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3. Deceleration capacity derived from a five-minute electrocardiogram predicts mortality in the general population

Author

Steger, Alexander, Barthel, Petra, Müller, Alexander, Rückert-Eheberg, Ina-Maria, Linkohr, Birgit, Allescher, Julia, Maier, Melanie, Hapfelmeier, Alexander, Martens, Eimo, Heidegger, Helene Hildegard, Müller, Arne Michael, Rizas, Konstantinos D., Kääb, Stefan, Sinner, Moritz F., Sinnecker, Daniel, Laugwitz, Karl-Ludwig, Peters, Annette, and Schmidt, Georg

Published
2024
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4. Plasma proteome association with coronary heart disease and carotid intima media thickness: results from the KORA F4 study

Author

Elhadad, Mohamed A., del C. Gómez-Alonso, Mónica, Chen, Chien-Wei, Neumeyer, Sonja, Delerue, Thomas, Rathmann, Wolfgang, Näbauer, Michael, Meisinger, Christa, Kääb, Stefan, Seissler, Jochen, Graumann, Johannes, Koenig, Wolfgang, Suhre, Karsten, Gieger, Christian, Völker, Uwe, Peters, Annette, Hammer, Elke, and Waldenberger, Melanie

Published
2024
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5. Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.

Author

Weinstock, Joshua, Gopakumar, Jayakrishnan, Burugula, Bala, Uddin, Md, Jahn, Nikolaus, Belk, Julia, Bouzid, Hind, Daniel, Bence, Miao, Zhuang, Ly, Nghi, Mack, Taralynn, Luna, Sofia, Prothro, Katherine, Mitchell, Shaneice, Laurie, Cecelia, Broome, Jai, Taylor, Kent, Guo, Xiuqing, Sinner, Moritz, von Falkenhausen, Aenne, Kääb, Stefan, Shuldiner, Alan, OConnell, Jeffrey, Lewis, Joshua, Boerwinkle, Eric, Barnes, Kathleen, Chami, Nathalie, Kenny, Eimear, Loos, Ruth, Fornage, Myriam, Hou, Lifang, Lloyd-Jones, Donald, Redline, Susan, Cade, Brian, Psaty, Bruce, Bis, Joshua, Brody, Jennifer, Silverman, Edwin, Yun, Jeong, Qiao, Dandi, Palmer, Nicholette, Freedman, Barry, Bowden, Donald, Cho, Michael, DeMeo, Dawn, Vasan, Ramachandran, Yanek, Lisa, Becker, Lewis, Kardia, Sharon, Peyser, Patricia, He, Jiang, Rienstra, Michiel, Van der Harst, Pim, Kaplan, Robert, Heckbert, Susan, Smith, Nicholas, Wiggins, Kerri, Arnett, Donna, Irvin, Marguerite, Tiwari, Hemant, Cutler, Michael, Knight, Stacey, Muhlestein, J, Correa, Adolfo, Raffield, Laura, Gao, Yan, de Andrade, Mariza, Rotter, Jerome, Rich, Stephen, Tracy, Russell, Konkle, Barbara, Johnsen, Jill, Wheeler, Marsha, Smith, J, Melander, Olle, Nilsson, Peter, Custer, Brian, Duggirala, Ravindranath, Curran, Joanne, Blangero, John, McGarvey, Stephen, Williams, L, Xiao, Shujie, Yang, Mao, Gu, C, Chen, Yii-Der, Lee, Wen-Jane, Kane, John, Pullinger, Clive, Shoemaker, M, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Zhou, Ying, Manson, JoAnn, Desai, Pinkal, Johnson, Andrew, Mathias, Rasika, and Blackwell, Thomas

Subjects
Animals, Humans, Mice, Alleles, Clonal Hematopoiesis, Genome-Wide Association Study, Hematopoiesis, Hematopoietic Stem Cells, Mutation, Promoter Regions, Genetic
Abstract

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

Published
2023

6. Inappropriate Therapy and Shock Rates Between the Subcutaneous and Transvenous Implantable Cardiac Defibrillator: A Secondary Analysis of the PRAETORIAN Trial

Author

Olde Nordkamp, Louise R.A., Pepplinkhuizen, Shari, Ghani, Abdul, Boersma, Lucas V.A., Kuschyk, Juergen, El-Chami, Mikhael F., Behr, Elijah R., Brouwer, Tom F., Kääb, Stefan, Mittal, Suneet, Quast, Anne-Floor B.E., van der Stuijt, Willeke, Smeding, Lonneke, de Veld, Jolien A., Tijssen, Jan G.P., Bijsterveld, Nick R., Richter, Sergio, Brouwer, Marc A., de Groot, Joris R., Kooiman, Kirsten M., Lambiase, Pier D., Neuzil, Petr, Vernooy, Kevin, Alings, Marco, Betts, Timothy R., Bracke, Frank A.L.E., Burke, Martin C., de Jong, Jonas S.S.G., Wright, David J., Jansen, Ward P.J., Whinnett, Zachary I., Nordbeck, Peter, Knaut, Michael, Philbert, Berit T., van Opstal, Jurren M., Chicos, Alexandru B., Allaart, Cornelis P., Borger van der Burg, Alida E., Dizon, Jose M., Miller, Marc A., Nemirovsky, Dmitry, Surber, Ralf, Upadhyay, Gaurav A., Weiss, Raul, de Weger, Anouk, Wilde, Arthur A.M., and Knops, Reinoud E.

Published
2024
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7. EYE-ECG: An RCT of the influence of student characteristics and expert eye-tracking videos with cued retrospective reporting on students’ ECG interpretation skills

Author

Scherff, Aline D., Kääb, Stefan, Fischer, Martin R., and Berndt, Markus

Subjects
eye-tracking, learning, electrocardiography, students, medical, clinical reasoning, diagnosis, Special aspects of education, LC8-6691, Medicine
Abstract

Objectives: Teaching of ECG interpretation frequently relies on visual schemas. However, subsequent student ECG interpretation skills are often poor. Expertise research shows that expert looking patterns frequently deviate from the steps taught in schema learning. The present study made a cardiology expert’s gaze interpreting ECGs visible – through eye-tracking videos with cued retrospective reporting (CRR) – and investigated the potential as an additional expert-driven route to improve medical students’ ECG interpretation skills.Methods: =91 Medical students participated in the RCT of an ECG e-learning session aimed at medical students’ ECG interpretation skills gain, either receiving the newly developed eye-tracking video with CRR audio commentary materials (=47) or studying via four clinical cases only (=44). Three outcome scores relating to different aspects of ECG interpretation skills were derived from pre-post MCQ ECG tests. The effect of the EYE-ECG training and additional characteristics (e.g., prior experience, interest) on student ECG interpretation skills were evaluated using t-tests and multivariate linear regression.Results: A small, non-significant advantage of the EYE-ECG training signifying a tendency for greater knowledge gain was observed, compared to training as usual. In multivariate regression models, the predictive value of clinical case 1 was an unexpected finding warranting further exploration.Conclusion: Additional gains after an only 9-minute intervention using videos of expert’s real-time gaze pattern in combination with hearing their thought processes during ECG interpretation is a promising finding. Furthermore, a number of specific performance characteristics enabling students to best benefit from ECG training were identified and possible modifications to the learning intervention suggested.

Published
2024
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9. The DZHK research platform: maximisation of scientific value by enabling access to health data and biological samples collected in cardiovascular clinical studies

Author

Hoffmann, Julia, Hanß, Sabine, Kraus, Monika, Schaller, Jens, Schäfer, Christian, Stahl, Dana, Anker, Stefan D., Anton, Gabriele, Bahls, Thomas, Blankenberg, Stefan, Blumentritt, Arne, Boldt, Leif-Hendrik, Cordes, Steffen, Desch, Steffen, Doehner, Wolfram, Dörr, Marcus, Edelmann, Frank, Eitel, Ingo, Endres, Matthias, Engelhardt, Stefan, Erdmann, Jeanette, Eulenburg, Katharina, Falk, Volkmar, Felix, Stephan B., Frank, Derk, Franke, Thomas, Frey, Norbert, Friede, Tim, Geidel, Lars, Germans, Lisa, Grabmaier, Ulrich, Halle, Martin, Hausleiter, Jörg, Jakobi, Vera, Jebran, Ahmad-Fawad, Jobs, Alexander, Kääb, Stefan, Karakas, Mahir, Katus, Hugo A., Klatt, Alexandra, Knosalla, Christoph, Krebser, Joachim, Landmesser, Ulf, Lee, Mahsa, Lehnert, Kristin, Lesser, Stephanie, Leyh, Katrin, Lorbeer, Roberto, Mach-Kolb, Stephanie, Meder, Benjamin, Nagel, Eike, Nolte, Christian H., Parwani, Abdul S., Petersmann, Astrid, Puls, Miriam, Rau, Henriette, Reiser, Maximilian, Rienhoff, Otto, Scharfe, Tabea, Schattschneider, Mario, Scheel, Heiko, Schnabel, Renate B., Schuster, Andreas, Schmitt, Boris, Seidler, Tim, Seiffert, Moritz, Stähli, Barbara-Elisabeth, Stas, Adriane, J. Stocker, Thomas, von Stülpnagel, Lukas, Thiele, Holger, Wachter, Rolf, Wakili, Reza, Weis, Tanja, Weitmann, Kerstin, Wichmann, Heinz-Erich, Wild, Philipp, Zeller, Tanja, Hoffmann, Wolfgang, Zeisberg, Elisabeth Maria, Zimmermann, Wolfram-Hubertus, Krefting, Dagmar, Kühne, Titus, Peters, Annette, Hasenfuß, Gerd, Massberg, Steffen, Sommer, Thomas, Dimmeler, Stefanie, Eschenhagen, Thomas, and Nauck, Matthias

Published
2023
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10. Contrast enhanced transesophageal echocardiography in patients with atrial fibrillation referred to electrical cardioversion improves atrial thrombus detection and may reduce associated thromboembolic events

