Raymond Noordam1, William J Young2, Reem Salman3, Jørgen K Kanters4, Marten E van den Berg5, Diana van Heemst6, Henry J Lin7, Sandhi Maria Barreto8, Mary L Biggs9, Ginevra Biino10, Eulalia Catamo11, Maria Pina Concas11, Jun Ding12, Daniel S Evans13, Luisa Foco14, Niels Grarup15, Leo-Pekka Lyytikäinen16, Massimo Mangino17, Hao Mei18, Peter J van der Most19, Martina Müller-Nurasyid20, Christopher P Nelson21, Yong Qian12, Linda Repetto22, M Abdullah Said23, Nabi Shah24, Katharina Schramm25, Pedro G Vidigal26, Stefan Weiss27, Jie Yao28, Nuno R Zilhao29, Jennifer A Brody30, Peter S Braund21, Marco Brumat31, Eric Campana31, Paraskevi Christofidou32, Mark J Caulfield33, Alessandro De Grandi14, Anna F Dominiczak34, Alex S F Doney35, Gudny Eiriksdottir29, Christina Ellervik36, Luana Giatti8, Martin Gögele14, Claus Graff37, Xiuqing Guo38, Pim van der Harst23, Peter K Joshi22, Mika Kähönen39, Bryan Kestenbaum40, Maria F Lima-Costa41, Allan Linneberg42, Arie C Maan43, Thomas Meitinger44, Sandosh Padmanabhan45, Cristian Pattaro14, Annette Peters46, Astrid Petersmann47, Peter Sever48, Mortiz F Sinner49, Xia Shen50, Alice Stanton51, Konstantin Strauch52, Elsayed Z Soliman53, Kirill V Tarasov54, Kent D Taylor38, Chris H L Thio19, André G Uitterlinden55, Simona Vaccargiu56, Melanie Waldenberger57, Antonietta Robino11, Adolfo Correa58, Francesco Cucca59, Steven R Cummings13, Marcus Dörr60, Giorgia Girotto61, Vilmundur Gudnason62, Torben Hansen15, Susan R Heckbert63, Christian R Juhl64, Stefan Kääb49, Terho Lehtimäki16, Yongmei Liu65, Paulo A Lotufo66, Colin N A Palmer35, Mario Pirastu56, Peter P Pramstaller67, Antonio Luiz P Ribeiro68, Jerome I Rotter38, Nilesh J Samani21, Harold Snieder19, Tim D Spector32, Bruno H Stricker5, Niek Verweij23, James F Wilson69, James G Wilson70, J Wouter Jukema43, Andrew Tinker33, Christopher H Newton-Cheh71, Nona Sotoodehnia72, Dennis O Mook-Kanamori73, Patricia B Munroe74, Helen R Warren33. 1. Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: r.noordam@lumc.nl. 2. Barts Heart Centre, St. Bartholomew's Hospital, London, United Kingdom; Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. 3. Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. 4. Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 5. Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands. 6. Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. 7. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California; Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. 8. Faculty of Medicine and Clinical Hospital, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. 9. Cardiovascular Health Research Unit, Department of Medicine, and Department of Biostatistics, University of Washington, Seattle, Washington. 10. Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy. 11. Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. 12. Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. 13. California Pacific Medical Center Research Institute, San Francisco, California. 14. Eurac Research, Institute for Biomedicine, affiliated to the University of Lübeck, Bolzano, Italy. 15. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 16. Department of Clinical Chemistry, Fimlab Laboratories, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 17. Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, United Kingdom. 18. Department of Data Science, University of Mississippi Medical Center, Jackson, Mississippi. 19. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 20. Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. 21. Cardiovascular Research Centre, Glenfield Hospital, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom. 22. Centre for Global Health Reasearch, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland. 23. Department of Cardiology and Thorax Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 24. Division of Molecular and Clinical Medicine, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom; Department of Pharmacy, COMSATS University Islamabad, Abbottabad, Pakistan. 25. Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany. 26. School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil. 27. Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany; German Centre for Cardiovascular Research, partner site Greifswald, Greifswald, Germany. 28. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California. 29. Icelandic Heart Association, Kópavogur, Iceland. 30. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington. 31. Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy. 32. Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom. 33. Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; National Institute for Health Research Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, United Kingdom. 34. Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. 35. Division of Molecular and Clinical Medicine, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom. 36. Department of Production, Research and Innovation, Region Zealand, SorØ, Denmark; Harvard Medical School, Boston, Massachusetts; Department of Laboratory Medicine, Boston Children's Hospital, Boston, Massachusetts; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 37. Department of Health Science and Technology, Aalborg University, Aalborg, Denmark. 38. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California. 39. Department of Clinical Physiology, Tampere University Hospital, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 40. Kidney Research Institute, University of Washington, Seattle, Washington. 41. Rene Rachou Reserch Institute, Oswaldo Cruz Foundation, Belo Horizonte, Brazil. 42. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark. 43. Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. 44. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany. 45. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom. 46. Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany. 47. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany. 48. National Heart and Lung Institute, Imperial College London, London, United Kingdom. 49. Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. 50. Centre for Global Health Reasearch, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Biostatistics Group, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. 51. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland. 52. Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute for Medical Information Processing, Biometry, and Epidemiology, Faculty of Medicine, Ludwig Maximilian University of Munich, Munich, Germany. 53. Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina; Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina; Department of Internal Medicine, Cardiology Section, Wake Forest School of Medicine, Winston Salem, North Carolina. 54. Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. 55. Human Genotyping Facility, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands. 56. Institute of Genetic and Biomedical Research, National Research Council of Italy, UOS of Sassari, Sassari, Italy. 57. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. 58. Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi. 59. Department of Biomedical Sciences, University of Sassari, Sassari, Italy. 60. German Centre for Cardiovascular Research, partner site Greifswald, Greifswald, Germany; Department of Internal Medicine B - Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Greifswald, Germany. 61. Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy; Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy. 62. Icelandic Heart Association, Kópavogur, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 63. Cardiovascular Health Research Unit and the Department of Epidemiology, University of Washington, Seattle, Washington. 64. Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. 65. Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina. 66. Medical School and Center for Clinical and Epidemiologic Research, University of São Paulo, São Paulo, Brazil. 67. Eurac Research, Institute for Biomedicine, affiliated to the University of Lübeck, Bolzano, Italy; Department of Neurology, General Central Hospital, Bolzano, Italy; Department of Neurology, University of Lübeck, Lübeck, Germany. 68. Hospital das Clínicas and School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. 69. Centre for Global Health Reasearch, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom. 70. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi. 71. Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 72. Cardiovascular Health Research Unit, Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington. 73. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands. 74. Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; National Institute for Health Research Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, United Kingdom. Electronic address: p.b.munroe@qmul.ac.uk.
Abstract
BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.
BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.
Authors: Hassaan A Bukhari; Carlos Sánchez; José Esteban Ruiz; Mark Potse; Pablo Laguna; Esther Pueyo Journal: Sensors (Basel) Date: 2022-04-12 Impact factor: 3.847
Authors: Maxime M Bos; Neil J Goulding; Diana van Heemst; Raymond Noordam; Deborah A Lawlor; Matthew A Lee; Amy Hofman; Mariska Bot; René Pool; Lisanne S Vijfhuizen; Xiang Zhang; Chihua Li; Rima Mustafa; Matt J Neville; Ruifang Li-Gao; Stella Trompet; Marian Beekman; Nienke R Biermasz; Dorret I Boomsma; Irene de Boer; Constantinos Christodoulides; Abbas Dehghan; Ko Willems van Dijk; Ian Ford; Mohsen Ghanbari; Bastiaan T Heijmans; M Arfan Ikram; J Wouter Jukema; Dennis O Mook-Kanamori; Fredrik Karpe; Annemarie I Luik; L H Lumey; Arn M J M van den Maagdenberg; Simon P Mooijaart; Renée de Mutsert; Brenda W J H Penninx; Patrick C N Rensen; Rebecca C Richmond; Frits R Rosendaal; Naveed Sattar; Robert A Schoevers; P Eline Slagboom; Gisela M Terwindt; Carisha S Thesing; Kaitlin H Wade; Carolien A Wijsman; Gonneke Willemsen; Aeilko H Zwinderman Journal: BMC Med Date: 2021-03-18 Impact factor: 8.775
Authors: Jorg Taubel; Dominic Pimenta; Samuel Thomas Cole; Claus Graff; Jørgen K Kanters; A John Camm Journal: Clin Res Cardiol Date: 2022-05-21 Impact factor: 6.138
Authors: William J Young; Helen R Warren; Dennis O Mook-Kanamori; Julia Ramírez; Stefan van Duijvenboden; Michele Orini; Andrew Tinker; Diana van Heemst; Pier D Lambiase; J Wouter Jukema; Patricia B Munroe; Raymond Noordam Journal: Circ Genom Precis Med Date: 2021-04-22