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1. 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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4. 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

5. 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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6. 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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8. 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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9. 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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10. 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

11. 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

12. 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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13. 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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15. 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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16. 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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18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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; https://orcid.org/0000-0003-1896-0803, Duru, Firat; https://orcid.org/0000-0002-4748-0158, Koskenvuo, Juha W, Cruz Marino, Tania, Tichnell, Crystal, Judge, Daniel P, Dooijes, Dennis, Lekanne Deprez, Ronald H, Basso, Cristina, Pilichou, Kalliopi, et al, 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; https://orcid.org/0000-0003-1896-0803, Duru, Firat; https://orcid.org/0000-0002-4748-0158, Koskenvuo, Juha W, Cruz Marino, Tania, Tichnell, Crystal, Judge, Daniel P, Dooijes, Dennis, Lekanne Deprez, Ronald H, Basso, Cristina, Pilichou, Kalliopi, and et al

Abstract

The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy. Graphical Abstract.

Published
2023

26. 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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27. 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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29. 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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30. Correction to: Opening‑ and closing‑wedge high tibial osteotomy are comparable and early full weight bearing is safe with angular stable plate fixation: a meta‑analysis (Knee Surgery, Sports Traumatology, Arthroscopy, (2022), 10.1007/s00167-022-07229-3)

Author

van Haeringen, M H, Kuijer, P P F M, Daams, J G, van Geenen, R C I, Brinkman, J M, Kerkhoffs, G M M J, van Heerwaarden, R J, Hoorntje, A, Public and occupational health, APH - Quality of Care, APH - Societal Participation & Health, AMS - Musculoskeletal Health, AMS - Sports, Medical Library, Orthopedic Surgery and Sports Medicine, AMS - Ageing & Vitality, AMS - Sports & Work, and AMS - Amsterdam Movement Sciences

Abstract

Authors would like to update the title of the Electronic Supplementary Material. The revised version of ESM files updated to the original publication. The original article has been corrected.

Published
2023

31. 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

32. 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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33. No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy.

Author

Edgar T Hoorntje, Anna Posafalvi, Petros Syrris, K Joeri van der Velde, Marieke C Bolling, Alexandros Protonotarios, Ludolf G Boven, Nuria Amat-Codina, Judith A Groeneweg, Arthur A Wilde, Nara Sobreira, Hugh Calkins, Richard N W Hauer, Marcel F Jonkman, William J McKenna, Perry M Elliott, Richard J Sinke, Maarten P van den Berg, Stephen P Chelko, Cynthia A James, J Peter van Tintelen, Daniel P Judge, and Jan D H Jongbloed

Subjects
Medicine, Science
Abstract

AIMS:Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure. METHODS:We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF]

Published
2018
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34. A randomized controlled trial of eplerenone in asymptomatic phospholamban p.Arg14del carriers.

Author

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

Subjects
PHOSPHOLAMBAN, ARRHYTHMIA, RANDOMIZED controlled trials, ARRHYTHMOGENIC right ventricular dysplasia, VENTRICULAR arrhythmia, HEART failure, CARDIAC magnetic resonance imaging
Abstract

Keywords: Phospholamban; Eplerenone; Fibrosis; Cardiomyopathy; Heart failure; Randomized clinical trial EN Phospholamban Eplerenone Fibrosis Cardiomyopathy Heart failure Randomized clinical trial 4284 4287 4 10/25/23 20231021 NES 231021 Introduction Phospholamban ( I PLN i ; p.Arg14del) cardiomyopathy is an inherited disease caused by the pathogenic p.Arg14del variant in the I PLN i gene. The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy. Future research into I PLN i p.Arg14del cardiomyopathy disease progression or modification - and more broadly, research into asymptomatic carriers of pathogenic variations associated with genetic cardiomyopathies - may be better designed using the knowledge obtained in this study. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. [Extracted from the article]

Published
2023
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36. Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (

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, and Jodie, Ingles

Abstract

Truncating variants in desmoplakin (Individuals withThere were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with aIn the largest series of individuals with

