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2. Scanning the solutions for the sustainable supply of forest ecosystem services in Europe

Author

Hernández-Morcillo, M., Torralba, M., Baiges, T., Bernasconi, A., Bottaro, G., Brogaard, S., Bussola, F., Díaz-Varela, Emilio Rafael, Geneletti, D., Grossmann, C. M., Kister, J., Klingler, M., Loft, L., Lovric, M., Mann, C., Pipart, N., Roces-Díaz, José V., Sorge, S., Tiebel, M., Tyrväinen, L., Varela, E., Winkel, G., Plieninger, T., Hernández-Morcillo, M., Torralba, M., Baiges, T., Bernasconi, A., Bottaro, G., Brogaard, S., Bussola, F., Díaz-Varela, Emilio Rafael, Geneletti, D., Grossmann, C. M., Kister, J., Klingler, M., Loft, L., Lovric, M., Mann, C., Pipart, N., Roces-Díaz, José V., Sorge, S., Tiebel, M., Tyrväinen, L., Varela, E., Winkel, G., and Plieninger, T.

Abstract

Forests are key components of European multifunctional landscapes and supply numerous forest ecosystem services (FES) fundamental to human well-being. The sustainable provision of FES has the potential to provide responses to major societal challenges, such as climate change, biodiversity loss, or rural development. To identify suitable strategies for the future sustenance of FES, we performed a solution scanning exercise with a group of transdisciplinary forest and FES experts from different European regions. We identified and prioritized fifteen major challenges hindering the balanced provision of multiple FES and identified a series of potential solutions to tackle each of them. The most prominent challenges referred to the increased frequency and impacts of extreme weather events and the normative mindset regarding forest management. The respective solutions pointed to the promotion of forest resilience via climate-smart forestry and mainstreaming FES-oriented management through a threefold strategy focusing on education, awareness raising, and networking. In a subsequent survey, most solutions were assessed as highly effective, transferable, monitorable, and with potential for being economically efficient. The implementation of the solutions could have synergistic effects when applying the notion of leverage points. Seven emerging pathways towards the sustainable supply of FES have been identified. These pathways build on each other and are organized based on their potential for transformation: (1) shifting forest management paradigms towards pluralistic ecosystem valuation; (2) using integrated landscape approaches; (3) increasing forest resilience; (4) coordinating actions between forest-related actors; (5) increasing participation in forest planning and management; (6) continuous, open, and transparent knowledge integration; and (7) using incentive-based instruments to support regulating and cultural FES. These pathways can contribute to the implementation o

Published
2022

3. Intravenous NPA for the treatment of infarcting myocardium early; InTIME-II, a double-blind comparison of single-bolus lanoteplase vs accelerated alteplase for the treatment of patients with acute myocardial infarction

