{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:58:38Z","timestamp":1790657918550,"version":"4.1.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background and aims<\/jats:title>\n                    <jats:p>Individuals with familial hypercholesterolemia (FH) require early lipid-lowering therapy (LLT). We compared rosuvastatin versus ezetimibe treatment and the role of major non-invasive arterial injury markers in children with heterozygous FH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this prospective, open-label, randomized study, 45 children with FH [median age 10.5 years (IQR 8.7\u201314.5)] received rosuvastatin 5\u2005mg OD or ezetimibe 10\u2005mg OD for 6.2 months. Carotid intima-media thickness (cIMT), reactive hyperemia index (RHI), pulse wave velocity (PWV), and beta stiffness were evaluated in relation to anthropometric and lipid-related variables.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Rosuvastatin produced a greater LDL-C reduction than ezetimibe (36.7% vs. 18.3%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&amp;lt;\u20090.001) with 9\/20 (45%) children achieving LDL-C &amp;lt;3.5\u2005mmol\/L compared to 2\/15 (13%) in ezetimibe group. No reports of myalgias, elevations in transaminases, or creatine kinase (CK) were observed in any of the groups. Markers at baseline correlated mainly with age and anthropometry. Beta stiffness decreased during LLT in the overall cohort (\u22120.24; 95% CI \u22120.51 to \u22120.03,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002) and in the rosuvastatin group (\u22120.4; 95% CI \u22120.7 to \u22120.1,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.028), with no between-group difference (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.266). This likely reflects regression to the mean, as LDL-C reduction and treatment allocation had only small effects across all markers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Rosuvastatin achieved greater LDL-C reduction than ezetimibe in children with FH, without difference in safety and tolerability profiles. Arterial injury markers correlated mainly with age and anthropometry, and their short-term changes were not treatment-related, likely due to limited power and the short follow-up.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1933757","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:38:32Z","timestamp":1790656712000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Effect of rosuvastatin and ezetimibe therapy on LDL-cholesterol reduction and non-invasive arterial injury markers in children with heterozygous familial hypercholesterolemia: a prospective, open-label, randomized study"],"prefix":"10.3389","volume":"13","author":[{"given":"Ajda","family":"Skarlovnik","sequence":"first","affiliation":[{"name":"Department of Vascular Diseases, Division of Internal Medicine, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tevz","family":"Gorjanc","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]},{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaka","family":"Sikonja","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]},{"name":"Department of Endocrinology, Diabetes and Metabolic Diseases, Division of Internal Medicine, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Kafol","sequence":"additional","affiliation":[{"name":"Department of Vascular Diseases, Division of Internal Medicine, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]},{"name":"Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matej","family":"Mlinaric","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Cugalj Kern","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]},{"name":"Clinical Institute of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Drole Torkar","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]},{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]},{"name":"Center for Rare Diseases, University Children's Hospital, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jernej","family":"Kovac","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]},{"name":"Clinical Institute of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Rodaro","sequence":"additional","affiliation":[{"name":"Clinical Department of Medical, Surgical and Health Science, University of Trieste","place":["Trieste, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadej","family":"Battelino","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]},{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urh","family":"Groselj","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]},{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]},{"name":"Center for Rare Diseases, University Children's Hospital, University Medical