What clinical and behavioral factors determine early vascular aging in children with familial hypercholesterolemia?

Introduction. Heterozygous familial hypercholesterolemia (heFH) is a hereditary disease that leads to significantly elevated low-density lipoprotein cholesterol (LDL-C) levels developing from childhood.

Aim. To determine independent predictors of common carotid intima-media thickness (CC-IMT) in children aged 6–18 years with familial hypercholesterolemia based on genetic, biochemical and behavioural factors.

Materials and methods. A retrospective analytical case control study was conducted at the premises of GBUZ “Children’s City Clinical Hospital named after ZA Bashlyaeva, Moscow Department of Health” (Moscow). A complete analysis of electronic medical records of the Children’s Cardiology Centre patients for the period from January 2020 to March 2025 was performed. The total number of patients between 6 yr to 18 yr was 629; the treatment group (n = 471): 207/471 (43.9%) boys and 264/471 (56.1%) girls; the age of 12.6 [9.0-17.5] years — the patients with at-least-probable clinical or genetically confirmed diagnosis of FH according to the Simon-Broom criteria; the control group (n = 158): 76/158 (48.1%) boys and 82/158 (51.9%) girls; the age of 13.1 [11.2-15.5] years — patients of the same centre with excluded dyslipidemia based on the results of clinical and biochemical examinations. Patients in the control cohort were matched for gender and age, according to frequency. A comprehensive analysis of clinical, biochemical and behavioural factors determining early vascular ageing in children and adolescents with FH was performed.

Results. A significant increase in the common carotid intima-media thickness (IMT) compared to the age-appropriate reference ranges was identified as early as at preschool and primary school age. Almost half of the boys and every fifth girl with FH by teen age (15–18 years) had an IMT greater than the 90th percentile of the reference range. The construction of a multivariate regression model allowed to explain 48% of the total variability of IMT. Pathogenic LDLR and APOB mutations, elevated levels of non-HDL cholesterol, lipoprotein (a), homocysteine, as well as smoking and low level of physical activity made the greatest contribution to the acceleration of vascular ageing.

Conclusion. The authors emphasize that early identification of children with FH is critical, and the personalized approach to prescribing lipid-lowering therapy with due account for identified genetic and metabolic characteristics, and individual behavioural factors is required. This approach can help timely identify patients who are at highest risk of developing CVDs.

1. Uzun N, Akıncı MA, Alp H. Cardiovascular Disease Risk in Children and Adolescents with Attention Deficit/Hyperactivity Disorder. Clin Psychopharmacol Neurosci. 2023;21(1):77–87. https://doi.org/10.9758/cpn.2023.21.1.77.

2. Königstein K, Büschges JC, Schmidt-Trucksäss A, Neuhauser H. Cardiovascular Risk in Childhood is Associated With Carotid Intima-Media Thickness and Stiffness in Adolescents and Young Adults: The KiGGS Cohort. J Adolesc Health. 2024;74(1):123–129. https://doi.org/10.1016/j.jadohealth.2023.08.019.

3. Luijendijk P, Lu H, Heynneman FB, Huijgen R, de Groot EE, Vriend JW et al. Increased carotid intima-media thickness predicts cardiovascular events in aortic coarctation. Int J Cardiol. 2014;176(3):776–781. https://doi.org/10.1016/j.ijcard.2014.07.090.

4. Dalla Pozza R, Ehringer-Schetitska D, Fritsch P, Jokinen E, Petropoulos A, Oberhoffer R. Intima media thickness measurement in children: A statement from the Association for European Paediatric Cardiology (AEPC) Working Group on Cardiovascular Prevention endorsed by the Association for European Paediatric Cardiology. Atherosclerosis. 2015;238(2):380–387. https://doi.org/10.1016/j.atherosclerosis.2014.12.029.

5. Drole Torkar A, Plesnik E, Groselj U, Battelino T, Kotnik P. Carotid IntimaMedia Thickness in Healthy Children and Adolescents: Normative Data and Systematic Literature Review. Front Cardiovasc Med. 2020;7:597768. https://doi.org/10.3389/fcvm.2020.597768.

6. Tada H, Takamura M, Kawashiri MA. Familial Hypercholesterolemia: A Narrative Review on Diagnosis and Management Strategies for Children and Adolescents. Vasc Health Risk Manag. 2021;17:59–67. https://doi.org/10.2147/VHRM.S266249.

7. Mainieri F, Tagi VM, Chiarelli F. Recent Advances on Familial Hypercholesterolemia in Children and Adolescents. Biomedicines. 2022;10(5):1043. https://doi.org/10.3390/biomedicines10051043.

