A 20-year follow-up study of patients who have been diagnosed with familial hypercholesterolemia in their youth

A 20-year follow-up study of patients who have been diagnosed with familial hypercholesterolemia in their youth | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A 20-year follow-up study of patients who have been diagnosed with familial hypercholesterolemia in their youth Kurt Widhalm, Karin Fallmann This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4942713/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aim Familial Hypercholesterolemia is an autosomal dominant inherited metabolic disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C). These cause atherosclerosis, premature cardiovascular (cv) disease and death. Despite high prevalence long-term data about FH patients is very limited. Therefore, this study presents data in regard to effects and outcomes of long-term treatment of FH-patients starting in childhood and adolescence. Methods A data collection of 13 FH patients was made for this follow up study. On average the FH diagnosis had been made 20 years ago (9 - 31 years). 86% of the included patients have a genetically confirmed FH diagnosis. The investigated parameters are family history, LDL-C at diagnosis, latest LDL-C, FH-causing mutations, therapy, compliance and if provided by the patient the intima media thickness of the carotid artery. Results The mean initial LDL-C at diagnosis was 277 mg/dl (494 mg/dl - 173 mg/dl). While the mean latest LDL-C was 112 mg/dl (208mg/dl - 70mg/dl). Equaling a mean LDL-C reduction of 59,6% from diagnosis to follow-up. No clinical signs of manifestation of cv diseases could be observed. Furthermore, there have not been any reports of side effects of the lipid-lowering therapy. Conclusions The long-term treatment of patients with FH beginning in childhood is feasible and successful. As shown in this study a therapy with statins lowers LDL-C levels by more than half and therefore most probably prevents the occurrence of later occurring cardiovascular diseases. Familial hypercholesterolemia diagnosis in childhood and adolescence treatment with statins follow up after 20 years Introduction Familial Hypercholesterolemia (FH) is a common autosomal co-dominant inherited metabolic disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C).( 1 ) Over time, LDL-C accumulates in the intima-media of arteries and forms atherosclerotic plaques.( 2 ) Therefore, affected individuals with this disorder have a significantly higher risk for early cardiovascular diseases (CVD).( 3 ) The prevalence for heterozygous FH (heFH) is estimated to be between 1:200 and 1:330( 4 , 5 ), while the prevalence of homozygous FH(hoFH) is estimated to be between 1:160.000 and 1:300.000( 6 , 7 ). Despite the unanimous consensus that initiation of treatment as early as possible reduces cardiovascular risk for patients significantly( 8 ), FH still remains severely underdiagnosed and undertreated. Approximately 90 percent of the affected individuals are not diagnosed and therefore live without treatment( 3 , 9 ). FH is caused by mutations in genes encoding for proteins in the catabolism of LDL-C. The LDL-receptor (LDLR) genes are most frequently affected, followed by the apolipoprotein B (APOB) genes, the Proprotein convertase subtilisin/kexin type 9 (PCSK9) genes and the LDL-receptor-adapter-protein 1 (LDLRAP1) genes( 10 ). The severity of FH is dependent on to the mutation and the zygosity ( 11 ). Subjects that inherit two mutated alleles suffer from homozygous FH which causes the most severe phenotype leading to a live expectancy of only about 30 years( 12 ). The clinical manifestation of FH is heterogenous, even though individuals affected by FH start do develop atherosclerosis in childhood and adolescence clinical symptoms mostly do not arise until severe atherosclerosis has formed ( 6 , 13 , 14 ). There are cutaneous manifestations of FH such as xanthomata, xanthelasmata, arcus cornealis and tendon xanthomata, which are cholesterol deposits in different tissues of the body( 15 ). The therapy of FH consists of three main approaches. First, lifestyle intervention including a low-fat diet, physical activity and nicotine abstinence. Second, pharmacological therapy, with Statins, Ezetimibe or PCSK9 inhibitors. ( 12 , 16 ) Statin therapy has been proven to be a safe and effective treatment for children with elevated LDL-C levels and FH. ( 17 , 18 ) Third, invasive therapy such as LDL apheresis, this procedure is primarily reserved for individuals with hoFH or with severe heFH who do not respond adequately to other treatments. ( 12 , 16 ) While there is a universal agreement about the significance and impact of early treatment for FH, there remains a lack of long-term outcome data for patients diagnosed with FH during their childhood or adolescence. Only a limited number of studies have been conducted on this subject. In this papter, detailed data of 13 patients diagnosed with FH in their childhood and adolescence, on average 20 years ago, will be presented and analyzed. Methods Data was collected from 13 FH patients, who were diagnosed in a pediatric practice during their childhood or adolescence. Informed consent has been obtained from all subjects and/or legal guardians. All experimental protocols were approved by a named institutional committee. On average the included patients have been diagnosed 20 years ago (range 9 to 31 