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1. Development and Validation of a Nordic Multimorbidity Index Based on Hospital Diagnoses and Filled Prescriptions

Author

Kristensen KB, Lund LC, Jensen PB, Broe A, Rotbain E, Damkier P, Pottegård A, Andersen JH, Højlund M, Olesen M, Rasmussen L, Hansen MR, Ernst MT, Wesselhoeft R, Henriksen DP, Reilev M, Bliddal M, and Hallas J

Subjects
multimorbidity, comorbidity, pharmacoepidemiology, prognosis, risk score, Infectious and parasitic diseases, RC109-216
Abstract

Kasper Bruun Kristensen,1 Lars Christian Lund,1 Peter Bjødstrup Jensen,1 Anne Broe,1 Emelie Rotbain,2 Per Damkier,1,3,4 Anton Pottegård,1 Jacob Harbo Andersen,1 Mikkel Højlund,1,5 Morten Olesen,1 Lotte Rasmussen,1 Morten Rix Hansen,1,3,4 Martin Thomsen Ernst,1 Rikke Wesselhoeft,1,6 Daniel Pilsgaard Henriksen,3 Mette Reilev,1 Mette Bliddal,1,7 Jesper Hallas1 1Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Department of Hematology, Odense University Hospital, Odense, Denmark; 3Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark; 4Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 5Department of Psychiatry Aabenraa, Mental Health Services in the Region of Southern Denmark, Aabenraa, Denmark; 6Child and Adolescent Psychiatry Odense, Mental Health Services in the Region of Southern Denmark, Odense, Denmark; 7Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Jesper Hallas, Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 19, 2, Odense, 5000, Denmark, Tel +4565503010, Email jhallas@health.sdu.dkPurpose: To develop the Nordic Multimorbidity Index (NMI), a multimorbidity measure specifically suited to the Nordic health and administrative registry data based on current diagnosis, treatment, and coding practices.Methods: The NMI was developed to predict 5-year mortality in a population-based cohort of randomly sampled Danish residents aged ≥ 40 years (n = 425,087) followed from 2013 to 2018. Included predictors were selected from hospital diagnoses and filled drug prescriptions based on a combination of subject matter knowledge and a data-driven approach using backwards elimination. The performance of the NMI was assessed in a temporal validation cohort of Danish residents followed from 2007 to 2012 and in six cohorts of new users of selected drugs. The discriminative performance of the NMI, Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) was assessed using the c-statistic from logistic regression models with 5-year mortality as dependent variable and the multimorbidity index score, age, and sex as independent variables.Results: The NMI included 50 predictors. In the temporal validation cohort, the c-statistic of the NMI (0.887, 95% CI 0.883– 0.890) exceeded that of the CCI (0.871, 95% CI 0.868– 0.874) and ECI (0.866, 95% CI 0.863– 0.870). In all new user cohorts, the NMI outperformed the other indices with c-statistics ranging from 0.781 (95% CI 0.779– 0.784) to 0.838 (95% CI 0.834– 0.842).Conclusion: The NMI predicted 5-year mortality in a general Danish population and six cohorts of new users of selected drugs and was superior to the CCI and ECI. The NMI could be preferred over these indices to quantify the level of multimorbidity for, eg, descriptive purposes or confounding control. The NMI should be validated in other patient populations and other Nordic countries.Keywords: multimorbidity, comorbidity, pharmacoepidemiology, prognosis, risk score

Published
2022

4. A Factor Two Difference in 21st‐Century Greenland Ice Sheet Surface Mass Balance Projections From Three Regional Climate Models Under a Strong Warming Scenario (SSP5‐8.5).

Author

Glaude, Q., Noel, B., Olesen, M., Van den Broeke, M., van de Berg, W. J., Mottram, R., Hansen, N., Delhasse, A., Amory, C., Kittel, C., Goelzer, H., and Fettweis, X.

Subjects
GREENLAND ice, GLOBAL warming, ATMOSPHERIC models, ICE sheets, POLAR climate
Abstract

