RESUMEN
The validation of the use of plasma plant sterols as a marker of cholesterol absorption is frail. Nevertheless, plant sterol concentrations are routinely used to describe treatment-induced changes in cholesterol absorption. Their use has also been advocated as a clinical tool to tailor cholesterol-lowering therapy. Prior to wider implementation, however, the validity of plant sterols as absorption markers needs solid evaluation. Therefore, we compared plasma plant sterol concentrations to gold-standard stable isotope-determined cholesterol absorption. Plasma campesterol/TC concentrations (camp/TC) were measured in a population of 175 mildly hypercholesterolemic individuals (age: 59.7 ± 5.6 years; BMI: 25.5 ± 2.9 kg/m(2); LDL-C: 4.01 ± 0.56 mmol/l). We compared cholesterol absorption according to the plasma dual-isotope method in subjects with the highest camp/TC concentrations (N = 41, camp/TC: 2.14 ± 0.68 µg/mg) and the lowest camp/TC concentrations (N = 39, camp/TC: 0.97 ± 0.22 µg/mg). Fractional cholesterol absorption did not differ between the groups (24 ± 12% versus 25 ± 16%, P = 0.60), nor was it associated with plasma camp/TC concentrations in the total population of 80 individuals (ß = 0.13; P = 0.30, adjusted for BMI and plasma triglycerides). Our findings do not support a relation between plasma plant sterol concentrations and true cholesterol absorption and, therefore, do not favor the use of these sterols as markers of cholesterol absorption. This bears direct consequences for the interpretation of earlier studies, as well as for future studies targeting intestinal regulation of cholesterol metabolism.
Asunto(s)
Colesterol/sangre , Fitosteroles/sangre , Colesterol/análogos & derivados , Estudios Transversales , Femenino , Humanos , Absorción Intestinal/fisiología , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
Low levels of statin adherence may compromise treatment outcomes. The aim of this study was to investigate whether nurse-led cardiovascular risk-factor counseling could improve statin adherence and lipid levels without increasing patients' anxiety. Patients with indications for statin therapy for primary or secondary prevention of cardiovascular disease were randomly assigned to receive routine care or extended care (EC) at baseline and at months 3, 9, and 18. Patients in the EC group received a personalized risk-factor passport, showing modifiable and unmodifiable individual risk factors and a graphical presentation of their calculated absolute 10-year cardiovascular disease risk as well as the target risk that could be reached if all modifiable risk factors were optimally treated. Lipid levels were assessed at each visit. Carotid intima-media thickness was measured at baseline and at month 18. Adherence, anxiety, quality of life, symptoms, and smoking status were assessed using a self-administered questionnaire at each visit. A total of 201 patients were included in the study. Statin adherence was significantly higher (p <0.01) and anxiety was significantly lower (p <0.01) in the EC group than in the routine care group. Low-density lipoprotein cholesterol was statistically significantly lower in the EC group than in the routine group (2.66 vs 3.00 mmol/L, respectively, p = 0.024) in primary prevention patients only. Intima-media thickness improved significantly from baseline (p <0.01) in all patients, irrespective of group assignment. In conclusion, cardiovascular risk-factor counseling resulted in improved lipid profiles in primary prevention patients and higher levels of adherence to statins and lower levels of anxiety in all patients.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/enfermería , Cumplimiento de la Medicación/estadística & datos numéricos , Enfermedades Cardiovasculares/etiología , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Hiperlipidemias/complicaciones , Hiperlipidemias/diagnóstico , Masculino , Persona de Mediana Edad , Países Bajos , Rol de la Enfermera , Atención al Paciente/métodos , Prevención Primaria/métodos , Mejoramiento de la Calidad , Valores de Referencia , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Screening for familial hypercholesterolemia (FH) within affected families is often based on cutoff values for low-density lipoprotein cholesterol (LDL-C). However, the diagnostic accuracy of LDL-C levels is influenced by the magnitude of the LDL-C overlap between FH patients and unaffected relatives. The purpose of the current study was to assess to what extent this overlap is influenced by the severity of specific FH mutations. METHODS AND RESULTS: Individuals were eligible if they underwent family screening for FH between 2003 and 2010. The entire cohort was then compared with those who were investigated for the presence of the most severe mutations (class 1). The area under the receiver operating characteristics curve and the sensitivity of the 90th percentile of LDL-C were calculated for both cohorts. We included 26 406 individuals, of whom 9169 (35%) carried an FH-causing mutation. In the entire cohort at baseline, mean LDL-C was 4.63 ± 1.44 mmol/L for FH carriers (n=5372) and 2.96 ± 0.96 mmol/L for unaffected relatives (n=15 148); P<0.001. The corresponding operating characteristics curve (95% CI) was 86.6% (85.9%-87.2%), and the cutoff level of LDL-C above the 90th percentile showed a sensitivity of 68.5%. The operating characteristics curve and sensitivity significantly improved when the 5933 individuals tested for class 1 mutations were assessed separately; 96.2% (95.3%-97.1%) and 91.3%, respectively. CONCLUSIONS: In summary, the overlap in terms of LDL-C levels between those with molecularly proven FH and unaffected relatives is to a large extent because of the high prevalence of modestly severe LDL-receptor mutations in the Netherlands.
