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Background and Aims: Familial Hypercholesterolemia (FH) is a monogenic disease that leads to early-onset atherosclerosis. Causative mutations in FH-related genes are found in 60-80 % of patients, while epigenetic factors may contribute to mutation-negative cases. This study analyzed miRNAs and proteins from plasma-derived extracellular vesicles (EVs) of FH patients to explore their contribution in FH diagnosis., Methods: Clinical and laboratory data were obtained from 54 FH patients and 38 normolipidemic individuals. FH-related gene variants were identified using exon-targeted gene sequencing. Plasma EVs miRNome and proteome were analysed using small RNA sequencing and liquid chromatography/mass spectrometry., Results: Thirteen FH patients carried LDLR deleterious variants (MD group), while 41 did not (non-MD group). Over 2000 miRNAs were detected in plasma EVs, with miR-122-5p higher in FH patients compared to controls, and miR-21-5p higher in the MD group than in the non-MD group (p < 0.05). Proteomic analysis identified 300 proteins with 18 out of 38 proteins more abundant in EVs than in total plasma. Eighteen EVs-derived proteins had differential abundance in FH patients compared to control group (p < 0.05). EV levels of miR-122-5p, miR-21-5p and 12 proteins were correlated with serum lipids (p < 0.05). The integrative analysis between dysregulated miRNAs (miR-122-5p and miR-21-5p) and altered proteins (APOD, APOF, MBL2 and MASP1) from EVs identified several common pathways involved in cholesterol metabolism., Conclusion: Co-regulation of plasma EVs miR-122-5p, miR-21-5p, APOD, APOF, MBL2 and MASP1 and their correlation with serum lipids suggest their involvement in impaired cholesterol metabolism and may be useful as biomarkers of FH severity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Rogers is employed by Intellia Therapeutics, but completed all work related to this study before this employment, while employed by Brigham and Women’s Hospital. Dr. Blaser is a consultant for BioMarin Pharmaceuticals, Inc. Dr E. Aikawa is on an advisory board for Elastrin Therapeutics Inc. The authors declare no other conflicts of interests]., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevated serum low-density lipoprotein cholesterol levels, tendon xanthomas, and an increased risk of atherosclerotic heart disease. Diagnosing familial hypercholesterolemia at an early age is crucial owing to its potential to lead to severe cardiovascular complications, including coronary heart disease and aortic valve disease. Early detection allows timely intervention, such as lifestyle modifications and pharmacological treatments, which can significantly reduce these risks., Case Presentation: In this case report, we present a case of familial hypercholesterolemia in a 13-year-old Bangladeshi girl residing in Faridpur, Bangladesh. The patient presented with a distinctive clinical profile, including the presence of tendon xanthoma in the hands and cutaneous xanthoma in the elbow, knee, and buttocks, as well as recent development of aortic valvular diseases. In addition, she experienced joint deformity in both hands, mimicking rheumatoid arthritis, which is uncommon. The patient was diagnosed and underwent treatment through both lifestyle changes and medication. Moreover, her family received genetic counseling, and she was scheduled for regular follow-up., Conclusion: This case underscores the significance of identifying important physical signs in the diagnosis and management of familial hypercholesterolemia, particularly in settings where genetic testing may be limited. Moreover, the unique coexistence of familial hypercholesterolemia with hand joint deformity and aortic valvular heart disease serves as a clinical clue that can facilitate diagnosis and appropriate therapeutic interventions. A high index of suspicion is essential for timely diagnosis and tailored management, thus reducing the burden of atherosclerotic heart disease in affected individuals., Competing Interests: Declarations. Ethics approval and consent to participate: Ethical principles were followed, and the participants provided consent before the case reports were written. Consent for publication: Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests: The author declares no competing interests., (© 2025. The Author(s).)

