Wendy S. Tzou, MD; Pamela S. Douglas, MD; Sathanur R. Srinivasan, PhD; Wei Chen, MD, PhD; Gerald Berenson, MD; James H. Stein, MD
Acknowledgment: The authors thank the participants in the Bogalusa Heart Study.
Grant Support: By the National Center for Research Resources (RR-1617601); the National Heart, Lung, and Blood Institute (HL-07936 and HL-38844); the National Institute on Aging (AG-16592); the National Institute of Child Health and Human Development (HD-043820); and the American Heart Association (0160261B).
Potential Financial Conflicts of Interest: Consultancies: J.H. Stein (LipoScience Inc.); Honoraria: J.H. Stein (LipoScience Inc.); Grants received: W.S. Tzou (National Heart, Lung, and Blood Institute, National Institutes of Health); S.R. Srinivasan (National Institute of Child Health and Human Development, National Institutes of Health), W. Chen (National Institute of Child Health and Human Development, National Institutes of Health), G. Berenson (National Heart, Lung, and Blood Institute, National Institute on Aging, National Institutes of Health), J.H. Stein (National Center for Research Resources, National Institutes of Health); Grants pending: G. Berenson (National Heart, Lung, and Blood Institute, National Institutes of Health).
Requests for Single Reprints: James H. Stein, MD, Department of Medicine, Section of Cardiovascular Medicine, University of Wisconsin Medical School, 600 Highland Avenue, G7/341 CSC (MC 3248), Madison, WI 53792.
Current Author Addresses: Dr. Tzou: Department of Medicine, Section of Cardiovascular Medicine, University of Wisconsin Medical School, 600 Highland Avenue, H6/349 CSC (MC 3248), Madison, WI 53792.
Dr. Douglas: Division of Cardiovascular Medicine, Duke University, Duke University Medical Center 3943, Duke North 7451A, Erwin Road, Durham, NC 27710.
Drs. Srinivasan, Chen, and Berenson: Tulane Center for Cardiovascular Health and Department of Epidemiology, Tulane University Health Sciences Center, 1430 Tulane Avenue SL 18, New Orleans, LA 70112-2699.
Dr. Stein: Department of Medicine, Section of Cardiovascular Medicine, University of Wisconsin Medical School, 600 Highland Avenue, G7/341 CSC (MC 3248), Madison, WI 53792.
Author Contributions: Conception and design: P.S. Douglas, S.R. Srinivasan, W. Chen, G. Berenson, J.H. Stein.
Analysis and interpretation of the data: W.S. Tzou, J.H. Stein.
Drafting of the article: W.S. Tzou.
Critical revision of the article for important intellectual content: W.S. Tzou, P.S. Douglas, G. Berenson, J.H. Stein.
Final approval of the article: P.S. Douglas, S.R. Srinivasan, W. Chen, G. Berenson.
Obtaining of funding: S.R. Srinivasan, W. Chen, G. Berenson, J.H. Stein.
Administrative, technical, or logistic support: P.S. Douglas, S.R. Srinivasan, G. Berenson, J.H. Stein.
Collection and assembly of data: S.R. Srinivasan, W. Chen.
Tzou W., Douglas P., Srinivasan S., Chen W., Berenson G., Stein J.; Advanced Lipoprotein Testing Does Not Improve Identification of Subclinical Atherosclerosis in Young Adults: The Bogalusa Heart Study. Ann Intern Med. 2005;142:742-750. doi: 10.7326/0003-4819-142-9-200505030-00009
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Published: Ann Intern Med. 2005;142(9):742-750.
Traditional lipoprotein testing methods do not directly measure low-density lipoprotein cholesterol, lipoprotein(a), lipid remnants, or particle size. Does measurement of these laboratory values improve prediction of atherosclerosis?
This cross-sectional study of 311 healthy young adults used vertical-spin density-gradient ultracentrifugation to directly measure multiple lipoprotein subclass patterns, lipoprotein(a), and intermediate-density lipoprotein cholesterol. These values did not predict carotid intima-media thickness better than traditionally measured lipid values.
