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18. Profibrotic, electrical, and calcium-handling remodeling of the atria in heart failure patients with and without atrial fibrillation

Author

Molina C.E., Abu-Taha I.H., Wang Q., Roselló-Díez E., Kamler M., Nattel S., Ravens U., Wehrens X.H.T., Hove-Madsen L., Heijman J., and Dobrev D.

Subjects
Ca2+ handling, Heart failure, Heart failure with reduced ejection fraction, Human atrial cardiomyocytes, Atrial fibrillation
Abstract

Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular diseases that often co-exist. Animal models have suggested complex AF-promoting atrial structural, electrical, and Ca2+handling remodeling in the setting of HF, but data in human samples are scarce, particularly regarding Ca2+-handling remodeling. Here, we evaluated atrial remodeling in patients with severe left ventricular (LV) dysfunction (HFrEF), long-standing persistent (‘chronic’) AF (cAF) or both (HFrEF-cAF), and sinus rhythm controls with normal LV function (Ctl) using western blot in right-atrial tissue, sharp-electrode action potential (AP) measurements in atrial trabeculae and voltage-clamp experiments in isolated right-atrial cardiomyocytes. Compared to Ctl, expression of profibrotic markers (collagen-1a, fibronectin, periostin) was higher in HFrEF and HFrEF-cAF patients, indicative of structural remodeling. Connexin-43 expression was reduced in HFrEF patients, but not HFrEF-cAF patients. AP characteristics were unchanged in HFrEF, but showed classical indices of electrical remodeling in cAF and HFrEF-cAF (prolonged AP duration at 20% and shorter AP duration at 50% and 90% repolarization). L-type Ca2+ current (ICa,L) was significantly reduced in HFrEF, cAF and HFrEF-cAF, without changes in voltage-dependence. Potentially proarrhythmic spontaneous transient-inward currents were significantly more frequent in HFrEF and HFrEF-cAF compared to Ctl, likely resulting from increased sarcoplasmic reticulum (SR) Ca2+ load (integrated caffeine-induced current) in HFrEF and increased ryanodine-receptor (RyR2) single-channel open probability in HFrEF and HFrEF-cAF. Although expression and phosphorylation of the SR Ca2+-ATPase type-2a (SERCA2a) regulator phospholamban were unchanged in HFrEF and HFrEF-cAF patients, protein levels of SERCA2a were increased in HFrEF-cAF and sarcolipin expression was decreased in both HFrEF and HFrEF-cAF, likely increasing SR Ca2+ uptake and load. RyR2 protein levels were decreased in HFrEF and HFrEF-cAF patients, but junctin levels were higher in HFrEF and relative Ser2814-RyR2 phosphorylation levels were increased in HFrEF-cAF, both potentially contributing to the greater RyR2 open probability. These novel insights into the molecular substrate for atrial arrhythmias in HF-patients position Ca2+-handling abnormalities as a likely trigger of AF in HF patients, which subsequently produces electrical remodeling that promotes the maintenance of the arrhythmia. Our new findings may have important implications for the development of novel treatment options for AF in the context of HF. © 2018 Molina, Abu-Taha, Wang, Roselló-Díez, Kamler, Nattel, Ravens, Wehrens, Hove-Madsen, Heijman and Dobrev.

Published
2018

19. 306The diagnostic role of cardiac magnetic resonance imaging when performed as initial test in suspected non-ST elevation myocardial infarction

Author

Van Cauteren, Y J M, primary, Smulders, M W, additional, Heijman, J, additional, Gerretsen, S C, additional, Theunissen, R A L J, additional, Mingels, A M A, additional, Van Kuijk, S M J, additional, Kim, R J, additional, Crijns, H J G M, additional, Wildberger, J E, additional, and Bekkers, S C A M, additional

Published
2019
Full Text
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26. Poster session 3

