Debunking Live High-Train Low

Despite its widespread application, whether 'live high-train low' (LHTL) increases exercise performance is still controversial. Robach et al (2012b) tested the hypotheses that (i) LHTL improves maximal oxygen uptake (VO_2max) and (ii) this improvement is related to hypoxia-induced increases in total haemoglobin mass (Hb_mass), not to improved maximal oxidative capacity of skeletal muscle. They determined VO_2max before and after LHTL, and also before and after the altitude-induced increases in Hb_mass had been abolished by isovolemic haemodilution. Ten of sixteen endurance-trained athletes were assigned to live for 16 h/day over 4 weeks in chamber hypoxia (3000 m) and train in normoxia. Six (controls) lived and trained in normoxia. VO_2max of the 10 with four-week LHTL increased 1.5% and controls rose 2.0% (ns). Hb_mass was increased 4.6% in 5 (of 10) LHTL subjects but this was not accompanied by a concurrent increase in VO_2max. In the subjects demonstrating an increase in Hb_mass, isovolemic haemodilution elicited a 5.8% decrease in VO_2max. Neither maximal capacity of oxidative phosphorylation nor mitochondrial efficiency was modified by time or LHTL. The authors suggest that LHTL has no positive effect on VO_2max in endurance-trained athletes because (i) muscle maximal oxidative capacity is not improved following LHTL and (ii) erythrocyte volume expansion after LHTL, if any, is too small to alter O₂ transport.

Debunking Exercise Hemolysis as Causing Low Red Cell Mass and Low VO₂ max.

To determine whether hemolysis is significant during extreme exercise, Robach et al (2012a) measured total red blood cell volume (RCV) in ultra-marathon runners before and after a 166-km long mountain ultra-endurance marathon with 9500 m of altitude gain/loss. Neither Hb_mass nor RCV were altered after the run. The 22 runners did show post-run hemodilution, mediated by a large plasma volume expansion and associated with a large increase in plasma aldosterone, probably responsible for the false idea of exercise ‘anemia’.

Debunking Exercise Role in Acute Mountain Sickness (AMS)

Schommer et al (2012) investigated whether moderate exercise worsens AMS in normobaric hypoxia (12% oxygen, equivalent to 4500 m) in 16 subjects exposed to hypoxia twice, once with work at 50% of VO₂ max, once without. There was no significant difference in AMS with and without exercise.

Debunking Pulse Oximetry in Predicting Acute Mountain Sickness (AMS) and Summit Success (SS)

Wagner, Knott and Fry (2012) report that SpO₂ on rapid arrival to 4260 m did not predict AMS or SS on a climb to 5640 m. 56 volunteers were transported from 2650 m to the Piedra Grande hut at 4260 m on Pico de Orizaba within 2 hours. After a median time of 10 hours at the hut, they climbed toward the summit (5640 m) and returned, with a median trip time of 14 hours. SpO₂ was not different between 37 successful summiteers and 19 nonsummiteers. HR just before the summit attempt was not related to AMS but was lower for summiteers than nonsummiteers (P=0.04).

Nitrate Intake in Hypoxic Exercise Improves SaO₂, Muscle SO₂ and Maximal Work

Many recent studies have found improved exercise performance by increased dietary nitrate. Masschelein et al (2012) investigated the effect of dietary nitrate supplementation on arterial, muscle and cerebral oxygenation status, symptoms of acute mountain sickness (AMS), and exercise tolerance at a simulated 5000m altitude in 15 young healthy volunteers. For 6 days prior to each session subjects received either beetroot juice delivering 0.07mmol nitrate per kg body weight per day (BR) or a control drink. Subjects cycled for 20 min @ 45% of peak VO₂ and then were timed to maximal incremental exercise. Muscle oxygenation was measured by near-infrared spectroscopy. During rest and 45% work, BR raised %SpO₂, increased muscle SO₂ 4–5%, and reduced whole body O₂ consumption vs control (P<0.05). With BR, muscle SO₂ was ∼4–5% higher in maximal work (P<0.05) and time to exhaustion was longer (P<0.05). Acute mountain sickness and cerebral oxygenation were unaffected by BR.

Comparing Selective and Nonselective Beta Blocker Effects on Altitude Work Limits

Valentini et al (2012) compared physiological decrements during work shortly after arriving at 4559 m altitude of selective (nebivolol) and nonselective (carvedilol) beta-blockers. Three groups of 9 healthy subjects were treated for 3 weeks with one drug or none. VO₂ max, peak heart rate and peak minute ventilation were significantly less impaired with nebivolol.

