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Background and Aims Familial hypercholesterolaemia (FH) is a highly prevalent monogenic disorder characterized by elevated LDL cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease. Sex disparities in diagnosis, lipid-lowering therapy, and achieved lipid levels have emerged worldwide, resulting in barriers to care in FH. A systematic review was performed to investigate sex-related disparities in treatment, response, and lipid target achievement in FH (PROSPERO, CRD42022353297). Methods MEDLINE, Embase, The Cochrane library, PubMed, Scopus, PsycInfo, and grey literature databases were searched from inception to 26 April 2023. Records were eligible if they described sex differences in the treatment of adults with FH. Results Of 4432 publications reviewed, 133 met our eligibility criteria. In 16 interventional clinical trials (eight randomized and eight non-randomized; 1840 participants, 49.4% females), there were no differences between males and females in response to fixed doses of lipid-lowering therapy, suggesting that sex was not a determinant of response. Meta-analysis of 25 real-world observational studies (129 441 participants, 53.4% females) found that females were less likely to be on lipid-lowering therapy compared with males (odds ratio.74, 95% confidence interval.66–.85). Importantly, females were less likely to reach an LDL-C < 2.5 mmol/L (odds ratio.85, 95% confidence interval.74–.97). Similarly, treated LDL-C levels were higher in females. Despite this, male sex was associated with a two-fold greater relative risk of major adverse cardiovascular events including myocardial infarction, atherosclerotic cardiovascular disease, and cardiovascular mortality. Conclusions Females with FH were less likely to be treated intensively and to reach guideline-recommended LDL-C targets. This sex bias represents a surmountable barrier to clinical care. [ABSTRACT FROM AUTHOR]

Novel lipid-lowering therapies are being introduced. Few studies exist of the real-world effectiveness of adenosine-tri-phosphate citrate lyase inhibition with bempedoic acid. This study audited bempedoic acid therapy in 216 consecutive patients from three hospital centres – a university hospital (n = 77) and two district general hospitals (n = 106 and 33). Cardiovascular disease (CVD) risk factors, prescription qualification criteria, efficacy and adverse effects were assessed. The population was aged 65.9 ± 11.0 years, 42% were male, 25% had type 2 diabetes, and 31% had familial hypercholesterolaemia. CVD was present in 19% and multibed vascular disease in 8%. Statin intolerance was reported in 92%. Bempedoic acid reduced total cholesterol by 1.58 ± 1.44 mmol/L (20%), LDL-C by 1.37 ± 1.31 mmol/L (27%), triglycerides by 0.22 mmol/L (2%) with an 0.06 mmol/L (1%) increase in HDL-C after 22 ± 9 months follow-up. An LDL-C <2.5 mmol/L was achieved in 40% and <2 mmol/L in 20%. Efficacy (r2 =.33) was predicted by baseline LDL-C (β =.54; p <.001). No significant changes were seen in transaminases, creatinine, creatine kinase, urate or HbA1c. Treatment was discontinued by 33% of patients and occurred due to myalgia (43%), lack of efficacy (16%) and gastrointestinal adverse effects (15%). No cases of gout were observed. In a logistic regression only the number of previous drug classes not tolerated (β = 1.60; p =.009) was a contributing factor to discontinuation. This audit suggests that bempedoic acid therapy is effective but that adverse effects and discontinuation are common. This suggests nocebo effects might be generalizable to all lipid-lowering drug therapies in susceptible individuals. [ABSTRACT FROM AUTHOR]

Over several decades, the approach to treating dyslipidaemias during pregnancy remains essentially unchanged. The lack of advancement in this field is mostly related to the fact that we lack clinical trials of pregnant patients both with available as well as new therapies. While there are numerous novel therapies developed for non-pregnant patients, there are still many limitations in dyslipidaemia treatment during pregnancy. Besides pharmacotherapy and careful clinical assessment, the initiation of behavioural modifications as well as pre-conception management is very important. Among the various lipid-lowering medications, bile acid sequestrants are the only ones officially approved for treating dyslipidaemia in pregnancy. Ezetimibe and fenofibrate can be considered if their benefits outweigh potential risks. Statins are still considered contraindicated, primarily due to animal studies and human case reports. However, recent systematic reviews and meta-analyses as well as data on familial hypercholesterolaemia (FH) in pregnant patients have indicated that their use may not be harmful and could even be beneficial in certain selected cases. This is especially relevant for pregnant patients at very high cardiovascular risk, such as those who have already experienced an acute cardiovascular event or have homozygous or severe forms of heterozygous FH. In these cases, the decision to continue therapy during pregnancy should weigh the potential risks of discontinuation. Bempedoic acid, olezarsen, evinacumab, evolocumab and alirocumab, and inclisiran are options to consider just before and after pregnancy is completed. In conclusion, decisions regarding lipid-lowering therapy for pregnant patients should be personalized. Despite the challenges in designing and conducting studies in pregnant women, there is a strong need to establish the safety and efficacy of dyslipidaemia treatment during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolaemia (FH) warrants early diagnosis to prevent premature atherosclerotic cardiovascular disease (CVD). However, underdiagnosis and undertreatment of FH persist. This study aimed to assess the knowledge and practice of FH care among general practitioners (GPs) in the Netherlands. Methods: An internationally standardised, online questionnaire was sent to Dutch GPs between February 2021 and July 2022. The survey assessed knowledge and awareness of FH, encompassing general familiarity, awareness of management guidelines, inheritance, prevalence, CVD risk, and clinical practice related to FH. Comparative analysis was performed using data on primary care physicians from Western Australia, the Asia-Pacific region and the United Kingdom. Results: Of the 221 participating GPs, 62.4% rated their familiarity with FH as above average (score > 4 on a 1–7 scale), with 91.4% considering themselves familiar with FH treatment and referral guidelines. Correct identification of the FH definition, typical lipid profile, inheritance pattern, prevalence and CVD risk was reported by 83.7%, 87.8%, 55.7%, 19.5%, and 13.6% of the respondents, respectively. Of the participants, 58.4% answered fewer than half of the 8 knowledge questions correctly. Dutch GPs reported greater FH familiarity and guideline awareness compared with their international counterparts but exhibited similar low performance on FH knowledge questions. Conclusion: Despite the Netherlands' relatively high FH detection rate, substantial knowledge gaps regarding FH persist among Dutch GPs, mirroring global trends. Enhanced FH education and awareness in primary care are imperative to improve FH detection and ensure adequate treatment. Targeting the global suboptimal understanding of FH might require international efforts. [ABSTRACT FROM AUTHOR]

Background: Studies utilising genotyping methods report the prevalence of familial hypercholesterolaemia to be as high as one in 137 of the adult population. Aim: To estimate the prevalence of familial hypercholesterolaemia measured by clinically coded diagnosis, associated treatments, and lipid measurements observed in UK primary care. Design and setting: This was a retrospective analysis using the Clinical Practice Research Datalink (CPRD) GOLD database. Method: Patients aged ≥18 years and actively registered on the index date (30 June 2018) formed the study cohort. Point prevalence of familial hypercholesterolaemia for 2018 was estimated overall and for each nation of the UK. Patients with familial hypercholesterolaemia were stratified into primary and secondary prevention groups, defined as those with/without a prior diagnosis of atherosclerotic cardiovascular disease. Prevalence estimates and extrapolations were replicated for these subgroups. Baseline demographic, lipid, and clinical characteristics for the prevalent cohort were presented. Results: In total, 4048 patients with familial hypercholesterolaemia formed the study cohort. The estimated familial hypercholesterolaemia prevalence for the UK was 16.4 per 10 000 (95% confidence interval [CI] = 16.0 to 16.9). Of these, 2646 (65.4%) patients with familial hypercholesterolaemia had a recent prescription for lipid-lowering therapy. Mean lipid levels were lower for those treated with lipid-lowering therapy compared with those untreated: 5.34 mmol/L (SD 1.50) versus 6.25 mmol/L (SD 1.55) for total cholesterol and 3.15 mmol/L (SD 1.34) versus 3.96 mmol/L (SD 1.36) for low-level density lipoprotein cholesterol. Conclusion: The estimated prevalence of familial hypercholesterolaemia was one in 608 of the population, less than expected from other studies, which may indicate that familial hypercholesterolaemia is under-recognised in UK primary care. Over one-third of diagnosed patients were undertreated and many did not achieve target goals, placing them at risk of cardiovascular events. [ABSTRACT FROM AUTHOR]

Background: Despite recent guidelines appropriate lipid-lowering treatment (LLT) remains suboptimal in everyday clinical practice. Aims: We aimed to describe clinical practice of use of LLT for at least high CV risk populations in a Hellenic real-world setting and assess how this relates to the European Society of Cardiology treatment guidelines. Methods: We analyzed data from a retrospective cohort study of the National Registry of patients with dyslipidemia between 1/7/2017 and 30/6/2019 who were at least of high CV risk and filled a dual or triple lipid-lowering treatment (dLLT, tLLT) prescription. The primary outcomes of interest of this analysis were to report on the patterns of LLT use in at least high CV risk patients. Results: A total of 994,255 (45.4% of Greeks on LLT) were of at least high CV risk and 120,490 (5.5%) were on dLLT or tLLT. The percentage of patients with reported statin intolerance ranged from 2 to 10%. While persistence was reported to be satisfactory (>85% for both dLLT or tLLT), adherence was low (ranging between 14 and 34% for dLLT). In 6-month intervals, the percentage of patients achieving a low-density lipoprotein cholesterol (LDL-C) target below 100 md/dL ranged from 20% to 23% for dLLT and 34%–37% for tLLT. Conclusions: The prevalence of at least high CV risk patients among patients receiving LLT in Greece is substantial. Despite the high persistence and probably due to the low adherence to treatment, LDL-C remains above targets in more than two thirds of patients.

