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2. Sex‐ and age‐related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long‐Term Registry

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Lainscak, M., Milinkovic, I., Polovina, M., Crespo-Leiro, M. G., Lund, L. H., Anker, S. D., Laroche, C., Ferrari, R., Coats, A. J. S., Mcdonagh, T., Filippatos, G., Maggioni, A. P., Piepoli, M. F., Rosano, G. M. C., Ruschitzka, F., Simic, D., Asanin, M., Eicher, J. -C., Yilmaz, M. B., Seferovic, P. M., Gale, C. P., Chair, G. B., Branko Beleslin, R. S., Andrzej Budaj, P. L., Ovidiu Chioncel, R. O., Nikolaos Dagres, D. E., Nicolas Danchin, F. R., David Erlinge, S. E., Jonathan Emberson, G. B., Michael Glikson, I. L., Alastair Gray, G. B., Meral Kayikcioglu, T. R., Aldo Maggioni, I. T., Klaudia Vivien Nagy, H. U., Aleksandr Nedoshivin, R. U., Anna-Sonia Petronio, I. T., Jolien Roos-Hesselink, N. L., Lars Wallentin, S. E., Uwe Zeymer, D. E., Crespo-Leiro, M., Anker, S., Mebazaa, A., Coats, A., A. Goda A. L., M. Diez A. R., A. Fernandez A. R., F. Fruhwald A. T., Fazlibegovic, E., P. Gatzov B. G., A. Kurlianskaya B. Y., R. Hullin C. H., T. Christodoulides C. Y., J. Hradec C. Z., O. Wendelboe Nielsen D. K., R. Nedjar D. Z., T. Uuetoa E. E., M. Hassanein E. G., J. F. Delgado Jimenez E. S., P. Harjola F. I., V, D. Logeart F. R., V. Chumburidze G. E., D. Tousoulis G. R., D. Milicic H. R., B. Merkely H. U., O'Donoghue IE, E., O. Amir I. L., A. Shotan I. L., D. Shafie I. R., M. Metra I. T., A. Matsumori J. P., E. Mirrakhimov K. G., A. Kavoliuniene L. T., A. Erglis L. V., Vataman, E., M. Otljanska M. K., E. Srbinovska Kostovska M. K., D. Cassar DeMarco M. T., J. Drozdz P. L., Fonseca, C., O. Chioncel R. O., M. Dekleva R. S., E. Shkolnik R. U., U. Dahlstrom S. E., M. Lainscak S. I., E. Goncalvesova S. K., A. Temizhan T. R., V. Estrago U. Y., G. Bajraktari X. K., Auer, J., Ablasser, K., Fruhwald, F., Dolze, T., Brandner, K., Gstrein, S., Poelzl, G., Moertl, D., Reiter, S., Podczeck-Schweighofer, A., Muslibegovic, A., Vasilj, M., Cesko, M., Zelenika, D., Palic, B., Pravdic, D., Cuk, D., Vitlianova, K., Katova, T., Velikov, T., Kurteva, T., Gatzov, P., Kamenova, D., Antova, M., Sirakova, V., Krejci, J., Mikolaskova, M., Spinar, J., Krupicka, J., Malek, F., Hegarova, M., Lazarova, M., Monhart, Z., Hassanein, M., Sobhy, M., El Messiry, F., El Shazly, A. H., Elrakshy, Y., Youssef, A., Moneim, A. A., Noamany, M., Reda, A., Dayem, T. K. A., Farag, N., Halawa, S. I., Hamid, M. A., Said, K., Saleh, A., Ebeid, H., Hanna, R., Aziz, R., Louis, O., Enen, M. A., Ibrahim, B. S., Nasr, G., Elbahry, A., Sobhy, H., Ashmawy, M., Gouda, M., Aboleineen, W., Bernard, Y., Luporsi, P., Meneveau, N., Pillot, M., Morel, M., Seronde, M. -F., Schiele, F., Briand, F., Delahaye, F., Damy, T., de Groote, P., Fertin, M., Lamblin, N., Isnard, R., Lefol, C., Thevenin, S., Hagege, A., Jondeau, G., Logeart, D., Le Marcis, V., J. -F., Ly, Coisne, D., Lequeux, B., Le Moal, V., Mascle, S., Lotton, P., Behar, N., Donal, E., Thebault, C., Ridard, C., Reynaud, A., Basquin, A., Bauer, F., Codjia, R., Galinier, M., Tourikis, P., Stavroula, M., Tousoulis, D., Stefanadis, C., Chrysohoou, C., Kotrogiannis, I., Matzaraki, V., Dimitroula, T., Karavidas, A., Tsitsinakis, G., Kapelios, C., Nanas, J., Kampouri, H., Nana, E., Kaldara, E., Eugenidou, A., Vardas, P., Saloustros, I., Patrianakos, A., Tsaknakis, T., Evangelou, S., Nikoloulis, N., Tziourganou, H., Tsaroucha, A., Papadopoulou, A., Douras, A., Polgar, L., Merkely, B., Kosztin, A., Nyolczas, N., Nagy, A. C., Halmosi, R., Elber, J., Alony, I., Shotan, A., Fuhrmann, A. V., Amir, O., Romano, S., Marcon, S., Penco, M., Di Mauro, M., Lemme, E., Carubelli, V., Rovetta, R., Metra, M., Bulgari, M., Quinzani, F., Lombardi, C., Bosi, S., Schiavina, G., Squeri, A., Barbieri, A., Di Tano, G., Pirelli, S., Fucili, A., Passero, T., Musio, S., Di Biase, M., Correale, M., Salvemini, G., Brognoli, S., Zanelli, E., Giordano, A., Agostoni, P., Italiano, G., Salvioni, E., Copelli, S., Modena, M. G., Reggianini, L., Valenti, C., Olaru, A., Bandino, S., Deidda, M., Mercuro, G., Dessalvi, C. C., Marino, P. N., Di Ruocco, M. V., Sartori, C., Piccinino, C., Parrinello, G., Licata, G., Torres, D., Giambanco, S., Busalacchi, S., Arrotti, S., Novo, S., Inciardi, R. M., Pieri, P., Chirco, P. R., Galifi, M. A., Teresi, G., Buccheri, D., Minacapelli, A., Veniani, M., Frisinghelli, A., Priori, S. G., Cattaneo, S., Opasich, C., Gualco, A., Pagliaro, M., Mancone, M., Fedele, F., Cinque, A., Vellini, M., Scarfo, I., Romeo, F., Ferraiuolo, F., Sergi, D., Anselmi, M., Melandri, F., Leci, E., Iori, E., Bovolo, V., Pidello, S., Frea, S., Bergerone, S., Botta, M., Canavosio, F. G., Gaita, F., Merlo, M., Cinquetti, M., Sinagra, G., Ramani, F., Fabris, E., Stolfo, D., Artico, J., Miani, D., Fresco, C., Daneluzzi, C., Proclemer, A., Cicoira, M., Zanolla, L., Marchese, G., Torelli, F., Vassanelli, C., Voronina, N., Erglis, A., Tamakauskas, V., Smalinskas, V., Karaliute, R., Petraskiene, I., Kazakauskaite, E., Rumbinaite, E., Kavoliuniene, A., Vysniauskas, V., Brazyte-Ramanauskiene, R., Petraskiene, D., Stankala, S., Switala, P., Juszczyk, Z., Sinkiewicz, W., Gilewski, W., Pietrzak, J., Orzel, T., Kasztelowicz, P., Kardaszewicz, P., Lazorko-Piega, M., Gabryel, J., Mosakowska, K., Bellwon, J., Rynkiewicz, A., Raczak, G., Lewicka, E., Dabrowska-Kugacka, A., Bartkowiak, R., Sosnowska-Pasiarska, B., Wozakowska-Kaplon, B., Krzeminski, A., Zabojszcz, M., Mirek-Bryniarska, E., Grzegorzko, A., Bury, K., Nessler, J., Zalewski, J., Furman, A., Broncel, M., Poliwczak, A., Bala, A., Zycinski, P., Rudzinska, M., Jankowski, L., Kasprzak, J. D., Michalak, L., Soska, K. W., Drozdz, J., Huziuk, I., Retwinski, A., Flis, P., Weglarz, J., Bodys, A., Grajek, S., Kaluzna-Oleksy, M., Straburzynska-Migaj, E., Dankowski, R., Szymanowska, K., Grabia, J., Szyszka, A., Nowicka, A., Samcik, M., Wolniewicz, L., Baczynska, K., Komorowska, K., Poprawa, I., Komorowska, E., Sajnaga, D., Zolbach, A., Dudzik-Plocica, A., Abdulkarim, A. -F., Lauko-Rachocka, A., Kaminski, L., Kostka, A., Cichy, A., Ruszkowski, P., Splawski, M., Fitas, G., Szymczyk, A., Serwicka, A., Fiega, A., Zysko, D., Krysiak, W., Szabowski, S., Skorek, E., Pruszczyk, P., Bienias, P., Ciurzynski, M., Welnicki, M., Mamcarz, A., Folga, A., Zielinski, T., Rywik, T., Leszek, P., Sobieszczanska-Malek, M., Piotrowska, M., Kozar-Kaminska, K., Komuda, K., Wisniewska, J., Tarnowska, A., Balsam, P., Marchel, M., Opolski, G., Kaplon-Cieslicka, A., Gil, R. J., Mozenska, O., Byczkowska, K., Gil, K., Pawlak, A., Michalek, A., Krzesinski, P., Piotrowicz, K., Uzieblo-Zyczkowska, B., Stanczyk, A., Skrobowski, A., Ponikowski, P., Jankowska, E., Rozentryt, P., Polonski, L., Gadula-Gacek, E., Nowalany-Kozielska, E., Kuczaj, A., Kalarus, Z., Szulik, M., Przybylska, K., Klys, J., Prokop-Lewicka, G., Kleinrok, A., Aguiar, C. T., Ventosa, A., Pereira, S., Faria, R., Chin, J., De