RESUMEN
OBJECTIVES: It has been suggested that a low plasma high-density lipoprotein cholesterol (HDL-C) level contributes to the high cardiovascular disease risk of patients with chronic kidney disease (CKD), especially those undergoing haemodialysis (HD). The present study was conducted to gain further understanding of the mechanism(s) responsible for the low HDL-C levels in patients with CKD and to separate the impact of HD from that of the underlying CKD. METHODS: Plasma lipids and lipoproteins, HDL subclasses and various cholesterol esterification parameters were measured in a total of 248 patients with CKD, 198 of whom were undergoing HD treatment and 40 healthy subjects. RESULTS: Chronic kidney disease was found to be associated with highly significant reductions in plasma HDL-C, unesterified cholesterol, apolipoprotein (apo)A-I, apoA-II and LpA-I:A-II levels in both CKD cohorts (with and without HD treatment). The cholesterol esterification process was markedly impaired, as indicated by reductions in plasma lecithin:cholesterol acyltransferase (LCAT) concentration and activity and cholesterol esterification rate, and by an increase in the plasma preß-HDL content. HD treatment was associated with a further lowering of HDL levels and impaired plasma cholesterol esterification. The plasma HDL-C level was highly significantly correlated with LCAT concentration (R = 0.438, P < 0.001), LCAT activity (R = 0.243, P < 0.001) and cholesterol esterification rate (R = 0.149, P = 0.031). Highly significant correlations were also found between plasma LCAT concentration and levels of apoA-I (R = 0.432, P < 0.001), apoA-II (R = 0.275, P < 0.001), LpA-I (R = 0.326, P < 0.001) and LpA-I:A-II (R = 0.346, P < 0.001). CONCLUSION: Acquired LCAT deficiency is a major cause of low plasma HDL levels in patients with CKD, thus LCAT is an attractive target for therapeutic intervention to reverse dyslipidaemia, and possibly lower the cardiovascular disease risk in these patients.
Asunto(s)
Hipoalfalipoproteinemias/etiología , Deficiencia de la Lecitina Colesterol Aciltransferasa/complicaciones , Insuficiencia Renal Crónica/complicaciones , Apolipoproteínas/metabolismo , Estudios de Casos y Controles , HDL-Colesterol/metabolismo , Esterificación/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Diálisis Renal/efectos adversos , Insuficiencia Renal Crónica/sangre , Triglicéridos/metabolismoRESUMEN
Epidemiologically, high-density lipoprotein (HDL) cholesterol levels have been inversely associated to cardiovascular (CV) events, although a Mendelian Randomisation Study had failed to establish a clear causal role. Numerous atheroprotective mechanisms have been attributed to HDL, the main being the ability to promote cholesterol efflux from arterial walls; anti-inflammatory effects related to HDL ligands such as S1P (sphingosine-1-phosphate), resolvins and others have been recently identified. Experimental studies and early clinical investigations have indicated the potential of HDL to slow progression or induce regression of atherosclerosis. More recently, the availability of different HDL formulations, with different phospholipid moieties, has allowed to test other indications for HDL therapy. Positive reports have come from studies on coronary stent biocompatibility, where the use of HDL from different sources reduced arterial cell proliferation and thrombogenicity. The observation that low HDL-C levels may be associated with an enhanced risk of heart failure (HF) has also suggested that HDL therapy may be applied to this condition. HDL infusions or apoA-I gene transfer were able to reverse heart abnormalities, reduce diastolic resistance and improve cardiac metabolism. HDL therapy may be effective not only in atherosclerosis, but also in other conditions, of relevant impact on human health.Key messagesHigh-density lipoproteins have as a major activity that of removing excess cholesterol from tissues (particularly arteries).Knowledge on the activity of high-density lipoproteins on health have however significantly widened.HDL-therapy may help to improve stent biocompatibility and to reduce peripheral arterial resistance in heart failure.
