CLINICAL RESEARCH: CORONARY ARTERY DISEASE
High-Density Lipoprotein Cholesterol, High-Density Lipoprotein Particle Size, and Apolipoprotein A-I: Significance for Cardiovascular RiskThe 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.
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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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