Asunto(s)
LDL-Colesterol/sangre , Hiperlipoproteinemia Tipo II/genética , Adulto , Área Bajo la Curva , Estudios de Cohortes , Estudios Transversales , Análisis Discriminante , Femenino , Genotipo , Humanos , Hiperlipoproteinemia Tipo II/epidemiología , Masculino , Persona de Mediana Edad , Mutación , Prevalencia , Curva ROC , Receptores de LDL/genéticaRESUMEN
A decade ago, in the initial stage of genetic testing for familial hypercholesterolaemia (FH) in The Netherlands, it was reported that such screening decreased access to affordable life insurance for mutation carriers. In 2003, in order to improve access to insurance for FH mutation carriers, insurers agreed to underwrite according to a set of guidelines. In this cross-sectional study, we assessed whether access to insurance has improved since the advent of these guidelines. We approached 2825 subjects that had participated in the genetic testing for FH between 1998 and 2003. We compared unconditional acceptance rates before and after FH diagnosis and before and after the guidelines were issued by means of logistic regression analysis. Our study outcome pertains to 414 FH patients who applied for life insurance. Unconditional acceptance of a policy before DNA diagnosis and before the issue of guidelines occurred in 182 out of 255 (71%) cases, versus 27 out of 35 (77%) cases after DNA diagnosis, but before the issue of guidelines. De facto, 107 out of 124 (86%) patients received unconditional acceptance after DNA diagnosis and after the issue of guidelines (P for trend=0.002). Access to life insurance improved for FH patients after molecular diagnosis and it improved even further after the guidelines were issued. Therefore, we argue that limited access to life insurance on the basis of 'DNA discrimination' is no longer a valid argument against genetic cascade testing for FH, at least not in our country.
Asunto(s)
Accesibilidad a los Servicios de Salud/economía , Hiperlipoproteinemia Tipo II/diagnóstico , Seguro de Vida/estadística & datos numéricos , Adolescente , Adulto , Estudios Transversales , Femenino , Pruebas Genéticas/economía , Genoma Humano , Guías como Asunto , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Humanos , Hiperlipoproteinemia Tipo II/economía , Hiperlipoproteinemia Tipo II/genética , Modelos Logísticos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECTIVE: To assess the follow-up of children diagnosed as having familial hypercholesterolemia (FH) in the nationwide DNA-based cascade screening program (the Netherlands). STUDY DESIGN: Questionnaires covering topics such as demographics, family history, physician consultation, and treatment were sent to parents of patients with FH (age 0-18 years), 18 months after diagnosis. RESULTS: We retrieved 207 questionnaires of patients aged 10.9 ± 4.2 years (mean ± SD) at diagnosis; 48% were boys, and the mean low-density lipoprotein cholesterol (LDL-C) level at diagnosis was 167 ± 51 mg/dL. Of these patients, 164 (79%) consulted a physician: a general practitioner (35%), lipid-clinic specialist (27%), pediatrician (21%), internist (11%), or another physician (6%). LDL-C level at diagnosis and a positive family history for cardiovascular disease were independent predictors for physician consultation. Of the patients who visited a physician, 62% reported to have received lifestyle advice, and 43 (26%) were prescribed statin treatment. Independent predictors for medication use were age, LDL-C level, and educational level of parents. CONCLUSION: The follow-up of children with FH after diagnosis established through cascade screening is inadequate. Better education of patients, parents, and physicians, with a structured follow-up after screening, should improve control of LDL-C levels and hence cardiovascular risk in children with FH.
