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

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

doi:https://doi.org/10.1007/s12265-023-10403-8

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

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

Research output: Contribution to journal › Article › Academic › peer-review

2 Citations (Scopus)

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. [Figure not available: see fulltext.].

Original language	English
Pages (from-to)	1276-1286
Number of pages	11
Journal	Journal of cardiovascular translational research
Volume	16
Issue number	6
Early online date	2023
DOIs	https://doi.org/10.1007/s12265-023-10403-8
Publication status	Published - Dec 2023

Keywords

ARVC
Arrhythmia
Composite endpoint
Desmosomal genes
Genetics
Multiple variants

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Nagyova, E., Hoorntje, E. T., Rijdt, W. P. T., Bosman, L. P., Syrris, P., Protonotarios, A., Elliott, P. M., Tsatsopoulou, A., Mestroni, L., Taylor, M. R. G., Sinagra, G., Merlo, M., Wada, Y., Horie, M., Mogensen, J., Christensen, A. H., Gerull, B., Song, L., Yao, Y., ... van Tintelen, J. P. (2023). A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients. Journal of cardiovascular translational research, 16(6), 1276-1286. https://doi.org/10.1007/s12265-023-10403-8

@article{c8785aae13824d0f8dbda07f4f17a724,

title = "A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients",

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. [Figure not available: see fulltext.].",

keywords = "ARVC, Arrhythmia, Composite endpoint, Desmosomal genes, Genetics, Multiple variants",

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

note = "Funding Information: AMS received educational grants through his institution from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, BMS/Pfizer, and Medtronic, and speaker fees from Bayer Healthcare, Daiichi-Sankyo, and Novartis. DPJ reports payments as a consultant from 4D Molecular Therapeutics, ADRx, Inc., Cytokinetics, Pfizer, and Tenaya Therapeutics outside of the scope of this work. CAJ receives salary support on a grant from Boston Scientific Corp through her institution and payment as a consultant from Pfizer and StrideBio, Inc. Consultant LQT Therapeutics (AW). Funding Information: The work was financially supported by the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (CardioVasculair Onderzoek Nederland (CVON) projects 2014–40 DOSIS, 2020B005 Double Dose, 2015–30 eDETECT and 2018–30 PREDICT2 (MH, WPtR, FWA, AW, PvT), NWO VENI grant [no. 016.176.136 to MH], The Independent Research Fund Denmark (Grant 0134-00363B, AHC), the Canadian Institute for Health Research (grant no. FRN: 123351, BG) and the Leducq Foundation CURE-PLaN project 18CVD01 (MH, WPtR, FWA, PvT) and the Netherlands Organisation for Scientific Research (NWO) 040.11.586, visitor{\textquoteright}s travel grant to C.A. James. The Zurich ARVC Program is supported by generous grants from the Georg and Bertha Schwyzer-Winiker-Stiftung, National Institute of Health (NIH) grants: R01HL69071, R01HL116906, R01HL147064 (LM, MRGT), R01HL109209 (MRGT), CRTrieste Foundation, Baugarten and Cassa di Risparmio of Gorizia Foundation, Leonie-Wild Foundation, Swiss Heart Foundation, and Swiss National Science Foundation. The Johns Hopkins ARVC Program is supported by the Leonie-Wild Foundation, the Leyla Erkan Family Fund for ARVD Research, the Dr. Francis P. Chiramonte Private Foundation, the Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella Family, the Patrick J. Harrison Family, the Peter French Memorial Foundation, and the Wilmerding Endowments (GS), Foundation Leducq 14-CVD03 Trans-Atlantic Network of Excellence (LM, MRGT, GS). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "https://doi.org/10.1007/s12265-023-10403-8",

language = "English",

volume = "16",

pages = "1276--1286",

journal = "Journal of cardiovascular translational research",

issn = "1937-5387",

publisher = "Springer New York",

number = "6",

}

Nagyova, E, Hoorntje, ET, Rijdt, WPT, Bosman, LP, Syrris, P, Protonotarios, A, Elliott, PM, Tsatsopoulou, A, Mestroni, L, Taylor, MRG, Sinagra, G, Merlo, M, Wada, Y, Horie, M, Mogensen, J, Christensen, AH, Gerull, B, Song, L, Yao, Y, Fan, S, Saguner, AM, Duru, F, Koskenvuo, JW, Cruz Marino, T, Tichnell, C, Judge, DP, Dooijes, D, Lekanne Deprez, RH, Basso, C, Pilichou, K, Bauce, B, Wilde, AAM, Charron, P, Fressart, VR, van der Heijden, JF, van den Berg, MP, Asselbergs, FW, James, CA, Jongbloed, JDH, Harakalova, M & van Tintelen, JP 2023, 'A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients', Journal of cardiovascular translational research, vol. 16, no. 6, pp. 1276-1286. https://doi.org/10.1007/s12265-023-10403-8

A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients. / Nagyova, Emilia; Hoorntje, Edgar T.; Rijdt, Wouter P. te et al.
In: Journal of cardiovascular translational research, Vol. 16, No. 6, 12.2023, p. 1276-1286.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients

AU - Nagyova, Emilia

AU - Hoorntje, Edgar T.