Author

Jung Philip H, Mueller Marisa, Schuhmann Christoph, Eickhoff Madeleine, Schneider Philip, Seemueller Gueler, Dutton Raphael, Rieber Johannes, Kääb Stefan, and Sohn Hae-Young

Subjects
Atrial fibrillation, Atrial thrombus, Contrast echocardiography, Transesophageal echocardiography, Cardioversion, Thromboembolic events, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Aims Transesophageal echocardiography (TEE) is the gold standard for the detection of thrombi in patients with atrial fibrillation (AF) before undergoing early electrical cardioversion (CV). However, TEE generates inconclusive results in a considerable number of patients. This study investigated the influence of contrast enhancement on interpretability of TEE for the detection of left atrial (LA) thrombi compared to conventional TEE and assessed, whether there are differences in the rate of thromboembolic events after electrical cardioversion. Methods Of 180 patients with AF (51 females, 65.2±13 years) who were referred to CV, 90 were examined with native imaging and contrast enhancement within the same examination (group 1), and 90 were examined with native TEE alone and served as control (group 2). Cineloops of the multiplane examination of the LA and LA appendage (LAA) were stored digitally before and, in group 1, after intravenous bolus application of a transpulmonary contrast agent. Images of group 1 were assessed offline and the diagnosis of LA thrombi was made semi-quantitatively: 1= thrombus present; 2=inconclusive result; 3=no thrombus. The presence of spontaneous echocontrast (SEC) was registered and flow velocity in the LA appendage (LAA-flow) was measured. All patients in whom CV was performed were followed up for 1 year or until relapse of AF. CV related adverse events were defined as any thromboembolic event within 1 week after CV. Results No serious adverse events occurred during TEE and contrast enhanced imaging. In group 1 atrial thrombi were diagnosed in 14 (15.6%) during native and in 10 (11.1%) patients during contrast enhanced imaging (p Conclusion In patients with AF planned for CV contrast enhancement renders TEE images more interpretable, facilitates the exclusion of atrial thrombi and may reduce the rate of embolic adverse events.

Published
2013
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11. Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features

Author

Hopfner Franziska, Schormair Barbara, Knauf Franziska, Berthele Achim, Tölle Thomas R, Baron Ralf, Maier Christoph, Treede Rolf-Detlef, Binder Andreas, Sommer Claudia, Maihöfner Christian, Kunz Wolfram, Zimprich Friedrich, Heemann Uwe, Pfeufer Arne, Näbauer Michael, Kääb Stefan, Nowak Barbara, Gieger Christian, Lichtner Peter, Trenkwalder Claudia, Oexle Konrad, and Winkelmann Juliane

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features. Methods In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons. Results A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA). Conclusions Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features.

Published
2011
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12. Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial

Author

Kopczak, Anna, Stringer, Michael S., van den Brink, Hilde, Kerkhofs, Danielle, Blair, Gordon W., van Dinther, Maud, Arteaga Reyes, Carmen, Jaime Garcia, Daniela, Onkenhout, Laurien, Wartolowska, Karolina A., Thrippleton, Michael J., Kampaite, Agniete, Duering, Marco, Staals, Julie, Lesnik-Oberstein, Saskia, Muir, Keith, Middeke, Martin, Norrving, Bo, Bousser, Marie-Germaine, Mansmann, Ulrich, Rothwell, Peter M., Doubal, Fergus N., van Oostenbrugge, Robert, Biessels, Geert Jan, Webb, Alastair J.S., Wardlaw, Joanna, Dichgans, Martin, André, Elisabeth, Kääb, Stefan, Anders, Hans-Joachim, Hack, Remco, Kaffe, Maria, Dewenter, Anna, Malik, Rainer, Stringer, Michael S, Blair, Gordon W, Reyes, Carmen Arteaga, Garcia, Daniela Jaime, Wartolowska, Karolina A, Thrippleton, Michael J, Muir, Keith W, Rothwell, Peter M, Doubal, Fergus N, Webb, Alastair J S, and Wardlaw, Joanna M

Published
2023
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13. Intensive heart rhythm monitoring to decrease ischemic stroke and systemic embolism—the Find-AF 2 study—rationale and design

Author

Wachter, Rolf, Gröschel, Klaus, Wasser, Katrin, Uhe, Tobias, Schäbitz, Wolf-Rüdiger, Köhrmann, Martin, Dichgans, Martin, Gröschel, Sonja, Uphaus, Timo, Hahn, Marianne, Zuhorn, Frederic, Wulff, Leonard, Plümer, Jorge, Kok, Lena, Janz, Marcel, Kitsiou, Alkisti, Gehmeyr, Julian, Dabbagh, Alhuda, Huber, Charlotte, Pelz, Johann, Wartenberg, Katja, Michalski, Dominik, Seidel, Mirko, Flissakowski, Oscar, Goschenhofer, Anna, Hussain, Rabia-Basari, Kim, Ina, Kinze, Stephan, Kroneberger, Christian, Lingnau, Michale, Lischewski, Dennis, Muhn, Florian, Rogge, Witold, Schieffer, Miriam, Setayesh-Roonizi, Anuscheh, Sparenberg, Paul, Schertel, Jill Marie, Ringleb, Peter, Purrucker, Jan, Berberich, Anne, Heyse, Miriam, Ungerer, Matthias, Bauer, Gregor, Reichardt, Christine, Etgen, Thorleif, Ebel, Bernhard, Milanković-Eberl, Dragana, Schwarte, Olav, Höcherl, Constanze, Asch, Eric-Manuel, Bojtschuk, Luisa, Frey, Maximilian, Dlouhy, Tomas, Ertl, Michael, Zickler, Philipp Patrick, Beier, Barbara, Braadt, Lino-Dominic, Gabrielyan, Inessa, Kermer, Pawel, Kaste, Matthias, Anter, Ahmed, Stirbulescu, Corina, Meleshchenco, Nataliia, Burgholte, Friederike, Lüers, Claus, Steiner, Thorsten, Cierpinski, Mari-Carmen, Lichti, Bethke, Florian, Bonowski, Lars, Eid, Hassan Abou, Vajda-Medina, Esteban, Probst, Mareike, Essa, Hisham, Frank, Benedikt, Stolte, Benjamin, Milles, Lennart, Soda, Hassan, Hiermann, Erich, Rascher, Renate Weinhardt Alexandra, Stan, Marius, Kääb, Stefan, Kellert, Lars, Dimitriadis, Konstantinos, Kopczak, Anna, Küster, Bettina, Sinner, Moritz, Steiger, Ignaz, Kaffe, Maria, Clauß, Sebastian, Janowitz, Daniel, Thaler, Raffael, Schellinger, Peter, Glahn, Jörg, Schubert, Jan, Jenniges, Simone, Markmann-Boenke, Silke, Putzer, Anne-Sophie, Straeten, Michael Schwarze Vera, Wiemer, Marcus, Kallmünzer, Bernd, Macha, Kosmas, Haupenthal, David, Balk, Stefanie, Kossel, Clara-Sophie, Häusler, Georg, Lehrieder, Dominik, Cidlinsky, Peter, Hametner, Christian, Vogl, Christine, Fischer, Thomas, Huttelmaier, Moritz, Nordbeck, Octavian Maniuc Peter, von Hardenberg, Albrecht, Jünemann, Martin, Braun, Tobias, Viard, Maxime, Gerner, Stefan, Omar, AlHaj, Genau, Sonja, Olbricht, Linus, Wassenberg, Matthias, Langguth, Niklas, Fräbel, Christian, Baumgart, Romy, Kalra, Love-Preet, Diel, Norma, Hoffmann, Frank, Kraft, Andrea, Schönmuth, Bettine, Giebler, Anja, Weber, Lorenz, Grond, Martin, Birringer, Jan, Lichte-Schneider, Sandra, Hütwohl, Daniela, Krause, Lars Udo, Petersen, Martina, Althaus, Katharina, Kirchmeier, Konstantin, Novikova, Liubov, Müller, Susanne, Schellong, Sebastian, Brudzinski, Mirko, Gerk, Ulrich, Palisch, Holger, Heinzel, Frank R., Fett, Jana, Suntha, Avinash, Burian, Katja, Schmitz, Bettina, Gutwinski, Anna, Angermüller, Veronika, Alhammoud, Tameem, Cakiroglu, Hüsniye, Bach, Ullrich, Nabavi, Darius, Offermann, Jens, Crome, Olaf, Dimitrijeski, Boris, Meincke, Carsten, Hamann, Gerhard, Alber, Burkhard, Müller, Robert, Pallesen, Lars-Peder, Pütz, Volker, Hartmann, Christian, Berrouschot, Jörg, Stoll, Anett, Keilitz, Janina, Klunk, Dietrich, Voigt, Roman, Kastrup, Andreas, Schröter, Andreas, Schmucker, Johannes, Pfeilschifter, Waltraud, Krämer, Christoffer, Wiemers, Milena, Simon, Micha, Finke, Alexander, Weiß, Christian, Hobohm, Carsten, Naupold, Katrin, Bley-Renning, Karen, Winter, Sabrina, Poli, Sven, Mengel, Annerose, Poli, Khouloud, Expósito, Alexandra Gómez, Mbroh, Joshua, Tieck, Maria, Rosenkranz, Michael, Boskamp, Stefan, Ritter, Nicolas, Seibel, Lena, Schöps, Christian, Ketzler, Rebecca, Nägele, Herbert, Sydow, Karsten, Kurka, Natalia, Schäfer, Jan Hendrik, Charisse, Daniel, Gruber, Katharina, Kohlhase, Konstantin, Lieschke, Franziska, Operhalski, Felix, Seiler, Alexander, Petzold, Gabor, Bode, Felix Jürgen, Stösser, Sebastian, Meißner, Julius, Ebrahimi, Taraneh, Nordsiek, Julia, Beckonert, Niklas, Weissenborn, Karin, Große, Gerrit Maximilian, Worthmann, Hans, Hennemann, Ann-Katrin, Jochmann, Svenja, Gründahl, Julius, Al-Ayoubi, Jana, Ernst, Johanna, Bähr, Oliver, Gruber, Herbert, Benesch, Sonka, Pollinger, Thomas, Alachkar, Nawar, Busch, Sonia, Butz, Steffi, Forkmann, Mathias, Mahnkopf, Christian, Mischke, Thomas, Schnupp, Steffen, Thomalla, Götz, Deb-Chatterji, Milani, Cheng, Bastian, Gelderblom, Mathias, Hoppe, Julia, Jensen, Märit, Schell, Maximilian, Schlemm, Eckhard, Marquardt, Lars, Kazarians, Haiko, Rheingans, Pia Franziska, Hötzer, Kai, Rose, Dietmar, Neumann-Haefelin, Tobias, Berthel, Jörg, Alijaj, Lirim, Krug, Joachim, Niethammer, Margit, Szöllösi, Géza-Attila, Obermann, Marc, Adochitei, Nicoletta, Strik, Herwig, Lenz, Arne, Steigerwald, Frank, Müller, Jörg, Honermann, Martin, Burgstaller, Marian Christoph, Kollmar, Rainer, Rashid, Maryam, Ganai, Ahmad Ajaz, Ossendorf, Saric, Majda, Tischer, Karl-Heinz, Toluli, Adela, Wollenweber, Frank Arne, Rahban, Laya, Silva, Thais Portugal, Lee, Miri, Grosch, Matthias Julius, Minnerup, Jens, Liman, Jan, Nückel, Martin, Böhm, Magdalena, Weber-Krüger, Mark, Brachmann, Johannes, Laufs, Ulrich, Gelbrich, Götz, Petroff, David, Prettin, Christiane, Schellinger, Peter D., Hamann, Gerhard F., Mende, Meinhard, and Wagner, Marcus

