Aims Cascade screening can identify individuals with elevated lipoprotein(a) [Lp(a)], a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). The aim of this study is to explore the effectiveness of cascade screening with asymptomatic children as index cases to identify family members with elevated Lp(a).Methods and results In this retrospective study we used our database consisting of all children referred for a tentative diagnosis of hereditary dyslipidaemia to the Amsterdam University Medical Centers paediatric lipid clinic (1989-2023). Elevated Lp(a) was defined as >= 30 mg/dL or >= 75 nmol/L. We evaluated two cascade screening approaches (opportunistic and systematic), calculated the number needed to screen (NNS) and repeated the analysis exclusively in children with FH as subgroup with particularly high cardiovascular risk. A total of 1931 children were included (732 indexes, mean age (SD) 11.7 (4.5) years; 1199 relatives, mean age (SD) 10.1 (4.4) years). In total, 480 (25%) of all children had elevated Lp(a) concentrations (>= 30 mg/dL or >= 75 nmol/L). Both opportunistic (732 indexes) and systematic (316 indexes) cascade screening identified relatives with elevated Lp(a). The NNS was of 3.7 (95% CI 3.3-4.3) for the systematic approach and 4.1 (95% CI 3.8-4.6) for the opportunistic approach. In the FH subgroup, NNS were 3.9 (95% CI 3.4-4.5) and 4.3 (95% CI 3.9-4.8), respectively.Conclusion Our findings suggest that cascade screening using children as index cases is an effective strategy to identify asymptomatic relatives at risk. Cardiovascular risk assessment should include Lp(a), especially in patients with FH who face an even higher cardiovascular risk. Until effective therapies become available, management should focus on modifiable risk factors. People with high concentrations of lipoprotein(a) (Lp[a]), have an increased risk of developing heart disease. As Lp(a) concentrations are mostly inherited, finding a high Lp(a) concentration in a child may help to identify other family members with the same condition, even if they do not have symptoms.The aim of this study was to explore the effectiveness of cascade screening with asymptomatic children as index cases to identify family members with elevated Lp(a).Our findings suggest that cascade screening using children as index cases is an effective strategy to identify asymptomatic relatives at risk.

Hemodynamic quantities are valuable biomedical risk factors for cardiovascular pathology such as atherosclerosis. Non-invasive, in-vivo measurement of these quantities can only be performed using a select number of modalities that are not widely available, such as 4D flow magnetic resonance imaging (MRI). In this work, we create a surrogate model for hemodynamic flow field estimation, powered by machine learning. We train graph neural networks that include priors about the underlying symmetries and physics, limiting the amount of data required for training. This allows us to train the model using moderately-sized, in-vivo 4D flow MRI datasets, instead of large in-silico datasets obtained by computational fluid dynamics (CFD), as is the current standard. We create an efficient, equivariant neural network by combining the popular PointNet++ architecture with group-steerable layers. To incorporate the physics-informed priors, we derive an efficient discretisation scheme for the involved differential operators. We perform extensive experiments in carotid arteries and show that our model can accurately estimate low-noise hemodynamic flow fields in the carotid artery. Moreover, we show how the learned relation between geometry and hemodynamic quantities transfers to 3D vascular models obtained using a different imaging modality than the training data. This shows that physics-informed graph neural networks can be trained using 4D flow MRI data to estimate blood flow in unseen carotid artery geometries.

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder marked by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels from birth and a very high risk of premature atherosclerotic cardiovascular disease (ASCVD). To address the global paucity of observational data, the HoFH International Clinical Collaborators (HICC) registry (NCT04815005) was established. To date, over 950 HoFH individuals from 45 countries have been included. The median age at diagnosis was 12 years (IQR: 5.5-27.0), and untreated LDL-C levels were markedly elevated [median 14.7 mmol/L (11.6-18.4)]. At diagnosis, 9% had ASCVD or (supra)aortic valve disease, and despite the widespread use of lipid-lowering therapy (LLT), only 4% achieved guideline-recommended LDL-C goals. Early initiation of lipoprotein-apheresis was associated with greater LDL-C reductions and delayed ASCVD onset. Cardiovascular burden remains substantial, with a median age at death of 37 years [20-50]. No sex differences were observed in age or clinical characteristics at diagnosis, treatment patterns, or timing of ASCVD, although the usual sex gap in cardiovascular disease onset was absent. Profound global disparities persist, including limited genetic screening, restricted access to LLT, and earlier onset of major adverse cardiovascular events in non-high-income countries. Reproductive care for women remains highly variable and understudied. The HICC aims to guide global stakeholders in improving clinical outcomes for individuals with HoFH through earlier diagnosis, equitable access to advanced therapies, and broader inclusion of underserved regions. By generating evidence from routine clinical care and patient-reported data, identifying gaps in care, and fostering international collaboration, HICC seeks to advance a more equitable and effective global approach to HoFH management.

