of primary varicose veins.
Br J Surg. 1994;81:1455-1458.
2. Danielsson G, Jungbeck C, Peterson K, Norgren L. Venous
function after restoring valve competence of the great saphenous vein. J Endovasc Ther. 2003;10:350-355.
3. Rautio T, Ohinmaa A, Perala J, et al. Endovenous obliteration versus conventional stripping operation in the treatment
of primary varicose veins: a randomized controlled trial with
comparison of the costs. J Vasc Surg. 2002;35:958-965.
4. Lurie F, Creton D, Eklof B, et al. Prospective randomised
study of endovenous radiofrequency obliteration (closure)
versus ligation and vein stripping (EVOLVeS) : two-year fol-
low-up. Eur J Vasc Endovasc Surg. 2005;29:67-73.
5. Barrett JM, Allen B, Ockelford A, Goldman MP. Microfoam
ultrasound-guided sclerotherapy treatment for varicose veins
in a subgroup with diameters at the junction of 10 mm or
greater compared with a subgroup of less than 10 mm. Dermatol Surg. 2004;30:1386-1390.
6. Fischer R, Chandler JG, De Maeseneer MG, et al. The unresolved problem of recurrent saphenofemoral reflux. J Am
Coll Surg. 2002;195:80-94.
7. Pichot O, Kabnick LS, Creton D, et al. Duplex ultrasound
scan findings two years after great saphenous vein radiofrequency endovenous obliteration. J Vasc Surg. 2004;39:
189-195.
V
Armando MANSILHA, MD
PhD, FEBVS, Department
of Vascular Surgery
Oporto Medical School
Hospital S. João, Alameda
Prof. Hernâni Monteiro
4200-319 Porto, PORTUGAL
(e-mail:
mansilha@netcabo.pt)
4
P. Pittaluga and S. Chastanet, France
I
Paul PITTALUGA, MD
Sylvain CHASTANET, MD
Corresponding author:
Paul Pittaluga
Riviera Vein Institute
6 rue Gounod Nice
06000 Nice, FRANCE
(e-mail:
paulpittaluga@hotmail.com)
n cases of great saphenous vein (GSV) reflux,
the ostial valve is often competent. The frequency of subostial or more distal trunk reflux
is estimated at around 50% in the literature.1-6
Endovenous treatments for GSV reflux that spare
the saphenofemoral junction (SFJ) during GSV
ablation have called into question the principle
of high ligation of the SFJ.7,8 Midterm results using endovenous techniques show anterograde
drainage of the SFJ collaterals toward the deep
vein in 85% to 100% of cases.9-11 Yet high ligation of the SFJ remains the rule when stripping
the GSV. Since October 2003, given the results
of endovenous treatment, we have stopped combining high ligation with surgical stripping, even
in cases of ostial reflux. We recently reported the
hemodynamic and clinical results of this new approach at the 19 th Annual Congress of the American Venous Forum, in San Diego, CA, USA. We
observed no reflux in the preserved SFJ in 98%
of cases over a mean follow-up of 24.4 months.
These results are at least comparable with, or
even superior to, the 80% to 97% absence of SFJ
reflux reported 2 years after endovenous radiofrequency or laser treatment.8-13 This prompts the
question: Does surgical stripping combined with
extensive phlebectomy improve the hemodynamics of the preserved SFJ, given that the GSV
cannot recanalize and, perhaps especially, that
the varicose reservoir has been ablated? The
hemodynamic benefits of varicose reservoir ablation are mentioned in the literature.14 Despite
inguinal surgery, the rate of inguinal neovascularization was very low in our series (1.8% at 2
years). This figure is no higher than the 0% to
2.8% recorded after endovenous treatment,8-11 and
much lower than in surgical studies of extended
high ligation with rates of 20% to 53%.15-17 Preserving the superficial abdominal and perineal
venous drainage by not dissecting the SFJ and
not disconnecting the collaterals appears to avoid
neovascularization. Using a limited inguinal approach without dissecting the SFJ does not therefore seem to cause more neovascularization
since it preserves the drainage of SFJ collaterals
into the femoral vein. Our clinical recurrence
rate (6.3%) can be compared with stripping combined with extended high ligation, where the
figures vary from 10% to 25% after 2 years.15,18
Our recurrence rate is also better than the 12%
to 15% observed after endovenous treatment with
an identical follow-up.9-11 It is difficult to compare
the different studies because none have quantified either the preoperative varices or varicose
reservoir resection. Moreover, in our study, clinical recurrence was independent of SFJ reflux in
6 cases out of 7, just as GSV ablation did not lead
to recurrence in the studies of endovenous treatment.9-11 These observations support the increasingly propounded theory that varicose disease
develops from the superficial distal venous network,3-6,19 rather than downwards from the junctions between deep and superficial venous networks, as in the conventional view.20,21 However,
we did observe one serious postoperative complication: SFJ thrombosis extending into the femoral
vein, with pulmonary embolism, but fortunately
no further serious sequelae. This potentially serious complication has been reported after endovenous treatment 9,22-24 and should probably be
taken into account by targeted prevention when
preserving the SFJ, for example by using low
molecular weight heparin or conventional high
ligation with multiple phlebectomy in patients
with thrombophilia, a history of thrombosis, or
a very dilated junction (>20 mm). Early postoperative Doppler ultrasonography (after 24-48
hours) could also be recommended for detecting
thromboembolic complications.24 In endovenous
treatment, conserving the SFJ is beneficial during
surgical ablation of the GSV because it preserves
physiological venous drainage of the inguinal
region and minimizes the mid-term risk of neovascularization and varicose recurrence. Further
studies are needed in order to assess the postoperative risk of SFJ thrombosis and the long-term
hemodynamic results of this surgical approach
and of SFJ-preserving endovenous techniques. REFERENCES
1. Abu-Own A, Scurr JH, Coleridge-Smith PD. Saphenous vein
reflux without incompetence at the saphenofemoral junction.
Br J Surg. 1994;81:1452-1454.
2. Labropoulos N, Delis K, Nicolaides AN, Leon M, Ramaswami
G. The role of the distribution and anatomic extent of reflux
in the development of signs and symptoms in chronic venous
insufficiency. J Vasc Surg. 1996;23:504-510.
3. Labropoulos N, Giannoukas AD, Delis K, et al. Where does
venous reflux start? J Vasc Surg. 1997;26:736-742.
4. Engelhorn CA, Engelhorn AL, Cassou MF, Salles-Cunha SX.
Patterns of saphenous reflux in women with primary varicose
veins. J Vasc Surg. 2005;41:645-651.
5. Labropoulos N, Leon L, Kwon S, et al. Study of the venous
reflux progression. J Vasc Surg. 2005;41:291-295.
6. Pittaluga P, Chastanet S, Réa B, Barbe R, Guex JJ, Locret T.
[Duplex ultrasonography scanning for superficial venous insufficiency: Correlation of mapping with age, symptoms and
signs]. Phlebologie. 2006;59:149-156.
7. Guex JJ, Min RJ, Pittaluga P, et al. [Treatment of great
saphenous vein incompetence by endovenous laser treatment: Technique and indications. Discussion]. Phlebologie.
2002;55:239-243.
8. Pichot O, Kabnick LS, Creton D, Merchant RF, SchullerPetroviae S, Chandler JG. Duplex ultrasound scan findings two
years after great saphenous vein radiofrequency endovenous
obliteration. J Vasc Surg. 2004;39:189-195.
9. Merchant RF, Pichot O. Long-term outcomes of endovenous
radiofrequency obliteration of saphenous reflux as a treatment
for superficial venous insufficiency. J Vasc Surg. 2005;42:
502-509.
10. Nicolini P; Closure Group. Treatment of primary varicose
veins by endovenous obliteration with the VNUS closure system: results of a prospective multicentre study. Eur J Vasc
Endovasc Surg. 2005;29:433-439.
11. Creton D; Closure Group. [Treatment of primary venous
insufficiency by radiofrequency obliteration with the VNUSClosure® system. Results of a 5-year multicenter prospective
study]. Phlebologie. 2006;59:67-72.
12. Min RJ, Khilnani N, Zimmet SE. Endovenous laser
treatment of saphenous vein reflux: long-term results. J Vasc
Interv Radiol. 2003;14:991-996.
13. Proebstle TM, Moehler T, Herdemann S. Reduced recanal-
ization rates of the great saphenous vein after endovenous
laser treatment with increased energy dosing: definition of a
threshold for the endovenous fluence equivalent. J Vasc Surg.
2006;44:834-839.
14. Pittaluga P, Réa B, Barbe R, Guex JJ. A.S.V.A.L. method:
principles and preliminary results. In: Becquemin JP, Alimi YS,
Watelet J, eds. Updates and Controversies in Vascular Surgery.
Turin, Italy: Minerva Medica; 2005:182-189.
15. Jones L, Braithwaite BD, Selwyn D, Cooke S, Earnshaw JJ.
Neovascularisation is the principal cause of varicose vein
recurrence: result of a randomised trial of stripping the long
saphenous vein. Eur J Vasc Endovasc Surg. 1996;12:442-445.
16. van Rij AM, Jiang P, Solomon C, Christie RA, Hill GB.
Recurrence after varicose vein surgery: a prospective longterm clinical study with duplex ultrasound scanning and air
plethysmography. J Vasc Surg. 2003;38:935-943.
17. Perrin MR, Labropoulos N, Leon LR Jr. Presentation of
the patient with recurrent varices after surgery (REVAS).
J Vasc Surg. 2006;43:327-334.
18. Rutgers PH, Kitslaar PJ. Randomized trial of stripping
versus high ligation combined with sclerotherapy in
the treatment of the incompetent greater saphenous vein.
5
Am J Surg. 1994;168:311-315.
19. Cooper DG, Hillman-Cooper CS, Barker SG, Hollingsworth
SJ. Primary varicose veins: the sapheno-femoral junction,
distribution of varicosities and patterns of incompetence. Eur J
Vasc Endovasc Surg. 2003;25:53-59.
20. Trendelenburg F. Ueber die Unterbindung der Vena saphena
magna bei Unterschenkelvaricen. Beitr Klin Chir. 1890;7:
195-210.
21. Ludbrook J, Beale G. Femoral venous valves in relation
to varicose veins. Lancet. 1962;1:79-81.
22. de Medeiros CA, Luccas GC. Comparison of endovenous
treatment with an 810 nm laser versus conventional stripping
of the great saphenous vein in patients with primary varicose
veins. Dermatol Surg. 2005;31:1685-1694.
23. Lurie F, Creton D, Eklof B, et al. Prospective randomised
study of endovenous radiofrequency obliteration (Closure)
versus ligation and vein stripping (EVOLVeS): two-year followup. Eur J Vasc Endovasc Surg. 2005;29:67-73.
24. Puggioni A, Kalra M, Carmo M, Mozes G, Gloviczki P.
Endovenous laser therapy and radiofrequency ablation of the
great saphenous vein: analysis of early efficacy and complications. J Vasc Surg. 2005;42:488-493.
A. Masegosa, Spain
L
Alberto MASEGOSA, MD
Servicio de Angiologia y
Cirurgía Vascular
Hospital General de Albacete
C/ Hermanos Falco, s/n
02002 Albacete, SPAIN
(e-mail: amasegosam@
sescam.jccm.es)
igation of the saphenofemoral junction
(SFJ) has for many years been considered
a mandatory part of the surgical treatment
for varicose veins. The need to ligate the great
saphenous vein (GSV) at this level is being questioned on the basis of better awareness of neovascularization in the groin and the development
of alternative techniques. The conventional and
perhaps oversimplified view is that neovascularization results from poor surgical technique. However, the evidence now suggests that it can occur
despite correct surgical technique. It is therefore
important to determine its frequency and identify
its causes, with particular regard to the following factors: stimulation of angiogenesis by the endothelium in the GSV stump, the role of inguinal
lymphovenous connections, the vasa vasorum of
the femoral vein, altered physiological drainage
of inguinal GSV tributaries, and constitutional
factors. Color Doppler ultrasonography is a particularly useful monitoring tool. In a follow-up of
1326 patients, Allegra et al found no residual reflux in the GSV trunk 3 weeks after varicose vein
surgery, but a 13% relapse rate at the SFJ after
5 years.1 Using the same technique in 100 patients,
De Maeseneer et al 2 noted that neovascularization was unlikely ever to develop in those in whom
it was not present at 1 year, thus giving an idea
of the odds of long-term relapse at the SFJ. Winterborn et al 3 monitored outcome 11 years after
surgery in 51 out of an original population of
100 patients, concluding that recurrence and the
need for reintervention were due to incompetence
in the groin, the commonest cause being neovascularization. They suggested that the presence
of a residual GSV may be contributory, a view
confirmed by Egan et al 4 who observed that all
recurrent varicose veins associated with duplexdiagnosed neovascularization are also associated
with persistent reflux in the GSV stump tributaries, thigh GSV, or both. These data force the
conclusion that so long as we continue to ligate
the SFJ, we must use correct surgical technique,
avoid leaving tributaries or incompetent GSV
segments in the thigh, develop a better understanding of neovascularization, and use postoperative color Doppler ultrasound scanning in
follow-up. Some authors believe that the use of
physical barriers, such as silicone patches, may
diminish neovascularization, particularly in repeat recurrence.5 Techniques such as endoluminal
radiofrequency, laser or sclerosing foam ablation
of the GSV avoid SFJ ligation. They have yielded
promising short-term results, but only long-term
comparative studies will ultimately determine
whether SFJ ligation is unnecessary. REFERENCES
1. Allegra C, Antignani PL, Carlizza A. Recurrent varicose
veins following surgical treatment: our experience with five
years follow-up. Eur J Vasc Endovasc Surg. 2007;33:751-756.
2. De Maeseneer MG, Vandenbroeck CP, Hendriks JM, Lauwers
PR, Van Schil PE. Accuracy of duplex evaluation one year after varicose vein surgery to predict recurrence at the saphenofemoral junction after five years. Eur J Vasc Endovasc Surg.
2005;29:308-312.
3. Winterborn R, Foy C, Earnshaw JJ. Causes of varicose vein
recurrence: late results of a randomized controlled trial of
stripping the long saphenous vein. J Vasc Surg. 2004;40:634-639.
5. De Maeseneer MG, Vandenbroeck CP, Van Schil PE. Silicone
patch saphenoplasty to prevent repeat recurrence after surgery
to treat recurrent saphenofemoral incompetence: long-term
follow-up study. J Vasc Surg. 2004;40:98-105.
6
A. Obermayer, Austria
uplex scanning has greatly enhanced
phlebology practice in recent years. New
endoluminal techniques such as duplexguided foam sclerotherapy have been developed
or modified for treating great saphenous vein
(GSV) incompetence. Current treatment options
include minimally invasive surgery with flush
ligation of the saphenofemoral junction (SFJ) and
all the tributaries, inversion stripping, miniphlebectomy, and various ultrasound-guided
endovascular procedures using heat (produced
by laser, radiofrequency, immersion, or steam)
or sclerosant foam, each of which approximates
and shrinks the vein walls, resulting in occlusion
of the incompetent GSV trunk. These procedures
dispense with the conventional surgical practice
of ligating all tributaries. Irrespective of the option chosen, every phlebologist faces the problem of recurrence. Published recurrence rates
vary from 5% to 60% depending on method and
time frame, but all treatments aim to eradicate
venous insufficiency.1,2 Recurrence can be due to
disease progression and technical error, but also
to neovascularization, since Nature seeks ways to
rebuild what surgeons extirpate.3 Angiogenesis
is a feature of all healing wounds and the remaining intimal cells of the saphenous stump
produce endothelial growth factor.4 The main
advantage of endovenous obliteration is that it
does not excise the incompetent trunk or shed
endothelial cells into tissue. Short- and midterm
outcome is comparable to that of minimally
invasive surgery, and with less recurrence, even
if the tributaries remain. El Wajeh et al 5 and Egan
et al 3 have suggested that a main factor in recurrence, rather than or in addition to neovascularization, lies in the abnormal hemodynamic
forces in the saphenofemoral area, such as the
high pressure in the first femoral segment distal
to the inguinal ligament and above the proximal
femoral valve, the so-called “unprotected venous
segment.” Activity-induced peaks of abdominal
pressure impact this unprotected venous segment
and escape through neovascular capillaries, re-
sulting in recurrent varicose veins. Another argument favoring endovenous obliteration is the
rapid recovery from a minor procedure under
local or regional anesthesia, hence an improved
quality of life.6 Our experience has also shown
similarly good results after minimally invasive
surgery under tumescent anesthesia. We would
confirm the long periods of pain along the GSV
reported by Proebstle et al 7 after endovenous
laser treatment, even if most studies have found
less pain than after conventional surgery.1,6
Whether the phlebologist chooses to ligate or
not to ligate is mainly a question of anatomy,
and it is solved by duplex scanning. In our experience, a diameter >10 mm, aneurysm, or nonlinear GSV close to the SFJ are indications for
minimally invasive surgery. In very slim patients
with light skin, hyperpigmentation may be a
negative cosmetic side effect of endovascular
obliteration. As for duplex-guided foam sclerotherapy, we use it routinely in the elderly, patients with comorbidities, and those who refuse
a minimally invasive technique. Short-term success can be measured by various parameters,
include closure of the culprit venous valves, venous reflux, visible varicose veins, quality of life,
recovery time, and pain. The main parameter of
long-term success is the recurrence rate, diagnosed by duplex scanning and described by the
presence of venous reflux. Although the shortand midterm results of endovenous obliteration
are good, we know that the recurrence rate after
venous surgery increases significantly after 10
years. Accurate comparison will require longterm results.1 Provided that endovascular GSV
obliteration works, the new nonligation techniques are highly promising because they do not
appear to induce neovascularization and recurrence is lower. It is therefore extremely astonishing that some practitioners combine GSV
obliteration with saphenofemoral ligation. Combining two great methods may not end up with
a result that is greater still, but with complete
cancellation of their respective benefits! REFERENCES
1. Noppeney T, Rewerk S, Winkler M, Nullen H, Schmedt HC.
[Primary varicosis]. Chirurg. 2007;78:620-629.
2. Winterborn RJ, Earnshaw JJ. Crossectomy and great
saphenous vein stripping. J Cardiovasc Surg. 2006;47:19-33.
4. Nyamekye I, Shephard NA, Davies B, Heather BP, Earnshaw JJ. Clinicopathological evidence that neovascularisation
is a cause of recurrent varicose veins. Eur J Vasc Endovasc
Surg. 1998;15:412-415.
5. El Wajeh Y, Giannoukas AD, Gulliford CJ, Suvarna SK,
Chan P. Saphenofemoral venous channels associated with
recurrent varicose veins are not neovascular. Eur J Vasc Endovasc Surg. 2004;28:590-594.
6. Lurie F, Creton D, Eklof B, et al. Prospective randomized
study of endovenous radiofrequency obliteration (closure
procedure) versus ligation and stripping in a selected patient
population (EVOLVeS Study). J Vasc Surg. 2003;38:207-214.
7. Proebstle TM, Gul D, Kargl A, Knop J. Endovenous laser
treatment of the lesser saphenous vein with a 940-nm diode
laser: early results. Dermatol Surg. 2003;29:357-361.
D
Alfred OBERMAYER, MD
Institute of Functional
Phlebologic Surgery
Karl Landsteiner Society
Himmelreichstrasse 15
A-3390 Melk, AUSTRIA
(e-mail: obermayer@
phlebosurgery.org)
7
K. L. Katsenis, Greece
he most common source of ambulatory venous hypertension is an incompetent superficial system, usually the great saphenous
vein (GSV). Alternatively, vein reflux may originate from the deep veins, perforating veins, or
any combination of the superficial, perforating,
and deep vein systems. It is critical to identify
the origin of venous hypertension and the most
proximal point of reflux by performing a thorough evaluation with duplex ultrasound imaging.
Superficial axial vein reflux may be corrected
by surgical, thermal, or chemical means. Interventions on the GSV at the saphenofemoral junction (SFJ) have been widely performed in the
belief that this could control gravitational reflux
and remove the hydrodynamic forces of perforator vein reflux. A cornerstone of varicose vein
surgery is high ligation of the GSV with tributary
stab avulsion, GSV stripping, and perforator ligation, with removal of bulging varicose veins when
visible and palpable on the skin surface.1 Simple
ligation of the GSV at the SFJ has been practiced
to control gravitational reflux while preserving
the vein for possible subsequent arterial bypass.2
It is true that the GSV is largely preserved after
proximal ligation. Unfortunately, reflux continues
and hydrodynamic forces are not controlled. Less
reflux persists when the GSV is stripped.3,4 Randomized trials confirm that stripping is associated with less recurrence than simple proximal
ligation.5,6 However, the period of disability after
stripping is greater than that after simple ligation.7 Attention eventually focused on the saphenous nerve injury associated with ankle to groin
stripping.8 It was concluded that stripping from
groin to ankle,9 or to the knee, caused less nerve
injury and did not adversely affect early venous
hemodynamic improvement.10,11 One disappointing outcome for surgeons and patients is recurrence, defined as the presence of varicose veins in
a lower limb previously operated on for varices,
with or without adjuvant therapies. This clinical
definition includes true recurrence, residual veins,
and varicose veins due to disease progression.
Some causes are obvious: insufficient understanding of venous anatomy and hemodynamics, inadequate preoperative assessment, and incorrect
or insufficient surgery. In the absence of surgical
error, junctional recurrence is found in less than
one third of re-examined extremities. Duplex ultrasound or re-exploration of the groin at the
level of the SFJ frequently shows neovascularization as the cause of recurrence.12 Research needs
to focus on the pathophysiological mechanisms
that could explain how new veins can develop
after correct SFJ ligation: angiogenic stimulation
in the free endothelium of the ligated stump,
transnodal lymphovenous connection, dilation of
small adventitial vessels in the vasa vasorum of
the femoral vein, or disturbed venous drainage
of the ligated tributaries of the SFJ. Neovascularization in the groin has been reduced by over-
T
Konstantinos L. KATSENIS
MD, Head of Vascular Unit
2nd Surgical Clinic of
University of Athens
Aretaieion Hospital
76 Vas. Sophias Avenue
Athens, GREECE
(e-mail:
katsenis@aretaieio.uoa.gr)
sewing the ligated SFJ with prolene to prevent
contact with surrounding tissue,13 inserting a
polytetrafluoroethylene (PTFE) patch over the
ligated junction,14 and closing the cribriform
fascia.15 In recent years, endovenous ablation of
the GSV without ligation has proved safe and
effective in eliminating the proximal portion of
the GSV from the venous circulation, giving even
faster recovery and better cosmetic results than
stripping.16,17 The two currently available methods
are the Closure® procedure using a radiofrequency
catheter and generator (VNUS Medical Technologies) and endovenous laser ablation, using a
laser fiber and generator (various manufacturers). The goal of endovenous treatment is the
ablation of abnormal blood reflux by durable occlusion of the vein lumen. This can be achieved
either by shrinking the vein until the lumen has
vanished completely, or by substantially damaging the endothelium and inner vein wall leading
to secondary occlusion of the lumen by thrombus, similar to the effect of a sclerosant. The degree of vein wall shrinkage appears important
because the residual lumen occluded by endovascular thrombus could be recanalized. The larger
the thrombus, the higher the risk of recanalization. Results are promising, both early (GSV occlusion was achieved in >90% of cases after both
procedures at 1 month) and in the midterm (recurrence at 36 months appeared similar to that
after conventional surgical management), although long-term follow-up and comparison with
standard GSV stripping are required to confirm
the durability of these endovenous procedures.
However, the absence of neovascularization is
striking, and these minimally invasive procedures
are also well accepted by both doctors and patients. The literature emphasizes the need for early ultrasound scanning in all patients after endovenous GSV ablation: veins still occluded 1 year
after the procedure remained occluded at further
follow-up to 3 years.18,19 Relevant complications
reported with endovenous treatment are rare. The
most important is deep vein thrombosis, which
further emphasizes the need for ultrasound
B-scanning after surgery. Thrombus protrusion
into the femoral vein is an indication for antithrombotic therapy. Deep vein thrombosis prophylaxis may be considered in patients >50 years
old.20 In the absence of significant complications,
endovenous procedures have important advantages in selected patients, offering less postoperative pain, earlier return to work and normal
activities, and apparent cost-effectiveness. Endovenous treatment can be combined with any
other technique (Muller’s phlebectomy, all forms
of sclerotherapy, perforator surgery, subfascial
endoscopic perforator surgery, and endovenous
laser occlusion of incompetent perforators). Concomitant tumescent anesthesia enables the vast
majority of patients to be treated in-office without general anesthesia or surgical incisions, at
the same time as maximizing outcome and
minimizing recurrence.21 Ultrasound-guided foam
sclerotherapy was introduced as a third alternative treatment. Foam is more effective than
liquid sclerotherapy and can be used to treat
large-diameter veins and even main superficial
trunks. Most vascular surgeons agree that sclerotherapy has been used for a very long time for
treating recurrent veins. The results are promis-
ing but still inconclusive.22 Thus endovenous
methods may be promising but GSV ligation and
stripping remains the gold standard. However,
there is an urgent need for prospective randomized trials of endovenous laser therapy against
conventional surgery, high ligation at the same
treatment session, and other endovenous techniques such as radiofrequency closure and sclerotherapy.23 REFERENCES
1. Perrin M, Guidicelli H, Rastel D. Surgical techniques used
for the treatment of varicose veins: survey of practice in France.
J Mal Vasc. 2003;28:277-286.
2. McMullin GM, Coleridge-Smith PD, Scurr JH. Objective
assessment of high ligation without stripping the long saphenous vein. Br J Surg. 1991;78:1139-1142.
3. Saarinen J, Heikkinen M, Suominen V, et al. Clinical disability scores and reflux in complicated and uncomplicated
primary varicose veins. Phlebology. 2003;18:73-77.
4. Cheatle T. The long saphenous vein: to strip or not to strip?
Semin Vasc Surg. 2005;18:10-14.
5. Winterborn RJ, Foy C, Earnshaw JJ. Causes of varicose
veins recurrence: late results of a randomized controlled trial
of stripping the long saphenous vein. J Vasc Surg. 2004;40:
634-639.
6. Butler CM, Scurr JH, Coleridge-Smith PD. Prospective
randomized trial comparing conventional (Babcock) stripping
with inverting stripping of the long saphenous vein. Phlebology.
2002;17:59-63.
7. Jakobsen BH. The value of different forms of treatment for
varicose veins. Br J Surg. 1979;66:182-184.
8. Munn SR, Morton JB, MacBeth WAAG, McLeish AR. To strip
or not to strip the long saphenous vein? A varicose veins trial.
Br J Surg. 1981;68:426-428.
9. Holme JB, Skajaa K, Holme K. Incidence of lesions of the
saphenous nerve after partial or complete stripping of the
long saphenous vein. Acta Chir Scand. 1990;156:145-148.