Author

Nanka, O., primary, Krejci, E., additional, Pesevski, Z., additional, Sedmera, D., additional, Smart, N., additional, Rossdeutsch, A., additional, Dube, K. N., additional, Riegler, J., additional, Price, A. N., additional, Taylor, A., additional, Muthurangu, V., additional, Turner, M., additional, Lythgoe, M. F., additional, Riley, P. R., additional, Kryvorot, S., additional, Vladimirskaya, T., additional, Shved, I., additional, Schwarzl, M., additional, Seiler, S., additional, Huber, S., additional, Steendijk, P., additional, Maechler, H., additional, Truschnig-Wilders, M., additional, Pieske, B., additional, Post, H., additional, Caprio, C., additional, Baldini, A., additional, Chiavacci, E., additional, Dolfi, L., additional, Verduci, L., additional, Meghini, F., additional, Cremisi, F., additional, Pitto, L., additional, Kuan, T.-C., additional, Chen, M.-C., additional, Yang, T.-H., additional, Wu, W.-T., additional, Lin, C. S., additional, Rai, H., additional, Kumar, S., additional, Sharma, A. K., additional, Mastana, S., additional, Kapoor, A., additional, Pandey, C. M., additional, Agrawal, S., additional, Sinha, N., additional, Orlowska-Baranowska, E. H., additional, Placha, G., additional, Gora, J., additional, Baranowski, R., additional, Abramczuk, E., additional, Hryniewiecki, T., additional, Gaciong, Z., additional, Verschuren, J. J. W., additional, Wessels, J. A. M., additional, Trompet, S., additional, Stott, D. J., additional, Sattar, N., additional, Buckley, B., additional, Guchelaar, H. J., additional, Jukema, J. W., additional, Gharanei, M., additional, Hussain, A., additional, Mee, C. J., additional, Maddock, H. L., additional, Wijnen, W. J., additional, Van Den Oever, S., additional, Van Der Made, I., additional, Hiller, M., additional, Tijsen, A. J., additional, Pinto, Y. M., additional, Creemers, E. E., additional, Nikulina, S. U. Y., additional, Chernova, A., additional, Petry, A., additional, Rzymski, T., additional, Kracun, D., additional, Riess, F., additional, Pike, L., additional, Harris, A. L., additional, Gorlach, A., additional, Katare, R., additional, Oikawa, A., additional, Riu, F., additional, Beltrami, A. P., additional, Cesseli, D., additional, Emanueli, C., additional, Madeddu, P., additional, Zaglia, T., additional, Milan, G., additional, Franzoso, M., additional, Pesce, P., additional, Sarais, C., additional, Sandri, M., additional, Mongillo, M., additional, Butler, T. J., additional, Seymour, A.-M. L., additional, Ashford, D., additional, Jaffre, F., additional, Bussen, M., additional, Flohrschutz, I., additional, Martin, G. R., additional, Engelhardt, S., additional, Kararigas, G., additional, Nguyen, B. T., additional, Jarry, H., additional, Regitz-Zagrosek, V., additional, Van Bilsen, M., additional, Daniels, A., additional, Munts, C., additional, Janssen, B. J. A., additional, Van Der Vusse, G. J., additional, Van Nieuwenhoven, F. A., additional, Montalvo, C., additional, Villar, A. V., additional, Merino, D., additional, Garcia, R., additional, Llano, M., additional, Ares, M., additional, Hurle, M. A., additional, Nistal, J. F., additional, Dembinska-Kiec, A., additional, Beata Kiec-Wilk, B. K. W., additional, Anna Polus, A. P., additional, Urszula Czech, U. C., additional, Tatiana Konovaleva, T. K., additional, Gerd Schmitz, G. S., additional, Bertrand, L., additional, Balteau, M., additional, Timmermans, A., additional, Viollet, B., additional, Sakamoto, K., additional, Feron, O., additional, Horman, S., additional, Vanoverschelde, J. L., additional, Beauloye, C., additional, De Meester, C., additional, Martinez, E., additional, Martin, R., additional, Miana, M., additional, Jurado, R., additional, Gomez-Hurtado, N., additional, Bartolome, M. V., additional, San Roman, J. A., additional, Lahera, V., additional, Nieto, M. L., additional, Cachofeiro, V., additional, Rochais, F., additional, Sturny, R., additional, Mesbah, K., additional, Miquerol, L., additional, Kelly, R. G., additional, Messaoudi, S., additional, Gravez, B., additional, Tarjus, A., additional, Pelloux, V., additional, Samuel, J. L., additional, Delcayre, C., additional, Launay, J. M., additional, Clement, K., additional, Farman, N., additional, Jaisser, F., additional, Hadyanto, L., additional, Castellani, C., additional, Vescovo, G., additional, Ravara, B., additional, Tavano, R., additional, Pozzobon, M., additional, De Coppi, P., additional, Papini, E., additional, Vettor, R., additional, Thiene, G., additional, Angelini, A., additional, Meloni, M., additional, Caporali, A., additional, Cesselli, D., additional, Fortunato, O., additional, Avolio, E., additional, Schindler, R., additional, Simrick, S., additional, Brand, T., additional, Smart, N. S., additional, Herman, A., additional, Roura Ferrer, S., additional, Rodriguez Bago, J., additional, Soler-Botija, C., additional, Pujal, J. M., additional, Galvez-Monton, C., additional, Prat-Vidal, C., additional, Llucia-Valldeperas, A., additional, Blanco, J., additional, Bayes-Genis, A., additional, Foldes, G., additional, Maxime, M., additional, Ali, N. N., additional, Schneider, M. D., additional, Harding, S. E., additional, Reni, C., additional, Mangialardi, G., additional, De Pauw, A., additional, Sekkali, B., additional, Friart, A., additional, Ding, H., additional, Graffeuil, A., additional, Catalucci, D., additional, Balligand, J. 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A., additional, Bourgonje, V. J. A., additional, Kok, G. J. M., additional, Van Veen, A. A. B., additional, Anderson, M. E., additional, Vos, M. A., additional, Bierhuizen, M. F. A., additional, Benes, J., additional, Sebestova, B., additional, Ghouri, I. A., additional, Kemi, O. J., additional, Kelly, A., additional, Burton, F. L., additional, Smith, G. L., additional, Ozdemir, S., additional, Acsai, K., additional, Doisne, N., additional, Van Der Nagel, R., additional, Beekman, H. D. M., additional, Van Veen, T. A. B., additional, Sipido, K. R., additional, Antoons, G., additional, Harmer, S. C., additional, Mohal, J. S., additional, Kemp, D., additional, Tinker, A., additional, Beech, D., additional, Burley, D. S., additional, Cox, C. D., additional, Wann, K. T., additional, Baxter, G. F., additional, Wilders, R., additional, Verkerk, A., additional, Fragkiadaki, P., additional, Germanakis, G., additional, Tsarouchas, K., additional, Tsitsimpikou, C., additional, Tsardi, M., additional, George, D., additional, Tsatsakis, A., additional, Rodrigues, P., additional, Barros, C., additional, Najmi, A. K., additional, Khan, V., additional, Akhtar, M., additional, Pillai, K. K., additional, Mujeeb, M., additional, Aqil, M., additional, Bayliss, C. R., additional, Messer, A. E., additional, Leung, M.-C., additional, Ward, D., additional, Van Der Velden, J., additional, Poggesi, C., additional, Redwood, C. S., additional, Marston, S., additional, Vite, A., additional, Gandjbakhch, E., additional, Gary, F., additional, Fressart, V., additional, Leprince, P., additional, Fontaine, G., additional, Komajda, M., additional, Charron, P., additional, Villard, E., additional, Falcao-Pires, I., additional, Gavina, C., additional, Hamdani, N., additional, Stienen, G. J. M., additional, Niessens, H. W. M., additional, Leite-Moreira, A. F., additional, Paulus, W. J., additional, Memo, M., additional, Marston, S. B., additional, Vafiadaki, E., additional, Qian, J., additional, Arvanitis, D. A., additional, Sanoudou, D., additional, Kranias, E. G., additional, Elmstedt, N., additional, Lind, B., additional, Ferm-Widlund, K., additional, Westgren, M., additional, Brodin, L.