Their discovery may mean that the battle against the nation's No. 1 killer could soon move to the gut, where probiotics, the friendly bacteria that aid digestion, may become a new tool for heart health.
A study by the researchers, published Wednesday, showed that people who eat high animal-fat diets are not predisposed to heart disease based on genetics alone but also on the composition of their gut bacteria and how these bacteria aid in the digestion of their food.
The research group, led by Dr. Stanley Hazen, section head of preventive cardiology at the Clinic, found that a byproduct of the breakdown of a common dietary fat, lecithin, was a 10-fold stronger predictor of heart disease risk than cholesterol.
It is such a good indicator that Hazen and his group believe that screening for the molecule will be an immediate way to identify people at risk who may otherwise have been missed.
The findings came as a complete surprise to the group, led by Hazen.
"We had never thought that lecithin could be linked to atherosclerosis," he said. "We also had no idea that gut flora would be linked to [this]. There's two new pieces in the puzzle for what causes heart disease."
Hazen's group found that three substances formed from the breakdown of lecithin in the gut -- choline, TMAO and betaine -- all had a "dose-dependent" association with the presence of heart disease in about 1,900 patients who came in for a cardiac evaluation.
That means that the more of each of the molecules the patients had in their blood, the more likely they were to have heart disease, including peripheral artery disease, coronary artery disease and a history of heart attack. The association held even when the researchers took medication use and traditional heart disease risk factors such as smoking, high blood pressure and physical inactivity into account.
It also means that the more lecithin you eat, as with a high animal-product diet, the higher your risk of heart disease. Current research has been largely focused on cholesterol, Hazen said.
"We know that lowering cholesterol isn't enough -- you still end up having a lot of residual cardiac risk, even though we can lower a person's cholesterol to the level it was when they were a baby," he said.
While gut bacteria have long been the focus of research on digestive health, there has been a recent surge of interest in the potential impact of these bacteria on metabolic diseases such as insulin resistance and non-alcoholic fatty-liver disease.
The researchers made the connection between gut bacteria and heart disease after reading obscure papers referencing the need for bacteria to produce TMAO.
To explore that, the group manipulated the diet and gut bacteria of mice to see how it would affect TMAO blood levels and the development of arterial plaque, the leading cause of heart attack, stroke and peripheral artery disease.
The results, as described in an editorial accompanying the study which was published online Wednesday in the journal Nature, were "striking."
In mice bred to be prone to atherosclerosis, increased dietary lecithin and choline led to increased blood levels of TMAO, and to greater accumulation of plaque in the arteries. Both are bad outcomes.
Sterile mice, carefully raised to lack gut bacteria, produced no TMAO when fed a lecithin-rich diet and, more importantly, did not build up plaque when fed a diet high in choline. No bacteria meant no TMAO and no heart disease, confirming the critical role of the intestinal flora in the pathway. The same happened in regular mice given antibiotics for several weeks.
This doesn't mean that gut bacteria are a bad thing, or that everyone should be on antibiotics, Hazen said. It simply means that what we eat, in this case an animal fat, is affected by the bacteria that aid digestion.
"If two similar people eat the same diet and one develops heart disease and the other doesn't, we would normally say that the person who developed heart disease is because they had genes that made them more susceptible," Hazen said.
"What this really shows us is that maybe more so that person has a different flora composition and may be metabolizing the food they eat differently than the person who doesn't get heart disease."
Being able to measure TMAO levels also could provide a glimpse into the heart-healthiness of a person's diet, because they are a good measure of the amount of choline consumed. Aside from animal products, lecithin and choline are found in many commercial baked goods, dietary supplements and vitamins.
Hazen's group is doing further studies to show how atherosclerosis is affected by the gut flora and they are looking for interventions that can block the development of heart disease.
The research is supported by a $3.8 million grant from the National Institutes of Health.