Residual Cardiovascular Risk: What’s TMAO Got to Do With It?

The entities abbreviated as LDL, HDL, LP(a), and A1C have occupied a substantial portion of study regarding cardiovascular (CV) risk reduction. There are times, however, when pharmacologic progress in these areas, impressive as it has been, hits a "proverbial wall.” Even with LDL values below the 70 mg/dL target, a prohibitive CV risk persists. Similar manipulations to lower other markers of risk also do not move CV risk to zero. Bottom line, there has to be a lot more to heart disease than is captured by LDL, HDL, LP(a), A1C, and other documented factors. Another approach to reducing residual risk may be to ask the dietary questions-and there are many. But to narrow it to a single one for this discussion: Are red meat and eggs bad for CV health? If so, why?

Let’s start with the intestinal bacteria and the way they share our meals. It has become clear that some bacterial breakdown products have pathologic potential. For example, in animal models, ingestion of foods that utilize the phosphatidylcholine-to-choline metabolic pathway-which produces a molecule abbreviated as TMAO (trimethylamine N-oxide) that is measured in plasma and urine-has contributed to coronary atherosclerosis.¹ Now there are data for the same cause and effect in humans. In a recent study,¹ participants ate 2 large hard-boiled eggs (250 mg of choline in each egg). The molecules and their by-products in question were radio-labeled. As expected, TMAO levels increased in plasma after the meal. Suppression of the intestinal microbiota with antibiotics blocked this rise in TMAO after repeating the study meal. Allowing the bacteria to repopulate later without antibiotics (Step 3) resulted in the same levels of TMAO as in step 1.¹

Looking at the study participants in more CV detail found that the individuals with more major adverse CV events also had higher baseline plasma levels of TMAO. In fact, compared with persons in the lowest quartile of TMAO levels, those in the highest quartile had a 2.54 hazard ratio (95% CI, 1.96 to 3.28; P < .001) for CV events.¹ Adjusting for other variables continued to implicate the TMAO level as a significant risk factor. The phosphatidylcholine-to-TMAO pathway is utilized by bacteria in the human intestines after meals containing eggs, liver, beef, and/or pork. This landmark study identifies excess TMAO production as a possible risk factor for CV disease.¹

The same research group looked at meals containing red meat as the protein source rather than eggs. After a good steak, the intestinal microbiota feast on L-carnitine, which also reaches a metabolic end point of TMAO.² Higher plasma L-carnitine levels in 2595 subjects who underwent cardiac evaluation predicted increased risks for prevalent cardiovascular disease and incident events such as myocardial infarction, stroke, or death.²

Who knew just a decade ago that today we would be indicting gut bacteria as contributors to CV risk?

The work referenced here is elegant and offers a plausible link between certain foods (sorry, I still like red meat and eggs [sometimes together]) and CV risk. There is going to be more research in this area over the next decade.

At one time, people laughed incredulously when antibiotics were recommended for peptic ulcer disease, targeting Helicobacter pylori. They may not be laughing when the same is suggested to prevent heart attacks.

References

1. Tang WH, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368:575-1584. (Abstract)
2.  Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19:576-585. (Abstract)