Dietary prevention of sudden cardiac death SCD the role of dietary fatty acids alcohol and antioxidants

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SCD is usually defined as death from a cardiac cause occurring within one hour from the onset of symptoms.1 In many studies, however, investigators used quite different definitions, with a time frame of 3 or even 24 hours in the old World Health Organization definition. The magnitude of the problem is considerable since SCD is a very common, and often the first, manifestation of CHD, and it accounts for about 50 per cent of cardiovascular mortality in developed countries.1 In most cases, SCD occurs without prodromal symptoms and out of hospital. As a matter of fact, this mode of death is a major public health issue. Since up to 80 per cent of SCD patients had CHD,2 the epidemiology and potential preventive approaches of SCD should, in theory, parallel those of CHD. In other words, any treatment aimed at reducing CHD should reduce the incidence of SCD.

We now examine whether diet (and more precisely, certain dietary factors) may prevent (or help prevent) SCD in patients with established CHD. We focus our analyses on the effects of the different families of fatty acids, antioxidants and alcohol.2

3.2.1 Fish, n-3 fatty acids and SCD

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 per cent) 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 ischaemia 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 compared with 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 that the mechanism of this protection results 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.7

Nair and colleagues have also 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 in n-3 PUFA.7 This illustrates the potential of diet to modify the structure and biochemical composition of cardiac cells. In the case of ischaemia, phospholipases and lipases quickly release new fatty acids from phospholipids, including n-3 fatty acids in higher amounts than the other fatty acids,7 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.8 One hypothesis is that the presence of the free form of n-3 PUFA in the membrane of cardiac muscle cells renders the myocardium more resistant to arrhythmias, probably by modulating the conduction of several membrane ion channels.9 So far, it seems that the very potent inhibitory effects of n-3 PUFA on the fast sodium current, INa,10'11 and the L-type calcium current, ICaL,12 are the major contributors to the anti-arrhythmic actions of these fatty acids in ischaemia. 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.

Another important aspect of the implication of n-3 PUFA in SCD is their role in the metabolisation 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 ischaemia and reperfusion.13,14

Other clinical data show suppression (by more than 70 per cent) of ventricular premature complexes in middle-aged patients with frequent ventricular extrasystoles randomly assigned to take either fish oil or placebo.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 randomised trials testing the effect of ethnic dietary patterns (instead of that of a single food or nutrient), i.e. a Mediterranean type of diet and an Asian vegetarian diet, in the secondary prevention of CHD.18'19 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 very 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 Siscovick and colleagues on the intake of n-3 PUFA among patients with primary cardiac arrest, compared with that of age- and sex-matched controls.20 Their data indicated that the intake of about 5-6 grams of n-3 PUFA per month (an amount provided by consuming fatty fish once or twice a week) was associated with a 50 per cent 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 compared with no fish intake.2122 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.23 They found that the risk of SCD was 50 per cent 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. These results are consistent with those of DART3 but differ from those of the Chicago Western Electric Study, in which there was a significant inverse association between fish consumption and non-sudden cardiac death, but not with SCD.24 Several methodological factors may explain the discrepancy between the two studies, especially the way of classifying deaths in the Western Electric Study.24 This again illustrates the limitations of observational studies and the obvious fact that only randomised trials can definitely provide a clear demonstration of causal relationships.

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 substitutes.25 Patients (n = 11 324) surviving a recent AMI (<3

Table 3.1 Clinical efficacy of (n-3) PUFA in the GISSI-Prevenzione Trial. See text for comments

Relative risk (95% confidence interval)

Death, nonfatal AMI and stroke

0.85 (0.70-0.99)

Overall mortality

0.80 (0.67-0.94)

Cardiovascular mortality

0.70 (0.56-0.87)

Sudden cardiac death

0.55 (0.40-0.76)

Nonfatal cardiovascular events

0.96 (0.76-1.21)

Fatal and nonfatal stroke

1.30 (0.87-1.96)

Source: modified from GISSI-Prevenzione investigators.25

Source: modified from GISSI-Prevenzione investigators.25

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 (300mg 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. The exact definition of SCD was not given in the paper. However, the clinical events were validated by an ad hoc committee of expert cardiologists,25 who presumably used the current definition of SCD. Treatment with n-3 PUFA significantly lowered the risk of the primary endpoint (the relative risk decreased by 15 per cent). Secondary analyses provided a clearer profile of the clinical effects of n-3 PUFA (Table 3.1). Overall mortality was reduced by 20 per cent and CV mortality by 30 per cent. However, it was the effect on SCD (45 per cent 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 randomised trial are consistent with previous controlled trials,3'18'19 large-scale observational studies21-24 and experimental studies,4-7 which 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 and low in saturated fats, but rich in oleic acid, various antioxidants and fibre, and associated with a moderate consumption of alcohol (see below for further comments).

