Long-term sex differences in atherosclerotic cardiovascular disease in individuals with heterozygous familial hypercholesterolaemia in Spain: a study using data from SAFEHEART, a nationwide, multicentre, prospective cohort study.

BACKGROUND: Sex differences in atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolaemia have been reported but are not fully established. We aimed to assess sex differences in the risk of ASCVD and life-time burden of ASCVD in patients with heterozygous familial hypercholesterolaemia. METHODS: SAFEHEART is a nationwide, multicentre, long-term prospective cohort study conducted in 25 tertiary care hospitals and one regional hospital in Spain. Participants in the SAFEHEART study aged 18 years or older with genetically confirmed familial hypercholesterolaemia were included in our analysis. Data were obtained between Jan 26, 2004, and Nov 30, 2022. ASCVD and age at onset were documented at enrolment and at follow-up. Our aim was to investigate the differences by sex in the risk and burden of ASCVD in patients with heterozygous familial hypercholesterolaemia, over the study follow-up and over the life course. The SAFEHEART study is registered with ClinicalTrials.gov, NCT02693548. FINDINGS: Of the 5262 participants in SAFEHEART at the time of analysis, 3506 (1898 [54·1%] female and 1608 [45·9%] male participants) met the inclusion criteria and were included in the current study. Mean age was 46·1 years (SD 15·5) and median follow-up was 10·3 years (IQR 6·4-13·0). Mean on-treatment LDL-cholesterol at follow-up was 3·1 mmol/L (SD 1·4) in females and 3·0 mmol/L (1·5) in males. LDL-cholesterol reductions over time were similar in both sexes (1·39 mmol/L [95% CI 1·30-1·47] absolute reduction in females vs 1·39 mmol/L [1·29-1·48] in males; p=0·98). At enrolment, 130 (6·8%) females and 304 (18·9%) males (p<0·0001) had cardiovascular disease. During follow-up, 134 (7·1%) females and 222 (13·8%) males (p<0·0001) had incident cardiovascular events. Median age at first ASCVD event (mostly due to coronary artery disease) was 61·6 years (IQR 50·0-71·4) in females and 50·6 years (42·0-58·6) in males (p<0·0001). The adjusted hazard ratio for ASCVD in males compared with females during follow-up was 1·90 (95% CI 1·49-2·42) and for cardiovascular death was 1·74 (1·11-2·73). Major adverse cardiovascular disease event (MACE)-free survival from birth was lower in males than females (hazard ratio 3·52 [95% CI 2·98-4·16]; p<0·0001). Median MACE-free survival time was 90·1 years (95% CI 86·5-not estimable) in females and 71·0 years (69·2-74·6) in males. The age at which 25% of female participants have had a MACE event was 74·9 years, this figure was 55·5 years in male participants. INTERPRETATION: Our findings suggest that the burden and risk of ASCVD are markedly lower in females than males with familial hypercholesterolaemia. The impact of sex needs to be considered to improve risk stratification and personalised management in patients with heterozygous familial hypercholesterolaemia. FUNDING: Fundación Hipercolesterolemia Familiar, the Instituto de Salud Carlos III, and Next Generation EU funds from the Recovery and Resilience Mechanism Program. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Established and Emerging Nucleic Acid Therapies for Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disease that leads to elevated low-density lipoprotein cholesterol levels and risk of coronary heart disease. Current therapeutic options for FH remain relatively limited and only partially effective in both lowering low-density lipoprotein cholesterol and modifying coronary heart disease risk. The unique characteristics of nucleic acid therapies to target the underlying cause of the disease can offer solutions unachievable with conventional medications. DNA- and RNA-based therapeutics have the potential to transform the care of patients with FH. Recent advances are overcoming obstacles to clinical translation of nucleic acid-based medications, including greater stability of the formulations as well as site-specific delivery, making gene-based therapy for FH an alternative approach for treatment of FH.

Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult.

Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is the initially responding site or if atherogenic dyslipidemia affects other organs simultaneously is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA sequencing revealed a Kupffer-cell-specific transcriptional program that was not activated by a high-fat diet alone or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins while simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis.

Biochemical and Anthropometric Outcomes in Paediatric Patients with Heterozygous Familial Hypercholesterolemia after COVID-19 Pandemic Lockdowns: An Exploratory Analysis.