Background Familial hypercholesterolaemia (FH) is an autosomal dominant genetic condition predominantly caused by the low-density lipoprotein receptor (LDLR) gene mutation. Case summary This is the case of a 54-year-old Malay woman with genetically confirmed FH complicated by premature coronary artery disease (PCAD). She was clinically diagnosed in primary care at 52 years old, fulfilling the Simon Broome Criteria (possible FH), Dutch Lipid Clinic Criteria (score of 8: probable FH), and Familial Hypercholesterolaemia Case Ascertainment Tool (relative risk score of 9.51). Subsequently, she was confirmed to have a heterozygous LDLR c.190+4A>T intron 2 pathogenic variant at the age of 53 years. She was known to have hypercholesterolaemia and was treated with statin since the age of 25. However, the lipid-lowering agent was not intensified to achieve the recommended treatment target. The delayed FH diagnosis has caused this patient to have PCAD and percutaneous coronary intervention (PCI) at the age of 29 years and a second PCI at the age of 49 years. She also has a very strong family history of hypercholesterolaemia and PCAD, where seven out of eight of her siblings were affected. Despite this, FH was not diagnosed early, and cascade screening of family members was not conducted, resulting in a missed opportunity to prevent PCAD. Discussion Familial hypercholesterolaemia can be clinically diagnosed in primary care to identify those who may require genetic testing. Multidisciplinary care focuses on improving identification, cascade screening, and management of FH, which is vital to improving prognosis and ultimately preventing PCAD. [ABSTRACT FROM AUTHOR]

Abstrac t: Background: Long non‐coding RNAs (lncRNAs) could be attractive circulating biomarkers for cardiovascular risk stratification in subjects at high atherosclerotic cardiovascular disease risk such as familial hypercholesterolaemia (FH). Our aim was to investigate the presence of lncRNAs carried by high‐density lipoprotein (HDL) in FH subjects and to evaluate the associations of HDL‐lncRNAs with lipoproteins and mechanical vascular impairment assessed by pulse wave velocity (PWV). Methods: This was a retrospective observational study involving 94 FH subjects on statin treatment. Biochemical assays, HDL purification, lncRNA and PWV analyses were performed in all subjects. Results: LncRNA HIF1A‐AS2, LASER and LEXIS were transported by HDL; moreover, HDL‐lncRNA LEXIS was associated with Lp(a) plasma levels (p <.01). In a secondary analysis, the study population was stratified into two groups based on the Lp(a) median value. The high‐Lp(a) group exhibited a significant increase of PWV compared to the low‐Lp(a) group (9.23 ±.61 vs. 7.67 ±.56, p <.01). While HDL‐lncRNA HIF1A‐AS2 and LASER were similar in the two groups, the high‐Lp(a) group exhibited a significant downregulation of HDL‐lncRNA LEXIS compared to the low‐Lp(a) group (fold change −4.4, p <.0001). Finally, Lp(a) and HDL‐lncRNA LEXIS were associated with PWV (for Lp(a) p <.01; for HDL‐lncRNA LEXIS p <.05). Conclusions: LncRNA HIF1A‐AS2, LASER and LEXIS were transported by HDL; moreover, significant relationships of HDL‐lncRNA LEXIS with Lp(a) levels and PWV were found. Our study suggests that HDL‐lncRNA LEXIS may be useful to better identify FH subjects with more pronounced vascular damage. [ABSTRACT FROM AUTHOR]

• Cascade testing for elevated Lp(a) from index cases with FH and elevated Lp(a) is effective by identifying 1 new case of elevated Lp(a) for every 2 children/adolescents tested. • Incorporating the detection of elevated Lp(a) into cascade testing for FH among children and adolescents is feasible. • More research is required to determine the clinical impact and value of identifying children and adolescents with elevated Lp(a). Elevated plasma lipoprotein(a) [Lp(a)] is a common, inherited condition independently causing cardiovascular disease. Recent expert recommendations suggest opportunistically testing for elevated Lp(a) during cascade testing for familial hypercholesterolaemia (FH). We investigated the effectiveness of detecting elevated Lp(a) in 103 children and adolescents who were first-degree relatives of 66 adult index FH cases as part of an established FH cascade screening program. The yield of detection of elevated Lp(a) using a threshold of ≥30 mg/dL in children and adolescents was assessed. Cascade testing from FH index cases with elevated Lp(a) ≥50 mg/dL identified 1 case of Lp(a) ≥30 mg/dL for every 2 children or adolescents tested. In contrast, opportunistic screening from index cases with FH but normal Lp(a) levels demonstrated 1 case of Lp(a) ≥30 mg/dL for every 7.5 children or adolescents tested (p < 0.001). In conclusion, cascade testing for elevated Lp(a) from index cases with FH and elevated Lp(a) is effective in identifying new cases of elevated Lp(a). [ABSTRACT FROM AUTHOR]

In the last few decades, atherosclerotic cardiovascular disease (ASCVD) risk has decreased dramatically among individuals affected by familial hypercholesterolaemia (FH) as a result of the early initiation of statin treatment in childhood. Contemporaneously important improvements in care for people with diabetes have also been made, such as the prevention of mortality from acute diabetic complications. However, individuals with type 1 diabetes still have a two to eight times higher risk of death than the general population. In the last 20 years, a few landmark studies on excess mortality in people with type 1 diabetes, in particular young adults, have been published. Although these studies were carried out in different populations, all reached the same conclusion: individuals with type 1 diabetes have a pronounced increased risk of ASCVD. In this review, we address the role of lipid abnormalities in the development of ASCVD in type 1 diabetes and FH. Although type 1 diabetes and FH are different diseases, lessons could be learned from the early initiation of statins in children with FH, which may provide a rationale for more stringent control of dyslipidaemia in children with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Purpose of Review: The UK National Health Service (NHS) has recently announced a Newborn Genomes Programme (NGP) to identify infants with treatable inherited disorders using whole genome sequencing (WGS). Here, we address, for familial hypercholesterolaemia (FH), the four principles that must be met for the inclusion of a disorder in the NGP. Recent Findings: Principle A: There is strong evidence that the genetic variants causing FH can be reliably detected. Principle B: A high proportion of individuals who carry an FH-causing variant are likely to develop early heart disease if left undiagnosed and not offered appropriate treatment. Principle C: Early intervention has been shown to lead to substantially improved outcomes in children with FH. Principle D: The recommended interventions are equitably accessible for all. Summary: FH meets all the Wilson and Jungner criteria for inclusion in a screening programme, and it also meets all four principles and therefore should be included in the Newborn Genomes Programme. [ABSTRACT FROM AUTHOR]

This is an overview of the EAS Familial Hypercholesterolaemia (FH) Studies Collaboration (FHSC) global consortium and registry (established 2015), which broadly addresses the global burden of FH. Eighty-seven National Lead Investigators from 74 countries form this expanding global consortium, and this global registry currently includes pooled data on 70,000 participants from participating countries to facilitate FH surveillance. Published first results from this global registry concluded that FH is diagnosed late, and management of LDL-cholesterol falls below guideline recommendations, and therefore earlier detection of FH and wider use of combination therapy is required. Further FHSC studies will follow on updated data including new countries, participants and variables, and non-DNA genetic information, and on the remaining cohorts in the registry. FHSC cross-sectional collaborative global studies are expected to promote FH detection earlier in life to subsequently initiate early lipid lowering therapy to reduce lifelong exposure to cumulative LDL-cholesterol thus reducing cardiovascular disease risk.

