Chemoreflex Sensitivity Research Articles

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.

Regulation of Coronary Blood Flow by the Carotid Body Chemoreceptors in Ovine Heart Failure.

Carotid bodies (CBs) are peripheral chemoreceptors, which are primary sensors of systemic hypoxia and their activation produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. We have previously shown that carotid chemoreceptor stimulation increases directly recorded cardiac sympathetic nerve activity (cardiac SNA) which increases coronary blood flow (CoBF) in conscious normal sheep. Previous studies have shown that chemoreflex sensitivity is augmented in heart failure (HF). We hypothesized that carotid chemoreceptor stimulation would increase CoBF to a greater extent in HF than control sheep. Experiments were conducted in conscious HF sheep and control sheep (n = 6/group) implanted with electrodes to record diaphragmatic electromyography (dEMG), flow probes to record CoBF as well as arterial pressure. There was a significant increase in mean arterial pressure (MAP), CoBF and coronary vascular conductance (CVC) in response to potassium cyanide (KCN) in both groups of sheep. To eliminate the effects of metabolic vasodilation, the KCN was repeated while the heart was paced at a constant level. In this paradigm, the increase in CoBF and CVC was augmented in the HF group compared to the control group. Pre-treatment with propranolol did not alter the CoBF or the CVC increase in the HF group indicating this was not mediated by an increase in cardiac sympathetic drive. The pressor response to CB activation was abolished by pre-treatment with intravenous atropine in both groups, but there was no change in the CoBF and vascular conductance responses. Our data suggest that in an ovine model of HF, carotid body (CB) mediated increases in CoBF and CVC are augmented compared to control animals. This increase in CoBF is mediated by an increase in cardiac SNA in the control group but not the HF group.

Low ventilatory responsiveness to transient hypoxia or breath-holding predicts fast marathon performance in healthy middle-aged and older men

The aim of this study was to test the utility of haemodynamic and autonomic variables (e.g. peripheral chemoreflex sensitivity [PCheS], blood pressure variability [BPV]) for the prediction of individual performance (marathon time and VO2max) in older men. The post-competition vasodilation and sympathetic vasomotor tone predict the marathon performance in younger men, but their prognostic relevance in older men remains unknown. The peripheral chemoreflex restrains exercise-induced vasodilation via sympathetically-mediated mechanism, what makes it a plausible candidate for the individual performance marker. 23 men aged ≥ 50 year competing in the Wroclaw Marathon underwent an evaluation of: resting haemodynamic parameters, PCheS with two methods: transient hypoxia and breath-holding test (BHT), cardiac barosensitivity, heart rate variability (HRV) and BPV, plasma renin and aldosterone, VO2max in a cardiopulmonary exercise test (CPET). All tests were conducted twice: before and after the race, except for transient hypoxia and CPET which were performed once, before the race. Fast marathon performance and high VO2max were correlated with: low ventilatory responsiveness to hypoxia (r = − 0.53, r = 0.67, respectively) and pre-race BHT (r = − 0.47, r = 0.51, respectively), (1) greater SD of beat-to-beat SBP (all p < 0.05). Fast performance was related with an enhanced pre-race vascular response to BHT (r = − 0.59, p = 0.005). The variables found by other studies to predict the marathon performance in younger men: post-competition vasodilation, sympathetic vasomotor tone (LF-BPV) and HRV were not associated with the individual performance in our population. The results suggest that PCheS (ventilatory response) predicts individual performance (marathon time and VO2max) in men aged ≥ 50 yeat. Although cause-effect relationship including the role of peripheral chemoreceptors in restraining the post-competition vasodilation via the sympathetic vasoconstrictor outflow may be hypothesized to underline these findings, the lack of correlation between individual performance and both, the post-competition vasodilation and the sympathetic vasomotor tone argues against such explanation. Vascular responsiveness to breath-holding appears to be of certain value for predicting individual performance in this population, however.

