Plasma fibroblast activation protein is decreased in acute heart failure despite cardiac tissue upregulation.

BACKGROUND: Cardiac fibroblast activation protein (FAP) has an emerging role in heart failure (HF). A paradoxical reduction in its levels in pathological conditions associated with acute processes has been observed. We aimed to identify FAP cardiac tissue expression and its relationship with the main cardiac fibrosis-related signaling pathways, and to compare plasma FAP levels in acute and chronic HF patients. METHODS: Transcriptomic changes were assessed via mRNA/ncRNA-seq in left ventricle tissue from HF patients (n = 57) and controls (n = 10). Western blotting and immunohistochemistry were used to explore FAP protein levels and localization in cardiac tissue. ELISA was performed to examine plasma FAP levels in acute HF (n = 48), chronic HF (n = 15) and control samples (n = 7). RESULTS: FAP overexpression in cardiac tissue is related to the expression of molecules directly involved in cardiac fibrosis, such as POSTN, THBS4, MFAP5, COL1A2 and COL3A1 (P < 0.001), and is directly and inversely related to pro- and antifibrotic microRNAs, respectively. The observed FAP overexpression is not reflected in plasma. Circulating FAP levels were lower in acute HF patients than in controls (P < 0.05), while chronic HF patients did not show significant changes. The clinical variables analyzed, such as functional class or etiology, do not affect plasma FAP concentrations. CONCLUSIONS: We determined that in HF cardiac tissue, FAP is related to the main cardiac fibrosis signaling pathways as well as to pro- and antifibrotic microRNAs. Additionally, an acute phase of HF decreases plasma FAP levels despite the upregulation observed in cardiac tissue and regardless of other clinical conditions.

Alterations in Mitochondrial Oxidative Phosphorylation System: Relationship of Complex V and Cardiac Dysfunction in Human Heart Failure.

Heart failure (HF) is a disease related to bioenergetic mitochondrial abnormalities. However, the whole status of molecules involved in the oxidative phosphorylation system (OXPHOS) is unknown. Therefore, we analyzed the OXPHOS transcriptome of human cardiac tissue by RNA-seq analyses (mRNA n = 36; ncRNA n = 30) in HF patients (ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM)) and control subjects. We detected 28 altered genes in these patients, highlighting greater deregulation in ICM. Specifically, we found a general overexpression of complex V (ATP synthase) elements, among them, ATP5I (ICM, FC = 2.04; p < 0.01), ATP5MJ (ICM, FC = 1.33, p < 0.05), and ATP5IF1 (ICM, FC = 1.81; p < 0.001), which presented a significant correlation with established echocardiographic parameters of cardiac remodeling and ventricular function as follows: left ventricular end-systolic (p < 0.01) and end-diastolic (p < 0.01) diameters, and ejection fraction (p < 0.05). We also detected an increase in ATP5IF1 protein levels (ICM, FC = 1.75; p < 0.01) and alterations in the microRNA expression levels of miR-208b-3p (ICM, FC = -1.44, p < 0.001), miR-483-3p (ICM, FC = 1.37, p < 0.01), regulators of ATP5I. Therefore, we observed the deregulation of the OXPHOS transcriptome in ICM patients, highlighting the overexpression of complex V and its relationship with cardiac remodeling and function.

Circulating long non-coding RNAs detection after heart transplantation and its accuracy in the diagnosis of acute cardiac rejection.

Long non-coding RNAs (lncRNAs) are closely implicated in biological processes and diseases with high inflammatory components. These molecules exhibit significant temporal and tissue specificity. However, the expression and function of lncRNAs have not been studied in patients after heart transplantation. Thus, we aimed to identify circulating lncRNAs in these patients and evaluate their diagnostic capacity as potential biomarkers for the non-invasive detection of acute cellular rejection (ACR). For them, we performed a transcriptomic study based on ncRNA-seq technology to detect lncRNAs in serum samples, matched to routine endomyocardial biopsies, from patients without rejection episode (0R, n = 12) and with mild (1R, n = 16) or moderate-severe (≥ 2R, n = 12) ACR. We identified 11,062 circulating lncRNAs in the serum of patients after heart transplantation. Moreover, 6 lncRNAs showed statistically significant expression when the different ACR grades were compared. Among them, AC008105.3, AC006525.1, AC011455.8, AL359220.1, and AC025279.1 had relevant diagnostic capacity for detection of ≥ 2R (AUC of 0.850 to 1.000) and 1R (AUC of 0.750 to 0.854) grades, along with high specificity and positive predictive values (≥ 83%). In addition, AL359220.1 and AC025279.1 were independent predictors for the presence of moderate-severe ACR (odds ratio = 31.132, p < 0.01 and C statistic = 0.939, p < 0.0001; odds ratio = 18.693, p < 0.05 and C statistic = 0.902, p < 0.001; respectively). In conclusion, we describe, for the first time, circulating lncRNAs after heart transplantation as potential candidates for non-invasive detection of ACR. AL359220.1 and AC025279.1 showed excellent diagnostic capability correlating with the severity episode and were strong independent predictors of rejection.

Human recombinant relaxin-2 (serelaxin) regulates the proteome, lipidome, lipid metabolism and inflammatory profile of rat visceral adipose tissue.

