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13. Small extracellular vesicles from epicardial fat of patients with atrial fibrillation induce inflammation, fibrosis and re-entrant arrhythmias

Author

Shaihov-Teper, O, primary, Ram, E, additional, Brzezinski, R, additional, Volvovitch, D, additional, Zuroff, E, additional, Amunts, S, additional, Schary, Y, additional, Naftali-Shani, N, additional, Ballan, N, additional, Gepstein, L, additional, Sternik, L, additional, Raanani, E, additional, and Leor, J, additional

Published
2020
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19. Replacing carmustine by thiotepa and cyclophosphamide for autologous stem cell transplantation in Hodgkin’s and non-Hodgkin’s B-cell lymphoma

Author

Joffe, E, primary, Rosenberg, D, additional, Rozovski, U, additional, Perry, C, additional, Kirgner, I, additional, Trestman, S, additional, Gur, O, additional, Aviv, F, additional, Sarid, N, additional, Kolomansky, A, additional, Gepstein, L, additional, Herishanu, Y, additional, and Naparstek, E, additional

Published
2017
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24. Poster Session 1

Author

Deshmukh, A., primary, Sharma, S. S., additional, Gobal, F. G., additional, Singla, S. S., additional, Hebbar, P. H., additional, Paydak, H. P., additional, Igarashi, M., additional, Tada, H., additional, Sekiguchi, Y., additional, Yamasaki, H., additional, Kuroki, K., additional, Machino, T., additional, Yoshida, K., additional, Aonuma, K., additional, Shavadia, J., additional, Otieno, H., additional, Yonga, G., additional, Jinah, A., additional, Qvist, J. F., additional, Soerensen, P. H., additional, Dixen, U., additional, Ramirez-Marrero, M. A., additional, Perez-Villardon, B., additional, Gaitan-Roman, D., additional, Jimenez-Navarro, M., additional, Delgado-Prieto, J. L., additional, De Teresa-Galvan, E., additional, De Mora-Martin, M., additional, Deshmukh, A., additional, Hebbar, P. B., additional, Wei, W. X., additional, Bardari, S., additional, Zecchin, M., additional, Salame', R., additional, Vitali Serdoz, L., additional, Di Lenarda, A., additional, Guerrini, N., additional, Barbati, G., additional, Sinagra, G., additional, Hanazawa, K., additional, Kaitani, K., additional, Nakagawa, Y., additional, Lenaerts, I., additional, Driesen, R., additional, Hermida, N., additional, Heidbuchel, H., additional, Janssens, S., additional, Balligand, J. L., additional, Sipido, K. R., additional, Willems, R., additional, Sehra, R., additional, Krummen, D., additional, Briggs, C., additional, Narayan, S., additional, Tanaka, Y., additional, Hirao, K., additional, Nakamura, T., additional, Inaba, O., additional, Yagishita, A., additional, Higuchi, K., additional, Hachiya, H., additional, Isobe, M., additional, Kallergis, E., additional, Kanoupakis, E. M., additional, Mavrakis, H. E., additional, Goudis, C. A., additional, Maliaraki, N. E., additional, Vardas, P. E., additional, Kiuchi, K., additional, Piorkowski, C., additional, Kircher, S., additional, Gaspar, T., additional, Watanabe, N., additional, Bollmann, A., additional, Hindricks, G., additional, Wauters, K., additional, Grosse, A., additional, Raffa, S., additional, Brunelli, M., additional, Geller, J. C., additional, Maggioni, A. P., additional, Gonzini, L., additional, Gussoni, G., additional, Vescovo, G., additional, Gulizia, M., additional, Pirelli, S., additional, Mathieu, G., additional, Di Pasquale, G., additional, Salame, R., additional, Magnani, S., additional, Sakamoto, T., additional, Kumagai, K., additional, Fuke, E., additional, Nishiuchi, S., additional, Hayashi, T., additional, Miki, Y., additional, Naito, S., additional, Oshima, S., additional, Hof, I. E., additional, Vonken, E., additional, Velthuis, B. K., additional, Meine, M., additional, Hauer, R. N. W., additional, Loh, K. P., additional, Na, J. O., additional, Choi, C. U., additional, Kim, E. J., additional, Rha, S. W., additional, Park, C. G., additional, Seo, H. S., additional, Oh, D. J., additional, Lim, H. E., additional, Wichterle, D., additional, Bulkova, V., additional, Fiala, M., additional, Chovancik, J., additional, Simek, J., additional, Peichl, P., additional, Cihak, R., additional, Kautzner, J., additional, Glick, A., additional, Viskin, S., additional, Belhassen, B., additional, Navarrete, A., additional, Conte, F., additional, Ishti, A., additional, Sai, D., additional, Moran, M., additional, Chitovova, Z., additional, Ahmed, H., additional, Mares, K., additional, Skoda, J., additional, Sediva, L., additional, Petru, J., additional, Reddy, V. Y., additional, Neuzil, P., additional, Schmidt, M., additional, Dorwarth, U., additional, Leber, A., additional, Wankerl, M., additional, Krieg, J., additional, Straube, F., additional, Reif, S., additional, Hoffmann, E., additional, Mikhaylov, E., additional, Tikhonenko, V., additional, Lebedev, D., additional, Shin, S. Y., additional, Yong, H. S., additional, Choi, J. I., additional, Kim, S. H., additional, Matsuo, S., additional, Yamane, T., additional, Hioki, M., additional, Ito, K., additional, Narui, R., additional, Date, T., additional, Sugimoto, K., additional, Yoshimura, M., additional, Rolf, S., additional, Sommer, P., additional, Batalov, R., additional, Popov, S., additional, Antonchenko, I., additional, Suslova, T., additional, Fichtner, S., additional, Czudnochowsky, U., additional, Estner, H. L., additional, Ammar, S., additional, Reents, T., additional, Jilek, C., additional, Hessling, G., additional, Deisenhofer, I., additional, Pokushalov, E., additional, Romanov, A., additional, Corbucci, G., additional, Artemenko, S., additional, Losik, D., additional, Shabanov, V., additional, Turov, A., additional, Elesin, D., additional, Abramov, M., additional, Sanders, P., additional, Jais, P., additional, Roberts-Thomson, K., additional, Fukumoto, K., additional, Takatsuki, S., additional, Kimura, T., additional, Nishiyama, N., additional, Aizawa, Y., additional, Sato, T., additional, Miyoshi, S., additional, Fukuda, K., additional, Roux, Y., additional, Tenkorang, J., additional, Carroz, P., additional, Schlaepfer, J., additional, Pascale, P., additional, Forclaz, A., additional, Fromer, M., additional, Pruvot, E., additional, Sknouril, L., additional, Nevralova, R., additional, Dorda, M., additional, Januska, J., additional, Santi, R., additional, Geller, C., additional, Nakamura, K., additional, Kasseno, K., additional, Taniguchi, K., additional, Wutzler, A., additional, Huemer, M., additional, Parwani, A., additional, Boldt, L. H., additional, Blaschke, D., additional, Dietz, R., additional, Haverkamp, W., additional, Coutu, B., additional, Malanuk, R., additional, Ait Said, M., additional, Vicentini, A., additional, Schade, S., additional, Ando, K., additional, Rousseauplasse, A., additional, Deering, T., additional, Picarra, B. C., additional, Santos, A. R., additional, Dionisio, P., additional, Semedo, P., additional, Matos, R., additional, Leitao, M., additional, Jacinto, A., additional, Trinca, M., additional, Wan, C., additional, Glad, J., additional, Szymkiewicz, S., additional, Habibovic, M., additional, Versteeg, H., additional, Pelle, A. J. M., additional, Theuns, D. A. M. J., additional, Jordaens, L., additional, Pedersen, S. S., additional, Pakarinen, S., additional, Toivonen, L., additional, Taggeselle, J., additional, Frey, A., additional, Birkenhagen, A., additional, Kohler, S., additional, Maier, S. K. G., additional, Lobitz, N., additional, Paule, S., additional, Becher, J., additional, Mustafa, G., additional, Ibrahim, A., additional, King, G., additional, Foley, B., additional, Wilkoff, B., additional, Freedman, R., additional, Hayes, D., additional, Kalbfleisch, S., additional, Kutalek, S., additional, Schaerf, R., additional, Fazal, I. A., additional, Tynan, M., additional, Plummer, C. J., additional, Mccomb, J. M., additional, Oto, A., additional, Aytemir, K., additional, Yorgun, H., additional, Canpolat, U., additional, Kaya, E. B., additional, Tokgozoglu, L., additional, Kabakci, G., additional, Ozkutlu, H., additional, Greenberg, S., additional, Hamati, F., additional, Styperek, R., additional, Alonso, J., additional, Peress, D., additional, Bolanos, O., additional, Augostini, R., additional, Pelini, M., additional, Zhang, S., additional, Stoycos, S., additional, Witsaman, S., additional, Mowrey, K., additional, Bremer, J., additional, Oza, A., additional, Ciconte, G., additional, Mazzone, P., additional, Paglino, G., additional, Marzi, A., additional, Vergara, P., additional, Sora, N., additional, Gulletta, S., additional, Della