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1. 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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3. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Ilaria, Gandin, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth JF, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thomas, Mitchell, Braxton D, Munzel, Thomas, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcus, and Ferrucci, Luigi

Subjects
Biological Sciences, Genetics, Human Genome, Heart Disease, Biotechnology, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Atrial Function, Atrioventricular Node, Electrocardiography, Electrophysiological Phenomena, Female, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Mutation, Missense, Risk Factors
Abstract

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

Published
2018

7. Effects of Calcium, Magnesium, and Potassium Concentrations on Ventricular Repolarization in Unselected Individuals

Author

Noordam, Raymond, Young, William J., Salman, Reem, Kanters, Jørgen K., van den Berg, Marten E., van Heemst, Diana, Lin, Henry J., Barreto, Sandhi Maria, Biggs, Mary L., Biino, Ginevra, Catamo, Eulalia, Concas, Maria Pina, Ding, Jun, Evans, Daniel S., Foco, Luisa, Grarup, Niels, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Mei, Hao, van der Most, Peter J., Müller-Nurasyid, Martina, Nelson, Christopher P., Qian, Yong, Repetto, Linda, Said, M. Abdullah, Shah, Nabi, Schramm, Katharina, Vidigal, Pedro G., Weiss, Stefan, Yao, Jie, Zilhao, Nuno R., Brody, Jennifer A., Braund, Peter S., Brumat, Marco, Campana, Eric, Christofidou, Paraskevi, Caulfield, Mark J., De Grandi, Alessandro, Dominiczak, Anna F., Doney, Alex S.F., Eiriksdottir, Gudny, Ellervik, Christina, Giatti, Luana, Gögele, Martin, Graff, Claus, Guo, Xiuqing, van der Harst, Pim, Joshi, Peter K., Kähönen, Mika, Kestenbaum, Bryan, Lima-Costa, Maria F., Linneberg, Allan, Maan, Arie C., Meitinger, Thomas, Padmanabhan, Sandosh, Pattaro, Cristian, Peters, Annette, Petersmann, Astrid, Sever, Peter, Sinner, Mortiz F., Shen, Xia, Stanton, Alice, Strauch, Konstantin, Soliman, Elsayed Z., Tarasov, Kirill V., Taylor, Kent D., Thio, Chris H.L., Uitterlinden, André G., Vaccargiu, Simona, Waldenberger, Melanie, Robino, Antonietta, Correa, Adolfo, Cucca, Francesco, Cummings, Steven R., Dörr, Marcus, Girotto, Giorgia, Gudnason, Vilmundur, Hansen, Torben, Heckbert, Susan R., Juhl, Christian R., Kääb, Stefan, Lehtimäki, Terho, Liu, Yongmei, Lotufo, Paulo A., Palmer, Colin N.A., Pirastu, Mario, Pramstaller, Peter P., Ribeiro, Antonio Luiz P., Rotter, Jerome I., Samani, Nilesh J., Snieder, Harold, Spector, Tim D., Stricker, Bruno H., Verweij, Niek, Wilson, James F., Wilson, James G., Jukema, J. Wouter, Tinker, Andrew, Newton-Cheh, Christopher H., Sotoodehnia, Nona, Mook-Kanamori, Dennis O., Munroe, Patricia B., and Warren, Helen R.

Published
2019
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10. Cardiac AC8 Over-Expression Increases Locomotion by Altering Heart-Brain Communication

Author

Agrimi, Jacopo, primary, Menicucci, Danilo, additional, Qu, Jia-Hua, additional, Laurino, Marco, additional, Mackey, Chelsea D., additional, Hasnain, Laila, additional, Tarasova, Yelena S., additional, Tarasov, Kirill V., additional, McDevitt, Ross A., additional, Hoover, Donald B., additional, Gemignani, Angelo, additional, Paolocci, Nazareno, additional, and Lakatta, Edward G., additional

Published
2023
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11. Age-associated failure of efficient cardiac proteostatic adaptations to chronic cAMP-stress is associated with accelerated heart aging

Author

Perino, Maria Grazia, primary, Barrera, Miguel Calvo-Rubio, additional, Agnetti, Giulio, additional, Ranek, Mark, additional, Riordon, Daniel R., additional, Morrell, Christopher H., additional, Chakir, Khalid, additional, Qu, Jia-Hua, additional, Tarasov, Kirill V, additional, Parveen, Admira, additional, Kadioglu, Hikmet, additional, De Cabo, Rafael, additional, and Lakatta, Edward G., additional

Published
2023
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12. 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 L. K., 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 J. F., 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, Roden, Dan M., Benjamin Shoemaker, M., Gustav Smith, J., Biggs, Mary L., Bis, Joshua C., Brody, Jennifer A., Psaty, Bruce M., Rice, Kenneth, Sotoodehnia, Nona, De Grandi, Alessandro, Fuchsberger, Christian, Pattaro, Cristian, Pramstaller, Peter P., Ford, Ian, Wouter Jukema, J., Macfarlane, Peter W., Trompet, Stella, Dörr, Marcus, Felix, Stephan B., Völker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Sääksjärvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome I., Taylor, Kent D., Yao, Jie, de Mutsert, Renée, Maan, Arie C., Mook-Kanamori, Dennis O., Noordam, Raymond, Cucca, Francesco, Ding, Jun, Lakatta, Edward G., Qian, Yong, Tarasov, Kirill V., Levy, Daniel, Lin, Honghuang, Newton-Cheh, Christopher H., Lunetta, Kathryn L., Murray, Alison D., Porteous, David J., Smith, Blair H., Stricker, Bruno H., Uitterlinden, André, van den Berg, Marten E., Haessler, Jeffrey, Jackson, Rebecca D., Kooperberg, Charles, Peters, Ulrike, Reiner, Alexander P., Whitsel, Eric A., Alonso, Alvaro, Arking, Dan E., Boerwinkle, Eric, Ehret, Georg B., Soliman, Elsayed Z., Avery, Christy L., Gogarten, Stephanie M., Kerr, Kathleen F., Laurie, Cathy C., Seyerle, Amanda A., Stilp, Adrienne, Assa, Solmaz, Abdullah Said, M., Yldau van der Ende, M., Lambiase, Pier D., Orini, Michele, Ramirez, Julia, Van Duijvenboden, Stefan, Arnar, David O., Gudbjartsson, Daniel F., Holm, Hilma, Sulem, Patrick, Thorleifsson, Gudmar, Thorolfsdottir, Rosa B., Thorsteinsdottir, Unnur, Benjamin, Emelia J., Tinker, Andrew, Stefansson, Kari, Ellinor, Patrick T., Jamshidi, Yalda, Lubitz, Steven A., and Munroe, Patricia B.