Author

Braunwald, E., Neuhaus, K. -L., Antman, E., Chew, P., Skene, A., Wilcox, R., Ambrosioni, E., Anderson, J., Apetrei, E., Bata, I., Carrageta, M., Col, J., Dalby, A., Davies, R., Deckers, J., Eichman, D., Grande, P., Greene, R., Gurfinkel, E., Heikkilä, J., Henry, T., Hillis, D., Hochman, J., Huber, K., Kostis, J., Klinke, P., López-Sendón, J., Mckendall, G., Móller, B., Moore, P., Morris, A., Mueller, H., Östör, E., Oto, A., Ruda, M., Sadowski, Z., Schweiger, M., Sequeira, R., Shah, P., Shannon, R., Smith, B., Sobel, B., Steingart, R., Tebbe, U., Toman, J., Traboulsi, M., Vahanian, A., Warnica, J. W., Willerson, J., Deitchman, D., Davidson, L., Folgia, T., Foxley, A., Goodman, J., Hauck, C., Henry, D., Mccabe, C., Pangerl, A., Thomson, A., Wagner, M., Kennedy, J. W., Cairns, J., Demets, D., Julian, D., Simoons, M., Charlesworth, A., Easton, J. D., Ferbert, A., Feske, S., Kuhn, P., Moseley, J., Rogg, J. M., Reichmann, H., Sloan, M., von Kummer, R., Zamani, A., Coulter, S., Giugliano, R., Skene, A. M., Ardill, R., Ince, Y., Peters, A., Ward, K., Wolf, L., Curtis, N., De Brés, J., Stead, S., Watson, S., Cutler, S., Friedman, J., Helfrick, R., Williams, S., Klimovsky, J., Kumagai, S., Adams, E., Anderson, C., Bauhuber, I., Bennett, L., Biro, E., Boyce, E., Bregman, B., Carvalho, P., Ciganovic, D., Csukas, M., Cuenca, P., De Cuyper, S., Diez, P., Dijkhuizen, M., Dille-Amo, C., Gonzalez-Santis, A., Gursoy, M., Hammarstrom, K., Harasta, E., Ingman, E., Kelemen, B., Keulen, I., Koren, A., Langthaler, G., Lemaire, F., Little, I., Montalban, C., Nijssen, K., Neumueller, I., Palander, M., Pekuri, T., Persson, U., Pilz, J., Oudotova, S., Pisklakov, V., Proinov, F., Ptaszynska, A., Read, J., Retei, S., Romeyer, F., Romanini, M., Saar, L., Salein, D., Samsonov, M., Simeon-Dubach, D., Simmonds, J., Skaza, M., Skvortsova, N., Smidlova, Z., Spitzerova, H., Strijdveen, I., Szajewski, T., Ugurnal, B., Valcarce, M., van Rompaey, I., Walker, A., Zak, E., Zimova, N., Barrero, C., Beck, E., Bruno, M. L., Caccavo, A., Cagide, A., Campo, A., Cermesoni, R., Chahin, M., Dutra, O., Estrada, J., Falu, E. A., Gagliardi, J., Garre, L. E., Liprandi, A. S., Luciardi, H., Mautner, B., Muntaner, J., Nau, G., Salzberg, S., Santopinto, J., Sinisi, A., Torres, H., Eber, B., Elliott, P., Hiemetsberger, H., Juhasz, M., Kühn, P., Leisch, F., Niktardjam, M., Reisinger, J., Schmalix, G., Schuster, R., Sihorsch, K., Silberhauer, K., Slany, J., Steinbach, K., Tragl, K. H., Valentin, A., Al Shwafi, K., Dasnoy, P., De Clippel, M., de Meester, A., De Raedt, H. J. L. P., Emonts, M., Evrard, P., Eycken, M., Geboers, M., Heyndrickx, G., Lauwers, K., Mitrie, K., Pirenne, B., Renard, M., Somers, Y., Timmermans, P., Van Kuyk, M., Van Mieghem, W., Vermeulen, J., Verrostte, J. M., Albuquerque, D., Ayoub, J. C. A., Carvalho, A., Cesar, L., Gebara, O., Golin, V., Knobel, E., Leaes, P., Neto, J. A. M., Nicolau, J. C., Piegas, L. S., Rabelo, A., Rassi, A., Sila, L., Simao, A. F., Ashton, T., Baillie, H., Bhargava, R., Bota, G., Cameron, W., Chan, N., Chan, Y. K., Daly, P. A., Darcel, I., Davies, E., Desjardin, L., Dhingra, S., Ducas, J., Ervin, F. L., Fortin, C., Fowlis, R., Fulop, J., Furey, M., Gagnon, S., Gebhardt, V., Giannaccro, P., Gosselin, G., Graham, J., Grondin, F., Heath, J. W., Henderson, M., Hilton, D. R., Hiscock, J., Hui, W., Kaza, L., Kesselman, T., Kouz, S., Kucerak, M., Lahoude, N., Lamothe, M., Lebouthillier, P., Lenis, J., Levesque, P., Lopez, J. F., Lubelsky, B., Macritchie, D., Mayer, J. -P., Mcdowell, J. D., Montigny, M., Orestien-Lyall, T., Parekh, P., Pistawka, K., Price, J. B., Pruneau, G., Quinn, B., Reid, B. R., Richmond, M., Rose, B., Schuld, R., Sharma, N. K., Shetty, P., Stanton, E., Strauss, H. D., Sussex, B., Theroux, P., Turabian, M., Turner, C., Vizel, S., Walker, M., Weeks, A., Winkler, L., Zacharias, G., Zimmerman, R., Bartolucci, J., Castro, P., Diaz, M. A., Illanes, G., Potthoff, S., Sanchez, E. C., Silva, L. M., Yovanovich, J., Zanetti, F. L., Alan, D., Balázová, K., Boček, P., Cerny, J., Fischerova, B., Holub, M., Hradec, J., Janota, T., Janský, P., Kasper, J., Klimsa, Z., Motovská, Z., Pleva, L., Pluhacek, L., Pšenčka, M., Semrád, B., Spinar, J., Staněk, V., Štípal, R., Suítil, P., Vítovec, J., Wichterie, D., Widimský, P., Zeman, K., Andersen, C. B., Kriegbaum, J., Nielsen, N., Nielsen, P. E., Schou, J. B., Teesalu, R., Voitk, J., Haapamäki, H. V. H., Halkosaari, M., Härkönen, M., Jägerholm, S., Kärjä-Koskenkari, P., Karthunen, P., Kesäniemi, Y. A., Koskivirta, H., Lehto, P., Lilja, M., Paakkinen, S., Palomäki, A. K., Pietilä, K., Tuominen, J., Viopio-Pulkki, L., Ylönen, H., Adi, I., Admant, P., Akadirik, A., Alagha, Z., Alhabaj, S., Amat, G., Andre, A. A., Apffel, F., Aswad, K., Baradat, G., Bareiss, P., Barthers, F. B., Baudet, M., Baudouy, M., Bearez, E. M., Berthou, J. D., Berzin, B., Bessede, G., Blanc, J. J., Bocara, A., Bonneau, A., Bourdad, C., Bouvier, J. M., Cassagnes, J., Cassat, A., Cazaux, P., Charbonnier, B., Clementy, J., Cohen, A., Coisne, D., Colin, P., Croizier, O., D’Hautefeuille, B., D’Ivernois, C., Daumas, P. L., Dauphin, C. L., Deforet, M. F., Degand, B., Dequeker, J. L., Dickele, M. C., Dugrand, P., Durand, S., Ebagosti, A., Elharrar, C., Equine, O., Fichter, E., Flork, L., Fouche, R., Fourchard, V., Fourme, T., Fournier, P. Y., Funck, F., Galley, D., Garbarz, E., Ghadban, W., Gladin, M., Grall, J. Y., Grand, A., Gryman, R., Guillard, N., Guillo, P., Haftel, Y., Hannebicque, G., Henry, R., Huret, J. F., Janin-Magnificat, L., Jarnier, J., Joly, A., Kamal, H., Khalife, A., Roynard, J. L., Lang, M., Lapeyssonnie, A., Ledain, L., Lejeune, P., Lemetayer, L., Lepori, R., Lombart, A., Lusson, J. R., Magnin, O., Marquand, A., Martelet, M. M., Martelli, A., Mathurin, C., Mentre, B., Messager, D., Morizot, M., Mouallem, M. J., Mouhoub, O., Mycimski, C., Nallet, O., Olive, T., Pacouret, G., Palcoux, M. C., Poulard, J. E., Pruvost, A., Quiret, J. C., Richard, C., Richard, P., Rickaud, P., Riehl-Aleil, V., Rifai, A., Rocher, R., Rotreff, P., Segrestin, B., Slama, M. S., Sultan, P., Tabone, X., Talbodec, A., Tissot, M. T., Toussaint, C., Veyrat, A., Zerrouk, Z., Adamczak, M., Altmann, E., Altybernd, B., Andreassen, G., Andresen, D., Appenrodt, H., Bachmann, S., Bäcker, U., Beckert, U., Behr, H. M., Beier, W., Beier, T., Berger, D., Bernsmeier, R., Beythien, R. D., Biechl, E., Biedermann, G., Bischoff, K. O., Blerich, J., Boch, H. B., Bonzel, T., Both, A. R., Breidenbach, K., Breuer, M., Breuer, H. W. M., Brunkhorst, F. B., Bruns, A., Bundschu, H. D., Burkhardt, W., Busse, H. J., Caesar, K., Cailloud, J., Chlosta, A., Chorlanopoulos, E., Consemüller, S., Decker, W., Dichgans, M., Dick, R., Diederich, K. W., Dienst, C., Dietz, A., Dißmann, R., Ditter, H., Doering, W., Drost, H., Dundalek, E. D., Eckardt, D., Edelmann, A., Eggeling, T., Eggert, G., Eichner, R., Endres, C., Engberding, R., Engel, H. J., Faehnrich, A., Fischer, J. L., Flor, A., Forycki, F. Z. F., Froböse, H. J., Fruehauf, T., Fuchs, M., Geiser, R., Geletneky, J., Gerdes, H., Gerecke, B., Gesing, S., Gieser, H., Girth, E., Glogner, P., Glover, M., Goetz, J., Goetz, H., Göttfert, G., Gottwik, M., Gregori, B., Grieshaber, M., Großmann, C., Gruber, G., Gunold, H., Häßler, W. H., Hackenjos, B., Hader, O., Hamer, H., Harmjanz, D., Hasst, G., Haun, H., Hauptmann, K. E., Hegge, F. J., Heinze, A., Heinze, R., Henrichs, K. J., Hergenröther, H., Herrmann, F., Herzig, C., Hey, D., Hill, S., Hinzmann, S., Hoffmann, S., Höfs, T., Höhler, H., Holle, G., Höltman, B. J., Horacek, T., Hossmann, V., Hübner, F. S., Hülskamp, C., Hunecke, R., Hust, M., Jaeckh, G., Jebens, C., Jennen, E., Jost, M., Justiz, R., Kallmann, L., Kalscheur, F., Kaschner, W., Kaspar, W., Kauder, E., Keitel, B., Keller, H., Kemkes, T., Kerler, N., Kester, M., Kettner, W., Kilp, M., Kirklies, A., Klaus, A., Klein, H. H., Klenböck, J. R., Kley, H. K., Klingenbeck, R., Koch, H., Kohler, B., Kohler, J., Kolloch, R., Konermann, M., Körber, H. G., Kother, T. K., Kötter, V., Kottwitz, B., Kozariszcsuk, G., Kracht, T., Kratzsch, G., Kreft, H. U., Kreuter, G., Krönert, H., Krönig, B., Krueger, E., Krülls-Münch, J., Kuckuk, H., Kuelschbach, M., Kuhrt-Lassay, O. W., Kummerhoff, P. W., Kunevt, R., Kurth, C. U., Lang, C., Lange, C., Langhoff, R., Laskus, A., Lazarus, P., Lehmann, H. U., Lenga, P., Lengfelder, W., Leupolz, W., Limbourg, P., Loos, U., Lucanus, W., Machill, K., Mäckel, P., Mackes, K. G., Maier, S., Makowski, B., Mandok, J., Manz, M., Mäurer, W., Meier, F., Meier, J., Menges, M., Merx, W., Meurers, G., Michels, U., Mickeler, C. H., Mons, D., Moos, E., Mueller, R., Müller, G., Nast, H. P., Naumann, G., Nebelsieck, H., Neubaur, J., Niederer, W., Nitsch, J., Noack, J., Nogai, K. F. W., Oberheiden, A., Obst, R., Ochs, H. R., Odemar, F., Odenthal, H. J. B., Offers, E., Öhl, S., Ohlmeier, H. A. R. M., Patzer, P., Pech, A., Peters, U., Petry, U., Pietschmann, G. J., Pistner, W., Plappert, B., Pohlmann, W. K., Pollock, B., Presser, H. J., Przytarski, K., Puerner, K. L., Raouf, N., Reike, N., Reil, G. H., Reinhard, U., Riebeling, V., Ritzmann, M., Rödder, J., Roth, E., Rüdelstein, R., Saborowski, F., Sauter, B., Sceffler, N., Schartl, A., Schifferdecker, E., Schlotterbeck, K. P., Schmidt, J., Schmidt-Dannert, D. R., Schmidt-Klewitz, H., Schmitz, H. J., Schnebelt, T., Schneider, H. L., Schneider, F. J., Schoeller, R., Scholz, D., Schoppe, W. D., Schreiner, G., Schroeder, J., Schuh, N., Schulte, K. L., Schulze, H., Schulze, H. D., Schuster, P., Schuster, H. P., Schweizer, P., Sechtem, U., Sedlmaier, H. P., Segel, S., Sehnert, W., Seidel, F., Siedentopf, K., Simon, H., Sodomann, C. P., Solbach, C., Sorges, E., Stabenow, S., Stadler, K. P., Stammwitz, E., Stein, U., Sternberg, H., Stiepak, C., Stockmann, M., Straus, W., Striegel, H., Struch, E., Strupp, G., Taubert, T. B. T., Thoeming, B., Thoß, A., Tinnappel, J., Tomsik, H., Topp, H., Troost, S., Öberreiter, A., Uebis, R., Ungler, T., Urbaszek, W., Vöhringer, H. F., von