Central Chemoreflex Sensitivity Research Articles

The ventilatory response to modified rebreathing is unchanged by hyperoxic severity: implications for the hyperoxic hyperventilation paradox.

Normobaric hyperoxia stimulates ventilation (V̇e) in a time- and dose-dependent manner. Whether this occurs via an oxygen (O2)-specific mechanism or secondary to carbon dioxide (CO2) retention at the central chemoreceptors remains unclear. We measured the ventilatory response to hyperoxic CO2 rebreathing with O2 clamped at increasingly higher pressures. We hypothesized that the V̇e versus Pco2 relationship is fixed and independent of Po2. On four occasions, 20 participants (10 F; mean ± SD age: 24 ± 4 yr) performed three repetitions of modified rebreathing in four, randomized, isoxic-hyperoxic conditions: mild: Po2 = 150 mmHg; moderate: Po2 = 200 mmHg; high: Po2 = 300 mmHg; and extreme: Po2 ≈ 700 mmHg. Breath-by-breath V̇e, end-tidal CO2 ([Formula: see text]), and O2 ([Formula: see text]) were measured by pneumotach and gas analyzer. For each rebreathing trial, the [Formula: see text] at which V̇e rose was identified as the ventilatory recruitment threshold (VRT, mmHg), data before VRT provided baseline V̇e (V̇eBSL, L·min-1) and the slope of the response above VRT gave central chemoreflex sensitivity (V̇eS, L·min-1·mmHg-1). For each condition, VRT, V̇eBSL, and V̇eS from like-trials were averaged, and repeated measures ANOVA assessed between-condition differences. There were no effects of [Formula: see text] on V̇eBSL (mild: 7.4 ± 4.2 L·min-1; moderate: 6.9 ± 4.2 L·min-1; high: 6.5 ± 3.7 L·min-1; extreme: 7.5 ± 2.7 L·min-1; P = 0.24), VRT (mild: 42.8 ± 3.2 mmHg; moderate: 42.5 ± 2.7 mmHg; high: 42.3 ± 2.7 mmHg; extreme: 41.8 ± 2.7 mmHg; P = 0.07), or V̇eS (mild: 4.88 ± 2.6 L·min-1·mmHg-1; moderate: 4.76 ± 2.2 L·min-1·mmHg-1; high: 4.81 ± 2.3 L·min-1·mmHg-1; extreme: 4.39 ± 1.9 L·min-1·mmHg-1; P = 0.41). The V̇e-Pco2 relationship is unaltered across a range of mild to extreme Po2. Brief exposure to normobaric hyperoxia may not independently stimulate breathing nor does it alter central chemoreflex sensitivity.NEW & NOTEWORTHY Normobaric hyperoxia stimulates ventilation (V̇e) in a time- and dose-dependent manner. Whether this occurs directly or indirectly through heightened central carbon dioxide pressure (Pco2) or via central chemoreflex sensitization is unclear. Participants who performed modified rebreathing at high oxygen pressures (Po2) of 150, 200, 300, and ≈700 mmHg exhibited no changes to their ventilatory responses to Pco2. Brief exposure to normobaric hyperoxia may not independently stimulate breathing nor does it alter central chemoreflex sensitivity.

