The study of flow-mediated vasodilation of the brachial artery and other markers of endothelial function in children with familial hypercholesterolemia

Objective. To study the state of endothelial function in children with familial hypercholesterolemia by evaluating the flow-dependent vasodilation of the brachial artery and serum nitric oxide and endothelin-1 levels.

Children characteristics and research methods. The study included total 62 children: 30 children (mean age 10,3 years ± 2,8) with a heterozygous form of familial hypercholesterolemia, not taking lipid-lowering therapy (main group), and 32 healthy children (mean age 10,3 years ± 2,8) in the control group. The content of endothelin-1 and nitric oxide in blood serum were determined by enzyme immunoassay. Flow-dependent vasodilation of brachial artery was measured using Philips Affinity 70 (Release 3,0.3, Philips Healthcare, USA).

Results. The analysis of endothelin-1 level did not reveal statistically significant differences between healthy children and patients with familial hypercholesterolemia (0,213 [0,012; 0,368] and 0,227 [0,15; 0,315] pmol/l accordingly; p=0,062). The level of nitrogen oxide in healthy children was 33,6 [20—51] pmol/l, while patients with familial hypercholesterolemia had statistically significantly higher level of nitrogen oxide — 103,7 [48—152] pmol/l, p=0,001). Flow-dependent brachial artery vasodilation in healthy children was 9,82 [7,8; 11,2]% and in patients with familial hypercholesterolemia this indicator was decreased — 9,46 [6,5; 10,8]% (p=0,742).

Conclusion. A study of endothelial function in children with familial hypercholesterolemia aged 7—11 years revealed an increase in the concentration of nitrogen oxide relative to healthy patients, probably of a compensatory nature. The flow-dependent vasodilation of the brachial artery and the level of endothelin-1 did not significantly differ from the control group. Due to possible cumulative effect of low-density proteins, it is necessary to monitor endothelial function in children with familial hypercholesterolemia in dynamics.

1. Clinical guidelines. Familial hypercholesterolemia. 2018 Electronic source. (in Russ.)

2. Mach F., Baigent C., Catapano A.L., Koskinas K.C., Casula M., Badimon L. et al. ESC Scientific Document Group, 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2020; 41(1): 111—188. Doi: 10.1093/eurheartj/ehz455.

3. Bays H.E., Jones P.H., Orringer W., Brown V., Jacobson T.A. National Lipid Association Annual Summary of Clinical Lip-idology. J Clin Lipidol 2016; 10(1): S1-S43. DOI:10.1016/j.jacl.2015.08.002

4. Vallejo-Vaz A.J., Kondapally Seshasai S.R., Cole D, Hovingh G.K., Kastelein J.J., Mata P. et al. Familial hypercho-lesterolaemia: a global call to arms. Atherosclerosis 2015; 243: 257-59. DOI: 10.1016/j.atherosclerosis.2015.09.021

5. Pecin I., Hartgers M.L., Hovingh G.K., Dent R., Reiner-et Z. Prevention of cardiovascular disease in patients with familial hypercholesterolaemia: the role of PCSK9 inhibitors. Eur J Prev Cardiol 2017; 24: 1383-1401. DOI: 10.1177/2047487317717346

6. Urbina E.M. Abnormalities of vascular structure and function in pediatric hypertension. Pediatr Nephrol 2016; 31: 10611070. DOI: 10.1007/s00467-015-3188-1

7. Litwin M., Niemirska A. Intima-media thickness measurements in children with cardiovascular risk factors. Pediatr Nephrol 2009; 24: 707-719. DOI: 10.1007/s00467-008-0962-3

8. Narverud I., Retterst0l K, Iversen P.O., Halvorsen B, Ueland T., Ulven, S.M. et al. Markers of atherosclerotic development in children with familial hypercholesterolemia: A literature review. Atherosclerosis 2014; 235(2): 299-309. DOI: 10.1016/j.atherosclerosis.2014.05.917

9. Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med Overseas Ed 1999; 340: 115-126.

10. Favero G., Paganelli C., Buffoli B., Rodella L.F., Rezzani R. Endothelium and Its Alterations in Cardiovascular Diseases: Life Style Intervention. Biomed Res Int 2014; 2014: 801896. DOI: 10.1155/2014/801896

11. Vita J.A. Endothelial Function. Circulation 2011; 124(25): e906-e912. DOI: 10.1161/CIRCULATIONAHA.111.078824

12. Sergeeva E.V., Sadykova D.I. Endothelin-1 as a marker of endothelial dysfunction in various forms of essential arterial hypertension in adolescents. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics) 2016; 61(4): 176-177. (in Russ.)

