Search

Background: Statins are the cornerstone treatment for patients with heterozygous familial hypercholesterolaemia but research suggests it could increase the risk of type 2 diabetes in the general population. A low prevalence of type 2 diabetes was reported in some familial hypercholesterolaemia cohorts, raising the question of whether these patients are protected against type 2 diabetes. Obesity is a well known risk factor for the development of type 2 diabetes. We aimed to investigate the associations of known key determinants of type 2 diabetes with its prevalence in people with heterozygous familial hypercholesterolaemia., Methods: This worldwide cross-sectional study used individual-level data from the EAS FHSC registry and included adults older than 18 years with a clinical or genetic diagnosis of heterozygous familial hypercholesterolaemia who had data available on age, BMI, and diabetes status. Those with known or suspected homozygous familial hypercholesterolaemia and type 1 diabetes were excluded. The main outcome was prevalence of type 2 diabetes overall and by WHO region, and in relation to obesity (BMI ≥30·0 kg/m 2 ) and lipid-lowering medication as predictors. The study population was divided into 12 risk categories based on age (tertiles), obesity, and receiving statins, and the risk of type 2 diabetes was investigated using logistic regression., Findings: Among 46 683 adults with individual-level data in the FHSC registry, 24 784 with heterozygous familial hypercholesterolaemia were included in the analysis from 44 countries. 19 818 (80%) had a genetically confirmed diagnosis of heterozygous familial hypercholesterolaemia. Type 2 diabetes prevalence in the total population was 5·7% (1415 of 24 784), with 4·1% (817 of 19 818) in the genetically diagnosed cohort. Higher prevalence of type 2 diabetes was observed in the Eastern Mediterranean (58 [29·9%] of 194), South-East Asia and Western Pacific (214 [12·0%] of 1785), and the Americas (166 [8·5%] of 1955) than in Europe (excluding the Netherlands; 527 [8·0%] of 6579). Advancing age, a higher BMI category (obesity and overweight), and use of lipid-lowering medication were associated with a higher risk of type 2 diabetes, independent of sex and LDL cholesterol. Among the 12 risk categories, the probability of developing type 2 diabetes was higher in people in the highest risk category (aged 55-98 years, with obesity, and receiving statins; OR 74·42 [95% CI 47·04-117·73]) than in those in the lowest risk category (aged 18-38 years, without obesity, and not receiving statins). Those who did not have obesity, even if they were in the upper age tertile and receiving statins, had lower risk of type 2 diabetes (OR 24·42 [15·57-38·31]). The corresponding results in the genetically diagnosed cohort were OR 65·04 (40·67-104·02) for those with obesity in the highest risk category and OR 20·07 (12·73-31·65) for those without obesity., Interpretation: Adults with heterozygous familial hypercholesterolaemia in most WHO regions have a higher type 2 diabetes prevalence than in Europe. Obesity markedly increases the risk of diabetes associated with age and use of statins in these patients. Our results suggest that heterozygous familial hypercholesterolaemia does not protect against type 2 diabetes, hence managing obesity is essential to reduce type 2 diabetes in this patient population., Funding: Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi-Sankyo, and Regeneron., Competing Interests: Declaration of interests CAA-S reports support from Amgen to their institution. MAb reports support from Amryt for lectures and from Newbridge and Amryt to attend meetings. MAr reports grants to their institution from Novartis, Ionis, Lilly, and Amgen; and honoraria from Viatris, Alfasigma, Sanofi, Amgen, PIAM, Amaryn, Novartis, Ionis, and Ultragenyx. MAv reports consultancy fees from Akcea, Amgen, Amrith, Aurora Biofarma, Daiichi-Sankyo, Menarini, Novartis, Sanofi (Genzyme), and Sobi; and honoraria from Amgen, Amrith, Aurora Biofarma, Daiichi-Sankyo, Menarini, Novartis, Sanofi (Genzyme), and Sobi. FA reports support, consultancy fees, honoraria, and participation on a data safety monitoring or advisory board from Amgen, Amryt, and Novartis. RA reports honoraria from Amgen, Novo Nordisk, Tecnofarma, Saval, Abbott, and PTC-Therapeutics; support to attend meetings from Amgen And PTC-Therapeutics; participation on a data safety monitoring or advisory board for PTC-Therapeutics; and leadership or fiduciary, society, committee or advocacy group for Chilean Atherosclerosis Working Group. MBa reports participation at speakers bureaus for Amgen, Daiichi-Sankyo, Krka, Polpharma, Novartis, Sanofi-Aventis, Teva, and Zentiva; being a consultant for Adamed, Amgen, Daiichi-Sankyo, Esperion, New Amsterdam, Novartis, and Sanofi-Aventis; and grants from Amgen, Daiichi-Sankyo, Novartis, and Sanofi. CJB reports funding to the Austrian Familial Hypercholesterolaemia Registry from Amgen, Daiichi-Sankyo, Sanofi, and Novartis; consultancy fees from Novartis And Daiichi-Sankyo; and honoraria from Amgen and Novartis. MBo reports a grant to their institution from the Portuguese Science and Technology Foundation and Portuguese Cardiology Society. JB reports grants from AstraZeneca and honoraria from Amgen. LRB reports consultancy fees from Ultragenyx and Amryt; and honoraria from Amgen, HLS Therapeutics, and Novartis. ALC reports grants from Amryt, Menarini, and Ultragenyx; and honoraria from Amarin, Amgen, Amryt, AstraZeneca, Daiichi-Sankyo, Esperion, Ionis Pharmaceutical, Medscape, Menarini, Merck, Novartis, Novo Nordisk, PeerVoice, Pfizer, Recordati Regeneron, Sandoz, Sanofi, The Corpus, Ultragenyx, and Viatris. PC reports grants to FASTA University from Amgen; and consultancy fees and other honoraria from Amgen and Novartis. DC reports consultancy fees, including data safety monitoring, from Ultragenyx, Organon, and Novartis; honoraria from Bial, Alexion (Synageva), Daiichi-Sankyo, Amgen, Novartis, Organon, and Servier; support for attending meetings from Servier, Daiichi-Sankyo, and Medinfar; is the vice president of the Portuguese Atherosclerosis Society; and is a board member and ex-deputy director health of the Portuguese Society of Internal Medicine. OSD reports grants to their institution from Daiichi-Sankyo and Novartis; consultancy fees from Sanofi and Daiichi-Sankyo; and honoraria from Sanofi, Viatris, Organon, Daiichi-Sankyo, Novartis, and Servier. KID reports grants to their institution from Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi-Sankyo, and Regeneron; and personal fees from Bayer and Regeneron. AE reports grants to their institution from Regeneron, Daiichi-Sankyo, and Amgen. TF reports grants to their institution from Ministry of Education, Youth, and Sports, National Institute for Research of Metabolic and Cardiovascular Diseases Programme (EXCELES; LX22NPO5104) funded by Next Generation EU; and consultancy fees and other honoraria from Novartis. DG reports honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Novartis, Pfizer, and Sanofi. UG reports grants from the Slovenian Research Agency and UMC Ljubljana Grant; honoraria from AstraZeneca and Novartis; and participation on a data safety monitoring board for Familial Hypercholesterolaemia Europe Foundation. KBH reports consultancy fees and other honoraria from Sanofi and participation in a scientific advisory board for Familial Hypercholesterolaemia Europe Foundation. GKH reports being a part-time employee of Novo Nordisk. MK reports honoraria for lectures and consultancy from Abbott, Abdi Ibrahim, Amryt, Novo Nordisk, and Tr-Pharma; funding from Amryt; participation in clinical trials with payments to their institution from Amgen, Ionis, Lib Therapeutics, Novo Nordisk, Sanofi, and Medpace; and participation in an unpaid advocacy group for Familial Hypercholesterolaemia-Türkiye and Familial Hypercholesterolaemia Europe Foundation. WK reports grants to their institution from Health Systems Research Institute; payments from Medical Council of Thailand, Royal College of Physicians of Thailand, Chulalongkorn University, Endocrine Society of Thailand, and Amgen; other honoraria from Amgen, Novartis, Boehringer, AstraZeneca, Abbot, and Thai Meiji; support to attend meetings from Amgen; and participation on an advisory board for Daiichi-Sankyo, Amgen, Kowa (Biopharm), Thai Meiji, Novartis, and Abbott. KL reports honoraria from Novartis, Novo Nordisk, AstraZeneca, and Boehringer. GL reports grants to their institution from Latvian Science Council (lzp-2020/1–0151), Latvian National Research Program Biomedicine for Public Health 2014–2017, the Ministry of Education and Science of the Republic of Latvia, and VPP-EM-BIOMEDICĪNA-2022/1–001 (State research project in the field of biomedicine, medical technologies and pharmacy); consultancy fees from Amgen, Novartis, Novo Nordisk, Boehringer Ingelheim, and Bayer; other honoraria from Pfizer, AstraZeneca, Servier, Sanofi, Novartis, Swixx BioPharma, Novo Nordisk, Boehringer Ingelheim, Bayer, Siemens Laboratories, Abbott Laboratories, and Roche Laboratories; support for attending meetings from Amgen, Bayer, Servier, and Sanofi; participation on data safety monitoring board for Amgen, Novartis, Novo Nordisk, Boehringer Ingelheim, and Bayer; and is a member of the certification council at the Latvian Medical Association Board, Latvian Society of Cardiology Board, and the Baltic Atherosclerosis Society. EL reports personal fees and non-financial support from Amgen, AstraZeneca, and Bayer; and personal fees from Servier, Boehringer Ingelheim, MSD, Lilly, Novartis, and Chiesi. ARML reports grants to their institution from Amgen, Daiichi-Sankyo, Regeneron, and Ultragenyx; and support for attending meetings from European Atherosclerosis Society. ADM reports grants from Medical Research Council Cape Heart Group; support to attend meetings from European Atherosclerosis Society; and is a board member and president of the Lipid and Atherosclerosis Society of Southern Africa. WM reports grants, consultancy fees, and other honoraria from Amgen, Sanofi, SYNLAB, Novartis, and Daiichi-Sankyo; and support to attend meetings from Daiichi-Sankyo. ARM reports grants from DiaGene Research Institute; grants and support to attend meetings from Sanofi and European Atherosclerosis Society; and is a president of Swiss Society for Familial Forms of Hypercholesterolemia. BGN reports consultancy fees from AstraZeneca, Sanofi, Regeneron, Ionis, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, Silence Therapeutics, and Ultragenyx; other honoraria from Sanofi, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Abbott, and Mankind; board participation for Ionis, Kowa, and Novartis; and research collaboration with AstraZeneca. AGP is a board member of the Cyprus Atherosclerosis Society. FJR reports grants and personal fees from Amgen, Regeneron Pharmaceuticals, Novartis, and Lib Therapeutics. KKR reports grants to their institution from Amgen, Sanofi, Regeneron, Daiichi-Sankyo, and Ultragenyx; consultancy fees for serving as a member of the steering committee or executive committee of clinical trials and roles as principal investigator and national lead investigator and for attending advisory boards, providing advice on data interpretation, and future lines of research from Novartis, Daiichi-Sankyo, Kowa, Esperion, Novo Nordisk, MSD, Lilly, Silence Therapeutics, Az, New Amsterdam Pharma, Bayer, Beren Therapeutics, Cleerly, EmendoBio, Scribe, Crispr, Vaxxinity, Amarin, Regeneron, Ultragenyx, Cargene, and Resverlogix; lecture fees from Novartis, Bi, Az, Novo Nordisk, Viatris, Amarin, Biologix Pharma, Sanofi, Amgen, Esperion, Daiichi-Sankyo, Macleod Pharma for symposia at international meetings; holding stock options from New Amsterdam Pharma and Pemi31; and serving as a president for the European Atherosclerosis Society. ŽR reports grants from Sanofi Aventis and Novartis. RDS reports grants from Kowa, Amgen, Sanofi, Regeneron, Novartis, and Esperion; consultancy fees from Amgen, Novartis, Novo Nordisk, Amryt, Pfizer, Hypera, and Sanofi; and support to attend meetings from Novo Nordisk and Daiichi-Sankyo. HSc reports grants from AstraZeneca and consultancy fees from Amgen, AstraZeneca, Bayer Vital, Bristol Myers Squibb, MSD, Novartis, Servier, Sanofi-Aventis, Boehringer Ingelheim, Daiichi-Sankyo, and SYNLAB. CATS reports grants to their institution from Pfizer, Amgen, MSD, Sanofi Aventis, Daiichi-Sankyo, and Regeneron. MT reports grants, consultancy fees, other honoraria, support to attend meetings, and participation on an advisory board for Novartis. AJV-V reports grants to their institution from Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi-Sankyo, and Regeneron; consultancy fees from Bayer and Regeneron; other honoraria from Ferrer, European Atherosclerosis Society, and USA National Lipid Association; and support for attending meetings from the European Atherosclerosis Society, USA National Lipid Association, and Spanish Atherosclerosis Society. BV reports consultancy fees from Novartis, Amgen, Sanofi, and Zentiva; support to attend meetings from Zentiva; participates on a board for Novartis and Zentiva; and is the president of the Slovak Association of Atherosclerosis. LW reports grants from the National Key Research and Development Program of China and National Natural Science Foundation of China. GFW