Roles of GDF-15 in Acute Heart Failure: from Mechanistic Insights to Clinical Applications.

Abstract

Acute heart failure (AHF) is a clinical syndrome characterized by the rapid or gradual onset of symptoms and signs of heart failure that are severe enough to require urgent evaluation and treatment. It may represent de novo heart failure or acute decompensation of pre-existing chronic heart failure. Natriuretic peptides remain the cornerstone biomarkers for diagnosis and risk assessment, but predominantly reflect hemodynamic stress and incompletely capture inflammation, oxidative injury, cellular damage, and multiorgan dysfunction. Growth differentiation factor-15 (GDF-15), a stress-responsive cytokine of the transforming growth factor-beta superfamily, may complement natriuretic peptides by reflecting these non-hemodynamic pathways. We conducted a targeted PubMed search from database inception to January 2025 and identified 16 original mechanistic and clinical studies relevant to GDF-15 in AHF. In cultured cardiomyocytes, biomechanical stretch increased GDF-15 expression approximately 24.8-fold, while recombinant GDF-15 reduced ischemia/reperfusion-related necrosis and apoptosis through phosphoinositide 3-kinase/Akt signaling and attenuated agonist-induced hypertrophy through SMAD2/3-associated pathways. In animal models, GDF-15 deficiency increased infarct size and cardiomyocyte apoptosis after ischemia/reperfusion and produced greater hypertrophy and an 84% reduction in contractile performance after 2 weeks of pressure overload, compared with a 25% reduction in wild-type mice. Clinical studies generally showed that higher admission or discharge GDF-15 concentrations and increasing serial levels were associated with mortality or heart-failure rehospitalization. For example, serial GDF-15 remained independently associated with adverse outcomes after simultaneous modelling with established biomarkers (adjusted hazard ratio 1.44 per 1-SD increase in log GDF-15), and a multimarker model incorporating GDF-15, NT-proBNP, and troponin I achieved an area under the curve of 0.785. GDF-15 is not currently recommended for routine heart-failure management since assays and thresholds are not standardized and no prospective trial has shown that GDF-15-guided treatment improves outcomes. Its most plausible near-term role is therefore as one component of a multimarker risk-stratification strategy.