Duration at High Altitude Influences the Onset of Arrhythmogenesis During Apnea

Excitation of both sympathetic and parasympathetic systems occur concurrently at high-altitude (chronic hypoxia), via the carotid chemoreflex. We have demonstrated this autonomic conflict manifests as cardiac arrhythmias during voluntary apnea. We sought to determine the duration of hypoxic exposure at high-altitude necessary to unmask cardiac arrhythmias during instances of voluntary apnea. We hypothesized that the occurrence of cardiac arrhythmias during apnea would be increased following 24 hours of high-altitude exposure. Measurements of oxygen saturation (SpO2; pulse oximetry) and continuous electrocardiogram (ECG; lead II) were collected in 22 participants (8 females) at low altitude (1045m) and over 8 consecutive days at high-altitude (3800m). Following a 2 minute baseline participants performed an end-expiratory apnea to volitional breakpoint. ECG rate and rhythm were evaluated at baseline and during apnea. The nadir heart rate was used to quantify bradycardia and abnormal ECG rhythm was classified based on origin (e.g., sinus node) and type (e.g., sinus arrest). Differences in resting ventilation, SpO2, and the heart rate response to apnea on each day at high-altitude (Day 1-8) were compared to that at low altitude (Day 0) using a repeated-measures ANOVA design, with a Holm-Sidak post-hoc analysis where main effect of time was significant. Baseline SpO2 was lower for all days at high-altitude (average of all days, 89±3) compared to low altitude (98 ± 2) (p<0.01). At high-altitude (all days), baseline heart rate was higher compared to low altitude (p<0.01). A main effect of time (p<0.01) was identified for the delta change in heart rate during apnea. At low altitude, the average apnea induced decrease in heart rate was -9±15bpm, whereas the average decrease in heart rate at high altitude (all days) was -24±16bpm. Bradycardia became more pronounced with acclimatization, with the greatest drop in heart rate (-31±16bpm) occurring on Day 5. At low altitude 14% (3/22) of participants developed arrhythmias during apnea. At high-altitude, cardiac arrhythmias during apnea became most prevalent (>50%) following Day 5. Changes in saturation during apnea and apnea duration were not associated with the magnitude of bradycardia during apnea (saturation, r= -0.007 p=0.92; apnea duration, r=0.005 p=0.94). Interestingly, the magnitude of bradycardia was correlated with the incidence (percentage) of arrhythmia per day (r=0.8; p=0.004), suggesting a similar underlying mechanism. Our data indicate chronic hypoxia is associated with a progressive increase in vagal tone, as indicated by augmented bradycardia during apnea and progressively increased incidence of arrhythmia at high-altitude. Additionally, the increased incidence of arrhythmia with acclimatization suggests that chemoreflex sensitization may play a role in this phenomenon. This study provides insight into cardiac electrophysiology at high-altitude and has implications as a future functional model for exploring the effects of heightened chemoreflex stress on autonomic control of heart.

Modulation of the initial stages of systemic inflammation by intervention in the NFkB signalling pathway

Sepsis is a systemic inflammatory state mediated by the innate immune system resulting in an excessive cellular response to severe infection, with high levels of morbidity and mortality. Furthermore, patients who survive sepsis, have long-term cognitive and functional impairment. Animal models are essential to clarify the pathophysiological mechanisms of sepsis. Herein, we characterise an animal model of lipopolysaccharide (LPS)-induced inflammation, evaluating neural and cardiac function, during the initial stages of infection. Male Wistar rats (12–20 wks, n = 24) were injected with LPS (E. coli serotype O127:B8; tail vein) and divided into 3 groups: LPS6 (6 mg/kg), LPS12 (12 mg/kg) and Sham (NaCl 0.9%; 0.1 ml/100g). At 6 and 24 h after LPS injection, an autonomic evaluation was performed in both conscious animals, with continuous radio-telemetry recording of blood pressure (BP) and heart rate (HR), and in anaesthetised animals (induction: sodium pentobarbital, 60 mg/kg, ip; maintenance: 20% solution, v/v) with BP, ECG, HR, tracheal pressure, respiratory frequency (RF) and body temperature continuously monitored. Baro and chemoreflex were evaluated with phenylephrine (0.2 ml, 25 µg/ml; iv) and lobeline (0.2 ml, 25 μg/ml; iv), respectively. Behavioural changes were also evaluated through the elevated-plus maze, open-field and Y-maze tests. Immunohistochemistry and RT-PCR were executed to determine heart and brain inflammatory state. Serum biomarkers levels for organ disfunction were also measured. Overall our results show a rise in BP and HR, and elevated RF due to increased chemoreflex sensitivity. 24 h following LPS injection, all groups have a significantly decreased baroreflex (p < 0.05), however, 6 h post-injection, LPS12 show a statistically significant increase in baroreceptor reflex (p < 0.05). At both time-points, the two LPS groups present an anxiety-like behaviour, associated with less locomotor/exploratory activity and highly significant cognitive impairment (p < .0001). The autonomic evaluation of the anaesthetised LPS12 group results in an increase of the autonomic tone at 6 h post-LPS followed by a decrease at 24 h. The LPS6 group shows the opposite profile. Interestingly, conscious animals reveal a slightly different profile in both groups, with a continuous increase in autonomic tone for LPS12 and a decrease 24 h post-LPS in LPS6 group. The molecular studies show reactive astrogliosis and microgliosis, due to inflammatory processes in the hippocampus, as well as, an upregulation of pro-inflammatory factors in the heart and brain. Serum analysis yielded higher levels of biomarkers for renal and liver dysfunction (p < .05) and pancreatic and neuromuscular injury (p < .05), in the LPS12 group. Concluding, LPS administration induces strong modifications in both cardiac and neurological systems, during the early stages of the systemic inflammatory response. Being a good model for further pathophysiological and pharmacological studies related to Sepsis.

