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AIMS: Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD). The exact prevalence of molecularly defined hoADH is unknown. Therefore, we investigated the prevalence and phenotypical characteristics of this disease in an open society, i.e. the Netherlands. METHODS AND RESULTS: The database of the nationwide ADH molecular diagnostic center was queried to identify all molecularly defined hoADH patients. Carriers of non-pathogenic mutations were excluded. Medical records were analysed for data regarding lipid levels and CVD events. Of 104,682 individuals screened for molecular defects, 49 were classified as hoADH (0.05%); 20 were true homozygotes, 25 were compound heterozygotes for LDLR mutations, and 4 were homozygous for APOB mutations. No bi-allelic PCSK9 mutation carriers were identified. Consequently, the prevalence of hoADH was estimated to be â¼1 : 300,000. Mean LDL-C levels prior to lipid-lowering treatment were 12.9 ± 5.1 mmol/L (range 4.4-21.5 mmol/L). Surprisingly, only 50% of the patients met the clinical criteria for hoADH (LDL-C >13.0 mmol/L); 29% of patients suffered from a CVD event. CONCLUSION: The prevalence of molecularly defined hoADH is much higher and the clinical phenotype is more variable than previously assumed. In light of the fact that novel therapies are, or will be registered for the treatment of hoADH patients, an uniform definition of hoADH either as a phenotypic or molecular entity is warranted in order to identify patients who are considered to be eligible for these novel agents.
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Hiperlipoproteinemia Tipo II/epidemiología , Adolescente , Adulto , Anciano , Apolipoproteína B-100/genética , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Niño , Preescolar , Estudios de Cohortes , Femenino , Heterocigoto , Homocigoto , Humanos , Hiperlipoproteinemia Tipo II/genética , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mutación/genética , Países Bajos/epidemiología , Fenotipo , Prevalencia , Pronóstico , Proproteína Convertasa 9 , Proproteína Convertasas/genética , Receptores de LDL/genética , Serina Endopeptidasas/genética , Adulto JovenRESUMEN
Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8-10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH.
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Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Adolescente , Adulto , Aterosclerosis/diagnóstico , Aterosclerosis/tratamiento farmacológico , Grosor Intima-Media Carotídeo , Niño , Técnicas de Laboratorio Clínico/métodos , Costo de Enfermedad , Consejo , Dieta , Suplementos Dietéticos , Diagnóstico Precoz , Economía Médica , Medicina Basada en la Evidencia , Femenino , Pruebas Genéticas , Heterocigoto , Homocigoto , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Esperanza de Vida , Cumplimiento de la Medicación , Persona de Mediana Edad , Embarazo , Complicaciones del Embarazo/etiología , Factores de Riesgo , Adulto JovenRESUMEN
AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. METHODS AND RESULTS: Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary. CONCLUSION: This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH.
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Hiperlipoproteinemia Tipo II/diagnóstico , Anticolesterolemiantes/uso terapéutico , Arco Senil/etiología , Aterosclerosis/diagnóstico , Eliminación de Componentes Sanguíneos/métodos , Enfermedades Cardiovasculares/etiología , LDL-Colesterol/metabolismo , Diagnóstico Diferencial , Diagnóstico Precoz , Frecuencia de los Genes/genética , Heterogeneidad Genética , Homocigoto , Humanos , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , Trasplante de Hígado/métodos , Mutación/genética , Linaje , Fenotipo , Guías de Práctica Clínica como Asunto , Xantomatosis/etiologíaRESUMEN
PURPOSE OF REVIEW: This review presents recent basic and clinical developments in familial combined hyperlipidemia (FCHL). RECENT FINDINGS: A variety of experiments have contributed to the elucidation of this complex disease. They consist of dynamic and gene expression studies in adipocytes, confirming the role of dysfunctional adipose tissue in the pathogenesis of FCHL and identifying potential new pathways, such as complement activation. Whole exome sequencing and classical linkage studies in FCHL pedigrees, some conducted with new traits (e.g. plasma proprotein convertase subtilisin/kexin type 9 [PCSK9] and phospholipid transfer protein activity), have revealed new genes of interest, among which SLC25A40 and LASS4. Finally, gene expression studies in liver biopsies and liver cell culture experiments have gained further insight in the role of upstream stimulatory factor 1, one of the most replicated genes in FCHL, in its pathogenesis.On the basis of these observations and recent phase II clinical trials, PCSK9 antagonizing is the most promising lipid-lowering therapy to be added to our current arsenal of statins and fibrates in FCHL treatment. SUMMARY: Ongoing basic research provides a steady growth in our knowledge on the genes that are involved in FCHL as well as their metabolic function(s). This field of research may be enhanced when data are expanded and integrated for systems biology approaches. Our growing insights in the cause of FCHL allow for better, targeted treatment of dyslipidemia and prevention of cardiovascular complications.
