Longitudinal evaluation of endothelial markers in children and adolescents with familial hypercholesterolemia. FMD in paediatric heFH

Main Article Content

Patrizia Bruzzi
Barbara Predieri
Simona Madeo
Francesca Lami
Lorenzo Iughetti


Flow mediated dilation; Familial hypercholesterolemia; Children; Endothelial function; Cardiovascular risk; LDL-cholesterol


Background and aim: Children with heterozygous familial hypercholesterolemia (heFH) are at risk of premature atherosclerosis. Aims of this study were: (a) to longitudinally evaluate the endothelial dysfunction, estimated through brachial flow mediated dilation (FMD), as first sign of subclinical atherogenesis in a group of children and adolescents affected by heFH in comparison to normo-lipidemic controls, and (b) to identify predictive factors influencing the endothelial function and its development in the same cohort of patients.

Methods: This is a prospective, longitudinal and cross-sectional study. Physical examination, plasma lipid profile and brachial artery FMD were measured at baseline and after follow-up.

Results: At baseline, FMD did not differ between heFH children (n.24, median age 9.71) and controls (n. 24, median age 10.29) (7.67 ± 9.26 vs. 11.18 ± 7.28 %, p 0.09). Nevertheless, during follow-up (median length of lipid-lowering diet 4.52 years), FMD got worse in 54% of heFH subjects and its worsening correlated to the increasing of low-density lipoprotein cholesterol (r -0.21, p < 0.05). Moreover, being male (β -0.46, p 0.03), undergoing puberty (β -0.61, p 0.03) and increasing of body mass index standard deviation score (β -0.39, p 0.03) were identified as main independent predictor factors of FMD drop.

Conclusions: During the first decades of life, not only hypercholesterolemia, but also clusters of pro-atherogenic conditions and their persistence, could affect the endothelial function and its trend. (www.actabiomedica.it)