-A., additional, Mansfield, C., additional, West, T., additional, Ferenczi, M., additional, Wijnker, P. J. M., additional, Foster, D. B., additional, Coulter, A., additional, Frazier, A., additional, Murphy, A. M., additional, Shah, M., additional, Sikkel, M. B., additional, Desplantez, T., additional, Collins, T. P., additional, O' Gara, P., additional, Lyon, A. R., additional, Macleod, K. T., additional, Ottesen, A. H., additional, Louch, W. E., additional, Carlson, C., additional, Landsverk, O. J. B., additional, Stridsberg, M., additional, Sjaastad, I., additional, Oie, E., additional, Omland, T., additional, Christensen, G., additional, Rosjo, H., additional, Cartledge, J., additional, Clark, L. A., additional, Ibrahim, M., additional, Siedlecka, U., additional, Navaratnarajah, M., additional, Yacoub, M. H., additional, Camelliti, P., additional, Terracciano, C. M., additional, Chester, A., additional, Gonzalez-Tendero, A., additional, Torre, I., additional, Garcia-Garcia, F., additional, Dopazo, J., additional, Gratacos, E., additional, Taylor, D., additional, Bhandari, S., additional, Seymour, A.-M., additional, Fliegner, D., additional, Jost, J., additional, Bugger, H., additional, Ventura-Clapier, R., additional, Carpi, A., additional, Campesan, M., additional, Canton, M., additional, Menabo, R., additional, Pelicci, P. 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C., additional, Thireau, J., additional, Roberge, S., additional, Lompre, A. M., additional, Jacotot, E., additional, Marks, A. M., additional, Lacampagne, A., additional, Dietel, B., additional, Altendorf, R., additional, Daniel, W. G., additional, Kollmar, R., additional, Garlichs, C. D., additional, Parente, V., additional, Balasso, S., additional, Pompilio, G., additional, Colombo, G., additional, Milano, G., additional, Squadroni, L., additional, Cotelli, F., additional, Pozzoli, O., additional, Capogrossi, M. C., additional, Ajiro, Y., additional, Saegusa, N., additional, Iwade, K., additional, Giles, W. R., additional, Stafforini, D. M., additional, Spitzer, K. W., additional, Sirohi, R., additional, Candilio, L., additional, Babu, G., additional, Roberts, N., additional, Lawrence, D., additional, Sheikh, A., additional, Kolvekar, S., additional, Yap, J., additional, Hausenloy, D. J., additional, Yellon, D. 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A., additional, Fornai, L., additional, Kiss, A., additional, Giskes, F., additional, Eijkel, G., additional, Fedrigo, M., additional, Valente, M. L., additional, Heeren, R. M. A., additional, Grdinic, A., additional, Vojvodic, D., additional, Djukanovic, N., additional, Grdinic, A. G., additional, Obradovic, S., additional, Majstorovic, I., additional, Rusovic, S., additional, Vucinic, Z., additional, Tavciovski, D., additional, Ostojic, M., additional, Lai, S.-C., additional, Chen, M.-Y., additional, Wu, H.-T., additional, Gouweleeuw, L., additional, Oberdorf-Maass, S. U., additional, De Boer, R. A., additional, Van Gilst, W. H., additional, Maass, A. H., additional, Van Gelder, I. C., additional, Benard, L., additional, Li, C., additional, Warren, D., additional, Shanahan, C. M., additional, Zhang, Q. P., additional, Bye, A., additional, Vettukattil, R., additional, Aspenes, S. T., additional, Giskeodegaard, G., additional, Gribbestad, I. S., additional, Wisloff, U., additional, Bathen, T. F., additional, Cubedo, J., additional, Alonso, R., additional, Mata, P., additional, Ivic, I., additional, Vamos, Z., additional, Cseplo, P., additional, Kosa, D., additional, Torok, O., additional, Hamar, J., additional, Koller, A., additional, Norita, K., additional, De Noronha, S. V., additional, Sheppard, M. N., additional, Amat-Roldan, I., additional, Iruretagoiena, I., additional, Psilodimitrakopoulos, S., additional, Crispi, F., additional, Artigas, D., additional, Loza-Alvarez, P., additional, Harrison, J. C., additional, Smart, S. D., additional, Besely, E. H., additional, Kelly, J. R., additional, Yao, Y., additional, Sammut, I. A., additional, Hoepfner, M., additional, Kuzyniak, W., additional, Sekhosana, E., additional, Hoffmann, B., additional, Litwinski, C., additional, Pries, A., additional, Ermilov, E., additional, Fontoura, D., additional, Lourenco, A. P., additional, Vasques-Novoa, F., additional, Pinto, J. P., additional, Roncon-Albuquerque, R., additional, Oyeyipo, I. P., additional, Olatunji, L. A., additional, Usman, T. O., additional, Olatunji, V. A., additional, Bacova, B., additional, Viczenczova, C., additional, Dosenko, V., additional, Goncalvesova, E., additional, Vanrooyen, J., additional, Maulik, S. K., additional, Seth, S., additional, Dinda, A. K., additional, Jaiswal, A., additional, Mearini, G., additional, Khajetoorians, D., additional, Kraemer, E., additional, Gedicke-Hornung, C., additional, Precigout, G., additional, Eschenhagen, T., additional, Voit, T., additional, Garcia, L., additional, Lorain, S., additional, Mendes-Ferreira, P., additional, Maia-Rocha, C., additional, Adao, R., additional, Cerqueira, R. J., additional, Mendes, M. J., additional, Castro-Chaves, P., additional, De Keulenaer, G. W., additional, Bras-Silva, C., additional, Ruiter, G., additional, Wong, Y. Y., additional, Lubberink, M., additional, Knaapen, P., additional, Raijmakers, P., additional, Lammertsma, A. A., additional, Marcus, J. T., additional, Westerhof, N., additional, Van Der Laarse, W. J., additional, Vonk-Noordegraaf, A., additional, Steinbronn, N., additional, Koch, E., additional, Steiner, G., additional, Berezin, A., additional, Lisovaya, O. A., additional, Soldatova, A. M., additional, Kuznetcov, V. A., additional, Yenina, T. N., additional, Rychkov, A. Y. U., additional, Shebeko, P. V., additional, Altara, R., additional, Hessel, M. H. M., additional, Hermans, J. J. R., additional, Blankesteijn, W. M., additional, Berezina, T. A., additional, Seden, V., additional, Bonanad, C., additional, Nunez, J., additional, Navarro, D., additional, Chilet, M. F., additional, Sanchis, F., additional, Bodi, V., additional, Minana, G., additional, Chaustre, F., additional, Forteza, M. J., additional, Llacer, A., additional, Galasso, G., additional, Ferrara, N., additional, Akhmedov, A., additional, Klingenberg, R., additional, Brokopp, C., additional, Hof, D., additional, Zoller, S., additional, Corti, R., additional, Gay, S., additional, Von Eckardstein, A., additional, Hoerstrup, S. P., additional, Luescher, T. F., additional, Heijman, J., additional, Zaza, A., additional, Johnson, D. M., additional, Rudy, Y., additional, Peeters, R. L. M., additional, Volders, P. G. A., additional, Westra, R. L., additional, Fujita, S., additional, Okamoto, R., additional, Taniguchi, M., additional, Konishi, K., additional, Goto, I., additional, Sugimoto, K., additional, Nakamura, M., additional, Shiraki, K., additional, Buechler, C., additional, and Ito, M., additional

