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1. A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients

Author

Nagyova, Emilia, Hoorntje, Edgar T., te Rijdt, Wouter P., Bosman, Laurens P., Syrris, Petros, Protonotarios, Alexandros, Elliott, Perry M., Tsatsopoulou, Adalena, Mestroni, Luisa, Taylor, Matthew R. G., Sinagra, Gianfranco, Merlo, Marco, Wada, Yuko, Horie, Minoru, Mogensen, Jens, Christensen, Alex H., Gerull, Brenda, Song, Lei, Yao, Yan, Fan, Siyang, Saguner, Ardan M., Duru, Firat, Koskenvuo, Juha W., Cruz Marino, Tania, Tichnell, Crystal, Judge, Daniel P., Dooijes, Dennis, Lekanne Deprez, Ronald H., Basso, Cristina, Pilichou, Kalliopi, Bauce, Barbara, Wilde, Arthur A. M., Charron, Philippe, Fressart, Véronique, van der Heijden, Jeroen F., van den Berg, Maarten P., Asselbergs, Folkert W., James, Cynthia A., Jongbloed, Jan D. H., Harakalova, Magdalena, and van Tintelen, J. Peter

Published
2023
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3. Location matters: spatial dynamics of tumor-infiltrating T cell subsets is prognostic in colon cancer

Author

Hehuan Zhu, Jessica Roelands, Eiman I. Ahmed, Imke Stouten, Rachel Hoorntje, Ronald L. P. van Vlierberghe, Marieke E. Ijsselsteijn, Xin Lei, Noel F. C. C. de Miranda, Rob A. E. M. Tollenaar, Alexander L. Vahrmeijer, Davide Bedognetti, Wouter R. L. Hendrickx, and Peter J. K. Kuppen

Subjects
colon cancer, multiplex immunofluorescence, T cell, spatial analysis, tumor microenvironment, immunologic constant of rejection, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundColon cancer is a heterogeneous disease and consists of various molecular subtypes. Despite advances in high-throughput expression profiling, limitations remain in predicting clinical outcome and assigning specific treatment to individual cases. Tumor-immune interactions play a critical role, with tumors that activate the immune system having better outcome for the patient. The localization of T cells within tumor epithelium, to enable direct contact, is essential for antitumor function, but bulk DNA/RNA sequencing data lacks spatial distribution information. In this study, we provide spatial T cell tumor distribution and connect these data with previously determined genomic data in the AC-ICAM colon cancer patient cohort.MethodsColon cancer patients (n=90) with transcriptome data available were selected. We used a custom multiplex immunofluorescence assay on colon tumor tissue sections for quantifying T cell subsets spatial distribution in the tumor microenvironment, in terms of cell number, location, mutual distance, and distance to tumor cells. Statistical analyses included the previously determined Immunologic Constant of Rejection (ICR) transcriptome correlation and patient survival, revealing potential prognostic value in T cell spatial distribution.ResultsT cell phenotypes were characterized and CD3+CD8-FoxP3- T cells were found to be the predominant tumor-infiltrating subtype while CD3+FoxP3+ T cells and CD3+CD8+ T cells showed similar densities. Spatial distribution analysis elucidated that proliferative T cells, characterized by Ki67 expression, and Granzyme B-expressing T cells were predominantly located within the tumor epithelium. We demonstrated an increase in immune cell density and a decrease in the distance of CD3+CD8+ T cells to the nearest tumor cell, in the immune active, ICR High, immune subtypes. Higher densities of stromal CD3+FoxP3+ T cells showed enhanced survival outcomes, and patients exhibited superior clinical benefits when greater spatial distances were observed between CD3+CD8-FoxP3- or CD3+CD8+ T cells and CD3+FoxP3+ T cells.ConclusionOur study’s in-depth analysis of the spatial distribution and densities of major T cell subtypes within the tumor microenvironment has provided valuable information that paves the way for further research into the intricate relationships between immune cells and colon cancer development.

Published
2024
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8. Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy

Author

Roberts, Jason D, Murphy, Nathaniel P, Hamilton, Robert M, Lubbers, Ellen R, James, Cynthia A, Kline, Crystal F, Gollob, Michael H, Krahn, Andrew D, Sturm, Amy C, Musa, Hassan, El-Refaey, Mona, Koenig, Sara, Aneq, Meriam Åström, Hoorntje, Edgar T, Graw, Sharon L, Davies, Robert W, Rafiq, Muhammad Arshad, Koopmann, Tamara T, Aafaqi, Shabana, Fatah, Meena, Chiasson, David A, Taylor, Matthew RG, Simmons, Samantha L, Han, Mei, van Opbergen, Chantal JM, Wold, Loren E, Sinagra, Gianfranco, Mittal, Kirti, Tichnell, Crystal, Murray, Brittney, Codima, Alberto, Nazer, Babak, Nguyen, Duy T, Marcus, Frank I, Sobriera, Nara, Lodder, Elisabeth M, van den Berg, Maarten P, Spears, Danna A, Robinson, John F, Ursell, Philip C, Green, Anna K, Skanes, Allan C, Tang, Anthony S, Gardner, Martin J, Hegele, Robert A, van Veen, Toon AB, Wilde, Arthur AM, Healey, Jeff S, Janssen, Paul ML, Mestroni, Luisa, van Tintelen, J Peter, Calkins, Hugh, Judge, Daniel P, Hund, Thomas J, Scheinman, Melvin M, and Mohler, Peter J

Subjects
Heart Disease, Cardiovascular, Clinical Research, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Animals, Ankyrins, Arrhythmogenic Right Ventricular Dysplasia, Disease Models, Animal, Female, Humans, Indoles, Male, Maleimides, Mice, Mice, Knockout, Myocardium, Wnt Signaling Pathway, beta Catenin, Arrhythmias, Cardiology, Cardiovascular disease, Cell Biology, Genetic diseases, Medical and Health Sciences, Immunology
Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.

Published
2019

9. Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST)

Author

te Rijdt, W. P., Hoorntje, E. T., de Brouwer, R., Oomen, A., Amin, A., van der Heijden, J. F., Karper, J. C., Westenbrink, B. D., Silljé, H. H. W., te Riele, A. S. J. M., Wiesfeld, A. C. P., van Gelder, I. C., Willems, T. P., van der Zwaag, P. A., van Tintelen, J. P., Hillege, J. H., Tan, H. L., van Veldhuisen, D. J., Asselbergs, F. W., de Boer, R. A., Wilde, A. A. M., and van den Berg, M. P.

