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1. Early Renal Outcomes Following Heart Transplantation Using Organs Procured After Circulatory Death

Author: Joyce C. Zhou, Meghan E. Sise, Kamila Drezek, Stanley B. Wolfe, Asishana A. Osho, Monica N. Prario, S. Alireza Rabi, Eriberto Michel, Lana Tsao, Erin Coglianese, Meaghan Doucette, Christopher Newton‐Cheh, Sunu Thomas, Van‐Khue Ton, Nilay Sutaria, Mark W. Schoenike, Anastasia M. Christ, Dane C. Paneitz, Mauricio Villavicencio, Joren C. Madsen, Richard Pierson, Gregory D. Lewis, David A. D'Alessandro, and Daniel A. Zlotoff
Subjects: acute kidney injury, donation after circulatory death, heart transplantation, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Transplantation using hearts obtained through donation after circulatory death (DCD) is increasing, but data on recipient renal outcomes are limited. Methods and Results Patients at a single institution who underwent heart transplantation using organs procured through DCD or donation after brain death (DBD) from April 2016 to August 2022 were included in this retrospective cohort study. Hemodynamic measures were collected via right heart catheterization performed 1 week after transplantation. Posttransplantation renal outcomes included estimated glomerular filtration rate at 1 week, 4 weeks, and 16 weeks, and the incidence of acute kidney injury (AKI) and renal replacement therapy within 1 week. The analysis included 225 patients (55 recipients of DCD). Baseline characteristics were comparable between recipients of DCD and DBD. Renal outcomes within 1 week posttransplantation in recipients of DCD were similar to recipients of DBD, including percent change in estimated glomerular filtration rate (−37.9% [−58.6 to −6.2] versus −31.9% [−52.4 to −9.9]; P=0.91), incidence of AKI (47.3% versus 46.5%; P>0.99) and incidence of renal replacement therapy (3.6% versus 4.7%; P>0.99). Recipients of DCD with AKI within 1 week (“early AKI”) did not recover to baseline estimated glomerular filtration rate (75.8 [60.2–91.3] mL/min per 1.73 m2) by week 16 (59.3 [46.9–73.6] mL/min per 1.73 m2; P=0.002), whereas recipients without early AKI exhibited comparable estimated glomerular filtration rate to baseline by week 4 (84.5 [70.8–98.5] mL/min per 1.73 m2; P=0.084). Similar trends were observed in recipients of DBD. Conclusions Recipients of DCD demonstrated similar renal outcomes compared with recipients of DBD, supporting the ongoing use of DCD transplantation. Early AKI was associated with persistent renal dysfunction for recipients of both DCD and DBD.
Published: 2024
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2. Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

Author: William J. Young, Najim Lahrouchi, Aaron Isaacs, ThuyVy Duong, Luisa Foco, Farah Ahmed, Jennifer A. Brody, Reem Salman, Raymond Noordam, Jan-Walter Benjamins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Linda Repetto, Maria Pina Concas, Marten E. van den Berg, Stefan Weiss, Antoine R. Baldassari, Traci M. Bartz, James P. Cook, Daniel S. Evans, Rebecca Freudling, Oliver Hines, Jonas L. Isaksen, Honghuang Lin, Hao Mei, Arden Moscati, Martina Müller-Nurasyid, Casia Nursyifa, Yong Qian, Anne Richmond, Carolina Roselli, Kathleen A. Ryan, Eduardo Tarazona-Santos, Sébastien Thériault, Stefan van Duijvenboden, Helen R. Warren, Jie Yao, Dania Raza, Stefanie Aeschbacher, Gustav Ahlberg, Alvaro Alonso, Laura Andreasen, Joshua C. Bis, Eric Boerwinkle, Archie Campbell, Eulalia Catamo, Massimiliano Cocca, Michael J. Cutler, Dawood Darbar, Alessandro De Grandi, Antonio De Luca, Jun Ding, Christina Ellervik, Patrick T. Ellinor, Stephan B. Felix, Philippe Froguel, Christian Fuchsberger, Martin Gögele, Claus Graff, Mariaelisa Graff, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Paul L. Huang, Heikki V. Huikuri, Nina Hutri-Kähönen, M. Arfan Ikram, Rebecca D. Jackson, Juhani Junttila, Maryam Kavousi, Jan A. Kors, Thiago P. Leal, Rozenn N. Lemaitre, Henry J. Lin, Lars Lind, Allan Linneberg, Simin Liu, Peter W. MacFarlane, Massimo Mangino, Thomas Meitinger, Massimo Mezzavilla, Pashupati P. Mishra, Rebecca N. Mitchell, Nina Mononen, May E. Montasser, Alanna C. Morrison, Matthias Nauck, Victor Nauffal, Pau Navarro, Kjell Nikus, Guillaume Pare, Kristen K. Patton, Giulia Pelliccione, Alan Pittman, David J. Porteous, Peter P. Pramstaller, Michael H. Preuss, Olli T. Raitakari, Alexander P. Reiner, Antonio Luiz P. Ribeiro, Kenneth M. Rice, Lorenz Risch, David Schlessinger, Ulrich Schotten, Claudia Schurmann, Xia Shen, M. Benjamin Shoemaker, Gianfranco Sinagra, Moritz F. Sinner, Elsayed Z. Soliman, Monika Stoll, Konstantin Strauch, Kirill Tarasov, Kent D. Taylor, Andrew Tinker, Stella Trompet, André Uitterlinden, Uwe Völker, Henry Völzke, Melanie Waldenberger, Lu-Chen Weng, Eric A. Whitsel, James G. Wilson, Christy L. Avery, David Conen, Adolfo Correa, Francesco Cucca, Marcus Dörr, Sina A. Gharib, Giorgia Girotto, Niels Grarup, Caroline Hayward, Yalda Jamshidi, Marjo-Riitta Järvelin, J. Wouter Jukema, Stefan Kääb, Mika Kähönen, Jørgen K. Kanters, Charles Kooperberg, Terho Lehtimäki, Maria Fernanda Lima-Costa, Yongmei Liu, Ruth J. F. Loos, Steven A. Lubitz, Dennis O. Mook-Kanamori, Andrew P. Morris, Jeffrey R. O’Connell, Morten Salling Olesen, Michele Orini, Sandosh Padmanabhan, Cristian Pattaro, Annette Peters, Bruce M. Psaty, Jerome I. Rotter, Bruno Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James F. Wilson, Dan E. Arking, Julia Ramirez, Pier D. Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-Cheh, and Patricia B. Munroe
Subjects: Science
Abstract: The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.
Published: 2022
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3. The genomics of heart failure: design and rationale of the HERMES consortium

Author: R. Thomas Lumbers, Sonia Shah, Honghuang Lin, Tomasz Czuba, Albert Henry, Daniel I. Swerdlow, Anders Mälarstig, Charlotte Andersson, Niek Verweij, Michael V. Holmes, Johan Ärnlöv, Per Svensson, Harry Hemingway, Neneh Sallah, Peter Almgren, Krishna G. Aragam, Geraldine Asselin, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Eric Boersma, Jeffrey Brandimarto, Michael R. Brown, Hans‐Peter Brunner‐La Rocca, David J. Carey, Mark D. Chaffin, Daniel I. Chasman, Olympe Chazara, Xing Chen, Xu Chen, Jonathan H. Chung, William Chutkow, John G.F. Cleland, James P. Cook, Simon deDenus, Abbas Dehghan, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Gunnar Engström, Tõnu Esko, Ghazaleh Fatemifar, Stephan B. Felix, Chris Finan, Ian Ford, Francoise Fougerousse, René Fouodjio, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Hongsheng Gui, Rebecca Gutmann, Christopher M. Haggerty, Pim van derHarst, Åsa K. Hedman, Anna Helgadottir, Hans Hillege, Craig L. Hyde, Jaison Jacob, J. Wouter Jukema, Frederick Kamanu, Isabella Kardys, Maryam Kavousi, Kay‐Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Bill Kraus, Karoline Kuchenbaecker, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian'an Luan, Patrik Magnusson, Anubha Mahajan, Douglas Mann, Kenneth B. Margulies, Nicholas A. Marston, Winfried März, John J.V. McMurray, Olle Melander, Giorgio Melloni, Ify R. Mordi, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Christopher Newton‐Cheh, Alexander Niessner, Teemu Niiranen, Christoph Nowak, Michelle L. O'Donoghue, Anjali T. Owens, Colin N.A. Palmer, Guillaume Paré, Markus Perola, Louis‐Philippe Lemieux Perreault, Eliana Portilla‐Fernandez, Bruce M. Psaty, Kenneth M. Rice, Paul M. Ridker, Simon P.R. Romaine, Carolina Roselli, Jerome I. Rotter, Christian T. Ruff, Marc S. Sabatine, Perttu Salo, Veikko Salomaa, Jessica vanSetten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Kari Stefansson, Steen Stender, David J. Stott, Garðar Sveinbjörnsson, Mari‐Liis Tammesoo, Jean‐Claude Tardif, Kent D. Taylor, Maris Teder‐Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp‐Pedersen, Stella Trompet, Danny Tuckwell, Benoit Tyl, Andre G. Uitterlinden, Felix Vaura, Abirami Veluchamy, Peter M. Visscher, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Peter E. Weeke, Raul Weiss, Harvey D. White, Kerri L. Wiggins, Heming Xing, Jian Yang, Yifan Yang, Laura M. Yerges‐Armstrong, Bing Yu, Faiez Zannad, Faye Zhao, Regeneron Genetics Center, Jemma B. Wilk, Hilma Holm, Naveed Sattar, Steven A. Lubitz, David E. Lanfear, Svati Shah, Michael E. Dunn, Quinn S. Wells, Folkert W. Asselbergs, Aroon D. Hingorani, Marie‐Pierre Dubé, Nilesh J. Samani, Chim C. Lang, Thomas P. Cappola, Patrick T. Ellinor, Ramachandran S. Vasan, and J. Gustav Smith
Subjects: Heart failure, Cardiomyopathy, Genetics, Biomarkers, Association studies, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P
Published: 2021
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4. Heart Failure Strategically Focused Research Network: Summary of Results and Future Directions

Author: G.Michael Felker, Peter Buttrick, Anthony Rosenzweig, E. Dale Abel, Larry A. Allen, Michael Bristow, Saumya Das, Adam D. DeVore, Stavros G. Drakos, James C. Fang, Jane E. Freedman, Adrian F. Hernandez, Dean Y. Li, Timothy A. McKinsey, Christopher Newton‐Cheh, Joseph G. Rogers, Ravi V. Shah, Svati H. Shah, Josef Stehlik, and Craig H. Selzman
Subjects: clinical trials, heart failure, metabolism, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Heart failure remains among the most common and morbid health conditions. The Heart Failure Strategically Focused Research Network (HF SFRN) was funded by the American Heart Association to facilitate collaborative, high‐impact research in the field of heart failure across the domains of basic, clinical, and population research. The Network was also charged with developing training opportunities for young investigators. Four centers were funded in 2016: Duke University, University of Colorado, University of Utah, and Massachusetts General Hospital‐University of Massachusetts. This report summarizes the aims of each center and major research accomplishments, as well as training outcomes from the HF SFRN.
Published: 2022
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5. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author: Sonia Shah, Albert Henry, Carolina Roselli, Honghuang Lin, Garðar Sveinbjörnsson, Ghazaleh Fatemifar, Åsa K. Hedman, Jemma B. Wilk, Michael P. Morley, Mark D. Chaffin, Anna Helgadottir, Niek Verweij, Abbas Dehghan, Peter Almgren, Charlotte Andersson, Krishna G. Aragam, Johan Ärnlöv, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Jeffrey Brandimarto, Michael R. Brown, Leonard Buckbinder, David J. Carey, Daniel I. Chasman, Xing Chen, Xu Chen, Jonathan Chung, William Chutkow, James P. Cook, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Michael E. Dunn, Gunnar Engström, Tõnu Esko, Stephan B. Felix, Chris Finan, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Rebecca Gutmann, Christopher M. Haggerty, Pim van der Harst, Craig L. Hyde, Erik Ingelsson, J. Wouter Jukema, Maryam Kavousi, Kay-Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian’an Luan, Patrik Magnusson, Anubha Mahajan, Kenneth B. Margulies, Winfried März, Olle Melander, Ify R. Mordi, Thomas Morgan, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Alexander Niessner, Teemu Niiranen, Michelle L. O’Donoghue, Anjali T. Owens, Colin N. A. Palmer, Helen M. Parry, Markus Perola, Eliana Portilla-Fernandez, Bruce M. Psaty, Regeneron Genetics Center, Kenneth M. Rice, Paul M. Ridker, Simon P. R. Romaine, Jerome I. Rotter, Perttu Salo, Veikko Salomaa, Jessica van Setten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Steen Stender, David J. Stott, Per Svensson, Mari-Liis Tammesoo, Kent D. Taylor, Maris Teder-Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Stella Trompet, Benoit Tyl, Andre G. Uitterlinden, Abirami Veluchamy, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Dawn Waterworth, Peter E. Weeke, Raul Weiss, Kerri L. Wiggins, Heming Xing, Laura M. Yerges-Armstrong, Bing Yu, Faiez Zannad, Jing Hua Zhao, Harry Hemingway, Nilesh J. Samani, John J. V. McMurray, Jian Yang, Peter M. Visscher, Christopher Newton-Cheh, Anders Malarstig, Hilma Holm, Steven A. Lubitz, Naveed Sattar, Michael V. Holmes, Thomas P. Cappola, Folkert W. Asselbergs, Aroon D. Hingorani, Karoline Kuchenbaecker, Patrick T. Ellinor, Chim C. Lang, Kari Stefansson, J. Gustav Smith, Ramachandran S. Vasan, Daniel I. Swerdlow, and R. Thomas Lumbers
Subjects: Science
Abstract: Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.
Published: 2020
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6. Virtual multidisciplinary care for heart failure patients with cardiac resynchronization therapy devices during the Coronavirus Disease 2019 pandemic

Author: Megan Zhao, Dingxin Qin, Giulio Cataldo, Krishan Sharma, Nupur Dandwate, Mary P Orencole, Christopher Newton-Cheh, E. Kevin Heist, William J. Hucker, Nasrien Ibrahim, Jagmeet P Singh, and Saumya Das
Subjects: CRT, Telemedicine, Multidisciplinary care, Patient outcomes, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background: Heart failure (HF) patients with CRT devices are a vulnerable patient population during the Coronavirus Disease 2019 (COVID-19) Pandemic. It is important to develop innovative virtual care models to deliver multidisciplinary care while minimizing the risk of SARS-CoV2 exposure. Objective: We aim to provide a description of how HF patients with CRT devices were assessed and managed in our virtual multidisciplinary clinic during the COVID-19 Pandemic. Clinical outcomes between this group of patients seen in virtual clinic and a historical cohort followed by in-person multi-disciplinary clinic prior to the pandemic were compared. Method: This is a retrospective cohort study of HF patients with CRT implants who were seen in the virtual multidisciplinary clinic from March 18th, 2020 to May 27th, 2020 (Virtual Visit Group, N = 43). A historical cohort of HF patients with CRT devices seen in the ReACT clinic in person during the same calendar time period in 2019 was used as a control group (In-Person Visit Group, N = 39). Both groups were followed until July 1st of the same calendar year (2020 or 2019) for clinical events. The primary outcome measure was a combined outcome of all-cause mortality and HF- or device-related hospitalizations during follow-up. The secondary outcome measures included patient satisfaction, COVID-19 infection, and other cardiovascular events. Results: In the Virtual-Visit Group, 21 patients (48.8%) had their initial ReACT clinic visit (first visit after CRT implant) as a virtual visit; 22 patients (51.2%) had prior in-person ReACT clinic visits before the first virtual visit. During the virtual visits, 12 patients had either potential cardiac symptoms or significant device interrogation findings that required clinical intervention. In post-virtual clinic patient satisfaction survey, all 22 patients surveyed (100%) reported being very satisfied or satisfied with the overall experience of the virtual clinic, and every patient (100%) said they would like to use telemedicine again. During a median follow-up period of 82 days (interquartile range [IQR] 61–96 days), one patient died from pneumonia of unclear etiology at an outside hospital, without documentation of COVID-19 positivity. No patient was hospitalized for HF- or arrhythmia-related complications. No patient was diagnosed with COVID-19. Compared with the In-Person Visit Group, there was no significant increase in mortality or major cardiovascular events in the Virtual-Visit Group (2.3% versus 5.1%, P = 0.60). Conclusions and Relevance: Virtual multidisciplinary care was feasible for HF patients with cardiac resynchronization therapy devices and achieved good patient satisfaction. Virtual care was not associated with short-term increase in adverse events for HF patients with CRT device during the COVID-19 Pandemic. This virtual care model could help promote the adoption of digital health methodology for high-risk patients with multiple cardiac comorbidities.
Published: 2021
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7. Effects of Vitamin D Supplementation on Cardiovascular and Glycemic Biomarkers

