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1.  Matrix Metalloproteinases as Potential Targets in the Venous Dilation Associated with Varicose Veins 
Current drug targets  2013;14(3):287-324.
Varicose veins (VVs) are a common venous disease of the lower extremity characterized by incompetent valves, venous reflux, and dilated and tortuous veins. If untreated, VVs could lead to venous thrombosis, thrombophlebitis and chronic venous leg ulcers. Various genetic, hormonal and environmental factors may lead to structural changes in the vein valves and make them incompetent, leading to venous reflux, increased venous pressure and vein wall dilation. Prolonged increases in venous pressure and vein wall tension are thought to increase the expression/activity of matrix metalloproteinases (MMPs). Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and others. MMPs are known to degrade various components of the extracellular matrix (ECM). MMPs may also affect the endothelium and vascular smooth muscle, causing changes in the vein relaxation and contraction mechanisms. ECs injury also triggers leukocyte infiltration, activation and inflammation, which lead to further vein wall damage. The vein wall dilation and valve dysfunction, and the MMP activation and superimposed inflammation and fibrosis would lead to progressive venous dilation and VVs formation. Surgical ablation is an effective treatment for VVs, but may be associated with high recurrence rate, and other less invasive approaches that target the cause of the disease are needed. MMP inhibitors including endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline, batimastat and marimastat, have been used as diagnostic and therapeutic tools in cancer, autoimmune and cardiovascular disease. However, MMP inhibitors may have side effects especially on the musculoskeletal system. With the advent of new genetic and pharmacological tools, specific MMP inhibitors with fewer undesirable effects could be useful to retard the progression and prevent the recurrence of VVs.
PMCID: PMC3584231  PMID: 23316963
MMP; endothelium; vascular smooth muscle; extracellular matrix; chronic venous insufficiency disease; TIMP
2.  Does venous function deteriorate in patients waiting for varicose vein surgery? 
We have looked at the deterioration in the condition of the lower limbs in a group of 36 patients who were waiting for a median time of 20 months for varicose vein surgery, using clinical examination, colour Duplex scanning and photoplethysmograph (95% refilling times). We found a significant deterioration in this group of patients, with four limbs initially unaffected developing reflux on Duplex scanning, of which three had clinical varicose veins (all four were offered surgery), and of the initial 56 involved limbs, 10 further sources of reflux were found (18%), necessitating alteration of the initial planned surgical procedure. No patient developed deep venous insufficiency or ulceration while on the waiting list, although there was one new case of lipodermatosclerosis. However, had surgery been undertaken after the first assessment, 14 patients (25%) would potentially have required further surgery, although accepting this as justification for allowing patients to wait takes no account of patients suffering or quality of life while waiting for operation.
PMCID: PMC1293817  PMID: 8423569
3.  Endovascular Radiofrequency Ablation for Varicose Veins 
Executive Summary
Objective
The objective of the MAS evidence review was to conduct a systematic review of the available evidence on the safety, effectiveness, durability and cost–effectiveness of endovascular radiofrequency ablation (RFA) for the treatment of primary symptomatic varicose veins.
Background
The Ontario Health Technology Advisory Committee (OHTAC) met on August 26th, 2010 to review the safety, effectiveness, durability, and cost-effectiveness of RFA for the treatment of primary symptomatic varicose veins based on an evidence-based review by the Medical Advisory Secretariat (MAS).
Clinical Condition
Varicose veins (VV) are tortuous, twisted, or elongated veins. This can be due to existing (inherited) valve dysfunction or decreased vein elasticity (primary venous reflux) or valve damage from prior thrombotic events (secondary venous reflux). The end result is pooling of blood in the veins, increased venous pressure and subsequent vein enlargement. As a result of high venous pressure, branch vessels balloon out leading to varicosities (varicose veins).
Symptoms typically affect the lower extremities and include (but are not limited to): aching, swelling, throbbing, night cramps, restless legs, leg fatigue, itching and burning. Left untreated, venous reflux tends to be progressive, often leading to chronic venous insufficiency (CVI). A number of complications are associated with untreated venous reflux: including superficial thrombophlebitis as well as variceal rupture and haemorrhage. CVI often results in chronic skin changes referred to as stasis dermatitis. Stasis dermatitis is comprised of a spectrum of cutaneous abnormalities including edema, hyperpigmentation, eczema, lipodermatosclerosis and stasis ulceration. Ulceration represents the disease end point for severe CVI. CVI is associated with a reduced quality of life particularly in relation to pain, physical function and mobility. In severe cases, VV with ulcers, QOL has been rated to be as bad or worse as other chronic diseases such as back pain and arthritis.
Lower limb VV is a very common disease affecting adults – estimated to be the 7th most common reason for physician referral in the US. There is a very strong familial predisposition to VV. The risk in offspring is 90% if both parents affected, 20% when neither affected and 45% (25% boys, 62% girls) if one parent affected. The prevalence of VV worldwide ranges from 5% to 15% among men and 3% to 29% among women varying by the age, gender and ethnicity of the study population, survey methods and disease definition and measurement. The annual incidence of VV estimated from the Framingham Study was reported to be 2.6% among women and 1.9% among men and did not vary within the age range (40-89 years) studied.
Approximately 1% of the adult population has a stasis ulcer of venous origin at any one time with 4% at risk. The majority of leg ulcer patients are elderly with simple superficial vein reflux. Stasis ulcers are often lengthy medical problems and can last for several years and, despite effective compression therapy and multilayer bandaging are associated with high recurrence rates. Recent trials involving surgical treatment of superficial vein reflux have resulted in healing and significantly reduced recurrence rates.
Endovascular Radiofrequency Ablation for Varicose Veins
RFA is an image-guided minimally invasive treatment alternative to surgical stripping of superficial venous reflux. RFA does not require an operating room or general anaesthesia and has been performed in an outpatient setting by a variety of medical specialties including surgeons and interventional radiologists. Rather than surgically removing the vein, RFA works by destroying or ablating the refluxing vein segment using thermal energy delivered through a radiofrequency catheter.
Prior to performing RFA, color-flow Doppler ultrasonography is used to confirm and map all areas of venous reflux to devise a safe and effective treatment plan. The RFA procedure involves the introduction of a guide wire into the target vein under ultrasound guidance followed by the insertion of an introducer sheath through which the RFA catheter is advanced. Once satisfactory positioning has been confirmed with ultrasound, a tumescent anaesthetic solution is injected into the soft tissue surrounding the target vein along its entire length. This serves to anaesthetize the vein, insulate the heat from damaging adjacent structures, including nerves and skin and compresses the vein increasing optimal contact of the vessel wall with the electrodes or expanded prongs of the RF device. The RF generator is then activated and the catheter is slowly pulled along the length of the vein. At the end of the procedure, hemostasis is then achieved by applying pressure to the vein entry point.
