RESUMEN
OBJECTIVE: Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI. METHODS: In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients. RESULTS: When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint). CONCLUSIONS: Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies. KEY MESSAGES: In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies.
Asunto(s)
Endotelina-1/sangre , Insuficiencia Cardíaca/sangre , Infarto del Miocardio/sangre , Péptido Natriurético Encefálico/sangre , Espironolactona/análogos & derivados , Disfunción Ventricular Izquierda/sangre , Anciano , Biomarcadores/sangre , Eplerenona , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/epidemiología , Valor Predictivo de las Pruebas , Espironolactona/uso terapéutico , Tasa de Supervivencia/tendencias , Factores de Tiempo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/epidemiologíaRESUMEN
OBJECTIVES: Parathyroid hormone (PTH) is a major systemic calcium-regulating hormone. Recent evidence has suggested that measurement of PTH might provide complementary information for the diagnosis and risk stratification of patients with heart failure (HF). The aim of our study was to compare intact and bioactive PTH assays in patients with severe heart failure. DESIGN AND METHODS: The following measurements were carried out in blood samples from 73 patients with severe heart failure: bioactive PTH (1-84) assay, intact PTH assay, non-PTH (1-84), 25-hydroxyvitamin D, B-type natriuretic peptide (BNP), N-terminal proBNP (Nt-proBNP), Galectin-3 and high sensitive troponin T (hsTnT). RESULTS: The correlation between intact and bioactive PTH assays was very high in HF patients. However, the bioactive PTH concentrations were lower than those measured with the intact assay. Intact and bioactive PTH as well as non-PTH (1-84) was significantly and positively correlated to BNP, Nt-proBNP, and galectin-3 but not to hsTnT. The strongest relationships with these cardiac biomarkers and with cardiovascular death were observed with the bioactive PTH assay. CONCLUSIONS: The PTH concentrations obtained with intact and bioactive assays are not comparable in patients with severe HF. The specificity of PTH assays might therefore impact on the potential diagnosis and prognosis values of PTH testing in patients with heart failure.
Asunto(s)
Insuficiencia Cardíaca/sangre , Hormona Paratiroidea/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Galectina 3/sangre , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Pronóstico , Troponina T/sangre , Vitamina D/análogos & derivados , Vitamina D/sangreRESUMEN
BACKGROUND: PTH is related to left ventricular hypertrophy and its circulating levels are associated with worse prognosis in patients with heart failure (HF). The objectives of our study were to measure the circulating levels of bioactive PTH 1-84 through third-generation assay in HF patients, to determine their association with the disease severity as well as their relation with recognized biomarkers of HF worsening and prognosis. METHODS: PTH 1-84 concentrations were determined in 76 HF patients and in 49 healthy volunteers. Circulating levels of amino-terminal proatrial natriuretic peptide (Nt-proANP), B-type natriuretic peptide (BNP), Nt-proBNP, proBNP, and big endothelin-1 (Big ET-1) were also measured. RESULTS: HF patients had in- creased PTH 1-84 levels in comparison to controls. A significant increase of the PTH 1-84 circulating concentrations was observed according to the New York Heart Association functional classes. PTH 1-84 circulating concentrations were also significantly correlated with Nt-proANP, BNP, Nt-proBNP, proBNP, and Big ET-1. CONCLUSIONS: PTH 1-84 circulating levels are significantly increased in HF patients in comparison to healthy individuals. Our study has also demonstrated that circulating concentrations of bioactive PTH are related to HF severity and well-established biomarkers of the worsening of the disease.