8. Ray KK, Pillas D, Hadjiphilippou S, Khunti K, Seshasai SRK, Vallejo-Vaz AJ et al. Premature morbidity and mortality associated with potentially undiagnosed familial hypercholesterolemia in the general population. Am J Prev Cardiol. 2023;15:100580. https://doi.org/10.1016/j.ajpc.2023.100580.

9. Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide Prevalence of Familial Hypercholesterolemia: Meta-Analyses of 11 Million Subjects. J Am Coll Cardiol. 2020;75(20):2553–2566. https://doi.org/10.1016/j.jacc.2020.03.057.

10. Burlutskaya AV, Tril VE, Statova AV, Saveleva NV, Naumenko GV, Polyanskiy AV et al. Family hypercholesterolemia in pediatric practice: a systematic review. Modern Problems of Science and Education. 2024;(3):117. (In Russ.) https://doi.org/10.17513/spno.33515.

11. Chubykina UV, Ezhov MV, Rozhkova ТА, Tamaeva ВМ, Sokolov АА, Ershova AI et al. A five-year follow-up period in homo- and heterozygous familial hypercholesterolemia patients of the RENAISSANCE registry. The Journal of Atherosclerosis and Dyslipidemias. 2023;50(1):5–18. (In Russ.) https://doi.org/10.34687/2219-8202.JAD.2023.01.0001.

12. Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M et al. European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015;36(36):2425–2437. https://doi.org/10.1093/eurheartj/ehv157.

13. Cuchel M, Raal FJ, Hegele RA, Al-Rasadi K, Arca M, Averna M et. al. 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance. Eur Heart J. 2023;44(25):2277–2291. https://doi.org/10.1093/eurheartj/ehad197.

14. Kusters DM, Wiegman A, Kastelein JJ, Hutten BA. Carotid intima-media thickness in children with familial hypercholesterolemia. Circ Res. 2014;114(2):307–310. https://doi.org/10.1161/CIRCRESAHA.114.301430.

15. Johansen AK, Bogsrud MP, Thoresen M, Christensen JJ, Narverud I, Langslet G et. al. Lipoprotein(a) in children and adolescents with genetically confirmed familial hypercholesterolemia followed up at a specialized lipid clinic. Atheroscler Plus. 2024;57:13–18. https://doi.org/10.1016/j.athplu.2024.06.002.

16. Moretti JB, Korban A, Alchourron É, Gervais S, El Jalbout R. Carotid artery intima-media thickness values in obese or overweight children: a metaanalysis. Eur Radiol. 2025;35(6):3305–3313. https://doi.org/10.1007/s00330-024-11284-4.

17. Al-Rasadi K, Al-Waili K, Al-Sabti HA, Al-Hinai A, Al-Hashmi K, Al-Zakwani I, Banerjee Y. Criteria for Diagnosis of Familial Hypercholesterolemia: A Comprehensive Analysis of the Different Guidelines, Appraising their Suitability in the Omani Arab Population. Oman Med J. 2014;29(2):85–91. https://doi.org/10.5001/omj.2014.22.

18. Aleksandrov AA, Kisliak OA, Leontyeva IV. Clinical guidelines on arterial hypertension diagnosis, treatment and prevention in children and adolescents. Systemic Hypertension. 2020;17(2):7–35. (In Russ.) https://doi.org/10.26442/2075082X.2020.2.200126.

19. Johri AM, Nambi V, Naqvi TZ, Feinstein SB, Kim ESH, Park MM et.al. Recommendations for the Assessment of Carotid Arterial Plaque by Ultrasound for the Characterization of Atherosclerosis and Evaluation of Cardiovascular Risk: From the American Society of Echocardiography. J Am Soc Echocardiogr. 2020;33(8):917–933. https://doi.org/10.1016/j.echo.2020.04.021.

20. Avis HJ, Vissers MN, Stein EA, Wijburg FA, Trip MD, Kastelein JJ, Hutten BA. A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2007;27(8):1803–1810. https://doi.org/10.1161/ATVBAHA.107.145151.

21. Tonstad S, Joakimsen O, Stensland-Bugge E, Leren TP, Ose L, Russell D, Bønaa KH. Risk factors related to carotid intima-media thickness and plaque in children with familial hypercholesterolemia and control subjects. Arterioscler Thromb Vasc Biol. 1996;16(8):984–991. https://doi.org/10.1161/01.atv.16.8.984.

22. Pérez de Isla L, Alonso R, Mata N, Saltijeral A, Muñiz O, Rubio-Marin P et al. Coronary Heart Disease, Peripheral Arterial Disease, and Stroke in Familial Hypercholesterolaemia: Insights From the SAFEHEART Registry (Spanish Familial Hypercholesterolaemia Cohort Study). Arterioscler Thromb Vasc Biol. 2016;36(9):2004–2010. https://doi.org/10.1161/ATVBAHA.116.307514.

