Chemoreflex Sensitivity Research Articles

Autonomic outcome is better after endarterectomy than after stenting in patients with asymptomatic carotid stenosis

Carotid endarterectomy and stenting have comparable efficacy in stroke prevention in asymptomatic carotid stenosis. In patients with carotid stenosis, cardiac events have a more than threefold higher incidence than cerebrovascular events. Autonomic dysfunction predicts cardiovascular morbidity and mortality, and carotid stenosis interferes with baroreceptor and chemoreceptor function. We assessed the effect of elective carotid revascularization (endarterectomy vs stenting) on autonomic function as a major prognostic factor of cardiovascular health. In 42 patients with ≥70% asymptomatic extracranial carotid stenosis, autonomic function was determined by analysis of heart rate variability (total band power [TP], high frequency band power [HF], low-frequency band power [LF], very low frequency band power [VLF]), baroreflex sensitivity (αHF, αLF), respiratory chemoreflex sensitivity (central apnea-hypopnea index), and cardiac chemoreflex sensitivity (hyperoxic TP, HF, LF, and VLF ratios) before and 30days after revascularization. Patients with endarterectomy were older than patients with stenting (69± 7 vs 62± 7years; P ≤ .008) but did not differ in gender distribution and preintervention autonomic function. Compared with stenting, postintervention heart rate variability was higher (ln TP, 6.7 [95% confidence interval (CI), 6.3-7.0] vs 6.1 [95% CI, 5.8-6.5; P ≤ .009]; ln HF, 4.5 [95% CI, 4.1-5.0] vs 4.0 [95% CI, 3.4-4.5; P ≤ .05]; ln VLF, 6.0 [95% CI, 5.7-6.4] vs 5.5 [95% CI, 5.2-5.9; P≤.02]); respiratory chemoreflex sensitivity (central apnea-hypopnea index, 5.5 [95% CI, 2.8-8.2] vs 10.0 [95% CI, 6.9-13.1; P ≤. 01]) and cardiac chemoreflex sensitivity (TP ratio, 1.2 [95% CI, 1.1-1.3] vs 1.0 [95% CI, 0.9-1.0; P ≤ .0001]; HF ratio, 1.4 [95% CI, 1.2-1.5] vs 0.9 [95% CI, 0.8-1.1; P ≤ .001]; LF ratio, 1.5 [95% CI, 1.3-1.6] vs 1.0 [95% CI, 0.8-1.1; P ≤ .0001]; VLF ratio, 1.2 [95% CI, 1.1-1.3) vs 1.0 [95% CI, 0.9-1.1; P ≤ .002]) were lower after endarterectomy. Postintervention baroreflex sensitivity did not differ after endarterectomy and stenting. Autonomic function was better after endarterectomy than after stenting. Better autonomic function after endarterectomy was based on restoration of chemoreceptor but not baroreceptor function and may improve cardiovascular long-term outcome.

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.

Exercise training attenuates the pressor response evoked by peripheral chemoreflex in rats with heart failure.

The effects of exercise training (ExT) on the pressor response elicited by potassium cyanide (KCN) in the rat model of ischemia-induced heart failure (HF) are unknown. We evaluated the effects of ExT on chemoreflex sensitivity and its interaction with baroreflex in rats with HF. Wistar rats were divided into four groups: trained HF (Tr-HF), sedentary HF (Sed-HF), trained sham (Tr-Sham), and sedentary sham (Sed-Sham). Trained animals underwent to a treadmill running protocol for 8 weeks (60 m/day, 5 days/week, 16 m/min). After ExT, arterial pressure (AP), baroreflex sensitivity (BRS), peripheral chemoreflex (KCN: 100 μg/kg body mass), and cardiac function were evaluated. The results demonstrate that ExT induces an improvement in BRS and attenuates the pressor response to KCN relative to the Sed-HF group (P < 0.05). The improvement in BRS was associated with a reduction in the pressor response following ExT in HF rats (P < 0.05). Moreover, ExT induced a reduction in left ventricular end-diastolic pressure and pulmonary congestion compared with the Sed-HF group (P < 0.05). The pressor response to KCN in the hypotensive state is decreased in sedentary HF rats. These results suggest that ExT improves cardiac function and BRS and attenuates the pressor response evoked by KCN in HF rats.