Jesus, I., Santos, R., Silva, P., Moreno, N., Queiros, C., Lourenco, C., Pereira, A., Castro, A., Andrade, A., Guimaraes, T. O., Martins, S., Placido, R., Lima, G., Brito, D., Francisco, A. R., Cardiga, R., Proenca, M., Araujo, I., Marques, F., Moura, B., Leite, S., Campelo, M., Silva-Cardoso, J., Rodrigues, J., Rangel, I., Martins, E., Correia, A. S., Peres, M., Marta, L., da Silva, G. F., Severino, D., Durao, D., Leao, S., Magalhaes, P., Moreira, I., Cordeiro, A. F., Ferreira, C., Araujo, C., Ferreira, A., Baptista, A., Radoi, M., Bicescu, G., Vinereanu, D., Sinescu, C. -J., Macarie, C., Popescu, R., Daha, I., Dan, G. -A., Stanescu, C., Dan, A., Craiu, E., Nechita, E., Aursulesei, V., Christodorescu, R., Otasevic, P., Simeunovic, D., Ristic, A. D., Celic, V., Pavlovic-Kleut, M., Lazic, J. S., Stojcevski, B., Pencic, B., Stevanovic, A., Andric, A., Iric-Cupic, V., Jovic, M., Davidovic, G., Milanov, S., Mitic, V., Atanaskovic, V., Antic, S., Pavlovic, M., Stanojevic, D., Stoickov, V., Ilic, S., Ilic, M. D., Petrovic, D., Stojsic, S., Kecojevic, S., Dodic, S., Adic, N. C., Cankovic, M., Stojiljkovic, J., Mihajlovic, B., Radin, A., Radovanovic, S., Krotin, M., Klabnik, A., Goncalvesova, E., Pernicky, M., Murin, J., Kovar, F., Kmec, J., Semjanova, H., Strasek, M., Iskra, M. S., Ravnikar, T., Suligoj, N. C., Komel, J., Fras, Z., Jug, B., Glavic, T., Losic, R., Bombek, M., Krajnc, I., Krunic, B., Horvat, S., Kovac, D., Rajtman, D., Cencic, V., Letonja, M., Winkler, R., Valentincic, M., Melihen-Bartolic, C., Bartolic, A., Vrckovnik, M. P., Kladnik, M., Pusnik, C. S., Marolt, A., Klen, J., Drnovsek, B., Leskovar, B., Anguita, M. J. F., Page, J. C. G., Martinez, F. M. S., Andres, J., Genis, A. B., Mirabet, S., Mendez, A., Garcia-Cosio, L., Roig, E., Leon, V., Gonzalez-Costello, J., Muntane, G., Garay, A., Alcade-Martinez, V., Fernandez, S. L., Rivera-Lopez, R., Puga-Martinez, M., Fernandez-Alvarez, M., Serrano-Martinez, J. L., Grille-Cancela, Z., Marzoa-Rivas, R., Blanco-Canosa, P., Paniagua-Martin, M. J., Barge-Caballero, E., Cerdena, I. L., Baldomero, I. F. H., Padron, A. L., Rosillo, S. O., Gonzalez-Gallarza, R. D., Montanes, O. S., Manjavacas, A. M. I., Conde, A. C., Araujo, A., Soria, T., Garcia-Pavia, P., Gomez-Bueno, M., Cobo-Marcos, M., Alonso-Pulpon, L., Cubero, J. S., Sayago, I., Gonzalez-Segovia, A., Briceno, A., Subias, P. E., Hernandez, M. V., Cano, M. J. R., Sanchez, M. A. G., Jimenez, J. F. D., Garrido-Lestache, E. B., Pinilla, J. M. G., de la Villa, B. G., Sahuquillo, A., Marques, R. B., Calvo, F. T., Perez-Martinez, M. T., Gracia-Rodenas, M. R., Garrido-Bravo, I. P., Pastor-Perez, F., Pascual-Figal, D. A., Molina, B. D., Orus, J., Gonzalo, F. E., Bertomeu, V., Valero, R., Martinez-Abellan, R., Quiles, J., Rodrigez-Ortega, J. A., Mateo, I., Elamrani, A., Fernandez-Vivancos, C., Valero, D. B., Almenar-Bonet, L., Sanchez-Lazaro, I. J., Marques-Sule, E., Facila-Rubio, L., Perez-Silvestre, J., Garcia-Gonzalez, P., Ridocci-Soriano, F., Garcia-Escriva, D., Pellicer-Cabo, A., de la Fuente Galan, L., Diaz, J. L., Platero, A. R., Arias, J. C., Blasco-Peiro, T., Julve, M. S., Sanchez-Insa, E., Aured-Guallar, C., Portoles-Ocampo, A., Melin, M., Hagglund, E., Stenberg, A., Lindahl, I. -M., Asserlund, B., Olsson, L., Dahlstrom, U., Afzelius, M., Karlstrom, P., Tengvall, L., Wiklund, P. -A., Olsson, B., Kalayci, S., Temizhan, A., Cavusoglu, Y., Gencer, E., Gunes, H., Lainscak, M., Milinkovic, I., Polovina, M., Crespo-Leiro, M. G., Lund, L. H., Anker, S. D., Laroche, C., Ferrari, R., Coats, A. J. S., Mcdonagh, T., Filippatos, G., Maggioni, A. P., Piepoli, M. F., Rosano, G. M. C., Ruschitzka, F., Simic, D., Asanin, M., Eicher, J. -C., Yilmaz, M. B., Seferovic, P. M., Gale, C. P., Chair, G. B., Branko Beleslin, R. S., Andrzej Budaj, P. L., Ovidiu Chioncel, R. O., Nikolaos Dagres, D. E., Nicolas Danchin, F. R., David Erlinge, S. E., Jonathan Emberson, G. B., Michael Glikson, I. L., Alastair Gray, G. B., Meral Kayikcioglu, T. R., Aldo Maggioni, I. T., Klaudia Vivien Nagy, H. U., Aleksandr Nedoshivin, R. U., Anna-Sonia Petronio, I. T., Jolien Roos-Hesselink, N. L., Lars Wallentin, S. E., Uwe Zeymer, D. E., Crespo-Leiro, M., Anker, S., Mebazaa, A., Coats, A., A. Goda A., L., M. Diez A., R., A. Fernandez A., R., F. Fruhwald A., T., Fazlibegovic, E., P. Gatzov B., G., A. Kurlianskaya B., Y., R. Hullin C., H., T. Christodoulides C., Y., J. Hradec C., Z., O. Wendelboe Nielsen D., K., R. Nedjar D., Z., T. Uuetoa E., E., M. Hassanein E., G., J. F. Delgado Jimenez E., S., V-, P. Harjola F. I., D. Logeart F., R., V. Chumburidze G., E., D. Tousoulis G., R., D. Milicic H., R., B. Merkely H., U., O'Donoghue IE, E., O. Amir I., L., A. Shotan I., L., D. Shafie I., R., M. Metra I., T., A. Matsumori J., P., E. Mirrakhimov K., G., A. Kavoliuniene L., T., A. Erglis L., V., Vataman, E., M. Otljanska M., K., E. Srbinovska Kostovska M., K., D. Cassar DeMarco M., T., J. Drozdz P., L., Fonseca, C., O. Chioncel R., O., M. Dekleva R., S., E. Shkolnik R., U., U. Dahlstrom S., E., M. Lainscak S., I., E. Goncalvesova S., K., A. Temizhan T., R., V. Estrago U., Y., G. Bajraktari X., K., Auer, J., Ablasser, K., Fruhwald, F., Dolze, T., Brandner, K., Gstrein, S., Poelzl, G., Moertl, D., Reiter, S., Podczeck-Schweighofer, A., Muslibegovic, A., Vasilj, M., Cesko, M., Zelenika, D., Palic, B., Pravdic, D., Cuk, D., Vitlianova, K., Katova, T., Velikov, T., Kurteva, T., Gatzov, P., Kamenova, D., Antova, M., Sirakova, V., Krejci, J., Mikolaskova, M., Spinar, J., Krupicka, J., Malek, F., Hegarova, M., Lazarova, M., Monhart, Z., Hassanein, M., Sobhy, M., El Messiry, F., El Shazly, A. H., Elrakshy, Y., Youssef, A., Moneim, A. A., Noamany, M., Reda, A., Dayem, T. K. A., Farag, N., Halawa, S. I., Hamid, M. A., Said, K., Saleh, A., Ebeid, H., Hanna, R., Aziz, R., Louis, O., Enen, M. A., Ibrahim, B. S., Nasr, G., Elbahry, A., Sobhy, H., Ashmawy, M., Gouda, M., Aboleineen, W., Bernard, Y., Luporsi, P., Meneveau, N., Pillot, M., Morel, M., Seronde, M. -F., Schiele, F., Briand, F., Delahaye, F., Damy, T., de Groote, P., Fertin, M., Lamblin, N., Isnard, R., Lefol, C., Thevenin, S., Hagege, A., Jondeau, G., Logeart, D., Le Marcis, V., Ly, J. -F., Coisne, D., Lequeux, B., Le Moal, V., Mascle, S., Lotton, P., Behar, N., Donal, E., Thebault, C., Ridard, C., Reynaud, A., Basquin, A., Bauer, F., Codjia, R., Galinier, M., Tourikis, P., Stavroula, M., Tousoulis, D., Stefanadis, C., Chrysohoou, C., Kotrogiannis, I., Matzaraki, V., Dimitroula, T., Karavidas, A., Tsitsinakis, G., Kapelios, C., Nanas, J., Kampouri, H., Nana, E., Kaldara, E., Eugenidou, A., Vardas, P., Saloustros, I., Patrianakos, A., Tsaknakis, T., Evangelou, S., Nikoloulis, N., Tziourganou, H., Tsaroucha, A., Papadopoulou, A., Douras, A., Polgar, L., Merkely, B., Kosztin, A., Nyolczas, N., Nagy, A. C., Halmosi, R., Elber, J., Alony, I., Shotan, A., Fuhrmann, A. V., Amir, O., Romano, S., Marcon, S., Penco, M., Di