Bella, P., additional, Nagashima, M., additional, Goya, M., additional, Soga, Y., additional, Hiroshima, K., additional, Andou, K., additional, Hayashi, K., additional, An, Y., additional, Nobuyoshi, M., additional, Kutarski, A., additional, Malecka, B., additional, Pietura, R., additional, Osmancik, P., additional, Herman, D., additional, Stros, P., additional, Kocka, V., additional, Tousek, P., additional, Linkova, H., additional, Bortnik, M., additional, Occhetta, E., additional, Dell'era, G., additional, Degiovanni, A., additional, Plebani, L., additional, Marino, P. N., additional, Gorev, M. V., additional, Alimov, D. G., additional, Raju, P., additional, Kully, S., additional, Ugni, S., additional, Furniss, S., additional, Lloyd, G., additional, Patel, N. R., additional, Richards, M. W., additional, Warren, C. E., additional, Anderson, M. H., additional, Hero, M., additional, Rey, J. L., additional, Ouali, S., additional, Azzez, S., additional, Kacem, S., additional, Hammas, S., additional, Ben Salem, H., additional, Neffeti, E., additional, Remedi, F., additional, Boughzela, E., additional, Kronborg, M. B., additional, Mortensen, P. T., additional, Poulsen, S. H., additional, Nielsen, J. C., additional, Simantirakis, E. N., additional, Kontaraki, J. E., additional, Arkolaki, E. G., additional, Chrysostomakis, S. I., additional, Nyktari, E. G., additional, Patrianakos, A. P., additional, Funck, R. C., additional, Harink, C., additional, Mueller, H. H., additional, Koelsch, S., additional, Maisch, B., additional, Bolzani, V., additional, Costandi, P., additional, Shehada, R. E., additional, Butala, N., additional, Coppola, B., additional, Taborsky, M., additional, Heinc, P., additional, Fedorco, M., additional, Doupal, V., additional, Di Cori, A., additional, Zucchelli, G., additional, Soldati, E., additional, Segreti, L., additional, De Lucia, R., additional, Viani, S., additional, Paperini, L., additional, Bongiorni, M. G., additional, Gutleben, K. J., additional, Kranig, W., additional, Barr, C., additional, Morgenstern, M. M., additional, Simon, M., additional, Dalal, Y. H., additional, Landolina, M., additional, Pierantozzi, A., additional, Agricola, T., additional, Lunati, M., additional, Pisano', E., additional, Lonardi, G., additional, Bardelli, G., additional, Zucchi, G., additional, Thibault, B., additional, Dubuc, M., additional, Karst, E., additional, Ryu, K., additional, Paiement, P., additional, Carlson, M. D., additional, Farazi, T., additional, Alhous, H., additional, Mont, L., additional, Porres, J. M., additional, Alzueta, J., additional, Beiras, X., additional, Fernandez-Lozano, I., additional, Macias, A., additional, Ruiz, R., additional, Brugada, J., additional, Viani, S. M., additional, Seifert, M., additional, Schau, T., additional, Moeller, V., additional, Meyhoefer, J., additional, Butter, C., additional, Ganiere, V., additional, Niculescu, V., additional, Domenichini, G., additional, Stettler, C., additional, Defaye, P., additional, Burri, H., additional, Stockburger, M., additional, De Teresa, E., additional, Lamas, G., additional, Desaga, M., additional, Koenig, C., additional, Cobo, E., additional, Navarro, X., additional, Wiegand, U., additional, Blich, M., additional, Carasso, S., additional, Suleiman, M., additional, Marai, I., additional, Gepstein, L., additional, Boulos, M., additional, Sasov, M., additional, Liska, B., additional, Margitfalvi, P., additional, Malacky, T., additional, Svetlosak, M., additional, Goncalvesova, E., additional, Hatala, R., additional, Takaya, Y., additional, Noda, T., additional, Yamada, Y., additional, Okamura, H., additional, Satomi, K., additional, Shimizu, W., additional, Aihara, N., additional, Kamakura, S., additional, Proclemer, A., additional, Boveda, S., additional, Oswald, H., additional, Scipione, P., additional, Da Costa, A., additional, Brzozowski, W., additional, Tomaszewski, A., additional, Wysokinski, A., additional, Arbelo, E., additional, Tamborero, D., additional, Vidal, B., additional, Tolosana, J. M., additional, Sitges, M., additional, Matas, M., additional, Botto, G. L., additional, Dicandia, C. D., additional, Mantica, M., additional, La Rosa, C., additional, D' Onofrio, A., additional, Molon, G., additional, Raciti, G., additional, Verlato, R., additional, Foley, P. W. X., additional, Chalil, S., additional, Ratib, K., additional, Smith, R. E. A., additional, Printzen, F., additional, Auricchio, A., additional, Leyva, F., additional, Abu Sham'a, R., additional, Buber, J., additional, Luria, D., additional, Kuperstein, R., additional, Feinberg, M., additional, Granit, H., additional, Eldar, M., additional, Glikson, M., additional, Vondrak, K., additional, Nof, E., additional, Lipchenca, I., additional, Vatasescu, R.- G., additional, Iorgulescu, C., additional, Caldararu, C., additional, Vasile, A., additional, Bogdan, S., additional, Constantinescu, D., additional, Dorobantu, M., additional, Sakaguchi, H., additional, Miyazaki, A., additional, Yamamoto, T., additional, Fujimoto, K., additional, Ono, S., additional, Ohuchi, H., additional, Martinelli, M., additional, Martins, S., additional, Molina, R., additional, Siqueira, S., additional, Nishioka, S. A. D., additional, Peixoto, G. L., additional, Alkmim-Teixeira, R., additional, Costa, R., additional, Meine, M. M., additional, Tuinenburg, A. E., additional, Doevendans, P. A., additional, Denollet, J., additional, Goscinska-Bis, K., additional, Zupan, I., additional, Van Der, H., additional, Anselme, F., additional, Hartog, H., additional, Block, M., additional, Borri, A., additional, Padeletti, L., additional, Toniolo, M., additional, Zanotto, G., additional, Rossi, A., additional, Raytcheva, E., additional, Tomasi, L., additional, Vassanelli, C., additional, Fernandez Lozano, I., additional, Mitroi, C., additional, Toquero Ramos, J., additional, Castro Urda, V., additional, Monivas Palomero, V., additional, Corona Figueroa, A., additional, Ruiz Bautista, L., additional, Alonso Pulpon, L., additional, Jadidi, A. S., additional, Sacher, F., additional, Shah, A. S., additional, Scherr, D., additional, Derval, N., additional, Hocini, M., additional, Haissaguerre, M., additional, Castrejon Castrejon, S., additional, Largo-Aramburu, C., additional, Sachar, J., additional, Gang, E., additional, Estrada, A., additional, Doiny, D., additional, De Miguel, E., additional, Merino, J. L., additional, Trevisi, N., additional, Ricco, A., additional, Petracca, F., additional, Baratto, F., additional, Bisceglie, A., additional, Maccabelli, G., additional, El-Damaty, A., additional, Sapp, J., additional, Warren, J., additional, Macinnis, P., additional, Horacek, M., additional, Dinov, B., additional, Schoenbauer, R., additional, Braunschweig, F., additional, Arya, A., additional, Andreu, D., additional, Berruezo, A., additional, Ortiz, J. T., additional, Silva, E., additional, De Caralt, T. M., additional, Fernandez-Armenta, J., additional, Perez-Silva, A., additional, Ortega, M., additional, Lopez-Sendon, J. L., additional, Regoli, F., additional, Faletra, F., additional, Nucifora, G., additional, Pasotti, E., additional, Moccetti, T., additional, Klersy, C., additional, Casella, M., additional, Dello Russo, A., additional, Moltrasio, M., additional, Zucchetti, M., additional, Fassini, G., additional, Di Biase, L., additional, Natale, A., additional, Tondo, C., additional, Matsuhashi, N., additional, Weig, H. J., additional, Kerst, G., additional, Weretk, S., additional, Seizer, P., additional, Gawaz, M. P., additional, Schreieck, J., additional, Sarquella-Brugada, G., additional, Prada, F., additional, Salling, C. M., additional, Kolb, C., additional, Pytkowski, M., additional, Maciag, A., additional, Farkowski, M., additional, Jankowska, A., additional, Kowalik, I., additional, Kraska, A., additional, Szwed, H., additional, Maury, P., additional, Duparc, A., additional, Mondoly, P., additional, Rollin, A., additional, Pap, R., additional, Kohari, M., additional, Bencsik, G., additional, Makai, A., additional, Saghy, L., additional, Forster, T., additional, Ebrille, E., additional, Scaglione, M., additional, Raimondo, C., additional, Caponi, D., additional, Di