High-Density Lipoprotein Particle Size and Concentration and Coronary Risk

  1. Karim El Harchaoui, MD;
  2. Benoit J. Arsenault, MSc;
  3. Remco Franssen, MD;
  4. Jean-Pierre Després, PhD;
  5. G. Kees Hovingh, MD, PhD;
  6. Erik S.G. Stroes, MD, PhD;
  7. James D. Otvos, PhD;
  8. Nicholas J. Wareham, MBBS, PhD;
  9. John J.P. Kastelein, MD, PhD;
  10. Kay-Tee Khaw, MBBChir; and
  11. S. Matthijs Boekholdt, MD, PhD
  1. From the Academic Medical Center, Amsterdam, the Netherlands; Quebec Heart Institute, Hôpital Laval Research Centre, Quebec City, Quebec, Canada; LipoScience, Raleigh, North Carolina; Medical Research Council Epidemiology Unit and Institute of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

    Abstract

    Background: High-density lipoprotein (HDL) cholesterol levels are inversely related to risk for coronary artery disease (CAD). Because HDL particles are heterogeneous in size and composition, they may be differentially associated with other cardiovascular risk factors and with cardiovascular risk.

    Objective: To study the independent relationships of HDL size and particle concentration to risk for future CAD.

    Design: Nested case–control study within the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk cohort; baseline survey between 1993 and 1997, follow-up until November 2003.

    Setting: Norfolk, United Kingdom.

    Participants: Case patients were 822 apparently healthy men and women who developed CAD during follow-up. Control participants were 1401 participants who remained without CAD and were matched to case patients by sex, age, and enrollment time.

    Measurements: First CAD event leading to either hospitalization or death.

    Results: Nuclear magnetic resonance spectroscopy–measured HDL particle concentration (mean, 33.9 μmol/L [SD, 5] vs. 32.9 μmol/L [SD, 6]; P < 0.001) and HDL size (mean, 8.9 nm [SD, 0.5] vs. 8.8 nm [SD, 0.5]; P < 0.001), as well as gradient gel electrophoresis–measured HDL size (mean, 8.9 nm [SD, 0.4] vs. 8.8 nm [SD, 0.4]; P = 0.005) were lower in case patients than in control participants. High-density lipoprotein size and HDL particle concentration were only weakly correlated (r = 0.08, for those measured with nuclear magnetic resonance spectroscopy; r = 0.10, for those measured with gradient gel electrophoresis). High-density lipoprotein size was strongly associated with risk factors characteristic of the metabolic syndrome, including waist-to-hip ratio, triglyceride level, and apolipoprotein B level, whereas HDL particle concentration was not. Both HDL size and HDL particle concentration were independently associated with CAD risk. The association between HDL size and CAD risk was abolished on adjustment for apolipoprotein B and triglyceride levels (adjusted odds ratio, 1.00 [95% CI, 0.71 to 1.39] for top vs. bottom quartile), whereas HDL particle concentration remained independently associated with CAD risk (adjusted odds ratio, 0.50 [CI, 0.37 to 0.66]).

    Limitation: Measurements were performed in nonfasting blood samples, and residual confounding cannot be excluded.

    Conclusion: Both HDL size and HDL particle concentration were independently associated with other cardiovascular risk factors and with the risk for CAD. The relationship between HDL size and CAD risk was explained by markers associated with the metabolic syndrome, indicating that part of the relationship between HDL cholesterol and CAD risk is merely a reflection of this metabolic risk.

    Funding: The Medical Research Council and Cancer Research UK, the European Union, Stroke Association, British Heart Foundation, United Kingdom Department of Health, Food Standards Agency, the Wellcome Trust, and the Future Forum.

    Article and Author Information

    • Grant Support: By program grants from the Medical Research Council and Cancer Research UK, with additional support from the European Union, Stroke Association, British Heart Foundation, United Kingdom Department of Health, Food Standards Agency, and the Wellcome Trust. An educational grant from the Future Forum funded part of the lipid and apolipoprotein measurements described in this article.

    • Potential Financial Conflicts of Interest: Employment: J.D. Otvos (LipoScience). Consultancies: E.S.G. Stroes (AstraZeneca, Novartis, Roche, JSIS, Merck), J.J.P. Kastelein (Pfizer, AstraZeneca, Merck, Schering-Plough, Roche, JSIS, Novartis). Honoraria: E.S.G. Stroes (AstraZeneca, Novartis, Roche, JSIS, Merck), J.J.P. Kastelein (Pfizer, AstraZeneca, Merck, Schering-Plough, Roche, JSIS, Novartis). Stock ownership or options (other than mutual funds): J.D. Otvos (LipoScience).

    • Reproducible Research Statement: Study protocol: Available from the EPIC-Norfolk team (e-mail, epic{at}srl.cam.ac.uk). Statistical code: Analytic syntaxes used to generate the results are available from Dr. Boekholdt (e-mail, s.m.boekholdt{at}amc.uva.nl). Data set: The complete EPIC-Norfolk database is not open access. However, limited data sets can be released to collaborators with written agreements (e-mail, s.m.boekholdt{at}amc.uva.nl).

    • Requests for Single Reprints: S. Matthijs Boekholdt, MD, PhD, Department of Cardiology, F4-159.2, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, the Netherlands; e-mail, s.m.boekholdt{at}amc.uva.nl.

    • Current Author Addresses: Drs. El Harchaoui, Franssen, Hovingh, Stroes, and Kastelein: Department of Vascular Medicine, F4-159.2, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

    • Mr. Arsenault and Dr. Després: Pavilion Marguerite D'Youville, 4th Floor, 2725 Chemin Sainte-Foy, Québec G1V 4G5, Canada.

    • Dr. Otvos: LipoScience, Inc., 2500 Sumner Boulevard, Raleigh, NC 27616.

    • Dr. Wareham: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Box 285, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom.

    • Dr. Khaw: Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital Box 251, Hills Road, Cambridge CB2 2QQ, United Kingdom.

    • Dr. Boekholdt: Department of Cardiology, F4-159.2, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, the Netherlands.

    • Author Contributions: Conception and design: E.S.G. Stroes, K.T. Khaw, S.M. Boekholdt.

    • Analysis and interpretation of the data: K. El Harchaoui, B.J. Arsenault, R. Franssen, J.P. Després, J.D. Otvos, J.J.P. Kastelein, K.T. Khaw, S.M. Boekholdt.

    • Drafting of the article: K. El Harchaoui, S.M. Boekholdt.

    • Critical revision of the article for important intellectual content: B.J. Arsenault, R. Franssen, J.P. Després, G.K. Hovingh, E.S.G. Stroes, J.D. Otvos, J.J.P. Kastelein, K.T. Khaw.

    • Final approval of the article: G.K. Hovingh, E.S.G. Stroes, J.D. Otvos, K.T. Khaw, S.M. Boekholdt.

    • Provision of study materials or patients: K.T. Khaw.

    • Statistical expertise: S.M. Boekholdt.

    • Obtaining of funding: K.T. Khaw.

    • Administrative, technical, or logistic support: B.J. Arsenault, J.P. Després, J.J.P. Kastelein, K.T. Khaw.

    • Collection and assembly of data: B.J. Arsenault, J.P. Després, J.D. Otvos, K.T. Khaw.

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    1. Ann Intern Med January 20, 2009 vol. 150 no. 2 84-93
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