Resumen ejecutivo de la actualización 2023 del consenso de actuación básica durante el ingreso hospitalario por insuficiencia cardiaca aguda / Executive summary of the 2023 update on the consensus regarding basic conduct during hospital admission for patients with acute heart failure

La insuficiencia cardiaca aguda (ICA) está asociada a una importante morbimortalidad, constituyendo la primera causa de hospitalización en mayores de 65 años en nuestro país. Las principales recomendaciones recogidas son: 1) al ingreso, se recomienda realizar una evaluación integral, considerando el tratamiento habitual y comorbilidades, ya que condicionan el pronóstico; 2) en las primeras horas de atención hospitalaria, el tratamiento descongestivo es prioritario, y se recomienda un abordaje terapéutico diurético precoz y escalonado en función de la respuesta; 3) durante la fase estable, se recomienda considerar el inicio y/o titulación del tratamiento con fármacos basados en la evidencia, es decir, sacubitrilo/valsartán o inhibidores de la enzima convertidora de angiotensina/antagonistas de los receptores de angiotensina II, betabloqueantes, antialdosterónicos e inhibidores SGLT2, y 4) en el momento del alta hospitalaria, es recomendable utilizar un listado —tipo check-list— para optimizar el manejo del paciente hospitalizado e identificar las opciones más eficientes para mantener la continuidad de cuidados tras el alta (AU)

Acute heart failure (AHF) is associated with significant morbidity and mortality and it stands as the primary cause of hospitalization for individuals over the age of 65 in Spain. This document outlines the main recommendations as follows: (1) upon admission, it is crucial to conduct a comprehensive assessment, taking into account the patient's standard treatment and comorbidities, as these factors determine the prognosis of the disease; (2) During the initial hours of hospital care, prioritizing decongestive treatment is essential. It is recommended to adopt an early staged diuretic therapeutic approach based on the patient's response; (3) In order to manage patients in the stable phase, it is advisable to consider initiating and/or adjusting evidence-based drug treatments such as sacubitril/valsartan or angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta blockers, aldosterone antagonists, and SGLT2 inhibitors; (4) Upon hospital discharge, utilizing a checklist is recommended to optimize the patient's management and identify the most efficient options for ensuring continuity of care post-discharge (AU)

Executive summary of the 2023 update on the consensus regarding basic conduct during hospital admission for patients with acute heart failure.

Acute heart failure (AHF) is associated with significant morbidity and mortality and it stands as the primary cause of hospitalization for individuals over the age of 65 in Spain. This document outlines the main recommendations as follows: (1) Upon admission, it is crucial to conduct a comprehensive assessment, taking into account the patient's standard treatment and comorbidities, as these factors determine the prognosis of the disease. (2) During the initial hours of hospital care, prioritizing decongestive treatment is essential. It is recommended to adopt an early staged diuretic therapeutic approach based on the patient's response. (3) In order to manage patients in the stable phase, it is advisable to consider initiating and/or adjusting evidence-based drug treatments such as sacubitril/valsartan or angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta blockers, aldosterone antagonists, and SGLT2 inhibitors. (4) Upon hospital discharge, utilizing a checklist is recommended to optimize the patient's management and identify the most efficient options for ensuring continuity of care post-discharge.

Consensus on basic conduct during the hospital admission of patients with acute heart failure.

Acute heart failure (AHF) is a highly prevalent clinical entity in individuals older than 45 years in Spain. AHF is associated with significant morbidity and mortality and is the leading cause of hospitalisation for individuals older than 65 years in Spain, a quarter of whom die within 1 year of the hospitalisation. In recent years, there has been an upwards trend in hospitalisations for AHF, which increased 76.7% from 2003 to 2013. Readmissions at 30 days for AHF have also increased (from 17.6% to 22.1%), at a relative mean rate of 1.36% per year, with the consequent increase in the use of resources and the economic burden for the healthcare system. The aim of this document (developed by the Heart Failure and Atrial Fibrillation Group of the Spanish Society of Internal Medicine) is to guide specialists on the most important aspects of treatment and follow-up for patients with AHF during hospitalisation and the subsequent follow-up. The main recommendations listed in this document are as follows: 1) At admission, perform a comprehensive assessment, considering the patient's standard treatment and comorbidities, given that these determine the disease prognosis to a considerable measure. 2) During the first few hours of hospital care, decongestive treatment is a priority, and a staged diuretic therapeutic approach based on the patient's response is recommended. 3) To manage patients in the stable phase, consider starting and/or adjusting evidence-based drug treatment (e.g., sacubitril/valsartan or angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta blockers and aldosterone antagonists). 4) At hospital discharge, use a checklist to optimise the patient's management and identify the most efficient options for maintaining continuity of care after discharge.

