Showing papers in "Vascular Medicine in 1998"

Lymphedema: classification, diagnosis and therapy:

Abstract: This review presents the diagnostic features, the pathophysiology and the available therapies for lymphedema. This disease is often able to be diagnosed by its characteristic clinic- cal presentation, yet, in some cases, ancillary tests might be necessary to establish the diag- nosis, particularly in the early stages of the disease and in edemas of mixed etiology. These diagnostic modalities are also useful in clinical studies. Available modalities include isotopic lymphoscintigraphy, indirect and direct lymphography, magnetic resonance imaging, computed tomography and ultrasonography. Lymphedema may be primary or secondary to the presence of other diseases and/or to the consequences of sur- gery. Primary lymphedema may occur at any phase of life but it most commonly appears at puberty. Secondary lymphedema is encountered more often. The most prevalent worldwide cause of lymphedema is filariasis, which is particularly common in south-east Asia. In the USA, postsurgical lymphedema of the extremity prevails. Complications of chronic limb lymphedema include recurrent cellulitis and lymphangiosarcoma. Most patients are treated conservatively, by means of various forms of compression therapy, including complex physical therapy, pneumatic pumps and compressive garments. Volume reducing surgery is performed rarely. Lymphatic microsurgery is still in an experimental stage, although a few centers consistently report favorable outcomes.

Vascular damage from smoking: disease mechanisms at the arterial wall:

Abstract: The products of tobacco combustion are absorbed into the systemic circulation. Absorbed nicotine stimulates the release of catecholamines, whilst other products (perhaps including nicotine) injure the arterial endothelium and promote atherogenesis. Free radicals and aromatic compounds diminish the endothelial synthesis of nitric oxide, causing impaired endothelium-dependent relaxation of arteries, the earliest clinical sign of endothelial dysfunction. Smoking alters the shear forces and rheology at the endothelial surface and these changes enhance the effects of products of tobacco combustion to upregulate leucocyte adhesion molecules on the endothelial surface. The increased oxidation of low density lipoprotein (LDL) in smokers has synergistic effects to promote monocyte adhesion and monocyte migration into the subintimal space. Continued stimulation of intimal cells by oxidized LDL leads to the development of atherosclerosis. Many of these effects are ameliorated by high concentrations of vitamin C. Smoking also potentiates thrombosis at the dysfunctional endothelium by increasing the concentration of plasma fibrinogen and altering the activity of platelets. All these proatherogenic effects of smoking to injure the endothelium also are observed, albeit to lesser extent, in passive smokers.

The generalized nature of atherosclerosis : how peripheral arterial disease may predict adverse events from coronary artery disease

Abstract: Non-invasive measurements, especially segmental pressure ratios and flow measurements, are useful for gauging the severity of peripheral arterial disease (PAD). Although the incidence of PAD is similar for men and women, men are more likely to have severe disease, while women usually have more moderate or asymptomatic disease. Published reports confirm the clinical impression that patients with PAD are more likely to have both coronary artery disease and cerebrovascular disease than those without PAD. However, the degree of overlap is a function of the sensitivity of the diagnostic assessments for the three conditions. A San Diego population study found that the incidence of PAD may be underestimated, with many patients being asymptomatic. Based on blood flow measurements, the study found that 11.9% of the study population had large vessel PAD. Morbidity from both coronary heart disease and stroke was increased in people with PAD, who were 2.5 times more likely to present with morbidity from cardiovascular disease (CVD) than those who did not have PAD. Several studies have now confirmed the strong predictive value of PAD for subsequent CVD mortality and that the risk of CVD mortality increases with the severity of PAD.

Diabetes, advanced glycation endproducts and vascular disease

Abstract: The high incidence of vascular complications in patients with diabetes mellitus remains incompletely understood. Several metabolic or endocrine abnormalities have been postulated as possible triggers for micro and macroangiopathies. This review article focuses on the consequences of hyperglycemia, leading to the formation of advanced glycation endproducts (AGE), on vascular function. Advanced glycation endproducts are the product of the binding of aldoses onto free amino groups of proteins or lipoproteins, which, after molecular rearrangement, result in a class of molecules of a brown color and specific fluorescence. Different cell membrane proteins have been shown to bind AGE and the best characterized receptor for AGE has been named RAGE. The AGE receptor is present on different cell types including endothelial cells, smooth muscle cells, lymphocytes and monocytes. Experimental studies have revealed that the binding of AGE to RAGE produces an activation of monocytes and endothelial cells. Activated endothelial cells produce interleukin and express vascular cell adhesion molecule and tissue factor. Advanced glycation endproducts, when infused into animals, induce an increase in vascular permeability. The blockade of RAGE by specific antibodies corrects the hypermeability observed in diabetic animals. The prevention of AGE formation by aminoguanidine treatment improves the microvascular lesions found in diabetic animals either in the retina or the glomerus. The infusion of recombinant RAGE in diabetic animals corrects hyperpermeability. The colocalization of RAGE and AGE at the microvascular site of the injury suggests that their interaction may play a significant role in the pathogenesis of diabetic vascular lesions.

