Wiggins, Chad C.

New Findings What is the central question of this study? Do humans with high‐affinity haemoglobin (HAH) demonstrate attenuated skeletal muscle deoxygenation during normoxic and hypoxic exercise? What is the main finding and its importance? Examination of near‐infrared spectroscopy‐derived muscle oxygenation profiles suggests that fractional oxygen extraction is blunted during hypoxic exercise in humans with HAH compared with control subjects. However, muscle tissue oxygen saturation levels were higher in humans with HAH during exercise in normoxia compared with control subjects. These alterations in fractional oxygen extraction in humans with HAH might influence blood flow regulation and exercise capacity during hypoxia. AbstractRecently, researchers in our laboratory have shown that humans with genetic mutations resulting in high‐affinity haemoglobin (HAH) demonstrate better maintained aerobic capacity and peak power output during hypoxic exercise versus normoxic exercise in comparison to humans with normal‐affinity haemoglobin. However, the influence of HAH on tissue oxygenation within exercising muscle during normoxia and hypoxia is unknown. Therefore, we examined near‐infrared spectroscopy‐derived oxygenation profiles of the vastus lateralis during graded cycling exercise in normoxia and hypoxia among humans with HAH (n = 5) and control subjects with normal‐affinity haemoglobin (n = 12). The HAH group elicited a blunted increase of deoxygenated haemoglobin + myoglobin during hypoxic exercise compared with the control group (P = 0.03), suggesting reduced fractional oxygen extraction in the HAH group. In addition, the HAH group maintained a higher level of muscle tissue oxygen saturation during normoxic exercise (HAH, 75 ± 4% vs. controls, 65 ± 3%, P = 0.049) and there were no differences between groups in muscle tissue oxygen saturation during hypoxic exercise (HAH, 68 ± 3% vs. controls, 68 ± 2%, P = 0.943). Overall, our results suggest that humans with HAH might demonstrate divergent patterns of fractional oxygen extraction during hypoxic exercise and elevated muscle tissue oxygenation during normoxic exercise compared with control subjects.

Background Humans with high O 2 affinity hemoglobin (HAH) have a markedly lower partial pressure of O 2 at which 50% of hemoglobin is saturated (P 50 ) and a leftward shift of the oxy‐hemoglobin dissociation curve. Humans with HAH have attenuated heart rate responses during both acute and chronic hypoxic exposure relative to humans with typical P 50 . Despite the attenuated heart rate responses to hypoxia, there are typically no blood pressure differences found in humans with HAH relative to humans with typical P 50 . Due to the blunted heart rate and normal blood pressure responses to hypoxia in humans with HAH, this study aimed to investigate the impact of HAH on cardiac autonomic function during normoxia and hypoxia. We hypothesized that humans with HAH would have lower cardiac baroreflex sensitivity (cBRS) and heart rate variability (HRV) during normoxia and hypoxia relative to individuals with typical P 50. Methods Nine humans with a HAH mutation (6 female, Age: 40±12yrs, P 50 : 16±1 mmHg) and 12 controls with typical affinity hemoglobin (6 female, Age: 40±10yrs, P 50 : 26±1 mmHg) laid supine for 10‐minutes prior to 20‐minutes of isocapnic hypoxia, titrated to reduce arterial O 2 pressure to ~50 mmHg (Avg. F i O 2 = 11.9±0.0%). Beat‐to‐beat arterial pressures (arterial catheter) and heart rate (electrocardiogram) were continuously recorded. Data were averaged in five‐minute segments starting with the last five minutes of supine normoxic rest. Spontaneous cBRS was quantified using the sequence method. HRV was measured in time and frequency domains. Standard deviation of the RR interval (SDRR) was calculated as the standard deviation of all RR intervals in a data segment. Low frequency (LF) HRV was calculated using Fast Fourier Transformation and assessed as absolute spectral intensity in the LF band (0.04‐0.15Hz). Results Arterial oxygen (P a O 2 ) and carbon dioxide (P a CO 2 ) pressures were not different between humans with HAH and controls during normoxia or isocapnic hypoxia [P a O 2 : (HAH vs. Control): 48±3 vs. 47±2 mmHg, p=0.612; P a CO 2 : (HAH vs. Control): 40±3 vs. 39±1 mmHg, p=0.328] exposure. cBRS was lower in humans with HAH compared to controls in normoxia and throughout isocapnic hypoxia [normoxia (HAH vs. Control): 7±4 vs. 16±10 ms/mmHg; hypoxia minutes 15‐20 (HAH vs. Control): 4±3 vs. 14±11 ms/mmHg; Hb type, p=0.024]. Several metrics of HRV were lower in humans with HAH relative to control (SDRR: Hb type, p≤0.001; LF: Hb type, p=0.030) and HRV was blunted to a similar extent in both groups with hypoxia (SDRR: time effect, p=0.009). Conclusion The findings of this study are twofold. Compared to controls, humans with HAH have: 1) attenuated cardiac baroreflex sensitivity and 2) lower heart rate variability in both normoxia and isocapnic hypoxia.