AIMS:Homozygous familial hypercholesterolaemia (HoFH) is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C). Most individuals with HoFH do not reach LDL-C targets with standard lipid-lowering therapies (LLTs). However, low density lipoprotein receptor (LDLR)-independent LLTs have demonstrated effectiveness in these individuals. METHODS:This post hoc subanalysis examined concomitant use of two LDLR-independent treatments, lipoprotein apheresis (LA) and evinacumab (an angiopoietin-like 3 inhibitor), in participants with HoFH from three clinical studies of evinacumab. We included participants with HoFH who received 15 mg/kg evinacumab in any Regeneron-sponsored clinical study. Participants were stratified by concurrent LA treatment at study baseline. The primary outcome was mean change in LDL-C from baseline to Week 24. Other outcomes included change in LA frequency and safety. Outcomes were examined descriptively. RESULTS:A total of 138 participants were included, 59 (43%) undergoing LA at baseline and 79 (57%) not undergoing LA at baseline. From baseline to Week 24, mean (standard deviation) LDL-C was reduced in participants undergoing LA at baseline (-42.9% [23.8]) and those who were not (-50.8% [30.5]). Reductions in LDL-C in both subgroups were observed across all examined timepoints. Among those undergoing LA at baseline, LA frequency was reduced in 17 (29%) participants and increased in two (3%) participants. Evinacumab was well-tolerated in both subgroups. CONCLUSION:This study demonstrated considerable benefit of evinacumab for individuals with HoFH, with or without concurrent LA. Evinacumab appeared to lessen LA burden for some individuals. This analysis suggests that LA and evinacumab can be combined without compromising efficacy or safety.

Aim Evinacumab is an ANGPTL-3 inhibitor developed for the treatment of homozygous familial hypercholesterolemia (HoFH), a rare condition characterized by extremely elevated LDL-cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease. Despite important sex-related disparities in lipid metabolism, females are still underrepresented in trials, limiting the generalizability of results. With 116 patients, of which 49 % were females, the ELIPSE-OLE study has the largest cohort of HoFH females involved in a clinical trial. The aim of this analysis was to compare response to evinacumab in females and males in the ELIPSE OLE study. Methods This study is a post hoc exploratory analysis of data on 57 females and 59 males, aged ≥12 years and on stable background lipid-lowering therapy (LLT) from ELIPSE OLE. Patients received evinacumab 15 mg/kg intravenously every 4 weeks. The primary efficacy endpoint was the reduction in LDL-C concentration from baseline to week-24. Results Baseline LDL-C [mean (SD)] tended to be higher in females aged 18 to <50 than males: 8.4(5.4) vs 6.4(3.5) mmol/L. Following treatment with evinacumab, the percent decrease in LDL-C reached at week-24 was 44 % in the overall cohort and was sustained over time. Evinacumab significantly decreased LDL-C in both sexes, regardless of age and background LLT. There was a trend, although not significant, toward higher relative precent decrease of LDL-C among females. Conclusion In a study where half of the participants were females, evinacumab led to substantial LDL-C reduction in HoFH patients of both sexes, regardless of genotype or background LLT.