Central chemoreflex sensitivity is augmented in treated human hypertension

Hypertension (HTN) is an independent risk factor for cardiovascular disease and stroke, but the underlying pathogenesis is incompletely understood. In animal models heightened central chemoreflex sensitivity is associated with HTN, sympatho-excitation and end-organ damage. Moreover, increased chemosensitivity to hypercapnia and hypoxia (i.e., combined central plus peripheral chemoreflex activation) is associated with poor outcomes in heart failure patients. Herein, we sought to determine whether central, and combined central plus peripheral, chemoreflex sensitivities are augmented in human HTN. Twenty eight volunteers (15 HTN, 13 normotension [NT]) performed two modified rebreathing protocols where the partial pressure of end-tidal carbon dioxide (PETCO2) progressively increased while the partial pressure of end-tidal oxygen (PETO2) was clamped at: 1) 150 mmHg (isoxic hyperoxic rebreathing; central chemoreflex activation) and 2) 50 mmHg (isoxic hypoxic rebreathing; combined central plus peripheral chemoreflex activation). Blood pressure (BP), muscle sympathetic nerve activity (MSNA) and ventilation (V̇E) were recorded. Chemoreflex sensitivity was calculated as MSNA vs. PETCO2slope (sympathetic chemoreflex sensitivity) and V̇E vs. PETCO2slope (ventilatory chemoreflex sensitivity). The sympathetic and ventilatory recruitment thresholds were taken as the PETCO2breakpoint at which MSNA and V̇E started to increase during rebreathing. HTN and NT groups were closely matched for age (68±5 vs. 65±6 years; P=0.100; mean±SD) and sex (women, 7 (47%) vs. 8 (62%); P=0.332). Resting systolic (153±15 vs. 123±17 mmHg; P<0.001) and diastolic (86±9 vs. 77±7 mmHg; P=0.043) BP were higher in HTN, while MSNA (27±5 vs. 25±7 bursts·min-1; P=0.723) and V̇E (13.1±3.8 vs. 12.5±2.5 L·min-1; P=0.872) were not different. Central sympathetic (3.32±1.90 vs. 1.77±0.62 a.u.·mmHg-1; P=0.034) and ventilatory (2.48±1.33 vs. 1.58±0.42 L·min-1·mmHg-1; P=0.030) chemoreflex sensitivities were greater in HTN. In contrast, there were no between-group differences in combined central plus peripheral sympathetic (P=0.831) and ventilatory (P=0.284) chemoreflex sensitivities. Sympathetic and ventilatory recruitment thresholds during central chemoreflex activation, and combined central plus ventilatory chemoreflex activation, did not differ between HTN and NT groups (all P>0.05). In summary, central ventilatory and sympathetic chemoreflex sensitivities are augmented in human HTN. Future studies are now required to reduce central chemoreflex sensitivity and assess whether this provides a novel approach to lower BP in HTN patients. Support was provided by the Auckland Medical Research Foundation (Ref# 1119008. JPF, JFRP, ALCS), the Health Research Council of New Zealand (Ref# 19/687. JPF, JFRP), and the Sidney Taylor Trust (JFRP). This is the full abstract presented at the American Physiology Summit 2023 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.

The Relationship Between Central and Peripheral Chemoreflex Sensitivities and V̇E‐V̇CO2 Slope Below and Above the Respiratory Compensation Point of Incremental Exercise

During incremental exercise, the ventilation (V̇E) versus carbon dioxide production (V̇CO2) relationship exhibits a double‐linear response with an inflection of slope at the transition from hyperpnea to hyperventilation (i.e., respiratory compensation point (RCP)). Whether peripheral or central chemoreflexes contribute to the hyperventilatory response to incremental exercise remains undetermined. This study tested the hypothesis that peripheral and not central chemoreflex sensitivity would relate to the magnitude of the V̇E‐V̇CO2 slope above RCP and that neither would relate to the sub‐RCP V̇E‐V̇CO2 slope. Seven healthy, caffeine‐free males (age: 27±5 years) performed a ramp‐incremental test to exhaustion on a cycle ergometer, during which ventilation and gas exchange were measured by metabolic cart. The V̇E‐V̇CO2 slope above and below RCP were determined by linear regression from the estimated lactate threshold to RCP, and from RCP to end‐exercise, respectively. On four separate days, 12 modified rebreathing tests were performed: six in isoxic‐hyperoxia (PO2=150 mmHg) and six in isoxic‐hypoxia (PO2=50 mmHg). Using ensemble‐average data, central chemoreflex sensitivity was measured as the mean hyperoxic V̇E versus end‐tidal partial pressure of carbon dioxide (PETCO2) slope (in L∙min‐1∙mmHgPETCO2‐1) and the peripheral chemoreflex sensitivity was determined from the difference of hypoxic and hyperoxic slopes. The mean V̇E‐V̇CO2 slopes above and below RCP were 35.0+3.7 (range: 28.3‐39.9) and 61.8+9.2 (range: 51.9‐78.3), respectively. Mean peripheral and central chemoreflex sensitivities were 1.6±1.3 L∙min‐1∙mmHgPETCO2‐1 (range: 0.1‐3.7) and 4.1±2.1 L∙min‐1∙mmHgPETCO2‐1 (range: 2.3‐8.4), respectively. Peripheral chemoreflex sensitivity did not relate to V̇E‐V̇CO2 slope below (r=0.44, p=0.32) or above (r=‐0.02, p=0.96) RCP. No relationships were found between central chemoreflex sensitivity and V̇E‐V̇CO2 slope below (r=0.06, p=0.90) or above (r=0.04, p=0.93) RCP. These preliminary observations suggest that neither central nor peripheral chemoreflex sensitivity factor into the magnitude of the hyperpneic or hyperventilatory response to incremental exercise.

