The hypothesis that eating fish may protect against SCD is derived from the results of a secondary prevention trial, the Diet And Reinfarction Trial (DART), which showed a significant reduction in total and cardiovascular mortality (both by about 30%) in patients who had at least two servings of fatty fish per week.3 The authors suggested that the protective effect of fish might be explained by a preventive action on ventricular fibrillation (VF), since no benefit was observed on the incidence of nonfatal acute myocardial infarction (AMI). This hypothesis was consistent with experimental evidence suggesting that n-3 polyunsaturated fatty acids (PUFA),the dominant fatty acids in fish oil and fatty fish, have an important effect on the occurrence of VF in the setting of myocardial ischemia and reperfusion in various animal models, both in vivo and in vitro.4 In the same studies, it was also apparent that saturated fatty acids are proarrhythmic as compared to unsaturated fatty acids. Using an elegant in vivo model of SCD in dogs, Billman and co-workers demonstrated a striking reduction of VF after intravenous administration of pure n-3 PUFA, including both the long chain fatty acids present in fish oil and alpha-linolenic acid, their parent n-3 PUFA occurring in some vegetable oils.4 These authors have found the mechanism of this protection to result from the electrophysiological effects of free n-3 PUFA when these are simply partitioned into the phospholipids of the sarcolemma without covalently bonding to any constituents of the cell membrane. After dietary intake, these fatty acids are preferentially incorporated into membrane phospholipids. It has also been shown that a very important pool of free (non-esterified) fatty acids exists in the normal myocardium and that the amount of n-3 PUFA in this pool is increased by supplementing the diet with n-3 PUFA. This illustrates the potential of diet to modify the structure and biochemical composition of cardiac cells. In ischemia, phospholipases and lipases quickly release new fatty acids from phospho-lipids, including n-3 fatty acids in higher amounts than the other fatty acids, thus further increasing the pool of free n-3 fatty acids that can exert an antiarrhythmic effect. It is important to remember that the lipoprotein lipase is particularly active following the consumption of n-3 PUFA. One hypothesis is that the presence of the free form of n-3 PUFA in the membrane of every cardiac muscle cell renders the myocardium more resistant to arrhythmias, probably by modulating the conduction of several membrane ion channels. So far, it seems that the very potent inhibitory effects of n-3 PUFA on the fast sodium current, INa, and the L-type calcium current, ICaL,4 are the major contributors to the antiarrhythmic actions of these fatty acids in ischemia. Briefly, n-3 PUFA act by shifting the steady-state inactivation potential to more negative values, as was also observed in other excitable tissues such as neurons.4
Another major aspect of that question is that most Western populations are severely deficient in omega-3 fatty acids from both the marine and terrestrial world. In the United States, experts from the American Heart Association claim that the average consumption of omega-3 fatty acids should be multiplied by 4 to attain the recommended intakes.5 Intake of vegetable omega-3 should be doubled. The same trends are observed in European countries such as France. Chronic deficiency in omega-3 fatty acids probably explains at least partly the high prevalence of cardiac death (and SCD) in these countries.
Another important aspect of the implication of n-3 PUFA in SCD is their role in the metaboliza-tion of eicosanoids. In competition with n-6 PUFA, they are the precursors to a broad array of structurally diverse and potent bioactive lipids (including eicosanoids, prostaglandins, and thromboxanes), which are thought to play a role in the occurrence of VF during myocardial ischemia and reperfusion. These fatty acids (both n-6 PUFA and n-3 PUFA) also play a role in the development of vascular inflammation and atherosclerosis through the leukotriene pathway.6
Other clinical data show suppression (by more than 70%) of ventricular premature complexes in middle-aged patients with frequent ventricular extrasystoles randomly assigned to take either fish oil or placebo. Also, survivors of AMI and healthy men receiving fish oil were shown to improve their measurements of heart rate variability, suggesting other mechanisms by which n-3 PUFA may be antiarrhythmic.