reports grants to their institution from Arrowhead Pharma, Amgen, Novartis, and Silence Therapeutics; consultancy fees from Amgen, Novartis, Sanofi, and Esperion; other honoraria from Amgen, Novartis, Sanofi, and Esperion; and support for attending meetings from Amgen, Novartis, Sanofi, and Esperion. ES reports consultancy fees to their institution from Amgen, Sanofi, Novo-Nordisk, Ionis, Merck, Novartis, and AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The familial hypercholesterolemia (FH) diagnosis is based on clinical and genetic criteria. A relevant proportion of FH patients fulfilling the criteria for definite FH have negative genetic testing. Increasing the identification of true genetic-based FH is a clinical challenge. Deepening the analysis of lipoprotein alterations could help increase the yield of genetic testing. We evaluated whether the number, size, and composition of lipoproteins assessed by 1H-NMR could increase the identification of FH patients with pathogenic gene variants., Methods: We studied 294 clinically definite FH patients, 222 (75.5%) with positive genetic testing, as the discovery cohort. As an external validation cohort, we studied 88 children with FH, 72 (81%) with positive genetic testing. The advanced lipoprotein test based on 1H-NMR (Liposcale®) was performed at baseline after a lipid-lowering drug washout of at least 6 weeks. The association of variables with genetic variants was evaluated by random forest and logistic regression. Areas under the curve (AUCs) were calculated. A predictive formula was developed and applied to the validation cohort., Results: A formula derived from nuclear magnetic resonance (NMR) lipoprotein analyses improved the identification of genetically positive FH patients beyond low-density lipoprotein (LDL)-cholesterol levels (AUC = 0.87). The parameters contributing the most to the identification formula were LDL particle number, high-density lipoprotein size, and remnant cholesterol. The formula also increases the classification of FH children with a pathogenic genetic variation., Conclusion: NMR lipoprotein profile analysis identifies differences beyond standard lipid parameters that help identify FH with a positive pathogenic gene variant, increasing the yield of genetic testing in FH patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Data describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials., Methods and Results: Following completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (LDL-C) goals [ASCVD: < 1.8 mmol/L (< 70 mg/dL); ASCVD risk equivalent: < 2.6 mmol/L (< 100 mg/dL)], percentage and absolute changes in LDL-C at end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. Mean age was 64.9 ± 9.9 years, 82.7% (n = 2709) had ASCVD, and mean baseline LDL-C was 2.9 ± 1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% [95% confidence interval (CI): 76.8, 80.0] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified., Conclusion: In the largest and longest follow-up to date with >12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile., Trial Registration Number: ClinicalTrials.gov identifier: NCT03814187., Competing Interests: Conflict of interest: R.S.W. reports receiving advisory board fees from Boehringer Ingelheim and past fees for consulting on lipid issues with The Medicines Company; F.J.R. reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, Novartis, and LIB Therapeutics; W.K. reports receiving consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen; consulting fees from Pfizer, The Medicines Company, Novartis, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Esperion, Genentech, OMEICOS, Novo Nordisk, LIB Therapeutics, Daiichi Sankyo, New Amsterdam Pharma, and TenSixteen Bio; lecture fees from Berlin-Chemie, Bristol-Myers Squibb, and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma; U.L. reports receiving grant support from Amgen, Bayer, and Novartis and advisory board fee from Novartis; L.A.L. reports grant support paid to his institution and advisory board fees and fees for CME from Amgen and Novartis; grant support paid to his institution and fees for serving on a steering committee from Kowa, The Medicines Company and Novartis; and advisory board fees and fees for CME from Amarin, AstraZeneca, HLS, Merck, New Amsterdam, Pfizer, and Sanofi; G.G.S. reports receiving research support paid to his institution from AstraZeneca, Sanofi, Silence Therapeutics, and The Medicines Company and a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado; K.K.R. reports receiving support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre; his institution (Imperial College London) receives support from the NIHR Applied Research Collaboration Northwest London. K.K.R. also reports receiving lecture fees from Aegerion Pharmaceuticals, Kowa, Cipla, Algorithm, and Zuelling Pharma; grant support paid to his institution; lecture fees and advisory board fees from Amgen, Regeneron Pharmaceuticals/Sanofi, and Pfizer; lecture fees and fees for serving on steering committees for trials from AstraZeneca and Eli Lilly; fees for serving on steering committees for trials from Cerenis Therapeutics, The Medicines Company, and Esperion; advisory board fees from Akcea Therapeutics, Novartis, Silence Therapeutics, Bayer, and Daiichi Sankyo; lecture fees and advisory board fees from Takeda, Boehringer Ingelheim, and Dr Reddy’s Laboratories; grant support and advisory board fees from Merck Sharp & Dohme; fees for serving on a clinical events adjudication committee from AbbVie; and fees for serving as principal investigator for a trial from Resverlogix; Z.T., S.V., and X.Z. are all employees of Novartis Pharmaceuticals Corp, East Hanover, New Jersey, USA and hold shares in Novartis; A.L. is employee of Novartis Pharma AG, Basel, Switzerland; P.M. was an employee of Novartis Pharma AG, Basel, Switzerland, at the time of conducting this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Familial hypercholesterolemia (FH) is a common monogenic autosomal dominant disorder, primarily mainly caused by pathogenic mutations in the low-density lipoprotein receptor (LDLR) gene. Through phenotypic-genetic linkage analysis, two LDLR pathogenic mutations were identified in FH families: c.G1027A (p.Gly343Ser) and c.G1879A (p.Ala627Thr)., Materials and Methods: Whole exome sequencing was conducted on the proband with familial hypercholesterolemia to identify the target gene and screen for potential pathogenic mutations. The suspicious responsible mutation sites in 14 family members were analyzed using Sanger sequencing to assess genotype-phenotype correlations. Mutant and wild type plasmids were constructed and transfected into HEK293T cells to evaluate LDLR mRNA and protein expression. In parallel, bioinformatics tools were employed to predict structural and functional changes in the mutant LDLR., Results: Immunofluorescence analysis revealed no significant difference in the intracellular localization of the p.Gly343Ser mutation, whereas protein expression of the p.Ala627Thr mutation was decreased and predominantly localized in the cytoplasm. Western blotting has showed that protein expression levels of the mutant variants were markedly declined in both cell lysates and supernatants. Enzyme linked immunosorbent assay has demonstrated that LDLR protein levels in the supernatant of cell culture medium was not significant different from those of the wild-type group. However, LDLR protein levels in the cell lysate of both the Gly343Ser and Ala627Thr variants groups were significantly lower than those in the wild-type group. Bioinformatic predictions further suggested that these mutations may affect post-translational modifications of the protein, providing additional insight into the mechanisms underlying the observed reduction in protein expression., Conclusions: In this study, we identified two heterozygous pathogenic variants in the LDLR gene, c.G1027A (p.Gly343Ser) and c.G1879A (p.Ala627Thr), in a family with familial hypercholesterolemia. We also conducted preliminary investigations into the mechanisms by which these mutations contribute to disease pathology., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aims: We tested the association of polygenic risk scores (PRS) for low-density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD) with LDL-C and risk of ischemic heart disease (IHD) in the Danish general population., Methods: We included a total of 21,485 individuals from the Copenhagen General Population Study and Copenhagen City Heart Study. For everyone, LDL-PRS and CAD-PRS were calculated, each based on >400,000 variants. We also genotyped four rare variants in LDLR or APOB known to cause familial hypercholesterolemia (FH)., Results: Heterozygous carriers of FH-causing variants in APOB or LDLR had a mean LDL-C of 5.40 and 6.09 mmol/L, respectively, and an odds ratio for IHD of 2.27 (95 % CI 1.43-3.51) when compared to non-carriers. The LDL-PRS explained 13.8 % of the total variation in LDL-C in the cohort. Individuals in the lowest and highest 1 % of LDL-PRS had a mean LDL-C of 2.49 and 4.75 mmol/L, respectively. Compared to those in the middle 20-80 %, those in the lowest and highest 1 % of LDL-PRS had odds ratios for IHD of 0.58 (95 % CI, 0.38-0.88) and 1.83 (95 % CI, 1.33-2.53). The corresponding odds ratios for CAD-PRS were 0.61 (95 % CI, 0.41-0.92) and 2.06 (95 % CI, 1.49-2.85)., Conclusions: The top 1 % of LDL-PRS and CAD-PRS conferred effects on LDL-C and risk of IHD comparable to those seen for carriers of rare FH-causing variants in APOB or LDLR. These results highlight the potential value of implementing such PRS clinically., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives and Aim: This study aimed to identify precise biomarkers and develop targeted therapeutic strategies for preventing premature atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia (FH) by investigating the quantitative and qualitative abnormalities in the metabolic network of lipids in these patients using an advanced lipidomics platform., Design & Methods: The study population comprised 18 homozygous (HoFH), 18 heterozygous (HeFH) FH patients, and 20 healthy controls. Cholesterol oxidation products (oxysterol, COPs) and main lipid classes were determined using gas chromatography-mass spectrometry. Results were expressed as percentages of total fat matter for lipid classes and percentages of total COPs for oxysterols. The principal component analysis (PCA) was also carried out, to highlight the correlation between studied parameters and groups investigated., Results: Patients (both HoFH and HeFH) showed lower content of free fatty acids (FFAs) and greater values of triacylglycerols (TAGs) in comparison to controls. HoFH showed lower monoacylglycerols (P<0.01) and higher free cholesterol (FC) (P<0.05) when compared to HeFH and controls. The total content of COPs ranged from 1.96 to 4.25 mg/dL, from 2.27 to 4.05 mg/dL, and from 0.79 to 4.12 mg/dL in healthy controls, HoFH and HeFH groups, respectively, with no significant differences between patients and controls. In general, the 7α-hydroxycholesterol (7α-HC) was greater than other COPs. However, no significant differences were found between the three studied groups. Moreover, an opposite trend was observed between 7α-HC and 7-ketocholesterol (7-KC). Additionally, when PCA was carried out, the first two PCs explained 92.13 % of the total variance, of which the PC1 describes 53.94 % of variance mainly correlated to TAGs, diacylglycerols (DAGs), and 7-KC. On the other hand, the PC2 was correlated primarily for FFAs, FC and esterified sterols (E-STE)., Conclusions: In conclusion, abnormal levels of TAGs, DAGs and 7-KC were associated with HeFH while HoFH was associated with the abnormal amount of E-STE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Coronary atherosclerotic burden and adverse coronary heart disease events are related phenotypes with likely shared genetic cause., Methods: We analyzed 6021 patients with available coronary angiography, genotyping, and exome sequencing data. We tested for associations of polygenic risk scores for coronary heart disease (PRS CHD ) with multiple measures of coronary artery disease (CAD) severity. We assessed the joint associations of PRS CHD and pathogenic/likely pathogenic variants in 3 familial hypercholesterolemia genes, with CAD severity. We performed mediation analyses to explore whether CAD severity mediated the association of PRS CHD with prevalent coronary heart disease and incident myocardial infarction., Results: A 1-SD increase in PRS CHD was associated with multiple measures of CAD severity, including the log Gensini score (β, 0.31 [95% CI, 0.28-0.33]). Carrying a pathogenic/likely pathogenic familial hypercholesterolemia variant was associated with a higher log Gensini score after adjustment for PRS CHD (β, 0.21 [95% CI, 0.03-0.38]). A 1-SD increase in PRS CHD was associated with incident myocardial infarction over a mean follow-up of 9.2 years (hazard ratio, 1.20 [95% CI, 1.13-1.27]; P =5×10 - 10 ), and the Gensini score mediated 90% of this association., Conclusions: PRS CHD was associated with multiple measures of CAD severity. The association of PRS CHD with incident myocardial infarction was almost fully mediated by CAD severity, indicating a considerable genetic overlap between the 2 phenotypes., Competing Interests: None.

