RESUMO
BACKGROUND: Autosomal dominant hypercholesterolemia (ADH) is due to deleterious variants in LDLR, APOB, or PCSK9 genes. Double heterozygote for these genes induces a more severe phenotype. More recently, a new causative variant of heterozygous ADH was identified in APOE. Here we study the phenotype of 21 adult patients, double heterozygotes for rare LDLR and rare APOE variants (LDLR+APOE) in a national wide French cohort. METHODS: LDLR, APOB, PCSK9, and APOE genes were sequenced in 5743 probands addressed for ADH genotyping. The lipid profile and occurrence of premature atherosclerotic cardiovascular diseases were compared between the LDLR+APOE carriers (n=21) and the carriers of the same LDLR causative variants alone (n=22). RESULTS: The prevalence of LDLR+APOE carriers in this French ADH cohort is 0.4%. Overall, LDL (low-density lipoprotein)-cholesterol concentrations were 23% higher in LDLR+APOE patients than in LDLR patients (9.14±2.51 versus 7.43±1.59 mmol/L, P=0.0221). When only deleterious or probably deleterious variants were considered, the LDL-cholesterol concentrations were 46% higher in LDLR+APOE carriers than in LDLR carriers (10.83±3.45 versus 7.43±1.59 mmol/L, P=0.0270). Two patients exhibited a homozygous familial hypercholesterolemia phenotype (LDL-cholesterol >13 mmol/L). Premature atherosclerotic cardiovascular disease was more common in LDLR+APOE patients than in LDLR carriers (70% versus 30%, P=0.026). CONCLUSIONS: Although an incomplete penetrance should be taken into account for APOE variant classification, these results suggest an additive effect of deleterious APOE variants on ADH phenotype highlighting the relevance of APOE sequencing.
Assuntos
Aterosclerose , Hiperlipoproteinemia Tipo II , Humanos , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , LDL-Colesterol , Fenótipo , Aterosclerose/epidemiologia , Aterosclerose/genética , Apolipoproteínas B/genética , Apolipoproteínas E/genética , Mutação , HeterozigotoRESUMO
Primary hypercholesterolemia is characterized by elevated LDL-cholesterol (LDL-C) levels isolated in autosomal dominant hypercholesterolemia (ADH) or associated with elevated triglyceride levels in familial combined hyperlipidemia (FCHL). Rare APOE variants are known in ADH and FCHL. We explored the APOE molecular spectrum in a French ADH/FCHL cohort of 5743 unrelated probands. The sequencing of LDLR, PCSK9, APOB, and APOE revealed 76 carriers of a rare APOE variant, with no mutation in LDLR, PCSK9, or APOB. Among the 31 APOE variants identified here, 15 are described in ADH, 10 in FCHL, and 6 in both probands. Five were previously reported with dyslipidemia and 26 are novel, including 12 missense, 5 synonymous, 2 intronic, and 7 variants in regulatory regions. Sixteen variants were predicted as pathogenic or likely pathogenic, and their carriers had significantly lower polygenic risk scores (wPRS) than carriers of predicted benign variants. We observed no correlation between LDL-C levels and wPRS, suggesting a major effect of APOE variants. Carriers of p.Leu167del were associated with a severe phenotype. The analysis of 11 probands suggests that carriers of an APOE variant respond better to statins than carriers of a LDLR mutation. Altogether, we show that the APOE variants account for a significant contribution to ADH and FCHL.
Assuntos
Apolipoproteínas E , Hiperlipoproteinemia Tipo II , Pró-Proteína Convertase 9 , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , LDL-Colesterol/genética , LDL-Colesterol/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/metabolismo , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismoRESUMO
BACKGROUND: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease. METHODS: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of data sets on gene expression and variants in human populations. RESULTS: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR. The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in nontransfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in nonalcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and 3 rare variants of one spliceosome gene, RBM25, are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared with overexpression of wild-type RBM25, overexpression of the 3 rare RBM25 mutants in Huh-7 cells led to lower LDL uptake. CONCLUSIONS: We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.
