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11. Idiopathic Ventricular Fibrillation and Early Repolarization

Author

Postema, Pieter G., Thomas, Remme, C., Cardiology, and ACS - Heart failure & arrhythmias

Subjects
medicine.medical_specialty, Benign early repolarization, business.industry, Cardiac electrophysiology, Sedation, Sudden cardiac arrest, Disease, Sudden death, QRS complex, Internal medicine, medicine, Cardiology, ST segment, medicine.symptom, business
Abstract

In this chapter, an overview is provided on idiopathic ventricular fibrillation (IVF) and early repolarization. Idiopathic ventricular fibrillation is a tragic and notoriously difficult disease entity to manage. The IVF patients in whom a cardiac arrest occurs are generally considered healthy and do not show any currently identifiable abnormalities that denote their increased risk for malignant and life-threatening arrhythmias. Importantly, IVF can be inheritable and tear through families. The number of patients who survive their first manifestation of the disease is low, and the recurrence rate of IVF is appreciable. Treatment in patients who survived their event is performed by implantation of a cardioverter defibrillator (ICD) and a decrease of the risk of IVF recurrence may be achieved by prescription of quinidine. During a VF storm, administration of isoproterenol can be essential, and possibly also sedation might be effective. Research into the origin and genetic underpinning of IVF is limited by its malignant character, yet has revealed genetic variants in the DPP6 gene and CALM1 gene that impact on cellular cardiac electrophysiology. In contrast, early repolarization is a description of electrocardiographic variants with elevation, slurring, or notching in the terminal QRS complex or early ST segment. Although considered a benign electrocardiographic characteristic for many decades, in the past decade associations have been made with a propensity to sudden cardiac arrest by VF. Importantly, early repolarization is of very common occurrence in many young and healthy individuals. The description of a rare malignant association has spurred scientific interest in this phenomenon. Fortunately, its benign prognosis is still valid for the vast majority of individuals who display an early repolarization pattern. The challenge for the future will be to delineate benign from malignant variants of early repolarization, the development of aids in risk stratification and a better understanding underlying pathophysiology on cellular and genetic level, to further guide clinicians and patients.

Published
2018

15. P791A common co-morbidity modulates disease expression and treatment efficacy in inherited cardiac sodium channelopathy

Author

Remme, C A, primary, Rivaud, M R, additional, Jansen, J A, additional, Postema, P G, additional, Nannenberg, E A, additional, Marchal, G A, additional, Rajamani, S R, additional, Belardinelli, L, additional, Van Tintelen, J P, additional, Tanck, M W, additional, Creemers, E E, additional, Wilde, A A, additional, Van Den Berg, M P, additional, Van Veen, TAB, additional, and Bezzina, C R, additional

Published
2018
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18. Genome-Wide Association Analysis Identifies 3 Common Variants Predisposing to Brugada Syndrome, a Rare Disease with High Risk of Sudden Cardiac Death

Author

Barc, J., primary, Bezzina, C., additional, Mizusawa, Y., additional, Remme, C., additional, Gourraud, J., additional, Verkerk, A., additional, Schwartz, P., additional, Guicheney, P., additional, Antzelevitch, C., additional, Schulze-Bahr, E., additional, Behr, E., additional, Tfelt-Hanson, J., additional, Kaab, S., additional, Watanabe, H., additional, Horie, M., additional, Makita, N., additional, Shimizu, W., additional, Roden, D., additional, Christoffels, V., additional, Gessler, M., additional, Wilde, A., additional, Probst, V., additional, Schott, J., additional, Dina, C., additional, and Redon, R., additional

Published
2013
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20. CDNA arrays: the ups and downs

Author

Remme, C. A., Lombardi, M. P., van den Hoff, M. J., Lekanne dit Deprez, R. H., and Other departments

Published
2001

24. Brugada syndrome

Author

Wilde, A. A. M., Remme, C. A., Derksen, R., Wever, E. F. D., Hauer, R. N. W., and Cardiology

Subjects
Cardiology and Cardiovascular Medicine
Published
2002

25. Combined reduction of intercellular coupling and membrane excitability differentially affects transverse and longitudinal cardiac conduction

Author

Stein, M., primary, van Veen, T. A.B., additional, Remme, C. A., additional, Boulaksil, M., additional, Noorman, M., additional, van Stuijvenberg, L., additional, van der Nagel, R., additional, Bezzina, C. R., additional, Hauer, R. N.W., additional, de Bakker, J. M.T., additional, and van Rijen, H. V.M., additional

Published
2009
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29. PDZ domain-binding motif of the cardiac sodium channel Nav1.5 regulates compartment-specific channel expression and cardiac conduction in cardiomyocytes.

Author

Shy, D., Gillet, L., Ogrodnik, J., Albesa, M., Verkerk, A. O., Essers, M. C., Wolswinkel, R., Syam, N., Marsman, R. F., van Mil, A. M., Rotman, S., Bezzina, C. R., Remme, C., and Abriel, H.