The Arctic is warming rapidly, significantly reducing the Greenland ice sheet (GrIS) surface mass balance (SMB) and raising its contribution to global sea‐level rise. Since these trends are expected to continue, it is essential to explore the GrIS SMB response to projected climate warming. We compare projections from three polar regional climate models, RACMO, MAR, and HIRHAM, forced by the Community Earth System Model CESM2 under a high‐end warming scenario (SSP5‐8.5, 1970–2099). We reveal different modeled SMB by 2100, including a twofold larger annual surface mass loss in MAR (−1735 Gt/yr) and HIRHAM (−1698 Gt/yr) relative to RACMO (−964 Gt/yr). Discrepancies primarily stem from differences in projected runoff, triggering melt‐albedo positive feedback and subsequent modeled ablation zone expansion. In addition, we find different responses of modeled meltwater production to similar atmospheric warming. Our analysis suggests clear avenues for model developments to further improve SMB projections and contribution to sea‐level rise. Plain Language Summary: We explore how three different polar climate models predict the future surface mass balance (SMB) of the Greenland ice sheet (GrIS), a major contributor to global sea‐level rise. Our results show that SMB projections among these models differ significantly by the end of the century. Differences primarily stem from how models convert meltwater into surface runoff toward the ocean, a crucial SMB component that directly contributes to sea‐level rise. Another key factor is the response of these models to climate warming, substantially affecting future melting rates. Our research highlights the need for further improvements of these climate models. By identifying and understanding the drivers behind model differences, we can improve SMB predictions and better estimate future global sea‐level rise. Key Points: With identical forcing, Greenland Ice Sheet surface mass balance from 3 regional climate models shows a two‐fold difference by 2100Different runoff projections stem from substantial discrepancies in projected ablation zone expansion, and reciprocallyThe response of meltwater production to similar atmospheric warming differs significantly among regional climate models [ABSTRACT FROM AUTHOR]

Published
2024
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11. Heterogeneity after harmonisation: A retrospective cohort study of bleeding and stroke risk after the introduction of direct oral anticoagulants in four Western European countries

Author

Komen, J. J., primary, Hunt, N. B., additional, Pottegård, A., additional, Hjemdahl, P., additional, Wettermark, B., additional, Olesen, M., additional, Bennie, M., additional, Mueller, T., additional, Carragher, R., additional, Karlstad, Ø., additional, Kjerpeseth, L. J., additional, Klungel, O. H., additional, and Forslund, T., additional

Published
2023
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17. Heterogeneity after harmonisation : A retrospective cohort study of bleeding and stroke risk after the introduction of direct oral anticoagulants in four Western European countries

Author

Komen, J. J., Hunt, N. B., Pottegård, A., Hjemdahl, P., Wettermark, Björn, Olesen, M., Bennie, M., Mueller, T., Carragher, R., Karlstad, Ø., Kjerpeseth, L. J., Klungel, O. H., Forslund, T., Komen, J. J., Hunt, N. B., Pottegård, A., Hjemdahl, P., Wettermark, Björn, Olesen, M., Bennie, M., Mueller, T., Carragher, R., Karlstad, Ø., Kjerpeseth, L. J., Klungel, O. H., and Forslund, T.

Abstract

Purpose: Database heterogeneity can impact effect estimates. Harmonisation provided by common protocols and common data models (CDMs) can increase the validity of pharmacoepidemiologic research. In a case study measuring the changes in the safety and effectiveness of stroke prevention therapy after the introduction of direct oral anticoagulants (DOACs), we performed an international comparison. Methods: Using data from Stockholm, Denmark, Scotland and Norway, harmonised with a common protocol and CDM, two calendar-based cohorts were created: 2012 and 2017. Patients with a diagnosis code of atrial fibrillation 5 years preceding the 1-year cohort window were included. DOAC, vitamin K antagonist and aspirin treat-ment were assessed in the 6 months prior to the start of each year while strokes and bleeds were assessed during the year. A Poisson regression generated incidence rate ratios (IRRs) to compare outcomes from 2017 to 2012 adjusted for changes in individual-level baseline characteristics. Results: In 280 359 patients in the 2012 cohort and 356 779 in the 2017 cohort, treatment with OACs increased on average from 45% to 65%, while treatment with aspirin decreased from 30% to 10%. In all countries except Scotland, there were decreases in the risk of stroke and no changes in bleeding risk, after adjustment for changes in baseline characteristics. In Scotland, major bleeding (IRR 1.09, 95% confidence interval [CI] [1.00; 1.18]) and intracranial haemorrhage (IRR 1.31, 95% CI [1.13; 1.52]) increased from 2012 to 2017. Conclusions: Stroke prevention therapy improved from 2012 to 2017 with a corre-sponding reduction in stroke risk without increasing the risk of bleeding in all countries, except Scotland. The heterogeneity that remains after methodological harmonisation can be informative of the underlying population and database.

Published
2023
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18. Heterogeneity after harmonisation: a retrospective cohort study of bleeding and stroke risk after the introduction of direct oral anticoagulants in four Western European countries

Author

Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, PECP - Centre for Pharmacoepidemiology, Komen, J. J., Hunt, N. B., Pottegård, A., Hjemdahl, P., Wettermark, B., Olesen, M., Bennie, M., Mueller, T., Carragher, R., Karlstad, Ø., Kjerpeseth, L. J., Klungel, O. H., Forslund, T., Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, PECP - Centre for Pharmacoepidemiology, Komen, J. J., Hunt, N. B., Pottegård, A., Hjemdahl, P., Wettermark, B., Olesen, M., Bennie, M., Mueller, T., Carragher, R., Karlstad, Ø., Kjerpeseth, L. J., Klungel, O. H., and Forslund, T.

