Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
N Engl J Med ; 381(16): 1547-1556, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31618540

RESUMO

BACKGROUND: Familial hypercholesterolemia is characterized by severely elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. The short-term efficacy of statin therapy in children is well established, but longer follow-up studies evaluating changes in the risk of cardiovascular disease are scarce. METHODS: We report a 20-year follow-up study of statin therapy in children. A total of 214 patients with familial hypercholesterolemia (genetically confirmed in 98% of the patients), who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected siblings. Participants completed a questionnaire, provided blood samples, and underwent measurements of carotid intima-media thickness. The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents. RESULTS: Of the original cohort, 184 of 214 patients with familial hypercholesterolemia (86%) and 77 of 95 siblings (81%) were seen in follow-up; among the 214 patients, data on cardiovascular events and on death from cardiovascular causes were available for 203 (95%) and 214 (100%), respectively. The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter (from 6.13 to 4.16 mmol per liter) - a decrease of 32% from the baseline level; treatment goals (LDL cholesterol <100 mg per deciliter [2.59 mmol per liter]) were achieved in 37 patients (20%). Mean progression of carotid intima-media thickness over the entire follow-up period was 0.0056 mm per year in patients with familial hypercholesterolemia and 0.0057 mm per year in siblings (mean difference adjusted for sex, -0.0001 mm per year; 95% confidence interval, -0.0010 to 0.0008). The cumulative incidence of cardiovascular events and of death from cardiovascular causes at 39 years of age was lower among the patients with familial hypercholesterolemia than among their affected parents (1% vs. 26% and 0% vs. 7%, respectively). CONCLUSIONS: In this study, initiation of statin therapy during childhood in patients with familial hypercholesterolemia slowed the progression of carotid intima-media thickness and reduced the risk of cardiovascular disease in adulthood. (Funded by the AMC Foundation.).


Assuntos
Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adolescente , Adulto , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Espessura Intima-Media Carotídea , Criança , LDL-Colesterol/sangue , Progressão da Doença , Feminino , Seguimentos , Humanos , Hiperlipoproteinemia Tipo II/sangue , Incidência , Masculino , Intervalo Livre de Progressão , Risco , Inquéritos e Questionários , Adulto Jovem
3.
Atherosclerosis ; 285: 87-92, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31048103

RESUMO

BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (hoFH) is a rare genetic disease, hallmarked by a lifelong exposure to very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated, patients can experience a cardiovascular event in the first decade of life. Early detection and monitoring of subclinical atherosclerosis in these patients is therefore extremely important. We set out to assess the diagnostic yield of low-dose coronary computed tomography angiography (cCTA) compared to echocardiography in detecting subclinical atherosclerosis. METHODS: For this single-center cross-sectional study, we included all pediatric hoFH patients treated with lipoprotein-apheresis (LA) in Amsterdam UMC. We performed both cCTA and echocardiography in all patients as part of routine follow-up. RESULTS: Six hoFH patients were included. Median ages at diagnosis, onset of LA and cardiovascular assessment (cCTA and echocardiography) were 2.6, 6.5, 10.8 and 11.1 years, respectively. Echocardiography revealed no signs of atherosclerosis in any of the six patients. In two patients, mild dilatation of the cardiac chambers was detected and two patients showed signs of mitral or aortic insufficiency. On cCTA, however, non-calcified plaques without stenosis were detected in four patients. In two patients calcified coronary plaques were found at the ostia of the right coronary artery or the left main coronary artery. Aortic root calcifications were found in two patients. CONCLUSIONS: Our findings suggest that in hoFH children, low-dose cCTA is superior to echocardiography for the detection of subclinical coronary and aortic root atherosclerosis and should therefore be considered in the routine cardiovascular monitoring of these high-risk children.

4.
J Clin Lipidol ; 13(2): 272-278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30795984

RESUMO

BACKGROUND: Homozygous familial hypercholesterolemia (hoFH) is either diagnosed on the identification of pathogenic genetic variants in LDLR, APOB, or PCSK9 or by phenotypic parameters of which an extremely elevated LDL-C level >13 mmol/L (>500 mg/dL) is the most prominent hallmark. Little is known about the clinical spectrum in children with hoFH. OBJECTIVE: We set out to investigate the phenotypical spectrum of genetically defined hoFH in our pediatric cohort and evaluated how many pediatric patients, now classified as heterozygous, carry a second mutation, which would reclassify these patients as hoFH. METHODS: We analyzed the data of a total of 1903 children with molecularly proven FH. Subsequently we performed candidate gene sequencing in the cohort of heterozygous familial hypercholesterolemia children in whom the LDL-C level was above the lowest level measured in the pediatric patients with hoFH. RESULTS: Of our 13 hoFH children, 8 (62%) had LDL-C levels below the clinical hoFH criteria of 13 mmol/L (500 mg/dL). In the remaining 1890 patients with heterozygous familial hypercholesterolemia, 64 (3.4%) had LDL-C levels equal to or above the lowest LDL-C level in a patient with hoFH carrying 2 deleterious variants (8.36 mmol/L or 323.3 mg/dL). No additional pathogenic variants in LDLR and APOB were identified. In 2 related patients, a PCSK9 gain of function mutation was found. CONCLUSION: We show that LDL-C levels vary among pediatric patients with molecularly proven hoFH, and that most of these patients do not meet the clinical LDL-C criteria for hoFH. The levels overlap with LDL-C levels in true heterozygous patients. This warrants a critical reappraisal of the current LDL-C cutoffs for the phenotypic diagnosis of hoFH in children.

