Robert C. Basner

Inflammation, Oxidative Stress, and Repair Capacity of the Vascular Endothelium in Obstructive Sleep Apnea

Background— Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea (OSA). We investigated directly whether dysfunction and inflammation occur in vivo in the vascular endothelium of patients with OSA. The effects of continuous positive airway pressure (CPAP) therapy on endothelial function and repair capacity were assessed. Methods and Results— Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied. Proteins that regulate basal endothelial nitric oxide (NO) production (endothelial NO synthase [eNOS] and phosphorylated eNOS) and inflammation (cyclooxygenase-2 and inducible NOS) and markers of oxidative stress (nitrotyrosine) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy. Vascular reactivity was measured by flow-mediated dilation. Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity. Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59% and 94%, respectively, in patients with OSA compared with control subjects. Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects, whereas inducible NOS expression was 56% greater. Expression of eNOS and phosphorylated eNOS significantly increased, whereas expression of nitrotyrosine, cyclooxygenase-2, and inducible NOS significantly decreased in patients who adhered to CPAP ≥4 hours daily. Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects, and both significantly increased in patients who adhered to CPAP ≥4 hours daily. Conclusions— OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity. Effective CPAP therapy is associated with the reversal of these alterations.

Sleep-disordered breathing in a predominantly African-American pediatric population.

The goal of this study was to characterize sleep and respiratory parameters in children with sleep‐disordered breathing (SDB) as compared to children without SDB. Data are from 198 children and adolescents referred for sleep center evaluation, 128 of whom were diagnosed with SDB. In children with SDB, obesity (> 95% wgt for age) was more common than being severely underweight (< 5% wgt for age), but only the older children with SDB were heavier than age‐matched normal sleepers. Children with SDB had increased EEG arousals; sleep architecture was not otherwise significantly different from the non‐SDB group. African‐American children with SDB had significantly greater oxygen desaturation with obstructive events compared to Caucasian and Latino children. It appears that the role of obesity as a risk factor for obstructive sleep apnea (OSA) increases in children above the age of 8‐years. Additionally, African‐American children with SDB may be at increased risk for hypoxemia and cardiovascular consequences of SDB.

Remediation of Sleep-Deprivation–Induced Working Memory Impairment with fMRI-Guided Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) was applied to test the role of selected cortical regions in remediating sleep-deprivation-induced deficits in visual working memory (WM) performance. Three rTMS targets were chosen using a functional magnetic resonance imaging (fMRI)-identified network associated with sleep-deprivation-induced WM performance impairment: 2 regions from the network (upper left middle occipital gyrus and midline parietal cortex) and 1 nonnetwork region (lower left middle occipital gyrus). Fifteen participants underwent total sleep deprivation for 48 h. rTMS was applied at 5 Hz during a WM task in a within-subject sham-controlled design. The rTMS to the upper-middle occipital site resulted in a reduction of the sleep-induced reaction time deficit without a corresponding decrease in accuracy, whereas stimulation at the other sites did not. Each subject had undergone fMRI scanning while performing the task both pre- and postsleep deprivation, and the degree to which each individual activated the fMRI network was measured. The degree of performance enhancement with upper-middle occipital rTMS correlated with the degree to which each individual failed to sustain network activation. No effects were found in a subset of participants who performed the same rTMS procedure after recovering from sleep deprivation, suggesting that the performance enhancements seen following sleep deprivation were state dependent.

Racial and Ethnic Disparities in Survival in Lung Transplant Candidates with Idiopathic Pulmonary Fibrosis

Minority patients have worse outcomes than nonminority patients in a variety of pulmonary diseases. We aimed to compare the survival of Black and Hispanic patients to that of others with idiopathic pulmonary fibrosis (IPF). We performed a retrospective cohort study of patients with IPF who were evaluated for lung transplantation at our center. Kaplan‐Meier survival curves and Cox proportional hazards models were used to compare survival between groups. Black and Hispanic patients had spirometry, lung volumes and diffusion capacity that were similar to others, but had worse exercise capacity. Minority patients had a significantly increased risk of death compared to others independent of transplantation status (hazard ratio = 3.3, 95% CI 1.2–8.9, p = 0.02). Differences in exercise capacity, pulmonary hemodynamics and socioeconomic factors appeared to account for some of the differences in survival. Black and Hispanic patients with IPF had an increased risk of death following referral for lung transplantation. This finding may be due to differences in disease progression and/or differences in access to medical care among minority patients. Future studies should confirm our findings in a larger cohort. The elimination of racial and ethnic disparities in outcome should be a priority for clinicians and researchers in this field.

