Skip to main content
SpringerLink
Log in

The Antiarrhythmic Effect of n-3 Polyunsaturated Fatty Acids: Modulation of Cardiac Ion Channels as a Potential Mechanism

  • Published:
The Journal of Membrane Biology Aims and scope Submit manuscript

Abstract

Sudden cardiac death remains one of the most serious medical challenges in Western countries. Increasing evidence in recent years has demonstrated that the n-3 polyunsaturated fatty acids (PUFAs) can prevent fatal ventricular arrhythmias in experimental animals and probably in humans. Dietary supplement of fish oils or intravenous infusion of the n-3 PUFAs prevents ventricular fibrillation caused by ischemia/reperfusion. Similar antiarrhythmic effects of these fatty acids are also observed in cultured mammalian cardiomyocytes. Based on clinical observations and experimental studies in vitro and in vivo, several mechanisms have been postulated for the antiarrhythmic effect of the n-3 PUFAs. The data from our laboratory and others have shown that the n-3 PUFAs are able to affect the activities of cardiac ion channels. The modulation of channel activities, especially voltage-gated Na+ and L-type Ca2+ channels, by the n-3 fatty acids may explain, at least partially, the antiarrhythmic action. It is not clear, however, whether one or more than one mechanism involves the beneficial effect of the n-3 PUFAs on the heart. This article summarizes our recent studies on the specific effects of the n-3 PUFAs on cardiac ion channels. In addition, the effect of the n-3 PUFAs on the human hyperpolarization-activated cyclic-nucleotide-modulated channel is presented.

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.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  1. Albert C.M., Hennekens C.H., O’Donnell C.J., Ajani U.A., Carey V.J., Willett W.C., Ruskin J.N., Manson J.E. 1998. Fish consumption and risk of sudden cardiac death. JAMA 279:23–28

    CAS  PubMed  Google Scholar 

  2. Albert C.M., Campos H., Stampfer M.J., Ridker P.M., Manson I.E., Willett W.C., Ma J. 2002. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N. Engl. J. Med. 346:1113–1118

    CAS  PubMed  Google Scholar 

  3. An R.H., Wang X.L., Kerem B., Benhorin J., Medina A., Goldmit M., Kass R.S. 1998. Novel LQT-3 mutation affects Na+ channel activity through interactions between alpha- and betal-subunits. Circ. Res. 83:141–146

    CAS  PubMed  Google Scholar 

  4. Ander B.P., Weber A.R., Rampersad P.P, Gilchrist J.S.C., Pierce G.N., Lukas A. 2004. Dietary flaxseed protects against ventricular fibrillation induced by ischemia-reperfusion in normal and hypercholesterolemic rabbits. J. Nutr. 134:3250–3256

    CAS  PubMed  Google Scholar 

  5. Andersen O.S., Nielsen C., Maer A.M., Lundbaek J.A., Goulian M., Koeppe II, R.E. 1999. Ion channels as tools to monitor lipid bilayer-mernbrane protein interactions: gramicidin channels as molecular force transducers. Meth. Enzymol. 294:208–224

    CAS  PubMed  Google Scholar 

  6. Bang H.O., Dyerberg J., Nielsen A. 1971. Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet. 1:1143–1145

    CAS  PubMed  Google Scholar 

  7. Billman G.E., Kang J.X., Leaf A. 1999. Prevention of sudden cardiac death by dietary pure {omega}-3 polyunsaturated fatty acids in dogs. Circulation 99:2452–2457

    CAS  PubMed  Google Scholar 

  8. Billman G.E., Hallaq H., Leaf A. 1994. Prevention of ischemia-induced arrhythmias by n-3 fatty acids. Proc. Natl. Acad. Sci. USA 91:4427–4430

    CAS  PubMed  Google Scholar 

  9. Bogdanov K.Y., Spurgeon H.A., Vinogradova T.M., Lakatta E.G. 1998. Modulation of the transient outward current in adult rat ventricular myocytes by polyunsaturated fatty acids. Am. J. Physiol. 274:H571–H579

