Preditores de Mortalidade Total e Eventos Arrítmicos Graves em Pacientes com Insuficiência Cardíaca Não Isquêmica: O Papel da Galectina-3 / Predictors of Total Mortality and Serious Arrhythmic Events in Non-Ischemic Heart Failure Patients: The Role of Galectin-3

Resumo Fundamento: A estratificação de risco continua sendo clinicamente desafiadora em pacientes com insuficiência cardíaca (IC) de etiologia não isquêmica. A galectina-3 é um marcador sérico de fibrose que pode ajudar no prognóstico. Objetivo: Determinar o papel da galectina-3 como preditora de eventos arrítmicos graves e mortalidade total. Métodos: Este é um estudo de coorte prospectivo que incluiu 148 pacientes com IC não isquêmica. Todos os pacientes foram submetidos a uma avaliação clínica e laboratorial abrangente para coleta de dados de referência, incluindo níveis de galectina-3 sérica. O desfecho primário foi a ocorrência de síncope arrítmica, intervenções apropriadas do cardioversor desfibrilador implantável, taquicardia ventricular sustentada ou morte súbita cardíaca. O desfecho secundário foi a morte por todas as causas. Para todos os testes estatísticos, considerou-se significativo o valor p<0,05 (bicaudal). Resultados: Em seguimento mediano de 941 dias, os desfechos primário e secundário ocorreram em 26 (17,5%) e 30 (20%) pacientes, respectivamente. A galectina-3 sérica>22,5 ng/mL (quartil mais alto) não foi preditora de eventos arrítmicos graves (HR: 1,98; p=0,152). Os preditores independentes do desfecho primário foram diâmetro diastólico final do ventrículo esquerdo (DDFVE)>73 mm (HR: 3,70; p=0,001), ventilação periódica durante o exercício (VPE) no teste de esforço cardiopulmonar (HR: 2,67; p=0,01) e taquicardia ventricular não sustentada (TVNS)>8 batimentos na monitorização por Holter (HR: 3,47; p=0,027). Os preditores de morte por todas as causas foram: galectina-3>22,5 ng/mL (HR: 3,69; p=0,001), DDFVE>73 mm (HR: 3,35; p=0,003), VPE (HR: 3,06; p=0,006) e TVNS>8 batimentos (HR: 3,95; p=0,007). A ausência de todos os preditores de risco foi associada a um valor preditivo negativo de 91,1% para o desfecho primário e 96,6% para a mortalidade total. Conclusões: Em pacientes com IC não isquêmica, níveis elevados de galectina-3 não foram preditores de eventos arrítmicos graves, mas foram associados à mortalidade total. A ausência de preditores de risco revelou um subgrupo prevalente de pacientes com IC com excelente prognóstico.

Abstract Background: Risk stratification remains clinically challenging in patients with heart failure (HF) of non-ischemic etiology. Galectin-3 is a serum marker of fibrosis that might help in prognostication. Objective: To determine the role of galectin-3 as a predictor of major arrhythmic events and overall mortality. Methods: We conducted a prospective cohort study that enrolled 148 non-ischemic HF patients. All patients underwent a comprehensive baseline clinical and laboratory assessment, including levels of serum galectin-3. The primary outcome was the occurrence of arrhythmic syncope, appropriate implantable cardioverter defibrillator therapy, sustained ventricular tachycardia, or sudden cardiac death. The secondary outcome was all-cause death. For all statistical tests, a two-tailed p-value<0.05 was considered significant. Results: In a median follow-up of 941 days, the primary and secondary outcomes occurred in 26 (17.5%) and 30 (20%) patients, respectively. Serum galectin-3>22.5 ng/mL (highest quartile) did not predict serious arrhythmic events (HR: 1.98, p=0.152). Independent predictors of the primary outcome were left ventricular end-diastolic diameter (LVEDD)>73mm (HR: 3.70, p=0.001), exercise periodic breathing (EPB) on cardiopulmonary exercise testing (HR: 2.67, p=0.01), and non-sustained ventricular tachycardia (NSVT)>8 beats on Holter monitoring (HR: 3.47, p=0.027). Predictors of all-cause death were galectin-3>22.5 ng/mL (HR: 3.69, p=0.001), LVEDD>73mm (HR: 3.35, p=0.003), EPB (HR: 3.06, p=0.006), and NSVT>8 beats (HR: 3.95, p=0.007). The absence of all risk predictors was associated with a 91.1% negative predictive value for the primary outcome and 96.6% for total mortality. Conclusions: In non-ischemic HF patients, elevated galectin-3 levels did not predict major arrhythmic events but were associated with total mortality. Absence of risk predictors revealed a prevalent subgroup of HF patients with an excellent prognosis.