Mauro, M., Lemme, E., Carubelli, V., Rovetta, R., Metra, M., Bulgari, M., Quinzani, F., Lombardi, C., Bosi, S., Schiavina, G., Squeri, A., Barbieri, A., Di Tano, G., Pirelli, S., Fucili, A., Passero, T., Musio, S., Di Biase, M., Correale, M., Salvemini, G., Brognoli, S., Zanelli, E., Giordano, A., Agostoni, P., Italiano, G., Salvioni, E., Copelli, S., Modena, M. G., Reggianini, L., Valenti, C., Olaru, A., Bandino, S., Deidda, M., Mercuro, G., Dessalvi, C. C., Marino, P. N., Di Ruocco, M. V., Sartori, C., Piccinino, C., Parrinello, G., Licata, G., Torres, D., Giambanco, S., Busalacchi, S., Arrotti, S., Novo, S., Inciardi, R. M., Pieri, P., Chirco, P. R., Galifi, M. A., Teresi, G., Buccheri, D., Minacapelli, A., Veniani, M., Frisinghelli, A., Priori, S. G., Cattaneo, S., Opasich, C., Gualco, A., Pagliaro, M., Mancone, M., Fedele, F., Cinque, A., Vellini, M., Scarfo, I., Romeo, F., Ferraiuolo, F., Sergi, D., Anselmi, M., Melandri, F., Leci, E., Iori, E., Bovolo, V., Pidello, S., Frea, S., Bergerone, S., Botta, M., Canavosio, F. G., Gaita, F., Merlo, M., Cinquetti, M., Sinagra, G., Ramani, F., Fabris, E., Stolfo, D., Artico, J., Miani, D., Fresco, C., Daneluzzi, C., Proclemer, A., Cicoira, M., Zanolla, L., Marchese, G., Torelli, F., Vassanelli, C., Voronina, N., Erglis, A., Tamakauskas, V., Smalinskas, V., Karaliute, R., Petraskiene, I., Kazakauskaite, E., Rumbinaite, E., Kavoliuniene, A., Vysniauskas, V., Brazyte-Ramanauskiene, R., Petraskiene, D., Stankala, S., Switala, P., Juszczyk, Z., Sinkiewicz, W., Gilewski, W., Pietrzak, J., Orzel, T., Kasztelowicz, P., Kardaszewicz, P., Lazorko-Piega, M., Gabryel, J., Mosakowska, K., Bellwon, J., Rynkiewicz, A., Raczak, G., Lewicka, E., Dabrowska-Kugacka, A., Bartkowiak, R., Sosnowska-Pasiarska, B., Wozakowska-Kaplon, B., Krzeminski, A., Zabojszcz, M., Mirek-Bryniarska, E., Grzegorzko, A., Bury, K., Nessler, J., Zalewski, J., Furman, A., Broncel, M., Poliwczak, A., Bala, A., Zycinski, P., Rudzinska, M., Jankowski, L., Kasprzak, J. D., Michalak, L., Soska, K. W., Drozdz, J., Huziuk, I., Retwinski, A., Flis, P., Weglarz, J., Bodys, A., Grajek, S., Kaluzna-Oleksy, M., Straburzynska-Migaj, E., Dankowski, R., Szymanowska, K., Grabia, J., Szyszka, A., Nowicka, A., Samcik, M., Wolniewicz, L., Baczynska, K., Komorowska, K., Poprawa, I., Komorowska, E., Sajnaga, D., Zolbach, A., Dudzik-Plocica, A., Abdulkarim, A. -F., Lauko-Rachocka, A., Kaminski, L., Kostka, A., Cichy, A., Ruszkowski, P., Splawski, M., Fitas, G., Szymczyk, A., Serwicka, A., Fiega, A., Zysko, D., Krysiak, W., Szabowski, S., Skorek, E., Pruszczyk, P., Bienias, P., Ciurzynski, M., Welnicki, M., Mamcarz, A., Folga, A., Zielinski, T., Rywik, T., Leszek, P., Sobieszczanska-Malek, M., Piotrowska, M., Kozar-Kaminska, K., Komuda, K., Wisniewska, J., Tarnowska, A., Balsam, P., Marchel, M., Opolski, G., Kaplon-Cieslicka, A., Gil, R. J., Mozenska, O., Byczkowska, K., Gil, K., Pawlak, A., Michalek, A., Krzesinski, P., Piotrowicz, K., Uzieblo-Zyczkowska, B., Stanczyk, A., Skrobowski, A., Ponikowski, P., Jankowska, E., Rozentryt, P., Polonski, L., Gadula-Gacek, E., Nowalany-Kozielska, E., Kuczaj, A., Kalarus, Z., Szulik, M., Przybylska, K., Klys, J., Prokop-Lewicka, G., Kleinrok, A., Aguiar, C. T., Ventosa, A., Pereira, S., Faria, R., Chin, J., De Jesus, I., Santos, R., Silva, P., Moreno, N., Queiros, C., Lourenco, C., Pereira, A., Castro, A., Andrade, A., Guimaraes, T. O., Martins, S., Placido, R., Lima, G., Brito, D., Francisco, A. R., Cardiga, R., Proenca, M., Araujo, I., Marques, F., Moura, B., Leite, S., Campelo, M., Silva-Cardoso, J., Rodrigues, J., Rangel, I., Martins, E., Correia, A. S., Peres, M., Marta, L., da Silva, G. F., Severino, D., Durao, D., Leao, S., Magalhaes, P., Moreira, I., Cordeiro, A. F., Ferreira, C., Araujo, C., Ferreira, A., Baptista, A., Radoi, M., Bicescu, G., Vinereanu, D., Sinescu, C. -J., Macarie, C., Popescu, R., Daha, I., Dan, G. -A., Stanescu, C., Dan, A., Craiu, E., Nechita, E., Aursulesei, V., Christodorescu, R., Otasevic, P., Simeunovic, D., Ristic, A. D., Celic, V., Pavlovic-Kleut, M., Lazic, J. S., Stojcevski, B., Pencic, B., Stevanovic, A., Andric, A., Iric-Cupic, V., Jovic, M., Davidovic, G., Milanov, S., Mitic, V., Atanaskovic, V., Antic, S., Pavlovic, M., Stanojevic, D., Stoickov, V., Ilic, S., Ilic, M. D., Petrovic, D., Stojsic, S., Kecojevic, S., Dodic, S., Adic, N. C., Cankovic, M., Stojiljkovic, J., Mihajlovic, B., Radin, A., Radovanovic, S., Krotin, M., Klabnik, A., Goncalvesova, E., Pernicky, M., Murin, J., Kovar, F., Kmec, J., Semjanova, H., Strasek, M., Iskra, M. S., Ravnikar, T., Suligoj, N. C., Komel, J., Fras, Z., Jug, B., Glavic, T., Losic, R., Bombek, M., Krajnc, I., Krunic, B., Horvat, S., Kovac, D., Rajtman, D., Cencic, V., Letonja, M., Winkler, R., Valentincic, M., Melihen-Bartolic, C., Bartolic, A., Vrckovnik, M. P., Kladnik, M., Pusnik, C. S., Marolt, A., Klen, J., Drnovsek, B., Leskovar, B., Anguita, M. J. F., Page, J. C. G., Martinez, F. M. S., Andres, J., Genis, A. B., Mirabet, S., Mendez, A., Garcia-Cosio, L., Roig, E., Leon, V., Gonzalez-Costello, J., Muntane, G., Garay, A., Alcade-Martinez, V., Fernandez, S. L., Rivera-Lopez, R., Puga-Martinez, M., Fernandez-Alvarez, M., Serrano-Martinez, J. L., Grille-Cancela, Z., Marzoa-Rivas, R., Blanco-Canosa, P., Paniagua-Martin, M. J., Barge-Caballero, E., Cerdena, I. L., Baldomero, I. F. H., Padron, A. L., Rosillo, S. O., Gonzalez-Gallarza, R. D., Montanes, O. S., Manjavacas, A. M. I., Conde, A. C., Araujo, A., Soria, T., Garcia-Pavia, P., Gomez-Bueno, M., Cobo-Marcos, M., Alonso-Pulpon, L., Cubero, J. S., Sayago, I., Gonzalez-Segovia, A., Briceno, A., Subias, P. E., Hernandez, M. V., Cano, M. J. R., Sanchez, M. A. G., Jimenez, J. F. D., Garrido-Lestache, E. B., Pinilla, J. M. G., de la Villa, B. G., Sahuquillo, A., Marques, R. B., Calvo, F. T., Perez-Martinez, M. T., Gracia-Rodenas, M. R., Garrido-Bravo, I. P., Pastor-Perez, F., Pascual-Figal, D. A., Molina, B. D., Orus, J., Gonzalo, F. E., Bertomeu, V., Valero, R., Martinez-Abellan, R., Quiles, J., Rodrigez-Ortega, J. A., Mateo, I., Elamrani, A., Fernandez-Vivancos, C., Valero, D. B., Almenar-Bonet, L., Sanchez-Lazaro, I. J., Marques-Sule, E., Facila-Rubio, L., Perez-Silvestre, J., Garcia-Gonzalez, P., Ridocci-Soriano, F., Garcia-Escriva, D., Pellicer-Cabo, A., de la Fuente Galan, L., Diaz, J. L., Platero, A. R., Arias, J. C., Blasco-Peiro, T., Julve, M. S., Sanchez-Insa, E., Aured-Guallar, C., Portoles-Ocampo, A., Melin, M., Hagglund, E., Stenberg, A., Lindahl, I. -M., Asserlund, B., Olsson, L., Dahlstrom, U., Afzelius, M., Karlstrom, P., Tengvall, L., Wiklund, P. -A., Olsson, B., Kalayci, S., Temizhan, A., Cavusoglu, Y., Gencer, E., Gunes, H., University of Zurich, and Seferović, Petar M

