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154 results on '"Rudic, B"'

1. Clinical findings and outcomes of Brugada syndrome in women

Author

Kruska, M K, primary, Perez, J P, additional, Wuerfel, S W, additional, Tueluemen, E T, additional, Fastner, C F, additional, Kuschyk, J K, additional, Borggrefe, M B, additional, Duerschmied, D D, additional, Akin, I A, additional, Liebe, V L, additional, and Boris Rudic, B R, additional

Published
2024
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5. Reproducible target transfer from electroanatomic mapping to radiotherapy planning systems for cardiac radioablation - cross-validation for the RAVENTA trial

Author

Hohmann, S, primary, Xie, J, additional, Grehn, M, additional, Karfoul, N, additional, Mehrhof, F, additional, Merten, R, additional, Rudic, B, additional, Krug, D, additional, Lyan, E, additional, Duncker, D, additional, Dunst, J, additional, Tilz, R, additional, Schweikard, A, additional, Blanck, O, additional, and Boda-Heggemann, J, additional

Published
2023
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6. Stereotactic Arrhythmia Radioablation (STAR) for refractory ventricular tachycardia (VT) - A preliminary report from the German multicenter RAVENTA study

Author

Krug, D, primary, Hohmann, S, additional, Boda-Heggemann, J, additional, Mehrhof, F, additional, Grehn, M, additional, Lyan, E, additional, Merten, R, additional, Rudic, B, additional, Boldt, L H, additional, Kirstein, B, additional, Rades, D, additional, Bonnemeier, H, additional, Dunst, J, additional, Tilz, R, additional, and Blanck, O, additional

Published
2023
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7. STereotactic Arrhythmia Radioablation (STAR): the Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary consortium (STOPSTORM.eu) and review of current patterns of STAR practice in Europe

Author

Grehn, M., Mandija, S., Miszczyk, M., Krug, D., Tomasik, B., Stickney, K. E., Alcantara, P., Alongi, F., Anselmino, M., Aranda, R. S., Balgobind, B. V., Boda-Heggemann, J., Boldt, L.-H., Bottoni, N., Cvek, J., Elicin, O., Ferrari, G. M., Hassink, R. J., Hazelaar, C., Hindricks, G., Hurkmans, C., Iotti, C., Jadczyk, T., Jiravsky, O., Jumeau, R., Kristiansen, S. B., Levis, M., López, M. A., Martí-Almor, J., Mehrhof, F., Møller, D. S., Molon, G., Ouss, A., Peichl, P., Plasek, J., Postema, P. G., Quesada, A., Reichlin, T., Rordorf, R., Rudic, B., Saguner, A. M., Ter, B., Rachel, M. A., Torrecilla, J. L., (0000-0001-9550-9050) Troost, E. G. C., Vitolo, V., Andratschke, N., Zeppenfeld, K., Blamek, S., Fast, M., Panfilis, L., Blanck, O., Pruvot, E., Verhoeff, J. J. C., Grehn, M., Mandija, S., Miszczyk, M., Krug, D., Tomasik, B., Stickney, K. E., Alcantara, P., Alongi, F., Anselmino, M., Aranda, R. S., Balgobind, B. V., Boda-Heggemann, J., Boldt, L.-H., Bottoni, N., Cvek, J., Elicin, O., Ferrari, G. M., Hassink, R. J., Hazelaar, C., Hindricks, G., Hurkmans, C., Iotti, C., Jadczyk, T., Jiravsky, O., Jumeau, R., Kristiansen, S. B., Levis, M., López, M. A., Martí-Almor, J., Mehrhof, F., Møller, D. S., Molon, G., Ouss, A., Peichl, P., Plasek, J., Postema, P. G., Quesada, A., Reichlin, T., Rordorf, R., Rudic, B., Saguner, A. M., Ter, B., Rachel, M. A., Torrecilla, J. L., (0000-0001-9550-9050) Troost, E. G. C., Vitolo, V., Andratschke, N., Zeppenfeld, K., Blamek, S., Fast, M., Panfilis, L., Blanck, O., Pruvot, E., and Verhoeff, J. J. C.