Published
2023
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14. An angiopoietin 2, FGF23, and BMP10 biomarker signature differentiates atrial fibrillation from other concomitant cardiovascular conditions

Author

Chua, Winnie, Cardoso, Victor R., Guasch, Eduard, Sinner, Moritz F., Al-Taie, Christoph, Brady, Paul, Casadei, Barbara, Crijns, Harry J. G. M., Dudink, Elton A. M. P., Hatem, Stéphane N., Kääb, Stefan, Kastner, Peter, Mont, Lluis, Nehaj, Frantisek, Purmah, Yanish, Reyat, Jasmeet S., Schotten, Ulrich, Sommerfeld, Laura C., Zeemering, Stef, Ziegler, André, Gkoutos, Georgios V., Kirchhof, Paulus, and Fabritz, Larissa

Published
2023
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16. Genetic insights into resting heart rate and its role in cardiovascular disease

Author

van de Vegte, Yordi J., Eppinga, Ruben N., van der Ende, M. Yldau, Hagemeijer, Yanick P., Mahendran, Yuvaraj, Salfati, Elias, Smith, Albert V., Tan, Vanessa Y., Arking, Dan E., Ntalla, Ioanna, Appel, Emil V., Schurmann, Claudia, Brody, Jennifer A., Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian’an, Hwang, Shih-Jen, Mononen, Nina, Auro, Kirsi, Jackson, Anne U., Bielak, Lawrence F., Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Müller-Nurasyid, Martina, Roselli, Carolina, Zhang, Weihua, Kleber, Marcus E., Guo, Xiuqing, Lin, Henry J., Pavani, Francesca, Galesloot, Tessel E., Noordam, Raymond, Milaneschi, Yuri, Schraut, Katharina E., den Hoed, Marcel, Degenhardt, Frauke, Trompet, Stella, van den Berg, Marten E., Pistis, Giorgio, Tham, Yih-Chung, Weiss, Stefan, Sim, Xueling S., Li, Hengtong L., van der Most, Peter J., Nolte, Ilja M., Lyytikäinen, Leo-Pekka, Said, M. Abdullah, Witte, Daniel R., Iribarren, Carlos, Launer, Lenore, Ring, Susan M., de Vries, Paul S., Sever, Peter, Linneberg, Allan, Bottinger, Erwin P., Padmanabhan, Sandosh, Psaty, Bruce M., Sotoodehnia, Nona, Kolcic, Ivana, Arnar, David O., Gudbjartsson, Daniel F., Holm, Hilma, Balkau, Beverley, Silva, Claudia T., Newton-Cheh, Christopher H., Nikus, Kjell, Salo, Perttu, Mohlke, Karen L., Peyser, Patricia A., Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari, Rao, Dabeeru C., Cornelis, Marilyn C., Faul, Jessica D., Smith, Jennifer A., Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie, Sinner, Moritz F., Strauch, Konstantin, Delgado, Graciela E., Taylor, Kent D., Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renée, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre, Macfarlane, Peter W., Tarasov, Kirill V., Tan, Nicholas, Felix, Stephan B., Tai, E-Shyong, Quek, Debra Q., Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia, Morris, Andrew P., Raitakari, Olli T., Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur, Timpson, Nicholas J., Morrison, Alanna C., Munroe, Patricia B., Strachan, David P., Grarup, Niels, Loos, Ruth J. F., Heckbert, Susan R., Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif, Wareham, Nicholas J., van Duijn, Cornelia M., Feitosa, Mary F., O’Donnell, Christopher J., Kähönen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes, Porteous, David J., Eriksson, Johan G., Bouchard, Claude, Moebus, Susanne, Kraft, Peter, Weir, David R., Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kääb, Stefan, Peters, Annette, Chambers, John C., Kooner, Jaspal S., März, Winfried, Rotter, Jerome I., Hicks, Andrew A., Smith, J. Gustav, Kiemeney, Lambertus A. L. M., Mook-Kanamori, Dennis O., Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James F., Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Dörr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi, Oldehinkel, Albertine J., Riese, Harriette, Lehtimäki, Terho, Verweij, Niek, and van der Harst, Pim

Published
2023
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18. Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

Author

Weng, Lu-Chen, Hall, Amelia Weber, Choi, Seung Hoan, Jurgens, Sean J, Haessler, Jeffrey, Bihlmeyer, Nathan A, Grarup, Niels, Lin, Honghuang, Teumer, Alexander, Li-Gao, Ruifang, Yao, Jie, Guo, Xiuqing, Brody, Jennifer A, Müller-Nurasyid, Martina, Schramm, Katharina, Verweij, Niek, van den Berg, Marten E, van Setten, Jessica, Isaacs, Aaron, Ramírez, Julia, Warren, Helen R, Padmanabhan, Sandosh, Kors, Jan A, de Boer, Rudolf A, van der Meer, Peter, Sinner, Moritz F, Waldenberger, Melanie, Psaty, Bruce M, Taylor, Kent D, Völker, Uwe, Kanters, Jørgen K, Li, Man, Alonso, Alvaro, Perez, Marco V, Vaartjes, Ilonca, Bots, Michiel L, Huang, Paul L, Heckbert, Susan R, Lin, Henry J, Kornej, Jelena, Munroe, Patricia B, van Duijn, Cornelia M, Asselbergs, Folkert W, Stricker, Bruno H, van der Harst, Pim, Kääb, Stefan, Peters, Annette, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Dörr, Marcus, Felix, Stephan B, Linneberg, Allan, Hansen, Torben, Arking, Dan E, Kooperberg, Charles, Benjamin, Emelia J, Lunetta, Kathryn L, Ellinor, Patrick T, and Lubitz, Steven A

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Research, Genetics, Heart Disease, Cardiovascular, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Atrial Fibrillation, Cardiac Myosins, Connectin, Electrocardiography, Genetic Variation, Genome-Wide Association Study, Homeodomain Proteins, Humans, Myosin Heavy Chains, NAV1.8 Voltage-Gated Sodium Channel, Quantitative Trait Loci, Transcription Factors, atrial fibrillation, electrophysiology, exome, genetic, genome-wide association studies, population, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundThe P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.MethodsFifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.ResultsWe identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk.ConclusionsOur results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

Published
2020

19. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Author

Ntalla, Ioanna, Weng, Lu-Chen, Cartwright, James H, Hall, Amelia Weber, Sveinbjornsson, Gardar, Tucker, Nathan R, Choi, Seung Hoan, Chaffin, Mark D, Roselli, Carolina, Barnes, Michael R, Mifsud, Borbala, Warren, Helen R, Hayward, Caroline, Marten, Jonathan, Cranley, James J, Concas, Maria Pina, Gasparini, Paolo, Boutin, Thibaud, Kolcic, Ivana, Polasek, Ozren, Rudan, Igor, Araujo, Nathalia M, Lima-Costa, Maria Fernanda, Ribeiro, Antonio Luiz P, Souza, Renan P, Tarazona-Santos, Eduardo, Giedraitis, Vilmantas, Ingelsson, Erik, Mahajan, Anubha, Morris, Andrew P, Del Greco M, Fabiola, Foco, Luisa, Gögele, Martin, Hicks, Andrew A, Cook, James P, Lind, Lars, Lindgren, Cecilia M, Sundström, Johan, Nelson, Christopher P, Riaz, Muhammad B, Samani, Nilesh J, Sinagra, Gianfranco, Ulivi, Sheila, Kähönen, Mika, Mishra, Pashupati P, Mononen, Nina, Nikus, Kjell, Caulfield, Mark J, Dominiczak, Anna, Padmanabhan, Sandosh, Montasser, May E, O'Connell, Jeff R, Ryan, Kathleen, Shuldiner, Alan R, Aeschbacher, Stefanie, Conen, David, Risch, Lorenz, Thériault, Sébastien, Hutri-Kähönen, Nina, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Raitakari, Olli T, Barnes, Catriona LK, Campbell, Harry, Joshi, Peter K, Wilson, James F, Isaacs, Aaron, Kors, Jan A, van Duijn, Cornelia M, Huang, Paul L, Gudnason, Vilmundur, Harris, Tamara B, Launer, Lenore J, Smith, Albert V, Bottinger, Erwin P, Loos, Ruth JF, Nadkarni, Girish N, Preuss, Michael H, Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Müller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D, Rienstra, Michiel, van de Vegte, Yordi J, van der Harst, Pim, Verweij, Niek, Kääb, Stefan, Schramm, Katharina, Sinner, Moritz F, Strauch, Konstantin, Cutler, Michael J, Fatkin, Diane, London, Barry, Olesen, Morten, and Roden, Dan M