Impact of COVID-19 on exercise pathophysiology: a combined cardiopulmonary and echocardiographic exercise study.

Survivors from COVID-19 pneumonia can present with persisting multisystem involvement (lung, pulmonary vessels, heart, muscle, red blood cells) that may negatively affect exercise capacity. We sought to determine the extent and the determinants of exercise limitation in patients with COVID-19 at the time of hospital discharge. Eighteen consecutive patients with COVID-19 and 1:1 age-, sex-, and body mass index-matched controls underwent: spirometry, echocardiography, cardiopulmonary exercise test and exercise echocardiography for the study of pulmonary circulation. Arterial blood was sampled at rest and during exercise in patients with COVID-19. Patients with COVID-19 lie roughly on the same oxygen consumption isophlets than controls both at rest and during submaximal exercise, thanks to supernormal cardiac output (P < 0.05). Oxygen consumption at peak exercise was reduced by 30% in COVID-19 (P < 0.001), due to a peripheral extraction limit. In addition, within COVID-19 patients, hemoglobin content was associated with peak oxygen consumption (R2 = 0.46, P = 0.002). Respiratory reserve was not exhausted (median [IRQ], 0.59 [0.15]) in spite of moderate reduction of forced vital capacity (79 ± 40%). Pulmonary artery pressure increase during exercise was not different between patients and controls. Ventilatory equivalents for carbon dioxide were higher in patients with COVID-19 than in controls (39.5 [8.5] vs. 29.5 [8.8], P < 0.001), and such an increase was mainly explained by increased chemosensitivity. When recovering from COVID-19, patients present with reduced exercise capacity and augmented exercise hyperventilation. Peripheral factors, including anemia and reduced oxygen extraction by peripheral muscles were the major determinants of deranged exercise physiology. Pulmonary vascular function seemed unaffected, despite restrictive lung changes.NEW & NOTEWORTHY At the time of hospital discharge, patients with COVID-19 present with reduced functional capacity and exercise hyperventilation. Peripheral factors, namely reduced oxygen extraction (myopathy) and anemia, which are not fully compensated by a supernormal cardiac output response, account for exercise limitation before exhaustion of the respiratory reserve. Enhanced chemoreflex sensitivity, rather increased dead space, mainly accounts for exercise hyperventilation. The pulmonary vascular response to exercise circulation of survived patients with COVID-19 does not present major pathological changes.

Relevance of differential control of sympathorespiratory response magnitudes in clinical assessments.

Relevance of differential control of sympathorespiratory response magnitudes in clinical assessments.

ОСОБЛИВОСТІ СТІЙКОСТІ ДО ГІПОКСІЇ У ХВОРИХ ПОХИЛОГО ВІКУ З ХРОНІЧНИМ ОБСТРУКТИВНИМ ЗАХВОРЮВАННЯМ ЛЕГЕНЬ

FEATURES OF RESISTANCE TO HYPOXIA IN ELDERLY PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE E. O. Asanov, Yu. I. Golubova, I. A. Dyba, S. O. Asanova Abstract Aim: to study the features of resistance to hypoxia in elderly patients with COPD. Material and methods. We examined 46 elderly patients with COPD and 18 apparently healthy elderly people. Hypoxia resistance was determined by performing a hypoxic test with inhalation of 12 % O2 for 20 minutes. The state of ventilation and blood saturation were assessed. Results. Hypoxia caused the reduction of SpO2 and the development of arterial hypoxemia in elderly patients with COPD, which were more significant than in healthy elderly people. It was found that among elderly patients with COPD and healthy elderly subjects there were people with preserved and reduced resistance to hypoxia. However, reduced resistance to hypoxia was much more common in elderly patients with COPD. Decreased resistance to hypoxia in elderly patients with COPD was associated with the degree of bronchial obstruction: deterioration of bronchial passability led to reduced resistance to hypoxia. Elderly patients with COPD with reduced resistance to hypoxia had a decrease in the ΔVE/ ΔSpO2 ratio and a slow ventilation response to hypoxic exposure. Conclusions. Among healthy elderly people and elderly patients with COPD there were subjects with reduced and preserved resistance to hypoxia. Decreased resistance to hypoxia was much more common in elderly patients with COPD. Decreased resistance to hypoxia was more common in patients with moderate than mild bronchial obstruction. Elderly patients with COPD with reduced resistance to hypoxia had reduced ventilation response to hypoxia and chemoreflex sensitivity. Key words: COPD, older age, resistance to hypoxia, ventilation, saturation. Ukr. Pulmonol. J. 2021;29(3):36–40:

Measuring Peripheral Chemoreflex Hypersensitivity in Heart Failure.

