American Association for Clinical Chemistry
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Clinical Laboratory Strategies: August 14, 2008

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Predicting Heart Attack Risk 
More Evidence Suggests Apolipoprotein Ratio Better Than Cholesterol Ratio

By Phil Kibak

Coronary heart disease is a leading killer of men and women worldwide, and its human and economic costs are not confined to developed countries. In 2004 researchers involved with the INTERHEART Study identified nine easily measured risk factors—smoking, lipids, hypertension, diabetes, obesity, diet, physical activity, alcohol consumption, and psychosocial factors—that account for over 90% of the risk of acute myocardial infarction (AMI). This issue of Strategies examines a new analysis of INTERHEART data suggesting that the ratio of apolipoprotein B (apoB) to apolipoprotein A-1 (apoA1) is superior to the ratio of total cholesterol (TC) to high density lipoprotein cholesterol (HDL-C) as a measure of heart attack risk.

The INTERHEART Study, which looked at more than 27,000 people in 52 countries on six continents, examined whether risk factors for AMI have a similar or different impact in people from different ethnic groups and different geographies. It showed that risk factors have a global similarity; however, scientists and clinicians differ on how to assess AMI risk with biochemical markers. The major guideline groups recommend using cholesterol and exclude apolipoproteins from clinical use. However, the American Diabetes Association and the American College of Cardiology have stated that apoB is the test of choice to assess the adequacy of statin treatment and should be used routinely. A newly published study in the Lancet suggests that the apoB:apoA1 ratio accounts for a significantly higher proportion of AMI risk than do elevated cholesterol levels (Lancet 2008;372:224–33).

Assessing Risk

“The major guidelines in preventive cardiology are based on the proposition that LDL cholesterol is the most clinically useful lipoprotein and that the ratio of total cholesterol to HDL cholesterol is an effective predictor of heart attack risk,” explained Matthew McQueen, MD, professor of pathology and molecular medicine at McMaster University in Hamilton, Ont., and lead author of the study. “But we wanted to see if the apoB to apoA1 ratio is an even better predictor of coronary artery disease risk than the established total cholesterol to HDL cholesterol ratio.”

This hypothesis has been the subject of previous investigations, he added, and has led to disputes among scientists and clinicians. “Every molecule of LDL cholesterol contains a molecule of apoB, so clearly there will be associations between the two. But apoB also is found on other atherogenic particles, such as intermediate-density lipoproteins and very-low-density lipoproteins, so a measurement of apoB gives us a better guide to the number of atherogenic particles within a person, McQueen noted. “And if you’re going to try to tease out if one [ratio] is more important than the other, you need a study that has a lot of heart attacks.”

McQueen and his colleagues analyzed non-fasting blood samples from 9,345 people with a first AMI and 12,120 age- and sex-matched control subjects from the INTERHEART Study. They examined concentrations of plasma lipids and lipoproteins, including total cholesterol, HDL-C, LDL-C, apoB and apoA1. In the next step of the analysis, the researchers determined population-attributable risk for each measure and for each ethnic group.

Ethnic groups included Europeans, Chinese, South Asian, other Asian, Latin American, Arab and Persian, black African, other African, and other.

Apolipoprotein Ratio More Potent Risk Predictor

The researchers found that the apoB:apoA1 ratio accounted for 54% of the population attributable risk for AMI while the TC:HDL-C ratio accounted for 32% of that risk. “Not only was the apoB:apoA1 ratio a more powerful measure of the risk of acute MI worldwide; overall, it proved to be a more powerful risk indicator among all ethnic groups being investigated, among men and women and among all age groups,” said McQueen.

The scientists noted that the highest apoB:apoA1 ratios were in South Asians, Arabs and Persians, and Latin Americans for men and women separately and combined. The lowest ratios were in the Chinese and black African populations. When median values for lipids and apolipoproteins were divided into deciles, increases showed a strong association with AMI, with the steepest increase observed for the apoB:apoA1 ratio.

While the data are promising, Lars Lind, MD, professor of medicine at Uppsala University in Sweden, pointed out in an accompanying editorial that “whether some lipid measures do equally well in countries with a lower lipid burden as in developed countries with a traditionally higher lipid intake is not obvious. Thus, the INTERHEART data strongly support increased use of the apolipoproteinB/A1 ratio, but prospective data are also needed to clarify this matter because lipid measurements in case-control studies might be affected by the disease state or treatment initiated before the sampling of blood.” (Lancet 2008; 372:185–6)

Can It Stand Alone?

The tests to determine apolipoprotein levels and the apoB:apoA1 ratio are relatively simple and relatively inexpensive, and they have an advantage over cholesterol testing in that people do not have to fast, explained McQueen. “But when we see patients, we’ll still want to know their other data—total cholesterol, HDL and LDL cholesterol, and triglycerides. The potential here is that once the physician knows how a patient responds to diet, exercise, weight changes, and medication, he can use information from the apoB:apoA1 ratio to guide how aggressive continuing therapy should be. In addition, patients who are frequently monitored and stable may be able to dispense with the entire lipid panel every time blood is drawn for testing, and just have the apolipoprotein measurement,” he said.

G. Russell Warnick, MS, MBA, chief scientific officer and vice president for lab operations at the Berkeley Heart Lab in Berkeley, Calif., agrees that the study provides more evidence for instituting apolipoprotein measurements into routine clinical practice to assess the potential for coronary artery disease. “Right now the only rationale for measuring LDL cholesterol is the historical precedent. But if you look at it objectively, there’s absolutely no question that we would measure apoB.”

Warnick added that he has long advocated changing the guidelines to make apoB equivalent to LDL cholesterol in terms of clinical utility. But, he said, because the demand for apoB assays has so far been limited to research applications, the companies that make the assays have not yet optimized them. “But I think with increasing demand, the companies will invest in R&D to improve them. You can’t do this sort of thing overnight, so it’s probably better to have a gradual transition from LDL cholesterol to apoB as a disease marker. And if we make that shift, it probably would make sense to shift from HDL cholesterol to apoA1.”

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