A worldwide research team assesses the evidence for nutrition-based solutions to the world?s number one killer
Active prevention of coronary heart disease (CHD) is usually started immediately after its first clinical manifestation. Secondary prevention focuses on risk reduction in people with established CHD who are at high risk of recurrent cardiac events and death. It is important to remember that the two main causes of death in these patients are sudden cardiac death (SCD) and heart failure, often resulting from myocardial ischemia and subsequent necrosis.
Most investigators agree that atherosclerosis is a chronic low-grade inflammation disease.1 Proinflammatory factors (free radicals produced by cigarette smoking, hyperhomocysteinaemia, diabetes, per oxidised lipids, hypertension, elevated and modified blood lipids) contribute to injure the vascular endothelium, which results in alterations of its anti-atherosclerotic and antithrombotic properties. This is thought to be a major step in the initiation and formation of arterial fibrostenotic lesions.1
Whatever the specific clinical aims of the programme, nutritional evaluation and counselling of each individual with CHD must be a key point of the preventive intervention. Nutrition is, however, only one component of such a programme.
Exercise training, behavioural interventions (particularly to help the patient abstain from smoking) and drug therapy have equally important roles.
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
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, which showed a significant reduction in total and cardiovascular mortality 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, since no benefit was observed on the incidence of nonfatal acute myocardial infarction.
Nair and colleagues have also shown that an 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.4 This illustrates the potential of diet to modify the structure and biochemical composition 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,4 thus further increasing the pool of free n-3 fatty acids that can exert an anti-arrhythmic effect.
A large prospective study (more than 20,000 participants with a follow-up of 11 years) examined the specific point that fish has anti-arrhythmic properties and may prevent SCD.5 Researchers 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 nonsudden cardiac death, suggesting that the main protective effect of fish (or n-3 PUFA) is related to an effect on arrhythmia.
An important point is that the protective effect of n-3 PUFA on SCD was greater in 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.
ANTIOXIDANTS AND SCD
Vitamin E: 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, there are discrepant findings between the expected benefits based on epidemiological observations and the results of clinical trials.6,7
In a recent controlled trial, a significant decrease in nonfatal acute myocardial infarction and a nonsignificant increase in cardiovascular mortality (in particular in the rate of SCD) were reported with a daily regimen of 400-800mg vitamin E in patients with established CHD.8
Because of certain methodological shortcomings, 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 SCD prevention.
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.9
However, the secondary analysis provides a clearer view of the clinical effect of vitamin E in CHD patients, which cannot be easily dismissed. In fact, among the 193 and 155 cardiac deaths that occurred in the control and vitamin E group, respectively, there were 99 and 65 SCDs, 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.9 These data suggest that vitamin E may be useful for the primary prevention of SCD in patients with established CHD.
Despite the mixed results when the outcome measures are myocardial infarction or stroke, there is considerable evidence that vitamin E has a positive effect on other measures of cardiovascular function. For example, a double-blind, placebo-controlled, randomised study found that 1000IU vitamin E (all-racemic alpha-tocopherol) for three months improved endothelial function and blood flow in patients with type I diabetes and reduced the oxidative susceptibility of LDL.10
Vitamin E therapy (eight weeks, chemical form not identified) was effective in improving brachial artery reactivity.11
Brachial artery reactivity measures the change in brachial artery diameter after release of an occluding cuff and is a measure of endothelial function. It is thought to be a useful marker for atherosclerosis and coronary artery disease.
Vitamin D: In addition to playing a potential role in atherosclerosis, vitamin D nutriture may also be an important factor in the pathogenesis of congestive heart failure.12,13 Congestive heart failure (CHF) can have multiple aetiologies but is characterised by a reduced amount of blood being pumped from the left ventricle of the heart and, therefore, a reduced amount of blood reaching other organ systems.
This disease is often the end stage of cardiac disease and, as more cardiac patients survive their initial problems, the opportunity for developing CHF increases. Observational studies have demonstrated an association of vitamin D deficiency in patients with severe CHF.14 These authors speculate that low circulating levels of vitamin D metabolites could contribute to the aetiology of CHF.
Co-Q10: Compared with vitamin E, there has been only very limited research on the potential cardiovascular benefits of co-Q10. Co-Q10 deficiency has been observed in a wide variety of cardiovascular disorders — congestive heart failure, angina pectoris, coronary artery disease, cardiomyopathy, hypertension, mitral value prolapse.15
In the apoE gene knockout mice (an excellent model of human atherosclerosis) supplementation with both vitamin E and co-Q10 was found to inhibit atherosclerosis better than with vitamin E or co-Q10 alone.16 It is not known, however, if co-Q10 supplementation in humans can decrease atherosclerosis.
Although co-Q10 may inhibit the formation of oxidised and atherogenic forms of LDL, it is likely that the primary mechanism whereby co-Q10 could prevent heart disease is through its ability to improve ATP synthesis in cells with a high ATP demand such as cardiac myocytes. As an antioxidant, it could also inhibit the free radical damage to the myocardium that arises during ischemia-reperfusion injury. It is logical to suggest that dietary co-Q10 supplementation could increase ATP production and thereby improve myocardial contractility.