Role of inflammation and metalloproteinases in plaque disruption and thrombosis.

Abstract: Numerous pathological, clinical, angiographic and angioscopic studies have demonstrated that acute coronary syndromes (unstable angina, acute myocardial infarction and ischemic sudden death) are most frequently the consequence of plaque disruption (plaque rupture or superficial plaque erosion) and consequent coronary thrombosis. Several serial angiographic studies have demonstrated that nearly 60-70% of acute coronary syndromes evolve from mildly to moderately obstructive atherosclerotic plaques. Coronary plaque disruption appears to be a function of both the composition of the plaque (plaque vulnerability ) as well as extrinsic triggers that may precipitate plaque disruption in a vulnerable plaque. Vulnerability for plaque disruption appears to be largely determined by the size of the lipid-rich atheromatous core, the thickness of the fibrous cap covering the core, and the presence of ongoing inflammation within and underneath the cap. Inflammatory cells may play a critical role in plaque disruption through the elaboration of matrix degrading metalloproteinases or MMPs (collagenases, gelatinases, stromelysins and matrilysin) and by inhibition of function and survival of matrix-synthesizing smooth muscle cells. Inflammatory cells may also play a critical role in triggering thrombosis following plaque disruption through the tissue factor pathway. In addition, stresses resulting from hemodynamic and mechanical forces may precipitate plaque disruption, particularly at points where the fibrous cap is weakest, such as at its shoulders. The degree of thrombosis following plaque disruption is determined by the thrombogenicity of the disrupted plaque, disturbed local rheology and systemic thrombotic-thrombolytic milieu. Surges in sympathetic activity provoked by sudden vigorous exercise, emotional stress -- including anger, or cold weather, may also trigger plaque disruption. These observations have led to the concept of plaque stabilization as a new clinical strategy for the prevention of acute coronary syndromes. Plaque stabilization can be achieved through pharmacologic and lifestyle-modifying interventions that reduce vulnerability to plaque disruption by altering plaque composition and/or inflammatory activity within the plaque.

The interface of atherosclerosis and thrombosis: basic mechanisms.

Abstract: Occlusive vascular disease most often results from thrombosis superimposed on atherosclerotic plaque. Disruption of plaque exposes thrombogenic substances within the plaque to blood and may result in thrombotic occlusion of the affected vessel. Mural thrombi may be incorporated into plaque, enhancing the evolution of atherosclerotic lesions. Inflammation plays a key role in the formation and complication of atherosclerosis. Inflammatory mediators regulate processes that determine the composition of the plaque's fibrous cap, a structure that separates blood from the thrombogenic lipid core. Several inflammatory mediators control the release of metalloproteinases (enzymes that break down cap constituents) from smooth muscle cells, macrophages and other cells within plaque. Inflammatory mediators also control the production of connective tissue matrix by cells in the plaque. Factors involved in coagulation, such as thrombin, can regulate non-thrombotic functions of vascular wall cells such as smooth muscle proliferation or cytokine release. The many mechanisms involved in arterial occlusive disease present numerous points at which intervention with pharmacologic agents may prove effective in lowering the risk of acute arterial thrombotic complications.

Non-invasive assessment of brachial artery endothelial vasomotor function: the effect of cuff position on level of discomfort and vasomotor responses.

Abstract: Non-invasive assessment of brachial artery flow-mediated dilation using cuff occlusion of the arm above or below the elbow to stimulate flow is emerging as a highly useful technique to examine endothelial vasomotor function in human subjects. In anticipation of a large-scale investigation, an important issue is the acceptability of the technique to participants. The purpose of this study was to determine the level of discomfort associated with the tech- nique and compare it to the commonly used procedure of venipuncture. Flow-mediated dilation was determined using cuff occlusion of the arm above the elbow and a blood sample was obtained by standard venipuncture from 54 subjects. The level of discomfort for each procedure was assessed and compared using a visual analogue scale and was found to be extremely low. When the occlusion cuff was positioned above the elbow, the discomfort was slightly more severe (1.9 6 1.9 cm) than venipuncture (1.0 6 1.3 cm, p = 0.003). In 27 subjects, the effect of cuff position (above or below the elbow) was compared: the below the elbow position was associated with a reduction in the percentage increase in flow (570 6 280% versus 900 6 560%, p = 0.005), flow-mediated dilation (6.8 6 3.8% versus 9.8 6 5.7%, p = 0.008) and discomfort (1.6 6 0.8 versus 3.7 6 2.2 cm, p = 0.008). When the cuff was located below the elbow, the level of discomfort was equivalent to that associated with venipuncture. Thus, non-invasive assessment of flow-mediated brachial artery dilation is well tolerated and appears to be suitable for a large-scale study of endothelial function.