Assuntos
Proteínas Nucleares/metabolismo , Splicing de RNA , Receptores de LDL/genética , Colesterol/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Lipoproteínas LDL/metabolismo , Fígado/metabolismo , Mutação , Proteínas Nucleares/genética , Receptores de LDL/metabolismo , Spliceossomos/metabolismoRESUMO
BACKGROUND: Familial Hypercholesterolemia (FH) is an underdiagnosed condition with an increased cardiovascular risk. It is unknown whether lipid accumulation plays a role in structural myocardial changes. Cardiovascular Magnetic Resonance (CMR) is the reference technique for the morpho-functional evaluation of heart chambers through cine sequences and for myocardial tissue characterization through late gadolinium enhancement (LGE) and T1 mapping images. We aimed to assess the prevalence of myocardial fibrosis in FH patients. METHODS: Seventy-two asymptomatic subjects with genetically confirmed FH (mean age 49·24, range 40 to 60 years) were prospectively recruited along with 31 controls without dyslipidaemia matched for age, sex, BMI, and other cardiovascular risk factors. All underwent CMR including cine, LGE, pre- and post-contrast T1 mapping. Extracellular volume (ECV) and enhancement rate of the myocardium (ERM = difference between pre- and post-contrast myocardial T1, normalized by pre-contrast myocardial T1) were calculated. FINDINGS: Five FH patients and none of the controls had intramyocardial LGE (p= 0·188). While no changes in Native T1 and ECV were found, post-contrast T1 was significantly lower (430·6 ± 55ms vs. 476·1 ± 43ms, p<0·001) and ERM was higher (57·44± 5·99 % vs 53·04±4·88, p=0·005) in HeFH patients compared to controls. Moreover, low post-contrast T1 was independently associated with the presence of xanthoma (HR 5·221 [1·04-26·28], p= 0·045). A composite score combining the presence of LGE, high native T1 and high ERM (defined as ≥ mean ± 1·5 SD) was found in 20·8% of the HeFH patients vs. 0% in controls (p<0·000, after adjustment for main confounders). INTERPRETATION: CMR revealed early changes in myocardial tissue characteristics in HeFH patients, that should foster further work to better understand and prevent the underlying pathophysiological processes.
Assuntos
Hiperlipoproteinemia Tipo II/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodos , Miocárdio/patologia , Adulto , Estudos de Casos e Controles , Feminino , Fibrose , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Estudos ProspectivosRESUMO
BACKGROUND AND AIMS: Patients with heterozygous familial hypercholesterolemia (HeFH) present elevated cardiovascular (CV) risk. Current CV risk stratification algorithms developed for the general population are not adapted for heFH patients. It is therefore of singular importance to develop and validate CV prediction tools, which are dedicated to the HeFH population. METHODS: Our first objective was to validate the Spanish SAFEHEART-risk equation (RE) in the French HeFH cohort (REFERCHOL), and the second to compare SAFEHEART-RE with the low-density-lipoprotein-cholesterol (LDL-C)-year-score for the prediction of CV events in the HeFH French population. RESULTS: We included HeFH (nâ¯=â¯1473) patients with a genetic or clinical diagnosis (DLCN score ≥8). Among them, 512 patients with a 5-year follow-up were included to validate the 5 year-CV-RE. A total of 152 events (10.3%) occurred in the entire population of 1473 patients during a mean follow-up of 3.9 years. Over the five-year follow-up, non-fatal CV events occurred in 103 patients (20.2%). Almost all the parameters used in the SAFEHEART-RE were confirmed as strong predictors of CV events in the REFERCHOL cohort. The C-statistic revealed a satisfactory performance of both the SAFEHEART-RE and LDL-C-year-scores in predicting CV events for all the patients (primary and secondary prevention) (C-index 0.77 and 0.70, respectively) as well as for those in primary prevention at inclusion (C-index 0.78 and 0.77, respectively). CONCLUSIONS: This analysis represents the first external validation of the SAFEHEART-RE and demonstrated that both SAFEHEART-RE and the LDL-C-year-score are good predictors of CV events in primary prevention HeFH patients.
