Advancements in the neurocirculatory reflex response to hypoxia.

Hypoxia is a pivotal factor in the pathophysiology of various clinical conditions, including obstructive sleep apnea, which has a strong association with cardiovascular diseases like hypertension, posing significant health risks. Although the precise mechanisms linking hypoxemia-associated clinical conditions with hypertension remains incompletely understood, compelling evidence suggests that hypoxia induces plasticity of the neurocirculatory control system. Despite variations in experimental designs and the severity, frequency, and duration of hypoxia exposure, evidence from animal and human models consistently demonstrates the robust effects of hypoxemia in triggering reflex-mediated sympathetic activation. Both acute and chronic hypoxia alters neurocirculatory regulation and, in some circumstances, leads to sympathetic outflow and elevated blood pressures that persist beyond the hypoxic stimulus. Dysregulation of autonomic control could lead to adverse cardiovascular outcomes and increase the risk of developing hypertension.

Later circadian timing and increased sleep timing variability are associated with attenuations in overnight blood pressure dipping among chronic nightshift workers.

OBJECTIVE: Determine relationships between overnight blood pressure, circadian phase, and sleep variability among dayshift and chronic nightshift nurses. METHODS: Twenty participants working dayshift (n = 10) or nightshift (n = 10) schedules participated in a 7-day cross-sectional study. Participants underwent an evening in-laboratory melatonin assessment and wore ambulatory blood pressure devices to assess 24-hour blood pressure patterns. Overnight blood pressure dipping was calculated from sleeping/waking systolic blood pressure ratio and salivary dim-light melatonin onset determined circadian phase. Sleep variability was assessed using the standard deviation of 7-day sleep onset. RESULTS: Nightshift workers had later circadian phase, greater sleep onset variability, and an attenuated overnight blood pressure dipping pattern. Later circadian phase was associated with attenuated dipping patterns and sleep onset variability was negatively correlated with blood pressure dipping magnitude in nightshift, but not dayshift workers. CONCLUSIONS: Chronic circadian disruption via higher sleep onset variability among nightshift workers may contribute to attenuated blood pressure dipping and cardiovascular risk in this population.

Pressure Building Against the Clock: The Impact of Circadian Misalignment on Blood Pressure.

PURPOSE OF REVIEW: Misalignment between the endogenous biological timing system and behavioral activities (i.e., sleep/wake, eating, activity) contributes to adverse cardiovascular health. In this review, we discuss the effects of recurring circadian misalignment on blood pressure regulation and the implications for hypertension development. Additionally, we highlight emerging therapeutic approaches designed to mitigate the negative cardiovascular consequences elicited by circadian disruption. RECENT FINDINGS: Circadian misalignment elicited by work schedules that require individuals to be awake during the biological night (i.e., shift work) alters 24-h blood pressure rhythms. Mechanistically, circadian misalignment appears to alter blood pressure via changes in autonomic nervous system balance, variations to sodium retention, dysregulation of endothelial vasodilatory responsiveness, and activation of proinflammatory mechanisms. Recurring circadian misalignment produced by a mismatch in sleep timing on free days vs. work days (i.e., social jetlag) appears to have no direct effects on prevailing blood pressure levels in healthy adults; though, circadian disruptions resulting from social jetlag may increase the risk of hypertension through enhanced sympathetic activation and/or obesity. Furthermore, social jetlag assessment may be a useful metric in shift work populations where the magnitude of circadian misalignment may be greater than in the general population. Circadian misalignment promotes unfavorable changes to 24-h blood pressure rhythms, most notably in shift working populations. While light therapy, melatonin supplementation, and the timing of drug administration may improve cardiovascular outcomes, interventions designed to target the effects of circadian misalignment on blood pressure regulation are warranted.

Sex-related Differences in Loop Gain during High-Altitude Sleep-disordered Breathing.