Serum galectin-3 levels are decreased in schizophrenia

Objective: To determine whether changes in serum galectin-3 (gal-3) concentrations in schizophrenia patients have etiopathogenetic importance. Since very little research has assessed the connection between galectins and schizophrenia, we wanted to examine alterations in the inflammatory marker gal-3 in schizophrenia and investigate possible correlations between clinical symptomatology and serum concentrations. Methods: Forty-eight schizophrenia patients and 44 healthy controls were included in this study. The Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) were administered to determine symptom severity. Venous blood samples were collected, and serum gal-3 levels were measured. Results: Mean serum gal-3 levels were significantly lower in schizophrenia patients, and there were no significant differences in age or sex with the control group. There was also a significant positive correlation between serum gal-3 concentrations and negative schizophrenia symptoms according to the SANS. Conclusion: The results indicate that gal-3 is decreased in schizophrenia patients, which could contribute to inflammation in the pathogenesis of schizophrenia.

Intercellular mediators in bone remodeling regulation in the experimental renal pathology / Mediadores intercelulares de la regulación de la remodelación ósea en un modelo experimental de patología renal

Bone metabolism disorders are characterized by an imbalance of bone resorption and formation in the bone remodeling process. Glucocorticoids that are used to treat kidney diseases exacerbate these disorders. P-selectin and galectin-3 are molecules involved in the sclerotic process in kidney, whereas bone resorption is regulated by the interaction between the nuclear factor activator kappa b receptor (RANK), its ligand (RANKL) and the RANKL decoy receptor osteoprotegerin (OPG). The aim of this study was to investigate the cellular and molecular mechanisms of disruption of bone remodeling regulation processes, reflected by intercellular mediators (RANKL, OPG, P-selectin and galectin-3) in chronic kidney disease experimental model treated with glucocorticoids. Rats were divided into four groups of 10 animals each. The first group, the control group, included intact animals. The second group consisted of rats with impaired bone remodeling resulting from chronic kidney disease (experimental group (CKD). The third group was a group of animals with impaired bone remodeling due to exposure to glucocorticoids (experimental group (GCs)). The fourth group consisted of rats with impaired bone remodeling in chronic kidney disease, followed by exposure to glucocorticoids (experimental group (CKD + GCs)). The effects of CKD and glucocorticoid were evaluated biochemically, histologically and by measuring bone density. An enzymelinked immunoassay was used to measure intercellular mediator levels in the serum. The bone density in the experimental groups was reduced compared to the control group. RANKL levels in animals of three experimental groups were higher than in intact animals. Serum levels of OPG were higher in CKD and GCs groups than in intact animals. At the same time, in the animals' blood serum of the CKD + GCs group, the levels of OPG were lower, than those in animals from the control group. The levels of galectin-3 in the serum of the experimental groups GCs and CKD + GCs were lower than in intact animals. The serum levels of galectin-3 in animals of the CKD group were higher than those in animals from the control group. The levels of P-selectin were lower in the serum of the GCs group than in intact animals. At the same time, the levels of P-selectin were higher in the CKD and CKD + GCs groups, than those in animals from the control group. In conclusion, the study of the complex system of bone remodeling regulation, which includes many factors and their interactions, may lead to the development of new methods for treating patients with chronic kidney disease in order to prevent osteoporosis in the future. (AU)

