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

• Brain-heart interactions form a bidirectional network through direct and indirect pathways. • Indirect crosstalk is mediated by the hypothalamic–pituitary–adrenal axis, immune response, exosomes and gut. • Direct communication relies on sympathetic, parasympathetic, and intracardiac nervous systems. • Brain disorders such as stroke, traumatic brain injury, and mental disorders induce cardiac dysfunction. • Cardiac conditions including myocardial infarction, heart failure, and arrhythmias impact cerebral function. • Unraveling brain–heart bidirectional mechanisms may unite them as integrated therapeutic targets. 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. 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. 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.