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3. ESICM LIVES 2016: part one: Milan, Italy. 1-5 October 2016

Author

Bos, L., Schouten, L., van Vught, L., Wiewel, M., Ong, D., Cremer, O., Artigas, A., Martin-Loeches, I., Hoogendijk, A., van der Poll, T., Horn, J., Juffermans, N., Schultz, M., de Prost, N., Pham, T., Carteaux, G., Dessap, A. Mekontso, Brun-Buisson, C., Fan, E., Bellani, G., Laffey, J., Mercat, A., Brochard, L., Maitre, B., Howells, P. A., Thickett, D. R., Knox, C., Park, D. P., Gao, F., Tucker, O., Whitehouse, T., McAuley, D. F., Perkins, G. D., Pham, T., Laffey, J., Bellani, G., Fan, E., Pisani, L., Roozeman, J. P., Simonis, F. D., Giangregorio, A., Schouten, L. R., Van der Hoeven, S. M., Horn, J., Neto, A. Serpa, Festic, E., Dondorp, A. M., Grasso, S., Bos, L. D., Schultz, M. J., Koster-Brouwer, M., Verboom, D., Scicluna, B., van de Groep, K., Frencken, J., Schultz, M., van der Poll, T., Bonten, M., Cremer, O., Ko, J. I., Kim, K. S., Suh, G. J., Kwon, W. Y., Kim, K., Shin, J. H., Ranzani, O. T., Prina, E., Menendez, R., Ceccato, A., Mendez, R., Cilloniz, C., Gabarrus, A., Ferrer, M., Torres, A., Urbano, A., Zhang, L. A., Swigon, D., Pike, F., Parker, R. S., Clermont, G., Scheer, C., Kuhn, S. O., Modler, A., Vollmer, M., Fuchs, C., Hahnenkamp, K., Rehberg, S., Gründling, M., Taggu, A., Darang, N., Öveges, N., László, I., Tánczos, K., Németh, M., Lebák, G., Tudor, B., Érces, D., Kaszaki, J., Huber, W., Trásy, D., Molnár, Z., Ferrara, G., Edul, V. S. Kanoore, Canales, H. S., Martins, E., Canullán, C., Murias, G., Pozo, M. O., Eguillor, J. F. Caminos, Buscetti, M. G., Ince, C., Dubin, A., Aya, H. D., Rhodes, A., Fletcher, N., Grounds, R. M., Cecconi, M., Jacquet-Lagrèze, M., Riche, M., Schweizer, R., Portran, P., Fornier, W., Lilot, M., Neidecker, J., Fellahi, J. L., Escoresca-Ortega, A., Gutiérrez-Pizarraya, A., Charris-Castro, L., Corcia-Palomo, Y., Fernandez-Delgado, E., Garnacho-Montero, J., Roger, C., Muller, L., Elotmani, L., Lipman, J., Lefrant, J. Y., Roberts, J. A., Muñoz-Bermúdez, R., Samper, M., Climent, C., Vasco, F., Sara, V., Luque, S., Campillo, N., Cerrato, S. Grau, Masclans, J. R., Alvarez-Lerma, F., Brugger, S. Carvalho, Jimenez, G. Jimenez, Torner, M. Miralbés, Cabello, J. Trujillano, Garrido, B. Balsera, Casals, X. Nuvials, Gaite, F. Barcenilla, Vidal, M. Vallverdú, Martínez, M. Palomar, Gusarov, V., Shilkin, D., Dementienko, M., Nesterova, E., Lashenkova, N., Kuzovlev, A., Zamyatin, M., Demoule, A., Carreira, S., Lavault, S., Palancca, O., Morawiec, E., Mayaux, J., Arnulf, I., Similowski, T., Rasmussen, B. S., Maltesen, R. G., Hanifa, M., Pedersen, S., Kristensen, S. R., Wimmer, R., Panigada, M., Bassi, G. Li, Ranzani, O. T., Kolobow, T., Zanella, A., Cressoni, M., Berra, L., Parrini, V., Kandil, H., Salati, G., Livigni, S., Amatu, A., Andreotti, A., Tagliaferri, F., Moise, G., Mercurio, G., Costa, A., Vezzani, A., Lindau, S., Babel, J., Cavana, M., Consonni, D., Pesenti, A., Gattinoni, L., Torres, A., Mansouri, P., Zand, F., Zahed, L., Dehghanrad, F., Bahrani, M., Ghorbani, M., Cambiaghi, B., Moerer, O., Mauri, T., Kunze-Szikszay, N., Ritter, C., Pesenti, A., Quintel, M., Vilander, L. M., Kaunisto, M. A., Vaara, S. T., Pettilä, V., Mulier, J. L. G. Haitsma, Rozemeijer, S., Spoelstra-de Man, A. M. E., Elbers, P. E., Tuinman, P. R., de Waard, M. C., Oudemans-van Straaten, H. M., Liberatore, A. M. A., Souza, R. B., Martins, A. M. C. R. P. F., Vieira, J. C. F., Koh, I. H. J., Martínez, M. Galindo, Sánchez, R. Jiménez, Gascón, L. Martínez, Mulero, M. D. Rodríguez, Freire, A. Ortín, Muñoz, A. Ojados, Acebes, S. Rebollo, Martínez, Á. Fernández, Aliaga, S. Moreno, Para, L. Herrera, Payá, J. Murcia, Mulero, F. Rodríguez, Guerci, P., Ince, Y., Heeman, P., Ergin, B., Ince, C., Uz, Z., Massey, M., Ince, Y., Papatella, R., Bulent, E., Guerci, P., Toraman, F., Ince, C., Longbottom, E. R., Torrance, H. D., Owen, H. C., Hinds, C. J., Pearse, R. M., O’Dywer, M. J., Trogrlic, Z., van der Jagt, M., Lingsma, H., Ponssen, H. H., Schoonderbeek, J. F., Schreiner, F., Verbrugge, S. J., Duran, S., van Achterberg, T., Bakker, J., Gommers, D. A. M. P. J., Ista, E., Krajčová, A., Waldauf, P., Duška, F., Shah, A., Roy, N., McKechnie, S., Doree, C., Fisher, S., Stanworth, S. J., Jensen, J. F., Overgaard, D., Bestle, M. H., Christensen, D. F., Egerod, I., Pivkina, A., Gusarov, V., Zhivotneva, I., Pasko, N., Zamyatin, M., Jensen, J. F., Egerod, I., Bestle, M. H., Christensen, D. F., Alklit, A., Hansen, R. L., Knudsen, H., Grode, L. B., Overgaard, D., Hravnak, M., Chen, L., Dubrawski, A., Clermont, G., Pinsky, M. R., Parry, S. M., Knight, L. D., Connolly, B. C., Baldwin, C. E., Puthucheary, Z. A., Denehy, L., Hart, N., Morris, P. E., Mortimore, J., Granger, C. L., Jensen, H. I., Piers, R., Van den Bulcke, B., Malmgren, J., Metaxa, V., Reyners, A. K., Darmon, M., Rusinova, K., Talmor, D., Meert, A. P., Cancelliere, L., Zubek, L., Maia, P., Michalsen, A., Decruyenaere, J., Kompanje, E., Vanheule, S., Azoulay, E., Vansteelandt, S., Benoit, D., Van den Bulcke, B., Piers, R., Jensen, H. I., Malmgren, J., Metaxa, V., Reyners, A. K., Darmon, M., Rusinova, K., Talmor, D., Meert, A. P., Cancelliere, L., Zubek, L., Maia, P., Michalsen, A., Decruyenaere, J., Kompanje, E., Vanheule, S., Azoulay, E., Vansteelandt, S., Benoit, D., Ryan, C., Dawson, D., Ball, J., Noone, K., Aisling, B., Prudden, S., Ntantana, A., Matamis, D., Savvidou, S., Giannakou, M., Gouva, M., Nakos, G., Koulouras, V., Aron, J., Lumley, G., Milliken, D., Dhadwal, K., McGrath, B. A., Lynch, S. J., Bovento, B., Sharpe, G., Grainger, E., Pieri-Davies, S., Wallace, S., McGrath, B., Lynch, S. J., Bovento, B., Grainger, E., Pieri-Davies, S., Sharpe, G., Wallace, S., Jung, M., Cho, J., Park, H., Suh, G., Kousha, O., Paddle, J., Gripenberg, L. Gamrin, Rehal, M. Sundström, Wernerman, J., Rooyackers, O., de Grooth, H. J., Choo, W. P., Spoelstra-de Man, A. M., Swart, E. L., Oudemans-van Straaten, H. M., Talan, L., Güven, G., Altıntas, N. D., Padar, M., Uusvel, G., Starkopf, L., Starkopf, J., Blaser, A. Reintam, Kalaiselvan, M. S., Arunkumar, A. S., Renuka, M. K., Shivkumar, R. L., Volbeda, M., ten Kate, D., Hoekstra, M., van der Maaten, J. M., Nijsten, M. W., Komaromi, A., Rooyackers, O., Wernerman, J., Norberg, Å., Smedberg, M., Mori, M., Pettersson, L., Norberg, Å., Rooyackers, O., Wernerman, J., Theodorakopoulou, M., Christodoulopoulou, T., Diamantakis, A., Frantzeskaki, F., Kontogiorgi, M., Chrysanthopoulou, E., Lygnos, M., Diakaki, C., Armaganidis, A., Gundogan, K., Dogan, E., Coskun, R., Muhtaroglu, S., Sungur, M., Ziegler, T., Guven, M., Kleyman, A., Khaliq, W., Andreas, D., Singer, M., Meierhans, R., Schuepbach, R., De Brito-Ashurst, I., Zand, F., Sabetian, G., Nikandish, R., Hagar, F., Masjedi, M., Maghsudi, B., Vazin, A., Ghorbani, M., Asadpour, E., Kao, K. C., Chiu, L. C., Hung, C. Y., Chang, C. H., Li, S. H., Hu, H. C., El