Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Medical Hypotheses

DOI: 10.1016/j.mehy.2026.111957

Authors: Uri Gabbay, Or Carmi

Institutions: Tel Aviv University, Rabin Medical Center, Meir Medical Center

Language: English

Topic: High Altitude and Hypoxia

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $2,820