5.
J Clin Lipidol ; 13(1): 31-39, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30553758

RESUMO

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder that may cause life-threatening cardiovascular disease (CVD) at childhood. Marginal effectiveness of statins in reducing low-density lipoprotein cholesterol (LDL-C) is the reason why extracorporeal removal of LDL-C by lipoprotein apheresis (LA) is recommended at the earliest possible age. OBJECTIVE: It is, however, unknown to what extent LA effectively reduces the burden of CVD in children with HoFH. We therefore systemically reviewed the literature on the efficacy and safety of LA in children with HoFH. METHODS: We conducted a systematic literature search using Embase Classic and Embase on studies that evaluated LA in patients with HoFH aged <19 years and reported on at least one of the following outcome measures: cholesterol levels, xanthoma, CVD, or surrogate outcome markers for CVD. Adverse events were also reported on. RESULTS: We selected 76 studies on 209 patients, 45 of these were case series and 31 were case reports. Mean LDL-C reduction per session was 63% and 71% for nonselective and selective modes of LA, respectively. HDL-C levels were best preserved with selective LA. Xanthomata regressed or disappeared in 83% of patients during LA treatment, surrogate parameters of CVD remained stable in most patients. Of 123 patients, 24 experienced a CVD event of whom 10 had experienced a CVD before LA onset. Six patients died at follow-up. Reported side effects were overall minor. CONCLUSION: LA seems to be a safe therapy and substantially reduces LDL-C and xanthomata in children with HoFH. The efficacy with respect to CVD protection as compared with only pharmacologic and dietary treatment remains unclear.

6.
J Cardiovasc Magn Reson ; 20(1): 86, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30567566

RESUMO

BACKGROUND: Cardiovascular magnetic resonance (CMR) allows for non-invasive assessment of arterial stiffness by means of measuring pulse wave velocity (PWV). PWV can be calculated from the time shift between two time-resolved flow curves acquired at two locations within an arterial segment. These flow curves can be derived from two-dimensional CINE phase contrast CMR (2D CINE PC CMR). While CMR-derived PWV measurements have proven to be accurate for the aorta, this is more challenging for smaller arteries such as the carotids due to the need for both high spatial and temporal resolution. In this work, we present a novel method that combines retrospectively gated 2D CINE PC CMR, high temporal binning of data and compressed sensing (CS) reconstruction to accomplish a temporal resolution of 4 ms. This enables accurate flow measurements and assessment of PWV in regional carotid artery segments. METHODS: Retrospectively gated 2D CINE PC CMR data acquired in the carotid artery was binned into cardiac frames of 4 ms length, resulting in an incoherently undersampled ky-t-space with a mean undersampling factor of 5. The images were reconstructed by a non-linear CS reconstruction using total variation over time as a sparsifying transform. PWV values were calculated from flow curves by using foot-to-foot and cross-correlation methods. Our method was validated against ultrasound measurements in a flow phantom setup representing the carotid artery. Additionally, PWV values of two groups of 23 young (30 ± 3 years, 12 [52%] women) and 10 elderly (62 ± 10 years, 5 [50%] women) healthy subjects were compared using the Wilcoxon rank-sum test. RESULTS: Our proposed method produced very similar flow curves as those measured using ultrasound at 1 ms temporal resolution. Reliable PWV estimation proved possible for transit times down to 7.5 ms. Furthermore, significant differences in PWV values between healthy young and elderly subjects were found (4.7 ± 1.0 m/s and 7.9 ± 2.4 m/s, respectively; p < 0.001) in accordance with literature. CONCLUSIONS: Retrospectively gated 2D CINE PC CMR with CS allows for high spatiotemporal resolution flow measurements and accurate regional carotid artery PWV calculations. We foresee this technique will be valuable in protocols investigating early development of carotid atherosclerosis.


