III – PATHOPHYSIOLOGY
JM. Romero-Carro (Spain)
Chronic venous insufficiency (CVI) is an extremely common disease with a multifactorial and complex basis, where the interaction between genetic and environmental factors creates a predisposition to disease development and progression. Despite the high prevalence of CVI, the hereditary component is still unknown. The purpose of this study was to quantify the genetic basis (heritability) of CVI and its relationship to other clinically important thromboembolic diseases.
895 individuals in 35 extended families were enrolled in the Genetic Analysis of Idiopathic Thrombophilia (GAIT). After history taking and clinical examination, blood samples were collected for phenotypic and genetic analysis of DNA & mRNA
52 individuals had CVI using the CEAP classification (CEAP C2-C6). Although 13 of them were classified as C0-C1, they were considered as patients with CVI because they had undergone surgery for varicose veins. 843 showed no CVI (CEAP C0-C1).
The heritability (h2: the relative proportion of the phenotypic variation that is attributable to additive genetic effects) of the trait studied (CVI) and correlation with other clinical parameters were estimated using maximum likelihood methods based on variant component analyses.
The study estimates that 97% of the variation in susceptibility to CVI is attributable to genetic factors (h2: 0.97, P=3.6×10-11). The study shows that the risk of developing CVI has a significant genetic correlation (0.72, P=0.01) with venous thrombosis, indicating that genes that influence susceptibility to CVI also influence the risk of venous thrombosis.
This study formally documents the high-risk genetic component of CVI, based on analysis of data in methodically recruited extended families, and allows conclusions to be drawn regarding the general population. Therefore, the high heritability of the risk of CVI justifies the search for genetic factors predisposing to this disease and shows a common genetic basis between CVI and thromboembolic disease.
Chairpersons: A. Scuderi, J. Strejcek
E. Rabe (Germany)
There has been little focus on the prevalence of symptoms in most epidemiological studies of primary chronic venous disease (PCVD). We must wait for more recent investigations, most of which have used the CEAP classification, to have some idea of the prevalence of symptomatic patients. However, these data remain elusive. Only the VEIN CONSULT Program, carried out under the auspices of the UIP, details the prevalence of symptoms and their association with the signs of PCVD. The prevalence of C0s, En, An, Pn patients, that is to say patients presenting with symptoms without any visible clinical signs and without reflux, is not well known, for the simple reason that this patient group is not considered as having PCVD. The VEIN CONSULT Program, set up by the UIP in 20 countries from 4 continents, shows that the prevalence of the C0s group was 20%. However, it would be interesting to know if these purely symptomatic patients progress to more severe stages of disease, and if their presenting symptoms are predictive of PCVD. The proportion of C0s patients can sometimes be found or calculated indirectly from existing studies: it varies from 4% to 20%,(1-4) a prevalence that should not be neglected.
In the VEIN CONSULT Program, the prevalence of symptoms, and in particular of heaviness and pain, increased with CVD severity. In summary, all patients, whatever the stage of their PCVD can be symptomatic. This observation is in agreement with previous findings in the literature (5).
In the literature, venous symptoms were found to be not always present (6), to be independent of trunk varices (6) or telangiectasias,(7) and to have little association with inflammatory mediators (8). In particular, venous pain varies according to sex (1,9), and according to geographical area. In the VEIN CONSULT Program, pain is more often reported in the Far and Middle East than in the other continents, even though the proportion of men there is higher than elsewhere. Latin America was in second position for the frequency of pain, and then Europe. Venous pain is difficult to define, which explains the variations in the wording used. Quality of life is greatly impaired by PCVD, more particularly when patients are symptomatic. In patients in relatively early stages of CVD (C0s to C4), an increase in pain intensity of 1 cm on a VAS was correlated with a loss of quality of life of 2.4 cm on CIVIQ (10). In patients with venous leg ulcers, pain was nearly always present and its effect on quality of life was felt as strongly as impairment in the case of heart failure (11). Although pain appears very early in CVD progression, there are few data on its predictive value for complications of the disease. In the Bonn Vein Study II, the symptom ‘sensation of swelling’ was found to be predictive of the development of venous insufficiency (C3-C6).
N. Danziger (France)
Pain is the chief complaint that leads to the diagnosis of venous disease and has a significant impact on patients’ quality of life. But for the clinician as well as the researcher, pain in venous disease is difficult to assess, both because of its multifaceted nature and due to the absence of a close relationship between pain as a symptom and the severity of venous disease.(12) Current hypotheses on the mechanisms of pain in venous disease emphasize a local inflammatory origin. However, although indicators suggesting an inflammatory reaction in varicose veins have accumulated dramatically over the last five years, the precise mechanisms governing the interaction between the mediators of inflammation and venous nociceptors, which may account for the variability of pain in venous disease, remain difficult to explain, both clinically and experimentally.(13)
Data obtained by electron microscopy show that veins are innervated by sensory nerve fibers whose cell body is located in the dorsal root ganglia of the spinal cord. These sensory fibers are located along the venous wall and are subdivided into collaterals, which have two possible destinations. Some collaterals cross the tunica adventitia and end in the venous wall between endothelial cells and smooth muscle cells of the tunica media. Other collaterals reach the connective tissue of the perivenous space where they branch into unmyelinated free nerve endings, in close contact with the microcirculation.
These subendothelial and perivascular nerve endings are nociceptors: they are the sole source for transmission of nociceptive afferent signals generated both in the venous wall itself and also in the perivenous connective tissue. The properties of venous and perivenous nociceptors account for the type of stimuli that can generate a painful sensation of venous origin. It is most likely that venous nociceptors are activated by inflammatory mediators in both the micro- and macrocirculation. The nociceptive response in venous disease is the same as in any visceral disease: venous pain is diffuse, difficult to describe, is felt by patients as unpleasant, and has a negative impact on quality of life. In addition, venous pain is not always associated with signs. For these reasons, such pain is underestimated and even denied by health care providers.
