GDF-15 and arrhythmogenesis: From cardiac stress signaling to risk stratification

Cardiac arrhythmias, particularly atrial fibrillation (AF), are an emerging clinical problem and need risk stratification beyond the traditional demographic factors. Growth Differentiation Factor-15 (GDF-15), a stress responsive cytokine of the transforming growth factor-beta (TGF-β) superfamily, has been explored as a biomarker of systemic inflammation, oxidative stress and extracellular matrix remodeling. The narrative review summarizes the molecular, diagnostic and prognostic role of GDF-15 in arrhythmogenesis. Higher levels of GDF-15 are associated with the degree of atrial fibrosis and structural remodeling in AF independently predicting recurrence of the disease and thromboembolic events. Its value in forecasting initial ventricular arrhythmias, however, is sometimes clouded by the severity of chronic heart failure. Mechanistically, GDF-15 connects cellular stress pathways with pro-fibrotic structural changes that favor electrical instability. GDF-15 improves multi-marker risk algorithms such as the ABC-AF score, however inconsistency in immunoassays and reliance on observational data limit its use in ordinary clinical practice. Future multi-omics studies and established reference cut-offs are needed to advance GDF-15 from an epidemiological marker to a specific clinical risk modifier.