Rationale: Central sleep apnea (CSA) is pervasive during sleep at high altitude, disproportionately impacting men and associated with increased peripheral chemosensitivity. Objectives: We aimed to assess whether biological sex affects loop gain (LGn) and CSA severity during sleep over 9-10 days of acclimatization to 3,800 m. We hypothesized that CSA severity would worsen with acclimatization in men but not in women because of greater increases in LGn in men. Methods: Sleep studies were collected from 20 (12 male) healthy participants at low altitude (1,130 m, baseline) and after ascent to (nights 2/3, acute) and residence at high altitude (nights 9/10, prolonged). CSA severity was quantified as the respiratory event index (REI) as a surrogate of the apnea-hypopnea index. LGn, a measure of ventilatory control instability, was quantified using a ventilatory control model fit to nasal flow. Linear mixed models evaluated effects of time at altitude and sex on respiratory event index and LGn. Data are presented as contrast means with 95% confidence intervals. Results: REI was comparable between men and women at acute altitude (4.1 [-9.3, 17.5] events/h; P = 0.54) but significantly greater in men at prolonged altitude (23.7 [10.3, 37.1] events/h; P = 0.0008). Men had greater LGn than did women for acute (0.08 [0.001, 0.15]; P = 0.047) and prolonged (0.17 [0.10, 0.25]; P < 0.0001) altitude. The change in REI per change in LGn was significantly greater in men than in women (107 ± 46 events/h/LGn; P = 0.02). Conclusions: The LGn response to high altitude differed between sexes and contributed to worsening of CSA over time in men but not in women. This sex difference in acclimatization appears to protect females from high altitude-related CSA. These data provide fundamental sex-specific physiological insight into high-altitude acclimatization in healthy individuals and may help to inform sex differences in sleep-disordered breathing pathogenesis in patients with cardiorespiratory disease.

Acute hypoxia elicits lasting reductions in the sympathetic action potential transduction of arterial blood pressure in males.

Post-hypoxia sympathoexcitation does not elicit corresponding changes in vascular tone, suggesting diminished sympathetic signalling. Blunted sympathetic transduction following acute hypoxia, however, has not been confirmed and the effects of hypoxia on the sympathetic transduction of mean arterial pressure (MAP) as a function of action potential (AP) activity is unknown. We hypothesized that MAP changes would be blunted during acute hypoxia but restored in recovery and asynchronous APs would elicit smaller MAP changes than synchronous APs. Seven healthy males (age: 24 (3) years; BMI: 25 (3) kg/m2 ) underwent 20 min isocapnic hypoxia (PET O2 : 47 (2) mmHg) and 30 min recovery. Multi-unit microneurography (muscle sympathetic nerve activity; MSNA) and continuous wavelet transform with matched mother wavelet was used to detect sympathetic APs during baseline, hypoxia, early (first 7 min) and late (last 7 min) recovery. AP groups were classified as synchronous APs, asynchronous APs (occurring outside an MSNA burst) and no AP activity. Sympathetic transduction of MAP was quantified using signal-averaging, with ΔMAP tracked following AP group cardiac cycles. Following synchronous APs, ΔMAP was reduced in hypoxia (+1.8 (0.9) mmHg) and early recovery (+1.5 (0.7) mmHg) compared with baseline (+3.1 (2.2) mmHg). AP group-by-condition interactions show that at rest asynchronous APs attenuate MAP reductions compared with no AP activity (-0.4 (1.1) vs. -2.2 (1.2) mmHg, respectively), with no difference between AP groups in hypoxia, early or late recovery. Sympathetic transduction of MAP is blunted in hypoxia and early recovery. At rest, asynchronous sympathetic APs contribute to neural regulation of MAP by attenuating nadir pressure responses. KEY POINTS: Acute isocapnic hypoxia elicits lasting sympathoexcitation that does not correspond to parallel changes in vascular tone, suggesting blunted sympathetic transduction. Signal-averaging techniques track the magnitude and temporal cardiovascular responses following integrated muscle sympathetic nerve activity (MSNA) burst and non-burst cardiac cycles. However, this does not fully characterize the effects of sympathetic action potential (AP) activity on blood pressure control. We show that hypoxia blunts the sympathetic transduction of mean arterial pressure (MAP) following synchronous APs that form integrated MSNA bursts and that sympathetic transduction of MAP remains attenuated into early recovery. At rest, asynchronous APs attenuate the reduction in MAP compared with cardiac cycles following no AP activity, thus asynchronous sympathetic APs appear to contribute to the neural regulation of blood pressure. The results advance our understanding of sympathetic transduction of arterial pressure during and following exposure to acute isocapnic hypoxia in humans.

Action potential amplitude and baroreflex resetting of action potential clusters mediate hypoxia-induced sympathetic long-term facilitation.