Asunto(s)
Insuficiencia Cardíaca/sangre , Hormona Paratiroidea/sangre , Adulto , Anciano , Anciano de 80 o más Años , Factor Natriurético Atrial/sangre , Endotelina-1/sangre , Femenino , Humanos , Inmunoensayo , Masculino , Persona de Mediana Edad , Análisis Multivariante , Péptido Natriurético Encefálico/sangre , Análisis de RegresiónRESUMEN
Urotensin II (UII) a potent vasoactive peptide is upregulated in the failing heart and promotes cardiomyocytes hypertrophy, in particular through mitogen-activated protein kinases. However, the regulation by UII of GSK-3beta, a recognized pivotal signaling element of cardiac hypertrophy has not yet been documented. We therefore investigated in adult cardiomyocytes, if UII phosphorylates GSK-3beta and Akt, one of its upstream regulators and stabilizes beta-catenin, a GSK-3beta dependent nuclear transcriptional co-activator. Primary cultures of adult rat cardiomyocytes were stimulated for 48h with UII. Cell size and protein/DNA contents were determined. Phosphorylated and total forms of Akt, GSK-3beta and the total amount of beta-catenin were quantified by western blot. The responses of cardiomyocytes to UII were also evaluated after pretreatment with the chemical phosphatidyl-inositol-3-kinase inhibitor, LY294002, and urantide, a competitive UII receptor antagonist. UII increased cell size and the protein/DNA ratio, consistent with a hypertrophic response. UII also increased phosphorylation of Akt and its downstream target GSK-3beta. beta-Catenin protein levels were increased. All of these effects of UII were prevented by LY294002, and urantide. The UII-induced adult cardiomyocytes hypertrophy involves the Akt/GSK-3beta signaling pathways and is accompanied by the stabilization of the beta-catenin. All these effects are abolished by competitive inhibition of the UII receptor, consistent with new therapeutic perspectives for heart failure treatment.
Asunto(s)
Glucógeno Sintasa Quinasa 3/metabolismo , Miocitos Cardíacos/enzimología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Urotensinas/farmacología , Animales , Tamaño de la Célula/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta , Masculino , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Ratas , beta Catenina/metabolismoRESUMEN
The available data suggest that Urocortin (UCN), a cardioprotective and vasoactive peptide known from fish neuroendocrinology, is involved in cardiac regulation. The aim of this study was to determine UCN plasma concentrations in patients with heart failure (HF). Plasma concentrations of UCN, measured in 42 fully treated HF patients. UCN, were determined using a specific ELISA assay after acidic extraction with Sep-Pak C18 columns. Circulating levels of other neurohormones Nt-proBNP, Nt-proANP and Big ET-1 were also determined. Reference values were obtained from 20 healthy age- and sex-matched subjects. In comparison with controls, UCN plasma concentrations (geometric mean [95% CI]) were significantly increased in HF patients (88 pmol/L [75-105] vs 46 [39-54], p<0.001). As expected, the other neurohormones were also significantly increased in HF patients (Nt-proBNP: 3501 pg/ml [2356-5202] vs 35 [24-51], Nt-proANP: 5498 pg/ml [4336-6971] vs 324 [255-411] and Big ET-1: 15.8 pg/ml [13.6-18.4] vs 5.9 [5.2-6.8]; p<0.01 for all vs controls). No significant correlation was observed between UCN and the other HF biomarkers. Our results demonstrate that plasma concentrations of UCN are significantly increased in patients with HF and that UCN may participate in the neurohumoral response of HF.
Asunto(s)
Insuficiencia Cardíaca/sangre , Urocortinas/sangre , Anciano , Envejecimiento/sangre , Factor Natriurético Atrial/sangre , Endotelina-1/sangre , Tasa de Filtración Glomerular/fisiología , Insuficiencia Cardíaca/diagnóstico , Humanos , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangreRESUMEN
Objective. To investigate the relationship between IGF-I and the nutritional status of West-African children hospitalised for nutritional rehabilitation. Patients and methods. A cohort study was performed in two centres for nutritional rehabilitation and education (CREN) in Burkina Faso. Children were followed and the anthropometric data as well as the capillary blood samples were taken on the 7th and on the 14th days after their admission. IGF-I levels were determined from dried blood spots on filter paper on IGF-I RIA, after separation of the IGF-I from its binding proteins, using Sep-Pak chromatography. Results. A total of 59 children was included in the cohort. The IGF-I mean geometric values (SD) were 6.3 (1.4) mug/L on admission, 8.6 (1.8) mug/L at day 7 and 13.6 (2.0) mug/L at day 14. The differences between these values were statistically significant (P < .001). There is a significant correlation between the changes of IGF-I with the change of weight for height Z-score (P = .01). Conclusion. These results suggest that IGF-I can be considered as a potential marker to follow the nutritional status of children admitted in hospital for protein and energy malnutrition.
