RESUMEN

AIM: To examine the long-term results and treatment effectiveness of liver transplantation (LT) in the treatment of homozygous familial hypercholesterolemia (HoFH) in children and adolescents. METHOD: Patients who underwent LT due to HoFH between 2007 and 2023 were included in the study. The patients' demographic data, clinical findings, preoperative and postoperative laboratory examinations, transplantation complications, and postoperative disease courses were evaluated. RESULTS: There were five boys with an average age of 6.2 (median: 6, range 4-10) years in the study. The average total cholesterol level of the patients before transplantation was 923 (median: 950, range: 780-1002) mg/dL and the average LDL-cholesterol level was 864 (median: 852, range: 770-957) mg/dL. No patients died of transplant-related complications. After an average follow-up of 9.2 (median: 9, range: 1.5-16) years, the average total cholesterol level of the patients was 197 (median: 164, range: 137-359) mg/dL, and the average LDL-cholesterol level was 138 (median: 92, range: 85-313) mg/dL. Four (80%) patients developed atherosclerotic cardiovascular disease during follow-up, and two (40%) died of this cause. CONCLUSION: LT in the treatment of HoFH did not help our patients reach the target LDL-cholesterol level after transplantation and did not prevent the development of cardiovascular disease. Therefore, LT alone is not curative in the treatment of HoFH.

Asunto(s)

LDL-Colesterol , Hiperlipoproteinemia Tipo II , Trasplante de Hígado , Humanos , Masculino , Niño , Hiperlipoproteinemia Tipo II/cirugía , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/terapia , Preescolar , Resultado del Tratamiento , LDL-Colesterol/sangre , Femenino , Estudios de Seguimiento , Homocigoto , Adolescente , Estudios Retrospectivos , Colesterol/sangre

RESUMEN

OBJECTIVES AND AIM: This study aimed to identify precise biomarkers and develop targeted therapeutic strategies for preventing premature atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia (FH) by investigating the quantitative and qualitative abnormalities in the metabolic network of lipids in these patients using an advanced lipidomics platform. DESIGN & METHODS: The study population comprised 18 homozygous (HoFH), 18 heterozygous (HeFH) FH patients, and 20 healthy controls. Cholesterol oxidation products (oxysterol, COPs) and main lipid classes were determined using gas chromatography-mass spectrometry. Results were expressed as percentages of total fat matter for lipid classes and percentages of total COPs for oxysterols. The principal component analysis (PCA) was also carried out, to highlight the correlation between studied parameters and groups investigated. RESULTS: Patients (both HoFH and HeFH) showed lower content of free fatty acids (FFAs) and greater values of triacylglycerols (TAGs) in comparison to controls. HoFH showed lower monoacylglycerols (P<0.01) and higher free cholesterol (FC) (P<0.05) when compared to HeFH and controls. The total content of COPs ranged from 1.96 to 4.25 mg/dL, from 2.27 to 4.05 mg/dL, and from 0.79 to 4.12 mg/dL in healthy controls, HoFH and HeFH groups, respectively, with no significant differences between patients and controls. In general, the 7α-hydroxycholesterol (7α-HC) was greater than other COPs. However, no significant differences were found between the three studied groups. Moreover, an opposite trend was observed between 7α-HC and 7-ketocholesterol (7-KC). Additionally, when PCA was carried out, the first two PCs explained 92.13 % of the total variance, of which the PC1 describes 53.94 % of variance mainly correlated to TAGs, diacylglycerols (DAGs), and 7-KC. On the other hand, the PC2 was correlated primarily for FFAs, FC and esterified sterols (E-STE). CONCLUSIONS: In conclusion, abnormal levels of TAGs, DAGs and 7-KC were associated with HeFH while HoFH was associated with the abnormal amount of E-STE.

Asunto(s)

Hiperlipoproteinemia Tipo II , Lipidómica , Oxiesteroles , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo II/genética , Oxiesteroles/metabolismo , Oxiesteroles/sangre , Masculino , Lipidómica/métodos , Femenino , Adulto , Persona de Mediana Edad , Estudios de Casos y Controles , Triglicéridos/sangre , Cromatografía de Gases y Espectrometría de Masas/métodos , Biomarcadores/sangre

RESUMEN

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.