Published
2022
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10. Which outcomes should always be measured in intervention studies for improving work participation for people with a health problem? An international multistakeholder Delphi study to develop a core outcome set for Work participation (COS for Work)

Author

Akizumi Tsutsumi, Lode Godderis, Stefania Curti, Alysha Meyers, Ute Bültmann, Emilie Friberg, William Shaw, Yeliz Prior, Ira Madan, Matthias Bethge, Miranda Langendam, Subas Neupane, Timo Hannu, Sosei Yamaguchi, Gunnel Hensing, Diane Lacaille, Jean François Gehanno, Petri Böckerman, Frederieke Schaafsma, Gary Macfarlane, Alexander Hoorntje, Nadine Foster, Clas-Håkan Nygård, Regina Kunz, Jos H Verbeek, Yogindra Samant, Shyam Pingle, Janice Hegewald, Ivan Steenstra, Paul Landsbergis, Per Lytsy, Johannes Anema, Donna Urquhart, Lene Aasdahl, Andreas Hoff, Margarita Ravinskaya, Suzanne M.M. Verstappen, Carel T.J. Hulshof, Jan L. Hoving, Debbie Berkowitz, Jonas Bühler, Trevor Coons, Caroline Crosse, Angela de Boer, Diana Dorstyn, Nicola Goodson, Christine Graveline, Douglas Gross, Karen Walseth Hara, Svenja Janssen, Raymond Lam, Maria Luiza Comper, Steve Mantis, Kohle Merry, Irene Larsen Oyeflaten, Alexis Snyder, Ingrid Sturkenboom, Yvonne Suijkerbuijk, Ilse van Ee, Yvonne van Zaanen, and Karen Walker Bone

Subjects
Medicine
Abstract

Objective Synthesising evidence of the effects of interventions to improve work participation among people with health problems is currently difficult due to heterogeneity in outcome measurements. A core outcome set for work participation is needed.Study design and setting Following the Core Outcome Measures in Effectiveness Trials methodology, we used a five-step approach to reach international multistakeholder consensus on a core outcome set for work participation. Five subgroups of stakeholders took part in two rounds of discussions and completed two Delphi voting rounds on 26 outcomes. A consensus of ≥80% determined core outcomes and 50%–80% consensus was required for candidate outcomes.Results Fifty-eight stakeholders took part in the Delphi rounds. Core outcomes were: ‘any type of employment including self-employment’, ‘proportion of workers that return to work after being absent because of illness’ and ‘time to return to work’. Ten candidate outcomes were proposed, among others: ‘sustainable employment’, ‘work productivity’ and ‘workers’ perception of return to work’.Conclusion As a minimum, all studies evaluating the impact of interventions on work participation should include one employment outcome and two return to work outcomes if workers are on sick leave prior to the intervention.

Published
2023
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12. Nationwide partial knee replacement uptake is influenced by volume and supplier––A Dutch arthroplasty register study

Author

Iris Koenraadt-van Oost, Koen LM Koenraadt, Alexander Hoorntje, Liza N van Steenbergen, Stefan BT Bolder, and Rutger CI van Geenen

Subjects
Orthopedic surgery, RD701-811
Abstract

Background Despite the established advantages of partial knee replacements (PKR), their usage remains limited. We investigated the effect of hospital knee arthroplasty (KA) volume and the availability of a frequently used PKR by the total KA supplier on the use of PKRs in a hospital. Methods A total of 190,204 total knee replacements (TKR) and 18,134 PKRs were identified in the Dutch Arthroplasty Register (LROI) from 2007 to 2016. For each hospital we determined the annual absolute KA volume (TKR+PKR) into quartiles (292 knee replacements/year), and determined whether the TKR supplier provided a frequently used PKR. Hospitals were divided in routine PKR users (≥13 PKRs/year) or occasional/non PKR users (

Published
2022
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14. Prognostic factors for return to work following knee arthroplasty

Author

Strijbos, Daniel O, additional, Straat, A Carlien, additional, van der Sluis, Geert, additional, Boymans, Tim, additional, Hoving, Jan L, additional, Pahlplatz, Thijs M.J., additional, Hoorntje, Alexander, additional, van Zaanen, Yvonne, additional, Coenen, Pieter, additional, Berenji, Manijeh, additional, Reneman, Michiel F, additional, and Kuijer, P Paul F M, additional

Published
2024
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15. Non-surgical treatment before hip and knee arthroplasty remains underutilized with low satisfaction regarding performance of work, sports, and leisure activities

Author

Yvonne Van Zaanen, Alexander Hoorntje, Koen L M Koenraadt, Leti Van Bodegom-Vos, Gino M M J Kerkhoffs, Suzanne Waterval-Witjes, Tim A E J Boymans, Rutger C I Van Geenen, and P Paul F M Kuijer

Subjects
Orthopedic surgery, RD701-811
Abstract

Background and purpose — Guidelines for managing hip and knee osteoarthritis (OA) advise extensive non-surgical treatment prior to surgery. We evaluated what percentage of hip and knee OA patients received non-surgical treatment prior to arthroplasty, and assessed patient satisfaction regarding alleviation of symptoms and performance of activities. Patients and methods — A multi-center cross-sectional study was performed in 2018 among 186 patients who were listed for hip or knee arthroplasty or had undergone surgery within the previous 6 months in the Netherlands. Questions concerned non-surgical treatments received according to the Stepped Care Strategy and were compared with utilization in 2013. Additionally, satisfaction with treatment effects for pain, swelling, stiffness, and activities of daily life, work, and sports/leisure was questioned. Results — The questionnaire was completed by 175 patients, age 66 years (range 38–84), 57% female, BMI 29 (IQR 25–33). Step 1 treatments, such as acetaminophen and lifestyle advice, were received by 79% and 60% of patients. Step 2 treatments, like exercise-based therapy and diet therapy, were received by 66% and 19%. Step 3—intra-articular injection—was received by 47%. Non-surgical treatment utilization was lower than in 2013. Nearly all treatments showed more satisfied patients regarding pain relief and fewer regarding activities of work/sports/leisure. Hip and knee OA patients were mostly satisfied with NSAIDs for all outcomes, while exercise-based therapy was rated second best. Interpretation — Despite international guideline recommendations, non-surgical treatment for hip and knee OA remains underutilized in the Netherlands. Of the patients referred for arthroplasty, more were satisfied with the effect of non-surgical treatment on pain than on work/sports/leisure participation.