A Strategy to Enhance Confidence in Respiratory Chemoreflex Characterization by Modified Rebreathing

Modelling breath‐by‐breath ventilation (V̇E) in response to carbon dioxide rebreathing in hyperoxic and hypoxic conditions (modified rebreathing) is used to characterize the central and peripheral respiratory chemoreflexes in humans. However, breath‐to‐breath variability produces uncertainty in the estimation of model parameters. We explored whether signal‐averaging of repeated rebreathing trials would improve chemoreflex sensitivity parameter estimation and confidence. Seven healthy males (age: 27±5 years) performed 6 repetitions of modified rebreathing tests in isoxic‐hypoxic (end‐tidal PO2 (PETO2)=50 mmHg) and ‐hyperoxic conditions (PETO2=150 mmHg) over the course of 4 days. End‐tidal PCO2 (PETCO2), PETO2 and V̇E were measured breath‐by‐breath by dual gas analyser and pneumotach. The slope of the V̇E vs PETCO2 relationship above the PETCO2 threshold in the hyperoxic test gave the central chemoreflex sensitivity (L∙min‐1∙mmHg‐1) and the difference in hypoxic versus hyperoxic test slopes provided peripheral chemoreflex sensitivity. Chemoreflex slopes modelled from a single trial versus ensemble‐average of 6 trials were compared by paired t‐test and effect size (Cohen’s d). Breath‐by‐breath data from the 6 trials were aligned to the same starting PETCO2, linearly interpolated to 0.1 mmHg of PETCO2, ensemble‐averaged, and averaged into 0.2 mmHg bins. Central chemoreflex sensitivity did not differ (p=0.94) between single (4.10±2.98 L∙min‐1∙mmHg‐1, 95%CI: 3.82–4.39) versus ensemble‐averaged data (4.13±2.14 L∙min‐1∙mmHg‐1, 95%CI: 3.99–4.27) but the 95%CI was reduced (p=0.031) by 0.29 L∙min‐1∙mmHg‐1 (effect size=1.5) with the ensemble‐averaged approach. Similarly, peripheral chemoreflex sensitivity did not differ (p=0.83) between single (1.69±1.14 L∙min‐1∙mmHg‐1, 95%CI: 1.54–1.84) versus ensemble‐averaged data (1.58±1.32 L∙min‐1∙mmHg‐1, 95%CI: 1.5 –1.66); 95%CI of the ensemble‐averaged data was 0.15 L∙min‐1∙mmHg‐1 lower than a single trial but this was not different (p=0.38; effect size=0.5). Signal averaging of multiple modified rebreathing trials reduces the confidence interval of respiratory chemoreflex sensitivity. This strategy could enhance the ability to detect differences in respiratory chemoreflex control in comparative or interventional studies where modified rebreathing is used.

Elevated exercise ventilation in mild COPD is not linked to enhanced central chemosensitivity

BackgroundThe purpose of this study was to determine if altered central chemoreceptor characteristics contributed to the elevated ventilation relative to carbon dioxide production (V̇E/V̇CO2) response during exercise in mild chronic obstructive pulmonary disease (COPD). MethodsTwenty-nine mild COPD and 19 healthy age-matched control participants undertook lung function testing followed by symptom-limited incremental cardiopulmonary exercise testing . On a separate day, basal (non-chemoreflex) ventilation (V̇EB), the central chemoreflex ventilatory recruitment threshold for CO2 (VRTCO2), and central chemoreflex sensitivity (V̇ES) were assessed using the modified Duffin’s CO2 rebreathing method. Resting arterialized blood gas data were also obtained. ResultsAt standardized exercise intensities, absolute V̇E and V̇E/V̇CO2 were consistently elevated and the end-tidal partial pressure of CO2 was relatively decreased in mild COPD versus controls (all p < 0.05). There were no between-group differences in resting arterialized blood gas parameters, basal V̇E, VRTCO2, or V̇ES (all p > 0.05). ConclusionThese data have established that excessive exercise ventilation in mild COPD is not explained by altered central chemosensitivity.

Heart to breathe: partial ablation of rostral ventrolateral medulla catecholaminergic neurons mediates disordered breathing in volume overload heart failure rats

Heart to breathe: partial ablation of rostral ventrolateral medulla catecholaminergic neurons mediates disordered breathing in volume overload heart failure rats

Cardiac diastolic and autonomic dysfunction are aggravated by central chemoreflex activation in heart failure with preserved ejection fraction rats.