Adequate and proper compression stockings and bandages are applied after the procedure to reduce the risk of venous thromboembolism and to reduce postoperative bruising and tenderness. Patients are encouraged to walk immediately after the procedure. Follow-up protocols vary, with most patients returning 1 to 3 weeks later for an initial follow-up visit. At this point, the initial clinical result is assessed and occlusion of the treated vessels is confirmed with ultrasound. Patients often have a second follow-up visit 1 to 3 months following RFA at which time clinical evaluation and ultrasound are repeated. If required, additional procedures such as phlebectomy or sclerotherapy may be performed during the RFA procedure or at any follow-up visits.
Regulatory Status
The Closure System® radiofrequency generator for endovascular thermal ablation of varicose veins was approved by Health Canada as a class 3 device in March 2005, registered under medical device license 67865. The RFA intravascular catheter was approved by Health Canada in November 2007 for the ClosureFast catheter, registered under medical device license 16574. The Closure System® also has regulatory approvals in Australia, Europe (CE Mark) and the United States (FDA clearance). In Ontario, RFA is not an insured service and is currently being introduced in private clinics.
Methods
Literature Search
The MAS evidence–based review was performed to support public financing decisions. The literature search was performed on March 9th, 2010 using standard bibliographic databases for studies published up until March, 2010.
Inclusion Criteria
English language full-reports and human studies Original reports with defined study methodologyReports including standardized measurements on outcome events such as technical success, safety, effectiveness, durability, quality of life or patient satisfaction Reports involving RFA for varicose veins (great or small saphenous veins)Randomized controlled trials (RCTs), systematic reviews and meta-analysesCohort and controlled clinical studies involving ≥ 1 month ultrasound imaging follow-up
Exclusion Criteria
Non systematic reviews, letters, comments and editorials Reports not involving outcome events such as safety, effectiveness, durability, or patient satisfaction following an intervention with RFAReports not involving interventions with RFA for varicose veinsPilot studies or studies with small samples (< 50 subjects)
Summary of Findings
The MAS evidence search on the safety and effectiveness of endovascular RFA ablation of VV identified the following evidence: three HTAs, nine systematic reviews, eight randomized controlled trials (five comparing RFA to surgery and three comparing RFA to ELT), five controlled clinical trials and fourteen cohort case series (four were multicenter registry studies).
The majority (12⁄14) of the cohort studies (3,664) evaluating RFA for VV involved treatment with first generation RFA catheters and the great saphenous vein (GSV) was the target vessel in all studies. Major adverse events were uncommonly reported and the overall pooled major adverse event rate extracted from the cohort studies was 2.9% (105⁄3,664). Imaging defined treatment effectiveness of vein closure rates were variable ranging from 68% to 96% at post-operative follow-up. Vein ablation rate at 6-month follow-up was reported in four studies with rates close to 90%. Only one study reported vein closure rates at 2 years but only for a minority of the eligible cases. The two studies reporting on RFA ablation with the more efficient second generation catheters involved better follow-up and reported higher ablation rates close to 100% at 6-month follow-up with no major adverse events. A large prospective registry trial that recruited over 1,000 patients at thirty-four largely European centers reported on treatment success in six overlapping reports on selected patient subgroups at various follow-up points up to 5 year. However, the follow-up for eligible recruited patients at all time points was low resulting in inadequate estimates of longer term treatment efficacy.
The overall level of evidence of randomized trials comparing RFA with surgical ligation and vein stripping (n = 5) was graded as low to moderate. In all trials RFA ablation was performed with first generation catheters in the setting of the operating theatre under general anaesthesia, usually without tumescent anaesthesia. Procedure times were significantly longer after RFA than surgery. Recovery after treatment was significantly quicker after RFA both with return to usual activity and return to work with on average a one week less of work loss. Major adverse events occurring after surgery were higher [(1.8% (n=4) vs. 0.4% (n = 1) than after RFA but not significantly. Treatment effectiveness measured by imaging defined vein absence or vein closure was comparable in the two treatment groups. Significant improvements in vein symptoms and quality of life over baseline were reported for both treatment groups. Improvements in these outcomes were significantly greater in the RFA group than the surgery group in the peri-operative period but not in later follow-up. Follow-up in these trials was inadequate to evaluate longer term recurrence for either treatment. Patient satisfaction was reported to be high for both treatments but was higher for RFA.
The studies comparing endovascular treatment approaches for VV (RFA and ELT) were more limited. Three RCT studies compared RFA (two with the second generation catheter) with ELT but mainly focused on peri-procedural outcomes such as pain, complications and recovery. Vein ablation rates were not evaluated in the trials, except for one small trial involving bilateral VV. Pain responses in patients undergoing ablation were extremely variable and up to 2 weeks, mean pain levels were significantly less with RFA than ELT ablation but differences were not significant at one month. Recovery, evaluated as return to usual activity or return to work, however, was similar in the treatment groups. Vein symptom and QOL improvements were improved in both groups but were significantly better in the RFA group than the ELT group at 2 weeks, but not at one month. Vein ablation rates were evaluated in several controlled clinical studies comparing the treatments between centers or within centers between individuals or over time. Comparisons in these studies were inconsistent with vein ablation rates for RFA reported to be similar to, higher than and lower than those with ELT.
Economic Analysis
RFA and surgical vein stripping, the main comparator reimbursed by the public system, are comparable in clinical benefits. Hence a cost-analysis was conducted to identify the differences in resources and costs between both procedures and a budgetary impact analysis (BIA) was conducted to project costs over a 5- year period in the province of Ontario. The target population of this economic analysis was patients with symptomatic varicose veins and the primary analytic perspective was that of the Ministry of Health and Long-Term Care.
The average case cost (based on Ontario hospital costs and medical resources) for surgical vein stripping was estimated to be $1,799. In order to calculate a procedural cost for RFA it was assumed that the hospital cost and physician labour fees, excluding anaesthesia and surgical assistance, were the same as vein stripping surgery. The manufacturer also provided details on the generator with a capital cost of $27,500 and a lifespan of 5 years and the disposables (catheter, sheath, guidewire) with a cost of $673 per case. The average case cost for RFA was therefore estimated to be $1,356. One-way sensitivity analysis was also conducted with hospital cost of RFA varied to 60% that of vein stripping surgery (average cost per case = $627.08) to calculate an impact to the province.
Historical volumes of vein stripping surgeries in Ontario were used to project surgeries in a linear fashion up to five years into the future. Volumes for RFA and ELT were calculated based on share capture from the surgery market based on discussion with clinical expert opinion and existing private data based on discussion with the manufacturer. RFA is expected to compete with ELT and capture some of the market. If ELT is reimbursed by the public sector then numbers will continue to increase from previous private data and share capture from the conventional surgical treatment market. Therefore, RFA cases will also increase since it will be capturing a share of the ELT market. A budget impact to the province was then calculated by multiplying volumes by the cost of the procedure.
RFA is comparable in clinical benefits to vein stripping surgery. It has the extra upfront cost of the generator and cost per case for disposables but does not require an operating theater, anaesthetist or surgical assistant fees. The impact to the province is expected to be 5 M by Year 5 with the introduction of new ELT and RFA image guided endovascular technologies and existing surgery for varicose veins.