years). The parameters investigated are: Family history: 1 + Diagnosed familial Hypercholesterolemia in a family member 2 + Myocardial infarction (MCI) and elevated cholesterol levels in a family member 3 + MCI at an early age (< 50 years old) in a family member initial LDL-C at diagnosis, latest LDL-C, FH related DNA mutations, Lipid lowering therapy, IMT of the carotid artery, Years since FH diagnosis, Compliance Not all the patients regularly underwent a measurement of their IMT, even though all of them were advised to do so. Some of the patients had their IMT measured at diagnosis but not regularly enough to be included in this study. Therefore, the progression of carotid IMT was only reported for the patients who had their carotid IMT measured at diagnosis, regularly afterwards and recently. The compliance was described as good, moderate, and not compliant by their physicians. To analyze the data differences in LDL-C since diagnosis in percent, the mean initial LDL-C, the mean latest LDL-C, as well as the mean difference in LDL-C levels from diagnosis to now have been calculated. Table 1: Follow-up Data Pat. Family history initial LDL-C (mg/dl) latest LDL-C (mg/dl) LDL-C ↓ Mutation Therapy IMT Years since diagnosis Compliance Patients age at diagnosis 1 2+ 150 (2005) 136 (2021) 9% Pos. Rosuvastatin 丄 17 good 15 2 2+ 214 (2001) 90 (2021) 58% Neg. Rosuvastatin 21 good 12 3 2+ 494 (1994) 109 (2020) 78% pos. E II Rosuvastatin 28 good 18 4 3+ 382 (1998) 113 (2021) 70% pos. Ex3 Rosuvastatin ↑ 24 good 17 5 3+ 244 (2003) 106 (2021) 57% pos. Ex3 Rosuvastatin ↑ + Plaques 19 good 16 6 2+ 245 (2001) 91 (2021) 63% Apo B Rosuvastatin 21 good 16 7 2+ 211 (2002) 103 (2021) 51% Apo B Rosuvastatin ↑ + Plaques 20 good 17 8 3+ 231 (1992) 86 (2021) 63% pos. Ex2 Rosuvastatin ↑ 30 good 12 9 1+ 173 (1999) 70 (2021) 60% unknown Rosuvastatin 23 good 14 10 3+ 253 (2010) 133 (2020) 47% pos. Ex 11 Rosuvastatin 12 good 11 11 3+ 400 (2004) 108 (2021) 73% pos. Dup. 2–6 Rosuvastatin 丄 18 good 4 12 2+ 225 (2014) 107 (2021) 52% Pos. Rosuvastatin 8 moderate 14 13 2+ 374 (2014) 208 (2021) 44% Pos. Rosuvastatin 8 moderate 15 Results Table 1: Follow-up Data In Table 1 the results of the analysis of the collected data are presented. It shows the patients family history, age of diagnosis, initial LDL-C, latest LDL-C, LDL-C reduction, DNA-Mutation, treatment, years since diagnosis and age at diagnosis. All 13 individuals have a positive family history for FH. The mean initial LDL-C at diagnosis was 277 mg/dl, ranging from 494 mg/dl to 173 mg/dl. The mean latest LDL-C was 112 mg/dl, ranging from 208mg/dl to 70mg/dl. This represents a mean reduction of LDL-C of 59,6% from diagnosis until the end of observation. None of the patients have experienced cardiovascular events up to this point. All included patients are taking Rosuvastatin, a high potent statin, to lower their LDL-C levels. No adverse effects of drug treatment had been reported by the treated subjects. All 13 subjects are described to have a good ( 11 ) or moderate ( 2 ) compliance by their physician. 12 of the 13 patients have genetically confirmed mutations causing their FH. Out of the 13 subjects, six underwent regular measurements of their carotid intima-media thickness (cIMT). Among these individuals, two did not exhibit any progression in their cIMT, while four subjects showed an observed progression of their cIMT. Discussion The present study clearly shows the success and feasibility of long-term treatment of FH-patients, who have been diagnosed in their childhood or adolescence.13 patients have been followed up for at least 8 and up to 30 years, a reduction of LDL-C could be observed in those who remained on the treatment with statins, all of them received rosuvastatin as a treatment. None of the patients had any symptoms of premature atherosclerosis or any manifestation of cardiovascular diseases. No major side effects of the statin therapy have been reported. In those patients who had a repeated measurement of their carotid IMT no major progression of atherosclerosis could be found. Nevertheless, it must be stated, that not even half the patients underwent these measurements regularly. As this highlights the challenge of adherence to therapy and regular diagnostic measurements in the management of people affected by FH it has been decided to publish the data even though they are not complete. These findings are similar to those of Luirink et al. who reported a mean LDL-C drop of 32% and a mean difference in progression of the IMT by 0,0001mm a year between patients and their unaffected siblings in their 20-year follow-up study of 184 FH patients.( 19 ) Carreau et al. recorded a mean LDL-C reduction between 21–24% in their observational study using medical files of 185 young FH patients treated with pravastatin in two French centers in 2011. Their follow up period ranged from three months to seven years, with a mean duration of two years and two months. Dropouts were not recorded in this study. ( 20 ) Elis et al. reviewed the records of 89 FH patients at the Chol. Treatment Center in Cincinnati in 2014. Their analysis even showed a mean decrease in LDL-C levels of 43% under lipid lowering therapy. The mean follow up period in this study is 13 ± 8 years. Dropouts were excluded from the study. ( 21 ) In 2015 Bramskamp et al. published the results of their prospective follow up study. The authors included 214 patients and had 9 dropouts. Their mean follow-up period was 10 years. They did not publish data for the LDL-C reduction within the adherent patients. Only the mean LDL-C for the 148 adherent patients (149mg/dl) and for non-adherent patients (302mg/dl) was published.