Omega 3 fatty acids supplement (Cavsor) intake with Beta Blockers for Ischemic Heart Disease

BENEFITS OF TAKING CAVSOR FOR PATIENTS WITH ISCHEMIC HEART DISEASE FOR SECONDARY PROPHYLAXIS OF MYOCARDIAL INFARCTION IN COMBINATION WITH STANDARD TREATMENTS (STATINS, ANTIPLATELET PRODUCTS, BETA-BLOCKERS, AND ACE INHIBITORS)

Ischemic heart disease (also called coronary heart disease or coronary artery disease) is caused by the narrowing of the coronary arteries, which supply the heart muscle with oxygen-rich blood; the narrowing, in turn, is caused by atherosclerosis, i.e. the build-up of fatty material (atheroma) in the artery walls [1, 2, 3]. Thus, ischemic heart disease is a direct consequence of atherosclerosis, and the two terms are sometimes considered synonymous [1]. It is estimated that about 17% of all deaths in men and 10% in women are caused by ischemic heart disease [2]. Ischemic heart disease is the major cause of myocardial infarction (heart attack) [4].

 

A number of studies have documented the beneficial cardiovascular effects of increased consumption of n-3 (also called omega-3) and n-6 (omega-6) polyunsaturated fatty acids (PUFAs) 5, [6, 7, 8]. The beneficial effects of PUFAs, in particular their ability to reduce the risk of fatal ischemic heart disease, are recognized by the Food and Agriculture Organization (FAO) of the United Nations [9]. Cavsor contains three n-3 (including eicosapentaenoic acid, or EPA, and docosahexaenoic acid, or DHA), two n-6, and one n-9 PUFAs. 

 

Although atherosclerosis was traditionally considered as a lipid (mainly cholesterol)-associated disease, the evidence accumulated since the late 1990s has resulted in its recognition as an inflammatory disease, in which both adaptive and innate immune responses play a role [10, 11]. For beneficial effects of PUFAs for patients with atherosclerosis that are due to their anti-inflammatory action. This article considers the available evidence regarding the effects of PUFA intake on secondary prophylaxis of myocardial infarction, i.e. prophylaxis in patients who already have ischemic heart disease and may have already had myocardial infarction.

 

Prophylaxis of myocardial infarction in patients with diabetes

A study conducted in Norway assessed the effects of supplementation with n-3 long-chain PUFAs on the risk of acute myocardial infarction in patients with ischemic heart disease and concomitant diabetes (95% type 2 and 5% type 1), pre-diabetes, and those without diabetes (2378 patients in total, 80% of them men) [12]. The authors found that high n-3 long-chain PUFA consumption was associated with a lower risk of acute myocardial infarction in patients with diabetes but with an increased risk of fatal acute myocardial infarction in those without diabetes. However, a potential confounding factor in this study may have been patients’ age, because patients with diabetes were statistically significantly older; they also had higher body mass index and more often had hypertension [12]. Nevertheless, this study suggests that patients who have ischemic heart disease and diabetes at the same time would benefit from taking n-3 PUFA–containing supplements.

 

A study conducted in Denmark enrolled 1014 diabetic patients who previously had myocardial infarction [13]. Each patient received one of three combinations of n-3 PUFAs or placebo. The authors found that patients who received a combination of α-linolenic acid (ALA), EPA, and DHA (i.e., n-3 PUFAs included in Cavsor) had fewer ventricular arrhythmia–related events and fatal myocardial infarctions in comparison with the placebo group [13].

 

Prophylaxis in patients with hypercholesterolemia undergoing statin treatment. Hypercholesterolemia (a high level of cholesterol in the blood) is a major risk factor for ischemic heart disease [2]. Statins, the inhibitors of HMG-CoA reductase, an enzyme necessary for cholesterol synthesis, are often used to reduce cholesterol levels. EPA (one of the components of Cavsor) has also been reported to reduce cholesterol levels in patients with hypercholesterolemia [14]; thus, one could assume that a combination of statin therapy with supplements containing n-3 PUFAs might be more efficient in reducing the risks associated with ischemic heart disease than each treatment alone. Another rationale for combining statins and n-3 PUFA supplementation is that some statins may reduce n-3 PUFA levels [15, 16], and this side effect appears to be associated with the increased volume of atherosclerotic plaques [17] and with the residual risk of cardiovascular events despite statin therapy [16]. In addition, hypertriglyceridemia (increased levels of triglycerides) is an independent risk factor for mortality in patients with ischemic heart disease [18], and n-3 PUFAs but not statin treatment reduce triglyceride levels [19]. 