Asunto(s)
Aterosclerosis/terapia , Insuficiencia Cardíaca/terapia , Lipoproteínas HDL , Terapia Molecular Dirigida , Animales , Materiales Biocompatibles , Terapia Genética , Humanos , Intervención Coronaria Percutánea , StentsRESUMEN
BACKGROUND: Lomitapide reduces low-density lipoprotein-cholesterol (LDL-C) but also high-density lipoprotein-cholesterol (HDL-C) levels. The latter may reduce the clinical efficacy of lomitapide. We investigated the effect of lomitapide on HDL-C levels and on cholesterol efflux capacity (CEC) of HDL in patients with homozygous familial hypercholesterolemia (HoFH). METHODS AND RESULTS: Four HoFH patients were treated with increasing dosages of lomitapide. Lomitapide decreased LDL-C (range -34 to -89%). Total HDL-C levels decreased (range -16 to -34%) with a shift to buoyant HDL. ABCA1-mediated CEC decreased in all patients (range -39 to -99%). The changes of total, ABCG1- and SR-BI-mediated CEC were less consistent. CONCLUSION: Lomitapide decreased LDL-C and HDL-C levels. Our report raises the hypothesis that the anti-atherogenic potential of HDL seems to be unaffected as total CEC did not seem to change consistently. Combined with the reduction of atherogenic lipoproteins, the net effect of lomitapide appears to be beneficial in HoFH patients.
Asunto(s)
Transportador 1 de Casete de Unión a ATP/genética , Bencimidazoles/farmacología , Lipoproteínas HDL/sangre , Lipoproteínas HDL/efectos de los fármacos , Adulto , Aterosclerosis , Colesterol/metabolismo , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Homocigoto , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/genética , Masculino , Fenotipo , Resultado del Tratamiento , Adulto JovenRESUMEN
The influence of apolipoprotein A-II (apoA-II) molecular structure on the capacity of high density lipoproteins (HDL) to promote cellular cholesterol efflux was investigated in cultured mouse peritoneal macrophages (MPM). Conversion by reduction and carboxamidomethylation of the naturally occurring dimeric apoA-II to its monomeric form in both native or reconstituted HDL did not change apolipoprotein secondary structure and lipoprotein size/composition. All particles containing monomeric apoA-II, i.e., native HDL3 or reconstituted HDL with or without apoA-I, showed a higher ability to promote cholesterol efflux originating from plasma membrane and intracellular stores, compared to particles containing dimeric apoA-II. These findings indicate that apolipoprotein molecular structure is a major determinant of HDL capacity to promote cholesterol efflux from cells.
Asunto(s)
Apolipoproteína A-II/metabolismo , Colesterol/metabolismo , Lipoproteínas HDL/metabolismo , Macrófagos Peritoneales/metabolismo , Animales , Apolipoproteína A-II/química , Arteriosclerosis/metabolismo , Membrana Celular/metabolismo , Lipoproteínas HDL/química , Ratones , Ratones Endogámicos BALB C , Estructura MolecularRESUMEN
Native and reduced-carboxamidomethylated (RCM) HDL3 are incubated with a lipoprotein-depleted plasma fraction in the presence of triacylglycerol-rich particles isolated from Intralipid. Unmodified HDL3 are mainly converted into large HDL2b particles (diameter: 9.84 +/- 0.15 nm); RCM-HDL3 are transformed into both large HDL2b (9.76 +/- 0.10 nm) and small HDL3c (7.68 +/- 0.07 nm). These findings indicate that the apo A-II dimers participate in the remodeling of HDL, by inhibiting the formation of small HDL particles.
