CLINICAL STUDY
Early statin therapy restores endothelial function in children with familial hypercholesterolemia
Saskia de Jongh, MD* , ,*,
Marc R. Lilien, MD ,,
Jos op’t Roodt, MSc,
Erik S. G. Stroes, MD, PhD,
Henk D. Bakker, MD, PhD* and
John J. P. Kastelein, MD, PhD
* Emma Children’s Hospital, AMC, Amsterdam, Netherlands
Department of Vascular Medicine, Academic Medical Center Amsterdam, Netherlands
Wilhelmina Children’s Hospital, Utrecht, Netherlands
Manuscript received March 18, 2002;
revised manuscript received June 6, 2002,
accepted July 18, 2002.
* Reprint requests and correspondence: Dr. Saskia de Jongh, Department of Vascular Medicine, Academic Medical Center, G1-146, Meibergdreef 9, PO Box 22660, 1100 DD, Amsterdam, Netherlands.
s.dejongh{at}amc.uva.nl
OBJECTIVES: This study was designed to determine whether simvastatin improves endothelial function in children with familial hypercholesterolemia (FH).
BACKGROUND: Endothelial function measured by flow-mediated dilation of the brachial artery (FMD) is used as a surrogate marker of cardiovascular disease (CVD). Adult studies have shown that statins reverse endothelial dysfunction and therefore reduce the risk for future CVD.
METHODS: The study included 50 children with FH (9 to 18 years) and 19 healthy, non-FH controls. Children with FH were randomized to receive simvastatin or placebo for 28 weeks. The FMD was performed at baseline and at 28 weeks of treatment.
RESULTS: At baseline, FMD was impaired in children with FH versus non-FH controls (p < 0.024). In the simvastatin FH group, FMD improved significantly, whereas the FMD remained unaltered in the placebo FH group throughout the study period (absolute increase 3.9% ± 4.3% vs. 1.2% ± 3.9%, p < 0.05). In the simvastatin FH group, FMD increased to a level similar to the non-FH controls (15.6% ± 6.8% vs. 15.5% ± 5.4%, p = 0.958). Upon treatment, the simvastatin FH group showed significant absolute reductions of total cholesterol (TC) (–2.16 ± 1.04 mmol/l, 30.1%) and low-density lipoprotein cholesterol (LDL-C) (–2.13 ± 0.99 mmol/l, 39.8%). The absolute change of FMD after 28 weeks of therapy was inversely correlated to changes of TC (r = –0.31, p < 0.05) and LDL-C (r = –0.31, p < 0.05).
CONCLUSIONS: Our data show significant improvement of endothelial dysfunction towards normal levels after short-term simvastatin therapy in children with FH. These results emphasize the relevance of statin therapy in patients with FH at an early stage, when the atherosclerotic process is still reversible.
|
Abbreviations and Acronyms
| | ALT | | alanine aminotransferase | | AST | | aspartate aminotransferase | | BMI | | body mass index | | CK | | creatine kinase | | CVD | | cardiovascular disease | | FH | | familial hypercholesterolemia | | FMD | | flow-mediated dilation | | HDL-C | | high-density lipoprotein cholesterol | | LDL-C | | low-density lipoprotein cholesterol | | TG | | triglycerides | | TC | | total cholesterol |
|
This article has been cited by other articles:
|
|
|
|
 
E. M. Urbina, R. V. Williams, B. S. Alpert, R. T. Collins, S. R. Daniels, L. Hayman, M. Jacobson, L. Mahoney, M. Mietus-Snyder, A. Rocchini, et al.
Noninvasive Assessment of Subclinical Atherosclerosis in Children and Adolescents: Recommendations for Standard Assessment for Clinical Research: A Scientific Statement From the American Heart Association
Hypertension,
November 1, 2009;
54(5):
919 - 950.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J H Baumer and J P H Shield
Hypercholesterolaemia in children guidelines review
Arch. Dis. Child. Ed. Pract.,
June 1, 2009;
94(3):
84 - 86.
[Full Text]
[PDF]
|
|
|
|
|
|
|
American Diabetes Association
Standards of Medical Care in Diabetes--2009
Diabetes Care,
January 1, 2009;
32(Supplement_1):
S13 - S61.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. K. Pasquali and J. S. Li
Prevention of Future Cardiovascular Disease in High-Risk Pediatric Patients: A Role for Lipid Lowering Therapy?
Circ Cardiovasc Qual Outcomes,
November 1, 2008;
1(2):
131 - 133.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. O. Kwiterovich Jr.