Assuntos
Doenças Cardiovasculares , Hiperlipoproteinemia Tipo II , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Colesterol , LDL-Colesterol , Estudos de Coortes , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Medição de RiscoRESUMO
Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated LDL-C levels leading to coronary heart disease. Four genes are implicated in ADH: LDLR, APOB, PCSK9 and APOE. Our aim was to identify new mutations in known genes, or in new genes implicated in ADH. Thirteen French families with ADH were recruited and studied by exome sequencing after exclusion, in their probands, of mutations in the LDLR, PCSK9 and APOE genes and fragments of exons 26 and 29 of APOB gene. We identified in one family a p.Arg50Gln mutation in the APOB gene, which occurs in a region not usually associated with ADH. Segregation and in-silico analysis suggested that this mutation is disease causing in the family. We identified in another family with the p.Ala3396Thr mutation of APOB, one patient with a severe phenotype carrying also a mutation in PCSK9: p.Arg96Cys. This is the first compound heterozygote reported with a mutation in APOB and PCSK9. Functional studies proved that the p.Arg96Cys mutation leads to increased LDL receptor degradation. This work shows that Next-Generation Sequencing (exome, genome or targeted sequencing) are powerful tools to find new mutations and identify compound heterozygotes, which will lead to better diagnosis and treatment of ADH.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Hiperlipoproteinemia Tipo II/genética , Mutação/genética , Apolipoproteínas B/genética , Segregação de Cromossomos/genética , Família , Feminino , Células HEK293 , Heterozigoto , Humanos , Masculino , Linhagem , Pró-Proteína Convertase 9/genéticaRESUMO
BACKGROUND: The identification of high-risk patients with heterozygous familial hypercholesterolemia (HeFH) that may benefit from early treatment is challenging. Coronary Artery Calcification (CAC) score accounts for coronary atherosclerotic burden. It has proven its accuracy in cardiovascular risk assessment in the general population but data in HeFH are lacking. OBJECTIVE: The aim of our study was to assess CAC prevalence and its relationship with lifelong cholesterol exposure, calculated by total cholesterol burden (TCB) in patients with HeFH. METHODS: A total of 112 HeFH patients (50% males, median age 45 years) regularly followed-up since diagnosis were prospectively recruited at Pitié-Salpêtrière Hospital, Paris, France. CAC score was assessed using noncontrast multi-detector computed tomography. TCB was calculated as total cholesterol (TC) × age at diagnosis plus annually assessed TC. RESULTS: The prevalence of CAC was 58%. Patients without CAC showed lower TCB than patients with CAC (298 ± 110 vs 417.9 ± 89 mmol-years/L, P < .001). Among patients aged <45 years (n = 56), 39% exhibited CAC and a higher TCB compared with patients without CAC (352 ± 71 vs 255 ± 88 mmol-years/L, P < .001) due to higher TC levels at diagnosis (10.2 ± 2 vs 8.7 ± 2 mmol/L, P = .01). Multivariate analysis indicated that TCB was independently associated to CAC. CONCLUSIONS: Asymptomatic HeFH subjects exhibit early coronary atherosclerosis directly associated with TCB burden. CAC score may be useful to identify higher risk HeFH patients who can benefit from earlier and more aggressive treatment.
Assuntos
Calcinose/complicações , Colesterol/metabolismo , Doença da Artéria Coronariana/complicações , Heterozigoto , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/metabolismo , Adulto , Feminino , Humanos , Hiperlipoproteinemia Tipo II/genética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited condition characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels, severe, accelerated atherosclerosis and premature coronary heart disease. We evaluated cardiovascular complications in HoFH patients over extended follow-up and investigated their association with changes in cholesterol over time, as well as total cholesterol burden. METHODS: In this retrospective single-centre study, 53 patients (baseline mean ± standard deviation [SD], total cholesterol 15.5 ± 3.7 mmol/L and LDL-C 13.2 ± 2.6 mmol/L) were followed for up to 38 years (21.2 ± 10 years). The primary outcome was an adverse clinical event, defined as cardiovascular death, nonfatal myocardial infarction, or angina. RESULTS: Twenty-eight patients experienced an event, of whom 8 died due to complications of major surgery (4), myocardial infarction (3) or stroke (1). While total cholesterol levels were comparable in patients with and without an event at baseline (20 mmol/L), those who subsequently experienced an event showed a slower decline in total cholesterol. Cumulative total cholesterol (i.e. total-cholesterol year score) was highly associated with the incidence of an adverse clinical event in a linear dose-response relation. A 100 mmol/L increase in cumulative total cholesterol (i.e. an average exposure of 10 mmol/L per 10 years or 20 mmol/L per 5 years) was associated with a doubling of the risk of a cardiovascular event (age-adjusted incidence rate ratio: 1.99, 95% CI, 1.16-3.41). CONCLUSIONS: Our findings reinforce the importance of early diagnosis and initiation of maximal treatment, including lipoprotein apheresis, to ensure long-term reduction in the cholesterol burden, expressed as the total-cholesterol year score, and risk of cardiovascular complications in HoFH.
