Wheatley, Courtney M.

Many individuals travel to high altitude each year. Acclimatization to altitude occurs over the course of several days as the body adequately adapts to function in an environment with reduced partial pressure of oxygen. However, with a faster accent to attitude, comes an increased potential for maladaptations to occur, leading to the development of acute mountain sickness (AMS). Each year scientists and support workers are transported by plane from McMurdo Station in Antarctica (sea level) to the Amundsen‐Scott South Pole Station (2835m). This uniform and rapid deployment to altitude provides a unique opportunity to study the effects of hypobaric hypoxia on gene expression, which may help to illustrate the body’s ability to acclimatize to these environmental conditions. Purpose To detect pathway specific gene expression changes associated with the development of AMS and help identify potential targets that may aid in the prediction of risk in the development of AMS symptoms due to rapid exposure to high altitude. Methods Venous blood samples were collected from 53 (height 176.65±8.91cm, weight: 80.49±14.36kg) healthy subjects (38 (27 males; 11 females) that did not develop AMS and 15 (10 males; 5 females) that did develop AMS, as defined by the Lake Louis symptom questionnaire, collected at 2 different time points, with the first being at sea level and the second being after 48hr of altitude exposure). Microarray analysis was performed on the peripheral blood mononuclear cells (PBMCs) from the collected samples, and a logistic regression was performed to determine probe set association with AMS. Results There was a total of 178 significant (p<0.05) probe sets, with 156 of the probe sets being associated with AMS and 22 of the probe sets being associated with no AMS. The probe sets were entered into the Reactome Pathway Database (reactome.org). Pathways identified in association with AMS involved immune system pathways (interleukin signaling) and cellular responses to stimuli pathways (oxidative stress induced senescence signaling), and gene transcription pathways (mitochondrial biogenesis signaling, differentiation of hematopoietic stem cells). Interestingly, pathways identified in association with no development of AMS involved cell cycling pathways (mitotic signaling), chromatin organization pathways (chromatin modifying enzymes), metabolism pathways (utilization of ketone bodies) and the circadian clock pathway (circadian gene expression signaling). Conclusion These findings indicate potential maladaptive responses within the immune system and mitochondrial function, may play a key role in why some individuals develop AMS symptoms. An individual’s ability to sufficiently utilize different metabolic fuel sources and adapt their circadian rhythm may also prevent the development of AMS symptoms.

Introduction: Heart failure (HF) is associated with limited blood flow reserve due to reduced cardiac output (Q). HF is also associated with generalized respiratory muscle weakness, despite patients being exposed to an increased work and cost of breathing due primarily to increased flow resistive work from an altered breathing pattern. We hypothesized that the use of a respiratory training device during aerobic exercise training would positively impact patients with HF by training the inspiratory muscles and modifying their respiratory response to exercise. Methods: 15 subjects completed all study visits (age 67.5±10.0 yr, Ht 179.3±6.1cm, BMI 28.8±5.7 m/cm 2 ). Patients diagnosed with HF and currently enrolled in cardiac rehabilitation (CR) completed the Minnesota living with heart failure questionnaire (MLHFQ), pulmonary function testing, and measures during exercise that included Q (soluble gas method), ventilation (V E ) and respiratory gas exchange. Measures were made at baseline and after completion of CR. Participants were randomized to no respiratory resistance (NR) or mild-moderate inspiratory resistance (MR, 15 to 20 cmH 2 O) provided by a respiratory resistance mask (Training Mask Co., Cadillac, MI) worn during aerobic portions of CR. Results: Participants completed on average 23.9 ± 2.5 CR sessions with 10 subjects in the MR group and 5 in the NR group. The MR group had a decrease on the MLHFQ score of 19.9±26.9 and the NR group had a decrease of 6.0±23.4 (p=0.330). At a matched workload of 30 Watts (W), V E declined by 4.0±7.0 L/min and increased by 2.2±13.1 L/min for subjects in the MR and NR groups, respectively (p=0.06). Respiratory rate (RR) decreased in MR by 1.2± 4.9 and decreased in NR by 0.67± 5.9 (p>0.05). Heart rate at 30W decreased with time in both the MR and NR groups 10.4±12.4 and 3.9±8.9 respectively (p=0.036, no difference between groups). Stroke volume at 30W tended to increase for both MR and NR (p>0.05, no difference between groups). Conclusion: The addition of moderate inspiratory resistance to the aerobic training during CR was well tolerated by HF patients and preliminarily suggests trends toward improved ventilatory responses when assessed during submaximal exercise.

