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John West is well known to the “Hypoxia” community for his many contributions to the physiology and Pathophysiology of high altitude and for his leadership of the 1981 American Medical Research Expedition to Everest. He is known to the wider medical world for his researches into respiratory physiology especially gas exchange in the lung and perhaps even more for his numerous books on these topics. His publication list numbers over 400 original papers. His research career started in the UK but since 1969 he has been Professor of Medicine at UCSD, leading a very productive team at La Jolla. He has been honoured by numerous prizes and named lectureships, the latest honour being to be elected to the Institute of Medicine, National Academies (USA).

I have probably had more fun doing high-altitude physiology than most people. Some 45 years ago I applied to be a member of Sir Edmund Hillary’s Silver Hut expedition and was accepted in spite of having no previous climbing experience. On this project a group of physiologists wintered at an altitude of 5800 m just south of Everest and carried out an extensive research program. Subsequently measurements were extended up to an altitude of 7440 m on Makalu. In fact the altitude of these field measurements of has never been exceeded. This led to a long interest in high-altitude medicine and physiology which culminated in the 1981 American Medical Research Expedition to Everest during which 5 people reached the summit and the first physiological measurements on the summit were made. Among the extraordinary findings were an extremely low alveolar PCO of 7–8 mmHg, an arterial pH (from the measured PCO and blood base excess) of over 7.7, and a of just over one liter/min. More recently a major interest has been the pathogenesis of high altitude pulmonary edema which we believe is caused by damage to pulmonary capillaries when the pressure inside some of them increases as a result of uneven hypoxic pulmonary vasoconstriction (“stress failure”). Another interest is improving the conditions of people who need to work at high altitude by oxygen enrichment of room air. This enhances well-being and productivity, and is now being used or planned for several high-altitude telescopes up to altitudes of 5600 m. Other recent high-altitude projects include establishing an international archive on high-altitude medicine and physiology at UCSD, several books in the area including the historical study , and editing the journal .

Many apparently healthy individuals experience pulmonary gas exchange limitations during exercise, and the term “exercise induced arterial hypoxemia” (EIAH) has been used to describe the increase in alveolar-arterial difference for oxygen (AaDO), which combined with a minimal alveolar hyperventilatory response, results in a reduction in arterial PO. Despite more than two decades of research, the mechanisms of pulmonary gas exchange limitations during exercise are still debated. Using data in 166 healthy normal subjects collated from several previously published studies it can be shown that ∼20% of the variation in PaO between individuals can be explained on the basis of variations in alveolar ventilation, whereas variations in AaDO explain ∼80%. Using multiple inert gas data the relative contributions of ventilation-perfusion (“ ”) inequality and diffusion limitation to the AaDO can be assessed. During maximal exercise, both in individuals with minimal (AaDO < 20 Torr, x = 13±5, means ±SD, n = 35) and moderate to severe (AaDO= 25–40 Torr, x = 33±6, n = 20) gas exchange limitations, inequality is an important contributor to the AaDO. However, in subjects with minimal gas exchange impairment, inequality accounts for virtually all of the AaDO (12±6 Torr), whereas in subjects with moderate to severe gas exchange impairment it accounts for less than 50% of the AaDO (15±6 Torr). Using this framework, the difficulties associated with unraveling the mechanisms of pulmonary gas exchange limitations during exercise are explored, and current data discussed.

