Perfusion of Intrapulmonary Arteriovenous Anastomoses Is Not Related to VO2max in Hypoxia and Is Unchanged by Oral Sildenafil.

Background: Perfusion of intrapulmonary arteriovenous anastomoses (IPAVA) is increased during exercise and in hypoxia and is associated with variations in oxygen saturation (SPO2), resulting in blood bypassing the pulmonary microcirculation. Sildenafil is a pulmonary vasodilator that improves SPO2 and endurance performance in hypoxia. The purpose of this study was to determine if 50 mg sildenafil would reduce IPAVA perfusion (QIPAVA) and if the decrement in maximal exercise capacity (VO2max) in hypoxia is related to QIPAVA. We hypothesized that during progressive levels of hypoxia at rest (FIO2 = 0.21, 0.14, 0.12), sildenafil would increase SPO2 and reduce bubble score (estimate of QIPAVA) compared to placebo, and that the decrement in VO2max in hypoxia would be positively correlated with bubble score at rest in hypoxia. Materials and Methods: Fourteen endurance-trained men performed a graded maximal exercise test at sea level and at a simulated altitude of 3000 m, followed by two experimental visits where, after randomly ingesting sildenafil or placebo, they underwent agitated saline contrast echocardiography during progressive levels of hypoxia at rest. Results: All participants experienced a decrement in power output in hypoxia that ranged from 9% to 19% lower than sea level values. Compared to normoxia, bubble score increased significantly in hypoxia (p < 0.001) with no effect of sildenafil (p = 0.580). There was a negative correlation between SPO2 and bubble score (p < 0.001). The decrement in peak power output at VO2max in hypoxia was unrelated to IPAVA perfusion in resting hypoxia (p = 0.32). Several participants demonstrated QIPAVA greater than zero in room air, indicating that arterial hypoxemia may not be the sole mechanism for QIPAVA. Conclusion: These results indicate that the VO2max decrement caused by hypoxia is not related to QIPAVA and that sildenafil does not improve VO2max in hypoxia through modulation of QIPAVA.

Sildenafil does not improve performance in 16.1 km cycle exercise time-trial in acute hypoxia.

Sildenafil is a pulmonary vasodilator that has potential to mitigate the decrement in endurance performance caused by hypoxic pulmonary vasoconstriction. The purpose of this study was to determine the effects of sildenafil on pulmonary artery pressure, cardiac output, pulse oxygen saturation, and exercise performance at moderate simulated altitude. We hypothesized that sildenafil would reduce the decline in exercise performance in hypoxia by blunting the rise in pulmonary artery pressure and causing a relative increase in cardiac output and oxygen saturation. Twelve endurance trained men performed three experimental cycling trials at sea level and simulated moderate altitude of 3,000m (FIO2 = 0.147) after ingesting either a placebo or sildenafil 50 mg capsule in a double blinded fashion. Each test consisted of a warmup period, a 15-minute steady state period at 60% of peak power output, and a 16.1 km time-trial. All subjects experienced a decline in maximal exercise capacity in hypoxia that ranged from 6% to 24%. This decline was correlated with the reduction in pulse oxygen saturation in hypoxic maximal exercise. Sildenafil had no effect on pulmonary artery pressure, cardiac output, or pulse oxygen saturation measured during steady state exercise. There was no effect of sildenafil on mean power output during the time-trial. During high intensity cycle exercise in acute, moderate hypoxia pulmonary artery pressure is unaffected by sildenafil and does not appear to influence cardiovascular function or exercise performance.

A Preliminary Genome-Wide Association Study of Acute Mountain Sickness Susceptibility in a Group of Nepalese Pilgrims Ascending to 4380 m.

There is significant interindividual variation in acute mountain sickness (AMS) susceptibility in humans. To identify genes related to AMS susceptibility, we used a genome-wide association study (GWAS) to simultaneously test associations between genetic variants dispersed throughout the genome and the presence and severity of AMS. DNA samples were collected from subjects who ascended rapidly to Gosainkunda, Nepal (4380 m), as part of the 2005, 2010, and 2012 Janai Purnima festivals. The Lake Louise Score was used to measure AMS severity. The primary analysis was based on 99 male subjects (43 with AMS; 56 without AMS). Genotyping for the GWAS was performed using Infinium Human Core Exome Bead Chips (542,556 single-nucleotide polymorphisms were assayed), and validation genotyping was performed with pyrosequencing in two additional cohorts (n = 101 for each). In total, 270,389 single nucleotide polymorphisms (SNPs) passed quality control, and 4 SNPs (one intronic, three nonsynonymous) in the FAM149A gene were associated with AMS severity after correcting for multiple hypothesis testing (p = 1.8E-7); however, in the validation cohorts, FAM149A was not associated with the presence or severity of AMS. No other genes were associated with AMS susceptibility at the genome-wide level. Due to the large influence of environmental factors (i.e., ascent rate and altitude attained) and the difficulties associated with the AMS phenotype (i.e., low repeatability, nonspecific symptoms, potentially independent ailments), we suggest that future studies addressing the variation in the acute human hypoxia response should focus on objective responses to acute hypoxia instead of AMS.

A Meta-Analysis of Exhaled Nitric Oxide in Acute Normobaric Hypoxia.