10. Rhodes JM, Gloviczki P, Canton L, Heaser TV, Rooke TW.
Endoscopic perforator vein division with ablation of superficial reflux improves venous hemodynamics. J Vasc Surg.
1998;28:839-847.
11. Miyazaki K, Nishibe T, Kudo F, et al. Hemodynamic
changes in stripping operation or saphenofemoral ligation of
the greater saphenous vein for primary varicose veins. Ann
Vasc Surg. 2004;18:465-469.
12. De Maesneer MG, Tielliu IF, Van Schil PE, De Hert SG,
Eyskens EJ. Clinical relevance of neovascularisation on duplex
ultrasound in the long term follow up after varicose vein op-
eration. Phlebology. 1999;14:118-122.
13. Frings N, Nelle A, Tran P, Fischer R, Krug W. Reduction
of neoreflux after correctly performed ligation of the saphenofemoral junction. A randomized trial. Eur J Vasc Endovasc
Surg. 2004;28:246-252.
14. Winterborn RJ, Earnshaw JJ. Randomised trial of polytetrafluoroethylene patch insertion for recurrent great saphenous
varicose veins. Eur J Vasc Endovasc Surg. 2007;34:367-373.
15. De Maeseneer MG, Philipsen TE, Vandenbroek CP, et al.
Closure of the cribriform fascia: an efficient anatomical barrier
against postoperative neovascularisation at the saphenofemoral
junction. Eur J Vasc Endovasc Surg. 2007;34:361-366.
study of endovenous radiofrequency obliteration (Closure
17. Morrison N. Saphenous ablation: what are the choices,
laser or RF energy? Semin Vasc Surg. 2005;18:15-18.
18. Min RJ, Khilnani NM, Zimmet SE. Endovenous laser treatment of saphenous vein reflux: long term results. J Vasc Interv Radiol. 2003;14:991-996.
19. Pichot O, Kabnick LS, Creton D, Merchant RF, SchullerPetrovic S, Chandler JG. Duplex ultrasound findings two
years after great saphenous vein radiofrequency endovenous
obliteration. J Vasc Surg. 2004;39:189-195.
20. Puggioni A, Kalra M, Carmo M, Moses G, Glovinski P.
Endovenous laser therapy and radiofrequency ablation of the
21. Chon MS, Seiger E, Goldman S. Ambulatory phlebectomy using the tumescent technique for local anesthesia. Dermatol Surg. 1995;21:315-318.
22. Rigby KA, Palfreyman SJ, Beverley C, Michaels JA. Surgery
versus sclerotherapy for the treatment of varicose veins.
Cochrane Database of Systematic Reviews. 2004;Issue 4:Art.
No.: CD004980. DOI: 10.1002/14651858.CD004980.
23. Bergan JJ. The Vein Book. San Diego, CA: Elsevier Academic Press; 2007.
8
L. Veverkova, Czech Republic
O
Lenka VEVERKOVA, MD, PhD
1st Department of Surgery
St Anne’s University Hospital
Pekarska 53, 60200 Brno
CZECH REPUBLIC
(e-mail: lvever@med.muni.cz)
ptimal treatment of varicose veins requires
exact identification of the source of venous
reflux. One of the biggest problems in
treatment is recurrence, which can reach 65%
within 5 years and currently accounts for 25%
of all varicose vein surgery. The best guarantee
of a good result lies in accurately identifying the
source of reflux and in removing it in the first
surgical procedure. Duplex scanning of the lower
extremity plays an important role in reducing the
rate of varicose recurrence. Duplex ultrasound
mapping is much more accurate than other methods of venous system examination. However, it
is still not accepted by all general or vascular surgeons because of the time and expense involved.
In my view, clinical examination and manual
Doppler ultrasound are insufficient in patients
with primary varicose veins. Duplex ultrasound
should be considered as standard, and as absolutely essential in patients with varicose recurrence. The problem of angiogenesis in the saphenofemoral junction (SFJ) stump following ligation
of the great saphenous vein (GSV) is a hot topic.
Experience tells us that primary surgery is often
incorrectly performed, predisposing to recurrence.
On the other hand, all surgeons have a proportion of patients with recurrence, whether or not
they believe the procedure they performed was
flawless. Perfect anatomical knowledge is essential, given the multiplicity of venous variants in
the SFJ region. The GSV has tributaries subinguinally—the medial and lateral accessory saphenous veins— as well as inguinally—superficial
circumflex iliac vein, superficial epigastric vein,
and external pudendal vein, including its superficial and deep branches. The external pudendal
vein can be double or triple, as can the GSV
(18.1% of cases). The number of SFJ tributaries
is also not constant. In 33.4% of cases, one or
more (junctional) tributaries join the GSV or
common femoral vein deep to the deep fascia.
Anatomical variation in the SFJ is important in
ensuring safe and appropriate management.1
Venous insufficiency is best treated using the least
invasive methods, such as percutaneous endovenous techniques which improve patient comfort
and accelerate return to work. Endovascular therapy gives promising midterm results for GSV
reflux. However, it also has certain pitfalls and is
therefore not suitable for all patients. One limitation is the diameter and tortuosity of the treated vein. The risk of thermal damage to surrounding structures should also be taken into account.
There are two schools of surgeons: one performs
standard ligation of the GSV followed by endovenous therapy, the other omits ligation, but both
claim comparable midterm results. No long-term
studies are available. Radiofrequency ablation
(the Closure® procedure) is based on endoluminal destruction of the endothelium and does not
comprise GSV ligation. In my experience, endovascular methods are often confined to patients
in stage C2 with no symptoms of chronic venous
insufficiency, thus clearly biasing results in the
method’s favor. Supporters of endovascular methods without GSV ligation claim that they avoid
neovascularization. However, Labropoulos et
al failed to confirm this.2 Improved diagnostic
methods give us a more accurate overview of
the hemodynamics, anatomy, and pathophysiology of the venous system of the lower extremities and thus help us to select the appropriate
therapeutic method. Crossectomy, conventional
stripping and external stenting to the SFJ will
definitely remain irreplaceable treatments for certain groups of patients, particularly in the light
of their favorable long-term results.3 Endovascular
procedures have proved to be good alternatives
to stripping, while sclerotherapy continues to
play an irreplaceable role. In addition, the therapeutic spectrum comprises venotonics and compression therapy. Treatment choice also depends
on the specific anatomic characteristics of the
patient’s venous system. The optimal procedure
is the one that most improves a particular patient’s quality of life. Only long-term comparative
studies that include a quality of life measure
can provide a conclusive answer to the question
“To ligate or not to ligate.” REFERENCES
1. Donnelly M, Tierney S, Feeley TM. Anatomical variation at
the saphenofemoral junction. Br J Surg. 2005;92:322-325.
2. Labropoulos N, Bhatti A, Leon L. Neovascularization after
great saphenous vein ablation. Eur J Vasc Endovasc Surg.
2006;31:219-222.
9
A. K. Bozkurt, Turkey
T
A. Kursat BOZKURT, MD
Professor of Cardiovascular
Surgery, Istanbul University
Cerrahpasa, Medical Faculty
Istanbul, TURKEY
(e-mail:
akbozkurt@yahoo.com)
he aim of varicose vein surgery is to remove
reflux and visible varicosities in order to
achieve the most favorable hemodynamic
and cosmetic result. High ligation is the crucial
step because it restores normal hemodynamics.
However, if the incompetent saphenous trunk
in the thigh is not stripped at the same time, it
remains patent and incompetent after surgery,
and may provoke recurrent reflux. For this reason, high ligation combined with stripping became
the standard treatment for truncal varicosities.1-3
On the other hand, venous grafts retrieved from
the great saphenous vein (GSV) are the best
conduits for vascular and some coronary reconstructions. The demand for such grafts is continuously rising as the population ages, confronting
surgeons with the problem of whether the saphenous trunk in patients with varicose veins may
be used for grafting or not, and if yes, what is the
price to be paid for preserving it? Hammarsten
et al showed that 78% of preserved saphenous
veins were suitable for use as arterial conduits
almost 5 years after high ligation,4 although
lowering the radicality of varicose vein surgery
increases recurrence. The saphenous trunk in
primary varicose veins is not always degenerate,
and may basically be compatible for use as a vascular or coronary artery conduit. Interestingly,
it does not dilate aneurysmatically when transplanted into the arterial circulation.5 We performed a prospective study to evaluate the longterm results of GSV-sparing surgery compared
with above-knee stripping. Fifty patients with
varicose veins were randomly treated with standard stripping of the GSV or high ligation. In both
groups, miniphlebectomies were carried out and
incompetent perforators ligated on the basis of
physical examination and duplex findings. Follow-up at 42±5 months showed recurrence rates,
defined by clinical and duplex findings, of 12%
in the stripping group vs 20% in the high ligation group (P<0.05). However, duplex scanning
showed that the preserved GSV was suitable for
use as an arterial conduit in most cases. These
results suggest that it is possible to perform
elective vein surgery for varicose veins with reasonably good results and preserve the GSV for
eventual arterial reconstruction. What is the role
of crossectomy and stripping in the modern era?
Revascularization in the strip track after GSV
stripping is a new concept in recurrence, and it
occurred in 3 of our 50 patients. Munasinghe
et al reported strip-track revascularization in
23% of patients at 1 year, all with duplex-proven
reflux.6 As an alternative to crossectomy and
stripping, minimally invasive saphenous ablation,
using endovenous radiofrequency or laser treatment, corrects and/or significantly improves the
hemodynamic abnormality and clinical symptoms associated with superficial venous reflux in
over 95% of cases. These techniques may also
reduce neovascularization in the groin. The critical question is what is the role of simple high
ligation in preserving the GSV? Despite current
recommendations, we still tend to perform this
procedure on patients with severe saphenofemoral
junction reflux, below-knee varicosities, and a
near normal-sized and normal-looking GSV. We
also discuss the situation with the patient and
explain the higher rate of recurrence. In the
event of recurrence, endovenous laser or radiofrequency obliteration is readily performed as an
outpatient procedure after high ligation of the
saphenofemoral junction. REFERENCES
1. Sarin S, Scurr JH, Coleridge-Smith PD. Stripping of the
long saphenous vein in the treatment of primary varicose
veins. Br J Surg. 1994;81:1455-1458.
2. Dwerryhouse S, Davies B, Harradine K, Earnshaw JJ.
Stripping the long saphenous vein reduces the rate of reoperation for recurrent varicose veins: five-year results of a randomized trial. J Vasc Surg. 1999;29:589-592.
3. Bergan J. Inversion stripping of the saphenous vein. In:
Bergan JJ, ed. The Vein Book. San Diego, Ca: Elsevier Academic
Press; 2007:231-237.
4. Hammarsten J, Pedersen P, Cederlund CG, Campanello M.
Long saphenous vein saving surgery for varicose veins. A
long-term follow-up. J Vasc Surg. 1990;4:361-364.
5. Recek C. Does saphenous vein saving surgery have a role
in the therapy of primary varices? Rozhl Chir. 2003;82:591595.
6. Munasinghe A, Smith C, Kianifard B, Price BA, Holdstock
JM, Whiteley MS. Strip-track revascularization after stripping of the great saphenous vein. Br J Surg. 2007;94:840-843.
10
C. E. Virgini-Magalhães, Brazil
U
Carlos E. VIRGINIMAGALHÃES, MD
Hospital Universitário
Pedro Ernesto, Secretaria
da Disciplina de Cirurgia
Vascular e Endovascular
Boulevard Vinte e Oito
de Setembro 77 sala 448
CEP: 20.551-030
Rio de Janeiro, BRAZIL
(e-mail: virgini@uerj.br)
ntil recently, saphenofemoral junction
(SFJ) ligation, with or without great
saphenous vein (GSV) stripping, was considered the treatment of choice for varicose veins
in the presence of an incompetent GSV, despite
the persistent and unacceptably high recurrence
rate after surgery.1-5 Endovenous laser treatment
(EVLT) and radiofrequency ablation (RFA) of
the GSV have brought new perspectives and new
questions concerning chronic venous disease intervention.6 Backed by the success and safety of
the first published results using these techniques,
most practitioners now perform these procedures
in the office setting under vascular ultrasound
guidance without SFJ ligation, to greater patient
satisfaction in terms of simplicity, comfort, and
cosmetic outcome.7-11 Nevertheless, the immediate
fate of the SFJ after endovenous treatment remains unclear, with many questions still unanswered. What is the real risk of pulmonary embolism with these new procedures? What is the
exact role of dissection and high ligation of the
SFJ as a cause of recurrent varicose veins?
For these reasons, further studies are still necessary for a better understanding of the postoperative clinical course of GSV ablation and the mechanisms underlying postoperative thrombosis.12,13,15
Deep venous thrombosis and pulmonary
embolism
With EVLT or RFA, the SFJ can be occluded and
ligated under direct vision through an inguinal
incision, or the catheter can be advanced under
duplex scanning control to just below the SFJ,
without the inguinal region needing to be surgically accessed. The duplex-guided procedure is simpler, faster, and more esthetic, but it carries the
risk of extending the thrombus from the SFJ into
the common femoral vein and may cause pulmonary embolism. In the literature, RFA has been
associated with 21 cases of deep vein thrombosis
(DVT) and at least two episodes of pulmonary embolism: Hingorani et al reported a 16% incidence
of DVT in 66 patients,12 while Mozes et al estimated the cumulative incidence of DVT as 2.1%
and of pulmonary embolism as 0.2%.13 As for
EVLT, a Mayo Clinic report cited three cases of
DVT, equivalent to 2.3% in 130 treated limbs.14
Conventional varicose surgery was associated with
5.7% DVT in 377 patients in a study by van Rij
et al.15 Other studies using duplex scanning cited
rates of 3% and 5%.16,17 Most cases associated
with conventional surgery are distal DVT in the
calf veins with a low tendency for propagation,
whereas those associated with EVLT and RFA involve the protrusion of thrombus originating in
the SFJ into the common femoral vein, representing a theoretical risk of pulmonary embolism.
Some reports have advocated the use of temporary
vena cava filters and prophylactic anticoagulation.
Neovascularization and recurrence
Recurrence is a common problem in the treatment of chronic venous disease.18 The use of minimally invasive techniques has led to a debate
over the role of inguinal surgical access and tributary ligation as causes of neovascularization
and recurrent varicose veins. Neovascularization
is an essential component of wound healing.19
New vessels arise due to angiogenic stimuli produced during surgery; arteriovenous connections
develop, promoting wound perfusion and healing.
Van Rij et al have argued that neovascularization
occurs not only at major ligation sites but also
wherever superficial veins are stripped, avulsed,
or injected with adjuvant sclerotherapy.20 New
vessels can extend significant distances in the
lower limb to make their reconnections and develop varicosities, although this process is still
the subject of debate and skepticism. Neovascularization has been implicated as the cause of recurrence in up to 94% of cases. Occluding the SFJ
using an endovascular technique free of the potential angiogenic stimuli in conventional surgery
is a very attractive option, at least in theory.20
Early results of EVLT and RFA do suggest that
recurrence is reduced. Even so, there are reports
of recurrent incompetence at the SFJ and of ultrasound evidence of neovascularization.21,22
Labropoulos et al found a 5% prevalence of small
arteriovenous fistulas following endovascular
treatments of the GSV. Such fistulas may be responsible for recanalizing ablated venous segments and subsequent recurrence.22 Winterborn
et al showed that neovascularization is a dynamic
and continuous phenomenon not restricted to
the healing period after surgery. They found increasing rates of neovascularization as a cause of
recurrence: 36%, 54%, and 65% at 2, 5, and 11
years of follow-up, respectively.18 Some authors
argue that ligation of competent tributaries is
unnecessary and can promote neovascularization.23 Theivacumar et al showed that despite SFJ
tributaries remaining patent and competent in
59% of 81 EVLT procedures, the overall number
of recurrences did not increase after 1 year of
follow-up.24 In conclusion, longer-term results
from prospective randomized studies comparing
stripping with new minimally invasive methods
are needed to determine the ultimate fate of the
GSV after EVLT and RFA. We still do not know if
SFJ ligation will become the villain or hero. REFERENCES
1. Stucker M, Netz K, Breuckmann F, Altmeyer P, Mumme A.
Histomorphologic classification of recurrent saphenofemoral
reflux. J Vasc Surg. 2004;39:816-822.
2. Blomgren L, Johanson G, Dahlberg-Akerman A, Thermaenius P, Berqvist D. Changes in superficial and perforating
vein reflux after varicose vein surgery. J Vasc Surg. 2005;42:
315-320.
3. Cheatle T. The long saphenous vein: to strip or not strip?
Semin Vasc Surg. 2005;18:10-14.
4. Lo YF, Yang CH. Stripping and ligation of the saphenous
vein. Semin Cutan Med Surg. 2005;24:200-208.
5. Perrin MR, Labropoulos N, Leon LR. Presentation of the
patient with recurrent varices after surgery (REVAS). J Vasc
Surg. 2006;43:327-334.
6. Huang Y, Jiang M, Li W, Lu X, Huang X, Lu M. Endovenous
laser treatment combined with a surgical treatment of venous
insufficiency in lower extremity: a report of 208 cases. J Vasc
Surg. 2005;42:494-501.
7. Merchant RF, DePalma RG, Kabnick LS. Endovascular
obliteration of saphenous reflux: a multicenter study. J Vasc
Surg. 2002;35:1190-1196.
9. Agus GB, Mancini S, Magi G. The first 1000 cases of Italian
Endovenous-laser Working Group (IEWG). Rationale, and
long-term outcomes for the 1999-2003 period. Int Angiol. 2006;
25:209. Abstract.
10. Sharif MA, Soong CV, Lau LL, Corvan R, Lee B, Hannon RJ.
Endovenous laser treatment for long saphenous vein incompetence. Br J Surg. 2006;93:831-835.
11. Rasmussen LH, Bjoern L, Lawaetz M, Blemings A,
Lawaetz B, Eklof B. Randomized trial comparing endovenous
laser ablation of the great saphenous vein with high ligation
and stripping in patients with varicose veins: short-term
results. J Vasc Surg. 2007;46:308-315.
12. Hingorani AP, Ascher E, Markevich N, et al. Deep venous
thrombosis after radiofrequency ablation of greater saphenous vein: a word of caution. J Vasc Surg. 2004;40:500-504.
13. Mozes G, Kalra M, Carmo M, Swenson L, Gloviczki P. Extension of saphenous thrombus into the femoral vein: a potential complication of new endovenous ablation techniques.
J Vasc Surg. 2005;41:130-135.
14. Puggioni A, Kalra M, Carmo M, Mozes G, Gloviczki P. En-
dovenous laser therapy and radiofrequency ablation of the
15. Van Rij AM, Chai J, Hill GB, Christie RA. Incidence of
deep vein thrombosis after varicose vein surgery. Br J Surg.
2004;91:1582-1585.
16. Gillet JL, Perrin M, Hiltbrand B, et al. Pre- and postoperative contribution of Doppler ultrasonography in superficial
venous surgery of the popliteal fossa. J Mal Vasc. 1997;22:330335.
17. Puttaswamy V, Fishe C, Applebery M. Venous thromboembolism following varicose vein surgery: a prospective analysis. Aust N Z J Surg. 2000;70(suppl). Abstract A150.
18. Winterborn RJ, Foy C, Earnshaw JJ. Causes of varicose veins
recurrence: late results of a randomized controlled trial of stripping the long saphenous vein. J Vasc Surg. 2004;40:634-639.
19. Wilmer NA, van Blijswik BC, Daí J, et al. VEGFR-3 in
adult angiogenesis. J Pathol. 2001;195:490-497.
20. van Rij AM, Jones GT, Hill GB, Jiang P. Neovascularization
and recurrent varicose veins: more histologic and ultrasound
evidence. J Vasc Surg. 2004;40:296-302.
21. Proebstle TM, Gul D, Lehr HÁ, Kargl A, Knop J. Infrequent
recanalization of greater saphenous vein after endovenous
laser treatment. J Vasc Surg. 2003;38:511-516.
22. Labropoulos N, Bhatti A, Leon L, Borge M, Rodriguez H,
Kalman P. Neovascularization after great saphenous vein ablation. Eur J Vasc Surg. 2006;31:219-222.
23. Chandler JG, Pichot O, Sessa C, Schuller-Petrovic S, Osse
FJ, Bergan JJ. Defining the role of extended saphenofemoral
junction ligation: a prospective comparative study. J Vasc
Surg. 2001;32:941-953.
24. Theivacumar NS, Dellagrammaticas D, Beale RJ, Mavor
AI, Gough MJ. Fate and clinical significance of saphenofemoral junction tributaries following endovenous laser ablation of great saphenous vein. Br J Surg. 2007;94:722-725.
D
A F L O N
500
M G
DAFLON 500 MG: PROTECTIVE AGAINST
VENOUS VALVE FAILURE
b y F. P i t s c h , F r a n c e
hronic venous disease (CVD) is an umbrella
term that encompasses a variety of clinical
presentations, which include venous symptoms and signs. A review of the literature shows that
the most commonly expressed CVD-related symptoms are heaviness, pain, sensation of swelling, restless legs, paresthesias, night time cramps, tiredness,
throbbing, and itching. The signs of chronic venous
disorders are described in the Clinical, Etiological,
Anatomical, Pathophysiological (CEAP) classification1 and comprise telangiectasia, varicose veins,
edema, skin changes, and healed and active venous
leg ulcers.
It seems likely that the progression of CVD stems
from prolonged periods of increased venous pressure in the legs. The abnormally elevated venous
pressure is called venous hypertension, and this
links all theories regarding the pathogenesis of the
disease.2
C
Françoise PITSCH
Servier International
Neuilly-sur-Seine
FRANCE
Hypertension is central to the
pathogenesis of chronic venous disease
During periods of standing without skeletal muscle activity, venous pressures in the legs are determined by capillary flow and the hydrostatic component that is related to the weight of the column
of blood from the right atrium to the foot. The pressure may reach 80 to 90 mm Hg. In addition to the
hydrostatic component, distal veins are submitted
to transiently increased pressures generated by contractions of the skeletal muscles of the leg that may
reach 150 mm Hg. Proximal veins may also be sub-
P
rimary chronic venous disease is a widespread disorder.
Its manifestations include symptoms in the form of pain
and heaviness, and signs in the form of telangiectasia,
varicose veins, skin changes, and chronic leg ulcers. Recent advances in the understanding of its pathophysiology have shown
that molecular mechanisms in the inflammatory cascade underlie these diverse manifestations. Venous hypertension and alteration of hemodynamic forces, such as blood pressure changes in
the wall and sheer stress, induce activation of leukocytes and
endothelial cells. This may initiate the cascade of inflammation
that results in adverse changes in the venous valve, venous wall,
and skin and leads to the many clinical manifestations of the disease. The disease symptoms and the telangiectasia, varicose veins,
and eventual venous leg ulcers appear to be a consequence of the
changes induced by venous hypertension and shear stress. Treat-
Daflon 500 mg: protective against venous valve failure – Pitsch
mitted to peaks of pressures, generated in this case
by abdominal pressure. Both components are profoundly influenced by the action of the venous
valves.
Many factors may play a role in raising hydrostatic pressure in the superficial venous system of
the lower limbs; in particular, prolonged standing
or sitting occupations, pathologic conditions of increased abdominal pressure and decreased calf pump
as is found in morbid obesity, and hormonal status.3
Genetic inheritance must be considered, because
CVD is seen in patients with a family history of varicose veins.4,5 In line with the observations regarding genetic influence, a deficiency has been found
in collagen type III in cultured venous smooth muscle cells from patients with varicose veins.6 The defect was found to be generalized within different
tissues in the same patients. One of the theories
thus put forward regarding the development of varicose veins is that the veins of affected individuals
are genetically more distensible than those of people with normal veins.2
SELECTED
AVF
CEAP
arteriovenous fistula
Clinical, Etiological, Anatomical,
Pathophysiological classification
CVD
RELIEF Reflux assEssment and quaLity of lIfe
improvEment with micronized
Flavonoids (study)
ment to inhibit inflammation may offer the greatest opportunity
to prevent progression of the disease and its related complications. Daflon 500 mg, an oral phlebotropic medication, attenuates
various elements of the inflammatory cascade, particularly the
leukocyte-endothelium interactions that are important in many
aspects of the disease. Such medication deserves more detailed
study to confirm its protective effect on venous structures.
Keywords: primary chronic venous disease; venous valve
failure; inflammatory cascade; leukocyte-endothelium interaction; protective effect; Daflon 500 mg
Address for correspondence: Françoise Pitsch, Servier International,
192 avenue Charles de Gaulle, 92578 Neuilly-sur-Seine Cedex, France
(e-mail: francoise.pitsch@fr.netgrs.com)
DAFLON 500
MG
There might also be a genetic component to the
alteration of remodeling in venous valves. A theory
linking the various observations to describe the
chronology of venous valve failure and venous insufficiency is, however, lacking.
A strong link is evoked between
venous hypertension and valve failure
Risk factors for chronic venous disease
Venous hypertension
Venous dilation
Increased hypertension
Valve distortion and leakage
Valve reflux
In most cases, venous hypertension is caused by reflux through incompetent venous valves.7 Examination of surgical specimens removed from limbs
with chronic venous insufficiency and, more recently, the direct observation offered by angioscopy,
has revealed lesions involving the venous wall, the
valvular annulus, and the valve cusps.8,9 Failure of
the valve and its annulus is responsible for progression of the disease via maintenance and further
increase of venous hypertension. Immunohistochemical studies using monoclonal antibodies specific for monocytes and macrophages have demonstrated monocyte/macrophage infiltration into the
valve leaflets and venous wall of patients with varicose veins (CEAP Class 2).10 Monoclonal antibody
studies have found that leukocyte infiltration is
greater within the base of the valve leaflets and in
the proximal venous wall. Venous valves have been
found to be prominent in regions of low shear stress
with venous eddies and recirculation.11 It may be
that these phenomena explain how the leukocytes
are preferentially deposited in these regions.
Ultimately, macrophages become the instrument
of tissue damage that softens the venous wall and
favors valve destruction.12 Venous valve failure and
subsequent reflux causing distal venous hypertension may contribute to the sustained and chronic
hypertension that is responsible for leukocyte activation within the endothelium and leukocyte destruction of skin and subcutaneous tissues at the
ankle. In addition to leukocyte activation, increased
mast cell infiltration into the venous wall may have
a role to play in the development of varicose veins.
Increased expression of intercellular adhesion molecule–1 (ICAM-1) and the presence of CD-68 on the
endothelial surface of venous walls in patients with
venous insufficiency has been confirmed and may
be related to this.12 These findings suggest a continuing inflammatory reaction that is related to venous wall remodeling.13,14 On the other hand, endothelial cells must be activated to allow leukocytes
to migrate through the cells into the tissue.12 It is
believed that endothelial stretching may induce
activation of the endothelium; as blood flow itself is
affected, fluid shear stress may change. Fluid shear
stress is a key regulatory component of endothelial
cells and a reduction in shear rates leads to enhanced
adhesion of leukocytes on the endothelium.10
INFLAMMATION
Capillary hypertension
Increased inflammation
Capillary leakage
Figure 1. The vicious
circle of venous
hypertension/venous
inflammation.