Results of the CAPRIE trial: efficacy and safety of clopidogrel

Abstract: The recent CAPRIE trial (clopidogrel versus aspirin in patients at risk of ischaemic events) compared clopidogrel with aspirin in reducing the risk of vascular events in 19,185 patients with clinical manifestations of atherosclerosis Participants were randomized to receive daily oral clopidogrel (75 mg) or aspirin (325 mg) Treatment periods ranged from 1 to 3 years The primary outcome measurement was an aggregate of myocardial infarction, ischemic stroke and vascular death Event rates of 532% and 583% were associated with clopidogrel and aspirin therapy, respectively Clopidogrel therapy resulted in a relative risk reduction of 87% (CI 03-165%) compared with aspirin therapy (p = 0043) Gastrointestinal hemorrhages occurred in 199% of patients treated with clopidogrel and 266% of patients treated with aspirin (p < 0002) There were no significant treatment-based differences in the rates of intracerebral hemorrhages and hemorrhagic deaths or thrombocytopenia These results indicate that clopidogrel is more effective and safer than aspirin in reducing adverse cardiovascular events in patients with atherosclerosis

A systematic review of compression therapy for venous leg ulcers

Abstract: The aim of the study was to determine the relative effectiveness of compression therapies used in the treatment of venous leg ulcers. Randomized controlled trials (RCT) were sought using a search strategy that aimed to identify relevant RCT by searching eight electronic databases (including Medline, Embase and CINHAL), conference proceedings and hand searching key journals. In addition, citations within papers were scrutinized to identify any relevant studies. Suitability for inclusion in this review was determined by a critical appraisal of key determinants of the quality of the trials. Trials that included patients of mixed ulcer aetiology were excluded unless the results of patients with venous disease were reported separately. Data was extracted independently by two reviewers and synthesized quantitatively and qualitatively. Losses to follow-up/withdrawals were assumed to be failures of treatment. A total of 132 articles were identified, and of these eight fulfilled the inclusion criteria. The remaining 126 trials were excluded due to trial design flaws, the inclusion of mixed/arterial aetiology ulcers or because they were non-RCT. Meta-analysis using a random-effects model showed the benefits of multi-layer and elastic compression bandages. It was concluded that more high-quality trials are required and that more emphasis should be placed on economic and quality of life data to try to ascertain the cost-effectiveness and utility of the treatment options available.

Reflex sympathetic dystrophy: facts and hypotheses

Abstract: Reflex sympathetic dystrophy (RSD) syndrome has been recognized clinically for many years. It is most often initiated by trauma to a nerve, neural plexus, or soft tissue. Diagnostic criteria are the presence of regional pain and other sensory changes following a noxious event. The pain is associated with changes in skin colour, skin temperature, abnormal sweating, oedema, and sometimes motor abnormalities. The clinical course is commonly divided into three stages: first (acute or hyperaemic), second (dystrophic or ischaemic), and third (atrophic) stage. The diagnosis is primarily clinical, but roentgenography, scintigraphy, thermography, electromyography and assessment of nerve conduction velocity can help to confirm the diagnosis. Although a wide variety of treatments have been recommended, the only therapies found to be effective in large studies aim at interfering with the activity of the sympathetic nervous system. To this end, efferent sympathetic nerve activity can be interrupted surgically or chemically. Alternatively, adrenoceptor blockers may be used to relieve pain. Numerous theories have been proposed to explain the pathophysiology. Sympathetic dysfunction, which often has been purported to play a pivotal role in RSD, has been suggested to consist of an increased rate of efferent sympathetic nerve impulses towards the involved extremity induced by increased afferent activity. However, the results of several experimental studies suggest that sympathetic dysfunction consists of supersensitivity to catecholamines induced by (partial) autonomic denervation. Besides, it has been suggested that excitation of sensory nerve fibres at axonal level causes release of neuropeptides at the peripheral endings of these fibres. These neuropeptides may induce vasodilation, increase vascular permeability, and excite surrounding sensory nerve fibres -- a phenomenon referred to as neurogenic inflammation. At the level of the central nervous system, it has been suggested that the increased input from peripheral nociceptors alters the central processing mechanisms.

