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Association of Small Low-Density Lipoprotein Particles With the Incidence of Coronary Artery Disease in Men and Women
Abstract
OBJECTIVE: To investigate the prospective association of low-density lipoprotein (LDL) particle diameter with the incidence of fatal and nonfatal coronary artery disease (CAD). DESIGN: A nested case-control study. SETTING: Cases and controls were identified from a population-based sample of men and women combining all of the 5 cross-sectional surveys conducted from 1979 to 1990 of the Stanford Five-City Project (FCP). PARTICIPANTS: Incident CAD cases were identified through FCP surveillance between 1979 and 1992. Controls were matched by sex, 5-year age groups, survey time point, ethnicity, and FCP treatment condition. The sample included 124 matched pairs: 90 pairs of men and 34 pairs of women. MAIN OUTCOME MEASURES: LDL peak particle diameter (LDL size) was determined by gradient gel electrophoresis on plasma samples collected during the cross-sectional surveys (stored at 70 degrees C for 5-15 years). Established CAD risk-factor data were available from FCP baseline measurements. RESULTS: LDL size was smaller among CAD cases than controls (mean +/- SD) (26.17 +/- 1.00 nm vs 26.68 +/- 0.90 nm; P<.001). The association was graded across control quintiles of LDL size. The significant case-control difference in LDL size was independent of levels of high-density lipoprotein cholesterol (HDL-C), non-HDL cholesterol (non-HDL-C), triglyceride, smoking, systolic blood pressure, and body mass index, but was not significant after adjusting for the ratio of total cholesterol (TC) to HDL-C (TC:HDL-C). Among all the physiological risk factors, LDL size was the best differentiator of CAD status in conditional logistic regression. However, when added to the physiological parameters above, the TC:HDL-C ratio was found to be a stronger independent predictor of CAD status. CONCLUSION: LDL size was significantly smaller in CAD cases than in controls in a prospective, population-based study. These findings support other evidence of a role for small, dense LDL particles in the etiology of atherosclerosis.
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“the reduction in ratio of total to HDL cholesterol, which has been identified as a predictor of coronary heart disease (35), was not significantly different between the 2 diets.”
From Effects of Low-Carbohydrate Diets Versus Low-Fat Diets on Metabolic Risk Factors: A Meta-Analysis of Randomized Controlled Clinical Trials (2012) · cites this paper as [35]
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Razquín, C., Toledo, E., Clish, C. B., Ruiz‐Canela, M., Dennis, C., Corella, D., Papandreou, C., Ros, E., Estruch, R., Guasch‐Ferré, M., et al. (2018) · Diabetes Care · doi:10.2337/dc18-0840 · Cited by 212
Low-density lipoprotein particle number and risk for cardiovascular disease
Cromwell, W. C., & Otvos, J. D. (2004) · Current Atherosclerosis Reports · doi:10.1007/s11883-004-0050-5 · Cited by 198
Roche, H. M., & Gibney, M. J. (2000) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/71.1.232s · Cited by 195
Sattar, N. A., Greer, I. A., Louden, J., Lindsay, G., McConnell, M., Shepherd, J., & Packard, C. J. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.8.4126 · Cited by 193
“Furthermore, recently reported prospective studies have demonstrated that the presence of small, dense LDL particles precedes CHD (15, 16 ) and predicts the development of noninsulin dependent diabetes mellitus (17).”
BackgroundDiagnosis, prevention, and intervention for the metabolic syndrome
SCOTT, C. L. (2003) · The American Journal of Cardiology · doi:10.1016/s0002-9149(03)00507-1 · Cited by 193
Tribble, D. L., Rizzo, M., Chait, A., Lewis, D. M., Blanche, P. J., & Krauss, R. M. (2001) · The American Journal of Medicine · doi:10.1016/s0002-9343(00)00700-2 · Cited by 185
Strawberries decrease atherosclerotic markers in subjects with metabolic syndrome
Basu, A., Fu, D. X., Wilkinson, M., Simmons, B. N., Wu, M., Betts, N. M., Du, M., & Lyons, T. J. (2010) · Nutrition Research · doi:10.1016/j.nutres.2010.06.016 · Cited by 192
“Distribution of lipoprotein sub-class profiles, such as variations in concentrations of small, medium and large particles, not reflected in conventional lipid analyses, has been inversely associated with vascular complications in diabetes and atherosclerosis [22,23].”
Lipoprotein atherogenicity: an overview of current mechanisms
Griffin, B. A. (1999) · Proceedings of The Nutrition Society · doi:10.1079/pns19990022 · Cited by 182
“There is now prospective evidence to show that small dense LDL is as predictive of CHD as many of the more traditional risk factors such as smoking and blood pressure (Gardner et al. 1996; Stampfer et al. 1996).”
BackgroundDevelopment of a Homogeneous Assay for Measurement of Small Dense LDL Cholesterol
Ito, Y., Fujimura, M., Ohta, M., & Hirano, T. (2010) · Clinical Chemistry · doi:10.1373/clinchem.2010.149559 · Cited by 181
Dietary Fats and Health: Dietary Recommendations in the Context of Scientific Evidence
Lawrence, G. D. (2013) · Advances in Nutrition · doi:10.3945/an.113.003657 · Cited by 178
“It was later found that LDL particle size was also significantly smaller in men with CAD than in case-matched controls (27), although another study showed the ratio of total serum cholesterol to HDL-C was a better predictor of CAD risk than LDL particle size (28).”