Subjects
ION channels, HEART cells, DYSTROPHIN
Abstract

Regulation of cardiac ion channels is essential for functional expression of ion channels and excitability of cardiac cells. Previous results with dystrophin-deficient (mdx) mice showed that disruption of the dystrophin-syntrophin macromolecular complex impairs excitability and impulse propagation by interfering with the interaction between the PDZ domain-binding motif of the cardiac sodium ion channel Nav1.5 and syntrophin at the lateral membrane of cardiomyocytes. In addition, interfering with the association between Nav1.5 and another PDZ domain-containing protein, SAP97 that is located at the intercalated discs, led to reduction of sodium current (INa). To study the in vivo significance of this PDZ domain-binding motif on Nav1.5 function, we created and characterized a homozygous knock-in mouse strain which removed this motif by truncating the last three amino acids, Ser-Ile-Val (ΔSIV), of the Nav1.5 C-terminus. Western blots detected a 25% decrease in Nav1.5 protein level in ΔSIV hearts, while levels of associating proteins were unaffected. Immunostainings revealed loss of Nav1.5 expression at the lateral cardiomyocyte membrane but not at the intercalated discs. This reduction corresponded to a 36% decrease of whole-cell INa in ΔSIV cardiomyocytes and a 62% reduction of INa, specifically at the lateral membrane, in macropatch recordings. A significant slowing of 35% of maximal upstroke velocity of the cardiac action potential was detected. On surface ECGs, ΔSIV mice displayed a pronounced QRS-interval prolongation, indicating impeded ventricular conduction. This was confirmed with optical mapping of ΔSIV hearts showing prolongation of activation time and increased anisotropy due to a preferential decrease in transversal conduction velocity. We also investigated the effects of a specific mutation within the PDZ domain-binding motif of Nav1.5 (p.V2016M) that was found in a patient with Brugada syndrome. This mutation changes the last amino acid of the PDZ domain-binding motif from valine to methionine (SIV to SIM) at the Nav1.5 C-terminus. HEK293 cell transfections of mutant V2016M channels revealed a 24% decrease in cell surface expression compared to WT in biotinylation experiments. Patch-clamp recordings of V2016M mutant channels revealed a 49% decrease in peak INa. Pull-down experiments with Nav1.5 WT or mutated C-terminus GST fusion proteins showed a significant decrease in the interaction of Nav1.5 and SAP97. Taken together, these results emphasize the importance of the Nav1.5 PDZ domain-binding motif in correct ion channel expression, protein interaction, and cardiac function. [ABSTRACT FROM AUTHOR]

Published
2013

30. Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2

Author

Giannetti, Federica, Barbieri, Miriam, Shiti, Assad, Casini, Simona, Sager, Philip T, Das, Saumya, Pradhananga, Sabindra, Srinivasan, Dinesh, Nimani, Saranda, Alerni, Nicolò, Louradour, Julien, Mura, Manuela, Gnecchi, Massimiliano, Brink, Paul, Zehender, Manfred, Koren, Gideon, Zaza, Antonio, Crotti, Lia, Wilde, Arthur A M, Schwartz, Peter J, Remme, Carol Ann, Gepstein, Lior, Sala, Luca, Odening, Katja E, Giannetti, F, Barbieri, M, Shiti, A, Casini, S, Sager, P, Das, S, Pradhananga, S, Srinivasan, D, Nimani, S, Alerni, N, Louradour, J, Mura, M, Gnecchi, M, Brink, P, Zehender, M, Koren, G, Zaza, A, Crotti, L, Wilde, A, Schwartz, P, Remme, C, Gepstein, L, Sala, L, and Odening, K

Subjects
Cellular electrophysiology, Physiology (medical), LQTS, Animal model, 610 Medicine & health, 610 Medizin und Gesundheit, Cardiology and Cardiovascular Medicine, Genotype-specific therapy, hiPSC, Mechanism-based therapy
Abstract

Aims Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. Methods and results Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM–10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3–10 µM (by 20–32%/25–30%/44–45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3–3 µM. Conclusion A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS.

Published
2023

31. ESC working group on cardiac cellular electrophysiology position paper: relevance, opportunities, and limitations of experimental models for cardiac electrophysiology research

Author

Dierk Thomas, Milan Stengl, Dobromir Dobrev, Matteo E. Mangoni, Jordi Heijman, Carol Ann Remme, Larissa Fabritz, Katja E. Odening, Godfrey L. Smith, Cristina E. Molina, Leonardo Sacconi, A.M. Gomez, Antonio Zaza, Frank R. Heinzel, Cardiologie, RS: Carim - H01 Clinical atrial fibrillation, RS: Carim - H04 Arrhythmogenesis and cardiogenetics, Cardiology, ACS - Heart failure & arrhythmias, APH - Methodology, University of Bern, Odening, K, Gomez, A, Dobrev, D, Fabritz, L, Heinzel, F, Mangoni, M, Molina, C, Sacconi, L, Smith, G, Stengl, M, Thomas, D, Zaza, A, Remme, C, and Heijman, J

Subjects
0301 basic medicine, TORSADE-DE-POINTES, Cardiac electrophysiology, Medizin, Cardiomyopathy, Arrhythmias, 030204 cardiovascular system & hematology, 0302 clinical medicine, BIO/09 - FISIOLOGIA, Mechanisms, Position paper, Induced pluripotent stem cell, LEFT-VENTRICULAR WALL, SINOATRIAL NODE, Atrial fibrillation, Animal models, 3. Good health, PRESERVED EJECTION FRACTION, Ion channels, cardiovascular system, HEART-FAILURE, Mechanism, Ion channel, Electrophysiologic Techniques, Cardiac, Cardiology and Cardiovascular Medicine, Experimental models, PLURIPOTENT STEM-CELLS, Arrhythmia, Myocarditis, Cellular electrophysiology, LONG-QT SYNDROME, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), SINUS NODE DYSFUNCTION, medicine, Animals, Humans, Animal model, Experimental model, business.industry, TRANSGENIC RABBIT MODEL, Cardiac arrhythmia, Models, Theoretical, medicine.disease, Electrophysiological Phenomena, 030104 developmental biology, Heart failure, ATRIAL-FIBRILLATION, business, Neuroscience
Abstract

