Elsevier

Heart Rhythm

Volume 19, Issue 3, March 2022, Pages 427-434
Heart Rhythm

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

https://doi.org/10.1016/j.hrthm.2021.11.009Get rights and content
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open access

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.

Keywords

Arrhythmogenic cardiomyopathy
Cardiogenetics
Low-voltage electrocardiogram
Personalized medicine phospholamban
Sex characteristics
Sex-related differences
Sex-specific differences

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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.