Arnim, T., von Leitner, E. R., von Löwis of Menar, A., von Mengden, H. J., von Smekal, P., Voss, W., Wacker, P., Warning, A., Warzecha, A., Wefers, U., Wehr, M., Weigel, H., Weissthanner, F., Weller, P., Werner, M., Wette, A., Wichert, H., Wielage, T., Wiese, U., Wilbrand, T. B., Wilhelms, E., Wilmsmann, G., Wolf, F. H., Wolf, T., Wonhas, F. C. M., Zastrow, B., Zeymer, U., Ziruler, S., Ziss, W., Zölch, K. A., Zwirner, K., Becker, D., Bosko, M., Csillag, I., Ermenyi, A., Fogas, J., Heltai, K., Jánosi, A., Katona, A., Kiraly, C., Kiss, B., Kutor, G., Mizik, R., Molnar, T., Mühl, M., Nagy, D., Palacti, I., Rudas, L., Sárosi, I., Simon, K., Sitkel, E., Sydó, T., Szaboki, F., Szikla, K., Szönyi, T., Timar, S., Vándor, L., Zamolyl, K., Walsh, M., Caspi, A., Swissa, M., Badano, L., Baldacci, G., Balli, E., Banda, D., Baretta, G., Boccalatte, A., Borgatti, M. L., Branzi, A., Burelli, C., Capelletti, D., Capucci, A., Caragiulo, D., Carbonieri, E., Cassin, M., Ceci, V., Cocchieri, M., Coletta, C., Conte, E., Contini, G. M., Corsini, G., D’Annunzio, E., De Blasi, M., De Luca, I., Delciterna, F., Di Pasquale, G., Diguardo, G., Fattore, L., Ferraiuulo, G., Finardi, A., Fioretti, P. M., Giunta, G., Guiducci, U., Guzzardi, G., Horando, G., Ignone, G., Lazzaroli, A., Levantesi, D., Liberati, R., Losi, E., Macor, F., Mangiameli, S., Martines, C., Meinardi, F., Morgera, T., Morozzi, L., Mostacci, M., Naccarella, F. F., Ottani, F., Palamara, A., Pani, A., Paperini, L., Pes, R., Pesola, A., Porzio, A., Raviele, A., Ricci, S., Rosi, A., Rossi, R., Rotiroti, D., Rusconi, L., Sabino, G., Saccone, V., Sanna, A., Scaramuzzino, G., Scorcu, G. P., Semprini, F., Severini, D., Staniscia, D., Tantalo, L., Tartagni, F., Terrosu, P., Tondelli, S., Trichero, R., Uslenghi, E., Vajola, S. F., Vetrano, A., Violi, E., Zardini, P., Zingarini, G. L., Zobbi, G., Zuin, G., Kalnins, U., Cârvekülg, A., Laanoca, J., Iacis, J., Lankiene, L., Laucevicius, A., Lukoseviciute, A., Palsauskaite, R., Petrauskiene, B., Soopóld, W., Uuetoa, H., Vilks, J., Vitonyte, R., Zakke, I., Dorantes, J., Hernández, H., Jerjes, C., Leva Garza, J. L., Martinez, C., Anneveldt, A., Baars, H. F., Baldew, S. C., Bendermacher, P. E. F., Boersma, L. V. A., Bos, R. J., Breedveld, R. W., Bruggink, P. W. F., Ciampricotti, R., Darmanata, J. I., de Porto, A. E., de Weerd, G. J., Deckers, J. W., Freericks, M. P., Hillebrand, F. A., Kerker, J. P., Koenen, J. C., Kofflard, M. G. M., Liem, K. L., Liem, A. H., Linssen, G. C. M., Lionarons, R. J., Peters, J. R. M., Posma, J. P., Saat, E. W. M., Savalle, L. H., Smits, W. C. G., Suttorp, M. J., Tans, A. C., Troquay, R. P. Th., van Beek, G. J., van Boven, A. J., Van der Heijden, R., Van Hessen, A., van Langeveld, R. A. M., van Lier, T. A. R., van Loo, L. W. H., van Wijngaarden, J., van Ziejl, L. G. P. M., Veerhoek, M. J., Vermer, F., Werner, H. A., Graven, T., Klykken, B., Meyerdieks, O., Omland, T. M., Otterstad, J. E., Pedersen, T., Rød, R., Banaszewski, M., Bednarkiewicz, Z., Bojarski, G., Ceremuzyñski, L., Czestochowska, E., Gajewski, M., Galewicz, M., Gorski, J., Grabczewska, Z. S., Gruchaka, M., Janicki, K., Janion, M., Jaworska, K., Jezewska, M., Kakol, J., Kizciuk, M., Kleinrok, A., Kolodziej, P., Komorowski, P., Konopka, A., Kopaczewski, J., Korecki, J., Kornacewicz-Jach, Z., Kowalewski, M., Kratochwil, D., Krolczyk, J., Krzminska-Pakula, M., Kurek, P., Kurowski, M., Kurpesa, M., Kurzawski, J., Kwiecien, R., Lenartowski, L., Lewandowski, M., Loboz-Grudzieñ, K., Luczak, G., Maliñski, A., Michalski, M., Musial, W., Nartowicz, E., Nowicka, A., Odyniec, A., Pasyk, S., Prastowski, W., Przybylski, A., Raczynska, A., Rodzik, J., Romanowski, M., Rynkiewicz, A., Rzyman, M., Sidorowicz, A., Sledziona, M., Sobiczewski, W., Sobkowicz, B., Sobolewska, J., Sokalski, L., Stepinska, J., Sterlinski, M., Stopinski, M., Świątecka, G., Szpernal, Z., Tarnowska, H., Trzos, E., Ujda, M., Wierzchowiecki, M., Wodynska, T., Wojciechowski, D., Wrabec, K., Wrzesinski, K., Zuk, P., Albuquergue, A., Costa, A., Cunha, D., Ferreira, D., Ferreira, R., Gaog Leiria, J. M., Pimenta, A., Rufino, E., Vasconcelos, J., Aldica, M., Balanescu, S., Bruckner, I. V., Capalneanu, R., Florescu, N., Georgescu, C. S., Cherasim, L., Ginshina, C., Merenta, A., Parvu, O., Radutiu, S., Savulescu, I., Vita, I., Averkov, O., Bokarev, I. N., Gratsiansky, N., Grigoriev, Y., Gruzdev, A., Kakhnovsky, I., Kheevehuk, T. V., Khrustalev, O., Kobalava, Y., Konoratieva, T. B., Koukline, Vladimir, Martiouchov, S., Pavlikova, E., Poskotinov, I., Rogalev, K., Sinopainikov, A., Syrkin, A., Tereschenko, S. T., Yavelov, I., Zavolghin, S., Čurilla, E., Kohn, R., Kovář, F., Murín, J., Poliačik, P., Drinovec, I., Horvat, M., Krivec, B., Markež, J., Pareznik, R., Pehnec, Z., Resman, J., Sifrer, F., Skale, R., Trinkaus, D., Voga, G., Baig, M. M. E., Blomerus, P., Botha, B. P., Burgess, L., Duncan, D., Duncan, D. I., Gillmer, D., Govender, N., Jardine, R. J., Kok, A., Manga, P., Naidu, R. K., Rajput, M. C., Ranjith, N., Roos, J. S., Snyders, F. A., Steingo, L., Stern, A., Tayob, F. Z., Vythilingum, S., Alonso-Orcajo, N., Arribas Jimenez, A., Ayestaran, J. I., Balsera, B. B. G., Barras, C., Castro, A., Cobo, N., Duque, A., Garcia, M. J., Goiriena, P., Gonzalez-Valdayo, M., Gulias Lopez, J. M., Jimenez Gomez, P., Lopez Garanda, V., Martín Santos, F., Nogueira, R., Pabon Osuna, P., Ponce De Leon, E., Quesada Dorador, A., Paya Serrano, R., Rodriguez, L., Rodriguez, M., Rubio, F., Ruiz-Salmeron, R., Solar, J., Toquero, J., Velasco, J., Vilar Herrero, V., Vizcaino, M., Wancisidor, X., Basilier, E., Birgersdotter, V., Björnsdotter, E., Bjurman, A., Hagström, D., Hallin, I., Hansen, O., Hemmingson, L. O., Lundkvist, L., Lycksell, M., Möller, B., Nolgard, P., Sjölund, G., Stjerna, A., Angehrn, W., de Benedetti, E., Diethelm, M., Gallino, A., Plebani, G., Vögelin, H. P., Wojtyna, W., Akgöz, H., Akgün, G., Akyürek, O., Batur, M. K., Bayata, S., Deger, N., Emel, O., Gürgün, C., Korkmaz, M. E., Kozan, O., Kumbasar, D., Muderrisoglu, H., Nisanci, Y., Ozin, B., Ozsaruhan, O., Payzin, S., Postaci, N., Sozcuer, H., Tamci, B., Topuzoglu, F., Türkoglu, C., Tutar, E., Ulucam, M., Ulusoy, T., Umman, B., Yalçinkaya, S., Yesil, M., Zoghi, M., Adams, P. C., Ahir, S., Ahsan, A. J., Akhtar, J., Albers, C. J., Al-Khafaji, M. N., Anderson, N., Bailey, R. J., Bain, R. J. I., Basu, A., Beal, A., Boyle, R. M., Brown, N., Campbell, S., Card, D., Cross, S. J., Davies, P., Davis, E. T. L., Dean, J. W., Deaner, A., Devine, M. A., Dhawan, J., Doig, J. C., Dubrey, S., Dunn, P. G., Dwight, J., Ecob, R., Fitzpatrick, H., Fletcher, S., Francis, C. M., Gershlick, A. H., Glennon, P. E., Goodfield, N. E., Grabau, W. J., Gray, M., Gray, K. E., Heath, J., Hendry, W. G., Highland, J., Hogg, K., Irving, J. B., James, M. A., Jennings, K., Joy, M., Kadr, H. H., Kahn, S., Keeling, P. J., Keir, P. M., Kemp, T. M., Kinaird, J., Kinsey, C., Knowles, K., Kooner, J. S., Lahiri, A., Lawson, C., Lewis, R., Macdermott, A. F. N., Mackay, A., Macleod, D. C., Mccance, A. J., Morrison, A., Mortimer, M., Mulvey, D., Murphy, J. J., Murray, S., Muthusamy, R., Myers, A., Nicolson, V. G., Northridge, D., Odemuyiwa, S., Oldroyd, K. G., Oliver, R. M., Pell, A. C. H., Pohl, J. E. F., Price, B., Quereshi, N., Rae, A. P., Reader, S., Reid, D. S., Reynolds, G. W., Robinson, A., Robson, R. H., Rodger, J. C., Rodrigues, E., Rose, E. L., Rowlands, D. B., Rowley, J. M., Rozkovec, A., Shreeve, J., Siklos, P., Smith, R. H., Sneddon, J. F., Somasundram, U., Squire, I., Stephens, J. D., Stephens-Lloyd, A., Strand, J. M., Stuart, J., Sutaria, N., Swan, J., Tait, G. W., Thomas, R. D., Thompson, M. A., Tildesley, G., Travill, C. M., Treadgold, J. A., Trelawney, J. M. S., Turner, D., Vallance, B. D., Wallbridge, D., Weissberg, P. L., White, E., Wicks, M., Wilcox, R. G., Wilkinson, P., Wiltshire, J. E., Wright, A., Andrea, B., Attassi, K., Bahr, R., Banas, J., Baran, K., Belknap, M., Bensman, M., Bertolet, B., Besley, D., Bethala, V., Betzu, R., Bhalla, R., Bhargava, M., Binder, A., Birkhead, R., Bodine, K., Brewer, D., Carey, S., Chengot, M., Coppola, J., Cragg, D., D’Arcy, B., Denny, D. M., Dilorenzo, P., Dixon, E., Doorey, A., Doty, D., Doty, W., Drossner, M., Eisenberg, P., Falco, T., Feldman, R., Freman, I., Frey, M., Garcia, J., Glassman, J., Goldman, S., Gomez, M., Gonzalez, M., Goodfield, P., Gottlieb, S., Grech, D., Hack, T., Haffey, T., Hanson, J., Havranek, E., Hermany, P., Hernandez, H., Herron, R., Hession, W., Hines, J., Hundley, R., Jacobs, W. C., Jerjes-Sanchez, C., Jerome, S., Josephson, R., Kalan, J., Kawalsky, D., Khan, A., Kmetzo, K., Kraemer, M., Lader, E., Landis, J., Lash, J., Leber, R., Leimbach, W., Leiva Garza, J. -L., Maddox, W., Magorien, R., Mahapatra, S., Mantecon, I., Mendelson, R., Miklin, J., Milas, J., Miller, R., Molk, B., Monrad, E. S., Morrison, J., Morse, H., Neustel, M., Nichols, D., Niederman, A., Nygaard, T., O’Connor, R., O’Riordan, W., Obermueller, S., Palmeri, S., Patel, R., Paul, T., Phiambolis, T., Piana, R., Polansky, B., Polinski, W., Ponce, G., Ribeiro, P., Roccario, E., Rogers, C. P., Rogers, W., Rosenblatt, A., Runyon, J. P., Scheel, F., Schmidt, P., Schneider, R., Schwartz, H., Shelhamer, L., Sheridan, F., Shine, W., Shook, T., Siskind, S., Slama, R., Spear, E., Stouffer, G., Strunk, B., Thadani, U., Timmis, G., Trautloff, R., Tse, A., Wohl, B., Zarren, H., Zucker, R., Kuster, F., and Pardie, J. P.