Cardiac arrhythmias are a major cause of death and disability. A large number of experimental cell and animal models have been developed to study arrhythmogenic diseases. These models have provided important insights into the underlying arrhythmia mechanisms and translational options for their therapeutic management. This position paper from the ESC Working Group on Cardiac Cellular Electrophysiology provides an overview of (i) currently available in vitro, ex vivo, and in vivo electrophysiological research methodologies, (ii) the most commonly used experimental (cellular and animal) models for cardiac arrhythmias including relevant species differences, (iii) the use of human cardiac tissue, induced pluripotent stem cell (hiPSC)-derived and in silico models to study cardiac arrhythmias, and (iv) the availability, relevance, limitations, and opportunities of these cellular and animal models to recapitulate specific acquired and inherited arrhythmogenic diseases, including atrial fibrillation, heart failure, cardiomyopathy, myocarditis, sinus node, and conduction disorders and channelopathies. By promoting a better understanding of these models and their limitations, this position paper aims to improve the quality of basic research in cardiac electrophysiology, with the ultimate goal to facilitate the clinical translation and application of basic electrophysiological research findings on arrhythmia mechanisms and therapies.

Published
2021

32. Genome-wide association analyses identify novel Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Author

Barc, Julien, Tadros, Rafik, Glinge, Charlotte, Chiang, David Y., Jouni, Mariam, Simonet, Floriane, Jurgens, Sean J., Baudic, Manon, Nicastro, Michele, Potet, Franck, Offerhaus, Joost A., Walsh, Roddy, Choi, Seung Hoan, Verkerk, Arie O., Mizusawa, Yuka, Anys, Soraya, Minois, Damien, Arnaud, Marine, Duchateau, Josselin, Wijeyeratne, Yanushi D., Muir, Alison, Papadakis, Michael, Castelletti, Silvia, Torchio, Margherita, Ortuño, Cristina Gil, Lacunza, Javier, Giachino, Daniela F., Cerrato, Natascia, Martins, Raphaël P., Campuzano, Oscar, Van Dooren, Sonia, Thollet, Aurélie, Kyndt, Florence, Mazzanti, Andrea, Clémenty, Nicolas, Bisson, Arnaud, Corveleyn, Anniek, Stallmeyer, Birgit, Dittmann, Sven, Saenen, Johan, Noël, Antoine, Honarbakhsh, Shohreh, Rudic, Boris, Marzak, Halim, Rowe, Matthew K., Federspiel, Claire, Le Page, Sophie, Placide, Leslie, Milhem, Antoine, Barajas-Martinez, Hector, Beckmann, Britt-Maria, Krapels, Ingrid P., Steinfurt, Johannes, Winkel, Bo Gregers, Jabbari, Reza, Shoemaker, Moore B., Boukens, Bas J., Škorić-Milosavljević, Doris, Bikker, Hennie, Manevy, Federico, Lichtner, Peter, Ribasés, Marta, Meitinger, Thomas, Müller-Nurasyid, Martina, Strauch, Konstantin, Peters, Annette, Schulz, Holger, Schwettmann, Lars, Leidl, Reiner, Heier, Margit, Veldink, Jan H., van den Berg, Leonard H., Van Damme, Philip, Cusi, Daniele, Lanzani, Chiara, Rigade, Sidwell, Charpentier, Eric, Baron, Estelle, Bonnaud, Stéphanie, Lecointe, Simon, Donnart, Audrey, Le Marec, Hervé, Chatel, Stéphanie, Karakachoff, Matilde, Bézieau, Stéphane, London, Barry, Tfelt-Hansen, Jacob, Roden, Dan, Odening, Katja E., Cerrone, Marina, Chinitz, Larry A., Volders, Paul G., van de Berg, Maarten P., Laurent, Gabriel, Faivre, Laurence, Antzelevitch, Charles, Kääb, Stefan, Arnaout, Alain Al, Dupuis, Jean-Marc, Pasquie, Jean-Luc, Billon, Olivier, Roberts, Jason D., Jesel, Laurence, Borggrefe, Martin, Lambiase, Pier D., Mansourati, Jacques, Loeys, Bart, Leenhardt, Antoine, Guicheney, Pascale, Maury, Philippe, Schulze-Bahr, Eric, Robyns, Tomas, Breckpot, Jeroen, Babuty, Dominique, Priori, Silvia G., Napolitano, Carlo, Defaye, Pascal, Anselme, Frédéric, Darmon, Jean Philippe, Wiart, François, de Asmundis, Carlo, Brugada, Pedro, Brugada, Ramon, Arbelo, Elena, Brugada, Josep, Mabo, Philippe, Behar, Nathalie, Giustetto, Carla, Molina, Maria Sabater, Gimeno, Juan R., Hasdemir, Can, Schwartz, Peter J., Crotti, Lia, McKeown, Pascal P., Sharma, Sanjay, Behr, Elijah R., Haissaguerre, Michel, Sacher, Frédéric, Rooryck, Caroline, Tan, Hanno L., Remme, Carol A., Postema, Pieter G., Delmar, Mario, Ellinor, Patrick T., Lubitz, Steven A., Gourraud, Jean-Baptiste, Tanck, Michael W., George, Alfred L., MacRae, Calum A., Burridge, Paul W., Dina, Christian, Probst, Vincent, Wilde, Arthur A., Schott, Jean-Jacques, Redon, Richard, Bezzina, Connie R., KORA-Study Group, Nantes Referral Ctr Inherited Card, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé - François Bonamy, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Amsterdam UMC - Amsterdam University Medical Center, The MINE study (J.H.V.) has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 772376—EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public–private partnerships. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. J. Barc is supported by the research program Etoiles montantes des Pays de la Loire REGIOCARD RPH081-U1087-REG-PDL, ANR JCJC LEARN (R21006NN, RPV21014NNA) and by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617). R.T. is supported by the Canadian Heart Rhythm Society’s George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair. D.Y.C. is supported by Fondation Leducq and National Institutes of Health (NIH) NHGRI T32 (no. 1T32HG010464-01). M. Baudic was supported by IRP—VERACITIES—New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES, an I-SITE NExT health and engineering initiative (Ecole Centrale and Nantes University) and by the IRP—GAINES—Genetic Architecture IN cardiovascular disEaSes funded by INSERM and CNRS. R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. S.C. is supported by the NHLBI BioData Catalyst Fellows Program. C.A.R. is supported by Fondation Leducq, the Dutch Heart Foundation (CVON PREDICT2) and the Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw, 91714371). Y.D.W. is supported by the Robert Lancaster Memorial Fund. M.P. is supported by Cardiac Risk in the Young. S.V.D. is supported by Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel, project ‘Unravelling the molecular genetic pathways of Brugada Syndrome by cardiomics research’, VUB IRP project ‘IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model’ and Innoviris BRIDGE 2017, project ‘IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases’. S.H. is supported by the Barts BRC. B.R. is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). B.G.W. is supported by the Danish Heart Foundation. M.B.S. is supported by K23HL127704. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. D.C. and C.L. are supported by HYPERGENES (HEALTH-F4-2007). D.R. is supported by R01 HL149826, P50 GM115305. P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05. P.V.D. is supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2). C.A. is supported by NIH HL47678 and HL138103, W.W. Smith Charitable Trust and Wistar Morris Fund. M.B. is Supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). P.D.L. is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. B.L. is supported by GOA—Antigone 33933. J.B. is supported by a Senior Clinical Fellowship of the Flemish Science Foundation (FWO). E.B. is supported by the British Heart Foundation including BHF Clinical Research Training Fellowship (FS/11/71/28918: Future diagnostic role and new genetic loci in SADS), Cardiac Risk in the Young and Robert Lancaster Memorial fund sponsored by McColl’s Ltd. Retail Group. H.L.T. is supported by the European Union’s Horizon 2020 research and innovation program under acronym ESCAPE-NET, registered under grant agreement no. 733381, and the Dutch Heart Foundation (CVON RESCUED and PREDICT2 projects). M.D. is supported by NIH-RO1 HL134328. P.T.E. was supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082) and by a research grant from Bayer AG to the Broad Institute. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. J.-B.G. received a grant from the Fédération Française de Cardiologie (PREVENT project). A.L.G. is supported by the Fondation Leducq. C.A.M.R. is supported by the Leducq Foundation and Burroughs Wellecome Fund. A.A.W. is supported by the Dutch Heart Foundation (CVON PREDICT2 project). J.-J.S. is supported by the Fondation pour la Recherche Médicale (DEQ20140329545). R.R. and P.G. are supported by the National Agency for Research (ANR-GENSUD-14-CE10-0001). C.R.B. is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02)., Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Cardiology, Graduate School, Medical Biology, ACS - Amsterdam Cardiovascular Sciences, ACS - Heart failure & arrhythmias, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, APH - Methodology, Epidemiology and Data Science, MUMC+: DA KG Polikliniek (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, and Cardiovascular Centre (CVC)