Published
2022

37. The effect of eplerenone on the disease onset and progression of phospholamban cardiomyopathy in presymptomatic mutation carriers: results of the i-PHORECAST trial

Author

R De Brouwer, W P Te Rijdt, E T Hoorntje, J C Karper, B D Westenbrink, A S J M Te Riele, J F Van Der Heijden, A Amin, J P Van Tintelen, F W Asselbergs, A A M Wilde, R A De Boer, and M P Van Den Berg

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Background A pathogenic variant in the gene encoding phospholamban (PLN; p.Arg14del) may cause cardiomyopathy, the pathophysiologic hallmark of which is cardiac fibrosis that may cause malignant ventricular arrhythmias and severe heart failure. There is no evidence-based therapy to modify disease progression in presymptomatic pathogenic variant carriers. Eplerenone is a selective mineralocorticoid receptor antagonist with established antifibrotic properties, and may be a potentially interesting treatment in PLN p.Arg14del mutation carriers. Purpose To investigate if preventive therapy with eplerenone attenuates disease onset and progression in PLN cardiomyopathy. Methods 84 presymptomatic PLN p.Arg14del mutation carriers (median age 39 [27–50] years, 44% males) were randomized 1:1 to receive eplerenone (50mg once daily) or no treatment, and endpoints were adjudicated in a blinded fashion (PROBE design). Baseline values were acquired including demographics, cardiac magnetic resonance imaging (CMR) parameters (ventricular volumes, systolic function, late gadolinium enhancement (LGE)), and electrocardiographic parameters (QRS voltages and ventricular ectopy per 24 hour). Subjects were re-evaluated every year and CMR was performed at baseline and after three years. The composite endpoint included LVEDV/RVEDV increase (>10%), LVEF/RVEF decrease (5%), newly developed LGE on CMR, increase in ventricular ectopy (>100% PVCs/24h if >1000 PVCs/24h), decrease in QRS voltage (>25%), non-sustained ventricular tachycardia, symptoms or arrhythmias necessitating treatment, and cardiovascular death. Results Two out of 84 subjects (2%) were lost to follow up. 49 out of 82 remaining subjects (60%) reached the composite end point, 25 (60%) in the control group, 24 (60%) in the treatment group (p=0.825). There was no significant difference between the groups when considering the individual end points, see Table 1. Baseline and follow up CMR was performed on 76 subjects, 39 in the control group, 37 in the treatment group. In total there were 10 (13%) cases of newly developed LGE, 6 (18%) in the control group, 4 (12%) in the treatment group (p=0.556), see Figure 1. Conclusions Eplerenone did not significantly attenuate disease onset and progression in presymptomatic PLN p.Arg14del mutation carriers. There was no significant difference in new incidence of LGE between the treatment and control groups. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was financially supported by the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (The Hague, Netherlands).

Published
2022
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39. Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features

Author

Ghidoni, A, Elliott, P, Syrris, P, Calkins, H, James, C, Judge, D, Murray, B, Barc, J, Probst, V, Schott, J, Song, J, Hauer, R, Hoorntje, E, Van Tintelen, J, Schulze-Bahr, E, Hamilton, R, Mittal, K, Semsarian, C, Behr, E, Ackerman, M, Basso, C, Parati, G, Gentilini, D, Kotta, M, Mayosi, B, Schwartz, P, Crotti, L, Ghidoni A., Elliott P. M., Syrris P., Calkins H., James C. A., Judge D. P., Murray B., Barc J., Probst V., Schott J. J., Song J. -P., Hauer R. N. W., Hoorntje E. T., Van Tintelen J. P., Schulze-Bahr E., Hamilton R. M., Mittal K., Semsarian C., Behr E. R., Ackerman M. J., Basso C., Parati G., Gentilini D., Kotta M. -C., Mayosi B. M., Schwartz P. J., Crotti L., Ghidoni, A, Elliott, P, Syrris, P, Calkins, H, James, C, Judge, D, Murray, B, Barc, J, Probst, V, Schott, J, Song, J, Hauer, R, Hoorntje, E, Van Tintelen, J, Schulze-Bahr, E, Hamilton, R, Mittal, K, Semsarian, C, Behr, E, Ackerman, M, Basso, C, Parati, G, Gentilini, D, Kotta, M, Mayosi, B, Schwartz, P, Crotti, L, Ghidoni A., Elliott P. M., Syrris P., Calkins H., James C. A., Judge D. P., Murray B., Barc J., Probst V., Schott J. J., Song J. -P., Hauer R. N. W., Hoorntje E. T., Van Tintelen J. P., Schulze-Bahr E., Hamilton R. M., Mittal K., Semsarian C., Behr E. R., Ackerman M. J., Basso C., Parati G., Gentilini D., Kotta M. -C., Mayosi B. M., Schwartz P. J., and Crotti L.

