College of American Pathologists
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July 2002

Anne Paxton

Are fully automated tests for the direct measurement of low-density lipoprotein cholesterol the way to go?

Atherotech thinks so. The Birmingham, Ala.-based company promotes its test as a sizable improvement over the routine calculation approach because it offers direct LDL measurement as opposed to traditional measurement, which calculates LDL based on directly measured total cholesterol, HDL, and triglycerides, or the Friedewald equation.

"The problem with the Friedewald LDL is that it gives you a falsely low LDL. The higher the triglycerides, the more falsely low this calculated LDL gets. Most clinicians know that when the triglycerides are 400, they don’t even report an LDL anymore," says Richard Lanman, MD, chief medical officer for Atherotech. "But what most doctors don’t realize is that at 200, there still might be five to 10 percent falsely low calculated LDL results."

Atherotech’s VAP II (vertical auto profile) technology measures two characteristics of lipoproteins—density and cholesterol content—using a combination of ultracentrifugation and spectrophotometry. The technology was developed in the early to mid-1990s, says Dr. Lanman, and is innovative for its ability to measure the cholesterol in seven HDL subclasses, four LDL subclasses, and three very-low-density lipoprotein subclasses.

Dr. Lanman reports that the PROCAM study (Prospective Cardiovascular M√ľnster Study) has found that adding direct measurement of LDL (as the VAP II does), adding also Lp(a), and including family history of premature heart disease in traditional testing can increase the detection rate to 83 percent. By including information on the size and density of LDL particles, 90 percent is closer to the mark, he says.

Small/dense LDL particles are more atherogenic than just having a high LDL cholesterol reading, he says, noting that half the men who have heart attacks have a small/dense LDL—a fact that would not be revealed by a traditional lipid panel. "If you know the LDL particles are small and dense, you can add 15 to 20 percent to the detection rate over the 30-year-old traditional lipid panel," he says.

The VAP test includes measures of the remnant lipoproteins IDL (intermediate-density lipoprotein) and VDL3 (small/dense VLDL). These particles also are highly atherogenic. ATP III mentions that Lp(a) and remnant lipoproteins may be an emerging risk factor to help guide treatment decisions. "If you combine several key risk markers—direct LDL, Lp(a), small/dense LDL pattern, IDL, HDL2—you can raise your ability to detect risk to 90 percent from 50 percent with the traditional panel," Dr. Lanman says.

For people with an indication for a comprehensive evaluation of heart disease risk, this should be the test of choice, he adds. "The people we’re studying are the very patients whose calculated LDLs would be falsely low because of triglycerides, so they are being underdetected and undertreated."

But the test could also be valuable for people at age 20 who have no apparent risk factors. "A lot of heart scans won’t be positive until relatively late in the development of atherosclerosis," says Dr. Lanman. "So let’s say you’re 20 and want to know how seriously you should diet and exercise. With your VAP panel, you might find an abnormality and know you’re at higher risk. It’s a very inexpensive way to understand who needs to get serious about diet and lifestyle."

Herbert Naito, PhD, of the Veterans Affairs Medical Center, Cleveland, believes the new cutpoints for HDL in the ATP III report are important. "But I think where we have a misunderstanding going on in the medical community is the role of triglycerides and LDL cholesterol in ruling out metabolic disease," he says. "I think it’s very important and very complicated, and the medical community has misunderstood it and not used the tests accurately." Atherotech’s system, he adds, addresses that measure because it guides clinicians through the process of ruling out metabolic syndrome, a prediabetes-like condition.

Atherotech doubled and redoubled in size last year as it began marketing its commercialized version of the test, which has been scaled down to make the cost comparable to a traditional lipid panel. The test is covered by Medicare at a payment of about $49 per panel and under a national agreement with Blue Cross Blue Shield at $68.