Abstract

The EU Horizon 2020 Framework-funded Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary (STOPSTORM) consortium has been established as a large research network for investigating STereotactic Arrhythmia Radioablation (STAR) for ventricular tachycardia (VT). The aim is to provide a pooled treatment database to evaluate patterns of practice and outcomes of STAR and finally to harmonize STAR within Europe. The consortium comprises 31 clinical and research institutions. The project is divided into nine work packages (WPs): (i) observational cohort; (ii) standardization and harmonization of target delineation; (iii) harmonized prospective cohort; (iv) quality assurance (QA); (v) analysis and evaluation; (vi, ix) ethics and regulations; and (vii, viii) project coordination and dissemination. To provide a review of current clinical STAR practice in Europe, a comprehensive questionnaire was performed at project start. The STOPSTORM Institutions' experience in VT catheter ablation (83% ≥ 20 ann.) and stereotactic body radiotherapy (59% > 200 ann.) was adequate, and 84 STAR treatments were performed until project launch, while 8/22 centres already recruited VT patients in national clinical trials. The majority currently base their target definition on mapping during VT (96%) and/or pace mapping (75%), reduced voltage areas (63%), or late ventricular potentials (75%) during sinus rhythm. The majority currently apply a single-fraction dose of 25 Gy while planning techniques and dose prescription methods vary greatly. The current clinical STAR practice in the STOPSTORM consortium highlights potential areas of optimization and harmonization for substrate mapping, target delineation, motion management, dosimetry, and QA, which will be addressed in the various WPs. © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

Published
2023

10. A step towards routine for stereotactic radioablation in refractory ventricular tachycardia – interim analysis on short term safety of the first prospective, multi-centre, multi-platform study RAVENTA

Author

Zaman, A, primary, Krug, D, additional, Eidinger, L, additional, Boda-Heggemann, J, additional, Rudic, B, additional, Mehrhof, F, additional, Boldt, L H, additional, Fleckenstein, J, additional, Kluge, A, additional, Siebert, F A, additional, Schweikard, A, additional, Vontlein, R, additional, Dunst, J, additional, Bonnemeier, H, additional, and Blanck, O, additional

Published
2022
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12. 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

13. 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

14. Septal myocardial scar burden predicts the response to cardiac contractility modulation in patients with heart failure

Author

Tülümen, Erol, Ansari, U.; Overhoff, D.; Burkhoff, D.; Fastner, C.; Yücel, G.; Röger, S.; Rudic, B.; Liebe, V.; Borggrefe, M.; Akın, I.; Kuschyk, J.; Papavassiliu, T., Koç University Hospital, School of Medicine, Tülümen, Erol, Ansari, U.; Overhoff, D.; Burkhoff, D.; Fastner, C.; Yücel, G.; Röger, S.; Rudic, B.; Liebe, V.; Borggrefe, M.; Akın, I.; Kuschyk, J.; Papavassiliu, T., Koç University Hospital, and School of Medicine

Abstract

We hypothesized that myocardial septal scarring, assessed by cardiac magnetic resonance (CMR) using late gadolinium enhancement (LGE), at the site of cardiac contractility modulation (CCM) lead placement may predict treatment response. Eligible heart failure (HF) patients underwent LGE CMR imaging before CCM device implantation. The response to CCM therapy at follow-up was determined by a change in NYHA class and echocardiographic left ventricular ejection fraction (LVEF) assessment. Patients were classified as responders, if they showed an improvement in either NYHA class or improvement of LVEF by >= 5%. 58 patients were included. 67% of patients were classified as responders according to improved NYHA; 55% according to LVEF improvement. 74% of patients were responders if either NYHA class or LVEF improvement was observed. 90% of responders (according to NYHA class) showed septal LGE < 25% at septal position of the leads, while 44% of non-responders showed septal LGE > 25% (p < 0.01). In patients treated with CCM, an improvement of NYHA class was observed when leads were placed at myocardial segments with a CMR- LGE burden less than 25%., Open Access funding enabled and organized by Projekt DEAL

Published
2022

15. Author Correction: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility (Nature Genetics, (2022), 54, 3, (232-239), 10.1038/s41588-021-01007-6)

Author

Julien Barc, 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, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, Connie R. Bezzina, Julien Barc, 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, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, and Connie R. Bezzina

Abstract

In the version of this article initially published, Federico Manevy’s name appeared with a middle initial in error. The name has been corrected in the HTML and PDF versions of the article.

Published
2022

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

Author

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, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, Connie R. Bezzina, 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, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, and Connie R. Bezzina

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 NaV1.5, 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 NaV1.5 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.