Heart failure with reduced ejection fraction (HFrEF) induces chronic sympathetic activation. This disturbance is a consequence of both compensatory reflex disinhibition in response to lower cardiac output and patient-specific activation of one or more excitatory stimuli. The result is the net adrenergic output that exceeds homeostatic need, which compromises cardiac, renal, and vascular function and foreshortens lifespan. One such sympatho-excitatory mechanism, evident in ~40–45% of those with HFrEF, is the augmentation of carotid (peripheral) chemoreflex ventilatory and sympathetic responsiveness to reductions in arterial oxygen tension and acidosis. Recognition of the contribution of increased chemoreflex gain to the pathophysiology of HFrEF and to patients’ prognosis has focused attention on targeting the carotid body to attenuate sympathetic drive, alleviate heart failure symptoms, and prolong life. The current challenge is to identify those patients most likely to benefit from such interventions. Two assumptions underlying contemporary test protocols are that the ventilatory response to acute hypoxic exposure quantifies accurately peripheral chemoreflex sensitivity and that the unmeasured sympathetic response mirrors the determined ventilatory response. This Perspective questions both assumptions, illustrates the limitations of conventional transient hypoxic tests for assessing peripheral chemoreflex sensitivity and demonstrates how a modified rebreathing test capable of comprehensively quantifying both the ventilatory and sympathoneural efferent responses to peripheral chemoreflex perturbation, including their sensitivities and recruitment thresholds, can better identify individuals most likely to benefit from carotid body intervention.

Acute inorganic nitrate supplementation and the hypoxic ventilatory response in patients with obstructive sleep apnea.

Patients with obstructive sleep apnea (OSA) have increased cardiovascular disease risk largely attributable to hypertension. Heightened peripheral chemoreflex sensitivity (i.e., exaggerated responsiveness to hypoxia) facilitates hypertension in these patients. Nitric oxide blunts the peripheral chemoreflex, and patients with OSA have reduced nitric oxide bioavailability. We therefore investigated the dose-dependent effects of acute inorganic nitrate supplementation (beetroot juice), an exogenous nitric oxide source, on blood pressure and cardiopulmonary responses to hypoxia in patients with OSA using a randomized, double-blind, placebo-controlled crossover design. Fourteen patients with OSA (53 ± 10 yr, 29.2 ± 5.8 kg/m2, apnea-hypopnea index = 17.8 ± 8.1, 43%F) completed three visits. Resting brachial blood pressure and cardiopulmonary responses to inspiratory hypoxia were measured before, and 2 h after, acute inorganic nitrate supplementation [∼0.10 mmol (placebo), 4.03 mmol (low dose), and 8.06 mmol (high dose)]. Placebo increased neither plasma [nitrate] (30 ± 52 to 52 ± 23 μM, P = 0.26) nor [nitrite] (266 ± 153 to 277 ± 164 nM, P = 0.21); however, both increased following low (29 ± 17 to 175 ± 42 μM, 220 ± 137 to 514 ± 352 nM) and high doses (26 ± 11 to 292 ± 90 μM, 248 ± 155 to 738 ± 427 nM, respectively, P < 0.01 for all). Following placebo, systolic blood pressure increased (120 ± 9 to 128 ± 10 mmHg, P < 0.05), whereas no changes were observed following low (121 ± 11 to 123 ± 8 mmHg, P = 0.19) or high doses (124 ± 13 to 124 ± 9 mmHg, P = 0.96). The peak ventilatory response to hypoxia increased following placebo (3.1 ± 1.2 to 4.4 ± 2.6 L/min, P < 0.01) but not low (4.4 ± 2.4 to 5.4 ± 3.4 L/min, P = 0.11) or high doses (4.3 ± 2.3 to 4.8 ± 2.7 L/min, P = 0.42). Inorganic nitrate did not change the heart rate responses to hypoxia (beverage-by-time P = 0.64). Acute inorganic nitrate supplementation appears to blunt an early-morning rise in systolic blood pressure potentially through suppression of peripheral chemoreflex sensitivity in patients with OSA.NEW & NOTEWORTHY The present study is the first to examine the acute effects of inorganic nitrate supplementation on resting blood pressure and cardiopulmonary responses to hypoxia (e.g., peripheral chemoreflex sensitivity) in patients with obstructive sleep apnea (OSA). Our data indicate inorganic nitrate supplementation attenuates an early-morning rise in systolic blood pressure potentially attributable to blunted peripheral chemoreflex sensitivity. These data show proof-of-concept that inorganic nitrate supplementation could reduce the risk of cardiovascular disease in patients with OSA.

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.

