Nutrients and Functional Foods in Cardiovascular Disease - Heart Disease
Antioxidants (Vitamins E and C, Carotenoids, and Flavonoids)
Evidence linking antioxidation to a reduced risk of cardiovascular disease is convincing; evidence in support of specific nutrients is generally not better than suggestive. This may be because antioxidants are most effective in as-yet-unidentified combinations or because other nutrient-mediated reactions are equally important. The principal mechanism by which antioxidants confer cardiovascular benefit is thought to be inhibition of LDL oxidation, although protection of nitric oxide is of nearly comparable interest. A diet rich in fruits and vegetables typically provides abundant antioxidants, including carotenoids, tocopherols, flavonoids, and ascorbate, and has been decisively linked to reduced cardiac risk.
A variety of antioxidants have been studied for cardioprotective effects. The overall weight of evidence does not support a protective role for β-carotene, although observational studies suggest that foods rich in β-carotene are almost certainly protective. The literature to date is supportive of protective effects of bioflavonoids, found particularly in dark chocolate/cocoa, tea, red wine, and grape juice, as well as the skins of many fruits and vegetables. There currently is no convincing evidence of a cardioprotective effect of vitamin C, although diets naturally high in ascorbate appear to be protective. One potential explanation for the inability to elucidate an independent benefit of vitamin C is that its mechanism of action may require interaction with fat-soluble antioxidants. Timimi et al. reported a beneficial effect of acute vitamin C infusion on endothelial function in diabetic subjects. Plotnick et al.reported prevention of dietary fat–induced endothelial dysfunction with concomitant vitamin C and E supplementation in healthy subjects. Such findings tend to perpetuate interest in the potential cardioprotective role of vitamin C despite the paucity of clear evidence to date.
Data from the Cambridge Heart Antioxidant Study suggested a benefit of supplemental vitamin E in the prevention of second MI, although evidence of a mortality benefit was not found . Beneficial effects of acute vitamin E supplementation on endothelial function have been reported. However, in the GISSI–Prevenzione Trial, patients with recent MI (n = 11,324) randomly assigned to vitamin E supplementation (300 mg) did no better than those assigned to placebo with regard to MI or death . Similarly, the HOPE trial demonstrated a significant benefit of angiotensin-converting enzyme inhibition with regard to both MI and death in high-risk coronary patients, whereas vitamin E (400 IU) failed to reveal such benefit . Thus, the most definitive trials to date fail to support a cardioprotective role of supplemental vitamin E, at least as an isolated intervention. The HOPE and GISSI trials further suggest that excessive intake of vitamin E may confer net harm. Vitamin E actually constitutes a family of compounds, encompassing tocopherals and tocotrienols, but studies have generally used alpha-tocopherol exclusively. Whether lack of benefit is a reliable finding or the result of using the wrong formulation and/or wrong dose of vitamin E is as yet unknown. A recent meta-analysis of antioxidant supplements reached the same conclusion. Isolated antioxidant supplementation cannot be recommended as a cardioprotective strategy at present; consumption of a diet naturally rich in antioxidants certainly can be.