Support for the hypothesis of a clinically significant antiarrhythmic effect of n-3 PUFA in the secondary prevention of CHD, as put forward in DART,3 came from two randomized trials testing the effect of ethnic dietary patterns (instead of that a single food or nutrient), i.e. a Mediterranean type of diet and an Asian vegetarian diet, in the secondary prevention of CHD.1,7 The two experimental diets included a high intake of essential alpha-linolenic acid, the main vegetable n-3 PUFA. Whereas the incidence of SCD
was markedly reduced in both trials, the number of cases was small and the antiarrhythmic effect cannot be entirely attributed to alpha-linolenic acid as these experimental diets were also high in other nutrients with potential antiarrhythmic properties, including various antioxidants.
These findings were extended by the population-based case-control study conducted by Sis-covick and colleagues on the intake of n-3 PUFA among patients with primary cardiac arrest, compared to that of age- and sex-matched controls.8 These data confirm the very low consumption of n-3 PUFA in the Western populations (especially in comparison with the Japanese) and indicated that the intake of about 5 to 6 grams of n-3 PUFA per month (an amount provided by consuming fatty fish once or twice a week) was associated with a 50% reduction in the risk of cardiac arrest. In that study, the use of a biomarker, the red blood cell membrane level of n-3 PUFA, considerably enhanced the validity of the findings, which also were consistent with the results of many (but not all) cohort studies suggesting that consumption of one to two servings of fish per week is associated with a marked reduction in CHD mortality as compared to no fish intake. In most studies, however, the SCD endpoint is not reported.
In a large prospective study (more than 20,000 participants with a follow-up of 11 years), Albert et al. examined the specific point that fish has antiarrhythmic properties and may prevent SCD.9 Again these investigators found a very low average consumption of n-3 PUFA. They found that the risk of SCD was 50% lower for men who consumed fish at least once a week than for those who had fish less than once a month. Interestingly, the consumption of fish was not related to non-sudden cardiac death, suggesting that the main protective effect of fish (or n-3 PUFA) is related to an effect on arrhythmia.
The GISSI-Prevenzione trial was aimed at helping in addressing the question of the health benefits of foods rich in n-3 PUFA (and also in vitamin E) and their pharmacological substi-tutes.10 Patients (n = 11,324) surviving a recent AMI (<3 months) and having received the prior advice to come back to a Mediterranean type of diet were randomly assigned supplements of n-3 PUFA (0.8 g daily), vitamin E (300 mg daily), both, or neither (control) for 3.5 years. The primary efficacy endpoint was the combination of death and nonfatal AMI and stroke. Secondary analyses included overall mortality, cardiovascular (CV) mortality, and SCD. Treatment with n-3 PUFA significantly lowered the risk of the primary endpoint (the relative risk decreased by 15%). Secondary analyses provided a clearer profile of the clinical effects of n-3 PUFA. Overall mortality was reduced by 20% and CV mortality by 30%. However, it was the effect on SCD (45% lower) that accounted for most of the benefits seen in the primary combined endpoint and both overall and CV mortality. There was no difference across the treatment groups for nonfatal CV events, a result comparable to that of DART.3 Thus, the results obtained in this randomized trial are consistent with previous controlled trials,1 large-scale observational studies,8'9 and experimental studies,4 which together strongly support an effect of n-3 PUFA in relation to SCD.
Regarding the physiopathology, administering n-3 PUFA intravenously to patients with an ICD (implanted defibrillator) and at very high risk of SCD seems to provide these patients with an extraordinary degree of protection against malignant ventricular arrhythmias.11 Recently, at the 2004 meeting of the European Society of Cardiology in Munich, Leaf and colleagues reported that the main protective effect of very long chain n-3 PUFA, eicosapentaenoic acid (EPA), and docosa-hexaenoic acid (DHA) probably results from the prevention of malignant arrhythmias. In fact, in the Fatty Acid Anti-Arrhythmia Trial (FAAT) conducted in more than 400 patients at high risk of SCD (and with ICDs), patients randomized to receive (double-blind protocol) a mix of 2.4g of EPA + DHA had a 40% reduction of the risk of malignant ventricular arrhythmias as recorded by the ICD compared with those receiving the placebo.
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