Baroreflex resetting permits sympathetic long-term facilitation (sLTF) following hypoxia; however, baroreflex control of action potential (AP) clusters and AP recruitment patterns facilitating sLTF is unknown. We hypothesized that baroreflex resetting of arterial pressure operating points (OPs) of AP clusters and recruitment of large-amplitude APs would mediate sLTF following hypoxia. Eight men (age: 24 (3) years; body mass index: 24 (3) kg/m2 ) underwent 20 min isocapnic hypoxia ( PETO2${P_{{\rm{ET}}{{\rm{O}}_{\rm{2}}}}}$ : 47 (2) mmHg) and 30 min recovery. Multi-unit microneurography (muscle sympathetic nerve activity; MSNA) and a continuous wavelet transform with matched mother wavelet was used to detect sympathetic APs during baseline, hypoxia, early (first 5 min), and late recovery (last 5 min). AP amplitude (normalized to largest baseline AP amplitude), percentage APs occurring outside a MSNA burst (percentage asynchronous APs), and proportion of APs firing in small (1-3), medium (4-6) and large (7-10) normalized cluster sizes was calculated. Normalized clusters were used to assess baroreflex OPs and sensitivity. Hypoxia increased total MSNA activity, which remained elevated during recovery (P < 0.0001). Baroreflex OPs were shifted rightward for all clusters in recovery, with no effect on slope. Compared to baseline, AP amplitude was elevated by 3 (2)% and 4 (2)% while asynchronous APs were reduced by 9 (5)% and 7 (6)% in early and late recovery, respectively. In early recovery, the proportion of APs firing in large clusters was increased compared to baseline. Hypoxia-induced sLTF is mediated by baroreflex resetting of AP clusters to higher OPs, reduced asynchronous AP firing, and increased contribution from large-amplitude APs. KEY POINTS: Acute isocapnic hypoxia resets the arterial baroreflex and permits long-lasting sympathoexcitation, termed sympathetic long-term facilitation. Our understanding of sympathetic long-term facilitation following hypoxia in humans is based on multiunit muscle sympathetic nerve activity and does not fully characterize the underlying baroreflex control of sympathetic neuronal subpopulations or their discharge/recruitment strategies. We show that sympathetic long-term facilitation is mediated by baroreflex resetting of sympathetic action potential clusters to higher arterial pressure operating points, a reduction in the percentage of action potentials firing asynchronously, and a shift toward larger amplitude action potential activity. The results advance our fundamental understanding of how the sympathetic nervous system mediates sympathetic long-term facilitation following exposure to acute isocapnic hypoxia in humans.

The coronary vascular response to the metaboreflex at low altitude and during acute and prolonged high altitude in males.

Myocardial oxygen delivery is primarily regulated through changes in vascular tone to match increased metabolic demands. In males, activation of the muscle metaboreflex during acute isocapnic hypoxia results in paradoxical coronary vasoconstriction. Whether coronary blood velocity is reduced by metaboreflex activation following travel and/or adaptation to high altitude is unknown. This study determined if the response of the coronary vasculature to muscle metaboreflex activation at low altitude differs from acute (1/2 days) and prolonged (8/9 days) high altitude. Healthy males (n = 16) were recruited and performed isometric handgrip exercise (30% max) followed by postexercise circulatory occlusion (PECO) to isolate the muscle metaboreflex at low altitude and following acute and prolonged high altitude (3,800 m). Mean left anterior descending coronary artery blood velocity (LADvmean, transthoracic Doppler echocardiography), heart rate, mean arterial pressure (MAP), ventilation, and respired gases were assessed during baseline and PECO at all time points. Coronary vascular conductance index (CVCi) was calculated as LADVmean/MAP. The change in LADvmean (acute altitude: -1.7 ± 3.9 cm/s, low altitude: 2.6 ± 3.4 cm/s, P = 0.01) and CVCi (acute altitude: -0.05 ± 0.04 cm/s/mmHg, low altitude: -0.01 ± 0.03 cm/s/mmHg, P = 0.005) induced by PECO differed significantly between acute high altitude and low altitude. The change in LADVmean and CVCi induced by PECO following prolonged high altitude was not different from low altitude. Our results suggest that coronary vasoconstriction with metaboreflex activation in males is greatest following acute ascent to high-altitude and restored to low-altitude levels following 8-9 days of acclimatization.NEW & NOTEWORTHY Coronary blood flow is regulated by both local metabolic signaling pathways and adrenergic activity in healthy humans. The integrated effects of these systems on coronary vascular physiology are not well understood. Using Doppler echocardiography, this study demonstrates that adrenergic stimulation caused by metaboreflex activation leads to greater reductions in coronary vascular conductance following acute high-altitude but not after prolonged high-altitude exposure.

Sex differences in the coronary vascular response to combined chemoreflex and metaboreflex stimulation in healthy humans.

