Author: "Fielitz, J" - Searchworks@Jio Institute Digital Library Search Results

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124 results on '"Fielitz, J"'

1. SPSB1-mediated inhibition of TGF-β receptor-II impairs myogenesis in inflammation

Author: Li, Y., Dörmann, N., Brinschwitz, B., Kny, M., Martin, E., Bartels, K., Li, N., Giri, P.V., Schwanz, S., Boschmann, M., Hille, S., Fielitz, B., Wollersheim, T., Grunow, J., Felix, S.B., Weber-Carstens, S., Luft, F.C., Müller, O.J., and Fielitz, J.
Subjects: Cardiovascular and Metabolic Diseases
Abstract: BACKGROUND: Sepsis-induced intensive care unit-acquired weakness (ICUAW) features profound muscle atrophy and attenuated muscle regeneration related to malfunctioning satellite cells. Transforming growth factor beta (TGF-β) is involved in both processes. We uncovered an increased expression of the TGF-β receptor II (TβRII)-inhibitor SPRY domain-containing and SOCS-box protein 1 (SPSB1) in skeletal muscle of septic mice. We hypothesized that SPSB1-mediated inhibition of TβRII signalling impairs myogenic differentiation in response to inflammation. METHODS: We performed gene expression analyses in skeletal muscle of cecal ligation and puncture- (CLP) and sham-operated mice, as well as vastus lateralis of critically ill and control patients. Pro-inflammatory cytokines and specific pathway inhibitors were used to quantitate Spsb1 expression in myocytes. Retroviral expression plasmids were used to investigate the effects of SPSB1 on TGF-β/TβRII signalling and myogenesis in primary and immortalized myoblasts and differentiated myotubes. For mechanistical analyses we used coimmunoprecipitation, ubiquitination, protein half-life, and protein synthesis assays. Differentiation and fusion indices were determined by immunocytochemistry, and differentiation factors were quantified by qRT-PCR and Western blot analyses. RESULTS: SPSB1 expression was increased in skeletal muscle of ICUAW patients and septic mice. Tumour necrosis factor (TNF), interleukin-1β (IL-1β), and IL-6 increased the Spsb1 expression in C2C12 myotubes. TNF- and IL-1β-induced Spsb1 expression was mediated by NF-κB, whereas IL-6 increased the Spsb1 expression via the glycoprotein 130/JAK2/STAT3 pathway. All cytokines reduced myogenic differentiation. SPSB1 avidly interacted with TβRII, resulting in TβRII ubiquitination and destabilization. SPSB1 impaired TβRII-Akt-Myogenin signalling and diminished protein synthesis in myocytes. Overexpression of SPSB1 decreased the expression of early (Myog, Mymk, Mymx) and late (Myh1, 3, 7) differentiation-markers. As a result, myoblast fusion and myogenic differentiation were impaired. These effects were mediated by the SPRY- and SOCS-box domains of SPSB1. Co-expression of SPSB1 with Akt or Myogenin reversed the inhibitory effects of SPSB1 on protein synthesis and myogenic differentiation. Downregulation of Spsb1 by AAV9-mediated shRNA attenuated muscle weight loss and atrophy gene expression in skeletal muscle of septic mice. CONCLUSIONS: Inflammatory cytokines via their respective signalling pathways cause an increase in SPSB1 expression in myocytes and attenuate myogenic differentiation. SPSB1-mediated inhibition of TβRII-Akt-Myogenin signalling and protein synthesis contributes to a disturbed myocyte homeostasis and myogenic differentiation that occurs during inflammation.
Published: 2023

2. Chronic heart failure as a sequel of severe burn injury: first insight into a novel pathological heart-skin axis

Author: Hundeshagen, G, primary, Mertin, V, additional, Busch, M, additional, Thiele, P, additional, Trogisch, F, additional, Heineke, J, additional, Egger, M, additional, Buerkert, H, additional, Van Linthout, S, additional, Fielitz, J, additional, Mayr, M, additional, Kneser, U, additional, and Most, P, additional
Published: 2022
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3. Hidden agenda - the involvement of endoplasmic reticulum stress and unfolded protein response in inflammation-induced muscle wasting

Author: Kny, M. and Fielitz, J.
Subjects: Cardiovascular and Metabolic Diseases
Abstract: Critically ill patients at the intensive care unit (ICU) often develop a generalized weakness, called ICU-acquired weakness (ICUAW). A major contributor to ICUAW is muscle atrophy, a loss of skeletal muscle mass and function. Skeletal muscle assures almost all of the vital functions of our body. It adapts rapidly in response to physiological as well as pathological stress, such as inactivity, immobilization, and inflammation. In response to a reduced workload or inflammation muscle atrophy develops. Recent work suggests that adaptive or maladaptive processes in the endoplasmic reticulum (ER), also known as sarcoplasmic reticulum, contributes to this process. In muscle cells, the ER is a highly specialized cellular organelle that assures calcium homeostasis and therefore muscle contraction. The ER also assures correct folding of proteins that are secreted or localized to the cell membrane. Protein folding is a highly error prone process and accumulation of misfolded or unfolded proteins can cause ER stress, which is counteracted by the activation of a signaling network known as the unfolded protein response (UPR). Three ER membrane residing molecules, protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1a (IRE1a), and activating transcription factor 6 (ATF6) initiate the UPR. The UPR aims to restore ER homeostasis by reducing overall protein synthesis and increasing gene expression of various ER chaperone proteins. If ER stress persists or cannot be resolved cell death pathways are activated. Although, ER stress-induced UPR pathways are known to be important for regulation of skeletal muscle mass and function as well as for inflammation and immune response its function in ICUAW is still elusive. Given recent advances in the development of ER stress modifying molecules for neurodegenerative diseases and cancer, it is important to know whether or not therapeutic interventions in ER stress pathways have favorable effects and these compounds can be used to prevent or treat ICUAW. In this review, we focus on the role of ER stress-induced UPR in skeletal muscle during critical illness and in response to predisposing risk factors such as immobilization, starvation and inflammation as well as ICUAW treatment to foster research for this devastating clinical problem.
Published: 2022

