Angiology

Lymph drainage is intimately linked with venous drainage in health and disease. Evidence exists to support the view that lymphatics frequently fail in venous disease, particularly in its advanced stages. The implications of this are to increase the risk of infection and the amount of edema, events which can only further the morbidity of venous disease.

Various techniques may be used to assess leg edema. The value of these investigations has been discussed in depth in the consensus statement made in Vaux de Cernay in 1997 and supported by Servier Research Group.

These techniques can be classified into three groups:

• The most simple is leg circumference measurement, which can be assessed by a tape measure, or more rigorously with a Leg-O-Meter. This device is a cheap and repro ducible method that has been validated and that takes into account the height at which the circumference has been measured. However, circumference measurement is not always correlated with leg (including foot) volume measurement.

• The second group of techniques assess leg volume. The most simple method is water displacement volumetry, which has been validated in terms of reproducibility. Several other devices have been used: optoelectronic methods, computed tomography, magnetic resonance imaging (high resolution), dual X-ray absorptiometry. These methods are expensive and not all of them have been validated, but these might be the future investigations of choice. (continued on next page)

• Some other investigations assess immediate variations in volume such as water displacement using dynamic foot volumetry, rheoplethysmography, strain gauge plethysmography, and air plethysmography. The assessment made by these methods (using postural, dynamic, or compressive maneuvers) is more an assessment of the venomuscular pump and/or venous outflow than volume assessment.

In conclusion, edema, an early and frequent sign of chronic venous insufficiency (CVI), can be precisely measured by several methods. This measurement can be considered one of the most objective ways of assessing treatment efficacy in CVI-associated edema.

An International Task Force made up of a panel of 16 experts has reviewed and objec tively evaluated all aspects of chronic venous disease of the leg (CVDL). All available publications on CVDL from 1983 to 1997 were identified through computerized search in Medline and by a manual search. Next, three different screenings were performed in order to select only relevant papers providing a level of scientific evidence that was considered moderate to strong. Final conclusions and further therapeutic recommenda tions were made based on these publications. Medication, compression, local therapy, sclerotherapy, and surgery are the accepted available therapeutic options for CVDL. For edema, the following recommendations can be made: edema is an early sign of CVDL, but before starting any treatment, nonvenous causes of edema should be excluded. Medication and compression are the therapeutic options for edema that are accepted by the Task Force. Evaluation of their efficacy is based on objective measures of edema. Several well-conducted, placebo-controlled trials have shown efficacy of drugs such as micronized purified flavonoid fraction, rutosides, calcium dobesilate, and coumarin rutin. Graduated compression stockings have been shown to be effective; compression needs to be exerted at least at 35 mm Hg. Bandages, if properly applied, both fixed and stretched, can produce favorable results. Sclerotherapy or surgery is not indicated unless there is saphenofemoral or saphenopopliteal reflux. In the absence of such reflux or following deep venous thrombosis, there is no evidence to support scle rotherapy or surgery.

Several phlebotropic drugs, or edema-protecting drugs, are available, the most important of which are found in the γ-benzopyrone family (flavonoids). γ-Benzopyrones can be plant extracts, semisynthetic preparations, or synthetic preparations. This family is divided into two different groups: flavones and flavonols, and flavanes (flavanones). The flavone group contains various types of molecule and includes diosmin. Here we discuss the pharmacologic aspects in edema associated with chronic venous insufficiency (CVI) of one of the reference phlebotropic drugs, micronized purified flavonoid fraction (MPFF*), a semisynthetic preparation from the diosmin group, which represents the latest improvement in flavonoid formulation. Before we detail the pharmacologic aspects, a brief summary of the pathophysiology of edema in CVI is necessary. Several factors are implicated: the veins, which create the conditions favorable to edema; the microcir culation, which is the site of fluid transfer into the interstitial tissue; and the lymphatics, which have a limited possibility to reduce edema. Major discoveries are currently being made in CVI and the microcirculation. Results of studies show that MPFF decreases capillary permeability and increases capillary resistance, which could partly be explained by inhibition of leukocyte activation, migration, and adhesion. This inhibition is linked to a significant decrease in plasma levels of endothelial adhesion molecules (VCAM-1 and ICAM-1) after MPFF treatment. Thus, the CVI-induced damage to the microcirculation is counteracted by MPFF. The lymphatic system is also improved by MPFF treatment. The lymphagogue activity of MPFF has been demonstrated in experimental animal models and confirmed by microlymphographic measurement in patients suffering from severe CVI. The pharmacologic activity of MPFF in lymphedema was observed in a study using an animal model of acute lymphedema and in a study in patients with upper limb lymphedema secondary to breast cancer treatment. All these findings point to the impor tance of acting on each factor involved in the formation and maintenance of edema. This pharmacologic activity is indeed reflected by the clinical efficacy on edema observed during treatment with MPFF.

