Brain-heart interaction: direct and indirect circuits in health and diseases

BACKGROUND: Epidemiological data indicate a significant global increase in both comorbidity and mutually induced rates between cardiovascular and neurological diseases. Among these, cardiovascular and cerebrovascular diseases share eleven co-localized loci. The critical role of the brain-heart axis in these processes has been increasingly recognized. This axis mediates dynamic bidirectional crosstalk via neuroendocrine, neuroimmune and related pathways, with key mediators including the hypothalamic-pituitary-adrenal (HPA) axis, gut-derived metabolites, extracellular vesicles (EVs), and autonomic nervous system (ANS). Conventional siloed care across cardiology and neurology specialties, alongside single-organ targeted therapies, fails to effectively disrupt the pathological vicious cycle of brain-heart interactions. Targeting key mediators of the brain-heart axis holds significant clinical potential for the treatment of neurological or cardiovascular diseases. AIM OF REVIEW: This review systematically summarizes the key advances in brain-heart crosstalk over the past decade, delineates the direct neural pathways and indirect regulatory mechanisms between the two organs. Against this backdrop, we outline the clinical potential of nervous system-targeted strategies for cardiac disease and related neurological complications, alongside the broad promise of cardiac function optimization to modulate immune and endocrine pathways for cardio-cerebral comorbidity management. KEY SCIENTIFIC CONCEPTS OF REVIEW: We discuss the mediators underlying brain-heart crosstalk, and delineate the distinct functional roles of the brain-heart axis across diverse cardiovascular diseases and psychiatric disorders, offering new conceptual frameworks for treating cardiocerebral comorbidities.