Download data is not yet available.
Abstract 329 | PDF Downloads 194


1. Iughetti L, Predieri B, Balli F, Calandra S. Rational approach to the treatment for heterozygous familial hypercholesterolemia in childhood and adolescence: a review. J Endocrinol Invest 2007;30(8):700-19
2. Rahalkar AR, Hegele RA. Monogenic pediatric dyslipidemia: classification, genetics and clinical spectrum. Mol Genet Metab.2008; 93: 282-294.
3. University College London (UCL) Genetics Institute. Familial Hypercholesterolemia (FH) Variant Databases. London UK. 2015. http://www.ucl.ac.uk/fh (Accessed 2015).
4. Usifo E, Leigh SE, Whittall RA, et al. Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Ann Hum Genet 2012; 76(5): 387-401.
5. Charakida M, Tousoulis D, Skoumas I, et al. Inflammatory and thrombotic processes are associated with vascular dysfunction in children with familial hypercholesterolemia. Atherosclerosis 2009; 204: 532–537.
6. Braamskamp MJ, Hutten BA, Wiegman A, Kastelein JJ. Management of hypercholesterolemia in children. Paediatr Drugs 2014; 16(2): 105-14.
7. Iughetti L, Predieri B, Bruzzi P. Hypercholesterolemia in Childhood. In: Hypercholesterolemia. Edited by Sekar Ashok Kumar, ISBN 978-953-51-2169-S, 232 pages, Publisher: Intech, 2015, pp. 33-53.
8. Pathobiological Determinants of Atheroscelrosis in the Youth (PDAY) Research Group. Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking. JAMA 1990; 264: 3018-3024.
9. Mundal L, Sarancic M, Ose L, et al. Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 1992-2010. J Am Heart Assoc 2014; 3(6): e001236.
10. Berenson GS, Srinivasan SR, Bao W, Newman WP, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998; 338: 1650-1656.
11. Soresen KE, Celermajer DS, Georgakopoulos D, Hatcher G, Betteridge DJ, Deanfield JE. Impairment of Endothelium-dependent Dilation Is an Early Event in Children with Familial Hypercholesterolemia and Is Related to the Lipoprotein (a) Level. J Clin Invest 1994; 93: 50-55.
12. Le J, Zhang D, Chen J, Raghuveer G. “Vascular age” is advanced in children with atherosclerosis promoting risk. Circ Cardiovasc Imaging 2010; 3(1): 8-14.
13. Narverud I, Retterstol K, Iversen PO, et al. Markers of atherosclerotic development in children with familial hypercholesterolemia: a literature review. Atherosclerosis 2014; 235: 299-309.
14. Bamba V. Update on screening, etiology, and treatment of dyslipidemia in children. J Clin Endocrinol Metab 2014; 99:3093-3102.
15. The American Heart Association's Diet and Lifestyle Recommendations. National Cholesterol Education Program ATP III: http://www.americanheart.org/presenter.jhtml?identifier=4764 (Accessed July 26, 2007).
16. Cacciari E, Milani S, Balsamo A, et al. Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest 2006; 29(7):581-93.
17. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969; 44: 291–303.
18. Bertolini S, Cantafora A, Averna M, et al. Clinical expression of familial hypercholesterolemia in clusters of mutations of LDL-receptor gene causing receptor-defective or receptor-negative phenotype. Arterioscler Thromb Vasc Biol 2000; 20:e41–52.
19. Koeijvoets KC, Wiegman A, Rodenburg J, Defesche JC, Kastelein JJP, Sijbrands EJG. Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study. Atherosclerosis 2005; 180(1): 93-9.
20. Hijmering ML, Stroes ES, Pasterkamp G, Sierevogel M, Banga JD, Rabelink TJ. Variability of flow mediated dilation: consequences for clinical application. Atherosclerosis 2000;157(2):369-73.
21. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002; 39(2):257-65.
22. Pires A, Sena C, Seiça R. Dyslipidemia and cardiovascular changes in children. Curr Opin Cardiol 2016; 31(1): 95-100.
23. Napoli C, D'Armiento FP, Mancini FP, et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 1997; 100(11): 2680-90.
24. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992; 340(8828): 1111-5.
25. Guangda X, Linshuang Z, Jie H, Ling Y, Huijuan X. Apo e4 allele is associated with endothelium-dependent arterial dilation in women with type 2 diabetes. Diabetes Res Clin Pract 2006, 72(2):155-61.
26. Suwaidi A, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000; 101: 948–954.
27. Galle J, Heermeier K, Wanner C. Atherogenic lipoproteins, oxidative stress, and cell death. Kidney Int 1999; Suppl 71: S62-5.
28. Iughetti L, Perugini C, Predieri B, et al. Low-density lipoprotein oxidizability in children with chronic renal failure. Pediatr Int 2008; 50(4):447-53.
29. Aggoun Y, Bonnet D, Sidi D, et al. Arterial mechanical changes in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2000; 20: 2070–2075.
30. de Jongh S, Lilien MR, op't Roodt J, Stroes ESG, Bakker HD, Kastelein JJP. Early statin therapy restores endothelial function in children with familial hypercholesterolemia. J Am Coll Cardiol 2002; 40: 2117–2121.
31. de Jongh S, Lilien MR, Bakker HD, Hutten BA, Kastelein JJP, Stroes ESG. Family history of cardiovascular events and endothelial dysfunction in children with familial hypercholesterolemia. Atherosclerosis 2002; 163: 193–197.
32. Mietus-Snyder M, Malloy MJ. Endothelial dysfunction occurs in children with two genetic hyperlipidemias: improvement with antioxidant vitamin therapy. J Pediatr 1998; 133: 35–40.
33. Vlahos AP, Naka KK, Bechlioulis A, et al. Endothelial dysfunction, but not structural atherosclerosis, is evident early in children with heterozygous familial hypercholesterolemia. Pediatr Cardiol 2014; 35(1):63-70.
34. Jehlicka P, Stozicky F, Mayer O Jr, et al. Asymmetric dimethylarginine and the effect of folate substitution in children with familial hypercholesterolemia and diabetes mellitus type 1. Physiol Res 2009; 58: 179–184.
35. Fabbri-Arrigoni FI, Clarke L, Wang G, et al. Levels of circulating endothelial cells and colony-forming units are influenced by age and dyslipidemia. Pediatr Res 2012; 72: 299–304.
36. Masoura C, Pitsavos C, Aznaouridis K, Skoumas I, Vlachopoulos C, Stefanadis C. Arterial endothelial function and wall thickness in familial hypercholesterolemia and familial combined hyperlipidemia and the effect of statins. A systematic review and meta-analysis. Atherosclerosis 2011; 214: 129–138.
37. Guardamagna O, Restagno G, Rolfo E, et al. The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. J Pediatr 2009; 155(2): 199-204.
38. Junyent M, Gilabert R, Jarauta E, et al. Impact of low-density lipoprotein receptor mutational class on carotid atherosclerosis in patients with familial hypercholesterolemia. Atherosclerosis 2010; 208(2): 437-41.
39. Kusters DM, Avis HJ, Braamskamp MJ, et al. Inheritance pattern of familial hypercholesterolemia and markers of cardiovascular risk. J Lipid Res 2013; 254: 2543-2549.
40. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004; 292(3): 331-337.
41.Malhotra A, Shafiq N, Arora A, Singh M, Kumar R, Malhotra S. Dietary interventions for familial hypercholesterolemia. Cochrane Database Syst Rev 2014; 6:CD001918.
42. Eissa MA, Mihalopoulos NL, Holubkov R, Dai S, Labarthe DR. Changes in Fasting Lipids during Puberty. J Pediatr 2016; 170:199-205.
43. Mascarenhas LP, Leite N, Titski AC, Brito LM, Boguszewski MC. Variability of lipid and lipoprotein concentrations during puberty in Brazilian boys. J Pediatr Endocrinol Metab 2015; 28(1-2): 125-31.
44. Daniels SR, Greer FR, Committee on Nutrition. American Academy of Pediatrics Committee on Nutrition. Lipid screening and cardiovascular Health in Childhood. Pediatrics 2008; 122: 198-208.

Most read articles by the same author(s)

1 2 > >>