Influence of Omega-3 PUFA on Non-invasive factors determining the risk of arrhYthmias eXcess and sudden cardiac death in patients with HFpEF with ischemic etiology (ONYX)

Aim Patients with heart failure with reduced left ventricular (LV) ejection fraction (HFrEF) who have had acute myocardial infarction have an unfavorable prognosis, largely due to ventricular arrhythmias (VA) and risk of sudden cardiac death (SCD). The optimal treatment (triple neurohormonal blockade plus implantable cardioverter defibrillator and cardiac resynchronization therapy) reduced the risk of SCD primarily due to reverse cardiac remodeling, but has not solved this problem completely. Efficacy of purified ω-3 polyunsaturated fatty acid esters (PUFA) in low doses (1 g/day) in reducing VA and risk of SCD in HFrEF patients was demonstrated in two large randomized clinical trials. The PUFA effects was suggested to be related also with increased heart rhythm variability (HRV) and chronotropic action, which might depend on the drug dose. The present open, prospective, randomized, comparative study in parallel groups evaluated the effect of Omacor in different doses on noninvasive markers of SCD risk in patients with ischemic HFrEF receiving the optimal drug therapy.
Methods Patients (n=40) were randomized at a 1:1:2 ratio to the control group (n=10), the Omacor 1 g/day treatment group (n=10), and the Omacor 2 g/day treatment group (n=20) and were followed up for 12 months. Clinical evaluation included changes in the CHF functional class (FC) and Clinical Condition Scale (CCS) score; concentration of N-terminal pro-hormone brain natriuretic peptide (NT-proBNP); and peak oxygen consumption during exercise (peak VO2). The LV function was evaluated by LVEF. Holter ECG monitoring was used for evaluation of HRV (SDNN), average 24-h heart rate (HR), number of ventricular extrasystoles (VE) per hour and severity of VA, and presence of paired VE and VT runs.
Results Improvement of CHF FC became significant only with the high-dose Omacor treatment (2 g/day). The CCS score showed a tendency towards decrease also with a lower dose (1 g/day) whereas the level of NT-proBNP significantly decreased with both Omacor doses. The increase in LV EF was significant only with the use of Omacor 2 g/day (+3 %, р=0.002). A negative chronotropic effect of ω-3 PUFA was observed. Average 24-h HR decreased by 8 bpm (р=0.05) and 11 bpm (р<0.001) with Omacor 1 g/day and 2 g/day, respectively. Either dose of ω-3 PUFA significantly improved VO2, which directly correlated with LV EF and inversely correlated with HR. The decrease in number of VE was associated not only with improved HRV (SDNN) but also with the decrease in 24-h HR, and thus Omacor 2 g/day significantly decreased the number of VE (by 16 per hour) and dangerous VA (paired VE and VT runs ceased to be detected in 40 % of patients).
Conclusion Since HR, HRV, and VA are closely interrelated, the effect of ω-3 PUFA specifically on these noninvasive markers apparently determines its ability to decrease the risk of SCD in patients with ischemic HFrEF. The antiarrhythmic effect of Omacor was greater with higher doses of this drug.

1. Belenkov I, Mareev Vi. The treatment of congestive heart failure in XXI century: questions and lessons of evidence based medicine. Kardiologiia. 2008;(2):6-16

2. Vaduganathan M, Claggett BL, Jhund PS et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet. 2020;396(10244). DOI:10.1016/S0140-6736(20)30748-0

3. Ситникова М.Ю., Лясникова Е.А., Юрченко А.В., Трукшина М.А., Либис Р.А., Кондратенко В.Ю., Дупляков Д.В., Хохлунов С.М., Шляхто E. Результаты Российского госпитального регистра хронической сердечной недостаточности в 3 субъектах Российской Федерации. Кардиология. 2015;55(10):5-13. https://www.elibrary.ru/item.asp?id=24872760. Accessed August 11, 2020

