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Original Research: Pulmonary Vascular Disease |

Chemoreceptor Responsiveness at Sea Level Does Not Predict the Pulmonary Pressure Response to High AltitudePulmonary Artery Pressure at High Altitude FREE TO VIEW

Ryan L. Hoiland, BHK; Glen E. Foster, PhD; Joseph Donnelly, MBChB; Mike Stembridge, MSc; Chris K. Willie, PhD; Kurt J. Smith, MSc; Nia C. Lewis, PhD; Samuel J. E. Lucas, PhD; Jim D. Cotter, PhD; David J. Yeoman, BSc; Kate N. Thomas, BSc; Trevor A. Day, PhD; Mike M. Tymko, BHSc; Keith R. Burgess, MD; Philip N. Ainslie, PhD
Author and Funding Information

From the Centre for Heart, Lung and Vascular Health (Messrs Hoiland, Smith, and Tymko and Drs Foster, Willie, Lewis, and Ainslie), School of Health and Exercise Sciences, University of British Columbia–Okanagan, Kelowna, BC, Canada; Division of Neurosurgery (Dr Donnelly), Department of Clinical Neuroscience, University of Cambridge, Cambridge, England; Department of Physiology (Drs Donnelly and Lucas and Ms Thomas) and School of Physical Education (Drs Lucas and Cotter), Sport and Exercise Sciences, University of Otago, Dunedin, New Zealand; Cardiff School of Sport (Mr Stembridge), Cardiff Metropolitan University, Cardiff, Wales; School of Sport, Exercise and Rehabilitation Sciences (Dr Lucas), University of Birmingham, Birmingham, England; Department of Cardiology (Mr Yeoman), Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Department of Biology (Dr Day), Faculty of Science and Technology, Mount Royal University, Calgary, AB, Canada; and Peninsula Sleep Laboratory (Dr Burgess) and Department of Medicine (Dr Burgess), University of Sydney, Sydney, NSW, Australia.

CORRESPONDENCE TO: Ryan L. Hoiland, BHK, Centre for Heart, Lung and Vascular Health, School of Health and Exercise Sciences, University of British Columbia–Okanagan, 3333 University Way, Kelowna, BC, V1V 1V7, Canada; e-mail: ryanleohoiland@gmail.com


FUNDING/SUPPORT: These studies were carried out within the framework of the Ev-K2-CNR Project in collaboration with the Nepal Academy of Science and Technology as foreseen by the memorandum of understanding between Nepal and Italy and contributions from the Italian National Research Council. The work in this project was supported by a Canada Research Chair, a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, the Otago Medical Research Foundation, and the Department of Physiology (University of Otago). Dr Willie is supported by a Vanier Canada graduate scholarship, and Ms Thomas and Mr Smith are supported by the NSERC Alexander Graham Bell Canada Graduate Scholarship and Heart and Stroke Foundation of Canada doctoral and postdoctoral fellowship, respectively. Dr Donnelly is supported by a Woolf Fisher scholarship.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(1):219-225. doi:10.1378/chest.14-1992
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BACKGROUND:  The hypoxic ventilatory response (HVR) at sea level (SL) is moderately predictive of the change in pulmonary artery systolic pressure (PASP) to acute normobaric hypoxia. However, because of progressive changes in the chemoreflex control of breathing and acid-base balance at high altitude (HA), HVR at SL may not predict PASP at HA. We hypothesized that resting oxygen saturation as measured by pulse oximetry (Spo2) at HA would correlate better than HVR at SL with PASP at HA.

METHODS:  In 20 participants at SL, we measured normobaric, isocapnic HVR (L/min · −%Spo2−1) and resting PASP using echocardiography. Both resting Spo2 and PASP measures were repeated on day 2 (n = 10), days 4 to 8 (n = 12), and 2 to 3 weeks (n = 8) after arrival at 5,050 m. These data were also collected at 5,050 m in life-long HA residents (ie, Sherpa [n = 21]).

RESULTS:  Compared with SL, Spo2 decreased from 98.6% to 80.5% (P < .001), whereas PASP increased from 21.7 to 34.0 mm Hg (P < .001) after 2 to 3 weeks at 5,050 m. Isocapnic HVR at SL was not related to Spo2 or PASP at any time point at 5,050 m (all P > .05). Sherpa had lower PASP (P < .01) than lowlanders on days 4 to 8 despite similar Spo2. Upon correction for hematocrit, Sherpa PASP was not different from lowlanders at SL but was lower than lowlanders at all HA time points. At 5,050 m, although Spo2 was not related to PASP in lowlanders at any point (all R2 ≤ 0.05, P > .50), there was a weak relationship in the Sherpa (R2 = 0.16, P = .07).

CONCLUSIONS:  We conclude that neither HVR at SL nor resting Spo2 at HA correlates with elevations in PASP at HA.

Figures in this Article

The initial increase in ventilation in response to hypoxia (ie, hypoxic ventilatory response [HVR]) is highly variable.1 In response to a decreased Po2 at high altitude (HA), pulmonary artery pressure (PAP) increases primarily through hypoxic pulmonary vasoconstriction (HPV).2 In some studies, a blunted HVR is characteristic of subjects susceptible to high altitude pulmonary edema (HAPE) who exhibit marked elevations in PAP.39 The latter findings highlight a link between HVR and PAP at altitude.

