This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Siscovick, D. S. Articles by Mozaffarian, D. Search for Related Content PubMed PubMed Citation Articles by Siscovick, D. S. Articles by Mozaffarian, D. Related Collections Arrhythmias, clinical electrophysiology, drugs Epidemiology Cardio-renal physiology/pathophysiology Related Article

(Circulation. 2003;107:2632.)
© 2003 American Heart Association, Inc.

Editorials

The Fish Story

A Diet–Heart Hypothesis With Clinical Implications: n-3 Polyunsaturated Fatty Acids, Myocardial Vulnerability, and Sudden Death

David S. Siscovick, MD, MPH; Rozenn N. Lemaitre, PhD, MPH; Dariush Mozaffarian, MD, MPH

From the Cardiovascular Health Research Unit, Departments of Medicine (D.S.S., R.N.L.) and Epidemiology (D.S.S.), and Veterans Affairs Puget Sound Health Care System (D.M.), University of Washington, Seattle, Wash.

Correspondence to David S. Siscovick, MD, MPH, CHRU, 1730 Minor Ave #1360, Seattle, WA 98101. E-mail dsisk{at}u.washington.edu

Key Words: Editorials • fish oils • fatty acids, n-3 polyunsaturated • diet • sudden death

Clinicians frequently are asked whether dietary fat intake influences the risk of coronary heart disease (CHD). However, many clinicians remain unclear about the role of dietary fat and fatty acids in the occurrence of CHD. The original diet–heart hypothesis focused on dietary saturated fat intake, serum cholesterol, and atherosclerosis; and, after more than 3 decades of research, it remains a source of controversy.¹ Recent studies have focused on other dietary fatty acids, the n-3 polyunsaturated fatty acids (PUFAs) found in fish oil, and on a specific manifestation of CHD, sudden cardiac death.^2–4 These studies suggest potentially large effects associated with modest dietary intake of n-3 PUFAs, but the findings also seem to conflict with other reports in the scientific literature.^5,6 As a result, there is considerable clinical skepticism about the role of dietary fat and fatty acids in efforts to reduce CHD.

See p 2646

The original diet–heart hypothesis was characterized by the following syllogism: (1) Dietary saturated fat intake increases serum cholesterol; (2) high serum cholesterol leads to atherosclerosis; and (3) atherosclerosis results in CHD morbidity and mortality. Taken individually, each element of this syllogism is supported by scientific evidence from one or more paradigms, including animal-experimental, genetic, pathological, nutritional, and ecological studies. However, epidemiological studies within populations have failed to consistently support the original diet–heart hypothesis. Some have attributed these negative studies to error in the measurement of saturated fat intake and/or a limited range in saturated fat intake within populations. Although a large, clinical primary prevention trial to test the original diet–heart hypothesis was considered, it was not conducted, in part, because of concerns about long-term adherence to dietary interventions to reduce saturated fat intake.

Recently, a new diet–heart hypothesis has emerged. This diet–heart hypothesis focuses on the n-3 PUFAs and sudden cardiac death, a major cause of CHD mortality in patients with and without clinically recognized CHD. The n-3 PUFAs include the long-chain n-3 PUFAs, eicosapentaenoic acid (EPA: 20:5n3) and docosahexaenoic acid (DHA: 22:6n-3), which are derived primarily from seafood, and the intermediate-chain n-3 PUFA, -linolenic acid (ALA: 18:3n3), which in Western diets is derived primarily from canola oil and walnuts. Importantly, the physiological effects of the n-3 PUFAs and their metabolic products differ from those of the n-6 PUFAs, the other major class of PUFAs. In Western diets, the major n-6 PUFA is the intermediate-chain n-6 PUFA, linoleic acid (LA: 18:2n6), primarily derived from vegetable seed oils.