The COVID-19 pandemic lockdowns affected the lifestyles of children and adolescents, leading to an increase in childhood obesity. Paediatric patients with familial hypercholesterolemia (FH) may be more susceptible to lockdown effects due to their increased cardiovascular risk. However, data are lacking. We investigated the effect of lockdowns on the metabolic profile of paediatric patients with FH. Blood lipids and anthropometry measured in September 2021-April 2022 were retrospectively compared with pre-pandemic values. Thirty participants were included (1-16 years; 57% female). From baseline to post-pandemic, median [P25, P75] blood LDL-C concentration was 125 [112, 150] mg/dL vs. 125 [100, 147] mg/dL (p = 0.894); HDL-C was 58 [52, 65] mg/dL vs. 56 [51, 61] mg/dL (p = 0.107); triglycerides were 64 [44, 86] mg/dL vs. 59 [42, 86] mg/dL (p = 0.178). The BMI z-score did not change significantly (0.19 [-0.58, 0.89] vs. 0.30 [-0.48, 1.10], p = 0.524). The lack of deterioration in metabolic profiles during lockdowns is positive, as some deterioration was expected. We speculate that patients and caregivers were successfully educated about healthy lifestyle and dietary habits. Our results should be interpreted with caution since the study sample was small and heterogeneous. Multicentre research is needed to better understand the impact of lockdowns on this population.

Asymptomatic Intracranial Artery Stenosis/Occlusion in Heterozygous Familial Hypercholesterolemia: Its Frequency and Implications for Cerebrovascular and Cardiovascular Events.

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

Emerging therapies for refractory hypercholesterolemia: a narrative review.

Refractory hypercholesterolemia (RH) is characterized by the failure of patients to achieve therapeutic targets for low-density lipoprotein-cholesterol (LDL-C) despite receiving maximal tolerable doses of standard lipid-lowering treatments. It predominantly impacts individuals with familial hypercholesterolemia (FH), thereby elevating the risk of cardiovascular complications. The prevalence of RH is now recognized to be substantially greater than previously thought. This review provides a comprehensive insight into current and emerging therapies for RH patients, including groundbreaking genetic-based therapeutic approaches. The review places emphasis on the dependency of therapies on low-density lipoprotein receptors (LDLRs) and highlights the critical role of considering LDLR activity in RH patients for individualization of the treatment.

Refractory hypercholesterolemia (RH) is a condition where patients are unable to get below target levels of 'bad' cholesterol despite receiving maximum doses of standard treatments. It is commonly present in those with a genetic disorder, called familial hypercholesterolemia (FH), known to increase the risk of heart complications. RH's prevalence is now understood to be higher than previously believed and this review offers insights into current and emerging therapies for RH, including genetic-based treatments. It stresses the importance of the mechanistic pathways behind cholesterol clearance, particularly low-density lipoprotein receptor (LDLR) activity, in RH treatment customization.

Potentials of artificial intelligence in familial hypercholesterolemia: Advances in screening, diagnosis, and risk stratification for early intervention and treatment.

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

Lipid Disorders and Pregnancy.

Practicing endocrinologists are likely to confront 2 major issues that occur with dyslipidemias during pregnancy. The most dramatic is the development of severe hypertriglyceridemia leading to acute pancreatitis. The second is the approach to treatment of familial hypercholesterolemia, a common genetic disorder. This article reviews the normal physiology and the pathophysiology of lipoproteins that occurs with pregnancy and then discusses the approaches to prevention and/or treatment of dyslipidemia in pregnancy with a focus on lifestyle and acceptable drug therapies.

Detecting familial hypercholesterolemia: An observational study leveraging mandatory universal pediatric total cholesterol screening in Slovakia.

BACKGROUND: In Slovakia, a mandatory national universal pediatric total cholesterol (TC) screening program is in place to identify cases of familial hypercholesterolemia (FH). However, the program's effectiveness has not been systematically assessed. OBJECTIVE: This study aimed to estimate the prevalence of FH among parents of children that had elevated TC levels identified during screening. METHODS: This prospective, non-interventional, observational study enrolled parents of 11-year-old children who underwent TC screening in 23 selected pediatric outpatient clinics between 2017 and 2018. FH was diagnosed using the Dutch Lipid Clinic Network (DLCN) criteria and targeted next-generation sequencing. The primary objective was to estimate the proportion of children with a TC level of >188 mg/dL (>4.85 mmol/L) who had a parent with a confirmed diagnosis of FH. RESULTS: A total of 112 parents of 56 children with an elevated TC level were enrolled. Five children (8.9%) had a parent in whom FH was genetically confirmed. Without genetic analysis, all five parents would only be diagnosed with "possible FH" by DLCN criteria. Of parents, 83.9% (n = 94/112) had an low-density lipoprotein cholesterol (LDL-C) level of >116 mg/dL (>3 mmol/L), but only 5.3% (n = 5/94) received lipid-lowering therapy. Among the five parents with genetically confirmed FH, all had an LDL-C level >116 mg/dL (>3 mmol/L), with a mean (±SD) of 191 (±24) mg/dL (4.94 [±0.61] mmol/L). Only two of these parents received lipid-lowering therapy. CONCLUSIONS: The present study demonstrates the significance of mandatory universal pediatric TC screening in identifying families with FH and other at-risk families in need of lipid-lowering therapy.