Centre Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1161\/CIRCULATIONAHA.120.046961","article-title":"What is familial hypercholesterolemia and why does it matter?","volume":"141","author":"Khera","year":"2020","journal-title":"Circulation"},{"key":"B2","doi-asserted-by":"publisher","first-page":"120484","DOI":"10.1016\/j.atherosclerosis.2025.120484","article-title":"Sex differences in cholesterol levels among prepubertal children","volume":"410","author":"Kafol","year":"2025","journal-title":"Atherosclerosis"},{"key":"B3","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/S0140-6736(23)01842-1","article-title":"Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study","volume":"403","author":"Dharmayat","year":"2024","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3209","DOI":"10.1093\/eurheartj\/ehac224","article-title":"Screening in children for familial hypercholesterolaemia: start now","volume":"43","author":"Groselj","year":"2022","journal-title":"Eur Heart J"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.1016\/j.gim.2022.06.","article-title":"Universal screening for familial hypercholesterolemia in 2 populations","volume":"24","author":"Sustar","year":"2022","journal-title":"Genet Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1093\/eurjpc\/zwaf352","article-title":"Proposal of a familial hypercholesterolemia pediatric diagnostic score (FH-PeDS)","volume":"33","author":"Kafol","year":"2026","journal-title":"Eur J Prev Cardiol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1161\/HYPERTENSIONAHA.109.192639","article-title":"Noninvasive assessment of subclinical atherosclerosis in children and adolescents","volume":"54","author":"Urbina","year":"2009","journal-title":"Hypertension"},{"key":"B8","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.atherosclerosis.2014.03.031","article-title":"Younger age is associated with lower reactive hyperemic index but not lower flow-mediated dilation among children and adolescents","volume":"234","author":"Kelly","year":"2014","journal-title":"Atherosclerosis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"5118","DOI":"10.3390\/molecules25215118","article-title":"High-sensitivity C-reactive protein and carotid intima media thickness as markers of subclinical inflammation and atherosclerosis in pediatric patients with hypercholesterolemia","volume":"25","author":"Blinc","year":"2020","journal-title":"Molecules"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2394","DOI":"10.1038\/s41390-025-04041-w","article-title":"A cross-sectional study of non-invasive markers of vascular health in children and adolescents","volume":"98","author":"Nasir","year":"2025","journal-title":"Pediatr Res"},{"key":"B11","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.atherosclerosis.2018.06.858","article-title":"Universal screening for familial hypercholesterolemia in children: the Slovenian model and literature review","volume":"277","author":"Groselj","year":"2018","journal-title":"Atherosclerosis"},{"key":"B12","first-page":"45","article-title":"The LMS method for constructing normalized growth standards","volume":"44","author":"Cole","year":"1990","journal-title":"Eur J Clin Nutr"},{"key":"B13","doi-asserted-by":"publisher","first-page":"4359","DOI":"10.1093\/eurheartj\/ehaf190","article-title":"2025 focused update of the 2019 ESC\/EAS guidelines for the management of dyslipidaemias: developed by the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)","volume":"46","author":"Mach","year":"2025","journal-title":"Eur Heart J"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1093\/eurheartj\/ehv157","article-title":"Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment","volume":"36","author":"Wiegman","year":"2015","journal-title":"Eur Heart J"},{"key":"B15","doi-asserted-by":"publisher","first-page":"118598","DOI":"10.1016\/j.atherosclerosis.2024.118598","article-title":"Efficacy and safety of statins, ezetimibe and statins-ezetimibe therapies for children and adolescents with heterozygous familial hypercholesterolaemia: systematic review, pairwise and network meta-analyses of randomised controlled trials","volume":"401","author":"Llewellyn","year":"2025","journal-title":"Atherosclerosis"},{"key":"B16","doi-asserted-by":"publisher","first-page":"S67","DOI":"10.1016\/j.jacl.2015.06.013","article-title":"Lipid-lowering medications for children and adolescents","volume":"9","author":"Miller","year":"2015","journal-title":"J Clin Lipidol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e2231097","DOI":"10.1001\/jamanetworkopen.2022.31097","article-title":"Analysis of insulin resistance among children and adolescents in Slovenia with hypercholesterolemia after treatment with