The new diet–heart hypothesis can be characterized by the following syllogism: (1) Dietary n-3 PUFA intake increases cell membrane and free fatty acid n-3 PUFA levels; (2) higher n-3 PUFA levels favorably alter cardiac ion channel function; (3) altered ion channel function modifies the cardiac action potential; and (4) alteration in the action potential reduces myocardial vulnerability to ventricular fibrillation, the major life-threatening arrhythmia that results in sudden cardiac death in the setting of myocardial ischemia. Taken individually, each element of this syllogism is now supported by evidence from one or more research paradigms, including animal-experimental, cell biology, genetic, nutritional, and epidemiological studies. Of particular importance, evidence from randomized clinical trials of either fatty fish intake or low-dose n-3 PUFA supplementation in post–myocardial infarction patients provides additional support for the new diet–heart hypothesis.^7,8

In the present issue of Circulation, Alexander Leaf and colleagues⁹ review recent research related to the clinical prevention of sudden cardiac death in the setting of CHD by n-3 PUFAs and suggest a hypothesized cellular mechanism through which n-3 PUFAs affect ion channels to reduce the risk of arrhythmia. Leaf et al note that clinical studies, including several epidemiological studies and clinical trials, now support the potential role of both dietary n-3 PUFA intake and low-dose n-3 PUFA supplements in the clinical prevention of sudden cardiac death. Additionally, they review the evidence from a variety of other research paradigms that suggests a plausible mechanism for the observations of a potentially beneficial effect of the n-3 PUFAs from seafood on sudden cardiac death in humans.

Both clinical and animal-experimental evidence suggests that the effect of n-3 PUFAs on the risk of sudden cardiac death relates primarily to reduced vulnerability to ventricular fibrillation, rather than to a reduction in atherosclerosis or nonfatal myocardial infarction. In epidemiological studies in which biomarkers of dietary n-3 PUFA intake were used, higher cell membrane, plasma phospholipid, and total blood n-3 PUFA levels have been associated with a markedly lower risk of sudden cardiac death among persons without clinically recognized CHD.^4,10 These studies used different study designs and were conducted in different populations. In GISSI Prevenzione, low-dose n-3 PUFA supplementation reduced sudden cardiac death by 45% among patients with a prior myocardial infarction and was safe and well tolerated.⁸ In animal-experimental models of ventricular fibrillation, feeding of n-3 PUFA–enriched diets for 3 months, compared with feeding of saturated fat, reduced the rate of ventricular fibrillation in the setting of ischemia and various triggers (eg, exercise and pharmacological stress),¹¹ and the acute intravenous infusion of n-3 PUFA free fatty acids also reduced the rate of ventricular fibrillation.⁹

Leaf and colleagues⁹ conducted a series of studies, reviewed in the present issue of Circulation, to explore a potential cellular mechanism for the observed reduced vulnerability to ventricular fibrillation. In cultured neonatal rat myocytes, n-3 PUFAs altered the physiological response to stimuli known to increase the risk of ventricular fibrillation, both preventing and terminating the abnormal physiological responses to a range of stimuli. In voltage-clamping studies of ion channels, n-3 PUFAs influenced both sodium and calcium ion channel function, decreasing myocyte excitability and reducing cytosolic calcium fluctuations. However, these effects were seen with both n-3 PUFAs and n-6 PUFAs.^12,13 Demonstration of the specificity of these effects for n-3 PUFAs and confirmation of these findings from other laboratories are needed to further build the case that this hypothesized mechanism accounts for both the clinical and the animal-experimental observations related to the new diet–heart hypothesis.

Because n-3 PUFAs have multiple effects, alternative mechanisms for the reduced CHD mortality associated with n-3 PUFAs, including the effects of n-3 PUFAs on serum lipids, inflammation, endothelial function, atherosclerosis, vulnerable plaque, and thrombosis, also have been suggested.³ However, there is little evidence from clinical or animal-experimental studies to suggest that these mechanisms account for the effect of n-3 PUFAs on the life-threatening arrhythmias that result in sudden cardiac death. Whether the nutritional doses and low-dose n-3 PUFA supplements impact one or more of these pathways in humans also is unknown.

As noted by Leaf et al,⁹ the work of their group was stimulated, in part, by the animal-experimental studies of McLennan et al.¹¹ We too were intrigued by these reports, and, with the support of National Heart, Lung and Blood Institute and the paramedic systems in King County, Wash, we conducted a population-based case-control study of dietary intake and cell membrane levels of n-3 PUFAs from seafood and the risk of sudden cardiac death.⁴ We found that both dietary intake and cell membrane levels of n-3 PUFAs were associated with a lower risk of sudden cardiac death. At the time, the findings appeared to conflict with several large cohort studies that did not observe an association of the frequency of fish intake with the risk of combined fatal and nonfatal CHD.^5,6 We hypothesized that our findings differed from other reports, in part, because of differences in the outcome examined (sudden cardiac death versus combined fatal and nonfatal CHD) and the dietary focus of the studies (modest consumption of fatty fish/n-3 PUFAs compared with no intake, versus more fish consumption compared with less).¹⁴ Subsequent reports from some of these same cohorts examined the associations of modest fish consumption and blood levels of long-chain n-3 PUFAs from seafood with the risk of sudden cardiac death, confirming our findings and suggesting that benefits are specific to fatal CHD, due primarily to a reduction in sudden cardiac death, rather than total CHD events.^2,3