Atherothrombosis: mechanisms and clinical therapeutic approaches

Abstract: Eroded or disrupted atherosclerotic plaques act as a substrate for thrombosis, leading to ischemic coronary artery and cerebrovascular disease. Plaques vary greatly in composition, size, and the degree of stenosis they cause. Plaques can be categorized based on these features, which helps to estimate the likelihood of rupture and subsequent thrombosis. Vascular plaques often begin at regions with low and oscillatory shear forces that cause chronic minimal endo- thelial damage or dysfunction. Lipoproteins enter the vessel wall, promoting the recruitment of monocytes, which imbibe lipids and become foam cells. Smooth muscle cells invade these early plaques, producing connective tissue fibrils that form a fibrous cap over the lipid center; rupture of this cap is an important cause of thrombosis. Passive plaque disruption occurs when physical forces cause cap rupture; active disruption occurs when the cap is attacked by macro- phages and proteolytic enzymes. Tissue factor is one of many factors within plaque that stimu- lates thrombosis.

Long-term outcomes after deep venous thrombosis of the lower extremities:

Abstract: Few natural history studies are available which describe long-term outcomes after venous thromboembolism. However, symptomatic deep-vein thrombosis (DVT) of the lower extremities carries a high risk for recurrent venous thromboembolism that persists for many years. This risk is higher among patients with permanent risk factors including inherited abnormalities of hemostasis than among patients who have suffered trauma or who are postoperative. The development of recurrent ipsilateral DVT carries a high risk for severe post-thrombotic syndrome, an otherwise rare problem in patients with a first episode of DVT adequately treated with anticoagulant drugs and wearing vascular compression stockings. Long-term survival following DVT is generally good in the absence of malignancy. Carefully designed randomized trials are needed to determine whether chronic anticoagulation can reduce further the risks of recurrent DVT and symptoms of post-thrombotic syndrome.

The natural history of asymptomatic moderate internal carotid artery stenosis by duplex ultrasound

Abstract: The purpose of this study was to determine the rate of progression of the degree of carotid stenosis and to determine the risk of continued observation in a group of asymptomatic patients with moderate stenosis of at least one internal carotid artery. Between 1989 and 1994, 2130 patients were found to have 60-79% stenosis of at least one internal carotid artery following a duplex ultrasound examination in the authors' vascular laboratory. Of these, 465 patients (255 men, 210 women) were asymptomatic and had more than one ultrasound examination, and they form the basis of this retrospective review. The mean +/- SD age was 68.8 +/- 9.0 years. The mean +/- SD number of ultrasound examinations was 3.1 +/- 1.4 (range 2-11). The mean +/- SD follow-up was 24.4 +/- 17.6 months (range 2-79 months). Over the period of follow-up 72 patients (15.5%) progressed to 80-99% stenosis (n = 71) or to occlusion (n = 1). The estimated percentage of patients who progressed by life table methods were 5 +/- 1% at 1 year, 11 +/- 2% at 2 years and 20 +/- 3% at 3 years. There was no statistically significant difference in the rate of progression in men compared with women. Twenty-one patients had a late ipsilateral TIA or stroke. Five out of 72 patients (6.9%) who progressed had a late ipsilateral TIA compared with nine out of 393 patients (2.3%) who did not progress (estimated risk ratio 16.1, P = 0.0001). Four out of 72 patients (5.6%) who progressed had a late ipsilateral stroke compared with three out of 393 patients (0.76%) who did not progress (estimated risk ratio 23.6, p = 0.0002). The cumulative ipsilateral stroke rate using life table methods was 0.22% at 1 year, 1% at 2 years and 2.4% at 3 years. In a large cohort of asymptomatic patients, the frequency of progression of 60-79% internal carotid artery stenosis was 5% at 1 year, 11% at 2 years and 20% at 3 years. Patients who progressed were more likely to have symptoms, but the rate of unheralded stroke was relatively low over a 3-year time period. Surveillance carotid ultrasound examinations should be performed in patients with moderate carotid stenosis. Because of the lack of clear benefit, carotid endarterectomy for asymptomatic 60-79% internal carotid artery stenosis cannot be justified.

Impaired endothelial regulation of vascular tone in patients with systemic arterial hypertension

Abstract: The discovery of the endothelium as a major regulator of vascular tone triggered intense research among basic and clinical investigators to unravel the physiologic and pathophysiologic significance of this phenomenon. Importantly, endothelial modulation of the contractile state of vascular smooth muscle has been shown to be impaired in atherosclerosis and in several conditions known to be associated with the premature development of atherosclerosis. Studies in several different animal models of arterial hypertension, and in patients with both essential and secondary hypertension, have demonstrated an association between elevated systemic blood pressure and impaired endothelium-dependent vascular relaxation. More recently, a diminished bioavailability of nitric oxide (NO) has been identified as a mechanism responsible for endothelial dysfunction in hypertensive patients. Different processes may, in turn, explain this decreased vascular activity of NO. The present review focuses on those clinical studies that are aimed at identifying the precise abnormality responsible for reduced NO-dependent vasodilation in patients with essential hypertension. Understanding of the basic mechanisms of this process may prove to be beneficial for the development of more specific therapies and ultimately for the outcome of hypertensive patients.

