Excessive gas exchange impairment during exercise in a subject with a history of bronchopulmonary dysplasia and high altitude pulmonary edema

A 27-year-old male subject (V(O2 max)), 92% predicted) with a history of bronchopulmonary dysplasia (BPD) and a clinically documented case of high altitude pulmonary edema (HAPE) was examined at rest and during exercise. Pulmonary function testing revealed a normal forced vital capacity (FVC, 98.1% predicted) and diffusion capacity for carbon monoxide (D(L(CO)), 91.2% predicted), but significant airway obstruction at rest [forced expiratory volume in 1 sec (FEV(1)), 66.5% predicted; forced expiratory flow at 50% of vital capacity (FEF(50)), 34.3% predicted; and FEV(1) /FVC 56.5%] that was not reversible with an inhaled bronchodilator. Gas exchange worsened from rest to exercise, with the alveolar to arterial P(O2) difference (AaD(O2)) increasing from 0 at rest to 41 mmHg at maximal normoxic exercise (VO(2) = 41.4 mL/kg/min) and from 11 to 31 mmHg at maximal hypoxic exercise (VO(2) = 21.9 mL/kg/min). Arterial P(O2) decreased to 67.8 and 29.9 mmHg at maximal normoxic and hypoxic exercise, respectively. These data indicate that our subject with a history of BPD is prone to a greater degree of exercise-induced arterial hypoxemia for a given VO(2) and F(I(O2)) than healthy age-matched controls, which may increase the subject's susceptibility to high altitude illness

AltitudeOmics: Baroreflex Sensitivity During Acclimatization to 5,260 m.

<b>Introduction:</b> Baroreflex sensitivity (BRS) is essential to ensure rapid adjustment to variations in blood pressure (BP). Little is known concerning the adaptive responses of BRS during acclimatization to high altitude at rest and during exercise. <b>Methods:</b> Twenty-one healthy sea-level residents were tested near sea level (SL, 130 m), the 1st (ALT1) and 16th day (ALT16) at 5,260 m using radial artery catheterization. BRS was calculated using the sequence method (direct interpretation of causal link between BP and heartrate). At rest, subjects breathed a hyperoxic mixture (250 mmHg O <sub>2</sub> , end tidal) to isolate the preponderance of CO <sub>2</sub> chemoreceptors. End-tidal CO <sub>2</sub> varied from 20 to 50 mmHg to assess peripheral chemoreflex. Rebreathing provoked incremental increase in CO <sub>2</sub> , increasing BP to assess baroreflex. During incremental cycling exercise to exhaustion, subjects breathed room air. <b>Results:</b> Resting BRS decreased in ALT1 which was exacerbated in ALT16. This decrease in ALT1 was reversible upon additional inspired CO <sub>2</sub> , but not in ALT16. BRS decrease during exercise was greater and occurred at lower workloads in ALT1 compared to SL. At ALT16, this decrease returned toward SL values. <b>Discussion/Conclusion:</b> This study is the first to report attenuated BRS in acute hypoxia, exacerbated in chronic hypoxia. In ALT1, hypocapnia triggered BRS reduction whilst in ALT16 resetting of chemoreceptor triggered BRS reduction. The exercise BRS resetting was impaired in ALT1 but normalized in ALT16. These BRS decreases indicate decreased control of BP and may explain deteriorations of cardiovascular status during exposure to high altitude

Differential Brain and Muscle Tissue Oxygenation Responses to Exercise in Tibetans Compared to Han Chinese