Published
2023

20. The rs13376333 risk allele mimics the effect of atrial fibrillation on SK-current density and afterdepolarizations in human atrial myocytes

Author

Jiménez-Sábado, Verónica, Tarifa, Carmen, Casabella, Sergi, Montiel, José, Rodriguez-Font, E., Olesen, M. S., and Hove-Madsen, Leif

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Trabajo presentado en el European Society of Cardiology Congress, celebrado en Barcelona (España), del 26 al 29 de agosto de 2022, Background: Various genome wide association studies have associated the single nucleotide polymorphism (SNP) rs13376333 with increased risk of atrial fibrillation. This SNP is intronic to the KCNN3 gene that codes for the small conductance calcium-activated potassium channel type 3 (SK3), but functional electrophysiological effects of the risk variant are not known. Purpose: This study aimed to study the effects of atrial fibrillation and the rs13376333 risk SNP on the apamine sensitive SK-current and on afterdepolarizations in human atrial myocytes. Methods: Myocytes were isolated from human right atrial samples, and subjected to perforated patch-clamp technique to measure the apamine (100 nM) sensitive SK-current elicited by a voltage-ramp protocol, spontaneous transient inward Na-Ca exchange currents (ITI) or afterdepolarizations at rest. To assess the impact of the rs13376333 risk variant, patients without atrial fibrillation were genotyped and divided into risk and control groups according to the genotype at rs13376333. Results: At membrane potentials above ¿40 mV, the SK-current density increased with increasing membrane potentials. At +20mV the density was significantly smaller (0.18±0.04 pA/pF) in 5 patients with atrial fibrillation than in 24 patients without this arrhythmia (0.65±0.12 pA/pF, p

Published
2022
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21. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

