La galectina-3, una nueva diana terapéutica para las alteraciones cardiovasculares asociadas al desarrollo de la estenosis aórtica severa

Aortic stenosis is one of the most common heart valve diseases, as well as one of the most common causes of heart failure in the elderly. Currently, there are no medical therapies to prevent or slow the progression of the disease. When symptoms develop alongside severe aortic stenosis, there is a poor prognosis unless aortic valve replacement is performed. Aortic stenosis is a heterogeneous disease with a complex pathophysiology involving structural and biological changes of the valve, as well as adaptive and maladaptive compensatory changes in the myocardium and vasculature in response to chronic pressure overload. Galectin-3 serves important functions in numerous biological activities including cell growth, apoptosis, differentiation, inflammation and fibrosis. With evidence emerging to support the function of Galectin-3, the current review aims to summarize the latest literature regarding the potential of Galectin-3 as therapeutic target in aortic valve and cardiovascular alterations associated with aortic stenosis.La estenosis aórtica severa degenerativa (EA) es una enfermedad muy prevalente, cuya incidencia se incrementará en los próximos años debido al envejecimiento de la población. Actualmente no existe ningún tratamiento farmacológico que retarde su progresión y, cuando aparecen los síntomas, la cirugía de recambio valvular es la única opción. La EA se caracteriza por la calcificación de la válvula aórtica y por la aparición de fibrosis miocárdica. Sin embargo, no se conocen los mecanismos fisiopatológicos de la EA necesarios para identificar y desarrollar nuevas estrategias terapéuticas adecuadas. La Galectina-3 (Gal-3) regula funciones biológicas como el crecimiento, la diferenciación, la apoptosis, la inflamación o la fibrosis. Esta revisión resume los principales trabajos que describen el potencial de la Gal-3 como diana terapéutica para las alteraciones cardíacas y valvulares asociadas con el desarrollo de EA

Targeting fatty acid-binding protein 4 improves pathologic features of aortic stenosis

Aortic stenosis (AS) is a fibrocalcific disease of the aortic valves (AVs). Sex-differences in AS pathophysiology have recently been described. High levels of fatty acid-binding protein 4 (FAPB4) in atherosclerotic plaques have been associated with increased local inflammation, endothelial dysfunction, and plaque vulnerability. FABP4 pharmacological blockade has been shown to be effective for the treatment of atherosclerosis by modulating metabolic and inflammatory pathways. We aimed to analyze the sex-specific expression of FABP4 in AS and its potential role as a therapeutic target. A total of 226 patients (61.5% men) with severe AS undergoing surgical AV replacement were recruited. The FABP4 levels were increased in the AVs of AS patients compared to the control subjects, showing greater expression in the fibrocalcific regions. Male AVs exhibited higher levels of FABP4 compared to females, correlating with markers of inflammation (IL-6, Rantes), apoptosis (Bax, caspase-3, Bcl-2), and calcification (IL-8, BMP-2 and BMP-4). VICs derived from AS patients showed the basal expression of FABP4 in vitro. Osteogenic media induced upregulation of intracellular and secreted FABP4 levels in male VICs after 7 days, along with increased levels of inflammatory, pro-apoptotic, and osteogenic markers. Treatment with BMS309403, a specific inhibitor of FABP4, prevented from all of these changes. Thus, we propose FABP4 as a new sex-specific pharmacological therapeutic target in AS.This research was funded by Miguel Servet contract CP13/00221 from the Instituto de Salud Carlos III-FEDER, Fondo de Investigaciones Sanitarias [PI18/01875; PI21/00280]. M.G. is supported by a Miguel Servet Foundation PhD studentship, E.M.-N. is supported by a Margarita Salas postdoctoral fellowship (ULL-MS-P14), L.M. is supported by a PFIS (FI19/00302) PhD studentship, E.J. (CD19/00251) is supported by a Sara Borrell postdoctoral fellowship

Characterization of the sex-specific pattern of angiogenesis and lymphangiogenesis in aortic stenosis

