Does Wheat Cause Coronary Heart Disease?

Introduction

Coronary heart disease (CHD) is the leading cause of deaths worldwide - killing 7 millions people every year. In the following text, we will see that wheat consumption is probably a risk factor for CHD.

Conventional Wisdom on Wheat

Most health organizations currently view wheat as a safe food except for people having celiac disease - affecting up to 1% of the population - and people having non-celiac gluten sensitivity. Also whole wheat - as part of whole-grains - is considered to be one of the healthiest food. In fact a diet rich in whole-grains is considered to be protective against CHD.

Why? Because observational studies consistently find that whole-grain consumption is associated with a decreased risk of CHD. Do these results contradict wheat consumption causing CHD?

Are Whole-Grains Protective Against CHD?

According to this study:

Whole-grain intake consistently has been associated with improved cardiovascular disease outcomes, but also with healthy lifestyles, in large observational studies. Intervention studies that assess the effects of whole-grains on biomarkers for CHD have mixed results.

Indeed many studies show that whole-grain consumption is associated with a decreased risk of CHD. But these studies are observational and can only show correlation but not causation.

In fact there is an health-conscious population bias in these studies: for example people consuming the most whole-grains also exercise more and smoke less:

Data from Majken K Jensen et al., Intakes of whole grains, bran, and germ and the risk of coronary heart disease in men, 2004

Of course researchers adjust the data with these risk factors. But it is very difficult, maybe impossible, to adjust for all risk factors. For example the two previously cited studies did not adjust for important risk factors like socioeconomic status or social support.

A classic example of an occurrence of this bias can be found in hormone replacement therapy (HRT): observational studies had found that HRT was decreasing the risk of heart disease risk while a controlled study finally found that HRT was indeed slightly increasing the risk of heart disease.

A proof that this health-conscious bias could explain the seemingly protective effect of whole-grains can be found in randomized controlled studies: many of them fail to find any beneficial effect of whole-grains compared to refined grains.

So according to these randomized controlled studies whole-grains are neutral toward CHD risks. How then can we say that wheat causes CHD?

Are All Grains Created Equal?

Many randomized controlled studies compared wheat with other grains. These trials are usually quite short. So instead of looking at the number of heart attacks, short-term studies focus on risk predictors of CHD like weight gain or markers of inflammations. Apolipoprotein B (ApoB) level is another risk factor. It represents the number of LDL particles - often called “bad cholesterol”. It is now considered to be a better predictor than LDL-C - the amount of cholesterol contained in LDL particles. The lower the level of ApoB the lower is the risk of CHD.

Here are some results of these studies:

• a study concluded that a bread diet may promote fat synthesis/accumulation compared with a rice diet
• wheat increased BMI compared to flaxseed in a 12 months study
• wheat increased ApoB level by 5.4% compared to flaxseed in a 3 weeks study
• wheat increased ApoB level by 7.5% compared to flaxseed in a 3 months study
• wheat increased ApoB level by 0.05 g/L compared to flaxseed in a 12 months study
• oat decreased ApoB level by 13.7% while wheat had no significant effect in a 21 days study
• wheat increased the number of LDL particles by 14% while oat decreased them by 5% in a 12 weeks study
• ApoA to ApoB ratio (a risk predictor similar in efficiency to ApoB alone - here the higher the better) was increased by 4.7% for oat bran and 3.9% for rice bran compared to wheat bran in a 4 weeks study

These studies show that some grains like oat improve the risk factors of CHD compared to wheat. In addition, these studies often show an absolute improvement of the CHD risk profile in groups eating oat and an absolute deterioration in groups eating wheat. Although we cannot say for sure, it would suggest that oat is protective against CHD - which is confirmed by other studies - while wheat increase the risk of CHD.

That could help explaining why people eating more whole-grains are healthier in observational studies since it looks like that they eat more grains like rice and oat and less typically wheat-made food like white bread, pasta and doughnuts:
Data from Andersson A. et al., Intakes of whole grains, bran, and germ and the risk of coronary heart disease in men, 2007

Now let’s have a look at studies linking wheat and CHD.

Observational Studies on Wheat

Some observational studies linked wheat and waist circumference gains - waist circumference being a strong predictor of CHD:

• a study showed a correlation between consumption of white bread and waist circumference gains
• a study concluded that: ”reducing white bread, but not whole-grain bread consumption, within a Mediterranean-style food pattern setting is associated with lower gains in weight and abdominal fat”
• a Chinese study found that ”vegetable-rich food pattern was associated with higher risk of obesity” but as noted by obesity researcher Stephan Guyenet the association between obesity is in fact stronger with wheat flour than with vegetables

A more pertinent result is found in the data of a large observational study in China. Researchers analysed these data and found a 0.67 correlation between wheat flour intake and CHD. They also found a 0.58 correlation between wheat intake and BMI.