    CAS  PubMed  Google Scholar 

  10. Calo L., Bianconi L., Colivicchi F., Lamberti F., Loricchio M.L., de Ruvo E., Meo A., Pandozi C., Staibano M., Santini M. 2005. N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J. Am. Coll. Cardiol. 45:1723–1728

    Article  CAS  PubMed  Google Scholar 

  11. Catterall W.A. 1989. Structure and function of voltage-sensitive ion channels. Science 242:50–61

    Google Scholar 

  12. Catterall W.A. 1992. Cellular and molecular biology of voltage-gated sodium channels. Physiol. Rev. 72:S15–S48

    CAS  PubMed  Google Scholar 

  13. Cheng T.O., Dallongeville J., Montaye M., Amouyel P., Yarnell J., Evans A., Ducimetiere P., Bingham A., Luc G., Arveiler D., Mass B., Ferrieres J., Ruidavets J.-B. 2004. Fish consumption and coronary artery disease in China * Response. Circulation 109:e155–e156

    PubMed  Google Scholar 

  14. Chung S., Jung W., Lee M.Y. 1999. Inward and outward rectifying potassium currents set membrane potentials in activated rat microglia. Neurosci. Lett. 262:121–124

    Article  CAS  PubMed  Google Scholar 

  15. Clarkson C.W., Hondeghem L.M. 1985. Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 62:396–405

    CAS  PubMed  Google Scholar 

  16. De Lorgeril M., Renaud S., Mamelle N., Salen P., Martin J.L., Monjaud L, Guidollet J., Touboul P., Delaye J. 1994. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 343:1454–1459

    PubMed  Google Scholar 

  17. Dyerberg J., Bang H.O., Hjorne N. 1975. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am. J. Clin. Nutr. 28:958–966

    CAS  PubMed  Google Scholar 

  18. Evans S.M., Cone E.J., Henningfield J.E. 1996. Arterial and venous cocaine plasma concentrations in humans: relationship to route of administration, cardiovascular effects and subjective effects. J. Pharmacol. Exp. Ther. 279:1345–1356

    CAS  PubMed  Google Scholar 

  19. Girshman J., Greathouse D.V., Koeppe II R.E., Andersen O.S. 1997. Gramicidin channels in phospholipid bilayers with unsaturated acyl chains. Biophys. J. 73:1310–1319

    CAS  PubMed  Google Scholar 

  20. GISSI-Prevention Investigators. 1999. 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 Soprawivenza nell'Infarto miocardico. Lancet 354:447–455

    Google Scholar 

  21. Gomez A.M., Cheng H., Lederer W.J., Bers D.M. 1996. Ca2+ diffusion and sarcoplasmic reticulum transport both contribute to [Ca2+]i decline during Ca2+ sparks in rat ventricular myocytes. J. Physiol. 496:575–581

    CAS  PubMed  Google Scholar 

  22. Hallaq H., Smith T. W., Leaf A. 1992. Modulation of dihydropyridine-sensitive calcium channels in heart cells by fish oil fatty acids. Proc. Natl. Acad. Sci. USA 89:1760–1764

    CAS  PubMed  Google Scholar 

  23. Honore E., Barhanin J., Attali B., Lesage R, Lazdunski M. 1994. External blockade of the major cardiac delayed-reetifier K+ (Kv1.5) by polyunsaturated fatty acids. Proc. Natl. Acad. Sci. USA 91:1937–1941

    CAS  PubMed  Google Scholar 

  24. Kang J.X., Leaf A. 1994. Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocytes. Proc. Natl. Acad. Sci. USA 91:9886–9890

    CAS  PubMed  Google Scholar 

  25. Kang J.X., Leaf A. 1996. Prevention and termination of arrhythmias induced by lysophosphatidyl choline and acylcarnitine in neonatal rat cardiac myocytes by free omega-3 polyunsaturated fatty acids. Eur. J. Pharmacol. 297:97–106

    Article  CAS  PubMed  Google Scholar 

  26. Kang J.X., Xiao Y.-F., Leaf A. 1995. Free long-chain polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes. Proc. Natl. Acad Sci. USA 92:3997–4001