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Hiperlipidemia Familiar Combinada/genética , Hiperlipidemia Familiar Combinada/metabolismo , Hiperlipidemia Familiar Combinada/terapia , Adipocitos/metabolismo , Adipocitos/patología , Regulación de la Expresión Génica/genética , Humanos , Hiperlipidemia Familiar Combinada/patología , Hígado/metabolismo , Hígado/patología , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proproteína Convertasa 9 , Proproteína Convertasas/genética , Proproteína Convertasas/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismoRESUMEN
Cardiovascular risk stratification could be improved by adding measures of atherosclerosis to current risk scores, especially in intermediate-risk individuals. We prospectively evaluated the additive value of different non-invasive risk markers (both individual and combined) for gender-specific cardiovascular risk stratification on top of traditional risk factors in a middle-aged population-based cohort. Carotid-plaques, IMT (intima-media thickness), ABI (ankle-brachial index), PWV (pulse-wave velocity), AIx (augmentation index), CAP (central augmented pressure) and CSP (central-systolic pressure) were measured in 1367 CVD (cardiovascular disease)-free participants aged 50-70 years old. Cardiovascular events were validated after a mean follow-up of 3.8 years. AUC (area-under-the-curve) and NRI (net reclassification improvement) analyses (total-NRI for all and clinical-NRI for intermediate-risk groups) were used to determine the additive value of individual and combined risk markers. Cardiovascular events occurred in 32 women and 39 men. Traditional cardiovascular risk factors explained 6.2% and 12.5% of the variance in CVD in women and men respectively. AUCs did not substantially increase by adding individual or combined non-invasive risk markers. Individual risk markers only improved reclassification in intermediate-risk women and more than in men; clinical-NRIs ranged between 48.0 and 173.1% in women and 8.9 and 20% in men. Combined non-invasive-risk markers improved reclassification in all women and even more in those at intermediate risk; 'IMT-presence-thickness-of-plaques' showed largest reclassification [total-NRI=33.8%, P=0.012; IDI (integrated-discrimination-improvement)=0.048, P=0.066; clinical-NRI=168.0%]. In men, combined non-invasive risk markers improved reclassification only in those at intermediate risk; 'PWV-AIx-CSP-CAP-IMT' showed the largest reclassification (total-NRI=14.5%, P=0.087; IDI=0.016, P=0.148; clinical-NRI=46.0%). In all women, cardiovascular risk stratification improved by adding combinations and in women at intermediate risk also by adding individual non-invasive risk markers. The additive value of individual and combined non-invasive risk markers in men is limited to men at intermediate risk only, and to a lesser extent than in women.
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Enfermedades Cardiovasculares/etiología , Medición de Riesgo/métodos , Anciano , Índice Tobillo Braquial , Presión Sanguínea/fisiología , Enfermedades Cardiovasculares/fisiopatología , Grosor Intima-Media Carotídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Rigidez Vascular/fisiologíaRESUMEN
OBJECTIVE: Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development. APPROACH AND RESULTS: Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low-density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis-prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% (P<0.05). In addition, Angptl4 overexpression decreased macrophage content (-41%; P<0.05) and numbers of monocytes adhering to the endothelium wall (-37%; P<0.01). Finally, plasma Angptl4 was independently and negatively associated with carotid artery sclerosis measured by 3-T MRI in subjects with metabolic syndrome and low-grade systemic inflammation. CONCLUSIONS: Angptl4 suppresses foam cell formation to reduce atherosclerosis development. Stimulation of Angptl4 in macrophages by oxidized low-density lipoprotein may protect against lipid overload.