Published
2020
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18. Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect

Author

Tadros, Rafik, Francis, Catherine, Xu, Xiao, Vermeer, Alexa M. C., Harper, Andrew R., Huurman, Roy, Kelu Bisabu, Ken, Walsh, Roddy, Hoorntje, Edgar T., te Rijdt, Wouter P., Buchan, Rachel J., van Velzen, Hannah G., van Slegtenhorst, Marjon A., Vermeulen, Jentien M., Offerhaus, Joost Allard, Bai, Wenjia, de Marvao, Antonio, Lahrouchi, Najim, Beekman, Leander, Karper, Jacco C., Veldink, Jan H., Kayvanpour, Elham, Pantazis, Antonis, Baksi, A. John, Whiffin, Nicola, Mazzarotto, Francesco, Sloane, Geraldine, Suzuki, Hideaki, Schneider-Luftman, Deborah, Elliott, Paul, Richard, Pascale, Ader, Flavie, Villard, Eric, Lichtner, Peter, Meitinger, Thomas, Tanck, Michael W. T., van Tintelen, J. Peter, Thain, Andrew, McCarty, David, Hegele, Robert A., Roberts, Jason D., Amyot, Julie, Dubé, Marie-Pierre, Cadrin-Tourigny, Julia, Giraldeau, Geneviève, L’Allier, Philippe L., Garceau, Patrick, Tardif, Jean-Claude, Boekholdt, S. Matthijs, Lumbers, R. Thomas, Asselbergs, Folkert W., Barton, Paul J. R., Cook, Stuart A., Prasad, Sanjay K., O’Regan, Declan P., van der Velden, Jolanda, Verweij, Karin J. H., Talajic, Mario, Lettre, Guillaume, Pinto, Yigal M., Meder, Benjamin, Charron, Philippe, de Boer, Rudolf A., Christiaans, Imke, Michels, Michelle, Wilde, Arthur A. M., Watkins, Hugh, Matthews, Paul M., Ware, James S., and Bezzina, Connie R.

Published
2021
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19. Prognostic factors for return to work following knee arthroplasty

Author

Strijbos, Daniel O., Straat, A. Carlien, van der Sluis, Geert, Boymans, Tim, Hoving, Jan L., Pahlplatz, Thijs M.J., Hoorntje, Alexander, van Zaanen, Yvonne, Coenen, Pieter, Berenji, Manijeh, Reneman, Michiel F., Kuijer, P. Paul F.M., Strijbos, Daniel O., Straat, A. Carlien, van der Sluis, Geert, Boymans, Tim, Hoving, Jan L., Pahlplatz, Thijs M.J., Hoorntje, Alexander, van Zaanen, Yvonne, Coenen, Pieter, Berenji, Manijeh, Reneman, Michiel F., and Kuijer, P. Paul F.M.

Abstract

Objectives: This is a protocol for a Cochrane Review (prognosis). The objectives are as follows:. We will examine four prognostic factors for return to work that can be used to manage patient expectations, enhance shared decision-making, and improve timely, multidisciplinary, work-directed care. The research question Which of the following four prognostic factors, categorised according to the International Classification of Functioning, Disability and Health (ICF) framework, are associated with return to work after primary knee arthroplasty in patients with a paid job: type of arthroplasty (health condition), sick leave before surgery (participation), physically demanding work (environmental factors), and patient expectations regarding return to work (personal factors)?. PICOTS We define our PICOTS as (Riley 2019): Patients (P): individuals engaged in paid employment who actively choose primary total knee arthroplasty or unicondylar knee arthroplasty as a treatment option for knee osteoarthritis. Index prognostic factors (I): we will consider these prognostic factors. Type of arthroplasty Duration of sick leave prior to surgery Engagement in physically demanding work Person's expectations regarding recovery Comparator (C): Type of arthroplasty: unicondylar knee arthroplasty versus total knee arthroplasty Duration of sick leave prior to surgery: short-term versus long-term Engagement in physically demanding work: light versus medium and heavy knee-demanding work Patient expectations regarding recovery: positive versus negative Outcomes (O): the primary outcome is the return to work, which is further classified by: Nature of return to work: initial, full, or undefined; Method of measurement: Dichotomous (yes/no): short- and long-term return to work; Scale: duration of return to work. Time (T): prognostic factors will be assessed preoperatively. The outcome, i.e. return to work, is measured as dichotomous data (short- and long-term) and on a scale. Short-term (≤ 6 m

Published
2024

20. Erratum: Return to Sport and Work after Randomization for Knee Distraction versus High Tibial Osteotomy: Is There a Difference? (Journal of Knee Surgery DOI: 10.1055/s-0040-1721027)

Author

MS Reumatologie/Immunologie/Infectie, Infection & Immunity, Regenerative Medicine and Stem Cells, Lab Reumatologie/Klinische Immunologie, Hoorntje, Alexander, Kuijer, P. Paul F.M., Koenraadt, Koen L.M., Waterval-Witjes, Suzanne, Kerkhoffs, Gino M.M.J., Mastbergen, Simon C., Marijnissen, Anne C.A., Jansen, Mylène P., van Geenen, Rutger C.I., MS Reumatologie/Immunologie/Infectie, Infection & Immunity, Regenerative Medicine and Stem Cells, Lab Reumatologie/Klinische Immunologie, Hoorntje, Alexander, Kuijer, P. Paul F.M., Koenraadt, Koen L.M., Waterval-Witjes, Suzanne, Kerkhoffs, Gino M.M.J., Mastbergen, Simon C., Marijnissen, Anne C.A., Jansen, Mylène P., and van Geenen, Rutger C.I.

Published
2024

23. Location matters: spatial dynamics of tumor-infiltrating T cell subsets is prognostic in colon cancer

Author

Zhu, Hehuan, primary, Roelands, Jessica, additional, Ahmed, Eiman I., additional, Stouten, Imke, additional, Hoorntje, Rachel, additional, van Vlierberghe, Ronald L. P., additional, Ijsselsteijn, Marieke E., additional, Lei, Xin, additional, de Miranda, Noel F. C. C., additional, Tollenaar, Rob A. E. M., additional, Vahrmeijer, Alexander L., additional, Bedognetti, Davide, additional, Hendrickx, Wouter R. L., additional, and Kuppen, Peter J. K., additional

Published
2024
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24. Improving the diagnostic yield of exome- sequencing by predicting gene–phenotype associations using large-scale gene expression analysis

Author

Patrick Deelen, Sipko van Dam, Johanna C. Herkert, Juha M. Karjalainen, Harm Brugge, Kristin M. Abbott, Cleo C. van Diemen, Paul A. van der Zwaag, Erica H. Gerkes, Evelien Zonneveld-Huijssoon, Jelkje J. Boer-Bergsma, Pytrik Folkertsma, Tessa Gillett, K. Joeri van der Velde, Roan Kanninga, Peter C. van den Akker, Sabrina Z. Jan, Edgar T. Hoorntje, Wouter P. te Rijdt, Yvonne J. Vos, Jan D. H. Jongbloed, Conny M. A. van Ravenswaaij-Arts, Richard Sinke, Birgit Sikkema-Raddatz, Wilhelmina S. Kerstjens-Frederikse, Morris A. Swertz, and Lude Franke

Subjects
Science
Abstract

A genetic diagnosis remains unattainable for many individuals with a rare disease because of incomplete knowledge about the genetic basis of many diseases. Here, the authors present the web-based tool GADO (GeneNetwork Assisted Diagnostic Optimization) that uses public RNA-seq data for prioritization of candidate genes.

