Xilong Zhang

Predictors of long-term adherence to continuous positive airway pressure therapy in patients with obstructive sleep apnea and cardiovascular disease in the SAVE study

STUDY OBJECTIVES To determine the clinical variables that best predict long- term continuous positive airway pressure (CPAP) adherence among patients with cardiovascular disease who have obstructive sleep apnea (OSA). DESIGN 12-mo prospective within-trial observational study. SETTING Centers in China, Australia, and New Zealand participating in the Sleep Apnea cardioVascular Endpoints (SAVE) study. PATIENTS There were 275 patients age 45-70 y with cardiovascular disease (i.e., previously documented transient ischemic attack, stroke, or coronary artery disease) and OSA (4% oxygen desaturation index (ODI) > 12) who were randomized into the CPAP arm of the SAVE trial prior to July 1, 2010. METHODS Age, sex, country of residence, type of cardiovascular disease, baseline ODI, severity of sleepiness, and Hospital Anxiety and Depression Scale (HADS) scores plus CPAP side effects and adherence at 1 mo were entered in univariate analyses in an attempt to identify factors predictive of CPAP adherence at 12 mo. Variables with P < 0.2 were then included in a multivariate analysis using a linear mixed model with sites as a random effect and 12-mo CPAP use as the dependent outcome variable. MEASUREMENTS AND RESULTS CPAP adherence at 1, 6, and 12 mo was (mean ± standard deviation) 4.4 ± 2.0, 3.8 ± 2.3, and 3.3 ± 2.4 h/night, respectively. CPAP use at 1 mo (effect estimate ± standard error, 0.65 ± 0.07 per h increase, P < 0.001) and side effects at 1 mo (-0.24 ± 0.092 per additional side effect, P = 0.009) were the only independent predictors of 12- mo CPAP adherence. CONCLUSION Continuous positive airway pressure use in patients with coexisting cardiovascular disease and moderate to severe obstructive sleep apnea decreases significantly over 12 months. This decline can be predicted by early patient experiences with continuous positive airway pressure (i.e., adherence and side effects at 1 month), raising the possibility that intensive early interventions could improve long-term continuous positive airway pressure compliance in this patient population. CLINICAL TRIALS REGISTER Clinical Trials, http://www.clinicaltrials.gov, NCT00738179.

Adiponectin protects rat myocardium against chronic intermittent hypoxia-induced injury via inhibition of endoplasmic reticulum stress.

Obstructive sleep apnea syndrome (OSAS) is associated with many cardiovascular disorders such as heart failure, hypertension, atherosclerosis, and arrhythmia and so on. Of the many associated factors, chronic intermittent hypoxia (CIH) in particular is the primary player in OSAS. To assess the effects of CIH on cardiac function secondary to OSAS, we established a model to study the effects of CIH on Wistar rats. Specifically, we examined the possible underlying cellular mechanisms of hypoxic tissue damage and the possible protective role of adiponectin against hypoxic insults. In the first treatment group, rats were exposed to CIH conditions (nadir O2, 5–6%) for 8 hours/day, for 5 weeks. Subsequent CIH-induced cardiac dysfunction was measured by echocardiograph. Compared with the normal control (NC) group, rats in the CIH-exposed group experienced elevated levels of left ventricular end-systolic dimension and left ventricular end-systolic volume and depressed levels of left ventricular ejection fraction and left ventricular fractional shortening (p<0.05). However, when adiponectin (Ad) was added in CIH + Ad group, we saw a rescue in the elevations of the aforementioned left ventricular function (p<0.05). To assess critical cardiac injury, we detected myocardial apoptosis by Terminal deoxynucleotidyl transfer-mediated dUTP nick end-labeling (TUNEL) analysis. It was showed that the apoptosis percentage in CIH group (2.948%) was significantly higher than that in NC group (0.4167%) and CIH + Ad group (1.219%) (p<0.05). Protein expressions of cleaved caspase-3, cleaved caspase-9, and cleaved-caspase-12 validated our TUNEL results (p<0.05). Mechanistically, our results demonstrated that the proteins expressed with endoplasmic reticulum stress and the expression of reactive oxygen species (ROS) were significantly elevated under CIH conditions, whereas Ad supplementation partially decreased them. Overall, our results suggested that Ad augmentation could improve CIH-induced left ventricular dysfunction and associated myocardial apoptosis by inhibition of ROS-dependent ER stress.