Background Pectus excavatum is the most common chest wall deformity. There is still controversy about cardiopulmonary limitations of this disease and benefits of surgical repair. This study evaluates the impact of pectus excavatum on the cardiopulmonary function of adult patients before and after a modified minimally invasive repair. Methods and Results In this retrospective cohort study, an electronic database was used to identify consecutive adult (aged ≥18 years) patients who underwent cardiopulmonary exercise testing before and after primary pectus excavatum repair at Mayo Clinic Arizona from 2011 to 2020. In total, 392 patients underwent preoperative cardiopulmonary exercise testing; abnormal oxygen consumption results were present in 68% of patients. Among them, 130 patients (68% men, mean age, 32.4±10.0 years) had post‐repair evaluations. Post‐repair tests were performed immediately before bar removal with a mean time between repair and post‐repair testing of 3.4±0.7 years (range, 2.5–7.0). A significant improvement in cardiopulmonary outcomes ( P <0.001 for all the comparisons) was seen in the post‐repair evaluations, including an increase in maximum, and predicted rate of oxygen consumption, oxygen pulse, oxygen consumption at anaerobic threshold, and maximal ventilation. In a subanalysis of 39 patients who also underwent intraoperative transesophageal echocardiography at repair and at bar removal, a significant increase in right ventricle stroke volume was found ( P <0.001). Conclusions Consistent improvements in cardiopulmonary function were seen for pectus excavatum adult patients undergoing surgery. These results strongly support the existence of adverse cardiopulmonary consequences from this disease as well as the benefits of surgical repair.

Energy Expenditure (EE) (kcal/day), a key element to guide obesity treatment, is measured from CO2 production, VCO2 (mL/min), and/or O2 consumption, VO2 (mL/min). Current technologies are limited due to the requirement of wearable facial accessories. A novel system, the Smart Pad, which measures EE via VCO2 from a room’s ambient CO2 concentration transients was evaluated. Resting EE (REE) and exercise VCO2 measurements were recorded using Smart Pad and a reference instrument to study measurement duration’s influence on accuracy. The Smart Pad displayed 90% accuracy (±1 SD) for 14–19 min of REE measurement and for 4.8–7.0 min of exercise, using known room’s air exchange rate. Additionally, the Smart Pad was validated measuring subjects with a wide range of body mass indexes (BMI = 18.8 to 31.4 kg/m2), successfully validating the system accuracy across REE’s measures of ~1200 to ~3000 kcal/day. Furthermore, high correlation between subjects’ VCO2 and λ for CO2 accumulation was observed (p < 0.00001, R = 0.785) in a 14.0 m3 sized room. This finding led to development of a new model for REE measurement from ambient CO2 without λ calibration using a reference instrument. The model correlated in nearly 100% agreement with reference instrument measures (y = 1.06x, R = 0.937) using an independent dataset (N = 56).

The remarkable success of cancer immunotherapies has provided new hope to cancer patients. Unfortunately, a significant proportion of patients remain unable to respond to immunotherapy or maintain durable clinical responses. The lack of objective responses likely results from profound immune dysfunction often observed in patients with cancer. There is substantial evidence that exercise and physical activity can reduce incidence and improve outcomes in cancer patients. As the immune system is highly responsive to exercise, one potential avenue to improve immune function is through exercise and physical activity. A single event of dynamic exercise results in the substantial mobilization of leukocytes with increased functional capacities into the circulation. Chronic, or long-term, exercise leads to higher physical fitness in terms of greater cardiorespiratory function and/or muscle strength and endurance. High aerobic capacity, as measured by maximal oxygen uptake, has been associated with the reduction of dysfunctional T cells and improvements in the abundance of some T cell populations. To be sure, however, the mechanisms of exercise-mediated immune changes are both extensive and diverse. Here, we examine the evidence and theorize how acute and chronic exercise could be used to improve responses to cancer immunotherapies including immune checkpoint inhibitors, dendritic cell vaccines, natural killer cell therapies, and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells. Although the parameters of optimal exercise to yield defined outcomes remain to be determined, the available current data provide a compelling justification for additional human studies and clinical trials investigating the adjuvant use of exercise in immuno-oncology.