Subjects
Humans, Cardiovascular Diseases, Genetic Predisposition to Disease, Electrocardiography, Gene Expression, Multifactorial Inheritance, Quantitative Trait Loci, Female, Male, Arrhythmias, Cardiac, Genetic Variation, Genome-Wide Association Study, Genetic Loci, Endophenotypes, Arrhythmias, Cardiac
Abstract

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Published
2020

20. Single beta-blocker or combined amiodarone therapy in implantable cardioverter-defibrillator and cardiac resynchronization therapy—defibrillator patients: Insights from the German DEVICE registry

Author

Wiedmann, Felix, Ince, Hüseyin, Stellbrink, Christoph, Kleemann, Thomas, Eckardt, Lars, Brachmann, Johannes, Gonska, Bernd-Dieter, Kääb, Stefan, Perings, Christian A., Jung, Werner, Lugenbiel, Patrick, Hochadel, Matthias, Senges, Jochen, Frey, Norbert, and Schmidt, Constanze

Published
2023
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22. Atrial fibrillation in the presence and absence of heart failure enhances expression of genes involved in cardiomyocyte structure, conduction properties, fibrosis, inflammation, and endothelial dysfunction

Author

Zeemering, Stef, Isaacs, Aaron, Winters, Joris, Maesen, Bart, Bidar, Elham, Dimopoulou, Christina, Guasch, Eduard, Batlle, Montserrat, Haase, Doreen, Hatem, Stéphane N., Kara, Mansour, Kääb, Stefan, Mont, Lluis, Sinner, Moritz F., Wakili, Reza, Maessen, Jos, Crijns, Harry J.G.M., Fabritz, Larissa, Kirchhof, Paulus, Stoll, Monika, and Schotten, Ulrich

Published
2022
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23. 2022 HRS expert consensus statement on evaluation and management of arrhythmic risk in neuromuscular disorders

Author

Groh, William J., Bhakta, Deepak, Tomaselli, Gordon F., Aleong, Ryan G., Teixeira, Ricardo Alkmim, Amato, Anthony, Asirvatham, Samuel J., Cha, Yong-Mei, Corrado, Domenico, Duboc, Denis, Goldberger, Zachary D., Horie, Minoru, Hornyak, Joseph E., Jefferies, John Lynn, Kääb, Stefan, Kalman, Jonathan M., Kertesz, Naomi J., Lakdawala, Neal K., Lambiase, Pier D., Lubitz, Steven A., McMillan, Hugh J., McNally, Elizabeth M., Milone, Margherita, Namboodiri, Narayanan, Nazarian, Saman, Patton, Kristen K., Russo, Vincenzo, Sacher, Frederic, Santangeli, Pasquale, Shen, Win-Kuang, Sobral Filho, Dario C., Stambler, Bruce S., Stöllberger, Claudia, Wahbi, Karim, Wehrens, Xander H.T., Weiner, Menachem Mendel, Wheeler, Matthew T., and Zeppenfeld, Katja

Published
2022
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25. Integration of genetic testing into diagnostic pathways for cardiomyopathies: a clinical consensus statement by the ESC Council on Cardiovascular Genomics.

Author

Elliott, Perry, Schunkert, Heribert, Bondue, Antoine, Behr, Elijah, Carrier, Lucie, Duijn, Cornelia Van, García-Pavía, Pablo, van der Harst, Pim, Kavousi, Maryam, Loeys, Bart, Lopes, Luis Rocha, Pinto, Yigal, Toro, Alessandro Di, Thum, Thomas, Kääb, Stefan, Urtis, Mario, and Arbustini, Eloisa

Subjects
GENETIC testing, PATIENTS' families, CARDIOMYOPATHIES, CARDIAC patients, PATIENT care
Abstract

In the modern era, cardiologists managing patients and families with cardiomyopathies need to be familiar with every stage of the diagnostic pathway from clinical phenotyping to the prescription and interpretation of genetic tests. This clinical consensus statement from the ESC Council for Cardiovascular Genomics aims to promote the integration of genetic testing into routine cardiac care of patients with cardiomyopathies, as recommended in the 2023 ESC guidelines for cardiomyopathies. The document describes the types of genetic tests currently available and provides advice on their prescription and for counselling after the return of genetic findings, including the approach in patients and families with variants of unknown significance. [ABSTRACT FROM AUTHOR]

Published
2025
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26. Diagnostic Efficacy of 123 Iodo-Metaiodobenzylguanidine SPECT/CT in Cardiac vs. Neurological Diseases: A Comparative Study of Arrhythmogenic Right Ventricular Cardiomyopathy and α-Synucleinopathies.

Author

Hagen, Johannes M., Scheifele, Maximilian, Zacherl, Mathias J., Katzdobler, Sabrina, Bernhardt, Alexander, Brendel, Matthias, Levin, Johannes, Höglinger, Günter U., Clauß, Sebastian, Kääb, Stefan, Todica, Andrei, Boening, Guido, and Fischer, Maximilian

Subjects
SINGLE-photon emission computed tomography, ARRHYTHMOGENIC right ventricular dysplasia, NEUROLOGICAL disorders, SYMPATHETIC nervous system, COMPUTED tomography
Abstract

Background/Objectives: 123Iodo-metaiodobenzylguanidine single photon emission computed tomography/computed tomography (123I-MIBG SPECT/CT) is used to evaluate the cardiac sympathetic nervous system in cardiac diseases such as arrhythmogenic right ventricular cardiomyopathy (ARVC) and α-synucleinopathies such as Parkinson's diseases. A common feature of these diseases is denervation. We aimed to compare quantitative and semi-quantitative cardiac sympathetic innervation using 123I-MIBG imaging of ARVC and α-synucleinopathies. Methods: Cardiac innervation was assessed using 123I-MIBG SPECT/CT in 20 patients diagnosed with definite ARVC and 8 patients with clinically diagnosed α-synucleinopathies. Heart-to-mediastinum-ratio (H/M-ratio), as semi-quantitative, was evaluated. Additionally, standardized uptake value (SUV), as quantitative, was measured as SUVmedian, SUVmax, and SUVpeak in the left ventricle (LV), the right ventricle (RV), and in the global heart, based on a CT scan following quantitative image reconstruction. Results: The quantification of 123I-MIBG uptake in the LV, the RV, and the global heart was feasible in patients suffering from α-synucleinopathies. SUVmedian, and SUVpeak demonstrated a significant difference between ARVC and α-synucleinopathies across all regions, with the α-synucleinopathy group showing a lower uptake. In addition, the H/M ratio showed significantly lower uptake in patients with α-synucleinopathies than in patients with ARVC. Conclusions: Patients with α-synucleinopathies demonstrate significantly lower cardiac innervation in semi-quantitative and quantitative examinations than ARVC patients. The comparison of semi-quantitative and quantitative examinations suggests that quantitative examination offers an advantage. Quantitative analysis can be performed separately for the LV, RV, and global heart. However, analyzing the LV or RV does not provide additional benefit over analyzing the global heart in distinguishing between α-synucleinopathies and ARVC. Considering the different clinical manifestations of these two diseases, the absolute SUV values should not be generalized across different pathologies, and disease-specific ranges should be used instead. [ABSTRACT FROM AUTHOR]

Published
2025
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27. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Author

Prins, Bram P, Mead, Timothy J, Brody, Jennifer A, Sveinbjornsson, Gardar, Ntalla, Ioanna, Bihlmeyer, Nathan A, van den Berg, Marten, Bork-Jensen, Jette, Cappellani, Stefania, Van Duijvenboden, Stefan, Klena, Nikolai T, Gabriel, George C, Liu, Xiaoqin, Gulec, Cagri, Grarup, Niels, Haessler, Jeffrey, Hall, Leanne M, Iorio, Annamaria, Isaacs, Aaron, Li-Gao, Ruifang, Lin, Honghuang, Liu, Ching-Ti, Lyytikäinen, Leo-Pekka, Marten, Jonathan, Mei, Hao, Müller-Nurasyid, Martina, Orini, Michele, Padmanabhan, Sandosh, Radmanesh, Farid, Ramirez, Julia, Robino, Antonietta, Schwartz, Molly, van Setten, Jessica, Smith, Albert V, Verweij, Niek, Warren, Helen R, Weiss, Stefan, Alonso, Alvaro, Arnar, David O, Bots, Michiel L, de Boer, Rudolf A, Dominiczak, Anna F, Eijgelsheim, Mark, Ellinor, Patrick T, Guo, Xiuqing, Felix, Stephan B, Harris, Tamara B, Hayward, Caroline, Heckbert, Susan R, Huang, Paul L, Jukema, JW, Kähönen, Mika, Kors, Jan A, Lambiase, Pier D, Launer, Lenore J, Li, Man, Linneberg, Allan, Nelson, Christopher P, Pedersen, Oluf, Perez, Marco, Peters, Annette, Polasek, Ozren, Psaty, Bruce M, Raitakari, Olli T, Rice, Kenneth M, Rotter, Jerome I, Sinner, Moritz F, Soliman, Elsayed Z, Spector, Tim D, Strauch, Konstantin, Thorsteinsdottir, Unnur, Tinker, Andrew, Trompet, Stella, Uitterlinden, André, Vaartjes, Ilonca, van der Meer, Peter, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Wilson, James G, Xie, Zhijun, Asselbergs, Folkert W, Dörr, Marcus, van Duijn, Cornelia M, Gasparini, Paolo, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hansen, Torben, Kääb, Stefan, Kanters, Jørgen K, Kooperberg, Charles, Lehtimäki, Terho, Lin, Henry J, Lubitz, Steven A, Mook-Kanamori, Dennis O, Conti, Francesco J, Newton-Cheh, Christopher H, Rosand, Jonathan, Rudan, Igor, and Samani, Nilesh J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Cardiovascular, Human Genome, Heart Disease, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, ADAMTS Proteins, Animals, Black People, Connexin 43, Electrocardiography, Exome, Female, Gene Expression, Gene Expression Profiling, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Mice, Middle Aged, Myocardium, Open Reading Frames, Polymorphism, Single Nucleotide, White People, Exome Sequencing, Exome chip, Conduction, ADAMTS6, Meta-analysis, Environmental Sciences, Information and Computing Sciences, Bioinformatics
Abstract

