Testing Whether Cerebral Oxygen Delivery Limits Incremental Exercise Performance

Previous studies have suggested that a reduction in cerebral oxygen delivery may limit motor drive, particularly in hypoxia. Subudhi et al (2011) tested whether increasing end-tidal PCO₂ during incremental exercise would increase cerebral blood flow (CBF) and oxygen delivery, thereby improving peak power output (W(peak)). Amateur cyclists performed two ramped exercise tests (25 W/min) in a counterbalanced order to compare the normal, poikilocapnic response against a clamped condition, in which PetCO₂ was held at 50 Torr throughout exercise. Tests were performed in normoxia (barometric pressure=630 mmHg, 1,650 m) and hypoxia (barometric pressure=425 mmHg, 4,875 m) in a hypobaric chamber. An additional trial in hypoxia investigated effects of clamping at a lower PetCO₂ (40 Torr) from approximately 75 to 100% W(peak). Metabolic gases, ventilation, middle cerebral artery CBF velocity (transcranial Doppler), forehead pulse oximetry, and cerebral (prefrontal) and muscle (vastus lateralis) hemoglobin oxygenation (near infrared spectroscopy) were monitored across trials. Clamping PetCO₂ at 50 Torr in both normoxia (n=9) and hypoxia (n=11) elevated CBF velocity (approximately 40%) and improved cerebral hemoglobin oxygenation (approximately 15%), but decreased W(peak) (6%) and peak oxygen consumption (11%). Clamping at 40 Torr near maximal effort in hypoxia (n=6) also improved cerebral oxygenation (approximately 15%), but again limited W(peak) (5%). These findings demonstrate that increasing mass cerebral oxygen delivery via CO₂ -mediated vasodilation does not improve incremental exercise performance, at least when accompanied by respiratory acidosis.

Richalet Lab Exercise Test of Hypoxic Ventilatory Response is Independent of Altitude

The hypoxic exercise test combining a 4,800-m simulated altitude and a cycloergometer exercise at 30% of normoxic maximal aerobic power (MAP) is used to evaluate the individual chemosensitivity to hypoxia in submaximal exercise conditions. This test allows the calculation of three main parameters: the decrease in arterial oxygen saturation induced by hypoxia at exercise (ΔSa(e)), the ventilatory (HVR(e)) and cardiac (HCR(e)) responses to hypoxia at exercise. Lhuissier et al (2012) report the influence of altitude and exercise intensity on the values of ΔSa(e), HVR(e), and HCR(e). Nine subjects performed hypoxic tests at three simulated altitudes (3,000 m, 4,000 m, and 4,800 m) and three exercise intensities (20%, 30%, and 40% MAP). ΔSa(e) increased with altitude and was higher for 40% MAP than for 20% or 30%. For a constant heart rate, the loss in power output induced by hypoxia, relative to ΔSa(e), was independent of altitude (4,000-4,800 m) and of exercise intensity. HVR(e) and HCR(e) were independent of altitude (3,000-4,800 m) and exercise intensity (20%-40% MAP). The authors suggest that HVR(e) and HCR(e) are invariant parameters that can be considered as intrinsic physiological characteristics of chemosensitivity to hypoxia.

Live-High-Train-Low (LHTL) Fails to Improve Elite Swimmer Performance

No clear post-altitude competitive advantage at sea level was seen in 26 elite swimmers who trained for 3 weeks at high altitude, whether they used the LHTL or classic training (13 in each group) but their performance was impaired both 1 day and 7 days after altitude training (Gough et al., 2012).

Altitude Anorexia Associated With Acylated Ghrelin Appetite Hormone

Wasse et al (2012) report that 7 hr of 12.7% O₂ (chamber) reduced appetite and acylated ghrelin both at rest and after an hour of running at 70% VO_2max as measured both by visual analog hunger scales and by at-hoc food consumption at 5.5 hr. The authors note that this association does not confirm a causal relationship of ghrelin to anorexia.