Animal studies have clearly demonstrated that higher peripheral chemoreceptor responsiveness attenuates HPV.10,11 For example, following mechanical ventilation of the lungs with 100% N2, stimulation of the carotid chemoreceptors through arterial hypoxemia reduces pulmonary vascular resistance (PVR) in cats and dogs.12,13 This neural modulation of PAP in hypoxia has been studied recently in humans by interpolating the pulmonary artery systolic pressure (PASP) response to hypoxia at an oxygen saturation as measured by pulse oximetry (Spo2) of 85%.14 Between-individual variability in HVR (indicative of peripheral chemoreceptor responsiveness) at sea level (SL) was moderately correlated (R2 = 0.38) with PASP in normobaric hypoxia.14 This finding is consistent with the aforementioned reports linking HVR to HAPE susceptibility and HAPE to excessive HPV. Furthermore, individuals with a blunted HVR will consequently have a lower Pao2 and, thus, a greater stimulus to HPV at any given altitude.14 However, the issue with extrapolating variability in HVR at SL to predict changes in PAP at HA is that in addition to acid-base adjustments, HVR represents a reflex arc with three components—afferent input, central integration, and efferent output15—all of which are likely changing, resulting in an overall change in HVR at HA.16,17 Because of the myriad physiologic changes at HA related to HVR1820 and HPV,21 we hypothesized that resting Spo2 at HA would correlate better than variability in HVR at SL to PASP at HA (ie, by virtue of Spo2 reflecting Pao2 and, hence, HPV). We also reasoned that long-term adaptation to HA, as seen in the Sherpa, would result in a higher resting Spo2 and lower PASP than that of lowlanders at HA.

Study Participants and Design

All experimental procedures and protocols were approved by the Clinical Research Ethics Board at the University of British Columbia, University of Otago, and the Nepal Health Medical Research Council and conformed to the Declaration of Helsinki (UBC IRB#: H11-03287). Twenty white lowlanders aged 34 ± 7 years (five women) and 21 Nepalese male highland Sherpa aged 31 ± 13 years provided informed consent and volunteered to participate in the study. One to 2 months prior to departure, white participants underwent a transthoracic echocardiographic assessment at or close to SL (see the Transthoracic Echocardiography section for details) and then again at day 2 (n = 10, from 2008), between days 4 to 8 (5.2 ± 0.8 [further referred to as day 5], n = 12, 10 from 2008, two from 2012), and between 2 and 3 weeks (16 ± 0.7 days, n = 8, from 2012) after arrival at the Ev-K2-CNR Pyramid Research Laboratory (Lobuche, Khumbu region, Nepal; 5,050 m) in the absence of acute mountain sickness (AMS) symptoms. Sherpa were assessed at 5,050 m only. All participants were free from respiratory and cardiovascular disease and were not taking prescription medications. The native Sherpa participants originated from and were residents of the Khumbu Valley at an altitude > 3,000 m and self-identified to be of Sherpa ethnicity. None of the Sherpa had traveled < 2,800 m for at least 6 months prior to testing. Height, body mass, BP, and Spo2 were recorded prior to each transthoracic echocardiographic assessment (see the Transthoracic Echocardiography section for details). Peripheral and central chemoreflex sensitivities were also assessed on a different day at SL (see the Chemoreflex Testing section for details). Prior to each experiment, participants abstained from exercise and alcohol for 24 h and caffeine for 12 h.

In different participants, SL data were collected in February 2008 (n = 10) in Dunedin, New Zealand (at approximately 10 m) and in April 2012 (n = 10) in Kelowna, British Columbia, Canada (at an altitude of 344 m). The HA experiments were completed over 2 weeks (2008) and 3 weeks (2012) at the Ev-K2-CNR Pyramid Research Laboratory, in April to May of 2008 (New Zealand group) and 2012 (Canada group). After travel to Nepal and 7 nights in Kathmandu (approximately 1,400 m), participants flew to Lukla (2,800 m) and began an 8- to 11-day ascent to the Pyramid Research Laboratory (5,050 m). A cautious ascent profile was adopted, with ≤ 700 m net gain per day and at least 2 days with no net change in altitude. Participants were given a low oral dose of acetazolamide (125 mg) bid as an AMS prophylactic.22 Acetazolamide was discontinued at approximately 4,300 m (Pheriche, Nepal) at least 1 day before ascending to the laboratory to allow sufficient time (≥ 48 h) for the drug to clear participants’ systems prior to the first data collection session at 5,050 m.23,24 Previously, pretreatment of acetazolamide resulted in an almost negligible difference of PASP (approximately 2 mm Hg; no statistical analyses were performed) 48 h after final drug treatment compared with individuals who received placebo treatment.25 Although unlikely to alter the findings, we were unable to rule out the possibility of persistent physiologic sequelae secondary to acetazolamide treatment during day 2 testing. Participants spent 1 to 3 days at Pheriche before the final ascent. Expedition members participating in this study had a minimum of 48 h between this and other studies involving pharmaceutical interventions or exercise to minimize contamination. Some of the data presented here (eg, chemosensitivity responses, pulmonary pressures) have been reported previously in other studies from these expeditions2629; however, the research question addressed here is distinct, and combining data from these two expeditions provides a novel dataset, with greater power to address the research question.30

Transthoracic Echocardiography

All echocardiographic images were recorded on a commercially available portable ultrasound system (Vivid I; GE Healthcare [2008] and Vivid Q; GE Medical Systems Israel Ltd [2012]). Images were captured by the same highly trained cardiac sonographer within each expedition (D. J. Y. in 2008 and M. S. in 2012) while the participant lay in the left lateral decubitus position. Following 10 min of supine rest, an apical four-chamber view was visualized for the recording of the systolic tricuspid regurgitation jet velocity (TRV) using continuous-wave Doppler echocardiography with the atrioventricular pressure gradient calculated using the simplified Bernoulli equation (4TRV2). PASP was then calculated with the addition of right atrial pressure estimated from the collapsibility of the inferior vena cava on inspiration.31 Heart rate was recorded through a three-lead ECG.

