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1. BIO FOr CARE: biomarkers of hypertrophic cardiomyopathy development and progression in carriers of Dutch founder truncating MYBPC3 variants—design and status

Author

Jansen, M. (M.), Christiaans, I. (Imke), van der Crabben, S.N. (Saskia N.), Michels, M. (Michelle), Huurman, R. (Roy), Hoedemaekers, Y.M. (Yvonne), Dooijes, D. (D.), Jongbloed, J.D.H. (Jan), Boven, L.G. (Ludolf), Lekanne Deprez, R.H., Wilde, A.A.M. (Arthur), Jans, J. (Judith), Velden, J. (Jolanda) van der, Boer, R.A. (Rudolf) de, van Tintelen, J.P. (J. P.), Asselbergs, F.W. (F. W.), Baas, A.F. (A. F.), Jansen, M. (M.), Christiaans, I. (Imke), van der Crabben, S.N. (Saskia N.), Michels, M. (Michelle), Huurman, R. (Roy), Hoedemaekers, Y.M. (Yvonne), Dooijes, D. (D.), Jongbloed, J.D.H. (Jan), Boven, L.G. (Ludolf), Lekanne Deprez, R.H., Wilde, A.A.M. (Arthur), Jans, J. (Judith), Velden, J. (Jolanda) van der, Boer, R.A. (Rudolf) de, van Tintelen, J.P. (J. P.), Asselbergs, F.W. (F. W.), and Baas, A.F. (A. F.)

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited. Aim: To create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression. Methods: In the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827C > T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥ 20 mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death). Results: So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects. Conclusion: BIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium.

Published
2021
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2. Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration

Author

Cadrin-Tourigny, J. (Julia), Bosman, L.P. (Laurens P.), Wang, W. (Weijia), Tadros, R. (Rafik), Bhonsale, A. (Aditya), Bourfiss, M. (Mimount), Lie, ØH. (Øyvind H), Saguner, A.M. (Ardan M.), Svensson, A. (Anneli), Andorin, A. (Antoine), Tichnell, C. (Crystal), Murray, B. (Brittney), Zeppenfeld, K. (Katja), Berg, M.P. (Maarten) van den, Asselbergs, F.W. (Folkert W.), Wilde, A.A.M. (Arthur), Krahn, A.D. (Andrew D.), Talajic, M. (Mario), Rivard, L. (Lena), Chelko, S. (Stephen), Zimmerman, S.L. (Stefan L.), Kamel, M.S. (Mohamed), Crosson, J.E. (Jane E.), Judge, D.P. (Daniel), Yap, S.-C. (Sing-Chien), Van der Heijden, J.F. (Jeroen F.), Tandri, H. (Harikrishna), Jongbloed, J.D.H. (Jan), van Tintelen, J.P. (J Peter), Platonov, P.G. (Pyotr G.), Duru, F. (Firat), Haugaa, K.H. (Kristina H.), Khairy, P. (Paul), Hauer, R.N.W. (Richard), Calkins, H. (Hugh), Riele, A.S. (Anneline) te, James, C.A. (Cynthia A.), Cadrin-Tourigny, J. (Julia), Bosman, L.P. (Laurens P.), Wang, W. (Weijia), Tadros, R. (Rafik), Bhonsale, A. (Aditya), Bourfiss, M. (Mimount), Lie, ØH. (Øyvind H), Saguner, A.M. (Ardan M.), Svensson, A. (Anneli), Andorin, A. (Antoine), Tichnell, C. (Crystal), Murray, B. (Brittney), Zeppenfeld, K. (Katja), Berg, M.P. (Maarten) van den, Asselbergs, F.W. (Folkert W.), Wilde, A.A.M. (Arthur), Krahn, A.D. (Andrew D.), Talajic, M. (Mario), Rivard, L. (Lena), Chelko, S. (Stephen), Zimmerman, S.L. (Stefan L.), Kamel, M.S. (Mohamed), Crosson, J.E. (Jane E.), Judge, D.P. (Daniel), Yap, S.-C. (Sing-Chien), Van der Heijden, J.F. (Jeroen F.), Tandri, H. (Harikrishna), Jongbloed, J.D.H. (Jan), van Tintelen, J.P. (J Peter), Platonov, P.G. (Pyotr G.), Duru, F. (Firat), Haugaa, K.H. (Kristina H.), Khairy, P. (Paul), Hauer, R.N.W. (Richard), Calkins, H. (Hugh), Riele, A.S. (Anneline) te, and James, C.A. (Cynthia A.)

Abstract

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD. METHODS: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping. RESULTS: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77-10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (P=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69-0.80) and calibration slope of 0.95 (95% CI, 0.94-0.98) indicating minimal over-optimism. CONCLUSION

Published
2021
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3. In Children and Adolescents from Brugada Syndrome-Families, only SCN5A Mutation Carriers Develop a Type-1 ECG Pattern Induced by Fever

Author

Peltenburg, P.J. (Puck J.), Blom, N.A. (Nico), Vink, A.S. (Arja S.), Kammeraad, J.A.E. (Janneke), Breur, H.J.M.P.J. (Hans J.M.P.J.), Rammeloo, L. (Lukas), Wilde, A.A.M. (Arthur), Clur, S.A. (Sally-Ann), Peltenburg, P.J. (Puck J.), Blom, N.A. (Nico), Vink, A.S. (Arja S.), Kammeraad, J.A.E. (Janneke), Breur, H.J.M.P.J. (Hans J.M.P.J.), Rammeloo, L. (Lukas), Wilde, A.A.M. (Arthur), and Clur, S.A. (Sally-Ann)

Published
2020
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4. The Netherlands Arrhythmogenic Cardiomyopathy Registry: design and status update

Author

Bosman, L.P. (L. P.), Verstraelen, T.E. (T. E.), van Lint, F.H.M. (F. H.M.), Cox, M.G.P.J. (Moniek), Groeneweg, J.A. (Judith), Mast, T.P. (T. P.), Zwaag, P.A. (Paul) van der, Volders, P.G.A. (Paul), Evertz, R. (Reinder), Wong, L. (L.), Groot, N.M.S. (Natasja) de, Zeppenfeld, K. (Katja), Heijden, J.F. (Jeroen) van der, Berg, M.P. (Maarten) van den, Wilde, A.A.M. (Arthur), Asselbergs, F.W. (Folkert), Hauer, R.N.W. (Richard), Riele, A.S. (Anneline) te, van Tintelen, J.P. (J. P.), Baas, A.F. (A. F.), Barge-Schaapveld, D.Q.C.M. (Daniela), Boekholdt, S.M. (Matthijs), Cramer, M.J.M. (M. J.M.), Dooijes, D. (D.), Jongbloed, J.D.H. (Jan), Loh, P. (Peter), Planken, R.N. (R. N.), Prakken, N.H.J. (N. H.J.), Smagt, J.J. (Jasper) van der, van der Wal, A.C. (A. C.), Teske, A.J. (A. J.), Veen, T.A.B. (Toon) van, Velthuis, B.K. (Birgitta), Vink, A. (Ard), Yap, S.C. (S. C.), Bosman, L.P. (L. P.), Verstraelen, T.E. (T. E.), van Lint, F.H.M. (F. H.M.), Cox, M.G.P.J. (Moniek), Groeneweg, J.A. (Judith), Mast, T.P. (T. P.), Zwaag, P.A. (Paul) van der, Volders, P.G.A. (Paul), Evertz, R. (Reinder), Wong, L. (L.), Groot, N.M.S. (Natasja) de, Zeppenfeld, K. (Katja), Heijden, J.F. (Jeroen) van der, Berg, M.P. (Maarten) van den, Wilde, A.A.M. (Arthur), Asselbergs, F.W. (Folkert), Hauer, R.N.W. (Richard), Riele, A.S. (Anneline) te, van Tintelen, J.P. (J. P.), Baas, A.F. (A. F.), Barge-Schaapveld, D.Q.C.M. (Daniela), Boekholdt, S.M. (Matthijs), Cramer, M.J.M. (M. J.M.), Dooijes, D. (D.), Jongbloed, J.D.H. (Jan), Loh, P. (Peter), Planken, R.N. (R. N.), Prakken, N.H.J. (N. H.J.), Smagt, J.J. (Jasper) van der, van der Wal, A.C. (A. C.), Teske, A.J. (A. J.), Veen, T.A.B. (Toon) van, Velthuis, B.K. (Birgitta), Vink, A. (Ard), and Yap, S.C. (S. C.)

Abstract

Background: Clinical research on arrhythmogenic cardiomyopathy (ACM) is typically limited by small patient numbers, retrospective study designs, and inconsistent definitions. Aim: To create a large national ACM patient cohort with a vast amount of uniformly collected high-quality data that is readily available for future research. Methods: This is a multicentre, longitudinal, observational cohort study that includes (1) patients with a definite ACM diagnosis, (2) at-risk relatives of ACM patients, and (3) ACM-associated mutation carriers. At baseline and every follow-up visit, a medical history as well information regarding (non-)invasive tests is collected (e. g. electrocardiograms, Holter recordings, imaging and electrophysiological studies, pathology reports, etc.). Outcome data include (non-)sustained ventricular and atrial arrhythmias, heart failure, and (cardiac) death. Data are collected on a research electronic data capture (REDCap) platform in which every participating centre has its own restricted data access group, thus empowering local studies while facilitating data sharing. Discussion: The Netherlands ACM Registry is a national observational cohort study of ACM patients and relatives. Prospective and retrospective data are obtained at multiple time points, enabling both cross-sectional and longitudinal research in a hypothesis-generating approach that extends beyond one specific research question. In so doing, this registry aims to (1) increase the scientific knowledge base on disease mechanisms, genetics, and novel diagnostic and treatment strategies of ACM; and (2) provide education for physicians and patients concerning ACM, e. g. through our website (www.acmregistry.nl) and patient conferences.

