Chemoreflex Sensitivity Research Articles

The effect of acute oral pyridoxine supplementation on peripheral chemoreflex sensitivity in human hypertension

ATP has been identified as an important signalling molecule in the carotid body. Animal models of hypertension have uncovered that ATP transmission via purinergic (P2) receptors increases carotid body tonicity and sensitivity, which drives sympathetic outflow and elevates blood pressure. A naturally occurring metabolite of pyridoxine (Vitamin B6), namely pyridoxal-5-phosphate, is a non-selective P2X receptor antagonist. In this study we tested the hypothesis that oral administration of pyridoxine reduces peripheral chemoreflex sensitivity and blood pressure in human hypertension. 14 treated hypertensive patients (4 men, 71±5 yr, 27±6 kg·m -2 , 156±19/83±8 mmHg) completed a double-blind placebo-controlled crossover study with either oral pyridoxine (600 mg) or placebo. Two-hours later, minute ventilation (V̇ E ), end-tidal partial pressures of oxygen and carbon dioxide (P ET O 2 and P ET CO 2 ), mean arterial pressure (MAP), and heart rate (HR) were recorded during an isocapnic hypoxic rebreathing protocol (target P ET O 2 45mmHg). Cardiorespiratory responses were taken as the change from baseline to peak rebreathing (final 15s). Arterial oxygen saturation (S a O 2 ) was calculated from P ET O 2 using the Severinghaus equation, and peripheral chemoreflex sensitivity taken as ΔV̇ E divided by ΔS a O 2 . Baseline V̇ E (13.02±3.26 vs. 12.68±4.13 L·min -1 , P=0.616), MAP (109±11 vs. 104±10 mmHg, P=0.058), and HR (63±11 vs. 62±8 BPM, P=0.463), were not different between pyridoxine and placebo conditions, respectively. The ΔV̇ E response to isocapnic hypoxia tended to be blunted with pyridoxine compared to placebo (6.88±3.94 vs. 9.87±7.69 L·min -1 ; P=0.188), but this did not reach statistical significance. Similarly, peripheral chemoreflex sensitivity was not different with pyridoxine compared to placebo (-0.46±0.31 vs. -0.64±0.49 L·min -1 ·% -1 , P=0.148). However, individuals with a higher peripheral chemoreflex sensitivity in the placebo condition, displayed a more marked reduction in peripheral chemoreflex sensitivity following pyridoxine (R 2 =0.63, P=0.005). While HR and MAP increased during isocapnic hypoxia (both P<0.001), the magnitude of this response did not differ with pyridoxine or placebo administration. In this preliminary study, oral pyridoxine lowered neither blood pressure nor peripheral chemoreflex sensitivity in human hypertension. However, oral pyridoxine did lower peripheral chemoreflex sensitivity in those hypertension patients in whom baseline peripheral chemoreflex sensitivity (i.e., placebo condition) was highest. It is possible that oral pyridoxine supplementation may be beneficial for those hypertensive patients who exhibit overactivation of their peripheral chemoreflex. Health Research Council of New Zealand (Ref# 19/687), the University of Auckland Faculty Research Development Fund, and the New Zealand Lottery Grants Board (R-LHR-2021-153114). 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.

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.

Central and peripheral chemoreflexes in humans with treated hypertension.

Increased peripheral chemoreflex sensitivity is a pathogenic feature of human hypertension (HTN), while both central and peripheral chemoreflex sensitivities are reportedly augmented in animal models of HTN. Herein, we tested the hypothesis that both central and combined central and peripheral chemoreflex sensitivities are augmented in HTN. Fifteen HTN participants (68±5years; mean±SD) and 13 normotensives (NT; 65±6years) performed two modified rebreathing protocols in which the partial pressure of end-tidal carbon dioxide ( ) progressively increased while the partial pressure of end-tidal oxygen was clamped at either 150mmHg (isoxic hyperoxia; central chemoreflex activation) or 50mmHg (isoxic hypoxia; combined central and peripheral chemoreflex activation). Ventilation ( ; pneumotachometer) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded, and ventilatory ( vs. slope) and sympathetic (MSNA vs. slope) chemoreflex sensitivities and recruitment thresholds (breakpoint) were calculated. Global cerebral blood flow (gCBF; duplex Doppler) was measured, and the association with chemoreflex responses was examined. Central ventilatory and sympathetic chemoreflex sensitivities were greater in HTN than NT (2.48±1.33 vs. 1.58±0.42Lmin-1 mmHg-1 , P=0.030: 3.32±1.90 vs. 1.77±0.62a.u.mmHg-1 , P=0.034, respectively), while recruitment thresholds were not different between groups. HTN and NT had similar combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities and recruitment thresholds. A lower gCBF was associated with an earlier recruitment threshold for (R2 =0.666, P<0.0001) and MSNA (R2 =0.698, P=0.004) during isoxic hyperoxic rebreathing. These findings indicate that central ventilatory and sympathetic chemoreflex sensitivities are augmented in human HTN and perhaps suggest that targeting the central chemoreflex may help some forms of HTN. KEY POINTS: In human hypertension (HTN) increased peripheral chemoreflex sensitivity has been identified as a pathogenic feature, and in animal models of HTN, both central and peripheral chemoreflex sensitivities are reportedly augmented. In this study, the hypothesis was tested that both central and combined central and peripheral chemoreflex sensitivities are augmented in human HTN. We observed that both central ventilatory and sympathetic chemoreflex sensitivities were augmented in HTN compared to age-matched normotensive controls, but no difference was found in the combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities. During central chemoreflex activation, the ventilatory and sympathetic recruitment thresholds were lower in those with lower total cerebral blood flow. These results indicate a potential contributory role of the central chemoreceptors in the pathogenesis of human HTN and support the possibility that therapeutic targeting of the central chemoreflex may help some forms of HTN.