Consenso de actuación básica durante el ingreso hospitalario por insuficiencia cardiaca aguda / Consensus on basic conduct during the hospital admission of patients with acute heart failure

La insuficiencia cardiaca aguda (ICA) es una entidad clínica con una elevada prevalencia en la población de más de 45años en España. Está asociada a una importante morbimortalidad, constituyendo la primera causa de hospitalización en mayores de 65años en nuestro país, de los cuales una cuarta parte fallecen al año del ingreso. En los últimos años se ha observado una tendencia al alza en las hospitalizaciones por ICA, que aumentaron un 76,7% en el período de 2003 a 2013. Los reingresos a los 30días por ICA también aumentaron (del 17,6 al 22,1%) a un ritmo medio relativo del 1,36% por año, con el consiguiente incremento en el uso de recursos y en la carga económica para el sistema sanitario. Este documento, elaborado por el grupo de Insuficiencia Cardiaca y Fibrilación Auricular de la Sociedad Española de Medicina Interna, tiene como objetivo orientar al especialista en los aspectos más importantes del tratamiento y seguimiento de los pacientes con ICA durante el ingreso y el seguimiento posterior. Las principales recomendaciones recogidas son: 1)en el momento del ingreso, realizar una evaluación integral, considerando el tratamiento habitual y comorbilidades del paciente, ya que condicionan en gran medida el pronóstico de la enfermedad; 2)en las primeras horas de atención hospitalaria, el tratamiento descongestivo es prioritario y se recomienda un abordaje terapéutico diurético escalonado en función de la respuesta; 3)en el manejo de la fase estable, considerar el inicio y/o ajustar el tratamiento con fármacos basados en la evidencia, es decir, sacubitrilo/valsartán o IECA/ARAII, betabloqueantes y antialdosterónicos; 4)en el momento del alta hospitalaria, utilizar un checklist para optimizar el manejo del paciente hospitalizado e identificar las opciones más eficientes para mantener la continuidad de cuidados tras el alta (AU)

Acute heart failure (AHF) is a highly prevalent clinical entity in individuals older than 45years in Spain. AHF is associated with significant morbidity and mortality and is the leading cause of hospitalisation for individuals older than 65years in Spain, a quarter of whom die within 1year of the hospitalisation. In recent years, there has been an upwards trend in hospitalisations for AHF, which increased 76.7% from 2003 to 2013. Readmissions at 30days for AHF have also increased (from 17.6% to 22.1%), at a relative mean rate of 1.36% per year, with the consequent increase in the use of resources and the economic burden for the healthcare system. The aim of this document (developed by the Heart Failure and Atrial Fibrillation Group of the Spanish Society of Internal Medicine) is to guide specialists on the most important aspects of treatment and follow-up for patients with AHF during hospitalisation and the subsequent follow-up. The main recommendations listed in this document are as follows: (1)At admission, perform a comprehensive assessment, considering the patient's standard treatment and comorbidities, given that these determine the disease prognosis to a considerable measure. (2)During the first few hours of hospital care, decongestive treatment is a priority, and a staged diuretic therapeutic approach based on the patient's response is recommended. (3)To manage patients in the stable phase, consider starting and/or adjusting evidence-based drug treatment (e.g., sacubitril/valsartan or angiotensin-converting enzyme inhibitors/angiotensinII receptor blockers, beta blockers and aldosterone antagonists). (4)At hospital discharge, use a checklist to optimise the patient's management and identify the most efficient options for maintaining continuity of care after discharge (AU)

Consensus on basic conduct during the hospital admission of patients with acute heart failure. / Consenso de actuación básica durante el ingreso hospitalario por insuficiencia cardiaca aguda.

Acute heart failure (AHF) is a highly prevalent clinical entity in individuals older than 45years in Spain. AHF is associated with significant morbidity and mortality and is the leading cause of hospitalisation for individuals older than 65years in Spain, a quarter of whom die within 1year of the hospitalisation. In recent years, there has been an upwards trend in hospitalisations for AHF, which increased 76.7% from 2003 to 2013. Readmissions at 30days for AHF have also increased (from 17.6% to 22.1%), at a relative mean rate of 1.36% per year, with the consequent increase in the use of resources and the economic burden for the healthcare system. The aim of this document (developed by the Heart Failure and Atrial Fibrillation Group of the Spanish Society of Internal Medicine) is to guide specialists on the most important aspects of treatment and follow-up for patients with AHF during hospitalisation and the subsequent follow-up. The main recommendations listed in this document are as follows: (1)At admission, perform a comprehensive assessment, considering the patient's standard treatment and comorbidities, given that these determine the disease prognosis to a considerable measure. (2)During the first few hours of hospital care, decongestive treatment is a priority, and a staged diuretic therapeutic approach based on the patient's response is recommended. (3)To manage patients in the stable phase, consider starting and/or adjusting evidence-based drug treatment (e.g., sacubitril/valsartan or angiotensin-converting enzyme inhibitors/angiotensinII receptor blockers, beta blockers and aldosterone antagonists). (4)At hospital discharge, use a checklist to optimise the patient's management and identify the most efficient options for maintaining continuity of care after discharge.

Role of TrkA signalling and mast cells in the initiation of osteoarthritis pain in the monoiodoacetate model.

OBJECTIVE: Aiming to delineate novel neuro-immune mechanisms for NGF/TrkA signalling in osteoarthritis (OA) pain, we evaluated inflammatory changes in the knee joints following injection of monoiodoacetate (MIA) in mice carrying a TrkA receptor mutation (P782S; TrkA KI mice). METHOD: In behavioural studies we monitored mechanical hypersensitivity following intra-articular MIA and oral prostaglandin D2 (PGD2) synthase inhibitor treatments. In immunohistochemical studies we quantified joint mast cell numbers, calcitonin gene-related peptide expression in synovia and dorsal root ganglia, spinal cord neuron activation and microgliosis. We quantified joint leukocyte infiltration by flow cytometry analysis, and PGD2 generation and cyclooxygenase-2 (COX-2) expression in mast cell lines by ELISA and Western blot. RESULTS: In TrkA KI mice we observed rapid development of mechanical hypersensitivity and amplification of dorsal horn neurons and microglia activation 7 days after MIA. In TrkA KI knee joints we detected significant leukocyte infiltration and mast cells located in the vicinity of synovial nociceptive fibres. We demonstrated that mast cells exposure to NGF results in up-regulation of COX-2 and increase of PGD2 production. Finally, we observed that a PGD2 synthase inhibitor prevented MIA-mechanical hypersensitivity in TrkA KI, at doses which were ineffective in wild type (WT) mice. CONCLUSION: Using the TrkA KI mouse model, we delineated a novel neuro-immune pathway and suggest that NGF-induced production of PGD2 in joint mast cells is critical for referred mechanical hypersensitivity in OA, probably through the activation of PGD2 receptor 1 in nociceptors: TrkA blockade in mast cells constitutes a potential target for OA pain.

Hyponatraemia and congestive heart failure refractory to diuretic treatment. Utility of tolvaptan. / Hiponatremia e insuficiencia cardiaca congestiva refractaria a tratamiento diurético. Utilidad del tolvaptán.

Heart failure (HF) is currently one of the most significant healthcare problems in Spain and has a continuously increasing prevalence. Advances in our understanding of the various biological responses that promote cardiac remodelling and pulmonary venous congestion constitute the basis of current treatment. This article, prepared by members of the HF groups of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine, discusses the current therapeutic strategies for patients with congestion refractory to diuretic treatment. The article includes our clinical experience with the use of tolvaptan as an additional treatment for congestion associated with hyponatraemia. To this end, we propose an algorithm for the use of tolvaptan in patients with congestive HF, natraemia <130mEq/l and poor response to conventional diuretic treatment.

Neurotrophin signaling: many exciting surprises!

Neurotrophins are growth factors implicated in the development and maintenance of different neuronal populations in the nervous system. Neurotrophins bind to two sets of receptors, Trk receptor tyrosine kinases and the p75NTR receptor, to activate several different signaling pathways that mediate various biological functions. While Trk receptor activation has been well-studied and triggers the well-characterized Ras/Rap-MAPK, PI3K-Akt, and PLCgamma-PKC cascades, p75NTR signaling is more complex, and its in vivo significance has not yet been completely determined. In the last few years, p75NTR has received much attention mainly due to recent findings describing pro-neurotrophins as new ligands for the receptor and the ability of the receptor to form different complexes with other transmembrane proteins. This review will update the neurotrophin signaling pathways known for Trk receptors to include newly identified Trk-interacting molecules and will address surprising new findings that suggest a role for p75NTR in different receptor complexes and functions.

Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury.

The unprocessed precursor of the neurotrophin nerve growth factor (NGF), proNGF, has been suggested to be a death-inducing ligand for the neurotrophin receptor p75. Whether proNGF is a true pathophysiological ligand that is secreted, binds p75, and activates cell death in vivo, however, has remained unknown. Here, we report that after brain injury, proNGF was induced and secreted in an active form capable of triggering apoptosis in culture. We further demonstrate that proNGF binds p75 in vivo and that disruption of this binding results in complete rescue of injured adult corticospinal neurons. These data together suggest that proNGF binding to p75 is responsible for the death of adult corticospinal neurons after lesion, and they help to establish proNGF as the pathophysiological ligand that activates the cell-death program by means of p75 after brain injury. Interference in the binding of proNGF to p75 may provide a therapeutic approach for the treatment of disorders involving neuronal loss.

A novel mutation within the extracellular domain of TrkA causes constitutive receptor activation.

The TrkA NGF receptor extracellular region contains three leucine repeats flanked by cysteine clusters and two immunoglobulin-like domains that are required for specific ligand binding. Deletion of the immunoglobulin-like domains abolishes NGF binding and causes ligand independent activation of the receptor. Here we report a specific mutation that increases the binding affinity of the TrkA receptor for NGF. A change of proline 203 to alanine (P203A) in the linker region between the leucine repeats and the first Ig-like domain increased NGF binding by decreasing the ligand rate of dissociation. This mutated receptor was appropriately expressed on the cell surface and promoted ligand-independent neurite outgrowth in PC12nnr5 cells. The mutant receptor was capable of spontaneous dimerization and was constitutively phosphorylated in the absence of ligand. Moreover, expression of TrkA-P203A receptor in fibroblasts induced DNA synthesis and transformation and generated tumours in nude mice. These data suggest that domains outside of the immunoglobulin-like structure contribute to ligand binding and constitutive activation of Trk receptors.

TrkA immunoglobulin-like ligand binding domains inhibit spontaneous activation of the receptor.

The extracellular region of the nerve growth factor (NGF) receptor, TrkA, contains two immunoglobulin (Ig)-like domains that are required for specific ligand binding. We have investigated the possible role of these two Ig-like domains in receptor dimerization and activation by using different mutants of the TrkA extracellular region. Deletions of each Ig-like domain, of both, and of the entire extracellular region were made. To probe the structural constraints on ligand-independent receptor dimerization, chimeric receptors were generated by swapping the Ig-like domains of the TrkA receptor for the third or fourth Ig-like domain of c-Kit. We also introduced single-amino-acid changes in conserved residues within the Ig-like domains of TrkA. Most of these TrkA variants did not bind NGF, and their expression in PC12nnr5 cells, which lack endogenous TrkA, promoted ligand-independent neurite outgrowth. Some TrkA mutant receptors induced malignant transformation of Rat-1 cells, as assessed by measuring proliferation in the absence of serum, anchorage-independent growth, and tumorigenesis in nude mice. These mutants exhibited constitutive phosphorylation and spontaneous dimerization consistent with their biological activities. Our data suggest that spontaneous dimerization of TrkA occurs when the structure of the Ig-like domains is altered, implying that the intact domains inhibit receptor dimerization in the absence of NGF.

Manifestaciones neuropsiquiátricas del lupus eritematoso sistémico / Neuropsychiatric manifestations of systemic erythematosus

El Lupus Eritematoso Sistémico es una enfermedad inflamatoria crónica de tipo autoinmune que afecta a múltiples órganos. Presenta gran variedad de manifestaciones clínicas y su evolución es fluctuante con sucesivas exacerbaciones y remisiones. Es relativamente frecuente encontrar alteraciones psiquiátricas en distintos momentos de esta enfermedad, siendo dificil establecer si la etiología de las mismas es consecuencia de la afectación primaria del Sistema Nervioso Central o secundaria a la cronicidad o los tratamientos utilizados. Un mayor conocimiento de los elementos implicados en la génesis y mantenimiento de las alteraciones psiquiátricas permitirá diseñar un abordaje integral y adoptar una actitud preventiva en estos pacientes (AU)

beta-adrenergic agonists stimulate Na+-K+-Cl- cotransport by inducing intracellular Ca2+ liberation in crypt cells.

Epinephrine and beta-adrenergic agonists (beta1 and beta2 for isoproterenol, beta1 for dobutamine, beta2 for salbutamol) stimulated K+ (or 86Rb) influx mediated by the Na+-K+-2Cl- cotransporter and the Na+-K+ pump in isolated colonic crypt cells. Preincubation with bumetanide abolished the epinephrine effect on the Na+-K+ pump, suggesting that the primary effect is on the cotransporter. Maximal effect was obtained with 1 microM epinephrine with an EC50 of 91.6 +/- 9.98 nM. Epinephrine-induced K+ transport was blocked by propranolol with an IC50 of 134 +/- 28.2 nM. alpha-Adrenergic drugs did not modify K+ transport mechanisms. Neither Ba2+ nor tetraethylammonium nor DIDS modified the adrenergic enhancement on the cotransporter. In addition, epinephrine did not affect K+ efflux. Dibutyryl cAMP did not alter K+ transport. Reduction of extracellular Ca2+ to 30 nM did not influence the response to epinephrine. However, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM abolished epinephrine-induced K+ transport. Ionomycin increased Na+-K+-2Cl- cotransport activity. Moreover, epinephrine increased intracellular Ca2+ concentration in a process inhibited by propranolol. In conclusion, epinephrine stimulated the Na+-K+-2Cl- cotransporter in a process mediated by beta1- and beta2-receptors and modulated by intracellular Ca2+ liberation.

Phospholipid fatty acid and lipid peroxidation in liver microsomes from guinea pigs fed oil related to the toxic oil syndrome.

The potential effects of oil specimens both related and unrelated to cases of Toxic Oil Syndrome (TOS) on the phospholipid fatty acid composition, some antioxidant enzyme activities, and lipid peroxidation in guinea pig liver microsomes were investigated. For 4 weeks, animals were fed diets supplemented with either oil related to cases of TOS or control oil, previously heated or not. In all cases, the fat diet produced the incorporation of approximately 7% of linoleic acid exclusively in the phosphatidylethanolamine (PE) of liver microsomes. A pronounced increase in lipid peroxidation products, measured as malondialdehyde (MDA) and 4-hydroxyalkenals, was detected in animals fed nonheated control oil. Heated oil diets produced significant increases in superoxide dismutase and glutathione peroxidase activities with concomitant decreases in the lipid peroxidation status. Heated oils also increased the oleic/stearic acid ratio in the phosphatidylserine plus phosphatidylinositol (PS + PI) fraction. This ratio was also increased in the same fraction from animals fed non heated case oil. The study shows that case oil produces a decrease in the lipid peroxidation products with minimal alterations in phospholipid fatty acid composition of liver microsomes, which is dependent rather on the composition of dietary fat than on toxic effects.