Author: Jennifer Miao, Katherine N. Bachmann, Shi Huang, Yan Ru Su, Jeffery Dusek, Christopher Newton‐Cheh, Pankaj Arora, and Thomas J. Wang
Subjects: high‐sensitivity C‐reactive protein, insulin resistance, lipids, meta‐analysis, vitamin D, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Experimental and observational studies have suggested a link between vitamin D and cardiovascular and metabolic disease, but this has not been confirmed in randomized controlled trials. We sought to determine whether vitamin D supplementation reduces biomarkers of insulin resistance, inflammation, neurohormonal activation, and lipids. Methods and Results This was a prespecified, secondary analysis of the DAYLIGHT (Vitamin D Therapy in Individuals at High Risk of Hypertension) randomized controlled trial. We measured circulating homeostatic model assessment of insulin resistance, hs‐CRP (high‐sensitivity C‐reactive protein), N‐terminal pro‐B‐type natriuretic peptide, renin, aldosterone, and lipids at baseline and at 6 months in 289 individuals with low vitamin D status (25‐hydroxyvitamin‐D [25‐OH‐D] ≤25 ng/mL) receiving low‐dose (400 IU/d) versus high‐dose (4000 IU/d) vitamin D3 for 6 months. A meta‐analysis of randomized controlled trials reporting biomarker changes after vitamin D supplementation was then performed. Levels of 25‐OH‐D increased in the high‐dose relative to the low‐dose vitamin D group (+15.5 versus +4.6 ng/mL, P
Published: 2021
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8. Genome-wide analysis yields new loci associating with aortic valve stenosis

Author: Anna Helgadottir, Gudmar Thorleifsson, Solveig Gretarsdottir, Olafur A. Stefansson, Vinicius Tragante, Rosa B. Thorolfsdottir, Ingileif Jonsdottir, Thorsteinn Bjornsson, Valgerdur Steinthorsdottir, Niek Verweij, Jonas B. Nielsen, Wei Zhou, Lasse Folkersen, Andreas Martinsson, Mahyar Heydarpour, Siddharth Prakash, Gylfi Oskarsson, Tomas Gudbjartsson, Arnar Geirsson, Isleifur Olafsson, Emil L. Sigurdsson, Peter Almgren, Olle Melander, Anders Franco-Cereceda, Anders Hamsten, Lars Fritsche, Maoxuan Lin, Bo Yang, Whitney Hornsby, Dongchuan Guo, Chad M. Brummett, Gonçalo Abecasis, Michael Mathis, Dianna Milewicz, Simon C. Body, Per Eriksson, Cristen J. Willer, Kristian Hveem, Christopher Newton-Cheh, J. Gustav Smith, Ragnar Danielsen, Gudmundur Thorgeirsson, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Hilma Holm, and Kari Stefansson
Subjects: Science
Abstract: Aortic valve stenosis (AS) is the most common valvular heart disease. Here the authors identify two new AS loci that also associate with bicuspid aortic valve, aortic root diameter and/or coronary artery disease implicating both developmental abnormalities and atherosclerosis-like processes in AS.
Published: 2018
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9. Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

Author: G. Todd Milne, on behalf of the Ironwood team, Peter Sandner, Kathleen A. Lincoln, Paul C. Harrison, Hongxing Chen, Hong Wang, Holly Clifford, Hu Sheng Qian, Diane Wong, Chris Sarko, Ryan Fryer, Jeremy Richman, Glenn A. Reinhart, Carine M. Boustany, Steven S. Pullen, Henriette Andresen, Lise Román Moltzau, Alessandro Cataliotti, Finn Olav Levy, Robert Lukowski, Sandra Frankenreiter, Andreas Friebe, Timothy Calamaras, Robert Baumgartner, Angela McLaughlin, Mark Aronovitz, Wendy Baur, Guang-Rong Wang, Navin Kapur, Richard Karas, Robert Blanton, Stefan Hell, Scott A. Waldman, Jieru E. Lin, Francheska Colon-Gonzalez, Gilbert W. Kim, Erik S. Blomain, Dante Merlino, Adam Snook, Jeanette Erdmann, Jana Wobst, Thorsten Kessler, Heribert Schunkert, Ulrich Walter, Oliver Pagel, Elena Walter, Stepan Gambaryan, Albert Smolenski, Kerstin Jurk, Rene Zahedi, James R. Klinger, Raymond L. Benza, Paul A. Corris, David Langleben, Robert Naeije, Gérald Simonneau, Christian Meier, Pablo Colorado, Mi Kyung Chang, Dennis Busse, Marius M. Hoeper, Jaime L. Masferrer, Sarah Jacobson, Guang Liu, Renee Sarno, Sylvie Bernier, Ping Zhang, Roger Flores-Costa, Mark Currie, Katherine Hall, Dorit Möhrle, Katrin Reimann, Steffen Wolter, Markus Wolters, Evanthia Mergia, Nicole Eichert, Hyun-Soon Geisler, Peter Ruth, Robert Feil, Ulrike Zimmermann, Doris Koesling, Marlies Knipper, Lukas Rüttiger, Yasutake Tanaka, Atsuko Okamoto, Takashi Nojiri, Motofumi Kumazoe, Takeshi Tokudome, Koichi Miura, Jun Hino, Hiroshi Hosoda, Mikiya Miyazato, Kenji Kangawa, Vikas Kapil, Amrita Ahluwalia, Nazareno Paolocci, Philip Eaton, James C. Campbell, Philipp Henning, Eugen Franz, Banumathi Sankaran, Friedrich W. Herberg, Choel Kim, M. Wittwer, Q. Luo, V. Kaila, S. A. Dames, Andrew Tobin, Mahmood Alam, Olena Rudyk, Susanne Krasemann, Kristin Hartmann, Oleksandra Prysyazhna, Min Zhang, Lan Zhao, Astrid Weiss, Ralph Schermuly, Amie J. Moyes, Sandy M. Chu, Reshma S. Baliga, Adrian J. Hobbs, Stylianos Michalakis, Regine Mühlfriedel, Christian Schön, Dominik M. Fischer, Barbara Wilhelm, Ditta Zobor, Susanne Kohl, Tobias Peters, Eberhart Zrenner, Karl Ulrich Bartz-Schmidt, Marius Ueffing, Bernd Wissinger, Mathias Seeliger, Martin Biel, RD-CURE consortium, Mark J. Ranek, Kristen M. Kokkonen, Dong I. Lee, Ronald J. Holewinski, Vineet Agrawal, Cornelia Virus, Donté A. Stevens, Masayuki Sasaki, Huaqun Zhang, Mathew M. Mannion, Peter P. Rainer, Richard C. Page, Jonathan C. Schisler, Jennifer E. Van Eyk, Monte S. Willis, David A. Kass, Manuela Zaccolo, Michael Russwurm, Jan Giesen, Corina Russwurm, Ernst-Martin Füchtbauer, Nadja I. Bork, Viacheslav O. Nikolaev, Luis Agulló, Martin Floor, Jordi Villà-Freixa, Ornella Manfra, Gaia Calamera, Nicoletta C. Surdo, Silja Meier, Alexander Froese, Kjetil Wessel Andressen, Annemarie Aue, Fabian Schwiering, Dieter Groneberg, Gzona Bajraktari, Jürgen Burhenne, Walter E. Haefeli, Johanna Weiss, Katharina Beck, Barbara Voussen, Alexander Vincent, Sean P. Parsons, Jan D. Huizinga, Fabiola Zakia Mónica, Edward Seto, Ferid Murad, Ka Bian, Joseph R. Burgoyne, Daniel Richards, Marianne Bjørnerem, Andrea Hembre Ulsund, Jeong Joo Kim, Sonia Donzelli, Mara Goetz, Kjestine Schmidt, Konstantina Stathopoulou, Jenna Scotcher, Christian Dees, Hariharan Subramanian, Elke Butt, Alisa Kamynina, S. Bruce King, Cor de Witt, Lars I. Leichert, Friederike Cuello, Hyazinth Dobrowinski, Moritz Lehners, Michael Paolillo Hannes Schmidt, Susanne Feil, Lai Wen, Martin Thunemann, Marcus Olbrich, Harald Langer, Meinrad Gawaz, Cor de Wit, Daniela Bertinetti, Hossein-Ardeschir Ghofrani, Friedrich Grimminger, Ekkehard Grünig, Yigao Huang, Pavel Jansa, Zhi Cheng Jing, David Kilpatrick, Stephan Rosenkranz, Flavia Menezes, Arno Fritsch, Sylvia Nikkho, Reiner Frey, Marc Humbert, Manuela Harloff, Joerg Reinders, Jens Schlossmann, Joon Jung, Jessica A. Wales, Cheng-Yu Chen, Linda Breci, Andrzej Weichsel, Sylvie G. Bernier, Robert Solinga, James E. Sheppeck, Paul A. Renhowe, William R. Montfort, Liying Qin, Ying-Ju Sung, Darren Casteel, Alexander Kollau, Andrea Neubauer, Astrid Schrammel, Bernd Mayer, Mika Takai, Chieri Takeuchi, Mai Kadomatsu, Shun Hiroi, Kanako Takamatsu, Hirofumi Tachibana, Marissa Opelt, Emrah Eroglu, Markus Waldeck-Weiermair, Roland Malli, Wolfgang F. Graier, John T. Fassett, Selene J. Sollie, Maria Hernandez-Valladares, Frode Berven, Kjetil W. Andressen, Miki Arai, Yutaka Suzuki, Meinoshin Okumura, Shinpei Kawaoka, Stefanie Peters, Hannes Schmidt, B. Selin Kenet, Sarah Helena Nies, Katharina Frank, Fritz G. Rathjen, Olga N. Petrova, Isabelle Lamarre, Michel Négrerie, Jerid W. Robinson, Jeremy R. Egbert, Julia Davydova, Laurinda A. Jaffe, Lincoln R. Potter, Nicholas Blixt, Leia C. Shuhaibar, Gordon L. Warren, Kim C. Mansky, Simone Romoli, Tobias Bauch, Karoline Dröbner, Frank Eitner, Mihály Ruppert, Tamás Radovits, Sevil Korkmaz-Icöz, Shiliang Li, Péter Hegedűs, Sivakanan Loganathan, Balázs Tamás Németh, Attila Oláh, Csaba Mátyás, Kálmán Benke, Béla Merkely, Matthias Karck, Gábor Szabó, Ulrike Scheib, Matthias Broser, Shatanik Mukherjee, Katja Stehfest, Christine E. Gee, Heinz G. Körschen, Thomas G. Oertner, Peter Hegemann, Deborah M. Dickey, Alexandre Dumoulin, Ralf Kühn, Laurinda Jaffe, Sophie Schobesberger, Peter Wright, Claire Poulet, Catherine Mansfield, Sian E. Harding, Julia Gorelik, Gerald Wölkart, Antonius C. F. Gorren, Gerburg K. Schwaerzer, Darren E. Casteel, Nancy D. Dalton, Yusu Gu, Shunhui Zhuang, Dianna M. Milewicz, Kirk L. Peterson, Renate Pilz, Aikaterini I. Argyriou, Garyfalia Makrynitsa, Ioannis I. Alexandropoulos, Andriana Stamopoulou, Marina Bantzi, Athanassios Giannis, Stavros Topouzis, Andreas Papapetropoulos, Georgios A. Spyroulias, Dennis J. Stuehr, Arnab Ghosh, Yue Dai, Saurav Misra, Boris Tchernychev, Inmaculada Silos-Santiago, Gerhard Hannig, Vu Thao-Vi Dao, Martin Deile, Pavel I. Nedvetsky, Andreas Güldner, César Ibarra-Alvarado, Axel Gödecke, Harald H. H. W. Schmidt, Angelos Vachaviolos, Andrea Gerling, Stefan Z. Lutz, Hans-Ulrich Häring, Marcel A. Krüger, Bernd J. Pichler, Michael J. Shipston, Sara Vandenwijngaert, Clara D. Ledsky, Obiajulu Agha, Dongjian Hu, Ibrahim J. Domian, Emmanuel S. Buys, Christopher Newton-Cheh, Donald B. Bloch, Nadine Mauro, Jonas Keppler, Wilson A. Ferreira, Hanan Chweih, Pamela L. Brito, Camila B. Almeida, Carla F. F. Penteado, Sara S. O. Saad, Fernando F. Costa, Paul S. Frenette, Damian Brockschnieder, Johannes-Peter Stasch, Nicola Conran, Daniel P. Zimmer, Jenny Tobin, Courtney Shea, Kimberly Long, Kim Tang, Peter Germano, James Wakefield, Ali Banijamali, G-Yoon Jamie Im, Albert T. Profy, and Mark G. Currie
Subjects: Therapeutics. Pharmacology, RM1-950, Toxicology. Poisons, RA1190-1270
Published: 2017
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10. Applications of machine learning in decision analysis for dose management for dofetilide.

Author: Andrew E Levy, Minakshi Biswas, Rachel Weber, Khaldoun Tarakji, Mina Chung, Peter A Noseworthy, Christopher Newton-Cheh, and Michael A Rosenberg
Subjects: Medicine, Science
Abstract: BACKGROUND:Initiation of the antiarrhythmic medication dofetilide requires an FDA-mandated 3 days of telemetry monitoring due to heightened risk of toxicity within this time period. Although a recommended dose management algorithm for dofetilide exists, there is a range of real-world approaches to dosing the medication. METHODS AND RESULTS:In this multicenter investigation, clinical data from the Antiarrhythmic Drug Genetic (AADGEN) study was examined for 354 patients undergoing dofetilide initiation. Univariate logistic regression identified a starting dofetilide dose of 500 mcg (OR 5.0, 95%CI 2.5-10.0, p
Published: 2019
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11. MicroRNA-425 and microRNA-155 cooperatively regulate atrial natriuretic peptide expression and cGMP production.

Author: Sara Vandenwijngaert, Clara D Ledsky, Obiajulu Agha, Connie Wu, Dongjian Hu, Aranya Bagchi, Ibrahim J Domian, Emmanuel S Buys, Christopher Newton-Cheh, and Donald B Bloch
Subjects: Medicine, Science
Abstract: AIMS:Atrial natriuretic peptide (ANP), secreted primarily by atrial cardiomyocytes, decreases blood pressure by raising cyclic 3',5'-guanosine monophosphate (cGMP) levels and inducing vasorelaxation, natriuresis, and diuresis. Raising the level of ANP has been shown to be an effective treatment for hypertension. To advance the future development of an anti-microRNA (miR) approach to increasing expression of ANP, we investigated the regulation of NPPA expression by two miRs: miR-425 and miR-155. We examined whether miR-425 and miR-155 have an additive effect on the expression and function of ANP. METHODS AND RESULTS:Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) were transfected with miR-425, miR-155, or a combination of the two miRs. Two days later, NPPA expression was measured using real time qPCR. Each of the miRs decreased NPPA expression over a wide range of concentrations, with a significant reduction at concentrations as low as 1 nM. The combination of miR-425 and miR-155 reduced NPPA expression to a greater extent than either miR-425 or miR-155 alone. An in vitro assay was developed to study the potential biological significance of the miR-induced decrease in NPPA expression. The cooperative effect of miR-425 and miR-155 on NPPA expression was associated with a significant decrease in cGMP levels. CONCLUSIONS:These data demonstrate that miR-425 and miR-155 regulate NPPA expression in a cooperative manner. Targeting both miRNAs with anti-miRs (possibly at submaximal concentrations) might prove to be a more effective strategy to modulate ANP levels, and thus blood pressure, than targeting either miRNA alone.
Published: 2018
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12. Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.