Swelling is one of the most frequent complaints of patients in daily clinical practice; leg edema is its objective confirmation. It can be associated with several diseases. Micronized purified flavonoid fraction (MPFF) is a phlebotropic drug commonly used to treat the signs and symptoms associated with chronic venous insufficiency (CVI). It has confirmed its clinical efficacy in different groups of patients suffering from edema: idiopathic cyclic edema, CVI-associated edema, postmastectomy lymphedema and might be beneficial in some of drug-induced edema. In a double-blind, placebo-controlled, randomized study including 30 outpatients suffering from idiopathic cyclic edema syndrome, MPFF 1000 mg/day for 6 weeks, normalized the capillary permeability, assessed by the Landis isotope test, in 3 out of 4 patients (p=0.01). The decrease in capillary hyperpermeability led to a clinically significant decrease in weight and edema. In 200 patients with functional or organic venous insufficiency of the lower limbs, a double-blind, placebo-controlled, randomized study with MPFF 1000 mg/day for 2 months provided strong evidence of a marked improvement in symptoms and signs. A significant reduction in supramalleolar edema (assessed by circumference measurement) was observed, whatever the origin of CVI: functional or organic. MPFF efficacy was also demonstrated in another randomized, multicenter controlled trial in 320 patients suffering from chronic venous insufficiency. In this study, a significant decrease in circumference of the most affected leg was observed after 2 months of treatment (p<0.001), whatever the schedule of administra tion of MPFF (1000 mg once daily or bid). The benefit of MPFF on edema has been further confirmed by the volometer technique (opto-electronic measuring system) which was performed in a population of 30 patients suffering from CVI and treated by MPFF 1000 mg/day over a 6-week period. The mean volume of the more affected lower leg decreased significantly after a 6-week period of treatment, correlating to a significant improvement in clinical symptoms. MPFF has been also tested on another type of edema, upper limb lymphedema secondary to mastectomy, during a double-blind, placebo- controlled, randomized study in 104 patients. MPFF 1000 mg/day improved all lymphoscintigraphic parameters such as half-life and clearance of the labelled colloid. With regard to evolution of lymphedema volume, a tendency in favor of MPFF was observed in the subgroup of patients with more severe lymphedema. Based on its action on capillary hyperpermeability, MPFF has been used with attractive results when combined with classic treatment for a pilot study carried out in patients with advanced breast cancer (n=21) or ovarian carcinoma (n=3), treated with docetaxel, which causes severe edema as a side effect, even when associated with corticoids. Further trials are under way to assess the possible benefit of MPFF in such patients. These results in different types of edema confirm that, by acting on all parameters involved in edema, veins, lymphatics, and microcirculation, MPFF represents a drug of choice for treating CVI-associated edema.

The RELIEF study (Reflux assEssment and quaLity of lIfe improvement with micronized Flavonoids in chronic venous insufficiency [CVI]) is a prospective, controlled, multi center, international study performed in patients with or without venous reflux. This study was conducted between March 1997 and December 1998 in 23 countries worldwide with the participation of more than 10,000 patients suffering from CVI. The European countries, the subject of this report, were represented by the Czech and Slovak Republics, Hungary, Poland, Russia, and Spain.

The principal aims of the study were:

1. To validate the first quality-of-life scale specific to chronic venous insufficiency (CIVIQ) in different languages and to assess the evolution of quality of life in patients suffering from CVI, with or without venous reflux, treated with micronized purified flavonoid fraction (MPFF*) (1,000 mg/day)

2. To collect international epidemiologic data on venous reflux assessed with pocket Doppler and photoplethysmography

3. To assess the evolution of symptoms and signs with a specific emphasis on edema through validated Leg-O-Meter measurement (heaviness, pain, cramps, sensation of swelling, edema) in patients suffering from CVI and treated with MPFF, 1,000 mg/day, during 6 months.

The first country-by-country statistical analysis and the European consolidated analysis are now available. The CIVIQ questionnaires adapted to each participating country have been validated with highly significant validity and reproducibility (p < 0.0001). All dimen sions have demonstrated a highly significant and evolving improvement during the study.

The results show several interesting findings concerning the epidemiologic data and, of these, two were particularly interesting:

• More than 50% of patients suffering from CVI (class 0 to 4 of the CEAP classification) were reflux-free, which means that they were suffering from functional CVI.

• Patient distribution between the different classes of the CEAP classification changed in a statistically significant manner after 6 months' treatment with MPFF; the number of patients in the more severe classes decreased to the benefit of the less severe classes.

Symptoms such as pain, leg heaviness, sensation of swelling, and cramps were signifi cantly improved (p=0.0001). This was associated with a significant decrease in edema, when present, measured by leg circumferences with the Leg-O-Meter (p=0.0001).

In conclusion, the European results of the RELIEF study showed the perfect validity and reproducibility of CIVIQ questionnaire adaptations, and the positive progression of quality-of-life scores on MPFF treatment. This progression was paralleled by clinical improvement of patients reflected not only by assessment of CVI symptoms and signs but also by evolution of the CEAP classification.