Enhanced carotid body chemoreflex function drives respiratory‐sympathetic coupling in systolic heart failure

Enhanced carotid body (CB) chemoreflex sensitivity in systolic heart failure (HF) has been linked to oscillatory breathing patterns and autonomic imbalance. Importantly, breathing pattern alterations and heightened chemoreflex‐mediated sympathetic nerve activity are both associated with higher morbidity and mortality in HF. Therefore, the objective of this study was to determine whether CB denervation (CBD) would improve respiratory stability and decrease sympathetic drive in HF. In rabbits with pacing‐induced HF, we measured resting breathing and renal sympathetic nerve activity (RSNA), before and after CBD. In addition, we assessed respiratory‐sympathetic coupling using power spectral analysis and the magnitude of the peak coherence function between tidal volume (Vt) and RSNA frequency spectra. Minute ventilation and RSNA responses to acute hypoxia were significantly augmented in HF compared to controls and were abolished by CBD. Resting RSNA was greater in HF compared to control animals (43 ± 5% max vs. 23 ± % max, p&lt;0.05). HF animals after CBD displayed resting RSNA levels similar to control animals. HF animals displayed altered breathing patterns characterized by oscillatory breathing and increases in the incidence of apneas/hypopneas. Remarkably, CBD totally normalized oscillatory breathing patterns in HF animals. Peak coherence between RSNA and Vt signals was increased in HF animals (control 0.49 ± 0.05; HF 0.79 ± 0.06), and was significantly attenuated by CBD (0.59 ± 0.05, p&lt;0.05 for all comparisons). Our data show that enhanced CB‐mediated chemoreflex drive contributes to tonic elevations in RSNA and breathing instability in HF. Additionally, a tonic increase in CB afferent discharge may also play an important role in strengthening a link between respiratory and sympathetic neural outflow in HF.Support or Funding InformationSupported by Fondecyt 1140275, NIH PO1‐HL62222 and NIH F32 HL108592‐01A1.

Recruitment Maneuver in Elderly Patients with Different Peripheral Chemoreflex Sensitivity during Major Abdominal Surgery.

The goal of the study was to evaluate the effect of a recruitment maneuver on respiratory biomechanics, oxygenation, and hemodynamics in patients suffering from chronic heart failure with different peripheral chemoreflex sensitivity. The study was conducted in 115 elderly patients which underwent major abdominal surgery under general/epidural surgery. Peripheral chemoreflex sensitivity (PCS) was evaluated with breath-holding duration (BHD) during breath-holding test. All patients were divided into two groups: group H had a high PCS (BHD = 38 seconds or less, n = 49); Group M had a middle PCS (BHD more than 38 seconds, n = 66). Recruitment maneuver improved oxygenation and respiratory biomechanics in all cases. However, cardiac output decreased by an average of 18%–31% in group H compared to 18%–28% in group M. SVR either remained unchanged or decreased by up to 14% of the initial value in group H, while, in group M, it had a tendency to increase, which was 24% of the initial value. So, recruitment maneuver is an effective method to improve oxygenation and biomechanical properties of the respiratory system but in patients with increased peripheral chemoreflex sensitivity it associates with the risk of hemodynamic disturbances.

Obstructive Sleep Apnoea Syndrome and Diabetes. Fortuitous Association or Interaction?

This review explores the relation between obstructive sleep apnoea syndrome (OSAS) and diabetes. It aims to address the following issues: 1. the epidemiological evidence of the association between OSAS and type 2 diabetes; 2. the independence of this association from the comorbidities shared by the two conditions; 3. the chronological and quantitative characteristics of this association (Which comes first? Is there severity interdependence? Is treatment of one condition able to modify the natural history of the other?); 4. the mechanisms that make interaction plausible; 5. the impact of the OSAS-diabetes relation on micro- and macrovascular diabetic complications. OSAS is common in type 2 diabetes. Despite the association being affected by the confounding action of type 2 diabetes comorbidities (also risk factors for OSAS), it does not seem to be fully attributable to them. There is also a relation between OSAS severity and glucose metabolism alteration. A link between OSAS and insulin resistance appears early, prior to impaired glucose tolerance and the onset of diabetes. Therefore, a debate is ongoing on the pathogenetic role of OSAS in type 2 diabetes development and any consequent relevance to diabetes treatment with no conclusive evidence to date. A multiplicity of hypothetical mechanisms may mediate this relation. Most experimental findings support sympathetic activation and changes in chemoreflex sensitivity based on the interaction between chemoreflex and baroreflex. Some studies suggest bidirectional relationship between OSAS and diabetes, additive or synergistic effects for diabetic complications and a reciprocal enhancement in their impact on hypertension and cardiovascular disease. Clarification of these items could benefit diabetes management and prevention of diabetic cardiovascular complications.