4. Lester R, Moss AJ, Bigger JT et al. Risk Stratification and Survival after Myocardial Infarction. N Engl J Med. 1983;309(6):331-336. DOI:10.1056/NEJM198308113090602

5. Kearney MT, Fox KAA, Lee AJ et al. Predicting sudden death in patients with mild to moderate chronic heart failure. Heart. 2004;90(10):1137-1143. DOI:10.1136/hrt.2003.021733

6. Huikuri H V., Castellanos A, Myerburg RJ. Medical progress: Sudden death due to cardiac arrhythmias. N Engl J Med. 2001;345(20):1473- 1482. DOI:10.1056/NEJMra000650

7. Shen L, Jhund PS, Petrie MC et al. Declining Risk of Sudden Death in Heart Failure. N Engl J Med. 2017;377(1):41-51. DOI:10.1056/NEJMoa1609758

8. De Diego C, González-Torres L, Núñez JM et al. Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices. Hear Rhythm. 2018;15(3):395-402. DOI:10.1016/j.hrthm.2017.11.012

9. Kramer DG, Trikalinos TA, Kent DM, Antonopoulos G V, Konstam MA, Udelson JE. Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: A meta-analytic approach. J Am Coll Cardiol. 2010;56(5):392-406. DOI:10.1016/j.jacc.2010.05.011

10. Ruwald MH, Solomon SD, Foster E et al. Left ventricular ejection fraction normalization in cardiac resynchronization therapy and risk of ventricular arrhythmias and clinical outcomes: Results from the multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy (MADIT-CRT) trial. Circulation. 2014;130(25):2278-2286. DOI:10.1161/CIRCULATIONAHA.114.011283

11. Køber L, Torp-Pedersen C, McMurray JJ V et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358(25):2678-87. DOI:10.1056/NEJMoa0800456

12. Bardy GH, Lee KL, Mark DB. et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352(3):225-37. DOI:10.1056/NEJMoa043399

13. Albert CM, Campos H, Stampfer MJ et al. Blood Levels of LongChain n–3 Fatty Acids and the Risk of Sudden Death. N Engl J Med. 2002;346(15):1113-1118. DOI:10.1056/NEJMoa012918

14. Pottala J V., Garg S, Cohen BE, Whooley MA, Harris WS. Blood eicosapentaenoic and docosahexaenoic acids predict all-cause mortality in patients with stable coronary heart disease: The heart and soul study. Circ Cardiovasc Qual Outcomes. 2010;3(4):406-412. DOI:10.1161/CIRCOUTCOMES.109.896159

15. GISSI-HF investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1223- 1230. DOI:10.1016/S0140-6736(08)61239-8

16. Marchioli R. Dietary supplementation with N-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSIPrevenzione trial. Lancet. 1999;354(9177):447-455. DOI:10.1016/ S0140-6736(99)07072-5

17. Macchia A, Levantesi G, Franzosi MG 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 Fail. 2005;7(5):904-909. DOI:10.1016/j.ejheart.2005.04.008

18. Kang JX, Leaf A. Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids. In: American Journal of Clinical Nutrition. Vol 71. American Society for Nutrition; 2000. DOI:10.1093/ajcn/71.1.202s

19. Christensen JH, Gustenhoff P, Ejlersen E et al. n-3 fatty acids and ventricular extrasystoles in patients with ventricular tachyarrhythmias. Nutr Res. 1995;15(1):1-8. DOI:10.1016/0271-5317(95)91647-U

20. Christensen JH, Gustenhoff P, Korup E et al. Effect of fish oil on heart rate variability in survivors of myocardial infarction: A double blind randomised controlled trial. Br Med J. 1996;312(7032):677-678. DOI:10.1136/bmj.312.7032.677

21. Von Schacky C, Fischer S, Weber PC. Long-term effects of dietary marine ω-3 fatty acids upon plasma and cellular lipids, platelet function, and eicosanoid formation in humans. J Clin Invest. 1985;76(4):1626- 1631. DOI:10.1172/JCI112147