Chemoreflex Testing

The respiratory chemoreflex responses to both hypoxia (an index of peripheral chemoreflex sensitivity [HVR]) and hypercapnia (an index of central chemoreflex sensitivity [hypercapnic ventilatory response (HCVR)]) were assessed at SL in the 2008 and 2012 studies; however, these tests differed slightly between investigations. Specifically, in the 2008 experiments, isocapnic hypoxia was induced for approximately 4 to 9 min through a 6-L rebreathing bag and soda lime reservoir. The isocapnic hypoxia was terminated when either (1) partial pressure of end-tidal oxygen (Peto2) reached 45 mm Hg at SL; (2) ventilation (expired volume per unit time [V. e]) exceeded 100 L/min; or (3) the participant reached the end of his or her tolerance. In the 2012 experiments, isocapnic hypoxia (Peto2 = 47 mm Hg) was maintained > 10 min through end-tidal forcing as described in depth elsewhere.29,32 Despite the different methods, in a subgroup of participants (n = 6) who underwent both tests, the peak HVR between tests was comparable (R2 = 0.46, P < .05) and not significantly different from each other (P = .6), indicating that they both reflected similar chemoreflex phenomena. In 2012, a subgroup (n = 8) of participants at SL underwent 10 min of poikilocapnic hypoxia (11% oxygen) to simulate 5,050 m. Although acute poikilocapnic hypoxia testing is more complicated than the commonly used isocapnic hypoxic testing because of the interactive effects of hypoxia and concomitant hypocapnia, it is more representative of the uncontrolled breathing environment at HA and, therefore, more applicable to such scenarios.

In 2008, HCVR was assessed from a 4-min steady-state hyperoxic hypercapnia gas mixture (7% CO2, 93% oxygen) after a 5-min room air baseline. In 2012, HCVR was assessed using end-tidal forcing where the partial pressure of end-tidal CO2 (Petco2) was clamped initially at baseline and then elevated in a stepwise fashion at +5, +10, and +15 mm Hg from individual baseline values while Peto2 was maintained at individual baseline values (approximately 100 mm Hg). In a subgroup of participants (n = 7) who underwent both tests, the relationship (R2) between HCVR tests was 0.53 (P < .01).

In both the 2008 and 2012 experiments, all respiratory parameters were acquired at 200 Hz using an analog-to-digital converter (PowerLab/16SP ML880; ADInstruments Inc) interfaced with a personal computer and analyzed with commercially available software (LabChart; ADInstruments Inc). Throughout all procedures, participants breathed through a mouthpiece (with nose clip) or face mask with an attached bacteriologic filter and a two-way nonrebreathing valve (2600 series; Hans Rudolph, Inc). Respired gas was sampled at the mouth and analyzed for Peto2 and Petco2 by a calibrated gas analyzer (ML206; ADInstruments Inc). Respiratory flow was measured near the mouth using a pneumotachograph (HR 800L; Hans Rudolph, Inc) and a differential pressure amplifier (ML141; ADInstruments Inc).

Calculations

For the 2008 studies, isocapnic HVR was calculated as the slope of the linear regression between V. e and Spo2, whereas HCVR was calculated as ΔV. e/ΔPetco2 from baseline to steady state. For the 2012 studies, isocapnic HVR was calculated as ΔV. e/ΔSpo2 from baseline to the peak ventilation during hypoxia. Peak poikilocapnic HVR was calculated in a similar manner, whereas delayed poikilocapnic HVR was calculated as ΔV. e/ΔSpo2 from baseline to the average of 10 to 15 min of hypoxia. The HCVR was calculated as the linear regression slope between V. e and Petco2.

To account for differences in hematocrit (HCT) between groups, we estimated PASP after correction of HCT to SL values (45%). First, we calculated PVR in all participants using the following equation31:
PVR=TRV/RVOTVTI10+0.16 
where TRV is measured in m/s, RVOT VTI (right ventricular outflow tract velocity time integral) is measured in centimeters, and the resulting PVR is expressed in Wood units. Once this was determined for both lowlanders and Sherpa at HA, we calculated PVR at an HCT of 45% in all individuals using the following equation33:
PVR(45%)=PVR(HCT%)=1φ1/30.234 

where φ represents the HCT at HA. Because pressure is proportional to resistance, we infer the calculated percent change in PVR to be representative of the percent change effect of HCT on PASP and, as such, adjusted PASP values to a 45% HCT estimate in all groups. For the day 2 group, we used an HCT value of 45.7%,27 whereas for day 5, 2 to 3 weeks, and Sherpa, the HCT values were 49.4%,27 49.4%,29 and 53.9%,29 respectively.

Statistical Analyses

Comparison of lowlanders at SL, day 2, day 5, and 2 to 3 weeks at altitude as well as of Sherpa were performed using a one-factor analysis of variance. The relationship among variables (Spo2, HVR, HCVR, and PASP) was assessed using least squares linear regression following conformation of a Gaussian distribution. The α value was set a priori to .05. All statistical analyses were performed using Prism version 5.0b (GraphPad Software, Inc) (2008) and SPSS version 21 (IBM Corporation) (2012) software.