Published
2022

19. 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 PG, Amin AS, Nannenberg EA, Ware JS, Whiffin N, Mazzarotto F, Škoric-Milosavljevic D, Krijger C, Arbelo E, Babuty D, Barajas-Martinez H, Beckmann BM, Bézieau S, Bos JM, Breckpot J, Campuzano O, Castelletti S, Celen C, Clauss S, Corveleyn A, Crotti L, Dagradi F, de Asmundis C, Denjoy I, Dittmann S, Ellinor PT, Ortuño CG, Giustetto C, Gourraud JB, Hazeki D, Horie M, Ishikawa T, Itoh H, Kaneko Y, Kanters JK, Kimoto H, Kotta MC, Krapels IPC, Kurabayashi M, Lazarte J, Leenhardt A, Loeys BL, Lundin C, Makiyama T, Mansourati J, Martins RP, Mazzanti A, Mörner S, Napolitano C, Ohkubo K, Papadakis M, Rudic B, Molina MS, Sacher F, Sahin H, Sarquella-Brugada G, Sebastiano R, Sharma S, Sheppard MN, Shimamoto K, Shoemaker MB, Stallmeyer B, Steinfurt J, Tanaka Y, Tester DJ, Usuda K, van der Zwaag PA, Van Dooren S, Van Laer L, Winbo A, Winkel BG, Yamagata K, Zumhagen S, Volders PGA, Lubitz SA, Antzelevitch C, Platonov PG, Odening KE, Roden DM, Roberts JD, Skinner JR, Tfelt-Hansen J, van den Berg MP, Olesen MS, Lambiase PD, Borggrefe M, Hayashi K, Rydberg A, Nakajima T, Yoshinaga M, Saenen JB, Kääb S, Brugada P, Robyns T, Giachino DF, Ackerman MJ, Brugada R, Brugada-Terradellas J, Gimeno JR, Hasdemir C, Guicheney P, Priori SG, Schulze-Bahr E, Makita N, Schwartz PJ, Shimizu W, Aiba T, Schott JJ, Redon R, Ohno S, Probst V, Behr ER, Barc J, Bezzina CR, and Nantes Referral Center for inherited cardiac arrhythmia

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, LQTS, variant interpretation, cardiovascular diseases, Brugada, ACMG/AMP guidelines
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

20. 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.G., Beekman, L., Walsh, R., Hasegawa, K., Barc, J., Ernsting, M., Turkowski, K.L., Mazzanti, A., Beckmann, B.M., Shimamoto, K., Diamant, U.B., Wijeyeratne, Y.D., Kucho, Y., Robyns, T., Ishikawa, T., Arbelo, E., Christiansen, M., Winbo, A., Jabbari, R., Lubitz, S.A., Steinfurt, J., Rudic, B., Loeys, B., Shoemaker, M.B., Weeke, P.E., Pfeiffer, R., Davies, B., Andorin, A., Hofman, N., Dagradi, F., Pedrazzini, M., Tester, D.J., Bos, J.M, Sarquella-Brugada, G., Campuzano, Ó., Platonov, P.G., Stallmeyer, B., Zumhagen, S., Nannenberg, E.A., Veldink, J.H., Berg, L.H. van den, Al-Chalabi, A., Shaw, C.E., Shaw, P.J., Morrison, K.E., Andersen, P.M., Müller-Nurasyid, M., Cusi, D., Barlassina, C., Galan, P., Lathrop, M., Munter, M., Werge, T., Ribasés, M., Aung, T., Khor, C.C., Ozaki, M., Lichtner, P., Meitinger, T., Tintelen, J.P. van, Hoedemaekers, Y.M., Denjoy, I., Leenhardt, A., Napolitano, C., Shimizu, W., Schott, J.J., Gourraud, J.B., Makiyama, T., Ohno, S., Itoh, H., Krahn, A.D., Antzelevitch, C., Roden, D.M., Saenen, J., Borggrefe, M., Odening, K.E., Ellinor, P.T., Tfelt-Hansen, J., Skinner, J.R., Berg, M.P., Olesen, M.S., Brugada, J., Brugada, R., Makita, N., Breckpot, J., Yoshinaga, M., Behr, E.R., Rydberg, A., Aiba, T., Kääb, S., Priori, S.G., Guicheney, P., Tan, H.L., Newton-Cheh, C., Ackerman, M.J., Schwartz, P.J., Lahrouchi, N., Tadros, R., Crotti, L., Mizusawa, Y., Postema, P.G., Beekman, L., Walsh, R., Hasegawa, K., Barc, J., Ernsting, M., Turkowski, K.L., Mazzanti, A., Beckmann, B.M., Shimamoto, K., Diamant, U.B., Wijeyeratne, Y.D., Kucho, Y., Robyns, T., Ishikawa, T., Arbelo, E., Christiansen, M., Winbo, A., Jabbari, R., Lubitz, S.A., Steinfurt, J., Rudic, B., Loeys, B., Shoemaker, M.B., Weeke, P.E., Pfeiffer, R., Davies, B., Andorin, A., Hofman, N., Dagradi, F., Pedrazzini, M., Tester, D.J., Bos, J.M, Sarquella-Brugada, G., Campuzano, Ó., Platonov, P.G., Stallmeyer, B., Zumhagen, S., Nannenberg, E.A., Veldink, J.H., Berg, L.H. van den, Al-Chalabi, A., Shaw, C.E., Shaw, P.J., Morrison, K.E., Andersen, P.M., Müller-Nurasyid, M., Cusi, D., Barlassina, C., Galan, P., Lathrop, M., Munter, M., Werge, T., Ribasés, M., Aung, T., Khor, C.C., Ozaki, M., Lichtner, P., Meitinger, T., Tintelen, J.P. van, Hoedemaekers, Y.M., Denjoy, I., Leenhardt, A., Napolitano, C., Shimizu, W., Schott, J.J., Gourraud, J.B., Makiyama, T., Ohno, S., Itoh, H., Krahn, A.D., Antzelevitch, C., Roden, D.M., Saenen, J., Borggrefe, M., Odening, K.E., Ellinor, P.T., Tfelt-Hansen, J., Skinner, J.R., Berg, M.P., Olesen, M.S., Brugada, J., Brugada, R., Makita, N., Breckpot, J., Yoshinaga, M., Behr, E.R., Rydberg, A., Aiba, T., Kääb, S., Priori, S.G., Guicheney, P., Tan, H.L., Newton-Cheh, C., Ackerman, M.J., and Schwartz, P.J.