Published
2019
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30. Author Correction: The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy

Author

Eijgenraam, Tim R., Boukens, Bastiaan J., Boogerd, Cornelis J., Schouten, E. Marloes, van de Kolk, Cees W. A., Stege, Nienke M., te Rijdt, Wouter P., Hoorntje, Edgar T., van der Zwaag, Paul A., van Rooij, Eva, van Tintelen, J. Peter, van den Berg, Maarten P., van der Meer, Peter, van der Velden, Jolanda, Silljé, Herman H. W., and de Boer, Rudolf A.

Published
2020
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31. The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy

Author

Eijgenraam, Tim R., Boukens, Bastiaan J., Boogerd, Cornelis J., Schouten, E. Marloes, van de Kolk, Cees W. A., Stege, Nienke M., te Rijdt, Wouter P., Hoorntje, Edgar T., van der Zwaag, Paul A., van Rooij, Eva, van Tintelen, J. Peter, van den Berg, Maarten P., van der Meer, Peter, van der Velden, Jolanda, Silljé, Herman H. W., and de Boer, Rudolf A.

Published
2020
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34. Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.

Author

Hoorntje, E.T., Burns, C., Marsili, L., Corden, B., Parikh, V.N., Meerman, G.J. Te, Gray, B., Adiyaman, A., Bagnall, R.D., Barge-Schaapveld, D.Q., Berg, M.P., Bootsma, M., Bosman, L.P., Correnti, G., Duflou, J., Eppinga, R.N., Fatkin, D., Fietz, M., Haan, E., Jongbloed, J.D., Hauer, A.D., Lam, L., Lint, F.H.M. van, Lota, A., Marcelis, C.L., McCarthy, H.J., Mil, A.M. van, Oldenburg, R.A., Pachter, N., Planken, R.N., Reuter, Chloe, Semsarian, C., Smagt, J.J. van der, Thompson, T., Vohra, J., Volders, P.G., Waning, J.I. van, Whiffin, N., Wijngaard, A. van den, Amin, A.S., Wilde, A.A., Woerden, G. van, Yeates, L., Zentner, D., Ashley, E.A., Wheeler, M.T., Ware, J.S., Tintelen, J.P. van, Ingles, J., Hoorntje, E.T., Burns, C., Marsili, L., Corden, B., Parikh, V.N., Meerman, G.J. Te, Gray, B., Adiyaman, A., Bagnall, R.D., Barge-Schaapveld, D.Q., Berg, M.P., Bootsma, M., Bosman, L.P., Correnti, G., Duflou, J., Eppinga, R.N., Fatkin, D., Fietz, M., Haan, E., Jongbloed, J.D., Hauer, A.D., Lam, L., Lint, F.H.M. van, Lota, A., Marcelis, C.L., McCarthy, H.J., Mil, A.M. van, Oldenburg, R.A., Pachter, N., Planken, R.N., Reuter, Chloe, Semsarian, C., Smagt, J.J. van der, Thompson, T., Vohra, J., Volders, P.G., Waning, J.I. van, Whiffin, N., Wijngaard, A. van den, Amin, A.S., Wilde, A.A., Woerden, G. van, Yeates, L., Zentner, D., Ashley, E.A., Wheeler, M.T., Ware, J.S., Tintelen, J.P. van, and Ingles, J.

Abstract

01 februari 2023, Item does not contain fulltext, BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Published
2023

35. A randomized controlled trial of eplerenone in asymptomatic phospholamban p.Arg14del carriers

Author

de Brouwer, Remco, te Rijdt, Wouter P., Hoorntje, Edgar T., Amin, Ahmad, Asselbergs, Folkert W., Cox, Moniek G.P.J., van der Heijden, Jeroen F., Hillege, Hans, Karper, Jacco C., Mahmoud, Belend, van der Meer, Peter, Oomen, Anton, te Riele, Anneline S.J.M., Silljé, Herman H.W., Tan, Hanno L., van Tintelen, Jan Peter, van Veldhuisen, Dirk J., Westenbrink, Berend Daan, Wiesfeld, Ans C.P., Willems, Tineke P., van der Zwaag, Paul A., Wilde, Arthur A.M., de Boer, Rudolf A., van den Berg, Maarten P., de Brouwer, Remco, te Rijdt, Wouter P., Hoorntje, Edgar T., Amin, Ahmad, Asselbergs, Folkert W., Cox, Moniek G.P.J., van der Heijden, Jeroen F., Hillege, Hans, Karper, Jacco C., Mahmoud, Belend, van der Meer, Peter, Oomen, Anton, te Riele, Anneline S.J.M., Silljé, Herman H.W., Tan, Hanno L., van Tintelen, Jan Peter, van Veldhuisen, Dirk J., Westenbrink, Berend Daan, Wiesfeld, Ans C.P., Willems, Tineke P., van der Zwaag, Paul A., Wilde, Arthur A.M., de Boer, Rudolf A., and van den Berg, Maarten P.

Abstract

Phospholamban (PLN; p.Arg14del) cardiomyopathy is an inherited disease caused by the pathogenic p.Arg14del variant in the PLN gene. Clinically, it is characterized by malignant ventricular arrhythmias and progressive heart failure.1,2 Cardiac fibrotic tissue remodelling occurs early on in PLN p.Arg14del carriers.3,4 Eplerenone was deemed a treatment candidate because of its beneficial effects on ventricular remodelling and antifibrotic properties.5,6 We conducted the multicentre randomized trial ‘intervention in PHOspholamban RElated CArdiomyopathy STudy’ (i-PHORECAST) to assess whether treatment with eplerenone of asymptomatic PLN p.Arg14del carriers attenuates disease onset and progression.