Hypoxic Rat Exercise Improved by Combined Cardiac Stimulant and Pulmonary Vasodilator

Radiloff et al (2012) report that pharmacological enhancement of the heart rate with theophylline, combined with reversal of hypoxic pulmonary vasoconstriction via endothelin blockade with sitaxsentan significantly increased the run time to exhaustion of rats in 12% O₂ (simulated high altitude, 4,267 m). This combination increased exercise pulmonary arterial pressure but not lung wet-to-dry weight ratio.

Does Added Dead Space Improve Sleep at Altitude?

By intermittently using a mask and 500 ml dead space in 12 mountaineers on arrival at 3500 m altitude, Lovis et al (2012) report that the 5 who showed severe disordered breathing in sleep had half as frequent apneic episodes with added dead space, while the other 7 were unaffected. However, microarousal index, sleep efficiency, and sleep architecture were not improved with dead space in either group, suggesting no benefit of adding dead space.

Carotid Body, Caffeine, and Altitude

Sustained hypoxia produces carotid body (CB) sensitization that leads to an increase in the carotid sinus nerve (CSN) activity. Over several weeks this effect gradually increases ventilation during acclimatization in man. Conde et al (2012) report that caffeine abolishes this CB acclimatization. Chronically hypoxic-caffeine-treated rats exhibited a decrease in carotid sinus nerve response to acute hypoxic tests compared to hypoxic controls, but maintained ventilation when compared to chronically hypoxic animals. To explain this paradox, the authors postulate that caffeine alters central integration of the CB input, increasing the gain of the chemoreflex. They show that expression of adenosine receptors was downregulated in CB but upregulated in petrosal ganglion in caffeine treated-chronically hypoxic rats. Both adenosine and dopamine release from CB chemoreceptor cells were increased in chronic hypoxia and in caffeine-treated chronic hypoxia groups.

Safety Consensus for High Altitude Athletes

The International Olympic Committee panel of panel of experts issued a consensus statement on thermoregulatory and altitude challenges for high-level athletes (Bergeron et al., 2012), adding to new guidelines issued by the IOC Medical Commission and International Sport Federations new guidelines.

Changes With Age of Cardio-Respiratory Hypoxic and Exercise Responses

By using their enormous data base over 20 years, Lhuissier, Canoulpoitrine and Richalet (2012) investigated age effects on ventilatory and cardiac responses and desaturation with acute hypoxia in 2789 men and 1886 women between 14 and 85 years old. Their hypoxic ventilatory response, ΔV/ΔSpO₂, increased with advancing age. Cardiac response to hypoxia was blunted with ageing in both genders. In trained subjects, although greater desaturation occurred with exercise than in untrained (due to greater effort, both cardiac and ventilatory responses were better preserved during ageing. Training limited the negative effects of menopause on cardiorespiratory response to hypoxia.

Pulmonary Vasoconstriction in Acute Altitude Exposure Declines with Age in Youth

In 118 healthy nonacclimatized children and adolescents, Allemann et al (2012) report that after 40 hr at 3,450 m altitude, mean pulmonary artery pressure (by Doppler) doubled to 35 mmHg. The rise was almost twice as much in 6–9 yr olds as in 14–16 yr olds. In all, right ventricular systolic function increased and none developed high altitude pulmonary edema.

Blood Lipid and Diastolic Pressure Correlate With Hemoglobin in Altiplano Adults

Lipids, hemoglobin and diastolic blood pressure were assessed in 158 males and 348 females aged 35 to 75 years living at 4,100 m altitude in Peru (Gonzales and Tapia, 2012). Hb and diastolic pressure correlated with total cholesterol (P<0.0010), low-density lipoprotein cholesterol (P<0.002), non-high density lipoprotein cholesterol (P<0.01), and triglycerides (P<0.01).

Is Endothelial Nitric Oxide Synthase (eNOS) Polymorphism Related to High Altitude Pulmonary Edema Susceptibilty (HAPE-s)?

Using meta-analysis of data from 5 studies of 360 HAPE susceptibles and 469 controls, Luo et al (2012a) found no significant association between carriers of the eNOS 894G and 894T polymorphism alleles with HAPE incidence.

Early Signs of Later High Altitude Pulmonary Edema (HAPE)

Clarenbach et al (2012) identified several early signs warning of forthcoming HAPE in 8 of 18 mountaineers during 3 days at 4559 m altitude. Early signs were a decline of FVC to 82% vs 93%, and in sleep, fall of SpO₂ to 60% vs 73% despite 69% higher ventilation, twice as many periodic breathing cycles and mean heart rates of 94 vs 79/min.