Acute Effects of I.V. Acetazolamide (ACZ)

ACZ is well known to increase cerebral blood flow acutely but not chronically at sea level and at altitude. In 12 sea level residents, at both sea level and after 7±2 days at the Pyramid Lab near Everest base camp, the authors tested the immediate effects (minutes) of 10 mg/kg of ACZ given IV on middle cerebral arterial blood flow velocity (MCAv, cm/s) by Doppler, and on end-tidal gases and arterial blood gases and pH. MCAv increased by 15% at sea level and 28% at altitude. The observed immediate minor reductions of PaO₂ and SpO₂ differ from the long term effects of the drug. A transient depression of ventilation was attributed to reduction of medullary CO₂ chemoreceptor tissue PCO₂ by washout by increased blood flow and to decreased CO₂ excretion as body stores increase. An “isocapnic hypoxic ventilatory response” data method was not clearly defined. It was based on analysis by others of phrenic neurograms of the hyperbolic ventilatory response to falling PaO₂, producing an undefined index relating to the curvature of the hyperbola. This index more than doubled at altitude but was not affected by ACZ. The test could not have been isocapnic while rebreathing with a soda lime CO₂ absorber as ventilation increased (Fan et al., 2012).

Brain Natriuretic Peptide Rises At Extreme Altitude Especially With Severe Acute Mountain Sickness (AMS)

Woods et al (2012) report brain natriuretic peptide (BNP) and NT-proBNP (pg ml⁻¹) in 20 climbers in Nepal, from a Kathmandu control to intermediate studies at 4270 m and after a climb to 5643 m and descent to 5150 m. BNP rose from 9 to 17 on arrival at 4270, rising to 29 the next morning, and rose again to 32 immediately after descent to 5150 m, remaining at 33 the next morning. In the 4 climbers with severe AMS at 5150 m (Lake Louise scores over 6), BNP mean was 58 whereas the other 16 averaged 23. Similar proportional rises were found in NT-proBNP in all subjects. This may provide a useful lead to the nature of AMS brain injury.

Coagulation and Fibrinolytic Abnormalities With High-Altitude Pulmonary Edema (HAPE)

Ren et al (2012) report increased plasma concentrations of D-dimer, fibrinogen, FDP and t-PA and PAI-1 in 61 patients who developed HAPE while climbing above 3600 m than in 20 climbing controls. These abnormalities were correlated with the severity of HAPE. The plasma concentrations of D-dimer and fibrinogen recovered to normal upon recovery from HAPE while t-PA, PAI-1 and FDP levels in HAPE patients still remained significantly increased over those of unacclimatized controls.

Nitric Oxide in Adaptation to Altitude

Beall, Laskowski and Erzurum (2012) review lung nitric oxide studies in natives and newcomers to altitude. NO levels in the lung fall within 2h at >2500 m altitude, return toward baseline by 48h and increase above baseline by 5days. NO levels are lower in HAPE (high altitude pulmonary edema). Tibetans have far higher NO lung levels while other highland populations are less elevated. Missing are long-term data on lowlanders at altitude and on Tibetans at low altitude.

High Serum Zinc and Testosterone Inversely Correlate with Chronic Mountain Sickness (CMS) Scores

Gonzales et al (2011) compared 33 men with excessive polycythemia (Hb>21 gm/dl) and 29 controls living in Cerro de Pasco, Peru, at 4340 m altitude, and with sea level controls. The severity of CMS signs and symptoms, while correlated with high Hb levels, were inversely correlated with high serum levels of nitric oxide, zinc and testosterone. The authors suggest that hormonal levels in some way modify the stresses of excessive polycythemia.

Exercise Capacity Unimpaired by Chronic Mountain Polycythemia

A study by Groepenhoff et al (2012) in Cerro de Pasco, Peru compared 13 CMS polycythemics with 15 normal highlanders and 15 lowlander newcomers, measuring NO and CO diffusing capacity, echo pulmonary arterial pressure and cardiac output before and during cycle ergometer exercise tests. The authors found that the aerobic exercise capacity of natives with chronic mountain sickness is preserved in spite of severe pulmonary hypertension and relative hypoventilation, probably by a combination of increased oxygen carrying capacity of the blood and lung diffusion, the latter being predominantly due to an increased capillary blood volume.

Muscle Wasting at Altitude

Chaudhary et al (2012) studied chronic hypobaric hypoxia mediated skeletal muscle wasting in rats at 7,620 m. altitude. Protein synthesis and degradation rates were determined by ¹⁴C-Leucine incorporation and tyrosine release. Although protein synthesis more than doubled, protein degradation was 5 fold higher leading to skeletal muscle atrophy due to upregulation of the chymotrypsin-like enzyme activity of the Ub-proteasome pathway and calpains enhanced protein degradation rate.

Decreases of Muscle Mitochondria With Ascent Over 6400 m Altitude

Levett et al (2011) measured gene and protein expression plus ultrastructure in muscle biopsies of lowlanders at sea level and 19 d after initiating ascent to Everest base camp, 5300 m. No mitochondrial loss was found. After 66 d at altitude and ascent beyond 6400 m, mitochondrial densities fell by 21%, with loss of 73% of subsarcolemmal mitochondria. Correspondingly, levels of the transcriptional coactivator PGC-1alpha fell by 35%, suggesting down-regulation of mitochondrial biogenesis. Sustained hypoxia also decreased expression of electron transport chain complexes I and IV and UCP3 levels. Mitochondrial biogenesis was deactivated and uncoupling down-regulated at extreme altitudes.

Cytokines in Altitude-Associated Preeclampsia

Preeclampsia (PE) is more common at high altitude and contributes to the altitude-related decline in birth weight. Davila et al (2012) compared inflammatory markers of PE in 6 early onset and 12 late onset PE patients with 15 gestational age matched normal pregnant Bolivian women residing since birth at high altitude (3600-4100 m). Maternal pro- and anti-inflammatory cytokines were measured using a multiplex bead-based assay. Women in both PE groups had higher levels of the pro-inflammatory cytokines IL-6 and IL-8 as well as higher levels of the anti-inflammatory cytokine IL-1ra, but only IL-6 levels were higher when gestational age was controlled. Women with early-onset PE had higher TNFalpha levels. Higher IL-6 was negatively correlated with birth weight. The authors conclude that pro-inflammatory factors influence both the timing and severity of PE at high altitude.

Acute Hypoxia Decreases Circulating Endothelial Progenitor Cells (EPC)

EPCs help maintain endothelial homeostasis. Colombo et al (2012) determined the concentration of EPC by flow cytometry in the peripheral blood of 10 young healthy adults and the percentage of apoptotic cells before and at 0.5, 1, 2 and 4 h at 4100 m altitude. The concentration of EPC decreased 30% at 0.5 hr, and 75% at 4 hr. By 0.5 hr, surface expression of chemokine CXCR-4 (a chemokine receptor essential for EPC migration and homing) increased 126% and plasmatic stromal derived cell factor-1 (SDF-1) increased 13%. This suggests cell marginalization as a possible cause of the rapid hypoxia-induced EPC reduction. Moreover, hypoxia exposure induced an increase in EPC apoptosis and markers of oxidative stress after 2 h.

Genetic Upregulation of Erythrocyte Differentiation from Hematopoietic Stem Cells At Extreme Altitude

Chen et al (2012) collected blood samples from four climbers at four stages on an expedition up Mount Xixiabangma (8,012 m) for mRNA and miRNA expression assays. Erythrocyte differentiation from hematopoietic stem cells was prominently upregulated. Increased expression at extreme altitude of OCT4, an important regulator in stem cells, can directly elevate the expression of hemoglobin genes.

High Altitude Exposure Increases Fetal Hemoglobin Expression

In humans, acute erythroid expansion can lead to maturation of red blood cell (RBC) precursors containing fetal hemoglobin (F red cells), e.g. in patients after recovery from bone marrow transplantation or affected by sickle cell or thalassemic syndromes. Risso et al (2012) analyzed RBCs from five subjects during and after 17 days spent at high altitude. By flow cytometry, they found a moderate increase of circulating F red cells. The increase was further confirmed by immunoblotting of young RBC hemolysates and quantitative RT-PCR of transcripts purified from a reticulocyte-enriched RBC fraction.

Hepcidin Suppression at Altitude Not Due to Iron Stores Deficiency

Enhanced erythropoietic drive and iron deficiency both influence iron homeostasis through the suppression of the iron regulatory hormone hepcidin. Hypoxia also suppresses hepcidin through a mechanism that is unknown. Talbot et al (2012) measured iron indices and plasma hepcidin levels in healthy volunteers during a 7-day sojourn to high altitude (4340 m above sea level), with and without prior intravenous iron loading. Without prior iron loading, a rapid reduction in plasma hepcidin was observed that was almost complete by the second day at altitude. This occurred before any index of iron availability had changed. Prior iron loading delayed the decrease in hepcidin until after the transferrin saturation had normalized. Thus hepcidin suppression by altitude hypoxia is not driven by a reduction in iron stores, refuting a prior study suggesting that falling iron levels were the cause of hepcidin suppression during a gradual ascent.