Breathing a low-density gas reduces respiratory muscle force development and marginally improves exercise performance in master athletes.

INTRODUCTION: We tested the hypothesis that breathing heliox, to attenuate the mechanical constraints accompanying the decline in pulmonary function with aging, improves exercise performance. METHODS: Fourteen endurance-trained older men (67.9 ± 5.9 year, [Formula: see text]O2max: 50.8 ± 5.8 ml/kg/min; 151% predicted) completed two cycling 5-km time trials while breathing room air (i.e., 21% O2-79% N2) or heliox (i.e., 21% O2-79% He). Maximal flow-volume curves (MFVC) were determined pre-exercise to characterize expiratory flow limitation (EFL, % tidal volume intersecting the MFVC). Respiratory muscle force development was indirectly determined as the product of the time integral of inspiratory and expiratory mouth pressure (∫Pmouth) and breathing frequency. Maximal inspiratory and expiratory pressure maneuvers were performed pre-exercise and post-exercise to estimate respiratory muscle fatigue. RESULTS: Exercise performance time improved (527.6 ± 38 vs. 531.3 ± 36.9 s; P = 0.017), and respiratory muscle force development decreased during inspiration (- 22.8 ± 11.6%, P < 0.001) and expiration (- 10.8 ± 11.4%, P = 0.003) with heliox compared with room air. EFL tended to be lower with heliox (22 ± 23 vs. 30 ± 23% tidal volume; P = 0.054). Minute ventilation normalized to CO2 production ([Formula: see text]E/[Formula: see text]CO2) increased with heliox (28.6 ± 2.7 vs. 25.1 ± 1.8; P < 0.001). A reduction in MIP and MEP was observed post-exercise vs. pre-exercise but was not different between conditions. CONCLUSIONS: Breathing heliox has a limited effect on performance during a 5-km time trial in master athletes despite a reduction in respiratory muscle force development.

Rethinking O2 , CO2 and breathing during wakefulness and sleep.

We have examined the importance of three long-standing questions concerning chemoreceptor influences on cardiorespiratory function which are currently experiencing a resurgence of study among physiologists and clinical investigators. Firstly, while carotid chemoreceptors (CB) are required for hypoxic stimulation of breathing, use of an isolated, extracorporeally perfused CB preparation in unanaesthetized animals with maintained tonic input from the CB, reveals that extra-CB hypoxaemia also provides dose-dependent ventilatory stimulation sufficient to account for 40-50% of the total ventilatory response to steady-state hypoxaemia. Extra-CB hyperoxia also provides a dose- and time-dependent hyperventilation. Extra-CB sites of O2 -driven ventilatory stimulation identified to date include the medulla, kidney and spinal cord. Secondly, using the isolated or denervated CB preparation in awake animals and humans has demonstrated a hyperadditive effect of CB sensory input on central CO2 sensitivity, so that tonic CB activity accounts for as much as 35-40% of the normal, air-breathing eupnoeic drive to breathe. Thirdly, we argue for a key role for CO2 chemoreception and the neural drive to breathe in the pathogenesis of upper airway obstruction during sleep (OSA), based on the following evidence: (1) removal of the wakefulness drive to breathe enhances the effects of transient CO2 changes on breathing instability; (2) oscillations in respiratory motor output precipitate pharyngeal obstruction in sleeping subjects with compliant, collapsible airways; and (3) in the majority of patients in a large OSA cohort, a reduced neural drive to breathe accompanied reductions in both airflow and pharyngeal airway muscle dilator activity, precipitating airway obstruction.

Control of Breathing.

Substantial advances have been made recently into the discovery of fundamental mechanisms underlying the neural control of breathing and even some inroads into translating these findings to treating breathing disorders. Here, we review several of these advances, starting with an appreciation of the importance of V̇A:V̇CO2:PaCO2 relationships, then summarizing our current understanding of the mechanisms and neural pathways for central rhythm generation, chemoreception, exercise hyperpnea, plasticity, and sleep-state effects on ventilatory control. We apply these fundamental principles to consider the pathophysiology of ventilatory control attending hypersensitized chemoreception in select cardiorespiratory diseases, the pathogenesis of sleep-disordered breathing, and the exertional hyperventilation and dyspnea associated with aging and chronic diseases. These examples underscore the critical importance that many ventilatory control issues play in disease pathogenesis, diagnosis, and treatment.

