Wiggins, Chad C.

Abstract In this article, we highlight the contributions of passive experiments that address important exercise‐related questions in integrative physiology and medicine. Passive experiments differ from active experiments in that passive experiments involve limited or no active intervention to generate observations and test hypotheses. Experiments of nature and natural experiments are two types of passive experiments. Experiments of nature include research participants with rare genetic or acquired conditions that facilitate exploration of specific physiological mechanisms. In this way, experiments of nature are parallel to classical “knockout” animal models among human research participants. Natural experiments are gleaned from data sets that allow population‐based questions to be addressed. An advantage of both types of passive experiments is that more extreme and/or prolonged exposures to physiological and behavioral stimuli are possible in humans. In this article, we discuss a number of key passive experiments that have generated foundational medical knowledge or mechanistic physiological insights related to exercise. Both natural experiments and experiments of nature will be essential to generate and test hypotheses about the limits of human adaptability to stressors like exercise. © 2023 American Physiological Society. Compr Physiol 13:4879‐4907, 2023.

Background : Maintaining oxygen delivery during conditions of hypoxia is important, particularly for patients with hemoglobinopathies.Evidence in comparative physiology indicates that high hemoglobin-oxygen (Hb-O2) affinity serves as a beneficial hematological adaptation to chronic hypoxia exposure. The improved hypoxia tolerance is likely due to an increase in arterial oxygen saturation with high Hb-O2 affinity. However, the relationship between high Hb-O2 affinity and hypoxia tolerance in humans is not well understood. Etavopivat is a potent, selective, once-daily, oral activator of the red blood cell (RBC) pyruvate kinase isozyme (PKR), with a half-life of ~13 hours, under investigation for the treatment of sickle cell disease (SCD) and other hematological conditions. Etavopivat has a multimodal mechanism of action in RBCs by decreasing 2,3-diphosphoglycerate (2,3-DPG) levels to increase Hb-O2 affinity and increasing adenosine triphosphate (ATP) levels to improve RBC health. In Phase 1 trials etavopivat increased Hb-O2 affinity in healthy volunteers (HVs; Forsyth et al. Clin Pharmacol Drug Dev 2022) and patients with SCD (Saraf et al. Blood Adv 2024) in room air. Aim: To investigate arterial oxygenation changes with etavopivat under conditions of moderate and severe hypoxia in HVs. Methods: HVs visited the laboratory for assessments at baseline and following 7 days of etavopivat exposure (400 mg once daily). Participants completed rhythmic handgrip exercises (rest, 10% and 20% maximum voluntary contraction [MVC]) during graded hypoxic exposure, breathing room air (21% O2), moderate hypoxic gas (15% O2), and severe hypoxic gas (10% O2), resulting in acute duration (~12 minutes) of exposure to each level of hypoxia. Hb-O2 affinity was assessed by partial pressure of oxygen at 50% Hb saturation (P50), measured using dual-wavelength spectrophotometry at a standardized pH (~7.4) and temperature (37 ºC). Arterial catheterization was used to collect samples for fractional oxygen saturation (FO2Hb) and Hb and to measure arterial blood pressure. Blood gases were analyzed after 5 minutes of resting exposure to each inspirate, then ~2.5 minutes after commencing each of the 3-minute handgrip exercises (10% followed by 20% MVC). Liquid chromatography-tandem mass spectrometry was used to evaluate 2,3-DPG and ATP levels in whole blood. Data for FO2Hb and heart rate were analyzed using separate repeated measures 2 (treatment) x 3 (intensity) ANOVA for each inspirate and all other hematological data pre vs post etavopivat were analyzed using paired-sample t-tests. Statistical significance was set at P<0.05. Data presented are mean ± standard deviation. Results: Sixteen HVs (five women) aged 32 ±8 years were enrolled. After 7 days of oral once-daily 400 mg etavopivat, P50 decreased from 28.6 ±1.6 at baseline to 24.8 ±1.3 mmHg (P<0.001). Hb concentration remained unchanged from baseline (14.6 ±1.1 g/dL), post etavopivat (14.5 ±1.1 g/dL; P>0.05). FO2Hb at rest decreased from 96.0% ±0.6 under normal oxygen conditions to 74.6% ±6.7 during severe hypoxic exposure; however, this decrease in FO2Hb was mitigated post etavopivat exposure (79.7% ±5.2, P<0.001). A similar mitigation of the FO2Hb decrease was observed during the handgrip exercise (20% MVC, P<0.001). Concentrations of 2,3-DPG decreased and RBC ATP increased following etavopivat exposure during both normoxia and moderate hypoxia (P<0.001). Mean arterial pressure was lower post etavopivat exposure under normoxia, but not during moderate or severe hypoxia. Heart rate showed no change post etavopivat exposure during normoxia and hypoxia (P>0.50). Etavopivat was well tolerated with no unexpected adverse events reported. Conclusions: Etavopivat enhanced FO2Hb during brief hypoxic episodes with an apparent relationship to hypoxia severity for which the greatest improvements were observed at more severe hypoxic exposure. In SCD, high Hb-O2 affinity is beneficial for maintaining Hb ‘R’ state, thereby reducing the risk of polymerization and associated sickling. Increased Hb-O2 affinity, together with maintenance of a high FO2Hb under hypoxic conditions, demonstrates etavopivat's ability to promote oxygen exchange and subsequent delivery. Together with projected improvement of RBC health, also achieved via PKR activation, this indicates a potential clinical benefit with etavopivat for hemoglobinopathies and beyond.