Recombinant human relaxin-2 (serelaxin) has been widely proven as a novel drug with myriad effects at different cardiovascular levels, which support its potential therapeutic efficacy in several cardiovascular diseases (CVD). Considering these effects, together with the influence of relaxin-2 on adipocyte physiology and adipokine secretion, and the connection between visceral adipose tissue (VAT) dysfunction and the development of CVD, we could hypothesize that relaxin-2 may regulate VAT metabolism. Our objective was to evaluate the impact of a 2-week serelaxin treatment on the proteome and lipidome of VAT from Sprague-Dawley rats. We found that serelaxin increased 1 polyunsaturated fatty acid and 6 lysophosphatidylcholines and decreased 4 triglycerides in VAT employing ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) based platforms, and that regulates 47 phosphoproteins using SWATH/MS analysis. Through RT-PCR, we found that serelaxin treatment also caused an effect on VAT lipolysis through an increase in the mRNA expression of hormone-sensitive lipase (HSL) and a decrease in the expression of adipose triglyceride lipase (ATGL), together with a reduction in the VAT expression of the fatty acid transporter cluster of differentiation 36 (Cd36). Serelaxin also caused an anti-inflammatory effect in VAT by the decrease in the mRNA expression of tumor necrosis factor α (TNFα), interleukin-1ß (IL-1ß), chemerin, and its receptor. In conclusion, our results highlight the regulatory role of serelaxin in the VAT proteome and lipidome, lipolytic function, and inflammatory profile, suggesting the implication of several mechanisms supporting the potential benefit of serelaxin for the prevention of obesity and metabolic disorders.

Molecular events accompanying aggregation-induced energy quenching in fucoxanthin-chlorophyll proteins.

In high light, the antenna system in oxygenic photosynthetic organisms switches to a photoprotective mode, dissipating excess energy in a process called non-photochemical quenching (NPQ). Diatoms exhibit very efficient NPQ, accompanied by a xanthophyll cycle in which diadinoxanthin is de-epoxidized into diatoxanthin. Diatoms accumulate pigments from this cycle in high light, and exhibit faster and more pronounced NPQ. The mechanisms underlying NPQ in diatoms remain unclear, but it can be mimicked by aggregation of their isolated light-harvesting complexes, FCP (fucoxanthin chlorophyll-a/c protein). We assess this model system by resonance Raman measurements of two peripheral FCPs, trimeric FCPa and nonameric FCPb, isolated from high- and low-light-adapted cells (LL,HL). Quenching is associated with a reorganisation of these proteins, affecting the conformation of their bound carotenoids, and in a manner which is highly dependent on the protein considered. FCPa from LL diatoms exhibits significant changes in diadinoxanthin structure, together with a smaller conformational change of at least one fucoxanthin. For these LL-FCPa, quenching is associated with consecutive events, displaying distinct spectral signatures, and its amplitude correlates with the planarity of the diadinoxanthin structure. HL-FCPa aggregation is associated with a change in planarity of a 515-nm-absorbing fucoxanthin, and, to a lesser extent, of diadinoxanthin. Finally, in FCPb, a blue-absorbing fucoxanthin is primarily affected. FCPs thus possess a plastic structure, undergoing several conformational changes upon aggregation, dependent upon their precise composition and structure. NPQ in diatoms may therefore arise from a combination of structural changes, dependent on the environment the cells are adapted to.

Inflamación y apoptosis en la hipertensión arterial. Importancia de la extensión de la lesión de órgano diana / Inflammation and apoptosis in hypertension. Relevance of the extent of target organ damage

Introducción y objetivos. Analizar la relación entre parámetros inflamatorios y marcadores de apoptosis con la gravedad y la extensión de la lesión de órgano diana en pacientes con hipertensión arterial esencial. Métodos. Se ha reclutado, de manera consecutiva, a 159 pacientes hipertensos tratados, a los que se realizó un estudio exhaustivo de daño orgánico cardiaco, renal y vascular, y se determinaron las concentraciones plasmáticas de diferentes moléculas relacionadas con la inflamación (interleucina 6 y receptor soluble tipo 2 del factor de necrosis tumoral alfa) y apoptosis (receptor soluble tipo 1 del factor de necrosis tumoral alfa y receptor soluble Fas). Se dividió a los pacientes en cuatro grupos: a) sin lesión de órgano diana (33 pacientes); b) lesión a un nivel (52 pacientes); c) lesión a dos niveles (44 pacientes) y d) lesión a tres niveles (30 pacientes). Resultados. Los pacientes con lesión de órgano diana presentaban valores plasmáticos significativamente más elevados de interleucina 6, receptor soluble tipo 1 del factor de necrosis tumoral alfa y receptor soluble tipo 2 del factor de necrosis tumoral alfa que los pacientes hipertensos sin lesión orgánica. Además se objetivó un incremento progresivo de estos marcadores a medida que aumentaba el número de lesiones con las cifras plasmáticas más elevadas en los pacientes con lesión de órgano diana a tres niveles (cardiaco, renal y vascular). No hubo diferencias en el receptor soluble Fas entre las diferentes poblaciones. El análisis de regresión logística mostró que los valores plasmáticos de interleucina 6 y receptor soluble tipo 1 del factor de necrosis tumoral alfa, junto con edad, diabetes, tabaquismo y perímetro abdominal, se asociaban de manera independiente con el número de lesiones de órgano diana. Conclusiones. Una enfermedad hipertensiva más generalizada y con mayor número de órganos diana afectados se asocia a mayor activación inflamatoria y apoptótica en pacientes hipertensos (AU)

Introduction and objectives. To investigate the relationship between inflammatory and apoptotic parameters and the severity and extent of target organ damage in patients with essential hypertension. Methods. We studied 159 consecutive patients with treated essential hypertension. An exhaustive evaluation of damage to heart, kidney, and blood vessels was performed and plasma levels of inflammatory (interleukin 6 and soluble receptor of tumor necrosis factor-alpha type 2) and apoptotic markers (soluble receptor of tumor necrosis factor-alpha type 1 and soluble Fas receptor) were determined. Patients were categorized into four groups: a) no organ damage (33 patients); b) 1 organ damaged (52 patients); c) 2 organs damaged (44 patients), and d) 3 organs damaged (30 patients). Results. Serum levels of interleukin 6, soluble receptor of tumor necrosis factor-alpha type 1 and soluble receptor of tumor necrosis factor-alpha type 2 were higher in patients with target organ damage than in hypertensive patients without organ damage. Increasing levels of these molecules were progressively associated with an increase in the number of organs damaged, and the highest levels were observed in the group with damage to 3 organs (heart, kidney, and blood vessels). There were no differences in soluble Fas receptor levels between groups. Logistic regression analysis showed that age, smoking, diabetes mellitus, abdominal circumference, interleukin 6, and soluble receptor of tumor necrosis factor-alpha type 1 were independently related to the number of target organs damaged. Conclusions. Extensive hypertensive disease with involvement of more target organs was associated with greater inflammatory and apoptotic activation in these hypertensive patients (AU)