Abstract

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. Methods: A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was performed. Results: Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%). Conclusions: In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

Published
2021

40. The effect of eplerenone on the disease onset and progression of phospholamban cardiomyopathy in presymptomatic mutation carriers: results of the i-PHORECAST trial

Author

De Brouwer, R, primary, Te Rijdt, W P, additional, Hoorntje, E T, additional, Karper, J C, additional, Westenbrink, B D, additional, Te Riele, A S J M, additional, Van Der Heijden, J F, additional, Amin, A, additional, Van Tintelen, J P, additional, Asselbergs, F W, additional, Wilde, A A M, additional, De Boer, R A, additional, and Van Den Berg, M P, additional

Published
2022
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41. Abstract 20814: High Rate of Atrial Arrhythmias in Individuals With Truncating Titin Mutations Including the First Dilated Cardiomyopathy Related Titin Founder Mutation

Author

Hoorntje, Edgar T, van Spaendonck-Zwarts, Karin Y, te Rijdt, Wouter P, Boven, Ludolf, Vink, Aryan, van der Smagt, Jasper J, Asselbergs, Folkert W, van Wijngaarden, Jan, Hennekam, Eric A, Pinto, Yigal, Lekanne Deprez, Ronald H, Barge-Schaapveld, Daniela Q, Bootsma, Marianne, Regieli, Jakub, Hoedemaekers, Yvonne M, Jongbloed, Jan D, van den Berg, Maarten P, and van Tintelen, J. P

Published
2017

44. Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy

Author

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

Subjects
Male, 0301 basic medicine, Indoles, Cardiac fibrosis, Cell- och molekylärbiologi, Cardiomyopathy, Arrhythmias, Cardiovascular, Medical and Health Sciences, Sudden cardiac death, Maleimides, Mice, 0302 clinical medicine, 2.1 Biological and endogenous factors, Aetiology, Wnt Signaling Pathway, Arrhythmogenic Right Ventricular Dysplasia, beta Catenin, Mice, Knockout, Ejection fraction, Cardiology, Cardiovascular disease, Cell Biology, Genetic diseases, Wnt signaling pathway, General Medicine, Phenotype, 3. Good health, Heart Disease, 030220 oncology & carcinogenesis, Female, Arrhythmia, Research Article, Ankyrins, Knockout, Immunology, 03 medical and health sciences, Rare Diseases, Clinical Research, ANK2, Journal Article, medicine, Animals, Humans, Loss function, Animal, business.industry, Myocardium, medicine.disease, Disease Models, Animal, 030104 developmental biology, Disease Models, Cancer research, business, Cell and Molecular Biology
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 beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-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 beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease. Funding Agencies|Marianne Barrie Philanthropic Fund; Canadian Institutes of Health Research [RN332805]; Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation; Dutch Federation of University Medical Centers; Netherlands Organisation for Health Research and Development; Royal Netherlands Academy of Sciences [CVON-PREDICT 2012-10]; Netherlands Cardiovascular Research Initiative - Dutch Heart Foundation [CVON2012-10 PREDICT CVON2018-30 PREDICT2, CVON2015-12 eDETECT]; Netherlands Organization for Scientific Research (NWO) [040.11.586]; Fondation Leducq [16 CVD 02]; Dr. Francis P. Chiramonte Private Foundation; Leyla Erkan Family Fund for ARVD Research; Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; NIH [HL135754, HL134824, HL139348, HL135096, HL114383, HL114893, HL137331, HL137325, 2UM1HG006542, UL1 TR 001079]; Ohio State Frick Center; JB Project