Baseline Characteristics

Consistent with previous reports of HVR and HCVR at 4,300 m,34,35 we found no significant sex differences for chemoreflexes at SL and both PASP and Spo2 at HA; therefore, data for men and women were pooled for statistical analysis. At HA, Spo2 decreased from its SL value of 98.6 ± 1.1% to 79.5 ± 2.9% (P < .001) on day 2, 83.4 ± 1.9% (P < .001) on day 5, and 80.5 ± 1.6% (P < .001) after 2 to 3 weeks acclimatization at 5,050 m; at these time points, PASP increased from 21.7 ± 2.1 mm Hg at SL to 36.6 ± 4.6 mm Hg (P < .001), 35.7 ± 5.5 mm Hg (P < .001), and 34.0 ± 4.5 mm Hg (P < .001), respectively. Isocapnic HVR at SL was 1.61 ± 0.94 L/min · −%Spo2−1, whereas peak and delayed poikilocapnic HVR were 0.46 ± 0.23 and 0.14 ± 0.08 L/min · −%Spo2−1, respectively. HCVR at SL was 3.00 ± 1.49 L/min · mm Hg Petco2−1. Correction of lowlander PASP to an HCT of 45% indicated that independent of blood viscosity, PASP still significantly increased from 21.7 ± 2.1 mm Hg at SL to 35.9 ± 4.5 mm Hg (P < .001) on day 2, 31.9 ± 5.0 mm Hg (P < .001) on day 5, and 30.4 ± 41 mm Hg (P < .01) after 2 to 3 weeks acclimatization.

Relationship Between Chemoreflexes and PASP at HA

Elevations in PASP at 5,050 m after 2 to 3 weeks acclimatization were unrelated to SL isocapnic HVR (R2 < 0.01, P = .97) (Fig 1), SL peak poikilocapnic HVR (R2 = 0.16, P = .38), and SL delayed poikilocapnic HVR (R2 = 0.13, P = .42). Variability in the HCVR was also unrelated to the changes in PASP (R2 = 0.08, P = .50). Poikilocapnic HVR (peak and delayed) and isocapnic HVR (Fig 1) were unrelated to Spo2 after 2 to 3 weeks acclimatization. These relationships remained insignificant when ventilatory tests were related to PASP and Spo2 values on day 2 and day 5 at 5,050 m. Furthermore, incorporating individual variability at SL and HA through calculation of Δ scores (ie, HA − SL) did not render any significant relationships.

Figure Jump LinkFigure 1 –  A, B, The relationship between sea level isocapnic HVR and both SpO2 (A) and PASP (B) in lowlanders within d 2 (, solid line), d 5 (, dashed line), and after 2 to 3 wk acclimatization (, dashed line). HVR was unrelated to SpO2 on d 2 (R2 = 0.24, P = .14), d 5 (R2 = 0.12, P = .27), and after 2 to 3 wk acclimatization (R2 = 0.10, P = .46). The relationship between sea level isocapnic HVR and PASP at high altitude on d 2 (R2 = 0.03, P = .64), d 5 (R2 = 0.25, P = .12), and after 2 to 3 wk acclimatization (R2 < 0.01, P = .97) were also insignificant. HVR = hypoxic ventilatory response; PASP = pulmonary artery systolic pressure; SpO2 = oxygen saturation as measured by pulse oximetry.Grahic Jump Location

Sherpa had higher Spo2 (82.8 ± 3.3% vs 79.5 ± 2.9%, P < .01) but lower PASP (29.8 ± 5.9 mm Hg vs 36.6 ± 4.6 mm Hg, P < .01) compared with lowlanders on day 2 at 5,050 m. However, on day 5, although Sherpa had comparable Spo2 (82.8 ± 3.3% vs 83.4 ± 1.9%, P = .56), PASP was still lower compared with lowlanders (29.8 ± 5.9 mm Hg vs 35.65 ± 5.5 mm Hg, P < .01). After 2 to 3 weeks acclimatization, Sherpa and lowlander Spo2 were not different (82.8 ± 3.3% vs 80.5 ± 1.6%, P = .07); however, PASP still tended to be lower in the Sherpa (29.8 ± 5.9 mm Hg vs 34.0 ± 4.5 mm Hg, P = .06). Upon correction for HCT to 45%, Sherpa PASP was reduced to 23.7 ± 4.7 mm Hg, which was not different from lowlanders at SL (P = .09) but was significantly lower than lowlanders at all HA time points (all P < .01). Regression analysis revealed similar nonsignificant correlations between HA Spo2 and PASP in lowlanders on day 2 at altitude (R2 = 0.03, P = .61), day 5 (R2 = 0.05, P = .51), and after 2 to 3 weeks acclimatization (R2 = 0.03, P = .69) as well as in Sherpa (R2 = 0.16, P = .07). On examination of the group regressions, the slopes for lowlanders on day 2, day 5, and after 2 to 3 weeks acclimatization as well as in Sherpa were −0.29, 0.67, −0.49, and −0.74 mm Hg · −%Spo2−1, respectively (Fig 2).

Figure Jump LinkFigure 2 –  The influence of SpO2 on PASP at high altitude in lowlanders on d 2 (, thin solid line), d 5 (, dashed line), and after 2 to 3 wk at altitude (, thick solid line) as well as in Sherpa (, dotted line). Regression analysis revealed nonsignificant correlations between high altitude SpO2 and PASP on d 2 (R2 = 0.03, P = .61), d 5 (R2 = 0.05, P = .51), and after 2 to 3 wk acclimatization (R2 = 0.03, P = .69) as well as in Sherpa (R2 = 0.16, P = .07). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

The primary finding of this study is the lack of correlation between both peripheral and central chemosensitivity at SL and PASP at HA, contrary to previous findings during SL hypoxia.14 Furthermore, at any time point, there was no relationship between HA Spo2 and resting PASP at 5,050 m in SL dwellers. Consistent with our second hypothesis, Sherpa had higher Spo2 and lower PASP than lowlanders on day 2 at HA. Early acclimatization eliminated the difference in Spo2 between Sherpa and lowlanders, whereas PASP was generally lower in the native highlanders.

