RESUMEN
BACKGROUND: Familial hypercholesterolemia (FH) features elevated oxidative stress and accelerated atherosclerosis driven by elevated levels of atherogenic lipoproteins relative to subnormal levels of atheroprotective high-density lipoprotein (HDL). Small, dense HDL3 potently protects low-density lipoprotein (LDL) against proinflammatory oxidative damage. OBJECTIVE: To determine whether antioxidative and/or anti-inflammatory activities of HDL are defective in FH and whether such defects are corrected by LDL apheresis. METHODS: Antioxidative and antiinflammatory activities of HDL were evaluated as protection of reference LDL from oxidative stress and capacity to prevent accumulation of proinflammatory oxidised lipids, respectively. Lipid surface rigidity of HDL was assessed using a fluorescent probe. HDL components were measured by analytical approaches. Systemic oxidative stress was characterized as plasma 8-isoprostanes. RESULTS: Pre-LDL-apheresis, FH patients (n = 10) exhibited elevated systemic oxidative stress (3.3-fold, P < 0.001) vs. sex- and age-matched normolipidemic controls (n = 10). Both antioxidative and antiinflammatory activity of HDL3 were impaired (up to -91%, P < 0.01) in FH. Sphingomyelin and saturated fatty acid contents were elevated in FH HDL3, resulting in enhanced lipid surface rigidity. The surface lipid content (phospholipids, free cholesterol) was reduced in FH (up to -15%, P < 0.001), whereas content of core lipids (cholesteryl esters, triglycerides) was elevated (up to +17%, P < 0.001). Molar apolipoprotein A-I content of HDL3 was subnormal in FH. A single LDL-apheresis session partially corrected (by up to 76%) deficient HDL antiatherogenic activities, attenuated systemic oxidative stress and partially normalised both the lipid composition and surface rigidity of HDL particles. CONCLUSIONS: FH features elevated oxidative stress and deficient antioxidative and anti-inflammatory activities of small, dense HDL3; such functional deficiency is intimately linked to anomalies in lipid and protein composition, which may impair the capacity of HDL to acquire and inactivate oxidized lipids.
Asunto(s)
Antioxidantes/química , Antioxidantes/metabolismo , Eliminación de Componentes Sanguíneos , Lipoproteínas HDL3/química , Lipoproteínas HDL3/metabolismo , Lipoproteínas LDL/sangre , Tamaño de la Partícula , Adulto , Femenino , Radicales Libres/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/terapia , Inflamación/metabolismo , Lipoproteínas HDL3/sangre , Masculino , Persona de Mediana Edad , Estrés OxidativoRESUMEN
Subnormal HDL-cholesterol (HDL-C) and apolipoprotein (apo)AI levels are characteristic of familial hypercholesterolemia (FH), reflecting perturbed intravascular metabolism with compositional anomalies in HDL particles, including apoE enrichment. Does LDL-apheresis, which reduces HDL-cholesterol, apoAI, and apoE by adsorption, induce selective changes in HDL subpopulations, with relevance to atheroprotection? Five HDL subpopulations were fractionated from pre- and post-LDL-apheresis plasmas of normotriglyceridemic FH subjects (n = 11) on regular LDL-apheresis (>2 years). Apheresis lowered both plasma apoE (-62%) and apoAI (-16%) levels, with preferential, genotype-independent reduction in apoE. The mass ratio of HDL2:HDL3 was lowered from ~1:1 to 0.72:1 by apheresis, reflecting selective removal of HDL2 mass (80% of total HDL adsorbed). Pre-LDL-apheresis, HDL2 subpopulations were markedly enriched in apoE, consistent with ~1 copy of apoE per 4 HDL particles. Large amounts (50-66%) of apoE-HDL were removed by apheresis, preferentially in the HDL2b subfraction (-50%); minor absolute amounts of apoE-HDL were removed from HDL3 subfractions. Furthermore, pre-ß1-HDL particle levels were subnormal following removal (-53%) upon apheresis, suggesting that cellular cholesterol efflux may be defective in the immediate postapheresis period. In LDL-receptor (LDL-R) deficiency, LDL-apheresis may enhance flux through the reverse cholesterol transport pathway and equally attenuate potential biglycan-mediated deposition of apoE-HDL in the arterial matrix.