statins","volume":"5","author":"Groselj","year":"2022","journal-title":"JAMA Netw Open"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1056\/NEJMoa1816454","article-title":"20-year follow-up of statins in children with familial hypercholesterolemia","volume":"381","author":"Luirink","year":"2019","journal-title":"N Engl J Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.3390\/biomedicines9091078","article-title":"Treatment of dyslipidaemia in children","volume":"9","author":"Fiorentino","year":"2021","journal-title":"Biomedicines"},{"key":"B20","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1007\/s00431-020-03785-3","article-title":"Vascular diameter and intima-media thickness to diameter ratio values of the carotid artery in 642 healthy children","volume":"180","author":"Semmler","year":"2021","journal-title":"Eur J Pediatr"},{"key":"B21","doi-asserted-by":"publisher","first-page":"327","DOI":"10.5935\/abc.20160030","article-title":"Assessment of intima-media thickness in healthy children aged 1 to 15 years","volume":"106","author":"Baroncini","year":"2016","journal-title":"Arq Bras Cardiol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"597768","DOI":"10.3389\/fcvm.2020.597768","article-title":"Carotid intima-media thickness in healthy children and adolescents: normative data and systematic literature review","volume":"7","author":"Drole Torkar","year":"2020","journal-title":"Front Cardiovasc Med"},{"key":"B23","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1590\/1984-0462\/;2019;37;4;00010","article-title":"Intima-media thickness of the carotid arteries is affected by pubertal maturation in healthy adolescents","volume":"37","author":"Zanini","year":"2019","journal-title":"Rev Paul Pediatr"},{"key":"B24","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1161\/CIRCRESAHA.114.301430","article-title":"Carotid intima-media thickness in children with familial hypercholesterolemia","volume":"114","author":"Kusters","year":"2014","journal-title":"Circ Res"},{"key":"B25","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/S0140-6736(04)15467-6","article-title":"Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia","volume":"363","author":"Wiegman","year":"2004","journal-title":"Lancet"},{"key":"B26","doi-asserted-by":"publisher","first-page":"S_687","DOI":"10.1161\/circ.118.suppl_18.S_687-b","article-title":"Abstract 2223: carotid intima media thickness progression is modest in statin-treated familial hypercholesterolemia patients\u2014results from a patient level meta-analysis of 1257 patients","volume":"118","author":"Vergeer","year":"2008","journal-title":"Circulation"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2014\/546863","article-title":"Comparison of carotid intima-media thickness in pediatric patients with metabolic syndrome, heterozygous familial hyperlipidemia and normals","volume":"2014","author":"Vijayasarathi","year":"2014","journal-title":"J Lipids"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3165","DOI":"10.2169\/internalmedicine.9249-21","article-title":"The assessment of carotid atherosclerotic plaque among young patients with familial hypercholesterolemia","volume":"61","author":"Shibayama","year":"2022","journal-title":"Intern Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1590\/S0034-8910.2015049005425","article-title":"Factors associated with arterial stiffness in children aged 9\u201310 years","volume":"49","author":"Batista","year":"2015","journal-title":"Rev Saude Publica"},{"key":"B30","doi-asserted-by":"publisher","first-page":"6919","DOI":"10.3390\/jcm12216919","article-title":"Wall properties of elastic and muscular arteries in children and adolescents at increased cardiovascular risk","volume":"12","author":"Genovesi","year":"2023","journal-title":"J Clin Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/1476-7120-9-13","article-title":"Doppler ultrasound in the measurement of pulse wave velocity: agreement with the Complior method","volume":"9","author":"Calabia","year":"2011","journal-title":"Cardiovasc Ultrasound"},{"key":"B32","doi-asserted-by":"publisher","first-page":"300","DOI":"10.3390\/life14030300","article-title":"The effect of age, hypertension, and overweight on arterial stiffness assessed using carotid wall echo-tracking in childhood and adolescence","volume":"14","author":"Jurko","year":"2024","journal-title":"Life (Basel)"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.5114\/aoms.2019.89450","article-title":"Pulse wave velocity as a measure of arterial stiffness in patients with familial hypercholesterolemia: a systematic review and meta-analysis","volume":"15","author":"Reiner","year":"2019","journal-title":"Arch Med Sci"},{"key":"B34","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1017\/S1047951115000657","article-title":"Noninvasive