Subjects
Male, Risk, Infusions, medicine.medical_treatment, Myocardial Infarction, Bolus lytic therapy, Acute myocardial infarction, Tissue plasminogen activator, Thrombolytic drug, Double-Blind Method, Fibrinolytic Agents, medicine, Humans, Thrombolytic Therapy, Myocardial infarction, Infusions, Intravenous, Stroke, Aged, business.industry, ST elevation, Lanoteplase, Emergency department, Middle Aged, medicine.disease, Survival Analysis, Regimen, Relative risk, Anesthesia, Tissue Plasminogen Activator, Female, Intracranial Hemorrhages, Cardiology and Cardiovascular Medicine, business, Intravenous, medicine.drug
Abstract

AIMS To compare the efficacy and safety of lanoteplase, a single-bolus thrombolytic drug derived from alteplase tissue plasminogen activator, with the established accelerated alteplase regimen in patients presenting within 6 h of onset of ST elevation acute myocardial infarction. METHODS AND RESULTS 15,078 patients were recruited from 855 hospitals worldwide and randomized in a 2:1 ratio to receive either lanoteplase 120 KU. kg(-1)as a single intravenous bolus, or up to 100 mg accelerated alteplase given over 90 min. The primary end-point was all-cause mortality at 30 days and the hypothesis was that the two treatments would be equivalent. By 30 days, 6.61% of alteplase-treated patients and 6.75% lanoteplase-treated patients had died (relative risk 1.02). Total stroke occurred in 1.53% alteplase- and 1.87% lanoteplase-treated patients (ns); haemorrhagic stroke rates were 0.64% alteplase and 1.12% lanoteplase (P=0.004). The net clinical deficit of 30-day death or non-fatal disabling stroke was 7.0% and 7.2%, respectively. By 6 months, 8.8% of alteplase-treated patients and 8.7% of lanoteplase-treated patients had died. CONCLUSION Single-bolus weight-adjusted lanoteplase is an effective thrombolytic agent, equivalent to alteplase in terms of its impact on survival and with a comparable risk-benefit profile. The single-bolus regimen should shorten symptoms to treatment times and be especially convenient for emergency department or out-of-hospital administration.

Published
2000

9. Lösungsmethoden für Variationsungleichungen

Author

Kummer, B., Großmann, C., Klatte, D., Ponomarenko, Andrej, Kummer, B., Großmann, C., Klatte, D., and Ponomarenko, Andrej

Abstract

Zusammenfassung Diese Arbeit ist ein Versuch, verschiedene klassische und neuere Methodender glatten bzw. nichtglatten Optimierung zu verallgemeinern und in ihrem Zusammenhang darzustellen. Als Hauptinstrument erweist sich dabei die sogenannte verallgemeinerte Kojima-Funktion. Neben reichlichen Beispielen setzen wir einen besonderen Akzent auf die Betrachtung von Variationsungleichungen, Komplementaritaetsaufgaben und der Standartaufgabeder mathematischen Programmierung. Unter natuerlichen Voraussetzungen an diese Probleme kann man u.a. Barriere-, Straf- und SQP-Typ-Methoden, die auf Newton-Verfahrenbasieren, aber auch Modelle, die sogenannte NCP-Funktionen benutzen, mittelsspezieller Stoerungen der Kojima-Funktion exakt modellieren. Daneben werdendurch explizite und natuerliche Wahl der Stoerungsparameter auch neue Methoden dieser Arten vorgeschlagen. Die Vorteile solcher Modellierungsind ueberzeugend vor allem wegen der direkt moeglichen (auf Stabilitaetseigenschaften der Kojima-Gleichung beruhendenden)Loesungsabschaetzungen und weil die entsprechenden Nullstellen ziemlich einfach als Loesungen bekannter Ersatzprobleme interpretiert werden koennen. Ein weiterer Aspekt der Arbeit besteht in der genaueren Untersuchungder "nichtglatten Faelle". Hier wird die Theorie von verschiedenen verallgemeinerten Ableitungen und dadurch entstehenden verallgemeinerten Newton-Verfahren, die im Buch "Nonsmooth Equations in Optimization" von B. Kummer und D. Klatte vorgeschlagen und untersucht wurde, intensiv benutzt. Entscheidend ist dabei, dass die benutzten verallgemeinerten Ableitungen auch praktisch angewandt werden koennen, da man sie exakt ausrechnen kann., This work attempts to generalize various classical and new methods of smooth or nonsmooth optimization and to show them in their interrelation. The main tool for doing this is the so-called generalized Kojima-function. In addition to numerous examples we specialy emphasize the consideration of variational inequalities, complementarity problems and the standard problem of mathematical programming. Under natural assumptions on these problems we can model e.g. barrier-, penalty-, and SQP-Type-methods basing on Newton methods, and also methods using the so-called NCP-function exactly by means of special perturbations of the Kojima-function. Furthermore, by the explicit and natural choice of the perturbation parameters new methods of these kinds are introduced. The benefit of such a modelling is obvious, first of all due to the direct solution estimation (basing on stability properties of the Kojima-equation) and because the corresponding zeros can easily be interpreted as solutions of known subproblems. A further aspect considered in this paper is the detailed investigation of "nonsmooth cases". The theory of various generalized derivatives and resulting generalized Newton methods, which is introduced and investigated in the book "Nonsmooth Equations in Optimization" of B. Kummer and D. Klatte, is intensely used here. The crucial point is the applicability of the used generalized derivatives in practice, since they can be calculated exactly.

Published
2003

25. T cell independent secondary antibody responses to the envelope protein of simian immunodeficiency virus

Author

Nabi Ghulam, Temchura Vladimir, Großmann Claudius, Kuate Seraphin, Tenbusch Matthias, and Überla Klaus

Subjects
SIV, HIV, Adenoviral vectors, T-independent antibody response, VLP, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background During human (HIV) and simian (SIV) immunodeficiency virus infection, loss of CD4+ T cells and progression to AIDS are associated with a decline in antibody titers to the viral Gag protein, while antibodies to the Env protein remain high, suggesting a T cell independent antibody response to Env. Results To explore differential regulation of Gag and Env antibody responses, immunocompetent BALB/c and T cell deficient nude mice were immunized with virus like particles (VLP) of simian immunodeficiency virus or adenoviral vectors expressing SIV Gag and Env. High levels of antibodies against Gag and Env could only be induced in immunocompetent mice, but not in the immunodeficient mice. Thus, neither cells expressing Env after adenoviral gene transfer nor VLPs induce a T cell independent primary anti-Env antibody response. However, secondary B cell responses to Env, but not to Gag, were observed in immunodeficient mice after transfer of primed B cells and boosting with VLPs or adenoviral vectors expressing Gag and Env. This T cell independent secondary antibody response to Env was reduced after stimulation with VLPs modified to contain monomeric membrane bound gp130 surface subunit of Env and undetectable after injection of soluble gp130. Conclusions Membrane-bound trimeric Env seems to be responsible for the maintenance of high levels of anti-Env antibodies during progression to AIDS. This T cell independent secondary antibody response may prevent T cell-dependent affinity maturation and thus contribute to viral immune escape by favoring persistence of non-protective antibodies.

