Abstract

The heart-brain axis has been widely acknowledged in medicine, but arguably it has not been particularly well understood until relatively recent times. For example, we have only recently come to appreciate the profound impact of the HBA on the development of vascular cognitive impairment and dementia (VCID). The complexity of these relationships is further reinforced by appreciating additional autonomic interconnectedness via the gut and metabolic pathways, as well as the spleen and immune pathways, in the form of the heart-brain-metabolism axis. Furthermore, the directionality of these pathways is complex, and all of these elements exert unique effects on the other. This multifaceted system is susceptible to pathologic processes involving multiple organ systems, namely, but not exclusively, the heart, vasculature, brain, autonomic nervous system, gut, and liver, with common clinical outcomes including VCID and cognitive frailty. In this state-of-the-art review, we explore the anatomic and physiologic interconnectedness between the heart, brain, gut, and metabolic systems. A focus has been placed on how relevant pathologic processes affect the cardiovascular and neurologic organ systems, as well as specific aspects of metabolism and the influence of the immune and gastrointestinal systems, all of which can contribute to both nervous system and cardiac dysfunction. Where relevant, we describe how therapeutic efforts should be focused on a preventative approach, with early identification of relevant cardiovascular and neurologic factors, to allow for the timely introduction of therapeutic measures to mitigate the risk of developing disease. Emerging approaches to cognitive risk prediction in cardiovascular disease include clinically accessible tools for older adults, brain imaging biomarkers linking stress-related neural activity to future cardiovascular events, and novel strategies such as gut microbiome modulation. Evidence supports the cognitive safety and potential neuroprotective benefit of statins, and ongoing trials and translational research aim to refine prevention through integrated cardiovascular, neurocognitive, and metabolic interventions.