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146 Biobehavioral Resilience to Stress

altitude or exercise (Young et al., 1987). Taken together, these fi ndings sug-
gest that changes in ammonia accumulation may play a key role in the meta-
bolic acclimatization and improved performance.
It is important to note, however, that acclimatization does not fully coun-
ter the effects of hypoxia. Acute performance decrements may have their basis

in oxidative stress (Howald & Hoppeler, 2003; Pfeiffer et al., 1999).* However,

no acute benefits to health or performance have been observed in relation to
the use of antioxidant supplements at altitude (Subudhi et al., 2004). Rather,
energy supplementation in the form of carbohydrate reliably improves
performance and helps to reduce symptoms of acute mountain sickness
(AMS) (Askew, 2004; Fulco et al., 2005).
Physiological and psychological functions and abilities are degraded at
altitude and acute illnesses do occur (e.g., AMS, high-altitude pulmonary
edema [HAPE], and high-altitude cerebral edema [HACE]). There is much

interest in clarifying the pathophysiology of these illnesses to better under-
stand biochemical and genetic markers of susceptibility and to design eff ec-

tive treatments and countermeasures. The picture is far from complete, but
recent studies have uncovered several interesting facts. For example, hypoxia
associated with high altitude increases the transcription factor hypoxia-
inducible factor-1α (HIF-1α). Mairbaurl et al. (2003) found that HIF-1α
mRNA increased in the leukocytes of subjects who developed HAPE but not
in those who remained well. HIF-1α is known to regulate the genes that con-

trol VEGF, which is important to capillary density. Thus, it has been hypoth-
esized that there should occur a measurable increase in capillary density
during acclimatization to high altitudes (Lundby et al., 2004). However, this

was not found to be the case. After 8 weeks of exposure to altitude (4100 m),
messenger RNA of human muscle VEGF did not increase. Maloney, Wang,
Duncan, Voelkel, and Ruoss (2000) also found that VEGF levels did not
increase with exposure to altitude (4300 m). Thus, the relevance of VEGF

to acclimatization remains unknown. Maloney et al. reported a relationship
between VEGF level and the incidence of AMS. Specifi cally, individuals who
had the lowest levels of VEGF at sea level were also the least likely to develop
AMS at altitude. Moreover, a subgroup of individuals who demonstrated a
decrease in VEGF level at altitude also did not develop AMS. Th e authors
concluded that “sustained plasma VEGF at altitude may reflect a phenotype

more susceptible to AMS.”
Other biochemical and enzymatic factors may predict susceptibility to
altitude-related illness. Hanaoka et al. (1998) performed a retrospective study
of the frequencies of human leukocyte antigen (HLA) alleles in individuals

* It appears that high-altitude inhabitants such as Sherpas have a greater antioxidant
capacity.

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