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2012
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28. Saturday, 17 July 2010

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Dimova, I., primary, Hlushchuk, R., additional, Makanya, A., additional, Djonov, V., additional, Theurl, M., additional, Schgoer, W., additional, Albrecht, K., additional, Beer, A., additional, Patsch, J. R., additional, Schratzberger, P., additional, Mahata, S., additional, Kirchmair, R., additional, Didie, M., additional, Christalla, P., additional, Rau, T., additional, Eschenhagen, T., additional, Schumacher, U., additional, Lin, Q., additional, Zenke, M., additional, Zimmmermann, W., additional, Hoch, M., additional, Fischer, P., additional, Stapel, B., additional, Missol-Kolka, E., additional, Erschow, S., additional, Scherr, M., additional, Drexler, H., additional, Hilfiker-Kleiner, D., additional, Diebold, I., additional, Petry, A., additional, Kennel, P., additional, Djordjevic, T., additional, Hess, J., additional, Goerlach, A., additional, Castellano, J., additional, Aledo, R., additional, Sendra, J., additional, Costales, P., additional, Badimon, L., additional, Llorente-Cortes, V., additional, Dworatzek, E., additional, Mahmoodzadeh, S., additional, Regitz-Zagrosek, V., additional, Posa, A., additional, Varga, C., additional, Berko, A., additional, Veszelka, M., additional, Szablics, P., additional, Vari, B., additional, Pavo, I., additional, Laszlo, F., additional, Brandenburger, M., additional, Wenzel, J., additional, Bogdan, R., additional, Richardt, D., additional, Reppel, M., additional, Hescheler, J., additional, Terlau, H., additional, Dendorfer, A., additional, Heijman, J., additional, Rudy, Y., additional, Westra, R., additional, Volders, P., additional, Rasmusson, R., additional, Bondarenko, V., additional, Ertas Gokhan, M. D., additional, Ural Ertan, M. D., additional, Karaoz Erdal, P. H. D., additional, Aksoy Ayca, P. H. D., additional, Kilic Teoman, M. D., additional, Kozdag Guliz, M. D., additional, Vural Ahmet, M. D., additional, Ural Dilek, M. D., additional, Poulet, C., additional, Christ, T., additional, Wettwer, E., additional, Ravens, U., additional, Van Der Pouw Kraan, C., additional, Schirmer, S., additional, Fledderus, J., additional, Moerland, P., additional, Leyen, T., additional, Piek, J., additional, Van Royen, N., additional, Horrevoets, A., additional, Fleissner, F., additional, Jazbutyte, V., additional, Fiedler, J., additional, Galuppo, P., additional, Mayr, M., additional, Ertl, G., additional, Bauersachs, J., additional, Thum, T., additional, Protze, S., additional, Bussek, A., additional, Li, F., additional, Hoo, R., additional, Lam, K., additional, Xu, A., additional, Subramanian, P., additional, Karshovska, E., additional, Megens, R., additional, Akhtar, S., additional, Heyll, K., additional, Jansen, Y., additional, Weber, C., additional, Schober, A., additional, Zafeiriou, M., additional, Noack, C., additional, Renger, A., additional, Dietz, R., additional, Zelarayan, L., additional, Bergmann, M., 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additional, Yiginer, O., additional, Bas, S., additional, Ipcioglu, O., additional, Ozmen, N., additional, Aparci, M., additional, Cingozbay, B., additional, Ivanes, F., additional, Hillaert, M., additional, Susen, S., additional, Mouquet, F., additional, Doevendans, P., additional, Jude, B., additional, Montalescot, G., additional, Van Belle, E., additional, Castellani, C., additional, Angelini, A., additional, De Boer, O., additional, Van Der Loos, C., additional, Gerosa, G., additional, Van Der Wal, A., additional, Dumitriu, I., additional, Baruah, P., additional, Kaski, J., additional, Maytham, O., additional, D Smith, J., additional, Rose, M., additional, Cappelletti, A., additional, Pessina, A., additional, Mazzavillani, M., additional, Calori, G., additional, Margonato, A., additional, Cassese, S., additional, D'anna, C., additional, Leo, A., additional, Silenzi, A., additional, Baca', M., additional, Biasucci, L., additional, Baller, D., additional, Gleichmann, U., additional, Holzinger, J., additional, Bitter, T., additional, Horstkotte, D., additional, Antonopoulos, A., additional, Miliou, A., additional, Triantafyllou, C., additional, Masson, W., additional, Siniawski, D., additional, Sorroche, P., additional, Casanas, L., additional, Scordo, W., additional, Krauss, J., additional, Cagide, A., additional, Huang, T., additional, Wiedon, A., additional, Lee, S., additional, Walker, K., additional, O'dea, K., additional, Perez Berbel, P., additional, Arrarte Esteban, V., additional, Garcia Valentin, M., additional, Sola Villalpando, M., additional, Lopez Vaquero, C., additional, Caballero, L., additional, Quintanilla Tello, M., additional, Sogorb Garri, F., additional, Duerr, G., additional, Elhafi, N., additional, Bostani, T., additional, Swieny, L., additional, Kolobara, E., additional, Welz, A., additional, Roell, W., additional, Dewald, O., additional, Kaludercic, N., additional, Takimoto, E., additional, Nagayama, T., additional, Chen, K., additional, Shih, J., additional, Kass, D., additional, Di Lisa, F., additional, Paolocci, N., additional, Vinet, L., additional, Pezet, M., additional, Briec, F., additional, Previlon, M., additional, Rouet-Benzineb, P., additional, Hivonnait, A., additional, Charpentier, F., additional, Mercadier, J., additional, Cobo, M., additional, Llano, M., additional, Montalvo, C., additional, Exposito, V., additional, Meems, L., additional, Westenbrink, B., additional, Biesmans, L., additional, Bito, V., additional, Driessen, R., additional, Huysmans, C., additional, Mourouzis, I., additional, Pantos, C., additional, Galanopoulos, G., additional, Gavra, M., additional, Perimenis, P., additional, Spanou, D., additional, Cokkinos, D., additional, Panasenko, T., additional, Partsch, S., additional, Harjung, C., additional, Bogdanova, A., additional, Mihov, D., additional, Mocharla, P., additional, Yakushev, S., additional, Vogel, J., additional, Gassmann, M., additional, Tavakoli, R., additional, Johansen, D., additional, Sanden, E., additional, Xi, C., additional, Sundset, R., additional, Ytrehus, K., additional, Bliksoen, M., additional, Rutkovskiy, A., additional, Mariero, L., additional, Vaage, I., additional, Stenslokken, K., additional, Pisarenko, O., additional, Shulzhenko, V., additional, Studneva, I., additional, Serebryakova, L., additional, Tskitishvili, O., additional, Pelogeykina, Y., additional, Timoshin, A., additional, Vanin, A., additional, Ziberna, L., additional, Lunder, M., additional, Drevensek, G., additional, Passamonti, S., additional, Gorza, L., additional, Ravara, B., additional, Scapin, C., additional, Vitadello, M., additional, Zigrino, F., additional, Gwathmey, J., additional, Del Monte, F., additional, Vilahur, G., additional, Juan-Babot, O., additional, Onate, B., additional, Casani, L., additional, Lemoine, S., additional, Calmettes, G., additional, Jaspard-Vinassa, B., additional, Duplaa, C., additional, Couffinhal, T., additional, Diolez, P., additional, Dos Santos, P., additional, Fusco, A., additional, Sorriento, D., additional, Cervero, P., additional, Feliciello, A., additional, Barnucz, E., additional, Kozichova, K., additional, Hlavackova, M., additional, Neckar, J., additional, Kolar, F., additional, Novakova, O., additional, Novak, F., additional, Barsanti, C., additional, Abraham, N., additional, Muntean, D., additional, Mirica, S., additional, Duicu, O., additional, Raducan, A., additional, Hancu, M., additional, Fira-Mladinescu, O., additional, Ordodi, V., additional, Voelkl, J., additional, Haubner, B., additional, Neely, G., additional, Moriell, C., additional, Seidl, S., additional, Pachinger, O., additional, Penninger, J., additional, and Metzler, B., additional

Published
2010
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29. Atrial arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia - is there a mechanistic link between sarcoplasmic reticulum Ca2+ leak and re-entry?

Author

Heijman, J., Wehrens, X. H. T., and Dobrev, D.

Subjects
*VENTRICULAR tachycardia, *GENETIC mutation
Abstract

An introduction is presented in which the editor discusses various studies within the issue on topics related to Catecholaminergic polymorphic ventricular tachycardia (CPVT) mutations.

Published
2013
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30. Percutaneous transluminal angioplasty of stenosed aortocoronary bypass grafts.

Author

El Gamal, M, Bonnier, H, Michels, R, Heijman, J, and Stassen, E

Abstract

During the period between October 1980 and December 1982, percutaneous transluminal angioplasty of stenosed aortocoronary bypass grafts was attempted 44 times in 31 patients who had developed disabling angina pectoris four months to seven years after coronary bypass surgery. The primary success rate was 93%. Two (4.5%) patients developed myocardial infarction related to the procedure. No emergency aortocoronary bypass surgery was required and there was no mortality. Although the primary success rate was high, the incidence of recurrence after one or more angioplasties was 50%. Despite this recurrence rate the condition of 10 of the first 16 (62%) patients was clinically improved after a mean follow up of 26 months. [ABSTRACT FROM PUBLISHER]

Published
1984
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32. 306 The diagnostic role of cardiac magnetic resonance imaging when performed as initial test in suspected non-ST elevation myocardial infarction.