Humans with high affinity hemoglobin (HAH) develop compensatory polycythemia, an elevated hematocrit, which increases blood viscosity and may compromise cardiac output during exercise. In addition, humans with HAH have shown alterations in muscle blood flow during exercise in normoxia and hypoxia. As such, we aimed to investigate the influence of HAH and compensatory polycythemia on the central hemodynamic response during both normoxic and hypoxic exercise. METHODS Seven humans with HAH (4 females, 36 ± 13 years) and 11 healthy controls with normal oxygen binding affinity (4 females, 39 ± 10 years) performed cycling exercise at two intensities, 1) at a power output corresponding to 15% below normoxic gas exchange threshold (GET) for four minutes and 2) at a power output requiring 85% of normoxic maximal aerobic capacity until exhaustion. This protocol was performed during both normoxia and hypoxia (21% O 2 and 15% O 2 , respectively). Hemodynamic measurements were taken after three minutes of cycling at 15% below normoxic GET, three minutes at 85% V̇O 2max , and at exhaustion. Cardiac output (Q̇) was estimated using an open‐circuit acetylene wash‐in technique. Stroke volume (SV) was calculated by dividing Q̇ by heart rate (HR). Baseline characteristics were compared between groups with student’s two‐tailed unpaired t‐tests. Hemodynamics were analyzed using a two‐way repeated measures analysis of variance to examine the effects of group and exercise intensity. RESULTS As expected, hematocrit was ~15% greater in the HAH group than the control group (HAH: 58 ± 7 % vs CTL: 43 ± 3 %, P<0.001). Both groups elicited an increase in Q̇ and HR as exercise intensity increased during both normoxia (P<0.001 for both) and hypoxia (P<0.001 and P=0.002, respectively). There was no significant difference in Q̇ between groups during normoxia (P=0.85) or hypoxia (P=0.69). In addition, neither HR nor SV were different between groups during exercise in normoxia (P=0.13 and P=0.39, respectively) or hypoxia (P=0.89 and P=0.73, respectively). There was no group by intensity interaction for Q̇, HR, or SV during normoxia (all, P>0.42) or hypoxia (all, P>0.63). CONCLUSION Our data suggest that cardiac output is not compromised during normoxic or hypoxic exercise in humans with HAH and compensatory polycythemia. Therefore, compensatory polycythemia may improve exercise capacity in humans with HAH by raising oxygen carrying capacity without limiting cardiac output.