BackgroundAtherosclerotic cardiovascular diseases (ASCVD) including myocardial infarction, stroke and peripheral arterial disease continue to be major causes of premature death, disability and healthcare expenditure globally. Preventing the accumulation of cholesterol-containing atherogenic lipoproteins in the vessel wall is central to any healthcare strategy to prevent ASCVD. Advances in current concepts about reducing cumulative exposure to apolipoprotein B (apo B) cholesterol-containing lipoproteins and the emergence of novel therapies provide new opportunities to better prevent ASCVD. The present update of the World Heart Federation Cholesterol Roadmap provides a conceptual framework for the development of national policies and health systems approaches, so that potential roadblocks to cholesterol management and thus ASCVD prevention can be overcome.MethodsThrough a review of published guidelines and research papers since 2017, and consultation with a committee composed of experts in clinical management of dyslipidaemias and health systems research in low-and-middle income countries (LMICs), this Roadmap identifies (1) key principles to effective ASCVD prevention (2) gaps in implementation of these interventions (knowledge-practice gaps); (3) health system roadblocks to treatment of elevated cholesterol in LMICs; and (4) potential strategies for overcoming these.ResultsReducing the future burden of ASCVD will require diverse approaches throughout the life-course. These include: a greater focus on primordial prevention; availability of affordable cholesterol testing; availability of universal cholesterol screening for inherited dyslipidaemias; risk stratification moving beyond 10-year risk to look at lifetime risk with adequate risk estimators; wider availability of affordable cholesterol-lowering therapies which should include statins as essential medications globally; use of adequate doses of potent statin regimens; and combination therapies with ezetimibe or other therapies in order to attain and maintain robust reductions in LDL-C in those at highest risk. Continuing efforts are needed on health literacy for both the public and healthcare providers, utilising multi-disciplinary teams in healthcare and applications that quantify both ASCVD risk and benefits of treatment as well as increased adherence to therapies.ConclusionsThe adverse effects of LDL-cholesterol and apo B containing lipoprotein exposure are cumulative and result in ASCVD. These are preventable by implementation of different strategies, aimed at efficiently tackling atherosclerosis at different stages throughout the human life-course. Preventive strategies should therefore be updated to implement health policy, lifestyle changes and when needed pharmacotherapies earlier with investment in, and a shift in focus towards, early preventive strategies that preserve cardiovascular health rather than treat the consequences of ASCVD.

Abstract Familial hypercholesterolaemia (FH) is a frequent genetic disorder characterised by high plasma levels of total and LDL-cholesterol and premature atherosclerosis. If left untreated, affected subjects have a high risk of cardiovascular disease, as they are exposed to very high levels of LDL-cholesterol from birth. Healthy dietary habits and lifestyle are the first treatment option and, if started from childhood, represent a milestone in the prevention of atherosclerotic disease, both as a starting point and in combination with drug therapy. In this work, based on the main consensus documents available so far, we have evaluated the most up-to-date indications of the dietetic-nutritional intervention for the treatment of FH, delving into the peculiar aspects of the diet of the child/adolescent affected by FH. After an analysis of the macro- and micronutrients and the most common dietary patterns currently recommended, we highlighted some practical aspects, some frequent errors and some risks we could fall into when dealing with paediatric nutritional treatment. In conclusion, the dietary intervention for the child/adolescent with FH is a complex task, that should be individualised and tailored taking into account, first of all, the nutritional adequacy for growth and development, but also the multiple aspects linked to the child/adolescent's age, tastes and preferences, the family they belong to, the socio-economic context and the Country they live in.

Background and Aims Lerodalcibep, a novel small recombinant fusion protein of a proprotein convertase subtilisin/kexin type 9 gene–binding domain (adnectin) and human serum albumin, demonstrated highly effective low-density lipoprotein cholesterol (LDL-C) reduction with monthly 300 mg in 1.2 mL subcutaneous dosing in Phase 2. In this global Phase 3 trial, the safety and efficacy of lerodalcibep were evaluated in heterozygous familial hypercholesterolaemia patients requiring additional LDL-C lowering. Methods Patients were randomized 2:1 to monthly subcutaneous injections of either lerodalcibep 300 mg or placebo for 24 weeks. The primary efficacy endpoints were the per cent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24. Results In 478 randomized subjects [mean age (range); 53 (18–80) years, 51.7% female, mean (SD) baseline LDL-C 3.88 (1.66) mmol/L], lerodalcibep reduced LDL-C, compared with placebo by an absolute amount of 2.08 (0.11) mmol/L [LS mean (SE); 95% confidence interval −2.30 to −1.87] with a percentage difference of −58.61 (3.25)% at Week 24 and by 2.28 (0.10) mmol/L (95% confidence interval −2.47 to −2.09) with a percentage difference of −65.0 (2.87)% at the mean of Weeks 22 and 24 (P <.0001 for all). With lerodalcibep, 68% of subjects achieved both a reduction in LDL-C ≥ 50% and the recommended European Society of Cardiology LDL-C targets during the study. Except for mild injection site reactions, treatment-emergent adverse events were similar between lerodalcibep and placebo. Conclusions Lerodalcibep, a novel anti-proprotein convertase subtilisin/kexin type 9 gene small binding protein dosed monthly as an alternative to monoclonal antibodies, significantly reduced LDL-C in subjects with heterozygous familial hypercholesterolaemia with a safety profile similar to placebo. [ABSTRACT FROM AUTHOR]

In this report, we describe a patient with a delayed cutaneous hypersensitivity reaction to evolocumab, a human monoclonal antibody directed against the serine protease proprotein convertase subtilisin/kexin type 9 used to reduce low-density lipoprotein concentrations in the treatment of familial hypercholesterolaemia. The patient developed erythematous exfoliative lesions on the skin after the third administration of evolocumab. After each of the next three consecutive doses, the lesions worsened for 24 h, persisted for approximately 7 days, and then went into partial remission. Discontinuation of evolocumab resulted in a complete remission. Hypersensitivity reactions induced by biological drugs are becoming an increasing problem, but knowledge of these reactions is still limited. Our case report convincingly demonstrates the causal relationship between repeated drug exposure and the development and exacerbation of clinical symptoms. It also highlights a dilemma in the management of such clinical situations: the 'treat-through' strategy versus withdrawal of vital treatment. [ABSTRACT FROM AUTHOR]

The p.(Tyr400_Phe402del) mutation in the LDL receptor (LDLR) gene is the most frequent cause of familial hypercholesterolaemia (FH) in Gran Canaria. The aim of this study was to determine the age and origin of this prevalent founder mutation and to explore its functional consequences. For this purpose, we obtained the haplotypic information of 14 microsatellite loci surrounding the mutation in one homozygous individual and 11 unrelated heterozygous family trios. Eight different mutation carrier haplotypes were identified, which were estimated to originate from a common ancestral haplotype 387 (110–1572) years ago. This estimation suggests that this mutation happened after the Spanish colonisation of the Canary Islands, which took place during the fifteenth century. Comprehensive functional studies of this mutation showed that the expressed LDL receptor was retained in the endoplasmic reticulum, preventing its migration to the cell surface, thus allowing us to classify this LDLR mutation as a class 2a, defective, pathogenic variant. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolaemia (FH) is a frequent genetic disorder characterised by high plasma levels of total and LDL-cholesterol and premature atherosclerosis. If left untreated, affected subjects have a high risk of cardiovascular disease, as they are exposed to very high levels of LDL-cholesterol from birth. Healthy dietary habits and lifestyle are the first treatment option and, if started from childhood, represent a milestone in the prevention of atherosclerotic disease, both as a starting point and in combination with drug therapy. In this work, based on the main consensus documents available so far, we have evaluated the most up-to-date indications of the dietetic-nutritional intervention for the treatment of FH, delving into the peculiar aspects of the diet of the child/adolescent affected by FH. After an analysis of the macro- and micronutrients and the most common dietary patterns currently recommended, we highlighted some practical aspects, some frequent errors and some risks we could fall into when dealing with paediatric nutritional treatment. In conclusion, the dietary intervention for the child/adolescent with FH is a complex task, that should be individualised and tailored taking into account, first of all, the nutritional adequacy for growth and development, but also the multiple aspects linked to the child/adolescent's age, tastes and preferences, the family they belong to, the socio-economic context and the Country they live in. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolaemia (FH) is associated with a significant increase in the risk of premature coronary artery disease. Pregnancy is likely a vulnerable time for atherosclerosis progression, with a physiological rise in low‐density lipoprotein cholesterol (LDL‐C) further exaggerated by the discontinuation of cholesterol‐lowering therapy. Materials and Methods: A retrospective review was undertaken of 13 women with familial hypercholesterolemia who were managed during pregnancy between 2007 and 2021 by a multidisciplinary team following individualised risk assessment. Results: Overall, pregnancy outcomes were good, with no maternal or fetal complications, including congenital abnormalities, maternal cardiac events or hypertensive complications. Loss of statin treatment time ranged between 12 months and 3.5 years resulting from the accumulation of the preconception, pregnancy and lactation periods and was magnified in women having more than one pregnancy. Of seven women treated with cholestyramine, one developed abnormal liver function with an elevated international normalisation ratio which was corrected with vitamin K. Conclusion: Pregnancy is associated with prolonged cessation of cholesterol‐lowering therapy, a concern with respect to the risk of coronary artery disease in FH. Continuation of statin therapy up to conception and even during pregnancy in patients at higher risk of cardiovascular disease may be justified, especially with increasing evidence supporting the safety of statin therapy during pregnancy. However, more long‐term maternal and fetal data are required for the routine use of statins during pregnancy. Guideline‐informed models of care covering family planning and pregnancy should be implemented for all women with FH. [ABSTRACT FROM AUTHOR]