4. ESICM LIVES 2016: part two: Milan, Italy. 1–5 October 2016

Author: Sivakumar, S., Taccone, F. S., Desai, K. A., Lazaridis, C., Skarzynski, M., Sekhon, M., Henderson, W., Griesdale, D., Chapple, L., Deane, A., Williams, L., Strickland, R., Lange, K., Heyland, D., Chapman, M., Rowland, M. J., Garry, P., Westbrook, J., Corkill, R., Antoniades, C. A., Pattinson, K. T., Fatania, G., Strong, A. J., Myers, R. B., Lazaridis, C., Jermaine, C. M., Robertson, C. S., Rusin, C. G., Hofmeijer, J., Sondag, L., Tjepkema-Cloostermans, M. C., Beishuizen, A., Bosch, F. H., van Putten, M. J. A. M., Carteron, L., Patet, C., Solari, D., Oddo, M., Ali, M. A., Dias, C., Almeida, R., Vaz-Ferreira, A., Silva, J., Monteiro, E., Cerejo, A., Rocha, A. P., Elsayed, A. A., Abougabal, A. M., Beshey, B. N., Alzahaby, K. M., Pozzebon, S., Ortiz, A. Blandino, Cristallini, S., Lheureux, O., Brasseur, A., Vincent, J. L., Creteur, J., Taccone, F. S., Hravnak, M., Yousef, K., Chang, Y., Crago, E., Friedlander, R. M., Abdelmonem, S. A., Tahon, S. A., Helmy, T. A., Meligy, H. S., Puig, F., Dunn-Siegrist, I., Pugin, J., Gupta, S., Govil, D., Srinivasan, S., Patel, S. J., N, J. K., Gupta, A., Tomar, D. S., Shafi, M., Harne, R., Arora, D. P., Talwar, N., Mazumdar, S., Papakrivou, E. E., Makris, D., Manoulakas, E., Tsolaki, B., Karadodas, B., Zakynthinos, E., Garcia, I. Palacios, Martin, A. Diaz, Encinares, V. Sanchez, Ibañez, M. Pachón, Montero, J. Garnacho, Labrador, G., Cangueiro, T. Cebrero, Poulose, V., Koh, J., Kam, J. W., Yeter, H., Kara, A., Aktepe, O., Topeli, A., Tsolakoglou, I., Intas, G., Stergiannis, P., Kolaros, A. A., Chalari, E., Athanasiadou, E., Martika, A., Fildisis, G., Faivre, V., Mengelle, C., Favier, B., Payen, D., Poppe, A., Winkler, M. S., Mudersbach, E., Schreiber, J., Wruck, M. L., Schwedhelm, E., Kluge, S., Zöllner, C., Tavladaki, T., Spanaki, A. M., Dimitriou, H., Kondili, E., Choulaki, C., Meleti, E., Kafetzopoulos, D., Georgopoulos, D., Briassoulis, G., la Torre, A. García-de, de la Torre-Prados, M. V., Tsvetanova-Spasova, T., Nuevo-Ortega, P., Rueda-Molina, C., Fernández-Porcel, A., Camara-Sola, E., Salido-Díaz, L., García-Alcántara, A., Tavladaki, T., Spanaki, A. M., Dimitriou, H., Kondili, E., Choulaki, C., Meleti, D. E., Kafetzopoulos, D., Georgopoulos, D., Briassoulis, G., Suberviola, B., Riera, J., Rellan, L., Sanchez, M., Robles, J. C., Lopez, E., Vicente, R., Miñambres, E., Santibañez, M., Le Guen, M., Moore, J., Mason, N., Windpassinger, M., Plattner, O., Mascha, E., Sessler, D. I., Research, Outcomes, Melia, U., Fontanet, J., van den Berg, J. P., Struys, M. M. R. F., Vereecke, H. E. M., Jensen, E. W., Rood, P. J. T., van de Schoor, F., van Tertholen, K., Pickkers, P., van den Boogaard, M., Beardow, Z. J., Redhead, H., Paramasivam, K., Numan, T., van den Boogaard, M., Kamper, A. M., Rood, P., Peelen, L. M., Zeman, P. M., Slooter, A. J., van Ewijk, C. E., Jacobs, G. E., Girbes, A. R. J., Myatra, S. N., Harish, M. M., Prabu, N. R., Siddiqui, S., Kulkarni, A. P., Divatia, J. V., Murbach, L. D., Leite, M. A., Osaku, E. F., Costa, C. R. L. M., Pelenz, M., Neitzke, N. M., Moraes, M. M., Jaskowiak, J. L., Silva, M. M. M., Zaponi, R. S., Abentroth, L. R. L., Ogasawara, S. M., Jorge, A. C., Duarte, P. A. D., Hernández-Sánchez, N., Sánchez-Hurtado, L. A., García-Guillen, F. J., Ñamendys-Silva, S. A., Maghsoudi, B., Emami, M., Khosravi, M. B., Zand, F., Tabatabaie, H. R., Masjedi, M., Sabetiyan, G., Mokri, A., Troubleyn, J., Diltoer, M., Jacobs, R., Nguyen, D. N., De Waele, E., De Regt, J., Honoré, P. M., Van Gorp, V., Spapen, H. D., Contreras, R. S., Toapanta, N. D., Moreno, G., Sabater, J., Torrado, H., Gonzalez, M., Marin, M., Farigola, E., Gonzalez, A., Fernandez, J., Vera, A., Gisbert, X., Juliá, C., Uya, J., Corral, L., Elias-Jones, I., Gemmell, L., MacKay, A., Randall, D., Adwaney, A., Blunden, M., Prowle, J. R., Kirwan, C. J., Thomas, N., Martin, A., Owen, H., Darwin, L., Conway, D., Atkinson, D., Sharman, M., Moore, J., Barbanti, C., Amour, J., Gaudard, P., Rozec, B., Mauriat, P., M’rini, M., Leger, P. L., Cambonie, G., Liet, J. M., Girard, C., Laroche, S., Damas, P., Assaf, Z., Loron, G., Lecourt, L., Pouard, P., Randall, D., Adwaney, A., Blunden, M., Prowle, J.R., Kirwan, C. J., Kim, S. H., Na, S., Kim, J., Oh, S. Y., Jung, C. W., Yoo, S. H., Min, S. H., Chung, E. J., Lee, H., Lee, N. J., Lee, K. W., Suh, K. S., Ryu, H. G., Marshall, D. C., Goodson, R. J., Salciccioli, J. D., Shalhoub, J., Potter, E. K., Kirk-Bayley, J., Karanjia, N. D., Forni, L. G., Creagh-Brown, B. C., Bossy, M., Nyman, M., Tailor, A., Creagh-Brown, B., D’Antini, D., Spadaro, S., Valentino, F., Sollitto, F., Cinnella, G., Mirabella, L., Calvo, F. J. Redondo, Bejarano, N., Padilla, D., Baladron, V., Villajero, P., Villazala, R., Redondo, J., Yuste, A. S., Liu, J., Shen, F., Teboul, J. L., Anguel, N., Beurton, A., Bezaz, N., Richard, C., Monnet, X., Fossali, T., Colombo, R., Ottolina, D., Rossetti, M., Mazzucco, C., Marchi, A., Porta, A., Catena, E., Tollisen, K. H., Andersen, G. Ø., Heyerdahl, F., Jacobsen, D., de Waard, M. C., Girbes, A. R. J., van IJzendoorn, M. C. O., Buter, H., Kingma, W. P., Navis, G. J., Boerma, E. C., Rulisek, J., Balik, M., Zacharov, S., Kim, H. S., Jeon, S. J., Namgung, H., Lee, E., Lee, E., Cho, Y. J., Lee, Y. J., Huang, A., Cioccari, L., Luethi, N., Mårtensson, J., Bellomo, R., Forsberg, M., Edman, G., Höjer, J., Forsberg, S., Freile, M. T. Chiquito, Hidalgo, F. N., Molina, J. A. Martinez, Lecumberri, R., Rosselló, A. Figuerola, Travieso, P. Medrano, Leon, G. Tuero, Sanchez, J. Gonzalez, Frias, L. Sahuquillo, Rosello, D. Balsells, Verdejo, J. A. Garcia, Serrano, J. A. Noria, Winterwerp, D., van Galen, T., Vazin, A., Karimzade, I., Zand, A., Ozen, E., Ekemen, S., Akcan, A., Sen, E., Yelken, B. Buyukkidan, Kureshi, N., Fenerty, L., Thibault-Halman, G., Erdogan, M., Walling, S., Green, R. S., Clarke, D. B., Briassoulis, P., Kalimeris, K., Ntzouvani, A., Nomikos, T., Papaparaskeva, K., Politi, E., Kostopanagiotou, G., Crewdson, K., Rehn, M., Weaver, A., Brohi, K., Lockey, D., Wright, S., Thomas, K., Baker, C., Mansfield, L., Stafford, V., Wade, C., Watson, G., Bryant, A., Chadwick, T., Shen, J., Wilkinson, J., Furneval, J., Henderson, A., Hugill, K., Howard, P., Roy, A., Bonner, S., Baudouin, S., Ramírez, C. Sánchez, Escalada, S. Hípola, Viera, M. A. Hernández, Santana, M. Cabrera, Balcázar, L. Caipe, Monroy, N. Sangil, Campelo, F. Artiles, Vázquez, C. F. Lübbe, Santana, P. Saavedra, Santana, S. Ruiz, Carteron, L., Patet, C., Quintard, H., Solari, D., Bouzat, P., Oddo, M., Wollersheim, T., Malleike, J., Haas, K., Carbon, N., Schneider, J., Birchmeier, C., Fielitz, J., Spuler, S., Weber-Carstens, S., Enseñat, L., Pérez-Madrigal, A., Saludes, P., Proença, L., Gruartmoner, G., Espinal, C., Mesquida, J., Huber, W., Eckmann, M., Elkmann, F., Gruber, A., Lahmer, T., Mayr, U., Herner, A., Schellnegger, R., Schneider, J., Schmid, R. M., Ayoub, W., Samy, W., Esmat, A., Battah, A., Mukhtar, S., Mongkolpun, W., Cortés, D. Orbegozo, Cordeiro, C. P. R., Vincent, J. L., Creteur, J., Funcke, S., Groesdonk, H., Saugel, B., Wagenpfeil, G., Wagenpfeil, S., Reuter, D. A., Fernandez, M. M., Fernandez, R., Magret, M., González-Castro, A., Bouza, M. T., Ibañez, M., García, C., Balerdi, B., Mas, A., Arauzo, V., Añón, J. M., Ruiz, F., Ferreres, J., Tomás, R., Alabert, M., Tizón, A. I., Altaba, S., Llamas, N., Goligher, E C., Fan, E., Herridge, M., Vorona, S., Sklar, M., Dres, M., Rittayamai, N., Lanys, A., Urrea, C., Tomlinson, G., Reid, W. D., Rubenfeld, G. D., Kavanagh, B. P., Brochard, L. J., Ferguson, N. D., Neto, A. Serpa, de Abreu, M. Gama, Pelosi, P., Schultz, M. J., Guérin, C., Papazian, L., Reignier, J., Ayzac, L., Loundou, A., Forel, J. M., Rolland-Debord, C., Bureau, C., Poitou, T., Clavel, M., Perbet, S., Terzi, N., Kouatchet, A., Similowski, T., Demoule, A., Hunfeld, N., Trogrlic, Z., Ladage, S., Osse, R. J., Koch, B., Rietdijk, W., Devlin, J., van der Jagt, M., Picetti, E., Ceccarelli, P., Mensi, F., Malchiodi, L., Risolo, S., Rossi, I., Antonini, M. V., Servadei, F., Caspani, M. L., Roquilly, A., Lasocki, S., Seguin, P., Geeraerts, T., Perrigault, P. F., Dahyot-Fizelier, C., Paugam-Burtz, C., Cook, F., Cinotti, R., dit Latte, D. Demeure, Mahe, P. J., Fortuit, C., Feuillet, F., Asehnoune, K., Marzorati, C., Spina, S., Scaravilli, V., Vargiolu, A., Riva, M., Giussani, C., Sganzerla, E., Citerio, G., Barbadillo, S., de Molina, F. J. González, Álvarez-Lerma, F., Rodríguez, A., Zakharkina, T., Martin-Loeches, I., Matamoros, S., Povoa, P., Torres, A., Kastelijn, J., Hofstra, J. J., de Jong, M., Schultz, M., Sterk, P., Artigas, A., Bos, L. J., Moreau, A. S., Martin-Loeches, I., Povoa, P., Salluh, J., Rodriguez, A., Nseir, S., de Jong, E., van Oers, J. A., Beishuizen, A., Girbes, A. R. J., Nijsten, M. W. N., de Lange, D. W., Bonvicini, D., Labate, D., Benacchio, L., Olivieri, A., Pizzirani, E., Lopez-Delgado, J. C., Gonzalez-Romero, M., Fuentes-Mila, V., Berbel-Franco, D., Romera-Peregrina, I., Martinez-Pascual, A., Perez-Sanchez, J., Abellan-Lencina, R., Ávila-Espinoza, R. E., Moreno-Gonzalez, G., Sbraga, F., Griffiths, S., Grocott, M. P. W., Creagh-Brown, B., Doyle, J., Wilkerson, P., Soon, Y., Huddart, S., Dickinson, M., Riga, A., Zuleika, A., Miyamoto, K., Kawazoe, Y., Morimoto, T., Yamamoto, T., Fuke, A., Hashimoto, A., Koami, H., Beppu, S., Katayama, Y., Ito, M., Ohta, Y., Yamamura, H., Rygård, S. L., Holst, L B., Wetterslev, J., Johansson, P. I., Perner, A., Soliman, I. W., de Lange, D. W., van Dijk, D., van Delden, J. J. M., Cremer, O. L., Slooter, A. J. C., Peelen, L. M., McWilliams, D., Snelson, C., Neves, A. Das, Loudet, C. I., Busico, M., Vazquez, D., Villalba, D., Veronesi, M., Lischinsky, A., López, F. J. L., Mori, L. Benito, Plotnikow, G., Díaz, A., Giannasi, S., Hernandez, R., Krzisnik, L., Cecotti, C., Viola, L., Lopez, R., Sottile, J. P., Benavent, G., Estenssoro, E., Chen, C. M., Lai, C. C., Cheng, K. C., Chou, W., Chan, K. S., Roeker, L. E., Horkan, C. M., Gibbons, F. K., Christopher, K. B., Weijs, P. J. M., Mogensen, K. M., Rawn, J. D., Robinson, M. K., Christopher, K. B., Tang, Z., Qiu, C., Ouyang, B., Cai, C., Guan, X., Regueira, T., Cea, L., Carlos, S. Juan, Elisa, B., Puebla, C., Vargas, A., Poulsen, M. K., Thomsen, L. P., Kjærgaard, S., Rees, S. E., Karbing, D. S., Wollersheim, T., Frank, S., Müller, M. C., Carbon, N. M., Skrypnikov, V., Pickerodt, P. A., Falk, R., Mahlau, A., Weber-Carstens, S., Lee, A., Inglis, R., Morgan, R., Barker, G., Kamata, K., Abe, T., Saitoh, D., Tokuda, Y., Green, R. S., Butler, M. B., Erdogan, M., Hwa, H. Tae, Gil, L. Jae, Vaquero, R. Hernández, Rodriguez-Ruiz, E., Lago, A. Lopez, Allut, J. L. Garcia, Gestal, A. Estany, Gonzalez, M. A. Garcia, Thomas-Rüddel, D. O., Schwarzkopf, D., Fleischmann, C., Reinhart, K., Suwanpasu, S., Sattayasomboon, Y., Filho, N. M. Filgueiras, Oliveira, J. C. A., Ballalai, C. S., De Lucia, C. V., Araponga, G. P., Veiga, L. N., Silva, C. S., Garrido, M. E., Ramos, B. B., Ricaldi, E. F., Gomes, S. S., Gemmell, L., MacKay, A., Wright, C., Docking, R. I., Doherty, P., Black, E., Stenhouse, P., Plummer, M. P., Finnis, M. E., Phillips, L. K., Kar, P., Bihari, S., Biradar, V., Moodie, S., Horowitz, M., Shaw, J. E., Deane, A. M., Yatabe, T., Inoue, S., Sakaguchi, M., Egi, M., Abdelhamid, Y. Ali, Plummer, M. P., Finnis, M. E., Phillips, L. K., Kar, P., Bihari, S., Biradar, V., Moodie, S., Horowitz, M., Shaw, J. E., Deane, A. M., Hokka, M., Egi, M., Mizobuchi, S., Kar, P., Plummer, M., Abdelhamid, Y. Ali, Giersch, E., Summers, M., Hatzinikolas, S., Heller, S., Chapman, M., Jones, K., Horowitz, M., Deane, A., Schweizer, R., Jacquet-Lagreze, M., Portran, P., Junot, S., Allaouchiche, B., Fellahi, J. L., Guerci, P., Ergin, B., Kapucu, A., Ince, C., Cioccari, L., Luethi, N., Crisman, M., Bellomo, R., Mårtensson, J., Shinotsuka, C. Righy, Fagnoul, D., Brasseur, A., Orbegozo, D., Vincent, J. L., Preiser, J. C., Preiser, J. C., Lheureux, O., Thooft, A., Brimioulle, S., Vincent, J. L., Iwasaka, H., Tahara, S., Nagamine, M., Ichigatani, A., Cabrera, A. Rugerio, Zepeda, E. Monares, Granillo, J. Franco, Sánchez, J. S. Aguirre, Montoya, A. A. Tanaka, Montenegro, A. Pedraza, Blanco, G. A. Gálvez, Robles, C. M. Coronado, Drolz, A., Horvatits, T., Roedl, K., Rutter, K., Kluge, S., Funk, G. C., Schneeweiss, B., Fuhrmann, V., Sabetian, G., Pooresmaeel, F., Zand, F., Ghaffaripour, S., Farbod, A., Tabei, H., Taheri, L., Anandanadesan, R., Metaxa, V., Teixeira, C., Pereira, S. M., Hernández-Marrero, P., Carvalho, A. S., Beckmann, M., Hartog, C. S., Schwarzkopf, D., Raadts, A., Robertsen, A., Førde, R., Skaga, N. O., Helseth, E., Honeybul, S., Ho, K., Lopez, P. Martinez, Gonzalez, M. Nieto, Ortega, P. Nuevo, Sola, E. Camara, Spasova, T., de la Torre-Prados, M. V., Kopecky, O., Rusinova, K., Waldauf, P., Cepeplikova, Z., Balik, M., Domínguez, J. Palamidessi, Almudevar, P. Matia, Carmona, S. Alcántara, Muñoz, J. J. Rubio, Castañeda, D. Palacios, Abellán, A. Naharro, Villamizar, P. Rodríguez, Ramos, J. Veganzones, Pérez, L. Pérez, Lucendo, A. Pérez, Ejarque, M. Camós, Estella, A., Camps, V. Lopez, Martín, M. C., Masnou, N., Barbosa, S., Varela, A., Palma, I., Cristina, L., Nunes, E., Pereira, I., Campello, G., Granja, C., Pande, R., Pandey, M., Varghese, S., Chanu, M., Van Dam, M. J., Ter Braak, E. W. M. T., Estella, A., Gracia, M., Viciana, R., Recuerda, M., Fontaiña, L. Perez, Tharmalingam, B., Kovari, F., Rose, L., Mcginlay, M., Amin, R., Burns, K., Connolly, B., Hart, N., Jouvet, P., Katz, S., Leasa, D., Mawdsley, C., Mcauley, D., Schultz, M., Blackwood, B., Denham, S., Worrall, R., Arshad, M., Isherwood, P., Khadjibaev, A., Sabirov, D., Rosstalnaya, A., Parpibaev, F., Sharipova, V., Blanco, G. A. Galvez, Guzman, C. I. Olvera, Sánchez, J. S. Aguirre, Granillo, J. Franco, Gupta, S., Govil, D., Srinivasan, S., Patel, S. J., N, J. K., Gupta, A., Shafi, M., Tomar, D. S., Harne, R., Arora, D. P., Talwar, N., Mazumdar, S., Cha, Y. S., Lee, S. J., Tyagi, N., Rajput, R. K., Taneja, S., Singh, V. K., Sharma, S. C., Mittal, S., Rao, B. K., Ayachi, J., Fraj, N., Romdhani, S., Khedher, A., Meddeb, K., Sma, N., Azouzi, A., Bouneb, R., Chouchene, I., El Ghardallou, M., Boussarsar, M., Jennings, R., Walter, E., Ribeiro, J. M., Moniz, I., Marçal, R., Santos, A. C., Candeias, C., e Silva, Z. Costa, Gomez, S. E. Zamora, Nieto, O. R. Perez, Gonzalez, J. A. Castanon, Cuellar, A. I. Vasquez, Mildh, H., Pettilä, V., Korhonen, A. M., Karlsson, S., Ala-Kokko, T., Reinikainen, M., Vaara, S. T., Zaleska-Kociecka, M., Grabowski, M., Dąbrowski, M., Wozniak, S., Piotrowska, K., Banaszewski, M., Imiela, J., Stepinska, J., Pérez, A. González, Ordoñez, P. Florez, Giribet, A., Cuervo, M. A. Alonso, Cuervo, R. Alonso, Esteban, M. A. Rodriguez, Fraile, L. Iglesias, Mittelbrum, C. Ponte, Albaiceta, G. Muñiz, Koeze, J., Keus, F., Dieperink, W., van der Horst, I. C. C., van Meurs, M., Zijlstra, J. G., Roberts, S., Caballero, C. 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W., Nashan, B., Sterneck, M., Faenza, S., Siniscalchi, A., Pierucci, E., Mancini, E., Ricci, D., Gemelli, C., Cuoghi, A., Magnani, S., Atti, M., Sotos, F., Cánovas, J., López, A., Burruezo, A., Torres, D., Herrera-Gutierrez, M. E., Barrueco-Francioni, J., Arias-Verdú, D., Lozano-Saez, R., Quesada-Garcia, G., Seller-Pérez, G., Figueiredo, A., Anzola, Y., Pereira, R., Bento, L., Arias-Verdú, D., Lai, M., Deiana, M., Barrueco-Francioni, J., Herrera-Gutierrez, M. E., Seller-Perez, G., Vardas, K., Ilia, S., Sertedaki, A., Charmadari, E., Stratakis, C. A., Briassouli, E., Goukos, D., Psarra, K., Botoula, E., Tsagarakis, S., Mageira, E., Routsi, C., Nanas, S., Briassoulis, G., Boscolo, A., Bertini, D., Campello, E., Lucchetta, V., Piasentini, E., Radu, C. M., Manesso, L., Simioni, P., Ori, C., Su, H., Lam, Y. M., Willis, K., Pullar, V., Hubner, R. P., Tsang, J. L., de Guadiana-Romualdo, L. García, Rebollo-Acebes, S., Esteban-Torrella, P., Jiménez-Sánchez, R., Jiménez-Santos, E., Ortín-Freire, A., Hernando-Holgado, A., Albaladejo-Otón, M. D., Coelho, L., Rabello, L., Salluh, J., Martin-Loeches, I., Rodriguez, A., Nseir, S., Póvoa, P., Varis, E., Pettilä, V., Poukkanen, M., Jacob, S., Karlsson, S., Perner, A., Takala, J., Wilkman, E., Lundberg, O. H. M., Bergenzaun, L., Rydén, J., Rosenqvist, M., Melander, O., Chew, M. S., Rodriguez-Ruiz, E., Vaquero, R. Hernández, Lago, A. Lopez, Allut, J. L. Garcia, Gestal, A. Estany, Gonzalez, M. A. Garcia, Kishihara, Y., Yasuda, H., Rebollo, S., de Guadiana-Romualdo, L. García, Jimenez, R., Torrella, P. Esteban, Fernandez, A., Sanchez, S., Ortin, A., Bassi, G. Li, Prats, R. Guillamat, Artigas, A., Aguilera, E., Marti, D., Ranzani, O. T., Rigol, M., Fernandez, L., Ferrer, M., Martin-Loeches, I., Torres, A., Lanziotti, V. S., Póvoa, P., Pulcheri, L., Ribeiro, M. O., Barbosa, A. P., e Silva, J. R. Lapa, Soares, M., Salluh, J. I. F., Garcia, I. Palacios, Martin, A. Diaz, Marqués, M. Gil, Moreno, A. Puppo, Pizarraya, A. Gutierrez, Diaz, J. Pachón, Ibañez, M. Pachón, Smani, Y., Connell, M. Mc, Zhang, L. A., Parker, R. S., Banerjee, I., Clermont, G., Norberg, E., Oras, J., Cuisinier, A., Maufrais, C., Payen, J. F., Nottin, S., Walther, G., Bouzat, P., Arib, S., Bilotta, F., Badenes, R., Rubulotta, F., Mirek, S., Crippa, I. A., Monfort, B., Stazi, E., Roig, A. Lozano, Creteur, J., Taccone, F. S., Magnoni, S., Marando, M., Pifferi, S., Conte, V., Ortolano, F., Carbonara, M., Bertani, G., Scola, E., Cadioli, M., Triulzi, F., Colombo, A., Stocchetti, N., Rotzel, H. B., Lázaro, A. Serrano, Prada, D. Aguillón, Guimillo, M. Rodriguez, Piqueras, C. Sanchís, Guia, J. Romero, Simon, M. García, Arizmendi, A. Mesejo, Carratalá, A., El Maraghi, S., Yehia, A., Bakry, M., Shoman, A., Backes, F. N., Bianchin, M. M., Vieira, S. R. R., de Souza, A., Backes, A. N., Klein, C., Kalaiselvan, M. S., Renuka, M. K., Arunkumar, A. S., Lozano, A., Lheureux, O., Badenes, R., Vincent, J. L., Creteur, J., Taccone, F. S., Gallaher, C., Cattlin, S., Gordon, S., Picard, J., Fontana, V., Bond, O., Nobile, L., Vincent, J. L., Creteur, J., Taccone, F. S., Mrozek, S., Delamarre, L., Capilla, F., Al-Saati, T., Fourcade, O., Geeraerts, T., Dominguez-Berrot, A. M., Gonzalez-Vaquero, M., Vallejo-Pascual, M. E., Gupta, D., Ivory, B. D., Chopra, M., McCarthy, J., Felderhof, C. L., MacNeil, C., Rubulotta, F., Waldauf, P., Maggiorini, M., Duska, F., Fumis, R. R. L., Junior, J. M. Vieira, Amarante, G., Skorko, A., Sanders, S., Aron, J., Kroll, R. J., Redfearn, C., Krishnan, P., Khalil, J. E., Kovari, F., Kongpolprom, N., Gulia, V., Lourenço, E., Melão, L., Duro, C., Baptista, G., Alves, A., Arminda, B., Rodrigues, M., Marreiros, A., Granja, C., Hayward, J., Baldwin, F., Gray, R., Katinakis, P. A., Stijf, M., Ten Kleij, M., Jansen-Frederiks, M., Broek, R., de Bruijne, M., Spronk, P. E., Sinha, K., Luney, M., Palmer, K., Keating, L., Abu-Habsa, M., Bahl, R., Baskaralingam, N., Ahmad, A., Kanapeckaite, L., Bhatti, P., Glace, S., Jeyabraba, S., Lewis, H. F., Kostopoulos, A., Raja, M., West, A., Ely, A., Turkoglu, L. M., Zolfaghari, P., Baptista, J. P., Marques, M. P., Martins, P., Pimentel, J., Gupta, D., Su, Y. C., Villacres, S., Stone, M. E., Parsikia, A., Medar, S., O’Dea, K. P., Porter, J., Tirlapur, N., Jonathan, J. M., Singh, S., Takata, M., Abu-Habsa, M., Ahmad, A., McWhirter, E., Lyon, R., Hariz, M. L., Azmi, E., Alkhan, J., Honeybul, S., Movsisyan, V., Petrikov, S., Marutyan, Z., Aliev, I., Evdokimov, A., Antonucci, E., Merz, T., Hartmann, C., Pelosi, P., Calzia, E., Radermacher, P., Nußbaum, B., Hartmann, C., Huber-Lang, M., Gröger, M., Radermacher, P., Nußbaum, B., Nußbaum, B., Antonucci, E., Calzia, E., Pelosi, P., Radermacher, P., Hartmann, C., Svoren-Jabalera, E., Davenport, E. E., Humburg, P., Knight, J., Hinds, C. J., Jun, I. J., Kim, W. J., Lee, E. H., Besch, G., Perrotti, A., Puyraveau, M., Carteron, L., Baltres, M., Samain, E., Chocron, S., Pili-Floury, S., Plata-Menchaca, E. P., Sabater-Riera, J., Estruch, M., Boza, E., Sbraga, F., Toscana-Fernández, J., Bruguera-Pellicer, E., Ordoñez-Llanos, J., Pérez-Fernández, X. L., Cavaleiro, P., Tralhão, A., Arrigo, M., Lopes, J.-P., Lebrun, M., Cholley, B., PerezVela, J. L., MarinMateos, H., Rivera, J. J. Jimenez, Llorente, M. A. Alcala, De Marcos, B. Gonzalez, Fernandez, F. J. Gonzalez, Laborda, C. Garcia, Zamora, D. Fernandez, Delgado, J. C. Lopez, Imperiali, C., Berbel-Franco, D., Dastis, M., Moreno-Gonzalez, G., Perez-Sanchez, J., Romera-Peregrina, I., Abellan-Lencina, R., Martinez-Pascual, A., Fuentes-Mila, V., Gonzalez-Romero, M., Górka, J., Górka, K., Iwaniec, T., Frołow, M., Polok, K., Fronczek, J., Kózka, M., Musiał, J., Szczeklik, W., Pérez, A. González, Ordoñez, P. Florez, Giribet, A., Cuervo, M. A. Alonso, Cuervo, R. Alonso, Esteban, M. A. Rodriguez, Fraile, L. Iglesias, Mittelbrum, C. Ponte, Albaiceta, G. Muñiz, Ampatzidou, F., Sileli, M., Kehagioglou, G., Madesis, A., Karaiskos, T., Moursia, C., Maleoglou, H., Leleki, K., Drossos, G., Uz, Z., Ince, Y., Papatella, R., Bulent, E., Guerci, P., Ince, C., De Mol, B., Vicka, V., Gineityte, D., Ringaitiene, D., Norkiene, I., Sipylaite, J., Möller, C., Fleischmann, C., Thomas-Rueddel, D. O., Vlasakov, V., Rochwerg, B., Theurer, P., Gattinoni, L., Reinhart, K., Hartog, C. S., Pérez, A. González, Al Sibai, J. Zanabili, Camblor, P. Martinez, Fernandez, P. Alvarez, Gala, J. M. García, Guisasola, J. Silba, Albaiceta, G. Muñiz, Tamura, T., Yatabe, T., Miyajima, I., Yamashita, K., Yokoyama, M., Ampatzidou, F., Kehagioglou, G., Dalampini, E., Nastou, M., Baddour, A., Ignatiadis, A., Asteri, T., Drossos, G., Hathorn, K. E., Purtle, S. W., Horkan, C. M., Gibbons, F. K., Christopher, K. B., Viana, M. V., Tonietto, T. A., Gross, L. A., Costa, V. L., Tavares, A. L. J., Lisboa, B. O., Moraes, R. B., Vieira, S. R., Viana, L. V., Azevedo, M. J., Ceniccola, G. D., Pequeno, R. S. F., Holanda, T. P., Mendonça, V. S., Araújo, W. M. C., Carvalho, L. S. F., Segaran, E., Vickers, L., Brinchmann, K., Wignall, I., Rubulotta, F., De Brito-Ashurst, I., del Olmo, R., Esteban, M. J., Vaquerizo, C., Carreño, R., Gálvez, V., Kaminsky, G., Nieto, B., Fuentes, M., De la Torre, M. A., Torres, E., Alonso, A., Velayos, C., Saldaña, T., Escribá, A., GRIP, J., Kölegård, R., Sundblad, P., Rooyackers, O., Naser, Ben, Jaziri, F., Jazia, A. Ben, Barghouth, M., Hentati, O., Skouri, W., El Euch, M., Mahfoudhi, M., Turki, S., Abdelghni, K. Ben, Abdallah, Ben, Maha, B. N. M., Cánovas, J., Sotos, F., López, A., Lorente, M., Burruezo, A., Torres, D., Polok, K., Włudarczyk, A., Górka, J., Hałek, A., Musiał, J., Szczeklik, W., Jazia, A. Ben, Jaziri, F., Bargouth, M., Bennasr, M., Turki, S., Abdelghani, K. Ben, Abdallah, T. Ben, de Grooth, H. J., Geenen, I. L., Parienti, J. J., Straaten, H. M. Oudemans-van, Shum, H. P., King, H. S., Chan, K. C., Yan, W. W., Londoño, J. Gonzalez, Cardenas, C. Lorencio, Pedrosa, M. Morales, Gubianas, C. Murcia, Bertolin, C. Fuster, Batllori, N. Vila, Sirvent, J. M., Wykes, K., Jack, J., Morgan, P., Mukhopadhyay, A., Chan, H. Y., Kowitlawakul, Y., Remani, D., Leong, C. S. F., Henry, C. J., Puthucheary, Z. A., Mendsaikhan, N., Begzjav, T., Lundeg, G., Dünser, M., Espinoza, E. D. Valenzuela, Welsh, S. P., Motta, M. F., Guerra, E., Zerpa, M. C. l., Zechner, F., Furche, M., Berdaguer, F., Birri, P. N. Rubatto, Risso-Vazquez, A., Dubin, A., Masevicius, F. D., Greaney, D., Magee, A., Fitzpatrick, G., Lugo-Cob, R. G., Sánchez-Hurtado, L. A., Arvizu-Tachiquín, P. C., Tejeda-Huezo, B. C., Cano-Oviedo, A. A., Baltazar-Torres, J. A., Aydogan, M. S., Togal, T., Taha, A., Chai, H. Z., Kam, C., Razali, S. S. Yang, Sivasamy, V., Kuan, L. Y., Poulose, V., Morales, M. A. Lopez, Castro, S., Pires, T., Melão, L., Krystopchuk, A., Pereira, I., Granja, C., Taniguchi, L. U., Pires, E. M. C., Vieira, Jr, J. M., Azevedo, L. C. P., Nurses of the Central and General ICUs of Shiraz Namazi Hospital, Sedation an Delirium Group Hospital Universitari de Bellvitge, SPACeR group (Surrey Peri-operative, Anaesthesia and Critical Care Collaborative Research Group), for the PRoVENT investigators and the PROVE Network, SEMICYUC/GETGAG Working Group, TAVeM study group, POPC-CB investigators, DESIRE (DExmedetomidine for Sepsis in ICU Randomized Evaluation) Trial Investigators, GEMINI, Bioethics work group of SEMICYUC, The FINNAKI Study Group, Queen Square Neuroanaesthesia and Neurocritical Care Resreach Group, Renal Transplantation HUVR, GEMINI, EDISVAL Group, EDISVAL Group, PLUG Working group, TAVeM study Group, The FINNAKI Study Group, on behalf of Department of Professional Development, ESICM, Critical Care Research Group, SIRAKI group, and Grupo ESBAGA
Published: 2016
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5. Pathophysiology of Cardiac AT1 and AT2 Receptors