Published
2019
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5. Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores

Author

Tadros, R. (Rafik), Tan, H.L. (Hanno), El Mathari, S. (Sulayman), Kors, J.A. (Jan), Postema, P.G. (Pieter), Lahrouchi, N. (Najim), Beekman, L. (Leander), Radivojkov-Blagojevic, M. (Milena), Amin, A.S. (Ahmad S.), Meitinger, T. (Thomas), Tanck, M.W.T. (Michael), Wilde, A.A.M. (Arthur), Bezzina, C.R. (Connie R.), Tadros, R. (Rafik), Tan, H.L. (Hanno), El Mathari, S. (Sulayman), Kors, J.A. (Jan), Postema, P.G. (Pieter), Lahrouchi, N. (Najim), Beekman, L. (Leander), Radivojkov-Blagojevic, M. (Milena), Amin, A.S. (Ahmad S.), Meitinger, T. (Thomas), Tanck, M.W.T. (Michael), Wilde, A.A.M. (Arthur), and Bezzina, C.R. (Connie R.)

Abstract

AIMS: Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG). METHODS AND RESULTS: In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose-response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P < 0.01 for all). PRSBrS, baseline QRS duration, presence of Type II or III BrS ECG at baseline, and family history of BrS are independently associated with the occurrence of a Type I BrS ECG, with good predictive accuracy (optimism-corrected C-statistic 0.74). CONCLUSION: We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a

Published
2019
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6. A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy

Author

Cadrin-Tourigny, J. (Julia), Bosman, L.P. (Laurens P.), Nozza, A. (Anna), Wang, W. (Weijia), Tadros, R. (Rafik), Bhonsale, A. (Aditya), Bourfiss, M. (Mimount), Fortier, A. (Annik), Lie, ØH. (Øyvind H), Saguner, A.M. (Ardan M.), Svensson, A. (Anneli), Andorin, A. (Antoine), Tichnell, C. (Crystal), Murray, B. (Brittney), Zeppenfeld, K. (Katja), Berg, M.P. (Maarten) van den, Asselbergs, F.W. (Folkert), Wilde, A.A.M. (Arthur), Krahn, A.D. (Andrew D.), Talajic, M. (Mario), Rivard, L. (Lena), Chelko, S. (Stephen), Zimmerman, S.L. (Stefan), Kamel, M.S. (Mohamed), Crosson, J.E. (Jane E.), Judge, D.P. (Daniel), Yap, S.-C. (Sing-Chien), Heijden, J.F. (Jeroen) van der, Tandri, H. (Harikrishna), Jongbloed, J.D.H. (Jan), Guertin, M.-C. (Marie-Claude), Tintelen, J.P. (Peter) van, Platonov, P.G. (Pyotr G.), Duru, F. (Firat), Haugaa, K.H. (Kristina H.), Khairy, P. (Paul), Hauer, R.N.W. (Richard), Calkins, H. (Hugh), Riele, A.S. (Anneline) te, James, C.A. (Cynthia), Cadrin-Tourigny, J. (Julia), Bosman, L.P. (Laurens P.), Nozza, A. (Anna), Wang, W. (Weijia), Tadros, R. (Rafik), Bhonsale, A. (Aditya), Bourfiss, M. (Mimount), Fortier, A. (Annik), Lie, ØH. (Øyvind H), Saguner, A.M. (Ardan M.), Svensson, A. (Anneli), Andorin, A. (Antoine), Tichnell, C. (Crystal), Murray, B. (Brittney), Zeppenfeld, K. (Katja), Berg, M.P. (Maarten) van den, Asselbergs, F.W. (Folkert), Wilde, A.A.M. (Arthur), Krahn, A.D. (Andrew D.), Talajic, M. (Mario), Rivard, L. (Lena), Chelko, S. (Stephen), Zimmerman, S.L. (Stefan), Kamel, M.S. (Mohamed), Crosson, J.E. (Jane E.), Judge, D.P. (Daniel), Yap, S.-C. (Sing-Chien), Heijden, J.F. (Jeroen) van der, Tandri, H. (Harikrishna), Jongbloed, J.D.H. (Jan), Guertin, M.-C. (Marie-Claude), Tintelen, J.P. (Peter) van, Platonov, P.G. (Pyotr G.), Duru, F. (Firat), Haugaa, K.H. (Kristina H.), Khairy, P. (Paul), Hauer, R.N.W. (Richard), Calkins, H. (Hugh), Riele, A.S. (Anneline) te, and James, C.A. (Cynthia)

Abstract

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

Published
2019
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7. Subsequent Event Risk in Individuals With Established Coronary Heart Disease