Conclusion
The conclusions on the comparative outcomes between endovascular RFA and surgical ligation and saphenous vein stripping and between endovascular RFA and laser ablation for VV treatment are summarized in the table below (ES Table 1).
Outcome comparisons of RFA vs. surgery and RFA vs ELT for varicose veins
ELT refers to endovascular laser ablation; RFA, radiofrequency ablation
The outcomes of the evidence-based review on these treatments for VV based on different perspectives are summarized below:
RFA First versus Second Generation Catheters and Segmental Ablation
Ablation with second generation catheters and segmental ablation offered technical advantages with improved ease and significant decreases in procedure time. RFA ablation with second generation catheters is also no longer restricted to smaller (< 12 mm diameter) saphenous veins. The safety profile with the new device and method of energy delivery is as good as or improved over the first generation device. No major adverse events were reported in two multicenter prospective cohort studies in 6 month follow-up with over 500 patients. Post-operative complications such as bruising and pain were significantly less with RFA ablation with second generation catheters than ELT in two RCT trials.RFA treatment with second generation catheters has ablation rates that are higher than with first generation catheters and are more comparable with the consistently high rates of ELT.
Endovascular RFA versus Surgery
RFA has a quicker recovery attributable to decreased pain and lower minor complications.RFA, in the short term was comparable to surgery in treatment effectiveness as assessed by imaging defined anatomic outcomes such as vein closure, flow or reflux. Other treatment outcomes such as symptomatic relief and HRQOL were significantly improved in both groups and between group differences in the early peri-operative period were likely influenced by pain experiences. Longer term follow-up was inadequate to evaluate recurrence after either treatment.Patient satisfaction was high after both treatments but was higher for RFA than surgery.
Endovascular RFA versus ELT
RFA has significantly less post-operative pain than ELT but differences were not significant when pain was adjusted for analgesic use and pain differences between groups did not persist at 1 month follow-up.Treatment effectiveness, measured as symptom relief and QOL improvement were similar between the endovascular treatments in the short term (within 1 month) Treatment effectiveness measured as imaging defined vein ablation was not measured in any RCT trials (only for bilateral VV disease) and results were inconsistently reported in observational trials.Longer term follow-up was not available to assess recurrence after either treatment.
System Outcomes – RFA Replacing Surgery or Competing with ELT
RFA may offer system advantages in that the treatment can be offered by several medical specialties in outpatient settings and because it does not require an operating theatre or general anaesthesia. The treatment may result in decanting of patients from OR with decreased pre-surgical investigations, demand on anaesthetists’ time, hospital stay and wait time for VV treatment. It may also provide more reliable outpatient scheduling. Procedure costs may be less for endovascular approaches than surgery but the budget impact may be greater with insurance of RFA because of the transfer of cases from the private market to the public payer system.Competition between RFA and ELT endovascular approaches is likely to continue to stimulate innovation and technical changes to advance patient care and result in competitive pricing.
PMCID: PMC3377553  PMID: 23074413
4.  Endovascular Laser Therapy for Varicose Veins 
Executive Summary
Objective
The objective of the MAS evidence review was to conduct a systematic review of the available evidence on the safety, effectiveness, durability and cost–effectiveness of endovascular laser therapy (ELT) for the treatment of primary symptomatic varicose veins (VV).
Background
The Ontario Health Technology Advisory Committee (OHTAC) met on November 27, 2009 to review the safety, effectiveness, durability and cost-effectiveness of ELT for the treatment of primary VV based on an evidence-based review by the Medical Advisory Secretariat (MAS).
Clinical Condition
VV are tortuous, twisted, or elongated veins. This can be due to existing (inherited) valve dysfunction or decreased vein elasticity (primary venous reflux) or valve damage from prior thrombotic events (secondary venous reflux). The end result is pooling of blood in the veins, increased venous pressure and subsequent vein enlargement. As a result of high venous pressure, branch vessels balloon out leading to varicosities (varicose veins).
Symptoms typically affect the lower extremities and include (but are not limited to): aching, swelling, throbbing, night cramps, restless legs, leg fatigue, itching and burning. Left untreated, venous reflux tends to be progressive, often leading to chronic venous insufficiency (CVI).
A number of complications are associated with untreated venous reflux: including superficial thrombophlebitis as well as variceal rupture and haemorrhage. CVI often results in chronic skin changes referred to as stasis dermatitis. Stasis dermatitis is comprised of a spectrum of cutaneous abnormalities including edema, hyperpigmentation, eczema, lipodermatosclerosis and stasis ulceration. Ulceration represents the disease end point for severe CVI.
CVI is associated with a reduced quality of life particularly in relation to pain, physical function and mobility. In severe cases, VV with ulcers, QOL has been rated to be as bad or worse as other chronic diseases such as back pain and arthritis.
Lower limb VV is a common disease affecting adults and estimated to be the seventh most common reason for physician referral in the US. There is a strong familial predisposition to VV with the risk in offspring being 90% if both parents affected, 20% when neither is affected, and 45% (25% boys, 62% girls) if one parent is affected. Globally, the prevalence of VV ranges from 5% to 15% among men and 3% to 29% among women varying by the age, gender and ethnicity of the study population, survey methods and disease definition and measurement. The annual incidence of VV estimated from the Framingham Study was reported to be 2.6% among women and 1.9% among men and did not vary within the age range (40-89 years) studied.
Approximately 1% of the adult population has a stasis ulcer of venous origin at any one time with 4% at risk. The majority of leg ulcer patients are elderly with simple superficial vein reflux. Stasis ulcers are often lengthy medical problems and can last for several years and, despite effective compression therapy and multilayer bandaging are associated with high recurrence rates. Recent trials involving surgical treatment of superficial vein reflux have resulted in healing and significantly reduced recurrence rates.
Endovascular Laser Therapy for VV
ELT is an image-guided, minimally invasive treatment alternative to surgical stripping of superficial venous reflux. It does not require an operating room or general anesthesia and has been performed in outpatient settings by a variety of medical specialties including surgeons (vascular or general), interventional radiologists and phlebologists. Rather than surgically removing the vein, ELT works by destroying, cauterizing or ablating the refluxing vein segment using heat energy delivered via laser fibre.
Prior to ELT, colour-flow Doppler ultrasonography is used to confirm and map all areas of venous reflux to devise a safe and effective treatment plan. The ELT procedure involves the introduction of a guide wire into the target vein under ultrasound guidance followed by the insertion of an introducer sheath through which an optical fibre carrying the laser energy is advanced. A tumescent anesthetic solution is injected into the soft tissue surrounding the target vein along its entire length. This serves to anaesthetize the vein so that the patient feels no discomfort during the procedure. It also serves to insulate the heat from damaging adjacent structures, including nerves and skin. Once satisfactory positioning has been confirmed with ultrasound, the laser is activated. Both the laser fibre and the sheath are simultaneously, slowly and continuously pulled back along the length of the target vessel. At the end of the procedure, homeostasis is then achieved by applying pressure to the entry point.