Published
2012
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26. Enhancement of the priming efficacy of DNA vaccines encoding dendritic cell-targeted antigens by synergistic toll-like receptor ligands

Author

Kornbluth Richard S, Stone Geoffrey W, Nabi Ghulam, Temchura Vladimir, Nchinda Godwin, Tenbusch Matthias, Grossmann Claudius, and Überla Klaus

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background Targeting of protein antigens to dendritic cells (DC) via the DEC205 receptor enhances presentation of antigen-derived peptides on MHC-I and MHC-II molecules and, in the presence of costimulatory signals, antigen-specific immune responses. The immunogenicity and efficacy of DNA vaccination can also be enhanced by fusing the encoded antigen to single chain antibodies directed against DEC205. To further improve this strategy, we evaluated different toll-like receptor ligands (TLR) and CD40 ligands (CD40L) as adjuvants for DNA vaccines encoding a DEC205-single-chain antibody fused to the ovalbumin model antigen or HIV-1 Gag and assessed the priming efficacy of DNA in a DNA prime adenoviral vector boost immunization regimen. Results Mice were primed with the adjuvanted DEC-205 targeted DNA vaccines and boosted with adenoviral vectors encoding the same antigens. CD8+ T cell responses were determined after the adenoviral booster immunization, to determine how well the different DNA immunization regimens prime for the adenoviral boost. In the absence of adjuvants, targeting of DNA-encoded ovalbumin to DCs suppressed CD8+ T-cell responses after the adenoviral booster immunization. CD8+ T-cell responses to the DEC205 targeted DNA vaccines increased only slightly by adding either the TLR-9 ligand CpG, the TLR-3 ligand Poly I:C, or CD40 ligand expression plasmids. However, the combination of both TLR-ligands led to a strong enhancement of CD8+ T-cell responses compared to a non-targeted DNA vaccine. This finding was confirmed using HIV Gag as antigen. Conclusion Although DNA prime adenoviral vector boost immunizations belong to the strongest inducers of cytotoxic T cell responses in different animal models and humans, the CD8+ T cell responses can be further improved by targeting the DNA encoded antigen to DEC205 in the presence of synergistic TLR ligands CpG and Poly I:C.

Published
2009
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32. Lösungsmethoden für Variationsungleichungen

Author

Ponomarenko, Andrej, Kummer, B., Großmann, C., and Klatte, D.

Subjects
regularity, 27 Mathematik, Barrieremethode, Stoerung, 510 Mathematik, Variationsungleichungen, NCP-function, Strafmethode, Kojima-function, perturbation, Stationaere Loesungen, veralgemeinerte Newton-Verfahren, generalized Newton method, nichtglatte Analysis, barrier-method, nonsmooth equations, stationary points, NCP-Funktion, Komplementaritaetsproblem, complementarity problem, Regularitaet, ddc:510, Kojima-Funktion, penalty-method, variational inequalities
Abstract

Zusammenfassung Diese Arbeit ist ein Versuch, verschiedene klassische und neuere Methodender glatten bzw. nichtglatten Optimierung zu verallgemeinern und in ihrem Zusammenhang darzustellen. Als Hauptinstrument erweist sich dabei die sogenannte verallgemeinerte Kojima-Funktion. Neben reichlichen Beispielen setzen wir einen besonderen Akzent auf die Betrachtung von Variationsungleichungen, Komplementaritaetsaufgaben und der Standartaufgabeder mathematischen Programmierung. Unter natuerlichen Voraussetzungen an diese Probleme kann man u.a. Barriere-, Straf- und SQP-Typ-Methoden, die auf Newton-Verfahrenbasieren, aber auch Modelle, die sogenannte NCP-Funktionen benutzen, mittelsspezieller Stoerungen der Kojima-Funktion exakt modellieren. Daneben werdendurch explizite und natuerliche Wahl der Stoerungsparameter auch neue Methoden dieser Arten vorgeschlagen. Die Vorteile solcher Modellierungsind ueberzeugend vor allem wegen der direkt moeglichen (auf Stabilitaetseigenschaften der Kojima-Gleichung beruhendenden)Loesungsabschaetzungen und weil die entsprechenden Nullstellen ziemlich einfach als Loesungen bekannter Ersatzprobleme interpretiert werden koennen. Ein weiterer Aspekt der Arbeit besteht in der genaueren Untersuchungder "nichtglatten Faelle". Hier wird die Theorie von verschiedenen verallgemeinerten Ableitungen und dadurch entstehenden verallgemeinerten Newton-Verfahren, die im Buch "Nonsmooth Equations in Optimization" von B. Kummer und D. Klatte vorgeschlagen und untersucht wurde, intensiv benutzt. Entscheidend ist dabei, dass die benutzten verallgemeinerten Ableitungen auch praktisch angewandt werden koennen, da man sie exakt ausrechnen kann. This work attempts to generalize various classical and new methods of smooth or nonsmooth optimization and to show them in their interrelation. The main tool for doing this is the so-called generalized Kojima-function. In addition to numerous examples we specialy emphasize the consideration of variational inequalities, complementarity problems and the standard problem of mathematical programming. Under natural assumptions on these problems we can model e.g. barrier-, penalty-, and SQP-Type-methods basing on Newton methods, and also methods using the so-called NCP-function exactly by means of special perturbations of the Kojima-function. Furthermore, by the explicit and natural choice of the perturbation parameters new methods of these kinds are introduced. The benefit of such a modelling is obvious, first of all due to the direct solution estimation (basing on stability properties of the Kojima-equation) and because the corresponding zeros can easily be interpreted as solutions of known subproblems. A further aspect considered in this paper is the detailed investigation of "nonsmooth cases". The theory of various generalized derivatives and resulting generalized Newton methods, which is introduced and investigated in the book "Nonsmooth Equations in Optimization" of B. Kummer and D. Klatte, is intensely used here. The crucial point is the applicability of the used generalized derivatives in practice, since they can be calculated exactly.

Published
2003

33. Low Left-Ventricular Ejection Fraction as a Predictor of Intraprocedural Cardiopulmonary Resuscitation in Patients Undergoing Transcatheter Aortic Valve Implantation.

Author

Gerfer S, Großmann C, Gablac H, Elderia A, Wienemann H, Krasivskyi I, Mader N, Lee S, Mauri V, Djordjevic I, Adam M, Kuhn E, Baldus S, Eghbalzadeh K, and Wahlers T

Abstract

Transcatheter aortic valve replacement (TAVR) has become an established alternative to surgical aortic valve replacement (AVR) for patients with moderate-to-high perioperative risk. Periprocedural TAVR complications decrease with growing expertise of implanters. Nevertheless, TAVR can still be accompanied by life-threatening adverse events such as intraprocedural cardiopulmonary resuscitation (CPR). This study analyzed the role of a reduced left-ventricular ejection fraction (LVEF) in intraprocedural complications during TAVR. Perioperative and postoperative outcomes from patients undergoing TAVR in a high-volume center (600 cases per year) were analyzed retrospectively with regard to their left-ventricular ejection fraction. Patients with a reduced left-ventricular ejection fraction (EF ≤ 40%) faced a significantly higher risk of perioperative adverse events. Within this cohort, patients were significantly more often in need of mechanical ventilation (35% vs. 19%). These patients also underwent CPR (17% vs. 5.8%), defibrillation due to ventricular fibrillation (13% vs. 5.4%), and heart-lung circulatory support (6.1% vs. 2.5%) more often. However, these intraprocedural adverse events showed no significant impact on postoperative outcomes regarding in-hospital mortality, stroke, or in-hospital stay. A reduced preprocedural LVEF is a risk factor for intraprocedural adverse events. With respect to this finding, the identified patient cohort should be treated with more caution to prevent intraprocedural incidents.

Published
2024
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34. Natural genetic variation in GLK1-mediated photosynthetic acclimation in response to light.

