(Circulation. 2001;104:744.)
© 2001 American Heart Association, Inc.
Editorial |
Plasma Nonesterified Fatty Acid Concentration as a Risk Factor for Sudden Cardiac Death
The Paris Prospective Study
From the Department of Medicine, Massachusetts General Hospital and the Harvard Medical School, Boston Mass.
Correspondence to Alexander Leaf, MD, Massachusetts General Hospital East, 149 13th Street, Room 4001, Charlestown, MA 02129. E-mail aleaf{at}partners.org
Key Words: Editorials • death, sudden • fatty acids
In the 1960s and 1970s, at the time the study by Jouven et al1 was initiated, there was much interest among cardiologists regarding the likelihood that elevated concentrations of free fatty acids in plasma occurring with myocardial ischemia might initiate ventricular arrhythmias resulting in sudden cardiac death. Nevertheless, it required far-sighted investigators to launch an epidemiological study with 5250 middle-aged men without known cardiovascular disease and the persistence to follow this cohort for a mean follow-up time of 22 years, making this a unique and valuable reference for the natural history of cardiovascular disease over a recent period in Western industrialized countries.
See p 756
Nonesterified fatty acids, or free fatty acids, are highly hydrophobic, shunning the aqueous medium of body fluids. They are generally toxic to cells and are kept at low nanomolar or micromolar concentrations in plasma; these levels can vary greatly depending on the hormonal, metabolic, and nutritional state of the individual. Some 99.9% of free fatty acids are carried in plasma bound to proteins, mainly serum albumin, which has some 5 to 8 or more binding sites per molecule ranging from high to low affinity. The low concentration of fatty acids is maintained in plasma by the competition between the affinity of albumin-binding sites and cell membrane phospholipids for free fatty acids. In heart cell membranes, concentrations in turn are kept low by the cells, which constitute a sink for the fatty acids they consume as metabolic fuel.
The free fatty acid levels in plasma result from the regulated turnover of lipid stores in adipose tissue by lipolysis and from phospholipids by phospholipases and is little affected by the immediate dietary consumption of fat. There is a differential rate of mobilization of fatty acids on the lipolysis of triglycerides stored in adipose cells.2 They are not liberated as free fatty acids into plasma at a rate that is simply proportional to their content in adipose tissue; rather mobilization seems influenced by their molecular structure, so that the more unsaturated the fatty acid, the more rapidly it is mobilized and the longer its acyl chain, the slower the mobilization. Thus, eicosapentaenoic acid (C20:5n-3) and arachidonic acid (C20:4n-6), precursors of 2 different classes of prostaglandins, were reported as the fatty acids with the highest mobilization into plasma.2 In phospholipids, fatty acid mobilization is also regulated. Saturated and monounsaturated fatty acids, which are arrhythmogenic, are preferentially accumulated in the Sn-1 position of the phospholipid molecule (bound to the first H-C-OH of the glycerol backbone of the phospholipid molecule), whereas the essential polyunsaturated fatty acids of the n-6 class (plant seed oils) and n-3 class (largely available from fish oil), if supplied in the diet, are preferentially stored in the Sn-2 position, from which they can be specifically and rapidly released by activated phospholipase A-2.
