Thousands of heart attack victims every year have none of the notorious risk factors before their crisis - not high cholesterol, not unhealthy triglycerides. Now the search for the mystery culprits has turned up some surprising suspects: the trillions of bacteria and other microbes living in the human gut.
In a study released on Wednesday, scientists discovered that some of the bugs turn lecithin - a nutrient in egg yolks, liver, beef, pork and wheat germ - into an artery-clogging compound called TMAO. They also found that blood levels of TMAO predict heart attack, stroke or death, and do so "independent of other risk factors," said Dr Stanley Hazen, chairman of cellular and molecular medicine at the Cleveland Clinic's Lerner Research Institute, who led the study.
That suggests a TMAO test could enter the arsenal of blood tests that signal possible cardiovascular problems ahead. "TMAO might identify people who are at risk (for heart attacks and strokes) despite having no other risk factors," Hazen said.
The discovery also suggests a new approach to preventing these cardiovascular events: altering gut bacteria so they churn out less TMAO.
The study joins a growing list of findings that link human "microbiota" - microbes in the gut, nose and genital tract, and on the skin - to health and disease. Research has shown that certain species of gut bacteria protect against asthma, for instance, while others affect the risk of obesity. Last week scientists reported that circumcision alters bacteria in the penis, and that this change (not only the anatomical one) helps protect men from HIV/AIDS, probably by reducing the number of bacteria that live in oxygen-free environments such as under the foreskin.
"It's very strong work," Dr Martin Blaser of New York University Langone Medical Center, a pioneer in studies of the microbiota, said of the TMAO study. "They show clearly that human microbiota play a key role in producing TMAO, suggesting new approaches to prevention and treatment" of cardiovascular disease.
Normal cholesterol, fatal heart attack
The new study builds on a 2011 discovery by the Cleveland Clinic team that, in lab mice, gut bacteria turn lecithin in food into TMAO, or trimethylamine-N-oxide, causing heart disease. In addition, they found, people with high levels of TMAO are more likely to have heart disease.
But that research left two questions hanging: Do human gut bacteria trigger the lecithin-to-TMAO alchemy, like those in mice? And do high levels of TMAO predict heart attacks and stroke in people many years out, not simply mark the presence of cardiovascular disease at the time of the blood test?
To answer the first question, Hazen and his colleagues had 40 healthy adults eat two hard-boiled eggs, which contain lots of lecithin. Just as in lab mice, TMAO levels in the blood rose. After a week of broad-spectrum antibiotics, however, the volunteers' TMAO levels barely budged after they ate eggs, the researchers reported in the New England Journal of Medicine.
"That showed that the intestinal bacteria (which antibiotics kill) are essential for forming TMAO," said Hazen.
Next, to see whether TMAO predicts cardiovascular events, the researchers measured its levels in 4,007 heart patients. After accounting for such risk factors as age and a past heart attack, they found that high levels of TMAO were predictive of heart attack, stroke and death over the three years that the patients were followed.
Moreover, TMAO predicted risk more accurately than triglyceride or cholesterol levels, Hazen said. And it did so in people without substantial coronary artery disease or dangerous lipid levels as well as in sicker patients.
Specifically, people in the top 25 percent of TMAO levels had 2.5 times the risk of a heart attack or stroke compared to people in the bottom quartile.
The reason TMAO is so potent is that it makes blood cholesterol build up on artery walls, causing atherosclerosis (hardening of the arteries) and, if the buildup ruptures and blocks an artery, stroke or heart attack.
Earlier this month, the Cleveland Clinic researchers reported that gut bugs also transform carnitine, a nutrient found in red meat and dairy products, into TMAO, at least in meat eaters. Vegetarians made much less TMAO even when eating carnitine as part of the study, suggesting that avoiding meat reduces the gut bacteria that turn carnitine into TMAO, while regular helpings of dead animals encourages their growth and thus the production of TMAO.
More studies are needed to show whether TMAO reliably predicts cardiovascular crises, and does so better than other blood tests. Experts disagree on how many people have no other risk factors but would be flagged by TMAO. Dr Gordon Tomaselli, chief of cardiology at Johns Hopkins University School of Medicine and past president of the American Heart Association, guesses it is less than 10 percent or so of the people who eventually have heart crises.
Someone with high levels of TMAO could reduce her cardiovascular risk by eating fewer egg yolks and less beef and pork. But someone with a two-eggs-a-day habit but low TMAO probably has gut microbes that aren't very adept at converting lecithin to TMAO, meaning she can eat eggs and the like without risking a coronary.
Just as statins control unhealthy cholesterol, prebiotics (compounds that nurture "healthy" gut microbes) or probiotics (the good bugs themselves) might control unhealthy TMAO. For now, however, no one knows which prebiotics or probiotics might do that. In one study, probiotics actually increased TMAO-producing bacteria - "not what you want," Hazen said.
Neither will popping antibiotics work: bacteria become resistant to the drugs. Developing compounds that crimp the ability of the bacteria to turn lecithin into TMAO, Hazen said, is more likely to succeed.