Author

Patel, R.S. (Riyaz), Tragante, V. (Vinicius), Schmidt, A.F. (Amand), McCubrey, R.O. (Raymond O.), Holmes, M.V. (Michael), Howe, L.J. (Laurence J.), Direk, K. (Kenan), Åkerblom, A. (Axel), Leander, K. (Karin), Virani, S.S. (Salim), Kaminski, K.A. (Karol A.), Muehlschlegel, J.D. (Jochen), Allayee, H. (Hooman), Almgren, P. (Peter), Alver, M. (Maris), Baranova, E.V. (Ekaterina V.), Behloui, H. (Hassan), Boeckx, B. (Bram), Braund, P.S. (Peter), Breitling, L.P. (Lutz), Delgado, G., Duarte, N.E. (Nubia E.), Dubé, G.P. (Gregory), Dufresne, L. (Line), Eriksson, N. (Niclas), Foco, L. (Luisa), Scholz, M. (Markus), Gijsberts, C.M. (Crystel M.), Glinge, C. (Charlotte), Gong, Y. (Yan), Hartiala, J. (Jaana), Heydarpour, M. (Mahyar), Hubacek, J.A. (Jaroslav A.), Kleber, M.E. (Marcus), Kofink, D. (Daniel), Kotti, S. (Salma), Kuukasjärvi, P. (Pekka), Lee, V.-V. (Vei-Vei), Leiherer, A. (Andreas), Lenzini, P.A. (Petra A.), Levin, D. (Daniel), Lyytikäinen, L.-P. (Leo-Pekka), Martinelli, N. (Nicola), Mons, U. (Ute), Nelson, C.P. (Christopher P.), Nikus, K. (Kjell), Pilbrow, A.P. (Anna P.), Ploski, R. (Rafal), Sun, Y.V. (Yan V.), Tanck, M.W.T. (Michael), Tang, W. (W.), Trompet, S. (Stella), van der Laan, S.W. (Sander W.), Setten, J. (Jessica) van, Vilmundarson, R.O. (Ragnar O.), Viviani Anselmi, C. (Chiara), Vlachopoulou, E. (Efthymia), Al Ali, L. (Lawien), Boerwinkle, E.A. (Eric), Briguori, C. (Carlo), Carlquist, J.F. (John), Carruthers, K.F. (Kathryn), Casu, G. (Gavino), Deanfield, J. (John), Deloukas, P. (Panos), Dudbridge, F. (Frank), Engstrøm, T. (Thomas), Fitzpatrick, N. (Natalie), Fox, K.M. (Kim), Gigante, B. (Bruna), James, S.K. (Stefan), Lokki, M.-L. (Marja-Liisa), Lotufo, P.A. (Paulo A.), Marziliano, N. (Nicola), Mordi, I.R. (Ify R.), Muhlestein, J.B. (Joseph), Newton-Cheh, C. (Christopher), Pitha, J. (Jan), Saely, C.H. (Christoph H.), Samman-Tahhan, A. (Ayman), Sandesara, P.B. (Pratik B.), Teren, A. (Andrej), Timmis, A. (Adam), Van de Werf, F. (Frans), Wilde, A.A.M. (Arthur), Ford, I. (Ian), Stott, D.J. (David. J.), Algra, A. (Ale), Andreassi, M.G. (Maria G.), Ardissino, D. (Diego), Arsenault, B.J. (Benoit J.), Ballantyne, C. (Christie), Bergmeijer, T.O. (Thomas O.), Bezzina, C.R. (Connie R.), Body, S.C. (Simon C.), Boersma, E.H. (Eric H.), Bogaty, P. (Peter), Bots, M.L. (Michiel), Brenner, H. (Hermann), Brugts, J.J. (Jasper), Burkhardt, R. (Ralph), Carpeggiani, C. (Clara), Condorelli, G. (Gianluigi), Cooper-Dehoff, R.M. (Rhonda), Cresci, S. (Sharon), Danchin, N. (Nicolas), Faire, U. (Ulf) de, Doughty, R.N. (Robert N.), Drexel, H. (Heinz), Engert, J.C. (James C.), Fox, K.A.A. (Keith), Girelli, D. (Domenico), Grobbee, D.E. (Diederick E.), Hagström, E. (Emil), Hazen, S.L. (Stanley), Held, C. (Claes), Hemingway, H., Hoefer, I.E. (Imo), Hovingh, G.K. (G Kees), Jabbari, R. (Reza), Johnson, J.A. (Jennifer ), Jukema, J.W. (Jan Wouter), Kaczor, M.P. (Marcin P.), Kähönen, M. (Mika), Kettner, J. (Jiri), Kiliszek, M. (Marek), Klungel, O.H. (Olaf), Lagerqvist, B. (Bo), Lambrechts, D. (Diether), Laurikka, J.O. (Jari O.), Lehtimäki, T. (Terho), Lindholm, D. (Daniel), Mahmoodi, B.K. (Bakhtawar K.), Maitland-van der Zee, A-H. (Anke-Hilse), McPherson, R. (Ruth), Melander, O. (Olle), Metspalu, A. (Andres), Niemcunowicz-Janica, A. (Anna), Olivieri, O. (Oliviero), Opolski, G. (Grzegorz), Palmer, C.N.A. (Colin), Pasterkamp, G. (Gerard), Pepine, C.J. (Carl), Pereira, A. (A.), Pilote, L. (Louise), Erdmann, J. (Jeanette), Richards, A.M. (A Mark), Sanak, M. (Marek), Siegbahn, A. (Agneta), Simon, T. (Tabassome), Sinisalo, J. (Juha), Smith, J.G. (J Gustav), Schwartz, S.M. (Stephen), Stender, S. (Steen), Stewart, A.F. (Alexandre F.), Szczeklik, W. (Wojciech), Szpakowicz, A. (Anna), Tardif, J.-C. (Jean-Claude), Berg, J.M. (Jurrien) ten, Tfelt-Hansen, J. (Jacob), Thanassoulis, G. (George), Thiery, J.P. (Joachim), Torp-Pedersen, C. (Christian Tobias), Graaf, Y. (Yolanda) van der, Visseren, F.L.J. (Frank), Waltenberger, J. (Johannes), Weeke, P.E. (Peter E.), Harst, P. (Pim) van der, Lang, C.C. (Chim C.), Sattar, N. (Naveed), Cameron, V.A. (Vicky A.), Anderson, J.L. (Jeffrey), Brophy, J.M. (James M.), Pare, G. (Guillame), Horne, B.D. (Benjamin), Ye, S. (Shu), Wallentin, L. (Lars), Wauters, E. (Els), Samani, N.J. (Nilesh), Hingorani, A. (Aroon), Asselbergs, F.W. (Folkert), Patel, R.S. (Riyaz), Tragante, V. (Vinicius), Schmidt, A.F. (Amand), McCubrey, R.O. (Raymond O.), Holmes, M.V. (Michael), Howe, L.J. (Laurence J.), Direk, K. (Kenan), Åkerblom, A. (Axel), Leander, K. (Karin), Virani, S.S. (Salim), Kaminski, K.A. (Karol A.), Muehlschlegel, J.D. (Jochen), Allayee, H. (Hooman), Almgren, P. (Peter), Alver, M. (Maris), Baranova, E.V. (Ekaterina V.), Behloui, H. (Hassan), Boeckx, B. (Bram), Braund, P.S. (Peter), Breitling, L.P. (Lutz), Delgado, G., Duarte, N.E. (Nubia E.), Dubé, G.P. (Gregory), Dufresne, L. (Line), Eriksson, N. (Niclas), Foco, L. (Luisa), Scholz, M. (Markus), Gijsberts, C.M. (Crystel M.), Glinge, C. (Charlotte), Gong, Y. (Yan), Hartiala, J. (Jaana), Heydarpour, M. (Mahyar), Hubacek, J.A. (Jaroslav A.), Kleber, M.E. (Marcus), Kofink, D. (Daniel), Kotti, S. (Salma), Kuukasjärvi, P. (Pekka), Lee, V.-V. (Vei-Vei), Leiherer, A. (Andreas), Lenzini, P.A. (Petra A.), Levin, D. (Daniel), Lyytikäinen, L.-P. (Leo-Pekka), Martinelli, N. (Nicola), Mons, U. (Ute), Nelson, C.P. (Christopher P.), Nikus, K. (Kjell), Pilbrow, A.P. (Anna P.), Ploski, R. (Rafal), Sun, Y.V. (Yan V.), Tanck, M.W.T. (Michael), Tang, W. (W.), Trompet, S. (Stella), van der Laan, S.W. (Sander W.), Setten, J. (Jessica) van, Vilmundarson, R.O. (Ragnar O.), Viviani Anselmi, C. (Chiara), Vlachopoulou, E. (Efthymia), Al Ali, L. (Lawien), Boerwinkle, E.A. (Eric), Briguori, C. (Carlo), Carlquist, J.F. (John), Carruthers, K.F. (Kathryn), Casu, G. (Gavino), Deanfield, J. (John), Deloukas, P. (Panos), Dudbridge, F. (Frank), Engstrøm, T. (Thomas), Fitzpatrick, N. (Natalie), Fox, K.M. (Kim), Gigante, B. (Bruna), James, S.K. (Stefan), Lokki, M.-L. (Marja-Liisa), Lotufo, P.A. (Paulo A.), Marziliano, N. (Nicola), Mordi, I.R. (Ify R.), Muhlestein, J.B. (Joseph), Newton-Cheh, C. (Christopher), Pitha, J. (Jan), Saely, C.H. (Christoph H.), Samman-Tahhan, A. (Ayman), Sandesara, P.B. (Pratik B.), Teren, A. (Andrej), Timmis, A. (Adam), Van de Werf, F. (Frans), Wilde, A.A.M. (Arthur), Ford, I. (Ian), Stott, D.J. (David. J.), Algra, A. (Ale), Andreassi, M.G. (Maria G.), Ardissino, D. (Diego), Arsenault, B.J. (Benoit J.), Ballantyne, C. (Christie), Bergmeijer, T.O. (Thomas O.), Bezzina, C.R. (Connie R.), Body, S.C. (Simon C.), Boersma, E.H. (Eric H.), Bogaty, P. (Peter), Bots, M.L. (Michiel), Brenner, H. (Hermann), Brugts, J.J. (Jasper), Burkhardt, R. (Ralph), Carpeggiani, C. (Clara), Condorelli, G. (Gianluigi), Cooper-Dehoff, R.M. (Rhonda), Cresci, S. (Sharon), Danchin, N. (Nicolas), Faire, U. (Ulf) de, Doughty, R.N. (Robert N.), Drexel, H. (Heinz), Engert, J.C. (James C.), Fox, K.A.A. (Keith), Girelli, D. (Domenico), Grobbee, D.E. (Diederick E.), Hagström, E. (Emil), Hazen, S.L. (Stanley), Held, C. (Claes), Hemingway, H., Hoefer, I.E. (Imo), Hovingh, G.K. (G Kees), Jabbari, R. (Reza), Johnson, J.A. (Jennifer ), Jukema, J.W. (Jan Wouter), Kaczor, M.P. (Marcin P.), Kähönen, M. (Mika), Kettner, J. (Jiri), Kiliszek, M. (Marek), Klungel, O.H. (Olaf), Lagerqvist, B. (Bo), Lambrechts, D. (Diether), Laurikka, J.O. (Jari O.), Lehtimäki, T. (Terho), Lindholm, D. (Daniel), Mahmoodi, B.K. (Bakhtawar K.), Maitland-van der Zee, A-H. (Anke-Hilse), McPherson, R. (Ruth), Melander, O. (Olle), Metspalu, A. (Andres), Niemcunowicz-Janica, A. (Anna), Olivieri, O. (Oliviero), Opolski, G. (Grzegorz), Palmer, C.N.A. (Colin), Pasterkamp, G. (Gerard), Pepine, C.J. (Carl), Pereira, A. (A.), Pilote, L. (Louise), Erdmann, J. (Jeanette), Richards, A.M. (A Mark), Sanak, M. (Marek), Siegbahn, A. (Agneta), Simon, T. (Tabassome), Sinisalo, J. (Juha), Smith, J.G. (J Gustav), Schwartz, S.M. (Stephen), Stender, S. (Steen), Stewart, A.F. (Alexandre F.), Szczeklik, W. (Wojciech), Szpakowicz, A. (Anna), Tardif, J.-C. (Jean-Claude), Berg, J.M. (Jurrien) ten, Tfelt-Hansen, J. (Jacob), Thanassoulis, G. (George), Thiery, J.P. (Joachim), Torp-Pedersen, C. (Christian Tobias), Graaf, Y. (Yolanda) van der, Visseren, F.L.J. (Frank), Waltenberger, J. (Johannes), Weeke, P.E. (Peter E.), Harst, P. (Pim) van der, Lang, C.C. (Chim C.), Sattar, N. (Naveed), Cameron, V.A. (Vicky A.), Anderson, J.L. (Jeffrey), Brophy, J.M. (James M.), Pare, G. (Guillame), Horne, B.D. (Benjamin), Ye, S. (Shu), Wallentin, L. (Lars), Wauters, E. (Els), Samani, N.J. (Nilesh), Hingorani, A. (Aroon), and Asselbergs, F.W. (Folkert)

Abstract

BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants a

Published
2019
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8. International external validation study of the 2014 European society of cardiology guidelines on sudden cardiac death prevention in hypertrophic cardiomyopathy (EVIDENCE-HCM)

Author

O'Mahony, C. (Constantinos), Jichi, F. (Fatima), Ommen, S.R. (Steve R.), Christiaans, I. (Imke), Arbustini, E. (Eloisa), Garcia-Pavia, P. (Pablo), Cecchi, F. (Franco), Olivotto, I. (Iacopo), Kitaoka, H. (Hiroaki), Gotsman, I. (Israel), Carr-White, G. (Gerald), Mogensen, J. (Jens), Antoniades, L. (Loizos), Mohiddin, S.A. (Saidi A.), Maurer, M.S. (Mathew S.), Tang, H.C. (Hak Chiaw), Geske, J.B. (Jeffrey B.), Siontis, K.C. (Konstantinos C.), Mahmoud, K.D. (Karim D.), Vermeer, A.M.C. (Alexa), Wilde, A.A.M. (Arthur), Favalli, V. (Valentina), Guttmann, O.P. (Oliver P.), Gallego-Delgado, M. (Maria), Dominguez, F. (Fernando), Tanini, I. (Ilaria), Kubo, T. (Toru), Keren, A. (Andre), Bueser, T. (Teofila), Waters, S. (Sarah), Issa, I.F. (Issa F.), Malcolmson, J. (James), Burns, T. (Tom), Sekhri, N. (Neha), Hoeger, C.W. (Christopher W.), Omar, R.Z. (Rumana Z.), Elliott, P.M. (Perry), O'Mahony, C. (Constantinos), Jichi, F. (Fatima), Ommen, S.R. (Steve R.), Christiaans, I. (Imke), Arbustini, E. (Eloisa), Garcia-Pavia, P. (Pablo), Cecchi, F. (Franco), Olivotto, I. (Iacopo), Kitaoka, H. (Hiroaki), Gotsman, I. (Israel), Carr-White, G. (Gerald), Mogensen, J. (Jens), Antoniades, L. (Loizos), Mohiddin, S.A. (Saidi A.), Maurer, M.S. (Mathew S.), Tang, H.C. (Hak Chiaw), Geske, J.B. (Jeffrey B.), Siontis, K.C. (Konstantinos C.), Mahmoud, K.D. (Karim D.), Vermeer, A.M.C. (Alexa), Wilde, A.A.M. (Arthur), Favalli, V. (Valentina), Guttmann, O.P. (Oliver P.), Gallego-Delgado, M. (Maria), Dominguez, F. (Fernando), Tanini, I. (Ilaria), Kubo, T. (Toru), Keren, A. (Andre), Bueser, T. (Teofila), Waters, S. (Sarah), Issa, I.F. (Issa F.), Malcolmson, J. (James), Burns, T. (Tom), Sekhri, N. (Neha), Hoeger, C.W. (Christopher W.), Omar, R.Z. (Rumana Z.), and Elliott, P.M. (Perry)