Published
2019
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46. Non-surgical treatment before hip and knee arthroplasty remains underutilized with low satisfaction regarding performance of work, sports, and leisure activities

Author

Leti van Bodegom-Vos, Alexander Hoorntje, Tim A.E.J. Boymans, Rutger C. I. van Geenen, Yvonne van Zaanen, P. Paul F. M. Kuijer, Koen L. M. Koenraadt, Gino M. M. J. Kerkhoffs, Suzanne Waterval-Witjes, MUMC+: MA Orthopedie (9), RS: CAPHRI - R3 - Functioning, Participating and Rehabilitation, Graduate School, APH - Quality of Care, APH - Societal Participation & Health, AMS - Amsterdam Movement Sciences, Orthopedic Surgery and Sports Medicine, Other Research, Coronel Institute of Occupational Health, and AMS - Musculoskeletal Health

Subjects
Male, musculoskeletal diseases, medicine.medical_specialty, Diet therapy, STEPPED CARE STRATEGY, medicine.medical_treatment, MEDLINE, Osteoarthritis, Conservative Treatment, Health Services Misuse, Osteoarthritis, Hip, Patient satisfaction, Activities of Daily Living, TOTAL JOINT REPLACEMENT, medicine, MANAGEMENT, Humans, Pain Management, Orthopedics and Sports Medicine, Arthroplasty, Replacement, Exercise, Netherlands, Orthopedic surgery, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Patient Preference, Non surgical treatment, General Medicine, Guideline, Middle Aged, Osteoarthritis, Knee, medicine.disease, Arthroplasty, Exercise Therapy, Cross-Sectional Studies, Treatment Outcome, Treatment utilization, OSTEOARTHRITIS, Preoperative Period, Physical therapy, Female, Surgery, business, RD701-811, Research Article
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

47. Editorial Commentary: Timely Surgery, Optimizing Perioperative Care, and Prospective Data Collection Are Next Steps to Improving Return to Sport and Work Outcomes After Knee Osteotomy

Author

Alexander Hoorntje, P. Paul F.M. Kuijer, Gino M.M.J. Kerkhoffs, Orthopedic Surgery and Sports Medicine, AMS - Sports & Work, APH - Quality of Care, APH - Societal Participation & Health, Amsterdam Movement Sciences, Public and occupational health, AMS - Musculoskeletal Health, AMS - Sports, and AMS - Ageing & Vitality

Subjects
Knee Joint, Tibia, Data Collection, Humans, Orthopedics and Sports Medicine, Osteoarthritis, Knee, Perioperative Care, Osteotomy, Return to Sport
Abstract

Knee osteotomy is a valuable treatment option for younger knee osteoarthritis patients. Improved surgical techniques, including double-level osteotomies to address femoral and tibial malalignment, have led to reappreciation of this joint-sparing alternative to knee arthroplasty. Yet, postoperative ability to resume sport and work at the desired level needs further improvement. We believe that timely surgery, optimized perioperative care, including evidence-based advice for resumption of activities, and prospective data collection are interesting next steps in this process.

Published
2022
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48. Participation in cardiac telerehabilitation

Author

V Houben, AOF Rikken, A Castro Conde, J Gomes Doblas, J Lozano Torres, C Hoorntje, and AWJ Van 'T Hof

