Skip to main content

Advertisement

SpringerLink
Log in

Eicosapentaenoic Acid Combined with Optimal Statin Therapy Improves Endothelial Dysfunction in Patients with Coronary Artery Disease

  • ORIGINAL ARTICLE
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

Eicosapentaenoic acid (EPA) has been reported to augment endothelial function and improve clinical outcomes in patients with coronary artery disease (CAD). The purpose of this study was to determine whether EPA could improve residual endothelial dysfunction despite adequate lipid-lowering with statin in CAD patients.

Methods

Eighty patients with established CAD, who had been on statin treatment and had serum low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dl, were randomly assigned to receive either 1,800 mg of EPA daily plus statin (EPA group, n = 40) or statin alone (Control group, n = 40). Lipid profiles and flow-mediated dilation (FMD) were assessed just before and after more than 3 months of treatment in both groups. Only patients who had impaired FMD (<6 %) before randomization were enrolled.

Results

After treatment for 5.2 ± 1.7 months, the EPA group showed a significant increase in the serum concentration of EPA and EPA to arachidonic acid (AA) (EPA/AA) ratio (62.5 ± 38.1 to 159.8 ± 53.8 μg/ml, 0.45 ± 0.34 to 1.20 ± 0.55, p < 0.01 for both). In the EPA group, serum triglycerides significantly decreased (150.7 ± 92.9 to 119.3 ± 60.7 mg/dl, p = 0.02), whereas no significant change was seen in the Control group. FMD, the primary study endpoint, showed a significant improvement in the EPA group (2.6 ± 1.6 % to 3.2 ± 1.6 %, p = 0.02), whereas no significant change was observed in the Control group (2.7 ± 1.6 % to 2.4 ± 1.7 %, p = 0.29).

Conclusions

EPA improved endothelial function and impaired FMD in patients with established CAD who were on optimal statin therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol. 2008;52:1769–81.

    Article  CAS  PubMed  Google Scholar 

  2. Brugts JJ, Yetgin T, Hoeks SE, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ. 2009;338:b2376.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–78.

    Article  CAS  PubMed  Google Scholar 

  4. ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.

    Article  Google Scholar 

  5. The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.

    Article  Google Scholar 

  6. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2:757–61.

    Article  CAS  PubMed  Google Scholar 

  7. GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico). Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354:447–55.

    Article  Google Scholar 

  8. Daviglus ML, Stamler J, Orencia AJ, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med. 1997;336:1046–53.

    Article  CAS  PubMed  Google Scholar 

  9. Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA. 2002;287:1815–21.

    Article  CAS  PubMed  Google Scholar 

  10. Iso H, Kobayashi M, Ishihara J, et al. Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I. Circulation. 2006;113:195–202.

    Article  CAS  PubMed  Google Scholar 

  11. Ueeda M, Doumei T, Takaya Y, et al. Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction. Heart Vessels. 2011;26:145–52.

    Article  PubMed  Google Scholar 

  12. Matsuzaki M, Yokoyama M, Saito Y, et al. Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease. Circ J. 2009;73:1283–90.

    Article  CAS  PubMed  Google Scholar 

  13. Nakamura N, Hamazaki T, Ohta M, et al. Joint effects of HMG-CoA reductase inhibitors and eicosapentaenoic acids on serum lipid profile and plasma fatty acid concentrations in patients with hyperlipidemia. Int J Clin Lab Res. 1999;29:22–5.

    Article  CAS  PubMed  Google Scholar 

  14. Carrepeiro MM, Rogero MM, Bertolami MC, Botelho PB, Castro N, Castro IA. Effect of n-3 fatty acids and statins on oxidative stress in statin-treated hypercholestorelemic and normocholesterolemic women. Atherosclerosis. 2011;217:171–8.

    Article  CAS  PubMed  Google Scholar 

  15. Widlansky ME, Gokce N, Keaney Jr JF, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003;42:1149–60.

    Article  CAS  PubMed  Google Scholar 

  16. Gokce N, Keaney Jr JF, Hunter LM, Watkins MT, Menzoian JO, Vita JA. Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation. 2002;105:1567–72.

    Article  PubMed  Google Scholar 

  17. Yeboah J, Crouse JR, Hsu FC, Burke GL, Herrington DM. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation. 2007;115:2390–7.