Recognition and Management of Dyslipidemia in Children and Adolescents
J. Clin. Endocrinol. Metab.,
November 1, 2008;
93(11):
4200 - 4209.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Daniels, F. R. Greer, and N. Stettler
An Assessment of the New Lipid Screening Guidelines: In Reply
Pediatrics,
October 1, 2008;
122(4):
906 - 907.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Kamerow
Should we screen for and treat childhood dyslipidaemia?
BMJ,
July 23, 2008;
337(jul23_2):
a886 - a886.
[Full Text]
|
|
|
|
|
|
|
B. Fernhall and S. Agiovlasitis
Arterial function in youth: window into cardiovascular risk
J Appl Physiol,
July 1, 2008;
105(1):
325 - 333.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Daniels, F. R. Greer, and and the Committee on Nutrition
Lipid Screening and Cardiovascular Health in Childhood
Pediatrics,
July 1, 2008;
122(1):
198 - 208.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. C. McGill Jr, C. A. McMahan, and S. S. Gidding
Preventing Heart Disease in the 21st Century: Implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study
Circulation,
March 4, 2008;
117(9):
1216 - 1227.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. G. Magnussen, O. T. Raitakari, R. Thomson, M. Juonala, D. A. Patel, J. S.A. Viikari, J. Marniemi, S. R. Srinivasan, G. S. Berenson, T. Dwyer, et al.
Utility of Currently Recommended Pediatric Dyslipidemia Classifications in Predicting Dyslipidemia in Adulthood: Evidence From the Childhood Determinants of Adult Health (CDAH) Study, Cardiovascular Risk in Young Finns Study, and Bogalusa Heart Study
Circulation,
January 1, 2008;
117(1):
32 - 42.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
American Diabetes Association
Standards of Medical Care in Diabetes--2008
Diabetes Care,
January 1, 2008;
31(Supplement_1):
S12 - S54.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. B. Vaughan, F. Ovalle, and E. Moreland
Vascular disease in paediatric type 2 diabetes: the state of the art
Diabetes and Vascular Disease Research,
December 1, 2007;
4(4):
297 - 304.
[Abstract]
[PDF]
|
|
|
|
|
|
|
P. A. Stapleton, Adam. G. Goodwill, M. E. James, and J. C. Frisbee
Altered mechanisms of endothelium-dependent dilation in skeletal muscle arterioles with genetic hypercholesterolemia
Am J Physiol Regulatory Integrative Comp Physiol,
September 1, 2007;
293(3):
R1110 - R1119.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. F. Green
Summary of Workgroup Meeting on Use of Family History Information in Pediatric Primary Care and Public Health
Pediatrics,
September 1, 2007;
120(SUPPLEMENT_2):
S87 - S100.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.J. Avis, M.N. Vissers, E.A. Stein, F.A. Wijburg, M.D. Trip, J.J.P. Kastelein, and B.A. Hutten
A Systematic Review and Meta-Analysis of Statin Therapy in Children With Familial Hypercholesterolemia
Arterioscler Thromb Vasc Biol,
August 1, 2007;
27(8):
1803 - 1810.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Haney, L. H. Huffman, C. Bougatsos, M. Freeman, R. D. Steiner, and H. D. Nelson
Screening and Treatment for Lipid Disorders in Children and Adolescents: Systematic Evidence Review for the US Preventive Services Task Force
Pediatrics,
July 1, 2007;
120(1):
e189 - e214.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. W. McCrindle and for the Writing Group
Summary of the American Heart Association's Scientific Statement on Drug Therapy of High-Risk Lipid Abnormalities in Children and Adolescents
Arterioscler Thromb Vasc Biol,
May 1, 2007;
27(5):
982 - 985.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. W. McCrindle, E. M. Urbina, B. A. Dennison, M. S. Jacobson, J. Steinberger, A. P. Rocchini, L. L. Hayman, and S. R. Daniels
Drug Therapy of High-Risk Lipid Abnormalities in Children and Adolescents: A Scientific Statement From the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, With the Council on Cardiovascular Nursing
Circulation,
April 10, 2007;
115(14):
1948 - 1967.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Strazzullo, S. M. Kerry, A. Barbato, M. Versiero, L. D'Elia, and F. P. Cappuccio
Do Statins Reduce Blood Pressure?: A Meta-Analysis of Randomized, Controlled Trials
Hypertension,
April 1, 2007;
49(4):
792 - 798.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Belay, P. F. Belamarich, and C. Tom-Revzon
The Use of Statins in Pediatrics: Knowledge Base, Limitations, and Future Directions
Pediatrics,
February 1, 2007;
119(2):
370 - 380.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R.-E. W. Kavey, V. Allada, S. R. Daniels, L. L. Hayman, B. W. McCrindle, J. W. Newburger, R. S. Parekh, and J. Steinberger
Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement From the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: Endorsed by the American Academy of Pediatrics
Circulation,
December 12, 2006;
114(24):
2710 - 2738.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. C. Reis, K. E. Kip, O. C. Marroquin, M. Kiesau, L. Hipps Jr, R. E. Peters, and S. E. Reis
Screening Children to Identify Families at Increased Risk for Cardiovascular Disease
Pediatrics,
December 1, 2006;
118(6):
e1789 - e1797.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kapiotis, G. Holzer, G. Schaller, M. Haumer, H. Widhalm, D. Weghuber, B. Jilma, G. Roggla, M. Wolzt, K. Widhalm, et al.