Clinical pharmacology of the adenosine diphosphate (ADP) receptor antagonist, clopidogrel

Abstract: Antiplatelet compounds interfere with the platelet activation cascade at different levels. The antiplatelet effect of the thienopyridine, clopidogrel, results from antagonism of a platelet ADP receptor, P2T, resulting in inhibition of platelet activation. This antagonism is non-competitive, irreversible, and results in a 50-70% inhibition of platelet fibrinogen binding. Additionally, clopidogrel may also antagonize the ADP-induced inhibition of adenylate cyclase, possibly resulting in an elevated platelet cyclic adenosine monophosphate level after stimulation by an appropriate agonist, such as prostacyclin. This spectrum of antiplatelet activities is different from that of aspirin. Further, clopidogrel is associated with a reduction in gastrointestinal hemorrhage, making it a valuable therapeutic alternative to aspirin in oral, long-term prevention of atherothrombotic vascular occlusion.

Myocardial angiotensin II receptor expression and ischemia-reperfusion injury

Abstract: The renin-angiotensin system plays an important role in myocardial ischemia-reperfusion injury. Angiotensin II (Ang II) contributes to the evolution of ischemic coronary events through its hemodynamic, hemostatic and mitogenic effects. Angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor antagonists have been shown to be cardioprotective in experimental animal models, with ischemia-reperfusion injury and in patients with congestive heart failure. Ang II receptors include at least two different subtypes, AT1 and AT2. Both AT1 and AT2 are expressed in the rat heart. Myocardial AT1 receptor density increases in association with ACE expression, and AT1 receptor activation is related to collagen formation following myocardial infarction in rats. Studies from the authors' laboratory have shown significant myocardial dysfunction in association with a concurrent increase in AT1 receptor expression in the rat myocardium immediately following a brief period of ischemia and reperfusion. Application of antisense oligodeoxynucleotides (AS-ODN) directed at AT1 receptor messenger RNA and AT1 receptor antagonist, losartan, significantly attenuates myocardial dysfunction induced by ischemia-reperfusion in the isolated rat heart. These observations suggest that myocardial AT1 receptor expression is involved in myocardial dysfunction following ischemia-reperfusion. Unlike losartan, which upregulates the plasma Ang II level, administration of AS-ODN does not affect plasma Ang II level. Although the reason for this is not clear, the difference in plasma Ang II levels implies that AS-ODN may be, at least theoretically, more beneficial than losartan in limiting ischemia-reperfusion-induced cardiac dysfunction. Apoptosis, or programmed cell death, also contributes to the outcome of myocardial ischemia-reperfusion injury. Recent studies from the authors' laboratory have demonstrated that Ang II induces apoptosis in cultured human coronary artery endothelial cells via activation of AT1 receptors and this can be blocked by losartan. These observations collectively underscore the importance of myocardial AT1 receptor expression in ischemia-reperfusion injury.

Calciphylaxis: a favorable outcome with hyperbaric oxygen

Abstract: A 66-year-old female with diabetes mellitus and end-stage renal disease presented with painful bilateral lower extremity livedo reticularis and necrotic ulcerations Her distal lower extremity pulses were intact and plethysmographic studies confirmed relatively normal large vessel arterial perfusion Extensive laboratory analysis was remarkable for an elevated calcium x phosphorous product and parathyroid hormone level An ulcer biopsy revealed small vessel medial calcinosis, and calciphylaxis was subsequently diagnosed Despite aggressive wound debridements, antibiotics and subtotal parathyroidectomy, her ulcers failed to improve significantly prompting a trial of hyperbaric oxygen therapy After 7 weeks of hyperbaric treatments, her ulcers had essentially healed

Long-term, low-dose warfarin among venous thrombosis patients with and without factor V Leiden mutation: rationale and design for the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial

Abstract: Standard therapy for patients with deep venous thrombosis and pulmonary embolism typically includes anticoagulation for a 3-6 month period with full dose warfarin. However, patients following this regimen experience high rates of recurrent thrombosis, re-hospitalization and mortality in the years immediately following cessation of anticoagulation. This is true for patients at average risk of disease recurrence, and for patients at elevated risk due to the presence of inherited defects of anticoagulation such as factor V Leiden mutation. Unfortunately, no clinical regimen currently available has proven to have sufficient benefit to support long-term prophylaxis. In particular, full dose warfarin is associated with substantially increased risks of hemorrhage when used on a long term basis. In contrast, while targeted low-dose warfarin (INR 1.5-2.0) is safe for long-term therapy, the efficacy of this approach in the prevention of recurrent venous thromboembolic disease has remained untested. The Prevention of Recurrent Venous Thromboembolism (PREVENT) trial will evaluate the efficacy of prolonged treatment with low-dose warfarin in the secondary prevention of venous thromboembolism (VTE). Patients with a history of documented idiopathic venous thrombosis who have completed a standard course of anticoagulation therapy will be enrolled in a randomized, double-blind, placebo-controlled trial comparing usual care plus targeted low-dose warfarin to usual care plus placebo for a period of up to 4 years. Trial endpoints will include recurrent VTE, major bleeding episodes and all-cause mortality in the total patient population and separately in those patients with factor V Leiden. The potential clinical impact of the PREVENT trial is broad since a positive finding would strongly support chronic low-intensity anticoagulation among patients with venous thrombosis who are at risk for recurrence following cessation of standard outpatient anticoagulation.

