Tibetans have been reported to present with a unique phenotypic adaptation to high altitude characterized by higher resting ventilation and arterial oxygen saturation, no excessive polycythemia, and lower pulmonary arterial pressures (Ppa) compared with other high-altitude populations. How this affects exercise capacity is not exactly known. We measured aerobic exercise capacity during an incremental cardiopulmonary exercise test, lung diffusing capacity for carbon monoxide (DlCO) and nitric oxide (DlNO) at rest, and mean Ppa (mPpa) and cardiac output by echocardiography at rest and at exercise in 13 Sherpas and in 13 acclimatized lowlander controls at the altitude of 5,050 m in Nepal. In Sherpas vs. lowlanders, arterial oxygen saturation was 86 ± 1 vs. 83 ± 2% (mean ± SE; P = nonsignificant), mPpa at rest 19 ± 1 vs. 23 ± 1 mmHg (P < 0.05), DlCO corrected for hemoglobin 61 ± 4 vs. 37 ± 2 ml·min−1·mmHg−1 (P < 0.001), DlNO 226 ± 18 vs. 153 ± 9 ml·min−1·mmHg−1 (P < 0.001), maximum oxygen uptake 32 ± 3 vs. 28 ± 1 ml·kg−1·min−1 (P = nonsignificant), and ventilatory equivalent for carbon dioxide at anaerobic threshold 40 ± 2 vs. 48 ± 2 (P < 0.001). Maximum oxygen uptake was correlated directly to DlCO and inversely to the slope of mPpa-cardiac index relationships in both Sherpas and acclimatized lowlanders. We conclude that Sherpas compared with acclimatized lowlanders have an unremarkable aerobic exercise capacity, but with less pronounced pulmonary hypertension, lower ventilatory responses, and higher lung diffusing capacity.
- lung diffusion
- V̇o2 max
- pulmonary arterial pressure
the adaptation to life at high altitudes is associated with a series of physiological changes, which include increased ventilation, polycythemia, and pulmonary hypertension, but with patterns depending on ethnicity (32). The adaptation pattern in Tibetans is characterized by relatively higher ventilation and lower hemoglobin (Hb) and oxygen saturation compared with Andeans (3, 4, 6, 32). Furthermore, Tibetans have little or no hypoxic pulmonary hypertension (15), which has been related to high endogenous nitric oxide (NO) production (5). This is in contrast with Andean dwellers known to have more pulmonary hypertension than acclimatized lowlanders at the same altitude (27). Recent studies show that Tibetans have a series of genetic changes related to hypoxia inducible factor-2α signaling (29). These changes likely explain the decreased expression of erythropoietin and lower red blood cell mass, but the correlation to higher ventilation, lower pulmonary vascular reactivity, and remodeling is less clear (32). With the exception of excessive polycythemia, predominantly seen in South American Quechua or Aymara, as a cause of chronic mountain sickness (CMS), phenotypic differences in altitude adaptation between Andeans and Tibetans have not been shown to have an impact on quality of life, survival, or exercise capacity (32).
Our laboratory has previously showed that lifelong high-altitude Quechua inhabitants have preserved aerobic exercise capacity but decreased ventilatory responses, increased lung diffusing capacity, higher Hb and oxygen saturation, and more pulmonary hypertension, compared with recently acclimatized lowlanders at the altitude of 4,350 m in Peru (13). In the present study, we report on the same measurements in high-altitude Sherpa (who are of Tibetan origin) at the altitude of 5,050 m in Nepal.
Thirteen healthy European Caucasian lowlanders (6 men and 7 women) without history of high-altitude intolerance, and 13 healthy highlanders (10 men and 3 women; lifelong exposure between 2,500 and 4,000 m) gave informed consent to the study, which was approved by the Ethical Committee of the Erasme University Hospital (Brussels). All participants were nonsmokers with a normal clinical examination. The highlanders considered themselves of the Sherpa ethnic group. Lowlanders and highlanders were matched for age, body mass index, and body surface area. The lowlanders were part of previously reported studies on the effects of altitude exposure on exercise capacity and the pulmonary circulation (25) and lung diffusion (9).