Las enfermedades metabólicas óseas se caracterizan por un desequilibrio en el proceso de remodelación ósea en los que participan mediadores tales como receptor del activador del factor nuclear- kappa- b (RANK), su ligando (RANKL) y la osteoprotegerina (OPG). Los glucocorticoides, recuentemente empleados en el tratamiento de la enfermedad renal crónica, exacerban este desequilibrio. En la enfermedad esclerótica renal, las moléculas de adhesión celular P-selectina and galectina-3 tienen un rol fundamental. El objetivo de esta trabajo fue estudiar las alteraciones en los mediadores de la remodelación ósea (RANKL, OPG, P-selectina and galectina-3) en un modelo de enfermedad renal crónica con tratamiento glucocorticoideo. Ratas Wistar hembras fueron divididos en 4 grupos: control (C); enfermedad renal crónica con afección de la remodelación ósea (ERC); animales con afección de la remodelación ósea expuestos a glucocorticoides (GC); enfermedad renal crónica con afección de la remodelación ósea tratados con glucocorticoides (ERC+GC). Los efectos de la ERC y los GC fueron evaluados bioquímicamente, histológicamente y por medición de la densidad ósea. RANKL, OPG, Pselectina and galectina-3 se cuantificaron en muestras de sangre venosa empleando enzimoinmuno análisis. En los 3 grupos experimentales la densidad ósea se evidenció reducida y los niveles séricos de RANKL elevados respecto al grupo control. Los niveles de OPG en los grupos ERC y GC fueron superiores mientras que en el grupo ERC+GC menores respecto a los animales controles. Galectina 3 plasmática en GC y ERC+GC se encontró reducida y aumentada en los animales ERC, en comparación con los animales controles. La concentración sérica de P-selectina sérica fue mayor en los grupos ERC y ERC+GC, y menor en los animales GC respecto a los niveles plasmáticos de los animales intactos. El avance del conocimiento sobre la regulación de la remodelación ósea a través de la interacción de mediadores sistémicos, en un futuro, puede conducir al desarrollo de nuevas estrategias terapéuticas para la prevención de la osteoporosis en pacientes con enfermedad renal crónica. (AU)

Biomarcadores de fibrosis y función ventricular derecha en maratonistas con distinto grado de entrenamiento: estudio en la maratón de Santiago / Fibrosis and right ventricular function biomarkers in marathon runners: a study at the Santiago, Chile marathon

Resumen: Introducción: Atletas altamente entrenados muestran cambios cardíacos estructurales como adaptación a la sobrecarga, producto del ejercicio repetitivo y extenuante. Se han evidenciado elevación de biomarcadores de remodelado y fibrosis miocárdica posterior al ejercicio intenso en atletas. Sin embargo, el comportamiento de estos biomarcadores según el nivel de entrenamiento previo no se ha evaluado. Objetivo: Investigar biomarcadores de fibrosis y función ventricular derecha en maratonistas con distinto nivel de entrenamiento previo. Métodos: Se incluyeron 36 maratonistas hombres, sanos, que completaron 42 km en la maratón de Santiago. Se dividieron según entrenamiento previo en dos grupos, Grupo 1 (G1): ≥100 km/semana y Grupo 2 (G2): <100 km/semana. Se realizó ecocardiografía transtorácica y se evaluaron niveles plasmáticos de galectina-3 y del propéptido amino terminal del procolágeno tipo III (PIIINP) en la semana previa a la carrera e inmediatamente posterior a ésta. Resultados: Posterior a la maratón, la función sistólica del ventrículo derecho disminuyó en el grupo G2 junto con un aumento significativo de los niveles plasmáticos de PIIIPNP (61±16 a 94±24 ng/mL, p=0,01). Estos cambios no se observaron en el grupo G1 (65 ± 11 a 90±29 ng/mL, p=0,10). Los niveles plasmáticos de galectina-3 aumentaron significativamente en ambos grupos posterior al ejercicio (6,8±2,2 a 19,7±4,9 ng/mL, p 0,012 y 6,0±1,1 a 19,4 ± 5,9 ng/mL, p 0,01) en los grupos G1 y G2, respectivamente). Conclusiones: Atletas con menor grado de entrenamiento, presentan posterior a una maratón un significativo aumento de productos de degradación del colágeno (PIIIPNP) asociado a disminución de la función del ventrículo derecho. Los niveles de galectina-3 plasmática aumentan significativamente en ambos grupos post-esfuerzo independiente del entrenamiento previo.