Changes in peripheral chemoreceptor responsiveness,19,36,37 central processing,18,20,38 and the consequent efferent output18 all affect the ventilatory response to hypoxia at altitude.16,17 The further effect of changes in acid-base balance and the complex nature of breathing at HA have been reviewed in detail.15 Therefore, although SL HVR has been correlated with PASP during normobaric hypoxia (Spo2 = 85%, n = 15),14 the lack of correlation (of both isocapnic and poikilocapnic HVR) to PASP at HA is perhaps not surprising because of the aforementioned changes in addition to changes in lung diffusion capacity,39 which occur upon exposure to altitude. Moreover, because HVR rapidly increases within the first week of exposure to HA16,17 and full ventilatory acclimatization may take up to 4 to 6 weeks at 5,050 m,15 it is also not surprising that SL HVR was unrelated to PASP at all HA time points. Although a blunted HVR has been reported in some studies to be related to HAPE susceptibility,40,41 we did not include any subjects susceptible to AMS or HAPE by design and ensured safe ascent and acclimatization. Because most studies derive their relationships through the use of two distinct phenotypes (ie, subjects who are AMS susceptible and nonsusceptible who often have a blunted and brisk HVR,4043 respectively), having a singular phenotype within the present participant group may preclude any relationship between HVR and PASP. However, this does not undermine the significance that biologic variability in SL HVR does not predict the marked variability in PASP at HA in a homogenous group.

An inverse relationship between Spo2 and PAP was reported as early as 1957 at 4,540 m.44 Because a reduction in Pao2 is the primary stimulus for HPV,2,45 we reasoned that Spo2 at HA would correlate more strongly with PASP than SL HVR. However, we acknowledge that the regulation of elevations in PAP upon exposure to HA involves the complex interaction of multiple factors and, hence, likely explains the unremarkable correlation found between Spo2 and PASP in lowlanders and Sherpa. This is evidenced by incomplete restoration of normal PAP in lowlanders3,46 and Sherpa29 upon alleviation of alveolar hypoxia. The present findings are consistent with earlier reports that Sherpa have higher resting Spo2 than lowlanders upon initial arrival to HAs (ie, > 4,000 m [day 2 in this investigation]). Similar Spo2 between Sherpa and lowlanders after 1 to 3 weeks acclimatization is likely due to progressive ventilatory acclimatization and consequent elevations in resting ventilation. Previous studies have reported a significant47 and trending48 inverse relationship between Spo2 and PAP; however, this is not a consistent finding.28,44 Furthermore, PASP has been reported as both lower48 and the same28,29 in Sherpa than in lowlanders at HA, with the differing results likely due to duration of time at altitude prior to assessment29 and small sample sizes. The present data, which include a larger sample size of Sherpa than previous investigations, show that despite similar Spo2 to lowlanders after approximately 5 days acclimatization, Sherpa continue to have lower PASP. Therefore, several other key factors that regulate PAP at HA in addition to Pao22,45 must be interacting in a different manner between Sherpa and lowlander populations. These factors likely include pulmonary vascular remodeling to life at HA,49 genetic adaptations, higher circulating nitric oxide in Sherpa than in lowlanders,50 and blood viscosity.29 To provide insight into this latter point, we corrected both lowlander and Sherpa PASP values to an SL HCT (45%). After correction, PASP in Sherpa fell within SL norms at approximately 24 mm Hg, therefore indicating that HCT and subsequently viscosity are predominantly responsible for elevated PASP in Sherpa at 5,050 m. This further provides evidence suggesting a differential regulation of PASP between lowlanders and HA natives and indicates that we and others28,29,48 have likely underestimated the difference in HPV between lowlanders and Sherpa without considering changes in HCT.33 In conclusion, because the multiple factors regulating breathing differ between SL and HA, the utility of SL chemoreflex tests (both poikilocapnic and isocapnic) to predict changes in PASP at HA is limited in otherwise healthy individuals.

Author contributions: P. N. A. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. R. L. H. contributed to the data collection and analysis, data interpretation, and drafting of the manuscript; G. E. F., J. D., C. K. W., K. J. S., N. C. L., S. J. E. L., J. D. C., K. N. T., T. A. D., M. M. T., and K. R. B. contributed to the data collection and critical review of manuscript; M. S. and D. J. Y. contributed to the data collection and analyses and critical review of manuscript; and P. N. A. contributed to the study design, data collection, data interpretation, and critical review of manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: The authors thank the other members of both research expeditions for invaluable help with logistical planning and implementation of this research study. The authors also thank Prof Greg Atkinson for advice and assistance with the statistical analysis.

AMS

acute mountain sickness

HA

high altitude

HAPE

high altitude pulmonary edema

HCT

hematocrit

HCVR

hypercapnic ventilatory response

HPV

hypoxic pulmonary vasoconstriction

HVR

hypoxic ventilatory response

PAP

pulmonary artery pressure

PASP

pulmonary artery systolic pressure

Petco2

partial pressure of end-tidal CO2

Peto2

partial pressure of end-tidal oxygen

PVR

pulmonary vascular resistance

SL

sea level

Spo2

oxygen saturation as measured by pulse oximetry

TRV

tricuspid regurgitation jet velocity

V. e

expired volume per unit time

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Ainslie PN, Lucas SJ, Burgess KR. Breathing and sleep at high altitude. Respir Physiol Neurobiol. 2013;188(3):233-256. [CrossRef] [PubMed]
 