B Vitamins
Accumulating evidence has pointed to the importance of elevations of serum homocysteine in up to one-third of all patients with coronary artery disease. Hyperhomocysteinemia is particularly likely to be seen in patients with coronary disease and normal serum lipids. Vitamins B6 and B12 and folate participate in the metabolism of methionine. Specific metabolic steps beyond the production of homocysteine are dependent on several B-complex vitamins. Folate levels are apparently most likely to contribute to elevated homocysteine. There is some evidence that intake of B vitamins above levels currently recommended may offer protection against cardiovascular disease. However, despite clear evidence that B vitamin supplementation can lower homocysteine levels, cardiac benefits are uncertain . Because B complex supplementation at or near RDA levels may be beneficial and is very unlikely to be harmful, recommendations for multivitamin supplementation to all patients attempting to reduce their risk of heart disease are reasonable but as yet not strongly supported by scientific evidence. Reliance on specific B vitamins for cardioprotective effects is unsubstantiated at present.Coenzyme Q10
Coenzyme Q10 is a benzoquinone, also known as ubiquinone because of its remarkably widespread distribution in nature. Minute quantities are found in virtually all plant-based foods. Coenzyme Q10 functions within the mitochondrion, where it facilitates electron transport and oxidative phosphorylation. Given the fundamental role of this coenzyme in energy metabolism, it is perhaps not surprising that its putative health effects are protean. An overview of the role of coenzyme Q10 is provided in Section VIE.With regard to cardiovascular disease, evidence is strongest for a beneficial role of coenzyme Q10 in heart failure and cardiomyopathy, where supplementation has been associated with improvement in left ventricular function, quality of life, and functional status. There is evidence of reduced complications post-MI , improved hemodynamics post-bypass grafting, and improved functional status and symptom relief in patients with angina . Coenzyme Q10 has been shown to have antihypertensive effects as well . Antioxidant effects of coenzyme Q10 apparently preserve levels of both ascorbate and α-tocopherol, enhancing both extracellular and intracellular antioxidant function. Finally, supplementation with coenzyme Q10 appears to reduce levels of lipoprotein (a) and preserve serum levels depleted by statin therapy. There are negative clinical trials in each of these areas as well, although beta error is possible due to generally small sample sizes.
In the aggregate, the evidence supporting a role for coenzyme Q10 in the amelioration of cardiovascular disease and the modification of risk factors is preliminary but suggestive. Large-scale trials are absent from the literature, but this may be due to the nonproprietary nature of the compound and the inability of an industry sponsor of such trials to generate correspondingly large profits as a result.
More widespread use of coenzyme Q10 in cardiology and primary care practice appears to warrant serious consideration. The usual doses in trials range from 100 to 300 mg per day, dosed b.i.d. Such doses appear to be safe, with virtually no reports of significant toxicity.
Alcohol
Epidemiologic evidence, both among and within populations, links moderate alcohol consumption to a reduced risk of cardiovascular disease. Observational data in the United States suggest a reduction in relative risk for angina or MI of as much as 30% in those consuming one drink per day compared to those who abstain. Results of an observational cohort study in France (1999) suggest that moderate alcohol consumption reduces all-cause mortality; evidence of benefit was stronger and more consistent for wine than beer. Although there is general consensus that ethanol is partly responsible for the cardioprotective effects of alcoholic beverages, red wine may confer additional benefit due to the polyphenolic compounds in the skin of the grape, with resveratrol receiving particular attention of late. A small study in 2000 demonstrated enhanced endothelial function following consumption of dealcoholized red wine, with no improvement following consumption of an equivalent amount of red wine with alcohol, but most studies suggest beneficial effects of ethanol in moderate doses. Mechanisms by which alcohol may attenuate cardiovascular risk include elevation of HDL, elevation of tissue plasminogen activator, and inhibition of platelet aggregation. At doses above 30 to 45 g per day, alcohol raises blood pressure and is associated with increased cardiac risk, as well as increased risk of other morbidity and mortality. Consumption of one to at most two drinks per day, preferably red wine, is reasonable with regard to cardiovascular risk reduction. Whether or not the practice should be advocated to a particular patient is dependent on other considerations. Despite the generally consistent evidence of cardiovascular benefit with moderate alcohol consumption, concern regarding the adverse effects of heavier drinking generally mitigates enthusiasm for recommending alcohol consumption for health promotion. Nonetheless, a dose of up to roughly one drink per day for women (15 g of ethanol) and two drinks per day for men (30 g of ethanol) is convincingly linked to reduced cardiac risk in men and women with and without overt cardiac risk factors and may be advised for that effect. Red wine features on a short list of foods in the so-called polymeal combination of foods designed, at least hypothetically, to confer maximal cardiac benefit.Iron