Author

Muino JM, Großmann C, Kleine T, and Kaufmann K

Subjects
Acclimatization genetics, Genetic Variation, Light, Photosynthesis genetics, Arabidopsis metabolism, Arabidopsis Proteins genetics, Arabidopsis Proteins metabolism, Transcription Factors genetics, Transcription Factors metabolism
Abstract

Background: GOLDEN-like (GLK) transcription factors are central regulators of chloroplast biogenesis in Arabidopsis and other species. Findings from Arabidopsis show that these factors also contribute to photosynthetic acclimation, e.g. to variation in light intensity, and are controlled by retrograde signals emanating from the chloroplast. However, the natural variation of GLK1-centered gene-regulatory networks in Arabidopsis is largely unexplored., Results: By evaluating the activities of GLK1 target genes and GLK1 itself in vegetative leaves of natural Arabidopsis accessions grown under standard conditions, we uncovered variation in the activity of GLK1 centered regulatory networks. This is linked with the ecogeographic origin of the accessions, and can be associated with a complex genetic variation across loci acting in different functional pathways, including photosynthesis, ROS and brassinosteroid pathways. Our results identify candidate upstream regulators that contribute to a basal level of GLK1 activity in rosette leaves, which can then impact the capacity to acclimate to different environmental conditions. Indeed, accessions with higher GLK1 activity, arising from habitats with a high monthly variation in solar radiation levels, may show lower levels of photoinhibition at higher light intensities., Conclusions: Our results provide evidence for natural variation in GLK1 regulatory activities in vegetative leaves. This variation is associated with ecogeographic origin and can contribute to acclimation to high light conditions., (© 2024. The Author(s).)

Published
2024
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35. Calcineurin Is a Universal Regulator of Vessel Function-Focus on Vascular Smooth Muscle Cells.

Author

Nolze A, Matern S, and Grossmann C

Subjects
Animals, Transcription Factors, Cell Differentiation, Aorta, Calcineurin, Muscle, Smooth, Vascular
Abstract

Calcineurin, a serine/threonine phosphatase regulating transcription factors like NFaT and CREB, is well known for its immune modulatory effects and role in cardiac hypertrophy. Results from experiments with calcineurin knockout animals and calcineurin inhibitors indicate that calcineurin also plays a crucial role in vascular function, especially in vascular smooth muscle cells (VSMCs). In the aorta, calcineurin stimulates the proliferation and migration of VSMCs in response to vascular injury or angiotensin II administration, leading to pathological vessel wall thickening. In the heart, calcineurin mediates coronary artery formation and VSMC differentiation, which are crucial for proper heart development. In pulmonary VSMCs, calcineurin/NFaT signaling regulates the release of Ca 2+ , resulting in increased vascular tone followed by pulmonary arterial hypertension. In renal VSMCs, calcineurin regulates extracellular matrix secretion promoting fibrosis development. In the mesenteric and cerebral arteries, calcineurin mediates a phenotypic switch of VSMCs leading to altered cell function. Gaining deeper insights into the underlying mechanisms of calcineurin signaling will help researchers to understand developmental and pathogenetical aspects of the vasculature. In this review, we provide an overview of the physiological function and pathophysiology of calcineurin in the vascular system with a focus on vascular smooth muscle cells in different organs. Overall, there are indications that under certain pathological settings reduced calcineurin activity seems to be beneficial for cardiovascular health.

Published
2023
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36. Major Adverse Cardiac and Cerebrovascular Events in Patients Undergoing Simultaneous Heart Surgery and Carotid Endarterectomy.

Author

Gerfer S, Bennour W, Chigri A, Elderia A, Krasivskyi I, Großmann C, Gaisendrees C, Ivanov B, Avgeridou S, Eghbalzadeh K, Rahmanian P, Kuhn-Régnier F, Mader N, Djordjevic I, Sabashnikov A, and Wahlers T

Abstract

Background: Patients with simultaneous relevant internal carotid artery stenosis and coronary artery heart or valve disease represent a high-risk collective with respect to cerebral or cardiovascular severe events when undergoing surgery. There exist several concepts regarding the timing and modality of carotid revascularization, which are controversially discussed in patients with heart disease. More data regarding outcome predictors and measures are needed to gain a better understanding of the best treatment option of the discussed patient collective., Methods: This single-center study retrospectively analyzed n = 111 patients undergoing heart surgery with coronary artery bypass grafting or heart-valve surgery and concomitant carotid surgery due to significant internal carotid artery stenosis. In order to do so, patients were divided into two groups with respect to postoperative major adverse cardiac and cerebrovascular events (MACCE) with thirty-day all-cause mortality, valve related mortality, myocardial infarction, stroke and transitory ischemic attack., Results: Preoperative patient's characteristic in the no-MACCE and MACCE group were mainly balanced, other than higher rates of chronic obstructive pulmonary disease, chronic kidney disease, instable angina pectoris and prior transitory ischemic attack in the MACCE cohort. The analysis of intraoperative characteristics revealed a higher number of intra-aortic balloon pump implantation, which is in line for a higher number of postoperative supports. Besides MACCE, patients suffered significantly more often from postoperative bleeding events and re-thoracotomy, cardiopulmonary reanimation, new onset postoperative dialysis and prolonged intensive care unit stay related complications., Conclusions: Within the reported patient population suffering from MACCE after a simultaneous carotid endarterectomy and heart surgery, a preoperative history of transitory ischemic attack and kidney disease might account for worse outcomes, as severe events were not only neurologically driven but also associated with postoperative cardiovascular complications following heart surgical procedures.

Published
2023
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37. Gender-Related Discrepancies in Short-Term Outcomes in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting Surgery.

Author

Krasivskyi I, Djordjevic I, Ivanov B, Eghbalzadeh K, Großmann C, Reichert S, Radwan M, Sandoval Boburg R, Sabashnikov A, Schlensak C, Wahlers T, and Rustenbach CJ

Abstract

The sex differences in patients undergoing off-pump coronary artery bypass grafting (OPCAB) surgery are still unclear. Our aim was to investigate the impact of gender on short-term outcomes in males and females after off-pump bypass procedures. Our research was designed as a double-center retrospective analysis. Generally, 343 patients (men (n = 255) and women (n = 88)) who underwent an OPCAB procedure were included in our study. To provide a statistical analysis of unequal cohorts, we created a propensity score-based matching (PSM) analysis (men, n = 61; women, n = 61). The primary endpoint was all-cause in-hospital mortality. Dialysis, transient ischemic attack (TIA), low cardiac output syndrome (LCOS), reoperation due to postoperative bleeding, wound infection and duration of hospital stay were secondary outcomes in our analysis. No significant differences were detected within the male and female groups regarding age ( p = 0.116), BMI ( p = 0.221), diabetes ( p = 0.853), cardiogenic shock (0.256), STEMI ( p = 0.283), NSTEMI ( p = 0.555) and dialysis ( p = 0.496). Males underwent significantly more frequently ( p = 0.005) total-arterial revascularization with T-graft technique ( p = 0.005) than females. In contrast, temporary pacer use was significantly higher ( p = 0.022) in females compared to males. The in-hospital mortality rate was not significantly higher ( p = 0.496) in the female group compared to the male group. Likewise, secondary outcomes did not differ significantly between the non-adjusted and the adjusted groups. Based on our findings, gender has no impact on short-term outcomes after OPCAB surgery.

Published
2023
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38. Consequences of Obesity on Short-Term Outcomes in Patients Who Underwent Off-Pump Coronary Artery Bypass Grafting Surgery.

Author

Krasivskyi I, Djordjevic I, Ivanov B, Eghbalzadeh K, Großmann C, Reichert S, Radwan M, Sandoval Boburg R, Sabashnikov A, Schlensak C, Wahlers T, and Rustenbach CJ

Abstract

The correlation between off-pump coronary artery bypass (OPCAB) surgery and obesity-related outcomes is still uncertain. The aim of our study was to analyse the pre-, intra-, and postoperative short-term outcomes between obese and non-obese patients after off-pump bypass surgery. We performed a retrospective analysis from January 2017 until November 2022, including a total of 332 (non-obese ( n = 193) and obese ( n = 139)) patients who underwent an OPCAB procedure due to coronary artery disease (CAD). The primary outcome was all-cause in-hospital mortality. Our results showed no difference regarding mean age of the study population between both groups. The use of the T-graft technique was significantly higher ( p = 0.045) in the non-obese group compared to the obese group. The dialysis rate was significantly lower in non-obese patients ( p = 0.019). In contrast, the wound infection rate was significantly higher ( p = 0.014) in the non-obese group compared to the obese group. The all-cause in-hospital mortality rate did not differ significantly ( p = 0.651) between the two groups. Furthermore, ST-elevation myocardial infarction (STEMI) and reoperation were relevant predictors for in-hospital mortality. Therefore, OPCAB surgery remains a safe procedure even in obese patients.

Published
2023
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39. Acute Limb Ischaemia during ECMO Support: A 6-Year Experience.

Author

Krasivskyi I, Großmann C, Dechow M, Djordjevic I, Ivanov B, Gerfer S, Bennour W, Kuhn E, Sabashnikov A, Rahmanian PB, Mader N, Eghbalzadeh K, and Wahlers T

Abstract

The use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock is rising. Acute limb ischaemia remains one of the main complications after ECMO initiation. We analysed 104 patients from our databank from January 2015 to December 2021 who were supported with mobile ECMO therapy. We aimed to identify the impact of acute limb ischaemia on short-term outcomes in patients placed on ECMO in our institution. The main indication for ECMO therapy was left ventricular (LV) failure with cardiogenic shock (57.7%). Diameters of arterial cannulas ( p = 0.365) showed no significant differences between both groups. Furthermore, concomitant intra-aortic balloon pump (IABP, p = 0.589) and Impella ( p = 0.385) implantation did not differ significantly between both groups. Distal leg perfusion was established in approximately 70% of patients in two groups with no statistically significant difference ( p = 0.960). Acute limb ischaemia occurred in 18.3% of cases (n = 19). In-hospital mortality was not significantly different ( p = 0.799) in both groups. However, the bleeding rate was significantly higher ( p = 0.005) in the limb ischaemia group compared to the no-limb ischaemia group. Therefore, early diagnosis and prevention of acute limb ischaemia might decrease haemorrhage complications in patients during ECMO therapy.

