From the Neurovascular Research Laboratory (Dr Bailey), Faculty of Life Sciences and Education, University of South Wales; the Department of Cardiology (Drs Rimoldi, Allemann, and Scherrer), University Hospital of Bern; the Department of Internal Medicine (Dr Sartori), Centre Hospitalier Universitaire Vaudois; the Botnar Center for Clinical Research (Dr Scherrer), Hirslanden Group, Lausanne, Switzerland; and the Departamento de Biología (Dr Scherrer), Universidad de Tarapacá, Arica, Chile.
Correspondence to: Damian M. Bailey, PhD, Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, CF37 2AT, Wales; e-mail: firstname.lastname@example.org
Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.
We thank Dr Jefferson and colleagues for their interest in our publication in CHEST1 describing the vascular implications of altered free radical metabolism during the course of human acclimatization to terrestrial high altitude. Our study revealed that, compared with lowlander control subjects, systemic free radical formation was moderately elevated in healthy well-adapted Andean highlanders, with more exaggerated increases observed in those suffering from the maladaptive syndrome of chronic mountain sickness (CMS).1
The authors have kindly brought to our attention one of their earlier studies highlighting similar findings, albeit using alternative biomarkers of lipid peroxidation.2 However, by their own admission, the study was conducted in participants exposed to heavy metal contamination from local mines, resulting in elevated blood cobalt levels among many and likely chronic tissue retention among most.3 Given that cobalt is an established pro-oxidant,4 it was impossible to establish whether increased oxidative stress in these highlanders was related to chronic cobalt contamination or high altitude per se.
Moreover, beyond the mechanistic insight gained through direct measurement of free radicals using electron paramagnetic resonance spectroscopy, by measuring vascular function our study places free radical formation at high altitude into clearer physiologic context. Indeed, given the link between free radicals and atherosclerosis, Dr Jefferson was among the first to express concerns over the clinical wellbeing of highlanders and whether sustained oxidative stress had the potential to reduce life expectancy.2
However, contrary to our (and presumably Dr Jefferson’s) expectations, the modest elevations in oxidative stress observed in the highlanders without CMS did not have any detectable detrimental effects, given they were healthy and vascular function was normal. This led us to suggest that free radical formation is a hormetic response that serves to optimize acclimatization to hypoxemic stress. Perhaps this may also help explain the inverse relationship shown to exist between altitude of residence and mortality from coronary heart disease and stroke.5 However, when this physiologic threshold of oxidative stress is surpassed, as indeed was the case in highlanders with CMS, the shift from a physiologic toward a more pathologic atherogenic arterial phenotype became readily apparent.
Much like Dr Jefferson, our current efforts are focused on reducing oxidative stress, although cobalt chelation using N-acetylcysteine is unlikely to provide benefit at least in our subset of patients with CMS, given they had no occupational history of mining, and serum cobalt levels would be expected to be normal.
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