Identification of disease-specific pathways and modifiers in phospholamban R14del cardiomyopathy: rationale, design and baseline characteristics of DECIPHER-PLN cohort
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background
Phospholamban (PLN) p.Arg14del (R14del, R14∆/+) is the most commonly identified pathogenic variant that causes cardiomyopathy in the Netherlands. Many disease characteristics are still unclear, including the phenotypic triggers, disease progression and disease-specific biomarkers. We aim to gain a better understanding of the R14∆/+ pathophysiology by establishing a cohort across the R14∆/+ disease spectrum.
Methods
The Disease spECifIc PatHways and modifiERs in PhosphoLambaN r14del cardiomyopathy (DECIPHER-PLN) cohort includes 101 participants, categorised as unaffected R14∆/+ (n = 21), early affected R14∆/+ (n = 42), end-stage R14∆/+ (n = 28) and heart failure (HF) of another aetiology (n = 10). R14∆/+ category was based on left ventricular ejection fraction, HF symptoms, electrocardiogram (ECG) and N‑terminal pro-brain natriuretic peptide concentrations. Of the 91 included R14∆/+ carriers, 46 (51%) were female, with a mean age of 55 years (standard deviation: 14). Low-voltage ECG older age, arrhythmias, and conduction and repolarisation abnormalities were common in (early) affected R14∆/+ carriers. Serum and plasma were collected from all participants. Induced pluripotent stem cells were generated from fibroblasts of end-stage R14∆/+ patients and unaffected R14∆/+ family members (n = 4) and differentiated into cardiomyocytes. Explanted heart tissue was obtained from R14∆/+ patients undergoing cardiac surgery and patients with other HF aetiologies as control. Abnormal PLN protein localisation was confirmed in R14∆/+ carriers.
Conclusion
DECIPHER-PLN comprises R14∆/+ carriers across the disease and non-disease spectrum and can be used to identify disease-specific biological pathways and modifiers that play a role in R14∆/+ cardiomyopathy. Using a multi-omics approach and in vitro disease modelling, we aim to identify novel biomarkers and improve our understanding of R14∆/+ pathophysiology. Material is available upon request.
Phospholamban (PLN) p.Arg14del (R14del, R14∆/+) is the most commonly identified pathogenic variant that causes cardiomyopathy in the Netherlands. Many disease characteristics are still unclear, including the phenotypic triggers, disease progression and disease-specific biomarkers. We aim to gain a better understanding of the R14∆/+ pathophysiology by establishing a cohort across the R14∆/+ disease spectrum.
Methods
The Disease spECifIc PatHways and modifiERs in PhosphoLambaN r14del cardiomyopathy (DECIPHER-PLN) cohort includes 101 participants, categorised as unaffected R14∆/+ (n = 21), early affected R14∆/+ (n = 42), end-stage R14∆/+ (n = 28) and heart failure (HF) of another aetiology (n = 10). R14∆/+ category was based on left ventricular ejection fraction, HF symptoms, electrocardiogram (ECG) and N‑terminal pro-brain natriuretic peptide concentrations. Of the 91 included R14∆/+ carriers, 46 (51%) were female, with a mean age of 55 years (standard deviation: 14). Low-voltage ECG older age, arrhythmias, and conduction and repolarisation abnormalities were common in (early) affected R14∆/+ carriers. Serum and plasma were collected from all participants. Induced pluripotent stem cells were generated from fibroblasts of end-stage R14∆/+ patients and unaffected R14∆/+ family members (n = 4) and differentiated into cardiomyocytes. Explanted heart tissue was obtained from R14∆/+ patients undergoing cardiac surgery and patients with other HF aetiologies as control. Abnormal PLN protein localisation was confirmed in R14∆/+ carriers.
Conclusion
DECIPHER-PLN comprises R14∆/+ carriers across the disease and non-disease spectrum and can be used to identify disease-specific biological pathways and modifiers that play a role in R14∆/+ cardiomyopathy. Using a multi-omics approach and in vitro disease modelling, we aim to identify novel biomarkers and improve our understanding of R14∆/+ pathophysiology. Material is available upon request.
Date Issued
2025-04-01
Date Acceptance
2025-01-28
Citation
Netherlands Heart Journal, 2025, 33 (4), pp.112-119
ISSN
1568-5888
Publisher
Springer Science and Business Media LLC
Start Page
112
End Page
119
Journal / Book Title
Netherlands Heart Journal
Volume
33
Issue
4
Copyright Statement
© The Author(s) 2025 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Publication Status
Published
Date Publish Online
2025-03-06