Heave-ho for homocysteine?

Content provided by the Faculty of the Harvard Medical School

Heave-ho for homocysteine?

High doses of B vitamins lower homocysteine but don't fix heart disease.

After a troubled and contentious birth, the homocysteine hypothesis grew up to be embraced by some doctors, researchers, and a public hoping for an easy and inexpensive fix for heart disease. According to this theory, homocysteine — a by-product of protein digestion — wreaks havoc in blood vessels and contributes to the artery-clogging process known as atherosclerosis. If that's true, then lowering homocysteine levels in the blood with a trio of B vitamins should fight atherosclerosis.

There's just one small problem. So far, this strategy isn't paying off where it counts — preventing heart attacks, strokes, and other forms of cardiovascular disease. Three large trials, two of them presented at the annual meeting of the American College of Cardiology and published in the April 13, 2006, New England Journal of Medicine, show no benefit from high-dose B vitamins.

Is it time to stop worrying about homocysteine? That depends on your point of view.

Mixed signals

The three major trials included almost 13,000 volunteers. Some had survived heart attacks or strokes; others had stable angina (chest pain), peripheral artery disease, or other signs of cholesterol-clogged arteries; and some had diabetes, which often leads to heart disease. Most had normal homocysteine levels. Half took high doses of folic acid, vitamins B₆ and B₁₂, half took dummy pills, and all were followed for several years.

Those taking B vitamins ended up with homocysteine levels about 30% lower than when they started. Yet heart attacks and strokes were just as common in the B vitamin–takers as they were among those taking placebos.

At the same time, a study suggests that small increases in folic acid in the diet may protect against stroke. In 1998, new laws in the United States and Canada required that flour and other grain products be fortified with folic acid. Since then, average blood levels of homocysteine have fallen in these two countries, but not in England and Wales, where folic acid fortification isn't required. More to the point, since 1998, death rates from stroke have fallen faster in the United States and Canada than in England and Wales.

Further complicating matters is the fact that in the laboratory, homocysteine is bad for blood vessels. It promotes oxidative stress, inflammation, the formation of blood clots, and the proliferation of cells inside arteries. In people, long-term follow-up studies show that those with high levels of homocysteine are more likely to develop heart disease than those with low levels.

So where's the truth?

Dueling explanations

There's no arguing with the key result of these trials: Lowering homocysteine doesn't prevent heart attacks or strokes in people with normal homocysteine levels who have cardiovascular disease. But there's wiggle room in the interpretation.

One straightforward explanation is that homocysteine isn't directly involved in heart disease, but is a bystander. When you have a fever, aspirin or ibuprofen cools you down but doesn't fight the infection causing it. It's possible that homocysteine is more like the fever than the infection.

It is also possible that lowering homocysteine helps prevent heart disease but doesn't do much once cholesterol-filled plaque has sprouted up in arteries throughout the body.

Researchers are raising a third, more ominous possibility: that the high doses of B vitamins used in the trials (see "Too much of a good thing?") may actually bolster the kind of artery damage they are supposed to prevent. Excess folic acid and vitamin B₁₂ might turn on or off genes involved in creating or stabilizing plaque. High doses could also hold back production of nitric oxide, a small molecule that arteries need to control blood flow.

Where does that leave us?

Back in 1870, philosopher-scientist Thomas Henry Huxley joked about "the great tragedy of Science — the slaying of a beautiful hypothesis by an ugly fact."

For the homocysteine hypothesis, the ugly fact is that taking high doses of B vitamins to lower homocysteine doesn't do much good for people who already have heart disease. Whether B vitamins might work to prevent heart attacks or strokes, especially in those with truly high levels of homocysteine, remains to be seen.

For now, paying attention to blood pressure and other proven risk factors will give most people a bigger payoff than worrying about homocysteine.

Last updated:	September 05, 2008