3.2.2 Saturated fatty acids, oleic acid, trans fatty acids and n-6 fatty acids

Regarding the other dietary fatty acids, animal experiments have clearly indicated that a diet rich in saturated fatty acids is associated with a high incidence of ischaemia- and reperfusion-induced ventricular arrhythmia, whereas PUFA of either the n-6 or n-3 family reduce that risk.4-6 Many (but not all) epidemiological studies have shown consistent associations between the intake of saturated fatty acids and CHD mortality.26 However, the SCD endpoint is usually not analysed in these studies. In addition, a clear demonstration of a causal relationship between dietary saturated fatty acids and SCD would require the organisation of a randomised trial, which is not ethically acceptable. Thus, besides the effect of saturated fatty acids on blood cholesterol levels, the exact mechanism(s) by which saturated fats increase CHD mortality remain unclear. If animal data, demonstrating a proarrhythmic effect of saturated fatty acids, are confirmed in humans, the first thing to do in order to prevent SCD in humans would be to drastically reduce the intake of saturated fats. In fact, this has been done in randomised dietary trials and, as expected, the rate of SCD decreased in the experimental groups.18'19 However, as written above about the same trials,22'23 the beneficial effect cannot be entirely attributed to the reduction of saturated fats, because other potentially antiarrhythmic dietary factors, including n-3 PUFA, were also modified in these trials.

In contrast to n-3 PUFA, few data have been published so far regarding the effect of n-6 PUFA on the risk of SCD. Roberts et al. have reported that the percentage content of linoleic acid (the dominant n-6 PUFA in the diet) in adipose tissue (an indicator of long-term dietary intake) was inversely related to the risk of SCD, which was defined in that study as instantaneous death or death within 24 hours of the onset of symptoms.27 This is in line with most animal data and may suggest that people at risk of SCD may benefit from increasing their dietary intake of n-6 PUFA, in particular linoleic acid, in the same way as for n-3 PUFA. However, n-3 PUFA were more effective on SCD than n-6 PUFA in most animal experiments.4-6

In addition, diets high in n-6 PUFA increase the linoleic acid acid content of lipoproteins and render them more susceptible to oxidation,28 which would be an argument against such diets because lipoprotein oxidation is a major step in the inflammatory process that renders atherosclerotic lesions unstable and

prone to rupture.

Erosion and rupture of atherosclerotic lesions were shown to trigger CHD complications (see below the section on plaque inflammation and rupture) and myocardial ischaemia and to considerably enhance the risk of SCD.32-35 As a matter of fact, in the secondary prevention of CHD, diets high in n-6 PUFA failed to improve the overall prognosis of the patients.36 Also, in the Dayton study, a mixed primary and secondary prevention trial, in which the chief characteristic of the experimental diet was the substitution of n-6 PUFA for saturated fat, the number of SCD was apparently lower in the experimental group than in the control group (18 vs. 27) but the number of deaths from other causes, in particular cancers, was higher in the experimental group (85 vs. 71), thus offsetting the potential protective effect of n-6 PUFA on SCD and having no effect at all on mortality.37 Such negative effects were not reported with n-3 PUFA. Thus, despite the beneficial effect of n-6 PUFA on lipoprotein levels, which could, in theory, reduce SCD in the long term by reducing the development of atherosclerosis, it seems preferable not to increase the consumption of n-6 PUFA beyond the amounts required to prevent deficiencies in the essential n-6 fatty acid, linoleic acid (approximately 4-6 per cent of the total energy intake), which are found in the current average Western diet. As a substitute for saturated fat, the best choice is obviously to increase the intake of vegetable monounsaturated fat (oleic acid) in accordance with the Mediterranean diet pattern. If oleic acid has apparently no effect on the risk of SCD (at least by comparison with n-3 and n-6 PUFA), its effects on blood lipoprotein levels are similar to those of n-6 PUFA and it has the great advantage of protecting lipoproteins against oxidation.38