22. Mehta J, Lawson D, Saldeen T. Reduction in plasminogen activator inhibitor-1 (PAI-1) with omega-3 polyunsaturated fatty acid (PUFA) intake. Am Heart J. 1988;116(5 PART 1):1201-1206. DOI:10.1016/0002-8703(88)90440-1

23. Poole CD, Halcox JP, Jenkins-Jones S et al. Omega-3 Fatty Acids and Mortality Outcome in Patients with and without Type 2 Diabetes After Myocardial Infarction: A Retrospective, Matched-Cohort Study. Clin Ther. 2013;35(1):40-51. DOI:10.1016/j.clinthera.2012.11.008

24. Kimmig LM, Karalis DG. Do Omega-3 Polyunsaturated Fatty Acids Prevent Cardiovascular Disease? A Review of the Randomized Clinical Trials. Lipid Insights. 2013;6:LPI.S10846. DOI:10.4137/LPI.S10846

25. Khler A, Bittner D, Löw A, Von Schacky C. Effects of a convenience drink fortified with n-3 fatty acids on the n-3 index. Br J Nutr. 2010;104(5):729-736. DOI:10.1017/S0007114510001054

26. Bhatt DL, Steg PG, Miller M et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. DOI:10.1056/NEJMoa1812792

27. Арболишвили Г.Н., Мареев В.Ю. Возможности применения омега-3 полиненасыщенных жирных кислот для вторичной профилактики у больных сердечной недостаточностью ишемической этиологии. Дизайн исследования “ОНИКС” (Влияние Омакора на НеИнвазивные маркеры внезапной сердечной смерти у больных. Журнал Сердечная недостаточность. 2008;9(2 (46)):73-78. https://www.elibrary.ru/item.asp?id=10439180. Accessed August 11, 2020

28. Abdelhamid AS, Martin N, Bridges C et al. Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;(11). DOI:10.1002/14651858.cd012345.pub3

29. Torshin IY, Gromova OA, Kobalava ZD. About Errors in Meta-Analyses of Cardiovascular Effects of Omega-3 PUFA Part 1. Pharmacological and Clinical Aspects of Validity in the Era of Post-Genomic Research, Artificial Intelligence and Big Data Analysis. Eff Pharmacother. 2019;15(9):26- 34. DOI:10.33978/2307-3586-2019-15-9-26-34

30. Mareev VY, Fomin I V., Ageev FT et al. Russian Heart Failure Society, Russian Society of Cardiology. Russian Scientific Medical Society of Internal Medicine Guidelines for Heart failure: chronic (CHF) and acute decompensated (ADHF). Diagnosis, prevention and treatment. Kardiologiia. 2018;17(S6):1-164. DOI:10.18087/cardio.2475

31. Ponikowski P, Voors AA, Anker SD et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37(27):2129-2200. DOI:10.1093/eurheartj/ehw128

32. Hu Y, Hu FB, Manson JAE. Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants. J Am Heart Assoc. 2019;8(19). DOI:10.1161/JAHA.119.013543

33. Poole-Wilson PA, Uretsky BF, Thygesen K, Cleland JGF, Massie BM, Rydén L. Mode of death in heart failure: Findings from the ATLAS trial. Heart. 2003;89(1):42-48. DOI:10.1136/heart.89.1.42

34. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A Randomized Study of the Prevention of Sudden Death in Patients with Coronary Artery Disease. N Engl J Med. 1999;341(25):1882-1890. DOI:10.1056/NEJM199912163412503

35. Bardy GH, Lee KL, Mark DB et al. Amiodarone or an Implantable Cardioverter–Defibrillator for Congestive Heart Failure. N Engl J Med. 2005;352(3):225-237. DOI:10.1056/NEJMoa043399

36. Køber L, Torp-Pedersen C, McMurray JJV et al. Increased Mortality after Dronedarone Therapy for Severe Heart Failure. N Engl J Med. 2008;358(25):2678-2687. DOI:10.1056/NEJMoa0800456