Subjects
EXPRESSION, [SDV]Life Sciences [q-bio], DIAGNOSIS, GUIDELINES, ANNOTATION, Article, NAV1.5 Voltage-Gated Sodium Channel, Young Adult, MANAGEMENT, Genetics, GWAS, Humans, Genetic Predisposition to Disease, 610 Medicine & health, SCN5A, Alleles, Brugada Syndrome, Allele, [SDV.GEN]Life Sciences [q-bio]/Genetics, HERITABILITY, Microtubule-Associated Protein, Brugada Syndrome, GWAS, SNPs, COMMON VARIANTS, Mutation, Disease Susceptibility, Human medicine, ENRICHMENT, Microtubule-Associated Proteins, SNPs, Human, GENERATION, Genome-Wide Association Study
Abstract

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na(V)1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na(V)1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings. Genome-wide association analyses identify new susceptibility loci for Brugada syndrome. Functional studies implicate microtubule-related trafficking effects on sodium channel expression as an underlying molecular mechanism., European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [772376-EScORIAL]; Health~Holland; Top Sector Life Sciences Health; Wellcome Trust [076113, 085475, 090355]; Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research; State of Bavaria; Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ; research program Etoiles montantes des Pays de la Loire [REGIOCARD RPH081-U1087-REG-PDL]; ANR JCJC LEARN [R21006NN, RPV21014NNA]; H2020-MSCA-IF-2014 Program of the European Commission [RISTRAD-661617]; Canadian Heart Rhythm Society's George Mines Award; European Society of Cardiology research award; Philippa and Marvin Carsley Cardiology Chair; Fondation Leducq; National Institutes of Health (NIH) NHGRI T32 [1T32HG010464-01]; IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Ecole Centrale); IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Nantes University); IRP-GAINES-Genetic Architecture IN cardiovascular disEaSes - INSERM; CNRS; Amsterdam Cardiovascular Sciences fellowship; NHLBI BioData Catalyst Fellows Program; Dutch Heart Foundation [CVON PREDICT2]; Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw) [91714371]; Robert Lancaster Memorial Fund; Cardiac Risk in the Young; Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel; VUB IRP project `IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model' and Innoviris BRIDGE 2017; project `IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases'; Barts BRC; DZHK (German Centre for Cardiovascular Research); BMBF (German Ministry of Education and Research); Danish Heart Foundation; IWT [140935]; ALS Liga Belgie; National Lottery of Belgium; KU Leuven Opening the Future Fund; HYPERGENES [HEALTH-F4-2007]; Leducq Foundation for Cardiovascular Research grant [18CVD05]; Netherlands CardioVascular Research Initiative [CVON PREDICT2]; NIH [HL47678, HL138103, 1RO1HL092577, R01HL128914, K24HL105780]; W.W. Smith Charitable Trust; Wistar Morris Fund; GOA-Antigone [33933]; Senior Clinical Fellowship of the Flemish Science Foundation (FWO); British Heart Foundation; BHF Clinical Research Training Fellowship [FS/11/71/28918]; Cardiac Risk in the Young and Robert Lancaster Memorial fund - McColl's Ltd. Retail Group; European Union's Horizon 2020 research and innovation program under acronym ESCAPE-NET [733381]; Dutch Heart Foundation; Fondation Leducq [14CVD01, 17CVD02]; American Heart Association [18SFRN34110082, 18SFRN34250007]; Bayer AG; NIH grant [1R01HL139731]; Federation Francaise de Cardiologie (PREVENT project); Leducq Foundation; Burroughs Wellecome Fund; Fondation pour la Recherche Medicale [DEQ20140329545]; National Agency for Research [ANR-GENSUD-14-CE10-0001]; Netherlands Organization for Scientific Research (VICI fellowship) [016.150.610]; [K23HL127704]; [R01 HL149826]; [P50 GM115305]; [NIH-RO1 HL134328], We are greatly indebted to the patients included in the study. We thank V. Cotard, C. Goutsmedt, M.-F. Le Cunff and N. Bourgeais for assistance in patient recruitment and L. Beekman for his technical support. We thank the biological resource centre for biobanking (CHU Nantes, Nantes Universite, Centre de ressources biologiques (BB0033-00040), F-44000 Nantes, France) for applying the following guidelines68. We are most grateful to the Genomics and Bioinformatics Core Facility of Nantes (GenoBiRD, Biogenouest, IFB) for its technical support. This research has been conducted using the UK Biobank resource; we are grateful to UK Biobank participants. The MINE study (J.H.V.) has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 772376-EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk.Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum Munchen-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. J. Barc is supported by the research program Etoiles montantes des Pays de la Loire REGIOCARD RPH081-U1087-REG-PDL, ANR JCJC LEARN (R21006NN, RPV21014NNA) and by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617). R.T. is supported by the Canadian Heart Rhythm Society's George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair. D.Y.C. is supported by Fondation Leducq and National Institutes of Health (NIH) NHGRI T32 (no. 1T32HG010464-01). M. Baudic was supported by IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES, an I-SITE NExT health and engineering initiative (Ecole Centrale and Nantes University) and by the IRP-GAINES-Genetic Architecture IN cardiovascular disEaSes funded by INSERM and CNRS. R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. S.C. is supported by the NHLBI BioData Catalyst Fellows Program. C.A.R. is supported by Fondation Leducq, the Dutch Heart Foundation (CVON PREDICT2) and the Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw; 91714371). Y.D.W. is supported by the Robert Lancaster Memorial Fund. M.P. is supported by Cardiac Risk in the Young. S.V.D. is supported by Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel, project `Unravelling the molecular genetic pathways of Brugada Syndrome by cardiomics research', VUB IRP project `IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model' and Innoviris BRIDGE 2017, project `IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases'. S.H. is supported by the Barts BRC. B.R.; is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). B.G.W. is supported by the Danish Heart Foundation. M.B.S. is supported by K23HL127704. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga Belgie, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. D.C. and C.L. are supported by HYPERGENES (HEALTH-F4-2007). D.R. is supported by R01 HL149826, P50 GM115305. P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05. P.V.D. is supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2). C.A. is supported by NIH HL47678 and HL138103, W.W. Smith Charitable Trust and Wistar Morris Fund. M.B. is Supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). P.D.L. is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. B.L. is supported by GOA-Antigone 33933. J.B. is supported by a Senior Clinical Fellowship of the Flemish Science Foundation (FWO). E.B. is supported by the British Heart Foundation including BHF Clinical Research Training Fellowship (FS/11/71/28918: Future diagnostic role and new genetic loci in SADS), Cardiac Risk in the Young and Robert Lancaster Memorial fund sponsored by McColl's Ltd. Retail Group. H.L.T. is supported by the European Union's Horizon 2020 research and innovation program under acronym ESCAPE-NET, registered under grant agreement no. 733381, and the Dutch Heart Foundation (CVON RESCUED and PREDICT2 projects). M.D. is supported by NIH-RO1 HL134328. P.T.E. was supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082) and by a research grant from Bayer AG to the Broad Institute. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. J.-B.G. received a grant from the Federation Francaise de Cardiologie (PREVENT project). A.L.G. is supported by the Fondation Leducq. C.A.M.R. is supported by the Leducq Foundation and Burroughs Wellecome Fund. A.A.W. is supported by the Dutch Heart Foundation (CVON PREDICT2 project). J.-J.S. is supported by the Fondation pour la Recherche Medicale (DEQ20140329545). R.R. and P.G. are supported by the National Agency for Research (ANR-GENSUD-14-CE10-0001). C.R.B. is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02).