Maraghi, S., Ali, M., Rageb, D., Helmy, M., Marin-Corral, J., Vilà, C., Masclans, J. R., Vàzquez, A., Martín-Loeches, I., Díaz, E., Yébenes, J. C., Rodriguez, A., Álvarez-Lerma, F., Varga, N., Cortina-Gutiérrez, A., Dono, L., Martínez-Martínez, M., Maldonado, C., Papiol, E., Pérez-Carrasco, M., Ferrer, R., Nweze, K., Morton, B., Welters, I., Houard, M., Voisin, B., Ledoux, G., Six, S., Jaillette, E., Nseir, S., Romdhani, S., Bouneb, R., Loghmari, D., Aicha, N. Ben, Ayachi, J., Meddeb, K., Chouchène, I., Khedher, A., Boussarsar, M., Chan, K. S., Yu, W. L., Marin-Corral, J., Vilà, C., Masclans, J. R., Nolla, J., Vidaur, L., Bonastre, J., Suberbiola, B., Guerrero, J. E., Rodriguez, A., Coll, N. Ramon, Jiménez, G. Jiménez, Brugger, S. Carvalho, Calero, J. Codina, Garrido, B. Balsera, García, M., Martínez, M. Palomar, Vidal, M. Vallverdú, de la Torre, M. C., Vendrell, E., Palomera, E., Güell, E., Yébenes, J. C., Serra-Prat, M., Bermejo-Martín, J. F., Almirall, J., Tomas, E., Escoval, A., Froe, F., Pereira, M. H. Vitoria, Velez, N., Viegas, E., Filipe, E., Groves, C., Reay, M., Chiu, L. C., Hu, H. C., Hung, C. Y., Chang, C. H., Li, S. H., Kao, K. C., Ballin, A., Facchin, F., Sartori, G., Zarantonello, F., Campello, E., Radu, C. M., Rossi, S., Ori, C., Simioni, P., Umei, N., Shingo, I., Santos, A. C., Candeias, C., Moniz, I., Marçal, R., e Silva, Z. Costa, Ribeiro, J. M., Georger, J. F., Ponthus, J. P., Tchir, M., Amilien, V., Ayoub, M., Barsam, E., Martucci, G., Panarello, G., Tuzzolino, F., Capitanio, G., Ferrazza, V., Carollo, T., Giovanni, L., Arcadipane, A., Sánchez, M. López, González-Gay, M. A., Díaz, F. J. Llorca, López, M. I. Rubio, Zogheib, E., Villeret, L., Nader, J., Bernasinski, M., Besserve, P., Caus, T., Dupont, H., Morimont, P., Habran, S., Hubert, R., Desaive, T., Blaffart, F., Janssen, N., Guiot, J., Pironet, A., Dauby, P., Lambermont, B., Zarantonello, F., Ballin, A., Facchin, F., Sartori, G., Campello, E., Pettenuzzo, T., Citton, G., Rossi, S., Simioni, P., Ori, C., Kirakli, C., Ediboglu, O., Ataman, S., Yarici, M., Tuksavul, F., Keating, S., Gibson, A., Gilles, M., Dunn, M., Price, G., Young, N., Remeta, P., Bishop, P., Zamora, M. D. Fernández, Muñoz-Bono, J., Curiel-Balsera, E., Aguilar-Alonso, E., Hinojosa, R., Gordillo-Brenes, A., Arboleda-Sánchez, J. A., Skorniakov, I., Vikulova, D., Whiteley, C., Shaikh, O., Jones, A., Ostermann, M., Forni, L., Scott, M., Sahatjian, J., Linde-Zwirble, W., Hansell, D., Laoveeravat, P., Srisawat, N., Kongwibulwut, M., Peerapornrattana, S., Suwachittanont, N., Wirotwan, T. O., Chatkaew, P., Saeyub, P., Latthaprecha, K., Tiranathanagul, K., Eiam-ong, S., Kellum, J. A., Berthelsen, R. E., Perner, A., Jensen, A. E. K., Jensen, J. U., Bestle, M. H., Gebhard, D. J., Price, J., Kennedy, C. E., Akcan-Arikan, A., Liberatore, A. M. A., Souza, R. B., Martins, A. M. C. R. P. F., Vieira, J. C. F., Kang, Y. R., Nakamae, M. N., Koh, I. H. J., Hamed, K., Khaled, M. M., Soliman, R. Aly, Mokhtar, M. Sherif, Seller-Pérez, G., Arias-Verdú, D., Llopar-Valdor, E., De-Diós-Chacón, I., Quesada-García, G., Herrera-Gutierrez, M. E., Hafes, R., Carroll, G., Doherty, P., Wright, C., Vera, I. G. Guerra, Ralston, M., Gemmell, M. L., MacKay, A., Black, E., Wright, C., Docking, R. I., Appleton, R., Ralston, M. R., Gemmell, L., Appleton, R., Wright, C., Docking, R. I., Black, E., Mackay, A., Rozemeijer, S., Mulier, J. L. G. Haitsma, Röttgering, J. G., Elbers, P. W. G., Spoelstra-de Man, A. M. E., Tuinman, P. R., de Waard, M. C., Oudemans-van Straaten, H. M., Mejeni, N., Nsiala, J., Kilembe, A., Akilimali, P., Thomas, G., Egerod, I., Andersson, A. E., Fagerdahl, A. M., Knudsen, V., Meddeb, K., Cheikh, A. Ben, Hamdaoui, Y., Ayachi, J., Guiga, A., Fraj, N., Romdhani, S., Sma, N., Bouneb, R., Chouchene, I., Khedher, A., Bouafia, N., Boussarsar, M., Amirian, A., Ziaian, B., Masjedi, M., Fleischmann, C., Thomas-Rueddel, D. O., Schettler, A., Schwarzkopf, D., Stacke, A., Reinhart, K., Filipe, E., Escoval, A., Martins, A., Sousa, P., Velez, N., Viegas, E., Tomas, E., Snell, G., Matsa, R., Paary, T. T. S., Kalaiselvan, M. S., Cavalheiro, A. M., Rocha, L. L., Vallone, C. S., Tonilo, A., Lobato, M. D. S., Malheiro, D. T., Sussumo, G., Lucino, N. M., Zand, F., Rosenthal, V. D., Masjedi, M., Sabetian, G., Maghsudi, B., Ghorbani, M., Dashti, A. Sanaei, Yousefipour, A., Goodall, J. R., Williamson, M., Tant, E., Thomas, N., Balci, C., Gonen, C., Haftacı, E., Gurarda, H., Karaca, E., Paldusová, B., Zýková, I., Šímová, D., Houston, S., D’Antona, L., Lloyd, J., Garnelo-Rey, V., Sosic, M., Sotosek-Tokmazic, V., Kuharic, J., Antoncic, I., Dunatov, S., Sustic, A., Chong, C. T., Sim, M., Lyovarin, T., Díaz, F. M. Acosta, Galdó, S. Narbona, Garach, M. Muñoz, Romero, O. Moreno, Bailón, A. M. Pérez, Pinel, A. Carranza, Colmenero, M., Gritsan, A., Gazenkampf, A., Korchagin, E., Dovbish, N., Lee, R. M., Lim, M. P. P., Chong, C. T., Lim, B. C. L., See, J. J., Assis, R., Filipe, F., Lopes, N., Pessoa, L., Pereira, T., Catorze, N., Aydogan, M. S., Aldasoro, C., Marchio, P., Jorda, A., Mauricio, M. D., Guerra-Ojeda, S., Gimeno-Raga, M., Colque-Cano, M., Bertomeu-Artecero, A., Aldasoro, M., Valles, S. L., Tonon, D., Triglia, T., Martin, J. C., Alessi, M. C., Bruder, N., Garrigue, P., Velly, L., Spina, S., Scaravilli, V., Marzorati, C., Colombo, E., Savo, D., Vargiolu, A., Cavenaghi, G., Citerio, G., Andrade, A. H. V., Bulgarelli, P., Araujo, J. A. P., Gonzalez, V., Souza, V. A., Costa, A., Massant, C., Filho, C. A. C. Abreu, Morbeck, R. A., Burgo, L. E., van Groenendael, R., van Eijk, L. T., Leijte, G. P., Koeneman, B., Kox, M., Pickkers, P., García-de la Torre, A., de la Torre-Prados, M., Fernández-Porcel, A., Rueda-Molina, C., Nuevo-Ortega, P., Tsvetanova-Spasova, T., Cámara-Sola, E., García-Alcántara, A., Salido-Díaz, L., Liao, X., Feng, T., Zhang, J., Cao, X., Wu, Q., Xie, Z., Li, H., Kang, Y., Winkler, M. S., Nierhaus, A., Mudersbach, E., Bauer, A., Robbe, L., Zahrte, C., Schwedhelm, E., Kluge, S., Zöllner, C., Morton, B., Mitsi, E., Pennington, S. H., Reine, J., Wright, A. D., Parker, R., Welters, I. D., Blakey, J. D., Rajam, G., Ades, E. W., Ferreira, D. M., Wang, D., Kadioglu, A., Gordon, S. B., Koch, R., Kox, M., Rahamat-Langedoen, J., Schloesser, J., de Jonge, M., Pickkers, P., Bringue, J., Guillamat-Prats, R., Torrents, E., Martinez, M. L., Camprubí-Rimblas, M., Artigas, A., Blanch, L., Park, S. Y., Park, Y. B., Song, D. K., Shrestha, S., Park, S. H., Koh, Y., Park, M. J., Hong, C. W., Lesur, O., Coquerel, D., Sainsily, X., Cote, J., Söllradl, T., Murza, A., Dumont, L., Dumaine, R., Grandbois, M., Sarret, P., Marsault, E., Salvail, D., Auger-Messier, M., Chagnon, F., Lauretta, M. P., Greco, E., Dyson, A., Singer, M., Preau, S., Ambler, M., Sigurta, A., Saeed, S., Singer, M., Sarıca, L. Topcu, Zibandeh, N., Genc, D., Gul, F., Akkoc, T., Kombak, E., Cinel, L., Akkoc, T., Cinel, I., Pollen, S. J., Arulkumaran, N., Singer, M., Torrance, H. D., Longbottom, E. R., Warnes, G., Hinds, C. J., Pennington, D. J., Brohi, K., O’Dwyer, M. J., Kim, H. Y., Na, S., Kim, J., Chang, Y. F., Chao, A., Shih, P. Y., Lee, C. T., Yeh, Y. C., Chen, L. W., Adriaanse, M., Trogrlic, Z., Ista, E., Lingsma, H., Rietdijk, W., Ponssen, H. H., Schoonderbeek, J. F., Schreiner, F., Verbrugge, S. J., Duran, S., Gommers, D. A. M. P. J., van