Published
2020
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15. Gender specific profiles of white coat and masked hypertension impacts on arterial structure and function in the SardiNIA study

Author

Scuteri, Angelo, Morrell, Christopher H., Orru’, Marco, AlGhatrif, Majid, Saba, Pier Sergio, Terracciano, Antonio, Ferreli, Liana Anna Pina, Loi, Francesco, Marongiu, Michele, Pilia, Maria Grazia, Delitala, Alessandro, Tarasov, Kirill V., Schlessinger, David, Ganau, Antonello, Cucca, Francesco, and Lakatta, Edward G.

Published
2016
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16. A remarkable adaptive paradigm of heart performance and protection emerges in response to the constitutive challenge of marked cardiac-specific overexpression of adenylyl cyclase type 8

Author

Tarasov, Kirill V., primary, Chakir, Khalid, additional, Riordon, Daniel R., additional, Lyashkov, Alexey E., additional, Ahmet, Ismayil, additional, Perino, Maria G., additional, Silvester, Allwin J., additional, Wang, Mingyi, additional, Lukyanenko, Yevgeniya O., additional, Qu, Jia-Hua, additional, Barrera, Miguel C.-R., additional, Tarasova, Yelena S., additional, Pacak, Karel, additional, Field, Loren, additional, and Lakatta, Edward G., additional

Published
2023
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17. A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8

Author

Tarasov, Kirill V, primary, Chakir, Khalid, additional, Riordon, Daniel R, additional, Lyashkov, Alexey E, additional, Ahmet, Ismayil, additional, Perino, Maria Grazia, additional, Silvester, Allwin Jennifa, additional, Zhang, Jing, additional, Wang, Mingyi, additional, Lukyanenko, Yevgeniya O, additional, Qu, Jia-Hua, additional, Barrera, Miguel Calvo-Rubio, additional, Juhaszova, Magdalena, additional, Tarasova, Yelena S, additional, Ziman, Bruce, additional, Telljohann, Richard, additional, Kumar, Vikas, additional, Ranek, Mark, additional, Lammons, John, additional, Bychkov, Rostislav, additional, de Cabo, Rafael, additional, Jun, Seungho, additional, Keceli, Gizem, additional, Gupta, Ashish, additional, Yang, Dongmei, additional, Aon, Miguel A, additional, Adamo, Luigi, additional, Morrell, Christopher H, additional, Otu, Walter, additional, Carroll, Cameron, additional, Chambers, Shane, additional, Paolocci, Nazareno, additional, Huynh, Thanh, additional, Pacak, Karel, additional, Weiss, Robert, additional, Field, Loren, additional, Sollott, Steven J, additional, and Lakatta, Edward G, additional

Published
2022
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19. Author response: A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8

Author

Tarasov, Kirill V, primary, Chakir, Khalid, additional, Riordon, Daniel R, additional, Lyashkov, Alexey E, additional, Ahmet, Ismayil, additional, Perino, Maria Grazia, additional, Silvester, Allwin Jennifa, additional, Zhang, Jing, additional, Wang, Mingyi, additional, Lukyanenko, Yevgeniya O, additional, Qu, Jia-Hua, additional, Barrera, Miguel Calvo-Rubio, additional, Juhaszova, Magdalena, additional, Tarasova, Yelena S, additional, Ziman, Bruce, additional, Telljohann, Richard, additional, Kumar, Vikas, additional, Ranek, Mark, additional, Lammons, John, additional, Bychkov, Rostislav, additional, de Cabo, Rafael, additional, Jun, Seungho, additional, Keceli, Gizem, additional, Gupta, Ashish, additional, Yang, Dongmei, additional, Aon, Miguel A, additional, Adamo, Luigi, additional, Morrell, Christopher H, additional, Otu, Walter, additional, Carroll, Cameron, additional, Chambers, Shane, additional, Paolocci, Nazareno, additional, Huynh, Thanh, additional, Pacak, Karel, additional, Weiss, Robert, additional, Field, Loren, additional, Sollott, Steven J, additional, and Lakatta, Edward G, additional

Published
2022
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24. A Remarkable Adaptive Paradigm Of Heart Performance And Protection Emerges In Response To The Constitutive Challenge Of Marked Cardiac-Specific Overexpression Of Adenylyl Cyclase Type 8

Author

Tarasov, Kirill V., primary, Chakir, Khalid, additional, Riordon, Daniel R., additional, Lyashkov, Alexey E., additional, Ahmet, Ismayil, additional, Perino, Maria Grazia, additional, Silvester, Allwin Jennifa, additional, Zhang, Jing, additional, Wang, Mingyi, additional, Lukyanenko, Yevgeniya O., additional, Qu, Jia-Hua, additional, Barrera, Miguel Calvo-Rubio, additional, Juhaszova, Magdalena, additional, Tarasova, Yelena S, additional, Ziman, Bruce, additional, Telljohann, Richard, additional, Kumar, Vikas, additional, Ranek, Mark, additional, Lammons, John, additional, Beshkov, Rostislav, additional, deCabo, Rafael, additional, Jun, Seungho, additional, Keceli, Gizem, additional, Gupta, Ashish, additional, Yang, Dongmei, additional, Aon, Miguel A., additional, Adamo, Luigi, additional, Morrell, Christopher H., additional, Otu, Walter, additional, Carroll, Cameron, additional, Chambers, Shane, additional, Paolocci, Nazareno, additional, Huynh, Thanh, additional, Pacak, Karel, additional, Weiss, Robert G, additional, Field, Loren, additional, Sollott, Steven J., additional, and Lakatta, Edward G, additional

Published
2022
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26. A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8.

Author

Tarasov, Kirill V., Chakir, Khalid, Riordon, Daniel R., Lyashkov, Alexey E., Ahmet, Ismayil, Perino, Maria Grazia, Silvester, Allwin Jennifa, Jing Zhang, Mingyi Wang, Lukyanenko, Yevgeniya O., Jia-Hua Qu, Calvo-Rubio Barrera, Miguel, Juhaszova, Magdalena, Tarasova, Yelena S., Ziman, Bruce, Telljohann, Richard, Kumar, Vikas, Ranek, Mark, Lammons, John, and Bychkov, Rostislav

Subjects
*NUCLEOTIDE synthesis, *CARDIAC hypertrophy, *FATTY acid oxidation, *PENTOSE phosphate pathway, *GENETIC overexpression
Abstract

