CLINICAL RESEARCH: ATHEROSCLEROSIS
Oxidized Low-Density Lipoprotein in Children With Familial Hypercholesterolemia and Unaffected Siblings
Effect of Pravastatin
Jessica Rodenburg, MD*,
Maud N. Vissers, PhD*,
Albert Wiegman, MD, PhD ,
Elizabeth R. Miller, BS ,
Paul M. Ridker, PhD, MD, FACC ,
Joseph L. Witztum, MD,
John J.P. Kastelein, PhD, MD* and
Sotirios Tsimikas, MD, FACC,*
* Department of Vascular Medicine, University of Amsterdam, Amsterdam, the Netherlands
Department of Paediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Department of Medicine, University of California, San Diego, California
Center for Cardiovascular Disease Prevention and Department of Medicine, Harvard Medical School, Boston, Massachusetts
Manuscript received August 4, 2005;
revised manuscript received October 24, 2005,
accepted December 12, 2005.
* Reprint requests and correspondence: Dr. Sotirios Tsimikas, Vascular Medicine Program, University of California San Diego, 9350 Campus Point Drive, Cardiology Suite 2B, La Jolla, California 92037-0975 (Email: stsimikas{at}ucsd.edu).
OBJECTIVES: To assess the role of oxidized phospholipids (OxPLs) in children with familial hypercholesterolemia (FH) and the effect of pravastatin.
BACKGROUND: Oxidized phospholipids are a major component of oxidized low-density lipoprotein (OxLDL) and are bound to lipoprotein (a) [Lp(a)]. The significance of OxPL markers in children is unknown.
METHODS: Children with FH were randomized to placebo (n = 88) or pravastatin (n = 90) after instruction on American Heart Association step II diet. Unaffected siblings (n = 78) served as controls. The OxPL content on apolipoprotein B-100 (apoB) detected by antibody E06 (OxPL/apoB ratio), immunoglobulin (Ig)G and IgM immune complexes per apoB (IC/apoB) and on all apoB particles (total apoB-IC = IC/apoB multiplied by plasma apoB levels), autoantibodies to malondialdehyde (MDA)–low-density lipoprotein (LDL), Lp(a), and apoB levels were measured at baseline and after two years of treatment.
RESULTS: Compared with unaffected siblings, children with FH had significantly lower levels of OxPL/apoB but higher levels of IgG and IgM total apoB-IC and IgM MDA-LDL autoantibodies. From baseline to two-year follow-up, compared with placebo pravastatin treatment resulted in a greater mean percentage change in apoB (–18.7% vs. 0.3%; p = 0.001), total IgG apoB-IC (–31.9% vs. –12.2%; p < 0.001), and total IgM apoB-IC (–25.5% vs. 13.2%; p = 0.001). Interestingly, pravastatin also resulted in higher OxPL/apoB (48.7% vs. 29.3%; p = 0.028) and Lp(a) levels (21.9% vs. 10.7%; p = 0.044).
CONCLUSIONS: Compared with unaffected siblings, children with FH are characterized by elevated levels of apoB-IC and IgM MDA-LDL autoantibodies. Compared with placebo, pravastatin led to a greater reduction in apoB-IC but also to a greater increase in OxPL/apoB and Lp(a), which may represent a novel mechanism of mobilization and clearance of OxPL.
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Abbreviations and Acronyms
| | ACS = acute coronary syndrome | | apoB = apolipoprotein B-100 | | CVD = cardiovascular disease | | FH = familial hypercholesterolemia | | IC = immune complexes | | Ig = immunoglobulin | | IMT = intima-media thickness | | LDL-C = low-density lipoprotein cholesterol | | Lp(a) = lipoprotein (a) | | MDA = malondialdehyde | | OxLDL = oxidized low-density lipoprotein | | OxPL = oxidized phospholipid |
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