Author: J Gustav Smith, Janine F Felix, Alanna C Morrison, Andreas Kalogeropoulos, Stella Trompet, Jemma B Wilk, Olof Gidlöf, Xinchen Wang, Michael Morley, Michael Mendelson, Roby Joehanes, Symen Ligthart, Xiaoyin Shan, Joshua C Bis, Ying A Wang, Marketa Sjögren, Julius Ngwa, Jeffrey Brandimarto, David J Stott, David Aguilar, Kenneth M Rice, Howard D Sesso, Serkalem Demissie, Brendan M Buckley, Kent D Taylor, Ian Ford, Chen Yao, Chunyu Liu, CHARGE-SCD consortium, EchoGen consortium, QT-IGC consortium, CHARGE-QRS consortium, Nona Sotoodehnia, Pim van der Harst, Bruno H Ch Stricker, Stephen B Kritchevsky, Yongmei Liu, J Michael Gaziano, Albert Hofman, Christine S Moravec, André G Uitterlinden, Manolis Kellis, Joyce B van Meurs, Kenneth B Margulies, Abbas Dehghan, Daniel Levy, Björn Olde, Bruce M Psaty, L Adrienne Cupples, J Wouter Jukema, Luc Djousse, Oscar H Franco, Eric Boerwinkle, Laurie A Boyer, Christopher Newton-Cheh, Javed Butler, Ramachandran S Vasan, Thomas P Cappola, and Nicholas L Smith
Subjects: Genetics, QH426-470
Abstract: Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.
Published: 2016
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13. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

Author: Xinchen Wang, Nathan R Tucker, Gizem Rizki, Robert Mills, Peter HL Krijger, Elzo de Wit, Vidya Subramanian, Eric Bartell, Xinh-Xinh Nguyen, Jiangchuan Ye, Jordan Leyton-Mange, Elena V Dolmatova, Pim van der Harst, Wouter de Laat, Patrick T Ellinor, Christopher Newton-Cheh, David J Milan, Manolis Kellis, and Laurie A Boyer
Subjects: genome-wide association study, epigenomics, heritability, enhancer, complex trait, Medicine, Science, Biology (General), QH301-705.5
Abstract: Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits.
Published: 2016
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14. Correction: The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits.

Author: Benjamin F. Voight, Hyun Min Kang, Jun Ding, Cameron D. Palmer, Carlo Sidore, Peter S. Chines, Noël P. Burtt, Christian Fuchsberger, Yanming Li, Jeanette Erdmann, Timothy M. Frayling, Iris M. Heid, Anne U. Jackson, Toby Johnson, Tuomas O. Kilpeläinen, Cecilia M. Lindgren, Andrew P. Morris, Inga Prokopenko, Joshua C. Randall, Richa Saxena, Nicole Soranzo, Elizabeth K. Speliotes, Tanya M. Teslovich, Eleanor Wheeler, Jared Maguire, Melissa Parkin, Simon Potter, N. William Rayner, Neil Robertson, Kathleen Stirrups, Wendy Winckler, Serena Sanna, Antonella Mulas, Ramaiah Nagaraja, Francesco Cucca, Inês Barroso, Panos Deloukas, Ruth J. F. Loos, Sekar Kathiresan, Patricia B. Munroe, Christopher Newton-Cheh, Arne Pfeufer, Nilesh J. Samani, Heribert Schunkert, Joel N. Hirschhorn, David Altshuler, Mark I. McCarthy, Gonçalo R. Abecasis, and Michael Boehnke
Subjects: Genetics, QH426-470
Published: 2013
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15. Novel loci associated with increased risk of sudden cardiac death in the context of coronary artery disease.

Author: Adriana Huertas-Vazquez, Christopher P Nelson, Xiuqing Guo, Kyndaron Reinier, Audrey Uy-Evanado, Carmen Teodorescu, Jo Ayala, Katherine Jerger, Harpriya Chugh, WTCCC, Peter S Braund, Panos Deloukas, Alistair S Hall, Anthony J Balmforth, Michelle Jones, Kent D Taylor, Sara L Pulit, Christopher Newton-Cheh, Karen Gunson, Jonathan Jui, Jerome I Rotter, Christine M Albert, Nilesh J Samani, and Sumeet S Chugh
Subjects: Medicine, Science
Abstract: Recent genome-wide association studies (GWAS) have identified novel loci associated with sudden cardiac death (SCD). Despite this progress, identified DNA variants account for a relatively small portion of overall SCD risk, suggesting that additional loci contributing to SCD susceptibility await discovery. The objective of this study was to identify novel DNA variation associated with SCD in the context of coronary artery disease (CAD).Using the MetaboChip custom array we conducted a case-control association analysis of 119,117 SNPs in 948 SCD cases (with underlying CAD) from the Oregon Sudden Unexpected Death Study (Oregon-SUDS) and 3,050 controls with CAD from the Wellcome Trust Case-Control Consortium (WTCCC). Two newly identified loci were significantly associated with increased risk of SCD after correction for multiple comparisons at: rs6730157 in the RAB3GAP1 gene on chromosome 2 (P = 4.93×10(-12), OR = 1.60) and rs2077316 in the ZNF365 gene on chromosome 10 (P = 3.64×10(-8), OR = 2.41).Our findings suggest that RAB3GAP1 and ZNF365 are relevant candidate genes for SCD and will contribute to the mechanistic understanding of SCD susceptibility.
Published: 2013
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16. The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits.

Author: Benjamin F Voight, Hyun Min Kang, Jun Ding, Cameron D Palmer, Carlo Sidore, Peter S Chines, Noël P Burtt, Christian Fuchsberger, Yanming Li, Jeanette Erdmann, Timothy M Frayling, Iris M Heid, Anne U Jackson, Toby Johnson, Tuomas O Kilpeläinen, Cecilia M Lindgren, Andrew P Morris, Inga Prokopenko, Joshua C Randall, Richa Saxena, Nicole Soranzo, Elizabeth K Speliotes, Tanya M Teslovich, Eleanor Wheeler, Jared Maguire, Melissa Parkin, Simon Potter, N William Rayner, Neil Robertson, Kathleen Stirrups, Wendy Winckler, Serena Sanna, Antonella Mulas, Ramaiah Nagaraja, Francesco Cucca, Inês Barroso, Panos Deloukas, Ruth J F Loos, Sekar Kathiresan, Patricia B Munroe, Christopher Newton-Cheh, Arne Pfeufer, Nilesh J Samani, Heribert Schunkert, Joel N Hirschhorn, David Altshuler, Mark I McCarthy, Gonçalo R Abecasis, and Michael Boehnke
Subjects: Genetics, QH426-470
Abstract: Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the "Metabochip," a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits.
Published: 2012
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17. Common genetic variants associated with sudden cardiac death: the FinSCDgen study.

Author: Annukka M Lahtinen, Peter A Noseworthy, Aki S Havulinna, Antti Jula, Pekka J Karhunen, Johannes Kettunen, Markus Perola, Kimmo Kontula, Christopher Newton-Cheh, and Veikko Salomaa
Subjects: Medicine, Science
Abstract: Sudden cardiac death (SCD) accounts for up to half of cardiac mortality. The risk of SCD is heritable but the underlying genetic variants are largely unknown. We investigated whether common genetic variants predisposing to arrhythmia or related electrocardiographic phenotypes, including QT-interval prolongation, are associated with increased risk of SCD.We studied the association between 28 candidate SNPs and SCD in a meta-analysis of four population cohorts (FINRISK 1992, 1997, 2002 and Health 2000, n = 27,629) and two forensic autopsy series (The Helsinki Sudden Death Study and The Tampere Autopsy Study, n = 694). We also studied the association between established cardiovascular risk factors and SCD. Causes of death were reviewed using registry-based health and autopsy data. Cox regression and logistic regression models were adjusted for age, sex, and geographic region. The total number of SCDs was 716. Two novel SNPs were associated with SCD: SCN5A rs41312391 (relative risk [RR] 1.27 per minor T allele, 95% CI 1.11-1.45, P = 3.4×10(-4)) and rs2200733 in 4q25 (RR 1.28 per minor T allele, 95% CI 1.11-1.48, P = 7.9×10(-4)). We also replicated the associations for 9p21 (rs2383207, RR 1.13 per G allele, 95% CI 1.01-1.26, P = 0.036), as well as for male sex, systolic blood pressure, diabetes, cigarette smoking, low physical activity, coronary heart disease, and digoxin use (P
Published: 2012
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18. Intracranial aneurysm risk locus 5q23.2 is associated with elevated systolic blood pressure.

Author: Emília Ilona Gaál, Perttu Salo, Kati Kristiansson, Karola Rehnström, Johannes Kettunen, Antti-Pekka Sarin, Mika Niemelä, Antti Jula, Olli T Raitakari, Terho Lehtimäki, Johan G Eriksson, Elisabeth Widen, Murat Günel, Mitja Kurki, Mikael von und Zu Fraunberg, Juha E Jääskeläinen, Juha Hernesniemi, Marjo-Riitta Järvelin, Anneli Pouta, International Consortium for Blood Pressure Genome-Wide Association Studies, Christopher Newton-Cheh, Veikko Salomaa, Aarno Palotie, and Markus Perola
Subjects: Genetics, QH426-470
Abstract: Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN) = 11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n = 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN) = 3.01E-05, p(ICBP-GWAS) = 0.0007, p(ALL) = 8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.
Published: 2012
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19. Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.

Author: Dan E Arking, M Juhani Junttila, Philippe Goyette, Adriana Huertas-Vazquez, Mark Eijgelsheim, Marieke T Blom, Christopher Newton-Cheh, Kyndaron Reinier, Carmen Teodorescu, Audrey Uy-Evanado, Naima Carter-Monroe, Kari S Kaikkonen, Marja-Leena Kortelainen, Gabrielle Boucher, Caroline Lagacé, Anna Moes, XiaoQing Zhao, Frank Kolodgie, Fernando Rivadeneira, Albert Hofman, Jacqueline C M Witteman, André G Uitterlinden, Roos F Marsman, Raha Pazoki, Abdennasser Bardai, Rudolph W Koster, Abbas Dehghan, Shih-Jen Hwang, Pallav Bhatnagar, Wendy Post, Gina Hilton, Ronald J Prineas, Man Li, Anna Köttgen, Georg Ehret, Eric Boerwinkle, Josef Coresh, W H Linda Kao, Bruce M Psaty, Gordon F Tomaselli, Nona Sotoodehnia, David S Siscovick, Greg L Burke, Eduardo Marbán, Peter M Spooner, L Adrienne Cupples, Jonathan Jui, Karen Gunson, Y Antero Kesäniemi, Arthur A M Wilde, Jean-Claude Tardif, Christopher J O'Donnell, Connie R Bezzina, Renu Virmani, Bruno H C H Stricker, Hanno L Tan, Christine M Albert, Aravinda Chakravarti, John D Rioux, Heikki V Huikuri, and Sumeet S Chugh
Subjects: Genetics, QH426-470
Abstract: Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).
Published: 2011
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20. Genome-wide association studies of the PR interval in African Americans.

Author: J Gustav Smith, Jared W Magnani, Cameron Palmer, Yan A Meng, Elsayed Z Soliman, Solomon K Musani, Kathleen F Kerr, Renate B Schnabel, Steven A Lubitz, Nona Sotoodehnia, Susan Redline, Arne Pfeufer, Martina Müller, Daniel S Evans, Michael A Nalls, Yongmei Liu, Anne B Newman, Alan B Zonderman, Michele K Evans, Rajat Deo, Patrick T Ellinor, Dina N Paltoo, Christopher Newton-Cheh, Emelia J Benjamin, Reena Mehra, Alvaro Alonso, Susan R Heckbert, Ervin R Fox, and Candidate-gene Association Resource (CARe) Consortium
Subjects: Genetics, QH426-470
Abstract: The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p
Published: 2011
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21. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

Author: Sandosh Padmanabhan, Olle Melander, Toby Johnson, Anna Maria Di Blasio, Wai K Lee, Davide Gentilini, Claire E Hastie, Cristina Menni, Maria Cristina Monti, Christian Delles, Stewart Laing, Barbara Corso, Gerjan Navis, Arjan J Kwakernaak, Pim van der Harst, Murielle Bochud, Marc Maillard, Michel Burnier, Thomas Hedner, Sverre Kjeldsen, Björn Wahlstrand, Marketa Sjögren, Cristiano Fava, Martina Montagnana, Elisa Danese, Ole Torffvit, Bo Hedblad, Harold Snieder, John M C Connell, Morris Brown, Nilesh J Samani, Martin Farrall, Giancarlo Cesana, Giuseppe Mancia, Stefano Signorini, Guido Grassi, Susana Eyheramendy, H Erich Wichmann, Maris Laan, David P Strachan, Peter Sever, Denis Colm Shields, Alice Stanton, Peter Vollenweider, Alexander Teumer, Henry Völzke, Rainer Rettig, Christopher Newton-Cheh, Pankaj Arora, Feng Zhang, Nicole Soranzo, Timothy D Spector, Gavin Lucas, Sekar Kathiresan, David S Siscovick, Jian'an Luan, Ruth J F Loos, Nicholas J Wareham, Brenda W Penninx, Ilja M Nolte, Martin McBride, William H Miller, Stuart A Nicklin, Andrew H Baker, Delyth Graham, Robert A McDonald, Jill P Pell, Naveed Sattar, Paul Welsh, Global BPgen Consortium, Patricia Munroe, Mark J Caulfield, Alberto Zanchetti, and Anna F Dominiczak
Subjects: Genetics, QH426-470
Abstract: Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10⁻¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.
Published: 2010
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22. Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.

Author: Ilja M Nolte, Chris Wallace, Stephen J Newhouse, Daryl Waggott, Jingyuan Fu, Nicole Soranzo, Rhian Gwilliam, Panos Deloukas, Irina Savelieva, Dongling Zheng, Chrysoula Dalageorgou, Martin Farrall, Nilesh J Samani, John Connell, Morris Brown, Anna Dominiczak, Mark Lathrop, Eleftheria Zeggini, Louise V Wain, Wellcome Trust Case Control Consortium, DCCT/EDIC Research Group, Christopher Newton-Cheh, Mark Eijgelsheim, Kenneth Rice, Paul I W de Bakker, QTGEN consortium, Arne Pfeufer, Serena Sanna, Dan E Arking, QTSCD consortium, Folkert W Asselbergs, Tim D Spector, Nicholas D Carter, Steve Jeffery, Martin Tobin, Mark Caulfield, Harold Snieder, Andrew D Paterson, Patricia B Munroe, and Yalda Jamshidi
Subjects: Medicine, Science
Abstract: To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P
Published: 2009
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23. Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae.

