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.

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.

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.

Carotid body hyperexcitability underlies heat-induced hyperventilation in exercising humans.

Physical activity is the most common source of heat strain for humans. The thermal strain of physical activity causes overbreathing (hyperventilation) and this has adverse physiological repercussions. The mechanisms underlying heat-induced hyperventilation during exercise are unknown, but recent evidence supports a primary role of carotid body hyperexcitability (increased tonic activity and sensitivity) underpinning hyperventilation in passively heated humans. In a repeated-measures crossover design, 12 healthy participants (6 female) completed two low-intensity cycling exercise conditions (25% maximal aerobic power) in randomized order, one with core temperature (TC) kept relatively stable near thermoneutrality, and the other with progressive heat strain to +2°C TC. To provide a complete examination of carotid body function under graded heat strain, carotid body tonic activity was assessed indirectly by transient hyperoxia, and its sensitivity estimated by responses to both isocapnic and poikilocapnic hypoxia. Carotid body tonic activity was increased by 220 ± 110% during cycling alone, and by 400 ± 290% with supplemental thermal strain to +1°C TC, and 600 ± 290% at +2°C TC (interaction, P = 0.0031). During exercise with heat stress at both +1°C and +2°C TC, carotid body suppression by hyperoxia decreased ventilation below the rates observed during exercise without heat stress (P < 0.0147). Carotid body sensitivity was increased by up to 230 ± 190% with exercise alone, and by 290 ± 250% with supplemental heating to +1°C TC and 510 ± 470% at +2°C TC (interaction, P = 0.0012). These data indicate that the carotid body is further activated and sensitized by heat strain during exercise and this largely explains the added drive to breathe.NEW & NOTEWORTHY Physical activity is the most common way humans increase their core temperature, and excess breathing in the heat can limit heat tolerance and performance, and may increase the risk of heat-related injury. Dose-dependent increases in carotid body tonic activity and sensitivity with core heating provide compelling evidence that carotid body hyperexcitability is the primary cause of heat-induced hyperventilation during exercise.

The physiology and pathophysiology of exercise hyperpnea.

In health, the near-eucapnic, highly efficient hyperpnea during mild-to-moderate intensity exercise is driven by three obligatory contributions, namely, feedforward central command from supra-medullary locomotor centers, feedback from limb muscle afferents, and respiratory CO2 exchange (V̇CO2). Inhibiting each of these stimuli during exercise elicits a reduction in hyperpnea even in the continuing presence of the other major stimuli. However, the relative contribution of each stimulus to the hyperpnea remains unknown as does the means by which V̇CO2 is sensed. Mediation of the hyperventilatory response to exercise in health is attributed to the multiple feedback and feedforward stimuli resulting from muscle fatigue. In patients with COPD, diaphragm EMG amplitude and its relation to ventilatory output are used to decipher mechanisms underlying the patients' abnormal ventilatory responses, dynamic lung hyperinflation and dyspnea during exercise. Key contributions to these exercise-limiting responses across the spectrum of COPD severity include high dead space ventilation, an excessive neural drive to breathe and highly fatigable limb muscles, together with mechanical constraints on ventilation. Major controversies concerning control of exercise hyperpnea are discussed along with the need for innovative research to uncover the link of metabolism to breathing in health and disease.

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.

Is the healthy respiratory system built just right, overbuilt, or underbuilt to meet the demands imposed by exercise?

In the healthy, untrained young adult, a case is made for a respiratory system (airways, pulmonary vasculature, lung parenchyma, respiratory muscles, and neural ventilatory control system) that is near ideally designed to ensure a highly efficient, homeostatic response to exercise of varying intensities and durations. Our aim was then to consider circumstances in which the intra/extrathoracic airways, pulmonary vasculature, respiratory muscles, and/or blood-gas distribution are underbuilt or inadequately regulated relative to the demands imposed by the cardiovascular system. In these instances, the respiratory system presents a significant limitation to O2 transport and contributes to the occurrence of locomotor muscle fatigue, inhibition of central locomotor output, and exercise performance. Most prominent in these examples of an "underbuilt" respiratory system are highly trained endurance athletes, with additional influences of sex, aging, hypoxic environments, and the highly inbred equine. We summarize by evaluating the relative influences of these respiratory system limitations on exercise performance and their impact on pathophysiology and provide recommendations for future investigation.

On the horizon of aging and physical activity research.

This viewpoint is the result of a Horizon Round Table discussion of Exercise and Aging held during the 2017 Saltin International Graduate School in Exercise and Clinical Physiology in Gatineau, Quebec. This expert panel discussed key issues and approaches to future research into aging, across human physiological systems, current societal concerns, and funding approaches. Over the 60-min round table discussion, 3 major themes emerged that the panel considered to be "On the Horizon" of aging research. These themes include (i) aging is a process that extends from womb to tomb; (ii) the importance of longitudinal experimental studies; and (iii) the ongoing need to investigate multiple systems using an integrative approach between scientists, clinicians, and knowledge brokers. With a focus on these themes, we aim to identify critical questions, challenges, and opportunities that face scientists in advancing the understanding of exercise and aging.

Central sleep apnea: misunderstood and mistreated!

Central sleep apnea is prevalent in patients with heart failure, healthy individuals at high altitudes, and chronic opiate users and in the initiation of "mixed" (that is, central plus obstructive apneas). This brief review focuses on (a) the causes of repetitive, cyclical central apneas as mediated primarily through enhanced sensitivities in the respiratory control system and (b) treatment of central sleep apnea through modification of key components of neurochemical control as opposed to the current universal use of positive airway pressure.