It is unclear to what extent genetic testing improves the ability to diagnose familial hypercholesterolaemia (FH). We investigated the percentage with FH among individuals referred to Danish lipid clinics, and evaluated the impact of genetic testing for a diagnosis of FH. From September 2020 through November 2021, all patients referred for possible FH to one of the 15 Danish lipid clinics were invited for study participation and >97% (n = 1488) accepted. The Dutch Lipid Clinical Network criteria were used to diagnose clinical FH. The decision of genetic testing for FH was based on local practice. A total of 1243 individuals were referred, of whom 25.9% were diagnosed with genetic and/or clinical FH. In individuals genetically tested (n = 705), 21.7% had probable or definite clinical FH before testing, a percentage that increased to 36.9% after genetic testing. In individuals with unlikely and possible FH before genetic testing, 24.4% and 19.0%, respectively, had a causative pathogenic variant. In a Danish nationwide study, genetic testing increased a diagnosis of FH from 22% to 37% in patients referred with hypercholesterolaemia suspected of having FH. Importantly, approximately 20% with unlikely or possible FH, who without genetic testing would not have been considered having FH (and family screening would not have been undertaken), had a pathogenic FH variant. We therefore recommend a more widespread use of genetic testing for evaluation of a possible FH diagnosis and potential cascade screening. [Display omitted] • Large nationwide study including all 1243 individuals referred to Danish lipid clinics for suspected FH in a 15 month period. • A total of 26% of the referred patients had FH despite only 705/1243 were genetically tested. • Genetic testing increased the diagnoses of FH from 22% to 37% in patients referred with hypercholesterolemia suspected of FH. • Approximately 20% with unlikely or possible FH according to DLCN criteria (before genetic testing) had causative FH mutations. [ABSTRACT FROM AUTHOR]

• 29 HoFH children were matched to 101 HeFH and 102 unaffected children. • Children with HoFH had the highest Lp(a) levels. • A gene-dose increase (zero, one, two pathogenic LDLR variants) in Lp(a) was found. • We recommend to measure Lp(a) in HoFH children to minimize (potential) ASCVD risk. Homozygous familial hypercholesterolaemia (HoFH) is a life-threatening disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels. Untreated, severe atherosclerotic cardiovascular disease (ASCVD), including aortic valve stenosis (AVS), may already occur in childhood. Another important genetic risk factor for ASCVD and AVS is elevated lipoprotein(a) [Lp(a)], which is highly prevalent in the general paediatric population. However, data on Lp(a) in children with HoFH are scarce. Therefore, we performed a cross-sectional study to evaluate Lp(a) levels in children with HoFH and compared them to children with heterozygous FH (HeFH) and unaffected children. Adjusted least-square mean (95% CI) Lp(a) levels in HoFH (n=29), HeFH (n=101) and unaffected children (n=102) were 18.7 (12.0-29.1), 15.3 (11.8-19.8) and 10.5 (8.3-13.2) mg/dL, respectively (p-for-trend=0.007). Lp(a) levels in children with HoFH were higher than in children with HeFH and in unaffected children. Given the very high ASCVD risk with HoFH, identifying other risk factors such as elevated Lp(a) in these children is important. Therefore, Lp(a) levels should be measured at least once in all children with HoFH. [ABSTRACT FROM AUTHOR]

Aims: We aimed to determine if coronary artery calcium (CAC) is associated with cardiovascular disease (CVD) events, defined as CVD-related death, unstable angina, myocardial infarction, or staged revascularization among patients with heterozygous familial hypercholesterolaemia (HeFH) under primary prevention settings. Methods and results: Data of patients with FH admitted to Kanazawa University Hospital between 2000 and 2020, who underwent CAC measurement and were followed up (n = 622, male = 306, mean age = 54 years), were retrospectively reviewed. Risk factors for CVD events were determined using the Cox proportional hazard model. The median follow-up duration was 13.2 years (interquartile range: 9.8–18.4 years). We observed 132 CVD events during the follow-up period. The event rate per 1000 person-years for CAC scores of 0 [n = 283 (45.5%)], 1–100 [n = 260 (41.8%)], and >100 [n = 79 (12.7%)] was 1.2, 17.0, and 78.8, respectively. Log (CAC score + 1) was a significant predictor of the occurrence of CVD events (hazard ratio: 3.24; 95% confidence interval: 1.68–4.80; P < 0.0001) in the multivariate Cox regression analysis, independent of other factors. The risk discrimination of CVD events was enhanced by adding CAC information to other conventional risk factors (C-statistics: 0.833–0.934; P < 0.0001). Conclusion: The CAC score helps in further risk stratification in patients with HeFH. Graphical Abstract [ABSTRACT FROM AUTHOR]

Aims Familial hypercholesterolaemia (FH) predisposes children to the early initiation of atherosclerosis and is preferably diagnosed by DNA analysis. Yet, in many children with a clinical presentation of FH, no mutation is found. Adult data show that high levels of lipoprotein(a) [Lp(a)] may underlie a clinical presentation of FH, as the cholesterol content of Lp(a) is included in conventional LDL cholesterol measurements. As this is limited to adult data, Lp(a) levels in children with and without (clinical) FH were evaluated. Methods and results Children were eligible if they visited the paediatric lipid clinic (1989–2020) and if Lp(a) measurement and DNA analysis were performed. In total, 2721 children (mean age: 10.3 years) were included and divided into four groups: 1931 children with definite FH (mutation detected), 290 unaffected siblings/normolipidaemic controls (mutation excluded), 108 children with probable FH (clinical presentation, mutation not detected), and 392 children with probable non-FH (no clinical presentation, mutation not excluded). In children with probable FH, 32% were found to have high Lp(a) [geometric mean (95% confidence interval) of 15.9 (12.3–20.6) mg/dL] compared with 10 and 10% [geometric means (95% confidence interval) of 11.5 (10.9–12.1) mg/dL and 9.8 (8.4–11.3) mg/dL] in children with definite FH (P = 0.017) and unaffected siblings (P = 0.002), respectively. Conclusion Lp(a) was significantly higher and more frequently elevated in children with probable FH compared with children with definite FH and unaffected siblings, suggesting that high Lp(a) may underlie the clinical presentation of FH when no FH-causing mutation is found. Performing both DNA analysis and measuring Lp(a) in all children suspected of FH is recommended to assess possible LDL cholesterol overestimation related to increased Lp(a). [ABSTRACT FROM AUTHOR]

Purpose of Review: Describe the application of implementation science to improve the detection and management of familial hypercholesterolaemia. Recent Findings: Gaps between evidence and practice, such as underutilization of genetic testing, family cascade testing, failure to achieve LDL-cholesterol goals and low levels of knowledge and awareness, have been identified through clinical registry analyses and clinician surveys. Implementation science theories, models and frameworks have been applied to assess barriers and enablers in the literature specific to local contextual factors (e.g. stages of life). The effect of implementation strategies to overcome these factors has been evaluated; for example, automated identification of individuals with FH or training and education to improve statin adherence. Clinical registries were identified as a key infrastructure to monitor, evaluate and sustain improvements in care. Summary: The expansion in evidence supporting the care of familial hypercholesterolaemia requires a similar expansion of efforts to translate new knowledge into clinical practice. [ABSTRACT FROM AUTHOR]