23. Kinnear FJ, Lithander FE, Searle A, Bayly G, Wei C, Stensel DJ et al. Reducing cardiovascular disease risk among families with familial hypercholesterolaemia by improving diet and physical activity: a randomised controlled feasibility trial. BMJ Open. 2020;10(12):e044200. https://doi.org/10.1136/bmjopen-2020-044200.

24. Christensen JJ, Ulven SM, Retterstøl K, Narverud I, Bogsrud MP, Henriksen T et al. Comprehensive lipid and metabolite profiling of children with and without familial hypercholesterolemia: a cross-sectional study. Atherosclerosis. 2017;266:48–57. https://doi.org/10.1016/j.atherosclerosis.2017.08.011.

25. Elshorbagy A, Vallejo-Vaz AJ, Barkas F, Lyons ARM, Stevens CAT, Dharmayat KI et al. Overweight, obesity, and cardiovascular disease in heterozygous familial hypercholesterolaemia: the EAS FH Studies Collaboration registry. Eur Heart J. 2025;46(12):1127–1140. https://doi.org/10.1093/eurheartj/ehae791.

26. Njie GJ, Kirksey Jones C, Jacques N, Adetokun A, Ross J, Owens A et al. Changes in Tobacco Product Use Among Students Aged 13 to 15 Years in 34 Countries, Global Youth Tobacco Survey, 2012–2020. Prev Chronic Dis. 2023;20:E68. https://doi.org/10.5888/pcd20.220410.

27. deGoma EM, Ahmad ZS, O’Brien EC, Kindt I, Shrader P, Newman CB et al. Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry. Circ Cardiovasc Genet. 2016;9(3):240–249. https://doi.org/10.1161/CIRCGENETICS.116.001381.

28. Luirink IK, Wiegman A, Kusters DM, Hof MH, Groothoff JW, de Groot E et al. 20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia. N Engl J Med. 2019;381(16):1547–1556. https://doi.org/10.1056/NEJMoa1816454.

29. Khera AV, Won HH, Peloso GM, Lawson KS, Bartz TM, Deng X et al. Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. J Am Coll Cardiol. 2016;67(22):2578–2589. https://doi.org/10.1016/j.jacc.2016.03.520.

30. Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM et al. EJ, Stitziel NO, Yamashita S, Wilemon KA, Ledbetter DH, Rader DJ; Convened by the Familial Hypercholesterolemia Foundation. Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72(6):662–680. https://doi.org/10.1016/j.jacc.2018.05.044.

31. Marduel M, Ouguerram K, Serre V, Bonnefont-Rousselot D, MarquesPinheiro A, Erik Berge K et al. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum Mutat. 2013;34(1):83–87. https://doi.org/10.1002/humu.22215.

32. Mariano C, Alves AC, Medeiros AM, Chora JR, Antunes M, Futema M et al. The familial hypercholesterolaemia phenotype: Monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes. Clin Genet. 2020;97(3):457–466. https://doi.org/10.1111/cge.13697.

33. Baroncini LA, Sylvestre Lde C, Pecoits Filho R. Assessment of Intima-Media Thickness in Healthy Children Aged 1 to 15 Years. Arq Bras Cardiol. 2016;106(4):327–332. https://doi.org/10.5935/abc.20160030.

34. Shu D, Chen F, Zhang C, Guo W, Dai S. Environmental tobacco smoke and carotid intima-media thickness in healthy children and adolescents: a systematic review. Open Heart. 2022;9(1):e001790. https://doi.org/10.1136/openhrt-2021-001790.

35. Winder B, Kiechl SJ, Bernar B, Gande N, Staudt A, Stock AK et al. The association of physical activity and carotid intima-media-thickness in adolescents-data of the prospective early vascular ageing-tyrol cohort study. Front Pediatr. 2025;13:1527132. https://doi.org/10.3389/fped.2025.1527132.

36. de Boer LM, Wiegman A, Kroon J, Tsimikas S, Yeang C, Peletier MC et al. Lipoprotein(a) and carotid intima-media thickness in children with familial hypercholesterolaemia in the Netherlands: a 20-year follow-up study. Lancet Diabetes Endocrinol. 2023;11(9):667–674. https://doi.org/10.1016/S2213-8587(23)00156-0.

37. Söbü E, Düzkalır HG, Özcabı B, Kaya Özçora GD. The association between vitamin B12, folate, homocysteine levels, and carotid intima-media thickness in children with obesity: a cross-sectional study. J Pediatr Endocrinol Metab. 2022;35(8):1051–1058. https://doi.org/10.1515/jpem-2022-0250.