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

Author: Ntalla, I. (Ioanna), Weng, L.-C., Cartwright, J.H. (James H.), Hall, A.W. (Amelia Weber), Sveinbjornsson, G. (Gardar), Tucker, N.R. (Nathan R.), Choi, S.H. (Seung Hoan), Chaffin, M.D. (Mark D.), Roselli, C. (Carolina), Barnes, M.J. (Michael), Mifsud, B. (Borbala), Warren, H.R. (Helen R.), Hayward, C. (Caroline), Marten, J. (Jonathan), Cranley, J.J. (James J.), Concas, M.P. (Maria Pina), Gasparini, P. (Paolo), Boutin, T. (Thibaud), Kolcic, I. (Ivana), Polasek, O. (Ozren), Rudan, I. (Igor), Araujo, N.M. (Nathalia M.), Lima-Costa, M.F. (Maria Fernanda), Ribeiro, A.L. (Antonio), Souza, R.P. (Renan P.), Tarazona-Santos, E. (Eduardo), Giedraitis, V. (Vilmantas), Ingelsson, E. (Erik), Mahajan, A. (Anubha), Morris, A.P. (Andrew), Del Greco M, F. (Fabiola), Foco, L. (Luisa), Gögele, M. (Martin), Hicks, A.A. (Andrew A.), Cook, J.P. (James P.), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Sundström, J. (Johan), Nelson, C.P. (Christopher P.), Riaz, M.B. (Muhammad B.), Samani, N.J. (Nilesh), Sinagra, G. (Gianfranco), Ulivi, S. (Shelia), Kähönen, M. (Mika), Mishra, P.P. (Pashupati P.), Mononen, N. (Nina), Nikus, K. (Kjell), Caulfield, M. (Mark), Dominiczak, A. (Anna), Padmanabhan, S. (Sandosh), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Ryan, K. (Kathleen), Shuldiner, A.R. (Alan R.), Aeschbacher, S. (Stefanie), Conen, D. (David), Risch, L. (Lorenz), Thériault, S. (Sébastien), Hutri-Kähönen, N. (Nina), Lehtimäki, T. (Terho), Lyytikäinen, L.-P. (Leo-Pekka), Raitakari, O. (Olli), Barnes, C.L.K. (Catriona L. K.), Campbell, H. (Harry), Joshi, P.K. (Peter), Wilson, J.F. (James), Isaacs, A.J. (Aaron), Kors, J.A. (Jan), Duijn, C.M. (Cornelia) van, Huang, P.L. (Paul L.), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara B.), Launer, L.J. (Lenore), Smith, A.V. (Albert), Bottinger, E.P. (Erwin), Loos, R.J.F. (Ruth), Nadkarni, G. (Girish), Preuss, M. (Michael), Correa, D.D., Mei, H. (Hao), Meitinger, T. (Thomas), Müller-Nurasyid, M. (Martina), Peters, A. (Annette), Waldenberger, M. (Melanie), Mangino, M. (Massimo), Spector, T.D. (Timothy), Rienstra, S.A., van de Vegte, Y.J. (Yordi J.), Harst, P. (Pim) van der, Verweij, N. (Niek), Kääb, S. (Stefan), Schramm, K. (Katharina), Sinner, M.F. (Moritz), Strauch, K. (Konstantin), Cutler, M.J. (Michael J.), Fatkin, D. (Diane), London, B. (Barry), Olesen, M.S. (Morten S.), Roden, D.M. (Dan M.), Benjamin Shoemaker, M. (M.), Gustav Smith, J. (J.), Biggs, M.L. (M.), Bis, J.C. (Joshua), Brody, J.A. (Jennifer A.), Psaty, B.M. (Bruce), Rice, K.M. (Kenneth), Sotoodehnia, N. (Nona), Grandi, A. (Alessandro) de, Fuchsberger, C. (Christian), Penninx, B.W.J.H., Pramstaller, P.P. (Peter Paul), Ford, I. (Ian), Jukema, J.W. (Jan Wouter), Macfarlane, P.W. (Peter W.), Trompet, S. (Stella), Dörr, M. (Marcus), Felix, S.B. (Stephan B.), Völker, U. (Uwe), Weiss, S. (Stefan), Havulinna, A.S. (Aki), Jula, A. (Antti), Sääksjärvi, K. (K.), Salomaa, V. (Veikko), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Lin, H.J. (Henry J.), Rotter, J.I. (Jerome I.), Taylor, K.D. (Kent), Yao, J. (Jie), Mutsert, R. (Reneé) de, Maan, A.C. (Arie C.), Mook-Kanamori, D.O. (Dennis O.), Noordam, R. (Raymond), Cucca, F. (Francesco), Ding, J. (Jun), Lakatta, E. (Edward), Qian, Y. (Yong), Tarasov, K.V. (Kirill V.), Levy, D. (Daniel), Lin, H. (Honghuang), Newton-Cheh, C. (Christopher), Lunetta, K.L. (Kathryn), Murray, A.D. (Alison D.), Porteous, D.J. (David J.), Smith, B.H. (Blair), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Berg, M.E. (Marten) van den, Haessler, J. (Jeff), Jackson, R.D. (Rebecca), Kooperberg, C. (Charles), Peters, U. (Ulrike), Reiner, A.P. (Alexander P.), Whitsel, E.A. (Eric), Alonso, A. (Alvaro), Arking, D.E. (Dan E.), Boerwinkle, E.A. (Eric), Ehret, G.B. (Georg B.), Soliman, E.Z. (Elsayed Z.), Avery, C.L., Gogarten, S.M., Kerr, K.F. (Kathleen), Laurie, C.C. (Cathy C.), Seyerle, A.A. (Amanda A.), Stilp, A. (Adrienne), Assa, S. (Solmaz), Abdullah Said, M. (M.), Yldau van der Ende, M. (M.), Lambiase, P.D. (Pier), Orini, M. (Michele), Ramirez, J. (Julia), Van Duijvenboden, S. (Stefan), Arnar, D.O. (David O.), Gudbjartsson, D.F. (Daniel), Holm, H. (Hilma), Sulem, P. (Patrick), Thorleifsson, G. (Gudmar), Thorolfsdottir, R.B. (Rosa B.), Thorsteinsdottir, U. (Unnur), Benjamin, E.J. (Emelia J.), Tinker, A. (Andrew), Zwart, J-A. (John-Anker), Ellinor, P.T. (Patrick), Jamshidi, Y. (Yalda), Lubitz, S.A. (Steven), Munroe, P. (Patricia), Ntalla, I. (Ioanna), Weng, L.-C., Cartwright, J.H. (James H.), Hall, A.W. (Amelia Weber), Sveinbjornsson, G. (Gardar), Tucker, N.R. (Nathan R.), Choi, S.H. (Seung Hoan), Chaffin, M.D. (Mark D.), Roselli, C. (Carolina), Barnes, M.J. (Michael), Mifsud, B. (Borbala), Warren, H.R. (Helen R.), Hayward, C. (Caroline), Marten, J. (Jonathan), Cranley, J.J. (James J.), Concas, M.P. (Maria Pina), Gasparini, P. (Paolo), Boutin, T. (Thibaud), Kolcic, I. (Ivana), Polasek, O. (Ozren), Rudan, I. (Igor), Araujo, N.M. (Nathalia M.), Lima-Costa, M.F. (Maria Fernanda), Ribeiro, A.L. (Antonio), Souza, R.P. (Renan P.), Tarazona-Santos, E. (Eduardo), Giedraitis, V. (Vilmantas), Ingelsson, E. (Erik), Mahajan, A. (Anubha), Morris, A.P. (Andrew), Del Greco M, F. (Fabiola), Foco, L. (Luisa), Gögele, M. (Martin), Hicks, A.A. (Andrew A.), Cook, J.P. (James P.), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Sundström, J. (Johan), Nelson, C.P. (Christopher P.), Riaz, M.B. (Muhammad B.), Samani, N.J. (Nilesh), Sinagra, G. (Gianfranco), Ulivi, S. (Shelia), Kähönen, M. (Mika), Mishra, P.P. (Pashupati P.), Mononen, N. (Nina), Nikus, K. (Kjell), Caulfield, M. (Mark), Dominiczak, A. (Anna), Padmanabhan, S. (Sandosh), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Ryan, K. (Kathleen), Shuldiner, A.R. (Alan R.), Aeschbacher, S. (Stefanie), Conen, D. (David), Risch, L. (Lorenz), Thériault, S. (Sébastien), Hutri-Kähönen, N. (Nina), Lehtimäki, T. (Terho), Lyytikäinen, L.-P. (Leo-Pekka), Raitakari, O. (Olli), Barnes, C.L.K. (Catriona L. K.), Campbell, H. (Harry), Joshi, P.K. (Peter), Wilson, J.F. (James), Isaacs, A.J. (Aaron), Kors, J.A. (Jan), Duijn, C.M. (Cornelia) van, Huang, P.L. (Paul L.), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara B.), Launer, L.J. (Lenore), Smith, A.V. (Albert), Bottinger, E.P. (Erwin), Loos, R.J.F. (Ruth), Nadkarni, G. (Girish), Preuss, M. (Michael), Correa, D.D., Mei, H. (Hao), Meitinger, T. (Thomas), Müller-Nurasyid, M. (Martina), Peters, A. (Annette), Waldenberger, M. (Melanie), Mangino, M. (Massimo), Spector, T.D. (Timothy), Rienstra, S.A., van de Vegte, Y.J. (Yordi J.), Harst, P. (Pim) van der, Verweij, N. (Niek), Kääb, S. (Stefan), Schramm, K. (Katharina), Sinner, M.F. (Moritz), Strauch, K. (Konstantin), Cutler, M.J. (Michael J.), Fatkin, D. (Diane), London, B. (Barry), Olesen, M.S. (Morten S.), Roden, D.M. (Dan M.), Benjamin Shoemaker, M. (M.), Gustav Smith, J. (J.), Biggs, M.L. (M.), Bis, J.C. (Joshua), Brody, J.A. (Jennifer A.), Psaty, B.M. (Bruce), Rice, K.M. (Kenneth), Sotoodehnia, N. (Nona), Grandi, A. (Alessandro) de, Fuchsberger, C. (Christian), Penninx, B.W.J.H., Pramstaller, P.P. (Peter Paul), Ford, I. (Ian), Jukema, J.W. (Jan Wouter), Macfarlane, P.W. (Peter W.), Trompet, S. (Stella), Dörr, M. (Marcus), Felix, S.B. (Stephan B.), Völker, U. (Uwe), Weiss, S. (Stefan), Havulinna, A.S. (Aki), Jula, A. (Antti), Sääksjärvi, K. (K.), Salomaa, V. (Veikko), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Lin, H.J. (Henry J.), Rotter, J.I. (Jerome I.), Taylor, K.D. (Kent), Yao, J. (Jie), Mutsert, R. (Reneé) de, Maan, A.C. (Arie C.), Mook-Kanamori, D.O. (Dennis O.), Noordam, R. (Raymond), Cucca, F. (Francesco), Ding, J. (Jun), Lakatta, E. (Edward), Qian, Y. (Yong), Tarasov, K.V. (Kirill V.), Levy, D. (Daniel), Lin, H. (Honghuang), Newton-Cheh, C. (Christopher), Lunetta, K.L. (Kathryn), Murray, A.D. (Alison D.), Porteous, D.J. (David J.), Smith, B.H. (Blair), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Berg, M.E. (Marten) van den, Haessler, J. (Jeff), Jackson, R.D. (Rebecca), Kooperberg, C. (Charles), Peters, U. (Ulrike), Reiner, A.P. (Alexander P.), Whitsel, E.A. (Eric), Alonso, A. (Alvaro), Arking, D.E. (Dan E.), Boerwinkle, E.A. (Eric), Ehret, G.B. (Georg B.), Soliman, E.Z. (Elsayed Z.), Avery, C.L., Gogarten, S.M., Kerr, K.F. (Kathleen), Laurie, C.C. (Cathy C.), Seyerle, A.A. (Amanda A.), Stilp, A. (Adrienne), Assa, S. (Solmaz), Abdullah Said, M. (M.), Yldau van der Ende, M. (M.), Lambiase, P.D. (Pier), Orini, M. (Michele), Ramirez, J. (Julia), Van Duijvenboden, S. (Stefan), Arnar, D.O. (David O.), Gudbjartsson, D.F. (Daniel), Holm, H. (Hilma), Sulem, P. (Patrick), Thorleifsson, G. (Gudmar), Thorolfsdottir, R.B. (Rosa B.), Thorsteinsdottir, U. (Unnur), Benjamin, E.J. (Emelia J.), Tinker, A. (Andrew), Zwart, J-A. (John-Anker), Ellinor, P.T. (Patrick), Jamshidi, Y. (Yalda), Lubitz, S.A. (Steven), and Munroe, P. (Patricia)
Abstract: The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduc
Published: 2020
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2. KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern

Author: Teumer, A. (Alexander), Trenkwalder, T. (Teresa), Kessler, T. (Thorsten), Jamshidi, Y. (Yalda), Berg, M.E. (Marten) van den, Kaess, B. (Bernhard), Nelson, C.P. (Christopher P.), Bastiaenen, R. (Rachel), de Bortoli, M. (Marzia), Rossini, A. (Alessandra), Deisenhofer, I. (Isabel), Stark, K. (Klaus), Assa, S. (Solmaz), Braund, P.S. (Peter), Cabrera, C. (Claudia), Dominiczak, A.F. (Anna F.), Gögele, M. (Martin), Hall, L.M. (Leanne M.), Ikram, M.A. (Arfan), Kavousi, M. (Maryam), Lackner, K.J. (Karl), Study, L.C. (Lifelines Cohort), Müller, C., Münzel, T. (Thomas), Nauck, M. (Matthias), Padmanabhan, S. (Sandosh), Pfeiffer, A.F.H. (Andreas), Spector, T.D. (Timothy), Uitterlinden, A.G. (André), Verweij, N. (Niek), Völker, U. (Uwe), Warren, H. (Helen), Zafar, M. (Mobeen), Felix, S.B. (Stephan), Kors, J.A. (Jan), Snieder, H. (Harold), Munroe, P. (Patricia), Penninx, B.W.J.H., Fuchsberger, C. (Christian), Schmidt, G. (Georg), Nolte, I.M. (Ilja), Schunkert, H. (Heribert), Pramstaller, P.P. (Peter Paul), Wild, P.S. (Philipp), Harst, P. (Pim) van der, Stricker, B.H.Ch. (Bruno), Schnabel, R.B. (Renate), Samani, N.J. (Nilesh), Hengstenberg, C. (Christian), Dörr, M. (Marcus), Behr, E.R. (Elijah), Reinhard, W. (Wibke), Teumer, A. (Alexander), Trenkwalder, T. (Teresa), Kessler, T. (Thorsten), Jamshidi, Y. (Yalda), Berg, M.E. (Marten) van den, Kaess, B. (Bernhard), Nelson, C.P. (Christopher P.), Bastiaenen, R. (Rachel), de Bortoli, M. (Marzia), Rossini, A. (Alessandra), Deisenhofer, I. (Isabel), Stark, K. (Klaus), Assa, S. (Solmaz), Braund, P.S. (Peter), Cabrera, C. (Claudia), Dominiczak, A.F. (Anna F.), Gögele, M. (Martin), Hall, L.M. (Leanne M.), Ikram, M.A. (Arfan), Kavousi, M. (Maryam), Lackner, K.J. (Karl), Study, L.C. (Lifelines Cohort), Müller, C., Münzel, T. (Thomas), Nauck, M. (Matthias), Padmanabhan, S. (Sandosh), Pfeiffer, A.F.H. (Andreas), Spector, T.D. (Timothy), Uitterlinden, A.G. (André), Verweij, N. (Niek), Völker, U. (Uwe), Warren, H. (Helen), Zafar, M. (Mobeen), Felix, S.B. (Stephan), Kors, J.A. (Jan), Snieder, H. (Harold), Munroe, P. (Patricia), Penninx, B.W.J.H., Fuchsberger, C. (Christian), Schmidt, G. (Georg), Nolte, I.M. (Ilja), Schunkert, H. (Heribert), Pramstaller, P.P. (Peter Paul), Wild, P.S. (Philipp), Harst, P. (Pim) van der, Stricker, B.H.Ch. (Bruno), Schnabel, R.B. (Renate), Samani, N.J. (Nilesh), Hengstenberg, C. (Christian), Dörr, M. (Marcus), Behr, E.R. (Elijah), and Reinhard, W. (Wibke)
Abstract: BACKGROUND: The presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown. METHODS: To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry. RESULTS. We identified a genome-wide significant (P < 5 × 10-8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10-12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery. CONCLUSIONS: In this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.
Published: 2019
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3. Corrigendum: Normal Values of Corrected Heart-Rate Variability in 10-Second Electrocardiograms for All Ages (Frontiers in Physiology, (2018), 9, (424), 10.3389/fphys.2018.00424)

Author: Berg, M.E. (Marten) van den, Rijnbeek, P.R. (Peter), Niemeijer, M.N. (Maartje), Hofman, A. (Albert), Herpen, G. (Gerard) van, Bots, M.L. (Michiel), Hillege, H.L. (Hans), Swenne, C.A. (Cees), Eijgelsheim, M. (Mark), Stricker, B.H.Ch. (Bruno), Kors, J.A. (Jan), Berg, M.E. (Marten) van den, Rijnbeek, P.R. (Peter), Niemeijer, M.N. (Maartje), Hofman, A. (Albert), Herpen, G. (Gerard) van, Bots, M.L. (Michiel), Hillege, H.L. (Hans), Swenne, C.A. (Cees), Eijgelsheim, M. (Mark), Stricker, B.H.Ch. (Bruno), and Kors, J.A. (Jan)
Abstract: In the original article, there was a mistake in Table S5 as published. The normal values for “SDNN” were given instead of for “RMSSD.” The corrected Table S5 appears below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
Published: 2019
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4. Normal Values of QT Variability in 10-s Electrocardiograms for all Ages