Interethnic comparisons were made between the Sherpas, 15 healthy Quechua highlanders, 13 Andeans with CMS investigated at the altitude of 4,350 m in Cerro de Pasco (13), and 57 acclimatized lowlanders investigated during four different expeditions at altitudes between 4,350 and 5,000 m (26), who served as historical controls. The anthropometric characteristics of the groups are summarized in Table 1. Body dimensions did not differ between groups, but the Andeans were older.
Sherpas and lowlanders underwent lung diffusing capacity measurements, followed by a Doppler echocardiography at rest to estimate pulmonary arterial pressure (Ppa), cardiac output (Q̇), and right ventricular (RV) function. To define pulmonary vascular function, measurements of mean Ppa (mPpa) and Q̇ were made at rest and repeated at two levels of exercise (Q̇ increased by 1 l·min−1·step−1) to obtain three-point mPpa-Q̇ relationships. Higher levels of exercise were not attempted as the local home-made portable exercise table was uncomfortable, and it was thought that three mPpa-Q̇ coordinates would be sufficient to define pulmonary vascular resistance (PVR) without pulmonary vasoconstriction or excessive left atrial pressure (Pla) elevation at higher workloads (21). After the stress echocardiographic measurements, the subjects rested for 30 min or more until heart rate (HR) returned to baseline values and then underwent an incremental maximal cycle ergometer cardiopulmonary exercise test (CPET). Blood pressure (BP), HR, and arterial oxygen saturation (SpO2) were measured at rest and at each level of exercise during the CPET.
The sequence of lung diffusing capacity, echocardiography, and CPET measurements was also obtained at sea level within the week before travelling to Nepal in the 13 participating lowlander controls. High-altitude measurements were performed at the Pyramid International Laboratory Observatory at 5,050 m, in the Khumbu area of the Sagarmatha National Park. The lowlanders reached this laboratory after a 1-wk hike at progressively increasing altitudes starting at Lukla (2,800 m). Measurements were performed within the first 2 days of arrival at 5,050 m.
Clinical assessment included a standard history and examination. BP was measured by sphygmomanometry, with mean pressure calculated as diastolic pressure + ⅓ pulse pressure. A three-lead ECG was used to measure HR. SpO2 was measured by ear lobe pulse oximetry (Konica Minolta Pulsox-3i; Konica Minolta Sensing, Osaka, Japan).
Pulmonary function measurements.
Lung diffusing capacities for carbon monoxide (DlCO) and NO (DlNO) were measured in the sitting position with corrections for Hb and inspired partial pressure of oxygen, using an automated device for calibrations, mixing of gases, and online calculations (Hyp'Air compact, Medisoft, Dinant, Belgium), as previously reported (9, 13, 26). Mixed gas is inspired (40 ppm of NO, 1,600 ppm of CO, 8% of helium, and 19% of O2 in nitrogen) with a breath-holding time of 4 s, and the composition of expired gas is analyzed with the first 0.8 liter of expired gas discarded. A breath holding of 4 s was chosen on the basis of previous experiments in healthy volunteers showing no different results between 3- and 9-s breath holds (24). Measurements were repeated two to three times, with the aim to obtain DlCO values within 5% and DlNO values within 10% of each other, and averaged.