Published
2023

36. Arrhythmogenic cardiomyopathy - beyond monogenetic disease

Author

Hoorntje, Edgar and Hoorntje, Edgar

Abstract

Interpreting genetic variants, describing their associated clinical characteristics, and identifying new genetic loci involved in arrhythmogenic cardiomyopathy (ACM) is the focus of this thesis. By investigating various aspects of these genetic variants, we were able to correctly classify two variants occurring in the lamin A/C (LMNA) and titin (TTN) gene. We demonstrated that the reduced force generation seen in cardiomyocytes with the LMNA variant (LMNA c.992G>A) is due to remodelling within the cardiomyocytes and that patients with this specific variant have a milder phenotype compared to what is known from other pathogenic LMNA variants. By extensive phenotyping of carriers of a truncating TTN variant (TTN c.59926+1G>A) we were the first to show that (paroxysmal) atrial fibrillation is an important clinical feature in carriers of truncated TTN variants, even in the absence of dilated cardiomyopathy, atrial enlargement or generally accepted risk factors for atrial fibrillation. Thanks to extensive international collaboration it was possible to compile one of the largest cohorts of patients carrying truncating variants in desmoplakin (DSP). We showed that the location of such a genetic variant within the gene is associated with disease severity. Moreover, these studies show that enrichment of truncating genetic variants in specific regions of DSP variants in ACM patients, when compared to controls, facilitating interpretation of such variants. The multifactorial nature of ACM was underscored in a systematic analysis of the clinical outcome of patients from ACM cohorts carrying multiple variants in ACM related genes, showing that carrying multiple variants influences disease severity. Finally, by analysing genes encoding the sarcomere, the contractile unit of the heart muscle and the plectin (PLEC) gene for rare variants in ACM patients, we showed that these genes do not have a major role in the development of ACM.

Published
2023

37. Variant Location Is a Novel Risk Factor for Individuals with Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant

Author

Hoorntje, Edgar T., Burns, Charlotte, Marsili, Luisa, Corden, Ben, Parikh, Victoria N., Te Meerman, Gerard J., Gray, Belinda, Adiyaman, Ahmet, Bagnall, Richard D., Barge-Schaapveld, Daniela Q.C.M., Van Den Berg, Maarten P., Bootsma, Marianne, Bosman, Laurens P., Correnti, Gemma, Duflou, Johan, Eppinga, Ruben N., Fatkin, Diane, Fietz, Michael, Haan, Eric, Jongbloed, Jan D.H., Hauer, Arnaud D., Lam, Lien, Van Lint, Freyja H.M., Lota, Amrit, Marcelis, Carlo, McCarthy, Hugh J., Van Mil, Anneke M., Oldenburg, Rogier A., Pachter, Nicholas, Planken, R. Nils, Reuter, Chloe, Semsarian, Christopher, Van Der Smagt, Jasper J., Thompson, Tina, Vohra, Jitendra, Volders, Paul G.A., Van Waning, Jaap I., Whiffin, Nicola, Van Den Wijngaard, Arthur, Amin, Ahmad S., Wilde, Arthur A.M., Van Woerden, Gijs, Yeates, Laura, Zentner, Dominica, Ashley, Euan A., Wheeler, Matthew T., Ware, James S., Van Tintelen, J. Peter, Ingles, Jodie, Hoorntje, Edgar T., Burns, Charlotte, Marsili, Luisa, Corden, Ben, Parikh, Victoria N., Te Meerman, Gerard J., Gray, Belinda, Adiyaman, Ahmet, Bagnall, Richard D., Barge-Schaapveld, Daniela Q.C.M., Van Den Berg, Maarten P., Bootsma, Marianne, Bosman, Laurens P., Correnti, Gemma, Duflou, Johan, Eppinga, Ruben N., Fatkin, Diane, Fietz, Michael, Haan, Eric, Jongbloed, Jan D.H., Hauer, Arnaud D., Lam, Lien, Van Lint, Freyja H.M., Lota, Amrit, Marcelis, Carlo, McCarthy, Hugh J., Van Mil, Anneke M., Oldenburg, Rogier A., Pachter, Nicholas, Planken, R. Nils, Reuter, Chloe, Semsarian, Christopher, Van Der Smagt, Jasper J., Thompson, Tina, Vohra, Jitendra, Volders, Paul G.A., Van Waning, Jaap I., Whiffin, Nicola, Van Den Wijngaard, Arthur, Amin, Ahmad S., Wilde, Arthur A.M., Van Woerden, Gijs, Yeates, Laura, Zentner, Dominica, Ashley, Euan A., Wheeler, Matthew T., Ware, James S., Van Tintelen, J. Peter, and Ingles, Jodie

Abstract

Background: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. Methods: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. Results: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). Conclusions: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Published
2023

38. A randomized controlled trial of eplerenone in asymptomatic phospholamban p.Arg14del carriers

Author

Cardiologie, Team Medisch, Team Onderzoek, Circulatory Health, Onderzoek Device, Genetica, Genetica Groep Van Tintelen, Child Health, de Brouwer, Remco, te Rijdt, Wouter P., Hoorntje, Edgar T., Amin, Ahmad, Asselbergs, Folkert W., Cox, Moniek G.P.J., van der Heijden, Jeroen F., Hillege, Hans, Karper, Jacco C., Mahmoud, Belend, van der Meer, Peter, Oomen, Anton, te Riele, Anneline S.J.M., Silljé, Herman H.W., Tan, Hanno L., van Tintelen, Jan Peter, van Veldhuisen, Dirk J., Westenbrink, Berend Daan, Wiesfeld, Ans C.P., Willems, Tineke P., van der Zwaag, Paul A., Wilde, Arthur A.M., de Boer, Rudolf A., van den Berg, Maarten P., Cardiologie, Team Medisch, Team Onderzoek, Circulatory Health, Onderzoek Device, Genetica, Genetica Groep Van Tintelen, Child Health, de Brouwer, Remco, te Rijdt, Wouter P., Hoorntje, Edgar T., Amin, Ahmad, Asselbergs, Folkert W., Cox, Moniek G.P.J., van der Heijden, Jeroen F., Hillege, Hans, Karper, Jacco C., Mahmoud, Belend, van der Meer, Peter, Oomen, Anton, te Riele, Anneline S.J.M., Silljé, Herman H.W., Tan, Hanno L., van Tintelen, Jan Peter, van Veldhuisen, Dirk J., Westenbrink, Berend Daan, Wiesfeld, Ans C.P., Willems, Tineke P., van der Zwaag, Paul A., Wilde, Arthur A.M., de Boer, Rudolf A., and van den Berg, Maarten P.