Subjects
Male, Registry, medicine.medical_specialty, Adverse outcomes, 610 Medicine & health, Angiotensin-Converting Enzyme Inhibitors, 030204 cardiovascular system & hematology, Independent predictor, 2705 Cardiology and Cardiovascular Medicine, Ventricular Function, Left, 03 medical and health sciences, Age, 0302 clinical medicine, Internal medicine, Age related, Hospitalization, Mortality, Sex, medicine, Humans, Registries, Medical prescription, Aged, Heart Failure, Ejection fraction, business.industry, Stroke Volume, medicine.disease, Ageing, Heart failure, 10209 Clinic for Cardiology, Female, Angiotensin Receptor Blockers, Cardiology and Cardiovascular Medicine, business
Abstract

[Abstract] Aims. This study aimed to assess age‐ and sex‐related differences in management and 1‐year risk for all‐cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results. Of 16 354 patients included in the European Society of Cardiology Heart Failure Long‐Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline‐directed medical therapy (GDMT) were high (angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, beta‐blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P ≤ 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1‐year follow‐up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all‐cause mortality were lower in women than in men (7.1% vs. 8.7%; P = 0.015), as were rates of all‐cause hospitalization (21.9% vs. 27.3%; P < 0.001) and there were no differences in causes of death. All‐cause mortality and all‐cause hospitalization increased with greater age in both sexes. Sex was not an independent predictor of 1‐year all‐cause mortality (restricted to patients with LVEF ≤45%). Mortality risk was significantly lower in patients of younger age, compared to patients aged >75 years. Conclusions. There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all‐cause mortality in patients with LVEF ≤45%.

Published
2019

3. Sex hormones, adiposity, and metabolic traits in men and women: a Mendelian randomisation study

Author

Loh, N.Y., Humphreys, E., Karpe, F., Tomlinson, J.W., Noordam, R., and Christodoulides, C.

Subjects
Male, Endocrinology, Endocrinology, Diabetes and Metabolism, Humans, Female, General Medicine, Mendelian Randomization Analysis, Gonadal Steroid Hormones, Adiposity
Abstract

Objective Epidemiological and clinical studies have highlighted important roles for sex hormones in the regulation of fat distribution and systemic metabolism. We investigated the bidirectional associations between bioavailable serum testosterone (BioT) in both sexes and oestradiol (E2) in men and adiposity and metabolic traits using Mendelian randomisation (MR). Design and Methods As genetic instruments for sex hormones, we selected all the genome-wide significant, independent signals from a genome-wide association studies (GWAS) in up to 425 097 European ancestry UK Biobank participants. European population-specific, summary-level data for adiposity, metabolic, and blood pressure traits were obtained from the largest publicly available GWAS. Sex-specific, two-sample MR analyses were used to estimate the associations of sex hormones with these traits and vice versa. Results In women, higher BioT was associated with obesity, upper-body fat distribution, and low HDL-cholesterol although, based on analyses modelling the sex hormone-binding globulin-independent effects of BioT, the last two associations might be indirect. Conversely, obesity and android fat distribution were associated with elevated serum BioT. In men, higher BioT was associated with lower hip circumference and lower fasting glucose. Reciprocally, obesity was associated with lower BioT and higher E2, while upper-body fat distribution and raised triglycerides were associated with lower E2. Conclusions Adipose tissue and metabolic dysfunction are associated with deranged sex hormone levels in both sexes. In women, elevated BioT might be a cause of obesity. Conversely, in men, higher BioT appears to have beneficial effects on adiposity and glucose metabolism.

Published
2022

5. A Retrospective Long-Term Study on Age at Menarche and Menstrual Characteristics in 85 Young Women with Transfusion-Dependent β-Thalassemia (TDT)

Author

Maio S. D., Marzuillo P., Mariannis D., Christou S., Ellinides A., Christodoulides C., de Sanctis V., Maio, S. D., Marzuillo, P., Mariannis, D., Christou, S., Ellinides, A., Christodoulides, C., and de Sanctis, V.