The Roughton and Forster equation states that 1/DlCO = 1/DmCO + 1/θVc and 1/DlNO = 1/DmNO + 1/θVc, where Dm is the membrane conductance, and θVc is the blood conductance of the transferred gas. The coefficient relating DlNO and Dm was set at 1.97 according to the solubility and molecular weights of both gases. Assuming linearity between 1/θCO and Po2, we used an equation proposed by Roughton and Forster (28) to calculate the blood conductance of CO (θCO) as a function of capillary Po2: where PcO2 is the capillary partial pressure of O2 estimated as: alveolar Po2 − V̇o2/(DlCO × 1.23) with partial pressures in mmHg, O2 uptake (V̇o2) in ml/min, and DlCO in ml·min−1·mmHg−1. Alveolar Po2 was calculated from the local barometric pressure and the mixed expired fraction of O2. V̇o2 was calculated by taking the mass balance of oxygen between inspiration and expiration during the maneuver. The fraction of oxygen in the residual volume preceding the inspiration was supposed to be similar to that found in the expired sample (mean 16.4%). We used DlCO × 1.23 as a surrogate for lung diffusing capacity for O2.
Hb concentrations were measured from venous blood samples, and DlCO values corrected accordingly for standard concentrations of Hb of 14.6 g/dl for men and 13.4 g/dl for women. To compare the sea level and altitude, DlCO values derived from the measurement at altitude using the hypoxic θCO value were used to calculate DlCO as if the subjects were at sea level by replacing the hypoxic θCO value by the normoxic one (9). Predicted values were calculated using previously reported equations (1). A DlNO-to-DlCO ratio (DlNO/DlCO) was calculated to identify relative changes in the components of lung diffusion (12).
The Doppler echocardiographic measurements were performed with a Vivid 7 ultrasound system at sea level and its Vivid I portable version at altitude (GE Ultrasound) following previously reported methodology (13, 17, 25). Q̇ was estimated from left ventricular (LV) outflow tract cross-sectional area and pulsed Doppler velocity-time integral measurements. LV ejection fraction (LVEF) has been estimated as previously described (17). Systolic Ppa (sPpa) was estimated from a trans-tricuspid gradient calculated from the maximum velocity of continuous Doppler tricuspid regurgitation, added to an estimation of right atrial pressure. mPpa was calculated as 0.61 × sPpa + 2 mmHg (13). Total PVR (R0) was calculated as mPpa/Q̇. Systolic RV function was estimated by M-mode measurement of the tricuspid annular plane systolic excursion (TAPSE). This measurement reflects longitudinal contraction of the RV and is well correlated to RV fractional area shortening as an estimation of ejection fraction, but more stable and reproducible (7). A composite index of RV function (Tei index) was calculated as by the ratio of the sum of isovolumic contraction and relaxation times to the ejection time. This measurement integrates changes in systolic and diastolic function and is accordingly also called the RV performance index (8). Both the TAPSE and the Tei index have been shown to predict survival in patients with severe pulmonary hypertension (8). The echocardiographic recordings were read blinded and in duplicate (S. Huez and V. Faoro).
The exercise stress echocardiographic measurements of mPpa (calculated from sPpa) and Q̇ of each subjects were described using a distensible model previously reported by Linehan et al. (20), which relates mPpa, Q̇, Pla, R0, and a resistive distensible factor α: Pla was assumed constant at 10 mmHg. The obtained mPpa-Q̇ curves were compared with previously determined limits of normal at sea level (2).
To account for the influence of hematocrit on the pressure-flow relationships in the Sherpas, Quechuas, and lowlanders, we calculated a relative R0 at a hematocrit of 45% for each group [R0(45%)] using an exponential relationship between resistance and hematocrit used by Linehan et al. (20) in perfused dog lungs. where φ represents the hematocrit level.
Cycle ergometer CPET.
Each subject performed a standardized maximal-exercise test in an erect position on an electronically braked cycle ergometer (Monark, Ergomedic 818 E, Vansbro, Sweden) with breath-by-breath measurements, through a tightly fitted facial mask, of minute ventilation (V̇e), V̇o2, and CO2 output (V̇co2) using a Cardiopulmonary Exercise System (Oxycon Mobile, Jaeger, Hoechberg, Germany), as previously reported (13, 25). After 6 min of warming up, the work rate was increased by 15–30 W/min [calculated according to previously measured maximum workload decreased by ∼35%, as previously described at this altitude, divided by the estimated time of testing (i.e., 10 min) until exhaustion]. Maximum V̇o2 was defined as the V̇o2 measured during the last 20 s of peak exercise. The respiratory exchange ratio (RER) was calculated as V̇co2/V̇o2, and O2 pulse as V̇o2/HR. The ventilatory equivalents for CO2 (V̇e/V̇co2) were calculated by dividing V̇e by V̇co2. V̇e/V̇co2 slopes were measured between warm up and anaerobic threshold (AT). The AT was estimated by the V-slope method. The predicted values were calculated using previously reported sea level normal values (31).