Taken together, the evidence from epidemiological studies suggests a possible threshold effect for n-3 PUFA intake. Compared with no (or very low) intake, modest dietary intake of fatty fish and n-3 PUFAs from seafood, the equivalent of 1 fatty fish meal a week, is associated with a marked (40% to 50%) reduction in sudden cardiac death.^2–4 Thus, some intake of n-3 PUFAs from seafood appears to be better than none. On the other hand, there is little evidence from epidemiological studies that greater dietary intake of fatty fish is better than modest intake; more does not appear to be better than less. These findings are consistent with a threshold effect at modest dietary n-3 PUFA intake from seafood, rather than a dose-response effect. Additionally, we recently reported that in contrast to fatty fish, consumption of fried fish, typically low in n-3 PUFAs and not associated with n-3 plasma phospholipid levels, was not associated with a lower risk of fatal CHD or arrhythmic death among older adults.¹⁵ The available evidence, therefore, supports the clinical and public health recommendation for dietary intake of at least 1 fatty fish meal (high in n-3 PUFAs) per week.

Clinicians also need to know that dietary n-3 PUFAs (and low-dose n-3 PUFA supplements) may reduce the risk of sudden cardiac death over a period of weeks to months. In our population-based case-control study, recent dietary intake and cell membrane levels of n-3 PUFAs at the time of the event were associated with a lower risk of sudden cardiac death.⁴ In the GISSI Prevenzione trial, low-dose n-3 PUFA supplements reduced the risk of sudden cardiac death among post–myocardial infarction patients within 4 months of initiating treatment.⁸ These observations are consistent with evidence from nutritional studies that dietary intake of n-3 PUFAs alters cell membrane and free fatty acid composition within days to weeks.

The influence, if any, of other dietary factors on the relationship between dietary n-3 PUFAs and risk of sudden cardiac death is unclear. As Leaf et al⁹ point out, eicosanoids derived from the n-6 PUFA linoleic acid oppose and counteract the actions of the eicosanoids derived from the n-3 PUFA -linolenic acid. For this reason, some have hypothesized that the ratio of n-6 PUFAs to n-3 PUFAs is critical.¹⁶ However, there is a lack of evidence from epidemiological studies to suggest that the effect of n-3 PUFAs on the risk of sudden cardiac death is modified by dietary n-6 PUFA intake.³

Current American Heart Association guidelines do not distinguish between dietary intake of the intermediate-chain n-3 PUFA -linolenic acid (ALA: 18:3n3) and the intermediate-chain n-6 PUFA linoleic acid (LA: 18:2n-6). There is some evidence from clinical, animal-experimental, and laboratory-based studies that the potential cardiac benefits of long-chain n-3 PUFAs can be achieved with dietary intake of -linolenic acid. Among female nurses, dietary intake of -linolenic acid was associated with a lower risk of fatal CHD.¹⁷ In a nested case-control study conducted within the Cardiovascular Health Study, higher plasma phospholipid levels of long-chain n-3 PUFAs and -linolenic acid were associated with a lower risk of fatal CHD but not nonfatal myocardial infarction.¹⁸ In contrast, higher plasma phospholipid levels of linoleic acid were not associated with a lower risk of fatal CHD. Leaf and colleagues⁹ review several studies using animal-experimental and cell biology paradigms that suggest that -linolenic acid may have effects similar to those of EPA/DHA. Additional clinical and epidemiological research is needed to determine whether -linolenic acid is associated with a lower risk of sudden cardiac death, particularly among persons who are not seafood eaters. If so, it is possible that canola oil, rich in -linolenic acid, may offer an alternative dietary intervention to reduce the risk of sudden cardiac death.