Author

Cauteren, Y J M Van, Smulders, M W, Heijman, J, Gerretsen, S C, Theunissen, R A L J, Mingels, A M A, Kuijk, S M J Van, Kim, R J, Crijns, H J G M, Wildberger, J E, and Bekkers, S C A M

Subjects
MYOCARDIAL infarction diagnosis, CORONARY disease, CONFERENCES & conventions, MAGNETIC resonance imaging, DIAGNOSIS
Published
2019
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33. Ziekenhuisopname verhoogt Kosten voor Infliximab bij Crohn

Author

Smits, S. R. J. G., Heijman, J. A., Rutten, W. J. M. J., Dullemen, H. M., Brouwers, J. R. B. J., Maarten Postma, and Center for Liver, Digestive and Metabolic Diseases

Subjects
musculoskeletal diseases, pharmacy, corticosteroid, budesonide, loperamide, drug cost, betamethasone sodium phosphate, protein concentrate plus carbohydrates plus lipids plus minerals plus vitamins, salazosulfapyridine, methotrexate, metronidazole, immune system diseases, ciprofloxacin, cost benefit analysis, controlled study, human, skin and connective tissue diseases, health care economics and organizations, clinical article, azathioprine, article, Crohn disease, health care cost, immunosuppressive agent, drug indication, stomatognathic diseases, hospital admission, hospital pharmacy, mesalazine, prednisone, infliximab, drug utilization, hospitalization
Abstract

This paper presents a cost analysis of the utilisation of infliximab for the treatment of Crohn's disease. The indication for infliximab for Dutch Crohn patients is an active disease with insufficient improvement on adequate therapy with corticosteroids and/or immunosuppressive therapy. We compared direct health-care costs (hospital and community pharmacy) before and after first infliximab treatment for 21 Crohn patients in the University Hospital Groningen who started infliximab during 1 January 2000 to 15 march 2001. Our study design was observational and patients served as their own controls with similar periods before and after infliximab per patient considered (minimally 3 months before and 3 months after infliximab). Drug costs for infliximab (including administration) were estimated at € 5800,- per patient-year. Excluding infliximab costs, costs per patient-year were € 6400,- and € 8600,-before and after first infliximab treatment, respectively. In both periods, the majority of the other costs was related to hospitalization. Also, drug costs in the community pharmacy were estimated to contribute relevant shares. Other researchers have found decreases in medical costs after the start of infliximab treatment. We found the opposite development. More experience and routine with infliximab treatment may lower costs in the future.

34. Toepassing van infliximab bij patiënten met de ziekte van Crohn; ervaringen bij 132 patiënten

Author

Smits, S. R. J. G., Heijman, J. A., Dullemen, H. M., Rutten, W. J. M. J., Annemans, L., Brouwers, J. R. B. J., Maarten Postma, Methods in Medicines evaluation & Outcomes research, and Center for Liver, Digestive and Metabolic Diseases

Subjects
Crohn Disease, Gastrointestinal Agents, Cost-Benefit Analysis, Prescription Fees, Antibodies, Monoclonal, Humans, Netherlands

38. ESC working group on cardiac cellular electrophysiology position paper: relevance, opportunities, and limitations of experimental models for cardiac electrophysiology research

Author

Dierk Thomas, Milan Stengl, Dobromir Dobrev, Matteo E. Mangoni, Jordi Heijman, Carol Ann Remme, Larissa Fabritz, Katja E. Odening, Godfrey L. Smith, Cristina E. Molina, Leonardo Sacconi, A.M. Gomez, Antonio Zaza, Frank R. Heinzel, Cardiologie, RS: Carim - H01 Clinical atrial fibrillation, RS: Carim - H04 Arrhythmogenesis and cardiogenetics, Cardiology, ACS - Heart failure & arrhythmias, APH - Methodology, University of Bern, Odening, K, Gomez, A, Dobrev, D, Fabritz, L, Heinzel, F, Mangoni, M, Molina, C, Sacconi, L, Smith, G, Stengl, M, Thomas, D, Zaza, A, Remme, C, and Heijman, J

Subjects
0301 basic medicine, TORSADE-DE-POINTES, Cardiac electrophysiology, Medizin, Cardiomyopathy, Arrhythmias, 030204 cardiovascular system & hematology, 0302 clinical medicine, BIO/09 - FISIOLOGIA, Mechanisms, Position paper, Induced pluripotent stem cell, LEFT-VENTRICULAR WALL, SINOATRIAL NODE, Atrial fibrillation, Animal models, 3. Good health, PRESERVED EJECTION FRACTION, Ion channels, cardiovascular system, HEART-FAILURE, Mechanism, Ion channel, Electrophysiologic Techniques, Cardiac, Cardiology and Cardiovascular Medicine, Experimental models, PLURIPOTENT STEM-CELLS, Arrhythmia, Myocarditis, Cellular electrophysiology, LONG-QT SYNDROME, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), SINUS NODE DYSFUNCTION, medicine, Animals, Humans, Animal model, Experimental model, business.industry, TRANSGENIC RABBIT MODEL, Cardiac arrhythmia, Models, Theoretical, medicine.disease, Electrophysiological Phenomena, 030104 developmental biology, Heart failure, ATRIAL-FIBRILLATION, business, Neuroscience
Abstract

Cardiac arrhythmias are a major cause of death and disability. A large number of experimental cell and animal models have been developed to study arrhythmogenic diseases. These models have provided important insights into the underlying arrhythmia mechanisms and translational options for their therapeutic management. This position paper from the ESC Working Group on Cardiac Cellular Electrophysiology provides an overview of (i) currently available in vitro, ex vivo, and in vivo electrophysiological research methodologies, (ii) the most commonly used experimental (cellular and animal) models for cardiac arrhythmias including relevant species differences, (iii) the use of human cardiac tissue, induced pluripotent stem cell (hiPSC)-derived and in silico models to study cardiac arrhythmias, and (iv) the availability, relevance, limitations, and opportunities of these cellular and animal models to recapitulate specific acquired and inherited arrhythmogenic diseases, including atrial fibrillation, heart failure, cardiomyopathy, myocarditis, sinus node, and conduction disorders and channelopathies. By promoting a better understanding of these models and their limitations, this position paper aims to improve the quality of basic research in cardiac electrophysiology, with the ultimate goal to facilitate the clinical translation and application of basic electrophysiological research findings on arrhythmia mechanisms and therapies.