Thus, the best fatty acid combination to prevent SCD (and other complications of CHD) and, in other words, the cumulative antiarrhythmic, antioxidant and hypolipidaemic effects, would result from the adoption of a diet close to the Mediterranean diet pattern.38'39

Finally, Roberts et al. reported no significant relationship between trans isomers of oleic and linoleic acids in adipose tissue and the risk of SCD40 whereas Lemaitre et al. found that cell membrane trans isomers of linoleic acid (but not of oleic acid) are associated with a large increase in the risk of primary cardiac arrest.41 As for the role of trans fatty acids on ventricular arrhythmias, it has not been investigated in experimental models.

Thus, although specific human data on the effect of saturated fatty acids on SCD are lacking, results of several trials suggest that it is important to reduce their intake in the secondary prevention of CHD. Despite a possible beneficial effect on the risk of SCD, increasing consumption of n-6 PUFA should not be recommended in clinical practice for patients with established CHD. Diets including low intakes of saturated fatty acid (as well as trans isomers of linoleic acid) and n-6 PUFA (but enough to provide the essential linoleic acid) and high intakes of n-3 PUFA and oleic acid (Mediterranean diet pattern) appear to be the best option to prevent both SCD and nonfatal AMI recurrence.19,38

3.2.3 Alcohol and SCD

The question of the effect of alcohol on heart and vessel diseases has been the subject of intense controversy in recent years. The consensus is now that moderate alcohol drinking is associated with reduced cardiovascular mortality, although the exact mechanism(s) by which alcohol is protective are still unclear. In contrast, chronic heavy drinking has been incriminated in the occurrence of atrial as well as ventricular arrhythmias in humans, an effect called 'the holiday heart' because it is often associated with binge drinking by healthy people, specifically during the weekend. Studies in animals have shown varying and apparently contradictory effects of alcohol on cardiac rhythm and conduction, depending on the animal species, the experimental model and the dose of alcohol. If given acutely to non-alcoholic animals, ethanol may even have antiarrhythmic properties.

In humans, few studies have specifically investigated the effect of alcohol on SCD. The hyperadrenergic state resulting from binge drinking, as well as from withdrawal in alcoholics, seems to be the main mechanism by which alcohol induces arrhythmias in humans. In the British Regional Heart Study, the relative risk of SCD in heavy drinkers (more than six drinks per day) was twice as high as in occasional or light drinkers.42 However, the effect of binge drinking on SCD was more evident in men with no pre-existing CHD than in those with established CHD. In contrast, in the Honolulu Heart Program,43 the risk of SCD among healthy middle-aged men was positively related to blood pressure, serum cholesterol, smoking and left ventricular hypertrophy but inversely related to alcohol intake. In fact, the effect of moderate 'social' drinking on the risk of SCD in non-alcoholic subjects has been addressed so far in only one study.

Investigators of the Physicians' Health Study assessed whether light-to-moderate alcohol drinkers apparently free of CHD at baseline have a decreased risk of SCD.44 After controlling for multiple confounders, men who consumed two to four drinks per week or five to six drinks per week at baseline had a significantly reduced risk of SCD (by 60-80 per cent) as compared with those who rarely or never consumed alcohol. Analyses were repeated after excluding deaths occurring during the first 4 years of follow-up (in order to exclude the possibility that some men who refrained from drinking at baseline did so because of early symptoms of heart diseases), and also using the updated measure of alcohol intake ascertained at year 7 to address potential misclassification in the baseline evaluation of alcohol drinking.44 These secondary analyses basically provided the same results and confirmed the potential protective effect of moderate drinking on the risk of SCD. Despite limitations (the selected nature of the cohort, an exclusively male study group, no information on beverage type and drinking pattern), this study suggests that a significant part of the cardioprotective effect of moderate drinking is related to the prevention of SCD. Further research should be directed at understanding the mechanism(s) by which moderate alcohol drinking may prevent ventricular arrhythmias and SCD.