der Jagt, M., Funcke, S., Sauerlaender, S., Saugel, B., Pinnschmidt, H., Reuter, D. A., Nitzschke, R., Perbet, S., Biboulet, C., Lenoire, A., Bourdeaux, D., Pereira, B., Plaud, B., Bazin, J. E., Sautou, V., Mebazaa, A., Constantin, J. M., Legrand, M., Boyko, Y., Jennum, P., Nikolic, M., Oerding, H., Holst, R., Toft, P., Nedergaard, H. K., Haberlandt, T., Jensen, H. I., Toft, P., Park, S., Kim, S., Cho, Y. J., Lim, Y. J., Chan, A., Tang, S., Nunes, S. L., Forsberg, S., Blomqvist, H., Berggren, L., Sörberg, M., Sarapohja, T., Wickerts, C. J., Hofhuis, J. G. M., Rose, L., Blackwood, B., Akerman, E., Mcgaughey, J., Egerod, I., Fossum, M., Foss, H., Georgiou, E., Graff, H. J., Kalafati, M., Sperlinga, R., Schafer, A., Wojnicka, A. G., Spronk, P. E., Zand, F., Khalili, F., Afshari, R., Sabetian, G., Masjedi, M., Maghsudi, B., Khodaei, H. Haddad, Javadpour, S., Petramfar, P., Nasimi, S., Vazin, A., Ziaian, B., Tabei, H., Gunther, A., Hansen, J. O., Sackey, P., Storm, H., Bernhardsson, J., Sundin, Ø., Bjärtå, A., Bienert, A., Smuszkiewicz, P., Wiczling, P., Przybylowski, K., Borsuk, A., Trojanowska, I., Matysiak, J., Kokot, Z., Paterska, M., Grzeskowiak, E., Messina, A., Bonicolini, E., Colombo, D., Moro, G., Romagnoli, S., De Gaudio, A. R., Corte, F. Della, Romano, S. M., Silversides, J. A., Major, E., Mann, E. E., Ferguson, A. J., Mcauley, D. F., Marshall, J. C., Blackwood, B., Fan, E., Diaz-Rodriguez, J. A., Silva-Medina, R., Gomez-Sandoval, E., Gomez-Gonzalez, N., Soriano-Orozco, R., Gonzalez-Carrillo, P. L., Hernández-Flores, M., Pilarczyk, K., Lubarksi, J., Wendt, D., Dusse, F., Günter, J., Huschens, B., Demircioglu, E., Jakob, H., Palmaccio, A., Dell’Anna, A. M., Grieco, D. L., Torrini, F., Iaquaniello, C., Bongiovanni, F., Antonelli, M., Toscani, L., Antonakaki, D., Bastoni, D., Aya, H. D., Rhodes, A., Cecconi, M., Jozwiak, M., Depret, F., Teboul, J. L., Alphonsine, J., Lai, C., Richard, C., Monnet, X., László, I., Demeter, G., Öveges, N., Tánczos, K., Németh, M., Trásy, D., Kertmegi, I., Érces, D., Tudor, B., Kaszaki, J., Molnár, Z., Hasanin, A., Lotfy, A., El-adawy, A., Nassar, H., Mahmoud, S., Abougabal, A., Mukhtar, A., Quinty, F., Habchi, S., Luzi, A., Antok, E., Hernandez, G., Lara, B., Enberg, L., Ortega, M., Leon, P., Kripper, C., Aguilera, P., Kattan, E., Bakker, J., Huber, W., Lehmann, M., Sakka, S., Bein, B., Schmid, R. M., Preti, J., Creteur, J., Herpain, A., Marc, J., Zogheib, E., Trojette, F., Bar, S., Kontar, L., Titeca, D., Richecoeur, J., Gelee, B., Verrier, N., Mercier, R., Lorne, E., Maizel, J., Dupont, H., Slama, M., Abdelfattah, M. E., Eladawy, A., Elsayed, M. A. Ali, Mukhtar, A., Montenegro, A. Pedraza, Zepeda, E. Monares, Granillo, J. Franco, Sánchez, J. S. Aguirre, Alejo, G. Camarena, Cabrera, A. Rugerio, Montoya, A. A. Tanaka, Lee, C., Hatib, F., Cannesson, M., Theerawit, P., Morasert, T., Sutherasan, Y., Zani, G., Mescolini, S., Diamanti, M., Righetti, R., Scaramuzza, A., Papetti, M., Terenzoni, M., Gecele, C., Fusari, M., Hakim, K. A., Chaari, A., Ismail, M., Elsaka, A. H., Mahmoud, T. M., Bousselmi, K., Kauts, V., Casey, W. F., Hutchings, S. D., Naumann, D., Wendon, J., Watts, S., Kirkman, E., Jian, Z., Buddi, S., Lee, C., Settels, J., Hatib, F., Pinsky, M. R., Bertini, P., Guarracino, F., Trepte, C., Richter, P., Haas, S. A., Eichhorn, V., Kubitz, J. C., Reuter, D. A., Soliman, M. S., Hamimy, W. I., Fouad, A. Z., Mukhtar, A. M., Charlton, M., Tonks, L., Mclelland, L., Coats, T. J., Thompson, J. P., Sims, M. R., Williams, D., Roushdy, D. Z., Soliman, R. A., Nahas, R. A., Arafa, M. Y., Hung, W. T., Chiang, C. C., Huang, W. C., Lin, K. C., Lin, S. C., Cheng, C. C., Kang, P. L., Wann, S. 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W., Kaymak, C., Okumus, N., Sari, A., Erdogdu, B., Aksun, S., Basar, H., Ozcan, A., Ozcan, N., Oztuna, D., Malmgren, J. A., Lundin, S., Torén, K., Eckerström, M., Wallin, A., Waldenström, A. C., Riccio, F. C., Pogson, D., Antonio, A. C. P., Leivas, A. F., Kenji, F., James, E., Morgan, P., Carroll, G., Gemmell, L., MacKay, A., Wright, C., Ballantyne, J., Jonnada, S., Gerrard, C. S., Jones, N., Salciccioli, J. D., Marshall, D. C., Komorowski, M., Hartley, A., Sykes, M. C., Goodson, R., Shalhoub, J., Villanueva, J. R. Fernández, Garda, R. Fernández, Lago, A. M. López, Ruiz, E. Rodríguez, Vaquero, R. Hernández, Rodríguez, C. Galbán, Pérez, E. Varo, Hilasque, C., Oliva, I., Sirgo, G., Martin, M. C., Olona, M., Gilavert, M. C., Bodí, M., Ebm, C., Aggarwal, G., Huddart, S., Quiney, N., Cecconi, M., Fernandes, S. M., Silva, J. Santos, Gouveia, J., Silva, D., Marques, R., Bento, H., Alvarez, A., Silva, Z. Costa, Diaz, D. Díaz, Martínez, M. Villanova, Herrejon, E. Palencia, de la Gandara, A. Martinez, Gonzalo, G., Lopez, M. A., de Gopegui Miguelena, P. Ruíz, Matilla, C. I. Bernal, Chueca, P. Sánchez, Longares, M. D. C. Rodríguez, Abril, R. Ramos, Aguilar, A. L. Ruíz, de Murillas, R. Garrido López, Fernández, R. Fernández, Laborías, P. Morales, Castellanos, M. A. Díaz, Laborías, M. E. Morales, Cho, J., Kim, J., Park, J., Woo, S., West, T., Powell, E., Rimmer, A., Orford, C., Jones, N., Williams, J., Matilla, C. I. Bernal, de Gopegui Miguelena, P. Ruiz, Chueca, P. Sánchez, Abril, R. Ramos, Longares, M. D. C. Rodríguez, Aguilar, A. L. Ruíz, de Murillas, R. Garrido López, Bourne, R. S., Shulman, R., Tomlin, M., Mills, G. H., Borthwick, M., Berry, W., Huertas, D. García, Manzano, F., Villagrán-Ramírez, F., Ruiz-Perea, A., Rodríguez-Mejías, C., Santiago-Ruiz, F., Colmenero-Ruiz, M., König, C., Matt, B., Kortgen, A., Hartog, C. S., Wong, A., Balan, C., Barker, G., Srisawat, N., Peerapornratana, S., Laoveeravat, P., Tachaboon, S., Eiam-ong, S., Paratz, J., Kayambu, G., Boots, R., Arzapalo, M. F. Aguilar, Vlasenko, R., Gromova, E., Loginov, S., Kiselevskiy, M., Dolgikova, Y., Tang, K. B., Chau, C. M., Lam, K. N., Gil, E., Suh, G. Y., Park, C. M., Park, J., Chung, C. R., Lee, C. T., Chao, A., Shih, P. Y., Chang, Y. F., Lai, C. H., Hsu, Y. C., Yeh, Y. C., Cheng, Y. J., Colella, V., Zarrillo, N., D’Amico, M., Forfori, F., Pezza, B., Laddomada, T., Beltramelli, V., Pizzaballa, M. L., Doronzio, A., Balicco, B., Kiers, D., van der Heijden, W., Gerretsen, J., de Mast, Q., el Messaoudi, S., Rongen, G., Gomes, M., Kox, M., Pickkers, P., Riksen, N. P., Kashiwagi, Y., Okada, M., Hayashi, K., Inagaki, Y., Fujita, S., Nakamae, M. N., Kang, Y. R., Souza, R. B., Liberatore, A. M. A., Koh, I. H. J., Blet, A., Sadoune, M., Lemarié, J., Bihry, N., Bern, R., Polidano, E., Merval, R., Launay, J. M., Lévy, B., Samuel, J. L., Mebazaa, A., Hartmann, J., Harm, S., and Weber, V.

