Identifying Predictors for Heart Failure Outcomes in Phospholamban p.(Arg14del)-Positive Individuals

Myrthe Y C van der Heide; Tom E Verstraelen; Remco de Brouwer; Esmée van Drie; Virginnio M Proost; Freyja H M van Lint; Laurens P Bosman; Arjan C Houweling; Cathelijne Dickhoff; Tjeerd Germans; Bas A Schoonderwoerd; Juan R Gimeno-Blanes; Laura M G Meems; Anneline S J M Te Riele; Karin Y van Spaendonck-Zwarts; Moniek G P J Cox; Ahmad S Amin; J Peter van Tintelen; Rudolf A de Boer; Aeilko H Zwinderman; Arthur A M Wilde

doi:10.1016/j.jchf.2025.102558

Identifying Predictors for Heart Failure Outcomes in Phospholamban p.(Arg14del)-Positive Individuals

Myrthe Y C van der Heide^*
, Tom E Verstraelen
, Remco de Brouwer
, Esmée van Drie
, Virginnio M Proost
, Freyja H M van Lint
, Laurens P Bosman
, Arjan C Houweling
, Cathelijne Dickhoff
, Tjeerd Germans
, Bas A Schoonderwoerd
, Juan R Gimeno-Blanes
, Laura M G Meems
, Anneline S J M Te Riele
, Karin Y van Spaendonck-Zwarts
, Moniek G P J Cox
, Ahmad S Amin
, J Peter van Tintelen
, Rudolf A de Boer
, Aeilko H Zwinderman

Arthur A M Wilde

^*Corresponding author for this work

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

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Abstract

BACKGROUND: Phospholamban (PLN) p.(Arg14del)-positive individuals are at high risk of developing PLN p.(Arg14del)-related cardiomyopathy, which can lead to progressive heart failure that is poorly amenable to standard heart failure treatment. Genetic therapies for patients with hereditary cardiomyopathy are rapidly advancing, but identifying patients who will benefit from and rely on these therapies is challenging because of reduced penetrance and highly variable expression.

OBJECTIVES: The aim of this study is to identify clinical predictors of heart failure outcomes in PLN p.(Arg14del)-positive individuals.

METHODS: Data were collected of 904 PLN p.(Arg14del)-positive individuals from the PLN/ACM Registry. The primary endpoint of the study was a composite endpoint of heart failure outcomes, defined as heart failure hospitalization, left ventricular or biventricular assist device implantation, heart transplantation, or heart failure-related death. Predictors of heart failure outcomes were identified using Least Absolute Shrinkage and Selection Operator Cox regression analyses with different penalization parameters.

RESULTS: During a median follow-up of 5.4 years (Q1-Q3: 2.3-9.7 years), 116 study participants (13%) reached the primary endpoint (heart failure hospitalization [75%], heart transplantation [10.3%], left ventricular or biventricular assist device implantation [9.5%], and heart failure-related death [5.2%]). The predictors that remained significant across all analyses were left ventricular ejection fraction, low-voltage electrocardiogram, and NYHA functional class ≥II, measured at first evaluation.

CONCLUSIONS: This study identified predictors for heart failure outcomes in PLN p.(Arg14del)-positive individuals that can improve risk prediction. Identifying those at risk for heart failure outcomes is of great importance given the rapid advancements in genetic therapies that may offer potential treatments for hereditary cardiomyopathy.

Original language	English
Article number	102558
Journal	JACC. Heart failure
Volume	13
Issue number	10
Early online date	8 Aug 2025
DOIs	https://doi.org/10.1016/j.jchf.2025.102558
Publication status	Published - Oct 2025

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Identifying Predictors for Heart Failure Outcomes in Phospholamban p.(Arg14del)–Positive IndividualsFinal published version, 1.06 MBLicence: CC BY

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van der Heide, M. Y. C., Verstraelen, T. E., de Brouwer, R., van Drie, E., Proost, V. M., van Lint, F. H. M., Bosman, L. P., Houweling, A. C., Dickhoff, C., Germans, T., Schoonderwoerd, B. A., Gimeno-Blanes, J. R., Meems, L. M. G., Te Riele, A. S. J. M., van Spaendonck-Zwarts, K. Y., Cox, M. G. P. J., Amin, A. S., van Tintelen, J. P., de Boer, R. A., ... Wilde, A. A. M. (2025). Identifying Predictors for Heart Failure Outcomes in Phospholamban p.(Arg14del)-Positive Individuals. JACC. Heart failure, 13(10), Article 102558. https://doi.org/10.1016/j.jchf.2025.102558