Author: Fielitz, J., Regitz-Zagrosek, V., Starke, K., editor, Born, G. V. R., editor, Eichelbaum, M., editor, Ganten, D., editor, Hofmann, F., editor, Kobilka, B., editor, Rosenthal, W., editor, Rubanyi, G., editor, Unger, Thomas, and Schölkens, Bernward A.
Published: 2004
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6. Myokardiale Angiotensin-Rezeptoren im menschlichen Herzen

Author: Regitz-Zagrosek, V., Fielitz, J., Fleck, E., Dominiak, Peter, editor, and Heusch, Gerd, editor
Published: 1999
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7. Riociguat attenuates left ventricular proteome and microRNA profile changes after experimental aortic stenosis in mice

Author: Benkner, A., Rüdebusch, J., Nath, N., Hammer, E., Grube, K., Gross, S., Dhople, V.M., Eckstein, G., Meitinger, T., Kaderali, L., Völker, U., Fielitz, J., and Felix, S.B.
Subjects: Tac, Cardiac Remodelling, Heart Failure, Microrna Sequencing, Proteomics, Riociguat, Soluble Guanylyl Cyclase Stimulator
Abstract: BACKGROUND AND PURPOSE: Development and progression of heart failure (HF) involve endothelial and myocardial dysfunction as well as a dysregulation of the nitric oxide - soluble guanylyl cyclase - cyclic guanosine monophosphate (NO-sGC-cGMP) signalling pathway. Recently, we reported that the sGC stimulator riociguat (RIO) has beneficial effects on cardiac remodelling and progression of HF in response to chronic pressure overload. Here, we examined if these favourable RIO effects are also reflected in alterations of the myocardial proteome and microRNA profiles. EXPERIMENTAL APPROACH: Male C57BL/6N mice underwent transverse aortic constriction (TAC) and sham operated mice served as controls. TAC and sham animals were randomised and treated with either RIO or vehicle for five weeks, starting three weeks post-surgery when cardiac hypertrophy was established. Afterwards we performed mass spectrometric proteome analyses and microRNA sequencing of proteins and RNAs, respectively, isolated from left ventricles (LV). KEY RESULTS: TAC-induced changes of the LV proteome were significantly reduced by RIO treatment. Bioinformatics analyses revealed that RIO improved TAC-induced cardiovascular disease related pathways, metabolism and energy production, e.g. reversed alterations in the levels of myosin heavy chain 7 (MYH7), cardiac phospholamban (PLN), and ankyrin repeat domain-containing protein 1 (ANKRD1). RIO also attenuated TAC-induced changes of microRNA levels in the LV. CONCLUSION AND IMPLICATIONS: The sGC stimulator RIO has beneficial effects on cardiac structure and function during pressure overload, which is accompanied by a reversal of TAC-induced changes of the cardiac proteome and microRNA profile. Our data support the potential of RIO as a novel HF therapeutic.
Published: 2022

8. Inhibition of the NLRP3/IL-1β axis protects against sepsis-induced cardiomyopathy

Author: Busch, K., Kny, M., Huang, N., Klassert, T.E., Stock, M., Hahn, A., Graeger, S., Todiras, M., Schmidt, S., Chamling, B., Willenbrock, M., Groß, S., Biedenweg, D., Heuser, A., Scheidereit, C., Butter, C., Felix, S.B., Otto, O., Luft, F.C., Slevogt, H., and Fielitz, J.
Subjects: Cancer Research, Cardiovascular and Metabolic Diseases, Technology Platforms
Abstract: BACKGROUND: Septic cardiomyopathy worsens the prognosis of critically ill patients. Clinical data suggest that interleukin-1β (IL-1β), activated by the NLRP3 inflammasome, compromises cardiac function. Whether or not deleting Nlrp3 would prevent cardiac atrophy and improve diastolic cardiac function in sepsis was unclear. Here, we investigated the role of NLRP3/IL-1β in sepsis-induced cardiomyopathy and cardiac atrophy. METHODS: Male Nlrp3 knockout (KO) and wild-type (WT) mice were exposed to polymicrobial sepsis by caecal ligation and puncture (CLP) surgery (KO, n = 27; WT, n = 33) to induce septic cardiomyopathy. Sham-treated mice served as controls (KO, n = 11; WT, n = 16). Heart weights and morphology, echocardiography and analyses of gene and protein expression were used to evaluate septic cardiomyopathy and cardiac atrophy. IL-1β effects on primary and immortalized cardiomyocytes were investigated by morphological and molecular analyses. IonOptix and real-time deformability cytometry (RT-DC) analysis were used to investigate functional and mechanical effects of IL-1β on cardiomyocytes. RESULTS: Heart morphology and echocardiography revealed preserved systolic (stroke volume: WT sham vs. WT CLP: 33.1 ± 7.2 μL vs. 24.6 ± 8.7 μL, P
Published: 2021

9. Out of control: the role of the ubiquitin proteasome system in skeletal muscle during inflammation

Author: Haberecht-Müller, S., Krüger, E., and Fielitz, J.
Subjects: Cardiovascular and Metabolic Diseases
Abstract: The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed.
Published: 2021

10. Loss of muscle mass and strength in experimental chronic pancreatitis

Author: Doller, J., primary, Sendler, M., additional, Weiss, F.U., additional, Wiese, M.L., additional, Fielitz, J., additional, Delcea, M., additional, Görs, S., additional, Metges, C., additional, Ehlers, L., additional, Bannert, K., additional, Jaster, R., additional, Lerch, M., additional, and Aghdassi, A., additional
Published: 2021
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11. Activation of Tripartite Motif Containing 63 Expression by Transcription Factor EB and Transcription Factor Binding to Immunoglobulin Heavy Chain Enhancer 3 Is Regulated by Protein Kinase D and Class IIa Histone Deacetylases

Author: Pablo Tortola, C., Fielitz, B., Li, Y., Rüdebusch, J., Luft, F.C., and Fielitz, J.
Subjects: muscle atrophy, TFE3, muscle ring finger protein 1, Cardiovascular and Metabolic Diseases, Physiology, Physiology (medical), transcription factor EB, HDAC = histone deacetylase, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, protein kinase D, Original Research
Abstract: RATIONALE: The ubiquitin-proteasome system (UPS) is responsible for skeletal muscle atrophy. We showed earlier that the transcription factor EB (TFEB) plays a role by increasing E3 ubiquitin ligase muscle really interesting new gene-finger 1(MuRF1)/tripartite motif-containing 63 (TRIM63) expression. MuRF 1 ubiquitinates structural proteins and mediates their UPS-dependent degradation. We now investigated how TFEB-mediated TRIM63 expression is regulated. OBJECTIVE: Because protein kinase D1 (PKD1), histone deacetylase 5 (HDAC5), and TFEB belong to respective families with close structural, regulatory, and functional properties, we hypothesized that these families comprise a network regulating TRIM63 expression. METHODS AND RESULTS: We found that TFEB and transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) activate TRIM63 expression. The class IIa HDACs HDAC4, HDAC5, and HDAC7 inhibited this activity. Furthermore, we could map the HDAC5 and TFE3 physical interaction. PKD1, PKD2, and PKD3 reversed the inhibitory effect of all tested class IIa HDACs toward TFEB and TFE3. PKD1 mediated nuclear export of all HDACs and lifted TFEB and TFE3 repression. We also mapped the PKD2 and HDAC5 interaction. We found that the inhibitory effect of PKD1 and PKD2 toward HDAC4, HDAC5, and HDAC7 was mediated by their phosphorylation and 14-3-3 mediated nuclear export. CONCLUSION: TFEB and TFE3 activate TRIM63 expression. Both transcription factors are controlled by HDAC4, HDAC5, HDAC7, and all PKD-family members. We propose that the multilevel PKD/HDAC/TFEB/TFE3 network tightly controls TRIM63 expression.
Published: 2021
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12. G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1

Author: Ferdaoussi, M., Bergeron, V., Zarrouki, B., Kolic, J., Cantley, J., Fielitz, J., Olson, E. N., Prentki, M., Biden, T., MacDonald, P. E., and Poitout, V.
Published: 2012
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13. Stimulation of soluble guanylyl cyclase (sGC) by riociguat attenuates heart failure and pathological cardiac remodelling

Author: Rüdebusch, J., Benkner, A., Nath, N., Fleuch, L., Kaderali, L., Grube, K., Klingel, K., Eckstein, G., Meitinger, T., Fielitz, J., and Felix, S.B.
Subjects: Cardiovascular and Metabolic Diseases
Abstract: BACKGROUND AND PURPOSE: Heart failure (HF) is associated with an impaired NO-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway, and its augmentation is thought to be beneficial in HF therapy. We hypothesized that stimulation of sGC by the sGC stimulator riociguat (Rio) prevents pathological cardiac remodelling and HF in response to chronic pressure overload. EXPERIMENTAL APPROACH: Transverse aortic constriction (TAC) or sham surgery was performed in C57BL/6N mice. After 3 weeks of TAC when HF was established, animals were randomized to receive either riociguat (Rio) or its solvent (Sol) for 5 additional weeks. Cardiac function was evaluated weekly by echocardiography. Eight weeks after surgery, histological analyses were performed to evaluate remodelling and the transcriptome of the left ventricles (LV) was analysed by RNA Sequencing. Cell culture experiments were used for mechanistically studies. KEY RESULTS: TAC resulted in a continuous decrease of LV ejection fraction (LVEF from 56.6±2.2 to 32.0±4.1%) and an increase in LV mass (LVM/BW from 3.7±0.2 to 6.1±0.3 mg/g) until week 3. Five weeks of riociguat treatment resulted in an improved LVEF (TAC+Rio 43.4±6.0% vs. TAC+Sol 20.9±4.3%; p
Published: 2020

14. Serum amyloid A1 mediates myotube atrophy via Toll-like receptors

Author: Hahn, A., Kny, M., Pablo-Tortola, C., Todiras, M., Willenbrock, M., Schmidt, S., Schmoeckel, K., Jorde, I., Nowak, M., Jarosch, E., Sommer, T., Bröker, B.M., Felix, S.B., Scheidereit, C., Weber-Carstens, S., Butter, C., Luft, F.C., and Fielitz, J.
Subjects: Cancer Research, Cardiovascular and Metabolic Diseases
Abstract: Background: Critically ill patients frequently develop muscle atrophy and weakness in the intensive-care-unit setting [intensive care unit-acquired weakness (ICUAW)]. Sepsis, systemic inflammation, and acute-phase response are major risk factors. We reported earlier that the acute-phase protein serum amyloid A1 (SAA1) is increased and accumulates in muscle of ICUAW patients, but its relevance was unknown. Our objectives were to identify SAA1 receptors and their downstream signalling pathways in myocytes and skeletal muscle and to investigate the role of SAA1 in inflammation-induced muscle atrophy. Methods: We performed cell-based in vitro and animal in vivo experiments. The atrophic effect of SAA1 on differentiated C2C12 myotubes was investigated by analysing gene expression, protein content, and the atrophy phenotype. We used the cecal ligation and puncture model to induce polymicrobial sepsis in wild type mice, which were treated with the IкB kinase inhibitor Bristol-Myers Squibb (BMS)-345541 or vehicle. Morphological and molecular analyses were used to investigate the phenotype of inflammation-induced muscle atrophy and the effects of BMS-345541 treatment. Results: The SAA1 receptors Tlr2, Tlr4, Cd36, P2rx7, Vimp, and Scarb1 were all expressed in myocytes and skeletal muscle. Treatment of differentiated C2C12 myotubes with recombinant SAA1 caused myotube atrophy and increased interleukin 6 (Il6) gene expression. These effects were mediated by Toll-like receptors (TLR) 2 and 4. SAA1 increased the phosphorylation and activity of the transcription factor nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB) p65 via TLR2 and TLR4 leading to an increased binding of NF-κB to NF-κB response elements in the promoter region of its target genes resulting in an increased expression of NF-κB target genes. In polymicrobial sepsis, skeletal muscle mass, tissue morphology, gene expression, and protein content were associated with the atrophy response. Inhibition of NF-κB signalling by BMS-345541 increased survival (28.6% vs. 91.7%, P < 0.01). BMS-345541 diminished inflammation-induced atrophy as shown by a reduced weight loss of the gastrocnemius/plantaris (vehicle: -21.2% and BMS-345541: -10.4%; P < 0.05), tibialis anterior (vehicle: -22.7% and BMS-345541: -17.1%; P < 0.05) and soleus (vehicle: -21.1% and BMS-345541: -11.3%; P < 0.05) in septic mice. Analysis of the fiber type specific myocyte cross-sectional area showed that BMS-345541 reduced inflammation-induced atrophy of slow/type I and fast/type II myofibers compared with vehicle-treated septic mice. BMS-345541 reversed the inflammation-induced atrophy program as indicated by a reduced expression of the atrogenes Trim63/MuRF1, Fbxo32/Atrogin1, and Fbxo30/MuSA1. Conclusions: SAA1 activates the TLR2/TLR4//NF-κB p65 signalling pathway to cause myocyte atrophy. Systemic inhibition of the NF-κB pathway reduced muscle atrophy and increased survival of septic mice. The SAA1/TLR2/TLR4//NF-κB p65 atrophy pathway could have utility in combatting ICUAW.
Published: 2020

15. Perforation des Coecums durch einen Zahnstocher – seltene Differentialdiagnose der akuten Appendicitis Falldarstellung und Literaturübersicht: Falldarstellung und Literaturübersicht

Author: Neumann, U., Fielitz, J., and Ehlert, H.-G.
Published: 2000
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16. Myocardial angiotensin receptors in human hearts

Author: Regitz-Zagrosek, V., Fielitz, J., and Fleck, E.
Published: 1998
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17. Pathophysiology of Cardiac AT1 and AT2 Receptors

Author: Fielitz, J., primary and Regitz-Zagrosek, V., additional
Published: 2004
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18. DCAF8, a novel MuRF1 interaction partner, promotes muscle atrophy

Author: Nowak, M., Suenkel, B., Porras, P., Migotti, R., Schmidt, F., Kny, M., Zhu, X., Wanker, E.E., Dittmar, G., Fielitz, J., and Sommer, T.
Subjects: Cancer Research, Cardiovascular and Metabolic Diseases, Technology Platforms, Function and Dysfunction of the Nervous System
Abstract: The muscle-specific RING-finger protein MuRF1 constitutes a bona fide ubiquitin ligase that routes proteins like Myosin heavy chain (MyHC) to proteasomal degradation during muscle atrophy. In two unbiased screens we identified DCAF8 as a new MuRF1 binding partner. MuRF1 physically interacts with DCAF8 and both proteins localize to overlapping structures in muscle cells. Noteworthy, similar to MuRF1, DCAF8 levels increase during atrophy and the down-regulation of either protein substantially impedes muscle wasting and MyHC degradation in C2C12 myotubes, a model system for muscle differentiation and atrophy. DCAF proteins typically serve as substrate receptors in Cullin 4-type (Cul4) ubiquitin ligases (CRL) and we demonstrate that DCAF8 and MuRF1 associate with the subunits of such a protein complex. Because genetic downregulation of DCAF8 and inhibition of Cullin activity also impair myotube atrophy in C2C12 cells, our data imply that the DCAF8 promotes muscle wasting by targeting proteins like MyHC as an integral substrate receptor of a CRL4A ubiquitin ligase.
Published: 2019

19. HDAC4 mutations cause diabetes and induce β-cell FoxO1 nuclear exclusion

Author: Gong, M., Yu, Y., Liang, L., Vuralli, D., Froehler, S., Kuehnen, P., Du Bois, P., Zhang, J., Cao, A., Liu, Y., Hussain, K., Fielitz, J., Jia, S., Chen, W., and Raile, K.
Subjects: Cancer Research, Cardiovascular and Metabolic Diseases, Technology Platforms, Function and Dysfunction of the Nervous System
Abstract: BACKGROUND: Studying patients with rare Mendelian diabetes has uncovered molecular mechanisms regulating β-cell pathophysiology. Previous studies have shown that Class IIa histone deacetylases (HDAC4, 5, 7, and 9) modulate mammalian pancreatic endocrine cell function and glucose homeostasis. METHODS: We performed exome sequencing in one adolescent nonautoimmune diabetic patient and detected one de novo predicted disease-causing HDAC4 variant (p.His227Arg). We screened our pediatric diabetes cohort with unknown etiology using Sanger sequencing. In mouse pancreatic β-cell lines (Min6 and SJ cells), we performed insulin secretion assay and quantitative RT-PCR to measure the β-cell function transfected with the detected HDAC4 variants and wild type. We carried out immunostaining and Western blot to investigate if the detected HDAC4 variants affect the cellular translocation and acetylation status of Forkhead box protein O1 (FoxO1) in the pancreatic β-cells. RESULTS: We discovered three HDAC4 mutations (p.His227Arg, p.Asp234Asn, and p.Glu374Lys) in unrelated individuals who had nonautoimmune diabetes with various degrees of β-cell loss. In mouse pancreatic β-cell lines, we found that these three HDAC4 mutations decrease insulin secretion, down-regulate β-cell-specific transcriptional factors, and cause nuclear exclusion of acetylated FoxO1. CONCLUSION: Mutations in HDAC4 disrupt the deacetylation of FoxO1, subsequently decrease the β-cell function including insulin secretion, resulting in diabetes.
Published: 2019

20. P1614Soluble guanylate cyclase as a therapeutic target in heart failure: myocardial gene expression in response to sGC stimulation in pressure overload

Author: Ruedebusch, J, primary, Benkner, A, additional, Nath, N, additional, Kaderali, L, additional, Klingel, K, additional, Eckstein, G, additional, Meitinger, T, additional, Fielitz, J, additional, Grube, K, additional, and Felix, S B, additional
Published: 2019
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21. Intracerebral hemorrhage in ICU: is it worth treating?