Biochemical and inflammatory changes in the exercising claudicant

Abstract: Intermittent claudication is an early manifestation of atherosclerosis in the leg. The prognosis for the claudicating limb is reasonably good, but patients have excess cardiovascular morbidity and mortality rates compared with a control population. Increasing evidence sug- gests that the calf pain experienced when walking followed by rest generates a low-grade inflammatory response. The cumulative effects of these individual events may have an adverse effect on the progression of atherosclerosis. A review of the literature was performed to identify studies measuring the exercise-induced inflammatory response in claudicants and to try to identify the role of cumulative inflammatory changes in the progression of atherosclerosis. The effect of exercise training on these markers is briefly explored. Walking until the onset of calf pain (ischaemia) followed by rest (reperfusion) results in the generation of oxygen-derived free radicals, neutrophil activation and a generalized increase in vascular permeability. Baseline levels of chronic inflammatory markers such as acute-phase proteins are elevated in claudicants compared with controls, suggesting that the transient acute inflammatory response has longer-term consequences. Therapeutic exercise training appears to lead to an attenuation of these inflammatory markers. Intermittent claudication can be considered as part of an inflammatory disease process. How- ever, the concerns that exercise training might potentiate the vascular inflammatory response appear to be unjustified, although further work is needed to clarify this. Exercise training should therefore be considered as an important treatment option for claudication.

Venous bypass and valve reconstruction: long-term efficacy

Abstract: Palma and Esperon described the first femoro-femoral cross-over bypass for iliac vein obstruction in 1958, and Kistner performed the first valve reconstruction for deep vein reflux in 1968. Such surgical development has stimulated better diagnostic methods that now form the foundation for a classification of chronic venous disease, and surgery has been supported by, and sometimes replaced by, the rapid progress in endovascular procedures with angioplasty and stenting. The ability now exists to relieve obstruction and repair reflux in the deep veins, and the results in the successful cases demonstrate the improvement that follows correction of the physiologic abnormalities. The detail in workup required to achieve an accurate diagnosis that is adequate enough to guide surgical treatment in these cases has set a new standard for the diagnosis of chronic venous disease that incorporates the clinical state, etiology, pathophysiology and anatomic distribution of the venous problem, and is incorporated in the CEAP (clinical, etiologic, anatomic, pathophysiologic) classification. The challenge at this time is to produce a reliable set of data that demonstrate the results of treatment in patients with chronic venous disease by conventional methods of bandaging, rest and elevation as well as specific surgical correction of venous obstruction and reflux and to follow these cases over a significant period of time.

Unfractionated versus low-molecular-weight heparin in the treatment of venous thromboembolism:

Abstract: Low-molecular-weight heparin (LMWH) fractions are prepared from standard unfrac- tionated heparin (UFH) and are thus similar to UFH in many aspects. The main advantages of this new class of antithrombotic agents as compared with UFH are: (1) an improved bioavail- ability and a prolonged half-life, which alleviate cumbersome laboratory monitoring and may permit one single daily subcutaneous injection; and (2) an improved efficacy-to-safety ratio, with less bleeding despite similar or improved efficacy. For these reasons, LMWH is progress- ively replacing UFH for preventing postoperative thromboembolism and for treating established deep vein thrombosis and pulmonary embolism. However, the effects of the new compounds need to be evaluated carefully in some other indications (arterial thrombosis, unstable angina, or myocardial infarction - the latter also in conjunction with thrombolytic treatment) before they can generally replace UFH in pharmacotherapy.

Clinical overview of venous thromboembolism.

Abstract: Pulmonary embolism and deep venous thrombosis constitute a major cause of vascular illness in the USA The mortality rate of pulmonary embolism is high, and recurrent events frequently occur The optimal duration of treatment with anticoagulation is unknown Diagnostic work-ups now often include plasma D-dimer levels and echocardiography in addition to conventional lung scanning and pulmonary angiography Among patients with right ventricular dysfunction, thrombolytic therapy is being used more often because this strategy may improve overall prognosis Since venous thromboembolism is difficult to diagnose and expensive to treat, prophylaxis against this disease is of paramount importance

Forearm blood flow measured by venous occlusion plethysmography in healthy subjects and in women with postmastectomy oedema

