Topic of the Month

Antioxidants in the Prevention of Cardiovascular Disease – Part 1: Epidemiological Studies

May 1, 2011

High concentrations of oxygen radicals in the body (oxidative stress) have been linked to the exacerbation of atherosclerosis and hence the onset of cardiovascular disease. At the same time, observation studies have consistently indicated that antioxidant micronutrients in the diet could have a protective effect in the context of cardiovascular disease.   

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It is evident that in the longer term the antioxidant enzymes synthesized by the body itself are not sufficient on their own to provide protection against the harmful effects of free radicals. Therefore antioxidants in the diet, especially vitamins C and E and beta-carotene, play an important role in prevention. In ideal circumstances the unavoidable occurrence of free radicals and the protective effect of antioxidants synthesized by the body and ingested in the diet are in balance.    

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The effects of free radicals

Without oxygen important metabolic processes for the generation of energy cannot take place. These complex reactions lead unavoidably to the occurrence of intermediate products of oxygen that are highly unstable and aggressive – the so-called “free radicals,” also known as reactive oxygen species or ROS. Some situations such as stress or extreme physical exertion (e.g., in professional sport) may result in increased production of these reactive molecules. In addition to the radicals generated within the human organism, there are others that enter the body from external sources. These sources of radicals include smoking, excessive alcohol consumption and medications (e.g., chemotherapy), as well as air pollution and UV radiation.

The effects of free radicals in an organism can be beneficial as well as adverse. Specialized cells such as macrophages utilize oxygen radicals for the immune system (i.e., as a defense reaction to pathogenic microorganisms). This is essential to life and health. The activities of external free radicals can also be useful: under the influence of UV-radiation, the hydroxyl radical formed from ozone and water in the atmosphere plays an important role in combating air pollution, for instance. But free radicals can also damage the body. When present in high concentrations (oxidative stress) they attack important metabolic proteins, cell membranes and even DNA and change their characteristics, which can lead to damage among various types cells of the body. Hence, oxidative stress facilitates the incidence and progression of atherosclerosis. Consequently vascular diseases like heart attack and stroke through the increased oxidation of lipids and damage to the internal cell lining of blood vessels (the endothelium) (1). In addition to numerous chronic diseases, normal signs of aging have been linked to progressive oxidative processes and the gene mutations they trigger – in particular in mitochondrial DNA. In the worst case scenario the result is uncontrolled cell proliferation (cancer).

To protect itself against cell damage due to free oxygen radicals, the body possesses an arsenal of highly potent enzymes (e.g., superoxide dismutase) that capture the aggressive molecules and neutralize them (i.e., they exhibit “ antioxidant ” activity). The functionality of these proteins depends on several essential trace elements (e.g., zinc). Apart from these enzymes the organism has at its disposal for defense fat-soluble coenzyme Q10, for instance, the production of which diminishes with increasing age, as well as other proteins and alpha-lipoic acid. In addition to these physiological systems, the network of antioxidants includes various substances that can be supplied to the organism: the essential vitamins C and E, requirements of which are well documented; polyphenols (e.g., flavonoids), requirements of which are comparatively poorly documented, since there are no known deficiency diseases; and carotenoids (e.g., beta-carotene), which are not true antioxidants but can absorb the energy of free radicals. Thanks to their structure these molecules exhibit various solvent properties and are therefore able to neutralize radicals, functioning as a network in all compartments of the cell – in both aqueous and lipid milieus. Ideally the unavoidable occurrence of free radicals is a balanced by the protective effect of antioxidants synthesized by the body and ingested in the diet (oxidative balance).    

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Testing the preventive effects of antioxidants in studies

Studies with experimental animals have shown that chronic diseases such as atherosclerosis and hypertension, as well as cancer and diabetes, can be brought on by oxidative stress. Based on these results a hypothesis was formulated that antioxidants could play a part in the prevention of chronic diseases. This hypothesis has been tested in epidemiological studies (case-control and cohort studies) and intervention studies (e.g., randomized controlled studies) with human subjects. In some instances case-control studiescompared patients and healthy subjects retrospectively, which can distort the results and lead to bias of selection and information. Due to the fact that relevant information is usually collected before the onset of the disease (prospectively) in cohort studies, they are less prone to this kind of distortion. However, confounding factors cannot be entirely excluded with either type of study when interpreting the results. In contrast, this can be achieved in intervention studies because in this case subjects are allocated to therapeutic or control groups randomly.

Whereas case-control and cohort studies that repeatedly show the same results do not provide proof of a link between cause (e.g., antioxidant intake) and effect (e.g., prevention of diseases), they can strengthen the evidence for a causal connection (causality). Intervention studies provide the best evidence of causality; however, their results can often only be generalized to a limited extent. Conclusions as to the causality of a link are drawn from the sum of all studies. This provides a more or less probable overall body of evidence. Diet-related effects may, however, be an indicator of another underlying process or influencing factor without being directly involved in the occurrence of chronic diseases. Finally, conclusions are also influenced by results from animal experiments and studies on cell cultures into possible mechanisms. 