Abstract

BACKGROUND: Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia. METHODS: This was an observational, retrospective, longitudinal cohort study. RESULTS: The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9-3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93-1.12), C-index of 0.70 (95% CI, 0.68-0.72), and D-statistic of 1.17 (95% CI, 1.05-1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of <4% (n=1524; 71%) had an observed 5-year SCD incidence of 1.4% (95% CI, 0.8-2.2); patients with a predicted risk of ≥6% (n=297; 14%) had an observed SCD incidence of 8.9% (95% CI, 5.96-13.1) at 5 years. For every 13 (297/23) implantable cardioverter defibrillator implantations in patients with an estimated 5-year SCD risk ≥6%, 1 patient can potentially be saved from SCD. CONCLUSIONS: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD.

Published
2018
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9. Dutch outcome in implantable cardioverter-defibrillator therapy (DO-IT)

Author

Van Barreveld, M. (M.), Dijkgraaf, M.G.W. (Marcel), Hulleman, M. (M.), Boersma, L. (Lucas), Delnoy, P.P.H.M. (Peter Paul), Meine, M. (Mathias), Tuinenburg, A.E. (A. E.), Theuns, D.A.M.J. (Dominic), Voort, P. (Pepijn) van der, Kimman, G-J.P. (Geert-Jan), Buskens, E. (Erik), Tijssen, J.P.G. (J. P.G.), Bruinsma, N. (N.), Verstraelen, T.E. (T. E.), Zwinderman, A.H. (Ailko), Van Dessel, P.H.F.M. (P. H.F.M.), Wilde, A.A.M. (Arthur), Van Barreveld, M. (M.), Dijkgraaf, M.G.W. (Marcel), Hulleman, M. (M.), Boersma, L. (Lucas), Delnoy, P.P.H.M. (Peter Paul), Meine, M. (Mathias), Tuinenburg, A.E. (A. E.), Theuns, D.A.M.J. (Dominic), Voort, P. (Pepijn) van der, Kimman, G-J.P. (Geert-Jan), Buskens, E. (Erik), Tijssen, J.P.G. (J. P.G.), Bruinsma, N. (N.), Verstraelen, T.E. (T. E.), Zwinderman, A.H. (Ailko), Van Dessel, P.H.F.M. (P. H.F.M.), and Wilde, A.A.M. (Arthur)

Abstract

Background Implantable cardioverter-defibrillators (ICDs) are widely used for the prevention of sudden cardiac death. At present, both clinical benefit and cost-effectiveness of ICD therapy in primary prevention patients are topics of discussion, as only a minority of these patients will eventually receive appropriate ICD therapy. Methods/design The DO-IT Registry is a nationwide prospective cohort with a target enrolment of 1,500 primary prevention ICD patients with reduced left ventricular function in a setting of structural heart disease. The primary outcome measures are death and appropriate ICD therapy for ventricular tachyarrhythmias. Secondary outcome measures are inappropriate ICD therapy, death of any cause, hospitalisation for ICD related complications and for cardiovascular reasons. As of December 2016, data on demographic, clinical, and ICD characteristics of 1,468 patients have been collected. Follow-up will continue up to 24 months after inclusion of the last patient. During follow-up, clinical and ICD data are collected based on the normal follow-up of these patients, assuming ICD interrogations take place every six months and clinical follow-up is

Published
2017
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10. Risk stratification for sudden cardiac death: Current status and challenges for the future

Author

Wellens, H.J.J. (Hein), Schwartz, P.J. (Peter), Lindemans, F.W. (Fred), Buxton, A.E. (Alice), Goldberger, J.J. (Jeffrey), Hohnloser, S.H. (Stefan), Huikuri, H.V. (Heikki), Kääb, S. (Stefan), La Rovere, M.T. (Maria Teresa), Malik, M. (M.), Myerburg, R.J. (Robert), Simoons, M.L. (Maarten), Swedberg, K. (Karl), Tijssen, J.G.P. (Jan), Voors, A.A. (Adriaan), Wilde, A.A.M. (Arthur), Wellens, H.J.J. (Hein), Schwartz, P.J. (Peter), Lindemans, F.W. (Fred), Buxton, A.E. (Alice), Goldberger, J.J. (Jeffrey), Hohnloser, S.H. (Stefan), Huikuri, H.V. (Heikki), Kääb, S. (Stefan), La Rovere, M.T. (Maria Teresa), Malik, M. (M.), Myerburg, R.J. (Robert), Simoons, M.L. (Maarten), Swedberg, K. (Karl), Tijssen, J.G.P. (Jan), Voors, A.A. (Adriaan), and Wilde, A.A.M. (Arthur)

Abstract

Sudden cardiac death (SCD) remains a daunting problem. It is a major public health issue for several reasons: from its prevalence (20% of total mortality in the industrialized world) to the devastating psycho-social impact on society and on the families of victims often still in their prime, and it represents a challenge for medicine, and especially for cardiology. This text summarizes the discussions and opinions of a group of investigators with a long-standing interest in this field. We addressed the occurrence of SCD in individuals apparently healthy, in patients with heart disease and mild or severe cardiac dysfunction, and in those with genetically based arrhythmic diseases. Recognizing the need for more accurate registries of the global and regional distribution of SCD in these different categories, we focused on the assessment of risk for SCD in these four groups, looking at the significance of alterations in cardiac function, of signs of electrical instability identified by ECG abnormalities or by autonomic tests, and of the progressive impact of genetic screening. Special attention was given to the identification of areas of research more or less likely to provide useful information, and thereby more or less suitable for the investment of time and of research funds.

Published
2014
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11. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author