Background and Aims: Lipoprotein(a) [Lp(a)] is a well-recognized risk factor for atherosclerotic cardiovascular disease (ASCVD). Few data are available on the distribution of Lp(a) levels among subjects at different cardiovascular risk and in subjects with monogenic and polygenic dyslipidemias (familial hypercholesterolemia, FH and familial hypobetalipoproteinemia type 1, FHBL1). The aim of this study was to investigate the distribution of Lp(a) plasma levels in subjects with high and low LDL-C levels (FH and FHBL1) and in the general population., Methods and Results: The study cohorts included 356 hypercholesterolemic patients, 212 carrying a FH causative mutation, 144 with clinical FH (mutation negative - FHneg), 52 FHBL1 and 797 free-living subjects. Lp(a) levels were significantly higher in FH subjects (both FH and FHneg) (median 12.46 mg/dl and 14.0 mg/dl, respectively) compared with FHBL1 and free-living subjects (7.68 mg/dl and 7.18 mg/dl, respectively). More, Lp(a) levels were similar in FH subjects carrying LDLR defective and null mutations and FHneg. Subjects at high and very high CV risk exhibited significant higher Lp(a) levels (median 10.68 mg/dl and 9.20 mg/dl, respectively) compared with low and moderate CV risk (median 5.72 mg/dl and 7.80 mg/dl, respectively) (p < 0.0008)., Conclusions: FH subjects exhibit higher Lp(a) levels than FHBL1 and general population. Lp(a) slightly contribute to hypercholesterolemia in FH patients. Subjects at high and very high CV risk exhibited significant higher Lp(a) levels compared with low and moderate CV risk. Combined evaluation of Lp(a) levels in FH subjects with other traditional risk factors could identify very high-risk individuals who may benefit from early aggressive treatments to avoid premature CV events., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Statins, ezetimibe and statins-ezetimibe combination therapy are recommended lipid-lowering therapies (LLTs) in children with heterozygous familial hypercholesterolaemia (HeFH). However, their relative effectiveness is not well understood. We aimed to compare the safety and efficacy of these therapies using direct and indirect comparisons., Methods: We conducted systematic review, pairwise and network meta-analyses (NMAs) of randomised-controlled trials (RCTs) of statins, ezetimibe and statins-ezetimibe combination therapy in people <18 years with HeFH. Comprehensive bibliographic searches were conducted in December 2022, and a Medline update in January 2024. NMA models accounted for drug class, statin type and dosage., Results: Thirteen RCTs were included (n = 1649, median age 13 years, follow-up 6 weeks-2 years). All LLTs reduced low-density lipoprotein cholesterol (LDL-C) and total cholesterol; statins led to increases in high-density lipoprotein cholesterol and reductions in triglycerides. Statins reduced LDL-C by 33.61 % against placebo (95 % CI 27.58 to 39.63, I 2  = 83 %). Adding ezetimibe to statins reduced LDL-C by an additional 15.85 % (95 % CI 11.91 to 19.79). NMAs showed intermediate-dose statins reduced LDL-C by an additional 4.77 % compared with lower-doses statins (95 % CrI -11.22 to 1.05); higher-dose statins and intermediate-dose statins + ezetimibe may be similarly effective and are probably superior to ezetimibe, intermediate-and lower-dose statins. There was no evidence of differences in maturation, safety or tolerability between LLTs and placebo., Conclusions: Statins, ezetimibe and statins-ezetimibe are all effective treatments for children with HeFH, but the magnitude of LDL-C reductions varies and may depend on treatment dosage and combination. No safety or tolerability issues were found. Longer-term safety and effectiveness are uncertain., Competing Interests: Declaration of competing interest SEH is the Medical Director of a UCL spin-off company (StoreGene) that offers genetic testing for cardiovascular risk including for FH. SEH also reports payment for expert testimony from Verve Therapeutics. BW sits on the Board of Directors for the York Health Economics Consortium (unpaid role). All other co-authors have no interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Despite advancements in early diagnosis and effective medications in last decade, most heterozygous familial hypercholesterolemia (heFH) patients still fail to achieve their low-density lipoprotein cholesterol (LDL-C) goals and remain at residual cardiovascular disease risk. We present recent data from the regional FH registry in Poland, highlighting the challenges and real-life clinical management of FH patients., Methods: The registry is held at the Regional Centre for Rare Diseases, founded in 2016, at the 2nd largest, supraregional hospital in Poland, where >80 different rare diseases in patients from all over Poland are diagnosed and treated, including phenotypically or genetically diagnosed FH patients. Our analysis focused on both children and adult FH patients, excluding those treated with inclisiran due to a small sample size (n = 5)., Results: We studied 173 consecutive heFH patients, median age for adult population was 40 years (range: 27-57), of whom 56.14 % were women. Among the population, 82.1 % were adults (n = 142), and 31 were children (17.92 %; median age 9 (8-13), females 58.16 %). Children exhibited lower total cholesterol and triglyceride levels compared to adults, with no significant differences in LDL-C and high-density lipoprotein cholesterol (HDL-C) levels. Molecular diagnosis in the whole population revealed that 76.6 % had an LDL receptor (LDLR) mutation, while 23.4 % had an apolipoprotein B (APOB) mutation. Risk assessment categorized patients into high (70.7 %), very high (22.1 %), and extremely high (7.1 %) risk groups. Triple therapy achieved treatment goals in 61.76 % of adults and 70.97 % of children. At baseline, 36.62 % of adult patients were not using statins. High-intensity statin therapy combined with ezetimibe was initiated for the remaining patients. Only 3.33 % of patients avoided statins due to complete intolerance. Ezetimibe was used in 57.27 % of patients (mostly in combination therapy), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were prescribed for 28.17 % FH patients. In adults receiving statin and ezetimibe therapy, median achieved LDL-C was 141 mg/dl (107-184). For triple therapy, median achieved LDL-C was 52.5 mg/dL (32-86.5). Overall median achieved LDL-C in the study population was 99.5 mg/dl (57.5-145.4). PCSK9 inhibitors reduced LDL-C by 165.6 mg/dl. Combination therapy did not significantly alter baseline lipoprotein(a) (Lp(a)) levels (p = 0.134), and PCSK9 inhibitors led to a mean Lp(a) reduction of 18.66 mg/dl (45 % reduction; p = 0.013). Multivariable regression analysis identified key factors for achieving LDL-C targets in FH patients: DLCN total score, DLCN category, ezetimibe use, and PCSK9 inhibitors., Conclusions: In Poland, FH patients are often diagnosed too late (usually over 40 years of age), and many still do not reach their LDL-C goals. Combination LLT double or triple therapy significantly increases the likelihood of achieving LDL-C targets - even up to fivefold. Therefore, unrestricted access to PCSK9 inhibitors for all FH patients is crucial, without the current limitations imposed by drug reimbursement programs like B101., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Lewek has received a speaker's fee from Amgen, Novartis, Sanofi; Dr. Banach has received research grant(s)/support from Amgen, Daiichi Sankyo, Sanofi and Viatris, and has served as a consultant/received speaker's fee for Amgen, Daiichi-Sankyo, Esperion, Kogen, KRKA, Menarini, MSD, Mylan/Viatris, Novartis, Novo-Nordisk, Polpharma, Sanofi, Servier, Teva, and Zentiva; all other author have nothing to declare in relation to the results of this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Importance: Disease characteristics of genetically mediated coronary artery disease (CAD) on coronary angiography and the association of genomic risk with outcomes after coronary angiography are not well understood., Objective: To assess the angiographic characteristics and risk of post-coronary angiography outcomes of patients with genomic drivers of CAD: familial hypercholesterolemia (FH), high polygenic risk score (PRS), and clonal hematopoiesis of indeterminate potential (CHIP)., Design, Setting, and Participants: A retrospective cohort study of 3518 Mass General Brigham Biobank participants with genomic information who underwent coronary angiography was conducted between July 18, 2000, and August 1, 2023., Exposures: The presence of a genomic risk factor of CAD, defined as FH variant, high CAD PRS, or CHIP driver variation., Main Outcomes and Measures: Coronary artery disease presentation (stable or acute), angiographic CAD characteristics (severity and burden), angiographic outcomes (repeat angiogram, revascularization, and in-stent restenosis), and clinical outcomes (heart failure and all-cause mortality)., Results: Among 3518 participants (2467 [70.1%] male; median age, 64.0 [IQR, 55.0-72.0] years), 1509 (42.9%) had at least 1 genomic driver of CAD (26 FH, 1191 high CAD PRS, and 466 CHIP) that was associated with the presentation of acute coronary syndromes (adjusted odds ratio, 2.67; 95% CI, 2.19-3.26) and with the presence, burden, and severity of angiographic CAD. This association was driven by FH and CAD PRS. One SD of CAD PRS was associated with a 12.51-point higher Gensini score. During 9 years of follow-up, there was an increased risk among FH carriers for a repeat angiogram (adjusted hazard ratio [AHR], 1.70; 95% CI, 1.02-2.83), and revascularization (AHR, 1.97; 95% CI, 1.02-3.80), and among people with high CAD PRS (repeat angiogram: AHR, 1.79; 95% CI, 1.45-2.22; revascularization: AHR, 1.85; 95% CI, 1.37-2.50; and in-stent restenosis: AHR, 3.89; 95% CI, 2.16-7.01). CHIP carriers had no significant increase in angiographic outcomes but were at higher risk of heart failure (AHR, 1.58; 95% CI, 1.04-2.40) and all-cause mortality (AHR, 1.78; 95% CI, 1.47-2.16)., Conclusions and Relevance: The findings of this study suggest that germline monogenic and polygenic risk are associated with acute coronary syndromes presentation, severity and burden of atherosclerosis, and risk of repeat angiogram, revascularization, and in-stent restenosis. CHIP variant status is associated with incident heart failure and mortality after coronary angiography.