Published
2016
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8. Mechanism of lidocaine block of late current in long Q-T mutant Na+ channels

Author

Dumaine, R. and Kirsch, G.E.

Subjects
Sodium channels -- Physiological aspects, Lidocaine -- Physiological aspects, Arrhythmia -- Physiological aspects, Biological sciences
Abstract

The effect of lidocaine on mutant cardiac sodium channels causing repolarization delays and the Q-T syndrome of ventricular arrhythmia expressed in heterologous Xenopus oocyte expression system is investigated. Lidocaine was shown to block the late over peak current and to inhibit dispersed reopenings and bursting in single isolated channels. The implications of these results on ventricular arrhythmia therapeutics are discussed.

Published
1998

11. Phenotypic characterization of a large European family with Brugada syndrome displaying a sudden unexpected death syndrome mutation in SCN5A

Author

Hong, K., Berruezo-Sanchez, A., Poungvarin, N., Oliva, A., Vatta, M., Brugada, J., Brugada, Pedro, Towbin, J., Dumaine, R., Piñero-Galvez, C., Antzelevitch, C., Brugada, R., and Internal Medicine Specializations

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Arrhythmias, Cardiac/genetics, Brugada syndrome, cardiovascular diseases
Abstract

INTRODUCTION: Brugada syndrome is characterized by sudden death secondary to malignant arrhythmias and the presence of ST segment elevation in leads V(1) to V(3) of patients with structurally normal hearts. This ECG pattern often is concealed but can be unmasked using potent sodium channel blockers. Like congenital long QT syndrome type 3 (LQT3) and sudden unexpected death syndrome, Brugada syndrome has been linked to mutations in SCN5A. METHODS AND RESULTS: We screened a large European family with Brugada syndrome. Three members (two female) had suffered malignant ventricular arrhythmias. Ten members showed an ECG pattern characteristic of Brugada syndrome at baseline, and eight showed the pattern only after administration of ajmaline (total 12 female). Haplotype analysis revealed that all individuals with positive ECG at baseline shared the SCN5A locus. Sequencing of SCN5A identified a missense mutation, R367H, previously associated with sudden unexpected death syndrome. Two of the eight individuals who displayed a positive ECG after the administration of ajmaline, but not before, did not have the R367H mutation, and sequencing analysis failed to identify any other mutation in SCN5A. The R367H mutation failed to generate any current when heterologously expressed in HEK cells. CONCLUSION: Our results support the hypothesis that (1) sudden unexpected death syndrome and Brugada syndrome are the same disease; (2) male predominance of the phenotype observed in sudden unexpected death syndrome does not apply to this family, suggesting that factors other than the specific mutation determine the gender distinction; and (3) ajmaline may provide false-positive results. These findings have broad implications relative to the diagnosis and risk stratification of family members of patients with the Brugada syndrome.

Published
2004

12. Incidence, diagnostic methods and evolution of left-ventricular thrombus for patients with anterior myocardial infarction and low left-ventricular ejection fraction: A prospective multicenter study

Author

Meurin, P., primary, Brandao Carreira, V., additional, Dumaine, R., additional, Shqueir, A., additional, Milleron, O., additional, Safar, B., additional, Perna, S., additional, Smadja, C., additional, Genest, M., additional, Garot, J., additional, Carette, B., additional, Payot, L., additional, and Tabet, J.Y., additional

Published
2014
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29. Modulation of I Kr inactivation by mutation N588K in KCNH2: A link to arrhythmogenesis in short QT syndrome

Author

Cordeiro, J.M., Brugada, R., Wu, Y.S., Hong, K., and Dumaine, R.

Subjects
HEART beat, HEART conduction system, ARRHYTHMIA, ORGANIC compounds
Abstract

Objective: Short QT syndrome (SQTS) is characterized by ventricular arrhythmias and sudden death. One form of SQTS is caused by mutation N588K in human ether-a-go-go-related gene (HERG). In this study we sought to determine the potential role of N588K in arrhythmias. Methods: We measured the characteristics of HERG current generated by wild-type (WT) KCNH2 and the N588K mutant channel expressed in mammalian TSA201 cells. Results: Whole-cell patch-clamp recordings of WT HERG currents showed the usual rapid onset of inactivation (rectification) at potentials more positive than +10 mV. In contrast, N588K currents rectified at potentials over +80 mV. Over the physiological range of potentials, N588K currents do not inactivate. During an action potential clamp, WT currents displayed a “hump” like waveform with slow activation kinetics and a rapid increase during phase 3 repolarization. In contrast, N588K currents were proportional to the amplitude of the action potential and displayed a dome-like configuration and a much larger current during the initial phases in the ventricle. Purkinje cell action potentials display a more negative phase 2 repolarization than the ventricle and elicited much smaller WT and N588K currents of similar amplitudes. Conclusions: Physiologically the N588K mutation abolishes rectification of HERG currents and specifically increases I Kr in the ventricle with minimal effects on the Purkinje fiber action potential duration. Such preferential prolongation may explain the separation of the T and U waves observed in the ECG of SQTS patients and lead to re-excitation of the ventricle endocardium. [Copyright &y& Elsevier]

Published
2005
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30. Contribution of neuronal sodium channels to the cardiac fast sodium current INa is greater in dog heart Purkinje fibers than in ventricles

Author

Haufe, V., Cordeiro, J.M., Zimmer, T., Wu, Y.S., Schiccitano, S., Benndorf, K., and Dumaine, R.

Subjects
SODIUM channels, PRESERVATION of organs, tissues, etc., MEMBRANE proteins, ACTIVE biological transport
Abstract

Abstract: Objective: To determine the presence and the potential contribution of neuronal sodium channels to dog cardiac function. Methods: We used a combination of electrophysiological (patch clamp), RT-PCR, biochemical and immunohistochemical techniques to identify and localize neuronal Na+ channels in dog heart and determine their potential contribution to the fast sodium current. Results: In all cardiac tissues investigated, Nav1.1, Nav1.2 and Nav1.3 transcripts were detected. In immunoblots, we found Nav1.1 and Nav1.2 proteins in the ventricle (V) and in Purkinje fibers (PF). Nav1.3 immunoblots suggested strong proteolytic activity against this isoform in the heart. Nav1.6 was not found in any of the tissues tested. Confocal immunofluorescence on cardiac myocytes showed that Nav1.1 was predominantly localized at the intercalated disks in V and PF and around the nucleus (V). Nav1.2 was only present at the Z lines (V). Consistent with the immunoblot data, an intense but diffuse intracellular staining was observed for Nav1.3. Nav1.6 fluorescence staining was faint and diffuse. Surprisingly, immunoblots indicated the presence of two Navβ2 variants: a 42-kDa protein that co-localized with Nav1.2 at the Z lines in V and a 34-kDa protein that co-localized with Nav1.1 at the intercalated disks in PF. In agreement with the biochemical data, electrophysiological results suggest that neuronal sodium channels generate 10±5% and 22±5% of the peak sodium current in dog ventricle and Purkinje fibers, respectively. Conclusions: Our results suggest that neuronal NaChs are more abundant in Purkinje fibers than in ventricles, and this suggests a role for them in cardiac conduction. [Copyright &y& Elsevier]

Published
2005
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33. Coordinated down-regulation of KCNQ1 and KCNE1 expression contributes to reduction of IKs in canine hypertrophied hearts

Author

Ramakers, C., Vos, M.A., Doevendans, P.A., Schoenmakers, M., Wu, Y.S., Scicchitano, S., Iodice, A., Thomas, G.P., Antzelevitch, C., and Dumaine, R.

Subjects
ARRHYTHMIA, HYPERTROPHY
Abstract

Objective: In animal models of hypertrophy, electrical remodeling giving rise to QT prolongation occurs rapidly and is associated with the development of torsade de pointes (TdP) arrhythmias and sudden death. Chronic AV block (CAVB)-induced hypertrophy in dogs has been associated with a reduction in the slow component (IKs) of the delayed rectifier potassium current (IK), which contributes to a prolongation of ventricular repolarization, the development of an acquired form of long QT, and the substrate for triggered activity and TdP. The present study was designed to probe the molecular basis for the decrease in IKs by studying the characteristics of KCNE1 and KCNQ1, the putative genes responsible for formation of the channel. Methods and Results: Using a combination of Northern blot, competitive multiplex PCR and immunoblot assays, we found that CAVB reduces KCNE1 and KCNQ1 RNA in the canine ventricles by 70 and 80%, respectively. Protein levels of KCNE1 and KCNQ1 were reduced by 60 and 50%, respectively. We also demonstrate at the molecular level the basis for inter-ventricular difference in IKs density previously reported in hearts of normal dogs and show the basis for reduction of this difference in the CAVB dog. Conclusions: Our results indicate that the CAVB-induced reduction in IKs is due to a down-regulation of KCNE1 and KCNQ1 transcription. The data suggest that electrical remodeling of the cardiac ventricle during hypertrophy involves regulation of the gene expression through modulation of transcriptional and translational regulatory pathways. The reduction in KCNE1 and KCNQ1 expression increases the dependence of ventricular repolarization on the rapid component of IK and may potentiate the action of Class III antiarrhythmic agents. [Copyright &y& Elsevier]

Published
2003
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34. Interaction of taurine with the fast Na-current in isolated rabbit myocytes.

Author

Schanne, O F and Dumaine, R

Abstract

We studied in whole cell configuration with the patch clamp method the effect of taurine on the macroscopic Na current in adult ventricular rabbit myocytes. Because these cells have a large surface [13,750 +/- 704 microns2 (19), mean +/- S.E.M. (n)], we reduced [Na]o to 45 mM and worked at room temperature to obtain acceptable voltage control. When the cells were held at -80 mV, taurine (20 mM) had the following effects: 1) The current voltage relationships crossed over so that taurine increased INa at potentials negative to -45 mV, and at more positive potentials it depressed the current; 2) taurine reduced the maximal Na conductance from 536.3 +/- 72.2 to 253.6 +/- 33.6 microS.cm-2; 3) the crossing over of the I/V curves was mainly caused by a hyperpolarizing shift of V1/2 of the steady-state activation by 6.3 mV; 4) the crossing over was independent of a -4.6 mV shift of V1/2 of the steady-state inactivation and 5) taurine increased significantly the time constant of reactivation between -90 and -70 mV, but we did not find evidence that taurine changed the time constant of inactivation between -40 and +20 mV. We conclude that positive to -45 mV taurine causes a block of INa channels that resembles that of local anesthetic antiarrhythmic drugs. Negative to -45 mV taurine counteracts the local anesthetic effect causing increased excitability and improved conduction in the range of the threshold potential and -45 mV.