Background and Aims: Familial hypercholesterolemia (FH) is a genetic disorder marked by high LDL cholesterol and an increased premature coronary artery disease (CAD) risk. Current dichotomous classification of LDL receptor gene (LDLR) variants may inadequately capture patient variability in LDL cholesterol levels and CAD risk. This study assessed a novel approach for determining LDLR variant severity using variant-specific LDL cholesterol percentiles., Methods: Participants of the Dutch FH cascade screening program were screened for 456 LDLR variants. For each LDLR variant carrier, a sex- and age-specific LDL cholesterol percentile was derived from the LDL cholesterol level measured at study entry, i.e. generally from the blood drawn for DNA analysis. These percentiles were used to calculate the mean LDL cholesterol percentile for each variant. Based on the variant-specific LDL cholesterol percentiles, carriers were grouped into the following LDL cholesterol strata: <75th, 75th-88th, 88th-92nd, 92nd-96.5th, 96.5th-98th, and ≥98th percentile. Additionally, variants were categorized into class 1 (LDLR deficient) and non-class 1 (often LDLR defective) variants. CAD risk between carriers in the different LDL cholesterol strata and non-carriers was compared using a Cox proportional hazard model., Results: Out of 35,067 participants, 12,485 (36 %) LDLR variant carriers (mean age 38.0 ± 20.0 years, 47.7 % male) were identified. Carriers had a 5-fold higher CAD risk compared with non-carriers. Hazard ratios for CAD increased gradually from 2.2 (95%CI 0.97-5.0) to 12.0 (95%CI 5.5-24.8) across the LDL cholesterol strata. A 7.3-fold and 3.9-fold increased CAD risk was observed in carriers of class 1 and non-class 1 LDLR variants, respectively., Conclusions: This study presents a refined approach for classifying LDLR variants based on their impact on LDL cholesterol levels, allowing for more precise, genotype-specific CAD risk estimation in FH patients compared with traditional methods., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LFR is cofounder of Lipid Tools and reports speakers fee from Ultragenyx, Novartis, and Daiichi Sankyo. JJPK is part time CSO of New Amsterdam Pharma and part time CMO of Staten Biotech and a consultant to AgBio, Scribe, Cincor, CSL Behring, CiVi Biopharma, Draupnir, Esperion Therapeutics, Madrigal, Menarini, Omeicos, Silence Therapeutics, Sirnaomics, TTxD and North Sea Therapeutics. GKH reports research grants from the Netherlands Organization for Scientific Research (vidi 016.156.445), CardioVascular Research Initiative, European Union and the Klinkerpad fonds, institutional research support from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis, Kowa, Pfizer, Regeneron, Roche, Sanofi, and The Medicines Company; speaker's bureau and consulting fees from Amgen, Aegerion, Sanofi, and Regeneron until April 2019 (fees paid to the academic institution); and part-time employment and stock holder of at Novo Nordisk A/S, Denmark since April 2019. ESGS has received ad-board/lecturing fees, paid to the institution, from: Amgen, Sanofi, Astra-Zeneca, Esperion, Daiichi Sankyo, NovoNordisk, Ionis/Akcea, Amarin. The other authors report no disclosures., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: As a mega-biobank linked to a national healthcare system, the Million Veteran Program (MVP) can directly improve the health care of participants. To determine the feasibility and outcomes of returning medically actionable genetic results to MVP participants, the program launched the MVP Return of Actionable Results (MVP-ROAR) Study, with familial hypercholesterolemia (FH) as an exemplar actionable condition., Methods: The MVP-ROAR Study consists of a completed single-arm pilot phase and an ongoing randomized clinical trial (RCT), in which MVP participants are recontacted and invited to receive clinical confirmatory gene sequencing testing and a telegenetic counseling intervention. The primary outcome of the RCT is 6-month change in low-density lipoprotein cholesterol (LDL-C) between participants receiving results at baseline and those receiving results after 6 months., Results: The pilot developed processes to identify and recontact participants nationally with probable pathogenic variants in low-density lipoprotein receptor (LDLR) on the MVP genotype array, invite them to clinical confirmatory gene sequencing, and deliver a telegenetic counseling intervention. Among participants in the pilot phase, 8 (100%) had active statin prescriptions after 6 months. Results were shared with 16 first-degree family members. Six-month ΔLDL-C (low-density lipoprotein cholesterol) after the genetic counseling intervention was -37 mg/dL (95% CI: -12 to -61; P = .03). The ongoing RCT will determine between-arm differences in this primary outcome., Conclusion: While underscoring the importance of clinical confirmation of research results, the pilot phase of the MVP-ROAR Study marks a turning point in MVP and demonstrates the feasibility of returning genetic results to participants and their providers. The ongoing RCT will contribute to understanding how such a program might improve patient health care and outcomes., Clinical Trial Registration: ClinicalTrials.gov ID NCT04178122., (Published by Elsevier Inc.)

Familial hypercholesterolemia (FH) poses a global health challenge due to high incidence rates and underdiagnosis, leading to increased risks of early-onset atherosclerosis and cardiovascular diseases. Early detection and treatment of FH is critical in reducing the risk of cardiovascular events and improving the long-term outcomes and quality of life for affected individuals and their families. Traditional therapeutic approaches revolve around lipid-lowering interventions, yet challenges persist, particularly in accurate and timely diagnosis. The current diagnostic landscape heavily relies on genetic testing of specific LDL-C metabolism genes, often limited to specialized centers. This constraint has led to the adoption of alternative clinical scores for FH diagnosis. However, the rapid advancements in artificial intelligence (AI) and machine learning (ML) present promising solutions to these diagnostic challenges. This review explores the intricacies of FH, highlighting the challenges that are encountered in the diagnosis and management of the disorder. The revolutionary potential of ML, particularly in large-scale population screening, is highlighted. Applications of ML in FH screening, diagnosis, and risk stratification are discussed, showcasing its ability to outperform traditional criteria. However, challenges and ethical considerations, including algorithmic stability, data quality, privacy, and consent issues, are crucial areas that require attention. The review concludes by emphasizing the significant promise of AI and ML in FH management while underscoring the need for ethical and practical vigilance to ensure responsible and effective integration into healthcare practices., (Copyright © 2023. Published by Elsevier B.V.)

Background and Objectives: Familial hypercholesterolemia (FH) is a genetic disease that is massively underdiagnosed worldwide. Affected patients are at high risk of cardiovascular events at young ages. Early intervention in childhood could help prevent heart attacks and cerebral strokes in these patients. Materials and Methods: We conducted an interventional study including 10 patients that previously underwent genetic testing for familial hypercholesterolemia. These patients received lifestyle and diet recommendations that they followed for a year before being reevaluated. Results: Patients with negative genetic testing were able to achieve lower levels in their lipid panel values compared to the patients with positive genetic testing, with lifestyle changes alone. LDL-cholesterol levels decreased by 18.5% in patients without FH while patients genetically confirmed with FH failed to achieve lower LDL-cholesterol levels without medication. Conclusions: Genetic testing for FH is not always part of screening algorithms for FH. Some studies even advise against it. Our study proved the importance of genetic testing for FH when suspecting this disorder and choosing the treatment course for patients.