Assuntos
Anticolesterolemiantes/uso terapêutico , Remoção de Componentes Sanguíneos , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Homozigoto , Hiperlipoproteinemia Tipo II/terapia , Mutação , Receptores de LDL/genética , Adolescente , Angina Pectoris/genética , Angina Pectoris/prevenção & controle , Biomarcadores/sangue , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/mortalidade , Criança , Pré-Escolar , Análise Mutacional de DNA , Intervalo Livre de Doença , Diagnóstico Precoce , Feminino , França , Predisposição Genética para Doença , Hereditariedade , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/mortalidade , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Infarto do Miocárdio/genética , Infarto do Miocárdio/prevenção & controle , Linhagem , Fenótipo , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Heterozygous familial hypercholesterolemia (heFH) is a genetic disease causing high levels of low-density lipoprotein cholesterol (LDL-C). Although this population is at high cardiovascular (CV) risk, the risk is variable within patients depending on additional risk factors. CV disease risk groups have been defined by the Nouvelle Société Francophone d'Athérosclérose (NSFA) and by the National Lipid Association recommendations. OBJECTIVES: The study aimed to describe a sample of French heFH patients, comparing patients at very high risk (VHR) and patients at high risk in terms of demographic and clinical characteristics as well as biological measurements and disease management. METHODS: Cross-sectional retrospective analysis on 734 patients hospitalized after 2005 in 5 academic centers. RESULTS: When considering NSFA classification, 550 (74.9%) patients belonged to the VHR group. Most patients in the VHR group presented more than 1 risk factor, the most prevalent ones being Lp(a) > 50 mg/dL and smoking. Patients in the VHR group were older (50.6 vs 45.0 years old, P = .0002), and presented a higher body mass index (25.5 kg/m(2) vs 23.3 kg/m(2), P < .0001). The proportion of patients with carotid arterial plaque was higher in the VHR group (59.8% vs 48.6%, P = .06). Total cholesterol (2.41 g/L on average) and LDL-C (1.65 g/L on average) were not found to be significantly different. Maximum level of lipid-lowering treatments were used in 34% of cases in the VHR group, significantly higher than 16% in the high-risk group (P = .001). Very similar results were found when using the National Lipid Association recommendations. CONCLUSION: This study provides a detailed description of French heFH patients according to their CV risk. Patients with very high CV risk had usually more advanced carotid plaques and were treated with heavier lipid-lowering drugs although their LDL-C level remained similar. This highlights the significant burden of this population.
Assuntos
Doenças Cardiovasculares/etiologia , Hiperlipoproteinemia Tipo II/patologia , Adulto , Idoso , Anticolesterolemiantes/uso terapêutico , Índice de Massa Corporal , Doenças Cardiovasculares/epidemiologia , Artérias Carótidas/fisiopatologia , Colesterol/sangue , LDL-Colesterol/sangue , Estudos Transversais , Feminino , França/epidemiologia , Humanos , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. METHODS AND RESULTS: We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). CONCLUSIONS: PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.