Asunto(s)
Apolipoproteína A-II/metabolismo , Lipoproteínas HDL/metabolismo , Animales , Emulsiones Grasas Intravenosas/metabolismo , Haplorrinos , Humanos , Lipoproteínas HDL/sangre , Oxidación-Reducción , Tamaño de la Partícula , Triglicéridos/metabolismoRESUMEN
The cholesterol esterification process was analyzed in 19 carriers of the apolipoprotein AIMilano (AIM) variant and in 19 age-sex matched controls by measuring lecithin:cholesterol acyltransferase (LCAT) mass, activity (i.e., cholesterol esterification with a standard proteoliposome substrate) and cholesterol esterification rate (i.e., cholesterol esterification in the presence of the endogenous substrate). The AIM subjects had lower LCAT mass (3.30 +/- 0.85 micrograms/ml), activity (71.1 +/- 36.4 nmol/ml per h) and cholesterol esterification rate (23.6 +/- 12.5 nmol/ml per h) compared to controls (5.22 +/- 0.74 micrograms/ml, 121.6 +/- 54.6 nmol/ml per h and 53.6 +/- 29.9 nmol/ml per h, respectively). The specific LCAT activity, i.e., LCAT activity per microgram of LCAT, was similar in the two groups, indicating that the LCAT protein in the AIM carriers is structurally and functionally normal. However, the specific cholesterol esterification rate was 23% lower in the AIM subjects (8.03 +/- 6.01 nmol/h per microgram) compared to controls (10.49 +/- 5.86 nmol/h per microgram; P less than 0.05). The capacity of HDL3, purified from both AIM and control plasma, to act as substrates for cholesterol esterification was similar, thus suggesting that other mechanism(s) may be in play. Carriers with a relative abundance of abnormal, small HDL3b particles had the most altered cholesterol esterification pattern. Upon evaluating all AIM subjects, a complex relationship between HDL structure, plasma lipid-lipoprotein levels and cholesterol esterification emerged, making the AIMilano condition a unique model for the study of the mechanisms regulating the cholesterol esterification-transfer process in man.
Asunto(s)
Apolipoproteínas A/genética , Variación Genética , Hipolipoproteinemias/enzimología , Deficiencia de la Lecitina Colesterol Aciltransferasa/enzimología , Adolescente , Adulto , Apolipoproteína A-I , Apolipoproteínas A/sangre , Niño , Ésteres del Colesterol/sangre , Humanos , Deficiencia de la Lecitina Colesterol Aciltransferasa/genética , Lipoproteínas HDL/sangre , Lipoproteínas HDL3 , Persona de Mediana Edad , Fosfatidilcolina-Esterol O-Aciltransferasa/sangre , Triglicéridos/sangreRESUMEN
The role of human apolipoprotein A-II (apoA-II) in the remodeling of human high density lipoproteins (HDL) was investigated during incubation of native and reduced-carboxamidomethylated (RCM) HDL3 with a lipoprotein-depleted plasma fraction (LPDP) in the presence of triglyceride-rich particles (TGRP) isolated from Intralipid. Reduction-carboxamidomethylation of HDL3 entirely converts the disulfide-linked apoA-II dimers into monomers, without affecting the structure, composition and particle size distribution of HDL3. Following incubation with LPDP and TGRP, unmodified HDL3 are mainly converted into large, HDL2 particles (diameter: 9.90 +/- 0.07 nm), enriched in triglycerides and depleted of cholesteryl esters. RCM-HDL3 are converted into both large HDL2 (9.86 +/- 0.07 nm) and small (7.53 +/- 0.06 nm) HDL3. The small products are protein-rich and cholesterol-poor, and consist of two different particles: a component with pre-beta mobility, containing only apoA-I, and a component with alpha mobility, containing both apoA-I and apoA-II. Kinetic studies suggest that a two-step process is involved in the formation of small, pre beta-HDL3, by which changes in lipid composition cause alterations in lipoprotein structure/stability, favoring the dissociation of apolipoproteins and reduction of particle size. These findings indicate that apolipoprotein structure is a major determinant of HDL remodeling, apoA-II potentially counteracting the anti-atherogenic properties of apoA-I by inhibiting the formation of small, pre-beta-migrating HDL.
