Control of breathing by orexinergic signaling in the nucleus tractus solitarii.

Orexin signaling plays a facilitatory role in respiration. Abnormalities in orexin levels correlate with disordered breathing patterns and impaired central respiratory chemoreception. Nucleus tractus solitarii (NTS) neurons expressing the transcription factor Phox2b contribute to the chemoreceptive regulation of respiration. However, the extent to which orexinergic signaling modulates respiratory activity in these Phox2b-expressing NTS neurons remains unclear. In the present study, the injection of orexin A into the NTS significantly increased the firing rate of the phrenic nerve. Further analysis using fluorescence in situ hybridization and immunohistochemistry revealed that orexin 1 receptors (OX1Rs) were primarily located in the ventrolateral subdivision of the NTS and expressed in 25% of Phox2b-expressing neurons. Additionally, electrophysiological recordings showed that exposure to orexin A increased the spontaneous firing rate of Phox2b-expressing neurons. Immunostaining experiments with cFos revealed that the OX1R-residing Phox2b-expressing neurons were activated by an 8% CO2 stimulus. Crucially, OX1R knockdown in these NTS neurons notably blunted the ventilatory response to 8% CO2, alongside an increase in sigh-related apneas. In conclusion, orexinergic signaling in the NTS facilitates breathing through the activation of OX1Rs, which induces the depolarization of Phox2b-expressing neurons. OX1Rs are essential for the involvement of Phox2b-expressing NTS neurons in the hypercapnic ventilatory response.

Clinical Predictors of Mixed Apneas in Patients with Obstructive Sleep Apnea (OSA).

Purpose: Mixed events in obstructive sleep apnea (OSA) patients (mixed-OSA) indicate respiratory regulation instability and are essential for OSA pathogenesis and prognosis. It also shows a decreased compliance with continuous positive airway pressure (CPAP). Using predictors to identify mixed-OSA has significant clinical guidance for OSA precise diagnosis and treatment. This study aimed to establish a simple and accessible method for rapid screening of mixed-OSA, thus promoting OSA precise diagnosis. Patients and Methods: A total of 907 patients with suspected OSA were screened, of which 513 OSA patients, including 344 with pure-OSA and 169 with mixed-OSA, were finally included in the study. The clinical characteristics and polysomnography (PSG) parameters of the two OSA groups were compared. Multivariate logistic regression analysis was used to investigate the factors affecting the morbidity of mixed-OSA. The receiver operating characteristic (ROC) curve was used to explore if some convenient PSG parameters can be used to predict mixed-OSA. Results: About 33% of OSA patients were identified as mixed-OSA. Multivariate logistic regression analysis showed that apnea hypopnea index (AHI) and lowest oxygen saturation (LSO2) were independently associated with mixed-OSA after adjusting for age, sex, body mass index (BMI), smoking, drinking, hypertension, and Epworth Sleepiness Score (ESS) (AHI: OR=1.046, 95% CI 1.032-1.060, P < 0.001; LSO2: OR=0.958, 95% CI 0.936-0.981, P < 0.001). ROC curve analysis showed that AHI > 47 or LSO2 < 77% indicated mixed-OSA. The sensitivity and specificity of AHI> 47 was 0.952 and 0.652, respectively, and 0.822 and 0.675 for LSO2 < 77%, respectively. Conclusion: Our research found that AHI > 47 or LSO2 < 77% are independently associated with mixed-OSA and can be used to quickly identify the occurrence of mixed-OSA. Therefore, this study can help detect mixed-OSA and precise individual diagnosis of OSA patients.

Inverse relationship of subjective daytime sleepiness to mortality in heart failure patients with sleep apnoea.

AIMS: Patients with sleep apnoea (SA) and heart failure (HF) are less sleepy than SA patients without HF. HF and SA both increase sympathetic nervous system activity (SNA). SNA can augment alertness. We previously showed that in HF patients, the degree of daytime sleepiness was not related to the severity of SA but was inversely related to SNA. Elevated SNA is associated with increased mortality in HF. Therefore, we hypothesized that in HF patients with SA, the degree of daytime sleepiness will be inversely related to mortality. METHODS AND RESULTS: In a prospective cohort study, 218 consecutive patients with systolic HF had overnight polysomnography. Among them, 80 subjects with SA (apnoea-hypopnoea index ≥15) were followed for a mean of 28 months to determine all-cause mortality rate. Subjective daytime sleepiness was assessed by the Epworth Sleepiness Scale (ESS). During follow-up, 20 patients died. The 5 year death rate in patients with ESS less than 6 (i.e. less sleepy) was significantly higher than in patients with an ESS at or above the median of 6 (i.e. sleepier) [21.3 deaths/100 patient-years vs. 6.2 deaths/100 patient-years, unadjusted hazard ratio (HR) 2.94, 95% confidence interval (CI) 1.20 to 7.20, P = 0.018]. After adjusting for confounding factors that included sex, history of hypertension, and mean arterial oxyhaemoglobin saturation, compared with the sleepier patients, less sleepy patients had greater risk of mortality (HR 2.56, 95% CI 1.01 to 6.47, P = 0.047). As a continuous variable, ESS scores were inversely related to mortality risk (HR 0.86, 95% CI 0.75 to 0.98, P = 0.022). CONCLUSIONS: In patients with HF and SA, the degree of subjective daytime sleepiness is inversely related to the mortality risk, suggesting that among HF patients with SA, those with the least daytime sleepiness are at greater risk of death. They may therefore have greater potential for mortality benefit from therapy of SA than those with greater daytime sleepiness.