Assuntos
Anticorpos Monoclonais/administração & dosagem , LDL-Colesterol/sangue , Doença da Artéria Coronariana , Hiperlipoproteinemia Tipo II , Mutação , Pró-Proteína Convertases , Serina Endopeptidases , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Método Duplo-Cego , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/antagonistas & inibidores , Pró-Proteína Convertases/genética , Pró-Proteína Convertases/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismoRESUMO
BACKGROUND: The identification of mutations in PCSK9 (proprotein convertase subtilisin kexin9) in autosomal dominant hypercholesterolemia (ADH), has revealed the existence of a new player in cholesterol homeostasis. PCSK9 has been shown to enhance the degradation of the LDL receptor (LDLR) at the cell surface. Gain-of-function mutations of PCSK9 induce ADH and are very rare, but their identification is crucial in studying PCSK9's role in hypercholesterolemia, its detailed trafficking pathway and its impact on the LDLR. METHODS: In order to identify new mutations and understand the exact mechanisms of action of mutated PCSK9, PCSK9 was sequenced in 75 ADH patients with no mutations in the LDLR or APOB genes. Functional analyses in cell culture were conducted and the impact of novel PCSK9 mutations on the quantitative and qualitative features of lipoprotein particles and on the HDL-mediated cellular cholesterol efflux was studied. RESULTS: Among these 75 ADH probands with no mutations in the LDLR or APOB genes, four gain-of-function mutations of PCSK9 were identified, of which two were novel: the p.Leu108Arg and the p.Asp35Tyr substitutions. In vitro studies of their consequences on the activity of PCSK9 on cell surface levels of LDLR showed that the p.Leu108Arg mutation clearly results in a gain-of-function, while the p.Asp35Tyr mutation created a novel Tyr-sulfation site, which may enhance the intracellular activity of PCSK9. CONCLUSION: These data further contribute to the characterization of PCSK9 mutations and to better understanding of the impact on cholesterol metabolism of this new therapeutic target.
Assuntos
Hiperlipoproteinemia Tipo II/genética , Mutação , Pró-Proteína Convertases/genética , Serina Endopeptidases/genética , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Biomarcadores/sangue , HDL-Colesterol/sangue , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Células HEK293 , Células Hep G2 , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/metabolismo , Masculino , Paris , Linhagem , Fenótipo , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Serina Endopeptidases/metabolismo , TransfecçãoRESUMO
BACKGROUND: Early identification of children with familial hypercholesterolemia (FH) makes it possible to start lipid-lowering therapy at a young age in order to prevent cardiovascular disease. Numerous randomized, often placebo-controlled, studies have assessed the efficacy and safety of statins in children with FH. OBJECTIVE: The aim of this pragmatic observational study was to evaluate pravastatin treatment efficacy and tolerability for a long period of time, and to assess how these results translate in 'real-life' clinical practice. METHODS: We analyzed all medical files of young hypercholesterolemic patients referred to two specialized French centers. This population of 185 pravastatin-treated children with FH, with a mean baseline cholesterol level above 300 mg/dL, in most of whom genetic diagnosis was achieved, was followed-up for a mean duration of 2 years 2 months. The mean age for starting pravastatin was 11 years; in one of five children, treatment was started before the age of 8 years, mostly because of severe hypercholesterolemia or a family history of coronary heart disease. RESULTS: A 16.9-19.2% decrease in total cholesterol level (21-24% for low-density lipoprotein cholesterol) was observed. Growth and puberty were not affected by statin treatment. A review of the medical files showed that 13% of children had side effects, most of which were minor; four of these children had muscular symptoms possibly related to the treatment. This frequency is lower than that observed in adults, and comparable to other studies in children. CONCLUSIONS: In this large cohort of FH children, the efficacy and tolerability of pravastatin therapy in real-life conditions was demonstrated to be similar to that in randomized controlled studies.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pravastatina/uso terapêutico , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , França , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hiperlipoproteinemia Tipo II/fisiopatologia , Masculino , Pravastatina/efeitos adversos , Índice de Gravidade de Doença , Fatores de Tempo , Adulto JovemRESUMO
Autosomal Dominant Hypercholesterolemia (ADH), characterized by isolated elevation of plasmatic LDL cholesterol and premature cardiovascular complications, is associated with mutations in 3 major genes: LDLR (LDL receptor), APOB (apolipoprotein B) and PCSK9(proprotein convertase subtilisin-kexin type 9). Through the French ADH Research Network, we collected molecular data from 1358 French probands from eleven different regions in France.Mutations in the LDLR gene were identified in 1003 subjects representing 391 unique events with 46.0% missense, 14.6% frameshift, 13.6% splice, and 11.3% nonsense mutations, 9.7% major rearrangements, 3.8% small in frame deletions/insertions, and 1.0% UTR mutations. Interestingly,175 are novel mutational events and represent 45% of the unique events we identified, highlighting a specificity of the LDLR mutation spectrum in France. Furthermore, mutations in the APOB gene were identified in 89 probands and in the PCSK9 gene in 10 probands. Comparison of available clinical and biochemical data showed a gradient of severity for ADH-causing mutations:FH=PCSK9>FDB>«Others¼ genes. The respective contribution of each known gene to ADH inthis French cohort is: LDLR 73.9%, APOB 6.6%, PCSK9 0.7%. Finally, in 19.0% of the probands,no mutation was found, thus underscoring the existence of ADH mutations located in still unknown genes.