NEW FINDINGS: What is the central question of this study? Coronary blood flow in healthy humans is controlled by both local metabolic signalling and adrenergic activity: does the integration of these signals during acute hypoxia and adrenergic activation differ between sexes? What are the main findings and its importance? Both males and females exhibit an increase in coronary blood velocity in response to acute hypoxia, a response that is constrained by adrenergic stimulation in males but not females. These findings suggest that coronary blood flow control differs between males and females. ABSTRACT: Coronary hyperaemia is mediated through multiple signalling pathways, including local metabolic messengers and adrenergic stimulation. This study aimed to determine whether the coronary vascular response to adrenergic stressors is different between sexes in normoxia and hypoxia. Young, healthy participants (n = 32; 16F) underwent three randomized trials of isometric handgrip exercise followed by post-exercise circulatory occlusion (PECO) to activate the muscle metaboreflex. End-tidal PO2 was controlled at (1) normoxic levels throughout the trial, (2) 50 mmHg for the duration of the trial (hypoxia trial), or (3) 50 mmHg only during PECO (mixed trial). Mean left anterior descending coronary artery velocity (LADVmean ; transthoracic Doppler echocardiography), heart rate and blood pressure were assessed at baseline and during PECO. In normoxia, there was no change in LADVmean or cardiac workload induced by PECO in males and females. Acute hypoxia increased baseline LADVmean to a greater extent in males compared with females (P < 0.05), despite a similar increase in cardiac workload. The change in LADVmean induced by PECO was similar between sexes in normoxia (P = 0.31), greater in males during the mixed trial (male: 12.8 (7.7) cm/s vs. female: 8.1 (6.3) cm/s; P = 0.02) and reduced in males but not females in acute hypoxia (male: -4.8 (4.5) cm/s vs. female: 0.8 (6.2) cm/s; P = 0.006). In summary, sex differences in the coronary vasodilatory response to hypoxia were observed, and metaboreflex activation during hypoxia caused a paradoxical reduction in coronary blood velocity in males but not females.

An open-source application for the standardized burst identification from the integrated muscle sympathetic neurogram.

Muscle sympathetic nerve activity (MSNA) can be acquired from humans using the technique of microneurography. The resulting integrated neurogram displays pulse-synchronous bursts of sympathetic activity, which undergoes processing for standard MSNA metrics including burst frequency, height, area, incidence, total activity, and latency. The procedure for detecting bursts of MSNA and calculating burst metrics is tedious and differs widely among laboratories worldwide. We sought to develop an open-source, cross-platform web application that provides a standardized approach for burst identification and a tool to increase research reproducibility for those measuring MSNA. We compared the performance of this web application against a manual scoring approach under conditions of rest, chemoreflex activation (n = 9, 20-min isocapnic hypoxia), and metaboreflex activation (n = 13, 2-min isometric handgrip exercise and 4-min postexercise circulatory occlusion). The intraclass correlation coefficient (ICC) indicated good to strong agreement between scoring approaches for burst frequency (ICC = 0.92-0.99), incidence (ICC = 0.94-0.99), height (ICC = 0.76-0.88), total activity (ICC = 0.85-0.99), and latency (ICC = 0.97-0.99). Agreement with burst area was poor to moderate (ICC = 0.04-0.67) but changes in burst area were similar with chemoreflex and metaboreflex activation. Scoring using the web application was highly efficient and provided data visualization tools that expedited data processing and the analysis of MSNA. We recommend the open-source web application be adopted by the community for the analysis of MSNA.NEW & NOTEWORTHY The basic analysis of muscle sympathetic nerve activity (MSNA) requires the identification of pulse-synchronous bursts from the integrated neurogram before standard MSNA metrics can be quantified. This process is a time-consuming task requiring an experienced microneurographer to visually identify and manually label bursts. We developed an open-source, cross-platform application permitting a standardized approach for sympathetic burst identification and present the performance of this application against a manual scorer under basal conditions and during sympathoexcitatory stresses.

Muscle Metaboreflex Control of Sympathetic Activity Is Preserved after Acute Intermittent Hypercapnic Hypoxia.

PURPOSE: In normotensive patients with obstructive sleep apnea (OSA), the muscle sympathetic nerve activity (MSNA) response to exercise is increased while metaboreflex control of MSNA is decreased. We tested the hypotheses that acute intermittent hypercapnic hypoxia (IHH) in males free from OSA and associated comorbidities would augment the MSNA response to exercise but attenuate the change in MSNA during metaboreflex activation. METHODS: Thirteen healthy males (age = 24 ± 4 yr) were exposed to 40 min of IHH. Before and after IHH, the pressor response to exercise was studied during 2 min of isometric handgrip exercise (at 30% maximal voluntary contraction), whereas the metaboreflex was studied during 4 min of postexercise circulatory occlusion (PECO). Mean arterial pressure (MAP), heart rate (HR), and fibular MSNA were recorded continuously. MSNA was quantified as burst frequency (BF) and total activity (TA). Mixed effects linear models were used to compare the exercise pressor and metaboreflex before and after IHH. RESULTS: As expected, IHH led to significant increases in MSNA BF, TA, and MAP at baseline and throughout exercise and PECO. However, during handgrip exercise, the change from baseline in MAP, HR, MSNA BF, and TA was similar before and after IHH (All P > 0.31). During PECO, the change from baseline in MSNA BF and TA was similar after IHH, whereas the change from baseline in MAP (Δ14 mm Hg, 95% CI = 7-19, vs Δ16 mm Hg, 95% CI = 10-21; P < 0.01) was modestly increased. CONCLUSION: After acute IHH, MSNA response to handgrip exercise and metaboreflex activation were preserved in healthy young males despite overall increases in resting MSNA and MAP. Chronic IHH and comorbidities often associated with OSA may be required to modulate the exercise pressor reflex and metaboreflex.

