CLINICAL RESEARCH
Oxidized Phospholipids Predict the Presence and Progression of Carotid and Femoral Atherosclerosis and Symptomatic Cardiovascular Disease
Five-Year Prospective Results From the Bruneck Study
Sotirios Tsimikas, MD*,*,
Stefan Kiechl, MD ,
Johann Willeit, MD,
Manuel Mayr, MD , ,
Elizabeth R. Miller, BS*,
Florian Kronenberg, MD¶,
Qingbo Xu, MD,,
Claes Bergmark, MD||,
Siegfried Weger, MD#,
Friedrich Oberhollenzer, MD# and
Joseph L. Witztum, MD*
* Department of Medicine, University of California San Diego, La Jolla, California
Department of Cardiological Sciences, St. George's Hospital Medical School, London, United Kingdom
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
|| Department of Vascular Surgery, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden
¶ Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
# Department of Internal Medicine, Bruneck Hospital, Bruneck, Italy
Manuscript received September 8, 2005;
revised manuscript received January 24, 2006,
accepted January 27, 2006.
* Reprint requests and correspondence: Dr. Sotirios Tsimikas, Vascular Medicine Program, University of California San Diego, 9500 Gilman Drive, BSB 1080, La Jolla, California 92093-0682 (Email: stsimikas{at}ucsd.edu).
OBJECTIVES: The purpose of this work was to determine the predictive value of oxidized phospholipids (OxPLs) present on apolipoprotein B-100 particles (apoB) in carotid and femoral atherosclerosis.
BACKGROUND: The OxPLs are pro-inflammatory and pro-atherogenic and may be detected using the antibody E06 (OxPL/apoB).
METHODS: The Bruneck study is a prospective population-based survey of 40- to 79-year-old men and women initiated in 1990. Plasma levels of OxPL/apoB and lipoprotein (a) [Lp(a)] were measured in 765 of 826 (92.6%) and 671 of 684 (98.1%) subjects alive in 1995 and 2000, respectively, and correlated with ultrasound measures of carotid and femoral atherosclerosis.
RESULTS: The distribution of the OxPL/apoB levels was skewed to lower levels and nearly identical to Lp(a) levels. The OxPL/apoB and Lp(a) levels were highly correlated (r = 0.87, p < 0.001), and displayed long-term stability and lacked correlations with most cardiovascular risk factors and lifestyle variables. The number of apolipoprotein (a) kringle IV-2 repeats was inversely related to Lp(a) mass (r = –0.48, p < 0.001) and OxPL/apoB levels (r = –0.46, p < 0.001). In multivariable analysis, OxPL/apoB levels were strongly and significantly associated with the presence, extent, and development (1995 to 2000) of carotid and femoral atherosclerosis and predicted the presence of symptomatic cardiovascular disease. Both OxPL/apoB and Lp(a) levels showed similar associations with atherosclerosis severity and progression, suggesting a common biological influence on atherogenesis.
CONCLUSIONS: This study suggests that pro-inflammatory oxidized phospholipids, present primarily on Lp(a), are significant predictors of the presence and extent of carotid and femoral atherosclerosis, development of new lesions, and increased risk of cardiovascular events. The OxPL biomarkers may provide valuable insights into diagnosing and monitoring cardiovascular disease.
|
Abbreviations and Acronyms
| | ACS = acute coronary syndromes | | apoB = apolipoprotein B-100 particles | | CAD = coronary artery disease | | CCA = common carotid artery | | CVD = cardiovascular disease | | ELISA = enzyme-linked immunoadsorbent assay | | ICA = internal carotid artery | | Lp(a) = lipoprotein (a) | | OxLDL = oxidized low-density lipoprotein | | OxPL = oxidized phospholipid | | PC = phosphorylcholine | | PCI = percutaneous coronary intervention | | POVPC = 1-palmitoyl-2-(5-oxovaleroyl)-phosphocholine |
|
This article has been cited by other articles:
|
|
|
|
 
C. Bergmark, A. Dewan, A. Orsoni, E. Merki, E. R. Miller, M.-J. Shin, C. J. Binder, S. Horkko, R. M. Krauss, M. J. Chapman, et al.
