Highlight HEALTH

Have you ever wondered if those healthy fast food meals are really any better for you? McDonald’s has the Fruit ‘n Yogurt Parfait, Wendy’s offers Garden Sensations salads and at Burger King you can even get a veggie burger.

Yogurt, salad, veggie burger … these are all healthy foods.

However, new research suggests that healthy fast food meals have the same effect on your cardiovascular system as a burger, fries and a soda.

The endothelium is a thin layer of cells that line the interior surface of blood vessels. Endothelial cells line the entire circulatory system, from small capillaries to veins and arteries to the heart. These cells are responsible for regulating blood flow and blood pressure through vasoconstriction and vasodilation.

High-fat meals have a negative effect on endothelial function, causing endothelial dysfunction, meaning there is less elasticity of blood vessels and reduced blood flow. Endothelial dysfunction is a marker for cardiovascular disease and can lead to atherosclerosis or high blood pressure, increasing the risk of heart disease and stroke.

Ten years ago, a study linked diet and endothelial dysfunction [1]. Twenty healthy men and women with normal levels of total and low-density lipoprotein cholesterol were fed four randomly administered breakfasts: a high-fat meal consisting of Egg and Sausage McMuffins with fried hash browns, a low-fat meal, a high-fat meal after taking the antioxidants vitamin C and vitamin E, and a low-fat meal with the same vitamin pretreatment. Ultrasound was then used to measure changes in blood vessel tone and blood flow in the brachial artery. The researchers found that decreased vasodilation occurred for up to 4 hours following the high-fat meal, while no significant changes were observed in blood vessel tone and brachial blood flow after the low-fat meal, the high-fat meal with vitamins or the low-fat meal with vitamin pretreatment. The study demonstrated the benefits of vitamins C and E, and the authors concluded that antioxidants help maintain normal endothelial function. Today, vitamin-rich side orders are prevalent throughout the fast food industry.

Researchers now have found that these presumably healthier alternatives to a burger and fries does not significantly differ with respect to their acute impairment of endothelial function [2]. Endothelial function, measured again using ultrasound, and cardiovascular disease risk markers were measured in 24 healthy volunteers who randomly received one of three fast food meals on three study days separated by 1 week:

• Big Mac with regular side orders (french fries, ketchup and Sprite)
• Vegetarian burger with regular side orders (french fries, ketchup and Sprite)
• Vegetarian burger with vitamin-rich side orders (salad, balsamic dressing, yogurt with fruit and Minute Maid orange juice)

Unexpectedly, all three meals resulted in decreased endothelial function. In contrast to the study ten years ago, even consumption of the vegetarian burger with vitamin-rich side orders resulted in decreased vasodilation. The researchers suggest that the reduced endothelial function may be attributable, at least in part, to the increase in baseline arterial diameter following a meal.

Why the conflicting results? The vitamin pretreatment given in the study 10 years ago was extremely high - over 10 times (1000 mg) the recommended daily intake of vitamin C and over 50 times (800 IU) the recommended daily intake of vitamin E [3]. While a salad, yogurt and orange juice are good, healthy foods, they contain substantially lower levels of antioxidants.

These results come in the wake of another study finding that fast food branding makes children prefer happy meals [4]. NewScientist reported that:

… children in the study were twice as likely to prefer the McDonalds-branded carrots as the plain-packaged ones. This suggests that marketing savvy could perhaps convince youngsters to make healthful choices. Some companies have already begun experimenting with this tactic by using Mickey Mouse cartoons to sell sliced fruit and placing Curious George stickers on bananas.
Last month McDonalds announced it would shift its advertising targeted to children under the age of 13 to focus on the 375-calorie Happy Meal, which it says meets current dietary standards outlined by the government.

What does all this mean? It means that eating a side salad with your burger or adding carrots in your child’s happy meal can’t prevent the harmful affects of fast food on the vascular system. Eating healthy doesn’t mean an apple here and a carrot there, it means a complete change in the types of meals we eat.

References

1. Plotnick et al. Effect of antioxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity following a single high-fat meal. JAMA. 1997 Nov 26;278(20):1682-6.
   View abstract
2. Rudolph et al. Acute effects of various fast-food meals on vascular function and cardiovascular disease risk markers: the Hamburg Burger Trial. Am J Clin Nutr. 2007 Aug;86(2):334-340.
   View abstract
3. Dietary Reference Intakes: Vitamins. U.S. Department of Agriculture National Agriculture Library.
4. Robinson et al. Effects of fast food branding on young children’s taste preferences. Arch Pediatr Adolesc Med. 2007 Aug;161(8):792-7.
   View abstract

In February 2007, researchers at Appalachian State University announced the results of a clinical study on the flavonoid quercetin at the Southeastern Regional Meeting of the American College of Sports Medicine, held in Charlotte, N.C. Their results showed that quercetin may help reduce illness and maintain mental performance in physcially stressed test subjects. I’ve written about the antioxidant quercetin in a previous article as an alternative to dichloroacetate (DCA), a chemotherapeutic agent that was recently shown to selectively inhibit cancer cell growth in lung, breast and brain tumor cells grown in culture and lung tumors grown in immunocompromisted rats.

