Seminars in vascular medicine最新文献

Given the pivotal role of thrombin in the pathogenesis of acute coronary syndromes (ACS) and its persistent activation at the site of arterial lesions, antithrombin agents are essential for the prevention of coronary events. Antiplatelet agents are used routinely in the prevention of ACS, but their inability to prevent thrombin generation might contribute to the remaining high rates of recurrent ischemic events after intense antithrombotic treatment in the acute phase. Combination treatment with antiplatelet agents and anticoagulants, such as low-molecular-weight heparins (LMWH) and vitamin K antagonists, provides improved efficacy in the secondary prevention of ACS but these agents have limitations that prevent widespread adoption of their use for long-term treatment. Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors (DTIs) and has considerable therapeutic potential in ACS. The DTIs are able to inhibit free and fibrin-bound thrombin by directly binding to the thrombin catalytic site. Furthermore, the oral administration and predictable pharmacokinetics of ximelagatran mean that it can be used at a fixed dose without coagulation monitoring and is convenient for long-term therapy. The efficacy of ximelagatran in the prevention of coronary events has been investigated in patients with recent myocardial infarction (MI) in the phase II Efficacy and Safety of the Oral Direct Thrombin inhibitor Ximelagatran in Patients with Recent Myocardial Damage (ESTEEM) trial. Ximelagatran (24 to 60 mg twice daily) added to aspirin (160 mg once daily) reduced the risk of the composite end point of death, MI, and severe recurrent ischemia by 24% versus aspirin alone, with no significant increase in major bleeding. Elevated serum transaminase enzymes developed during the first 1 to 6 months of treatment in a proportion of patients given ximelagatran. These elevations usually abated without clinical sequelae whether or not treatment was continued. The ESTEEM results highlight the potential for ximelagatran as an efficacious and well-tolerated long-term treatment for the prevention of arterial thrombotic events.

Patients undergoing major lower-extremity orthopedic surgery such as total hip replacement (THR) and total knee replacement (TKR) are at an increased risk of venous thromboembolism (VTE). Routine prophylaxis is necessary to reduce the risk of deep vein thrombosis (DVT), which may progress to potentially fatal pulmonary embolism and secondary complications such as postthrombotic syndrome, recurrent DVT, and chronic pulmonary hypertension. Prophylaxis in patients undergoing TKR, THR, and hip fracture surgery is now standard practice and generally involves anticoagulant treatment with either low-molecular-weight heparin (LMWH) or warfarin for a period of 7 to 10 days, with extended prophylaxis in those with ongoing risk factors such as obesity, cancer, or previous VTE. Data from clinical practice suggest that there is a general trend toward longer postsurgical prophylaxis and shorter hospital stays, making practicality of treatment an important consideration. LMWH is effective for the prophylaxis of VTE, but the parenteral route of administration is not convenient for use in the outpatient setting. Warfarin, on the other hand, can be administered orally but requires the infrastructure for careful patient monitoring and dose adjustments because of its unpredictable dose-response relationship. The development of new anticoagulants has been pursued with the aim of improving efficacy, predictability, consistency of response, safety, and convenience. A recently approved anticoagulant, fondaparinux, has been proven to provide superior efficacy for the prevention of VTE compared with LMWH, but this agent requires parenteral administration and does not overcome the convenience issue. Ximelagatran is the oral form of the direct thrombin inhibitor melagatran, which is available for subcutaneous administration. Ximelagatran has a consistent anticoagulant response allowing fixed oral dosing without the need for coagulation monitoring. The efficacy and safety profile of melagatran/ximelagatran prophylaxis for VTE following THR and TKR has compared favorably with standard LMWH prophylaxis, as seen in the European METHRO II and III trials and EXPRESS trial, and with warfarin prophylaxis, as seen in the North American EXULT A and B trials. Several prophylactic treatment regimens have been evaluated in the European trials to determine the optimal dosing and timing of first dose of melagatran to achieve the best balance of efficacy and safety. Preoperative initiation of melagatran was more effective than when prophylactic treatment was initiated postoperatively, and the lowest rates of bleeding were associated with a postoperative initiation of prophylaxis. Early administration of the first postoperative melagatran dose (4 to 8 hours) was also associated with better prophylactic efficacy relative to a later postoperative start (8 to 12 hours). The results of the comprehensive international clinical trial program and in particular the optimal balance of efficacy

The oral direct thrombin inhibitor ximelagatran is the first oral anticoagulant since the introduction of the vitamin K antagonists in the early 1940s. A comparison of the discovery and early clinical development of the two classes of oral anticoagulants reveals some similarities but also several differences that illustrate the change in drug discovery over the last half century.

Several case studies are briefly introduced, followed by a description of the clinical problem from an epidemiological point of view. The evidence for established management strategies is reviewed and, finally, practical handling of the case is considered.