( 22 ) Bogsrud et al. conducted a retrospective study in 2018, reviewing records of 302 children visiting the Lipid Clinic of the Oslo university hospital. On average the children had been diagnosed 4,4 years before. Drop-out data is not included. The main decrease in LDL-C levels the authors recorded was 38%. ( 23 ) Considering the present study and all the other follow-up studies mentioned above there is still a lot of research to do in the field of long-term management of people affected by FH. Especially when thinking about the prevalence of FH and the easy treatment options when the condition is diagnosed and treated at a young age. The awareness for this metabolic disorder must be further increased in order to ensure the best possible care for FH patients. Conclusions The data of the present study on long-term treatment (mean 20 years) of patients who had been diagnosed with heterozygous FH at a young age show a mean reduction of LDL-C of 59,6%. No clinical signs of manifestation of cardiovascular diseases could have been observed during the follow-up period. No side effects of the lipid-lowering therapy have been reported. Thus, it is concluded that long-term treatment of patients with FH beginning in childhood and adolescents is feasible and obviously successful. Declarations The authors declare, that all methods were carried out in accordance with relevant guidelines and regulations. The authors declare that there is no conflict of financial or non-financial interest. The data is from the private office for pediatrics and all patients/participants agreed the summary and publication of data. All data included in this study are available upon request by contact with the corresponding author. Authors Information: Corresponding Author: Univ.-Prof. Dr. Kurt Widhalm Medical University of Vienna, Department of Pediatrics Austrian Academic Institute for Clinical Nutrition [email protected] (Corresponding Email-adress) Alser Straße 14/4a 1090 Vienna Austria Co-Author: Karin Fallmann, MSc. Austrian Academic Institute for Clinical Nutrition [email protected] Alser Straße 14/4a 1090 Vienna Austria References Singh S, Bittner V. Familial Hypercholesterolemia—Epidemiology, Diagnosis, and Screening. Curr Atheroscler Rep. 2015 Feb;17(2):3. Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nat Rev Dis Primers. 2019 Aug 16;5(1):56. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society. European Heart Journal. 2013 Dec 1;34(45):3478–90. Akioyamen LE, Genest J, Shan SD, Reel RL, Albaum JM, Chu A, et al. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. BMJ Open. 2017 Sep;7(9):e016461. Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide Prevalence of Familial Hypercholesterolemia. Journal of the American College of Cardiology. 2020 May;75(20):2553–66. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. European Heart Journal. 2014 Aug 2;35(32):2146–57. Sjouke B, Kusters DM, Kindt I, Besseling J, Defesche JC, Sijbrands EJG, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype–phenotype relationship, and clinical outcome. European Heart Journal. 2015 Mar 1;36(9):560–5. Robinson JG. Management of Familial Hypercholesterolemia: A Review of the Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. JMCP. 2013 Mar;19(2):139–49. Representatives of the Global Familial Hypercholesterolemia Community, Wilemon KA, Patel J, Aguilar-Salinas C, Ahmed CD, Alkhnifsawi M, et al. Reducing the Clinical and Public Health Burden of Familial Hypercholesterolemia: A Global Call to Action. JAMA Cardiol. 2020 Feb 1;5(2):217. Berberich AJ, Hegele RA. The complex molecular genetics of familial hypercholesterolaemia. Nat Rev Cardiol. 2019 Jan;16(1):9–20. Santos RD, Gidding SS, Hegele RA, Cuchel MA, Barter PJ, Watts GF, et al. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. The Lancet Diabetes & Endocrinology. 2016 Oct;4(10):850–61. Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015 Sep 21;36(36):2425–37. Widhalm K, Binder CB, Kreissl A, Aldover-Macasaet E, Fritsch M, Kroisboeck S, et al. Sudden Death in a 4-Year-Old Boy: A Near-Complete Occlusion of the Coronary Artery Caused by an Aggressive Low-Density Lipoprotein Receptor Mutation (W556R) in Homozygous Familial Hypercholesterolemia. The Journal of Pediatrics. 2011 Jan;158(1):167. Widhalm K, Benke IM, Fritz M, Geiger H, Helk O, Fritsch M, et al. Homozygous familial hypercholesterolemia: Summarized case reports. Atherosclerosis. 2017 Feb;257:86–9. Katzmann JL, Lehmann M, Tünnemann-Tarr A, an Haack I, Dressel A, März W, et al. Cutaneous manifestations in familial hypercholesterolaemia. Atherosclerosis. 2021 Sep;333:116–23. Raal FJ, Hovingh GK, Catapano AL. Familial hypercholesterolemia treatments: Guidelines and new therapies. Atherosclerosis. 2018 Oct;277:483–92. Humphries SE, Cooper J, Dale P, Ramaswami U. The UK Paediatric Familial Hypercholesterolaemia Register: Statin-related safety and 1-year growth data. Journal of Clinical Lipidology. 2018 Jan;12(1):25–32. Kavey REW, Manlhiot C, Runeckles K, Collins T, Gidding SS, Demczko M, et al. Effectiveness and Safety of Statin Therapy in Children: A Real-World Clinical Practice Experience. CJC Open. 2020 Nov;2(6):473–82. 