Relación entre modelado miocárdico y función diastólica en pacientes con hipertensión esencial / Relationship between myocardial modelling and diastolic function in patients with essential hypertension

Fundamento y objetivo: Analizar la relación entre las citoquinas antiapoptóticas, sFas y receptor soluble tipo 1 del factor de necrosis tumoral (sTNF-R1) con el fragmento aminoterminal del propéptido de procolágeno tipo iii (PIIINP) y tipo i (PINP) y la función diastólica en la hipertensión arterial (HTA). Pacientes y método: Se estudió un grupo de 253 pacientes con HTA, con una edad media (DE) de 60 (13) años; 139 eran varones. Se les realizó un examen físico, estudio eco-Doppler y determinación sérica de las moléculas. Resultados: Los valores séricos de PINP y PIIINP estuvieron elevados en pacientes hipertróficos frente a no-hipertróficos (media de 41 [extremos 31-52] frente a 35 [28-47] μg/l, p=0,010; y 4,33 [3,71-5,29] frente a 3,98 [3,49-4,58] μg/l, p=0,005, respectivamente). Además, se encontraron elevadas las concentraciones de sFas y sTNF-R1 (media de 1,47 [extremos 1,2-1,77] frente a 1,37 [1,1-1,59] ng/ml, p=0,012; y 466 [331-657] frente a 317 [260-427] pg/ml, p<0,0001, respectivamente). Por otra parte, los valores de PIIINP se relacionaron con sFas (r=0,386, p<0,0001) y sTNF-R1 (r=0,298, p<0,001); también se asoció PINP con estas citoquinas (r=0,158, p=0,011 y r=0,241, p<0,0001, respectivamente). En el análisis multivariable, sFas (p<0,0001) y sTNF-R1 (p<0,0001) fueron factores independientes de PIIINP. Por último, las concentraciones de los marcadores se relacionaron significativamente con los parámetros de función diastólica del ventrículo izquierdo. Conclusión:Las concentraciones de procolágeno y de citoquinas antiapoptóticas estuvieron elevadas en pacientes con hipertrofia ventricular. Además, sFas y sTNF-R1 son factores independientes de los valores en suero de PIIINP y se relacionan con los parámetros de función diastólica ventricular (AU)

Background and objectives: To analyze the relationship between sFas and soluble TNF receptor 1 (sTNF-R1) with type iii (PIIINP) and i (PINP) amino-terminal propeptide procollagens, and diastole in hypertension (HT). Patients and methods: A group of 253 Caucasian asymptomatic hypertensive patients (age 60±13 years, 139 males) were studied, in whom a physical examination, laboratory analyses (determination of serum PIIINP, PINP, sFas and by radioimmunoassay and ELISA, respectively), and echo-Doppler study were performed. Results: Serum PINP and PIIINP were increased in left ventricular hypertrophy compared to non-hypertrophy [41 (31-52) vs. 35 (28-47) μg/l, P=.010; and 4.33 (3.71-5.29) vs. 3.98 (3.49-4.58) μg/l, P=.005, respectively]. Furthermore, sFas and sTNF-R1 were also elevated [1.47 (1.2-1.77) vs. 1.37 (1.1-1.59), P=.012; and 466 (331-657) vs. 317 (260-427) μg/l, P<.0001, respectively]. Moreover, serum PIIINP was associated with sFas (r=.386, P<.0001) and sTNF-R1 (r=.298, P<.001); PINP was also associated with these cytokines (r=0.158, P=.011 and r=.241, P<.0001, respectively). Multivariable analyses included sFas (P<.0001) and sTNF-R1 (P<.0001) as independent factors related with serum PIIINP. Finally, marker concentrations were significantly related with left ventricular diastolic function parameters. Conclusion: Procollagen and anti-apoptotic cytokine levels were increased in our hypertrophic patients. Furthermore, sFas and sTNF-R1 are independent related factors of serum PIIINP. Diastolic parameters were associated with myocardial fibrosis and anti-apoptotic cytokines (AU)

Alteraciones inmunológicas y de los valores de selectinas en pacientes hipertensos tratados según criterios actuales / Immunological alterations and selectin values in hypertensive patients treated according to current criteri

Fundamento y objetivo: Calcular la relación entre las selectinas P y E, y los cambios inmunológicos que se producen en la hipertensión esencial. Pacientes y método:Se incluyeron 261 pacientes con hipertensión esencial con y sin hipertrofia del ventrículo izquierdo (HVI), a los que se les determinó las concentraciones de selectinas y citocinas específicas. Resultados:Los valores de selectina-P y E estuvieron elevados respecto al grupo control (media [DE] de 75 [51] ng/mL frente a 45 [17] ng/mL, p<0,0001, y 47 [18] ng/mL frente a 38 [15] ng/mL, p=0,049), así como las concentraciones de citocinas (p<0,0001). Además, las selectinas se relacionaron significativamente con los cambios en marcadores inmunológicos. El análisis multivariado mostró que la citocina interleucina (IL) 1ra (p<0,0001) y selectina-P (p=0,013) fueron factores independientes de los valores de selectina-E. Para selectina-P, lo fueron IL-1ra (p=0,005), IL-8 (p<0,0001), y selectina-E (p=0,013). Por último, las concentraciones de selectinas no fueron diferentes entre pacientes con y sin hipertrofia ventricular. Conclusiones: La activación inmunológica influye en los valores de selectinas en pacientes asintomáticos con hipertensión esencial. La HVI no indujo cambios significativos (AU)