Iron may act as a pro-oxidant, generating speculation that it might contribute to the risk of cardiac disease in men and that its depletion in menstruating women might contribute to risk reduction. Epidemiologic evidence supports a potential role for high iron levels in cardiovascular disease risk, but the evidence to date is inconclusive. A potential role for iron in cardiovascular disease received a surge of attention when trials such as HERS and the WHI refuted a cardioprotective effect of hormone-replacement therapy (HRT) at menopause, hinting that something other than hormones might protect premenopausal women from heart disease. There is some concern that our measures of body iron stores are inadequate to gauge the potential pro-oxidant effects of iron. A potential association between iron and heart disease risk remains speculative and somewhat controversial; current knowledge would suggest that supplements be avoided barring a clear indication for their use. The American Heart Association formally offered guidance for dietary iron intake, but no longer does, perhaps indicative of the topical state of flux.Magnesium
Serum magnesium concentrations have been found to be inversely associated with cardiovascular disease risk. However, serum levels may merely be a measure of overall dietary pattern, including intake of fruits and vegetables. Magnesium is known to have antiarrhythmic properties and has corresponding, potential therapeutic applications in acute cardiac care beyond the scope of this discussion. Clinical trial data on the role of supplemental magnesium in cardiac risk reduction are by and large equivocal, although evidence of a hypotensive effect is conclusive. Any beneficial effects of magnesium on cardiovascular disease risk may be mediated in particular by its association with reduced blood pressure. Magnesium is discussed further in Section VIE. For most patients, a generous intake of magnesium from dietary sources is to be encouraged, whereas supplementation as a matter of routine, other than at doses incorporated into multivitamin/mineral preparations, need not be.Calcium and Potassium
Cardiovascular benefit of calcium and potassium is associated with blood pressure–lowering effects in particular.Cocoa/Dark Chocolate
The cardiovascular effects of dark chocolate consumption are convincingly favorable across a wide array of measures.Plant Stanols/Sterols
The hypolipidemic effects of plant stanols and sterols are well established. These naturally occurring compounds are found in small quantities in a large range of plant foods. Stanols and sterols interfere with cholesterol absorption in the gut, both from food and from enterohepatic circulation. A dose of roughly 2 g per day has been shown to induce meaningful reductions in LDL. The inclusion of higher doses of plant stanols as part of a dietary portfolio designed for optimal lipid lowering resulted in effects rivaling those of statins (250). Benecol is a commercial spread alternative to margarines or butter that contains stanol esters and is designed to provide a lipid-lowering effect.Garlic
There has long been interest in potential lipid-lowering and blood pressure–lowering effects of garlic and the putative active ingredient. A recent clinical trial refutes a lipid-lowering effect, and the blood pressure–lowering effect is uncertain. While the inclusion of garlic in the diet is healthful, its use to achieve targeted cardiovascular benefit cannot be recommended on the basis of available evidence.Walnuts, Almonds, and Other Nuts
Nut intake is convincingly and consistently associated with beneficial effects on cardiac risk factors in intervention studies and with reduced event rates in observational studies. Despite their energy density, nuts are not clearly associated with risk of weight gain. There is, however, some risk of weight gain if nuts are added to the diet to reduce cardiac risk; longitudinal studies demonstrating that cardiac benefit but not weight gain results from the addition of nuts to the diet are needed. Overall, the evidence of benefit is greatest for walnuts, which offer a particularly favorable fatty acid profile. Almonds are also consistently associated with cardiac benefit and have been included in the polymeal designed to bundle cardioprotective foods, if only in theory.Interesterified Fats
Interesterified oils are unsaturated oils modified in labs in a process that links them to saturated oils, to give them longer shelf life and more heat tolerance. Like trans fat, interesterifed fats are the product on an industrial process, and these two categories of fat may share adverse health effects as well. Interesterified fats are not yet in wide use, and in light of their unfavorable health effects, they should probably never be.
