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Background Increased pulmonary capillary pressure and a possible desensitization of lung β 2 adrenergic receptors (β 2 AR) involved in fluid removal mechanisms may increase extravascular lung water (E LW ) in stable heart failure (HF) patients. Whether these patients exhibit increased E LW remains controversial. Purpose To determine if HF patients have elevated E LW versus controls (CTL) and if acute β 2 AR agonist inhalation stimulates fluid removal. Methods/Results 14 stable HF patients and 19 healthy age/gender matched CTL were studied. Lung tissue volume (V tis ) (includes tissue, blood and water) and pulmonary capillary blood volume (Vc) were assessed pre and post nebulized albuterol via CT and rebreathe, respectively. E LW was derived as V tis – Vc. Pre albuterol, E LW was greater in HF vs. CTL (861±241 vs. 739±143 ml, P <0.01), with no difference in V tis (938±246 vs. 830±151 ml, P =0.08). Albuterol decreased V tis (–4±2%, P =0.02) but did not change E LW (739±143 vs. 724±132 ml) ( P >0.05) in CTL. In HF, albuterol decreased both V tis (–5±3%) and E LW (– 4±2%) ( P <0.05). There was a negative relationship between baseline values and the pre to post albuterol change for V tis ( r 2 =0.38) and E LW ( r 2 =0.42) ( P <0.01) in HF. Conclusion Lung fluid is elevated in stable HF patients relative to healthy subjects. Stimulation of β 2 ARs appears to enhance fluid removal in HF, especially in patients with elevated lung water at rest.

Background Whether lung fluid accumulates in acclimating individuals at high altitude (HA) remains controversial. Purpose To assess the effect of HA on lung fluid regulation. Methods/Results Systolic pulmonary artery pressure (sPAP) (echo), lung diffusing capacity for CO (DLCO), pulmonary capillary blood volume (Vc), alveolar‐capillary conductance (Dm) (single breath method), ultrasound lung comets (ULCs) and pulmonary function (PFTs) were assessed in 8 healthy adults at sea‐level and after 1 and 9 days at Mt. Everest Base Camp (EBC), Nepal (5150 m). Also, after 5 days at EBC, DLCO and PFTs were assessed in 5 subjects pre‐and post‐acute albuterol administration. EBC was reached after an 8 d hike at progressively increasing altitudes starting at 2800 m. Altitude exposure increased sPAP, had no effect on DLCO, increased Dm and decreased Vc with a subsequent increase in Dm/Vc, and decreased the number of ULCs (Table 1). There was no change in FVC or FEV 1 but an increase in MEF 50 . Albuterol administration increased PEF (11.85±1.52 vs. 12.40±1.45 L/s) and MEF 50 (4.85±0.77 vs. 6.00±1.30 L/s) but had no effect on DLCO, Dm or Dm/Vc. Conclusion These data suggest that lung fluid is decreased in acclimating healthy humans at high altitude. Funding: Mayo Clinic & The North Face.

Background Heart failure (HF) is associated with impaired exercise pulmonary gas exchange (PGX) that is likely related to the development and severity of pulmonary hypertension (PH). Purpose To determine whether PGX measures differentiate HF patients with reactive PH from patients with passive PH or no PH. Methods/Results Pulmonary arterial pressure (P AP ), pulmonary wedge pressure (P WP ), transpulmonary pressure gradient (TPG) and PGX indices [end‐tidal CO 2 (P ET CO 2 ), ventilatory efficiency (V E /VCO 2 ), O 2 pulse, estimated pulmonary arterial capacitance (GX CAP )] were assessed simultaneously at rest and during cycle exercise in 38 HF patients undergoing right heart catheterization. Post hemodynamic evaluation, patients were classified as having no PH ( n = 12), passive PH ( n = 10) or reactive PH ( n = 16). TPG increased during exercise in all groups but was greater at end exercise in the reactive PH vs. the passive PH and no PH patients (21±9 vs. 14±7 vs. 12±7 mmHg). At an equivalent VO 2 , P ET CO 2 , O 2 pulse and GX CAP were higher and V E /VCO 2 ratio lower in the no PH and, to a lesser extent, in the passive PH vs. the reactive PH subjects (Figure 1). Conclusion Noninvasive measures of PGX during exercise appear to differentiate HF patients with reactive PH from patients with passive PH or no PH and may be a useful adjunct to invasive catheterization in assessing PH type and severity. HL71478, AHA12POST12070084, Gilead Science