Prediction of the Effectiveness of Spontaneous Breathing in Patients with Brain Damage of Various Etiologies.

The aim of the study was to develop an informative method for assessing chemoreflex sensitivity and to evaluate its prognostic capacity for restoring spontaneous breathing in patients with brain damage of various etiologies. The study included 16 healthy volunteers and 38 patients on prolonged mechanical ventilation (VE) after a traumatic brain injury, anoxic brain damage, and cerebrovascular events. The external respiration variables were assessed from the initial level to the development of the first episode of desaturation with spO2 in the range of 90–80% against the background of normobaric hypoxia as indicators reflecting the development of adaptive ventilatory response and characterizing the state of peripheral chemoreflex sensitivity (PCS). The peripheral chemoreflex sensitivity index (PCSI) was calculated using the equation: PCSI = [RR(e) : RR(i)] × [Vt(e) : Vt(i)] × [VE(e) : VE(i)] × Vt(e) × VE(e), where PCSI is the peripheral chemoreflex sensitivity index in L2/min; RR(i) and RR(e); Vt(i) and Vt(e); VE(i) and VE(e) are the respiratory rate, tidal volume, minute ventilation initially (i), before a functional stress test, and during a functional test of normobaric hypoxia with spO2 in the range of 90–80% (e). With the PCSI values ≥15.6 L2/min, successful weaning from ventilators and recovery of spontaneous breathing are predicted. The sensitivity and specificity of PCSI were 78.57 [95% CI: 49.2–95.26] and 83.3% [95% CI: 62.6–95.26], respectively. The sensitivity and specificity of the traditional indicator of the success rate of weaning from ventilators and recovery of spontaneous breathing, Rapid Shallow Breathing Index (RSBI), in this cohort of patients was 69.23 [95% CI: 38.6–90.9] and 28.0% [95% CI: 12.03–49.3], respectively. A predictor of the patient’s weaning from mechanical ventilation is the assessment of peripheral chemoreflex sensitivity, which can be measured by a simple non-invasive bedside test based on measuring the difference in external ventilation parameters before and during a functional normobaric hypoxic trial.

Effects of maternal protein restriction on central and peripheral renin-angiotensin systems in male rat offspring

AimsWe investigated the involvement of the renin angiotensin system (RAS) on the cardiorespiratory control in rats from dams fed with a low-protein diet. Main methodsMale offspring were obtained from dams fed a normoprotein diet (NP, 17% casein) and low-protein diet (LP, 8% casein) during pregnancy and lactation. Direct measurements of arterial pressure (AP), heart rate (HR) and respiratory frequency (RF) were recorded in awake 90-day-old at resting and after losartan potassium through either intracerebroventricular (ICV) microinjections or intravenous (IV) administration. Cardiovascular variability was evaluated by spectral analysis. Peripheral chemoreflex sensitivity was assessed through the potassium cyanide (KCN; 40 μg/0.1 ml/rat, IV). Gene expression was evaluated by qPCR, and MAPK (Mitogen Activated Protein Kinase) expression was evaluated by western blot. Key findingsThe LP offspring had higher mean AP (MAP) and RF than NP offspring. In the spectral analysis, the LP rats also showed higher low frequency of systolic AP (NP: 2.7 ± 0.3 vs. LP: 5.0 ± 1.0 mmHg). After ICV losartan, MAP and RF in LP rats remained higher than those in NP rats, but without changes in HR. The peripheral chemoreflex was similar between the groups. LP group had lower gene expression of Rac1 (Ras-related C3 botulinum toxin substrate 1) (NP: 1.13 ± 0.06 vs. LP: 0.88 ± 0.08). Peripherally, LP rats had larger delta of MAP after IV losartan (NP: −9.8 ± 2 vs. LP: −23 ± 6 mmHg), without changes in HR and RF. SignificanceIn rats, the RAS participates peripherally, but not centrally, in the maintenance of arterial hypertension in male offspring induced by maternal protein restriction.

Amelioration of sleep-disordered breathing with supplemental oxygen in older adults.