NFkB Proposed as Mediator of Nifedipine Therapy in High Altitude Pulmonary Edema

While nifedipine is well established as the best treatment and preventative in high altitude pulmonary edema (HAPE), whether HAPE is partly or mainly an inflammatory process is controversial. Sarada et al (2012) demonstrate that the activation of the transcription factor nuclear factor kappa B, NFkB, during hypoxia in rats is diminished by nifedipine. Their data shows that nifedipine in normoxia increases NFkB slightly more than when combined with hypoxia, less than hypoxia alone. Nifedipine blocks the hypoxic rise of ROS and MDA, and prevents the hypoxic reductions of GSH, GpxU and SOD, supporting the claim of lung inflammation in hypoxia. The authors conclude that the positive therapeutic effect of nifedipine is a result of reduction of NDkB, but I do not see direct evidence linking NFkB as the mediator of all the changes of inflammatory substances in HAPE.

Genes Associated with Altitude Illnesses in Han Newcomers and Tibetan Natives

Buroker et al (2012) identified four genes associated with both acute mountain sickness (AMS) in 153 Han newcomers and with chronic polycythemia (CMS) in 79 Tibetan natives. SpO₂ was associated with VEGF-A in Hans with AMS. CMS was associated with AKT3, eNOS3 and VEGF-A in Tibetans. The authors conclude that these nucleotide alterations have physiological effects at altitude.

Rare Mitochondrial DNA Polymorphisms And (HAPE-S) in Han Chinese.

The high incidence of HAPE among Han newcomers to the Tibetan plateau has facilitated comparison of rare gene abnormality associations among large groups. Luo et al (2012b) report a 2.3% incidence of single-nucleotide polymorphisms of mtDNA 3397 and 3552 in patients with HAPE (n=132) compared with none among their matched control subjects (n=233), P=.021. The frequency of mtDNA 3552A in the HAPE group (6.8%) also was significantly higher than in the control group (1.7%), P=.012.

The Yak Genome and Adaptation to Life at High Altitude.

Comparison between genomes of yak and the closely related low-altitude cattle should reveal selections favoring animal adaptation to high altitude. Qiu et al (2012) identify an expansion in yak of gene families related to sensory perception and energy metabolism, as well as an enrichment of protein domains involved in sensing the extracellular environment and hypoxic stress. Positively selected and rapidly evolving genes in the yak lineage are also found to be significantly enriched in functional categories and pathways related to hypoxia and nutrition metabolism. Three yak positively selected groups comprise two important regulators (Adam17 and Arg2) and one target gene (Mmp3) of hypoxia-inducible factor–1α (Hif-1α). As a master regulator of the cellular response to hypoxia, Hif-1α triggers wide transcription of genes involved in angiogenesis, vasodilatation and energy metabolism. Notably, alleles of human Adam17 were previously shown to be present at significantly different frequencies in Tibetans and low-altitude dwellers, indicating a possible role for this gene in altitude adaptation.

Anti-oxidants Protect Pregnant Andeans More Than Europeans From Preeclampsia and Small Babies

Oxidative stress is associated with small-for-gestational-age (SGA) births. Andeans are protected relative to Europeans from the altitude-associated incidence rise in SGA. Julian et al (2012) tested Europeans and Andeans during pregnancy at altitude to determine whether alterations in maternal antioxidant status or oxidative stress contributed to their protection. They found that catalase was higher at high altitude in both groups, but declined with pregnancy only in Europeans (n=24). During pregnancy, SOD activity remained constant in Andeans (n=14 at 20 wks, 47 at 36 wks) but declined in Europeans (n24, each point). In both groups of mothers at altitude that later delivered SGA infants, SOD was 14% below normal at week 20 (n=8) and 11% below normal at week 36 (n=11).

Oxygen Free Radicals at Altitude in Newcomers, Healthy Natives and Polycythemics

Acute exposure to high altitude stimulates free radical formation in lowlanders. Bailey et al (2012) led a multi-institutional study of similar free radicals in 12 healthy (H) and 13 polycythemic (CMS) natives at 3,600 m altitude, with matched controls at sea level and acute hypoxia. They measured oxidative-nitrosative stress as ascorbate radicals (A*^-) and nitrites (NO₂^-). They also measured flow-mediated dilatation, arterial stiffness and carotid intima-media thickness. Compared to normoxic lowlanders, A*^- was moderately increased in H whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders. Both A*^- and NO₂^- responses were markedly exaggerated in CMS, associated with systemic vascular dysfunction.