13. Akhmetzyanov V.F., Latfullin I.A., Nig-matullina R.R. Current views on the role of the serotonergic system in the regulation of cardiovascular activity in normal and pathological conditions. Kazanskii meditsinskii zhurnal (Kazan medical journal) 2006; 2: 119-121 (in Russ.)

14. Davies P.F., Spaan J.A., Krams R. Shear stress biology of the endothelium. Ann of Biomed Engin 2005; 33(12): 17141718. DOI: 10.1007/s10439-005-8774-0

15. Khaddaj Mallat R., Mathew John C., Kendrick D.J., Braun A.P. The vascular endothelium: A regulator of arterial tone and interface for the immune system. Crit Rev Clin Lab Sci 2017; 54(7-8): 458-470. DOI: 10.1080/10408363.2017.1394267

16. Dremina N.N., Shurygin M.G., Shurygina I.A. En-dothelin normal and pathological. Mezhdunarodnyj zhurnal prikladnykh i fundamental’nykh issledovanij (Int J Appl Basic Res) 2016; 10: 210-214. (in Russ.)

17. Iglarz M., Schiffrin E.L. Role of endothelin-1 in hypertension. Curr Hypertens Rep 2003; 5(2): 144-148. DOI: 10.1007/s11906-003-0071-4

18. Chan E.A., Buckley B., Farraj A.K., Thompson L.C. The heart as an extravascular target of endothelin-1 in particulate matter-induced cardiac dysfunction. Pharmacol Ther 2016; 165: 63-78. DOI: 10.1016/j.pharmthera.2016.05.006

19. Cesari M., Pavan E., Sacchetto A., Rossi G.P. Endothelin-1: a scientist’s curiosity, or a real player in ischemic heart disease? Am Heart J 1996; 132(6): 1236-1243. DOI: 10.1016/s0002-8703(96)90468-8

20. Marin E., Sessa W.C. Role of endothelial-derived nitric oxide in hypertension and renal disease. Curr Opin Nephrol Hypertens 2007; 16(2): 105-110. DOI: 10.1097/MNH.0b013e328017f893

21. Incalza M.A., D’Oria R., Natalicchio A., Perrini S., Lavio-la L., Giorgino F. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul Pharmacol 2018; 100: 1-19. DOI: 10.1016/j.vph.2017.05.005

22. Barath A., Turi S., Nemeth I., Bereczki C., Gellen B., Haszon I. et al. Different pathomechanisms of essential and obesity-associated hypertension in adolescents. Pediatr Nephrol 2006; 21(10): 1419-1425. DOI: 10.1007/s00467-006-0215-2

23. Neunteufl T., Heher S., Katzenschlager R., Wolfl G., Kost-ner K., Maurer G. et al. Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol 2000; 86(2): 207-210. DOI: 10.1016/S0002-9149(00)00857-2

24. Suwaidi J.A., Hamasaki S., Higano S.T., Nishimura R.A., Holmes Jr.D.R., Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunc-tion. Circulation 2000; 101: 948-954. DOI: 10.1161/01.cir.101.9.948

25. Neil H.A., Hammond T., Huxley R., Matthews D.R., Humphries S.E. Extent of underdiagnosis of familial hypercho-lesterolaemia in routine practice: prospective registry study. BMJ 2000; 321(7254): 148. DOI: 10.1136/bmj.321.7254.148

26. Corretti M.C., Anderson T.J., Benjamin E.J., Celermajer D., Charbonneau F., Creager M.A. et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery. J Am Coll Cardiol 2002; 39(2): 257-265. DOI: 10.1016/s0735-1097(01)01746-6

27. Nishiyama H., Richardson R.S. Ultrasound Assessment of Flow-Mediated Dilation: A Tutorial. Hypertension 2010; 55(5): 1075-1085. DOI: 0.1161/HYPERTENSIONA-HA.110.150821

28. Tousoulis D., Kampoli A.-M., Tentolouris Nikolaos Papageor-giou C, Stefanadis C. The Role of Nitric Oxide on Endothelial Function. Curr Vasc Pharmacol 2012; 10(1): 4-18. DOI: 10.2174/157016112798829760

29. Aflyatumova G.N., Nigmatullina R.R., Sadykova D.I., Chi-bireva M.D., Fugetto F, Serra R. Endothelin-1, nitric oxide, serotonin and high blood pressure in male adolescents. Vasc Health Risk Manag 2018; 14: 213-223. DOI: 10.2147/VHRM.S170317