From Denise Minger
But this is just a single unadjusted correlation and does not prove much. However blogger Denise Minger thoroughly analysed the data of this study and found that the association held strongly after multivariate analysis with any other variable available like latitude, BMI, smoking habits, fish consumption, etc.

Since it is an observational study it cannot prove anything but it is yet another evidence suggesting that wheat consumption causes CHD. Let’s now have a look at randomized controlled trials.

Randomized Controlled Trials on Wheat

In addition to the previous randomized controlled trials comparing wheat with other grains there are two additional studies suggesting that wheat consumption causes CHD.

The first one is a study involving rabbits. While studies involving animals are not always relevant to humans - especially studies with herbivore animals like rabbit - the results of this study are quite interesting.

The researchers fed rabbits an atherogenesis diet (i.e. promoting formation of fatty masses in arterial walls) with a supplement of cottonseed oil, hydrogenated cottonseed oil, wheat germ or sucrose. And as they concludes:

Severity of atherosclerosis after 5 months was greatest on the wheat germ-supplemented diet, whereas there were no differences among the other three groups.

The second study is the Diet And Reinfarction Trial (DART). In this 2-year randomized controlled trial, people who already had recovered from an heart attack were split into groups receiving various advices. The main result of this study was that the group advised to eat fatty fish had a reduction in mortality from CHD.

One other advice - the fibre advice - was:

to eat at least six slices of wholemeal bread per day, or an equivalent amount of cereal fibre from a mixture of wholemeal bread, high-fibre breakfast cereals and wheat bran

Seeing this advice we can guess that most of cereal fibres intake by this group was from wheat although we cannot be sure.

This advice resulted on a 22% death increase:
From Stephan Guyenet
However this result bordered on statistical significance: the 95% confidence interval being 0.99–1.65.
For people not familiar with statistics, a result is usually defined as statistically significant when there is less than 5% chance that the result is due to luck alone. Here there is a 95% probability that the relative risk is between 0.99 (1% decreased chance of dying) and 1.67 (67% increased chance of dying).

Since the probability that the fibre advice resulted in a protective or neutral effect was a little too high, this result has been quite overlooked. Had the study last a little longer, it would have raised way more suspicion toward whole-grains.

In fact, researchers found this effect to be statistically significant in a follow-up study. After adjusting for pre-existing conditions and medication use, we can see in the table 4 of this study an hazard ratio of 1.35 (95% CI 1.02, 1.80) for the 2-year period of the randomized controlled trial.

These results are quite telling: according to these researchers, a 2 year randomized controlled trial showed that advising people recovering from an heart attack to eat at least six slices of wholemeal bread per day resulted in a statistically significant 35% percent chance increase of CHD compared to people not receiving this advice.

Wheat, Vitamin D Deficiency And Heart Disease

Many studies found that vitamin D deficiency is associated with CHD.
However vitamin D deficiency does not seem to cause heart disease. For example several studies found that vitamin D supplementation did not prevent heart disease.
As this study concludes:

A lower vitamin D status was possibly associated with higher risk of cardiovascular disease. As a whole, trials showed no statistically significant effect of vitamin D supplementation on cardiometabolic outcomes.

Wheat consumption causing CHD could help explaining these results. A study found that wheat consumption depletes vitamin D reserves. That could explain why vitamin D deficiency is associated with heart disease and why it does not seem to cause it: both vitamin D deficiency and heart disease could be consequences of wheat consumption.

Of course this is not the only explanation. For example the DART study shows that fish consumption prevents CHD and fish is a food rich in vitamin D.

Not the Perfect Culprit

To be clear, if it seems likely that wheat consumption is a risk factor of CHD it is not the only one nor the primary one. There are many other factors like smoking, hypertension, lack of exercice or stress. Even among dietary factors wheat is probably not the main one. For example the DART study shows that the protective effect of fish intake is stronger than the adverse effect of wheat.

In addition, deleterious wheat effects might not affect everybody. One study showed that the ApoB level variation following wheat and oat bran intake was different depending on the genotype of the individuals. In another study whole-wheat intake worsened the lipid profile only in people having a specific genotype compared to refined wheat.

How the wheat is cooked may have a role too. Studies show that sourdough bread improve mineral bioavailability (such as magnesium, iron, and zinc) compared to yeast bread or uncooked whole-wheat. Also content in proteins with potential adverse consequences like gluten or wheat germ agglutinin differs depending of the food type.