A Proinflammatory State Is Detectable in Obese Children and Is Accompanied by Functional and Morphological Vascular Changes
Arterioscler Thromb Vasc Biol,
November 1, 2006;
26(11):
2541 - 2546.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. S. Gidding
New Cholesterol Guidelines for Children?
Circulation,
September 5, 2006;
114(10):
989 - 991.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Rodenburg, M. N. Vissers, A. Wiegman, E. R. Miller, P. M. Ridker, J. L. Witztum, J. J.P. Kastelein, and S. Tsimikas
Oxidized Low-Density Lipoprotein in Children With Familial Hypercholesterolemia and Unaffected Siblings: Effect of Pravastatin
J. Am. Coll. Cardiol.,
May 2, 2006;
47(9):
1803 - 1810.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. A. Miettinen, M. Railo, M. Lepantalo, and H. Gylling
Reply
J. Am. Coll. Cardiol.,
April 4, 2006;
47(7):
1497 - 1498.
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. T. Raitakari, T. Ronnemaa, M. J. Jarvisalo, T. Kaitosaari, I. Volanen, K. Kallio, H. Lagstrom, E. Jokinen, H. Niinikoski, J. S.A. Viikari, et al.
Endothelial Function in Healthy 11-Year-Old Children After Dietary Intervention With Onset in Infancy: The Special Turku Coronary Risk Factor Intervention Project for Children (STRIP)
Circulation,
December 13, 2005;
112(24):
3786 - 3794.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. T. Mallare, A. H. Karabell, P. Velasquez-Mieyer, S. R.S. Stender, and M. L. Christensen
Current and Future Treatment of Metabolic Syndrome and Type 2 Diabetes in Children and Adolescents
Diabetes Spectr,
October 1, 2005;
18(4):
220 - 228.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Charakida, A. E. Donald, H. Green, C. Storry, M. Clapson, M. Caslake, D. T. Dunn, J. P. Halcox, D. M. Gibb, N. J. Klein, et al.
Early Structural and Functional Changes of the Vasculature in HIV-Infected Children: Impact of Disease and Antiretroviral Therapy
Circulation,
July 5, 2005;
112(1):
103 - 109.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Wiegman, B. A. Hutten, E. de Groot, J. Rodenburg, H. D. Bakker, H. R. Buller, E. J. G. Sijbrands, and J. J. P. Kastelein
Efficacy and Safety of Statin Therapy in Children With Familial Hypercholesterolemia: A Randomized Controlled Trial
JAMA,
July 21, 2004;
292(3):
331 - 337.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Greene and P. Durrington
Clinical management of children and young adults with heterozygous familial hypercholesterolaemia in the UK
J R Soc Med,
May 1, 2004;
97(5):
226 - 229.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Gielen and R. Hambrecht
The Childhood Obesity Epidemic: Impact on Endothelial Function
Circulation,
April 27, 2004;
109(16):
1911 - 1913.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Jarvisalo, M. Raitakari, J. O. Toikka, A. Putto-Laurila, R. Rontu, S. Laine, T. Lehtimaki, T. Ronnemaa, J. Viikari, and O. T. Raitakari
Endothelial Dysfunction and Increased Arterial Intima-Media Thickness in Children With Type 1 Diabetes
Circulation,
April 13, 2004;
109(14):
1750 - 1755.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Engler, M. B. Engler, M. J. Malloy, E. Y. Chiu, M. C. Schloetter, S. M. Paul, M. Stuehlinger, K. Y. Lin, J. P. Cooke, J. D. Morrow, et al.
Antioxidant Vitamins C and E Improve Endothelial Function in Children With Hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial
Circulation,
September 2, 2003;
108(9):
1059 - 1063.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