Objective: We aim to analyze sex-related dierences in angiogenesis and lymphangiogenesis in aortic valves (AVs) and valve interstitial cells (VICs) from aortic stenosis (AS) patients. Approach and Results: Totally 230 patients (59% men) with severe AS undergoing surgical valve replacement were recruited. The density of total neovessels was higher in AVs from men as compared to women. Both small and medium neovessels were more abundant in men’s AVs. Accordingly, male AVs exhibited higher CD31 and VE-cadherin expressions. The levels of the pro-angiogenic markers, such as vascular endothelial growth factor (VEGF)-A, VEGF receptor (VEGFR)1, VEGFR2, insulin-like growth factor-binding protein-2 (IGFBP-2), interleukin (IL)-8, chemerin, and fibroblast growth factor (FGF)-7, were increased in AVs from men. Transforming growth factor-β expression was higher in male AVs. The expression of antiangiogenic molecules thrombospondin (Tsp)-1, endostatin, and CD36 was upregulated in male AVs, although the levels of Tsp-2, IL-4, IL-12p70, and chondromodulin-1 were similar between both sexes. The number of lymphatic vessels and the expression of the lymphangiogenic markers Lyve-1 and D2-40 was higher in men’s AV as well as VEGF-C, VEGF-D, and VEGFR3. Multivariate analyses adjusted for confounders further validated the sex-dependent expression of these targets. VICs isolated from men’s AVs secreted higher amounts of the pro-angiogenic factors, VEGF-A, VEGFR1, IGFBP-2, and FGF-7, as well as the pro-lymphangiogenic factors, VEGF-C, VEGF-D, and VEGFR3, than women without changes in antiangiogenic markers. Conclusion: Our data show that aberrant angiogenic and lymphangiogenic cues are over-represented in male AVs. Importantly, the VIC is a relevant source of multiple morphogens involved in angiogenesis and lymphangiogenesis likely endowing the AV of men with the predominant calcific AS phenotypes.This work was supported by a Miguel Servet contract (CP13/00221) and by Fondo de Investigaciones Sanitarias (PI18/01875; PI21/00280) from the Instituto de Salud Carlos III - FEDER. LM was supported by a PFIS Ph.D. studentship (FI19/00302). EJ was supported by a Sara Borrell postdoctoral fellowship (CD19/00251). EM-N was supported by a Margarita Salas postdoctoral fellowship (ULL-MS-P14). MG was supported by a Miguel Servet Foundation Ph.D. studentship

Sex-dependent expression of neutrophil gelatinase-associated lipocalin in aortic stenosis

Background: Accumulating evidence suggest the existence of sex-related differences in the pathogenesis of aortic stenosis (AS) with inflammation, oxidative stress, fibrosis and calcification being over-represented in men. Neutrophil gelatinase-associated lipocalin (NGAL) is expressed in a myriad of tissues and cell types, and it is associated with acute and chronic pathological processes comprising inflammation, fibrosis or calcification. Sex-dependent signatures have been evidenced for NGAL which expression has been associated predominantly in males to metabolic and cardiovascular disorders. We aimed to analyse sex-related differences of NGAL in AS and its role in the inflammatory and fibrocalcific progression of AS. Methods and results: 220 (60.45% men) patients with severe AS elective for surgical aortic valve (AV) replacement were recruited. Immunohistochemistry revealed higher expression of NGAL in calcific areas of AVs and that was validated by qPCR in in 65 (60% men) donors. Valve interstitial cells (VICs) were a source of NGAL in these samples. Proteome profiler analyses evidenced higher expression of NGAL in men compared to women, and that was further validated by ELISA. NGAL expression in the AV was correlated with inflammation, oxidative stress, and osteogenic markers, as well as calcium score. The expression of NGAL, both intracellular and secreted (sNGAL), was significantly deregulated only in calcifying male-derived VICs. Depletion of intracellular NGAL in calcifying male-derived VICs was associated with pro-inflammatory profiles, dysbalanced matrix remodelling and pro-osteogenic profiles. Conversely, exogenous NGAL mediated inflammatory and dysbalanced matrix remodelling in calcifying VICs, and all that was prevented by the pharmacological blockade of NGAL. Conclusions: Owing to the over-expression of NGAL, the AV from men may be endowed with higher expression of inflammatory, oxidative stress, matrix remodelling and osteogenic markers supporting the progression of calcific AS phenotypes. The expression of NGAL in the VIC emerges as a potential therapeutic checkpoint, with its effects being potentially reverted by the pharmacological blockade of extracellular NGAL.This research was funded by Miguel Servet contract CP13/00221 from Instituto de Salud Carlos III-FEDER, Fondo de Investigaciones Sanitarias [PI18/01875; PI21/00280]. M.G. is supported by a Miguel Servet Foundation PhD studentship, E.M.-N is supported by a Margarita Salas postdoctoral fellowship (ULL-MS-P14), L.M. is supported by a PFIS (FI19/00302) PhD studentship, E.J. (CD19/00251) is supported by a Sara Borrell postdoctoral fellowship

Anesthesic and surgical guidelines for the treatment of the ascending aorta andaortic arch. Consensus document of the Spanish Societies of Anesthesia and Cardiovascular Surgerya