The Tibetans’ better aerobic exercise capacity at altitude remains ill-understood. We tested the hypothesis that Tibetans display better muscle and brain tissue oxygenation during exercise in hypoxia. Using near-infrared spectrometry (NIRS) to provide indices of tissue oxygenation, we measured oxy- and deoxy-hemoglobin ([O2Hb] and [HHb], respectively) responses of the vastus lateralis muscle and the right prefrontal cortex in ten Han Chinese and ten Tibetans during incremental cycling to exhaustion in a pressure-regulated chamber at simulated sea-level (air at 1 atm: normobaric normoxia) and 5,000 m (air at 0.5 atm: hypobaric hypoxia). Hypoxia reduced aerobic capacity by ∼22% in both groups (d = 0.8, p < 0.001 vs. normoxia), while Tibetans consistently outperformed their Han Chinese counterpart by ∼32% in normoxia and hypoxia (d = 1.0, p = 0.008). We found cerebral [O2Hb] was higher in Tibetans at normoxic maximal effort compared Han (p = 0.001), while muscle [O2Hb] was not different (p = 0.240). Hypoxic exercise lowered muscle [O2Hb] in Tibetans by a greater extent than in Han (interaction effect: p < 0.001 vs. normoxic exercise). Muscle [O2Hb] was lower in Tibetans when compared to Han during hypoxic exercise (d = 0.9, p = 0.003), but not during normoxic exercise (d = 0.4, p = 0.240). Muscle [HHb] was not different between the two groups during normoxic and hypoxic exercise (p = 0.778). Compared to Han, our findings revealed a higher brain tissue oxygenation in Tibetans during maximal exercise in normoxia, but lower muscle tissue oxygenation during exercise in hypoxia. This would suggest that the Tibetans privileged oxygenation of the brain at the expense of that of the muscle

Structural basis for activation of a diguanylate cyclase required for bacterial predation in Bdellovibrio

The bacterial second messenger cyclic-di-GMP is a widespread, prominent effector of lifestyle change. An example of this occurs in the predatory bacterium Bdellovibrio bacteriovorus, which cycles between free-living and intraperiplasmic phases after entering (and killing) another bacterium. The initiation of prey invasion is governed by DgcB (GGDEF enzyme) that produces cyclic-di-GMP in response to an unknown stimulus. Here, we report the structure of DgcB, and demonstrate that the GGDEF and sensory forkhead-associated (FHA) domains form an asymmetric dimer. Our structures indicate that the FHA domain is a consensus phosphopeptide sensor, and that the ligand for activation is surprisingly derived from the N-terminal region of DgcB itself. We confirm this hypothesis by determining the structure of a FHA:phosphopeptide complex, from which we design a constitutively-active mutant (confirmed via enzyme assays). Our results provide an understanding of the stimulus driving DgcB-mediated prey invasion and detail a unique mechanism of GGDEF enzyme regulation

Hypoxia, not pulmonary vascular pressure induces blood flow through intrapulmonary arteriovenous anastomoses

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) is increased with exposure to acute hypoxia and has been associated with pulmonary artery systolic pressure (PASP). We aimed to determine the direct relationship between blood flow through IPAVA and PASP in 10 participants with no detectable intracardiac shunt by comparing: (1) isocapnic hypoxia (control); (2) isocapnic hypoxia with oral administration of acetazolamide (AZ; 250 mg, three times-a-day for 48 h) to prevent increases in PASP, and (3) isocapnic hypoxia with AZ and 8.4% NaHCO3 infusion (AZ+HCO3-) to control for AZ-induced acidosis. Isocapnic hypoxia (20 min) was maintained by end-tidal forcing, blood flow through IPAVA was determined by agitated saline contrast echocardiography and PASP was estimated by Doppler ultrasound. Arterial blood samples were collected at rest before each isocapnic-hypoxia condition to determine pH, [HCO3-], and PaCO2. AZ decreased pH (-0.08 ± 0.01), [HCO3-] (-7.1 ± 0.7 mmol/l), and PaCO2 (-4.5 ± 1.4 mmHg; p<0.01), while intravenous NaHCO3 restored arterial blood gas parameters to control levels. Although PASP increased from baseline in all three hypoxic conditions (p<0.05), a main effect of condition expressed an 11 ± 2% reduction in PASP from control (p<0.001) following AZ administration while intravenous NaHCO3 partially restored the PASP response to isocapnic hypoxia. Blood flow through IPAVA increased during exposure to isocapnic hypoxia (p<0.01) and was unrelated to PASP, cardiac output and pulmonary vascular resistance for all conditions. In conclusion, isocapnic hypoxia induces blood flow through IPAVA independent of changes in PASP and the influence of AZ on the PASP response to isocapnic hypoxia is dependent upon the H+ concentration or PaCO2. Abbreviations list: AZ, acetazolamide; FEV1, forced expiratory volume in 1 second; FIO2, fraction of inspired oxygen; FVC, forced vital capacity; Hb, total haemoglobin; HPV, hypoxic pulmonary vasoconstriction; HR, heart rate; IPAVA, intrapulmonary arteriovenous anastomoses; MAP, mean arterial pressure; PASP, pulmonary artery systolic pressure; PETCO2, end-tidal partial pressure of carbon dioxide; PETO2, end-tidal partial pressure of oxygen; PFO, patent foramen ovale; PVR, pulmonary vascular resistance; Q̇c, cardiac output; RVOT, right ventricular outflow tract; SpO2, oxyhaemoglobin saturation; SV, stroke volume; TRV, tricuspid regurgitant velocity; V̇E, minute ventilation; VTI, velocity-time integra

