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VENOUS MORPHOLOGY PREDICTS CLASS OF CHRONIC VENOUS INSUFFICIENCY
Jones GT, Solomon C, Moaveni A, van Rij AM, Thomson IA, Galvin I
Eur J Vasc Endovasc Surg 1999; 18:349-54

COMMENTARY BY:
Kenneth Myers, MS, FACS, FRACS
Vascular Surgeon
Monash Medical Centre & Epworth Hospital
Melbourne, Australia

This article addresses the perennial question of why some patients with varicose veins go on to develop complications while others do not. The authors describe a model of the arterialized vein showing degeneration of elastin and increased endothelial cell density and raise the hypothesis that similar changes may be responsible.

Samples of otherwise disturbed veins were obtained from below the knee in patients without varicose veins (usually during removal for arterial bypass grafting) and from those with varicose veins treated by surgical excision. Limbs without varicose veins were described as CEAP clinical class 0. Limbs with varicose veins were separated into those without complications (class 2) and those with complications (classes 4, 5, and 6). These limbs were also assessed by air plethysmography. Apparently, limbs with deep venous reflux shown by duplex scanning were excluded.

The specimens were subjected to macroscopic examination of the valves and histologic examination by various studies of elastic tissue and endothelial cells. These included percentage of elastic tissue along the intimal medial border, average elastic tissue fragment length, and endothelial cell nuclei density.

Veins from limbs without varicose veins showed intact valve cusps, high measures of elastic tissue, and low endothelial cell densities. Veins from limbs with varicose veins usually showed absent valve cusps. The percentage of elastic tissue along the intimal medial border was not different for class 0 when compared to class 2 but was significantly lower for classes 4, 5, and 6 when compared to class 0 or class 2. The average elastic tissue fragment length was significantly shorter for classes 4, 5, and 6 when compared to classes 0 or 2. Endothelial cell nuclei density was significantly higher for classes 2, 4, 5, and 6 when compared to class 0.

Only the venous filling time from air plethysmography showed a relationship to histological changes and then only to the average elastic tissue fragment length. Changes in endothelial measurements were related to age. Thus, veins from limbs with uncomplicated varicose veins had similar elastic measurements but higher endothelial cell measurements when compared to veins from limbs without varicose veins. In addition, veins from limbs with skin changes from varicose veins had similar endothelial cell measurements but lower elastic tissue measurements compared to veins from limbs with uncomplicated varicose veins.

COMMENTARY

What do these findings mean? Uncomplicated varicose veins develop increased endothelial cell density, and complicated varicose veins then lose elastin. The authors properly ask whether these differences in vein morphology may "help explain why eventual clinical outcomes can be so different" or if they "simply reflect differences in the present grade of reflux." Is it cause or effect? The title of this article is clever because it suggests that the authors favor the former without actually committing themselves.

My personal iconoclastic suspicion is that the changes are simply one of many unexplained observations in the progression from normal to uncomplicated to complicated varicose veins. I suspect there is an as-yet-unidentified systemic process that results in progressive physiologic and pathologic weakening with eventual destruction of both large and small veins which then precipitates change in the surrounding skin and subcutaneous tissues.

This observation is far from new. There are many studies that have explored the changes from the tissue level up to the small veins. This article adds a new dimension from the changes demonstrated in the large veins. Further studies of other cellular activities within the veins may help to unravel the process.

Undoubtedly, histological findings will one day be related to the site and extent of reflux shown by duplex scanning. Although there is no consensus to date, a unifying explanation will eventually emerge. ivdfmye3

PROXIMAL LONG SAPHENOUS VEIN VALVES IN PRIMARY VENOUS INSUFFICIENCY
Corcos L, DeAnna D, Dini M, Macchi C, Ferrari PA, Dini S
J des Maladies Vasculaires (Paris) 2000; 25(1):27-36

ABSTRACT AND COMMENTARY BY:
Prof. dr. hab. med. Zygmunt Mackiewicz
Professor of Surgery
Head, Department of General & Vascular Surgery
Bydgoszcz, Poland

Today, primary venous insufficiency may be explained by one of two theories: Primary vein wall dilatation and/or primary valve degeneration. In the opinion of these authors, this traditional explanation is unsatisfactory. The aim of this study was to detect relationships between venous wall alterations and valve cusps and to define cusp atrophy and its clinical significance. The authors wanted to clarify the pathophysiology of primary venous insufficiency in order to perform a more detailed diagnostic assessment of venous valves before reconstructive surgery.

Components of 65 proximal valves of the long saphenous vein were subjected to histopathologic examination. The valvular sinus thickness was evaluated proximal to the cusp insertion in longitudinal section and and in cross section in approximately the midportion of the valve pocket. Valve agger thickness was measured close to the annulus wall and also at the proximal leaflet in its middle third. Valves were taken from patients having saphenectomy for varicose veins. Measurements and morphological evaluations were performed by optimal microscopy. The authors present the results in two tables, with and without significant correlations.

The valvular sinus, agger, and proximal portion of the cusp exhibited similar variations in thickness. Thickening of the proximal portion of cusp was related to increase in smooth muscle cells in the agger as well as elastic layer dissociation. Thickening of the distal portion of cusp depended on collagen content. When a commissural aneurysm was present, the vein wall was usually thinner than in the valvular sinus. Alterations in the intima, in the elastic membrane, and in the media of the valvular annulus were found in 98%.

COMMENTARY

This kind of investigtion is interesting and may give us insight into the pathophysiology of primary venous insufficiency. The conclusion that valvular atrophy seems to come from a prevalence of structural thinning as is seen in the distal part of the leaflet, the valve sinus, and the commissural aneurysm may be important. Atrophy of these structures is due to a reduction of collagen component in the leaflet as well as smooth muscle in the media and valve annulus. Primary venous insufficiency may be explained by interaction between structural degeneration and mechanical injury due to reflux.

The practical aspect of this investigation could be rational selection of surgical treatment such as external valvuloplasty. It is possible that atrophy of the valves could be an indication for an external cuff operation. Alterations of the cusps could be an indication for internal valvuloplasty. These suggestions should be proved by further investigations. In my opinion, valves in the deep vein system and in the superficial system are different and cannot be compared. This problem needs a new investigation.

I agree with the authors that analysis of alterations of the valves in the superficial and deep vein sytems should be meticulous and done by duplex scan and angioscopy. The challenge for the future is to find the correlation between microscopic and clinical examinations. ivdfmac4

VENOUS HEMODYNAMIC CHANGES AFTER EXTERNAL BANDING VALVULOPLASTY WITH VARICOSECTOMY IN THE TREATMENT OF PRIMARY VARICOSE VEINS
Kim DI, Lee BB, Bergan JJ
J Cardiovasc Surg 1999; 40:567-70

COMMENTARY BY:
Prof. Lars Norgren
Lund, Sweden

The authors studied 79 limbs in an attempt to evaluate venous hemodynamics after greater saphenous vein banding. All patients had a primary saphenofemoral incompetence without further complications (those with previous deep venous thrombosis or other deep vein incompetence were excluded). Duplex ultrasonography was used to detect reflux and, in this study, a reverse flow 0.75 seconds was considered a sign of incompetence. To study venous hemodynamics, air plethysmography (APG) was performed in 51/79 limbs with calculation of venous volume, venous filling index, ejection fraction, and residual volume fraction. The surgical procedure consisted of greater saphenous vein dissection at the location of the terminal and/or subterminal valve, mapped out with duplex scanning. As part of the procedure, all tributaries of the greater saphenous vein were ligated within the area dissected. Polyester-tailored mesh was used to narrow the vein to the same extent as during spasm. Local extirpation of varicose veins was also performed.

At examination after surgery, 80% of the limbs had no reverse flow. Thrombus developed in two cases and reflux was still present in the remainder. Hemodynamic parameters, as evaluated by air plethysmography, improved in the 51 limbs (65%) examined. The authors conclude that valvular reflux may be corrected by this method. While this implies improved venous hemodynamics, this is a limited followup.