Author

Walsh, R, Lahrouchi, N, Tadros, R, Kyndt, F, Glinge, C, Postema, P, Amin, A, Nannenberg, E, Ware, J, Whiffin, N, Mazzarotto, F, Skoric-Milosavljevic, D, Krijger, C, Arbelo, E, Babuty, D, Barajas-Martinez, H, Beckmann, B, Bezieau, S, Bos, J, Breckpot, J, Campuzano, O, Castelletti, S, Celen, C, Clauss, S, Corveleyn, A, Crotti, L, Dagradi, F, de Asmundis, C, Denjoy, I, Dittmann, S, Ellinor, P, Ortuno, C, Giustetto, C, Gourraud, J, Hazeki, D, Horie, M, Ishikawa, T, Itoh, H, Kaneko, Y, Kanters, J, Kimoto, H, Kotta, M, Krapels, I, Kurabayashi, M, Lazarte, J, Leenhardt, A, Loeys, B, Lundin, C, Makiyama, T, Mansourati, J, Martins, R, Mazzanti, A, Morner, S, Napolitano, C, Ohkubo, K, Papadakis, M, Rudic, B, Molina, M, Sacher, F, Sahin, H, Sarquella-Brugada, G, Sebastiano, R, Sharma, S, Sheppard, M, Shimamoto, K, Shoemaker, M, Stallmeyer, B, Steinfurt, J, Tanaka, Y, Tester, D, Usuda, K, van der Zwaag, P, Van Dooren, S, Van Laer, L, Winbo, A, Winkel, B, Yamagata, K, Zumhagen, S, Volders, P, Lubitz, S, Antzelevitch, C, Platonov, P, Odening, K, Roden, D, Roberts, J, Skinner, J, Tfelt-Hansen, J, van den Berg, M, Olesen, M, Lambiase, P, Borggrefe, M, Hayashi, K, Rydberg, A, Nakajima, T, Yoshinaga, M, Saenen, J, Kaab, S, Brugada, P, Robyns, T, Giachino, D, Ackerman, M, Brugada, R, Brugada, J, Gimeno, J, Hasdemir, C, Guicheney, P, Priori, S, Schulze-Bahr, E, Makita, N, Schwartz, P, Shimizu, W, Aiba, T, Schott, J, Redon, R, Ohno, S, Probst, V, Arnaout, A, Amelot, M, Anselme, F, Billon, O, Defaye, P, Dupuis, J, Jesel, L, Laurent, G, Maury, P, Pasquie, J, Wiart, F, Behr, E, Barc, J, Bezzina, C, Walsh R., Lahrouchi N., Tadros R., Kyndt F., Glinge C., Postema P. G., Amin A. S., Nannenberg E. A., Ware J. S., Whiffin N., Mazzarotto F., Skoric-Milosavljevic D., Krijger C., Arbelo E., Babuty D., Barajas-Martinez H., Beckmann B. M., Bezieau S., Bos J. M., Breckpot J., Campuzano O., Castelletti S., Celen C., Clauss S., Corveleyn A., Crotti L., Dagradi F., de Asmundis C., Denjoy I., Dittmann S., Ellinor P. T., Ortuno C. G., Giustetto C., Gourraud J. -B., Hazeki D., Horie M., Ishikawa T., Itoh H., Kaneko Y., Kanters J. K., Kimoto H., Kotta M. -C., Krapels I. P. C., Kurabayashi M., Lazarte J., Leenhardt A., Loeys B. L., Lundin C., Makiyama T., Mansourati J., Martins R. P., Mazzanti A., Morner S., Napolitano C., Ohkubo K., Papadakis M., Rudic B., Molina M. S., Sacher F., Sahin H., Sarquella-Brugada G., Sebastiano R., Sharma S., Sheppard M. N., Shimamoto K., Shoemaker M. B., Stallmeyer B., Steinfurt J., Tanaka Y., Tester D. J., Usuda K., van der Zwaag P. A., Van Dooren S., Van Laer L., Winbo A., Winkel B. G., Yamagata K., Zumhagen S., Volders P. G. A., Lubitz S. A., Antzelevitch C., Platonov P. G., Odening K. E., Roden D. M., Roberts J. D., Skinner J. R., Tfelt-Hansen J., van den Berg M. P., Olesen M. S., Lambiase P. D., Borggrefe M., Hayashi K., Rydberg A., Nakajima T., Yoshinaga M., Saenen J. B., Kaab S., Brugada P., Robyns T., Giachino D. F., Ackerman M. J., Brugada R., Brugada J., Gimeno J. R., Hasdemir C., Guicheney P., Priori S. G., Schulze-Bahr E., Makita N., Schwartz P. J., Shimizu W., Aiba T., Schott J. -J., Redon R., Ohno S., Probst V., Arnaout A. A., Amelot M., Anselme F., Billon O., Defaye P., Dupuis J. -M., Jesel L., Laurent G., Maury P., Pasquie J. -L., Wiart F., Behr E. R., Barc J., Bezzina