Results are presented as means ± SE. The statistical analysis consisted of repeated-measures analysis of variance calculations. When the F-ratio of the analysis of variance reached a P < 0.05 critical value, paired Student's t-test were applied to evaluate the effect of high-altitude acclimatization in lowlanders, and unpaired Student's t-test were applied to compare the different ethnic groups. Correlations were calculated by linear regression analysis.
Effects of altitude on lowlanders.
None of the lowlander controls complained of altitude intolerance. Altitude exposure was associated with a decreased SpO2 and increases in mean BP (mBP), HR, Q̇, LVEF, mPpa, PVR, and Tei index, while TAPSE remained unchanged (Table 2). The mPpa-Q̇ relationships were shifted to higher pressures (Figure 1). Alveolar volume (Va) and DlCO corrected for Hb concentration increased, DlNO did not change, and the DlNO/DlCO decreased (Table 3). The CPET was markedly altered, with decreases in maximum workload, maximum O2 uptake (V̇o2 max), O2 pulse, SpO2, maximum HR, and V̇o2 at the AT, and increases in maximum V̇e and V̇e/V̇co2 slope, while maximum mBP and maximum RER did not change (Table 4).
Comparison between Sherpa highlanders and acclimatized lowlanders.
In the Sherpas compared with the lowlanders at high altitude, resting HR, SpO2, mBP, and Q̇ were not different, while LVEF, mPpa, and R0 were lower, and mPpa-Q̇ relationships shifted to lower Ppa (Table 2, Fig. 1). Despite lower PVR, TAPSE was lower, and the Tei index higher (Table 2). Va, DlNO, and DlCO were markedly increased, while the DlNO/DlCO was decreased (Table 3). The CPET showed similar workload, HR, SpO2, mBP, V̇e, O2 pulse, and V̇o2 at maximal exercise, but RER and end-tidal carbon dioxide partial pressure (PetCO2) were higher, and V̇e/V̇co2 at AT and AT expressed as percentage of V̇o2 max were lower (Table 4).
At high altitude, the slope of mPpa-Q̇ was inversely correlated to V̇o2 max (Fig. 2), and the DlCO was directly correlated to V̇o2 max (Fig. 3) in both ethnic groups. No other relevant correlations were found.
Interethnic comparison between the Sherpa and Quechua highlanders and acclimatized lowlanders at high altitudes.
A comparison between pulmonary hemodynamic, lung diffusing capacity, and CPET variables in Sherpa highlanders at 5,050 m with previously reported Quechua at 4,350 m and lowlanders recently acclimatized at altitudes > 4,000 m (mean ± SD: 4,710 ± 310 m) during four different expeditions is presented in Table 5 and Figs. 4 and 5. Quechuas had a lower V̇e/V̇co2 slope and higher SpO2, mPpa, and Hb compared with Sherpas. The R0 at a reference hematocrit of 45% [R0(45%)] was not significantly different between the Sherpa and Quechua. Higher PVR persisted in some of the Quechua and lowlanders after a correction for hematocrit (Fig. 4). The V̇e/V̇co2 vs. PetCO2 relationships at the AT were the highest in lowlanders at 5,050 m, followed by the Sherpas at 5,050 m, the healthy Quechuas at 4,350 m, the Quechuas with CMS at 4,350 m, and the lowlanders at sea level. Acclimatized lowlanders differed from both groups of highlanders by lower diffusion capacity and Hb, and higher mPpa and R0(45%).