Asunto(s)

Aterosclerosis , Modelos Animales de Enfermedad , Macrófagos del Hígado , Hígado , Macrófagos del Hígado/metabolismo , Animales , Hígado/metabolismo , Hígado/patología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Masculino , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/patología , Dislipidemias/metabolismo , Ratones Endogámicos C57BL , Triglicéridos/sangre , Triglicéridos/metabolismo , Apolipoproteínas B/metabolismo , Apolipoproteínas B/sangre , Colesterol/metabolismo , Colesterol/sangre , Dieta Alta en Grasa/efectos adversos , Apolipoproteína B-100/metabolismo , Femenino

RESUMEN

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.

Asunto(s)

Colesterol , Hiperlipoproteinemia Tipo II , Tamizaje Masivo , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/genética , Eslovaquia/epidemiología , Niño , Masculino , Femenino , Colesterol/sangre , Tamizaje Masivo/métodos , Estudios Prospectivos , Adulto , LDL-Colesterol/sangre , Padres

RESUMEN

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.

Asunto(s)

Hiperlipoproteinemia Tipo II , Lipoproteínas HDL , Fosfolípidos , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/metabolismo , Masculino , Femenino , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/sangre , Adulto , Fosfolípidos/metabolismo , Fosfolípidos/sangre , Persona de Mediana Edad , Estudios de Casos y Controles , HDL-Colesterol/sangre , HDL-Colesterol/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/sangre

RESUMEN

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.

Asunto(s)

Tendón Calcáneo , Hiperlipoproteinemia Tipo II , Proproteína Convertasa 9 , Receptores de LDL , Humanos , Tendón Calcáneo/diagnóstico por imagen , Tendón Calcáneo/patología , Femenino , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/diagnóstico , Receptores de LDL/genética , Persona de Mediana Edad , Proproteína Convertasa 9/genética , Rosuvastatina Cálcica/uso terapéutico , Aterosclerosis/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , LDL-Colesterol/sangre , Mutación Missense , Japón , Pueblos del Este de Asia

RESUMEN

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.

Asunto(s)

LDL-Colesterol , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/sangre , Femenino , Masculino , Factores Sexuales , LDL-Colesterol/sangre , Anticolesterolemiantes/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico

RESUMEN

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.

Asunto(s)

Enfermedades Asintomáticas , Hiperlipoproteinemia Tipo II , Angiografía por Resonancia Magnética , Humanos , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Heterocigoto , Adulto , Factores de Riesgo , Estudios Retrospectivos , Constricción Patológica , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/etiología , Anciano , LDL-Colesterol/sangre , Japón/epidemiología

RESUMEN

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.

Asunto(s)

COVID-19 , Hiperlipoproteinemia Tipo II , SARS-CoV-2 , Humanos , COVID-19/prevención & control , COVID-19/epidemiología , Femenino , Masculino , Niño , Hiperlipoproteinemia Tipo II/sangre , Adolescente , Estudios Retrospectivos , Preescolar , Antropometría , Lactante , LDL-Colesterol/sangre , Triglicéridos/sangre , Obesidad Infantil/epidemiología , Índice de Masa Corporal , Pandemias , HDL-Colesterol/sangre , Cuarentena , Lípidos/sangre

RESUMEN

Aim: Methylation of LDLR, PCSK9 and LDLRAP1 CpG sites was assessed in patients with familial hypercholesterolemia (FH). Methods: DNA methylation of was analyzed by pyrosequencing in 131 FH patients and 23 normolipidemic (NL) subjects.Results:  LDLR, PCSK9 and LDLRP1 methylation was similar between FH patients positive (MD) and negative (non-MD) for pathogenic variants in FH-related genes. LDLR and PCSK9 methylation was higher in MD and non-MD groups than NL subjects (p < 0.05). LDLR, PCSK9 and LDLRAP1 methylation profiles were associated with clinical manifestations and cardiovascular events in FH patients (p < 0.05).Conclusion: Differential methylation of LDLR, PCSK9 and LDLRAP1 is associated with hypercholesterolemia and cardiovascular events. This methylation profile maybe useful as a biomarker and contribute to the management of FH.