The purpose of sympathetic neuronal discharge and the recruitment of neuronal subpopulations for human circulatory homeostasis remains unknown. This study tested the hypothesis that sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y (NPY) bioavailability. Across baseline and an intravenous dexmedetomidine infusion (α2-adrenergic agonist) sympathetic action potential (AP) frequency and total sympathetic AP clusters were associated with NPY bioavailability. This is the first study to report that sympathetic neuronal discharge and recruitment patterns regulate NPY bioavailability to support circulatory homeostasis in humans.

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, we estimated the number of actual inpatient lives saved by CCP treatment in the United States of America based on CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimate the potential number of lives saved if CCP had been deployed for 100% of hospitalized patients or used in 15 to 75% of outpatients. Depending on the assumptions modeled in stratified analyses, we estimated that CCP saved between 16,476 and 66,296 lives. The CCP ideal use might have saved as many as 234,869 lives and prevented 1,136,133 hospitalizations. CCP deployment was a successful strategy for ameliorating the impact of the COVID-19 pandemic in the USA. This experience has important implications for convalescent plasma use in future infectious disease emergencies.

Three-dimensional reconstruction of airways has shown increased luminal area in patients with COVID-19 and post-acute sequelae of COVID-19 when compared with healthy controls. These findings suggest the role of large conducting airways in the pathogenesis of post-acute sequelae of COVID 19.

AbstractThe present study investigated the impact of central α2‐adrenergic mechanisms on sympathetic action potential (AP) discharge, recruitment and latency strategies. We used the microneurographic technique to record muscle sympathetic nerve activity and a continuous wavelet transform to investigate postganglionic sympathetic AP firing during a baseline condition and an infusion of a α2‐adrenergic receptor agonist, dexmedetomidine (10 min loading infusion of 0.225 µg kg−1; maintenance infusion of 0.1–0.5 µg kg h−1) in eight healthy individuals (28 ± 7 years, five females). Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg, P < 0.001) but did not alter heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.748). Dexmedetomidine reduced sympathetic AP discharge (126 ± 73 to 27 ± 24 AP 100 beats−1, P = 0.003) most strongly for medium‐sized APs (normalized cluster 2: 21 ± 10 to 5 ± 5 AP 100 beats−1; P < 0.001). Dexmedetomidine progressively de‐recruited sympathetic APs beginning with the largest AP clusters (12 ± 3 to 7 ± 2 clusters, P = 0.002). Despite de‐recruiting large AP clusters with shorter latencies, dexmedetomidine reduced AP latency across remaining clusters (1.18 ± 0.12 to 1.13 ± 0.13 s, P = 0.002). A subset of six participants performed a Valsalva manoeuvre (20 s, 40 mmHg) during baseline and the dexmedetomidine infusion. Compared to baseline, AP discharge (Δ 361 ± 292 to Δ 113 ± 155 AP 100 beats−1, P = 0.011) and AP cluster recruitment elicited by the Valsalva manoeuvre were lower during dexmedetomidine (Δ 2 ± 1 to Δ 0 ± 2 AP clusters, P = 0.041). The reduction in sympathetic AP latency elicited by the Valsalva manoeuvre was not affected by dexmedetomidine (Δ –0.09 ± 0.07 to Δ –0.07 ± 0.14 s, P = 0.606). Dexmedetomidine reduced baroreflex gain, most strongly for medium‐sized APs (normalized cluster 2: –6.0 ± 5 to –1.6 ± 2 % mmHg−1; P = 0.008). These data suggest that α2‐adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans. imageKey points Sympathetic postganglionic neuronal subpopulations innervating the human circulation exhibit complex patterns of discharge, recruitment and latency. However, the central neural mechanisms governing sympathetic postganglionic discharge remain unclear. This microneurographic study investigated the impact of a dexmedetomidine infusion (α2‐adrenergic receptor agonist) on muscle sympathetic postganglionic action potential (AP) discharge, recruitment and latency patterns. Dexmedetomidine infusion inhibited the recruitment of large and fast conducting sympathetic APs and attenuated the discharge of medium sized sympathetic APs that fired during resting conditions and the Valsalva manoeuvre. Dexmedetomidine infusion elicited shorter sympathetic AP latencies during resting conditions but did not affect the reductions in latency that occurred during the Valsalva manoeuvre. These data suggest that α2‐adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans.

