Chung S. Lim

A study to compare disease-specific quality of life with clinical anatomical and hemodynamic assessments in patients with varicose veins

OBJECTIVE The wide variety of outcome measures to evaluate patients with varicose veins poses significant difficulties when comparing clinical trials. In addition, the relationship between different outcome measures is poorly understood. The aim of this study was to compare anatomical, hemodynamic, and clinical outcomes with disease-specific quality-of-life tools in patients undergoing treatment for varicose veins. METHODS Patients undergoing treatment for symptomatic veins in a single unit were studied. Assessments included duplex ultrasonography, digital photoplethysmography, evaluation of Venous Clinical Severity Scores and CEAP scores, generic (Short Form 12 [SF12]) and disease-specific (Aberdeen Varicose Vein Questionnaire [AVVQ], and Specific Quality-of-life and Outcome Response-Venous [SQOR-V]) questionnaires. Patients were reviewed at 6 weeks when hemodynamic, clinical, and quality-of-life assessments were repeated. The relationships between these outcomes were assessed. RESULTS The AVVQ showed a strong positive correlation with the SQOR-V (Spearman coefficient 0.702; P < .001) and weaker, but significant correlations with the SF12 physical and mental component scores and the Venous Clinical Severity Score (VCSS) (P < .001, P = .019, and P < .001, respectively, Spearman correlation). No correlations were observed between the AVVQ and photoplethysmography results (Spearman coefficient -0.042; P = .606), and weak correlations were observed with the AVVQ and anatomical reflux. At 6 weeks, functional, clinical, and hemodynamic measurements were all responsive to changes following interventions; however, correlations observed between changes in disease-specific quality-of-life and generic, clinical, and hemodynamic outcomes were weak. CONCLUSIONS Both the AVVQ and SQOR-V questionnaire are sensitive and responsive disease-specific questionnaires, which correlate with generic and clinical outcomes to some extent. Anatomical and hemodynamic measurements correlated poorly with functional outcomes both preoperatively and following interventions.

Prolonged Mechanical Stretch is Associated with Upregulation of Hypoxia-Inducible Factors and Reduced Contraction in Rat Inferior Vena Cava

BACKGROUND Decreased venous tone and vein wall dilation may contribute to varicose vein formation. We have shown that prolonged vein wall stretch is associated with upregulation of matrix metalloproteases (MMPs) and decreased contraction. Because hypoxia-inducible factors (HIFs) expression also increases with mechanical stretch, this study tested whether upregulation of HIFs is an intermediary mechanism linking prolonged vein wall stretch to the changes in MMP expression and venous contraction. METHODS Segments of rat inferior vena cava (IVC) were suspended in tissue bath under 0.5-g basal tension for 1 hour, and a control contraction to phenylephrine (PHE, 10(-5)M) and KCl (96 mM) was elicited. The veins were then exposed to prolonged 18 hours of tension at 0.5 g, 2 g, 2 g plus HIF inhibitor U0126 (10(-5)M), 17-[2-(dimethylamino)ethyl] amino-17-desmethoxygeldanamycin (17-DMAG, 10(-5)M), or echinomycin (10(-6)M), or 2 g plus dimethyloxallyl glycine (DMOG; 10(-4)M), a prolyl-hydroxylase inhibitor that stabilizes HIF. The fold-change in PHE and KCl contraction was compared with the control contraction at 0.5-g tension for 1 hour. Vein tissue homogenates were analyzed for HIF-1α, HIF-2α, MMP-2, and MMP-9 messenger RNA (mRNA) and protein amount using real-time reverse transcription polymerase chain reaction and Western blots. RESULTS Compared with control IVC contraction at 0.5-g tension for 1 hour, the PHE and KCl contraction after prolonged 0.5-g tension was 2.0 ± 0.35 and 1.1 ± 0.06, respectively. Vein contraction to PHE and KCl after prolonged 2-g tension was significantly reduced (0.87 ± 0.13 and 0.72 ± 0.05, respectively). PHE-induced contraction was restored in IVC exposed to prolonged 2-g tension plus the HIF inhibitor U0126 (1.38 ± 0.15) or echinomycin (1.99 ± 0.40). U0126 and echinomycin also restored KCl-induced contraction in IVC exposed to prolonged 2-g tension (1.14 ± 0.05 and 1.11 ± 0.15, respectively). Treatment with DMOG further reduced PHE- and KCl-induced contraction in veins subjected to prolonged 2-g tension (0.47 ± 0.06 and 0.57 ± 0.01, respectively). HIF-1α and HIF-2α mRNA were overexpressed in IVC exposed to prolonged 2-g tension, and the overexpression was reversed by U0126. The overexpression of HIF-1α and HIF-2α in stretched IVC was associated with increased MMP-2 and MMP-9 mRNA. The protein amount of HIF-1α, HIF-2α, MMP-2, and MMP-9 was also increased in IVC exposed to prolonged 2-g wall tension. CONCLUSIONS Prolonged increases in vein wall tension are associated with overexpression of HIF-1α and HIF-2α, increased MMP-2 and MMP-9 expression, and reduced venous contraction in rat IVC. Together with our report that MMP-2 and MMP-9 inhibit IVC contraction, the data suggest that increased vein wall tension induces HIF overexpression and causes an increase in MMP expression and reduction of venous contraction, leading to progressive venous dilation and varicose vein formation.