Abstract

Contains fulltext : 230155.pdf (Publisher’s version ) (Open Access)

Published
2020

21. Target Volume Definition for the RAVENTA (RAdiosurgery for VENtricular TAchycardia) Study: the first interdisciplinary, multicenter Benchmark Case

Author

Boda-Heggemann, J., Rudic, B., Tueluemen, E., Boldt, L. -H, Stauber, A., Saguner, A., Krug, D., Buergy, D., Mehrhof, F., Celik, E., Andratschke, N., Zaman, A., Kluge, A. K., Baus, W. W., Ehrbar, S., Bloedorn, S., Schweikard, A., Giordano, F. A., Dunst, J., Bonnemeier, H., Blanck, O., Boda-Heggemann, J., Rudic, B., Tueluemen, E., Boldt, L. -H, Stauber, A., Saguner, A., Krug, D., Buergy, D., Mehrhof, F., Celik, E., Andratschke, N., Zaman, A., Kluge, A. K., Baus, W. W., Ehrbar, S., Bloedorn, S., Schweikard, A., Giordano, F. A., Dunst, J., Bonnemeier, H., and Blanck, O.

Published
2020

25. P2279First clinical evaluation of subcutaneous implantable cardiac defibrillator in Brugada patients

Author

Probst, V, primary, Clerici, G, additional, Babuty, D, additional, Badenco, N, additional, Marquie, C, additional, Leenhardt, A, additional, Maury, P, additional, Blangy, H, additional, Deharo, J C, additional, Tfelt-Hansen, J, additional, Rudic, B, additional, Behar, N, additional, Mansourati, J, additional, Sacher, F, additional, and Gourraud, J B, additional

Published
2019
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27. SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Author