Disentangling the role of breathing in the cardiovascular response to meditation

Meditation practices are often associated with changes in respiratory pattern, which are known to independently affect cardiovascular responses. In this study we aim to isolate the specific effect of meditation on the cardiovascular system by systematically controlling for the role of respiration. Forty participants without prior meditation experience were tested while pacing breathing at predetermined rates, in the presence or absence of Mantra meditation instructions, and in a body-scan meditation that did not involved controlled breathing. Continuous recordings were acquired for respiratory excursion, electrocardiogram, skin vasomotion, arterial and brain oxygenation and blood pressure. Mantra meditation decreased heart rate and cerebral tissue oxygenation compared to baseline, significantly more than paced breathing (p 0.01). Moreover, meditation dampened the cardiorespiratory reactions to the concurrent control of breathing, preventing an increase in oxygen saturation and reducing the increase in chemoreflex sensitivity (p 0.05), tidal volume (p 0.01) and ventilation (p 0.05), compared to paced breathing. Body-scan meditation reproduced the pattern observed during Mantra meditation, despite the absence of change in respiratory frequency compared to baseline. Post-meditation resting recordings showed a persistence of slowed heart rate (p 0.001) and reduced respiratory rate (p 0.001) compared to initial baseline. Meditation induces a hypometabolic state that does not solely depend on respiratory changes, but is linked to the meditation practice per se.

Tetraplegia is associated with enhanced peripheral chemoreflex sensitivity and ventilatory long-term facilitation.

Cardiorespiratory plasticity induced by acute intermittent hypoxia (AIH) may contribute to recovery following spinal cord injury (SCI). We hypothesized that patients with cervical SCI would demonstrate higher minute ventilation (V̇e) following AIH compared with subjects with thoracic SCI and able-bodied subjects who served as controls. Twenty-four volunteers (8 with cervical SCI, 8 with thoracic SCI, and 8 able-bodied) underwent an AIH protocol during wakefulness. Each subject experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2), 8% O2, and 40% CO2 to achieve oxygen saturation ≤90% followed by room air (RA). Measurements were obtained before, during, and 40 min after AIH to obtain ventilation and heart rate variability data [R-R interval (RRI) and low-frequency/high-frequency power (LF/HF)]. AIH results were compared with those of sham studies conducted in RA during the same time period. Individuals with cervical SCI had higher V̇e after AIH compared with able-bodied controls (117.9 ± 23.2% vs. 97.9 ± 11.2%, P < 0.05). RRI decreased during hypoxia in all individuals (those with cervical SCI, from 1,009.3 ± 65.0 ms to 750.2 ± 65.0 ms; those with thoracic SCI, from 945.2 ± 65.0 ms to 674.9 ± 65.0 ms; and those who were able-bodied, from 949 ± 75.0 to 682.2 ± 69.5 ms; P < 0.05). LH/HF increased during recovery in individuals with thoracic SCI and those who were able-bodied (0.54 ± 0.22 vs. 1.34 ± 0.22 and 0.67 ± 0.23 vs. 1.82 ± 0.23, respectively; P < 0.05) but remained unchanged in the group with cervical SCI. Our conclusion is that patients with cervical SCI demonstrate ventilatory long-term facilitation following AIH compared with able-bodied controls. Heart rate responses to hypoxia are acutely present in patients with cervical SCI but are absent during posthypoxic recovery.

Time of day affects the frequency and duration of breathing events and the critical closing pressure during NREM sleep in participants with sleep apnea.