Asunto(s)
Pruebas Genéticas , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/terapia , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Hipercolesterolemia/genética , Lactante , MasculinoRESUMEN
BACKGROUND: Genetic cascade screening for heterozygous familial hypercholesterolemia (FH) revealed that 15% of individuals given this diagnosis do not exhibit elevated low-density lipoprotein cholesterol (LDL-C) levels. We assessed whether cardiovascular risk for these individuals differs from that of hypercholesterolemic FH heterozygotes and unaffected relatives. METHODS AND RESULTS: Individuals aged 18 to 55 years were recruited within 18 months after genetic screening. Three groups were studied: subjects given a molecular diagnosis of FH and with LDL-C levels at genetic screening below the 75th percentile (FH-low), subjects with FH and an LDL-C level above the 90th percentile (FH-high), and subjects without FH (no-FH). We measured carotid intima-media thickness (IMT) by ultrasonography. Differences in carotid IMT among the groups were assessed using multivariate linear regression analyses. Mean carotid IMT of 114 subjects in the FH-low group (0.623 mm; 95% CI, 0.609 to 0.638 mm) was significantly smaller than that of 162 subjects in the FH-high group (0.664 mm; 95% CI, 0.648 to 0.679 mm; P<0.001) and did not significantly differ from the mean carotid IMT in 145 subjects in the no-FH group (0.628 mm; 95% CI, 0.613 to 0.642 mm; P=0.67). CONCLUSIONS: Our findings suggest that the risk of cardiovascular disease in patients with FH to a large extent is related to LDL-C levels and not to the presence of a mutation per se. Consequently, this study cautiously suggests that individuals with an FH genotype without expression of hypercholesterolemia may not require a pharmaceutical intervention that is as aggressive as the standard for subjects with FH.
Asunto(s)
Apolipoproteínas B/genética , Enfermedades de las Arterias Carótidas/diagnóstico , Colesterol/sangre , Mutación , Receptores de LDL/genética , Adolescente , Adulto , Enfermedades Cardiovasculares/etiología , Grosor Intima-Media Carotídeo , LDL-Colesterol/sangre , Estudios Transversales , Femenino , Humanos , Hiperlipoproteinemia Tipo II , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease. Mutations in the genes encoding for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) underlie ADH. Nevertheless, a proportion of individuals who exhibit the ADH phenotype do not carry mutations in any of these 3 genes. Estimates of the percentage of such cases among the ADH phenotype vary widely. We therefore investigated a large pediatric population with an unequivocal ADH phenotype to assess the molecular basis of hereditary hypercholesterolemia and to define the percentage of individuals with unexplained dyslipidemia. METHODS AND RESULTS: We enrolled individuals with low-density lipoprotein cholesterol levels above the 95th percentile for age and gender and an autosomal dominant inheritance pattern of hypercholesterolemia from a large referred pediatric cohort of 1430 children. We excluded children with thyroid dysfunction, nephrotic syndrome, autoimmune disease, liver disease, primary biliary cirrhosis, and obesity (body mass index >75th percentile for age and gender), as well as children referred via a cascade screening program and those from families with a known molecular diagnosis. Of the 269 children who remained after the exclusion criteria were applied, 255 (95%) carried a functional mutation (LDLR, 95%; APOB, 5%). CONCLUSION: In the vast majority of children with an ADH phenotype, a causative mutation can be identified, strongly suggesting that most of the large-effect genes underlying ADH are known to date.
