In the absence of a generally accepted definition, SCD is usually defined as death from a cardiac cause occurring within 1 hour from the onset of symptoms.1 The magnitude of the problem is considerable because SCD is a very common, and often the first, manifestation of CHD and accounts for about 50% of cardiovascular mortality in developed countries.1 In most cases, SCD occurs outside a hospital and without prodromal symptoms. We shall now examine whether diet (more precisely, certain dietary factors) may prevent (or help prevent) SCD in patients with established CHD. We will focus our analyses on the effects of the different families of fatty acids, antioxidants, and alcohol.2
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 ate 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 (PUFAs), the dominant fatty acids in fish oil and fatty fish, have important effects on the occurrence of VF in the setting of myocardial ischemia and reperfusion in various animal models, both in vivo and in vitro.4,5 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 colleagues recently 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.6 These authors found the mechanism of this protection to result from the electrophysiolog-ical effects of free n-3 PUFAs when they are simply partitioned into the phospho-lipids of the sarcolemma without covalently bonding to any constituents of the cell membranes. After dietary intake, these fatty acids are preferentially incorporated into membrane phospholipids.7 Nair and colleagues have also shown that a very important pool of free (nonesterified) fatty acids exists in the normal myocardium and that the amount of n-3 PUFA in this pool is increased by supplementing n-3 PUFA in the diet.7 They noted a huge increase in n-3 PUFA concentrations, in particular for the nonesterified fraction, in the myocardia of pigs fed fish oil. This illustrates the potential of diet to modify the structures and biochemical compositions of cardiac cells.
In the case of ischemia, phospholipases and lipases quickly release new fatty acids from phospholipids, including n-3 fatty acids in higher amounts than the other fatty acids,7 further increasing the pool of free n-3 fatty acids that can exert an antiarrhythmic effect. It is important to remember that the lipase lipoprotein is particularly active following the consumption of n-3 PUFA.8 One hypothesis is that the presence of the free form of the 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.9 It seems that the very potent inhibitory effects of n-3 PUFA on the fast sodium current (Ina)1011 and the L-type calcium current (IcaL)12 are the major contributors to the antiarrhythmic actions of these fatty acids in ischemia. Briefly, n-3 PUFAs act by shifting the steady-state inactivation potential to more negative values, as was observed in other excitable tissues such as neurons.
Another important aspect of the implications of n-3 PUFAs in SCD is their role in the metabolization of eicosanoids. In competition with n-6 PUFAs, they are the precursors to a broad array of structurally diverse and potent bioactive lipids (including eicosanoids, prostaglandins, and thromboxanes) that are thought to play a role in the occurrence of VF during myocardial ischemia and reperfusion.1314
Other clinical data show suppression (by more than 70%) of ventricular premature complexes in middle-aged patients with frequent ventricular extrasystoles after random assignment of either fish oil or placebo doses.15 Also, survivors of AMI16 and healthy men17 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 effects of ethnic dietary patterns (instead of effects of a single food or nutrient), i.e., a Mediterranean type of diet and an Asian vegetarian diet, in the secondary prevention of CHD.1819 The two experimental diets included high intake of essential alpha-linolenic acid, the main vegetable n-3 PUFA. While the incidence of SCD was markedly reduced in both trials, the number of cases was very small and the antiarrhythmic effect cannot be entirely attributed to alpha-linolenic because the experimental diets were also high in other nutrients with potential antiarrhythmic properties, including various antioxidants.
These findings were extended by a population-based case-control study conducted by Siscovick and colleagues on the intake of n-3 PUFA among patients with primary cardiac arrest, compared to age- and sex-matched controls.20 Their data indicated that the intake of about 5 to 6 g 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 that were consistent with the results of many (but not all) cohort studies. This suggests 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.2122 In most studies, however, the SCD endpoint is not reported.
In a large prospective study (more than 20,000 participants and follow-up of 11 years), Albert et al. examined the specific point that fish has antiarrhythmic properties and may prevent SCD.23 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 nonsudden cardiac death, suggesting that the main protective effect of fish (or n-3 PUFA) is related to an effect on arrhythmia. These results are consistent with those of DART3 but differ from those of the Chicago Western Electric Study that noted a significant inverse association between fish consumption and nonsudden cardiac death, but not with SCD.24 Several methodological factors may explain the discrepancy, especially the way of classifying deaths in the Western Electric Study. This again illustrates the limitations of observational studies and the obvious fact that only randomized trials can definitely provide clear demonstrations of causal relationships.
The GISSI Prevenzione Trial was aimed at helping address the question of the health benefits of foods rich in n-3 PUFA (and also in vitamin E) and their pharmacological substitutes.25 Patients (n = 11,324) surviving recent AMIs (<3 months) and having been instruct to return 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 none (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. No difference was noted across the treatment groups for nonfatal CV events — a result comparable to that of DART.3 Thus, the results obtained in this randomized trial were consistent with previous controlled trials,3,18,19 large-scale observational studies,21-24 and experimental studies4-7 that together strongly support an effect of n-3 PUFA in relation with SCD. An important point is that the protective effect of n-3 PUFA on SCD was greater in the groups of patients who complied more strictly with the Mediterranean diet. This suggests a positive interaction between n-3 PUFA and some components of the Mediterranean diet which is, by definition, not high in n-6 PUFA, low in saturated fats, rich in oleic acid, various antioxidants, and fibre, and associated with a moderate consumption of alcohol.
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