Leptin Signaling in the Carotid Body Regulates a Hypoxic Ventilatory Response Through Altering TASK Channel Expression.

Leptin is an adipose-derived hormone that plays an important role in the regulation of breathing. It has been demonstrated that obesity-related hypoventilation or apnea is closely associated with leptin signaling pathways. Perturbations of leptin signaling probably contribute to the reduced sensitivity of respiratory chemoreceptors to hypoxia/hypercapnia. However, the underlying mechanism remains incompletely understood. The present study is to test the hypothesis that leptin signaling contributes to modulating a hypoxic ventilatory response. The respiratory function was assessed in conscious obese Zucker rats or lean littermates treated with an injection of leptin. During exposure to hypoxia, the change in minute ventilation was lower in obese Zucker rats than chow-fed lean littermates or high fat diet-fed littermates. Such a change was abolished in all groups after carotid body denervation. In addition, the expression of phosphorylated signal transducers and activators of transcription 3 (pSTAT3), as well as putative O2-sensitive K+ channels including TASK-1, TASK-3 and TASK-2 in the carotid body, was significantly reduced in obese Zucker rats compared with the other two phenotype littermates. Chronic administration of leptin in chow-fed lean Zucker rats failed to alter basal ventilation but vigorously increased tidal volume, respiratory frequency, and therefore minute volume during exposure to hypoxia. Likewise, carotid body denervation abolished such an effect. In addition, systemic leptin elicited enhanced expression of pSTAT3 and TASK channels. In conclusion, these data demonstrate that leptin signaling facilitates hypoxic ventilatory responses probably through upregulation of pSTAT3 and TASK channels in the carotid body. These findings may help to better understand the pathogenic mechanism of obesity-related hypoventilation or apnea.

[Nocturnal heart rhythm disorder in patients with obstructive sleep apnea syndrome].

OBJECTIVE: To explore the clinical characteristics of patients with obstructive sleep apnea syndrome (OSAS) and nocturnal arrhythmia. METHODS: During September 2010 to August 2011, a total of 446 subjects were recruited from Department of Sleep Breathing Disorder, Third Hospital, Hebei Medical University to receive polysomnography examination and electrocardiogram monitoring. According to the results, they were classified as mild (5 ≤ AHI < 15/h) or moderate (15 ≤ AHI < 40/h) or severe (AHI ≥ 40/h) OSAS. Then the incidence of different types of arrhythmias, risk factors and the relationship with OSAS severity were examined. RESULTS: Among 446 patients, the incidence of arrhythmia was 24.4% (109/446). The severity of OSAS (r = 1.857, P = 0.043) and age (r = 1.030, P = 0.003) had a positive relationship with the incidence of arrhythmias.Sinus bradycardia (79.8%, 87/109) and accidental ventricular premature beat (54.1%, 59/109) were most likely to occur than other types of arrhythmias (P < 0.01).In moderate and severity OSAS patients, the incidence of sinus bradycardia, frequent atrial premature beat, combined over two kinds of arrhythmias, atrial fibrillation and atrioventricular block were 50.0%, 0, 42.9%, 7.1%,0 and 90.9%, 14.8%, 57.9%, 4.5%, 5.7% respectively. And they were significantly higher than those of mild patients (all = 0) (all P < 0.05). CONCLUSIONS: Age and severity of OSAS have a positive relationship with the incidence of nocturnal arrhythmias.Sinus bradycardia and ventricular premature beat are the most likely to occur in OSAS patients.In moderate and severe group, sinus bradycardia, frequent atrial premature beat, combined over two kinds of arrhythmias, atrial fibrillation and atrioventricular block are more commonly encountered.

Relation of periodic leg movements during sleep and mortality in patients with systolic heart failure.