Asunto(s)
Apolipoproteína A-II/farmacología , Lipoproteínas HDL/biosíntesis , Lipoproteínas HDL/efectos de los fármacos , Adulto , Sangre/metabolismo , Ditiotreitol/química , Lipoproteínas de Alta Densidad Pre-beta , Humanos , Yodoacetamida/química , Lipoproteínas HDL/química , Oxidación-Reducción , Tamaño de la Partícula , Triglicéridos/metabolismoRESUMEN
BACKGROUND: Carriers of the apolipoprotein A-I(Milano) (apoA-I(M)) mutant present with very low plasma HDL cholesterol and moderate hypertriglyceridemia, apparently not leading to premature coronary heart disease. The objective of this study was to establish whether this high-risk lipid/lipoprotein profile is associated with structural changes in the carotid arteries and heart, indicative of preclinical atherosclerosis. METHODS AND RESULTS: Twenty-one A-I(M) carriers were compared with age- and sex-matched control subjects from the same kindred and with 2 series of matched subjects with primary hypoalphalipoproteinemia (HA). Structural changes in the carotid arteries were defined as the intima-media thickness (IMT) measured by B-mode ultrasound. HA subjects, both recruited among patients attending our Lipid Clinic and blood donors, showed significant thickening of the carotids (average IMT, 0.86+/-0.25 and 0.88+/-0.29 mm, respectively) compared with control subjects (average IMT, 0.64+/-0.12 mm); the apoA-I(M) carriers instead showed normal arterial thickness (average IMT, 0.63+/-0.10 mm). Moreover, a significantly higher prevalence of atherosclerotic plaques was found in patients and blood donors with HA (both 57%) compared with apoA-I(M) carriers (33%) and control subjects (21%). Echocardiographic findings and maximal treadmill ECG did not differ significantly between apoA-I(M) carriers and control subjects, apart from a slight increase in left ventricular end-diastolic dimension in the carriers. CONCLUSIONS: Despite severe HA, carriers of the apoA-I(M) mutant do not show structural changes in the arteries and heart, in contrast to HA subjects, who are characterized by a marked increase in carotid IMT and increased prevalence of atherosclerotic plaques.
Asunto(s)
Apolipoproteína A-I/genética , Enfermedades de las Arterias Carótidas/diagnóstico , Heterocigoto , Hipertrigliceridemia/genética , Lipoproteínas HDL/genética , Adulto , Apolipoproteína A-I/sangre , Gasto Cardíaco/genética , Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/sangre , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , VLDL-Colesterol/sangre , Ecocardiografía , Electrocardiografía , Prueba de Esfuerzo , Femenino , Humanos , Hipertrigliceridemia/sangre , Hipertrigliceridemia/diagnóstico , Lipoproteínas HDL/sangre , Lipoproteínas HDL/deficiencia , Masculino , Triglicéridos/sangre , Túnica Íntima/diagnóstico por imagen , Túnica Media/diagnóstico por imagenRESUMEN
Reverse cholesterol transport identifies a series of metabolic events resulting in the transport of excess cholesterol from peripheral tissues to the liver. High-density lipoproteins (HDL) are the vehicle of cholesterol in this reverse transport, a function believed to explain the inverse correlation between plasma HDL levels and atherosclerosis. An attempt to stimulate, by the use of drugs, this transport process may hold promise in the prevention and treatment of arterial disease. Among the agents affecting lipoprotein metabolism, only probucol exerts significant effects on reverse cholesterol transport, by stimulating the activity of the cholesteryl ester transfer protein and, consequently, altering HDL subfraction composition/distribution. Another approach to the stimulation of reverse cholesterol transport consists of raising plasma HDL levels; studies in animals, either by exogenous supplementation or by endogenous overexpression, have shown a consistent benefit in terms of atherosclerosis regression and/or non-progression. Thus, it is time to consider different future treatments of atherosclerosis, combining the classical lipid-lowering treatments with innovative methods to promote cholesterol removal from the arterial wall.
Asunto(s)
Anticolesterolemiantes/farmacología , Colesterol/metabolismo , Probucol/farmacología , Animales , Transporte Biológico/efectos de los fármacos , HDL-Colesterol/sangre , Etanol/farmacología , Ácidos Grasos Omega-3/farmacología , Hormonas Esteroides Gonadales/fisiología , Humanos , Hígado/metabolismo , Esterol O-Aciltransferasa/metabolismoRESUMEN
Lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with hypoalphalipoproteinemia, generally a predisposing factor for premature coronary heart disease. The evidence of accelerated atherosclerosis in LCAT-deficient subjects is however controversial. In this study, the effect of LCAT deficiency on vascular tone and endothelial function was investigated in LCAT knockout mice, which reproduce the human lipoprotein phenotype. Aortas from wild-type (Lcat(wt)) and LCAT knockout (Lcat(KO)) mice exposed to noradrenaline showed reduced contractility in Lcat(KO) mice (P<0.005), whereas acetylcholine exposure showed a lower NO-dependent relaxation in Lcat(KO) mice (P<0.05). Quantitative PCR and Western blotting analyses suggested an adequate eNOS expression in Lcat(KO) mouse aortas. Real-time PCR analysis indicated increased expression of ß2-adrenergic receptors vs wild-type mice. Aorta stimulation with noradrenaline in the presence of propranolol, to abolish the ß-mediated relaxation, showed the same contractile response in the two mouse lines. Furthermore, propranolol pretreatment of mouse aortas exposed to L-NAME prevented the difference in responses between Lcat(wt) and Lcat(KO) mice. The results indicate that LCAT deficiency leads to increased ß2-adrenergic relaxation and to a consequently decreased NO-mediated vasodilation that can be reversed to guarantee a correct vascular tone. The present study suggests that LCAT deficiency is not associated with an impaired vascular reactivity.