Donna, P., additional, Blandino, A., additional, Delcre, S. D. L., additional, Gaita, F., additional, Roca Luque, I., additional, Dos, L. D. S., additional, Rivas, N. R. G., additional, Pijuan, A. P. D., additional, Perez, J., additional, Casaldaliga, J., additional, Garcia-Dorado, D. G. D., additional, Moya, A. M. M., additional, Sato, H., additional, Yagi, T., additional, Yambe, T., additional, Streitner, F., additional, Dietrich, C., additional, Mahl, E., additional, Schoene, N., additional, Veltmann, C., additional, Borggrefe, M., additional, Kuschyk, J., additional, Sadarmin, P. P., additional, Wong, K. C. K., additional, Rajappan, K., additional, Bashir, Y., additional, Betts, T. R., additional, Leclercq, C., additional, Martins, R., additional, Daubert, J. C., additional, Mabo, P., additional, Koide, M., additional, Hamano, G., additional, Taniguchi, T., additional, Yamato, M., additional, Sasaki, N., additional, Hirooka, K., additional, Ikeda, Y., additional, Yasumura, Y., additional, Dichtl, W., additional, Wolber, T., additional, Paoli, U., additional, Bruellmann, S., additional, Berger, T., additional, Stuehlinger, M., additional, Duru, F., additional, Hintringer, F., additional, Kanoupakis, E., additional, Mavrakis, H., additional, Koutalas, E., additional, Saloustros, I., additional, Goudis, C., additional, Chlouverakis, G., additional, Vardas, P., additional, Herre, J. M., additional, Saeed, M., additional, Saberi, L., additional, Neuman, S., additional, Yamaji, K., additional, Iwabuchi, M., additional, Baranchuk, A., additional, Femenia, F., additional, Miranda Hermosilla, R., additional, Lopez Diez, J. C., additional, Serra, J. L., additional, Valentino, M., additional, Retyk, E., additional, Galizio, N., additional, Kwasniewski, W., additional, Filipecki, A., additional, Orszulak, W., additional, Urbanczyk-Swic, D., additional, Trusz - Gluza, M., additional, Piot, O., additional, Degand, B., additional, Donofrio, A., additional, Scanu, P., additional, Quesada, A., additional, Kloppe, A., additional, Mijic, D., additional, Bogossian, H., additional, Zarse, M., additional, Lemke, B., additional, Tyler, J., additional, Comfort, G., additional, Deering, T. F., additional, Epstein, A. E., additional, Greenberg, S. M. G., additional, Goldman, D. S., additional, Rhude, J., additional, Majewski, J. P., additional, Lelakowski, J., additional, Tomala, I., additional, Santos, C. M., additional, Miranda, R. S., additional, Sousa, P. J., additional, Cavaco, D. M., additional, Adragao, P. P., additional, Knops, R. E., additional, Wilde, A. A., additional, Belhameche, M., additional, Hermida, J. S., additional, Dovellini, E., additional, Frohlig, G., additional, Siot, P., additional, Duray, G. Z., additional, Israel, C. W., additional, Brachmann, J., additional, Seidl, K. H., additional, Foresti, M., additional, Birkenhauer, F., additional, Hohnloser, S. H., additional, Ferreira, C., additional, Mateus, P., additional, Ribeiro, H., additional, Carvalho, S., additional, Ferreira, A., additional, Moreira, J., additional, Kadro, W., additional, Rahim, H., additional, Turkmani, M., additional, Abu Lebdeh, M., additional, Altabban, A., additional, Cerrato, N., additional, Rivera, S., additional, Scazzuso, F., additional, Albina, G., additional, Klein, A., additional, Laino, R., additional, Sammartino, V., additional, Giniger, A., additional, Kvantaliani, T., additional, Akhvlediani, M., additional, Namdar, M., additional, Steffel, J., additional, Jetzer, S., additional, Bayrak, F., additional, Chierchia, G. B., additional, Jenni, R., additional, Brugada, P., additional, Bakos, Z., additional, Medvedev M, M. M., additional, Jonas Carlsson, J. C., additional, Fredrik Holmqvist, F. H., additional, Pyotr Platonov, P. P., additional, Nurbaev, T., additional, Pirnazarov, M., additional, Nikishin, A., additional, Aagaard, P., additional, Sahlen, A., additional, Bergfeldt, L., additional, Simeonidou, E., additional, Kastellanos, S., additional, Varounis, C., additional, Michalakeas, C., additional, Koniari, C., additional, Nikolopoulou, A., additional, Anastasiou-Nana, M., additional, Furukawa, Y., additional, Yamada, T., additional, Morita, T., additional, Tanaka, K., additional, Iwasaki, Y., additional, Kawasaki, M., additional, Kuramoto, Y., additional, Fukunami, M., additional, Blanche, C., additional, Tran, N., additional, Rigamonti, F., additional, Zimmermann, M., additional, Okisheva, E., additional, Tsaregorodtsev, D., additional, Sulimov, V., additional, Novikova, D., additional, Popkova, T., additional, Udachkina, E., additional, Korsakova, Y., additional, Volkov, A., additional, Novikov, A., additional, Alexandrova, E., additional, Nasonov, E., additional, Arsenos, P., additional, Gatzoulis, K., additional, Manis, G., additional, Dilaveris, P., additional, Gialernios, T., additional, Kartsagoulis, E., additional, Asimakopoulos, S., additional, Stefanadis, C., additional, Marocolo, M., additional, Barbosa Neto, O., additional, Carvalho, A. C., additional, Marques Neto, S. R., additional, Mota, G. R., additional, Barbosa, P. R. B., additional, Fernandez-Fernandez, A., additional, Manzano Fernandez, S., additional, Pastor-Perez, F. J., additional, Barquero-Perez, O., additional, Goya-Esteban, R., additional, Salar, M., additional, Rojo-Alvarez, J. L., additional, Garcia-Alberola, A., additional, Takigawa, M., additional, Kawamura, M., additional, Aiba, T., additional, Sakaguchi, T., additional, Itoh, H., additional, Horie, M., additional, Igarashi, T., additional, Negishi, J., additional, Toyota, N., additional, Yamada, O., additional, Papavasileiou, M., additional, Cabrera Bueno, F., additional, Molina Mora, M. J., additional, Alzueta Rodriguez, J., additional, Barrera Cordero, A., additional, De Teresa Galvan, E., additional, Revishvili, A. S., additional, Dzhordzhikiya, T., additional, Sopov, O., additional, Simonyan, G., additional, Lyadzhina, O., additional, Fetisova, E., additional, Kalinin, V., additional, Balt, J. C., additional, Steggerda, R. C., additional, Boersma, L. V. A., additional, Wijffels, M. C. E. F., additional, Wever, E. F. D., additional, Ten Berg, J. M., additional, Ricci, R. P., additional, Morichelli, L., additional, D'onofrio, A., additional, Vaccari, D., additional, Calo', L., additional, Buja, G., additional, Rovai, N., additional, Gargaro, A., additional, Sperzel, J., additional, Speca, G., additional, Santini, L., additional, Haarbo, J., additional, Dubin, K., additional, Carlson, M., additional, Garcia Quintana, A., additional, Mendoza-Lemes, H., additional, Garcia Perez, L., additional, Led Ramos, S., additional, Caballero Dorta, E., additional, Matinez De Espronceda, M., additional, Piro Mastracchio, V., additional, Serrano Arriezu, L., additional, Sciarra, L., additional, Marziali, M., additional, Marras, E., additional, Rebecchi, M., additional, Allocca, G., additional, Lioy, E., additional, Delise, P., additional, Santobuono, V. E., additional, Iacoviello, M., additional, Nacci, F., additional, Luzzi, G., additional, Puzzovivo, A., additional, Memeo, M., additional, Quadrini, F., additional, Favale, S., additional, Trucco, M. E., additional, Arce, M., additional, Palazzolo, J., additional, Uribe, W., additional, Maggi, R., additional, Furukawa, T., additional, Croci, F., additional, Solano, A., additional, Brignole, M., additional, Lebreiro, A., additional, Sousa, A., additional, Correia, A. S., additional, Lourenco, P., additional, Oliveira, S., additional, Paiva, M., additional, Freitas, J., additional, Maciel, M. J., additional, Linker, N., additional, Rieger, G., additional, Garutti, C., additional, Edvardsson, N., additional, Salguero Bodes, R., additional, De Riva Silva, M., additional, Fontenla Cerezuela, A., additional, Lopez Gil, M., additional, Mejia Martinez, E., additional, Jurado Roman, A., additional, Garcia Alvarez, S., additional, Arribas Ynsaurriaga, F., additional, Petix, N. R., additional, Del Rosso, A., additional, Guarnaccia, V., additional, Zipoli, A., additional, Rabajoli, F., additional, Foglia Manzillo, G., additional, Tolardo, C., additional, Checchinato, C., additional, Chiaravallotti, S., additional, Santarone, M., additional, Spinnler, M. T., additional, Podoleanu, C., additional, Frigy, A., additional, Dobreanu, D., additional, Ginghina, C., additional, and Carasca, E., additional