Background and objective: To calculate the relationsship of E and P selectins with immunological changes in essential hypertension.Patients and method: We included 261 patients with essential hypertension with or without left ventricular hypertrophy (LVH), in whom selectins and specific cytokines were quantified. Results:E-and P-selectins were increased in hypertension compared to controls [75(51) ng/mL versus 45(17) ng/mL, (p<0.0001) and 47(18) ng/mL versus 38(15) ng/mL, (p=0.049), respectively], as well as cytokine concentrations (p<0.0001). Furthermore, selectin values were significantly correlated with changes in immunological markers. The multivariate analysis showed that IL-1ra (p<0.0001) and P-selectin (p=0.013) were independent factors of E-selectin values. For P-selectin, IL-1ra (p=0.005), IL-8 (p<0.0001) and selectin-E (p=0.013) influenced on its concentration. Finally, selectin values were similar between patients with or without left ventricular hypertrophy. Conclusions: Immunological activation influenced on selectin concentrations in cardiologic asymptomatic patients with essential hypertension. LVH did not induce significant changes (AU)

Valor pronóstico a largo plazo de los valores séricos y urinarios del fragmento N-terminal del péptido natriurético tipo B y del filtrado glomerular en pacientes con insuficiencia cardíaca / Long-term prognosis of serum and urine n-terminal proBNP levels and glomerular filtration rate in heart failure patients

Fundamento y objetivo: El amino-terminal pro-brain natriuretic peptide (NT-proBNP, ‘fragmento N terminal del péptino natriurético tipo B’) y el filtrado glomerular renal (eFGR) están relacionados con el pronóstico a corto plazo en la insuficiencia cardíaca (IC). Este estudio evalúa el poder predictivo de los valores NT-proBNP séricos y urinarios, así como del eFGR en pacientes con IC en un seguimiento a 60 meses. Pacientes y método: Se estudiaron 93 pacientes diagnosticados de IC (66 varones, edad: 65±12 años). El episodio primario fue muerte cardiovascular y el episodio combinado fue mortalidad o ingreso de origen cardíaco. Resultados: Solamente los valores séricos de NT-proBNP tuvieron un área bajo la curva significativa para la presencia de mortalidad cardíaca y episodios combinados: 0,70 (p=0,004) y 0,67 (p=0,019), respectivamente. El NT-proBNP urinario y el eFGR no obtuvieron áreas bajo la curva significativas. Los pacientes con altos valores de NT-proBNP en suero tuvieron una peor supervivencia (44 [IC del 95%: 38–50] versus 56 [IC del 95%: 53–59] meses; p=0,0006) y pronóstico para episodios (33 [IC del 95%: 28–38] versus 42 [IC del 95%: 28–38] meses; p=0,027). Al englobar la concentración del péptido y la disfunción renal, los pacientes con NT-proBNP sérico alto y bajo eFGR tuvieron la peor supervivencia (42 [IC del 95%: 33–52] meses; p=0,010). Por último, sólo los valores de NT-proBNP séricos mayores de 933pg/ml y de 550pg/ml predicen muerte cardiovascular (hazard ratio=2,81; p=0,033) y episodios (hazard ratio=1,79; p=0,049), respectivamente. Conclusiones: Los valores de NT-proBNP séricos fueron un factor predictivo de mortalidad y episodios cardiovasculares a 60 meses, superior a los valores urinarios de NT-proBNP y eFGR, en pacientes diagnosticados de insuficiencia cardíaca con disfunción renal moderada (AU)

Background and objective: The amino-terminal pro-brain natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR) values are related to short prognosis in patients with heart failure (HF). This study evaluates the prognostic power of serum and urinary NT-proBNP levels, and eGFR values, in HF patients during a 60-month follow-up. Patients and Methods: We studied 93 HF outpatients (66 males, age 65±12). Primary endpoint was defined as cardiovascular mortality and secondary endpoint as cardiovascular mortality or admissions. Results: Only serum NT-proBNP levels had a significant area under the curve for the prognosis of 60-month mortality and combined events, 0.70 (p=0.004) and 0.67 (p=0.019), respectively. Urinary NT-proBNP and eGFR did not have statistical significant areas under the curve. Patients with high serum NT-proBNP had the highest risk of cardiovascular death [44 (IC 95% 38–50) vs. 56 (IC 95% 53–59) months, p=0.0006] and combined events [33 (IC 95% 28–38) vs. 42 (IC 95% 28–38) months; p=0.027]. After the integration of serum NT-proBNP and renal function, patients with high peptide levels and low eGFR had the worst survival [42 (IC 95% 33–52) months; p=0.010]. Finally, only serum NT-proBNP concentration above 933pg/mL was a predictor of poor survival (hazard ratio=2.81, p=0.033) and NT-proBNP above 550pg/mL for combined events (hazard ratio=1.79, p=0.049). Conclusions: Serum NT-proBNP levels were superior to urine NT-proBNP and eGFR values for predicting 60-month cardiovascular death and combined events in HF patients (AU)

NT-proBNP urinario. Su valor en la caracterización de pacientes con hipertensión esencial / Urinary NT-proBNP. A valuable marker in the assessment of patients with essential hypertension

El objetivo fue evaluar el poder predictivo para diagnosticar hipertrofia del ventrículo izquierdo (HVI) de la concentración urinaria del fragmento N-terminal del propéptido natriurético tipo B (NT-proBNP) en 160 pacientes asintomáticos diagnosticados de hipertensión esencial (HT). Las concentraciones urinarias de NT-proBNP/creatinina estuvieron incrementadas en pacientes con HVI al compararlos con no hipertróficos (p < 0,0001) y controles (p < 0,0001). El análisis de regresión lineal múltiple mostró que la edad (p = 0,034), el índice de masa del ventrículo izquierdo (IMVI) (p = 0,026) y el NT-proBNP sérico (p = 0,001) predicen la concentración urinaria del péptido. El área bajo la curva de NT-proBNP/creatinina fue 0,71 ± 0,04 (p < 0,0001) para la detección de HVI, y el análisis de regresión logística mostró que NT-proBNP urinario/ creatinina predice la HVI (odds ratio = 4,074; p = 0,009). En conclusión, la concentración de NT-proBNP en orina es un nuevo marcador que puede ser de utilidad para detectar HVI en sujetos con HT esencial (AU)