    CAS  PubMed  Google Scholar 

  27. Kang J.X., Leaf A. 1996. Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel protein. Proc. Natl. Acad Sci. USA 93:3542–3546

    Article  CAS  PubMed  Google Scholar 

  28. Klausner R.D., Kleinfeld A.M., Hoover R.L., Karnovsky M.J. 1980. Lipid domains in membranes. J. Biol. Chem. 255:1286–1295

    CAS  PubMed  Google Scholar 

  29. Leaf A., Kang J.X., Xiao Y.-F., Billman G.E. 2003. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation 107:2646–2652

    Article  PubMed  Google Scholar 

  30. Leaf A., Xiao Y.-F., Kang J.X., Billman G.E. 2003. Prevention of sudden cardiac death by n-3 polyunsaturated fatty acids. Pharmacol. Ther. 98:355–377

    Article  CAS  PubMed  Google Scholar 

  31. Leaf A., Xiao Y.-F. 2001. The modulation of ionic currents in excitable tissues by n-3 polyunsaturated fatty acids. J. Membrane Biol. 184:263–271

    Article  CAS  Google Scholar 

  32. Ludwig A., Zong X., Jeglitsch M., Hofmann F., Biel M. 1998. A family of hyperpolarization-activated mammalian cation channels. Nature 393:587–591

    CAS  PubMed  Google Scholar 

  33. Lundbaek J.A., Maer A.M., Andersen O.S. 1997. Lipid bilayer energy, curvature stress and assembly of gramicidin channels. Biochemistry 36:5695–5701

    CAS  PubMed  Google Scholar 

  34. Lundbaek J.A., Birn P., Hansen A.J., Sogaard R., Nielsen C., Girshman J., Bruno M.J., Tape S.E., Egebjerg J., Greathouse D.V., Mattice G.L., Koeppe II, R.E., Andersen O.S. 2004. Regulation of sodium channel function by bilayer elasticity: The importance of hydrophobic coupling. effects of micelle-forming amphiphiles and cholesterol. J. Gen. Physiol 123:599–621

    Article  CAS  PubMed  Google Scholar 

  35. Makielski J.C., Limberis J.T., Chang S.Y., Fan Z., Kyle J.W. 1996. Coexpression of β1 with cardiac sodium channel α subunits in oocytes decreases lidocaine block. Mol. Pharmacol. 49:30–39

    CAS  PubMed  Google Scholar 

  36. Marchioli R., Valagussa F., et al. on behalf of GISSI-Prevenzione investigators. 2000. The results of the GISSI-Prevenzione trial in the general framework of secondary prevention. Eur. Heart J. 21:949–952

    Article  CAS  PubMed  Google Scholar 

  37. McLennan P.L. 1993. Relative effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on cardiac arrhythmias in rats. Am. J. Clin. Nutr. 57:207–212

    CAS  PubMed  Google Scholar 

  38. McLennan P.L., Bridle T.M, Abeywardena M.Y., Charnock J.S. 1993. Comparative efficacy of n-3 and n-6 polyunsaturated fatty acids in modulating ventricular fibrillation threshold in marmoset monkeys. Am. J. Clin. Nutr. 58:666–669

    CAS  PubMed  Google Scholar 

  39. Mouhaffel A.H., Madu E.C., Satmary W.A., Fraker T.D. 1995. Cardiovascular complications of cocaine: review. Chest 107:1426–1434

    CAS  PubMed  Google Scholar 

  40. Mozaffarian D., Ascherio A., Hu F.B., Stampfer M.J., Willett W.C., Siscovick D.S., Rimm E.B. 2005. Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men. Circulation 111:157–164

    Article  CAS  PubMed  Google Scholar 

  41. Mubagwa K., Flameng W., Carmeliet E. 1994. Resting and action potentials of nonischemic and chronically ischemic human ventricular muscle. J. Cardiovasc. Electrophysiol 5:659–671