The present results show that Sherpas compared with acclimatized lowlanders have a markedly increased lung diffusing capacity, decreased ventilatory response to exercise, lower PVR, but no difference in aerobic exercise capacity. Compared with Quechuas, the difference in pulmonary circulation response profile usually described between the two ethnic groups is attenuated after correction for increased Hb levels.
It has been recently shown that aerobic exercise capacity at sea level is higher in lowlanders with shallow slopes of mPpa-Q̇ relationships, early pulmonary transit of agitated contrast, and high lung diffusing capacity (2, 18, 19). These results are in keeping with the hypothesis that a high pulmonary vascular reserve, or ability of the pulmonary circulation to accommodate high flows at exercise without excessive increase in pressures, would allow for higher levels of exercise with lesser increase in RV afterload (18). Our laboratory recently reviewed measurements of pulmonary circulation and gas exchange at exercise in lowlanders performed during four expeditions at high altitudes, confirming better preservation of aerobic exercise capacity with lower PVR and higher lung diffusing capacity (26). In these studies, it could also be shown that the subjects with the highest V̇o2 max also had the shallowest slopes of V̇e/V̇co2, in keeping with previous notion that higher lung diffusing capacity allows for preserved gas exchange at a lower ventilatory cost (10). In the present study, Sherpa highlanders also demonstrate a very high lung diffusing capacity and low ventilatory responses to exercise, along with shallow slopes of mPpa-Q̇ relationships. Despite relatively low mPpa, V̇o2 max was still inversely correlated to the slope of mPpa-Q̇ as a refined measure of PVR. This is similar to what was previously found in lowlanders at high altitudes (26). It is thus apparent that a high “pulmonary vascular reserve” underlies preserved aerobic exercise capacity in Tibetans at high altitudes.
In the present study, V̇o2 max and maximum workload were slightly higher in Sherpa than in acclimatized lowlanders, even though the difference was not significant. A type II error would not be excluded in this small-sized study. The difference could also be related to a higher proportion of women in the controls (related to the need to match for body size and the fact that lowlander women are smaller) and to a higher level of physical training in Sherpa used to carrying heavy loads and strenuous trekking. The higher V̇o2 at the AT in the acclimatized lowlanders argues against this interpretation. However, V̇o2 at the AT is often an unstable measurement, with relatively poor reproductibility and, therefore, not recommended in the clinical practice of exercise testing (32).
The finding that maximum workload and V̇o2 max are essentially the same in matched healthy highlander Sherpa and high-altitude newcomers contrasts with the widespread belief that high-altitude natives have a higher aerobic exercise capacity than their acclimatized lowlander counterparts (27, 32). A recent review of the literature of aerobic exercise testing reported no difference or a slight tendency to higher V̇o2 max in high-altitude natives compared with high-altitude newcomers, but the author underscored many uncertainties about adequate matching and possible selection biases (8). Our laboratory previously reported no significant aerobic exercise capacity difference in highlander Quechua compared with acclimatized lowlanders (13). The term “V̇o2 paradox” has been coined to refer to unremarkable aerobic exercise capacities measured as by a V̇o2 max contrasting with superior field performance of Andean or Tibetan natives at high altitudes (8). In the present study, as previously reported (13), maximum workload was not higher in highlanders than in acclimatized lowlanders either. This negative result would require further studies on larger groups with measurements of endurance times, potentially more sensitive to small differences in aerobic exercise capacity than V̇o2 max or maximum workload determinations (32).