Arking, D.E. (Dan), Pulit, S.L. (Sara), Crotti, L. (Lia), Harst, P. (Pim) van der, Munroe, P. (Patricia), Koopmann, T.T. (Tamara), Sotoodehnia, N. (Nona), Rossin, E. (Elizabeth), Morley, M. (Michael), Wang, X. (Xinchen), Johnson, A.D. (Andrew), Lundby, A. (Alicia), Gudbjartsson, D.F. (Daniel), Noseworthy, P.A. (Peter), Eijgelsheim, M. (Mark), Bradford, Y. (Yuki), Tarasov, K.V. (Kirill), Dörr, M. (Marcus), Müller-Nurasyid, M. (Martina), Lahtinen, A.M. (Annukka), Nolte, I.M. (Ilja), Smith, A.V. (Davey), Bis, J.C. (Joshua), Isaacs, A.J. (Aaron), Newhouse, S.J. (Stephen), Evans, D.S. (Daniel), Post, W.S. (Wendy S.), Waggott, D. (Daryl), Lyytikäinen, L.-P. (Leo-Pekka), Hicks, A.A. (Andrew), Eisele, L. (Lewin), Ellinghaus, D. (David), Hayward, C. (Caroline), Navarro, P. (Pau), Ulivi, S. (Shelia), Tanaka, T. (Toshiko), Tester, D.J. (David), Chatel, S. (Stéphanie), Gustafsson, S. (Stefan), Kumari, M. (Meena), Morris, R.W. (Richard), Naluai, A.T. (Asa), Padmanabhan, S. (Sandosh), Kluttig, A. (Alexander), Strohmer, B. (Bernhard), Panayiotou, A.G. (Andrie), Torres, M. (Maria), Knoflach, M. (Michael), Hubacek, J.A. (Jaroslav A.), Slowikowski, K. (Kamil), Raychaudhuri, S. (Soumya), Kumar, R.D. (Runjun), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Shuldiner, A.R. (Alan), Alonso, A. (Alvaro), Bader, J.S. (Joel), Ehret, G.B. (Georg), Huang, H. (Hailiang), Kao, W.H.L. (Wen), Strait, J.B. (James), Macfarlane, P.W. (Peter), Brown, M.J. (Morris), Caulfield, M. (Mark), Samani, N.J. (Nilesh), Kronenberg, F. (Florian), Willeit, J. (Johann), Smith, J.G. (J. Gustav), Greiser, K.H. (Karin Halina), Zu Schwabedissen, H.M. (Henriette Meyer), Werdan, K. (Karl), Carella, C. (Cintia), Zelante, L. (Leopoldo), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), Kolcic, I. (Ivana), Polasek, O. (Ozren), Wright, A.F. (Alan), Griffin, M. (Maura), Daly, M.J. (Mark), Arnar, D.O. (David), Hólm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Denny, J.C. (Joshua), Roden, D.M. (Dan), Zuvich, R.L. (Rebecca), Emilsson, V. (Valur), Plump, A.S. (Andrew), Larson, M.G. (Martin), O'Donnell, C.J. (Christopher), Yin, X. (Xiaoyan), Bobbo, M. (Marco), Adamo, P. (Pio) d', Iorio, A. (Annamaria), Sinagra, G. (Gianfranco), Carracedo, A. (Angel), Cummings, S.R. (Steven), Nalls, M.A. (Michael), Jula, A. (Antti), Kontula, K.K. (Kimmo), Marjamaa, A. (Annukka), Oikarinen, L. (Lasse), Perola, M. (Markus), Porthan, K. (Kimmo), Erbel, R. (Raimund), Hoffmann, P. (Per), Jöckel, K.-H. (Karl-Heinz), Kälsch, H. (Hagen), Nöthen, M.M. (Markus), Hoed, M. (Marcel) den, Loos, R.J.F. (Ruth), Thelle, D.S. (Dag), Gieger, C. (Christian), Meitinger, T. (Thomas), Perz, S. (Siegfried), Peters, A. (Annette), Prucha, H. (Hanna), Sinner, M.F. (Moritz), Waldenberger, M. (Melanie), Boer, R.A. (Rudolf) de, Franke, L. (Lude), Vleuten, P.A. (Pieter) van der, Beckmann, B.M. (Britt), Martens, E. (Eimo), Bardai, A. (Abdennasser), Hofman, N. (Nynke), Wilde, A.A.M. (Arthur), Behr, E.R. (Elijah), Dalageorgou, C. (Chrysoula), Giudicessi, J.R. (John), Medeiros-Domingo, A. (Argelia), Barc, J. (Julien), Kyndt, F. (Florence), Probst, V. (Vincent), Ghidoni, A. (Alice), Insolia, R. (Roberto), Hamilton, R.M. (Robert), Scherer, S.W. (Stephen), Brandimarto, J. (Jeffrey), Margulies, K. (Kenneth), Moravec, C.E. (Christine), Del Greco, F. (Fabiola), Fuchsberger, C. (Christian), O'Connell, J.R. (Jeffery), Lee, W.K. (Wai), Watt, G.C.M. (Graham), Campbell, H. (Harry), Wild, S.H. (Sarah), El Mokhtari, N.E. (Nour), Frey, N. (Norbert), Asselbergs, F.W. (Folkert), Leach, I.M. (Irene Mateo), Navis, G. (Gerjan), Berg, M.P. (Maarten) van den, Veldhuisen, D.J. (Dirk) van, Kellis, M. (Manolis), Krijthe, B.P. (Bouwe), Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Kedenko, L. (Lyudmyla), Lamina, C. (Claudia), Oostra, B.A. (Ben), Abecasis, G.R. (Gonçalo), Lakatta, E. (Edward), Mulas, A. (Antonella), Orrù, M. (Marco), Schlessinger, D. (David), Uda, M. (Manuela), Markus, M.R.P. (Marcello R. P.), Völker, U. (Uwe), Snieder, H. (Harold), Spector, T.D. (Timothy), Ärnlöv, J. (Johan), Lind, L. (Lars), Sundstrom, J. (Johan), Syvanen, A.C., Kivimaki, M. (Mika), Kähönen, M. (Mika), Mononen, K. (Kari), Raitakari, O. (Olli), Viikari, J. (Jorma), Adamkova, V. (Vera), Kiechl, S. (Stefan), Brion, M.-J. (Maria), Nicolaides, A.N. (Andrew), Paulweber, B. (Bernhard), Haerting, J. (Johannes), Dominiczak, A. (Anna), Nyberg, F. (Fredrik), Whincup, P.H. (Peter), Hingorani, A. (Aroon), Schott, J.-J. (Jean-Jacques), Bezzina, C.R. (Connie), Ingelsson, E. (Erik), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Wilson, J.F. (James), Rudan, I. (Igor), Franke, A. (Andre), Mühleisen, T.W. (Thomas), Pramstaller, P.P. (Peter Paul), Lehtimäki, T. (Terho), Paterson, A.D. (Andrew), Parsa, A. (Afshin), Liu, Y. (YongMei), Duijn, C.M. (Cornelia) van, Siscovick, D.S. (David), Gudnason, V. (Vilmundur), Jamshidi, Y. (Yalda), Salomaa, V. (Veikko), Felix, S.B. (Stephan), Sanna, S. (Serena), Ritchie, M.D. (Marylyn), Stricker, B.H.Ch. (Bruno), Zwart, J-A. (John-Anker), Boyer, L.A. (Laurie), Cappola, T.P. (Thomas), Olsen, J.V. (Jesper), Lage, P. (Pedro), Schwartz, P.J. (Peter), Kääb, S. (Stefan), Chakravarti, A. (Aravinda), Ackerman, M. (Margaret), Pfeufer, A. (Arne), Bakker, P.I.W. (Paul) de, Newton-Cheh, C. (Christopher), Arking, D.E. (Dan), Pulit, S.L. (Sara), Crotti, L. (Lia), Harst, P. (Pim) van der, Munroe, P. (Patricia), Koopmann, T.T. (Tamara), Sotoodehnia, N. (Nona), Rossin, E. (Elizabeth), Morley, M. (Michael), Wang, X. (Xinchen), Johnson, A.D. (Andrew), Lundby, A. (Alicia), Gudbjartsson, D.F. (Daniel), Noseworthy, P.A. (Peter), Eijgelsheim, M. (Mark), Bradford, Y. (Yuki), Tarasov, K.V. (Kirill), Dörr, M. (Marcus), Müller-Nurasyid, M. (Martina), Lahtinen, A.M. (Annukka), Nolte, I.M. (Ilja), Smith, A.V. (Davey), Bis, J.C. (Joshua), Isaacs, A.J. (Aaron), Newhouse, S.J. (Stephen), Evans, D.S. (Daniel), Post, W.S. (Wendy S.), Waggott, D. (Daryl), Lyytikäinen, L.-P. (Leo-Pekka), Hicks, A.A. (Andrew), Eisele, L. (Lewin), Ellinghaus, D. (David), Hayward, C. (Caroline), Navarro, P. (Pau), Ulivi, S. (Shelia), Tanaka, T. (Toshiko), Tester, D.J. (David), Chatel, S. (Stéphanie), Gustafsson, S. (Stefan), Kumari, M. (Meena), Morris, R.W. (Richard), Naluai, A.T. (Asa), Padmanabhan, S. (Sandosh), Kluttig, A. (Alexander), Strohmer, B. (Bernhard), Panayiotou, A.G. (Andrie), Torres, M. (Maria), Knoflach, M. (Michael), Hubacek, J.A. (Jaroslav A.), Slowikowski, K. (Kamil), Raychaudhuri, S. (Soumya), Kumar, R.D. (Runjun), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Shuldiner, A.R. (Alan), Alonso, A. (Alvaro), Bader, J.S. (Joel), Ehret, G.B. (Georg), Huang, H. (Hailiang), Kao, W.H.L. (Wen), Strait, J.B. (James), Macfarlane, P.W. (Peter), Brown, M.J. (Morris), Caulfield, M. (Mark), Samani, N.J. (Nilesh), Kronenberg, F. (Florian), Willeit, J. (Johann), Smith, J.G. (J. Gustav), Greiser, K.H. (Karin Halina), Zu Schwabedissen, H.M. (Henriette Meyer), Werdan, K. (Karl), Carella, C. (Cintia), Zelante, L. (Leopoldo), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), Kolcic, I. (Ivana), Polasek, O. (Ozren), Wright, A.F. (Alan), Griffin, M. (Maura), Daly, M.J. (Mark), Arnar, D.O. (David), Hólm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Denny, J.C. (Joshua), Roden, D.M. (Dan), Zuvich, R.L. (Rebecca), Emilsson, V. (Valur), Plump, A.S. (Andrew), Larson, M.G. (Martin), O'Donnell, C.J. (Christopher), Yin, X. (Xiaoyan), Bobbo, M. (Marco), Adamo, P. (Pio) d', Iorio, A. (Annamaria), Sinagra, G. (Gianfranco), Carracedo, A. (Angel), Cummings, S.R. (Steven), Nalls, M.A. (Michael), Jula, A. (Antti), Kontula, K.K. (Kimmo), Marjamaa, A. (Annukka), Oikarinen, L. (Lasse), Perola, M. (Markus), Porthan, K. (Kimmo), Erbel, R. (Raimund), Hoffmann, P. (Per), Jöckel, K.-H. (Karl-Heinz), Kälsch, H. (Hagen), Nöthen, M.M. (Markus), Hoed, M. (Marcel) den, Loos, R.J.F. (Ruth), Thelle, D.S. (Dag), Gieger, C. (Christian), Meitinger, T. (Thomas), Perz, S. (Siegfried), Peters, A. (Annette), Prucha, H. (Hanna), Sinner, M.F. (Moritz), Waldenberger, M. (Melanie), Boer, R.A. (Rudolf) de, Franke, L. (Lude), Vleuten, P.A. (Pieter) van der, Beckmann, B.M. (Britt), Martens, E. (Eimo), Bardai, A. (Abdennasser), Hofman, N. (Nynke), Wilde, A.A.M. (Arthur), Behr, E.R. (Elijah), Dalageorgou, C. (Chrysoula), Giudicessi, J.R. (John), Medeiros-Domingo, A. (Argelia), Barc, J. (Julien), Kyndt, F. (Florence), Probst, V. (Vincent), Ghidoni, A. (Alice), Insolia, R. (Roberto), Hamilton, R.M. (Robert), Scherer, S.W. (Stephen), Brandimarto, J. (Jeffrey), Margulies, K. (Kenneth), Moravec, C.E. (Christine), Del Greco, F. (Fabiola), Fuchsberger, C. (Christian), O'Connell, J.R. (Jeffery), Lee, W.K. (Wai), Watt, G.C.M. (Graham), Campbell, H. (Harry), Wild, S.H. (Sarah), El Mokhtari, N.E. (Nour), Frey, N. (Norbert), Asselbergs, F.W. (Folkert), Leach, I.M. (Irene Mateo), Navis, G. (Gerjan), Berg, M.P. (Maarten) van den, Veldhuisen, D.J. (Dirk) van, Kellis, M. (Manolis), Krijthe, B.P. (Bouwe), Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Kedenko, L. (Lyudmyla), Lamina, C. (Claudia), Oostra, B.A. (Ben), Abecasis, G.R. (Gonçalo), Lakatta, E. (Edward), Mulas, A. (Antonella), Orrù, M. (Marco), Schlessinger, D. (David), Uda, M. (Manuela), Markus, M.R.P. (Marcello R. P.), Völker, U. (Uwe), Snieder, H. (Harold), Spector, T.D. (Timothy), Ärnlöv, J. (Johan), Lind, L. (Lars), Sundstrom, J. (Johan), Syvanen, A.C., Kivimaki, M. (Mika), Kähönen, M. (Mika), Mononen, K. (Kari), Raitakari, O. (Olli), Viikari, J. (Jorma), Adamkova, V. (Vera), Kiechl, S. (Stefan), Brion, M.-J. (Maria), Nicolaides, A.N. (Andrew), Paulweber, B. (Bernhard), Haerting, J. (Johannes), Dominiczak, A. (Anna), Nyberg, F. (Fredrik), Whincup, P.H. (Peter), Hingorani, A. (Aroon), Schott, J.-J. (Jean-Jacques), Bezzina, C.R. (Connie), Ingelsson, E. (Erik), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Wilson, J.F. (James), Rudan, I. (Igor), Franke, A. (Andre), Mühleisen, T.W. (Thomas), Pramstaller, P.P. (Peter Paul), Lehtimäki, T. (Terho), Paterson, A.D. (Andrew), Parsa, A. (Afshin), Liu, Y. (YongMei), Duijn, C.M. (Cornelia) van, Siscovick, D.S. (David), Gudnason, V. (Vilmundur), Jamshidi, Y. (Yalda), Salomaa, V. (Veikko), Felix, S.B. (Stephan), Sanna, S. (Serena), Ritchie, M.D. (Marylyn), Stricker, B.H.Ch. (Bruno), Zwart, J-A. (John-Anker), Boyer, L.A. (Laurie), Cappola, T.P. (Thomas), Olsen, J.V. (Jesper), Lage, P. (Pedro), Schwartz, P.J. (Peter), Kääb, S. (Stefan), Chakravarti, A. (Aravinda), Ackerman, M. (Margaret), Pfeufer, A. (Arne), Bakker, P.I.W. (Paul) de, and Newton-Cheh, C. (Christopher)