Background Homozygous familial hypercholesterolemia (HoFH), characterized by extremely elevated low‐density lipoprotein cholesterol (LDL‐C) due to severely impaired LDL‐C clearance from circulation, remains challenging to treat. Here, we investigated clinical benefits of monoclonal antibody, evinacumab, inhibiting angiopoietin‐like 3, recently approved in children with homozygous familial hypercholesterolemia. Methods This retrospective, observational study included 13 children with homozygous familial hypercholesterolemia on oral lipid‐lowering therapy and assessed their attainment of LDL‐C goal, need for lipoprotein apheresis (LA), and cardiac plaque formation at initiation of evinacumab and at follow‐up of 2.0 (1.3–3.0) years. Results Evinacumab, initiated at age 11 (8.5–13.5) years, increased number of patients reaching LDL‐C goal from none before initiation to 9 of 13 (69%; P =0.004) at follow‐up. Mean±SD LDL‐C at follow‐up was 111 (44) mg/dL, compared with 206 (61) mg/dL before evinacumab (mean difference, −95 mg/dL [95% CI, −142 to −47]; P <0.001). Before initiation of evinacumab, 11 of 13 children received LA with average interval of 7.8 days. At follow‐up, LA frequency decreased in 7 of 11 children with average interval of 18.9 days; increase between LA sessions was 11.0 days (3.5–18.5; P =0.008), 42% longer session interval. For 3 (15%) children, due to evinacumab initiation, LA remained dispensable over the course of treatment. Coronary computed tomography angiography showed plaque stabilization (n=5), regression (n=3), and no formation (n=2), in 10 of 13 (77%) children, and plaque progression in 3 (23%) children. Conclusions Add‐on evinacumab increased number of children with homozygous familial hypercholesterolemia reaching and maintaining LDL‐C goal, concomitant reduction in LA frequency, and in most patients, stabilization or improvement in coronary computed tomography angiography findings.

AIMS:Children with heterozygous familial hypercholesterolaemia (HeFH) show greater carotid intima-media thickness (cIMT). Evolocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody, substantially reduced LDL cholesterol (LDL-C) in children with HeFH. We investigated evolocumab's effect on cIMT progression. METHODS AND RESULTS:HAUSER-RCT was a randomized, placebo-controlled trial. One hundred fifty-seven paediatric patients with FH (age: 10-17 years) and LDL-C > 130 mg/dL despite statin therapy received monthly evolocumab 420 mg or placebo for 24 weeks. Patients who continued into an open-label extension (OLE) (HAUSER-OLE; n = 150) received 80 weeks of monthly evolocumab plus statins. Carotid intima-media thickness was measured by B-mode ultrasound scanning of right and left common carotid artery at baseline; Week 24 of randomized controlled trial (RCT) (Day 1 OLE); and Weeks 24, 48, and 80 of OLE. Descriptive analysis of cIMT was a pre-specified HAUSER secondary endpoint, and inferential tests reported here were post hoc. One hundred fifty-one patients had evaluable cIMT summary scores at ≥ 1 visit. From RCT baseline to Week 24, mean cIMT increased by 0.006 mm (SD = 0.05) with placebo (n = 37) and decreased by 0.003 mm (SD = 0.05) with evolocumab (n = 76). From RCT baseline to OLE Week 80, mean cIMT summary score decreased by 0.019 mm (SD = 0.04) and 0.012 mm (SD = 0.05), respectively, in patients who initially received placebo (n = 34, P = 0.007) vs. receiving evolocumab throughout (n = 59, P = 0.067). Across patients who received evolocumab in OLE, mean cIMT significantly decreased by 0.011 mm (SD = 0.05) from OLE Day 1 to Week 80 (n = 94, P = 0.034). CONCLUSION:In children with HeFH, evolocumab plus statin treatment up to 104 weeks led to regression in carotid arterial wall thickening. REGISTRATION:ClinicalTrials.gov: NCT02624869.

