Mountainside to bedside: reality or fiction?

This editorial describes how the study of healthy individuals at high altitude may advance the development of treatments for respiratory disease.

Case report: a 35-year-old male presented with a 1-month history of breathlessness, exacerbated by minimal exertion and associated with sleep disruption consequent upon frequent nocturnal waking episodes gasping for breath. He complained of a persistent nonproductive cough and 8 kg of weight loss. He had no significant medical history, was a nonsmoker and took no regular medication. Upon examination he was dyspneic and unable to complete full sentences. Dependent edema of the face and peripheries was noted. His respiratory rate was 40 breaths/min with marked recruitment of the accessory muscles. He had a regular pulse of 120 beats/min and peripheral oxygen saturations of 60% on 2 l of oxygen. Auscultation revealed fine widespread crepitations. An arterial blood gas on ambient air revealed an arterial partial pressure of oxygen (P_aO₂) of 2.55 kPa (19.1 mmHg) … shortly after he had reached the summit of Mount Everest.

Of mountains & men

As part of the Caudwell Xtreme Everest Project in 2007, four climbers directly measured their P_aO₂ at 8400 m on descent from the summit of Mount Everest. Their mean P_aO₂ was 3.28 kPa (24.6 mmHg) with a mean calculated arterial oxygen saturation of 54% while they rested without supplemental oxygen [1]. Among this group, one individual had a P_aO₂ of 2.55 kPa (19.1 mmHg), the lowest ever reported in an adult human [1].

Despite their low peripheral saturations, these climbers’ arterial oxygen content had been remarkably well maintained in the weeks preceding their summit attempt (due to elevated hemaglobin levels) [1], none of them suffered from high-altitude illness, and all successfully climbed to the summit and returned safely. This poses a fundamental question: how much oxygen is enough? And is administering oxygen to achieve ‘normal’ blood gases always in our patients’ best interests? Interestingly, the idea of permissive hypoxemia has been proposed previously, but studies to address this important clinical question are lacking [2].

While there may be some skepticism regarding the relevance of high-altitude research to clinical practice, the study of healthy humans under physiological strain in hypoxic environments that they voluntarily visit is an ethical and practical approach to understanding the effects of hypoxemia on integrated human physiology. Clinical studies in patients with multiple comorbidities present a high ‘signal-to-noise’ ratio, along with multiple confounding factors. These problems are greatly diminished in healthy individuals exposed to hypoxia as a result of ascending mountains.

Thus, might knowledge gained from high-altitude studies provide novel insights into the mechanisms of clinical disease and allow more refined targeting of therapeutic strategies in the patient at sea level?

Central to this approach is the recognition that substantial inter-individual variability in almost all elements of human adaptation to environmental hypoxia at high altitude provide cardinal signals to guide further research [3]. Physiological and genetic differences between good and poor responders, for any specific phenotype, may illuminate underlying mechanisms and suggest potential therapeutic avenues.

Some specific examples illustrating this approach include the effects of hypoxia on weight and muscle mass changes, the governance of hypoxic ventilatory response by genetic factors, and the implications of hypoxia-inducible factor and reactive oxygen species (ROS) in the pathogenesis of hypoxic disease states. In the context of critically ill patients, we have previously explored elsewhere the genetic parallels that exist, and the concept of altered metabolic efficiency (alteration in the oxygen cost of ATP generated in the mitochondrion) as an adaptive response to sustained hypoxia [4].