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 Oct 17;381(16):1547–56. Carreau V, Girardet JP, Bruckert E. Long-Term Follow-Up of Statin Treatment in a Cohort of Children with Familial Hypercholesterolemia: Efficacy and Tolerability. Pediatric Drugs. 2011 Aug;13(4):267–75. Elis A, Zhou R, Stein EA. Treatment of familial hypercholesterolaemia in children and adolescents in the last three decades. Cardiol Young. 2014 Jun;24(3):437–41. Braamskamp MJAM, Kusters DM, Avis HJ, Smets EMA, Wijburg FA, Kastelein JJP, et al. Long-Term Statin Treatment in Children with Familial Hypercholesterolemia: More Insight into Tolerability and Adherence. Pediatr Drugs. 2015 Apr;17(2):159–66. Bogsrud MP, Langslet G, Wium C, Johansen D, Svilaas A, Holven KB. Treatment goal attainment in children with familial hypercholesterolemia: A cohort study of 302 children in Norway. Journal of Clinical Lipidology. 2018 Mar;12(2):375–82. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4942713","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":359228750,"identity":"a41203a3-99de-4094-a8f3-694d5bb0a588","order_by":0,"name":"Kurt Widhalm","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIiWNgGAWjYDAC5oMPDjAw2ABZjA1EamFLNgBqSSNRC5A8TIK7+NmYGQ/8qDgvx89+uPEBQ8U9O4J2SbYxMxzsOXPbWLInsdmA4UxxMkEtBvf7DxxmbLuduOFAYpsEY1tCMkGHGRxjZjjM+O9c4v7zD9t/kKCl4UDiBonENgagFjuCWiB+OZZsLHHjYbNEwpmEBIJagCHG/OFHjZ0cf3/6ww8fKhLsCWpBBUArEhtI1MPAQKoto2AUjIJRMAIAAM/MPrLUYT2bAAAAAElFTkSuQmCC","orcid":"","institution":"Medical University of Vienna","correspondingAuthor":true,"prefix":"","firstName":"Kurt","middleName":"","lastName":"Widhalm","suffix":""},{"id":359228751,"identity":"c9a8a233-ced1-4f3d-b736-e5727027d772","order_by":1,"name":"Karin Fallmann","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Karin","middleName":"","lastName":"Fallmann","suffix":""}],"badges":[],"createdAt":"2024-08-20 06:59:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4942713/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4942713/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":76724557,"identity":"b1a35cd2-d0a7-4e35-ada7-1a7c12c4bcfb","added_by":"auto","created_at":"2025-02-20 05:09:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":481737,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4942713/v1/3f3624bf-1dfd-4235-ba50-93c139f9133b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A 20-year follow-up study of patients who have been diagnosed with familial hypercholesterolemia in their youth","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFamilial Hypercholesterolemia (FH) is a common autosomal co-dominant inherited metabolic disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C).(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Over time, LDL-C accumulates in the intima-media of arteries and forms atherosclerotic plaques.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Therefore, affected individuals with this disorder have a significantly higher risk for early cardiovascular diseases (CVD).(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe prevalence for heterozygous FH (heFH) is estimated to be between 1:200 and 1:330(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), while the prevalence of homozygous FH(hoFH) is estimated to be between 1:160.000 and 1:300.000(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Despite the unanimous consensus that initiation of treatment as early as possible reduces cardiovascular risk for patients significantly(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), FH still remains severely underdiagnosed and undertreated. Approximately 90 percent of the affected individuals are not diagnosed and therefore live without treatment(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFH is caused by mutations in genes encoding for proteins in the catabolism of LDL-C. The LDL-receptor (LDLR) genes are most frequently affected, followed by the apolipoprotein B (APOB) genes, the Proprotein convertase subtilisin/kexin type 9 (PCSK9) genes and the LDL-receptor-adapter-protein 1 (LDLRAP1) genes(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The severity of FH is dependent on to the mutation and the zygosity (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Subjects that inherit two mutated alleles suffer from homozygous FH which causes the most severe phenotype leading to a live expectancy of only about 30 years(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The clinical manifestation of FH is heterogenous, even though individuals affected by FH start do develop atherosclerosis in childhood and adolescence clinical symptoms mostly do not arise until severe atherosclerosis has formed (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). There are cutaneous manifestations of FH such as xanthomata, xanthelasmata, arcus cornealis and tendon xanthomata, which are cholesterol deposits in different tissues of the body(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe therapy of FH consists of three main approaches. First, lifestyle intervention including a low-fat diet, physical activity and nicotine abstinence. Second, pharmacological therapy, with Statins, Ezetimibe or PCSK9 inhibitors. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) Statin therapy has been proven to be a safe and effective treatment for children with elevated LDL-C levels and FH. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) Third, invasive therapy such as LDL apheresis, this procedure is primarily reserved for individuals with hoFH or with severe heFH who do not respond adequately to other treatments. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eWhile there is a universal agreement about the significance and impact of early treatment for FH, there remains a lack of long-term outcome data for patients diagnosed with FH during their childhood or adolescence. Only a limited number of studies have been conducted on this subject.\u003c/p\u003e \u003cp\u003eIn this papter, detailed data of 13 patients diagnosed with FH in their childhood and adolescence, on average 20 years ago, will be presented and analyzed.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eData was collected from 13 FH patients, who were diagnosed in a pediatric practice during their childhood or adolescence. Informed consent has been obtained from all subjects and/or legal guardians. All experimental protocols were approved by a named institutional committee. On average the included patients have been diagnosed 20 years ago (range 9 to 31 years).\u003c/p\u003e\u003cp\u003eThe parameters investigated are:\u003c/p\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003eFamily history:\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e\n\u003ch3\u003e1 + Diagnosed familial Hypercholesterolemia in a family member\u003c/h3\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2\u0026thinsp;+\u0026thinsp;Myocardial infarction (MCI) and elevated cholesterol levels in a family member\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003e3\u0026thinsp;+\u0026thinsp;MCI at an early age (\u0026lt;\u0026thinsp;50 years old) in a family member\u003c/h2\u003e \u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e initial LDL-C at diagnosis, latest LDL-C, FH related DNA mutations, Lipid lowering therapy, IMT of the carotid artery, Years since FH diagnosis, Compliance\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e \u003cp\u003eNot all the patients regularly underwent a measurement of their IMT, even though all of them were advised to do so. Some of the patients had their IMT measured at diagnosis but not regularly enough to be included in this study. Therefore, the progression of carotid IMT was only reported for the patients who had their carotid IMT measured at diagnosis, regularly afterwards and recently.\u003c/p\u003e \u003cp\u003eThe compliance was described as good, moderate, and not compliant by their physicians.\u003c/p\u003e \u003cp\u003eTo analyze the data differences in LDL-C since diagnosis in percent, the mean initial LDL-C, the mean latest LDL-C, as well as the mean difference in LDL-C levels from diagnosis to now have been calculated.\u003c/p\u003e\u003cp\u003eTable 1: Follow-up Data\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePat.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFamily history\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003einitial\u003c/p\u003e \u003cp\u003eLDL-C (mg/dl)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003elatest\u003c/p\u003e \u003cp\u003eLDL-C\u003c/p\u003e \u003cp\u003e(mg/dl)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLDL-C \u0026darr;\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMutation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTherapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIMT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYears since diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCompliance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003ePatients age at diagnosis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e150 (2005)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e136 (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePos.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e丄\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e214 (2001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90 (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNeg.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e494 (1994)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e109 (2020)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e78%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003epos. E II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e382 (1998)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e113 (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e70%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003epos. Ex3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026uarr;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e244 (2003)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e106 (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e57%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003epos. Ex3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026uarr; + Plaques\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e245 (2001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91 (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e63%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eApo B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e211 (2002)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e103 (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eApo B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026uarr; + Plaques\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e231 (1992)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86 (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e63%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003epos. Ex2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026uarr;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e173 (1999)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eunknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e253 (2010)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e133 (2020)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003epos. Ex 11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e400 (2004)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e108 (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e73%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003epos. Dup. 2\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e丄\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e225 (2014)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e107 (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e52%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePos.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003emoderate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e374 (2014)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e208 (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePos.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRosuvastatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003emoderate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cem\u003eTable\u0026nbsp;1: Follow-up Data\u003c/em\u003e \u003c/p\u003e \u003cp\u003eIn Table\u0026nbsp;1 the results of the analysis of the collected data are presented. It shows the patients family history, age of diagnosis, initial LDL-C, latest LDL-C, LDL-C reduction, DNA-Mutation, treatment, years since diagnosis and age at diagnosis. All 13 individuals have a positive family history for FH. The mean initial LDL-C at diagnosis was 277 mg/dl, ranging from 494 mg/dl to 173 mg/dl. The mean latest LDL-C was 112 mg/dl, ranging from 208mg/dl to 70mg/dl. This represents a mean reduction of LDL-C of 59,6% from diagnosis until the end of observation. None of the patients have experienced cardiovascular events up to this point. All included patients are taking Rosuvastatin, a high potent statin, to lower their LDL-C levels. No adverse effects of drug treatment had been reported by the treated subjects. All 13 subjects are described to have a good (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) or moderate (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) compliance by their physician. 12 of the 13 patients have genetically confirmed mutations causing their FH. Out of the 13 subjects, six underwent regular measurements of their carotid intima-media thickness (cIMT). Among these individuals, two did not exhibit any progression in their cIMT, while four subjects showed an observed progression of their cIMT.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study clearly shows the success and feasibility of long-term treatment of FH-patients, who have been diagnosed in their childhood or adolescence.13 patients have been followed up for at least 8 and up to 30 years, a reduction of LDL-C could be observed in those who remained on the treatment with statins, all of them received rosuvastatin as a treatment.\u003c/p\u003e \u003cp\u003eNone of the patients had any symptoms of premature atherosclerosis or any manifestation of cardiovascular diseases. No major side effects of the statin therapy have been reported.\u003c/p\u003e \u003cp\u003eIn those patients who had a repeated measurement of their carotid IMT no major progression of atherosclerosis could be found. Nevertheless, it must be stated, that not even half the patients underwent these measurements regularly. As this highlights the challenge of adherence to therapy and regular diagnostic measurements in the management of people affected by FH it has been decided to publish the data even though they are not complete.\u003c/p\u003e \u003cp\u003eThese findings are similar to those of Luirink et al. who reported a mean LDL-C drop of 32% and a mean difference in progression of the IMT by 0,0001mm a year between patients and their unaffected siblings in their 20-year follow-up study of 184 FH patients.(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eCarreau et al. recorded a mean LDL-C reduction between 21\u0026ndash;24% in their observational study using medical files of 185 young FH patients treated with pravastatin in two French centers in 2011. Their follow up period ranged from three months to seven years, with a mean duration of two years and two months. Dropouts were not recorded in this study. (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eElis et al. reviewed the records of 89 FH patients at the Chol. Treatment Center in Cincinnati in 2014. Their analysis even showed a mean decrease in LDL-C levels of 43% under lipid lowering therapy. The mean follow up period in this study is 13\u0026thinsp;\u0026plusmn;\u0026thinsp;8 years. Dropouts were excluded from the study. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn 2015 Bramskamp et al. published the results of their prospective follow up study. The authors included 214 patients and had 9 dropouts. Their mean follow-up period was 10 years. They did not publish data for the LDL-C reduction within the adherent patients. Only the mean LDL-C for the 148 adherent patients (149mg/dl) and for non-adherent patients (302mg/dl) was published.