Author: Berg, M.E. (Marten) van den, Kors, J.A. (Jan), Herpen, G. (Gerard) van, Bots, M.L. (Michiel), Hillege, H. (Hans), Swenne, C.A. (Cees), Stricker, B.H.Ch. (Bruno), Rijnbeek, P.R. (Peter), Berg, M.E. (Marten) van den, Kors, J.A. (Jan), Herpen, G. (Gerard) van, Bots, M.L. (Michiel), Hillege, H. (Hans), Swenne, C.A. (Cees), Stricker, B.H.Ch. (Bruno), and Rijnbeek, P.R. (Peter)
Abstract: Aims: QT variability is a promising electrocardiographic marker. It has been studied as a screening tool for coronary artery disease and left ventricular hypertrophy, and increased QT variability is a known risk factor for sudden cardiac death. Considering that comprehensive normal values for QT variability were lacking, we set out to establish these in standard 10-s electrocardiograms (ECGs) covering both sexes and all ages. Methods: Ten-second, 12-lead ECGs were provided by five Dutch population studies (Pediatric Normal ECG Study, Leiden University Einthoven Science Project, Prevention of Renal and Vascular End-stage Disease Study, Utrecht Health Project, Rotterdam Study). ECGs were recorded digitally and processed by well-validated analysis software. We selected cardiologically healthy participants, 46% being women. Ages ranged from 11 days to 91 years. After quality control, 13,828 ECGs were available. We assessed three markers: standard deviation of QT intervals (SDqt), short-term QT variability (STVqt), and QT variability index (QTVI). Results: For SDqt and STVqt, the median and the lower limit of normal remained stable with age. The upper limit of normal declined until around age 45, and increased strongly in the elderly, notably so in women. This implies that a subset of the population, small enough not to have appreciable effect on the median, shows a high degree of QT variability with a possible risk of arrhythmias or worse, especially in women. Otherwise, sex differences were negligible in all three measurements. For QTVI, median, and normal limits decreased until age 20, and steadily went up afterwards except for the lower limit of normal, which flattens off after age 65. Conclusion: We report the first set of normal values for QT variability based on 10-s ECGs, for all ages and both sexes.
Published: 2019
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5. ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals

Author: Bihlmeyer, N.A. (Nathan A.), Brody, J.A. (Jennifer A.), Smith, A.V. (Albert), Warren, H. (Helen), Lin, H. (Honghuang), Isaacs, A. (Aaron), Liu, C.-T. (Ching-Ti), Marten, J. (Jonathan), Radmanesh, F. (Farid), Hall, L.M. (Leanne M.), Grarup, N. (Niels), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Huffman, J.E. (Jennifer E.), Verweij, N. (Niek), Guo, X. (Xiuqing), Yao, J. (Jie), Li-Gao, R. (Ruifang), Berg, M.E. (Marten) van den, Weiss, S. (Stefan), Prins, B.P. (Bram P.), Setten, J. (Jessica) van, Haessler, J. (Jeff), Lyytikäinen, L.-P. (Leo-Pekka), Li, M. (Man), Alonso, A. (Alvaro), Soliman, E.Z. (Elsayed Z.), Bis, J.C. (Joshua), Austin, T. (Tom), Chen, Y.D.I. (Yii-Der Ida), Psaty, B.M. (Bruce M.), Harrris, T.B. (Tamara B.), Launer, L.J. (Lenore), Padmanabhan, S. (Sandosh), Dominiczak, A. (Anna), Huang, P.L. (Paul L.), Xie, Z. (Zhijun), Ellinor, P.T. (Patrick), Kors, J.A. (Jan), Campbell, A. (Archie), Murray, A.D. (Alison D.), Nelson, C.P. (Christopher P.), Tobin, M.D. (Martin), Bork-Jensen, J. (Jette), Hansen, T. (Torben), Pedersen, O. (Oluf), Linneberg, A. (Allan), Sinner, M.F. (Moritz), Peters, A. (Annette), Waldenberger, M. (Melanie), Meitinger, T. (Thomas), Perz, S. (Siegfried), Kolcic, I. (Ivana), Rudan, I. (Igor), Boer, R.A. (Rudolf) de, Meer, P. (Peter) van der, Lin, H.J. (Henry J.), Taylor, K.D. (Kent), Mutsert, R. (Reneé) de, Trompet, S. (Stella), Jukema, J.W. (Jan Wouter), Maan, A.C. (Arie C.), Stricker, B.H.Ch. (Bruno), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A. (André), Völker, U. (Uwe), Homuth, G. (Georg), Völzke, H. (Henry), Felix, S.B. (Stephan), Mangino, M. (Massimo), Spector, T.D. (Timothy), Bots, M.L. (Michiel), Perez, M. (Marco), Raitakari, O. (Olli), Kähönen, M. (Mika), Mononen, N. (Nina), Gudnason, V. (Vilmundur), Munroe, P. (Patricia), Lubitz, S.A. (Steven A.), Duijn, C.M. (Cornelia) van, Newton-Cheh, C. (Christopher), Hayward, C. (Caroline), Rosand, J. (Jonathan), Samani, N.J. (Nilesh J.), Kanters, J.K., Wilson, J.F. (James), Kääb, S. (Stefan), Polasek, O. (Ozren), van der Harst, P. (Pim), Heckbert, S.R. (Susan), Rotter, J.I. (Jerome I.), Mook-Kanamori, D.O. (Dennis O.), Eijgelsheim, M. (Mark), Dörr, M. (Marcus), Jamshidi, Y. (Yalda), Asselbergs, F.W. (Folkert W.), Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Arking, D.E. (Dan), Sotoodehnia, N. (Nona), Bihlmeyer, N.A. (Nathan A.), Brody, J.A. (Jennifer A.), Smith, A.V. (Albert), Warren, H. (Helen), Lin, H. (Honghuang), Isaacs, A. (Aaron), Liu, C.-T. (Ching-Ti), Marten, J. (Jonathan), Radmanesh, F. (Farid), Hall, L.M. (Leanne M.), Grarup, N. (Niels), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Huffman, J.E. (Jennifer E.), Verweij, N. (Niek), Guo, X. (Xiuqing), Yao, J. (Jie), Li-Gao, R. (Ruifang), Berg, M.E. (Marten) van den, Weiss, S. (Stefan), Prins, B.P. (Bram P.), Setten, J. (Jessica) van, Haessler, J. (Jeff), Lyytikäinen, L.-P. (Leo-Pekka), Li, M. (Man), Alonso, A. (Alvaro), Soliman, E.Z. (Elsayed Z.), Bis, J.C. (Joshua), Austin, T. (Tom), Chen, Y.D.I. (Yii-Der Ida), Psaty, B.M. (Bruce M.), Harrris, T.B. (Tamara B.), Launer, L.J. (Lenore), Padmanabhan, S. (Sandosh), Dominiczak, A. (Anna), Huang, P.L. (Paul L.), Xie, Z. (Zhijun), Ellinor, P.T. (Patrick), Kors, J.A. (Jan), Campbell, A. (Archie), Murray, A.D. (Alison D.), Nelson, C.P. (Christopher P.), Tobin, M.D. (Martin), Bork-Jensen, J. (Jette), Hansen, T. (Torben), Pedersen, O. (Oluf), Linneberg, A. (Allan), Sinner, M.F. (Moritz), Peters, A. (Annette), Waldenberger, M. (Melanie), Meitinger, T. (Thomas), Perz, S. (Siegfried), Kolcic, I. (Ivana), Rudan, I. (Igor), Boer, R.A. (Rudolf) de, Meer, P. (Peter) van der, Lin, H.J. (Henry J.), Taylor, K.D. (Kent), Mutsert, R. (Reneé) de, Trompet, S. (Stella), Jukema, J.W. (Jan Wouter), Maan, A.C. (Arie C.), Stricker, B.H.Ch. (Bruno), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A. (André), Völker, U. (Uwe), Homuth, G. (Georg), Völzke, H. (Henry), Felix, S.B. (Stephan), Mangino, M. (Massimo), Spector, T.D. (Timothy), Bots, M.L. (Michiel), Perez, M. (Marco), Raitakari, O. (Olli), Kähönen, M. (Mika), Mononen, N. (Nina), Gudnason, V. (Vilmundur), Munroe, P. (Patricia), Lubitz, S.A. (Steven A.), Duijn, C.M. (Cornelia) van, Newton-Cheh, C. (Christopher), Hayward, C. (Caroline), Rosand, J. (Jonathan), Samani, N.J. (Nilesh J.), Kanters, J.K., Wilson, J.F. (James), Kääb, S. (Stefan), Polasek, O. (Ozren), van der Harst, P. (Pim), Heckbert, S.R. (Susan), Rotter, J.I. (Jerome I.), Mook-Kanamori, D.O. (Dennis O.), Eijgelsheim, M. (Mark), Dörr, M. (Marcus), Jamshidi, Y. (Yalda), Asselbergs, F.W. (Folkert W.), Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Arking, D.E. (Dan), and Sotoodehnia, N. (Nona)
Abstract: BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.
Published: 2018
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6. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Author: Prins, B.P. (Bram P.), Mead, T.J. (Timothy J.), Brody, J.A. (Jennifer A.), Sveinbjornsson, G. (Gardar), Ntalla, I. (Ioanna), Bihlmeyer, N.A. (Nathan A.), Berg, M.E. (Marten) van den, Bork-Jensen, J. (Jette), Cappellani, S. (Stefania), Van Duijvenboden, S. (Stefan), Klena, N.T. (Nikolai T.), Gabriel, G.C. (George C.), Liu, X. (Xiaoqin), Gulec, C. (Cagri), Grarup, N. (Niels), Haessler, J. (Jeff), Hall, L.M. (Leanne M.), Iorio, A. (Annamaria), Isaacs, A. (Aaron), Li-Gao, R. (Ruifang), Lin, H. (Honghuang), Liu, C.-T. (Ching-Ti), Lyytikäinen, L.-P. (Leo-Pekka), Marten, J. (Jonathan), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Orini, M. (Michele), Padmanabhan, S. (Sandosh), Radmanesh, F. (Farid), Ramirez, J. (Julia), Robino, A. (Antonietta), Schwartz, M. (Molly), Setten, J. (Jessica) van, Smith, A.V. (Albert), Verweij, N. (Niek), Warren, H. (Helen), Weiss, S. (Stefan), Alonso, A. (Alvaro), Arnar, D.O. (David O.), Bots, M.L. (Michiel), Boer, R.A. (Rudolf) de, Dominiczak, A. (Anna), Eijgelsheim, M. (Mark), Ellinor, P.T. (Patrick), Guo, X. (Xiuqing), Felix, S.B. (Stephan), Harris, T.B. (Tamara), Hayward, C. (Caroline), Heckbert, S.R. (Susan), Huang, P.L. (Paul L.), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kors, J.A. (Jan), Lambiase, P.D. (Pier), Launer, L.J. (Lenore), Li, M. (Man), Linneberg, A. (Allan), Nelson, C.P. (Christopher P.), Pedersen, O. (Oluf), Perez, M. (Marco), Peters, A. (Annette), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Raitakari, O. (Olli), Rice, K.M. (Kenneth), Rotter, J.I. (Jerome I.), Sinner, M.F. (Moritz), Soliman, E.Z. (Elsayed Z.), Spector, T.D. (Timothy), Strauch, K. (Konstantin), Thorsteinsdottir, U. (Unnur), Tinker, A. (Andrew), Trompet, S. (Stella), Uitterlinden, A.G. (André), Vaartjes, I. (Ilonca), Meer, P. (Peter) van der, Völker, U. (Uwe), Völzke, H. (Henry), Waldenberger, M. (Melanie), Wilson, J.F. (James), Xie, Z. (Zhijun), Asselbergs, F.W. (Folkert W.), Dörr, M. (Marcus), Duijn, C.M. (Cornelia) van, Gasparini, P. (Paolo), Gudbjartsson, D.F. (Daniel), Gudnason, V. (Vilmundur), Hansen, T. (Torben), Kääb, S. (Stefan), Kanters, J.K., Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Lin, H.J. (Henry J.), Lubitz, S.A. (Steven A.), Mook-Kanamori, D.O. (Dennis O.), Conti, F.J. (Francesco J.), Newton-Cheh, C. (Christopher), Rosand, J. (Jonathan), Rudan, I. (Igor), Samani, N.J. (Nilesh J.), Sinagra, G. (Gianfranco), Smith, B.H. (Blair), Holm, H. (Hilma), Stricker, B.H.Ch. (Bruno), Ulivi, S. (Sheila), Sotoodehnia, N. (Nona), Apte, S.S. (Suneel S.), van der Harst, P. (Pim), Zwart, J-A. (John-Anker), Munroe, P. (Patricia), Arking, D.E. (Dan), Lo, C.W. (Cecilia W.), Jamshidi, Y. (Yalda), Prins, B.P. (Bram P.), Mead, T.J. (Timothy J.), Brody, J.A. (Jennifer A.), Sveinbjornsson, G. (Gardar), Ntalla, I. (Ioanna), Bihlmeyer, N.A. (Nathan A.), Berg, M.E. (Marten) van den, Bork-Jensen, J. (Jette), Cappellani, S. (Stefania), Van Duijvenboden, S. (Stefan), Klena, N.T. (Nikolai T.), Gabriel, G.C. (George C.), Liu, X. (Xiaoqin), Gulec, C. (Cagri), Grarup, N. (Niels), Haessler, J. (Jeff), Hall, L.M. (Leanne M.), Iorio, A. (Annamaria), Isaacs, A. (Aaron), Li-Gao, R. (Ruifang), Lin, H. (Honghuang), Liu, C.-T. (Ching-Ti), Lyytikäinen, L.-P. (Leo-Pekka), Marten, J. (Jonathan), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Orini, M. (Michele), Padmanabhan, S. (Sandosh), Radmanesh, F. (Farid), Ramirez, J. (Julia), Robino, A. (Antonietta), Schwartz, M. (Molly), Setten, J. (Jessica) van, Smith, A.V. (Albert), Verweij, N. (Niek), Warren, H. (Helen), Weiss, S. (Stefan), Alonso, A. (Alvaro), Arnar, D.O. (David O.), Bots, M.L. (Michiel), Boer, R.A. (Rudolf) de, Dominiczak, A. (Anna), Eijgelsheim, M. (Mark), Ellinor, P.T. (Patrick), Guo, X. (Xiuqing), Felix, S.B. (Stephan), Harris, T.B. (Tamara), Hayward, C. (Caroline), Heckbert, S.R. (Susan), Huang, P.L. (Paul L.), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kors, J.A. (Jan), Lambiase, P.D. (Pier), Launer, L.J. (Lenore), Li, M. (Man), Linneberg, A. (Allan), Nelson, C.P. (Christopher P.), Pedersen, O. (Oluf), Perez, M. (Marco), Peters, A. (Annette), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Raitakari, O. (Olli), Rice, K.M. (Kenneth), Rotter, J.I. (Jerome I.), Sinner, M.F. (Moritz), Soliman, E.Z. (Elsayed Z.), Spector, T.D. (Timothy), Strauch, K. (Konstantin), Thorsteinsdottir, U. (Unnur), Tinker, A. (Andrew), Trompet, S. (Stella), Uitterlinden, A.G. (André), Vaartjes, I. (Ilonca), Meer, P. (Peter) van der, Völker, U. (Uwe), Völzke, H. (Henry), Waldenberger, M. (Melanie), Wilson, J.F. (James), Xie, Z. (Zhijun), Asselbergs, F.W. (Folkert W.), Dörr, M. (Marcus), Duijn, C.M. (Cornelia) van, Gasparini, P. (Paolo), Gudbjartsson, D.F. (Daniel), Gudnason, V. (Vilmundur), Hansen, T. (Torben), Kääb, S. (Stefan), Kanters, J.K., Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Lin, H.J. (Henry J.), Lubitz, S.A. (Steven A.), Mook-Kanamori, D.O. (Dennis O.), Conti, F.J. (Francesco J.), Newton-Cheh, C. (Christopher), Rosand, J. (Jonathan), Rudan, I. (Igor), Samani, N.J. (Nilesh J.), Sinagra, G. (Gianfranco), Smith, B.H. (Blair), Holm, H. (Hilma), Stricker, B.H.Ch. (Bruno), Ulivi, S. (Sheila), Sotoodehnia, N. (Nona), Apte, S.S. (Suneel S.), van der Harst, P. (Pim), Zwart, J-A. (John-Anker), Munroe, P. (Patricia), Arking, D.E. (Dan), Lo, C.W. (Cecilia W.), and Jamshidi, Y. (Yalda)
Abstract: Background: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
Published: 2018
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7. A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy

Author: Silva Aldana, C.T. (Claudia), Zorkoltseva, I.V. (Irina), Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Amin, N. (Najaf), Demirkan, A. (Ayşe), Van Leeuwen, E. (Elisa), Iglesias, A.I. (Adriana I.), Piñeros-Hernández, L.B. (Laura B.), Restrepo, C.M. (Carlos M.), Kors, J.A. (Jan), Kirichenko, A.V. (Anatoly), Willemsen, R. (Rob), Oostra, B.A. (Ben), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Axenovich, T.I. (Tatiana I.), Duijn, C.M. (Cornelia) van, Isaacs, A.J. (Aaron), Silva Aldana, C.T. (Claudia), Zorkoltseva, I.V. (Irina), Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Amin, N. (Najaf), Demirkan, A. (Ayşe), Van Leeuwen, E. (Elisa), Iglesias, A.I. (Adriana I.), Piñeros-Hernández, L.B. (Laura B.), Restrepo, C.M. (Carlos M.), Kors, J.A. (Jan), Kirichenko, A.V. (Anatoly), Willemsen, R. (Rob), Oostra, B.A. (Ben), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Axenovich, T.I. (Tatiana I.), Duijn, C.M. (Cornelia) van, and Isaacs, A.J. (Aaron)
Abstract: Background: Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them. Methods: The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data. Results: We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied. Conclusions: We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH.
Published: 2018
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8. Normal values of corrected heart-rate variability in 10-second electrocardiograms for all ages