RESUMEN
Decrease of muscle IGF-I plays a critical role in muscle atrophy caused by glucocorticoids (GCs) because IGF-I gene electrotransfer prevents muscle atrophy caused by GCs. The goal of the present study was to identify the intracellular mediators responsible for the IGF-I anti-atrophic action in GC-induced muscle atrophy. We first assessed the IGF-I transduction pathway alterations caused by GC administration and their reversibility by local IGF-I overexpression performed by electrotransfer. Muscle atrophy induced by dexamethasone (dexa) administration occurred with a decrease in Akt (-53%; P<0.01) phosphorylation together with a decrease in beta-catenin protein levels (-40%; P<0.001). Prevention of atrophy by IGF-I was associated with restoration of Akt phosphorylation and beta-catenin levels. We then investigated whether muscle overexpression of these intracellular mediators could mimic the IGF-I anti-atrophic effects. Overexpression of a constitutively active form of Akt induced a marked fiber hypertrophy in dexa-treated animals (+175% of cross-sectional area; P<0.001) and prevented dexa-induced atrophy. This hypertrophy was associated with an increase in phosphorylated GSK-3beta (+17%; P<0.05) and in beta-catenin content (+35%; P<0.05). Furthermore, overexpression of a dominant-negative GSK-3beta or a stable form of beta-catenin increased fiber cross-sectional area by, respectively, 23% (P<0.001) and 29% (P<0.001) in dexa-treated rats, preventing completely the atrophic effect of GC. In conclusion, this work indicates that Akt, GSK-3beta, and beta-catenin probably contribute together to the IGF-I anti-atrophic effect in GC-induced muscle atrophy.
Asunto(s)
Citoprotección/genética , Glucocorticoides/efectos adversos , Glucógeno Sintasa Quinasa 3/fisiología , Factor I del Crecimiento Similar a la Insulina/genética , Atrofia Muscular/inducido químicamente , Proteínas Proto-Oncogénicas c-akt/fisiología , beta Catenina/fisiología , Animales , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3 beta , Masculino , Atrofia Muscular/genética , Especificidad de Órganos/genética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Ratas , Ratas Wistar , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Transducción de Señal/fisiología , Transfección , beta Catenina/genéticaRESUMEN
OBJECTIVES: The aims of this study were to validate the use of filter paper to measure insulin-like growth factor-I (IGF-I) and to establish normal levels of IGF-I in children appearing healthy, from birth to 5 years of age in an African population. METHODS: We determined IGF-I from blood collected on filter paper. We validated this method by comparing the IGF-I values from dried blood spots on filter paper (kept at 4 degrees C and ambient temperature) and from serum among 13 children under 5. IGF-I were measured by the classical IGF-I RIA, after separation of the IGF-I from its binding proteins, using Sep-Pak chromatography. To establish normal levels of IGF-I, we conducted a cross-sectional study and collected blood samples with filter paper among 360 children in Ouagadougou (Burkina Faso). RESULTS: IGF-I determined from dried blood spots on filter paper were in good agreement with IGF-I levels obtained from blood serum, whether the filter papers were kept at 4 degrees C or at ambient temperature. The results of IGF-I-levels in apparently healthy children showed that geometric mean IGF-I ranged from 27 microg/l in boys younger than five months to 31 microg/l in 5-year-old boys. In girls, mean IGF-I ranged from 29 microg/l for girls younger than five months to 45 microg/l at the age of 5. From birth to 24 months, IGF-I decreased by 0.32+/-0.08 microg/l/month in boys and by 0.27+/-0.06 microg/l/month in girls and these decreases were not significantly different (p=0.95). After the age of 24 months, there was an increase in IGF-I of 4.9+/-1.3 microg/l/year in boys and of 8.4+/-0.8 microg/l/year in girls. This increase was indeed significantly different (p<0.001). CONCLUSIONS: Reference values of IGF-I for African boys and girls were determined. They will be used for endocrine evaluations and nutritional monitoring.