Author: Sivakumar, S, Taccone, F, Desai, K, Lazaridis, C, Skarzynski, M, Sekhon, M, Henderson, W, Griesdale, D, Chapple, L, Deane, A, Williams, L, Strickland, R, Lange, K, Heyland, D, Chapman, M, Rowland, M, Garry, P, Westbrook, J, Corkill, R, Antoniades, C, Pattinson, K, Fatania, G, Strong, A, Myers, R, Jermaine, C, Robertson, C, Rusin, C, Hofmeijer, J, Sondag, L, Tjepkema Cloostermans, M, Beishuizen, A, Bosch, F, van Putten, M, Carteron, L, Patet, C, Solari, D, Oddo, M, Ali, M, Dias, C, Almeida, R, Vaz Ferreira, A, Silva, J, Monteiro, E, Cerejo, A, Rocha, A, Elsayed, A, Abougabal, A, Beshey, B, Alzahaby, K, Pozzebon, S, Ortiz, A, Cristallini, S, Lheureux, O, Brasseur, A, Vincent, J, Creteur, J, Hravnak, M, Yousef, K, Chang, Y, Crago, E, Friedlander, R, Abdelmonem, S, Tahon, S, Helmy, T, Meligy, H, Puig, F, Dunn Siegrist, I, Pugin, J, Gupta, S, Govil, D, Srinivasan, S, Patel, S, N, J, Gupta, A, Tomar, D, Shafi, M, Harne, R, Arora, D, Talwar, N, Mazumdar, S, Papakrivou, E, Makris, D, Manoulakas, E, Tsolaki, B, Karadodas, B, Zakynthinos, E, Garcia, I, Martin, A, Encinares, V, Ibañez, M, Montero, J, Labrador, G, Cangueiro, T, Poulose, V, Koh, J, Kam, J, Yeter, H, Kara, A, Aktepe, O, Topeli, A, Tsolakoglou, I, Intas, G, Stergiannis, P, Kolaros, A, Chalari, E, Athanasiadou, E, Martika, A, Fildisis, G, Faivre, V, Mengelle, C, Favier, B, Payen, D, Poppe, A, Winkler, M, Mudersbach, E, Schreiber, J, Wruck, M, Schwedhelm, E, Kluge, S, Zöllner, C, Tavladaki, T, Spanaki, A, Dimitriou, H, Kondili, E, Choulaki, C, Meleti, E, Kafetzopoulos, D, Georgopoulos, D, Briassoulis, G, la Torre, A, de la Torre Prados, M, Tsvetanova Spasova, T, Nuevo Ortega, P, Rueda Molina, C, Fernández Porcel, A, Camara Sola, E, Salido Díaz, L, García Alcántara, A, Meleti, D, Suberviola, B, Riera, J, Rellan, L, Sanchez, M, Robles, J, Lopez, E, Vicente, R, Miñambres, E, Santibañez, M, Le Guen, M, Moore, J, Mason, N, Windpassinger, M, Plattner, O, Mascha, E, Sessler, D, Research, O, Melia, U, Fontanet, J, 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Trauner, M, Pischke, S, Fischer, L, Thaiss, F, Koch, M, Bangert, K, Lohse, A, Nashan, B, Sterneck, M, Faenza, S, Siniscalchi, A, Pierucci, E, Mancini, E, Ricci, D, Gemelli, C, Cuoghi, A, Magnani, S, Atti, M, Sotos, F, Cánovas, J, López, A, Burruezo, A, Torres, D, Herrera Gutierrez, M, Barrueco Francioni, J, Arias Verdú, D, Lozano Saez, R, Quesada Garcia, G, Seller Pérez, G, Figueiredo, A, Anzola, Y, Pereira, R, Bento, L, Lai, M, Deiana, M, Seller Perez, G, Vardas, K, Ilia, S, Sertedaki, A, Charmadari, E, Stratakis, C, Briassouli, E, Goukos, D, Psarra, K, Botoula, E, Tsagarakis, S, Mageira, E, Routsi, C, Nanas, S, Campello, E, Radu, C, Su, H, Lam, Y, Willis, K, Pullar, V, Hubner, R, Tsang, J, de Guadiana Romualdo, L, Rebollo Acebes, S, Esteban Torrella, P, Jiménez Sánchez, R, Jiménez Santos, E, Ortín Freire, A, Hernando Holgado, A, Albaladejo Otón, M, Coelho, L, Rabello, L, Póvoa, P, Varis, E, Poukkanen, M, Jacob, S, Takala, J, Wilkman, E, Lundberg, O, Bergenzaun, L, Rydén, J, Rosenqvist, M, Melander, O, Chew, M, Kishihara, Y, Yasuda, H, Jimenez, R, Torrella, P, Fernandez, A, Sanchez, S, Ortin, A, Prats, R, Aguilera, E, Marti, D, Fernandez, L, Ferrer, M, Lanziotti, V, Pulcheri, L, Ribeiro, M, Barbosa, A, E. Silva, J, Soares, M, Marqués, M, Moreno, A, Pizarraya, A, Smani, Y, Connell, M, Zhang, L, Parker, R, Banerjee, I, Clermont, G, Norberg, E, Oras, J, Cuisinier, A, Maufrais, C, Payen, J, Nottin, S, Walther, G, Arib, S, Bilotta, F, Badenes, R, Rubulotta, F, Mirek, S, Monfort, B, Stazi, E, Roig, A, Magnoni, S, Marando, M, Pifferi, S, Conte, V, Ortolano, F, Carbonara, M, Bertani, G, Scola, E, Cadioli, M, Triulzi, F, Colombo, A, Stocchetti, N, Rotzel, H, Lázaro, A, Prada, D, Guimillo, M, Piqueras, C, Guia, J, Simon, M, Arizmendi, A, Carratalá, A, El Maraghi, S, Yehia, A, Bakry, M, Shoman, A, Backes, F, Bianchin, M, Vieira, S, de Souza, A, Backes, A, Klein, C, Arunkumar, A, Lozano, A, Gallaher, C, Cattlin, S, Gordon, S, Picard, J, Fontana, V, Bond, O, Nobile, L, Mrozek, S, Delamarre, L, Capilla, F, Al Saati, T, Fourcade, O, Dominguez Berrot, A, Gonzalez Vaquero, M, Vallejo Pascual, M, Gupta, D, Ivory, B, Chopra, M, Mccarthy, J, Felderhof, C, Macneil, C, Maggiorini, M, Duska, F, Fumis, R, Junior, J, Amarante, G, Skorko, A, Sanders, S, Aron, J, Kroll, R, Redfearn, C, Krishnan, P, Khalil, J, Kongpolprom, N, Gulia, V, Lourenço, E, Duro, C, Baptista, G, Alves, A, Arminda, B, Rodrigues, M, Hayward, J, Baldwin, F, Gray, R, Katinakis, P, Stijf, M, Ten Kleij, M, Jansen Frederiks, M, Broek, R, de Bruijne, M, Spronk, P, Sinha, K, Luney, M, Palmer, K, Keating, L, Abu Habsa, M, Bahl, R, Baskaralingam, N, Ahmad, A, Kanapeckaite, L, Bhatti, P, Glace, S, Jeyabraba, S, Lewis, H, Kostopoulos, A, Raja, M, West, A, Ely, A, Turkoglu, L, Zolfaghari, P, Baptista, J, Marques, M, Martins, P, Pimentel, J, Su, Y, Villacres, S, Stone, M, Parsikia, A, Medar, S, O'Dea, K, Porter, J, Tirlapur, N, Jonathan, J, Singh, S, Takata, M, Mcwhirter, E, Lyon, R, Hariz, M, Azmi, E, Alkhan, J, Movsisyan, V, Petrikov, S, Marutyan, Z, Aliev, I, Evdokimov, A, Antonucci, E, Merz, T, Hartmann, C, Calzia, E, Radermacher, P, Nußbaum, B, Huber Lang, M, Gröger, M, Svoren Jabalera, E, Davenport, E, Humburg, P, Knight, J, Hinds, C, Jun, I, Kim, W, Besch, G, Perrotti, A, Puyraveau, M, Baltres, M, Samain, E, Chocron, S, Pili Floury, S, Plata Menchaca, E, Sabater Riera, J, Estruch, M, Boza, E, Toscana Fernández, J, Bruguera Pellicer, E, Ordoñez Llanos, J, Pérez Fernández, X, Cavaleiro, P, Tralhão, A, Arrigo, M, Lopes, J, Lebrun, M, Cholley, B, Perezvela, J, Marinmateos, H, Rivera, J, Llorente, M, De Marcos, B, Fernandez, F, Laborda, C, Zamora, D, Delgado, J, Imperiali, C, Dastis, M, Górka, J, Górka, K, Iwaniec, T, Frołow, M, Polok, K, Fronczek, J, Kózka, M, Musiał, J, Szczeklik, W, Sileli, M, Moursia, C, Maleoglou, H, Leleki, K, Uz, Z, Ince, Y, Papatella, R, Bulent, E, De Mol, B, Vicka, V, Gineityte, D, Ringaitiene, D, Norkiene, I, Sipylaite, J, Möller, C, Thomas Rueddel, D, Vlasakov, V, Rochwerg, B, Theurer, P, Al Sibai, J, Camblor, P, Fernandez, P, Gala, J, Guisasola, J, Tamura, T, Miyajima, I, Yamashita, K, Yokoyama, M, Dalampini, E, Nastou, M, Baddour, A, Ignatiadis, A, Asteri, T, Hathorn, K, Purtle, S, Viana, M, Tonietto, T, Gross, L, Costa, V, Tavares, A, Lisboa, B, Moraes, R, Viana, L, Azevedo, M, Ceniccola, G, Pequeno, R, Holanda, T, Mendonça, V, Araújo, W, Carvalho, L, Segaran, E, Vickers, L, Brinchmann, K, Wignall, I, De Brito Ashurst, I, Del Olmo, R, Vaquerizo, C, Carreño, R, Gálvez, V, Kaminsky, G, Nieto, B, Fuentes, M, De la Torre, M, Torres, E, Alonso, A, Velayos, C, Saldaña, T, Escribá, A, Grip, J, Kölegård, R, Sundblad, P, Rooyackers, O, Naser, B, Jaziri, F, Jazia, A, Barghouth, M, Hentati, O, Skouri, W, El Euch, M, Mahfoudhi, M, Turki, S, Abdelghni, K, Abdallah, B, Maha, B, Lorente, M, Włudarczyk, A, Hałek, A, Bargouth, M, Bennasr, M, Abdelghani, K, Abdallah, T, Geenen, I, Parienti, J, Shum, H, King, H, Yan, W, Londoño, J, Cardenas, C, Pedrosa, M, Gubianas, C, Bertolin, C, Batllori, N, Sirvent, J, Mukhopadhyay, A, Chan, H, Kowitlawakul, Y, Remani, D, Leong, C, Henry, C, Puthucheary, Z, Mendsaikhan, N, Begzjav, T, Lundeg, G, Dünser, M, Welsh, S, Guerra, E, Zerpa, M, Zechner, F, Berdaguer, F, Risso Vazquez, A, Masevicius, F, Greaney, D, Magee, A, Fitzpatrick, G, Lugo Cob, R, Tejeda Huezo, B, Cano Oviedo, A, Aydogan, M, Togal, T, Taha, A, Chai, H, Kam, C, Razali, S, Sivasamy, V, Kuan, L, Morales, M, Pires, T, and Azevedo, L
Subjects: intracerebral haemorrhage in intensive care
Published: 2016

22. Risk profile analysis and complications after surgery for autoimmune thyroid disease

Author: Thomusch, Oliver, Sekulla, C., Billmann, F., Seifert, G., Dralle, H., Lorenz, K., Vorländer, C., Freitag, M., Jähne, J., Steinmüller, T., Trupka, A., Steinert, F., Schabram, J., Heinzmann, B., Lang, H., Cotte, J., Hoffmann, T.F., Dette, K., Gellert, K., Henne-Bruns, D., Boese-Landgraf, J., Simon Evangelisches, D., Kube, R., Lorenz, E.P.M., Pross, M., Hartel, M., Thomschke, D., Pistorius, G., Hopt, U.T., Franke, C., Rose, U., Steuer, W., Schwenk, W., Ebert, K.-H., Kelm, C., Witzigmann, H., Rampf, W., Ridwelski, K., Knoefel, W.T., Bechstein, W.O., Grothe, D., Anthuber, M., Mirow, L., Probst, W., Thews, A., Fleck, U., Kärgel, W., Schimmelpenning, H., Fielitz, J., Schöffauer, T., Asperger, W., Zaage, J., Dorn, H.-U., Weitz, J., Neubauer, M., Klar, E., Lautermann, J., Senkal, M., Lippert, H., Lück, R., Ziesche, M., Kröll, K.-P., Skrobisz, J., Lorenc, Z., Dudešek, Bohumil, Smutny, S., Brauckhoff, M., Längle, F., Wenzl, E., the Prospective Evaluation Study of Thyroid Surgery (PETS 2) Study Group, Thomusch, Oliver, Sekulla, C., Billmann, F., Seifert, G., Dralle, H., Lorenz, K., Vorländer, C., Freitag, M., Jähne, J., Steinmüller, T., Trupka, A., Steinert, F., Schabram, J., Heinzmann, B., Lang, H., Cotte, J., Hoffmann, T.F., Dette, K., Gellert, K., Henne-Bruns, D., Boese-Landgraf, J., Simon Evangelisches, D., Kube, R., Lorenz, E.P.M., Pross, M., Hartel, M., Thomschke, D., Pistorius, G., Hopt, U.T., Franke, C., Rose, U., Steuer, W., Schwenk, W., Ebert, K.-H., Kelm, C., Witzigmann, H., Rampf, W., Ridwelski, K., Knoefel, W.T., Bechstein, W.O., Grothe, D., Anthuber, M., Mirow, L., Probst, W., Thews, A., Fleck, U., Kärgel, W., Schimmelpenning, H., Fielitz, J., Schöffauer, T., Asperger, W., Zaage, J., Dorn, H.-U., Weitz, J., Neubauer, M., Klar, E., Lautermann, J., Senkal, M., Lippert, H., Lück, R., Ziesche, M., Kröll, K.-P., Skrobisz, J., Lorenc, Z., Dudešek, Bohumil, Smutny, S., Brauckhoff, M., Längle, F., Wenzl, E., and the Prospective Evaluation Study of Thyroid Surgery (PETS 2) Study Group
Abstract: Background: Surgical approaches to autoimmune thyroid disease are currently hampered by concerns over postoperative complications. Risk profiles and incidences of postoperative complications have not been investigated systematically, and studies with sufficient power to show valid data have not been performed. Methods: A prospective multicentre European study was conducted between July 2010 and December 2012. Questionnaires were used to collect data prospectively on patients who had surgery for autoimmune thyroid disease and the findings were compared with those of patients undergoing surgery for multinodular goitre. Logistic regression analysis was used to evaluate risk factors for thyroid surgery-specific complications, transient and permanent recurrent laryngeal nerve (RLN) palsy and hypoparathyroidism. Results: Data were available for 22 011 patients, of whom 18 955 were eligible for analysis (2488 who had surgery for autoimmune thyroid disease and 16 467 for multinodular goitre). Surgery for multinodular goitre and that for autoimmune thyroid disease did not differ significantly with regard to general complications. With regard to thyroid surgery-specific complications, the rate of temporary and permanent vocal cord palsy ranged from 2·7 to 6·7 per cent (P = 0·623) and from 0·0 to 1·4 per cent (P = 0·600) respectively, whereas the range for temporary and permanent hypoparathyroidism was 12·9 to 20·0 per cent (P < 0·001) and 0·0 to 7·0 per cent (P < 0·001) respectively. In logistic regression analysis of transient and permanent vocal cord palsy, autoimmune thyroid disease was not an independent risk factor. Autoimmune thyroid disease, extent of thyroid resection, number of identified parathyroid glands and no autotransplantation were identified as independent risk factors for both transient and permanent hypoparathyroidism. Conclusion: Surgery for autoimmune thyroid disease is safe in comparison with surgery for multinodular goitre in terms of general complicati
Published: 2018

23. Risk profile analysis and complications after surgery for autoimmune thyroid disease

Author: Thomusch, O, primary, Sekulla, C, additional, Billmann, F, additional, Seifert, G, additional, Dralle, H, additional, Lorenz, K, additional, Vorländer, C, additional, Freitag, M, additional, Jähne, J, additional, Steinmüller, T, additional, Trupka, A, additional, Steinert, F, additional, Schabram, J, additional, Heinzmann, B, additional, Lang, H, additional, Cotte, J, additional, Hoffmann, T F, additional, Dette, K, additional, Gellert, K, additional, Henne-Bruns, D, additional, Boese-Landgraf, J, additional, Simon Evangelisches, D, additional, Kube, R, additional, Lorenz, E P M, additional, Pross, M, additional, Hartel, M, additional, Thomschke, D, additional, Pistorius, G, additional, Hopt, U T, additional, Franke, C, additional, Rose, U, additional, Steuer, W, additional, Schwenk, W, additional, Ebert, K-H, additional, Kelm, C, additional, Witzigmann, H, additional, Rampf, W, additional, Ridwelski, K, additional, Knoefel, W T, additional, Bechstein, W O, additional, Grothe, D, additional, Anthuber, M, additional, Mirow, L, additional, Probst, W, additional, Thews, A, additional, Fleck, U, additional, Kärgel, W, additional, Schimmelpenning, H, additional, Fielitz, J, additional, Schöffauer, T, additional, Asperger, W, additional, Zaage, J, additional, Dorn, H-U, additional, Weitz, J, additional, Neubauer, M, additional, Klar, E, additional, Lautermann, J, additional, Senkal, M, additional, Lippert, H, additional, Lück, R, additional, Ziesche, M, additional, Kröll, K-P, additional, Skrobisz, J, additional, Lorenc, Z, additional, Dudesek, B, additional, Smutny, S, additional, Brauckhoff, M, additional, Längle, F, additional, and Wenzl, E, additional
Published: 2018
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24. ESICM LIVES 2016: part two