The superior cervical ganglion is involved in chronic chemoreflex sensitization during recovery from acute lung injury.

Introduction: Acute lung injury (ALI) initiates an inflammatory cascade that impairs gas exchange, induces hypoxemia, and causes an increase in respiratory rate (fR). This stimulates the carotid body (CB) chemoreflex, a fundamental protective reflex that maintains oxygen homeostasis. Our previous study indicated that the chemoreflex is sensitized during the recovery from ALI. The superior cervical ganglion (SCG) is known to innervate the CB, and its electrical stimulation has been shown to significantly sensitize the chemoreflex in hypertensive and normotensive rats. We hypothesized that the SCG is involved in the chemoreflex sensitization post-ALI. Methods: We performed a bilateral SCG ganglionectomy (SCGx) or sham-SCGx (Sx) in male Sprague Dawley rats 2weeks before inducing ALI (Week -2 i.e., W-2). ALI was induced using a single intra-tracheal instillation of bleomycin (bleo) (day 1). Resting-fR, Vt (Tidal Volume), and V̇ E (Minute Ventilation) were measured. The chemoreflex response to hypoxia (10% O2, 0% CO2) and normoxic-hypercapnia (21% O2, 5% CO2) were measured before surgery on W (-3), before bleo administration on W0 and on W4 post-bleo using whole-body plethysmography (WBP). Results: SCGx did not affect resting fR, Vt and V̇E as well as the chemoreflex responses to hypoxia and normoxic hypercapnia in either group prior to bleo. There was no significant difference in ALI-induced increase in resting fR between Sx and SCGx rats at W1 post-bleo. At W4 post-bleo, there were no significant differences in resting fR, Vt, and V̇E between Sx and SCGx rats. Consistent with our previous study, we observed a sensitized chemoreflex (delta fR) in response to hypoxia and normoxic hypercapnia in Sx rats at W4 post-bleo. However, at the same time, compared to Sx rats, the chemoreflex sensitivity was significantly less in SCGx rats in response to either hypoxia or normoxic hypercapnia. Discussion: These data suggest that SCG is involved in the chemoreflex sensitization during ALI recovery. Further understanding of the underlying mechanism will provide important information for the long-term goal of developing novel targeted therapeutic approaches to pulmonary diseases to improve clinical outcomes.

Hypoxic breathing produces more intense hypoxemia in elderly women than in elderly men.

Background: Brief hypoxic exposures are increasingly applied as interventions for aging-related conditions. To optimize the therapeutic impact of hypoxia, knowledge of the sex-related differences in physiological responses to hypoxia is essential. This study compared hypoxia-induced hypoxemic responses in elderly men and women. Methods: Seven elderly men (70.3 ± 6.0years old) and nine women (69.4 ± 5.5years old) breathed 10% O2 for 5min while arterial (SaO2; transcutaneous photoplethysmography) and cerebral tissue O2 saturation (ScO2; near-infrared spectroscopy), ventilatory frequency, tidal volume, minute-ventilation, and partial pressures of end-tidal O2 (PETO2) and CO2 (mass spectrometry) were continuously monitored. Cerebral tissue oxygen extraction fraction (OEF) equaled (SaO2-ScO2)/SaO2. Results: During 5min hypoxia SaO2 fell from 97.0 ± 0.8% to 80.6 ± 4.6% in the men and from 96.3 ± 1.4% to 72.6 ± 4.0% in the women. The slope ΔSaO2/min was steeper in the women than the men (-4.71 ± 0.96 vs. -3.24 ± 0.76%/min; p = 0.005). Although SaO2 fell twice as sharply per unit decrease in PETO2 in the women than the men (-1.13 ± 0.11 vs. -0.54 ± 0.06%/mmHg; p = 0.003), minute-ventilation per unit hypoxemia increased less appreciably in the women (-0.092 ± 0.014 vs. -0.160 ± 0.021L/min/%; p = 0.023). OEF fell with hypoxia duration in the women, but remained stable in the men. Conclusion: During 5min hypoxic breathing, elderly women experience more intense hypoxemia and reduced chemoreflex sensitivity vs. their male counterparts, which may lower OEF stability in women despite augmented O2 dissociation from hemoglobin during hypoxia. These sex-related differences merit attention when implementing brief hypoxic exposures for therapeutic purposes.