Muscle sympathetic single-unit responses during rhythmic handgrip exercise and isocapnic hypoxia in males: the role of sympathoexcitation magnitude.

A small proportion of postganglionic muscle sympathetic single units can be inhibited during sympathoexcitatory stressors in humans. However, whether these responses are dependent on the specific stressor or the level of sympathoexcitation remains unclear. We hypothesize that, when matched by sympathoexcitatory magnitude, different stressors can evoke similar proportions of inhibited single units. Multiunit and single-unit muscle sympathetic nerve activity (MSNA) were recorded in seven healthy young males at baseline and during 1) rhythmic handgrip exercise (40% of maximum voluntary contraction) and 2) acute isocapnic hypoxia (partial pressure of end-tidal O2 47 ± 3 mmHg). Single units were classified as activated, nonresponsive, or inhibited if the spike frequency was above, within, or below the baseline variability, respectively. By design, rhythmic handgrip and isocapnic hypoxia similarly increased multiunit total MSNA [Δ273 ± 208 vs. Δ254 ± 193 arbitrary units (AU), P = 0.84] and single-unit spike frequency (Δ8 ± 10 vs. Δ12 ± 13 spikes/min, P = 0.12). Among 19 identified single units, the proportions of activated (47% vs. 68%), nonresponsive (32% vs. 16%), and inhibited (21% vs. 16%) single units were not different between rhythmic handgrip and isocapnic hypoxia (P = 0.42). However, only 9 (47%) single units behaved with concordant response patterns across both stressors (7 activated, 1 nonresponsive, and 1 inhibited during both stressors). During the 1-min epoch with the highest increase in total MSNA during hypoxia (Δ595 ± 282 AU, P < 0.01) only one single unit was inhibited. These findings suggest that the proportions of muscle sympathetic single units inhibited during stress are associated with the level of sympathoexcitation and not the stressor per se in healthy young males.NEW & NOTEWORTHY Subpopulations of muscle sympathetic single units can be inhibited during mild sympathoexcitatory stress. We demonstrate that rhythmic handgrip exercise and isocapnic hypoxia, when matched by multiunit sympathoexcitation, induce similar proportions of single-unit inhibition, highlighting that heterogeneous single-unit response patterns are related to the level of sympathoexcitation independent of the stressor type. Interestingly, only 47% of single units behaved with concordant response patterns between stressors, suggesting the potential for functional specificity within the postganglionic neuronal pool.

Acute intermittent hypercapnic hypoxia and cerebral neurovascular coupling in males and females.

The decline in cognition observed in obstructive sleep apnea is linked to intermittent hypercapnic hypoxia (IHH), which is known to impair cerebrovascular reactivity. Whether acute IHH impairs the matching of cerebral blood flow to metabolism (i.e., neurovascular coupling, NVC) is unknown. We hypothesized that acute IHH would reduce cerebral NVC. Healthy participants (N = 17, 8 females, 9 males; age: 22 ± 3 years) had cerebral NVC measured at baseline and following 40-min of IHH at 1-min cycles with 40-s of hypercapnic hypoxia (target PETO2 = 50 mmHg, PETCO2 = +4 mmHg above baseline) and 20-s of normoxia. Cerebral NVC was quantified as the absolute and relative posterior cerebral artery blood velocity (PCAV; transcranial Doppler) and conductance (PCACVC; PCAV/mean arterial pressure [MAP]) response to a visual stimulus paradigm. Following IHH, resting PCAV was unchanged, MAP increased (+4 ± 6 mmHg, P < 0.01) and PCACVC was reduced (-0.05 ± 0.04 cm/s/mmHg, P < 0.01). The peak PCAV response to visual stimuli was unchanged following IHH, but the absolute and relative peak PCACVC response was increased (+0.011 ± 0.019 cm/s/mmHg, P < 0.05 and +4.8 ± 6.1%, P < 0.01, respectively) suggesting an increased cerebral vasodilatory response. No change occurred in the plateau cerebral NVC response following IHH. Changes in resting MAP induced by IHH did not correlate with changes in relative peak PCACVC (r2 = 0.095, P = 0.23). Cerebral NVC did not differ between sexes across all time points and was unchanged following a time-matched air-breathing control. In summary, acute IHH increases peak but not plateau cerebral NVC potentially through IHH mediated neuroplasticity.