@article{885e4de74da441e5bf0244afda1e1259,

title = "Identifying Predictors for Heart Failure Outcomes in Phospholamban p.(Arg14del)-Positive Individuals",

abstract = "BACKGROUND: Phospholamban (PLN) p.(Arg14del)-positive individuals are at high risk of developing PLN p.(Arg14del)-related cardiomyopathy, which can lead to progressive heart failure that is poorly amenable to standard heart failure treatment. Genetic therapies for patients with hereditary cardiomyopathy are rapidly advancing, but identifying patients who will benefit from and rely on these therapies is challenging because of reduced penetrance and highly variable expression.OBJECTIVES: The aim of this study is to identify clinical predictors of heart failure outcomes in PLN p.(Arg14del)-positive individuals.METHODS: Data were collected of 904 PLN p.(Arg14del)-positive individuals from the PLN/ACM Registry. The primary endpoint of the study was a composite endpoint of heart failure outcomes, defined as heart failure hospitalization, left ventricular or biventricular assist device implantation, heart transplantation, or heart failure-related death. Predictors of heart failure outcomes were identified using Least Absolute Shrinkage and Selection Operator Cox regression analyses with different penalization parameters.RESULTS: During a median follow-up of 5.4 years (Q1-Q3: 2.3-9.7 years), 116 study participants (13\%) reached the primary endpoint (heart failure hospitalization [75\%], heart transplantation [10.3\%], left ventricular or biventricular assist device implantation [9.5\%], and heart failure-related death [5.2\%]). The predictors that remained significant across all analyses were left ventricular ejection fraction, low-voltage electrocardiogram, and NYHA functional class ≥II, measured at first evaluation.CONCLUSIONS: This study identified predictors for heart failure outcomes in PLN p.(Arg14del)-positive individuals that can improve risk prediction. Identifying those at risk for heart failure outcomes is of great importance given the rapid advancements in genetic therapies that may offer potential treatments for hereditary cardiomyopathy.",

author = "\{van der Heide\}, \{Myrthe Y C\} and Verstraelen, \{Tom E\} and \{de Brouwer\}, Remco and \{van Drie\}, Esm{\'e}e and Proost, \{Virginnio M\} and \{van Lint\}, \{Freyja H M\} and Bosman, \{Laurens P\} and Houweling, \{Arjan C\} and Cathelijne Dickhoff and Tjeerd Germans and Schoonderwoerd, \{Bas A\} and Gimeno-Blanes, \{Juan R\} and Meems, \{Laura M G\} and \{Te Riele\}, \{Anneline S J M\} and \{van Spaendonck-Zwarts\}, \{Karin Y\} and Cox, \{Moniek G P J\} and Amin, \{Ahmad S\} and \{van Tintelen\}, \{J Peter\} and \{de Boer\}, \{Rudolf A\} and Zwinderman, \{Aeilko H\} and Wilde, \{Arthur A M\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = oct,

doi = "10.1016/j.jchf.2025.102558",

language = "English",

volume = "13",

journal = "JACC. Heart failure",

issn = "2213-1779",

publisher = "Elsevier",

number = "10",

}

van der Heide, MYC, Verstraelen, TE, de Brouwer, R, van Drie, E, Proost, VM, van Lint, FHM, Bosman, LP, Houweling, AC, Dickhoff, C, Germans, T, Schoonderwoerd, BA, Gimeno-Blanes, JR, Meems, LMG, Te Riele, ASJM, van Spaendonck-Zwarts, KY, Cox, MGPJ, Amin, AS, van Tintelen, JP, de Boer, RA, Zwinderman, AH & Wilde, AAM 2025, 'Identifying Predictors for Heart Failure Outcomes in Phospholamban p.(Arg14del)-Positive Individuals', JACC. Heart failure, vol. 13, no. 10, 102558. https://doi.org/10.1016/j.jchf.2025.102558

TY - JOUR

T1 - Identifying Predictors for Heart Failure Outcomes in Phospholamban p.(Arg14del)-Positive Individuals