Abstract: A chronic swelling of the arm may develop following damage to axillary lymph ves- sels during breast cancer treatment. Certain unusual pathophysiological features of postmastec- tomy oedema indicate that factors additional to lymphatic damage are important. One factor postulated previously is a haemodynamic abnormality. Forearm blood flow was therefore mea- sured by venous occlusion plethysmography using both a conventional mercury strain gauge and a newer optical volumeter (Perometer ® ). The latter was initially assessed in healthy sub- jects. When forearm blood flow was measured using the two methods simultaneously, the strain gauge and Perometer ® did not differ significantly for healthy or oedematous arms. Dominant and non-dominant arm blood flow in healthy subjects was similar but with greater variation between sides with the Perometer ® . Using the strain gauge, blood flow in the oedematous arm (2.51 6 1.33 ml/100 ml per min) was significantly lower than in the opposite unaffected arm (3.77 6 2.29 ml/100 ml per min; p = 0.026). The Perometer ® results showed a similar but non- significant trend (p = 0.105). Taking into account the greater limb volume on the affected side, total forearm blood flow was essentially the same in each arm (unaffected: 40.72 6 28.70 ml/min; oedematous: 41.78 6 22.11 ml/min). The reduced blood flow per unit volume of arm was therefore likely to be due to a simple 'dilution' effect of the increase in volume. The results indicate that it is unlikely that raised blood flow contributes to oedema formation, contrary to the haemodynamic concept.

Atherosclerotic aneurysms of the superficial femoral artery: report of two ruptured cases and review of the literature.

Abstract: Isolated arteriosclerotic aneurysms of the superficial femoral artery are rare. In citing the literature a total of 30 cases in 28 patients in the last 25 years were found. In addition to the above cases, two aged patients with ruptured aneurysms of the superficial femoral artery are reported; these were managed successfully with partial aneurysmectomy and restoration of the circulation of the extremity with a synthetic graft. The prognosis for this type of aneurysm following surgical therapy is good, despite the advanced age of the patients, and amputation is relatively rare, occurring in only two out of the 30 aneurysms (6.6%) reported. The risk of rupture is 46.6% (14/30) and is greater than that found in peripheral aneurysms. This, in association with the possibility of the creation of thrombosis (5/30; 16.6%) or embolization (1/30; 3.3%), threatens the extremity itself as well as the life of the patient, increasing the risk of complications and even death at a rate of 66.6% (20/30). Timely diagnosis, immediate surgical reconstruction and prompt mobilization, however, can guarantee a good prognosis for these aged patients.

Percutaneous venous interventions

Abstract: Percutaneous procedures by interventional radiologists are becoming an increasingly frequent part of the overall care of patients with complex venous thrombotic diseases. Inferior vena caval filters are used in the setting of failed or contraindicated anticoagulation. Catheter-directed thrombolysis is considered for patients with extensive iliofemoral deep venous thrombosis. Venous angioplasty is often indicated for patients with dialysis shunt venous stenoses, upper extremity venous stenoses and for stenoses within venous bypass grafts. Venous stenting is often employed following angioplasty to ensure long-term procedural success. Finally, suction and mechanical thrombectomy and embolectomy are relatively new procedures that are available to optimize patient management.

An objective method to estimate the severity of Raynaud phenomenon: digital blood pressure response to cooling

Abstract: The treatment efficacy of patients with Raynaud phenomenon (RP) is determined from the decrease in severity of this condition, usually based on a decrease in frequency of RP attacks as reported by patients in a diary. Although subjective, this method is still the main endpoint measure in clinical trials. The results of patients' digital blood pressure responses to cooling were compared with the reported RP attack frequency to determine whether the former could be used to estimate the severity of RP. The effect of local finger cooling on the digital systolic blood pressure was tested at 30 degrees C, 20 degrees C, 15 degrees C and 10 degrees C on 136 subjects with RP. The RP attack frequency was dichotomized into daily versus less than daily attacks. The frequency of attacks and the digital systolic pressure (DSP) showed a significant association at all cooling temperatures (those with daily attacks showed lower DSP than those with less frequent attacks). In addition, patients experiencing daily attacks of RP showed a zero reopening pressure at higher local temperatures than those with less frequent RP attacks. These results demonstrate that the response of the digital systolic blood pressure to cooling is closely associated with the RP attack frequency and therefore can be considered as an objective estimate of RP severity. This physiological measurement should be most useful in evaluating the clinical course of RP and the effect of its treatment, provided it is measured under standardized conditions.

Diagnosis and treatment of chronic lower extremity ischemia

Abstract: Chronic lower extremity ischemia is due to progressive atherosclerosis of the aorto-iliac and/or infrainguinal arteries. This disease process is of great importance as millions of patients are affected by lower extremity arterial occlusive disease. Most of these patients are asymptomatic but a growing number of them are symptomatic, with complaints ranging from mild claudication to gangrene. The increasing number of patients affected by lower extremity atherosclerosis is, in part, due to the 'graying' of the general population and to the medical improvements of the past three decades that have allowed patients with generalized atherosclerosis to survive longer. Fortunately, the diagnosis and management of peripheral arterial occlusive disease has also significantly progressed leading to improved graft patency, limb salvage rates, and quality of life for patients.