Author: Berg, M.E. (Marten) van den, Rijnbeek, P.R. (Peter), Niemeijer, M.N. (Maartje), Hofman, A. (Albert), Herpen, G. (Gerard van), Bots, M.L. (Michiel), Hillege, H.L. (Hans), Swenne, C.A. (Cees), Eijgelsheim, M. (Mark), Stricker, B.H. (Bruno H.), Kors, J.A. (Jan), Berg, M.E. (Marten) van den, Rijnbeek, P.R. (Peter), Niemeijer, M.N. (Maartje), Hofman, A. (Albert), Herpen, G. (Gerard van), Bots, M.L. (Michiel), Hillege, H.L. (Hans), Swenne, C.A. (Cees), Eijgelsheim, M. (Mark), Stricker, B.H. (Bruno H.), and Kors, J.A. (Jan)
Abstract: Purpose: Heart-rate variability (HRV) measured on standard 10-s electrocardiograms (ECGs) has been associated with increased risk of cardiac and all-cause mortality, but age- and sex-dependent normal values have not been established. Since heart rate strongly affects HRV, its effect should be taken into account. We determined a comprehensive set of normal values of heart-rate corrected HRV derived from 10-s ECGs for both children and adults, covering both sexes. Methods: Five population studies in the Netherlands (Pediatric Normal ECG Study, Leiden University Einthoven Science Project, Prevention of Renal and Vascular End-stage Disease Study, Utrecht Health Project, Rotterdam Study) provided 10-s, 12-lead ECGs. ECGs were stored digitally and analyzed by well-validated analysis software. We included cardiologically healthy participants, 42% being men. Their ages ranged from 11 days to 91 years. After quality control, 13,943 ECGs were available. Heart-rate correction formulas were derived using an exponential model. Two time-domain HRV markers were analyzed: the corrected standard deviation of the normal-to-normal RR intervals (SDNNc) and corrected root mean square of successive RR-interval differences (RMSSDc). Results: There was a considerable age effect. For both SDNNc and RMSSDc, the median and the lower limit of normal decreased steadily from birth until old age. The upper limit of normal decreased until the age of 60, but increased markedly after that age. Differences of the median were minimal between men and women. Conclusion: We report the first comprehensive set of normal values for heart-rate corrected 10-s HRV, which can be of value in clinical practice and in further research.
Published: 2018
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9. QT Variability and Other Electrocardiographic Predictors of Sudden Cardiac Death

Author: Berg, M.E. (Marten) van den and Berg, M.E. (Marten) van den
Abstract: This thesis investigates sudden cardiac death, focusing of QT variability, heart-rate variability and other electrocardiographic markers. Topics include: - Normal values for heart-rate variability - Normal values for QT variability - The association of QT variability with sudden cardiac death - The association of QT variability with Heart Failure - The association of thyroid function and Sudden cardiac death - The association of thyroid function with QT variability - The association of COPD with sudden cardiac death
Published: 2017

10. Discovery of novel heart rate-associated loci using the Exome Chip

Author: Berg, M.E. (Marten) van den, Warren, H. (Helen), Cabrera, C.P. (Claudia P.), Verweij, N. (Niek), Mifsud, B. (Borbala), Haessler, J. (Jeff), Bihlmeyer, N.A. (Nathan A.), Fu, Y.-P. (Yi-Ping), Weiss, S. (Stefan), Lin, H.J. (Henry J.), Grarup, N. (Niels), Li-Gao, R. (Ruifang), Pistis, G. (Giorgio), Shah, N. (Nisha), Brody, J.A. (Jennifer A.), Müller-Nurasyid, M. (Martina), Lin, H. (Honghuang), Mei, H. (Hao), Smith, A.V. (Albert V.), Lyytikäinen, L.-P. (Leo-Pekka), Hall, L.M. (Leanne M.), Setten, J. (Jessica) van, Trompet, S. (Stella), Prins, B.P. (Bram P.), Isaacs, A.J. (Aaron), Radmanesh, F. (Farid), Marten, J. (Jonathan), Entwistle, A. (Aiman), Kors, J.A. (Jan), Silva Aldana, C.T. (Claudia), Alonso, A. (Alvaro), Bis, J.C. (Joshua), Boer, R.A. (Rudolf) de, Haan, H.G. (Hugoline) de, Mutsert, R. (Reneé) de, Dedoussis, G.V. (George), Dominiczak, A. (Anna), Doney, A.S.F. (Alex), Ellinor, P.T. (Patrick), Eppinga, R.N. (Ruben N.), Felix, S.B. (Stephan), Guo, X. (Xiuqing), Hagemeijer, Y. (Yanick), Hansen, T. (T.), Harris, T.B. (Tamara), Heckbert, S.R. (Susan), Huang, P.L. (Paul L.), Hwang, S.-J. (Shih-Jen), Kähönen, M. (Mika), Kanters, J.K., Kolcic, I. (Ivana), Launer, L.J. (Lenore), Li, M. (Man), Yao, J. (Jiefen), Linneberg, A. (Allan), Liu, S. (Simin), MacFarlane, P.W. (Peter), Mangino, M. (Massimo), Morris, A.D. (Andrew D.), Mulas, A. (Antonella), Murray, A.D. (Alison D.), Nelson, C.P. (Christopher P.), Orrù, M. (Marco), Padmanabhan, S. (Sandosh), Peters, A. (Annette), Porteous, D.J. (David J.), Poulter, N.R. (Neil), Psaty, B.M. (Bruce M.), Qi, L. (Lihong), Raitakari, O.T. (Olli T.), Rivadeneira, F. (Fernando), Roselli, C. (Carolina), Rudan, I. (Igor), Sattar, N. (Naveed), Sever, P. (Peter), Sinner, M.F. (Moritz), Soliman, E.Z. (Elsayed), Spector, T.D. (Timothy), Stanton, A. (Alice), Stirrups, K. (Kathy), Taylor, K.D. (Kent), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Vaartjes, I. (Ilonca), Hoes, A.W. (Arno), van der Meer, P. (Peter), Völker, U. (Uwe), Waldenberger, M. (Melanie), Xie, Z. (Zhijun), Zoledziewska, M. (Magdalena), Tinker, A. (Andrew), Polasek, O. (Ozren), Rosand, J. (Jonathan), Jamshidi, Y. (Yalda), Duijn, C.M. (Cornelia) van, Zeggini, E. (Eleftheria), Jukema, J.W. (Jan Wouter), Asselbergs, F.W. (Folkert), Samani, N.J. (Nilesh), Lehtimäki, T. (Terho), Gudnason, V. (Vilmundur), Wilson, J.F. (James), Lubitz, S.A. (Steven A.), Kääb, S. (Stefan), Sotoodehnia, N. (Nona), Caulfield, M. (Mark), Palmer, C.N.A. (Colin), Sanna, S. (Serena), Mook-Kanamori, D.O. (Dennis), Deloukas, P. (Panos), Pedersen, O. (Oluf), Rotter, J.I. (Jerome I.), Dörr, M. (Marcus), O'Donnell, C.J. (Christopher J.), Hayward, C. (Caroline), Arking, D.E. (Dan), Kooperberg, C. (Charles), van der Harst, P. (Pim), Eijgelsheim, M. (Mark), Stricker, B.H.Ch. (Bruno), Munroe, P. (Patricia), Berg, M.E. (Marten) van den, Warren, H. (Helen), Cabrera, C.P. (Claudia P.), Verweij, N. (Niek), Mifsud, B. (Borbala), Haessler, J. (Jeff), Bihlmeyer, N.A. (Nathan A.), Fu, Y.-P. (Yi-Ping), Weiss, S. (Stefan), Lin, H.J. (Henry J.), Grarup, N. (Niels), Li-Gao, R. (Ruifang), Pistis, G. (Giorgio), Shah, N. (Nisha), Brody, J.A. (Jennifer A.), Müller-Nurasyid, M. (Martina), Lin, H. (Honghuang), Mei, H. (Hao), Smith, A.V. (Albert V.), Lyytikäinen, L.-P. (Leo-Pekka), Hall, L.M. (Leanne M.), Setten, J. (Jessica) van, Trompet, S. (Stella), Prins, B.P. (Bram P.), Isaacs, A.J. (Aaron), Radmanesh, F. (Farid), Marten, J. (Jonathan), Entwistle, A. (Aiman), Kors, J.A. (Jan), Silva Aldana, C.T. (Claudia), Alonso, A. (Alvaro), Bis, J.C. (Joshua), Boer, R.A. (Rudolf) de, Haan, H.G. (Hugoline) de, Mutsert, R. (Reneé) de, Dedoussis, G.V. (George), Dominiczak, A. (Anna), Doney, A.S.F. (Alex), Ellinor, P.T. (Patrick), Eppinga, R.N. (Ruben N.), Felix, S.B. (Stephan), Guo, X. (Xiuqing), Hagemeijer, Y. (Yanick), Hansen, T. (T.), Harris, T.B. (Tamara), Heckbert, S.R. (Susan), Huang, P.L. (Paul L.), Hwang, S.-J. (Shih-Jen), Kähönen, M. (Mika), Kanters, J.K., Kolcic, I. (Ivana), Launer, L.J. (Lenore), Li, M. (Man), Yao, J. (Jiefen), Linneberg, A. (Allan), Liu, S. (Simin), MacFarlane, P.W. (Peter), Mangino, M. (Massimo), Morris, A.D. (Andrew D.), Mulas, A. (Antonella), Murray, A.D. (Alison D.), Nelson, C.P. (Christopher P.), Orrù, M. (Marco), Padmanabhan, S. (Sandosh), Peters, A. (Annette), Porteous, D.J. (David J.), Poulter, N.R. (Neil), Psaty, B.M. (Bruce M.), Qi, L. (Lihong), Raitakari, O.T. (Olli T.), Rivadeneira, F. (Fernando), Roselli, C. (Carolina), Rudan, I. (Igor), Sattar, N. (Naveed), Sever, P. (Peter), Sinner, M.F. (Moritz), Soliman, E.Z. (Elsayed), Spector, T.D. (Timothy), Stanton, A. (Alice), Stirrups, K. (Kathy), Taylor, K.D. (Kent), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Vaartjes, I. (Ilonca), Hoes, A.W. (Arno), van der Meer, P. (Peter), Völker, U. (Uwe), Waldenberger, M. (Melanie), Xie, Z. (Zhijun), Zoledziewska, M. (Magdalena), Tinker, A. (Andrew), Polasek, O. (Ozren), Rosand, J. (Jonathan), Jamshidi, Y. (Yalda), Duijn, C.M. (Cornelia) van, Zeggini, E. (Eleftheria), Jukema, J.W. (Jan Wouter), Asselbergs, F.W. (Folkert), Samani, N.J. (Nilesh), Lehtimäki, T. (Terho), Gudnason, V. (Vilmundur), Wilson, J.F. (James), Lubitz, S.A. (Steven A.), Kääb, S. (Stefan), Sotoodehnia, N. (Nona), Caulfield, M. (Mark), Palmer, C.N.A. (Colin), Sanna, S. (Serena), Mook-Kanamori, D.O. (Dennis), Deloukas, P. (Panos), Pedersen, O. (Oluf), Rotter, J.I. (Jerome I.), Dörr, M. (Marcus), O'Donnell, C.J. (Christopher J.), Hayward, C. (Caroline), Arking, D.E. (Dan), Kooperberg, C. (Charles), van der Harst, P. (Pim), Eijgelsheim, M. (Mark), Stricker, B.H.Ch. (Bruno), and Munroe, P. (Patricia)
Abstract: Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.
Published: 2017
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11. Validation of automatic measurement of QT interval variability