Background: Familial hyperlipidemia (familial hypercholesterolemia, FH) is an autosomal genetic disorder. It includes type heterozygous familial hyperlipidemia (heterozygous familial hypercholesterolemia). HeFH is mainly caused by mutations in the LDLR, APOB, and PCSK9 genes and is characterized by elevated plasma low-density lipoprotein cholesterol levels., Methods: We present a case of HeFH attributed to an APOB gene mutation. The whole-genome DNA of peripheral blood was extracted from the blood of the proband and their parents, and the exons of peripheral blood were sequenced through high-throughput sequencing. The selected mutation sites were verified by sequencing using the Sanger method., Results: A heterozygous mutation, c.6551A>G (p.Y2184C), in exon 26 of the APOB gene (Chr2-21233189) was identified in both the proband and the mother. Combined with the clinical features, HeFH caused by this mutation was initially considered., Conclusions: For patients with a high degree of clinical suspicion of FH, a definitive diagnosis should be established through genetic testing, enabling patients to receive early treatment and effectively prevent the occurrence of cardiovascular events.

Background: Familial hypercholesterolemia (FH) is an inherited disorder mainly marked by increased low-density lipoprotein cholesterol (LDL-C) concentrations and a heightened risk of early-onset arteriosclerotic cardiovascular disease (ASCVD). This study seeks to characterize the genetic spectrum and genotype‒phenotype correlations of FH in Chinese pediatric individuals., Methods: Data were gathered from individuals diagnosed with FH either clinically or genetically at multiple hospitals across mainland China from January 2016 to June 2024., Results: In total, 140 children and adolescents (mean age of 6.00 years) with clinically and genetically diagnosed FH were enrolled in the study, with 87 distinct variants identified in the LDLR, APOB and PCSK9 genes. Among the variants, 11 variants were newly identified worldwide, with 9 classified as "pathogenic" or "likely pathogenic", and 2 classified as "variants of uncertain significance". Additionally, the 5 most common variants in the study were c.1448G > A (p.W483*), c.1879G > A (p.A627T), c.1216C > A (p.R406R), and c.1747C > T (p.H583Y) in the LDLR gene, as well as c.10579C > T (p.R3527W) in the APOB gene, accounting for 49.29% (69/140) of all patients. These variants are primarily observed in the Asian or Chinese population and are distinct from those present in Caucasian groups. In this cohort, 105 patients were diagnosed with heterozygous FH (HeFH), while 35 were diagnosed with homozygous FH (HoFH). Finally, only 28.57% of the patients (40/140) were using lipid-lowering medications with 33.33% of HoFH patients initiating treatment after the age of 8. Additionally, only 3 compound heterozygous patients (2.14%) underwent liver transplantation because of significantly high lipid levels., Conclusion: This study reveals the variable genotypes and phenotypes of children with FH in China and illustrates that the genotypes in the Chinese population differ from those in Caucasians, providing a valuable dataset for the clinical genetic screening of FH in China. Furthermore, the older age at diagnosis and treatment highlights the underdiagnosis and undertreatment of Chinese FH pediatric patients, suggesting that early identification should be improved through lipid or genetic screening, and that more timely and regular pharmacological treatments should be implemented., Competing Interests: Declarations. Ethics approval and consent to participate: The study received approval from the Ethics Committee of the Children’s Hospital of Zhejiang University School of Medicine. Written informed consent was obtained from all participants or their legal guardians prior to the performance of whole exome sequencing (WES). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Familial hypercholesterolemia (FH) is a genetic disease, usually with onset during childhood, characterized by elevated blood LDL cholesterol levels and potentially associated with severe cardiovascular complications. Concerning mutated genes in FH, such as LDLR , a small subset of FH patients presents a homozygous genotype, resulting in homozygous FH (HoFH) disease with a generally aggressive phenotype. Besides statins, ezetimibe and PCSK9 inhibitors, lomitapide (an anti-ApoB therapy) was also approved in 2012-2013 as an adjunctive treatment for HoFH. Despite its clinical efficacy, lomitapide administration should be done with caution because of the possible occurrence of side effects, such as hepatosteatosis, increased blood transaminase levels and gastrointestinal symptoms, as well as the possible deleterious interactions with other drugs. In this context, we decided to report the main available evidence on the management and monitoring of HoFH patients treated with lomitapide and to accompany this literature review with a description of our clinical experience with a subset of six HoFH patients. In conclusion, this paper aims to address an important topic for HoFH-related clinical practice that, to our knowledge, is not yet formally regulated by proper national and/or international guidelines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Iannuzzo, Calcaterra, Gentile, Stanzione, de Ruberto, di Taranto, Cardiero, Fortunato and Minno.)