Published
2023

39. Variant Location Is a Novel Risk Factor for Individuals with Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant

Author

Arts Assistenten Cardiologie, Genetica, Genetica Groep Van Tintelen, Genetica Klinische Genetica, Circulatory Health, Cancer, Child Health, Hoorntje, Edgar T., Burns, Charlotte, Marsili, Luisa, Corden, Ben, Parikh, Victoria N., Te Meerman, Gerard J., Gray, Belinda, Adiyaman, Ahmet, Bagnall, Richard D., Barge-Schaapveld, Daniela Q.C.M., Van Den Berg, Maarten P., Bootsma, Marianne, Bosman, Laurens P., Correnti, Gemma, Duflou, Johan, Eppinga, Ruben N., Fatkin, Diane, Fietz, Michael, Haan, Eric, Jongbloed, Jan D.H., Hauer, Arnaud D., Lam, Lien, Van Lint, Freyja H.M., Lota, Amrit, Marcelis, Carlo, McCarthy, Hugh J., Van Mil, Anneke M., Oldenburg, Rogier A., Pachter, Nicholas, Planken, R. Nils, Reuter, Chloe, Semsarian, Christopher, Van Der Smagt, Jasper J., Thompson, Tina, Vohra, Jitendra, Volders, Paul G.A., Van Waning, Jaap I., Whiffin, Nicola, Van Den Wijngaard, Arthur, Amin, Ahmad S., Wilde, Arthur A.M., Van Woerden, Gijs, Yeates, Laura, Zentner, Dominica, Ashley, Euan A., Wheeler, Matthew T., Ware, James S., Van Tintelen, J. Peter, Ingles, Jodie, Arts Assistenten Cardiologie, Genetica, Genetica Groep Van Tintelen, Genetica Klinische Genetica, Circulatory Health, Cancer, Child Health, Hoorntje, Edgar T., Burns, Charlotte, Marsili, Luisa, Corden, Ben, Parikh, Victoria N., Te Meerman, Gerard J., Gray, Belinda, Adiyaman, Ahmet, Bagnall, Richard D., Barge-Schaapveld, Daniela Q.C.M., Van Den Berg, Maarten P., Bootsma, Marianne, Bosman, Laurens P., Correnti, Gemma, Duflou, Johan, Eppinga, Ruben N., Fatkin, Diane, Fietz, Michael, Haan, Eric, Jongbloed, Jan D.H., Hauer, Arnaud D., Lam, Lien, Van Lint, Freyja H.M., Lota, Amrit, Marcelis, Carlo, McCarthy, Hugh J., Van Mil, Anneke M., Oldenburg, Rogier A., Pachter, Nicholas, Planken, R. Nils, Reuter, Chloe, Semsarian, Christopher, Van Der Smagt, Jasper J., Thompson, Tina, Vohra, Jitendra, Volders, Paul G.A., Van Waning, Jaap I., Whiffin, Nicola, Van Den Wijngaard, Arthur, Amin, Ahmad S., Wilde, Arthur A.M., Van Woerden, Gijs, Yeates, Laura, Zentner, Dominica, Ashley, Euan A., Wheeler, Matthew T., Ware, James S., Van Tintelen, J. Peter, and Ingles, Jodie

Published
2023

40. A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients

Author

Arts Assistenten Cardiologie, Genetica Sectie Genoomdiagnostiek, Circulatory Health, Cardiologie, Team Medisch, Onderzoek Precision medicine, Genetica Groep Van Tintelen, Cancer, Child Health, Nagyova, Emilia, Hoorntje, Edgar T, Rijdt, Wouter P Te, Bosman, Laurens P, Syrris, Petros, Protonotarios, Alexandros, Elliott, Perry M, Tsatsopoulou, Adalena, Mestroni, Luisa, Taylor, Matthew R G, Sinagra, Gianfranco, Merlo, Marco, Wada, Yuko, Horie, Minoru, Mogensen, Jens, Christensen, Alex H, Gerull, Brenda, Song, Lei, Yao, Yan, Fan, Siyang, Saguner, Ardan M, Duru, Firat, Koskenvuo, Juha W, Cruz Marino, Tania, Tichnell, Crystal, Judge, Daniel P, Dooijes, Dennis, Lekanne Deprez, Ronald H, Basso, Cristina, Pilichou, Kalliopi, Bauce, Barbara, Wilde, Arthur A M, Charron, Philippe, Fressart, Véronique, van der Heijden, Jeroen F, van den Berg, Maarten P, Asselbergs, Folkert W, James, Cynthia A, Jongbloed, Jan D H, Harakalova, Magdalena, van Tintelen, J Peter, Arts Assistenten Cardiologie, Genetica Sectie Genoomdiagnostiek, Circulatory Health, Cardiologie, Team Medisch, Onderzoek Precision medicine, Genetica Groep Van Tintelen, Cancer, Child Health, Nagyova, Emilia, Hoorntje, Edgar T, Rijdt, Wouter P Te, Bosman, Laurens P, Syrris, Petros, Protonotarios, Alexandros, Elliott, Perry M, Tsatsopoulou, Adalena, Mestroni, Luisa, Taylor, Matthew R G, Sinagra, Gianfranco, Merlo, Marco, Wada, Yuko, Horie, Minoru, Mogensen, Jens, Christensen, Alex H, Gerull, Brenda, Song, Lei, Yao, Yan, Fan, Siyang, Saguner, Ardan M, Duru, Firat, Koskenvuo, Juha W, Cruz Marino, Tania, Tichnell, Crystal, Judge, Daniel P, Dooijes, Dennis, Lekanne Deprez, Ronald H, Basso, Cristina, Pilichou, Kalliopi, Bauce, Barbara, Wilde, Arthur A M, Charron, Philippe, Fressart, Véronique, van der Heijden, Jeroen F, van den Berg, Maarten P, Asselbergs, Folkert W, James, Cynthia A, Jongbloed, Jan D H, Harakalova, Magdalena, and van Tintelen, J Peter