Asunto(s)
Recolección de Muestras de Sangre/métodos , Factor I del Crecimiento Similar a la Insulina/análisis , Filtros Microporos , Recolección de Muestras de Sangre/instrumentación , Burkina Faso , Preescolar , Femenino , Pruebas Hematológicas/normas , Humanos , Lactante , Recién Nacido , Masculino , Estado Nutricional , Valores de Referencia , Clase SocialRESUMEN
AIM: To measure circulating osteopontin levels in a cohort of type 2 diabetic patients and to determine whether osteopontin could be associated with lower limb arteries calcifications, either intimal (atherosclerotic) or medial (mediacalcinosis). METHODS: Osteopontin was measured in 60 patients with type 2 diabetes who were subdivided in three groups: group 1 (n=19) was characterized by the absence of peripheral vascular calcifications on plain soft tissue radiograms; group 2 (n=18) presented intimal calcifications without mediacalcinosis; in group 3 (n=23), mediacalcinosis was the dominant pattern. RESULTS: Osteopontin levels were significantly higher in patients with mediacalcinosis (558 ng/ml [140-2289], median [range]) than in subjects without vascular calcifications (337 [134-841], P = 0.024) or in individuals with intimal lesions (340 [140-1154], P = 0.05). No correlation was observed between osteopontin, glycaemic control or HOMA test results. Osteopontin was correlated with creatinine clearance (P = 0.037). CONCLUSION: In type 2 diabetic patients, circulating levels of osteopontin were higher in the presence of medial calcifications than in subjects without vascular lesions or in individuals with calcifications limited to the intimal
Asunto(s)
Arteriopatías Oclusivas/sangre , Calcinosis/sangre , Diabetes Mellitus Tipo 2/sangre , Osteopontina/sangre , Túnica Media/patología , Anciano , Anciano de 80 o más Años , Arteriopatías Oclusivas/etiología , Bélgica , Biomarcadores/sangre , Calcinosis/etiología , Estudios de Cohortes , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Humanos , Pierna , Masculino , Persona de Mediana Edad , Túnica Íntima/patologíaRESUMEN
Glucocorticoids mediate muscle atrophy in many catabolic states. Myostatin expression, a negative regulator of muscle growth, is increased by glucocorticoids and myostatin overexpression is associated with lower muscle mass. This suggests that myostatin is required for the catabolic effects of glucocorticoids. We therefore investigated whether myostatin gene disruption could prevent muscle atrophy caused by glucocorticoids. Male myostatin knockout (KO) and wild-type mice were subjected to dexamethasone treatment (1 mg/kg.d for 10 d or 5 mg/kg.d for 4 d). In wild-type mice, daily administration of low-dose dexamethasone for 10 d resulted in muscle atrophy (tibialis anterior: -15%; gastrocnemius: -13%; P < 0.01) due to 15% decrease in the muscle fiber cross-sectional area (1621 +/- 31 vs. 1918 +/- 64 microm(2), P < 0.01). In KO mice, there was no reduction of muscle mass nor fiber cross-sectional area after dexamethasone treatment. Muscle atrophy after 4 d of high-dose dexamethasone was associated with increased mRNA of enzymes involved in proteolytic pathways (atrogin-1, muscle ring finger 1, and cathepsin L) and increased chymotrypsin-like proteasomal activity. In contrast, the mRNA of these enzymes and the proteasomal activity were not significantly affected by dexamethasone in KO mice. Muscle IGF-I mRNA was paradoxically decreased in KO mice (-35%, P < 0.05); this was associated with a potentially compensatory increase of IGF-II expression in both saline and dexamethasone-treated KO mice (2-fold, P < 0.01). In conclusion, our results show that myostatin deletion prevents muscle atrophy in glucocorticoid-treated mice, by blunting the glucocorticoid-induced enhanced proteolysis, and suggest an important role of myostatin in muscle atrophy caused by glucocorticoids.