Background: Familial hypercholesterolemia (FH) is a genetically inherited disorder caused by monogenic mutations or polygenic deleterious variants. Patients with FH innate with significantly elevated risks for coronary heart disease (CHD). FH prevalence based on genetic testing in Chinese CHD patients is missing. Whether classical index of coronary atherosclerosis severity can be used as indicators of FH needs to be explored. To investigate the FH prevalence in Chinese CHD patients and the association of SYNTAX I score with FH genotype., Methods: The monogenic and polygenic FH related genes were genotyped in 400 consecutively enrolled CHD patients. The clinical characteristics and SYNTAX I scores were analyzed in a retrospective nested case-control study., Results: The prevalence of genetically confirmed FH in our CHD cohort was 8.75%. The cLDL-C level, SYNTAX I scores and incidences of triple vessel lesions in FH patients were significantly higher, while cLDL-C and SYNTAX I scores were independent risk factors for FH. Furthermore, cLDL-C levels of polygenic FH were significantly lower than monogenic FH, while their severity of coronary atherosclerosis was comparable., Conclusions: Our study revealed that the SYNTAX I score was an independent risk factor for FH. Besides, polygenic origin of FH should be taken into consideration for CHD patients suspected of FH., Competing Interests: Declarations. Ethics approval and consent for participate: The study protocol was approved by the ethics committee of Beijing Chaoyang Hospital, Capital Medical University and performed in accordance with the ethical standers laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consents were obtained from all participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Patients with genetically-based hyperlipidemias exhibit a wide phenotypic variability. Investigation of clinical and biochemical features is important for identifying genetically-based hyperlipidemias, determining disease prognosis, and initiating timely treatment. We analyzed genetic data from 3374 samples and compared clinical data, lipid levels (low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, and lipoprotein (a)), frequency, age at onset of coronary heart disease (CHD), and the severity of carotid and femoral atherosclerosis (plaque number, maximum stenosis, total stenosis, maximum plaque height, and plaque score) among patients with familial hypercholesterolemia (FH), familial dysbetalipoproteinemia (FD), polygenic hypercholesterolemia (HCL), severe HCL, and those without lipid disorders (n = 324). FH patients exhibited the highest LDL-C (median 8.03 mmol/L, p < 0.001). FD patients had elevated triglyceride levels (median 4.10 mmol/L), lower LDL-C (median 3.57 mmol/L), and high-density lipoprotein cholesterol (median 1.03 mmol/L) compared to FH, polygenic HCL, and severe HCL, p < 0.05. FH and FD patients had similar early onset of CHD, with a median age of 44 and 40 years and comparable frequencies of 29.5% and 31.0%, respectively. They were more likely to develop CHD than subjects without lipid disorders (p = 0.042 and p < 0.001, respectively). Additionally, FH patients had higher a carotid plaque number, total carotid stenosis, and carotid plaque score. This study presents the first simultaneous comparison of clinical and biochemical features among FD, FH, polygenic, and severe HCL, along with the first comprehensive evaluation of carotid and femoral atherosclerosis ultrasound parameters in FD patients. The results highlight distinct phenotypic features unique to each hyperlipidemia analyzed and underscore FH and FD as the most atherogenic hyperlipidemias., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Blokhina 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.)

Despite the implementation of next-generation sequencing-based genetic testing on patients with clinical familial hypercholesterolemia (FH), most cases lack complete genetic characterization. We aim to investigate the utility of the polygenic risk score (PRS) in specifying the genetic background of patients from the Latvian Registry of FH (LRFH). We analyzed the whole-genome sequencing (WGS) data of the clinically diagnosed FH patients (n = 339) and controls selected from the Latvian reference population (n = 515). Variant pathogenicity in FH patients was classified according to the ACMG/AMP guidelines. The low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) (LPA) PRS were calculated based on the WGS data. We identified unique causative variants in 80 (23.6%) of the tested individuals (39 variants in FH genes and 4 variants in phenocopy genes, with 6 variants being novel). The LDL-C PRS was highly discriminative compared to the LPA PRS. Nevertheless, both PRS were able to explain the genetic cause of hypercholesterolemia in 26.3% of the remaining non-monogenic patients. The combined genetic analysis of monogenic and polygenic hypercholesterolemia resulted in 43.7% genetically explained hypercholesterolemia cases. Even though the application of PRS alone does not exclude monogenic testing in clinical FH patients, it is a valuable tool for diagnosis specification.

Background and Aims: PCSK9 is a key regulator of LDL-cholesterol levels. PCSK9 gain of function variants (GOFVs) cause autosomal dominant hypercholesterolemia (ADH). The first described PCSK9-GOFV, p.Ser127Arg, almost exclusively reported in France, represents 67 % of the PCSK9 French GOFVs due to a founder effect. Few other carriers are reported in South Africa and Norway. This study aims to estimate when the common ancestor lived and to describe a cohort of p.Ser127Arg carriers., Methods: Eight families and 14 p.Ser127Arg carriers were genotyped and phenotyped. Haplotypes were constructed using 11 microsatellites around PCSK9 and 6 intragenic single nucleotide polymorphisms (SNPs). To add to the biological analysis, eight additional p.Ser127Arg carriers, 12 carriers of other PCSK9-GOFVs, 93 LDLR loss of function variant (LOFV) carriers and 49 non-carriers subjects were phenotyped., Results: The most common ancestor of p.Ser127Arg was estimated to have lived 775 years ago [95 % CI: 575-1075]. French Protestants exiled after the revocation of the Edict of Nantes in 1685 AD likely brought the variant to South Africa and Norway. As expected for ADH subjects, carriers of LDLR-LOFV, the p.Ser127Arg, or other PCSK9-GOFVs showed significantly higher LDL-C levels than that of the non-carriers. Interestingly, LDL-C levels are higher for LDLR-LOFVs and for the reduced secreted p.Ser127Arg than for secreted PCSK9-GOFVs, suggesting a greater effect of the p.Ser127Arg. Conversely, HDL-C was significantly lower for LDLR-LOFV and p.Ser127Arg carriers., Conclusions: This first report from a large cohort of PCSK9-p.Ser127Arg carriers provides observations suggesting a stronger hypercholesterolemic potential of the mutated pro-PCSK9 compared with the secreted mature protein. This work also provides additional data to support the association between PCSK9 and HDL metabolism, and molecular evidence that this variant appeared in France around 1248 AD (Graphical Abstract = Fig. 1)., 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.)