• Lp(a)-associated cholesterol is not accounted for in the Friedwald equation. • Adjusting estimated LDL-C by Lp(a) improves accuracy of FH diagnostic criteria. • However, this approach may lead to patients with an FH mutation being missed. Familial hypercholesterolaemia (FH) diagnostic tools help prioritise patients for genetic testing and include LDL-C estimates commonly calculated using the Friedewald equation. However, cholesterol contributions from lipoprotein(a) (Lp(a)) can overestimate 'true' LDL-C, leading to potentially inappropriate clinical FH diagnosis. To assess how adjusting LDL-C for Lp(a)-cholesterol affects FH diagnoses using Simon Broome (SB) and Dutch Lipid Clinic Network (DLCN) criteria. Adults referred to a tertiary lipid clinic in London, UK were included if they had undergone FH genetic testing based on SB or DLCN criteria. LDL-C was adjusted for Lp(a)-cholesterol using estimated cholesterol contents of 17.3%, 30% and 45%, and the effects of these adjustments on reclassification to 'unlikely' FH and diagnostic accuracy were determined. Depending on the estimated cholesterol content applied, LDL-C adjustment reclassified 8-23% and 6-17% of patients to 'unlikely' FH using SB and DLCN criteria, respectively. The highest reclassification rates were observed following 45% adjustment in mutation-negative patients with higher Lp(a) levels. This led to an improvement in diagnostic accuracy (46% to 57% with SB, and 32% to 44% with DLCN following 45% adjustment) through increased specificity. However all adjustment factors led to erroneous reclassification of mutation-positive patients to 'unlikely' FH. LDL-C adjustment for Lp(a)-cholesterol improves the accuracy of clinical FH diagnostic tools. Adopting this approach would reduce unnecessary genetic testing but also incorrectly reclassify mutation-positive patients. Health economic analysis is needed to balance the risks of over- and under-diagnosis before LDL-C adjustments for Lp(a) can be recommended. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolaemia (FH), a common monogenic disorder, is a preventable cause of premature coronary artery disease and death. Up to 35 million people worldwide have FH, but most remain undetected and undertreated. Several clinical guidelines have addressed the gaps in care of FH, but little focus has been given to implementation science and practice. The International Atherosclerosis Society (IAS) has developed an evidence-informed guidance for the detection and management of patients with FH, supplemented with implementation strategies to optimize contextual models of care. The guidance is partitioned into detection, management and implementation sections. Detection deals with screening, diagnosis, genetic testing and counselling. Management includes risk stratification, treatment of adults and children with heterozygous and homozygous FH, management of FH during pregnancy, and use of lipoprotein apheresis. Specific and general implementation strategies, guided by processes specified by the Expert Recommendations for Implementing Change taxonomy, are provided. Core generic implementation strategies are given for improving care. Nation-specific cholesterol awareness campaigns should be utilized to promote better detection of FH. Integrated models of care should be underpinned by health policy and adapted to meet local, regional and national needs. Clinical centres of excellence are important for taking referrals from the community. General practitioners should work seamlessly with multidisciplinary teams. All health-care providers must receive training in essential skills for caring for patients and families with FH. Management should be supported by shared decision-making and service improvement driven by patient-reported outcomes. Improvements in services require sharing of existing resources that can support care. Advocacy should be utilized to ensure sustainable funding. Digital health technologies and clinical quality registries have special value. Finally, academic-service partnerships need to be developed to identify gaps in care and set priorities for research. This new IAS guidance on FH complements the recent World Heart Federation Cholesterol Roadmap.

This study aimed to ascertain how the long-term benefits and costs of diagnosis and treatment of familial hypercholesterolaemia (FH) vary by prognostic factors and 'cholesterol burden', which is the effect of long-term exposure to low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) risk. A new cost-effectiveness model was developed from the perspective of the UK National Health Service (NHS), informed by routine data from individuals with FH. The primary outcome was net health gain (i.e., health benefits net of the losses due to costs), expressed in quality-adjusted life years (QALYs) at the £15,000/QALY threshold. Prognostic factors included pre-treatment LDL-C, age, gender, and CVD history. If cholesterol burden is considered, diagnosis resulted in positive net health gain (i.e., it is cost-effective) in all individuals with pre-treatment LDL-C ≥ 4 mmol/L, and in those with pre-treatment LDL-C ≥ 2 mmol/L aged ≥50 years or who have CVD history. If cholesterol burden is not considered, diagnosis resulted in lower net health gain, but still positive in children aged 10 years with pre-treatment LDL-C ≥ 6 mmol/L and adults aged 30 years with pre-treatment LDL-C ≥ 4 mmol/L. Diagnosis and treatment of most people with FH results in large net health gains, particularly in those with higher pre-treatment LDL-C. Economic evaluations of FH interventions should consider the sensitivity of the study conclusions to cholesterol burden, particularly where interventions target younger patients, and explicitly consider prognostic factors such as pre-treatment LDL-C, age, and CVD history. [Display omitted] • The benefits of diagnosis and treatment of people with familial hypercholesterolaemia are large. • Considering cholesterol burden in cost-effectiveness modelling shows larger benefits from diagnosis and treatment. • The magnitude of benefits also depends on prognostic factors, in particular age and low-density lipoprotein cholesterol. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolaemia (FH) is caused by mutations in lipid metabolism genes, predominantly in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin-type 9 (PCSK9) and LDL receptor adaptor protein 1 (LDLRAP1). The prevalence of genetically confirmed FH and the detection rate of pathogenic variants (PV) amongst clinically diagnosed patients is not well established. Targeted next-generation sequencing of LDLR, APOB, PCSK9 and LDLRAP1 was performed on 372 clinically diagnosed Malaysian FH subjects. Out of 361 variants identified, 40 of them were PV (18 = LDLR, 15 = APOB, 5 = PCSK9 and 2 = LDLRAP1). The majority of the PV were LDLR and APOB, where the frequency of both PV were almost similar. About 39% of clinically diagnosed FH have PV in PCSK9 alone and two novel variants of PCSK9 were identified in this study, which have not been described in Malaysia and globally. The prevalence of genetically confirmed potential FH in the community was 1:427, with a detection rate of PV at 0.2% (12/5130). About one-fourth of clinically diagnosed FH in the Malaysian community can be genetically confirmed. The detection rate of genetic confirmation is similar between potential and possible FH groups, suggesting a need for genetic confirmation in index cases from both groups. Clinical and genetic confirmation of FH index cases in the community may enhance the early detection of affected family members through family cascade screening. [ABSTRACT FROM AUTHOR]

Aim. To characterize patients receiving PCSK9 inhibitors, and assess the efficiency of their treatment in a specialized lipid center.Material and methods. A retrospective analysis of the medical records of patients who visited the Lipid clinic of the National Medical Research Center for Therapy and Preventive Medicine (Moscow, Russia), receiving PCSK9 inhibitor and having lipid profile in dynamics, was carried out (n=77). Cardiovascular risk (CVR) and low-density lipoprotein cholesterol (LDL-C) target levels were evaluated in accordance with the Russian guidelines for the diagnostics and correction of dyslipidemias 2020.Results. Of 77 patients taking PCSK9 inhibitors (44.2% males, the median of age 56 [47; 66] years), the majority (64.0%) had a probable or definite familial hypercholesterolemia (FH). The proportion of other lipid metabolism disorders, pure hypercholesterolemia and combined hyperlipidemia was 21% and 15%. More than half of the patients (68.8%) had a very high CVR, mainly due to the presence of coronary heart disease (84.9%). The proportion of patients receiving PCSK9 inhibitors as monotherapy was 7.8%, in combination with high-intensity statin therapy – 33.8%, as part of triple lipid-lowering therapy (high-intensity statin, ezetimibe, PCSK9 inhibitors) – 50.6%. Addition of PCSK9 inhibitors to combined lipid-lowering therapy enabled to reduce the LDL-C level to 1.02 [0.62; 1.39] mmol/l with its total decrease from the baseline by 87.3%. While taking PCSK9 inhibitors, LDL-C

Objective: This study aimed to assess the quality and readability of web-based information on familial hypercholesterolaemia. Design, setting and methods: Internet searches using the terms 'familial hypercholesterolemia', 'hypercholesterolemia', 'inherited high cholesterol', 'hereditary high cholesterol' and 'inherited high LDL' were conducted with the Google, Yahoo! and Bing search engines using default settings during August 2021. The first 50 web links that appeared using each search engine were evaluated using the Flesch Reading Ease Score (FRES) and DISCERN instrument for readability and the quality of the website. The LIDA tool was used to assess reliability and usability. Results: In all, 750 websites were accessed and 38 websites were included in the analysis. The majority of the websites (29, 76.3%) were owned by non-governmental institutions. Twelve (30.8%) websites were certified by the Health On the Net Foundation (HON) code of conduct. Only 17 websites (44.7%) had a stated author. Twenty-nine (76.3%) websites had a stated date of publication. Only 16 (42.1%) provided references for the statements made. Infographics were used in 17 (44.7%) websites. The median FRES was 47.15 (range: 22.3–91.8), which is equivalent to college-level readability. The median LIDA usability and reliability score was 38.00 (range: 25–46) and 15.00 (range: 7–24), respectively. The median DISCERN score was 45.00 (range: 17–76). The DISCERN score was significantly associated with the FRES (0.047) and whether the website was governmental or not (0.028). Conclusion: According to this study, the readability, reliability, usability and quality of the majority of websites were inadequate. Due to the rapid growth in the use of the Internet, steps need to be taken to standardise and regulate patient education websites for this and perhaps other health conditions. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to assess the impact and cost-effectiveness of offering population genomic screening to all young adults in Australia to detect heterozygous familial hypercholesterolaemia (FH). Methods and results We designed a decision analytic Markov model to compare the current standard of care for heterozygous FH diagnosis in Australia (opportunistic cholesterol screening and genetic cascade testing) with the alternate strategy of population genomic screening of adults aged 18–40 years to detect pathogenic variants in the LDLR/APOB/PCSK9 genes. We used a validated cost-adaptation method to adapt findings to eight high-income countries. The model captured coronary heart disease (CHD) morbidity/mortality over a lifetime horizon, from healthcare and societal perspectives. Risk of CHD, treatment effects, prevalence, and healthcare costs were estimated from published studies. Outcomes included quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratio (ICER), discounted 5% annually. Sensitivity analyses were undertaken to explore the impact of key input parameters on the robustness of the model. Over the lifetime of the population (4 167 768 men; 4 129 961 women), the model estimated a gain of 33 488years of life lived and 51 790 QALYs due to CHD prevention. Population genomic screening for FH would be cost-effective from a healthcare perspective if the per-test cost was ≤AU$250, yielding an ICER of