Heart failure with preserved ejection fraction (HFpEF) is associated with disordered breathing patterns, and sympatho-vagal imbalance. Although it is well accepted that altered peripheral chemoreflex control plays a role in the progression of heart failure with reduced ejection fraction (HFrEF), the pathophysiological mechanisms underlying deterioration of cardiac function in HFpEF are poorly understood. We found that central chemoreflex is enhanced in HFpEF and neuronal activation is increased in pre-sympathetic regions of the brainstem. Our data showed that activation of the central chemoreflex pathway in HFpEF exacerbates diastolic dysfunction, worsens sympatho-vagal imbalance and markedly increases the incidence of cardiac arrhythmias in rats with HFpEF. Heart failure (HF) patients with preserved ejection fraction (HFpEF) display irregular breathing, sympatho-vagal imbalance, arrhythmias and diastolic dysfunction. It has been shown that tonic activation of the central and peripheral chemoreflex pathway plays a pivotal role in the pathophysiology of HF with reduced ejection fraction. In contrast, no studies to date have addressed chemoreflex function or its effect on cardiac function in HFpEF. Therefore, we tested whether peripheral and central chemoreflexes are hyperactive in HFpEF and if chemoreflex activation exacerbates cardiac dysfunction and autonomic imbalance. Sprague-Dawley rats (n=32) were subjected to sham or volume overload to induce HFpEF. Resting breathing variability, chemoreflex gain, cardiac function and sympatho-vagal balance, and arrhythmia incidence were studied. HFpEF rats displayed [mean±SD; chronic heart failure (CHF) vs. Sham, respectively] a marked increase in the incidence of apnoeas/hypopnoeas (20.2±4.0 vs. 9.7±2.6eventsh-1 ), autonomic imbalance [0.6±0.2 vs. 0.2±0.1 low/high frequency heart rate variability (LF/HFHRV )] and cardiac arrhythmias (196.0±239.9 vs. 19.8±21.7eventsh-1 ). Furthermore, HFpEF rats showed increase central chemoreflex sensitivity but not peripheral chemosensitivity. Accordingly, hypercapnic stimulation in HFpEF rats exacerbated increases in sympathetic outflow to the heart (229.6±43.2% vs. 296.0±43.9% LF/HFHRV , normoxia vs. hypercapnia, respectively), incidence of cardiac arrhythmias (196.0±239.9 vs. 576.7±472.9eventsh-1 ) and diastolic dysfunction (0.008±0.004 vs. 0.027±0.027mmHgμl-1 ). Importantly, the cardiovascular consequences of central chemoreflex activation were related to sympathoexcitation since these effects were abolished by propranolol. The present results show that the central chemoreflex is enhanced in HFpEF and that acute activation of central chemoreceptors leads to increases of cardiac sympathetic outflow, cardiac arrhythmogenesis and impairment in cardiac function in rats with HFpEF.

Prediction of the Chemoreflex Gain by Common Clinical Variables in Heart Failure.

BackgroundPeripheral and central chemoreflex sensitivity, assessed by the hypoxic or hypercapnic ventilatory response (HVR and HCVR, respectively), is enhanced in heart failure (HF) patients, is involved in the pathophysiology of the disease, and is under investigation as a potential therapeutic target. Chemoreflex sensitivity assessment is however demanding and, therefore, not easily applicable in the clinical setting. We aimed at evaluating whether common clinical variables, broadly obtained by routine clinical and instrumental evaluation, could predict increased HVR and HCVR.Methods and results191 patients with systolic HF (left ventricular ejection fraction—LVEF—<50%) underwent chemoreflex assessment by rebreathing technique to assess HVR and HCVR. All patients underwent clinical and neurohormonal evaluation, comprising: echocardiogram, cardiopulmonary exercise test (CPET), daytime cardiorespiratory monitoring for breathing pattern evaluation. Regarding HVR, multivariate penalized logistic regression, Bayesian Model Averaging (BMA) logistic regression and random forest analysis identified, as predictors, the presence of periodic breathing and increased slope of the relation between ventilation and carbon dioxide production (VE/VCO2) during exercise. Again, the above-mentioned statistical tools identified as HCVR predictors plasma levels of N-terminal fragment of proBNP and VE/VCO2 slope.ConclusionsIn HF patients, the simple assessment of breathing pattern, alongside with ventilatory efficiency during exercise and natriuretic peptides levels identifies a subset of patients presenting with increased chemoreflex sensitivity to either hypoxia or hypercapnia.

Age-related reflex responses from peripheral and central chemoreceptors in healthy men.