Author: Sivakumar, S., Taccone, F. S., Desai, K. A., Lazaridis, C., Skarzynski, M., Sekhon, M., Henderson, W., Griesdale, D., Chapple, L., Deane, A., Williams, L., Strickland, R., Lange, K., Heyland, D., Chapman, M., Rowland, M. J., Garry, P., Westbrook, J., Corkill, R., Antoniades, C. A., Pattinson, K. T., Fatania, G., Strong, A. J., Myers, R. B., Jermaine, C. M., Robertson, C. S., Rusin, C. G., Hofmeijer, J., Sondag, L., Tjepkema-Cloostermans, M. C., Beishuizen, A., Bosch, F. H., van Putten, M. J. A. M., Carteron, L., Patet, C., Solari, D., Oddo, M., Ali, M. A., Dias, C., Almeida, R., Vaz-Ferreira, A., Silva, J., Monteiro, E., Cerejo, A., Rocha, A. P., Elsayed, A. A., Abougabal, A. M., Beshey, B. N., Alzahaby, K. M., Pozzebon, S., Ortiz, A. Blandino, Cristallini, S., Lheureux, O., Brasseur, A., Vincent, J. L., Creteur, J., Hravnak, M., Yousef, K., Chang, Y., Crago, E., Friedlander, R. M., Abdelmonem, S. A., Tahon, S. A., Helmy, T. A., Meligy, H. S., Puig, F., Dunn-Siegrist, I., Pugin, J., Gupta, S., Govil, D., Srinivasan, S., Patel, S. J., N, J. K., Gupta, A., Tomar, D. S., Shafi, M., Harne, R., Arora, D. P., Talwar, N., Mazumdar, S., Papakrivou, E. E., Makris, D., Manoulakas, E., Tsolaki, B., Karadodas, B., Zakynthinos, E., Garcia, I. Palacios, Martin, A. Diaz, Encinares, V. Sanchez, Ibañez, M. Pachón, Montero, J. Garnacho, Labrador, G., Cangueiro, T. Cebrero, Poulose, V., Koh, J., Kam, J. W., Yeter, H., Kara, A., Aktepe, O., Topeli, A., Tsolakoglou, I., Intas, G., Stergiannis, P., Kolaros, A. A., Chalari, E., Athanasiadou, E., Martika, A., Fildisis, G., Faivre, V., Mengelle, C., Favier, B., Payen, D., Poppe, A., Winkler, M. S., Mudersbach, E., Schreiber, J., Wruck, M. L., Schwedhelm, E., Kluge, S., Zöllner, C., Tavladaki, T., Spanaki, A. M., Dimitriou, H., Kondili, E., Choulaki, C., Meleti, E., Kafetzopoulos, D., Georgopoulos, D., Briassoulis, G., la Torre, A. García-de, de la Torre-Prados, M. V., Tsvetanova-Spasova, T., Nuevo-Ortega, P., Rueda-Molina, C., Fernández-Porcel, A., Camara-Sola, E., Salido-Díaz, L., García-Alcántara, A., Meleti, D. E., Suberviola, B., Riera, J., Rellan, L., Sanchez, M., Robles, J. C., Lopez, E., Vicente, R., Miñambres, E., Santibañez, M., Le Guen, M., Moore, J., Mason, N., Windpassinger, M., Plattner, O., Mascha, E., Sessler, D. I., Research, Outcomes, Melia, U., Fontanet, J., van den Berg, J. P., Struys, M. M. R. F., Vereecke, H. E. M., Jensen, E. W., Rood, P. J. T., van de Schoor, F., van Tertholen, K., Pickkers, P., van den Boogaard, M., Beardow, Z. J., Redhead, H., Paramasivam, K., Numan, T., Kamper, A. M., Rood, P., Peelen, L. M., Zeman, P. M., Slooter, A. J., van Ewijk, C. E., Jacobs, G. E., Girbes, A. R. J., Myatra, S. N., Harish, M. M., Prabu, N. R., Siddiqui, S., Kulkarni, A. P., Divatia, J. V., Murbach, L. D., Leite, M. A., Osaku, E. F., Costa, C. R. L. M., Pelenz, M., Neitzke, N. M., Moraes, M. M., Jaskowiak, J. L., Silva, M. M. M., Zaponi, R. S., Abentroth, L. R. L., Ogasawara, S. M., Jorge, A. C., Duarte, P. A. D., Hernández-Sánchez, N., Sánchez-Hurtado, L. A., García-Guillen, F. J., Ñamendys-Silva, S. A., Maghsoudi, B., Emami, M., Khosravi, M. B., Zand, F., Tabatabaie, H. R., Masjedi, M., Sabetiyan, G., Mokri, A., Troubleyn, J., Diltoer, M., Jacobs, R., Nguyen, D. N., De Waele, E., De Regt, J., Honoré, P. M., Van Gorp, V., Spapen, H. D., Contreras, R. S., Toapanta, N. D., Moreno, G., Sabater, J., Torrado, H., Gonzalez, M., Marin, M., Farigola, E., Gonzalez, A., Fernandez, J., Vera, A., Gisbert, X., Juliá, C., Uya, J., Corral, L., Elias-Jones, I., Gemmell, L., MacKay, A., Randall, D., Adwaney, A., Blunden, M., Prowle, J. R., Kirwan, C. J., Thomas, N., Martin, A., Owen, H., Darwin, L., Conway, D., Atkinson, D., Sharman, M., Barbanti, C., Amour, J., Gaudard, P., Rozec, B., Mauriat, P., M’rini, M., Leger, P. L., Cambonie, G., Liet, J. 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P., Hamidfar, R., Jourdain, M., Darmon, M., Schlemmer, B., Chevret, S., Lemiale, V., Azoulay, E., Benoit, D., Martins-Branco, D., Sousa, M., Marum, S., Bouw, M. J., Galstyan, G., Makarova, P., Parovichnikova, E., Kuzmina, L., Troitskaya, V., Drize, N., Gemdzhian, E., Savchenko, V., Chao, H. C., Kılıc, E., Demiriz, B., Uygur, M. L., Sürücü, M., Cınar, K., Yıldırım, A. E., Kiss, K., Köves, B., Csernus, V., Molnár, Z., Ntantana, A., Matamis, D., Savvidou, S., Giannakou, M., Gouva, M., Nakos, G., Koulouras, V., Gaffney, S., Docking, R., Judge, C., Drew, T., Misran, H., Munshi, R., McGovern, L., Coyle, M., Dunne, L., Deasy, E., Lavin, P., Fahy, A., Darcy, D. M., Donnelly, M., Ismail, N. H., Hall, T., Wykes, K., Jack, J., Ngu, W. C., Morgan, P., Ruiz-Ramos, J., Ramirez, P., Gordon, M., Villarreal, E., Frasquet, J., Poveda-Andrés, J. L., Castellanos, A., Ijssennagger, C. E., ten Hoorn, S., van Wijk, A., van den Broek, J. M., Tuinman, P. R., Elmenshawy, A. M., Hammond, B. 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Cambronero, Jiménez, R., Rebollo, S., Alejandro, O., Fernández, A., Moreno, S., Herrera, L., Ojados, A., Galindo, M., Murcia, J., Contreras, M., Sánchez-Argente, S., Bonilla, Y., Rodríguez, M. D., Allegue, J. M., Cakin, Ö., Parlak, H., Kirca, H., Mutlu, F., Aydınlı, B., Cengiz, M., Ramazanoglu, A., Jung, E.-J., Oh, S.-Y., Domenech, J. Cebrián, Montalvo, A. Pinos, Chornet, T. Ciges, Martinez, P. Concha, Ribas, M. Piñol, Costa, R. Gimeno, Ortega, A. Castellanos, Forbes, C., Prescott, H., Lal, A., Khan, F. A., Dela Pena, E. G., Dizon, J. S., Perez, P. P. P., Wong, C. M. J., Garach, M. Muñoz, Romero, O. Moreno, Puerta, R. Ramirez, Diaz, F. Acosta, Bailon, A. M. Perez, Pinel, A. Carranza, Maldonado, L. Peñas, Kalaiselvan, M. S., kumar, R. L. Siva, Renuka, M. K., Kumar, A. S. Arun, De Rosa, S., Ferrari, F., Checcacci, S. Carboni, Rigobello, A., Joannidis, M., Politi, F., Pellizzari, A., Bonato, R., Fernandez-Carmona, A., Macias-Guarasa, I., Gutierrez-Rodriguez, R., Martinez-Lopez, P., Diaz-Castellanos, M. A., Arias-Diaz, M., Aguilar-Alonso, E., Nikandish, R. N., Artemenko, V., Budnyuk, A., Bassi, G. Li, Senussi, T., Idone, F., Xiol, E. Aguilera, Travierso, C., Chiurazzi, C., Motos, A., Amaro, R., Hua, Y., Fernández-Barat, L., Ranzani, O. T., Bobi, Q., Rigol, M., Youn, A., Hwang, J. Gyung, Ossorio, M. E. Yuste, Figueira, H., Oliveira, R., Mota, A., Kamp, O., Cruciger, O., Aach, M., Kaczmarek, C., Waydhas, C., Schildhauer, T. A., Hamsen, U., Camprubí-Rimblas, M., Chimenti, L., Guillamat-Prats, R., Lebouvier, T., Bringué, J., Tijero, J., Gómez, M. N., Blanch, L., Tagliabue, G., Ji, M., Jagers, J. V. Suneby, Easton, P. A., Martins, A. M. C. R. P. F., Hong, J. Y., Shin, M. H., Park, M. S., Pomprapa, A., Hofferberth, M. B. T., Russ, M., Braun, W., Walter, M., Francis, R., Lachmann, B., Leonhardt, S., Landaverde-López, A., Canedo-Castillo, N. A., Esquivel-Chávez, A., Arvizu-Tachiquín, P. C., Baltazar-Torres, J. A., Cardoso, V., Krystopchuk, A., Castro, S., Melão, L., Firmino, S., Marreiros, A., Almaziad, S., Kubbara, A., Barnett, W., Nakity, R., Alamoudi, W., Altook, R., Tarazi, T., Fida, M., Safi, F., Assaly, R., Santini, A., Milesi, M., Maraffi, T., Pugni, P., Cavenago, M., Gattinoni, L., Protti, A., Perchiazzi, G., Borges, J. B., Bayat, S., Porra, L., Broche, L., Hedenstierna, G., Larsson, A., Roneus, A., Segelsjö, M., Vestito, M. C., Gremo, E., Nyberg, A., Castegren, M., Pikwer, A., Yoshida, T., Engelberts, D., Otulakowski, G., Katira, B., Post, M., Brochard, L., Amato, M. B. P., Koch, N., Hoellthaler, J., Mair, S., Phillip, V., Beitz, A., Baladrón, V., Villarejo, P., Steenstra, R. J., Banierink, H., Hof, J., van der Horst, I. C., Nijsten, M. W., Hoekstra, M., Sterz, F., Horvatits, K., Herkner, H., Kott, M., Zitta, K., Brandt, B., Schildhauer, C., Elke, G., Hummitzsch, L., Albrecht, M., González, L. Rey, Alonso, D. Cabestrero, Sánchez, R. de Pablo, Lucas, J. Higuera, Ferlitsch, A., Fauler, G., Trauner, M., Pischke, S., Fischer, L., Thaiss, F., Koch, M., Bangert, K., Lohse, A. W., Nashan, B., Sterneck, M., Faenza, S., Siniscalchi, A., Pierucci, E., Mancini, E., Ricci, D., Gemelli, C., Cuoghi, A., Magnani, S., Atti, M., Sotos, F., Cánovas, J., López, A., Burruezo, A., Torres, D., Herrera-Gutierrez, M. E., Barrueco-Francioni, J., Arias-Verdú, D., Lozano-Saez, R., Quesada-Garcia, G., Seller-Pérez, G., Figueiredo, A., Anzola, Y., Pereira, R., Bento, L., Lai, M., Deiana, M., Seller-Perez, G., Vardas, K., Ilia, S., Sertedaki, A., Charmadari, E., Stratakis, C. A., Briassouli, E., Goukos, D., Psarra, K., Botoula, E., Tsagarakis, S., Mageira, E., Routsi, C., Nanas, S., Campello, E., Radu, C. M., Su, H., Lam, Y. M., Willis, K., Pullar, V., Hubner, R. P., Tsang, J. L., de Guadiana-Romualdo, L. García, Rebollo-Acebes, S., Esteban-Torrella, P., Jiménez-Sánchez, R., Jiménez-Santos, E., Ortín-Freire, A., Hernando-Holgado, A., Albaladejo-Otón, M. D., Coelho, L., Rabello, L., Póvoa, P., Varis, E., Poukkanen, M., Jacob, S., Takala, J., Wilkman, E., Lundberg, O. H. M., Bergenzaun, L., Rydén, J., Rosenqvist, M., Melander, O., Chew, M. S., Kishihara, Y., Yasuda, H., Jimenez, R., Torrella, P. Esteban, Fernandez, A., Sanchez, S., Ortin, A., Prats, R. Guillamat, Aguilera, E., Marti, D., Fernandez, L., Ferrer, M., Lanziotti, V. S., Pulcheri, L., Ribeiro, M. O., Barbosa, A. P., e Silva, J. R. Lapa, Soares, M., Salluh, J. I. F., Marqués, M. Gil, Moreno, A. Puppo, Pizarraya, A. Gutierrez, Diaz, J. Pachón, Smani, Y., Connell, M. Mc, Zhang, L. A., Parker, R. S., Banerjee, I., Clermont, G., Norberg, E., Oras, J., Cuisinier, A., Maufrais, C., Payen, J. F., Nottin, S., Walther, G., Arib, S., Bilotta, F., Badenes, R., Rubulotta, F., Mirek, S., Monfort, B., Stazi, E., Roig, A. Lozano, Magnoni, S., Marando, M., Pifferi, S., Conte, V., Ortolano, F., Carbonara, M., Bertani, G., Scola, E., Cadioli, M., Triulzi, F., Colombo, A., Stocchetti, N., Rotzel, H. B., Lázaro, A. Serrano, Prada, D. Aguillón, Guimillo, M. Rodriguez, Piqueras, C. Sanchís, Guia, J. Romero, Simon, M. García, Arizmendi, A. Mesejo, Carratalá, A., El Maraghi, S., Yehia, A., Bakry, M., Shoman, A., Backes, F. N., Bianchin, M. M., Vieira, S. R. R., de Souza, A., Backes, A. N., Klein, C., Arunkumar, A. S., Lozano, A., Gallaher, C., Cattlin, S., Gordon, S., Picard, J., Fontana, V., Bond, O., Nobile, L., Mrozek, S., Delamarre, L., Capilla, F., Al-Saati, T., Fourcade, O., Dominguez-Berrot, A. M., Gonzalez-Vaquero, M., Vallejo-Pascual, M. E., Gupta, D., Ivory, B. D., Chopra, M., McCarthy, J., Felderhof, C. L., MacNeil, C., Maggiorini, M., Duska, F., Fumis, R. R. L., Junior, J. M. Vieira, Amarante, G., Skorko, A., Sanders, S., Aron, J., Kroll, R. J., Redfearn, C., Krishnan, P., Khalil, J. E., Kongpolprom, N., Gulia, V., Lourenço, E., Duro, C., Baptista, G., Alves, A., Arminda, B., Rodrigues, M., Hayward, J., Baldwin, F., Gray, R., Katinakis, P. A., Stijf, M., Ten Kleij, M., Jansen-Frederiks, M., Broek, R., de Bruijne, M., Spronk, P. E., Sinha, K., Luney, M., Palmer, K., Keating, L., Abu-Habsa, M., Bahl, R., Baskaralingam, N., Ahmad, A., Kanapeckaite, L., Bhatti, P., Glace, S., Jeyabraba, S., Lewis, H. F., Kostopoulos, A., Raja, M., West, A., Ely, A., Turkoglu, L. M., Zolfaghari, P., Baptista, J. P., Marques, M. P., Martins, P., Pimentel, J., Su, Y. C., Villacres, S., Stone, M. E., Parsikia, A., Medar, S., O’Dea, K. P., Porter, J., Tirlapur, N., Jonathan, J. M., Singh, S., Takata, M., McWhirter, E., Lyon, R., Hariz, M. L., Azmi, E., Alkhan, J., Movsisyan, V., Petrikov, S., Marutyan, Z., Aliev, I., Evdokimov, A., Antonucci, E., Merz, T., Hartmann, C., Calzia, E., Radermacher, P., Nußbaum, B., Huber-Lang, M., Gröger, M., Svoren-Jabalera, E., Davenport, E. E., Humburg, P., Knight, J., Hinds, C. J., Jun, I. J., Kim, W. J., Lee, E. H., Besch, G., Perrotti, A., Puyraveau, M., Baltres, M., Samain, E., Chocron, S., Pili-Floury, S., Plata-Menchaca, E. P., Sabater-Riera, J., Estruch, M., Boza, E., Toscana-Fernández, J., Bruguera-Pellicer, E., Ordoñez-Llanos, J., Pérez-Fernández, X. L., Cavaleiro, P., Tralhão, A., Arrigo, M., Lopes, J.-P., Lebrun, M., Cholley, B., PerezVela, J. L., MarinMateos, H., Rivera, J. J. Jimenez, Llorente, M. A. Alcala, De Marcos, B. Gonzalez, Fernandez, F. J. Gonzalez, Laborda, C. Garcia, Zamora, D. Fernandez, Delgado, J. C. Lopez, Imperiali, C., Dastis, M., Górka, J., Górka, K., Iwaniec, T., Frołow, M., Polok, K., Fronczek, J., Kózka, M., Musiał, J., Szczeklik, W., Sileli, M., Moursia, C., Maleoglou, H., Leleki, K., Uz, Z., Ince, Y., Papatella, R., Bulent, E., De Mol, B., Vicka, V., Gineityte, D., Ringaitiene, D., Norkiene, I., Sipylaite, J., Möller, C., Thomas-Rueddel, D. O., Vlasakov, V., Rochwerg, B., Theurer, P., Al Sibai, J. Zanabili, Camblor, P. Martinez, Fernandez, P. Alvarez, Gala, J. M. García, Guisasola, J. Silba, Tamura, T., Miyajima, I., Yamashita, K., Yokoyama, M., Dalampini, E., Nastou, M., Baddour, A., Ignatiadis, A., Asteri, T., Hathorn, K. E., Purtle, S. W., Viana, M. V., Tonietto, T. A., Gross, L. A., Costa, V. L., Tavares, A. L. J., Lisboa, B. O., Moraes, R. B., Vieira, S. R., Viana, L. V., Azevedo, M. J., Ceniccola, G. D., Pequeno, R. S. F., Holanda, T. P., Mendonça, V. S., Araújo, W. M. C., Carvalho, L. S. F., Segaran, E., Vickers, L., Brinchmann, K., Wignall, I., De Brito-Ashurst, I., del Olmo, R., Esteban, M. J., Vaquerizo, C., Carreño, R., Gálvez, V., Kaminsky, G., Nieto, B., Fuentes, M., De la Torre, M. A., Torres, E., Alonso, A., Velayos, C., Saldaña, T., Escribá, A., GRIP, J., Kölegård, R., Sundblad, P., Rooyackers, O., Naser, Ben, Jaziri, F., Jazia, A. Ben, Barghouth, M., Hentati, O., Skouri, W., El Euch, M., Mahfoudhi, M., Turki, S., Abdelghni, K. Ben, Abdallah, Ben, Maha, B. N. M., Lorente, M., Włudarczyk, A., Hałek, A., Bargouth, M., Bennasr, M., Abdelghani, K. Ben, Abdallah, T. Ben, Geenen, I. L., Parienti, J. J., Straaten, H. M. Oudemans-van, Shum, H. P., King, H. S., Chan, K. C., Yan, W. W., Londoño, J. Gonzalez, Cardenas, C. Lorencio, Pedrosa, M. Morales, Gubianas, C. Murcia, Bertolin, C. Fuster, Batllori, N. Vila, Sirvent, J. M., Mukhopadhyay, A., Chan, H. Y., Kowitlawakul, Y., Remani, D., Leong, C. S. F., Henry, C. J., Puthucheary, Z. A., Mendsaikhan, N., Begzjav, T., Lundeg, G., Dünser, M., Welsh, S. P., Guerra, E., Zerpa, M. C. l., Zechner, F., Berdaguer, F., Risso-Vazquez, A., Masevicius, F. D., Greaney, D., Magee, A., Fitzpatrick, G., Lugo-Cob, R. G., Tejeda-Huezo, B. C., Cano-Oviedo, A. A., Aydogan, M. S., Togal, T., Taha, A., Chai, H. Z., Kam, C., Razali, S. S. Yang, Sivasamy, V., Kuan, L. Y., Morales, M. A. Lopez, Pires, T., and Azevedo, L. C. P.
Subjects: Meeting Abstracts
Abstract: Introduction In addition to systemic hemodynamics, the management\ud of neurocritically ill patients is often informed by neuromonitoring. In\ud the absence of high-level evidence clinicians are often guided by personal\ud and local expertise. Little is known about practices as they pertain\ud to the use of such monitoring in patients with acute brain injury (ABI).\ud Objectives To investigate practices in bedside monitoring for ABI patients.\ud Particularly interested in differences among “neurointensivists”\ud (NIs; defined here as intensivists whose clinical practice is comprised\ud > 1/3 by neurocritical care) and other intensivists (OIs). Also, to\ud explore patterns specific to traumatic brain injury (TBI) and subarachnoid\ud hemorrhage (SAH), as well as preferences and availability of\ud particular technologies/devices.\ud Methods Electronic survey of 22 items including two case-based scenarios;\ud endorsed by SCCM (9,000 recipients) and ESICM (on-line\ud newsletter) in 2013. A sample size of 370 was calculated based on a\ud population of 10,000 physician members, a 5 % margin error, and\ud 95 % confidence interval. We summarized results using descriptive\ud statistics (proportions with 95 % confidence intervals). A chi-square\ud test was used to compare proportions of responses between NIs and\ud OIs with a significance p < 0.05.\ud Results There were 655 responders (66 % completion rate); 422(65 %)\ud were classified as OIs and 226(35 %) as NIs. More NIs follow\ud hemodynamic protocols for neurocritically-ill patients (56 % vs. 43 %, p\ud 0.001), in TBI (44.5 % vs. 33.3 %, p 0.007), and in SAH (38.1 % vs. 21.3 %,\ud p < 000.1). For delayed cerebral ischemia (DCI), more NIs target cardiac\ud index (CI) (35 % vs. 21 %, p 0.0001), and fluid responsiveness (62 % vs.\ud 53 %, p 0.03), use more bedside ultrasound (BUS) (42 % vs. 29 %, p\ud 0.005) and arterial waveform analysis (40 % vs. 29 %, p 0.02). For DCI\ud neuromonitoring, NIs use more angiography (57 % vs. 43 %, p 0.004),\ud TCD (46 % vs. 38 %, p 0.0001), and CTP (32 % vs.16 %, p 0.0001). For\ud CPP optimization in TBI, NIs use more arterial waveform analysis (45 %\ud vs. 35 %, p 0.019), and BUS (37 % vs. 27.7 %, p 0.023), while more OIs\ud monitor mixed venous oxygen saturation (54.1 % vs. 45 %, p 0.045). For\ud TBI neuromonitoring, NIs use more PbtO2 (28 % vs. 10 %, p 0.0001). In\ud the case scenario of raised ICP/low PbtO2, most employ analgosedation\ud (47 %) and osmotherapy (38 %). Fewer make use of preserved pressure\ud reactivity, particularly OIs (vasopressor use 23 % vs. 34 %, p 0.014).\ud Conclusions There is large heterogeneity in the use of monitoring protocols,\ud variables, and technologies/devices. “Neurointensivists” not only\ud employ more neuromonitoring but also more hemodynamic monitoring\ud in patients with acute brain injury. ICP/CPP remain the most commonly\ud followed neuro-variables in TBI patients, with low use of other\ud brain-physiology parameters, sugg
Published: 2016