Author: Jennifer K Lowe, Julian B Maller, Itsik Pe'er, Benjamin M Neale, Jacqueline Salit, Eimear E Kenny, Jessica L Shea, Ralph Burkhardt, J Gustav Smith, Weizhen Ji, Martha Noel, Jia Nee Foo, Maude L Blundell, Vita Skilling, Laura Garcia, Marcia L Sullivan, Heather E Lee, Anna Labek, Hope Ferdowsian, Steven B Auerbach, Richard P Lifton, Christopher Newton-Cheh, Jan L Breslow, Markus Stoffel, Mark J Daly, David M Altshuler, and Jeffrey M Friedman
Subjects: Genetics, QH426-470
Abstract: It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining >/=5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment.
Published: 2009
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24. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author: Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar
Subjects: Advanced and Specialized Nursing, Incidence, risk assessment, Smoking/epidemiology, intracranial aneurysm, genetic heterogeneity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Risk Factors, Intracranial Aneurysm/epidemiology, Humans, Subarachnoid Hemorrhage/epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, genetics, Neurology (clinical), aneurysmal subarachnoid hemorrhage, genetic, Cardiology and Cardiovascular Medicine
Abstract: Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
Published: 2023

25. Case 32-2022: A 76-Year-Old Man with Postoperative Cardiogenic Shock and Diffuse Rash

Author: Akshay S. Desai, David M. Dudzinski, Matthew T. Stib, Steven T. Chen, Christopher Newton-Cheh, Kimberly G. Blumenthal, and James R. Stone
Subjects: Male, Surgical Procedures, Operative, Shock, Cardiogenic, Humans, Postoperative Period, General Medicine, Exanthema, Aged
Published: 2022

26. Sex-Specific Differences in Ventricular Remodeling and Response After Cardiac Resynchronization Therapy

Author: Dimitrios Varrias, Miguel Armengol De La Hoz, Megan Zhao, Margarida Pujol, Mary Orencole, Vikramaditya Samala Venkata, Magdi Atef Zordok, Katherine Luong, Farhan Rana, Emily Lau, Nasrein Ibrahim, Christopher Newton-Cheh, Kevin Heist, Jagmeet Singh, and Saumya Das
Subjects: Cardiac Resynchronization Therapy, Heart Failure, Male, Electrocardiography, Treatment Outcome, Ventricular Remodeling, Bundle-Branch Block, Humans, Arrhythmias, Cardiac, Female, Stroke Volume, Cardiology and Cardiovascular Medicine, Ventricular Function, Left
Abstract: In this study, we investigated the baseline characteristics and "trajectories" of clinical response in men and women after cardiac resynchronization therapy (CRT) implantation. Although women enjoy improved echocardiographic response after CRT compared with men, the kinetics of this response and its relation to functional performance and outcomes are less clear. We identified 592 patients who underwent CRT implantation at our center between 2004 and 2017 and were serially followed in a multidisciplinary clinic. Longitudinal linear mixed effects regression for cardiac response was specified, including interaction terms between time after CRT and sex , and Cox regression models were used to assess differences in all-cause mortality by gender after CRT. Women in our cohort were younger than men, had less frequent ischemic etiology of heart failure (24% vs 60% in men), a shorter QRS (151 vs 161 ms) and more frequent left bundle branch block (77% vs 52%) at baseline. Women had a greater improvement in left ventricular ejection fraction that was evident starting at approximately 1-month after CRT. We did not observe effect modification by gender in New York Heart Association class or 6-minute walk distance after CRT. Although women had improved mortality after CRT, after adjustment for potential confounders, gender was not associated with mortality after CRT. In conclusion, women were more likely to have CRT implantation for left bundle branch block and exhibited improved echocardiographic but not functional response within the first year after CRT. Clinical outcomes after CRT were not associated with gender in adjusted analysis.
Published: 2022

27. Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19

Author: Caroline F. Hilburn, Michael S. Marshall, Yin P Hung, Daniel J. Shepherd, Aram J. Krauson, Javier E. Mendez-Pena, Julian A. Villalba, Isabela Delfino, Liana Bonanno, T. Leif Helland, Baris Boyraz, Ivan Chebib, Cynthia K. Harris, Christopher Newton-Cheh, Mayara Bearse, James R. Stone, Bailey Hutchison, and Soma Jobbagy
Subjects: 0301 basic medicine, medicine.medical_specialty, Pathology, Myocarditis, Lymphocyte, medicine.medical_treatment, Autopsy, Inflammation, Gastroenterology, Virus, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, skin and connective tissue diseases, medicine.diagnostic_test, business.industry, CD68, Immunosuppression, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine.symptom, business, Electrocardiography
Abstract: COVID-19 has been associated with cardiac injury and dysfunction. While both myocardial inflammatory cell infiltration and myocarditis with myocyte injury have been reported in patients with fatal COVID-19, clinical-pathologic correlations remain limited. The objective was to determine the relationships between cardiac pathological changes in patients dying from COVID-19 and cardiac infection by SARS-CoV-2, laboratory measurements, clinical features, and treatments. In a retrospective study, 41 consecutive autopsies of patients with fatal COVID-19 were analyzed for the associations between cardiac inflammation, myocarditis, cardiac infection by SARS-CoV-2, clinical features, laboratory measurements, and treatments. Cardiac infection was assessed by in situ hybridization and NanoString transcriptomic profiling. Cardiac infection by SARS-CoV-2 was present in 30/41 cases: virus+ with myocarditis (n = 4), virus+ without myocarditis (n = 26), and virus- without myocarditis (n = 11). In the cases with cardiac infection, SARS-CoV-2+ cells in the myocardium were rare, with a median density of 1 cell/cm2. Virus+ cases showed higher densities of myocardial CD68+ macrophages and CD3+ lymphocytes, as well as more electrocardiographic changes (23/27 vs 4/10; P = 0.01). Myocarditis was more prevalent with IL-6 blockade than with nonbiologic immunosuppression, primarily glucocorticoids (2/3 vs 0/14; P = 0.02). Overall, SARS-CoV-2 cardiac infection was less prevalent in patients treated with nonbiologic immunosuppression (7/14 vs 21/24; P = 0.02). Myocardial macrophage and lymphocyte densities overall were positively correlated with the duration of symptoms but not with underlying comorbidities. In summary, cardiac infection with SARS-CoV-2 is common among patients dying from COVID-19 but often with only rare infected cells. Cardiac infection by SARS-CoV-2 is associated with more cardiac inflammation and electrocardiographic changes. Nonbiologic immunosuppression is associated with lower incidences of myocarditis and cardiac infection by SARS-CoV-2.
Published: 2021

28. Hemodynamic and Clinical Performance of Hearts Donated After Circulatory Death

Author: David A. D’Alessandro, Stanley B. Wolfe, Asishana A. Osho, Kamila Drezek, Monica N. Prario, S. Alireza Rabi, Eriberto Michel, Lana Tsao, Erin Coglianese, Meaghan Doucette, Daniel A. Zlotoff, Christopher Newton-Cheh, Sunu S. Thomas, Van-Khue Ton, Nilay Sutaria, Mark W. Schoenike, Anastasia M. Christ, Dane C. Paneitz, Mauricio Villavicencio, Joren C. Madsen, Richard Pierson, and Gregory D. Lewis
Subjects: Heart Failure, Hemodynamics, Humans, Heart, Pulmonary Artery, Cardiology and Cardiovascular Medicine, Retrospective Studies
Abstract: Donor organ demand continues to outpace supply in heart transplantation. Utilization of donation after circulatory death (DCD) hearts could significantly increase heart donor availability for patients with advanced heart failure.The purpose of this study was to describe hemodynamic and clinical profiles of DCD hearts in comparison to standard of care (SOC) hearts donated after brain death (DBD).This single-center retrospective cohort study of consecutive heart transplant recipients analyzed right heart catheterization measurements, inotrope scores, echocardiograms, and clinical outcomes between DCD and DBD heart recipients.Between April 2016 and February 2022, 47 DCD and 166 SOC hearts were transplanted. Median time from DCD consent to transplant was significantly shorter compared with SOC waiting list time (17 days [6-28 days] vs 70 days [23-240 days]; P 0.001). Right heart function was significantly impaired in DCD recipients compared with SOC recipients 1 week post-transplant (higher median right atrial pressure (10 mm Hg [8-13 mm Hg] vs 7 mm Hg [5-11 mm Hg]; P 0.001), higher right atrial pressure to pulmonary capillary wedge pressure ratio (0.64 [0.54-0.82] vs 0.57 [0.43-0.73]; P = 0.016), and lower pulmonary arterial pulsatility index (1.66 [1.27-2.50] vs 2.52 [1.63-3.82]; P 0.001), but was similar between groups by 3 weeks post-transplant. DCD and SOC recipient mortality was similar at 30 days (DCD 0 vs SOC 2%; P = 0.29) and 1 year post-transplant (DCD 3% vs SOC 8%; P = 0.16).DCD heart utilization is associated with transient post-transplant right heart dysfunction and short-term clinical outcomes otherwise similar to transplantation using DBD hearts.
Published: 2022

29. Genome-wide analysis in over 1 million individuals reveals over 2,000 independent genetic signals for blood pressure

Author: Helen Warren, Todd Edwards, Ahmad Vaez, Jacob Keaton, Zoha Kamali, Tian Xie, Alireza Ani, Evangelos Evangelou, Jacklyn Hellwege, Loïc Yengo, William Young, Matthew Traylor, Ayush Giri, Peter Visscher, Daniel Chasman, Andrew Morris, Mark Caulfield, Shih-Jen Hwang, Jaspal Kooner, David Conen, John Attia, Alanna Morrison, Ruth Loos, Kati Kristiansson, Reinhold Schmidt, Andrew Hicks, Peter Pramstaller, Christopher Nelson, Nilesh Samani, Lorenz Risch, Ulf Gyllensten, Olle Melander, Harriëtte Riese, James Wilson, Harry Campbell, Bruce Psaty, Yingchang Lu, Jerome Rotter, Xiuqing Guo, Kenneth Rice, Peter Vollenweider, Johan Sundstrom, Claudia Langenberg, Martin Tobin, Vilmantas Giedraitis, Jian'an Luan, Jaakko Tuomilehto, Zoltan Kutalik, Samuli Ripatti, Veikko Salomaa, Giorgia Girotto, Stella Trompet, J Wouter Jukema, Pim van der Harst, Paul Ridker, Franco Giulianini, Veronique Vitart, Anuj Goel, Hugh Watkins, Sarah Harris, Ian Deary, Peter van der Most, Albertine Oldehinkel, Bernard Keavney, Caroline Hayward, Archie Campbell, Michael Boehnke, Laura Scott, Thibaud Boutin, Chrysovalanto Mamasoula, Marjo-Riitta Jarvelin, Annette Peters, Christian Gieger, Edward Lakatta, Francesco Cucca, Jennie Hui, Paul Knekt, Stefan Enroth, Martin de Borst, Ozren Polasek, Maria Pina Concas, Eulalia Catamo, Massimiliano Cocca, Ruifang Li-Gao, Edith Hofer, Helena Schmidt, Beatrice Spedicati, Melanie Waldenberger, David Strachan, Maris Laan, Alexander Teumer, Marcus Dörr, Vilmundur Gudnason, James Cook, Daniela Ruggiero, Ivana Kolcic, Eric Boerwinkle, Michela Traglia, Terho Lehtimäki, Olli Raitakari, Andrew Johnson, Christopher Newton-Cheh, Morris Brown, Anna Dominiczak, Peter Sever, Neil Poulter, John Chambers, Roberto Elosua, David Siscovick, Tōnu Esko, Andres Metspalu, Rona Strawbridge, Markku Laakso, Anders Hamsten, Jouke-Jan Hottenga, Eco de Geus, Colin Palmer, Ilja Nolte, Yuri Milaneschi, Jonathan Marten, Alan Wright, Eleftheria Zeggini, Joanna Howson, Christopher O'Donnell, Tim Spector, Mike Nalls, Eleanor Simonsick, Yongmei Liu, Cornelia van Duijn, Adam Butterworth, John Danesh, Cristina Menni, Nick Wareham, Kay Khaw, Joshua Denny, Daniel Levy, Patricia Munroe, and Harold Snieder
Abstract: Hypertension is a leading cause of premature death affecting more than a billion individuals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N = 1,028,980 European-descent individuals). We identified 2,103 independent genetic signals (P − 8) for BP traits, including 113 novel loci. These associations explain ~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p = 9.08×10− 73) and hypertension risk (OR 5.41; 95% CI 4.12 to 7.10; P = 9.71×10− 33) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI = 0.781–0.801) to 0.814 (95% CI = 0.805–0.824, ∆AUC = 0.023, P = 2.27x10− 22). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.
Published: 2022

30. Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020

Author: Lilian M. Abbo, Shuba Balan, Julie Hand, Sapna Bamrah Morris, Ermias D. Belay, Daniel P. Eiras, Sharon E. Fox, Emer Smith, Aaron Kofman, Vennus Ballen, Zachary Ende, Marie Dorsinville, Bobbi Bryant, Pragna Patel, Rachel Paneth-Pollak, Gillian Richardson, Ellen H. Lee, Anita Geevarughese, Noah G. Schwartz, Sarah Lim, Maura K. Lash, Nora T. Oliver, Shana Godfred-Cato, Patricia Stogsdill, Christopher Newton-Cheh, Laura Beauchamps, Deblina Datta, and Sara Robinson
Subjects: Adult, Male, medicine.medical_specialty, Abdominal pain, Health (social science), Epidemiology, Health, Toxicology and Mutagenesis, Pneumonia, Viral, 01 natural sciences, Virus, Pathogenesis, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Health Information Management, Internal medicine, Pandemic, medicine, Humans, 030212 general & internal medicine, Full Report, 0101 mathematics, Young adult, Pandemics, biology, business.industry, 010102 general mathematics, COVID-19, General Medicine, Middle Aged, medicine.disease, Systemic Inflammatory Response Syndrome, United Kingdom, United States, Systemic inflammatory response syndrome, Pneumonia, biology.protein, Female, medicine.symptom, Antibody, business, Coronavirus Infections
Abstract: During the course of the coronavirus disease 2019 (COVID-19) pandemic, reports of a new multisystem inflammatory syndrome in children (MIS-C) have been increasing in Europe and the United States (1-3). Clinical features in children have varied but predominantly include shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers, including C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6 (1). Since June 2020, several case reports have described a similar syndrome in adults; this review describes in detail nine patients reported to CDC, seven from published case reports, and summarizes the findings in 11 patients described in three case series in peer-reviewed journals (4-6). These 27 patients had cardiovascular, gastrointestinal, dermatologic, and neurologic symptoms without severe respiratory illness and concurrently received positive test results for SARS-CoV-2, the virus that causes COVID-19, by polymerase chain reaction (PCR) or antibody assays indicating recent infection. Reports of these patients highlight the recognition of an illness referred to here as multisystem inflammatory syndrome in adults (MIS-A), the heterogeneity of clinical signs and symptoms, and the role for antibody testing in identifying similar cases among adults. Clinicians and health departments should consider MIS-A in adults with compatible signs and symptoms. These patients might not have positive SARS-CoV-2 PCR or antigen test results, and antibody testing might be needed to confirm previous SARS-CoV-2 infection. Because of the temporal association between MIS-A and SARS-CoV-2 infections, interventions that prevent COVID-19 might prevent MIS-A. Further research is needed to understand the pathogenesis and long-term effects of this newly described condition.
Published: 2020

31. Abstract 13271: Combined Assessments of Monogenic and Polygenic Risk for Dilated Cardiomyopathy

Author: Krishna G Aragam, Kiran Biddinger, Sean J Jurgens, Minxian Wang, James Pirruccello, Dimitri Maamari, Mark Chaffin, Seung H Choi, Valerie Morrill, Christopher Newton-cheh, Amit V Khera, Steven A Lubitz, and Patrick T Ellinor
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract: Introduction: Genetic testing for non-ischemic dilated cardiomyopathy (DCM) currently comprises assessment of rare (monogenic) mutations in DCM-relevant genes. The role of a common-variant (polygenic) predictor for DCM has yet to be evaluated. Methods: Leveraging genotyping array and exome-sequencing data from UK Biobank, we curated monogenic, predicted loss-of-function (LOF) mutations in 91 genes on clinical genetic testing panels for DCM, and tested their prevalence and penetrance. Next, we constructed and evaluated a polygenic score for DCM from measures of left ventricular structure and function by cardiac magnetic resonance imaging. Finally, we combined monogenic carrier status with the polygenic score to estimate aggregate genetic risk for DCM. Results: Among study participants (N= 166,690), mean age was 57 (SD, 8.1) years, 75,154 (41%) were male, and 336 (0.21%) had DCM. 14.4% of DCM cases harbored a disease-relevant LOF mutation, including 8.8% within cardiac exons of the sarcomeric gene TTN . LOF mutations in TTN (OR, 25.36), DSP (OR, 17.55), and RBM20 (OR, 12.85) were the most strongly associated with dilated cardiomyopathy (all P < 0.001). 0.7% of all LOF carriers - and 4.0% of LOF carriers in TTN - developed DCM. A polygenic score comprising 2.3 million common genetic variants was strongly associated with DCM in all participants (OR per SD=1.62, p=8.61E-39), and in non-carriers (OR per SD=1.60, p=6.28E-15; N=159,811) and carriers (OR per SD=1.79, p=4.76E-05; N=6,879) of LOF mutations. Comparing the top and bottom 20% of the polygenic score, a >3-fold risk difference was observed among non-carriers of TTN LOF, and a >10-fold risk difference among TTN LOF carriers. TTN LOF carriers with high polygenic risk were at 46-fold odds of developing DCM as compared to non-carriers with intermediate polygenic risk (p=4.16E-29). Conclusions: Combining monogenic and polygenic risk expands the scope and improves the precision of clinical genetic testing for DCM.
Published: 2021

32. Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

Author: Peter W. Macfarlane, Niels Grarup, Ruth J. F. Loos, Marcus Dörr, Peter P. Pramstaller, Torben Hansen, James F. Wilson, Lu-Chen Weng, Eduardo Tarazona-Santos, Honghuang Lin, Yong Qian, Jeffrey R. O'Connell, Maria Pina Concas, Claudia Schurmann, Michele Orini, Joshua C. Bis, Archie Campbell, Susan R. Heckbert, Jie Yao, Eulalia Catamo, Claus Graff, James G. Wilson, Pashupati P. Mishra, Massimo Mangino, Martina Müller-Nurasyid, Borbala Mifsud, Linda Repetto, Stephan B. Felix, Julia Ramirez, Rebecca D. Jackson, Eric Boerwinkle, Monika Stoll, Elsayed Z. Soliman, Maryam Kavousi, David J. Porteous, Nina Mononen, Dan E. Arking, Laura Andreasen, Lorenz Risch, Antonio Luiz Pinho Ribeiro, Pier D. Lambiase, Mika Kähönen, Xia Shen, Kenneth Rice, Eric A. Whitsel, Nona Sotoodehnia, Victor Nauffal, Konstantin Strauch, Jørgen K. Kanters, Henry Völzke, Daniel S. Evans, Jonas L. Isaksen, Alessandro De Grandi, Hao Mei, Alexander P. Reiner, Christy L. Avery, Thiago P. Leal, Alanna C. Morrison, Christian Fuchsberger, M. Arfan Ikram, Moritz Sinner, Yongmei Liu, Bruno H. Stricker, Francesco Cucca, Allan Linneberg, Patricia B. Munroe, Christina Ellervik, Olli T. Raitakari, Melanie Waldenberger, Reem Salman, Xiuqing Guo, Sandosh Padmanabhan, ThuyVy Duong, Dawood Darbar, Stefan Weiss, Arden Moscati, Alvaro Alonso, Cornelia M. van Duijn, Gianfranco Sinagra, Luisa Foco, Matthias Nauck, Kathleen A. Ryan, Kjell Nikus, Gustav Ahlberg, Helen R. Warren, Kent D. Taylor, Niek Verweij, Rebecca Freudling, Cristian Pattaro, Michael Preuss, Charles Kooperberg, Anne Richmond, David Conen, Oliver Hines, Juhani Junttila, Leo-Pekka Lyytikäinen, Nina Hutri-Kähönen, Kirill V. Tarasov, Ulrich Schotten, M. Benjamin Shoemaker, Marten E. van den Berg, Jerome I. Rotter, Michael J. Cutler, Adolfo Correa, Bruce M. Psaty, Caroline Hayward, Yalda Jamshidi, Pau Navarro, J W Benjamins, Patrick T. Ellinor, Massimo Mezzavilla, William J Young, Stefan Kääb, Lars Lind, Antonio De Luca, Heikki V. Huikuri, Marjo-Riitta Järvelin, Guillaume Paré, Stefan van Duijvenboden, Uwe Völker, Maria Fernanda Lima-Costa, Philippe Froguel, Jan A. Kors, Annette Peters, David Schlessinger, Christopher Newton-Cheh, J. Wouter Jukema, Andrew Tinker, Dennis O. Mook-Kanamori, Antoine R Baldassari, Stefanie Aeschbacher, Mariaelisa Graff, Najim Lahrouchi, Henry J. Lin, Giorgia Girotto, Giulia Pelliccione, Jeffrey Haessler, Aaron Isaacs, Rebecca N. Mitchell, Carolina Roselli, Massimiliano Cocca, Sina A. Gharib, Rozenn N. Lemaitre, Raymond Noordam, Morten S. Olesen, Steven A. Lubitz, Jun Ding, May E. Montasser, Jennifer A. Brody, Stella Trompet, Traci M. Bartz, Dania Raza, Thomas Meitinger, Andrew P. Morris, James P. Cook, Sébastien Thériault, Martin Gögele, André G. Uitterlinden, Pim van der Harst, Alan Pittman, Farah Ahmed, Simin Liu, Casia Nursyifa, Paul L. Huang, Kristen K. Patton, and Terho Lehtimäki
Subjects: medicine.medical_specialty, business.industry, Locus (genetics), Atrial fibrillation, medicine.disease, QT interval, Genetic architecture, Sudden cardiac death, QRS complex, Internal medicine, cardiovascular system, medicine, Cardiology, Repolarization, cardiovascular diseases, business, Ventricular depolarization
Abstract: The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
Published: 2021

33. Multisystem Inflammatory Syndrome in Adults After Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection and Coronavirus Disease 2019 (COVID-19) Vaccination

Author: Jennifer DeCuir, Paige Marquez, Shana Godfred Cato, Elizabeth D. Barnett, Christopher Newton-Cheh, W Wyatt Wilson, Elizabeth P. Schlaudecker, Lu Meng, Sarah Lim, Ermias D. Belay, Agam K Rao, Sapna Bamrah Morris, Karen R. Broder, Kawsar R. Talaat, Joseph Y. Abrams, Kathryn M. Edwards, John R. Su, Heather N Grome, Michael Melgar, Angela P Campbell, and Brandon J. Webb
Subjects: Microbiology (medical), Adult, Male, medicine.medical_specialty, COVID-19 Vaccines, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus, MIS-C, MIS-A, Internal medicine, Pandemic, medicine, Major Article, Humans, Adverse effect, Connective Tissue Diseases, business.industry, SARS-CoV-2, Vaccination, Authorization, COVID-19, Disease control, Systemic Inflammatory Response Syndrome, multisystem inflammatory syndrome in adults, Infectious Diseases, AcademicSubjects/MED00290, Female, business, Reporting system
Abstract: Background Multisystem inflammatory syndrome in adults (MIS-A) was reported in association with the coronavirus disease 2019 (COVID-19) pandemic. MIS-A was included in the list of adverse events to be monitored as part of the emergency use authorizations issued for COVID-19 vaccines. Methods Reports of MIS-A patients received by the Centers for Disease Control and Prevention (CDC) after COVID-19 vaccines became available were assessed. Data collected on the patients included clinical and demographic characteristics and their vaccine status. The Vaccine Adverse Events Reporting System (VAERS) was also reviewed for possible cases of MIS-A. Results From 14 December 2020 to 30 April 2021, 20 patients who met the case definition for MIS-A were reported to CDC. Their median age was 35 years (range, 21–66 years), and 13 (65%) were male. Overall, 16 (80%) patients had a preceding COVID-19-like illness a median of 26 days (range 11–78 days) before MIS-A onset. All 20 patients had laboratory evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Seven MIS-A patients (35%) received COVID-19 vaccine a median of 10 days (range, 6–45 days) before MIS-A onset; 3 patients received a second dose of COVID-19 vaccine 4, 17, and 22 days before MIS-A onset. Patients with MIS-A predominantly had gastrointestinal and cardiac manifestations and hypotension or shock. Conclusions Although 7 patients were reported to have received COVID-19 vaccine, all had evidence of prior SARS-CoV-2 infection. Given the widespread use of COVID-19 vaccines, the lack of reporting of MIS-A associated with vaccination alone, without evidence of underlying SARS-CoV-2 infection, is reassuring., Seven of 20 MIS-A patients received COVID-19 vaccination before illness onset. All patients had evidence of prior SARS-CoV-2 infection. Given widespread COVID-19 vaccinations in the United States, the lack of reporting of MIS-A associated with vaccination alone is reassuring.
Published: 2021

34. The genomics of heart failure: design and rationale of the HERMES consortium

Author: Svati H. Shah, Olle Melander, Neneh Sallah, Quinn S. Wells, Jerome I. Rotter, Faye Zhao, Charlotte Andersson, Guðmundur Thorgeirsson, Ghazaleh Fatemifar, Alex S. F. Doney, Michael E. Dunn, David E. Lanfear, Ian Ford, Eric Boersma, Sonia Shah, Christopher Newton-Cheh, Douglas L. Mann, Niek Verweij, Carolina Roselli, Laura M. Yerges-Armstrong, Jian Yang, Christian Torp-Pedersen, Veikko Salomaa, Mary L. Biggs, Alaa Shalaby, Christoph Nowak, Stefan Gross, Patrick T. Ellinor, Mari Liis Tammesoo, Diane T. Smelser, Peter M. Visscher, Hans L. Hillege, Ruth C. Lovering, Honghuang Lin, Colin N. A. Palmer, Louis Philippe Lemieux Perreault, Jeffrey Brandimarto, Uwe Völker, Perttu Salo, Andrea Koekemoer, Rebecca Gutmann, Åsa K. Hedman, Nilesh J. Samani, Heming Xing, Faiez Zannad, Jaison Jacob, Harry Hemingway, Michael R. Brown, Franco Giulianini, Anubha Mahajan, Xing Chen, Alexander Niessner, Peter Almgren, Daniel I. Swerdlow, Gunnar Engström, Lars Lind, Tõnu Esko, Tomasz Czuba, Anna Helgadottir, Harvey D. White, David J. Stott, Johan Ärnlöv, Lars Køber, Chim C. Lang, Krishna G. Aragam, Kent D. Taylor, Anders Mälarstig, Frederick K. Kamanu, Kenneth B. Margulies, Michelle L. O'Donoghue, Andrew D. Morris, Sahar Ghasemi, J. Wouter Jukema, Jessica van Setten, Abbas Dehghan, Guillaume Paré, Luca A. Lotta, Giorgio E. M. Melloni, Albert Henry, Bruce M. Psaty, Paul M. Ridker, David J. Carey, Marie-Pierre Dubé, John S. Gottdiener, Xiaosong Wang, Per H. Svensson, Xu Chen, Patrik K. E. Magnusson, Claudia Langenberg, Alexander Teumer, Vilmantas Giedraitis, Simon de Denus, Michael W. Nagle, Marcus Dörr, Thomas P. Cappola, André G. Uitterlinden, Michael Morley, Eliana Portilla-Fernandez, J. Gustav Smith, Abirami Veluchamy, Peter Weeke, Ify R. Mordi, Unnur Thorsteinsdottir, Naveed Sattar, Folkert W. Asselbergs, Daniel I. Chasman, Daníel F. Guðbjartsson, Jonathan H. Chung, Marcus E. Kleber, Raul Weiss, Christopher P. Nelson, Spiros Denaxas, Bing Yu, Simon P. R. Romaine, Nicholas A Marston, Anjali T. Owens, Cecilia M. Lindgren, John J.V. McMurray, Joshua D. Backman, Michael V. Holmes, Stella Trompet, Hilma Holm, Kerri L. Wiggins, Jian'an Luan, Stephan B. Felix, Yifan Yang, Jemma B. Wilk, Maryam Kavousi, Markus Perola, Christian T. Ruff, Jean-Claude Tardif, G Sveinbjörnsson, Samuel C. Dudley, Nicholas J. Wareham, Teemu J. Niiranen, Andrew P. Morris, Danny Tuckwell, Maris Teder-Laving, R. Thomas Lumbers, James P. Cook, Géraldine Asselin, William A. Chutkow, Winfried März, Steven A. Lubitz, John G.F. Cleland, Bill Kraus, Ramachandran S. Vasan, Christopher M. Haggerty, Olympe Chazara, Chris Finan, Heather L. Bloom, Hans-Peter Brunner-La Rocca, Francoise Fougerousse, Kenneth Rice, Craig L. Hyde, Graciela E. Delgado, Mark Chaffin, Marc S. Sabatine, Alanna C. Morrison, Kay-Tee Khaw, Kari Stefansson, Felix Vaura, Barry London, Isabella Kardys, Aroon D. Hingorani, Hongsheng Gui, Steen Stender, René Fouodjio, Mohsen Ghanbari, Pim van der Harst, Nicholas L. Smith, Karoline Kuchenbaecker, Adriaan A. Voors, Benoit Tyl, University College of London [London] (UCL), University College London Hospitals (UCLH), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Lund University [Lund], Pfizer, Karolinska Institutet [Stockholm], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Groningen [Groningen], University of Oxford [Oxford], Dalarna University, Massachusetts General Hospital [Boston], Montreal Heart Institute - Institut de Cardiologie de Montréal, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, University of Washington [Seattle], Emory University [Atlanta, GA], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Pennsylvania [Philadelphia], The University of Texas Health Science Center at Houston (UTHealth), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), AstraZeneca, Novartis Institutes for BioMedical Research (NIBR), University of Glasgow, University of Liverpool, Université de Montréal (UdeM), Imperial College London, University of Heidelberg, Medical Faculty, University of Dundee, Universität Greifswald - University of Greifswald, University of Minnesota Medical School, University of Minnesota System, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Uppsala University, University of Maryland School of Medicine, University of Maryland System, University of Iceland [Reykjavik], deCODE genetics [Reykjavik], Henry Ford Hospital, Carver College of Medicine, University of Iowa, Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), ICIN - Netherlands Heart Institute, Leiden University Medical Center (LUMC), Netherlands Heart Institute, Partenaires INRAE, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, University of Leicester, Duke University [Durham], University of Iowa [Iowa City], Genentech, Inc., Genentech, Inc. [San Francisco], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Skane University Hospital [Malmo], University of Edinburgh, Medizinische Universität Wien = Medical University of Vienna, University of Turku, National Institute for Health and Welfare [Helsinki], McMaster University [Hamilton, Ontario], Kaiser Permanente Washington Health Research Institute [Seattle] (KPWHRI), Harbor UCLA Medical Center [Torrance, Ca.], University Medical Center [Utrecht], University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), University of Tartu, Aalborg University [Denmark] (AAU), Leiden University, University of Queensland [Brisbane], Ohio State University [Columbus] (OSU), Auckland City Hospital, GlaxoSmithKline, Glaxo Smith Kline, University of Texas Health Science Center, Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Duke University Medical Center, Regeneron Pharmaceuticals [Tarrytown], Vanderbilt University [Nashville], European Project, Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Cardiology, University of Oxford, University of Pennsylvania, Universiteit Leiden, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Epidemiology, and Internal Medicine
Subjects: Male, Study Designs, Cardiomyopathy, Disease, 030204 cardiovascular system & hematology, 0302 clinical medicine, AFRICAN ANCESTRY, Epidemiology, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, Cardiac and Cardiovascular Systems, AGING RESEARCH, RISK, Aged, 80 and over, 0303 health sciences, Kardiologi, Genomics, Middle Aged, Prognosis, 3. Good health, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Heart failure, CLASSIFICATION, Heart Failure/genetics, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Genetic model, medicine, Genetics, Diseases of the circulatory (Cardiovascular) system, Humans, Allele frequency, Genotyping, METAANALYSIS, 030304 developmental biology, Aged, Association studies, Study Design, business.industry, Odds ratio, ADULTS, COHORTS, medicine.disease, RC666-701, REPLICATION, business, Biomarkers, Genome-Wide Association Study
Abstract: Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
Published: 2021

35. Effects of Vitamin D Supplementation on Cardiovascular and Glycemic Biomarkers

Author: Pankaj Arora, Jeffery A Dusek, Christopher Newton-Cheh, Yan Ru Su, Thomas J. Wang, Shi Huang, Katherine N. Bachmann, and Jennifer Miao
Subjects: Adult, Blood Glucose, Male, medicine.medical_specialty, Adolescent, 030209 endocrinology & metabolism, vitamin D, 030204 cardiovascular system & hematology, Gastroenterology, law.invention, lipids, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Insulin resistance, Randomized controlled trial, Double-Blind Method, law, high‐sensitivity C‐reactive protein, Internal medicine, insulin resistance, Clinical Studies, Vitamin D and neurology, Medicine, Humans, Metabolic disease, Preventive Cardiology, Glycemic, Original Research, Inflammation, Metabolic Syndrome, Vitamin d supplementation, Lipids and Cholesterol, Dose-Response Relationship, Drug, business.industry, Vitamins, Middle Aged, medicine.disease, meta‐analysis, Cardiovascular Diseases, Meta-analysis, Dietary Supplements, Observational study, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract: Background Experimental and observational studies have suggested a link between vitamin D and cardiovascular and metabolic disease, but this has not been confirmed in randomized controlled trials. We sought to determine whether vitamin D supplementation reduces biomarkers of insulin resistance, inflammation, neurohormonal activation, and lipids. Methods and Results This was a prespecified, secondary analysis of the DAYLIGHT (Vitamin D Therapy in Individuals at High Risk of Hypertension) randomized controlled trial. We measured circulating homeostatic model assessment of insulin resistance, hs‐CRP (high‐sensitivity C‐reactive protein), N‐terminal pro‐B‐type natriuretic peptide, renin, aldosterone, and lipids at baseline and at 6 months in 289 individuals with low vitamin D status (25‐hydroxyvitamin‐D [25‐OH‐D] ≤25 ng/mL) receiving low‐dose (400 IU/d) versus high‐dose (4000 IU/d) vitamin D3 for 6 months. A meta‐analysis of randomized controlled trials reporting biomarker changes after vitamin D supplementation was then performed. Levels of 25‐OH‐D increased in the high‐dose relative to the low‐dose vitamin D group (+15.5 versus +4.6 ng/mL, P P Conclusions In the DAYLIGHT randomized controlled trial, high‐dose vitamin D supplementation did not improve biomarkers of glycemia, inflammation, neurohormonal activation, or lipids. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01240512.
Published: 2021