C. R., Walsh, R, Lahrouchi, N, Tadros, R, Kyndt, F, Glinge, C, Postema, P, Amin, A, Nannenberg, E, Ware, J, Whiffin, N, Mazzarotto, F, Skoric-Milosavljevic, D, Krijger, C, Arbelo, E, Babuty, D, Barajas-Martinez, H, Beckmann, B, Bezieau, S, Bos, J, Breckpot, J, Campuzano, O, Castelletti, S, Celen, C, Clauss, S, Corveleyn, A, Crotti, L, Dagradi, F, de Asmundis, C, Denjoy, I, Dittmann, S, Ellinor, P, Ortuno, C, Giustetto, C, Gourraud, J, Hazeki, D, Horie, M, Ishikawa, T, Itoh, H, Kaneko, Y, Kanters, J, Kimoto, H, Kotta, M, Krapels, I, Kurabayashi, M, Lazarte, J, Leenhardt, A, Loeys, B, Lundin, C, Makiyama, T, Mansourati, J, Martins, R, Mazzanti, A, Morner, S, Napolitano, C, Ohkubo, K, Papadakis, M, Rudic, B, Molina, M, Sacher, F, Sahin, H, Sarquella-Brugada, G, Sebastiano, R, Sharma, S, Sheppard, M, Shimamoto, K, Shoemaker, M, Stallmeyer, B, Steinfurt, J, Tanaka, Y, Tester, D, Usuda, K, van der Zwaag, P, Van Dooren, S, Van Laer, L, Winbo, A, Winkel, B, Yamagata, K, Zumhagen, S, Volders, P, Lubitz, S, Antzelevitch, C, Platonov, P, Odening, K, Roden, D, Roberts, J, Skinner, J, Tfelt-Hansen, J, van den Berg, M, Olesen, M, Lambiase, P, Borggrefe, M, Hayashi, K, Rydberg, A, Nakajima, T, Yoshinaga, M, Saenen, J, Kaab, S, Brugada, P, Robyns, T, Giachino, D, Ackerman, M, Brugada, R, Brugada, J, Gimeno, J, Hasdemir, C, Guicheney, P, Priori, S, Schulze-Bahr, E, Makita, N, Schwartz, P, Shimizu, W, Aiba, T, Schott, J, Redon, R, Ohno, S, Probst, V, Arnaout, A, Amelot, M, Anselme, F, Billon, O, Defaye, P, Dupuis, J, Jesel, L, Laurent, G, Maury, P, Pasquie, J, Wiart, F, Behr, E, Barc, J, Bezzina, C, Walsh R., Lahrouchi N., Tadros R., Kyndt F., Glinge C., Postema P. G., Amin A. S., Nannenberg E. A., Ware J. S., Whiffin N., Mazzarotto F., Skoric-Milosavljevic D., Krijger C., Arbelo E., Babuty D., Barajas-Martinez H., Beckmann B. M., Bezieau S., Bos J. M., Breckpot J., Campuzano O., Castelletti S., Celen C., Clauss S., Corveleyn A., Crotti L., Dagradi F., de Asmundis C., Denjoy I., Dittmann S., Ellinor P. T., Ortuno C. G., Giustetto C., Gourraud J. -B., Hazeki D., Horie M., Ishikawa T., Itoh H., Kaneko Y., Kanters J. K., Kimoto H., Kotta M. -C., Krapels I. P. C., Kurabayashi M., Lazarte J., Leenhardt A., Loeys B. L., Lundin C., Makiyama T., Mansourati J., Martins R. P., Mazzanti A., Morner S., Napolitano C., Ohkubo K., Papadakis M., Rudic B., Molina M. S., Sacher F., Sahin H., Sarquella-Brugada G., Sebastiano R., Sharma S., Sheppard M. N., Shimamoto K., Shoemaker M. B., Stallmeyer B., Steinfurt J., Tanaka Y., Tester D. J., Usuda K., van der Zwaag P. A., Van Dooren S., Van Laer L., Winbo A., Winkel B. G., Yamagata K., Zumhagen S., Volders P. G. A., Lubitz S. A., Antzelevitch C., Platonov P. G., Odening K. E., Roden D. M., Roberts J. D., Skinner J. R., Tfelt-Hansen J., van den Berg M. P., Olesen M. S., Lambiase P. D., Borggrefe M., Hayashi K., Rydberg A., Nakajima T., Yoshinaga M., Saenen J. B., Kaab S., Brugada P., Robyns T., Giachino D. F., Ackerman M. J., Brugada R., Brugada J., Gimeno J. R., Hasdemir C., Guicheney P., Priori S. G., Schulze-Bahr E., Makita N., Schwartz P. J., Shimizu W., Aiba T., Schott J. -J., Redon R., Ohno S., Probst V., Arnaout A. A., Amelot M., Anselme F., Billon O., Defaye P., Dupuis J. -M., Jesel L., Laurent G., Maury P., Pasquie J. -L., Wiart F., Behr E. R., Barc J., and Bezzina C. R.