Familial hypercholesterolemia (FH) is a genetic disorder that results in elevated low-density lipoprotein cholesterol (LDL-C) levels, which manifest early in the first decades of life. It is a major cause of premature coronary artery disease worldwide, leading to significant public health challenges. The prevalence of genetically determined FH in patients with premature coronary artery disease remains underestimated, particularly in developing countries. This study aimed to assess the prevalence of genetically defined FH in Vietnamese patients with premature acute myocardial infarction (AMI) in the Vietnamese population. This cross-sectional study enrolled 218 consecutive patients diagnosed with premature AMI who underwent coronary angiography. The low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin-kexin type 9 genes were analyzed by next-generation sequencing. FH was diagnosed according to Dutch Lipid Clinic Network criteria. Among the patients with premature AMI who underwent coronary angiography, the mean age was 46.9 ± 6.1 years, with a predominance of males (83.9%). The prevalence of potential FH diagnosed using Dutch Lipid Clinic Network criteria was 14.7% (definite FH, 6.0%; probable FH, 8.7%). Pathogenic or likely pathogenic variants in LDLR, apolipoprotein B, and proprotein convertase subtilisin-kexin type 9 were found in 9 of 218 patients (4.1%), all of which were causative mutations in LDLR. Patients with premature AMI and FH had significantly greater LDL-C levels (217.6 vs 125.7 mg/dL) and more severe coronary artery lesions, as assessed by the Gensini score (100.3 vs 60.5), than did those in the No FH group. The prevalence of genetically determined FH among Vietnamese patients with premature AMI is relatively high. Screening and diagnosis of hereditary conditions in patients with premature AMI are essential to improve early detection and management and reduce the burden of coronary artery disease in this population., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Familial hypercholesterolemia (FH) is the most significant inherited risk factor for coronary heart disease (CHD). Current guidelines focus on monogenic FH, but the polygenic form is more common and less understood. This study aimed to assess the clinical utility of an 8-SNP LDLC polygenic score in a central Romanian cohort. The cohort included 97 healthy controls and 125 patients with premature (P)CHD. The weighted LDLC polygenic risk score (wPRS) was analyzed for associations with relevant phenotypic traits, PCHD risk, and clinical FH diagnosis. The wPRS positively correlated with LDLC and DLCN scores, and LDLC concentrations could be predicted by wPRS. A trend of increasing LDLC and DLCN scores with wPRS deciles was observed. A +1 SD increase in wPRS was associated with a 36% higher likelihood of having LDLC > 190 mg/dL and increases in LDLC (+0.20 SD), DLCN score (+0.16 SD), and BMI (+0.15 SD), as well as a decrease in HDLC (-0.14 SD). Although wPRS did not predict PCHD across the entire spectrum of values, individuals above the 90th percentile were three times more likely to have PCHD compared to those within the 10th or 20th percentiles. Additionally, wPRS > 45th percentile identified "definite" clinical FH (DLCN score > 8) with 100% sensitivity and 45% specificity. The LDLC polygenic score correlates with key phenotypic traits, and individuals with high scores are more likely to have PCHD. Implementing this genetic tool may enhance risk prediction and patient stratification. These findings, the first of their kind in Romania, are consistent with the existing literature.

Familial hypercholesterolemia (FH) is a genetic disease that leads to elevated low-density lipoprotein cholesterol levels and risk of coronary heart disease. Current therapeutic options for FH remain relatively limited and only partially effective in both lowering low-density lipoprotein cholesterol and modifying coronary heart disease risk. The unique characteristics of nucleic acid therapies to target the underlying cause of the disease can offer solutions unachievable with conventional medications. DNA- and RNA-based therapeutics have the potential to transform the care of patients with FH. Recent advances are overcoming obstacles to clinical translation of nucleic acid-based medications, including greater stability of the formulations as well as site-specific delivery, making gene-based therapy for FH an alternative approach for treatment of FH., Competing Interests: None.

Background: The atherogenic characteristics of heterozygous familial hypercholesterolemia (HeFH) increase the risk of premature atherosclerotic cardiovascular disease including not only coronary artery disease but ischemic stroke. Asymptomatic intracranial artery stenosis/occlusion (IASO) is a major cause of ischemic stroke, but it has not yet been fully characterized in patients with HeFH., Methods and Results: This study analyzed 147 clinically diagnosed subjects with HeFH who underwent magnetic resonance imaging/magnetic resonance angiography imaging for evaluation of IASO (≥50% diameter stenosis). Major adverse cerebrovascular and cardiovascular events (cardiac death, ischemic stroke, and acute coronary syndrome) were compared in patients with HeFH with and without asymptomatic IASO. Asymptomatic IASO was observed in 13.6% of patients with HeFH. The untreated low-density lipoprotein cholesterol level (240±95 versus 244±75 mg/dL; P =0.67) did not differ between the 2 groups. Despite the use of lipid-lowering therapies (statin, P =0.71; high-intensity statin, P =0.81; ezetimibe, P =0.33; proprotein convertase subxilisin/kexin type 9 inhibitor, P =0.39; low-density lipoprotein apheresis, P =0.14), on-treatment low-density lipoprotein cholesterol level in patients with both HeFH and IASO was still suboptimally controlled (97±62 versus 105±50 mg/dL; P =0.17), accompanied by a higher triglyceride level (median, 109 versus 79 mg/dL; P =0.001). During the 12.4-year observational period (interquartile range, 6.2-24.6 years), asymptomatic IASO exhibited a 4.04-fold greater likelihood of experiencing a major adverse cardiovascular event (95% CI, 1.71-9.55; P =0.001) in patients with HeFH. This increased risk of a major adverse cardiovascular event was consistently observed in a multivariate Cox proportional hazards model adjusting clinical characteristics (hazard ratio, 4.32 [95% CI, 1.71-10.9]; P =0.002)., Conclusions: A total of 13.6% of Japanese subjects with HeFH presented with asymptomatic IASO. Despite lipid-lowering therapies, patients with both HeFH and IASO more likely had elevated risk of cerebrovascular and cardiovascular events. Our findings highlight asymptomatic IASO as a phenotypic feature of HeFH-related atherosclerosis, which ultimately affects future outcomes.

Purpose of Review: Autosomal dominant hypercholesterolemia is a common cause of cardiovascular disease. In addition to the classic genes that cause hypercholesterolemia, LDLR, APOB and PCSK9 , a new locus has emerged as a candidate to be the cause of this hyperlipidemia, the p.(Leu167del) mutation in the APOE gene., Recent Findings: Various studies have demonstrated the involvement of the p.(Leu167del) mutation in the APOE gene in hypercholesterolemia: Studies of family segregation, lipoprotein composition by ultracentrifugation and proteomic techniques, and functional studies of VLDL-carrying p.(Leu167del) internalization with cell cultures have demonstrated the role of this mutation in the cause of hypercholesterolemia. The phenotype of individuals carrying the p.(Leu167del) in APOE is indistinguishable from familial hypercholesterolemia individuals with mutations in the classic genes. However, a better response to lipid-lowering treatment has been demonstrated in these APOE mutation carrier individuals., Summary: Therefore, APOE gene should be considered a candidate locus along with LDLR, APOB , and PCSK9 to be investigated in the genetic diagnosis of familial hypercholesterolemia., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Familial Hypercholesterolemia (FH) is a common genetic disorder characterized by lifelong elevation of severely elevated plasma low-density lipoprotein cholesterol. Atherosclerotic cardiovascular disease (ASCVD) risk accelerates after age 20. Early diagnosis allows for treatment of children with FH and creates an opportunity to identify affected relatives through reverse cascade screening (RCS). Historically, cascade screening has had little impact on identifying individuals with FH., Recent Findings: Universal cholesterol screening (UCS) to identify youth with FH, beginning at 9-11 years-of-age, is currently recommended in the U.S. The European Atherosclerosis Society has called for UCS worldwide, emphasizing the need for educational programs to increase awareness amongst healthcare professions. Underdiagnoses and undertreatment of FH remain high. Improved rates of UCS and a systematic approach to RCS are needed. The absence of a coordinated RCS program limits the benefits of UCS. Further research is needed to identify barriers to cholesterol screening in youth., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Familial hypercholesterolemia (FH) is a genetic disorder affecting the metabolism of lipoprotein, characterized by elevated levels of plasma concentrations of low-density lipoprotein cholesterol (LDLC). The most common FH cause is mutations within the gene that encodes for the LDL receptor (LDLR) protein. Two induced pluripotent stem cell (iPSC) lines were generated from patients with FH, each carrying a single heterozygous mutation in the LDLR gene, one is a missense mutation, c.631C > T, and the other is a splice-site mutation, c.313 + 1G > A. Both iPSC lines exhibited strong expression of pluripotency markers, demonstrated the ability to differentiate into derivatives of the three germ layers, and maintained normal karyotypes. These derived iPSC lines represent powerful tools for in vitro modeling FH and offer a promising platform for therapeutic development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JCW is a co-founder and scientific advisory board member of Greenstone Biosciences. The other authors affirm that they do not possess any known competing financial interests or personal relationships that could have influenced the work presented in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Familial Hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism that causes an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Although early diagnosis and treatment of FH can significantly improve the cardiovascular prognosis, this disorder is underdiagnosed and undertreated. For these reasons the Italian Society for the Study of Atherosclerosis (SISA) assembled a Consensus Panel with the task to provide guidelines for FH diagnosis and treatment., Data Synthesis: Our guidelines include: i) an overview of the genetic complexity of FH and the role of candidate genes involved in LDL metabolism; ii) the prevalence of FH in the population; iii) the clinical criteria adopted for the diagnosis of FH; iv) the screening for ASCVD and the role of cardiovascular imaging techniques; v) the role of molecular diagnosis in establishing the genetic bases of the disorder; vi) the current therapeutic options in both heterozygous and homozygous FH. Treatment strategies and targets are currently based on low-density lipoprotein cholesterol (LDL-C) levels, as the prognosis of FH largely depends on the magnitude of LDL-C reduction achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment. Addition of novel medications like PCSK9 inhibitors, ANGPTL3 inhibitors or lomitapide in homozygous FH results in a further reduction of LDL-C levels. LDL apheresis is indicated in FH patients with inadequate response to cholesterol-lowering therapies., Conclusion: FH is a common, treatable genetic disorder and, although our understanding of this disease has improved, many challenges still remain with regard to its identification and management., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, which increases the risk of premature coronary artery disease. Early detection and treatment are vital, especially in children. To improve FH diagnosis in children, the Japan Atherosclerosis Society (JAS) released new guidelines in July 2022. This study assessed and compared the sensitivity and specificity of the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022., Methods: From September 2020 to March 2023, 69 children with elevated plasma LDL-C levels (≥ 140 mg/dL) were included in a pediatric FH screening project in Kagawa. The children were evaluated using genetic testing alongside the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022., Results: Using the JAS pediatric FH 2017 criteria, eight children were diagnosed as FH-positive and 61 children as FH-negative. The JAS pediatric FH 2022 criteria identified 15 children with definite FH, 31 with probable FH, and 23 with possible FH. Genetic testing detected FH pathogenic variants in 24 children. The sensitivity and specificity for the JAS pediatric FH 2017 criteria were 0.292 and 0.978, respectively. For the JAS pediatric FH 2022 criteria, the sensitivity was 0.542 for definite FH with a specificity of 0.956, and 0.917 for probable FH with a specificity of 0.467., Conclusion: The clinical diagnostic criteria of the JAS pediatric FH 2022 guidelines demonstrated improved diagnostic efficiency compared with those of 2017, as evidenced by the increased sensitivity while preserving specificity.

