High-altitude exposure and ischemic stroke: pathophysiological mechanisms and current perspectives

Stroke remains the second leading cause of death worldwide and the third leading cause of disability-adjusted life year lost. In recent years, environmental and geographic determinants have been increasingly recognized as key contributors to stroke risk. High-altitude environments-characterized by chronic hypoxia, hypobaria, and elevated ultraviolet radiation-exert profound effects on cardiovascular and cerebrovascular physiology and substantially elevate stroke burden. A comprehensive understanding of how high altitude modulates the pathophysiology of ischemic stroke is therefore critical to optimizing prevention and tailored management in high-altitude populations. This narrative review synthesizes current evidence from peer-reviewed, English-language studies identified primarily through PubMed and supplemented by Google Scholar up to December 2025. We focus on three interrelated domains: physiological adaptation, maladaptive injury, and their implications on ischemic stroke under high-altitude conditions. Under mild-to-moderate hypoxic exposure, the human body achieves acclimatization via coordinated compensatory responses, including hematologic remodeling, enhanced ventilatory function, regulation of cerebral blood flow, and adaptive cardiac remodeling. With progressive increases in altitude or prolonged hypoxic exposure, however, these compensatory mechanisms become inadequate and shift toward maladaptation. This maladaptive transition is characterized by excessive erythropoiesis, heightened blood viscosity, hypercoagulability, endothelial dysfunction, blood-brain barrier disruption, amplified neuroinflammation, and oxidative stress. Collectively, these pathological cascades promote thrombogenesis and neuronal injury, thereby increasing susceptibility to ischemic stroke at high altitude. Future research priorities include the clarification of mechanisms governing the transition from physiological acclimatization to maladaptive injury, the identification of factors influencing individual responses to hypoxic exposure, the evaluation of targeted interventions capable of preserving beneficial adaptation or attenuating pathological processes, and the establishment of evidence-based prevention and management strategies for ischemic stroke in high-altitude populations.