Peripheral chemoreflex contribution to ventilatory long-term facilitation induced by acute intermittent hypercapnic hypoxia in males and females.

KEY POINTS: Ventilatory long-term facilitation (vLTF) refers to respiratory neuroplasticity that develops following intermittent hypoxia in both healthy and clinical populations. A sustained hypercapnic background is argued to be required for full vLTF expression in humans. We determined whether acute intermittent hypercapnic hypoxia elicits vLTF during isocapnic-normoxic recovery in healthy males and females. We further assessed whether tonic peripheral chemoreflex drive is necessary and contributes to the expression of vLTF. Following 40 min of intermittent hypercapnic hypoxia, minute ventilation was increased throughout 50 min of isocapnic-normoxic recovery. Inhibition of peripheral chemoreflex drive with hyperoxia attenuated the magnitude of vLTF. Males and females achieve vLTF through different respiratory recruitment patterns. ABSTRACT: Ventilatory long-term facilitation (vLTF) refers to respiratory neuroplasticity that manifests as increased minute ventilation ( V̇I ) following intermittent hypoxia. In humans, hypercapnia sustained throughout intermittent hypoxia and recovery is considered necessary for vLTF expression. We examined whether acute intermittent hypercapnic hypoxia (IHH) induces vLTF, and if peripheral chemoreflex drive contributes to vLTF throughout isocapnic-normoxic recovery. In 19 individuals (9 females, age: 22 ± 3 years; mean ± SD), measurements of tidal volume (VT ), breathing frequency (fB ), V̇I , and end-tidal gases ( PETO2 and PETCO2 ), were made at baseline, during IHH and 50 min of recovery. Totalling 40 min, IHH included 1 min intervals of 40 s hypercapnic hypoxia (target PETO2  = 50 mmHg and PETCO2  = +4 mmHg above baseline) and 20 s normoxia. During baseline and recovery, dynamic end-tidal forcing maintained resting PETO2 and PETCO2 and delivered 1 min of hyperoxia ( PETO2  = 355 ± 7 mmHg) every 5 min. The depression in V̇I during hyperoxia was considered an index of peripheral chemoreflex drive. Throughout recovery V̇I was increased 4.6 ± 3.7 l min-1 from baseline (P < 0.01). Hyperoxia depressed V̇I at baseline, and augmented depression was evident following IHH (Δ V̇I  = -0.8 ± 0.9 vs. -1.7 ± 1.3 l min-1 , respectively, P < 0.01). The vLTF was similar between sexes (P = 0.15), but males had larger increases in VT than females (sex-by-time interaction, P = 0.03), and females tended to increase fB (P = 0.09). During isocapnic-normoxic recovery following IHH: (1) vLTF is expressed in healthy humans; (2) vLTF expression is attenuated but not abolished with peripheral chemoreflex inhibition by hyperoxia, suggesting a contribution from central nervous pathways in vLTF expression; and (3) males and females develop similar vLTF through different ventilatory recruitment strategies.

Case Studies in Physiology: Sympathetic neural discharge patterns in a healthy young male during end-expiratory breath hold-induced sinus pause.

This case study reports the efferent muscle sympathetic nerve activity (MSNA) discharge patterns during a sinus pause observed during a maximal end-expiratory apnea in a young healthy male (age = 26 yr). During a 15.3-s end-expiratory apnea following a bout of intermittent hypercapnic hypoxia, we observed a 5.2-s (R-R interval) sinus pause and integrated MSNA recording, demonstrating a square-wave discharge pattern atypical of sharp MSNA burst peaks entrained to cardiac cycles or during preventricular contractions. This abnormal MSNA discharge pattern was observed again during a follow-up experiment, where an end-expiratory apnea at baseline resulted in pronounced bradycardia (R-R intervals >2.5-s) but failed to reproduce the 5.2-s sinus pause. Action potential (AP) discharge patterns during MSNA bursts were detected using a continuous wavelet transform approach. AP discharge increased by 300% during the end-expiratory apnea with 5.2-s sinus pause compared with baseline and involved increased firing (i.e., rate-coding) of AP clusters (bins of AP with similar morphology) already present during baseline and pronounced recruitment of larger-amplitude AP clusters not present at baseline. Large-amplitude AP clusters continued to discharge during sinus pause. In summary, we show MSNA discharge during sinus pause and pronounced bradycardia during end-expiratory apnea, which demonstrates a square-wave discharge with recruitment of latent larger-amplitude AP clusters. The MSNA discharge was terminated before systole following sinus pause potentially through an inhibitory influence of inspiration, or cardiac mechanoreceptor feedback causing burst termination.NEW & NOTEWORTHY We characterize the occurrence of a square-wave discharge pattern of efferent muscle sympathetic nerve activity during a sinus pause in a young healthy male. This discharge pattern comprised large recruited action potential clusters undetected at baseline that continuously discharged during the sinus pause. Notably, this discharge pattern was still contained within a single cardiac cycle.