BackgroundGenome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.ResultsHere, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.ConclusionsOur approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

Published
2018

28. A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Author

Ashar, Foram N, Mitchell, Rebecca N, Albert, Christine M, Newton-Cheh, Christopher, Brody, Jennifer A, Müller-Nurasyid, Martina, Moes, Anna, Meitinger, Thomas, Mak, Angel, Huikuri, Heikki, Junttila, M Juhani, Goyette, Philippe, Pulit, Sara L, Pazoki, Raha, Tanck, Michael W, Blom, Marieke T, Zhao, XiaoQing, Havulinna, Aki S, Jabbari, Reza, Glinge, Charlotte, Tragante, Vinicius, Escher, Stefan A, Chakravarti, Aravinda, Ehret, Georg, Coresh, Josef, Li, Man, Prineas, Ronald J, Franco, Oscar H, Kwok, Pui-Yan, Lumley, Thomas, Dumas, Florence, McKnight, Barbara, Rotter, Jerome I, Lemaitre, Rozenn N, Heckbert, Susan R, O’Donnell, Christopher J, Hwang, Shih-Jen, Tardif, Jean-Claude, VanDenburgh, Martin, Uitterlinden, André G, Hofman, Albert, Stricker, Bruno HC, de Bakker, Paul IW, Franks, Paul W, Jansson, Jan-Hakan, Asselbergs, Folkert W, Halushka, Marc K, Maleszewski, Joseph J, Tfelt-Hansen, Jacob, Engstrøm, Thomas, Salomaa, Veikko, Virmani, Renu, Kolodgie, Frank, Wilde, Arthur AM, Tan, Hanno L, Bezzina, Connie R, Eijgelsheim, Mark, Rioux, John D, Jouven, Xavier, Kääb, Stefan, Psaty, Bruce M, Siscovick, David S, Arking, Dan E, and Sotoodehnia, Nona

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Heart Disease - Coronary Heart Disease, Cardiovascular, Genetics, Human Genome, Prevention, Heart Disease, Clinical Research, 2.1 Biological and endogenous factors, Good Health and Well Being, Arrhythmias, Cardiac, Body Mass Index, Coronary Artery Disease, Death, Sudden, Cardiac, Female, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Sex Factors, Sudden cardiac arrest, Genome-wide association study, Mendelian randomization, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

AimsSudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.Methods and resultsWe carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.ConclusionsOur findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

Published
2018

29. Multi-ethnic genome-wide association study for atrial fibrillation

Author

Roselli, Carolina, Chaffin, Mark D, Weng, Lu-Chen, Aeschbacher, Stefanie, Ahlberg, Gustav, Albert, Christine M, Almgren, Peter, Alonso, Alvaro, Anderson, Christopher D, Aragam, Krishna G, Arking, Dan E, Barnard, John, Bartz, Traci M, Benjamin, Emelia J, Bihlmeyer, Nathan A, Bis, Joshua C, Bloom, Heather L, Boerwinkle, Eric, Bottinger, Erwin B, Brody, Jennifer A, Calkins, Hugh, Campbell, Archie, Cappola, Thomas P, Carlquist, John, Chasman, Daniel I, Chen, Lin Y, Chen, Yii-Der Ida, Choi, Eue-Keun, Choi, Seung Hoan, Christophersen, Ingrid E, Chung, Mina K, Cole, John W, Conen, David, Cook, James, Crijns, Harry J, Cutler, Michael J, Damrauer, Scott M, Daniels, Brian R, Darbar, Dawood, Delgado, Graciela, Denny, Joshua C, Dichgans, Martin, Dörr, Marcus, Dudink, Elton A, Dudley, Samuel C, Esa, Nada, Esko, Tonu, Eskola, Markku, Fatkin, Diane, Felix, Stephan B, Ford, Ian, Franco, Oscar H, Geelhoed, Bastiaan, Grewal, Raji P, Gudnason, Vilmundur, Guo, Xiuqing, Gupta, Namrata, Gustafsson, Stefan, Gutmann, Rebecca, Hamsten, Anders, Harris, Tamara B, Hayward, Caroline, Heckbert, Susan R, Hernesniemi, Jussi, Hocking, Lynne J, Hofman, Albert, Horimoto, Andrea RVR, Huang, Jie, Huang, Paul L, Huffman, Jennifer, Ingelsson, Erik, Ipek, Esra Gucuk, Ito, Kaoru, Jimenez-Conde, Jordi, Johnson, Renee, Jukema, J Wouter, Kääb, Stefan, Kähönen, Mika, Kamatani, Yoichiro, Kane, John P, Kastrati, Adnan, Kathiresan, Sekar, Katschnig-Winter, Petra, Kavousi, Maryam, Kessler, Thorsten, Kietselaer, Bas L, Kirchhof, Paulus, Kleber, Marcus E, Knight, Stacey, Krieger, Jose E, Kubo, Michiaki, Launer, Lenore J, Laurikka, Jari, Lehtimäki, Terho, Leineweber, Kirsten, Lemaitre, Rozenn N, Li, Man, Lim, Hong Euy, Lin, Henry J, and Lin, Honghuang

Subjects
Biological Sciences, Genetics, Cardiovascular, Prevention, Heart Disease, Human Genome, 2.1 Biological and endogenous factors, Atrial Fibrillation, Case-Control Studies, Ethnicity, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Quantitative Trait Loci, Transcriptome, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Published
2018

30. Telemedical cardiac risk assessment by implantable cardiac monitors in patients after myocardial infarction with autonomic dysfunction (SMART-MI-DZHK9): a prospective investigator-initiated, randomised, multicentre, open-label, diagnostic trial

Author

May, Andreas, Seitzer, Peter, Schmidt, Roland, Keta, Dritan, Janke, Viktoria, Schläger, Christian, André, Elisabeth, Brandt, Niels, Schön, Alexandra, Zollner, Alfred, Freyer, Luisa, Hamm, Wolfgang, Beil, Johannes, Strüven, Anna Katharina, Loew, Anja, Fichtner, Stephanie, Lange, Philipp, Krasniqi, Aresa, Grabmeier, Ulrich, Estner, Heidi, Bengel, Philipp, Lüthje, Lars, Kirova, Aleksandra, Fischer, Thomas, Bergau, Leonard, Herting, Jonas, Schlögl, Simon, Haarmann, Helge, Schlögl (Illes), Klaudia, Uecer, Ekrem, Sag, Sabine, Tafelmeier, Maria, Jungbauer, Carsten, Fredersdorf-Hahn, Sabine, Strack, Christina, Seither, Benedikt, Seegers, Joachim, Millenaar, Dominic, Wintrich, Jan, Fischer, Patrick, Buob, Axel, Razouk, Amjad, Demming, Thomas, Frank, Johanne, Kühl, Constantin, Ellendt, Ulrike, Sandrock, Sarah, Gänsbacher, Julia, Cupa, Janosch, Sinnecker, Daniel, Laugwitz, Karl-Ludwig, Steger, Alexander, Berkefeld, Anna, Schinke, Karin, Barthel, Petra, Dommasch, Michael, Amadei, Maiwand, Hindricks, Gerhard, Obradovic, Danilo, Döring, Michael, Bode, Kerstin, Hilbert, Sebastian, Löbe, Susanne, Knopp, Helge, König, Sebastian, John, Silke, Schöne, Katharina, Hartung, Philipp, Binner, Christian, Meyer-Zürn, Christine, Duckheim, Martin, Eick, Christian, Simpfle, Fabian, Schreieck, Jürgen, Mizera, Lars, Tscholl, Verena, Steinbeck, Lisa, Güc, Nadija, Schatz, Anne-Sophie, Attanasio, Philipp, Heuberger, Andrea, Roser, Mattias, Bellmann, Barbara, Nagel, Patrick, Biewener, Sebastian, Suhail, Saba, Juri, Benjamin, Meyer, Christian, Wiilems, Stephan, Jungen, Christiane, Schmitt, Susanne, Münkerer, Paula, Vogler, Julia, Kaiser, Lukas, Schäffer, Benjamin, Nies, Moritz, Tönnis, Tobias, Fluschnik, Nina, Grahn, Hanno, Waldeyer, Christoph, Kany, Shinwan, Sörensen, Nils Arne, Winkelmann, Simon, Akbulak, Özge, Gosau, Nils Arne, Würger, Tilman, Arnold, Natalie, Geßler, Nele, Jobs, Alexander, Münkler, Paula, Rausch, Stefan, Köster, Jelena, Brüggemann, Ben, Abdin, Amr, Wacker, Christian, Grotherr, Philipp, Fries, Bastian, Faust, Maximilian, Steuer, Stefanie, Swojanowsky, Patrick, Willems, Stephan, Portz, Nathaniel, Ujeyl, Amar, Krüger, Matthias, Gramlich, Robert, Köhler, Till, Sause, Armin, Nover, Ina, Ziakos, Athanasios-Panagiotis, Ciobanu, Veaceslav, Spelsberg, Norman, Siebermair, Johannes, Mahabadi, Amir-Abbas, Köhler, Miriam, Vonderlin, Nadine, Riesinger, Lisa, Abdiu, Edison, Bachmann, Anja, Frenzel, Marie, Hummel, Astrid, Lehnert, Kristin, Krüger, Anne, Busse, Franke, Napp, Andreas, Müller-Wieland, Dirk, Battermann, Simone, Lacour, Philipp, Trippel, Tobias, Beetz, Nick Lasse, Schleußner, Leonhard, Zach, Veronika, Rozados, Christina, Mudra, Harald, Staubach, Stephan, Illmann, Alexander, Joner, Michael, Bock, Matthias, Kolb, Christof, Koch, Tobias, Fröhlich, Rebecca, Lennerz, Carsten, Lenz, Tobias, Fuchs, Patrick, Freißmuth, Markus, Grebmer, Christian, Kuschyk, Jürgen, Kranert, Malte, Fastenrath, Fabian, Yücel, Gökhan, Rudic, Boris, Würfel, Sarah, Römer, Albrecht, Böhmer, Andreas, Honold, Jörg, Georgopoulos, Stamatis, Gleirscher, Lukas, Lederle, Susanne, Chaplygin, Artem, Pauschinger, Matthias, Brinker-Paschke, Andrea, Kropacek, Jana, Eckardt, Lars, Ellermann, Christian, Bode, Niklas, Reinke, Florian, Engelke, Hauke, Höllriegel, Robert, Woitek, Felix, Winzer, Ephraim, Ibrahim, Karim, Pflücke, Christian, Ende, Georg, Speiser, Uwe, Haußig, Stephan, Wachter, Rolf, Uhe, Tobias, Konrad, Torsten, Zitron, Edgar, Destani, Jeton, Fu, Fangyi, Al Said, Samer, Kaya, Ziya, Schgör, Wilfried, Senoner, Thomas, Bauer, Axel, Sappler, Nikolay, von Stülpnagel, Lukas, Klemm, Mathias, Schreinlechner, Michael, Wenner, Felix, Schier, Johannes, Al Tawil, Amani, Dolejsi, Theresa, Eiffener, Elodie, Bongarth, Christa, Stühlinger, Markus, Huemer, Martin, Gori, Tommaso, Wakili, Reza, Sahin, Riza, Schwinger, Robert, Lutz, Matthias, Luik, Armin, Gessler, Nele, Clemmensen, Peter, Linke, Axel, Maier, Lars S, Hinterseer, Martin, Busch, Mathias C, Blaschke, Florian, Sack, Stefan, Licka, Manuela, Tilz, Roland R, Ukena, Christian, Ehrlich, Joachim R, Zabel, Markus, Schmidt, Georg, Mansmann, Ulrich, Kääb, Stefan, Rizas, Konstantinos D, and Massberg, Steffen