Baruteau, A, Kyndt, F, Behr, E, Vink, A, Lachaud, M, Joong, A, Schott, J, Horie, M, Denjoy, I, Crotti, L, Shimizu, W, Bos, J, Stephenson, E, Wong, L, Abrams, D, Davis, A, Winbo, A, Dubin, A, Sanatani, S, Liberman, L, Kaski, J, Rudic, B, Kwok, S, Rieubland, C, Tfelt-Hansen, J, Van Hare, G, Guyomarc'h-Delasalle, B, Blom, N, Wijeyeratne, Y, Gourraud, J, Le Marec, H, Ozawa, J, Fressart, V, Lupoglazoff, J, Dagradi, F, Spazzolini, C, Aiba, T, Tester, D, Zahavich, L, Beauséjour-Ladouceur, V, Jadhav, M, Skinner, J, Franciosi, S, Krahn, A, Abdelsayed, M, Ruben, P, Yung, T, Ackerman, M, Wilde, A, Schwartz, P, Probst, V, Baruteau, AE, Behr, ER, Vink, AS, Schott, JJ, Bos, JM, Stephenson, EA, Abrams, DJ, Davis, AM, Dubin, AM, Kaski, JP, Kwok, SY, Van Hare, GF, Blom, NA, Wijeyeratne, YD, Gourraud, JB, Lupoglazoff, JM, Tester, DJ, Zahavich, LA, Skinner, JR, Krahn, AD, Ruben, PC, Yung, TC, Ackerman, MJ, Wilde, AA, Schwartz, PJ, Probst, V., Baruteau, A, Kyndt, F, Behr, E, Vink, A, Lachaud, M, Joong, A, Schott, J, Horie, M, Denjoy, I, Crotti, L, Shimizu, W, Bos, J, Stephenson, E, Wong, L, Abrams, D, Davis, A, Winbo, A, Dubin, A, Sanatani, S, Liberman, L, Kaski, J, Rudic, B, Kwok, S, Rieubland, C, Tfelt-Hansen, J, Van Hare, G, Guyomarc'h-Delasalle, B, Blom, N, Wijeyeratne, Y, Gourraud, J, Le Marec, H, Ozawa, J, Fressart, V, Lupoglazoff, J, Dagradi, F, Spazzolini, C, Aiba, T, Tester, D, Zahavich, L, Beauséjour-Ladouceur, V, Jadhav, M, Skinner, J, Franciosi, S, Krahn, A, Abdelsayed, M, Ruben, P, Yung, T, Ackerman, M, Wilde, A, Schwartz, P, Probst, V, Baruteau, AE, Behr, ER, Vink, AS, Schott, JJ, Bos, JM, Stephenson, EA, Abrams, DJ, Davis, AM, Dubin, AM, Kaski, JP, Kwok, SY, Van Hare, GF, Blom, NA, Wijeyeratne, YD, Gourraud, JB, Lupoglazoff, JM, Tester, DJ, Zahavich, LA, Skinner, JR, Krahn, AD, Ruben, PC, Yung, TC, Ackerman, MJ, Wilde, AA, Schwartz, PJ, and Probst, V.

Abstract

Aims: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve theirrisk stratification. Methods and results: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between1990 and 2015. All patients <_16 years of age diagnosed with a genetically confirmed SCN5A mutation wereincluded in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children{55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families wereincluded; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiacconduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolatedBrugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a medianfollow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutationlocalized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation,age <_1 year at diagnosis in probands and age <_1 year at diagnosis in non-probands were independent predictorsof CE.Conclusion In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the mostprevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent riskfactors were identified, including age <_1 year at diagnosis, compound mutation, and mutation with both gain- andloss-of-function.

Published
2018

28. P4691Presence of late gadolinium enhancement and left atrial ejection fraction as predictors of stroke and thrombembolism in patients with hypertrophic cardiomyopathy - a cardiovascular MRI study

Author

Hohneck, A H, primary, Doesch, C, additional, Sandberg, R, additional, Lossnitzer, D, additional, Rudic, B, additional, Tueluemen, E, additional, Fatar, M, additional, Platten, M, additional, Schoenberg, S O, additional, Borggrefe, M, additional, and Papavassiliu, T, additional

Published
2018
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29. 4288A cellular model of Brugada Syndrome with CACNB2 mutation of human-induced pluripotent stem cell-derived cardiomyocytes

Author

El-Battrawy, I, primary, Schimanski, T, additional, Lan, H, additional, Cyganek, L, additional, Zhao, Z, additional, Lang, S, additional, Diecke, S, additional, Zimmermann, W H, additional, Utikal, J, additional, Wieland, T, additional, Rudic, B, additional, Tueluemen, E, additional, Borggrefe, M, additional, Zhou, X B, additional, and Akin, I, additional

Published
2018
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30. 3298First clinical evaluation of subcutaneous implantable cardiac defibrillator in brugada patients

Author

Probst, V, primary, Clerici, G, additional, Babuty, D, additional, Badenco, N, additional, Marquie, C, additional, Leenhardt, A, additional, Maury, P, additional, Blangy, H, additional, Deharo, J L, additional, Tfelt-Hansen, J, additional, Rudic, B, additional, Behar, N, additional, Mansourati, J, additional, Sacher, F, additional, and Gourraud, J B, additional

