{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T09:38:15Z","timestamp":1786527495962,"version":"build-2736575974"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Excitation\u2013contraction coupling is central to cardiovascular physiology, but the prospective relevance of circulating proteins involved in this pathway remains uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated a prespecified seven-protein excitation\u2013contraction coupling panel (EC7: NEXN, SLMAP, ITPR1, CACNB1, HRC, RYR1, and CACNA1C) in the UK Biobank proteomics cohort in relation to incident stroke, heart failure, acute myocardial infarction, and angina recorded during the available observation period. Outcome-specific logistic-regression models estimated odds ratios per 1-standard-deviation higher relative protein level after adjustment for demographic and clinical factors, with false-discovery-rate correction across 28 primary tests. Predictive analyses used locked training\/test partitions, screening of 13 candidate algorithms, nested cross-validation, frozen calibration and thresholds, and comparisons with clinical features and five established cardiovascular proteins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 52,995 participants in the analysis source proteomics cohort, 39,691 had complete EC7 measurements. Higher ITPR1 (odds ratio, 1.088; 95% confidence interval, 1.033\u20131.146; q\u2009=\u20090.022) and HRC (odds ratio, 1.246; 95% confidence interval, 1.191\u20131.305; q\u2009&amp;lt;\u20090.001) were associated with incident heart failure; no other primary association survived correction. Logistic regression was selected for all outcomes. Adding EC7 proteins to clinical features did not improve locked-test predictive performance after multiplicity correction; for heart failure, changes were +0.0054 in ROC-AUC (q\u2009=\u20090.112) and +0.0084 in average precision (q\u2009=\u20090.217). Established comparator proteins consistently outperformed EC7 in biomarker-only comparisons.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Circulating excitation\u2013contraction coupling proteins showed outcome-specific associations, particularly with heart failure, but limited incremental predictive performance. These findings support further mechanistic investigation and validation in independent cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1841253","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T09:10:17Z","timestamp":1786525817000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Circulating excitation\u2013contraction coupling proteins and incident cardiovascular outcomes: associations and incremental predictive performance in the UK Biobank"],"prefix":"10.3389","volume":"13","author":[{"given":"Dan","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Cardiology, Fuwai Central China Cardiovascular Hospital, Central China Fuwai Hospital of Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gao","sequence":"additional","affiliation":[{"name":"Department 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