36. A NOS1AP gene variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin

Author: Negin, Soroush, Albert-Jan, Aarnoudse, Maryam, Kavousi, Jan A, Kors, M Arfan, Ikram, Christopher, Newton-Cheh, Fariba, Ahmadizar, and Bruno H, Stricker
Subjects: Aged, 80 and over, Male, Digoxin, Cardiotonic Agents, Genotype, Genetic Variation, Middle Aged, Electrocardiography, Long QT Syndrome, Treatment Outcome, Linear Models, Humans, Female, Longitudinal Studies, Prospective Studies, Adaptor Proteins, Signal Transducing, Aged, Follow-Up Studies
Abstract: Digoxin is characterized by a small therapeutic window and a QT-interval shortening effect. Moreover, it has been shown that the genetic variants of the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. We investigated whether the rs10494366 variant of the NOS1AP gene decreases the QT-interval shortening effect of digoxin in patients using this drug. We included 10,057 individuals from the prospective population-based cohort of the Rotterdam Study during a median of 12.2 (interquartile range (IQR) 6.7-18.1) years of follow-up. At study entry, the mean age was 64 years and almost 59% of participants were women. A total of 23,179 ECGs were longitudinally recorded, of which 334 ECGs were from 249 individuals on digoxin therapy. The linear mixed model analysis was used to estimate the effect of the rs10494366 variant on the association between digoxin use and QT-interval duration, adjusted for age, sex, RR interval, diabetes, heart failure, and history of myocardial infarction. In non-users of digoxin, the GG genotype was associated with a significant 6.5 ms [95% confidence interval (CI) 5.5; 7.5] longer QT-interval duration than the TT variant. In current digoxin users, however, the GG variant was associated with a significantly -23.9 [95%CI -29.5; -18.5] ms shorter mean QT-interval duration than in those with the TT variant with -15.9 [95%CI -18.7; -13.1]. This reduction was strongest in the high digoxin dose category [≥0.250 mg/day] with the GG genotype group, with -40.8 [95%CI -52.5; -29.2] ms changes compared to non-users. Our study suggests that the minor homozygous GG genotype group of the NOS1AP gene rs10494366 variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin in a population of European ancestry.
Published: 2021

37. Elevated Blood Pressure Increases Pneumonia Risk: Epidemiological Association and Mendelian Randomization in the UK Biobank

Author: Michael C. Honigberg, James P. Pirruccello, Puja Kohli, Pradeep Natarajan, Christopher Newton-Cheh, Elizabeth W. Karlson, Hongyu Zhao, and Seyedeh M. Zekavat
Subjects: medicine.medical_specialty, hypertension, pulmonary, Diastole, Blood Pressure, Polymorphism, Single Nucleotide, Pulmonary function testing, Internal medicine, Epidemiology, Mendelian randomization, medicine, Humans, pneumonia, Prospective Studies, Prospective cohort study, Biological Specimen Banks, business.industry, population genetics, Clinical Advances, General Medicine, Mendelian Randomization Analysis, medicine.disease, Biobank, United Kingdom, United States, Pneumonia, Blood pressure, epidemiology, business, Genome-Wide Association Study, high blood pressure
Abstract: Background Small studies have correlated hypertension with pneumonia risk; whether this is recapitulated in larger prospective studies, and represents a causal association, is unclear. Methods We estimated the risk for prevalent hypertension with incident respiratory diseases over mean follow-up of 8 years among 377,143 British participants in the UK Biobank. Mendelian randomization of blood pressure on pneumonia was implemented using 75 independent, genome-wide significant variants associated with systolic and diastolic blood pressures among 299,024 individuals not in the UK Biobank. Secondary analyses with pulmonary function tests were performed. Findings In total, 107,310 participants (30%) had hypertension at UK Biobank enrollment, and 9,969 (3%) developed pneumonia during follow-up. Prevalent hypertension was independently associated with increased risk for incident pneumonia (HR: 1.36; 95% CI: 1.29–1.43; p < 0.001), as well as other incident respiratory diseases. Genetic predisposition to a 5 mm Hg increase in blood pressure was associated with increased risk for incident pneumonia for systolic blood pressure (HR: 1.08; 95% CI: 1.04–1.13; p < 0.001) and diastolic blood pressure (HR: 1.11; 95% CI: 1.03–1.20; p = 0.005). Additionally, consistent with epidemiologic associations, increased blood pressure genetic risk was significantly associated with reduced performance on pulmonary function tests (p < 0.001). Conclusions These results suggest that elevated blood pressure increases risk for pneumonia. Maintaining adequate blood pressure control, in addition to other measures, may reduce risk for pneumonia. Funding S.M.Z. (1F30HL149180-01), M.H. (T32HL094301-07), and P.N. (R01HL1427, R01HL148565, and R01HL148050) are supported by the National Institutes of Health. J.P. is supported by the John S. LaDue Memorial Fellowship., Graphical Abstract, Highlights We linked high BP and incident pneumonia in the UK Biobank using epidemiology and genetics Hypertension was associated with increased risk for incident pneumonia Genetically elevated BP increased risk for incident pneumonia Hypertension and genetically elevated BP also reduced pulmonary function, Context and Significance Epidemiologic analyses have correlated hypertension with pneumonia risk. Whether this represents a direct consequence of hypertension or the influence of co-morbid risk factors such as age, diabetes mellitus, or smoking is unclear. Here, across 377,143 individuals from the UK Biobank, we show that hypertension is independently associated with significantly increased risk for incident pneumonia. Additionally, using Mendelian randomization, we show that a genetic predisposition to elevated blood pressure across 75 independent genetic variants is associated with increased risk for incident pneumonia and reduced pulmonary function test performance. These results suggest that elevated blood pressure may be a causal risk factor for pneumonia. Maintaining adequate blood pressure control, in addition to other measures, may reduce risk for pneumonia., Through epidemiological and genetic association analyses in the UK Biobank (N = 377,143), Zekavat et al. link high blood pressure with increased risk for incident pneumonia and reduced performance on pulmonary function tests. These results suggest that maintaining adequate blood pressure control may reduce risk for pneumonia and improve pulmonary function.
Published: 2021
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38. Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19

Author: Mayara, Bearse, Yin P, Hung, Aram J, Krauson, Liana, Bonanno, Baris, Boyraz, Cynthia K, Harris, T Leif, Helland, Caroline F, Hilburn, Bailey, Hutchison, Soma, Jobbagy, Michael S, Marshall, Daniel J, Shepherd, Julian A, Villalba, Isabela, Delfino, Javier, Mendez-Pena, Ivan, Chebib, Christopher, Newton-Cheh, and James R, Stone
Subjects: Male, SARS-CoV-2, Myocardium, Anticoagulants, COVID-19, COVID-19 Drug Treatment, Electrocardiography, Myocarditis, Echocardiography, Humans, Female, Autopsy, Immunosuppressive Agents, Aged, Retrospective Studies
Abstract: COVID-19 has been associated with cardiac injury and dysfunction. While both myocardial inflammatory cell infiltration and myocarditis with myocyte injury have been reported in patients with fatal COVID-19, clinical-pathologic correlations remain limited. The objective was to determine the relationships between cardiac pathological changes in patients dying from COVID-19 and cardiac infection by SARS-CoV-2, laboratory measurements, clinical features, and treatments. In a retrospective study, 41 consecutive autopsies of patients with fatal COVID-19 were analyzed for the associations between cardiac inflammation, myocarditis, cardiac infection by SARS-CoV-2, clinical features, laboratory measurements, and treatments. Cardiac infection was assessed by in situ hybridization and NanoString transcriptomic profiling. Cardiac infection by SARS-CoV-2 was present in 30/41 cases: virus
Published: 2020

39. B-PO05-149 ASSESSMENT OF DRUG-INDUCED QT PROLONGATION USING AN AI-ECG ALGORITHM ON A MOBILE 6-LEAD ECG PLATFORM

Author: Jennifer L. Dugan, Dave Albert, Peter A. Noseworthy, Christopher Newton-Cheh, Johan M Bos, Paul A. Friedman, Zachi Itzhak Attia Msee, Matthew Schram, John R. Giudicessi, and Michael J. Ackerman
Subjects: medicine.medical_specialty, business.industry, Physiology (medical), Internal medicine, medicine, Cardiology, Drug-induced QT prolongation, Cardiology and Cardiovascular Medicine, Lead (electronics), business
Published: 2021

40. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

Author: Yvonne M. Hoedemaekers, M. Ben Shoemaker, Pascale Guicheney, Antoine Leenhardt, Andrea Mazzanti, Minoru Horie, Jan H. Veldink, Isabelle Denjoy, Yu Kucho, Chiea Chuen Khor, Tomas Robyns, Carlo Napolitano, Peter Weeke, J. Martijn Bos, David J. Tester, Hanno L. Tan, Annika Rydberg, Patrick T. Ellinor, Pilar Galan, Taisuke Ishikawa, Seiko Ohno, Peter J. Schwartz, Masao Yoshinaga, Thomas Werge, Marta Ribasés, Bart Loeys, Jean-Jacques Schott, Jacob Tfelt-Hansen, Ulla-Britt Diamant, Marko Ernsting, Georgia Sarquella-Brugada, Yuka Mizusawa, Michael Christiansen, Pyotr G. Platonov, Annika Winbo, Thomas Meitinger, Keiko Shimamoto, Cristina Barlassina, Pieter G. Postema, Takeru Makiyama, Maarten P. van den Berg, Yanushi D. Wijeyeratne, Wataru Shimizu, Charles Antzelevitch, Christopher Newton-Cheh, Martina Müller-Nurasyid, Dan M. Roden, Vincent Probst, Takeshi Aiba, Lia Crotti, Daniele Cusi, Britt M. Beckmann, Johan Saenen, Peter Lichtner, Oscar Campuzano, Tin Aung, Nynke Hofman, Morten S. Olesen, Matteo Pedrazzini, Elijah R. Behr, Karen E. Morrison, Najim Lahrouchi, Katja E. Odening, Andrew D. Krahn, Kari L. Turkowski, J. Peter van Tintelen, Steven A. Lubitz, Federica Dagradi, Josep Brugada, Julien Barc, Birgit Stallmeyer, Stefan Kääb, Sven Zumhagen, Jonathan R. Skinner, Michael W.T. Tanck, Christopher Shaw, Brianna Davies, Eric Schulze-Bahr, Mineo Ozaki, Roddy Walsh, Antoine Andorin, Leonard H. van den Berg, Silvia G. Priori, Johannes Steinfurt, Jean-Baptiste Gourraud, Eline A. Nannenberg, Mark Lathrop, Rafik Tadros, Ramon Brugada, Leander Beekman, Peter M. Andersen, Ryan Pfeiffer, Boris Rudic, Reza Jabbari, Kanae Hasegawa, Jeroen Breckpot, Naomasa Makita, Michael J. Ackerman, Arthur A.M. Wilde, Hideki Itoh, Martin Borggrefe, Elena Arbelo, Connie R. Bezzina, Pamela J. Shaw, Ammar Al-Chalabi, Markus Munter, Cardiology, Graduate School, ACS - Heart failure & arrhythmias, ACS - Amsterdam Cardiovascular Sciences, Human Genetics, Epidemiology and Data Science, APH - Methodology, ACS - Atherosclerosis & ischemic syndromes, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences. Amsterdam University Medical Center, University of Amsterdam, European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart (ERN GUARD-Heart), Institut de Cardiologie de Montreal, Université de Montréal (UdeM), Istituto Auxologico Italiano, Shiga University of Medical Science, University of Fukui [Bunkyo], Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Lahrouchi, N, Tadros, R, Crotti, L, Mizusawa, Y, Postema, P, Beekman, L, Walsh, R, Hasegawa, K, Barc, J, Ernsting, M, Turkowski, K, Mazzanti, A, Beckmann, B, Shimamoto, K, Diamant, U, Wijeyeratne, Y, Kucho, Y, Robyns, T, Ishikawa, T, Arbelo, E, Christiansen, M, Winbo, A, Jabbari, R, Lubitz, S, Steinfurt, J, Rudic, B, Loeys, B, Shoemaker, M, Weeke, P, Pfeiffer, R, Davies, B, Andorin, A, Hofman, N, Dagradi, F, Pedrazzini, M, Tester, D, Bos, J, Sarquella-Brugada, G, Campuzano, Ó, Platonov, P, Stallmeyer, B, Zumhagen, S, Nannenberg, E, Veldink, J, van den Berg, L, Al-Chalabi, A, Shaw, C, Shaw, P, Morrison, K, Andersen, P, Müller-Nurasyid, M, Cusi, D, Barlassina, C, Galan, P, Lathrop, M, Munter, M, Werge, T, Ribasés, M, Aung, T, Khor, C, Ozaki, M, Lichtner, P, Meitinger, T, van Tintelen, J, Hoedemaekers, Y, Denjoy, I, Leenhardt, A, Napolitano, C, Shimizu, W, Schott, J, Gourraud, J, Makiyama, T, Ohno, S, Itoh, H, Krahn, A, Antzelevitch, C, Roden, D, Saenen, J, Borggrefe, M, Odening, K, Ellinor, P, Tfelt-Hansen, J, Skinner, J, van den Berg, M, Olesen, M, Brugada, J, Brugada, R, Makita, N, Breckpot, J, Yoshinaga, M, Behr, E, Rydberg, A, Aiba, T, Kääb, S, Priori, S, Guicheney, P, Tan, H, Newton-Cheh, C, Ackerman, M, Schwartz, P, Schulze-Bahr, E, Probst, V, Horie, M, Wilde, A, Tanck, M, Bezzina, C, and Cardiovascular Centre (CVC)
Subjects: Multifactorial Inheritance, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, Severity of Illness Index, Sudden cardiac death, Electrocardiography, 0302 clinical medicine, inheritance pattern, Medicine, Cardiac and Cardiovascular Systems, Age of Onset, Genetics, 0303 health sciences, Kardiologi, Genetic disorder, genome-wide association study, Prognosis, 3. Good health, Phenotype, Medical genetics, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Genotype, Long QT syndrome, 610 Medicine & health, BIO/18 - GENETICA, QT interval, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Physiology (medical), long QT syndrome, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Alleles, Genetic Association Studies, MED/01 - STATISTICA MEDICA, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, inheritance patterns, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Heritability, medicine.disease, Genetic architecture, Genome-wide Association Study, Inheritance Patterns, Long Qt Syndrome, Case-Control Studies, Human medicine, business
Abstract: Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P −8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P −6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 −3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P P Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
Published: 2020

41. Case 24-2020: A 44-Year-Old Woman with Chest Pain, Dyspnea, and Shock

Author: Masaki Funamoto, Andrey Rupasov, Daniel A. Zlotoff, Jerome C. Crowley, Judy Hung, and Christopher Newton-Cheh
Subjects: Tachycardia, Adult, Chest Pain, Fever, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Diagnostico diferencial, Pneumonia, Viral, Shock, Cardiogenic, 030204 cardiovascular system & hematology, Chest pain, Diagnosis, Differential, 03 medical and health sciences, Betacoronavirus, Electrocardiography, 0302 clinical medicine, medicine, Humans, Case Records of the Massachusetts General Hospital, 030212 general & internal medicine, Lung, Pandemics, medicine.diagnostic_test, business.industry, SARS-CoV-2, COVID-19, General Medicine, medicine.disease, respiratory tract diseases, Pneumonia, Dyspnea, Echocardiography, Shock (circulatory), Anesthesia, Female, medicine.symptom, Differential diagnosis, business, Cardiomyopathies, Coronavirus Infections, Tomography, X-Ray Computed
Abstract: A Woman with Chest Pain, Dyspnea, and Shock A 44-year-old woman presented with cough, dyspnea, and chest pain. On examination, she had tachycardia and hypotension. Evaluation revealed SARS-CoV-2 RN...
Published: 2020

42. Influence of blood pressure on pneumonia risk: Epidemiological association and Mendelian randomisation in the UK Biobank

