Fish and N-3 fatty acids for the prevention and treatment of coronary heart disease: nutrition is not pharmacology

Since investigators suggested that the lower mortality rate of coronary heart disease observed in Eskimos in Greenland may be due to a seafood-rich diet (1), the dietary benefits of fish have attracted considerable scientific interest. While most epidemiological studies have reported a protective effect associated with the consumption of even small amounts of fish, there have been negative reports (2,3), as well as inconsistent findings (4,5). This variability could be due to differences in the methods of assessing fish intake (4); consumption of different types of fish (e.g., fatty fish versus lean fish) or fish from various sources (Table) (5); potential contamination of fish by toxic heavy metals (6); subjects being aware of the cardioprotective effects of fish consumption, which may result in an “effect-cause” relation (2,3); differences in the methods used to validate and classify endpoints, with only a few studies reporting, for instance, on both sudden and nonsudden cardiac death; or differences in risk levels among different populations (7). However, when assessing more precisely (whenever possible) the cause of cardiac death, the data suggest that the benefit of eating fish is a reduction in the risk of sudden cardiac death. Two studies (8,9) reported that modest fish intake is associated with a 50% decrease in the risk of sudden cardiac death but no decrease in the risk of nonsudden cardiac death or myocardial infarction (9). Other evidence of an effect of the long-chain n-3 fatty acids (Figure), which are abundant in fatty fish in the form of docosahexanoic and eicosapentaenoic acids, on sudden cardiac death come from laboratory and clinical research. For instance, the electrophysiological effects of n-3 fatty acids in cultured cardiac myocytes, as well as their antiarrhythmic effects in laboratory animals (10), have been reported, as has their administration intravenously to prevent sudden cardiac death during myocardial ischemia (11). Christensen et al. investigated the effects of n-3 fatty acids on heart rate variability in patients with recent acute myocardial infarction and a low left ventricular ejection fraction (12), and found a positive correlation between n-3 fatty acids in the diet (and blood) and baroreflex sensitivity (12), the latter being associated with good outcomes in patients who survive a recent acute coronary event (13). They also showed that the intake of n-3 fatty acids was associated with increased heart rate variability in a dose-dependent manner (14). The beneficial effects of n-3 fatty acids on the risk of sudden cardiac death may therefore be partly related to an antiarrhythmic effect due to a favorable shift in the vagal/sympathetic balance, which decreases susceptibility to ventricular arrhythmias (15). Although the details of the antiarrhythmic action of n-3 fatty acids remain to be elucidated (relative importance of the effect on cardiac ion channels, on the autonomic nervous system or on the local production of proarrhythmic and antiarrhythmic eicosanoids), the consensus is that n-3 fatty acids have an important cardioprotective effect in patients with established coronary heart disease, and that physicians should recommend the inclusion of fish in their patients’ diets (15–17). In addition, the cardioprotective effects of longchain n-3 fatty acids at low doses are due to an effect on the ischemic myocardium, and not on blood lipids and hemostasis. Conversely, alpha-linolenic acid, the parent compound of long-chain n-3 fatty acids (Figure) that is found in some vegetable oils, may protect through both myocardial and nonmyocardial mechanisms. Indeed, for persons who cannot (or will not) eat fish or other seafood that is rich in n-3 fatty acids, consumption of foods containing alpha-linolenic acid is an alternative. In addition to its own direct effect on cardiac arrhythmias (10,11), dietary alpha-linolenic acid does not accumulate within cells, induces a marked shift in the endogenous metabolism of n-6 fatty acids (18), and inhibits the elongation and desaturation of linoleic acid (18:2 n-6) into arachidonic acid (19). Because arachidonic acid (20:4 n-6), in competition with eicosapentaenoic acid, affects inflammation as the precursor of the proinflammatory eicosanoids and leukotrienes, modifying its amount and the amount of its fatty acid precursors would affect the prevalence and severity of eicosanoid-related disorders, including atherosclerotic complications and sudden cardiac death (18,19). Indeed, dietary alpha-linolenic acid has been shown to be associated inversely with the risk of fatal coronary heart disease (20). Thus, for many authors, it is the balance between n-3 and n-6 fatty acids, rather than the absolute amounts of n-3 fatty acids in the diet, which is critical for disease prevention (21–23), and the Am J Med. 2002;112:316 –319. From the Laboratoire du Stress Cardiovasculaire et Pathologies Associees, Universite Joseph Fourier de Grenoble, Grenoble, France. Requests for reprints should be addressed to Michel de Lorgeril, MD, Laboratoire du Stress Cardiovasculaire et Pathologies Associees, UFR de Medecine et Pharmacie, Domaine de la Merci, 38706 La Tronche, Grenoble, France. Manuscript submitted October 22, 2001.