Published
2023

41. A randomized controlled trial of eplerenone in asymptomatic phospholamban p.Arg14del carriers

Author

de Brouwer, Remco, primary, te Rijdt, Wouter P, additional, Hoorntje, Edgar T, additional, Amin, Ahmad, additional, Asselbergs, Folkert W, additional, Cox, Moniek G P J, additional, van der Heijden, Jeroen F, additional, Hillege, Hans, additional, Karper, Jacco C, additional, Mahmoud, Belend, additional, van der Meer, Peter, additional, Oomen, Anton, additional, te Riele, Anneline S J M, additional, Silljé, Herman H W, additional, Tan, Hanno L, additional, van Tintelen, Jan Peter, additional, van Veldhuisen, Dirk J, additional, Westenbrink, Berend Daan, additional, Wiesfeld, Ans C P, additional, Willems, Tineke P, additional, van der Zwaag, Paul A, additional, Wilde, Arthur A M, additional, de Boer, Rudolf A, additional, and van den Berg, Maarten P, additional

Published
2023
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43. Airway Obstruction Worsens in Young Adults with Asthma Who Become Obese

Author

Williams, Paul, Lasley, Mary V., Chinn, Tamara, Hinatsu, Michele, Furukawa, Clifton T., Altman, Leonard C., Virant, Frank S., Kennedy, Michael S., Tilles, Stephen, Becker, Jonathan W., Bierman, C. Warren, Crawford, Dan, DuHamel, Thomas, Eliassen, Heather, Hammond, Babi, MacLaren, Miranda, Minotti, Dominick A., Reagan, Chris, Shapiro, Gail, Sharpe, Marian, Tatum, Ashley, White, Grace, Wighton, Timothy G., Fuhlbrigge, Anne, Plunkett, Anne, Madden, Nancy, Anderson, Susan, Boehnert, Mark, Feins, Anita, Gentile, Amanda, Kandror, Natalia, MacAulay, Kelly, Sampong, Ernestina, Weiss, Scott, Torda, Walter, Tata, Martha, Babigian, Sally, Barrant, Peter, Benson, Linda, Caicedo, Jose, Calder, Tatum, Darcy, Christine, DeFilippo, Anthony, Dorsainvil, Cindy, Erickson, Julie, Fulton, Phoebe, Grace, Mary, Gilbert, Jennifer, Greineder, Dirk, Haynes, Stephanie, Higham, Margaret, Jakubowski, Deborah, Kelleher, Susan, Koslof, Jay, Mandel, Dana, Martin, Patricia, Martinez, Agnes, McAuliffe, Jean, Nakamoto, Erika, Pacella, Paola, Parks, Paula, Sagarin, Johanna, Seligsohn, Kay, Swords, Susan, Syring, Meghan, Traylor, June, Van Horn, Melissa, Wells, Carolyn, Whitman, Ann, Grasemann, Hartmut, Miki, Melody, Solomon, Melinda, Subbarao, Padmaja, MacLusky, Ian, Reisman, Joe, Levison, Henry, Hall, Anita, Benedet, Yola, Carpenter, Susan, Chay, Jennifer, Collinson, Michelle, Finlayson-Kulchin, Jane, Gore, Kenneth, Hipolito, Nina, Holmes, Noreen, Hoorntje, Erica, Klassen, Sharon, Quenneville, Joseé, Sananes, Renée, Wasson, Christine, Wilson, Margaret, Adkinson, N. Franklin, Jr., Bull, Deborah, Philips, Stephanie, Eggleston, Peyton, Huss, Karen, Plotnick, Leslie, Pulsifer, Margaret, Rand, Cynthia, Aylward, Elizabeth, Bollers, Nancy, Pessaro, Kathy, Wheeler, Barbara, Szefler, Stanley, Covar, Ronina, Nelson, Harold S., Bender, Bruce, Liu, Andrew, Sundström, D., Phillips, Melanie, White, Michael P., Gleason, Melanie, Brelsford, Kristin, Bridges, Jessyca, Ciacco, Jody, Eltz, Michael, Feeley, Jeryl, Flynn, Michael, Junk-Blanchard, Tara, Hassell, Joseph, Hefner, Marcia, Hendrickson, Caroline, Hettleman, Daniel, Irvin, Charles G., Kamada, Alan, Krawiec, Marzena, Larsen, Gary, Nimmagadda, Sai, Sandoval, Kendra, Sheridan, Jessica, Spahn, Joseph, Spears, Gayle, Washington, Trella, Willcutt, Eric, Cardona, Ivan, Carel, Kirstin, Doshi, Jayna, Hendershot, Rich, Jacobs, Jeffrey, Jain, Neal, Kang, June-ku Brian, Kruzick, Tracy, Leo, Harvey, Macomber, Beth, Malka, Jonathan, Mjaanes, Chris, Prpich, John, Stewart, Lora, Song, Ben, Tamesis, Grace, Zeiger, Robert S., Friedman, Noah, Mellon, Michael H., Schatz, Michael, Long, Terrie, Macaraeg, Travis, Christensen, Sandra, Easton, James G., Feinberg, M., Galbreath, Linda L., Gulczynski, Jennifer, Harden, Kathleen, Hansen, Ellen, Jalowayski, Al, Jenson, Elaine, Lincoln, Alan, Kaufman, Jennie, King, Shirley, Lopez, Brian, Magiari-Ene, Michaela, Mostafa, Kathleen, Moscona, Avraham, Nelle, Catherine A., Powers, Jennifer, Rodriguez, Elsa, Rodriguez, Eva, Sandoval, Karen, Wilson, Nevin W., Raissy, Hengameh H., Jacobs, Aaron, Kelly, H. William, Spicher, Mary, Batson, Christina, Harkings, Michelle, McCallum, Katie, Annett, Robert, Archibeque, Teresa, Bashir, Naim, Bereket, H. Selda, Braun, Marisa, Bush, Carrie, Bush, Shannon C., Clayton, Michael, Colon-Semidey, Angel, Devault, Sara, Esparham, Anna, Grad, Roni, Hunt, David, Larsson, Jeanne, McClelland, Sandra, McWilliams, Bennie, Montoya, Elisha, Moreshead, Margaret, Murphy, Shirley, Ortega, Barbara, Weers, David, Zayas, Jose, Strunk, Robert C., Bacharier, Leonard, Rodgers, Denise, Albers, Ellen, Belle, Gregg, Bloomberg, Gordon R., Buchanan, W. Patrick, Caesar, Mary, Corry, James M., DeMuth, Karen, Dolinsky, Marisa, Fisher, Edwin B., Gaioni, Stephen J., Glynn, Emily, Heckman, Bernadette D., Kemp, Debra, Kertz, Lila, Lawhon, Claire, Morgan, Valerie, Moseid, Cynthia, Oliver-Welker, Tina, Richardson, Diana, Ryan, Elizabeth, Sagal, Sharon, Smith, Thomas F., Sylvia, Susan, Turner, Carl, White, Deborah K., Tonascia, James, Belt, Patricia, Collins, Karen, Collison, Betty, Dodge, John, Donithan, Michele, Ewing, Cathleen, Jackson, Rosetta, May, Patrick, Meinert, Jill, Reyes, Girlie, Smith, Michael, Sternberg, Alice L., Van Natta, Mark L., Wagoner, Annette, Wilson, Laura, Wise, Robert, Yates, Katherine, Taggart, Virginia, Eggers, Lois, Kiley, James, Moore, Howard, Zheng, Gang, Albert, Paul, Hurd, Suzanne, Parker, Sydney, Randall, Pamela, Wu, Margaret, Cloutier, Michelle, Connett, John, Cuttler, Leona, Gilliland, Frank, Davis, Clarence E., Eigen, Howard, Evans, David, Kattan, Meyer, Menendez, Rogelio, Simons, F. Estelle R., Leikin, Sanford, Strunk, Robert, Adkinson, N. Franklin, Cherniack, Reuben, DuHamel, Thomas R., Meinert, Curtis L., Shapiro, Gail G., Zeiger, Robert, Colvin, Ryan, Bacharier, Leonard B., Forno, Erick, Arbelaez, Ana Maria, and Tantisira, Kelan G.