Sleep disordered breathing in patients with acutely decompensated heart failure

OBJECTIVE The purpose of this study is to systematically characterize sleep disordered breathing (SDB) during acute heart failure (HF) decompensation. BACKGROUND SDB, both Cheyne-Stokes breathing (CSB) and obstructive sleep apnea, is common in stable congestive HF patients, but its presence and characteristics in decompensated HF is unknown. METHODS Eighteen men and 11 women (mean age 57+/-17 years, plasma brain-natriuretic peptide 1660+/-1179pg/ml, left ventricular ejection fraction 20+/-6%) admitted with decompensated systolic HF without other active cardiorespiratory morbidity underwent echocardiography and overnight bedside polysomnography within 48h of admission. Ten patients underwent follow-up polysomnography just before or immediately after hospital discharge. RESULTS Twenty-eight of 29 patients demonstrated an apnea+hypopnea index (AHI)>5 events/h (mean AHI 41+/-29/h); 22 patients had an AHI>15/h. SDB was predominantly CSB (central events 39+/-29/h; obstructive events 2+/-2/h, p<0.001). Time in CSB was 51+/-33% of total sleep time (TST); nadir oxygen saturation (SaO2) was 81+/-10%. SDB was similar on admission vs. follow-up polysomnography (mean AHI 44+/-39/h vs. 38+/-31/h; CSB 53+/-38% vs. 46+/-37% TST). Follow-up polysomnography showed a higher nadir SaO2 than admission (84+/-11% vs. 79+/-12%, p=0.05), but TST with SaO2<90% was not reduced. CONCLUSIONS CSB is common and severe in patients hospitalized with decompensated HF. Acute treatment of HF does not consistently improve CSB. The effect of CSB on ventricular function and prognosis in decompensated HF remains to be demonstrated.

Quality improvement in neurology: Amyotrophic lateral sclerosis quality measures Report of the Quality Measurement and Reporting Subcommittee of the American Academy of Neurology

Amyotrophic lateral sclerosis (ALS) is a lethal, progressive neurodegenerative disease characterized by loss of motor neurons.1 Patients with ALS lose function in the limbs, speech, swallowing, and breathing muscles. The cause of the disease is still not known for most patients. Approximately 25,000 people in the United States have ALS, and 5,000 people are diagnosed with ALS annually in the United States.1 Most patients die from respiratory failure 2 to 5 years after onset of symptoms. Cognitive dysfunction is seen in 20% to 50% of patients.2 The disease burden for patients and caregivers is enormous. The average cost of care has been estimated at

Pulmonary Hyperinflation and Left Ventricular Mass The Multi-Ethnic Study of Atherosclerosis COPD Study

50,000 per patient per year.3

The effect of ventilation on spectral analysis of heart rate and blood pressure variability during exercise.

