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

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Precision Medicine

Background:

• Incomplete penetrance in genetic cardiomyopathy, particularly the phospholamban (PLN) p.Arg14del (R14Δ/+) mutation, presents a challenge in understanding disease variability.
• Identifying circulating molecular signatures is crucial for predicting disease progression and outcomes in mutation carriers.

Purpose of the Study:

• To investigate the plasma molecular signature in R14Δ/+ carriers.
• To associate these molecular profiles with clinical phenotypes, disease progression, and risk stratification.

Main Methods:

• Targeted proteomics, metabolomics, and lipidomics on plasma from 87 R14Δ/+ carriers.
• Unsupervised clustering of proteomic data to identify subgroups.
• Integration of metabolomic and lipidomic data with clinical parameters (HF symptoms, LVEF, NT-proBNP) and follow-up data.

Main Results:

• Five distinct clusters of R14Δ/+ carriers were identified based on plasma proteomics.
• Clusters associated with advanced disease (higher NT-proBNP, lower LVEF) showed elevated levels of specific metabolites (e.g., SDMA, SAMe, AICAR).
• Asymptomatic carriers in Cluster 1 exhibited elevated apoptosis markers, indicating early cardiac damage and increased risk for adverse events (HF hospitalization, mortality).

Conclusions:

• Molecular profiling identifies distinct risk subgroups within R14Δ/+ cardiomyopathy carriers.
• Early detection of cardiac damage markers enables risk stratification and timely intervention.
• Understanding molecular signatures can improve insights into disease variability and progression.