Despite the availability of multiple classes of lipoprotein-lowering medications, some high-risk patients have persistent hypercholesterolemia and may require nonpharmacologic therapy. Lipoprotein apheresis (LA) is a valuable but underused adjunctive therapeutic option for low-density lipoprotein cholesterol and lipoprotein(a) lowering, particularly in children and adults with familial hypercholesterolemia. In addition to lipid lowering, LA reduces serum levels of proinflammatory and prothrombotic factors, reduces blood viscosity, increases microvascular myocardial perfusion, and may provide beneficial effects on endothelial function. Multiple observational studies demonstrate strong evidence for improved cardiovascular outcomes with LA; however, use in the United States is limited to a fraction of its Food and Drug Administration-approved indications. In addition, there are limited data regarding LA benefit for refractory focal segmental glomerulosclerosis. In this scientific statement, we review the history of LA, mechanisms of action, cardiovascular and renal outcomes data, indications, and options for treatment.

Background: Myocardial infarction (MI) is a complex disease caused by both lifestyle and genetic factors. This study aims to investigate the predictive value of genetic risk, in addition to traditional cardiovascular risk factors, for recurrent events following early-onset MI., Methods: The Italian Genetic Study of Early-Onset Myocardial Infarction is a cohort study enrolling patients with MI before 45 years. Monogenic variants causing familial hypercholesterolemia were identified, and a coronary artery disease polygenic score (PGS) was calculated. Ten-fold cross-validated Cox proportional hazards models were fitted sequentially including all clinical variables, the PGS, and monogenic variants on the composite outcome of cardiovascular death, recurrent MI, stroke, or revascularization., Results: During a 19.9-year follow-up, 847 (50.7%) patients experienced recurrent events. Each 1-SD higher PGS was associated with a 21% higher hazard of recurrent events (hazard ratio, 1.21 [95% CI, 1.13-1.31]; P =4.04×10 -6 ). Except for secondary prevention, PGS was the strongest determinant of recurrent event risk (C index, 0.56 [95% CI, 0.54-0.58]) compared with clinical risk factors. Overall, predictive performance of clinical risk factors (C index, 0.69 [95% CI, 0.67-0.71]) improved after adding the PGS (C index, 0.69 [95% CI, 0.68-0.71]; P =0.006). When dividing the population by PGS quintiles, the highest fifth had a 57% higher hazard of recurrent events than the lowest fifth (hazard ratio, 1.57 [95% CI, 1.26-1.96]; P =5.57×10 -5 )., Conclusions: When compared with other clinical risk factors, PGS was the strongest predictor of event recurrence among patients with an early-onset MI. Though the discriminative power of recurrent event prediction in this cohort was modest, the addition of PGS significantly improved discrimination., Competing Interests: Dr Natarajan reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/Roche, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis; scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio; scientific cofounder of TenSixteen Bio; equity in MyOme, Preciseli, and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. Dr Honigberg reports consulting fees from CRISPR Therapeutics and Comanche Biopharma, advisory board service for Miga Health, and grant support from Genentech, all unrelated to the present work. Dr Inouye is a trustee of the Public Health Genomics Foundation, a member of the Scientific Advisory Board of Open Targets, and has a research collaboration with AstraZeneca PLC, which is unrelated to this study. Dr Butterworth reports institutional grants from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Novartis, Regeneron, and Sanofi. The other authors report no conflicts.