AltitudeOmics: Spontaneous Baroreflex Sensitivity During Acclimatization to 5,260 m: A Comparison of Methods

Baroreflex sensitivity (BRS) is essential to ensure rapid adjustment to variations in blood pressure (BP). Spontaneous baroreflex function can be assessed using continuous recordings of blood pressure. The goal of this study was to compare four methods for BRS quantification [the sequence, Bernardi's (BER), frequency and transfer function methods] to identify the most consistent method across an extreme range of conditions: rest and exercise, in normoxia, hypoxia, hypocapnia, and hypercapnia. Using intra-radial artery BP in young healthy participants, BRS was calculated and compared using the four methods in normoxia, acute and chronic hypoxia (terrestrial altitude of 5,260 m) in hypocapnia (hyperventilation), hypercapnia (rebreathing) and during ramp exercise to exhaustion. The sequence and BER methods for BRS estimation showed good agreement during the resting and exercise protocols, whilst the ultra- and very-low frequency bands of the frequency and transfer function methods were more discrepant. Removing respiratory frequency from the blood pressure traces affected primarily the sequence and BER methods and occasionally the frequency and transfer function methods. The sequence and BER methods contained more respiratory related information than the frequency and transfer function methods, indicating that the former two methods predominantly rely on respiratory effects of BRS. BER method is recommended because it is the easiest to compute and even though it tends to overestimate BRS compared to the sequence method, it is consistent with the other methods, whilst its interquartile range is the smallest

Reduced blood flow through intrapulmonary arteriovenous anastomoses at rest and during exercise in lowlanders during acclimatization to high altitude

Blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) is elevated during exercise at sea level (SL) and at rest in acute normobaric hypoxia. Following high altitude (HA) acclimatization, resting QIPAVA is similar to SL, but it is unknown if this is true during exercise at HA. We reasoned that exercise at HA (5,050 m) would exacerbate QIPAVA due to heightened pulmonary arterial pressure. Using a supine cycle ergometer, seven healthy adults free from intracardiac shunts underwent an incremental exercise test at SL (25, 50, 75% of SL VO2peak ) and at HA (25, 50% of SL VO2peak ). Echocardiography was used to determine cardiac output (Q) and pulmonary artery systolic pressure (PASP) and agitated saline contrast was used to determine QIPAVA (bubble score; 0-5). The principal findings were: (1) Q was similar at SL-rest (3.9 +/- 0.47 l min-1 ) compared with HA-rest (4.5 +/- 0.49 l min-1 ; P = 0.382), but increased from rest during both SL and HA exercise (P < 0.001); (2) PASP increased from SL-rest (19.2 +/- 0.7 mmHg) to HA-rest (33.7 +/- 2.8 mmHg; P = 0.001) and, compared with SL, PASP was further elevated during HA exercise (P = 0.003); (3) QIPAVA was increased from SL-rest (0) to HA-rest (median = 1; P = 0.04) and increased from resting values during SL exercise (P < 0.05), but were unchanged during HA exercise (P = 0.91), despite significant increases in Q and PASP. Theoretical modeling of microbubble dissolution suggests that the lack of QIPAVA in response to exercise at HA is unlikely caused by saline contrast instability