Published
1992

35. Enoxaparin in unstable angina patients who would have been excluded from randomized pivotal trials.

Author

Collet J, Montalescot G, Fine E, Golmard J, Dalby M, Choussat R, Ankri A, Dumaine R, Lesty C, Vignolles N, Thomas D, Collet, Jean Philippe, Montalescot, Gilles, Fine, Erika, Golmard, Jean Louis, Dalby, Miles, Choussat, Rémi, Ankri, Annick, Dumaine, Raphaëlle, and Lesty, Claude

Abstract

Objectives: In the present study, we describe the characteristics and examine the anticoagulation levels and safety of subcutaneous enoxaparin in unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI) patients who would not have been eligible in the Efficacy Safety Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) and Thrombolysis In Myocardial Infarction (TIMI)-11B trials.Background: It is not known whether the benefit shown with enoxaparin in the selected population of pivotal trials can be extended to the real world.Methods: In our center, all patients with UA/NSTEMI are anticoagulated with subcutaneous enoxaparin adjusted to creatinine clearance. Among 515 consecutive patients, we identified 174 who would not have been eligible for ESSENCE or TIMI-11B ("EP" group for excluded patients). We evaluated cardiovascular death or non-fatal myocardial infarction (MI), as well as major and minor bleeding events, at 30 days in the EP group and in patients without any of the exclusion criteria ("NEP" group for non-excluded patients).Results: This EP group was older, had a higher female/male ratio, and more frequently had a history of MI or a diagnosis of non-Q MI on admission than the NEP group. The distribution of the anti-Xa activity was similar in both groups. The bleeding rates (major and minor) at 30 days were similar in the EP and NEP groups (2.3% vs. 2.9%, respectively, P = NS). On multivariate analysis, the use of glycoprotein IIb/IIIa inhibitors and the presence of hypertension were the only independent predictors of bleeding found in the whole population. Compared with the NEP group, the EP group had a fourfold increased rate of death or MI at 30 days (15.5% vs. 4.1%, p < 0.01). On multivariate analysis, the independent predictors of death or MI at 30 days were NSTEMI on admission, creatinine clearance, and heart failure.Conclusions: Patients who do not fit the enrollment criteria of ESSENCE/TIMI-11B have higher risk baseline characteristics for both bleeding and ischemic events. In these patients, enoxaparin with dose adjustment to creatinine clearance provides adequate anti-Xa levels and no excess of bleeding. [ABSTRACT FROM AUTHOR]

Published
2003
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36. Beta-Blocker Interruption or Continuation after Myocardial Infarction.

Author

Silvain J, Cayla G, Ferrari E, Range G, Puymirat E, Delarche N, Guedeney P, Cuisset T, Ivanes F, Lhermusier T, Petroni T, Lemesle G, Bresoles F, Labeque JN, Pommier T, Dillinger JG, Leclercq F, Boccara F, Lim P, Besseyre des Horts T, Fourme T, Jourda F, Furber A, Lattuca B, Redjimi N, Thuaire C, Deharo P, Procopi N, Dumaine R, Slama M, Payot L, El Kasty M, Aacha K, Diallo A, Vicaut E, and Montalescot G

Subjects
Aged, Female, Humans, Male, Middle Aged, Drug Administration Schedule, Follow-Up Studies, Hospitalization statistics & numerical data, Kaplan-Meier Estimate, Stroke Volume drug effects, Stroke Volume physiology, Withholding Treatment, Adrenergic beta-Antagonists administration & dosage, Adrenergic beta-Antagonists adverse effects, Myocardial Infarction epidemiology, Myocardial Infarction physiopathology, Myocardial Infarction prevention & control, Myocardial Infarction psychology, Quality of Life, Secondary Prevention methods
Abstract

Background: The appropriate duration of treatment with beta-blocker drugs after a myocardial infarction is unknown. Data are needed on the safety and efficacy of the interruption of long-term beta-blocker treatment to reduce side effects and improve quality of life in patients with a history of uncomplicated myocardial infarction., Methods: In a multicenter, open label, randomized, noninferiority trial conducted at 49 sites in France, we randomly assigned patients with a history of myocardial infarction, in a 1:1 ratio, to interruption or continuation of beta-blocker treatment. All the patients had a left ventricular ejection fraction of at least 40% while receiving long-term beta-blocker treatment and had no history of a cardiovascular event in the previous 6 months. The primary end point was a composite of death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for cardiovascular reasons at the longest follow-up (minimum, 1 year), according to an analysis of noninferiority (defined as a between-group difference of <3 percentage points for the upper boundary of the two-sided 95% confidence interval). The main secondary end point was the change in quality of life as measured by the European Quality of Life-5 Dimensions questionnaire., Results: A total of 3698 patients underwent randomization: 1846 to the interruption group and 1852 to the continuation group. The median time between the last myocardial infarction and randomization was 2.9 years (interquartile range, 1.2 to 6.4), and the median follow-up was 3.0 years (interquartile range, 2.0 to 4.0). A primary-outcome event occurred in 432 of 1812 patients (23.8%) in the interruption group and in 384 of 1821 patients (21.1%) in the continuation group (risk difference, 2.8 percentage points; 95% confidence interval [CI], <0.1 to 5.5), for a hazard ratio of 1.16 (95% CI, 1.01 to 1.33; P = 0.44 for noninferiority). Beta-blocker interruption did not seem to improve the patients' quality of life., Conclusions: In patients with a history of myocardial infarction, interruption of long-term beta-blocker treatment was not found to be noninferior to a strategy of beta-blocker continuation. (Funded by the French Ministry of Health and ACTION Study Group; ABYSS ClinicalTrials.gov number, NCT03498066; EudraCT number, 2017-003903-23.)., (Copyright © 2024 Massachusetts Medical Society.)

Published
2024
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37. Ticagrelor vs Clopidogrel for Complex Percutaneous Coronary Intervention in Chronic Coronary Syndrome.

Author

Lattuca B, Mazeau C, Cayla G, Ducrocq G, Guedeney P, Laredo M, Dumaine R, El Kasty M, Kala P, Nejjari M, Hlinomaz O, Morel O, Varenne O, Leclercq F, Payot L, Spaulding C, Beygui F, Rangé G, Motovska Z, Portal JJ, Vicaut E, Collet JP, Montalescot G, and Silvain J

Subjects
Humans, Clopidogrel adverse effects, Clopidogrel therapeutic use, Platelet Aggregation Inhibitors adverse effects, Platelet Aggregation Inhibitors therapeutic use, Ticagrelor adverse effects, Ticagrelor therapeutic use, Treatment Outcome, Acute Coronary Syndrome diagnostic imaging, Acute Coronary Syndrome therapy, Acute Coronary Syndrome complications, Myocardial Infarction etiology, Percutaneous Coronary Intervention adverse effects
Abstract

Background: Whether ticagrelor in chronic coronary syndrome patients undergoing complex percutaneous coronary intervention (PCI) can prevent cardiovascular events is unknown., Objectives: The authors sought to evaluate outcomes of complex PCI and the efficacy of ticagrelor vs clopidogrel in stable patients randomized in the ALPHEUS (Assessment of Loading with the P2Y 12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting) trial., Methods: All PCI procedures were blindly reviewed and classified as complex if they had at least 1 of the following criteria: stent length >60 mm, 2-stent bifurcation, left main, bypass graft, chronic total occlusion, use of atherectomy or guiding catheter extensions, multiwire technique, multiple stents. The primary endpoint was a composite of type 4a or b myocardial infarction (MI) and major myocardial injury during the 48 hours after PCI. We compared the event rates according to the presence or not of complex PCI criteria and evaluated the interaction with ticagrelor or clopidogrel., Results: Among the 1,866 patients randomized, 910 PCI (48.3%) were classified as complex PCI. The primary endpoint was more frequent in complex PCI (45.6% vs 26.6%; P < 0.001) driven by higher rates of type 4 MI and angiographic complications (12.2% vs 4.8 %; P < 0.001 and 19.3% vs 8.6%; P < 0.05, respectively). The composite of death, MI, and stroke at 48 hours (12.7% vs 5.1 %; P < 0.05) and at 30 days (13.4% vs 5.3%; P < 0.05) was more frequent in complex PCI. No interaction was found between PCI complexity and the randomized treatment for the primary endpoint (P interaction  = 0.47) nor the secondary endpoints., Conclusions: In chronic coronary syndrome, patients undergoing a complex PCI have higher rates of periprocedural and cardiovascular events that are not reduced by ticagrelor as compared with clopidogrel., Competing Interests: Funding Support and Author Disclosures The ALPHEUS trial was led by the ACTION Study Group, an academic research organization based at the Pitié-Salpêtrière Hospital (Paris, France). The study was sponsored by Assistance Publique-Hopitaux de Paris and was funded by an unrestricted grant from AstraZeneca. The present work was supported by a grant of the French Federation of Cardiology. Prof Lattuca has received research grants from Biotronik, Boston Scientific, Daiichi Sankyo, Fédération Française de Cardiologie, and the Institute of CardioMetabolism and Nutrition; consulting fees from Daiichi Sankyo and Eli Lilly; and lecture fees from AstraZeneca, Medtronic, and Novartis. Prof Cayla has received consulting fees from Edwards Lifesciences, Medtronic, and Microport CRM; and lecture fees from Amgen, AstraZeneca, Abbott, Bayer, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Microport, Medtronic, Pfizer, and Sanofi. Prof Ducrocq has received speaker and consulting fees from Abbott, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Novo Nordisk, and Sanofi; has served on steering committees for Amgen, Novo Nordisk, and Janssen; and has been a proctor for Boston Scientific. Dr Laredo has received speaker or consulting fees from Abbott and Biotronik. Dr Kala has received consulting fees from Boston Scientific; and lecture fees from AstraZeneca, Edwards Lifesciences, Novartis, Servier, and Terumo. Prof Varenne has received research grants from Abbott and Boston Scientific; and lecture fees from Abbott, AstraZeneca, Boston Scientific, and Servier. Prof Spaulding has received consulting fees from Edwards Lifesciences, Medtronic, Sonivie, Techwald, and Valcare; has received speaker fees from Amgen and Edwards Lifesciences; and is stock shareholder of Techwald and Valcare. Prof Beygui has received consulting and lecture fees from Medtronic, Novartis, and Pfizer; and research grants from Biosensors and Medtronic. Dr Rangé has received speaker or consulting fees from Abbott and Microport. Prof Vicaut has received consulting or speaker fees from Abbott, Amgen, Bristol Myers Squibb, Celgene, LFB, Pfizer, and Sanofi. Prof Collet has received consulting and lecture fees from AstraZeneca, Boston Scientific, Bristol Myers Squibb, COR2ED, Lead-Up, Medtronic, and WebMD. Prof Montalescot has received research grants and consulting or speaker fees from Abbott, Amgen, AstraZeneca, Ascendia, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, Celecor, CSL Behring, Idorsia, Lilly, Novartis, Novo, Opalia, Pfizer, Quantum Genomics, Sanofi, and Terumo. Prof Silvain has received research grants and consulting or speaker fees from AstraZeneca, Bayer HealthCare SAS, Abbott Medical, Biotronik, Boehringer Ingelheim France, CSL Behring SA, Gilead Science, and Sanofi France; and is stock Shareholder of Pharmaseeds, Terumo, and Zoll. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Published
2024
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38. P2Y 12 Inhibitor Loading Time Before Elective PCI and the Prevention of Myocardial Necrosis.