The aim was to evaluate the usefulness of urinary N-terminal fragment of B-type natriuretic peptide (NT-proBNP) measurement for predicting the presence of left ventricular hypertrophy (LVH) in 160 asymptomatic patients with essential hypertension. The urinary NT-proBNP/creatinine ratio was higher in patients with LVH than in either those without LVH (P < .0001) or control subjects (P < .0001). Multivariate linear regression analysis identified age (P=.034), left ventricular mass index (P=.026) and serum NT-proBNP level (P=.001) as predictors of the urinary peptide level. The area under the curve for the NT-proBNP/creatinine ratio was 0.71±0.04 (P < .0001) for identifying LVH. Logistic regression analysis showed that the NT-proBNP: creatinine ratio was a predictor of LVH (odds ratio=4.074; P=.009). In conclusion, the urinary NT-proBNP concentration is a new marker that could be useful for identifying LVH in subjects with essential hypertension (AU)

Valor pronóstico de big endotelina-1 en pacientes con insuficiencia cardíaca y clase funcional moderadamente sintomática / Prognostic value of big endothelin-1 prognostic value in patients with heart failure and moderately symptomatic functional class

Fundamento y objetivo: Existen estudios sobre el papel de la big endotelina 1 (big ET-1) como marcador de mortalidad en pacientes con insuficiencia cardíaca (IC) grave. Sin embargo, no se ha encontrado valor pronóstico en pacientes con clase funcional moderadamente sintomática. Nuestro objetivo fue evaluar, en un seguimiento a 24 meses, el poder pronóstico de big ET-1 en pacientes con IC y clase funcional moderadamente deteriorada. Material y método: Se determinaron los valores de big ET-1 en una cohorte de 90 pacientes ambulatorios (edad media [desviación estándar] de 64 [13] años, 70% varones) con IC. Se clasificó a los pacientes funcionalmente según la clasificación de la New York Heart Association (NYHA). Resultados: Obtuvimos un valor mediano de big ET-1 de 0,86 (extremos 0,61 1,20)fmol/ml. Evaluamos su poder para la detección de mortalidad cardiovascular y obtuvimos un área bajo la curva (ABC) de 0,68 (0,08) (p=0,02), punto de corte óptimo 0,98fmol/ml (sensibilidad del 69%, especificidad del 75%). En el análisis de regresión logística, la big ET-1 resultó también un predictor independiente de mortalidad (odds ratio [OR]=5,851; p=0,009). Conclusiones: La determinación de la big ET-1 tiene valor para la predicción de mortalidad cardiovascular en pacientes con IC y clase funcional moderadamente sintomática (AU)

Background and objective: Several studies have analyzed big endothelin-1 as a marker of mortality in patients with severe heart failure (HF). However, it has not proven prognostic value in patients with moderately symptomatic functional class. Our objective was to evaluate, in a 24 months follow-up, the prognostic power of big endothelin-1 in patients with HF and moderately deteriorated functional class. Material and method: Big endothelin-1 levels were measured in a cohort of 90 outpatients (age 64 (13), 70% males) diagnosed with HF. Patients were functionally classified (NYHA).Results: For the whole population, big endothelin-1 was 0.86 (0.61 1.20)fmol/ml. We evaluated its predictive value in detecting cardiovascular mortality, obtaining an AUC of 0.68 (0.08) (P=.02), and a cut-off value of 0.98fmol/ml (sensitivity 69%, specificity 75%). When a logistic regression analysis was performed, big endothelin-1 was also an independent predictor of mortality (OR=5.851, P=.009). Conclusions: Big endothelin-1 predicts cardiovascular mortality in patients diagnosed of HF and moderately symptomatic functional class (AU)

Utilidad de la trimetazidina en la lesión por isquemia-reperfusión: Estudio experimental en un modelo canino de aturdimiento miocárdico / Usefulness of trimetazidine in ischemia-reperfusion lesion: experimental study in myocardial stunning model

Objetivo: Evaluar la acción de la trimetazidina en el deterioro de la función sistólica que se produce en el miocardio tras una isquemia única y prolongada. Métodos: Se analizaron 13 perros mestizos, de uno u otro sexo, asignados al azar a tratamiento oral con trimetazidina (6 perros) o placebo (7 perros) durante 7 días. Se realizó un protocolo de isquemia bajo anestesia consistente en una obstrucción completa de la arteria coronaria descendente anterior de 15 minutos de duración, seguida de 60 minutos de reperfusión. Las variables analizadas durante la obstrucción y la reperfusión fueron: Frecuencia cardíaca (FC), presión ventricular izquierda (PVI), dP/dt y las curvas de función regional de la zona isquémica y de una zona testigo (longitud telediastólica, telesistólica y fracción de acortamiento). Resultados: Las variables hemodinámicas (FC, PVI y dP/dt), no presentaron diferencias significativas entre ambos grupos, con poca variabilidad de sus valores respecto a los basales durante la isquemia-reperfusión. La fracción de acortamiento de la zona isquémica experimentó una disminución estadísticamente significativa durante la obstrucción coronaria en ambas series, alcanzando valores de discinesia, con persistencia de la disfunción contráctil tras 60 minutos de reperfusión, y sin diferencias entre ambas series (50% serie Placebo; 41% serie Trimetazidina). Conclusiones: La recuperación de la contractilidad miocárdica tras una isquemia completa en la serie tratada con TMZ no mostró diferencias significativas respecto a la serie Placebo, a diferencia de lo que ocurre con períodos de oclusión más cortos y repetidos.

