TMAO – Smoking gun or passive observer?

Once again, a new study suggests a correlation between a metabolite trimethylamine N-oxide (TMAO) and heart disease risk. But does TMAO cause heart disease or is it a marker of other conditions that often go along with heart disease?

Another study, published in Journal of the American College of Cardiology (JACC), suggests an association between TMAO and risk of heart disease. As we have covered before, TMAO is produced by our gut bacteria and changes based on our diet. Eating more vegetables can decrease TMAO, and eating more meat can increase TMAO. But is TMAO causative of heart disease?

Some interpret the body of evidence as confirming that TMAO is causative.

But, as with most epidemiology research, this study does not support that claim.

In the JACC study, scientists measured baseline TMAO levels in 760 healthy women in 1989, and again ten years later. The authors determined how many women had heart attacks and then tried to correlate heart attack risk with blood levels of TMAO. Those with the highest baseline level of TMAO and the greatest increase in TMAO had a risk of heart disease of between 1.33 and 1.79.

However, women with the highest TMAO levels who had a heart attack, compared to those who did not have heart attacks, were also much more likely to have hypertension (32% vs 19%), diabetes (7.9% vs 1.3%), and to be a current smoker (4.5% vs 1.8%). [Note that this data is only available in the supplemental tables and is not included in the article.] So, once again, it is unclear if the TMAO level had anything to do with the increased risk of heart events, or if it was simply a marker that coincided with unhealthy lifestyles or “unhealthy user bias.”

TMAO advocates commonly point out that levels rise as subjects eat more red meat. Therefore, many will conclude this study shows we need to avoid meat to reduce our heart risk. But that is not what the study shows; it’s a gross misinterpretation of the results.

Why did some with elevated TMAO have heart attacks and others did not? It appears to be related to other known risk factors (like hypertension, diabetes, and smoking status), rather than to the absolute elevation of TMAO levels.

Does this mean that we can ignore TMAO? Not necessarily. If someone has hypertension, diabetes, or is a current smoker, then TMAO may be a marker of increased risk. But in the absence of those comorbid conditions, it is not clear that the impact is significant enough to alter an already healthy lifestyle, even (especially?) if it includes eating meat.

For more information, please see our evidence-based guide to red meat, and our coverage of the GRADE assessments of how science does not support limiting red meat or even processed meat.

Thanks for reading,
Bret Scher, MD FACC

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