Folate is a water-soluble vitamin that occurs in different chemical forms distinguished by their oxidation state and the specific type of one-carbon substitution. Folates occur in natural food sources as reduced methylated or formylated tetrahydrofolate. Folic acid is a synthetic analogue with no metabolic activity of its own. Pharmacological doses of folic acid cause it to appear in plasma, where it has unknown, but potentially adverse, effects. This review discusses folate absorption, body distribution, and intracellular folate metabolism. The main physiological functions of folate can be classified as methylation and DNA synthesis. Several mechanisms act in concert to regulate the folate metabolic pathways to ensure that both functions of folate are fulfilled properly. B-vitamin deficiencies and genetic polymorphisms (particularly the C677T mutation in the methylenetetrahydrofolatereductase gene) have multiple effects on folate metabolism. Impairment of the methylation cycle, for example, leads to hyperhomocysteinemia, a proposed atherothrombotic factor. However, methylation disturbances also result in hypomethylation of DNA and other molecules, which may also contribute to the pathogenesis of cardiovascular disease. As cardiovascular researchers, we should try to develop a more integrative view on folate metabolism, rather than focusing merely on hyperhomocysteinemia.

Hyperhomocysteinemia (Hhcy) is an established risk factor for various pathologies including arterial vascular disease and venous thrombosis, congenital malformations and other pregnancy complications, and dementia. Homocysteine remethylation, transsulfuration, and export to the blood/extracellular compartment determine homocysteine concentrations. Any disturbance in these routes may lead to Hhcy and potentially increase risk of disease. In this report, we aim to review all known polymorphisms involved in homocysteine and B-vitamin metabolism that have been assessed for their effect on tHcy. In the last section, we summarize the polymorphisms, for which the obtained data provides evidence for their involvement in Hhcy at the population level, and discuss how to continue our search for genetic determinants of tHcy.

Dietary supplementation with B-vitamins that lower plasma total homocysteine concentrations are expected to lower the risk of cardiovascular disease. Folic acid and vitamin B (12) lower blood homocysteine concentrations by about 25-30% in populations without folic acid fortification, but by only 10-15% in populations with fortification. In observational studies, 25% lower homocysteine is associated with about 10% less coronary heart disease (CHD) and about 20% less stroke. This review examines the current status of 12 large-scale randomized trials of B-vitamin supplementation and risk of cardiovascular disease. Seven of these trials are being performed in populations without fortification (five involving participants with prior CHD, two with prior stroke) and five in populations with fortification (two with prior CHD, two with renal disease, and one with prior stroke). Many of these trials may not have included a sufficient number of people or lasted long enough to have adequate power to exclude false-negative results. Taken together, however, these trials involve 32,000 patients with prior vascular disease in unfortified populations and 20,000 (14,000 with vascular disease and 6000 with renal disease) patients in fortified populations. A metaanalysis of these trials should have adequate power to determine whether homocysteine-lowering vitamin supplements can reduce the risk of cardiovascular disease.

The number of pregnancies affected by neural tube defects has been estimated to be 4000/year in Europe, with a higher prevalence in Celtic populations and in women of low socioeconomic status. Since the 1980s, it has been shown that supplementation with folic acid during the periconceptual period reduces the risk of neural tube defects in the fetus. However, in view of the period during which supplementation should be taken (< 4 weeks before conception until 8-10 weeks after) and the fact that in some countries 30-50% of pregnancies are unplanned, a public health initiative based solely on increasing dietary folate intake or recommendations on use of folic acid supplements is likely to be insufficient. Mandatory fortification has been started in 38 countries throughout the world. Several European countries have advocated mandatory flour folic acid fortification over the last 6 years, but none has introduced it. A recent public health decision in Hungary stimulated flour fortification on a voluntary basis, but it remains the only European country to take this action. Many European countries have deferred a decision to introduce fortification because of concerns about possible masking of vitamin B (12) deficiency. This review advocates a proposal for combined fortification of folic acid and vitamin B (12) to address possible hazards of fortification with folic acid alone.

The endothelium plays a key role in the pathophysiology of vascular disease. Impaired flow-mediated dilatation (FMD) is a measure of endothelial dysfunction resulting from reduced bioavailability of nitric oxide (NO). Patients with homocystinuria manifest with impaired FMD, but in mild hyperhomocysteinemia, the evidence is conflicting. Oral loading with methionine or homocysteine impairs FMD, but it remains unproven that this effect is mediated directly by homocysteine. In addition, there is no clear consensus as to a mechanisms by which homocysteine would induce endothelial dysfunction. Folate administration lowers plasma homocysteine and enhances FMD. However, the effect of folate only appears to occur at high doses and with a time course that would indicate that it is acting by a mechanism independent of homocysteine lowering. It is possible that folate, in pharmacological doses, may enhance the NO activity by influencing NO-tetrahydrobiopterin interactions. These studies provide some insights and raise intriguing questions concerning the relationship between homocysteine, folate, and endothelial function. However, changes in FMD may not translate into vascular endpoints, and the outcomes of clinical intervention trials with different doses of folic acid are awaited with interest.