Within-breath sympathetic baroreflex sensitivity is modulated by lung volume but unaffected by acute intermittent hypercapnic hypoxia in men.

Muscle sympathetic nerve activity (MSNA) exhibits well-described within-breath respiratory modulation, but the interactive contributions of the arterial baroreflex remain unclear. The present study assessed 1) within-breath modulation of sympathetic baroreflex sensitivity (BRS) and 2) the effect of acute intermittent hypercapnic hypoxia (IHH) on within-breath sympathetic BRS and respiratory-sympathetic entrainment. Seventeen men (24 ± 4 yr) underwent an 8- to 10-min spontaneously breathing baseline while continuous measures of blood pressure (BP), heart rate, MSNA, ventilation, and end-tidal gases were collected. A subset of 12 participants subsequently underwent a 40-min IHH exposure composed of 40 consecutive 1-min breathing cycles: 40 s of hypercapnic hypoxia and 20 s of normoxia. Data were compared between inspiration and expiration and low and high lung volume (calculated from the integral of spirometry-derived flow). Sympathetic BRS was determined by the slope of the weighted linear regression between diastolic BP and MSNA burst incidence. Respiratory-sympathetic entrainment was quantified as percentage of MSNA bursts during each respiratory epoch relative to the total burst count. Sympathetic BRS was similar between inspiration and expiration (-3.9 ± 2.0 vs. -3.6 ± 1.8 bursts·100 heartbeats-1·mmHg-1; P = 0.61) but greater during low versus high lung volumes (-4.6 ± 2.3 vs. -2.1 ± 1.6 bursts·100 heartbeats-1·mmHg-1; P < 0.01). High (r = -0.64; P < 0.01)- but not low (r = -0.24; P = 0.35)-lung volume sympathetic BRS was associated with resting MSNA. IHH increased resting MSNA burst frequency (15 ± 7 vs. 20 ± 7 bursts/min; P < 0.01) and diastolic BP (68 ± 5 vs. 77 ± 9 mmHg; P = 0.02), without altering resting or within-breath sympathetic BRS or respiratory-sympathetic entrainment (all P > 0.05). These findings provide novel insight into the mechanisms controlling within-breath modulation of sympathetic outflow in humans.NEW & NOTEWORTHY In resting spontaneously breathing men, the present study observed that sympathetic baroreflex sensitivity (BRS) was higher during low versus high lung volumes but not different between inspiration and expiration. High- but not low-lung volume BRS was negatively associated with resting muscle sympathetic nerve activity (MSNA). Acute intermittent hypercapnic hypoxia increased resting MSNA and diastolic blood pressure, without altering within-breath BRS. These findings provide novel insight into mechanisms controlling within-breath modulation of MSNA in humans.

Acute intermittent hypercapnic hypoxia and sympathetic neurovascular transduction in men.

KEY POINTS: Intermittent hypoxia leads to long-lasting increases in muscle sympathetic nerve activity and blood pressure, contributing to increased risk for hypertension in obstructive sleep apnoea patients. We determined whether augmented vascular responses to increasing sympathetic vasomotor outflow, termed sympathetic neurovascular transduction (sNVT), accompanied changes in blood pressure following acute intermittent hypercapnic hypoxia in men. Lower body negative pressure was utilized to induce a range of sympathetic vasoconstrictor firing while measuring beat-by-beat blood pressure and forearm vascular conductance. IH reduced vascular shear stress and steepened the relationship between diastolic blood pressure and sympathetic discharge frequency, suggesting greater systemic sNVT. Our results indicate that recurring cycles of acute intermittent hypercapnic hypoxia characteristic of obstructive sleep apnoea could promote hypertension by increasing sNVT. ABSTRACT: Acute intermittent hypercapnic hypoxia (IH) induces long-lasting elevations in sympathetic vasomotor outflow and blood pressure in healthy humans. It is unknown whether IH alters sympathetic neurovascular transduction (sNVT), measured as the relationship between sympathetic vasomotor outflow and either forearm vascular conductance (FVC; regional sNVT) or diastolic blood pressure (systemic sNVT). We tested the hypothesis that IH augments sNVT by exposing healthy males to 40 consecutive 1 min breathing cycles, each comprising 40 s of hypercapnic hypoxia ( PETCO2 : +4 ± 3 mmHg above baseline; PETO2 : 48 ± 3 mmHg) and 20 s of normoxia (n = 9), or a 40 min air-breathing control (n = 7). Before and after the intervention, lower body negative pressure (LBNP; 3 min at -15, -30 and -45 mmHg) was applied to elicit reflex increases in muscle sympathetic nerve activity (MSNA, fibular microneurography) when clamping end-tidal gases at baseline levels. Ventilation, arterial pressure [systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP)], brachial artery blood flow ( Q̇BA ), FVC ( Q̇BA /MAP) and MSNA burst frequency were measured continuously. Following IH, but not control, ventilation [5 L min-1 ; 95% confidence interval (CI) = 1-9] and MAP (5 mmHg; 95% CI = 1-9) were increased, whereas FVC (-0.2 mL min-1  mmHg-1 ; 95% CI = -0.0 to -0.4) and mean shear rate (-21.9 s-1 ; 95% CI = -5.8 to -38.0; all P < 0.05) were reduced. Systemic sNVT was increased following IH (0.25 mmHg burst-1  min-1 ; 95% CI = 0.01-0.49; P < 0.05), whereas changes in regional forearm sNVT were similar between IH and sham. Reductions in vessel wall shear stress and, consequently, nitric oxide production may contribute to heightened systemic sNVT and provide a potential neurovascular mechanism for elevated blood pressure in obstructive sleep apnoea.

