HDL Cholesterol, HDL Particle Size and Apolipoprotein A-I: Significance for Cardiovascular Risk — The IDEAL & EPIC-Norfolk Studies

Wim A. van der Steeg, M.D.; Christopher P. Cannon, M.D., F.A.C.C.



In This Article

Apolipoproteins for Risk Assessment

So, LDL-P may play a useful role in patient management by helping judge the adequacy of LDL-lowering therapy, particularly among those with elevated triglycerides and reduced HDL-C. Such a role also has been proposed for apolipoprotein B (apo B). Indeed, both non-HDL-C and apo B have been proposed as secondary treatment targets after LDL-C goals have been achieved.

A few months after the 2007 JACC study was published, many of the same investigators — this time led by Wim A. van der Steeg, MD — published a paper looking at the role of the apo B-apolipoprotein A-I (apo B-apo A-I) ratio in cardiovascular risk assessment.[2] Prior to this analysis, recent studies had shown that the apo B apoA-I ratio was strongly associated with future CAD. This association and the ability to measure apolipoprotein in nonfasting blood samples had led to recommendations that the apo B-apo A-I ratio be used in routine clinical care,[3] despite the fact that it was not known whether this ratio is better than traditional lipid values for risk assessment and prediction and whether it adds predictive value to the Framingham risk score.

The EPIC-Norfolk investigation was used to select cases, who were apparently healthy men and women (45 to 79 years of age) who developed fatal or nonfatal CAD (n = 869), and controls (n = 1,511), who were persons without CAD and again were matched for age, sex, and enrollment period. (Note: Few people with diabetes and no one using lipid-lowering medication participated in the study.) The apo B-apo A-I ratio was associated with future CAD events, independent of traditional lipid values (adjusted odds ratio, 1.85 [95% CI, 1.15 to 2.98]), including the total cholesterol-HDL-C ratio, and independent of the Framingham risk score (adjusted odds ratio, 1.77 [CI, 1.31 to 2.39]).

However, it did no better than lipid values at discriminating between CAD cases and controls and added little to the predictive value of the Framingham risk score. Moreover, it incorrectly classified 41.1% of cases and 50.4% of controls.

In the February 12th, 2008 issue of JACC, van der Steeg et al. assessed the relationships of plasma HDL-C and HDL particle size with CAD risk, with a particular emphasis on very high values of these parameters.[4] They also evaluated the relationship for apoA-I. This post-hoc analysis used data from the EPIC-Norfolk study as well as the large Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trial (n = 8,888), which compared the efficacy of high-dose to usual-dose statin treatment for the secondary prevention of cardiovascular events (Figure 2).[5] The IDEAL dataset contained data on HDL-C and apoA-I, whereas the EPIC-Norfolk dataset (858 cases, 1,491 control patients) additionally had values of HDL particle size as measured by nuclear magnetic resonance (NMR) spectroscopy.

Figure 2.

Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering (IDEAL)

When researchers adjusted for levels of apo B and apo A-I, very high values of HDL-C (>70 mg/dl) and HDL particle size (>9.5 nm) were associated with increased risk of CAD (Figure 3 and Figure 4). These results suggest that large HDL particles increase cardiac risk, possibly by serving as cholesterol donors rather than scavengers.

Figure 3.

Effect of HDL-C on MACE in the IDEAL Trial

Figure 4.

Effect of HDL-C Particle Size on MCE in the EPIC-Norfolk Trial

This summary, prepared for Cardiosource by Wim A. van der Steeg, MD, of the University of Amsterdam, Amsterdam, Netherlands, discusses this new study in JACC and how the observations may have important consequences for future CAD risk assessment and novel treatment strategies.


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