Author: Rijnbeek, P.R. (Peter), Berg, M.E. (Marten) van den, Herpen, G. (Gerard) van, Ritsema Van Eck, H.J. (Henk J.), Kors, J.A. (Jan), Rijnbeek, P.R. (Peter), Berg, M.E. (Marten) van den, Herpen, G. (Gerard) van, Ritsema Van Eck, H.J. (Henk J.), and Kors, J.A. (Jan)
Abstract: Background Increased variability of beat-to-beat QT-interval durations on the electrocardiogram (ECG) has been associated with increased risk for fatal and non-fatal cardiac events. However, techniques for the measurement of QT variability (QTV) have not been validated since a gold standard is not available. In this study, we propose a validation method and illustrate its use for the validation of two automatic QTV measurement techniques. Methods Our method generates artificial standard 12-lead ECGs based on the averaged P-QRS-T complexes from a variety of existing ECG signals, with simulated intrinsic (QT interval) and extrinsic (noise, baseline wander, signal length) variations. We quantified QTV by a commonly used measure, short-term QT variability (STV). Using 28,800 simulated ECGs, we assessed the performance of a conventional QTV measurement algorithm, resembling a manual QTV measurement approach, and a more advanced algorithm based on fiducial segment averaging (FSA). Results The results for the conventional algorithm show considerable median absolute differences between the simulated and estimated STV. For the highest noise level, median differences were 4±6 ms in the absence of QTV. Increasing signal length generally yields more accurate STV estimates, but the difference in performance between 30 or 60 beats is small. The FSA algorithm proved to be very accurate, with most median absolute differences less than 0.5 ms, even for the highest levels of disturbance. Conclusions Artificially constructed ECGs with a variety of disturbances allow validation of QTV measurement procedures. The FSA algorithm provides highly accurate STV estimates under varying signal conditions, and performs much better than traditional beat-by-beat analysis. The fully automatic operation of the FSA algorithm enables STV measurement in large sets of ECGs.
Published: 2017
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12. A combined linkage and exome sequencing analysis for electrocardiogram parameters in the Erasmus Rucphen family study

Author: Silva Aldana, C.T. (Claudia), Zorkoltseva, I.V. (Irina), Amin, N. (Najaf), Demirkan, A. (Ayşe), Leeuwen, E.M. (Elisa) van, Kors, J.A. (Jan), Berg, M.E. (Marten) van den, Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Kirichenko, A.V. (Anatoly), Witteman, J.C.M. (Jacqueline), Willemsen, R. (Rob), Oostra, B.A. (Ben), Axenovich, T.I. (Tatiana), Duijn, C.M. (Cornelia) van, Isaacs, A.J. (Aaron), Silva Aldana, C.T. (Claudia), Zorkoltseva, I.V. (Irina), Amin, N. (Najaf), Demirkan, A. (Ayşe), Leeuwen, E.M. (Elisa) van, Kors, J.A. (Jan), Berg, M.E. (Marten) van den, Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Kirichenko, A.V. (Anatoly), Witteman, J.C.M. (Jacqueline), Willemsen, R. (Rob), Oostra, B.A. (Ben), Axenovich, T.I. (Tatiana), Duijn, C.M. (Cornelia) van, and Isaacs, A.J. (Aaron)
Abstract: Electrocardiogram (ECG) measurements play a key role in the diagnosis and prediction of cardiac arrhythmias and sudden cardiac death. ECG parameters, such as the PR, QRS, and QT intervals, are known to be heritable and genome-wide association studies of these phenotypes have been successful in identifying common variants; however, a large proportion of the genetic variability of these traits remains to be elucidated. The aim of this study was to discover loci potentially harboring rare variants utilizing variance component linkage analysis in 1547 individuals from a large family-based study, the Erasmus Rucphen Family Study (ERF). Linked regions were further explored using exome sequencing. Five suggestive linkage peaks were identified: two for QT interval (1q24, LOD = 2.63; 2q34, LOD = 2.05), one for QRS interval (1p35, LOD = 2.52) and two for PR interval (9p22, LOD = 2.20; 14q11, LOD = 2.29). Fine-mapping using exome sequence data identified a C > G missense variant (c.713C > G, p.Ser238Cys) in the FCRL2 gene associated with QT (rs74608430; P = 2.8 × 10-4, minor allele frequency = 0.019). Heritability analysis demonstrated that the SNP explained 2.42% of the trait's genetic variability in ERF (P = 0.02). Pathway analysis suggested that the gene is involved in cytosolic Ca2+ levels (P = 3.3 × 10-3) and AMPK stimulated fatty acid oxidati
Published: 2016
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13. Chronic obstructive pulmonary disease and sudden cardiac death: A systematic review

Author: Berg, M.E. (Marten) van den, Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Lahousse, L. (Lies), Berg, M.E. (Marten) van den, Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), and Lahousse, L. (Lies)
Abstract: Both chronic obstructive pulmonary disease (COPD) and sudden cardiac death (SCD) are major health burdens. A number of studies have addressed their interrelationship, but currently no systematic review has been published. Our objective is to give an overview of the literature of the association between COPD and SCD. A search on PubMed with both MeSH headings and free-text keywords was performed. We selected all original articles of studies in humans that assessed COPD on the one hand and SCD, electrocardiographic markers for SCD, ventricular arrhythmias, or asystole on the other. The electronic search yielded 251 articles, from which 27 full publications were selected after careful evaluation of the full-text articles. In these studies, COPD was associated with a prolonged and shortened QT interval. In patients with a myocardial infarction (MI), COPD was associated with an increased risk of ventricular arrhythmias and decreased survival. COPD was a risk factor for SCD both in cardiovascular patient groups and in community-based studies, independent from cardiovascular risk profile. Studies of the potential impact of respiratory treatment on the occurrence of SCD showed conflicting results. In conclusion, cumulating evidence associates COPD with an increased risk of SCD. Asystole and pulseless electric activity could be more common than VT/VF in deaths associated with COPD. Underlying mechanisms explaining this association require further investigation.
Published: 2016
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14. Serum magnesium and the risk of death from coronary heart disease and sudden cardiac death