Published
2022
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31. Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Author

Barc, Julien, Tadros, Rafik, Glinge, Charlotte, Chiang, David Y., Jouni, Mariam, Simonet, Floriane, Jurgens, Sean J., Baudic, Manon, Nicastro, Michele, Potet, Franck, Offerhaus, Joost A., Walsh, Roddy, Choi, Seung Hoan, Verkerk, Arie O., Mizusawa, Yuka, Anys, Soraya, Minois, Damien, Arnaud, Marine, Duchateau, Josselin, Wijeyeratne, Yanushi D., Muir, Alison, Papadakis, Michael, Castelletti, Silvia, Torchio, Margherita, Ortuño, Cristina Gil, Lacunza, Javier, Giachino, Daniela F., Cerrato, Natascia, Martins, Raphaël P., Campuzano, Oscar, Van Dooren, Sonia, Thollet, Aurélie, Kyndt, Florence, Mazzanti, Andrea, Clémenty, Nicolas, Bisson, Arnaud, Corveleyn, Anniek, Stallmeyer, Birgit, Dittmann, Sven, Saenen, Johan, Noël, Antoine, Honarbakhsh, Shohreh, Rudic, Boris, Marzak, Halim, Rowe, Matthew K., Federspiel, Claire, Le Page, Sophie, Placide, Leslie, Milhem, Antoine, Barajas-Martinez, Hector, Beckmann, Britt-Maria, Krapels, Ingrid P., Steinfurt, Johannes, Winkel, Bo Gregers, Jabbari, Reza, Shoemaker, Moore B., Boukens, Bas J., Škorić-Milosavljević, Doris, Bikker, Hennie, Manevy, Federico C., Lichtner, Peter, Ribasés, Marta, Meitinger, Thomas, Müller-Nurasyid, Martina, Veldink, Jan H., van den Berg, Leonard H., Van Damme, Philip, Cusi, Daniele, Lanzani, Chiara, Rigade, Sidwell, Charpentier, Eric, Baron, Estelle, Bonnaud, Stéphanie, Lecointe, Simon, Donnart, Audrey, Le Marec, Hervé, Chatel, Stéphanie, Karakachoff, Matilde, Bézieau, Stéphane, London, Barry, Tfelt-Hansen, Jacob, Roden, Dan, Odening, Katja E., Cerrone, Marina, Chinitz, Larry A., Volders, Paul G., van de Berg, Maarten P., Laurent, Gabriel, Faivre, Laurence, Antzelevitch, Charles, Kääb, Stefan, Arnaout, Alain Al, Dupuis, Jean-Marc, Pasquie, Jean-Luc, Billon, Olivier, Roberts, Jason D., Jesel, Laurence, Borggrefe, Martin, Lambiase, Pier D., Mansourati, Jacques, Loeys, Bart, Leenhardt, Antoine, Guicheney, Pascale, Maury, Philippe, Schulze-Bahr, Eric, Robyns, Tomas, Breckpot, Jeroen, Babuty, Dominique, Priori, Silvia G., Napolitano, Carlo, de Asmundis, Carlo, Brugada, Pedro, Brugada, Ramon, Arbelo, Elena, Brugada, Josep, Mabo, Philippe, Behar, Nathalie, Giustetto, Carla, Molina, Maria Sabater, Gimeno, Juan R., Hasdemir, Can, Schwartz, Peter J., Crotti, Lia, McKeown, Pascal P., Sharma, Sanjay, Behr, Elijah R., Haissaguerre, Michel, Sacher, Frédéric, Rooryck, Caroline, Tan, Hanno L., Remme, Carol A., Postema, Pieter G., Delmar, Mario, Ellinor, Patrick T., Lubitz, Steven A., Gourraud, Jean-Baptiste, Tanck, Michael W., George, Jr., Alfred L., MacRae, Calum A., Burridge, Paul W., Dina, Christian, Probst, Vincent, Wilde, Arthur A., Schott, Jean-Jacques, Redon, Richard, and Bezzina, Connie R.

Published
2022
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34. ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals

Author

Bihlmeyer, Nathan A, Brody, Jennifer A, Smith, Albert Vernon, Warren, Helen R, Lin, Honghuang, Isaacs, Aaron, Liu, Ching-Ti, Marten, Jonathan, Radmanesh, Farid, Hall, Leanne M, Grarup, Niels, Mei, Hao, Müller-Nurasyid, Martina, Huffman, Jennifer E, Verweij, Niek, Guo, Xiuqing, Yao, Jie, Li-Gao, Ruifang, van den Berg, Marten, Weiss, Stefan, Prins, Bram P, van Setten, Jessica, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Li, Man, Alonso, Alvaro, Soliman, Elsayed Z, Bis, Joshua C, Austin, Tom, Chen, Yii-Der Ida, Psaty, Bruce M, Harrris, Tamara B, Launer, Lenore J, Padmanabhan, Sandosh, Dominiczak, Anna, Huang, Paul L, Xie, Zhijun, Ellinor, Patrick T, Kors, Jan A, Campbell, Archie, Murray, Alison D, Nelson, Christopher P, Tobin, Martin D, Bork-Jensen, Jette, Hansen, Torben, Pedersen, Oluf, Linneberg, Allan, Sinner, Moritz F, Peters, Annette, Waldenberger, Melanie, Meitinger, Thomas, Perz, Siegfried, Kolcic, Ivana, Rudan, Igor, de Boer, Rudolf A, van der Meer, Peter, Lin, Henry J, Taylor, Kent D, de Mutsert, Renée, Trompet, Stella, Jukema, J Wouter, Maan, Arie C, Stricker, Bruno HC, Rivadeneira, Fernando, Uitterlinden, André, Völker, Uwe, Homuth, Georg, Völzke, Henry, Felix, Stephan B, Mangino, Massimo, Spector, Timothy D, Bots, Michiel L, Perez, Marco, Raitakari, Olli T, Kähönen, Mika, Mononen, Nina, Gudnason, Vilmundur, Munroe, Patricia B, Lubitz, Steven A, van Duijn, Cornelia M, Newton-Cheh, Christopher H, Hayward, Caroline, Rosand, Jonathan, Samani, Nilesh J, Kanters, Jørgen K, Wilson, James G, Kääb, Stefan, Polasek, Ozren, van der Harst, Pim, Heckbert, Susan R, Rotter, Jerome I, Mook-Kanamori, Dennis O, Eijgelsheim, Mark, Dörr, Marcus, Jamshidi, Yalda, Asselbergs, Folkert W, Kooperberg, Charles, Lehtimäki, Terho, Arking, Dan E, and Sotoodehnia, Nona

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Prevention, Heart Disease, Cardiovascular, 1.1 Normal biological development and functioning, Antiporters, DNA-Binding Proteins, Electrocardiography, Exome, Genome-Wide Association Study, Humans, Long QT Syndrome, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptors, Calcium-Sensing, Transcription Factors, arrhythmias, cardiac, death, sudden, cardiac, genetics, genome, humans, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundQT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.Methods and resultsWe performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.ConclusionsOur analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.