Sherpas compared with lowlanders have lower mPpa with no difference in cardiac index, indicating lower PVR. Groves et al. (15) previously reported on invasive pulmonary hemodynamics in five young adult Tibetan lifelong residents of >3,600 m. Resting mPpa ranged from 12 to 20 mmHg (mean: 15 mmHg) with Q̇ ranging from 4.4 to 5.8 l/min (mean: 5.1 l/min). The recalculated mean slope of mPpa-Q̇ was 1.5 mmHg·l−1·min−1, well within the normal sea level range for young healthy adults (2). Hoit et al. (16) reported on echocardiographic measurements of the pulmonary circulation in 47 healthy young Tibetan adults investigated at 4,200 m. Cardiac index ranged from 1.9 to 4.6 l·min−1·m−2 and sPpa from 17 to 56 mmHg (mean: 31.5 mmHg), corresponding to a mPpa ranging from 12 to 36 mmHg (mean: 21 mmHg). These subjects exhaled less NO than sea level controls, but the rate of transfer of NO out of the airways was higher. Furthermore, exhaled NO was correlated to cardiac index. The authors' interpretation of these findings was that a high level of endogenous NO contributes to low PVR in high-altitude Tibetans. This is in keeping with a series of studies that showed that Tibetans have higher levels of NO and derived metabolites than high-altitude populations, in contrast to transient decrease followed by unchanged NO in acclimatized lowlanders (5). The present data confirm lower mPpa and slope of mPpa-Q̇ in Tibetans compared with Quechua highlanders and acclimatized lowlanders, but with considerable individual variation and overlap.
Indexes of ventricular function, the RV Tei index and TAPSE, and LVEF were slightly depressed in Sherpa compared with lowlanders. Similar findings have been reported in healthy high-altitude Aymara (17). An increased RV Tei index has also been reported in Aymara patients with CMS (22). Depressed echocardiographic indexes of ventricular function might relate to a lesser degree of sympathetic nervous activation in permanent highlanders than in acclimatized lowlanders and different volume status, which is always difficult to assess at high altitudes. However, a negative inotropic effect of long-term hypoxic exposure cannot be excluded.
A remarkable finding of the present study was the very high lung diffusing capacity measured in the Sherpas, very much in keeping with previous reports in Quechuas (13). Both DlNO and DlCO increased, but there was a slight decrease of the DlNO/DlCO. This points out to some predominance of increased capillary blood volume, probably reflecting pulmonary capillary distension (12). It has to be emphasized that increased DlCO and DlNO still amounted to, respectively, 168 and 130% predicted after correction for Va and Hb. This would not be explained by capillary recruitment and distension only, but probably by an increased amount of vessel, which could be related to hypoxia-triggered angiogenesis. Both DlCO and low slope of mPpa-Q̇ predicted a higher V̇o2 max in Sherpas, as previously shown in acclimatized lowlanders (26). Increased lung diffusing capacity thus is likely to contribute to the adaptation to high altitude with no evidence for ethnic disparities.
The Sherpa compared with acclimatized lowlanders demonstrated decreased ventilatory responses to exercise at high altitude, but less pronounced than previously reported in Quechua at the altitude of 4,350 m. This was clearly shown when ventilatory responses were quantified as V̇e/V̇co2 vs. PetCO2 relationships measured at the AT (Fig. 5). This presentation showed increased chemosensitivity at high altitude, which was most pronounced in lowlanders, less so in Sherpa, followed by Quechua without and with CMS. A difference in altitude of 700 m with relatively higher alveolar and arterial Po2 could partly explain the difference between Sherpa and Quechua. Resting ventilation and ventilatory responses to hypoxia have been previously reported to be 1.5 to 2 times higher in 320 Tibetan vs. 542 Aymara native residents at 3,800–4,065 m (6). In that study, Tibetans were more hypoxic, but this was estimated to account for only a minor part of the difference. We are not aware of direct comparison of ventilatory responses to hypercapnia in both ethnic groups. In the present study, V̇e/V̇co2 slopes probably relate to central/peripheral chemosensitivity to CO2, however, modulated by the severity of hypoxemia.
