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BACKGROUND: Pediatric arterial ischemic stroke (AIS) is a rare disorder, associated with severe morbidity. In adults, elevated lipoprotein(a) (Lp(a)), a cholesterol-like particle, is associated with ischemic stroke. However, data on Lp(a) and pediatric AIS are scarce. Therefore, we evaluated the association between Lp(a) levels and pediatric AIS. METHODS: We included children who suffered an AIS (≤18 years) and were treated in a tertiary center in Amsterdam, the Netherlands. Two groups of children with AIS were identified: (i) neonates and (ii) children older than 29 days. A case-control study was performed, with the latter group as cases and children without AIS as control group. Cases and controls were matched for age of Lp(a) testing and sex. Multivariable logistic regression models were used. RESULTS: Thirteen neonates and 23 children were included. Mean (SD) age of AIS was 0.6 (2.0) days and 9.2 (6.3) years, respectively. Children with AIS were matched to 62 controls. Lp(a) levels of greater than 50 mg/dL were more prevalent in children with AIS compared to controls (21.7% vs. 3.2%, p = .02). A significant association was found between Lp(a) and AIS (odds ratio [OR] adjusted for age at Lp(a) testing, body mass index [BMI], measurement assay: 1.36 per 10 mg/dL increase of Lp(a), 95% confidence interval [CI]: 1.02-1.82, p = .041). CONCLUSIONS: In this study, Lp(a) levels were positively associated with the risk of AIS in children, suggesting that high Lp(a) might be an independent risk factor for AIS. This underlines the importance of Lp(a) measurement in children with AIS.
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AVC Isquêmico , Lipoproteína(a) , Humanos , Lipoproteína(a)/sangue , Estudos de Casos e Controles , Masculino , Feminino , AVC Isquêmico/sangue , AVC Isquêmico/etiologia , Criança , Recém-Nascido , Pré-Escolar , Lactente , Adolescente , Fatores de Risco , Seguimentos , PrognósticoRESUMO
Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.
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Remoção de Componentes Sanguíneos , Consenso , Homozigoto , Humanos , Remoção de Componentes Sanguíneos/métodos , Criança , Resultado do Tratamento , Lipoproteína(a)/sangue , LDL-Colesterol/sangue , Adolescente , Transplante de Fígado , Biomarcadores/sangue , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/terapia , Hiperlipoproteinemia Tipo I/sangue , Hiperlipoproteinemia Tipo I/genética , Fenótipo , Hiperlipoproteinemia Tipo II/terapia , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Pré-Escolar , Lipoproteínas/sangue , Predisposição Genética para DoençaRESUMO
Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is well established since three decades, lowering serum LDL-C levels by more than 70% per session. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment targets and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.
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BACKGROUND: Elevated lipoprotein(a) and familial hypercholesterolaemia are both independent risk conditions for cardiovascular disease. Although signs of atherosclerosis can be observed in children with familial hypercholesterolaemia, it is unknown whether elevated lipoprotein(a) is an additional risk factor for atherosclerosis in these young patients. Therefore, we aimed to assess the contribution of lipoprotein(a) concentrations to arterial wall thickening (as measured by carotid intima-media thickness) in children with familial hypercholesterolaemia who were followed up into adulthood. METHODS: We conducted a 20-year follow-up study of 214 children (aged 8-18 years) with heterozygous familial hypercholesterolaemia who were randomly assigned in a statin trial in Amsterdam (Netherlands) between Dec 7, 1997, and Oct 4, 1999. At baseline, and at 2, 10, and 20 years thereafter, blood samples were taken and carotid intima-media thickness was measured. Linear mixed-effects models were used to evaluate the association between lipoprotein(a) and carotid intima-media thickness during follow-up. We adjusted for sex, age, corrected LDL-cholesterol, statin use, and BMI. FINDINGS: Our study population comprised 200 children who had a carotid intima-media thickness measurement and a measured lipoprotein(a) concentration from at least one visit available. Mean age at baseline was 13·0 years (SD 2·9), 106 (53%) children were male, and 94 (47%) were female. At baseline, median lipoprotein(a) concentration was 18·5 nmol/L (IQR 8·7-35·5) and mean carotid intima-media thickness was 0·4465 mm (SD 0·0496). During follow-up, higher lipoprotein(a) concentrations contributed significantly to progression of carotid intima-media thickness (ß adjusted 0·0073 mm per 50 nmol/L increase in lipoprotein(a) [95% CI 0·0013-0·0132]; p=0·017). INTERPRETATION: Our findings suggest that lipoprotein(a) concentrations contribute significantly to arterial wall thickening in children with familial hypercholesterolaemia who were followed-up until adulthood, suggesting that lipoprotein(a) is an independent and additional risk factor for early atherosclerosis in those already at increased risk. Lipoprotein(a) measurement in young patients with familial hypercholesterolaemia is crucial to identify those at potentially highest risk for cardiovascular disease. FUNDING: Silence Therapeutics.