Familial hypercholesterolemia is an inherited disease characterized by a significant increase in LDL-C from birth. Patients are at increased risk of premature cardiovascular disease. The aim of the study was to examine the clinical manifestations of atherosclerosis in patients with familial hypercholesterolaemia. The results showed the highest proportion of patients with possible familial hypercholesterolaemia. There is a predominance of cases of coronary artery disease versus cerebrovascular and peripheral arterial diseases. About 20% of people with coronary heart disease have experienced at least one acute myocardial infarction, with an average number of implanted medical stents of 2. A high cost/efficacy per quality adjusted life year was found when using percutaneous intervention to treat coronary artery disease compared to treating dyslipidemia as a risk factor for coronary atherosclerosis. Familial hypercholesterolemia has been associated with coronary artery disease, but additional and deeper research is needed for searching involvement other of non-coronary vascular systems. The right and cost-effective approach for prevention of atherosclerosis is to treat the risk factors to reduce the financial burden on our health system. [ABSTRACT FROM AUTHOR]

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: Familial Hypercholesterolaemia (FH) is a monogenic disorder that causes high levels of low-density lipoprotein (LDL) cholesterol. Cascade testing, where relatives of known individuals with FH ('index') are genetically tested, is effective and cost-effective, but implementation in the UK varies., Objective: This study aims to provide evidence on current UK FH cascade yields and to identify common obstacles cascade services face and individual- and service-level predictors of success., Methods: Electronic health records from 875 index families and 5,958 linked relatives in the UK's Welsh and Wessex FH services (2019) were used to explore causes for non-testing and to estimate testing rates, detection yields, and how relative characteristics and contact methods relate to the probability of relatives being tested (using logistic regression)., Results: In Wales (Wessex), families included 7.35 (7.01) members on average, with 2.41 (1.66) relatives tested and 1.35 (0.96) diagnosed with FH per index. Cascade testing is limited by individualised circumstances (too young, not at-risk, etc.) and FH services' reach, with approximately one in four relatives out-of-area. In Wales, first-degree relatives (odds ratio (OR):1.55 [95 % confidence interval (CI):1.28,1.88]) and directly contacted relatives (OR:2.11 [CI:1.66,2.69]) were more likely to be tested. In Wales and Wessex, women were more likely to be tested than men (ORs:1.53 [CI:1.28,1.85] and 1.74 [CI:1.32,2.27])., Conclusion: In Wales and Wessex less than a third of relatives of an index are tested for FH. Improvements are likely possible by integrating geographically dispersed families into cascade testing, services directly contacting relatives where possible, and finding new ways to encourage participation, particularly amongst men., Competing Interests: Declaration of competing interest BW sits on the board of directors for the York Health Economics Consortium (unremunerated role). Since this work was completed, RF has become an employee of Astellas Pharma Europe Ltd. All authors declare no other competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Background. The prevalence of heterozygous familial hypercholesterolaemia (HeFH) comprises 1 per 250 people. The risk of premature cardiovascular disease (CVD) is 20 times higher in HeFH patients among the general population. CVD develops in HeFH patients under 20 years of age, and they usually do not survive to 30 years. Therefore, the primary treatment track here is correction of dyslipidaemia to prevent atherosclerosis progression and CVD. Clinical Case Descriptions. The article describes the clinical cases of familial dyslipidaemia in 47-yo patient M. and his 75-yo mother P. The patient had a visit related to blood pressure (BP) surges up to 140/90 mm Hg. In history: acute myocardial infarction (AMI) in maternal grandfather at 50 years and own uncle at 32 years. The patient’s cardiovascular risk factors: male gender, dyslipidaemia (total cholesterol (TC) 15.8 mmol/L), overweight (body mass index 29.9 kg/m2), familial history of young CVD, sedentary lifestyle (employed as manager), psychological and socioeconomic factors (work-related stress pressure), resting heart rate 88 beats/min. The patient was immediately ordered a combined hypolipidaemic therapy including rosuvastatin 20 mg, ezetimibe 10 mg, telmisartan 40 mg once daily for blood pressure correction. In 1-month therapy, cholesterol dropped to 4.4 mmol/L, low-density lipoprotein (LDL) cholesterol – to 2.2, but triglycerides remained high at 3.9 mmol/L. Fenofi brate added to therapy at 145 mg 1 time. Another 1-month therapy allowed the overall reduction of TC to 3.7, LDL cholesterol to 1.9, triglycerides to 2.17 and high-density lipoproteins to 1.19 mmol/L. Past 3 months, a further drop was observed in triglycerides to 1.7 mmol/L. Hence, a triple hypolipidaemic therapy facilitated the target LDL and triglyceride values without involving expensive medications like PCSK9 blockers. The patient’s mother also achieved the target basic lipidogram owing to a triple lipid-lowering therapy.Conclusion. The case is of interest to exemplify a successful triple lipid-lowering therapy in patients with familial hypercholesterolaemia.

Background: Atherosclerotic cardiovascular diseases (ASCVD) including myocardial infarction, stroke and peripheral arterial disease continue to be major causes of premature death, disability and healthcare expenditure globally. Preventing the accumulation of cholesterol-containing atherogenic lipoproteins in the vessel wall is central to any healthcare strategy to prevent ASCVD. Advances in current concepts about reducing cumulative exposure to apolipoprotein B (apo B) cholesterol-containing lipoproteins and the emergence of novel therapies provide new opportunities to better prevent ASCVD. The present update of the World Heart Federation Cholesterol Roadmap provides a conceptual framework for the development of national policies and health systems approaches, so that potential roadblocks to cholesterol management and thus ASCVD prevention can be overcome. Methods: Through a review of published guidelines and research papers since 2017, and consultation with a committee composed of experts in clinical management of dyslipidaemias and health systems research in low-and-middle income countries (LMICs), this Roadmap identifies (1) key principles to effective ASCVD prevention (2) gaps in implementation of these interventions (knowledge-practice gaps); (3) health system roadblocks to treatment of elevated cholesterol in LMICs; and (4) potential strategies for overcoming these. Results: Reducing the future burden of ASCVD will require diverse approaches throughout the life-course. These include: a greater focus on primordial prevention; availability of affordable cholesterol testing; availability of universal cholesterol screening for inherited dyslipidaemias; risk stratification moving beyond 10-year risk to look at lifetime risk with adequate risk estimators; wider availability of affordable cholesterol-lowering therapies which should include statins as essential medications globally; use of adequate doses of potent statin regimens; and combination therapies with ezetimibe or other therapies in order to attain and maintain robust reductions in LDL-C in those at highest risk. Continuing efforts are needed on health literacy for both the public and healthcare providers, utilising multi-disciplinary teams in healthcare and applications that quantify both ASCVD risk and benefits of treatment as well as increased adherence to therapies. Conclusions: The adverse effects of LDL-cholesterol and apo B containing lipoprotein exposure are cumulative and result in ASCVD. These are preventable by implementation of different strategies, aimed at efficiently tackling atherosclerosis at different stages throughout the human life-course. Preventive strategies should therefore be updated to implement health policy, lifestyle changes and when needed pharmacotherapies earlier with investment in, and a shift in focus towards, early preventive strategies that preserve cardiovascular health rather than treat the consequences of ASCVD.