Published
2018

35. Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

Author

Young, William J., Lahrouchi, Najim, Isaacs, Aaron, Duong, ThuyVy, Foco, Luisa, Ahmed, Farah, Brody, Jennifer A., Salman, Reem, Noordam, Raymond, Benjamins, Jan-Walter, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Repetto, Linda, Concas, Maria Pina, van den Berg, Marten E., Weiss, Stefan, Baldassari, Antoine R., Bartz, Traci M., Cook, James P., Evans, Daniel S., Freudling, Rebecca, Hines, Oliver, Isaksen, Jonas L., Lin, Honghuang, Mei, Hao, Moscati, Arden, Müller-Nurasyid, Martina, Nursyifa, Casia, Qian, Yong, Richmond, Anne, Roselli, Carolina, Ryan, Kathleen A., Tarazona-Santos, Eduardo, Thériault, Sébastien, van Duijvenboden, Stefan, Warren, Helen R., Yao, Jie, Raza, Dania, Aeschbacher, Stefanie, Ahlberg, Gustav, Alonso, Alvaro, Andreasen, Laura, Bis, Joshua C., Boerwinkle, Eric, Campbell, Archie, Catamo, Eulalia, Cocca, Massimiliano, Cutler, Michael J., Darbar, Dawood, De Grandi, Alessandro, De Luca, Antonio, Ding, Jun, Ellervik, Christina, Ellinor, Patrick T., Felix, Stephan B., Froguel, Philippe, Fuchsberger, Christian, Gögele, Martin, Graff, Claus, Graff, Mariaelisa, Guo, Xiuqing, Hansen, Torben, Heckbert, Susan R., Huang, Paul L., Huikuri, Heikki V., Hutri-Kähönen, Nina, Ikram, M. Arfan, Jackson, Rebecca D., Junttila, Juhani, Kavousi, Maryam, Kors, Jan A., Leal, Thiago P., Lemaitre, Rozenn N., Lin, Henry J., Lind, Lars, Linneberg, Allan, Liu, Simin, MacFarlane, Peter W., Mangino, Massimo, Meitinger, Thomas, Mezzavilla, Massimo, Mishra, Pashupati P., Mitchell, Rebecca N., Mononen, Nina, Montasser, May E., Morrison, Alanna C., Nauck, Matthias, Nauffal, Victor, Navarro, Pau, Nikus, Kjell, Pare, Guillaume, Patton, Kristen K., Pelliccione, Giulia, Pittman, Alan, Porteous, David J., Pramstaller, Peter P., Preuss, Michael H., Raitakari, Olli T., Reiner, Alexander P., Ribeiro, Antonio Luiz P., Rice, Kenneth M., Risch, Lorenz, Schlessinger, David, Schotten, Ulrich, Schurmann, Claudia, Shen, Xia, Shoemaker, M. Benjamin, Sinagra, Gianfranco, Sinner, Moritz F., Soliman, Elsayed Z., Stoll, Monika, Strauch, Konstantin, Tarasov, Kirill, Taylor, Kent D., Tinker, Andrew, Trompet, Stella, Uitterlinden, André, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Weng, Lu-Chen, Whitsel, Eric A., Wilson, James G., Avery, Christy L., Conen, David, Correa, Adolfo, Cucca, Francesco, Dörr, Marcus, Gharib, Sina A., Girotto, Giorgia, Grarup, Niels, Hayward, Caroline, Jamshidi, Yalda, Järvelin, Marjo-Riitta, Jukema, J. Wouter, Kääb, Stefan, Kähönen, Mika, Kanters, Jørgen K., Kooperberg, Charles, Lehtimäki, Terho, Lima-Costa, Maria Fernanda, Liu, Yongmei, Loos, Ruth J. F., Lubitz, Steven A., Mook-Kanamori, Dennis O., Morris, Andrew P., O’Connell, Jeffrey R., Olesen, Morten Salling, Orini, Michele, Padmanabhan, Sandosh, Pattaro, Cristian, Peters, Annette, Psaty, Bruce M., Rotter, Jerome I., Stricker, Bruno, van der Harst, Pim, van Duijn, Cornelia M., Verweij, Niek, Wilson, James F., Arking, Dan E., Ramirez, Julia, Lambiase, Pier D., Sotoodehnia, Nona, Mifsud, Borbala, Newton-Cheh, Christopher, and Munroe, Patricia B.

Published
2022
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36. Apixaban versus PhenpRocoumon: Oral AntiCoagulation plus antiplatelet tHerapy in patients with Acute Coronary Syndrome and Atrial Fibrillation (APPROACH-ACS-AF): Rationale and design of the prospective randomized parallel-group, open-label, blinded-endpoint, superiority, multicenter-trial of a triple therapy versus a dual therapy in patients with Atrial Fibrillation and Acute Coronary Syndrome undergoing coronary stenting

Author

Riesinger, Lisa, Strobl, Claudia, Leistner, David M., Gori, Tommaso, Akin, Ibrahim, Mehr, Michael, Kellnar, Antonia, Mahabadi, Amir A., Bogossian, Harilaos, Block, Michael, Edelmann, Frank, Sarafoff, Nikolaus, Sibbing, Dirk, Ince, Hüseyin, Rassaf, Tienush, Mansmann, Ulrich, Mehilli, Julinda, Kääb, Stefan, Hausleiter, Jörg, Massberg, Steffen, and Wakili, Reza

Published
2021
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37. Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial

Author

Bantkowiak, Marcin, Baur, Gabriele, Baylacher, Monika, Beaucamp, Marcel, Berger, Manuel, Besch, Lisa, Brunner, Stefan, Budweiser, Stephan, Bugger, Heiko, Coletti, Raffaele, Dorwarth, Uwe, Egresits, Jozsef, Eiffener, Elodie, Faul, Christian, Finkenstedt, Armin, Gatos, Konstantinos, Gauchel, Nadine, Gindele, Frank, Grander, Wilhelm, Gunschl, Markus, Hartig, Frank, Hecht, Moritz, Heer, Tobias, Heger, Lukas, Hentrich, Marcus, Horvath, Lena, Keta, Dritan, Kiechl, Stefan, Kirchmaier, Rudolf, Klein, Andreas, Klemm, Mathias, Kolesnik, Ewald, König, Andreas, Kossmann, Hans Christian, Kropacek, Jana, Lanser, Lukas, Lother, Achim, Löw, Anja, Mahabadi, Amir-Abbas, Malleier, Stefan, Mayer, Gert, Müller, Christoph, Müller-Wieland, Dirk, Nagel, Bernhard, Neuwirt, Hannes, Olivier, Christoph, Raunegger, Thomas, Reindl, Martin, Reinstadler, Sebastian, Riesinger, Lisa, Schäffner, Michael, Schier, Johannes, Schock, Julia, Schönherr, Peter, Schulz, Martina, Schütz, Thomas, Schwarz, Johannes, Siebermair, Johannes, Siry, Marcus, Spaur, Anna, Sturm, Wolfgang, Tessadri, Kristin, Theurl, Fabian, Theurl, Markus, Thommes, Liz, Tiller, Christina, Toifl, Michael, Totzeck, Matthias, von zur Mühlen, Hedda, Vonderlin, Nadine, Wakili, Reza, Wendtner, Clemens, Wenner, Felix, Wimmert-Roidl, Daniela, Zabernigg, August, Bauer, Axel, Schreinlechner, Michael, Sappler, Nikolay, Dolejsi, Theresa, Tilg, Herbert, Aulinger, Benedikt A, Weiss, Günter, Bellmann-Weiler, Rosa, Adolf, Christian, Wolf, Dominik, Pirklbauer, Markus, Graziadei, Ivo, Gänzer, Hannes, von Bary, Christian, May, Andreas E, Wöll, Ewald, von Scheidt, Wolfgang, Rassaf, Tienush, Duerschmied, Daniel, Brenner, Christoph, Kääb, Stefan, Metzler, Bernhard, Joannidis, Michael, Kain, Hans-Ulrich, Kaiser, Norbert, Schwinger, Robert, Witzenbichler, Bernhard, Alber, Hannes, Straube, Florian, Hartmann, Niels, Achenbach, Stephan, von Bergwelt-Baildon, Michael, von Stülpnagel, Lukas, Schoenherr, Sebastian, Forer, Lukas, Embacher-Aichhorn, Sabine, Mansmann, Ulrich, Rizas, Konstantinos D, and Massberg, Steffen

Published
2021
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39. Vascular neutrophilic inflammation and immunothrombosis distinguish severe COVID‐19 from influenza pneumonia

Author

Nicolai, Leo, Leunig, Alexander, Brambs, Sophia, Kaiser, Rainer, Joppich, Markus, Hoffknecht, Marie‐Louise, Gold, Christoph, Engel, Anouk, Polewka, Vivien, Muenchhoff, Maximilian, Hellmuth, Johannes C., Ruhle, Adrian, Ledderose, Stephan, Weinberger, Tobias, Schulz, Heiko, Scherer, Clemens, Rudelius, Martina, Zoller, Michael, Keppler, Oliver T., Zwißler, Bernhard, von Bergwelt‐Baildon, Michael, Kääb, Stefan, Zimmer, Ralf, Bülow, Roman D., von Stillfried, Saskia, Boor, Peter, Massberg, Steffen, Pekayvaz, Kami, and Stark, Konstantin

Published
2021
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41. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