Adequate and proper compression stockings and bandages are applied after the procedure to reduce the risk of venous thromboembolism, and to reduce postoperative bruising and tenderness. Patients are encouraged to walk immediately after the procedure and most patients return to work or usual activity within a few days. Follow-up protocols vary, with most patients returning 1-3 weeks later for an initial follow-up visit. At this point, the initial clinical result is assessed and occlusion of the treated vessels is confirmed with ultrasound. Patients often have a second follow-up visit 1-3 months following ELT at which time clinical evaluation and ultrasound are repeated. If required, sclerotherapy may be performed during the ELT procedure or at any follow-up visits.
Regulatory Status
Endovascular laser for the treatment of VV was approved by Health Canada as a class 3 device in 2002. The treatment has been an insured service in Saskatchewan since 2007 and is the only province to insure ELT. Although the treatment is not an insured service in Ontario, it has been provided by various medical specialties since 2002 in over 20 private clinics.
Methods
Literature Search
The MAS evidence-based review was performed as an update to the 2007 health technology review performed by the Australian Medical Services Committee (MSAC) to support public financing decisions. The literature search was performed on August 18, 2009 using standard bibliographic databases for studies published from January 1, 2007 to August 15, 2009. Search alerts were generated and reviewed for additional relevant literature up until October 1, 2009.
Inclusion Criteria
English language full-reports and human studies
Original reports with defined study methodology
Reports including standardized measurements on outcome events such as technical success, safety, effectiveness, durability, quality of life or patient satisfaction
Reports involving ELT for VV (great or small saphenous veins)
Randomized controlled trials (RCTs), systematic reviews and meta-analyses
Cohort and controlled clinical studies involving > 1 month ultrasound imaging follow-up
Exclusion Criteria
Non systematic reviews, letters, comments and editorials
Reports not involving outcome events such as safety, effectiveness, durability, or patient satisfaction following an intervention with ELT
Reports not involving interventions with ELT for VV
Pilot studies or studies with small samples ( < 50 subjects)
Summary of Findings
The MAS evidence search identified 14 systematic reviews, 29 cohort studies on safety and effectiveness, four cost studies and 12 randomized controlled trials involving ELT, six of these comparing endovascular laser with surgical ligation and saphenous vein stripping.
Since 2007, 22 cohort studies involving 10,883 patients undergoing ELT of the great saphenous vein (GSV) have been published. Imaging defined treatment effectiveness of mean vein closure rates were reported to be greater than 90% (range 93%- 99%) at short term follow-up. Longer than one year follow-up was reported in five studies with life table analysis performed in four but the follow up was still limited at three and four years. The overall pooled major adverse event rate, including DVT, PE, skin burns or nerve damage events extracted from these studies, was 0.63% (69/10,883).
The overall level of evidence of randomized trials comparing ELT with surgical ligation and vein stripping (n= 6) was graded as moderate to high. Recovery after treatment was significantly quicker after ELT (return to work median number of days, 4 vs. 17; p= .005). Major adverse events occurring after surgery were higher [(1.8% (n=4) vs. 0.4% (n = 1) 1 but not significantly. Treatment effectiveness as measured by imaging vein absence or closure, symptom relief or quality of life similar in the two treatment groups and both treatments resulted in statistically significantly improvements in these outcomes. Recurrence was low after both treatments at follow up but neovascularization (growth of new vessels, a key predictor of long term recurrence was significantly more common (18% vs. 1%; p = .001) after surgery. Although patient satisfaction was reported to be high (>80%) with both treatments, patient preferences evaluated through recruitment process, physician reports and consumer groups were strongly in favour of ELT. For patients minimal complications, quick recovery and dependability of outpatient scheduling were key considerations.
As clinical effectiveness of the two treatments was similar, a cost-analysis was performed to compare differences in resources and costs between the two procedures. A budget impact analysis for introducing ELT as an insured service was also performed. The average case cost (based on Ontario hospital costs and medical resources) for surgical vein stripping was estimated to be $1,799. Because of the uncertainties with resources associated with ELT, in addition to the device related costs, hospital costs were varied and assumed to be the same as or less than (40%) those for surgery resulting in an average ELT case cost of $2,025 or $1,602.
Based on the historical pattern of surgical vein stripping for varices a 5-year projection was made for annual volumes and costs. In Ontario in 2007/2008, 3481 surgical vein stripping procedures were performed, 28% for repeat procedures. Annual volumes of ELT currently being performed in the province in over 20 private clinics were estimated to be approximately 840. If ELT were publicly reimbursed, it was assumed that it would capture 35% of the vein stripping market in the first year and increase to 55% in subsequent years. Based on these assumptions if ELT were not publicly reimbursed, the province would be paying approximately $5.9 million and if ELT were reimbursed the province would pay $8.2 million if the hospital costs for ELT were the same as surgery and $7.1 million if the hospital costs were less (40%) than surgery.
The conclusions on the comparative outcomes between laser ablation and surgical ligation and saphenous vein stripping are summarized in the table below (ES Table 1).
Outcome comparisons of ELT vs. surgery for VV
The outcomes of the evidence-based review on these treatments based on three different perspectives are summarized below:
Patient Outcomes – ELT vs. Surgery
ELT has a quicker recovery attributable to the decreased pain, lower minor complications, use of local anesthesia with immediate ambulation.
ELT is as effective as surgery in the short term as assessed by imaging anatomic outcomes, symptomatic relief and HRQOL outcomes.
Recurrence is similar but neovascularization, a key predictor of long term recurrence, is significantly higher with surgery.
Patient satisfaction is equally high after both treatments but patient preference is much more strongly for ELT. Surgeons performing ELT are satisfied with treatment outcomes and regularly offer ELT as a treatment alternative to surgery.
Clinical or Technical Advantages – ELT Over Surgery
An endovascular approach can more easily and more precisely treat multilevel disease and difficult to treat areas
ELT is an effective and a less invasive treatment for the elderly with VV and those with venous leg ulcers.
System Outcomes – ELT Replacing Surgery
ELT may offer system advantages in that the treatment can be offered by several medical specialties in outpatient settings and because it does not require an operating theatre or general anesthesia.
The treatment may result in ↓ pre-surgical investigations, decanting of patients from OR, ↓ demand on anesthetists time, ↓ hospital stay, ↓decrease wait time for VV treatment and provide more reliable outpatient scheduling.
Depending on the reimbursement mechanism for the treatment, however, it may also result in closure of outpatient clinics with an increasingly centralization of procedures in selected hospitals with large capital budgets resulting in larger and longer waiting lists.
Procedure costs may be similar for the two treatments but the budget impact may be greater with insurance of ELT because of the transfer of the cases from the private market to the public payer system.
PMCID: PMC3377531  PMID: 23074409
5.  Varicose veins 
Clinical Evidence  2007;2007:0212.
Key Points
Varicose veins are considered to be enlarged tortuous superficial veins of the leg. Varicose veins are caused by poorly functioning valves in the veins, and decreased elasticity of the vein wall, allowing pooling of blood within the veins, and their subsequent enlargement.Varicose veins affect up to 40% of adults and are more common in obese people, and in women who have had more than two pregnancies.