Published
2021

39. Repolarization instability and arrhythmia by IKr block in single human-induced pluripotent stem cell-derived cardiomyocytes and 2D monolayers

Author

Antonio Zaza, Paul G.A. Volders, Roel L.H.M.G. Spätjens, Cristina Altrocchi, Tessa de Korte, Joyce Bernardi, Jordi Heijman, Stefan R. Braam, Cardiologie, RS: Carim - H04 Arrhythmogenesis and cardiogenetics, RS: Carim - H01 Clinical atrial fibrillation, MUMC+: MA Med Staf Spec Cardiologie (9), Altrocchi, C, de Korte, T, Bernardi, J, Spatjens, R, Braam, S, Heijman, J, Zaza, A, and Volders, P

Subjects
CURRENTS, Induced Pluripotent Stem Cells, Action Potentials, Dofetilide, 030204 cardiovascular system & hematology, Multi-electrode array, CALCIUM, Afterdepolarization, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Basic Science, Physiology (medical), medicine, Human-induced pluripotent stem cell-derived cardiomyocyte, Repolarization, Humans, Myocytes, Cardiac, AcademicSubjects/MED00200, Calcium handling, Induced pluripotent stem cell, Arrhythmia inducibility, Multi-electrode arrays, Ion channel, SODIUM CURRENT, health care economics and organizations, 030304 developmental biology, Human-induced pluripotent stem cell-derived cardiomyocytes, 0303 health sciences, business.industry, Cardiac arrhythmia, Arrhythmias, Cardiac, Electrophysiological Phenomena, Electrophysiology, chemistry, Biophysics, Cardiology and Cardiovascular Medicine, Caffeine, business, Beat-to-beat variability of repolarization, medicine.drug
Abstract

Aims Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have proven valuable for studies in drug discovery and safety, although limitations regarding their structural and electrophysiological characteristics persist. In this study, we investigated the electrophysiological properties of Pluricyte® CMs, a commercially available hiPSC-CMs line with a ventricular phenotype, and assessed arrhythmia incidence by IKr block at the single-cell and 2D monolayer level. Methods and results Action potentials were measured at different pacing frequencies, using dynamic clamp. Through voltage-clamp experiments, we determined the properties of INa, IKr, and ICaL. Intracellular Ca2+ measurements included Ca2+-transients at baseline and during caffeine perfusion. Effects of IKr block were assessed in single hiPSC-CMs and 2D monolayers (multi-electrode arrays). Action-potential duration (APD) and its rate dependence in Pluricyte® CMs were comparable to those reported for native human CMs. INa, IKr, and ICaL revealed amplitudes, kinetics, and voltage dependence of activation/inactivation similar to other hiPSC-CM lines and, to some extent, to native CMs. Near-physiological Ca2+-induced Ca2+ release, response to caffeine and excitation–contraction coupling gain characterized the cellular Ca2+-handling. Dofetilide prolonged the APD and field-potential duration, and induced early afterdepolarizations. Beat-to-beat variability of repolarization duration increased significantly before the first arrhythmic events in single Pluricyte® CMs and 2D monolayers, and predicted pending arrhythmias better than action-potential prolongation. Conclusion Taking their ion-current characteristics and Ca2+ handling into account, Pluricyte® CMs are suitable for in vitro studies on action potentials and field potentials. Beat-to-beat variability of repolarization duration proved useful to evaluate the dynamics of repolarization instability and demonstrated its significance as proarrhythmic marker in hiPSC-CMs during IKr block.

Published
2019

40. Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis

Author

Ronald L. Westra, Daniel M. Johnson, Ralf Peeters, Jordi Heijman, Paul G.A. Volders, Yoram Rudy, Antonio Zaza, RS: CARIM School for Cardiovascular Diseases, Promovendi CD, Carim, Cardiologie, Heijman, J, Zaza, A, Johnson, D, Rudy, Y, Peeters, R, Volders, P, and Westra, R

Subjects
Cardiac function curve, QH301-705.5, Heart Ventricles, Medizin, Biophysics, Action Potentials, Stimulation, Gating, 030204 cardiovascular system & hematology, Arrhythmias, Cardiovascular, Ion Channels, Toxicology, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Dogs, BIO/09 - FISIOLOGIA, Heart Conduction System, Heart Rate, Genetics, medicine, Myocyte, Repolarization, Animals, Computer Simulation, Myocytes, Cardiac, Biology (General), Molecular Biology, Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Proarrhythmia, 0303 health sciences, action potential stability, beat-to-beat variability, modeling, Ecology, Chemistry, Models, Cardiovascular, Computational Biology, medicine.disease, Cardiovascular physiology, Electrophysiology, Computational Theory and Mathematics, Modeling and Simulation, Linear Models, Medicine, Research Article
Abstract

Beat-to-beat variability of repolarization duration (BVR) is an intrinsic characteristic of cardiac function and a better marker of proarrhythmia than repolarization prolongation alone. The ionic mechanisms underlying baseline BVR in physiological conditions, its rate dependence, and the factors contributing to increased BVR in pathologies remain incompletely understood. Here, we employed computer modeling to provide novel insights into the subcellular mechanisms of BVR under physiological conditions and during simulated drug-induced repolarization prolongation, mimicking long-QT syndromes type 1, 2, and 3. We developed stochastic implementations of 13 major ionic currents and fluxes in a model of canine ventricular-myocyte electrophysiology. Combined stochastic gating of these components resulted in short- and long-term variability, consistent with experimental data from isolated canine ventricular myocytes. The model indicated that the magnitude of stochastic fluctuations is rate dependent due to the rate dependence of action-potential (AP) duration (APD). This process (the “active” component) and the intrinsic nonlinear relationship between membrane current and APD (“intrinsic component”) contribute to the rate dependence of BVR. We identified a major role in physiological BVR for stochastic gating of the persistent Na+ current (INa) and rapidly activating delayed-rectifier K+ current (IKr). Inhibition of IKr or augmentation of INa significantly increased BVR, whereas subsequent β-adrenergic receptor stimulation reduced it, similar to experimental findings in isolated myocytes. In contrast, β-adrenergic stimulation increased BVR in simulated long-QT syndrome type 1. In addition to stochastic channel gating, AP morphology, APD, and beat-to-beat variations in Ca2+ were found to modulate single-cell BVR. Cell-to-cell coupling decreased BVR and this was more pronounced when a model cell with increased BVR was coupled to a model cell with normal BVR. In conclusion, our results provide new insights into the ionic mechanisms underlying BVR and suggest that BVR reflects multiple potentially proarrhythmic parameters, including increased ion-channel stochasticity, prolonged APD, and abnormal Ca2+ handling., Author Summary Every heartbeat has an electrical recovery (repolarization) interval that varies in duration from beat to beat. Excessive beat-to-beat variability of repolarization duration has been shown to be a risk marker of potentially fatal heart-rhythm disorders, but the contributing subcellular mechanisms remain incompletely understood. Computational models have greatly enhanced our understanding of several basic electrophysiological mechanisms. We developed a detailed computer model of the ventricular myocyte that can simulate beat-to-beat changes in repolarization duration by taking into account stochastic changes in the opening and closing of individual ion channels responsible for all main ion currents. The model accurately reproduced experimental data from isolated myocytes under both physiological and pathological conditions. Using the model, we identified several mechanisms contributing to repolarization variability, including stochastic gating of ion channels, duration and morphology of the repolarization phase, and intracellular calcium handling, thereby providing insights into its basis as a proarrhythmic marker. Our computer model provides a detailed framework to study the dynamics of cardiac electrophysiology and arrhythmias.

Published
2013

41. Impaired Intracellular Calcium Buffering Contributes to the Arrhythmogenic Substrate in Atrial Myocytes From Patients With Atrial Fibrillation.