Elderly adults demonstrate increased propensity for breathing instability during sleep compared with younger adults, and this may contribute to increased prevalence of sleep-disordered breathing (SDB) in this population. Hence, in older adults with SDB, we examined whether addition of supplemental oxygen (O2) will stabilize breathing during sleep and alleviate SDB. We hypothesized that exposure to supplemental O2 during non-rapid eye movement (NREM) sleep will stabilize breathing and will alleviate SDB by reducing ventilatory chemoresponsiveness and by widening the carbon dioxide (CO2) reserve. We studied 10 older adults with mild-to-moderate SDB who were randomized to undergo noninvasive bilevel mechanical ventilation with exposure to room air or supplemental O2 (Oxy) to determine the CO2 reserve, apneic threshold (AT), and controller and plant gains. Supplemental O2 was introduced during sleep to achieve a steady-state O2 saturation ≥95% and fraction of inspired O2 at 40%-50%. The CO2 reserve increased significantly during Oxy versus room air (-4.2 ± 0.5 mmHg vs. -3.2 ± 0.5 mmHg, P = 0.03). Compared with room air, Oxy was associated with a significant decline in the controller gain (1.9 ± 0.4 L/min/mmHg vs. 2.5 ± 0.5 L/min/mmHg, P = 0.04), with reductions in the apnea-hypopnea index (11.8 ± 2.0/h vs. 24.4 ± 5.6/h, P = 0.006) and central apnea-hypopnea index (1.7 ± 0.6/h vs. 6.9 ± 3.9/h, P = 0.03). The AT and plant gain were unchanged. Thus, a reduced slope of CO2 response resulted in an increased CO2 reserve. In conclusion, supplemental O2 reduced SDB in older adults during NREM sleep via reduction in chemoresponsiveness and central respiratory events.NEW & NOTEWORTHY This study demonstrates for the first time in elderly adults without heart disease that intervention with supplemental oxygen in the clinical range will ameliorate central apneas and hypopneas by decreasing the propensity to central apnea through decreased chemoreflex sensitivity, even in the absence of a reduction in the plant gain. Thus, the study provides physiological evidence for use of supplemental oxygen as therapy for mild-to-moderate SDB in this vulnerable population.

Autonomic innervation of the carotid body as a determinant of its sensitivity: implications for cardiovascular physiology and pathology.

The motivation for this review comes from the emerging complexity of the autonomic innervation of the carotid body (CB) and its putative role in regulating chemoreceptor sensitivity. With the carotid bodies as a potential therapeutic target for numerous cardiorespiratory and metabolic diseases, an understanding of the neural control of its circulation is most relevant. Since nerve fibres track blood vessels and receive autonomic innervation, we initiate our review by describing the origins of arterial feed to the CB and its unique vascular architecture and blood flow. Arterial feed(s) vary amongst species and, unequivocally, the arterial blood supply is relatively high to this organ. The vasculature appears to form separate circuits inside the CB with one having arterial venous anastomoses. Both sympathetic and parasympathetic nerves are present with postganglionic neurons located within the CB or close to it in the form of paraganglia. Their role in arterial vascular resistance control is described as is how CB blood flow relates to carotid sinus afferent activity. We discuss non-vascular targets of autonomic nerves, their possible role in controlling glomus cell activity, and how certain transmitters may relate to function. We propose that the autonomic nerves sub-serving the CB provide a rapid mechanism to tune the gain of peripheral chemoreflex sensitivity based on alterations in blood flow and oxygen delivery, and might provide future therapeutic targets. However, there remain a number of unknowns regarding these mechanisms that require further research that is discussed.

Variations in loop gain and arousal threshold during NREM sleep are affected by time of day over a 24-hour period in participants with obstructive sleep apnea.

We investigated whether time of day affects loop gain (LG) and the arousal threshold (AT) during non-rapid eye movement (NREM) sleep. Eleven men with obstructive sleep apnea (apnea-hypopnea index > 5 events/h) completed a constant-routine protocol that comprised 3-h sleep sessions in the evening [10 PM (1) to 1 AM], morning (6 AM to 9 AM), afternoon (2 PM to 5 PM), and subsequent evening [10 PM (2) to 1 AM]. During each sleep session LG and the AT were measured during NREM sleep with a model-based approach. Our results showed the presence of a rhythmicity in both LG (P < 0.0001) and the AT (P < 0.001) over a 24-h period. In addition, LG and the AT were greater in the morning compared with both evening sessions [6 AM vs. 10 PM (1) vs. 10 PM (2): LG (1 cycle/min): 0.71 ± 0.23 vs. 0.60 ± 0.22 (P = 0.01) vs. 0.56 ± 0.10 (P < 0.001), AT (fraction of eupneic breathing): 1.45 ± 0.47 vs. 1.28 ± 0.36 (P = 0.02) vs. 1.20 ± 0.18 (P = 0.001)]. No difference in LG and the AT existed between the evening sessions (LG: P = 0.27; AT: P = 0.24). LG was correlated to measures of the hypocapnic ventilatory response (i.e., a measure of chemoreflex sensitivity) (r = 0.72 and P = 0.045) and the critical closing pressure (i.e., a measure of airway collapsibility) (r = 0.77 and P = 0.02) that we previously published. We conclude that time of day, independent of hallmarks of sleep apnea, affects LG and the AT during NREM sleep. These modifications may contribute to increases in breathing instability in the morning compared with other periods throughout the day/night cycle in individuals with obstructive sleep apnea. In addition, efficaciousness of treatments for obstructive sleep apnea that target LG and the AT may be modified by a rhythmicity in these variables.NEW & NOTEWORTHY Loop gain and the arousal threshold during non-rapid eye movement (NREM) sleep are greater in the morning compared with the afternoon and evening. Loop gain measures are correlated to chemoreflex sensitivity and the critical closing pressure measured during NREM sleep in the evening, morning, and afternoon. Breathing (in)stability and efficaciousness of treatments for obstructive sleep apnea may be modulated by a circadian rhythmicity in loop gain and the arousal threshold.