Author: Kieboom, B.C.T. (Brenda), Niemeijer, M.N. (Maartje), Leening, M.J.G. (Maarten), Berg, M.E. (Marten) van den, Franco, O.H. (Oscar), Deckers, J.W. (Jaap), Hofman, A. (Albert), Zietse, R. (Bob), Stricker, B.H.Ch. (Bruno), Hoorn, E.J. (Ewout), Kieboom, B.C.T. (Brenda), Niemeijer, M.N. (Maartje), Leening, M.J.G. (Maarten), Berg, M.E. (Marten) van den, Franco, O.H. (Oscar), Deckers, J.W. (Jaap), Hofman, A. (Albert), Zietse, R. (Bob), Stricker, B.H.Ch. (Bruno), and Hoorn, E.J. (Ewout)
Abstract: Background-Low serum magnesium has been implicated in cardiovascular mortality, but results are conflicting and the pathway is unclear. We studied the association of serum magnesium with coronary heart disease (CHD) mortality and sudden cardiac death (SCD) within the prospective population-based Rotterdam Study, with adjudicated end points and long-term follow-up. Methods and Results-Nine-thousand eight-hundred and twenty participants (mean age 65.1 years, 56.8% female) were included with a median follow-up of 8.7 years. We used multivariable Cox proportional hazard models and found that a 0.1 mmol/L increase in serum magnesium level was associated with a lower risk for CHD mortality (hazard ratio: 0.82, 95% CI 0.70-0.96). Furthermore, we divided serum magnesium in quartiles, with the second and third quartile combined as reference group (0.81-0.88 mmol/L). Low serum magnesium (=0.80 mmol/L) was associated with an increased risk of CHD mortality (N=431, hazard ratio: 1.36, 95% CI 1.09-1.69) and SCD (N=217, hazard ratio: 1.54, 95% CI 1.12-2.11). Low serum magnesium was associated with accelerated subclinical atherosclerosis (expressed as increased carotid intima-media thickness: +0.013 mm, 95% CI 0.005-0.020) and increased QT-interval, mainly through an effect on heart rate (RR-interval: -7.1 ms, 95% CI -13.5 to -0.8). Additional adjustments for carotid intima-media thickness and heart rate did not change the associations with CHD mortality and SCD. Conclusions-Low serum magnesium is associated with an increased risk of CHD mortality and SCD. Although low magnesium was associated with both carotid intima-media thickness and heart rate, this did not explain the relationship between serum magnesium and CHD mortality or SCD. Future studies should focus on why magnesium associates with CHD mortality and SCD and whether intervention reduces these risks.
Published: 2016
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15. Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram

Author: Verweij, N. (Niek), Leach, I.M. (Irene Mateo), Isaacs, A.J. (Aaron), Arking, D.E. (Dan), Bis, J.C. (Joshua), Pers, T.H. (Tune), Berg, M.E. (Marten) van den, Lyytikäinen, L.-P. (Leo-Pekka), Barnett, P. (Phil), Wang, X. (Xinchen), Soliman, E.Z. (Elsayed Z.), Duijn, C.M. (Cornelia) van, Kähönen, M. (Mika), Van Veldhuisen, D.J. (Dirk J.), Kors, J.A. (Jan), Raitakari, O.T. (Olli T.), Silva Aldana, C.T. (Claudia), Lehtimäki, T. (Terho), Hillege, H.L. (Hans), Hirschhorn, J.N. (Joel), Boyer, L.A. (Laurie A.), Gilst, W.H. (Wiek) van, Alonso, A. (Alvaro), Sotoodehnia, N. (Nona), Eijgelsheim, M. (Mark), Boer, R.A. (Rudolf) de, Bakker, P.I.W. (Paul) de, Franke, L. (Lude), Harst, P. (Pim) van der, Klauw, M. (Melanie van der), Navis, G. (Gerjan), Ormel, H. (Hans), Postma, D.S. (Dirkje), Rosmalen, J.G.M. (Judith), Slaets, J.P.J. (Joris), Stolk, R.P., Wolffenbuttel, B.H.R. (Bruce H. R.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Bruinenberg, M. (M.), Festen, N. (Noortje), Snieder, H. (Harold), Wijmenga, C. (Cisca), Verweij, N. (Niek), Leach, I.M. (Irene Mateo), Isaacs, A.J. (Aaron), Arking, D.E. (Dan), Bis, J.C. (Joshua), Pers, T.H. (Tune), Berg, M.E. (Marten) van den, Lyytikäinen, L.-P. (Leo-Pekka), Barnett, P. (Phil), Wang, X. (Xinchen), Soliman, E.Z. (Elsayed Z.), Duijn, C.M. (Cornelia) van, Kähönen, M. (Mika), Van Veldhuisen, D.J. (Dirk J.), Kors, J.A. (Jan), Raitakari, O.T. (Olli T.), Silva Aldana, C.T. (Claudia), Lehtimäki, T. (Terho), Hillege, H.L. (Hans), Hirschhorn, J.N. (Joel), Boyer, L.A. (Laurie A.), Gilst, W.H. (Wiek) van, Alonso, A. (Alvaro), Sotoodehnia, N. (Nona), Eijgelsheim, M. (Mark), Boer, R.A. (Rudolf) de, Bakker, P.I.W. (Paul) de, Franke, L. (Lude), Harst, P. (Pim) van der, Klauw, M. (Melanie van der), Navis, G. (Gerjan), Ormel, H. (Hans), Postma, D.S. (Dirkje), Rosmalen, J.G.M. (Judith), Slaets, J.P.J. (Joris), Stolk, R.P., Wolffenbuttel, B.H.R. (Bruce H. R.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Bruinenberg, M. (M.), Festen, N. (Noortje), Snieder, H. (Harold), and Wijmenga, C. (Cisca)
Abstract: The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.
Published: 2016
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16. Drugs and ventricular repolarization in a general population: The Rotterdam Study

Author: Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Stricker, B.H.Ch. (Bruno), Eijgelsheim, M. (Mark), Rijnbeek, P.R. (Peter), Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Stricker, B.H.Ch. (Bruno), Eijgelsheim, M. (Mark), and Rijnbeek, P.R. (Peter)
Abstract: Purpose: Prolonged ventricular repolarization (measured as heart-rate corrected QT (QTc) prolongation or JT-interval prolongation) is a risk factor for ventricular arrhythmias and can be drug-induced. Drugs can be classified as having known or possible QTc-prolonging properties. Regulatory agencies recommend avoiding concomitant use of multiple QTc-prolonging drugs, but evidence is lacking to what degree ventricular repolarization is influenced by concomitant use of these drugs. Methods: Within a population-based cohort of persons aged 45years and older, with up to five electrocardiograms recorded per participant between 1991 and 2010, we used generalised estimating equations to study the association between concomitant use of multiple QTc-prolonging drugs and repolarization duration. Results: The study population consisted of 13009 participants with 26908 electrocardiograms. With the addition of a second or third QTc-prolonging drug there was no substantial increase in QTc and JT interval and no increased risk of a prolonged QTc interval, compared to use of one QTc-prolonging drug. There was a large difference between the effect of one known or one possible QTc-prolonging drugs on QTc interval: 15ms for known, and 3ms for possible QTc-prolonging drugs. Conclusions: In this study, the added prolongation in users of two or three QTc-prolonging drugs on QTc was small. There was a large difference in QTc prolongation between known and possible QTc-prolonging drugs. Further research in larger or high-risk populations is needed to establish whether it is safe to use multiple QTc-prolonging drugs concomitantly to prevent that the current advice might unnecessarily withhold beneficial drugs from patients.
Published: 2015
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17. Declining incidence of sudden cardiac death from 1990-2010 in a general middle-aged and elderly population: The Rotterdam Study

Author: Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Leening, M.J.G. (Maarten), Hofman, A. (Albert), Franco, O.H. (Oscar), Deckers, J.W. (Jaap), Heeringa, J. (Jan), Rijnbeek, P.R. (Peter), Stricker, B.H.Ch. (Bruno), Eijgelsheim, M. (Mark), Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Leening, M.J.G. (Maarten), Hofman, A. (Albert), Franco, O.H. (Oscar), Deckers, J.W. (Jaap), Heeringa, J. (Jan), Rijnbeek, P.R. (Peter), Stricker, B.H.Ch. (Bruno), and Eijgelsheim, M. (Mark)
Abstract: BACKGROUND: Although sudden cardiac death (SCD) is relatively common, contemporary data on its incidence are lacking. OBJECTIVE: The purpose of this study was to investigate the current incidence of SCD and its trend over the past 2 decades in a general middle-aged and elderly population. METHODS: This study was performed within the Rotterdam Study, a prospective population-based cohort study of persons aged 45 years and older. Age-standardized incidence rates of SCD were calculated. To study trends in incidence, we compared 2 subcohorts within the total study population, 1 followed from 1990-2000 and the other from 2001-2010. RESULTS: From 1990-2010, 5512 of 14,628 participants died, of whom 583 (4.0%) were classified as SCD. The overall incidence was 4.2 per 1000 person-years. The incidence was higher in men (5.2 per 1000 person-years) than in women (3.6 per 1000 person-years). Age-adjusted hazard ratio (HR) 1.84 (95% confidence [CI] 1.56-2.17) and risk of SCD increased with age (HR 1.10 per year; 95% CI 1.09 -1.11). The incidence rate from 1990-2000 was 4.7 per 1000 person-years vs 2.1 per 1000 person-years from 2001-2010 (age- and sex-adjusted HR of SCD 0.60, 95% CI 0.44-0.80). To check for cohort effects, we also analyzed the incidence of total mortality and found an age- and sex-adjusted HR of total mortality of 0.82 (95% CI 0.75-0.90) for the second compared to the first subcohort, which was significantly higher than the decline in SCD incidence. CONCLUSION: We found an incidence of SCD of 4.2 per 1000 person-years. The incidence decreased from 1990-2010, a period during which the diagnosis and treatment of heart disease greatly improved.
Published: 2015
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18. Chronic obstructive pulmonary disease and sudden cardiac death: The Rotterdam study

