ApoB, but not LDL particle size, provides predictive value in assessment of risk

March 30, 2006

Montreal, QC - Two new studies published in the April 1, 2006 issue of the American Journal of Cardiology evaluate whether any additional information can be gleaned from LDL particle size and apolipoprotein B (ApoB) for the prediction of fatal MI and coronary heart disease risk.

In the first study, led by Dr Annie St-Pierre (Laval University, Ste-Foy, Quebec), researchers investigated the extent to which ApoB added any prognostic information on the long-term risk of coronary heart disease in men. Using data from the Quebec Cardiovascular Study, investigators found that ApoB levels improved the ability to predict incident heart disease in patients with high LDL-cholesterol levels [1].

"While we recognize that LDL cholesterol is a very important risk factor, it is not perfect," Dr Beno î t Lamarche (Laval University) told heart wire . "There are a lot of people who have heart disease who don't necessarily have high LDL-cholesterol levels. Among those with high LDL-cholesterol levels, not all of them will go on to develop heart disease. This is a question of trying to refine our ability to assess risk in any given individual. While ApoB does correlate quite strongly with LDL cholesterol, there is some discordance between the two variables, and we believe that measuring ApoB on top of LDL could be of value for assessing future heart-disease risk."

Lamarche and colleagues conducted the analysis in a cohort of 2072 men aged 35 to 64 years who were free from incident coronary heart disease at baseline and who had a full metabolic and risk-factor profile. With a follow-up of 13 years, 173 subjects had a nonfatal MI and 57 subjects had a fatal coronary event.

Investigators found that subjects with increased plasma ApoB levels—those in the highest tertile—had a 90% increased risk of CHD compared with those with lower plasma ApoB levels. High plasma LDL was also associated with a twofold greater risk of heart disease after adjustment for lipid and nonlipid risk factors.

Investigators then looked at the combined effect of variations in ApoB and LDL-cholesterol levels and found that ApoB modulated the risk of CHD associated with variations in LDL-cholesterol concentrations. Among men with high LDL-cholesterol levels (>4.3 mmol/L, approximately 166 mg/dL), patients with an ApoB level <128 mg/dL were not at an additional increased risk of heart disease. However, among those with high LDL-cholesterol and high ApoB levels (>128 mg/dL), there was a significant twofold increase in the risk of CHD beyond that conferred by elevated LDL-cholesterol levels.

Lamarche noted that the findings show that future risk of heart disease is not homogenous across the entire cohort of individuals with elevated LDL-cholesterol levels. As it is those with elevated ApoB levels who appear to be at greater risk, the information can help clinicians who need more information to determine the overall cardiovascular risk of the patient.

"It's a question of how far you want to go in terms of defining risk," said Lamarche. "You could obviously stop after measuring LDL cholesterol or after using the Framingham risk algorithm, but these data show that a simple measurement of ApoB can go further in assessing risk in certain individuals."

As previously reported by heart wire , some experts have questioned whether the predictive gains of ApoB are worth the significantly greater cost. It has been pointed out that LDL-cholesterol testing is inexpensive and non-HDL cholesterol is already listed as secondary target in cholesterol guidelines. Lamarche said elderly patients with elevated LDL-cholesterol levels as the only risk factor for CHD might be good candidates for ApoB testing, as this would help clinicians gauge how aggressively to treat.

Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) told heart wire that with the price of assay coming down and the test becoming more standardized, it is reasonable to use ApoB when triglyceride levels are greater than 130 mg/dL, a range when the calculated LDL cholesterol is not as accurate.

The investigators did not address the increased predictive value of ApoB over other lipid measures, such as non-HDL cholesterol.

Small, dense LDL particles not predictive of risk

In the second study, led by Dr Ingmar Jungner (Karolinska Institute, Stockholm, Sweden), investigators performed an updated analysis of the Apolipoprotein-Related Mortality Risk (AMORIS) study, an analysis that included 125 000 male and female subjects followed for over 10 years [2]]. In AMORIS, baseline ApoA-1 and ApoB serum levels and the ApoB/ApoA-1 ratio were all predictive of future cardiac risk, providing predictive information beyond conventional risk factors, including total cholesterol and triglycerides[3].

The purpose of this most recent analysis was to determine whether LDL particle size influenced the risk of fatal MI and, if so, whether this was independent of atherogenic particle number as measured by ApoB and if it was independent of the ApoB/ApoA-1 ratio, the strongest determinant of risk in AMORIS.

In their paper, the authors point out that many in vitro studies have shown that small, dense LDL particles might be more atherogenic than large, buoyant particles, a finding that is supported by some cross-sectional and case-control studies. In many of these studies, however, the small, dense LDL cholesterol fails to predict future cardiovascular risk after multivariate analysis, likely because small, dense LDL are often associated with other atherogenic findings, such as hypertriglyceridemia and low HDL-cholesterol levels.

With the LDL-cholesterol/ApoB ratio used as a surrogate for LDL particle size, there was an inverse relationship between the risk of fatal MI and the LDL-cholesterol/ApoB ratio after adjustment for age and gender, indicating that risk increases as LDL size decreases. When adjusted for triglycerides, however, the relationship was no longer statistically significant.

There was also a statistically significant 34% increase in risk of nonfatal MI with increasing ApoB levels after adjustment for age and gender. When investigators examined the relationship between ApoB levels and risk of MI after adjusting for the LDL-cholesterol/ApoB ratio, there was no change in risk, "indicating that the effect of LDL size on risk is no longer significant once ApoB is taken into account," report Jungner and colleagues. When investigators plotted the relationship between the ApoB/ApoA-1 ratio and risk of nonfatal MI, there was a 41% increase in risk, greater than the 34% observed with ApoB alone, indicating that ApoA-1, but not LDL particle size, adds significant predictive power to ApoB.

In this analysis, the investigators did not evaluate the predictive strength of ApoB/ApoA-1 over other ratios, such as the total/HDL-cholesterol or LDL/HDL-cholesterol ratios.

Silencing the ApoB gene

Moving away from risk prediction, a new study, published online March 26, 2006 in Nature, has highlighted the potential for one day creating a class of drugs to specifically target ApoB [4]. Scientists at Alnylam Pharmaceuticals and Protiva Biotherapeutics have been able to utilize RNA interference (RNAi) to silence the ApoB gene in the liver, thus disrupting the protein that plays a critical role in the assembly and secretion of very-low-density lipoprotein (vLDL) and LDL cholesterol.

Led by Dr Tracy Zimmermann (Alnylam Pharmaceuticals Inc, Cambridge, MA), researchers used small interfering RNA (siRNA) to target the ApoB gene of monkeys. The siRNAs were delivered systemically by encapsulating the molecules in stable nucleic-acid lipid particles. One single siRNA intravenous injection resulted in a dose-dependent silencing of ApoB messenger-RNA expression in the liver 48 hours after administration.

More important, there was a significant 75% reduction in ApoB levels, a 60% reduction in serum cholesterol, and a more than 80% reduction in LDL-cholesterol levels. These effects were observed as early as 24 hours after treatment and lasted for 11 days after the single injection. There were no treatment-related effects, except for a transient increase in liver enzymes in the monkeys that received the highest dose.

According to Zimmermann and colleagues, the study highlights the potential for therapeutic gene silencing using systemic RNAi in humans, and the rapid and long-lasting silencing of ApoB using RNAi might represent a new strategy for reducing LDL cholesterol in various clinical settings.


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