    CAS  PubMed  Google Scholar 

  42. Negretti N., Pérez M.R., Walker D., O’Neill S.C. 2000. Inhibition of sarcoplasmic reticulum function by polyunsaturated fatty acids in intact, isolated myocytes from rat ventricular muscle. J. Physiol. 523:367–375

    Article  CAS  PubMed  Google Scholar 

  43. Noma A., Nakayama T., Kurachi Y, Irisawa H. 1984. Resting K conductances in pacemaker and non-pacemaker heart cells of the rabbit. Jpn. J. Physiol. 34:245–254

    CAS  PubMed  Google Scholar 

  44. Pancrazio J.J., Frazer M.J., Lynch C. 1993. Barbiturate anesthetics depress the resting K+ conductance of myocardium. J. Pharmacol. Exp. Ther. 265:358–365

    CAS  PubMed  Google Scholar 

  45. Pepe S., Bogdanov K., Hallaq H., Spurgeon H., Leaf A., Lakatta E 1994. ω3 Polyunsaturated fatty acid modulates dihydropyridine effects on L-type Ca2+ channels, cytosolic Ca2+, and contraction in adult rat cardiac myocytes. Proc. Natl. Acad. Sci. USA 91:8832–8836

    CAS  PubMed  Google Scholar 

  46. Pound E.M., Kang J.X., Leaf A. 2001. Partition of polyunsaturated fatty acids, which prevent arrhythmias, into phospholipids cell membranes. J. Lipid Research 42:346–351

    CAS  Google Scholar 

  47. Qu Y., Isom L.L., Westenbroek R.E., Rogers J.C., Tanada T.N., McCormick K.A., Scheuer T., Catterall W.A. 1995. Modulation of cardiac Na+ channel expression in Xenopus oocytes by β1 subunit. J. Biol. Chem. 270:25696–25701

    CAS  PubMed  Google Scholar 

  48. Santoro B., Liu D.T., Yao H., Bartsch D., Kandel E.R., Siegelbaum S.A., Tibbs G.R. 1998. Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell 93:717–729

    Article  CAS  PubMed  Google Scholar 

  49. Schrepf R., Limmer, t., Claus Weber P., Theisen K., Sellmayer A. 2004. Immmediate effects of n-3 fatty acid infusion on the induction of sustained ventricular tachycardia. Lancet 363:1412–1413

    Article  Google Scholar 

  50. Singh R.B., Niaz M.A., Sharma J.P., Kumar R., Soshin M. 1997. Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction; the India experiment of infarct survival. Cardiovasc. Drugs Ther. 3:485–491

    Google Scholar 

  51. Siscovick D.S., Raghunathan I.E., King I., Weinmann S., Wicklund K.G., Albright J., Bovbjerg V., Arbogast P., Smith H., Kushi L.H., Cobb L.A., Copass M.K., Psaty B.M., Lenaite R., Retzlaff B., Childs M., Knopp R.H. 1995. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA 274:1363–1367

    Article  CAS  PubMed  Google Scholar 

  52. Talavera K., Staes M., Janssens A., Droogmans G., Nilius B. 2004. Mechanism of arachidonic acid modulation of the T-type Ca2+ channel {alpha} 1G. J. Gen. Physiol 124:225–238

    Article  CAS  PubMed  Google Scholar 

  53. Tiknonov, D.B., Zhorov, B.S. 2005. Sodium channel activators: Model of binding inside the pore and a possible mechanism of action. FEBS Lett. 579: 4207–4212

    Google Scholar 

  54. Wang O.K., Russell C., Wang S.Y. 2003. State-dependent block of wild-type and inactivation-deficient Na+ channels by flecainide. J. Gen. Physiol. 122:365–374

    Article  CAS  PubMed  Google Scholar 

  55. Xiao Y.-F., Kang J.X., Morgan J.P., Leaf A. 1995. Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes. Proc.Natl Acad. Sci. USA 92:1000–11004

    Google Scholar 

  56. Xiao Y.-F., Gomez A.M., Morgan J.P., Lederer W.J., Leaf A. 1997. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat cardiac myocytes. Proc. Natl. Acad. Sci. USA 94:4182–4187