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Angiopoyetinas/sangre , Angiopoyetinas/metabolismo , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Estenosis Carotídea/prevención & control , Macrófagos/metabolismo , Proteína 4 Similar a la Angiopoyetina , Angiopoyetinas/genética , Animales , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Apolipoproteína E3/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Arterias Carótidas/patología , Estenosis Carotídea/sangre , Estenosis Carotídea/patología , Línea Celular , Quimiotaxis , Colesterol/sangre , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Femenino , Células Espumosas/metabolismo , Humanos , Ligandos , Lipoproteínas LDL/metabolismo , Activación de Macrófagos , Macrófagos/efectos de los fármacos , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Factores de Tiempo , Receptor Toll-Like 3/agonistas , Receptor Toll-Like 3/metabolismo , Receptor Toll-Like 4/agonistas , Receptor Toll-Like 4/metabolismo , Triglicéridos/sangre , Regulación hacia ArribaRESUMEN
AIMS: The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). METHODS AND RESULTS: Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD. CONCLUSION: Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.
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Enfermedad Coronaria/prevención & control , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/terapia , Adulto , Anticolesterolemiantes/uso terapéutico , Aterosclerosis/diagnóstico , Niño , Preescolar , LDL-Colesterol/sangre , Análisis Costo-Beneficio , Atención a la Salud , Diagnóstico Precoz , Femenino , Predicción , Heterocigoto , Homocigoto , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemia Tipo II/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Linaje , Medición de Riesgo , Resultado del TratamientoRESUMEN
In people living with HIV (PLHIV), integrase strand transfer inhibitors (INSTIs) are part of the first-line combination antiretroviral therapy (cART), while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are alternatives. Distinct cART regimens may variably influence the risk for non-AIDS comorbidities. We aimed to compare the metabolome and lipidome of INSTI and NNRTI-based regimens. The 2000HIV study includes asymptomatic PLHIV (n = 1646) on long-term cART, separated into a discovery cohort with 730 INSTI and 617 NNRTI users, and a validation cohort encompassing 209 INSTI and 90 NNRTI users. Baseline plasma samples from INSTI and NNRTI users were compared using mass spectrometry-based untargeted metabolomic (n = 500) analysis. Perturbed metabolic pathways were identified using MetaboAnalyst software. Subsequently, nuclear magnetic resonance spectroscopy was used for targeted lipoprotein and lipid (n = 141) analysis. Metabolome homogeneity was observed between the different types of INSTI and NNRTI. In contrast, higher and lower levels of 59 and 45 metabolites, respectively, were found in the INSTI group compared to NNRTI users, of which 77.9% (81/104) had consistent directionality in the validation cohort. Annotated metabolites belonged mainly to 'lipid and lipid-like molecules', 'organic acids and derivatives' and 'organoheterocyclic compounds'. In pathway analysis, perturbed 'vitamin B1 (thiamin) metabolism', 'de novo fatty acid biosynthesis', 'bile acid biosynthesis' and 'pentose phosphate pathway' were detected, among others. Lipoprotein and lipid levels in NNRTIs were heterogeneous and could not be compared as a group. INSTIs compared to individual NNRTI types showed that HDL cholesterol was lower in INSTIs compared to nevirapine but higher in INSTIs compared to doravirine. In addition, LDL size was lower in INSTIs and nevirapine compared to doravirine. NNRTIs show more heterogeneous cardiometabolic effects than INSTIs, which hampers the comparison between these two classes of drugs. Targeted lipoproteomic and lipid NMR spectroscopy showed that INSTI use was associated with a more unfavorable lipid profile compared to nevirapine, which was shifted to a more favorable profile for INSTI when substituting nevirapine for doravirine, with evidently higher fold changes. The cardiovascular disease risk profile seems more favorable in INSTIs compared to NNRTIs in untargeted metabolomic analysis using mass-spectrometry.