A confounding factor in the comparison of ventilatory responses to hypoxic exercise is the Hb concentration. Polycythemia acts to limit ventilatory responses through an increased CO2 content of the blood, allowing for maintained V̇co2 at lower mixed venous to capillary Pco2 differences, and thus a relatively lower level of ventilation. Thus bloodletting in polycythemic highlanders is associated with increased ventilation and decreased arterial Pco2 (24). This could have contributed to decreased ventilatory responses to exercise in Quechua compared with Tibetans. The highest ventilatory responses were recorded in the partially acclimatized lowlanders, who also presented with the lowest Hb concentrations. Another confounding factor could be the higher lung diffusing capacity allowing for increased V̇co2 at a lower level of ventilation, even though this factor would not explain differences between Andeans and Tibetans.
Previous studies have shown that Tibetans compared with Aymaras living at altitudes of 3,800–4,100 m have ∼3 g/dl less Hb (4). In the present study, Hb averaged 15.9 g/dl in the Sherpas at 5,050 m and 17.6 g/dl in the Quechuas at 4,350 m, confirming these ethnic differences (although attenuated by the altitude difference). Recalculated R0 for differences in Hb and associated difference in viscosity [R0(45%)] showed no difference in both ethnic groups (Table 5). Moreover, correction of mPpa-Q̇ relationships for Hb levels reduced the difference in pulmonary hemodynamics, and slopes returned within sea level limits of normal in all of the Sherpas, 12 of the 15 Quechuas, and 25 of the 28 lowlanders (Fig. 4). Sea level exercise is known to be associated with higher increase than normal mPpa in a proportion of randomly selected lowlanders (2). Moreover, there is a large interspecies and interindividual variability of hypoxic pulmonary pressor responses, with brisk increases in Ppa in probably a few percentages of normal sea level dwellers (13). A high pulmonary vascular reactivity to hypoxia may be a cause of high-altitude pulmonary edema or right heart failure and is, therefore, a decreased survival trait in high-altitude populations and a cause of avoidance of high-altitude travels in lowlanders (28). This may explain absence or only mild pulmonary hypertension in the Quechua, Sherpa, and lowlanders included in the present study.
In summary, the cardiorespiratory exercise profile of life-long high-altitude adaptation includes a combination of markedly increased lung diffusion and decreased ventilatory response. This is observed in both Sherpa and Quechua, with, as difference between these two ethnic groups, a higher Hb in Quechua and possibly a milder increase in Ppa in Sherpa, even though this should be confirmed on larger sample sizes with hematocrit-corrected determinations of PVR. Both high-altitude dwellers and sojourners who are able to maintain a higher aerobic exercise capacity have more pulmonary vascular reserve defined as a combination of low PVR and high lung diffusing capacity.
This study was 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 thanks to contributions from the Italian National Research Council. The study was supported by a grant from Pfizer.
No conflicts of interest, financial or otherwise, are declared by the author(s).
Author contributions: V.F., S.H., C.d.B., and R.N. conception and design of research; V.F., S.H., H. Groepenhoff, C.d.B., J.-B.M., M.L., and R.N. performed experiments; V.F., S.H., R.R.V., H. Groepenhoff, C.d.B., A.P., H. Guénard, and R.N. analyzed data; V.F., S.H., R.R.V., H. Groepenhoff, A.P., H. Guénard, and R.N. interpreted results of experiments; V.F., R.R.V., and R.N. prepared figures; V.F., S.H., R.R.V., and R.N. drafted manuscript; V.F., S.H., R.R.V., H. Groepenhoff, C.d.B., J.-B.M., M.L., A.P., H. Guénard, and R.N. edited and revised manuscript; V.F., S.H., R.R.V., H. Groepenhoff, C.d.B., J.-B.M., M.L., A.P., H. Guénard, and R.N. approved final version of manuscript.
We are grateful to GE Healthcare ultrasound Belgium for the loan of the Vivid i. The assistance of Mickaël Moreels, Régine Bastin, Saskia Boldingh, Saroj Neupane, Kathleen Retailleau, and Sarah Martinez was greatly appreciated.
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