The overlooked significance of plasma volume for successful adaptation to high altitude in Sherpa and Andean natives

In contrast to Andean natives, high altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e. no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also elevated in Sherpa compared to lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and towards a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude

Global REACH 2018: Renal oxygen delivery is maintained during early acclimatization to 4330 m

Early acclimatization to high-altitude is characterized by various respiratory, hematological, and cardiovascular adaptations that serve to restore oxygen delivery to tissue. However, less is understood about renal function and the role of renal oxygen delivery (RDO2) during high altitude acclimatization. We hypothesized that: 1) RDO2 would be reduced after 12-hours of high-altitude exposure (high-altitude day1) but restored to sea-level values after one-week (high altitude day7); and 2) RDO2 would be associated with renal reactivity (RR), an index of acid base compensation at high-altitude. Twenty-four healthy lowlander participants were tested at sea-level (344m; Kelowna, Canada), on day1 and day7 at high-altitude (4330m; Cerro de Pasco, Peru). Cardiac output, renal blood flow, arterial and venous blood sampling for renin angiotensin-aldosterone-system hormones and NT pro-B type natriuretic peptides were collected at each time point. RR was calculated as: (Δ arterial bicarbonate)/(Δ partial pressure of arterial carbon dioxide) between sea-level and high-altitude day1, and sea-level and high-altitude day7. The main findings were: 1) RDO2 was initially decreased at high-altitude compared to sea-level (ΔRDO2: -22±17%, P<0.001), but was restored to sea-level values on high-altitude day7 (ΔRDO2: -6±14%, P=0.36). The observed improvements in RDO2 resulted from both changes in renal blood flow (Δ from high-altitude day1: +12±11%; P=0.008), and arterial oxygen content (Δ from high-altitude day1 +44.8±17.7%; P=0.006); and 2) RR was positively correlated with RDO2 on high-altitude day7 (r=0.70; P<0.001), but not high-altitude day1 (r=0.26; P=0.29). These findings characterize the temporal responses of renal function during early high-altitude acclimatization, and the influence of RDO2 in the regulation of acid-base

Highs and Lows of Sympathetic Neuro-cardiovascular Transduction: Influence of Altitude Acclimatization and Adaptation

High-altitude (>2500m) exposure results in increased muscle sympathetic nervous activity (MSNA) in acclimatizing lowlanders. However, little is known about how altitude affects MSNA in 66 indigenous high-altitude populations. Additionally, the relationship between MSNA and blood 67 pressure regulation (i.e., neurovascular transduction) at high-altitude is unclear. We sought to 68 determine 1) how high-altitude effects neuro-cardiovascular transduction and 2) whether 69 differences exist in neuro-cardiovascular transduction between low and high-altitude 70 populations. Measurements of MSNA (microneurography), mean arterial blood pressure (MAP; 71 finger photoplethysmography), and heart rate (electrocardiogram) were collected in: I) 72 lowlanders (n=14) at low (344m) and high-altitude (5050m), II) Sherpa highlanders (n=8; 73 5050m), and III) Andean (with and without excessive erythrocytosis) highlanders (n=15; 74 4300m). Cardiovascular responses to MSNA burst sequences (i.e. singlet, couplet, triplet, and 75 quadruplets) were quantified using custom software (coded in MATLAB, v2015b). Slopes were 76 generated for each individual based on peak responses and normalized total MSNA. High 77 altitude reduced neuro-cardiovascular transduction in lowlanders (MAP slope: high-altitude, 78 0.0075±0.0060 vs low-altitude, 0.0134±0.080; p=0.03). Transduction was elevated in Sherpa 79 (MAP slope, 0.012±0.007) compared to Andeans (0.003±0.002; p=0.001). MAP transduction 80 was not statistically different between acclimatizing lowlanders and Sherpa (MAP slope, p=0.08) 81 or Andeans (MAP slope, p=0.07). When accounting for resting MSNA (ANCOVA), transduction 82 was inversely related to basal MSNA (bursts/min) independent of population (RRI, r= 0.578 83 p<0.001; MAP, r= -0.627 p<0.0001). Our results demonstrate transduction is blunted in 84 individuals with higher basal MSNA, suggesting blunted neuro-cardiovascular transduction is a 85 physiological adaptation to elevated MSNA rather than an effect or adaptation specific to 86 chronic hypoxic exposure