As coronary interventional technology improves, the influence of lesion length (LL) on procedural success and device selection may vary. Thus, the authors prospectively analyzed 957 consecutive coronary interventions (CI) in 1,404 stenoses to ascertain the influence of lesion length on CI outcome. Stenosis morphology was prospectively classi fied by the AHA/ACC criteria. LL was analyzed both as dichotomous (S: < 10 mm, L: > 10 mm) variables and by the three-tiered AHA/ACC criteria (I: < 10 mm, II: 10-20 mm, III: > 20 mm). There was a significant univariate relationship between CI success and S stenosis (S: 95.8% vs L: 91.8%, p = 0.002 and I: 96.0%, II: 91.7%, III: 89.3%). Numerous interrelationships involving the morphologic characteristics were noted: lesion morphologies associated with S lesions were concentric (p = 0.0001) and had smooth contour (p = 0.0001), ostial location (p = 0.05) and little calcification (p = 0.0007), while irregular contour (p = 0.0001), calcification (p = 0.0076), eccentric (p = 0.0001), thrombus (p = 0.0001), recent (p = 0.0001) or chronic (p = 0.001) total occlusion were associated with L lesions. When these relationships were taken into account by multiple logistic regression analysis, lesion length was not predictive of procedural outcome (p = 0.099). One morphologic type was associated with increased CI success: irregular contour (p = 0.022); recent (p < 0.0001) or chronic (< 0.0001) occlusions were associ- ated with decreased CI success. Another factor considered was device selection: S lesions were associated with greater balloon angioplasty usage (p = 0.002), whereas more coronary stents (p = 0.024) and rotoblator (p = 0.018) devices were used in L lesions. More balloon angioplasty was performed in concentric (p < 0.0001) lesions; interven tional devices were employed more often in eccentric (p < 0.0001) and irregular lesions (p < 0.0001). More complications were noted in lesions with thrombus (p = 0.0002), but lesion length was not predictive (p = NS). Lesion length is not a significant predictor of procedural success when adjusted for other lesion morphologies in the modern inter ventional era. The availability of new devices has improved the results in longer lesions since the AHA/ACC criteria were originally proposed.

Aortic pulse wave velocity (PWV) is a noninvasive technique that can estimate aortic stiffness or organic change quantitatively. The authors examined the correlation between age and the PWV value in 113 subjects and also examined the relationship between ather osclerotic associated diseases and PWV. A positive correlation was observed between age and the PWV value. No significant difference was found in the PWV value between groups with and without risk factors of atherosclerosis. No significant difference was observed in the PWV value between groups with and without a history of atherosclerotic disease.

The authors reviewed the clinical value of platelet scintigraphy by using autologous platelets labeled with indium-111-oxine to detect thrombotic activity at vascular throm bosis sites. Thirty-nine patients with deep vein thrombosis, 28 with arteriosclerosis oblit erans, and 10 with pulmonary embolism were the subjects of this study. Platelet accu mulation on scintigrams had a tendency to correlate with aggravation of acute thrombotic symptoms in deep vein thrombosis and arteriosclerosis obliterans. In addition, appro priate thrombolytic and anticoagulant therapy resulted in reduced platelet accumulation in conjunction with improvement of acute symptoms. On the other hand, this type of scintigraphy was not so sensitive for assessment of pulmonary embolism. Platelet scintig raphy could facilitate the assessment of thrombotic activity and might be useful for deter mining the optimal indication of thrombolytic and anticoagulant therapy for acute vascular thrombosis.

Prognosis in Takayasu's arteritis is limited owing to renovascular hypertension. The authors report a patient with Takayasu's arteritis who had been unilaterally nephrec tomized and presented with malignant hypertension due to renal artery stenosis. Hypertension was refractory to conventional antihypertensive treatment, and stenosis was not accessible by interventional angioplasty. Initiation of enalapril and losartan therapy was successful in improving blood pressure without deterioration of renal function due to ischemic failure. Antihypertensive treatment resulted in dramatically stimulated endogenous nitric oxide (NO) synthesis, while elevated plasma endothelin-1 levels were unchanged. Renovascular hypertension in Takayasu's arteritis is associated with an imbalance of vasoconstrictor peptide endothelin-1 and vasodilator peptide NO. Successful treatment of hypertension by enalapril or losartan results in improved endoge nous NO synthesis, which putatively counterbalances excessive vasoconstrictor actions and may retard the progression of renal failure.

Longer existing atherosclerotic lesions may contain calcifications; lamellar bone rarely develops within them. A 59-year-old man was referred with a progressive stroke. A high- grade stenosis of the left common carotid artery, formed by an ulcerating atherosclerotic plaque with a free-floating thrombus, was detected on angiography. An urgent endarterectomy was performed. Surprisingly this plaque contained pieces of lamellar bone, proved by histologic examination.

Percutaneous balloon mitral valvuloplasty (PBMV) provides an effective alternative to surgery in a selective group of patients with symptomatic mitral stenosis. The Inoue balloon technique involves transseptal catheterization followed by catheter manipulation to cross the mitral valve. The authors describe a case of successful percutaneous balloon mitral valvuloplasty in a patient with severe mitral stenosis and pulmonary hyperten sion. Left ventricular systolic pressure was used as a guide to locate and to advance the balloon catheter across the mitral valve. This technique to cross the mitral valve has not been reported in the literature.