Venous disease is a common vascular condition affecting the lower limbs and causes considerable morbidity in affected patients. National Health Service (NHS) treatment costs are substantial and there is a large demand for treatment much of which cannot be met. Roughly half a million people in the United Kingdom contact their general practitioner each year about varicose veins and associated clinical symptoms. In order to assign priorities and target interventions properly, authorities need to know which patients with venous disease will progress. Although many epidemiological studies have investigated the prevalence of venous disease, information on deterioration is scarce. The overall aim of this study is to determine the natural history of venous disease in the population and to identify lifestyle and clinical factors related to deterioration which might aid clinical decision making and health services policy. The specific objectives were to determine which risk factors were associated with deterioration of venous disease and venous reflux, and to ascertain the natural history of asymptomatic venous incompetence in terms of deteriorating to overt trunk varicose veins and chronic venous insufficiency. The study design was a population based cohort in the Edinburgh Vein Study which the survivors of the 1566 individuals aged 18 to 64 randomly sampled years from the general population at baseline underwent a 13-year follow-up examination. Details of the 1566 participants in the baseline study were sent to the Practitioner Services Division (PSD) of the NHS in Scotland who provided updated addresses and general practitioner registration details. Information collected on each subject at a follow-up clinic included lifestyle factors and medical history, height and weight measurement (by means of a questionnaire), clinical examination for classification of venous disease according to the Basle and CEAP systems, and duplex scanning to assess incompetence of venous valves in the deep and superficial systems of ten vein segments in each leg. Of the subjects from the baseline, 880 participated in the follow-up study, and 576 did not participate, providing a response rate of 60.4% of which 490 were female (55.7%) and 390 were male (44.3%). The study subjects were generally older and slightly more affluent than residents of the City of Edinburgh. For trunk varicose veins, the baseline prevalence was higher in males compared to females (p<0.01), but there was no difference in prevalence among subjects at the follow-up stage of the study (p=0.56). The overall rate of deterioration in trunk varicose veins was 3.55% per annum. More females than males deteriorated (p=0.04). Among subjects who showed deterioration in their trunk varicose veins, the commonest deterioration was from Basle Grade I (mild) at baseline to Grade II (moderate) at follow-up in both the right and left leg (28.1% and 32.9% respectively). Subjects older than 55 years of age (OR=1.59, 95% CI 1.01-2.51), who had a positive family history of varicose veins or venous ulcer (OR=1.92, 95% CI 1.20-3.07), and sat down at work for more than half the working day (OR=1.69, 95% CI 1.04-2.73) had increased risk of deteriorating trunk varicose veins. There was no significant difference between males and females in the prevalence of chronic venous insufficiency (CVI) among subjects at both the baseline and follow-up stage of the study (p=0.15 and 0.16 respectively). The rate of deterioration in CVI was 1.76% per annum. Similarly, among subjects who deteriorated, the commonest deterioration was from Grade I (mild) to Grade II (moderate) CEAP classification in both the right and left leg (42.4% and 45.5% respectively). The risk of worsening of CVI among those older than 55 was nearly three times more than those aged less than 55 (OR=2.85, 95% CI 1.18-6.87), and was still significant when adjusted for gender. The prevalence of telangiectasia was higher in females than in males in both the baseline and follow-up stages of the study (both p<0.01). The rate of deterioration in telangiectasia was 1.6% per annum. The commonest deterioration was from grade I (mild) at baseline to grade II (moderate) follow-up in the left and right leg (using the Basle Classification). Females subjects (OR=1.87, 95% CI 1.35-2.64), those older than 55 (OR=1.68, 95% CI 1.19-2.36), with a positive family history of venous disease (OR=1.60 