In December 2005, the Defense Advanced Research Projects Agency (DARPA) awarded Appalachian State University 1.1 million to fund a two-year study of the effects of quercetin [1]. DARPA is seeking ways to maintain troop immune systems during times of physical and cognitive stress. Dr. David Nieman is the principal investigator of the study and a professor in the Department of Health, Leisure and Exercise Science at Appalachian State University. He has been investigating the influence of exercise and nutrition on the immmune system for the last 23 years.

The double-blind, randomized, placebo-controlled study provided 1,000 mg/day of high-purity quercetin, a polyphenol, plus niacin and vitamin C to aid in absorption, to 20 trained cyclists for five weeks. A second group of 20 cyclists received a placebo. Three weeks into the study, participants rode a bicycle to the point of exhaustion three hours per day for three days. Blood and tissue samples were collected and analyzed to track any physicological changes that occurred.

Only 5% of the group that received quercetin reported illness after being physically stressed, compared with 45% of the participants who received placebo. No adverse side effects were observed. Surprisingly, the immune-boosting properties of quercetin weren’t readily observable until after the three-day intense exercise period. Additionally, when given an alertness test, those participants that were given quercetin better maintained their ability to react after exhaustion.

Said Dr. Nieman [2]:

It appears that it takes significant stress to bring out quercetin’s infection-fighting properties. This all happened when athletes were under high oxidative stress, when stress hormones were high, and they were also undergoing muscle damage.

Nieman plans a follow-up study to see if quercetin has any benefits for people who are undergoing everyday mental stress.

More about quercetin can be found in these posts:

• Quercetin
• Alternative to Dichloroacetate

References

1. Defense Dept Funds $1.1 Million for Research. The College of Fine & Applied Arts, Appalicain State University. 2005 Dec 7.
2. Research at Appalachian State Indicates Natural Plant Substance Helps Reduce Illness in Physically Stressed Athletes; Findings May Have Military Application. Appalachian State University News. 2007 Feb 8.
3. Sampson et al. Flavonol and flavone intakes in US health professionals. J Am Diet Assoc. 2002 Oct;102(10):1414-20.
   View abstract

A study published in The Journal of the American Medical Association (JAMA) made headlines recently. The review, “Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis”, assessed the effect of antioxidant supplementation on mortality in randomized primary and secondary prevention trials and concluded that beta carotene, vitamin A and vitamin E supplementation are positively correlated with death and may increase mortality.

The Copenhagen University Hospital research group searched electronic databases and bibliographies published prior to November 2005 and included 68 randomized trials (385 publications) with 232,606 participants. The authors have published two other articles recently using a similar methodology and demonstrated similar results [1-2].

The study, not a clinical trial itself, but a study of studies (i.e. a meta-analysis), has a number of problems, notably flawed methodology and over-analysis of the data.

Flawed methodology
According to the article, the goal of the analysis was:

“… to analyze the effects of antioxidant supplements (beta carotene, vitamin A, vitamin E, vitamin C and selenium) on all-cause mortality of adults included in primary and secondary prevention trials.”

However, the researchers specifically excluded 405 studies that reported no deaths during a trial period or follow-up.

Did you get that?

The researchers are studying effects on mortality but failed to include any studies that were death-free. They excluded six times as many potentially eligible studies because no one died during a trial period or follow-up.

In addition, 47 of the 68 trials included in the meta-analysis were secondary prevention trials conducted on subjects that were diagnosed with disease. The goal of these trials was to establish whether intervention would slow disease progression or reduce the risk of death from disease. Only 21 were primary prevention trials conducted on healthy subjects (the goal of these trials was to establish a benefit to health). Thus, not only did all studies included in the meta-analysis report deaths during a trial period or follow-up, but over two thirds of the studies were trials on people that were already diagnosed with a disease.

I agree with Marc’s conclusion over at Marc Joseph Nutrition:

Bottom-line, as a meta-review analysis, this study is subject to selection bias* and the interpretation of the researchers.

* Selection bias is the error of distorting a statistical analysis by pre- or post-selecting the samples. Typically this causes measures of statistical significance to appear much stronger than they are, but it is also possible to cause completely illusory artifacts.

Over-analysis of the data
Trials were classified according to the risk of bias based on the quality of the methods used in the study, either low-bias risk (high methodological quality) or high-bias risk (low methodological quality). The abstract indicates that “randomization, blinding, and follow-up were considered markers of bias in the included trials”. Nevertheless, when all low- and high-bias risk trials of antioxidant supplements were pooled together, there was no significant association between supplement use and mortality.