(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eBogsrud et al. conducted a retrospective study in 2018, reviewing records of 302 children visiting the Lipid Clinic of the Oslo university hospital. On average the children had been diagnosed 4,4 years before. Drop-out data is not included. The main decrease in LDL-C levels the authors recorded was 38%. (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eConsidering the present study and all the other follow-up studies mentioned above there is still a lot of research to do in the field of long-term management of people affected by FH. Especially when thinking about the prevalence of FH and the easy treatment options when the condition is diagnosed and treated at a young age. The awareness for this metabolic disorder must be further increased in order to ensure the best possible care for FH patients.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe data of the present study on long-term treatment (mean 20 years) of patients who had been diagnosed with heterozygous FH at a young age show a mean reduction of LDL-C of 59,6%. No clinical signs of manifestation of cardiovascular diseases could have been observed during the follow-up period. No side effects of the lipid-lowering therapy have been reported.\u003c/p\u003e \u003cp\u003eThus, it is concluded that long-term treatment of patients with FH beginning in childhood and adolescents is feasible and obviously successful.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe authors declare, that all methods were carried out in accordance with relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no conflict of financial or non-financial interest.\u003c/p\u003e\n\u003cp\u003eThe data is from the private office for pediatrics and all patients/participants agreed the summary and publication of data.\u003c/p\u003e\n\u003cp\u003eAll data included in this study are available upon request by contact with the corresponding author.\u003c/p\u003e\u003cp\u003e\u003cu\u003eAuthors Information:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Corresponding Author:\u003cbr\u003e\u003cem\u003eUniv.-Prof. Dr. Kurt Widhalm\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003c/em\u003eMedical University of Vienna, Department of Pediatrics\u003cbr\u003e\u0026nbsp;Austrian Academic Institute for Clinical Nutrition\u003cbr\[email protected] (Corresponding Email-adress)\u003cbr\u003e\u003cem\u003eAlser Stra\u0026szlig;e 14/4a\u003cbr\u003e\u0026nbsp;1090 Vienna\u0026nbsp;\u003cbr\u003e\u0026nbsp;Austria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCo-Author:\u003cbr\u003e\u003cem\u003eKarin Fallmann, MSc.\u003cbr\u003e\u0026nbsp;\u003c/em\u003eAustrian Academic Institute for Clinical Nutrition\u003cbr\[email protected]\u003cbr\u003e\u003cem\u003eAlser Stra\u0026szlig;e 14/4a\u003cbr\u003e\u0026nbsp;1090 Vienna\u0026nbsp;\u003cbr\u003e\u0026nbsp;Austria\u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSingh S, Bittner V. Familial Hypercholesterolemia\u0026mdash;Epidemiology, Diagnosis, and Screening. Curr Atheroscler Rep. 2015 Feb;17(2):3. \u003c/li\u003e\n\u003cli\u003eLibby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nat Rev Dis Primers. 2019 Aug 16;5(1):56. \u003c/li\u003e\n\u003cli\u003eNordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society. European Heart Journal. 2013 Dec 1;34(45):3478\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eAkioyamen LE, Genest J, Shan SD, Reel RL, Albaum JM, Chu A, et al. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. BMJ Open. 2017 Sep;7(9):e016461. \u003c/li\u003e\n\u003cli\u003eBeheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide Prevalence of Familial Hypercholesterolemia. Journal of the American College of Cardiology. 2020 May;75(20):2553\u0026ndash;66. \u003c/li\u003e\n\u003cli\u003eCuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. European Heart Journal. 2014 Aug 2;35(32):2146\u0026ndash;57. \u003c/li\u003e\n\u003cli\u003eSjouke B, Kusters DM, Kindt I, Besseling J, Defesche JC, Sijbrands EJG, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype\u0026ndash;phenotype relationship, and clinical outcome. European Heart Journal. 2015 Mar 1;36(9):560\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eRobinson JG. Management of Familial Hypercholesterolemia: A Review of the Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. JMCP. 2013 Mar;19(2):139\u0026ndash;49. \u003c/li\u003e\n\u003cli\u003eRepresentatives of the Global Familial Hypercholesterolemia Community, Wilemon KA, Patel J, Aguilar-Salinas C, Ahmed CD, Alkhnifsawi M, et al. Reducing the Clinical and Public Health Burden of Familial Hypercholesterolemia: A Global Call to Action. JAMA Cardiol. 2020 Feb 1;5(2):217. \u003c/li\u003e\n\u003cli\u003eBerberich AJ, Hegele RA. The complex molecular genetics of familial hypercholesterolaemia. Nat Rev Cardiol. 2019 Jan;16(1):9\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eSantos RD, Gidding SS, Hegele RA, Cuchel MA, Barter PJ, Watts GF, et al. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. The Lancet Diabetes \u0026amp; Endocrinology. 