Published
2011
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29. Circadian pattern of life-threatening ventricular arrhythmia in patients with sleep-disordered breathing and implantable cardioverter-defibrillators.

Author

Zeidan-Shwiri T, Aronson D, Atalla K, Blich M, Suleiman M, Marai I, Gepstein L, Lavie L, Lavie P, Boulos M, Zeidan-Shwiri, Tawfiq, Aronson, Doron, Atalla, Khalid, Blich, Miry, Suleiman, Mahmoud, Marai, Ibrahim, Gepstein, Lior, Lavie, Lena, Lavie, Peretz, and Boulos, Monther

Abstract

Background: Sleep-disordered breathing (SDB) has been associated with various benign cardiac arrhythmias occurring during sleep.Objective: The purpose of this study was to demonstrate that SDB contributes to the development of life-threatening ventricular arrhythmias in patients with an established arrhythmic substrate.Methods: We prospectively studied the association between SDB and timing of life-threatening ventricular arrhythmic events in 45 patients with an implantable cardioverter-defibrillator (ICD). SDB was defined as an apnea-hypopnea index (AHI) >10 events/hour based on an overnight sleep study. The primary outcome measure was appropriate ICD therapy, defined as antitachycardia pacing or shock for ventricular tachycardia or ventricular fibrillation during 1-year follow-up.Results: SDB was present in 26 (57.8%) patients. Appropriate ICD therapies were higher among patients with SDB (73% vs 47%, P = .02). Logistic regression identified SDB as a predictor of any appropriate ICD therapy (odds ratio 4.4, 95% confidence interval 1.4-15.3, P = .01). The risk for ventricular arrhythmias was higher in patients with SDB solely due to an increase in events occurring between midnight and 6 AM (odds ratio 5.6, 95% confidence interval 2.0-15.6, P = .001) with no discernible effect on appropriate ICD therapy during nonsleeping hours (odds ratio 0.7, 95% confidence interval 0.2-2.3, P = .61).Conclusion: Patients with an ICD and SDB have a striking increase in the onset of life-threatening ventricular arrhythmic events during sleeping hours. These findings provide a rationale for SDB screening in patients with appropriate ICD therapy if device interrogation reveals a predominance of nocturnal onset of arrhythmias. [ABSTRACT FROM AUTHOR]