La patología de la aorta supone un reto para la medicina. Tanto a nivel diagnóstico, como terapéutico,el volumen de variables implicado ha hecho que dicha patología sea abordada por una ingente cantidad de especialistas. El manejo quirúrgico de dichas patologías implica un esfuerzo extraordinario por parte de muchos profesionales, dada la complejidad técnica y tecnológica empleada. A lo largo de estos a˜nos,dichos esfuerzos están dando sus frutos en forma de mejoras de resultados, gracias a un abordaje sis-temático y protocolizado en el seno de un grupo de expertos (Comités de aorta o “Aortic team”) en el que se han de implicar cardiólogos, cirujanos cardíacos, cirujanos vasculares, anestesiólogos y radiólogos, principalmente. En este documento, consensuado entre los grupos de trabajo de Aorta de las sociedades españolas de Anestesiología (SEDAR) y Cirugía Torácica-cardiovascular (SECTCV) se busca difundir los modos de trabajo más consensuados entre los centros de mayor actividad del país por parte de ambas especialidades, en lo que al tratamiento quirúrgico se refiere de la patología de aorta ascendente y arco aórtico se refiere, así como del tratamiento de la disección aguda de aorta. Somos conscientes de la evolución constante de la terapéutica, lo cual sin duda puede hacer cuestionables algunas opiniones aquí expresadas y que sin duda irán modificándose en futuras edicionestThe pathology of the aorta is a challenge for medicine. Diagnostic and therapeutica move a huge volumeof variables. This has let this pathology to be addressed by a big number of specialists. The surgicalmanagement of these pathologies implies an extraordinary effort on the part of many professionals,given the technical and technological complexity employed. Throughout these years, these efforts arepaying off in the form of improved results, thanks to a systematic and protocolized approach within agroup of experts (Aortic Committees or “Aortic team”) in which they have to involve cardiologists, cardiacsurgeons, vascular surgeons, anesthesiologists and radiologists, mainly.In this document, agreed between the Aorta working groups of the Spanish societies of Anesthesiology(SEDAR) and Thoracic-Cardiovascular Surgery (SECCE), it is sought to disseminate the most agreed work-ing modes among the centers of greatest activity in the country by both specialties, as far as surgicaltreatment is concerned with ascending aortic and aortic arch pathology, as well as the treatment of acuteaortic dissection.We are aware of the constant evolution of therapeutics, which can undoubtedly make some of the opinionsexpressed here questionable and that will undoubtedly be modified in future editions.This document aims to be a working tool for the different professionals involved in the treatment of aorticpathology

Impacto de la COVID-19 en los servicios de cirugía cardiovascular en España: Análisis de los grupos relacionados con el diagnóstico (Estudio SECCE-COVID-19 fase 2)

Introducción y objetivos La pandemia por COVID-19 causada por infección del virus SARS-CoV-2 ha saturado al sistema sanitario español, afectándose la atención de las enfermedades cardiovasculares. Queremos cuantificar el impacto de la pandemia en el número de las intervenciones quirúrgicas cardíacas analizando los grupos relacionados con el diagnóstico (GRD) más prevalentes de nuestra especialidad. Métodos A instancias de la Sociedad Española de Cirugía Cardiovascular y Endovascular, se solicitó a todos los centros nacionales que quisieron participar, los datos de los códigos de GRD números 162 (cirugía sobre válvulas cardíacas con infarto o diagnóstico complejo), 163 (cirugía sobre válvulas cardíacas sin infarto o diagnóstico complejo), 165 (bypass coronario con infarto o diagnóstico complejo), 166 (bypass coronario sin infarto o diagnóstico complejo) y 167 (otros procedimientos cardiotorácicos o vasculares torácicos) entre el 1 de marzo de 2020 y el 30 de septiembre de 2020 (siete meses), y como período control las mismas fechas de 2019. Resultados Se recibieron los datos de 24 hospitales, 22 públicos y dos privados. Existió un descenso global en el número de intervenciones del 30% (rango -19 a -42%, p < 0,001) de 4.648 en 2019 a 3.262 en 2020 (-1.386 de diferencia), siendo +7% para el GRD 162 (p = 0,500), -37% para el 163 (p = 0,001), -9% para el 165 (p = 0,304), -32% para el 166 (p = 0,001), y -16% para el 167 (p = 0,062). Conclusiones Existió un descenso global de cirugías estadísticamente significativo en 2020 del 30% respecto del 2019 entre el 1 de marzo y el 30 de septiembre