Author: Puja Kohli, Pradeep Natarajan, Christopher Newton-Cheh, James P. Pirruccello, Elizabeth W. Karlson, Seyedeh M. Zekavat, Hongyu Zhao, and Michael C. Honigberg
Subjects: 0303 health sciences, medicine.medical_specialty, education.field_of_study, business.industry, Respiratory disease, Hazard ratio, Population, Respiratory infection, 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, 03 medical and health sciences, Pneumonia, 0302 clinical medicine, Blood pressure, Internal medicine, Epidemiology, medicine, Risk factor, education, business, 030304 developmental biology
Abstract: ObjectivesTo determine whether elevated blood pressure influences risk for respiratory infection.DesignProspective, population-based epidemiological and Mendelian randomisation studies.SettingUK Biobank.Participants377,143 self-identified British descent (54% women; median age 58 years) participants in the UK Biobank.Main outcome measuresFirst incident pneumonia over an average of 8 follow-up years.Results107,310 (30%) participants had hypertension at UK Biobank enrolment, and 9,969 (3%) developed a pneumonia during follow-up. Prevalent hypertension at baseline was significantly associated with increased risk for incident respiratory disease including pneumonia (hazard ratio 1.36 (95% confidence interval 1.29 to 1.43), P2, sex, smoking status, BMI, prevalent diabetes mellitus, prevalent coronary artery disease, and principal components of ancestry. Mendelian randomisation analyses indicated that genetic predisposition to a 5 mmHg increase in blood pressure was associated with increased risk of incident pneumonia for SBP (1.08, (1.04 to 1.13), PConclusionsThese results strongly suggest that elevated blood pressure independently increases risk for pneumonia and reduces pulmonary function. Maintaining adequate blood pressure control, in addition to other measures, may reduce risk for pneumonia. Whether the present findings are generalizable to novel coronavirus disease 2019 (COVID-19) require further study.Summary BoxSection 1: What is already known on this topicHypertension has been associated with pneumonia in small observational studies.Based on early epidemiologic analyses, hypertension is described as a risk factor for SARS-CoV-2 infection and associated novel coronavirus disease 2019 (COVID-19).The influence of hypertension on pneumonia risk is difficult to assess in traditional observational studies.Section 2: What this study addsOur pre-COVID-19 analyses are consistent with a causal relationship between increased blood pressure and increased risk for incident respiratory infections, as well as between increased blood pressure and reduced pulmonary function.These results support hypertension as a pneumonia risk factor; efforts to optimize blood pressure may reduce risk for pneumonia.
Published: 2020

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

Author: Dennis O. Mook-Kanamori, Yalda Jamshidi, Peter K. Joshi, Seung Hoan Choi, Henry J. Lin, Rebecca D. Jackson, Alison D. Murray, May E. Montasser, Veikko Salomaa, Charles Kooperberg, Moritz F. Sinner, Gianfranco Sinagra, Luisa Foco, James G. Wilson, Johan Sundström, Kathleen A. Ryan, Eric A. Whitsel, Bruno H. Stricker, Sandosh Padmanabhan, Christopher Newton-Cheh, Ozren Polasek, Unnur Thorsteinsdottir, Niek Verweij, Pier D. Lambiase, Nathan R. Tucker, Stefan Kääb, Jun Ding, Stefan Weiss, Daniel F. Gudbjartsson, David Conen, Lars Lind, Ivana Kolcic, Lu-Chen Weng, J. Wouter Jukema, Kirill V. Tarasov, Xiuqing Guo, Stella Trompet, Patricia B. Munroe, Albert V. Smith, Elsayed Z. Soliman, Andrew Tinker, Antti Jula, J. Gustav Smith, Alexander P. Reiner, Sébastien Thériault, Kathryn L. Lunetta, Vilmundur Gudnason, Mika Kähönen, Massimo Mangino, Raymond Noordam, Joshua C. Bis, Alan R. Shuldiner, Tim D. Spector, Borbala Mifsud, Stefan van Duijvenboden, Jeffrey R. O'Connell, Emelia J. Benjamin, M. Benjamin Shoemaker, Stephan B. Felix, Peter W. Macfarlane, Lorenz Risch, Uwe Völker, Stephanie M. Gogarten, Maria Fernanda Lima-Costa, Julia Ramirez, Morten S. Olesen, Konstantin Strauch, Annette Peters, Aaron Isaacs, Steven A. Lubitz, Eric Boerwinkle, Carolina Roselli, James H. Cartwright, Nathalia M. Araujo, Ruth J. F. Loos, Diane Fatkin, Harry Campbell, Blair H. Smith, Thomas Meitinger, André G. Uitterlinden, Paul L. Huang, Tamara B. Harris, Kathleen F. Kerr, David J. Porteous, Martina Müller-Nurasyid, Francesco Cucca, Michiel Rienstra, Davíð O. Arnar, Amanda A. Seyerle, Caroline Hayward, M. Abdullah Said, Catriona L. K. Barnes, Kent D. Taylor, Nona Sotoodehnia, Nina Mononen, Dan M. Roden, Jonathan Marten, Terho Lehtimäki, Dan E. Arking, Anna F. Dominiczak, Jan A. Kors, Olli T. Raitakari, Igor Rudan, Yordi J. van de Vegte, Christopher P. Nelson, Erik Ingelsson, Ulrike Peters, Girish N. Nadkarni, Eduardo Tarazona-Santos, Edward G. Lakatta, Nina Hutri-Kähönen, Bruce M. Psaty, Patrick T. Ellinor, Christian Fuchsberger, Katharina Schramm, Amelia W. Hall, M. Yldau van der Ende, Alvaro Alonso, James F. Wilson, Sheila Ulivi, Rosa B. Thorolfsdottir, Stefanie Aeschbacher, Mary L. Biggs, Marten E. van den Berg, Nilesh J. Samani, Thibaud Boutin, Vilmantas Giedraitis, Honghuang Lin, Kjell Nikus, Helen R. Warren, Arie C. Maan, James J. Cranley, Adolfo Correa, Martin Gögele, Ian Ford, Katri Sääksjärvi, Georg Ehret, Michele Orini, Susan R. Heckbert, Cecilia M. Lindgren, Jie Yao, Maria Pina Concas, Pim van der Harst, Ioanna Ntalla, Jeffrey Haessler, Jerome I. Rotter, Pashupati P. Mishra, Michael J. Cutler, Erwin P. Bottinger, Cornelia M. van Duijn, Jennifer A. Brody, Paolo Gasparini, Lenore J. Launer, Andrew P. Morris, Renée de Mutsert, Aki S. Havulinna, James P. Cook, Hilma Holm, Patrick Sulem, Alessandro De Grandi, Cristian Pattaro, Gardar Sveinbjornsson, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Gudmar Thorleifsson, Marcus Dörr, Muhammad B. Riaz, Peter P. Pramstaller, Yong Qian, Anubha Mahajan, Cathy C. Laurie, Kenneth Rice, Mark Chaffin, Kari Stefansson, Andrew A. Hicks, Solmaz Assa, Hao Mei, Leo-Pekka Lyytikäinen, Fabiola Del Greco M, Renan P. Souza, Michael Preuss, Adrienne M. Stilp, Barry London, Melanie Waldenberger, Christy L. Avery, Daniel Levy, Michael R. Barnes, Medical Informatics, Epidemiology, Internal Medicine, Weng, Lu-Chen [0000-0003-1475-4930], Hall, Amelia Weber [0000-0002-7915-0313], Tucker, Nathan R [0000-0002-5071-4218], Chaffin, Mark D [0000-0002-1234-5562], Roselli, Carolina [0000-0001-5267-6756], Barnes, Michael R [0000-0001-9097-7381], Mifsud, Borbala [0000-0003-3429-3094], Hayward, Caroline [0000-0002-9405-9550], Concas, Maria Pina [0000-0003-3598-2537], Boutin, Thibaud [0000-0003-4754-1675], Kolcic, Ivana [0000-0001-7918-6052], Rudan, Igor [0000-0001-6993-6884], Souza, Renan P [0000-0002-9479-4432], Giedraitis, Vilmantas [0000-0003-3423-2021], Ingelsson, Erik [0000-0003-2256-6972], Mahajan, Anubha [0000-0001-5585-3420], Morris, Andrew P [0000-0002-6805-6014], Hicks, Andrew A [0000-0001-6320-0411], Sundström, Johan [0000-0003-2247-8454], Nelson, Christopher P [0000-0001-8025-2897], Riaz, Muhammad B [0000-0002-5512-1745], Sinagra, Gianfranco [0000-0003-2700-8478], Mishra, Pashupati P [0000-0001-5177-3431], Caulfield, Mark J [0000-0001-9295-3594], Dominiczak, Anna [0000-0003-4913-3608], Risch, Lorenz [0000-0003-2692-6699], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Isaacs, Aaron [0000-0001-5037-4834], van Duijn, Cornelia M [0000-0002-2374-9204], Gudnason, Vilmundur [0000-0001-5696-0084], Smith, Albert V [0000-0003-1942-5845], Loos, Ruth JF [0000-0002-8532-5087], Preuss, Michael H [0000-0001-5266-8465], Correa, Adolfo [0000-0002-9501-600X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Waldenberger, Melanie [0000-0003-0583-5093], Mangino, Massimo [0000-0002-2167-7470], Rienstra, Michiel [0000-0002-2581-070X], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Fatkin, Diane [0000-0002-9010-9856], Brody, Jennifer A [0000-0001-8509-148X], Rice, Kenneth [0000-0002-3071-7278], Pattaro, Cristian [0000-0002-4119-0109], Wouter Jukema, J [0000-0002-3246-8359], Weiss, Stefan [0000-0002-3553-4315], Havulinna, Aki S [0000-0002-4787-8959], Sääksjärvi, Katri [0000-0002-5061-4911], Salomaa, Veikko [0000-0001-7563-5324], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Lakatta, Edward G [0000-0002-4772-0035], Lin, Honghuang [0000-0003-3043-3942], Lunetta, Kathryn L [0000-0002-9268-810X], Murray, Alison D [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Smith, Blair H [0000-0002-5362-9430], Uitterlinden, André [0000-0002-7276-3387], Peters, Ulrike [0000-0001-5666-9318], Alonso, Alvaro [0000-0002-2225-8323], Ehret, Georg B [0000-0002-5730-0675], Soliman, Elsayed Z [0000-0001-5632-8150], Gogarten, Stephanie M [0000-0002-7231-9745], Kerr, Kathleen F [0000-0002-6438-9583], Abdullah Said, M [0000-0003-2920-7745], Orini, Michele [0000-0001-5773-0344], Ramirez, Julia [0000-0003-4130-5866], Van Duijvenboden, Stefan [0000-0001-8897-558X], Gudbjartsson, Daniel F [0000-0002-5222-9857], Sulem, Patrick [0000-0001-7123-6123], Thorolfsdottir, Rosa B [0000-0001-7475-0398], Benjamin, Emelia J [0000-0003-4076-2336], Stefansson, Kari [0000-0003-1676-864X], Ellinor, Patrick T [0000-0002-2067-0533], Jamshidi, Yalda [0000-0003-0151-6482], Lubitz, Steven A [0000-0002-9599-4866], Munroe, Patricia B [0000-0002-4176-2947], Apollo - University of Cambridge Repository, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Cardiovascular Centre (CVC), Ntalla, I., Weng, L. -C., Cartwright, J. H., Hall, A. W., Sveinbjornsson, G., Tucker, N. R., Choi, S. H., Chaffin, M. D., Roselli, C., Barnes, M. R., Mifsud, B., Warren, H. R., Hayward, C., Marten, J., Cranley, J. J., Concas, M. P., Gasparini, P., Boutin, T., Kolcic, I., Polasek, O., Rudan, I., Araujo, N. M., Lima-Costa, M. F., Ribeiro, A. L. P., Souza, R. P., Tarazona-Santos, E., Giedraitis, V., Ingelsson, E., Mahajan, A., Morris, A. P., Del Greco M, F., Foco, L., Gogele, M., Hicks, A. A., Cook, J. P., Lind, L., Lindgren, C. M., Sundstrom, J., Nelson, C. P., Riaz, M. B., Samani, N. J., Sinagra, G., Ulivi, S., Kahonen, M., Mishra, P. P., Mononen, N., Nikus, K., Caulfield, M. J., Dominiczak, A., Padmanabhan, S., Montasser, M. E., O'Connell, J. R., Ryan, K., Shuldiner, A. R., Aeschbacher, S., Conen, D., Risch, L., Theriault, S., Hutri-Kahonen, N., Lehtimaki, T., Lyytikainen, L. -P., Raitakari, O. T., Barnes, C. L. K., Campbell, H., Joshi, P. K., Wilson, J. F., Isaacs, A., Kors, J. A., van Duijn, C. M., Huang, P. L., Gudnason, V., Harris, T. B., Launer, L. J., Smith, A. V., Bottinger, E. P., Loos, R. J. F., Nadkarni, G. N., Preuss, M. H., Correa, A., Mei, H., Wilson, J., Meitinger, T., Muller-Nurasyid, M., Peters, A., Waldenberger, M., Mangino, M., Spector, T. D., Rienstra, M., van de Vegte, Y. J., van der Harst, P., Verweij, N., Kaab, S., Schramm, K., Sinner, M. F., Strauch, K., Cutler, M. J., Fatkin, D., London, B., Olesen, M., Roden, D. M., Benjamin Shoemaker, M., Gustav Smith, J., Biggs, M. L., Bis, J. C., Brody, J. A., Psaty, B. M., Rice, K., Sotoodehnia, N., De Grandi, A., Fuchsberger, C., Pattaro, C., Pramstaller, P. P., Ford, I., Wouter Jukema, J., Macfarlane, P. W., Trompet, S., Dorr, M., Felix, S. B., Volker, U., Weiss, S., Havulinna, A. S., Jula, A., Saaksjarvi, K., Salomaa, V., Guo, X., Heckbert, S. R., Lin, H. J., Rotter, J. I., Taylor, K. D., Yao, J., de Mutsert, R., Maan, A. C., Mook-Kanamori, D. O., Noordam, R., Cucca, F., Ding, J., Lakatta, E. G., Qian, Y., Tarasov, K. V., Levy, D., Lin, H., Newton-Cheh, C. H., Lunetta, K. L., Murray, A. D., Porteous, D. J., Smith, B. H., Stricker, B. H., Uitterlinden, A., van den Berg, M. E., Haessler, J., Jackson, R. D., Kooperberg, C., Peters, U., Reiner, A. P., Whitsel, E. A., Alonso, A., Arking, D. E., Boerwinkle, E., Ehret, G. B., Soliman, E. Z., Avery, C. L., Gogarten, S. M., Kerr, K. F., Laurie, C. C., Seyerle, A. A., Stilp, A., Assa, S., Abdullah Said, M., Yldau van der Ende, M., Lambiase, P. D., Orini, M., Ramirez, J., Van Duijvenboden, S., Arnar, D. O., Gudbjartsson, D. F., Holm, H., Sulem, P., Thorleifsson, G., Thorolfsdottir, R. B., Thorsteinsdottir, U., Benjamin, E. J., Tinker, A., Stefansson, K., Ellinor, P. T., Jamshidi, Y., Lubitz, S. A., Munroe, P. B., Fysiologie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Arrhythmias, Genome-wide association studies, CALCINEURIN, Electrocardiography, 0302 clinical medicine, Cardiovascular Disease, Multi-ancestry GWAS, ELEMENTS, Medicine, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, RISK, DECREASE, education.field_of_study, Multidisciplinary, Kardiologi, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, Atrial fibrillation, 3142 Public health care science, environmental and occupational health, 3. Good health, Endophenotype, Arrhythmias, Cardiac, Cardiovascular Diseases, Endophenotypes, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Quantitative Trait Loci, cardiovascular system, Cardiology, medicine.symptom, Erfðarannsóknir, Cardiac, Medical Genetics, Human, Bradycardia, medicine.medical_specialty, Science, GENOME-WIDE ASSOCIATION, ATRIAL-FIBRILLATION, MUTATIONS, DURATION, CARDIOMYOPATHY, BRADYCARDIA, Population, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, Cardiac conduction, PR interval, education, Medicinsk genetik, business.industry, Cardiovascular genetics, General Chemistry, Arfgengi, medicine.disease, 030104 developmental biology, lcsh:Q, business
Abstract: Publisher's version (útgefin grein), 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., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.
Published: 2020

