Topic of the Month

Antioxidants in the Prevention of Cardiovascular Disease – Part 3: Individual Requirements and Conclusions

July 1, 2011

Many observational studies have shown that a lack of antioxidants represents an additional risk for cardiovascular disease (see Part 1). However, the following intervention studies, which were intended to provide evidence of the effectiveness of antioxidant micronutrients in the prevention of cardiovascular diseases, were designed as though the antioxidants could produce an additional health benefit irrespective of the supply status of the individual (see Part 2).


Numerous unsuccessful studies highlighted the fact that the preventive effect, as a rule, was only measurable among study participants who had a deficiency prior to the study. The occasionally observed positive result would seem to be due to the unplanned inclusion of study participants with an antioxidant deficiency or a higher requirement. However, when, as in recent studies, subjects with insufficient antioxidant micronutrients to maintain health were targeted for inclusion, they experienced health benefits from a supplemental intake of vitamin C, vitamin E and/or beta-carotene in the long term.  


Indicators for individual antioxidant requirements

There is no doubt that antioxidant micronutrient consumption is necessary for effective protection against oxidative damage. However, the question remains as to how much an individual needs and how adequate intake can be assured. The amounts needed differ from one individual to another and are dependent on age, sex, health status, genetic disposition and lifestyle, among other things. This means that, for various reasons, some segments of the population are exposed to greater oxidative stress than others. This may be true for example of older people with weakened immune function, diabetics, who experience a massive accumulation of free radicals after meals, allergy sufferers, professional athletes and people with certain genetic variations. These and other groups have a higher antioxidant requirement and may therefore benefit from increased consumption.

Recommendations for micronutrient intakes are based on the assumption that there are daily amounts that meet the average needs of almost all healthy populations of the same age and sex living under similar circumstances. The example of vitamin C, however, has shown that these estimates are not universally valid. The outcomes of several studies which recorded varying intakes and plasma concentrations of vitamin C were pooled in a meta-analysis (1). Based on the data the average intakes and the range (deviations) needed to achieve an estimated optimal vitamin C concentration of 50 μmol/L (2) was calculated. On average, the calculated intake for adults was 100 mg per day, which corresponds approximately to the recommendations of most European nutrition organizations (e.g., 3) and the US Food and Nutrition Board (4). The variation did not follow a normal distribution curve, but showed a bias toward higher intakes, which indicates that there are segments of the population who need to consume larger amounts of vitamin C to reach the recommended plasma concentration of 50 μmol/L. This concurs with studies which suggested a recommended intake of up to 150 mg per day for healthy adults (2).

Moreover, there are increasing indications that certain population groups have genetic variations (polymorphisms) that influence their micronutrient status and, hence, their intake requirements. Recent research with female volunteers showed that almost 50 percent of the population has a genetic variation that reduces their ability to produce sufficient amounts of vitamin A from beta-carotene. Studies have shown that younger women who carry this genetic variation are especially at risk: they have a tendency to consume too little vitamin A rich food and are therefore very dependent on the beta-carotene form of the nutrient (5). As part of a recent study blood samples from over 15,000 women were analyzed and a polymorphism was found in a gene that encodes a transport protein responsible for the uptake of vitamin C in the intestine (6). The genetic variant was associated with low concentrations of ascorbic acid in the blood, which is possibly linked to restricted transport function. It is not yet clear whether this polymorphism increases the risk of an inadequate supply of vitamin C and associated diseases (7).

