Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS).

BACKGROUND: Japan EPA Lipid Intervention Study (JELIS) was a large-scale clinical trial examining the effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemic patients. Herein, we focused on risk factors other than low-density lipoprotein cholesterol (LDL-C) to investigate the effects of EPA on CAD among JELIS primary prevention cases. METHODS: Hypercholesterolemic patients on statin therapy but without evidence of CAD (n=14,981) were randomly assigned to an EPA group (n=7503) or a control group (n=7478). The relationships between incident CAD, the number of CAD risk factors (hypercholesterolemia; obesity; high triglyceride (TG) or low high-density lipoprotein cholesterol (HDL-C); diabetes; and hypertension) and EPA treatment were investigated. RESULTS: For the control and EPA groups combined, a higher number of risk factors was directly associated with an increased incidence of CAD. Incidence was lower for the EPA group than for the control group regardless of the numbers of risk factors. Compared to patients with normal serum TG and HDL-C levels, those with abnormal levels (TG >or=150 mg/dL; HDL-C <40 mg/dL) had significantly higher CAD hazard ratio (HR: 1.71; 95% CI: 1.11-2.64; P=0.014). In this higher risk group, EPA treatment suppressed the risk of CAD by 53% (HR: 0.47; 95% CI: 0.23-0.98; P=0.043). CONCLUSIONS: Multiple risk factors besides cholesterol are associated with markedly increased incidence of CAD. High TG with low HDL-C represents a particularly potent risk factor. EPA was effective in reducing the incidence of CAD events for patients with this dyslipidemic pattern, suggesting that EPA may be especially beneficial in patients who with abnormal TG and HDL-C levels.

Gonadal hormones and frontocortical expression of vascular endothelial growth factor in male stroke-prone, spontaneously hypertensive rats, a model for attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (AD/HD) is a common pediatric behavioral disorder associated, in part, with male preponderance and reduced regional cerebral blood flow (rCBF). However, mechanism(s) underlying male preponderance and reduced rCBF in AD/HD are unclear. The present study profiles the expression of angiogenic and hormonal factors likely to underlie these symptoms using a recently characterized AD/HD animal model, juvenile male stroke-prone spontaneously hypertensive rats (SHRSP). Because vascular endothelial growth factor (VEGF) signaling cascade and gonadal steroids are key regulators of angiogenesis and gender-based behavior, respectively, we profiled their patterns of expression in the frontal cortex of SHRSP to elucidate their roles in the genesis of AD/HD male preponderance and rCBF. Interestingly, levels of VEGF, VEGF receptors (KDR, Flt-1), endothelial nitric oxide synthase, phosphorylated Akt (pAkt), estrogen receptor-alpha, aromatase, and capillary density in sham-operated SHRSP were remarkably down-regulated, whereas androgen receptor levels were up-regulated, compared with age-matched genetic control, Wistar-Kyoto rats. Castration, estrogen, and androgen receptor antagonist (flutamide) counteracted these effects. Dihydrotestosterone, but not testosterone, reversed the beneficiary effects of castration. Estrogen receptor-beta levels remained unchanged in all groups examined. We postulate that changes in androgen metabolism that tend to up-regulate local dihydrotestosterone concentration and diminish estrogen synthesis, in the frontal cortex of juvenile male SHRSP, may lower levels and/or activity of VEGF and its signaling cascade and, subsequently, reduce rCBF. These findings could, in part, help explain the pathogenesis of reduced rCBF and male preponderance in AD/HD.