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Infecciones por VIH , Inhibidores de Integrasa VIH , Inhibidores de la Transcriptasa Inversa , Humanos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Inhibidores de Integrasa VIH/uso terapéutico , Metaboloma/efectos de los fármacos , Fármacos Anti-VIH/uso terapéutico , Metabolómica , Estudios de Cohortes , Terapia Antirretroviral Altamente ActivaRESUMEN
BACKGROUND: IL-32 has been previously shown to promote inflammation in rheumatoid arthritis patients and to contribute to IL-1ß-induced ICAM-1 as well as other proinflammatory cytokines synthesis in human umbilical endothelial cells (HUVECs). Given the high rate of atherosclerosis in RA, these observations suggest that IL-32 may be involved in the inflammatory pathways of atherosclerosis. METHODS: mRNA and protein levels of IL-32 were determined in human atherosclerotic arterial vessel wall tissue by quantitative real-time PCR and immunohistochemistry. HUVEC and M1/M2 macrophages were stimulated with proinflammatory cytokines and TLR ligands to assess IL-32 mRNA induction. Human THP1 macrophages were transduced with AdIL-32γ, to investigate induction of several proatherosclerotic mediators. Finally, aortas from IL-32γ transgenic mice were studied and compared with aortas from age-matched wild-type mice. RESULTS: IL-32 expression was detectable in human atherosclerotic arterial vessel wall, with the expression of IL-32ß and IL-32γ mRNA significantly enhanced. TLR3-ligand Poly I:C in combination with IFNγ were the most potent inducers of IL-32 mRNA expression in both HUVEC and M1/M2 macrophages. Adenoviral overexpression of IL-32γ in human THP1 macrophages resulted in increased production of CCL2, sVCAM-1, MMP1, MMP9, and MMP13. The IL-32γ transgenic mice chow a normal fat diet exhibited vascular abnormalities resembling atherosclerosis. CONCLUSIONS: IL-32 acts as a proinflammatory factor and may be implicated in the inflammatory cascade contributing to atherosclerosis. By promoting the synthesis of matrix metalloproteinases, it may further contribute to plaque instability. Further studies are warranted to investigate whether IL-32 may serve as a potential therapeutic target in fighting atherosclerosis.
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Aorta/inmunología , Aterosclerosis/inmunología , Inflamación/inmunología , Interleucinas/metabolismo , Animales , Aorta/citología , Aorta/metabolismo , Aterosclerosis/metabolismo , Quimiocina CCL2/biosíntesis , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Interferón gamma/metabolismo , Interleucinas/genética , Macrófagos/citología , Macrófagos/inmunología , Metaloproteinasa 1 de la Matriz/biosíntesis , Metaloproteinasa 13 de la Matriz/biosíntesis , Metaloproteinasa 9 de la Matriz/biosíntesis , Ratones , Ratones Transgénicos , ARN Mensajero/biosíntesis , Molécula 1 de Adhesión Celular Vascular/biosíntesisRESUMEN
Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.
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Hiperfagia , Resistencia a la Insulina , Interleucina-18/deficiencia , Obesidad , Animales , Peso Corporal , Ingestión de Alimentos , Metabolismo Energético , Gluconeogénesis/fisiología , Glucosa/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Homeostasis , Hiperfagia/genética , Hiperfagia/metabolismo , Resistencia a la Insulina/genética , Resistencia a la Insulina/fisiología , Péptidos y Proteínas de Señalización Intercelular , Interleucina-18/genética , Subunidad alfa del Receptor de Interleucina-18 , Hígado/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Obesidad/genética , Obesidad/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores de Interleucina-18 , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
PURPOSE OF REVIEW: Guideline groups have issued contradictory decisions as to the value of noninvasive tests in asymptomatic adults at intermediate cardiovascular risk. Reclassification has only recently been accepted as a critical criterion to determine the utility of a diagnostic test. The present review examines potential limitations in reclassification and evaluates the utility of carotid ultrasound, pulse wave velocity and ankle brachial index from a clinical perspective. RECENT FINDINGS: Reclassification is less useful than generally believed, because therapy is already indicated in the majority of patients at intermediate risk and it is far from clear that treatment should be withheld in those who are downgraded in risk. Moreover, the additional benefit from more intensive therapy is much less than often thought. Reproducibility, standardization and reference values of noninvasive tests are obligatory before introduction in clinical care. SUMMARY: Routine screening of all those at intermediate risk does not appear to be justified. Screening should be performed on those individuals in whom the noninvasive test changes clinical care, which is most apparent for individuals at intermediate risk with LDL level less than 2.5âmmol/l, in whom positive noninvasive tests will result in the start of statin treatment. The primary value of these tests should not be to determine risk but to identify preclinical anatomic disease.