Asunto(s)
Hiperlipoproteinemia Tipo II/genética , Adolescente , Apolipoproteínas B/sangre , Apolipoproteínas B/genética , Niño , Preescolar , LDL-Colesterol/sangre , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Mutación , Fenotipo , Receptores de LDL/genéticaRESUMEN
BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an independent risk factor of cardiovascular disease and a target of treatment. Lp-PLA(2) levels in children have not been previously reported. The effect of statin therapy on Lp-PLA(2) mass and activity in children with familial hypercholesterolemia (FH) is also not known. METHODS: Lp-PLA(2) mass and activity levels were measured at baseline and after 2 years in 178 children with FH randomized to pravastatin or placebo and in 78 unaffected and untreated siblings. At the end of the randomized period, all FH children were then placed on pravastatin for an additional 2 years, and Lp-PLA(2) mass and activity levels were correlated with changes in carotid intima-media thickness during 4 years of follow-up. RESULTS: Baseline levels of Lp-PLA(2) mass and activity were significantly greater in children with FH compared with unaffected siblings (mass: 240.3 ± 41.6 vs 222.1 ± 36.5 ng/mL, P = .002; activity: 205.7 ± 41.6 vs 124.3±23.0 nmol/min/mL, P < .0001). In the randomized FH cohort, after 2 years treatment, Lp-PLA(2) mass (217.8 ± 35.0 vs 231.5 ± 34.8 ng/mL, P = .001) and activity (178.8 ± 37.3 vs 206.2 ± 33.5 nmol/min/mL, P < .0001) were significantly reduced by pravastatin compared with placebo. Change in Lp-PLA(2) activity was related to change in low-density lipoprotein cholesterol (pravastatin: r = 0.53, P < .0001, placebo: r = 0.23, P < .001) but change in Lp-PLA(2) mass was not related to change in low-density lipoprotein cholesterol. Baseline levels of Lp-PLA(2) mass and activity were not significantly associated with carotid intima-media thickness at baseline or at 4 years. CONCLUSION: Lp-PLA(2) mass and activity are significantly elevated in children with heterozygous FH compared with unaffected siblings and are significantly reduced by pravastatin therapy.
Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Pravastatina/uso terapéutico , Adolescente , Arterias Carótidas/patología , Estudios de Casos y Controles , Niño , Método Doble Ciego , Pruebas de Enzimas , Estudios de Seguimiento , Heterocigoto , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/genética , Hermanos , Túnica Íntima/patologíaRESUMEN
OBJECTIVE: It is unknown whether elevated maternal low-density lipoprotein cholesterol (LDL-C) levels lead to dyslipidemia in the offspring. Because this could have important consequences for cardiovascular prevention in mother and child, we explored the relationship between maternal familial hypercholesterolemia (FH) and lipids in adult offspring. METHODS AND RESULTS: In a large cohort of both Dutch and Canadian origin, we compared lipid profiles between patients, aged 18 to 85 years, who inherited FH maternally (n=1069) and those who inherited FH paternally (n=1270). This relationship was evaluated using multivariate regression analyses. Levels of total cholesterol (TC), LDL-C, and apolipoprotein B 100 (ApoB100) were significantly elevated in patients who inherited FH maternally compared with patients who inherited FH paternally (adjusted differences in TC: 0.156 mmol/L, P=0.037; LDL-C: 0.187 mmol/L, P=0.012; ApoB: 0.064 g/L, P=0.022). CONCLUSIONS: Our data show that maternal hereditary hypercholesterolemia slightly increases TC, LDL-C, and ApoB levels in their offspring later in life. Although the molecular mechanisms underlying these observations still require elucidation, our data suggest that maternal hypercholesterolemia during pregnancy may program lipid metabolism to a certain extent in the fetus.
Asunto(s)
Hiperlipoproteinemia Tipo II/genética , Metabolismo de los Lípidos/genética , Efectos Tardíos de la Exposición Prenatal/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteínas B/sangre , Biomarcadores/sangre , Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Hiperlipoproteinemia Tipo II/sangre , Masculino , Persona de Mediana Edad , Países Bajos , Linaje , Fenotipo , Embarazo , Quebec , Análisis de Regresión , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Regulación hacia Arriba , Adulto JovenRESUMEN