IntroductionFamilial Hypercholesterolemia (FH) is one of the most common genetic disorders, with an estimated global prevalence of 1:200-500, which leads to premature cardiovascular disease. Nevertheless, public and professional awareness of FH is often lacking, with an estimated 20,000 largely undiagnosed cases in Ireland.PurposeThe overall aim of the project was to test the feasibility of a model of care that would include electronic record screening, clinical assessment, and coding of possible FH patients across a network of general practices in Ireland. In addition, a secondary aim was to gauge the awareness and knowledge of FH across the network.MethodsThis study took part in multiple phases, employing a mixed methods design. The study included a validated questionnaire, tailored online educational resources, a retrospective chart review of patients with a history of elevated LDL cholesterol (LDLc) and an active review with a selection of those patients. Results were analyzed using SPSS V27, where descriptive statistics and relevant correlation tests were employed.ResultsEighteen general practices agreed to take part in the study. In the initial survey, respondents rated their personal and practice familiarity with FH as slightly below average. Around one-third of respondents were not aware of FH guidelines. Of over 55,000 adult patient records searched, only 0.2% had a recorded FH diagnosis and 3.9% had ever had an LDLc above 4.9 mmol/l. Eight practices completed 198 chart reviews. Among these, 29.8% of patients had a family history recorded, and 22.2% had a family history of CVD recorded. Female patients had higher averages for highest and recent LDLc. Seventy patients underwent a clinical review—with 27% of these patients identified as “probable” or “definite FH.” There was a statistically significant (p = 0.002) relationship between FH status and whether the patient had other CVD risk factors.ConclusionGeneral practitioners in Ireland had similar levels of awareness of FH compared to findings from elsewhere. The activities discussed encouraged clinicians to consider FH when talking to their patients, especially those with elevated LDLc at an early age. Broader awareness of the condition could increase conversations about FH and benefit patient outcomes.

The p.(Tyr400_Phe402del) mutation in the LDL receptor (LDLR) gene is the most frequent cause of familial hypercholesterolaemia (FH) in Gran Canaria. The aim of this study was to determine the age and origin of this prevalent founder mutation and to explore its functional consequences. For this purpose, we obtained the haplotypic information of 14 microsatellite loci surrounding the mutation in one homozygous individual and 11 unrelated heterozygous family trios. Eight different mutation carrier haplotypes were identified, which were estimated to originate from a common ancestral haplotype 387 (110–1572) years ago. This estimation suggests that this mutation happened after the Spanish colonisation of the Canary Islands, which took place during the fifteenth century. Comprehensive functional studies of this mutation showed that the expressed LDL receptor was retained in the endoplasmic reticulum, preventing its migration to the cell surface, thus allowing us to classify this LDLR mutation as a class 2a, defective, pathogenic variant.

Familial hypercholesterolaemia (FH) is a highly penetrant monogenic disorder present from birth that markedly elevates plasma low‐density lipoprotein (LDL)‐cholesterol (LDL‐C) concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). At a prevalence of 1:250 individuals, with over 90% undiagnosed, recent estimates suggest that there are approximately 22 000 children and adolescents with FH in Australia and New Zealand. However, the overwhelming majority remain undetected and inadequately treated until adulthood or after their first cardiac event. The guidance in this paper aims to increase awareness about paediatric FH and provide practical advice for the diagnosis and management of FH in children and adolescents. Recommendations are given on the detection, diagnosis, assessment and management of FH in children and adolescents. Recommendations are also made on genetic testing, including counselling and the potential for universal screening programmes. Practical guidance on management includes treatment of non‐cholesterol risk factors, and safe and appropriate use of LDL‐C lowering therapies, including statins, ezetimibe, PCSK9 inhibitors and lipoprotein apheresis. Models of care for FH need to be adapted to local and regional health care needs and available resources. Targeting the detection of FH as a priority in children and young adults has the potential to alter the natural history of atherosclerotic cardiovascular disease and recognise the promise of early detection for improving long‐term health outcomes. A comprehensive implementation strategy, informed by further research, including assessments of cost–benefit, will be required to ensure that this new guidance benefits all families with or at risk of FH. [ABSTRACT FROM AUTHOR]

Background and aims: Familial Hypercholesterolaemia (FH) is characterised by a genetic alteration in the transport and metabolism of cholesterol that leads to elevated levels of total cholesterol (CT) and low-density lipoprotein cholesterol (LDL-C) and early onset of atherosclerosis. According to the current guidelines, diet and promotion of healthy habits are first-line treatments. Little is known about the effectiveness of cholesterol-lowering diet and healthy lifestyle habits on plasma cholesterol and lipid profile in children and adolescents with FH. The aim of the study is to investigate the effect of the nutritional counseling on plasma lipid profile in FH children at the first step of treatment. Methods: 115 FH children (2–17 years) were included in the study; dietary habits were evaluated through a Food Frequency Questionnaire (FFQ) and blood samples for lipid profile were collected at the enrollment (T0) and six months later (T1). Results: the lipid profile at T0 and T1, expressed as mean ± standard deviation in mg/dL, was, respectively: total cholesterol 285.9 ± 51.1 and 276.6 ± 46.8 (paired test difference p value < 0.01), LDL-cholesterol 214.9 ± 47.7 and 206.4 ± 46.6 (p value < 0.01), HDL-cholesterol 52.9 ± 13 and 54.4 ± 11.5 (p value 0.07), triglycerides 87 ± 46.7 and 82.2 ± 38.4 (p value 0.4), non-HDL cholesterol 233 ± 51.4 and 222.2 ± 47.4 (p < 0.01). In the dietary habits (weekly portions) we observed an improvement (p ≤ 001) for fruit and vegetables, fish, pulses, whole foods, and a reduction (p < 0.01) for meat, sausages, cheese, junk foods consumption. Conclusions: In FH children we have highlighted an improvement of the plasma lipid profile and in healthy dietary habits after nutritional counseling. [ABSTRACT FROM AUTHOR]

Atherosclerosis predisposes to myriad cardiovascular complications, including myocardial infarction and stroke. Statins have revolutionised cholesterol management but they do not work for all patients, particularly those with familial hypercholesterolaemia (FH). Genome-wide association studies have linked SNPs at orphan G protein-coupled receptor 146 (GPR146) to human atherosclerosis but how GPR146 influences serum cholesterol homeostasis was only recently described. Gpr146 deletion in mice reduces serum cholesterol and atherosclerotic plaque burden, confirming GPR146 as a potential therapeutic target for managing circulating cholesterol. Critically, this effect was independent of the low-density lipoprotein receptor. While still an orphan, the activation of GPR146 by serum suggests identification of its endogenous ligand is tantalisingly close. Herein, we discuss the evidence for GPR146 inhibition as a treatment for atherosclerosis. Genome-wide association studies have linked SNPs adjacent to, or within, the coding sequence of G-protein-coupled receptor 146 (GPR146) to human atherosclerosis. GPR146 –/– mouse models have reduced plasma cholesterol levels and are significantly protected against developing atherosclerotic lesions. The protection against atherosclerosis in mouse models was independent of the low-density lipoprotein receptor (LDLR), indicating that targeting GPR146 to reduce cholesterol levels may be an important alternative to currently used lipid-lowering drugs, which are dependent on the LDLR. Serum stimulation in vitro and feeding in vivo causes GPR146-specific signalling through Gαs and extracellular signal-regulated protein kinases 1 and 2, indicating that GPR146 is activated by a factor involved in the feeding axis. Identification of the active component in serum may translate to deorphanisation of GPR146 and subsequent drug design opportunities to manage atherosclerosis. [ABSTRACT FROM AUTHOR]

• Fibronectin, encoded by FN1 , is a key component of atherosclerotic plaques. • An FN1 variant, rs1250229-T, is associated with higher cardiovascular (CV) risk. • We found lower risk with rs1250229-T in familial hypercholesterolaemia. • Any mechanistic basis for this discrepancy is speculative. • Our findings are hypothesis-generating and require confirmation in other cohorts. Increased risk of coronary artery disease (CAD) in familial hypercholesterolaemia (FH) is modified by factors beyond defects in the low-density lipoprotein receptor pathway. The rs1250229-T single nucleotide polymorphism (SNP) in the FN1 gene is associated with CAD in genome-wide association studies and is in linkage disequilibrium with another SNP (rs1250259-T) in FN1 that is associated with decrease fibronectin secretion. We investigated whether rs1250229-T was also associated with prevalent CAD in patients with genetically confirmed FH. We collected clinical data from 256 patients with genetically confirmed FH. The FN1 rs1250229 SNP was genotyped on a SEQUENOM platform. The association between rs1250229-T and prevalent CAD was assessed using simple and multiple regression analyses. In patients with FH, the FN1 rs1250229-T (minor) allele was a significant negative predictor of prevalent CAD (odds ratio [OR] 0.353; 95% confidence interval [CI] 0.193 - 0.647; P = 0.001). FN1 rs1250229-T remained a significant predictor of prevalent CAD after adjusting for age, sex, obesity, hypertension, smoking status and lipoprotein(a) concentration (OR 0.200; 95% CI 0.091 - 0.441; P < 0.001). The FN1 rs1250229-T allele is inversely associated with CAD in patients with genetically confirmed FH, independently of traditional risk factors. While this finding requires replication, it suggests that the biology of fibronectin may contribute to variation in the risk of CAD in FH. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolaemia (FH) is a common inherited condition causing elevated cholesterol, premature heart disease, and early death. Although FH can be effectively treated, over 80% of people with FH remain undetected.Aim: To explore patient and health professional experiences of introducing genetic testing with case finding for FH in primary care.Design and Setting: Qualitative study in UK general practice.Method: Semi-structured interviews with a purposeful sample of 41 participants (24 patients and 17 health professionals) from eight practices, using an electronic case-finding tool (FAMCAT) to identify patients with higher likelihood of having FH and who were then offered diagnostic genetic testing in primary care. Data were analysed thematically.Results: While prior awareness of FH was low, patients were unsurprised to be identified as being at risk, and positive about being offered genetic testing by their practice. Patients not found to have FH were relieved, although some felt frustrated that their high cholesterol lacked a clear cause. Those confirmed to have FH largely expected and accepted this outcome. Practitioners saw detection of FH as an important new opportunity for preventive care. They found the case-finding tool easy to apply and noted patients' high uptake of genetic testing. While they were comfortable referring appropriate patients for further specialist management, GPs sought clearer definition about responsibility for identification and long- term care of FH in future care pathways.Conclusion: Introducing genetic testing with electronic case finding for FH in primary care was positively experienced by patients and practitioners. Further development of this approach could help improve detection of FH in the general population. [ABSTRACT FROM AUTHOR]