Published
2022

33. Investigation on Sudden Unexpected Death in the Young (SUDY) in Europe: results of the European Heart Rhythm Association Survey

Author

Elijah R. Behr, Katie Frampton, Carol Ann Remme, Eloi Marijon, Chiara Scrocco, Eric Schulze-Bahr, Serge Boveda, Konstantinos Iliodromitis, Giulio Conte, Kristine Jubele, Irina Rudaka, Jacob Tfelt-Hansen, Carlo de Asmundis, Arthur A.M. Wilde, Georgia Sarquella Brugada, Jedrzej Kosiuk, Lia Crotti, Nynke Hofman, R Behr, E, Scrocco, C, M Wilde, A, Marijon, E, Crotti, L, E Iliodromitis, K, A Remme, C, Kosiuk, J, Rudaka, I, Sarquella Brugada, G, Frampton, K, Schulze-Bahr, E, Jubele, K, de Asmundis, C, Hofman, N, Tfelt-Hansen, J, Boveda, S, Conte, G, Clinical sciences, Heartrhythmmanagement, Cardiology, ACS - Heart failure & arrhythmias, and APH - Methodology

Subjects
medicine.medical_specialty, European Heart Rhythm Association survey, Genetic testing, Inherited cardiac condition, Autopsy, Computer-assisted web interviewing, Sudden death, Provocation testing, Surveys and Questionnaires, Physiology (medical), Health care, medicine, Humans, Genetic Predisposition to Disease, Sudden Arrhythmic Death Syndrome, Association (psychology), medicine.diagnostic_test, business.industry, Sudden Unexplained Death in the Young, Death Syndrome, Cardiac arrhythmia, Arrhythmias, Cardiac, Focus group, Europe, Sudden Arrhythmic, Death, Sudden, Cardiac, Family medicine, Cardiology and Cardiovascular Medicine, business, Inherited cardiac conditions
Abstract

The aims of this centre-based survey, promoted and disseminated by the European Heart Rhythm Association (EHRA) was to investigate the current practice for the investigation of Sudden Unexplained Death in the Young (SUDY) amongst European countries. An online questionnaire composed of 21 questions was submitted to the EHRA Research Network, European Cardiac Arrhythmia Genetics (ECGen) Focus Group members, and European Reference Network GUARD-Heart healthcare partners. There were 81 respondents from 24 European countries. The majority (78%) worked in a dedicated clinic focusing on families with inherited cardiac conditions and/or SUDY or had easy access to a nearby one. On average, an autopsy was performed in 43% of SUDY cases. Macroscopic examination of the body and all organs were completed in 71% of cases undergoing autopsy, and expert cardiac examination in 32%. Post-mortem genetic testing was requested on average in 37% of Sudden Arrhythmic Death Syndrome (SADS) cases, but not at all by 20% of survey respondents. Psychological support and bereavement counselling for SADS/SUDY families were available for ≤50% of participants. Whilst electrocardiogram (ECG) and echocardiography were largely employed to investigate SADS relatives, there was an inconsistent approach to the use of provocative testing with exercise ECG, sodium channel blocking drugs, and/or epinephrine and genetic testing. The survey highlighted a significant heterogeneity of service provision and variable adherence to current recommendations for the investigation of SUDY, partly attributable to the availability of dedicated units and specialist tests, genetic evaluation, and post-mortem examination.

Published
2022

34. Sex-Related Differences in Cardiac Channelopathies: Implications for Clinical Practice

Author

Yael Ben-Haim, Lauren Yee, Stephan Dobner, Laurent Roten, Katja E. Odening, Helge Servatius, Argelia Medeiros-Domingo, Tobias Reichlin, Andrew D. Krahn, Babken Asatryan, Hildegard Tanner, Carol Ann Remme, Elijah R. Behr, Philippe Chevalier, Jonathan R. Skinner, Lia Crotti, Asatryan, B, Yee, L, Ben-Haim, Y, Dobner, S, Servatius, H, Roten, L, Tanner, H, Crotti, L, Skinner, J, Remme, C, Chevalier, P, Medeiros-Domingo, A, Behr, E, Reichlin, T, Odening, K, Krahn, A, Cardiology, ACS - Heart failure & arrhythmias, and APH - Methodology

Subjects
Male, medicine.medical_specialty, cardiac, Long QT syndrome, Torsades de pointes, Sudden cardiac death, Sex Factors, death, Physiology (medical), medicine, Genetic predisposition, long QT syndrome, Humans, sex, genetics, Brugada syndrome, gender identity, 610 Medicine & health, Intensive care medicine, Cardiac channelopathy, sudden, business.industry, death, sudden, cardiac, Sex related, arrhythmias, cardiac, medicine.disease, Clinical Practice, Cardiovascular Diseases, Channelopathies, Female, genetic, Cardiology and Cardiovascular Medicine, business, arrhythmias
Abstract

Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.