Time-dependent alteration in the chemoreflex post-acute lung injury.

Acute lung injury (ALI) induces inflammation that disrupts the normal alveolar-capillary endothelial barrier which impairs gas exchange to induce hypoxemia that reflexively increases respiration. The neural mechanisms underlying the respiratory dysfunction during ALI are not fully understood. The purpose of this study was to investigate the role of the chemoreflex in mediating abnormal ventilation during acute (early) and recovery (late) stages of ALI. We hypothesized that the increase in respiratory rate (fR) during post-ALI is mediated by a sensitized chemoreflex. ALI was induced in male Sprague-Dawley rats using a single intra-tracheal injection of bleomycin (Bleo: low-dose = 1.25mg/Kg or high-dose = 2.5mg/Kg) (day 1) and respiratory variables- fR, Vt (Tidal Volume), and VE (Minute Ventilation) in response to 10% hypoxia (10% O2, 0% CO2) and 5% hypercapnia/21% normoxia (21% O2, 5% CO2) were measured weekly from W0-W4 using whole-body plethysmography (WBP). Our data indicate sensitization (∆fR = 93 ± 31bpm, p < 0.0001) of the chemoreflex at W1 post-ALI in response to hypoxic/hypercapnic gas challenge in the low-dose bleo (moderate ALI) group and a blunted chemoreflex (∆fR = -0.97 ± 42bpm, p < 0.0001) at W1 post-ALI in the high-dose bleo (severe ALI) group. During recovery from ALI, at W3-W4, both low-dose and high-dose groups exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia. We then hypothesized that the blunted chemoreflex at W1 post-ALI in the high-dose bleo group could be due to near maximal tonic activation of chemoreceptors, called the "ceiling effect". To test this possibility, 90% hyperoxia (90% O2, 0% CO2) was given to bleo treated rats to inhibit the chemoreflex. Our results showed no changes in fR, suggesting absence of the tonic chemoreflex activation in response to hypoxia at W1 post-ALI. These data suggest that during the acute stage of moderate (low-dose bleo) and severe (high-dose bleo) ALI, chemoreflex activity trends to be slightly sensitized and blunted, respectively while it becomes significantly sensitized during the recovery stage. Future studies are required to examine the molecular/cellular mechanisms underlying the time-course changes in chemoreflex sensitivity post-ALI.

Respiratory and heart rate dynamics during peripheral chemoreceptor deactivation compared to targeted sympathetic and sympathetic/parasympathetic (co-)activation.

The importance of peripheral chemoreceptors for cardiorespiratory neural control is known for decades. Pure oxygen inhalation deactivates chemoreceptors and increases parasympathetic outflow. However, the relationship between autonomic nervous system (ANS) activation and resulting respiratory as well as heart rate (HR) dynamics is still not fully understood. In young adults the impact of (1) 100% pure oxygen inhalation (hyperoxic cardiac chemoreflex sensitivity (CHRS) testing), (2) the cold face test (CFT) and (3) the cold pressor test (CPT) on heart rate variability (HRV), hemodynamics and respiratory rate was investigated in randomized order. Baseline ANS outflow was determined assessing respiratory sinus arrhythmia via deep breathing, baroreflex sensitivity and HRV. Baseline ANS outflow was normal in all participants (23±1years, 7 females, 3 males). Hyperoxic CHRS testing decreased HR (after 60±3 vs before 63±3min-1, p=0.004), while increasing total peripheral resistance (1053±87 vs 988±76dyne*s+m2/cm5, p=0.02) and mean arterial blood pressure (93±4 vs 91±4mmHg, p=0.02). HRV indicated increased parasympathetic outflow after hyperoxic CHRS testing accompanied by a decrease in respiratory rate (15±1vs 19±1min-1, p=0.001). In contrast, neither CFT nor CPT altered the respiratory rate (18±1 vs 18±2min-1, p=0.38 and 18±1 vs 18±1min-1, p=0.84, respectively). Changes in HR characteristics during deactivation of peripheral chemoreceptors but not during the CFT and CPT are related with a decrease in respiratory rate. This highlights the need of respiratory rate assessment when evaluating adaptations of cardiorespiratory chemoreceptor control.

From Molecular to Functional Effects of Different Environmental Lead Exposure Paradigms.