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Índice Tobillo Braquial/clasificación , Enfermedades Cardiovasculares/prevención & control , Grosor Intima-Media Carotídeo/clasificación , Tamizaje Masivo/métodos , Guías de Práctica Clínica como Asunto , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Estenosis Carotídea/diagnóstico por imagen , Humanos , Pulso Arterial , Valores de Referencia , Factores de RiesgoRESUMEN
BACKGROUND: Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown. METHODS: We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries. RESULTS: The primary outcome, the mean (+/-SE) change in the carotid-artery intima-media thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups. CONCLUSIONS: In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 [ClinicalTrials.gov].).
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Azetidinas/uso terapéutico , LDL-Colesterol/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Simvastatina/uso terapéutico , Adulto , Anticolesterolemiantes/efectos adversos , Azetidinas/efectos adversos , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Colesterol/sangre , Método Doble Ciego , Quimioterapia Combinada , Ezetimiba , Femenino , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/patología , Humanos , Hiperlipoproteinemia Tipo II/patología , Masculino , Persona de Mediana Edad , Simvastatina/efectos adversos , Resultado del Tratamiento , Triglicéridos/sangre , Túnica Íntima/diagnóstico por imagen , Túnica Íntima/patología , Túnica Media/diagnóstico por imagen , Túnica Media/patología , UltrasonografíaRESUMEN
BACKGROUND: We applied a diagnostic algorithm using apolipoprotein B (apoB) in combination with triglycerides (TG) and total cholesterol to determine the prevalence of dyslipoproteinemias in the general population. We also characterized the overall cardiovascular (CV) risk profiles, including arterial structure and function as measured with a panel of noninvasive parameters. DESIGN: Clinical and biochemical characteristics and noninvasive measurements of atherosclerosis (NIMA) were determined in 1517 individuals, aged 50-70 years. RESULTS: In general, all dyslipoproteinemias were characterized by a worse CV risk profile and deteriorated outcomes of NIMA compared to those with normal apolipoprotein B (< 1·2 g L(-1)) and TG (< 1·5 mM) levels. The prevalence of hyperapoB-hyperTG was 15·1%, and these individuals showed the most abnormal atheroma-related parameters: reduced ankle-brachial-index at rest (-3·5%) and after exercise (-9·8%), increased intima-media thickness (+5·5%) and more carotid plaques (+39·1%). The prevalence of normoapoB-hyperTG because of increased VLDL was 18·1% and 2·3% because of increased chylomicrons and VLDL, and in these groups, the parameters related to stiffness (e.g. pulse-wave-velocity +7·6% and +5·2%, respectively) were most abnormal. Adjustment for apolipoprotein B (apoB) reduced differences in NIMA in the hyperapoB-hyperTG group, whereas adjustment for TG reduced differences in NIMA in the normoapoB-hyperTG group. CONCLUSIONS: The overall prevalence of dyslipoproteinemias according to the algorithm was approximately 40% in the Dutch population. The different dyslipoproteinemias showed a less favourable CV risk profile and deteriorated NIMA parameters, reflecting increased subclinical atherosclerosis. Furthermore, different effects on different NIMA parameters were observed in the different dyslipoproteinemias.