 

A randomized, open-label, blind study, named the Japan EPA Lipid Intervention Study (JELIS), was designed to investigate the effect of EPA (1.8 g daily) administered in combination with statins in patients with hypercholesterolemia [20]. This study, which included as many as 18,645 patients in total, found a statistically significant 19% reduction in major coronary events, including myocardial infarction, in patients taking the supplement [21]. Further analysis of the data for 1,050 patients with prior myocardial infarction showed that EPA administration significantly reduced the incidence of major coronary events (by approximately 25%) [22]. The results of this study and the above considerations indicate that supplements containing n-3 PUFAs should be beneficial for patients with ischemic heart disease undergoing statin therapy.

 

Prophylaxis in patients undergoing antiplatelet (antithrombotic) treatment

Treatment with antiplatelet (antithrombotic) agents such as aspirin and/or clopidogrel is widely used in patients with ischemic heart disease [23]; for example, the use of aspirin moderately reduces the risk of myocardial infarction (either fatal or non-fatal) in such patients [24]. The OMEGA-PCI (Omega-3 Fatty Acids After PCI to Modify Responsiveness to Dual Antiplatelet Therapy) trial, a prospective, double-blind, placebo-controlled, randomized study that included patients undergoing aspirin plus clopidogrel therapy, found that supplementation with n-3 PUFAs (1g daily for 4 weeks) significantly potentiated platelet response to antiplatelet treatment [25]. In a follow-up study, the authors found that n-3 PUFA supplementation in these patients also significantly reduced thrombin formation, attenuated oxidative stress and favorably changed fibrin clot properties [26].

 

Supplementation with n-3 PUFAs in patients treated with beta-blockers and ACE inhibitors

Beta-blockers (β-adrenoceptor–blocking agents) [27, 28] and angiotensin-converting enzyme (ACE) inhibitors [29] have long been used in patients with various cardiovascular diseases, including ischemic heart disease; beta-blockers improve the survival of these patients. A recent study conducted in Finland (985 participants) suggested an inverse association between the level of the n-3 PUFA docosapentaenoic acid (DPA) and the level the natriuretic peptide NT-proBNP (natriuretic peptides are considered as markers for cardiovascular disease), particularly among patients treated with beta-blockers [30]; this observation suggests a possible synergistic effect of treatment with beta-blockers and n-3 PUFA supplementation. However, a large study conducted in Italy (GISSI-Prevenzione; 9630 patients with prior myocardial infarction) found that n-3 PUFA supplementation significantly reduced mortality in a manner independent of the effects of either beta-blockers or ACE inhibitors [31]. Curiously, PUFAs, especially EPA, ALA, and DHA (all of which are included in Cavsor) have been reported to suppress ACE activity in isolated leukocytes [32] and thus have been hypothesized to act as endogenous ACE inhibitors [33]. Whether n-3 PUFAs act synergistically with or independently from beta-blockers and ACE inhibitors, these data suggest that it makes sense to use them in combination with these well-established therapies.

 