44. Influence of Hypertension on Pneumonia Risk: Epidemiological Association and Mendelian Randomization in the UK Biobank

Author: Seyedeh M. Zekavat, James P. Pirruccello, Elizabeth W. Karlson, Hongyu Zhao, Michael C. Honigberg, Puja Kohli, Pradeep Natarajan, and Christopher Newton-Cheh
Subjects: medicine.medical_specialty, business.industry, Diastole, medicine.disease, Pulmonary function testing, Pneumonia, Blood pressure, Internal medicine, Mendelian randomization, Epidemiology, medicine, Genetic predisposition, Prospective cohort study, business
Abstract: Background: Small studies have correlated hypertension with pneumonia risk; whether this is recapitulated in larger prospective studies, and represents a causal association, is unclear. Methods and Results: We estimated the risk of prevalent hypertension with incident respiratory diseases over mean 8 follow-up years among 377,143 British participants in the UK Biobank. Mendelian randomization of blood pressure on pneumonia was implemented using 75 independent, genome-wide significant variants associated with systolic and diastolic blood pressures among 299,024 individuals not in the UK Biobank. Secondary analyses with pulmonary function tests were performed.107,310 (30%) participants had hypertension at UK Biobank enrollment, and 9,969 (3%) developed a pneumonia during follow-up. Prevalent hypertension was independently associated with increased risk for incident pneumonia (HR: 1.36; 95% CI: 1.29 to 1.43; P
Published: 2020

45. Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology

Author: C M van Duijn, James S. Floyd, Maarit A. Laaksonen, André G. Uitterlinden, Colleen M. Sitlani, Y-Di Chen, H J Lin, Christopher Newton-Cheh, Kent D. Taylor, Albert V. Smith, Til Stürmer, Kari E. North, Peter W. Macfarlane, Dennis O. Mook-Kanamori, Raymond Noordam, Yun Li, Jun Li, Tamar Sofer, Raul Mendez-Giraldez, Adrienne M. Stilp, Cathy C. Laurie, Ian Ford, Christy L. Avery, Stella Trompet, Nona Sotoodehnia, Jeffrey Roach, T.B. Harris, Jennifer A. Brody, Susan R. Heckbert, L. A. Cupples, J. C. Bis, Ruifang Li-Gao, Christopher J. O'Donnell, Vilmundur Gudnason, Robert C. Kaplan, Brendan M. Buckley, R. de Mutsert, Jan A. Kors, Steve Cummings, Elsayed Z. Soliman, Xiaohui Li, Kati Kristiansson, Linda Broer, Alexander P. Reiner, Joop Jukema, Aaron Isaacs, Evan L. Busch, Craig R. Lee, Amanda A. Seyerle, Heather M. Highland, Kathleen F. Kerr, Bruce M. Psaty, Leslie A. Lange, Qing Duan, Veikko Salomaa, Kenneth Rice, James D. Stewart, Stephanie M. Gogarten, E. A. Whitsel, Kirk C. Wilhelmsen, Daniel S. Evans, Yongmei Liu, Bruno H. Stricker, Fangui Sun, Kimmo Porthan, A. Hofman, Gina M. Peloso, L. J. Launer, Kerri L. Wiggins, Melanie D. Napier, Jerome I. Rotter, Frits R. Rosendaal, James G. Wilson, Ramachandran S. Vasan, Kardiologian yksikkö, Department of Medicine, Clinicum, Genetica & Celbiologie, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, Epidemiology, Internal Medicine, Medical Informatics, and Erasmus MC other
Subjects: Male, 0301 basic medicine, Influencing antihypertensive response, Aging, Sodium Chloride Symporter Inhibitors, Blood-pressure response, Gene-environment interactions, Ethnic populations, VARIANTS, Cardiovascular, Bioinformatics, Cohort Studies, Electrocardiography, Cardiovascular drugs, Heart Rate, Polymorphism (computer science), HYPERTENSIVE PATIENTS, Epidemiology, 80 and over, Ethnicity, WIDE ASSOCIATION, Pharmacology & Pharmacy, Longitudinal Studies, Aged, 80 and over, Wide association, Genomewide association, Variants, Single Nucleotide, Pharmacology and Pharmaceutical Sciences, Genomics, Middle Aged, CARDIOVASCULAR DRUGS, 3. Good health, 317 Pharmacy, Molecular Medicine, Female, Cohort study, medicine.drug, Adult, medicine.medical_specialty, INFLUENCING ANTIHYPERTENSIVE RESPONSE, MEDLINE, UNITED-STATES, Polymorphism, Single Nucleotide, QT interval, Article, 03 medical and health sciences, BLOOD-PRESSURE RESPONSE, Genetics, medicine, Humans, Polymorphism, Thiazide, Hypertensive patients, Aged, Pharmacology, Selection bias, SELECTION BIAS, business.industry, Human Genome, R1, GENE-ENVIRONMENT INTERACTIONS, United States, 030104 developmental biology, Pharmacogenetics, Pharmacogenomics, GENOMEWIDE ASSOCIATION, business
Abstract: Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P
Published: 2018

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

Author: Barbara McKnight, Martina Müller-Nurasyid, Raha Pazoki, Michael W.T. Tanck, Thomas Engstrøm, Arthur A.M. Wilde, Man Li, Martin VanDenburgh, Marieke T. Blom, Reza Jabbari, Thomas Meitinger, Philippe Goyette, Anna Moes, Rebecca N. Mitchell, Christine M. Albert, Aravinda Chakravarti, Dan E. Arking, Jean-Claude Tardif, Rozenn N. Lemaitre, Foram N. Ashar, Pui-Yan Kwok, Frank D. Kolodgie, Jacob Tfelt-Hansen, Renu Virmani, Susan R. Heckbert, Angel C.Y. Mak, David S. Siscovick, Vinicius Tragante, Xavier Jouven, Hanno L. Tan, John D. Rioux, Mark Eijgelsheim, Ronald J. Prineas, Nona Sotoodehnia, Xiaoqing Zhao, Stefan A. Escher, Heikki V. Huikuri, Bruce M. Psaty, Charlotte Glinge, Albert Hofman, Oscar H. Franco, Florence Dumas, Bruno H. Stricker, M. Juhani Junttila, Folkert W. Asselbergs, Josef Coresh, Christopher J. O'Donnell, Paul W. Franks, Shih-Jen Hwang, Veikko Salomaa, Jan-Håkan Jansson, Stefan Kääb, Christopher Newton-Cheh, Joseph J. Maleszewski, Paul I.W. de Bakker, Jennifer A. Brody, Aki S. Havulinna, André G. Uitterlinden, Georg Ehret, Jerome I. Rotter, Thomas Lumley, Connie R. Bezzina, Marc K. Halushka, Sara L. Pulit, Epidemiology, Internal Medicine, Ehret, Georg Benedikt, Cardiology, Epidemiology and Data Science, APH - Methodology, ACS - Heart failure & arrhythmias, and APH - Health Behaviors & Chronic Diseases
Subjects: Male, Genome-wide association study, Coronary Artery Disease, Cardiorespiratory Medicine and Haematology, Arrhythmias, 030204 cardiovascular system & hematology, VARIANTS, Cardiovascular, Bioinformatics, Body Mass Index, Sudden cardiac death, Coronary artery disease, 0302 clinical medicine, Risk Factors, 2.1 Biological and endogenous factors, Medicine, 030212 general & internal medicine, Family history, Aetiology, Cardiac/genetics/physiopathology, reproductive and urinary physiology, POPULATION, 0303 health sciences, education.field_of_study, Coronary Artery Disease/genetics, ATHEROSCLEROSIS-RISK, DEATH, hemic and immune systems, Mendelian Randomization Analysis, Single Nucleotide, 3. Good health, Death, Heart Disease, MENDELIAN RANDOMIZATION, Medical genetics, Female, FIBRILLATION, medicine.symptom, Cardiology and Cardiovascular Medicine, Cardiac, Cardiac/etiology, medicine.medical_specialty, Clinical Sciences, Population, Single-nucleotide polymorphism, 610 Medicine & health, Biology, Genetic correlation, Polymorphism, Single Nucleotide, Risk Assessment, Heart Conduction System/physiopathology, 03 medical and health sciences, Sex Factors, Sudden cardiac arrest, Clinical Research, Heart Conduction System, 360 Social problems & social services, RISK-FACTOR, Mendelian randomization, Genetics, Journal Article, Humans, INTERVAL, Polymorphism, Risk Assessment/methods, education, Heart Disease - Coronary Heart Disease, 030304 developmental biology, business.industry, Prevention, Human Genome, Arrhythmias, Cardiac, medicine.disease, Sudden, Genetic architecture, Good Health and Well Being, Death, Sudden, Cardiac, Cardiovascular System & Hematology, business
Abstract: BackgroundSudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. While several risk factors are observationally associated with SCA, the genetic architecture of SCA in the general population remains unknown. Furthermore, understanding which risk factors are causal may help target prevention strategies.MethodsWe carried out a large genome-wide association study (GWAS) for SCA (n=3,939 cases, 25,989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA.ResultsNo 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 (1) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (2) height and BMI, and (3) electrical instability traits (QT and atrial fibrillation), suggesting etiologic 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 highrisk populations and the general community.
Published: 2018

47. What Can We Learn From Common Genetic Variants With Weak Effects on Cardiovascular Disease Risk?

Author: Christopher Newton-Cheh
Subjects: Genotype, business.industry, MEDLINE, Genetic variants, Coronary Artery Disease, Bioinformatics, medicine.disease, Coronary artery disease, Migraine, Cardiovascular Diseases, Risk Factors, Heart failure, Disease risk, Humans, Medicine, Cardiology and Cardiovascular Medicine, business
Published: 2019

48. B-AB13-01 TRANS-ANCESTRY GWAS OF 252,730 INDIVIDUALS IDENTIFIES 114 NOVEL LOCI ASSOCIATED WITH THE QT INTERVAL

Author: Aaron Isaacs, Borbala Mifsud, Najim Lahrouchi, William J Young, Patricia B. Munroe, Nona Sotoodehnia, and Christopher Newton-Cheh
Subjects: Genetics, business.industry, Physiology (medical), Medicine, Genome-wide association study, Cardiology and Cardiovascular Medicine, business, QT interval
Published: 2021

49. Virtual multidisciplinary care for heart failure patients with cardiac resynchronization therapy devices during the Coronavirus Disease 2019 pandemic

Author: Jagmeet P. Singh, E. Kevin Heist, Nasrien E. Ibrahim, Dingxin Qin, Saumya Das, William J. Hucker, Christopher Newton-Cheh, Nupur Dandwate, Mary Orencole, Giulio Cataldo, Megan Zhao, and Krishan Sharma
Subjects: Telemedicine, medicine.medical_specialty, business.industry, Multidisciplinary care, Cardiac Resynchronization Therapy Devices, Retrospective cohort study, 030204 cardiovascular system & hematology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Patient satisfaction, Interquartile range, Patient outcomes, RC666-701, Heart failure, Emergency medicine, Etiology, CRT, Diseases of the circulatory (Cardiovascular) system, Medicine, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business, Adverse effect
Abstract: Background Heart failure (HF) patients with CRT devices are a vulnerable patient population during the Coronavirus Disease 2019 (COVID-19) Pandemic. It is important to develop innovative virtual care models to deliver multidisciplinary care while minimizing the risk of SARS-CoV2 exposure. Objective We aim to provide a description of how HF patients with CRT devices were assessed and managed in our virtual multidisciplinary clinic during the COVID-19 Pandemic. Clinical outcomes between this group of patients seen in virtual clinic and a historical cohort followed by in-person multi-disciplinary clinic prior to the pandemic were compared. Method This is a retrospective cohort study of HF patients with CRT implants who were seen in the virtual multidisciplinary clinic from March 18th, 2020 to May 27th, 2020 (Virtual Visit Group, N = 43). A historical cohort of HF patients with CRT devices seen in the ReACT clinic in person during the same calendar time period in 2019 was used as a control group (In-Person Visit Group, N = 39). Both groups were followed until July 1st of the same calendar year (2020 or 2019) for clinical events. The primary outcome measure was a combined outcome of all-cause mortality and HF- or device-related hospitalizations during follow-up. The secondary outcome measures included patient satisfaction, COVID-19 infection, and other cardiovascular events. Results In the Virtual-Visit Group, 21 patients (48.8%) had their initial ReACT clinic visit (first visit after CRT implant) as a virtual visit; 22 patients (51.2%) had prior in-person ReACT clinic visits before the first virtual visit. During the virtual visits, 12 patients had either potential cardiac symptoms or significant device interrogation findings that required clinical intervention. In post-virtual clinic patient satisfaction survey, all 22 patients surveyed (100%) reported being very satisfied or satisfied with the overall experience of the virtual clinic, and every patient (100%) said they would like to use telemedicine again. During a median follow-up period of 82 days (interquartile range [IQR] 61–96 days), one patient died from pneumonia of unclear etiology at an outside hospital, without documentation of COVID-19 positivity. No patient was hospitalized for HF- or arrhythmia-related complications. No patient was diagnosed with COVID-19. Compared with the In-Person Visit Group, there was no significant increase in mortality or major cardiovascular events in the Virtual-Visit Group (2.3% versus 5.1%, P = 0.60). Conclusions and Relevance Virtual multidisciplinary care was feasible for HF patients with cardiac resynchronization therapy devices and achieved good patient satisfaction. Virtual care was not associated with short-term increase in adverse events for HF patients with CRT device during the COVID-19 Pandemic. This virtual care model could help promote the adoption of digital health methodology for high-risk patients with multiple cardiac comorbidities.
Published: 2021

50. Blood Pressure-Associated Genetic Variants in the Natriuretic Peptide Receptor 1 Gene Modulate Guanylate Cyclase Activity

Author: Connie R. Bezzina, Sara Vandenwijngaert, Najim Lahrouchi, John L. Diener, Clara D. Ledsky, Daniel Bloch, Lisa Ames, Florian Wunderer, Toshiyuki Honda, Mohsin A.F. Khan, Christopher Newton-Cheh, Emmanuel S. Buys, Cardiology, Graduate School, and ACS - Heart failure & arrhythmias
Subjects: 0301 basic medicine, medicine.medical_specialty, medicine.drug_class, Blood Pressure, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Guanosine monophosphate, medicine, Natriuretic peptide, Animals, Humans, Allele frequency, Chemistry, Guanylate cyclase activity, Genetic Variation, General Medicine, Brain natriuretic peptide, NPR1, Minor allele frequency, 030104 developmental biology, Endocrinology, Guanylate Cyclase, Hypertension, Atrial natriuretic peptide receptor, Receptors, Atrial Natriuretic Factor
Abstract: Background: Human genetic variation in the NPR1 (natriuretic peptide receptor 1 gene, encoding NPR-A, atrial natriuretic peptide receptor 1) was recently shown to affect blood pressure (BP). NPR-A catalyzes the intracellular conversion of guanosine triphosphate to cGMP (cyclic 3′,5′-guanosine monophosphate) on binding of ANP, BNP (atrial or brain natriuretic peptide). Increased levels of cGMP decrease BP by inducing natriuresis, diuresis, and vasodilation. Methods: We performed a meta-analysis of low-frequency and rare NPR1 variants for BP association in up to 491 584 unrelated individuals. To examine whether the identified BP-associated variants affect NPR-A function, the cGMP response to ANP and BNP was measured in cells expressing wild-type NPR1 and cells expressing the NPR1 variants. Results: In this study, we identified BP associations of 3 amino acid altering variants of NPR1 . The minor alleles of rs35479618 (p.E967K, gnomAD non-Finnish European allele frequency 0.017) and rs116245325 (p.L1034F, allele frequency 0.0007) were associated with higher BP ( P =4.0×10 −25 and P =9.9×10 −8 , respectively), while the minor allele of rs61757359 (p.G541S, allele frequency 0.003) was associated with lower BP ( P =1.8×10 −9 ). Cells transiently expressing 967K or 1034F NPR-A displayed decreased cGMP production in response to ANP and BNP (all P –6 ), while cells expressing 541S NPR-A produced more cGMP compared with cells expressing wild-type NPR-A ( P ≤4.13×10 −5 for ANP and P ≤4.24×10 −3 for BNP). Conclusions: In summary, the loss or gain of guanylate cyclase activity for these NPR1 allelic variants could explain the higher or lower BP observed for carriers in large population-based studies.
Published: 2019

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