Ezetimibe stimulates faecal neutral sterol (FNS) excretion in mice, which cannot be explained by cholesterol absorption inhibition alone. We investigated whether these effects are mediated via the sterol exporter ATP binding cassette transporter G8 (abcg8). Ezetimibe increased FNS excretion 2.7-fold in WT mice and 1.5-fold in abcg8(-/-) mice, without affecting biliary cholesterol secretion. Daily FNS excretion exceeded the sum of dietary cholesterol intake and biliary secretion by about 60%. Ezetimibe enhanced this 'extra' FNS excretion by 3.5-fold and 1.5-fold in wildtype (WT) and abcg8(-/-) mice, respectively. Ezetimibe stimulates fecal sterol excretion of non-biliary and non-dietary origin, probably through stimulation of trans-intestinal cholesterol excretion. We show that this effect depends on intact abcg8 function.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Azetidinas/farmacología , Lipoproteínas/metabolismo , Esteroles/metabolismo , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8 , Transportadoras de Casetes de Unión a ATP/genética , Animales , Bilis/metabolismo , Transporte Biológico Activo/efectos de los fármacos , Colesterol/metabolismo , Ezetimiba , Heces/química , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Lipoproteínas/deficiencia , Lipoproteínas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Genetic variation at the ABCG5/G8 locus has been associated with markers of cholesterol homeostasis. As data originate from small-scale studies, we performed a meta-analysis to study these associations in a large dataset. We first investigated associations between five common ABCG5/G8 polymorphisms (p.Q604E, p.D19H, p.Y54C, p.T400K, and p.A632V) and plasma sterol levels in 245 hypercholesterolaemic individuals. No significant associations were found. Subsequently, our data were pooled into a meta-analysis that comprised 3,364 subjects from 16 studies (weighted mean age, 46.7 ± 10.5 years; BMI, 23.9 ± 3.5 kg/m(2)). Presence of the minor 632V allele correlated with reduced LDL-C concentrations (n = 367) compared with homozygosity for the 632A variant [n = 614; -0.11 mmol/l (95% CI, range: -0.20 to -0.02 mmol/l); P = 0.01]. The remaining polymorphisms were not associated with plasma lipid levels. Carriers of the 19H allele exhibited lower campesterol/TC (n = 83; P < 0.001), sitosterol/TC (P < 0.00001), and cholestanol/TC (P < 0.00001), and increased lathosterol/TC ratios (P = 0.001) compared with homozygous 19D allele carriers (n = 591). The ABCG8 632V variant was associated with a clinically irrelevant LDL-C reduction, whereas the 19H allele correlated with decreased cholesterol absorption and increased synthesis without affecting the lipid profile. Hence, associations between frequently studied missense ABCG5/G8 polymorphisms and markers of cholesterol homeostasis are modest at best.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Colesterol/sangre , Lipoproteínas/genética , Polimorfismo Genético , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5 , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8 , Transportadoras de Casetes de Unión a ATP/metabolismo , Adulto , Colesterol/genética , Genotipo , Humanos , Hipercolesterolemia/genética , Lipoproteínas/metabolismo , Persona de Mediana EdadRESUMEN
Patients with familial hypercholesterolemia (FH) have elevated LDL-C levels, usually above the 90th percentile (P90) for age and gender. However, large-scale genetic cascade screening for FH showed that 15% of the LDL-receptor (LDLR) or Apolipoprotein B (APOB) mutation carriers have LDL-C levels below P75. Nonpathogenicity of sequence changes may explain this phenomenon. To assess pathogenicity of a mutation we proposed three criteria: (1) mean LDL-C 4P75 in untreated mutation carriers; (2) higher mean LDL-C level in untreated carriers than in untreated noncarriers; and (3) higher percentage of medication users in carriers than in noncarriers at screening. We considered a mutation nonpathogenic when none of the three criteria were met. We applied these criteria to mutations that had been determined in more than 50 untreated adults. Segregation analysis was performed to confirm nonpathogenicity. Forty-six mutations had been tested in more than 50 untreated subjects, and three were nonpathogenic according to our criteria: one in LDLR (c.108C4A, exon 2) and two in APOB (c.13154T4C and c.13181T4C, both in exon 29). Segregation analysis also indicated nonpathogenicity. According to our criteria, three sequence variants were nonpathogenic. The criteria may help to identify nonpathogenic sequence changes in genetic cascade screening programs.