Abstract

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes—rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10−18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10−13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case–control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

Published
2021

25. Loss-of-function variants in founder population highlight atrial myopathy as susceptibility to atrial fibrillation

Author

Paludan-Muller, C, primary, Vad, O B, additional, Kahnert, K, additional, Ahlberg, G, additional, Monfort, L M, additional, Rand, S A, additional, Trudsoe, L C, additional, Andreasen, L, additional, Christensen, A H, additional, Bundgaard, H, additional, Lundby, A, additional, Svendsen, J H, additional, and Olesen, M S, additional

Published
2022
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30. Haloperidol for the Treatment of Delirium in ICU Patients

Author

Andersen-Ranberg, N, Poulsen, L, Perner, A, Wetterslev, J, Estrup, S, Hästbacka, J, Morgan, M, Citerio, G, Caballero, J, Lange, T, Kjær, M, Ebdrup, B, Engstrøm, J, Olsen, M, Oxenbøll Collet, M, Mortensen, C, Weber, S, Andreasen, A, Bestle, M, Uslu, B, Scharling Pedersen, H, Gramstrup Nielsen, L, Toft Boesen, H, Jensen, J, Nebrich, L, La Cour, K, Laigaard, J, Haurum, C, Olesen, M, Overgaard-Steensen, C, Westergaard, B, Brand, B, Kingo Vesterlund, G, Thornberg Kyhnauv, P, Mikkelsen, V, Hyttel-Sørensen, S, de Haas, I, Aagaard, S, Nielsen, L, Eriksen, A, Rasmussen, B, Brix, H, Hildebrandt, T, Schønemann-Lund, M, Fjeldsøe-Nielsen, H, Kuivalainen, A, Mathiesen, O, Andersen-Ranberg, Nina C, Poulsen, Lone M, Perner, Anders, Wetterslev, Jørn, Estrup, Stine, Hästbacka, Johanna, Morgan, Matt, Citerio, Giuseppe, Caballero, Jesus, Lange, Theis, Kjær, Maj-Brit N, Ebdrup, Bjørn H, Engstrøm, Janus, Olsen, Markus H, Oxenbøll Collet, Marie, Mortensen, Camilla B, Weber, Sven-Olaf, Andreasen, A Sofie, Bestle, Morten H, Uslu, Bülent, Scharling Pedersen, Helle, Gramstrup Nielsen, Louise, Toft Boesen, Hans C, Jensen, Jacob V, Nebrich, Lars, La Cour, Kirstine, Laigaard, Jens, Haurum, Cecilie, Olesen, Marie W, Overgaard-Steensen, Christian, Westergaard, Bo, Brand, Björn, Kingo Vesterlund, Gitte, Thornberg Kyhnauv, Pernille, Mikkelsen, Vibe S, Hyttel-Sørensen, Simon, de Haas, Inge, Aagaard, Søren R, Nielsen, Line O, Eriksen, Anne S, Rasmussen, Bodil S, Brix, Helene, Hildebrandt, Thomas, Schønemann-Lund, Martin, Fjeldsøe-Nielsen, Hans, Kuivalainen, Anna-Maria, Mathiesen, Ole, Andersen-Ranberg, N, Poulsen, L, Perner, A, Wetterslev, J, Estrup, S, Hästbacka, J, Morgan, M, Citerio, G, Caballero, J, Lange, T, Kjær, M, Ebdrup, B, Engstrøm, J, Olsen, M, Oxenbøll Collet, M, Mortensen, C, Weber, S, Andreasen, A, Bestle, M, Uslu, B, Scharling Pedersen, H, Gramstrup Nielsen, L, Toft Boesen, H, Jensen, J, Nebrich, L, La Cour, K, Laigaard, J, Haurum, C, Olesen, M, Overgaard-Steensen, C, Westergaard, B, Brand, B, Kingo Vesterlund, G, Thornberg Kyhnauv, P, Mikkelsen, V, Hyttel-Sørensen, S, de Haas, I, Aagaard, S, Nielsen, L, Eriksen, A, Rasmussen, B, Brix, H, Hildebrandt, T, Schønemann-Lund, M, Fjeldsøe-Nielsen, H, Kuivalainen, A, Mathiesen, O, Andersen-Ranberg, Nina C, Poulsen, Lone M, Perner, Anders, Wetterslev, Jørn, Estrup, Stine, Hästbacka, Johanna, Morgan, Matt, Citerio, Giuseppe, Caballero, Jesus, Lange, Theis, Kjær, Maj-Brit N, Ebdrup, Bjørn H, Engstrøm, Janus, Olsen, Markus H, Oxenbøll Collet, Marie, Mortensen, Camilla B, Weber, Sven-Olaf, Andreasen, A Sofie, Bestle, Morten H, Uslu, Bülent, Scharling Pedersen, Helle, Gramstrup Nielsen, Louise, Toft Boesen, Hans C, Jensen, Jacob V, Nebrich, Lars, La Cour, Kirstine, Laigaard, Jens, Haurum, Cecilie, Olesen, Marie W, Overgaard-Steensen, Christian, Westergaard, Bo, Brand, Björn, Kingo Vesterlund, Gitte, Thornberg Kyhnauv, Pernille, Mikkelsen, Vibe S, Hyttel-Sørensen, Simon, de Haas, Inge, Aagaard, Søren R, Nielsen, Line O, Eriksen, Anne S, Rasmussen, Bodil S, Brix, Helene, Hildebrandt, Thomas, Schønemann-Lund, Martin, Fjeldsøe-Nielsen, Hans, Kuivalainen, Anna-Maria, and Mathiesen, Ole

Abstract

Background Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited. Methods In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization. Results A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P=0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group. Conclusions Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo.

Published
2022

32. Left atrial remodeling and cerebrovascular disease assessed by magnetic resonance imaging in patients undergoing continuous heart rhythm monitoring

Author

Bertelsen, L, primary, Diederichsen, S Z, additional, Frederiksen, K S, additional, Haugan, K J, additional, Brandes, A, additional, Graff, C, additional, Krieger, D, additional, Hoejberg, S, additional, Olesen, M S, additional, Biering-Soerensen, T, additional, Koeber, L, additional, Vejlstrup, N, additional, Hasselbalch, S G, additional, and Svendsen, J H, additional

Published
2021
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35. Integration of Scandinavian genetic data with UK biobank data implicates the RBM20 gene with atrial fibrillation pathogenesis

Author

Vad, O. B., Angeli, E., Liss, M., Ahlberg, G., Andreasen, L., Christophersen, I. E., Tveit, A., Haunsoe, S., Svendsen, J. H., Lundegaard, P. R., Gotthardt, M., Olesen, M. S., Vad, O. B., Angeli, E., Liss, M., Ahlberg, G., Andreasen, L., Christophersen, I. E., Tveit, A., Haunsoe, S., Svendsen, J. H., Lundegaard, P. R., Gotthardt, M., and Olesen, M. S.

Published
2021

36. Lymphocytic colitis: a retrospective clinical study of 199 Swedish patients

Author

Olesen, M., Eriksson, S., Bohr, J., Jarnerot, G., and Tysk, C.

Subjects
Lymphocytes -- Health aspects -- Research, Colitis -- Care and treatment -- Research, Diarrhea -- Care and treatment -- Research, Health, Care and treatment, Research, Health aspects
Abstract

Gut 2004;53:536-541. doi: 10. 1136/gut.2003.023440 Background: Lymphocytic colitis is characterised by chronic diarrhoea and specific microscopic changes in a macroscopically normal colonic mucosa. We report clinical features and treatment outcome [...]