BACKGROUND AND AIMS:New therapies targeting Lipoprotein(a) (Lp(a)) are anticipated to enter clinical practice soon. We aimed to estimate the benefits of Lp(a) lowering therapy and threshold price at which treatment with Lp(a)-lowering therapies for people with high Lp(a) in high-risk primary or secondary prevention would be cost-effective from a healthcare and societal perspective using genetic and epidemiological data in the absence of phase III cardiovascular outcome trials. METHODS:We constructed and validated a multi-state microsimulation Markov model for primary and secondary prevention populations (n=10,000 each, selected randomly from the UK Biobank) aged between 40 and 69, followed until age 85 years. Risk of atherosclerotic cardiovascular disease (CVD) was proportional to cumulative Lp(a) and other established cardiovascular (CV) risk factors; risk was adjusted using Mendelian randomisation estimates. We simulated Lp(a) testing of high-risk individuals from the primary and all individuals from the secondary prevention population. Individuals with an Lp(a) level ≥192 nmol/L (90 mg/dL) were treated with Lp(a)-lowering therapy that lowered Lp(a) by 97.5%. The control was standard of care, without Lp(a)-lowering therapy. The primary analyses were conducted from the Australian and UK healthcare and societal perspectives in 2023 AUD and GBP, with annual discounting of 5% (Australia) and 3.5% (UK). We estimated the effect of varying the threshold for Lp(a)-lowering therapy initiation from 105 nmol/L (50 mg/dL) to 236 nmol/L (110 mg/dL) in scenario analyses. Additional analyses extended to other high-income countries, including Austria, Canada, France, Germany, Italy, The Netherlands, Spain, and the USA. RESULTS:Lp(a) testing and treatment prevented 53 and 306 CV events in the primary and secondary prevention populations (n=10,000 each), respectively. The maximum annual price at which Lp(a)-lowering therapy would be cost-effective was $250 (Australia) and £150 (UK) in primary and ≥$6000 (Australia) and £5500 (UK) in secondary prevention populations. Estimated maximum annual prices were similar from the societal perspective and in other high-income countries. In secondary prevention, the number of cardiovascular events prevented increased with a decreasing Lp(a) threshold for initiation of Lp(a)-lowering therapy - 496, 420, 306, and 238 with thresholds of 105 nmol/L (50 mg/dL), 149 nmol/L (70 mg/dL), 192 nmol/L (90 mg/dL; base case) and 236 nmol/L (110 mg/dL), respectively. CONCLUSION:Novel Lp(a)-lowering therapies are likely to be cost-effective for the secondary prevention of CVD if priced similarly to current siRNA or antibody-based therapies for LDL-C reduction based on the available genetic and epidemiological evidence.

Familial hypercholesterolaemia (FH) is a common genetic disorder characterized by lifelong elevated LDL cholesterol (LDL-C) concentrations. FH exists in two forms: heterozygous FH (HeFH), which affects around 1 in 300 people worldwide, and homozygous FH (HoFH), which affects around 1 in 300 000. Individuals with FH are at increased risk of premature atherosclerotic cardiovascular disease (ASCVD) and death, and those with HoFH are, if untreated, at extreme risk of ASCVD manifestations even before adulthood. Early diagnosis and treatment in childhood can extend or normalize life expectancy, but limited awareness, underdiagnosis, and undertreatment remain major challenges. This consensus statement aims to address these challenges, supported by increased knowledge of the pathogenesis of FH and the availability of an increasing range of lipid-lowering therapies (LLTs) that can be used from early ages. To increase the detection rate of FH, all countries are encouraged to establish a paediatric screening programme and, given that current diagnostic criteria often fail to identify children with an FH-causing genetic variant, revised diagnostic criteria are presented. Updated LDL-C treatment goals are proposed, and the importance of starting LLTs before puberty in children with HeFH, and, if needed, from 6 years, is highlighted. Guidance on how to manage FH is provided, including treatment algorithms for use in children with either HeFH or HoFH and a discussion on how to promote a smooth transition to adult care. Early detection and optimal treatment as advocated in this consensus statement are crucial to improving life expectancy for children and adolescents with FH.