Simple SummaryOur comparative study brings new insights regarding the effects of environmental lead exposure on the cardiorespiratory and nervous systems. We show how various kinds of exposure can lead to different toxicities, with various degrees of nefarious effects. The developmental period is of utmost importance to the toxicity of environmental lead; however, we found that the duration of exposure is the prime reason for stronger effects, even though the dual effect of intermittent exposure causes greater molecular neuronal alterations. Lead is a heavy metal whose widespread use has resulted in environmental contamination and significant health problems, particularly if the exposure occurs during developmental stages. It is a cumulative toxicant that affects multiple systems of the body, including the cardiovascular and nervous systems. Chronic lead exposure has been defined as a cause of behavioral changes, inflammation, hypertension, and autonomic dysfunction. However, different environmental lead exposure paradigms can occur, and the different effects of these have not been described in a broad comparative study. In the present study, rats of both sexes were exposed to water containing lead acetate (0.2% w/v), from the fetal period until adulthood. Developmental Pb-exposed (DevPb) pups were exposed to lead until 12 weeks of age (n = 13); intermittent Pb exposure (IntPb) pups drank leaded water until 12 weeks of age, tap water until 20 weeks, and leaded water for a second time from 20 to 28 weeks of age (n = 14); and the permanent (PerPb) exposure group were exposed to lead until 28 weeks of age (n = 14). A control group (without exposure, Ctrl), matched in age and sex was used. After exposure protocols, at 28 weeks of age, behavioral tests were performed for assessment of anxiety (elevated plus maze test), locomotor activity (open-field test), and memory (novel object recognition test). Metabolic parameters were evaluated for 24 h, and the acute experiment was carried out. Blood pressure (BP), electrocardiogram, and heart (HR) and respiratory (RF) rates were recorded. Baroreflex gain, chemoreflex sensitivity, and sympathovagal balance were calculated. Immunohistochemistry protocol for NeuN, Syn, Iba-1, and GFAP staining was performed. All Pb-exposed groups showed hypertension, concomitant with a decrease in baroreflex gain and chemoreceptor hypersensitivity, without significant changes in HR and RF. Long-term memory impairment associated with reactive astrogliosis and microgliosis in the dentate gyrus of the hippocampus, indicating the presence of neuroinflammation, was also observed. However, these alterations seemed to reverse after lead abstinence for a certain period (DevPb) and were enhanced when a second exposure occurred (IntPb), along with a synaptic loss. These results suggest that the duration of Pb exposure is more relevant than the timing of exposure, since the PerPb group presented more pronounced effects and a significant increase in the LF and HF bands and anxiety levels. In summary, this is the first study with the characterization and comparison of physiological, autonomic, behavioral, and molecular changes caused by different low-level environmental lead exposures, from the fetal period to adulthood, where the duration of exposure was the main factor for stronger adverse effects. These kinds of studies are of immense importance, showing the importance of the surrounding environment in health from childhood until adulthood, leading to the creation of new policies for toxicant usage control.

Enhanced-Dose Statins for ST-Segment Elevation Myocardial Infarction Patients after Emergency Percutaneous Coronary Intervention.

Background Acute ST-segment elevation myocardial infarction (STEMI) is a serious multiple acute cardiovascular disease. This study investigated the effect of statins on the efficacy and prognosis of STEMI patients after emergency PCI. Methods From October 2019 to January 2021, 98 patients with STEMI in our hospital were selected and divided into study group and control group. The study group took atorvastatin 40 mg 2 hours before surgery, 40 mg/day after surgery, and 20 mg/day 1 week later. The control group received 20 mg of atorvastatin every night after admission. The cardiac output, left ventricular ejection fraction, blood flow classification, vagus nerve function, heart rate deceleration force and chemoreflex sensitivity were compared between the two groups, and recorded the incidence of adverse reactions before and after treatment and 3 months after treatment. The number of major adverse cardiac events (MACEs) was also recorded. Results Before treatment, there were no differences in CO, CI, and LVEF between the study and control groups. After treatment, CO, CI, and LVEF in the study group were significantly higher than those in the control group. Before treatment, there was no significant difference in TIMI blood flow classification among the groups, and after treatment, the study group was better than the control group. DC and ChRS were significantly higher in the study group than in the control group. There was no difference in the incidence of adverse reactions between the study group and the control group. However, the incidence of MACE in the study group was lower than that in the control group. Conclusion Enhanced-dose atorvastatin for STEMI patients improved PCI treatment effect, cardiac function, and vagus nerve function and reduced the incidence of adverse cardiac events. Thus, statins are safe and worth considering.

Chemoreflex and Baroreflex Sensitivity Hold a Strong Prognostic Value in Chronic Heart Failure