Asthma, chronic obstructive pulmonary disease, and other respiratory disorders often occur concurrently with heart failure (HF). HF patients with respiratory disease can improve lung function and, therefore, quality of life with β‐agonists. Beta‐agonist use remains controversial as it has been linked with increased mortality risk; however, recent studies that account for co‐morbidities find no association between β‐agonist use and mortality. Previous studies exploring the cardiovascular effect of β‐agonist use in HF are primarily retrospective and focus on heart rate (HR). We have previously demonstrated altered cardiovascular function in response to albuterol in healthy subjects. In the present study we sought to comprehensively assess the cardiovascular effects of albuterol sulfate using cardiac output (Q), stroke volume (SV), HR, systolic, diastolic, and mean arterial blood pressure (SBP, DBP, MAP, respectively) and systemic vascular resistance (SVR). We hypothesized that cardiovascular parameters would be altered 30‐minutes following albuterol administration, and that HF patients using β‐blockers would have an attenuated response. Twenty‐two healthy and twenty‐two HF subjects were recruited (age=56±13 vs. 62±12yrs; height=175±10 vs. 176±9cm; weight=78±15 vs. 93±20; BMI=26±4 vs. 30±6; and BSA=2.08±0 vs. 1.93±0m 2 , for healthy and HF, respectively, p<0.05 for weight, BMI, and BSA). We found that HR and Q increased in healthy but not HF subjects at 30min following albuterol. Patients who were not on β‐blockers (n=4, 18%) had an increase in SV and a decrease in SVR with albuterol, while there was no change in patients who were on β‐blockers (n=14, 64%). These data suggest that HF patients have an attenuated cardiovascular response to inhaled albuterol, particularly with concurrent β‐blocker usage.

Background It is documented that cognitive performance can diminish with altitude, but the sensitivity of specific tests have not been investigated. Our objective was to assess and compare cognitive performance from several tests and relate this to quality of sleep and acute mountain sickness (AMS). Methods During an Everest expedition, 3 cognitive tests (Stroop, Trail Making, and a proprietary motor accuracy test) were used along with a questionnaire to assess sleep and AMS. Six athlete climbers and 9 core team members were assessed pre and post‐expedition and at several time points during the expedition (up to 17,500 ft). Results To normalize for individual differences, scores were assessed as % change from baseline. There was no difference in the variation between repeated attempts in a single testing session (0.19<p<0.87), demonstrating that each test was reproducible. There was no decrement in test scores with altitude, nor was there an association with reported sleep quality. The Stroop performance was associated with AMS (p<0.05) and trending with headache (p< 0.15). The in‐house motor test trended towards an association with AMS and headache (p<0.15). However, the trail making test was not associated with AMS/headache. Conclusion With appropriate acclimatization, cognitive performance is maintained at altitude but is linked to presence of headache and AMS. Mayo Clinic and TNF.

BACKGROUND High altitude (HA) exposure influences appetite, protein synthesis and breakdown, and aerobic capacity. Thus, HA exposure typically causes weight (wt) loss, while the impact on aerobic capacity upon return to sea level is more variable. OBJECTIVE To examine the influence of hypobaric hypoxia on body composition and exercise capacity in elite HA climbers (n=4, 2 female) acclimating at ≥5,150 m over 2 mo. relative to trekkers (n=8, 0 female) acclimating at 5,150 m over 2 wks (Mt. Everest, Nepal). Each elite climber successfully summited Mt. Everest. METHODS Body composition (DEXA, skin folds, wt) and exercise capacity (treadmill) were assessed before and within 2 wks post HA. RESULTS HA exposure increased Hct and Hb, with peak values of 52±5% and 18±2 g/dl, and 50±3% and 17±1 g/dl for the climbers and trekkers, respectively. HA decreased lean and fat tissue in both the climbers (lean −4.4±2.3%, fat −8.2±4.0%) and trekkers (lean −1.8±1.6%, fat −5.8±6.1%) (all P ≤0.06). No change was observed in skin folds for either group. Wt decreased in the climbers (−5±2%, P <0.03) and trekkers (−3±1%, P <0.01). There was no change in VO 2max pre‐to post‐HA in either group (climbers 3.26 ± 0.37 vs. 3.27 ± 0.61 L/min; trekkers 3.60 ± 0.54 vs. 3.66 ± 0.43 L/min). CONCLUSION HA results in both lean and fat tissue loss in well acclimatized climbers and trekkers with little subsequent impact on aerobic capacity. Mayo Clinic & TNF.

Background Fluid flux in the lungs is influenced by factors altering accumulation or removal (e.g., stimulation of epithelium sodium channels, ENaC). Purpose To determine if ENaC are necessary in the normal fluid regulation with simulated altitude exposure. Methods/Results On separate occasions, 19 healthy subjects (27 ± 5 y) received either nebulized amiloride (ENaC antagonist) or placebo (nebulized saline) during 17 h normobaric hypoxia (FIO2 = 12.5%) in a randomized, double‐blind fashion. Lung diffusing capacity for carbon monoxide (DLCO), alveolar‐capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) were measured via a rebreathe method before and after hypoxic exposure. DLCO was not different at baseline for the amiloride vs. placebo treatments (19 ± 5 vs. 21 ± 8 mL/min/mmHg). Hypoxic exposure increased Vc but did not change Dm in both treatments (Placebo: Vc = 43 ± 22 vs. 59±23 mL p=0.011, Dm = 35 ± 10 vs. 37 ± 12 mL/min/mmHg p=0.312; Amiloride: Vc = 38 ± 17 vs. 57 ± 22 mL p<0.01, Dm = 31 ± 8 vs. 34 ± 10 mL/min/mmHg p= 0.206). Conclusion Normobaric hypoxia did not differentially affect alveolar‐capillary conductance in amiloride and placebo conditions, suggesting that ENaC do not have a role in normal lung fluid regulation during acute hypoxic exposure. HL71478