Background/Synopsis Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) and atherosclerotic cardiovascular disease (ASCVD) with onset in childhood. Early initiation of lipid-lowering treatment is associated with improved clinical outcomes. However, data on the management of very young children (≤5 years) diagnosed with HoFH remain limited. Objective/Purpose To assess current management practices and identify challenges in treating HoFH patients 5 years or younger. Methods An online survey was sent to clinicians through the HoFH International Clinical Collaborators (HICC) consortium and via personal contacts and professional networking. The survey addressed current management strategies for very young HoFH patients, preferred approaches under conditions of unrestricted access to resources, and perspectives on newborn screening. Results Forty-eight clinicians across 17 countries reported direct experience treating 194 HoFH patients ≤5 years. Seventy-five percent reported initiating treatment within 4 weeks of diagnosis. Based on current access to therapies, 60% used statin, 21% evinacumab, and 11% lifestyle and diet as first-line treatment. In a hypothetical scenario of unrestricted access, 40% of clinicians would use evinacumab as first-line. Inclusion of HoFH in newborn screening was supported by 88% of surveyed clinicians; 94% were comfortable establishing the diagnosis and 71% were comfortable managing treatment following a positive screening result. Conclusions Statins are currently used as first-line treatment in very young HoFH patients by the majority of clinicians; however, many would ideally prescribe evinacumab, now approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use in infants. The findings also demonstrate strong support for newborn screening of HoFH.

Aims Familial hypercholesterolemia (FH) significantly increases cardiovascular risk from childhood yet remains widely underdiagnosed. This cross-sectional study aimed to evaluate existing paediatric FH diagnostic criteria in real-world cohorts and to develop two novel diagnostic tools: a semi-quantitative scoring system (FH-PeDS) and a machine learning model (ML-FH-PeDS) to enhance early FH detection. Methods and results Five established FH diagnostic criteria were assessed (Dutch Lipid Clinics Network [DLCN], Simon Broome, EAS, Simplified Canadian, and Japanese Atherosclerosis Society) in Slovenian (N = 1360) and Portuguese (N = 340) paediatric hypercholesterolemia cohorts, using FH-causing variants as the reference standard. FH-PeDS was developed from the Slovenian cohort, and ML-FH-PeDS was trained and tested using a 60%/40% split before external validation in the Portuguese cohort. Only 47.4% of genetically confirmed FH cases were identified by all established criteria, while 10.9% were missed entirely. FH-PeDS outperformed DLCN in the combined cohort (AUC 0.897 vs. 0.857; P < 0.01). ML-FH-PeDS showed superior predictive power (AUC 0.932 in training, 0.904 in testing vs. 0.852 for DLCN; P < 0.01) and performed best as a confirmatory test in the testing subgroup (39.7% sensitivity, 87.7% PPV at 98% specificity). In the Portuguese cohort, ML-FH-PeDS maintained strong predictive performance (AUC 0.867 vs. 0.815 for DLCN; P < 0.01) despite population differences. Conclusion Current FH diagnostic criteria perform sub-optimally in children. FH-PeDS and ML-FH-PeDS provide tools to improve FH detection, particularly where genetic testing is limited. They also help guide genetic testing decisions for hypercholesterolemic children. By enabling earlier diagnosis and intervention, these tools may reduce long-term cardiovascular risk and improve outcomes.

BACKGROUND AND AIMS:To reduce the increased premature cardiovascular risk in children with heterozygous familial hypercholesterolemia (FH), statins are the first pharmacological step. This study aims to assess the incidence of statin-associated symptoms (SAS) and statin intolerance in pediatric FH patients. METHODS:Children (<18 years) with FH who received statins in our pediatric lipid clinic at the Amsterdam UMC - location AMC between October 2009 and October 2024 were eligible. Data were retrospectively collected from electronic medical records, including medical history, statin type and dose, SAS, statin intolerance and blood samples. Data were evaluated at three time points: statin initiation (T1), following adjustment of statin dose and/or type (T2), and if changed, at the last prescribed dose (T3). RESULTS:A total of 696 children were included (329 girls, 47.3%) with a median age (IQR) at statin initiation of 11.0 (8.3 - 14.0) years. SAS were reported in 1 in 8.5 children at T1, 1 in 8.2 children at T2, and 1 in 8.2 at T3. The majority of symptoms were transient and mild. Muscle symptoms without clinically significant creatine kinase (CK) elevation (≤3 × upper limit of normal) were most frequently reported. No cases of rhabdomyolysis or other adverse events requiring hospital admission were reported. In total, 13 children (1.9%) were statin intolerant due to persistent symptoms leading to permanent discontinuation of statin therapy. CONCLUSIONS:This study shows that SAS were common, but generally transient and mild, whereas statin into-lerance was relatively uncommon in children with FH. Proactive management of SAS and consideration of alternative therapies are crucial to maintain adherence and reduce their increased cardiovascular risk. Future research should focus on identifying risk factors to enable personalized treatment strategies.

BACKGROUND:Inclisiran, a small interfering RNA targeting hepatic PCSK9, was previously studied in various adult patient populations, but it has not yet been assessed in paediatric patients with heterozygous familial hypercholesterolaemia (HeFH), a genetic disorder characterised by elevated LDL cholesterol. The ORION-16 study aimed to evaluate the efficacy and safety of inclisiran treatment in adolescents with HeFH. METHODS:ORION-16 was a two-part (1-year double-blind, 1-year open-label), randomised, phase 3 trial at 51 sites across 26 countries. In Part 1, adolescents (aged 12 to <18 years) with HeFH and elevated LDL cholesterol on maximally tolerated statin treatment with or without other lipid-lowering therapy were randomly assigned 2:1 (via interactive response technology) to either inclisiran sodium 300 mg subcutaneously or placebo (administered on days 1, 90, and 270); in Part 2, all patients received inclisiran (days 360 [only patients previously assigned to receive placebo], 450, and 630). The primary endpoint was the percentage change in LDL cholesterol from baseline to day 330, assessed in all randomly assigned patients. Safety was assessed in all patients who received at least one dose of study drug. Endpoints in Part 2 were analysed in all patients who entered and received at least one dose of study drug in Part 2. ORION-16 is registered at ClinicalTrials.gov (NCT04652726) and is completed. FINDINGS:Between Feb 17, 2021, and Dec 14, 2022, 141 patients were randomly assigned (93 to inclisiran, 48 to placebo; median age 15·1 years [IQR 13·4-16·8]; 75 [53%] female; 128 [91%] White). In Part 1, the least squares mean percentage change in LDL cholesterol from baseline to day 330 was -27·1% in the inclisiran group and 1·4% in the placebo group, with a between-group difference of -28·5% (95% CI -35·8 to -21·3; p<0·0001). In Part 2, at day 720, a mean percentage change in LDL cholesterol from baseline of -33·7% (SD 24·0) was observed. Inclisiran was well tolerated, with a safety profile comparable to studies in adults. Injection site reactions were more frequent with inclisiran (15 [16%] of 93 patients) than with placebo (three [6%] of 48) in Part 1 (13 [9%] of 139 in Part 2); all were mild and did not lead to study drug discontinuation. There were no treatment-related serious adverse events, and no deaths during the study. INTERPRETATION:In adolescents with HeFH, inclisiran was effective in lowering LDL cholesterol, with sustained efficacy over 2 years, and was well tolerated. These results support inclisiran as a potentially useful addition for the treatment of adolescents with HeFH, providing an infrequent dosing regimen. FUNDING:Novartis Pharma.

Treatment of familial hypercholesterolemia is directed toward the moment of the medical encounter. However, risk for heart disease as a consequence of having familial hypercholesterolemia is related to lifelong exposure to elevated low‐density lipoprotein cholesterol, rather than low‐density lipoprotein cholesterol level at a specific time point. The purpose of this review is to reassess contemporary research on treatment of familial hypercholesterolemia and current evidence‐based guidelines, to present an approach that emphasizes treatment across the life course, and to recognize the importance of family experiences to care. To accomplish this, we review the changing treatment needs that emerge across the life course, from birth through childhood, adolescence, young adulthood, peripregnancy, middle age, and late in life. Special attention is paid to improving adherence to treatment, the potential role of monitoring atherosclerosis in a lifelong model of care, and medical issues related to care transitions: from pediatric to internal medicine care, peripregnancy, after a cardiac event, and care after age 70 years in the absence of a cardiac event. Novel considerations related to treatment of homozygous familial hypercholesterolemia are discussed. The summary identifies research gaps that need to be closed to move from the current point‐of‐care model to one that considers treatment over the life course.