Abstract

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Published
2014
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12. The role of renin-angiotensin-aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

Author

Kolder, I.C.R.M. (Iris), Michels, M. (Michelle), Christiaans, I. (Imke), Cate, F.J. (Folkert) ten, Majoor-Krakauer, D.F. (Danielle), Danser, A.H.J. (Jan), Lekanne Deprez, R.H., Tanck, M.W.T. (Michael), Wilde, A.A.M. (Arthur), Bezzina, C.R. (Connie), Dooijes, D. (Dennis), Kolder, I.C.R.M. (Iris), Michels, M. (Michelle), Christiaans, I. (Imke), Cate, F.J. (Folkert) ten, Majoor-Krakauer, D.F. (Danielle), Danser, A.H.J. (Jan), Lekanne Deprez, R.H., Tanck, M.W.T. (Michael), Wilde, A.A.M. (Arthur), Bezzina, C.R. (Connie), and Dooijes, D. (Dennis)

Abstract

The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P=0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM.

Published
2012
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13. Rationale and design of the PRAETORIAN trial: A Prospective, RAndomizEd comparison of subcuTaneOus and tRansvenous ImplANtable cardioverter- defibrillator therapy

Author

Olde Nordkamp, L.R.A. (Louise R.A.), Knops, R.E. (Reinoud), Bardy, G.H. (Gust), Blaauw, Y. (Yuri), Boersma, L. (Lucas), Bos, J.S. (Johannes), Delnoy, P.P.H.M. (Peter Paul), Pascal, P.F.H.M. van, Driessen, A.H.G. (Antoine), Groot, J.R. (Joris) de, Herrman, J.P.R., Jordaens, L.J.L.M. (Luc), Kooiman, K.M. (Kirsten), Maass, A.H. (Alexander), Meine, M. (Mathias), Mizusawa, Y. (Yuka), Molhoek, S.G. (Sander), Opstal, J. (Jurjen) van, Tijssen, J.G.P. (Jan), Wilde, A.A.M. (Arthur), Olde Nordkamp, L.R.A. (Louise R.A.), Knops, R.E. (Reinoud), Bardy, G.H. (Gust), Blaauw, Y. (Yuri), Boersma, L. (Lucas), Bos, J.S. (Johannes), Delnoy, P.P.H.M. (Peter Paul), Pascal, P.F.H.M. van, Driessen, A.H.G. (Antoine), Groot, J.R. (Joris) de, Herrman, J.P.R., Jordaens, L.J.L.M. (Luc), Kooiman, K.M. (Kirsten), Maass, A.H. (Alexander), Meine, M. (Mathias), Mizusawa, Y. (Yuka), Molhoek, S.G. (Sander), Opstal, J. (Jurjen) van, Tijssen, J.G.P. (Jan), and Wilde, A.A.M. (Arthur)

Abstract

Background: Implantable cardioverter-defibrillators (ICDs) are widely used to prevent fatal outcomes associated with life-threatening arrhythmic episodes in a variety of cardiac diseases. These ICDs rely on transvenous leads for cardiac sensing and defibrillation. A new entirely subcutaneous ICD overcomes problems associated with transvenous leads. However, the role of the subcutaneous ICD as an adjunctive or primary therapy in patients at risk for sudden cardiac death is unclear. Study Design: The PRAETORIAN trial is an investigator-initiated, randomized, controlled, multicenter, prospective 2-arm trial that outlines the advantages and disadvantages of the subcutaneous ICD. Patients with a class I or IIa indication for ICD therapy without an indication for bradypacing or tachypacing are included. A total of 700 patients are randomized to either the subcutaneous or transvenous ICD (1:1). The study is powered to claim noninferiority of the subcutaneous ICD with respect to the composite primary endpoint of inappropriate shocks and ICD-related complications. After noninferiority is established, statistical analysis is done for potential superiority. Secondary endpoint comparisons of shock efficacy and patient mortality are also made. Conclusion: The PRAETORIAN trial is a randomized trial that aims to gain scientific evidence for the use of the subcutaneous ICD compared with the transvenous ICD in a population of patients with conventional ICD with respect to major ICD-related adverse events. This trial is registered at ClinicalTrials.gov with trial ID NCT01296022.

Published
2012
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14. The Entirely Subcutaneous Implantable Cardioverter-Defibrillator. Initial Clinical Experience in a Large Dutch Cohort

Author

Olde Nordkamp, L.R.A. (Louise R.A.), Dabiri Abkenari, L. (Lara), Boersma, L. (Lucas), Maass, A.H. (Alexander), Groot, J.R. (Joris) de, Oostrom, A.J.H.H.M. van, Theuns, D.A.M.J. (Dominic), Jordaens, L.J.L.M. (Luc), Wilde, A.A.M. (Arthur), Knops, R.E. (Reinoud), Olde Nordkamp, L.R.A. (Louise R.A.), Dabiri Abkenari, L. (Lara), Boersma, L. (Lucas), Maass, A.H. (Alexander), Groot, J.R. (Joris) de, Oostrom, A.J.H.H.M. van, Theuns, D.A.M.J. (Dominic), Jordaens, L.J.L.M. (Luc), Wilde, A.A.M. (Arthur), and Knops, R.E. (Reinoud)

Abstract

Objectives: The purpose of the study was to evaluate the efficacy and safety of the entirely subcutaneous implantable cardioverter-defibrillator (S-ICD). Background: A new entirely S-ICD has been introduced, that does not require lead placement in or on the heart. The authors report the largest multicenter experience to date with the S-ICD with a minimum of 1-year follow-up in the first 118 Dutch patients who were implanted with this device. Methods: Patients were selected if they had a class I or IIa indication for primary or secondary prevention of sudden cardiac death. All consecutive patients from 4 high-volume centers in the Netherlands with an S-ICD implanted between December 2008 and April 2011 were included. Results: A total of 118 patients (75% males, mean age 50 years) received the S-ICD. After 18 months of follow-up, 8 patients experienced 45

Published
2012
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15. A complex double deletion in LMNA underlies progressive cardiac conduction disease, atrial arrhythmias, and sudden death

Author

Marsman, R.F. (Roos), Bardai, A. (Abdennasser), Postma, A.V. (Alex), Res, J.C.J. (Jan), Koopmann, T.T. (Tamara), Beekman, L. (Leander), Wal, A.C. (Allard) van der, Pinto, Y.M. (Yigal), Deprez, R.H.L., Wilde, A.A.M. (Arthur), Jordaens, L.J.L.M. (Luc), Bezzina, C.R. (Connie), Marsman, R.F. (Roos), Bardai, A. (Abdennasser), Postma, A.V. (Alex), Res, J.C.J. (Jan), Koopmann, T.T. (Tamara), Beekman, L. (Leander), Wal, A.C. (Allard) van der, Pinto, Y.M. (Yigal), Deprez, R.H.L., Wilde, A.A.M. (Arthur), Jordaens, L.J.L.M. (Luc), and Bezzina, C.R. (Connie)

Abstract

Background-Cardiac conduction disease is a clinically and genetically heterogeneous disorder characterized by defects in electrical impulse generation and conduction and is associated with sudden cardiac death. Methods and Results-We studied a 4-generation family with autosomal dominant progressive cardiac conduction disease, including atrioventricular conduction block and sinus bradycardia, atrial arrhythmias, and sudden death. Genome-wide linkage analysis mapped the disease locus to chromosome 1p22-q21. Multiplex ligation-dependent probe amplification analysis of the LMNA gene, which encodes the nuclear-envelope protein lamin A/C, revealed a novel gene rearrangement involving a 24-bp inversion flanked by a 3.8-kb deletion upstream and a 7.8-kb deletion downstream. The presence of short inverted sequence homologies at the breakpoint junctions suggested a mutational event involving serial replication slippage in trans during DNA replication. Conclusions-We identified for the first time a complex

Published
2011
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16. Health care utilisation after defibrillator implantation for primary prevention according to the guidelines in 2 Dutch academic medical centres