In practice, the current state of our knowledge suggests that in CHD patients at risk of SCD, there is no reason not to allow moderate alcoholic drinking. From a practical point of view, we advise drinking no more than one or two drinks per day, preferably wine, preferably during the evening meal, and never before driving a car or undertaking dangerous work.

3.2.4 Antioxidants and SCD

The issue about the effect of dietary antioxidants on the risk of CHD in general and on SCD in particular is more controversial. Regarding vitamin E, for instance, the most widely studied dietary antioxidant, discrepant findings between the expected benefits based on epidemiological observations45,46 and the results of clinical trials47 48 were published. In a recent controlled trial, a significant decrease in nonfatal AMI and a non-significant increase in cardiovascular mortality (in particular in the rate of SCD) were reported with a daily regimen of 400—800 mg of vitamin E in patients with established CHD.49 Because of certain methodological shortcomings (which we will not discuss here), this trial was said to confuse rather than clarify the question of the usefulness of vitamin E supplementation in CHD, and provided no indication about possible links between vitamin E and the prevention of SCD.

The GISSI-Prevenzione trial brings new information in this regard. Unlike those of n-3 PUFA, the results of vitamin E supplementation do not support a significant effect on the primary endpoint, namely a combination of death and nonfatal AMI and stroke.25 However, the secondary analysis provides a clearer view of the clinical effect of vitamin E in CHD patients, which cannot be easily dismissed (see Table 3.2). In fact, among the 193 and 155 cardiac deaths that occurred in the control and vitamin E group, respectively, during the trial (a difference of 38, P<0.05), there were 99 and 65 SCDs (a difference of 34, P <0.05), which indicated that the significant decrease in cardiovascular mortality (by 20 per cent) in the vitamin E group was almost entirely due to a decrease in the incidence of SCD (by 35 per cent). In contrast, nonfatal cardiac events and non-sudden cardiac deaths were not influenced.25 These data suggest that vitamin E may be useful for the primary prevention of SCD in patients with established CHD.

The vitamin E data of the GISSI trial do not stand in isolation. In an in vivo dog model of myocardial ischaemia,50 we also reported a protective effect of vitamin E on the incidence of VF (the main mechanism of SCD) with a 16 per cent rate in the vitamin E group and 44 per cent in the placebo group (P <0.05). Also in line with the GISSI results, infarct size, which is the main determinant of acute heart failure and non-sudden cardiac death, was larger in the supplemented

Table 3.2 Clinical efficacy of vitamin E in the GISSI-Prevenzione Trial. See text for comments

Relative risk (95% confidence interval)

Death, nonfatal AMI and stroke Overall mortality Cardiovascular mortality Sudden cardiac death Nonfatal cardiovascular events Fatal and nonfatal

0.89 (0.77-1.03) 0.86 (0.72-1.02) 0.80 (0.65-0.99) 0.65 (0.48-0.89) 1.02 (0.81-1.28) 0.95 (0.61-1.47)

Source: modified from GISSI-Prevenzione investigators.25

group (58.5 per cent of the ischaemic area) than in the placebo group (41.9 per cent, P <0.05). Such ambivalent effects of vitamin E may at least partly explain why its effects were neutral or non-significant in many studies, with the negative effects hiding the beneficial ones. Nevertheless, the GISSI trial showed that cardiovascular mortality and SCD were significantly reduced by vitamin E, and the effect on overall mortality showed a favourable trend (P = 0.07). Finally, the recently published HOPE trial, testing the effect of 400 IU of vitamin E daily in patients at high risk of CHD (therefore in primary prevention) and reporting an apparent lack of effect of vitamin E, does not help us to solve the issue of whether or not vitamin E is protective against SCD.51 In that trial, it is not clear whether the patients actually took the capsules during meals (a prerequisite for intestinal absorption of vitamin E), whether the patients were more or less deficient in vitamin E (no blood measurement), whether some of them were taking vitamin supplements (a common practice nowadays among certain populations), and SCD was apparently not among the predefined endpoints. In addition, patients with left ventricular dysfunction, a major determinant of the risk of SCD, were not eligible.

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Alcohol No More

Alcohol No More

Do you love a drink from time to time? A lot of us do, often when socializing with acquaintances and loved ones. Drinking may be beneficial or harmful, depending upon your age and health status, and, naturally, how much you drink.

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