Neutrophil function in peripheral arterial occlusive disease: the effects of prostaglandin E1:

Abstract: The role of polymorph nuclear neutrophils (PMN) in limb ischemia and reperfusion has been recognized only in recent years. The present study aimed to investigate the systemic and local (in femoral venous blood) effects of intra-arterially or intravenously applied prostag- landin E1 (PGE1) on systemic and ischemia-induced local changes in neutrophil function. Thirty patients with intermittent claudication were randomly assigned to intra-arterial or intravenous infusion of prostaglandin E1 (10 m gI A or 15mg IV over 30 min). Prior to infusion femoral arterial and venous blood samples were obtained from the predominantly affected leg under resting conditions and immediately after a 3-min period of ischemia induced by suprasystolic thigh compression. After 24 h additional blood samples were obtained at baseline, following infusion of prostaglandin E1, and again after another 3-min period of ischemia following the prostaglan- din E1 infusion. Intra-arterially administered prostaglandin E1 caused an increase in the PMN count by 3.5 ∠ 2% (p,0.05) and a decrease in free oxygen radical production by 13 ∠ 8% (p,0.05) meas- ured by whole blood chemiluminescence. Additionally, a trend for lower PMN filterabilities (9 ∠ 12%, NS) was observed. Intra-arterially infused prostaglandin E1 significantly reduced the ischemia-induced decrease in neutrophil filterability (arterial and venous blood difference after ischemia - control: 22 ∠ 17% (p,0.05); IA PGE1 :8 ∠ 11% (NS), each compared to baseline). Intra- venously administered prostaglandin E1 showed similar systemic effects as the intra-arterial application, but did not affect the ischemia-induced changes in neutrophil filterability. In con- clusion, prostaglandin E1 reduces PMN activation in patients with peripheral arterial occlus- ive disease. the therapeutic effects of PGE1 in patients with peripheral arterial occlusive disease. The purpose of the present study was to investigate the effects of intra-arterially and intra- venously applied PGE1 on systemic and ischemia-induced changes in neutrophil function in patients with peripheral arterial occlusive disease.

Whole-body exercise thallium imaging in smokers:

Abstract: Whole-body exercise thallium imaging (WBEI) can show abnormalities of leg muscle perfusion in patients with symptomatic peripheral artery disease (PAD). This study compared the exercise distribution of thallium-201 at different levels of the legs in asymptomatic smokers and non-smokers who performed a maximal graded treadmill test. A group of 74 smokers (more than 20 pack-years) with (n = 51) or without coronary artery disease (CAD) (n = 23) were included in group 1 and 64 non-smokers with a low probability of PAD and CAD in group 2. Patients in group 1 were older than the patients in group 2 (58 6 9 versus 48 6 12 years, p , 0.0001). Indexes of asymmetry were significantly higher in group 1, at each level of the legs, both in anterior and posterior views (0.001 , p , 0.05), except at thigh level in anterior view. Fractional uptake indexes of thallium-201 were significantly lower in group 1 than in group 2 at calf level (p = 0.0001 in anterior and posterior views) and buttocks (p = 0.006 and p = 0.009 in anterior view only). Interextremity asymmetry was four to six times more frequent at calf level in smokers than in non-smokers. These WBEI abnormalities in smokers are highly sugges- tive of silent PAD or at least decreased vascular reactivity in clinically uninvolved vessels.

Heparin attenuates norepinephrine-induced venoconstriction

Abstract: Reversal by heparin of norepinephrine-induced constriction of normal hand veins was studied. Venous size was measured using a linear variable differential transformer (LVDT) dur- ing infusions of saline, norepinephrine, insulin and norepinephrine, and graded doses of hep- arin with norepinephrine. Heparin reduced the venoconstrictive effects of norepinephrine (p , 0.01), with the effects beginning at 18.5 nmol/min (0.05 U/min) and reaching a maximum between 185 nmol/min and 1.85 mmol/min (0.5 and 5 U/min). Maximal heparin-induced venore- laxation correlated with the maximal insulin effect within individuals (r = 0.8, p , 0.01) and was unchanged by the addition of insulin. Methylene blue, a non-specific inhibitor of the nitric oxide cGMP cascade, reduced heparin-induced venorelaxation. In conclusion, heparin in either physi- ologic or pharmacologic concentrations attenuated norepinephrine-induced venoconstriction. A common mechanism of venorelaxation by heparin and insulin is not excluded given the correlation and lack of additivity of maximum effects and their inhibition by methylene blue.