Clinicians are aware of the limitations of the research paradigms used to examine the effects of n-3 PUFAs. Observational studies in human populations are potentially limited by problems of measurement, bias, and generalizability. Clinical trials of dietary interventions and n-3 PUFA supplementation have focused on secondary prevention, and findings may not be generalizable to other populations. The response to dietary and pharmacological interventions in animal-experimental models may not adequately predict the response to these interventions in humans because of differences in the exposure (dose or method of administration) or comparative physiology. Studies of isolated rat neonatal myocytes and voltage-clamping studies of ion channels are conducted in the absence of neural and hormonal input. Additionally, bathing cells or infusing n-3 PUFAs may result in nonspecific effects that alter the outcomes examined. Nevertheless, the consistency of the findings related to n-3 PUFAs, arrhythmia, and sudden cardiac death from research using a variety of paradigms suggests that a new diet–heart hypothesis focused on n-3 PUFAs and sudden cardiac death may have important implications for the heart health of the public that merit further attention by clinicians, researchers, and policymakers.

As noted by Leaf et al,⁹ clinical cardiology has been slow to acknowledge the potential importance of this growing body of science and to translate these findings into practice. The messages from Alexander Leaf and colleagues⁹ are clear. For clinicians, it is time to implement the current American Heart Association dietary guidelines that recommend the dietary intake of 1 to 2 fish meals, particularly fatty fish, each week. For policymakers, there is a need to consider a new indication for treatment with low-dose n-3 PUFA supplements—the prevention of sudden cardiac death in patients with a prior myocardial infarction. For researchers, there is a need to continue both clinical studies and studies that explore the mechanism through which n-3 PUFAs influence the risk of sudden cardiac death. Randomized clinical trials evaluating dietary long-chain and intermediate-chain n-3 PUFA interventions and low-dose long-chain n-3 PUFA supplements are needed to demonstrate that these interventions reduce mortality from sudden cardiac death in patients with and without clinically recognized CHD.

Although mortality from sudden cardiac death has declined, it continues to account for approximately 50% of CHD mortality, and the prevention of sudden cardiac death in the community remains a challenge. Implantable cardioverter defibrillators can reduce mortality in clinical subsets at high risk for sudden cardiac death, but few drug therapies have been demonstrated to reduce the risk of sudden cardiac death. Dietary intake of modest amounts of n-3 PUFAs from seafood (the equivalent of 1 to 2 fatty fish meals a week) in the population and low-dose n-3 PUFA supplementation (850 mg/d of EPA/DHA) in patients with a prior myocardial infarction are low-cost, low-risk interventions. Leaf and colleagues⁹ call attention to the translational research focused on n-3 PUFAs, arrhythmia, and sudden cardiac death—research that suggests that modest intake of n-3 PUFAs has the potential to reduce mortality from sudden cardiac death in the community. It’s time for increased attention by clinicians, researchers, and policymakers to this new diet–heart hypothesis and for the translation of this considerable body of experimental, epidemiological, and clinical evidence into clinical practice.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

1. Taubes G. Nutrition: the soft science of dietary fat. Science. 2001; 291: 2536–2545.[Free Full Text]
   
2. Albert CM, Hennekens CH, O’Donnell CJ, et al. Fish consumption and risk of sudden cardiac death. JAMA. 1998; 279: 23–28.[Abstract/Free Full Text]
   
3. Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA. 2002; 287: 1815–1821.[Abstract/Free Full Text]
   
4. 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. JAMA. 1995; 274: 1363–1367.[Abstract]
   
5. Ascherio A, Rimm EB, Stampfer MJ, et al. Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men. N Engl J Med. 1995; 332: 977–982.[Abstract/Free Full Text]
   
6. Morris MC, Manson JE, Rosner B, et al. Fish consumption and cardiovascular disease in the Physicians’ Health Study: a prospective study. Am J Epidemiol. 1995; 142: 166–175.[Abstract/Free Full Text]
   
7. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989; 2: 757–761.[Medline] [Order article via Infotrieve]
   
8. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)–Prevenzione. Circulation. 2002; 105: 1897–1903.[Abstract/Free Full Text]
   
9. Leaf A, Kang JX, Xiao YF, et al. The clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and the mechanism of the prevention of arrhythmias by n-3 fish oils. Circulation. 2003; 107: 2646–2652.[Free Full Text]
   
10. 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: 1113–1118.[Abstract/Free Full Text]
    
11. McLennan PL, Bridle TM, Abeywardena MY, et al. Dietary lipid modulation of ventricular fibrillation threshold in the marmoset monkey. Am Heart J. 1992; 123: 1555–1561.[CrossRef][Medline] [Order article via Infotrieve]
    