The great interest in the 1960s and 1970s regarding the possible role of elevated concentrations of free fatty acids in plasma and myocardial infarctions resulted in a considerable number of experimental studies in patients and in animals that seemed fairly convincingly to either support or negate this possibility. A basis for this dichotomy of results may be that not all fatty acids are equal in their propensity to cause arrhythmias. Murnaghan3 reported that in an ex vivo perfused rabbit heart mounted in a Langendorff preparation, long-chain saturated fatty acids do not affect the ventricular arrhythmia threshold under normoxia but potentiate the lowering effect of hypoxia on the ventricular arrhythmia threshold. He also found that polyunsaturated fatty acids prevented this arrhythmogenic action of saturated fatty acids in his perfused rabbit heart preparation. McLennan4 reported that when saturated or monounsaturated fatty acids were the major fat in the diets of rats, >40% of the rats died of irreversible ventricular fibrillation when their coronary arteries were ligated, but if tuna fish oil was the major dietary fat, ventricular fibrillation was essentially prevented. This has been confirmed in rats by others. My colleagues and I confirmed the potent antiarrhythmic effect of fish oil in a reliable dog model of ischemic cardiac death (P<0.005)5 and showed that pure decosahexaenoic acid or eicosapentaenoic acid were the specific ingredients of the fish oil responsible for its antiarrhythmic action.6 There have now been several clinical studies7–10 that have found a significant reduction in sudden cardiac death attributable to n-3 fatty acids; an epidemiological study and a case-control retrospective study have also illustrated similar findings.11,12 There are at least 3 clinical trials of n-3 fatty acids currently in progress.
The findings of Jouven et al1 suggest, not surprisingly now, that the subjects included in the Paris Prospective Study were consuming diets low in n-3 fatty acids, as has been the case during the past century in Western industrialized countries, where n-3 polyunsaturated fatty acids have been disappearing from the diet while consumption of saturated fats and plant seed n-6 polyunsaturated fatty acids have been increasing. The increase in n-6 fatty acids has occurred at the urging of governmental agencies and heart associations in the United States that have been recommending more polyunsaturated fatty acids in the diet without distinguishing the difference between the 2 classes of essential n-6 and n-3 fatty acids. The result of their advice is that many people have been ingesting more of the common vegetable oils from plant seeds (eg, corn, safflower, sunflower, and peanut oils), which provide a very high intake of n-6 fatty acids but no n-3 fatty acids. Fortunately, last November, the American Heart Association revised its dietary recommendations to include advice to eat 2 fish meals weekly for a healthy heart.
These 2 classes of fatty acids differ in their functions in the body and, in very important instances, each antagonizes the actions of an excess amount of the other. Highly significant to the present discussion is the fact that when n-6 fatty acids, especially linoleic acid (C18:2n-6; the parent n-6 fatty acid), that are rich in the commonly used dietary plant seed oils are ingested, the linoleic acid can be elongated and desaturated to arachidonic acid, from which important 2-series prostaglandins are formed by the oxygenation of arachidonic acid by cyclooxygenase. My colleagues and I found that all the prostaglandins and thromboxane produced from arachidonic acid (that were tested) are potent arrhythmogenic agents, except prostacyclin, whereas none of the comparable 3-series cyclooxygenase products of eicosapentaenoic acid were arrhythmogenic.13 Only relatively small amounts of n-3 fatty acids seem needed for protection, perhaps 600 to 1000 mg of eicosapentaenoic acid plus decosahexaenoic acid daily,14 but this intake must be accompanied by a reduction of n-6 fatty acids to provide a ratio closer to 1:1 of dietary n-6 to n-3 polyunsaturated fatty acids rather than ratios of 10:1 or greater, as in the diets of most Americans and Europeans. This dietary change is, perhaps, the main prevention of sudden cardiac death that Jouven et al1 thought was needed.
Another interesting point made in the report by Jouven et al1 is the fact that although elevated plasma free fatty acid concentrations were predictive of sudden cardiac death, they were not predictive of fatal myocardial infarction. Coronary heart disease, the overwhelming cause of most cardiac ischemic events including myocardial infarctions, is also the cardiac disease most commonly associated with sudden cardiac arrhythmic deaths. That a risk factor has been identified for sudden arrhythmic deaths but not for fatal myocardial infarctions reminds us that there are other causes of sudden arrhythmic deaths besides cardiac ischemia (eg, prolonged QT intervals induced by drugs or genetically based toxicity from elevated extracellular calcium concentrations, toxic concentrations of cardiac glycosides,15 etc). In addition to modulating the voltage-gated Na+ currents in cardiomyocytes,16–18 which initiate action potentials, the n-3 fatty acids also modulate L-type Ca2+ channel conductance and prevent the excessive cytosolic free Ca2+ fluctuations that create delayed afterpotentials, which can cause arrhythmias.19,20
This long-term, primary prospective, observational, clinical study has provided valuable information regarding the natural history of cardiac disease in our era in the United States and Europe and is likely to continue to do so.
