106 research outputs found

    Tubo digestivo e inflamación en la insuficiencia cardiaca. Aspectos fisiopatológicos e implicaciones a nivel pronóstico y terapéutico.

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    En las últimas décadas, las bases de la fisiopatología de la IC han sufrido importantes cambios. La IC ha pasado a entenderse como un trastorno sistémico, neurohormonal e inflamatorio en el que se ven implicados numerosos sistemas y órganos, contribuyendo la afectación de estos últimos a la progresión clínica de la enfermedad. En este sentido, la participación del intestino y la microbiota intestinal ha despertado considerable interés, tanto por verse implicado en la fisiopatología de la IC como por su contribución en el pronóstico de la enfermedad. Desde un punto de vista teórico, las alteraciones hemodinámicas presentes en la IC pueden producir alteraciones en la morfología y función del tubo digestivo. Una baja perfusión por bajo gasto cardiaco o un aumento de la presión venosa central por congestión sistémica, aumenta el riesgo de isquemia intestinal. La combinación de la anoxia y el sobrecrecimiento de bacterias gram-negativas provocaría un aumento de la permeabilidad y favorecería el transporte de bacterias y/o sus productos a través de la pared intestinal. El acúmulo de productos bacterianos en el torrente circulatorio podría explicar el incremento característico de biomarcadores inflamatorios en los pacientes con IC asociados a una peor progresión de la enfermedad. Por tanto, resultaría de gran interés poder detectar este perfil de pacientes con alteraciones de la microbiota intestinal de forma sencilla ya que podrían encontrarse bajo un riesgo mayor de presentar episodios adversos. En este sentido, el estudio de la actividad bacteriana intestinal a partir de los test del aliento para la determinación del sobrecrecimiento bacteriano del intestino delgado (SBID) podría ser una herramienta útil. Estos tests son fáciles de utilizar, están ampliamente disponibles, son no invasivos y de bajo coste. El test consiste en administrar un sustrato carbohidratado y más tarde cuantificar el H2 o CH4 resultante en el aliento. Se basa en la capacidad de la flora bacteriana de fermentar los carbohidratos de la luz intestinal liberando ambos gases. Una parte de los gases producidos por las bacterias se absorbe a través de la pared del intestino delgado, del intestino grueso, o de ambos, y son transportados hasta los pulmones, donde se liberan por el aliento permitiendo su medición. Así, postulamos que la cuantificación del SBID mediante la prueba de aliento de medición de H2 y CH4 espirado tras la ingesta oral de lactulosa se asociaría a mayor gravedad de la enfermedad y de manera independiente, a factores de riesgo establecidos y a un aumento del riesgo de episodios adversos clínicos. El objetivo primario del estudio fue conocer la prevalencia de SBID en esta población y evaluar si la estimación del SBID mediante el test del aire espirado midiendo H2 y CH4 tras la sobrecarga de lactulosa, aporta información a nivel pronóstico independiente con respecto al riesgo de muerte, ingresos o visitas al hospital no planeadas en una población de pacientes con IC avanzada. En concreto los episodios adversos clínicos que se evaluaron fueron: a) el episodio combinado de muerte por todas las causas y/o reingreso por cualquier causa; b) el compuesto de muerte por todas las causas y/o reingreso por cualquier causa y/o visita a urgencias muerte por todas las causas; c) el riesgo de reingresar repetidas veces por IC y d) riesgo de presentar repetidos ingresos de cualquier causa. Los objetivos secundarios fueron: a) evaluar la posible relación entre la concentración de H2 y CH4 en el aire espirado y el riesgo de muerte por todas las causas y el episodio combinado de muerte por todas las causas y/o reingreso por IC aguda; b) describir la relación existente entre la estimación del SBID mediante el test del aire espirado tras sobrecarga de lactulosa y los niveles de biomarcadores de actividad inflamatoria; c) describir cuáles son las variables clínicas que predicen significativa e independientemente los niveles de H2 y CH4 espirado tras el test del aire espirado. Para ello, se incluyeron 102 pacientes que cumplían con todos los criterios de inclusión y ninguno de exclusión. Tras firmar el consentimiento informado, se programó una visita clínica en el siguiente día laborable. Esta visita que consistía en: una valoración clínica, un electrocardiograma, un ecocardiograma (si no se disponía de uno previo en los 3 últimos meses), un análisis clínico (que incluyó la determinación de proteína-C-reactiva (PCR), procalcitonina (PCT), interleuquina-1(IL-1), interleuquina-10 (IL-10), interleuquina-6 (IL-6) y factor de necrosis tumoral-? (TNF-?)) y la realización del test de estimación de SBID a partir de pruebas del aliento con lactulosa como sustrato glucídico (Gastro-kit-ISOMED©). A partir de este momento, comenzó el registro de los datos demográficos, clínicos y analíticos. El seguimiento de los pacientes se llevó a cabo a partir de la historia clínica electrónica y por las vistas programadas a la unidad de IC del centro. Para el análisis estadístico, las diferencias entre grupos de distribuciones no paramétricas se