Conclusion

There are strong evidences that wheat consumption is a risk factor for CHD. People at risk of CHD should avoid wheat as should those trying to lose weight. In all cases, stopping wheat consumption for a month for example to see how one feel without wheat is always a good idea since there is currently no available method to diagnose non-celiac wheat sensitivities and that even for celiac disease the average delay in diagnostic is 11 years in the US.

More studies looking at the links between wheat and CHD are urgently needed since CHD is the leading cause of deaths while wheat is the second most widely consumed food and whole-wheat is often advised to lower risk of CHD. Studies considering grains as a whole are bound to give inconsistent results since different grains seem to have opposite effects in the case of CHD. So as much as possible future studies should treat grains separately and consider things like type of wheat products and genetic variability.

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Red Meat and trimethylamine N-oxide - Kresser

Red Meat and TMAO: Cause for Concern, or Another Red Herring?

By Chris Kresser on April 10, 2013 

 

 

I’m sure many of you have seen reports on a recent study published in the journal Nature suggesting a possible mechanism linking red meat consumption to heart disease. The day after one such report was published in the New York Times, I received numerous emails and numerous Facebook and Twitter messages from concerned red meat enthusiasts. This is understandable, but rest assured it’s not yet time to switch over to soy burgers.

 

The researchers in this study published a paper a while back proposing that a chemical called TMAO (trimethylamine N-oxide) increases the risk of heart disease. In this study, they hypothesized that eating red meat may increase levels of TMAO in the bloodstream, which would intern ramp up your chances of having a heart attack. Sounds plausible, right?

 

There’s another hypothesis that also seemed plausible for why red meat increases the risk of heart disease (if we even accept that, which I do not; more on this in a moment). It’s called the “diet-heart hypothesis”, and you’re all very well aware of it whether you know it by name or not. It holds that eating cholesterol and saturated fat increase cholesterol levels in the blood, and high cholesterol levels in the blood cause heart disease. This theory became so widely accepted that few people even question it anymore. The problem is it’s simply not true. Recent research has shown that dietary saturated fat and cholesterol are not associated with heart disease after all, and even if they were, high cholesterol levels in the blood are not the culprit. I’ve written about this extensively in the past, and I will be starting a brand new series with updated information this month.

 

The mistaken blame of saturated fat and cholesterol as drivers of heart disease led to a decades-long campaign to encourage low-fat, high-carbohydrate diets. Unfortunately, the effects of this campaign were not harmless. Not only did it unnecessarily deprive people of nutrient-dense, nourishing (and delicious!) foods like meat, butter and eggs, it may have indirectly contributed to the epidemics of obesity, heart disease and diabetes. Studies have shown that when people replace saturated fat with carbohydrates, the risk of heart disease doesn’t go down—it goes up. (1) This is not because of the carbohydrates, per se, but because 85% of the grain consumed in the U.S. is in the highly refined form. (2)

 

The diet-heart hypothesis should be a cautionary tale that prevents us from jumping to rash conclusions based on limited evidence. Alas, the almost complete lack of criticism or scrutiny in the popular media reports on this study indicate that caution has been thrown to the wind. Let’s now examine three reasons why I’m not yet ready to take the conclusions of this study (i.e. red meat causes heart disease via TMAO) at face value.

Epidemiological evidence is inconsistent

If red meat consumption elevates TMAO, and elevated TMAO increases the risk of heart disease, we’d expect to see higher rates of heart disease in people that eat more red meat. The epidemiological evidence examining this question is mixed. A large meta-analysis published in Circulation by Micha et al. covering over 1.2 million participants found that consumption of fresh, unprocessed red meat is not associated with increased risk of coronary heart disease (CHD), stroke or diabetes. (3) On the other hand, a smaller prospective study including about 121,000 participants from the Nurses Health Study and Health Professionals Follow-up Study did find an association between red meat consumption (both fresh and processed) and total mortality, cardiovascular disease (CVD) and cancer. (4)

 

If eating meat increases heart disease risk we might expect lower rates in vegans and vegetarians. Early studies suggested this was true, but later, better-controlled studies suggest it’s not. The early studies were poorly designed and subject to confounding factors (i.e. vegetarians tend to be more health conscious on average than general population, so there could be other factors explaining their longevity, such as more exercise, less smoking, etc.). Newer, higher quality studies that have attempted to control for these confounding factors haven’t found any survival advantage in vegetarians. For example, one study compared the mortality of people who shopped in health food stores (both vegetarians and omnivores) to people in the general population. They found that both vegetarians and omnivores in the health food store group lived longer than people in the general population. (5) This suggests, of course, that eating meat in the context of a healthy diet does not have the same effect as eating meat in the context of an unhealthy diet. (Hold this thought: we’ll be coming back to it shortly.) A very large study performed in the U.K. in 2003 including over 65,000 subjects corroborated these results: no difference in mortality was observed between vegetarians and omnivores. (6)