BackgroundNovel treatments targeting in baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS) heart failure (HF) are grounded on small prognostic studies, partly performed in the pre–beta-blockade era. ObjectivesThis study assesses the clinical/prognostic significance of BRS and CRS in a large cohort of patients with chronic HF on modern treatments. MethodsOutpatients with chronic HF with either reduced (≤40%) or mildly reduced left ventricular ejection fraction (LVEF) (41% to 49%) underwent BRS (SD method) and CRS to hypoxia and hypercapnia (rebreathing technique) assessment and were followed up for a composite endpoint of cardiac death, implantable cardioverter-defibrillator shock, or HF hospitalization. ResultsA total of 425 patients were enrolled (65 ± 12 years of age, LVEF 32% [IQR: 25%-38%], 94% on beta blockers). Patients with decreased BRS (n = 96 of 267, 36%) had lower exercise tolerance and heart rate variability (P < 0.05), whereas those with increased CRS to both hypoxia and hypercapnia (n = 74 of 369, 20%) had higher plasma norepinephrine and central apneas across the 24-hour period (P < 0.01). During a median 50-month follow-up (IQR: 24-94 months), the primary endpoint occurred more often in patients with decreased BRS (log-rank: 11.64; P = 0.001), mainly for increased cardiac deaths/implantable cardioverter-defibrillator shocks, and in those with increased CRS (log-rank: 34.81; P < 0.001), mainly for increased HF hospitalizations. Patients with both abnormal BRS and CRS showed the worst outcome. Reduced BRS (HR: 2.76 [95% CI: 1.36-5.63]; P = 0.005) and increased CRS (HR: 2.91 [95% CI: 1.34-6.31]; P = 0.007) were independently associated with the primary outcome and increased risk stratification when added to standard HF prognosticators (P < 0.05). ConclusionsIn subjects with HF on modern treatment, abnormal BRS and CRS are frequently observed. BRS and CRS elicit autonomic imbalance, exercise limitation, unstable ventilation, and predict adverse outcomes.

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.

Reproducibility of Respiratory Chemoreflex Characterization by Modified Rebreathing

Modified hypoxic and hyperoxic rebreathing is used to characterize central and peripheral respiratory chemoreflexes in humans. This study examined within‐ and between‐day reproducibility of the key parameters that are identified by this method: ventilatory recruitment threshold (VRT) and chemoreflex sensitivity. Seven healthy males (mean ± SD; age: 27±5 years) visited the laboratory on 4 occasions to performrepetitions of modified rebreathing tests in isoxic‐hypoxic (end‐tidal PO2 (PETO2) =50 mmHg) and ‐hyperoxic conditions (PETO2=150 mmHg). Days 1 and 2 consisted of three repeatedhyperoxic and three hypoxic trials, respectively; Days 3 and 4 included both a hyperoxic and a hypoxic trial completed in a counterbalanced order. Ventilation, end‐tidal PCO2 (PETCO2) and PETO2 were measured breath‐by‐breath by pneumotach and dual gas analyser. For each rebreathing trial, the PETCO2 at which ventilation began to rise was identified as the VRT (mmHg) and the slope of the response above VRT provided respiratory chemoreflex sensitivity (L∙min‐1∙mmHg‐1). Within‐ and between‐day reproducibility was assessed by one‐way ANOVA and intraclass correlation (ICC) analyses. The VRT was not different between trials performed on a single day for bothhyperoxic (44±2, 45±3, vs 44±3 mmHg; for Trials 1, 2, vs 3, respectively; p=0.50; ICC=0.926) and hypoxic rebreathing (40±3, 40±4, vs 40±4 mmHg; p=0.66; ICC=0.994). Chemoreflex sensitivity also was not different between trials performed on the same day in hyperoxic (4.3±2.2, 5.0±3.1, vs4.8±2.3 L∙min‐1∙mmHg‐1; p=0.33; ICC=0.955) or hypoxic conditions (5.6±2.2, 6.2±2.7, 5.7±2.0 L∙min‐1∙mmHg‐1; p=0.33; ICC=0.953). Between days, the VRT was not different for hyperoxic rebreathing (44±3 vs 44±2 vs 45±2 mmHg for Days 1, 3, vs 4, respectively; p=0.10; ICC=0.813) but was different for hypoxic rebreathing (40±3 vs 40±2 vs 41±3 mmHg for Days 2‐4, respectively; p=0.01; ICC=0.931). Chemoreflex sensitivity was not different between days for either hyperoxic (4.8±2.5,4.4±2.7, vs 4.9±2.0 L∙min‐1∙mmHg‐1; p=0.01; ICC=0.906) or hypoxic rebreathing (5.8±2.2, 5.8±2.6, vs 7.8±2.8 L∙min‐1∙mmHg‐1; p=0.01; ICC=0.750). Collectively, these data indicate that model parameters derived from hyperoxic and hypoxic modified rebreathing have good‐to‐excellent test‐retest reproducibility when repeated on the same or different days.