30. Klinger J.R., Abman S.H., Gladwin M.T. Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med 2013; 188(6): 639-646. DOI: 10.1164/rccm.201304-0686PP

31. Lo H.C., Lin S.C., Wang Y.M. The relationship among serum cytokines, chemokine, nitric oxide, and leptin in children with type 1 diabetes mellitus. Clin Biochem 2004; 37(8): 666— 672. DOI: 10.1016/j.clinbiochem.2004.02.002

32. Hsu C.N., Lu P.C., Lo M.H., Lin I.C., Tain Y.L. The Association between Nitric Oxide Pathway, Blood Pressure Abnormalities, and Cardiovascular Risk Profile in Pediatric Chronic Kidney Disease. Int J Mol Sci 2019; 20(21): 5301. DOI: 10.3390/ijms20215301

33. Sorensen K.E., Celermajer D.S., Georgakopoulos D., Hatcher G, Betteridge D.J., Deanfield J.E. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipopro-tein(a) level. J Clin Invest 1994; 93: 50-55.

34. Celermajer D.S., Sorensen K.E., Gooch V.M., Spiegelhal-ter D.J., Miller O.I., Sullivan I.D. et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992; 340: 1111e5.

35. Aggoun Y., Szezepanski I., Bonnet D. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events in children. Pediatr Res 2005; 58: 173-178. DOI: 10.1203/01.PDR.0000170900.35571.CB

36. Aggoun Y., Bonnet D., Sidi D., Girardet J.P., Bucker E., Polak M. et al. Arterial mechanical changes in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2000; 20: 2070-2075. DOI: 10.1161/01.atv.20.9.2070

37. Vlahos A.P., Naka K.K., Bechlioulis A., Theoharis P., Vaka-lis K., Moutzouri E. et al. Endothelial Dysfunction, But Not Structural Atherosclerosis, Is Evident Early in Children With Heterozygous Familial Hypercholesterolemia. Pediatr Cardiol 2013; 35(1): 63-70. DOI: 10.1007/s00246-013-0742-0

38. Mietus-Snyder M., Malloy M.J. Endothelial dysfunction occurs in children with two genetic hyperlipidemias: Improvement with antioxidant vitamin therapy. J Pediatrics 1998; 133(1): 35-40. DOI: 10.1016/s0022-3476(98)70174-x

39. De Jongh S., Lilien M.R., Bakker H.D., Hutten B.A., Kaste-lein J.J.P., Stroes E.S.G. Family history of cardiovascular events and endothelial dysfunction in children with familial hypercholesterolemia. Atherosclerosis 2002; 163(1): 193197. DOI: 10.1016/s0021-9150(02)00003-5

40. Jehlicka P., Stozicky F., Mayer Jr. O., Varvarovska J., Racek J., Trefil L. 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.

41. Fabbri-Arrigoni F.I., Clarke L., Wang G., Charakida M., Ellins E., Halliday N. et al. Levels of circulating endothelial cells and colony-forming units are influenced by age and dys-lipidemia. Pediatr Res 2012; 72(3): 299-304. DOI: 10.1038/pr.2012.76

42. Kade A.H., Zanin S.A., Gubareva E.A., Turovaja A.Yu., Bogdanova Yu.A., Apsaljamova S.O., Merzljakova S.N. Physiological functions of the vascular endothelium. Fundamental’nye issledovaniya (Basic research) 2011; 11(3): 611-617. (in Russ.)

43. Golivets T.P., Dubonosova D.G., Osipova O.A., Petrova G.D. Effects of endothelin-1 in the development and progression of the metabolic syndrome and other socially significant noncommunicable diseases (literature review). Nauchnye vedomosti BelGU (Scientific reports of BelSU) Series: Medicine. Pharmacy 2017;19(268): 5-19. (in Russ.)

44. Boren J., Chapman M.J., Krauss R.M., Packard C.J., Bent-zon J.F., Binder C. et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020; 1(24): 2313-2330. DOI: 10.1093/eurheartj/ehz962

45. Grundy S.M., Stone N.J., Bailey A.L., Beam C., Birt-cher K.K., Blumenthal R.S. et al. 2018 AhA/ACC/AaCvPR/ AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019; 139(25): e1082-e1143. DOI: 10.1161/CIR.0000000000000625

46. Luirink I.K., Wiegman A., Kusters D.M., Hof M.H., Groothoff J.W., de Groot E. et al. 20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia. New Engl J Med 2019; 381(16): 1547-1556. DOI: 10.1056/nejmoa1816454