Author

Roule V, Beygui F, Cayla G, Rangé G, Motovska Z, Delarche N, Jourda F, Goube P, Guedeney P, Zeitouni M, El Kasty M, Laredo M, Dumaine R, Ducrocq G, Derimay F, Van Belle E, Manigold T, Cador R, Combaret N, Vicaut E, Montalescot G, and Silvain J

Subjects
Humans, Clopidogrel therapeutic use, Ticagrelor therapeutic use, Purinergic P2Y Receptor Antagonists therapeutic use, Platelet Aggregation Inhibitors therapeutic use, Treatment Outcome, Percutaneous Coronary Intervention methods, Myocardial Infarction etiology
Abstract

Background: There are dated and conflicting data about the optimal timing of initiation of P2Y 12 inhibitors in elective percutaneous coronary intervention (PCI). Peri-PCI myocardial necrosis is associated with poor outcomes. We aimed to assess the impact of the P2Y 12 inhibitor loading time on periprocedural myocardial necrosis in the population of the randomized Assessment of Loading With the P2Y 12 Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting (ALPHEUS) trial, which compared ticagrelor with clopidogrel in high-risk patients who received elective PCI., Methods: The ALPHEUS trial divided 1809 patients into quartiles of loading time. The ALPHEUS primary outcome was used (type 4 [a or b] myocardial infarction or major myocardial injury) as well as the main secondary outcome (type 4 [a or b] myocardial infarction or any type of myocardial injury)., Results: Patients in the first quartile group (Q1) presented higher rates of the primary outcome (P = 0.01). When compared with Q1, incidences of the primary outcome decreased in patients with longer loading times (adjusted odds ratio [adjOR], 0.70 [0.52.-0.95]; P = 0.02 for Q2; adjOR 0.65 [0.48-0.88]; P < 0.01 for Q3; adjOR 0.66 [0.49-0.89]; P < 0.01 for Q4). Concordant results were found for the main secondary outcome. There was no interaction with the study drug allocated by randomization (clopidogrel or ticagrelor). Bleeding complications (any bleeding ranging between 4.9% and 7.3% and only 1 major bleeding at 48 hours) and clinical ischemic events were rare and did not differ among groups., Conclusions: In elective PCI, administration of the oral P2Y 12 inhibitor at the time of PCI could be associated with more frequent periprocedural myocardial necrosis than an earlier administration. The long-term clinical consequences remain unknown., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Published
2024
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39. βeta blocker interruption after uncomplicated myocardial infarction: rationale and design of the randomized ABYSS trial.

Author

Silvain J, Cayla G, Ferrari E, Range G, Puymirat E, Delarche N, Collet JP, Dumaine R, Slama M, Payot L, Kasty ME, Aacha K, Vicaut E, and Montalescot G

Subjects
Humans, Stroke Volume, Quality of Life, Ventricular Function, Left, Adrenergic beta-Antagonists, Treatment Outcome, Myocardial Infarction complications, Heart Failure drug therapy
Abstract

Background: The long-term use of β-blocker after myocardial infarction (MI) when global left ventricular ejection fraction (LVEF) is preserved has not been studied in the era of modern myocardial reperfusion and secondary prevention therapies. It is unknown whether β-blockers are useful in stable post-MI patients without reduced LVEF and without heart failure., Methods: The Assessment of β-blocker interruption 1 Year after an uncomplicated myocardial infarction on Safety and Symptomatic cardiac events requiring hospitalization (ABYSS) Trial enrolled in 49 centers in France, 3,700 patients with a prior (>6 months) history of MI and a LVEF >40%, chronically treated with a β-blocker and without any major cardiovascular event (MACE) in the past 6 months. These patients were randomized to interruption or continuation of their β-blocker therapy. The primary objective is to demonstrate the noninferiority of interruption vs continuation of the β-blocker therapy on the primary composite endpoint of all-cause death, stroke, MI, hospitalization for any cardiovascular reason at the end of follow-up (accrual follow-up) with a one-year minimum follow-up for the last randomized patient. Secondary objectives will focus on patient reported outcomes with the evaluation of the quality of life before and after randomization with the EQ5D-5L questionnaire. Enrolment has been completed., Conclusion: The ABYSS trial evaluates the cardiovascular safety of β-blocker interruption in stabilized post-MI patients without heart failure nor reduced LVEF. ABYSS trial is a reappraisal of β-blockers life-long therapy in stable post-MI patients without reduced LVEF., Clinical Trial Registration: NCT03498066 (clinicaltrials.gov)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Published
2023
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40. Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current I Na by Lamotrigine; A Potential for Acquired Arrythmias.

Author

Contreras Vite JA, Vega Valle C, Biekeu Mbem H, Boivin SM, and Dumaine R

Abstract

Lamotrigine is widely prescribed to treat bipolar neurological disorder and epilepsy. It exerts its antiepileptic action by blocking voltage-gated sodium channels in neurons. Recently, the US Food and Drug Administration issued a warning on the use of Lamotrigine after observations of conduction anomalies and Brugada syndrome patterns on the electrocardiograms of epileptic patients treated with the drug. Brugada syndrome and conduction disturbance are both associated with alterations of the cardiac sodium current (I Na ) kinetics and amplitude. In this study, we used the patch clamp technique on cardiomyocytes from epileptic rats to test the hypothesis that Lamotrigine also blocks I Na in the heart. We found that Lamotrigine inhibited 60% of I Na peak amplitude and reduced cardiac excitability in epileptic rats but had little effect in sham animals. Moreover, Lamotrigine inhibited 67% of I NaL and, more importantly, prolonged the action potential refractory period in epileptic animals. Our results suggest that enhanced affinity of Lamotrigine for I Na may in part explain the clinical phenotypes observed in epileptic patients.

Published
2022
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41. The neuronal potassium current I A is a potential target for pain during chronic inflammation.

Author

Biet M, Dansereau MA, Sarret P, and Dumaine R

Subjects
Animals, Calcium Channels, L-Type metabolism, Cells, Cultured, Ganglia, Spinal cytology, Ganglia, Spinal metabolism, Ganglia, Spinal physiology, Male, Neurons, Afferent drug effects, Neurons, Afferent physiology, Nociception, Nociceptive Pain physiopathology, Rats, Rats, Sprague-Dawley, Sodium Channel Blockers pharmacology, Sodium Channels metabolism, Tetrodotoxin pharmacology, Action Potentials, Neurons, Afferent metabolism, Nociceptive Pain metabolism, Potassium Channels, Voltage-Gated metabolism
Abstract

Voltage-gated ion channels play a key role in the action potential (AP) initiation and its propagation in sensory neurons. Modulation of their activity during chronic inflammation creates a persistent pain state. In this study, we sought to determine how peripheral inflammation caused by complete Freund's adjuvant (CFA) alters the fast sodium (I Na ), L-type calcium (I CaL ), and potassium (I K ) currents in primary afferent fibers to increase nociception. In our model, intraplantar administration of CFA induced mechanical allodynia and thermal hyperalgesia at day 14 post-injection. Using whole-cell patch-clamp recording in dissociated small (C), medium (Aδ), and large-sized (Aβ) rat dorsal root ganglion (DRG) neurons, we found that CFA prolonged the AP duration and increased the amplitude of the tetrodotoxin-resistant (TTX-r) I Na in Aβ fibers. In addition, CFA accelerated the recovery of I Na from inactivation in C and Aδ nociceptive fibers but enhanced the late sodium current (I NaL ) only in Aδ and Aβ neurons. Inflammation similarly reduced the amplitude of I CaL in each neuronal cell type. Fourteen days after injection, CFA reduced both components of I K (I Kdr and I A ) in Aδ fibers. We also found that I A was significantly larger in C and Aδ neurons in normal conditions and during chronic inflammation. Our data, therefore, suggest that targeting the transient potassium current I A represents an efficient way to shift the balance toward antinociception during inflammation, since its activation will selectively decrease the AP duration in nociceptive fibers. Altogether, our data indicate that complex interactions between I K , I Na , and I CaL reduce pain threshold by concomitantly enhancing the activity of nociceptive neurons and reducing the inhibitory action of Aβ fibers during chronic inflammation., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Published
2021
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42. Ticagrelor versus clopidogrel in elective percutaneous coronary intervention (ALPHEUS): a randomised, open-label, phase 3b trial.