We investigated if the number and duration of breathing events coupled to upper airway collapsibility were affected by the time of day. Male participants with obstructive sleep apnea completed a constant routine protocol that consisted of sleep sessions in the evening (10 PM to 1 AM), morning (6 AM to 9 AM), and afternoon (2 PM to 5 PM). On one occasion the number and duration of breathing events was ascertained for each sleep session. On a second occasion the critical closing pressure that demarcated upper airway collapsibility was determined. The duration of breathing events was consistently greater in the morning compared with the evening and afternoon during N1 and N2, while an increase in event frequency was evident during N1. The critical closing pressure was increased in the morning (2.68 ± 0.98 cmH2O) compared with the evening (1.29 ± 0.91 cmH2O; P ≤ 0.02) and afternoon (1.25 ± 0.79; P ≤ 0.01). The increase in the critical closing pressure was correlated to the decrease in the baseline partial pressure of carbon dioxide in the morning compared with the afternoon and evening (r = -0.73, P ≤ 0.005). Our findings indicate that time of day affects the duration and frequency of events, coupled with alterations in upper airway collapsibility. We propose that increases in airway collapsibility in the morning may be linked to an endogenous modulation of baseline carbon dioxide levels and chemoreflex sensitivity (12), which are independent of the consequences of sleep apnea.

The effect of prenatal maternal infection on respiratory function in mouse offspring: evidence for enhanced chemosensitivity.

Systemic maternal inflammation is implicated in preterm birth and bronchopulmonary dysplasia (BPD) and may induce morbidities including reduced pulmonary function, sleep-disordered breathing, and cardiovascular disorders. Here we test the hypothesis that antenatal maternal inflammation per se causes altered alveolar development and increased chemoreflex sensitivity that persists beyond infancy. Pregnant C57BL/6 mice were administered lipopolysaccharide (LPS) (150 μg/kg ip) to induce maternal inflammation or saline (SHAM) at embryonic day 16 (randomized). Pups were weighed daily. On days 7, 28, and 60 (D07, D28, and D60), unrestrained wholebody plethysmography quantified ventilation and chemoreflex responses to hypoxia (10%), hypercapnia (7%), and asphyxia (hypoxic hypercapnia). Lungs were harvested to quantify alveolar number, size, and septal thickness. LPS pups had reduced baseline ventilation per unit bodyweight (∼40%, P < 0.001) vs. SHAM. LPS increased ventilatory responses to hypoxia (D07: 66% vs. 28% increase in ventilation; P < 0.001) hypercapnia (170% vs. 88%; P < 0.001), and asphyxia (249% vs. 154%; P < 0.001); hypersensitive hypoxic responsiveness persisted until D60 (P < 0.001). LPS also increased apnea frequency (P < 0.01). LPS caused thicker alveolar septae (D07, P < 0.001), diminished alveolar number (D28, P < 0.001) vs. SHAM, but effects were minimal by D60. Pups delivered from mothers exposed to antenatal inflammation exhibit deficits in lung structure and hypersensitive responses to respiratory stimuli that persist beyond the newborn period. Antenatal inflammation may contribute to impaired gas exchange and unstable breathing in newborn infants and adversely affect long-term health.

Maternal Protein Restriction Increases Respiratory and Sympathetic Activities and Sensitizes Peripheral Chemoreflex in Male Rat Offspring1–3