    CAS  PubMed  Google Scholar 

  57. Xiao Y.-F., Morgan J.P., Leaf A. 2002. Effects of polyunsaturated fatty acids on cardiac voltage-activated K+ currents in adult ferret cardiomyocytes. Sheng Li Xue Bao 54:271–281

    CAS  PubMed  Google Scholar 

  58. Xiao Y.-F, Wright S.N., Wang O.K., Morgan J.P., Leaf A. 1998. Fatty acids suppress voltage-gated Na+ currents in HEK293t cells transfected with the a-subunit of the human cardiac Na+ channel. Proc. Natl. Acad. Sci. USA 95:2680–2685

    CAS  PubMed  Google Scholar 

  59. Xiao Y.-F, Wright S.N., Wang O.K., Morgan J.P., Leaf A. 2000. Coexpression with beta(1)-subunit modifies the kinetics and fatty acid block of hH1 (alpha) Na+ channels. Am. J. Physiol. 279:H35–H46

    CAS  Google Scholar 

  60. Xiao Y.-F, Ke Q., Wang S.Y., Yang Y., Wang O.K., Morgan J.P., Leaf A. 2001. Point mutations in alpha-subunit of human cardiac Na+ channels alter Na+ current kinetics. Biochem. Biophys. Res. Commun. 281:45-52

    Article  CAS  PubMed  Google Scholar 

  61. Xiao Y.-F., Ke Q., Wang S.Y., Auktor K., Yang Y., Wang O.K., Morgan J.P., Leaf A. 2001. Single point mutations affect fatty acid block of human myocardial sodium channel alpha subunit Na+ channels. Proc. Natl. Acad. Sci. USA 98:3606–3611

    CAS  PubMed  Google Scholar 

  62. Xiao, Y.-F., Ma, L., Wang, S.Y., Josephson, M.E., Wang, G.K., Morgan, J.P., Leaf, A. 2005. Potent block of inactivation-deficient Na+ channels by n-3 polyunsaturated fatty acids. Am. J. Physiol. In press.

  63. Xiao Y.-F, Ke Q., Wang S.Y., Yang Y., Chen Y., Wang O.K., Morgan J.P., Cox B., Leaf A. 2004. Electrophysiologic properties of lidocaine, cocaine, and n-3 fatty-acids block of cardiac Na+ channels. Eur. J. Pharmacol. 485:31–41

    Article  CAS  PubMed  Google Scholar 

  64. Xiao, Y.-F., Sigg, D.C. 2005. Hyperpolarization-activated cyclic-nucleotide-gated channel and cardiac biological pacemaker. Mol. Cardiol. of China 5: 513–522

    Google Scholar 

  65. Xiao Y.-F., Ke Q., Chen Y., Morgan J.P., Leaf A. 2004. Inhibitory effect of n-3 fish oil fatty acids on cardiac Na+/Ca2+ exchange currents in HEK293t cells. Biochem. Biophys. Res. Commun. 321:116–123

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Our studies have been supported in part by grants DK38165 from NIDDK and by HL62284 from NHLBI of the National Institutes of Health (AL) and American Heart Association (Y-FX). We wish to thank our colleagues who have contributed to the project for several years.

Author information

Authors and Affiliations

  1. Cardiac Rhythm Management, Medtronic Inc., Minneapolis, MN, 55432, USA

    Y.-F. Xiao & D.C. Sigg

  2. Departments of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA

    Y.-F. Xiao & A. Leaf

Authors
  1. Y.-F. Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D.C. Sigg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Leaf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y.-F. Xiao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xiao, YF., Sigg, D. & Leaf, A. The Antiarrhythmic Effect of n-3 Polyunsaturated Fatty Acids: Modulation of Cardiac Ion Channels as a Potential Mechanism. J Membrane Biol 206, 141–154 (2005). https://doi.org/10.1007/s00232-005-0786-z

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00232-005-0786-z

Keywords

Search

Navigation