Purpose of Review: Familial hypercholesterolemia (FH) registries can capture unique data on FH concerning real-world practice, clinic epidemiology, natural history, cascade testing, cardiovascular consequences of late diagnosis, and use of healthcare resources. Such registries are also valuable for identifying and bridging the gaps between guidelines and clinical practice. We reviewed recent findings from the principal FH registries., Recent Findings: Most adult patients with heterozygous FH (HeFH) are diagnosed late, undertreated, and do not reach guideline-recommended low density lipoprotein-cholesterol (LDL-C) goals. In children and adolescents with HeFH, detection relies principally on genetic testing and measurement of LDL-C levels. Similarly, the majority of patients with homozygous FH (HoFH) receive sub-optimal cholesterol-lowering treatments and do not attain recommended LDL-C goals, gaps being wider in lower income than higher income countries. In HeFH patients, men have a higher risk of atherosclerotic cardiovascular disease than women., Summary: The evolving data from FH registries provide real-world evidence for developing implementation strategies to address gaps across the continuum of care of FH worldwide., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Universal Screening programmes to identify subjects with familial hypercholesterolaemia (FH) have been the subject of much recent interest. However, any screening programme can cause harm as well as having potential benefits. Here we review recent papers using different ages and strategies to identify subjects with FH, and examine to what extent the publications provide quantitative or qualitative evidence of benefit or harm to children and adults., Recent Findings: Three studies have been published over the last 2 years where Universal Screening for FH has been carried out in infancy, at the time of routine vaccinations, or at preschool age. Next-generation sequencing of all known FH-causing genes has been used to determine the proportion of screened individuals, who have total or low-density lipoprotein cholesterol (LDL-C) concentrations above a predetermined threshold (such as >95th percentile), with genetically confirmed FH., Summary: While we fully support the concept of Universal Screening for FH, which appears feasible and of potential clinical utility at all of the different ages examined, there is little data to document potential benefit or how to mitigate potential harms. Future study protocols should include collection of such data to strengthen the case of roll out of Universal Screening programmes., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: Elevated levels of cholesterol in the bloodstream, also referred to as hypercholesterolemia, pose a significant risk for the onset of cardiovascular and cerebrovascular diseases. Oxysterols, cholesterol-derived oxidized compounds that form enzymatically or non-enzymatically, contribute to the development of atherosclerosis and coronary artery disease. This study aimed to examine the critical oxysterol levels in children and adolescents with hypercholesterolemia and explore the correlation between these levels, oxidative stress, and atherosclerosis progression., Materials and Methods: The study included 20 patients with familial hypercholesterolemia (FH) and 20 healthy individuals aged between 6 and 18 years. Participants were categorized into children (6-9 years) and adolescents (10-18 years). Pediatric and adolescent patients were selected from among subjects with LDL-C ≥ 130 mg/dL and diagnosed with heterozygous familial hypercholesterolemia (HeFH) based on the presence of mutations in the LDL receptor (LDL-R) gene. Patients with HeFH who were receiving regular atorvastatin therapy were included in the study., Results: There were no notable differences in catalase and paraoxonase (PON1) activities among the groups. However, the patient group displayed substantially higher levels of malondialdehyde (MDA) (P = 0.0108) and superoxide dismutase (SOD) activity (P = 0.0103). Compared to the healthy control group, serum chitotriosidase (CHITO) activity (P = 0.037) and chitinase 3-like protein 1 (YKL-40) levels (P = 0.0027) were significantly elevated in the patient group. Furthermore, the carotid intima-media thickness (CIMT) measurements of the patient group were significantly greater than those of the healthy group (**P < 0.0001****). The patient group exhibited significantly elevated levels of 5,6-α-epoxycholesterol, Cholestane-3β,5α,6β-triol (C-triol), and 7-ketocholesterol (7-KC), whereas 27-hydroxycholesterol (27-OHC) was significantly more abundant in the healthy group. On the other hand, while 27-OHC/Total cholesterol (Total-C) levels were significantly higher in healthy individuals, the C-Triol/Total-C ratio was significantly higher in patients. No significant differences were found between the groups in terms of 7-KC/Total-C and 5,6-α-epoxycholesterol/Total-C levels., Conclusion: This study highlights the key roles of oxysterols, oxidative stress, and macrophage activation in the development of atherosclerosis in pediatric and adolescent patients with FH. Elevated C-Triol levels in FH patients, alongside increased CIMT, point to early vascular changes despite atorvastatin therapy. In contrast, higher 27-OHC levels in healthy controls suggest differential oxysterol regulation due to cholesterol-lowering treatments in FH patients. C-Triol and 27-OHC/Total-C ratios showed potential as biomarkers to distinguish patients with FH. These findings emphasize the need for therapies targeting oxidative stress and macrophage activation in addition to cholesterol-lowering interventions., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of the Ege University Faculty of Medicine (Ethics Committee Approval No: 20-8T/31). Written informed consent was obtained from the legal guardian, and the child provided assent. All methods were performed in accordance with relevant guidelines and regulations. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Aims: Homozygous familial hypercholesterolaemia (HoFH) is a rare disorder characterized by markedly elevated circulating low-density lipoprotein cholesterol (LDL-C) from birth. This review aimed to critically evaluate treatments for HoFH with respect to their efficacy, safety, accessibility, overall context and position within the treatment pathway., Methods and Results: A mixed-methods review was undertaken to systematically identify and characterize primary interventional studies on HoFH, with a focus on LDL-C reduction as the primary outcome. Interventions assessed were ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), lomitapide, evinacumab, with or without LDL apheresis. Twenty-six seminal studies reporting unique patient data were identified. Four studies were randomized controlled trials (RCTs) with the remainder being single-arm trials or observational registries. Data extracted were heterogeneous and not suitable for meta-analyses. Two RCTs, assessed at being low risk of bias, demonstrated PCSK9i were safe and moderately effective. A randomized controlled trial (RCT) demonstrated evinacumab was safe and effective in all HoFH subgroups. Lomitapide was reported to be efficacious in a single-arm trial, but issues with adverse events, tolerability, and adherence were identified. An RCT on ezetimibe showed it was moderately effective when combined with a statin. LDL apheresis was reported as effective, but its evidence base was at very high risk of bias. All interventions lowered LDL-C, but the magnitude of this, and certainty in the supporting evidence, varied., Conclusion: In practice, multiple treatments are required to treat HoFH. The sequencing of these should be made on an individualized basis, with consideration made to the benefits of each intervention., Competing Interests: Conflicts of interest: F.J.R. has received research grants, honoraria, or consulting fees for professional input and/or delivered lectures from Sanofi, Regeneron, Amgen, Novartis, and LIB Therapeutics. R.N.G. is an employee and shareholder of Ultragenyx Pharmaceutical Inc. J.G. and Y.X. are employees of, and hold stocks and shares in, Regeneron Pharmaceuticals, Inc. H.K.C. was an employee and shareholder of Ultragenyx Pharmaceutical Inc at the time the work was conducted and is currently an employee of Neurocrine Biosciences, Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: The weight-adjusted-waist index (WWI) is a novel obesity measurement indicator, and this study aims to determine the relationship between WWI and Familial hypercholesterolemia (FH)., Methods: Using data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to March 2020, cross-sectional data from 3698 participants were analyzed. The study examined the correlation between WWI and FH using multivariate logistic regression and smooth curve fitting, and conducted subgroup analysis and interaction tests., Results: The study sample consisted of 3698 subjects for whom the overall probable prevalence of FH was 5.43% and increased with WWI tertile (quantile 1: 4.00%; quantile 2: 4.94%; quantile 3: 7.34%); individuals with the highest WWI tertile were significantly more likely to have FH than those with the lowest tertile (OR = 4.60,95% CI: 2.00-10.60). Subgroup analysis and interaction tests showed significant significance between WWI and personal history of early Atherosclerotic cardiovascular disease (ASCVD), family history of early ASCVD and probable prevalence of FH (p < 0.05)., Conclusion: This study demonstrates a nonlinear positive correlation between WWI and FH. This may provide new ideas for the prevention and treatment of FH in the future., Competing Interests: Declarations Ethics approval and consent to participate The portions of this study involving human participants, human materials, or human data were conducted in accordance with the Declaration of Helsinki and were approved by the National Center for Health Statistics (NCHS) Ethics Review Board. The patients/participants provided their written informed consent to participate in this study. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Aims: To investigate the prevalence of familial hypercholesterolaemia (FH) and compare the performance of clinical criteria and genetic testing in patients undergoing coronary angiography., Methods and Results: The prevalence of FH was determined with the Dutch Lipid Clinical Network (DLCN), US 'Make Early Diagnosis to Prevent Early Death' (US-MEDPED), Simon Broome (SB) criteria, the 'familial hypercholesterolaemia case ascertainment tool' (FAMCAT), and a clinical algorithm. Genetic screening was conducted with a custom array from Affymetrix (CARRENAL array) harbouring 944 FH mutations.The study cohort consisted of 3267 patients [78.6% with coronary artery disease (CAD)]. FH was diagnosed in 2.8%, 2.2%, 3.9%, and 7.9% using the DLCN, US-MEDPED, SB criteria, and the FAMCAT. The clinical algorithm identified the same patients as the SB criteria. Pathogenic FH mutations were found in 1.2% (1.2% in patients with CAD, 1.0% in patients without CAD). FH was more frequently diagnosed in younger patients. With genetic testing as reference, the clinical criteria achieved areas under the ROC curve [area under the curves (AUCs)] in the range of 0.56-0.68. Using only low-density lipoprotein cholesterol (LDL-C) corrected for statin intake, an AUC of 0.68 was achieved., Conclusion: FH is up to four-fold more prevalent in patients undergoing coronary angiography than in contemporary cohorts representing the general population. Different clinical criteria yield substantially different diagnosis rates, overestimating the prevalence of FH compared with genetic testing. LDL-C testing alone may be sufficient to raise the suspicion of FH, which then needs to be corroborated by genetic testing., Lay Summary: In this study, we investigated the frequency of familial hypercholesterolaemia-a common genetic condition leading to markedly elevated low-density lipoprotein (LDL) cholesterol and increased risk of atherosclerosis-in 3267 patients undergoing coronary angiography according to commonly used diagnostic scoring systems and genetic testing., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Evolocumab is the first monoclonal antibody against proprotein convertase subtilisin/kexin type 9 approved in Japan for familial hypercholesterolemia (FH) and hypercholesterolemia; however, data on its safety and effectiveness in the real-world setting in Japan are limited., Methods and Results: This real-world, postmarketing, single-arm study assessed the safety and effectiveness of low-density lipoprotein cholesterol lowering with evolocumab in patients with homozygous/heterozygous familial hypercholesterolemia and hypercholesterolemia with high risk in Japan (668 sites). The primary safety end point was the incidence (percentage) and number of patients with adverse drug reactions and serious adverse events during the 104-week follow-up. Primary effectiveness end points included the percentage change in low-density lipoprotein cholesterol levels from baseline to week 12, assessed using 2-sided paired t tests. The safety and effectiveness sets comprised 3724 (homozygous FH, n=108; heterozygous FH, n=2009; hypercholesterolemia with high risk, n=1607) and 2797 (homozygous FH, n=91; heterozygous FH, n=1615; hypercholesterolemia with high risk, n=1091) patients, respectively. Overall, mean age and disease duration were 63.2 and 12.3 years, respectively. Serious adverse drug reactions and serious adverse events were experienced by 0.5% and 10.3% of patients; the incidence rates of myocardial infarction and stroke were 0.7% and 0.3%, respectively. A significant mean±SD percentage change in low-density lipoprotein cholesterol levels was observed at week 12 among patients with homozygous FH (-45.7%±28.2; P <0.001), heterozygous FH (-55.9%±28.8; P <0.001), and hypercholesterolemia with high risk (-63.3%±23.7; P <0.001)., Conclusions: Evolocumab was well tolerated, and real-world patients with familial hypercholesterolemia and hypercholesterolemia with high risk in Japan had sustained low-density lipoprotein cholesterol reduction., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02808403.

