| Title: | Plasma proteomics improves risk prediction in heart failure and reveals unique biology in chronic chagas cardiomyopathy |
| Journal: | PLOS Neglected Tropical Diseases |
| Published: | 8 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42258512/ |
| DOI: | https://doi.org/10.1371/journal.pntd.0014370 |
Publication 20739
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Abstract
BACKGROUND: Chronic Chagas cardiomyopathy (CCC) remains a major cause of heart failure (HF)-related mortality in Latin America and is increasingly recognized as a global health concern. Prognostic models developed in non-Chagas populations often perform poorly in CCC, highlighting the need for etiology-specific risk stratification.</p>
METHODOLOGY/PRINCIPAL FINDINGS: We applied high-throughput plasma proteomics to evaluate 2-year mortality risk in CCC compared with other HF etiologies. Baseline plasma from 1,212 adults with heart failure with reduced ejection fraction (HFrEF; LVEF <50%) was analyzed to quantify 734 circulating proteins. CCC was confirmed in 191 participants (16%) by dual Trypanosoma cruzi serology. Two-year mortality was higher in CCC than in the overall HF cohort (26% vs. 16%, p < 0.01). Feature-selection methods identified a nine-protein panel (P9: C1QA, CCL4, REN, EGLN1, COL9A1, GP1BA, ITM2A, CNPY2, NT-proBNP) that improved risk classification compared with NT-proBNP alone, increasing F1-macro by 20% (0.674 vs. 0.560) and integrated time-dependent discrimination for 2-year mortality (iAUC) by 6%. Performance gains varied by HF etiology. Improvements were greatest in hypertensive (+40%) and ischemic (+21%) HF, whereas in CCC the P9 panel underperformed NT-proBNP alone (-16%), suggesting distinct underlying disease biology. External validation in the UK Biobank confirmed generalizability: compared with NT-proBNP, P9 improved F1-macro by 18% and iAUC by 7.4%, reaching an F1-macro of 0.612 in the highest-risk tertile. Pathway enrichment identified 14 CCC-specific pathways, mainly related to fibrosis, integrin signaling, immune dysregulation, and impaired protein trafficking. Exploratory analyses also highlighted potential pathway-linked therapeutic targets consistent with distinct CCC mechanisms.</p>
CONCLUSIONS/SIGNIFICANCE: The P9 proteomic panel improved mortality risk prediction beyond NT-proBNP and the MAGGIC clinical score across most HF etiologies and showed consistent performance in an independent population-based cohort. In contrast, in CCC P9 underperformed NT-proBNP alone, highlighting the distinct biological features of this disease. These findings underscore the limitations of universal biomarker models in CCC and support the need for etiology-specific risk stratification strategies.</p>
14 Keywords
- Adult
- Aged
- Biomarkers
- Blood Proteins
- Chagas Cardiomyopathy
- Chronic Disease
- Female
- Heart Failure
- Humans
- Male
- Middle Aged
- Prognosis
- Proteomics
- Risk Assessment
7 Authors
- José S. L. Patané
- Fernando R. Giugni
- Rogério S. Rosa
- Fabiana G. Marcondes-Braga
- Alfredo J. Mansur
- Alexandre C. Pereira
- Jose E. Krieger
1 Application
| Application ID | Title |
|---|---|
| 519993 | Multi-Biomarker Models for Improved Prognostication in Heart Failure |
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