on behalf of the GISSI-Prevenzione InvestigatorsBackground-Our purpose was to assess the time course of the benefit of n-3 polyunsaturated fatty acids (PUFAs) on mortality documented by the GISSI-Prevenzione trial in patients surviving a recent (Ͻ3 months) myocardial infarction. Methods and Results-In this study, 11 323 patients were randomly assigned to supplements of n-3 PUFAs, vitamin E (300 mg/d), both, or no treatment (control) on top of optimal pharmacological treatment and lifestyle advice. Intention-to-treat analysis adjusted for interaction between treatments was carried out. Early efficacy of n-3 PUFA treatment for total, cardiovascular, cardiac, coronary, and sudden death; nonfatal myocardial infarction; total coronary heart disease; and cerebrovascular events was assessed by right-censoring follow-up data 12 times from the first month after randomization up to 12 months. Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk [RR] 0.59; 95% CI 0.36 to 0.97; Pϭ0.037). The reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months (RR 0.47; 95% CI 0.219 to 0.995; Pϭ0.048). A similarly significant, although delayed, pattern after 6 to 8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths. Conclusions-The early effect of low-dose (1 g/d) n-3 PUFAs on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of this drug. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, and epidemiological and clinical studies.

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Diabetes mellitus is associated with platelet hyperactivity, which leads to increased morbidity and mortality from cardiovascular disease. This is coupled with enhanced levels of thromboxane (TX), an eicosanoid that facilitates platelet aggregation. Although intensely studied, the mechanism underlying the relationship among hyperglycemia, TX generation, and platelet hyperactivity remains unclear. We sought to identify key signaling components that connect high levels of glucose to TX generation and to examine their clinical relevance. In human platelets, aldose reductase synergistically modulated platelet response to both hyperglycemia and collagen exposure through a pathway involving ROS/PLCγ2/PKC/p38α MAPK. In clinical patients with platelet activation (deep vein thrombosis; saphenous vein graft occlusion after coronary bypass surgery), and particularly those with diabetes, urinary levels of a major enzymatic metabolite of TX (11-dehydro-TXB 2 [TX-M]) were substantially increased. Elevated TX-M persisted in diabetic patients taking low-dose aspirin (acetylsalicylic acid, ASA), suggesting that such patients may have underlying endothelial damage, collagen exposure, and thrombovascular disease. Thus, our study has identified multiple potential signaling targets for designing combination chemotherapies that could inhibit the synergistic activation of platelets by hyperglycemia and collagen exposure. IntroductionAccelerated atherosclerosis and microvascular disease contribute to the morbidity and mortality associated with diabetes mellitus (DM) (1-3). Vascular inflammation, endothelial dysfunction associated with hyperglycemia, impaired fibrinolysis, and increased coagulation factors as well as abnormal platelet function are typical for DM, contributing to the increased thrombotic events and development of arteriosclerosis (4). Altered platelet function in DM, including altered adhesion and aggregation, may contribute to the pathogenesis of DM vascular complications by promoting microthrombus formation, contributing to enhanced risk of small vessel occlusions and accelerated atherothrombotic diseases (5, 6). Patients with type 2 DM (T2DM) exhibit platelet hyperreactivity both in vitro and in vivo, coupled with biochemical evidence of persistently increased thromboxane-dependent (TX-dependent) platelet activation (7,8). Despite many important studies, the mechanism by which platelets transduce glucose levels into enhanced TX generation independently of endothelial and other blood cell-derived factors remains unclear. Similarly, optimal antiplatelet therapy for DM patients remains to be achieved.Aldose reductase (AR) is the first enzyme of the polyol pathway, and it represents a minor source of glucose utilization, accounting for less than 3% of glucose consumption during euglycemia.

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Naturally occurring antioxidants such as vitamin E, beta-carotene, and vitamin C can inhibit the oxidative modification of low density lipoproteins. This action could positively influence the atherosclerotic process and, as a consequence, the progression of coronary heart disease. A wealth of experimental studies provide a sound biological rationale for the mechanisms of action of antioxidants, whereas epidemiologic studies strongly sustain the "antioxidant hypothesis." To date, however, clinical trials with beta-carotene supplements have been disappointing, and their use as a preventive intervention for cancer and coronary heart disease should be discouraged. Only scanty data from clinical trials are available for vitamin C. As to vitamin E, discrepant results have been obtained by the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study with a low-dose vitamin E supplementation (50 mg/d) and the Cambridge Heart Antioxidant Study (400-800 mg/d). The results of the GISSI-Prevenzione (300 mg/d) and HOPE (400 mg/d) trials suggest the absence of relevant clinical effects of vitamin E on the risk of cardiovascular events. Currently ongoing are several large-scale clinical trials that will help in clarifying the role of vitamin E in association with other antioxidants in the prevention of atherosclerotic coronary disease.