Prevention of ischemia-induced cardiac Sudden death by n−3 polyunsaturated fatty acids in dogs
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
The objective of this study was to obtain functional information associated with the prevention by n−3 polyunsaturated fatty acids (PUFA) of ischemia-induced fatal cardiac ventricular arrhythmias in the intact, conscious, exercising dog. Thirteen dogs suceptible to ischemia-induced ventricular fibrillation were prepared surgically by ligation of their anterior descending left coronary artery and placement of an inflatable cuff around their left circumflex artery. After 4 wk of recovery, exercise-plus-ischemia tests were performed without and then with an intravenous infusion of an emulsion of free n−3 PUFA just prior to occluding the left circumflex artery while the animals were running on a treadmill. One week later the exercise-plus-ischemia test was repeated but with a control infusion replacing the emulsion of n−3 PUFA. The infusion of the free n−3 PUFA in quantities of 1.0 to 10 g prevented ventricular fibrillation in 10 of the 13 dogs tested (P<0.005), apparently without esterification of the PUFA into membrane phospholipids. The antiarrhythmic effect of the n−3 PUFA was associated with slowing of the heart rate, shortening of the QT-interval (electrical action potential duration), reduction of left ventricular systolic pressure, and prolongation of the electrocardiographic atrial-ventricular conduction time (P-R interval). These effects are comparable with those we have reported in studies with cultured neonatal rat cardiac myocytes.
- American Heart Association, Heart and Stroke Facts: Statistical Supplement (1995) Amercan Heart Association, Dallas.
- Gudbjarnason, S., and Hallgrimsson, J. (1975) The Role of Myocardial Membrane Lipids in the Development of Cardiac Necrosis. Acta Med. Scand. suppl. 587, 17–26.
- Murnaghan, M.F. (1975) Effects of Fatty Acids on the Ventricular Arrhythmia Threshold in the Isolated Heart of Rabbits, Br. J. Pharmacol., 73, 909–915.
- McLennan, P.L. (1993) Relative Dietary Effects of Dietary Saturated. Monounsaturated, and Polyunsaturated Fatty Acids on Cardiac Arrhythmias in Rats. Am. J. Clin. Nutr. 57, 207–212.
- McLennan, P.L., Abeywardena, M.Y., and Charnock J.S. (1985) Influence of Dietary Lipid on Arrhythmias and Infarction After Coronary Artery Ligation in Rats, Can. J. Physiol. Pharmacol. 63, 1411–1417.
- McLennan, P.L., Bridle, T.M., Abeywardena, M.Y., and Charnock, J.S. (1992) Dietary Lipid Modulation of Ventricular Fibrillation Threshold in the Marmoset, Am. Heart J. 123, 1555–1561. CrossRef
- Billman, G.E., Hallaq, H., and Leaf, A. (1994) Prevention of Ischemia-Induced Ventricular Fibrillation by ω3 Fatty Acids. Proc. Natl. Acad. Sci. USA, 91, 4427–4430. CrossRef
- Billman, G.E. (1989) Effect of Calcium Channel Antagonists on Susceptibility to Sudden Death: Protection from Ventricular Fibrillation, J. Pharmacol. Exp. Therap. 248, 1334–1342.
- Billman, G.E., Schwartz, P.J., and Stone, H.L. (1989) Baroreceptor Reflex Control of Heart Rate: A Predictor of Sudden Cardiac Death, Circulation, 66, 874–880.
- Schwartz, P.J., Billman, G.E., and Stone, H. (1984) Autonomic Mechanisms in Ventricular Fibrillation Induced by Myocardial Ischemia During Exercise in Dogs with Healed Myocardial Infarction: an Experimental Preparation for Sudden Cardiac Death. Circulation 69, 790–800.
- Weylandt, K.H., Kang, J.X., and Leaf, A. (1996) Polyunsaturated Fatty Acids Exert Antiarrhythmic Actions as Free Fatty Acids Rather Than in Phospholipids, Lipids 31, 977–982. CrossRef
- Bazett, H.C. (1920) An Analysis of Time Relations of the Electrocardiogram. Heart 7, 353–370.
- Kang, J.X., and 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. CrossRef
- Billman, G.E., and Leaf, A. (1996) Purified ω3 Fatty Acids Prevent Ventricular Fibrillation Induced by Myocardial Ischemia, Circulation, 94, I-307 (Abstract).
- Kamp, F., and Hamilton, J.A. (1992) pH Gradients Across Phospholipid Membranes Caused by Fast Flip-Flop of Un-ionized Fatty Acids, Proc. Natl. Acad. Sci. USA 89, 11367–11370. CrossRef
- Noy, N., Donnelly, T.M., and Zakim, D. (1986) Physical Chemical Model for the Entry of Water-Insoluble Compounds into Cells. Studies of Fatty Acid Uptake by the Liver. Biochemistry, 25, 2013–2021. CrossRef
- Xiao, Y-F., Gomez, A.M., Morgan, J.P., Lederer, W.J., and Leaf, A. (1997) Suppression of Voltage-gated L Type Ca2+ Currents by Polyunsaturated Fatty Acids in Adult and Neonatal Rat Ventricular Myocytes, Proc. Natl. Acad Sci. USA, 94, in press.
- Richieri, G.V., and Kleinfeld, A.M. (1995) Unbound (Free) Fatty Acids in Human Serum, J. Lipid Res. 36, 229–240.
