Clinical implications of discordance between low-density lipoprotein cholesterol and particle number

doi:10.1016/j.jacl.2011.02.001

Journal of Clinical Lipidology

Volume 5, Issue 2, March–April 2011, Pages 105-113

https://doi.org/10.1016/j.jacl.2011.02.001 Get rights and content

Background

The amount of cholesterol per low-density lipoprotein (LDL) particle is variable and related in part to particle size, with smaller particles carrying less cholesterol. This variability causes concentrations of LDL cholesterol (LDL-C) and LDL particles (LDL-P) to be discordant in many individuals.

Methods

LDL-P measured by nuclear magnetic resonance spectroscopy, calculated LDL-C, and carotid intima-media thickness (IMT) were assessed at baseline in the Multi-Ethnic Study of Atherosclerosis, a community-based cohort of 6814 persons free of clinical cardiovascular disease (CVD) at entry and followed for CVD events (n = 319 during 5.5-year follow-up). Discordance, defined as values of LDL-P and LDL-C differing by ≥12 percentile units to give equal-sized concordant and discordant subgroups, was related to CVD events and to carotid IMT in models predicting outcomes for a 1 SD difference in LDL-C or LDL-P, adjusted for age, gender, and race.

Results

LDL-C and LDL-P were associated with incident CVD overall: hazard ratios (HR 1.20, 95% CI [CI] 1.08−1.34; and 1.32, 95% CI 1.19−1.47, respectively, but for those with discordant levels, only LDL-P was associated with incident CVD (HR 1.45, 95% CI 1.19−1.78; LDL-C HR 1.07, 95% CI 0.88−1.30). IMT also tracked with LDL-P rather than LDL-C, ie, adjusted mean IMT of 958, 932, and 917 μm in the LDL-P > LDL-C discordant, concordant, and LDL-P < LDL-C discordant subgroups, respectively, with the difference persisting after adjustment for LDL-C (P = .002) but not LDL-P (P = .60).

Conclusions

For individuals with discordant LDL-C and LDL-P levels, the LDL-attributable atherosclerotic risk is better indicated by LDL-P.

Section snippets

Study population

Study participants were enrolled in MESA, a multicenter cohort initiated by the National Heart, Lung, and Blood Institute to characterize subclinical atherosclerosis and its progression.¹³ Eligible participants were 6814 community-based men and women, ages 45–84 years of age and free of self-reported cardiovascular disease, recruited from 4 diverse racial/ethnic groups (African American, Hispanic, white, and Chinese American) at 6 centers in the United States. For examining LDL characteristics

Results

The study population was ethnically diverse (39% white, 13% Chinese American, 25% African American, 23% Hispanic), with a mean age (±SD) of 62 (±10) years and 51% women.

LDL-C and LDL-P levels were highly correlated (Fig. 1A; r = 0.75) but often discordant. The prevalence and magnitude of this discordance can be seen in Figure 1B, which displays the percentile rank values corresponding to the LDL-C and LDL-P concentrations of each study participant. Although many individuals had concordant

Discussion

The present study confirms in a large multiethnic cohort the wide variability of the cholesterol content of LDL particles. The consequence of this variability is that LDL-C levels either overrepresent or under-represent the concentration of LDL-P in many people. Because it is not obvious from a pathophysiologic standpoint which of the 2 LDL measures would be expected to have a closer link with atherosclerotic risk, we assessed prospective associations with CVD events and cross-sectional

Conclusion

When LDL-P and LDL-C were discordant, LDL-P was more strongly associated with risk of CVD events and with carotid IMT than was LDL-C. This finding has potentially important implications regarding our understanding of the etiology of atherosclerotic cardiovascular disease. The relevance of these findings to the management of risk for cardiovascular disease deserves additional study.

Acknowledgments

The authors thank the other investigators, staff, and participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. We also thank Dr. Robyn McClelland of the MESA Coordinating Center at the University of Washington for performing independent verification of all statistical analyses.

References (29)

W.C. Cromwell et al.
LDL particle number and risk for future cardiovascular disease in the Framingham Offspring Study—implications for LDL management
J Clin Lipidol
(2007)
J.D. Brunzell et al.
Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation
J Am Coll Cardiol
(2008)
E.J. Jeyarajah et al.
Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy
Clin Lab Med
(2006)
R.S. Rosenson et al.
Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) Trial
Am J Cardiol
(2002)
S. Mora et al.
LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis
Atherosclerosis
(2007)
K. El Harchaoui et al.
Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study
J Am Coll Cardiol
(2007)
A.D. Sniderman
Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy: implications for clinical practice
J Clin Lipidol
(2008)
A.D. Sniderman et al.
Concordance/discordance between plasma apolipoprotein B levels and cholesterol indexes of atherosclerotic risk
Am J Cardiol
(2003)
K.K. Berneis et al.
Metabolic origins and clinical significance of LDL heterogeneity
J Lipid Res
(2002)
W.C. Cromwell et al.
Heterogeneity of low-density lipoprotein particle number in patients with type 2 diabetes mellitus and low-density lipoprotein cholesterol <100 mg/dL
Am J Cardiol
(2006)

P. Deedwania et al.

Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study

Lancet

(2006)

J.T. Kuvin et al.

Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease

Am J Cardiol

(2006)

J.D. Otvos et al.

Measurement issues related to lipoprotein heterogeneity

Am J Cardiol

(2002)

I. Tabas et al.

Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications

Circulation

(2007)

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Original ArticleClinical implications of discordance between low-density lipoprotein cholesterol and particle number

Background

Methods

Results

Conclusions

Section snippets

Study population

Results

Discussion

Conclusion

Acknowledgments

J Clin Lipidol

J Am Coll Cardiol

Clin Lab Med

Am J Cardiol

Atherosclerosis

J Am Coll Cardiol

J Clin Lipidol

Am J Cardiol

J Lipid Res

Am J Cardiol

Lancet

Am J Cardiol

Measurement issues related to lipoprotein heterogeneity

Am J Cardiol

Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications

Circulation

Original Article
Clinical implications of discordance between low-density lipoprotein cholesterol and particle number