Martin J. MacInnis

Evidence for a Genetic Basis for Altitude Illness: 2010 Update

Altitude illness refers to a group of environmentally mediated pathophysiologies. Many people will suffer acute mountain sickness shortly after rapidly ascending to a moderately hypoxic environment, and an unfortunate few will develop potentially fatal conditions such as high altitude pulmonary edema or high altitude cerebral edema. Some individuals seem to be predisposed to developing altitude illness, suggesting an innate contribution to susceptibility. The implication that there are altitude-sensitive and altitude-tolerant individuals has stimulated much research into the contribution of a genetic background to the efficacy of altitude acclimatization. Although the effect of altitude attained and rate of ascent on the etiology of altitude illness is well known, there are only tantalizing, but rapidly accumulating, clues to the genes that may be involved. In 2006, we reviewed what was then known about the genetics of altitude illness. This article updates that review and attempts to tabulate all the available genetic data pertaining to these conditions. To date, 58 genes have been investigated for a role in altitude illness. Of these, 17 have shown some association with the susceptibility to, or the severity of, these conditions, although in many cases the effect size is small or variable. Caution is recommended when evaluating the genes for which no association was detected, because a number of the investigations reviewed in this article were insufficiently powered to detect small effects. No study has demonstrated a clear-cut altitude illness gene, but the accumulating data are consistent with a polygenic condition with a strong environmental component. The genes that have shown an association affect a variety of biological pathways, suggesting that either multiple systems are involved in altitude pathophysiology or that gene-gene interactions play a role. Although numerous studies have been performed to investigate specific genes, few have looked for evidence of heritability or familial transmission, or for epidemiological patterns that would be consistent with genetically influenced conditions. Future trends, such as genome-wide association studies and epigenetic analysis, should lead to enhanced understanding of the complex interactions within the genome and between the genome and hypoxic environments that contribute to an individuals capacity to acclimatize rapidly and effectively to altitude.

Sessile snails, dynamic genomes: gene rearrangements within the mitochondrial genome of a family of caenogastropod molluscs

BackgroundWidespread sampling of vertebrates, which comprise the majority of published animal mitochondrial genomes, has led to the view that mitochondrial gene rearrangements are relatively rare, and that gene orders are typically stable across major taxonomic groups. In contrast, more limited sampling within the Phylum Mollusca has revealed an unusually high number of gene order arrangements. Here we provide evidence that the lability of the molluscan mitochondrial genome extends to the family level by describing extensive gene order changes that have occurred within the Vermetidae, a family of sessile marine gastropods that radiated from a basal caenogastropod stock during the Cenozoic Era.ResultsMajor mitochondrial gene rearrangements have occurred within this family at a scale unexpected for such an evolutionarily young group and unprecedented for any caenogastropod examined to date. We determined the complete mitochondrial genomes of four species (Dendropoma maximum, D. gregarium, Eualetes tulipa, and Thylacodes squamigerus) and the partial mitochondrial genomes of two others (Vermetus erectus and Thylaeodus sp.). Each of the six vermetid gastropods assayed possessed a unique gene order. In addition to the typical mitochondrial genome complement of 37 genes, additional tRNA genes were evident in D. gregarium (trnK) and Thylacodes squamigerus (trnV, trnLUUR ). Three pseudogenes and additional tRNAs found within the genome of Thylacodes squamigerus provide evidence of a past duplication event in this taxon. Likewise, high sequence similarities between isoaccepting leucine tRNAs in Thylacodes, Eualetes, and Thylaeodus suggest that tRNA remolding has been rife within this family. While vermetids exhibit gene arrangements diagnostic of this family, they also share arrangements with littorinimorph caenogastropods, with which they have been linked based on sperm morphology and primary sequence-based phylogenies.ConclusionsWe have uncovered major changes in gene order within a family of caenogastropod molluscs that are indicative of a highly dynamic mitochondrial genome. Studies of mitochondrial genomes at such low taxonomic levels should help to illuminate the dynamics of gene order change, since the telltale vestiges of gene duplication, translocation, and remolding have not yet been erased entirely. Likewise, gene order characters may improve phylogenetic hypotheses at finer taxonomic levels than once anticipated and aid in investigating the conditions under which sequence-based phylogenies lack resolution or prove misleading.

Comments on Point: Counterpoint: Hypobaric hypoxia induces/does not induce different responses from normobaric hypoxia.