Significant influences of dosage on mortality were found for beta-carotene, vitamin A, selenium and bias risk. Doses of vitamin A ranged from 1333 IU per day to 200,000 IU per day (mean value 20,219 IU), well above the upper tolerable limit. Notably, there was no increased risk for vitamin C or vitamin E in either single or combined regimen, duration of supplementation, or primary or secondary prevention. Selenium had a statistically significant protective effect by dose. However, when multiple variables were used in the meta-regression, dose of selenium for low-bias risk trials was associated with significantly higher mortality. Beta carotene and vitamin A, as well as the other antioxidants, failed to show increased risk.

On his Livejournal page, Phil explains the inverted-J-shaped response curve of vitamins. As with any medication, mortality will be observed if dosage exceeds toxic levels. In addition, he points out that all the antioxidants suggested to increase mortality (beta carotene, vitamin A and vitamin E) are fat soluble vitamins, which are stored in the body for long periods of time and can build up toxic levels when taken in high doses.

Regina over at Weight of Evidence did an extensive review of the study and summarizes the results for each antioxidant as follows:

• Beta carotene by itself, bad; combined, nothing; exlude some study data and again it’s bad.
• Vitamin A alone or in combination, nothing; exclude some study data, bad.
• Vitamin E alone, in combination, in high dose - nothing; exclude some study data, it’s bad.
• Vitamin C alone, in combination and when excluding some study data, nothing.
• Selenium alone or in combination, nothing; data analyzed together singly or in combination, benefit; exclude some data, nothing.

The meta-analysis did not investigate causes of death, but it’s likely given that 69% of the trials analyzed were secondary prevention that the deaths occurring were principally due to previously diagnosed disease and not antioxidant supplementation. The authors also failed to analyze for potential outcome differences between primary and secondary prevention trials.

Thus, there are many problems with this meta-analysis. Unfortunately, the media has focused only on the results of the low risk bias group, which showed a 16% increase in mortality rate. Here’s the rest of the story:

1. Intervention effect of antioxidant supplements vs placebo on mortality in trials with low risk of bias
   Antioxidants: 15,366 out of 99,095 participants (15.5%)
   Control: 9,131 out of 81,843 participants (11.1%)
   Relative to control: 15.5% - 11.1% = 4.4% (Not 16% as reported by the media)
   Relative risk: 1.05, mortality significantly increased
2. Intervention effect of antioxidant supplements vs placebo or no intervention on mortality in trials with high risk of bias
   Antioxidants: 2,532 out of 36,940 participants (6.9%)
   Control: 1,027 out of 14,728 participants (7.0%)
   Relative to control: 6.9% - 7.0% = -0.1%
   Relative risk: 0.91, mortality significantly decreased
3. Pooled low- and high-risk bias
   Antioxidants: 17,898 out of 136,035 (13.2%)
   Control: 10,158 out of 96,571 (10.5%)
   Relative to control: 13.2% - 10.5% = 2.7%
   Relative risk: 1.02, no significant effect on mortality

Note that there was a significant decrease in mortality in trials with high risk of bias.

Rebuttal
The Council for Responsible Nutrition (CRN) has rebuked the meta-analysis review, noting several problems including:

• The meta-analysis combined studies that differ vastly from each other in a number of important ways that compromise the results, including dosage, duration, study population and nutrients tested.
• Many of the clinical trials included in the meta-analysis tested nutrients beyond those that were the focus of the article including lutein and zinc, making it difficult to appropriately evaluate the contribution of those trials to the overall meta-analysis.
• The overwhelming majority of the clinical trials included in the meta-analysis tested for secondary prevention.
• Many of the treatment trials had limitations, including the expectation that a simple antioxidant vitamin could be expected to overturn serious illness, such as cancer or heart disease.

Andrew Shao, vice president for science and regulatory affairs at CRN, said:

“The study authors concluded that overall there was no effect of antioxidant supplements on all-cause mortality. It was only after the researchers divided the chosen clinical trials into ‘high risk bias’ and ‘low risk bias’ groups, using their own criteria, that they observed a statistically significant effect on mortality. This meta-analysis appears to be a predetermined conclusion in search of a method to support it.”

On a final note, the study authors acknowledge that their results are in conflict with observational studies that have shown beneficial effects of supplemental antioxidants, even in secondary prevention trials [3-5].

References

1. Bjelakovic et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet. 2004 Oct 2-8;364(9441):1219-28.
   View abstract
2. Bjelakovic et al. Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma. Aliment Pharmacol Ther. 2006 Jul 15;24(2):281-91.
   View abstract
3. Fleischauer et al. Antioxidant supplements and risk of breast cancer recurrence and breast cancer-related mortality among postmenopausal women. Nutr Cancer. 2003;46(1):15-22.
   View abstract
4. Baron et al. Neoplastic and antineoplastic effects of beta-carotene on colorectal adenoma recurrence: results of a randomized trial. J Natl Cancer Inst. 2003 May 21;95(10):717-22.
   View abstract
5. Whelan et al. Vitamin and calcium supplement use is associated with decreased adenoma recurrence in patients with a previous history of neoplasia. Dis Colon Rectum. 1999 Feb;42(2):212-7.
   View abstract