Pain Following 980-nm Endovenous Laser Ablation and Segmental Radiofrequency Ablation for Varicose Veins: A Prospective Observational Study:

Objectives: The aim of this study was to evaluate postoperative pain following endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) and identify risk factors for increased pain. Methods: Patients undergoing either segmental RFA (VNUS Closure Fast TM, VNUS Medical Technologies, San Jose, California) or EVLA (980 nm) for varicose veins completed a preoperative disease-specific quality-of-life questionnaire (Aberdeen Varicose Vein Questionnaire [AVVQ]) and a diary card recording postoperative pain, return to normal activities, and return to work. Median 3- and 10-day pain scores were calculated. Results: In all, 81 patients returned diary cards (RFA = 45, EVLA = 36). Patients receiving RFA reported less postoperative pain than those receiving EVLA at 3 days (14.5 vs 25.8 mm, P = .053, Mann-Whitney U test) and 10 days (13 vs 23.3 mm, P = .014, Mann-Whitney U test) and returned to work earlier than those receiving EVLA (median 5 vs 9 days, P = .022). Conclusions: Patients treated with segmental RFA had less postoperative pain and returned to work quicker than those treated with EVLA.

Intra-procedural pain score in a randomised controlled trial comparing mechanochemical ablation to radiofrequency ablation: The Multicentre Venefit™ versus ClariVein® for varicose veins trial

Objective Endovenous techniques are, at present, the recommended choice for truncal vein treatment. However, the thermal techniques require tumescent anaesthesia, which can be uncomfortable during administration. Non-tumescent, non-thermal techniques would, therefore, have potential benefits. This randomised controlled trial is being carried out to compare the degree of pain that patients experience while receiving mechanochemical ablation or radiofrequency ablation. The early results of this randomised controlled trial are reported here. Methods Patients attending for the treatment of primary varicose veins were randomised to receive mechanochemical ablation (ClariVein®) or radiofrequency ablation (Covidien® Venefit™). The most symptomatic limb was randomised. The primary outcome measure was intra-procedural pain using a validated visual analogue scale. The secondary outcome measures were change in quality of life and clinical scores, time to return to normal activities and work as well as the occlusion rate. Results One-hundred and nineteen patients have been randomised (60 in the mechanochemical ablation group). Baseline characteristics were similar. Maximum pain score was significantly lower in the mechanochemical ablation group (19.3 mm, standard deviation ±19 mm) compared to the radiofrequency ablation group (34.5 mm ± 23 mm; p < 0.001). Average pain score was also significantly lower in the mechanochemical ablation group (13.4 mm ± 16 mm) compared to the radiofrequency ablation group (24.4 mm ± 18 mm; p = 0.001). Sixty-six percent attended follow-up at one month, and the complete or proximal occlusion rates were 92% for both groups. At one month, the clinical and quality of life scores for both groups had similar improvements. Conclusion Early results show that the mechanochemical ablation is less painful than the radiofrequency ablation procedure. Clinical and quality of life scores were similarly improved at one month. The long-term data including occlusion rates at six months and quality of life scores are being collected.