Published
2015
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44. A randomized controlled trial of eplerenone in asymptomatic phospholamban p.Arg14del carriers

Author

Remco de Brouwer, Wouter P te Rijdt, Edgar T Hoorntje, Ahmad Amin, Folkert W Asselbergs, Moniek G P J Cox, Jeroen F van der Heijden, Hans Hillege, Jacco C Karper, Belend Mahmoud, Peter van der Meer, Anton Oomen, Anneline S J M te Riele, Herman H W Silljé, Hanno L Tan, Jan Peter van Tintelen, Dirk J van Veldhuisen, Berend Daan Westenbrink, Ans C P Wiesfeld, Tineke P Willems, Paul A van der Zwaag, Arthur A M Wilde, Rudolf A de Boer, and Maarten P van den Berg

Subjects
Cardiology and Cardiovascular Medicine
Published
2023
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46. Current MitraClip experience, safety and feasibility in the Netherlands

Author

Rahhab, Z., Kortlandt, F. A., Velu, J. F., Schurer, R. A. J., Delgado, V., Tonino, P., Boven, A. J., Van den Branden, B. J. L., Kraaijeveld, A. O., Voskuil, M., Hoorntje, J., van Wely, M., van Houwelingen, K., Bleeker, G. B., Rensing, B., Kardys, I., Baan jr., J., Van der Heyden, J. A. S., and Van Mieghem, N. M.

Published
2017
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48. Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant

Author

Edgar T. Hoorntje, Charlotte Burns, Luisa Marsili, Ben Corden, Victoria N. Parikh, Gerard J. te Meerman, Belinda Gray, Ahmet Adiyaman, Richard D. Bagnall, Daniela Q.C.M. Barge-Schaapveld, Maarten P. van den Berg, Marianne Bootsma, Laurens P. Bosman, Gemma Correnti, Johan Duflou, Ruben N. Eppinga, Diane Fatkin, Michael Fietz, Eric Haan, Jan D.H. Jongbloed, Arnaud D. Hauer, Lien Lam, Freyja H.M. van Lint, Amrit Lota, Carlo Marcelis, Hugh J. McCarthy, Anneke M. van Mil, Rogier A. Oldenburg, Nicholas Pachter, R. Nils Planken, Chloe Reuter, Christopher Semsarian, Jasper J. van der Smagt, Tina Thompson, Jitendra Vohra, Paul G.A. Volders, Jaap I. van Waning, Nicola Whiffin, Arthur van den Wijngaard, Ahmad S. Amin, Arthur A.M. Wilde, Gijs van Woerden, Laura Yeates, Dominica Zentner, Euan A. Ashley, Matthew T. Wheeler, James S. Ware, J. Peter van Tintelen, Jodie Ingles, Cardiovascular Centre (CVC), Human Genetics, Graduate School, ACS - Heart failure & arrhythmias, AII - Cancer immunology, Amsterdam Reproduction & Development (AR&D), Radiology and Nuclear Medicine, ACS - Pulmonary hypertension & thrombosis, ACS - Atherosclerosis & ischemic syndromes, Cardiology, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, and Clinical Genetics

Subjects
cardiomyopathies, All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], sudden cardiac, death, death, sudden cardiac, primary, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], General Medicine, desmoplakins, genetic testing
Abstract

Background: Truncating variants in desmoplakin ( DSP tv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSP tv cardiomyopathy. Methods: Individuals with DSP tv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSP tv performed. Results: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSP tv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSP tv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P Conclusions: In the largest series of individuals with DSP tv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Published
2023

49. Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin ( DSP ) Truncating Variant

Author

Hoorntje, Edgar T., primary, Burns, Charlotte, additional, Marsili, Luisa, additional, Corden, Ben, additional, Parikh, Victoria N., additional, te Meerman, Gerard J., additional, Gray, Belinda, additional, Adiyaman, Ahmet, additional, Bagnall, Richard D., additional, Barge-Schaapveld, Daniela Q.C.M., additional, van den Berg, Maarten P., additional, Bootsma, Marianne, additional, Bosman, Laurens P., additional, Correnti, Gemma, additional, Duflou, Johan, additional, Eppinga, Ruben N., additional, Fatkin, Diane, additional, Fietz, Michael, additional, Haan, Eric, additional, Jongbloed, Jan D.H., additional, Hauer, Arnaud D., additional, Lam, Lien, additional, van Lint, Freyja H.M., additional, Lota, Amrit, additional, Marcelis, Carlo, additional, McCarthy, Hugh J., additional, van Mil, Anneke M., additional, Oldenburg, Rogier A., additional, Pachter, Nicholas, additional, Planken, R. Nils, additional, Reuter, Chloe, additional, Semsarian, Christopher, additional, van der Smagt, Jasper J., additional, Thompson, Tina, additional, Vohra, Jitendra, additional, Volders, Paul G.A., additional, van Waning, Jaap I., additional, Whiffin, Nicola, additional, van den Wijngaard, Arthur, additional, Amin, Ahmad S., additional, Wilde, Arthur A.M., additional, van Woerden, Gijs, additional, Yeates, Laura, additional, Zentner, Dominica, additional, Ashley, Euan A., additional, Wheeler, Matthew T., additional, Ware, James S., additional, van Tintelen, J. Peter, additional, and Ingles, Jodie, additional

Published
2023
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