Brain heart crosstalk after ischemic stroke toward a unified framework for pathophysiology and precision medicine

Abstract

Background Acute ischemic stroke and cardiac dysfunction engage in a complex bidirectional interplay that critically determines patient outcomes. Despite growing recognition of the brain-heart axis, a comprehensive mechanistic framework integrating traditional and emerging pathways remains lacking. Moreover, existing reviews have predominantly focused on descriptive mechanisms without systematically evaluating the strength of evidence, addressing knowledge gaps, or proposing testable hypotheses for precision medicine. Recent advances This review systematically delineates the pathophysiology, clinical spectrum, and management of brain-heart crosstalk following acute ischemic stroke. We first establish the core mechanisms: autonomic dysregulation with catecholamine surge, hypothalamic pituitary adrenal axis activation, neuroinflammation and systemic immune suppression, mechanical coupling via mechanosensitive Piezo1 and Piezo2 channels, and the gut brain-heart axis mediated by trimethylamine N oxide. Critically, we identify where evidence is robust versus preliminary, highlighting inconsistencies such as the divergent roles of Piezo1 versus Piezo2 in cardiac pathology and the unresolved causal relationship between trimethylamine N oxide and post stroke outcomes. We then examine the clinical consequences including Takotsubo syndrome, atrial fibrillation, QT prolongation, left ventricular dysfunction, and secondary brain injury, and critically appraise current management strategies such as hemodynamic control, beta blockers, anti-inflammatory agents, and neuromodulation. Key challenges and future directions Major knowledge gaps persist regarding the temporal dynamics of autonomic dysregulation, the narrow therapeutic window for beta blockade in acute stroke, the lack of stroke specific anti-inflammatory trials, and the underexplored potential of gut microbiota modulation as a therapeutic target. We propose a testable precision medicine paradigm integrating multimodal biomarkers to identify high risk individuals and guide targeted interventions. Conclusion The brain-heart axis is a pivotal determinant of post stroke prognosis. However, current evidence remains predominantly observational or derived from non-stroke populations. Moving beyond descriptive integration toward mechanism based, hypothesis driven, and personalized strategies will be essential to improve long term outcomes in this vulnerable population.