Perspectives of bilateral thoracic sympathectomy for treatment of heart failure

Surgical neuromodulation therapies are still considered a last resort when standard therapies have failed for patients with progressive heart failure (HF). Although a number of experimental studies have provided robust evidence of its effectiveness, the lack of strong clinical evidence discourages practitioners. Thoracic unilateral sympathectomy has been extensively studied and has failed to show significant clinical improvement in HF patients. Most recently, bilateral sympathectomy effect was associated with a high degree of success in HF models, opening the perspective to be investigated in randomized controlled clinical trials. In addition, a series of clinical trials showed that bilateral sympathectomy was associated with a decreased risk of sudden death, which is an important outcome in patients with HF. These aspects indicates that bilateral sympathectomy could be an important alternative in the treatment of HF wherein pharmacological treatment barely reaches the target dose

Fibroblast growth factor-2, but not the adipose tissue-derived stromal cells secretome, inhibits TGF-beta 1-induced differentiation of human cardiac fibroblasts into myofibroblasts

Transforming growth factor-beta 1 (TGF-beta 1) is a potent inducer of fibroblast to myofibroblast differentiation and contributes to the pro-fibrotic microenvironment during cardiac remodeling. Fibroblast growth factor-2 (FGF-2) is a growth factor secreted by adipose tissue-derived stromal cells (ASC) which can antagonize TGF-beta 1 signaling. We hypothesized that TGF-beta 1-induced cardiac fibroblast to myofibroblast differentiation is abrogated by FGF-2 and ASC conditioned medium (ASC-CMed). Our experiments demonstrated that TGF-beta 1 treatment-induced cardiac fibroblast differentiation into myofibroblasts, as evidenced by the formation of contractile stress fibers rich in alpha SMA. FGF-2 blocked the differentiation, as evidenced by the reduction in gene (TAGLN, p <0.0001; ACTA2, p = 0.0056) and protein (alpha SMA, p = 0.0338) expression of mesenchymal markers and extracellular matrix components gene expression (COL1A1, p <0.0001; COL3A1, p = 0.0029). ASC-CMed did not block myofibroblast differentiation. The treatment with FGF-2 increased matrix metalloproteinases gene expression (MMP1, p <0.0001; MMP14, p = 0.0027) and decreased the expression of tissue inhibitor of metalloproteinase gene TIMP2 (p = 0.0023). ASC-CMed did not influence these genes. The proliferation of TGF-beta 1-induced human cardiac fibroblasts was restored by both FGF-2 (p = 0.0002) and ASC-CMed (p = 0.0121). The present study supports the anti-fibrotic effects of FGF-2 through the blockage of cardiac fibroblast differentiation into myofibroblasts. ASC-CMed, however, did not replicate the anti-fibrotic effects of FGF-2 in vitro

Adipose tissue-derived stromal cells' conditioned medium modulates endothelial-mesenchymal transition induced by IL-1β/TGF-β2 but does not restore endothelial function

OBJECTIVES: Endothelial cells undergo TGF-β-driven endothelial-mesenchymal transition (EndMT), representing up to 25% of cardiac myofibroblasts in ischaemic hearts. Previous research showed that conditioned medium of adipose tissue-derived stromal cells (ASC-CMed) blocks the activation of fibroblasts into fibrotic myofibroblasts. We tested the hypothesis that ASC-CMed abrogates EndMT and prevents the formation of adverse myofibroblasts. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVEC) were treated with IL-1β and TGF-β2 to induce EndMT, and the influence of ASC-CMed was assessed. As controls, non-treated HUVEC or HUVEC treated only with IL-1β in the absence or presence of ASC-CMed were used. Gene expression of inflammatory, endothelial, mesenchymal and extracellular matrix markers, transcription factors and cell receptors was analysed by RT-qPCR. The protein expression of endothelial and mesenchymal markers was evaluated by immunofluorescence microscopy and immunoblotting. Endothelial cell function was measured by sprouting assay. RESULTS: IL-1β/TGF-β2 treatment induced EndMT, as evidenced by the change in HUVEC morphology and an increase in mesenchymal markers. ASC-CMed blocked the EndMT-related fibrotic processes, as observed by reduced expression of mesenchymal markers TAGLN (P = 0.0008) and CNN1 (P = 0.0573), as well as SM22α (P = 0.0501). The angiogenesis potential was impaired in HUVEC undergoing EndMT and could not be restored by ASC-CMed. CONCLUSIONS: We demonstrated that ASC-CMed reduces IL-1β/TGF-β2-induced EndMT as observed by the loss of mesenchymal markers. The present study supports the anti-fibrotic effects of ASC-CMed through the modulation of the EndMT process