Published
2021

35. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Author

Jade Violleau, Stefan Kääb, Susan Bartkowiak, Richard Redon, Antoine Leenhardt, Hanno L. Tan, Jean-Baptiste Gourraud, Peter Weeke, Rachel Bastiaenen, Rianne Wolswinkel, Federica Dagradi, Vincent M. Christoffels, Jacob Tfelt-Hansen, Jean-Jacques Schott, Hervé Le Marec, Manfred Gessler, Françoise Gros, Pascale Guicheney, Julien Barc, Arthur A.M. Wilde, Simon Lecointe, Akihiko Nogami, Tohru Minamino, Sven Zumhagen, Margherita Torchio, Elijah R. Behr, Rainer Schimpf, Carol Ann Remme, Florence Kyndt, Lia Crotti, Yuka Mizusawa, Morten S. Olesen, Vincent Probst, Naoto Endo, Naomasa Makita, Eric Charpentier, Philippe Froguel, Arie O. Verkerk, Minoru Horie, Takeshi Aiba, Christian Dina, Peter J. Schwartz, Kanae Hasegawa, Floriane Simonet, Véronique Fressart, Seiko Ohno, Cornelia Wiese, Eric Schulze-Bahr, Stéphane Bézieau, Hiroshi Watanabe, Vincent Portero, Wataru Shimizu, Beverley Balkau, Martin Borggrefe, Britt M. Beckmann, Charles Antzelevitch, Bas J. Boukens, Dan M. Roden, Pierre Lindenbaum, Aurore Despres, David Weber, Olivier Lantieri, Connie R. Bezzina, Stéphanie Chatel, Ruben Coronel, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Medical Biology, Other departments, ARD - Amsterdam Reproduction and Development, Bezzina, C, Barc, J, Mizusawa, Y, Remme, C, Gourraud, J, Simonet, F, Verkerk, A, Schwartz, P, Crotti, L, Dagradi, F, Guicheney, P, Fressart, V, Leenhardt, A, Antzelevitch, C, Bartkowiak, S, Borggrefe, M, Schimpf, R, Schulze-Bahr, E, Zumhagen, S, Behr, E, Bastiaenen, R, Tfelt-Hansen, J, Olesen, M, Kääb, S, Beckmann, B, Weeke, P, Watanabe, H, Endo, N, Minamino, T, Horie, M, Ohno, S, Hasegawa, K, Makita, N, Nogami, A, Shimizu, W, Aiba, T, Froguel, P, Balkau, B, Lantieri, O, Torchio, M, Wiese, C, Weber, D, Wolswinkel, R, Coronel, R, Boukens, B, Bézieau, S, Charpentier, E, Chatel, S, Despres, A, Gros, F, Kyndt, F, Lecointe, S, Lindenbaum, P, Portero, V, Violleau, J, Gessler, M, Tan, H, Roden, D, Christoffels, V, Le Marec, H, Wilde, A, Probst, V, Schott, J, Dina, C, and Redon, R

Subjects
Male, Qrs Duration, Bioinformatics, Sodium Channels, NAV1.5 Voltage-Gated Sodium Channel, Sudden cardiac death, Genome-Wide Association, Mice, Atrial Gene-Expression, Basic Helix-Loop-Helix Transcription Factors, Odds Ratio, Brugada Syndrome, Brugada syndrome, Mice, Knockout, St-Segment Elevation, SECS-S/01 - STATISTICA, cardiovascular system, Cardiology, Chromosomes, Human, Pair 6, Female, Chromosomes, Human, Pair 3, medicine.medical_specialty, Bundle-Branch Block, BIO/18 - GENETICA, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, NAV1.8 Voltage-Gated Sodium Channel, Internal medicine, Genetic variation, Cardiac conduction, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, cardiovascular diseases, HEY2, Alleles, Heart-Rate, Genetic Variation, Cardiac arrhythmia, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Qt Interval Duration, Repressor Proteins, Ventricular-Fibrillation, Pr Interval, Death, Sudden, Cardiac, Case-Control Studies, Conduction System, Genome-Wide Association Study, Rare disease
Abstract

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Published
2013

36. K(ATP) channel opening during ischemia: effects on myocardial noradrenaline release and ventricular arrhythmias.

Author

Remme CA, Schumacher CA, de Jong JW, Fiolet JW, de Groot JR, Coronel R, and Wilde AA

Subjects
Adenosine Triphosphate metabolism, Animals, Coronary Circulation drug effects, Cromakalim pharmacology, Female, Glyburide pharmacology, Heart drug effects, Heart physiopathology, Heart Ventricles, Hypoglycemic Agents pharmacology, In Vitro Techniques, Male, Myocardial Ischemia metabolism, Potassium metabolism, Rabbits, Time Factors, Vasodilator Agents pharmacology, Arrhythmias, Cardiac physiopathology, Myocardial Ischemia physiopathology, Myocardium metabolism, Norepinephrine metabolism, Potassium Channels metabolism
Abstract