ObjectiveThe study aimed: (i) to characterize reflex responses from peripheral and central chemoreceptors in different age groups of healthy men (<50 years old vs ≥50 years old) and, (ii) to assess, within these groups, whether there is any relationship between ventilatory and hemodynamic responses from chemoreceptors and indices of autonomic nervous system (ANS).MethodsPeripheral chemoreflex sensitivity was assessed by the transient hypoxia method and respiratory, heart rate (HR) and blood pressure responses were calculated. Central chemoreflex sensitivity was assessed by the rebreathing method and respiratory response was calculated. ANS was assessed using heart rate variability indices and baroreflex sensitivity (BRS).ResultsSixty-seven healthy men were divided into 2 groups: <50 years (n = 38, mean age: 32 ± 10 years) and ≥50 years (n = 29, mean age: 61 ± 8 years). There were no differences in respiratory response from central and peripheral chemoreceptors between the older and younger groups of healthy males. We found a significantly different pattern of hemodynamic responses from peripheral chemoreceptors between the older and the younger groups. The former expressed attenuated HR acceleration and exaggerated blood pressure increase in response to transient hypoxia. Blunted HR response was related to reduced BRS and sympathovagal imbalance characterized by reduced vagal tone. Blood pressure responses seemed to be independent of sympathovagal balance and BRS.InterpretationAgeing impacts hemodynamic rather than respiratory response from chemoreceptors. Impaired arterial baroreflex and sympathovagal imbalance related to ageing may contribute to decreased heart rate response, but not to increased blood pressure response from peripheral chemoreceptors.

Chiari 1 Malformation Presenting as Central Sleep Apnea during Pregnancy: A Case Report, Treatment Considerations, and Review of the Literature.

Purpose: Chiari malformation (CM) type-1 frequently causes obstructive or central sleep-disordered breathing (SDB) in both adults and children, although SDB is relatively rare as a presenting manifestation in the absence of other neurological symptoms. The definitive treatment of symptomatic CM is surgical decompression. We report a case that is, to our knowledge, a novel manifestation of central sleep apnea (CSA) due to CM type-1 with severe exacerbation and initial clinical presentation during pregnancy.Methods: Case report from tertiary care comprehensive sleep medicine center with literature review of SDB manifestations associated with CM type-1. PubMed search was conducted between January 1982 and October 2013.Results: We report a 25-year-old woman with severe CSA initially presenting during her first pregnancy that eventually proved to be caused by CM type-1. The patient was successfully treated preoperatively by adaptive servoventilation (ASV), with effective resolution of SDB following surgical decompression, and without recurrence in a subsequent pregnancy. Our literature review found that 58% of CM patients with SDB had OSA alone, 28% had CSA alone, 8 (10%) had mixed OSA/CSA, and 6 (8%) had hypoventilation. Of CM patients presenting with SDB, 50% had OSA, 42% had CSA, 8% had mixed OSA/CSA, and 10.4% had hypoventilation. We speculate that CSA may develop in CM patients in whom brainstem compression results in excessive central chemoreflex sensitivity with consequent hypocapnic CSA.Conclusion: Chiari malformation type-1 may present with a diversity of SDB manifestations, and timely recognition and surgical referral are necessary to prevent further neurological deficits. ASV therapy can effectively manage CSA caused by CM type-1, which may initially present during pregnancy.

Effect of chronic ethanol exposure on rat ventilatory responses to hypoxia and hypercapnia

OBJECTIVE:The effect of chronic ethanol exposure on chemoreflexes has not been extensively studied in experimental animals. Therefore, this study tested the hypothesis that known ethanol-induced autonomic, neuroendocrine and cardiovascular changes coincide with increased chemoreflex sensitivity, as indicated by increased ventilatory responses to hypoxia and hypercapnia.METHODS:Male Wistar rats were subjected to increasing ethanol concentrations in their drinking water (first week: 5% v/v, second week: 10% v/v, third and fourth weeks: 20% v/v). At the end of each week of ethanol exposure, ventilatory parameters were measured under basal conditions and in response to hypoxia (evaluation of peripheral chemoreflex sensitivity) and hypercapnia (evaluation of central chemoreflex sensitivity).RESULTS:Decreased respiratory frequency was observed in rats exposed to ethanol from the first until the fourth week, whereas minute ventilation remained unchanged. Moreover, we observed an increased tidal volume in the second through the fourth week of exposure. The minute ventilation responses to hypoxia were attenuated in the first through the third week but remained unchanged during the last week. The respiratory frequency responses to hypoxia in ethanol-exposed rats were attenuated in the second through the third week but remained unchanged in the first and fourth weeks. There was no significant change in tidal volume responses to hypoxia. With regard to hypercapnic responses, no significant changes in ventilatory parameters were observed.CONCLUSIONS:Our data are consistent with the notion that chronic ethanol exposure does not increase peripheral or central chemoreflex sensitivity.

