The influence of hemoconcentration on hypoxic pulmonary vasoconstriction in acute, prolonged, and lifelong hypoxemia

Red blood cell concentration influences the pulmonary vasculature via direct frictional force and vasoactive signaling, but whether the magnitude of the response is modified with duration of exposure is not known. By assessing the pulmonary vascular response to hemodilution in acute normobaric and prolonged hypobaric hypoxia in lowlanders and lifelong hypobaric hypoxemia in Andean natives, we demonstrated that a reduction in red cell concentration augments the vasoconstrictive effects of hypoxia in lowlanders. In high-altitude natives, hemodilution lowered pulmonary vascular resistance, but a compensatory increase in cardiac output following hemodilution rendered PASP unchanged.

Geographical ancestry affects normal hemoglobin values in high-altitude residents

Increasing the hemoglobin (Hb) concentration is a major mechanism adjusting arterial oxygen content to decreased oxygen partial pressure of inspired air at high altitude. Approximately 5% of the world’s population living at altitudes higher than 1,500 m shows this adaptive mechanism. Notably, there is a wide variation in the extent of increase in Hb concentration among different populations. This short review summarizes available information on Hb concentrations of high-altitude residents living at comparable altitudes (3,500–4,500 m) in different regions of the world. An increased Hb concentration is found in all high-altitude populations. The highest mean Hb concentration was found in adult male Andean residents and in Han Chinese living at high altitude, whereas it was lowest in Ethiopians, Tibetans, and Sherpas. A lower plasma volume in Andean high-altitude natives may offer a partial explanation. Indeed, male Andean high-altitude natives have a lower plasma volume than Tibetans and Ethiopians. Moreover, Hb values were lower in adult, nonpregnant females than in males; differences between populations of different ancestry were less pronounced. Various genetic polymorphisms were detected in high-altitude residents thought to favor life in a hypoxic environment, some of which correlate with the relatively low Hb concentration in the Tibetans and Ethiopians, whereas differences in angiotensin-converting enzyme allele distribution may be related to elevated Hb in the Andeans. Taken together, these results indicate different sensitivity of oxygen dependent control of erythropoiesis or plasma volume among populations of different geographical ancestry, offering explanations for differences in the Hb concentration at high altitude.

Life Ascending: Mechanism and Process in Physiological Adaptation to High-Altitude Hypoxia

To cope with the reduced availability of O2 at high altitude, air-breathing vertebrates have evolved myriad adjustments in the cardiorespiratory system to match tissue O2 delivery with metabolic O2 demand. We explain how changes at interacting steps of the O2 transport pathway contribute to plastic and evolved changes in whole-animal aerobic performance under hypoxia. In vertebrates native to high altitude, enhancements of aerobic performance under hypoxia are attributable to a combination of environmentally induced and evolved changes in multiple steps of the pathway. Additionally, evidence suggests that many high-altitude natives have evolved mechanisms for attenuating maladaptive acclimatization responses to hypoxia, resulting in counter-gradient patterns of altitudinal variation for key physiological phenotypes. For traits that exhibit counteracting environmental and genetic effects, evolved changes in phenotype may be cryptic under field conditions and can only be revealed by rearing representatives of high- and low-altitude populations under standardized environmental conditions to control for plasticity.

Regulation of catecholamine release from the adrenal medulla is altered in deer mice (Peromyscus maniculatus) native to high altitudes

High-altitude natives have evolved to overcome environmental hypoxia and provide a compelling system to understand physiological function during reductions in oxygen availability. The sympathoadrenal system plays a key role in responses to acute hypoxia, but prolonged activation of this system in chronic hypoxia may be maladaptive. Here, we examined how chronic hypoxia exposure alters adrenal catecholamine secretion and how adrenal function is altered further in high-altitude natives. Populations of deer mice ( Peromyscus maniculatus) native to low and high altitudes were each born and raised in captivity at sea level, and adults from each population were exposed to normoxia or hypobaric hypoxia for 5 mo. Using carbon fiber amperometry on adrenal slices, catecholamine secretion evoked by low doses of nicotine (10 µM) or acute hypoxia (Po2∼15–20 mmHg) was reduced in lowlanders exposed to hypobaric hypoxia, which was attributable mainly to a decrease in quantal charge rather than event frequency. However, secretion evoked by high doses of nicotine (50 µM) was unaffected. Hypobaric hypoxia also reduced plasma epinephrine and protein expression of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase in the adrenal medulla of lowlanders. In contrast, highlanders were unresponsive to hypobaric hypoxia, exhibiting typically low adrenal catecholamine secretion, plasma epinephrine, and DOPA decarboxylase. Highlanders also had consistently lower catecholamine secretion evoked by high nicotine, smaller adrenal medullae with fewer chromaffin cells, and a larger adrenal cortex compared with lowlanders across both acclimation environments. Our results suggest that plastic responses to chronic hypoxia along with evolved changes in adrenal function attenuate catecholamine release in deer mice at high altitude.