Subjects
Menarche, Menstrual cycles, Nutritional status, Nutritional statu, Transfusion-dependent β-thalassemia, Iron overload, Original Article, Menstrual cycle, Secondary amenorrhea
Abstract

Background: Menarche is an important milestone in a feminine reproductive life, and regular menstrual cycles reflect normal functioning of the hypothalamic-pituitary-ovarian axis, a vital sign of women's general health. Aim of the study: We explored the age at menarche and the following menstrual cycles characteristics among 85 unmarried Transfusion-Dependent β-Thalassemia (TDT) women, born between 1965 and 1995, concerning iron chelation therapy (ICT) with desferrioxamine (DFO) and nutritional status, assessed by body mass index (BMI). Results: 53 adolescents who had begun ICT before the age of 10 years experienced menarche at 13,7 ± 1,6 years (mean ± DS), whereas 32 who began treatment after ten years experienced menarche significantly later (15.5 ± 1.9 yrs; p: 0.001). At the age of menarche: BMI-Z score (n= 67, - 0,09 ±1) was inversely correlated with both age at starting ICT (r = - 0,39; p = 0001) and age at menarche (- 0,45, p = 0,0001). Serum ferritin levels (SF) were significantly correlated with the age at starting chelation therapy (n = 79; r = 0,34; p = 0,022). In 56 TDT adolescents who developed secondary amenorrhea (SA), the SF levels were significantly higher (4,098 ± 1,907 ng/mL) compared to 23 TDT adolescents with regular menstrual cycles (2,913±782 ng/mL; p = 0,005). Nutritional status of "thinness" at menarche was associated with a lower prevalence of subsequent regular menstrual cycles and a higher prevalence of early SA. Conclusion: An early ICT in TDT patients was associated with a normal "tempo" of pubertal onset and a higher frequency of subsequent regular menstrual cycles. In TDT patients, who developed SA, a diagnosis of acquired central hypogonadism was made, mainly due to the chronic exposure to iron overload, however other potential causes linked to nutritional status, deficient levels of circulating nutrients, and the chronic disease itself cannot be fully excluded.

Published
2021

9. Investigating the relationships between unfavorable sleep and metabolomic traits: Evidence from multi-cohort multivariable regression and mendelian randomization analyses

Author

Bos, M.M., primary, Goulding, N.J., additional, Lee, M., additional, Hofman, A., additional, Bot, M., additional, Pool, R., additional, Vijfhuizen, L., additional, Zhang, X., additional, Li, C., additional, Mustafa, R., additional, Neville, M.J., additional, Li-Gao, R., additional, Trompet, S., additional, Beekman, M., additional, Biermasz, N.R., additional, Boomsma, D.I., additional, De Boer, I., additional, Christodoulides, C., additional, Dehghan, A., additional, Van Dijk, K. Willems, additional, Ford, I., additional, Ghanbari, M., additional, Heijmans, B.T., additional, Ikram, M.A., additional, Jukema, J.W., additional, Mook-Kanamori, D.O., additional, Karpe, F., additional, Luik, A.I., additional, Lumey, L., additional, Van Den Maagdenberg, A.M., additional, Mooijaart, S.P., additional, De Mutsert, R., additional, Penninx, B.W.J.H., additional, Rensen, P.C.N., additional, Richmond, R.C., additional, Rosendaal, F.R., additional, Sattar, N., additional, Schoevers, R., additional, Slagboom, P.E., additional, Terwindt, G.M., additional, Thesing, C.S., additional, Wade, K., additional, Wijsman, C.A., additional, Willemsen, G., additional, Zinderman, A., additional, Verwoert, G.C., additional, Noordam, R., additional, and Lawlor, D.A., additional

Published
2021
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10. Higher thyroid stimulating hormone leads to cardiovascular disease and an unfavorable lipid profile: EVidence from multi-cohort Mendelian randomization and metabolomic profiling

Author

Van Vliet, N.A., primary, Bos, M.M., additional, Thesing, C.S., additional, Chaker, L., additional, Pietzner, M., additional, Houtman, E., additional, Neville, M.J., additional, Li-Gao, R., additional, Trompet, S., additional, Mustafa, R., additional, Ahmadizar, F., additional, Beekman, M., additional, Bot, M., additional, Budde, K., additional, Christodoulides, C., additional, Dehghan, A., additional, Delles, C., additional, Elliott, P., additional, Evangelou, M., additional, Gao, H., additional, Ghanbari, M., additional, Van Herwaarden, A.E., additional, Ikram, M.A., additional, Jaeger, M., additional, Jukema, J.W., additional, Karaman, I., additional, Karpe, F., additional, Kloppenburg, M., additional, Meessen, J.M.T.A., additional, Meulenbelt, I., additional, Milaneschi, Y., additional, Mooijaart, S.P., additional, Mook-Kanamori, D.O., additional, Netea, M.G., additional, Netea-Maier, R.T., additional, Peeters, R.P., additional, Penninx, B.W.J.H., additional, Sattar, N., additional, Slagboom, P.E., additional, Suchiman, H.E.D., additional, Völzke, H., additional, Van Dijk, K. Willems, additional, and Noordam, R., additional

Published
2021
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12. Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling

Author

Vliet, N.A. van, Bos, M.M., Thesing, C.S., Chaker, L., Pietzner, M., Houtman, E., Neville, M.J., Li-Gao, R., Trompet, S., Mustafa, R., Ahmadizar, F., Beekman, M., Bot, M., Budde, K., Christodoulides, C., Dehghan, A., Delles, C., Elliott, P., Evangelou, M., Gao, H., Ghanbari, M., Herwaarden, A.E. van, Ikram, M.Arfan, Jaeger, M., Jukema, J.W., Karaman, I., Karpe, F., Kloppenburg, M., Meessen, J., Meulenbelt, I., Milaneschi, Y., Mooijaart, S.P., Mook-Kanamori, D.O., Netea, M.G., Netea, R.T., Peeters, R.P., Penninx, B., Sattar, N., Slagboom, P.Eline, Suchiman, H. Eka D., Völzke, H., Dijk, K.W van, Noordam, R., Heemst, D. van, Vliet, N.A. van, Bos, M.M., Thesing, C.S., Chaker, L., Pietzner, M., Houtman, E., Neville, M.J., Li-Gao, R., Trompet, S., Mustafa, R., Ahmadizar, F., Beekman, M., Bot, M., Budde, K., Christodoulides, C., Dehghan, A., Delles, C., Elliott, P., Evangelou, M., Gao, H., Ghanbari, M., Herwaarden, A.E. van, Ikram, M.Arfan, Jaeger, M., Jukema, J.W., Karaman, I., Karpe, F., Kloppenburg, M., Meessen, J., Meulenbelt, I., Milaneschi, Y., Mooijaart, S.P., Mook-Kanamori, D.O., Netea, M.G., Netea, R.T., Peeters, R.P., Penninx, B., Sattar, N., Slagboom, P.Eline, Suchiman, H. Eka D., Völzke, H., Dijk, K.W van, Noordam, R., and Heemst, D. van

Abstract

Contains fulltext : 245686.pdf (Publisher’s version ) (Open Access), BACKGROUND: Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. METHODS: Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. RESULTS: Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99-1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96-1.04; p value 0.5

Published
2021

13. Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses

Author

Bos, Maxime, Goulding, NJ, Lee, MA, Hofman, Bert, Bot, M, Pool, R, Vijfhuizen, LS, Zhang, K, Li, CH, Mustafa, R, Neville, MJ, Li-Gao, R, Trompet, S, Beekman, M, Biermasz, NR, Boomsma, DI, Boer, I, Christodoulides, C, Dehghan, A, van Dijk, KW, Ford, I, Ghanbari, Mohsen, Heijmans, BT, Ikram, Arfan, Jukema, JW, Mook, Dennis, Karpe, F, Luik, Annemarie, Lumey, LH, van den Maagdenberg, A, Mooijaart, SP, de Mutsert, R, Penninx, B, Rensen, PCN, Richmond, Rebecca, Rosendaal, FR, Sattar, N, Schoevers, RA, Slagboom, PE, Terwindt, GM, Thesing, CS, Wade, KH, Wijsman, CA, Willemsen, G, Zwinderman, AH, van Heemst, D, Noordam, R, Lawlor, DA, Bos, Maxime, Goulding, NJ, Lee, MA, Hofman, Bert, Bot, M, Pool, R, Vijfhuizen, LS, Zhang, K, Li, CH, Mustafa, R, Neville, MJ, Li-Gao, R, Trompet, S, Beekman, M, Biermasz, NR, Boomsma, DI, Boer, I, Christodoulides, C, Dehghan, A, van Dijk, KW, Ford, I, Ghanbari, Mohsen, Heijmans, BT, Ikram, Arfan, Jukema, JW, Mook, Dennis, Karpe, F, Luik, Annemarie, Lumey, LH, van den Maagdenberg, A, Mooijaart, SP, de Mutsert, R, Penninx, B, Rensen, PCN, Richmond, Rebecca, Rosendaal, FR, Sattar, N, Schoevers, RA, Slagboom, PE, Terwindt, GM, Thesing, CS, Wade, KH, Wijsman, CA, Willemsen, G, Zwinderman, AH, van Heemst, D, Noordam, R, and Lawlor, DA

Abstract

Background: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD)[95% confidence interval (CI) − 0.12, − 0.03] in AMV and − 0.03SD [− 0.07, − 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (− 0.04SD [− 0.08, 0.00] in AMV and − 0.05SD [− 0.09, − 0.02] in MR), and lower phospholipids in very large HDL particles (− 0.04SD [− 0.08, 0.002] in AMV and − 0.05SD [− 0.08, − 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.