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Asunto(s)

Metilación de ADN , Hiperlipoproteinemia Tipo II , Proteína Asociada a Proteínas Relacionadas con Receptor de LDL , Proproteína Convertasa 9 , Receptores de LDL , Humanos , Proproteína Convertasa 9/genética , Receptores de LDL/genética , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/sangre , Masculino , Femenino , Persona de Mediana Edad , Adulto , Proteína Asociada a Proteínas Relacionadas con Receptor de LDL/genética , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/etiología , Islas de CpG , Proteínas Adaptadoras Transductoras de Señales

RESUMEN

BACKGROUND: Long-term control of cardiovascular risk factors after acute coronary syndrome (ACS) is the cornerstone for preventing recurrence. We investigated the extent of cardiovascular risk factor management in males and females with and without familial hypercholesterolemia (FH) 5 years after ACS. METHODS: We studied patients hospitalized for ACS between 2009 and 2017 in a Swiss multicenter prospective cohort study. FH was defined based on clinical criteria from the Dutch Lipid Clinic Network and Simon Broome definitions. Five years post-ACS, we assessed low-density lipoprotein-cholesterol (LDL-c) levels, lipid-lowering therapy (LLT), and other cardiovascular risk factors, comparing males to females with and without FH using generalized estimating equations. RESULTS: A total of 3139 patients were included; mean age was 61.4 years (SD, 12.1), 620 (19.8%) were female, and 747 (23.5%) had possible FH. Compared with males at 5-years post-ACS, females were more likely to not use statins (odds ratio, 1.61 [95% CI, 1.28-2.03]) and less likely to have combination LLT (odds ratio, 0.72 [95% CI, 0.55-0.93]), without difference between patients with FH and without FH. Females in both FH and non-FH groups less frequently reached LDL-c values ≤1.8 mmol/L (odds ratio, 0.78 [95% CI, 0.78-0.93]). Overall, patients with FH were more frequently on high-dose statins compared with patients without FH (51.0% versus 42.9%; P=0.001) and presented more frequently with a combination of 2 or more LLT compared with patients without FH (33.8% versus 17.7%; P<0.001), but less frequently reached LDL-c targets of ≤1.8 mmol/L (33.5% versus 44.3%; P<0.001) or ≤2.6 mmol/L (70.2% versus 78.1%; P=0.001). CONCLUSIONS: Five years after ACS, females had less intensive LLT and were less likely to reach target LDL-c levels than males, regardless of FH status. Males and females with FH had less optimal control of LDL-c despite more frequently taking high-dose statins or combination LLT compared with patients without FH. Long-term management of patients with ACS and FH, especially females, warrants optimization.

Asunto(s)

Síndrome Coronario Agudo , Biomarcadores , LDL-Colesterol , Factores de Riesgo de Enfermedad Cardiaca , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hiperlipoproteinemia Tipo II , Humanos , Masculino , Femenino , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/epidemiología , Síndrome Coronario Agudo/terapia , Síndrome Coronario Agudo/sangre , Persona de Mediana Edad , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/complicaciones , Factores Sexuales , Anciano , Factores de Tiempo , Estudios Prospectivos , Resultado del Tratamiento , LDL-Colesterol/sangre , Suiza/epidemiología , Medición de Riesgo , Biomarcadores/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Recurrencia , Disparidades en Atención de Salud , Prevención Secundaria , Disparidades en el Estado de Salud

RESUMEN

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.

Asunto(s)

Hiperlipoproteinemia Tipo II , Investigación Biomédica Traslacional , Humanos , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/sangre , Proteína 3 Similar a la Angiopoyetina , LDL-Colesterol/sangre , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología , Anticuerpos ampliamente neutralizantes , Animales , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/farmacología , Anticolesterolemiantes/administración & dosificación , Receptores de LDL/metabolismo , Receptores de LDL/genética

RESUMEN

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.

Asunto(s)

Hiperlipoproteinemia Tipo II , Tamizaje Masivo , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/sangre , Niño , Tamizaje Masivo/métodos , Diagnóstico Precoz , LDL-Colesterol/sangre , Aterosclerosis/diagnóstico

RESUMEN

Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder causing elevated low density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. Universal cholesterol screening in childhood leads to children serving as the index case for their family, but efficacy of cascade screening and genetic counseling in this population is not well understood. The institutional pediatric lipid clinic database was queried from 2011 to 2022 for subjects <18 years who met clinical HeFH diagnostic criteria (N = 256). Median peak LDL-C was 198 mg/dL (interquartile range 179-238 mg/dL) and 69.5 % of subjects were the index case. The number of new HeFH cases identified per index case was 3.55 ± 1.87. Genetic counseling was offered to 38.7 % of subjects and genetic testing was completed by 10.9 %, 53.6 % of whom had a pathogenic or likely pathogenic genetic variant for HeFH. Our findings highlight the effectiveness of cascade screening from pediatric index cases identified through universal screening. However, genetic counseling and genetic testing may be underutilized in this population.