Published
2018
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34. 209Peri-infarct scar on late gadolinium enhancement cardiac magnetic resonance imaging: a supplementary parameter to improve the risk stratification in patients with ischemic cardiomyopathy

Author

Tulumen, E T, primary, Rudic, B, additional, Ringlage, H, additional, Hohneck, A, additional, El-Battrawy, I, additional, Behnes, M, additional, Roeger, S, additional, Liebe, V, additional, Kuschyk, J, additional, Akin, I, additional, Borggrefe, M, additional, and Papavassiliu, T, additional

Published
2018
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35. P5835Characterization of a novel genetic variant associated with Brugada syndrome: beta-2-syntrophin mutation impairs interaction with SCN5A and reduces Na+ current in human cardiomyocytes

Author

Schmidt, C., primary, Wiedmann, F., additional, El-Battrawy, I., additional, Fritz, M., additional, Ratte, A., additional, Lang, S., additional, Rudic, B., additional, Karck, M., additional, Borggrefe, M., additional, Katus, H., additional, Zhou, X.B., additional, and Thomas, D., additional

Published
2017
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36. Plötzlicher Herztod

Author

Rudic, B., primary, Tülümen, E., additional, Liebe, V., additional, Kuschyk, J., additional, Akin, I., additional, and Borggrefe, M., additional

Published
2017
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43. Early repolarization pattern is associated with ventricular fibrillation in patients with acute myocardial infarction.

Author

Rudic B, Veltmann C, Kuntz E, Behnes M, Elmas E, Konrad T, Kuschyk J, Weiss C, Borggrefe M, Schimpf R, Rudic, Boris, Veltmann, Christian, Kuntz, Esther, Behnes, Michael, Elmas, Elif, Konrad, Torsten, Kuschyk, Jürgen, Weiss, Christel, Borggrefe, Martin, and Schimpf, Rainer

Abstract

Background: For years early repolarization (ER) has been considered as a benign electrocardiographic finding. However, recent reports show that ER is associated with a higher incidence of ventricular fibrillation (VF) and sudden cardiac death in patients without structural heart disease. Sporadic case studies have pointed out that ER might be related to an adverse outcome in patients with stable coronary artery disease.Objective: To evaluate the incidence of ER in patients with acute myocardial infarction complicated by VF.Methods: The study population consisted of 60 patients (80% men; mean age 61.8 ± 13.1 years) with acute myocardial infarction. Thirty consecutive patients (80% men; mean age 63.3 ± 12 years) admitted to our hospital had documented VF during myocardial infarction and were successfully resuscitated before hospital admission. A matched control group consisted of 30 patients (80% men; mean age 60.2 ± 14.2 years) with myocardial infarction without ventricular tachyarrhythmias. Twelve-lead electrocardiograms were analyzed for ER defined as J-point elevation ≥ 0.1 mV and "notching" and "slurring" of the terminal part of the QRS complex in at least 2 lateral or inferior leads.Results: The ER pattern was observed in 18 of the 60 patients with acute myocardial infarction. Mean elevation of the J point was 0.151 ± 0.46 mV. Notching of the J wave was observed in 14 of the 18 patients and slurring in 4 of the 18 patients. ER was more common in patients with myocardial infarction complicated by VF than in patients with myocardial infarction without ventricular tachyarrhythmias (47% vs 13%; P = .005). There have been no statistical differences in the distribution of ER in the 12-lead electrocardiogram (inferior 39% vs lateral 33% vs inferolateral 28%; P >.05).Conclusion: Early repolarization pattern seems to be associated with ventricular tachyarrhythmias in the setting of acute myocardial infarction. [ABSTRACT FROM AUTHOR]

Published
2012
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44. Drug-induced QT-interval shortening following antiepileptic treatment with oral rufinamide.

