Sex-specific aspects of phospholamban cardiomyopathy: The importance and prognostic value of low-voltage electrocardiograms

Remco de Brouwer, Laura M.G. Meems, Tom E. Verstraelen, Belend Mahmoud, Virginnio Proost, Arthur A.M. Wilde, Laurens P. Bosman, Esmée van Drie, Paul A. van der Zwaag, J. Peter van Tintelen, Arjan C. Houweling, Maarten P. van den Berg, Rudolf A. de Boer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

Abstract

Background: A pathogenic variant in the gene encoding phospholamban (PLN), a protein that regulates calcium homeostasis of cardiomyocytes, causes PLN cardiomyopathy. It is characterized by a high arrhythmic burden and can progress to severe cardiomyopathy. Risk assessment guides implantable cardioverter-defibrillator therapy and benefits from personalization. Whether sex-specific differences in PLN cardiomyopathy exist is unknown. Objective: The purpose of this study was to improve the accuracy of PLN cardiomyopathy diagnosis and risk assessment by investigating sex-specific aspects. Methods: We analyzed a multicenter cohort of 933 patients (412 male, 521 female) with the PLN p.(Arg14del) pathogenic variant following up on a recently developed PLN risk model. Sex-specific differences in the incidence of risk model components were investigated: low-voltage electrocardiogram (ECG), premature ventricular contractions, negative T waves, and left ventricular ejection fraction. Results: Sustained ventricular arrhythmias (VAs) occurred in 77 males (18.7%) and 61 females (11.7%) (P = .004). Of the 933 cohort members, 287 (31%) had ≥1 low-voltage ECG during follow-up (180 females [63%], 107 males [37%]; P = .006). Female sex, age, age at clinical presentation, and proband status predicted low-voltage ECG during follow-up (area under the curve: 0.78). Sustained VA-free survival was lowest in males with low-voltage ECG (P <.001). Conclusion: Low-voltage ECGs predict sustained VA and are a component of the PLN risk model. Low-voltage ECGs are more common in females, yet prognostic value is greater in males. Future studies should determine the impact of this difference on the risk prediction of PLN cardiomyopathy and possibly other cardiomyopathies.

Original languageEnglish
Pages (from-to)427-434
Number of pages8
JournalHeart Rhythm
Volume19
Issue number3
DOIs
Publication statusPublished - Mar 2022
Externally publishedYes

Bibliographical note

Funding Information:
Funding Sources: This work was supported by a grant from the Leducq Foundation [Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN)]; by grants from the Netherlands Heart Foundation (CVON PREDICT2 Grant 2018-30 ); by other grants (CVON-eDETECT Grant 2015-12, CVON SHE-PREDICTS-HF Grant 2017-21, CVON RED-CVD Grant 2017-11, CVON DOUBLE DOSE Grant 2020B005); and by a grant from the European Research Council (ERC CoG 818715, SECRETE-HF).

Funding Information:
Funding Sources: This work was supported by a grant from the Leducq Foundation [Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN)]; by grants from the Netherlands Heart Foundation (CVON PREDICT2 Grant 2018-30); by other grants (CVON-eDETECT Grant 2015-12, CVON SHE-PREDICTS-HF Grant 2017-21, CVON RED-CVD Grant 2017-11, CVON DOUBLE DOSE Grant 2020B005); and by a grant from the European Research Council (ERC CoG 818715, SECRETE-HF).Disclosures: The UMCG, which employs several of the authors, received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. Dr de Boer received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. Dr Wilde is a member of the steering committee of LQT Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Publisher Copyright:
© 2021 Heart Rhythm Society

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