{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:05:26Z","timestamp":1789380326654,"version":"build-2803163510"},"reference-count":117,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"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:p>Heart failure (HF) is a major global health burden associated with high mortality after decompensation, particularly in older patients with multimorbidity. Although established biomarkers such as natriuretic peptides remain essential for initial risk stratification, they capture only a fraction of mortality risk in biologically heterogeneous aging populations. Because HF-related death arises from diverse pathophysiological mechanisms, no single biomarker can capture this mechanistic diversity. This narrative review synthesizes current evidence on circulating biomarkers associated with HF mortality and maps these molecules to specific pathways of cardiac aging and systemic disease. Aging fundamentally reshapes biomarker interpretation: chronic low-grade inflammation, increased vascular stiffness, impaired organ clearance, and endocrine remodeling can alter baseline biomarker concentrations and modify the clinical significance of their longitudinal changes. The evidence reviewed here provides a rationale for a mechanism-driven, pathway-based framework rather than the pursuit of a single prognostic predictor. This framework should be regarded as conceptual and hypothesis-generating. Key biomarker domains include fibro-inflammatory remodeling and myocardial stress, represented by soluble suppression of tumorigenicity 2, galectin-3, growth differentiation factor 15, and heart-type fatty acid-binding protein, which provide overlapping information on myocardial strain, fibrosis, and systemic stress. Markers of congestion, endothelial dysfunction, and vascular aging, including carbohydrate antigen 125, bioactive adrenomedullin, mid-regional pro-adrenomedullin, and endothelin-1, may provide complementary information on hemodynamic, serosal, right-sided, and vascular stress. Markers of cardiorenal and multiorgan reserve, including neutrophil gelatinase-associated lipocalin, albumin, and composite renal or nutritional indices, highlight that HF mortality may reflect systemic vulnerability rather than isolated ventricular dysfunction. Metabolic stress and inflammation, reflected by fibroblast growth factor 21, amino-acid metabolites, and inflammatory mediators, may help characterize metabolic exhaustion and frailty trajectories. Finally, proteomic and metabolomic approaches are promising tools for identifying molecular phenotypes, although assay heterogeneity, insufficient age-specific validation, uncertain incremental clinical utility, and limited bedside interpretability remain barriers. In conclusion, HF mortality may arise from the convergence of myocardial injury and systemic biological aging. Prospective biomarker-guided studies in older, multimorbid HF populations are required before pathway-based panels can be routinely used to inform treatment and care planning.<\/jats:p>","DOI":"10.3389\/fcvm.2026.1936855","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:31:52Z","timestamp":1789378312000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel blood biomarkers for heart failure mortality: mechanistic pathways, aging biology, and risk stratification"],"prefix":"10.3389","volume":"13","author":[{"given":"Xiaofeng","family":"Zeng","sequence":"first","affiliation":[{"name":"Health Management Center of West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwu","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Integrated Therapy, Fudan University Shanghai 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