Assuntos
Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Compressão de Dados , Interpretação de Imagem Assistida por Computador/métodos , Imagem Cinética por Ressonância Magnética/métodos , Rigidez Vascular , Adulto , Velocidade do Fluxo Sanguíneo , Técnicas de Imagem de Sincronização Cardíaca , Artérias Carótidas/fisiopatologia , Doenças das Artérias Carótidas/fisiopatologia , Eletrocardiografia , Feminino , Humanos , Imagem Cinética por Ressonância Magnética/instrumentação , Masculino , Pessoa de Meia-Idade , Imagens de Fantasmas , Valor Preditivo dos Testes , Análise de Onda de Pulso , Fluxo Sanguíneo Regional , Reprodutibilidade dos Testes , Ultrassonografia
7.
J Clin Lipidol ; 12(5): 1199-1207, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30318065

RESUMO

BACKGROUND: Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is safe and effective in reducing low-density lipoprotein cholesterol in adults with familial hypercholesterolemia. A dedicated study, HAUSER-RCT, is being conducted to examine the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia (HeFH). OBJECTIVE: To present the rationale and design of the HAUSER-RCT study. METHODS: The HAUSER-RCT study is a double-blind, randomized, multicenter, placebo-controlled study designed to characterize the efficacy, safety, and tolerability of evolocumab treatment as an add-on to diet and lipid-lowering therapy, including a stable, optimized dose of statin, in pediatric patients aged 10 to 17 years with HeFH. Approximately, 150 patients will be randomized in a 2:1 ratio to receive 24 weeks of monthly evolocumab or placebo. The study will include approximately 51 sites located in North America, South America, Europe, South Africa, Australia, and New Zealand. The primary efficacy endpoint is the percent change in low-density lipoprotein cholesterol from baseline to week 24. A key secondary efficacy endpoint is the percent change in other lipid parameters from baseline to week 24. Other assessments include Tanner staging, carotid intima-media thickness, and cognitive tests. At the end of the study, consenting patients can participate in an 18-month open-label extension study (HAUSER-OLE). RESULTS: The study is ongoing and the results will be communicated at the end of the study. CONCLUSIONS: The HAUSER-RCT study, the largest randomized, placebo-controlled study with proprotein convertase subtilisin/kexin type 9 inhibitors being conducted in the pediatric HeFH population, aims to provide efficacy, safety, and tolerability data of evolocumab as an add-on therapy in these patients.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Heterozigoto , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Segurança , Adolescente , Anticorpos Monoclonais Humanizados , Criança , Feminino , Humanos , Masculino
8.
Curr Cardiol Rep ; 17(9): 629, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26275368

RESUMO

Cardiovascular disease (CVD) is still the most prominent cause of death and morbidity in the world, and one of the major risk factors for developing CVD is hypercholesterolemia. Familial hypercholesterolemia (FH) is a dominantly inherited disorder characterized by markedly elevated plasma low-density lipoprotein cholesterol and premature coronary heart disease. Currently, several treatment options are available for children with FH. Lifestyle adjustments are the first step in treatment. If this is not sufficient, statins are the preferred initial pharmacological therapy and they have been proven effective and safe. However, treatment goals are often not achieved and, hence, there is a need for novel treatment options. Currently, several options are being studied in adults and first results are promising. However, studies in children are still to be awaited.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/terapia , Anamnese/métodos , Comportamento de Redução do Risco , Adolescente , Doenças Cardiovasculares/genética , Criança , Pré-Escolar , Feminino , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/prevenção & controle , Masculino , Países Baixos/epidemiologia , Fenótipo , Fatores de Risco
9.
J Am Soc Nephrol ; 21(8): 1299-308, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20595685

RESUMO

Toll-like receptors (TLRs) can orchestrate an inflammatory response upon activation by pathogen-associated motifs and release of endogenous stress ligands during tissue injury. The kidney constitutively expresses most TLRs, including TLR4. The function of TLR4 during the inflammation, tubular atrophy, and fibrosis that accompany progressive renal injury is unknown. Here, we subjected wild-type (WT) and TLR4-deficient mice to unilateral ureteral obstruction and observed elevated levels of TLR4 mRNA in the kidney after obstruction. One day after unilateral ureteral obstruction, TLR4-deficient mice had fewer proliferating tubular epithelial cells and more tubular damage than WT mice; however, TLR4-deficient mice developed considerably less renal fibrosis despite decreased matrix metalloproteinase activity and without significant differences in myofibroblast accumulation. In vitro, TLR4-deficient primary tubular epithelial cells and myofibroblasts produced significantly less type I collagen mRNA after TGF-beta stimulation than WT cells. The reduced fibrosis in TLR4-deficient mice associated with an upregulation of Bambi, a negative regulator of TGF-beta signaling. In conclusion, TLR4 attenuates tubular damage but promotes renal fibrosis by modulating the susceptibility of renal cells to TGF-beta. These data suggest that TLR4 signaling may be a therapeutic target for the prevention of renal fibrosis.


Assuntos
Rim/patologia , Insuficiência Renal , Receptor 4 Toll-Like/fisiologia , Animais , Progressão da Doença , Fibrose/etiologia , Túbulos Renais/patologia , Camundongos , Insuficiência Renal/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA