Insuficiencia cardiaca y trasplante

The mission of the Heart Failure and Heart Transplantation Section of the Spanish Society of Cardiology is to study, promote interest in, and disseminate information about all aspects of myocardial dysfunction and heart transplantation. Heart failure is a highly prevalent disorder that consumes a substantial proportion of healthcare resources. Consequently, there is a very high level of interest in the condition and a wide range of preclinical and clinical research is being carried out, including research into new ways of looking at the disease that will increase our understanding. The aim of this article was to describe current developments concerning this disease and its treatment. Firstly, the latest publications on heart failure are summarized. Then, the most recent studies on advanced heart failure and ventricular assist devices are reviewed. Finally, the latest findings on heart transplantation are reported.     

Liver and kidney damage induced by 4-aminopyridine in a repeated dose (28 days) oral toxicity study in rats: Gene expression profile of hybrid cell death

4-Aminopyridine (4-AP) is an orphan drug indicated for the treatment of neuromuscular disorders. There is a great controversy around the use of this drug because of its narrow safety index and because a large number of adverse effects have been reported. Moreover, it was shown to induce cell death in different cell lines, being reported mainly apoptosis and necrosis as the principal pathways of cell death mediated by blockage of K channels or the Na, K-ATPase, but until now it was not described in vivo cell death induced by 4-aminipyridine. To provide new subchronic toxicity data and specifically, evaluate if 4-AP is able to induce in vivo cell death process and the main pathways related to it, a repeated dose (28 days) oral toxicity study, at therapeutic range of doses, was conducted in rats. The anatomical pathology, the biochemical and hematological parameters were analyzed and a real-time PCR array analysis was developed with an Ingenuity Pathway Analysis (IPA). The leucocytes number, the lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) enzymatic activity were increased at all dose but the erythrocytes number, the hemoglobin concentration, the alkaline phosphatase (FAL) and alanine aminotransferase (ALT) enzymatic activity were increased only at highest dose studied. However, glucose levels decreased at all doses. The biochemical results are indicative of hepatic damage. The anatomy pathology studies showed cell death only on liver and kidney, and the real-time PCR array on liver tissue expressed a gene expression profile of necrotic and apoptotic induced cell death. The present work shows for the first time in vivo cell death on liver and kidney with features of apoptosis and necrosis induced by 4-AP and the gene expression profile shows that the cell death is mediated by necrotic and apoptotic pathways that support this finding.     

Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation,a target of melatonin

The connection between the innate immune system, clock genes, and mitochondrial bioenergetics was analyzed during aging and sepsis in mouse heart. Our results suggest that the sole NF‐κB activation does not explain the inflammatory process underlying aging; the former also triggers the NLRP3 inflammasome that enhances caspase‐1‐dependent maturation of IL‐1β. In this way, aged mice enter into a vicious cycle as IL‐1β further activates the NF‐κB/NLRP3 inflammasome link. The origin of NF‐κB activation was related to the age‐dependent Bmal1/Clock/RORα/Rev‐Erbα loop disruption, which lowers NAD⁺ levels, reducing the SIRT1 deacetylase ability to inactivate NF‐κB. Consequently, NF‐κB binding to DNA increases, raising the formation of proinflammatory mediators and inducing mitochondrial impairment. The cycle is then closed with the subsequent NLRP3 inflammasome activation. This paired contribution of the innate immune pathways serves as a catalyst to magnify the response to sepsis in aged compared with young mice. Melatonin administration blunted the septic response, reducing inflammation and oxidative stress, and enhancing mitochondrial function at the levels of nonseptic aged mice, but it did not counteract the age‐related inflammation. Together, our results suggest that, although with different strengths, chronoinflammaging constitutes the biochemical substrate of aging and sepsis, and identifies the NLRP3 inflammasome as a new molecular target for melatonin, providing a rationale for its use in NLRP3‐dependent diseases.     

Ochronotic arthropathy as a paradigm of metabolically induced degenerative joint disease. A case-based review

Clinical Rheumatology - Alkaptonuria is a rare, hereditary metabolic disorder in which a deficiency in the homogentisate 1,2-dioxygenase enzyme results in an accumulation of homogentisic acid....