Resting pulmonary haemodynamics and shunting: a comparison of sea-level inhabitants to high altitude Sherpas

The incidence of blood flow through intracardiac shunt and intrapulmonary arteriovenous anastomoses (IPAVA) may differ between Sherpas permanently residing at high altitude (HA) and sea-level (SL) inhabitants as a result of evolutionary pressure to improve gas exchange and/or resting pulmonary haemodynamics. To test this hypothesis we compared sea-level inhabitants at SL (SL-SL; n = 17), during acute isocapnic hypoxia (SL-HX; n = 7) and following 3 weeks at 5050 m (SL-HA; n = 8 non-PFO subjects) to Sherpas at 5050 m (n = 14). inline image, heart rate, pulmonary artery systolic pressure (PASP) and cardiac index (Qi) were measured during 5 min of room air breathing at SL and HA, during 20 min of isocapnic hypoxia (SL-HX; inline image = 47 mmHg) and during 5 min of hyperoxia (inline image = 1.0; Sherpas only). Intracardiac shunt and IPAVA blood flow was evaluated by agitated saline contrast echocardiography. Although PASP was similar between groups at HA (Sherpas: 30.0 ± 6.0 mmHg; SL-HA: 32.7 ± 4.2 mmHg; P = 0.27), it was greater than SL-SL (19.4 ± 2.1 mmHg; P < 0.001). The proportion of subjects with intracardiac shunt was similar between groups (SL-SL: 41%; Sherpas: 50%). In the remaining subjects, IPAVA blood flow was found in 100% of subjects during acute isocapnic hypoxia at SL, but in only 4 of 7 Sherpas and 1 of 8 SL-HA subjects at rest. In conclusion, differences in resting pulmonary vascular regulation, intracardiac shunt and IPAVA blood flow do not appear to account for any adaptation to HA in Sherpas. Despite elevated pulmonary pressures and profound hypoxaemia, IPAVA blood flow in all subjects at HA was lower than expected compared to acute normobaric hypoxia

AltitudeOmics: Red Blood Cell metabolic adaptation to high altitude hypoxia

Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia  through  the so-called  oxygen-dependent  metabolic  regulation,  which  involves  the competitive  binding  of  deoxyhemoglobin  and  glycolytic  enzymes  to  the  N-terminal  cytosolic domain  of  band  3.  This  mechanism  promotes  the  accumulation  of  2,3-DPG,  stabilizing  the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the  Bohr  effect.  Despite  in  vitro  studies,  in  vivo adaptations  to  hypoxia  have  not  yet  been completely elucidated. Within  the  framework  of  the AltitudeOmics  study,  erythrocytes  were  collected  from  21 healthy volunteers at sea level, after exposure to high altitude (5260m) for 1, 7 and 16days, and following  reascent  after  7days  at 1525m.  UHPLC-MS  metabolomics  results  were  correlated  to physiological and athletic performance parameters. Immediate  metabolic  adaptations  were  noted as early as a few hours from ascending  to >5000m, and maintained for 16 days at high altitude.  Consistent with the mechanisms elucidated in vitro, hypoxia promoted glycolysis and deregulated the pentose phosphate pathway, as well purine catabolism, glutathione homeostasis, arginine/nitric oxide and sulphur/H2S metabolism. Metabolic adaptations were preserved one week after descent, consistently with improved physical performances in comparison to the first ascendance, suggesting a mechanism of metabolic memory