AU - Rijdt, Wouter P. te

AU - Bosman, Laurens P.

AU - Syrris, Petros

AU - Protonotarios, Alexandros

AU - Elliott, Perry M.

AU - Tsatsopoulou, Adalena

AU - Mestroni, Luisa

AU - Taylor, Matthew R. G.

AU - Sinagra, Gianfranco

AU - Merlo, Marco

AU - Wada, Yuko

AU - Horie, Minoru

AU - Mogensen, Jens

AU - Christensen, Alex H.

AU - Gerull, Brenda

AU - Song, Lei

AU - Yao, Yan

AU - Fan, Siyang

AU - Saguner, Ardan M.

AU - Duru, Firat

AU - Koskenvuo, Juha W.

AU - Cruz Marino, Tania

AU - Tichnell, Crystal

AU - Judge, Daniel P.

AU - Dooijes, Dennis

AU - Lekanne Deprez, Ronald H.

AU - Basso, Cristina

AU - Pilichou, Kalliopi

AU - Bauce, Barbara

AU - Wilde, Arthur A. M.

AU - Charron, Philippe

AU - Fressart, V. ronique

AU - van der Heijden, Jeroen F.

AU - van den Berg, Maarten P.

AU - Asselbergs, Folkert W.

AU - James, Cynthia A.

AU - Jongbloed, Jan D. H.

AU - Harakalova, Magdalena

AU - van Tintelen, J. Peter

N1 - Funding Information: AMS received educational grants through his institution from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, BMS/Pfizer, and Medtronic, and speaker fees from Bayer Healthcare, Daiichi-Sankyo, and Novartis. DPJ reports payments as a consultant from 4D Molecular Therapeutics, ADRx, Inc., Cytokinetics, Pfizer, and Tenaya Therapeutics outside of the scope of this work. CAJ receives salary support on a grant from Boston Scientific Corp through her institution and payment as a consultant from Pfizer and StrideBio, Inc. Consultant LQT Therapeutics (AW). Funding Information: The work was financially supported by the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (CardioVasculair Onderzoek Nederland (CVON) projects 2014–40 DOSIS, 2020B005 Double Dose, 2015–30 eDETECT and 2018–30 PREDICT2 (MH, WPtR, FWA, AW, PvT), NWO VENI grant [no. 016.176.136 to MH], The Independent Research Fund Denmark (Grant 0134-00363B, AHC), the Canadian Institute for Health Research (grant no. FRN: 123351, BG) and the Leducq Foundation CURE-PLaN project 18CVD01 (MH, WPtR, FWA, PvT) and the Netherlands Organisation for Scientific Research (NWO) 040.11.586, visitor’s travel grant to C.A. James. The Zurich ARVC Program is supported by generous grants from the Georg and Bertha Schwyzer-Winiker-Stiftung, National Institute of Health (NIH) grants: R01HL69071, R01HL116906, R01HL147064 (LM, MRGT), R01HL109209 (MRGT), CRTrieste Foundation, Baugarten and Cassa di Risparmio of Gorizia Foundation, Leonie-Wild Foundation, Swiss Heart Foundation, and Swiss National Science Foundation. The Johns Hopkins ARVC Program is supported by the Leonie-Wild Foundation, the Leyla Erkan Family Fund for ARVD Research, the Dr. Francis P. Chiramonte Private Foundation, the Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella Family, the Patrick J. Harrison Family, the Peter French Memorial Foundation, and the Wilmerding Endowments (GS), Foundation Leducq 14-CVD03 Trans-Atlantic Network of Excellence (LM, MRGT, GS). Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - 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. [Figure not available: see fulltext.].

AB - 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. [Figure not available: see fulltext.].

KW - ARVC

KW - Arrhythmia

KW - Composite endpoint

KW - Desmosomal genes

KW - Genetics

KW - Multiple variants

UR - http://www.scopus.com/inward/record.url?scp=85164170998&partnerID=8YFLogxK

U2 - https://doi.org/10.1007/s12265-023-10403-8

DO - https://doi.org/10.1007/s12265-023-10403-8

M3 - Article

C2 - 37418234

SN - 1937-5387

VL - 16

SP - 1276

EP - 1286

JO - Journal of cardiovascular translational research

JF - Journal of cardiovascular translational research

IS - 6

ER -

Nagyova E, Hoorntje ET, Rijdt WPT, Bosman LP, Syrris P, Protonotarios A et al. A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients. Journal of cardiovascular translational research. 2023 Dec;16(6):1276-1286. Epub 2023. doi: https://doi.org/10.1007/s12265-023-10403-8

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

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Keywords

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