Published
2011
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34. Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2

Author

Giannetti, Federica, Barbieri, Miriam, Shiti, Assad, Casini, Simona, Sager, Philip T, Das, Saumya, Pradhananga, Sabindra, Srinivasan, Dinesh, Nimani, Saranda, Alerni, Nicolò, Louradour, Julien, Mura, Manuela, Gnecchi, Massimiliano, Brink, Paul, Zehender, Manfred, Koren, Gideon, Zaza, Antonio, Crotti, Lia, Wilde, Arthur A M, Schwartz, Peter J, Remme, Carol Ann, Gepstein, Lior, Sala, Luca, Odening, Katja E, Giannetti, F, Barbieri, M, Shiti, A, Casini, S, Sager, P, Das, S, Pradhananga, S, Srinivasan, D, Nimani, S, Alerni, N, Louradour, J, Mura, M, Gnecchi, M, Brink, P, Zehender, M, Koren, G, Zaza, A, Crotti, L, Wilde, A, Schwartz, P, Remme, C, Gepstein, L, Sala, L, and Odening, K

Subjects
Cellular electrophysiology, Physiology (medical), LQTS, Animal model, 610 Medicine & health, 610 Medizin und Gesundheit, Cardiology and Cardiovascular Medicine, Genotype-specific therapy, hiPSC, Mechanism-based therapy
Abstract

Aims Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. Methods and results Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM–10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3–10 µM (by 20–32%/25–30%/44–45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3–3 µM. Conclusion A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS.

Published
2023

36. Ser194Leu DSG2 mutation, associated with arrhythmogenic left ventricular cardiomyopathy and ventricular tachycardia.

Author

Blich M, Zohar Y, Cohen-Kaplan V, Minkov I, Asleh R, Horowitz-Cederboim S, Weiss K, Paperna T, Lessick J, Abadi S, Khoury A, Gepstein L, Suleiman M, and Caspi O

Subjects
Humans, Connexin 43 genetics, Connexin 43 metabolism, Mutation genetics, Arrhythmias, Cardiac complications, Myocytes, Cardiac metabolism, Desmoglein 2 genetics, Desmoglein 2 metabolism, Arrhythmogenic Right Ventricular Dysplasia genetics, Cardiomyopathies complications, Tachycardia, Ventricular genetics, Tachycardia, Ventricular complications
Abstract

Introduction: Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibro-fatty replacement of cardiomyocytes, leading to life-threatening ventricular arrhythmia and heart failure. Pathogenic variants of desmoglein2 gene (DSG2) have been reported as genetic etiologies of AC. In contrast, many reported DSG2 variants are benign or variants of uncertain significance. Correct genetic variant classification is crucial for determining the best medical therapy for the patient and family members., Methods: Pathogenicity of the DSG2 Ser194Leu variant that was identified by whole exome sequencing in a patient, who presented with ventricular tachycardia and was diagnosed with AC, was investigated by electron microscopy and immunohistochemical staining of endomyocardial biopsy sample., Results: Electron microscopy demonstrated a widened gap in the adhering junction and a less well-organized intercalated disk region in the mutated cardiomyocytes compared to the control. Immunohistochemical staining in the proband diagnosed with AC showed reduced expression of desmoglein 2 and connexin 43 and intercalated disc distortion. Reduced expression of DSG2 and Connexin 43 were observed in cellular cytoplasm and gap junctions. Additionally, we detected perinuclear accumulation of DSG2 and Connexin 43 in the proband sample., Conclusion: Ser194Leu is a missense pathogenic mutation of DSG2 gene associated with arrhythmogenic left ventricular cardiomyopathy., (© 2024 Wiley Periodicals LLC.)

Published
2024
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37. Utilizing Human-Induced Pluripotent Stem Cells to Study Cardiac Electroporation Pulsed-Field Ablation.

Author

Maizels L, Heller E, Landesberg M, Glatstein S, Huber I, Arbel G, Gepstein A, Aronson D, Sharabi S, Beinart R, Segev A, Maor E, and Gepstein L

Subjects
Humans, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac surgery, Anti-Arrhythmia Agents therapeutic use, Myocytes, Cardiac metabolism, Electroporation, Induced Pluripotent Stem Cells metabolism, Catheter Ablation methods
Abstract

Background: Electroporation is a promising nonthermal ablation method for cardiac arrhythmia treatment. Although initial clinical studies found electroporation pulsed-field ablation (PFA) both safe and efficacious, there are significant knowledge gaps concerning the mechanistic nature and electrophysiological consequences of cardiomyocyte electroporation, contributed by the paucity of suitable human in vitro models. Here, we aimed to establish and characterize a functional in vitro model based on human-induced pluripotent stem cells (hiPSCs)-derived cardiac tissue, and to study the fundamentals of cardiac PFA., Methods: hiPSC-derived cardiomyocytes were seeded as circular cell sheets and subjected to different PFA protocols. Detailed optical mapping, cellular, and molecular characterizations were performed to study PFA mechanisms and electrophysiological outcomes., Results: PFA generated electrically silenced lesions within the hiPSC-derived cardiac circular cell sheets, resulting in areas of conduction block. Both reversible and irreversible electroporation components were identified. Significant electroporation reversibility was documented within 5 to 15-minutes post-PFA. Irreversibly electroporated regions persisted at 24-hours post-PFA. Per single pulse, high-frequency PFA was less efficacious than standard (monophasic) PFA, whereas increasing pulse-number augmented lesion size and diminished reversible electroporation. PFA augmentation could also be achieved by increasing extracellular Ca 2+ levels. Flow-cytometry experiments revealed that regulated cell death played an important role following PFA. Assessing for PFA antiarrhythmic properties, sustainable lines of conduction block could be generated using PFA, which could either terminate or isolate arrhythmic activity in the hiPSC-derived cardiac circular cell sheets., Conclusions: Cardiac electroporation may be studied using hiPSC-derived cardiac tissue, providing novel insights into PFA temporal and electrophysiological characteristics, facilitating electroporation protocol optimization, screening for potential PFA-sensitizers, and investigating the mechanistic nature of PFA antiarrhythmic properties., Competing Interests: Disclosures None.

Published
2024
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38. The role of early cardiac resynchronization therapy implantation in dilated cardiomyopathy patients with narrow QRS carrying lamin A/C mutation.