Periodic leg movements during sleep (PLMs) are a disorder characterized by regularly recurring movements of the legs during sleep. Although PLMs are common in patients with heart failure (HF), their clinical significance is unknown. The aim of this study was to determine whether, in patients with HF, PLMs are associated with increased mortality risk. In a prospective cohort study, 218 consecutive patients with systolic HF newly referred to an HF clinic from 1997 to 2004 who underwent overnight polysomnography, regardless of symptoms or signs of sleep disorders, were enrolled. The frequency of PLMs per hour of sleep was quantified as the PLM index (PLMI). Patients were classified as either normal (PLMI <5) or abnormal (PLMI ≥5). Eighty-one of the patients (37%) had PLMIs ≥5. During a mean follow-up period of 32.9 months, complete follow-up data were obtained in 95%. Patients with PLMIs ≥5 were older and had lower left ventricular ejection fractions and higher New York Heart Association classes than patients with PLMIs <5. The mortality rate was significantly higher in patients with PLMIs ≥5 than those with PMLIs <5 (10.4 vs 3.4 deaths/100 patient-years, p = 0.002). After adjusting for significant confounding factors, the presence of PLMI ≥5 remained a significant independent risk for death (hazard ratio 2.42, 95% confidence interval 1.16 to 5.02, p = 0.018). In conclusion, in patients with systolic HF, the presence of PLMI ≥5 is associated with an increased mortality risk, but these findings do not establish a cause-effect relation.

[Changes of the characteristics of sleep apnea in heart failure patients and the associated factors].

OBJECTIVE: To investigate the changes of the characteristics of sleep apnea in heart failure patients with periodic breathing disorder and to explore the influencing factors. METHODS: According to the characteristics of sleep apnea after polysomnography (PSG) for 2 nights, 54 patients with heart failure were divided into 3 groups: obstructive sleep apnea (OSA), central sleep apnea (CSA) and OSA-CSA switching groups, with 18 patients each. t test was used for comparison between the first and the second PSG data, left ventricular ejection fraction (LVEF), periodic breathing cycle length (PBCL) and lung to finger circulation time (LFCT) in the same patient. Analysis of variance was performed for comparison within groups and Pearson correlation test was used for correlation analysis between 2 variables. RESULTS: When the events of sleep apnea changed from OSA to CSA, the mean wake and sleep stage II (S2) PtcCO(2) decreased significantly [(41.0 +/- 1.3) cm H(2)O vs (34.9 +/- 1.0) cm H(2)O, 1 cm H(2)O = 0.098 kPa, P < 0.01;(42.1 +/- 1.2) cm H(2)O vs (36.3 +/- 1.1) cm H(2)O, P < 0.01], while PBCL and LCFT increased significantly [(51.9 +/- 2.1) s vs (62.3 +/- 1.9) s, P < 0.01, (54.4 +/- 1.8) s vs (65.3 +/- 1.6) s, P < 0.01]. Furthermore, there was a significant decrease in LVEF [(32.1 +/- 2.5)% vs (19.9 +/- 3.5)%, P < 0.05], and LVEF was negatively correlated with PBCL and LFCT (r = 0.687, P < 0.05;r = -0.591, P < 0.05). When sleep apnea changed from CSA to OSA, the mean wake and S2 PtcCO(2) increased significantly [(39.2 +/- 0.5) cm H(2)O vs (42.7 +/- 1.0) cm H(2)O, P < 0.05], while PBCL and LFCT decreased significantly [(61.5 +/- 3.4) s vs (49.7 +/- 2.8) s, P < 0.05, (66.1 +/- 2.1) s vs (52.1 +/- 1.6) s, P < 0.01)]. In addition, there was a negative correlation between PtcCO(2) and PBCL (r = -0.586, P < 0.05). However, PtcCO(2) showed no significant correlation with LFCT (r = -0.381, P > 0.05). There were no statistical differences between the first and the second mean wake and S2 PtcCO(2), PBCL and LFCT in the OSA and the CSA group, but AHI showed a significant correlation with LVEF in the CSA group (r = -0.474, P < 0.05). CONCLUSIONS: The characteristics of sleep apnea can change when periodic breathing happens in heart failure patients with OSA or CSA. The change can be affected by wake and sleep PtcCO(2), PBCL and LFCT, and possibly by heart function.

Subjective sleepiness in heart failure patients with sleep-related breathing disorder.

