p38γ/δ activation alters cardiac electrical activity and predisposes to ventricular arrhythmia

We gratefully acknowledge L. Sen-Martín, J. Alegre-Cebollada (CNIC, Madrid) and L. Carrier (University Medical Center HamburgEppendorf and DZHK, Hamburg) for the cMyBP3-C KO cardiac tissue; D. Roiz-Valle and C. López-Otín (IUOPA; Universidad de Oviedo, Oviedo) for the LmnaG609G/G609G cardiac tissue; and R. J. Davis for the MKK6 KO mice. We thank G. Giovinazzo and the CNIC Pluripotent Cell Technology Unit (CNIC, Madrid) for the hiPSCs. We thank S. Bartlett and F. Chanut (CNIC, Madrid) for English editing, and R. R. Mondragon (University of Michigan, Ann Arbor) for technical support. We are grateful to R. J. Davis (University of Massachusetts Chan Medical School, Worcester), A. Padmanabhan (University of California, San Francisco) and M. Costa and C. López-Otín (IUOPA; Universidad de Oviedo, Oviedo) for critical reading of the manuscript. We thank the staf at the CNIC Genomics and Bioinformatics Units for technical support and help with data analysis and A. C. Silva for help with figure editing and design. This work was funded by a CNIC Intramural Project Severo Ochoa (Expediente 12- 2016 IGP) to G.S. and J.J. G.S. is supported by the following projects: PMP21/00057 IMPACT-2021, funded by the Instituto de Salud Carlos III (ISCIII), and PDC2021-121147-I00 and PID2019-104399RB-I00, funded by MCIN/AEI/10.13039/501100011033—all funded by the European Union (FEDER/FSE); ‘Una manera de hacer Europa’/‘El FSE invierte en tu futuro’/Next Generation EU and co-funded by the European Union/Plan de Recuperación, Transformación y Resiliencia (PRTR). R.R.B. is a fellow of the FPU Program (FPU17/03847). B.G.T. was a fellow of the FPI Severo Ochoa CNIC Program (SVP‐2013‐067639) and an American Heart Association Postdoctoral Fellow (18POST34080175). The following grants provided additional funding: Instituto de Salud Carlos III, PDC2021-121147-I00 Convocatoria: Proyectos Prueba de Concepto 2021 Ministerio de Ciencia e Innovación and PID2022-138525OB-I00 Ministerio de Ciencia e Innovación; US National Heart, Lung, and Blood Institute (R01 grant HL122352); Fondos FEDER, Madrid, Spain, and Fundación Bancaria ‘La Caixa (project HR19/52160013) to J.J.; American Heart Association Postdoctoral Fellowship 14POST17820005 to D.P.B.; and MICINN PGC2018-097019-B-I00, ISCIII-SGEFI/ERDF (PRB3-IPT17/0019, ProteoRed), the Fundació Marató TV3 (grant 122/C/2015) and ‘la Caixa’ Banking Foundation (project code HR17- 00247) to J.V. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S, funded by MICIN/AEI/10.13039/501100011033).S

NADPH Oxidases and Oxidative Stress in the Pathogenesis of Atrial Fibrillation.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and its prevalence increases with age. The irregular and rapid contraction of the atria can lead to ineffective blood pumping, local blood stasis, blood clots, ischemic stroke, and heart failure. NADPH oxidases (NOX) and mitochondria are the main sources of reactive oxygen species in the heart, and dysregulated activation of NOX and mitochondrial dysfunction are associated with AF pathogenesis. NOX- and mitochondria-derived oxidative stress contribute to the onset of paroxysmal AF by inducing electrophysiological changes in atrial myocytes and structural remodeling in the atria. Because high atrial activity causes cardiac myocytes to expend extremely high energy to maintain excitation-contraction coupling during persistent AF, mitochondria, the primary energy source, undergo metabolic stress, affecting their morphology, Ca2+ handling, and ATP generation. In this review, we discuss the role of oxidative stress in activating AF-triggered activities, regulating intracellular Ca2+ handling, and functional and anatomical reentry mechanisms, all of which are associated with AF initiation, perpetuation, and progression. Changes in the extracellular matrix, inflammation, ion channel expression and function, myofibril structure, and mitochondrial function occur during the early transitional stages of AF, opening a window of opportunity to target NOX and mitochondria-derived oxidative stress using isoform-specific NOX inhibitors and mitochondrial ROS scavengers, as well as drugs that improve mitochondrial dynamics and metabolism to treat persistent AF and its transition to permanent AF.http://deepblue.lib.umich.edu/bitstream/2027.42/191308/2/NADPH Oxidases and Oxidative Stress in the Pathogenesis of Atrial Fibrillation.pdfPublished onlineDescription of NADPH Oxidases and Oxidative Stress in the Pathogenesis of Atrial Fibrillation.pdf : Published versio

Guidelines for the diagnosis and treatment of extrahepatic portal vein obstruction (EHPVO) in children

Introduction. Extrahepatic portal vein obstruction is an important cause of portal hypertension among children. The etiology is heterogeneous and there are few evidences related to the optimal treatment. Aim and methods. To establish guidelines for the diagnosis and treatment of EHPVO in children, a group of gastroenterologists and pediatric surgery experts reviewed and analyzed data reported in the literature and issued evidence-based recommendations.Results. Pediatric EHPVO is idiopathic in most of the cases. Digestive hemorrhage and/or hypersplenism are the main symptoms. Doppler ultrasound is a non-invasive technique with a high degree of accuracy for the diagnosis. Morbidity is related to variceal bleeding, recurrent thrombosis, portal biliopathy and hypersplenism. Endoscopic therapy is effective in controlling acute variceal hemorrhage and it seems that vasoactive drug therapy can be helpful. For primary prophylaxis of variceal bleeding, there are insufficient data for the use of beta blockers or endoscopic therapy. For secondary prophylaxis, sclerotherapy or variceal band ligation is effective; there is scare evidence to recommend beta-blockers. Surgery shunt is indicated in children with variceal bleeding who fail endoscopic therapy and for symptomatic hypersplenism; spleno-renal or meso-ilio-cava shunting is the alternative when Mesorex bypass is not feasible due to anatomic problems or in centers with no experience.Conclusions. Prospective control studies are required for a better knowledge of the natural history of EHPVO, etiology identification including prothrombotic states, efficacy of beta-blockers and comparison with endoscopic therapy on primary and secondary prophylaxis