BACKGROUND It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. METHODS We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. RESULTS The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P = 0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P = 0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P = 0.82). CONCLUSIONS Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized.

Ultraviolet radiation absorption is responsible for the production of free radicals in damaged cells. This side effect may be neutralized using antioxidant substances. It has been reported that ascorbic acid and d-alpha-tocopherol scavenge reactive oxygen species. In a single-blind controlled clinical trial we studied 45 healthy volunteers divided into three groups. Group 1 received d-alpha-tocopherol 1,200 I.U. daily; Group 2 ascorbic acid 2 g daily and Group 3 ascorbic acid 2 g plus d-alpha-tocopherol 1,200 I.U. daily. Treatment was sustained for one week. Before and after treatment, the minimal erythema dose was determined in all participants. The results show that the median minimal erythema dose increased from 60 to 65 mJ/cm2 in Group 1 and from 50 to 70 mJ/cm2 in Group 3. No modifications were observed in Group 2. We conclude that d-alpha-tocopherol prescribed in combination with ascorbic acid produces the best photoprotective effect.

In adult rabbit ventricular preparations, action potential duration is significantly increased when stimulation frequency is increased from 0.1 to 1.0 Hz. In neonatal preparations, a similar change in stimulation frequency produced no significant increase in action potential duration. To identify the ionic basis for this difference, we studied different outward currents in single myocytes from papillary muscle and from epicardial tissue of adult and neonatal rabbits. The densities of the outward currents in neonatal cells were about one-half of the current density in adult cells. The density of the voltage-activated transient outward current (I(to1)) was smaller in cells from papillary muscle than in cells from epicardium in adult and newborn rabbits. We found major differences in the kinetic behavior of I(to1) between adult and neonatal cells: 1) the rate of apparent inactivation was faster in neonatal cells, and 2) the recovery from inactivation was significantly faster in neonatal cells, with a time constant of 113 vs. 1,356 ms. We propose that this marked difference in the recovery from inactivation of I(to1) is the basis for the difference in frequency dependence of action potential duration.

Imipramine is a tricyclic antidepressant drug that also exhibits antiarrhythmic effects and whose clinical spectrum of activity is similar to that of quinidine. It has been previously demonstrated that imipramine inhibits the aggregate time-dependent outward K' current (IK). IK is composed of at least two components: a slowly activating La3"-resistant delayed rectifying current (IKS) and a rapidly activating sensitive current (IK,r). To assess the effects of imipramine on IK,r and IK,S, single guinea pig ventricular myocytes were studied using the nystatin-perforated patch-clamp technique in the absence and in the presence of La3`. Imipramine inhibited IK,, and IK,S in a concentration-dependent manner.The effects of imipramine on the aggregate time-dependent outward current were more marked than those on lK, alone.Thus, 1 ,umol/L imipramine decreased the tail currents elicited on return to -30 mV after long depolarizing pulses (5 seconds, from -40 to +50 mV) in the absence and in the presence of La3+ by 27±4% and 15±3% (n=6), respectively. Moreover, the inhibition induced by imipramine was greater after short (0.5-second) pulses than after 5-second depolarizing pulses, both in the absence and in the presence of La3+ (53+±3% and 30+5%, respectively; n=6; P<.05). Imipramine did not significantly modify either the activation midpoint or the slope factor of the aggregate IK and K,s activation curves. The reduction of 'K,S by imipramine was voltage dependent and was more marked at negative membrane potentials. In the presence of 1 ,umol/L imipramine, the ratio of tail current to time-dependent current remained constant at 0.37+0.03, regardless of the test pulse duration at +50 mV. Thus, the envelope-of-tails test was satisfied in the presence of 1 ,umol/L imipramine, which indicates that imipramine, at this concentration, blocks IK,r. Imipramine (1, 5, and 10 ,umol/L) had no effect on the kinetics of the later phase of 'K activation but delayed the beginning of the activation of lK, by 62±22, 74+23, and 155±53 milliseconds in the presence of 1, 5, and 10 ,umol/L imipramine, respectively. These results suggest that imipramine preferentially blocks rapidly activating K+ channels. In addition, experiments performed in the presence of 30 gmol/L La3+ suggest that the drug preferentially binds, but maybe not exclusively, to a closed state of the slowly activating

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