COMMENTARY

Ludbrook's thesis that varicose disease always starts with incompetence of the greater saphenous vein terminal valve may not be entirely correct but it is valid in a great number of cases. If one could stop the dilating process of the greater saphenous vein early, that might change or even stop (?) development of the disease. In such a case, it would be of great benefit to restore the valvular function. However, the problem is that very few cases will be found in this stage. Still, there is great enthusiasm to find an appropriate method to stop reflux in the greater saphenous vein either by external valvuloplasty (banding), heat shrinking of the vein, or high tie without removal of the vein. The question is to what extent these procedures are durable and, if one of the aims could be achieved, the vein could be useful as an arterial conduit in the future.

Banding valvuloplasty of the superficial femoral vein has been tried to treat recurrent varicose veins1 and superficial veins2 with the same rationale as in the present study. The latter study2 compared high ligation and external banding. With regard to hemodynamics, both operations were found equally effective.

The present study could be criticized for several reasons. First, only two-thirds of the patients were investigated for hemodynamic changes even though the title is "hemodynamic changes." Second, spasm in the vein was achieved by dissection of the vein, and banding was done to the very diameter that was achieved during spasm. This is a very imprecise measure. It would have been of great advantage if a duplex ultrasound scan had been done during the procedure to evaluate clearly when reflux stopped. Although the milking test was used, this is not as accurate as an ultrasound scan.

More importantly this study deals only with immediate followup (actually, the authors do not describe when postoperative measurement was made). It would have been of great benefit if a second examination at least one month postoperatively had been done to determine if hemodynamic improvement was still the same. Also, the local varicose veins which had been extirpated during surgery were undoubtedly a part of the hemodynamic improvement.

Finally, this paper describes use of the student's t-test with a p value of < 0.5 as the level of significance. The authors changed terminology which means not all readers will be familiar with the presentation of the statistical results.

It is hoped that the authors will reevaluate this group of patients to find out to what extent the hemodynamic improvement remains. ivdfnor2

REFERENCES

1. Guarnera G, Furgiucle S, Mascellari L, Bianchini G, Camilli S. External banding valvuloplasty of the superficial femoral vein in the treatment of recurrent varicose veins. Int Angiol 1998; 17:268-71.

2. Corcos L, De Ann D, Zamboni P, et al. Reparative surgery of valves in the treatment of superficial vein insufficiency: External banding valvuloplasty versus higher ligation or disconnection. A prospective multicentric trial. J des Malaides Vasculaires 1997; 22:128-36.

CLINICAL AND HEMODYNAMIC INVESTIGATION INTO THE ROLE OF PERFORATING VEINS IN PATIENTS WITH VENOUS ULCERATION AND DEEP VENOUS INCOMPETENCE
Scriven JM, Bianchi V, Hartshone T, Bell PRF, Naylor AR, London NJM
Eur J Vasc Endovasc Surg 1998; 16:148-52

DEVELOPMENT OF ENDOSCOPIC DISSECTION OF PERFORATING VEINS AND FASCIOTOMY FOR TREATMENT OF CHRONIC VENOUS INSUFFICIENCY
Hauer G, Bergan JJ, Werner AD, Mitterhusen M, Narsalla F
Ann Vasc Surg 1999; 13:357-64

DEVELOPMENT OF OPEN-SCOPE SUBFASCIAL PERFORATING VEIN SURGERY: LESSONS LEARNED FROM THE FIRST 67 CASES
Murray JD, Bergan JJ, Riffenburgh RH
Ann Vasc Surg 1999; 13:372-77

COMMENTARY BY:
Michel Perrin, MD
Vascular Surgery
Chassieu, France

Perforating veins are in. Three articles devoted to this topic are summarized briefly here for your general reference.

The first article reports clinical and hemodynamic results of subfascial endoscopic perforator surgery (SEPS) in patients with combined primary, deep (except one postthrombotic), and perforating vein incompetence. All patients were class 6 (active ulcer) and had undergone prior high ligation and stripping at least 12 months prior to entry into the study. Photoplethysmography (PPG) to quantify the venous refilling time (VRT) and duplex scan to locate the incompetent perforators were used in the investigations. Results were assessed postoperatively at one month using the same investigations. No ulcer had healed and surface area had increased (p = 0.07). No postoperative compression of the limb was utilized. The VRT was unchanged and all perforators identified preoperatively had been ligated.