A meta-analysis of eight randomised controlled studies looking at the effect of dietary co-Q10 supplementation on congestive heart failure indicates an improvement in stoke volume, ejection fraction, cardiac output, cardiac index, and end diastolic volume index.17 These results certainly support a role for dietary co-Q10 supplementation as an adjunctive treatment for congestive heart failure.
The three lipid-soluble nutrients reviewed above all have antioxidant properties and antioxidants are, in general, anti-inflammatory. Dietary supplementation with vitamin E or vitamin D is associated with decreased levels of CRP, which is a marker for inflammation and increased risk of cardiovascular disease as well as in type 2 diabetes.18,19
Surprisingly, there are no published studies on the potential role of co-Q10 in reducing plasma CRP levels. In the case of vitamin E, there should be increased consideration for the non-alpha-tocopherol forms, particularly the potential anti-inflammatory properties of gamma-tocopherol.
For co-Q10, the available data strongly supports a role for supplementation (along with conventional therapy) for the treatment of congestive heart failure. Vitamin D is remarkably under-researched considering its very promising role as an anti-atherogenic factor. Lifestyle modifications, ie, reasonable exposure to sunlight, may be more important than nutritional considerations in the case of vitamin D.
Moreover, as Steinberg and Witzum suggested,20 the antioxidants might be effective in inhibiting the initial stages of human atherosclerosis and yet ineffective or much less effective in reducing plaque instability and rupture.
If this were the case, it might be necessary to find some way to assess early stages of lesion development (eg, high-resolution ultrasound or magnetic resonance imaging) rather than relying on the usual late clinical endpoints. Of course, if the development of early lesions were successfully inhibited, there should eventually be a decrease in the frequency of clinical events, but in that case, the trials might need to extend beyond the conventional five years.
FLAVONOIDS AND CARDIO HEALTH
Clinical observations, basic science and several epidemiological studies have contributed to an emerging body of evidence for a potential role of flavonoids in the prevention of cardiovascular disease (CVD).21 Flavonoids have been shown to inhibit the oxidation of plasma LDL, decrease platelet function and modulate cytokines and eicosanoids involved in inflammatory responses.22,23 Several epidemiological studies suggest a protection of a high flavonoid intake on the mortality of CHD.24,25,26,27
Some prospective studies on major flavonoid sources, such as tea, have, however, shown large discrepancies in the relative risk of death from CHD with relative risks ranging from 0.42,28 0.62,27 1.0825 to 1.6.29
Also, a recent study on the risk of CVD in women failed to show a protective effect of flavonoid intake on the risk of CVD.30
Although the picture from epidemiological studies on the relationship between risk of CVD and intake of flavonoids is inconsistent, the majority of the studies suggest an inverse association between intake of flavonoids and the risk of CVD, which is supported by basic and clinical studies on flavonoids. These indicate that flavonoids may have a protective action that deserves further investigation before final conclusions can be drawn.
The flavonoids constitute a large class of polyphenols that are found ubiquitously in the plant kingdom and are thus present in fruits and vegetables regularly consumed by humans. They account for a variety of colours in flowers, berries and fruits, from yellow to red and dark purple.
Several studies have investigated the effect of flavonoids on platelet activation and aggregation.31,32 Recent studies on the flavonoids in cocoa have shown that epicatechin and its related oligomers, the procyanidins, also have potent anti-inflammatory properties.33
The low-molecular-weight procyanidins and epicatechin itself were shown to be a potent inhibitor of human 5-lipoxygenase,34 and procyanidins from cocoa were demonstrated to decrease platelet function significantly in vivo in humans.23
Furthermore, another study showed that the combination of quercetin and catechin synergistically inhibited platelet function in collagen-induced platelet aggregation by antagonising the intracellular production of hydrogen peroxide.35
A recent study on flavonoids and the platelet-activating factor and related phospholipids in endothelial cells during oxidative stress showed that the flavonoids hesperedin, naringenin and quercetin were able to mediate these enzy-mes, and thereby limit the inflammatory response.36
Studies on anthocyanins have also demonstrated that they are able to inhibit platelet aggregation. Treatment of humans with blueberry anthocyanins for 60 days was found to reduce the ex vivo platelet aggregation.37
This observation was supported in a study finding after one week of treatment a reduced platelet aggregation by red grape juice, but not by orange or grapefruit juice.38 Further indications of a beneficial effect were observed by researchers who found inhibitory effects on platelet aggregation in dogs and humans by red wine and red grape juice, but not by white wine, which could point to an anti-atherosclerotic effect of the anthocyanins.39,40
The flavonoids may furthermore mediate other anti-inflammatory mechanisms involved in the development of cardiovascular disease. Studies indicate that they are implicated in the modulation of the monocyte adhesion in the inflammatory process of atherosclerosis.
The expression of intercellular adhesion molecule-1, playing a pivotal role in the inflammatory response, was, for example, shown to be mediated by quercetin in human endothelial cells.41
Plasma metabolites of (+)-catechin and quercetin modulated monocyte adhesion to human aortic endothelial cells; these researchers also found that the plasma metabolites of catechin, but not of quercetin, were potent inhibitors.42
This underlines the importance of investigating the biological effects of the metabolites present in vivo, eg the flavonoid glucuronic and sulphate conjugates instead of the parent compounds.
