Observational and trial data have accumulated to support the hypothesis that increased consumption of the long-chain n-3 polyunsaturated
fatty acids found in fish, especially eicosapentaenoic and docosahexaenoic acids, lower the risk of sudden death from coronary heart disease, and interest has focused on the anti-arrhythmic properties of these fatty acids. In the late 1980s, McClennan et al were the first to show anti-arrhythmic properties associated with these fatty acids in animal models. Billman et al confirmed and expanded on these experiments in a dog model. Further experiments reported plausible cellular mechanisms for the anti-arrhythmic effects, including modulation of sodium, potassium, and calcium channels. Omega-3 fatty acids might also have favourable actions on heart rate variability, and therefore could be exerting anti-arrhythmic actions through effects on the autonomic nervous system.
Burr et al published the first randomised trial of the
effect of fish consumption on death from coronary heart disease, the
Diet and Reinfarction Trial (DART). In DART, just over 2000 men with a history of
myocardial infarction were randomised to three dietary strategies (lowering saturated fat, increasing fibre, and increasing fatty-fish intake). There was a 29% reduction in total mortality in the participants who received advice to eat at least two portions of fatty fish a week, but no difference in total events for coronary heart disease because more non-fatal myocardial infarctions occurred in the fish-advice group. To explain these apparently discordant effects on
fatal versus non-fatal events, Burr et al suggested that fish consumption might reduce the risk of fatal arrhythmias, and therefore preferentially affect mortality after myocardial infarction. Siscovick et al addressed this hypothesis by studying whether dietary intake and blood levels of n-3 fatty acids were associated with risk of a primary cardiac arrest, in a retrospective population-based case-control design.
Perhaps the most compelling clinical evidence to date for an anti-arrhythmic mechanism of action of the long-chain n-3 polyunsaturated fatty acids comes from the largest randomised trial, the
GISSI-Prevenzione Trial. Over 11000 patients surviving a recent myocardial infarction were assigned at random, in an unblinded fashion, to fish oil and/or vitamin E in a two-by-two factorial design. The patients assigned to fish oil had a significant reduction in the primary endpoint (death, non-fatal myocardial infarction, and non-fatal stroke) due to a statistically significant reduction in total mortality (20%). Again, as in DART, there was no benefit on non-fatal cardiovascular events. When investigated further, much of the benefit on mortality was attributable to a 53% reduction in sudden cardiac death that emerged at 4 months of follow-up.
There are two possible mechanism of action, relating to direct and indirect effect of omega-3 following its consumption. The direct mechanism refers to the antiarrhythmic effect of omega-3 as a free fatty acid which inhibits the fast, voltage-dependent sodium current along with the L-type calcium currents. This reduces the action potential of cardiac myocytes, reducing the susceptibility to arrhythmia. The indirect mechanism refers to the effect of omega-3 on cardiac arrhythmias by modifying the balance of different eicosanoids which are produced as end-products from chain elongation of their parent polyunsaturated fatty acids. Eicosanoids derived from long chain omega-6 PUFAs are proarrhythmic while those from omega-3 seem to be antiarrhythmic.
Key points:
EPA and DHA has cardioprotective activity. Consumption of 450 and 1000 mg/d is recommended for those without and with known coronary heart disease, respectively.
The PUFAs act by stabilizing electrically every cardiac myocyte by modulating conductance of ion channels in the sarcolemma, particularly the fast, voltage-dependentsodiumcurrent and the L-type calcium currents, though other ion currents are also affected.
Another mechanisms for this cardio-protective effect focused on the effects of n-3 fatty acids on eicosanoid metabolism, inflammation, beta oxidation, endothelial dysfunction, cytokine growth factors, and gene expression of adhesion molecules;
Further, n-3 fatty acids can increase parasympathetic tone leading to an increase in heart rate variability and thus, protect the myocardium against ventricular arrhythmias.
EPA supplementation increases the (Ca(2+)-Mg2+)-ATPase activity within myocardial membranes that is involved in Ca2+ metabolism in myocardial cells by increasing the ratio of EPA to AA within cellular membranes. These cellular alterations are likely to reduce the severity of ventricular arrhythmias by inhibiting the rapid accumulation of intracellular Ca2+ following ischemia.
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