Publications

The sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P) pathway, known to determine the fate and growth of various cell types, can enhance cardiac myocyte survival in vitro and provide cardioprotection in acute ex vivo heart preparations. However, the relevance of these findings to chronic cardiac pathology has never been demonstrated. We hypothesized that S1P signaling is impaired during chronic remodeling of the uninfarcted ventricle during the evolution of post-myocardial infarction (MI) cardiomyopathy and that a therapeutic enhancement of S1P signaling would ameliorate ventricular dysfunction. SphK expression and activity were measured in the remote, uninfarcted myocardium (RM) of C57Bl/6 mice subjected to coronary artery ligation. The mRNA expression of S1P receptor isoforms was also measured, as was the activation of the downstream S1P receptor mediators. A cardioprotective role for S1P(1) receptor agonism was tested via the administration of the S1P(1)-selective agonist SEW2871 during and after MI. As a result, the expression data suggested that a dramatic reduction in SphK activity in the RM early after MI may reflect a combination of posttranscriptional and posttranslational modulation. SphK activity continued to decline gradually during chronic post-MI remodeling, when S1P(1) receptor mRNA also fell below baseline. The S1P(1)-specific agonism with oral SEW2871 during the first 2-wk after MI reduced apoptosis in the RM and resulted in improved myocardial function, as reflected in the echocardiographic measurement of fractional shortening. In conclusion, these results provide the first documentation of alterations in S1P-mediated signaling during the in situ development of cardiomyopathy and suggest a possible therapeutic role for the pharmacological S1P receptor agonism in the post-MI heart.

BACKGROUND

The Raloxifene Use for The Heart (RUTH) trial showed that raloxifene, a selective estrogen receptor modulator, had no overall effect on the incidence of coronary events in women with established coronary heart disease or coronary heart disease risk factors. We provide detailed results of the effect of raloxifene on coronary outcomes over time and for 24 subgroups (17 predefined, 7 post hoc).

METHODS AND RESULTS

Postmenopausal women (n=10 101; mean age, 67 years) were randomized to raloxifene 60 mg/d or placebo for a median of 5.6 years. Coronary outcomes were assessed by treatment group in women with coronary heart disease risk factors and those with established coronary heart disease. Raloxifene had no effect on the incidence of coronary events in any subgroup except in the case of a post hoc age subgroup analysis using age categories defined in the Women's Health Initiative randomized trials. The effect of raloxifene on the incidence of coronary events differed significantly by age (interaction P=0.0118). The incidence of coronary events in women <60 years of age was significantly lower in those assigned raloxifene (50 events) compared with placebo (84 events; hazard ratio, 0.59; 95% confidence interval, 0.41 to 0.83; P=0.003; absolute risk reduction, 36 per 1000 women treated for 1 year). No difference was found between treatment groups in the incidence of coronary events in women > or =60 and <70 or > or =70 years of age.

CONCLUSIONS

In postmenopausal women at increased risk of coronary events, the overall lack of benefit of raloxifene was similar across the prespecified subgroups.