Contribution of the carotid body to thermally mediated hyperventilation in humans.

Humans hyperventilate under heat and cold strain. This hyperventilatory response has detrimental consequences including acid-base dysregulation, dyspnoea, decreased cerebral blood flow and accelerated brain heating. The ventilatory response to hypoxia is exaggerated under whole-body heating and cooling, indicating that altered carotid body function might contribute to thermally mediated hyperventilation. To address whether the carotid body might contribute to heat- and cold-induced hyperventilation, we indirectly measured carotid body tonic activity via hyperoxia, and carotid body sensitivity via hypoxia, under graded heat and cold strain in 13 healthy participants in a repeated-measures design. We hypothesised that carotid body tonic activity and sensitivity would be elevated in a dose-dependent manner under graded heat and cold strain, thereby supporting its role in driving thermally mediated hyperventilation. Carotid body tonic activity was increased in a dose-dependent manner with heating, reaching 175% above baseline (P < 0.0005), and carotid body suppression with hyperoxia removed all of the heat-induced increase in ventilation (P = 0.9297). Core cooling increased carotid body activity by up to 250% (P < 0.0001), but maximal values were reached with mild cooling and thereafter plateaued. Carotid body sensitivity to hypoxia was profoundly increased by up to 180% with heat stress (P = 0.0097), whereas cooling had no detectable effect on hypoxic sensitivity. In summary, cold stress increased carotid body tonic activity and this effect was saturated with mild cooling, whereas heating had clear dose-dependent effects on carotid body tonic activity and sensitivity. These dose-dependent effects with heat strain indicate that the carotid body probably plays a primary role in driving heat-induced hyperventilation. KEY POINTS: Humans over-breathe (hyperventilate) when under heat and cold stress, and though this has detrimental physiological repercussions, the mechanisms underlying this response are unknown. The carotid body, a small organ that is responsible for driving hyperventilation in hypoxia, was assessed under incremental heat and cold strain. The carotid body drive to breathe, as indirectly assessed by transient hyperoxia, increased in a dose-dependent manner with heating, reaching 175% above baseline; cold stress similarly increased the carotid body drive to breathe, but did not show dose-dependency. Carotid body sensitivity, as indirectly assessed by hypoxic ventilatory responses, was profoundly increased by 70-180% with mild and severe heat strain, whereas cooling had no detectable effect. Carotid body hyperactivity and hypersensitivity are two interrelated mechanisms that probably underlie the increased drive to breathe with heat strain, whereas carotid body hyperactivity during mild cooling may play a subsidiary role in cold-induced hyperventilation.

Excess ventilation and exertional dyspnoea in heart failure and pulmonary hypertension.

Increased ventilation relative to metabolic demands, indicating alveolar hyperventilation and/or increased physiological dead space (excess ventilation), is a key cause of exertional dyspnoea. Excess ventilation has assumed a prominent role in the functional assessment of patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction, pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). We herein provide the key pieces of information to the caring physician to 1) gain unique insights into the seeds of patients' shortness of breath and 2) develop a rationale for therapeutically lessening excess ventilation to mitigate this distressing symptom. Reduced bulk oxygen transfer induced by cardiac output limitation and/or right ventricle-pulmonary arterial uncoupling increase neurochemical afferent stimulation and (largely chemo-) receptor sensitivity, leading to alveolar hyperventilation in HFrEF, PAH and small-vessel, distal CTEPH. As such, interventions geared to improve central haemodynamics and/or reduce chemosensitivity have been particularly effective in lessening their excess ventilation. In contrast, 1) high filling pressures in HFpEF and 2) impaired lung perfusion leading to ventilation/perfusion mismatch in proximal CTEPH conspire to increase physiological dead space. Accordingly, 1) decreasing pulmonary capillary pressures and 2) mechanically unclogging larger pulmonary vessels (pulmonary endarterectomy and balloon pulmonary angioplasty) have been associated with larger decrements in excess ventilation. Exercise training has a strong beneficial effect across diseases. Addressing some major unanswered questions on the link of excess ventilation with exertional dyspnoea under the modulating influence of pharmacological and nonpharmacological interventions might prove instrumental to alleviate the devastating consequences of these prevalent diseases.