Asunto(s)
Adrenérgicos/farmacología , Deficiencia de la Lecitina Colesterol Aciltransferasa/tratamiento farmacológico , Deficiencia de la Lecitina Colesterol Aciltransferasa/metabolismo , Lecitinas/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Vasodilatación/efectos de los fármacosRESUMEN
To examine the effects of the two newest monophasic oral contraceptives on liver microsomal drug metabolism, plasma kinetics and urinary metabolite excretion of antipyrine, a model substrate for liver microsomes, were evaluated. Plasma lipid and lipoprotein levels, and in particular the high-density lipoprotein subfractions, were also monitored in view of their apparent regulation by a P450-dependent system. Ten healthy volunteers were treated with each contraceptive for a period of 3 months in a crossover trial. Both contraceptives significantly reduced antipyrine clearance by 34.6% (gestodene) and 43.3% (desogestrel) by impairing the oxidative metabolism, particularly to the 4-hydroxy and 3-hydroxymethyl metabolites, with little difference between the two associations. In addition, with both a comparable highly significant rise of plasma triglyceride levels, apolipoproteins A-I and A-II and the high-density lipoprotein-3 subfraction was observed. Treatment with these new monophasic contraceptives may reduce the metabolism of concomitantly given drugs undergoing oxidative transformations.
Asunto(s)
Antipirina/metabolismo , Anticonceptivos Orales/farmacología , Norpregnenos/farmacología , Adulto , Antipirina/farmacocinética , HDL-Colesterol/sangre , Anticonceptivos Orales/administración & dosificación , Desogestrel , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lípidos/sangre , Lipoproteínas/sangre , Norpregnenos/administración & dosificaciónRESUMEN
The protein components of human lipoproteins, apolipoproteins, allow the redistribution of cholesterol from the arterial wall to other tissues and exert beneficial effects on systems involved in the development of arterial lesions, like inflammation and hemostasis. Because of these properties, the antiatherogenic apolipoproteins, particularly apo A-I and apo E, may provide an innovative approach to the management of vascular diseases. The recent availability of extractive or biosynthetic molecules is allowing a detailed overview of their therapeutic potential in a number of animal models of arterial disease. Infusions of apo E, or more dramatically, of apo A-I, both recombinant or extractive, cause a direct reduction of the atherosclerotic burden in experimental animals. Naturally, as the apo A-I(Milano) (apo A-I(M)) dimer, or engineered recombinant apolipoproteins with prolonged permanence in plasma and improved function may offer an even better approach to the therapeutic handling of arterial disease. This progress will go on in parallel with innovations in the technologies for direct, non invasive assessments of human atherosclerosis, thus allowing closer monitoring of this potential new approach to therapy.
Asunto(s)
Apolipoproteína A-I/uso terapéutico , Apolipoproteínas E/uso terapéutico , Arteriosclerosis/terapia , Proteínas Recombinantes/uso terapéutico , Animales , HumanosRESUMEN
Changes in cardiovascular risk after lipid lowering medications are generally expressed as relative risk reduction (RRR). Comparison of the eight major studies published in this last decade indicates that the RRRs ranged from a minimum (19%) for the LRC Study with cholestyramine, to maximal values of 34-37% for studies such as the HHS, 4S and AFCAPS/TexCAPS. These RRRs were barely related to the drugs' effects on major lipid parameters, e.g. LDL cholesterol. Instead, by using the absolute risk reduction (ARRs), easily calculated by subtracting the percentage end points for the drug treated from these values of the placebo group in all studies, a wide range of values was found, also adding to the series a non pharmacological study such as the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial. Calculated ARRs were directly correlated to the baseline cardiovascular (CV) risk in all studies, thus allowing an easy prediction of a drug's effect in the selected population. Drugs with different mechanisms (statins, fibrates and resins) all fitted into this correlation nomogram. These findings clearly indicate that the CV effects of lipid changes, such as LDL cholesterol and triglyceride reduction or HDL rises, are in the same direction, and can be well predicted. The similar, almost identical behavior of drugs affecting LDL cholesterolemia to a different degree or not at all, indicates that novel approaches should be sought to improve risk reduction and that individual therapy should be ideally pursued, rather than a 'one drug' approach.