Parasympathetic activation by pyridostigmine on chemoreflex sensitivity in heart-failure rats

We evaluated the effects of parasympathetic activation by pyridostigmine (PYR) on chemoreflex sensitivity in a rat model of heart failure (HF rats). HF rats demonstrated higher pulmonary ventilation (PV), which was not affected by PYR. When HF and control rats treated or untreated with PYR were exposed to 15% O2, all groups exhibited prompt increases in respiratory frequency (RF), tidal volume (TV) and PV. When HF rats were exposed to 10% O2 they showed greater PV response which was prevented by PYR. The hypercapnia triggered by either 5% CO2 or 10% CO2 promoted greater RF and PV responses in HF rats. PYR blunted the RF response in HF rats but did not affect the PV response. In conclusion, PYR prevented increased peripheral chemoreflex sensitivity, partially blunted central chemoreflex sensitivity and did not affect basal PV in HF rats.

Obstructive sleep apnea is associated with increased chemoreflex sensitivity in patients with metabolic syndrome.

Obstructive sleep apnea (OSA) is often observed in patients with metabolic syndrome (MetS). In addition, the association of MetS and OSA substantially increases sympathetic nerve activity. However, the mechanisms involved in sympathetic hyperactivation in patients with MetS + OSA remain to be clarified. We tested the hypothesis that chemoreflex sensitivity is heightened in patients with MetS and OSA. Prospective clinical study. Forty-six patients in whom MetS was newly diagnosed (ATP-III) were allocated into: (1) MetS + OSA (n = 24, 48 ± 1.8 yr); and (2) MetS - OSA (n = 22, 44 ± 1.7 yr). Eleven normal control subjects were also studied (C, 47 ± 2.3 yr). OSA was defined as an apnea-hypopnea index ≥ 15 events/hr (polysomnography). Muscle sympathetic nerve activity (MSNA) was measured by microneurography technique. Peripheral chemoreflex sensitivity was assessed by inhalation of 10% oxygen and 90% nitrogen (carbon dioxide titrated), and central chemoreflex sensitivity by 7% carbon dioxide and 93% oxygen. Physical characteristics and MetS measures were similar between MetS + OSA and MetS - OSA. MSNA was higher in MetS + OSA patients compared with MetS - OSA and C (33 ± 1.3 versus 28 ± 1.2 and 18 ± 2.2 bursts/min, P < 0.05). Isocapnic hypoxia caused a greater increase in MSNA in MetS + OSA than MetS - OSA and C (P = 0.03). MSNA in response to hyperoxic hypercapnia was greater in MetS + OSA compared with C (P = 0.005). Further analysis showed a significant association between baseline MSNA and peripheral (P < 0.01) and central (P < 0.01) chemoreflex sensitivity. Min ventilation in response to hyperoxic hypercapnia was greater in MetS + OSA compared with C (P = 0.001). OSA increases sympathetic peripheral and central chemoreflex response in patients with MetS, which seems to explain, at least in part, the increase in sympathetic nerve activity in these patients. In addition, OSA increases ventilatory central chemoreflex response in patients with MetS.

A computerized integrated system for the assessment of central and peripheral chemoreflex sensitivity

The assessment of chemoreflex sensitivity (CRS) is of major importance in studies investigating the adaptation of ventilation to the needs of human body. Increased sensitivity of chemoreceptors to both hypoxia and hypercapnia has recently been shown to be a powerful and independent prognosticator in heart failure (HF) patients, thus highlighting the importance of the assessment of CRS also in the clinical setting. In spite of this, the measurement of CRS is currently limited to the research setting. One possible reason might be the lack of suitable commercial equipments.On the basis of these considerations, we designed a system to carry out a comprehensive assessment of CRS, including both central and peripheral chemoreceptors. The system is based on the integration of different commercial devices and is entirely managed by a custom software written in Matlab language. The main features of our system are: (1) the implementation of standard methods (the Read's rebreathing test, the CO2 single breath test and the transient hypoxia test) suitable for both pathological and healthy subjects, (2) data quality assurance and reduction of subjective judgment in the analysis through advanced analysis procedures and statistical outliers rejection, and (3) full interactive control of every step of the recording and analysis procedures.The system is currently used in our Institution in the assessment of CRS in HF patients, chronic obstructive pulmonary disease patients and healthy subjects. It has proven to be very effective and easy to use even by clinical personnel without a specific background in respiratory function assessment.

Redox regulation of neurovascular function by acetazolamide: complementary insight into mechanisms underlying high‐altitude acclimatisation

We read with interest the study by Fan and colleagues describing how the carbonic anhydrase (CA) inhibitor acetazolamide reduced periodic breathing and accelerated acclimatisation to high altitude in native lowlanders (Fan et al. 2012). Intravenous infusion was shown to increase resting cerebral blood flow (CBF) and cerebrovascular reactivity to carbon dioxide () independently of altered peripheral or central chemoreflex sensitivity. The authors concluded that the improvement in breathing stability was attributable to an increase in the ‘CO2 reserve’. We would like to extend their elegant findings by suggesting a complementary mechanism albeit secondary to classical CA inhibition that may have equally contributed to the neurovascular benefits as observed.