Asunto(s)
Algoritmos , Apolipoproteínas B , Aterosclerosis/etiología , Enfermedades Cardiovasculares/etiología , Dislipidemias/diagnóstico , Anciano , Apolipoproteínas B/metabolismo , Colesterol/metabolismo , Dislipidemias/complicaciones , Dislipidemias/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Valor Predictivo de las Pruebas , Factores de Riesgo , Triglicéridos/metabolismoRESUMEN
OBJECTIVE: Familial combined hyperlipidemia (FCH) is a common familial lipid disorder characterized by increases in plasma total cholesterol, triglyceride, and apolipoprotein B-100 levels. In light of prior metabolic and genetic research, our purpose was to ascertain whether FCH cases had significant abnormalities of plasma markers of cholesterol synthesis and absorption as compared to unaffected kindred members. METHODS AND RESULTS: Plasma levels of squalene, desmosterol, and lathosterol (cholesterol synthesis markers) and campesterol, sitosterol, and cholestanol (cholesterol absorption markers) were measured by gas-liquid chromatography in 103 FCH patients and 240 normolipidemic relatives (NLR). Squalene, desmosterol, and lathosterol levels were 6% (0.078), 31%, (P<0.001) and 51% (P<0.001) higher in FCH as compared to NLR, and these differences were especially pronounced in women. An interaction with obesity was also noted for a subset of these markers. We did not observe any apparent differences for the cholesterol absorption markers among FCH patients and NLR. CONCLUSIONS: Our data indicate that both men and women with FCH have alterations in the cholesterol synthesis pathway, resulting in 51% higher levels of lathosterol (and additionally desmosterol in women). Plasma levels of the cholesterol precursor sterol squalene were only slightly increased (6%), suggesting enhanced conversion of squalene to lathosterol in this disorder.
Asunto(s)
Biomarcadores/sangre , Colesterol/biosíntesis , Colesterol/sangre , Hiperlipidemia Familiar Combinada/metabolismo , Absorción Intestinal/fisiología , Adulto , Anciano , Colestanol/sangre , Colesterol/análogos & derivados , Desmosterol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fitosteroles/sangre , Caracteres Sexuales , Sitoesteroles/sangre , Escualeno/sangreRESUMEN
OBJECTIVE: The concept that intraarticular crystals of uric acid by themselves trigger episodes of painful gouty arthritis is inconsistent with the clinical reality. Patients with large deposits of monosodium urate monohydrate (MSU) crystals (tophi) do not necessarily experience gouty attacks. In fact, it is the excessive consumption of food or alcohol that elicits the inflammation of the acute gout attack. The aim of this study was to identify the precise mechanism that initiates flares of gouty arthritis. METHODS: Human peripheral blood mononuclear cells (PBMCs) and murine macrophages were stimulated in vitro with MSU, free fatty acids (FFAs), or both in combination. Thereafter, production of interleukin-1ß (IL-1ß) and activation of caspase 1 were determined. Gouty arthritis was induced in mice with deficiencies in the genes for caspase 1, ASC, NALP3, or IL-1ß, and the lack of inflammasome activity during joint swelling or other joint pathologic features was investigated in these mice. RESULTS: MSU crystals had no biologic effects on PBMCs from healthy subjects, whereas the FFA C18:0 in the presence of MSU crystals induced the release of large amounts of IL-1ß following engagement of Toll-like receptor 2 (TLR-2). Interaction of FFAs, but not alcohol, with TLR-2 synergized with MSU crystals to induce an inflammatory reaction. An important event of MSU/FFA-induced acute joint inflammation is the activation of the inflammasome. MSU/FFA-induced release of IL-1ß was dependent on activation of caspase 1 and ASC, but surprisingly, not NALP3. CONCLUSION: The synergistic effect between FFAs and MSU crystals leads to ASC/caspase 1-driven IL-1ß release. This mechanism could explain how constitutionally derived metabolic events initiate attacks of gout via the induction of IL-1ß-mediated joint inflammation.