Asunto(s)

Pruebas Genéticas , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/sangre , Niño , Masculino , Femenino , Adolescente , Preescolar , LDL-Colesterol/sangre , Tamizaje Masivo/métodos , Asesoramiento Genético

RESUMEN

PURPOSE: Familial hypercholesterolemia (FH) leads to elevated low-density lipoprotein cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). Since the first functional and morphologic changes of the arterial wall occur in childhood, treatment should start early in childhood to mitigate the elevated risk of ASCVD. Pediatricians play an important role in the detection and care of children with FH. In this study, we aim to explore potential gaps in FH care amongst Dutch pediatricians, in order to enhance their knowledge and awareness of detecting and treating children with FH. METHODS: An anonymous online survey, deployed using Google Forms, including 26 closed and semi-closed questions on FH care in children was distributed by the Dutch Association of Pediatrics via a newsletter to which the majority of the practicing Dutch pediatricians subscribe. In addition, we requested that the pediatric departments of all Dutch hospitals in the Netherlands distribute this survey personally among their employed pediatricians. Respondents were instructed to answer the questions without any help or use of online resources. RESULTS: Between September 1st, 2023 and November 1st, 2023, 158 (an estimated 11% response rate) Dutch pediatricians completed the survey. They reported a median (IQR) of 15.0 (6.0-22.0) years of experience as a pediatrician, and 34 (21.5%) were working in academic hospitals. The majority (76.6%) of pediatricians correctly identified a typical FH lipid profile but 68 (43.0%) underestimated the true prevalence of FH (1:300). Underestimation and unawareness of the increased risk of FH patients for ASCVD were reported by 37.3% and 25.9% of pediatricians, respectively. Although 70.9% of the pediatricians correctly defined FH, only 67 (42.4%) selected statins and ezetimibe to treat severe hypercholesterolemia. CONCLUSIONS: The results of this study suggest significant gaps in knowledge and awareness of FH in children among Dutch pediatricians. FH care in children needs improvement through educational and training initiatives to mitigate the life-long risk of ASCVD from early life. WHAT IS KNOWN: • Familial hypercholesterolemia (FH) leads to elevated LDL-cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). • The process of atherosclerosis starts in childhood • Pediatricians play an important role in the detection and treatment of children with FH. WHAT IS NEW: • Our results highlight significant gaps in care for children with FH amongst pediatricians and this may lead to suboptimal detection and treatment. • FH care in children needs improvement by educational initiatives to ultimately prevent ASCVD in adulthood.

Asunto(s)

Hiperlipoproteinemia Tipo II , Pediatras , Pautas de la Práctica en Medicina , Humanos , Países Bajos/epidemiología , Hiperlipoproteinemia Tipo II/terapia , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Pediatras/estadística & datos numéricos , Masculino , Pautas de la Práctica en Medicina/estadística & datos numéricos , Femenino , Niño , Encuestas y Cuestionarios , Adulto , Brechas de la Práctica Profesional/estadística & datos numéricos

RESUMEN

Despite elevated low-density lipoprotein (LDL) cholesterol levels, some older subjects with heterozygous familial hypercholesterolemia (HeFH) do not develop atherosclerotic cardiovascular disease (ACVD) during their lifetime. The factors related to this resilient state have not been fully established. The aim of this study was to evaluate differential characteristics between older HeFH subjects with and without ACVD and factors associated with the presence of ACVD. Subjects were part of the Spanish Atherosclerosis Society Dyslipidemia Registry, and those ≥ 70 years old and with HeFH were included. Baseline characteristics of these subjects with and without ACVD were compared. A multivariate analysis was performed to assess factors associated with the presence of ACVD. A total of 2148 subjects with HeFH were included. Resilient subjects were mostly female, younger and presented fewer comorbidities with respect to the ACVD group. Subjects without ACVD had higher baseline high-density lipoprotein (HDL) cholesterol (55.8 ± 17.1 vs. 47.9 ± 15.4 mg/dL; p < 0.001) and lower lipoprotein(a) [Lp(a)] (53.4 ± 67.9 vs. 66.6 ± 85.6 mg/dL; p < 0.001) levels with respect to those in the ACVD group. Lp(a) and the presence of ≥3 risk factors were associated with the presence of ACVD.

Asunto(s)

Heterocigoto , Hiperlipoproteinemia Tipo II , Humanos , Femenino , Masculino , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/genética , Anciano , Factores de Riesgo , LDL-Colesterol/sangre , Aterosclerosis/sangre , Aterosclerosis/etiología , Aterosclerosis/genética , HDL-Colesterol/sangre , Lipoproteína(a)/sangre , Anciano de 80 o más Años

RESUMEN

BACKGROUND: Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH. METHODS: We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease. RESULTS: Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant. CONCLUSIONS: Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.

