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Circulating excitation-contraction coupling proteins and incident cardiovascular outcomes: associations and
Dan Hu1, Yang Gao1, Jing Wang1
1Department of Cardiology, Fuwai Central China Cardiovascular Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China.
Introduction:
Excitation-contraction coupling is central to cardiovascular physiology, but the prospective relevance of circulating proteins involved in this pathway remains uncertain.
Methods:
We evaluated a prespecified seven-protein excitation-contraction 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.
Results:
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, 1.033-1.146; q = 0.022) and HRC (odds ratio, 1.246; 95% confidence interval, 1.191-1.305; q < 0.001) 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 = 0.112) and +0.0084 in average precision (q = 0.217). Established comparator proteins consistently outperformed EC7 in biomarker-only comparisons.
Discussion:
Circulating excitation-contraction 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.
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