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Familial hypercholesterolaemia (FH) and elevated plasma lipoprotein(a) [Lp(a)] are inherited conditions independently associated with atherosclerotic cardiovascular disease. This study investigated the detection of new cases of elevated Lp(a) during cascade testing of relatives of probands with a definite diagnosis of FH and elevated Lp(a) (≥50 mg/dL). Relatives from 62 adult probands were tested for FH genetically and for elevated Lp(a) using an immunoassay. The prevalence and yield of new cases of FH with or without elevated Lp(a) among relatives and the association between the detection of elevated Lp(a) and the Lp(a) concentration of the probands were assessed. Among 162 relatives tested (136 adults and 26 children), the prevalence of FH and elevated Lp(a) was 60.5% and 41.4%, respectively: FH alone was detected in 31.5%, elevated Lp(a) alone in 12.3%, FH with elevated Lp(a) in 29.0%, and neither disorder in 27.2% of the relatives. Cascade testing detected a new case of FH, elevated Lp(a) and FH with elevated Lp(a) for every 1.5, 2.1 and 3.0 relatives tested, respectively. The proportion of relatives detected with elevated Lp(a) was significantly higher when tested from probands with Lp(a) ≥100 mg/dL compared with those from probands with Lp(a) between 50 and 99 mg/dL (53% vs 34%, p = 0.018). The concordance between the detection of FH and elevated Lp(a) was 56.2% (kappa statistic 0.154), indicating a poor agreement. A dual approach to cascade testing families for FH and high Lp(a) from appropriate probands can effectively identify not only new cases of FH, but also new cases of elevated Lp(a) with or without FH. The findings accord with the co-dominant and independent heritability of FH and Lp(a). [Display omitted] • FH and elevated Lp(a) are both causal risk factors for ASCVD, but most cases remain undiagnosed in the community. • Cascade testing from probands with FH and high Lp(a) can identify 1 case of elevated Lp(a) for every 2 relatives tested. • 1 case of FH and 1 case of FH plus elevated Lp(a) can also be identified for every 2 and 3 relatives tested, respectively. • A dual approach to cascade testing families for FH and high Lp(a) can identify both new cases of FH and elevated Lp(a). [ABSTRACT FROM AUTHOR]

• Compound heterozygote is the most frequent type of HoFH in China. • The diagnosis and treatment of HoFH is delayed and uncontrolled. • HoFH patients often have structural cardiac abnormalities since early childhood. • True HoFH have worse survival rates compared to other genotype probands. There is a lack of large-scale data on the clinical and genotype characteristics of homozygous familial hypercholesterolemia (HoFH) patients in Asia. To define the characteristics of phenotypic and genetic HoFH probands from mainland China. We collected data from patients with suspected HoFH from ten clinical hospitals across mainland China from 2003 to 2019. Clinical data and DNA testing were obtained in all patients. The Kaplan-Meier method was used to generate survival curves, and the groups were compared with the log-rank test. A total of 108 unrelated probands with suspected HoFH (mean age 14.9 years) were included. The three most common variants were W483X (c.1448 G>A), A627T (c.1879 G>A), H583Y (c.1747 C>T). The majority (64.8%) were compound heterozygotes (n = 70), 23 (21.3%) were true HoFH patients. True HoFH showed higher LDL-C levels compared to compound HoFH (16.8±3.6 mmol/L vs. 15.0±3.1 mmol/L, P = 0.022). During follow-up, only 21.2% patients exhibited an LDL-C reduction of more than 50%. Kaplan-Meier analysis showed that the true HoFH probands had significantly worse survival rates compared to other genotype probands (13-year survival; 20.3% vs. 76.7%, respectively; P = 0.016). In addition, true HoFH shows that 2.8-fold (P = 0.022) increase any death and 3.0-fold (P = 0.023) increase cardiovascular death risk in relative to other FH. This report shows that HoFH has devastating consequences, and that patients are often only diagnosed after they have been exposed to severely elevated LDL-C for years. Systematic screening and early intensive treatment are an absolute requirement for these young individuals with HoFH. [ABSTRACT FROM AUTHOR]

Objective: Familial hypercholesterolaemia (FH), an autosomal dominant disorder causing elevated low-density lipoprotein (LDL) cholesterol from birth resulting in premature cardiovascular disease, is only diagnosed in 10% of affected patients. This study involved partnering with patients with FH and with primary care providers (PCPs) to understand health priorities and translate them into hypotheses for future research and enhancement of health practices via electronic health records (EHRs). The goal was to strengthen genetic health education for clinicians and for patients and their families, including improved diagnosis, knowledge and treatment. Perceptions regarding genetic health education and healthcare related to FH facilitated by the use of an EHR for diagnosis and treatment have not been studied. Design: Mixed-methods exploratory qualitative research and surveys. Setting: Qualitative research included five focus groups, 34 semi-structured key informant interviews and open-ended survey items with patients and PCPs at a large medical centre in Western New York. Method: Data were thematically coded to identify themes as formative work for the improvement of relevant EHR features, diagnosis, treatment and genetic health education via information sharing between clinicians and patients. Results: Themes included genetic health knowledge; the importance of being diagnosed; communication between patients, family members and medical professionals; outreach via patients' own advocacy; and treatment, technology, motivation, trust, outside resources (for further genetic health education and support) and awareness of effective treatments. Conclusion: Patients and clinicians can contribute to the development of EHR support for the genetic health education of patients and their families, and for improved diagnosis and treatment of FH. Using their ideas in the development of effective strategies could improve the currently low rate of FH diagnosis and cascade screening (for family members), as well as enhance physician and patient genetic health knowledge and self-empowerment. [ABSTRACT FROM AUTHOR]

Abstract Background Primary care physicians (PCP) play an important role in detecting Familial Hypercholesterolaemia (FH) early. However, knowledge, awareness and practice (KAP) regarding FH among Malaysian PCP are not well established, and there was no validated tool to assess their FH KAP. Thus, the aim of this study was to adapt an FH KAP questionnaire and determine its validity and reliability among Malaysian PCP. Methods This cross-sectional validation study involved Malaysian PCP with ≥ 1-year work experience in the primary care settings. In Phase 1, the original 19-item FH KAP questionnaire underwent content validation and adaptation by 7 experts. The questionnaire was then converted into an online survey instrument and was face validated by 10 PCP. In Phase 2, the adapted questionnaire was disseminated through e-mail to 1500 PCP. Data were collected on their KAP, demography, qualification and work experience. The construct validity was tested using known-groups validation method. The hypothesis was PCP holding postgraduate qualification (PCP-PG-Qual) would have better FH KAP compared with PCP without postgraduate qualification (PCP-noPG-Qual). Internal consistency reliability was calculated using Kuder Richardson formula-20 (KR-20) and test–retest reliability was tested on 26 PCP using kappa statistics. Results During content validation and adaptation, 10 items remained unchanged, 8 items were modified, 1 item was moved to demography and 7 items were added. The adapted questionnaire consisted of 25 items (11 knowledge, 5 awareness and 9 practice items). A total of 130 out of 1500 PCP (response rate: 8.7%) completed the questionnaire. The mean percentage knowledge score was found to be significantly higher in PCP-PG-Qual compared with PCP-noPG-Qual (53.5, SD ± 13.9 vs. 35.9, SD ± 11.79), t(128) = 6.90, p