Microneurographic recordings in these individuals developed a direct link between PAP rise and sympathetic nervous system over-activation, which could explain the exaggerated response to hypoxia in these persons.Endothelial tissue dysfunction has also been linked to development of HAPE, including reduced synthesis of NO (a potent vasodilator), increased levels of endothelin (a potent vasconstrictor), and an impaired ability to transport sodium and water across the epithelium and out of the alveoli.Data on the genetic basis for HAPE susceptibility is conflicting and interpretation is difficult. Genes implicated in the development of HAPE include those in the renin-angiotensin system (RAS), NO pathway, and hypoxia-inducible factor pathway (HIF). Future genomic testing could provide a clearer picture of the genetic factors that contribute to HAPE. Pathophysiology
Though it remains a topic of intense investigation, multiple studies and reviews over the last several years have helped to elucidate the proposed mechanism of HAPE. The inciting factor of HAPE is the decrease in partial pressure of arterial oxygen caused by the lower air pressure at high altitudes (pulmonary gas pressures). The resultant hypoxemia is then thought to precipitate the development of:

Increased pulmonary arterial and capillary pressures (pulmonary hypertension) secondary to hypoxic pulmonary vasoconstriction. Increased capillary pressure (hydrostatic pressure) with over-distention of the capillary beds and increased permeability of the vascular endothelium, also known as "stress failure." This leads to subsequent leakage of cells and proteins into the alveoli, aka pulmonary edema.Hypoxic pulmonary vasoconstriction (HPV) occurs diffusely, leading to arterial vasoconstriction in all areas of the lung.
The most reliable sign of HAPE is severe fatigue or exercise intolerance, especially in a climber that was previously not displaying this symptom. Risk factors
There are multiple factors that can contribute to the development of HAPE, including sex (male), genetic factors, prior development of HAPE, ascent rate, cold exposure, peak altitude, intensity of physical exertion, and certain underlying medical conditions (e.g., pulmonary hypertension). Anatomic abnormalities that are predisposing include congenital absence of pulmonary artery, and left-to-right intracardiac shunts (e.g., atrial and ventricular septal defects), both of which increase pulmonary blood flow. HAPE-susceptible (HAPE-s) individuals were also found to be four times more likely to have a patent foramen ovale (PFO) than those who were HAPE-resistant. There is currently no indication or recommendation for people with PFO to pursue closure prior to extreme altitude exposure.In studies performed at sea level, HAPE-s people were found to have exaggerated circulatory response to both hypoxia at rest and during exercise. In these individuals, the pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) were shown to be abnormally high.