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Identification of disease-specific pathways and modifiers in phospholamban R14del cardiomyopathy: rationale, design
Frederik E Deiman1, Remco de Brouwer1, Lukas Baumhove1
1Department of Cardiology, University Medical Centre Groningen, Groningen, The Netherlands.
Insights
The DECIPHER-PLN cohort studies phospholamban (PLN) p.Arg14del cardiomyopathy, identifying disease pathways and potential biomarkers. This research aims to improve understanding of this genetic heart condition.
Area of Science:
- Cardiology
- Genetics
- Biomarker Discovery
Background:
- Phospholamban (PLN) p.Arg14del (R14∆/+) is a common cause of cardiomyopathy in the Netherlands.
- Key aspects of R14∆/+ cardiomyopathy, such as triggers, progression, and biomarkers, remain unclear.
- The DECIPHER-PLN cohort was established to investigate R14∆/+ pathophysiology across the disease spectrum.
Purpose of the Study:
- To establish a comprehensive cohort of R14∆/+ carriers.
- To identify disease-specific biological pathways and modifiers in R14∆/+ cardiomyopathy.
- To discover novel biomarkers and enhance understanding of R14∆/+ pathophysiology.
Main Methods:
- The DECIPHER-PLN cohort includes 101 participants: unaffected R14∆/+ (n=21), early affected R14∆/+ (n=42), end-stage R14∆/+ (n=28), and HF controls (n=10).
- Categorization based on ejection fraction, HF symptoms, ECG, and NT-proBNP.
- Utilized induced pluripotent stem cell-derived cardiomyocytes and explanted heart tissue for multi-omics analysis and in vitro modeling.
Main Results:
- Low-voltage ECG, older age, arrhythmias, and conduction/repolarization abnormalities were frequent in affected R14∆/+ carriers.
- Abnormal PLN protein localization was confirmed in R14∆/+ carriers.
- The cohort provides a foundation for multi-omics studies and in vitro disease modeling.
Conclusions:
- The DECIPHER-PLN cohort enables the identification of disease-specific pathways and modifiers in R14∆/+ cardiomyopathy.
- Multi-omics approaches and in vitro modeling are key to discovering biomarkers and understanding R14∆/+ pathophysiology.
- Data and materials from the cohort are available upon request for further research.
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.
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