Asunto(s)
Anticolesterolemiantes/administración & dosificación , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Ensayos Clínicos como Asunto , Femenino , Humanos , Incidencia , Modelos Lineales , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Medición de Riesgo , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
Elevations of plasma cholesterol and/or triglycerides, and the prevalence of small, dense LDL particles remarkably increase coronary risk in patients with familial combined hyperlipidemia (FCHL). A total of 14 FCHL patients were studied, to investigate the ability of Omacor, a drug containing the n-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA and DHA), to favorably correct plasma lipid/lipoprotein levels and LDL particle distribution. The patients received four capsules daily of Omacor (providing 3.4 g EPA+DHA per day) or placebo for 8 weeks in a randomized, double-blind, cross-over study. Omacor significantly lowered plasma triglycerides and VLDL-cholesterol levels, by 27 and 18%, respectively. Total cholesterol did not change but LDL-cholesterol and apolipoprotein B (apoB) concentrations increased by 21 and 6%. As expected, LDL particles were small (diameter=24.9+/-0.3 nm) and apoB-rich (LDL-cholesterol/apoB ratio=1.27+/-0.26) in the selected subjects. After Omacor treatment LDL became enriched in cholesterol (LDL-cholesterol/apoB ratio=1.40+/-0.17), mainly cholesteryl esters, indicating accumulation in plasma of more buoyant and core enriched LDL particles. Indeed, the separation of LDL subclasses by rate zonal ultracentrifugation showed an increase of the plasma concentration of IDL and of the more buoyant, fast floating LDL-1 and LDL-2 subclasses after Omacor, with a parallel decrease in the concentration of the denser, slow floating LDL-3 subclass. However, the average LDL size did not change after Omacor (25.0+/-0.3 nm). The resistance of the small LDL pattern to drug-induced modifications implies that a maximal lipid-lowering effect must be achieved to reduce coronary risk in FCHL patients.
Asunto(s)
Ácidos Docosahexaenoicos/uso terapéutico , Ácido Eicosapentaenoico/uso terapéutico , Hiperlipidemia Familiar Combinada/sangre , Hiperlipidemia Familiar Combinada/tratamiento farmacológico , Lípidos/sangre , Lipoproteínas LDL/sangre , Adulto , Colesterol/sangre , Colesterol/clasificación , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Femenino , Humanos , Lipoproteínas LDL/clasificación , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
The two more widely available techniques for the extracorporeal removal of low density lipoproteins (LDL), dextran sulfate cellulose column and double membrane filtration, were comparatively tested in severe familial hypercholesterolemic patients, both acutely and during a continued 3-month treatment. The selective dextran sulfate procedure removed close to 60% of LDL and 16% of high density lipoproteins (HDL) upon each apheresis, vs. 42% and 32%, respectively, in the case of the semi-selective double membrane filtration. Upon long term biweekly treatments, LDL-cholesterol (LDL-C) decreased, with the selective procedure, from a pre-treatment level of 406.0 +/- 40.7 mg/dl to a value fluctuating between 295.4 +/- 33.8 mg/dl and 116.9 +/- 22.0 mg/dl (highest vs. lowest levels) whereas, in the case of double membrane filtration, LDL-C levels ranged between 334.8 +/- 39.8 mg/dl and 192.3 +/- 49.9 mg/dl. HDL-cholesterol levels were somewhat raised, to a higher extent with dextran sulfate apheresis. The LDL/HDL-cholesterol "atherogenic ratio", decreased from a pre-treatment value of 10.27 +/- 3.04 to values ranging between 3.61 and 6.82 with dextran sulfate and between 6.70 and 7.68 with double membrane plasmapheresis.