The authors conclude that perforator vein surgery had no influence on ulcer healing or venous function for the treatment of venous ulceration in limbs with primary deep vein incompetence. However, this conclusion cannot be completely endorsed for several reasons. The number of patients was too small, different techniques were used to close the perforators (open surgery, SEPS, and coil embolization), the PPG is not reliable in assessing venous function, and the followup was too short. In addition, the aim of perforator ligation is not to heal the ulcer but rather to prevent ulcer recurrence.

Hauer was one of the first promoters of SEPS in the 1980s. The second article summarizes two of his patient groups.

In the first group, 96 patients (140 limbs) were operated on between 1983 and 1984, of which only 14.3% were CEAP class 5 or class 6. Perforators were interrupted using the single-port technique with the first-generation scopes manufactured by the Wolf company. Results were assessed retrospectively (followup 1 to 24 months) using seven criteria each on a four-point scale. Very good results were obtained in 48.6% and good results in 37.9% of limbs.

In the second group, 39 patients (56 limbs) were studied prospectively. Their clinical status was more severe (77.3% CEAP class 5 and 6). Perforators were interrupted by the single-port technique with second-generation instrumentation developed by the Wolf company. Complementary fasciotomy was done in 22 of 56 limbs. All patients except one (95.4%) had no recurrence of ulcer. Unfortunately, however, the followup duration is not clearly stated.

The most relevant and interesting aspect of Hauer's article is the improvement in instrumentation used. The authors believe that the new videoendoscopic technique is easier and more efficient.

I agree with the authors' conclusion that SEPS is unnecessary with simple varicose veins and should be reserved for limbs class 5 and 6. Unfortunately, the data does not allow comparison of results between patients who presented with isolated superficial venous insufficiency and those who presented with deep venous insufficiency associated with or without superficial venous insufficiency. This point is very important in selecting precisely the group of limbs which may benefit from SEPS.

The third article reports experience of a pioneer group from the United States. Using a single-port technique with an open scope, the authors operated on 62 patients (67 limbs) on a same-day basis (< 24 hours). A total of 85% were class 5 and 6 and 32% were postthrombotic. Associated procedures were done to correct all identifiable superficial reflux. Major complications (6%) and minor complications (28%) are reported in detail. The ulcer recurrence rate was 23% (75% occurring in the postthrombotic group).

From this well-documented report on 67 limbs, two points can be emphasized. First, the results are similar to those published using more sophisticated and expensive techniques. Second, it seems clear that the results are less favorable in postthrombotic syndrome as pointed out in the NA-SEPS study.1 In this subgroup, should reconstructive surgery for obstruction or deep venous reflux be done or should these be reserved for recurring ulcers? ivdfper2

REFERENCE

1. Gloviczki P, Bergan JJ, Rhodes JM, Canton LG, Harmsen S, Listup DM, and the North American Study Group. Mid-term results of endoscopic perforator vein interruption for chronic venous insufficiency: Lessons learned from the North American Subfascial Endoscopic Perforator Surgery (NA-SEPS) Registry. J Vasc Surg 1999; 29:489-502.

DERMAL TISSUE FIBROSIS IN PATIENTS WITH CHRONIC VENOUS INSUFFICIENCY IS ASSOCIATED WITH INCREASED TRANSFORMING GROWTH FACTOR-�1 GENE EXPRESSION AND PROTEIN PRODUCTION
Pappas PJ, You R, Rameshwar P et al.
J Vasc Surg 1999; 30:1129-45

COMMENTARY BY:
Nicos Labropoulos, M.D.
Loyola University Medical Center
Maywood, Illinois, USA

This very important article focuses on the role of transforming growth factor-� (TGF-�1) in the development of skin changes and ulceration due to chronic venous insufficiency (CVI).

A total of 40 patients were studied (17 with CVI CEAP class 4, 13 class 5, 10 class 6, and 12 controls). Patients in class 4 were younger (p < 0.05). All patients had CVI documented by duplex scanning and air plethysmography.