Silent hypoxaemia in COVID-19 patients.

The clinical presentation of COVID-19 due to infection with SARS-CoV-2 is highly variable with the majority of patients having mild symptoms while others develop severe respiratory failure. The reason for this variability is unclear but is in critical need of investigation. Some COVID-19 patients have been labelled with 'happy hypoxia', in which patient complaints of dyspnoea and observable signs of respiratory distress are reported to be absent. Based on ongoing debate, we highlight key respiratory and neurological components that could underlie variation in the presentation of silent hypoxaemia and define priorities for subsequent investigation.

The need for specificity in quantifying neurocirculatory vs. respiratory effects of eucapnic hypoxia and transient hyperoxia.

KEY POINTS: The carotid chemoreceptor mediates the ventilatory and muscle sympathetic nerve activity (MSNA) responses to hypoxia and contributes to tonic sympathetic and respiratory drives. It is often presumed that both excitatory and inhibitory tests of chemoreflex function show congruence in the end-organ responses. Ventilatory and neurocirculatory (MSNA, blood pressure and heart rate) responses to chemoreflex inhibition elicited by transient hyperoxia and to chemoreflex excitation produced by steady-state eucapnic hypoxia were measured in a cohort of 82 middle-aged individuals. Ventilatory and MSNA responsiveness to hyperoxia and hypoxia were not significantly correlated within individuals. It was concluded that ventilatory responses to hypoxia and hyperoxia do not predict MSNA responses and it is recommended that tests using the specific outcome of interest, i.e. MSNA or ventilation, are required. Transient hyperoxia is recommended as a sensitive and reliable means of quantifying tonic chemoreceptor-driven levels of sympathetic nervous system activity and respiratory drive. ABSTRACT: Hypersensitivity of the carotid chemoreceptor leading to sympathetic nervous system activation and ventilatory instability has been implicated in the pathogenesis and consequences of several common clinical conditions. A variety of treatment approaches aimed at lessening chemoreceptor-driven sympathetic overactivity are now under investigation; thus, the ability to quantify this outcome variable with specificity and precision is crucial. Accordingly, we measured ventilatory and neurocirculatory responses to chemoreflex inhibition elicited by transient hyperoxia and chemoreflex excitation produced by exposure to graded, steady-state eucapnic hypoxia in middle-aged men and women (n = 82) with continuous positive airway pressure-treated obstructive sleep apnoea. Progressive, eucapnic hypoxia produced robust and highly variable increases in ventilation (+83 ± 59%) and muscle sympathetic nerve activity (MSNA) burst frequency (+55 ± 31%), whereas transient hyperoxia caused marked reductions in these variables (-35 ± 14% and -42 ± 16%, respectively). Coefficients of variation for ventilatory and MSNA burst frequency responses, indicating test-retest reproducibility, were respectively 9% and 24% for hyperoxia and 35% and 28% for hypoxia. Based on statistical measures of rank correlation or even comparisons across quartiles of corresponding ventilatory and MSNA responses, we found that the magnitudes of ventilatory inhibition with hyperoxia or excitation with eucapnic hypoxia were not correlated with corresponding MSNA responses within individuals. We conclude that, in conscious, behaving humans, ventilatory sensitivities to progressive, steady-state, eucapnic hypoxia and transient hyperoxia do not predict MSNA responsiveness. Our findings also support the use of transient hyperoxia as a reliable, sensitive, measure of the carotid chemoreceptor contribution to tonic sympathetic nervous system activity and respiratory drive.

Pathophysiology of sleep apnea.

Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anatomically compromised, collapsible airway, the sleep-induced loss of compensatory tonic input to the upper airway dilator muscle motor neurons leads to collapse of the pharyngeal airway. In turn, the ability of the sleeping subject to compensate for this airway obstruction will determine the degree of cycling of these events. Several of the classic neurotransmitters and a growing list of neuromodulators have now been identified that contribute to neurochemical regulation of pharyngeal motor neuron activity and airway patency. Limited progress has been made in developing pharmacotherapies with acceptable specificity for the treatment of sleep-induced airway obstruction. We review three types of major long-term sequelae to severe OSA that have been assessed in humans through use of continuous positive airway pressure (CPAP) treatment and in animal models via long-term intermittent hypoxemia (IH): 1) cardiovascular. The evidence is strongest to support daytime systemic hypertension as a consequence of severe OSA, with less conclusive effects on pulmonary hypertension, stroke, coronary artery disease, and cardiac arrhythmias. The underlying mechanisms mediating hypertension include enhanced chemoreceptor sensitivity causing excessive daytime sympathetic vasoconstrictor activity, combined with overproduction of superoxide ion and inflammatory effects on resistance vessels. 2) Insulin sensitivity and homeostasis of glucose regulation are negatively impacted by both intermittent hypoxemia and sleep disruption, but whether these influences of OSA are sufficient, independent of obesity, to contribute significantly to the "metabolic syndrome" remains unsettled. 3) Neurocognitive effects include daytime sleepiness and impaired memory and concentration. These effects reflect hypoxic-induced "neural injury." We discuss future research into understanding the pathophysiology of sleep apnea as a basis for uncovering newer forms of treatment of both the ventilatory disorder and its multiple sequelae.

Humans In Hypoxia: A Conspiracy Of Maladaptation?!

We address adaptive vs. maladaptive responses to hypoxemia in healthy humans and hypoxic-tolerant species during wakefulness, sleep, and exercise. Types of hypoxemia discussed include short-term and life-long residence at high altitudes, the intermittent hypoxemia attending sleep apnea, or training regimens prescribed for endurance athletes. We propose that hypoxia presents an insult to O2 transport, which is poorly tolerated in most humans because of the physiological cost.

Ensemble Input of Group III/IV Muscle Afferents to CNS: A Limiting Factor of Central Motor Drive During Endurance Exercise from Normoxia to Moderate Hypoxia.

We recently hypothesized that across the range of normoxia to severe hypoxia the major determinant of central motor drive (CMD) during endurance exercise switches from a predominantly peripheral origin to a hypoxic-sensitive central component of fatigue. We found that peripheral locomotor muscle fatigue (pLMF) is the prevailing factor limiting central motor drive and therefore exercise performance from normoxia to moderate hypoxia (SaO2 > 75 %). In these levels of arterial hypoxemia, the development of pLMF is confined to a certain limit which varies between humans-pLMF does not develop to this limit in more severe hypoxia (SaO2 < 70 %) and exercise is prematurely terminated presumably to protect the brain from insufficient O2 supply. Based on the observations from normoxia to moderate hypoxia, we outlined a model suggesting that group III/IV muscle afferents impose inhibitory influences on the determination of CMD of working humans during high-intensity endurance exercise with the purpose to regulate and restrict the level of exercise-induced pLMF to an "individual critical threshold." To experimentally test this model, we pharmacologically blocked somatosensory pathways originating in the working limbs during cycling exercise in normoxia. After initial difficulties with a local anesthetic (epidural lidocaine, L3-L4) and associated loss of locomotor muscle strength we switched to an intrathecally applied opioid analgesic (fentanyl, L3-L4). These experiments were the first ever to selectively block locomotor muscle afferents during high-intensity cycling exercise without affecting maximal locomotor muscle strength. In the absence of opioid-mediated neural feedback from the working limbs, CMD was increased and end-exercise pLMF substantially exceeded, for the first time, the individual critical threshold of peripheral fatigue. The outcome of these studies confirm our hypothesis claiming that afferent feedback inhibits CMD and restricts the development of pLMF to an individual critical threshold as observed from normoxia up to moderate hypoxia.

Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2 : role of carotid body CO2.