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Results from epidemiological studies

Results from case-control and cohort studies indicate that the antioxidant vitamins C and E and also beta-carotene could have an important role to play in the primary prevention of cardiovascular disease. Antioxidants in the studies were found to be most effective in the early stages of atherosclerosis – the cause of heart attacks, stroke and peripheral vascular disease. Those with low levels of vitamins C and E and beta-carotene will benefit especially from a higher intake of these micronutrients. Low levels can be caused by low consumption and/or higher requirements (e.g., in smokers and any one consuming a lot of alcohol or certain medications, and/or people with genetic variations (polymorphisms) that impair the activity of enzymes of the micronutrient metabolism). If intake of antioxidants or blood levels in a whole study population were in the optimal range or higher, there was usually no discernable additional risk reduction.

Today it is thought that a reduction in the risk of developing such complex chronic diseases is achieved through the interaction of a number of different factors across the lifestyle spectrum (circumstances and habits). As one of these factors, antioxidants can act directly and/or via other mechanisms to prevent the occurrence of cardiovascular diseases. A prerequisite for this appears to be optimal intake together with correspondingly high plasma levels. The antioxidants act in combination, and are interchangeable to only a limited degree.

Influence of antioxidant supplementation and blood concentrations on cardiovascular disease:

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Vitamin C

In numerous cohort studies an estimated daily intake of vitamin C between 45 and 113 mg/day was linked to a reduced risk of cardiovascular disease. Consumption of more than 45 mg/day vitamin C – compared to less than 28 mg/day – was associated with a 60 percent lower risk of stroke (1). The risk for coronary heart disease was reduced by around 20 percent. The First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study with a cohort of more than 11,000 adults showed a reduction in cardiovascular mortality of 42 percent for men and 25 percent for women who consumed at least 50 mg vitamin C daily in the diet and also regularly took supplements containing vitamin C (2).

Numerous epidemiological studies revealed that vitamin C plasma levels below 41 micromol/liter (μmol/L) were associated with an increased risk of developing cardiovascular disease. In the EPIC Norfolk Study of over 20,000 men and women, subjects with baseline vitamin C levels over 66 μmol/L had an around 42 percent lower risk of suffering a stroke compared to those with levels below 41 μmol/L, after adjusting for biological and social risk and lifestyle factors that have a proven association with strokes (3). In the Second National Health and Nutrition Examination Survey, a representative study of 6,624 men and women, the relative risk for coronary heart disease and strokes was reduced by around 27 percent and 26 percent respectively with serum vitamin C levels of 63 to 153 μmol/L as compared with levels between 6 and 23 μmol/L (4). In contrast, in the US Health Professionals’ Follow-up Study of almost 40,000 men employed in the health sector, daily vitamin C consumption in the range of 149 to 1,162 mg/day compared to 92 mg was not associated with a reduced risk of coronary heart disease (5).

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Vitamin E

In three large-scale prospective cohort studies on men and women an association was observed between increased intake of vitamin E and a reduced risk of coronary heart disease. A study involving 87,245 nurses revealed a risk reduction for coronary heart disease with daily consumption of food supplements containing vitamin E at a dose of more than 100 IU for at least two years (6). In contrast, the Iowa Women’s Health Study found a reduction in risk only with dietary vitamin E, not with food supplements (7). However, in this study only a few women consumed large doses of vitamin E. A further study found a non-significant reduction in coronary heart disease risk both with total vitamin E intake and with supplement consumption (5).

A study with data from 16 European countries showed that low vitamin E blood levels are linked to an increased risk of dying of cardiovascular diseases (8). In the MONICA Augsburg Study (9) cohort study, no evidence was found of a significant association between vitamin E blood levels and myocardial infarction. However, in similar trials the mean plasma vitamin E concentration of subjects was relatively high and was over the probably “protective” concentration of around 27 to 28 micromol/liter (μmol/L) of vitamin E (10).

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Beta-carotene

In the US Health Professionals’ Follow-up Study the relative risk for cardiovascular diseases was 29 percent lower for those with the highest beta-carotene consumption than it was for those with the lowest consumption (5). The preventive effect also depended on smoking status: it was observed only for current or former smokers, not for people who have never smoked. In a cohort study of postmenopausal women no reduction in cardiovascular disease risk was found (7).