The application of artificial intelligence (AI) has provided new capabilities to develop advanced medical monitoring sensors for detection of clinical conditions of low circulating blood volume such as hemorrhage. The purpose of this study was to compare for the first time the discriminative ability of two machine learning (ML) algorithms based on real-time feature analysis of arterial waveforms obtained from a non-invasive continuous blood pressure system (Finometer®) signal to predict the onset of decompensated shock: the compensatory reserve index (CRI) and the compensatory reserve metric (CRM). One hundred ninety-one healthy volunteers underwent progressive simulated hemorrhage using lower body negative pressure (LBNP). The least squares means and standard deviations for each measure were assessed by LBNP level and stratified by tolerance status (high vs. low tolerance to central hypovolemia). Generalized Linear Mixed Models were used to perform repeated measures logistic regression analysis by regressing the onset of decompensated shock on CRI and CRM. Sensitivity and specificity were assessed by calculation of receiver-operating characteristic (ROC) area under the curve (AUC) for CRI and CRM. Values for CRI and CRM were not distinguishable across levels of LBNP independent of LBNP tolerance classification, with CRM ROC AUC (0.9268) being statistically similar (p = 0.134) to CRI ROC AUC (0.9164). Both CRI and CRM ML algorithms displayed discriminative ability to predict decompensated shock to include individual subjects with varying levels of tolerance to central hypovolemia. Arterial waveform feature analysis provides a highly sensitive and specific monitoring approach for the detection of ongoing hemorrhage, particularly for those patients at greatest risk for early onset of decompensated shock and requirement for implementation of life-saving interventions.