Asunto(s)

LDL-Colesterol , Enfermedad de la Arteria Coronaria , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hiperlipoproteinemia Tipo II , Lipoproteína(a) , Herencia Multifactorial , Fenotipo , Sistema de Registros , Humanos , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Femenino , Masculino , Persona de Mediana Edad , LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico , Medición de Riesgo , Lipoproteína(a)/sangre , Lipoproteína(a)/genética , Adulto , Anciano , Canadá/epidemiología , Reino Unido/epidemiología , Índice de Severidad de la Enfermedad , Factores de Riesgo , Estudios de Casos y Controles , Biomarcadores/sangre , Incidencia

RESUMEN

BACKGROUND: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence. METHODS: In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis. FINDINGS: The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037). INTERPRETATION: Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life. FUNDING: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.

Asunto(s)

Eliminación de Componentes Sanguíneos , Enfermedades Cardiovasculares , Hiperlipoproteinemia Tipo II , Sistema de Registros , Humanos , Femenino , Masculino , Hiperlipoproteinemia Tipo II/terapia , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/complicaciones , Niño , Eliminación de Componentes Sanguíneos/métodos , Adolescente , Preescolar , Estudios de Seguimiento , Enfermedades Cardiovasculares/prevención & control , Lactante , LDL-Colesterol/sangre , Lipoproteínas/sangre , Estudios de Cohortes , Resultado del Tratamiento , Homocigoto

RESUMEN

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) remain at very high cardiovascular risk despite the best standard of care lipid-lowering treatment. The addition of evinacumab, an angiopoietin-like protein 3 monoclonal antibody, more than halves low-density lipoprotein cholesterol in short-term studies. This study evaluated whether the evinacumab response was durable in the long term and improved cardiovascular outcome. METHODS: The OLE ELIPSE HoFH (Open-Label Extension to Evinacumab Lipid Studies in Patients With HoFH) study included newly diagnosed patients and those completing the ELIPSE HoFH trial, on stable lipid-lowering therapy including lipoprotein apheresis but not lomitapide. All patients received evinacumab (15 mg/kg intravenously) every 4 weeks, with no change in concomitant lipid-lowering treatment during the first 6 months. The primary efficacy end points were the mean absolute and percentage changes in low-density lipoprotein cholesterol from baseline to 6 months. A key secondary end point was cardiovascular event-free survival, which was compared with a control HoFH cohort not treated with evinacumab or lomitapide and matched for age, sex, and lipoprotein apheresis, derived from French Registry of Familial hypercholesterolemia. RESULTS: Twelve patients, 5 women and 7 men (12-57 years), were enrolled in 3 centers in France. At 6 months, the mean low-density lipoprotein cholesterol reduction with evinacumab was 3.7 mmol/L or 56% (from 6.5 mmol/L at baseline to 2.8 mmol/L; P<0.0001) and was sustained over the median 3.5-year follow-up. No patients on evinacumab experienced cardiovascular events versus 13 events for 5/21 (24%) over 4 years in the control cohort (likelihood P=0.0267). CONCLUSIONS: Real-life, long-term evinacumab adjunctive to lipid-lowering therapy including lipoprotein apheresis led to sustained low-density lipoprotein cholesterol lowering and improved cardiovascular event-free survival of patients with HoFH.

Asunto(s)

Proteína 3 Similar a la Angiopoyetina , Anticolesterolemiantes , LDL-Colesterol , Homocigoto , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/mortalidad , Masculino , Femenino , LDL-Colesterol/sangre , Adulto , Persona de Mediana Edad , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Eliminación de Componentes Sanguíneos , Biomarcadores/sangre , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Factores de Tiempo , Supervivencia sin Progresión , Adulto Joven , Resultado del Tratamiento , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/epidemiología , Adolescente

RESUMEN

BACKGROUND: Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high-density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid-modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events. METHODS AND RESULTS: BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietary intervention and maximally tolerated lipid-modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a), and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2,532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024. CONCLUSION: These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well-tolerated.

Asunto(s)

Anticolesterolemiantes , Aterosclerosis , LDL-Colesterol , Humanos , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/administración & dosificación , Método Doble Ciego , LDL-Colesterol/sangre , Masculino , Femenino , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , HDL-Colesterol/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/complicaciones , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lipoproteína(a)/sangre , Persona de Mediana Edad