25. Cancer cachexia-when proteasomal inhibition is not enough

Author: Fielitz, J.
Subjects: Cardiovascular and Metabolic Diseases
Published: 2016

26. Metabolische Veränderungen nach akutem Myocardinfarkt werden teilweise durch Behandlung mit dem ACE Hemmer Quinapril aufgehoben

Author: Westermann, D, Riad, A, Regitz-Zagrosek, V, Tschöpe, C, and Fielitz, J
Subjects: ddc: 610
Published: 2004

27. Metabolic changes following acute myocardial infarction are partially reversed after treatment with the ACE inhibitor quina

Author: Westermann, D, Riad, A, Regitz-Zagrosek, V, Tschöpe, C, Fielitz, J, Westermann, D, Riad, A, Regitz-Zagrosek, V, Tschöpe, C, and Fielitz, J
Published: 2004

28. Early type II fiber atrophy in intensive care unit patients with nonexcitable muscle membrane.

Author: Bierbrauer J, Koch S, Olbricht C, Hamati J, Lodka D, Schneider J, Luther-Schröder A, Kleber C, Faust K, Wiesener S, Spies CD, Spranger J, Spuler S, Fielitz J, and Weber-Carstens S
Published: 2012
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29. Up-regulation of PPARgamma in myocardial infarction.

Author: Fliegner D, Westermann D, Riad A, Schubert C, Becher E, Fielitz J, Tschöpe C, Regitz-Zagrosek V, Fliegner, Daniela, Westermann, Dirk, Riad, Alexander, Schubert, Carola, Becher, Eva, Fielitz, Jens, Tschöpe, Carsten, and Regitz-Zagrosek, Vera
Abstract: Background: Peroxisome proliferator activated receptors (PPARs) are key regulators for cardiac energy metabolism after myocardial injury. We hypothesized, that PPARs are regulated in myocardial infarction (MI) and their activity is modulated by angiotensin receptor blockers (ARBs).Methods: Following induction of MI, male rats were treated with placebo or the ARB irbesartan for three weeks. PPARalpha, beta/delta and gamma protein expression and gene expression of PPAR target genes and glucose transporters were measured. PPARgamma-protein expression was analyzed by immunofluorescence.Results: MI decreased LVP and dp/dtmax and increased LVEDP, this effect was counteracted by irbesartan. PPARalpha and PPARbeta/delta protein expression was not altered in MI and was not affected by irbesartan. PPARgamma protein content was increased in the infarcted area and localized to cardiac myocytes and fibroblasts. In parallel, expression of CTGF was increased 10-fold in the infarcted zone. PPAR target genes (CD36, MCAD, ACO and GLUT4) were significantly decreased in infarcted tissue, and this was unaffected by irbesartan. However, CD36 and ACO in the non-infarcted areas were up-regulated by irbesartan.Conclusion: Endogenous up-regulation of PPARgamma in MI is insufficient to counteract the decrease in metabolic genes, but parallels an increase in the profibrotic mediator CTGF. Irbesartan increases fatty acid oxidating enzymes after MI independent of PPARgamma regulation. [ABSTRACT FROM AUTHOR]
Published: 2008
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30. DNA replication in asynchronous and synchronous ehrlich ascites cells in different conditions of growth

Author: Probst, H., primary, Blütters, R., additional, and Fielitz, J., additional
Published: 1980
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31. Protein Kinase D Plays a Crucial Role in Maintaining Cardiac Homeostasis by Regulating Post-Translational Modifications of Myofilament Proteins.

Author: Herwig M, Begovic M, Budde H, Delalat S, Zhazykbayeva S, Sieme M, Schneider L, Jaquet K, Mügge A, Akin I, El-Battrawy I, Fielitz J, and Hamdani N
Subjects: Mice, Animals, Connectin metabolism, Myocytes, Cardiac metabolism, Phosphorylation, Microfilament Proteins metabolism, Homeostasis, Inflammation metabolism, Calcium metabolism, Mammals metabolism, Myofibrils metabolism, Protein Processing, Post-Translational, Protein Kinase C
Abstract: Protein kinase D (PKD) enzymes play important roles in regulating myocardial contraction, hypertrophy, and remodeling. One of the proteins phosphorylated by PKD is titin, which is involved in myofilament function. In this study, we aimed to investigate the role of PKD in cardiomyocyte function under conditions of oxidative stress. To do this, we used mice with a cardiomyocyte-specific knock-out of Prkd1, which encodes PKD1 (Prkd1 loxP/loxP ; αMHC-Cre ; PKD1 cKO), as well as wild type littermate controls (Prkd1 loxP/loxP ; WT). We isolated permeabilized cardiomyocytes from PKD1 cKO mice and found that they exhibited increased passive stiffness (F passive ), which was associated with increased oxidation of titin, but showed no change in titin ubiquitination. Additionally, the PKD1 cKO mice showed increased myofilament calcium (Ca 2+ ) sensitivity (pCa 50 ) and reduced maximum Ca 2+ -activated tension. These changes were accompanied by increased oxidation and reduced phosphorylation of the small myofilament protein cardiac myosin binding protein C (cMyBPC), as well as altered phosphorylation levels at different phosphosites in troponin I (TnI). The increased F passive and pCa 50 , and the reduced maximum Ca 2+ -activated tension were reversed when we treated the isolated permeabilized cardiomyocytes with reduced glutathione (GSH). This indicated that myofilament protein oxidation contributes to cardiomyocyte dysfunction. Furthermore, the PKD1 cKO mice exhibited increased oxidative stress and increased expression of pro-inflammatory markers interleukin (IL)-6, IL-18, and tumor necrosis factor alpha (TNF-α). Both oxidative stress and inflammation contributed to an increase in microtubule-associated protein 1 light chain 3 (LC3)-II levels and heat shock response by inhibiting the mammalian target of rapamycin (mTOR) in the PKD1 cKO mouse myocytes. These findings revealed a previously unknown role for PKD1 in regulating diastolic passive properties, myofilament Ca 2+ sensitivity, and maximum Ca 2+ -activated tension under conditions of oxidative stress. Finally, we emphasized the importance of PKD1 in maintaining the balance of oxidative stress and inflammation in the context of autophagy, as well as cardiomyocyte function.
Published: 2024
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32. Increased Expression of Proinflammatory Genes in Peripheral Blood Cells Is Associated with Cardiac Cachexia in Patients with Heart Failure with Reduced Ejection Fraction.

Author: Sandek A, Gertler C, Valentova M, Jauert N, Wallbach M, Doehner W, von Haehling S, Anker SD, Fielitz J, and Volk HD
Abstract: Background : Cardiac cachexia (CC) in chronic heart failure with reduced ejection fraction (HFrEF) is characterized by catabolism and inflammation predicting poor prognosis. Levels of responsible transcription factors like signal transducer and activator of transcription (STAT)1, STAT3, suppressor of cytokine signaling (SOCS)1 and SOCS3 in peripheral blood cells (PBC) are underinvestigated in CC. Expression of mediators was related to patients' functional status, body composition (BC) and metabolic gene expression in skeletal muscle (SM). Methods : Gene expression was quantified by qRT-PCR in three cohorts: non-cachectic patients (ncCHF, n = 19, LVEF 31 ± 7%, BMI 30.2 ± 5.0 kg/m 2 ), cachectic patients (cCHF; n = 18, LVEF 27 ± 7%, BMI 24.3 ± 2.5 kg/m 2 ) and controls ( n = 17, LVEF 70 ± 7%, BMI 27.6 ± 4.6 kg/m 2 ). BC was assessed by dual-energy X-ray absorptiometry. Blood inflammatory markers were measured. We quantified solute carrier family 2 member 4 (SLC2A4) and protein degradation by expressions of proteasome 20S subunit beta 2 and calpain-1 catalytic subunit in SM biopsies. Results : TNF and IL-10 expression was higher in cCHF than in ncCHF and controls (all p < 0.004). cCHF had a lower fat mass index (FMI) and lower fat-free mass index (FFMI) compared to ncCHF and controls ( p < 0.05). STAT1 and STAT3 expression was higher in cCHF vs. ncCHF or controls (1.1 [1.6] vs. 0.8 [0.9] vs. 0.9 [1.1] RU and 4.6 [5.5] vs. 2.5 [4.8] vs. 3.0 [4.2] RU, all ANOVA- p < 0.05). The same applied for SOCS1 and SOCS3 expression (1.1 [1.5] vs. 0.4 [0.4] vs. 0.4 [0.5] and 0.9 [3.3] vs. 0.4 [1.1] vs. 0.8 [0.9] RU, all ANOVA- p < 0.04). In cCHF, higher TNF and STAT1 expression was associated with lower FMI (r = 0.5, p = 0.053 and p < 0.05) but not with lower FFMI ( p > 0.4). In ncCHF, neither cytokine nor STAT/SOCS expression was associated with BC (all p > 0.3). SLC2A4 was upregulated in SM of cCHF vs. ncCHF ( p < 0.03). Conclusions : Increased STAT1, STAT3, SOCS1 and SOCS3 expression suggests their involvement in CC. In cCHF, higher TNF and STAT-1 expression in PBC were associated with lower FMI. Increased SLC2A4 in cachectic SM biopsies indicates altered glucose metabolism.
Published: 2024
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33. Metabolic remodeling in cardiac hypertrophy and heart failure with reduced ejection fraction occurs independent of transcription factor EB in mice.

Author: Dörmann N, Hammer E, Struckmann K, Rüdebusch J, Bartels K, Wenzel K, Schulz J, Gross S, Schwanz S, Martin E, Fielitz B, Pablo Tortola C, Hahn A, Benkner A, Völker U, Felix SB, and Fielitz J
Abstract: Background: A metabolic shift from fatty acid (FAO) to glucose oxidation (GO) occurs during cardiac hypertrophy (LVH) and heart failure with reduced ejection fraction (HFrEF), which is mediated by PGC-1α and PPARα. While the transcription factor EB (TFEB) regulates the expression of both PPARGC1A /PGC-1α and PPARA /PPARα, its contribution to metabolic remodeling is uncertain., Methods: Luciferase assays were performed to verify that TFEB regulates PPARGC1A expression. Cardiomyocyte-specific Tfeb knockout (cKO) and wildtype (WT) male mice were subjected to 27G transverse aortic constriction or sham surgery for 21 and 56 days, respectively, to induce LVH and HFrEF. Echocardiographic, morphological, and histological analyses were performed. Changes in markers of cardiac stress and remodeling, metabolic shift and oxidative phosphorylation were investigated by Western blot analyses, mass spectrometry, qRT-PCR, and citrate synthase and complex II activity measurements., Results: Luciferase assays revealed that TFEB increases PPARGC1A /PGC-1α expression, which was inhibited by class IIa histone deacetylases and derepressed by protein kinase D. At baseline, cKO mice exhibited a reduced cardiac function, elevated stress markers and a decrease in FAO and GO gene expression compared to WT mice. LVH resulted in increased cardiac remodeling and a decreased expression of FAO and GO genes, but a comparable decline in cardiac function in cKO compared to WT mice. In HFrEF, cKO mice showed an improved cardiac function, lower heart weights, smaller myocytes and a reduction in cardiac remodeling compared to WT mice. Proteomic analysis revealed a comparable decrease in FAO- and increase in GO-related proteins in both genotypes. A significant reduction in mitochondrial quality control genes and a decreased citrate synthase and complex II activities was observed in hearts of WT but not cKO HFrEF mice., Conclusions: TFEB affects the baseline expression of metabolic and mitochondrial quality control genes in the heart, but has only minor effects on the metabolic shift in LVH and HFrEF in mice. Deletion of TFEB plays a protective role in HFrEF but does not affect the course of LVH. Further studies are needed to elucidate if TFEB affects the metabolic flux in stressed cardiomyocytes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Dörmann, Hammer, Struckmann, Rüdebusch, Bartels, Wenzel, Schulz, Gross, Schwanz, Martin, Fielitz, Pablo Tortola, Hahn, Benkner, Völker, Felix and Fielitz.)
Published: 2024
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34. Mammalian target of rapamycin inhibition impacts energy homeostasis and induces sex-specific body weight loss in humans.

Author: Mannaa M, Pfennigwerth P, Fielitz J, Gollasch M, and Boschmann M
Subjects: Male, Adult, Humans, Female, Everolimus pharmacology, Everolimus therapeutic use, Sirolimus pharmacology, Sirolimus therapeutic use, Body Weight, Weight Loss, TOR Serine-Threonine Kinases metabolism, Homeostasis, Glucose, Cachexia etiology, Polycystic Kidney, Autosomal Dominant complications
Abstract: Background: Previous data from a 2-year randomized controlled trial (CRAD001ADE12) indicated that mammalian target of rapamycin (mTOR) inhibition by everolimus slowed cyst growth in patients with autosomal-dominant polycystic kidney disease (ADPKD). During the trial, we noted body weight loss in some patients, particularly in women. We hypothesized that everolimus causes body weight reduction by reduced food intake and/or metabolic changes, which could lead to cachexia., Methods: Within a sub-analysis of the CRAD001ADE12 trial, body weight course was investigated regarding sex-specific differences in 433 adult ADPKD patients (everolimus, n = 215; placebo, n = 218). One hundred four out of 111 patients who participated in the clinical trial centre in Berlin were evaluated under everolimus/placebo therapy (on drug: everolimus, n = 48; placebo, n = 56) and after therapy (off drug: everolimus, n = 15; placebo, n = 18). Eating habits and nutrient/caloric intake were evaluated by validated questionnaires. Systemic and local metabolism was evaluated in four patients after an oral glucose load (OGL) by using calorimetry and adipose/muscle tissue microdialysis., Results: Within the 2-year CRAD001ADE12 trial, a significant body weight loss was observed in female patients on everolimus versus placebo (P = 0.0029). Data of the Berlin Cohort revealed that weight loss was greater in women on everolimus versus men (P < 0.01). After 9 months, women and men had lost 2.6 ± 3.8 and 0.8 ± 1.5 kg (P < 0.05) in body weight, respectively, and after 21 months, they had lost 4.1 ± 6.6 and 1.0 ± 3.3 kg (P < 0.05), respectively. On everolimus, caloric intake was significantly lower in women versus men (1510 ± 128 vs. 2264 ± 216 kcal/day, P < 0.05), caused mainly by a lower fat and protein intake in women versus men. Cognitive restraints, disinhibition and hunger remained unchanged. In a subgroup of patients resting metabolic rate was unchanged whereas OGL-induced thermogenesis was reduced (7 ± 2 vs. 11 ± 2 kcal, P < 0.05). Fasting and OGL-induced fat oxidation was increased (P < 0.05) on versus off everolimus. In adipose tissue, fasting lipolytic activity was increased, but lipolytic activity was inhibited similarly after the OGL on versus off everolimus, respectively. In skeletal muscle, postprandial glucose uptake and aerobic glycolysis was reduced in patients on everolimus., Conclusions: mTOR inhibition by everolimus induces body weight reduction, specifically in female patients. This effect is possibly caused by a centrally mediated reduced food (fat and protein) intake and by centrally/peripherally mediated increased fat oxidation (systemic) and mobilization (adipose tissue). Glucose uptake and oxidation might be reduced in skeletal muscle. This could lead to cachexia and, possibly, muscle wasting. Therefore, our results have important implications for patients recieving immune-suppressive mTOR inhibition therapy., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)
Published: 2023
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35. Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function.

