Aims Despite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains. Icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, added to a statin was shown to reduce initial CV events by 25% and total CV events by 32% in the REDUCE-IT trial, with the mechanisms of benefit not yet fully explained. The EVAPORATE trial sought to determine whether IPE 4 g/day, as an adjunct to diet and statin therapy, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in statin-treated patients. Methods and results A total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis as documented by MDCT (one or more angiographic stenoses with ≥20% narrowing), be on statin therapy, and have persistently elevated triglyceride (TG) levels. Patients underwent an interim scan at 9 months and a final scan at 18 months with coronary computed tomographic angiography. The pre-specified primary endpoint was changed in low-attenuation plaque (LAP) volume at 18 months between IPE and placebo groups. Baseline demographics, vitals, and laboratory results were not significantly different between the IPE and placebo groups; the median TG level was 259.1 ± 78.1 mg/dL. There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061). There were significant differences in rates of progression between IPE and placebo at study end involving other plaque volumes including fibrous, and fibrofatty (FF) plaque volumes which regressed in the IPE group and progressed in the placebo group (P < 0.01 for all). When further adjusted for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups remained significantly different, P < 0.01. Only dense calcium did not show a significant difference between groups in multivariable modelling (P = 0.053). Conclusions Icosapent ethyl demonstrated significant regression of LAP volume on MDCT compared with placebo over 18 months. EVAPORATE provides important mechanistic data on plaque characteristics that may have relevance to the REDUCE-IT results and clinical use of IPE.
We tested the hypothesis that chronic treatment with sildenafil attenuates myocardial infarction (MI)-induced heart failure. Sildenafil has potent protective effects against necrosis and apoptosis following ischemia-reperfusion in the intact heart and cardiomyocytes. ICR mice underwent MI by left anterior descending coronary artery ligation and were treated with sildenafil (0.71 mg/kg bid) or saline for 4 wk. Infarct size (IS) was measured 24 h postinfarction, and apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Left ventricular end-diastolic diameter (LVEDD) and fractional shortening (FS) were measured by echocardiography. Sildenafil reduced IS (40.0 +/- 4.6%) compared with that in saline (69.6 +/- 4.1%, P < 0.05). NG-nitro-l-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor (15 mg/kg bid), blocked the protective effect of sildenafil (IS, 60.2 +/- 1.6%, P < 0.05 vs. sildenafil). Western blot analysis revealed a significant increase in endothelial NOS/inducible NOS proteins 24 h post-MI after treatment with sildenafil versus saline. Apoptosis decreased from 2.4 +/- 0.3% with saline to 1.2 +/- 0.1% with sildenafil (P < 0.05) on day 7 and from 2.0 +/- 0.2% with saline to 1.2 +/- 0.1% with sildenafil on day 28 (P < 0.05), which was associated with an early increase in the Bcl-2-to-Bax ratio. LVEDD increased from baseline value of 3.6 +/- 0.1 to 5.2 +/- 0.2 and to 5.5 +/- 0.1 mm on days 7 and 28, respectively, with saline (P < 0.05) but was attenuated to 4.4 +/- 0.2 and 4.4 +/- 0.1 mm following sildenafil treatment on days 7 and 28, respectively (P > 0.05 vs. baseline). FS significantly improved post-MI with sildenafil. A marked decline in cardiac hypertrophy was observed with sildenafil, which paralleled a reduction in pulmonary edema. Survival rate was lower with saline (36%) compared with sildenafil (93%, P < 0.05). Sildenafil attenuates ischemic cardiomyopathy in mice by limiting necrosis and apoptosis and by preserving left ventricular function possibly through a nitric oxide-dependent pathway.
We tested the hypothesis that chronic treatment with sildenafil attenuates myocardial infarction (MI)-induced heart failure. Sildenafil has potent protective effects against necrosis and apoptosis following ischemia-reperfusion in the intact heart and cardiomyocytes. ICR mice underwent MI by left anterior descending coronary artery ligation and were treated with sildenafil (0.71 mg/kg bid) or saline for 4 wk. Infarct size (IS) was measured 24 h postinfarction, and apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Left ventricular end-diastolic diameter (LVEDD) and fractional shortening (FS) were measured by echocardiography. Sildenafil reduced IS (40.0 +/- 4.6%) compared with that in saline (69.6 +/- 4.1%, P < 0.05). NG-nitro-l-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor (15 mg/kg bid), blocked the protective effect of sildenafil (IS, 60.2 +/- 1.6%, P < 0.05 vs. sildenafil). Western blot analysis revealed a significant increase in endothelial NOS/inducible NOS proteins 24 h post-MI after treatment with sildenafil versus saline. Apoptosis decreased from 2.4 +/- 0.3% with saline to 1.2 +/- 0.1% with sildenafil (P < 0.05) on day 7 and from 2.0 +/- 0.2% with saline to 1.2 +/- 0.1% with sildenafil on day 28 (P < 0.05), which was associated with an early increase in the Bcl-2-to-Bax ratio. LVEDD increased from baseline value of 3.6 +/- 0.1 to 5.2 +/- 0.2 and to 5.5 +/- 0.1 mm on days 7 and 28, respectively, with saline (P < 0.05) but was attenuated to 4.4 +/- 0.2 and 4.4 +/- 0.1 mm following sildenafil treatment on days 7 and 28, respectively (P > 0.05 vs. baseline). FS significantly improved post-MI with sildenafil. A marked decline in cardiac hypertrophy was observed with sildenafil, which paralleled a reduction in pulmonary edema. Survival rate was lower with saline (36%) compared with sildenafil (93%, P < 0.05). Sildenafil attenuates ischemic cardiomyopathy in mice by limiting necrosis and apoptosis and by preserving left ventricular function possibly through a nitric oxide-dependent pathway.
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