calcularon por el test de Mann-Whitney y para aquellas de distribución normal, las diferencias entre grupos se calcularon mediante el test t de Student. Las características de la población se evaluaron por el área bajo la curva que describe la concentración de hidrógeno (AUC-H2) y metano (AUC-CH4) a partir del método de los trapecios. La cantidad total de gases se calculó a partir de la adición de los valores de AUC-H2 a los de AUC-CH4, constituyendo el área bajo la curva de ambos gases acumulados (AUC-H2-CH4). El tiempo hasta el primer episodio adverso estratificado de acuerdo a los cuartiles del AUC-H2, AUC-CH4 y AUC-H2-CH4 se representó mediante las curvas de Kaplan-Meier y sus diferencias estimadas mediante el peto-peto test. La asociación, independiente de reconocidas variables de interés pronóstico y el tiempo hasta el primer episodio adverso clínico se evaluó mediante regresión de riesgos proporcionales de COX y sus resultados fueron expresados como Hazard Ratios (HR) y sus respectivos intervalos de confianza del 95%. La capacidad discriminativa y la asunción de proporcionalidad se evaluó mediante el estadístico C de Harrell y los residuos de Schoenfeld, respectivamente. Las hospitalizaciones recurrentes se analizaron mediante el método de regresión binomial negativa con ajuste simultáneo por muerte como episodios adverso final. Las estimaciones de riesgo se presentaron como incidence rate ratios (IRR). Para determinar los factores de riesgo que predecían el logaritmo del AUC-H2 (log AUC-H2) y el logaritmo del AUC-CH4 (log AUC-CH4) se realizó un análisis de regresión lineal multivariante. Se consideró como significativa una p de dos colas<0.05 en todos los casos. Para todos los análisis se realizaron utilizando la plataforma estadística STATA 14.1. La prevalencia de SBID evaluado mediante el test del aliento, fue elevada. De acuerdo al criterio diagnóstico que ofrece mayor sensibilidad, hasta un 65,69% de los pacientes con IC obtuvieron un resultado positivo en el test de SBID. La concentración de H2 y CH4 en el test del aliento se relacionó con un aumento del riesgo de presentar episodios adversos durante el seguimiento a medio-largo plazo. Así, y en particular la concentración de H2 espirado, se asoció de forma independiente con el tiempo hasta presentar el episodio combinado de muerte y/o reingreso por cualquier causa. En el análisis univariante y en el análisis multivariante (ajustado por reconocidas variables de interés clínico) de AUC-H2 (por el incremento de 1000 unidades) y el tiempo hasta el episodio combinado muerte y/o reingreso por cualquier causa (HR= 1,25; IC 95%:1,08-1,45; p=0,003 y HR=1,23; IC 95%:1,05-1,45; p=0,009, respectivamente) se obtuvo una asociación independiente. Del mismo modo, las curvas de Kaplan-Meier revelaron un aumento progresivo del riesgo de presentar el episodio vinculado a un aumento del AUC-H2. AUC-H2 también se asoció de forma independiente con el tiempo hasta el episodio combinado más completo (muerte/reingreso/visitas a urgencias), se alcanzó la significación estadística en el análisis univariante (HR=1,19, IC 95%: 1,04-1,36, p=0,011). En el análisis de riesgo multivariante (ajustado por diabetes mellitus, clase NYHA, historia de bloqueo de rama en el electrocardiograma (ECG), FEVI, frecuencia cardiaca, urea, sodio y dosis de diuréticos de asa) también se obtuvo una relación lineal e independiente (HR=1,27, IC 95%: 1,09-1.47, p=0,002). En ninguno de los casos el AUC-CH4 se relacionó con los episodios adversos clínicos. Así mismo, se halló una relación lineal significativa e independiente entre AUC-H2 y el riesgo de ingresos recurrentes, tanto por IC aguda como por todas las causas posibles (IRR=1,27; IC 95%:1,06-1,52; p=0,010 y (IRR=1,14; IC 95%:1,03-1,27; p=0,014, respectivamente). Por último, la concentración de H2 y CH4 en el aire espirado se asoció de manera positiva con parámetros relacionados con la gravedad de la enfermedad. El logaritmo de AUC-H2 (logAUC-H2) y algunos parámetros inflamatorios característicos en la IC guardaron una correlación significativa pero por lo general débil: IL-1? (r=0,21; p=0,032), TNF-? (r=0,23; p=0,018) e IL-10 (r=0,22; p=0,029). LogAUC-CH4 también se asoció de forma significativa pero débil con IL-1? (r=0,24; p=0,018). En el análisis multivariante utilizando regresión múltiple robusta, los predictores independientes de logAUC-H2 fueron la FEVI, la interacción edemas periféricos*dosis de diuréticos (valor de p para la interacción<0.001), la interacción ingreso reciente*edemas periféricos (valor de p para la interacción=0,017), el recuento linfocitario porcentual, el TNF-alfa, y la presión arterial pulmonar evaluada mediante ecocardiograma. En el análisis multivariante de regresión múltiple robusta los predictores independientes del logaritmo de AUC-CH4 (logAUC-CH4) fueron: Índice de Charlson, una descompensación reciente y la interacción edemas periféricos*dosis de diuréticos (valor de p para la interacción=0,018). La concentración en sangre de triglicéridos y la PAPS mostraron una correlación lineal y negativa con logAUC-CH4. Específicamente, tanto logAUC-H2 como logAUC-CH4 se asociaron con el estado más avanzado (clínico y hemodinámico), una mayor actividad inflamatoria y signos clínicos de mayor sobrecarga hídrica