Familial hypercholesterolemia is an autosomal hereditary disease defined by an increased level of low-density lipoprotein cholesterol (LDL-C), which predisposes significant risks for premature cardiovascular disorders. We present a family trio study: proband, a 13-year-old Kazakh girl with homozygous familial hypercholesterolemia (HoFH) and her parents. HoFH is much more rare and severe than a heterozygous form of the disorder. HoFH patients generally present with LDL-C levels exceeding 13 mmol/L, resulting in early and life-threatening cardiovascular events within the first decades of life. In cases of neglected treatment, young patients have a risk of death from coronary diseases before the age of 30. The aim of this research was to identify genetic mutations in the affected patient and her parents. Genetic testing was necessary due to highly elevated LDL-C levels and the presence of multiple xanthomas. Targeted next-generation sequencing (NGS) was performed in this study using the Illumina TruSight cardio panel, which targets 174 genes related to cardiac disorders. The girl was diagnosed with HoFH based on the results of genetic testing. A biallelic mutation was observed in exon 3 of the low-density lipoprotein receptor ( LDLR ): c. 295 G>A (p.Glu99Lys). Sanger sequencing confirmed that the mutant gene was inherited from both parents. After confirming the genetic diagnosis of HoFH, the patient was treated with LDL apheresis and statins. This case report is the first study of HoFH in a pediatric patient from the Central Asian region. Globally, it emphasizes the need for increased clinical awareness among healthcare providers, as early detection and intervention are important for improving outcomes, particularly in pediatric patients with this rare genetic disorder.