Author

Blich M, Darawsha W, Eyal A, Shehadeh F, Boulous M, Gepstein L, and Suleiman M

Abstract

Background: Dilated cardiomyopathy (DCM) caused by Lamin A/C gene (LMNA) mutation is complicated with atrioventricular conduction disturbances, malignant ventricular arrhythmias and progressive severe heart failure., Objective: We hypothesized that early cardiac resynchronization therapy (CRT) implantation in LMNA mutation carriers with an established indication for pacemaker or implantable cardioverter defibrillator (ICD), may preserve ejection fraction, and delay disease progression to end stage heart failure., Methods: We compared the primary outcomes: time to heart transplantation, death due to end stage heart failure or ventricular tachycardia (VT) ablation and secondary outcomes: change in left ventricular ejection fraction (EF) and ventricular arrhythmia burden between LMNA DCM patients in the early CRT and non-CRT groups., Results: Of ten LMNA DCM patients (age 51±10 years, QRS 96±14 msec, EF 55±7%) with indication for pacemaker or ICD implantation, five underwent early CRT-D implantation. After 7.2±4 years, three patients (60%) in the non-CRT group reached the primary outcome, compared to no patients in the CRT group (P=0.046). Four patients in non-CRT group (80%) experienced sustained ventricular tachycardia or received appropriate ICD shock compared to 1 patient (20%) in the CRT group (P=0.058). LMNA patients without early CRT had a higher burden of VPC/24 h in 12-lead holter (median 2352 vs 185, P=0.09). Echocardiography showed statistically lower LVEF in the non-CRT group compared to CRT group [(32±15)% vs (61±4)%, 95% CI: 32.97-61.03, P=0.016]., Conclusion: Early CRT implantation in LMNA cardiomyopathy patients, with an indication for pacemaker or ICD, may reduce heart failure deterioration and life-threatening heart failure complications., Competing Interests: None., (AJCD Copyright © 2024.)

Published
2024

39. Electro-metabolic coupling in multi-chambered vascularized human cardiac organoids.

Author

Ghosheh M, Ehrlich A, Ioannidis K, Ayyash M, Goldfracht I, Cohen M, Fischer A, Mintz Y, Gepstein L, and Nahmias Y

Subjects
Animals, Humans, Arrhythmias, Cardiac, Myocardial Contraction physiology, Organoids, Myocytes, Cardiac metabolism, Biochemical Phenomena
Abstract

The study of cardiac physiology is hindered by physiological differences between humans and small-animal models. Here we report the generation of multi-chambered self-paced vascularized human cardiac organoids formed under anisotropic stress and their applicability to the study of cardiac arrhythmia. Sensors embedded in the cardiac organoids enabled the simultaneous measurement of oxygen uptake, extracellular field potentials and cardiac contraction at resolutions higher than 10 Hz. This microphysiological system revealed 1 Hz cardiac respiratory cycles that are coupled to the electrical rather than the mechanical activity of cardiomyocytes. This electro-mitochondrial coupling was driven by mitochondrial calcium oscillations driving respiration cycles. Pharmaceutical or genetic inhibition of this coupling results in arrhythmogenic behaviour. We show that the chemotherapeutic mitoxantrone induces arrhythmia through disruption of this pathway, a process that can be partially reversed by the co-administration of metformin. Our microphysiological cardiac systems may further facilitate the study of the mitochondrial dynamics of cardiac rhythms and advance our understanding of human cardiac physiology., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2023
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40. Utilizing human induced pluripotent stem cells to study atrial arrhythmias in the short QT syndrome.

Author

Shiti A, Arbil G, Shaheen N, Huber I, Setter N, and Gepstein L

Subjects
Humans, Myocytes, Cardiac metabolism, Potassium metabolism, Action Potentials genetics, Induced Pluripotent Stem Cells, Atrial Fibrillation genetics, Atrial Fibrillation metabolism
Abstract

Background: Among the monogenic inherited causes of atrial fibrillation is the short QT syndrome (SQTS), a rare channelopathy causing atrial and ventricular arrhythmias. One of the limitations in studying the mechanisms and optimizing treatment of SQTS-related atrial arrhythmias has been the lack of relevant human atrial tissues models., Objective: To generate a unique model to study SQTS-related atrial arrhythmias by combining the use of patient-specific human induced pluripotent stem cells (hiPSCs), atrial-specific differentiation schemes, two-dimensional tissue modeling, optical mapping, and drug testing., Methods and Results: SQTS (N588K KCNH2 mutation), isogenic-control, and healthy-control hiPSCs were coaxed to differentiate into atrial cardiomyocytes using a retinoic-acid based differentiation protocol. The atrial identity of the cells was confirmed by a distinctive pattern of MLC2v downregulation, connexin 40 upregulation, shorter and triangular-shaped action potentials (APs), and expression of the atrial-specific acetylcholine-sensitive potassium current. In comparison to the healthy- and isogenic control cells, the SQTS-hiPSC atrial cardiomyocytes displayed abbreviated APs and refractory periods along with an augmented rapidly activating delayed-rectifier potassium current (I Kr ). Optical mapping of a hiPSC-based atrial tissue model of the SQTS displayed shortened APD and altered biophysical properties of spiral waves induced in this model, manifested by accelerated spiral-wave frequency and increased rotor curvature. Both AP shortening and arrhythmia irregularities were reversed by quinidine and vernakalant treatment, but not by sotalol., Conclusions: Patient-specific hiPSC-based atrial cellular and tissue models of the SQTS were established, which provide examples on how this type of modeling can shed light on the pathogenesis and pharmacological treatment of inherited atrial arrhythmias., (Copyright © 2023. Published by Elsevier Ltd.)

Published
2023
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41. The role of genetic testing in the prevention, diagnosis, and prognosis of sudden cardiac arrest in children.

Author

Blich M, Oron H, Darawsha W, Suleiman M, Gepstein L, Boulos M, Lorber A, and Kchoury A

Abstract

Background: Determining the pathogenesis of sudden cardiac arrest (SCA) in children is crucial for its management and prognosis. Our aim is to analyze the role of broad genetic testing in the prevention, diagnosis, and prognosis of SCA in Children., Methods: ECG, 12-lead holter, exercise testing, cardiac imaging, familial study, and genetic testing were used to study 29 families, in whom a child experienced SCA., Results: After a thorough clinical and genetic evaluation a positive diagnosis was reached in 24/29 (83%) families. Inherited channelopathies (long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) were the most prevalent 20/29 (69%) diagnosis, followed by cardiomyopathy 3/29 (10%). Broad genetic testing was positive in 17/24 (71%) cases. Using the Mann-Whitney test, we found that genetic testing (effect size = 0.625, p  = 0.003), ECG (effect size = 0.61, p  = 0.009), and exercise test (effect size = 0.63, p  = 0.047) had the highest yield in reaching the final diagnosis. Genetic testing was the only positive test available for five (17%) families. Among 155 family members evaluated through cascade screening, 73 (47%) had a positive clinical evaluation and 64 (41%) carried a pathologic mutation. During 6 ± 4.8 years of follow-up, 58% of the survived children experienced an arrhythmic event. Of nine family members who had an ICD implant for primary prevention, four experienced appropriate ICD shock., Conclusions: The major causes of SCA among children are genetic etiology, and genetic testing has a high yield. Family screening has an additional role in both the diagnosis and preventing of SCA., Competing Interests: Authors declare no conflict of interests for this article., (© 2023 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Published
2023
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42. Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2.