    Uso de neumocitos de tipo II en el tratamiento de enfermedades pulmonares asociadas con fibrosis pulmonar

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    Se describe el empleo de neumocitos tipo II como agentes inhibidores de la proliferación de fibroblastos, por lo que pueden ser utilizados en la elaboración de un medicamento para el tratamientode enfermedades pulmonares que cursan con fibrosis pulmonar.Peer reviewedConsejo Superior de Investigaciones Científicas (España)T3 Traducción de patente europe

    In vivo antioxidant treatment protects against bleomycin-induced lung damage in rats

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    This study examines the activity of the antioxidant N-acetylcysteine on bleomycin-induced pulmonary fibrosis in rats with emphasis on the early inflammatory phase. Rats receiving N-acetylcysteine (300 mg kg−1 day−1, intraperitoneal) had less augmented lung wet weight, and lower levels of proteins, lactate dehydrogenase, neutrophil and macrophage counts in bronchoalveolar lavage fluid and lung myeloperoxidase activity with a betterment of histological score at 3 days postbleomycin. A diminished lung GSH/GSSG ratio and augmented lipid hydroperoxides were observed 3 days postbleomycin. These changes were attenuated by N-acetylcysteine. Alveolar macrophages from bleomycin-exposed rats released augmented amounts of superoxide anion and nitric oxide. N-Acetylcysteine did not modify superoxide anion generation but reduced the increased production of nitric oxide. N-Acetylcysteine suppressed the bleomycin-induced increased activation of lung NF-κB (shift assay and immunohistochemistry), and decreased the augmented levels of the early inflammatory cytokines, tumour necrosis factor-α, interleukin-β, interleukin-6 and macrophage inflammatory protein-2 observed in bronchoalveolar lavage fluid at 1 and 3 days postbleomycin exposure. At 15 days postbleomycin, N-acetylcysteine decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content: 6351±669 and 4626±288 μg per lung in drug vehicle- and N-acetylcysteine-treated rats, respectively; P<0.05). Semiquantitative histological assessment at this stage showed less collagen deposition in N-acetylcysteine-treated rats compared to those receiving bleomycin alone. These results indicate that N-acetylcysteine reduces the primary inflammatory events, thus preventing cellular damage and the subsequent development of pulmonary fibrosis in the bleomycin rat model.This work was supported by Grant 1FD97-1143 from the European Union (Regional Development Funds, FEDER), CICYT (Spanish Government), Regional Government (Generalitat Valenciana) and Grant FIS98/1367 (Spanish Ministry of Health).Peer reviewe

    Improved Alveolar Dynamics and Structure After Alveolar Epithelial Type II Cell Transplantation in Bleomycin Induced Lung Fibrosis