Fluid clearance from the alveolar space is critically dependent on epithelial sodium channels (ENaC). A common polymorphism in the gene encoding the ENaC alpha subunit results in an alanine to threonine substitution (A663T), with higher ENaC channel activity. This variant influences ion and fluid regulation in the lung during exercise and in response to albuterol. We investigated the influence of the threonine variant (T663; AT/TT group) on the lung fluid response to exercise in conditions of normobaric hypoxia, which challenges lung fluid balance. Lung fluid balance was assessed using Exhaled Na + (ENa + ) and the diffusing capacity for carbon monoxide and nitric oxide (DLCO and DLNO, respectively) to determine alveolar‐capillary membrane conductance (Dm). 19 healthy subjects were grouped by ENaC genotype (n=8 vs. 11 for AA and AT/TT, %female=50 vs. 62%, age=27±1 vs. 28±2yrs., ht=171±3 vs. 173±2cm, wt=69±6 vs.72±3kg , BMI=23±1 vs.24±1kg/m 2 ) and completed two overnight visits in a hypoxic tent simulating just over 5,400m. The visits were randomized to inhaled placebo or inhaled amiloride (1.5mg in 5ml normal saline, used to inhibit ENaC activity) with ENa + , DLCO, and Dm assessed at baseline, following 12 hours of hypoxic exposure, and following hypoxic exercise at 65% peak power on a cycle ergometer. We found significant effects of the interaction between gender and ENaC genotype on DLCO, Dm, and Dm corrected for pulmonary capillary blood volume (p<0.05). Specifically, females with the more active T663 variant had a greater diffusing capacity and less ENa + under placebo conditions, suggesting a greater removal of Na + and fluid from the airspace. These results suggest that genetic variation of ENaC may influence lung fluid balance during hypoxia and hypoxic exercise. Grant Funding Source : Supported by HL71478, HL108962‐03, and HL007249

Background Exposure to hypoxia causes pulmonary vasoconstriction (HPV) and may contribute to the pathogenesis of HAPE. The site of HPV, however, is controversial. While the majority of data suggests HPV occurs in the pulmonary arterioles (precapillary), there is evidence that HPV may also occur in postcapillary vessels. Expansion of pulmonary capillary blood volume (Vc) is primarily passive and thus closely linked to cardiac output (Q). Purpose To examine relationships between Q and Vc during exposure to hypoxia and fluid loading. Methods/Results Healthy adults (n=25, age=31±2 yr) reported to the lab for 2 exposures: 1) 17‐h 12.5% F I O 2 in a hypoxia tent, and 2) fluid loading using IV saline (30 ml/kg over ~15 min). Q, Vc and Dm (alveolar‐capillary conductance) were measured using a rebreathe method with small amounts of C 2 H 2 , CO and NO gas. Saline infusion caused an increase in Q (32±6%, P <0.01) and Vc (39±13%, P <0.05), and a decrease in Dm (−9±3%, P <0.05). Vc/Q was not different pre‐ vs post‐saline (17±2 vs 18±3, P =0.40). Hypoxic exposure caused an increase in pulmonary arterial pressure (67±11%, P <0.01), Vc (57±20%, P =0.04) and Dm (35±6%, P <0.01) despite no change in Q (0.2±2.8%, P =0.98). Vc/Q was greater post‐ vs. pre‐hypoxia (24±4 vs. 17±2, P =0.06). Conclusion The rise in Vc with a constant Q during hypoxic exposure suggests a post capillary site for HPV causing the expansion of the pulmonary capillary bed. HL71478.

There are growing concerns that the COVID-19 pandemic has facilitated a sedentary shift in our physical activity habits. A reduction in physical activity during the pandemic may be secondary to restrictive policies implemented at the government-level, typically those policies which limit interpersonal contact; for example, physical/social distancing. It is without question that social distancing is a necessary measure to mitigate community transmission of the novel virus; however, these policies often limit the public’s opportunities to engage in physical activity. The strictest enforcement of social distancing occurs during an authority-mandated ‘lockdown’ (also known as a ‘shelter-in-place’ or ‘stay-at-home’ order). This Viewpoint focuses on the current evidence demonstrating that physical activity declines during a COVID-19 ‘lockdown’. We highlight the point that most of the available evidence stems from investigations using non-validated, self-reported measures of physical activity and discuss the caveats therewith. This Viewpoint explores whether current evidence reflects an ‘actual’ or rather a ‘perceived’ reduction in physical activity, and raises the question of whether this distinction matters in the end.