ResultCharbonnel, B., Schernthaner, G., Brunetti, P., Matthews, D. R., Urquhart, R., Tan, M. H., & Hanefeld, M. (2005) · Diabetologia · doi:10.1007/s00125-005-1751-1 · Cited by 170
“Compositional alterations in LDL particles can be potentially atherogenic [31–34].”
Bittner, V., Hardison, R., Kelsey, S. F., Weiner, B. H., Jacobs, A. K., & Sopko, G. (2002) · Circulation · doi:10.1161/01.cir.0000038496.57570.06 · Cited by 168
Lipids and Glucose in Type 2 Diabetes
Boden, G. H., & Laakso, M. (2004) · Diabetes Care · doi:10.2337/diacare.27.9.2253 · Cited by 168
“Some (3,4) but not all (5) studies have demonstrated that increased levels of small, dense LDL are associated with an elevated risk of cardiovascular disease.”
BackgroundThe effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism
Clifton-Bligh, P. B., Baber, R., Fulcher, G., Nery, M.-L., & Moreton, T. (2001) · Menopause The Journal of The North American Menopause Society · doi:10.1097/00042192-200107000-00007 · Cited by 166
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“The human IR phenotype is characterized by accumulation of small dense LDL particles as opposed to large LDL particles (Carr et al. 1999; Gardner et al. 1996; Kohen-Avramoglu et al. 2003) and by suppression of large HDL particles (Brown et al. 1990; Deeb et al. 2003; Garvey et al. 2003; Goff et al.…”
BackgroundDavy, B. M., Davy, K. P., Ho, R. C., Beske, S. D., Davrath, L. R., & Melby, C. L. (2002) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/76.2.351 · Cited by 161
“An elevated LDL particle number, often indicated by high apolipoprotein B concentrations, has also been linked to an increased CAD risk (8, 13).”
BackgroundInfluentialSystematic review: association of low-density lipoprotein subfractions with cardiovascular outcomes.
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“…case–control 68 70 100 17 63 (ever smoked) LDL-c: 142 mg/dL Mykkänen et al, 1999 (27) GE Nested case–control 69 100 50 33 20 (current) TC–HDL-c ratio: 6.09 Gardner et al, 1996 (26) GE Nested case–control 59 33 73 No data 42 (not defined) Non–HDL-c: 176 mg/dL CAD coronary artery disease; CHD…”
InfluentialGazi, I. F., Lourida, E. S., Filippatos, T. D., Tsimihodimos, V., Elisaf, M., & Tselepis, A. D. (2005) · Clinical Chemistry · doi:10.1373/clinchem.2005.058404 · Cited by 162
Fernández, M. L., & Volek, J. S. (2006) · Nutrition & Metabolism · doi:10.1186/1743-7075-3-17 · Cited by 162
“Small dense LDL particles classified as pattern B are associated with a much higher risk for cardiovascular disease [ 51 ], thus this important feature of carbohydrate restriction in increasing the size of LDL is quite beneficial, specifically for patients with the metabolic syndrome and type II diabetes, which have a…”
BackgroundNovel Risk Factors for Atherosclerosis
Kullo, I. J., Gau, G. T., & Tajik, A. J. (2000) · Mayo Clinic Proceedings · doi:10.4065/75.4.369 · Cited by 160
Statin-fibrate combination therapy for hyperlipidaemia: a review
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Unfavorable lipid profile in women with endometriosis
Melo, A. S., Rosa-e-Silva, J. C., Rosa-e-Silva, A. C. J. D. S., Poli-Neto, O. B., Ferriani, R. A., & Vieira, C. S. (2010) · Fertility and Sterility · doi:10.1016/j.fertnstert.2009.08.043 · Cited by 143
März, W., Scharnagl, H., Winkler, K., Tiran, A., Nauck, M., Boehm, B., & Winkelmann, B. (2004) · Circulation · doi:10.1161/01.cir.0000146898.06923.80 · Cited by 143
Dreon, D. M., Fernstrom, H. A., Williams, P. T., & Krauss, R. M. (1999) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/69.3.411 · Cited by 149
Metadata
- Authors
- Gardner, C. D.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Gardner, Christopher D.
- Venue
- JAMA: The Journal of the American Medical Association
- Publisher
- American Medical Association (AMA)
- Published
- 1996-09-18
- Volume
- 276
- Issue
- 11
- Pages
- 875
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2050758709
- Cited by
- 843
- References
- 53
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 10 · 2022: 10 · 2021: 16 · 2020: 23 · 2019: 14 · 2018: 7 · 2017: 16 · 2016: 10 · 2015: 23 · 2014: 14 · 2013: 33 · 2012: 22
- FWCI
- 37.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01hl018574-26, 5r01hl021906-19)
- National Heart, Lung, and Blood Institute (T32HL007034, HL21906, HL-18574, 5 T32 HL07034)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- small dense LDL, LDL particle size, coronary artery disease, atherosclerosis, cardiovascular risk factors, TC/HDL-C ratio, HDL cholesterol, non-HDL cholesterol, triglycerides, sex differences
- MeSH terms
- Adult, Aged, Coronary Disease, Cross-Sectional Studies, Electrophoresis, Polyacrylamide Gel, Female, Humans, Lipids, Lipoproteins, LDL, Male, Middle Aged, Prospective Studies, Risk Factors, Body Mass Index, Incidence, Linear Models, Logistic Models, Case-Control Studies
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