Author

Fakuade FE, Hubricht D, Möller V, Sobitov I, Liutkute A, Döring Y, Seibertz F, Gerloff M, Pronto JRD, Haghighi F, Brandenburg S, Alhussini K, Ignatyeva N, Bonhoff Y, Kestel S, El-Essawi A, Jebran AF, Großmann M, Danner BC, Baraki H, Schmidt C, Sossalla S, Kutschka I, Bening C, Maack C, Linke WA, Heijman J, Lehnart SE, Kensah G, Ebert A, Mason FE, and Voigt N

Subjects
Humans, Animals, Mice, Male, Induced Pluripotent Stem Cells metabolism, Female, Calcium Signaling, Middle Aged, Aged, Action Potentials, Atrial Fibrillation metabolism, Atrial Fibrillation pathology, Atrial Fibrillation physiopathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Calcium metabolism, Heart Atria metabolism, Heart Atria pathology
Abstract

Background: Alterations in the buffering of intracellular Ca 2+ , for which myofilament proteins play a key role, have been shown to promote cardiac arrhythmia. It is interesting that although studies report atrial myofibrillar degradation in patients with persistent atrial fibrillation (persAF), the intracellular Ca 2+ buffering profile in persAF remains obscure. Therefore, we aimed to investigate the intracellular buffering of Ca 2+ and its potential arrhythmogenic role in persAF., Methods: Transmembrane Ca 2+ fluxes (patch-clamp) and intracellular Ca 2+ signaling (fluo-3-acetoxymethyl ester) were recorded simultaneously in myocytes from right atrial biopsies of sinus rhythm (Ctrl) and patients with persAF, alongside human atrial subtype induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). Protein levels were quantified by immunoblotting of human atrial tissue and induced pluripotent stem cell-derived cardiac myocytes. Mouse whole heart and atrial electrophysiology were measured on a Langendorff system., Results: Cytosolic Ca 2+ buffering was decreased in atrial myocytes of patients with persAF because of a depleted amount of Ca 2+ buffers. In agreement, protein levels of selected Ca 2+ binding myofilament proteins, including cTnC (cardiac troponin C), a major cytosolic Ca 2+ buffer, were significantly lower in patients with persAF. Small interfering RNA (siRNA)-mediated knockdown of cTnC (si-cTNC) in atrial iPSC-CM phenocopied the reduced cytosolic Ca 2+ buffering observed in persAF. Si-cTnC treated atrial iPSC-CM exhibited a higher predisposition to spontaneous Ca 2+ release events and developed action potential alternans at low stimulation frequencies. Last, indirect reduction of cytosolic Ca 2+ buffering using blebbistatin in an ex vivo mouse whole heart model increased vulnerability to tachypacing-induced atrial arrhythmia, validating the direct mechanistic link between impaired cytosolic Ca 2+ buffering and atrial arrhythmogenesis., Conclusions: Our findings suggest that loss of myofilament proteins, particularly reduced cTnC protein levels, causes diminished cytosolic Ca 2+ buffering in persAF, thereby potentiating the occurrence of spontaneous Ca 2+ release events and atrial fibrillation susceptibility. Strategies targeting intracellular buffering may represent a promising therapeutic lead in persAF management., Competing Interests: None.

Published
2024
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42. Beneficial normalization of cardiac repolarization by carnitine in transgenic SQT1 rabbit models.

Author

Bodi I, Mettke L, Michaelides K, Hornyik T, Meier S, Nimani S, Perez-Feliz S, El-Battrawy I, Bugger H, Zehender M, Brunner M, Heijman J, and Odening KE

Abstract

Aims: Short-QT-syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in HERG underlying the rapid delayed-rectifier K+ current (IKr), leading to QT-shortening, ventricular arrhythmias, and sudden cardiac death. Data on efficient pharmaco-therapy for SQT1 are scarce. In patients with primary carnitine-deficiency, acquired-SQTS has been observed and rescued by carnitine-supplementation. Here, we assessed whether carnitine exerts direct beneficial (prolonging) effects on cardiac repolarization in genetic SQTS., Methods and Results: Adult wild-type (WT) and transgenic SQT1 rabbits (HERG-N588K, gain of IKr) were used. In vivo ECGs, ex vivo monophasic action potentials (APs) in Langendorff-perfused hearts, and cellular ventricular APs and ion currents were assessed at baseline and during L-Carnitine/C16-Carnitine-perfusion. 2D computer simulations were performed to assess reentry-based VT-inducibility.L-Carnitine/C16-Carnitine prolonged QT intervals in WT and SQT1, leading to QT-normalization in SQT1. Similarly, monophasic and cellular AP duration (APD) was prolonged by L-Carnitine/C16-Carnitine in WT and SQT1. As underlying mechanisms, we identified acute effects on the main repolarizing ion currents: IKr-steady, which is pathologically increased in SQT1, was reduced by L-Carnitine/C16-Carnitine and deactivation kinetics were accelerated. Moreover, L-Carnitine/C16-Carnitine decreased IKs-steady and IK1. In silico modelling identified IKr-changes as main factor for L-Carnitine/C16-Carnitine-induced APD-prolongation. 2D-simulations revealed increased sustained reentry-based arrhythmia formation in SQT1 compared to WT, which was decreased to the WT-level when adding carnitine-induced ion current changes., Conclusion: L-Carnitine/C16-Carnitine prolong/normalize QT and whole heart/cellular APD in SQT1 rabbits. These beneficial effects are mediated by acute effects on IKr. L-Carnitine may serve as potential future QT-normalizing, anti-arrhythmic therapy in SQT1., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Published
2024
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44. Computational modeling of cardiac electrophysiology and arrhythmogenesis: toward clinical translation.

Author

Trayanova NA, Lyon A, Shade J, and Heijman J

Subjects
Humans, Animals, Computer Simulation, Translational Research, Biomedical, Myocytes, Cardiac physiology, Electrophysiological Phenomena physiology, Action Potentials physiology, Arrhythmias, Cardiac physiopathology, Models, Cardiovascular
Abstract

The complexity of cardiac electrophysiology, involving dynamic changes in numerous components across multiple spatial (from ion channel to organ) and temporal (from milliseconds to days) scales, makes an intuitive or empirical analysis of cardiac arrhythmogenesis challenging. Multiscale mechanistic computational models of cardiac electrophysiology provide precise control over individual parameters, and their reproducibility enables a thorough assessment of arrhythmia mechanisms. This review provides a comprehensive analysis of models of cardiac electrophysiology and arrhythmias, from the single cell to the organ level, and how they can be leveraged to better understand rhythm disorders in cardiac disease and to improve heart patient care. Key issues related to model development based on experimental data are discussed, and major families of human cardiomyocyte models and their applications are highlighted. An overview of organ-level computational modeling of cardiac electrophysiology and its clinical applications in personalized arrhythmia risk assessment and patient-specific therapy of atrial and ventricular arrhythmias is provided. The advancements presented here highlight how patient-specific computational models of the heart reconstructed from patient data have achieved success in predicting risk of sudden cardiac death and guiding optimal treatments of heart rhythm disorders. Finally, an outlook toward potential future advances, including the combination of mechanistic modeling and machine learning/artificial intelligence, is provided. As the field of cardiology is embarking on a journey toward precision medicine, personalized modeling of the heart is expected to become a key technology to guide pharmaceutical therapy, deployment of devices, and surgical interventions.

Published
2024
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45. Targeting the NLRP3 inflammasome signalling for the management of atrial fibrillation.