Background: Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH., Methods: We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease., Results: Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant., Conclusions: Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH., Competing Interests: Disclosures L.R. Brunham reports advisory fees from Amgen, HLS Therapeutics, Novartis, Novo Nordisk, and Ultragenyx. A. Baass reports advisory fees from Akcea, Amgen, and Sanofi. R.A. Hegele reports advisory fees from Akcea, Amgen, HLS Therapeutics, Novartis, Pfizer, Regeneron, Sanofi, and Ultragenyx. J. Genest reports advisory fees from Amgen, Novartis, Sanofi, and Ultragenyx. The other authors report no conflicts.

Background: In Slovakia, a mandatory national universal pediatric total cholesterol (TC) screening program is in place to identify cases of familial hypercholesterolemia (FH). However, the program's effectiveness has not been systematically assessed., Objective: This study aimed to estimate the prevalence of FH among parents of children that had elevated TC levels identified during screening., Methods: This prospective, non-interventional, observational study enrolled parents of 11-year-old children who underwent TC screening in 23 selected pediatric outpatient clinics between 2017 and 2018. FH was diagnosed using the Dutch Lipid Clinic Network (DLCN) criteria and targeted next-generation sequencing. The primary objective was to estimate the proportion of children with a TC level of >188 mg/dL (>4.85 mmol/L) who had a parent with a confirmed diagnosis of FH., Results: A total of 112 parents of 56 children with an elevated TC level were enrolled. Five children (8.9%) had a parent in whom FH was genetically confirmed. Without genetic analysis, all five parents would only be diagnosed with "possible FH" by DLCN criteria. Of parents, 83.9% (n = 94/112) had an low-density lipoprotein cholesterol (LDL-C) level of >116 mg/dL (>3 mmol/L), but only 5.3% (n = 5/94) received lipid-lowering therapy. Among the five parents with genetically confirmed FH, all had an LDL-C level >116 mg/dL (>3 mmol/L), with a mean (±SD) of 191 (±24) mg/dL (4.94 [±0.61] mmol/L). Only two of these parents received lipid-lowering therapy., Conclusions: The present study demonstrates the significance of mandatory universal pediatric TC screening in identifying families with FH and other at-risk families in need of lipid-lowering therapy., Competing Interests: Declaration of Competing Interest K. R. received lecture fees from Amgen, Novartis, Sanofi, Novo Nordisk, Mylan, and Boehringer Ingelheim. T. F. was supported by the National Institute for Research of Metabolic and Cardiovascular Diseases (Program EXCELES, ID Project No. LX22NPO5104), funded by the European Union – Next Generation EU. T. F. also received honoraria from Novartis in the last three years outside the submitted work. B. V. received honoraria from Amgen, Novartis, Sanofi, Novo Nordisk, Viatris, Zentiva, and Boehringer Ingelheim in the last three years outside of the submitted work. I. B., D. B., and M. Z. are employees of Amgen and hold Amgen stock. V. D., K. G., A. K., and L. T. declare that they have no known competing financial interests or personal relationships that may have influenced the work reported in this study., (Copyright © 2024. Published by Elsevier Inc.)

Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder causing elevated low density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. Universal cholesterol screening in childhood leads to children serving as the index case for their family, but efficacy of cascade screening and genetic counseling in this population is not well understood. The institutional pediatric lipid clinic database was queried from 2011 to 2022 for subjects <18 years who met clinical HeFH diagnostic criteria (N = 256). Median peak LDL-C was 198 mg/dL (interquartile range 179-238 mg/dL) and 69.5 % of subjects were the index case. The number of new HeFH cases identified per index case was 3.55 ± 1.87. Genetic counseling was offered to 38.7 % of subjects and genetic testing was completed by 10.9 %, 53.6 % of whom had a pathogenic or likely pathogenic genetic variant for HeFH. Our findings highlight the effectiveness of cascade screening from pediatric index cases identified through universal screening. However, genetic counseling and genetic testing may be underutilized in this population., Competing Interests: Declaration of competing interest Ms. Lentz, Dr. Zhang, and Ms. Benoy declare no conflict of interest. Dr. Peterson's work has been funded by the NIH. She serves as a steering committee member for Novartis Pharmaceuticals but receives no compensation for this role., (Copyright © 2024. Published by Elsevier Inc.)

Background: Familial Hypercholesterolaemia (FH) is a greatly underdiagnosed and treatable genetic lipid disorder which significantly increases risk of premature cardiovascular disease. The prevalence of monogenic FH is thought to be 1 in 250-350. The NHS Long Term Plan aims to increase FH detection to at least 25% over 5 years in collaboration with primary care, supported by the NHS genomics programme., Aim: This systematic review evaluates systematic screening methods for FH in adults aged ≥18 years in primary care., Method: Seven databases [Cochrane, PubMed, Ovid, CINAHL, ProQuest, Web of Science, Scopus], four clinical trial registries [ISRCTN, ANZCTR, Clinicaltrials.gov, WHO-ICTRP] and relevant grey literature [OpenGrey] from March 2020 to May 2023 were searched. Only studies including adults were eligible. Risk of bias was assessed using ROBINS-I., Results: 831 records were screened. No randomised, controlled studies were identified. From full-text review, five eligible non-randomised studies out of 57 (6.90%) were identified. The included studies all used automated FH case-identification from electronic medical records (EMR) and were high quality studies with a moderate risk of bias. Narrative synthesis reported outcomes which included three algorithmic studies, with a pooled detection rate, DR 14.4% (95%CI 11.67-16.62), one supervised Machine Learning [Ensemble] study, DR 15.5% (95%CI 15.47-15.53) and one study utilising a hybrid diagnostic EMR model and/or FH genotype confirmation DR 25.0% (95%CI 16.30-35.8). No adverse effects were reported in these studies., Conclusion: Incorporating automated case-finding from EMR with clinical follow-up in primary care can enhance FH identification. Pathways incorporating genotyping showed the best detection rate., (© British Journal of General Practice 2024.)

Background: Familial hypercholesterolemia (FH), while highly prevalent, is a significantly underdiagnosed monogenic disorder. Improved detection could reduce the large number of cardiovascular events attributable to poor case finding. We aimed to assess whether machine learning algorithms outperform clinical diagnostic criteria (signs, history, and biomarkers) and the recommended screening criteria in the United Kingdom in identifying individuals with FH-causing variants, presenting a scalable screening criteria for general populations., Methods and Results: Analysis included UK Biobank participants with whole exome sequencing, classifying them as having FH when (likely) pathogenic variants were detected in their LDLR , APOB , or PCSK9 genes. Data were stratified into 3 data sets for (1) feature importance analysis; (2) deriving state-of-the-art statistical and machine learning models; (3) evaluating models' predictive performance against clinical diagnostic and screening criteria: Dutch Lipid Clinic Network, Simon Broome, Make Early Diagnosis to Prevent Early Death, and Familial Case Ascertainment Tool. One thousand and three of 454 710 participants were classified as having FH. A Stacking Ensemble model yielded the best predictive performance (sensitivity, 74.93%; precision, 0.61%; accuracy, 72.80%, area under the receiver operating characteristic curve, 79.12%) and outperformed clinical diagnostic criteria and the recommended screening criteria in identifying FH variant carriers within the validation data set (figures for Familial Case Ascertainment Tool, the best baseline model, were 69.55%, 0.44%, 65.43%, and 71.12%, respectively). Our model decreased the number needed to screen compared with the Familial Case Ascertainment Tool (164 versus 227)., Conclusions: Our machine learning-derived model provides a higher pretest probability of identifying individuals with a molecular diagnosis of FH compared with current approaches. This provides a promising, cost-effective scalable tool for implementation into electronic health records to prioritize potential FH cases for genetic confirmation.

Background: Familial hypercholesterolemia (FH) is a common inherited metabolic disease that causes premature atherosclerosis, cardiovascular disease, and even death at a young age. Approximately 95% of FH-causing genetic variants that have been identified are in the LDLR gene. However, only 10% of the FH population worldwide has been diagnosed and adequately treated, due to the existence of numerous unidentified variants, uncertainties in the pathogenicity scoring of many variants, and a substantial number of individuals lacking access to genetic testing., Objective: The aim of this study was to identify a novel variant in the LDLR gene that causes FH in a Chinese family, thereby expanding the spectrum of FH-causing variants., Methods: Patients were recruited from Beijing Anzhen Hospital, Capital Medical University. FH diagnosis was made according to the Dutch Lipid Clinical Network (DLCN) criteria. Whole-exome sequencing (WES) was conducted to identify the FH-causing variant in the proband, and amplicon sequencing was used to verify the variant in his family members., Results: A three-generation Chinese family was recruited, and two FH patients were clinically diagnosed, both without known FH-causing variants. These two FH patients and another possible patient carried a novel variant, NC&#95;000019.9(NM&#95;000527.5):c.89&#95;92dup (NP&#95;000518.1:p.Phe32Argfs*21), in the ligand-binding domain of the low-density lipoprotein (LDL) receptor that led to a frameshift. The FH adults in the family showed severe clinical symptoms and statin therapy resistance., Conclusion: This study identified a novel pathogenic LDLR variant, c.89&#95;92dup, associated with severe FH clinical manifestations and statin therapy resistance., (© 2024. The Author(s).)