Shear stress and flow-mediated dilation in the normoxic and hypoxic human

The endothelium is a single cell layer that plays a critical role in determining the health and function of blood vessels. Endothelial function is shaped by shear stress, the frictional force exerted by the speed of blood flow, and the thickness (viscosity) of the blood. Exposure to shear stress that reverses direction back-and-forth impairs endothelial function in young men. Whether women are equally susceptible to this perturbation and the isolated impact of a low level of shear stress with and without reversal of shear had not been investigated. Hypoxia, the low levels of oxygen that are experienced at high altitude, has been shown to influence flow reversal and impair endothelial function. However, no previous study had accounted for the changes in blood thickness, and hence shear stress that occur at high altitude. This may be especially important in the context of excessive erythrocytosis, a high-altitude disease characterized by exceptionally thick blood and increased cardiovascular risk. This thesis examined (i) whether there are sex differences in the impact of exposure to low and reversing shear stress on endothelial function; (ii) whether isolated low shear stress impairs endothelial function; (iii) the impact of reversing shear stress on endothelial function in short-term exposure to low levels of oxygen and after trekking to 5050 m in the Himalayas; and (iv) the role of high levels of blood viscosity on endothelial function in high-altitude natives in Cerro de Pasco, Peru (4330 m), with excessive erythrocytosis. We identified that (i) premenopausal women have some protection against reductions in endothelial function after being exposed to reversing shear stress; (ii) isolated low shear stress impaired endothelial function; (iii) short-term exposure to low levels of oxygen and sustained high-altitude exposure reduced endothelial function, while superimposing reversing shear stress had no effect; and (iv) high levels of hemoglobin and blood viscosity contributed to lower endothelial function in Andean high-altitude natives with excessive erythrocytosis. Altogether, this dissertation advances our understanding of how the components of shear stress (the pattern, magnitude, and blood viscosity) impact endothelial function in humans under normoxic (normal levels of oxygen) and hypoxic (low levels of oxygen, such as high-altitude) conditions.

Chromosomal Q-heterochromatin Variability and Sport

In the process of studying the variability of chromosomal Q-heterochromatin regions (Q-HRs) in human populations living permanently in different climatogeographic conditions of Eurasia and Africa, as well as in newcomers, who have successfully adapted to some extreme natural conditions, the data were obtained that, perhaps, the amount of this genetic material in the genome may be important for some sports. In particular, it turned out that in the genome of mountaineers the number of chromosomal Q-HRs was significantly lower than in the control sample and was close to that of the high-altitude natives. The same results were obtained in a comparative study of newcomers who have been working in the extreme climatic conditions of the Far North of West Siberia. We believe that these observations can be explained by cell thermoregulation (??) the level of which depends on the number of chromosomal Q-HRs. The essence of ?? is elimination of the temperature difference between the nucleus and cytoplasm. The effect of CT can be indirectly assessed by the level of the body heat conductivity (BHC). An individual with high BHC cannot make much progress in mountaineering and water sports due to the fact that their body cools rapidly. However, this individual can be more successful in sports which require effective heat-loss. Keywords: Chromosomal Q-heterochromatin; Cell thermoregulation; Body heat conductivity; Sport genetics; Marathon, Mountaineering

Evolved Mechanisms of Aerobic Performance and Hypoxia Resistance in High-Altitude Natives

Comparative physiology studies of high-altitude species provide an exceptional opportunity to understand naturally evolved mechanisms of hypoxia resistance. Aerobic capacity (VO2max) is a critical performance trait under positive selection in some high-altitude taxa, and several high-altitude natives have evolved to resist the depressive effects of hypoxia on VO2max. This is associated with enhanced flux capacity through the O2transport cascade and attenuation of the maladaptive responses to chronic hypoxia that can impair O2transport. Some highlanders exhibit elevated rates of carbohydrate oxidation during exercise, taking advantage of its high ATP yield per mole of O2. Certain highland native animals have also evolved more oxidative muscles and can sustain high rates of lipid oxidation to support thermogenesis. The underlying mechanisms include regulatory adjustments of metabolic pathways and to gene expression networks. Therefore, the evolution of hypoxia resistance in high-altitude natives involves integrated functional changes in the pathways for O2and substrate delivery and utilization by mitochondria.