Asunto(s)
Hiperlipoproteinemia Tipo II/terapia , Lipoproteínas LDL , Plasmaféresis/métodos , Adulto , Celulosa , Colesterol/sangre , Sulfato de Dextran , Dextranos , Femenino , Filtración/métodos , Humanos , Hiperlipoproteinemia Tipo II/sangre , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
The distribution and structure of high density lipoprotein (HDL) subfractions were examined by rate zonal ultracentrifugation in 200 consecutive subjects, 86 of whom showed a stable hypertriglyceridemia, 22 with coronary artery disease. Among the remaining 114 normotriglyceridemic subjects, 75 were healthy and 39 had coronary disease. The serum levels of the HDL2 subfraction were reduced by 22% in the 39 normotriglyceridemic coronary patients, and by 21% in the whole group of hypertriglyceridemic subjects. No difference in the HDL3 levels was found in any of the studied group. There was a clear negative correlation between HDL2 levels and triglyceridemia in the case of healthy people, not in coronary patients. By contrast, triglyceridemia was negatively correlated with the HDL3 flotation rate, both in healthy subjects and coronary patients at all triglyceride levels. Compositional data indicate that in hypertriglyceridemic subjects, HDL2 levels are reduced because of an enhanced transfer-exchanged process between the enlarged VLDL pool and HDL; in contrast, in coronary patients, a defective maturation of the HDL3 particle is the most likely underlying mechanism. Both in hypertriglyceridemic individuals, as well as in coronary patients, the HDL subfraction distribution is rather similar and drastically different from that of normotriglyceridemic healthy subjects. The mechanisms of the two conditions are probably different and, whereas a low concentration of HDL2 is definitely a major risk factor for normotriglyceridemic individuals, in the case of hypertriglyceridemics other factors may come into play in the final determination of the coronary risk.
Asunto(s)
Enfermedad de la Arteria Coronaria/sangre , Lipoproteínas HDL/sangre , Triglicéridos/sangre , Adulto , Anciano , Colesterol/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Metabolic and hemostatic effects of 2 low dose oral contraceptives (OCs), a triphasic (ethinylestradiol + (-)-norgestrel) and a monophasic (ethinylestradiol + desogestrel) preparation, were compared in a cross-over trial in fertile women over 35 years of age. Both combinations moderately affected plasma lipids, with 17-24% increases of total triglyceridemia. Triglycerides accumulate in low density lipoproteins, thus suggesting the possible formation of an atherogenic lipoprotein particle. Only the monophasic preparation increased high density lipoprotein (HDL)-cholesterol levels significantly, with a rise in HDL3 mass and cholesterol. OC treatment led to slight changes in HDL2 and HDL3 structure, with a rise of the cholesteryl ester and triglyceride contents, indicative of a stimulated cholesterol esterification and reverse transport. Changes in the hemostatic indexes (fibrinogen, antithrombin III and protein C) were negligible. The new low dose OCs, even when prescribed to relatively older women, affect to a relatively small extent lipid/lipoprotein metabolism, with the exception of changes in the low density lipoprotein composition.