Baroreceptor unloading in postural tachycardia syndrome augments peripheral chemoreceptor sensitivity and decreases central chemoreceptor sensitivity

While orthostatic tachycardia is the hallmark of postural tachycardia syndrome (POTS), orthostasis also initiates increased minute ventilation (Ve) and decreased end-tidal CO(2) in many patients. We hypothesized that chemoreflex sensitivity would be increased in patients with POTS. We therefore measured chemoreceptor sensitivity in 20 POTS (16 women and 4 men) and 14 healthy controls (10 women and 4 men), 16-35 yr old by exposing them to eucapneic hyperoxia (30% O(2)), eucapneic hypoxia (10% O(2)), and hypercapnic hyperoxia (30% O(2) + 5% CO(2)) while supine and during 70° head-upright tilt. Heart rate, mean arterial pressure, O(2) saturation, end-tidal CO(2), and Ve were measured. Peripheral chemoreflex sensitivity was calculated as the difference in Ve during hypoxia compared with room air divided by the change in O(2) saturation. Central chemoreflex sensitivity was determined by the difference in Ve during hypercapnia divided by the change in CO(2). POTS subjects had an increased peripheral chemoreflex sensitivity (in l·min(-1)·%oxygen(-1)) in response to hypoxia (0.42 ± 0.38 vs. 0.19 ± 0.17) but a decreased central chemoreflex sensitivity (l·min(-1)·Torr(-1)) CO(2) response (0.49 ± 0.38 vs. 1.04 ± 0.18) compared with controls. CO(2) sensitivity was also reduced in POTS subjects when supine. POTS patients are markedly sensitized to hypoxia when upright but desensitized to CO(2) while upright or supine. The interactions between orthostatic baroreflex unloading and altered chemoreflex sensitivities may explain the hyperventilation in POTS patients.

Baroreflex unloading blunts chemoreceptor sensitivity in Postural Tachycardia Syndrome (POTS)

POTS have increased minute ventilation (VE) and decreased end tidal carbon dioxide (ETCO2) compared to healthy subjects. Chemoreceptor sensitivity was measured in 18 POTS (14F, 4M), 10 healthy controls (6F, 4M) 16–35 years old by exposing them to eucapneic hyperoxia‐30%oxygen, eucapneic hypoxia (10%oxygen) and hypercapnia 30%oxygen+5%carbon dioxide) in supine and HUT70 position. We measured heart Rate (HR), mean arterial pressure (MAP) oxygen saturation, ETCO2, mean cerebral blood flow velocity (mCFV) and VE. Chemoreflex sensitivity was ascertained by comparing slopes determined from eucapneic hypoxia‐hyperoxia to measure peripheral chemoreflex sensitivity, and hyperoxic hypercapnia –eucapnia to measure central chemoreflex sensitivity. POTS had significantly higher resting HR, lower MAP, stroke volume (SV) and mCFV as compared to controls (p&lt;0.05). Hypoxia and hypercapnia increased the HR, MAP, CO, mCFV and VE (p&lt;0.05). POTS had increases in VE during supine hypoxia (POTS vs. controls, 3.6± 0.9 vs. 1.6± 0.2, p=0.003) which reversed in HUT70 (1.96± 0.3 vs. 5.4± 1.2). In both POTS and controls, hypercapnia resulted in similar increases in VE when supine but no further increases when HUT70. POTS have higher peripheral chemoreflex sensitivity than controls which attenuates during unloading of baroreflexes.

The increased ventilatory response to exercise in pregnancy reflects alterations in the respiratory control systems ventilatory recruitment threshold for CO2

