The autonomic nervous system is central to homeostatic regulation of the heart across physiological states. In the setting of chronic cardiac injury, initially protective adaptive mechanisms orchestrated by the autonomic nervous system become deleterious. Structural and functional remodelling of neuronal and non-neuronal elements comprising reflex heart-brain circuits promote maladaptive processes that worsen cardiac function and enhance arrhythmias. Employing approaches ranging from in silico to mechanistic clinical studies, our work elucidates mechanisms governing adverse neural remodelling and develops interventions targeting nexus points within heart-brain reflex circuits to treat chronic heart disease.