Oxidative stress during myocardial ischaemia and heart failure

As the terminaI electron acceptor for oxidative phosphorylation, molecular oxygen plays a key role in many ofthe metabolic processes associated with aerobic existence. Such 'thirst' for e\ectrons, however, also Ieads to the formation of a variety ·of reactive oxygen intermediates; oxygen species, which have either unpaired electrons (Le. O2' OH') or the ability to attract electrons from other molecules (Le. H202) [4]. Reactive oxygen intermediates react with cellular macromolecules, either damaging them directly or setting in motion a chain reaction wherein the free radicaI is passed from one macromolecule to another, resuIting in extensive damage to cellular structures, such as membranes. This paradoxical need for an ultimately toxic oxygen species must have presented a major hurdle during the earliest stages of aerobic evolution. In order to exploit O2 as a terminai electron acceptor for respiratory energy production, early Iife forms had to simultaneously develop an effective defensive system to cope with unwanted and toxic oxygen species. This latter requirement took the form of an elaborate arsenal of antioxidants, which function in concert to both scavenge and detoxify. Consequently, aerobic existence is accompanied by a persistent state of oxidative siege, wherein the survival of a given cell is determined by its balance of reactive oxygen intermediates and antioxidants

Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

BACKGROUND Vorapaxar is a new oral protease-activated–receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan–Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P = 0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P = 0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage