Molecular profiling identified asymptomatic PLN R14del carriers at higher risk for disease progression, with cluster 1 showing elevated markers of cardiac damage.
Does plasma proteomics stratification identify phospholamban R14del carriers at risk for disease progression?
Plasma multi-omics profiling can stratify phospholamban R14del mutation carriers into distinct risk clusters, enabling the early identification of seemingly asymptomatic individuals at high risk for heart failure progression.
Abstract Background Incomplete penetrance is common in genetic cardiomyopathy, yet the molecular mechanisms underlying variable disease expression remain poorly understood. The phospholamban (PLN) p.Arg14del (R14del) mutation causes heart failure (HF), with a high degree of heterogeneity in clinical presentation and progression among carriers. Purpose Here, we investigate the circulating molecular signature in a cohort of patients with the PLN R14del mutation and its association with disease variability and progression. Methods Targeted proteomics, metabolomics and lipidomics was performed on plasma from 88 PLN R14del carriers across the disease spectrum. Unsupervised clustering of plasma proteomics classified PLN R14del carriers into clusters, which were evaluated using clinical data, including HF symptoms, echocardiographic parameters and clinical follow-up. Metabolomics and lipidomics data were integrated. Results Five clusters of PLN R14del carriers were identified based on plasma proteomics (N=2616 proteins). Clusters 3, 4 and 5 were enriched for higher NT-proBNP levels, and lower left ventricular ejection fraction (LVEF), compared to clusters 1 and 2. Ninety-six out of 148 metabolites were differentially expressed across the clusters. Levels of symmetric dimethylarginine (SDMA), N-acetyl aspartate, cis-aconitic acid, S-adenosyl-L methionine (SAMe), acadesine (AICAR) and succinate were elevated in disease condition clusters 3, 4 and 5. Levels of energy metabolism-related metabolites (such as ATP and nicotinamide), were elevated in clusters 1, 3 and 4, and correlated strongly with apoptosis markers, indicating ongoing cardiac damage. Lipid species PC(16:0/22:2) and PC(18:0/22:2) were elevated, while LPE(18:2) was reduced in cluster 4. Cluster 1 and 2 represent seemingly asymptomatic PLN R14del carriers with cluster 1 suspected at risk for cardiac damage due to elevated apoptosis markers. Cluster 3 shows an intermediate phenotype and cluster 4 and 5 consist of PLN R14del carriers with end-stage HF. Clinical follow-up confirmed cluster 1 at risk for PLN R14del cardiomyopathy progression due to increased adverse events (HF hospitalization, all-cause mortality or cardiac device implantation). Conclusion Molecular profiling of PLN R14del 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.For image description, please refer to the figure legend and surrounding text. For image description, please refer to the figure legend and surrounding text.
Deiman et al. (2026) studied this question. Molecular profiling identified asymptomatic PLN R14del carriers at higher risk for disease progression, with cluster 1 showing elevated markers of cardiac damage.