Extreme pregnancy: maternal physical activity at Everest Base Camp

High-altitude natives employ numerous physiological strategies to survive and reproduce. However, the concomitant influence of altitude and physical activity during pregnancy has not been studied above 3,700 m. We report a case of physical activity, sleep behavior, and physiological measurements on a 28-yr-old third-trimester pregnant native highlander (Sherpa) during ascent from 3,440 m to Everest Base Camp (~5,300 m) over 8 days in the Nepal Himalaya and again ~10 mo postpartum during a similar ascent profile. The participant engaged in 250–300 min of moderate to vigorous physical activity per day during ascent to altitude while pregnant, with similar volumes of moderate to vigorous physical activity while postpartum. There were no apparent maternal, fetal, or neonatal complications related to the superimposition of the large volumes of physical activity at altitude. This report demonstrates a rare description of physical activity and ascent to high altitude during pregnancy and points to novel questions regarding the superimposition of pregnancy, altitude, and physical activity in high-altitude natives.

Chemoreflex mediated arrhythmia during apnea at 5,050 m in low- but not high-altitude natives

Peripheral chemoreflex mediated increases in both parasympathetic and sympathetic drive under chronic hypoxia may evoke bradyarrhythmias during apneic periods. We determined whether 1) voluntary apnea unmasks arrhythmia at low (344 m) and high (5,050 m) altitude, 2) high-altitude natives (Nepalese Sherpa) exhibit similar cardiovagal responses at altitude, and 3) bradyarrhythmias at altitude are partially chemoreflex mediated. Participants were grouped as Lowlanders ( n = 14; age = 27 ± 6 yr) and Nepalese Sherpa ( n = 8; age = 32 ± 11 yr). Lowlanders were assessed at 344 and 5,050 m, whereas Sherpa were assessed at 5,050 m. Heart rate (HR) and rhythm (lead II ECG) were recorded during rest and voluntary end-expiratory apnea. Peripheral chemoreflex contributions were assessed in Lowlanders ( n = 7) at altitude after 100% oxygen. Lowlanders had higher resting HR at altitude (70 ± 15 vs. 61 ± 15 beats/min; P < 0.01) that was similar to Sherpa (71 ± 5 beats/min; P = 0.94). High-altitude apnea caused arrhythmias in 11 of 14 Lowlanders [junctional rhythm ( n = 4), 3° atrioventricular block ( n = 3), sinus pause ( n = 4)] not present at low altitude and larger marked bradycardia (nadir −39 ± 18 beats/min; P < 0.001). Sherpa exhibited a reduced bradycardia response during apnea compared with Lowlanders ( P < 0.001) and did not develop arrhythmias. Hyperoxia blunted bradycardia (nadir −10 ± 14 beats/min; P < 0.001 compared with hypoxic state) and reduced arrhythmia incidence (3 of 7 Lowlanders). Degree of bradycardia was significantly related to hypoxic ventilatory response (HVR) at altitude and predictive of arrhythmias ( P < 0.05). Our data demonstrate apnea-induced bradyarrhythmias in Lowlanders at altitude but not in Sherpa (potentially through cardioprotective phenotypes). The chemoreflex is an important mechanism in genesis of bradyarrhythmias, and the HVR may be predictive for identifying individual susceptibility to events at altitude. NEW & NOTEWORTHY The peripheral chemoreflex increases both parasympathetic and sympathetic drive under chronic hypoxia. We found that this evoked bradyarrhythmias when combined with apneic periods in Lowlanders at altitude, which become relieved through supplemental oxygen. In contrast, high-altitude residents (Nepalese Sherpa) do not exhibit bradyarrhythmias during apnea at altitude through potential cardioprotective adaptations. The degree of bradycardia and bradyarrhythmias was related to the hypoxic ventilatory response, demonstrating that the chemoreflex plays an important role in these findings.