Acid-base balance at high altitude in lowlanders and indigenous highlanders

International audienceHigh-altitude exposure results in a hyperventilatory-induced respiratory alkalosis followed by renal compensation (bicarbonaturia) to return arterial blood pH (pHa) toward sea-level values. However, acid-base balance has not been comprehensively examined in both lowlanders and indigenous populations-where the latter are thought to be fully adapted to high altitude. The purpose of this investigation was to compare acid-base balance between acclimatizing lowlanders and Andean and Sherpa highlanders at various altitudes (∼3,800, ∼4,300, and ∼5,000 m). We compiled data collected across five independent high-altitude expeditions and report the following novel findings: 1) at 3,800 m, Andeans (n = 7) had elevated pHa compared with Sherpas (n = 12; P < 0.01), but not to lowlanders (n = 16; 9 days acclimatized; P = 0.09); 2) at 4,300 m, lowlanders (n = 16; 21 days acclimatized) had elevated pHa compared with Andeans (n = 32) and Sherpas (n = 11; both P < 0.01), and Andeans had elevated pHa compared with Sherpas (P = 0.01); and 3) at 5,000 m, lowlanders (n = 16; 14 days acclimatized) had higher pHa compared with both Andeans (n = 66) and Sherpas (n = 18; P < 0.01, and P = 0.03, respectively), and Andean and Sherpa highlanders had similar blood pHa (P = 0.65). These novel data characterize acid-base balance acclimatization and adaptation to various altitudes in lowlanders and indigenous highlanders.NEW & NOTEWORTHY Lowlander, Andean, and Sherpa arterial blood data were combined across five independent high-altitude expeditions in the United States, Nepal, and Peru to assess acid-base status at ∼3,800, ∼4,300, and ∼5,000 m. The main finding was that Andean and Sherpa highlander populations have more acidic arterial blood, due to elevated arterial carbon dioxide and similar arterial bicarbonate compared with acclimatizing lowlanders at altitudes ≥4,300 m

Influence of iron manipulation on hypoxic pulmonary vasoconstriction and pulmonary reactivity during ascent and acclimatization to 5050 m

To examine the adaptational role of iron bioavailability on the pulmonary vascular responses to acute and chronic hypobaric hypoxia, the hematological and cardiopulmonary profile of lowlanders and Sherpa were determined during: 1) a nine-day ascent to 5050m (20 lowlanders; 12 Sherpa), and 2) following partial acclimatization (11±4 days) to 5050m (18 lowlanders; 20 Sherpa), where both groups received either an i.v. infusion of iron (iron (III)-hydroxide sucrose) or an iron chelator (desferrioxamine). During ascent, there were reductions in iron status in both lowlanders and Sherpa; however, Sherpa appeared to demonstrate a more efficient capacity to mobilize stored iron, compared to lowlanders, when expressed as a hepcidin per unit change in either body iron or the soluble transferrin receptor index, between 3400-5050m (p=0.016 and p=0.029 respectively). The rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders during ascent; however, PASP was comparable in both groups upon arrival to 5050m. Following partial acclimatization, despite Sherpa demonstrating a blunted hypoxic ventilatory response and greater resting hypoxemia, they had similar hypoxic pulmonary vasoconstriction when compared to lowlanders at rest. Iron-infusion attenuated PASP in both groups at rest (p=0.005), while chelation did not exaggerate PASP in either group at rest or during exaggerated hypoxemia (PIO2=67 mmHg). During exercise at 25% peak wattage, PASP was only consistently elevated in Sherpa, which persisted following both iron infusion or chelation. These findings provide new evidence on the complex interplay of iron regulation on pulmonary vascular regulation during acclimatization and adaptation to high altitude