Assuntos
Hiperlipoproteinemia Tipo II/genética , Mutação , Apolipoproteínas B/genética , Colesterol/sangue , Estudos de Coortes , Análise Mutacional de DNA , Feminino , França , Variação Genética , Humanos , Hiperlipoproteinemia Tipo II/sangue , Masculino , Pró-Proteína Convertase 9 , Pró-Proteína Convertases , Receptores de LDL/química , Receptores de LDL/genética , Serina Endopeptidases/genéticaRESUMO
Overt hypothyroidism is associated with an increased prevalence of cardiovascular heart disease (CHD). The role of subclinical hypothyroidism as risk factor for cardiovascular diseases is supported by recent meta-analysis. However it still remains to be established whether hypothyroidism favors atherosclerosis independently of its effects on cardiovascular risk factors, such as hypercholesterolemia or hypertension. To assess whether hypothyroidism might be a risk factor per se, we analyzed carotid lesions assessed by US examination in two large populations with similar risk factors and displaying hypo- or euthyroidism. We selected, among a population of patients referred for assessment of hyperlipidemia, 794 hypothyroid patients (TSH>4mU/L), and 1588 euthyroid patients matched for the main cardiovascular risk factors (age, gender, lipid levels, hypertension, diabetes, smoking habits and obesity). All the patients had evaluation of their arterial carotid plaques, and about half of them had measurement of carotid intima-media thickness (IMT). Our hypothyroid population included 90% of patients with normal FT4 levels (subclinical hypothyroidism). We found that neither prevalence nor severity of carotid plaques nor carotid IMT were significantly different between hypothyroid patients and controls. To assess whether thyroid hormones may predict carotid atherosclerosis, we performed multivariate regression analyses, and we showed that, in both populations of hypothyroid and euthyroid patients, neither the TSH values nor the FT4 concentrations were independent risk factors for carotid atherosclerosis. In conclusion, we showed that, among a population of hyperlipidemic patients, hypothyroidism is not associated with an increased risk for carotid atherosclerosis when cardiovascular risk factors are accounted for.
Assuntos
Doenças Cardiovasculares/diagnóstico , Doenças das Artérias Carótidas/complicações , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Hipotireoidismo/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de RiscoRESUMO
OBJECTIVE: To describe the cardiovascular morbidity and mortality and associated risk factors of a population of patients with dyslipidemia seen ten years earlier for a cardiovascular risk assessment in the endocrinology department of a French hospital. METHODS: Patients seen for a cardiovascular risk assessment between 1988 and 1992 were re-examined in the department, or contacted by mail or their vital status (and cause of death, if any) was obtained from the INSERM Cepi-Dc database. RESULTS: Vital status was available for 89.7% of the patients. The standard risk factors associated with cardiovascular mortality were found in the patients who died of these causes, that is, age, sex, smoking, diabetes, total cholesterol, and previous vascular status. After adjustment for risk factors, myocardial infarction was significantly associated with age, sex and total cholesterol in patients who received primary prevention care. CONCLUSION: This study showed the feasibility of tracing a cohort of dyslipidemic patients with cardiovascular risk factors seen in an endocrinology department. It enabled a pragmatic assessment of a specific at-risk French population and a description of the compliant and noncompliant patients.