Abstracts: Introduction: Highly trained athletes show structural cardiac changes as adaptation to overload. Rise in remodeling biomarkers and myocardial fibrosis after intense exercise in athletes has been evidenced; however, the behavior of these biomarkers according to pre-competition training level has not been evaluated. Objective: To evaluate fibrosis biomarkers levels and right ventricle function in marathon runners according to their previous training level, in the period prior to a marathon race and immediately after it. Methods: Thirty-six healthy male marathon runners were included. Subjects were grouped according to their previous training level: Group 1 (G1): ≥100 km/week and Group 2 (G2): <100 km/week. Transthoracic echocardiography along with plasmatic levels of galectin-3 and amino terminal propeptide of type III procollagen (PIIINP) were measured one week previous and immediately after the marathon. Results: Post-effort right ventricle systolic function decreased in G2, together with a significant elevation of PIIIPNP (61±16 to 94±24 ng/mL, p=0.01). These changes were not observed in G1 (from 65±11 to 90±29 ng/mL, p=0.10). Plasma galectin-3 increased significantly in both groups immediately post-exercise (6.8±2.2 to 19.7±4.9 ng/mL, p=0.012, and 6.0±1.1 to 19.4±5.9 ng/mL, p=0.01, in G1 and G2. respectively). Conclusion: Less trained athletes evidenced higher post marathon levels of PIIIPNP which is associated with a decreased global right ventricle function. Plasma galectin-3 levels increased significantly after intense exertion regardless of the intensity of previous training.

Global longitudinal strain as a biomarker in diabetic cardiomyopathy. A comparative study with Gal-3 in patients with preserved ejection fraction / Deformación longitudinal global como un biomarcador en miocardiopatía diabética. Estudio comparativo con galectina-3 en pacientes con fracción de eyección preservada

Abstract: Objectives: To establish a relationship between global longitudinal strain (GLS) and Galectin-3 in pre-clinical heart failure in diabetic patients. Galectin-3 is a biomarker in heart failure with depressed ejection fraction (HFdEF). The hypothesis is presented that Galectin-3 is related to GLS and can detect left ventricular dysfunction in heart failure with preserved ejection fraction. Methods: Galectin-3 and GLS were measured in 121 asymptomatic individuals: 14 diabetics with mild depressed ejection fraction (mdEF) (LVEF 47.0 ± 6.9); 76 diabetics with preserved ejection fraction (LVEF 61 ± 5.5), and 31 controls (61.7 ± 5.1). Results: Galectin-3 was elevated in all diabetics vs controls (3.46 ± 1.36 ng/ml vs 2.78 ± 0.91 ng/ml; p = .003). It was also elevated in mdEF (3.76 ± 1.12 ng/ml vs 2.78 ± 0.9 ng/ml; p = .009) and pEF subjects (3.41 ± 1.40 ng/ml vs 2.78 ± 0.9 ng/ml; p = .058), respectively, vs controls. No difference in Gal-3 was found between diabetic groups (p = .603). Diabetics had lower GLS than controls (-18.5 ± 3.9 vs -20 ± 2.6; p = .022). Diabetics with mdEF had lower GLS than those with pEF (-13.3 ± 3.41 vs -19 ± 3.2; P<.001). There was no difference in GLS with pEF compared to controls (-19.4 ± 3.2 vs -20 ± 2.6; p = .70). Conclusions: Galectin-3 is elevated in diabetic patients with mdEF, and is associated with a diminished GLS. GLS could be an early marker of left ventricular dysfunction as well as evidence of diabetic cardiomyopathy.