Author

Giannetti F, Barbieri M, Shiti A, Casini S, Sager PT, Das S, Pradhananga S, Srinivasan D, Nimani S, Alerni N, Louradour J, Mura M, Gnecchi M, Brink P, Zehender M, Koren G, Zaza A, Crotti L, Wilde AAM, Schwartz PJ, Remme CA, Gepstein L, Sala L, and Odening KE

Subjects
Animals, Humans, Rabbits, Glucocorticoids, KCNQ1 Potassium Channel genetics, Arrhythmias, Cardiac genetics, Myocytes, Cardiac physiology, Action Potentials physiology, Long QT Syndrome drug therapy, Long QT Syndrome genetics, Induced Pluripotent Stem Cells
Abstract

Aims: Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2., Methods and Results: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM., Conclusion: A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Published
2023
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43. Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischemic injury.

Author

Shakked A, Petrover Z, Aharonov A, Ghiringhelli M, Umansky KB, Kain D, Elkahal J, Divinsky Y, Nguyen PD, Miyara S, Friedlander G, Savidor A, Zhang L, Perez DE, Sarig R, Lendengolts D, Bueno-Levy H, Kastan N, Levin Y, Bakkers J, Gepstein L, and Tzahor E

Abstract

Cardiomyocyte proliferation and dedifferentiation have fueled the field of regenerative cardiology in recent years, whereas the reverse process of redifferentiation remains largely unexplored. Redifferentiation is characterized by the restoration of function lost during dedifferentiation. Previously, we showed that ERBB2-mediated heart regeneration has these two distinct phases: transient dedifferentiation and redifferentiation. Here we survey the temporal transcriptomic and proteomic landscape of dedifferentiation-redifferentiation in adult mouse hearts and reveal that well-characterized dedifferentiation features largely return to normal, although elements of residual dedifferentiation remain, even after the contractile function is restored. These hearts appear rejuvenated and show robust resistance to ischemic injury, even 5 months after redifferentiation initiation. Cardiomyocyte redifferentiation is driven by negative feedback signaling and requires LATS1/2 Hippo pathway activity. Our data reveal the importance of cardiomyocyte redifferentiation in functional restoration during regeneration but also protection against future insult, in what could lead to a potential prophylactic treatment against ischemic heart disease for at-risk patients., Competing Interests: Competing interests The authors declare no competing interests.

Published
2023
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44. Elevated thrombin generation levels in the left atrial appendage in patients with atrial fibrillation.

Author

Elias A, Khoury Y, Shehadeh F, Ron G, Boulos M, Nashashibi J, Zukermann R, Elias M, Gepstein L, and Suleiman M

Abstract

Background: Atrial Fibrillation (AF) is the most common sustained tachi-arrhythmia. Thrombus formation in the left atrial appendage (LAA) increases the risk of stroke and systemic embolism in patients with AF., Objectives: The aim of this study was to compare thrombin generation in the LAA to the LA among patients with AF., Methods: A cross-sectional study of consecutive patients with AF undergoing pulmonary veins catheter ablation. Blood samples from the femoral vein (FV), right atrium (RA), left atrium (LA), and LAA were collected during the catheter ablation procedures. Thrombin generation was assessed by a Calibrated Automated Thrombogram. The LAA-calibrated automated thrombogram parameters were compared with the RA, LA, and FV., Results: A total of 47 consecutive patients were enrolled in the study. The endogenous thrombin potential and peak height were significantly higher in the LAA compared with the LA, the mean differences and 95% CI between the LA and LAA were -378.9 (-680.5, -77.2) (nM∗min) and -66.7 (-119.6, -13.8) (nM) in the endogenous thrombin potential and peak height respectively., Conclusion: In patients with AF undergoing catheter ablation, the LAA demonstrated increased thrombin generation compared with the LA. This finding might contribute to the understanding of why the LAA is more predisposed to thrombus formation than the LA., Clinical Trials Registration: NCT03795883., (© 2023 The Author(s).)

Published
2023
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46. Synthetic cells with self-activating optogenetic proteins communicate with natural cells.

Author

Adir O, Albalak MR, Abel R, Weiss LE, Chen G, Gruber A, Staufer O, Kurman Y, Kaminer I, Shklover J, Shainsky-Roitman J, Platzman I, Gepstein L, Shechtman Y, Horwitz BA, and Schroeder A

Subjects
Light, Luciferases, Signal Transduction, Artificial Cells, Optogenetics methods
Abstract

Development of regulated cellular processes and signaling methods in synthetic cells is essential for their integration with living materials. Light is an attractive tool to achieve this, but the limited penetration depth into tissue of visible light restricts its usability for in-vivo applications. Here, we describe the design and implementation of bioluminescent intercellular and intracellular signaling mechanisms in synthetic cells, dismissing the need for an external light source. First, we engineer light generating SCs with an optimized lipid membrane and internal composition, to maximize luciferase expression levels and enable high-intensity emission. Next, we show these cells' capacity to trigger bioprocesses in natural cells by initiating asexual sporulation of dark-grown mycelial cells of the fungus Trichoderma atroviride. Finally, we demonstrate regulated transcription and membrane recruitment in synthetic cells using bioluminescent intracellular signaling with self-activating fusion proteins. These functionalities pave the way for deploying synthetic cells as embeddable microscale light sources that are capable of controlling engineered processes inside tissues., (© 2022. The Author(s).)

Published
2022
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47. shRNAs Targeting a Common KCNQ1 Variant Could Alleviate Long-QT1 Disease Severity by Inhibiting a Mutant Allele.

Author

Cócera-Ortega L, Wilders R, Kamps SC, Fabrizi B, Huber I, van der Made I, van den Bout A, de Vries DK, Gepstein L, Verkerk AO, Pinto YM, and Tijsen AJ

Subjects
Adult, Alleles, Humans, RNA, Small Interfering, Severity of Illness Index, KCNQ1 Potassium Channel genetics, KCNQ1 Potassium Channel metabolism, Romano-Ward Syndrome genetics
Abstract

Long-QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1 . Patients heterozygous for such a mutation co-assemble both mutant and wild-type KCNQ1 -encoded subunits into tetrameric Kv7.1 potassium channels. Here, we investigated whether allele-specific inhibition of mutant KCNQ1 by targeting a common variant can shift the balance towards increased incorporation of the wild-type allele to alleviate the disease in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). We identified the single nucleotide polymorphisms (SNP) rs1057128 (G/A) in KCNQ1 , with a heterozygosity of 27% in the European population. Next, we determined allele-specificity of short-hairpin RNAs (shRNAs) targeting either allele of this SNP in hiPSC-CMs that carry an LQT1 mutation. Our shRNAs downregulated 60% of the A allele and 40% of the G allele without affecting the non-targeted allele. Suppression of the mutant KCNQ1 allele by 60% decreased the occurrence of arrhythmic events in hiPSC-CMs measured by a voltage-sensitive reporter, while suppression of the wild-type allele increased the occurrence of arrhythmic events. Furthermore, computer simulations based on another LQT1 mutation revealed that 60% suppression of the mutant KCNQ1 allele shortens the prolonged action potential in an adult cardiomyocyte model. We conclude that allele-specific inhibition of a mutant KCNQ1 allele by targeting a common variant may alleviate the disease. This novel approach avoids the need to design shRNAs to target every single mutation and opens up the exciting possibility of treating multiple LQT1-causing mutations with only two shRNAs.

