Cardiovascular research · 2026
Plasma proteomics stratification identifies phospholamban R14del carriers at risk for disease progression.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Deiman Frederik E, Arslan Taner, de Brouwer Remco, Henry Ian, Löfgren Lars, Cavallin Anders, Michopoulos Filippos, Nilsson Ralf, Henricsson Marcus, Ahlstrom Christine, Davidsson Pia, Bomer Nils, Grote Beverborg Niels, van der Meer Peter
Аннотация
AIMS: 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.
METHODS AND RESULTS: 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).
CONCLUSION: 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.
METHODS AND RESULTS: 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).
CONCLUSION: 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.