assessment of endothelial function in children with obesity and lipid disorders","volume":"26","author":"Hudgins","year":"2016","journal-title":"Cardiol Young"},{"key":"B35","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1253\/circj.CJ-16-0994","article-title":"Endothelial function in children and adolescents is mainly influenced by age, sex and physical activity\u2014an analysis of reactive hyperemic peripheral artery tonometry","volume":"81","author":"Mueller","year":"2017","journal-title":"Circ J"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e002270","DOI":"10.1161\/JAHA.115.002270","article-title":"Prognostic value of flow-mediated vasodilation in brachial artery and fingertip artery for cardiovascular events: a systematic review and meta-analysis","volume":"4","author":"Matsuzawa","year":"2015","journal-title":"JAHA"},{"key":"B37","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/j.jpeds.2012.04.033","article-title":"Puberty and microvascular function in healthy children and adolescents","volume":"161","author":"Radtke","year":"2012","journal-title":"J Pediatr"},{"key":"B38","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1093\/ije\/dyh299","article-title":"Regression to the mean: what it is and how to deal with it","volume":"34","author":"Barnett","year":"2004","journal-title":"Int J Epidemiol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1093\/ajh\/hpab178","article-title":"Clinical applications measuring arterial stiffness: an expert consensus for the application of cardio-ankle vascular index","volume":"35","author":"Budoff","year":"2022","journal-title":"Am J Hypertens"},{"key":"B40","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1177\/0003319720975635","article-title":"The effect of long-term atorvastatin therapy on carotid intima-media thickness of children with dyslipidemia","volume":"72","author":"Karapostolakis","year":"2021","journal-title":"Angiology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1186\/s12967-025-07432-z","article-title":"Translating the effect of dual lipid reduction with PCSK9 inhibitors on a mechanical vascular instrumental biomarker in familial hypercholesterolemia subjects","volume":"23","author":"Bosco","year":"2025","journal-title":"J Transl Med"},{"key":"B42","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1016\/S2213-8587(24)00221-3","article-title":"Association of BMI, lipid-lowering medication, and age with prevalence of type 2 diabetes in adults with heterozygous familial hypercholesterolaemia: a worldwide cross-sectional study","volume":"12","year":"2024","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1093\/eurheartj\/ehae791","article-title":"Overweight, obesity, and cardiovascular disease in heterozygous familial hypercholesterolaemia: the EAS FH studies collaboration registry","volume":"46","author":"Elshorbagy","year":"2025","journal-title":"Eur Heart J"},{"key":"B44","doi-asserted-by":"publisher","first-page":"e238141","DOI":"10.1001\/jamanetworkopen.2023.8141","article-title":"Evaluation of body mass index, overweight and obesity status, and cholesterol levels in younger children","volume":"6","author":"Sustar","year":"2023","journal-title":"JAMA Netw Open"},{"key":"B45","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1097\/MOL.0000000000000880","article-title":"Assessment of atherosclerosis: should coronary calcium score and intima-media thickness be replaced by ultrasound measurement of carotid plaque burden and vessel wall volume?","volume":"34","author":"Spence","year":"2023","journal-title":"Curr Opin Lipidol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"618294","DOI":"10.3389\/fcvm.2021.618294","article-title":"Exercise training duration and intensity are associated with thicker carotid intima-media thickness but improved arterial elasticity in active children and adolescents","volume":"8","author":"Baumgartner","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"B47","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1177\/1741826711410821","article-title":"Asymmetrical distribution of atherosclerosis in the carotid artery: identical patterns across age, race, and gender","volume":"19","author":"Tajik","year":"2012","journal-title":"Eur J Prev Cardiol"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1933757\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:38:46Z","timestamp":1790656726000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1933757\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":47,"alternative-id":["10.3389\/fcvm.2026.1933757"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2026.1933757","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"article-number":"1933757"}}