Asunto(s)
Apolipoproteínas B/genética , Hiperlipoproteinemia Tipo II/genética , Mutación , Receptores de LDL/genética , Adulto , Anciano , LDL-Colesterol/sangre , Estudios de Cohortes , Femenino , Pruebas Genéticas , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/diagnóstico , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
IMPORTANCE OF THE FIELD: Atherosclerosis, the condition underlying cardiovascular disease (CVD), often begins in childhood. A disturbance in lipoprotein metabolism is one of the major modifiable risk factors for the development of atherosclerosis and ensuing CVD. Therefore, strategies to prevent CVD should be implemented at an early age, especially in populations at high risk. AREAS COVERED IN THIS REVIEW: We discuss the current treatment options for a number of primary and secondary dyslipidaemias. A literature search was done using PubMed, and references from 1973 to 2009 are cited. WHAT THE READER WILL GAIN: The reader will gain a comprehensive review on pharmacological and non-pharmacological treatment options for primary and secondary dyslipidaemia in childhood. TAKE HOME MESSAGE: Dyslipidaemia may require early diagnosis and management, especially when it is familial with elevated cholesterol levels from birth onwards. If target goals for low-density lipoprotein reduction cannot be reached with lifestyle modification, drug therapy can be considered.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Dislipidemias/terapia , Hipolipemiantes/uso terapéutico , Adolescente , Aterosclerosis/etiología , Aterosclerosis/prevención & control , Enfermedades Cardiovasculares/etiología , Niño , Preescolar , LDL-Colesterol/sangre , Dislipidemias/complicaciones , Dislipidemias/diagnóstico , Humanos , Lactante , Estilo de Vida , Guías de Práctica Clínica como Asunto , Factores de RiesgoRESUMEN
BACKGROUND: The risk of premature cardiovascular disease in patients with familial hypercholesterolemia (FH) can be profoundly reduced by cholesterol-lowering therapy, and current guidelines for FH advocate ambitious low-density lipoprotein cholesterol (LDL-C) goals. In the present study, we determined whether these goals are reflected in current clinical practice once FH has been diagnosed. METHODOLOGY/PRINCIPAL FINDINGS: In 2008, we sent questionnaires to all subjects (aged 18-65 years) who were molecularly diagnosed with FH in the year 2006 through the screening program in The Netherlands. Of these 1062 subjects, 781 completed the questionnaire (46% males; mean age: 42+/-12 years; mean LDL-C at molecular diagnosis (baseline): 4.1+/-1.3 mmol/L). The number of persons that used cholesterol-lowering therapy increased from 397 (51%) at baseline to 636 (81%) after diagnosis. Mean treated LDL-C levels decreased significantly to 3.2+/-1.1 mmol/L two years after diagnosis. Only 22% achieved the LDL-C target level of < or = 2.5 mmol/L. CONCLUSIONS/SIGNIFICANCE: The proportion of patients using cholesterol-lowering medication was significantly increased after FH diagnosis through genetic cascade screening. The attained LDL-C levels were lower than those reported in previous surveys on medication use in FH, which could reflect the effect of more stringent lipid target levels. However, only a minority of the medication users reached the LDL-C target.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Adolescente , Adulto , Anciano , Apolipoproteínas B/genética , Estudios de Seguimiento , Pruebas Genéticas , Humanos , Hiperlipoproteinemia Tipo II/genética , Persona de Mediana Edad , Mutación , Países Bajos , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Receptores de LDL/genética , Encuestas y Cuestionarios , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The present review aims to highlight the consequences for mother and child of profound hypercholesterolemia during pregnancy of women with familial hypercholesterolemia. RECENT FINDINGS: Familial hypercholesterolemia is increasingly diagnosed in younger patients due to the existence of screening programs and more widespread cholesterol testing. Increasing numbers of young female patients with familial hypercholesterolemia raise the issue of pregnancy and its consequences for the familial hypercholesterolemia patient herself but also for her offspring. When pregnancy is considered, lipid-lowering drugs are often discontinued because of the fear for teratogenic effects. The evidence for teratogenesis associated with statin use is scant and conflicting. On the other hand, several studies do suggest that pronounced hypercholesterolemia during pregnancy has adverse effects on both fetus and mother. In fact, human and animal studies reveal an enhanced tendency toward atherosclerosis in the offspring of women who suffer from hypercholesterolemia during pregnancy. In animal studies, some evidence exists that this can be reversed by treatment with lipid-lowering and antioxidative agents. Until today, however, no human studies exist that have evaluated efficacy or safety of lipid-lowering interventions in pregnant women with familial hypercholesterolemia. SUMMARY: Altogether, the suggested relationship between severe hypercholesterolemia and enhanced atherosclerosis in offspring and possibly the mother warrants further confirmation and, consequently, studies that focus on therapeutic strategies that can safely lower cholesterol levels during pregnancy in these women.
Asunto(s)
Aterosclerosis/etiología , Hipercolesterolemia/complicaciones , Complicaciones del Embarazo , Animales , Femenino , Enfermedades Fetales/etiología , Humanos , Hipercolesterolemia/genética , Recién Nacido , Intercambio Materno-Fetal , EmbarazoRESUMEN
Atherosclerosis, the condition underlying cardiovascular disease (CVD), often begins in childhood. Therefore, strategies to prevent CVD should be implemented at an early age, especially in populations at high risk for CVD. In addition to lifestyle interventions, these strategies include pharmacological treatment of dyslipidemia, a well-established risk factor for CVD in adults. Several lipid-lowering agents have been evaluated in children; however, long-term safety and efficacy data are lacking. As in adults, statins are the preferred pharmacological agents in pediatric practice due to excellent efficacy and tolerability, with few adverse safety outcomes observed to date. Nevertheless, more studies are needed to confirm the lifelong benefit of lipid-lowering therapy initiated in childhood.
