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.