A Japanese Case of Familial Hypercholesterolemia with a Protein-truncating Variant in LDLR and a PCSK9 Variant without Significant Atherosclerosis but Showing Remarkable Achilles Tendon Thickening.

The patient was a 54-year-old woman with familial hypercholesterolemia and remarkable Achilles tendon thickening. At 20 years old, the patient had a total cholesterol level of approximately 300 mg/dL. She started receiving rosuvastatin (5 mg/day) for low-density lipoprotein cholesterol (LDL-C) 235 mg/dL at 42 years old, which was increased to 10 mg/day at 54 years old, decreasing her serum LDL-C level to approximately 90 mg/dL. The serum Lp (a) level was 9 mg/dL. A computed tomography coronary angiogram showed no significant stenosis. Next-generation sequencing revealed a frameshift variant in LDL receptor (LDLR) (heterozygous) and a missense variant in proprotein convertase subtilisin/kaxin type 9 (PCSK9) (heterozygous). Continued statin therapy, in addition to low Lp (a) and female sex, can help prevent cardiovascular disease.

Communication: High-Density Lipoprotein-Specific Phospholipid Efflux in Familial Hypercholesterolemia.

OBJECTIVE: Familial hypercholesterolemia (FH) is characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD). Although the role of LDL-C in FH has been studied, the contribution of high-density lipoproteins (HDL) to CVD in FH remains unknown. This study aimed at highlighting the role of HDL in FH. METHODS: HDL-specific phospholipid efflux (HDL-SPE) assay was developed to predict CVD risk. HDL-SPE was examined in FH patients (n=30) and compared with age- and sex-matched non-FH controls (n=60). RESULTS: FH patients had significantly lower HDL-SPE levels (0.90±0.12) than controls (1.12±0.10; p<0.05), despite similar HDL-cholesterol levels in both groups (FH: 57.9±18.7 mg/dl; controls: 57.1±13.8 mg/dl). These differences remained significant after adjusting for confounders. CONCLUSIONS: These findings suggest there may be dysfunctionality of HDL in FH.

Evinacumab: Mechanism of action, clinical, and translational science.

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

Hypercholesterolaemia treated with inclisiran.

In this case report, a 31-year-old woman with heterozygous familial hypercholesterolaemia (FH) underwent treatment with statins and PCSK9 inhibitor but had to discontinue due to elevated creatine kinase levels and neurological and muscular side effects. In 2021, the patient received inclisiran therapy, the first known instance of its application in Denmark. No side effects were reported, and LDL cholesterol levels were significantly reduced. This case report highlights the potential of inclisiran as an effective and well-tolerated treatment for individuals with heterozygous FH.

Evinacumab in homozygous familial hypercholesterolaemia: long-term safety and efficacy.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH. METHODS: In this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15 mg/kg every 4 weeks with stable lipid-lowering therapy. RESULTS: A total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively. CONCLUSIONS: In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.

Generation of two familial hypercholesterolemia patient-specific induced pluripotent stem cell lines harboring heterozygous mutations in the LDLR gene.

Familial hypercholesterolemia (FH) is a genetic disorder affecting the metabolism of lipoprotein, characterized by elevated levels of plasma concentrations of low-density lipoprotein cholesterol (LDLC). The most common FH cause is mutations within the gene that encodes for the LDL receptor (LDLR) protein. Two induced pluripotent stem cell (iPSC) lines were generated from patients with FH, each carrying a single heterozygous mutation in the LDLR gene, one is a missense mutation, c.631C > T, and the other is a splice-site mutation, c.313 + 1G > A. Both iPSC lines exhibited strong expression of pluripotency markers, demonstrated the ability to differentiate into derivatives of the three germ layers, and maintained normal karyotypes. These derived iPSC lines represent powerful tools for in vitro modeling FH and offer a promising platform for therapeutic development.

Improving the Detection of Potential Cases of Familial Hypercholesterolemia: Could Machine Learning Be Part of the Solution?

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

The Role of Reverse Cascade Screening in Children with Familial Hypercholesterolemia: A Literature Review and Analysis.

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