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Sun 1 Jul 2007 12:00 AM

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A question of time?

When it comes to cholesterol, how long it’s under control is as important as how low it goes.

For the last few years, "How low can you go?" has been the big question driving cholesterol researchers. Elbowed to the sidelines is an equally important question: When should you start thinking about cholesterol?

New work on simple mutations that influence blood levels of low-density lipoprotein (LDL), the so-called bad cholesterol, may turn the spotlight on this topic. The upshot of this work may be that we pay more attention to cholesterol levels before middle age, when damage to arteries is already under way. It may also lead to new strategies for keeping cholesterol in check.

It's in the genes

Back in 1999, French researchers found that a specific stretch along human chromosome 1 was linked with naturally high levels of LDL in some people. Further work pinpointed the source of the problem, a mutation in a gene for proprotein convertase subtilisin/kexin 9, blessedly shortened to PCSK9.

That prompted a team from the University of Texas Southwestern Medical Center to search for other PCSK9 variations. They found three that cause naturally low levels of LDL. Two of them are more common in African Americans, the other in European Americans. These gene variants probably work by increasing the number of LDL receptors in the liver, making the liver better able to pull excess LDL out of the bloodstream.

To look at the impact of these gene variations, the researchers turned to a landmark long-term, multicultural study of heart disease risks, the Atherosclerosis Risk in Communities (ARIC) study. They tested blood samples the volunteers had given at the beginning of the study for PCSK9, and tallied up who did, and did not, develop heart disease over the course of the 15-year study.

As expected, volunteers with one of the three PCSK9 variations had LDL levels that were 15%-30% lower than those with a normal PCSK9. Did these naturally lower levels translate into protection against heart disease? Did they ever!

Blacks with one of the unusual genes had a whopping 88% lower risk of having a heart attack, needing bypass surgery or artery-opening angioplasty, or dying of heart disease over a 15-year period than those with the normal PCSK9 gene. Among whites, the reduction was 47%. And these reductions were in spite of the fact that many of the PCSK9 carriers were overweight, had high blood pressure, smoked, or had diabetes - all potent risk factors for heart disease. The results were reported in the March 23, 2006, New England Journal of Medicine.

Working for years

What's interesting about this work is the relationship between the average percentage reduction in LDL caused by the gene and the reduction in heart disease risk.

Taking a cholesterol-lowering statin knocks down the amount of LDL in the bloodstream. On average, lowering LDL with a statin by 39 mg/dL reduces the risk of developing heart disease by 36%. Yet in blacks with a PCSK9 variant, whose LDL levels were 38 mg/dL lower than their counterparts with the usual PCSK9 gene, the risk of heart disease was 88% lower.

Does this mean there's something special about the unusual PCSK9 genes that makes them more powerful - gasp - than statins?

That's possible. But there is a simpler and perhaps more useful explanation. Someone with a helpful PCSK9 variation, or with any gene that naturally lowers LDL, has less harmful cholesterol in the bloodstream from birth onward. That makes a difference in the artery-clogging process known as atherosclerosis, which largely depends on LDL.

We tend to think of atherosclerosis as a disease of middle and old age. It actually starts in adolescence and young adulthood, and creeps slowly through arteries throughout the body. It makes sense, then, that the longer you have low LDL, the more protected you are against heart attack, stroke, peripheral artery disease, and the other consequences of atherosclerosis.

Get an early start

US national guidelines urge everyone over age 20 to have their cholesterol checked at least once every five years, and more often for those with risk factors for heart disease such as excess weight, smoking, high blood pressure, and a family history of early heart disease. In reality, though, cholesterol isn't on the radar for most people until middle age. The work with PCSK9 and other genes that influence LDL suggest that it should be.

Science magazine asked Michael Brown and Joseph Goldstein, who won the 1985 Nobel Prize in medicine for making the molecular link between LDL and atherosclerosis, to write a commentary on the PCSK9 findings. They noted that heart disease deaths are directly related to average LDL levels. Data from a classic study of heart disease in seven countries show a low of about 7 coronary heart disease deaths per 1,000 people in Japan, where at the time of the study the average LDL was under 100 mg/dL, up to about 50 per 1,000 in Finland, where the average LDL was around 180 mg/dL.

Brown and Goldstein argued that preventing heart disease means controlling LDL before atherosclerosis gets a chance to do much damage. Starting early means you could get a big benefit from keeping LDL at or around 100 mg/dL, rather than trying to drive it down to 70 or below as is now the case for people with heart disease.

It's certainly possible to maintain LDL under 100 mg/dL. Starting a statin or other cholesterol-lowering drug early in life is one option, especially now that there are powerful, less expensive generic statins on the market. But a lifetime of drug therapy isn't an appealing option. There's also a drug-free option, and it will help more than just your cholesterol. It starts with a good diet. The essential elements are choosing foods low in saturated and trans fats, those with whole grains instead of highly refined grains, and plenty of fruits and vegetables. Exercising and maintaining a healthy weight are also key strategies.

This article is provided courtesy of Harvard Medical International. © 2007 President and Fellows of Harvard College.

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