Angiology

Many contributing factors are involved in the genesis of varicose disease of the lower limbs such as age, sex, heredity, sedentary life style among others. For physicians the decisive role played by heredity leaves no doubt. Few studies have, however, attempted to prove the impor tance of the hereditary factor on a clinical level, and no study has been conducted in molecular genetics. The impact of the hereditary factor is variably estimated and its nature is open to discussion. Despite the numerous limits of the research focusing on the hereditary aspect of varicose disease, the authors can nevertheless claim that the genetic factor definitively exists and has a great impact. There are few studies conducted among twins. The data collected in these studies point to the reality of various types of heredity. With the predominant impact of the hereditary factor, and despite the role played by environmental factors, it can be supposed that a single genetic anomaly may be the determining factor of the disease in a given family. Thus we have conducted an original study in order to identify one or several mutations predis posing to varicose disease, based on the approach called "reverse genetic" and linkage study. The study of a first family whose varicose disease segregates in an autosomal dominant manner allowed us to identify 3 potential loci, if we accept the hypothesis of 2 or 3 pheno copies. No candidate gene has been singled out in these regions in the first analysis. The study of a second family whose phenotype of the varicose disease is particularly homogeneous and segregates in an autosomal dominant manner did not confirm any of the previously identified loci, probably related to a genetic heterogeneity of the varicose disease. As a consequence, the second part of this study was devoted to determining the complete genotype of each indi vidual within this family, in order to identify new loci of interest. A potential locus has just been identified. The third part of this research, currently being pursued, is devoted to the sequencing of potential genes. In parallel, the analysis of new large families is underway. The presentation will include an update on the hereditary and genetic aspects of varicose disease, and secondly identify the limits and difficulties of the genetic study of the families.

Varicose vein disease is a common condition. Its pathology is not well characterized. A disor ganization of smooth muscle cells and extracellular matrix components in the venous wall have been described. The objective of this paper is to offer an explanation for the abnormal distensibility of varicose veins. The content of hydroxyproline was quantified in control and varicose human saphenous veins. The synthesis of collagen types I, III, and V was quantified in cultured venous smooth muscle cells and dermal fibroblasts of control subjects and patients with varicose veins. The proportion of collagen type III in the heterofibrils composed by collagen types I, III, and V was calculated. The level of hydroxyproline was increased in varicose veins, suggesting an increased content of collagen. This augmentation of collagen in diseased tissues appears to be correlated with an increase of collagen type I since the collagen I mRNA was overexpressed in varicose veins, whereas collagen type III mRNA was not altered. The quan tification of collagen synthesis in cultured cells shows that proportion of collagen type III was significantly decreased in cultured smooth muscle cells and dermal fibroblasts derived from patients with varicose veins. The results indicate a deficiency in collagen type III in patients with varicose veins. Since collagen type III is involved in tissue elasticity, these results offer an explanation for the abnormal distensibility of varicose veins. Moreover, this defect seems to be generalized in different tissues and argues in favor of a genetic alteration of remodeling in these patients.

The present article focuses on the prevalence and risk factors for varicose veins and the severe stage of chronic venous insufficiency (CVI). The evaluation was made by reviewing the results of specific well-designed studies performed on the general population (case-control studies, cross-sectional studies, and large case series). Data from the literature were compared with the results of a recent multicenter cross-sectional study in Poland, in which 40,095 indi viduals from 803 registers of primary care physicians were clinically examined and assigned a clinical CEAP class. Analysis of the associations between varicose veins or severe CVI preva lence and factors that are usually considered as representing a risk for the development of CVI was performed. In Poland, a prevalence of varicose veins and severe CVI (skin changes, leg ulcer) similar to that observed in the other developed countries was reported. It was more common in women, but female sex was not found to be a strong risk factor. Among the risk factors most closely associated with CVI were age, family history of varicose veins, and consti pation, whatever the sex. This is in keeping with findings from recent epidemiologic studies. Obesity and lack of physical activity were strongly associated with CVI in women, more so than in men. The number of pregnancies (more than 2 pregnancies) significantly distinguished between women with and without CVI. Regarding these latter risk factors, the Polish results do not contradict the commonly held beliefs that are found in the literature. A modest asso ciation was found with female sex, previous injury in legs (DVT), and remaining in the standing position for a long time, although these parameters are usually among those mostly agreed as being risk factors. The role of the prolonged sitting position was not established. The Polish epidemiologic survey provided updated figures on the prevalence of and risk factors for varicose veins and severe CVI, using clear and globally accepted clinical definitions for the venous disease based on the CEAP classification.

This article reviews the mechanisms by which micronized purified flavonoid fraction (MPFF; Daflon 500 mg) acts on symptoms as well as on edema in patients with chronic venous disease, in the light of new advances in the understanding of the pathophysiology of this chronic condition. Deterioration of venous wall tone followed by valve dysfunction leading eventually to varicose veins are the key pathophysiologic features that produce venous hyper tension. Both mechanical and biological factors are responsible for the deterioration of the venous wall in large veins. These are decreased shear stress and hypoxia of the media and of the endothelium, which act as triggering factors for biochemical reactions leading to inflam mation. There is a body of evidence that inflammation in chronic venous insufficiency (CVI) plays a role right from the early stages of venous dysfunction and venous valve restructuring. The whole process of venous wall stretching and dilation is painful and may present as leg heaviness, a sensation of swelling, and paresthesia. Daflon 500 mg relieves symptoms, edema, and red blood cell aggregation, which cause paresthesia and restless legs. At the level of the microcirculation, dysfunction of microvessels is observed, characterized by an increase in capillary permeability followed by skin changes. The earliest manifestation of microcirculatory disorder is edema. At this level, Daflon 500 mg acts favorably on microcirculatory complica tions by normalizing the synthesis of prostaglandins and free radicals. It decreases bradykinin- induced microvascular leakage and inhibits leukocyte activation, trapping, and migration. Its efficacy in decreasing CVI edema and ankle swelling has been proven in rigorous studies that are reviewed in this paper. Daflon 500 mg, a well-established oral flavonoid that consists of 90% micronized diosmin and 10% flavonoids expressed as hesperidin, may be prescribed from the very beginning of the disease for the relief of pain and edema, and in any CVI patient presenting with symptoms as well. Daflon 500 mg is thus the first-line treatment for edema and symptoms of CVI at any stage of the disease. At advanced disease stages, Daflon 500 mg may be used in conjunction with sclerotherapy, surgery, and/or compression therapy or as an alternative treatment when other treatments are not indicated or not feasible.

The standard treatments for venous diseases of the lower limb include compression bandaging and stockings as well as surgical removal of varicose veins. There are a number of conditions in which these conventional treatments are ineffective, particularly in the management of leg ulceration. Drug treatments for healing venous leg ulcers have yet to be developed to the stage of good clinical efficacy, but these may assist in the management of patients. Flavonoid drugs have been widely used in the management of the symptoms of venous disease for many years and have recently been studied in some detail to assess their effects on the microcir culation. Work in animal models of ischemia-reperfusion show that MPFF (micronized purified flavonoid fraction) modulates leukocyte adhesion and prevents endothelial damage. Similar biochemical effects have been observed in patients with venous disease and may explain the efficacy of this drug in the management of edema and other symptoms of venous disease. There is clinical evidence that MPFF modifies venous leg ulcer healing.