Hypoxia-Inducible Factor-1 in Arterial Disease: A Putative Therapeutic Target

Hypoxia-inducible factor-1 (HIF-1) is a nuclear transcription factor that is upregulated in hypoxia and co-ordinates the adaptive response to hypoxia by driving the expression of over 100 genes. In facilitating tissues to adapt to hypoxia, HIF-1 may have a role in reducing the cellular damage induced by ischaemia, such as that seen in peripheral arterial disease (PAD), or following acute ischaemic insults such as stroke and myocardial infarction. This therefore raises the possibility of HIF-1 modulation in such contexts to reduce the consequences of ischaemic injury. HIF1 has further been implicated in the pathogenesis of atherosclerosis, abdominal aortic aneurysm (AAA) formation, pulmonary hypertension and systemic hypertension associated with obstructive sleep apnoea. Through a better understanding of the role of HIF-1 in these disease processes, novel treatments which target HIF-1 pathway may be considered. This review summarises the role of HIF-1 in arterial disease, specifically its role in atherosclerosis, ischaemic heart disease, in-stent restenosis following coronary revascularisation, stroke, PAD, AAA formation, pulmonary artery hypertension and systemic hypertension. The potential for exploiting the HIF-1 signalling pathway in developing therapeutics for these conditions is discussed, including progress made so far, with attention given to studies looking into the use of prolyl-hydroxylase inhibitors.

The treatment of varicose veins: an investigation of patient preferences and expectations

Objectives A number of modalities are now available for the treatment of varicose veins. The aim of the study was to investigate the factors considered important by patients when contemplating treatment of their varicose veins. Methods Consecutive new patients referred to a vascular surgery service were invited to complete a short anonymous questionnaire prior to their consultation. The questionnaire consisted of 13 multiple choice questions relating to symptoms, potential varicose vein treatments and patient knowledge of existing therapies. Results Of 111 patients, there were 83 complete responses (75%). Symptoms of pain or aching were reported as moderate or severe by 77/103 (75%) of patients and significantly limited the activities of 47/101 (47%). Although the majority (89/103 [86%]) of patients were aware of surgery, only 52/103 (51%) knew of the existence of endothermal ablation (either laser or radiofrequency) and only 23/103 (22%) were aware of foam sclerotherapy. Some 58/92 (63%) were in favour of local anaesthetic treatment. Most patients (74/103, 72%) felt inadequately informed to express a preference regarding treatment type prior to their consultation, although 24/103 (23%) expressed a preference for endovenous treatment. Interestingly, 74/92 (80%) stated that the opinion of their vascular surgeon would be likely to or definitely influence their treatment decision and the majority of patients stated that what they had read in magazines (54/80, 64%) or on the Internet (51/85, 60%) would have no influence on their decision regarding treatment, respectively. Conclusion Only a minority of patients referred with varicose veins were aware of endovenous treatments or felt adequately informed to express a treatment preference prior to consultation. Over half of patients expressed a preference for local anaesthetic therapy and a preference for a single visit treatment, although most would be strongly influenced by the opinion of their vascular surgeon and not influenced by media advertising.