Adapted from reference 7:
Bergan JJ, Schmid-Schönbein
G, Coleridge-Smith P, Nicolaides A, Boisseau M, Eklof B.
Chronic venous disease.
N Engl J Med. 2006;355:
488-498. Copyright © 2006,
Massachusetts Medical Society.
Skin changes
Ulcer
Edema
To elucidate the possible mechanisms involved
in the destruction of valves in chronic venous hypertension, Takase et al examined saphenous vein
valves in a rat model in which femoral venous hypertension was elevated for a period of 3 weeks by a
femoral arteriovenous fistula (AVF).15 In this model, venous reflux developed in response to venous
hypertension. Examination of vein morphology revealed that valve failure occurred as a result of dilation of the venous wall and shortening of valve
leaflets to the point of incomplete valve closure
and subsequent reflux. Assessment of the valves for
molecular inflammatory markers revealed enhanced
leukocyte infiltration with granulocytes, monocytes,
and T-lymphocytes. In addition, the expression of
the endothelial cell membrane adhesion molecules
P-selectin and ICAM-1 on the endothelial cells of the
saphenous vein wall was increased. In this study, the
leaflets were still able to close properly in the early
stages after placement of the AVF, suggesting that
pressure per se is not necessarily the variable that
can compromise the leaflets. However, at the time
the leaflets failed and reflux occurred, a reduction in
the leaflet dimensions was observed. A possible explanation for the sequence of events that leads to
the morphologic abnormalities in venous valves
is that as the venous wall dilates, a point may be
reached at which reflux develops across the leaflets.
An abnormal fluid shear field produced at the surface of the leaflets during venous reflux would be
highly inflammatory for the endothelial cells on the
valve leaflets, and could trigger destruction of the
leaflets, increasing venous hypertension. This would
maintain a vicious circle of venous hypertension/
venous inflammation (Figure 1).
The inflammatory reaction in
chronic venous disease might be
a new target for drugs
Clinical observations are
confirmed by animal models
Since the mechanisms responsible for venous valve
failure in primary CVD cannot be investigated in
vivo in human beings, animal models were set up
for the purpose of experimental research.
Altered blood flow and shear stress
Valve and wall changes
*Also registered as Ardium®,
Alvenor®, Arvenum® 500,
Capiven®, Detralex®, Elatec®,
Flebotropin®, Variton®,
and Venitol®.
Intervention in the inflammatory reaction that occurs as part of the progress of the disease may be a
new pharmacological target. For this reason, the
model by Takase et al was used to assess the effect
of a drug treatment: Daflon 500 mg*.
DAFLON 500
Therapeutic consequences of
the protective effect of Daflon 500 mg
Daflon 500 mg is the only venoactive drug with
proven early protective properties on venous valves
and the venous wall. This is probably one of the
mechanisms by which Daflon 500 mg is efficient
right from the early symptoms of CVD.
In one double-blind, placebo-controlled, randomized study19 including 40 patients with CVD, several symptoms were considered, and were classified
into “functional” symptoms (functional discomfort,
leg heaviness, pain, fatigue when standing, night
cramps, paresthesia, burning sensation, itching)
and “objective” symptoms (sensation of edema in
the evening, redness and cyanosis, sensation of heat,
and sensation of skin induration). According to the
intensity of each parameter and its repercussion on
daily activities, the patient quantified the parameters using a 4-point scale. Global scores were calculated for functional and objective symptoms. In the
Daflon 500 mg group, after a 2-month period of
treatment, patients demonstrated a significantly
better improvement in global (P<0.001 for functional score and P=0.034 for objective symptom
score) and separated symptom scores (P value different depending on the symptom, from P<0.001
for functional discomfort to P=0.033 for sensation
of burning). In this trial, the presence of venous disease and treatment efficacy were confirmed by testing parameters using strain gauge plethysmography and edema measurement.
Another double-blind, placebo-controlled, randomized study20 included 160 symptomatic patients
with CVD related to either post-thrombotic syndrome (24 patients), primary varicose veins (59 patients) or other conditions (77 patients). Patients
were equally distributed into 2 groups and treated
either with placebo or with Daflon 500 mg, 2 tablets
daily for 8 weeks. Evaluation of venous symptoms
was the primary end point of the study. Each symptom (functional discomfort, heaviness, pain, night
cramps, sensation of swelling, paresthesia, redness
12
Free reflux rate (mL/min)
The ability of Daflon 500 mg to mitigate or even
block the effects of chronic inflammation at the level of both the micro- and macrocirculation has been
demonstrated in rat models of venous hypertension.
In a model of venous occlusion and reperfusion, the
subsequent elevation of venous blood pressure increased the inflammatory cascade and tissue injury.16 In Daflon 500 mg–treated animals, markers
of inflammation were decreased in a dose-dependent manner. Daflon 500 mg also served to significantly reduce parenchymal cell death as well as leukocyte rolling, adhesion to postcapillary venules,
and migration.17
Important data supporting the protective effect
of Daflon 500 mg at the level of the macrocirculation have been provided by the rat fistula model of
venous hypertension.15 In this model, the venous
hypertension caused by a femoral AVF resulted in
the development of venous reflux and an inflammatory reaction in venous valves. In animals treated
with Daflon 500 mg, there was a significant, dosedependent reduction in the reflux rate (Figure 2).
Daflon 500 mg also reduced several indicators of
the inflammatory reaction including expression of
the endothelial cell adhesion molecules, P-selectin
and ICAM-1, and leukocyte infiltration, and reduced
the level of apoptosis in a dose-dependent manner.
By delaying and even blocking the inflammatory
reaction, these data suggest that Daflon 500 mg may
delay the development of reflux and suppress damage to the valve structures in the rat model of venous hypertension. These observations were recently confirmed in a new study using the same animal
model. The administration of Daflon 500 mg reduced the edema and the fistula blood flow produced by the acute AVF. Daflon 500 mg also reduced
granulocyte and macrophage infiltration to the
valves, in line with the previous study.18 Daflon
500 mg may be protective against valve alterations.
MG
10
Vehicle (n=6)
MPFF 50 (n=6)
MPFF 100 (n=6)
8
6
4
2
0
Figure 2. Reflux flow rates across the saphenous venous
valve measured after 3 weeks of venous hypertension
in vehicle control and Daflon 500 mg treatment groups
at a dose of 50 mg/kg/day and 100 mg/kg/day. N is the
number of rats in each treatment group. P<0.05 compared with control. MPFF, micronized purified flavonoid
fraction.
Reproduced from reference 15: Takase S, Pascarella L, Bergan J,
Schmid-Schönbein G. Venous hypertension, inflammation and valve
remodeling. Eur J Vasc Endovasc Surg. 2004;28:484-493. Copyright © 2004, Elsevier Ltd.
and/or cyanosis, sensation of heat and/or burning)
was rated 0 (no symptom), 1 (moderate symptoms
without repercussion on daily activities), 2 (appreciable symptoms but allowing daily activities) or 3
(severe symptoms, causing discomfort or hampering daily activities). At the end of the study and
compared with the placebo group, the changes in
the symptoms were significantly better in the Daflon
500 mg group (from P<0.001 for functional discomfort, sensation of heaviness, and sensation of swelling, up to P=0.027 for pain; the only symptom without significant improvement was redness/cyanosis).
These changes were significant after 4 weeks of treatment for the functional discomfort, sensation of
heaviness, nocturnal cramps, and sensation of swelling. Improvement in other objective parameters of
edema and trophic skin changes paralleled the improvement in symptoms.
The Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids (RELIEF)
study21 involved 5052 symptomatic patients from
DAFLON 500
MG
Global index score on CIVIQ (points)
190
80
70
*
*
*
*
*
*
nous insufficiency. (chronic venous insufficiency
implies that reflux is present). Although other theories exist, the fundamental cause of skin damage
in CVD has been ascribed to leukocyte trapping, adhesion of leukocytes to the endothelium and neutrophils, and their subsequent activation.23 It is
hypothesized that the primary injury to the skin is
caused by extravasation of macromolecules such as
fibrinogen, α-macroglobulin, and red blood cells
into the dermal interstitium. Red blood cell degradation products and interstitial protein extravasation are potent chemoattractants and presumably
present the initial inflammatory signal that results
in leukocyte recruitment and migration into the
dermis.5 The cascade of pathologic events occurs
during leukocyte migration into the dermis, and the
end product of these is dermal fibrosis.
Systemic medications have been used in addition
to standard treatments, because of a theoretical ability to address one or more of the factors that have
been identified in the pathophysiology of venous ulceration. A small number of drugs have been used
with varying success. The way in which Daflon 500
mg speeds ulcer healing might be to modulate
leukocyte-L-selectin interaction with endothelial
selectins responsible for the initial stages of adhesion. By reducing the likelihood of leukocyte adhesion, Daflon 500 mg presumably acts through an
anti-inflammatory mechanism.24 Thus, among the
many mechanisms at work in the pathogenesis of
venous ulceration, the mechanism involving leukocyte activation and interaction with the endothelium seems currently to be the one most responsive
to pharmacological treatment.
A meta-analysis of randomized prospective studies using Daflon 500 mg in adjunction to conventional treatment confirmed the results of previous
trials; namely, that such oral medication accelerates
the healing of leg ulcers.25 Five prospective, randomized, controlled studies involving 723 patients
with venous ulcers who had received treatment between 1996 and 2001 were included in the analy-
Baseline
Month 2
Month 4
Month 6
60
50
40
30
20
10
0
Patients with
venous reflux
Patients without
venous reflux
Figure 3. Improvement in health-related quality-of-life scores with Daflon
500 mg. Improvements in the global index score of the ChronIc Venous Insufficiency Questionnaire (CIVIQ) with two tablets of Daflon 500 mg daily
for 6 months in 3656 patients with symptoms of chronic venous disease with
or without venous reflux able to be evaluated in an unblinded multinational
study. CIVIQ scores range from 0-100 where 100 indicates a very good healthrelated quality of life. *P=0.0001 versus baseline.
Reproduced from reference 21: Jantet G; the RELIEF Study Group. Chronic venous insufficiency—worldwide results of the RELIEF study. Angiology. 2002;53:245-256. Copyright ©
2002, Sage Publications.
The skin is the final target
of chronic venous hypertension
Patients
349
372
1.0
Treatment
Control
Daflon 500
0.6
0.4
0.2
0
0
The complications of CVD are expressed in the skin
and are related to chronic venous hypertension. The
skin is the final target of chronic venous hypertension. The hypertension is a cause of chronic inflammation manifested by persistent and sustained injury. Ultimately it is the capillary circulation that
is most severely impaired in limbs with chronic ve-
Events
148
209
0.8
Probability
23 countries treated for 6 months with Daflon 500
mg. In this study, the sensation of swelling, cramps,
and leg heaviness were assessed by a 4-point scale
(0=absent, 1=mild, 2=significant, 3=severe). Pain
was measured using a 10 cm visual analog scale (0
representing “no pain” and 10 cm “maximal pain”).
All symptoms showed a significant and progressive
improvement. Improvement in the patients’ quality of life was paralleled by symptom improvement
(Figure 3).
Daflon 500 mg has demonstrated its efficacy on
symptoms in the long term. Two tablets of Daflon
500 mg daily maintained its efficacy in the longterm treatment of patients with symptoms of CVD
in a nonblind, multicenter trial of 12 months’ duration.22 In this 1-year trial in 170 evaluable patients,
a significant reduction from baseline values in
physician-assessed clinical symptoms (functional
discomfort, cramps, and evening edema), ankle and
calf circumference, and patient overall assessment
of symptom severity was demonstrated at each 2month evaluation (P<0.001). The rapid reductions
observed during the first 2 months of treatment represented approximately 50% of the total improvements ultimately observed after 1 year of treatment.
6
12
18
24
30
36
Time to recovery (weeks)
Figure 4. Life-table analysis showing the cumulative percentage of patients
with complete ulcer healing. Comparison of cumulative healing rates between
the Daflon 500 mg group (green line) and the control group (gray line).
Adapted from reference 25: Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer : a metaanalysis of adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc
Surg. 2005;30:198-208. Copyright © 2005, Elsevier Ltd.
DAFLON 500
sis. Conventional treatment (compression and local
care) in addition to Daflon 500 mg was compared
with conventional treatment plus placebo in two
studies (n=309), and with conventional treatment
alone in three studies (n=414). The primary end
point was complete ulcer healing at 6 months. The
results were expressed as a reduction in the relative
risk (RRR) of healing, which should be positive to
indicate a benefit for adjunctive Daflon 500 mg
therapy over conventional therapy alone. At 2
months, the results were statistically significant
and the chance of an ulcer healing was 44% better
in patients treated with adjunctive Daflon 500 mg
than in those managed by conventional therapy
alone (RRR, 44%; confidence interval [CI], 7%-94%;
P=0.015). This difference was present at month 6
(RRR, 32%; CI, 3%-70%; P=0.0035), and was associated with a shorter time to healing (16 weeks vs
21 weeks; P=0.0034) (Figure 4).
REFERENCES
1. Porter JM, Moneta GL; International Consensus
Committee on Chronic Venous Disease. Reporting
standards in venous disease: an update. J Vasc Surg.
1995;21:635-645.
2. Nicolaides AN. Investigation of chronic venous insufficiency; a consensus statement. Circulation. 2000;
102:e126-e163.
3. Pascarella L, Schmid-Schönbein G. Causes of telangiectasias, reticular veins, and varicose veins. Semin
Vasc Surg. 2005;18:2-4.
4. Cornu-Thénard A, Boivin P, Baud JM, et al. Importance of the familial factor in varicose disease. Clinical study of 134 families. J Dermatol Surg Oncol.
1994;20:318-326.
5. Pistorius MA. Chronic venous insufficiency: the genetic influence. Angiology. 2003;54:S5-S12.
6. Sansilvestri-Morel P, Rupin A, Jaisson S, et al. Synthesis of collagen is dysregulated in cultured fibroblasts derived from skin of subjects with varicose veins
as it is in venous smooth muscle cells. Circulation.
2002;106:479-483.
7. Bergan JJ, Schmid-Schönbein G, Coleridge-Smith
P, Nicolaides A, Boisseau M, Eklof B. Chronic venous
disease. N Engl J Med. 2006;355:488-498.
8. Corcos L, De Anna D, Dini M, Macchi C, Ferrari PA,
Dini S. Proximal long saphenous vein valves in primary venous insufficiency. J Mal Vasc. 2000;25:27-36.
9. Van Cleef JF, Hugentobler JP, Desvaux P, Griton P,
Cloarec M. Endoscopic study of reflux of the saphenous valve. J Mal Vasc. 1992;17(suppl B):113-116.
DAFLON 500
MG
Venous valve protection is to be
closely studied since it opens up
the perspective of targeted
pharmacological intervention
The practical purpose of elucidating the molecular
steps involved in the development of valve lesions
is to intervene with a targeted treatment. The sequence of leukocyte adhesion, endothelial interaction, activation, and migration and its association
with valvular damage has focused attention on
available molecules with known ability to modify
this chain of events.
Daflon 500 mg currently possess the most appropriate profile, since the previously published observations of an anti-inflammatory effect of Daflon 500
mg under acute situations show that it may have
a protective effect on the venous valves in chronic
conditions of venous hypertension. 10. Ono T, Bergan JJ, Schmid-Schönbein GN, Takase
S. Monocyte infiltration into venous valves. J Vasc
Surg. 1998;27:158-166.
11. Lurie F, Kistner RL, Eklof B, Kessler D. Mechanism
of venous valve closure and role of the valve in circulation: a new concept. J Vasc Surg. 2003;38:955-961
12. Takase S, Bergan JJ, Schmid-Schönbein GW.
Expression of adhesion molecules and cytokines on
saphenous veins in chronic venous insufficiency. Ann
Vasc Surg. 2000;14:427-435.
13. Jacobs MP, Badier-Commander C, Fontaine V, et
al. Extracellular matrix remodeling in the vascular
wall. Pathol Biol. 2001;49:326-332.
14. Badier-Commander C, Jacobs MP, Michel JB. Varicose remodeling [translated from French]. MT. 2000;
6:718-723.
15. Takase S, Pascarella L, Bergan J, Schmid-Schönbein G. Venous hypertension, inflammation and valve
remodeling. Eur J Vasc Endovasc Surg. 2004;28:484493.
16. Takase S, Lerond L, Bergan JJ, Schmid-Schönbein GW. Enhancement of reperfusion injury by elevation of microvascular pressures. Am J Physiol Heart
Circ. 2002;282:H1387-H1394.
17. Takase S, Delano FA, Lerond L, et al. Inflammation
in chronic venous insufficiency: is the problem insurmountable? J Vasc Res. 1999;36(suppl 1):3-10.
18. Pascarella L, Lulic D, Alsaigh T, et al. Venous hypertension induced venous insufficiency ameliorated
by Daflon 500 mg. In: Book of Abstracts of the Tripar-
:
MG
tite Meeting of the European Venous Forum, June 29July 1, 2006. London, England: Edizioni Minerva Medica (Turin) ;2006:16.
19. Chassignolle JF, Amiel M, Lanfranchi G, et al. Activité thérapeutique de Daflon 500 mg dans l’insuffisance
veineuse fonctionnelle. JIM. 1987;99(suppl): 32-35.
20. Gilly R, Pillion G, Frileux C. Evaluation of a new
vasoactive micronized flavonoid fraction (S 5682) in
symptomatic disturbances of the venolymphatic circulation of the lower limb: a double-blind, placebocontrolled study. Phlebology. 1994;9:67-70.
21. Jantet G; the RELIEF Study Group. Chronic venous insufficiency—worldwide results of the RELIEF
study. Angiology. 2002;53:245-256.
22. Guillot B, Guilhou JJ, de Champvallins M, et al. A
long term treatment with a venotropic drug: results
on efficacy and safety of Daflon 500 mg in chronic venous insufficiency. Int Angiol.1989;8(suppl 4):67-71.
23. Coleridge-Smith PD, Thomas P, Scurr JH, Domandy JA. Causes of venous ulceration: a new hypothesis. BMJ. 1988;296:1693-1695.
24. Shoab SS, Porter J, Scurr JH, Coleridge-Smith
PD. Endothelial activation response to oral micronised flavonoid therapy in patients with chronic venous disease—a prospective study. Eur J Vasc Endovasc Surg. 1999;17:313-318.
25. Coleridge-Smith P, Lok C, Ramelet AA. Venous leg
ulcer : a meta-analysis of adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc Surg. 2005;30:198-208.
PROTÈGE CONTRE LA MALADIE VALVULAIRE VEINEUSE
a maladie veineuse chronique essentielle est très répandue.
Elle est définie par la présence de symptômes tels que douleurs et lourdeurs de jambes, et/ou de signes tels que télangectasies, varices, troubles trophiques et ulcère veineux. La physiopathologie de cette maladie reste encore mal connue mais de
récentes avancées ont mis le doigt sur le rôle déterminant des mécanismes inflammatoires dans son déclenchement et sa progression. L’action conjuguée de l’hyperpression veineuse et des modifications des forces hémodynamiques exercées sur la paroi des
veines et des valves peuvent induire une activation des leucocytes
et de l’endothélium pariétal, initiant une cascade inflammatoire.
Il en résulte un profond remaniement des structures valvulaires
et pariétales, puis des capillaires de la peau, ce remodelage se traduit par les diverses manifestations cliniques décrites dans cette
maladie. Ainsi les symptômes veineux, les télangectasies, les va-
L
rices puis les complications ulcéreuses sont-ils la conséquence
des changements induits par les modifications des forces hémodynamiques et de pression. Le rôle prédominant de l’inflammation dans la genèse et la progression de cette maladie pourrait
avoir d’importantes implications thérapeutiques. Des traitements
pharmacologiques capables d’enrayer le cercle vicieux de l’inflammation permettraient de prévenir les complications. Daflon
500 mg, un phlébotrope largement utilisé dans le traitement des
symptômes et de l’œdème liés à la maladie veineuse, a démontré
sa capacité à atténuer l’inflammation veineuse, et plus particulièrement l’intéraction leucocyte-endothélium dont on connaît
l’impact dans le mécanisme de développement de la maladie. Ce
mécanisme d’action prometteur nécessite d’être approfondi pour
confirmer les effets protecteurs du produit sur les structures veineuses et plus particulièrement les valves.
I
N T E R V I E W
ANIMAL MODELS
IN CHRONIC VENOUS DISEASE
I n t e r v i e w w i t h G . T. J o n e s , N e w Z e a l a n d
Gregory Thomas JONES,
PhD
Vascular Research Group
Otago Medical School
Otago, NEW ZEALAND
Tell us about the animal model you
have set up
ur group is interested in the
pathobiology of varicose veins.
In order to study the complete time
course of this condition, it is necessary
to examine veins early in their pathogenesis and preferably with reference to
control material. Clearly it is not possible
to use human material for such studies,
and a suitable animal model has, therefore, been sought. Unfortunately varicose
veins do not occur spontaneously in lower animals1 and it has been necessary to
develop experimental animal models in
an attempt to mimic the human state. As
such, we have aimed to establish a chronic, large animal model of primary superficial varicose veins. It is important to be
aware that there have been a number of
animal models for venous disease devel-
O
P
oped by other investigators, and there is
a need to be very clear as to which condition each model is trying to mimic.
Our model, which is of the chronic superficial varicose vein, involves the fashioning of a femoral arteriovenous fistula
in adult pigs. The fistula is fashioned
adjacent to the intact saphenofemoral
junction (SFJ). It is interesting that in
the pig, the saphenous vein is formed by
superficial tributaries and passes more
deeply into its own fascial compartment
in the thigh before penetrating the fascia
cribrosa and joining the femoral vein.
Unlike the human situation, the saphenous vein runs parallel to a small saphenous artery, forming a saphenous bundle within its own fascia. What is also
slightly unusual about the pig is that this
particular length of saphenous vein has
numerous (8-10) valves. We believe that
these valves are critical to the model, as
they appear to fail sequentially following
creation of the femoral fistulae. As such,
they appear to “protect” the vessels within the superficial compartment from direct arterialization in the acute phase of
fistula maturation. After approximately
1 to 2 weeks, the superficial saphenous
tributaries begin to become varicose in
revious animal models of venous disease, while suited to
the study of venous hypertension and valvular insufficiency, do not produce superficial varicose veins. Our group
aimed to develop a pig-based model of superficial varicose veins.
The pathophysiology of this model was assessed by intravenous
blood pressure measurement, duplex ultrasound, and histology, and was compared with that of the human condition. Right
femoral arteriovenous fistulae were surgically fashioned in adult
pigs. Patency of the fistulae was confirmed by transcutaneous
ultrasound. Animals were re-examined postoperatively for up to
15 weeks to determine both pressure and blood flow velocities
within the superficial thigh veins. Histology was used to characterize the resulting structural venous alterations with those
of human superficial varicose veins. In this model, gross superficial varicosities developed after an initial lag period of 1 to 2 weeks.
Varices appeared to have a postural component to their filling and
were associated with a mild (nonpulsatile) venous hypertension.
This physiological profile is distinct from the near-arterial pres154 MEDICOGRAPHIA, VOL 30, No. 2, 2008
a consistent pattern radiating out from
the saphenous vein. These veins progressively enlarge, resulting in the formation
of an extensive network of large (1-5 mm
in diameter), tortuous, superficial varicose veins overlying the medial thigh
and extending into the superficial epigastic veins. Although animals are initially
operated upon at a body weight of 35 kg,
they grow rapidly and are typically 80 to
100 kg by the time measurements are
made (8-15 weeks postoperatively). An
advantage of this model is that the size
of the animal and associated veins allows
for physiological (pressure and ultrasound) evaluation, which would not be
possible in smaller animals.
Physiologically, these vessels are characterized by retrograde flow with a mild
nonpulsatile venous hypertension (2035 mm Hg in a supine position). Venous
pressures decline with increased distance
from the fistula-fed saphenous vein. Increased intra-abdominal pressure elevates
SELECTED
AVF
SFJ
arteriovenous fistulae
sure profiles typically observed in smaller animals with arteriovenous fistulae. Venous blood flow velocities were elevated to
15 to 25 cm/second in varicose veins. Structurally, pig varicose
veins were enlarged, tortuous, had focal medial atrophy with or
without overlying intimal thickening, and valvular degeneration. In conclusion, the superficial varicose veins, which developed
within this porcine model, have a pathophysiology that is consistent with that observed in humans. The suitability of other animal models of venous disease for the evaluation of therapeutic
agents for the treatment of varicose veins is discussed.
Keywords: animal model; arteriovenous fistula; chronic venous
disease; superficial varicose vein; therapeutic evaluation
Address for correspondence: Gregory T. Jones, Research Director,
Vascular Research Group, Otago Medical School, New Zealand.
(e-mail: greg.jones@otago.ac.nz)
Animal models in chronic venous disease – Jones
INTERVIEW
superficial venous pressures. Supine superficial venous blood flow velocities were
elevated from approximately 1 to 4 cm/
second in controls to 15 to 25 cm/second
in animals with patent fistulae. While duplex waveforms within the saphenous vein
displayed an arterialized pattern, particularly at the proximal end near the fistula,
the waveforms within the superficial veins
indicated continuous (elevated) flow.
An important feature of this model
is the intermittent distension noted in
relation to posture. In the supine anesthetized pigs, the enlarged superficial
veins are clearly visible but not distended.
When the unconscious animal is lifted
into an erect position, the veins become
noticeably more filled. Lateral flank varicose veins were only observed in ambulating animals, particularly postexercise.
The most pronounced, distended veins
were noted in conscious animals placed
in an erect position; this induced a Valsalva-like maneuver in all animals, resulting in extensive bulging of the superficial varices.
We examined the global soluble protein
expression profile of pig varicose veins
using two-dimensional electrophoresis.
An advantage of conducting such experiments in an animal model system was
the availability of completely healthy venous tissue for use as reference material. Proteins upregulated in pig varicose
veins included smooth muscle motilityrelated proteins, heat shock proteins, and
ATP synthases. Taken together, this profile suggests a process of inflammatoryinduced fibrosis in the developing pig
varicose veins. These observations are encouraging as they match the reported
gene expression profiles of human primary varicose veins.2
Histopathological changes in superficial vein structure included increased
diameter and tortuosity of veins within
the hypodermis, focal medial atrophy with
or without overlying intimal thickening,
valve degeneration (tearing and fibrosis),
mild periadventitial inflammation, and
loss of elastic tissue constituents in both
the media and adventitia. Alterations
were not limited to the large hypodermal venous drainage network, but also
extended into tributaries of these veins.