Published
2004

44. The firn meltwater Retention Model Intercomparison Project (RetMIP): evaluation of nine firn models at four weather station sites on the Greenland ice sheet

Author

Vandecrux, Baptiste Robert Marcel, Mottram, R., L. Langen, P., S. Fausto, R., Olesen, M., M. Stevens, C., Verjans, V., Leeson, A., Ligtenberg, S., Kuipers Munneke, P., Marchenko, S., van Pelt, W., R. Meyer, C., Simonsen, Sebastian B., Heilig, A., Samimi, S., Marshall, S., Machguth, Horst, MacFerrin, M., Niwano, M., Miller, O., I. Voss, C., E. Box, J., Vandecrux, Baptiste Robert Marcel, Mottram, R., L. Langen, P., S. Fausto, R., Olesen, M., M. Stevens, C., Verjans, V., Leeson, A., Ligtenberg, S., Kuipers Munneke, P., Marchenko, S., van Pelt, W., R. Meyer, C., Simonsen, Sebastian B., Heilig, A., Samimi, S., Marshall, S., Machguth, Horst, MacFerrin, M., Niwano, M., Miller, O., I. Voss, C., and E. Box, J.

Abstract

Perennial snow, or firn, covers 80 % of the Greenland ice sheetand has the capacity to retain surface meltwater, influencing the ice sheetmass balance and contribution to sea-level rise. Multilayer firn models aretraditionally used to simulate firn processes and estimate meltwaterretention. We present, intercompare and evaluate outputs from nine firnmodels at four sites that represent the ice sheet's dry snow, percolation,ice slab and firn aquifer areas. The models are forced by mass and energyfluxes derived from automatic weather stations and compared to firn density,temperature and meltwater percolation depth observations. Models agreerelatively well at the dry-snow site while elsewhere their meltwaterinfiltration schemes lead to marked differences in simulated firncharacteristics. Models accounting for deep meltwater percolation overestimate percolation depth and firn temperature at the percolation andice slab sites but accurately simulate recharge of the firn aquifer. Modelsusing Darcy's law and bucket schemes compare favorably to observed firntemperature and meltwater percolation depth at the percolation site, butonly the Darcy models accurately simulate firn temperature and percolationat the ice slab site. Despite good performance at certain locations, nosingle model currently simulates meltwater infiltration adequately at allsites. The model spread in estimated meltwater retention and runoffincreases with increasing meltwater input. The highest runoff was calculatedat the KAN_U site in 2012, when average total runoff acrossmodels (±2σ) was 353±610 mm w.e. (water equivalent), about 27±48 % of the surface meltwater input. We identify potential causes for themodel spread and the mismatch with observations and provide recommendationsfor future model development and firn investigation.

Published
2020

45. Transethnic genome-wide association study provides insights in the genetic architecture and heritability of long QT syndrome

Author

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, Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant UB, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott JJ, Gourraud JB, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, Schulze-Bahr E, Probst V, Horie M, Wilde AA, Tanck MWT, Bezzina CR., 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, Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant UB, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott JJ, Gourraud JB, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, Schulze-Bahr E, Probst V, Horie M, Wilde AA, Tanck MWT, and Bezzina CR.

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 (P5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P10-6). 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 (rg=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 c

Published
2020

46. Highly sensitive quantification of optic neuritis intrathecal biomarker CXCL13

Author

Olesen, M. N., Nilsson, A. C., Pihl-Jensen, G., Soelberg, K. K., Olsen, D. A., Brandslund, I., Lillevang, S. T., Madsen, J. S., Frederiksen, J. L., Asgari, N., Olesen, M. N., Nilsson, A. C., Pihl-Jensen, G., Soelberg, K. K., Olsen, D. A., Brandslund, I., Lillevang, S. T., Madsen, J. S., Frederiksen, J. L., and Asgari, N.

Abstract

Background: Elevation of CXCL13, a key regulator of B-cell recruitment in cerebrospinal fluid (CSF) is implicated in multiple sclerosis (MS). Objective: to evaluate if measurement of CXCL13 using a highly sensitive assay is of value in acute optic neuritis (ON) patients for the prediction of later MS. Method: CXCL13 was measured by Simoa in two independent treatment-naïve ON cohorts, a training cohort (TC, n = 33) originating from a population-based cohort, a validation cohort (VC, n = 30) consecutively collected following principles for population studies. Prospectively, 14/33 TC and 12/30 VC patients progressed to MS (MS-ON) while 19/33 TC and 18/30 VC patients, remained as isolated ON (ION). Results: CXCL13 was detectable in all samples and were higher in ON compared with healthy controls (HC) (p = 0.012). In the TC, CSF levels in MS-ON were higher compared with ION patients and HC (p = 0.0001 and p<0.0001). In the VC, we confirmed the increase of CXCL13 in MS-ON compared to ION (p = 0.0091). Logistic regression analysis revealed an area under receiver operating characteristic curve of 0.83 [95% C.I: 0.73–0.93]. Conclusions: The highly sensitive CXCL13 Simoa assay demonstrated ability to identify ON patients and separate MS-ON from ION, and predictive diagnostic values indicates a promising potential of this assay.