Author: Zhu XX, Wang X, Jiao SY, Liu Y, Shi L, Xu Q, Wang JJ, Chen YE, Zhang Q, Song YT, Wei M, Yu BQ, Fielitz J, Gonzalez FJ, Du J, and Qu AJ
Subjects: Humans, Male, Mice, Animals, Myocytes, Cardiac metabolism, PPAR alpha metabolism, Lipopolysaccharides, Mitochondria metabolism, Mice, Knockout, Disease Models, Animal, Fatty Acids metabolism, Cardiomyopathies drug therapy, Cardiomyopathies prevention & control, Cardiomyopathies metabolism, Heart Diseases
Abstract: Clinically, cardiac dysfunction is a key component of sepsis-induced multi-organ failure. Mitochondria are essential for cardiomyocyte homeostasis, as disruption of mitochondrial dynamics enhances mitophagy and apoptosis. However, therapies targeted to improve mitochondrial function in septic patients have not been explored. Transcriptomic data analysis revealed that the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the heart was the most significantly decreased in the cecal ligation puncture-treated mouse heart model, and PPARα was the most notably decreased among the three PPAR family members. Male Ppara fl/fl (wild-type), cardiomyocyte-specific Ppara-deficient (Ppara ΔCM ), and myeloid-specific Ppara-deficient (Ppara ΔMac ) mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxic cardiac dysfunction. PPARα signaling was decreased in LPS-treated wild-type mouse hearts. To determine the cell type in which PPARα signaling was suppressed, the cell type-specific Ppara-null mice were examined. Cardiomyocyte- but not myeloid-specific Ppara deficiency resulted in exacerbated LPS-induced cardiac dysfunction. Ppara disruption in cardiomyocytes augmented mitochondrial dysfunction, as revealed by damaged mitochondria, lowered ATP contents, decreased mitochondrial complex activities, and increased DRP1/MFN1 protein levels. RNA sequencing results further showed that cardiomyocyte Ppara deficiency potentiated the impairment of fatty acid metabolism in LPS-treated heart tissue. Disruption of mitochondrial dynamics resulted in increased mitophagy and mitochondrial-dependent apoptosis in Ppara △CM mice. Moreover, mitochondrial dysfunction caused an increase of reactive oxygen species, leading to increased IL-6/STAT3/NF-κB signaling. 3-Methyladenine (3-MA, an autophagosome formation inhibitor) alleviated cardiomyocyte Ppara disruption-induced mitochondrial dysfunction and cardiomyopathy. Finally, pre-treatment with the PPARα agonist WY14643 lowered mitochondrial dysfunction-induced cardiomyopathy in hearts from LPS-treated mice. Thus, cardiomyocyte but not myeloid PPARα protects against septic cardiomyopathy by improving fatty acid metabolism and mitochondrial dysfunction, thus highlighting that cardiomyocyte PPARα may be a therapeutic target for the treatment of cardiac disease., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Published: 2023
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36. SPSB1-mediated inhibition of TGF-β receptor-II impairs myogenesis in inflammation.

Author: Li Y, Dörmann N, Brinschwitz B, Kny M, Martin E, Bartels K, Li N, Giri PV, Schwanz S, Boschmann M, Hille S, Fielitz B, Wollersheim T, Grunow J, Felix SB, Weber-Carstens S, Luft FC, Müller OJ, and Fielitz J
Subjects: Animals, Mice, Cytokines, Inflammation, Muscle Development, Muscle, Skeletal metabolism, Myogenin genetics, Transforming Growth Factor beta metabolism, Tumor Necrosis Factor-alpha, Interleukin-6, Proto-Oncogene Proteins c-akt
Abstract: Background: Sepsis-induced intensive care unit-acquired weakness (ICUAW) features profound muscle atrophy and attenuated muscle regeneration related to malfunctioning satellite cells. Transforming growth factor beta (TGF-β) is involved in both processes. We uncovered an increased expression of the TGF-β receptor II (TβRII)-inhibitor SPRY domain-containing and SOCS-box protein 1 (SPSB1) in skeletal muscle of septic mice. We hypothesized that SPSB1-mediated inhibition of TβRII signalling impairs myogenic differentiation in response to inflammation., Methods: We performed gene expression analyses in skeletal muscle of cecal ligation and puncture- (CLP) and sham-operated mice, as well as vastus lateralis of critically ill and control patients. Pro-inflammatory cytokines and specific pathway inhibitors were used to quantitate Spsb1 expression in myocytes. Retroviral expression plasmids were used to investigate the effects of SPSB1 on TGF-β/TβRII signalling and myogenesis in primary and immortalized myoblasts and differentiated myotubes. For mechanistical analyses we used coimmunoprecipitation, ubiquitination, protein half-life, and protein synthesis assays. Differentiation and fusion indices were determined by immunocytochemistry, and differentiation factors were quantified by qRT-PCR and Western blot analyses., Results: SPSB1 expression was increased in skeletal muscle of ICUAW patients and septic mice. Tumour necrosis factor (TNF), interleukin-1β (IL-1β), and IL-6 increased the Spsb1 expression in C2C12 myotubes. TNF- and IL-1β-induced Spsb1 expression was mediated by NF-κB, whereas IL-6 increased the Spsb1 expression via the glycoprotein 130/JAK2/STAT3 pathway. All cytokines reduced myogenic differentiation. SPSB1 avidly interacted with TβRII, resulting in TβRII ubiquitination and destabilization. SPSB1 impaired TβRII-Akt-Myogenin signalling and diminished protein synthesis in myocytes. Overexpression of SPSB1 decreased the expression of early (Myog, Mymk, Mymx) and late (Myh1, 3, 7) differentiation-markers. As a result, myoblast fusion and myogenic differentiation were impaired. These effects were mediated by the SPRY- and SOCS-box domains of SPSB1. Co-expression of SPSB1 with Akt or Myogenin reversed the inhibitory effects of SPSB1 on protein synthesis and myogenic differentiation. Downregulation of Spsb1 by AAV9-mediated shRNA attenuated muscle weight loss and atrophy gene expression in skeletal muscle of septic mice., Conclusions: Inflammatory cytokines via their respective signalling pathways cause an increase in SPSB1 expression in myocytes and attenuate myogenic differentiation. SPSB1-mediated inhibition of TβRII-Akt-Myogenin signalling and protein synthesis contributes to a disturbed myocyte homeostasis and myogenic differentiation that occurs during inflammation., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)
Published: 2023
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37. Longitudinal Clinical Features of Post-COVID-19 Patients-Symptoms, Fatigue and Physical Function at 3- and 6-Month Follow-Up.

Author: Steinmetz A, Gross S, Lehnert K, Lücker P, Friedrich N, Nauck M, Bahlmann S, Fielitz J, and Dörr M
Abstract: Post-COVID-19 syndrome (PCS) has been described as 'the pandemic after the pandemic' with more than 65 million people worldwide being affected. The enormous range of symptoms makes both diagnosis complex and treatment difficult. In a post-COVID rehabilitation outpatient clinic, 184 patients, mostly non-hospitalized, received a comprehensive, interdisciplinary diagnostic assessment with fixed follow-up appointments. At baseline, three in four patients reported more than 10 symptoms, the most frequent symptoms were fatigue (84.9%), decreased physical capacity (83.0%), tiredness (81.1%), poor concentration (73.6%), sleeping problems (66.7%) and shortness of breath (67.3%). Abnormalities were found in the mean values of scores for fatigue (FAS = 34.3), cognition (MoCA = 25.5), psychological alterations (anxiety, depression, post-traumatic stress disorder), limitation of lung function (CAT) and severity scores for PCS (PCFS, MCRS). Clinical abnormalities were found in elevated values of heart rate, breathing rate at rest, blood pressure and NT-proBNP levels. As the frequency of the described symptoms decreases only slowly but most often significantly over the course, it is important to monitor the patients over a longer period of time. Many of them suffer from an immense symptom burden, often without pre-existing clinical correlates. Our results show a clear association with objectifiable assessments and tests as well as pronounced symptoms.
Published: 2023
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38. The Greifswald Post COVID Rehabilitation Study and Research (PoCoRe)-Study Design, Characteristics and Evaluation Tools.

Author: Steinmetz A, Bahlmann S, Bergelt C, Bröker BM, Ewert R, Felix SB, Flöel A, Fleischmann R, Hoffmann W, Holtfreter S, Nauck M, Riemann K, Scheer C, Stahl D, Vogelgesang A, Völker U, Wiesmann U, Klinger-König J, Walk R, Grabe HJ, Gross S, Lehnert K, Fielitz J, and Dörr M
Abstract: (1) Background: COVID-19 is often associated with significant long-term symptoms and disability, i.e., the long/post-COVID syndrome (PCS). Even after presumably mild COVID-19 infections, an increasing number of patients seek medical help for these long-term sequelae, which can affect various organ systems. The pathogenesis of PCS is not yet understood. Therapy has so far been limited to symptomatic treatment. The Greifswald Post COVID Rehabilitation Study (PoCoRe) aims to follow and deeply phenotype outpatients with PCS in the long term, taking a holistic and comprehensive approach to the analysis of their symptoms, signs and biomarkers. (2) Methods: Post-COVID outpatients are screened for symptoms in different organ systems with a standardized medical history, clinical examination, various questionnaires as well as physical and cardiopulmonary function tests. In addition, biomaterials are collected for the analysis of immunomodulators, cytokines, chemokines, proteome patterns as well as specific (auto)antibodies. Patients are treated according to their individual needs, adhering to the current standard of care. PoCoRe's overall aim is to optimize diagnostics and therapy in PCS patients.
Published: 2023
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39. Riociguat attenuates the changes in left ventricular proteome and microRNA profile after experimental aortic stenosis in mice.

Author: Benkner A, Rüdebusch J, Nath N, Hammer E, Grube K, Gross S, Dhople VM, Eckstein G, Meitinger T, Kaderali L, Völker U, Fielitz J, and Felix SB
Subjects: Animals, Disease Models, Animal, Heart Ventricles, Male, Mice, Mice, Inbred C57BL, Proteome, Pyrazoles, Pyrimidines, Ventricular Remodeling, Aortic Valve Stenosis, Heart Failure drug therapy, MicroRNAs
Abstract: Background and Purpose: Development and progression of heart failure involve endothelial and myocardial dysfunction as well as a dysregulation of the NO-sGC-cGMP signalling pathway. Recently, we reported that the sGC stimulator riociguat has beneficial effects on cardiac remodelling and progression of heart failure in response to chronic pressure overload. Here, we examined if these beneficial effects of riociguat were also reflected in alterations of the myocardial proteome and microRNA profiles., Experimental Approach: Male C57BL/6N mice underwent transverse aortic constriction (TAC) and sham-operated mice served as controls. TAC and sham animals were randomised and treated with either riociguat or vehicle for 5 weeks, starting 3 weeks after surgery, when cardiac hypertrophy was established. Afterwards, we performed mass spectrometric proteome analyses and microRNA sequencing of proteins and RNAs, respectively, isolated from left ventricles (LVs)., Key Results: TAC-induced changes of the LV proteome were significantly reduced by treatment with riociguat. Bioinformatics analyses revealed that riociguat improved TAC-induced cardiovascular disease-related pathways, metabolism and energy production, for example, reversed alterations in the levels of myosin heavy chain 7, cardiac phospholamban and ankyrin repeat domain-containing protein 1. Riociguat also attenuated TAC-induced changes of microRNA levels in the LV., Conclusion and Implications: The sGC stimulator riociguat exerted beneficial effects on cardiac structure and function during pressure overload, which was accompanied by a reversal of TAC-induced changes of the cardiac proteome and microRNA profile. Our data support the potential of riociguat as a novel therapeutic agent for heart failure., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Published: 2022
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40. High-Mobility Group Box Protein 1 Is an Independent Prognostic Marker for All-Cause Mortality in Patients With Dilated Cardiomyopathy.

Author: Kümmel A, Gross S, Feldtmann R, Chamling B, Strohbach A, Lehnert K, Bahls M, Loerzer L, Moormann K, Witte J, Riad A, Dörr M, Fielitz J, and Felix SB
Subjects: Biomarkers, Female, Humans, Middle Aged, Natriuretic Peptide, Brain, Peptide Fragments, Prognosis, Proportional Hazards Models, Cardiomyopathy, Dilated complications, HMGB1 Protein
Abstract: High-mobility group box protein 1 (HMGB1) is released during tissue damage and activates the innate immune system through toll-like receptor 4. Because mortality in dilated cardiomyopathy (DCM) is associated with activation of the innate immune system, we hypothesized that HMGB1 possesses a prognostic value in estimating mortality in patients with DCM. We determined HMGB1 and N-terminal B-type natriuretic peptide (NT-proBNP) levels in 67 patients with DCM (12 women, mean age 53.6 ± 1.5 years). Kaplan-Meier analyzes revealed that higher levels of HMGB1 and NT-proBNP are related to increased all-cause mortality. Multivariable Cox regression confirmed HMGB1 as a risk factor for mortality in patients with DCM, independent of NT-proBNP, age, and gender (hazard ratio per 1 SD 1.920, 95% confidence interval 1.401 to 2.631, p <0.001). HMGB1 is a promising candidate to estimate the prognosis of patients with DCM., (Copyright © 2022 Elsevier Inc. All rights reserved.)
Published: 2022
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41. Myeloid differentiation factor-2 activates monocytes in patients with dilated cardiomyopathy.

Author: Feldtmann R, Kümmel A, Chamling B, Strohbach A, Lehnert K, Gross S, Loerzer L, Riad A, Lindner D, Westermann D, Fielitz J, Dörr M, and Felix SB
Subjects: Animals, Endothelial Cells metabolism, Humans, Inflammation metabolism, Lipopolysaccharides pharmacology, Mice, Monocytes metabolism, Myeloid Differentiation Factor 88 metabolism, NF-kappa B metabolism, Toll-Like Receptor 4 metabolism, Cardiomyopathy, Dilated metabolism, Lymphocyte Antigen 96 metabolism
Abstract: Plasma levels of myeloid differentiation factor-2 (MD-2), a co-receptor of toll-like-receptor 4 (TLR4), independently predict mortality in patients with dilated cardiomyopathy (DCM). We tested whether monocyte activation by MD-2 contributes to immune activation and inflammatory status in DCM patients. We found increased MD-2 plasma levels in 25 patients with recent-onset DCM (1250 ± 80.7 ng/ml) compared to 25 age- and gender-matched healthy controls (793.4 ± 52.0 ng/ml; p < 0.001). Monocytes isolated from DCM patients showed a higher expression (141.7 ± 12.4%; p = 0.006 vs. controls) of the MD-2 encoding gene, LY96 and an increased NF-κB-activation. Further, the TLR4-activator lipopolysaccharide (LPS) caused a higher increase in interleukin (IL)-6 in monocytes from DCM patients compared to controls (mean fluorescence intensity: 938.7 ± 151.0 vs. 466.9 ± 51.1; p = 0.005). MD-2 increased IL-6 secretion in a TLR4/NF-κB-dependent manner in monocyte-like THP-1-cells as demonstrated by TLR4-siRNA and NF-κB-inhibition. Since endothelial cells (ECs) are responsible for recruiting monocytes to the site of inflammation, ECs were treated with MD-2 leading to an activation of Akt and increased secretion of monocyte-chemoattractant-protein-1 (MCP-1). Activation of ECs by MD-2 was accompanied by an increased expression of the adhesion molecules CD54, CD106 and CD62E, resulting in an increased monocyte recruitment, which was attenuated by CD54 inhibition. In addition, in murine WT but not LY96-KO bone marrow-derived macrophages LPS increased the amount of CD54 and CD49d/CD29. MD-2 facilitates a pro-inflammatory status of monocytes and EC-mediated monocyte recruitment via TLR4/NF-κB. Elevated MD-2 plasma levels are possibly involved in monocyte-related inflammation-promoting disease progression in DCM. Our results suggest that MD-2 contributes to increasing monocytic inflammatory activity and triggers the recruitment of monocytes to ECs in DCM., (© 2022 The Authors. Immunology published by John Wiley & Sons Ltd.)
Published: 2022
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42. Muscular myostatin gene expression and plasma concentrations are decreased in critically ill patients.

Author: Grunow JJ, Reiher K, Carbon NM, Engelhardt LJ, Mai K, Koch S, Schefold JC, Z'Graggen W, Schaller SJ, Fielitz J, Spranger J, Weber-Carstens S, and Wollersheim T
Subjects: Gene Expression, Humans, Muscle, Skeletal metabolism, Muscular Atrophy, Prospective Studies, Retrospective Studies, Critical Illness, Myostatin genetics, Myostatin metabolism
Abstract: Background: The objective was to investigate the role of gene expression and plasma levels of the muscular protein myostatin in intensive care unit-acquired weakness (ICUAW). This was performed to evaluate a potential clinical and/or pathophysiological rationale of therapeutic myostatin inhibition., Methods: A retrospective analysis from pooled data of two prospective studies to assess the dynamics of myostatin plasma concentrations (day 4, 8 and 14) and myostatin gene (MSTN) expression levels in skeletal muscle (day 15) was performed. Associations of myostatin to clinical and electrophysiological outcomes, muscular metabolism and muscular atrophy pathways were investigated., Results: MSTN gene expression (median [IQR] fold change: 1.00 [0.68-1.54] vs. 0.26 [0.11-0.80]; p = 0.004) and myostatin plasma concentrations were significantly reduced in all critically ill patients when compared to healthy controls. In critically ill patients, myostatin plasma concentrations increased over time (median [IQR] fold change: day 4: 0.13 [0.08/0.21] vs. day 8: 0.23 [0.10/0.43] vs. day 14: 0.40 [0.26/0.61]; p < 0.001). Patients with ICUAW versus without ICUAW showed significantly lower MSTN gene expression levels (median [IQR] fold change: 0.17 [0.10/0.33] and 0.51 [0.20/0.86]; p = 0.047). Myostatin levels were directly correlated with muscle strength (correlation coefficient 0.339; p = 0.020) and insulin sensitivity index (correlation coefficient 0.357; p = 0.015). No association was observed between myostatin plasma concentrations as well as MSTN expression levels and levels of mobilization, electrophysiological variables, or markers of atrophy pathways., Conclusion: Muscular gene expression and systemic protein levels of myostatin are downregulated during critical illness. The previously proposed therapeutic inhibition of myostatin does therefore not seem to have a pathophysiological rationale to improve muscle quality in critically ill patients., Trial Registration: ISRCTN77569430 -13th of February 2008 and ISRCTN19392591 17th of February 2011., (© 2022. The Author(s).)
Published: 2022
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43. Stimulation of soluble guanylyl cyclase (sGC) by riociguat attenuates heart failure and pathological cardiac remodelling.

Author: Rüdebusch J, Benkner A, Nath N, Fleuch L, Kaderali L, Grube K, Klingel K, Eckstein G, Meitinger T, Fielitz J, and Felix SB
Subjects: Animals, Cyclic GMP metabolism, Mice, Mice, Inbred C57BL, Pyrazoles, Pyrimidines, Soluble Guanylyl Cyclase, Heart Failure pathology, Ventricular Remodeling
Abstract: Background and Purpose: Heart failure is associated with an impaired NO-soluble guanylyl cyclase (sGC)-cGMP pathway and its augmentation is thought to be beneficial for its therapy. We hypothesized that stimulation of sGC by the sGC stimulator riociguat prevents pathological cardiac remodelling and heart failure in response to chronic pressure overload., Experimental Approach: Transverse aortic constriction or sham surgery was performed in C57BL/6N mice. After 3 weeks of transverse aortic constriction when heart failure was established, animals receive either riociguat or its vehicle for 5 additional weeks. Cardiac function was evaluated weekly by echocardiography. Eight weeks after surgery, histological analyses were performed to evaluate remodelling and the transcriptome of the left ventricles (LVs) was analysed by RNA sequencing. Cell culture experiments were used for mechanistically studies., Key Results: Transverse aortic constriction resulted in a continuous decrease of LV ejection fraction and an increase in LV mass until week 3. Five weeks of riociguat treatment resulted in an improved LV ejection fraction and a decrease in the ratio of left ventricular mass to total body weight (LVM/BW), myocardial fibrosis and myocyte cross-sectional area. RNA sequencing revealed that riociguat reduced the expression of myocardial stress and remodelling genes (e.g. Nppa, Nppb, Myh7 and collagen) and attenuated the activation of biological pathways associated with cardiac hypertrophy and heart failure. Riociguat reversed pathological stress response in cultivated myocytes and fibroblasts., Conclusion and Implications: Stimulation of the sGC reverses transverse aortic constriction-induced heart failure and remodelling, which is associated with improved myocardial gene expression., Linked Articles: This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc., (© 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Published: 2022
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44. The Transcription Factor EB (TFEB) Sensitizes the Heart to Chronic Pressure Overload.