World record speeds at different distances for men and women in different age categories are used to develop a model to predict running performance as a function of race distance, age, and sex. This empirical model quantifies the decline in running speed with distance and age in a way that provides insight into the aerobic and anaerobic contributions to running speed and may help with developing training strategies for different age groups at various distances.

This study aimed to investigate the impact of central α2-adrenergic mechanisms on arterial baroreflex control of sympathetic and cardiovagal outflow in healthy humans. R-R interval (ECG), blood pressure (brachial arterial catheter), and muscle sympathetic nerve activity (MSNA; peroneal microneurography) were measured in eight healthy participants (5 females; 28±7 years). Sympathetic action potentials (AP) were extracted from the filtered MSNA neurogram (continuous wavelet transform) during a 5-minute baseline (BSL) and an intravenous dexmedetomidine infusion consisting of a loading dose (LD; 10 minutes at 0.225 μg/kg/hr) and a maintenance dose (MD; ~0.15 μg/kg/hr). Sympathetic AP baroreflex threshold gain was measured as the slope of the linear relationship between AP discharge probability and diastolic blood pressure. The linear relationship between R-R interval and systolic blood pressure (sequence technique) quantified cardiovagal baroreflex gain. Mixed-effects analyses and post-hoc t-tests were performed. Data are reported as mean ± SD. Dexmedetomidine reset the baroreflex threshold operating points for all sympathetic AP clusters downwards to lower firing probabilities (cluster 4; BSL: 20±6, LD: 13±8, MD: 6±5%, both p<0.01 vs. BSL) and leftwards to lower diastolic pressures (BSL: 72±9, LD: 69±8, MD: 65±10 mmHg, both p<0.01 vs. BSL). Dexmedetomidine reduced baroreflex threshold gain for the subpopulation of medium-sized sympathetic APs (cluster 4; BSL: -6.5±2.0, LD: -2.6±1.6, MD: -2.0±0.7 %/mmHg, both p<0.01 vs. BSL). Dexmedetomidine did not affect baroreflex threshold gain of small (cluster 1; BSL: -1.9±1.1, LD: -1.3±1.6, MD: -1.1±0.8 %/mmHg, both P>0.88 vs. BSL) or large AP clusters (cluster 9; BSL: -0.8±0.4, LD: -0.8±1.0, MD: -0.2±0.7 %/mmHg, both P>0.98 vs. BSL). Dexmedetomidine reset the cardiovagal baroreflex to lower systolic pressures but did not affect R-R interval (BSL: 1035±261, LD: 1025±308, MD: 1005±292ms, Main effect P=0.45) or gain (BSL: 24±11, LD: 30±20, MD: 26±25 ms/mmHg, Main effect P=0.63). These findings suggest that central α2-adrenergic mechanisms differentially affect arterial baroreflex control of sympathetic and cardiovagal outflow in humans by minimally affecting cardiovagal baroreflex gain but strongly affecting the baroreflex gain for the subpopulation of medium-sized sympathetic APs. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hypoxia exacerbates fatigue via central mechanisms after ischemic single-leg exercise. The greater fatigue observed during ischemic dynamic fatiguing exercise with hypoxia inspirate did not differ between the sexes. Hypoxia-induced central limitations are present in acute ischemic exercise and do not appear different in males and females.