Weight loss

The central element of hypoxia-induced gene expression is believed to be the pluripotent hypoxia-inducible factor (HIF)-1. The transcription, activity and stability of the subunit HIF-1α is regulated by oxygen-dependent hydroxylation [5]. Among the spectrum of cellular processes that are upregulated through the activation of HIF-1α, the stimulation of glycolytic enzymes and induction of the leptin gene have a likely role in the pathogenesis of weight loss. Leptin is a hormone produced predominantly in white adipose tissue that plays an important role in regulating body weight by signaling satiety to the hypothalamus [6]. This is relevant both at altitude, where undesired weight loss is common but of highly variable magnitude in different individuals, and is also increasingly recognized as an important contributor to function in patients with respiratory disease. Patients with chronic obstructive pulmonary disease (COPD) manifest raised leptin levels when compared with healthy controls [7] and this correlates with disease exacerbation; the corollary of which would be the consideration of leptin’s predictive value pre or peri-exacerbation [8,9]. In patients, heterogeneity of underlying disease pathology as well as variation in administered treatments may obscure the relationship between mediator and consequence. Conversely, a controlled experiment at altitude may more easily identify the physiological and biochemical mediators of leptin downstream of HIF-1α without the confounders of disease and treatment variation.

Skeletal muscle loss

Loss of muscle mass is common at altitude and in COPD patients with hypoxemia [10–12]. In both cases, there is a disproportionate loss of muscle mass when compared with fat mass [13]. This unusual pattern of mass loss cannot be accounted for by energy deficit alone and suggests an underlying catabolic process that may relate to the generation of ROS and oxidative stress, promoting an inflammatory process similar to that seen with cachexia [14].

In 1986, Hoppeler was the first to show a markedly reduced mean muscle fiber cross-sectional area in climbers returning from altitudes greater than 8500 m without the use of oxygen [15]. This same preferential loss of muscle mass has been observed in the skeletal muscle biopsies of patients with COPD [16,17]. These changes in muscle structure might be hypothesized to confer advantage by reducing the amount of metabolically active tissue in a fuel (oxygen)-constrained environment. While this adaptation may make physiological sense as an adaptive mechanism for short exposures to altitude (days to weeks), it might be highly deleterious for patients exposed to chronic hypoxemia during prolonged illness. An improved understanding of the mechanisms underlying this phenomenom has the potential to provide therapeutic approaches to counteract this wasting process.

Oxidative stress

In addition to the macroscopic loss of muscle fibers, Hoppeler and others also reported increased levels of lipofuscin and other degradation products associated with oxidative stress in the muscle cells of mountaineers [18]. Koechlin subsequently demonstrated a similar elevation in the muscles of hypoxemic patients with COPD [19]. Moreover, COPD patients with hypoxamia had higher levels of oxidatively damaged lipids and proteins in the vastus lateralis muscle both at baseline and after resistance exercise. These substances are normally produced in exercising skeletal muscle but, crucially, in patients with COPD they are not as effectively buffered by the antioxidant systems, and therefore accumulate. This mismatch between scavenging mechanisms and oxidative stress may provide important targets for therapy. An interesting example of this is observed in the relationship between the physical activity of patients with COPD and disease prognosis; thought to be mediated through the effect of exercise on muscle redox phenotype. This would suggest that physical endurance training might be a means of increasing antioxidant activity. Such increased gene expression and tissue levels of free radical scavenger enzymes have already been demonstrated in patients with chronic heart failure during 6 months of exercise training [20,21].

An intriguing and possibly related observation is that exercise capacity is improved in patients with right heart failure and subjects at high altitude with the use of sildenafil [22,23]. While this might be intuitively explained by the direct effect of sildenafil as a pulmonary dilator, the improvement in exercise capacity at altitude occurred in the absence of pulmonary hemodynamic changes [24]. Alternative mechanisms may therefore be responsible, including alterations in ROS metabolism and nitric oxide synthase activity, which may in part explain some of the benefits of sildenafil in patients at sea level [25].

Given the importance of muscle conditioning in chronic respiratory conditions, should we give further consideration to such interventions as adjunctive therapies during programs to improve exercise capacity in patients? Exercise performance studies in chronic hypobaric hypoxia may allow us to elucidate the mechanisms of benefit of such treatments.

