Identification of disease-specific pathways and modifiers in phospholamban R14del cardiomyopathy: rationale, design and baseline characteristics of DECIPHER-PLN cohort.

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.