Author

Silvain J, Lattuca B, Beygui F, Rangé G, Motovska Z, Dillinger JG, Boueri Z, Brunel P, Lhermusier T, Pouillot C, Larrieu-Ardilouze E, Boccara F, Labeque JN, Guedeney P, El Kasty M, Laredo M, Dumaine R, Ducrocq G, Collet JP, Cayla G, Blanchart K, Kala P, Vicaut E, and Montalescot G

Subjects
Clopidogrel adverse effects, Clopidogrel therapeutic use, Elective Surgical Procedures, Female, Humans, Male, Middle Aged, Treatment Outcome, Percutaneous Coronary Intervention adverse effects, Platelet Aggregation Inhibitors adverse effects, Platelet Aggregation Inhibitors therapeutic use, Purinergic P2Y Receptor Antagonists therapeutic use, Ticagrelor therapeutic use
Abstract

Background: Percutaneous coronary intervention (PCI)-related myonecrosis is frequent and can affect the long-term prognosis of patients. To our knowledge, ticagrelor has not been evaluated in elective PCI and could reduce periprocedural ischaemic complications compared with clopidogrel, the currently recommended treatment. The aim of the ALPHEUS study was to examine if ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing high-risk elective PCI., Methods: The ALPHEUS study, a phase 3b, randomised, open-label trial, was done at 49 hospitals in France and Czech Republic. Patients with stable coronary artery disease were eligible for the study if they had an indication for PCI and at least one high-risk characteristic. Eligible patients were randomly assigned (1:1) to either ticagrelor (180 mg loading dose, 90 mg twice daily thereafter for 30 days) or clopidogrel (300-600 mg loading dose, 75 mg daily thereafter for 30 days) by use of an interactive web response system, and stratified by centre. The primary outcome was a composite of PCI-related type 4 (a or b) myocardial infarction or major myocardial injury and the primary safety outcome was major bleeding, both of which were evaluated within 48 h of PCI (or at hospital discharge if earlier). The primary analysis was based on all events that occurred in the intention-to-treat population. The trial was registered with ClinicalTrials.gov, NCT02617290., Findings: Between Jan 9, 2017, and May 28, 2020, 1910 patients were randomly assigned at 49 sites, 956 to the ticagrelor group and 954 to the clopidogrel group. 15 patients were excluded from the ticagrelor group and 12 from the clopidogrel group. At 48 h, the primary outcome was observed in 334 (35%) of 941 patients in the ticagrelor group and 341 (36%) of 942 patients in the clopidogrel group (odds ratio [OR] 0·97, 95% CI 0·80-1·17; p=0·75). The primary safety outcome did not differ between the two groups, but minor bleeding events were more frequently observed with ticagrelor than clopidogrel at 30 days (105 [11%] of 941 patients in the ticagrelor group vs 71 [8%] of 942 patients in the clopidogrel group; OR 1·54, 95% CI 1·12-2·11; p=0·0070)., Interpretation: Ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis after elective PCI and did not cause an increase in major bleeding, but did increase the rate of minor bleeding at 30 days. These results support the use of clopidogrel as the standard of care for elective PCI., Funding: ACTION Study Group and AstraZeneca., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Published
2020
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43. Blunting periprocedural myocardial necrosis: Rationale and design of the randomized ALPHEUS study.

Author

Silvain J, Cayla G, Beygui F, Range G, Lattuca B, Collet JP, Dillinger JG, Boueri Z, Brunel P, Pouillot C, Boccara F, Christiaens L, Labeque JN, Lhermusier T, Georges JL, Bellemain-Appaix A, Le Breton H, Hauguel-Moreau M, Saint-Etienne C, Caussin C, Jourda F, Motovska Z, Guedeney P, El Kasty M, Laredo M, Dumaine R, Ducrocq G, Vicaut E, and Montalescot G

Subjects
Aged, Humans, Coronary Angiography, Randomized Controlled Trials as Topic, Clinical Trials, Phase III as Topic, Multicenter Studies as Topic, Clopidogrel therapeutic use, Coronary Disease therapy, Myocardial Infarction etiology, Myocardial Infarction prevention & control, Percutaneous Coronary Intervention adverse effects, Platelet Aggregation Inhibitors therapeutic use, Purinergic P2Y Receptor Antagonists therapeutic use, Ticlopidine therapeutic use
Abstract

Background: Clopidogrel associated with aspirin is the recommended treatment for patients undergoing elective percutaneous coronary intervention (PCI). Although severe PCI-related events are rare, evidence suggests that PCI-related myocardial infarction and myocardial injury are frequent complications that can impact the clinical prognosis of the patients. Antiplatelet therapy with a potent P2Y 12 receptor inhibitor such as ticagrelor may reduce periprocedural ischemic complications while maintaining a similar safety profile as compared with conventional dual antiplatelet therapy by aspirin and clopidogrel in this setting., Methods: Assessment of Loading with the P2Y 12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting (ALPHEUS) (NCT02617290) is an international, multicenter, randomized, parallel-group, open-label study in patients with stable coronary artery disease who are planned for an elective PCI. In total, 1,900 patients will be randomized before a planned PCI to a loading dose of ticagrelor 180 mg or a loading dose of clopidogrel (300 or 600 mg) in addition to aspirin. Patients will then receive a dual antiplatelet therapy with aspirin and ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 30 days. The primary ischemic end point is PCI-related myocardial infarction (myocardial infarction type 4a or 4b) or major myocardial injury within 48 hours (or at hospital discharge if earlier) after elective PCI/stent. Safety will be evaluated by major bleeding events (Bleeding Academic Research Consortium type 3 or 5) at 48 hours (or discharge if it occurs earlier)., Conclusion: ALPHEUS is the first properly sized trial comparing ticagrelor to clopidogrel in the setting of elective PCI and is especially designed to show a reduction in periprocedural events, a surrogate end point for mortality., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Published
2020
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44. Early exercise training feasibility after aortic valve repair: A multicentre prospective French survey on behalf of the Aortic Valve repair International Registry (AVIATOR).

Author

Tabet JY, Meurin P, Ben Driss A, Weber H, Dumaine R, Renaud N, Grosdemouge A, Defrance C, Peyrot S, Debauchez M, and Lansac E

Subjects
Adult, Aortic Valve diagnostic imaging, Aortic Valve physiopathology, Exercise Tolerance, Feasibility Studies, Female, France, Heart Valve Diseases diagnostic imaging, Heart Valve Diseases physiopathology, Humans, Male, Middle Aged, Prospective Studies, Recovery of Function, Registries, Risk Factors, Stroke Volume, Time Factors, Treatment Outcome, Ventricular Function, Left, Aortic Valve surgery, Cardiac Valve Annuloplasty adverse effects, Cardiac Valve Annuloplasty instrumentation, Exercise Therapy adverse effects, Heart Valve Diseases surgery, Heart Valve Prosthesis Implantation adverse effects, Heart Valve Prosthesis Implantation instrumentation
Abstract

Background: Standardization of aortic valve repair by the external ring annuloplasty approach is an alternative to valve replacement to avoid prosthetic valve-related events. Although the benefit of exercise training to improve postoperative exercise tolerance has been demonstrated in many conditions after cardiac surgery, it has never been described after aortic valve repair., Objectives: To evaluate the feasibility of an early exercise training programme after aortic valve repair., Methods: Consecutive patients were prospectively included in 13 postoperative centres. Patients underwent an exercise training programme for approximately 3-5 weeks. Transthoracic echocardiography and a cardiopulmonary exercise test were performed before and after the exercise training programme., Results: Fifty patients (mean±standard deviation [SD] age: 50±13 years) were included a mean of 13.6±12.0 days after aortic valve repair. The preoperative degree of aortic insufficiency was moderate to severe in 35 patients (70%) and the aortic valve was bicuspid in 24 patients (48%). Valve-sparing root replacement and isolated aortic valve repair (including 10% supracoronary aorta replacement) were performed in 64% and 36% of patients, respectively. We found no aortic insufficiency occurrence or worsening and no adverse clinical events after the exercise training programme. Mean left ventricular ejection fraction increased significantly (from 54%±8% to 57%±9%; P=0.0007). Mean peak oxygen consumption and first ventilatory threshold increased from 17.0±5.3 to 22.5±7.8mL/kg/min (32% increase) and from 12.0±3.9 to 14.3±5.2mL/kg/min (19% increase), respectively (both P<0.05)., Conclusion: Exercise training early after aortic valve repair is safe and seems to significantly improve exercise capacity., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Published
2020
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45. In utero exposure to nicotine abolishes the postnatal response of the cardiac sodium current to isoproterenol in newborn rabbit atrium.

Author

Biet M, Ton AT, Delabre JF, Morin N, and Dumaine R

Subjects
Action Potentials drug effects, Adrenergic beta-Agonists pharmacology, Animals, Animals, Newborn, Disease Models, Animal, Female, Heart Atria metabolism, Long QT Syndrome physiopathology, Nicotine pharmacology, Patch-Clamp Techniques, Pregnancy, Rabbits, Sinoatrial Node physiopathology, Action Potentials physiology, Heart Atria physiopathology, Isoproterenol pharmacology, Long QT Syndrome metabolism, Myocytes, Cardiac metabolism, Pregnancy, Animal, Sodium metabolism
Abstract

Background: In utero exposure to tobacco smoke is associated with sudden infant death syndrome (SIDS) and cardiac arrhythmias in newborns. The arrhythmogenic mechanisms seem linked to alterations of the cardiac sodium current (I Na ). We previously reported that in utero exposure to nicotine delays the postnatal development of the heart sinoatrial node in rabbits and altered expression of the sodium channels Na V 1.5 and Na V 1.1 in the atrium surrounding it. These channels react differently to sympathetic stimulation., Objective: The purpose of this study was to test whether nicotine altered the response of I Na to stimulation by the β-adrenoreceptor agonist isoproterenol in atrial myocytes. Our hypothesis is that changes in the sympathetic response of sinoatrial node peripheral cells may create a substrate for arrhythmia., Methods: Using the patch-clamp technique we measured the effect of nicotine on the response of I Na to adrenergic stimulation in isolated cardiomyocytes., Results: Isoproterenol increased I Na by 50% in newborn sham rabbits but had no effect in newborn rabbits exposed to nicotine in utero. Our data also show that nicotine increases the late sodium current, an effect that may promote QT prolongation., Conclusion: We provide the first evidence linking fetal exposure to nicotine to long-term alterations of I Na response to isoproterenol. These changes may impair I Na adaptation to sympathetic tone and prevent awakening from sleep apnea, thus leading to arrhythmias that could potentially be involved in SIDS. Our data also raise concerns about the use of nicotine replacement therapies for pregnant women., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Published
2019
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46. Apelin-13 Regulates Vasopressin-Induced Aquaporin-2 Expression and Trafficking in Kidney Collecting Duct Cells.