Corrosion vascular casts demonstrated
terminal tributary valvular incompetence
leading to reflux in incompetent microvenous networks. As such, this model
may not only have utility with regard to
primary varicose veins, but also chronic
venous insufficiency. All these histopathological changes were consistent with
those typically observed in human primary varicose veins.3,4
Tell us about previous animal models
of venous disease
revious animal models of venous disease can be categorized
into four groups; those utilizing (i) vessel occlusion/obstruction; (ii) valvular
incompetence; (iii) augmented hemodynamics; or (iv) a combination of these
models. Depending on the desired outcome, each method has its own strengths
and weaknesses. Our approach has been
to focus on the development of a model
of varicose veins, and only secondarily
on the generation of the tissue changes
of chronic venous insufficiency. Unfortunately, other models have not achieved
this, although they have contributed to
the study of other venous conditions,
such as acute venous obstruction, thrombophlebitis or valvular insufficiency.
Since chronic venous hypertension
is widely accepted as a key pathological
mechanism of chronic venous insufficiency, venous occlusion models have
been employed in an attempt to raise
venous pressures by limiting outflow.
Despite an acute elevation, venous occlusion models in themselves do not appear
to maintain chronically elevated venous
pressures.5,6 Burnand concluded that
this was due to the formation of collateral drainage, which he demonstrated
on phlebograms.5
Valvular incompetence is a common
feature of chronic venous insufficiency.
Lalka, Dalsing, and colleagues7 described
a simple, reproducible model of hindlimb valve disruption (in the greyhound)
that represents a useful model of venous
valvular insufficiency, particularly in the
evaluation of valve reconstruction procedures. Animals developed an immediate increase in post-stimulation segmental venous pressure that persisted
for as long as 14 weeks. While phlebography demonstrated reflux in the segments with the disrupted valves, there
was no indication of extension into tributaries and no evidence of varicose veins,
even at the most chronic time point.
Other aspects that should be considered
when assessing this model’s suitability
include the acute nature of the valve degeneration, which abruptly exposes the
vein to increased pressure, and the relatively short hydrostatic column present
in the quadruped hind limb. The third
group of venous disease models involves
the fashioning of arteriovenous fistulae
(AVF). Dart and colleagues formed acute
AVF in the dog, but noted an arterialized
pressure profile within the distal veins.
Burnand produced a more mild chronic
venous hypertension in the greyhound
P
that was associated with sustained resting and ambulatory pressures.5 Unfortunately, the associated acute phase arterial pressure profile is inconsistent with
chronic venous disease. More importantly, none of these AVF venous disease
models have reported the formation of
associated superficial varicose veins.
Models combining the above mechanisms have also been developed. Most
notably, the combination of AVF and outflow obstruction has been used in order
to produce sustained venous hypertension. Van Bemmelen applied this model
to rats in order to study valve remodeling.8 Although valve incompetence and
remodeling were noted as early as 24
hours postoperatively, no pressure profiles were recorded and the animals did
not develop varicosities. More recently,
a detailed series of studies conducted by
Bergan’s group has utilized the same
model and reported arterial-like pressure
profiles with mean venous pressures in
the order of 100 mm Hg.9 Vein alterations
reported included media atrophy, wall
fibrosis, increased protease expression,
progressive valve degeneration, and dilation of the commissures. Using this rat
model, valvular inflammation has been
identified as a key pathologic feature in
the development of reflux.9
What does this new model bring that
the others did not?
he principal feature of the pig
femoral AVF model is the formation of chronic superficial varicose
veins. Such pathological changes have
not been reported in any previous model of venous disease. The heterogenous
venous pathohistology of this model is
consistent with the range of alterations
observed in human superficial varicose
veins, including medial atrophy, intimal
thickening, connective tissue degeneration, fibrosis, and chronic valvular degeneration. These changes appear to be
due to physiological alterations that are
not simply an acute arterialization, but
are more consistent with that associated
with chronic varicose veins in humans.
Venous filling has an intermittent pattern,
influenced by posture, and driven by a
mild nonpulsatile venous hypertension.
The use of a human sized experimental animal allows for a greater range of
physiological evaluations to be performed
and results in much larger tissue volumes for biochemical evaluation.
Another exciting feature is the suggestion that venular changes also occur in
the draining tissues, comparable with
some of the changes seen in chronic
T
INTERVIEW
terbalanced by the quality and relevance
of the resulting pathophysiological information compared with that obtained in
other venous disease models in smaller
animals.
his depends of course on what
particular action of a drug is to
be tested, whether it is to demonstrate
effects on chronic degeneration of the venous valves and wall and the formation
of varicose veins, or the effects on acute
events of valve disruption or venous oc-
clusion. The pig model is clearly preferred
for the study of the effect of drugs on the
formation of varicose veins.
In addition, smaller animals such as
the rat, and to a lesser extent the dog,
have always been considered to have an
advantage for drug evaluation studies
because large numbers can be evaluated
at a reasonable cost. However, we would
argue that the similar size and physiology
of the pig to humans also makes them
suitable for use in studying drug effects.
Drug delivery and tissue/fluid sampling
for bioavailability studies is straightforward, and large sample volumes can be
obtained for analysis. Physiological and
ultrasound evaluations are also not only
more comparable but also more reliably
done in the larger animal. While adult
pigs are associated with a high per animal
cost, we believe that in the case of our
varicose vein model, this is easily coun-
hile no animal model is a perfect representation of the
human pathophysiological state, we believe that drug evaluation study results
based on our pig model of varicose veins
will translate well to humans, because of
the similarities in the underlying pathobiology. The model also has the distinct
advantage that the primary outcomes,
namely, the development and severity of
superficial varicose veins, match the key
clinical features that any phlebotrophic
drug would aim to target. REFERENCES
1. Foote RR. Varicose Veins, a Practical Manual. 2nd
ed. London, England: Butterworth; 1954.
2. Lee S, Lee W, Choe Y, et al. Gene expression profiles
in varicose veins using complementary DNA microarray. Dermatol Surg. 2005;31:391-395.
3. Bergan JJ, Schmid-Schonbein GW, Smith PD, et al.
Chronic venous disease. New Engl J Med. 2006;355:
488-498.
4. Jones GT, Solomon C, Moaveni A, et al. Venous morphology predicts class of chronic venous insufficien-
cy. Eur J Vasc Endovasc Surg. 1999;18:349-354.
5. Burnand KG, Clemenson G, Whimster I, et al. The
effect of sustained venous hypertension on the skin
capillaries of the canine hind limb. Brit J Surg.1982;
69:41-44.
6. Hobson RW 2nd, Howard EW, Wright CB, et al.
Hemodynamics of canine femoral venous ligation: significance in combined arterial and venous injuries.
Surgery. 1973;74:824-829.
7. Lalka SG, Unthank JL, Dalsing MC, et al. Venous
hemodynamics in a chronic venous valvular insufficiency model. Arch Surg. 1990;125:1579-1583.
8. van Bemmelen SP, Hoynck van Papendrecht AA,
Hodde KC, et al. A study of valve incompetence that
developed in an experimental model of venous hypertension. Arch Surg. 1986;121:1048-1052.
9. Pascarella L, Schmid-Schonbein GW, Bergan J. An
animal model of venous hypertension: the role of inflammation in venous valve failure. J Vasc Surg. 2005;
41:303-311.
venous insufficiency. This does raise an
important issue with regard to venous
disease models and the likelihood of being able to produce skin changes that
are comparable with those seen in humans. Most animals studied are young
and have a very dense hypodermis, so
that even in the presence of appropriate
venous hypertension in the larger superficial veins, the microcirculation is extremely well protected.
In your opinion, which model is the
most appropriate for the study of drugs?
T
LES
Could results drawn from the new model
be easily translated to human beings?
W
MODÈLES ANIMAUX DANS LA MALADIE VEINEUSE CHRONIQUE
L
es précédents modèles animaux de maladie veineuse convenaient à l’étude de l’hypertension veineuse et de l’insuffisance valvulaire mais ne s’appliquent pas aux varices superficielles. C’était le but de notre groupe de développer un modèle porcin de varices superficielles. La physiopathologie de ce
modèle a été évaluée par mesure de la pression sanguine intraveineuse, écho-Doppler et histologie ; elle a été comparée à la physiopathologie humaine. Des fistules artérioveineuses fémorales
droites ont été créées chirurgicalement chez des porcs adultes.
La perméabilité de la fistule a été confirmée par Doppler transcutané. Pression et débit veineux des veines superficielles de la
cuisse ont été déterminés en postopératoire jusqu’à 15 semaines
après. Les altérations veineuses structurales résultantes ont été
comparées histologiquement avec celles des varices humaines superficielles. Dans ce modèle, les grosses varices superficielles se
sont développées après un décalage initial de 1 à 2 semaines, elles
avaient une composante posturale en phase de remplissage et
étaient associées à une légère hypertension veineuse (non pulsatile). Ce profil physiologique diffère des profils de pression presque
artérielle typiquement observés chez des animaux plus petits avec
fistule artérioveineuse. Les débits veineux s’élevaient à 15 à 25
cm/s dans les varices. La structure des varices porcines est large,
tortueuse, atrophique au niveau de la media avec ou sans épaississement sus-jacent de l’intima et il existe une dégénérescence
valvulaire. En conclusion, la physiopathologie des varices superficielles développées dans ce modèle porcin est cohérente avec
celle des varices humaines. La pertinence d’autres modèles animaux de maladie veineuse pour l’évaluation des médicaments du
traitement des varices est discutée.
F
O C U S
CUT POINT ON NORMAL AND
PATHOLOGICAL VALUES OF REFLUX
by N. Labropoulos, USA
ost veins in the human body contain valves.
The number and size of the valves varies
with their location.1 Their function is to allow blood flow toward the heart and to prevent back
flow. Normal valves in the lower extremity allow
some retrograde flow (RF) before their closure. The
duration of the RF varies with the location and size
of the vein and valve. Reflux is a prolonged duration of RF beyond the normal limits. It occurs as a
result of valve absence or incompetence from recanalization, dilatation or denervation.2 Several
studies on the definition of reflux in the superficial
and deep veins have reported cutoff values of >0.5
second or >1.0 second.2-5 The sample size of these
reports has been small, however, and only a few sites
have been assessed in the lower extremity veins.
Limited work has been done to define perforator
vein reflux. These veins — particularly in the calf
and ankle — exhibit inward and outward flow, but
incompetent perforating veins have shown a net
flow toward the superficial veins.6 A later study from
my group determined the upper limits of normal in
terms of duration and maximum velocity of RF in
lower extremity veins.7 The results of these and other recent relevant studies will be presented and discussed.
M
Nicos LABROPOULOS, MD
Vascular Laboratory
Department of Surgery
Stony Brook University
Medical Center
Stony Brook, NY USA
Function of the venous valve
The venous valves are stationed in different vein
segments, some of which are constant such as the
terminal valve in the saphenofemoral junction or
the most proximal valve in the femoral vein.8 In
T
he lower extremity veins can develop retrograde flow that
continues for longer than a normal valve closure would
allow. The increased pressure in the veins during activity
leads to signs and symptoms of chronic venous disease. The duration of retrograde flow that determines what is normal and what
is pathological has been evaluated in a few studies with duplex ultrasound, which has been shown to be the best method for evaluating reflux. The results of these studies are examined here, together with the largest and only prospective study on this subject.
It was found that for superficial veins, the deep femoral veins,
and the deep calf veins, the best cutoff value for abnormal retrograde flow duration was >500 ms. For the perforator veins, most
experts have extrapolated the same value as is used for the superficial veins. However, the best value that separates normal from
pathological was found to be >350 ms. In the common femoral,
Cut point on normal and pathological values of reflux – Labropoulos
order to better understand their function, the cycle of the venous valve has to be explained: this was
carried out in detail by Lurie et al,9 who studied the
most proximal femoral vein valve and a proximal
vein valve from the great saphenous vein in 20 normal volunteers (10 males and 10 females). It was
shown that the pattern of flow events was consistent in every cycle as the blood passes through the
valves. The characteristics of this pattern were related to the variations in flow velocity in and around
the valve. The flow pattern also varied with the body
position and the limb activity. The valve cycle was
defined as the time taken to complete two valve closures. Four phases were identified: the opening
phase, during which the cusps move from the closed
position toward the wall (mean duration 0.025±
0.05 s). When the valves cease opening, they enter
the equilibrium phase, during which the leaflets are
suspended, with oscillations in the flowing blood
(mean duration 0.65±0.08 s). Then the closing phase
begins, during which the leaflets move toward the
center of the lumen and take a symmetric position,
having the same distance from the opposing walls
(mean duration 0.41 ±0.07 s). At the end, the closed
phase occurs, during which the cusps remain closed
(mean duration 0.45±0.05 s).
SELECTED
CVD
DU
RF
duplex ultrasound
retrograde flow
femoral, and popliteal veins, the best value was found to be
>1000 ms. The best position for performing the reflux test was
standing. The duration and the peak retrograde flow velocity
had great variability, while the latter had no association with the
presence of prolonged retrograde flow. Reflux development and
progression affects all the veins, and it can occur in an ascending, descending, and multifocal manner.
Keywords: retrograde flow; pathophysiologic; reflux; venous
valve; venous segment; cutoff point
Address for correspondence: Nicos Labropoulos, Professor of Surgery and Radiology,
Vascular Laboratory, Department of Surgery, HSC T19 Room 91, Stony Brook
University Medical Center, Stony Brook, NY 11794-8191, USA
(e-mail: nlabrop@yahoo.com)
FOCUS
The valve cycle and the duration of the four phases are affected by the position of the body. During
standing, the cycle lasts 2.9 to 3.2 seconds, giving
a frequency of 18.8 to 20.4 cycles per minute. In the
supine position, the cycle duration is 1.7 to 1.8 seconds, giving a frequency of 34.2 to 36.1 cycles per
minute. In the latter position, both respiration and
the pressure in the right atrium influence the valve
cycle. Dorsal and plantar flexion of the foot reduce
the closing phase. The venous valve causes a stenosis that occupies about a third of the lumen. This
leads to an increased velocity at the exit of the
stenosis (end of leaflets), which enhances the outflow. The rhythmic activity of the valve cusps and
the pulsatility of the venous flow create vortical
streams and prevent stasis in the valve pockets, thus
decreasing the chance for thrombus formation.
Changes in venous valves
Venous reflux is important in the development of
venous hypertension, which is responsible for the
signs and symptoms of chronic venous disease
(CVD).10 Many studies have shown that valve dysfunction leads to venous reflux, which increases the
ambulatory pressure in the lower extremity veins.11,12
Valvular dysfunction is most often primary and mediated by changes in the venous wall, the valve
leaflets or a combination of both. With the use of an
angioscope, changes and damage to the valves have
been observed such as stretching, splitting, tearing, thinning, and adhesion of valve leaflets.13 Patients with CVD may have fewer valves per unit
length.14 Infiltration of the venous wall and the valve
leaflets by monocytes and macrophages has been
demonstrated in all vein specimens from patients
with CVD, but not in those specimens from controls.15 Infiltration from the inflammatory cells was
found in areas of endothelium that expressed intercellular adhesion molecule–1 (ICAM-1).16
Changes in the valves are also seen after vein
thrombosis.17 This is due to the direct effect of
thrombus on the valves and the vein wall. Many
natural history studies have demonstrated the damaging effect of thrombosis on the valve/wall leading to reflux.18,19 Reflux is seen after both partial or
complete recanalization of the previously thrombosed segments. More evidence regarding this has
been provided by the effects of early thrombus removal with chemical and pharmacomechanical
thrombolysis, which reduces the development of
postthrombotic reflux.20,21
Valve atrophy and aplasia have also been reported.22 In these cases, the affected vein segments are
found to have severe reflux. The reasons for the failure of the valves to develop are not known, but this
condition is very rare and only small series or cases
reports have been published.
strain gauge, and photoplethysmography, light reflection rheography, and foot volumetry.23 The plethysmographic tests measure the refilling time, and
the percentage or absolute change in volume from
the supine to standing position or after knee bends
or tiptoe movements. The shorter the refilling time
the more severe the amount of reflux. These methods are very good for evaluating the overall venous
hemodynamics, and are great for use in natural history studies or to assess the effect of treatment. However, when used alone, they cannot guide treatment
as they cannot evaluate which veins are affected.
The imaging tests involve phlebography and duplex ultrasound (DU). Descending and ascending
phlebography are invasive and are used only in selected cases requiring deep vein reconstruction.
Currently, the method of choice for detecting reflux
in all the lower extremity veins is DU. The distribution and extent of reflux is determined so that treatment can be tailored to the individual patient needs.
In addition, a differentiation between primary and
secondary disease can be made. The names of the
veins,24 the anatomic definitions as visualized by
DU, and the methods of testing have been described
in detail.25,26 The best position for determining reflux with DU is standing.7 In this position, the hydrostatic column is highest and the veins have their
largest diameter. Also, dilated veins and varicosities
are more easily seen and it therefore makes the examination more accurate. With the patient rotating in various positions, it is best to access all areas
in the lower extremity.
Different maneuvers are used to elicit reflux.
Manual compression followed by sudden release below the tested vein segment is good to determine
reflux in routine examinations. However, standardized pressure with the same inflation and deflation
duration is necessary when longitudinal studies are
performed, particularly when different types of treatment are tested. The Valsalva maneuver is used only
in the groin. Other tests, such as dorsi/plantar flexion, are useful in the calf and ankle in patients with
edema.7 Other factors that affect the duration of RF
and that should be taken into consideration, are the
time of day that the test is performed, the temperature of the examining room, and in females of
childbearing age, the time of their menstrual cycle.
Criteria for venous reflux
Relatively few studies have been performed regarding the definition of venous reflux in the lower extremity veins and its standardization.2-5,7 All of the
reports are in agreement regarding the best cutoff
value in the superficial veins, which is >0.5 second.
Even fewer studies have assessed the perforator,
muscular, and deep axial veins. The results of the
only study to have evaluated all of the veins is presented below.
Methods for diagnosing reflux
Patients and methods
There are both physiologic and imaging methods
for diagnosing reflux. The physiologic evaluation includes invasive tests with direct vein pressure measurements, and plethysmographic tests such as air,
A total of 80 limbs in 40 healthy volunteers and 60
limbs in 45 patients with CVD were examined with
DU in the standing and supine positions. Reflux was
FOCUS
assessed at 16 vein segments: the common femoral,
deep femoral, and proximal and distal femoral veins;
the proximal and distal popliteal veins; the gastrocnemial vein; the anterior and posterior tibial veins;
the peroneal vein; the great saphenous vein at the
saphenofemoral junction, thigh, upper calf, and
lower calf; and the small saphenous vein at the
saphenopopliteal junction and mid calf. Perforator
veins detected along the course of these veins were
also evaluated.
In healthy volunteers, 1553 vein segments were
assessed, including 480 superficial vein segments,
800 deep vein segments, and 273 perforator vein
segments. In the patients, 1272 vein segments were
assessed, including 360 superficial vein segments,
600 deep vein segments, and 312 perforator vein
segments. Rapid-inflation pneumatic cuffs (Aircast,
Summit NJ) with pressure set at 80 mm Hg were
used to elicit reflux. The cuffs were placed on the
lower thigh for groin and proximal thigh vein measurements, and for the other veins, they were placed
on the lower calf. The inflation time to maximal
pressure was 0.3 second, inflation was maintained
for 1.0 second, and deflation was achieved in less
than 1.0 second.
The Doppler tracings were set so as not to have
overgain, with the background appearing dark and
the signal bright. The scale was reduced to the lowest necessary point to detect low flow velocities, and
was optimized to show the whole trace. Immediately after release of compression, the tracings were
allowed to run until the RF ended. At this point, the
durations of RF and peak vein velocity were measured in both the standing and supine positions.
Results and interpretation
All data for each vein segment were analyzed individually for the supine and standing positions. The
definition of abnormal RF was calculated at the best
separation point and in comparison with the data
from the healthy controls. Statistical analysis of the
data was performed for the differences in proportions using the chi-squared test and with 95% confidence intervals (CI). Examples of different waveforms and flow patterns obtained are shown in
Figures 1 to 8 (page 160).
Superficial veins
In the control group, the mean duration of RF was
210 ms (range, 0-2400 ms; 95% CI, 206-214), and in
16 vein segments (3.3%), RF was >500 ms. In the
patients, RF was >500 ms in 202 segments (56%;
P<0.0001 compared with controls). If other segments of the main saphenous veins, tributary vessels, and nonsaphenous superficial veins were included in the analysis, then 93% would have RF
>500 ms. Varicose veins had RF >500 ms. It is important to note that of the 202 segments with RF
>500 ms, 114 segments (56%) were dilated but had
no varicosities, and 18 segments (9%) had a normal diameter or had a diameter of <2.5 mm.
From the above findings and in accord with others, RF >500 ms identifies reflux with great certainty. It has been shown that the larger the diameter
of a vein, the higher the chance of it being incompetent. However, many vein segments with a normal diameter, and also some with a small diameter,
can have reflux. This has been observed in all types
of superficial veins (saphenous, accessory, tributaries, and nonsaphenous veins) in many locations
in the lower extremity.
Perforator veins
Because it has been shown that perforator veins can
exhibit bidirectional flow,4,6 the outward flow component was taken as the RF. Most perforator veins
were found below the knee (n=214; thigh, n=59).
The mean RF duration in the control group was
170 ms, ranging from 0 to 760 ms. Only 3 perforator veins (1%) in the calf and none in the thigh had
RF >500 ms. RF duration in the calf (180 ms, 95%
CI, 176-184) was longer than in the thigh (150 ms,
95% CI 145-155; P<0.0001). The best cutoff value
for reflux was RF >350 ms. In the patients, 71 of 312
perforator veins had RF >500 ms (P>0.0001 compared with controls). Setting the cutoff at 350 ms,
82 perforator veins would have had abnormal RF.
Incompetence in the perforator veins is controversial, as the impact of these veins on CVD is not
clear. However, the number of incompetent perforator veins and their size increase with the severity
of the disease.27,28 The diameter of a perforator vein
has been found to correlate well with the presence
of reflux, as those >3.0 mm are most often incompetent.6,29 However, as in the superficial veins, many
incompetent perforators have a smaller diameter.
In patients with primary CVD, the perforator reflux
develops in continuity with that of the superficial
veins.30 In the absence of superficial vein reflux, the
perforator veins are normal.
Deep veins
In the deep veins, RF ranged from 0 to 2600 ms.
Deep femoral and calf veins had a mean RF duration of 190 ms (95% CI, 188-192). The RF was
>500 ms in only 1 deep femoral vein (1.2%) and 7
calf veins (2.2%). Common femoral, femoral, and
popliteal veins had a mean RF duration of 280 ms
(95% CI, 375-385), which was significantly longer
than all other veins (P<0.0001). In 21 of 400 femoropopliteal segments in controls, the RF duration
ranged from 510 to 2600 ms, but in 99% of these
veins, RF was <990 ms. Using 1000 ms as the cutoff for abnormal RF, only 4 of 400 segments (1%)
would have reflux. In the patients, 152 of 600 segments had RF >500 ms (P<0.0001 compared with
controls). In the femoropopliteal veins, the prevalence of RF >500 ms was 29% (87 of 300 veins;
P<0.0001 compared with controls). Using a cutoff
value of 1000 ms, the prevalence of abnormal RF
was significantly reduced at 18% (54 of 300 veins;
P<0.002).
In primary CVD, reflux in deep veins is associated with reflux in superficial veins.31 In fact, it has
been shown that correction of superficial vein reflux corrects deep vein reflux in most patients.32,33
The prevalence of deep vein reflux increases with
severity of CVD, and is significantly more common
in patients with skin damage.28 This is probably
FOCUS
Figure 1. Normal popliteal vein, without any retrograde
flow.
Figure 2. Normal popliteal vein with a retrograde flow
duration of 820 ms.
Figure 3. Popliteal vein reflux with a retrograde flow duration of 1.4 seconds.
Figure 4. Proximal femoral vein reflux with a retrograde
flow duration of 1.84 seconds.
Figure 5. Reflux in the saphenopopliteal junction with a
retrograde flow duration of 3.5 seconds. The popliteal
vein just distal to the junction is normal, whereas at the
junctional level, it is incompetent. After treatment of the
small saphenous vein, the popliteal vein became normal.
Figure 6. Reflux in the small saphenous vein in the upper
calf with a retrograde flow duration of 1.8 seconds. The
vein has a small diameter measuring only 2.2 mm.
Figure 7. Reflux in the great saphenous vein in continuity
with a tributary in the lower thigh. On Doppler spectrum,
the retrograde flow duration was 5.2 seconds and the peak
flow velocity was 34 cm/s. The proximal incompetent vein
segment has a larger diameter than the distal normal vein
segment just below the tributary (4.6 mm vs 3.4 mm).
Figure 8. A nonfunctioning valve in a posteromedial tributary overlying the medial head of the gastrocnemius
muscle. The valve in the near wall has become atrophic
and in the far wall it is elongated and frozen.
FOCUS
because the extent of superficial disease and the
duration of CVD are longer, and the prevalence of
thrombosis is significantly higher compared with
patients presenting with varicose veins.28
Supine compared with standing position
In the control group, 37 vein segments (2.4%) had
RF >500 ms in the supine position. Of these segments, only 22 (59%) had RF >500 ms in the standing position. Of the 48 vein segments (3.1%) with
RF >500 ms in the standing position, RF was <500
ms in 6 of these (13%) in the supine position. Similar observations were noted in patient veins, where
some vein segments with reflux in the supine position became normal in the standing position, and
some others became worse in the standing position.
These findings indicate that both the specificity
and sensitivity for detecting pathologic reflux are
best in the standing position. Standing is a more
physiologic position and more meaningful in clinical practice, as the hydrostatic pressure in the lower limbs is highest and the diameter of all veins is
larger. This allows a longer period of RF to occur in
diseased vein segments. During standing, there is
a definitive closure of competent valves and clearly
more challenge is offered to incompetent valves. A
cutoff value of >2 seconds was suggested for veins
tested in the supine position.34 Given our findings
and the reasons discussed above, when possible, reflux should only be tested in the standing position.
Another smaller study that examined patients in
both positions also found that the standing position
was superior for reflux testing.35
Waveform characteristics
The peak RF velocity, which was identified immediately after the release of the compression, showed
a wide range in both controls (8-35 cm/s) and patients (9-83 cm/s). Vein segments with reflux had
higher peak velocity (mean 23.5 cm/s; 95% CI, 20.226.8) compared with normal vein segments (mean
15 cm/s; 95% CI, 14.8-15.2; P<0.0001). In the patients, vein segments with reflux had a mean peak
RF velocity of 41 cm/s; 95% CI, 36-48.5, compared
with 18 cm/s; 95% CI, 14.5-24.2, in the normal vein
segments (P<0.0001). It was not possible to determine peak RF cutoff velocity values for reflux, as
RF duration and peak RF velocity had great variation. More importantly, reflux occurred at both low
and high peak RF velocities. In a previous study, no
association was found between the peak RF velocity and reflux.36 Many factors are responsible for the
velocity characteristics, such as the diameter and
length of the incompetent vein segment, wall compliance, the network of veins where this segment
empties, and the condition of other veins in contiREFERENCES
1. Gottlob R, May R. Occurrence and distribution of
venous valves. In: Gottlob and May, eds. Venous Valves.