Published
2021

14. HOTAIR interacts with PRC2 complex regulating the regional preadipocyte transcriptome and human fat distribution

Author

Kuo, F-C, Neville, MJ, Sabaratnam, R, Wesolowska-Andersen, A, Phillips, D, Wittemans, LBL, van Dam, AD, Loh, NY, Todorčević, M, Denton, N, Kentistou, KA, Joshi, PK, Christodoulides, C, Langenberg, C, Collas, P, Karpe, F, Pinnick, KE, Kentistou, Katherine [0000-0002-5816-664X], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
subcutaneous adipose tissue, Polycomb Repressive Complex 2/genetics, Polycomb Repressive Complex 2, Estrogens, Transcriptome/genetics, Promoter Regions, Genetic/genetics, epigenetic regulation, General Biochemistry, Genetics and Molecular Biology, Chromatin, adipogenesis, HOTAIR, lncRNA, fat distribution, Humans, CP: Molecular biology, RNA, Long Noncoding, RNA, Long Noncoding/genetics, Promoter Regions, Genetic, Transcriptome
Abstract

Mechanisms governing regional human adipose tissue (AT) development remain undefined. Here, we show that the long non-coding RNA HOTAIR (HOX transcript antisense RNA) is exclusively expressed in gluteofemoral AT, where it is essential for adipocyte development. We find that HOTAIR interacts with polycomb repressive complex 2 (PRC2) and we identify core HOTAIR-PRC2 target genes involved in adipocyte lineage determination. Repression of target genes coincides with PRC2 promoter occupancy and H3K27 trimethylation. HOTAIR is also involved in modifying the gluteal adipocyte transcriptome through alternative splicing. Gluteal-specific expression of HOTAIR is maintained by defined regions of open chromatin across the HOTAIR promoter. HOTAIR expression levels can be modified by hormonal (estrogen, glucocorticoids) and genetic variation (rs1443512 is a HOTAIR eQTL associated with reduced gynoid fat mass). These data identify HOTAIR as a dynamic regulator of the gluteal adipocyte transcriptome and epigenome with functional importance for human regional AT development.

Published
2020

15. Evaluation of endocrine complications in beta-thalassemia intermedia (β-TI): a cross-sectional multicenter study

Author

Karimi, M. Zarei, T. Haghpanah, S. Azarkeivan, A. Kattamis, C. Ladis, V. Kattamis, A. Kilinc, Y. Daar, S. Alyaarubi, S. Khater, D. Wali, Y. Elshinawy, M. Almadhani, A. Yassin, M. Soliman, A.T. Canatan, D. Obiedat, M. Al-Rimawi, H. Mariannis, D. Christodoulides, C. Christou, S. Tzoulis, P. Campisi, S. Di Maio, S. De Sanctis, V.

Abstract

Background: Data on the prevalence and type of endocrine disorders in β-thalassemia intermedia (β-TI) patients are scarce. This multicenter study was designed to determine the prevalence of endocrine complications and the associated risk factors in a large group of β-TI patients. Methods: In this cross-sectional multicenter study, 726 β-TI patients, aged 2.5–80 years, registered at 12 thalassemic centers, from nine countries, were enrolled during 2017. In a subgroup of 522 patients (mean age 30.8 ± 12.1; range: 2.5–80 years) from Qatar, Iran, Oman, Cyprus, and Jordan detailed data were available. Results: Overall, the most prevalent complications were osteopenia/osteoporosis (22.3%), hypogonadism (10.1%), and primary hypothyroidism (5.3%). In the subgroup multivariate analysis, older age was a risk factor for osteoporosis (Odds ratio: 7.870, 95% CI: 4.729–13.099, P < 0.001), hypogonadism (Odds ratio: 6.310, 95% CI: 2.944–13.521, P < 0.001), and non-insulin-dependent diabetes mellitus (NIDDM; Odds ratio: 17.67, 95% CI: 2.217–140.968, P = 0.007). Splenectomy was a risk factor for osteoporosis (Odds ratio: 1.736, 95% CI: 1.012–2.977, P = 0.045). Hydroxyurea was identified as a “protective factor” for NIDDM (Odds ratio: 0.259, 95% CI: 0.074–0.902, P = 0.034). Conclusions: To the best of our knowledge, this is the largest cohort of β-TI patients with endocrine disorders evaluated in extremely heterogenic thalassemic populations for age, clinical, hematological, and molecular composition. The study demonstrates that endocrine complications are less common in patients with β-TI compared with β-TM patients. However, regular monitoring with timely diagnosis and proper management is crucial to prevent endocrine complications in β-TI patients. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Published
2020

16. WNT10B mutations in human obesity

Author

Christodoulides, C., Scarda, A., Granzotto, M., Milan, G., Dalla Nora, E., Keogh, J., De Pergola, G., Stirling, H., Pannacciulli, N., Sethi, J. K., Federspil, G., Vidal-Puig, A., Farooqi, I. S., O’Rahilly, S., and Vettor, R.

Published
2006
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21. Marital status and paternity in patients with Transfusion- Dependent Thalassemia (TDT) and Non Transfusion- Dependent Thalassemia (NTDT): An ICET - A survey in different countries

Author

de Sanctis, V. Soliman, A.T. El-Hakim, I. Christou, S. Mariannis, D. Karimi, M. Ladis, V. Kattamis, A. Daar, S. Yassin, M. Canatan, D. Galati, M.C. Raiola, G. Campisi, S. Kakkar, S. Kaleva, V. Saki, F. Ellinides, A. Pikis, G. Christodoulides, C. Abdulla, M. Di Maio, S. Theodoridis, C. Elsedfy, H. Kattamis, C.

Abstract

Background: More than five decades ago, thalassemia major (TDT) was fatal in the first decade of life. Survival and quality of life have improved progressively thanks to the implementation of a significant advance in diagnostic and therapeutic methods, consisting mainly of a frequent transfusion program combined with intensive chelation therapy. Improvement also includes imaging methods used to measure liver and cardiac iron overload. Improved survival has led to a growing number of adults requiring specialised care and counselling for specific life events, such as sexual maturity and acquisition of a family. Aims of the study: The main aim is to present the results of a survey on the marital and paternity status in a large population of adult males with TDT and NTDT living in countries with a high prevalence of thalassemia and a review of current literature using a systematic search for published studies. Results: Ten out of 16 Thalassemia Centres (62.5%) of the ICET-A Network, treating a total of 966 male patients, aged above 18 years with β- thalassemias (738 TDT and 228 NTDT), participated in the study. Of the 966 patients, 240 (24.8%) were married or lived with partners, and 726 (75.2%) unmarried. The mean age at marriage was 29.7 ± 0.3 years. Of 240 patients, 184 (76.6%) had children within the first two years of marriage (2.1 ± 0.1 years, median 2 years, range 1.8 - 2.3 years). The average number of children was 1.32 ± 0.06 (1.27 ± 0.07 in TDT patients and 1.47 ± 0.15 in NTDT patients; p: >0.05). Whatever the modality of conception, 184 patients (76.6%) had one or two children and 1 NTDT patient had 6 children. Nine (4.8%) births were twins. Of 184 patients, 150 (81.5%) had natural conception, 23 (12.5%) required induction of spermatogenesis with gonadotropins (hCG and hMG), 8 (4.3%) needed intracytoplasmic sperm injection (ICSI) and 3 adopted a child. 39 patients with TDT and NTDT asked for medical help as they were unable to father naturally: 7 TDT patients (17.9%) were azoospermic, 17 (37.7%) [13 with TDT and 4 with NTDT] had dysspermia and 15 (33.3%) [13 with TDT and 2 with NTDT] had other “general medical and non-medical conditions”. Conclusions: Our study provides detailed information in a novel area where there are few contemporary data. Understanding the aspects of male reproductive health is important for physicians involved in the care of men with thalassemias to convey the message that prospects for fatherhood are potentially good due to progressive improvements in treatment regimens and supportive care. © 2019, Mattioli 1885. All rights reserved.

