8284c92da10b0b4a39caaba473cf1035 ijms-26-09527.pdf b096f496b023bea633df2368b68d6c45d4ddcd77 ijms-26-09527.pdf 75d489daea92c97b758bb950f19d75f7758f58dd33eb61adcfd627535cd31b56 ijms-26-09527.pdf Title: Cytokine Networks and Heart Failure Outcomes: CA125 as a Bridge Between Congestion and Inflammation Subject: Inflammation and congestion constitute fundamental mechanisms underlying heart failure (HF). Carbohydrate Antigen 125 (CA125) is a well-established biomarker in HF, primarily associated with congestion, but also it may act as a functional ligand amplifying the inflammatory response in HF. Our aim was to evaluate the potential modulatory effect of CA125 on inflammation, assessed by a set of cytokines (interleukin [IL]-6, IL-10, IL-1, and tumor necrosis factor [TNF]). We prospectively included 284 patients admitted for acute HF in which cytokines and CA125 were assessed at admission. Study endpoints were all-cause mortality and total HF rehospitalizations. At a median follow-up of 4.2 years (interquartile range: 1.3–7.5), a total of 211 patients (74.3%) died, and 117 patients (41.2%) experienced 249 HF readmissions. In the multivariable analysis, a significant interaction between IL-6 and IL-10 and CA125 was observed for both outcomes (p-value for interactions < 0.05 for all comparisons). Among patients with CA125 > 35 U/mL, both IL-6 and IL-10 showed a positive, linear relationship with the risk of death or HF readmissions. In contrast, we did not find a significant association in patients with CA125 35 U/mL. In conclusion, the association between IL-6 and IL-10 with long-term adverse events was significantly modulated by CA125 status, being significantly associated with poor prognosis only when CA125 was upregulated. These findings support a potential modulatory role for CA125 in the inflammatory response in HF. Keywords: heart failure; inflammation; antigen carbohydrate 125; cytokines Author: Enrique Santas, Arancha Martí-Martínez, Sandra Villar, Rafael de la Espriella, Enrique Rodriguez-Borja, Elena Revuelta-López, Arantxa González-Miqueo, Antoni Bayés-Genís, Juan Sanchis and Julio Núñez Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Mon Sep 29 12:34:16 2025 CEST ModDate: Mon Sep 29 12:59:12 2025 CEST Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1506647 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- GHFCEQ+URWPalladioL-Ital Type 1 Custom yes yes yes 135 0 PQYZFJ+URWPalladioL-Bold Type 1 Custom yes yes yes 136 0 AIRHKL+VnURWPalladioL Type 1 Custom yes yes yes 137 0 VVSYYB+EURM10 Type 1 Builtin yes yes yes 138 0 OCKDVI+URWPalladioL-Roma Type 1 Custom yes yes yes 139 0 TNBSFT+CMSY10 Type 1 Builtin yes yes yes 140 0 QLBIEB+URWPalladioL-BoldItal Type 1 Custom yes yes yes 182 0 HXQUJZ+PalatinoLinotype-BoldItalic TrueType WinAnsi yes yes yes 210 0 CXCVRJ+PalatinoLinotype-Bold TrueType WinAnsi yes yes yes 211 0 GLDTVB+PalatinoLinotype-Roman TrueType WinAnsi yes yes yes 212 0 PJRVRJ+PalatinoLinotype-Italic TrueType WinAnsi yes yes yes 213 0 THRTVB+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 214 0 ZYYJXI+EURB10 Type 1 Builtin yes yes yes 256 0 CXCVRJ+PalatinoLinotype-Bold TrueType WinAnsi yes yes yes 249 0 GLDTVB+PalatinoLinotype-Roman TrueType WinAnsi yes yes yes 250 0 PJRVRJ+PalatinoLinotype-Italic TrueType WinAnsi yes yes yes 251 0 THRTVB+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 252 0 CXCVRJ+PalatinoLinotype-Bold TrueType WinAnsi yes yes yes 268 0 GLDTVB+PalatinoLinotype-Roman TrueType WinAnsi yes yes yes 269 0 PJRVRJ+PalatinoLinotype-Italic TrueType WinAnsi yes yes yes 270 0 THRTVB+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 271 0 *Calibri-Bold-2400-Identity-H CID Type 0C Identity-H yes no yes 298 0 *Times New Roman-2398-Identity-H CID Type 0C Identity-H yes no yes 299 0 *Times New Roman-2399-Identity-H CID Type 0C Identity-H yes no yes 300 0 *Arial-Bold-2402-Identity-H CID Type 0C Identity-H yes no yes 301 0 *Calibri-Bold-2401-Identity-H CID Type 0C Identity-H yes no yes 302 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-04-16 03:09:27 CEST RepresentationInformation: ijms-26-09527.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-04-15 16:29:32 CEST Size: 1506647 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 537 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Item: Title: Results Children: Item: Title: Study Outcomes Item: Title: Cytokine Network and Risk of Adverse Clinical Events in the Whole Sample Item: Title: The Modifying Prognostic Role of Cytokine Network Across CA125: Long-Term Mortality Item: Title: The Modifying Prognostic Role of Cytokine Network Across CA125: HF Readmissions Item: Title: Discussion Children: Item: Title: Prognostic Role of Inflammation in HF Item: Title: CA125 as a Potential Inflammatory Modulator in HF Item: Title: Clinical Implications Item: Title: Limitations Item: Title: Materials and Methods Children: Item: Title: Study Group and Protocol Item: Title: Biomarker Measurements Item: Title: Follow-Up and Endpoints Item: Title: Statistical Analysis Item: Title: Conclusions Item: Title: Appendix A Item: Title: References Info: Title: Cytokine Networks and Heart Failure Outcomes: CA125 as a Bridge Between Congestion and Inflammation Author: Enrique Santas, Arancha Martí-Martínez, Sandra Villar, Rafael de la Espriella, Enrique Rodriguez-Borja, Elena Revuelta-López, Arantxa González-Miqueo, Antoni Bayés-Genís, Juan Sanchis and Julio Núñez Subject: Inflammation and congestion constitute fundamental mechanisms underlying heart failure (HF). Carbohydrate Antigen 125 (CA125) is a well-established biomarker in HF, primarily associated with congestion, but also it may act as a functional ligand amplifying the inflammatory response in HF. Our aim was to evaluate the potential modulatory effect of CA125 on inflammation, assessed by a set of cytokines (interleukin [IL]-6, IL-10, IL-1, and tumor necrosis factor [TNF]). We prospectively included 284 patients admitted for acute HF in which cytokines and CA125 were assessed at admission. Study endpoints were all-cause mortality and total HF rehospitalizations. At a median follow-up of 4.2 years (interquartile range: 1.3–7.5), a total of 211 patients (74.3%) died, and 117 patients (41.2%) experienced 249 HF readmissions. In the multivariable analysis, a significant interaction between IL-6 and IL-10 and CA125 was observed for both outcomes (p-value for interactions < 0.05 for all comparisons). Among patients with CA125 > 35 U/mL, both IL-6 and IL-10 showed a positive, linear relationship with the risk of death or HF readmissions. In contrast, we did not find a significant association in patients with CA125 35 U/mL. In conclusion, the association between IL-6 and IL-10 with long-term adverse events was significantly modulated by CA125 status, being significantly associated with poor prognosis only when CA125 was upregulated. These findings support a potential modulatory role for CA125 in the inflammatory response in HF. 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