BACKGROUND: The effect of hypoxia on the exhaled nitric oxide (NO) of humans is unresolved. Many studies have measured the fraction of exhaled NO (FENO) or the partial pressure of exhaled NO (PENO) in normobaric and hypobaric hypoxia, with differing results. METHODS: To better understand NO physiology and altitude acclimatization, we employed a random effects meta-analysis to determine the effect of acute normobaric hypoxia on the PENO of humans. A total of 93 subjects from 7 published studies (with 9 groups) were included. The median duration of exposure was 30 min and the mean hypoxic PIo2 was 95 (SD=10) mmHg. RESULTS: The weighted standardized mean difference (SMD) in PENO measured at baseline and during an acute exposure to normobaric hypoxia was not significantly different from zero (SMD=0.09; 95% CI=-0.17, 0.34; z=0.65). CONCLUSION: Based on this meta-analysis, acute normobaric hypoxia does not affect the PENO measured from the mouths of humans. This result should be considered for interpretations of high-altitude (and hypobaric) measurements of exhaled NO. As the PENO is a potential biomarker for altitude-illness susceptibility, recognizing that normobaric hypoxia does not affect the PENO will be important for understanding previous associations between low exhaled NO and poor acclimatization to hypoxia.

Acute mountain sickness is not repeatable across two 12-hour normobaric hypoxia exposures.

OBJECTIVE: The purposes of this experiment were to determine the repeatability of acute mountain sickness (AMS), AMS symptoms, and physiological responses across 2 identical hypoxic exposures. METHODS: Subjects (n = 25) spent 3 nights at simulated altitude in a normobaric hypoxia chamber: twice at a partial pressure of inspired oxygen (PIO2) of 90mmHg (4000 m equivalent; "hypoxia") and once at a PIO2 of 132 mmHg (1000 m equivalent; "sham") with 14 or more days between exposures. The following variables were measured at hours 0 and 12 of each exposure: AMS severity (ie, Lake Louise score [LLS]), AMS incidence (LLS ≥3), heart rate, oxygen saturation, blood pressure, and the fraction of exhaled nitric oxide. Oxygen saturation and heart rate were also measured while subjects slept. RESULTS: The incidence of AMS was not statistically different between the 2 exposures (84% vs 56%, P > .05), but the severity of AMS (ie, LLS) was significantly lower on the second hypoxic exposure (mean [SD], 3.1 [1.8]) relative to the first hypoxic exposure (4.8 [2.3]; P < .001). Headache was the only AMS symptom to have a significantly greater severity on both hypoxic exposures (relative to the sham exposure, P < .05). Physiological variables were moderately to strongly repeatable (intraclass correlation range 0.39 to 0.86) but were not associated with AMS susceptibility (P > .05). CONCLUSIONS: The LLS was not repeatable across 2 identical hypoxic exposures. Increased familiarity with the environment (not acclimation) could explain the reduced AMS severity on the second hypoxic exposure. Headache was the most reliable AMS symptom.

Individual susceptibility to high altitude and immersion pulmonary edema and pulmonary lymphatics.

BACKGROUND: High-altitude pulmonary edema (HAPE) and immersion pulmonary edema (IPE) are potentially life-threatening conditions that affect athletes, including high-altitude climbers, long-distance swimmers, and underwater divers. The objectives of this study were to measure lung density (before and after exercise) and quantify the pulmonary lymphatic network in individuals susceptible and resistant to HAPE/IPE. METHODS: Eighteen male (N = 10) and female (N = 8) subjects were recruited. Based on medical histories, nine subjects were susceptible to HAPE/IPE, and nine were resistant. Subjects were matched for gender, age, height, weight, and cold-water diving or high-altitude trekking experiences. Lung mass and density (at three slice locations) were determined using computed tomography at rest and after intense exercise. Lung mass and density were calculated from X-ray attenuation values. Two blinded investigators counted interlobular septal lines according to criteria established by the research group. RESULTS: At rest, susceptible subjects had a lower lung density [Susceptible: 0.192 (0.035 SD) g ml 1'; Resistant: 0.22 (0.029 SD) g ml(-1))], a significantly lower lung mass [Susceptible: 132.1 (24.16 SD) g; Resistant: 156.1 (19.19 SD) g], and significantly fewer interlobular septa [Susceptible: 17 (4.5 SD); Resistant: 23 (7.1 SD)] compared to resistant subjects. The differences in density and mass were not affected by intense exercise. DISCUSSION: Subjects susceptible to HAPE/IPE had lower lung density, significantly lower lung mass, and fewer interlobular septa than subjects resistant to HAPE/IPE, suggesting a smaller pulmonary lymphatic network. The observed differences in lymphatics could represent either predisposing factors to, or sequelae of, these potentially lethal conditions.

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.

Immersion pulmonary edema in female triathletes.

Pulmonary edema has been reported in SCUBA divers, apnea divers, and long-distance swimmers however, no instances of pulmonary edema in triathletes exist in the scientific literature. Pulmonary edema may cause seizures and loss of consciousness which in a water environment may become life threatening. This paper describes pulmonary edema in three female triathletes. Signs and symptoms including cough, fatigue, dyspnea, haemoptysis, and rales may occur within minutes of immersion. Contributing factors include hemodynamic changes due to water immersion, cold exposure, and exertion which elevate cardiac output, causing pulmonary capillary stress failure, resulting in extravasation of fluid into the airspace of the lung. Previous history is a major risk factor. Treatment involves immediate removal from immersion and in more serious cases, hospitalization, and oxygen administration. Immersion pulmonary edema is a critical environmental illness of which triathletes, race organizers, and medical staff, should be made aware.