White DP, Gleeson K, Pickett CK, Rannels AM, Cymerman A, Weil JV. Altitude acclimatization: influence on periodic breathing and chemoresponsiveness during sleep. J Appl Physiol (1985). 1987;63(1):401-412. [PubMed]
 
Sato M, Severinghaus JW, Powell FL, Xu FD, Spellman MJ Jr. Augmented hypoxic ventilatory response in men at altitude. J Appl Physiol (1985). 1992;73(1):101-107. [PubMed]
 
Dwinell MR, Powell FL. Chronic hypoxia enhances the phrenic nerve response to arterial chemoreceptor stimulation in anesthetized rats. J Appl Physiol (1985). 1999;87(2):817-823. [PubMed]
 
Barnard P, Andronikou S, Pokorski M, Smatresk N, Mokashi A, Lahiri S. Time-dependent effect of hypoxia on carotid body chemosensory function. J Appl Physiol (1985). 1987;63(2):685-691. [PubMed]
 
Gallman EA, Millhorn DE. Two long-lasting central respiratory responses following acute hypoxia in glomectomized cats. J Physiol. 1988;395:333-347. [CrossRef] [PubMed]
 
Swenson ER. Hypoxic pulmonary vasoconstriction. High Alt Med Biol. 2013;14(2):101-110. [CrossRef] [PubMed]
 
Basnyat B, Gertsch JH, Holck PS, et al. Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol. 2006;7(1):17-27. [CrossRef] [PubMed]
 
Ritschel WA, Paulos C, Arancibia A, Agrawal MA, Wetzelsberger KM, Lücker PW. Pharmacokinetics of acetazolamide in healthy volunteers after short- and long-term exposure to high altitude. J Clin Pharmacol. 1998;38(6):533-539. [CrossRef] [PubMed]
 
Richalet J-P, Rivera M, Bouchet P, et al. Acetazolamide: a treatment for chronic mountain sickness. Am J Respir Crit Care Med. 2005;172(11):1427-1433. [CrossRef] [PubMed]
 
Ke T, Wang J, Swenson ER, et al. Effect of acetazolamide and gingko biloba on the human pulmonary vascular response to an acute altitude ascent. High Alt Med Biol. 2013;14(2):162-167. [CrossRef] [PubMed]
 
Donnelly J, Cowan DC, Yeoman DJ, et al. Exhaled nitric oxide and pulmonary artery pressures during graded ascent to high altitude. Respir Physiol Neurobiol. 2011;177(3):213-217. [CrossRef] [PubMed]
 
Lucas SJE, Burgess KR, Thomas KN, et al. Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m. J Physiol. 2011;589(pt 3):741-753. [CrossRef] [PubMed]
 
Stembridge M, Ainslie PN, Hughes MG, et al. Ventricular structure, function, and mechanics at high altitude: chronic remodeling in Sherpa vs short-term lowlander adaptation. J Appl Physiol (1985). 2014;117(3):334-343. [CrossRef] [PubMed]
 
Foster GE, Ainslie PN, Stembridge M, et al. Resting pulmonary haemodynamics and shunting: a comparison of sea-level inhabitants to high altitude Sherpas. J Physiol. 2014;592(pt 6):1397-1409. [CrossRef] [PubMed]
 
Ainslie PN. On the nature of research at high altitude: packing it all in! Exp Physiol. 2014;99(5):741-742. [CrossRef] [PubMed]
 
Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23(7):685-713. [CrossRef] [PubMed]
 
Querido JS, Ainslie PN, Foster GE, et al. Dynamic cerebral autoregulation during and following acute hypoxia: role of carbon dioxide. J Appl Physiol (1985). 2013;114(9):1183-1190. [CrossRef] [PubMed]
 
Naeije R, Vanderpool R. Pulmonary hypertension and chronic mountain sickness. High Alt Med Biol. 2013;14(2):117-125. [CrossRef] [PubMed]
 
Muza SR, Rock PB, Fulco CS, et al. Women at altitude: ventilatory acclimatization at 4,300 m. J Appl Physiol (1985). 2001;91(4):1791-1799. [PubMed]
 
Bhaumik G, Sharma RP, Dass D, et al. Hypoxic ventilatory response changes of men and women 6 to 7 days after climbing from 2100 m to 4350 m altitude and after descent. High Alt Med Biol. 2003;4(3):341-348. [CrossRef] [PubMed]
 
Nielsen AM, Bisgard GE, Vidruk EH. Carotid chemoreceptor activity during acute and sustained hypoxia in goats. J Appl Physiol (1985). 1988;65(4):1796-1802. [PubMed]
 
Vizek M, Pickett CK, Weil JV. Increased carotid body hypoxic sensitivity during acclimatization to hypobaric hypoxia. J Appl Physiol (1985). 1987;63(6):2403-2410. [PubMed]
 
Dwinell MR, Huey KA, Powell FL. Chronic hypoxia induces changes in the central nervous system processing of arterial chemoreceptor input. Adv Exp Med Biol. 2000;475:477-484. [PubMed]
 
Agostoni P, Swenson ER, Bussotti M, et al; HIGHCARE Investigators. High-altitude exposure of three weeks duration increases lung diffusing capacity in humans. J Appl Physiol (1985). 2011;110(6):1564-1571. [CrossRef] [PubMed]
 
Hackett PH, Roach RC, Schoene RB, Harrison GL, Mills WJ Jr. Abnormal control of ventilation in high-altitude pulmonary edema. J Appl Physiol (1985). 1988;64(3):1268-1272. [PubMed]
 
Hohenhaus E, Paul A, McCullough RE, Kücherer H, Bärtsch P. Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema. Eur Respir J. 1995;8(11):1825-1833. [CrossRef] [PubMed]
 
