Cardiovascular Drugs and Therapy

, Volume 23, Issue 1, pp 5–15 | Cite as

The Role of n-3 PUFAs in Preventing the Arrhythmic Risk in Patients with Idiopathic Dilated Cardiomyopathy

  • Savina Nodari
  • Marco Metra
  • Giuseppe Milesi
  • Alessandra Manerba
  • Bruno Mario Cesana
  • Mihai Gheorghiade
  • Livio Dei Cas



N-3 polyunsaturated fatty acids (n-3 PUFAs) intake is associated with a reduction in sudden cardiac death in patients with ischemic heart disease. Their effects in patients with heart failure caused by idiopathic dilated cardiomyopathy (IDC) are unknown.


We compared with placebo the effects of n-3 PUFAs administration in 44 patients with IDC and with frequent or repetitive ventricular arrhythmias at Holter monitoring using a randomized, double-blind design. Arrhythmic risk was assessed by microvolt T-wave analysis (MTWA), signal averaged ECG (SAECG), Holter monitoring, power spectral analysis of heart rate (HR) variability, catecholamine and cytokine plasma levels, at baseline and after 6 months.


At MTWA, 7/12 patients (58%) initially positive became negative after n-3 PUFAs while one patient became positive after placebo (p = 0.019). N-3 PUFAs administration was also associated to normalization of SAECG (11/15 patients, p < 0.0015), decrease in non-sustained ventricular tachycardia (NSVT) episodes (p = 0.0002) and NSVT HR (p = 0.0003), improvement in HR variability and decrease in catecholamine and cytokine plasma levels. The ratio of plasma n-6 PUFAs to n-3 PUFAs decreased from 12.01 to 3.48 after n-3 PUFAs.


N-3 PUFAs administration is associated with favorable effects on parameters related to arrhythmic risk in patients with idiopathic dilated cardiomyopathy. These results are consistent with antiarrhythmic activity independent from their antiischemic effects.