Asunto(s)
Dexametasona/farmacología , Eliminación de Gen , Glucocorticoides/farmacología , Atrofia Muscular/fisiopatología , Factor de Crecimiento Transformador beta/genética , Animales , Peso Corporal , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/genética , Masculino , Ratones , Ratones Endogámicos , Ratones Noqueados , Fibras Musculares Esqueléticas/enzimología , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Atrofia Muscular/inducido químicamente , Atrofia Muscular/patología , Miofibrillas/enzimología , Miofibrillas/patología , Miostatina , Tamaño de los Órganos , Péptido Hidrolasas/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/genética , Ubiquitina/metabolismoAsunto(s)
Diabetes Mellitus Tipo 2/sangre , Osteopontina/sangre , Fumar/sangre , Adulto , Femenino , Humanos , Masculino , Cese del Hábito de FumarRESUMEN
Urotensin II (UII) is a potent vasoactive cyclic peptide thought to play a role in myocardial hypertrophy and remodelling. We therefore determined UII plasma levels in congestive heart failure (CHF) patients and its relationship with the severity of the disease and well-established markers of left ventricular function. UII was significantly higher in CHF patients (n = 57) than in controls (n = 48) [geometric mean (pg/ml), 95% PI: 1.32 (0.67-2.59) versus 0.84 (0.31-1.61), p < 0.0001], was related to the functional class of the disease and correlated negatively with left ventricular ejection fraction (r = -0.316, P = 0.016). Furthermore, UII correlated significantly with Big-ET1 (r = 0.32, p = 0.03), BNP (r = 0.42, p = 0.005) but poorly with Nt-proANP (r = 0.28, p = 0.07). Our results suggest that UII could play a role in worsening the course of congestive heart failure and is associated with established markers of cardiovascular dysfunction.
Asunto(s)
Insuficiencia Cardíaca/sangre , Hormonas/metabolismo , Miocardio/patología , Urotensinas/sangre , Anciano , Femenino , Ventrículos Cardíacos/patología , Humanos , Masculino , Persona de Mediana Edad , Neurotransmisores/metabolismo , Péptidos Cíclicos/química , Radioinmunoensayo , Disfunción Ventricular Izquierda/sangreRESUMEN
Catabolic states caused by injury are characterized by a loss of skeletal muscle. The anabolic action of IGF-I on muscle and the reduction of its muscle content in response to injury suggest that restoration of muscle IGF-I content might prevent skeletal muscle loss caused by injury. We investigated whether local overexpression of IGF-I protein by gene transfer could prevent skeletal muscle atrophy induced by glucocorticoids, a crucial mediator of muscle atrophy in catabolic states. Localized overexpression of IGF-I in tibialis anterior (TA) muscle was performed by injection of IGF-I cDNA followed by electroporation 3 d before starting dexamethasone injections (0.1 mg/kg.d sc). A control plasmid was electroporated in the contralateral TA muscle. Dexamethasone induced atrophy of the TA muscle as illustrated by reduction in muscle mass (403 +/- 11 vs. 461 +/- 19 mg, P < 0.05) and fiber cross-sectional area (1759 +/- 131 vs. 2517 +/- 93 mum(2), P < 0.05). This muscle atrophy was paralleled by a decrease in the IGF-I muscle content (7.2 +/- 0.9 vs. 15.7 +/- 1.4 ng/g of muscle, P < 0.001). As the result of IGF-I gene transfer, the IGF-I muscle content increased 2-fold (15.8 +/- 1.2 vs. 7.2 +/- 0.9 ng/g of muscle, P < 0.001). In addition, the muscle mass (437 +/- 8 vs. 403 +/- 11 mg, P < 0.01) and the fiber cross-sectional area (2269 +/- 129 vs. 1759 +/- 131 mum(2), P < 0.05) were increased in the TA muscle electroporated with IGF-I DNA, compared with the contralateral muscle electroporated with a control plasmid. Our results show therefore that IGF-I gene transfer by electroporation prevents muscle atrophy in glucocorticoid-treated rats. Our observation supports the important role of decreased muscle IGF-I in the muscle atrophy caused by glucocorticoids.