Moore LG, Harrison GL, McCullough RE, et al. Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness. J Appl Physiol (1985). 1986;60(4):1407-1412. [PubMed]
 
Milledge JS, Beeley JM, Broome J, Luff N, Pelling M, Smith D. Acute mountain sickness susceptibility, fitness and hypoxic ventilatory response. Eur Respir J. 1991;4(8):1000-1003. [PubMed]
 
Canepa A, Chavez R, Hurtado A, Rotta A, Velasquez T. Pulmonary circulation at sea level and at high altitudes. J Appl Physiol. 1956;9(3):328-336. [PubMed]
 
Euler U, Liljestrand G. Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand. 1946;12(4):301-320. [CrossRef]
 
Kronenberg RS, Safar P, Leej, et al. Pulmonary artery pressure and alveolar gas exchange in man during acclimatization to 12,470 ft. J Clin Invest. 1971;50(4):827-837. [CrossRef] [PubMed]
 
Penaloza D, Arias-Stella J. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation. 2007;115(9):1132-1146. [CrossRef] [PubMed]
 
Faoro V, Huez S, Vanderpool R, et al. Pulmonary circulation and gas exchange at exercise in Sherpas at high altitude. J Appl Physiol (1985). 2014;116(7):919-926. [CrossRef] [PubMed]
 
Welsh DJ, Peacock AJ. Cellular responses to hypoxia in the pulmonary circulation. High Alt Med Biol. 2013;14(2):111-116. [CrossRef] [PubMed]
 
Beall CM, Laskowski D, Strohl KP, et al. Pulmonary nitric oxide in mountain dwellers. Nature. 2001;414(6862):411-412. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  A, B, The relationship between sea level isocapnic HVR and both SpO2 (A) and PASP (B) in lowlanders within d 2 (, solid line), d 5 (, dashed line), and after 2 to 3 wk acclimatization (, dashed line). HVR was unrelated to SpO2 on d 2 (R2 = 0.24, P = .14), d 5 (R2 = 0.12, P = .27), and after 2 to 3 wk acclimatization (R2 = 0.10, P = .46). The relationship between sea level isocapnic HVR and PASP at high altitude on d 2 (R2 = 0.03, P = .64), d 5 (R2 = 0.25, P = .12), and after 2 to 3 wk acclimatization (R2 < 0.01, P = .97) were also insignificant. HVR = hypoxic ventilatory response; PASP = pulmonary artery systolic pressure; SpO2 = oxygen saturation as measured by pulse oximetry.Grahic Jump Location
Figure Jump LinkFigure 2 –  The influence of SpO2 on PASP at high altitude in lowlanders on d 2 (, thin solid line), d 5 (, dashed line), and after 2 to 3 wk at altitude (, thick solid line) as well as in Sherpa (, dotted line). Regression analysis revealed nonsignificant correlations between high altitude SpO2 and PASP on d 2 (R2 = 0.03, P = .61), d 5 (R2 = 0.05, P = .51), and after 2 to 3 wk acclimatization (R2 = 0.03, P = .69) as well as in Sherpa (R2 = 0.16, P = .07). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Tables

References

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Fitzgerald RS, Dehghani GA, Sham JS, Shirahata M, Mitzner WA. Peripheral chemoreceptor modulation of the pulmonary vasculature in the cat. J Appl Physiol (1985). 1992;73(1):20-29. [PubMed]
 
Albert TJ, Swenson ER. Peripheral chemoreceptor responsiveness and hypoxic pulmonary vasoconstriction in humans. High Alt Med Biol. 2014;15(1):15-20. [CrossRef] [PubMed]
 
Ainslie PN, Lucas SJ, Burgess KR. Breathing and sleep at high altitude. Respir Physiol Neurobiol. 2013;188(3):233-256. [CrossRef] [PubMed]
 
White DP, Gleeson K, Pickett CK, Rannels AM, Cymerman A, Weil JV. Altitude acclimatization: influence on periodic breathing and chemoresponsiveness during sleep. J Appl Physiol (1985). 1987;63(1):401-412. [PubMed]
 
Sato M, Severinghaus JW, Powell FL, Xu FD, Spellman MJ Jr. Augmented hypoxic ventilatory response in men at altitude. J Appl Physiol (1985). 1992;73(1):101-107. [PubMed]
 
Dwinell MR, Powell FL. Chronic hypoxia enhances the phrenic nerve response to arterial chemoreceptor stimulation in anesthetized rats. J Appl Physiol (1985). 1999;87(2):817-823. [PubMed]
 
Barnard P, Andronikou S, Pokorski M, Smatresk N, Mokashi A, Lahiri S. Time-dependent effect of hypoxia on carotid body chemosensory function. J Appl Physiol (1985). 1987;63(2):685-691. [PubMed]
 
Gallman EA, Millhorn DE. Two long-lasting central respiratory responses following acute hypoxia in glomectomized cats. J Physiol. 1988;395:333-347. [CrossRef] [PubMed]
 
Swenson ER. Hypoxic pulmonary vasoconstriction. High Alt Med Biol. 2013;14(2):101-110. [CrossRef] [PubMed]
 
Basnyat B, Gertsch JH, Holck PS, et al. Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol. 2006;7(1):17-27. [CrossRef] [PubMed]
 
Ritschel WA, Paulos C, Arancibia A, Agrawal MA, Wetzelsberger KM, Lücker PW. Pharmacokinetics of acetazolamide in healthy volunteers after short- and long-term exposure to high altitude. J Clin Pharmacol. 1998;38(6):533-539. [CrossRef] [PubMed]
 