Background: Maternal protein restriction in rats increases the risk of adult offspring arterial hypertension through unknown mechanisms.Objectives: The aims of the study were to evaluate the effects of a low-protein (LP) diet during pregnancy and lactation on baseline sympathetic and respiratory activities and peripheral chemoreflex sensitivity in the rat offspring.Methods: Wistar rat dams were fed a control [normal-protein (NP); 17% protein] or an LP (8% protein) diet during pregnancy and lactation, and their male offspring were studied at 30 d of age. Direct measurements of baseline arterial blood pressure (ABP), heart rate (HR), and respiratory frequency (Rf) as well as peripheral chemoreflex activation (potassium cyanide: 0.04%) were recorded in pups while they were awake. In addition, recordings of the phrenic nerve (PN) and thoracic sympathetic nerve (tSN) activities were obtained from the in situ preparations. Hypoxia-inducible factor 1α (HIF-1α) expression was also evaluated in carotid bifurcation through a Western blotting assay.Results: At 30 d of age, unanesthetized LP rats exhibited enhanced resting Rf (P = 0.001) and similar ABP and HR compared with the NP rats. Despite their similar baseline ABP values, LP rats exhibited augmented low-frequency variability (∼91%;P = 0.01). In addition, the unanesthetized LP rats showed enhanced pressor (P = 0.01) and tachypnoeic (P = 0.03) responses to peripheral chemoreflex activation. The LP rats displayed elevated baseline tSN activity (∼86%;P = 0.02) and PN burst frequency (45%;P = 0.01) and amplitude (53%;P = 0.001) as well as augmented sympathetic (P = 0.01) and phrenic (P = 0.04) excitatory responses to peripheral chemoreflex activation compared with the NP group. Furthermore, LP rats showed an increase of ∼100% in HIF-1α protein density in carotid bifurcation compared with NP rats.Conclusion: Sympathetic-respiratory overactivity and amplified peripheral chemoreceptor responses, potentially through HIF-1α–dependent mechanisms, precede the onset of hypertension in juvenile rats exposed to protein undernutrition during gestation and lactation.

Effects of Exercise Training and Intermittent Hypoxia on Ventilatory Chemoreflex Sensitivity in Humans

Exercise training exerts profound beneficial effects on cardiovascular function, reduces cardiovascular risk and improves outcome in patients who suffered cardiovascular events. The underlying mechanisms are incompletely understood but altered autonomic neural regulation may be involved. We recently found that short‐term intermittent hypoxia induced by 30 serial hypoxic breathholds raises sympathetic activity and blood pressure, and enhances chemoreflex sensitivity to hypoxia. Because chemoreflex activity is a marker of cardiovascular risk, here we tested the hypothesis that chemoreflex sensitization induced by intermittent hypoxia is attenuated by exercise conditioning. Eleven young healthy subjects (5M/6F, age 25±1 yrs, body‐mass‐index 24±1 kg/m2) were studied before and following 2 months of endurance training (peak VO2 pre vs. post: 36.4±1.4 vs. 40.1±1.7 ml/min/kg; P&lt;0.05). Chemoreflex sensitivity was determined by the ventilatory responses to a series of 2‐8 breaths of N2 inhalation before and after 30 min of intermittent hypoxia (1 episode/min; O2 saturation nadir ~80%). Exercise training did not affect basal blood pressure or chemoreflex sensitivity but lowered resting heart rate. Pre training, intermittent hypoxia raised chemoreflex sensitivity from 0.261±0.032 to 0.305±0.032 L/min/%O2 desaturation (P&lt;0.06). In contrast, post training chemoreflex sensitivity was unchanged by intermittent hypoxia (from 0.290±0.044 to 0.262±0.036 L/min/%O2 desaturation; P=NS). These data suggest that endurance training attenuates chemoreflex sensitization induced by intermittent hypoxia. Whether this is due to an antioxidant effect of exercise training requires further study. (Supported by HL098379)

Reduced Carotid Body KLF2 Expression Contributes to Autonomic and Respiratory Dysfunction in Chronic Heart Failure

Oscillatory breathing (OB) and increased sympathetic nerve activity (SNA) are associated with increased mortality in chronic heart failure (CHF) and may be caused by increased carotid chemoreflex (CC) sensitivity. Reduced blood flow plays an important role in enhanced CC sensitivity. Our objective was to determine if down-regulation of the shear-sensitive transcription factor Krüppel-like Factor 2 (KLF2) mediates increases in CC sensitivity in CHF. Ventilation, renal SNA (RSNA), and ECG was measured at rest and in response to CC activation with isocapnic hypoxia (IsoH). OB was quantified and expressed as the apnea-hypopnea index (AHI). AHI (control 6±1/h, CHF 35±5/h), RSNA (control 22±2 % max, CHF 43±5 %max) and arrhythmia incidence (control 50±10/h, CHF 300±100/h) were increased in CHF (all p<0.05 vs. control), as were CC responses to IsoH. Adenoviral transfection of KLF2 to the carotid bodies (CB) in CHF animals resulted in attenuation of AHI (7±2/h), RSNA (18±2 % max), and arrhythmia incidence (46±13/h) (all p<0.05 vs. CHF). CC responses to IsoH were attenuated as well. Protein expression of KLF2 in the CB was decreased in CHF animals, and was restored with adenoviral transfection. Conversely, KLF2 knockdown with lentiviral KLF2 siRNA resulted in decreased CB KLF2 expression and increases in AHI (14±3/h) and RSNA (32±4 % max). Our findings indicate that increased CC sensitivity, OB, and RSNA during CHF may be caused by down-regulation of KLF2 in the CB. This work was supported by NIH PO-1 HL62222, and NIH 1F32HL108592-01A1.

