BACKGROUND The purpose of this study was to compare combination antithrombotic therapy with aspirin plus anticoagulation versus aspirin alone, when added to conventional antianginal therapy in patients with unstable rest angina or non-Q-wave myocardial infarction who were nonprior aspirin users. METHODS AND RESULTS Two hundred fourteen patients were randomized; 109 were randomized to receive aspirin alone (162.5 mg daily) and 105 to receive a combination of aspirin plus anticoagulation, ie, aspirin 162.5 mg daily plus heparin (activated partial thromboplastin time, two times control) followed by aspirin 162.5 mg daily plus warfarin (international normalized ratio, 2 to 3). Trial therapy was begun by 9.5 +/- 8.8 hours of qualifying pain and was continued for 12 weeks. Primary end points were recurrent angina with ECG changes, myocardial infarction, and/or death. Analysis by intention to treat of primary events at 12 weeks was performed. At 14 days, there was a significant reduction in total ischemic events in the combination group versus aspirin alone (10.5% versus 27%, P = .004). An efficacy analysis of primary events at 12 weeks also revealed a large reduction in total ischemic events in the combination group versus aspirin alone (13% versus 25%, P = .06). Bleeding complications were slightly more common with combination therapy. CONCLUSIONS In nonprior aspirin users, combination antithrombotic therapy with aspirin plus anticoagulation significantly reduces recurrent ischemic events in the early phase of unstable angina.

Mildly elevated plasma homocysteine levels are an independent risk factor for atherothrombotic vascular disease in the coronary, cerebrovascular, and peripheral arterial circulation. Endothelial dysfunction as manifested by impaired endothelium-dependent regulation of vascular tone and blood ow, by increased recruitment and adhesion of circulating in ammatory cells to the endothelium, and by a loss of endothelial cell antithrombotic function contributes to the vascular disorders linked to hyperhomocysteinemia. Increased vascular oxidant stress through imbalanced thiol redox status and inhibition of important antioxidant enzymes by homocysteine results in decreased bioavailability of the endothelium-derived signaling molecule nitric oxide via oxidative inactivation. This plays a central role in the molecular mechanisms underlying the effects of homocysteine on endothelial function. Supplementation of folic acid and vitamin B 1 2 has been demonstrated to be ef cient in lowering mildly elevated plasma homocysteine levels and in reversing homocysteine-induced impairment of endothelium-dependent vasoreactivity. Results from ongoing intervention trials will determine whether homocysteine-lowering therapies contribute to the prevention and reduction of atherothrombotic vascular disease and may thereby provide support for the causal relationship between hyperhomocysteinemia and atherothrombosis.

Abstract. The efficacy of the heparin-induced extracorporeal LDL-precipitation (HELP)-apheresis procedure has been studied in an open prospective multicentre trial. After 2 years of regular weekly HELP-treatment the data from 39 of 51 patients could be evaluated according to the study criteria. Twelve of the initially recruited study patients were omitted from the evaluation either because of premature termination of the treatment or because they did not fulfil the exact guidelines of the study protocol. A mean of 2.83 1 plasma was regularly treated on average every 7.85 days. The mean pre-/post-apheresis LDLcholesterol levels decreased from 286/121 mgdl-' at the first HELP treatment to 203/77mgdl-l after 1 year and to 205/77mgdl-' after 2 years of regular apheresis; the corresponding values for fibrinogen were 314/144, 246/98 and 250/105 mgdl-', respectively. In contrast, the mean pre-/post-apheresis HDLcholesterol levels rose from 41/38 through 511 44mgdl-' after 1 year to 52/43mgdl-' after 2 years of treatment. The overall result was a normalization of the atherogenic index (LDL-/HDL-cholesterol ratio) from 6.9/3.2 to 4*0/1.9. The angiographies from 33 patients obtained before and after 2 years of regular treatment could be evaluated blindly using the cardiovascular angiography analysis system. The mean degree of stenosis of all segments decreased from (26.7%) segments, whereas 29/187 (15.5%) segments showed progression. In 108/187 (57.8%) segments the lesions were stable (< 8% deviation) over 2 years. We conclude that regular treatment with HELP-LDLapheresis is able to stabilize progressive atherosclerotic disease and to induce almost twice as much regression as progression of atherosclerotic lesions.