Asunto(s)
Artritis Gotosa/metabolismo , Caspasa 1/metabolismo , Proteínas del Citoesqueleto/metabolismo , Ácidos Grasos/metabolismo , Interleucina-1beta/biosíntesis , Receptor Toll-Like 2/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis , Artritis Gotosa/inducido químicamente , Proteínas Adaptadoras de Señalización CARD , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Humanos , Inflamación/metabolismo , Articulación de la Rodilla/metabolismo , Leucocitos Mononucleares/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Estadísticas no Paramétricas , Ácido ÚricoRESUMEN
PURPOSE OF REVIEW: Familial combined hyperlipidemia (FCHL) and type 2 diabetes mellitus (T2DM) are prevalent entities that share many features of the metabolic syndrome. Recent findings suggest that FCHL and T2DM are less distinct than initially anticipated, which could offer new insights for their therapeutic approach. RECENT FINDINGS: Genetic association studies have provided evidence for a common genetic background (upstream transcription factor 1, activating transcription factor 6, transcription factor 7-like 2 and hepatocyte nuclear factor 4 alpha) between FCHL and T2DM. The metabolic overlap can be illustrated by the presence of ectopic fat accumulation and insulin resistance (muscle, adipose tissue and liver). We have shown that FCHL patients are at increased risk to develop T2DM. This indicates that both entities are not static, but instead the former is able to migrate to the latter as insulin resistance progresses. Given these new findings, it can be anticipated that FCHL patients could also benefit from insulin-sensitizing therapy such as pioglitazone and metformin. Indeed, pilot studies have demonstrated that pioglitazone might be advantageous in FCHL patients. SUMMARY: Recent studies suggest that FCHL patients have an increased risk to develop T2DM, which has important clinical implications. Further studies are necessary to evaluate whether FCHL patients can be protected from new-onset T2DM and premature cardiovascular events with insulin-sensitizing therapy.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Hiperlipidemia Familiar Combinada/tratamiento farmacológico , Hiperlipidemia Familiar Combinada/genética , Resistencia a la Insulina/genética , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , LDL-Colesterol/genética , LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Descubrimiento de Drogas , Hígado Graso/genética , Hígado Graso/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Hiperlipidemia Familiar Combinada/complicaciones , Hiperlipidemia Familiar Combinada/metabolismo , Insulina/metabolismo , Masculino , Síndrome Metabólico/etiología , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , Metformina/administración & dosificación , Modelos Biológicos , Obesidad/genética , Obesidad/metabolismo , Pioglitazona , Factores de Riesgo , Tiazolidinedionas/administración & dosificación , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Triglicéridos/genética , Triglicéridos/metabolismoRESUMEN
PURPOSE OF REVIEW: Despite the use of currently available lipid-lowering therapies, a significant proportion of patients with severe hypercholesterolaemia do not reach treatment goals and consequently remain at increased risk for cardiovascular disease (CVD). On the basis of clinical experience, these patients tend to have the most severe forms of familial hypercholesterolaemia or markedly elevated LDL cholesterol (LDL-C) levels but are unable to tolerate statin therapy. RECENT FINDINGS: LDL apheresis is currently the best treatment option (or treatment rescue) to bring these patients closer to therapeutic LDL objectives, and has been shown to reduce the risk of CVD along with LDL-C levels. However, criteria for LDL apheresis eligibility and the percentage of patients receiving treatment vary widely from country to country across Europe. Despite the proven benefits of LDL apheresis, access to this procedure remains limited because of its high cost and low availability, reflecting inherent limitations of this treatment modality. SUMMARY: There is a need to both better define the patient population eligible for LDL apheresis and to create unified European guidelines governing the use of apheresis. In addition to improving access to apheresis where appropriate, new therapies are needed to further decrease LDL-C and reduce the ongoing CVD risk in patients with severe hypercholesterolaemia.
Asunto(s)
Eliminación de Componentes Sanguíneos , Enfermedades Cardiovasculares/prevención & control , LDL-Colesterol , Hipercolesterolemia , Guías de Práctica Clínica como Asunto/normas , Adulto , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/terapia , Niño , LDL-Colesterol/sangre , Determinación de la Elegibilidad , Europa (Continente) , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/epidemiología , Hipercolesterolemia/fisiopatología , Hipercolesterolemia/prevención & control , Hipercolesterolemia/terapia , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de RiesgoRESUMEN
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
BACKGROUND: Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor [corrected] (RADIANCE) trials, which assessed the impact of torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome. METHODS AND RESULTS: Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076+/-0.0011 versus 0.0025+/-0.0011 mm/y; P=0.0014). Subjects treated with torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change. CONCLUSIONS: These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.