The following example shows how such genetic variants can influence study outcomes and their interpretation: in neither the HOPE Study nor its follow-up, HOPE-TOO, did results in the form of the average values for all participants indicate an association between the daily intake of 400 IU vitamin E and a reduced risk of suffering from heart and vascular diseases (heart attack, stroke, heart failure, etc.) (8). However, closer analysis of the data obtained from these studies showed that some patients had benefited greatly from supplementation with vitamin E: these were type 2 diabetics who carry a particular genetic variant of the hemoglobin transporter “haptoglobin” (Hp). This genotype (Hp 2-2) is characterized by haptoglobin with comparatively modest antioxidant activity.Cardiovascular disease deaths and non-fatal myocardial infarctions were markedly rarer in type 2 diabetics who were HP 2-2 carriers and consumed supplemental vitamin E (9). Evidently diabetics with this genotype have an increased requirement for antioxidant micronutrients and were able to derive health benefits from the targeted consumption of vitamin E. A more recent study with subjects suffering from type 2 diabetes and carrying Hp 2-2 confirmed this observation: the risk of cardiovascular illness among participants who took vitamin E was substantially lower (10). The effect was so striking that it led to early termination of the study: it would not have been ethical to stop the placebo group taking the vitamin E preparations. It is estimated that the frequency of the Hp 2-2 genotype in western populations is around 36 percent.

These and other factors should be taken into consideration when planning future intervention studies and developing intake recommendations for the prevention of cardiovascular and other diseases.



By the middle of the 1990s comprehensive epidemiological studies had indicated that the antioxidant micronutrients vitamin C,vitamin E and beta-carotene could potentially help prevent cardiovascular diseases. Suggestions for optimal serum concentrations for prevention were proposed at the time (11): a minimum of 0.4 μmol/L for beta-carotene, 50 μmol/L for vitamin C and 30 μmol/L for vitamin E (alpha-tocopherol) – values that were confirmed at a consensus conference held in 1997 (2). In addition, estimated values were given for the amounts of micronutrients needing to be consumed daily in the diet to achieve these values: for vitamin C these were 75 to 150 mg, for vitamin E 15 to 30 mg and for beta-carotene 2 to 4 mg (12). However, controversial outcomes of more recent intervention studies conflict with the results of the many epidemiological studies relating to cardiovascular disease: sometimes associations were found between an increased intake of antioxidants and a reduction in disease risk, but in many other cases there was no evidence of significant differences. Analysis of the observation and intervention studies indicated that their results were crucially related to the micronutrient status of the subjects at the start and on completion of the study. The antioxidant status of study participants at the beginning of the trials was the deciding factor in what extent beneficial health effects would be seen after antioxidant administration. Thus no health benefit was detected in intervention studies with subjects who already had optimal blood levels of antioxidants when they consumed additional food supplements with vitamins C and E and beta-carotene. However, it is absolutely necessary to establish the baseline status of individuals and take their antioxidant status into account when allocating participants to trial groups (supplementation or placebo) for the assessment of micronutrient-dependent preventive effects. When participants with inadequate levels of antioxidants (at the start of the trial) were targeted for recruitment to studies, supplemental intake (as part of the study) – and thus the correction of the detrimental deficiency – did have preventive effects.

These results indicate that analysis of blood levels and the establishment and maintenance of optimal serum values of each antioxidant micronutrient is of primary importance. When intake from the diet is sufficient, a targeted additional intake of antioxidants through food supplements or fortified foods is not an effective strategy for preventing cardiovascular diseases. If the antioxidant status is unsatisfactory, it should be established whether underlying health problems make a higher intake of antioxidants necessary or whether a poor or deficient diet is possibly the triggering factor. If the inadequate intake is of a temporary nature, short-term consumption of antioxidant supplements may well be the solution. Long-term consumption could well be beneficial to older people, for example, who often find it difficult to meet antioxidant requirements from their diet because of their lower energy needs. The amounts consumed should always meet the official recommendations – but overdosing has proved ineffectual in studies. Ideally, dietary habits should be reviewed and adjusted as necessary. While vitamin E is found above all in plant oils and nuts, vitamin C and beta-carotene are present in fruit and vegetables. These foodstuffs also contain many other antioxidant substances (e.g., plant polyphenols) in addition to vitamins, carotenoids and minerals and trace elements.