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Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II , Humanos , Masculino , Criança , Feminino , Adolescente , Espessura Intima-Media Carotídea , Seguimentos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteína(a) , Países Baixos/epidemiologia , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/epidemiologia , Fatores de Risco , Aterosclerose/epidemiologia , Aterosclerose/etiologiaRESUMO
Homozygous familial hypercholesterolaemia (HoFH) is a life-threatening disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels. Untreated, severe atherosclerotic cardiovascular disease (ASCVD), including aortic valve stenosis (AVS), may already occur in childhood. Another important genetic risk factor for ASCVD and AVS is elevated lipoprotein(a) [Lp(a)], which is highly prevalent in the general paediatric population. However, data on Lp(a) in children with HoFH are scarce. Therefore, we performed a cross-sectional study to evaluate Lp(a) levels in children with HoFH and compared them to children with heterozygous FH (HeFH) and unaffected children. Adjusted least-square mean (95% CI) Lp(a) levels in HoFH (n=29), HeFH (n=101) and unaffected children (n=102) were 18.7 (12.0-29.1), 15.3 (11.8-19.8) and 10.5 (8.3-13.2) mg/dL, respectively (p-for-trend=0.007). Lp(a) levels in children with HoFH were higher than in children with HeFH and in unaffected children. Given the very high ASCVD risk with HoFH, identifying other risk factors such as elevated Lp(a) in these children is important. Therefore, Lp(a) levels should be measured at least once in all children with HoFH.
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Estenose da Valva Aórtica , Aterosclerose , Hipercolesterolemia Familiar Homozigota , Hiperlipoproteinemia Tipo II , Humanos , Criança , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/epidemiologia , Lipoproteína(a) , Estudos Transversais , LDL-ColesterolRESUMO
BACKGROUND: Statins are the primary therapy in patient with heterozygous familial hypercholesterolemia (HeFH). Non-adherence to statin therapy is associated with increased cardiovascular risk. OBJECTIVE: We constructed a dynamic prediction model to predict statin adherence for an individual HeFH patient for each upcoming statin prescription. METHODS: All patients with HeFH, identified by the Dutch Familial Hypercholesterolemia screening program between 1994 and 2014, were eligible. National pharmacy records dated between 1995 and 2015 were linked. We developed a dynamic prediction model that estimates the probability of statin adherence (defined as proportion of days covered >80%) for an upcoming prescription using a mixed effect logistic regression model. Static and dynamic patient-specific predictors, as well as data on a patient's adherence to past prescriptions were included. The model with the lowest AIC (Akaike Information Criterion) value was selected. RESULTS: We included 1094 patients for whom 21,171 times a statin was prescribed. Based on the model with the lowest AIC, age at HeFH diagnosis, history of cardiovascular event, time since HeFH diagnosis and duration of the next statin prescription contributed to an increased adherence, while adherence decreased with higher untreated LDL-C levels and higher intensity of statin therapy. The dynamic prediction model showed an area under the curve of 0.63 at HeFH diagnosis, which increased to 0.85 after six years of treatment. CONCLUSION: This dynamic prediction model enables clinicians to identify HeFH patients at risk for non-adherence during statin treatment. These patients can be offered timely interventions to improve adherence and further reduce cardiovascular risk.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , LDL-Colesterol , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/complicações , Hipercolesterolemia/complicaçõesRESUMO
AIMS: Familial hypercholesterolaemia (FH) predisposes children to the early initiation of atherosclerosis and is preferably diagnosed by DNA analysis. Yet, in many children with a clinical presentation of FH, no mutation is found. Adult data show that high levels of lipoprotein(a) [Lp(a)] may underlie a clinical presentation of FH, as the cholesterol content of Lp(a) is included in conventional LDL cholesterol measurements. As this is limited to adult data, Lp(a) levels in children with and without (clinical) FH were evaluated. METHODS AND RESULTS: Children were eligible if they visited the paediatric lipid clinic (1989-2020) and if Lp(a) measurement and DNA analysis were performed. In total, 2721 children (mean age: 10.3 years) were included and divided into four groups: 1931 children with definite FH (mutation detected), 290 unaffected siblings/normolipidaemic controls (mutation excluded), 108 children with probable FH (clinical presentation, mutation not detected), and 392 children with probable non-FH (no clinical presentation, mutation not excluded). In children with probable FH, 32% were found to have high Lp(a) [geometric mean (95% confidence interval) of 15.9 (12.3-20.6) mg/dL] compared with 10 and 10% [geometric means (95% confidence interval) of 11.5 (10.9-12.1) mg/dL and 9.8 (8.4-11.3) mg/dL] in children with definite FH (P = 0.017) and unaffected siblings (P = 0.002), respectively. CONCLUSION: Lp(a) was significantly higher and more frequently elevated in children with probable FH compared with children with definite FH and unaffected siblings, suggesting that high Lp(a) may underlie the clinical presentation of FH when no FH-causing mutation is found. Performing both DNA analysis and measuring Lp(a) in all children suspected of FH is recommended to assess possible LDL cholesterol overestimation related to increased Lp(a).