A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma
J. Lipid Res.,
October 1, 2008;
49(10):
2230 - 2239.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Merki, M. J. Graham, A. E. Mullick, E. R. Miller, R. M. Crooke, R. E. Pitas, J. L. Witztum, and S. Tsimikas
Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein(a) Transgenic Mice
Circulation,
August 12, 2008;
118(7):
743 - 753.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ye, J. Willeit, F. Kronenberg, Q. Xu, and S. Kiechl
Association of Genetic Variation on Chromosome 9p21 With Susceptibility and Progression of Atherosclerosis: A Population-Based, Prospective Study
J. Am. Coll. Cardiol.,
July 29, 2008;
52(5):
378 - 384.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. H. Choi, A. Chae, E. Miller, M. Messig, F. Ntanios, A. N. DeMaria, S. E. Nissen, J. L. Witztum, and S. Tsimikas
Relationship Between Biomarkers of Oxidized Low-Density Lipoprotein, Statin Therapy, Quantitative Coronary Angiography, and Atheroma Volume Observations From the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) Study.
J. Am. Coll. Cardiol.,
July 1, 2008;
52(1):
24 - 32.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Ky, A. Burke, S. Tsimikas, M. L. Wolfe, M. G. Tadesse, P. O. Szapary, J. L. Witztum, G. A. FitzGerald, and D. J. Rader
The Influence of Pravastatin and Atorvastatin on Markers of Oxidative Stress in Hypercholesterolemic Humans
J. Am. Coll. Cardiol.,
April 29, 2008;
51(17):
1653 - 1662.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Tabas, K. J. Williams, and J. Boren
Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis: Update and Therapeutic Implications
Circulation,
October 16, 2007;
116(16):
1832 - 1844.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tsimikas, L. D. Tsironis, and A. D. Tselepis
New Insights Into the Role of Lipoprotein(a)-Associated Lipoprotein-Associated Phospholipase A2 in Atherosclerosis and Cardiovascular Disease
Arterioscler. Thromb. Vasc. Biol.,
October 1, 2007;
27(10):
2094 - 2099.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kiechl, J. Willeit, M. Mayr, B. Viehweider, M. Oberhollenzer, F. Kronenberg, C. J. Wiedermann, S. Oberthaler, Q. Xu, J. L. Witztum, et al.
Oxidized Phospholipids, Lipoprotein(a), Lipoprotein-Associated Phospholipase A2 Activity, and 10-Year Cardiovascular Outcomes: Prospective Results From the Bruneck Study
Arterioscler. Thromb. Vasc. Biol.,
August 1, 2007;
27(8):
1788 - 1795.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kiechl, G. Schett, J. Schwaiger, K. Seppi, P. Eder, G. Egger, P. Santer, A. Mayr, Q. Xu, and J. Willeit
Soluble Receptor Activator of Nuclear Factor-{kappa}B Ligand and Risk for Cardiovascular Disease
Circulation,
July 24, 2007;
116(4):
385 - 391.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Dieplinger, A. Lingenhel, N. Baumgartner, W. Poelz, H. Dieplinger, M. Haltmayer, F. Kronenberg, and T. Mueller
Increased Serum Lipoprotein(a) Concentrations and Low Molecular Weight Phenotypes of Apolipoprotein(a) Are Associated with Symptomatic Peripheral Arterial Disease
Clin. Chem.,
July 1, 2007;
53(7):
1298 - 1305.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tsimikas, M. Aikawa, F. J. Miller Jr, E. R. Miller, M. Torzewski, S. R. Lentz, C. Bergmark, D. D. Heistad, P. Libby, and J. L. Witztum
Increased Plasma Oxidized Phospholipid:Apolipoprotein B-100 Ratio With Concomitant Depletion of Oxidized Phospholipids From Atherosclerotic Lesions After Dietary Lipid-Lowering: A Potential Biomarker of Early Atherosclerosis Regression
Arterioscler. Thromb. Vasc. Biol.,
January 1, 2007;
27(1):
175 - 181.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Watson
Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Lipidomics: a global approach to lipid analysis in biological systems
J. Lipid Res.,
October 1, 2006;
47(10):
2101 - 2111.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