Comparative experimental study between L-Hydro treated pulmonary homograft and fresh pulmonary homograft

OBJETIVO: Buscando novas formas de preservação de tecidos utilizamos o polietileno-glicol, método L-Hydro (LH), que consiste na extração controlada de substâncias antigênicas e incorporação de agente antinflamatório e antitrombótico. MÉTODOS: Em dez carneiros jovens, substituímos o tronco pulmonar, em sete, por homoenxertos pulmonares (HP) tratados pelo processo L-H e, em três, por HP a fresco, implantados ortotopicamente, seguidos por 320 dias. Os carneiros foram avaliados por exames laboratoriais e ecocardiográficos. Ao cabo dos 320 dias foram sacrificados, procedendo-se à avaliação hemodinâmica, radiológica, macro/microscópica, óptica e eletrônica, varredura e transmissão. Resultados foram analisados pelo teste t de Student de amostras independentes para dados contínuos, análise de variância para medidas repetidas, pelo teste exato de Fisher para dados categóricos. RESULTADOS: Evolução clínica e exames laboratoriais não conseguiram estabelecer diferenças significativas entre os grupos. Ecocardiograma revelou diferença quanto ao gradiente médio pulmonar, significativa aos 10 meses, maior no grupo controle. Avaliação radiológica e macroscópica não estabeleceu diferenças. Na avaliação microscópica, óptica/eletrônica, células de revestimento e intersticiais foram encontradas nos dois grupos igualmente. O porcentual de revestimento celular calculado nos dois grupos foi semelhante. Nódulos de celularidade foram observados somente no grupo de homoenxertos a fresco. CONCLUSÕES: Estes dados indicam que os dois grupos apresentaram desempenho clínico e hemodinâmico semelhante. Ao ecocardiograma o grupo LH apresentou melhor desempenho, e evidências histológicas de repopulação celular intersticial e endotelial. Na análise macro/microscópica, óptica/eletrônica, o grupo L-Hydro apresentou macroscopia, estrutura histológica e ultraestrutural semelhante ao homoenxerto fresco, à exceção de nódulos de maior celularidade intersticial, presentes apenas no homoenxerto a fresco.OBJECTIVE: In an effort to make available homografts preserved in a simpler and less costly way, we evaluated the polyethyleneglycol, L-Hydro (LH) method, that consists in the controlled extraction of antigenic substances and the incorporation of anti-inflammatory and anti-thrombotic agent. METHODS: We substituted the pulmonary trunk in ten ovines, seven received LH treated pulmonary homografts and three, fresh pulmonary homografts, orthotopically implanted and followed-up for 320 days. Ovines where evaluated by means of laboratory tests, echocardiographic exams. At the 320 days, were euthanized, hemodynamic, radiology, macroscopic, optic/electronic microscopic, scanning/transmission evaluations were performed. Results were analyzed by Student t test of independent samples for continuous data, by variance analysis of repeated measures, and by Fisher exact test for categorical data. RESULTS: We couldn't establish relevant differences in clinical evolution and laboratory tests between groups. Echocardiogram revealed difference in pulmonary medium gradient, which was significant 10 months follow-up, higher in the control group. Radiologic and macroscopic evaluations didn't established differences. In the optic/electronic microscopic evaluation, liner and interstitial cells were equally found in both groups. The cell liner percent calculated in both groups was similar. Cellularity nodules were observed only infresh homograft group. CONCLUSIONS: These data indicate that both groups presented similar clinical/hemodynamic performances. The LH group's echocardiogram presented a better performance. It also presented histological evidences of interstitial and endothelial cell repopulation. In the macro/optic and electronic microscopic analysis, group L-H presented macroscopy/histological structure and ultra-structural similar to the fresh group, with the exception of nodules with higher interstitial cellularity, present only in the fresh homograft group.Fapes