 

Taken together, these data do not suggest a strong relationship between red meat and heart disease. It’s also crucial to remember that epidemiological evidence does not prove causality. Even if red meat intake is associated with a higher risk of CVD (or any other health problem), such studies don’t tell us that red meat is causing the problem. If you’re new to this concept, I suggest reading these excellent articles by Denise Minger and Chris Masterjohn.

The “healthy user bias” strikes again

The healthy user bias is the scientific way of explaining the phenomenon I described above, where people that engage in one behavior that is perceived as healthy (whether it is or not) are more likely to engage in other behaviors that are healthy. (7, 8) Of course the flip-side is also true: those that engage in behaviors perceived to be unhealthy are more likely to engage in other unhealthy behaviors. The healthy user bias is one of the main reasons it’s so difficult to infer causality from epidemiological relationships. For example, say a study shows that eating processed meats like bacon and hot dogs increases your risk of heart disease. (9) Let’s also say, as the healthy user bias predicts, that those who eat more bacon and hot dogs also eat a lot more refined flour (hot dog and hamburger buns), sugar and industrial seed oils, and a lot less fresh fruits, vegetables and soluble fiber. They also drink and smoke more, exercise less and generally do not take care of themselves very well. How do we know, then, that it’s the processed meat that is increasing the risk of heart disease rather than these other things—or perhaps some combination of these other things and the processed meat? The answer is, we don’t. Good studies attempt to control for some of these confounding factors, but inevitably some will not be controlled for. And one of the most important potential confounding factors that is never controlled for is the gut microbiome.

 

Numerous studies, which I’ve written about on this blog and spoken about on my podcast, suggest that the balance of bacteria in our gut may be one of the most important factors—if not the most important—that determines our overall health. Gut dysbiosis (an imbalance between healthy and unhealthy bacteria in the gut) and small intestine bacterial overgrowth (SIBO, a condition involving an inappropriate overgrowth of bacteria in the gut) have been linked to health problems as diverse as skin disease, depression, anxiety, autoimmunity, and hair loss.

 

The study we’re discussing here found that those who eat red meat produce TMAO, whereas vegans and vegetarians who hadn’t eaten meat for at least a year do not. The researchers claimed that this means eating red meat must alter the gut flora in a way that predisposes toward TMAO production. However, there’s another explanation that I believe is much more plausible: the red meat eaters are engaging in unhealthy behaviors that have led to dysbiosis and/or SIBO. This could include eating fewer fruits and vegetables and less soluble fiber, and more processed and refined flour, sugar and seed oils. All of these behaviors have been shown to be more common in the “average” red meat eater, and all of them have been associated with undesirable changes in the gut microbiota. (10, 11, 12) In other words, the problem isn’t the red meat, it’s the gut bacteria. This is supported by the finding in the study that the red meat eaters did not produce TMAO after a course of antibiotics. It is also supported by data indicating that a breakdown in the intestinal barrier, which occurs in dysbiosis and SIBO, may increase heart disease risk by elevating the number of circulating LDL particles in the bloodstream. (13) I will be covering this (i.e. the connection between LDL particles and heart disease) in my updated series on heart disease.

 

In the last section I presented evidence suggesting that eating meat in the context of a healthy diet does not have the same effect as eating it in the context of an unhealthy diet. This study is likely yet another example. In order to know whether red meat is really to blame for changes in the gut flora that increase TMAO production, we’d have to do another study with two groups: one that follows a Paleo diet rich with fruits, vegetables and soluble fiber, as well as red meat; and another vegan/vegetarian diet with equivalent amounts of plant matter and no meat. If the Paleo diet followers still had higher levels of TMAO, this hypothesis would be a lot stronger.

The jury is still out on TMAO

The evidence linking TMAO production to eating red meat, and serum TMAO levels to heart disease, is not as cut-and-dry as the study authors suggest. For example:

• The Nature paper on TMAO contained data from two studies: an epidemiological study on humans, and a clinical study on mice. The human study compares a single vegan that they managed to convince to eat a steak to a single “representative” meat-eater. A single person in each group is not an adequate sample size, and is hardly convincing given the wide variation in the response to carnitine (see next bullet) among meat-eaters.