Vienna, Austria: Springer-Verlag; 1986:16-24.
2. van Bemmelen PS, Bedford G, Beach K, Strandness
DE. Quantitative segmental evaluation of venous valvular reflux with duplex ultrasound scanning. J Vasc
Surg. 1989;10:425-431.
3. Araki CT, Back TL, Padberg FT, Thompson PN,
Duran WN, Hobson RW. Refinement in the ultrason-
nuity. Also, the severity of the disease and the degree
of inflammation may affect these values, as blood
flow in the limb may be affected locally or in its entirety.37 Other RF parameters may be important for
the severity of the disease, but do not discriminate
between normal and pathologic values.38 It was
shown that the RF duration has a qualitative value,
whereas the peak RF velocity and the average flow
velocity better reflected the severity of venous incompetence.
Effect of different maneuvers
Manual compression or rapid inflation cuffs may
not be adequate stimulus to elicit reflux in some
patients. In 13 vein segments (great saphenous vein,
3; small saphenous vein, 1; femoral vein, 1; popliteal
vein, 1; gastrocnemial veins, 2; peroneal vein, 1; perforator veins, 4) in patients with significant pitting
edema, RF was normal. RF became abnormal only
during active dorsiflexion or plantar flexion. We
have also observed this in routine clinical practice,
where some very obese patients and those with edema may need active dorsi/plantar flexion where the
deep veins are compressed with higher force directly from the muscles. In the groin area, if the test is
negative with distal compression, the Valsalva maneuver is performed, because the challenge to the
valves at that level is stronger and reflux may only
be demonstrated in this manner.
Progression of reflux
Reflux develops in an ascending, descending, and
multifocal manner.39,40 It can also exist in independent locations that do not anatomically communicate. It has also been shown that the progression of
reflux occurs in the same manner.30,41 All veins can
be affected by reflux, but the superficial veins are
most often involved in primary disease. In patients
with thrombosis, reflux progresses in the postthrombotic veins, but reflux in veins that were remote to thrombosis can be affected as well. Across
the whole spectrum of CVD, reflux is most common
in the superficial veins. Superficial vein reflux affects the perforator veins either in an ascending
manner as progression of vein wall disease, in a descending manner at a re-entry point via the high
flow rate that may dilate the perforator veins, or in
both directions. In the descending path, wall disease may also be important, together with, or separate from, increased flow. The perforator veins, in
turn, affect the deep veins that they are communicating with, and in time will render these incompetent as well. In a similar manner, the saphenous
and gastrocnemial junctions can make the femoral
and popliteal veins incompetent. ic detection of popliteal vein reflux. J Vasc Surg.1993;
18:742-748.
4. Sarin S, Sommerville K, Farrah J, Scurr JH, Coleridge Smith PD. Duplex ultrasonography for assessment of venous valvular function of the lower limb.
Br J Surg. 1994;81:1591-1595.
5. Lagattolla NR, Donald A, Lockhart S, Burnand KG.
Retrograde flow in the deep veins of subjects with
normal venous function. Br J Surg. 1997;84:36-39.
6. Labropoulos N, Mansour MA, Kang SS, Gloviczki P,
Baker WH. New insights into perforator vein incompetence. Eur J Vasc Endovasc Surg.1999;18:228-234.
7. Labropoulos N, Tiongson J, Landon P, et al. Definition of venous reflux in lower extremity veins. J Vasc
Surg. 2003;38:793-798.
8. Maros T. Data regarding the typology and functional significance of the venous valves. Morphol Embryol (Bucur). 1981;27:195-214.
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9. Lurie F, Kistner RL, Eklof B, Kessler D. Mechanism
of venous valve closure and role of the valve in circulation: a new concept. J Vasc Surg. 2003;38:955-961.
10. Bergan JJ, Schmid-Schonbein GW, Smith PD,
Nicolaides AN, Boisseau MR, Eklof B. Chronic venous
disease. N Engl J Med. 2006:355:488-498.
11. Nicolaides AN, Hussein MK, Szendro G, Christopoulos D, Vasdekis S, Clarke H. The relation of venous
ulceration with ambulatory venous pressure measurements. J Vasc Surg. 1993;17:414-419.
12. Neglen P, Rajus S. Differences in pressures of the
popliteal, long saphenous, and dorsal foot veins. J Vasc
Surg. 2000;32:894-901.
13. Van Cleef JF, Hugentobler JP, Desvaux P, Griton P,
Cloarec M. Étude endoscopique des reflux valvulaires
saphéniens. J Mal Vasc. 1992;17(suppl B):113-116.
14. Sales CM, Rosenthal D, Petrillo KA, et al. The
valvular apparatus in venous insufficiency: a problem
of quantity? Ann Vasc Surg. 1998;12:153-155.
15. Ono T, Bergan JJ, Schmid-Schönbein GW, Takase
S. Monocyte infiltration into venous valves. J Vasc
Surg. 1998;27:158-166.
16. Takase S, Bergan JJ, Schmid-Schönbein GW.
Expression of adhesion molecules and cytokines on
saphenous veins in chronic venous insufficiency. Ann
Vasc Surg. 2000;14:427-435.
17. Prandoni P, Lensing A, Cogo A, et al. The longterm clinical course of acute deep venous thrombosis.
Ann Intern Med. 1996;125:1-7.
18. Johnson B, Manzo R, Bergelin O, Strandness D.
The site of residual abnormalities in the leg veins in
long term follow-up after deep vein thrombosis and
their relationship to the development of the postthrombotic syndrome. Intern Angiol. 1996;15:14-19.
19. Meissner M, Caps M, Zierler B, et al. Determinants
of chronic venous disease after acute deep venous
thrombosis. J Vasc Surg. 1998;28:826-833.
20. Comerota AJ, Gravett MH. Iliofemoral venous
thrombosis. J Vasc Surg. 2007;46:1065-1076.
21. Laiho MK, Oinonen A, Sugano N, et al. Preserva-
SEUIL
tion of venous valve function after catheter-directed
and systemic thrombolysis for deep venous thrombosis. Eur J Vasc Endovasc Surg. 2004;28:391-396.
22. Plate G, Brudin L, Eklöf B, Jensen R, Ohlin P.
Physiologic and therapeutic aspects in congenital vein
valve aplasia of the lower limb. Ann Surg. 1983;198:
229-233.
23. Nicolaides AN. Investigation of chronic venous
insufficiency: a consensus statement. Circulation.
2000;102:E126-E163.
24. Caggiati A, Bergan JJ, Gloviczki P, Eklof B, Allegra
C, Partsch H; International Interdisciplinary Consensus Committee on Venous Anatomical Terminology. Nomenclature of the veins of the lower limb: extensions, refinements, and clinical application. J Vasc
Surg. 2005;41:719-724.
25. Coleridge-Smith P, Labropoulos N, Partsch H,
Myers K, Nicolaides A, Cavezzi A. Duplex ultrasound
investigation of the veins in chronic venous disease of
the lower limbs—UIP Consensus Document. Part I.
Basic principles. Eur J Vasc Endovasc Surg. 2006;31:
83-92.
26. Cavezzi A, Labropoulos N, Partsch H, et al. Duplex
ultrasound investigation of the veins in chronic venous disease of the lower limbs—UIP Consensus Document. Part II. Anatomy. Eur J Vasc Endovasc Surg.
2006;31:288-299.
27. Labropoulos N. Hemodynamic changes according
to the CEAP classification. Phlebolymphology. 2003;
40:103-106.
28. Labropoulos N, Patel PJ, Tiongson JE, Pryor L,
Leon LR Jr, Tassiopoulos AK. Patterns of venous reflux and obstruction in patients with skin damage due
to chronic venous disease. Vasc Endovascular Surg.
2007;41:33-40.
29. Sandri JL, Barros FS, Pontes S, Jacques C, SallesCunha SX. Diameter-reflux relationship in perforating veins of patients with varicose veins. J Vasc Surg.
1999;30:867-874.
30. Labropoulos N, Tassiopoulos AK, Bhatti A, Leon L.
Development of reflux in the perforator veins in primary venous disease. J Vasc Surg. 2006;43:558-562.
31. Labropoulos N, Tassiopoulos AK, Kang SS, Mansour MA, Littooy FN, Baker WH. Prevalence of deep
venous reflux in patients with primary superficial
vein incompetence. J Vasc Surg. 2000;32:663-668.
32. Walsh JC, Bergan JJ, Beeman S, Comer TP.
Femoral venous reflux abolished by greater saphenous
vein stripping. Ann Vasc Surg. 1994;8:566-570.
33. Sales CM, Bilof ML, Petrillo KA, Luka NL. Correction of lower extremity deep venous incompetence
by ablation of superficial venous reflux. Ann Vasc
Surg. 1996;10:186-189.
34. Manzo R. Duplex evaluation of chronic venous
disease. In: Strandness DE, ed. Duplex Scanning in
Vascular Disorders. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002:368-378.
35. Foldes MS, Blackburn MC, Hogan J, et al. Standing versus supine positioning in venous reflux evaluation. J Vasc Tech. 1991;15:321-324.
36. van Ramshorst B, van Bemmelen PS, Hoeneveld
H, Eikelboom BC. The development of valvular incompetence after deep vein thrombosis: a follow-up
study with duplex scanning. J Vasc Surg. 1994;19:
1059-1066.
37. Labropoulos N, Leder DM, Kang SS, Mansour MA,
Baker WH. Inflammation parallels severity of chronic venous insufficiency. Phlebology. 2003;18:78-82.
38. Neglén P, Egger JF 3rd, Olivier J, Raju S. Hemodynamic and clinical impact of ultrasound-derived venous
reflux parameters. J Vasc Surg. 2004;40:303-310.
39. Labropoulos N, Giannoukas AD, Delis K, et al.
Where does venous reflux start? J Vasc Surg.1997;26:
736-742.
40. Caggiati A, Rosi C, Heyn R, Franceschini M, Acconcia MC. Age-related variations of varicose veins
anatomy. J Vasc Surg. 2006;44:1291-1295.
41. Labropoulos N, Leon L, Kwon S, et al. Study of the
venous reflux progression. J Vasc Surg. 2005;41:291295.
DES VALEURS NORMALES ET PATHOLOGIQUES DU REFLUX
n reflux se prolongeant plus longtemps que ne le permettrait une fermeture valvulaire normale peut se développer
dans les membres inférieurs. Des signes et symptômes de
maladie veineuse chronique surviennent pendant l’activité à cause de l’augmentation de la pression veineuse. L’écho-Doppler, la
meilleure méthode d’évaluation du reflux, a évalué sa durée dans
quelques études, déterminant les situations normale et pathologique. La plus grande et seule étude prospective sur le sujet est
analysée ici avec les résultats de ces études. La meilleure valeur
seuil pour la durée d’un reflux anormal était supérieure à 500 ms
pour les veines superficielles, les veines fémorales profondes et les
U
veines profondes du mollet. Pour les veines perforantes, la plupart
des experts ont extrapolé la même valeur que celle utilisée pour
les veines superficielles. La meilleure valeur séparant le normal
du pathologique est néanmoins celle supérieure à 350 ms. En ce
qui concerne les veines fémorale commune, fémorale et poplitée,
la meilleure valeur est celle supérieure à 1 000 ms. L’orthostatisme est la meilleure position pour réaliser le test du reflux. La
durée et la vitesse maximale du reflux sont très variables, la vitesse n’ayant aucun rapport avec la présence d’un reflux prolongé. La progression et le développement du reflux touchent toutes
les veines et de façon ascendante, descendante et multifocale.
U
P D A T E
VENOUS VALVE DYSFUNCTION
RESTORATION BY SURGERY
IN PRIMARY CHRONIC VENOUS DISEASE
by M. R. Perrin, France
alve dysfunction can be described as an abnormality that is responsible for reflux in the
affected vein. Primary venous insufficiency is
chronic venous dysfunction whose cause is neither
congenital nor clearly identifiable. Valve dysfunction is the result of structural abnormalities in the
vein wall and in the valve itself. Redundant, malopposed cusps and venous dilation permit valve prolapse and reflux. Unlike in the post-thrombotic syndrome, there is no evidence of previous thrombosis
near the valve. A rare cause of reflux is the complete
or partial absence of valves. This anomaly can be
primary or congenital. Valvular incompetence can
V
SELECTED
ASVAL
CHIVA
DS
DVR
RCT
SFJ
A
Michel R. PERRIN, MD
Clinique du Grand Large
Décines, FRANCE
Surgical methods for
treatment of valve dysfunction
Superficial venous system
In the superficial venous system, two kinds of treatment methods can be used—indirect and direct.
Indirect procedures
Indirect procedures have in common the preservation of the saphenous trunk with restoration of
its valve function via modification of the hemodynamics (Figure 1, page 164). All of these procedures
need a very precise preoperative duplex scanning
(DS) evaluation and mapping.
Selective Ablation of Varices under
Local Anesthesia (French acronym)
duplex scanning
deep venous reflux
randomized controlled trial
s stated by Arkadiusz Jawien in this issue of Medicographia, surgical techniques for venous valve dysfunction
have evolved. Resection surgery, consisting of ablation of
the impaired organ or system when it was not indispensable in
terms of survival or normal physiological function, has progressively been replaced by organ or system repair. Incompetent venous valves responsible for disabling reflux, which can lead to
chronic venous disease, can be mainly found in two systems; the
superficial and the deep venous systems. As it is known that ablation of the superficial venous system can be performed without
major disturbance to the venous circulation, this method became
the gold standard up until 20 years ago, when new procedures
including direct or indirect valve function restoration were developed and used. Indirect restoration of valve function in the superficial venous system can be achieved by two methods: suppression of the leak points from the deep system to the superficial
system without ablation of the saphenous trunk (Conservative
Hemodynamic treatment of Incompetent Varicose veins in Ambulatory patients [CHIVA], high ligation plus tributaries phlebectomy plus/ minus perforator ablation), or suppression of the
be identified in both the upper and lower limbs, the
other veins in the thorax and abdomen being mostly valveless, but the adverse consequences resulting in chronic venous disease are only found in the
lower limbs.
Below the inguinal ligament, there are three venous systems: the superficial, perforator, and deep
systems. Consequently, valve dysfunction can be
identified in all of them, but restoration of valve
function by surgery is only performed in the superficial and deep systems.
distal reservoir, ie, stab avulsion of the incompetent tributaries
to restore valve competence by reducing the diameter of the
saphenous trunk (ambulatory phlebectomy, Selective Ablation
of Varices under Local Anesthesia [ASVAL]). Direct valve repair
in the superficial venous system can be achieved through vein external cuffing or bandaging at the valve station. Extensive deep
venous system ablation is not possible without major perturbation of the venous return function, and ligation has proven to be
ineffective. The most common procedure used in this situation is
valve repair, with valve transfer or use of a prosthetic venous valve
also used less frequently. Techniques, treatment outcomes, and
indications for venous valve restoration by surgery will be discussed with respect to primary chronic venous disease.
Keywords: primary chronic venous disease; venous reflux,
valvuloplasty; valve transfer; valve bandaging; venous surgery;
phlebectomy; varicose vein
Address for correspondence: Michel R. Perrin, 26 Chemin de Décines,
69680 Chassieu, France (e-mail: m.perrin.chir.vasc@wanadoo.fr)
Venous valve dysfunction restoration by surgery in primary chronic venous disease – Perrin
UPDATE
2
1
3
4
A
B
C
D
E
Figure 1. Hemodynamic techniques for restoration of the valves of the saphenous
trunk. A shows a diagram of primary varicose veins. 1, deep vein; 2, great saphenous
vein (GSV) or short saphenous vein (SSV) trunk; 3, GSV or SSV tributaries; 4, perforator. B illustrates the CHIVA technique: high ligation plus ligation of the saphenous
trunk below the re-entry perforator plus disconnection of the venous shunts or tributary phlebectomy. C illustrates valvuloplasty or wrapping (shown here) of the GSV
termination plus tributary phlebectomy plus perforator ligation. D illustrates high
ligation resection plus tributary phlebectomy plus perforator ligation. E shows tributary phlebectomy (ASVAL). X, vein resection; , ligation.
Figure 1 and Figure 2 reproduced from reference 1:
Perrin M. Chirurgie à ciel ouvert de l’insuffisance veineuse
superficielle. Principes.
Techniques. Résultats. EMC
(Elsevier Masson SAS, Paris),
Techniques Chirurgicales—
Chirurgie Vasculaire. 2007;
43-161-B. Copyright © 2007,
Elsevier Masson SAS.
Deep venous system
In the deep venous system, valve repair techniques
for treating deep venous reflux (DVR) can be classified into three groups: those that involve phlebotomy, those that do not involve phlebotomy, and those
utilizing percutaneous placed devices.
Techniques with phlebotomy
– Internal valvuloplasty
Since the first internal valvuloplasty procedure described in 1968 by Kistner, involving the use of a
longitudinal phlebotomy (Figure 3),21 various procedures have been proposed. Raju22 advocated a
supravalvular transverse venotomy, while Sottiurai23 utilized a hybrid T-shaped supravalvular incision (Figure 4). In 2002, Tripathi proposed the use
of an internal trapdoor valvuloplasty.24 In all cases,
the redundant valve cup is plicated to the vein wall
using multiple interrupted or continuous 7-0 Prolene reefing sutures. It has been estimated that plication of approximately 20% of the leaflet length
should restore competence, although the best gauge
remains visual inspection.
– Venous segment transfer
Venous segment transfer was devised for patients
with a competent great saphenous or deep femoral
vein valve in their proximal segment (Figure 5) and
DVR in the femoropopliteal axis. The purpose of
venous segment transfer is to transpose a competent valve-bearing venous segment into the axial
deep venous system, ie, the femoropopliteal axis at
the groin level. Several surgical variations of venous
– Conservative Hemodynamic treatment
of Incompetent Varicose veins in Ambulatory
patients (CHIVA)
The CHIVA procedure (Figure 1B), developed by
Franceschi, is based on the fact that even though
varicose disease is associated with weakness of the
vein wall, the breaking of the pressure column and
the suppression of venous shunting can restore the
valve function in the saphenous trunk.2 According
to the different patterns of reflux in the superficial
system identified by DS, various procedures can be
tailored to the individual patient.3-5
– High ligation plus tributaries phlebectomy
plus/minus perforator ablation
High ligation plus tributaries phlebectomy plus/
minus perforator ablation (Figure 1D), first reported by Hammarsten, is used only for treating insufficiency in the great saphenous vein.6 The main
difference between this procedure and the CHIVA
procedure is the systematic ligation-resection of the
saphenofemoral junction (SFJ).
– Tributaries stab avulsion, Selective Ablation of
Varices under Local Anesthesia (ASVAL)
In 1956, Muller brought back a very ancient method
known as tributaries stab avulsion (Figure 1E),
which involved stab avulsion of incompetent tributaries in patients presenting with incompetent
valves in the saphenous trunk. He updated his experience in 1996.7 Recently, Pittaluga has promoted this technique with some refinement on the basis of information provided by DS investigation.8
Direct procedures
Various direct techniques have been used, including SFJ plication plus/minus tributary phlebectomy,9,10 and SFJ wrapping or bandaging with Dacron,
polytetrafluoroethylene (PTFE) or a specific device
(Venocuff I and II) plus/minus tributary phlebectomy plus/minus perforator ligation (Figure 1C,
Figure 2).11-19
3 cm
Figure 2. External stenting. Left panel: above, the Venocuff II set. Below, schematics of incompetent venous valve (BEFORE) and competent
valve following external stenting (AFTER). Right panel: angioscopic view
after stenting.
Figure 3. Internal valvuloplasty according to Kistner. Using a longitudinal phlebotomy, each valve is repaired by interrupting a series of
sutures placed at the commissures. Each suture progressively shortens
the leading edge of the cusp.
UPDATE
a
a
(i)
d
(ii)
(i)
(ii)
d
c
(iii)
b
Figure 4. Internal valvuloplasty according to Sottiurai. Left panel: (i)
T-shaped phlebotomy; (ii) a bird’s eye view of the floppy valve. Right
panel: (i) after clamping and systemic heparinization, a vertical phlebotomy originating from the midpoint of the transverse phlebotomy is
made extending into the valvular sinus using right angle Potts’ scissors;
(ii) the needle of a double-ended suture (7-0 polypropylene suture)
is inserted to penetrate both cusps of the valve at the commissure;
(iii) after completion of 3 to 4 tackings at each commissure, the valve
cusp apposition is obtained.
segment transfer have been employed using endto-end or side-to-end anastomosis according to the
state of competence of the different valves in the
veins of the groin.25
– Vein valve transplantation
In vein valve transplantation (Figure 6), a 2-3 cm
segment of axillary vein is inserted as an interposition graft at the termination of the femoral vein
just below the junction between the deep femoral
vein and the femoral vein or at the popliteal vein.
– Neovalve creation
Maleti created a valvular cusp by dissection of the
femoral venous wall to obtain a single or a bicuspid
valve (Figure 7).26 He has used this technique mainly in cases of secondary etiology (post-thrombotic
syndrome) but also in valvular agenesis that is probably not primary but congenital, but this original
technique deserves to be mentioned.
Techniques without phlebotomy
– Wrapping, banding, cuffing, and external stenting
Wrapping, banding, cuffing, and external stenting
Distal
superficial
femoral
vein
b
c
Figure 5. Venous segment transfer. The refluxive femoral vein (c) may
be transposed into the great saphenous vein (d) or the profunda femoral
vein (b), provided they have a competent proximal valve at their termination. a, common femoral vein.
Figure 3, Figure 4, Figure 5,
and Figure 6 reproduced from
reference 20:
Perrin M. Repair of venous
valves in severe chronic venous
insufficiency. In: Bergan JJ,
Shortell CK, eds. Venous Ulcers.
Amsterdam, Holland; Boston,
Ma: Elsevier Academic Press;
2007:243-257. Copyright ©
2007, Elsevier, Ltd.
was developed initially for saphenous vein incompetence, and later for primary deep vein incompetence.27,28
– External valvuloplasty
The first step in external valvuloplasty consists of
adventitial dissection until the valve’s insertion lines
are clearly identifiable as an inverted V shape. The
commissural angle is normally acute, but in refluxive valves it is widened. Kistner introduced external
valvuloplasty in 1990.29 In the transmural valvuloplasty technique, an external row of sutures is placed
along the diverging margins of the valve cusp in
the vein wall. Sutures for external repair are commenced at each commissure on both sides of the
vein. The interrupted sutures are carried inferiorly
until the valve becomes competent by strip testing
(Figure 8, page 166).
Transcommissural valvuloplasty (Figure 9, page
166), developed by Raju, differs from transmural
valvuloplasty by the use of a transluminal suture.
As described in his paper; “A through-and-through
transluminal resuspension suture (7-0 Prolene) was
placed obliquely across the inverted V, traversing
the valve cusps ‘blindly’ near their wall attachment
to pull them up.” 31
Posterior
tibial artery
Popliteal
vein
Posterior
tibial vein
Figure 6. Valve transplant. Above-knee or below-knee axillary vein-topopliteal vein transplantation with end-to-end anastomosis.
Figure 7. Valve construction according to Maleti (by courtesy). Left
panel: valve agenesia. The flap is created. Right panel: the flap is fixed
at the opposite site to create a neovalve.
UPDATE
A
B
comparing this method with conventional surgery
did not show any statistical difference in terms of
clinical results at 4-year follow-up.6,36 Two case series
using ASVAL have been reported with 7.8 (mean),
and 36 months follow-up, respectively.8,37 The recurrence rate was found to be less than 10% in both.
Direct procedures
It is more difficult to assess the outcome of direct
procedures, as a variety of procedures have been
used. However, three RCTs comparing valve bandaging to classical surgery are available, with 9.4
(mean), 12, and 42 months of follow-up, respectively.13,15,16 No difference in terms of outcome—including varices recurrence—has been found.
C
Figure 8. External valvuloplasty: the transmural
technique according to
Kistner.
– Angioscopy-assisted external valve repair
In angioscopy-assisted external valve repair, the sutures are passed from outside to inside the lumen,
directed by video-enhanced, magnified angioscopic
imaging, allowing for precise approximation of the
valve cusps.32
Percutaneous placed devices
The percutaneous placed device, the Portland valve,
consists of a square stent and porcine small intestinal submucosa covering, and is currently in a clinical phase I study.33
Reproduced from reference 30:
Bergan JJ. The Vein Book. San
Diego, CA: Elsevier Academic
Press; 2007. Copyright © 2007,
Elsevier, Ltd.
Clinical trial outcomes for
surgical procedures
Superficial venous system
In all case series involving surgery to the superficial
venous system in which the outcome on varices was
reported, no assessment data is available on the value of the saphenous trunk as a potential arterial
substitute.
Indirect procedures
Several nonrandomized controlled studies have been
reported on the use of CHIVA, with both good clinical and hemodynamic outcomes at 3-year followup.3,4,34,35 Unfortunately, no randomized controlled
trial (RCT) versus conventional surgery is available.
With regard to high ligation plus tributaries phlebectomy plus/minus perforator ablation, two RCTs
A
B
A
C
Recommended indications
B
D
Figure 9. External valvuloplasty: the transcommissural technique according to Raju and Neglen.
Reproduced from reference 31: Raju S, Berry MA, Neglen P. Transcommissural valvuloplasty: technique and results. J Vasc Surg. 2000;32:969-976. Copyright © 2000, Society
for Vascular Surgery and The American Association for Vascular Surgery, a Chapter
of the International Society for Cardiovascular Surgery.
Deep venous system
The results of DVR surgery are somewhat difficult
to assess, as superficial venous surgery and/or perforator surgery are often performed in combination with DVR surgery. In primary DVR, the most
frequent procedure used is valvuloplasty. Results are
summarized in Table I.24,31,38-43 On the whole, valvuloplasty is credited with achieving a good result in
70% of cases in terms of clinical outcome, defined
as freedom from ulcer recurrence and a reduction
in pain, valve competence, and hemodynamic improvement over a follow-up period of more than 5
years. In all series, a good correlation was observed
among these three criteria. External transmural
valvuloplasty does not seem to be as reliable as internal valvuloplasty for providing long-term valve
competence or ulcer-free survival.41
Only two series provide information about the
outcome of patients presenting with severe chronic venous insufficiency without ulcer who are treated with valvuloplasty.40,42 No patients in either series
developed an ulcer during the long-term follow-up,
presumably due to successful prevention of disease
progression by the operative intervention. Other
procedures used in primary deep reflux, including
angioscopic repair and wrapping, are more difficult
to assess, because the case series have a relatively
short follow-up, with the exception of Lane’s series
(Table II).27,28,41,44
As valve transfer has been used mainly in postthrombotic syndrome, the outcomes in primary
DVR cannot be precisely assessed.