P2X3 Receptor Antagonism Reduces Peripheral Chemoreceptor Reflex Hypersensitivity and Blood Pressure in the Spontaneously Hypertensive Rat

Arterial hypertension is associated with increased peripheral chemoreceptor reflex sensitivity. We have shown that bilateral carotid body (CBR) resection in spontaneously hypertensive (SH) rats reduces arterial pressure (AP). Since ATP is a major participant in CB transduction signalling, and P2X3 receptors are associated with visceral afferent sensitisation, we hypothesized that P2X3 antagonism would reduce chemoreflex hypersensitivity and lower AP in SH rats.SH and Wistar rats were implanted with telemeters to record AP. Doses of a P2X3 receptor antagonist (AF‐219) were administered as an i.v. bolus: 0.5 (n=4), 1 (n=4), 2 (n=5), 4 (n=5) and 8 mg/kg (n=4), and changes in both basal AP and chemoreflex sensitivity assessed. The chemoreflex was stimulated with sodium cyanide (NaCN; 120 μg/kg i.v.).At all doses, AF‐219 diminished NaCN evoked AP responses (P=0.084) in SH rats. In SH rats, basal AP was reduced by AF‐219 (P&lt;0.05): ‐8±3 mmHg, 0.5mg/kg; ‐16±1 mmHg, 1mg/kg: ‐18±3 mmHg, 2mg/kg; ‐13±1 mmHg, 4mg/kg; ‐13±2 mmHg, 8mg/kg. In normotensive Wistars, AF‐219 did not reduce AP vs. baseline (‐4±2 mmHg, 1 mg/kg; P&gt;0.05). Injections of vehicle had no effect in either rat strain (n=4). In SH rats, CBR blunted the 1 mg/kg AF‐219 induced fall in AP vs. non‐CBR rats. However, the fall versus baseline in AP in SH‐CBR rats remained significant (‐8±1 mmHg,P&lt;0.01).P2X3 receptor antagonism depresses chemoreflex hypersensitivity and lowers AP in SH rats to a level observed after selective CBR. P2X3 receptor antagonism may provide a novel way to attenuate CB tonicity in SH rats and as such become a novel target for controlling hypertension.Supported by: British Heart Foundation and the NIH

Acute Activation of Carotid Chemoreceptors Increases Ventilatory Instability in Healthy Humans

Patients with sleep apnea exhibit ventilatory instability and increased carotid chemoreceptor activity. Whether ventilatory instability is directly related to altered chemoreceptor activity has not been examined in humans. Therefore we tested the hypothesis that acute activation of the carotid chemoreflex with hypoxia (10% O2) would increase breathing variability (assessed by coefficient of variation of tidal volume {%CV}) and blunting the peripheral chemoreflex with IV dopamine would attenuate the response. To test this hypothesis, nine healthy subjects (3 M/6 F) were studied on two separate study days: 1) saline or 2) low‐dose dopamine infusion. Individualized dopamine dose (1‐4 mg/kg/min), that maximally blunted chemoreflex sensitivity, was identified during a separate screening visit. Respiratory rate (RR), tidal volume (TV), end tidal CO2 (ETCO2)and O2 (ETO2) were measured. Baseline measures were similar between days. Saline infusion did not affect RR, TV, end tidal gases, or %CV. However, dopamine infusion significantly increased %CV (25 ± 5 to 32 ± 6 %; p&lt;0.05) and ETCO2 (0.3 ± 0.1 %; p&lt;0.0001) without affecting RR, or TV. Hypoxia increased %CV during saline infusion (18 ± 3 to 29 ± 3%; p&lt;0.05), and this effect was blunted during dopamine infusion (31 ± 6 to 38 ± 6%; p&gt;0.05). These data indicate hypoxia increases respiratory variability and this effect is mediated by the carotid chemoreceptors. Furthermore, the effect of increased chemoreceptor drive on ventilatory instability, such as that seen in sleep apnea, may be blunted by low‐dose dopamine in humans. These data provide a potential therapeutic target for improving ventilatory instability in human disease.&#x0D; Funding:NIH DK090541