Subjects
Epidemiology, Cardiology and Cardiovascular Medicine
Abstract

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EIT Health Campus Rationale Cardiac rehabilitation (CR) programmes are successful in educating patients and lowering their cardiovascular (CV) risk. However attendance before COVID was between 8 and 50%. Because of short duration of CR programmes sustainability in behaviour change is often suboptimal. The COVID pandemic has shown us the need for high quality remote CR. Mobile guided CR (mCR) has proven to be equally effective as centre-based CR and has the potential to increase participation rates. It also provides possibilities to extend the CR programme. Extending CR programmes with ehealth solutions have shown mixed results on sustainable behaviour change. It is still unknown what type of patients prefer mCR above regular CR when offered as standard care. REHAB+ Rehab+ is a mobile CR program, offered for one year to patients after myocardial infarction as an alternative to the regular CR program. It offers an optimised digital platform and regular interaction with the healthcare team. Patients are able to measure and register physical activity, heart frequency and intensity (BORG scale) and can monitor progress. A care professional (coach) also has access to a portal to monitor progress of different patients, advice on rehabilitation approach and stimulate compliance. Rehab+ is co-created with patients and rehab centres. In 2022, it will conclude its pilot and evaluation in 4 centres (Spain and the Netherlands), and scaled to more in the EU. Objectives 1. To assess whether mCR programmes result in better sustained effects, as compared to the regular CR programme. 2. To explore what type of patients prefer mCR above a regular CR programme. Study population 900 Post myocardial infarction patients (300 mCR, 600 regular CR) who are indicated for CR. (See figure 1) Patients not able or willing to participate will be registered in an exclusion log. mCR patients will be coached for 12 months with decreasing amounts of touchpoints. Regular CR patients receive no coaching after the end of the regular CR program. Study design Prospective, matched control observational trial Follow-up Patients will be monitored at (see table 1): - T0: baseline characteristics, exercise test, laboratory tests, Fägerstrom test, IPAQ questionnaire, SF-36 questionnaire - T1 (3 months): Physical exam, medication, ECG, laboratory tests, adherence and compliance (mCR only),Fägerstrom test, IPAQ questionnaire, SF-36 questionnaire, eHIQ questionnaire - T2 (12 months): Physical exam, medication, ECG, laboratory tests, exercise test, adherence and compliance (mCR only),Fägerstrom test, IPAQ questionnaire, SF-36 questionnaire, eHIQ questionnaire Conclusion Inclusion will start in November 2021. The results of this study will give insight in what type of patients choose to participate in mCR. With this information mCR programmes can be further optimised and adjusted. It may help to further increase participation rates in CR.

Published
2022
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49. Final benefit of primary percutaneous coronary intervention for ST-elevation myocardial infarction in older patients:long-term results of a randomised trial

Author

De Boer, M-J, Ottervanger, J. P., Van't Hof, A. W. J., Hoorntje, J. C. A., Suryapranata, H., Zijlstra, F., De Boer, M-J, Ottervanger, J. P., Van't Hof, A. W. J., Hoorntje, J. C. A., Suryapranata, H., and Zijlstra, F.

Abstract

Background Although the short-term benefit of primary percutaneous coronary intervention (PCI) in elderly patients with ST-elevation myocardial infarction (STEMI) has been demonstrated, the final long-term survival benefit is as yet unknown. Aim To assess the final survival benefit of primary PCI as compared to thrombolytic therapy in patients over 75 years of age. Methods Patients > 75 years with STEMI were randomised to either primary PCI or thrombolysis. Long-term data on survival were available for all patients. Results A total of 46 patients were randomised to primary PCI, 41 to thrombolysis. There were no significant differences in baseline variables. After a maximum of 20 years' follow-up, all patients had passed away. The patients randomised to thrombolysis died after a mean follow-up duration of 5.2 years (SD 4.9) compared to 6.7 years (SD 4.8) in patients randomised to primary PCI (p = 0.15). Thus, the mean final survival benefit of primary PCI was 1.5 years. Conclusion The final survival benefit of primary PCI as compared to thrombolysis in elderly patients with STEMI is 1.5 years and their life expectancy increases by 28.8%.

Published
2022

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

Author

Team Medisch, Circulatory Health, Research UMC Utrecht, Arts Assistenten Cardiologie, Genetica, 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., van den Berg, M. P., Team Medisch, Circulatory Health, Research UMC Utrecht, Arts Assistenten Cardiologie, Genetica, 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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