This review presents evidence for the recruitment of intrapulmonary arteriovenous shunts (IPAVS) during exercise in normal healthy humans. Support for pre-capillary connections between the arterial and venous circulation in lungs of humans and animals have existed for over one-hundred years. Right-to-left physiological shunt has not been detected during exercise with gas exchange-dependent techniques. However, fundamental assumptions of these techniques may not allow for measurement of a small (1–3%) anatomical shunt, the magnitude of which would explain the entire A-aDO typically observed during normoxic exercise. Data from contrast echocardiograph studies are presented demonstrating the development of IPAVS with exercise in 90% of subjects tested. Technetium-99m labeled macroaggregated albumin studies also found exercise IPAVS and calculated shunt to be ∼2% at max exercise. These exercise IPAVS appear strongly related to the alveolar to arterial PO difference, pulmonary blood flow and mean pulmonary artery pressure. Hypoxic exercise was found to induce IPAVS at lower workloads than during normoxic exercise in 50% of subjects, while all subjects continued to shunt during recovery from hypoxic exercise, but only three subjects demonstrated intrapulmonary shunt during recovery from normoxic exercise. We suggest that these previously under-appreciated intrapulmonary arteriovenous shunts develop during exercise, contributing to the impairment in gas exchange typically observed with exercise. Future work will better define the conditions for shunt recruitment as well as their physiologic consequence.

Reductions in arterial O saturation (−5 to −10 % SaO < rest) occur over time during sustained heavy intensity exercise in a normoxic environment, due primarily to the effects of acid pH and increased temperature on the position of the HbO dissociation curve. We prevented the desaturation via increased FO (.23 to .29) and showed that exercise time to exhaustion was increased. We used supramaximal magnetic stimulation (1 – 100 Hz) of the femoral nerve to test for quadriceps fatigue. We used mildly hyperoxic inspirates (FO .23 to .29) to prevent O desaturation. We then compared the amount of quadriceps fatigue incurred following cycling exercise at SaO 98% vs. 91% with each trial carried out at equal exercise intensities (90% Max) and for equal durations. Preventing the normal exercise-induced O desaturation prevented about one-half the amount of exercise-induced quadriceps fatigue; plasma lactate and effort perception were also reduced. We conclude that the normal exercise-induced O desaturation during heavy intensity endurance exercise contributes significantly to exercise performance limitation in part because of its effect on locomotor muscle fatigue. These effects of EIAH were confirmed in mild environmental hypoxia (FIO .17, SaO 88%) which significantly augmented the magnitude of exercise-induced quadriceps fatigue observed in normoxia.

At altitude normal people often develop periodic breathing in sleep - regularly recurring periods of hyperpnea and apnea. This phenomenon is probably explained by instability of the negative feedback system for controlling ventilation. Such systems can be modeled by sets of differential equations that describe behavior of key components of the system and how they interact. Mathematical models of the breathing control system have increased in complexity and the accuracy with which they simulate human physiology. Recent papers by Zbigniew Topor et al. (5,6) describe a model with two separate feedback loops, one simulating peripheral and the other central chemoreceptor reflexes, as well as accurate representations of blood components, circulatory loops and brain blood flow. This model shows unstable breathing when one chemoreceptor loop has high gain while the other has low gain, but not when both have high gain. It also behaves in counter-intuitive way by becoming more stable when brain blood flow is reduced and unresponsive to blood. gas changes. Insights from such models may bring us closer to understanding high altitude periodic breathing.

During wakefulness, cerebral blood flow (CBF) is closely coupled to regional cerebral metabolism; however CBF is also strongly modulated by breathing, increasing in response to both hypercapnia and hypoxia. During stage III/IV non-rapid eye (NREM) sleep, cerebral metabolism and CBF decrease whilst the partial pressure of arterial CO increases due to a reduction in alveolar ventilation. The reduction in CBF during NREM sleep therefore occurs despite a relative state of hypercapnia. We have used transcranial Doppler ultrasound to determine middle cerebral artery velocity, as an index of CBF, and have determined that NREM sleep is associated with a reduction in the cerebrovascular response to hypercapnia. This reduction in reactivity would, at least in part, allow the observed reductions in CBF in this state. Similarly, we have observed that the CBF response to hypoxia is absent during stage III/IV NREM sleep. Nocturnal hypoxia and hypercapnia are major pathogenic factor associated with cardio-respiratory diseases. These marked changes in cerebrovascular control that occur during sleep suggest that the cerebral circulation may be particularly vulnerable to cardio-respiratory insults during this period.

