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.



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High plasma levels of high-density lipoprotein cholesterol (HDL-C) are inversely related to the risk of coronary artery disease (CAD).[6,7] For apolipoprotein A-I (apo A-I), which is the main protein constituent of the HDL particle, identical results have been reported.[8] These observations have led to the development of novel therapies that raise plasma levels of HDL-C or apoA-I in order to further decrease risk of CAD.

Recently, a couple of clinical studies were published, evaluating the effect of elevation of plasma HDL-C levels via torcetrapib, which is an inhibitor of the cholesteryl ester transfer protein.[9,10,11,12] In these studies, considerable increases of plasma HDL-C and apoA-I were observed in patients receiving torcetrapib. Nevertheless, torcetrapib did not induce the expected regression of atherosclerosis. In fact, an increase of atherosclerosis was observed.

As extensively discussed in literature, this unexpected outcome is hypothesized to relate to the rise of systolic blood pressure observed in patients receiving torcetrapib. However, a second possible explanation pertains to the structural changes of the HDL particle induced by CETP inhibition. In fact, it has been hypothesised that the very large HDL particles, which become predominant when HDL-C levels rise upon CETP inhibition, may be less effective in exerting antiatherogenic functions.

This would suggest that the previously reported inverse relationships of HDL-C and apo A-I with CAD do not hold true for very high levels of these parameters. Therefore, the present study was conducted to reassess the relationship of HDL-C, HDL particle size and apo A-I with the occurrence of CAD, with a focus on the effect of very high values of these parameters.

To accomplish this, we performed a post-hoc analysis of two prospective studies: the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trial (n=8,888) comparing the efficacy of high-dose to usual-dose statin treatment for the secondary prevention of cardiovascular events,[4] and the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk case-control study, including apparently healthy individuals who did (cases, n=858) or did not (controls, n=1,491) develop CAD during follow-up.[4] In IDEAL, only HDL-C and apo A-I were available; in EPIC-Norfolk, HDL particle sizes determined by nuclear magnetic resonance (NMR) were also available.

The occurrence of a major adverse coronary event (MACE) was selected as the outcome variable for this analysis. In the IDEAL study, this was the primary endpoint, defined as coronary death, non-fatal myocardial infarction, or resuscitation after cardiac arrest. In EPIC-Norfolk, MACE included fatal or nonfatal CAD, defined as codes 410-414 according to the International Classification of Diseases, 9th revision.

In the IDEAL dataset, the relationships of HDL-C and apo A-I with MACE were calculated by a Cox proportional hazards model, yielding values for relative risk (RR) for a one standard deviation (SD) increase of HDL-C or apo A-I. The basic regression model included covariates for age, sex, and smoking status (current, former, never) recorded at baseline. Body mass index (BMI) was not taken into account because this parameter did not significantly contribute to the regression models. Data on alcohol consumption were not available in the IDEAL database.

In EPIC-Norfolk, the relationships of HDL-C, HDL particle size, and apo A-I with MACE were determined by conditional logistic regression analysis that took into account the matching for age, gender, and enrollment period, and included the covariates smoking status (current, former, never), BMI, and alcohol consumption (number of units per week) (basic model). MACE risk estimates were expressed as odds ratios (OR) for a one SD increase of HDL-C, HDL particle size, or apo A-I, with 95% confidence intervals.

When HDL-C and HDL particle size were evaluated, the regression models were additionally adjusted for confounding by apo A-I. When apo A-I was evaluated, additional adjustment was performed for HDL-C or HDL particle size. Finally, all statistical models included apo B to account for differences in the proatherogenic lipoprotein fraction.

In the IDEAL study, we observed that plasma levels of HDL-C were indeed inversely related to MACE following adjustment for the basic covariates as well as for apo A-I and apo B. However, at very high levels of HDL-C (≥70 mg/dL), this inverse relationship disappeared. In fact, HDL-C turned out to be a statistically significant risk factor at these high values.

Identical results were obtained for HDL particle size in EPIC-Norfolk. This parameter was inversely related to the occurrence of MACE, but turned to a significant risk factor in the tail of its distribution upon adjustment for the basic covariates and apo A-I and apo B. In contrast, apo A-I remained negatively associated across the major part of its distribution in both studies.

These data demonstrate that when apoA-I and apoB are kept constant, HDL-C and HDL particle size may confer risk at very high values. This may suggest that the unexpected outcome of the torcetrapib trials indeed results from factors related to the induced increase of HDL-C or the size of this lipoprotein. However, additional studies are required to further substantiate this hypothesis.

There is no clear biological explanation how HDL can become proatherogenic. This only permits speculation when it comes to biological mechanisms for our observations. First, some of the exchange of cholesterol esters between HDL and peripheral cells is known to be bidirectional, in part mediated by the scavenger receptor class B1.[13]

This observation gives rise to the hypothesis that very large HDL, which are cholesterol enriched, may at some point become a cholesterol donor instead of an acceptor. Second, although it has widely been acknowledged that the anti-inflammatory capacity of HDL contributes to its antiatherogenic potency, several studies have demonstrated that HDL can also turn into a proinflammatory particle.[14] Possibly, via these two latter mechanisms, a very high plasma concentration of large HDL particles might in fact induce a proatherogenic lipoprotein profile. However, whether any of these two mechanisms has any physiological relevance in humans needs certainly to be confirmed in further studies.

Guidelines: Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.

Grundy SM, Cleeman JI, Merz CN; Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:720-32.


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