Objective: The aim of this study is to evaluate the effect of trimetazidine (TMZ) on myocardial systolic dysfunction resulting from an isolated episode of induced coronary ischemia. Methods: In a double-blinded randomized design we studied 13 mongrel anesthetized dogs of either sex (6 of them treated with oral TMZ previously). The anterior descending coronary artery was totally occluded during 15 minutes followed by 60 minutes of reperfusion. Global and regional cardiac variables were recorded in control and ischemic areas. Results: There were no significant differences between TMZ and placebo series with respect to global cardiac function variables. Both series showed no significant variations in global variables during the ischemia-reperfusion process. The shortening fraction in the ischemic area fell significantly during the ischemic period in both TMZ and placebo series reaching dyskinetic values. Myocardial contractility dysfunction persisted after 60 minutes of reperfusion in both series with no significant differences (41% vs 50% placebo). Conclusions: Contrary to shorter and repeated occlusion periods, myocardial contractility recovery after a complete episode of ischemia did not show significant differences between TMZ-treated and placebo series.

Cambios nucleares y expresión de p62 en la miocardiopatía isquémica y dilatada / Nuclear changes and p62 expression in ischemic and dilated cardiomyopathy

Los objetivos fueron analizar, en el cardiomiocito humano con insuficiencia cardiaca de origen isquémico (MCI) o dilatado (MCD), la estereología nuclear, así como determinar los valores de p62, proteína implicada en el transporte nuclear. Estudiamos 23 corazones humanos, 10 con MCI, 10 con MCD y 3 controles (CNT). Los corazones con MCI y MCD mostraron un aumento en el tamaño nuclear y nucleolar (el 60% y el 66%, p = 0,03; el 59%, p = 0,02; y el 75%, p = 0,03, respectivamente), frente al grupo CNT. Los valores de p62 aumentaron en ambas miocardiopatías (MCI, 110%, p = 0,01; MCD, 145%, p = 0,04). En la MCI, los valores de p62 estuvieron correlacionados con el área del núcleo (r = 0,615; p = 0,05) y el porcentaje de heterocromatina (r = -0,707; p = 0,02). En conclusión, los corazones con MCI y MCD mostraron alteraciones en la morfología nuclear. Las cifras de p62 se duplicaron en ambas miocardiopatías y en correlación con alteraciones nucleares en la MCI (AU)

The study's objectives were to investigate nuclear stereology and to determine the level of p62, a protein involved in nuclear transport, in human cardiomyocytes from patients with heart failure due to ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM). We studied 23 human hearts: 10 had ICM, 10 had DCM, and three were from control subjects. The size of the nucleus was significantly increased in ICM and DCM hearts compared with those from controls (by 60% and 66%, respectively, P=.03), as was the size of the nucleolus (by 59%, P=.02 and 75%, P=.03, respectively). In addition, the p62 level was significantly increased in both forms of cardiomyopathy compared with controls (ICM 110%, P=.01; and DCM 145%, P=.04). In the ICM group, there were correlations between the p62 level and nuclear size (r=0.615, P=.05) and between the p62 level and the heterochromatin percentage (r=-0.707; P=.02). In conclusion, cardiomyocytes from hearts affected by ICM and DCM showed changes in nuclear and nucleolar morphology. The p62 level had doubled in both forms of cardiomyopathy and, in ICM hearts, there was a correlation with nuclear changes (AU)

NT-proBNP en orina y su relación con los parámetros de la función ventricular en la insuficiencia cardiaca / Urinary NT-proBNP level: relationship with ventricular function parameters in heart failure

Introducción y objetivos. La concentración plasmática de N-terminal propéptido natriurético cerebral (NT-proBNP) es un marcador sensible de disfunción ventricular. Se ha demostrado el valor diagnóstico y pronóstico de sus concentraciones urinarias. Nuestro objetivo es determinar la relación entre parámetros consolidados de la función ventricular y concentraciones urinarias de NT-proBNP. Métodos. Hemos estudiado 74 pacientes diagnosticados de insuficiencia cardiaca (54 varones, edad 66 ± 12 años). Se les realizó un estudio eco-Doppler y se determinaron el desplazamiento del plano auriculoventricular (DPAV) (mm), la fracción de eyección (FE), la velocidad de propagación del flujo mitral (Vp) (cm/s) y la relación E/A. Se midieron las concentraciones plasmáticas y urinarias de NT-proBNP y las de aldosterona (pg/ml). Resultados. Para toda la población, los valores plasmáticos de NT-proBNP fueron 948 ± 961 pg/ml, los urinarios 88,7 ± 17,8 pg/ml y los de aldosterona 165 ± 145 pg/ml. Correlacionamos las concentraciones urinarias de NT-proBNP con el DPAV (r = -0,5; p < 0,0001), la FE (r = -0,3; p < 0,01) y con Vp (r = -0,24; p < 0,05). Dividimos los valores de DPAV y FE en cuartiles y en cada uno calculamos el NT-proBNP urinario (C1: 103 ± 28, C2: 89 ± 9, C3: 86 ± 9, C4: 78 ± 9; p < 0,0001 y C1: 101 ± 26, C2: 85 ± 12, C3: 83 ± 10, C4: 85 ± 11; p < 0,05). Al realizar un análisis de regresión lineal múltiple se muestra que NT-proBNP plasmático es un factor pronóstico independiente de NT-proBNP urinario (p < 0,0001). Si excluimos el NT-proBNP plasmático surgen de manera alternativa, como factores pronóstico independientes, el DPAV y la FE (p < 0,05). Conclusiones. El NT-proBNP en la orina se correlaciona con parámetros de función del ventrículo izquierdo. Este estudio da soporte al papel del NT-proBNP urinario como marcador bioquímico de la función ventricular en pacientes con insuficiencia cardiaca (AU)