Key words

Ventricular arrhythmias Heart failure n-3 PUFAs 


  1. 1.
    Kim D, Duff RA. Regulation of K+ channels in cardiac myocytes by free fatty acids. Circ Res. 1990;67:1040–6.PubMedGoogle Scholar
  2. 2.
    Kang JX, Leaf A. Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel proteins. Proc Natl Acad Sci USA. 1996;93:3542–6.PubMedCrossRefGoogle Scholar
  3. 3.
    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. BMJ 1996;312:677–8.PubMedGoogle Scholar
  4. 4.
    Christensen JH, Korup E, Aaroe J, et al. Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction. Am J Cardiol. 1997;79:1670–3.PubMedCrossRefGoogle Scholar
  5. 5.
    Bendahhou S, Cummins TR, Agnew WS. Mechanism of modulation of the voltage-gated skeletal and cardiac muscle sodium channels by fatty acids. Am J Physiol. 1997;272:C592–600.PubMedGoogle Scholar
  6. 6.
    Dei Cas L, Nodari S. Ruolo degli acidi grassi poliinsaturi PUFA n-3 nella prevenzione della morte improvvisa. Basel: Excerpta Medica; 2003.Google Scholar
  7. 7.
    Leaf A, Kang JX, Xiao YF, Billman GE. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation 2003;107:2646–52.PubMedCrossRefGoogle Scholar
  8. 8.
    De Caterina R, Zampolli A, Del Turco S, Madonna R, Massaro M. Nutritional mechanisms that influence cardiovascular disease. Am J Clin Nutr. 2006;83:421S–6S.PubMedGoogle Scholar
  9. 9.
    Calder PC. n-3 fatty acids, inflammation, and immunity—relevance to postsurgical and critically ill patients. Lipids 2004;39:1147–61.PubMedCrossRefGoogle Scholar
  10. 10.
    Billman GE, Hallaci H, Leaf A. Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids. Proc Natl Acad Sci USA. 1994;91:4427–30.PubMedCrossRefGoogle Scholar
  11. 11.
    Billman GE, Kang JX, Leaf A. Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs. Circulation 1999;99:2452–7.PubMedGoogle Scholar
  12. 12.
    Priori SG, Aliot E, Blomstrom-Lundqvist C, et al. Task force on sudden cardiac death of the European Society of Cardiology. Eur Heart J. 2001;22:1374–450.PubMedCrossRefGoogle Scholar
  13. 13.
    Bucher HC, Hengstler P, Sdiindler C, Meier G. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med. 2002;112:298–308.PubMedCrossRefGoogle Scholar
  14. 14.
    Gissi Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. Lancet 1999;354:447–55.CrossRefGoogle Scholar
  15. 15.
    Raitt MH, Connor WE, Morris C, et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA 2005;293:2884.PubMedCrossRefGoogle Scholar
  16. 16.
    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;112:2762–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Brouwer IA, Zock PL, Camm AJ, et al. Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators. The Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) Randomized Trial. JAMA 2006;295:2613–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Jenkins DJA, Josse AR, Beyene J, Dorian P, Burr ML, LaBelle R, et al. Fish-oil supplementation in patients with implantable cardioverter defibrillators: a meta-analysis. CMAJ 2008;178:157–64.PubMedGoogle Scholar
  19. 19.
    Mozaffarian D, Stein PK, Prineas RJ, Siscovick DS. Dietary fish and omega-3 fatty acid consumption and heart rate variability in US adults. Circulation 2008;117:1130–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Narayan SM. T-wave alternans and the susceptibility to ventricular arrhythmias. J Am Coll Cardiol. 2006;47:269–81.PubMedCrossRefGoogle Scholar
  21. 21.
    Cantillon DJ, Stein KM, Markowitz SM, et al. Predictive value of microvolt T-wave alternans in patients with left ventricular dysfunction. J Am Coll Cardiol. 2007;50:166–73.PubMedCrossRefGoogle Scholar
  22. 22.
    Kaufman ES, Bloomfield DM, Steinman RC, Namerow PB, Costantini O, Cohen RJ, et al. “Indeterminate” microvolt T-wave alternans tests predict high risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol. 2006;48:1399–404.PubMedCrossRefGoogle Scholar
  23. 23.
    Klingenheben T. Microvolt T-wave alternans for arrhythmia risk stratification in left ventricular dysfunction: which patients benefit. J Am Coll Cardiol. 2007;50:174–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Smith JM, Clancy EA, Valeri CR, et al. Electrical alternans and cardiac electrical instability. Circulation 1988;77:110–21.PubMedGoogle Scholar
  25. 25.
    Klingenheben T, Zabel M, D’Agostino RB, et al. Predictive value of T-wave alternans for arrhythmic events in patients with congestive heart failure. Lancet 2000;356:651–2.PubMedCrossRefGoogle Scholar
  26. 26.
    Savard P, Rouleau JL, Ferguson MD, et al. Risk stratification after myocardial infarction using signal averaged electrocardiographic criteria adjusted for sex, age and myocardial infarction location. Circulation 1997;96:202–13.PubMedGoogle Scholar
  27. 27.
    Yi G, Hnatkova K, Mahon NG, Keeling PJ, Reardon M, Camm AJ, et al. Predictive value of wavelet decomposition of the signal-averaged electrocardiogram in idiopathic dilated cardiomyopathy. Eur Heart J. 2000;21:1015–22.PubMedCrossRefGoogle Scholar
  28. 28.
    Binkley PF, Nunziata E, Haas GJ, Nelson SD, Cody RJ. Parasympathetic withdrawal is an integral component of autonomic imbalance in congestive heart failure: demonstration in human subjects and verification in a paced canine model. J Am Coll Cardiol. 1991;18:464–72.PubMedCrossRefGoogle Scholar
  29. 29.
    Hayano J, Mukai S, Sakakibara M, Okada A, Takata K, Fujinami T. Effects of respiratory interval on vagal modulation of heart rate. Am J Physiol. 1994;267:H33–40.PubMedGoogle Scholar
  30. 30.
    Krantz DS, Santiago HT, Kop WJ, Bairey Merz CN, Rozanski A, Gottdiener JS. Prognostic value of mental stress testing in coronary artery disease. Am J Cardiol. 1999;84:1292–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Nodari S, Metra M, Dei Cas L. Beta-blocker treatment of patients with diastolic heart failure and arterial hypertension. A prospective, randomized, comparison of the long-term effects of atenolol vs. nebivolol. Eur J Heart Fail. 2003;5:621–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Ferrari R, Bacchetti T, Confortini R, et al. Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation 1995;92:1479–86.PubMedGoogle Scholar