Author

Smith, T., Pascal, P.F.H.M. van, Theuns, D.A.M.J. (Dominic), Muskens-Heemskerk, A. (Agnes), Domburg, R.T. (Ron) van, Wilde, A.A.M. (Arthur), Jordaens, L.J.L.M. (Luc), Smith, T., Pascal, P.F.H.M. van, Theuns, D.A.M.J. (Dominic), Muskens-Heemskerk, A. (Agnes), Domburg, R.T. (Ron) van, Wilde, A.A.M. (Arthur), and Jordaens, L.J.L.M. (Luc)

Abstract

Background The benefit of implantable defibrillators (ICDs) for primary prevention remains debated. We analysed the implications of prophylactic ICD implantation according to the guidelines in 2 tertiary hospitals, and made a healthcare utilisation inventory. Methods The cohort consisted of all consecutive patients with coronary artery disease (CAD) or dilated cardiomyopathy (DCM) receiving a primary prophylactic ICD in a contemporary setting (2004-2008). Follow-up was obtained from hospital databases, and mortality checked at the civil registry. Additional data came from questionnaires sent to general practitioners. Results There were no demographic differences between the 2 centres; one had proportionally more CAD patients and more resynchronisation therapy (CRT-D). The 587 patients were followed over a median of 28 months, and 50 (8.5%) patients died. Appropriate ICD intervention occurred in 123 patients (21%). There was a small difference in interventionfree survival between the 2 centres. The questionnaires revealed 338 hospital admissions in 52% of the responders. Device-related admissions happened on 68 occasions, in 49/ 276 responders. The most frequently reported ICD-related admission was due to shocks (20/49 patients); for other cardiac problems it was mainly heart failure (52/99). Additional outpatient visits occurred in 19%. Conclusion Over a median follow-up of 2 years, one fifth of prophylactic ICD patients receive appropriate interventions. A substantial group undergoes readmission and additional visits. The high number of admissions points to a very ill population. Overall mortality was 8.5%. The 2 centres employed a similar procedure with respect to patient selection. One centre used more CRT-D, and observed more appropriate ICD interventions.

Published
2011
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17. Journal metrics for the Netherlands heart journal

Author

Wall, E.E. (Ernst) van der, Boer, M.J. (Menko Jan) de, Doevendans, P.A. (Pieter), Wilde, A.A.M. (Arthur), Zijlstra, F.J. (Freek), Wall, E.E. (Ernst) van der, Boer, M.J. (Menko Jan) de, Doevendans, P.A. (Pieter), Wilde, A.A.M. (Arthur), and Zijlstra, F.J. (Freek)

Published
2011
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18. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: Pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study

Author

Cox, M.G.P.J. (Moniek), Zwaag, P.A. (Paul) van der, Werf, C. (Christian) van der, Smagt, J.J. (Jasper) van der, Noorman, M. (Maartje), Bhuiyan, Z.A. (Zahir), Wiesfeld, A.C.P. (Ans), Volders, P.G.A. (Paul), Langen, I.M. (Irene) van, Dooijes, D. (Dennis), Wijngaard, A. (Arthur) van den, Houweling, A.C. (Arjan), Jongbloed, J.D.H. (Jan), Jordaens, L.J.L.M. (Luc), Cramer, M.-J. (Maarten-Jan), Doevendans, P.A. (Pieter), Bakker, J.M.T. (Jacques) de, Wilde, A.A.M. (Arthur), Tintelen, J.P. (Peter) van, Hauer, R.N.W. (Richard), Atsma, D.E. (Douwe), Cox, M.G.P.J. (Moniek), Zwaag, P.A. (Paul) van der, Werf, C. (Christian) van der, Smagt, J.J. (Jasper) van der, Noorman, M. (Maartje), Bhuiyan, Z.A. (Zahir), Wiesfeld, A.C.P. (Ans), Volders, P.G.A. (Paul), Langen, I.M. (Irene) van, Dooijes, D. (Dennis), Wijngaard, A. (Arthur) van den, Houweling, A.C. (Arjan), Jongbloed, J.D.H. (Jan), Jordaens, L.J.L.M. (Luc), Cramer, M.-J. (Maarten-Jan), Doevendans, P.A. (Pieter), Bakker, J.M.T. (Jacques) de, Wilde, A.A.M. (Arthur), Tintelen, J.P. (Peter) van, Hauer, R.N.W. (Richard), and Atsma, D.E. (Douwe)

Abstract

Background-: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. Methods and Results-: One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V1 to V3, especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations). Conclusions-: Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal

Published
2011
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19. The sense and nonsense of direct-to-consumer genetic testing for cardiovascular disease

Author

Janssens, A.C.J.W. (Cécile), Wilde, A.A.M. (Arthur), Langen, I.M. (Irene) van, Janssens, A.C.J.W. (Cécile), Wilde, A.A.M. (Arthur), and Langen, I.M. (Irene) van

Abstract

Expectations are high that increasing knowledge of the genetic basis of cardiovascular disease will eventually lead to personalised medicine-to preventive and therapeutic interventions that are targeted to at-risk individuals on the basis of their genetic profiles. Most cardiovascular diseases are caused by a complex interplay of many genetic variants interacting with many non-genetic risk factors such as diet, exercise, smoking and alcohol consumption. Since several years, genetic susceptibility testing for cardiovascular diseases is being offered via the internet directly to consumers. We discuss five reasons why these tests are not useful, namely: (1) the predictive ability is still limited; (2) the risk models used by the companies are based on assumptions that have not been verified; (3) the predicted risks keep changing when new variants are discovered and added to the test; (4) the tests do not consider non-genetic factors in the prediction of cardiovascular disease risk; and (5) the test results will not change recommendations of preventive interventions. Predictive genetic testing for multifactorial forms of cardiovascular disease clearly lacks benefits for the public. Prevention of disease should therefore remain focused on family history and on non-genetic risk factors as diet and physical activity that can have the strongest impact on disease risk, regardless of genetic susceptibility.

Published
2011
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20. Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in european ancestry individuals

Author

Arking, D.E. (Dan), Junttila, M.J. (Juhani), Goyette, P. (Philippe), Huertas-Vazquez, A. (Adriana), Eijgelsheim, M. (Mark), Blom, M.T. (Marieke), Newton-Cheh, C. (Christopher), Reinier, K. (Kyndaron), Teodorescu, C. (Carmen), Uy-Evanado, A. (Audrey), Carter-Monroe, N. (Naima), Kaikkonen, K.S. (Kari), Kortelainen, M.-L., Boucher, G. (Gabrielle), Lagacé, C. (Caroline), Moes, A. (Anna), Zhao, X., Kolodgie, F. (Frank), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Witteman, J.C.M. (Jacqueline), Uitterlinden, A.G. (André), Marsman, R.F. (Roos), Pazoki, R. (Raha), Bardai, A. (Abdennasser), Koster, R.W. (Rudolph), Dehghan, A. (Abbas), Hwang, S.J., Bhatnagar, P. (Pallav), Post, W. (Wendy), Hilton, G. (Gina), Prineas, R.J. (Ronald), Li, M. (Man), Köttgen, A. (Anna), Ehret, G.B. (Georg), Boerwinkle, E.A. (Eric), Coresh, J. (Josef), Kao, W.H.L. (Wen), Psaty, B.M. (Bruce), Tomaselli, G.F. (Gordon), Sotoodehnia, N. (Nona), Siscovick, D.S. (David), Burke, G.L. (Greg), Marbán, E. (Eduardo), Spooner, P.M. (Peter), Cupples, L.A. (Adrienne), Jui, J. (Jonathan), Gunson, K. (Karen), Kesaniemi, Y.A. (Antero), Wilde, A.A.M. (Arthur), Tardif, J.-C. (Jean-Claude), O'Donnell, C.J. (Christopher), Bezzina, C.R. (Connie), Virmani, R. (Renu), Stricker, B.H.Ch. (Bruno), Tan, H.L. (Hanno), Albert, C.M. (Christine), Chakravarti, A. (Aravinda), Rioux, J.D. (John), Huikuri, H.V. (Heikki), Chugh, S.S. (Sumeet), Arking, D.E. (Dan), Junttila, M.J. (Juhani), Goyette, P. (Philippe), Huertas-Vazquez, A. (Adriana), Eijgelsheim, M. (Mark), Blom, M.T. (Marieke), Newton-Cheh, C. (Christopher), Reinier, K. (Kyndaron), Teodorescu, C. (Carmen), Uy-Evanado, A. (Audrey), Carter-Monroe, N. (Naima), Kaikkonen, K.S. (Kari), Kortelainen, M.-L., Boucher, G. (Gabrielle), Lagacé, C. (Caroline), Moes, A. (Anna), Zhao, X., Kolodgie, F. (Frank), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Witteman, J.C.M. (Jacqueline), Uitterlinden, A.G. (André), Marsman, R.F. (Roos), Pazoki, R. (Raha), Bardai, A. (Abdennasser), Koster, R.W. (Rudolph), Dehghan, A. (Abbas), Hwang, S.J., Bhatnagar, P. (Pallav), Post, W. (Wendy), Hilton, G. (Gina), Prineas, R.J. (Ronald), Li, M. (Man), Köttgen, A. (Anna), Ehret, G.B. (Georg), Boerwinkle, E.A. (Eric), Coresh, J. (Josef), Kao, W.H.L. (Wen), Psaty, B.M. (Bruce), Tomaselli, G.F. (Gordon), Sotoodehnia, N. (Nona), Siscovick, D.S. (David), Burke, G.L. (Greg), Marbán, E. (Eduardo), Spooner, P.M. (Peter), Cupples, L.A. (Adrienne), Jui, J. (Jonathan), Gunson, K. (Karen), Kesaniemi, Y.A. (Antero), Wilde, A.A.M. (Arthur), Tardif, J.-C. (Jean-Claude), O'Donnell, C.J. (Christopher), Bezzina, C.R. (Connie), Virmani, R. (Renu), Stricker, B.H.Ch. (Bruno), Tan, H.L. (Hanno), Albert, C.M. (Christine), Chakravarti, A. (Aravinda), Rioux, J.D. (John), Huikuri, H.V. (Heikki), and Chugh, S.S. (Sumeet)

