d14104cadae85850921e4528ccda6d77 medsci-14-00266-v2.pdf 4ebb1e67b2383f53d774cd2f8ab2003c363bf30e medsci-14-00266-v2.pdf 721d65769b537de772e5449e20c4620c9571ae8b9acdfbcc55aeea10facb0e35 medsci-14-00266-v2.pdf Title: Cardiac Lymphatic Dysfunction in Heart Failure: A New Paradigm for Congestion, Inflammation, and Therapy Subject: Background: Heart failure (HF) has traditionally been interpreted through hemodynamic, neurohormonal, and cardiorenal frameworks. Although these models explain many aspects of clinical decompensation, they do not fully account for persistent tissue congestion, unresolved myocardial edema, chronic sterile inflammation, and progressive fibrosis despite optimized therapy. Objectives: To review the anatomy, physiology, and pathobiological relevance of the cardiac lymphatic system in HF and to evaluate whether cardiac lymphatic dysfunction constitutes a mechanistic bridge linking congestion, inflammation, and adverse remodeling. Methods: This narrative review was based on a structured literature search of PubMed/MEDLINE, supplemented by manual backward reference screening and bibliographic verification through journal webpages. The search covered January 2000 to 15 April 2026, with emphasis on 2018 onward and on seminal mechanistic studies. Search domains included cardiac lymphatics, heart failure, lymphangiogenesis, myocardial edema, congestion, inflammation, myocardial infarction, pressure overload, and HFpEF. Results: Cardiac lymphatics regulate myocardial clearance of interstitial fluid, proteins, cytokines, lipids, and immune cells. Preclinical experimental evidence, mainly derived from myocardial infarction, pressure-overload, and lymphatic-insufficiency models, indicates that impaired lymphatic transport or insufficient lymphangiogenic adaptation promotes myocardial edema, inflammatory persistence, fibroblast activation, collagen deposition, and ventricular dysfunction. Human observational and early translational studies suggest that lymphatic dysregulation may also be relevant in selected HF phenotypes, although direct clinical evidence remains limited. Conversely, lymphangiogenic and lymphatic-restorative strategies, especially through the VEGF-C/VEGFR-3 axis, reduce edema, enhance inflammatory resolution, attenuate fibrosis, and improve ventricular performance in preclinical models. Conclusions: Cardiac lymphatic dysfunction provides a compelling conceptual framework that links congestion and inflammation in HF. Rather than acting as a passive bystander, the cardiac lymphatic circulation appears to be an active determinant of myocardial homeostasis and disease progression. Recognition of lymphatic insufficiency as a pathogenic component of HF may open new diagnostic and therapeutic avenues, including tissue-focused decongestion, lymphatic phenotyping, and targeted lymphatic repair. Keywords: heart failure; cardiac lymphatics; myocardial edema; inflammation; fibrosis Author: Francisco Epelde Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Thu May 28 18:04:09 2026 CEST ModDate: Thu May 28 18:08:20 2026 CEST Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 615714 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- VYTEJA+URWPalladioL-Bold Type 1 Custom yes yes yes 107 0 PPFYNZ+URWPalladioL-Roma Type 1 Custom yes yes yes 108 0 BZMGDP+URWPalladioL-Ital Type 1 Custom yes yes yes 109 0 RLECUX+VnURWPalladioL Type 1 Custom yes yes yes 110 0 CGFELB+PalatinoLinotype TrueType WinAnsi yes yes no 196 0 CGFELB+PalatinoLinotype TrueType WinAnsi yes yes no 309 0 CGFEKP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 310 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-06-17 03:58:37 CEST RepresentationInformation: medsci-14-00266-v2.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-06-16 12:55:30 CEST Size: 615714 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 550 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: Methods of Literature Search and Bibliographic Extraction Item: Title: Cardiac Lymphatic Anatomy, Development, and Physiological Function Item: Title: Myocardial Edema as a Pathogenic Process Item: Title: Cardiac Lymphatics in Myocardial Infarction and Post-Infarction Remodeling Item: Title: Pressure Overload and Chronic Hemodynamic Stress Item: Title: Cardiac Lymphatic Insufficiency as a Cause of Diastolic Dysfunction Item: Title: Cardiac Lymphatics as the Link Between Congestion and Inflammation Item: Title: Relevance to Heart Failure Phenotypes Item: Title: Diagnostics: Toward a Lymphatic Phenotype of Heart Failure Item: Title: Therapeutic Implications Item: Title: Challenges and Future Directions Item: Title: Conclusions Item: Title: References Info: Title: Cardiac Lymphatic Dysfunction in Heart Failure: A New Paradigm for Congestion, Inflammation, and Therapy Author: Francisco Epelde Subject: Background: Heart failure (HF) has traditionally been interpreted through hemodynamic, neurohormonal, and cardiorenal frameworks. Although these models explain many aspects of clinical decompensation, they do not fully account for persistent tissue congestion, unresolved myocardial edema, chronic sterile inflammation, and progressive fibrosis despite optimized therapy. Objectives: To review the anatomy, physiology, and pathobiological relevance of the cardiac lymphatic system in HF and to evaluate whether cardiac lymphatic dysfunction constitutes a mechanistic bridge linking congestion, inflammation, and adverse remodeling. Methods: This narrative review was based on a structured literature search of PubMed/MEDLINE, supplemented by manual backward reference screening and bibliographic verification through journal webpages. The search covered January 2000 to 15 April 2026, with emphasis on 2018 onward and on seminal mechanistic studies. Search domains included cardiac lymphatics, heart failure, lymphangiogenesis, myocardial edema, congestion, inflammation, myocardial infarction, pressure overload, and HFpEF. Results: Cardiac lymphatics regulate myocardial clearance of interstitial fluid, proteins, cytokines, lipids, and immune cells. Preclinical experimental evidence, mainly derived from myocardial infarction, pressure-overload, and lymphatic-insufficiency models, indicates that impaired lymphatic transport or insufficient lymphangiogenic adaptation promotes myocardial edema, inflammatory persistence, fibroblast activation, collagen deposition, and ventricular dysfunction. Human observational and early translational studies suggest that lymphatic dysregulation may also be relevant in selected HF phenotypes, although direct clinical evidence remains limited. Conversely, lymphangiogenic and lymphatic-restorative strategies, especially through the VEGF-C/VEGFR-3 axis, reduce edema, enhance inflammatory resolution, attenuate fibrosis, and improve ventricular performance in preclinical models. Conclusions: Cardiac lymphatic dysfunction provides a compelling conceptual framework that links congestion and inflammation in HF. Rather than acting as a passive bystander, the cardiac lymphatic circulation appears to be an active determinant of myocardial homeostasis and disease progression. Recognition of lymphatic insufficiency as a pathogenic component of HF may open new diagnostic and therapeutic avenues, including tissue-focused decongestion, lymphatic phenotyping, and targeted lymphatic repair. 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