Mechanisms of Atrial Fibrillation in Heart Failure: Uncovering Therapeutic Targets in the Atrial Substrate

Atrial fibrillation (AF) and heart failure (HF) frequently coexist, yet therapeutic progress is hindered by limited understanding of the atrial substrate that sustains AF in HF. This review summarizes key mechanisms through which HF promotes a pro-arrhythmic atrial environment. Hemodynamic stress, neurohormonal activation, fibrosis, proteostasis derailment, mitochondrial dysfunction, calcium-handling defects, DNA damage, and inflammation collectively drive atrial structural and electrical remodeling. Although guideline-directed HF therapies and catheter ablation improve outcomes, AF recurrence remains high, underscoring the need to target upstream molecular pathways. Emerging studies identify several druggable mechanisms, including heat shock protein induction, HDAC6-dependent cytoskeletal remodeling, NAD⁺/mitochondrial preservation, PARP1/DNA damage signaling, CaMKII and stress-kinase regulation, NLRP3 inflammasome inhibition, and modulation of mechanosensitive channels such as TRPC6 and Piezo1. Targeting the atrial substrate represents a promising strategy to reduce AF burden in HF. Biomarker-guided mechanistic trials and rational combination therapies will be essential to translate these insights into effective treatments.