Peripheral Chemoreflex Sensitivity is Augmented in Human Type 2 Diabetes

IntroductionThe peripheral chemoreceptors have been implicated in the pathogenesis of type 2 diabetes. Our main objective was to examine peripheral chemosensitivity in individuals with type 2 diabetes, as well as the contribution of the peripheral chemoreceptors to basal cardiovascular control. We hypothesized individuals with type 2 diabetes exhibit exaggerated peripheral chemoreflex sensitivity to hypoxia compared to healthy, non‐diabetic controls. We further hypothesized the peripheral chemoreceptors contribute to cardiovascular dysfunction in type 2 diabetes.MethodsEight adults with diagnosed type 2 diabetes (3M/5F, 54±3 yrs, HbA1c 8.1±0.6%) and nineteen healthy controls (8M/11F, 50±3 yrs, HbA1c 5.3±0.1%) participated (IRB #2010295 and #2018486). Ventilatory and hemodynamic responses to acute hypoxia were assessed to determine peripheral chemosensitivity [i.e., hypoxic ventilatory (HVR), heart rate (HHRR) and blood pressure (HBPR) response]. Separately, heart rate, blood pressure and forearm blood flow (Doppler ultrasound) were measured while breathing normoxic or hyperoxic air (100% O2; Modified Dejours test) to acutely attenuate peripheral chemoreceptor activity. Forearm blood flow was normalized for mean arterial blood pressure for measures of vascular resistance.ResultsPeripheral chemosensitivity was augmented in adults with type 2 diabetes compared to control as assessed via the HVR (‐1.10±0.16 vs ‐0.50±0.10 L/min/%, p&lt;0.01) and HBPR (‐0.92±0.17 vs ‐0.42±0.19 mmHg/%, p=0.06), with no differences in HHRR (‐0.68±0.22 vs ‐0.56±0.12 beats/min/%, p=0.64). Higher HVR and HBPR were associated with higher fasting insulin (R=‐0.58, p&lt;0.01 and R=‐0.38, p=0.06) and HbA1c (R=‐0.60, p&lt;0.01 and R=‐0.39, p=0.05). Attenuation of peripheral chemoreceptor activity with acute hyperoxia decreased heart rate (p&lt;0.01) and blood pressure (p=0.02), with no effect on forearm vascular resistance (p=0.55); any effect of hyperoxia did not differ between adults with type 2 diabetes and controls (p&gt;0.05).ConclusionIndividuals with type 2 diabetes exhibit exaggerated peripheral chemoreflex sensitivity which is associated with disease severity (i.e., HbA1c). In contrast, the contribution of the peripheral chemoreceptors to basal cardiovascular function in type 2 diabetes does not differ from non‐diabetic controls. Results advance our understanding of the pathogenesis of type 2 diabetes and related complications.

Longer Bouts of Intermittent Hypoxia Coupled with Increased Levels of Sustained Hypercapnia Lead to Increases in the Magnitude of Ventilatory Long‐Term Facilitation in African Americans Compared to Caucasians

IntroductionVentilatory long term facilitation (vLTF) is a form of neural plasticity that results in a sustained increase in minute ventilation following exposure to MIH. A number of studies have shown that mild intermittent hypoxia (MIH) when accompanied by slight hypercapnia elicits vLTF in humans. However, the impact of race on the magnitude of vLTF remains unknown. Therefore, we examined the impact of race on the magnitude of vLTF.MethodsData was collected from 47 participants that identified as either African American or Caucasian. These individuals completed one of two MIH protocols. Both protocols began with a ten‐minute normoxic baseline followed by a ten‐minute period characterized by sustained hypercapnia. One protocol (P1) was characterized by 12 two‐minute bouts of hypoxia interspersed with 2 minutes of normoxia. During P1, the partial pressure of end‐tidal carbon dioxide (PETCO2) was maintained 2 mmHg above baseline. The other protocol (P2) was characterized by 12 four‐minute bouts of hypoxia interspersed with 4 minutes of normoxia. During P2, PETCO2 was maintained 4 mmHg above baseline. Exposure to intermittent hypoxia was followed by a 30‐minute recovery period in both protocols. The magnitude of vLTF was calculated by dividing minute ventilation during recovery by baseline values (i.e. 10 minute period of sustained hypercapnia).ResultsResting minute ventilation was similar between groups (11.6 ± 2.6 vs 11.4 ± 2.1 L/min, P ≥ 0.9). By design, PETCO2was significantly higher in P2 compared to P1 during the baseline period characterized by sustained hypercapnia (41.2 ± 2.9 vs 42.2 ± 1.6 mmHg, P ≤ 0.05). The chemoreflex sensitivity to CO2 was similar between groups (1.6 ± 2.3 vs 1.5 ± 1.5, P ≥ 0.9). In both protocols, minute ventilation during recovery was significantly higher than baseline (P1: 17.8 ± 3.9 vs. 11.6 ± 2.6, P2: 20.7 ± 4.2 vs. 11.4 ± 2.1, P ≤ 0.01). Moreover, minute ventilation was significantly greater during recovery in P2 compared to P1 (P ≤ 0.01). When standardized to baseline, vLTF was significantly greater in P2 compared to P1 (1.3 ± 0.2 vs 1.2 ± 0.2, P ≤ 0.01). No difference in the magnitude of vLTF was evident in the Caucasian group compared to the African American group when both absolute (17.3 ± 3.7 vs 18.5 ± 4.3, P ≥ 0.3) and standardized measures (1.2 ± 0.1 vs 1.3 ± 0.2, P ≥ 0.8) of minute ventilation were compared following P1. However, the magnitude of LTF (i.e. standardized to baseline) was reduced in the Caucasian group compared to the African American group following the completion of P2 (1.3 ± 0.2 vs. 1.4 ± 0.1, P ≤ 0.04).ConclusionsvLTF was evident following the completion of both protocols. However, the magnitude of vLTF was greater after P2. Likewise, the magnitude of vLTF was greater in African Americans compared to Caucasians following P2. Our data indicate that the magnitude of LTF may be impacted by race, particularly if longer bouts of intermittent hypoxia coupled to a higher sustained level of carbon dioxide is employed.

