{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T22:10:49Z","timestamp":1780697449881,"version":"3.54.1"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>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, R14\u0394\/+) pathogenic variant underlying R14\u0394\/+ cardiomyopathy and its association with disease variability and progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Targeted proteomics, metabolomics, and lipidomics were performed on plasma from 87 R14\u0394\/+ carriers across the disease spectrum. Unsupervised clustering of plasma proteomics classified R14\u0394\/+ 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 R14\u0394\/+ 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\u2013related 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 R14\u0394\/+ 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 R14\u0394\/+ carriers with end-stage HF. Clinical follow-up confirmed Cluster 1 at risk for R14\u0394\/+ cardiomyopathy progression due to increased adverse events (HF hospitalization, all-cause mortality, or cardiac device implantation).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Molecular profiling of R14\u0394\/+ 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag089","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T11:38:26Z","timestamp":1776944306000},"page":"1104-1118","source":"Crossref","is-referenced-by-count":1,"title":["Plasma proteomics stratification identifies phospholamban R14del carriers at risk for disease progression"],"prefix":"10.1093","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9793-4683","authenticated-orcid":false,"given":"Frederik E","family":"Deiman","sequence":"first","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Center Groningen , 9713 GZ Groningen ,","place":["The 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