Author: Wundersitz S, Pablo Tortola C, Schmidt S, Oliveira Vidal R, Kny M, Hahn A, Zanders L, Katus HA, Sauer S, Butter C, Luft FC, Müller OJ, and Fielitz J
Subjects: Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Disease Models, Animal, Echocardiography, Hypertrophy, Left Ventricular pathology, Male, Mice, Mice, Inbred C57BL, Myocytes, Cardiac metabolism, Ventricular Remodeling, Heart Failure metabolism, Ventricular Dysfunction, Left metabolism
Abstract: The transcription factor EB (TFEB) promotes protein degradation by the autophagy and lysosomal pathway (ALP) and overexpression of TFEB was suggested for the treatment of ALP-related diseases that often affect the heart. However, TFEB-mediated ALP induction may perturb cardiac stress response. We used adeno-associated viral vectors type 9 (AAV9) to overexpress TFEB (AAV9-Tfeb) or Luciferase-control (AAV9-Luc) in cardiomyocytes of 12-week-old male mice. Mice were subjected to transverse aortic constriction (TAC, 27G; AAV9-Luc: n = 9; AAV9-Tfeb: n = 14) or sham (AAV9-Luc: n = 9; AAV9-Tfeb: n = 9) surgery for 28 days. Heart morphology, echocardiography, gene expression, and protein levels were monitored. AAV9-Tfeb had no effect on cardiac structure and function in sham animals. TAC resulted in compensated left ventricular hypertrophy in AAV9-Luc mice. AAV9-Tfeb TAC mice showed a reduced LV ejection fraction and increased left ventricular diameters. Morphological, histological, and real-time PCR analyses showed increased heart weights, exaggerated fibrosis, and higher expression of stress markers and remodeling genes in AAV9-Tfeb TAC compared to AAV9-Luc TAC. RNA-sequencing, real-time PCR and Western Blot revealed a stronger ALP activation in the hearts of AAV9-Tfeb TAC mice. Cardiomyocyte-specific TFEB-overexpression promoted ALP gene expression during TAC, which was associated with heart failure. Treatment of ALP-related diseases by overexpression of TFEB warrants careful consideration.
Published: 2022
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45. Hidden Agenda - The Involvement of Endoplasmic Reticulum Stress and Unfolded Protein Response in Inflammation-Induced Muscle Wasting.

Author: Kny M and Fielitz J
Subjects: Humans, Inflammation metabolism, Muscle, Skeletal pathology, Muscular Atrophy etiology, Unfolded Protein Response, Endoplasmic Reticulum Stress physiology, Muscular Diseases
Abstract: Critically ill patients at the intensive care unit (ICU) often develop a generalized weakness, called ICU-acquired weakness (ICUAW). A major contributor to ICUAW is muscle atrophy, a loss of skeletal muscle mass and function. Skeletal muscle assures almost all of the vital functions of our body. It adapts rapidly in response to physiological as well as pathological stress, such as inactivity, immobilization, and inflammation. In response to a reduced workload or inflammation muscle atrophy develops. Recent work suggests that adaptive or maladaptive processes in the endoplasmic reticulum (ER), also known as sarcoplasmic reticulum, contributes to this process. In muscle cells, the ER is a highly specialized cellular organelle that assures calcium homeostasis and therefore muscle contraction. The ER also assures correct folding of proteins that are secreted or localized to the cell membrane. Protein folding is a highly error prone process and accumulation of misfolded or unfolded proteins can cause ER stress, which is counteracted by the activation of a signaling network known as the unfolded protein response (UPR). Three ER membrane residing molecules, protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1a (IRE1a), and activating transcription factor 6 (ATF6) initiate the UPR. The UPR aims to restore ER homeostasis by reducing overall protein synthesis and increasing gene expression of various ER chaperone proteins. If ER stress persists or cannot be resolved cell death pathways are activated. Although, ER stress-induced UPR pathways are known to be important for regulation of skeletal muscle mass and function as well as for inflammation and immune response its function in ICUAW is still elusive. Given recent advances in the development of ER stress modifying molecules for neurodegenerative diseases and cancer, it is important to know whether or not therapeutic interventions in ER stress pathways have favorable effects and these compounds can be used to prevent or treat ICUAW. In this review, we focus on the role of ER stress-induced UPR in skeletal muscle during critical illness and in response to predisposing risk factors such as immobilization, starvation and inflammation as well as ICUAW treatment to foster research for this devastating clinical problem., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kny and Fielitz.)
Published: 2022
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46. Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting.

Author: Zanders L, Kny M, Hahn A, Schmidt S, Wundersitz S, Todiras M, Lahmann I, Bandyopadhyay A, Wollersheim T, Kaderali L, Luft FC, Birchmeier C, Weber-Carstens S, and Fielitz J
Subjects: Animals, Humans, Mice, Muscle, Skeletal physiopathology, Cytokine Receptor gp130 genetics, Cytokine Receptor gp130 metabolism, Interleukin-6 genetics, Interleukin-6 metabolism, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Muscular Atrophy etiology, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Sepsis complications, Sepsis metabolism
Abstract: Background: Sepsis and inflammation can cause intensive care unit-acquired weakness (ICUAW). Increased interleukin-6 (IL-6) plasma levels are a risk factor for ICUAW. IL-6 signalling involves the glycoprotein 130 (gp130) receptor and the JAK/STAT-pathway, but its role in sepsis-induced muscle wasting is uncertain. In a clinical observational study, we found that the IL-6 target gene, SOCS3, was increased in skeletal muscle of ICUAW patients indicative for JAK/STAT-pathway activation. We tested the hypothesis that the IL-6/gp130-pathway mediates ICUAW muscle atrophy., Methods: We sequenced RNA (RNAseq) from tibialis anterior (TA) muscle of cecal ligation and puncture-operated (CLP) and sham-operated wildtype (WT) mice. The effects of the IL-6/gp130/JAK2/STAT3-pathway were investigated by analysing the atrophy phenotype, gene expression, and protein contents of C2C12 myotubes. Mice lacking Il6st, encoding gp130, in myocytes (cKO) and WT controls, as well as mice treated with the JAK2 inhibitor AG490 or vehicle were exposed to CLP or sham surgery for 24 or 96 h., Results: Analyses of differentially expressed genes in RNAseq (≥2-log2-fold change, P < 0.01) revealed an activation of IL-6-signalling and JAK/STAT-signalling pathways in muscle of septic mice, which occurred after 24 h and lasted at least for 96 h during sepsis. IL-6 treatment of C2C12 myotubes induced STAT3 phosphorylation (three-fold, P < 0.01) and Socs3 mRNA expression (3.1-fold, P < 0.01) and caused myotube atrophy. Knockdown of Il6st diminished IL-6-induced STAT3 phosphorylation (-30.0%; P < 0.01), Socs3 mRNA expression, and myotube atrophy. JAK2 (- 29.0%; P < 0.01) or STAT3 inhibition (-38.7%; P < 0.05) decreased IL-6-induced Socs3 mRNA expression. Treatment with either inhibitor attenuated myotube atrophy in response to IL-6. CLP-operated septic mice showed an increased STAT3 phosphorylation and Socs3 mRNA expression in TA muscle, which was reduced in septic Il6st-cKO mice by 67.8% (P < 0.05) and 85.6% (P < 0.001), respectively. CLP caused a loss of TA muscle weight, which was attenuated in Il6st-cKO mice (WT: -22.3%, P < 0.001, cKO: -13.5%, P < 0.001; WT vs. cKO P < 0.001). While loss of Il6st resulted in a reduction of MuRF1 protein contents, Atrogin-1 remained unchanged between septic WT and cKO mice. mRNA expression of Trim63/MuRF1 and Fbxo32/Atrogin-1 were unaltered between CLP-treated WT and cKO mice. AG490 treatment reduced STAT3 phosphorylation (-22.2%, P < 0.05) and attenuated TA muscle atrophy in septic mice (29.6% relative reduction of muscle weight loss, P < 0.05). The reduction in muscle atrophy was accompanied by a reduction in Fbxo32/Atrogin-1-mRNA (-81.3%, P < 0.05) and Trim63/MuRF1-mRNA expression (-77.6%, P < 0.05) and protein content., Conclusions: IL-6 via the gp130/JAK2/STAT3-pathway mediates sepsis-induced muscle atrophy possibly contributing to ICUAW., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)
Published: 2022
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47. Skeletal muscle derived Musclin protects the heart during pathological overload.

Author: Szaroszyk M, Kattih B, Martin-Garrido A, Trogisch FA, Dittrich GM, Grund A, Abouissa A, Derlin K, Meier M, Holler T, Korf-Klingebiel M, Völker K, Garfias Macedo T, Pablo Tortola C, Boschmann M, Huang N, Froese N, Zwadlo C, Malek Mohammadi M, Luo X, Wagner M, Cordero J, Geffers R, Batkai S, Thum T, Bork N, Nikolaev VO, Müller OJ, Katus HA, El-Armouche A, Kraft T, Springer J, Dobreva G, Wollert KC, Fielitz J, von Haehling S, Kuhn M, Bauersachs J, and Heineke J
Subjects: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase genetics, 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase metabolism, Aged, Aged, 80 and over, Animals, Cachexia metabolism, Cachexia physiopathology, Cachexia prevention & control, Case-Control Studies, Cyclic AMP-Dependent Protein Kinases genetics, Cyclic AMP-Dependent Protein Kinases metabolism, Cyclic GMP-Dependent Protein Kinases genetics, Cyclic GMP-Dependent Protein Kinases metabolism, Disease Models, Animal, Endomyocardial Fibrosis metabolism, Endomyocardial Fibrosis physiopathology, Endomyocardial Fibrosis prevention & control, Female, Gene Expression Regulation, Heart Failure metabolism, Heart Failure physiopathology, Heart Failure prevention & control, Heart Function Tests, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle Proteins agonists, Muscle Proteins antagonists & inhibitors, Muscle Proteins deficiency, Muscular Atrophy metabolism, Muscular Atrophy physiopathology, Muscular Atrophy prevention & control, Myocardium metabolism, Myocardium pathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, Transcription Factors agonists, Transcription Factors antagonists & inhibitors, Transcription Factors deficiency, Cachexia genetics, Endomyocardial Fibrosis genetics, Heart Failure genetics, Muscle Proteins genetics, Muscle, Skeletal metabolism, Muscular Atrophy genetics, Transcription Factors genetics
Abstract: Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy., (© 2022. The Author(s).)
Published: 2022
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48. Physical Performance and Non-Esterified Fatty Acids in Men and Women after Transcatheter Aortic Valve Implantation (TAVI).

Author: Härdrich M, Haase-Fielitz A, Fielitz J, Boschmann M, Pivovarova-Ramich O, Pfeiffer AFH, Rudovich N, Weylandt KH, and Butter C
Subjects: Aged, Aged, 80 and over, Aortic Valve Stenosis surgery, Bicycling, Body Mass Index, Female, Humans, Male, Prospective Studies, Reference Values, Risk Factors, Sex Factors, Treatment Outcome, Walking, Biomarkers blood, Fatty Acids, Nonesterified blood, Physical Functional Performance, Transcatheter Aortic Valve Replacement
Abstract: Background: Men and women with valvular heart disease have different risk profiles for clinical endpoints. Non-esterified fatty acids (NEFA) are possibly involved in cardio-metabolic disease. However, it is unclear whether NEFA concentrations are associated with physical performance in patients undergoing transcatheter aortic valve implantation (TAVI) and whether there are sex-specific effects., Methods: To test the hypothesis that NEFA concentration is associated with sex-specific physical performance, we prospectively analysed data from one hundred adult patients undergoing TAVI. NEFA concentrations, physical performance and anthropometric parameters were measured before and 6 and 12 months after TAVI. Physical performance was determined by a six-minute walking test (6-MWT) and self-reported weekly bicycle riding time., Results: Before TAVI, NEFA concentrations were higher in patients (44 women, 56 men) compared to the normal population. Median NEFA concentrations at 6 and 12 months after TAVI were within the reference range reported in the normal population in men but not women. Men but not women presented with an increased performance in the 6-MWT over time ( p = 0.026, p = 0.142, respectively). Additionally, men showed an increased ability to ride a bicycle after TAVI compared to before TAVI ( p = 0.034). NEFA concentrations before TAVI correlated with the 6-MWT before TAVI in women (Spearman's rho -0.552; p = 0.001) but not in men (Spearman's rho -0.007; p = 0.964). No association was found between NEFA concentrations and physical performance 6 and 12 months after TAVI., Conclusions: NEFA concentrations improved into the reference range in men but not women after TAVI. Men but not women have an increased physical performance after TAVI. No association between NEFA and physical performance was observed in men and women after TAVI.
Published: 2022
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49. Muscle Mass and Inflammation in Older Adults: Impact of the Metabolic Syndrome.

Author: Buchmann N, Fielitz J, Spira D, König M, Norman K, Pawelec G, Goldeck D, Demuth I, and Steinhagen-Thiessen E
Subjects: Absorptiometry, Photon, Aged, Body Composition, C-Reactive Protein metabolism, Cross-Sectional Studies, Female, Humans, Inflammation complications, Inflammation metabolism, Interleukin-10 metabolism, Interleukin-6 metabolism, Male, Muscles metabolism, Metabolic Syndrome complications, Metabolic Syndrome epidemiology, Metabolic Syndrome metabolism, Sarcopenia complications, Sarcopenia epidemiology
Abstract: Background: Inflammatory processes are a cause of accelerated loss of muscle mass. Metabolic syndrome (MetS) is a highly prevalent age-related condition, which may promote and be promoted by inflammation. However, whether inflammation in MetS (metaflammation) is associated with lower muscle mass is still unclear., Methods: Complete cross-sectional data on body composition, MetS, and the inflammatory markers interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF), and C-reactive protein (CRP) were available for 1,377 BASE-II participants (51.1% women; 68 ± 4 years old). Appendicular lean mass (ALM) was assessed by dual-energy X-ray absorptiometry. Low muscle mass (low ALM-to-BMI ratio [ALMBMI]) was defined according to the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project. Regression models, adjusted for an increasing number of confounders (sex, age, physical activity, morbidities, diabetes mellitus type II, TSH, albumin, HbA1c, smoking habits, alcohol intake, education, and energy intake/day), were used to calculate the association between low ALMBMI and high inflammation (tertile 3) according to MetS., Results: MetS was present in 36.2% of the study population, and 9% had low ALMBMI. In the whole study population, high CRP (odds ratio [OR]: 2.7 [95% CI: 1.6-4.7; p = 0.001]) and high IL-6 (OR: 2.1 [95% CI: 1.2-1.9; p = 0.005]) were associated with low ALMBMI. In contrast, no significant association was found between TNF, IL-10, or IL-1β with low ALMBMI. When participants were stratified by MetS, results for IL-6 remained significant only in participants with MetS., Conclusions: Among BASE-II participants, low ALMBMI was associated with inflammation. Low-grade inflammation triggered by disease state, especially in the context of MetS, might favor loss of muscle mass, so a better control of MetS might help to prevent sarcopenia. Intervention studies to test whether strategies to prevent MetS might also prevent loss of muscle mass seem to be promising., (© 2022 The Author(s). Published by S. Karger AG, Basel.)
Published: 2022
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50. Inhibition of the NLRP3/IL-1β axis protects against sepsis-induced cardiomyopathy.

Author: Busch K, Kny M, Huang N, Klassert TE, Stock M, Hahn A, Graeger S, Todiras M, Schmidt S, Chamling B, Willenbrock M, Groß S, Biedenweg D, Heuser A, Scheidereit C, Butter C, Felix SB, Otto O, Luft FC, Slevogt H, and Fielitz J
Subjects: Animals, Humans, Inflammasomes, Interleukin-1beta, Male, Mice, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Rats, Cardiomyopathies etiology, Sepsis complications
Abstract: Background: Septic cardiomyopathy worsens the prognosis of critically ill patients. Clinical data suggest that interleukin-1β (IL-1β), activated by the NLRP3 inflammasome, compromises cardiac function. Whether or not deleting Nlrp3 would prevent cardiac atrophy and improve diastolic cardiac function in sepsis was unclear. Here, we investigated the role of NLRP3/IL-1β in sepsis-induced cardiomyopathy and cardiac atrophy., Methods: Male Nlrp3 knockout (KO) and wild-type (WT) mice were exposed to polymicrobial sepsis by caecal ligation and puncture (CLP) surgery (KO, n = 27; WT, n = 33) to induce septic cardiomyopathy. Sham-treated mice served as controls (KO, n = 11; WT, n = 16). Heart weights and morphology, echocardiography and analyses of gene and protein expression were used to evaluate septic cardiomyopathy and cardiac atrophy. IL-1β effects on primary and immortalized cardiomyocytes were investigated by morphological and molecular analyses. IonOptix and real-time deformability cytometry (RT-DC) analysis were used to investigate functional and mechanical effects of IL-1β on cardiomyocytes., Results: Heart morphology and echocardiography revealed preserved systolic (stroke volume: WT sham vs. WT CLP: 33.1 ± 7.2 μL vs. 24.6 ± 8.7 μL, P < 0.05; KO sham vs. KO CLP: 28.3 ± 8.1 μL vs. 29.9 ± 9.9 μL, n.s.; P < 0.05 vs. WT CLP) and diastolic (peak E wave velocity: WT sham vs. WT CLP: 750 ± 132 vs. 522 ± 200 mm/s, P < 0.001; KO sham vs. KO CLP: 709 ± 152 vs. 639 ± 165 mm/s, n.s.; P < 0.05 vs. WT CLP) cardiac function and attenuated cardiac (heart weight-tibia length ratio: WT CLP vs. WT sham: -26.6%, P < 0.05; KO CLP vs. KO sham: -3.3%, n.s.; P < 0.05 vs. WT CLP) and cardiomyocyte atrophy in KO mice during sepsis. IonOptix measurements showed that IL-1β decreased contractility (cell shortening: IL-1β: -15.4 ± 2.3%, P < 0.001 vs. vehicle, IL-1RA: -6.1 ± 3.3%, P < 0.05 vs. IL-1β) and relaxation of adult rat ventricular cardiomyocytes (time-to-50% relengthening: IL-1β: 2071 ± 225 ms, P < 0.001 vs. vehicle, IL-1RA: 564 ± 247 ms, P < 0.001 vs. IL-1β), which was attenuated by an IL-1 receptor antagonist (IL-1RA). RT-DC analysis indicated that IL-1β reduced cardiomyocyte size (P < 0.001) and deformation (P < 0.05). RNA sequencing showed that genes involved in NF-κB signalling, autophagy and lysosomal protein degradation were enriched in hearts of septic WT but not in septic KO mice. Western blotting and qPCR disclosed that IL-1β activated NF-κB and its target genes, caused atrophy and decreased myosin protein in myocytes, which was accompanied by an increased autophagy gene expression. These effects were attenuated by IL-1RA., Conclusions: IL-1β causes atrophy, impairs contractility and relaxation and decreases deformation of cardiomyocytes. Because NLRP3/IL-1β pathway inhibition attenuates cardiac atrophy and cardiomyopathy in sepsis, it could be useful to prevent septic cardiomyopathy., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)
Published: 2021
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