  33. 33.
    Marangoni F, Colombo C, Galli C. A method for the direct evaluation of the fatty acid status in a drop of blood from a fingertip in humans: applicability to nutritional and epidemiological studies. Anal Biochem. 2004;326:267–72.PubMedCrossRefGoogle Scholar
  34. 34.
    Nazarian S, Bluemke DA, Lardo AC, et al. Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy. Circulation 2005;112:2821–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Assomull RG, Prasad SK, Lyne J, Smith G, et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol. 2006;48:1977–85.PubMedCrossRefGoogle Scholar
  36. 36.
    Gehi AK, Stein RH, Metz LD, et al. Microvolt T-wave alternans fort he risk stratification of ventricular tachyarrhythmic events: a meta-analysis. J Am Coll Cardiol. 2005;46:75–82.PubMedCrossRefGoogle Scholar
  37. 37.
    Taylor JA, Studinger P. Counterpoint: cardiovascular variability is not an index of autonomic control of the circulation. J Appl Physiol. 2006;101:678–81.PubMedGoogle Scholar
  38. 38.
    Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J. 1996;17:354–81.Google Scholar
  39. 39.
    Parati G, Mancia G, Di Rienzo M, Castiglioni P. Point: cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol. 2006;101:676–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Doval HC, Nul DR, Grancelli HO, et al. Nonsustained ventricular tachycardia in severe heart failure. Independent marker of increased mortality due to sudden death. GESICA–GEMA Investigators. Circulation 1996;94:3198–203.PubMedGoogle Scholar
  41. 41.
    Singh SN, Fisher SG, Carson PE, Fletcher RD, Department of Veterans Affairs CHF STAT Invest. Prevalence and significance of nonsustained ventricular tachycardia in patients with premature ventricular contractions and heart failure treated with vasodilator therapy. J Am Coll Cardiol. 1998;32:942–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Zecchin M, Di Lenarda A, Gregori D, et al. Prognostic role of non-sustained ventricular tachycardia in a large cohort of patients with idiopathic dilated cardiomyopathy. Ital Heart J. 2005;6:721–7.PubMedGoogle Scholar
  43. 43.
    Hamer WF, Rubin SA, Peter CT. Factors that predict syncope during ventricular tachycardia in patients. Am Heart J. 1994;27:1102–6.Google Scholar
  44. 44.
    Steinback KK, Oliver M, Frohner K, et al. Hemodynamics during ventricular tachyarrhythmias. Am Heart J. 1994;127:1102–6.CrossRefGoogle Scholar
  45. 45.
    Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781–8.PubMedGoogle Scholar
  46. 46.
    Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med. 2002;346:1113–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Leaf A, Xiao YF, Kang JX, Billman GE. Membrane effects of the n-3 fish oil fatty acids, which prevent fatal ventricular arrhythmias. J Membr Biol. 2005;206:129–39.PubMedCrossRefGoogle Scholar
  48. 48.
    London B, Albert C, Anderson ME, et al. Omega-3 fatty acids and cardiac arrhythmias: prior studies and recommendations for future research: a report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements Omega-3 Fatty Acids and their Role in Cardiac Arrhythmogenesis Workshop. Circulation 2007;116:e320–35.PubMedCrossRefGoogle Scholar
  49. 49.
    Xiao YF, Ma L, Wang SY, Josephson ME, Wang GK, Morgan JP, et al. Potent block of inactivation-deficient Na+ channels by n-3 polyunsaturated fatty acids. Am J Physiol Cell Physiol. 2006;290:C362–70.PubMedCrossRefGoogle Scholar
  50. 50.
    Seidler T, Hasenfuss G, Maier LS. Targeting altered calcium physiology in the heart: translational approaches to excitation, contraction, and transcription. Physiology (Bethesda). 2007;22:328–34.Google Scholar
  51. 51.
    Xiao YF, Ke Q, Chen Y, Morgan JP, Leaf A. Inhibitory effect of n-3 fish oil fatty acids on cardiac Na+/Ca2+ exchange currents in HEK293t cells. Biochem Biophys Res Commun. 2004;321:116–23.PubMedCrossRefGoogle Scholar
  52. 52.
    Canetti M, Akhter MW, Lerman A, Karaalp IS, Zell JA, Singh H, et al. Evaluation of myocardial blood flow reserve in patients with chronic congestive heart failure due to idiopathic dilated cardiomyopathy. Am J Cardiol. 2003;92:1246–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Metra M, Nodari S, Parrinello G, et al. The role of plasma biomarkers in acute heart failure. Serial changes and independent prognostic value of NT-proBNP and cardiac troponin-T. Eur J Heart Fail. 2007;9:776–86.PubMedCrossRefGoogle Scholar
  54. 54.
    Mozaffarian D, Geelen A, Brouwer IA, Geleijnse JM, Zock PL, Katan MB. Effect of fish oil on heart rate in humans: a meta-analysis of randomized controlled trials. Circulation 2005;112:1945–52.PubMedCrossRefGoogle Scholar
  55. 55.
    Nerheim P, Birger-Botkin S, Piracha L, Olshansky B. Heart failure and sudden death in patients with tachycardia-induced cardiomyopathy and recurrent tachycardia. Circulation 2004;110:247–52.PubMedCrossRefGoogle Scholar
  56. 56.
    Chonchol M, Goldenberg I, Moss AJ, McNitt S, Cheung AK. Risk factors for sudden cardiac death in patients with chronic renal insufficiency and left ventricular dysfunction. Am J Nephrol. 2007;27:7–14.PubMedCrossRefGoogle Scholar
  57. 57.
    Marchioli R on behalf of the GISSI-Prevenzione investigators. Treatment with n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione Trial. Eur Heart J Suppl. 2001;3:D85–97.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Savina Nodari
    • 1
  • Marco Metra
    • 1
  • Giuseppe Milesi
    • 1
  • Alessandra Manerba
    • 1
  • Bruno Mario Cesana
    • 2
  • Mihai Gheorghiade
    • 3
  • Livio Dei Cas
    • 1
  1. 1.Section of Cardiovascular Diseases, Department of Experimental and Applied MedicineUniversity of BresciaBresciaItaly
  2. 2.Section of Medical Statistics and Biometry, Department of Biomedical Sciences and BiotechnologiesUniversity of BresciaBresciaItaly
  3. 3.Division of Cardiology, Feinberg School of MedicineNorthwestern UniversityChicagoUSA

Personalised recommendations