Increased activation of the hypoxia-inducible factor pathway in varicose veins

BACKGROUND Venous hypoxia has been postulated to contribute to varicose vein (VV) formation. Direct measurements of vein wall oxygen tension have previously demonstrated that the average minimum oxygen tensions were significantly lower in VVs compared with non-varicose veins (NVVs). Hypoxia-inducible factors (HIFs) are nuclear transcriptional factors that regulate the expression of several genes of oxygen homeostasis. This study aimed to investigate if hypoxia was associated with VVs by assessing the expression of HIF-1α, HIF-2α, HIF target genes, and upstream HIF regulatory enzymes in VVs and NVVs, and their regulation by hypoxia. METHODS VVs and NVVs were surgically retrieved and immediately snap-frozen or used for organ culture preparation. The relative expression of HIF-1α, HIF-2α, HIF target genes, and HIF regulatory enzymes in VVs and NVVs was analyzed with quantitative polymerase chain reaction (Q-PCR) and Western blot. VV and NVV organ ex vivo cultures were exposed to 16 hours of normoxia, hypoxia (oxygen tension 1%), or the hypoxia mimetic dimethyloxallyl glycine (DMOG) 1 mM in normoxia. The vein organ cultures were then analyzed for HIF-1α, HIF-2α, and their target gene expression with Q-PCR and Western blot. RESULTS HIF-1α and HIF-2α mRNA were significantly upregulated in VVs compared with NVVs (89.8 ± 18.6 vs 10.4 ± 7.2 and 384.9 ± 209.4 vs 8.1 ± 4.2, respectively). HIF target gene mRNA expression was also significantly elevated in VVs compared with NVVs, namely glucose transporter-1 (GLUT-1; 8.7 ± 2.1 vs 1.0 ± 0.3), carbonic anhydrase-9 (CA9; 8.5 ± 2.1 vs 2.8 ± 1.2), vascular endothelial growth factor (VEGF; 7.5 ± 2.1 vs 0.9 ± 0.2), and BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP-3; 4.5 ± 0.7 vs 1.4 ± 0.3). The upregulation of HIF-1α, HIF-2α, and HIF target genes in VVs was also reflected at protein level. Of the HIF regulatory enzymes, the expression of prolyl-hydroxylase domain (PHD)-2 and PHD-3 was found to be elevated in VVs compared with NVVs. Exposure of VV and NVV organ cultures to hypoxia or DMOG was associated with increases in HIF-1α and HIF-2α protein and HIF target gene expression compared with normoxia only. CONCLUSIONS The study concluded, we believe for the first time, an increased activation of the HIF pathway, with upregulation of the expression of HIF-1α and HIF-2α transcription factors, and HIF target genes, in VVs compared with NVVs. Exposure of VVs and NVVs to hypoxic conditions was associated with increased expression of HIF-1α and HIF-2α protein and HIF target genes. The data suggest that the HIF pathway may be associated with several pathophysiologic changes in the VV wall, and that hypoxia may be a feature contributing to VV pathogenesis.

A Review of Familial, Genetic, and Congenital Aspects of Primary Varicose Vein Disease

Varicose veins are a common manifestation of chronic venous disease (CVD) and present as excessively dilated, tortuous, and elongated superficial veins in the lower limbs. Varicose veins arise either secondary to vein wall remodeling or valvular incompetence leading to blood stasis and venous hypertension.1 Patients may experience lower limb pain, muscle cramps, bleeding, swelling, and skin changes, which include lipodermatosclerosis and eventual ulceration.2 To date, no specific cause for the development of varicose veins has been identified. However, various genetic and environmental risk factors have been ascribed to their formation. Primary varicose veins have been shown to affect up to one third of the Western adult population and are a major cause of morbidity. Estimates of prevalence range from 2% to 56% in men and 1% to 60% in women.3,4 This inconsistency between reports may be due to heterogeneity of study populations, study designs, and experimental methodologies used as well as actual variations in the general population. Some reports suggest that varicose veins are more common in women than men,5–8 whereas others have shown the opposite.2,3,9,10 A cross-sectional survey in Edinburgh, UK, involving a total of 1566 patients, showed an age-adjusted prevalence of Grade 1 truncal varices in 33.3% of men compared with 26.2% of women.10 It has also been reported that there is a significant correlation between CVD onset and sex with females showing first symptoms at a mean age of 30.8 years and males at 36.8 years.8 Besides sex, the prevalence of varicose veins increases with age. The Edinburgh Vein Study reported the prevalence of varicose veins increases from 11.5% in 18 to 24 year olds age to 55.7% in 55 to 64 year olds.10 Similarly, other studies have reported …