Published
2022
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48. Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling.

Author

Hopton C, Tijsen AJ, Maizels L, Arbel G, Gepstein A, Bates N, Brown B, Huber I, Kimber SJ, Newman WG, Venetucci L, and Gepstein L

Subjects
Calcium metabolism, Calcium Signaling, Carvedilol, Humans, Mutation, Myocytes, Cardiac metabolism, Nebivolol metabolism, Induced Pluripotent Stem Cells metabolism, Ryanodine Receptor Calcium Release Channel genetics, Ryanodine Receptor Calcium Release Channel metabolism
Abstract

Heterozygous missense variants of the cardiac ryanodine receptor gene (RYR2) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These missense variants of RYR2 result in a gain of function of the ryanodine receptors, characterized by increased sensitivity to activation by calcium that results in an increased propensity to develop calcium waves and delayed afterdepolarizations. We have recently detected a nonsense variant in RYR2 in a young patient who suffered an unexplained cardiac arrest. To understand the mechanism by which this variant in RYR2, p.(Arg4790Ter), leads to ventricular arrhythmias, human induced pluripotent stem cells (hiPSCs) harboring the novel nonsense variant in RYR2 were generated and differentiated into cardiomyocytes (RYR2-hiPSC-CMs) and molecular and calcium handling properties were studied. RYR2-hiPSC-CMs displayed significant calcium handling abnormalities at baseline and following treatment with isoproterenol. Treatment with carvedilol and nebivolol resulted in a significant reduction in calcium handling abnormalities in the RYR2-hiPSC-CMs. Expression of the mutant RYR2 allele was confirmed at the mRNA level and partial silencing of the mutant allele resulted in a reduction in calcium handling abnormalities at baseline. The nonsense variant behaves similarly to other gain of function variants in RYR2. Carvedilol and nebivolol may be suitable treatments for patients with gain of function RYR2 variants., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Published
2022
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49. Targeted therapies in genetic dilated and hypertrophic cardiomyopathies: from molecular mechanisms to therapeutic targets. A position paper from the Heart Failure Association (HFA) and the Working Group on Myocardial Function of the European Society of Cardiology (ESC).

Author

de Boer RA, Heymans S, Backs J, Carrier L, Coats AJS, Dimmeler S, Eschenhagen T, Filippatos G, Gepstein L, Hulot JS, Knöll R, Kupatt C, Linke WA, Seidman CE, Tocchetti CG, van der Velden J, Walsh R, Seferovic PM, and Thum T

Subjects
Humans, Myocardium pathology, Cardiology, Cardiomyopathies genetics, Cardiomyopathy, Dilated genetics, Cardiomyopathy, Dilated therapy, Cardiomyopathy, Hypertrophic genetics, Cardiomyopathy, Hypertrophic therapy, Heart Failure genetics, Heart Failure therapy
Abstract

Genetic cardiomyopathies are disorders of the cardiac muscle, most often explained by pathogenic mutations in genes encoding sarcomere, cytoskeleton, or ion channel proteins. Clinical phenotypes such as heart failure and arrhythmia are classically treated with generic drugs, but aetiology-specific and targeted treatments are lacking. As a result, cardiomyopathies still present a major burden to society, and affect many young and older patients. The Translational Committee of the Heart Failure Association (HFA) and the Working Group of Myocardial Function of the European Society of Cardiology (ESC) organized a workshop to discuss recent advances in molecular and physiological studies of various forms of cardiomyopathies. The study of cardiomyopathies has intensified after several new study setups became available, such as induced pluripotent stem cells, three-dimensional printing of cells, use of scaffolds and engineered heart tissue, with convincing human validation studies. Furthermore, our knowledge on the consequences of mutated proteins has deepened, with relevance for cellular homeostasis, protein quality control and toxicity, often specific to particular cardiomyopathies, with precise effects explaining the aberrations. This has opened up new avenues to treat cardiomyopathies, using contemporary techniques from the molecular toolbox, such as gene editing and repair using CRISPR-Cas9 techniques, antisense therapies, novel designer drugs, and RNA therapies. In this article, we discuss the connection between biology and diverse clinical presentation, as well as promising new medications and therapeutic avenues, which may be instrumental to come to precision medicine of genetic cardiomyopathies., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Published
2022
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50. Optogenetic Control of Human Induced Pluripotent Stem Cell-Derived Cardiac Tissue Models.

Author

Gruber A, Edri O, Glatstein S, Goldfracht I, Huber I, Arbel G, Gepstein A, Chorna S, and Gepstein L

Subjects
Action Potentials physiology, Arrhythmias, Cardiac, HEK293 Cells, Humans, Myocytes, Cardiac metabolism, Optogenetics methods, Induced Pluripotent Stem Cells metabolism
Abstract

Background Optogenetics, using light-sensitive proteins, emerged as a unique experimental paradigm to modulate cardiac excitability. We aimed to develop high-resolution optogenetic approaches to modulate electrical activity in 2- and 3-dimensional cardiac tissue models derived from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. Methods and Results To establish light-controllable cardiac tissue models, opsin-carrying HEK293 cells, expressing the light-sensitive cationic-channel CoChR, were mixed with hiPSC-cardiomyocytes to generate 2-dimensional hiPSC-derived cardiac cell-sheets or 3-dimensional engineered heart tissues. Complex illumination patterns were designed with a high-resolution digital micro-mirror device. Optical mapping and force measurements were used to evaluate the tissues' electromechanical properties. The ability to optogenetically pace and shape the tissue's conduction properties was demonstrated by using single or multiple illumination stimulation sites, complex illumination patterns, or diffuse illumination. This allowed to establish in vitro models for optogenetic-based cardiac resynchronization therapy, where the electrical activation could be synchronized (hiPSC-derived cardiac cell-sheets and engineered heart tissue models) and contractile properties improved (engineered heart tissues). Next, reentrant activity (rotors) was induced in the hiPSC-derived cardiac cell-sheets and engineered heart tissue models through optogenetics programmed- or cross-field stimulations. Diffuse illumination protocols were then used to terminate arrhythmias, demonstrating the potential to study optogenetics cardioversion mechanisms and to identify optimal illumination parameters for arrhythmia termination. Conclusions By combining optogenetics and hiPSC technologies, light-controllable human cardiac tissue models could be established, in which tissue excitability can be modulated in a functional, reversible, and localized manner. This approach may bring a unique value for physiological/pathophysiological studies, for disease modeling, and for developing optogenetic-based cardiac pacing, resynchronization, and defibrillation approaches.

Published
2022
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