Adult (3 month) mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an increased cAMP-induced cardiac workload (~30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here, we show classical cardiac hypertrophy markers were absent in TGAC8, and that total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes, and a network of small interstitial proliferative non-cardiac myocytes compared to wild type (WT) littermates; Protein synthesis, proteosome activity, and autophagy were enhanced in TGAC8 vs WT, and Nrf-2, Hsp90α, and ACC2 protein levels were increased. Despite increased energy demands in vivo LV ATP and phosphocreatine levels in TGAC8 did not differ from WT. Unbiased omics analyses identified more than 2,000 transcripts and proteins, comprising a broad array of biological processes across multiple cellular compartments, which differed by genotype; compared to WT, in TGAC8 there was a shift from fatty acid oxidation to aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, marked overexpression of AC8 engages complex, coordinate adaptation "circuity" that has evolved in mammalian cells to defend against stress that threatens health or life (elements of which have already been shown to be central to cardiac ischemic pre-conditioning and exercise endurance cardiac conditioning) that may be of biological significance to allow for proper healing in disease states such as infarction or failure of the heart. [ABSTRACT FROM AUTHOR]

Published
2023
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27. Phosphoprotein Phosphatase 1 but Not 2A Activity Modulates Coupled-Clock Mechanisms to Impact on Intrinsic Automaticity of Sinoatrial Nodal Pacemaker Cells

Author

Sirenko, Syevda Tagirova, primary, Zahanich, Ihor, additional, Li, Yue, additional, Lukyanenko, Yevgeniya O., additional, Lyashkov, Alexey E., additional, Ziman, Bruce D., additional, Tarasov, Kirill V., additional, Younes, Antoine, additional, Riordon, Daniel R., additional, Tarasova, Yelena S., additional, Yang, Dongmei, additional, Vinogradova, Tatiana M., additional, Maltsev, Victor A., additional, and Lakatta, Edward G., additional

Published
2021
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28. Cardiac adenylyl cyclase type 8 overexpression increases locomotor activity in mice by modulating EEG-gamma oscillations

Author

Agrimi, Jacopo, primary, Menicucci, Danilo, additional, Qu, Jia-Hua, additional, Laurino, Marco, additional, Mackey, Chelsea D, additional, Hasnain, Laila, additional, Tarasova, Yelena S, additional, Tarasov, Kirill V, additional, McDevitt, Ross A, additional, Hoover, Donald B, additional, Gemignani, Angelo, additional, Paolocci, Nazareno, additional, and Lakatta, Edward G, additional

Published
2021
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30. Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke

Author

Simard, J Marc, Chen, Mingkui, Tarasov, Kirill V, Bhatta, Sergei, Ivanova, Svetlana, Melnitchenko, Ludmila, Tsymbalyuk, Natalya, West, G Alexander, and Gerzanich, Volodymyr

Abstract

Pathological conditions in the central nervous system, including stroke and trauma, are often exacerbated by cerebral edema. We recently identified a nonselective cation channel, the NC[sub.Ca-ATP] channel, in ischemic astrocytes that is regulated by sulfonylurea receptor 1 (SUR1), is opened by depletion of ATP and, when opened, causes cytotoxic edema. Here, we evaluated involvement of this channel in rodent models of stroke. SUR1 protein and mRNA were newly expressed in ischemic neurons, astrocytes and capillaries. Upregulation of SUR1 was linked to activation of the transcription factor Sp1 and was associated with expression of functional NC[sub.Ca-ATP] but not K[sub.ATP] channels. Block of SUR1 with low-dose glibenclamide reduced cerebral edema, infarct volume and mortality by 50%, with the reduction in infarct volume being associated with cortical sparing. Our findings indicate that the NC[sub.Ca-ATP] channel is crucially involved in development of cerebral edema, and that targeting SUR1 may provide a new therapeutic approach to stroke., Author(s): J Marc Simard (corresponding author) [1, 2, 3]; Mingkui Chen [1]; Kirill V Tarasov [1]; Sergei Bhatta [1]; Svetlana Ivanova [1]; Ludmila Melnitchenko [1]; Natalya Tsymbalyuk [1]; G Alexander [...]

Published
2006
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34. Genome-wide association analysis identifies multiple loci related to resting heart rate

Author

Eijgelsheim, Mark, Newton-Cheh, Christopher, Sotoodehnia, Nona, de Bakker, Paul I.W., Müller, Martina, Morrison, Alanna C., Smith, Albert V., Isaacs, Aaron, Sanna, Serena, Dörr, Marcus, Navarro, Pau, Fuchsberger, Christian, Nolte, Ilja M., de Geus, Eco J.C., Estrada, Karol, Hwang, Shih-Jen, Bis, Joshua C., Rückert, Ina-Maria, Alonso, Alvaro, Launer, Lenore J., Hottenga, Jouke Jan, Rivadeneira, Fernando, Noseworthy, Peter A., Rice, Kenneth M., Perz, Siegfried, Arking, Dan E., Spector, Tim D., Kors, Jan A., Aulchenko, Yurii S., Tarasov, Kirill V., Homuth, Georg, Wild, Sarah H., Marroni, Fabio, Gieger, Christian, Licht, Carmilla M., Prineas, Ronald J., Hofman, Albert, Rotter, Jerome I., Hicks, Andrew A., Ernst, Florian, Najjar, Samer S., Wright, Alan F., Peters, Annette, Fox, Ervin R., Oostra, Ben A., Kroemer, Heyo K., Couper, David, Völzke, Henry, Campbell, Harry, Meitinger, Thomas, Uda, Manuela, Witteman, Jacqueline C.M., Psaty, Bruce M., Wichmann, H-Erich, Harris, Tamara B., Kääb, Stefan, Siscovick, David S., Jamshidi, Yalda, Uitterlinden, André G., Folsom, Aaron R., Larson, Martin G., Wilson, James F., Penninx, Brenda W., Snieder, Harold, Pramstaller, Peter P., van Duijn, Cornelia M., Lakatta, Edward G., Felix, Stephan B., Gudnason, Vilmundur, Pfeufer, Arne, Heckbert, Susan R., Stricker, Bruno H.Ch., Boerwinkle, Eric, and OʼDonnell, Christopher J.