Central apnoeas and ticagrelor-related dyspnoea in patients with acute coronary syndrome.

Dyspnoea often occurs in patients with acute coronary syndrome (ACS) treated with ticagrelor compared with other anti-platelet agents and is a cause of drug discontinuation. We aimed to explore the contribution of central apnoeas (CA) and chemoreflex sensitization to ticagrelor-related dyspnoea in patients with ACS. Sixty consecutive patients with ACS, preserved left ventricular ejection fraction, and no history of obstructive sleep apnoea, treated either with ticagrelor 90 mg b.i.d. (n = 30) or prasugrel 10 mg o.d. (n = 30) were consecutively enrolled. One week after ACS, all patients underwent two-dimensional Doppler echocardiography, pulmonary static/dynamic testing, carbon monoxide diffusion capacity assessment, 24-h cardiorespiratory monitoring for hypopnoea-apnoea detection, and evaluation of the chemosensitivity to hypercapnia by rebreathing technique. No differences were found in baseline demographic and clinical characteristics, echocardiographic, and pulmonary data between the two groups. Patients on ticagrelor, when compared with those on prasugrel, reported more frequently dyspnoea (43.3% vs. 6.7%, P = 0.001; severe dyspnoea 23.3% vs. 0%, P = 0.005), and showed higher apnoea-hypopnoea index (AHI) and central apnoea index (CAI) during the day, the night and the entire 24-h period (all P < 0.001). Similarly, they showed a higher chemosensitivity to hypercapnia (P = 0.001). Among patients treated with ticagrelor, those referring dyspnoea had the highest AHI, CAI, and chemosensitivity to hypercapnia (all P < 0.05). Central apnoeas are a likely mechanism of dyspnoea and should be screened for in patients treated with ticagrelor. A drug-related sensitization of the chemoreflex may be the cause of ventilatory instability and breathlessness in this setting.

Acetylcholinesterase inhibition prevents alterations in cardiovascular autonomic control and gastric motility in L-NAME-induced hypertensive rats

AimsAutonomic dysfunction in arterial hypertension affects cardiorespiratory control and gastric motility and has been characterized by increased sympathetic and reduced parasympathetic activity. In the present work we investigated the effects of anticholinesterase drugs [donepezil (DON) or pyridostigmine (PYR)] on cardiovascular, autonomic, and gastric parameters in L-NAME-induced hypertensive rats. Materials and methodsDaily oral gavage of L-NAME (70 mg/kg/day) was performed over 14 days in male Wistar rats (180-220 g), whereas daily oral gavage of DON or PYR (1.6 and 22 mg/kg/day, respectively) started 2 days after the L-NAME treatment initiation and lasted 12 days. The development of hypertension was verified by tail plethysmography technique. After the end of treatments, the animals were subjected to experimental protocols (6–12 animals per group; total number of animals used: 78). Key findingsL-NAME hypertensive animals had no alterations in heart rate (HR) and intrinsic HR, but showed reduction in baroreflex sensitivity, parasympathetic tone, and gastric motility; and the sympathetic tone, chemoreflex sensitivity, and the LF (low frequency) band of systolic arterial pressure (SAP) variability were increased. DON or PYR attenuated the increase in mean arterial pressure (MAP) induced by L-NAME. Both anticholinesterase drugs were effective in preventing the decrease in baroreflex sensitivity, parasympathetic tone and gastric motility, and also prevented the increases in peripheral chemoreflex response and cardiac sympathetic tone. SignificanceAcetylcholinesterase inhibition with DON or PYR is a promising pharmacological approach to increase parasympathetic function, thus preventing the hypertension-induced alterations in the cardiovascular, gastrointestinal and autonomic systems.

