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I need assistance in placing a new order. Message: Good morning. I need a review article on New Trends and Therapies for Familial Hypercholesterolemia. In 4000 words. Please follow the following: 1-Quick introduction about FH : definition, Ho and HeFH , frequency, elevated risk of ASCVD(1, 2) 2-Impact of statin therapy and ezetimibe on LDL-C and ASCVD in both He and Ho FH (Quote impact on LDL-C and observational studies showing reduction in ASCVD ex- Versmissen et al (3); Besseling (4) in HeFH and in HoFH Raal (5); Thompson (6) 3-Say that despite this most FH patients persist with elevated LDL-C cholesterol (7-9) 4-Current and specific new therapies PCSK9 inhibitors A-monoclonal antibodies (alirocumab and evolocumab)for HE and Ho FH (10-12) B-small interference RNA (inclisiran)(13) C-Oral PCSK9 I (Check if there is any publication already) Bempedoic acid for HEFH (no specific study but has patients with FH on the studies of patients with high LDL) ANGPTL3 inhibitors for Ho and refractory HeFH (14, 15) MTP inhibitors (lomitapide Cuchel et al(16) long term studies ex- Blom et al(17). Lower registry(18), CETP inhibitors specifically : Obicetrapib Genetic therapies CRISPR/Cas9 for HEFH Viral vectors for HoFH Trends: discuss restricted access in most parts of the world, high cost, need for risk stratification for greater cost effectiveness of therapies(2, 19-23) discuss risk heterogeneity and how to identify higher risk FH patients (severe vs. resilient FH phenotypes)(22, 24) References Vancouver (Using endnote reference software) 1. Defesche JC, Gidding SS, Harada-Shiba M, Hegele RA, Santos RD, Wierzbicki AS. Familial hypercholesterolaemia. Nat Rev Dis Primers. 2017;3:17093. 2. Rocha VZ, Santos RD. Past, Present, and Future of Familial Hypercholesterolemia Management. Methodist Debakey Cardiovasc J. 2021;17(4):28-35. 3. Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ (Clinical research ed). 2008;337:a2423. 4. Besseling J, Hovingh GK, Huijgen R, Kastelein JJP, Hutten BA. Statins in Familial Hypercholesterolemia: Consequences for Coronary Artery Disease and All-Cause Mortality. Journal of the American College of Cardiology. 2016;68(3):252-60. 5. Raal FJ, Pilcher GJ, Panz VR, van Deventer HE, Brice BC, Blom DJ, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation. 2011;124(20):2202-7. 6. Thompson GR, Blom DJ, Marais AD, Seed M, Pilcher GJ, Raal FJ. Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol. Eur Heart J. 2018;39(14):1162-8. 7. Perez de- Isla L, Alonso R, Watts GF, Mata N, Saltijeral A, Muñiz O, et al. Attainment of LDL Cholesterol Treatment Goals in Patients with Familial Hypercholesterolemia at 5-year Follow-up: SAFEHEART Registry. J Am Coll Cardiol. 2016;67:1278-85. 8. Collaboration EASFHS. Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Lancet. 2021;398(10312):1713-25. 9. Blom DJ, Almahmeed W, Al-Rasadi K, Azuri J, Daclin V, Kayikcioglu M, et al. Low-density lipoprotein cholesterol goal achievement in patients with familial hypercholesterolemia in countries outside Western Europe: The International ChoLesterol management Practice Study. J Clin Lipidol. 2019;13(4):594-600. 10. Santos RD, Stein EA, Hovingh GK, Blom DJ, Soran H, Watts GF, et al. Long-Term Evolocumab in Patients With Familial Hypercholesterolemia. J Am Coll Cardiol. 2020;75(6):565-74. 11. Raal FJ, Hovingh GK, Blom D, Santos RD, Harada-Shiba M, Bruckert E, et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes & Endocrinology. 2017;5(4):280-90. 12. Blom DJ, Harada-Shiba M, Rubba P, Gaudet D, Kastelein JJP, Charng MJ, et al. Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial. J Am Coll Cardiol. 2020;76(2):131-42. 13. Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, et al. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. The New England journal of medicine. 2020;382(16):1520-30. 14. Rosenson RS, Burgess LJ, Ebenbichler CF, Baum SJ, Stroes ESG, Ali S, et al. Evinacumab in Patients with Refractory Hypercholesterolemia. The New England journal of medicine. 2020;383(24):2307-19. 15. Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, et al. Evinacumab for Homozygous Familial Hypercholesterolemia. The New England journal of medicine. 2020;383(8):711-20. 16. Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381(9860):40-6. 17. Blom DJ, Averna MR, Meagher EA, du Toit Theron H, Sirtori CR, Hegele RA, et al. Long-Term Efficacy and Safety of the Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide in Patients With Homozygous Familial Hypercholesterolemia. Circulation. 2017;136(3):332-5. 18. Underberg JA, Cannon CP, Larrey D, Makris L, Blom D, Phillips H. Long-term safety and efficacy of lomitapide in patients with homozygous familial hypercholesterolemia: Five-year data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER). J Clin Lipidol. 2020;14(6):807-17. 19. Miname MH, Santos RD. Reducing cardiovascular risk in patients with familial hypercholesterolemia: Risk prediction and lipid management. Prog Cardiovasc Dis. 2019;62(5):414-22. 20. Miname MH, Bittencourt MS, Moraes SR, Alves RIM, Silva PRS, Jannes CE, et al. Coronary Artery Calcium and Cardiovascular Events in Patients With Familial Hypercholesterolemia Receiving Standard Lipid-Lowering Therapy. JACC Cardiovascular imaging. 2019;12(9):1797-804. 21. Mszar R, Grandhi GR, Valero-Elizondo J, Virani SS, Blankstein R, Blaha M, et al. Absence of Coronary Artery Calcification in Middle-Aged Familial Hypercholesterolemia Patients Without Atherosclerotic Cardiovascular Disease. JACC Cardiovascular imaging. 2020;13(4):1090-2. 22. Perez de Isla L, Watts GF, Muniz-Grijalvo O, Diaz-Diaz JL, Alonso R, Zambon D, et al. A resilient type of familial hypercholesterolaemia: case-control follow-up of genetically characterized older patients in the SAFEHEART cohort. Eur J Prev Cardiol. 2021. 23. Gallo A, Perez de Isla L, Charriere S, Vimont A, Alonso R, Muniz-Grijalvo O, et al. The Added Value of Coronary Calcium Score in Predicting Cardiovascular Events in Familial Hypercholesterolemia. JACC Cardiovascular imaging. 2021. 24. 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. Lancet Diabetes Endocrinol. 2016;4(10):850-61. 25. Fahad Alnouri a, Mohammad Athar , Faisal A. Al-Allaf, Zainularifeen Abduljaleel , Mohiuddin M. Taher, Abdellatif Bouazzaoui , Dalal Al Ammari , Hussam Karrar, Monirah Albabtain. Novel combined variants of LDLR and LDLRAP1 gene causing severe familial hypercholesterolemia. Atherosclerosis. 2018 Oct;277:425-433. 26. Niki Katsikia, Dimitri P. Mikhailidisb, Gani Bajraktaric, Andre R. Miserezf, Arrigo . Ciceroh, Eric Bruckerti, Maria-Corina Serbanj, Erkin Mirrakhimovk, Fahad Alnouril, et al. Statin therapy in athletes and patients performing regular intense exercise – Position paper from the International Lipid Expert Panel (ILEP). Pharmacological Research Volume 155, May 2020, 104719 27. Antonio J. Vallejo-Vaz, Christophe . Stevens, Alexander . Lyons, Kanika I. Dharmayat, Tomas Freiberger, G. Kees Hovingh, Pedro Mata, Frederick J. Raal, Raul D. Santos, Handrean Soran, Gerald F. Watts, Marianne Abifadel, Carlos A. Aguilar-Salinas, Khalid F. Alhabib, Mutaz Alkhnifsawi, Wael Almahmeed, Fahad Alnouri, et al. Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). The Lancet 398(10312)