Asunto(s)
Apolipoproteínas E/sangre , Aterosclerosis/prevención & control , Eliminación de Componentes Sanguíneos , Lipoproteínas de Alta Densidad Pre-beta/sangre , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/terapia , Lipoproteínas LDL/sangre , Adsorción , Adulto , Aterosclerosis/complicaciones , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Lipoproteínas de Alta Densidad Pre-beta/química , Humanos , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/metabolismo , Inflamación/sangre , Lipoproteínas LDL/química , Masculino , Proteoma/metabolismo , Receptores de LDL/deficiencia , Estudios RetrospectivosRESUMEN
BACKGROUND: Central retinal vein occlusion (CRVO) leads to poor visual outcome in most eyes. Abnormal hemorheology was suspected to play a major role in its pathogenesis. CRVO treatment is still a matter of debate but several studies have pointed out the efficacy of isovolumic hemodilution. The aim of this study was to assess the feasibility and efficacy of hemodilution using automated erythrocytapheresis in recent-onset CRVO. METHODS: In this prospective randomized controlled multicenter study, 61 consecutive CRVO patients were enrolled when they met the following criteria: CRVO lasting for 3 weeks or less, visual acuity ranging from 20/200 to 20/32, age between 18 and 85 years, no diabetes, no uncontrolled systemic hypertension, no antiplatelet or anticoagulant therapy, hematocrit higher than 38%, and signed informed consent. Patients were randomly assigned to the hemodilution group (n = 31) or to the control group (n = 30). Hemodilution therapy consisted of one session of erythrocytapheresis on outpatient basis, followed by additional session(s) for 6 weeks if needed. Target hematocrit was 35%. Follow-up was 12 months. RESULTS: No statistical differences in age, associated risk factors, or CRVO characteristics were observed at baseline between both groups. Mean visual acuity was equivalent to 20/80 in the hemodilution group and to 20/63 in the control group (non-significant difference). In the treated group, mean number of hemodilution sessions was 3.3 (range, 1 to 6), and no major side-effects occurred. At the 12-month follow-up visit, 64.5% of the hemodilution group had visual acuity of 20/40 or better compared to 40% of the control group (p = .048). Visual change was a gain of 1.7 ETDRS line in the hemodilution group versus a loss of 2.3 lines in the control group (p = .007). There was less conversion into an ischemic form in the hemodilution group (11%) than in the control group (50%, p = .004). Mean final retinal thickness was 289 µm in the hemodilution group versus 401 µm in the control group (p = .068). CONCLUSIONS: This multicenter controlled randomized study demonstrated that automated erythrocytapheresis is a safe and effective tool for performing hemodilution and confirmed that hemodilution therapy can improve the final prognosis of CRVO when applied in the early phase of the disease.
Asunto(s)
Citaféresis , Hemodilución/métodos , Oclusión de la Vena Retiniana/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Viscosidad Sanguínea , Eritrocitos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Oclusión de la Vena Retiniana/fisiopatología , Agudeza Visual/fisiología , Adulto JovenRESUMEN
We report two patients with myopathy associated with anti-signal recognition particle Ab, refractory to conventional therapy, who were treated with prednisone and plasma exchange, followed by rituximab. A marked response was observed in both patients, with partial to complete recovery of muscle strength, which was sustained.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Músculo Esquelético/patología , Enfermedades Musculares/terapia , Intercambio Plasmático/métodos , Prednisona/administración & dosificación , Partícula de Reconocimiento de Señal/inmunología , Adulto , Antiinflamatorios/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Formación de Anticuerpos/efectos de los fármacos , Formación de Anticuerpos/inmunología , Autoanticuerpos/inmunología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Protocolos Clínicos/normas , Progresión de la Enfermedad , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Masculino , Músculo Esquelético/inmunología , Músculo Esquelético/fisiopatología , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/fisiopatología , Rituximab , Resultado del TratamientoRESUMEN
OBJECTIVE: The combination of LDL apheresis with high doses of a potent hepatic hydroxymethylglutaryl coenzyme A reductase inhibitor, such as atorvastatin, has been the best therapy available for the prevention of cardiovascular disease in patients with homozygous familial hypercholesterolemia (HFH). However, some concerns have been made about the effect of atorvastatin on HDL cholesterol levels in these patients. METHODS AND RESULTS: HDL cholesterol levels were determined bimonthly over the course of 2 years of treatment with high-dose atorvastatin in genotypically defined HFH patients either receptor-defective (n=6) or receptor-negative (n=6) under long-term treatment with LDL apheresis. We additionally stratified the atorvastatin effect on HDL cholesterol according to the genotype as an indicator of residual in vivo LDL receptor activity. Our findings indicate that (1) an early and transitory reduction of plasma HDL cholesterol levels occurs during the first 4 weeks of atorvastatin treatment; (2) the degree of the transient HDL reduction is higher in receptor-negative than in receptor-defective patients (-21+/-11 versus -10+/-4%; P=0.01); and (3) after long-term treatment, HDL cholesterol concentration remains higher in receptor-defective than receptor-negative patients (P=0.026). CONCLUSIONS: The present study reveals that HDL cholesterol reduction after high-dose atorvastatin is an early and transient event in HFH patients which magnitude depends on the presence of a residual LDL-R activity.