2016 Oct;4(10):850\u0026ndash;61. \u003c/li\u003e\n\u003cli\u003eWiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015 Sep 21;36(36):2425\u0026ndash;37. \u003c/li\u003e\n\u003cli\u003eWidhalm K, Binder CB, Kreissl A, Aldover-Macasaet E, Fritsch M, Kroisboeck S, et al. Sudden Death in a 4-Year-Old Boy: A Near-Complete Occlusion of the Coronary Artery Caused by an Aggressive Low-Density Lipoprotein Receptor Mutation (W556R) in Homozygous Familial Hypercholesterolemia. The Journal of Pediatrics. 2011 Jan;158(1):167. \u003c/li\u003e\n\u003cli\u003eWidhalm K, Benke IM, Fritz M, Geiger H, Helk O, Fritsch M, et al. Homozygous familial hypercholesterolemia: Summarized case reports. Atherosclerosis. 2017 Feb;257:86\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eKatzmann JL, Lehmann M, T\u0026uuml;nnemann-Tarr A, an Haack I, Dressel A, M\u0026auml;rz W, et al. Cutaneous manifestations in familial hypercholesterolaemia. Atherosclerosis. 2021 Sep;333:116\u0026ndash;23. \u003c/li\u003e\n\u003cli\u003eRaal FJ, Hovingh GK, Catapano AL. Familial hypercholesterolemia treatments: Guidelines and new therapies. Atherosclerosis. 2018 Oct;277:483\u0026ndash;92. \u003c/li\u003e\n\u003cli\u003eHumphries SE, Cooper J, Dale P, Ramaswami U. The UK Paediatric Familial Hypercholesterolaemia Register: Statin-related safety and 1-year growth data. Journal of Clinical Lipidology. 2018 Jan;12(1):25\u0026ndash;32. \u003c/li\u003e\n\u003cli\u003eKavey REW, Manlhiot C, Runeckles K, Collins T, Gidding SS, Demczko M, et al. Effectiveness and Safety of Statin Therapy in Children: A Real-World Clinical Practice Experience. CJC Open. 2020 Nov;2(6):473\u0026ndash;82. \u003c/li\u003e\n\u003cli\u003eLuirink 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 Oct 17;381(16):1547\u0026ndash;56. \u003c/li\u003e\n\u003cli\u003eCarreau V, Girardet JP, Bruckert E. Long-Term Follow-Up of Statin Treatment in a Cohort of Children with Familial Hypercholesterolemia: Efficacy and Tolerability. Pediatric Drugs. 2011 Aug;13(4):267\u0026ndash;75. \u003c/li\u003e\n\u003cli\u003eElis A, Zhou R, Stein EA. Treatment of familial hypercholesterolaemia in children and adolescents in the last three decades. Cardiol Young. 2014 Jun;24(3):437\u0026ndash;41. \u003c/li\u003e\n\u003cli\u003eBraamskamp MJAM, Kusters DM, Avis HJ, Smets EMA, Wijburg FA, Kastelein JJP, et al. Long-Term Statin Treatment in Children with Familial Hypercholesterolemia: More Insight into Tolerability and Adherence. Pediatr Drugs. 2015 Apr;17(2):159\u0026ndash;66. \u003c/li\u003e\n\u003cli\u003eBogsrud MP, Langslet G, Wium C, Johansen D, Svilaas A, Holven KB. Treatment goal attainment in children with familial hypercholesterolemia: A cohort study of 302 children in Norway. Journal of Clinical Lipidology. 2018 Mar;12(2):375\u0026ndash;82. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Familial hypercholesterolemia, diagnosis in childhood and adolescence, treatment with statins, follow up after 20 years","lastPublishedDoi":"10.21203/rs.3.rs-4942713/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4942713/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eAim\u003c/b\u003e\u003c/p\u003e\n\u003cp\u003eFamilial Hypercholesterolemia is an autosomal dominant inherited metabolic disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C). These cause atherosclerosis, premature cardiovascular (cv) disease and death.\u003c/p\u003e\n\u003cp\u003eDespite high prevalence long-term data about FH patients is very limited. Therefore, this study presents data in regard to effects and outcomes of long-term treatment of FH-patients starting in childhood and adolescence.\u003c/p\u003e\n\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\n\u003cp\u003eA data collection of 13 FH patients was made for this follow up study. On average the FH diagnosis had been made 20 years ago (9 - 31 years). 86% of the included patients have a genetically confirmed FH diagnosis. The investigated parameters are family history, LDL-C at diagnosis, latest LDL-C, FH-causing mutations, therapy, compliance and if provided by the patient the intima media thickness of the carotid artery.\u003c/p\u003e\n\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\n\u003cp\u003eThe mean initial LDL-C at diagnosis was 277 mg/dl (494 mg/dl - 173 mg/dl). While the mean latest LDL-C was 112 mg/dl (208mg/dl - 70mg/dl). Equaling a mean LDL-C reduction of 59,6% from diagnosis to follow-up.\u003c/p\u003e\n\u003cp\u003eNo clinical signs of manifestation of cv diseases could be observed. Furthermore, there have not been any reports of side effects of the lipid-lowering therapy.\u003c/p\u003e\n\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e\n\u003cp\u003eThe long-term treatment of patients with FH beginning in childhood is feasible and successful. As shown in this study a therapy with statins lowers LDL-C levels by more than half and therefore most probably prevents the occurrence of later occurring cardiovascular diseases.\u003c/p\u003e","manuscriptTitle":"A 20-year follow-up study of patients who have been diagnosed with familial hypercholesterolemia in their youth","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-30 09:15:52","doi":"10.21203/rs.3.rs-4942713/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cad4a4b5-056f-4d25-bda4-65c46722c844","owner":[],"postedDate":"September 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-20T05:08:33+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-30 09:15:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4942713","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4942713","identity":"rs-4942713","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}