Transvenous Phrenic Nerve Stimulation in Patients With Cheyne-Stokes Respiration and Congestive Heart Failure A Safety and Proof-of-Concept Study

BACKGROUND Cheyne-Stokes respiration (CSR), which often occurs in patients with congestive heart failure (CHF), may be a predictor for poor outcome. Phrenic nerve stimulation (PNS) may interrupt CSR in patients with CHF. We report the clinical use of transvenous PNS in patients with CHF and CSR. METHODS Nineteen patients with CHF and CSR were enrolled. A single stimulation lead was placed at the junction between the superior vena cava and brachiocephalic vein or in the left-side pericardiophrenic vein. PNS stimulation was performed using Eupnea System device (RespiCardia Inc). Respiratory properties were assessed before and during PNS. PNS was assessed at a maximum of 10 mA. RESULTS Successful stimulation capture was achieved in 16 patients. Failure to capture occurred in three patients because of dislocation of leads. No adverse events were seen under maximum normal stimulation parameters for an overnight study. When PNS was applied following a series of central sleep apneic events, a trend toward stabilization of breathing and heart rate as well as improvement in oxygen saturation was seen. Compared with pre-PNS, during PNS there was a significant decrease in apnea-hypopnea index (33.8 ± 9.3 vs 8.1 ± 2.3, P = .00), an increase in mean and minimal oxygen saturation as measured by pulse oximetry (89.7% ± 1.6% vs 94.3% ± 0.9% and 80.3% ± 3.7% vs 88.5% ± 3.3%, respectively, all P = .00) and end-tidal CO2 (38.0 ± 4.3 mm Hg vs 40.3 ± 3.1 mm Hg, P = .02), but no significant difference in sleep efficiency (74.6% ± 4.1% vs 73.7% ± 5.4%, P = .36). CONCLUSIONS The preliminary results showed that in a small group of patients with CHF and CSR, 1 night of unilateral transvenous PNS improved indices of CSR and was not associated with adverse events.

Relationship between Rad51 G135C and G172T Variants and the Susceptibility to Cancer: A Meta-Analysis Involving 54 Case-Control Studies

Background The associations between Rad51 gene polymorphisms (G135C and G172T) and risk of cancer have been investigated, but the results were inconclusive. To get a comprehensive evaluation of the association above, we performed a meta-analysis of published studies. Methods A computerized search of PubMed, Embase and Web of Knowledge databases for all relevant studies was performed and the data were analyzed in a meta-analysis. The overall odds ratio (OR) with the 95% confidence interval (95% CI) was calculated to assess the strength of the association between Rad51 polymorphisms and cancer risk. Data were analyzed using fixed- or random-effects model when appropriate. Sensitivity analysis and publication bias test were also estimated. Results Overall, a total of 54 case-control studies were included in the current meta-analysis, among which 42 studies with 19,142 cases and 20,363 controls for RAD51 G135C polymorphism and 12 studies with 6,646 cases and 6,783 controls for G172T polymorphism. For G135C polymorphism, the pooled results indicated that significantly increased risk was found in overall cancers (homozygote model: OR = 1.776, 95% CI = 1.288–2.449; allelic genetic model: OR = 1.169, 95% CI = 1.016–1.345; recessive model: OR = 1.946, 95% CI = 1.336–2.835), especially in breast cancer (homozygote model: OR = 1.498, 95% CI = 1.026–2.189; recessive model: OR = 1.732, 95% CI  =  1.170–2.562). For G172T polymorphism, a decreased cancer risk was observed in head and neck cancer (homozygote model: OR  =  0.621, 95% CI  =  0.460–0.837; allelic genetic model: OR  =  0.824, 95% CI  =  0.716–0.948; recessive model: OR  =  0.639, 95% CI = 0.488–0.837). Conclusions Our results suggested that the Rad51 G135C polymorphism is a candidate for susceptibility to overall cancers, especially to breast cancer, and that the Rad51 G172T might play a protective role in the development of head and neck cancer.

Adiponectin Alleviates Genioglossal Mitochondrial Dysfunction in Rats Exposed to Intermittent Hypoxia

