Add-on Therapy of EPA Reduces Oxidative Stress and Inhibits the Progression of Aortic Stiffness in Patients with Coronary Artery Disease and Statin Therapy: A Randomized Controlled Study

Abstract

Aim:We examined the anti-oxidant mechanisms of combined therapy of eicosapentaenoic acid (EPA) plus statin on the progression of atherosclerosis. Methods: Patients receiving statin therapy for dyslipidemia and with coronary artery disease (CAD) were assigned randomly in an open-label manner to the EPA (1,800 mg/day) -plus-statin group (n 25; combined-therapy group) or to the statin-only group (n 25), and followed for 48 weeks. At baseline and 48 weeks after enrollment, oxidative stress, brachial-ankle pulse wave velocity (baPWV) and stiffness parameter -index of the carotid were measured. Results: The lipid profile remained unchanged throughout the study. Although the median value of baPWV increased more in the statin-only group than in the combined-therapy group, this difference was not significant (p 0.29); however, a decrease in baPWV was associated with combined-therapy treatment by multiple regression analysis adjusted for age and mean blood pressure (p 0.04). In addition, the -index of the carotid was lower in the combined-therapy group than in the statin-only group (p 0.02). Furthermore, although the difference in the reduction of the urinary concentration of 8-isoprostane between the two groups did not reach statistical significance, this concentration was significantly lower in the combined-therapy group with higher baseline levels ( ≥ 183 pg/mL · Cr) of urinary 8-isoprostane (p 0.004). Conclusions: EPA may reduce oxidative stress and inhibit the progression of arterial stiffness more efficiently than statin-only therapy in patients with dyslipidemia and CAD. J Atheroscler Thromb, 2011; 18:857-866.

An Increase in the EPA/AA Ratio is Associated with Improved Arterial Stiffness in Obese Patients with Dyslipidemia

“…Our results were also compatible with previous reports showing the beneficial effects of EPA on atherogenic indices, such as the carotid artery IMT, brachial-ankle PWV (baPWV) and arterial stiffness assessed by the strain rate using tissue Doppler imaging [38][39][40] . The CAVI is correlated with the carotid IMT, an independent predictor of cardiovascular events, and is associated with the cardiac function and coronary atherosclerosis 41,42) .…”

Can pleiotropic effects of eicosapentaenoic acid (EPA) impact residual cardiovascular risk?

“…• Significant decreases in lumen diameter (P = 0.020) and % stenosis (P = 0.026) in EPA-plus-statin group vs. statin-alone group [36] • EPA was significantly associated with prevention of plaque progression compared with EPA plus DHA (P = 0.0061) in statin-treated patients with ACS [37] MDCT • Significant reduction in soft-plaque volume in EPA group but not in ezetimibe group; significant improvements in EPA group in plaque area (P = 0.017), lumen area (P = 0.004), and plaque volume vs. ezetimibe group (P = 0.036) [38] Carotid ultrasound • Significant decrease in IMT with EPA treatment vs. baseline (P < 0.05); IMT correlated with blood EPA concentration and EPA/AA ratio (P < 0.01) [39] • Significant annual decrease in mean IMT (P = 0.029) and maximal IMT (P = 0.0008) in EPA group vs. control group [40] • Significant decrease from baseline in maximal IMT with EPA treatment (P < 0.0001 after 6 and 12 months) [41] • No difference in change in baPWV observed between EPA/statin vs. statin-alone groups (P = 0.29); carotid β index was decreased in EPA/ statin group vs. statin-alone group (P = 0.02) [42] IVUS and IB-IVUS • Significant reduction in coronary plaque volume (total atheroma volume and % change in atheroma volume) in EPA-plus-statin group vs. statin-alone group (P < 0.01) [43] • Significant reduction in lipid volume (P = 0.005) and significant increase in fibrous volume (P = 0.01) in EPA-plus-statin group vs. statin-alone group [44] • Significant reductions in plaque and lipid volumes in EPA-plus-statin group vs. statin-alone group (P-value not given) [45] OCT…”

“…Multiple clinical studies have evaluated the effects of EPA (often in combination with a statin) on atherosclerotic plaques using a range of plaque imaging modalities including coronary angiography, computed tomographic angiography, multidetector computed tomography, and carotid artery intimamedia thickness as measured by ultrasound, intravascular ultrasound, and optical coherence tomography [21,[36][37][38][39][40][41][42][43][44][45][46][47]. Key results of these studies are highlighted in Table 1.…”

Eicosapentaenoic Acid Improves Glycemic Control in Elderly Bedridden Patients with Type 2 Diabetes

“…One mechanism attributed to the anti-atherosclerotic effects of EPA/DHA, such as these highlighted above, is that EPA/ DHA are PPAR-gamma (PPARγ) ligands that improve insulin resistance by stimulating PPARγ activity, while they inhibit inflammatory reactions, such as the activation of macrophages and IL-6 secretion, by suppressing nuclear factor kappa B (NF-κB) activity (Li et al 2005;Draper et al 2011;Jung et al 2012). EPA/DHA was recently reported to induce the Nrf2 signaling pathway, which leads to the suppression of oxidative stress, resulting in the inhibition of macrophage activation and of inflammation (Massaro et al 2008;Wang et al 2010;Majkova et al 2011;Takaki et al 2011;Contreras et al 2012;Malekshahi Moghadam et al 2012). EPA is also thought to activate macrophages and to suppress the secretion of MCP-1 and inflammatory cytokines, by modifying the decomposition of very low density lipoprotein (VLDL) in macrophages (Jinno et al 2011;Majkova et al 2011).…”