Asunto(s)
Dexametasona/farmacología , Terapia Genética , Factor I del Crecimiento Similar a la Insulina/genética , Músculo Esquelético/patología , Atrofia Muscular/terapia , Animales , Electroporación , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Proteínas Musculares/análisis , Miofibrillas/patología , Ratas , Ratas Wistar , TransfecciónRESUMEN
The pathogenesis of pulmonary arterial hypertension (PAH) remains uncertain. Both the serotonin and endothelin (ET) systems are believed to be involved. Recent studies pointed to the importance of the serotonin 2B receptor as a limiting step. The current authors investigated the lung tissue expression of serotonin receptors and of the serotonin transporter (5-HTT) by real-time-quantitative polymerase chain reaction in chronic overcirculation-induced PAH in growing piglets, with and without treatment with the dual ET receptor blocker bosentan. Pulmonary haemodynamic changes were described by pulmonary arterial impedance spectra. Three months after the surgical anastomosis of the left subclavian artery to the pulmonary arterial trunk, there was a shift of the impedance spectra to higher ratios of pressure and flow moduli, with increases in both 0 Hz impedance and characteristic impedance, and these changes were completely prevented by bosentan therapy. There was an increase in the expression of the serotonin 1B receptor. There was no change in the expression of the 5-HTT, and of the serotonin 2B, 1D, and 4 receptors. The overexpression of the serotonin 1B receptor was partially prevented by bosentan therapy. The present authors conclude that this early pulmonary arterial hypertension model is characterised by an endothelin receptor-dependent increased expression of the serotonin 1B receptor.
Asunto(s)
Hipertensión Pulmonar/metabolismo , Pulmón/metabolismo , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Receptor de Serotonina 5-HT1B/biosíntesis , Animales , Antihipertensivos/uso terapéutico , Bosentán , Proteínas Portadoras/biosíntesis , Hipertensión Pulmonar/tratamiento farmacológico , Glicoproteínas de Membrana/biosíntesis , Reacción en Cadena de la Polimerasa , Circulación Pulmonar , Receptores de Endotelina/fisiología , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Sulfonamidas/uso terapéutico , PorcinosRESUMEN
BACKGROUND: Endothelin-1 (ET-1) and cardiac natriuretic peptide plasma concentrations have prognostic significance in congestive heart failure (CHF). However, their respective prognostic values in this setting have never been directly compared. METHODS AND RESULTS: We studied the prognostic performances of ET-1, N-terminal proatrial natriuretic factor (N-proANF), and brain natriuretic peptide (BNP) to predict the long-term cardiac mortality in fully treated patients with CHF. Peripheral plasma concentrations of the 3 peptides were measured in 109 patients (left ventricular ejection fraction [LVEF] < 35%) in New York Heart Association (NYHA) functional classes II (n = 65) or III to IV (n = 44). The outcome of the patients was evaluated 3 years after the beginning of the study, and a Cox regression model was used to identify predictors of death. Plasma concentrations of the 3 peptides increased with the severity of heart failure. By univariate analysis, 6 parameters were significantly associated with death during follow-up: ET-1 level, NYHA classes III to IV, N-proANF level, BNP level, LVEF, and age (all P < .01). By multivariate analysis, only ET-1 level and, to a lesser extent, N-proANF level contributed significantly and independently to risk stratification (chi2 = 53.4 and 12.8; P < .0001 and P < .001, respectively). CONCLUSION: In a group of patients in whom the vast majority were administered angiotensin-converting enzyme inhibitor therapy, plasma ET-1 and N-proANF concentrations identify better than several clinical markers a very high-risk group, fairly amenable to heart transplantation or new therapies.
Asunto(s)
Factor Natriurético Atrial/sangre , Endotelina-1/sangre , Insuficiencia Cardíaca/sangre , Péptido Natriurético Encefálico/sangre , Precursores de Proteínas/sangre , Anciano , Bélgica/epidemiología , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The aims of this study were to investigate (1) hormonal activation before and during dobutamine cardiac stress testing (DST) in a canine model of early left ventricular dysfunction (ELVD) induced by rapid right ventricular pacing (RRVP) and (2) the relationship between this hormonal profile and carnitine concentrations. Before the pacing period, the 6 dogs were assigned to 2 groups according their baseline total plasma carnitine concentration. A DST was performed on each dog before activation of the pacemaker and every 3 to 4 days during development of 3 progressive stages of ELVD (stages 1, 2 and 3). Plasma atrial natriuretic factor (ANF), angiotensin II (ANG II) and endothelin-1 (ET-1) levels were measured at the start and at the end of each DST. Effects of ELVD, DST and plasma carnitine concentration on these measurements were tested. The RRVP induced a significant increase of ANF and ANG II and a non significant trend toward increase of ET-1 in all dogs. Before the pacing period, ANF remained constant during the DST in dogs with normal total plasma carnitine concentration, while it significantly decreased in dogs with low total plasma carnitine concentration. Dobutamine stress testing induced a significant decrease in ANF in all dogs in ELVD. Dobutamine infusion induced a significant increase in ANG II in all dogs before as well as during the pacing period while ET-1 was unchanged. These results suggest that investigation of the hormonal profile before and after a dobutamine challenge might provide important diagnostic information in dogs with asymptomatic or mildly symptomatic cardiac dysfunction of different origins.