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    Idiopathic pulmonary fibrosis (IPF) is a progressively and ultimately fatal lung disease. Previously it has been shown that intratracheal administration of alveolar epithelial type II cells (AE2C) in the animal model of bleomycin-induced pulmonary fibrosis is able to reverse fibrosis and restore surfactant protein levels. However, to date, it has not been evaluated whether these changes involve any improvement in alveolar dynamics. Consequently, the aim of the present work was to study lung physiology after AE2C transplantation at different time points during the development of injury and fibrosis. Lung fibrosis was induced by intratracheal instillation of bleomycin (4U/kg) in rat lungs. The animals were transplanted with AE2C (2.5 x 10(6) cells/animal) 3 or 7 days after bleomycin instillation. Assessments were done at day 7 and 14 after the induction of fibrosis to plot time dependent changes in lung physiology and mechanics. To assess the pressures and rates at which closed alveoli reopens invasive pulmonary tests using a small-animal mechanical ventilator (Flexivent (R), Scireq, Canada) including de-recruitability tests and forced oscillation technique as well as quasi-static pressure volume loops were performed. Afterwards lungs were fixed by vascular perfusion and subjected to design-based stereological evaluation at light and electron microscopy level. AE2C delivered during the lung injury phase (3 days) of the disease are only able to slightly recover the volume of AE2C and volume fraction of LB in AE2C. However, it did not show either positive effects regarding ventilated alveolar surface nor any increase of lung compliance. On the other hand, when AE2C are delivered at the beginning of the fibrotic phase (7 days after bleomycin instillation), an increased ventilated alveolar surface to control levels and reduced septal wall thickness can be observed. Moreover, transplanted animals showed better lung performance, with increased inspiratory capacity and compliance. In addition, a detailed analysis of surfactant active forms [mainly tubular myelin, lamellar body (LB)-like structures and multilamellar vesicles (MLV)], showed an effective recovery during the pro-fibrotic phase due to the healthy AE2C transplantation. In conclusion, AE2C transplantation during fibrogenic phases of the disease improves lung performance, structure and surfactant ultrastructure in bleomycin-induced lung fibrosis

    Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosisdisease progression

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    Angiotensin II is a growth factor that plays a key role in the physiopathology of idiopathic pulmonary fibrosis (IPF). A nucleotide substitution of an adenine instead of a guanine (G-6A) in the proximal promoter region of angiotensinogen (AGT), the precursor of angiotensin II, has been associated with an increased gene transcription rate. In order to investigate whether the G-6A polymorphism of the AGT gene is associated with IPF development, severity and progression, the present study utilised a case–control study design and genotyped G-6A in 219 patients with IPF and 224 control subjects. The distribution of G-6A genotypes and alleles did not significantly differ between cases and controls. The G-6A polymorphism of the AGT gene was not associated with disease severity at diagnosis. The presence of the A allele was strongly associated with increased alveolar arterial oxygen tension difference during follow-up, after controlling for the confounding factors. Higher alveolar arterial oxygen tension changes over time were observed in patients with the AA genotype (0.37¡0.7 mmHg (0.049¡0.093 kPa) per month) compared to GA genotype (0.12¡1 mmHg (0.016¡0.133 kPa) per month) and GG genotype (0.2¡0.6 mmHg (0.027¡0.080 kPa) per month). G-6A polymorphism of the angiotensinogen gene is associated with idiopathic pulmonary fibrosis progression but not with disease predisposition. This polymorphism could have a predictive significance in idiopathic pulmonary fibrosis patients.Supported by grants from FIS-PI; FISPI060064, FIS-IDIBAPS CM05/00118, Sociedad Española de Neumologia y Cirugia Torácica (SEPAR)-Fundación Respira and Faculdade Capivari, Spain.Peer reviewe

    Short-term changes in klotho and FGF23 in heart failure with reduced ejection fraction—a substudy of the DAPA-VO2 study