BACKGROUND: Previous studies show that sleep-related breathing disorder (SRBD) is common in patients with heart failure (HF) and is associated with increased mortality. This study aimed to determine whether there was significant difference of subjective daytime sleepiness between HF patients with and without SRBD. METHODS: We enrolled, prospectively, 195 consecutive HF patients with left ventricular ejection fractions (LVEF) < or = 45% and all subjects underwent polysomnography to measure the sleep structure between 2005 and 2008. Patients were then assigned to those with SRBD including obstructive and central sleep apnea (apnea-hypopnea index (AHI) > or = 5/hour of sleep) and those without SRBD (AHI < 5/hour) according to the sleep study. The subjective sleepiness was assessed with Epworth sleepiness scale (ESS). RESULTS: Among 195 HF patients, the prevalence of obstructive sleep apnea (OSA) was 53% and of central sleep apnea (CSA) was 27%. There was no significant difference of ESS scores between patients without SRBD (NSA) and with SRBD (NSA vs OSA: 6.7 +/- 0.6 vs 7.6 +/- 0.4, P = 0.105 and NSA vs CSA: 6.7 +/- 0.6 vs 7.4 +/- 0.5, P = 0.235, respectively), indicating that SRBD patients had no more subjective daytime sleepiness. Compared with NSA, patients with SRBD had increased arousal index (ArI) (NSA vs OSA: 14.1 +/- 1.4 vs 26.3 +/- 1.5, P < 0.001 and NSA vs CSA: 14.1 +/- 1.4 vs 31.3 +/- 3.5, P < 0.001, respectively), more awake number after sleep onset (NSA vs OSA: 19.2 +/- 1.5 vs 26.2 +/- 1.4, P = 0.01 and NSA vs CSA: 19.2 +/- 1.5 vs 36.9 +/- 4.4, P < 0.001, respectively), and reduced proportion of slow-wave sleep (SWS) (NSA vs OSA: 13.8 +/- 1.7 vs 9.3 +/- 0.7, P = 0.024 and NSA vs CSA: 13.8 +/- 1.7 vs 8.9 +/- 0.9, P = 0.024, respectively). CONCLUSIONS: OSA and CSA remain common in patients with HF on optimal contemporary therapy. Patients with both HF and SRBD have no significant subjective daytime sleepiness compared with patients without SRBD, despite of significantly increased awake number, arousal and decreased proportion of deep sleep stages. It is not a credible way and means to exclude SRBD in patients with HF according to the absence of subjective daytime sleepiness.

Prevalence and physiological predictors of sleep apnea in patients with heart failure and systolic dysfunction.

BACKGROUND: Previous studies reported high prevalences of obstructive and central sleep apnea (OSA and CSA, respectively) in patients with heart failure (HF). However, these preceded widespread use of beta-blockers and spironolactone that might have reduced their prevalences. We therefore determined, in patients with HF, prevalences and predictors of OSA and CSA and the influence of changes in HF therapy on prevalences. METHODS AND RESULTS: A total of 218 HF patients with left ventricular ejection fraction (LVEF) or=15 hours of sleep, either OSA or CSA), or mild to no sleep apnea. The prevalence of moderate to severe OSA was 26% and of CSA was 21%. Predictors of OSA were older age, male sex, and greater body mass index, and of CSA were older age, male sex, atrial fibrillation, hypocapnia, and diuretic use. Between 1997 and 2004, the prevalences of OSA and CSA did not change significantly (P(trend) =.460, P(trend) =.211, respectively) despite increased use of beta-blockers and spironolactone (P(trend) < .001, P(trend) < .001, respectively), and an increase in LVEF (P(trend)=.005). CONCLUSIONS: OSA and CSA remain common in patients with HF, despite increases in beta-blocker and spironolactone use.

Influence of obstructive sleep apnea on mortality in patients with heart failure.

OBJECTIVES: This study sought to determine, in patients with heart failure (HF), whether untreated moderate to severe obstructive sleep apnea (OSA) is associated with a higher mortality rate than in patients with mild to no sleep apnea (M-NSA). BACKGROUND: Obstructive sleep apnea is common in patients with HF and exposes the heart and circulation to adverse mechanical and autonomic effects. However, its effect on mortality rates of patients with HF has not been reported. METHODS: In a prospective study involving 164 HF patients with left ventricular ejection fractions (LVEFs) < or =45%, we performed polysomnography and compared death rates between those with M-NSA (apnea-hypopnea index [AHI] <15/h of sleep) and those with untreated OSA (AHI > or =15/h of sleep). RESULTS: During a mean (+/- SD) of 2.9 +/- 2.2 and a maximum of 7.3 years of follow-up, the death rate was significantly greater in the 37 untreated OSA patients than in the 113 M-NSA patients after controlling for confounding factors (8.7 vs. 4.2 deaths per 100 patient-years, p = 0.029). Although there were no deaths among the 14 patients whose OSA was treated by continuous positive airway pressure (CPAP), the mortality rate was not significantly different from the untreated OSA patients (p = 0.070). CONCLUSIONS: In patients with HF, untreated OSA is associated with an increased risk of death independently of confounding factors.