Published
2023
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40. ECMO Retrieval Program: What Have We Learned So Far.

Author

Krasivskyi I, Großmann C, Dechow M, Djordjevic I, Ivanov B, Gerfer S, Bennour W, Kuhn E, Sabashnikov A, Mader N, Eghbalzadeh K, and Wahlers T

Abstract

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used for patients with cardiogenic shock or cardiac arrest. However, survival rates remain low. It is unclear to what extent ECMO patients benefit from the ECMO team learning curve. Therefore, we aimed to analyze our mobile ECMO program patients from the past seven years to evaluate if a learning curve benefits patients’ outcomes. We analyzed 111 patients from our databank who were supported with a VA-ECMO and brought to our hospital from January 2015 to December 2021. Patients were divided into two groups: survival (n = 70) and non-survival (n = 41). As expected, complications after ECMO implantation were more severe in the non-survivor group. The incidence of thromboembolic events (p = 0.002), hepatic failure (p < 0.001), renal failure (p = 0.002), dialysis (p = 0.002) and systemic inflammatory response syndrome (SIRS, p = 0.044) occurred significantly more often compared with the survivor group. We were able to show that despite our extensive experience in terms of ECMO retrieval program the high mortality and morbidity rates stay fairly the same over the years. This displays that we have to focus even more on patient selection and ECMO indication.

Published
2023
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41. Sex-Associated Differences in Short-Term Outcomes in Patients with Deep Sternal Wound Infection after Open-Heart Surgery.

Author

Krasivskyi I, Ivanov B, Eghbalzadeh K, Fehlau F, Gerfer S, Großmann C, Elderia A, Sabashnikov A, Rahmanian PB, Mader N, Djordjevic I, and Wahlers T

Abstract

Deep sternal wound infection (DSWI) is a feared complication after cardiac surgery. The impact of sex-related differences on wound infection prevalence is poorly understood. Our aim was to evaluate the effect of sex on short-term outcomes in patients with DSWI after open-heart surgery. The study was a retrospective cohort study. A total of 217 patients with DSWI were identified and retrospectively analyzed using our institutional database. Patients were divided into two groups: males ( n = 150) and females ( n = 67). This study also includes a propensity score based matching (PSM) analysis (male group ( n = 62) and female group ( n = 62)) to examine the unequal groups. Mean age ( p = 0.088) and mean body mass index (BMI) ( p = 0.905) did not significantly differ between both groups. Vacuum assisted closure (VAC) therapy was performed among most patients (82.3% (male group) vs. 83.9% (female group), p = 0.432). The most commonly isolated bacteria from the wounds were Staphylococcus epidermidis and Staphylococcus aureus in both groups. Acute renal failure was significantly higher ( p = 0.010) in the male group compared to the female group. However, dialysis rate did not significantly differ ( p = 0.491) between male and female groups. Further secondary outcomes showed no major differences between the groups. Likewise, in-hospital mortality rate did not differ significantly ( p = 0.680) between both groups. Based on our data, sex has no impact on deep wound infection prevalence after cardiac surgery.

Published
2022
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42. Impact of Obesity on Early In-Hospital Outcomes after Coronary Artery Bypass Grafting Surgery in Acute Coronary Syndrome: A Propensity Score Matching Analysis.

Author

Krasivskyi I, Eghbalzadeh K, Ivanov B, Gerfer S, Großmann C, Sabashnikov A, Kuhn E, Mader N, Djordjevic I, and Wahlers T

Abstract

Recent advances in perioperative care have considerably improved outcomes after coronary artery bypass graft (CABG) surgery. However, obesity can increase postoperative complication rates and can lead to increased morbidity and mortality. Between June 2011 and October 2019, a total of 1375 patients with acute coronary syndrome (ACS) underwent cardiac surgery and were retrospectively analyzed. Patients were divided into 2 groups: non-obese (body mass index (BMI) < 30 kg/m2, n = 967) and obese (BMI ≥ 30 kg/m2, n = 379). Underweight patients (n = 29) were excluded from the analysis. To compare the unequal patient groups, a propensity score-based matching (PSM) was applied (non-obese group (n = 372) vs. obese group (n = 372)). The mean age of the mentioned groups was 67 ± 10 (non-obese group) vs. 66 ± 10 (obese group) years, p = 0.724. All-cause in-hospital mortality did not significantly differ between the groups before PSM (p = 0.566) and after PSM (p = 0.780). The median length of ICU (p = 0.306 before PSM and p = 0.538 after PSM) and hospital stay (p = 0.795 before PSM and p = 0.131 after PSM) was not significantly higher in the obese group compared with the non-obese group. No significant differences regarding further postoperative parameters were observed between the unadjusted and the adjusted group. Obesity does not predict increased all-cause in-hospital mortality in patients undergoing CABG procedure. Therefore, CABG is a safe procedure for overweight patients.

Published
2022
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43. Importance of Micromilieu for Pathophysiologic Mineralocorticoid Receptor Activity-When the Mineralocorticoid Receptor Resides in the Wrong Neighborhood.

Author

Griesler B, Schuelke C, Uhlig C, Gadasheva Y, and Grossmann C

Subjects
Ligands, DNA, Transcription Factors, Water, Glucose, Receptors, Mineralocorticoid genetics, Receptors, Mineralocorticoid metabolism, Aldosterone metabolism
Abstract

The mineralocorticoid receptor (MR) is a member of the steroid receptor family and acts as a ligand-dependent transcription factor. In addition to its classical effects on water and electrolyte balance, its involvement in the pathogenesis of cardiovascular and renal diseases has been the subject of research for several years. The molecular basis of the latter has not been fully elucidated, but an isolated increase in the concentration of the MR ligand aldosterone or MR expression does not suffice to explain long-term pathologic actions of the receptor. Several studies suggest that MR activity and signal transduction are modulated by the surrounding microenvironment, which therefore plays an important role in MR pathophysiological effects. Local changes in micromilieu, including hypoxia, ischemia/reperfusion, inflammation, radical stress, and aberrant salt or glucose concentrations affect MR activation and therefore may influence the probability of unphysiological MR actions. The surrounding micromilieu may modulate genomic MR activity either by causing changes in MR expression or MR activity; for example, by inducing posttranslational modifications of the MR or novel interaction with coregulators, DNA-binding sites, or non-classical pathways. This should be considered when developing treatment options and strategies for prevention of MR-associated diseases.

Published
2022
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44. Structural and molecular determinants of mineralocorticoid receptor signalling.

Author

Grossmann C, Almeida-Prieto B, Nolze A, and Alvarez de la Rosa D

Subjects
Aldosterone, Receptors, Glucocorticoid, Receptors, Mineralocorticoid metabolism, Signal Transduction
Abstract

During the past decades, the mineralocorticoid receptor (MR) has evolved from a much-overlooked member of the steroid hormone receptor family to an important player, not only in volume and electrolyte homeostasis but also in pathological changes occurring in an increasing number of tissues, especially the renal and cardiovascular systems. Simultaneously, a wealth of information about the structure, interaction partners and chromatin requirements for genomic signalling of steroid hormone receptors became available. However, much of the information for the MR has been deduced from studies of other family members and there is still a lack of knowledge about MR-specific features in ligand binding, chromatin remodelling, co-factor interactions and general MR specificity-conferring mechanisms that can completely explain the differences in pathophysiological function between MR and its closest relative, the glucocorticoid receptor. This review aims to give an overview of the current knowledge of MR structure, signalling and co-factors modulating its activity. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Published
2022
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45. Protein Phosphatase 2A Improves Cardiac Functional Response to Ischemia and Sepsis.

Author

Gergs U, Jahn T, Schulz N, Großmann C, Rueckschloss U, Demus U, Buchwalow IB, and Neumann J

Subjects
Animals, Heart Function Tests, Lipopolysaccharides metabolism, Mice, Phosphorylation, Protein Processing, Post-Translational, Ischemia metabolism, Myocytes, Cardiac metabolism, Protein Phosphatase 2 genetics, Protein Phosphatase 2 metabolism, Sepsis metabolism
Abstract

Reversible protein phosphorylation is a posttranslational modification of regulatory proteins involved in cardiac signaling pathways. Here, we focus on the role of protein phosphatase 2A (PP2A) for cardiac gene expression and stress response using a transgenic mouse model with cardiac myocyte-specific overexpression of the catalytic subunit of PP2A (PP2A-TG). Gene and protein expression were assessed under basal conditions by gene chip analysis and Western blotting. Some cardiac genes related to the cell metabolism and to protein phosphorylation such as kinases and phosphatases were altered in PP2A-TG compared to wild type mice (WT). As cardiac stressors, a lipopolysaccharide (LPS)-induced sepsis in vivo and a global cardiac ischemia in vitro (stop-flow isolated perfused heart model) were examined. Whereas the basal cardiac function was reduced in PP2A-TG as studied by echocardiography or as studied in the isolated work-performing heart, the acute LPS- or ischemia-induced cardiac dysfunction deteriorated less in PP2A-TG compared to WT. From the data, we conclude that increased PP2A activity may influence the acute stress tolerance of cardiac myocytes.