Primary superficial venous insufficiency
As very few RCTs are available comparing direct
or indirect valve restoration procedures to classical
surgery, only weak recommendations can be stated
concerning their use. Furthermore, new techniques
such as echo-guided foam sclerotherapy and endovenous techniques such as radiofrequency and endovenous laser have recently emerged as valuable
alternatives to traditional vein stripping.
It therefore looks difficult to recommend any particular procedure sparing the saphenous trunk (usually the great saphenous vein), but in young patients
and particularly in women who have children and
are considering future pregnancies, ablation surgery
might not be the ideal recommendation.
UPDATE
Surgical
technique
Number of limbs
treated (number of
valves repaired)
Etiology
PVI/Total
Eriksson 38
I
27
27/27
(49)
Masuda 39
I
32
N/A
Perrin 40
I
85 (94)
Raju 31,41
I
TMEV
TCEV
TMEV
Rosales 42
Sottiurai
43
Tripathi 24
Hemodynamic results
AVP
VRT
N/A
19/27 (70)
81% (av)
50% (av)
48-252 (127)
(28)
24/31 (77)*
81% (av)
56% (av)
65/85
12-96 (58)
10/35 (29)
64/83 (77)
Normalized
56% (av)
68 (71)
47 (111)
141 (179)
N/A
N/A
98/41
12-144
12-70
1-42
16/68 (26)
14/47 (30)
(37)
30/71 (42)
72/111
(59)
N/A
N/A
81% (av)
Normalized
100%
17 (40)
17/17
3-122 (60)
3/7 (43)
(52)
Competent
valve (%)
50% (av)
Study author
Follow-up
Ulcer
months
recurrence or
(mean) unhealed ulcer (%)
I
143
17/17
3-122 (60)
3/7 (43)
(52)
N/A
I
TMEV
TCEV
90 (144)
12 (19)
96/118
(24)
(372)
(50)
(79.8)
(31.5)
N/A
N/A
* no reflux or moderate reflux (<1 s) in 9 patients.
Table I.
Number of extremities
treated (number of
valves repaired)
Site
Akesson 27
(Venocuff I)
20 (27)
Etiology
PVI /Total
F, P
Follow-up
Ulcer
months
recurrence or
(mean) unhealed ulcer (%)
7/20
5-32 (19)
2/10 (20)
both PTS
Hemodynamic results
Competent
AVP
valve (%)
VRT
PVI 7/7(100)
PTS 7/10 (4)
PVI
81% (av)
Study author
(material used)
50% (av)
PVI
81% (av)
50% (av)
54
F
54/54
4-63
N/A
41/54 (76)
Lane 28 (Venocuff II)
42 (125)
F, P
36/42
64-141 (93)
(20)
(90)
N/A
?
Camilli 44 (Dacron)
100% (av)
41
Raju (Dacron)
28
F, P, T
N/A
12-134
6/22 (27)
60/72 (83)
N/A
Table II.
Table I. Valvuloplasty
clinical study results.
Abbreviations: av, average; AVP,
ambulatory venous pressure; I,
internal valvuloplasty ; N/A, not
applicable; PVI, primary venous
insufficiency; TCEV, transcommissural external valvuloplasty;
TMEV, transmural external valvuloplasty; VRT, venous refill
time; improved.
Table II. Banding, cuffing,
external stent, and wrapping clinical study results.
Abbreviations: av, average; AVP,
ambulatory venous pressure;
F, femoral; N/A, not applicable;
P, popliteal; PTS, post-thrombotic syndrome; PVI, primary
venous insufficiency; T, tibial
(posterior); improved.
Indications for deep valve repair are based on clinical severity, hemodynamics, and imaging.
Clinical severity
Most authors recommend surgery in patients classified as C6, and particularly with recurrent ulcer.
In addition, given the good results associated with
valve repair for primary reflux, I feel that valve repair
should be considered in young and active patients
presenting with severe edema or C4b findings, in
order to avoid the lifetime use of compression garments. When superficial and perforator venous insufficiency occur in association with DVR, they must
be treated as well, either as the first step in therapy
or in a staged fashion. Contraindications to reconstructive surgery include uncorrectable hypercoagulable state or ineffective calf pump of any etiology.
Hemodynamics and imaging
Only reflux that is considered grade 3 to 4 based on
Kistner’s criteria45 is usually appropriate for DVR
surgery. It is generally recognized that to be significantly abnormal, the value for venous refill time
Primary deep venous insufficiency
must be less than 12 seconds, and the difference between pressure at rest and after standardized exercise in the standing position must be less than 40%.
The decision to operate should be based on the clinical status of the patient, not the noninvasive data,
since the patient’s symptoms and signs may not correlate with the laboratory findings.46 In addition to
meeting the clinical criteria, patients selected for
surgery should be highly motivated to participate
in their recovery, since ultimate success is dependent on their compliance with postoperative management.
In summary, primary reflux reconstructive surgery is recommended after failure of conservative
treatment and in young and active patients reluctant to wear permanent compression. Valvuloplasty
is the most suitable technique, with Tripathi, Kistner, Perrin, and Sottiurai favoring internal valvuloplasty,24,39,40,43 Raju recommends transcommissural
external valvuloplasty31 and Rosales favors transmural valuloplasty.42 Some, but not all, authors recommend repairing several valves.24,42 MEDICOGRAPHIA, VOL 30, No. 2, 2008 167
UPDATE
REFERENCES
1. Perrin M. Chirurgie à ciel ouvert de l’insuffisance
veineuse superficielle. Principes. Techniques. Résultats. EMC (Elsevier Masson SAS, Paris), Techniques
Chirurgicales—Chirurgie Vasculaire. 2007;43-161-B.
2. Francheschi C. Theorie et Pratique de la Cure Hémodynamique de l’Insuffisance Veineuse en Ambulatoire. Paris, France: De l’Armançon; 1989.
3. Zamboni P, Marcellino MG, Cappelli M, et al. Saphenous vein sparing surgery : principles, techniques and
results. J Cardiovasc Surg. 1998;39:151-162.
4. Zamboni P, Cisno C, Marchetti F, Quaglio D, Mazza
P, Liboni A. Reflux elimination without any ablation
or disconnection of the saphenous vein. A haemodynamic model for venous surgery. Eur J Vasc Endovasc
Surg. 2001 ;21:361-369.
5. Franceschi C. Fractionnement dynamique de la
pression hydrostatique, shunts fermés et ouverts, évolutivité veineuse vicariante. En quoi ces concepts ontils fait évoluer le traitement des varices? Phlébologie.
2003;56:61-66.
6. Hammarsten J, Pederson P, Cederlund CG, Campanello M. Long saphenous vein saving surgery for
varicose vein. A long term follow-up. Eur J Vasc Surg.
1990;4:361-364.
7. Muller R. Mise au point sur la phlébectomie ambulatoire selon Muller. Phlébologie. 1996;49:335-344.
8. Pittaluga P, Rea B, Barbe C. Méthode ASVAL (ablation selective des varices sous anesthésie locale).
Principes et résultats préliminaires. Phlébologie. 2005;
58:175-181.
9. Belcaro G. Plication of the saphenofemoral junction
Phlebology. 1991;7:121-124.
10. Belcaro G, Errichi BM. Selective saphenous valve
repair: a 5-year follow-up study. Phlebology.1992;7:
121-124.
11. Zamboni P, Liboni A. External valvuloplasty of the
saphenofemoral junction using perforated prosthesis. Phlebology. 1991;6:159-165.
12. Lane RJ, McMahon C, Cuzilla M. The treatment of
varicose veins using the venous valve cuff. Phlebology. 1994;9:136-145.
13. Schanzer H, Skladany M. Varicose vein surgery
with preservation of the saphenous vein : a comparison between high ligation-avulsion versus saphenofemoral banding valvuloplasty avulsion. J Vasc Surg.
1994;20:684-687.
14. Sakatowa H, Hoshino S, Igari T, Takase S, Ogawa
T. Angioscopic external valvuloplasty in the treatment
of varicose veins. Phlebology. 1997;12:136-141.
15. Corcos L, De Anna D, Zamboni P, et al. Reparative surgery of valves in the treatment of superficial
venous insufficiency. J Mal Vasc. 1997;22:128-136.
LA
16. Agus GB, Bavera PM, Mondani P, Santuari D. External valve-support for saphenofemoral junction incompetence: randomized trial at 3 years follow-up.
Acta Phlebologica. 2002;3:101-106.
17. Camilli S. Le manchonnage périveineux de la terminaison saphéno-fémorale dans le traitement de l’insuffisance de la grande veine saphène et la prévention
des récidives. Phlébologie. 2002;55:343-349.
18. Geier B, Geier B, Voigt I, et al. External valvuloplasty in the treatment of greater saphenous insufficiency: a five-year follow-up. Phlebology. 2003;18:
137-142.
19. Lane RJ, Graiche JA, Coroneos JC, Cuzilla ML.
Long term comparison of external valvular stenting
and stripping of varicose veins. ANZ J Surg. 2003;73:
605-609.
20. Perrin M. Repair of venous valves in severe chronic venous insufficiency. In: Bergan JJ, Shortell CK, eds.
Venous Ulcers. Amsterdam, Holland; Boston, Ma: Elsevier Academic Press; 2007:243-257.
21. Kistner RL. Surgical repair of a venous valve.
Straub Clin Proc. 1968;24:41-43.
22. Raju S. Venous insufficiency of the lower limb
and stasis ulceration. Ann Surg. 1983;197:688-697.
23. Sottiurai VS. Technique in direct venous valvuloplasty. J Vasc Surg. 1988;8:646-648.
24. Tripathi R, Sieunarine K, Abbas M, Durrani N. Deep
venous valve reconstruction for non-healing leg ulcers:
techniques and results. ANZ J Surg. 2004;74:34-39.
25. Kistner RL. Transposition techniques. In: JJ Bergan, RL Kistner, eds. Atlas of Venous Surgery.Philadelphia, PA: WB Saunders; 1992:153-156.
26. Maleti O. Venous valvular reconstruction in postthrombotic syndrome. A new technique. J Mal Vasc.
2002;27:218-221.
27. Akesson A, Risberg B, Bjôrgell O. External support
valvuloplasty in the treatment of chronic deep vein incompetence of the legs. Intern Angiol.1999;18:233-238.
28. Lane RJ, Cuzilla ML, McMahon CG. Intermediate
to long-term results of repairing incompetent multiple deep venous valves using external stenting. ANZ
J Surg. 2003;73:267-274.
29. Kistner RL. Surgical technique of external venous
valve repair. Straub Found Proc. 1990;55:15-16.
30. Bergan JJ. The Vein Book. San Diego, CA: Elsevier
Academic Press; 2007.
31. Raju S, Berry MA, Neglen P. Transcommissural
valvuloplasty: technique and results. J Vasc Surg.
2000;32:969-976.
32. Gloviczki P, Merrel SW, Bower TC. Femoral vein
valve repair under direct vision without venotomy:
a modified technique with use of angioscopy. J Vasc
Surg. 1991;14:645-648.
33. Pavcnik D, Uchida BT, Timmermans HA, et al. Percutaneous bioprosthetic venous valve: a long term
study in sheep. J Vasc Surg. 2002;35:598-602.
34. Escribano JM, Juan J, Bofill R, et al. Durability of
reflux by a minimal invasive CHIVA procedure on patients with varicose veins. Eur J Vasc Endovasc Surg.
2003;25:159-163.
35. Maeso J, Juan J, Escribano JL, et al. Résultats cliniques comparés du stripping et de la cure CHIVA
dans le traitement des varices des membres inférieurs.
Ann Chir Vasc. 2001;15:661-665.
36. Campanello M, Hammarsten J, Forsberg C, Bernland P, Henrikson O, Jensen J. Standard stripping versus long saphenous vein saving surgery for primary
varicose veins: a prospective, randomized study with
the patients as their own controls. Phlebology.1996;
11:45-49.
37. Large J. Surgical treatment of the saphenous
varices, with preservation of the main great saphenous
trunk. J Vasc Surg. 1985;2:886-891.
38. Eriksson I, Almgren B. Surgical reconstruction of
incompetent deep vein valves. Ups J Med Sci. 1988;
93:139-143.
39. Masuda EM, Kistner RL. Long term results of venous valve reconstruction: a four to twenty-one year
follow-up. J Vasc Surg. 1994;19:391-403.
40. Perrin M. Reconstructive surgery for deep venous
reflux. Cardiovasc Surg. 2000;8:246-255.
41. Raju S, Fredericks R, Neglen P, Bass JD. Durability of venous valve reconstruction for primary and
postthrombotic reflux. J Vasc Surg.1996;23:357-367.
42. Rosales A, Slagsvold CE, Kroese AJ, Stranden E,
Risum O, Jorgensen JJ. External venous valveplasty
(EVVP) on patients with primary chronic venous insufficiency (PCVI). Eur J Vasc Endovasc Surg.2006;32:
570-576.
43. Sottiurai VS. Current surgical approaches to venous hypertension and valvular reflux. J Int Angiol.
1996;5:49-54.
44. Camilli S, Guarnera G. External banding valvuloplasty of the superficial femoral vein in the treatment
of primary deep valvular incompetence. Int Angiol.
1994;13:218-222.
45. Kistner RL, Ferris RG, Randhawa G, Kamida CB.
A method of performing descending venography. J Vasc
Surg. 1986;4:464-468.
46. Iafrati MD, Welch H, O’Donnel TF, Belkin M, Umphrey S, MacLaughlin R. Correlation of venous noninvasive tests with the Society for Vascular Surgery
clinical classification of chronic venous insufficiency.
J Vasc Surg. 1994;19:1001-1007.
CHIRURGIE RESTAURATRICE DANS LE TRAITEMENT DU REFLUX VEINEUX D’ÉTIOLOGIE PRIMITIVE
omme le souligne Arkadiusz Jawien dans ce numéro de
Medicographia, les techniques chirurgicales ont évolué dans
la mesure où la restauration de la fonction d’un organe ou
d’un système a remplacé son exérèse. Cette dernière était la technique la plus souvent utilisée dans la mesure où sa suppression
était possible en termes de survie ou n’entraînait pas de perturbations physiologiques majeures. L’incompétence valvulaire est
essentiellement identifiée dans les réseaux veineux superficiel et
profond ; elle est la cause d’un reflux qui peut entraîner une maladie veineuse chronique. La suppression du réseau veineux superficiel pathologique était la technique de base jusqu’à ces 20
dernières années car elle n’entraînait pas de trouble majeur de la
circulation de retour, mais depuis des techniques nouvelles se sont
développées qui visent à supprimer le reflux par des procédés directs ou indirects. Deux types de méthodes indirectes peuvent être
identifiées : (1) celles qui visent à supprimer les points de fuite
du réseau veineux profond vers le réseau veineux superficiel en
conservant le tronc saphène : cure hémodynamique de l’insuffi-
C
sance veineuse ambulatoire (CHIVA), ligature résection de la
jonction saphéno-fémorale et/ou saphéno-poplitée associée à une
phlébectomie des collatérales +/– ligature des perforantes ; (2)
celles qui se proposent de restaurer la fonction valvulaire en réduisant le calibre des troncs saphènes par suppression du réservoir distal : phlébectomie ambulatoire, ablation sélective des
varices sous anesthésie locale (ASVAL). La réparation directe
valvulaire par manchonnage ou valvuloplastie externe est plus
rarement entreprise pour traiter l’insuffisance veineuse superficielle. La suppression du réseau veineux profond incontinent
n’est pas possible car elle entraîne des troubles majeurs de la circulation de retour et sa ligature n’est pas efficace. La technique
de choix est donc la reconstruction valvulaire ou valvuloplastie ;
le transfert valvulaire ou les valves prothétiques sont exceptionnellement réalisés dans cette étiologie. Sont successivement développés dans cet article les techniques, les résultats et enfin les
indications de la chirurgie restauratrice de la fonction valvulaire
dans l’insuffisance veineuse primitive.
A
T
O U C H
O F
F
R A N C E
Christian RÉGNIER, MD
Praticien Attaché des Hôpitaux de Paris
Société Internationale d’Histoire de la Médecine
9 rue Bachaumont, 75002 Paris, FRANCE
(e-mail: dr.christian.regnier@wanadoo.fr)
The sciences under
Louis XVI
A king torn between
enlightenment and revolution
b y C . R é g n i e r, F r a n c e
L
ouis XVI was 20 years of age when he acceded to the throne of France and Navarre in 1774 on the
death of his grandfather Louis XV the well-beloved (born in 1710). Born at Versailles on August 23,
1754, Louis XVI lost his father when he was 11 years old and his mother when he was 13 years old.
As Duke of Berry, he received a strict religious education under the guardianship of the obscure
Duke de La Vauguyon (1706-1772) and Bishop Jean Gilles de Coëtlosquet (1700-1784), who also
saw to the education of his three brothers. He was a hard-working pupil whose favorite subjects
were Latin, mathematics, physics, the maritime sciences, history, and geography. He was a frequent visitor to the workshop that Jean-Antoine Nollet (1700-1770), priest and experimental physicist, had installed
in Versailles. He was the first French monarch to be fluent in English, reading House of Commons debates,
translating English works, and building a collection of English periodicals and newspapers. In addition,
and on his own initiative, he learned Italian and Spanish. Although his tutor, de La Vauguyon, took great
care to isolate him from the philosophy of the Enlightenment, he nevertheless read The Spirit of the Laws
(L’Esprit des Lois) by Montesquieu (1689-1785). The future Louis XVI was not keen on the military arts,
despite his reputation as an excellent horseman.
T
he main political problem during the reign of Louis XVI, compounded by the expense of French
aid during the American War of Independence, was the constant undermining by the nobility
and senior clergy of attempts to abolish their privileges. The forces most hostile to change were forever marshaled against the King, who failed to attract support from the more enlightened elements of
the nobility. Reserved, shy, and modest, Louis XVI knew what he wanted but was loath to give orders.
He was a reluctant participant in Court ceremonial, thus indirectly depriving the nobility of their representational social role. His main failing was an inability to command. He was forever torn between the
reformist ideas of the Enlightenment and deep attachment to tradition. Although respectful of the fundamental laws of the land and unwilling to contravene them, he appointed reforming ministers—only to
dismiss them shortly afterward. The last absolute French monarch by divine right, he had a natural interest in scientific experiment, research, and discovery. He lost no opportunity of offering moral and financial support to new undertakings that might advance human knowledge and improve the condition
of the masses: expansion of the Academy of Sciences, creation of the Royal Society of Medicine, the hotair balloon and steam engine trials, the voyage of La Pérouse, implementation of hospital hygiene, and
institutions for the blind and deaf-and-dumb. Long misunderstood in French history and often despised,
the biographies of Louis XVI and Marie-Antoinette in the pre-Revolution political context are now being
rewritten.
The sciences under Louis XVI. A king torn between enlightenment and revolution – Régnier
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On May 16, 1770, he married Archduchess Marie-Antoinette of Austria (1755-1793), the younger daughter of Emperor Francis I of Lorraine. Husband and wife were 15 and 14 years of age. Their marriage embodied the alliance between the kingdoms of France and Austria. Louis XVI and Marie-Antoinette had four
children: Marie Thérèse (1778-1851), known as Madame Royale, Louis Joseph (1781-1789), Louis Charles
(1785-1795), the future Louis XVII, who was to meet a tragic fate, and Sophie Béatrice (1786-1787).1-4
Portrait of Louis XVI by
Antoine-François Callet,
1788. © Krause, Johansen/
Archivo Iconografico,
SA/CORBIS.
The years in waiting: an unconventional prince
When 2 years old, the young Duke had teething problems
and was losing weight. The Genevan physician Théodore
Tronchin (1709-1781), author of the article on “inoculation” in the Encyclopédie and senior physician to the
Duke of Orléans, was visiting Versailles at the time. He
recommended exposing the royal children to fresh air.
Tronchin had the ear of the Court, yet was also a friend
of Voltaire (1694-1778), Denis Diderot (1713-1784), and
Jean-Jacques Rousseau (1712-1778). He was an Enlightenment physician and an advocate of smallpox inoculation using Variola minor (variolation).
After staying nearby to Meudon Forest, the young
Duke of Berry and his brothers returned to Versailles.
Louis was brought up with his elder brother, the Duke
of Burgundy, who died in 1761 from pulmonary tuberculosis aged 10, leaving Louis to inherit the crown by
default. His childhood was marked by loneliness, lack of
affection, and a succession of bereavements: after his
elder brother, came his father (1765), mother (1767), and
grandfather Louis XV (1774).1,2
“My grandson is not very passionate,” Louis XV wrote
the Infant of Parma in June 1770, deploring the future
King’s lack of alacrity in consummating his marriage to
Marie-Antoinette, “…[he is] unlike other men.” In July,
2 months after the wedding, the Dauphin was examined
by Germain Pichault de la Martinière (1697-1783), surgeon to the King, for any anatomical abnormality that
might explain the absence of sexual relations (the young Duke was almost 16 and Marie-Antoinette 14).
The surgeon found no abnormality, in particular no phimosis (“narrowness of the passage”). He suggested
that “constitutional frigidity” might be responsible, a diagnosis confirmed in 1773 by the King’s physician,
Jean-Marie François de Lassonne (1717-1778). We should recall that the young prince was being educated
in the puritanical Jansenist moral code by a tutor who taught that “children conceived by too young a
father are of a delicate constitution and do not live long,” and that “there is also a risk that their father
becomes a libertine.” The unconsummated marriage became an affair of State and the focus of all malicious gossip at Court; the Count of Fuentès, the Spanish ambassador, saw it as a case of “constitutional
frigidity induced by the teachings of Duke de La Vauguyon.”1,2,4
Other factors included the fact that the young prince’s interests were not shared by his wife. Whereas
her tastes ran to singing, dancing, balls, music, and fine clothes, Louis liked hunting and all kinds of manual work, with locks, clocks, and carpentry. His cabinet was equipped with a forge, workbench, a couple
of anvils, and numerous tools. He took untold pleasure in joining craftsmen at their work “moving materials, planks, and cobblestones, and undertaking such heavy exercise for hours at a time that he sometimes came back more exhausted than any laborer forced into such work.” In 1773, de Lassonne prescribed
the young prince some cinchona and “Mars balls” (alcoholic concoctions of iron filings and tartar) in an
attempt to kick-start his libido.3,4
As for the Dauphine, she was somewhat offhand in her compliance with the practices of the French court.
She kept company with a coterie of young people with scant respect for etiquette. This attitude brought
reprimands from her mother, Maria-Theresa, who wrote to her: “It is said that you are beginning to make
fun of people, to burst out laughing in their faces… By going out of your way to please five or six young
ladies or gentlemen, you risk alienating everyone else.”4
On May 10, 1774, Louis XV died of smallpox, having refused to inoculate his family (only the Duke of
Orléans, who was more open to modern ideas, had had variolation performed on his children). “The King
is dead! Long live the King!”
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King Henri IV touching
scrofula sufferers. Engraving
by André de Laurens, 1609.
The « Royal Touch » was
believed to cure scrofula, or
“King’s Evil,” aka, cervical
tuberculous lymphadenopathy.
Philip I was the first French
king to start the practice,
which all French kings, including Louis XI, continued up
to King Charles X on 29 May
1825. © Roger Viollet.
Louis XVI was crowned in Reims on June 10, 1715. Four days later, he conducted the age-old ceremony
of the royal touch, a time-honored rite performed by French kings since Robert the Pious in the 10th century. In the park of the abbey of Saint Rémi in Reims, bareheaded and wearing the cloak of the Holy Ghost,
he touched some 2400 patients afflicted with scrofula, the “King’s evil,” making the sign of the Cross over
them, and speaking the words: “The King toucheth thee; the Lord healeth thee” (the chronicle of the event
recorded four cures). Louis XVI repeated this medieval ceremony five times in the course of his reign.4
Successes and setbacks in the reign
Louis’ grandfather, Louis XV, his father (the Dauphin), and his tutor, de La Vauguyon, inculcated the young
prince with their patriarchal monarchy ethic. Kings were both shepherd and father to their flock. This
conception of the exercise of royal power was influenced by a religiously inspired moral philosophy that
taught the subservience of the temporal domain to the demands of its spiritual counterpart. Clearly, no
such principle had been espoused by the Sun King, Louis XIV, for whom radiance of the monarch, reason
of State, preeminence of law, and national prestige outweighed all other moral or religious considerations.
A diligent worker and regular attendee at the Council of Dispatches (which received administrative
reports from provincial governors) and Council of State, Louis XVI set about becoming an exemplary “good
king.” He sought to do good and keep to the fundamental laws of the kingdom. His reign was dotted with
gestures of generosity: restoration of the regional or city
parliaments (1774), creation of the pawnshop in Paris to
discourage usury (1777), abolition of torture (1780), abolition of craft guild privileges and of the corvée royale,
by which peasants donated their labor on royal highways (1780), institution of an extensive public works
program, abolition of the poll tax on Jews (1784), and
the granting of civil status to Protestants (1788).3
Louis XVI’s intelligence shone best in foreign policy.