E. Bouskela (Brazil)
In the experiment on the effect of MPFF at a dose of 500 mg on microcirculatory and inflammatory parameters, women were investigated using the orthogonal polarization spectral technique (noninvasive method), and measurements of functional capillary density (FCD, number of capillaries with flowing red blood cells/mm2), capillary morphology (CM, % of abnormal capillaries/mm2), and diameters (μm) of dermal papilla (DDP), capillary bulk (DCB) and capillary limb (CD) were determined in the medial perimalleolar region and later analyzed using CapImage software. Included were women with regular menstrual cycles, and suffering from PCVD class C2 to C4. The double-blind, placebo-controlled trial included 100 patients in each group: a treatment group with MPFF at a dose of 500 mg, 2 tablets a day for 4 consecutive cycles, and a placebo group. The female patients were young, 34 to 39 years old on average. This is explained by the recruitment of nonmenopausal women, undertaken to avoid any effects of hormonal cycles on the microcirculation. The young age of the patients can also explain the relatively low BMI, as well as the mild symptoms (low VAS and VCSS scores). The majority had complained of pain and other symptoms for at least 13 years and had reported signs of venous disorders for at least 9 years.
In the control group, the mean diameter of capillary bulk (DCB) and diameter of dermal papilla (DDP) increased with CEAP class in the study population, reflecting the morphological changes and increased capillary leaks that lead to edema. The capillary diameter (CD) remained, but the number of functional capillaries (FCD) decreased uniformly with increasing CEAP class, indicating a loss in terms of capillary number and function.
In the MPFF at a dose of 500 mg group, a tendency to reduce DCB and DDP compared with placebo was shown, mainly in patients over 40 years of age or in overweight C2 and C3 patients, indicating a possible protective effect of MPFF at a dose of 500 mg against the morphologic changes occurring in the capillaries and an ability to prevent capillary leaks. In C3 patients with a BMI <26, there was a tendency for a reduction in capillary diameter (CD), and in C1 patients for a maintenance in the number of functioning capillaries (FCD), indicating an effect of MPFF at a dose of 500 mg on capillary number and function. In terms of the biochemical parameters, MPFF at a dose of 500 mg significantly reduced PAI- 1 in C2 to C4 patients, suggesting it has a fibrinolytic effect, which would avoid the fibrin deposits characteristic of the complications of CVD. The tendency for a reduction in some selectins (in particular sP- and sL-selectins), which are proteins implicated in venous inflammation, was noted with MPFF at a dose of 500 mg in patients with trophic skin changes (C4). The same was observed for MMP-9 in C3 patients, implying that MPFF at a dose of 500 mg limits venous remodeling and morphologic changes in the capillaries. As for the angiopoietins, the level of Ang-2 slightly decreased with MPFF at a dose of 500 mg while that of Ang-1 was increased, suggesting a protective effect of MPFF at a dose of 500 mg on the endothelial capillary wall. It can be assumed that the protective effect of MPFF at a dose of 500 mg against the morphologic changes occurring in the capillaries will maintain their functioning and avoid plasma leaks, throughout the progression of CVD. Less plasma leakage means less subcutaneous edema and, indirectly, less pain. The reduction of some biomarkers with MPFF at a dose of 500 mg suggests it may have a protective effect on endothelial structures and the microcirculation, both of which are subject to inflammation during disease progression. With fewer inflammatory mediators circulating during MPFF at a dose of 500 mg treatment, there will be fewer nociceptive messages and perhaps less pain.
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(2) Rabe E. et al. Phlebologie 2003;32:1-14
(3) Jawien A. et al. Phlebology 2003;18:110-122
(4) Langer et al. Arch Int Med 2005;165:1420-1424
(5) Carpentier et al. J Vasc Surg 2003;37:827-833
(6) Evans et al. J Vasc Surg 1998;28:767-776
(7) Ruckley et al. Eur J Vasc Endovasc Surg 2008;36:719-724
(8) Howlader et al. J Vasc Surg 2003;38:950-954
(9) Isaacs MN. Dermatol Surg. 1995;21:321-323
(10) Perrin M. Medicographia 2006;28:146-152
(11) Andreozzi GM. et al. Int Angiol 2005;24:272-277
(12) Danziger N. J Mal Vasc 2007; 32:1-7
(13) Strigo IA. et al. Pain 97 2002;235-246
E. Bouskela (Brazil)
The authors tested the effect of MPFF at a dose of 500 mg on perivascular inflammation after sclerotherapy in an experimental model of rabbit ear vein. 48 rabbits were given MPFF at a dose of 500 mg (in an adequate dose) or placebo (lactose solution). The therapy started 7 days before sclerotherapy and lasted 30 days. Several parameters were measured with the help of intravital microscopy: arterial and venous diameter, functional capillary density (ie, the number of capillaries with flowing red blood cells per cm2; this parameter is a good indicator of skin nourishment), leukocyte adhesion (leukocyte considered adherent if it sticks to the endothelium for more than 20 seconds), macromolecular permeability. Histology was also evaluated. In the MPFF group, the authors observed a significant decrease in macromolecular permeability and leukocyte adhesion as well as better preserved functional capillary density in comparison with controls. The efficacy in the reduction of inflammation and endothelial permeability by MPFF at a dose of 500 mg in an animal experimental model and may therefore improve the results of sclerotherapy by limiting its side effects. The results should be confirmed in humans.