Compression stockings are often used as first-line treatment for varicose veins, but we don't know whether they reduce symptoms compared with no treatment.
Injection sclerotherapy may be more effective than compression stockings, but less effective than surgery, at improving symptoms and cosmetic appearance. We don't know which sclerotherapy agent is the best to use.
Surgery (saphenofemoral ligation,stripping of the long saphenous vein, oravulsion) is likely to be beneficial in reducing recurrence, and improving cosmetic appearance, compared with sclerotherapy alone. We don't know whether stripping the long saphenous vein after saphenofemoral ligation improves outcomes compared with avulsion alone after ligation, or what the best method is for vein stripping. Powered phlebectomy may be as effective as avulsion, but may cause pain, bruising, and discolouration.We don't know whether radiofrequency ablation or self help are effective in people with varicose veins.
PMCID: PMC2943819  PMID: 19450366
6.  Ultrasound Doppler Evaluation of the Pattern of Involvement of Varicose Veins in Indian Patients 
The Indian Journal of Surgery  2010;73(2):125-130.
Doppler evaluation of lower limb veins was performed to evaluate the pattern of involvement of various sites of incompetence in Indian patients with varicose veins. A prospective Doppler study of 100 consecutive limbs in patients who presented with varicose veins to the vascular surgery department of a tertiary care hospital in India. The Clinico-Etiological Anatomical and Pathological (CEAP) classification was applied for assessment. Doppler evaluation of both superficial and deep venous system of the lower limbs was performed. The data of various sites of reflux was analysed to find the patterns of venous involvement in the affected patients. Superficial venous reflux was seen in all the patients. Deep venous reflux was seen in 50% of the lower limbs examined. Doppler is a simple non-invasive test, and is well tolerated by the patients. Deep venous reflux is common in Indian population, though it rarely occurs in isolation, and is usually associated with superficial reflux.
doi:10.1007/s12262-010-0195-0
PMCID: PMC3077159  PMID: 22468062
Varicose veins; Lower limb; Doppler evaluation; Venous reflux
7.  Venous Distensibility in Patients with Varicose Veins 
Canadian Medical Association Journal  1966;94(25):1293-1297.
Forearm veins were studied to determine whether patients with primary varicosity of the saphenous veins had a generalized abnormality of the venous system. Distensibility of the superficial forearm and hand veins was measured in 25 patients with varicosity of the saphenous veins, and in 25 control subjects. Patients with saphenous varicosity had a significantly greater distensibility of the undistorted forearm veins than control subjects. Hysteresis of distensibility curves was more prnounced in patients with varicosity than in control subjects; mean hysteresis index was 0.65 ± 0.06 versus 0.28 ± 0.02 in controls. These investigations suggest that an increased distensibility of the venous system is the predisposing factor in the development of varicose veins.
PMCID: PMC1936709  PMID: 5943339
8.  The Hemodynamic Paradox as a Phenomenon Triggering Recurrent Reflux in Varicose Vein Disease 
A curious hemodynamic phenomenon emerging as a consequence of the treatment of varicose veins can offer a reasonable explanation why varicose vein and reflux recurrences occur tenaciously irrespective of the applied therapeutic procedure. Saphenous reflux is the most important hemodynamic factor in varicose vein disease: it is responsible for the hemodynamic disturbance, ambulatory venous hypertension, clinical symptoms, and chronic venous insufficiency. Abolition of saphenous reflux eliminates the hemodynamic disturbance and restores physiological hemodynamic and pressure conditions, but at the same time it unavoidably evokes a pressure difference between the femoral vein and the incompetent superficial veins in the thigh during calf pump activity. The pressure difference increases flow and enhances fluid shear stress on the endothelium in pre-existing minor communicating channels between the femoral vein and the saphenous system in the thigh, which triggers release of biochemical agents nitride oxide and vascular endothelial growth factor; the consequence is enlargement (vascular remodeling) of the communicating channels, and ultimately reflux recurrence.
Hence, the abolition of saphenous reflux creates preconditions for the comeback of the previous pathological situation. This phenomenon—starting the same trouble while fixing the problem—has been called hemodynamic paradox; is explains why varicose vein and reflux recurrence can occur after any mode of therapy.
doi:10.1055/s-0032-1325168
PMCID: PMC3578628  PMID: 23997567
varicose vein recurrence; venous hemodynamics; hemodynamic paradox
9.  Histopathological changes in venous grafts and in varicose and non-varicose veins. 
Journal of Clinical Pathology  1993;46(7):603-606.
AIMS--To examine veins histologically from different sites in the body to study the effect of venous pressure; and to examine veins used as aortocoronary grafts. METHODS--The axillary vein, femoral vein at the inguinal ligament, the short saphenous vein at the knee and the long saphenous vein at the ankle were removed from 24 necropsy cases of patients aged 2 months to 80 years. Fifteen varicose saphenous veins and 12 aortocoronary grafts removed at surgery were obtained. All were examined histologically. RESULTS--Varying degrees of intimal thickening composed of collagen, elastin, and smooth muscle were found. These changes were most noticeable in the varicose veins. Intimal changes were also seen related to valves and to adjacent arteries. No clinically relevant lipid was seen in the native veins, though atheromatous changes were seen in the grafts. CONCLUSIONS--Venous changes are related to venous pressure, to local haemodynamic effects, and probably to hypoxia. The changes are often focal and seem to be sequential in their formation. True atheroma is seen in the aortocoronary grafts but is not seen in native veins and this may be the result of additional factors.
Images
PMCID: PMC501385  PMID: 8157743
10.  Surgical Treatment of Varicose Veins: Effect of Rationing 
INTRODUCTION
A substantial part of vascular surgical workload is devoted to the treatment of varicose veins. To control demand for cosmetic venous surgery, primary care trusts in Somerset introduced clinical criteria in 2000 for the referral and treatment of varicose veins based on the presence of skin change or ulceration, a history of bleeding, or two or more episodes of thrombophlebitis.
PATIENTS AND METHODS
A comparison of workload and case mix for the referral and treatment of new patients presenting with varicose veins to the Taunton and Somerset Hospital was carried out over two 6-month periods, before and after the introduction of clinically based assessment criteria.
RESULTS
A total of 134 operations for varicose veins were carried out in 2000 and 85 such operations in 2002/03 after the introduction of new referral criteria (P = 0.001). Of these, 69% (92/134) were day-case procedures in 2000 compared to only 48% (41/85) in 2002/03 (P = 0.004). There was no significant difference in the type of cases (e.g. single, bilateral or recurrent surgery) performed as a day-case (P = 0.34) or as an in-patient (P = 0.43) over the two periods. There was, however, a significant difference (P = 0.007) in the mean ages of patients in the two periods (48.5 years in period 1; 57.8 years in period 2) and in the average ASA grade (1.15 in period 1; 1.42 in period 2; P = 0.0002).