95% CI 1.14-2.24) were associated with an increased risk of deterioration from telangiectasia compared to male subjects under 55 years of age and with no family history of the disease. The risk of telangiectasia deterioration was more than twice as high in subjects with venous reflux in the greater saphenous vein (origin) (OR=2.34, 95% CI 1.53-3.57), the greater saphenous vein (lower third of the thigh) (OR=2.28, 95% CI 1.59-3.27) and in the small saphenous vein (1.89, 95% CI 1.06-3.36) compared to those with no segments affected. The age and gender adjusted risk was also more than twice as high in subjects with venous reflux in two segments of the superficial system compared to subjects with no venous reflux in any segment (OR=2.06, 95% CI 1.23-3.44), and almost four times as high in subjects with reflux in more than three segments of the superficial system (OR=3.97, 95% CI 2.16-7.31) compared to subjects with no segments affected. On duplex scanning, the prevalence of reflux was higher in females than in males in the superficial system at baseline and follow-up stages of the study (p<0.01 respectively). In the deep system, the prevalence was higher in males than females at the baseline stage (p<0.01) with no significant difference at the follow-up stage (p=0.85). The rate of deterioration in venous reflux was 1.28% per annum. Most subjects deteriorated from one to two vein segments affected in the leg, the majority of which had reflux in the greater saphenous vein (thigh) at baseline and developed reflux in the greater saphenous vein (origin) at follow-up. Subjects more than 55 years of age had significantly more deterioration than those aged less than 55 (p<0.01). Obese or overweight subjects (OR=1.59, 95% CI 1.32-3.67), those aged more than 55 (OR=2.20, 95% CI 1.32-3.67), with a family history of varicose veins (among female subjects only, OR=2.55, 95% CI 1.16-5.56), and who sat down at work more than half the working time (among male subjects only) (OR=2.26, 95%CI 0.97-5.23) had increased risk of showing deterioration in reflux in any leg and in any vein segment from baseline to follow-up. Subjects with venous reflux at baseline were over two and half times more likely to show deterioration in trunk varicose veins compared to those with no reflux (OR=2.69, 95%CI 1.44-5.01), and four times more likely to deteriorate in either trunk varicose veins or chronic venous insufficiency (OR=4.20, 95% CI 2.42-7.29). Subjects with venous reflux at baseline were twice as likely to develop new trunk varicose veins (OR=2.08, 95%CI 1.25-3.46), and 1.78 times more likely to develop either trunk varicose veins or chronic venous insufficiency (OR=1.78, 95%CI 1.12-2.80). Age and gender adjusted risk of trunk varicose veins increased more than fourfold among subjects with venous reflux in the greater saphenous veins (OR=4.04, 95% CI 2.36-6.92), and more than threefold in the greater saphenous vein (lower third of the thigh) (OR=3.13, 95% CI 1.85-5.27) and the small saphenous vein (OR=3.17, 95% CI 1.55-6.48). Subjects with venous reflux in two or more than three vein segments in the superficial system were more than five times more likely to deteriorate from trunk varicose veins (OR=5.39, 95% CI 2.64-10.99 and OR=5.96, 95% CI 2.71-13.10 respectively). The Edinburgh Vein Study follow-up identified factors linked to deterioration of trunk varicose veins and CVI. The findings of this follow-up study have important implications in decision making in NHS and a prognostic tool could be produced to assist clinicians in deciding who should receive treatment or maintained under surveillance. Increasing age, and family history will likely lead to worsening of trunk varicose veins and CVI. The findings also confirm the association between asymptomatic and symptomatic venous valvular incompetence with worsening and developing new cases of venous disease. Such information will be essential for policy makers facing difficult decisions over prioritisation of services in the future. Further research might include trials of surgical and non-surgical interventions designed to limit deterioration in high risk individuals and enable surgeons to target interventions appropriately. Larger prognostic studies of many factors, including genotype, might be conducted to link progression of venous disease, and to provide further information on high risk individuals who might benefit from treatment.