Published
2010
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35. Mammalian γ2 AMPK regulates intrinsic heart rate

Author

Yavari, Arash, Bellahcene, Mohamed, Bucchi, Annalisa, Sirenko, Syevda, Pinter, Katalin, Herring, Neil, Jung, Julia J., Tarasov, Kirill V., Sharpe, Emily J., Wolfien, Markus, Czibik, Gabor, Steeples, Violetta, Ghaffari, Sahar, Nguyen, Chinh, Stockenhuber, Alexander, Clair, Joshua R. St., Rimmbach, Christian, Okamoto, Yosuke, Yang, Dongmei, Wang, Mingyi, Ziman, Bruce D., Moen, Jack M., Riordon, Daniel R., Ramirez, Christopher, Paina, Manuel, Lee, Joonho, Zhang, Jing, Ahmet, Ismayil, Matt, Michael G., Tarasova, Yelena S., Baban, Dilair, Sahgal, Natasha, Lockstone, Helen, Puliyadi, Rathi, de Bono, Joseph, Siggs, Owen M., Gomes, John, Muskett, Hannah, Maguire, Mahon L., Beglov, Youlia, Kelly, Matthew, dos Santos, Pedro P. N., Bright, Nicola J., Woods, Angela, Gehmlich, Katja, Isackson, Henrik, Douglas, Gillian, Ferguson, David J. P., Schneider, Jürgen E., Tinker, Andrew, Wolkenhauer, Olaf, Channon, Keith M., Cornall, Richard J., Sternick, Eduardo B., Paterson, David J., Redwood, Charles S., Carling, David, Proenza, Catherine, David, Robert, Baruscotti, Mirko, DiFrancesco, Dario, Lakatta, Edward G., Watkins, Hugh, and Ashrafian, Houman

Subjects
Adult, Magnetic Resonance Spectroscopy, Science, Magnetic Resonance Imaging, Cine, AMP-Activated Protein Kinases, Article, Mice, Sarcolemma, Microscopy, Electron, Transmission, Heart Rate, Physical Conditioning, Animal, MD Multidisciplinary, Bradycardia, Animals, Humans, lcsh:Science, Exercise, Sinoatrial Node, Myocardium, Heart, Ryanodine Receptor Calcium Release Channel, Mutation, Electrocardiography, Ambulatory, Physical Endurance, lcsh:Q, Calcium
Abstract

AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αβγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that γ2 AMPK activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower heart rate, including sarcolemmal hyperpolarization-activated current (I f) and ryanodine receptor-derived diastolic local subsarcolemmal Ca2+ release. In contrast, loss of γ2 AMPK induces a reciprocal phenotype of increased heart rate, and prevents the adaptive intrinsic bradycardia of endurance training. Our results reveal that in mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ-specific manner to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to exercise by modulating intrinsic sinoatrial cell behavior., AMPK regulates cellular energy balance using its γ subunit as an energy sensor of cellular AMP and ADP to ATP ratios. Here, the authors show that γ2 AMPK activation lowers heart rate by reducing the activity of pacemaker cells, whereas loss of γ2 AMPK increases heart rate and prevents the adaptive bradycardia of endurance training in mice.

Published
2017

37. Basal Spontaneous Firing of Rabbit Sinoatrial Node Cells is Regulated by Dual Phosphodiesterase 3 and 4 Activation

Author

Vinogradova, Tatiana M., Sirenko, Syevda, Lukyanenko, Yevgeniya O., Yang, Dongmei, Tarasov, Kirill V., Lyashkov, Alexey E., Varghese, Nevin J., Li, Yue, Chakir, Khalid, Ziman, Bruce, and Lakatta, Edward G.

Subjects
Action Potentials, Ryanodine Receptor Calcium Release Channel, Phosphodiesterase 3 Inhibitors, Cyclic AMP-Dependent Protein Kinases, Article, Cyclic Nucleotide Phosphodiesterases, Type 3, Cyclic Nucleotide Phosphodiesterases, Type 4, Enzyme Activation, Kinetics, Biological Clocks, Heart Rate, Cyclic AMP, Animals, Calcium Signaling, Phosphodiesterase 4 Inhibitors, Rabbits, Sinoatrial Node
Abstract

BACKGROUND: Spontaneous firing of sinoatrial node cells (SANC) is regulated by cAMP-mediated, PKA-dependent (cAMP/PKA) local subsarcolemmal Ca(2+) releases (LCRs) from ryanodine receptors (RyR). LCRs occur during diastolic depolarization (DD) and activate an inward Na(+)/Ca(2+) exchange current that accelerates DD rate prompting the next action potential (AP). Phosphodiesterases (PDEs) regulate cAMP-mediated signaling; PDE3/PDE4 represent major PDE activities in SANC, but how they modulate LCRs and basal spontaneous SANC firing remains unknown. METHODS AND RESULTS: PDE3A, PDE4B and PDE4D were the major PDE subtypes (real-time PCR, western blot) expressed in rabbit SANC, and PDE3A (immunostaining) was co-localized with α-actinin, PDE4D, SERCA and phospholamban in Z-lines. Inhibition of PDE3 (cilostamide) or PDE4 (rolipram) alone increased spontaneous SANC firing (perforated patch) by ∼20% (P0.05) respectively, but concurrent PDE3+PDE4 inhibition increased spontaneous firing by ∼45% (P0.05), respectively, and phospholamban phosphorylation by ∼20% (P>0.05) each, but dual PDE3+PDE4 inhibition increased I(Ca,L) by ∼100% (P