Asunto(s)
Anticonceptivos Sintéticos Orales/administración & dosificación , Hemostasis/efectos de los fármacos , Lipoproteínas/sangre , Adulto , Antitrombina III/análisis , Colesterol/sangre , HDL-Colesterol/sangre , Anticonceptivos Sintéticos Orales/farmacología , Desogestrel , Etinilestradiol/administración & dosificación , Etinilestradiol/farmacología , Femenino , Fibrinógeno/análisis , Humanos , Lipoproteínas LDL/sangre , Norgestrel/administración & dosificación , Norgestrel/farmacología , Norpregnenos/administración & dosificación , Norpregnenos/farmacología , Proteína C/análisis , Triglicéridos/sangreRESUMEN
The proband is a 50 year-old woman born from a consanguineous marriage. She has been suffering from angina pectoris since the age of 38 and underwent coronary bypass surgery for three-vessel disease at 48. The presence of low plasma levels of total cholesterol and high density lipoprotein (HDL) cholesterol (2.4 and 0.1 mmol/l) and apo AI (<15 mg/dl), associated with corneal lesions and a mild splenomegaly suggested the diagnosis of Tangier disease. However, none of the other features of Tangier disease, including hepatomegaly, anemia and peripheral neuropathy, were present. The analysis of the dinucleotide microsatellites located in chromosome 9q31 region demonstrated that the proband was homozygous for the alleles of D9S53, D9S1784 and D9S1832. The mother and son of the proband, both with low levels of HDL cholesterol, shared one of the proband's haplotypes, whereas neither of these haplotypes was present in the normolipidemic proband's sister. The sequence of ATP-binding cassette transporter 1 (ABC1-1) cDNA obtained by reverse transcription-PCR (RT-PCR) of total RNA isolated from cultured fibroblasts showed that the proband was homozygous for a C>T transition in exon 13, which caused a tryptophane for arginine substitution (R527W). This mutation was confirmed by direct sequencing of exon 13 amplified from genomic DNA. It can be easily screened, as the nucleotide change introduces a restriction site for the enzyme Afl III. R527W substitution occurs in a highly conserved region of the NH2 cytoplasmic domain of ABC1 protein. R527W co-segregates with the low HDL phenotype in the family and was not found in 200 chromosomes from normolipidemic individuals.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Enfermedad Coronaria/genética , Glicoproteínas/genética , Mutación Puntual , Enfermedad de Tangier/genética , Transportador 1 de Casete de Unión a ATP , Secuencia de Aminoácidos/genética , Secuencia de Bases/genética , Cromosomas Humanos Par 9/genética , Enfermedad Coronaria/fisiopatología , Femenino , Pruebas Genéticas , Genotipo , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación/genética , Linaje , Fenotipo , Polimorfismo Genético , Índice de Severidad de la EnfermedadRESUMEN
Paraoxonase is a high density lipoprotein (HDL) associated enzyme with a hypothesised role in the protection of low density lipoproteins (LDL) from oxidative stress. The present study examined paraoxonase in several genetically distinct HDL deficiency states. Despite reduction or even absence of detectable HDL, enzyme activity was present in sera from A-I-Pisa, A-I-Helsinki, A-I-Milano and Tangier patients. Both enzyme activities and peptide concentrations were modulated (reduced) but specific activities were broadly similar to controls, suggesting an impact on peptide concentration rather than an inhibition of enzyme activity. Despite the absence of HDL in A-I-Pisa and Tangier subjects, there was no association of paraoxonase with very low density lipoproteins or LDL. Paraoxonase function is maintained in HDL deficient states. It implies that certain HDL-associated anti-atherogenic processes may not be entirely compromised by HDL deficiency. This has important implications for the cardiovascular risk associated with modulated HDL concentrations.
Asunto(s)
Esterasas/sangre , Hipolipoproteinemias/enzimología , Adulto , Apolipoproteína A-I/deficiencia , Arildialquilfosfatasa , Western Blotting , Femenino , Humanos , Hipolipoproteinemias/sangre , Masculino , Persona de Mediana Edad , Enfermedad de Tangier/sangre , Enfermedad de Tangier/enzimologíaRESUMEN
The effects of probucol (500 mg twice daily) on high-density lipoprotein (HDL) subfractions and cholesteryl ester transfer from HDL to lower density lipoproteins were tested in a series of patients with Type II hypercholesterolemia. In this placebo-controlled crossover trial, patients received probucol or placebo for 8 weeks, then switched to the other agent for another 8 weeks. Probucol significantly lowered total, low-density lipoprotein and HDL cholesterol levels. HDL subfractions, separated by rate zonal ultracentrifugation, showed a dramatic reduction in HDL2, whereas changes in HDL3 were not significant. Both subfractions eluted at a characteristically lower volume, indicating a reduced flotation rate. These findings were confirmed by gradient gel electrophoretic separation, which showed a typical reduction or disappearance of HDL2b particles and the prevalence of particles in the HDL3a-HDL3b electrophoretic range in almost all patients. After treatment, cholesteryl ester transfer from HDL to lower density lipoproteins was significantly increased in all patients. These data suggest that probucol may accelerate HDL particle conversion, leading to improvement in reverse cholesterol transport from the periphery to the liver, through HDL and very low density lipoprotein.