Seventy-eight (78) punch biopsies (0.6 mm) were taken from the lower calf areas with skin changes as well as from healthy skin of the ipsilateral lower thigh. Specimens were analyzed for TGF-�1 gene expression with quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The amount of active TGF-�1 was evaluated with a certified cell line 64 milk lung epithelial bioassay. Light and electron microscopy with immunohistochemistry and immunogold labeling were used to determine the location of TGF-�1.

The findings of the study support the fact that gene expression of TGF-�1 is increased in CVI CEAP classes 4, 5, and 6. TGF-�1 originates from activated leukocytes which target interstitial dermal fibrosis. When it binds to fibroblasts, collagen is produced. This causes tissue fibrosis and local skin dysfunction.

COMMENTARY

Skin changes and dermal fibrosis usually appear many years after the development of venous reflux. Fibrosis of the venous wall occurs before the onset of skin changes. Fibrosis of both the arterial and the venous wall is seen with aging and is associated with increased pressure. In organs such as kidney and lung, it is a result of inflammation. It may be that fibrosis has, as an initial stage, a protective role; i.e., to withstand high pressures. However, with time and with continuous tissue remodeling, excess tissue fibrosis leads to derangement of the vascular wall and perivascular space leading to local organ dysfunction.

In this study, increased levels of TGF-�1 were found in patients with skin damage. It was shown that such tissue fibrosis could be the result of fibroblast activation after binding with TGF-�1. Skin change is the first clinical sign in CVI and it is the downfall of an extremity in this disease process. Previous papers have shown that mast cells, fibroblasts, and macrophages are found in the perivascular space of extremities with CVI skin changes. This is a chronic inflammatory process that leads to ulceration in some patients.

Many studies have shown that there are no significant hemodynamic differences between limbs with CVI classes 4 to 6. It remains unknown what factors determine if a patient will develop skin changes and eventual ulceration but most likely the soft tissue cellular biology and the compensatory mechanisms that occur in each affected limb are involved.

Dr. Pappas and colleagues have significantly increased our understanding of the pathophysiology of chronic venous insufficiency with this current study and their previous studies. This is true both at a clinical and cellular level. We are in a new era where molecular biology is unraveling fundamental mechanisms in the development of CVI. Hopefully, this will open new avenues of treatment. ivdflab2

EFFECTIVENESS OF MESOGLYCAN TOPICAL TREATMENT OF LEG ULCERS IN SUBJECTS WITH CHRONIC VENOUS INSUFFICIENCY
La Marca G, Pumilla G, Martino A
Minerva Cardioangiol 1999; 47:315-19

COMMENTARY BY:
Prof. Massimo D'Addato
Bologna, Italy

This study focuses on topical treatment of venous leg ulcers, an issue widely discussed in the literature and still unresolved.

The authors studied a series of 40 patients with venous ulcers of the lower limbs measuring 1 to 78 cm2. They were categorized into two randomized groups for local medical treatment. All were treated with elastic bandaging and daily medications with either vegetal stimulins or mesoglycan. After 15 days of treatment, the mean ulcer dimension was reduced 35% in the mesoglycan group and 26% in the stimulins group. At the end of the two-month study period, the healing rate was 95% in the mesoglycan group and 80% in the stimulins group. From these data, the authors believe that mesoglycan is efficacious and suggest further study on its mechanism of action.

COMMENTARY

This study has several problems in study design and in presentation of data. No details are given of the kind of venous disease present, the etiology of the venous insufficiency, possible treatment prior to enrollment in the study, or the presence of a newly formed ulcer versus a recurrent ulcer. Surprisingly, no hemodynamic details are given in the description of the clinical cases. The randomization method is not described. The statistical method used is not given; therefore, it is difficult to understand the significance of the results. The mechanism of action of mesoglycan is unclear and this study does not add any insight on this. While other aspects of the article need wide discussion as well, the above points are sufficient to cloud the study and its conclusions.