Background Genioglossal dysfunction is involved in the pathophysiology of obstructive sleep apnea hypoxia syndrome (OSAHS) characterized by nocturnal chronic intermittent hypoxia (CIH). The pathophysiology of genioglossal dysfunction and possible targeted pharmacotherapy for alleviation of genioglossal injury in CIH require further investigation. Methodology/Principal Findings Rats in the control group were exposed to normal air, while rats in the CIH group and CIH+adiponectin (AD) group were exposed to the same CIH condition (CIH 8 hr/day for 5 successive weeks). Furthermore, rats in CIH+AD group were administrated intravenous AD supplementation at the dosage of 10 µg, twice a week for 5 consecutive weeks. We found that CIH-induced genioglossus (GG) injury was correlated with mitochondrial dysfunction, reduction in the numbers of mitochondrias, impaired mitochondrial ultrastructure, and a reduction in type I fibers. Compared with the CIH group, impaired mitochondrial structure and function was significantly improved and a percentage of type I fiber was elevated in the CIH+AD group. Moreover, compared with the control group, the rats’ GG in the CIH group showed a significant decrease in phosphorylation of LKB1, AMPK, and PGC1-α, whereas there was significant rescue of such reduction in phosphorylation within the CIH+AD group. Conclusions CIH exposure reduces mitochondrial biogenesis and impairs mitochondrial function in GG, while AD supplementation increases mitochondrial contents and alleviates CIH-induced mitochondrial dysfunction possibly through the AMPK pathway.

Adiponectin protects the rats liver against chronic intermittent hypoxia induced injury through AMP-activated protein kinase pathway

This study was performed to assess the effect of chronic intermittent hypoxia (CIH) on the liver, the associated mechanisms and the potential therapeutic roles of adiponectin (Ad). Sixty rats were randomly assigned to four groups: the normal control (NC), NC and Ad supplement (NC + Ad), CIH, and CIH and Ad supplement (CIH + Ad) groups. The rats in the CIH and CIH + Ad groups were exposed to a hypoxic environment for 4 months. Rats in the NC + Ad and CIH + Ad groups were also treated with an intravenous injection of Ad (10 ug), twice a week. The plasma levels of hepatic enzymes, serum triglyceride, liver triglyceride, fasting blood glucose and hepatic cell apoptosis in hepatic tissue, were higher in the CIH group than in the NC and NC + Ad groups. However, the Ad supplementation in the CIH + Ad group rescued the hepatic tissue insult by activating the AMP-activated protein kinase (AMPK) pathway. In conclusion, Ad could protect against CIH-induced hepatic injury partly through the AMPK pathway.

Prevalence and risk factors of sleep disordered breathing in patients with rheumatic valvular heart disease.

STUDY OBJECTIVES Sleep disordered breathing (SDB) is common in patients with chronic heart failure secondary to non-valvular heart disease; however, the prevalence and characteristics of SDB in patients with rheumatic valvular heart disease (RVHD) are unclear. This study was designed to determine the prevalence, characteristics, and risk factors for SDB in RVHD patients. METHODS A cross-sectional study was conducted in 260 RVHD patients. The following data were recorded: types of heart valve lesions, electrocardiographic, echocardiographic, arterial blood gas analysis findings, baseline medication, 6-minute walk test (6MWT) distance, and sleep parameters. RESULTS Compared to patients with single leftsided valve lesions, patients with left- and rightsided valve lesions had a higher prevalence of SDB (46.2% vs. 31.2%, p = 0.013); the increased prevalence of SDB only involved central sleep apnea (CSA) (31.1% vs. 14.1%, p = 0.001). Patients with obstructive sleep apnea (OSA) or CSA were older and had a shorter 6MWT distance, lower left ventricle ejection fraction and PaO₂, a longer lung-to-finger circulation time, and a higher prevalence of atrial fibrillation (AF) and hypertension (all p < 0.05) as compared with patients without SDB. Multinomial logistic regression analysis showed that PaO2 ≤ 85 mm Hg was the only risk factor for OSA. Male gender, AF, 6MWT distance ≤ 300 m, PaO₂ ≤ 85 mmHg, and PaCO₂ ≤ 40 mm Hg were risk factors for CSA. CONCLUSIONS Patients with RVHD had a high prevalence of SDB (predominantly CSA). RVHD patients with SDB, particularly those who had CSA, manifested more severe symptoms and greater impairment of cardiac function. Assessments of clinical manifestations of cardiac dysfunction may be important for predicting the risk factors for SDB.

Safety and feasibility of chronic transvenous phrenic nerve stimulation for treatment of central sleep apnea in heart failure patients.

Central sleep apnea (CSA) is common in patients with heart failure (HF) and is associated with poor quality of life and prognosis. Early acute studies using transvenous phrenic nerve stimulation (PNS) to treat CSA in HF have shown a significantly reduction of CSA and improvement of key polysomnographic parameters. In this study, we evaluated the safety of and efficiency chronic transvenous PNS with an implanted neurostimulator in HF patients with CSA.