A multi-centre randomised controlled trial comparing radiofrequency and mechanical occlusion chemically assisted ablation of varicose veins – Final results of the Venefit versus Clarivein for varicose veins trial:

Background Endovenous thermal ablation has revolutionised varicose vein treatment. New non-thermal techniques such as mechanical occlusion chemically assisted endovenous ablation (MOCA) allow treatment of entire trunks with single anaesthetic injections. Previous non-randomised work has shown reduced pain post-operatively with MOCA. This study presents a multi-centre randomised controlled trial assessing the difference in pain during truncal ablation using MOCA and radiofrequency endovenous ablation (RFA) with six months’ follow-up. Methods Patients undergoing local anaesthetic endovenous ablation for primary varicose veins were randomised to either MOCA or RFA. Pain scores using Visual Analogue Scale and number scale (0–10) during truncal ablation were recorded. Adjunctive procedures were completed subsequently. Pain after phlebectomy was not assessed. Patients were reviewed at one and six months with clinical scores, quality of life scores and duplex ultrasound assessment of the treated leg. Results A total of 170 patients were recruited over a 21-month period from 240 screened. Patients in the MOCA group experienced significantly less maximum pain during the procedure by Visual Analogue Scale (MOCA median 15 mm (interquartile range 7–36 mm) versus RFA 34 mm (interquartile range 16–53 mm), p = 0.003) and number scale (MOCA median 3 (interquartile range 1–5) versus RFA 4 mm (interquartile range 3–6.5), p = 0.002). ‘Average’ pain scores were also significantly less in the MOCA group; 74% underwent simultaneous phlebectomy. Occlusion rates, clinical severity scores, disease specific and generic quality of life scores were similar between groups at one and six months. There were two deep vein thromboses, one in each group. Conclusion Pain secondary to truncal ablation is less painful with MOCA than RFA with similar short-term technical, quality of life and safety outcomes.

A study of patient satisfaction following endothermal ablation for varicose veins.

Objective: To evaluate patient satisfaction following endothermal ablation for varicose veins (VVs). Methods: A 12-question survey was sent to consecutive patients treated with endothermal ablation—questions related to preprocedure symptoms, recurrence, further treatments, and patient satisfaction. Results: Questionnaires sent a median 12 (range 6-22) months postintervention were returned by 177 (60.0%) of 295 patients; 63 (35.6%) of 177 received treatment for recurrent VVs. Preintervention symptoms included aching (141 [79.7%] of 177), swelling (86 [48.6%] of 177), and heaviness (72 [40.7%] of 177). Improvements in preoperative symptoms were reported by 82.5% (146 of 177). Postintervention recurrence was reported by 87 (49.4%) of 177; 61 (70.1%) of 87 reported a few recurrent varicosities only. Further treatment was required by 11 (6.2%) of 177; 79 (44.6%) of 177 of patients reported no complications. The majority (151 [85.8%] of 176) were satisfied with their treatment. In all, 16 (25.4%) of 62 of patients treated for recurrent VVs were dissatisfied versus 9 (7.9%) of 114 of those with primary VVs (P = .0026). Conclusions: The majority of patients are satisfied with results following endothermal ablation. Dissatisfaction may be more likely following treatment for recurrent VVs.