    Article  PubMed  Google Scholar 

  18. Smith Jr SC, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. 2011;124:2458–73.

    Article  PubMed  Google Scholar 

  19. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39:257–65.

    Article  PubMed  Google Scholar 

  20. Tomiyama H, Matsumoto C, Yamada J, et al. The relationships of cardiovascular disease risk factors to flow-mediated dilatation in Japanese subjects free of cardiovascular disease. Hypertens Res. 2008;31:2019–25.

    Article  PubMed  Google Scholar 

  21. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090–8.

    Article  CAS  PubMed  Google Scholar 

  22. Nodari S, Metra M, Milesi G, et al. The role of n-3 PUFAs in preventing the arrhythmic risk in patients with idiopathic dilated cardiomyopathy. Cardiovasc Drugs Ther. 2009;23:5–15.

    Article  CAS  PubMed  Google Scholar 

  23. Baumann KH, Hessel F, Larass I, et al. Dietary omega-3, omega-6, and omega-9 unsaturated fatty acids and growth factor and cytokine gene expression in unstimulated and stimulated monocytes. A randomized volunteer study. Arterioscler Thromb Vasc Biol. 1999;19:59–66.

    Article  CAS  PubMed  Google Scholar 

  24. Engler MB. Vascular relaxation to omega-3 fatty acids: comparison to sodium nitroprusside, nitroglycerin, papaverine, and D600. Cardiovasc Drugs Ther. 1992;6:605–10.

    Article  CAS  PubMed  Google Scholar 

  25. Fleischhauer FJ, Yan WD, Fischell TA. Fish oil improves endothelium-dependent coronary vasodilation in heart transplant recipients. J Am Coll Cardiol. 1993;21:982–9.

    Article  CAS  PubMed  Google Scholar 

  26. Goodfellow J, Bellamy MF, Ramsey MW, Jones CJ, Lewis MJ. Dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. J Am Coll Cardiol. 2000;35:265–70.

    Article  CAS  PubMed  Google Scholar 

  27. Knapp HR. Dietary fatty acids in human thrombosis and hemostasis. Am J Clin Nutr. 1997;65:1687S–98S.

    CAS  PubMed  Google Scholar 

  28. Jacobson TA. Role of n-3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease. Am J Clin Nutr. 2008;87:1981S–90S.

    CAS  PubMed  Google Scholar 

  29. Kawano H, Yano T, Mizuguchi K, Mochizuki H, Saito Y. Changes in aspects such as the collagenous fiber density and foam cell size of atherosclerotic lesions composed of foam cells, smooth muscle cells and fibrous components in rabbits caused by all-cis-5, 8, 11, 14, 17-icosapentaenoic acid. J Atheroscler Thromb. 2002;9:170–7.

    CAS  PubMed  Google Scholar 

  30. Takase B, Uehata A, Akima T, et al. Endothelium-dependent flow-mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease. Am J Cardiol. 1998;82:1535–9.

    Article  CAS  PubMed  Google Scholar 

  31. Cohn JN, Quyyumi AA, Hollenberg NK, Jamerson KA. Surrogate markers for cardiovascular disease: functional markers. Circulation. 2004;109:IV31–46.

    Article  PubMed  Google Scholar 

  32. Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol. 2002;40:505–10.

    Article  PubMed  Google Scholar 

  33. Kubota Y, Miyamoto M, Takagi G, et al. The dipeptidyl peptidase-4 inhibitor sitagliptin improves vascular endothelial function in type 2 diabetes. J Korean Med Sci. 2012;27:1364–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Westerink J, Deanfield JE, Imholz BP, et al. High-dose statin monotherapy versus low-dose statin/ezetimibe combination on fasting and postprandial lipids and endothelial function in obese patients with the metabolic syndrome: The PANACEA study. Atherosclerosis. 2013;227:118–24.

    Article  CAS  PubMed  Google Scholar 

  35. Nakamura T, Hirano M, Kitta Y, et al. A comparison of the efficacy of combined ezetimibe and statin therapy with doubling of statin dose in patients with remnant lipoproteinemia on previous statin therapy. J Cardiol. 2012;60:12–7.