Effects of obstructive sleep apnea on hemodynamic parameters in patients entering cardiac rehabilitation.

PURPOSE: Obstructive sleep apnea (OSA) is a prevalent form of sleep-disordered breathing. Evidence suggests that OSA may lead to cardiac remodeling, although the literature is equivocal. Previous literature suggests a high percentage of individuals entering a cardiac rehabilitation (CR) program also have OSA. The objective of this study was to determine whether resting hemodynamic variables were altered in OSA subjects entering CR compared with those without OSA, as determined by impedance cardiography. METHODS: Subjects entering an early outpatient CR program were screened for OSA using an at-home screening device and verified by a sleep physician. Subjects were divided into an OSA group (n = 48) or a control group (n = 25) on the basis of the screening results. Hemodynamic variables were measured during supine rest using impedance cardiography. A 6-minute walk test was performed to assess functional capacity. RESULTS: The proportion of cardiac diagnoses was similar between groups. Overall, 66% of the subjects were positive for OSA. Subject groups did not differ by age, body mass index, heart rate, diastolic blood pressure, or functional capacity. Cardiac output, cardiac index, stroke volume, contractility index, and left cardiac work index were all significantly decreased in the OSA group compared with the control group (P < .05). CONCLUSIONS: Findings suggest that OSA results in decreased cardiac function in patients entering CR, likely because of pressure and volume changes associated with apneic events. This may place those individuals at a disadvantage in recovering from their cardiac event, and place them at increased risk for secondary complications.

Independent and combined effects of carbohydrate and caffeine ingestion on aerobic cycling performance in the fed state.

The purpose of this study was to examine the independent and combined effects of carbohydrate and caffeine ingestion on performance and various physiological parameters during aerobic cycling (∼1 h). Ten male cyclists (28 ± 9 years, 73 ± 6 kg, 66 ± 9 mL·kg(-1)·min(-1) maximal oxygen consumption) performed 20 min of steady-state (SS) cycling (60% peak power (W(max))) followed by a simulated 20-km time trial (TT) under placebo (PLA), carbohydrate (CHO), caffeine (CAF), and combined CAF-CHO conditions, all of which were performed in the fed state. CAF-CHO improved TT performance by 3.4% ± 2% (84 ± 57 s) compared with PLA (p < 0.05), whereas no differences were detected among CHO, CAF, and PLA. The SS respiratory exchange ratio was elevated in CHO (0.92 ± 0.03), CAF (0.96 ± 0.07), and CAF-CHO (0.95 ± 0.02) compared with PLA (0.89 ± 0.03) (p < 0.05). Post-SS and post-TT blood glucose levels were also elevated in CAF-CHO (88.3 ± 16.7 mg·dL(-1) and 111.2 ± 33.5 mg·dL(-1), respectively) compared with PLA (74.5 ± 9.8 mg·dL(-1) and 85.4 ± 17.6 mg·dL(-1), respectively) (p < 0.05). Treatment conditions did not differentially impact SS pulmonary ventilation, oxygen consumption, heart rate, peak quadriceps muscle strength, rating of perceived exertion, or blood lactate. CAF and CHO improved TT performance when taken together but not independently. Although the present work did not yield any definitive physiological mechanisms for the performance findings, these data suggest that cyclists in the fed state should ingest carbohydrate and caffeine together to improve time trial performance.