Carotid intima-media thickness is an imperfect measure of clinically important atherosclerosis. Associations between lipoproteins and carotid intima-media thickness may differ between healthy people and older people with known atherosclerosis.
James H. Stein
University of Wisconsin Medical School
June 15, 2005
Response to Letter to the Editor
Dr. Ziajka criticized the reproducibility of CIMT measurements in the Bogalusa Heart Study by comparing them to those in the Atherosclerosis Risk in Young Adults (ARYA) Study; however, this comparison is not valid. Our study's conclusions were based on a composite of common, bulb, and internal CIMT measurements, whereas the ARYA study reported common carotid CIMT only (1). Furthermore, because the mean and standard deviation CIMT values in our study were higher than in ARYA, cross-study reproducibility comparisons are not reliable. Nevertheless, CIMT reproducibility in our study was similar to many recent studies and measurement precision in the Bogalusa Heart Study has been strong enough to identify expected associations between CIMT and both traditional and emerging cardiovascular risk factors (2-4).
The major advance of the VAP-II test is better resolution of lipoprotein(a) and intermediate-density lipoprotein cholesterol levels (5). If this difference really was clinically important, improved prediction would have been expected in our study, but none of our models that incorporated lipoprotein(a), intermediate-density lipoprotein, or "real" LDL cholesterol levels, either individually or in combination with each other or with LDL subclass, improved prediction of increased CIMT.
Small differences between low and high CIMT categories are commonly observed in epidemiological and clinical trials and identify important differences in cardiovascular risk. Small differences in CIMT are akin to small differences in blood pressure that are near the resolution of clinical measurements, but predict major differences in cardiovascular outcomes.
Dr. Ziajka incorrectly stated that "More than two-thirds of the population were healthy, very low risk women." Only 58% of our subjects were women and the cardiovascular risks in our study and ARYA are not known. Event rates have not been reported for either study and the young ages preclude accurate risk prediction using standard algorithms. This emphasizes the importance of using a well-validated surrogate marker, such as CIMT, for research in young adults. Directly measuring vascular changes that are associated with future cardiovascular events "“ instead of simply relying on blood tests with risk associations in older adults "“ allows atherogenesis in young adults to be studied in a meaningful way. It is well known that subclinical atherosclerosis begets clinical atherosclerosis and future cardiovascular events. Although there may be patient subsets in which advanced lipoprotein testing using vertical spin density gradient ultracentrifugation may be useful, it does not appear to be clinically necessary in most young adults.
Wendy S. Tzou, M.D. James H. Stein, M.D. University of Wisconsin Medical School
References 1. Oren A, Vos LE, Uiterwaal CS, Grobbee DE, Bots ML. Cardiovascular risk factors and increased carotid intima-media thickness in healthy young adults: the Atherosclerosis Risk in Young Adults (ARYA) Study. Arch Intern Med. 2003;163:1787-92. 2. Urbina EM, Srinivasan SR, Tang R, Bond MG, Kieltyka L, Berenson GS, et al. Impact of multiple coronary risk factors on the intima-media thickness of different segments of carotid artery in healthy young adults (The Bogalusa Heart Study). Am J Cardiol. 2002;90:953-8. 3. Kanters SD, Algra A, van Leeuwen MS, Banga JD. Reproducibility of in vivo carotid intima-media thickness measurements: a review. Stroke. 1997;28:665-71. 4. Tang R, Hennig M, Thomasson B, Scherz R, Ravinetto R, Catalini R et al. Baseline reproducibility of B-mode ultrasonic measurement of carotid artery intima-media thickness: the European Lacidipine Study on Atherosclerosis (ELSA). J Hypertens. 2000;18:197-201. 5. Kulkarni KR, Garber DW, Jones MK, Segrest JP. Identification and cholesterol quantification of low density lipoprotein subclasses in young adults by VAP-II methodology. J Lipid Res. 1995;36:2291-302.
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