He built up a royal navy powerful enough to rival that
of England, as shown during the American War of Independence. Signed at Versailles on September 3, 1783,
the Treaty of Paris marked the creation of the United
States of America. It reflected France’s military and economic commitment to the rebels and erased the humiliation of the Treaty of Paris signed 20 years previously,
marking the loss of the French possessions in North
French Map of the Battle of the Chesapeake on September 5, 1781,
America. It also signaled the return of France as an arbetween a French fleet led by Rear-Admiral Comte de Grasse and a
British fleet, led by Rear-Admiral Sir Thomas Graves. As a result,
biter of European policy.2,4
the Royal Navy was unable to resupply the forces of General Lord
However clear-sighted he may have been in foreign
Cornwallis, who surrendered after at Yorktown to George Washingpolicy,
Louis XVI had difficulty in imposing his authorton and his French ally, General Rochambeau. The battle ended
6 years of war and won American independence. © CORBIS.
ity within France. He dismissed his ministers as soon
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as any obstacle emerged that appeared insurmountable, in particular, resistance by the parliaments. Yet
MAXIMS AND THOUGHTS OF LOUIS XVI
he did not hesitate to appoint men of the Enlighten“A country can never be governed against its
ment as his ministers. Determined to push through
habits.”
fiscal reforms, he called on Jacques Turgot (1727“An absolutely essential maxim in govern1781) in 1774, then on the Geneva banker Jacques
ment is to prevent the population from falling
Necker (1732-1804) in 1776, dismissing both before
into the sort of indifference that makes them
they could complete their stabilization of the royal
think that it matters not whether they live unfinances. At the instigation of the Controller-Generder one kind of dominion or another.”
al of Finance, Charles Alexandre de Calonne (1734“A sovereign can do nothing more useful
1802), the King convened the Assembly of Notables
than inspire the idea of their own greatness in
in 1787 with a view to carrying out fiscal and finanhis people.”
cial reform. King and minister sought to establish
“It’s legal because I want it.”
equality in taxation by seeking contributions from
the notables themselves, setting up provincial assemblies that would rule on public finance issues, abolishing internal customs barriers, and freeing up
the grain trade. The Assembly disbanded without reaching a conclusion. Senior clergy and nobility refused
to pay the tax. Calonne was dismissed. His successor, Bishop Étienne Charles Loménie de Brienne (17271794), faced a parliamentary revolt. On the advice of Necker, Louis XVI convened the Estates-General, comprising clergy, nobility, and Third Estate (middle class). However, voting was to proceed by estate, enabling
the clergy and nobility to outvote the Third Estate, rather than by overall poll, which would have enabled
the numerically much superior Third Estate to carry the day.1,3,5
Louis XVI was not against a measure of reform. On July 17, 1789, 3 days after the Paris insurrection that
followed the dismissal of Necker, the King went to the city hall proudly sporting the revolutionary cocade
(white, the French royal color, framed by red and blue, the colors of Paris). But this well-received gesture
was marred on August 4 by his refusal to sign the Declaration of the Rights of Man or the decree abolishing feudal privileges. Forced back to Paris from
Versailles, Louis XVI appeared to accept his role
as constitutional monarch, no longer King of
France by divine right, but King of the French.
At the Champ-de-Mars, on July 14, 1790, the
King went to the feast of the Federation, took
his oath to the Constitution, and was acclaimed
by the crowd. But his faith could not accept the
transformation of the clergy into civil servants.
His last hopes resting with an armed coup de
force, he fled with his family in the night of
June 20 to 21, 1791. His prestige and credit
were at rock bottom, and he was imprisoned in
the Temple prison. On August 10, 1792, he was
condemned to death, then guillotined on January 21, 1793. His bravery in the face of death
sent a wave of emotion sweeping through European courts and inspired the first military
coalition against the fledgling republic.1,2,4,5
Execution of King
Louis XVI, on today’s
Place de la Concorde, in
Paris, on January 21,
1793. © Bettmann/
CORBIS
Influence of the Encyclopédie on the intellectual climate
With its 600 000 inhabitants, Paris was the largest city in the Western world after London. The Bourbon
capital was the center of intellectual and financial life, a hub for the arts and sciences. It was only natural
that Paris should have been the setting for a remarkable intellectual event: the publication of the sum of
human knowledge, revised and corrected in the light of philosophical thought.
In the 1750s, triggered by the writings of Voltaire, a break occurred in the customs and traditions of
conventional philosophical thought. Cornerstones of this enlightened thinking included: a belief in the
elimination of ignorance through scientific progress; trust in observation and experimentation; aspiration to individual happiness; glorification of reason as opposed to religious dogma; and concern for a new
civil and democratic morality.
This was the intellectual climate that welcomed the birth of a monument to Western knowledge. The
first volume of the Encyclopédie (Encyclopedia, or a systematic dictionary of the sciences, arts, and crafts)
appeared in 1751; 28 volumes of text and 15 volumes of plates were published up to 1780. This unprece-
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dented publication comprised 17 000 articles written by 140 contributors of differing backgrounds and
specialties. According to Diderot and Jean le Rond d’Alembert (1717-1783), the Encyclopédie aimed “to
gather together the knowledge scattered across the surface of the globe and expose its general system to
those who will come after us so that the work of centuries past will not have been in vain for the centuries
that follow.” What was novel about the Encyclopédie was not only its exhaustive determination to record
the sum of human knowledge, but to articulate theory closely with practice “in one and the same vision
of progress.” The publication was also innovatory in its systemic cross-referencing, thereby emphasizing
its determination to break down the barriers between the different disciplines within human knowledge.
The Encyclopédie interpreted the sum of knowledge in the light of critical reason and integrated this
knowledge into a consistent philosophical system. “All our direct knowledge can be reduced to what we receive through our
senses,” wrote D’Alembert, “whence it follows that we owe all
our ideas to our sensations.” 6,7
Financed by subscription, the work was published in Paris
(first seven volumes), then from March 1759 onward in Neuchâtel (Switzerland). Because it espoused sensualist and materialist theories that questioned the spirituality of the soul
and justified atheism, the Encyclopédie was not well received
by the authorities. The Paris Parliament issued a ban in 1759
and ordered the seven volumes already published to be destroyed. Despite bans and other forms of obstruction, the Encyclopédie and its numerous pirated foreign versions found
a wide public among notables, including magistrates, civil servants, cultured bourgeois, artists, merchants, and the enlightened nobility (ie, those sectors who were to prove most active
in the Revolution). It was even supported in many circles up
to and including the Court: a portrait by Maurice Quentin de
la Tour (1704-1788) depicted Louis XV’s favorite, Madame de
Pompadour, turning the pages of the Encyclopédie. The Encyclopedists also received unfailing backing from Malesherbes
(1721-1794), the director of the book trade and royal censor- Engraved plate from Diderot’s Encyclopedia.
ship from 1750 to 1763, who enjoyed the esteem of the young Louis XVI was a fervent amateur locksmith,
Louis XVI. After first reading the Encyclopédie in 1777, and and enjoyed lockwork as much as he did
hunting. All rights reserved.
recognizing its scientific and technical qualities, the King ordered the establishment of a Museum of Sciences and Technology in 1781. It was the forerunner of the
present-day Museum of Arts and Crafts (Musée des Arts et Métiers).6,7 The philosophy of the Enlightenment,
embodied in the Encyclopédie, bore within it the seeds of the 1789 revolution: the progress of universal
knowledge would free mankind from the irrational beliefs responsible for fanaticism. The philosophers
of the Enlightenment did not separate the order of reason and nature from the moral and social order. Men
were born free and equal, and social rank was to be determined on merit alone. The implications behind
an intellectual project of this kind could not escape the notice of those in power, and they also won over
a number of enlightened minds.
On the other hand, there are historians who believe that the Revolution invented the Enlightenment
in order to legitimize itself through a corpus of philosophical knowledge. In defense of this view, it must be
recognized that the Enlightenment never addressed the masses.4,6,7
The King as enlightened protector of the sciences
Under Louis XVI, the Academy of Sciences, which had been founded in 1666 by Jean-Baptiste Colbert (16191683), grew by three new sections: general physics, natural history, and mineralogy, thereby complementing its six other sections (geometry, astronomy, mechanics, anatomy, chemistry, and botany). Scientists
from around the world working in the leading learned societies came to Paris to test and add to their knowledge. Between 1720 and 1780, the proportion of scientific publications doubled, to the detriment of their
theological counterparts. In the spirit of the Encyclopédie, during the reign of Louis XVI, the 39 academies
in Paris and the provinces were keen to report any scientific discoveries and innovations with the potential for directly transforming daily life. The King took a great interest in the activities of these engineers
and scientists and encouraged their experiments and initiatives.4
Louis XVI had been fascinated by science since childhood. He could handle calculations in algebra, had
a solid grounding in physics, was acquainted with Boyle’s law, and knew how to do section drawings of
buildings and instruments. Proud of his epoch’s discoveries, he had no hesitation in sporting a bouquet of
A T
OUCH
OF
FRANCE
Agronomist Antoine Augustin Parmentier presenting
Louis XVI with a bunch of potato flowers. Potatoes were
first grown in France in the sandy ground at Les Sablons,
in Neuilly, near Paris.Legend has it that the crop was
guarded by heavily armed royal troops so that the populace, very mistrustful of the palatability of this new plant,
would be convinced it was very precious, for it to be so
protected. © Roger-Viollet.
potato blossom in his buttonhole in honor of the tuber raised from pigsty to dining table by the chemist
Antoine Parmentier (1737-1813). Following the
recognition by the Paris Faculty of Medicine in 1772
(for which Parmentier was largely responsible) that
the potato was harmless to human health, the King
granted Parmentier the Sablons plain near Neuilly
to develop his crop. Large-scale potato cultivation
was to play a considerable role in eradicating the
famines that periodically ravaged the French countryside when climatic disasters decimated the grain
harvest; during such crises, potato replaced cereal in the baking of bread (the staple food of the French).
Even so, during the Revolution, Louis XVI’s endorsement of Parmentier was to make the chemist suspect
in the new regime’s eyes.8,9
In 1783, Louis XVI drew on his own resources to finance the hot-air balloon experiments by the Montgolfier brothers. The first test of a spherical balloon took place in Annonay on June 5. The 800 m3 balloon
inflated with hot air weighed 225 kg. It rose 1000 meters into the sky and traveled 2 kilometers. Looking
for financial backing, and supported by the Academy of Sciences, Jacques-Étienne Montgolfier (1745-1799)
went to Paris and gave a demonstration at Versailles on September 19 before King and Court. This time,
the blue taffeta balloon decorated with fleur-de-lis was larger (1000 m3), and carried a sheep, rooster, and
duck in a basket. The King asked for explanations, and was shown the huge straw-fired stove that produced
hot air to propel the balloon. The trial was successful, with the animals returning alive. The King gave
permission for an experiment with a human being. On June 23, 1784, the Marie-Antoinette, a balloon decorated with the French and Swedish coats of arms, lifted off in Versailles in front of the royal family and
Gustav III, King of Sweden. It transported its two passengers, Jean-François Pilâtre de Rozier (1754-1785)
and Louis Proust (1754-1826), senior pharmacist at the Salpêtrière Hospital, all the way to the Forest of
Chantilly, a distance of 52 kilometers. Bowled over by the invention, the King awarded Jacques-Étienne
the ribbon of St Michael, gifted an annuity to his brother Joseph Michel (1740-1810), ennobled their father,
and granted the two brothers a substantial sum to continue their hotair experiments.8,10 Louis XVI also encouraged industrial applications
of the steam engine. He would regularly arrange to be presented with
novel ideas, in some cases supporting them from the privy purse. This
was not the case for the Périer brothers, Jacques-Constantin (1742-1818)
and Auguste Charles, who had to use their own funds to build a pump
at Chaillot to supply Paris with water from the Seine; the pump was
driven by two steam engines. The Périer brothers were skilled mechanics, and they applied their pressurized steam method to blast furnaces,
enabling them to manufacture cylinders, pendulums, and new cotton
spinning machines.8,11
In 1783, Louis XVI backed attempts by the Marquis Jouffroy d’Abbans
(1751-1832) to fit the steam engine into boats. Newspapers of the time
reported the progress of a paddle steamer, the Pyroscaphe, on the Saône
near Mâcon. Unfortunately, opposition from the Academy of Sciences
and the intervention of the Revolution meant that glory never came the
way of Jouffroy d’Abbans.8,12
Man’s first ascent from Earth, on November 21,
1783. Pilâtre de Rozier and Marquis d’Arlandes
wave from the gallery of their Montgolfier air
balloon as they set out from Paris. © Bettman/
CORBIS.
“Have we any news of Monsieur de la Pérouse?”
During his adolescence, Louis XVI read the account published in 1771
by Louis Antoine de Bougainville (1729-1811) of his circumnavigation
of the globe (1766-1769). He was also interested in the archipelago that
Yves-Joseph de Kerguelen de Trémarec (1734-1797) discovered in the
southern Indian Ocean. In his apartments in Versailles, Louis XVI was
surrounded by astrolabes, barometers, thermometers, chronometers,
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FRANCE
sighting instruments, and Delille’s nautical charts (renowned for their accuracy). He even translated the
journals of Captain James Cook (1728-1779), having a particular appreciation for the scientific objectives behind Cook’s travels (the attempts to resolve certain problems of astronomy and mathematics in
order to correct longitude errors on nautical charts).4,8 Louis was keen for France to punch at its weight in
advancing geographic and maritime science. His personal choice for this mission fell on Jean-François
de Galaup, Comte de La Pérouse (1741-?1788). He annotated the report by the Minister for Naval Affairs
in his own hand and set the commercial and maritime aims of the voyage:
As for the reconnoitering part, the main points are reconnoitering the north west part of America, which
converges with the commercial part, and reconnoitering the Sea of Japan, which also converges with the
commercial part; but for that, I think that the season proposed in the Report is a poor choice for reconnoitering the Solomon Islands and the south west of New Holland (Australia). All the other points ought to be
subordinated to the former; we should restrict ourselves to what is most useful, and to what can be done comfortably, within the three years proposed.8,13,14
After the Anglo-French peace treaty of 1783, Louis XVI developed an ambitious colonial policy and
mapped out clear political and commercial objectives for the expedition: monitoring English navy activity; inspecting Dutch and Spanish trading posts; studying Russian trade in the Kamchatka peninsula;
moving into the fur trade; and setting up a network of safe and strategic ports and trading posts across
the Pacific for expanding trade with Russia and China. The expedition also had
a medical objective: to test a diet that
would prevent scurvy, typhus, and typhoid fever. Special attention was paid
to the method of storing water, flour,
and food; molasses were loaded against
scurvy, modeled on Cook’s success in
preventing the disease.
Four surgeons were recruited; their
medicine chests contained 157 different
remedies, and the King insisted that he
would regard “completion without the
loss of a single life as the expedition’s
happiest outcome.”13,14 Alas, there were
to be no survivors from the expedition,
but up to his final log, filed from Botany
Bay, La Pérouse reported virtually no case
of scurvy.
On August 1, 1785, the Boussole and
Louis XVI, on June 29, 1785, giving his instructions to La Pérouse about to set out
the Astrolabe left Brest, carrying scienon his voyage around the world. Painting by Monsiau Nicolas André, oil on canvas,
tists, botanists, cartographers, natural2.72 2.7 m, at the Musée du Château de Versailles, 1817. © Gérard Blot/RMN.
ists, and watchmakers (to ensure the accuracy of the marine chronometers that were essential for plotting longitude). At each port of call, La
Pérouse sent the King a copy of his logbook. The expedition lasted over 21/2 years and finished with the
disappearance of the 200 crew off Vanikoro (Solomon Islands) in February 1788. Legend has it that a few
hours before his execution, Louis XVI asked: “Have we any news of Monsieur de La Pérouse?” 8,13,14
The King’s creation of the Royal Society of Medicine
Numerous epidemics had ravaged France since the last visit by plague in 1720: smallpox (1776-1786),
measles (1776-1786), dysentery (1779, 1792), and pneumonia (1784-1785). On April 29, 1776, in an attempt
to study and prevent such afflictions, the King set up a Commission of medicine in Paris to maintain correspondence with physicians in the provinces on all that may pertain to human and animal epidemic
disease. Turgot, Controller-General of Finances, entrusted the anatomist Félix Vicq d’Azyr (1748-1794) with
the founding of the Commission that became the Royal Society of Medicine by letters patent on August 20,
1778. A member of the Academy of Sciences, Vicq d’Azyr was the author of the article on morbid anatomy
in the Encyclopédie. The Royal Society of Medicine (half-way between academy and government thinktank) boasted the most progressive physicians of the Enlightenment era among its members. It met in
the Louvre in the courtroom of the Secretary of State for the King’s Household. Attacked from its inception by the Paris Faculty of Medicine, the Society was inspired by a pioneering spirit. Its aim was to collect
serial data on the epidemiology of infectious disease, the state of the soil and water supply, medical topography, and meteorology, all on a monthly basis, right across France. The survey was hugely ambitious in
A T
OUCH
OF
Félix Vicq d’Azyr
(1746-1794),
physician and
anatomist, and the
last physician
of Queen MarieAntoinette, whom
he tried to protect.
Founded the Royal
Society of Medicine,
which did groundbreaking work in
epidemiology.
© Bibliothèque
Nationale, Paris,
France/Lauros/
Giraudon/The
Bridgeman Art
Library.
Colored engraving
of the brain, by
Vicq d’Azyr, in his
Traité d’Anatomie
et de Physiology
(1786). He described
the locus ceruleus,
the locus niger, and
the band of Vicq
d’Azyr. © Bridgeman
Art Library.
FRANCE
that it sought not only to map French epidemiological risk but to lay down general principles of hygiene
applicable to prisons, hospitals, schools, barracks, ports, and ships. In return, corresponding physicians in
France and abroad were to receive information on the clinical aspects of infections and their treatment.
Considered as the largest administrative survey ever undertaken in the 18th century, the study remained
under the authority of the Controller-General of Finances who authorized no other institution, even the
Academy of Sciences, to concern itself with statistics in its place. As a result, the conduct of the study remained under the supervision of royal civil servants.15-17
To ensure that measurements were reliable, Vicq d’Azyr asked physicians to purchase mercury instruments from Paris or London and to calibrate them using the method of Charles Messier (1730-1817) in
the case of barometers and the method of René de Réaumur (1683-1757) in the case of thermometers. In
practice, many corresponding physicians did not have the instruments
for recording temperature, hygrometry, pluviometry, or pressure three
times a day, once a month, for 15 years (!). However, the archives of the
Royal Society of Medicine (119 boxes and 12 registers stored in the
Academy of Medicine) reflect on the part of the physicians, despite their
little training in data recording and management, a fierce determination to achieve accuracy, as if they were shot through by absolute confidence in the idea of progress. Of the near 200 physicians who took part
in the survey, around 50 performed their measurements for nearly
10 years. From 1776 to 1792, the Society collected almost 8300 of the
35 000 anticipated report cards. The comments and observations that
physicians included with their data contained much information on
medical practice and the state of French society in the immediate preRevolutionary era.15-17
Although the great disparity in responses made it impossible to draw
up the comprehensive epidemiological map of France that the survey
sponsors had intended, the partial information collected threw accurate
light on the routes of contamination of certain infections. The reports
received by the Royal Society of Medicine inspired Vicq d’Azyr in 1790
when he drafted his New plan for the constitution of medicine in France.
Antoine de Fourcroy (1755-1809), physician, chemist, and Convention
deputy, was to draw on this text when instigating the decree of 4 Frimaire Year III (December 4, 1794) that reopened the faculties of medicine
in Paris, Montpellier, and Strasbourg as Schools of Health.
By demanding meticulous attention to measurement and emphasizing the importance of the results, the Royal Society of Medicine accelerated the switch from a medicine of philosophical and nosological
speculation to one of enlightened scientific reasoning.15-17
Medicine held little interest for Louis XVI as a “science”— unsurprisingly, in that the healing art, in the late 18th century, was still deeply
enmeshed in abstruse philosophical considerations. As a profoundly
religious person, the King was moved by the fate of the ill and infirm.
The measures he took were dictated mainly by pragmatism, charity, and
religiously inspired commiseration. In 1778, Louis gifted 6000 livres to
Charles-Michel de l’Épée (Abbé de l’Épée) (1712-1789), the inventor of a more comprehensive signing language, to help found an institution to care for the young deaf-and-dumb. The same year, he made an identical grant to Valentin Hauÿ (1745-1822) to found a school for the blind; years later, on December 26, 1786,
26 blind youngsters who had learned to read and write were presented to the King at Versailles.
In 1780, the King commanded military hospitals to treat enemy wounded as “the King’s own subjects.”
The same year, he ordered “light and well-ventilated infirmaries” to be constructed at his expense in the
kingdom’s prisons.
In 1781, after an incognito visit to the Hôtel-Dieu Hospital in Paris, Louis was upset to see patients
piled three or four to a bed in unhealthy rooms. He decided to set up a system of individual beds and to
separate patients by type of infection. The same year, he approved the creation in Paris of a hospital for
children with infectious disease, the Sick Children’s Hospital. It was in this public health spirit, in 1785,
after the Hôtel-Dieu Hospital was destroyed by fire, that Louis XVI entrusted the surgeon Jacques René
Tenon (1724-1816) and seven other members of the Academy of Sciences with drafting a report on the reconstruction of the Hôtel-Dieu. This report inspired Tenon’s celebrated 1788 Memoirs on the hospitals
of Paris itemizing the concrete measures to be applied for refitting Paris hospitals according to the new
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Abbé (Father) Charles-Michel de l’Épée
(1712-1789), trained as a Catholic priest
but denied ordination because he refused
to condemn Jansenism, dedicated himself
to the education of the deaf and founded
the world’s first school for the deaf, which
exists to this day, in Paris. © Bibliothèque
Inter-Universitaire de Médecine (BIUM).
OF
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Hand signs for the deaf “signes méthodiques,” created by Abbé de l’Épée,
now known as “Old French Sign Language,” the precursor of all the
sign languages used throughout the world today, such as the “American
Sign Language (ASL). © Roger-Viollet.
principles of hygiene: ventilated wards with high ceilings and a fixed number of patients, reorganization
of nursing duties, isolation of contagious patients, and special arrangements for obstetric deliveries, catering, staff and patient clothing, baths, showers, and disinfection facilities.4,17,18
Epilogue
Militant hagiographies penned by die-hard monarchists aside, the royal couple suffers from an appalling
image in French historiography. Studies offering an objective and subtle analysis of the personalities of the
two monarchs are relatively rare. Louis XVI is often described as a somewhat weak and insignificant king
whose sole hobbies were hunting and the dismantling and repairing of locks. When hunting, he preferred
the company of his masters of hounds and stablemen to that of his guests. His master locksmith reported
that he had to help the King hide from Court and Queen “to file and forge with me. (…) The King was good,
shy, tolerant, and inquisitive.” Louis has also been depicted as improvident, indecisive, overburdened by
responsibilities, and under the dual influence of courtiers’ intrigues and Marie-Antoinette.4
During his lifetime, this image was bandied about (in amplified form) by the Court, the Paris circles
close to the Viennese throne, and both his brothers, the Counts of Provence (the future Louis XVIII) and
Artois (the future Charles X). The economic and institutional reforms proposed by his ministers (Turgot,
Necker) threatened the privileges to which his 10 000 courtiers were so attached.2,3
Louis XVI was unrestrainedly caricatured. Shortsightedness compounded his tendency to absentmindedness. He was sometimes unable to put a name to those he spoke to. His great height, chubbiness, and
“noble features tinged by melancholy” increased the distance that he created with those who came into
contact with him. The King’s personality was complex. He often appeared retiring. Liking jokes, he gave
Bernard Poyet’s plans for the reconstruction of the Hôtel-Dieu
hospital, in Paris (1785). © Archives de l’AP-HP.
Frontispiece
from the
Mémoire sur
les Hôpitaux
de Paris, by
Jacques René
Tenon (1788).
© Coll. InterActivités.
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an impression of familiarity, but in fact detested it. In 1774, Lord Stormont, the English ambassador to
Paris, wrote: “As he is very reserved and indeed proud to be so, one guesses rather than knows what he is
thinking.” His style was curt, terse, and plain. Often he did not answer those with whom he was speaking.
“I prefer my silences to be interpreted rather than my words,” he told Malesherbes, who defended him at
his trial in 1792. His memory was formidable, allowing him to correct and annotate memoranda and dispatches from his ministers and advisers with considerable ease and accuracy.1,3,4 However, his faults are hard
to conceal: the King was shy and awkward in public and did not look his interlocutors in the eye. He lacked
self-confidence and resolve. “There were two men in him, the man who knew and the man who wanted,”
wrote his biographer, Jean-Louis Soulavie (1751-1813), priest, geologist, and historian. “The qualities of
the first were most varied and extensive. But in the great affairs of state, the King who wanted and commanded was almost never to be found.” Louis’ excess of modesty and discretion probably aided the decline
in the prestige and cult of the monarchy.4,19 The blurred image of Louis XVI is not helped by the meager
writings he left behind him: a diary began as Dauphin in January 1766, and a diary continued as King,
which ended on July 31, 1792 with the word “Nothing.” There is little if anything else. Both diaries were
simply hunting notebooks. They were not diaries in the proper sense, nor chronicles of a reign. Louis also
kept a book of the annuities and gifts he bestowed, and another for private expenditure. In the following
centuries, the void was filled by a multitude of counterfeit manuscripts, circulated in attempts either to
rehabilitate the King or to flesh out the portrait of a weak and conspiratorial monarch.1,3,4 REFERENCES
1. Lever E. Louis XVI. Paris, France: Éditions Fayard; 1985.
2. Taillemite É. Louis XVI ou le Navigateur Immobile. Paris,
France: Payot; 2002.
3. Félix J. Louis XVI et Marie-Antoinette: un Couple en Politique.
Paris, France: Payot & Rivages; 2006.
4. Petitfils JC. Louis XVI. Paris, France: Perrin; 2005.
5. de Viguerie J. Louis XVI, le Roi Bienfaisant. Paris, France: Éditions du Rocher; 2003.
6. Corcos M. Comment la grande encyclopédie mène à la révolution de 1789. Médecine Pratique. 1989;87:7.
7. Moureau F. Le Roman Vrai de l’Encyclopédie. Paris, France:
Gallimard; 1990.
8. Capefigue M. Louis XVI. Paris, France: Belin-Leprieur; 1844.
9. Muratori-Philip A. Parmentier, 2nd ed. Paris, France: Plon; 2006.
10. Reynaud MH. Les Frères Montgolfier et leurs Étonnantes Machines. Paris, France: De Plein Vent; 1982.
11. Payen J. Capital et Machine à Vapeur au 18e Siècle. Paris,
France: Éditions de l’École des Hautes Études en Sciences Sociales; 1969.
12. Mologni J. Claude Dorothée de Jouffroy d’Abbans, le Génial
Marquis. Besançon, France: Éditions du Sekoya; 2007.
LES
SCIENCES SOUS
LOUIS XVI. UN
13. Minguet H. Le Voyage au Tour du Monde de Lapérouse. Paris,
France: Maspero; 1989.
14. Gaziello C. L’Expédition Lapérouse, Réplique Française aux
Voyages de Cook. Paris, France: Comité des Travaux Historiques
et Scientifiques; 1988.
15. Meyer P, Triadou P. Leçons d’Histoire de la Pensée Médicale.
Paris, France: Éditions Odile Jacob; 1996.
16. Desaive JP, Goubert JP, Le Roy Ladurie E, Meyer J, Muller O,
Peter JP. Médecins, Climat et Epidémies à la Fin du XVIII e Siècle.
Paris, France: Éditions de l’École Pratique des Hautes Études –
Mouton; 1972.
17. Goubert JP, Rey R, Bertrand J, Laclau A. Atlas de la Révolution Française – Médecine et Santé, vol 7. Paris, France: Éditions
de l’École Pratique des Hautes Études en Sciences Sociales; 1993.
18. Tenon J. Mémoires sur les Hôpitaux de Paris (facsimile of the
1788 edition). Paris, France: Doin-Assistance Publique-Hôpitaux
de Paris; 1998 [English translation: Tenon J. Memoirs on Paris
Hospitals, Weiner DB, ed. Canton, Ma : Science History Publications; 1996].