Aims: The availability of novel lipid-lowering therapies (LLTs) has remarkably changed the clinical management of homozygous familial hypercholesterolaemia (HoFH). The impact of these advances was evaluated in a cohort of 139 HoFH patients followed in a real-world clinical setting., Methods and Results: The clinical characteristics of 139 HoFH patients, along with information about LLTs and low-density lipoprotein cholesterol (LDL-C) levels at baseline and after a median follow-up of 5 years, were retrospectively retrieved from the records of patients enrolled in the LIPid transport disorders Italian GEnetic Network-Familial Hypercholesterolaemia (LIPIGEN-FH) Registry. The annual rates of major atherosclerotic cardiovascular events (MACE-plus) during follow-up were compared before and after baseline. Additionally, the lifelong survival free from MACE-plus was compared with that of the historical LIPIGEN HoFH cohort. At baseline, LDL-C level was 332 ± 138 mg/dL. During follow-up, the potency of LLTs was enhanced and, at the last visit, 15.8% of patients were taking quadruple therapy. Consistently, LDL-C decreased to an average value of 124 mg/dL corresponding to a 58.3% reduction (Pt < 0.001), with the lowest value (∼90 mg/dL) reached in patients receiving proprotein convertase subtilisin/kexin type 9 inhibitors and lomitapide and/or evinacumab as add-on therapies. The average annual MACE-plus rate in the 5-year follow-up was significantly lower than that observed during the 5 years before baseline visit (21.7 vs. 56.5 per 1000 patients/year; P = 0.0016)., Conclusion: Our findings indicate that the combination of novel and conventional LLTs significantly improved LDL-C control with a signal of better cardiovascular prognosis in HoFH patients. Overall, these results advocate the use of intensive, multidrug LLTs to effectively manage HoFH., Competing Interests: Conflict of interest: Mar.A. received research grant support from Amryt Pharmaceutical, Amgen, IONIS, Akcea Therapeutics, Daiichi-Sankyo, Novartis, Pfizer, and Regeneron; served as a consultant for Amgen, Akcea Therapeutics, Daiichi-Sankyo, and Ultragenyx; and received fees for lecturing, congress participation, and advisory board participation from Amgen, Amryt Pharmaceutical, Daiichi-Sankyo, Regeneron, Sanofi, Amarin, and Ultragenyx. R.A. received consulting fees from GSK-Galaxosmithline. Si.B. received fees for lectures from SOBI; detains stock options of Eli Lilly, UnitedHealth, Novo Nordisk, Merck, and Thermo Fisher Scientific; and received grants for meeting participation from Novartis. M.B. received fees for lectures from Menarini, Servier, Alfasigma, Neopharmed, Aurora, Biopharma, Amryt, Novartis, Sanofi, and Viatris and received fees for participations in meeting from Ultragenyx, Daiichi-Sankyo, Lusofarmaco, and Sanofi. Carubbi F received grants for lectures and meeting participation from Amgen and Amryt, received funding for grants from Sanofi and Amgen, and received funding for data monitoring and lectures from Sanofi. A.L.C. received funding for consulting, lectures, and meeting attendance from Amgen, AstraZeneca, Aegerion, Amryt, Daiichi-Sankyo, Esperion, Kowa, Ionis Pharma, Mylan, Merck, Menarini, Novartis, Recordati, Regeneron, Sandoz, Sanofi, and Viatris and also received research grants from Sanofi, Eli Lilly, Amgen, Menarini, Sanofi-Regeneron, and Mylan. L.D. received personal fees for public speaking or consultancy or grant support from Amryt Pharmaceutical, Akcea Therapeutics, SOBI, AuroraBiopharma, Novartis, Amarin, Daiichi-Sankyo, Bayer, and Sandoz. F.F. received consulting funds from Merck. G.I. received funds for research grants from Amryt and Ultragenix; lecture fees from Novartis, Sanofi, Lusofarmaco, and Agaton; funds for meeting attendance from Ultragenix; and funds for data monitoring from Novartis, Agaton, and Sanofi; G.M. received research grants from Daiichi-Sankyo and Novartis; lecture fees from Amgen, Eli Lilly, and Neopharmed; fund for meeting attendance from Amgen; and funds for data monitoring from Sanofi-Aventis, Daiichi-Sankyo, Amrin, and Novo Nordisk. F.N. received fees for consulting, lectures, and data monitoring from Sanofi. C.P. received fees for lectures from SOBI. L.P. received fees for lectures from Amgen, Sanofi, and Amryt and received funding for meeting attendance from Sanofi, Ultragenyx, and Daiichi-Sankyo; D.T. received fees for lectures from SOBI. J.P.W. received fees for lectures from Servier, Novartis, Daiichi-Sankyo, Sanofi, and Amgen and received funding for meeting attendance from Daiichi-Sankyo, Amgen, and MSD. A.Z. received fees for lectures from Amgen, Sanofi, Amarin, Amryt, Abbott, Viatris, Novartis, Daiichi-Sankyo, Alfasigma, and Servier. The other authors have no conflicts of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Familial hypercholesterolemia is an underdiagnosed genetic metabolic condition limiting the clearance of low-density lipoprotein cholesterol and increasing lifetime risk of cardiovascular disease. Population genetic screening in unselected individuals could quickly identify cases of familial hypercholesterolemia and enable early prevention, but the economic impact of widespread screening on patients has not been studied., Methods: We assessed the cost-effectiveness of population genetic screening for familial hypercholesterolemia in 20 and 35-year-old adults in the United States from the perspective of patients. We developed a decision tree Markov hybrid model to examine diagnoses, cardiovascular disease, cardiac events, quality of life, and costs under population genetic screening compared to family-based cascade testing., Results: While population genetic screening increased diagnoses and reduced incidence of cardiovascular disease, population genetic screening was not cost-effective compared to cascade testing at current levels of willingness to pay. Lower genetic testing costs, combined screening with other genetic conditions, and support to maintain lipid-lowering therapy use over time could improve the cost-effectiveness of population genetic screening., Conclusions: Future research is needed to examine how cost-sharing strategies may affect the cost-effectiveness of screening to patients and how families and providers experience the clinical and economic outcomes of population screening., Competing Interests: Declaration of competing interest LEH received predoctoral fellowship funding from Bristol Myers Squibb. MCR's spouse holds stock in Merck and Thermo Fisher Scientific. LPS has received salary support paid to her institution for an unrelated study from AstraZeneca. CT, DMC, and KCT have no conflicts of interest to report., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Patients with homozygous familial hypercholesterolemia (HoFH) remain at very high cardiovascular risk despite the best standard of care lipid-lowering treatment. The addition of evinacumab, an angiopoietin-like protein 3 monoclonal antibody, more than halves low-density lipoprotein cholesterol in short-term studies. This study evaluated whether the evinacumab response was durable in the long term and improved cardiovascular outcome., Methods: The OLE ELIPSE HoFH (Open-Label Extension to Evinacumab Lipid Studies in Patients With HoFH) study included newly diagnosed patients and those completing the ELIPSE HoFH trial, on stable lipid-lowering therapy including lipoprotein apheresis but not lomitapide. All patients received evinacumab (15 mg/kg intravenously) every 4 weeks, with no change in concomitant lipid-lowering treatment during the first 6 months. The primary efficacy end points were the mean absolute and percentage changes in low-density lipoprotein cholesterol from baseline to 6 months. A key secondary end point was cardiovascular event-free survival, which was compared with a control HoFH cohort not treated with evinacumab or lomitapide and matched for age, sex, and lipoprotein apheresis, derived from French Registry of Familial hypercholesterolemia., Results: Twelve patients, 5 women and 7 men (12-57 years), were enrolled in 3 centers in France. At 6 months, the mean low-density lipoprotein cholesterol reduction with evinacumab was 3.7 mmol/L or 56% (from 6.5 mmol/L at baseline to 2.8 mmol/L; P <0.0001) and was sustained over the median 3.5-year follow-up. No patients on evinacumab experienced cardiovascular events versus 13 events for 5/21 (24%) over 4 years in the control cohort (likelihood P =0.0267)., Conclusions: Real-life, long-term evinacumab adjunctive to lipid-lowering therapy including lipoprotein apheresis led to sustained low-density lipoprotein cholesterol lowering and improved cardiovascular event-free survival of patients with HoFH., Competing Interests: Disclosures S. Béliard reports grants/honoraria from Ultragenyx for clinical trials and consultancy and from Amarin, Amgen, Amryt Novartis, Sanofi for clinical trials, conferences and consultancy. R. Valero reports personal or institutional honoraria for speakers’ bureaux, consultancy, clinical trials and travel/accommodation for professional purposes from Adelia Médical, Akcea, Amarin, Amgen, AstraZeneca, Boehringer-Ingelheim, Dinno Santé, Ionis, Janssen, Lilly, Merck and Co., Nestlé, Novartis, Novo Nordisk, Orkyn, Pfizer, Sanofi-Regeneron, Servier. E. Bruckert reports grants/honoraria for clinical trials/consultancy from MSD, Astra Zeneca, Genfit, Amgen, Sanofi-Aventis, Aegerion/Amryt, Lilly, Mylan/Viatris, Novartis, Pfizer, Servier, Organon, Akcea Therapeutics, and Ultragenyx. M. Farnier reports consultancy honoraria from Abbott, Amarin, Amgen, AstraZeneca, Austell, Kowa, Merck and Co., Organon, Pfizer, Recordati, Sanofi/Regeneron, Servier, SMB, Ultragenyx, and Viatris. A. Gallo reports research grants and honoraria from Amgen, Sanofi and Regeneron, Mylan Viatris, Merck and Co., Akcea Therapeutics, Amryt, Novartis, Servier, Ultragenyx, Amarin, and Eli Lilly. The other authors report no conflicts.

