Plasma proteomics stratification identifies phospholamban R14del carriers at risk for disease progression

Incomplete penetrance is common in genetic cardiomyopathy, but poorly understood. Here, we investigate the circulating molecular signature in a cohort of patients with one specific phospholamban (PLN) p.Arg14del (R14del, R14Δ/+) pathogenic variant underlying R14Δ/+ cardiomyopathy and its association with disease variability and progression.

Targeted proteomics, metabolomics, and lipidomics were performed on plasma from 87 R14Δ/+ carriers across the disease spectrum. Unsupervised clustering of plasma proteomics classified R14Δ/+ carriers into clusters, which were evaluated using clinical data, including heart failure (HF) symptoms, echocardiographic parameters, and clinical follow-up. Metabolomics and lipidomics data were integrated. Five clusters of R14Δ/+ carriers were identified based on plasma proteomics (N = 2612 proteins). Clusters 3, 4, and 5 were enriched for higher N-terminal pro-B-type natriuretic peptide levels, and lower left ventricular ejection fraction, compared with Clusters 1 and 2. Ninety-six out of 148 metabolites were differentially expressed across the clusters. Levels of symmetric dimethylarginine, N-acetyl aspartate, cis-aconitic acid, S-adenosyl-L-methionine, acadesine, and succinate were elevated in disease condition Clusters 3, 4, and 5. Levels of energy metabolism-related metabolites (i.e. adenosine triphosphate and nicotinamide) were elevated in Clusters 1, 3, and 4 and correlated strongly with apoptosis markers, indicating ongoing cardiac damage. Clusters 1 and 2 represent seemingly asymptomatic R14Δ/+ carriers with Cluster 1 suspected at risk for cardiac damage due to elevated apoptosis markers. Cluster 3 shows an intermediate phenotype, and Clusters 4 and 5 consist of R14Δ/+ carriers with end-stage HF. Clinical follow-up confirmed Cluster 1 at risk for R14Δ/+ cardiomyopathy progression due to increased adverse events (HF hospitalization, all-cause mortality, or cardiac device implantation).

Molecular profiling of R14Δ/+ carriers reveals subgroups with very distinct risk profiles. Early markers of cardiac damage suggest that stratification may enable timely identification of high-risk individuals and improve understanding of disease variability.