Objective The slope ratio (SR) is a metric that uses maximal expiratory flow‐volume (MEFV) curves to quantify lung‐emptying dynamics. SR values between 0.5–2.5 indicate homogeneous lung‐emptying, while values >2.5 are suggestive of heterogeneous lung‐emptying. Albuterol and exercise are commonly used to improve airflow in patients with cystic fibrosis (CF); however, the effects of these treatments on lung‐emptying dynamics are unknown. We hypothesized that SR values would decrease following albuterol and/or exercise, and that these decreases would be more pronounced following albuterol‐with‐exercise. Methods Nine patients (25±2 yrs, n=4 male, 5 female) diagnosed (genotype or sweat chloride) with CF underwent three interventions: i) albuterol (2.5 mg in 3 mL saline), ii) 30 mins of exercise (50% peak wattage), and iii) albuterol and exercise together. MEFV curves (spirometry) were obtained at 10 time points: immediately before (Pre) and 15 minutes after (T15) interventions. Forced expiratory volume in 1 second (FEV 1 ) and forced expiratory flow for 25–75% (FEF 25–75 ) of the forced vital capacity (FVC) were calculated for each curve. SR was calculated along the MEFV curve as the ratio between the tangent and chord slopes at serial volumes (200 mL increments), and SR values from 80%‐20% FVC were averaged to produce a single SR for each MEFV curve. Results Compared to exercise, albuterol and albuterol‐with‐exercise elicited greater increases in FEV 1 (Pre: 3.00±0.26 vs 2.99±0.25 vs 3.06±0.23 L, p>0.05; T15: 3.00±0.27 vs 3.27±0.30 vs 3.34±0.28 L, p=0.03; exercise vs albuterol vs exercise‐with‐albuterol, for each comparison respectively), FEF 25–75 (Pre: 2.52±0.40 vs 2.53±0.40 vs 2.57±0.36 L/s, p>0.05; T15: 2.48±0.39 vs 3.04±0.54 vs 3.10±0.43 L/s, p=0.04), and FVC (Pre: 4.19±0.38 vs 4.17±0.38 vs 4.22±0.37 L, p>0.05; T15: 4.16±0.39 vs 4.35±0.38 vs 4.40±0.41 L, p=0.02), as well as greater decreases in SR (Pre: 1.51±0.15 vs 1.56±0.12 vs 1.58±0.12, p>0.05; T15: 1.54±0.15 vs 1.46±0.17 vs 1.43±0.17, p=0.02). Changes in FEV 1 , FEF 25–75 , FVC, and SR were not different between albuterol and albuterol‐with‐exercise conditions (p>0.05). Reductions in SR were related to increases in FEV 1 following interventions (r=−0.55, p<0.01). Conclusions In contrast to exercise, albuterol caused CF patients to exhibit greater increases in FEV 1 , FEF 25–75 , and FVC, along with greater decreases in SR. There was no additive effect of exercise on albuterol. Changes in FEV 1 and SR were inversely correlated. These data suggest that albuterol promotes bronchodilation and homogeneous lung‐emptying in CF patients, and that the SR metric is effective for assessing patterns of bronchodilation following administration of different bronchodilators. Support or Funding Information Supported by HL131151 (SEB) and Mayo Clinic Internal Funding This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Background Exercise tolerance is strongly related the physiological components of the primary (PC) and slow components (SC) of oxygen uptake. Exercise tolerance is reduced in clinical populations and during acute exposure to altitude by factors affecting skeletal muscle oxygenation. The practice of ischemic preconditioning has been shown to improve exercise tolerance or performance in a variety of different testing methods, but the mechanisms behind the improvements in exercise tolerance following IPC are still unclear. Methods Thirteen men (age= 24 ± 4 years, V̇O 2 max= 63.1 ± 5.1 ml·kg −1 ·min −1 ) completed four randomized trials of each combination of hypoxia (F I O 2 = 0.16) or normoxia (F I O 2 = 0.21) with a resting pre‐exercise IPC protocol (4 × 5 min at 220 mmHg) or SHAM procedure. Following the IPC/SHAM protocol subjects completed two constant load cycling bouts at power outputs corresponding to 1) 15% below the normoxic gas exchange threshold (CL #1) and 2) 85% of normoxic V̇O 2 max (CL #2). Breath‐by‐breath V̇O 2 , oxyhemoglobin saturation, and skeletal muscle oxygenation/extraction (measured via near‐infrared spectroscopy) were continuously monitored throughout the trials. V̇O 2 and NIRS kinetics were quantified using a single (for CL#1) or double (for CL#2) exponential term equation with independent time delays for the V̇O 2 /NIRS primary and slow components. Results There was a significant effect of inspirate on deoxyhemoglobin time constant (τ) during CL#1 (Hypoxia: 5.58 ± 2.82 s vs. Normoxia: 8.01 ± 4.71s, P < 0.05) with no effect of IPC treatment (P = 0.84). During CL #2, there was a significant effect of inspirate on V̇O 2 primary amplitude (PC) (Normoxia: 3.13 ± 0.36 L/min vs. Hypoxia: 2.92 ± 0.39 L/min, P < 0.05). IPC did preserve microvascular oxygen extraction during high‐intensity cycling (CL #2) in Hypoxia (IPC: 21.3 ± 11.0 μM vs. SHAM: 19.9 ± 9.9 μM, P < 0.05), but did not affect any of the NIRS or V̇O 2 parameters in Normoxia. Conclusion Oxygen uptake and peripheral oxygen delivery are compromised during high‐intensity exercise in hypoxia. Ischemic preconditioning prior to high‐intensity bouts is effective at mitigating the declines in microvascular oxygen extraction seen during exercise in hypoxia, however the rates (τ) of microvascular extraction and oxygen uptake are not altered following treatment with IPC. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

AbstractIn the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID‐19), including among patients with innate or acquired immunosuppression. However, the association between COVID‐19‐associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched‐control registry study of 143 COVID‐19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID‐19 patients with immunosuppression. We review clinical features and treatment protocols of COVID‐19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID‐19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune‐deficient and immune‐suppressed patients with COVID‐19 warrants further investigation.

World-class athletes are substantively faster, wearing marathon racing shoes with technological advancements than other shoes when competing in the marathon. Our findings suggest that technological advances in footwear contributed to the recent improvements in marathon finishing times among elite runners and in record-setting marathon performances. This investigation highlights the importance of sports analytics and may have broad implications for the regulation of running footwear during competition.

Environmental stressors, such as heat or altitude, elicit dissimilar physiological adaptations to endurance training programs. Whether these differences (i.e., increased hemoglobin mass vs plasma volume) differentially influence performance is debated. We review data in support of our novel hypothesis, which proposes altitude as the preferred environmental training stimulus for elite endurance athletes preparing to compete in temperate, sea-level climates (5°C–18°C).