Asunto(s)
Aterosclerosis/prevención & control , Enfermedades Cardiovasculares/prevención & control , Dislipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Adolescente , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Azetidinas/uso terapéutico , Ácidos y Sales Biliares/metabolismo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/metabolismo , Niño , Colesterol/metabolismo , Ácido Clofíbrico/uso terapéutico , Progresión de la Enfermedad , Dislipidemias/complicaciones , Dislipidemias/metabolismo , Ezetimiba , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipolipemiantes/efectos adversos , Resinas de Intercambio Iónico/uso terapéutico , Niacina/uso terapéutico , Guías de Práctica Clínica como Asunto , Resultado del TratamientoRESUMEN
OBJECTIVES: The study evaluated the efficacy and safety of long-term coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia (HeFH). BACKGROUND: Aggressive intervention to achieve lipid goals for adolescents with HeFH is recommended to reduce risk of premature cardiovascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled study, 248 male and female subjects ages >or=10 and Asunto(s)
Anticolesterolemiantes/administración & dosificación
, Azetidinas/administración & dosificación
, Hiperlipoproteinemia Tipo II/tratamiento farmacológico
, Simvastatina/administración & dosificación
, Adolescente
, Método Doble Ciego
, Quimioterapia Combinada
, Ezetimiba
, Femenino
, Humanos
, Masculino
, Factores de Tiempo
, Resultado del Tratamiento
RESUMEN
OBJECTIVE: To determine lipoprotein particle concentrations and size in children with familial hypercholesterolemia (FH) and investigate the effect of pravastatin therapy on these measures. STUDY DESIGN: Lipoprotein particle concentrations and sizes were examined by nuclear magnetic resonance (NMR) spectroscopy in 144 children with FH and 45 unaffected siblings. The effect of pravastatin therapy (20 to 40 mg) on lipoprotein particle concentration and size were compared with placebo after 1 year of treatment, using analysis of covariance. RESULTS: Compared with the unaffected siblings, the children with FH had significantly higher concentrations of very-low-density lipoprotein (VLDL) particles (115.6 nmol/L vs 51.2 nmol/L; P < .001) and low-density lipoprotein (LDL) particles (1726.8 nmol/L vs 955.3 nmol/L; P < .001), and lower concentrations of high-density lipoprotein (HDL) particles (23.2 micromol/L vs 26.9 micromol/L; P < .001). Compared with placebo, pravastatin therapy decreased the concentration of VLDL particles by 35.9 nmol/L (P < .001), of total LDL particles by 342.7 nmol/L (P < .001), of large LDL particles by 189.5 nmol/L (P < .001), and of small LDL particles by 156.2 nmol/L (P = .152), but increased the concentration of total HDL particles by 2.2 micromol/L (P < .001), of large HDL particles by 1.0 micromol/L (P = .006), and of medium HDL particles by 1.1 micromol/L (P = .003). VLDL particle size increased by 1.0 nm (P = .032). CONCLUSIONS: Compared with their healthy siblings, children with FH have an atherogenic lipoprotein profile based on their lipoprotein distribution and lipoprotein particle diameter. Pravastatin therapy can improve, but not fully restore, these lipoprotein abnormalities toward normal levels in these children.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , Pravastatina/uso terapéutico , Adolescente , Niño , Femenino , Humanos , Masculino , Tamaño de la PartículaAsunto(s)
Abetalipoproteinemia/genética , Apolipoproteínas B/genética , Mutación , Adulto , Humanos , Masculino , LinajeRESUMEN
Heterozygous familial hypercholesterolemia is associated with elevated levels of LDL-cholesterol and the development of premature cardiovascular disease. The condition is considerably under-diagnosed and under-treated. Statins are the first choice treatment for all patients with heterozygous familial hypercholesterolemia. For those patients who do not reach their treatment target or who are unable to use adequate statin dose, several alternative treatment modalities can be used, either as add-on therapy or as monotherapy. In this review the various treatment options are discussed.