Published
2018

38. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Author

Ntalla, Ioanna, primary, Weng, Lu-Chen, additional, Cartwright, James H., additional, Hall, Amelia Weber, additional, Sveinbjornsson, Gardar, additional, Tucker, Nathan R., additional, Choi, Seung Hoan, additional, Chaffin, Mark D., additional, Roselli, Carolina, additional, Barnes, Michael R., additional, Mifsud, Borbala, additional, Warren, Helen R., additional, Hayward, Caroline, additional, Marten, Jonathan, additional, Cranley, James J., additional, Concas, Maria Pina, additional, Gasparini, Paolo, additional, Boutin, Thibaud, additional, Kolcic, Ivana, additional, Polasek, Ozren, additional, Rudan, Igor, additional, Araujo, Nathalia M., additional, Lima-Costa, Maria Fernanda, additional, Ribeiro, Antonio Luiz P., additional, Souza, Renan P., additional, Tarazona-Santos, Eduardo, additional, Giedraitis, Vilmantas, additional, Ingelsson, Erik, additional, Mahajan, Anubha, additional, Morris, Andrew P., additional, Fabiola Del, Greco M., additional, Foco, Luisa, additional, Gögele, Martin, additional, Hicks, Andrew A., additional, Cook, James P., additional, Lind, Lars, additional, Lindgren, Cecilia M., additional, Sundström, Johan, additional, Nelson, Christopher P., additional, Riaz, Muhammad B., additional, Samani, Nilesh J., additional, Sinagra, Gianfranco, additional, Ulivi, Sheila, additional, Kähönen, Mika, additional, Mishra, Pashupati P., additional, Mononen, Nina, additional, Nikus, Kjell, additional, Caulfield, Mark J., additional, Dominiczak, Anna, additional, Padmanabhan, Sandosh, additional, Montasser, May E., additional, O’Connell, Jeff R., additional, Ryan, Kathleen, additional, Shuldiner, Alan R., additional, Aeschbacher, Stefanie, additional, Conen, David, additional, Risch, Lorenz, additional, Thériault, Sébastien, additional, Hutri-Kähönen, Nina, additional, Lehtimäki, Terho, additional, Lyytikäinen, Leo-Pekka, additional, Raitakari, Olli T., additional, Barnes, Catriona L. K., additional, Campbell, Harry, additional, Joshi, Peter K., additional, Wilson, James F., additional, Isaacs, Aaron, additional, Kors, Jan A., additional, van Duijn, Cornelia M., additional, Huang, Paul L., additional, Gudnason, Vilmundur, additional, Harris, Tamara B., additional, Launer, Lenore J., additional, Smith, Albert V., additional, Bottinger, Erwin P., additional, Loos, Ruth J. F., additional, Nadkarni, Girish N., additional, Preuss, Michael H., additional, Correa, Adolfo, additional, Mei, Hao, additional, Wilson, James, additional, Meitinger, Thomas, additional, Müller-Nurasyid, Martina, additional, Peters, Annette, additional, Waldenberger, Melanie, additional, Mangino, Massimo, additional, Spector, Timothy D., additional, Rienstra, Michiel, additional, van de Vegte, Yordi J., additional, van der Harst, Pim, additional, Verweij, Niek, additional, Kääb, Stefan, additional, Schramm, Katharina, additional, Sinner, Moritz F., additional, Strauch, Konstantin, additional, Cutler, Michael J., additional, Fatkin, Diane, additional, London, Barry, additional, Olesen, Morten, additional, Roden, Dan M., additional, Shoemaker, M. Benjamin, additional, Smith, J. Gustav, additional, Biggs, Mary L., additional, Bis, Joshua C., additional, Brody, Jennifer A., additional, Psaty, Bruce M., additional, Rice, Ken, additional, Sotoodehnia, Nona, additional, De Grandi, Alessandro, additional, Fuchsberger, Christian, additional, Pattaro, Cristian, additional, Pramstaller, Peter P., additional, Ford, Ian, additional, Jukema, J. Wouter, additional, Macfarlane, Peter W., additional, Trompet, Stella, additional, Dörr, Marcus, additional, Felix, Stephan B., additional, Völker, Uwe, additional, Weiss, Stefan, additional, Havulinna, Aki S., additional, Jula, Antti, additional, Sääksjärvi, Katri, additional, Salomaa, Veikko, additional, Guo, Xiuqing, additional, Heckbert, Susan R., additional, Lin, Henry J., additional, Rotter, Jerome I., additional, Taylor, Kent D., additional, Yao, Jie, additional, de Mutsert, Renée, additional, Maan, Arie C., additional, Mook-Kanamori, Dennis O., additional, Noordam, Raymond, additional, Cucca, Francesco, additional, Ding, Jun, additional, Lakatta, Edward G., additional, Qian, Yong, additional, Tarasov, Kirill V., additional, Levy, Daniel, additional, Lin, Honghuang, additional, Newton-Cheh, Christopher H., additional, Lunetta, Kathryn L., additional, Murray, Alison D., additional, Porteous, David J., additional, Smith, Blair H., additional, Stricker, Bruno H., additional, Uitterlinden, André, additional, van den Berg, Marten E., additional, Haessler, Jeffrey, additional, Jackson, Rebecca D., additional, Kooperberg, Charles, additional, Peters, Ulrike, additional, Reiner, Alexander P., additional, Whitsel, Eric A., additional, Alonso, Alvaro, additional, Arking, Dan E., additional, Boerwinkle, Eric, additional, Ehret, Georg B., additional, Soliman, Elsayed Z., additional, Avery, Christy L., additional, Gogarten, Stephanie M., additional, Kerr, Kathleen F., additional, Laurie, Cathy C., additional, Seyerle, Amanda A., additional, Stilp, Adrienne, additional, Assa, Solmaz, additional, Said, M. Abdullah, additional, van der Ende, M. Yldau, additional, Lambiase, Pier D., additional, Orini, Michele, additional, Ramirez, Julia, additional, Van Duijvenboden, Stefan, additional, Arnar, David O., additional, Gudbjartsson, Daniel F., additional, Holm, Hilma, additional, Sulem, Patrick, additional, Thorleifsson, Gudmar, additional, Thorolfsdottir, Rosa B., additional, Thorsteinsdottir, Unnur, additional, Benjamin, Emelia J., additional, Tinker, Andrew, additional, Stefansson, Kari, additional, Ellinor, Patrick T., additional, Jamshidi, Yalda, additional, Lubitz, Steven A., additional, and Munroe, Patricia B., additional

Published
2019
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39. Overexpression of a Neuronal Type Adenylyl Cyclase (Type 8) in Sinoatrial Node Markedly Impacts Heart Rate and Rhythm

Author

Moen, Jack M., primary, Matt, Michael G., additional, Ramirez, Christopher, additional, Tarasov, Kirill V., additional, Chakir, Khalid, additional, Tarasova, Yelena S., additional, Lukyanenko, Yevgeniya, additional, Tsutsui, Kenta, additional, Monfredi, Oliver, additional, Morrell, Christopher H., additional, Tagirova, Syevda, additional, Yaniv, Yael, additional, Huynh, Thanh, additional, Pacak, Karel, additional, Ahmet, Ismayil, additional, and Lakatta, Edward G., additional

Published
2019
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41. Cardiac Overexpression of Human Adenylyl Cyclase Type 8 in Mice Elicits Phosphorylation- Dependent Mechanisms that Permit Perpetual Heart Exercise while Conferring Protection Against Excessive Camp-PKA Signaling

Author

Chakir, Khalid, primary, Lyashkov, Alexey E., additional, Tarasov, Kirill V., additional, Ahmet, Ismayil, additional, Yang, Dongmei, additional, Tarasova, Yelena S., additional, Riordon, Daniel, additional, Lukyanenko, Yevgeniya O., additional, Huynh, Thanh, additional, Pacak, Karel, additional, and Lakatta, Edward G., additional

Published
2019
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43. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