19. Soulavie JL. Mémoires Historiques et Politiques du Règne de
Louis XVI. Paris, France: Treuttel & Würtz; 1801.
ROI ENTRE LUMIÈRES ET RÉVOLUTION
L
e problème politique majeur du règne de Louis XVI réside dans ce travail de sape incessant de la
noblesse et du haut clergé contre l’abolition de certains de leurs privilèges. La question économique occupe une place essentielle dans ce règne marquée par la très coûteuse guerre d’Indépendance américaine (1776-1783). Le roi trouve toujours dressé devant lui les forces les plus hostiles au changement; il ne sait pas s’appuyer sur la frange éclairée de la noblesse. Secret, timide
et modeste, Louis XVI veut mais n’ordonne pas. Le roi se plie difficilement au cérémonial de la
cour privant indirectement la noblesse de son rôle social de représentation. Louis XVI présente le principal défaut de ne pas savoir commander les hommes; sensible à la modernité des Lumières, il est constamment écartelé entre ses idées réformistes et son attachement profond à la tradition. Le roi demeure respectueux des lois fondamentales du royaume et refuse de les transgresser; il nomme pourtant des ministres
réformateurs mais les congédie prématurément. Par goût et par nécessité, Louis XVI, dernier monarque
française de droit divin au pouvoir absolu, se passionne pour les expériences, les recherches et les découvertes scientifiques. Il ne manque aucune occasion d’apporter son appui moral et financier à de nouveaux
projets susceptibles de faire progresser les connaissances humaines et d’améliorer le sort de la multitude.
C’est ainsi qu’il favorise le développement de l’Académie des sciences, la création de la Société Royale
de Médecine, les expérimentations de l’aérostat et de la machine à vapeur, l’expédition maritime de La
Pérouse, l’application des règles d’hygiène aux hôpitaux, la fondation d’institutions pour aveugles et sourdsmuets. Personnages incompris et souvent méprisés de l’histoire de France, Louis XVI et Marie-Antoinette
bénéficient aujourd’hui d’une réécriture de leurs biographies dans le contexte politique qui précède la
Révolution française.
A
T
O U C H
O F
F
R A N C E
Isabelle SPAAK, Journalist
37 rue des Plantes
745014 Paris, FRANCE
(e-mail: isabelle.spaak@wanadoo.fr)
Marie-Antoinette
Queen of France, Queen of Style
by I. Spaak, France
T
Portrait of
Marie-Antoinette de
Habsbourg-Lorraine
(1755-1793). French
school, 18th century.
Musée Antoine Lécuyer,
Saint-Quentin, France.
© Bridgeman Art Library.
o reach the Petit Trianon, you need to leave the Château of
Versailles behind you, leave the straight lines of the formal gardens, and bid farewell to the geometrical precision of the landscapes
and vistas designed by Le Nôtre. Walk along the edge of the Ornamental Pools on the Terrace, go around the Latona Basin, make your
way between the Chestnut Grove and the Dauphin’s Grove, carry on
between the Colonnade Grove and the Dome Grove, head toward the Grand
Canal, and turn off to the right. The Pavilion is straight ahead of you, at the
end of the path. A masterpiece of neoclassical architecture, this modestly proportioned palace was built between 1763 and 1768 by Ange-Jacques Gabriel
(1698-1782) at the request of Louis XV, who wanted to give it to Madame de
Pompadour, his favorite. But the marquise died too soon and never had the
chance to enjoy her beautiful gift. The Comtesse du Barry, another of the
King’s mistresses, enjoyed it in her stead. With this stunning, square building, embellished with Corinthian pillars on the court side and columns overlooking the formal garden, the King’s architect, who also designed the buildings of the Place de la Concorde
and the Ecole Militaire, as well as the “Grand Project” in Versailles, surpassed himself. The harmony is perfect. The accommodation is delightful, the rooms on the bel étage perfectly proportioned and tastefully
decorated. The residence was designed, first and foremost, to be in harmony with nature. Surrounded by
a veritable botanical laboratory entrusted from 1759 to the great naturalist Bernard Jussieu, who was commissioned to classify the species so carefully nurtured and maintained by the domain’s gardeners, the
T
wenty-five minutes at a slow walking pace. That’s all it takes to pass from one world into another, to leave behind the glitz of the Château of Versailles and step into the simplicity of the Petit
Trianon. It’s a journey that Queen Marie-Antoinette made a thousand times to escape the Court formalities. Here, just minutes from the salons where the courtiers conducted their intrigues, the Austrian princess born in Vienna on November 2, 1755 who became Queen of France on May 10, 1774 at
the age of 19 years, created a small paradise for herself, away from the stringencies of etiquette that
she found intolerable. Surrounded by the charm of the French Pavilion designed by Gabriel, the landscaped
garden, and the contrived simplicity of the cottages in the Queen’s Hamlet where she played the shepherdess, Marie-Antoinette would say: “I am not the Queen, I am me.” The Petit Trianon was her personal
domain, a thoughtful gift from Louis XVI that released his capricious bride from the yoke of monarchy.
Today, despite the ravages of time and the Revolution, the place still reflects the Queen’s personality, tastes,
and aspirations. “To know someone, you must visit their home. The Trianon is Marie-Antoinette,” notes
historian Evelyne Lever. Here, in her carefully restored domain, in the exquisite apartments or the garden
she loved so much, visitors come close to this beautiful woman who was so passionate about the arts and
the pleasures of life, but whose life was changed from frivolity to martyrdom by history.
Marie-Antoinette, Queen of France, Queen of Style – Spaak
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FRANCE
building is a celebration of the plant world even in its internal decor. The paneling in the great dining room
is decorated with carvings of orange tree branches and bowls of fruit; and the drawing room walls are
decorated with the cipher of Louis XV intertwined with a crown of wild lilies. Garlands of flowers, birds, and
rustic motifs are a recurring theme in the fabrics, paneling, furniture, and wall paintings.
Marie-Antoinette received this magnificent gift from her husband on August 15, 1774, just a few months
after his accession to the throne. “You love flowers, and I have a whole bouquet of them for you!” he said
gallantly as he handed her a key encrusted with 531 diamonds. The Queen could not have imagined a
more beautiful tribute. She who so detested the Court now reigned over a kingdom modeled in her image,
where she could live as she wished.
The Château de Versailles,
with, in the foreground,
a fountain with an allegorical
figure of a French river
holding a staff. © Robert
Holmes/CORBIS.
Freedom to bloom
It was a relief. The young Queen struggled with the rigors of etiquette. In Versailles, closely watched by her
Mistress of the Household, Madame de Noailles, life weighed heavily on her. The Queen found it difficult
to accept “that she belonged not to herself but entirely to the kingdom of France,” explains Evelyne Lever.
“Placed above mere mortals in a society organized along extreme hierarchical lines, her slightest gesture
had the significance of a public act.” She could not get used to it.
From what she wore to what she ate, from the moment she got up in the morning to the moment she
went to bed at night, her every gesture was scrutinized, and regulated down to the finest detail by immutable rules. The old nobility vied for her favors, and encroached upon her privacy. Her daily life took
place under the eyes of a host of courtiers, ladies-in-waiting, valets, and footmen.
At the Trianon, she shut them out so that she could live as she wished and give free rein to her own desires and personality. She reclaimed her right to a private life and imposed her own style. Her kingdom
belonged to her. Nothing and no one could enter this small, enchanted domain without her permission.
Even her husband was allowed in by her invitation only. As a rule, he came simply to dine. He was never
to sleep in the bedroom with the red silk drapes that Marie-Antoinette had set aside for him on the second
floor. To the great horror of all the courtiers, rules were posted in the gardens. They were rules set “by order
of the Queen” and not “by order of the King.”
Marie-Antoinette withdrew, surrounding herself with a clique of young intriguers whom she liked to
think of as her friends. Nobody spied on her, nobody judged her. So at least she thought. But tongues were
wagging. Her solitary retreats displeased the Court, and its members distanced themselves, injured by her
neglect. The Queen didn’t care. Ignoring all the gossip, she continued to assert her freedom as a woman.
She even went as far as endowing a boudoir with “movable mirrors,” where an elaborate system of sliding
panels enabled her to cover the windows. She restricted access to the sumptuous feasts she held in her
haven of peace, even though the Court was, by tradition, public. She shut herself away.
Far from all the conventions, but also far from her subjects. “Trianon is a world in miniature,” wrote
Austrian novelist Stefan Zweig in his classic biography of his compatriot, published in 1933. “From her
windows—symbolically and literally—she could not see the town, or Paris, or the countryside, or anything
that had any connection with real life. Her little patch of land could be crossed in a few moments, yet this
A TOUCH
OF
FRANCE
The Petit Trianon,
built for Louis XV
between 1751 and
1768, was given to
Marie-Antoinette by
Louis XVI and became
her favorite retreat.
© Adam Woolfit/
CORBIS.
tiny space was of enormous significance and meant more to Marie-Antoinette than all of France and its
twenty million inhabitants,” continued Zweig. Ah, the garden! Although, initially, the Queen did not alter
the decor of the French Pavilion designed by Gabriel for Madame du Barry, the same did not apply to
the parkland surrounding her new residence. She did not like the precision of Le Nôtre’s landscapes and
vistas— his straight pathways and alleys, his contrived use of perspective, his trimmed boxwood, and artificial groves. Marie-Antoinette dreamed of intricate, fairytale landscapes. The squares of rare plants so
scrupulously collected since 1759 by the botanist, Charles Jussieu, by the order of Louis XV, were too severe. They had to go. The young woman was a romantic. She fell in love with the landscaped gardens of the
English, and adored a mass of rambling, untamed vegetation. She ordered her architect, Mique, to redesign
the gardens, drawing inspiration from the works of the Comte de Caraman (whose designs included the
Parc Monceau in Paris, which still exists today), and from the ancient ruins depicted in the paintings by
Hubert Robert, who was enamored of Italy.
“Hurried on by the Queen’s impatience, hundreds of workers began to implement the architects’ and
designers’ plans, undertaking works that would, like magic, make the real world disappear, to be replaced
by the most natural and picturesque landscape imaginable,” wrote Stefan Zweig.
The place was transformed. A gentle stream meandered through fields where the air was now scented
with the rare fragrances of plants from North America, such as the tulip tree from Virginia, cypress from
Louisiana, massive oaks. Paths wound their way between overflowing flowerbeds. Broad clearings offered
views of the follies built here and there according to the Queen’s fancy, ravishing buildings made for conversation and amusement. There was, for example, The Temple of Love, built on a little island surrounded
by reeds; a charming octagonal belvedere overlooking an ornamental lake; and a Chinese tilting ring, a
game in which players try to mount multicolored wooden horses made to look like peacocks or dragons.
The Queen’s playground: one of the cottages, built in 1783, in the “model
village” where Marie-Antoinette would dress up as a peasant. The village
totaled 12 cottages and a watermill, and was situated near the Petit Trianon.
© Guy Thouvenin/ Robert Harding World Imagery/CORBIS.
Harp belonging to Marie-Antoinette.
Musée de la Ville de Paris, Musée
Carnavalet, Paris. © Bridgeman
Art Library.
A T
OUCH
OF
FRANCE
PORTRAITS OF A QUEEN
Marie-Antoinette knew nothing about painting. She judged artists’ talent simply by their ability to render her
likeness or at least a reflection of her own notion of her beauty. Several well-known artists tried their hand. Liotard,
Jean-Baptiste Charpentier, François-Hubert Drouais, and Joseph Krantzinger, whose depiction of the young Queen
as an amazon so shocked Empress Maria Teresa. “I’m fated to find no painter able to capture my likeness,” the young
Queen complained to her mother.
In 1778, Elisabeth Vigée-Lebrun, a fashionable young portrait artist, tried her luck. The initial meeting went well.
“At the first sitting, I found the Queen’s imposing air prodigiously intimidating to begin with,” wrote the artist.
“But Her Majesty spoke to me so kindly that her gentle good grace soon dispelled this feeling.” She forgot etiquette
to focus on the gracious features and perfect figure of her model. “The most striking thing about her face was the
radiance of her complexion,” she said later. The two young women were the same age. They became friends. During the long sittings, Elisabeth Vigée-Lebrun was to become the Queen’s confidante. They shared the same love of
singing, and of freedom. It is to Madame Vigée-Lebrun that we owe a painting of the Queen wearing a simple muslin
dress and a straw hat decorated with feathers and bound by a ribbon. This was the kind of costume that the Queen
loved to wear in her gardens at the Trianon. Exhibited in 1783, the canvas was found shocking in its simplicity.
It had to be quickly replaced by an identical picture of the Queen with a rose in her hand, but this time wearing a
dress of blue-grey satin trimmed with an abundance of lace.
Marie-Antoinette and her Children, by Elisabeth Louise Vigée-Le Brun, painted as an
attempt to portray the Queen as an affectionate mother and so ingratiate her with
public opinion. The empty cradle alludes to
the death of Sophie-Beatrix, who died while
the painting was being executed. From left
to right, daughter Madame Royale, and two
sons, Louis-Joseph and the future Louis XVII.
Oil on canvas, 275 215 cm, Château de
Versailles. © Bridgeman Art Library.
Portrait of
Marie-Antoinette
“À la Rose” by
Elisabeth Louise
Vigée-Le Brun, who
was to become the
confidante of the
Queen. Oil on canvas,
11387 cm,
Château de Versailles.
© Photo RMN.
And finally, the Grotto. Designed for romantic encounters and intimate conversations, the Grotto was
Marie-Antoinette’s secret refuge. You approach it via a little hidden pathway that enables you to see before
being seen. This is where she was, some 15 years later on October 5, 1789, when she received the news that
the people were marching on Versailles.
A refined world
Meanwhile, with all its charm and contrived delicacy, this little patch of land just a few kilometers square
became the Queen’s entire universe. Equipped even with its own theater, the “world in miniature” enchanted her. “Trianon is for Marie-Antoinette a secret, blessed land dedicated entirely to chivalry and pleasure,” noted Stefan Zweig ironically. For the whims of a frivolous girl barely 20 years old were not to everyone’s liking. The expenditure was profligate. To the extreme.
“I thought I had gone mad or was dreaming when I found that the large greenhouse (the most costly
and best designed in Europe) had been replaced by tall mountains, a large rock, waterfalls, and a stream.
Never have two acres of land been so totally changed, nor cost so much money,” lamented the Duc de Croÿ
A TOUCH
OF
FRANCE
The Salon des
Nobles at Versailles,
redecorated in 1785
by Marie-Antoinette.
© Bridgeman Art
Library.
when he discovered the extent of the works ordered by Marie-Antoinette. A style icon, obsessed by her
clothes and appearance, infatuated with hairstyles, jewelry, finery, and especially herself, the Queen next
launched herself with equal enthusiasm into redesigning the interior of her home. It was the ideal activity to stave off boredom and give meaning to her life, and she devoted herself to it wholeheartedly. Before
tackling the refurbishment of her cherished Trianon, she began with a makeover of her apartments in the
Château de Versailles. She fitted doors and windows with locks bearing her cipher, ordered new furniture,
MONSTER OR MARTYR? FROM THE REVOLUTION TO SOFIA COPPOLA
From feather-brained macaroon addict to a woman with a passion for pleasure and consumption,
from “the Austrian woman” to the victim of the liturgy of Versailles, the public image of Marie-Antoinette is many-faceted and has constantly changed over the centuries.
The author of several biographies of the Queen, including “Marie-Antoinette, the last Queen of
France” (Framan, Strauss & Giroux, 2000), which inspired film director Sofia Coppola, French historian Evelyne Lever takes stock of these shifts in public opinion.
Kirsten Dunst starring
as Marie-Antoinette,
in the film written and
directed by Sofia Coppola
and released by Columbia
Pictures in 2006. © Sony
Pictures Entertainment/
Columbia Pictures/
SIPA Press.
Marie-Antoinette has always fascinated people. But perceptions of her have changed. In the 19th century, she was
seen as a martyred queen whose cult was maintained by the nobility. They were not looking at her life; she was
merely being held up as a symbol of a murderous Republic. This version was cultivated in every aristocratic family. At the same time, in Republican circles following the Second Empire, Marie-Antoinette was seen as a bad queen
who sucked the people’s blood. The two currents of thought co-existed during the same period. They merely varied from one circle to another. In 1858, the Goncourt brothers published the first real biography of the Queen in
this expiatory spirit. It was not until the end of the First World War that
the historian and curator of Versailles, Pierre de Nolhac, did some proper
research. He drew on several works by scholars who had begun to classify
Marie-Antoinette’s letters. He succeeded in providing a coherent picture
of the Queen, demonstrating that she was not simply a saint. Certainly she
was a victim of the Republicans, but he stressed her political role, her sensitivity, and her growth into maturity.
It was the Austrian novelist Stefan Zweig, influenced by psychoanalysis,
who wrote the finest biography in the 1930s. In the Viennese archives, he
had discovered some letters that had been censored but cast a fascinating
light on her sexual life, and on the problems she had had with Louis XVI
before she succeeded in providing an heir to the throne of France. According to Zweig, Marie-Antoinette was a princess of unexceptional intelligence whose tragic destiny transformed her
into an exceptional person. In his view, the Queen played a genuine political role from 1787 onwards.
In the 1950s, the French public fell in love with this woman who arrived in a carriage and was taken to the
scaffold in a cart. Today, Sofia Coppola’s film has turned Marie-Antoinette into a fashion icon. The exaggerated
frivolity and whirlwind of pleasure fascinates young people, who now appear to confuse the Queen’s fate with
that of Lady Diana. Insufficiently loved in life, she is now never more adored than in death.
A T
OUCH
OF
FRANCE
and selected the finest silks. In 1781, she transformed her library and refurbished the former cabinet of
Queen Marie Leszcynska. Overlooking a dark and gloomy courtyard, the somber room became a charming
boudoir lit up by the careful use of mirrors and pale-colored paneling. Known as “La Meridienne,” it is a
model of elegance. Visitors can still admire the pretty little sofa tucked into its corner, the mirrors framed
with stems of roses and bronze foliage accompanied by the eagle of the Hapsburgs and the attributes of
Love. Of course, Marie-Antoinette often changed her mind. She hesitated, reconsidered, started again, spent
fortunes, gave orders, and counter-orders. But the result was delightful.
In 1783, some 230 craftsmen were employed in transforming the inner
Grand Cabinet (the Gold Room) at Versailles. In the Chamber of Ceremonies, Marie-Antoinette had the walls and chairs covered with sumptuous white satin brocaded with arabesques and embroidered with wild
flowers. It was not to last. Four years later, she tired of it. The whole room
was empanelled in white and gold.
Entranced by novelty, she bought lots of expensive trinkets. Chinese
lacquers and porcelains, boxes, fans, seashells with gilt bronze mounts,
jaspers, crystals, and fossilized wood littered every available surface. And
every item of furniture bore a famous name. Jean-Henri Riesener was
her cabinetmaker, supplying magnificent roll-top writing desks, tables
of every shape and kind, and all sorts of corner pieces embellished with
bronzes by Gouthière. Sofas, armchairs, and love seats bore the signatures of Georges Jacob, Foliot, and Boulard. The silks came from the
workshops of Jean Charton. Faithful to her suppliers, Marie-Antoinette
Copy of the famous diamond necklace that was at the
was midwife to a new style. Combining the elegant and the rococo, it
center of an intrigue to discredit Marie-Antoinette,
was inspired by the classical world but adapted to offer the comfort and
with rumors of lovers’ trysts and embezzlement,
and which led to the banishment of a Cardinal and
feminine grace of which she prided herself on being the finest examlingering suspicion against the Queen. © Photo
ple. Obsessed with her image, she reigned over the decorative arts with
RMN/ All rights reserved.
the same blend of sophistication and simplicity that she liked to express
in her clothes. She imposed her tastes. “She doesn’t really deserve the credit,” Evelyne Lever reminded us.
“As Queen, she had only to choose among the items presented to her by the most talented craftsmen of the
period. She never actually influenced them.” That may well be so. But she was their patron. She introduced
new blood, swept away the cobwebs, did away with the heaviness of the rocaille style. She let in a breath of
fresh, more lighthearted air. She loved simple lines, wall hangings, and foliage. She had bouquets embroidered on curtains, chairs, and bedspreads. Lightness, sophistication, and delicacy became her trademark.
In 1786 at Versailles, she had the Salon des Jeux stripped of its marble decor. She wanted to give the
rooms “a light, clean feeling,” and banish the “mean and heavy feel of the bronze and lead” ornaments
commissioned by Louis XV. She didn’t like Lebrun’s ceiling. So she had it painted over in sky blue.
At the Petit Trianon, she made few changes to the original decor. She contented herself with affirming
a style, introducing daylight and delicacy. She had a preference for rustic designs, which she used and
abused, both for her numerous sets of porcelain tableware with their background of gold, and for her famous “wheat-ear” furniture, whose polychromatic shapes are laden with lily of the valley, jasmine, and fir
cones, while the chairs were covered with pale silk embroidered with bouquets and garlands of flowers.
MARIE-ANTOINETTE
Exhibition at the Galeries Nationales du Grand Palais,
March 15 through June 16, 2008
Bringing together more than 300 works from all over Europe,
including an extraordinary collection of paintings (Vigée Le
Brun), sculptures (Lemoyne, Boizot, and Lecomte), and decorative arts (Carlin, Riesener, Weisweiler), the exhibition seeks
to convey the various aspects of Marie-Antoinette’s personality, in terms of her education and upbringing and as regards the
arts and politics. It invites the public to walk in this exceptional woman’s footsteps, from her birth in 1755 at the Austrian
Court to her last days at the Conciergerie, and her death on October 16, 1793. Not since 1955 will she have received such dazzling homage.
MARIE-ANTOINETTE’S ESTATE
AT VERSAILLES
The creation of “Marie-Antoinette’s Estate”
is part of the “Grand Versailles.” It includes
access to the Petit Trianon, Chapel, French
Pavilion, Queen’s Theatre, Belvedere, Temple
of Love, Grotto, Landscaped Garden, Refreshments Dairy, Queen’s Hamlet, and Farm.
The Estate and Petit Trianon are open daily,
except on some French public holidays and
during official ceremonies. April 3 through
October 31: noon to 7.30 PM.
Information: 01.30.83.78.00
www.chateauversailles.fr
A TOUCH
OF
FRANCE
There was nothing pompous or particularly sumptuous in her choices, rather “a perfect harmony, from
bed to powder case, from harpsichord to ivory fan, from chaise longue to miniature, using only the finest
materials in the most discreet forms, fragile in appearance yet long-lasting.” Incorrectly called Louis XVI,
this style owes much to the Queen, since it is wholly associated with her light and elegant silhouette.
Too frivolous a game
In her Petit Trianon domain, known as the “little Schœnbrunn” in acknowledgement of her Austrian origins, she wore charming muslin dresses and straw hats, favoring modesty. “Compared with the luxury of
Versailles, the Petit Trianon seemed simplicity itself,” comments historian Jean-Christian Petitfils. “A bedchamber full of muslin and silk embroideries, a boudoir, several cabinets and garde-robes, an elegant library, a bathroom with a white marble bath. And throughout, a symphony of soft pastel tones of green,
lilac, blue, white, and gold.”
Her cardboard cutout haven became an obsession. Very soon, Gabriel’s French Pavilion, the garden, and
its novelties were no longer enough for her. To “make the fantasy even more real,” joked Stefan Zweig,
she commissioned her architect, Mique, to build eleven cottages and a tower to satisfy her need for rusticity. Thatched roofs, fake lizards on the walls, pigs, sheep, and peasants were all included in this puppet
show in which the Queen entertained herself by playing the farmer. This final caprice cost her her throne.
Wrapped up in her escapist dreams, she failed to face reality. The more she amused herself, the worse the
political situation became. In 1785, the Low Countries revolted, putting the Franco-Austrian alliance
severely to the test. Poverty knocked on the doors of her domain. She was deaf and blind to it all. After her
difficulties in giving the realm an heir, her unbridled behavior and romantic escapades, whether real or
imaginary, offended both Court and people. That same year, the “Diamond Necklace Affair,” a ludicrous
conspiracy against her, marked the beginning of her fall from grace. Her private paradise could do nothing
to save her. Lies proliferated. The people’s hatred multiplied tenfold. The nobility distanced itself. Despite
the courage she was to show on October 6, 1789 before the market women who came to seek her and her
family at the Château de Versailles, despite her years of imprisonment, her separation from her children,
her isolation, and the dignity of her last moments
before the scaffold, nothing could make people forget the heedlessness of her youth. She was to pay
with her life, the symbol of her frivolity. Queen Marie-Antoinette’s poignant last note hastily
written shortly before her execution. “This 16th of October at 41/2 in the morning. My God! Have mercy upon
me! My eyes have no tears left to cry over you, over my
poor children! Farewell, farewell! Marie-Antoinette.”
Châlons-sur-Marne Library. © Roger-Viollet.
MARIE-ANTOINETTE, REINE
DE
FRANCE, REINE
DU
STYLE
V
ingt-cinq minutes en marchant à petits pas. Il n’en faut pas plus pour passer d’un monde
à un autre, pour quitter les dorures du château de Versailles et rallier la simplicité du petit
Trianon. Un trajet que la Reine Marie-Antoinette a fait maintes fois pour échapper à la rigidité
de la Cour. Ici, à quelques minutes des salons où se disputaient les courtisans, la petite princesse
autrichienne née à Vienne le 2 novembre 1755 et devenue Reine de France, le 10 mai 1774 à 19 ans,
s’était aménagé un petit paradis intime loin des lourdeurs de l’étiquette qu’elle ne supportait pas.
Entre le charme du pavillon Gabriel, les jardins à l’anglaise et la simplicité factice des chaumières du
Hameau où elle se plaisait à jouer à la bergère, Marie-Antoinette aimait répéter « Je ne suis pas la reine,
je suis moi ». Le petit Trianon, c’est son domaine. Louis XVI le lui avait offert en juin 1774, au début de
son règne. L’attention était délicate. Le cadre était idéal pour permettre à sa jeune épouse capricieuse
de se libérer du joug sacré de la monarchie. Aujourd’hui, malgré les assauts du temps et ceux de la révolution, ce domaine reste emprunt de la personnalité de la reine. Il reflète ses goûts, témoigne de ses aspirations. « Pour connaître quelqu’un, il faut visiter sa maison. Trianon, c’est la reine », rappelle l’historienne
Evelyne Lever, spécialiste de Marie-Antoinette. Ici, dans son domaine réhabilité minutieusement, dans
l’atmosphère exquise de ses appartements ou dans ce jardin qu’elle chérissait, le visiteur fait véritablement connaissance avec cette jolie femme férue d’art et de plaisirs dont l’histoire bascula de la frivolité
au martyr.
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