Published
2022
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46. Impact of Porphyrin Binding to GENOMES UNCOUPLED 4 on Tetrapyrrole Biosynthesis in planta .

Author

Fölsche V, Großmann C, and Richter AS

Abstract

Plant tetrapyrrole biosynthesis (TPS) provides the indispensable chlorophyll (Chl) and heme molecules in photosynthetic organisms. Post-translational mechanisms control the enzymes to ensure a balanced flow of intermediates in the pathway and synthesis of appropriate amounts of both endproducts. One of the critical regulators of TPS is GENOMES UNCOUPLED 4 (GUN4). GUN4 interacts with magnesium chelatase (MgCh), and its binding of the catalytic substrate and product of the MgCh reaction stimulates the insertion of Mg 2+ into protoporphyrin IX. Despite numerous in vitro studies, knowledge about the in vivo function of the GUN4:porphyrin interaction for the whole TPS pathway, particularly in plants, is still limited. To address this, we focused on two highly conserved amino acids crucial for porphyrin-binding to GUN4 and analyzed GUN4-F191A, R211A, and R211E substitution mutants in vitro and in vivo . Our analysis confirmed the importance of these amino acids for porphyrin-binding and the stimulation of plant MgCh by GUN4 in vitro . Expression of porphyrin-binding deficient F191A, R211A, and R211E in the Arabidopsis gun4-2 knockout mutant background revealed that, unlike in cyanobacteria and green algae, GUN4:porphyrin interactions did not affect the stability of GUN4 or other Arabidopsis TPS pathway enzymes in vivo . In addition, although they shared diminished porphyrin-binding and MgCh activation in vitro , expression of the different GUN4 mutants in gun4-2 had divergent effects on the TPS and the accumulation of Chl and Chl-binding proteins. For instance, expression of R211E , but not R211A , induced a substantial decrease of ALA synthesis rate, lower TPS intermediate and Chl level, and strongly impaired accumulation of photosynthetic complexes compared to wild-type plants. Furthermore, the presence of R211E led to significant growth retardation and paler leaves compared to GUN4 knockdown mutants, indicating that the exchange of R211 to glutamate compromised TPS and Chl accumulation more substantially than the almost complete lack of GUN4. Extensive in vivo analysis of GUN4 point mutants suggested that F191 and R211 might also play a role beyond porphyrin-binding., 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 Fölsche, Großmann and Richter.)

Published
2022
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47. Influence of miR-221/222 on cardiomyocyte calcium handling and function.

Author

Knyrim M, Rabe S, Grossmann C, Gekle M, and Schreier B

Abstract

Background: Cardiovascular disease is the leading cause of death worldwide. Cardiac electrical remodeling including altered ion channel expression and imbalance of calcium homeostasis can have detrimental effects on cardiac function. While it has been extensively reported that miR-221/222 are involved in structural remodeling, their role in electrical remodeling still has to be evaluated. We previously reported that subunits of the L-type Ca 2+ channel (LTCC) are direct targets of miR-221/222. Furthermore, HL-1 cells transfected with miR-221 or -222 mimics showed a reduction in LTCC current density while the voltage-dependence of activation was not altered. The aim of the present study was to determine the influence of miR-221/222 on cardiomyocyte calcium handling and function., Results: Transient transfection of HL-1 cells with miR-221/222 mimics led to slower depolarization-dependent Ca 2+ entry and increased proportion of non-responding cells. Angiotensin II-induced Ca 2+ release from the SR was not affected by miR-221/222. In miR-222-transfected neonatal cardiomyocytes the isoprenaline-induced positive inotropic effect on the intracellular Ca 2+ transient was lost and the positive chronotropic effect on spontaneous beating activity was strongly reduced. This could have severe consequences for cardiomyocytes and could lead to a reduced contractility and systolic dysfunction of the whole heart., Conclusions: This study adds a new role of miR-221/222 in cardiomyocytes by showing the impact on β-adrenergic regulation of LTCC function, calcium handling and beating frequency. Together with the previous report that miR-221/222 reduce GIRK1/4 function and LTCC current density, it expands our knowledge about the role of these miRs on cardiac ion channel regulation., (© 2021. The Author(s).)

Published
2021
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48. The mineralocorticoid receptor leads to increased expression of EGFR and T-type calcium channels that support HL-1 cell hypertrophy.

Author

Stroedecke K, Meinel S, Markwardt F, Kloeckner U, Straetz N, Quarch K, Schreier B, Kopf M, Gekle M, and Grossmann C

Subjects
Aldosterone genetics, Animals, Cardiovascular System drug effects, Cardiovascular System pathology, Cell Line, Female, Genotype, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mineralocorticoid Receptor Antagonists pharmacology, Myocytes, Cardiac drug effects, Polymorphism, Single Nucleotide genetics, Rats, Calcium Channels, T-Type genetics, ErbB Receptors genetics, Hypertrophy genetics, Receptors, Mineralocorticoid genetics
Abstract

The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important effector of the renin-angiotensin-aldosterone-system and elicits pathophysiological effects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR-mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. We identified a SNP within the EGFR promoter that modulates MR-induced EGFR expression. In RNA-sequencing and qPCR experiments in heart tissue of EGFR KO and WT mice, changes in EGFR abundance led to differential expression of cardiac ion channels, especially of the T-type calcium channel CACNA1H. Accordingly, CACNA1H expression was increased in WT mice after in vivo MR activation by aldosterone but not in respective EGFR KO mice. Aldosterone- and EGF-responsiveness of CACNA1H expression was confirmed in HL-1 cells by Western blot and by measuring peak current density of T-type calcium channels. Aldosterone-induced CACNA1H protein expression could be abrogated by the EGFR inhibitor AG1478. Furthermore, inhibition of T-type calcium channels with mibefradil or ML218 reduced diameter, volume and BNP levels in HL-1 cells. In conclusion the MR regulates EGFR and CACNA1H expression, which has an effect on HL-1 cell diameter, and the extent of this regulation seems to depend on the SNP-216 (G/T) genotype. This suggests that the EGFR may be an intermediate for MR-mediated cardiovascular changes and that SNP analysis can help identify subgroups of patients that will benefit most from MR antagonists.

Published
2021
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49. miR-208b Reduces the Expression of Kcnj5 in a Cardiomyocyte Cell Line.

Author

Hupfeld J, Ernst M, Knyrim M, Binas S, Kloeckner U, Rabe S, Quarch K, Misiak D, Fuszard M, Grossmann C, Gekle M, and Schreier B

Abstract

MicroRNAs (miRs) contribute to different aspects of cardiovascular pathology, among them cardiac hypertrophy and atrial fibrillation. Cardiac miR expression was analyzed in a mouse model with structural and electrical remodeling. Next-generation sequencing revealed that miR-208b-3p was ~25-fold upregulated. Therefore, the aim of our study was to evaluate the impact of miR-208b on cardiac protein expression. First, an undirected approach comparing whole RNA sequencing data to miR-walk 2.0 miR-208b 3'-UTR targets revealed 58 potential targets of miR-208b being regulated. We were able to show that miR-208b mimics bind to the 3' untranslated region (UTR) of voltage-gated calcium channel subunit alpha1 C and Kcnj5, two predicted targets of miR-208b. Additionally, we demonstrated that miR-208b mimics reduce GIRK1/4 channel-dependent thallium ion flux in HL-1 cells. In a second undirected approach we performed mass spectrometry to identify the potential targets of miR-208b. We identified 40 potential targets by comparison to miR-walk 2.0 3'-UTR, 5'-UTR and CDS targets. Among those targets, Rock2 and Ran were upregulated in Western blots of HL-1 cells by miR-208b mimics. In summary, miR-208b targets the mRNAs of proteins involved in the generation of cardiac excitation and propagation, as well as of proteins involved in RNA translocation (Ran) and cardiac hypertrophic response (Rock2).

Published
2021
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50. Posttranslational Modifications of the Mineralocorticoid Receptor and Cardiovascular Aging.

Author

Gadasheva Y, Nolze A, and Grossmann C

Abstract

During aging, the cardiovascular system is especially prone to a decline in function and to life-expectancy limiting diseases. Cardiovascular aging is associated with increased arterial stiffness and vasoconstriction as well as left ventricular hypertrophy and reduced diastolic function. Pathological changes include endothelial dysfunction, atherosclerosis, fibrosis, hypertrophy, inflammation, and changes in micromilieu with increased production of reactive oxygen and nitrogen species. The renin-angiotensin-aldosterone-system is an important mediator of electrolyte and blood pressure homeostasis and a key contributor to pathological remodeling processes of the cardiovascular system. Its effects are partially conveyed by the mineralocorticoid receptor (MR), a ligand-dependent transcription factor, whose activity increases during aging and cardiovascular diseases without correlating changes of its ligand aldosterone. There is growing evidence that the MR can be enzymatically and non-enzymatically modified and that these modifications contribute to ligand-independent modulation of MR activity. Modifications reported so far include phosphorylation, acetylation, ubiquitination, sumoylation and changes induced by nitrosative and oxidative stress. This review focuses on the different posttranslational modifications of the MR, their impact on MR function and degradation and the possible implications for cardiovascular aging and diseases., 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 © 2021 Gadasheva, Nolze and Grossmann.)

Published
2021
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