Regulation of Coronary Blood Flow by the Carotid Body Chemoreceptors in Ovine Heart Failure

BackgroundThe carotid body (CB) is an arterial chemoreceptor organ located in the carotid bifurcation, which carries out essential functions in cardiorespiratory control. In response to hypoxia, carotid chemosensory discharge produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. Previous studies have shown that chemoreflex sensitivity is augmented animal models of heart failure (HF). However, the role of the chemoreflex in modulating coronary blood flow during HF is not clear. We hypothesized that carotid chemoreceptor stimulation would increase coronary blood flow in both normal sheep and sheep with HF.MethodsHeart failure was induced by the microembolization technique and instrumentation was performed when ejection fraction was below 40%. Both groups of sheep were implanted with a coronary artery flow probe and an arterial pressure catheter. The responses of mean arterial pressure (MAP) and coronary blood flow (CoBF) were determined in conscious sheep following CB stimulation with intracarotid potassium cyanide (KCN; 30μg/kg). To determine the cardiac vagal contribution to the CoBF response, CB activation was repeated following atropine infusion (8 mg bolus followed by 24 mg/h infusion for 30 minutes).ResultsIn control animals, activation of the CB increased MAP (114±1%) and CoBF (116±4%) but coronary vascular conductance (CVC) was unaltered. In the HF group, CB stimulation increased MAP (108±1%), CoBF (126±3%), and CVC (114±2%). The MAP increase was significantly attenuated after atropine infusion in both animal groups, however, the CoBF and CVC responses to KCN were unchanged. These responses persisted when the heart was paced at a constant rate to eliminate the role of altered metabolic demand.DiscussionOur data indicate that in an ovine model of HF, carotid body mediated increases in MAP are attenuated compared to control animals. There was a significant increase in coronary vascular conductance in the HF animals following CB activation which was absent in the normal animals. Overall, our data suggest that the hyperactive carotid body chemoreflex may serve to increase coronary blood flow in the HF condition.Support or Funding InformationHealth Research Council of New Zealand, National Heart Foundation of New Zealand

Blood Pressure is Positively Associated with Glycosylated Hemoglobin but not the Hypoxic Ventilatory Response in Obstructive Sleep Apnea Patients

Study ObjectiveThe hypoxic ventilatory response (HVR) is considered an index of peripheral chemoreflex sensitivity. Previous work has suggested that an increase in the HVR is responsible for acute nocturnal blood pressure surges that ultimately lead to chronic elevations in blood pressure. Previous results have also indicated that glycosylation of hemoglobin (HbA1C) impairs nitric oxide (NO) relaxation of vascular smooth muscle leading to chronic elevations in blood pressure. Given these findings, we hypothesized that the HVR and HbA1C would be positively associated with blood pressure during sleep before and 3 weeks after treatment with mild intermittent hypoxia (MIH) in humans with obstructive sleep apnea (OSA).MethodsEight hypertensive participants with OSA were exposed to twelve 2‐minute episodes of hypoxia (PETO2 ≈ 50 mmHg) separated by 2‐minute normoxic intervals during wakefulness for 15 days over 3 weeks. PETCO2 was sustained at 2 mmHg above baseline during MIH administration. HbA1C was measured prior to completion of the protocol on Day 1 and 15. Moreover, blood pressure was measured over a period of 24 hours, before and after completion of the MIH protocol.ResultsOn Day 1, the HVR was negatively associated with HbA1C (−0.74, p &lt; 0.04) and systolic (SBP) (R = −0.73, p &lt; 0.05), diastolic (DBP) (R = −0.69, p &lt; 0.05) and mean arterial blood pressure (MAP) (R = −0.71, p &lt; 0.05) recorded during the sleep period of a 24 hour cycle. In contrast, HbA1C was positively associated with measures of SBP (R = 0.82, p &lt; 0.01), DBP (R = 0.81, p &lt; 0.01) and MAP (R = 0.86, p &lt; 0.01) during sleep. Following treatment with MIH, blood pressure during sleep decreased (Before vs. After MIH: SBP 131.9 ± 4.1 vs. 122.9 ± 3.1, DBP 77.8 ± 3.9 vs. 72.8 ± 3.9, MAP 95.8 ± 3.8 vs. 89.5 ± 3.4, P &lt; 0.02). The change (Δ) in SBP during sleep following MIH was correlated to the Δ HbA1C (R = 0.85, p ≤ 0.01). Moreover, the degree to which SBP dipped before vs. after MIH was also correlated to Δ HbA1C (R = 0.87, p ≤ 0.01). In contrast, Δ HVR was not correlated to the Δ in blood pressure parameters.ConclusionAlthough peripheral chemoreflex sensitivity may be responsible for acute surges in blood pressure, this factor does not appear to be a strong predictor of chronic changes in blood pressure. In contrast, modifications in local signaling molecules may ultimately have the greatest impact on chronic modifications in blood pressure. Indeed, our findings lend support to previous results which suggest that increases in blood pressure may be coupled to the impairment of nitric oxide in response to glycosylated hemoglobin. This relationship may exist in the presence of a blunted HVR.Support or Funding InformationDepartment of Veterans Affairs (I01CX000125 &amp; 15SRCS003 JHM, 1IK1RX002945 GSP), and NIH (R56HL142757 &amp; R01HL142757 JHM).