Sleep disordered breathing is characterised by periodic breathing, episodes of hypoxia and repeated arousals from sleep; symptoms include excessive daytime sleepiness, impairment of memory, learning and attention. Recent evidence from animal studies suggests that both intermittent hypoxia and sleep fragmentation can independently lead to neuronal defects in the hippocampus and pre frontal cortex; areas known to be closely associated with neural processing of memory and executive function. We have previously shown that sleep disordered breathing is associated with loss of gray matter concentration within the left hippocampus (47). We have now confirmed and extended this rinding in 22 right handed, newly diagnosed male patients (mean (sd): age 51.8 (15.4) yrs, apnea / hypopnea index 53.1 (14.0) events/hr, minimum nocturnal oxygen saturation 75 (8.4) %) and 17 controls matched for age and handedness. Voxel-based morphometry, an automated unbiased technique, was used to characterise changes in gray matter concentration. The magnetic resonance images were segmented and grey matter concentration determined voxel by voxel. Analysis of variance was then preformed, adjusted for overall image intensity, with age as a covariant. Additional to the deficit in the left hippocampus, we found more extensive loss of gray matter bilaterally in the parahippocampus. No additional focal lesions were seen in other brain regions. Based on our findings and data from other human and animal studies, we speculate that in patients with sleep disordered breathing intermittent hypoxia is associated with neural deficit, and further that such lesions may lead to cognitive dysfunction.

The complete sequencing the human genome and recent analytical advances have provided the opportunity to perform genome-wide studies of human variation. There is substantial potential for such population-genomic approaches to assist efforts to uncover the historical and demographic histories of human populations. Additionally, these genome-wide datasets allow for investigations of variability among genomic regions. Although all genomic regions in a population have experienced the same demographic events, they have not been affected by these events in precisely the same way. Much of the variability among genomic regions is simply the result of genetic drift (, gene frequency changes resulting from the effects of small breeding -population size), but some is also the result of genetic adaptation, which will only affect the gene under selection and nearby regions. We have used a new DNA typing assay that allows for the genotyping of thousands of SNPs on hundreds of samples to identify regions most likely to have been affected by genetic adaptation. Populations that have inhabited different niches (, high-altitude regions) can be used to identify genes underlying the physiological differences. We have used two methods (admixture mapping and genome scans for genetic adaptation) founded on the population-genomic paradigms to search for genes underlying population differences in response to chronic hypoxia. There is great promise that together these methods will facilitate the discovery of genes influencing hypoxic response.

Coordinated maternal/fetal responses to pregnancy are required to ensure continuous O delivery to the developing organism. Mammals employ distinctive reproductive strategies that afford their young an improved chance of survival through the completion or the reproductive period. Thus, mortality prior to the end of the reproductive period is concentrated in the earliest phases of the lifecycle. At high altitude, fetal growth restriction reduces birth weight and likely compromises survival during the early postnatal period. Population variation in the frequency of the altitude-associated increase in intrauterine growth restriction (IUGR) demonstrates that multigenerational Tibetan and Andean high-altitude populations are protected compared with shorter duration, European or Han (Chinese) residents. This experiment of nature permits testing the hypothesis that genetic factors (a) influence susceptibility to altitude-associated IUGR, (b) act on maternal vascular adjustments to pregnancy determining uteroplacental blood flow, and (c) involve genes which regulate and/or are regulated by hypoxia-inducible factors (HIFs). Serial, studies during pregnancy as well as postpartum in Andean and European residents of high (3600 m) and low (300 m) altitude will permit evaluation of whether uteroplacental O delivery is lower in the European than Andean women and, if so, the physiological factors responsible. Comparisons of HIF-targeted vasoactive substances and SNPs in or near HIF-regulatory or targeted genes will permit determination of whether these regions are distinctive in the Andean population. Studies coupling genetic and genomic approaches with more traditional physiological measures may be productively employed for determining the genetic mechanisms influencing physiological adaptation to high altitude.