Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Similar content being viewed by others
References
Kim D, Duff RA. Regulation of K+ channels in cardiac myocytes by free fatty acids. Circ Res. 1990;67:1040–6.
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.
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.
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.
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.
Dei Cas L, Nodari S. Ruolo degli acidi grassi poliinsaturi PUFA n-3 nella prevenzione della morte improvvisa. Basel: Excerpta Medica; 2003.
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.
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.
Calder PC. n-3 fatty acids, inflammation, and immunity—relevance to postsurgical and critically ill patients. Lipids 2004;39:1147–61.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Narayan SM. T-wave alternans and the susceptibility to ventricular arrhythmias. J Am Coll Cardiol. 2006;47:269–81.
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.
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.
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.
Smith JM, Clancy EA, Valeri CR, et al. Electrical alternans and cardiac electrical instability. Circulation 1988;77:110–21.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Taylor JA, Studinger P. Counterpoint: cardiovascular variability is not an index of autonomic control of the circulation. J Appl Physiol. 2006;101:678–81.
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.
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.
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.
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.
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.
Hamer WF, Rubin SA, Peter CT. Factors that predict syncope during ventricular tachycardia in patients. Am Heart J. 1994;27:1102–6.
Steinback KK, Oliver M, Frohner K, et al. Hemodynamics during ventricular tachyarrhythmias. Am Heart J. 1994;127:1102–6.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Conflict of interest
The authors have no conflict of interest to disclose.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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 23, 5–15 (2009). https://doi.org/10.1007/s10557-008-6142-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10557-008-6142-7