AU - van der Heide, Myrthe Y C

AU - Verstraelen, Tom E

AU - de Brouwer, Remco

AU - van Drie, Esmée

AU - Proost, Virginnio M

AU - van Lint, Freyja H M

AU - Bosman, Laurens P

AU - Houweling, Arjan C

AU - Dickhoff, Cathelijne

AU - Germans, Tjeerd

AU - Schoonderwoerd, Bas A

AU - Gimeno-Blanes, Juan R

AU - Meems, Laura M G

AU - Te Riele, Anneline S J M

AU - van Spaendonck-Zwarts, Karin Y

AU - Cox, Moniek G P J

AU - Amin, Ahmad S

AU - van Tintelen, J Peter

AU - de Boer, Rudolf A

AU - Zwinderman, Aeilko H

AU - Wilde, Arthur A M

PY - 2025/10

Y1 - 2025/10

N2 - BACKGROUND: Phospholamban (PLN) p.(Arg14del)-positive individuals are at high risk of developing PLN p.(Arg14del)-related cardiomyopathy, which can lead to progressive heart failure that is poorly amenable to standard heart failure treatment. Genetic therapies for patients with hereditary cardiomyopathy are rapidly advancing, but identifying patients who will benefit from and rely on these therapies is challenging because of reduced penetrance and highly variable expression.OBJECTIVES: The aim of this study is to identify clinical predictors of heart failure outcomes in PLN p.(Arg14del)-positive individuals.METHODS: Data were collected of 904 PLN p.(Arg14del)-positive individuals from the PLN/ACM Registry. The primary endpoint of the study was a composite endpoint of heart failure outcomes, defined as heart failure hospitalization, left ventricular or biventricular assist device implantation, heart transplantation, or heart failure-related death. Predictors of heart failure outcomes were identified using Least Absolute Shrinkage and Selection Operator Cox regression analyses with different penalization parameters.RESULTS: During a median follow-up of 5.4 years (Q1-Q3: 2.3-9.7 years), 116 study participants (13%) reached the primary endpoint (heart failure hospitalization [75%], heart transplantation [10.3%], left ventricular or biventricular assist device implantation [9.5%], and heart failure-related death [5.2%]). The predictors that remained significant across all analyses were left ventricular ejection fraction, low-voltage electrocardiogram, and NYHA functional class ≥II, measured at first evaluation.CONCLUSIONS: This study identified predictors for heart failure outcomes in PLN p.(Arg14del)-positive individuals that can improve risk prediction. Identifying those at risk for heart failure outcomes is of great importance given the rapid advancements in genetic therapies that may offer potential treatments for hereditary cardiomyopathy.

AB - BACKGROUND: Phospholamban (PLN) p.(Arg14del)-positive individuals are at high risk of developing PLN p.(Arg14del)-related cardiomyopathy, which can lead to progressive heart failure that is poorly amenable to standard heart failure treatment. Genetic therapies for patients with hereditary cardiomyopathy are rapidly advancing, but identifying patients who will benefit from and rely on these therapies is challenging because of reduced penetrance and highly variable expression.OBJECTIVES: The aim of this study is to identify clinical predictors of heart failure outcomes in PLN p.(Arg14del)-positive individuals.METHODS: Data were collected of 904 PLN p.(Arg14del)-positive individuals from the PLN/ACM Registry. The primary endpoint of the study was a composite endpoint of heart failure outcomes, defined as heart failure hospitalization, left ventricular or biventricular assist device implantation, heart transplantation, or heart failure-related death. Predictors of heart failure outcomes were identified using Least Absolute Shrinkage and Selection Operator Cox regression analyses with different penalization parameters.RESULTS: During a median follow-up of 5.4 years (Q1-Q3: 2.3-9.7 years), 116 study participants (13%) reached the primary endpoint (heart failure hospitalization [75%], heart transplantation [10.3%], left ventricular or biventricular assist device implantation [9.5%], and heart failure-related death [5.2%]). The predictors that remained significant across all analyses were left ventricular ejection fraction, low-voltage electrocardiogram, and NYHA functional class ≥II, measured at first evaluation.CONCLUSIONS: This study identified predictors for heart failure outcomes in PLN p.(Arg14del)-positive individuals that can improve risk prediction. Identifying those at risk for heart failure outcomes is of great importance given the rapid advancements in genetic therapies that may offer potential treatments for hereditary cardiomyopathy.

U2 - 10.1016/j.jchf.2025.102558

DO - 10.1016/j.jchf.2025.102558

M3 - Article

C2 - 40782726

SN - 2213-1779

VL - 13

JO - JACC. Heart failure

JF - JACC. Heart failure

IS - 10

M1 - 102558

ER -

Identifying Predictors for Heart Failure Outcomes in Phospholamban p.(Arg14del)-Positive Individuals

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