CONCLUSION
The introduction of clinical criteria for the referral and treatment of varicose veins reduced workload by 37%.
doi:10.1308/003588406X82998
PMCID: PMC1963610  PMID: 16460638
Varicose veins; Management; Clinical criteria; Rationing
11.  Varicose Vein Surgery 
ABSTRACT
The treatment of superficial venous disease and chronic venous insufficiency continues to evolve, and the interest in venous disease has matched that in arterial disease in vascular medicine. A better understanding of venous anatomy and pathophysiology and the development of newer, more efficient diagnostic technology have allowed clinicians to utilize minimally invasive techniques in the treatment of varicose veins. These techniques have reduced recurrence and improved overall quality of life (postoperative pain and bruising) following these procedures. This article provides an overview of basic venous surgical anatomy and pathophysiology, along with several older and newer surgical options in the treatment of superficial venous disease. Advantages and disadvantages of each approach are briefly discussed so that the reader may gain better understanding of the options available in the treatment of chronic venous insufficiency.
doi:10.1055/s-2005-921951
PMCID: PMC3036286  PMID: 21326692
Chronic venous insufficiency; varicose veins; neovascularization; endovenous vein obliteration
12.  Case report: Varicosity of the communicating vein between the left renal vein and the left ascending lumbar vein mimicking a renal artery aneurysm: Report of an unusual site of varicose veins and a novel hypothesis to explain its association with abdominal pain 
A communicating vein between the left renal vein and the left ascending lumbar vein has only rarely been reported in the imaging literature. There are very few reports of varicosity of this communicating vein. Nonetheless, awareness about this communicating vein is of utmost importance for surgeons performing aortoiliac surgeries and nephrectomies as it may pose technical difficulties during surgery or cause life-threatening retroperitoneal hemorrhage. Varicosity of this venous channel may be mistaken for paraaortic lymphadenopathy, adrenal pseudo-mass, or renal artery aneurysm. We report a case of a patient with varicosity of this communicating vein, which mimicked a left renal artery aneurysm. A novel hypothesis is also proposed to explain the relationship with abdominal pain.
doi:10.4103/0971-3026.76050
PMCID: PMC3056365  PMID: 21431029
Ascending lumbar vein; communicating vein; renal artery; renal vein; varicosity
13.  Varicose veins: optimum compression following sclerotherapy. 
There is uncertainty regarding the most satisfactory technique of lower limb compression following sclerotherapy for varicose veins. We have compared a standard bandaging technique with a high pressure compression stocking in a randomised trial. Efficacy was judged on the success of injections, complications of the treatment and patient satisfaction. In the stockinged legs 144 of 156 injections were successful, compared with 117 of 147 in the bandaged group (P less than 0.001) (Chi squared). The incidence of superficial thrombophlebitis was also reduced in the stocking group. In addition, the stocking technique costs less in materials than conventional bandaging. We would recommend compression stockings for evaluation in sclerotherapy of varicose veins.
PMCID: PMC2498276  PMID: 3883876
14.  Critical Pitfall: Varices in Cancer Patients mimicking Lymphadenopathy; Differentiation of varicose veins and enlarged lymph nodes in routine staging 
Two patients, each with a history of multiple cancers, were referred to our institution for routine cancer staging. Contrast enhanced multislice-CT showed round and oval shaped inguinal and retroperitoneal masses in one patient and inguinal mass lesions in the other patient. The mass lesions were suspicious of lymphadenopathy related to cancer recurrence. Additional MR-Imaging, however, showed tortuous varicose veins as well as suspicious lymph nodes in one patient and solely venous convolutes in the other patient. Regarding the routine contrast enhanced CT-scan in the portovenous phase, varices showed no significant difference in radiodensity compared to enlarged lymph nodes.
doi:10.3941/jrcr.v5i9.778
PMCID: PMC3303457  PMID: 22470814
Varices; Lymphadenopathy; Oncology; Computed Tomography; Magnetic Resonance Tomography
15.  The management of recurrent varicose veins. 
Recurrent varicose veins are due to unidentified connections between the deep and superficial venous systems. Conventional clinical and radiological methods of identification are inefficient. In a series of 662 operations the rate of recurrence was over 40%. By changing to a different radiological technique, using an image intensifier, it was found that the gastrocnemius veins in the popliteal fossa were a common cause of recurrence. This radiological technique also differentiated between those recurrences that required a second operation and those which ought to be treated by Fegan's method.
Images
PMCID: PMC2493956  PMID: 7294688
16.  Varicose Veins: Role of Mechanotransduction of Venous Hypertension 
Varicose veins affect approximately one-third of the adult population and result in significant psychological, physical, and financial burden. Nevertheless, the molecular pathogenesis of varicose vein formation remains unidentified. Venous hypertension exerted on veins of the lower extremity is considered the principal factor in varicose vein formation. The role of mechanotransduction of the high venous pressure in the pathogenesis of varicose vein formation has not been adequately investigated despite a good progress in understanding the mechanomolecular mechanisms involved in transduction of high blood pressure in the arterial wall. Understanding the nature of the mechanical forces, the mechanosensors and mechanotransducers in the vein wall, and the downstream signaling pathways will provide new molecular targets for the prevention and treatment of varicose veins. This paper summarized the current understanding of mechano-molecular pathways involved in transduction of hemodynamic forces induced by blood pressure and tries to relate this information to setting of venous hypertension in varicose veins.
doi:10.1155/2012/538627
PMCID: PMC3303599  PMID: 22489273
17.  Prolonged Increases in Vein Wall Tension Increase Matrix Metalloproteinases and Decrease Constriction in Rat Vena Cava. Potential Implications in Varicose Veins 
Background
Increased venous hydrostatic pressure plays a role in the pathogenesis of varicose veins. Increased expression of matrix metalloproteinases (MMPs) has been identified in varicose veins. Also, we have shown that MMP-2 inhibits venous contraction. However, the relation between venous pressure, MMP expression and venous dysfunction is unclear. The purpose of this study was to test the hypothesis that prolonged increases in vein wall tension cause overexpression of MMPs and decreased contractility, which in turn promote venous dilation.
Methods
Circular segments of inferior vena cava (ICV) were isolated from male Sprague-Dawley rats, and suspended between two wires in Krebs solution. Preliminary vein wall tension-contraction relation showed maximal KCl (96 mmol/L) contraction at 0.5g basal tension, which remained steady with increases in tension up to 2g. Vein segments were subjected to either control (0.5g) or high (2g) basal tension for short (1 hr) or long duration (24 hr). Isometric contraction in response to phenylephrine (Phe, 10−5 mol/L), angiotensin II (AngII, 10−6 mol/L), and KCl was measured. The veins were frozen to determine the expression and localization of MMPs using immunoblots and immunohistochemistry.
Results
In IVC segments subjected to 0.5g tension for 1 hr Phe and AngII produced significant contraction. At higher 2g basal tension for 24 hr, both Phe and AngII contractions were significantly reduced. Reduction in KCl contraction was also observed at high 2g basal tension for 24 hr, suggesting that the reduction in vein contraction is not specific to a particular receptor, and likely involves inhibition of a post-receptor contraction mechanism. In vein segments under 2g tension for 24 hr and treated with TIMP-1, Phe, AngII, and KCl contractions were partially restored, suggesting the involvement of MMPs. IVC immunoblot analysis demonstrated prominent bands corresponding to MMP-2 and MMP-9 protein. High 2g wall tension for 24 hr was associated with marked increase in the amount of MMP-2 and -9 relative to the housekeeping protein actin. There was a correlation between MMP expression and decreased vein contraction. Also, significant increases in MMP-2 and -9 immunostaining were observed in IVC segments subjected to high 2g tension for 24 hr. Both MMP-2 and MMP-9 caused significant inhibition of Phe contraction in IVC segments.