    Article  PubMed  Google Scholar 

  36. Nishimura M, Nanbu A, Komori T, Ohtsuka K, Takahashi H, Yoshimura M. Eicosapentaenoic acid stimulates nitric oxide production and decreases cardiac noradrenaline in diabetic rats. Clin Exp Pharmacol Physiol. 2000;27:618–24.

    Article  CAS  PubMed  Google Scholar 

  37. Omura M, Kobayashi S, Mizukami Y, et al. Eicosapentaenoic acid (EPA) induces Ca(2+)-independent activation and translocation of endothelial nitric oxide synthase and endothelium-dependent vasorelaxation. FEBS Lett. 2001;487:361–6.

    Article  CAS  PubMed  Google Scholar 

  38. Domei T, Yokoi H, Kuramitsu S, et al. Ratio of serum n-3 to n-6 polyunsaturated fatty acids and the incidence of major adverse cardiac events in patients undergoing percutaneous coronary intervention. Circ J. 2012;76:423–9.

    Article  CAS  PubMed  Google Scholar 

  39. Tapiero H, Ba GN, Couvreur P, Tew KD. Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies. Biomed Pharmacother. 2002;56:215–22.

    Article  CAS  PubMed  Google Scholar 

  40. Chowienczyk PJ, Watts GF, Wierzbicki AS, Cockcroft JR, Brett SE, Ritter JM. Preserved endothelial function in patients with severe hypertriglyceridemia and low functional lipoprotein lipase activity. J Am Coll Cardiol. 1997;29:964–8.

    Article  CAS  PubMed  Google Scholar 

  41. Rizza S, Tesauro M, Cardillo C, et al. Fish oil supplementation improves endothelial function in normoglycemic offspring of patients with type 2 diabetes. Atherosclerosis. 2009;206:569–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Griffin MD, Sanders TA, Davies IG, et al. Effects of altering the ratio of dietary n-6 to n-3 fatty acids on insulin sensitivity, lipoprotein size, and postprandial lipemia in men and postmenopausal women aged 45–70 y: the OPTILIP Study. Am J Clin Nutr. 2006;84:1290–8.

    CAS  PubMed  Google Scholar 

  43. Nordoy A, Bonaa KH, Sandset PM, et al. Effect of omega-3 fatty acids and simvastatin on hemostatic risk factors and postprandial hyperlipemia in patients with combined hyperlipemia. Arterioscler Thromb Vasc Biol. 2000;20:259–65.

    Article  CAS  PubMed  Google Scholar 

  44. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504.

    Article  CAS  PubMed  Google Scholar 

  45. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–35.

    Article  CAS  PubMed  Google Scholar 

  46. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs. usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437–45.

    Article  CAS  PubMed  Google Scholar 

  47. Meyer BJ. Are we consuming enough long chain omega-3 polyunsaturated fatty acids for optimal health? Prostaglandins Leukot Essent Fatty Acids. 2011;85:275–80.

    Article  CAS  PubMed  Google Scholar 

  48. Sekikawa A, Kadowaki T, El-Saed A, et al. Differential association of docosahexaenoic and eicosapentaenoic acids with carotid intima-media thickness. Stroke. 2011;42:2538–43.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Conflict of Interest

There is no conflict of interest for this work.

Author information

Authors and Affiliations

  1. Department of Cardiology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan

    Kentaro Toyama, Toshihiko Nishioka, Ami Isshiki, Toshiyuki Ando, Yoshiro Inoue, Masato Kirimura, Tetsuo Kamiyama, Osamu Sasaki, Hiroyuki Ito, Yoshiaki Maruyama & Nobuo Yoshimoto

Authors
  1. Kentaro Toyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshihiko Nishioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ami Isshiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshiyuki Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshiro Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masato Kirimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tetsuo Kamiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Osamu Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroyuki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshiaki Maruyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nobuo Yoshimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kentaro Toyama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Toyama, K., Nishioka, T., Isshiki, A. et al. Eicosapentaenoic Acid Combined with Optimal Statin Therapy Improves Endothelial Dysfunction in Patients with Coronary Artery Disease. Cardiovasc Drugs Ther 28, 53–59 (2014). https://doi.org/10.1007/s10557-013-6496-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-013-6496-3

Keywords

Search

Navigation