Author

Niskala A, Heijman J, Dobrev D, Jespersen T, and Saljic A

Abstract

Inflammatory signalling via the nod-like receptor (NLR) family pyrin domain-containing protein-3 (NLRP3) inflammasome has recently been implicated in the pathophysiology of atrial fibrillation (AF). However, the precise role of the NLRP3 inflammasome in various cardiac cell types is poorly understood. Targeting components or products of the inflammasome and preventing their proinflammatory consequences may constitute novel therapeutic treatment strategies for AF. In this review, we summarise the current understanding of the role of the inflammasome in AF pathogenesis. We first review the NLRP3 inflammasome pathway and inflammatory signalling in cardiomyocytes, (myo)fibroblasts and immune cells, such as neutrophils, macrophages and monocytes. Because numerous compounds targeting NLRP3 signalling are currently in preclinical development, or undergoing clinical evaluation for other indications than AF, we subsequently review known therapeutics, such as colchicine and canakinumab, targeting the NLRP3 inflammasome and evaluate their potential for treating AF., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Published
2024
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46. Digital twins for cardiac electrophysiology: state of the art and future challenges.

Author

Cluitmans MJM, Plank G, and Heijman J

Subjects
Humans, Precision Medicine trends, Precision Medicine methods, Forecasting, Electrophysiologic Techniques, Cardiac trends, Death, Sudden, Cardiac prevention & control, Computer Simulation, Arrhythmias, Cardiac therapy, Arrhythmias, Cardiac diagnosis, Arrhythmias, Cardiac physiopathology
Abstract

Cardiac arrhythmias remain a major cause of death and disability. Current antiarrhythmic therapies are effective to only a limited extent, likely in large part due to their mechanism-independent approach. Precision cardiology aims to deliver targeted therapy for an individual patient to maximize efficacy and minimize adverse effects. In-silico digital twins have emerged as a promising strategy to realize the vision of precision cardiology. While there is no uniform definition of a digital twin, it typically employs digital tools, including simulations of mechanistic computer models, based on patient-specific clinical data to understand arrhythmia mechanisms and/or make clinically relevant predictions. Digital twins have become part of routine clinical practice in the setting of interventional cardiology, where commercially available services use digital twins to non-invasively determine the severity of stenosis (computed tomography-based fractional flow reserve). Although routine clinical application has not been achieved for cardiac arrhythmia management, significant progress towards digital twins for cardiac electrophysiology has been made in recent years. At the same time, significant technical and clinical challenges remain. This article provides a short overview of the history of digital twins for cardiac electrophysiology, including recent applications for the prediction of sudden cardiac death risk and the tailoring of rhythm control in atrial fibrillation. The authors highlight the current challenges for routine clinical application and discuss how overcoming these challenges may allow digital twins to enable a significant precision medicine-based advancement in cardiac arrhythmia management., (© 2024. The Author(s).)

Published
2024
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47. The challenges of research data management in cardiovascular science: a DGK and DZHK position paper-executive summary.

Author

Steffens S, Schröder K, Krüger M, Maack C, Streckfuss-Bömeke K, Backs J, Backofen R, Baeßler B, Devaux Y, Gilsbach R, Heijman J, Knaus J, Kramann R, Linz D, Lister AL, Maatz H, Maegdefessel L, Mayr M, Meder B, Nussbeck SY, Rog-Zielinska EA, Schulz MH, Sickmann A, Yigit G, and Kohl P

Subjects
Humans, Data Management, Reproducibility of Results, Heart, Cardiovascular System, Biomedical Research
Abstract

The sharing and documentation of cardiovascular research data are essential for efficient use and reuse of data, thereby aiding scientific transparency, accelerating the progress of cardiovascular research and healthcare, and contributing to the reproducibility of research results. However, challenges remain. This position paper, written on behalf of and approved by the German Cardiac Society and German Centre for Cardiovascular Research, summarizes our current understanding of the challenges in cardiovascular research data management (RDM). These challenges include lack of time, awareness, incentives, and funding for implementing effective RDM; lack of standardization in RDM processes; a need to better identify meaningful and actionable data among the increasing volume and complexity of data being acquired; and a lack of understanding of the legal aspects of data sharing. While several tools exist to increase the degree to which data are findable, accessible, interoperable, and reusable (FAIR), more work is needed to lower the threshold for effective RDM not just in cardiovascular research but in all biomedical research, with data sharing and reuse being factored in at every stage of the scientific process. A culture of open science with FAIR research data should be fostered through education and training of early-career and established research professionals. Ultimately, FAIR RDM requires permanent, long-term effort at all levels. If outcomes can be shown to be superior and to promote better (and better value) science, modern RDM will make a positive difference to cardiovascular science and practice. The full position paper is available in the supplementary materials., (© 2023. The Author(s).)

Published
2024
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48. Is ageing a modifiable risk factor for atrial fibrillation?

Author

Heijman J and Madreiter-Sokolowski CT

Subjects
Humans, Age Factors, Risk Assessment, Risk Factors, Aged, Animals, Heart Disease Risk Factors, Prognosis, Atrial Fibrillation physiopathology, Atrial Fibrillation diagnosis, Atrial Fibrillation epidemiology, Aging
Abstract

Competing Interests: Conflict of interest: none declared.

Published
2024
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50. Effectiveness of trauma-focused art therapy (TFAT) for psychological trauma: study protocol of a multiple-baseline single-case experimental design.

Author

Heijman J, Wouters H, Schouten KA, and Haeyen S

Subjects
Humans, Psychotherapy methods, Research Design, Randomized Controlled Trials as Topic, Art Therapy, Psychological Tests, Psychological Trauma, Resilience, Psychological, Stress Disorders, Post-Traumatic therapy, Stress Disorders, Post-Traumatic psychology
Abstract

Introduction: Treatments such as eye movement desensitisation and reprocessing and (narrative) exposure therapies are commonly used in psychological trauma. In everyday practice, art therapy is also often used, although rigorous research on its efficacy is lacking. Patients seem to benefit from the indirect, non-verbal experiential approach of art therapy. This protocol paper describes a study to examine the effectiveness of a 10-week individual trauma-focused art therapy (TFAT) intervention., Methods and Analysis: A mixed-methods multiple-baseline single-case experimental design will be conducted with 25-30 participants with psychological trauma. Participants will be randomly assigned to a baseline period lasting 3-5 weeks, followed by the TFAT intervention (10 weeks) and follow-up (3 weeks). Quantitative measures will be completed weekly: the Beck Depression Inventory-II, the Mental Health Continuum Short Form, the Resilience Scale, the Rosenberg Self-Esteem Scale and the Self-expression and Emotion Regulation in Art Therapy Scale. The Post-Traumatic Stress Disorder Checklist-5 will be completed at week 1 and week 10. Qualitative instruments comprise a semistructured interview with each individual patient and therapist, and a short evaluation for the referrer. Artwork will be used to illustrate the narrative findings. Quantitative outcomes will be analysed with linear mixed models using the MultiSCED web application. Qualitative analyses will be performed using thematic analysis with ATLAS.ti., Ethics and Dissemination: This study has been approved by the ethics committee of the HAN University of Applied Sciences (ECO 394.0922). All participants will sign an informed consent form and data will be treated confidentially. Findings will be published open access in peer-reviewed journals., Trial Registration Number: NCT05593302., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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