References

  1. National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health & Human Services. What is coronary heart disease? https://www.nhlbi.nih.gov/health/health-topics/topics/cad (2015).
  1. National Health Service, U.K. Coronary heart disease. http://www.nhs.uk/Conditions/Coronary-heart-disease/Pages/Introduction.aspx (2014).
  2. British Heart Foundation. Coronary heart disease. https://www.bhf.org.uk/heart-health/conditions/coronary-heart-disease.aspx (2016).
  3. British Heart Foundation. Heart attack. https://www.bhf.org.uk/heart-health/conditions/heart-attack(2016).
  4. Ander, B.P., Dupasquier, C.M., Prociuk, M.A. & Pierce, G.N. Polyunsaturated fatty acids and their effects on cardiovascular disease. Exp Clin Cardiol 8, 164-172 (2003).
  5. Jakobsen, M.U. et al. Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr 89, 1425-1432 (2009).
  6. Mozaffarian, D. & Rimm, E.B. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA 296, 1885-1899 (2006).
  7. Mozaffarian, D., Micha, R. & Wallace, S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS Med 7, e1000252 (2010).
  8. Food and Agriculture Organization of the United Nations. Fats and fatty acids in human nutrition. http://www.fao.org/3/a-i1953e.pdf (2008).
  9. Seneviratne, A.N. & Monaco, C. Role of inflammatory cells and toll-like receptors in atherosclerosis. Curr Vasc Pharmacol 13, 146-160 (2015).
  10. Stoll, G. & Bendszus, M. Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. Stroke 37, 1923-1932 (2006).
  11. Strand, E. et al. Dietary intake of n-3 long-chain polyunsaturated fatty acids and risk of myocardial infarction in coronary artery disease patients with or without diabetes mellitus: a prospective cohort study. BMC Med 11, 216 (2013).
  12. Kromhout, D. et al. n-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes. Diabetes Care 34, 2515-2520 (2011).
  13. Nozaki, S. et al. Effects of purified eicosapentaenoic acid ethyl ester on plasma lipoproteins in primary hypercholesterolemia. Int J Vitamin Nutr Res 62, 256-260 (1992).
  14. Nozue, T. et al. Effects of statins on serum n-3 to n-6 polyunsaturated fatty acid ratios in patients with coronary artery disease. J Cardiovasc Pharmacol Therapeutics 18, 320-326 (2013).
  15. Kurisu, S. et al. Effects of lipid-lowering therapy with strong statin on serum polyunsaturated fatty acid levels in patients with coronary artery disease. Heart Vessels 28, 34-38 (2013).
  16. Nozue, T. et al. Comparison of effects of serum n-3 to n-6 polyunsaturated fatty acid ratios on coronary atherosclerosis in patients treated with pitavastatin or pravastatin undergoing percutaneous coronary intervention. Am J Cardiol 111, 1570-1575 (2013).
  17. Klempfner, R. et al. Elevated triglyceride level is independently associated with increased all-cause mortality in patients with established coronary heart disease: Twenty-two-year follow-up of the bezafibrate infarction prevention study and registry. Circ Cardiovasc Qual Outcomes 9, 100-108 (2016).
  18. Tomei, R. et al. Efficacy and tolerability of simvastatin and omega-3 fatty acid combination in patients with coronary disease, hypercholesterolemia and hypertriglyceridemia. Cardiologia 38, 773-778 (1993).
  19. Yokoyama, M. & Origasa, H. Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J 146, 613-620 (2003).
  20. Yokoyama, M. et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet369, 1090-1098 (2007).
  21. Matsuzaki, M. et al. Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease. Circ J 73, 1283-1290 (2009).
  22. Schulman, S. & Spencer, F.A. Antithrombotic drugs in coronary artery disease: risk benefit ratio and bleeding. J Thromb Haemost 8, 641-650 (2010).
  23. Baigent, C. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373, 1849-1860 (2009).
  24. Gajos, G., Rostoff, P., Undas, A. & Piwowarska, W. Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: the OMEGA-PCI (OMEGA-3 fatty acids after pci to modify responsiveness to dual antiplatelet therapy) study. J Am Coll Cardiol 55, 1671-1678 (2010).
  25. Gajos, G. et al. Reduced thrombin formation and altered fibrin clot properties induced by polyunsaturated omega-3 fatty acids on top of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (OMEGA-PCI clot). Arterioscler Thromb Vasc Biol 31, 1696-1702 (2011).
  26. Elgendy, I.Y., Mahmoud, A. & Conti, C.R. Beta-blockers in the management of coronary artery disease: are we on the verge of a new paradigm shift? Recent Pat Cardiovasc Drug Discov 9, 11-21 (2014).
  27. Boudonas, G.E. beta-Blockers in coronary artery disease management. Hippokratia 14, 231-235 (2010).
  28. Donnelly, R. & Manning, G. Angiotensin-converting enzyme inhibitors and coronary heart disease prevention. J Renin Angiotensin Aldosterone Syst. 8, 13-22 (2007).
  29. Daneshmand, R., Kurl, S., Tuomainen, T.P. & Virtanen, J.K. Associations of serum n-3 and n-6 polyunsaturated fatty acids with plasma natriuretic peptides. Eur J Clin Nutr (2016).
  30. Macchia, A. et al. Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids. Eur J Heart Failure 7, 904-909 (2005).
  31. Kumar, K.V. & Das, U.N. Effect of cis-unsaturated fatty acids, prostaglandins, and free radicals on angiotensin-converting enzyme activity in vitro. Proc Soc Exp Biol Med 214, 374-379 (1997).
  32. Das, U.N. Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules. Lipids Health Dis 7, 37 (2008).