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Hiperlipoproteinemia Tipo II , Lipoproteína(a) , Criança , Humanos , LDL-Colesterol/análise , Estudos Transversais , DNA/análise , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Lipoproteína(a)/análise , MutaçãoRESUMO
INTRODUCTION: Elevated lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). With the advent of the antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) targeted at LPA, that are highly effective for lowering Lp(a) levels, this risk factor might be managed in the near future. Given that Lp(a) levels are mostly genetically determined and once elevated, present from early age, we have evaluated future directions for the treatment of children with high Lp(a) levels. AREAS COVERED: In the current review, we discuss different pharmacological treatments in clinical development and provide an in-depth overview of the effects of ASOs and siRNAs targeted at LPA. EXPERT OPINION: Since high Lp(a) is an important risk factor for ASCVD and given the promising effects of both ASOs and siRNAs targeted at apo(a), there is an urgent need for well-designed prospective studies to assess the impact of elevated Lp(a) in childhood. If the Lp(a)-hypothesis is confirmed in adults, and also in children, the rationale might arise for treating children with high Lp(a) levels. However, we feel that this should be limited to children with the highest cardiovascular risk including familial hypercholesterolemia and potentially pediatric stroke.
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Aterosclerose , Doenças Cardiovasculares , Hiperlipoproteinemia Tipo II , Criança , Humanos , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Lipoproteína(a) , Oligonucleotídeos Antissenso/uso terapêutico , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: Elevated lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. In clinical practice, Lp(a) is mostly measured only once assuming that it does not change with age nor vary within individuals. This is mainly based on adult data and data on Lp(a) levels during childhood is scarce. Therefore, we evaluated whether Lp(a) levels changed with age and determined the intra-individual variation of Lp(a) in a large cohort of children. METHODS: We collected all Lp(a) measurements of children referred to the pediatric lipid clinic of the Amsterdam UMC between 1989 and 2017. The association between Lp(a) and age, as well as the intra-individual variation of Lp(a), was assessed using mixed models. We stratified for lipid-lowering medication use. RESULTS: In total, we included 2740 children. From the age of 8 years onwards, mean Lp(a) increased with 22% in children that reached adulthood without lipid-lowering medication (n = 2254). In statin-users (n = 418) and children that used ezetimibe additionally (n = 65), Lp(a) increased with 43% and 9%, respectively. The intra-individual variation of Lp(a) was 70%. CONCLUSIONS: Lp(a) levels increase with age and exhibit considerable variation within children referred to a lipid clinic. Measuring Lp(a) only once during childhood might therefore lead to substantial over- or underestimation and possibly result in over- or under treatment in the future. Thus, to more accurately assess the Lp(a) level, we suggest measuring Lp(a) more than once during childhood and to repeat this in adulthood if a patient only has childhood assessment of Lp(a).
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Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Adolescente , Adulto , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Criança , Ezetimiba , Humanos , Lipoproteína(a) , Fatores de Risco , Adulto JovemRESUMO
AIMS: Lipoprotein(a) [Lp(a)] is a causal and independent risk factor for cardiovascular disease (CVD). People with elevated Lp(a) are often prescribed statins as they also often show elevated low-density lipoprotein cholesterol (LDL-C) levels. While statins are well-established in lowering LDL-C, their effect on Lp(a) remains unclear. We evaluated the effect of statins compared to placebo on Lp(a) and the effects of different types and intensities of statin therapy on Lp(a). METHODS AND RESULTS: We conducted a systematic review and meta-analysis of randomized trials with a statin and placebo arm. Medline and EMBASE were searched until August 2019. Quality assessment of studies was done using Cochrane risk-of-bias tool (RoB 2). Mean difference of absolute and percentage changes of Lp(a) in the statin vs. the placebo arms were pooled using a random-effects meta-analysis. We compared effects of different types and intensities of statin therapy using subgroup- and network meta-analyses. Certainty of the evidence was determined using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Overall, 39 studies (24 448 participants) were included. Mean differences (95% confidence interval) of absolute and percentage changes in the statin vs. the placebo arms were 1.1 mg/dL (0.5-1.6, P < 0.0001) and 0.1% (-3.6% to 4.0%, P = 0.95), respectively (moderate-certainty evidence). None of the types of statins changed Lp(a) significantly compared to placebo (very low- to high-certainty evidence), as well as intensities of statin therapy (low- to moderate-certainty evidence). CONCLUSION: Statin therapy does not lead to clinically important differences in Lp(a) compared to placebo in patients at risk for CVD. Our findings suggest that in these patients, statin therapy will not change Lp(a)-associated CVD risk.