Introduction and objectives. The plasma N-terminal probrain natriuretic peptide (NT-proBNP) level is a sensitive marker of ventricular dysfunction. The diagnostic and prognostic value of urinary NT-proBNP measurement has been demonstrated. The objective of this study was to determine the relationship between established parameters of ventricular function and the urinary NT-proBNP level. Methods. The study involved 74 patients with heart failure (54 male, age 66 [12] years). A Doppler echocardiographic study was performed to measure atrioventricular plane displacement (AVPD), ejection fraction, mitral flow propagation velocity, and E/A. Urinary and plasma NT-proBNP levels, and the plasma aldosterone level were measured. Results. In the whole group, the plasma NT-proBNP level was 948 (961) pg/mL, the urinary NT-proBNP level was 88.7 (17.8) pg/mL, and the aldosterone level, 165 (145) pg/mL. There were correlations between urinary NT-proBNP level and AVPD (r=-0.5; P<.0001), ejection fraction (r=-0.3; P<.01), and mitral flow propagation velocity (r=-0.24; P<.05). On dividing AVPD and ejection fraction measurements into quartiles, respectively, the urinary NT-proBNP levels for these quartiles were Q1: 103 (28) pg/mL, Q2: 89 (9) pg/mL, Q3: 86 (9) pg/mL, and Q4: 78 (9) pg/mL (P<.0001) and Q1: 101 (26) pg/mL, Q2: 85 (12) pg/mL, Q3: 83 (10) pg/mL, and Q4: 85 (11) pg/mL (P<.05), respectively. Multiple linear regression analysis showed that the plasma NT-proBNP level was an independent predictor of the urinary NT-proBNP level (P<.0001). When the plasma NT-proBNP level was excluded, AVPD and ejection fraction appeared as alternative independent predictors (P<.05). Conclusions. There is a correlation between the urinary NT-proBNP level and left ventricular function parameters. This study supports the use of the urinary NT-proBNP level as a biochemical marker of ventricular function in heart failure patients (AU)

Valores de 8-hidroxi-2'-desoxiguanosina y de peroxidación lipídica en pacientes con insuficiencia cardiaca / 8-Hydroxy-2'-deoxyguanosine and lipid peroxidation in patients with heart failure

Introducción y objetivos. La insuficiencia cardiaca está asociada con un incremento en la producción de radicales libres, llegándose al estado de estrés oxidativo. Se conocen diversos marcadores de estrés oxidativo, como la 8-hidroxi-2'-desoxiguanosina, marcador del daño oxidativo en el ADN, y la peroxidación lipídica que permite cuantificar el daño en las estructuras ricas en lípidos. El propósito de este estudio es comparar los valores de 8-hidroxi-2'-desoxiguanosina y de peroxidación lipídica en pacientes con insuficiencia cardiaca y sujetos sanos, y evaluar la influencia de la etiología. Métodos. Estudiamos a 78 pacientes (57 varones, edad 64 ± 14 años) diagnosticados de insuficiencia cardiaca y a 12 controles. Los pacientes completaron un cuestionario y fueron clasificados de acuerdo con la New York Heart Association. Se les realizó un estudio eco-Doppler y extracción de sangre. Medimos las concentraciones de 8-hidroxi-2'-desoxiguanosina y de peroxidación lipídica. Resultados. Al comparar los valores de 8-hidroxi-2'-desoxiguanosina y peroxidación lipídica entre pacientes y controles obtuvimos diferencias significativas (0,34 ± 0,54 frente a 0,04 ± 0,07 ng/ml, p < 0,05 y 18 ± 10 frente a 8 ± 3 μmol/l, p < 0,01, respectivamente). Cuando comparamos las concentraciones de los 2 marcadores según la etiología de la insuficiencia cardiaca encontramos diferencias significativas en ambos (p < 0,05), que fueron mayores en la miocardiopatía hipertensiva. Conclusiones. Los valores de 8-hidroxi-2'-desoxiguanosina y peroxidación lipídica se encuentran aumentados en los pacientes con insuficiencia cardiaca al compararlos con los controles. El incremento más importante lo encontramos en pacientes con miocardiopatía hipertensiva

Introduction and objectives. Heart failure is associated with increased free radical production, which leads to a state of oxidative stress. Known markers of oxidative stress include 8-hydroxy-2'-deoxyguanosine, which reflects oxidative damage to DNA, and lipid peroxidation, which can be used to quantify damage to lipid-rich structures. The aims of this study were to compare 8-hydroxy-2'-deoxyguanosine and lipid peroxidation levels in heart failure patients and healthy subjects and to assess how these levels are influenced by heart failure etiology. Methods. The study included 78 patients (57 male, age 64 [14] years) with heart failure and 12 control subjects. Patients completed a questionnaire and were graded according to the New York Heart Association classification. Doppler echocardiography was performed and blood samples were obtained. 8-hydroxy-2'-deoxyguanosine and lipid peroxidation levels were determined. Results. Significant differences were observed between patients and control subjects in 8-hydroxy-2'-deoxyguanosine and lipid peroxidation levels, at 0.34 (0.54) ng/mL vs 0.04 (0.07) ng/mL (P<.05), and 18 (10) μM vs 8 (3) μM (P<.01), respectively. Subsequent analysis showed that heart failure etiology had a significant effect on the levels of the two markers (P<.05), which were highest in patients with hypertensive cardiomyopathy. Conclusions. Levels of 8-hydroxy-2'-deoxyguanosine and lipid peroxidation were higher in heart failure patients than in control subjects. The most significant increases were found in patients with hypertensive cardiomyopathy

Relación de los valores plasmáticos de big endotelina-1 con NT-proBNP y la función ventricular de pacientes con insuficiencia cardíaca / Plasma concentration of big endothelin-1 and its relation with plasma NT-proBNP and ventricular function in heart failure patients