- Rose, H., Convetz, M., Fischer, Y., Jungling, E., Hennecke, T., and Kammermeir, H. (1994) Long-Chain Fatty Acid-Binding to Albumin: Reevaluation with Directly Measured Concentrations. Biochim. Biophys. Acta 1215, 321–326.
- Kinoshita, I., Utoh, K., Nishiuda-Nakai, M., Hirota, H., Otsuji, S., and Shibato, N., (1994) Antiarrhythmic Effects of Eicosapentaenoic Acid During Myocardial Infarction, Jap. Circ. J. 58, 903–912.
- Kang, J.X., and Leaf, A. (1995) Prevention and Termination of the β-Adrenergic Agonist-Induced Arrhythmias by Free Polyunsaturated Fatty Acids in Neonatal Rat Cardiac Myocytes, Biochem. Biophys. Res., Commun. 208, 629–636. CrossRef
- Kang, J.X., Xiao, Y-F., and 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. CrossRef
- Xiao, Y.F., Kang, J.X., Morgan, J., and Leaf, A. (1995) Blocking Effects of Polyunsaturated Fatty Acids on Na+ Channels of Neonatal Rat Ventricular Myocytes. Proc. Natl. Acad. Sci. USA 92, 11000–11004. CrossRef
- Knapp, H.R., and FitzGerald, G.A. (1989) The Antihypertensive Effects of Fish Oil: A Controlled Study of Polyunsaturated Fatty Acids Supplements in Essential Hypertension, N. Engl. J. Med., 320, 1037–1043. CrossRef
- Shimokawa, H., and Vanhoutte, P.M. (1988) Dietary n−3 Fatty Acids and Endothelium-Dependent Relaxations in Porcine Coronary Arteries. Am. J. Physiol. 254, H968-H973.
- Malis, C.D., Leaf, A., Varadarajan, G.S., Newell, J.B., Weber, P.C., Force, T., and Bonventre, J.V. (1991) Effect of Dietary Omega-3 Fatty Acids on Vascular Contractility and Post-Anoxic Aortic Rings. Circulation, 84, 1393–1401.
- Hock, C.E., Beck, L.D., Bodon, R.C., and Reibel, D.K. (1990) Influence of Dietary n−3 Fatty Acids on Myocardial Ischemia and Reperfusion, Am. J. Physiol., 259, H1518-H1526.
- Burr, L.M., Gilbert, F.J., Holliday, M.R., Elwood, P.C., Fehily, M.A., Rogers, S., Sweetnam, M.P., and Deadman, M.N. (1989) Effects of Changes in Fat, Fish, and Fibre Intakes on Death and Myocardial Reinfarction (DART), Lancet 334, 757–776. CrossRef
- de Logeril, M., Renaud, S., Mamelle, N., Salen, P., Martin, J.L., Monjaud, I., Guidollet, J., Touboul, P., and Delaye, J. (1994) Mediterranean Alpha-Linolenic Acid-Rich Diet in Secondary Prevention of Coronary Heart Disease, Lancet 343, 1454–1459. CrossRef
- Kang, J.X., and Leaf, A. (1996) Evidence That Free Polyunsaturated Fatty Acids Modify Na+ Channels by Directly Binding to the channel Proteins, Proc. Natl. Acad. Sci. USA, 94, 2724–2728. CrossRef
- Vaughan Williams, E.M. (1984) A Classification of Antiarrhythmic Actions Reassessed After a Decade of New Drugs, Clin. Pharmacol., 24, 129–147.
- Kirber, M.T., Ordway, R.W., Clapp, L.H., Walsh, J.V. Jr., and Singer, J.J. (1992) Both Membrane Stretch and Fatty Acids Directly Activate Large Conductance Ca2+-activated K+ Channels in Vascular Smooth Muscle Cells, Fed. Exp. Biol. Soc., 297, 24–28.
- Ordway, R.W., Walsh, J.V., Jr., and Singer, J.J. (1989) Arachidonic Acid and Other Fatty Acids Directly Activate Potassium Channels in Smooth Muscle Cells, Science 244, 1176–1179. CrossRef
- Poling, J.S., Karanian, J.W., Salem, N., Jr., and Vicini, S. (1995) Time- and Voltage-Dependent Block of Delayed Rectifier Potassium Channels by Docosahexaenoic Acid, Mol. Pharmacol. 47, 381–390.
- Schmitt, H., and Meves, H. (1995) Modulation of Neuronal Calcium Channels by Arachidonic Acid and Related Substances, J. Membrane Biol., 145, 233–244. CrossRef
- Shimada, T., and Somlyo, A.P. (1992) Modulation of Voltage-Dependent Ca2+ Channel Current by Arachidonic Acid and Other Long-Chain Fatty Acids in Rabbit Intestinal Smooth Muscle, J. Gen. Physiol., 100, 27–44. CrossRef
- Vreugdenhil, M., Bruehl, C., Voskuyl, R., Kang, J.X., Leaf, A., and Wadman, W.J. (1996) Polyunsaturated Fatty Acids Modulate Sodium and Calcium Currents in CA1 Neurons. Proc. Nat. Acad. Sci. USA 93, 12559–12563. CrossRef
- Prevention of ischemia-induced cardiac Sudden death by n−3 polyunsaturated fatty acids in dogs
Volume 32, Issue 11 , pp 1161-1168
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Industry Sectors
- Author Affiliations
- 1. Department of Physiology, The Ohio State University, 45210, Columbus, Ohio
- 2. Department of Medicine, Massachusetts General Hospital, 02114, Boston, Massachusetts
- 3. Harvard Medical School, 02115, Boston, Massachusetts