Plasma proteomics stratification identifies phospholamban R14del carriers at risk for disease progression.
This study highlights that plasma molecular profiling can identify distinct risk profiles among carriers of the phospholamban p.Arg14del variant, which may help in understanding disease progression.
Where it sits
this study against the rest of the aicar (acadesine) corpusSummary and findings
This study investigated the plasma proteomic, metabolomic, and lipidomic profiles of 87 carriers of the phospholamban p.Arg14del variant to understand disease progression. Five distinct clusters were identified based on proteomic data, with varying levels of cardiac biomarkers and metabolites. Notably, clusters associated with higher risk for disease progression showed elevated levels of specific metabolites, including acadesine.
Abstract
<h4>Aims</h4>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.<h4>Methods and results</h4>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).<h4>Conclusion</h4>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.
Background
The paper addresses the clinical question of how plasma proteomics can be utilized to identify individuals carrying the phospholamban R14del mutation who are at risk for disease progression. Previous research has established a link between this mutation and cardiac dysfunction, but the specific proteomic markers that indicate risk have not been thoroughly explored. This study is significant as it seeks to provide a stratification method that could lead to earlier interventions for at-risk individuals.
Methods
Not reported in abstract.
Results
Not reported in abstract.
Interpretation
Not reported in abstract.
Key findings
- Not reported in abstract.
Limitations
- Not reported in abstract.