Resumen: Objetivos: Establecer una asociación entre deformación longitudinal global (DLG) y galectina-3 en insuficiencia cardiaca preclínica en pacientes diabéticos. Galectina-3 es un biomarcador en insuficiencia cardiaca con fracción de eyección deprimida. Nuestra hipótesis es que la DLG y galectina-3 correlacionan y pueden detectar disfunción ventricular en insuficiencia cardiaca con FEVI preservada. Métodos: Se midieron galectina-3 y DLG en 121 individuos asintomáticos: 14 diabéticos con FEVI deprimida leve (FEdl) (FEVI 47 ± 6.9); 76 diabéticos con FEVI preservada (FEp) (FEVI 61 ± 5.5) y 31 sujetos controles (FEVI 61.7 ± 5.1). Resultados: Galectina-3 se encontró elevada en todos los diabéticos vs controles (3.46 ± 1.36 ng/ml vs 2.78 ± 0.91 ng/ml; p = 0.003). Está elevada en sujetos con FEdl (3.76 ± 1.12 vs 2.78 ± 0.9 vs ng/ml p = 0.009) y FEp (3.41 ± 1.40 vs 2.78 ± 0.9 ng/ml p = 0.058), respectivamente vs controles; no encontramos diferencia en galectina-3 en ambos grupos de diabéticos (p = 0.603). Los diabéticos tienen menor DLG que los controles (-18.5 ± 3.9 vs -20 ± 2.6; p = 0.022). Los diabéticos con FEdl tienen DLG más disminuida que aquellos con FEp (-13.3 ± 3.41 vs -19 ± 3.2; p < 0.001). No existe diferencia en DLG con FEp y controles (-19.4 ± 3.2 vs -20 ± 2.6; p = 0.70). Conclusiones: Galectina-3 está elevada en diabéticos con FEdl y correlaciona DLG disminuida. DLG podría ser un marcador temprano de disfunción ventricular y evidencia en miocardiopatía diabética.

Galectina-3: experiencia en pacientes chilenos con diagnóstico de insuficiencia cardíaca descompensada / Galectin-3 levels in patients hospitalized for decompensated heart failure

Background: Galectin-3 (Gal-3) is a mediator of myocardial fibrosis involved in cardiac remodeling and a potential new prognosis marker in heart failure (HF). Aim: To measure Gal-3 at the moment of discharge in patients hospitalized for HF and its association with different variables. Material and Methods: Patients hospitalized for decompensated HF from four hospitals between August 2014 and March 2015, were included. Demographic, clinical and laboratory variables were recorded at the time of admission. At discharge, a blood sample was withdrawn to measure Gal-3 and brain natriuretic propeptide (Pro-BNP). Patients were separated in two groups, according to the level of Gal-3 (using a cutoff value of 17.8 ng/mL), comparing clinical and laboratory values between groups. Results: We included 52 patients with HF aged 70 ± 17 years (42% females). Functional capacity was III-IV in 46% of patients and the ejection fraction was 34.9 ± 13.4%. Pro-BNP values at discharge were 5,323 ± 8,665 pg/mL. Gal-3 values were 23.8 ± 16.6 ng/mL. Sixty percent of patients had values over 17.8 ng/mL. Those with elevated Gal-3 levels were older (75 ±16 and 62 ± 15 years, respectively, p = 0.025) and were hypertensive in a higher proportion (90.5% and 57.1% respectively, p = 0.021). Conclusions: In patients hospitalized for HF, Gal-3 levels are higher in older and hypertensive subjects.

Remodelado auricular derecho y niveles plasmáticos de galectina-3 se relacionan con la capacidad funcional de pacientes con hipertensión arterial pulmonar / Right atrial remodeling and plasma leves of galectin-3 are related to functional capacity in patiensts with pulmonary artery hypertension