Regarding blood levels of beta-carotene, after exclusion of 3 study locations with anomalous values (all Finnish locations) a study of healthy men from 16 study locations in Europe showed a clear association between low plasma concentrations of beta-carotene and a higher rate of mortality from ischemic heart disease (8). Men in the Basel Prospective Study cohort who had had low baseline beta-carotene blood concentrations were at increased risk of mortality from stroke over the 12-year study period (11, 12). In the Physicians’ Health Study higher baseline plasma beta-carotene levels tended to be associated with lower risk of myocardial infarction among current and former smokers, but not among livelong non-smokers (13).

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Meta-analyses

Results from meta-analyses of epidemiological studies into the reduction of risk of cardiovascular disease through increased intake of antioxidant micronutrients in the diet or as food supplements diverge in some cases – as do those from the studies they examine. Protective effects of varying degrees were established for individual antioxidants. This is not surprising, since the observations were made in different study populations who had consumed varying amounts and doses of micronutrients, singly or in combination. Critical review of these studies – alone or in the context of a meta-analysis – shows that many study participants were already well supplied with antioxidant micronutrients in their diet. Thus no further risk reduction was to be expected from the consumption of food supplements. Moreover, many study participants already had a health problem, meaning there was no longer an option for primary prevention through antioxidants.

Meta-analysis of 15 cohort studies on the consumption of vitamins C and E and beta-carotene revealed a significantly reduced risk for coronary heart disease with a high intake of vitamins C and E in the diet (14). Consumption of food supplements was associated with a risk reduction only for vitamin E. An analysis of 9 cohort studies revealed a significant reduction in the risk of coronary heart disease through supplementation with vitamin C (15). Risk reductions through increased beta-carotene and vitamin E intake were comparatively modest. In a further meta-analysis, increased intake from fruit and vegetables resulted in a reduced risk of coronary heart disease in smokers (16). Analysis of the results from two large cohort studies showed that increased consumption of fruit and vegetables tended to be associated with a reduced risk of death from cardiovascular disease (17).  

References

  1. Gale C. R. et al. Vitamin C and risk of death from stroke and coronary heart disease in cohort of elderly people. Br Med J. 1995; 310:1563–1566.
  2. Enstrom J. E. et al. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992; 3:194–202.
  3. Myint P. K. et al. Plasma vitamin C concentrations predict risk of incident stroke over 10 y in 20 649 participants of the European Prospective Investigation into Cancer Norfolk prospective population study. Am J Clin Nutr. 2008; 87:64–69.
  4. Simon J. A. et al. Serum ascorbic acid and cardiovascular disease prevalence in US adults. Epidemiology. 1998; 9:316–321.
  5. Rimm E. B. et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993; 328:1450–1456.
  6. Stampfer M. J. et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993; 328:1444–1449.
  7. Kushi L. H. et al. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996; 334:1156–1162.
  8. Gey K. F. et al. Increased risk of cardiovascular disease at suboptimal plasma concentrations of essential antioxidants: An epidemiological update with special attention to carotene and vitamin C. Am J Clin Nutr. 1993; 57:787–797.
  9. Hense H. W. et al. Lack of an association between serum vitamin E and myocardial infarction in a population with high vitamin E levels. Atherosclerosis. 1993; 103:21–28.
  10. Gey K. F. Vitamin E and other essential antioxidants regarding coronary heart disease: risk assessment studies. Epidemiological basis of the antioxidant hypothesis of cardiovascular disease. In: Packer, L.; Fuchs, J., eds. Vitamin E in health and disease. NewYork, NY:Marcel Dekker, Inc.; 1993:589–633.
  11. Eichholzer M. et al. Inverse correlation between essential antioxidants in plasma and subsequent risk to develop cancer, ischemic heart disease and stroke respectively: 12-year follow-up of the Prospective Basel Study. Exp Suppl. 1992; 62:398–410.
  12. Gey K. F. et al. Poor plasma status of carotene and vitamin C is associated with higher mortality from ischemic heart disease and stroke: Basel Prospective Study. Clin Invest. 1993; 71:3–6.
  13. Hak A. E. et al. Plasma carotenoids and tocopherols and risk of myocardial infarction in a low-risk population of US male physicians. Circulation. 2003; 108:802–807.
  14. Ye Z. and Song H. Antioxidant vitamins intake and the risk of coronary heart disease: meta-analysis of cohort studies. Eur J Cardiovasc Prev Rehabil. 2008; 15:26–34.
  15. Knekt P. et al. Antioxidant vitamins and coronary heart disease risk: a pooled analysis of 9 cohorts. Am J Clin Nutr. 2004; 80(6):1508–1520.
  16. Dauchet L. et al. Fruit and vegetable consumption and risk of coronary heart disease: a meta-analysis of cohort studies. J Nutr. 2006; 136:2588–2593.
  17. Hung H. C. et al. Fruit and vegetable intake and risk of major chronic disease. J Natl Cancer Inst. 2004; 96(21):1577–1584.