Background and Aims: Familial hypercholesterolemia (FH) is a highly prevalent genetic disorder resulting in markedly elevated LDL cholesterol levels and premature coronary artery disease. FH underdiagnosis and undertreatment require novel detection methods. This study evaluated the effectiveness of using an LDL cholesterol cut-off ≥99.5th percentile (sex- and age-adjusted) to identify clinical and genetic FH, and investigated underutilization of genetic testing and undertreatment in FH patients., Methods: Individuals with at least one prior LDL cholesterol level ≥99.5th percentile were selected from a laboratory database containing lipid profiles of 590,067 individuals. The study comprised three phases: biochemical validation of hypercholesterolemia, clinical identification of FH, and genetic determination of FH., Results: Of 5614 selected subjects, 2088 underwent lipid profile reassessment, of whom 1103 completed the questionnaire (mean age 64.2 ± 12.7 years, 48% male). In these 1103 subjects, mean LDL cholesterol was 4.0 ± 1.4 mmol/l and 722 (65%) received lipid-lowering therapy. FH clinical diagnostic criteria were met by 282 (26%) individuals, of whom 85% had not received guideline-recommended genetic testing and 97% failed to attain LDL cholesterol targets. Of 459 individuals consenting to genetic validation, 13% carried an FH-causing variant, which increased to 19% in clinically diagnosed FH patients., Conclusions: The identification of a substantial number of previously undiagnosed and un(der)treated clinical and genetic FH patients within a central laboratory database highlights the feasibility and clinical potential of this targeted screening strategy; both in identifying new FH patients and in improving treatment in this high-risk population., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure and stability., Methods: Clinical and laboratory data were obtained from 144 adult FH patients treated with statins. A panel of 32 PD genes was analyzed by exon-targeted gene sequencing. Deleterious variants were identified using prediction algorithms and their structural effects were analyzed by molecular modeling studies., Results: A total of 102 variants were predicted as deleterious (83 missense, 8 stop-gain, 4 frameshift, 1 indel, 6 splicing). The variants ABCA1 rs769705621 (indel), LPA rs41267807 (p.Tyr2023Cys) and KIF6 rs20455 (p.Trp719Arg) were associated with reduced low-density lipoprotein cholesterol (LDLc) response to statins, and the LPL rs1801177 (p.Asp36Asn) with increased LDLc response (P < 0.05). LPA rs3124784 (p.Arg2016Cys) was predicted to increase statin response (P = 0.022), and ABCA1 rs769705621 to increase the risk of statin-related adverse events (SRAE) (P = 0.027). LPA p.Arg2016Cys and LPL p.Asn36Asp maintained interactions with solvent, LPA p.Tyr2023Cys reduced intramolecular interaction with Gln1987, and KIF6 p.Trp719Arg did not affect intramolecular interactions. DDMut analysis showed that LPA p.Arg2016Cys and p.Tyr2023Cys and LPL p.Asp36Asn caused energetically favorable changes, and KIF6 p.Trp719Arg resulted in unfavorable energetic changes, affecting protein stability., Conclusion: Deleterious variants in ABCA1, LPA, LPL and KIF6 are associated with variability in LDLc response to statins, and ABCA1 rs769705621 is associated with SRAE risk in FH patients. Molecular modeling studies suggest that LPA p.Tyr2023Cys and KIF6 p.Trp719Arg disturb protein conformational structure and stability., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic condition characterized by premature cardiovascular disease due to severely elevated low-density lipoprotein cholesterol (LDL-C). HoFH primarily results from loss-of-function (LOF) mutations in the LDL receptor (LDLR), reducing LDL-C clearance such that patients experience severe hypercholesterolemia, exacerbating the risk of developing cardiovascular events. Treatment options such as statins, lomitapide, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and apheresis help lower LDL-C; however, many patients with HoFH still fail to reach their target LDL-C levels and many of these lipid-lowering therapies are not indicated for pediatric use. Angiopoietin-like protein 3 (ANGPTL3) has been identified as a target to treat elevated LDL-C by acting as a natural inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL), enzymes involved in the hydrolysis of the triglyceride and phospholipid content of very low-density lipoproteins. Persons heterozygous for LOF mutations in ANGPTL3 were reported to have lower LDL-C than non-carriers and lower risk of coronary artery disease. Evinacumab is a first-in-class human monoclonal antibody that specifically binds to ANGPTL3 to prevent its inhibition of LPL and EL. In clinical trials, a 15 mg/kg intravenous dose every 4 weeks has shown a mean percent change from baseline in LDL-C of ~50% in adult, adolescent, and pediatric patients with HoFH. This mini review article describes the mechanism of action of evinacumab, evinacumab population PK and PD modeling, and clinical development history of evinacumab for the treatment of HoFH., (© 2024 Regeneron Pharmaceuticals, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: To find out whether inclisiran sodium has different efficacy in heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH) patient groups., Methods: We conducted the systematic review and meta-analysis of ORION clinical trials. PubMed, Embase, and Clinicaltrials.gov databases were searched for the relevant studies. Atheroscalerotic parameters considered for our objective were low-density lipoprotein cholesterol, total cholesterol, proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B, and nonhigh-density lipoprotein cholesterol. Primary outcomes were the percentage difference in atheroscalerotic parameters at follow-up relative to baseline values. Our study examined these primary outcomes to determine whether there is a statistically significant difference between the HeFH and HoFH groups. Risk of bias was assessed by the Cochrane risk of bias tool. Meta-analysis was performed when at least 2 studies reported on the same variable., Results: Four ORION clinical trials provided the data related to the mean difference in the atheroscalerotic parameters at follow-up relative to baseline, of HeFH and HoFH patient populations, after administration of 300 mg inclisiran subcutaneously. We pooled together these mean differences for each group and applied a statistical test to analyze if the values were significantly different between the groups. The results of our study unveiled the significant difference in pooled mean differences in low-density lipoprotein cholesterol (HeFH: -48.62%; HoFH: -9.12%; P < 0.05), total cholesterol (HeFH: -30.31%; HoFH: -11.50%; P < 0.05), apolipoprotein (HeFH: -39.97%; HoFH: -14.68%; P < 0.05), and nonhigh-density lipoprotein (HeFH: -44.51%; HoFH: -12.22%; P < 0.05) between HeFH and HoFH groups. However, the difference in pooled mean difference in PCSK9 values (HeFH: -68.41%; HoFH: -56.25%; P = 0.2) between HeFH and HoFH groups was statistically insignificant. Studies were of high quality., Conclusions: There was a significant difference in the reductions in atherosclerotic lipid parameters in heterozygous and homozygous populations after the administration of inclisiran except for PCSK9 parameter. Further studies are needed to support this conclusion., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: This review provides an overview of genetic and non-genetic causes of premature coronary artery disease (pCAD)., Recent Findings: pCAD refers to coronary artery disease (CAD) occurring before the age of 65 years in women and 55 years in men. Both genetic and non-genetic risk factors may contribute to the onset of pCAD. Recent advances in the genetic epidemiology of pCAD have revealed the importance of both monogenic and polygenic contributions to pCAD. Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with atherosclerotic pCAD. However, clinical overreliance on monogenic genes can result in overlooked genetic causes of pCAD, especially polygenic contributions. Non-genetic factors, notably smoking and drug use, are also important contributors to pCAD. Cigarette smoking has been observed in 25.5% of pCAD patients relative to 12.2% of non-pCAD patients. Finally, myocardial infarction (MI) associated with spontaneous coronary artery dissection (SCAD) may result in similar clinical presentations as atherosclerotic pCAD. Recognizing the genetic and non-genetic causes underlying pCAD is important for appropriate prevention and treatment. Despite recent progress, pCAD remains incompletely understood, highlighting the need for both awareness and research., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: We aimed to describe clinical and genetic characteristics, lipid-lowering treatment and atherosclerotic cardiovascular disease (ASCVD) outcomes over a long-term follow-up in homozygous familial hypercholesterolemia (HoFH)., Methods: SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) is a long-term study in molecularly diagnosed FH. Data analyzed in HoFH were prospectively obtained from 2004 until 2022. ASCVD events, lipid profile and lipid-lowering treatment were determined., Results: Thirty-nine HoFH patients were analyzed. The mean age was 42 ± 20 years and nineteen (49%) were women. Median follow-up was 11 years (IQR 6,18). Median age at genetic diagnosis was 24 years (IQR 8,42). At enrolment, 33% had ASCVD and 18% had aortic valve disease. Patients with new ASCVD events and aortic valve disease at follow-up were six (15%), and one (3%), respectively. Median untreated LDL-C levels were 555 mg/dL (IQ 413,800), and median LDL-C levels at last follow-up was 122 mg/dL (IQR 91,172). Most patients (92%) were on high intensity statins and ezetimibe, 28% with PCSK9i, 26% with lomitapide, and 23% with lipoprotein-apheresis. Fourteen patients (36%) attained an LDL-C level below 100 mg/dL, and 10% attained an LDL-C below 70 mg/dL in secondary prevention. Patients with null/null variants were youngers, had higher untreated LDL-C and had the first ASCVD event earlier. Free-event survival is longer in patients with defective variant compared with those patients with at least one null variant (p=0.02)., Conclusions: HoFH is a severe life threating disease with a high genetic and phenotypic variability. The improvement in lipid-lowering treatment and LDL-C levels have contributed to reduce ASCVD events., Competing Interests: Declaration of competing interest RA reports personal fees and non-financial support from Tecnofarma Chile, NovoNordisk Chile, and personal fees from Novartis Chile, Amgen Spain, and Teva Chile, outside the submitted work. JLDD received honoraria for research activities from Merck Sharp and Dhome Spain, Amgen Spain, and Sanofi Spain. PM, received research grants from Amgen USA and Sanofi Spain., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: Familial hypercholesterolemia leads to elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth onwards due to a pathogenetic variation in genes in cholesterol metabolism. Early screening to identify and subsequently treat children with familial hypercholesterolemia is crucial to reduce the risk of premature atherosclerotic cardiovascular disease (ASCVD). This review focuses on recent insights in the field of pediatric familial hypercholesterolemia., Recent Findings: Screening in childhood and early initiation of optimal lipid-lowering therapy (LLT) have shown promising outcomes in the prevention of ASCVD. In addition, cost-effectiveness research has demonstrated highly favorable results. With the availability of novel therapies, familial hypercholesterolemia has become a well treatable disease., Summary: Children with familial hypercholesterolemia benefit from early detection and optimal treatment of their elevated LDL-C levels., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Familial hypercholesterolemia (FH) is one of the most common autosomal dominant diseases. FH causes a lifelong increase in low-density lipoprotein cholesterol (LDL-C) levels, which in turn leads to atherosclerotic cardiovascular disease. The incidence of FH is widely underestimated and undertreated, despite the availability and effectiveness of lipid-lowering therapy. Patients with FH have an increased cardiovascular risk; therefore, early diagnosis and treatment are vital. To address the burden of FH, several countries have implemented national FH screening programmes. The currently used method for FH detection in Lithuania is mainly based on opportunistic testing with subsequent cascade screening of index cases' first-degree relatives., Methods: A total of 428 patients were included in this study. Patients with suspected FH are referred to a lipidology center for thorough evaluation. Patients who met the criteria for probable or definite FH according to the Dutch Lipid Clinic Network (DLCN) scoring system and/or had LDL-C > = 6.5 mmol/l were subjected to genetic testing. Laboratory and instrumental tests, vascular marker data of early atherosclerosis, and consultations by other specialists, such as radiologists and ophthalmologists, were also recorded., Results: A total of 127/428 (30%) patients were genetically tested. FH-related mutations were found in 38.6% (n = 49/127) of the patients. Coronary artery disease (CAD) was diagnosed in 13% (n = 57/428) of the included patients, whereas premature CAD was found in 47/428 (11%) patients. CAD was diagnosed in 19% (n = 9/49) of patients with FH-related mutations, and this diagnosis was premature for all of them., Conclusions: Most patients in this study were classified as probable or possible FH without difference of age and sex. The median age of FH diagnosis was 47 years with significantly older females than males, which refers to the strong interface of this study with the LitHir programme. CAD and premature CAD were more common among patients with probable and definite FH, as well as those with an FH-causing mutation. The algorithm described in this study is the first attempt in Lithuania to implement a specific tool which allows to maximise FH detection rates, establish an accurate diagnosis of FH, excluding secondary causes of dyslipidaemia, and to select patients for cascade screening initiation more precisely., (© 2024. The Author(s).)

Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare inherited condition that affects approximately one in 300,000 people. The disorder is characterized by extremely high, life-threatening levels of low-density lipoprotein (LDL) cholesterol from birth, leading to significant premature cardiovascular morbidity and mortality, if left untreated. Homozygous familial hypercholesterolemia is severely underdiagnosed and undertreated in the United States (US), despite guidelines recommendations for universal pediatric lipid screening in children aged 9-11. Early diagnosis and adequate treatment are critical in averting premature cardiovascular disease in individuals affected by HoFH. Yet, an unacceptably high number of people living with HoFH remain undiagnosed, misdiagnosed, and/or receive a late diagnosis, often after a major cardiovascular event. The emergence of novel lipid-lowering therapies, along with the realization that diagnosis is too often delayed, have highlighted an urgency to implement policies that ensure timely detection of HoFH in the US. Evidence from around the world suggests that a combination of universal pediatric screening and cascade screening strategies constitutes an effective approach to identifying heterozygous familial hypercholesterolemia (HeFH). Nevertheless, HoFH and its complications manifest much earlier in life compared to HeFH. To date, little focus has been placed on the detection of HoFH in very young children and/or infants. The 2023 Updated European Atherosclerosis Society Consensus Statement on HoFH has recommended, for the first time, broadening pediatric guidelines to include lipid screening of newborn infants. Some unique aspects of HoFH need to be considered before implementing newborn screening. As such, insights from pilot studies conducted in Europe may provide some preliminary guidance. Our paper proposes a set of actionable measures that states can implement to reduce the burden of HoFH. It also outlines key research and policy gaps that need to be addressed in order to pave the way for universal newborn screening of HoFH in the US., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Background and Aims: Elderly familial hypercholesterolemia (FH) patients are at high risk of coronary heart disease (CHD) due to high cholesterol burden and late onset of effective cholesterol-lowering therapies. A subset of these individuals remains free from any CHD event, indicating the potential presence of protective factors. Identifying possible cardioprotective gene expression profiles could contribute to our understanding of CHD prevention and future preventive treatment. Therefore, this study aimed to investigate gene expression profiles in elderly event-free FH patients., Methods: Expression of 773 genes was analysed using the Nanostring Metabolic Pathways Panel, in peripheral blood mononuclear cells (PBMCs) from FH patients ≥65 years without CHD (FH event-free, n = 44) and with CHD (FH CHD, n = 39), and from healthy controls ≥70 years (n = 39)., Results: None of the genes were differentially expressed between FH patients with and without CHD after adjusting for multiple testing. However, at nominal p < 0.05, we found 36 (5%) differentially expressed genes (DEGs) between the two FH groups, mainly related to lipid metabolism (e.g. higher expression of ABCA1 and ABCG1 in FH event-free) and immune responses (e.g. lower expression of STAT1 and STAT3 in FH event-free). When comparing FH patients to controls, the event-free group had fewer DEGs than the CHD group; 147 (19%) and 219 (28%) DEGs, respectively., Conclusions: Elderly event-free FH patients displayed a different PBMC gene expression profile compared to FH patients with CHD. Differences in gene expression compared to healthy controls were more pronounced in the CHD group, indicating a less atherogenic gene expression profile in event-free individuals. Overall, identification of cardioprotective factors could lead to future therapeutic targets., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MPB has received research grants and/or personal fees from Amgen and Sanofi, none of which are related to the content of this manuscript. JJC has received research grants and/or personal fees from Mills DA and Amgen, none of which are related to the content of this manuscript. AR has received personal fees from Rimfrost AS that are not related to the content of this manuscript. KR has received research grants and/or personal fees from Akcea, Amgen, Mills, Sanofi and Sunnovion, none of which are related to the content of this manuscript. KBH has received research grants and/or personal fees from Sanofi that are related to the content of this manuscript. The other authors have no financial relationships relevant to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation., Competing Interests: Declaration of competing interest SDdF received grants from the National Institutes of Health/National Heart, Lung, and Blood Institute of the National Institutes of Health, the Family Heart Foundation and holds a patent for UpToDate, with royalties paid. AG received grants and personal fees from Amgen, Sanofi and Regeneron, Mylan Viatris, MSD, Akcea Therapeutics, Amryt, Servier, Novartis and Ultragenyx. SGP received study funding from Amgen. JH received a research grant from the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number K23HL145109. DI received advisory honoraria from Amryt, and honoraria for lectures from Sanofi, Sobi and Novartis. CPS received advisory honoraria from Baxter, Iperboreal and Stadapharma, lecturing honoraria from Fresenius and research funding from Baxter. MK received honoraria from Abbott, Abdi Ibrahim, Amryt, LIB Therapeutics, NovoNordisk, and TR-pharma; research funding from Amryt Pharma, and participated in clinical trials with Amgen, Ionis, LIB Therapeutics, Novo Nordisk, Sanofi. RK, as head of the Apheresis Research GmbH, Cologne, Germany received financial grants for scientific research projects, honoraria for consulting and presentation of lectures including travel expenses from the companies Diamed, Cologne, Germany, and Asahi Kasei Medical, Tokyo, Japan. GK has given talks, attended conferences, received consultancy fees and participated in trials sponsored by Amgen, Novartis, Sanofi, Servier, Amryt. AW received research grants from Amgen, Regeneron, Novartis, Silence Therapeutics, Esperion, and Ultragenyx and advisory honoraria from Amryt, and Novartis. KA, EJD, LMdB, JWG, LCH, GDK, JO, RNP, MDR, CS and CT have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The goal of the study was to provide an individual and precise genetic and molecular biological basis for the early prevention, diagnosis, and treatment of local FH by analyzing the risk factors for the development of FH in Han and Mongolian patients in the Hulunbuir, comparing the lipid levels of FH patients of the two ethnicities, and assessing differences in mutations to two genes between the two ethnic groups., Methods: Twenty cases each of Han Chinese and Mongolian healthy controls and fifty patients who each met the inclusion criteria from November 2021 to December 2022 in five general hospitals in Hulunbuir were selected. Multifactor logistic analysis was used to analyze the risk factors associated with the development of FH. We used t-tests to analyze statistical differences in lipid levels between the groups, and Sanger sequencing to detect the dis-tribution of common mutation sites of PCSK9 and APOB in all study subjects. The mutation rates and differences between regions and ethnic groups were summarized and compared., Results: 1) Gender, age, alcohol consumption, dietary status, and a family history of FH were risk factors associated with the development of FH. 2) TC, LDL-C, and APOB were significantly higher in Mongolian cases than Han cases (p < 0.05). sdLDL-C was not statistically different between the two ethnicities (p > 0.05). 3) We detected four (8%) heterozygous mutations at the PCSK9 gene E670G mutation site in the Han case group and a total of nine (18%) mutations at this site in the Mongolian cases, including one (2%) homozygous and eight (16%) heterozygous mutations. One case of a heterozygous mutation was detected in the Mongolian control group. We detected a total of ten (20%) mutations at the APOB gene rs1367117 mutation site in the Han case group, including eight (16%) heterozygous and two (4%) homozygous mutations, 11 cases (22%) of heterozygous mutations in the Mongolian case group, two cases of heterozygous mutations in the Han control group, and one case of a heterozygous mutation in the Mongolian control group. 4) The D374Y and S127R mutation sites of PCSK9 and the R3500Q mutation site of APOB were not detected in any of the study subjects., Conclusions: The mutation sites of the PCSK9 and APOB genes in FH patients in Hulunbuir are different from other regions, and the mutation rate is higher than in other regions. Therefore, we recommend that the mutation sites of the PCSK9 and APOB genes described herein be used as clinical detection indicators to assist the diagnosis of FH in this region.

Background and Aims: Premature atherosclerotic cardiovascular disease (CVD) is a clinic characteristic of familial hypercholesterolemia (FH). Coronary calcium score (CCS) is a highly used imaging modality to evidence atherosclerotic plaque burden. microRNAs (miRNAs) are non-coding RNAs that epigenetically regulate gene expression. Here, we investigated whether CCS associates with a specific miRNA-signature in FH-patients., Methods: Patients with genetic diagnosis of FH (N = 86) from the nationwide SAFEHEART-cohort were investigated by computed tomography angiography imaging and classified depending on the presence of coronary calcification in FH-CCS (+) and FH-CCS (-) groups by the Agatston score. Differential miRNA profiling was performed in two stages: first by Affymetrix microarray technology (high-throughput differential profiling-studies) and second by RT-PCR using TaqMan-technology (analytical RT-qPCR study) in plasma of the two patient groups., Results: miR-193a-5p, miR-30e-5p and miR-6821-5p levels were significantly higher in FH-CCS (+) compared to FH-CCS (-). miR-6821-5p was the best miRNA to discriminate FH-patients CCS(+), according to receiver operating characteristic (ROC) analysis (AUC: 0.70 ± 0.06, p = 0.006). High miR-6821-5p levels were associated with older age (p = 0.03) and high LDL-burden (p = 0.014) using a ROC-derived cut-off value. However, miR-6821-5p did not correlate with age in either the CCS- or CCS + group. Genes involved in calcification processes were identified by in silico analysis. The relation of cell-calcification and expression levels of miR-6821-5p, BMP2 and SPP1 was validated experimentally in human vascular smooth muscle cell cultures., Conclusions: Up-regulated levels of miR-6821-5p are found in the plasma of asymptomatic FH-patients with coronary calcified atherosclerotic plaques, as well as in isolated human vascular smooth muscle cells expressing the pro-calcification genes BMP2 and SPP1. These findings highlight the impact of epigenetic regulation on the development of subclinical atherosclerosis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LB declares to have acted as SAB member of Sanofi, Ionnis, Pfizer and NovoNordisk; to have a Research Grant of AstraZeneca; to have received speaker fees from Sanofi and Bayer and to have founded the Spin-offs Glycardial Diagnostics SL and Ivastatin Therapeutics SL (all unrelated to this work). TP declares to be co-founder of the Spin-offs Glycardial Diagnostics SL and Ivastatin Therapeutics SL (all unrelated to this work). The remaining authors have nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Familial hypercholesterolemia (FH) and obesity are well-established risk factors of atherosclerotic cardiovascular disease (ASCVD). Despite high prevalence, their joint association with ASCVD remains largely unknown., Objective: To investigate the association of obesity with prevalent ASCVD in individuals with heterozygous FH (HeFH) enrolled in the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH)., Methods: FH diagnosis was based on Dutch Lipid Clinic Network (DLCN) criteria. Adults with at least possible FH diagnosis (DLCN score ≥3) and available body mass index (BMI) values were included. Homozygous FH individuals were excluded., Results: 1655 HeFH adults (mean age 51.0 ± 14.4 years, 48.6% female) were included; 378 (22.8%) and 430 (26.0%) were diagnosed with probable and definite FH, respectively. Furthermore, 371 participants (22.4%) had obesity and 761 (46.0%) were overweight. Prevalence of ASCVD risk factors increased progressively with BMI. Prevalence of coronary artery disease (CAD) was 23.4% (3.2% for stroke and 2.7% for peripheral artery disease [PAD]), and increased progressively across BMI groups. After adjusting for traditional ASCVD risk factors and lipid-lowering medication, individuals with obesity had higher odds of established CAD (OR: 1.54, 95% CI: 1.04-2.27, p = 0.036) as well as premature CAD (OR: 1.74, 95% CI: 1.17-2.60, p = 0.009) compared with those with normal BMI. No association was found with stroke or PAD., Conclusions: Over half of adults with HeFH have overweight or obesity. Obesity was independently associated with increased prevalence of CAD in this population., (Copyright © 2024. Published by Elsevier Inc.)