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. An increasing body of evidence has implicated oxidative stress as being contributory to homocysteine's deleterious effects on the vasculature. Elevated levels of homocysteine may lead to increased generation of superoxide by a biochemical mechanism involving nitric oxide synthase, and, to a lesser extent, by an increase in the chemical oxidation of homocysteine and other aminothiols in the circulation. The resultant increase in superoxide levels is further amplified by homocysteinedependent alterations in the function of cellular antioxidant enzymes such as cellular glutathione peroxidase or extracellular superoxide dismutase. One direct clinical consequence of elevated vascular superoxide levels is the inactivation of the vasorelaxant messenger nitric oxide, leading to endothelial dysfunction. Scavenging of superoxide anion by either superoxide dismutase or 4,5-dihydroxybenzene 1,3-disulfonate (Tiron) reverses endothelial dysfunction in hyperhomocysteinemic animal models and in isolated aortic rings incubated with homocysteine. Similarly, homocysteine-induced endothelial dysfunction is also reversed by increasing the concentration of the endogenous antioxidant glutathione or overexpressing cellular glutathione peroxidase in animal models of mild hyperhomocysteinemia. Taken together, these findings strongly suggest that the adverse vascular effects of homocysteine are at least partly mediated by oxidative inactivation of nitric oxide.

Objective-Previous studies have shown that elevated homocysteine (Hcy) levels promote the development of atherosclerotic lesions in atherosclerosis-prone animal models. There is evidence that oxidant stress contributes to Hcy's deleterious effects on the vasculature. The accumulation and adhesion of monocytes to the vascular endothelium is a critical event in the development of atherosclerosis. We investigated the effects of Hcy on the interaction between human endothelial cells (EC) (EC line EA.hy 926 and primary human umbilical vein EC [HUVEC]) and the monocytic cell line THP-1, and the impact of vascular oxidant stress and redox-sensitive signaling pathways on these events. Methods and Results-L-Hcy, but not D-Hcy, increases the production of reactive oxygen species inside EC, enhances nuclear factor(NF)-B activation, and stimulates intercellular adhesion molecule-1 (ICAM-1) RNA transcription and cell surface expression. This leads to a time-and dose-dependent increase in monocyte adhesion to ECs. Pretreatment of ECs with superoxide scavengers (MnTBAP and Tiron) or with an inhibitor of NF-B activation abolished Hcy-induced monocyte adhesion, ICAM-1 expression, and nuclear translocation of NF-B. Conclusions-These findings suggest that reactive oxygen species produced under hyperhomocysteinemic conditions may induce a proinflammatory situation in the vessel wall that initiates and promotes atherosclerotic lesion development. A key event in the vascular pathobiology associated with hyperhomocysteinemia is the induction of endothelial dysfunction. 1 This can be detected by impaired endotheliumdependent vasodilator function in animal models of mild hyperhomocystinemia 2-4 and in patients with either acutely 5 or chronically 6 elevated plasma homocysteine (Hcy) levels. It indicates a reduction in bioavailable nitric oxide (NO). This is thought to be caused by increased vascular oxidant stress under hyperhomocysteinemic conditions leading to inactivation of NO 7 and/or to elevated plasma levels of the NO synthase inhibitor asymmetrical dimethylarginine leading to decreased synthesis. 8,9 Endothelial dysfunction not only impairs regulation of vasomotion but also affects the regulation of interactions of the endothelium with circulating inflammatory cells, of endothelium-dependent thrombotic and fibrinolytic mechanisms, and of cell growth within the vessel wall. 10 Recently it has been shown that exposure of cultured endothelial cells (ECs) to Hcy leads to endothelial activation resulting in increased expression of chemokines 11 and adhesion molecules. 12-14 Furthermore, increased P-selectin expression by activated EC and/or platelets has been shown in plasma and aortic sections of mildly hyperhomocysteinemic heterozygous cystathionine ␤ synthase-deficient mice. 4 Induction of hyperhomocysteinemia in apolipoprotein E-null mice enhanced the expression of receptors for advanced glycation end products, vascular cell adhesion molecule (VCAM)-1, E-selectin, tissue factor (TF), and matrix metalloproteinase (MMP)-9 in th...