Chronic Venous Insufficiency (CVI) is characterized by chronic venous hypertension from blood pooling in the lower limbs. The resulting symptoms include leg pain, varicose veins, fatigue, venous edema, skin pigmentation, inflammation, induration, and ulceration. Reflux from incompetent venous valves is a factor in up to 94% of individuals with CVI. Current treatments of CVI include compression stockings, drug therapy, vein disabling, venous stenting, and surgical correction with varying rates of success. However, a minimally invasive correction of deep venous reflux does not currently exist. A transcatheter prosthetic venous valve has the potential to be an effective, minimally invasive treatment for deep venous reflux which could treat up to 1.4 million individuals in the United States suffering from venous ulceration and make more than 1.7 billion dollars each year. Previously developed prosthetic venous valves have had problems with competency, patency, thrombogenicity, biocompatibility, and incorrect sizing. To meet the clinical need a prosthetic valve needs to be developed which succeeds where previous valves have failed. This thesis describes the design, analysis, pre-clinical testing, and evaluation of a novel prosthetic venous valve. Design specifications for an effective prosthetic venous valve were created. Verification tests were developed and performed which demonstrated that the valve met every design specification. Finite element and computational fluid dynamics simulations were performed to analyze the valve and calculated a maximum shear rate of 2300 s-1 in the valve during the high forward flow after a Valsalva maneuver. The valve is made of a biocompatible material that has low thrombogenicity, Poly(vinyl-alcohol) cryogel. On the average, the valve allows less than 0.5 mL/min of reflux at low and high retrograde pressures even after 500,000 cycles, indicating that it will reduce the reflux of individuals with venous reflux by more than 99.4%. The valve closes in less than 0.07 seconds and allows the distal pressure to rise to an average of 7% of the equilibrium pressure 30 seconds after a simulated ankle flexion. The valve increases the outflow resistance an average of 2.3 mmHg*min/L which is much less than obstruction levels,≥ 5 mmHg*min/L. The valve can fit in a 16 French catheter and is capable of percutaneous delivery. The base of the valve is 1.5 times the diameter of the vein in which it is to be implanted to help correct orientation upon deployment. Fluid behind the valve’s leaflets is ejected with a forward flow rate of 400 mL/min, suggesting that thrombus formation will not occur at this location. A stented valve remained patent in a porcine blood flow loop for 3 hours. The valve remains competent without buckling in a constricted vein at rest. The valve can expand to fit a vein with a maximum diameter 1.4 times the valve's initial diameter with low risk of tearing or leaflet prolapse. An IACUC protocol for a 12 week study to test the valve in sheep was prepared and approved. A study to evaluate the valve in humans is proposed with endpoints that can be tested for statistical significance and compared with other treatments for CVI. A set of valves which will correct reflux in the majority of common femoral, femoral, and popliteal deep veins is proposed and a sizing guide for surgeons is provided. The minimum distance between prosthetic valves placed in the same vein segment is 13 cm. A comparison of this valve with previously developed prosthetic venous valves and recommendations for work to be performed in the future are given. The valve proposed in this work is the only valve to meet all design specification for an effective prosthetic venous valve, and therefore shows great potential to be a minimally invasive treatment for deep venous reflux.

Chronic venous disease (CVD) affects about 0.5 to 3.0% of the population. The venous ulcer (UV) is the most advanced stage of CVD and affects the patient-age, worsening their quality of life and burdens the welfare system. Venous reflux is related to the genesis, development and maintenance of UV. To evaluate venous reflux in patients with UV. A cross-sectional study was performed, observational Vascular Surgery Service at the Federal University of Sergipe - Aracaju-SE, in a sample of 162 patients with active UV divided into two groups for evaluation of reflux: G1 (primary etiology) and G2 ( etiopathogenesis secondary) seen consecutively in the period of 03 / 2009-10 / 2010. Five patients were excluded because they had chronic ischemia, because they have two non-recanalized vein thrombosis and one for being pregnant. We investigated the age, gender, distribution of venous reflux in the superficial venous system (SVS), the deep venous system (DVS) and perforating veins (PVs), location of reflux in the SVS, types of reflux in the saphenous vein (GSV ) and saphenous vein (VSP) and distribution of reflux in the DVS. Statistical method: the database and statistical analysis were performed using the SPSS 18.0. Quantitative variables were summarized as mean and standard deviation. Categorical variables were described by simple frequency and percentages with their respective confidence intervals for 95%. The mean age was 53.7 years with a predominance of women (79%). The distribution of reflux was observed that all patients in G1 had reflux in the SVS without reflux in the DVS, VPs with 92% in G2 and 83.3% had reflux in the SVS, with 100% DVS and 92.3% in the