Author

Boulkeroua C, Ayari H, Khalfaoui T, Lafrance M, Besserer-Offroy É, Ekindi N, Sabbagh R, Dumaine R, Lesur O, Sarret P, and Chraibi A

Subjects
Animals, Apelin Receptors metabolism, Aquaporin 2 genetics, Cell Line, Cyclic AMP metabolism, HEK293 Cells, Humans, Kidney Tubules, Collecting cytology, Kidney Tubules, Collecting metabolism, Mice, Phosphorylation drug effects, Aquaporin 2 metabolism, Deamino Arginine Vasopressin pharmacology, Gene Expression Regulation drug effects, Intercellular Signaling Peptides and Proteins pharmacology, Protein Transport drug effects
Abstract

Background/aims: Apelin and its G protein-coupled receptor APJ (gene symbol Aplnr) are strongly expressed in magnocellular vasopressinergic neurons suggesting that the apelin/APJ system plays a key role at the central level in regulating salt and water balance by counteracting the antiduretic action of vasopressin (AVP). Likewise, recent studies revealed that apelin exerts opposite effects to those of vasopressin induced on water reabsorption via a direct action on the kidney collecting duct. However, the underlying mechanisms of the peripheral action of apelin are not clearly understood. Here, we thus investigated the role of the apelin/APJ system in the regulation of water balance in the kidney, and more specifically its involvement in modulating the function of aquaporin-2 (AQP2) in the collecting duct., Methods: Mouse cortical collecting duct cells (mpkCCD) were incubated in the presence of dDAVP and treated with or without apelin-13. Changes in AQP2 expression and localization were determined by immunoblotting and confocal immunofluorescence staining., Results: Herein, we showed that the APJ was present in mpkCCD cells. Treatment of mpkCCD with apelin-13 reduced the cAMP production and antagonized the AVP-induced increase in AQP2 mRNA and protein expressions. Immunofluorescent experiments also revealed that the AVP-induced apical cell surface expression of AQP2, and notably its phosphorylated isoform AQP2-pS269, was considerably reduced following apelin-13 application to mpkCCD cells., Conclusion: Our data reinforce the aquaretic role of the apelin/APJ system in the fine regulation of body fluid homeostasis at the kidney level and its physiological opposite action to the antiduretic activity of AVP., Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Published
2019
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47. A novel three base-pair deletion in domain two of the cardiac sodium channel causes Brugada syndrome.

Author

Tan BY, Wang L, Uttamchandani M, Barajas-Martinez H, Dumaine R, Morin N, Ching CK, Ho KL, Chong DTT, Chow W, Yap EPH, Moochhala S, Hu D, Yong RYY, and Teo WS

Subjects
Adult, Brugada Syndrome complications, Female, Humans, Male, Pedigree, Phenotype, Syncope etiology, Brugada Syndrome genetics, NAV1.5 Voltage-Gated Sodium Channel genetics, Sequence Deletion
Abstract

Introduction: Mutations within SCN5A are found in a significant proportion (15-30%) of Brugada syndrome (BrS) cases and impair sodium transport across excitable cardiac cells that mediate ventricular contractions. Genetic testing offers a means to clinically assess and manage affected individuals and their family members., Methods and Results: The proband at age 44 years old exhibited a syncopal event during exercise, and presented later with a spontaneous type-I BrS pattern on 12‑lead resting electrocardiogram (ECG). Mutational analysis performed across all SCN5A exons revealed a unique three base-pair deletion p.M741&#95;T742delinsI (c.2223&#95;2225delGAC), in a heterozygous state in the proband and 2 siblings. This mutation was not seen in a cohort of 105 ethnicity-matched controls or in public genome databases. Patch clamp electrophysiology study conducted in TSA201 cells showed an abolishment of sodium current (I Na ). The proband, and several relatives, also harboured a known SCN5A variant, p.R1193Q (c.3578G>A)., Conclusion: Our study has demonstrated the deleterious effect of a novel SCN5A mutation p.M741&#95;T742delinsI (c.2223&#95;2225delGAC). The findings highlight the complex effects of gender and age in phenotype manifestation. It also offers insights into improving the long-term management of BrS, and the utility of cascade genetic screening for risk stratification., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2018
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48. The hypotensive effect of activated apelin receptor is correlated with β-arrestin recruitment.

Author

Besserer-Offroy É, Bérubé P, Côté J, Murza A, Longpré JM, Dumaine R, Lesur O, Auger-Messier M, Leduc R, Marsault É, and Sarret P

Subjects
Animals, Antihypertensive Agents chemistry, Cyclic AMP metabolism, HEK293 Cells, Humans, Hypotension drug therapy, Hypotension metabolism, Intercellular Signaling Peptides and Proteins chemistry, Male, Rats, Sprague-Dawley, Receptors, G-Protein-Coupled metabolism, Signal Transduction drug effects, Antihypertensive Agents pharmacology, Apelin Receptors metabolism, Blood Pressure drug effects, Intercellular Signaling Peptides and Proteins pharmacology, beta-Arrestins metabolism
Abstract

The apelinergic system is an important player in the regulation of both vascular tone and cardiovascular function, making this physiological system an attractive target for drug development for hypertension, heart failure and ischemic heart disease. Indeed, apelin exerts a positive inotropic effect in humans whilst reducing peripheral vascular resistance. In this study, we investigated the signaling pathways through which apelin exerts its hypotensive action. We synthesized a series of apelin-13 analogs whereby the C-terminal Phe 13 residue was replaced by natural or unnatural amino acids. In HEK293 cells expressing APJ, we evaluated the relative efficacy of these compounds to activate Gα i1 and Gα oA G-proteins, recruit β-arrestins 1 and 2 (βarrs), and inhibit cAMP production. Calculating the transduction ratio for each pathway allowed us to identify several analogs with distinct signaling profiles. Furthermore, we found that these analogs delivered i.v. to Sprague-Dawley rats exerted a wide range of hypotensive responses. Indeed, two compounds lost their ability to lower blood pressure, while other analogs significantly reduced blood pressure as apelin-13. Interestingly, analogs that did not lower blood pressure were less effective at recruiting βarrs. Finally, using Spearman correlations, we established that the hypotensive response was significantly correlated with βarr recruitment but not with G protein-dependent signaling. In conclusion, our results demonstrated that the βarr recruitment potency is involved in the hypotensive efficacy of activated APJ., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Published
2018
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49. A Systematic Exploration of Macrocyclization in Apelin-13: Impact on Binding, Signaling, Stability, and Cardiovascular Effects.

Author

Trân K, Murza A, Sainsily X, Coquerel D, Côté J, Belleville K, Haroune L, Longpré JM, Dumaine R, Salvail D, Lesur O, Auger-Messier M, Sarret P, and Marsault É

Subjects
Animals, Azetidines pharmacokinetics, Brain diagnostic imaging, Brain enzymology, Brain metabolism, Carbon Radioisotopes, Fluorine Radioisotopes, Intercellular Signaling Peptides and Proteins pharmacokinetics, Macaca mulatta, Male, Mice, Radioactive Tracers, Radiopharmaceuticals pharmacokinetics, Rats, Sprague-Dawley, Substrate Specificity, Tissue Distribution, Azetidines chemical synthesis, Intercellular Signaling Peptides and Proteins chemical synthesis, Monoacylglycerol Lipases chemistry, Positron-Emission Tomography methods, Radiopharmaceuticals chemical synthesis
Abstract

The apelin receptor generates increasing interest as a potential target across several cardiovascular indications. However, the short half-life of its cognate ligands, the apelin peptides, is a limiting factor for pharmacological use. In this study, we systematically explored each position of apelin-13 to find the best position to cyclize the peptide, with the goal to improve its stability while optimizing its binding affinity and signaling profile. Macrocyclic analogues showed a remarkably higher stability in rat plasma (half-life >3 h versus 24 min for Pyr-apelin-13), accompanied by improved affinity (analogue 15, K i 0.15 nM and t 1/2 6.8 h). Several compounds displayed higher inotropic effects ex vivo in the Langendorff isolated heart model in rats (analogues 13 and 15, maximum response at 0.003 nM versus 0.03 nM of apelin-13). In conclusion, this study provides stable and active compounds to better characterize the pharmacology of the apelinergic system.

Published
2018
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50. In-utero exposure to nicotine alters the development of the rabbit cardiac conduction system and provides a potential mechanism for sudden infant death syndrome.

Author

Ton AT, Biet M, Delabre JF, Morin N, and Dumaine R

Subjects
Animals, Animals, Newborn, Cotinine blood, Female, Heart Rate physiology, Humans, Infant, Myocytes, Cardiac physiology, NAV1.1 Voltage-Gated Sodium Channel metabolism, NAV1.5 Voltage-Gated Sodium Channel metabolism, Patch-Clamp Techniques, Pregnancy, Prenatal Exposure Delayed Effects, Rabbits, Sinoatrial Node physiopathology, Nicotine toxicity, Sinoatrial Node physiology, Sudden Infant Death etiology
Abstract

In-utero exposure to tobacco smoke remains the highest risk factor for sudden infant death syndrome (SIDS). To alleviate the risks, nicotine replacement therapies are often prescribed to women who wish to quit smoking during their pregnancy. Cardiac arrhythmias is considered the final outcome leading to sudden death. Our goal in this study was to determine if exposing rabbit fetus to nicotine altered the cardiac conduction system of newborn kittens in a manner susceptible to cause SIDS. Using neuronal markers and a series of immunohistological and electrophysiological techniques we found that nicotine delayed the development of the cardiac pacemaker center (sinoatrial node) and decreased its innervation. At the molecular level, nicotine favored the expression of cardiac sodium channels with biophysical properties that will tend to slow heart rate and diminish electrical conduction. Our results show that alterations of the cardiac sodium current may contribute to the bradycardia, conduction disturbances and other cardiac arrhythmias often associated to SIDS and raise awareness on the use of replacement therapy during pregnancy.

Published
2017
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