Researchbureau DHL, Onderzoek Precision medicine, Circulatory Health, Genetica, Epi Kanker Team B, Infection & Immunity, van Setten, Jessica, Brody, Jennifer A., Jamshidi, Yalda, Swenson, Brenton R., Butler, Anne M., Campbell, Harry, Del Greco, Fabiola M., Evans, Daniel S., Gibson, Quince, Gudbjartsson, Daniel F., Kerr, Kathleen F., Krijthe, Bouwe P., Lyytikäinen, Leo Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M., Padmanabhan, Sandosh, Ritchie, Marylyn D., Robino, Antonietta, Smith, Albert V., Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O., Asselbergs, Folkert W., Bader, Joel S., Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M., Chung, Mina K., Crawford, Dana, den Hoed, Marcel, Denny, Josh C., Dominiczak, Anna F., Ehret, Georg B., Eijgelsheim, Mark, Ellinor, Patrick T., Felix, Stephan B., Franco, Oscar H., Franke, Lude, Harris, Tamara B., Holm, Hilma, Ilaria, Gandin, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A., Lakatta, Edward G., Launer, Lenore J., Lin, Honghuang, Lin, Henry J., Loos, Ruth J.F., Lubitz, Steven A., Macfarlane, Peter W., Magnani, Jared W., Leach, Irene Mateo, Meitinger, Thomas, Mitchell, Braxton D., Munzel, Thomas, Papanicolaou, George J., Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P., Raitakari, Olli T., Rotter, Jerome I., Rudan, Igor, Samani, Nilesh J., Schlessinger, David, Silva Aldana, Claudia T., Sinner, Moritz F., Smith, Jonathan D., Snieder, Harold, Soliman, Elsayed Z., Spector, Timothy D., Stott, David J., Strauch, Konstantin, Tarasov, Kirill V., Thorsteinsdottir, Unnur, Uitterlinden, Andre G., Van Wagoner, David R., Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S., Zeller, Tanja, Alonso, Alvaro, Avery, Christy L., Bandinelli, Stefania, Benjamin, Emelia J., Cucca, Francesco, Dörr, Marcus, Ferrucci, Luigi, Gasparini, Paolo, Gudnason, Vilmundur, Hayward, Caroline, Heckbert, Susan R., Hicks, Andrew A., Jukema, J. Wouter, Kääb, Stefan, Lehtimäki, Terho, Liu, Yongmei, Munroe, Patricia B., Parsa, Afshin, Polasek, Ozren, Psaty, Bruce M., Roden, Dan M., Schnabel, Renate B., Sinagra, Gianfranco, Stefansson, Kari, Stricker, Bruno H., van der Harst, Pim, van Duijn, Cornelia M., Wilson, James F., Gharib, Sina A., de Bakker, Paul I.W., Isaacs, Aaron, Arking, Dan E., Sotoodehnia, Nona, Researchbureau DHL, Onderzoek Precision medicine, Circulatory Health, Genetica, Epi Kanker Team B, Infection & Immunity, van Setten, Jessica, Brody, Jennifer A., Jamshidi, Yalda, Swenson, Brenton R., Butler, Anne M., Campbell, Harry, Del Greco, Fabiola M., Evans, Daniel S., Gibson, Quince, Gudbjartsson, Daniel F., Kerr, Kathleen F., Krijthe, Bouwe P., Lyytikäinen, Leo Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M., Padmanabhan, Sandosh, Ritchie, Marylyn D., Robino, Antonietta, Smith, Albert V., Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O., Asselbergs, Folkert W., Bader, Joel S., Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M., Chung, Mina K., Crawford, Dana, den Hoed, Marcel, Denny, Josh C., Dominiczak, Anna F., Ehret, Georg B., Eijgelsheim, Mark, Ellinor, Patrick T., Felix, Stephan B., Franco, Oscar H., Franke, Lude, Harris, Tamara B., Holm, Hilma, Ilaria, Gandin, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A., Lakatta, Edward G., Launer, Lenore J., Lin, Honghuang, Lin, Henry J., Loos, Ruth J.F., Lubitz, Steven A., Macfarlane, Peter W., Magnani, Jared W., Leach, Irene Mateo, Meitinger, Thomas, Mitchell, Braxton D., Munzel, Thomas, Papanicolaou, George J., Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P., Raitakari, Olli T., Rotter, Jerome I., Rudan, Igor, Samani, Nilesh J., Schlessinger, David, Silva Aldana, Claudia T., Sinner, Moritz F., Smith, Jonathan D., Snieder, Harold, Soliman, Elsayed Z., Spector, Timothy D., Stott, David J., Strauch, Konstantin, Tarasov, Kirill V., Thorsteinsdottir, Unnur, Uitterlinden, Andre G., Van Wagoner, David R., Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S., Zeller, Tanja, Alonso, Alvaro, Avery, Christy L., Bandinelli, Stefania, Benjamin, Emelia J., Cucca, Francesco, Dörr, Marcus, Ferrucci, Luigi, Gasparini, Paolo, Gudnason, Vilmundur, Hayward, Caroline, Heckbert, Susan R., Hicks, Andrew A., Jukema, J. Wouter, Kääb, Stefan, Lehtimäki, Terho, Liu, Yongmei, Munroe, Patricia B., Parsa, Afshin, Polasek, Ozren, Psaty, Bruce M., Roden, Dan M., Schnabel, Renate B., Sinagra, Gianfranco, Stefansson, Kari, Stricker, Bruno H., van der Harst, Pim, van Duijn, Cornelia M., Wilson, James F., Gharib, Sina A., de Bakker, Paul I.W., Isaacs, Aaron, Arking, Dan E., and Sotoodehnia, Nona

Published
2018

44. A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells

Author

Tsutsui, Kenta, primary, Monfredi, Oliver J., additional, Sirenko-Tagirova, Syevda G., additional, Maltseva, Larissa A., additional, Bychkov, Rostislav, additional, Kim, Mary S., additional, Ziman, Bruce D., additional, Tarasov, Kirill V., additional, Tarasova, Yelena S., additional, Zhang, Jing, additional, Wang, Mingyi, additional, Maltsev, Alexander V., additional, Brennan, Jaclyn A., additional, Efimov, Igor R., additional, Stern, Michael D., additional, Maltsev, Victor A., additional, and Lakatta, Edward G., additional

Published
2018
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46. Self-Organization of Functional Coupling between Membrane and Calcium Clock in Arrested Human Sinoatrial Nodal Cells in Response to Camp

Author

Tsutsui, Kenta, primary, Monfredi, Oliver, additional, Sirenko, Syevda, additional, Bychkov, Rostialav, additional, Maltseva, Larissa A., additional, Kim, Mary S., additional, Ziman, Bruce D., additional, Tarasov, Kirill V., additional, Wang, Mingyi, additional, Maltsev, Alexander V., additional, Brennan, Jaclyn A., additional, Efimov, Igor R., additional, Stern, Michael D., additional, Maltsev, Victor A., additional, and Lakatta, Edward G., additional

Published
2018
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47. Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