Published
2020

50. Human iPSC modeling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes

Author

Benzoni, P, Campostrini, G, Landi, S, Bertini, V, Marchina, E, Iascone, M, Ahlberg, G, Olesen, M, Crescini, E, Mora, C, Bisleri, G, Muneretto, C, Ronca, R, Presta, M, Poliani, P, Piovani, G, Verardi, R, Pasquale, E, Consiglio, A, Raya, A, Torre, E, Lodrini, A, Milanesi, R, Rocchetti, M, Baruscotti, M, Difrancesco, D, Memo, M, Barbuti, A, Dell'Era, P, Benzoni, Patrizia, Campostrini, Giulia, Landi, Sara, Bertini, Valeria, Marchina, Eleonora, Iascone, Maria, Ahlberg, Gustav, Olesen, Morten Salling, Crescini, Elisabetta, Mora, Cristina, Bisleri, Gianluigi, Muneretto, Claudio, Ronca, Roberto, Presta, Marco, Poliani, Pier Luigi, Piovani, Giovanna, Verardi, Rosanna, Pasquale, Elisa Di, Consiglio, Antonella, Raya, Angel, Torre, Eleonora, Lodrini, Alessandra Maria, Milanesi, Raffaella, Rocchetti, Marcella, Baruscotti, Mirko, DiFrancesco, Dario, Memo, Maurizio, Barbuti, Andrea, Dell'Era, Patrizia, Benzoni, P, Campostrini, G, Landi, S, Bertini, V, Marchina, E, Iascone, M, Ahlberg, G, Olesen, M, Crescini, E, Mora, C, Bisleri, G, Muneretto, C, Ronca, R, Presta, M, Poliani, P, Piovani, G, Verardi, R, Pasquale, E, Consiglio, A, Raya, A, Torre, E, Lodrini, A, Milanesi, R, Rocchetti, M, Baruscotti, M, Difrancesco, D, Memo, M, Barbuti, A, Dell'Era, P, Benzoni, Patrizia, Campostrini, Giulia, Landi, Sara, Bertini, Valeria, Marchina, Eleonora, Iascone, Maria, Ahlberg, Gustav, Olesen, Morten Salling, Crescini, Elisabetta, Mora, Cristina, Bisleri, Gianluigi, Muneretto, Claudio, Ronca, Roberto, Presta, Marco, Poliani, Pier Luigi, Piovani, Giovanna, Verardi, Rosanna, Pasquale, Elisa Di, Consiglio, Antonella, Raya, Angel, Torre, Eleonora, Lodrini, Alessandra Maria, Milanesi, Raffaella, Rocchetti, Marcella, Baruscotti, Mirko, DiFrancesco, Dario, Memo, Maurizio, Barbuti, Andrea, and Dell'Era, Patrizia

Abstract

AIMS: Atrial fibrillation (AF) is the most common type of cardiac arrhythmias, whose incidence is likely to increase with the aging of the population. It is considered a progressive condition, frequently observed as a complication of other cardiovascular disorders. However, recent genetic studies revealed the presence of several mutations and variants linked to AF, findings that define AF as a multifactorial disease. Due to the complex genetics and paucity of models, molecular mechanisms underlying the initiation of AF are still poorly understood. Here we investigate the pathophysiological mechanisms of a familial form of AF, with particular attention to the identification of putative triggering cellular mechanisms, using patient's derived cardiomyocytes (CMs) differentiated from induced pluripotent stem cells (iPSCs). METHODS AND RESULTS: Here we report the clinical case of three siblings with untreatable persistent AF whose whole-exome sequence analysis revealed several mutated genes. To understand the pathophysiology of this multifactorial form of AF we generated three iPSC clones from two of these patients and differentiated these cells towards the cardiac lineage. Electrophysiological characterization of patient-derived CMs (AF-CMs) revealed that they have higher beating rates compared to control (CTRL)-CMs. The analysis showed an increased contribution of the If and ICaL currents. No differences were observed in the repolarizing current IKr and in the sarcoplasmic reticulum calcium handling. Paced AF-CMs presented significantly prolonged action potentials and, under stressful conditions, generated both delayed after-depolarizations of bigger amplitude and more ectopic beats than CTRL cells. CONCLUSIONS: Our results demonstrate that the common genetic background of the patients induces functional alterations of If and ICaL currents leading to a cardiac substrate more prone to develop arrhythmias under demanding conditions. To our knowledge this is the first rep

Published
2020

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