Author: Lahousse, L. (Lies), Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Rijnbeek, P.R. (Peter), Joos, G.F. (Guy), Hofman, A. (Albert), Franco, O.H. (Oscar), Deckers, J.W. (Jaap), Eijgelsheim, M. (Mark), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Lahousse, L. (Lies), Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Rijnbeek, P.R. (Peter), Joos, G.F. (Guy), Hofman, A. (Albert), Franco, O.H. (Oscar), Deckers, J.W. (Jaap), Eijgelsheim, M. (Mark), Stricker, B.H.Ch. (Bruno), and Brusselle, G.G. (Guy)
Published: 2015
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19. Consistency of heart rate-QTc prolongation consistency and sudden cardiac death: The Rotterdam Study

Author: Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Deckers, J.W. (Jaap), Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Stricker, B.H.Ch. (Bruno), Rijnbeek, P.R. (Peter), Eijgelsheim, M. (Mark), Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Deckers, J.W. (Jaap), Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Stricker, B.H.Ch. (Bruno), Rijnbeek, P.R. (Peter), and Eijgelsheim, M. (Mark)
Abstract: Background A prolonged heart rate-corrected QT (QTc) interval is a well-known risk indicator for sudden cardiac death (SCD) and a contraindication for drugs with potentially arrhythmogenic adverse effects. Objective We aimed to study the consistency of QTc interval prolongation and whether a consistent QTc interval prolongation correlates differently with SCD than does an inconsistently prolonged QTc interval. Methods We used a population-based cohort study of persons 55 years and older. We excluded participants using QTc-prolonging drugs or with bundle branch block. The QT interval was corrected for heart rate using Bazett and Fridericia formulas. Using a Cox regression model, we assessed the association between QTc interval prolongation consistency and the occurrence of SCD. Results A total of 3484 participants had electrocardiograms (ECGs) recorded on 2 consecutive visits. In 96%-98% of participants with a normal QTc interval on the first ECG, the QTc interval remained normal, but only in 27%-35% of those with a prolonged QTc interval, the QTc interval was prolonged on the second ECG after a median of 1.8 years. A consistently prolonged QTc interval was associated with an increased risk of SCD as compared with a consistently normal QTc interval (Bazett: hazard ratio 2.23; 95% confidence interval 1.17-4.24, Fridericia: hazard ratio 6.67; 95% confidence interval 2.96-15.06). A prolonged QTc interval preceded or followed by a normal QTc interval was not significantly associated with an increased risk of SCD. Conclusion Persons with an inconsistently prolonged QTc interval did not have a higher risk of SCD than those with a consistently normal QTc interval. Persons with a consistently prolonged QTc interval did have a higher risk of SCD. Our results suggest that repeated measurements of the QTc interval could enhance risk stratification.
Published: 2015
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20. Pharmacogenetics of Drug-Induced QT Interval Prolongation: An Update

Author: Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Eijgelsheim, M. (Mark), Rijnbeek, P.R. (Peter), Stricker, B.H.Ch. (Bruno), Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Eijgelsheim, M. (Mark), Rijnbeek, P.R. (Peter), and Stricker, B.H.Ch. (Bruno)
Abstract: A prolonged QT interval is an important risk factor for ventricular arrhythmias and sudden cardiac death. QT prolongation can be caused by drugs. There are multiple risk factors for drug-induced QT prolongation, including genetic variation. QT prolongation is one of the most common reasons for withdrawal of d
Published: 2015
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21. Use of selective serotonin re-uptake inhibitors and the heart rate corrected QT interval in a real-life setting: The population-based Rotterdam Study

Author: Maljuric, N.M. (Nevena M.), Noordam, R., Aarts, N. (Nikkie), Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Hofman, A. (Albert), Kors, J.A. (Jan), Stricker, B.H.Ch. (Bruno), Visser, L.E. (Loes), Maljuric, N.M. (Nevena M.), Noordam, R., Aarts, N. (Nikkie), Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Hofman, A. (Albert), Kors, J.A. (Jan), Stricker, B.H.Ch. (Bruno), and Visser, L.E. (Loes)
Abstract: Aims Selective serotonin re-uptake inhibitors (SSRIs), specifically citalopram and escitalopram, are thought to cause QTc prolongation, although studies have shown contradictory results. Nevertheless, a maximum citalopram dosage of 20 mg in high risk patients (e.g. >60 years of age) is recommended. We aimed to investigate the association between use of (individual) SSRIs and QTc in a population-based study in older adults. Methods This study, which was part of the prospective Rotterdam Study (period 1991-2012), included participants with up to five electrocardiograms (ECGs). We used linear mixed models to compare QTcF (QT corrected according to Fridericia) measured during use of individual SSRIs with QTcF measured during non-use of any antidepressant. For citalopram, analyses were additionally restricted t
Published: 2015
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22. Short-term QT variability markers for the prediction of ventricular arrhythmias and sudden cardiac death: A systematic review

Author: Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Eijgelsheim, M. (Mark), Herpen, G. (Gerard) van, Stricker, B.H.Ch. (Bruno), Kors, J.A. (Jan), Rijnbeek, P.R. (Peter), Niemeijer, M.N. (Maartje), Berg, M.E. (Marten) van den, Eijgelsheim, M. (Mark), Herpen, G. (Gerard) van, Stricker, B.H.Ch. (Bruno), Kors, J.A. (Jan), and Rijnbeek, P.R. (Peter)
Abstract: Sudden cardiac death (SCD) is a major health burden and is primarily caused by ventricular arrhythmias. Currently, the most well-known marker for the risk of ventricular arrhythmias is QT/QTc prolongation. Animal studies indicate that QT variability might be a better indicator. Our objective was to give an overview of the literature on QT variability in humans, therefore we performed a free-text search in PubMed and Embase from inception through February 2013. We identified nine QT variability markers in 109 studies reporting on QT variability markers, measured on the surface ECG. QT variability can be distinguished using two characteristics: heart rate normalisation and whether QT interval is measured on consecutive beats. Most study populations were small (median 48 subjects, range 1-805) and different methods, time intervals and leads for measurement were used. QT variability markers were determinants for the risk of ventricular arrhythmias, (sudden) cardiac death and total mortality. Few studies compared the predictive value of QT variability with that of QT/QTc prolongation. A study compari
Published: 2014
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22 results on '"Berg, M.E. (Marten) van den"'

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

2. KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern

3. Corrigendum: Normal Values of Corrected Heart-Rate Variability in 10-Second Electrocardiograms for All Ages (Frontiers in Physiology, (2018), 9, (424), 10.3389/fphys.2018.00424)

4. Normal Values of QT Variability in 10-s Electrocardiograms for all Ages

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

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

7. A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy

8. Normal values of corrected heart-rate variability in 10-second electrocardiograms for all ages

9. QT Variability and Other Electrocardiographic Predictors of Sudden Cardiac Death

10. Discovery of novel heart rate-associated loci using the Exome Chip

11. Validation of automatic measurement of QT interval variability

12. A combined linkage and exome sequencing analysis for electrocardiogram parameters in the Erasmus Rucphen family study

13. Chronic obstructive pulmonary disease and sudden cardiac death: A systematic review

14. Serum magnesium and the risk of death from coronary heart disease and sudden cardiac death

15. Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram

16. Drugs and ventricular repolarization in a general population: The Rotterdam Study

17. Declining incidence of sudden cardiac death from 1990-2010 in a general middle-aged and elderly population: The Rotterdam Study

18. Chronic obstructive pulmonary disease and sudden cardiac death: The Rotterdam study

19. Consistency of heart rate-QTc prolongation consistency and sudden cardiac death: The Rotterdam Study

20. Pharmacogenetics of Drug-Induced QT Interval Prolongation: An Update

21. Use of selective serotonin re-uptake inhibitors and the heart rate corrected QT interval in a real-life setting: The population-based Rotterdam Study

22. Short-term QT variability markers for the prediction of ventricular arrhythmias and sudden cardiac death: A systematic review

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