RESUMEN
Glucocorticoids are potent inhibitors of growth. In this work, we investigated whether glucocorticoids inhibit the stimulatory action of GH on IGF-I gene expression in rat hepatocytes. GH increased IGF-I mRNA levels 11-fold after 24 h, whereas high doses of DXM (10(-6)M) caused a slight (2.6-fold) increase of IGF-I mRNA levels. However, high doses of DXM (10(-6)M) inhibited the induction of IGF-I mRNA by GH. To assess the role of GHR in this inhibition, we investigated the regulation of GHR expression. High doses of DXM decreased GHR mRNA levels. This effect was already detectable 6 h after addition of 10(-6)M DXM and was dose-dependent, with a maximal inhibition observed at a concentration of 10(-6)M. In conclusion, our results show that high doses of DXM inhibits the GH-induced IGF-I gene expression and the GHR gene expression. The parallel decrease of GHR and GH-induced IGF-I mRNA suggests that the GH resistance caused by DXM is mediated by diminished GH receptor synthesis.
Asunto(s)
Dexametasona/farmacología , Glucocorticoides/farmacología , Hormona del Crecimiento/antagonistas & inhibidores , Factor I del Crecimiento Similar a la Insulina/genética , Hígado/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , Receptores de Somatotropina/genética , Animales , Northern Blotting , División Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Expresión Génica/efectos de los fármacos , Hígado/citología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas WistarRESUMEN
Both starvation and sepsis are characterized by growth hormone (GH) insensitivity, which leads to a reduction in circulating insulin-like growth factor (IGF)-I. Because of the anabolic properties of this growth factor, its decline may contribute to the growth arrest and the catabolic reaction observed in starvation and sepsis. This review focuses on the mechanisms responsible for the reduction in circulating IGF-I and impairment of GH responsiveness that occur during starvation and sepsis. A clearer understanding of the complex nature of GH resistance should lead to the development of new therapeutic strategies aimed at restoring the beneficial effects of anabolic agents such as GH and IGF-I.
Asunto(s)
Hormona de Crecimiento Humana/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Sepsis/metabolismo , Inanición/metabolismo , Ingestión de Energía , Glucocorticoides/fisiología , Hormona de Crecimiento Humana/fisiología , Humanos , Insulina/fisiologíaRESUMEN
This time-course study further explored the mechanisms whereby monoclonal antibodies (MAbs) may enhance growth hormone (GH) effects. Hypophysectomized rats were killed 0, 1, 3, 6, 12, 24, and 48 h after a single injection of bovine (b) GH alone or complexed with an anti-bGH MAb. Serum insulin-like growth factor I (IGF-I) concentrations were increased more and for a longer period after MAb-GH complexes (peak at 24 h: 295 +/- 24 ng/ml) than after bGH alone (peak at 12 h: 219 +/- 37 ng/ml; P < 0.01), whereas liver IGF-I mRNA was similar at 12 h in both groups but remained higher at 24 h (by 65%, P < 0.001) and 48 h (by 64%, P < 0.001) in the presence of the MAb. Induction of serum insulin-like growth factor-binding protein (IGFBP)-3 and liver IGFBP-3 mRNA by bGH also was markedly amplified by the MAb (3.6- and 2-fold at 24 h, respectively; P < 0.01). GH receptors (GHR) remained occupied for a longer period after MAb-GH injection (36 +/- 16 and 35 +/- 8% at 6 and 12 h, respectively) compared with bGH alone (0 +/- 28 and -15 +/- 11%), whereas total liver GH-binding sites and GHR mRNA levels were not affected by the MAb. We conclude that MAbs against GH amplify and prolong the serum IGF-I response to GH, which may result from both a prolongation of liver IGF-I synthesis and an enhanced induction of IGFBP-3. These two effects may in turn be the consequences of sustained GH binding to its liver receptors in the presence of MAb.