Author

Schimpf R, Veltmann C, Papavassiliu T, Rudic B, Göksu T, Kuschyk J, Wolpert C, Antzelevitch C, Ebner A, Borggrefe M, Brandt C, Schimpf, Rainer, Veltmann, Christian, Papavassiliu, Theano, Rudic, Boris, Göksu, Turgay, Kuschyk, Jürgen, Wolpert, Christian, Antzelevitch, Charles, and Ebner, Alois

Abstract

Background: The arrhythmogenic potential of short QT intervals has recently been highlighted in patients with a short QT syndrome. Drug-induced QT-interval prolongation is a known risk factor for ventricular tachyarrhythmias. However, reports on drug-induced QT-interval shortening are rare and proarrhythmic effects remain unclear.Objective: Recently, rufinamide, a new antiepileptic drug for the add-on treatment of Lennox-Gastaut syndrome, was approved in the European Union and the United States. Initial trials showed drug-induced QT-interval shortening. The aim of our study was to evaluate the effects of rufinamide on QT intervals in patients with difficult-to-treat epilepsies.Methods: Nineteen consecutive patients with Lennox-Gastaut syndrome and other epilepsy syndromes were included (n = 12 men; mean age 41 ± 12 years). QRS, QT, and T(peak)-T(end) intervals were analyzed before and during rufinamide treatment.Results: The mean QT interval shortened significantly following rufinamide administration (QT interval 349 ± 23 ms vs 327 ± 17 ms; corrected QT interval 402 ± 22 ms vs 382 ± 16 ms; P = .002). T(peak)-T(end) intervals were 79 ± 17 ms before and 70 ± 20 ms on treatment (P = .07). The mean reduction of the corrected QT interval was 20 ± 18 ms. During follow-up (3.04 ± 1.09 years), no adverse events including symptomatic cardiac arrhythmias or sudden cardiac deaths were observed.Conclusion: QTc-interval shortening following oral rufinamide administration in a small patient group was not associated with significant clinical adverse effects. These observations notwithstanding, the ability of rufinamide to significantly shorten the QT interval portends a potential arrhythmogenic risk that may best be guarded against by periodic electrocardiographic recordings. [ABSTRACT FROM AUTHOR]

Published
2012
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48. Septal myocardial scar burden predicts the response to cardiac contractility modulation in patients with heart failure

Author

Uzair Ansari, Daniel Overhoff, Daniel Burkhoff, Christian Fastner, Gökhan Yücel, Susanne Röger, Boris Rudic, Volker Liebe, Martin Borggrefe, Ibrahim Akin, Jürgen Kuschyk, Theano Papavassiliu, Erol Tülümen, Tülümen, Erol, Ansari, U., Overhoff, D., Burkhoff, D., Fastner, C., Yücel, G., Röger, S., Rudic, B., Liebe, V., Borggrefe, M., Akın, I., Kuschyk, J., Papavassiliu, T., Koç University Hospital, and School of Medicine

Subjects
Heart Failure, Cicatrix, Multidisciplinary, Humans, Contrast Media, Stroke Volume, Gadolinium, Science and technology, Contrast media, Heart failure, Ventricular Function, Left
Abstract

We hypothesized that myocardial septal scarring, assessed by cardiac magnetic resonance (CMR) using late gadolinium enhancement (LGE), at the site of cardiac contractility modulation (CCM) lead placement may predict treatment response. Eligible heart failure (HF) patients underwent LGE CMR imaging before CCM device implantation. The response to CCM therapy at follow-up was determined by a change in NYHA class and echocardiographic left ventricular ejection fraction (LVEF) assessment. Patients were classified as responders, if they showed an improvement in either NYHA class or improvement of LVEF by >= 5%. 58 patients were included. 67% of patients were classified as responders according to improved NYHA; 55% according to LVEF improvement. 74% of patients were responders if either NYHA class or LVEF improvement was observed. 90% of responders (according to NYHA class) showed septal LGE < 25% at septal position of the leads, while 44% of non-responders showed septal LGE > 25% (p < 0.01). In patients treated with CCM, an improvement of NYHA class was observed when leads were placed at myocardial segments with a CMR- LGE burden less than 25%., Open Access funding enabled and organized by Projekt DEAL