• The mouse study used a carnitine supplement. While it is well established that free carnitine increases TMAO production, previous studies have not shown that carnitine-rich foods like red meat increase TMAO. In fact, in one 1999 study, out of 46 different foods tested, including red meat, only one food elevated TMAO levels in the participants: seafood (see graph to right, from Chris Masterjohn’s article referenced below). This makes perfect sense since trimethylamine occurs naturally in seafood. Does this mean we should cut back on fish and shellfish because they’re going to give us a heart attack?(15)

Another obvious question we should ask is whether there are alternative explanations for why we see elevated TMAO levels in meat or seafood eaters (if indeed we do see them in a wide sample of meat eaters, which at least one earlier study didn’t support)? According to a 2011 article by Chris Masterjohn touching on TMAO in a different context: (16)

Elevated TMAO could reflect dietary trimethylamine or TMAO from seafood, but it could also reflect impaired excretion into the urine, or enhanced conversion of trimethylamine to TMAO in the liver.

The enzyme Fmo3 carries out this conversion, mainly in the liver, as reviewed here. There are a number of genetic variants affecting the activity of this enzyme, some of which appear only in certain ethnicities, and the enzyme also processes a number of drugs used to treat psychoses, infections, arthritis, gastro-esophageal reflux disease (GERD), ulcers, and breast cancer. Iron or salt overload may also increase the activity of the enzyme. TMAO could, then, be a marker for ethnicity, drug exposure, genetically determined drug efficacy, or other conditions.

As you can see, it’s overly simplistic to suggest that eating red meat causes elevated TMAO; there are many other factors at work.

But even if Paleo meat eaters have higher TMAO levels than vegans and vegetarians, we still don’t have evidence proving a causal relationship between TMAO and CVD. Once again, the supposed link between cholesterol and saturated fat and heart disease should serve as a reminder not to jump to hasty conclusions that unnecessarily deprive people of nutrient-dense, healthy foods. It is virtually impossible to control for all of the possible confounding factors, and the study we’re discussing in this article only further highlights this problem.

Conclusions

I’d like to end with an observation from the discussion section of the TMAO paper. The authors state:

Numerous studies have suggested a decrease in atherosclerotic disease risk in vegan and vegetarian individuals compared to omnivores; reduced levels of dietary cholesterol and saturated fat have been suggested as the mechanism explaining this decreased risk. Notably, a recent 4.8-year randomized dietary study showed a 30% reduction in cardiovascular events in subjects consuming a Mediterranean diet (with specific avoidance of red meat) compared to subjects consuming a control diet.

This might sound like damning evidence against red meat. However, when you look at Table One in Mediterranean Diet trial, you’ll find that the Mediterranean diet allowed more red meat than the control diet (a low-fat diet)! The Mediterranean Diet allowed for “one serving or less of red or processed meat per day“, whereas the low-fat diet only permitted “one serving or less of red or processed meat per week“. (You can see this for yourself. Click here to access the PDF version of the study, then scroll down to Table One.) Clearly this paper does not support the authors’ conclusion that red meat increases the risk of heart disease.

They also claim that vegan and vegetarian diets reduce the risk of atherosclerotic disease compared to omnivorous diets; but the studies they reference fail to adequately control for the “healthy user bias”.

The study I mentioned in the beginning of this article compared heart disease risk amongst omnivores and vegetarians that shop at health food stores (which is a big step toward reducing healthy user bias), and did not find a difference in deaths from heart disease, stroke or all causes.
If you read the media reports and full-text of this study, you might have noticed something interesting. The study itself, and even most of the media article about it, quite simply and without much fanfare stated that saturated fat and cholesterol have little to do with the supposed increase in heart disease observed with red meat consumption. Hold the press! Shouldn’t THAT be front-page news?!? Apparently not. Of course, they’re only willing to admit this publicly in the context of an article where they’re proposing yet another mechanism for how red meat will kill you.

Finally, the most remarkable and sad part of this for me is seeing just how deep most people’s fear and distrust of red meat is, even if they’ve been following a Paleo diet for a long time. The day after the TMAO study was published, I woke up to no fewer than 20 emails and the same number of Facebook messages and Tweets from people expressing concern that their choice to eat red meat might be killing them. It really is a testament to the power of brainwashing. Most of us grew up with the idea that red meat is harmful, and it’s perhaps not so easy to leave that behind—even when you think you have.

Chris Masterjohn is working on a detailed analysis of the data from this paper, which should be ready soon. I believe we may be seeing more “red meat is bad because of TMAO” studies in the near future, so as always, when you see a media report on such a study, take it with a heavy grain of salt (which, by the way, doesn’t cause high blood pressure in most people!).
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