We asked if the type of carotid body (CB) chemoreceptor stimulus influenced the ventilatory gain of the central chemoreceptors to CO2 . The effect of CB normoxic hypocapnia, normocapnia and hypercapnia (carotid body PCO2 ≈ 22, 41 and 68 mmHg, respectively) on the ventilatory CO2 sensitivity of central chemoreceptors was studied in seven awake dogs with vascularly-isolated and extracorporeally-perfused CBs. Chemosensitivity with one CB was similar to that in intact dogs. In four CB-denervated dogs, absence of hyper-/hypoventilatory responses to CB perfusion with PCO2 of 19-75 mmHg confirmed separation of the perfused CB circulation from the brain. The group mean central CO2 response slopes were increased 303% for minute ventilation (V̇I)(P ≤ 0.01) and 251% for mean inspiratory flow rate (VT /TI ) (P ≤ 0.05) when the CB was hypercapnic vs. hypocapnic; central CO2 response slopes for tidal volume (VT ), breathing frequency (fb ) and rate of rise of the diaphragm EMG increased in 6 of 7 animals but the group mean changes did not reach statistical significance. Group mean central CO2 response slopes were also increased 237% for V̇I(P ≤ 0.01) and 249% for VT /TI (P ≤ 0.05) when the CB was normocapnic vs. hypocapnic, but no significant differences in any of the central ventilatory response indices were found between CB normocapnia and hypercapnia. These hyperadditive effects of CB hyper-/hypocapnia agree with previous findings using CB hyper-/hypoxia.We propose that hyperaddition is the dominant form of chemoreceptor interaction in quiet wakefulness when the chemosensory control system is intact, response gains physiological, and carotid body chemoreceptors are driven by a wide range of O2 and/or CO2 .

Are type III-IV muscle afferents required for a normal steady-state exercise hyperpnoea in humans?

When tested in isolation, stimuli associated with respiratory CO2 exchange, feedforward central command and type III-IV muscle afferent feedback have each been shown to be capable of eliciting exercise-like cardio-ventilatory responses, but their relative contributions in a setting of physiological exercise remains controversial. We reasoned that in order to determine whether any of these regulators are obligatory to the exercise hyperpnoea each needs to be removed or significantly diminished in a setting of physiological steady-state exercise, during which all recognized stimuli (and other potential modulators) are normally operative. In the past few years we and others have used intrathecal fentanyl, a µ-opiate receptor agonist, in humans to reduce the input from type III-IV opiate-sensitive muscle afferents. During various types of intensities and durations of exercise a sustained hypoventilation, as well as reduced systemic pressure and cardioacceleration, were consistently observed with this blockade. These data provide the basis for the hypothesis that type III-IV muscle afferents are obligatory to the hyperpnoea of mild to moderate intensity rhythmic, large muscle, steady-state exercise. We discuss the limitations of these studies, the reasons for their disagreement with previous negative findings, the nature of the muscle afferent feedback stimulus and the need for future investigations.

Pathophysiology of human ventilatory control.

We review the substantial recent progress made in understanding the underlying mechanisms controlling breathing and the applicability of these findings to selected human diseases. Emphasis is placed on the sites of central respiratory rhythm and pattern generation as well as newly described functions of the carotid chemoreceptors, the integrative nature of the central chemoreceptors, and the interaction between peripheral and central chemoreception. Recent findings that support critical contributions from cortical central command and muscle afferent feedback to exercise hyperpnoea are also reviewed. These basic principles, and the evidence supporting chemoreceptor and ventilatory control system plasticity during and following constant and intermittent hypoxaemia and stagnant hypoxia, are applied to: 1) the pathogenesis, consequences and treatment of obstructive sleep apnoea; and 2) exercise hyperpnoea and its control and limitations with ageing, chronic obstructive pulmonary disease and congestive heart failure.

Respiratory influences on muscle sympathetic nerve activity and vascular conductance in the steady state.

In patients with hypertension, volitional slowing of the respiratory rate has been purported to reduce arterial pressure via withdrawal of sympathetic tone. We examined the effects of paced breathing at 7, 14, and 21 breaths/min, with reciprocal changes in tidal volume, on muscle sympathetic nerve activity, forearm blood flow, forearm vascular conductance, and blood pressure in 21 men and women, 8 of whom had modest elevations in systemic arterial pressure. These alterations in breathing frequency and volume did not affect steady-state levels of sympathetic activity, blood flow, vascular conductance, or blood pressure (all P > 0.05), even though they had the expected effect on sympathetic activity within breaths (i.e., increased modulation during low-frequency/high-tidal volume breathing) (P < 0.001). These findings were consistent across subjects with widely varied baseline levels of sympathetic activity (4-fold), mean arterial pressure (78-110 mmHg), and vascular conductance (15-fold), and those who became hypocapnic during paced breathing vs. those who maintained normocapnia. These findings challenge the notion that slow, deep breathing lowers arterial pressure by suppressing steady-state sympathetic outflow.