High Risk Characteristics for Recurrent Cardiovascular Events among Patients with Obstructive Sleep Apnoea in the SAVE Study

Background Obstructive sleep apnoea (OSA) is a common comorbidity in patients with cardiovascular (CV) disease. We aimed to identify specific OSA clinical phenotypes relating to risks of serious CV events and response to continuous positive airway pressure (CPAP) treatment. Methods Post-hoc analyses of the Sleep Apnea Cardiovascular Endpoints (SAVE) study in participants with moderate-to-severe OSA and coronary artery disease (CAD) and/or cerebrovascular disease (CeVD) randomised to CPAP plus usual care or usual care alone. Latent class analysis (LCA) was used to identify OSA clinical phenotypes among 2649 (out of 2687 total) patients with complete data on 19 patient-centered variables, supported by Bayesian information criteria and clinical interpretability. Cox regression models were used to evaluate risks of composite cardiac and stroke outcome events in phenotype groups. Preferential response to CPAP treatment was evaluated using interaction terms as well as the Chi-square test. Findings LCA identified four OSA clinical phenotypes: CAD alone and with diabetes mellitus (CAD + DM), and CeVD alone and with DM (CeVD + DM), in 39%, 15%, 37% and 9% of participants, respectively. The rates of composite CV events were the highest in CAD + DM phenotype (HR 2.08, 95% CI 1.57–2.76) and for stroke were highest in CeVD + DM phenotype (HR 6.84, 95% CI 3.77–12.42). Adherence to CPAP treatment (nil or < 4 h vs ≥ 4 h in the first two years of the study) was shown to influence the risk of composite CV outcome in the phenotypes (P-interaction = 0.04); CPAP adherent patients of the CeVD + DM phenotype had the lowest risk of CV outcome (P = 0.02). Interpretation High risk clinical phenotypes were identified in relation to CV events and response to CPAP treatment, which may allow improved targeting of therapies in OSA patients. Funding The National Health and Medical Research Council (NHMRC) of Australia, Fisher & Paykel Healthcare, and ResMed.

Electrical Stimulation of the Genioglossus in Patients with Residual Obstructive Sleep Apnea Post-UPPP Surgery

Objective: Genioglossus is a major upper-airway dilator muscle, which leads to upper-airway obstruction when its activity is decreased. We evaluated the effect and safety of genioglossus stimulation for patients with residual mild-to-moderate obstructive sleep apnea (OSA) after uvulopalatopharyngoplasty (UPPP). Methods: We enrolled 23 patients diagnosed with OSA by polysomnography (PSG) 6 months after UPPP, who underwent nightly transcutaneous genioglossus stimulation (TGS) therapy. Apnea hypopnea index (AHI), microarousal index (MAI), the ratio of duration of SpO2 < 90% to total sleep time (T90) and Epworth sleepiness scale (ESS) before and during TGS treatment were compared. We first observed the overall effect of TGS, and then compared its influence on patients with mild and moderate sleep apnea. Results: Compared with non-TGS therapy, there was a significant decrease in AHI, MAI, T90, and ESS (9.15 ± 4.21 vs. 17.90 ± 6.85, p < 0.0001; 6.33 ± 3.75 vs. 10.93 ± 4.90, p < 0.0001; 4.87 ± 4.02 vs. 9.13 ± 4.24, p < 0.0001; 8.65 ± 3.35 vs. 9.30 ± 3.10, p = 0.002, respectively), and a significant increase in mean SpO2 and minimal SpO2 (mini SpO2) (95.52% ± 0.95% vs. 94.43% ± 1.12%, p < 0.0001; 88.74% ± 2.94% vs. 85.17% ± 4.67%, p < 0.0001, respectively) during TGS treatment. Patients in the mild and moderate groups had the same variation trend between TGS and non-TGS therapy nights. However, the moderate group had a higher absolute value of changed AHI (AHI; 11.12 ± 3.95 vs. 5.66 ± 1.70, p < 0.05) and MAI (MAI; 5.8 (3.3, 8.6) vs. 2.5 (1.05, 5.6), p < 0.05) than the mild group. There were no significant differences in absolute changed mean SpO2 (mean SpO2), absolute changed miniSpO2 (miniSpO2), changed T90 (T90) and absolute changed ESS (ESS) between the two groups. Moreover, the percentage of AHI was not different between the two groups (47.89% ± 13.79% vs. 51.04% ± 13.32%, p = 0.587). There was no perceived discomfort during TGS therapy and no procedure-related adverse events. Conclusion: Submental transcutaneous electrical stimulation of the genioglossus led to a significant reduction in AHI and improvement of daytime sleepiness for existing mild-to-moderate OSA patient’s post-UPPP surgery.