Published
2019

25. Dielectric studies on glass transitions in biological systems

Author

Pissis, P., Anagnostopoulo-Konsta, A., Apekis, L., Daoukaki-Diamanti, D., Christodoulides, C., and Sideris, E.G.

Subjects
Biological systems -- Research, Dielectric relaxation -- Research, Business, Engineering and manufacturing industries, Science and technology
Abstract

Despite several reports in the last years on glass transitions in different biological systems, their existence is still controversial. In this work we use the method of thermally stimulated depolarization currents, which is very sensitive to transitions and has been widely used in the study of glass transitions in synthetic polymeric systems, to investigate this question. The thermograms obtained with different systems (plant tissue, proteins, saccharides) show, at high water contents, transitions in the temperature range 170 to 200 K, which shift to higher temperatures with decreasing water content. Three features of the transitions, namely the dependence of their dynamics on water content, the dependence of their activation energies on temperature and the validity of compensation effects, reveal, in analogy to synthetic polymeric systems, the existence of two glass transitions, probably due to the hydration water and the matrix structure, respectively.

Published
1992

26. An ICET-A survey on occult and emerging endocrine complications in patients with β-thalassemia major: Conclusions and recommendations

Author

De Sanctis, V. Soliman, A.T. Canatan, D. Tzoulis, P. Daar, S. Di Maio, S. Elsedfy, H. Yassin, M.A. Filosa, A. Soliman, N. Karimi, M. Saki, F. Sobti, P. Kakkar, S. Christou, S. Albu, A. Christodoulides, C. Kilinc, Y. Al Jaouni, S. Khater, D. Alyaarubi, S.A. Lum, S.H. Campisi, S. Anastasi, S. Galati, M.C. Raiola, G. Wali, Y. Elhakim, I.Z. Mariannis, D. Ladis, V. Kattamis, C.

Abstract

In adult thalassemia major (TM) patients, a number of occult and emerging endocrine complications, such as: central hypothyroidism (CH), thyroid cancer, latent hypocortisolism, and growth hormone deficiency (GHD) have emerged and been reported. As the early detection of these complications is essential for appropriate treatment and follow-up, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) promoted a survey on these complications in adult TM patients, among physicians (pediatricians, hematologists and endocrinologists) caring for TM patients in different countries. The data reported by 15 countries are presented.The commonest endocrine complications registered in 3.114 TM adults are CH and GHD (4.6 % and 3.0 %, respectively), followed by latent hypocortisolism (1.2%). In 13 patients (0.41%) a cytological papillary or follicular thyroid carcinoma was diagnosed in 11 and 2 patients, respectively, and a lobectomy or thyroidectomy was carried out. Of 202 TM patients below the age of 18 years, the reported endocrine complications were: GHD in 4.5%, latent hypocortisolism in 4.4% and central hypothyrodisim in 0.5%. Transition phase was an area of interest for many clinicians, especially as patients with complex chronic health conditions are responding to new treatments extending their lifespan beyond imagination.. In conclusion, our survey provides a better understanding of physicians’ current clinical practices and beliefs in the detection, prevention and treatment of some endocrine complications prevailing in adult TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended. (www.actabiomedica.it). © Mattioli 1885.

Published
2018

28. Comparison of regional fat measurements by dual-energy X-ray absorptiometry and conventional anthropometry and their association with markers of diabetes and cardiovascular disease risk

Author

Vasan, SK, Osmond, C, Canoy, D, Christodoulides, C, Neville, MJ, Di Gravio, C, Fall, CHD, Karpe, F, Vasan, SK, Osmond, C, Canoy, D, Christodoulides, C, Neville, MJ, Di Gravio, C, Fall, CHD, and Karpe, F

Abstract

Background/Objectives:Fat distribution is a strong and independent predictor of type 2 diabetes (T2D) and cardiovascular disease (CVD) and is usually determined using conventional anthropometry in epidemiological studies. Dual-energy X-ray absorptiometry (DXA) can measure total and regional adiposity more accurately. Nonetheless, whether DXA provides more precise estimates of cardiovascular risk in relation to total and regional adiposity is not known. We determined the strength of the associations between DXA-and conventional anthropometry determined fat distribution and T2D and CVD risk markers.Subjects/Methods:Waist (WC) and hip circumference (HC) and DXA was used to measure total and regional adiposity in 4950 (2119 men) participants aged 29-55 years from the Oxford Biobank without pre-existing T2D or CVD. Cross-sectional associations were compared between WC and HC vs. DXA-determined regional adiposity (all z-score normalised) with impaired fasting glucose, hypertriglyceridemia, hypertension and insulin resistance (IR).Results:Following adjustment for total adiposity, upper body adiposity measurements showed consistently increased risk of T2D and CVD risk markers except for abdominal subcutaneous fat in both sexes, and arm fat in men, which showed protective associations. Among upper adiposity depots, visceral fat mass showed stronger odds ratios (OR) ranging from 1.69 to 3.64 compared with WC 1.07-1.83. Among lower adiposity depots, HC showed modest protection for IR in both sexes (men: OR 0.80 (95% confidence interval 0.67, 0.96); women: 0.69 (0.56, 0.86)), whereas gynoid fat and in particular leg fat showed consistent and strong protective effects for all outcomes in both men and women. The differential effect of body fat distribution on CVD and T2D were more pronounced at higher levels of total adiposity.Conclusions:Compared with DXA, conventional anthropometry underestimates the associations of regional adiposity with T2D and CVD risk markers. After correc

Published
2018

29. Comparison of regional fat measurements by dual-energy X-ray absorptiometry and conventional anthropometry and their association with markers of diabetes and cardiovascular disease risk

Author

Vasan, S, Osmond, C, Canoy, D, Christodoulides, C, Neville, M, Di Gravio, C, Fall, C, and Karpe, F

Subjects
Adult, Male, Anthropometry, Middle Aged, Absorptiometry, Photon, Cross-Sectional Studies, Adipose Tissue, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Risk Factors, Body Size, Humans, Female, Original Article
Abstract

BACKGROUND/OBJECTIVE: Fat distribution is a strong and independent predictor of type 2 diabetes (T2D) and cardiovascular disease (CVD) and is usually determined using conventional anthropometry in epidemiological studies. Dual-energy X-ray absorptiometry (DXA) can measure total and regional adiposity more accurately. Nonetheless, whether DXA provides more precise estimates of cardiovascular risk in relation to total and regional adiposity is not known. We determined the strength of the associations between DXA- and conventional anthropometry determined fat distribution and T2D and CVD risk. SUBJECTS/METHODS: Waist (WC) and hip circumference (HC) and DXA was used to measure total and regional adiposity in 4950 (2119 men) participants aged 29–55 years from the Oxford Biobank without pre-existing T2D or CVD. Cross-sectional associations were compared between WC and HC vs DXA-determined regional adiposity (all z-score normalized) with impaired fasting glucose, hypertriglyceridemia, hypertension and insulin resistance (IR). RESULTS: Following adjustment for total adiposity, upper body adiposity measurements showed consistently increased risk of T2D and CVD risk markers except for abdominal subcutaneous fat in both sexes, and arm fat in men, which showed protective associations. Among upper adiposity depots, visceral fat mass showed stronger odds ratios (OR) ranging from 1.69–3.64 compared with WC 1.07–1.83. Among lower adiposity depots, HC showed modest protection for IR in both sexes [men: OR 0.80 (95%CI 0.67, 0.96); women: 0.69 (0.56, 0.86)] whereas gynoid fat and in particular leg fat showed consistent and strong protective effects for all outcomes in both men and women. The differential effect of body fat distribution on CVD and T2D were more pronounced at higher levels of total adiposity. CONCLUSIONS: Compared with DXA, conventional anthropometry underestimates the associations of regional adiposity with T2D and CVD risk markers. After correcting for overall adiposity, greater subcutaneous fat mass in particular in the lower body is protective relative to greater android or VAT mass.