12. Kang JX, Leaf A. Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids. Am J Clin Nutr. 2000; 71: 202S–207S.[Abstract/Free Full Text]
    
13. Kang JX, Leaf A. Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel proteins. Proc Natl Acad Sci U S A. 1996; 93: 3542–3546.[Abstract/Free Full Text]
    
14. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. Am J Clin Nutr. 2000; 71: 208S–212S.[Abstract/Free Full Text]
    
15. Mozaffarian D, Lemaitre RN, Kuller LH, et al. Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the Cardiovascular Health Study. Circulation. 2003; 107: 1372–1377.[Abstract/Free Full Text]
    
16. Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr. 1999; 70: 560S–569S.[Abstract/Free Full Text]
    
17. Hu FB, Stampfer MJ, Manson JE, et al. Dietary intake of alpha-linolenic acid and risk of fatal ischemic heart disease among women. Am J Clin Nutr. 1999; 69: 890–897.[Abstract/Free Full Text]
    
18. Lemaitre RN, King IB, Mozaffarian D, et al. n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study. Am J Clin Nutr. 2003; 77: 319–325.[Abstract/Free Full Text]
    

Related Article:

Clinical Prevention of Sudden Cardiac Death by n-3 Polyunsaturated Fatty Acids and Mechanism of Prevention of Arrhythmias by n-3 Fish Oils

Alexander Leaf, Jing X. Kang, Yong-Fu Xiao, and George E. Billman
Circulation 2003 107: 2646-2652. [Full Text]

This article has been cited by other articles:

				D. Mozaffarian Fish and n-3 fatty acids for the prevention of fatal coronary heart disease and sudden cardiac death Am. J. Clinical Nutrition, June 1, 2008; 87(6): 1991S - 1996S. [Abstract] [Full Text] [PDF]

				M. E. Surette PhD The science behind dietary omega-3 fatty acids Can. Med. Assoc. J., January 15, 2008; 178(2): 177 - 180. [Full Text] [PDF]

				D. Mozaffarian and E. B. Rimm Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA, October 18, 2006; 296(15): 1885 - 1899. [Abstract] [Full Text] [PDF]

				J. McGuinness, T.G. Neilan, A. Sharkasi, D. Bouchier-Hayes, and J.M. Redmond Myocardial protection using an omega-3 fatty acid infusion: Quantification and mechanism of action J. Thorac. Cardiovasc. Surg., July 1, 2006; 132(1): 72 - 79. [Abstract] [Full Text] [PDF]

				C.-Q. Lai, D. Corella, S. Demissie, L. A. Cupples, X. Adiconis, Y. Zhu, L. D. Parnell, K. L. Tucker, and J. M. Ordovas Dietary Intake of n-6 Fatty Acids Modulates Effect of Apolipoprotein A5 Gene on Plasma Fasting Triglycerides, Remnant Lipoprotein Concentrations, and Lipoprotein Particle Size: The Framingham Heart Study Circulation, May 2, 2006; 113(17): 2062 - 2070. [Abstract] [Full Text] [PDF]

				D. Mozaffarian, C. L. Bryson, R. N. Lemaitre, G. L. Burke, and D. S. Siscovick Fish Intake and Risk of Incident Heart Failure J. Am. Coll. Cardiol., June 21, 2005; 45(12): 2015 - 2021. [Abstract] [Full Text] [PDF]

				D. Mozaffarian, A. Ascherio, F. B. Hu, M. J. Stampfer, W. C. Willett, D. S. Siscovick, and E. B. Rimm Interplay Between Different Polyunsaturated Fatty Acids and Risk of Coronary Heart Disease in Men Circulation, January 18, 2005; 111(2): 157 - 164. [Abstract] [Full Text] [PDF]

				T. O. Cheng, J. Dallongeville, M. Montaye, P. Amouyel, J. Yarnell, A. Evans, P. Ducimetiere, A. Bingham, G. Luc, D. Arveiler, et al. Fish Consumption and Coronary Artery Disease in China * Response Circulation, March 9, 2004; 109 (9): e155 - e156. [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Siscovick, D. S. Articles by Mozaffarian, D. Search for Related Content PubMed PubMed Citation Articles by Siscovick, D. S. Articles by Mozaffarian, D. Related Collections Arrhythmias, clinical electrophysiology, drugs Epidemiology Cardio-renal physiology/pathophysiology Related Article