Acknowledgments
Studies cited from the author’s laboratory were supported in part by grant H62284 from the NHLBI of the National Institutes of Health.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1.
Jouven X, Charles M-A, Desnos M, et al. Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population. Circulation. 2001; 104: 756–761.
2. Connor WE, Lin DS, Colvis C. Differential mobilization of fatty acids from adipose tissue. J Lipid Res. 1996; 37: 290–298.[Abstract]
3. Murnaghan MF. Effects of fatty acids on the ventricular arrhythmia threshold in the isolated heart of the rabbit. Br J Pharmacol. 1985; 73: 909–915.[Medline] [Order article via Infotrieve]
4.
McLennan PL. Relative effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on cardiac arrhythmias in rats. Am J Clin Nutr. 1993; 57: 207–212.
5. Billman GE, Kang JX, Leaf A. Prevention of ischemia-induced cardiac sudden death by n-3 polyunsaturated fatty acids. Lipids. 1997; 32: 1161–1168.[Medline] [Order article via Infotrieve]
6.
Billman GE, Kang JX, Leaf A. Prevention of ischemia-induced cardiac sudden death by pure n-3 polyunsaturated fatty acids. Circulation. 1999; 99: 2452–2457.
7. Burr M, Gilbert JF, Holliday RM, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989; 334: 757–761.
8. de Logeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994; 143: 1454–1459.
9. Singh RB, Niaz MA, Sharma JP, et al. Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival. Cardiovasc Drugs Ther. 1997; 11: 485–491.[Medline] [Order article via Infotrieve]
10. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction. Lancet. 1999; 354: 447–455.[Medline] [Order article via Infotrieve]
11.
Albert CM, Hennekens CH, O’Donnell CJ, et al. Fish consumption and risk of sudden cardiac death. J Am Med Assoc. 1998; 279: 23–28.
12.
Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. J Am Med Assoc. 1995; 274: 1363–1367.
13. Li Y, Kang JX, Leaf A. Differential effects of various eicosanoids on the production or prevention of arrhythmias in cultured neonatal rat cardiac myocytes. Prostaglandins. 1997; 54: 511–530.[Medline] [Order article via Infotrieve]
14. Dolecek TA. Epidemiologic evidence of relationships between dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial. Proc Soc Exp Biol Med. 1992; 200: 177–182.[Medline] [Order article via Infotrieve]
15.
Kang JX, Leaf A. Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocytes. Proc Natl Acad Sci U S A. 1994; 91: 9886–9890.
16. Xiao Y-F, Kang JX, Morgan JP, et al. Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes. Proc Natl Acad Sci U S A. 1995; 92: 1000–11004.
17.
Xiao Y-F, Wright SN, Wang GK, et al. N-3 fatty acids suppress voltage-gated Na+ currents in HEK293t cells transfected with the 
-subunit of the human cardiac Na+ channel. Proc Natl Acad Sci U S A. 1998; 95: 2680–2685.
18.
Xiao Y-F, Wright SN, Wang GK, et al. Coexpression with ß1-subunit modifies the kinetics and fatty acid block of hH1 NA+ channels. Am J Physiol. 2000; 279: H35–H46.
19.
Xiao Y-F, Gomez AM, Morgan JP, et al. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat cardiac myocytes. Proc Natl Acad Sci U S A. 1997; 94: 4182–4187.
20. Kang JX, Leaf A. Prevention and termination of arrhythmias induced by lysophosphatidyl choline and acyl carnitine in neonatal rat cardiomyocytes by free omega-3 fatty acids. Eur J Pharmacol. 1996; 297: 97–106.[Medline] [Order article via Infotrieve]
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