Atherosclerosis or cancer and other, typical diseases of age are not, by definition, micronutrient deficiency diseases. On the other hand there is well-founded biochemical and epidemiological evidence that an inadequate supply of antioxidants promotes degeneration of cell structures (e.g., the linings of arteries), facilitates tumor genesis and impairs immune function. A pressing problem is the earliest possible identification of an antioxidant deficiency. While specific health conditions caused by a chronic deficiency of single micronutrients are relatively easily recognized by experienced diagnosticians due to their characteristic symptoms, diagnosis in the presence of complex, multi-factorial diseases whose progression can be exacerbated by an inadequate supply of several micronutrients is more difficult. Micronutrient deficiency is often overlooked as a risk factor or complication of the underlying ailment. It is even more difficult to diagnose an early-stage, latent deficiency (i.e., still without obvious symptoms). This threshold deficiency is particularly common and at the same time hard to recognize. As a result, it may go unnoticed for decades.

Until now little is known about the long-term consequences of latent antioxidant insufficiency. Scientific trials have been too focused on the short-term to show with certainty the extent to which an optimal intake of antioxidants over a lifespan can ensure a longer, healthier life (see too “The Triage Theory”). Nevertheless, the results of current research in the cases of vitamins C and E and beta-carotene emphasize the importance of establishing micronutrient status and adhering to intake recommendations. In this context, determining blood levels alone may not suffice to diagnose an insufficiency – as body cell stores may be considerably depleted even, while serum concentrations are within the normal range. In expert circles the issue of “optimal” micronutrient intakes with “maximum” health benefits is debated just as hotly as the question of the point at which an intake might be considered “less than optimal”. Nutrition experts have established recommendations for the daily intake allowances of micronutrients, such as the “RDA” (recommended daily allowance), which are intended to cover the requirements for almost all the healthy population of the same age and sex living under similar circumstances. Many experts criticize that the current recommendations are based on the “average allowance for healthy people” and that individual needs – e.g., because of genetic variations – and higher intakes that could possibly provide health benefits are ignored.

There is currently an ongoing debate about how micronutrient status could be measured at routine examinations. Methods for diagnosing individual micronutrient requirements and consequent tailoring of intake recommendations are of great interest. Health risks from existing insufficiencies could then be identified early and corrections made. In the final instance, a long or medium-term prevention of cardiovascular disease through (lifelong) optimal antioxidant intake – as one of several health-promoting measures – could significantly lower the cost of medical care.


  1. Brubacher D. et al. Vitamin C concentrations in plasma as a function of intake: a meta-analysis. Int J Vitam Nutr Res. 2000; 70(5):226–237.
  2. Biesalski H. K. et al. Antioxidant vitamins in prevention. Clin Nutr. 1997; 16:151–155.
  3. Referenzwerte für die Nährstoffzufuhr (2000). Deutsche Gesellschaft für Ernährung, Österreichische Gesellschaft für Ernährung, Schweizerische Gesellschaft für Ernährungsforschung. Umschau Braus GmbH, Frankfurt am Main.
  4. Food and Nutrition Board, Institute of Medicine (2000). Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. National Academic Press, Washington DC.
  5. Leung W. C. et al. Two common single nucleotide polymorphisms in the gene encoding beta-carotene 15,15'-monoxygenase alter beta-carotene metabolism in female volunteers. The FASEB Journal. 2009; 23:1041–1053.
  6. Timpson N. J. et al. Genetic variation at the SLC23A1 locus is associated with circulating concentrations of L-ascorbic acid (vitamin C): evidence from 5 independent studies with > 15,000 participants. American Journal of Clinical Nutrition. 2010; 92:375–382.
  7. Michels A. J. et al. A new twist on an old vitamin: human polymorphisms in the gene encoding the sodium-dependent vitamin C transporter 1. American Journal of Clinical Nutrition. 2010; 92:271–272.
  8. Lonn E. et al. HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005; 293:1338–1347.
  9. Levy Y. et al. The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes. Diabetes Care. 2004; 27(11):2767.
  10. Milman U. et al. Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both Type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective, double-blinded clinical trial. Art Thromb Vasc Biol. 2008; 28:341–347.
  11. Gey K. F. Optimum plasma levels of antioxidant micronutrients; ten years of antioxidant hypothesis on arteriosclerosis. Bibl Nutr Dieta. 1994; 51:84–99.
  12. Blot W. J. et al. The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr. 1995; 62 (6):1424–1427.