112:1788-1794, 2012. ; J Appl Physiol Joshua C. Weavil, Peter Bartsch and Charles F. Nelatury Samuel Verges, Patrick Levy, Eric M. Snyder, Bruce D. Johnson, Jonathon L. Stickford, Y. Millet, Benjamin D. Levine, James H. Wessel III, Bernard Wuyam, Renaud Tamisier, MacInnis, Michael S. Koehle, Thomas Rupp, Marc Jubeau, Stephane Perrey, Guillaume Laymon, Jack A. Loeppky, Matiram Pun, Kai Schommer, Mary C. Vagula, Martin J. S. Chapman, Johnny Conkin, Hugo Nespoulet, Darren P. Casey, Bryan J. Taylor, Abigail Olivier Girard, Michael S. Koehle, Jordan A. Guenette, Samuel Verges, Robert F. normobaric hypoxia induces/does not induce different responses from Comments on Point:Counterpoint: Hypobaric hypoxia

Is Poor Sleep Quality at High Altitude Separate from Acute Mountain Sickness? Factor Structure and Internal Consistency of the Lake Louise Score Questionnaire

BACKGROUND The factor structure and internal consistency of the Lake Louise Score Questionnaire (LLSQ) have not been determined in a large population at high altitude; however, a single-factor structure and a high internal consistency are preferable for accurate clinical and research applications of the LLSQ. METHODS A large group of Nepalese pilgrims (n=491) were assessed for acute mountain sickness with a verbal Nepali translation of the LLSQ after rapidly ascending from 1950 m to 4380 m. The factor structure and internal consistency of the LLSQ were determined with a confirmatory factor analysis (CFA) and the ordinal alpha coefficient, respectively. RESULTS A one-factor structure with all five items of the LLSQ was accepted. Four items (headache, gastrointestinal upset, fatigue/weakness, and dizziness/lightheadedness) loaded strongly on this factor (>0.70), but sleep quality had a low factor loading (0.33). The internal consistency (ordinal alpha coefficient) was 0.79, but removing the sleep quality item improved this value to 0.84. CONCLUSIONS The sleep quality item of the LLSQ was weakly related to the other items of the LLSQ. Future research should further investigate whether impaired sleep at altitude should be considered separately from other symptoms of AMS.

Acute Beetroot Juice Supplementation Does Not Improve Cycling Performance in Normoxia or Moderate Hypoxia

Beetroot juice (BR) has been shown to lower the oxygen cost of exercise in normoxia and may have similar effects in hypoxia. We investigated the effect of BR on steady-state exercise economy and 10-km time trial (TT) performance in normoxia and moderate hypoxia (simulated altitude: ~2500 m). Eleven trained male cyclists (VO 2peak ≥ 60 ml · kg(-1) · min(-1)) completed four exercise trials. Two hours before exercise, subjects consumed 70 mL BR (~6 mmol nitrate) or placebo (nitrate-depleted BR) in a randomized, double-blind manner. Subjects then completed a 15-min self-selected cycling warm-up, a 15-min steady-state exercise bout at 50% maximum power output, and a 10-km time trial (TT) in either normoxia or hypoxia. Environmental conditions were randomized and single-blind. BR supplementation increased plasma nitrate concentration and fraction of exhaled nitric oxide relative to PL (p < .05 for both comparisons). Economy at 50% power output was similar in hypoxic and normoxic conditions (p > .05), but mean power output was greater in the normoxic TT relative to the hypoxic TT (p < .05). BR did not affect economy, steady-state SpO2, mean power output, or 10-km TT completion time relative to placebo in either normoxia or hypoxia (p > .05 in all comparisons). In conclusion, BR did not lower the oxygen cost of steady-state exercise or improve exercise performance in normoxia or hypoxia in a small sample of well-trained male cyclists.

The Genetics of Altitude Tolerance: The Evidence for Inherited Susceptibility to Acute Mountain Sickness

Objective: Acute mountain sickness (AMS) has become a significant environmental health issue as improvements in transportation, “environmental tourism,” and resource development lure more people to the highlands. Whether there is a genetic contribution to AMS susceptibility is a central question in high-altitude medicine. This article provides a systematic review of the evidence supporting such an innate predisposition. Methods: Scientific literature databases were screened using the terms “acute mountain sickness/AMS” and “altitude illness” combined with the terms “DNA,” “gene,” “genetic,” or “polymorphism.” Results: Sixteen genes from a variety of pathways have been tested for association with AMS and variants in eight showed positive associations suggesting that AMS is an environmentally mediated polygenic disorder. Conclusions: The data suggest that genotype contributes to capacity to rapidly and efficiently acclimatize to altitude; nevertheless, the mechanisms by which this occurs have yet to be elucidated.

Inhaled salbutamol does not affect athletic performance in asthmatic and non-asthmatic cyclists

Rationale Salbutamol may affect lung function and exercise performance differently in individuals with and without asthma. Objectives To compare the effects of inhaled salbutamol on lung function, exercise performance and respiratory parameters during cycling exercise in athletes with a positive response to a eucapnic voluntary hyperpnoea (EVH+) and negative (EVH−) challenge, indicative of exercise-induced bronchoconstriction. Methods In a randomised controlled trial with a crossover design, a total of 49 well-trained male athletes (14 EVH+ and 35 EVH−) performed two simulated 10 km time-trials on a cycle ergometer 60 min after the inhalation of either 400 μg of salbutamol or a placebo. Lung function, assessed by forced expiratory volume in 1 s, was measured immediately before and 30 min after inhalation. Performance was measured by mean power output. Measurements & main results Despite a significant increase in lung function after the inhalation of salbutamol compared to the placebo (p<0.001), salbutamol did not affect athletes’ perceptions of dyspnoea (p>0.05) or leg exertion (p>0.05) during exercise. Salbutamol did not affect mean power output: EVH+ and EVH− athletes averaged 4.0 (0.5) and 4.1 (0.5) W/kg after salbutamol and 4.0 (0.5) W/kg and 4.0 (0.4) W/kg after placebo, respectively (p>0.05 for each comparison). Conclusions The inhalation of salbutamol induced a significant increase in resting lung function in EVH+ and EVH− athletes but this improvement in lung function did not translate to improved exercise performance. Salbutamol had no discernible effect on key ventilatory and exercise parameters regardless of EVH challenge outcome.