The endothelial function plays an important role in regulating the vascular function, and endothelial dysfunction is associated with increased CVD risk. Several animal and human studies have shown that flavonoids also may have favourable effects on the vascular endothelial function.43
Since the Zutphen Study in 1993,28 a number of epidemiological studies have been undertaken on the association between dietary flavonoid intake and the risk of CVD. The majority of studies revealed an inverse association with the risk of CVD, although the outcomes of some of the studies are conflicting.
Overall, the protective effect of flavonoids was strongest against the mortality of CHD, whereas the effect on risk of nonfatal incidences of CVD was weaker or nonexisting.
The average daily flavonoid intake in studies ranges from 2.6mg/day to 28.6mg/day, with quercetin as the dominating flavonoid in most of the studies. However, the flavonoid intake in these epidemiological studies was based mainly on the food composition tables generated by Hertog et al, covering only the content of selected flavonols and flavones in the food.44,45
TEA AND WINE TIME
If intake data on additional flavonoids had been included in these studies (eg the citrus flavonoids, the catechins, the anthocyanins and the isoflavonoids), the flavonol quercetin would probably not have been the major dietary flavonoid in the cohorts. Further, tea would perhaps be a less important flavonoid source, and the outcome of studies would then possibly have been different. The quercetin intake originated mainly from tea intake, but apples and onions were also important sources of quercetin in some studies25,28
Early studies showed a highly protective effect of both quercetin and tea against CVD.28,46 However, some of the later and larger cohort studies, trying to confirm these early studies, found no association or even aggravating effects of flavonoids and especially of tea consumption.25,29,30,47
The association of tea and incidences of CVD were later further investigated in several cohort studies. These studies have all been reviewed in a recent meta-analysis on the relationship between tea consumption and stroke, myocardial infarction and all CHD in 10 cohort studies and seven case-control studies.48
The incidence rate of myocardial infarction was concluded to be weakly inversely associated (11 per cent) with an increase in tea consumption of three cups per day. However, the authors, stressing that the heterogeneity of the studies and the risk of bias due to the larger number of smaller studies show a protective effect, urge caution in interpreting this result.
The mechanism of the protective effect of tea has recently been investigated and does, however, support a beneficial effect of tea intake. For example, consumption of 900 ml black tea for four weeks reversed the endothelial vasomotor dysfunction in patients with proven coronary artery disease.49
It has been suggested that the catechin content in tea could be the protective factor, and researchers in 2001 thus estimated the catechin intake to 72 +/-47.8mg/day in the Zutphen Elderly Study and found a significant negative association between ischemic heart disease and intake of tea catechins.50
However, in another study on catechin intake by the same authors, in post-menopausal women from Iowa, a protective effect of catechins was seen from only dietary sources other than tea.51
The intake of red wine has been postulated to explain the French paradox — the low incidence of CHD in France despite the main risk factors for this disease being similar to those in northern European countries.52
Other cohort studies have, however, found equally beneficial effects of all alcoholic beverages, and there is no general agreement on this matter.56
It has been proposed that the possible lower mortality by CVD in wine drinkers could be due in part to differences in lifestyle ? that is, in dietary habits and exercise, since factors such as dietary fat composition, little exercise and hypertension are major risk factors on the development of atherosclerosis.57
The overall picture of the flavonoids as a protective agent against cardiovascular disease has been consolidated during the past decade. The mechanism of action of the flavonoids is, however, still unknown, but recent studies have moved the focus away from the antioxidant properties of the compounds toward a broader view on the potential mechanisms of action including especially the anti-inflammatory effects of flavonoids.
The early research on the dietary protective action of flavonoids has mainly focused on the flavonols, especially on quercetin, in part because of limitations in the available analytical methods at that time, which merely restricted the investigations to this class of compounds.
However, within the past few years, flavonoid research has produced evidence for the importance of other dietary flavonoid classes and subgroups with potential health protective properties and with a similar or even greater impact on our total daily flavonoid intake. Examples are the citrus flavonoids, the red-coloured anthocyanins, the tea catechins, and the procyanidins present in cocoa and wine.
Furthermore, there are indications of the importance of a diet rich in a range of different flavonoids, rather than containing a high concentration of an individual compound, since some studies have shown additive or even synergistically effects of flavonoids.58
Authors: N-3 fatty acids: M de Lorgeril and P Salen, Universite Joseph Fourier de Grenoble, France. Fat-soluble antioxidants: W L Stone and G Krishnaswamy, East Tennessee State University, US, and H Yang, Yunnan College of Traditional Chinese Medicine, China. Flavonoids: S E Rasmussen, Danish Institute for Food and Veterinary Research, Denmark.
Excerpted from Functional Foods, Cardiovascular Disease and Diabetes, A Arnoldi, editor. ISBN 1 85573 735 3. Published by Woodhead Publishing Ltd, England. www.woodheadpublishing.com Respond: editor[email protected]
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