Research points to a new culprit in heart disease

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It was breakfast time and the people participating in a study of red meat and its consequences had hot, sizzling sirloin steaks plopped down in front of them. The researcher himself bought a George Foreman grill for the occasion and the nurse assisting him did the cooking.

For the sake of science, these six men and women ate every last juicy bite of the 8-ounce steaks. Then they waited to have their blood drawn.

Stanley Hazen of the Cleveland Clinic, a nonprofit academic medical center, who led the study, and his colleagues had accumulated evidence for a surprising new explanation of why red meat may contribute to heart disease. And they were testing it with this early morning experiment.

The researchers had come to believe that what damaged hearts was not just the thick edge of fat on steaks, or the delectable marbling of their tender interiors. The real culprit, they proposed, was a little-studied chemical that is burped out by bacteria in the stomach after people eat red meat. It is quickly converted by the liver into yet another little-studied chemical called TMAO that gets into the blood and increases the risk of heart disease.

The questions that morning were: Would a burst of TMAO show up in peoples' blood after they ate steak? And would the same thing happen to a vegan who had not had meat for at least a year and who consumed the same meal?

The answers were: Yes, there was a TMAO burst in the five meat-eaters, and no, the vegan did not have it. And TMAO levels turned out to predict heart attack risk in humans, the researchers found.

The researchers also found that TMAO actually caused heart disease in mice. Additional studies with 23 vegetarians and vegans and 51 meat-eaters showed that meat-eaters normally had more TMAO in their blood and that they, unlike those who spurned meat, readily made TMAO after swallowing pills with the chemical transformed by the bacteria, carnitine.

"It's really a beautiful combination of mouse studies and human studies to tell a story I find quite plausible," said Daniel Rader, a heart disease researcher at the University of Pennsylvania School of Medicine, who was not involved in the research.

Researchers say the work could lead to new treatments for heart disease -- perhaps even an antibiotic to specifically wipe out the bacterial culprit -- and also to a new way to assess heart disease risk by looking for TMAO in the blood.

Critical questions remain. Would people reduce their heart attack risk if they lowered their blood TMAO levels? An association between TMAO levels in the blood and heart disease risk does not necessarily mean that one causes the other. And which gut bacteria in particular are the culprits?

There also are questions about the safety of supplements, like energy drinks and those used in body building. Such supplements often contain carnitine, a substance found mostly in red meat.

But the investigators' extensive experiments in both humans and animals, published Sunday in Nature Medicine, have persuaded scientists not connected with the study to seriously consider this new theory of why red meat eaten too often might be bad for people.

Dr. Hazen, the chairman of the department of cellular and molecular medicine at the Lerner Research Institute of the Cleveland Clinic, began his research five years ago with a scientific fishing expedition.

In a study of 10,000 patients who came to the Cleveland Clinic for evaluations and were at risk for heart disease, the patients agreed to provide blood samples and to be followed so the researchers would know if any of them had a heart attack or died of heart disease in the three years after the first visit. Those samples enabled Dr. Hazen to look for small molecules in the blood to see whether any were associated with heart attacks or deaths.

That study and a series of additional experiments led to the discovery that a red meat substance no one had suspected -- carnitine -- seemed to be a culprit. It is also found in many foods, Dr. Hazen noted, including fish and chicken and even dairy products, but in small amounts. Red meat, he said, is the major source.

The researchers found that carnitine was not dangerous by itself. Instead, the problem arose when it was metabolized by bacteria in the intestines and ended up as TMAO in the blood.

That led to the steak-eating study. It turned out that within a couple of hours of a regular meat-eater having a steak, TMAO levels in the blood soared.



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