37. Moss AJ, Hall WJ, Cannom DS et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009;361(14):1329-38. DOI:10.1056/NEJMoa0906431

38. Marchioli R, Barzi F, Bomba E et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105(16):1897-903. http://www.ncbi.nlm.nih.gov/pubmed/11997274. Accessed June 14, 2018

39. Lavie CJ, Milani R V., Mehra MR, Ventura HO. Omega-3 Polyunsaturated Fatty Acids and Cardiovascular Diseases. J Am Coll Cardiol. 2009;54(7):585-594. DOI:10.1016/j.jacc.2009.02.084

40. Schrepf R, Limmert T, Weber PC, Theisen K, Sellmayer A. Immediate effects of n-3 fatty acid infusion on the induction of sustained ventricular tachycardia. Lancet. 2004;363(9419):1441-1442. DOI:10.1016/S0140-6736(04)16105-9.

41. Leaf A, Albert CM, Josephson M et al. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation. 2005;112(18):2762-2768. DOI:10.1161/CIRCULATIONAHA.105.549527

42. Brouwer IA, Raitt MH, Dullemeijer C et al. Effect of fish oil on ventricular tachyarrhythmia in three studies in patients with implantable cardioverter defibrillators. Eur Heart J. 2009;30(7):820-6. DOI:10.1093/eurheartj/ehp003

43. Finzi AA, Latini R, Barlera S et al. Effects of n-3 polyunsaturated fatty acids on malignant ventricular arrhythmias in patients with chronic heart failure and implantable cardioverter-defibrillators: A substudy of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca (GISSI-HF) trial. Am Heart J. 2011;161(2). DOI:10.1016/j.ahj.2010.10.032

44. Ghio S, Scelsi L, Latini R et al. Effects of n-3 polyunsaturated fatty acids and of rosuvastatin on left ventricular function in chronic heart failure: A substudy of GISSI-HF trial. Eur J Heart Fail. 2010;12(12):1345-1353. DOI:10.1093/eurjhf/hfq172

45. Nodari S, Triggiani M, Campia U et al. Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2011;57(7):870-879. DOI:10.1016/j.jacc.2010.11.017

46. Heydari B, Abdullah S, Pottala J V. et al. Effect of omega-3 acid ethyl esters on left ventricular remodeling after acute myocardial infarction. Circulation. 2016;134(5):378-391. DOI:10.1161/CIRCULATIONAHA.115.019949

47. Mareev Y, Gerasimova V, Goryunova G et al. Factors which determine prognosis in chronic heart failure: role of QRS duration and morphology. Russ Hear Fail J. 2012;5:255-266. DOI:DOI: 10.18087/rhfj.2012.5.1722

48. Чухнин Е.В., Амиров Н.Б., Морозова Н.И. Риск внезапной смерти и частота сердечных сокращений – Фундаментальные исследования (научный журнал). Фундаментальные исследования. 2011;(9(3)):558-560. https://www.fundamental-research.ru/ru/article/view?id=28556. Accessed August 12, 2020

49. Мареев В.Ю., Арболишвили, Г.Н. Орлова Я.А., Беленков Ю.Н. Вариабельность ритма сердца при ХСН и ее роль в прогнозе заболевания. Кардиология. 2006;46(12)

50. Scirica BM, Braunwald E, Belardinelli L et al. Relationship Between Nonsustained Ventricular Tachycardia After Non–ST-Elevation Acute Coronary Syndrome and Sudden Cardiac Death. Circulation. 2010;122(5):455-462. DOI:10.1161/CIRCULATIONAHA.110.937136

51. Moertl D, Hammer A, Steiner S, Hutuleac R, Vonbank K, Berger R. Dosedependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: A double-blind, placebo-controlled, 3-arm study. Am Heart J. 2011;161(5):915.e1-915.e9. DOI:10.1016/j.ahj.2011.02.011