Central Apneas Are More Detrimental in Female Than in Male Patients With Heart Failure.

BackgroundCentral apneas (CA) are a frequent comorbidity in patients with heart failure (HF) and are associated with worse prognosis. The clinical and prognostic relevance of CA in each sex is unknown.Methods and ResultsConsecutive outpatients with HF with either reduced or mildly reduced left ventricular ejection fraction (n=550, age 65±12 years, left ventricular ejection fraction 32%±9%, 21% women) underwent a 24‐hour ambulatory polygraphy to evaluate CA burden and were followed up for the composite end point of cardiac death, appropriate implantable cardioverter‐defibrillator shock, or first HF hospitalization. Compared with men, women were younger, had higher left ventricular ejection fraction, had lower prevalence of ischemic etiology and of atrial fibrillation, and showed lower apnea‐hypopnea index (expressed as median [interquartile range]) at daytime (3 [0–9] versus 10 [3–20] events/hour) and nighttime (10 [3–21] versus 23 [11–36] events/hour) (all P<0.001), despite similar neurohormonal activation and HF therapy. Increased chemoreflex sensitivity to either hypoxia or hypercapnia (evaluated in 356 patients, 65%, by a rebreathing test) was less frequent in women (P<0.001), but chemoreflex sensitivity to hypercapnia was a predictor of apnea‐hypopnea index in both sexes. At adjusted survival analysis, daytime apnea‐hypopnea index ≥15 events/hour (hazard ratio [HR], 2.70; 95% CI, 1.06–7.34; P=0.037), nighttime apnea‐hypopnea index ≥15 events/hour (HR, 2.84; 95% CI, 1.28–6.32; P=0.010), and nighttime CA index ≥10 events/hour (HR, 5.01; 95% CI, 1.88–13.4; P=0.001) were independent predictors of the primary end point in women but not in men (all P>0.05), also after matching women and men for possible confounders.ConclusionsIn chronic HF, CA are associated with a greater risk of adverse events in women than in men.

Implications of a patent foramen ovale for environmental physiology and pathophysiology: do we know the 'hole' story?

The foramen ovale is an essential component of the fetal circulation contributing to oxygenation and carbon dioxide elimination that remains patent under certain circumstances in ∼30% of the healthy adult population, without major negative sequelae in most. Adults with a patent foramen ovale (PFO) have a greater tendency to develop symptoms of acute mountain sickness and high-altitude pulmonary oedema upon ascent to high altitude, and PFO presence is associated with worse cardiopulmonary function in chronic mountain sickness. This increase in altitude illness prevalence may be related to dysregulated cerebral blood flow associated with altered respiratory chemoreflex sensitivity; however, the mechanisms remain to be elucidated. Interestingly, men with a PFO appear to have a shift in thermoregulatory control to higher internal temperatures, both at rest and during exercise, and they have blunted thermal hyperpnoea. The teleological 'reason' for this thermoregulatory shift is unclear, but the shift of ∼0.5°C in core body temperature does not appear to be sufficient to have any significant negative consequences in terms of risk of heat illness. Further work in this area is needed, particularly in women, to evaluate mechanisms of heat storage and dissipation in these individuals compared to people without a PFO. Consequences of a PFO in SCUBA divers include a greater incidence of unprovoked decompression sickness, but whether PFO is beneficial or detrimental to breath hold diving remains unexplored. Whether PFO presence will explain interindividual variability in responses to, and consequences from, other environmental stressors such as spaceflight remain entirely unknown.

GLP1R Attenuates Sympathetic Response to High Glucose via Carotid Body Inhibition.

Aberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically sympathetic nerve activity remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity and tonic drive from the peripheral chemoreceptors, the cause of which is unknown. We have previously shown hypertension to be critically dependent on the carotid body (CB) input in spontaneously hypertensive rat, a model that also exhibits a number of diabetic traits. CB overstimulation by insulin and leptin has been similarly implicated in the development of increased sympathetic nerve activity in metabolic syndrome and obesity. Thus, we hypothesized that in hypertensive diabetic state (spontaneously hypertensive rat), the CB is sensitized by altered metabolic signaling causing excessive sympathetic activity levels and dysfunctional reflex regulation. Using a hypothesis-free RNA-seq approach, we investigated potential molecular targets implicated in energy metabolism mediating CB sensitization and its regulation of sympathetic outflow in experimental hypertension. Identified targets were characterized using molecular and functional techniques assessing peripheral chemoreflex sensitivity in situ and in vivo. We discovered GLP1R (glucagon-like peptide-1 receptor) expression in the CBs of rat and human and showed that its decreased expression is linked to sympathetic hyperactivity in rats with cardiometabolic disease. We demonstrate GLP1R to be localized to CB chemosensory cells, while targeted administration of GLP1R agonist to the CB lowered its basal discharge and attenuated chemoreflex-evoked blood pressure and sympathetic responses. Importantly, hyperglycemia-induced peripheral chemoreflex sensitization and associated basal sympathetic overactivity were abolished by GLP1R activation in the CB suggesting a role in a homeostatic response to high blood glucose. We show that GLP1 (glucagon-like peptide-1) modulates the peripheral chemoreflex acting on the CB, supporting this organ as a multimodal receptor. Our findings pinpoint CBs as potential targets for ameliorating excessive sympathetic activity using GLP1R agonists in the hypertensive-diabetic condition.

Autonomic and cardiac evaluation upon sub-therapeutic doxorubicin administration

Abstract Doxorubicin (DOX) is a chemotherapeutic agent that improves the survival and quality of life of patients with solid tumours. However, these improvements are counterbalanced by various dose-dependent side effects including cardiac dysfunction, which may occur in a subset of patients leading to treatment discontinuation. In addition, despite overall insufficiently studied, available data clearly show that women are more susceptible to drugs toxicity due to sex differences in drug metabolism or sensitivity. Regarding doxorubicin, apart its acute toxicity, women are also more vulnerable to late cardiotoxicity. Currently, there are no robust clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline and, despite treatment personalization, subclinical signs of toxicity are not yet well identified. Thus, in the present work, we sought to characterize the toxic effects of a sub-therapeutic dose of doxorubicin upon cardiovascular and autonomic function. For that, adult healthy female wistar rats (n=14), aged &amp;gt;3 months, were intraperitoneally treated with doxorubicin (2 mg/kg) at weekly intervals for up to 4 weeks. A control (Ctrl, n=7) group received saline solution 0,9% NaCl as a vehicle. Rats underwent an echocardiographic evaluation at 4 weeks. Blood pressure, heart rate and respiratory frequency were assessed in an acute experiment. Cardiovascular variability studies in the time-frequency domain (LF, HF and LF/HF calculation) and cardiorespiratory reflexes assessment were performed. T-Student test for paired observations was applied (level significance p&amp;lt;0.05) DOX-treated animals showed a severe bradypnea and hypotension, significant decrease in ejection fraction and fractional shortening, sympatho-inhibition and reduced baroreceptor reflex gain and chemoreflex sensitivity. Our functional results might be due to cellular respiratory dysfunction and vascular adaptations induced by doxorubicin via TNF alpha actions at central nervous system (CNS) and peripheral level. In fact, peripheral TNF alpha release elicits NO production, which through vasodilation will induce hypotension and baroreceptor reflex adjustments. Reinforcing these actions, and despite doxorubicin low ability to pass BBB, TNF alpha acting at CNS induces neuronal apoptosis and impairment of mitochondrial function which might also contribute to affect autonomic and respiratory function, expressed by a decreased chemoreflex sensitivity and sympathetic tone. In conclusion, sub-therapeutic doses of doxorubicin are able to produce per se the impairment of autonomic and cardiac functions. Thus, a tight monitoring of these functions in patients treated with therapeutic doses of doxorubicin is highly recommended. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundação para a Ciência e a Tecnologia

Exercise intolerance in volume overload heart failure is associated with low carotid body mediated chemoreflex drive

Mounting an appropriate ventilatory response to exercise is crucial to meeting metabolic demands, and abnormal ventilatory responses may contribute to exercise-intolerance (EX-inT) in heart failure (HF) patients. We sought to determine if abnormal ventilatory chemoreflex control contributes to EX-inT in volume-overload HF rats. Cardiac function, hypercapnic (HCVR) and hypoxic (HVR) ventilatory responses, and exercise tolerance were assessed at the end of a 6 week exercise training program. At the conclusion of the training program, exercise tolerant HF rats (HF + EX-T) exhibited improvements in cardiac systolic function and reductions in HCVR, sympathetic tone, and arrhythmias. In contrast, HF rats that were exercise intolerant (HF + EX-inT) exhibited worse diastolic dysfunction, and showed no improvements in cardiac systolic function, HCVR, sympathetic tone, or arrhythmias at the conclusion of the training program. In addition, HF + EX-inT rats had impaired HVR which was associated with increased arrhythmia susceptibility and mortality during hypoxic challenges (~ 60% survival). Finally, we observed that exercise tolerance in HF rats was related to carotid body (CB) function as CB ablation resulted in impaired exercise capacity in HF + EX-T rats. Our results indicate that: (i) exercise may have detrimental effects on cardiac function in HF-EX-inT, and (ii) loss of CB chemoreflex sensitivity contributes to EX-inT in HF.