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    Dapagliflozin; Fibroblast growth factor 23; Functional capacityDapagliflozin; Factor de crecimiento de fibroblastos 23; Capacidad funcionalDapagliflozin; Factor de creixement de fibroblasts 23; Capacitat funcionalThe klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and FGF-23 levels 1-month after dapagliflozin in patients with stable heart failure and reduced ejection fraction (HFrEF). The study included 29 patients (32.2% of the total), with 14 assigned to the placebo group and 15 to the dapagliflozin, as part of the double-blind, randomized clinical trial [DAPA-VO2 (NCT04197635)]. Blood samples were collected at baseline and after 30 days, and Klotho and FGF-23 levels were measured using ELISA Kits. Between-treatment changes (raw data) were analyzed by using the Mann-Whitney test and expressed as median (p25%–p75%). Linear regression models were utilized to analyze changes in the logarithm (log) of klotho and FGF-23. The median age was 68.3 years (60.8–72.1), with 79.3% male and 81.5% classified as NYHA II. The baseline medians of left ventricular ejection fraction, glomerular filtration rate, NT-proBNP, klotho, and FGF-23 were 35.8% (30.5–37.8), 67.4 ml/min/1.73 m2 (50.7–82.8), 1,285 pg/ml (898–2,305), 623.4 pg/ml (533.5–736.6), and 72.6 RU/ml (62.6–96.1), respectively. The baseline mean peak oxygen uptake was 13.1 ± 4.0 ml/kg/min. Compared to placebo, patients on dapagliflozin showed a significant median increase of klotho [Δ+29.5, (12.9–37.2); p = 0.009] and a non-significant decrease of FGF-23 [Δ−4.6, (−1.7 to −5.4); p = 0.051]. A significant increase in log-klotho (p = 0.011) and a decrease in log-FGF-23 (p = 0.040) were found in the inferential analysis. In conclusion, in patients with stable HFrEF, dapagliflozin led to a short-term increase in klotho and a decrease in FGF-23.This work was supported in part by an unrestricted grant from Astra Zeneca (ESR-17-13447), Unidad de Investigación Clínica y Ensayos Clínicos INCLIVA Health Research Institute, Spanish Clinical Research Network (SCReN; PT17/0017/0003 y PT20/00100), RICORS2040 (RD21/0005/0013), and CIBER Cardiovascular [grant number 16/11/00420]

    Losartan prevents heart fibrosis induced by long-term intensive exercise in an animal model

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    Rationale Recently it has been shown that long-term intensive exercise practice is able to induce myocardial fibrosis in an animal model. Angiotensin II is a profibrotic hormone that could be involved in the cardiac remodeling resulting from endurance exercise. Objective This study examined the antifibrotic effect of losartan, an angiotensin II type 1 receptor antagonist, in an animal model of heart fibrosis induced by long-term intense exercise. Methods and Results Male Wistar rats were randomly distributed into 4 experimental groups: Exercise, Exercise plus losartan, Sedentary and Sedentary plus losartan. Exercise groups were conditioned to run vigorously for 16 weeks. Losartan was orally administered daily before each training session (50 mg/kg/day). Time-matched sedentary rats served as controls. After euthanasia, heart hypertrophy was evaluated by histological studies; ventricular collagen deposition was quantified by histological and biochemical studies; and messenger RNA and protein expression of transforming growth factor-β1, fibronectin-1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, procollagen-I and procollagen-III was evaluated in all 4 cardiac chambers. Daily intensive exercise caused hypertrophy in the left ventricular heart wall and originated collagen deposition in the right ventricle. Additionally long-term intensive exercise induced a significant increase in messenger RNA expression and protein synthesis of the major fibrotic markers in both atria and in the right ventricle. Losartan treatment was able to reduce all increases in messenger RNA expression and protein levels caused by exercise, although it could not completely reverse the heart hypertrophy. Conclusions Losartan treatment prevents the heart fibrosis induced by endurance exercise in training animals

    Novel experimental model of maintained acute lung injury

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    Trabajo presentado en el 23rd Annual Congress European Respiratory Society (ERS) celebrado del 7 al 11 de septiembre de 2013 en Barcelona (España)Abstract publicado en "European Respiratory Journal" 42 (Suppl 57): 50s-51s (2013)Rationale: Several animal models have been developed to study acute lung injury (ALI); however the majority of these studies are focused on different mechanisms within the acute phase. These models do not allow studying the mechanisms in the later phases or testing any possible long-term treatment. The aim of this study was to develop an experimental ALI model simulating bronchial aspiration of gastric contents with bacterial superinfection with alveolar epithelial damage persisting over time. Methods: Sprague-Dawley rats (200-250g) were anesthetized with isofl uorane. ALI was induced by intratracheal instillation of HCl (1 μl/g, 0.1 mol/L pH=1.4) followed by instillation of LPS from Escherichia coli O55:B5 (0, 10, 20, 30 or 40μg/g b.w.) two hours later. Control rats were treated with intratracheal instillations of saline. After 72h, the animals were sacrifi ced and bronchoalveolar lavage fl uid (BALF) was sampled for further analysis of total protein concentration by bicinchoninic acid method. Results: At 72 h, rats suffered a signifi cant loss of weight proportional to the administered dose of LPS (5.6% with 10μg/g b.w, 12.6% with 20μg/g b.w, 14.2% with 30μg/g b.w and 17.7% with 40μg/g b.w). Control rats gained in weight at 72h. LPS at 10, 20, 30 and 40μg/g b.w induced a 1.7, 2.5, 2.9 and 3.4 fold increase in total protein concentration in BAL fl uid, respectively, refl ecting a substantial increase proportional to the LPS dose. Conclusion: The degree of weight loss and the increase of total protein concentration in BAL fl uid in the current model may refl ect disease severity and progression. This model would be useful in future for new therapeutical optionsGrant acknowledgements: FIS-PI12/02548 and Fundació Parc TaulíPeer Reviewe