A Prospective Epidemiological Study of Acute Mountain Sickness in Nepalese Pilgrims Ascending to High Altitude (4380 m)

Background Each year, thousands of pilgrims travel to the Janai Purnima festival in Gosainkunda, Nepal (4380 m), ascending rapidly and often without the aid of pharmaceutical prophylaxis. Methods During the 2012 Janai Purnima festival, 538 subjects were recruited in Dhunche (1950 m) before ascending to Gosainkunda. Through interviews, subjects provided demographic information, ratings of AMS symptoms (Lake Louise Scores; LLS), ascent profiles, and strategies for prophylaxis. Results In the 491 subjects (91% follow-up rate) who were assessed upon arrival at Gosainkunda, the incidence of AMS was 34.0%. AMS was more common in females than in males (RR = 1.57; 95% CI = 1.23, 2.00), and the AMS incidence was greater in subjects >35 years compared to subjects ≤35 years (RR = 1.63; 95% CI = 1.36, 1.95). There was a greater incidence of AMS in subjects who chose to use garlic as a prophylactic compared to those who did not (RR = 1.69; 95% CI = 1.26, 2.28). Although the LLS of brothers had a moderate correlation (intraclass correlation = 0.40, p = 0.023), sibling AMS status was a weak predictor of AMS. Conclusions The incidence of AMS upon reaching 4380 m was 34% in a large population of Nepalese pilgrims. Sex, age, and ascent rate were significant factors in the development of AMS, and traditional Nepalese remedies were ineffective in the prevention of AMS.

Exhaled nitric oxide is associated with acute mountain sickness susceptibility during exposure to normobaric hypoxia.

Nitric oxide is a gaseous signaling molecule that participates in a large variety of physiological functions and may have a role in the pathology of altitude illnesses, such as acute mountain sickness (AMS). The effect of normobaric hypoxia on the fraction of exhaled NO ( [Formula: see text] ) is a controversial area of high altitude physiology, with the effect varying widely across studies. We exposed 19 male subjects to normobaric hypoxia for 6h and measured [Formula: see text] and AMS (via Lake Louise Score) each hour. For data analysis, subjects were divided into AMS-positive and AMS-negative groups based on their Lake Louise Scores during exposure. Eighteen subjects completed the study, and the incidence of AMS was 50%. Mean [Formula: see text] was unchanged at hour 1 but was significantly elevated above baseline for the remainder of the normobaric hypoxia exposure (p<0.001). Subjects who developed AMS had a significantly lower mean [Formula: see text] at baseline compared to resistant subjects (p=0.013). Further investigations are warranted to confirm our results and to understand the physiological basis of this association.

Methods to Estimate V˙O2max upon Acute Hypoxia Exposure.

INTRODUCTION Altitude and an individuals V˙O2max contribute to a decrease in V˙O2max under hypoxic conditions. The purpose of this study was to update previous reviews with recent research in order to quantitatively determine the individual and interacting effects of altitude and baseline V˙O2max on V˙O2max upon acute exposure to hypoxia while developing a statistical model to predict an individuals V˙O2max under hypoxic conditions. METHODS Meta-regression was conducted on 105 independent groups of participants (n = 958 subjects from 80 different studies). A series of regression models was tested. The final model included altitude, baseline V˙O2max, Alt2, baseline V˙O2max2, and the interaction of altitude with baseline V˙O2max. RESULTS A curvilinear model provided the best fit for metadata, explaining almost 80% of the variance in the null model. Nonlinear effects of Alt2 (β = -0.078; 95% confidence interval, -0.15 to -0.002) and baseline V˙O2max2 (β = -0.003; 95% confidence interval, -0.004 to -0.001) showed that V˙O2max decreases as altitude increases and that the decrease is greater in individuals with higher aerobic capacities. The interaction of these effects (β = -0.028; 95% confidence interval, -0.042 to -0.015) also showed that the effects of altitude were augmented with higher baseline aerobic capacities. Furthermore, the predictions of the model were fairly accurate in predicting individual decreases in V˙O2max (root-mean-squared error, 3.9 mL·kg(-1)·min(-1)). CONCLUSIONS These data provide a robust quantitative framework for the curvilinear and interacting effects of altitude and baseline V˙O2max in determining an individuals effective V˙O2max at altitude. This predictive model is useful for a priori power calculations, design of future experimental studies, and prediction of aerobic capacity declines in applied settings.