Abstract

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10-10). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs

Published
2011
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21. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: Data from the European Long-QT syndrome implantable cardioverter-defibrillator (LQTS ICD) registry

Author

Schwartz, P.J. (Peter), Spazzolini, C. (Carla), Priori, S.G. (Silvia), Crotti, L. (Lia), Vicentini, A. (Alessandro), Landolina, M. (Maurizio), Gasparini, M. (Maurizio), Wilde, A.A.M. (Arthur), Knops, R.E. (Reinoud), Denjoy, I. (Isabelle), Toivonen, L. (Lauri), Mönnig, G. (Gerold), Al-Fayyadh, M. (Majid), Jordaens, L.J.L.M. (Luc), Borggrefe, M. (Martin), Holmgren, C. (Christina), Brugada, P. (Pedro), Roy, L. (Luc) de, Hohnloser, S.H. (Stefan), Brink, P.A. (Paul), Schwartz, P.J. (Peter), Spazzolini, C. (Carla), Priori, S.G. (Silvia), Crotti, L. (Lia), Vicentini, A. (Alessandro), Landolina, M. (Maurizio), Gasparini, M. (Maurizio), Wilde, A.A.M. (Arthur), Knops, R.E. (Reinoud), Denjoy, I. (Isabelle), Toivonen, L. (Lauri), Mönnig, G. (Gerold), Al-Fayyadh, M. (Majid), Jordaens, L.J.L.M. (Luc), Borggrefe, M. (Martin), Holmgren, C. (Christina), Brugada, P. (Pedro), Roy, L. (Luc) de, Hohnloser, S.H. (Stefan), and Brink, P.A. (Paul)

Abstract

Background-: A rapidly growing number of long-QT syndrome (LQTS) patients are being treated with an implantable cardioverter-defibrillator (ICD). ICDs may pose problems, especially in the young. We sought to determine the characteristics of the LQTS patients receiving an ICD, the indications, and the aftermath. Methods And Results-: The study population included 233 patients. Beginning in 2002, data were collected prospectively. Female patients (77%) and LQT3 patients (22% of genotype positive) were overrepresented; mean QTc was 516±65 milliseconds; mean age at implantation was 30±17 years; and genotype was known in 59% of patients. Unexpectedly, 9% of patients were asymptomatic before implantation. Asymptomatic patients, almost absent among LQT1 and LQT2 patients, represented 45% of LQT3 patients. Patients with cardiac symptoms made up 91% of all study participants, but only 44% had cardiac arrest before ICD implantation. In addition, 41% of patients received an ICD without having first been on LQTS therapy. During follow-up, 4.6±3.2 years, at least 1 appropriate shock was received by 28% of patients, and adverse events occurred in 25%. Appropriate ICD therapies were predicted by age <20 years at implantation, a QTc >500 milliseconds, prior cardiac arrest, and cardiac events despite therapy; within 7 years, appropriate shocks occurred in no patients with none of these factors and in 70% of those with all factors. Conclusions-: Reflecting previous concepts, ICDs were implanted in some LQTS patients whose high risk now appears questionable. Refined criteria for implantation, reassessment of pros and cons, ICD reprogramming, and consideration for other existing therapeutic options are necessary.

Published
2010
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22. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Diagnostic Task Force Criteria impact of new Task Force Criteria

Author

Cox, M.G.P.J. (Moniek), Smagt, J.J. (Jasper) van der, Noorman, M. (Maartje), Wiesfeld, A.C.P. (Ans), Volders, P.G.A. (Paul), Langen, I.M. (Irene) van, Atsma, D.E. (Douwe), Dooijes, D. (Dennis), Houweling, A.C. (Arjan), Loh, P. (Peter), Jordaens, L.J.L.M. (Luc), Arens, Y.H.J.M. (Yvonne), Cramer, M.-J. (Maarten-Jan), Doevendans, P.A. (Pieter), Tintelen, J.P. (Peter) van, Wilde, A.A.M. (Arthur), Hauer, R.N.W. (Richard), Cox, M.G.P.J. (Moniek), Smagt, J.J. (Jasper) van der, Noorman, M. (Maartje), Wiesfeld, A.C.P. (Ans), Volders, P.G.A. (Paul), Langen, I.M. (Irene) van, Atsma, D.E. (Douwe), Dooijes, D. (Dennis), Houweling, A.C. (Arjan), Loh, P. (Peter), Jordaens, L.J.L.M. (Luc), Arens, Y.H.J.M. (Yvonne), Cramer, M.-J. (Maarten-Jan), Doevendans, P.A. (Pieter), Tintelen, J.P. (Peter) van, Wilde, A.A.M. (Arthur), and Hauer, R.N.W. (Richard)

Abstract

Background-Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Diagnostic Task Force Criteria (TFC) proposed in 1994 are highly specific but lack sensitivity. A new international task force modified criteria to improve diagnostic yield. A comparison of diagnosis by 1994 TFC versus newly proposed criteria in 3 patient groups was conducted. Methods and Results-In new TFC, scoring by major and minor criteria is maintained. Structural abnormalities are quantified and TFC highly specific for ARVD/C upgraded to major. Furthermore, new criteria are added: terminal activation duration of QRS ≥55 ms, ventricular tachycardia with left bundle-branch block morphology and superior axis, and genetic criteria. Three groups were studied: (1) 105 patients with proven ARVD/C according to 1994 TFC, (2) 89 of their family members, and (3) 39 patients with probable ARVD/C (ie, 3 points by 1994 TFC). All were screened for pathogenic mutations in desmosomal genes. Three ARVD/C patients did not meet the new sharpened criteria on structural abnormalities and thereby did not fulfill new TFC. In 62 of 105 patients with proven ARVD/C, mutations were found: 58 in the gene encoding Plakophilin2 (PKP2), 3 in Desmoglein2, 3 in Desmocollin2, and 1 in Desmoplakin. Three patients had bigenic involvement. Ten additional relatives (11%) fulfilled new TFC: 9 (90%) were female, and all carried PKP2 mutations. No rela

Published
2010
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23. An entirely subcutaneous implantable cardioverter-defibrillator

Author

Bardy, G.H. (Gust), Smith, W.M. (Warren), Hood, A.M. (Margaret), Crozier, I.G. (Ian), Melton, I.C. (Iain Craig), Jordaens, L.J.L.M. (Luc), Theuns, D.A.M.J. (Dominic), Park, E. (Robert), Wright, D.J. (David Justin), Connelly, D.T. (Derek), Fynn, S.P. (Simon Patrick), Murgatroyd, F.D. (Francis), Sperzel, J. (Johannes), Neuzner, J. (Jörg), Spitzer, S.G. (Stefan), Ardashev, A.V. (Andrey), Oduro, A. (Amo), Boersma, L. (Lucas), Maass, A.H. (Alexander), Gelder, I.C. (Isabelle) van, Wilde, A.A.M. (Arthur), Pascal, P.F.H.M. van, Knops, R.E. (Reinoud), Barr, C.S. (Craig), Lupo, P. (Pierpaolo), Cappato, R. (Riccardo), Grace, A.A. (Andrew), Bardy, G.H. (Gust), Smith, W.M. (Warren), Hood, A.M. (Margaret), Crozier, I.G. (Ian), Melton, I.C. (Iain Craig), Jordaens, L.J.L.M. (Luc), Theuns, D.A.M.J. (Dominic), Park, E. (Robert), Wright, D.J. (David Justin), Connelly, D.T. (Derek), Fynn, S.P. (Simon Patrick), Murgatroyd, F.D. (Francis), Sperzel, J. (Johannes), Neuzner, J. (Jörg), Spitzer, S.G. (Stefan), Ardashev, A.V. (Andrey), Oduro, A. (Amo), Boersma, L. (Lucas), Maass, A.H. (Alexander), Gelder, I.C. (Isabelle) van, Wilde, A.A.M. (Arthur), Pascal, P.F.H.M. van, Knops, R.E. (Reinoud), Barr, C.S. (Craig), Lupo, P. (Pierpaolo), Cappato, R. (Riccardo), and Grace, A.A. (Andrew)

Abstract

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) prevent sudden death from cardiac causes in selected patients but require the use of transvenous lead systems. To eliminate the need for venous access, we designed and tested an entirely subcutaneous ICD system. METHODS: First, we conducted two shortterm clinical trials to identify a suitable device configuration and assess energy requirements. We evaluated four subcutaneous ICD configurations in 78 patients who were candidates for ICD implantation and subsequently tested the best configuration in 49 additional patients to determine the subcutaneous defibrillation thresh old in comparison with that of the standard transvenous ICD. Then we evaluated the longterm use of subcutaneous ICDs in a pilot study, involving 6 patients, which was followed by a trial involving 55 patients. RESULTS: The best device configuration consisted of a parasternal electrode and a left lateral thoracic pulse generator. This configuration was as effective as a transvenous ICD for terminating induced ventricular fibrillation, albeit with a significantly higher mean (±SD) energy requirement (36.6±19.8 J vs. 11.1±8.5 J). Among patients who received a permanent subcutaneous ICD, ventricular fibrillation was successfully detected in 100% of 137 induced episodes. Induced ventricular fibrillation was converted twice in 58 of 59 patients (98%) with the delivery of 65J shocks in two consecutive tests. Clinically significant adverse events included two pocket infections and four lead revisions. After a mean of 10±1 months, the device had successfully detected and treated all 12 episodes of spontaneous, sustained ventricular tachyarrhythmia. CONCLUSIONS: In small, nonrandomized studies, an entirely subcutaneous ICD consistently detected and converted ventricular fibrillation induced during electrophysiological testing. The device also successfully detected and treated all 12 episodes of spontaneous, sustained ventricular tachyarrhythmia. (Clin

Published
2010
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