Background: Familial hypercholesterolemia (FH) is a frequently underdiagnosed genetic disorder characterized by elevated low-density lipoprotein (LDL) levels. Genetic testing of LDLR, APOB, and PCSK9 genes can identify variants in up to 80% of clinically diagnosed patients. However, limitations in time, scalability, and cost have hindered effective next-generation sequencing of these genes. Additionally, pharmacogenomic variants are associated with statin-induced adverse effects in FH patients. To address these challenges, we developed a multiplex primer-based amplicon sequencing approach for FH genetic testing., Methods: Multiplex primers were designed for the exons of the LDLR, APOB, and PCSK9 genes, as well as for pharmacogenomic variants rs4149056 (SLCO1B1:c.521T > A), rs2306283 (SLCO1B1:c.388A > G), and rs2231142 (ABCG2:c.421C > A). Analytical validation using samples with known pathogenic variants and clinical validation with 12 FH-suspected probands were conducted. Library preparation was based on a bead-based tagmentation method, and sequencing was conducted on the NovaSeq 6000 platform., Results: Our approach ensured no amplicon dropouts, with over 100× coverage on each amplicon. Known variants in 2 samples were successfully detected. Further, we identified one heterozygous LDLR (p.Glu228Ter) variant and 2 homozygous cases of LDLR (p.Lys294Ter) and LDLR (p.Ser177Leu) variants in patients. Pharmacogenomic analysis revealed that overall 3 patients may require reduced statin doses. Our approach offered reduced library preparation time (approximately 3 h), greater scalability, and lower costs (under $50) for FH genetic testing., Conclusions: Our method effectively sequences LDLR, APOB, and PCSK9 genes including pharmacogenomic variants that will guide appropriate screening and statin dosing, thus increasing both efficiency and affordability., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Familial hypercholesterolemia (FH) is a hereditary disease caused mainly by mutations in the gene encoding the low-density lipoprotein receptor (LDLR). This study aimed to confirm the pathogenicity of the LDLR c.97C>T (p.Gln33Ter) mutation through in vitro functional validation and determine whether this nonsense mutation induces nonsense-mediated mRNA decay (NMD)., Methods: The proband and his family were included in accordance with Chinese Expert Consensus on FH screening. The disease-causing mutations were fund using whole-exome sequencing and were confirmed using bidirectional Sanger sequencing. The pathogenicity of the mutation was predicted using in silico analysis. The LDLR c.97C>T (p.Gln33Ter) mutation was generated using site-directed mutagenesis and expressed in HEK293T cells lacking endogenous LDLR expression. The effects of this alteration on LDLR expression and LDL uptake were assessed using flow cytometry, quantitative polymerase chain analysis, western blotting, and confocal laser scanning microscopy., Results: The mutation that causes FH in this family was LDLR c.97C>T (p.Gln33Ter), and family members with this mutation exhibited elevated levels of low-density lipoprotein cholesterol (LDL-C). The cell experiment results showed that this mutation prevented the synthesis of LDLR protein and caused the cells to lose their LDL uptake ability., Conclusion: LDLR c.97C>T (p.Gln33Ter) is a pathogenic FH mutation. However, this nonsense mutation did not induce NMD., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

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 causal relationship between familial hypercholesterolemia (FH) and various vitamin deficiencies has not yet been elucidated. Therefore, this study investigated the cause-and-effect relationship between FH and the risk of multiple vitamin deficiencies in humans., Methods: Mendelian randomization (MR) analysis was performed by extracting six datasets for FH, FH with ischemic heart disease (IHD), and vitamin deficiency (vitamin A, thiamine, other B-group vitamins, and vitamin D) from the FinnGen study, covering a total of 329,115; 316,290; 354,932; 354,949; 355,411 and 355,238 individuals, respectively., Results: FH was suggestively associated with higher odds of thiamine deficiency [inverse variance weighted odds ratio (OR IVW ) 95% confidence interval (CI): 1.62 (1.03, 2.55), P = 0.036] and vitamin D deficiencies [OR IVW CI: 1.35 (1.04, 1.75), P = 0.024], low-density lipoprotein receptor ( LDLR ) rs112898275 variant, rs11591147 and rs499883 in proprotein convertase subtilisin/kexin 9 ( PCSK9 ), rs9644862 in cyclin-dependent kinase inhibitor 2 B antisense RNA1 ( CDKN2B-AS1 ), and rs142834163 in dedicator of cytokinesis 6 ( DOCK6 ) and rs115478735 in ABO blood group ( ABO ) strongly influenced the risk of thiamine deficiency, while the rs7412 variant in apolipoprotein E ( APOE ) mostly influenced the risk of vitamin D deficiency. FH with IHD was suggestively associated with higher odds of vitamin D deficiency (OR IVW, weighted median [WM][95%CI]: 1.31 [1.05, 1.64]; 1.47 [1.10, 1.97]) ( P = 0.018; 0.010) without any single significant SNPs observed., Conclusion: FH was positively associated with increased risks of thiamine and vitamin D deficiencies, revealing a prospective and unfortunate complication of FH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Wei, Zhou and Liu.)

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.)

Familial hypercholesterolaemia (FH) is a monogenic hereditary disease with an estimated prevalence of 1:220-1:250 in Denmark; the majority have not yet been diagnosed. Untreated FH is associated with a considerably increased risk of premature cardiovascular disease. Early treatment significantly reduces risk, stressing the importance of early diagnosis and treatment initiation. General practicians have a key role in screening and referring patients. Diagnosis, cascade screening, and treatment of FH are handled by Lipids Clinics. For FH, this review finds that initiation of treatment is recommended from age 7-10., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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.)

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.)

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: 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.)

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.)

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: 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 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.

Background: The 2022 Japan Atherosclerosis Society familial hypercholesterolemia (FH) clinical criteria were modified. In particular, the cutoff value of Achilles tendon thickness (ATT) on radiography was changed from ≥9 mm in both sexes to ≥8.0 mm in men and ≥7.5 mm in women., Methods: A total of 872 patients with FH were retrospectively reviewed. Patients were categorized by an ATT of <7.5/8.0 mm (group 1), ≥7.5/8.0 and <9.0 mm (group 2, new group with FH by ATT), and ≥9 mm (group 3)., Results: In total, 492 patients fell into group 1, 102 in group 2, and 263 in group 3, and 14.0%, 55.9%, and 79.8% of patients in groups 1, 2, and 3, respectively, were positive for a FH mutation. Further, among patients with low-density lipoprotein cholesterol >180 mg/dL, 37.3%, 77.3%, and 86.5% of patients had a FH mutation in groups 1, 2, and 3, respectively. The proportion of patients with protein-truncating mutation (3.8%, 16.7%, and 53.2%, respectively) differed significantly across groups 1 through 3, respectively. Interestingly, only a very small proportion of the patients in groups 2 and 3 had palpable xanthomas (3.0% and 14.4% respectively)., Conclusions: This study validates the new radiographic ATT criteria, since the vast majority of patients in the intermediate ATT category had true FH, as shown by positive genetic testing, whereas the old ATT criteria left them with just a deferred diagnosis of FH. In addition, use of physical examination alone for the presence of tendon xanthoma may lead to underdiagnosis of FH., (Copyright © 2024. Published by Elsevier Inc.)

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.)

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.)

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.)

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.)

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.