Background— Left ventricular (LV) mass is an important predictor of heart failure and cardiovascular mortality, yet determinants of LV mass are incompletely understood. Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) may contribute to changes in intrathoracic pressure that increase LV wall stress. We therefore hypothesized that residual lung volume in COPD would be associated with greater LV mass. Methods and Results— The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers 50 to 79 years of age who were free of clinical cardiovascular disease. LV mass was measured by cardiac magnetic resonance. Pulmonary function testing was performed according to guidelines. Regression models were used to adjust for age, sex, body size, blood pressure, and other cardiac risk factors. Among 119 MESA COPD Study participants, the mean age was 69±6 years, 55% were male, and 65% had COPD, mostly of mild or moderate severity. Mean LV mass was 128±34 g. Residual lung volume was independently associated with greater LV mass (7.2 g per 1-SD increase in residual volume; 95% confidence interval, 2.2–12; P =0.004) and was similar in magnitude to that of systolic blood pressure (7.6 g per 1-SD increase in systolic blood pressure; 95% confidence interval, 4.3–11; P <0.001). Similar results were observed for the ratio of LV mass to end-diastolic volume ( P =0.02) and with hyperinflation measured as residual volume to total lung capacity ratio ( P =0.009). Conclusions— Pulmonary hyperinflation, as measured by residual lung volume or residual lung volume to total lung capacity ratio, is associated with greater LV mass. # Clinical Perspective {#article-title-62}Background— Left ventricular (LV) mass is an important predictor of heart failure and cardiovascular mortality, yet determinants of LV mass are incompletely understood. Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) may contribute to changes in intrathoracic pressure that increase LV wall stress. We therefore hypothesized that residual lung volume in COPD would be associated with greater LV mass. Methods and Results— The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers 50 to 79 years of age who were free of clinical cardiovascular disease. LV mass was measured by cardiac magnetic resonance. Pulmonary function testing was performed according to guidelines. Regression models were used to adjust for age, sex, body size, blood pressure, and other cardiac risk factors. Among 119 MESA COPD Study participants, the mean age was 69±6 years, 55% were male, and 65% had COPD, mostly of mild or moderate severity. Mean LV mass was 128±34 g. Residual lung volume was independently associated with greater LV mass (7.2 g per 1-SD increase in residual volume; 95% confidence interval, 2.2–12; P=0.004) and was similar in magnitude to that of systolic blood pressure (7.6 g per 1-SD increase in systolic blood pressure; 95% confidence interval, 4.3–11; P<0.001). Similar results were observed for the ratio of LV mass to end-diastolic volume (P=0.02) and with hyperinflation measured as residual volume to total lung capacity ratio (P=0.009). Conclusions— Pulmonary hyperinflation, as measured by residual lung volume or residual lung volume to total lung capacity ratio, is associated with greater LV mass.

Delayed Diagnosis of Obstructive Sleep Apnea: Don't Ask, Don't Tell.

Heart rate variability (HRV) and systolic blood pressure variability (BPV) during incremental exercise at 50, 75, and 100% of previously determined ventilatory threshold (VT) were compared to that of resting controlled breathing (CB) in 12 healthy subjects. CB was matched with exercise-associated respiratory rate, tidal volume, and end-tidal CO(2) for all stages of exercise. Power in the low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, >0.15-0.4 Hz) for HRV and BPV were calculated, using time-frequency domain analysis, from beat-to-beat ECG and non-invasive radial artery blood pressure, respectively. During CB absolute and normalized power in the LF and HF of HRV and BPV were not significantly changed from baseline to maximal breathing. Conversely, during exercise HRV, LF and HF power significantly decreased from baseline to 100% VT while BPV, LF and HF power significantly increased for the same period. These findings suggest that the increases in ventilation associated with incremental exercise do not significantly affect spectral analysis of cardiovascular autonomic modulation in healthy subjects.

Patient-ventilator asynchrony with nocturnal noninvasive ventilation in ALS

To define the patterns of referral of adult patients with obstructive sleep apnea syndrome (OSAS) for diagnostic sleep testing, we studied 97 consecutive patients with OSAS (Apnea/Hypopnea Index ≥ 20) referred to the Center for Sleep and Ventilatory Disorders, an American Sleep Disorders Association-accredited university sleep center. Chart review and semi-structured patient telephone interview quantified the time between the onset of any major feature of OSAS and referral to the sleep center, as well as the time between the first OSAS complaint to a health care provider and referral to the center. The average time elapsed between first recognition by the patient of a major feature of OSAS to sleep center referral was 87.5 months (range, 1 to 480 months). Only 4% of referrals were made as a result of the clinician eliciting a history of sleep-related complaints. Once OSAS-related features were apparent to the clinician, the average time to referral for diagnostic testing was 7.9 months (range, 0 to 128 months). These data suggest that both a lack of reporting of symptoms by OSAS patients and a lack of obtaining appropriate sleep history by health care providers contribute to a significant delay in diagnosis of OSA.