    Profibrotic role of inducible heat shock protein 90α isoform in systemic sclerosis

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    Systemic sclerosis (SSc) is an autoimmune disease that affects skin and multiple internal organs. TGF-β, a central trigger of cutaneous fibrosis, activates fibroblasts with the involvement of the stress-inducible chaperone heat shock protein 90 isoform α (Hsp90α). Available evidence supports overexpression and secretion of Hsp90α as a feature in profibrotic pathological conditions. The aim of this work is to investigate the expression and function of Hsp90α in experimental models of skin fibrosis such as human fibroblasts, C57BL/6 mice, and in human SSc. For this purpose, we generated a new experimental model based on doxorubicin administration with improved characteristics with respect to the bleomycin model. We visualized disease progression in vivo by fluorescence imaging. In this work, we obtained Hsp90α mRNA overexpression in human skin fibroblasts, in bleomycin- and doxorubicin-induced mouse fibrotic skin, and in lungs of bleomycin- and doxorubicin-treated mice. Hsp90α-deficient mice showed significantly decreased skin thickness compared with wild-type mice in both animal models. In SSc patients, serum Hsp90α levels were increased in patients with lung involvement and in patients with the diffuse form of SSc (dSSc) compared with patients with the limited form of SSc. The serum Hsp90α levels of patients dSSc were correlated with the Rodnan score and the forced vital capacity variable. These results provide new supportive evidence of the contribution of the Hsp90α isoform in the development of skin fibrosis. In SSc, these results indicated that higher serum levels were associated with dSSc and lung fibrosis.This work was supported by Spanish Ministerio de Economía, Industria y Competitividad, Gobierno de España Grant RTI2018-095214-B-I00, as well as by the Instituto de Formación e Investigación Marqués de Valdecilla IDIVAL (InnVal 17/22; InnVal 20/34), 2020UCI22-PUB-0003 Gobierno de Cantabria (to A.V.V.), SAF2016-75195-R (to J.M.), SAF2017-82905-R (to R.M.), and (NextVal 18/14) to A.P

    Homocysteine and long-term recurrent infarction following an acute coronary syndrome

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    Background: There are no well-established predictors of recurrent ischemic coronary events after an acute coronary syndrome (ACS). Higher levels of homocysteine have been reported to be associated with an increased atherosclerotic burden. The primary endpoint was to assess the relationship between homocysteine at discharge and very long-term recurrent myocardial infarction (MI).Methods: 1306 consecutive patients with ACS were evaluated (862 with non-ST-segment elevation ACS [NSTEACS] and 444 with ST-segment elevation myocardial infarction [STEMI]) discharged from October 2000 to June 2003 in a single teaching-center. The relationship between homocysteine at discharge and recurrent MI was evaluated through bivariate negative binomial regression accounting for mortality as a competitive event.Results: The mean age was 66.8 ± 12.4 years, 69.1% were men, and 32.2% showed prior diabetes mellitus. Most of the patients were admitted for an NSTEACS (66.0%). The median (interquartile range) GRACE risk score, Charlson comorbidity index, and homocysteine were 144 (122–175) points, 1 (1–2) points, and 11.9 (9.3–15.6) μmol/L, respectively. In-hospital revascularization was performed in 26.3% of patients. At a median follow-up of 9.7 (4.5–15.1) years, 709 (54.3%) deaths were registered and 779 recurrent MI in 478 (36.6%) patients. The rates of recurrent MI were higher in patients in the upper homocysteine quartiles (p &lt; 0.001). After a multivariate adjustment, homocysteine along its continuum remained almost linearly associated with a higher risk of recurrent MI (p = 0.001) and all-cause mortality (p &lt; 0.001).Conclusions: In patients with ACS, higher homocysteine levels identified those at a higher risk of recurrent MI at very long-term follow-up
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