High-Density Lipoprotein Cholesterol, High-Density Lipoprotein Particle Size, and Apolipoprotein A-I: Significance for Cardiovascular Risk
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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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Epidemiological studies have not provided conclusive evidence that measurement of HDL size contributes to risk prediction.
“Epidemiological studies have not provided conclusive evidence that measurement of HDL size contributes to risk prediction (36, 50 -55).”
From Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline (2012) · cites this paper as [55]
A retrospective study showed that very high concentrations of HDL-C might not be associated with decreased risk.
“Similar to us, a retrospective showed that very high concentrations of HDL-C might be not associated with decreased risk [77].”
From Comparisons of the effects of different flaxseed products consumption on lipid profiles, inflammatory cytokines and anthropometric indices in patients with dyslipidemia related diseases: systematic review and a dose-response meta-analysis of randomized controlled trials (2021) · cites this paper as [77]
Very high concentrations of HDL-C may be associated with increased cardiovascular risk.
“Retrospective investigations of the EPIC Norfolk and of the IDEAL study show that very high concentrations of HDL-C may be associated with increased risk [4].”
From HDL cholesterol: reappraisal of its clinical relevance (2017) · cites this paper as [4]
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- Authors
- van der Steeg, W. A., Holme, I., Boekholdt, S. M., Larsen, M. L., Lindahl, C., Stroes, E. S. G., Tikkanen, M. J., Wareham, N. J., Faergeman, O., Olsson, A. G., Pedersen, T. R., Khaw, K.-T., & Kastelein, J. J. P.
- Affiliations
- Oslo University Hospital (NO)
- Amsterdam UMC Location University of Amsterdam (NL)
- Pfizer (Sweden) (SE)
- Helsinki University Hospital (FI)
- MRC Epidemiology Unit (GB)
- Linköping University Hospital (SE)
- University of Cambridge (GB)
- Corresponding author
- Kastelein, John J.P.
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 51
- Issue
- 6
- Pages
- 634-642
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W1900263313
- Cited by
- 374
- References
- 30
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 10 · 2023: 17 · 2022: 20 · 2021: 29 · 2020: 11 · 2019: 13 · 2018: 19 · 2017: 15 · 2016: 12 · 2015: 22 · 2014: 16 · 2013: 30 · 2012: 28
- FWCI
- 40.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Stroke Association
- Medical Research Council
- European Commission
- British Heart Foundation
- Pfizer
- Wellcome Trust
- Cancer Research UK
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- HDL cholesterol, HDL particle size, apolipoprotein A-I, apolipoprotein B, coronary artery disease, cardiovascular risk, large HDL particles, statin therapy, secondary prevention, IDEAL trial, EPIC-Norfolk study
- MeSH terms
- Aged, Apolipoproteins B, Cardiovascular Diseases, Coronary Artery Disease, Female, Humans, Cholesterol, HDL, Male, Middle Aged, Prospective Studies, Risk Factors, Biomarkers, Case-Control Studies, Apolipoprotein A-I, Risk Assessment, Hydroxymethylglutaryl-CoA Reductase Inhibitors
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