Resultado do tratamento cirúrgico das cardiopatias congênitas acianóticas

The authors make on analysis of the results of surgical treatment of acyanotic congenital heart diseases. They considere separately the following anomalies: coarctation of the aorta, aorta stenosis, pulmonary stenosis, interatrial septal defect, atrioventricular canal defects, interventricular septal defects and patient ductus arteriosus in new of the late results in these anomalies coments are made on operative techniques that may influence long term evolution.Os autores realizam análise dos resultados do tratamento cirúrgico das cardiopatias congênitas acianóticas. Consideram em separado as anomalias mais freqüentes: coartação da aorta, estenoses aórticas, estenoses pulmonares, comunicação interatrial, "atrioventricularis comunis", comunicação interventricular e persistência do canal arterial. Objetivando o estudo dos resultados tardios dessas cardiopatias comentam aspectos operatórios que podem se relacionar com a evolução tardia

Bioactive decellularized cardiac extracellular matrix-based hydrogel as a sustained-release platform for human adipose tissue-derived stromal cell-secreted factors

The administration of trophic factors (TFs) released by mesenchymal stromal cells (MSCs) as therapy for cardiovascular diseases requires a delivery vehicle capable of binding and releasing the TF in a sustained manner. We hypothesized that hydrogels derived from cardiac decellularized extracellular matrix (cardiac dECM) bind MSC secretome-derived TF and release these in a sustained fashion. Pig-derived ventricular tissue was decellularized, milled to powder, digested, and assembled as a hydrogel upon warming at 37 degrees C. The conditioned medium (CMed) of adipose tissue-derived stromal cells (ASC) was collected, concentrated, and incorporated into the hydrogel at 1x, 10x, and 100x the original concentration. The release of 11 ASC-secreted factors (angiopoietin-1, angiopoietin-2, fibroblast growth factor-1, hepatocyte growth factor, platelet-derived growth factor-AA, vascular endothelial growth factor, interleukin-1 beta, interleukin-6, interleukin-8, CCL2, and matrix metalloproteinase-1) from hydrogels was immune assessed. Bioactivity was determined by endothelial cell proliferation, function, and assessment of endothelial mesenchymal transition. We showed that dECM hydrogels could be loaded with human ASC-secreted TFs, which are released in a sustained manner for several days subsequently. Different trophic factors had different release kinetics, which correlates with the initial concentration of CMed in the hydrogel. We observed that the more concentrated was the hydrogel, the more inflammation-related cytokines, and the less pro-regenerative TFs were released. Finally, we showed that the factors secreted by the hydrogel are biologically active as these influence cell behavior. The use of dECM hydrogels as a platform to bind and release paracrine factors secreted by (mesenchymal) cells is a potential alternative in the context of cardiovascular regeneration

17b-Estradiol, a potential ally to alleviate SARS-CoV- 2 infection

Considering that female sexual hormones may modulate the inflammatory response and also exhibit direct effects on the cells of the immune system, herein, we intend to discuss the sex differences and the role of estradiol in modulating the lung and systemic inflammatory response, focusing on its possible application as a treatment modality for SARS-CoV-2 patients. COVID-19 patients develop severe hypoxemia early in the course of the disease, which is silent most of the time. Small fibrinous thrombi in pulmonary arterioles and a tumefaction of endothelial were observed in the autopsies of fatal COVID-19 cases. Studies showed that the viral infection induces a vascular process in the lung, which included vasodilation and endothelial dysfunction. Further, the proportions of CD4 + T and CD8 + T lymphocytes were strongly reduced in patients with severe SARS-CoV-2 infection. Estradiol is connected with CD4 + T cell numbers and increases T-reg cell populations, affecting immune responses to infection. It is known that estradiol exerts a protective effect on endothelial function, activating the generation of nitric oxide (NO) via endothelial nitric oxide synthase. Estrogen attenuates the vasoconstrictor response to various stimuli and induces vasodilation in the pulmonary vasculature during stress situations like hypoxia. It exerts a variety of rapid actions, which are initiated after its coupling with membrane receptors, which in turn, may positively modulate vascular responses in pulmonary disease and help to maintain microvascular flow. Direct and indirect mechanisms underlying the effects of estradiol were investigated, and the results point to a possible protective effect of estradiol against COVID-19, indicating that it may be considered as an adjuvant therapeutic element for the treatment of patients affected by the novel coronavi