Conclusions
In rat IVC, increases in magnitude and duration of wall tension is associated with reduced contraction and overexpression of MMP-2 and -9. In light of our findings that MMP-2 and -9 promote IVC relaxation, the data suggest that protracted increases in venous pressure and wall tension increase MMPs expression, which in turn reduce venous contraction and lead to progressive venous dilation.
doi:10.1016/j.jvs.2008.03.004
PMCID: PMC2575039  PMID: 18502086
18.  Varicose Veins in Women Cotton Workers. An Epidemiological Study in England and Egypt* 
British Medical Journal  1969;2(5657):591-595.
The prevalence of varicose veins was studied in 504 women cotton workers in England and 467 in Egypt, by a standardized questionary and a specially developed method of examination. The English mill population showed a much higher prevalence of varicose veins than the Egyptian, probably owing to environmental rather than ethnic reasons.
Among the European women the prevalence of varicose veins was significantly related to age, parity, body weight, type of corsetry, and occupation—that is, whether or not they stood at their work. After standardizing for the other variables there was a statistically significant excess of varicose veins in women wearing corsets and roll-ons compared with those wearing less-constrictive garments. After a similar standardization a significant excess was found in women who stood at their work compared with those whose jobs entailed walking or sitting.
Images
PMCID: PMC1983630  PMID: 5798468
19.  Functional Adaptation of Venous Smooth Muscle Response to Vasoconstriction in Proximal, Distal and Varix Segments of Varicose Veins 
Background
Varicose Veins (VarV) is a common disorder of venous dilation and turtuosity with unclear mechanism. Although venous smooth muscle constitutes a significant component of the vein wall, the functional integrity and the ability of various regions of the VarV to constrict is unclear. The objective of this study was to test the hypothesis that the different degrees of venodilation in different regions of VarV reflect segmental differences in the responsiveness to receptor-dependent vasoconstrictive stimuli and/or in the post-receptor signaling mechanisms of vasoconstriction.
Methods
Varix segments and adjacent proximal and distal segments were obtained from patients undergoing VarV stripping. Control greater saphenous vein specimens were obtained from patients undergoing lower extremity arterial bypass and coronary artery bypass graft (CABG). Circular vein segments were equilibrated under 2 g of tension in a tissue bath, and the changes in isometric constriction in response to angiotensin II (AngII, 10−11−10−7 M), phenylephrine (PHE, 10−9−10−4 M), and KCl (96 mM) were recorded. The amount of angiotensin type 1 receptor (AT1R) was measured in vein tissue homogenate using Western blot analysis.
Results
AngII caused concentration-dependent constriction in control vein (max 35.3±9.6 mg/mg tissue, pED50 8.48±0.34). AngII caused less contraction and was less potent in proximal (max 7.9±2.5, pED50 6.85±0.61), distal (max 5.7±1.2, pED50 6.74±0.68) and varix segments of VarV (max 7.2±2.0, pED50 7.11±0.50), suggesting reduced AT1R-receptor-mediated contractile mechanisms. Western blot analysis revealed similar amount of AT1R in VarV compared to control veins. α-adrenergic receptor stimulation with PHE caused concentration-dependent constriction in control veins (max 73.0±13.9 mg/mg tissue, pED50 5.48±0.12), that was greater in magnitude than that of AngII. PHE produced similar constriction and was equally potent in varix and distal segments, but produced less constriction and was less potent in proximal segments of VarV (max 32.1±6.4 mg/mg tissue, pED50 4.89±0.13) as compared to control veins. Membrane depolarization by 96 mM KCl, a receptor-independent Ca2+-dependent response, produced significant constriction in control veins, and similar contractile response in proximal, distal and varix segments of VarV, indicating tissue viability and intact Ca2+-dependent contraction mechanisms.
Conclusions
Compared with control veins, different regions of VarV display reduced AngII-mediated venoconstriction, which may play a role in the progressive dilation in VarV. Post-receptor Ca2+-dependent contraction mechanisms remain functional in VarV. The maintained α-adrenergic responses in distal and varix segments, and the reduced constriction in the upstream proximal segments, may represent a compensatory adaptation of human venous smooth muscle to facilitate venous return from the dilated varix segments of VarV.
doi:10.1016/j.jvs.2009.11.037
PMCID: PMC2847596  PMID: 20347695
adrenergic receptors; angiotensin; vascular smooth muscle; calcium
20.  Expression of Matrix Metalloproteinase-2 and -13 and Tissue Inhibitor of Metalloproteinase-4 in Varicose Veins 
Background
The relationship between the degree of expression of matrix metalloproteinases or tissue inhibitor of metalloproteinases and venous reflux remains to be investigated.
Materials and Methods
Primary varicose vein tissues were obtained from 23 patients, 18 females and 5 males, aged from 19 to 73. Cephalic or basilic veins were obtained for the control group from 10 patients who underwent vascular access for maintenance hemodialysis. Two operative techniques (high ligation with stripping or endovenous laser coagulation) were used. The expression of matrix metalloproteinase-2 and 13 and tissue inhibitor of metalloproteinase-4 in the varicose vein group and control group was assessed semi-quantitatively by immunohistochemical slides stained with primary antibodies.
Results
Twenty (87%) of the varicose vein group patients had greater or lesser saphenous vein diseases with reflux. The focal weak (+) stain for matrix metalloproteinases-2, and 13, and tissue inhibitor of matrix metalloproteinase-4 was dominant in the varicose vein group; the focal or diffuse strong stain (++ or +++) was prevalent in the control group. The differences were statistically significant (p<0.01). The degree of reflux and the duration of symptoms were not significantly related to the expression of MMP-13 (p=0.317 and p=0.654, respectively).
Conclusion
Further study should be performed to investigate the relationship between the clinical characteristics related to venous hypertension or reflux and expression of MMPs and TIMP in varicose veins.
doi:10.5090/kjtcs.2011.44.6.387
PMCID: PMC3270279  PMID: 22324022
Veins; Varicose veins; Extracellular matrix
21.  MANAGEMENT OF VARICOSE VEINS DURING PREGNANCY 
California Medicine  1957;87(6):365-367.
The incidence of recurrences after radical venous operations done during pregnancy or where pregnancy has occurred subsequently is much higher than it is in cases in which pregnancy is not a factor. These discouraging results are due to increased venous pressure, obstruction to the venous drainage of the lower extremities and hormonal factors. The management of varicose veins during pregnancy should be by conservative means consisting of proper elastic support, elevation of the extremities at night and during rest periods in the day, avoiding static dependency of the legs, and control of body weight. In event of venous stasis and severe symptoms of varicosis that cannot be controlled by conservative measures, limited surgical intervention is indicated. This should consist of high ligation and division of the involved venous trunk and the immediate tributaries. Radical extirpation of varicose veins should be reserved until further pregnancy is not contemplated.