Cardioprotection by K(ATP) channel openers during ischemia is well documented although ill understood. Proarrhythmic effects may be an important drawback. K(ATP) channel modulation influences neurotransmitter release during ischemia in brain synaptosomes. Therefore, we studied the effects of K(ATP) channel modulation on myocardial noradrenaline release and arrhythmias in ischemic rabbit hearts. Isolated rabbit hearts were perfused according to Langendorff and stimulated. Local electrograms were recorded and K+-selective electrodes were inserted in the left ventricular free wall. Cromakalim (3 microM) or glibenclamide (3 microM) was added 20 min prior to induction of global ischemia. After 15, 20, or 30 min of ischemia, hearts were reperfused and noradrenaline content of the first 100 ml of reperfusate was measured. Cromakalim (n = 16) prevented the second rise of extracellular [K(+)] in accordance with its cardioprotective effect. Cromakalim significantly reduced noradrenaline release after 15 min (mean, 169 +/- SEM 97 pmol/gr dry weight vs. control 941 +/- 278; p < 0.05) and 20 min of ischemia (230 +/- 125 pmol/gr dry wt vs. control 1,460 +/- 433; p < 0.05), but after 30 min of ischemia, the difference in noradrenaline release was no longer significant (cromakalim 2,703 +/- 1,195 pmol/gr dry wt vs. control 5,413 +/- 1,310; p = 0.08). Ventricular fibrillation or ventricular tachycardia occurred in 10 of 13 control hearts (77%) (n = 19), in six of 10 glibenclamide-treated hearts (60%) (n = 15), and in six of 14 cromakalim-treated hearts (43%) (p = NS). Cromakalim significantly accelerated onset of ventricular tachycardia or fibrillation (mean +/- SEM onset after 12.5 +/- 1.6 min ischemia vs. control 16.2 +/- 0.7 min; p < 0.05). Noradrenaline release occurred only in cromakalim-treated hearts with early-onset arrhythmias whereas no noradrenaline release was observed in cromakalim-treated hearts without ventricular tachycardia or fibrillation. Our results show that activation of the K(ATP) channel by cromakalim during ischemia reduces myocardial noradrenaline release and postpones the onset of irreversible damage, contributing to the cardioprotective potential of K(ATP) openers during myocardial ischemia.

Published
2001
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37. Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart. Role of electrical cellular coupling.

Author

de Groot JR, Wilms-Schopman FJ, Opthof T, Remme CA, and Coronel R

Subjects
Animals, Cell Communication physiology, Death, Sudden, Cardiac etiology, Electrocardiography, Female, Glycogen metabolism, Heart Conduction System physiopathology, L-Lactate Dehydrogenase metabolism, Male, Myocardium metabolism, Organ Culture Techniques, Swine, Tachycardia, Ventricular metabolism, Myocardial Ischemia complications, Tachycardia, Ventricular etiology
Abstract

Objective: Acute ischemia comes with two phases of life-threatening arrhythmias, early (within 10 minutes, 1A) and late (after about 15 minutes, 1B). The mechanism of the latter is unknown and in this paper, we test the hypothesis that a phase of intermediate coupling between surviving epicardium and inexcitable midmyocardium underlies 1B arrhythmias., Methods: Pig hearts (n=26) were retrogradely perfused with a blood Tyrode's mixture. The left anterior descending artery was occluded. We investigated (1) inducibility of ventricular fibrillation (VF) with programmed stimulation, (2) tissue impedance (Rt) heterogeneity within the ischemic zone, (3) multiple subepicardial and midmyocardial electrograms, (4) subepicardial lactate dehydrogenase (LDH) and glycogen content., Results: In nine of ten hearts, one--three premature stimuli caused VF between 14 and 53 min of ischemia. This typically happened when the Rt of the ischemic zone had increased up to 40% of its final value. More uncoupling terminated the period of VF inducibility. The excitability of the surviving subepicardial layer was depressed during the same period with partial uncoupling, but recovered when the uncoupling from the midmyocardium had progressed further., Conclusions: We show that 1B-VF can be induced within a distinct time window and coincides with a distinct range of Rt rise. Subepicardium is electrically depressed, presumably through coupling with midmyocardium, complete uncoupling causes subepicardial recovery and terminates the substrate for 1B-VF. Hence, we suggest that the substrate for 1B-VF consists of intermediate coupling of subepicardium and midmyocardium.

Published
2001
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38. CDNA arrays: the ups and downs.

Author

Remme CA, Lombardi MP, van den Hoff MJ, and Lekanne dit Deprez RH

Subjects
Animals, Humans, Rats, Software, Cardiovascular Diseases genetics, Oligonucleotide Array Sequence Analysis trends
Published
2001
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39. KATP channel openers, myocardial ischemia, and arrhythmias--should the electrophysiologist worry?

Author

Remme CA and Wilde AA

Subjects
ATP-Binding Cassette Transporters, Animals, Arrhythmias, Cardiac prevention & control, Electrophysiology, Humans, Ischemic Preconditioning, KATP Channels, Myocardial Ischemia prevention & control, Potassium Channels metabolism, Potassium Channels, Inwardly Rectifying, Arrhythmias, Cardiac physiopathology, Myocardial Ischemia physiopathology, Potassium Channels physiology
Published
2000
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40. Prediction of progression of radiologic damage in newly diagnosed rheumatoid arthritis.

Author

van der Heide A, Remme CA, Hofman DM, Jacobs JW, and Bijlsma JW

Subjects
Adult, Aged, Antirheumatic Agents therapeutic use, Arthritis, Rheumatoid drug therapy, Disease Progression, Female, Humans, Male, Middle Aged, Prospective Studies, Radiography, Regression Analysis, Rheumatoid Factor analysis, Arthritis, Rheumatoid diagnostic imaging
Abstract

Objective: To investigate the extent to which early radiologic damage is predicted by joint inflammation in patients with newly diagnosed rheumatoid arthritis (RA)., Methods: Regression analysis was performed on 1-year progression of total radiologic damage for baseline characteristics and cumulative disease activity measures, and the effects of continued joint inflammation on the progression of damage in separate joint groups were investigated., Results: Odds ratios for progression of total damage were 12 for the presence of rheumatoid factor, 5 for the presence of damage at baseline, and 2 for cumulative joint inflammation. A positive association between continued joint inflammation and progression of damage was found to be statistically significant for most joint groups., Conclusion: Progression of radiologic damage in patients with newly diagnosed RA is independently associated with the presence of rheumatoid factor and damage at baseline and with cumulative joint inflammation.

Published
1995
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