Treatment of venous ulcers is exceptionally complex and not close to being solved. While there are universally accepted fundamentals (elastic compression, treatment of underlying venous disease, adequate wound treatment), no definitive answers have been reached on the type of topical treatment or on the prevention of recurrences. I do not believe that this study brings us any closer to the final conclusion. ivdfdad3

L'INCONTINENCE DE LA PETITE VEIN SAPHENE EST-ELLE EN RELATION AVEC LA HAUTEUR DE SON ABOUCHEMENT DANS LA VOIE PROFONDE? (Is Insufficiency of the Short Saphenous Vein Related to the Level of its Anastomosis to the Deep Vein?)
Creton D, Kohler F
Phl�bologie 2000; 53(1):7-12

COMMENTARY BY:
Marianne Vandendriessche, MD, FRCS (Belg)
Gent, Belgium

The authors observed a statistically significant difference in the distribution of the level of the termination of the short saphenous vein between patients with incompetent short saphenous veins and control groups with competent short saphenous veins. The level of the junction was defined as:

Group I: Junction between 0 and 7 cm above the popliteal crease

Group II: Junction more than 7 cm above the popliteal crease

Group III: Junction below the popliteal crease

A meta-analysis of incompetent short saphenous veins (2275 cases determined by preoperative duplex, perioperative or preoperative venography, operative findings) showed that 80% of the junctions were situated in Group I compared with 62.6% in the control group (p > 0.05, not significant). A total of 13.8% incompetent short saphenous veins were located in group II compared with 29.5% in the control group. These differences are not statistically significant. The authors suggest that the lower the level of the junction between the short saphenous vein and the deep vein, the greater the possibility of incompetence. They explain that this is due to the embryological development of the venous system.

COMMENTARY

Although this article is interesting from anatomical, statistical and embryological point of view, it does not help the surgeon operate on a given leg. Whether an incompetent short saphenous vein belongs to the statistical majority or not is of little, if any, importance. It must be tied flush on the deep vein insuring that the vein of Giacomini and other tributaries, if present, are divided to prevent recurrence. On the rare occasion when the short saphenous vein is joined by the gastrocnemius vein before reaching the deep vein, both veins should be tied to prevent recurrence.

In my opinion, this article confirms that after a proper clinical examination, every leg must be precisely studied preoperatively either by duplex ultrasonography, venography, or a more-specific varicography. A probable explanation to why the saphenopopliteal junction at the popliteal crease is more likely to become incompetent is mechanical. The popliteal fossa is a congested space where muscles, nerves, bones, and vascular structures are in close proximity and subjected to frequent distortion by flexion/extension movements of the knee joint. Some anatomical variations render the venous element prone to compression by division of the sciatic nerve, possibly causing dilatation and secondary incompetence. ivdfvan4

MINI ABSTRACTS
John J. Bergan, M.D.
Items of Interest Which Have Crossed the Editor's Desk
(Provided for reference purposes and general interest)

Hereditary Benign Telangiectasia: First Family in Northern Ireland
McNicholl F, McMullin MF, Nevin NC, McMillan C
Case Report, The Ulster Medical Society, 1999

Generalized Essential Telangiectasias in a Patient with Graves' Disease: Should the Spectrum of Autoimmune Diseases Associated with Generalized Telangiectasias be Expanded?
Buckley R, Smith KJ, Skelton HG
Cutis 2000; 65:175-77

The condition described in these presentations is rare. Widespread sheets of linear telangiectasias occur not only on the legs and arms but also on the abdomen. The pathogenesis is unknown but may be due to an autosomal-dominant gene. The suggestion that this is an autoimmune disease is attractive.

Lymphoscintigraphy in Yellow Nail Syndrome
Bilen N, Bayramg�rler D, Devge C, et al.
Int'l J Dermatol 1998; 37:433-53

The yellow nail syndrome has been linked to lymphatic insufficiency and in this case, lymphoscintigraphy reveals slowed lymphatic drainage in the affected extremities.

Pulsatile Varicose Veins
Barnett N, Collyer TC, Weston M, Sparks JI, Scott DJA
J R Soc Med 2000; 93:29-30

The pulsatile veins are usually attributed to arteriovenous fistula. However, pulsatile femoral and saphenous veins are associated with tricuspid valvular regurgitation.