Mentoring through teamwork: lessons learned.

This essay is simply a highly personal account of how one mentor has joined with a team of mentors, combined with special "permanent" employees, lively group interactions and high expectations for trainees to provide a fertile environment for the training of scientists. I also need to acknowledge the deep personal friendships that have developed and intensified with the Rankin Lab trainees and their families over the past 47 years. How fortunate we mentors are to have the opportunity to experience and learn with continuously refreshed bands of young, eager minds every year. I am eternally grateful to my mentors for providing such broad shoulders to stand on, to my colleagues for sharing their passion for teaching and science and especially to all of our trainees who chose the Rankin Lab to begin their journey in science. I am especially grateful for having my wife Barbara to share with me the joy of having been a part of this team. Good on ya Babs! To comment on this article, go to www.the-aps.org/forum-teamwork.

Is the Lung Built for Exercise? Advances and Unresolved Questions.

ABSTRACT: Nearly 40 yr ago, Professor Dempsey delivered the 1985 ACSM Joseph B. Wolffe Memorial Lecture titled: "Is the lung built for exercise?" Since then, much experimental work has been directed at enhancing our understanding of the functional capacity of the respiratory system by applying complex methodologies to the study of exercise. This review summarizes a symposium entitled: "Revisiting 'Is the lung built for exercise?'" presented at the 2022 American College of Sports Medicine annual meeting, highlighting the progress made in the last three-plus decades and acknowledging new research questions that have arisen. We have chosen to subdivide our topic into four areas of active study: (i) the adaptability of lung structure to exercise training, (ii) the utilization of airway imaging to better understand how airway anatomy relates to exercising lung mechanics, (iii) measurement techniques of pulmonary gas exchange and their importance, and (iv) the interactions of the respiratory and cardiovascular system during exercise. Each of the four sections highlights gaps in our knowledge of the exercising lung. Addressing these areas that would benefit from further study will help us comprehend the intricacies of the lung that allow it to meet and adapt to the acute and chronic demands of exercise in health, aging, and disease.

New perspectives concerning feedback influences on cardiorespiratory control during rhythmic exercise and on exercise performance.

The cardioaccelerator and ventilatory responses to rhythmic exercise in the human are commonly viewed as being mediated predominantly via feedforward 'central command' mechanisms, with contributions from locomotor muscle afferents to the sympathetically mediated pressor response. We have assessed the relative contributions of three types of feedback afferents on the cardiorespiratory response to voluntary, rhythmic exercise by inhibiting their normal 'tonic' activity in healthy animals and humans and in chronic heart failure. Transient inhibition of the carotid chemoreceptors during moderate intensity exercise reduced muscle sympathetic nerve activity (MSNA) and increased limb vascular conductance and blood flow; and reducing the normal level of respiratory muscle work during heavier intensity exercise increased limb vascular conductance and blood flow. These cardiorespiratory effects were prevented via ganglionic blockade and were enhanced in chronic heart failure and in hypoxia. Blockade of µ opioid sensitive locomotor muscle afferents, with preservation of central motor output via intrathecal fentanyl: (a) reduced the mean arterial blood pressure (MAP), heart rate and ventilatory responses to all steady state exercise intensities; and (b) during sustained high intensity exercise, reduced O(2) transport, increased central motor output and end-exercise muscle fatigue and reduced endurance performance. We propose that these three afferent reflexes - probably acting in concert with feedforward central command - contribute significantly to preserving O(2) transport to locomotor and to respiratory muscles during exercise. Locomotor muscle afferents also appear to provide feedback concerning the metabolic state of the muscle to influence central motor output, thereby limiting peripheral fatigue development.