Author

van Setten, Jessica, primary, Brody, Jennifer A., additional, Jamshidi, Yalda, additional, Swenson, Brenton R., additional, Butler, Anne M., additional, Campbell, Harry, additional, Fabiola Del Greco, M., additional, Evans, Daniel S., additional, Gibson, Quince, additional, Gudbjartsson, Daniel F., additional, Kerr, Kathleen F., additional, Krijthe, Bouwe P., additional, Lyytikäinen, Leo-Pekka, additional, Müller, Christian, additional, Müller-Nurasyid, Martina, additional, Nolte, Ilja M., additional, Padmanabhan, Sandosh, additional, Ritchie, Marylyn D., additional, Robino, Antonietta, additional, Smith, Albert V., additional, Steri, Maristella, additional, Tanaka, Toshiko, additional, Teumer, Alexander, additional, Trompet, Stella, additional, Ulivi, Sheila, additional, Verweij, Niek, additional, Yin, Xiaoyan, additional, Arnar, David O., additional, Asselbergs, Folkert W., additional, Bader, Joel S., additional, Barnard, John, additional, Bis, Josh, additional, Blankenberg, Stefan, additional, Boerwinkle, Eric, additional, Bradford, Yuki, additional, Buckley, Brendan M., additional, Chung, Mina K., additional, Crawford, Dana, additional, den Hoed, Marcel, additional, Denny, Josh, additional, Dominiczak, Anna F., additional, Ehret, Georg B., additional, Eijgelsheim, Mark, additional, Ellinor, Patrick T., additional, Felix, Stephan B., additional, Franco, Oscar H., additional, Franke, Lude, additional, Harris, Tamara B., additional, Holm, Hilma, additional, Ilaria, Gandin, additional, Iorio, Annamaria, additional, Kähönen, Mika, additional, Kolcic, Ivana, additional, Kors, Jan A., additional, Lakatta, Edward G., additional, Launer, Lenore J., additional, Lin, Honghuang, additional, Lin, Henry J., additional, Loos, Ruth J.F., additional, Lubitz, Steven A., additional, Macfarlane, Peter W., additional, Magnani, Jared W., additional, Mateo Leach, Irene, additional, Meitinger, Thomas, additional, Mitchell, Braxton D., additional, Munzel, Thomas, additional, Papanicolaou, George J., additional, Peters, Annette, additional, Pfeufer, Arne, additional, Pramstaller, Peter P., additional, Raitakari, Olli T., additional, Rotter, Jerome I., additional, Rudan, Igor, additional, Samani, Nilesh J., additional, Schlessinger, David, additional, Silva Aldana, Claudia T., additional, Sinner, Moritz F., additional, Smith, Jonathan D., additional, Snieder, Harold, additional, Soliman, Elsayed Z., additional, Spector, Timothy D., additional, Stott, David J., additional, Strauch, Konstantin, additional, Tarasov, Kirill V., additional, Uitterlinden, Andre G., additional, van Wagoner, David R., additional, Völker, Uwe, additional, Völzke, Henry, additional, Waldenberger, Melanie, additional, Westra, Harm Jan, additional, Wild, Philipp S., additional, Zeller, Tanja, additional, Alonso, Alvaro, additional, Avery, Christy L., additional, Bandinelli, Stefania, additional, Benjamin, Emelia J., additional, Cucca, Francesco, additional, Dörr, Marcus, additional, Ferrucci, Luigi, additional, Gasparini, Paolo, additional, Gudnason, Vilmundur, additional, Hayward, Caroline, additional, Heckbert, Susan R., additional, Hicks, Andrew A., additional, Jukema, J. Wouter, additional, Kääb, Stefan, additional, Lehtimäki, Terho, additional, Liu, Yongmei, additional, Munroe, Patricia B., additional, Parsa, Afshin, additional, Polasek, Ozren, additional, Psaty, Bruce M., additional, Roden, Dan M., additional, Schnabel, Renate B., additional, Sinagra, Gianfranco, additional, Stefansson, Kari, additional, Stricker, Bruno H., additional, van der Harst, Pim, additional, van Duijn, Cornelia M., additional, Wilson, James F., additional, Gharib, Sina, additional, de Bakker, Paul I.W., additional, Isaacs, Aaron, additional, Arking, Dan E., additional, and Sotoodehnia, Nona, additional

Published
2018
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48. 52 Genetic Loci Influencing Myocardial Mass

