Delayed acclimatization and persistent hyperdynamic circulation amplify capillary stress in severe high-altitude illness

• Severe high-altitude illness arises from temporal mismatch between cardiac output and microvascular adaptation during early acclimatization. • Hyperdynamic circulation amplifies capillary stress when flow remains excessive relative to narrowing pulmonary and cerebral microvasculature. • Flow-resistance mismatch explains delayed onset, patchy edema, HAPE-HACE co-occurrence, and paradoxical susceptibility of young fit individuals. • The hypothesis generates testable predictions through cardiac output-stratified hypoxia studies and perfusion imaging. • Preventive strategies targeting early hyperdynamic responses may reduce severe high-altitude illness risk. Severe high-altitude illnesses (HAI), including high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema (HACE), are classically attributed to hypoxemia, hypoxic pulmonary vasoconstriction, endothelial dysfunction, and individual susceptibility. However, these organ-specific frameworks do not fully explain the delayed clinical onset, the low incidence yet frequent co-occurrence of HAPE and HACE, or the paradoxical vulnerability of young, physically fit individuals. Physiological evidence shows that acute hypoxia triggers sympathetic activation and a transient increase in cardiac output (CO). This hyperdynamic response normally decreases during early acclimatization as plasma volume contracts and vascular resistance rises. We propose that in a susceptible subset of individuals, this decrease is delayed or incomplete, creating a temporal mismatch between forward blood flow and the rapidly narrowing pulmonary and cerebral microvasculature. As a result, flow becomes inappropriately high for the available capillary network, amplifying capillary wall stress even as absolute CO normalizes or declines. Exercise-induced increases in cardiac output may further exacerbate this mismatch. In the pulmonary circulation, this mismatch promotes regional overperfusion and capillary stress failure, producing the protein-rich edema characteristic of HAPE. In the cerebral circulation, elevated flow combined with impaired autoregulation and endothelial vulnerability lowers the threshold for vasogenic edema and progression to HACE. This flow-resistance mismatch model provides a unifying physiological explanation for delayed clinical deterioration, patchy edema distribution, and the paradoxical susceptibility of young, physiologically robust individuals. By integrating cardiac output, microvascular dynamics, and endothelial function, it explains variable clinical outcomes under uniform hypoxic stress and generates testable predictions for the prevention, monitoring, and treatment of severe high-altitude illness.