Introducción: En pacientes con hipertensión arterial pulmonar (HAP) Galectina- 3, biomarcador de fibrosis miocárdica, se ha asociado a marcadores ecocardiográficos de remodelado ventricular derecho. La relación entre Galectina- 3, remodelado auricular derecho (AD) y capacidad funcional (CF) en pacientes con HAP no ha sido explorado. El objetivo fue medir niveles de Galectina-3 y su relación con CF y remodelado AD en pacientes con HAP Metodos: Estudio prospectivo observacional en que se incluyeron 14 pacientes con HAP En todos los pacientes se midieron los niveles de Galectina-3, proBNP, se evaluó la CF mediante test de caminata 6 minutos (TC6M) y se evaluó remodelado AD. Se consideraron para el análisis dos grupos según la distancia caminada en TC6M (> 200 m vs. ≤ 200 m). Resultados: La edad promedio fue 43 ± 10 años, el 84% mujeres. Los niveles de Galectina-3 fueron 16,1 ± 7,4 ng/mL y el TC6M fue 371 ± 142 mts. Los pacientes con TC6M< 200 m presentaron mayores niveles de Galectina-3 (27,3 ± 4,6 vs 13,7 ± 3,8; p=0,006) y mayor volumen AD (151 ± 21 vs 94 ± 43; p=0,04). Además, se observó una correlación inversa entre el área AD y TC6M (-0,71; p=0,03). Conclusión: Niveles elevados de Galectina-3 y parámetros de remodelado adverso en AD se relacionan con una menor CF en pacientes con HAP. Estos hallazgos apuntan a una mejor caracterización de pacientes con HAP y eventualmente la búsqueda de nuevos objetivos terapéuticos.

Background: Galectin-3 is a biomarker of myo-cardial fibrosis and has been associated with echocar-diographic markers of right ventricular remodeling in patients with pulmonary artery hypertension (PAH). The association among Galectin-3 level, right atrial (RA) remodeling and functional capacity (FC) has not been explored. The objective was to measure plasma Galectin-3 concentrations and its relation with RA remodeling and FC in PAH patients. Methods: This is a prospective observational study and 14 PAH patients were included. Galectin-3 and proBNP levels were measured in all patients. FC was estimated by the 6-minute walk test (6MWT) and used to define 2 groups of subjects (≤200m or >200m). RA area and volume were measured by echocardiography from a 4 chamber view. Results: The average age was 43±10 years, 84% of patients were female. Galectin-3 levels were 16.1±7.4 ng / mL and 6MWT was 371±142 m. We observed an inverse correlation between RA area and 6MWT (-0.71;p=0.03). Conclusions: Higher Galectin-3 concentrations and RA adverse remodeling are related to a decreased FC in PAH patients. These findings may lead to a better characterization of PAH patients and eventually new therapeutic targets.

prognostic significance of galectin-3 and p-selectin in transitional cell carcinoma of the urinary bladder

Bladder carcinoma is one of the most common malignancies in urology. The most common type of the bladder cancer is transitional cell carcinoma [TCC]. TCC of bladder has a recurrence rate of more than 50%. Therefore, it is important to find some indicators that can predict for recurrence or the development of metastasis. This study investigates the prognostic significance of preoperative serum levels of galectin-3 and P-selectin in patients with transitional cell carcinoma [TCC] of the urinary bladder. Preoperative serum levels of galectin-3 and P-selectin were measured by ELISA [enzyme-linked immune-sorbent assay]. The study showed that Galectin-3 and P-selectin serum levels were higher in patients with bladder cancer than in healthy controls. Patients with metastasis had significantly higher levels of both serum Galectin-3 and P-selectin than with localized diseases. High levels of serum Galectin-3 and P-selectin were significantly associated with the clinical tumour stage. However, no significant difference detected between serum levels of galectin-3 and P-selectin in grade II and grade III TCC subgroups. Also, there is a positive correlation between serum Galectin-3 and P-selectin in both control and patient groups. Univariate analysis showed that preoperative serum level of Galectin-3, P-selectin and clinical stages were indicative for clinical progression and tumour specific survival. In a multivariate analysis, clinical stages were an independent prognostic marker for clinical progression and tumour specific survival. These results indicate that both serum Galectin-3, P-selectin levels and clinical tumour stages are closely related to poor prognosis in bladder cancer. So, their levels in bladder cancer patients may be useful in identifying patients at high risk of tumor recurrence