Author

Broad Institute of MIT and Harvard, Raychaudhuri, Soumya, van der Harst, Pim, van Setten, Jessica, Verweij, Niek, Vogler, Georg, Franke, Lude, Maurano, Matthew T., Wang, Xinchen, Mateo Leach, Irene, Eijgelsheim, Mark, Sotoodehnia, Nona, Hayward, Caroline, Sorice, Rossella, Meirelles, Osorio, Lyytikäinen, Leo-Pekka, Polašek, Ozren, Tanaka, Toshiko, Arking, Dan E., Ulivi, Sheila, Trompet, Stella, Müller-Nurasyid, Martina, Smith, Albert V., Dörr, Marcus, Kerr, Kathleen F., Magnani, Jared W., Fabiola Del Greco, M., Zhang, Weihua, Nolte, Ilja M., Silva, Claudia T., Padmanabhan, Sandosh, Tragante, Vinicius, Esko, Tõnu, Abecasis, Gonçalo R., Adriaens, Michiel E., Andersen, Karl, Barnett, Phil, Bis, Joshua C., Bodmer, Rolf, Buckley, Brendan M., Campbell, Harry, Cannon, Megan V., Chakravarti, Aravinda, Chen, Lin Y., Delitala, Alessandro, Devereux, Richard B., Doevendans, Pieter A., Dominiczak, Anna F., Ferrucci, Luigi, Ford, Ian, Gieger, Christian, Harris, Tamara B., Haugen, Eric, Heinig, Matthias, Hernandez, Dena G., Hillege, Hans L., Hirschhorn, Joel N., Hofman, Albert, Hubner, Norbert, Hwang, Shih-Jen, Iorio, Annamaria, Kahonen, Mika, Kellis, Manolis, Kolcic, Ivana, Kooner, Ishminder K., Kooner, Jaspal S., Kors, Jan A., Lakatta, Edward G., Lage, Kasper, Launer, Lenore J., Levy, Daniel, Lundby, Alicia, Macfarlane, Peter W., May, Dalit, Meitinger, Thomas, Metspalu, Andres, Nappo, Stefania, Naitza, Silvia, Neph, Shane, Nord, Alex S., Nutile, Teresa, Okin, Peter M., Olsen, Jesper V., Oostra, Ben A., Penninger, Josef M., Pennacchio, Len A., Pers, Tune H., Perz, Siegfried, Peters, Annette, Pinto, Yigal M., Pfeufer, Arne, Pilia, Maria Grazia, Pramstaller, Peter P., Prins, Bram P., Raitakari, Olli T., Rice, Ken M., Rossin, Elizabeth J., Rotter, Jerome I., Schafer, Sebastian, Schlessinger, David, Schmidt, Carsten O., Sehmi, Jobanpreet, Silljé, Herman H.W., Sinagra, Gianfranco, Sinner, Moritz F., Slowikowski, Kamil, Soliman, Elsayed Z., Spector, Timothy D., Spiering, Wilko, Stamatoyannopoulos, John A., Stolk, Ronald P., Strauch, Konstantin, Tan, Sian-Tsung, Tarasov, Kirill V., Trinh, Bosco, Uitterlinden, Andre G., van den Boogaard, Malou, van Duijn, Cornelia M., van Gilst, Wiek H., Viikari, Jorma S., Visscher, Peter M., Vitart, Veronique, Völker, Uwe, Waldenberger, Melanie, Weichenberger, Christian X., Westra, Harm-Jan, Wijmenga, Cisca, Wolffenbuttel, Bruce H., Yang, Jian, Bezzina, Connie R., Munroe, Patricia B., Snieder, Harold, Wright, Alan F., Rudan, Igor, Boyer, Laurie A., Asselbergs, Folkert W., van Veldhuisen, Dirk J., Stricker, Bruno H., Psaty, Bruce M., Ciullo, Marina, Sanna, Serena, Lehtimäki, Terho, Wilson, James F., Bandinelli, Stefania, Alonso, Alvaro, Gasparini, Paolo, Jukema, J. Wouter, Kääb, Stefan, Gudnason, Vilmundur, Felix, Stephan B., Heckbert, Susan R., de Boer, Rudolf A., Newton-Cheh, Christopher, Hicks, Andrew A., Chambers, John C., Jamshidi, Yalda, Visel, Axel, Christoffels, Vincent M., Isaacs, Aaron, Samani, Nilesh J., de Bakker, Paul I.W., Broad Institute of MIT and Harvard, Raychaudhuri, Soumya, van der Harst, Pim, van Setten, Jessica, Verweij, Niek, Vogler, Georg, Franke, Lude, Maurano, Matthew T., Wang, Xinchen, Mateo Leach, Irene, Eijgelsheim, Mark, Sotoodehnia, Nona, Hayward, Caroline, Sorice, Rossella, Meirelles, Osorio, Lyytikäinen, Leo-Pekka, Polašek, Ozren, Tanaka, Toshiko, Arking, Dan E., Ulivi, Sheila, Trompet, Stella, Müller-Nurasyid, Martina, Smith, Albert V., Dörr, Marcus, Kerr, Kathleen F., Magnani, Jared W., Fabiola Del Greco, M., Zhang, Weihua, Nolte, Ilja M., Silva, Claudia T., Padmanabhan, Sandosh, Tragante, Vinicius, Esko, Tõnu, Abecasis, Gonçalo R., Adriaens, Michiel E., Andersen, Karl, Barnett, Phil, Bis, Joshua C., Bodmer, Rolf, Buckley, Brendan M., Campbell, Harry, Cannon, Megan V., Chakravarti, Aravinda, Chen, Lin Y., Delitala, Alessandro, Devereux, Richard B., Doevendans, Pieter A., Dominiczak, Anna F., Ferrucci, Luigi, Ford, Ian, Gieger, Christian, Harris, Tamara B., Haugen, Eric, Heinig, Matthias, Hernandez, Dena G., Hillege, Hans L., Hirschhorn, Joel N., Hofman, Albert, Hubner, Norbert, Hwang, Shih-Jen, Iorio, Annamaria, Kahonen, Mika, Kellis, Manolis, Kolcic, Ivana, Kooner, Ishminder K., Kooner, Jaspal S., Kors, Jan A., Lakatta, Edward G., Lage, Kasper, Launer, Lenore J., Levy, Daniel, Lundby, Alicia, Macfarlane, Peter W., May, Dalit, Meitinger, Thomas, Metspalu, Andres, Nappo, Stefania, Naitza, Silvia, Neph, Shane, Nord, Alex S., Nutile, Teresa, Okin, Peter M., Olsen, Jesper V., Oostra, Ben A., Penninger, Josef M., Pennacchio, Len A., Pers, Tune H., Perz, Siegfried, Peters, Annette, Pinto, Yigal M., Pfeufer, Arne, Pilia, Maria Grazia, Pramstaller, Peter P., Prins, Bram P., Raitakari, Olli T., Rice, Ken M., Rossin, Elizabeth J., Rotter, Jerome I., Schafer, Sebastian, Schlessinger, David, Schmidt, Carsten O., Sehmi, Jobanpreet, Silljé, Herman H.W., Sinagra, Gianfranco, Sinner, Moritz F., Slowikowski, Kamil, Soliman, Elsayed Z., Spector, Timothy D., Spiering, Wilko, Stamatoyannopoulos, John A., Stolk, Ronald P., Strauch, Konstantin, Tan, Sian-Tsung, Tarasov, Kirill V., Trinh, Bosco, Uitterlinden, Andre G., van den Boogaard, Malou, van Duijn, Cornelia M., van Gilst, Wiek H., Viikari, Jorma S., Visscher, Peter M., Vitart, Veronique, Völker, Uwe, Waldenberger, Melanie, Weichenberger, Christian X., Westra, Harm-Jan, Wijmenga, Cisca, Wolffenbuttel, Bruce H., Yang, Jian, Bezzina, Connie R., Munroe, Patricia B., Snieder, Harold, Wright, Alan F., Rudan, Igor, Boyer, Laurie A., Asselbergs, Folkert W., van Veldhuisen, Dirk J., Stricker, Bruno H., Psaty, Bruce M., Ciullo, Marina, Sanna, Serena, Lehtimäki, Terho, Wilson, James F., Bandinelli, Stefania, Alonso, Alvaro, Gasparini, Paolo, Jukema, J. Wouter, Kääb, Stefan, Gudnason, Vilmundur, Felix, Stephan B., Heckbert, Susan R., de Boer, Rudolf A., Newton-Cheh, Christopher, Hicks, Andrew A., Chambers, John C., Jamshidi, Yalda, Visel, Axel, Christoffels, Vincent M., Isaacs, Aaron, Samani, Nilesh J., and de Bakker, Paul I.W.

Abstract

Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8. These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

Published
2017

49. Human AC8 Overexpression Increases the Ca 2+ Mediated Ensemble and Imparts Improved Rhythmicity to the Sinoatrial Node In Vivo and Ex Vivo

Author

Moen, Jack M., primary, Matt, Michael G., additional, Sirenko, Syevda G., additional, Tarasov, Kirill V., additional, Ahmet, Ismayil, additional, Ramirez, Chris, additional, Monfredi, Oliver, additional, Tsutsui, Kenta, additional, Ziman, Bruce, additional, Yaniv, Yael, additional, and Lakatta, Edward G., additional

Published
2017
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