PMCID: PMC1512200  PMID: 13489493
22.  Matrix Metalloproteinase-2 Induced Venous Dilation via Hyperpolarization and Activation of K+ Channels. Relevance to Varicose Vein Formation 
Background
Varicose veins are a common disorder of extensive venous dilation and remodeling with as yet unclear mechanism. Studies have shown elevated plasma and tissue levels of matrix metalloproteinases (MMPs) in human varicose veins and animal models of venous hypertension. Although the effects of MMPs are generally attributed to extracellular matrix degradation, their effects on the mechanisms of venous contraction/relaxation are unclear. Our preliminary experiments have demonstrated that MMP-2 causes inhibition of phenylephrine (Phe)-induced venous contraction. The purpose of this study was to determine whether MMP-induced inhibition of venous contraction involves an endothelium-dependent and/or -independent pathway.
Methods
Circular segments of the inferior vena cava (IVC) were isolated from male Sprague-Dawley rats and suspended between two wire hooks in a tissue bath, and the effects of MMP-2 on Phe- and KCl-induced contraction were measured. To study the role of endothelium-derived vasodilators, experiments were performed in the presence and absence of endothelium; L-NAME, inhibitor of nitric oxide (NO) synthesis; indomethacin, inhibitor of prostacyclin (PGI2) synthesis; cromakalim, activator of ATP-sensitive K+ channel (KATP); and iberiotoxin, blocker of large conductance Ca2+-dependent K+ channel (BKCa) and smooth muscle hyperpolarization.
Results
In endothelium-intact IVC segments, Phe (10−5 mol/L) caused significant contraction that slowly declined to 82.0% in 30 min. Addition of MMP-2 (1 μg/mL) caused a gradual decrease of Phe contraction to 39.5% at 30 min. In endothelium-denuded IVC MMP-2 induced greater reduction of Phe contraction to 7.6%. In presence of L-NAME (10−4 mol/L), MMP-2 caused marked decrease in Phe contraction to 4.4%. Large MMP-2 induced inhibition of Phe contraction was also observed in IVC treated with L-NAME plus indomethacin. MMP-2 caused relaxation of Phe contraction in IVC pretreated with cromakalim (10−7 mol/L), activator of KATP channel. MMP-2 induced inhibition of Phe contraction was abrogated in the presence of iberiotoxin (10−8 mol/L), blocker of BKCa. MMP-2 did not inhibit venous contraction during membrane depolarization by 96 mmol/L KCl, a condition that prevents outward K+ conductance and cell hyperpolarization.
Conclusions
MMP-2 causes significant IVC relaxation that is potentiated in the absence of endothelium or during blockade of endothelium-mediated NO and PGI2 synthesis. The lack of effects of MMP-2 on KCl contraction and in iberiotoxin treated veins suggests MMP-2 induced smooth muscle hyperpolarization and activation of BKCa channel, a novel effect of MMP that may play a role in the early stages of venous dilation and varicose vein formation.
doi:10.1016/j.jvs.2006.10.041
PMCID: PMC1794684  PMID: 17264019
23.  Tissue remodeling investigation in varicose veins 
Although the etiology of varicose veins remains unknown, recent studies have focused on endothelial cell integrity and function because the endothelium regulates vessel tone and synthesizes many pro- and anti-inflammatory factors. The aim of this study was to investigate the evidence involving the endothelium in the development of varicose vein disease. In addition, tissue remodeling was investigated in varicose veins to determine the expression of different types of collagen. Tissue specimens of superficial varicose veins and control saphenous vein were used for immunohistochemical and transmission electron microscope (TEM). α-smooth muscle actin, and collagen I, III, IV antibodies were applied for immunohistochemical investigation. Findings of this study showed alterations of the intima, such as focal intimal discontinuity and denudation of endothelium; and the media, such as irregular arrangements of smooth muscle cells and collagen fibres in varicose veins. Our findings showed some changes in terms of distribution of types I, III and IV collagen in the intima and media of varicose vein walls compared with controls. These alterations to the media suggest that the pathological abnormality in varicose veins may be due to the loss of muscle tone as a result of the breakup of its regular structure by the collagen fibres. These findings only described some changes in terms of distribution of these types of collagen in the intima and media of varicose vein walls which may result in venous wall dysfunction in varicosis.
PMCID: PMC3920493  PMID: 24551759
Varicose vein disease; endothelial cells; transmission electron microscopy; collagen fibres
24.  The place of duplex scanning for varicose veins and common venous problems. 
Duplex scanning has become the 'gold standard' for confirming reflux and demonstrating anatomy in cases of lower limb venous disease. However, the large numbers of patients presenting with varicose veins (or with skin changes and ulcers) mean that routine use of duplex is impractical, and this investigation has still not become well established in many hospitals. In order to determine the proportion of patients likely to require duplex scanning (and other special tests-photoplethysmography and ascending venography) we reviewed a consecutive series of 201 patients referred to the vascular clinic of a district general hospital with 283 symptomatic limbs affected by varicose veins and/or skin changes and ulcers. Patients were examined clinically and with hand-held Doppler. Duplex scanning was then requested to check for reflux in the popliteal fossa and to examine the groin and residual long saphenous vein in some cases of recurrent varicose veins. Duplex scanning was required in 51 (18%) limbs, venography in 8 (3%), and photoplethysmography in only one limb. In total, special tests were needed in 60 (21%) limbs. Subsequently, 198 (70%) limbs were referred for surgery. We would now (in 1996) duplex scan every case with popliteal fossa reflux and most recurrences. Had all these been scanned, then 79 (28%) would have had special tests. This knowledge should help in planning the implications of a duplex scanning service for varicose veins, skin changes and ulcers.
PMCID: PMC2502872  PMID: 8943629
25.  Varicose Vein Management: Considerations for the Diagnostic Radiology Group Practice 
ABSTRACT
The purpose of this brief article is to suggest some specific considerations that diagnostic radiology groups must make prior to embarking upon a varicose veins practice component. There are many excellent sources for further information, including the Web sites and practice management components of organizations such as the Society of Interventional Radiology, American College of Phlebology, International Vein Congress, and Union Internationale Phlebologie, all of which also hold excellent meetings or sections. Major points addressed in the article will include business plans, physician and group requirements, physical space and equipment requirements, and personnel issues. Though vein practice is clearly a major undertaking, the nature of varicose venous disease is such that there is a serendipitous overlap between the skill sets of the interventional radiologists and those required of the treating phlebologist. Consequently, with the proper motivation, self-education, and ongoing training, the addition of a varicose vein practice component can be extremely gratifying and rewarding for the physician, his radiology group, and most importantly the patients whom they serve.
doi:10.1055/s-2005-869581
PMCID: PMC3036254  PMID: 21326671
Varicose vein; practice management; interventionalist

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