Although even brief episodes of hypoxia induce HIF-1α activity, the mechanism of induction differs between acute and chronic hypoxic stimuli [26]. Obstructive sleep apnoea (OSA) is a prime example of a condition associated with chronic intermittent hypoxia. A major contributor to morbidity in patients with OSA is the development of systemic hypertension. The induction of HIF1-α in chronic intermittent hypoxia is potentiated by increased ROS. Scavenging these ROS with the administration of superoxide scavangers has been shown to ameliorate systemic hypertension in animal models [27]. Such a ‘mopping up’ manipulation of the downstream byproducts of hypoxia holds considerable potential for therapy in a condition that effects an increasingly obese population and is also estimated to complicate 30% of essential hypertension [28,29]. The response of redox systems to different hypoxic stimuli in chamber and field studies has provided novel insights into these mechanisms [30], and this is another area where well-controlled experiments at altitude may provide a useful model of clinically important phenomena.

Hypoxic ventilatory response

Increased ventilation is an effective mechanism for maintaining oxygenation in a hypoxic environment by increasing gas volume exchange. However, the degree to which this occurs is highly variable between individuals and is dependent on the hypoxic ventilatory response (HVR). HVR is the increased ventilatory drive resulting from the stimulation of peripheral chemoreceptors within the carotid and aortic bodies in response to a fall in the P_aO₂, resulting in an increased rate and depth of ventilation. It may also be an important component of acclimatization in acute exposure to hypobaric hypoxia, since failure to mount a response has been associated with an increased incidence of high-altitude illness in studies of lowlanders [31]. However, profound differences exist between brisk (high ventilatory rate) and blunted (low ventilatory rate) responders, which may have significant implications in disease.

Clinically, HVR is a first-line defense against hypoxia; particularly in COPD and asthma when episodes of acute hypoxic exacerbation are associated with high mortality. Inter-individual variability of response may be attributed to genetic differences that have been observed in normal subjects [32] (twin studies [33,34]) and high-altitude populations of different regions [35,36].

Thus, could a heritable component of ventilatory control determine the phenotype of respiratory disease states? The blood gas profiles and clinical phenotypes (e.g., the out-dated yet vivid ‘pink puffer’/‘blue bloater’ description) of patients with COPD often do not correlate with the degree of airway obstruction [37,38] or prognosis [39], but are likely to be genetically determined. The study of large cohorts at altitude for prolonged periods provides a means of evaluating the HVR over a period of chronic adaption to hypoxia, such as our patients undergo in disease states. Since these genetic factors antedate disease, they may represent an identifiable premorbid risk factor. A number of family studies in patients with COPD and their healthy offspring have identified such an association [40], but genetic studies of important physiological markers such as HVR may provide the most definitive proof of concept. With the availability of evolving technologies such as in silico linkage analysis of genotypes in order to identify loci for studying specific phenotypes of interest, the possibilities are within reach, and high-altitude studies provide the means for the construction of such a reference database for the study of this ‘geneto-pathophysiology’ [41].

Conclusion

As studies at altitude become larger, better controlled and more rigorous, this approach to exploring human physiology may yield significant clinical benefit. Like any model, this one has its limitations. However, the ability to study integrated responses in whole humans in sufficient numbers to explore the determinants of inter-individual variability may prove a fruitful method of exploring adaptive mechanisms. Furthermore, it may have significant advantages over the study of different species or isolated cells under artificial conditions. Reality or fiction? Only time will tell.

Financial & competing interests disclosure

Caudwell Xtreme Everest was supported by John Caudwell, BOC Medical (now part of Linde Gas Therapeutics), Eli Lilly, the London Clinic, Smiths Medical, Deltex Medical, the Rolex Foundation (unrestricted grants), the Association of Anaesthetists of Great Britain and Ireland, the United Kingdom Intensive Care Foundation and the Sir Halley Stewart Trust. Some of this work was undertaken at University College London Hospital–University College London Comprehensive Biomedical Research Centre, which received a proportion of funding from the United Kingdom Department of Health’s NIH Research Biomedical Research Centres funding scheme. Caudwell Xtreme Everest is a research project coordinated by the Centre for Altitude, Space, and Extreme Environment Medicine, University College London. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.