Autonomic nervous system dysregulation as a driver of atrial fibrillation: pathways, modulators, and therapies

Cardiac arrhythmias affect 1%-5% of the global population, with atrial fibrillation (AF) being the most common and clinically relevant. While AF is traditionally linked to electrical and structural remodeling of the atria, growing evidence highlights a critical yet underexplored contributor: dysfunction of the autonomic nervous system (ANS). The ANS regulates heart rate and rhythm through sympathetic and parasympathetic inputs, and its imbalance can initiate and sustain AF by promoting ectopic activity, shortening refractory periods, and enhancing reentry circuits. Autonomic dysregulation is further impacted by lifestyle and environmental influences. Excessive alcohol intake, chronic stress, sleep deprivation, and extreme physical exertion have all been shown to modulate autonomic activity and elevate the risk of AF. Additionally, social determinants such as socioeconomic status and healthcare access indirectly influence AF susceptibility through chronic activation of neurocardiac stress pathways. Mechanistically, emerging research implicates sympathetic hyperinnervation, neuroinflammation, and dysfunction of intrinsic cardiac ganglionated plexi as key contributors to arrhythmogenic remodeling. However, current animal models often fail to capture the complexity of human neuro-cardiac interactions due to species-specific differences in cardiac anatomy, innervation patterns, and immune responses. Human induced pluripotent stem cell (iPSC)-derived models offer an alternative, patient-specific platform to study ANS-driven mechanisms in AF. This review focuses on the role of the ANS in AF pathophysiology, examining the cellular and molecular mechanisms by which autonomic dysregulation promotes arrhythmia. We explore current therapeutic interventions of autonomic-driven AF and discuss the potential of new models to improve mechanistic insight and therapeutic development.