Richalet J-P, Rivera M, Bouchet P, et al. Acetazolamide: a treatment for chronic mountain sickness. Am J Respir Crit Care Med. 2005;172(11):1427-1433. [CrossRef] [PubMed]
 
Ke T, Wang J, Swenson ER, et al. Effect of acetazolamide and gingko biloba on the human pulmonary vascular response to an acute altitude ascent. High Alt Med Biol. 2013;14(2):162-167. [CrossRef] [PubMed]
 
Donnelly J, Cowan DC, Yeoman DJ, et al. Exhaled nitric oxide and pulmonary artery pressures during graded ascent to high altitude. Respir Physiol Neurobiol. 2011;177(3):213-217. [CrossRef] [PubMed]
 
Lucas SJE, Burgess KR, Thomas KN, et al. Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m. J Physiol. 2011;589(pt 3):741-753. [CrossRef] [PubMed]
 
Stembridge M, Ainslie PN, Hughes MG, et al. Ventricular structure, function, and mechanics at high altitude: chronic remodeling in Sherpa vs short-term lowlander adaptation. J Appl Physiol (1985). 2014;117(3):334-343. [CrossRef] [PubMed]
 
Foster GE, Ainslie PN, Stembridge M, et al. Resting pulmonary haemodynamics and shunting: a comparison of sea-level inhabitants to high altitude Sherpas. J Physiol. 2014;592(pt 6):1397-1409. [CrossRef] [PubMed]
 
Ainslie PN. On the nature of research at high altitude: packing it all in! Exp Physiol. 2014;99(5):741-742. [CrossRef] [PubMed]
 
Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23(7):685-713. [CrossRef] [PubMed]
 
Querido JS, Ainslie PN, Foster GE, et al. Dynamic cerebral autoregulation during and following acute hypoxia: role of carbon dioxide. J Appl Physiol (1985). 2013;114(9):1183-1190. [CrossRef] [PubMed]
 
Naeije R, Vanderpool R. Pulmonary hypertension and chronic mountain sickness. High Alt Med Biol. 2013;14(2):117-125. [CrossRef] [PubMed]
 
Muza SR, Rock PB, Fulco CS, et al. Women at altitude: ventilatory acclimatization at 4,300 m. J Appl Physiol (1985). 2001;91(4):1791-1799. [PubMed]
 
Bhaumik G, Sharma RP, Dass D, et al. Hypoxic ventilatory response changes of men and women 6 to 7 days after climbing from 2100 m to 4350 m altitude and after descent. High Alt Med Biol. 2003;4(3):341-348. [CrossRef] [PubMed]
 
Nielsen AM, Bisgard GE, Vidruk EH. Carotid chemoreceptor activity during acute and sustained hypoxia in goats. J Appl Physiol (1985). 1988;65(4):1796-1802. [PubMed]
 
Vizek M, Pickett CK, Weil JV. Increased carotid body hypoxic sensitivity during acclimatization to hypobaric hypoxia. J Appl Physiol (1985). 1987;63(6):2403-2410. [PubMed]
 
Dwinell MR, Huey KA, Powell FL. Chronic hypoxia induces changes in the central nervous system processing of arterial chemoreceptor input. Adv Exp Med Biol. 2000;475:477-484. [PubMed]
 
Agostoni P, Swenson ER, Bussotti M, et al; HIGHCARE Investigators. High-altitude exposure of three weeks duration increases lung diffusing capacity in humans. J Appl Physiol (1985). 2011;110(6):1564-1571. [CrossRef] [PubMed]
 
Hackett PH, Roach RC, Schoene RB, Harrison GL, Mills WJ Jr. Abnormal control of ventilation in high-altitude pulmonary edema. J Appl Physiol (1985). 1988;64(3):1268-1272. [PubMed]
 
Hohenhaus E, Paul A, McCullough RE, Kücherer H, Bärtsch P. Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema. Eur Respir J. 1995;8(11):1825-1833. [CrossRef] [PubMed]
 
Moore LG, Harrison GL, McCullough RE, et al. Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness. J Appl Physiol (1985). 1986;60(4):1407-1412. [PubMed]
 
Milledge JS, Beeley JM, Broome J, Luff N, Pelling M, Smith D. Acute mountain sickness susceptibility, fitness and hypoxic ventilatory response. Eur Respir J. 1991;4(8):1000-1003. [PubMed]
 
Canepa A, Chavez R, Hurtado A, Rotta A, Velasquez T. Pulmonary circulation at sea level and at high altitudes. J Appl Physiol. 1956;9(3):328-336. [PubMed]
 
Euler U, Liljestrand G. Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand. 1946;12(4):301-320. [CrossRef]
 
Kronenberg RS, Safar P, Leej, et al. Pulmonary artery pressure and alveolar gas exchange in man during acclimatization to 12,470 ft. J Clin Invest. 1971;50(4):827-837. [CrossRef] [PubMed]
 
Penaloza D, Arias-Stella J. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation. 2007;115(9):1132-1146. [CrossRef] [PubMed]
 
Faoro V, Huez S, Vanderpool R, et al. Pulmonary circulation and gas exchange at exercise in Sherpas at high altitude. J Appl Physiol (1985). 2014;116(7):919-926. [CrossRef] [PubMed]
 
Welsh DJ, Peacock AJ. Cellular responses to hypoxia in the pulmonary circulation. High Alt Med Biol. 2013;14(2):111-116. [CrossRef] [PubMed]
 
Beall CM, Laskowski D, Strohl KP, et al. Pulmonary nitric oxide in mountain dwellers. Nature. 2001;414(6862):411-412. [CrossRef] [PubMed]
 
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