We tested the hypothesis that the magnitude of the pregnancy-induced increase in exercise hyperpnea is predictable based on the level at which Pa CO2 is regulated at rest. We performed a detailed retrospective analysis of previous data from 25 healthy young women who performed exercise and rebreathing tests in the third trimester (TM(3); 36.5+/-0.2 weeks gestation; mean+/-SEM) and again 20.4+/-1.7 weeks post-partum (PP). At rest, arterialized venous blood was obtained for the estimation of Pa CO2, [H(+)] and [HCO(3)(-)]; and serum progesterone ([P(4)]) and 17beta-estradiol ([E(2)]) concentrations. Duffin's modified hyperoxic rebreathing procedure was used to evaluate changes in central ventilatory chemoreflex control characteristics at rest. Breath-by-breath ventilatory and gas exchange variables were measured at rest and during symptom-limited incremental cycle exercise tests. At rest in TM(3) compared with PP: Pa CO2, [H(+)], [HCO(3)(-)] and the central chemoreflex ventilatory recruitment threshold for Pa CO2 (VRT CO2) decreased, while ventilation (V E), [P(4)], [E(2)] and central chemoreflex sensitivity (V ES) increased (all p<or=0.001). The slope of the linear relation between V E and V CO2 during exercise was significantly higher in TM(3) vs. PP (31.2+/-0.6 vs. 27.5+/-0.5, p<0.001). The magnitude of this change in the VE-V CO2 slope correlated significantly with concurrent reductions in each of the VRT CO2 (R(2)=0.619, p<0.001), Pa CO2 (R(2)=0.203, p=0.024) and [HCO(3)(-)] (R(2)=0.189, p=0.030); and was independent (p>0.05) of changes in [P(4)], [E(2)] and V ES. In conclusion, the increased ventilatory response to exercise in pregnancy can be explained, in large part, by reductions in the respiratory control system's resting Pa CO2 equilibrium point as manifest primarily by reductions in the VRT CO2.

Amplified respiratory–sympathetic coupling in the spontaneously hypertensive rat: does it contribute to hypertension?

Sympathetic nerve activity (SNA) is elevated in established hypertension. We tested the hypothesis that SNA is elevated in neonate and juvenile spontaneously hypertensive (SH) rats prior to the development of hypertension, and that this may be due to augmented respiratory-sympathetic coupling. Using the working heart-brainstem preparation, perfusion pressure, phrenic nerve activity and thoracic (T8) SNA were recorded in male SH rats and normotensive Wistar-Kyoto (WKY) rats at three ages: neonates (postnatal day 9-16), 3 weeks old and 5 weeks old. Perfusion pressure was higher in SH rats at all ages reflecting higher vascular resistance. The amplitude of respiratory-related bursts of SNA was greater in SH rats at all ages (P < 0.05). This was reflected in larger Traube-Hering pressure waves in SH rats (1.4 +/- 0.8 versus 9.8 +/- 1.5 mmHg WKY versus SH rat, 5 weeks old, n = 5 per group, P < 0.01). Recovery from hypocapnic-induced apnoea and reinstatement of Traube-Hering waves produced a significantly greater increase in perfusion pressure in SH rats (P < 0.05). Differences in respiratory-sympathetic coupling in the SH rat were not secondary to changes in central or peripheral chemoreflex sensitivity, nor were they related to altered arterial baroreflex function. We have shown that increased SNA is already present in SH rats in early postnatal life as revealed by augmented respiratory modulation of SNA. This is reflected in an increased magnitude of Traube-Hering waves resulting in elevated perfusion pressure in the SH rat. We suggest that the amplified respiratory-related bursts of SNA seen in the neonate and juvenile SH rat may be causal in the development of their hypertension.

Effect of menopause on the chemical control of breathing and its relationship with acid-base status

This study examined the role of alterations in the chemoreflex control of breathing, acid-base balance, and their interaction in postmenopausal ventilatory adaptations. A modified iso-oxic hyperoxic and hypoxic CO(2)-rebreathing procedure was employed to evaluate central and peripheral chemoreflex drives to breathe, respectively, in 15 healthy postmenopausal and 20 premenopausal women of similar age. Arterialized venous blood samples were collected at rest for the estimation of arterial Pco(2) (Pa(CO(2))) and H(+) concentration ([H(+)]), plasma strong ion difference ([SID]) and total weak acid ([A](tot)) concentrations, and serum progesterone ([P(4)]) and 17beta-estradiol ([E(2)]) concentrations. In post- compared with premenopausal women, Pa(CO(2)), [SID], and the central chemoreflex ventilatory recruitment threshold for Pco(2) (VRTco(2)) were higher, whereas [P(4)] and [E(2)] were lower (all P < 0.05), with no significant change in central or peripheral chemoreflex sensitivity, peripheral chemoreflex VRTco(2), and [A](tot). The acidifying effect of an increased Pa(CO(2)) was offset by the alkalizing effect of an increased [SID], such that [H(+)] was preserved in post- compared with premenopausal women. Pa(CO(2)) correlated positively with the central chemoreflex VRTco(2) (r = 0.67, P < 0.01), which in turn correlated positively with [SID] (r = 0.53, P < 0.01) within the pooled data. In conclusion, the relative alveolar hypoventilation and attendant arterial hypercapnia in healthy post- compared with premenopausal women could be explained, in part, by the interaction of 1) reduced central, but not peripheral, chemoreflex VRTco(2), 2) increased [SID], and 3) reduced circulating female sex steroid hormone concentrations.