Growing evidence suggests that the larger conducting airways are smaller in women than men; however, evidence of this sex‐difference in airway geometry is yet to be demonstrated in a large cohort of adult, healthy non‐smokers. Furthermore, it is not known whether these sex differences persist after airway size is adjusted for its allometric relationship with absolute lung size. Purpose We examined the effect of sex on airway size in a large cohort of non‐smoking healthy adults after adjusting for the possible confounding effect of absolute lung size. Methods A total of 133 (75 men; 58 women) non‐smoking adults (50 ± 18 yrs) with normal pulmonary function (>80% pred.) participated in this study. Full thoracic CT scans were obtained in each participant during a breath‐hold at full inflation. Commercial software was used to automatically segment airways and assign 32 anatomical labels ranging from the 0 th to the 5 th generation. Intraluminal hydraulic diameters ( D h ) were obtained for each airway. An allometric relationship was assumed between D h and absolute lung size, as given by: D h = TLV β · e k , where TLV is the total lung volume at full inflation, β is the allometric scaling exponent, and k allowed for proportional effects of confounding variables. This allometric equation was log‐log transformed such that it could be examined using linear regression: e.g., ln( D h ) = β ·ln(TLV) + k . Sex, age and their interaction were allowed to contribute to both β and k as covariates. The model also included a term for reconstructed voxel size. Model averaging was used to provide parameter estimates of the log‐log transformed allometric equation. Results The allometric exponent, β , assigned to TLV was significant for all 32 anatomically labelled airways ( P < 0.05); neither sex nor age affected β . On the other hand, sex and age were significant mediators of k for the extra‐parenchymal airways only (Trachea, RMB, LMB, BronInt, see Figure 1, P < 0.05). Conclusions Our findings indicate that sex differences in D h remain present despite accounting for the allometric relationship between airway and lung size (see Figure 1). Importantly, however, this sex‐difference in airway size is seemingly confined to the extra‐parenchymal airways. Support or Funding Information This work was supported by NIH Grant HL71478. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Pulmonary artery capacitance (Pa CAP ) is the ability of the pulmonary artery to accept a volume of blood at a given pressure. Measured invasively with heart catheterization; Pa CAP can be estimated non‐invasively through the measurement of end‐tidal CO 2 (P ETCO2 ) and stroke volume (SV), known as gas‐exchange capacitance (GX CAP ). We have shown that GX CAP is decreased at rest as well as during peak exercise in patients with cystic fibrosis (CF), when compared to healthy subjects. To determine whether GX CAP is different in CF and controls at a workload that matches for SV. 9 CF patients (age=22±3yrs, BMI=23±1kg/m 2 , VO 2 =19±1mL/kg/min, FEV 1 =81±8%pred.) and 13 healthy subjects (age=28±3yrs, BMI=25±1kg/m 2 , VO 2 =23±2L/min, FEV 1 =93±3%pred.) were studied. Exercise testing was performed on a cycle ergometer. P ETCO2 was assessed using a metabolic cart, SV was calculated from heart rate and cardiac output (Q) using the acetylene rebreathe technique and GX CAP was calculated as the product of P ETCO2 and SV. When matched for workload which sought to match SV, there was a significant difference in CF and healthy subjects in workload (Watts=72±6 vs. 90±4W), but no difference in percent of max watts (%MaxW=63±4 vs. 66±5W), Q (11±1 vs. 13±1L/min), or SV (89±4 vs. 90±4ml/beat). When matched, the previous difference in GX CAP in healthy and CF was abolished (GX CAP =32±2 vs. 32±2mL/BEAT • min). P ETCO2 was similar between CF and healthy subjects (P ETCO2 36±1 and 35±1mmHg). When matched for SV, GX CAP was statistically similar in CF. In relatively healthy CF there is no evidence of pulmonary vasculature dysfunction. NIH RO1 HL108962‐02

Background Although lower vs. healthy individuals, diffusion capacity of lungs for carbon monoxide (DL CO ) and nitric oxide (DL NO ) (may influence oxygen uptake, VO 2 ) are higher during exercise vs. rest in cystic fibrosis patients (CF). Thus, because the Fick equation suggests cardiac output (Q) increases linearly with VO 2 , we sought to study relationships between VO 2 with cardiac function from rest to peak exercise as increases in Q, DL CO and DL NO occur during exercise in CF. Methods 50 individuals participated (ages 22 ± 2 vs. 27 ± 2, BSA = 1.7 ± 0.1 vs. 1.8 ± 0.0 m 2 , VO 2peak = 24 ± 2 vs. 35 ± 2 ml/kg/min, CF (n = 19) vs. controls (CTL, n = 31), mean ± SEM, p<0.05 for all). Acetylene rebreathe was used to assess Q and calculate stroke volume (SV), and standard gas‐exchange was used to assess VO 2 (mL/kg/min). Cardiac power (CP, Q i × MAP) and stroke work (SW, SV i × MAP) were calculated. Q and SV were indexed to BSA (Q i and SV i ). Results Linear regression (R 2 ) between VO 2 with SV i , Q i , CP, and SW at rest were similarly negligible for CF vs. CTL (p=ns). At 50 % VO 2peak , R 2 between VO 2 with SV i (0.25 and 0.43, p<0.05), Q i (0.37 and 0.41, p<0.05), CP (0.18, p=ns and 0.25, p<0.05), and SW (0.12 and 0.30, p=ns) improved for CF and CTL, respectively. At VO 2peak , stronger R 2 between VO 2 with SV i (0.41, p<0.05), Q i (0.47, p<0.05), CP (0.24, p<0.05), and SW (0.19, p=ns) occurred in CF; but, R 2 weakened in CTL (0.28, p<0.05; 0.33, p<0.05; 0.07, p=ns; 0.02, p=ns, respectively). Conclusions From rest to VO 2peak the relationship between VO 2 with cardiac function improves in CF patients. Participation in exercise may benefit relationships between gas‐transfer with cardiac hemodynamics in CF patients.