Author

Walsh, Roddy, Lahrouchi, Najim, Tadros, Rafik, Kyndt, Florence, Glinge, Charlotte, Postema, Pieter G., Amin, Ahmad S., Nannenberg, Eline A., Ware, James S., Whiffin, Nicola, Mazzarotto, Francesco, Škorić-Milosavljević, Doris, Krijger, Christian, Arbelo, Elena, Babuty, Dominique, Barajas-Martinez, Hector, Beckmann, Britt M., Bézieau, Stéphane, Bos, J. Martijn, Breckpot, Jeroen, Campuzano, Oscar, Castelletti, Silvia, Celen, Candan, Clauss, Sebastian, Corveleyn, Anniek, Crotti, Lia, Dagradi, Federica, de Asmundis, Carlo, Denjoy, Isabelle, Dittmann, Sven, Ellinor, Patrick T., Ortuño, Cristina Gil, Giustetto, Carla, Gourraud, Jean-Baptiste, Hazeki, Daisuke, Horie, Minoru, Ishikawa, Taisuke, Itoh, Hideki, Kaneko, Yoshiaki, Kanters, Jørgen K., Kimoto, Hiroki, Kotta, Maria-Christina, Krapels, Ingrid P.C., Kurabayashi, Masahiko, Lazarte, Julieta, Leenhardt, Antoine, Loeys, Bart L., Lundin, Catarina, Makiyama, Takeru, Mansourati, Jacques, Martins, Raphaël P., Mazzanti, Andrea, Mörner, Stellan, Napolitano, Carlo, Ohkubo, Kimie, Papadakis, Michael, Rudic, Boris, Molina, Maria Sabater, Sacher, Frédéric, Sahin, Hatice, Sarquella-Brugada, Georgia, Sebastiano, Regina, Sharma, Sanjay, Sheppard, Mary N., Shimamoto, Keiko, Shoemaker, M.Benjamin, Stallmeyer, Birgit, Steinfurt, Johannes, Tanaka, Yuji, Tester, David J., Usuda, Keisuke, van der Zwaag, Paul A., Van Dooren, Sonia, Van Laer, Lut, Winbo, Annika, Winkel, Bo G., Yamagata, Kenichiro, Zumhagen, Sven, Volders, Paul G.A., Lubitz, Steven A., Antzelevitch, Charles, Platonov, Pyotr G., Odening, Katja E., Roden, Dan M., Roberts, Jason D., Skinner, Jonathan R., Tfelt-Hansen, Jacob, van den Berg, Maarten P., Olesen, Morten S., Lambiase, Pier D., Borggrefe, Martin, Hayashi, Kenshi, Rydberg, Annika, Nakajima, Tadashi, Yoshinaga, Masao, Saenen, Johan B., Kääb, Stefan, Brugada, Pedro, Robyns, Tomas, Giachino, Daniela F., Ackerman, Michael J., Brugada, Ramon, Brugada, Josep, Gimeno, Juan R., Hasdemir, Can, Guicheney, Pascale, Priori, Silvia G., Schulze-Bahr, Eric, Makita, Naomasa, Schwartz, Peter J., Shimizu, Wataru, Aiba, Takeshi, Schott, Jean-Jacques, Redon, Richard, Ohno, Seiko, Probst, Vincent, Arnaout, Alain Al, Amelot, Mathieu, Anselme, Frédéric, Billon, Olivier, Defaye, Pascal, Dupuis, Jean-Marc, Jesel, Laurence, Laurent, Gabriel, Maury, Philippe, Pasquie, Jean-Luc, Wiart, Francois, Behr, Elijah R., Barc, Julien, and Bezzina, Connie R.

Published
2021
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42. Nocturnal respiratory rate predicts ICD benefit: A prospective, controlled, multicentre cohort study

Author

Dommasch, Michael, Steger, Alexander, Barthel, Petra, Huster, Katharina M, Müller, Alexander, Sinnecker, Daniel, Laugwitz, Karl-Ludwig, Penzel, Thomas, Lubinski, Andrzej, Flevari, Panagiota, Harden, Markus, Friede, Tim, Kääb, Stefan, Merkely, Bela, Sticherling, Christian, Willems, Rik, Huikuri, Heikki V., Bauer, Axel, Malik, Marek, Zabel, Markus, and Schmidt, Georg

Published
2021
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43. 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families

Author

Stiles, Martin K., Wilde, Arthur A.M., Abrams, Dominic J., Ackerman, Michael J., Albert, Christine M., Behr, Elijah R., Chugh, Sumeet S., Cornel, Martina C., Gardner, Karen, Ingles, Jodie, James, Cynthia A., Jimmy Juang, Jyh-Ming, Kääb, Stefan, Kaufman, Elizabeth S., Krahn, Andrew D., Lubitz, Steven A., MacLeod, Heather, Morillo, Carlos A., Nademanee, Koonlawee, Probst, Vincent, Saarel, Elizabeth V., Sacilotto, Luciana, Semsarian, Christopher, Sheppard, Mary N., Shimizu, Wataru, Skinner, Jonathan R., Tfelt-Hansen, Jacob, and Wang, Dao Wu

Published
2021
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45. New challenges in cardiac intensive care units

Author

Lüsebrink, Enzo, Kellnar, Antonia, Scherer, Clemens, Krieg, Kathrin, Orban, Mathias, Petzold, Tobias, Peterss, Sven, Kääb, Stefan, Brunner, Stefan, Braun, Daniel, Hagl, Christian, Hausleiter, Jörg, Massberg, Steffen, and Orban, Martin

Published
2021
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46. PITX2 deficiency leads to atrial mitochondrial dysfunction.

Author

Reyat, Jasmeet S, Sommerfeld, Laura C, O'Reilly, Molly, Cardoso, Victor Roth, Thiemann, Ellen, Khan, Abdullah O, O'Shea, Christopher, Harder, Sönke, Müller, Christian, Barlow, Jonathan, Stapley, Rachel J, Chua, Winnie, Kabir, S Nashitha, Grech, Olivia, Hummel, Oliver, Hübner, Norbert, Kääb, Stefan, Mont, Lluis, Hatem, Stéphane N, and Winters, Joris

Subjects
INDUCED pluripotent stem cells, CELL respiration, PLURIPOTENT stem cells, ACTION potentials, LEFT heart atrium
Abstract

Aims Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation (AF). PITX2 is restricted to left atrial cardiomyocytes (aCMs) in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy, and AF are not fully understood. Methods and results To identify mechanisms linking PITX2 deficiency to AF, we generated and characterized PITX2 -deficient human aCMs derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2 -deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganized sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared with isogenic controls. Mitochondrial protein expression was altered in PITX2 -deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2 -deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2 -deficient hiPSC-derived atrial cardiomyocytes. PITX2 -deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with AF compared with 43 patients with sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. Conclusion PITX2 deficiency causes atrial mitochondrial dysfunction and a metabolic shift to glycolysis in human aCMs. PITX2 -dependent metabolic changes can contribute to the structural and functional defects found in PITX2 -deficient atria. [ABSTRACT FROM AUTHOR]

Published
2024
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47. Catheter‐based ablation to improve outcomes in patients with atrial fibrillation and heart failure with preserved ejection fraction: Rationale and design of the CABA‐HFPEF‐DZHK27 trial.

Author

Parwani, Abdul S., Kääb, Stefan, Friede, Tim, Tilz, Roland Richard, Bauersachs, Johann, Frey, Norbert, Hindricks, Gerhard, Lewalter, Thorsten, Rienstra, Michiel, Rillig, Andreas, Scherr, Daniel, Steven, Daniel, Kirchhof, Paulus, and Pieske, Burkert

Subjects
*ACUTE coronary syndrome, *HEART failure patients, *CATHETER ablation, *MEDICAL care, *HEART failure
Abstract

Aims: Atrial fibrillation (AF) is common in heart failure (HF) and negatively impacts outcomes. The role of ablation‐based rhythm control in patients with AF and HF with preserved (HFpEF) or mildly reduced ejection fraction (HFmrEF) is not known. The CABA‐HFPEF‐DZHK27 (CAtheter‐Based Ablation of atrial fibrillation compared to conventional treatment in patients with Heart Failure with Preserved Ejection Fraction) trial will determine whether early catheter ablation for AF can prevent adverse cardiovascular outcomes in patients with HFpEF or HFmrEF. Methods: CABA‐HFPEF‐DZHK27 (NCT05508256) is an investigator‐initiated, prospective, randomized, open, interventional multicentre strategy trial with blinded outcome assessment. Approximately 1548 patients with paroxysmal or persistent AF diagnosed within 24 months prior to enrolment and HFpEF or HFmrEF will be randomized to early catheter ablation within 4 weeks after randomization or to usual care. All patients receive anticoagulation, rate control, and HF management according to current guideline recommendations. Usual care can include rhythm control in symptomatic patients. Patients will be followed until the end of the trial for the primary outcome, a composite of cardiovascular death, stroke, and total unplanned hospitalizations for HF or acute coronary syndrome. The safety outcome comprises complications of catheter ablation and death. The trial is powered for a rate ratio of 0.75 (two‐sided alpha = 0.05, 1‐beta = 0.8). Conclusion: CABA‐HFPEF‐DZHK27 will define the role of systematic and early catheter ablation in patients with AF and HFpEF or HFmrEF. [ABSTRACT FROM AUTHOR]

Published
2024
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48. Lifetime cumulative activity burden is associated with symptomatic heart failure and arrhythmic risk in patients with arrhythmogenic right ventricular cardiomyopathy: a retrospective cohort study.

Author

Binzenhöfer, Leonhard, Clauss, Sebastian, Strauß, Katharina, Höpler, Julia, Kraft, Marie, Hoffmann, Sabine, Brunner, Stefan, Tomsits, Philipp, Schüttler, Dominik, Massberg, Steffen, Kääb, Stefan, and Lüsebrink, Enzo

Abstract

Aims Sports-related physical activity is associated with an increased risk of ventricular dysfunction and arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). However, there are currently no standardized strategies for activity assessment. Thresholds for harmful levels of physical activity suggested by previous studies vary substantially and neither lifetime activity burden nor continuous modelling approaches were considered. Methods and results For this single-centre retrospective study, ARVC patients were interviewed to assess sports-related and non-sports-related physical activity between the age of 10 years and the last follow-up. Activity data were aggregated to the median metabolic equivalent of task—hours (METh) per week for each year. The association between cumulative physical activity burden and clinical study endpoints was investigated using Cox regression models. A total of 124 patients (median age: 39.5 years, 48% male) were included in the analysis, of whom 93 had been diagnosed with definite ARVC. Study participants reported a median overall activity of 202.3 METh/week, with 38.7 METh/week attributed to sports-related activity. In the continuous model, cumulative overall activity burden was associated with the occurrence of symptomatic heart failure [hazard ratio (HR) per 100 METh/week: 1.017, 95% CI (1.003, 1.032), P = 0.015], sustained ventricular tachycardia [HR: 1.021, 95% CI (1.006, 1.037), P = 0.007], and implantable cardioverter defibrillator interventions [HR: 1.017, 95%CI (1.000, 1.034), P = 0.048]. This finding was consistent when considering sports-related activity separately as a predictor variable, whereas the resulting hazard ratios did not show a significant association for non-sports-related physical activity. Conclusion This study demonstrates for the first time that cumulative physical activity as a continuous predictor variable is associated with symptomatic heart failure and arrhythmic risk in ARVC patients. Collaborative research is required in larger cohorts to investigate the influence of potential confounders on event occurrence and to develop threshold recommendations for clinical practice. [ABSTRACT FROM AUTHOR]

Published
2024
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