SUN-081 Eicosapentaenoic Acid Administration Ameliorates Cardiac Remodeling In Humans And Protects Against Ang Ii-induced Cardiovascular Remodeling Via Attenuation Of Oxidative Stress In Mice.

Background & Objective: Eicosapentaenoic acid (EPA), the major n-3 polyunsaturated fatty acid, reduces risk of cardiovascular events. However, the molecular mechanism underlying the cardiovascular protection by EPA remains unclear. Therefore, we evaluated the clinical effects of EPA against cardiac remodeling in subjects with cardiovascular risk factors and assessed mechanisms of EPA in cardiovascular remodeling of an angiotensin II-treated mouse model. Methods & Results: Clinical study: A total of 25 Japanese subjects were orally administered purified EPA (average dosage of 1630 mg per day) and underwent echocardiographic examinations before and after medication (average observation period of 14 months). Although EPA treatment did not affect left ventricular systolic function, EPA supplementation reduced left ventricular mass index (103.1±23.4 to 98.4±22.3 g/m(2), p<0.05) and ameliorated the ratio of peak E velocity to early diastolic mitral annulus velocity (E/e' ratio) (10.73±3.95 to 7.77±2.76, P<0.01) as a surrogate marker of left ventricular diastolic dysfunction. Animal study: Eight-week-old C57BL/6 male mice were fed normal diet chow (control group) or EPA-rich diet (5% EPA) (EPA group) and infused with angiotensin II (Ang II) (2.0 mg/kg/day) for 14 days. Ang II stimulation markedly increased medial thickness and perivascular fibrosis of the coronary artery and aorta and caused cardiac concentric change with increased interstitial cardiac fibrosis in the control group; however, EPA administration significantly ameliorated those Ang II-induced cardiovascular adverse phenotypes. In addition, EPA administration reduced surrogate markers of oxidative stress, such as urinary excretion of 8-hydroxy-2'-deoxyguanosine, plasma level of derivatives of reactive oxygen metabolites and cardiovascular superoxide production with attenuation of gene expression levels of NADPH oxidase components, including p22 phox and p67 phox, and Rac1 activation. Conclusions: EPA administration ameliorates cardiac remodeling in humans and protects against Ang II-induced cardiovascular remodeling via attenuation of oxidative stress in mice.