Introducción y objetivos. Las concentraciones elevadas de big endotelina 1 (big ET-1) se relacionan con la gravedad y el pronóstico de los pacientes con insuficiencia cardíaca (IC), mientras que N-terminal proBNP (NTproBNP) es un marcador de remodelado ventricular. El objetivo de nuestro estudio fue relacionar los valores debig ET-1 con NT-proBNP y con la función miocárdica. Pacientes y método. Estudiamos a 103 pacientes (75varones; 63 ± 13 años) diagnosticados de IC. Cada participante completó un cuestionario y fue sometido a un estudio eco-Doppler para la medición de la fracción de eyección (FE), la velocidad de propagación del flujo mitral (Vp) y el desplazamiento del plano auriculo ventricular(DPAV). Se realizó una extracción de sangre para determinarlos valores de big ET-1, aldosterona y NT-proBNP. Resultados. Para toda la población, el valor de big ET-1 fue de 1,03 ± 0,75 fmol/ml, el de NT-proBNP de 619(307-1.328) pg/ml, el de aldosterona de 168 ± 102 pg/ml,la FE de 37 ± 10, la Vp de 37 ± 11 cm/s y el DPAV de 8,0± 1,7 mm. La big ET-1 se correlacionó positivamente con el NT-proBNP (r = 0,50; p < 0,0001) e inversamente conla FE (r = -0,30; p < 0,01), la Vp (r = -0,30; p < 0,01) y elDPAV (r = -0,21; p < 0,05). Al dividir la big ET-1 en cuartiles y comparar los valores de NT-proBNP, FE, Vp y DPAV obtuvimos diferencias estadísticamente significativas(ANOVA p < 0,0001, p < 0,01, p < 0,05 y p < 0,05,respectivamente). Conclusiones. Los valores plasmáticos de big ET-1muestran una correlación positiva con los de NT-pro BNP y una correlación inversa con la FE, la Vp y el DPAV. Estos hallazgos ayudan a esclarecer las relaciones entre la función ventricular y la activación neurohormonal en la insuficiencia cardíaca y facilitan la búsqueda de nuevas intervención es terapéuticas

Introduction and objectives. Elevated plasma concentrations of big endothelin-1 (big ET-1) are related with severity and prognosis in patients with heart failure, and N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of ventricular remodeling. The purpose of this study was to investigate the relationship between plasma levels of bigET-1 and NT-proBNP, and between the former and ventricular function. Patients and method. We studied 103 patients with heart failure (75 men, mean age 63 [13] years). Each participant completed a questionnaire and underwent Doppler echocardiographic study to measure ejection fraction(EF), mitral flow propagation velocity (Vp) and atrioventricular plane displacement (AVPD). Blood samples were also taken to determine plasma levels of big ET-1, aldosterone and NT-proBNP. Results. For the whole population big ET-1 concentration was 1.03 [0.75] fmol/m, NT-proBNP 619 (307-1328)pg/mL, aldosterone 168 [102] pg/mL, EF 37 [10], Vp 37[11] cm/s, and AVPD 8.0 [1.7] mm. Plasma big ET-1 correlated positively with plasma NT-proBNP (r=0.50,P<.0001). However, a negative correlation was found between big ET-1 and EF (r=-0.30, P<.01), Vp, (r=-0.30,P<.01) and AVPD (r=-0.21, P<.05). When ET-1 levels were divided into quartiles and the corresponding NT proBNP, EF, Vp and AVPD values were compared, we found significant differences (ANOVA P<.0001, P<.01,P<.05 and P<.05, respectively). Conclusions. Plasma levels of big ET-1 correlated positively with NT-proBNP levels and inversely with EF, Vpand AVPD. These findings help clarify the relationships between ventricular function and the neurohormonal activation involved in heart failure, and may aid the search for therapeutic interventions

La troponina T como posible marcador del daño miocárdico menor. su aplicación en el miocardio aturdido y en la isquemia silente / Troponine T as Possible Myocardial Injury Marker. Its Application in Myocardial Stunning and Silent Ischemia

Introducción y objetivos. La necesidad de disponer de marcadores bioquímicos más precoces y de mayor especificidad y sensibilidad para la detección del infarto agudo de miocardio ha impulsado la continua evaluación de métodos alternativos a la isoenzima MB de la creatincinasa (CK-MB). Nuestro objetivo ha sido conocer la utilidad de las determinaciones de la troponina T (TnT), frente a otros marcadores, para detectar procesos de isquemia transitoria en ausencia de necrosis. Métodos. Se ha utilizado un modelo canino experimental de isquemias muy breves y repetidas (series I y II), y un modelo de isquemia única de 15 min de duración, y 60 min de reperfusión (serie III). En la serie I el oclusor coronario se situó en la zona proximal de la arteria coronaria descendente anterior (DA), y en las series II y III en la zona distal de la DA. Las muestras de plasma se han obtenido de sangre venosa periférica (SVP) y coronaria (SVC), en distintas fases del estudio. Las concentraciones de adenosina, TnT, CK y CK-MB se determinaron por procedimientos bioquímicos. Se estudiaron los parámetros de función regional y general, y se realizó un estudio anatomopatológico para conocer el tamaño del área de riesgo. Resultados. En la serie I se produjo hipocinesia que persistió 10 días, y en las series II y III la función regional se había recuperado a las 24 h. Las concentraciones de CK y CK-MB aumentaron ya significativamente tras la apertura del tórax (p < 0,05) en las tres series, alcanzando el máximo valor a las 24 h del protocolo isquémico. La adenosina se elevó significativamente sólo tras la isquemia (p < 0,05). Los valores de TnT se elevaron con la isquemia hasta los 5 días en las tres series en SVP. No hubo correlación entre la función regional del miocardio aturdido y el incremento de troponina T. Conclusiones. La troponina T se eleva en ausencia de necrosis, preferentemente cuando los episodios isquémicos son prolongados (AU)