Published
2017

30. A cellular model for the investigation of depot-specific human adipocyte biology

Author

Pinnick, K, Hodson, L, Karpe, F, Todorcevic, M, Hilton, C, Christodoulides, C, and McNeil, C

Abstract

Upper-body adiposity is associated with increased metabolic disease risk, whilst lower-body adiposity is paradoxically protective. Efforts to understand the underlying mechanisms require appropriate and reproducible in vitro culture models. We have therefore generated immortalised (im) human preadipocyte (PAD) cell lines derived from paired subcutaneous abdominal and gluteal adipose tissue. These cell lines, denoted imAPAD and imGPAD display enhanced proliferation and robust adipogenic capacities. Differentiated imAPAD and imGPAD adipocytes synthesise triglycerides de novo and respond lipolytically to catecholamine-stimulation. Importantly the cells retain their depot-of-origin ‘memory’ as reflected by inherent differences in fatty acid metabolism and expression of depot-specific developmental genes. These features make these cell lines an invaluable tool for the in vitro investigation of depot-specific human adipocyte biology.

Published
2017

34. In-patient management of diabetes mellitus and patient satisfaction

Author

Bhattacharyya, A, Christodoulides, C, Kaushal, K, New, JP, and Young, RJ

Abstract

AIMS: To devise a system for assessing in-patient glycaemic control and care satisfaction in diabetic patients admitted to hospital for reasons other than their diabetes. METHODS: Consecutive January to March 2001 case-notes were reviewed. Admissions with acute metabolic complications, acute myocardial infarction and pregestational or gestational diabetes were excluded. Glycaemic control, frequency of blood monitoring and management of hyperglycaemia were recorded. The diabetes treatment satisfaction questionnaire was used to assess preadmission satisfaction with care. Post-admission a 12-stem questionnaire was used to assess satisfaction with in-patient diabetes management. RESULTS: Hypoglycaemia was common. Although none developed a hyperglycaemic emergency, high blood glucose was prevalent and, frequently, persistent hyperglycaemia or recurrent hypoglycaemia was not acted on appropriately. The overall score for in-patient satisfaction with treatment was fair (4.1 +/- 1.8 on a six-point scale; 6 = very satisfied and 1 = very dissatisfied). Scores were higher among patients on surgical wards than on medical wards (P = 0.008), but satisfaction did not vary when patients were stratified according to sex, age and mode of treatment. CONCLUSION: Current systems are not achieving satisfactory in-patient glycaemic control and there is poor satisfaction with medical in-patient diabetes care. Following changes intended to produce improvements, this assessment system can be used recurrently to monitor in-patient care and satisfaction.

Published
2016

38. Peak parameters from peak area to height ratio in thermally stimulated depolarization and thermoluminescence.

Author

Christodoulides, C., Apekis, L., and Pissis, P.

Subjects
*THERMOLUMINESCENCE, *POLARIZATION (Nuclear physics)
Abstract

Focuses on a method for using the area under a peak and the peak height in evaluating the activation energy and preexponential factor of thermally stimulated depolarization or thermoluminescence peaks. Discussion of the accuracy achieved by the mathematical approximation used; Application of the method to a number of experimental peaks; Systematic errors inherent in the method.

Published
1988
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42. The magnetic field produced at a focus of a current-carrying conductor in the shape of a conic section

Author

Christodoulides, C.

Subjects
Magnetic fields -- Analysis, Electric conductors -- Magnetic properties, Electric conductors -- Mechanical properties, Cross sections (Geometry) -- Research, Physics
Abstract

We determine the magnetic field at the focus of a conic section due to a current along the conic section. For a given current I, it is shown that this magnetic field is the same and equal to [[mu].sub.0]I/2p for all conics with the same semilatus rectum p. [DOI: 10.1119/1.3183888]

Published
2009

43. Wnt signaling in cardiovascular physiology

Author

Marinou, K. Christodoulides, C. Antoniades, C. Koutsilieris, M.

Abstract

Wnt signaling pathways play a key role in cardiac development, angiogenesis, and cardiac hypertrophy; emerging evidence suggests that they are also involved in the pathophysiology of atherosclerosis. Specifically, an important role for Wnts has been described in the regulation of endothelial inflammation, vascular calcification, and mesenchymal stem cell differentiation. Wnt signaling also induces monocyte adhesion to endothelial cells and is crucial for the regulation of vascular smooth-muscle cell (VSMC) behavior. We discuss how the Wnt pathways are implicated in vascular biology and outline the role of Wnt signaling in atherosclerosis. Dissecting Wnt pathways involved in atherogenesis and cardiovascular disease may provide crucial insights into novel mechanisms with therapeutic potential for atherosclerosis.

Published
2012

44. The role of adiponectin in human vascular physiology

Author

Vaiopoulos, A.G. Marinou, K. Christodoulides, C. Koutsilieris, M.

Subjects
animal structures, hormones, hormone substitutes, and hormone antagonists
Abstract

Adiponectin (ApN) is an adipose tissue-derived hormone which is involved in a wide variety of physiological processes including energy metabolism, inflammation, and vascular physiology via actions on a broad spectrum of target organs including liver, skeletal muscle, and vascular endothelium. Besides possessing insulin sensitizing and anti-inflammatory properties ApN also exerts a pivotal role in vascular protection through activation of multiple intracellular signaling cascades. Enhancement of nitric oxide generation and attenuation of reactive oxygen species production in endothelial cells along with reduced vascular smooth muscle cell proliferation and migration constitute some of ApN's vasoprotective actions. Additionally, recent data indicate that ApN has direct myocardio-protective effects. Decreased plasma ApN levels are implicated in the pathogenesis of the metabolic syndrome and atherosclerosis and may serve as a diagnostic and prognostic biomarker as well as a rational pharmaco-therapeutic target to treat these disorders. This review article summarizes recent work on the cardiovascular actions of ApN. © 2011 Elsevier Ireland Ltd. All rights reserved.

Published
2012

45. Polymer segmental dynamics and solvent thermal transitions in Poly(ethyl acrylate)/p-xylene mixtures

Author

Stathopoulos, A.T., Kyritsis, A., Romero Colomer, Francisco José, Gómez Ribelles, José Luís, Shinyashiki, N., Christodoulides, C., and Pissis, P.

Subjects
Poly (ethyl acrylate), Mixing, FISICA APLICADA, Plasticization, MAQUINAS Y MOTORES TERMICOS, Differential scanning calorimetry (DSC), Thermally stimulated depolarization currents, Noncrystallized solvent, Glass transition, P-xylene
Abstract

A poly(ethyl acrylate) polymer network was swollen with different concentrations of the nonpolar solvent p-xylene, cpx, from xerogel until saturation (0 cpx 0.85). Differential scanning calorimetry (DSC) and thermally stimulated depolarization currents (TSDC) techniques were employed to study the polymer segmental dynamics and the solvent thermal transitions in homogeneous (cpx < 0.20) and partially crystallized (cpx 0.20) PEA/p-xylene mixtures. Our DSC measurements indicate that p-xylene undergoes cold crystallization for intermediate solvent concentrations, 0.20 cpx 0.30 while for higher cpx values crystallization takes place during cooling. The results show that for cpx 0.30 the Tg decreases with increasing cpx (plasticization effect) obeying the respective Fox equation. For the same cpx range we found that both the dielectric strength and the heat capacity increment of the segmental (a) relaxation process increase gradually with cpx whereas the distribution of relaxation times for the underlying molecular relaxations does not change. For cpx > 0.30 the partially crystallized mixtures exhibit a constant Tg corresponding to the gel phase of PEA with an amount of p-xylene which is not able to crystallize under any conditions. The concentration of this noncrystallized p-xylene, cUCpx, has been estimated to be between 0.12 and 0.15, independent of the total p-xylene concentration in the mixtures. When a separate p-xylene crystal phase is formed (for cpx > 0.30) the segmental dielectric strength and heat capacity increment decrease significantly exhibiting values significantly lower than those measured for the homogeneous gels. In addition, we found that the presence of p-xylene crystals may induce marginal spatial heterogeneity of polymer (or p-xylene) concentration within the gel phase affecting thus slightly the breath of the segmental relaxation of PEA. We attribute these results to restrictions of polymer segmental configurations due to constraints imposed by the p-xylene crystals and/or to the immobilization of a part of the polymer chains. VC 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 49: 455¿466, 2011, A.T.S. thanks the Department of Physics, National Technical University of Athens for the financial support of this work.

Published
2011
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