Efficacy and safety of open lung ventilation in patients with impaired peripheral chemoreflex sensitivity

Mechanical ventilation during anesthesia leads to the development of atelectasis, poor oxygenation and postoperative pulmonary complications. Application of PEEP and recruitment maneuver (RM) can significantly reduce the severity of atelectasis and improve lung function. But the application of this strategy often leads to hemodynamic instability, which may be associated with impaired reactivity of the cardiovascular system. The purpose of this study was to evaluate the efficacy and safety of RM in patients with increased sensitivity of peripheral chemoreceptors (SPCR), which reflects the decreasing reactivity of the cardiovascular system.

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.

Central role of carotid body chemoreceptors in disordered breathing and cardiorenal dysfunction in chronic heart failure.

Oscillatory breathing (OB) patterns are observed in pre-term infants, patients with cardio-renal impairment, and in otherwise healthy humans exposed to high altitude. Enhanced carotid body (CB) chemoreflex sensitivity is common to all of these populations and is thought to contribute to these abnormal patterns by destabilizing the respiratory control system. OB patterns in chronic heart failure (CHF) patients are associated with greater levels of tonic and chemoreflex-evoked sympathetic nerve activity (SNA), which is associated with greater morbidity and poor prognosis. Enhanced chemoreflex drive may contribute to tonic elevations in SNA by strengthening the relationship between respiratory and sympathetic neural outflow. Elimination of CB afferents in experimental models of CHF has been shown to reduce OB, respiratory-sympathetic coupling, and renal SNA, and to improve autonomic balance in the heart. The CB chemoreceptors may play an important role in progression of CHF by contributing to respiratory instability and OB, which in turn further exacerbates tonic and chemoreflex-evoked increases in SNA to the heart and kidney.

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.

Essential role of RVL medullary neuronal activity in the long term maintenance of hypertension in conscious SHR.

It is well established that sympathetic nervous system is responsible for the onset, development and maintenance of neurogenic hypertension. The rostroventrolateral medulla (RVLM) and medullo-cervical pressor area (MCPA) are important central sympathoexcitatory regions whose role on neurogenic hypertension remains unknown. To establish RVLM and MCPA roles in the long-term regulation of blood pressure by depressing their neuron activity through the over-expression of hKir2.1-potassium channel in conscious spontaneously hypertensive rats (SHR). In SHR, a lentiviral vector LVV-hKir2.1 was microinjected into RVLM or MCPA areas. A sham group was injected with LVV-eGFP. Blood pressure (BP) and heart rate (HR) were continuously monitored for 75 days. Baroreflex and chemoreflex functions were evaluated. Baroreflex gain, chemoreflex sensitivity, BP and HR variability were calculated. LVV-hKir2.1 expression in RVLM, but not in MCPA, produced a significant time-dependent decrease in systolic, diastolic, mean-BP and LF of systolic BP at 60-days post-injection. No significant changes were seen in LVV-eGFP RVLM injected SHR. Data show that chronic expression of Kir2.1 in the RVLM of conscious SHR caused a marked and sustained decrease in BP without changes in the baro- and peripheral chemoreceptor reflex evoked responses. This decrease was mostly due to a reduction in sympathetic output revealed indirectly by a decrease in the power density of the SBP-LF band. Our data are amongst the firsts to demonstrate the role of the RVLM in maintaining BP levels in hypertension in conscious SHR. We suggest that a decrease in RVLM neuronal activity is an effective anti-hypertensive treatment strategy.