VPs. Regarding the location of reflux in the SVS group G1 showed reflux in 96% in GSV and 14% VSP and G2 showed reflux in GSV 70% and 13% in VSP. Considering the types of saphenous vein reflux in G1 90% of the type I had reflux in the GSV and 71.5% type IV in VSP in G2 while 84% of reflux in the GSV type I and type IV 85.7% in VSP. In Group G2 approximately 70% of patients had reflux in these veins of the legs and 54% in the popliteal veins. The superficial system reflux was present in all patients with primary venous insufficiency and in most patients with secondary failure. The finding most often found in the superficial venous system was the GSV reflux. The reflux in the GSV type I and type IV reflux in VSP findings were more often found in the superficial venous system of patients in both groups. Approximately 70% of deep venous reflux was located in the leg, the popliteal vein being the most frequently affected. / A doença venosa crônica (DVC) atinge cerca de 0,5 a 3,0% da população. A úlcera venosa (UV) é o estágio mais avançado da DVC e atinge o paciente em idade produtiva, piora a sua qualidade de vida e onera o sistema previdenciário. O refluxo venoso está relacionado com a gênese, desenvolvimento e manutenção da UV. Avaliar o refluxo venoso nos portadores de UV. Realizado estudo de corte transversal, observacional no Serviço de Cirurgia Vascular da Universidade Federal de Sergipe - Aracaju SE, em amostra de 162 pacientes com UV em atividade dividida em dois grupos para avaliação do refluxo: G1 (etiopatogenia primária) e G2 (etiopatogenia secundária) atendidos consecutivamente no período de 03/ 2009 a 10/ 2010. Foram excluídos cinco pacientes por apresentarem isquemia crônica, dois por apresentarem trombose venosa não recanalizada e um por estar gestante. Foram pesquisadas as variáveis idade, gênero, distribuição do refluxo venoso no sistema venoso superficial (SVS), no sistema venoso profundo (SVP) e em veias perfurantes (VPs); localização do refluxo no SVS; tipos de refluxo na veia safena magna (VSM) e em veia safena parva (VSP) e distribuição do refluxo no SVP. Método estatístico: o banco de dados e a análise estatística foram efetuados no programa SPSS 18.0. As variáveis quantitativas foram sumarizadas como média e desvio-padrão. As variáveis categóricas foram descritas mediante frequência simples e porcentagens com seus respectivos intervalos de confiança para 95%. A idade média foi de 53,7 anos com predomínio de mulheres (79%). Quanto a distribuição do refluxo observou-se que no G1 todos pacientes apresentaram refluxo no SVS, sem refluxo no SVP, com 92% em VPs e no grupo G2 83,3% tinham refluxo no SVS, com 100% no SVP e 92,3% VPs. Em relação a localização do refluxo no SVS do grupo G1 96% apresentaram refluxo em VSM e 14% em VSP e do G2 70% apresentaram refluxo em VSM e 13% em VSP. Considerando os tipos de refluxo em veias safenas no G1 90% apresentaram refluxo do tipo I em VSM e 71,5% do tipo IV em VSP enquanto que no G2 84% de refluxo do tipo I em VSM e 85,7% do tipo IV em VSP. No Grupo G2 aproximadamente 70% dos pacientes apresentaram refluxo em veias de pernas e destes 54% em veias poplíteas. O refluxo no sistema superficial esteve presente em todos os pacientes com insuficiência venosa primária e na maioria dos pacientes com insuficiência secundária. O achado mais frequentemente encontrado no SVS foi o refluxo VSM. O refluxo tipo I em VSM, bem como o refluxo tipo IV em VSP foram os achados mais frequentemente encontrados no SVS de pacientes dos dois grupos. Aproximadamente 70% do refluxo venoso profundo estava localizado na perna, sendo a veia poplítea a mais frequentemente acometida.

Indiana University-Purdue University Indianapolis (IUPUI) / The passive properties of the venous wall are important in the development of venous pathology. Increase in venous pressure due to retrograde flow (reflux) and obstruction of venous flow by intrinsic and extrinsic means are the two possible mechanisms for venous hypertension. Reflux is the prevailing theory in the etiology of venous insufficiency. The objective of this thesis is to quantify the passive biomechanical response and structural remodeling of veins subjected to chronic venous reflux and hypertension. To investigate the effects of venous reflux on venous mechanics, the tricuspid valve was injured chronically in canines by disrupting the chordae tendineae. The conventional inflation-extension protocol in conjunction with intravascular ultrasound (IVUS) was utilized to investigate the passive biomechanical response of both control common iliac veins (from 9 dogs) and common iliac veins subjected to chronic venous reflux and hypertension (from 9 dogs). The change in thickness and constituent composition as a result of chronic venous reflux and hypertension was quantified using multiphoton microscopy (MPM) and histological evaluation. Biomechanical results indicate that the veins stiffened and became less compliant when exposed to eight weeks of chronic venous reflux and hypertension. The mechanical stiffening was found to be a result of a significant increase in wall thickness (p < 0.05) and a significant increase in the collagen to elastin ratio (p < 0.05). After eight weeks of chronic reflux, the circumferential Cauchy stress significantly reduced (p < 0.05) due to wall thickening, but was not restored to control levels. This provided a useful model for development and further analysis of chronic venous insufficiency and assessment of possible intervention strategies.