Published
2022

49. 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

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

Author

Charles Antzelevitch, Ahmad S. Amin, Bo Gregers Winkel, Dan M. Roden, Stefan Kääb, Jonathan R. Skinner, Seiko Ohno, Julien Barc, Birgit Stallmeyer, Carla Giustetto, Connie R. Bezzina, Francesco Mazzarotto, Tomas Robyns, Carlo Napolitano, Stellan Mörner, Doris Škorić-Milosavljević, Sven Dittmann, Kenichiro Yamagata, Sonia Van Dooren, Anniek Corveleyn, Carlo de Asmundis, Ramon Brugada, K Usuda, Yuji Tanaka, Sven Zumhagen, Tadashi Nakajima, Johan Saenen, Elijah R. Behr, Hector Barajas-Martinez, Stéphane Bézieau, Masao Yoshinaga, Georgia Sarquella-Brugada, Paul G.A. Volders, Juan R. Gimeno, Lia Crotti, Charlotte Glinge, Andrea Mazzanti, Ingrid P.C. Krapels, Nicola Whiffin, Sebastian Clauss, Yoshiaki Kaneko, James S. Ware, Minoru Horie, Keiko Shimamoto, Isabelle Denjoy, Pieter G. Postema, Christian Krijger, Takeshi Aiba, Masahiko Kurabayashi, Pyotr G. Platonov, Regina Sebastiano, Cristina Gil Ortuño, Annika Rydberg, Roddy Walsh, Michael J. Ackerman, Hideki Itoh, M. Benjamin Shoemaker, Can Hasdemir, Pascale Guicheney, J. Martijn Bos, Frederic Sacher, Takeru Makiyama, Julieta Lazarte, Maarten P. van den Berg, Dominique Babuty, David J. Tester, Silvia Castelletti, Jacques Mansourati, Antoine Leenhardt, Paul A. van der Zwaag, Sanjay Sharma, Elena Arbelo, Candan Celen, Pier D. Lambiase, Maria Christina Kotta, Johannes Steinfurt, Jean-Baptiste Gourraud, Pedro Brugada, Wataru Shimizu, Josep Brugada, Jørgen K. Kanters, Eline A. Nannenberg, Silvia G. Priori, Mary N. Sheppard, Richard Redon, Morten S. Olesen, Jeroen Breckpot, Britt M. Beckmann, Naomasa Makita, Martin Borggrefe, Rafik Tadros, Jean-Jacques Schott, Jacob Tfelt-Hansen, Steven A. Lubitz, Hatice Şahin, Najim Lahrouchi, Michael Papadakis, Daisuke Hazeki, Kenshi Hayashi, Oscar Campuzano, Katja E. Odening, Federica Dagradi, Eric Schulze-Bahr, Boris Rudic, Hiroki Kimoto, Vincent Probst, Jason D. Roberts, Raphaël P. Martins, Bart Loeys, Daniela F. Giachino, F. Kyndt, Kimie Ohkubo, Taisuke Ishikawa, Catarina Lundin, Lut Van Laer, Patrick T. Ellinor, Maria Sabater Molina, Peter J. Schwartz, Annika Winbo, Wellcome Trust, Rosetrees Trust, British Heart Foundation, 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, 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)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Pontchaillou [Rennes], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ege Üniversitesi, Cardiovascular Centre (CVC), Nantes Referral Ctr Inherited Car, Cardiology, Graduate School, ACS - Heart failure & arrhythmias, Human Genetics, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, MUMC+: DA KG Polikliniek (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical sciences, Heartrhythmmanagement, Medical Genetics, Reproduction and Genetics, and Cardio-vascular diseases

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Nantes Referral Center for inherited cardiac arrhythmia, Disease, Arrhythmias, 030105 genetics & heredity, ACMG/AMP guidelines, Brugada, LQTS, variant interpretation, Medicine, Genetics (clinical), Brugada Syndrome, Brugada syndrome, Genetics, Genetics & Heredity, education.field_of_study, medicine.diagnostic_test, Molecular pathology, 3. Good health, Long QT Syndrome, Medical genetics, Population Control, Cardiology and Cardiovascular Medicine, Cardiac, Medical Genetics, Life Sciences & Biomedicine, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Long QT syndrome, Population, 610 Medicine & health, BIO/18 - GENETICA, Article, 03 medical and health sciences, Humans, Genetic Testing, cardiovascular diseases, education, Medicinsk genetik, Genetic testing, 0604 Genetics, Science & Technology, business.industry, Genetic heterogeneity, MUTATIONS, ACMG/AMP guideline, Arrhythmias, Cardiac, 1103 Clinical Sciences, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Mutation, 030104 developmental biology, Human medicine, business
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 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 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., Amsterdam Cardiovascular Sciences fellowship; Dutch Heart Foundation (CVON Predict-2/Concor-genes); Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [VICI 016.150.610]; Fondation LeducqLeducq Foundation, R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. C.R.B. is supported by the Dutch Heart Foundation (CVON Predict-2/Concor-genes), Netherlands Organization for Scientific Research (VICI 016.150.610), and Fondation Leducq. See Supplement for all Acknowledgements.

Published
2020

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