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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

High-Density Lipoprotein Cholesterol, High-Density Lipoprotein Particle Size, and Apolipoprotein A-I: Significance for Cardiovascular Risk

The IDEAL and EPIC-Norfolk Studies

Wim A. van der Steeg, MD^_*, Ingar Holme, PhD, S. Matthijs Boekholdt, MD, PhD^_*, Mogens Lytken Larsen, MD, DMSc, Christina Lindahl, MD, Erik S.G. Stroes, MD, PhD^_*, Matti J. Tikkanen, MD, PhD^||, Nicholas J. Wareham, MBBS, PhD^¶, Ole Faergeman, MD, DMSc, Anders G. Olsson, MD, PhD^#, Terje R. Pedersen, MD, PhD, Kay-Tee Khaw, MBBChir^_** and John J.P. Kastelein, MD, PhD^_*,_*

^_* Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
Center for Preventive Medicine, Ullevål University Hospital, Oslo, Norway
Department of Medicine-Cardiology A, Århus, Denmark
Pfizer Sweden, Täby, Sweden
^|| Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
^¶ Medical Research Council Epidemiology Unit, Cambridge, United Kingdom
^# Department of Internal Medicine, University Hospital, Linköping, Sweden
^_** Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom.

Manuscript received July 30, 2007; revised manuscript received September 13, 2007, accepted September 24, 2007.

^_* Reprint requests and correspondence: Dr. John J. P. Kastelein, Academic Medical Center, Department of Vascular Medicine, Room F4-159.2, P. O. Box 22660, 1100 DD, Amsterdam, the Netherlands. (Email: j.j.kastelein{at}amc.uva.nl).

Objectives: This study was designed to assess the relationship of high-density-lipoprotein cholesterol (HDL-C), HDL particle size, and apolipoprotein A-I (apoA-I) with the occurrence of coronary artery disease (CAD), with a focus on the effect of very high values of these parameters.

Background: High plasma levels of HDL-C and apoA-I are inversely related to the risk of CAD. However, recent data suggest that this relationship does not hold true for very high HDL-C levels, particularly when a preponderance of large HDL particles is observed.

Methods: We conducted a post-hoc analysis of 2 prospective studies: the IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering; n = 8,888) trial comparing the efficacy of high-dose to usual-dose statin treatment for the secondary prevention of cardiovascular events, and the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk case-control study, including apparently healthy individuals who did (cases, n = 858) or did not (control patients, n = 1,491) develop CAD during follow-up. In IDEAL, only HDL-C and apoA-I were available; in EPIC-Norfolk, nuclear magnetic resonance spectroscopy-determined HDL particle sizes were also available.

Results: In the IDEAL study, higher HDL-C proved a significant major cardiac event risk factor following adjustment for age, gender, smoking, apoA-I, and apoB. A similar association was observed for HDL particle size in EPIC-Norfolk. Increased risk estimates were particularly present in the high ends of the distributions. In contrast, apoA-I remained negatively associated across the major part of its distribution in both studies.

Conclusions: When apoA-I and apoB are kept constant, HDL-C and HDL particle size may confer risk at very high values. This does not hold true for very high levels of apoA-I at fixed levels of HDL-C and apoB. These findings may have important consequences for assessment and treatment of CAD risk.

Abbreviations and Acronyms   ApoA-I = apolipoprotein A-I   ApoB = apolipoprotein B   CAD = coronary artery disease   CETP = cholesteryl ester transfer protein   HDL-C = high-density lipoprotein cholesterol   LDL-C = low-density lipoprotein cholesterol   MCE = major coronary event   MI = myocardial infarction   NMR = nuclear magnetic resonance   OR = odds ratio   RR = relative risk

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