Population-based epidemiologic studies have uncovered the high prevalence and wide severity spectrum of undiagnosed obstructive sleep apnea, and have consistently found that even mild obstructive sleep apnea is associated with significant morbidity. Evidence from methodologically strong cohort studies indicates that undiagnosed obstructive sleep apnea, with or without symptoms, is independently associated with increased likelihood of hypertension, cardiovascular disease, stroke, daytime sleepiness, motor vehicle accidents, and diminished quality of life. Strategies to decrease the high prevalence and associated morbidity of obstructive sleep apnea are critically needed. The reduction or elimination of risk factors through public health initiatives with clinical support holds promise. Potentially modifiable risk factors considered in this review include overweight and obesity, alcohol, smoking, nasal congestion, and estrogen depletion in menopause. Data suggest that obstructive sleep apnea is associated with all these factors, but at present the only intervention strategy supported with adequate evidence is weight loss. A focus on weight control is especially important given the expanding epidemic of overweight and obesity in the United States. Primary care providers will be central to clinical approaches for addressing the burden and the development of cost-effective case-finding strategies and feasible treatment for mild obstructive sleep apnea warrants high priority.

Epidemiology of obstructive sleep apnea: a population health perspective.

Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anat...

Pathophysiology of Sleep Apnea

Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing.

Sleep-related breathing disorders are highly prevalent in patients with established cardiovascular disease. Obstructive sleep apnea (OSA) affects an estimated 15 million adult Americans and is present in a large proportion of patients with hypertension and in those with other cardiovascular disorders, including coronary artery disease, stroke, and atrial fibrillation.1–14 In contrast, central sleep apnea (CSA) occurs mainly in patients with heart failure.15–19 The purpose of this Scientific Statement is to describe the types and prevalence of sleep apnea and its relevance to individuals who either are at risk for or already have established cardiovascular disease. Special emphasis is given to recognizing the patient with cardiovascular disease who has coexisting sleep apnea, to understanding the mechanisms by which sleep apnea may contribute to the progression of the cardiovascular condition, and to identifying strategies for treatment. This document is not intended as a systematic review but rather seeks to highlight concepts and evidence important to understanding the interactions between sleep apnea and cardiovascular disease, with particular attention to more recent advances in patient-oriented research. Implicit in this first American Heart Association/American College of Cardiology Scientific Statement on Sleep Apnea and Cardiovascular Disease is the recognition that, although holding great promise, this general area is in need of a substantially expanded knowledge base. Specific questions include whether sleep apnea is important in initiating the development of cardiac and vascular disease, whether sleep apnea in patients with established cardiovascular disease accelerates disease progression, and whether treatment of sleep apnea results in clinical improvement, fewer cardiovascular events, and reduced mortality.

Experimental approaches directed at addressing these issues are limited by several considerations. First, the close association between obesity and OSA often obscures differentiation between the effects of obesity, the effects of OSA, and the effects of synergies between these conditions. Second, multiple comorbidities, …

Sleep Apnea and Cardiovascular Disease An American Heart Association/American College of Cardiology Foundation Scientific Statement From the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing In Collaboration With the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health)

Background: Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older. Methods and Findings: We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: ,5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: $30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80– 1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleepdisordered breathing showed a pattern of association similar to all-cause mortality. Conclusions: Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing. Please see later in the article for the Editors’ Summary.

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Sleep-disordered breathing and mortality: A prospective cohort study

A common clinical dilemma faced by sleep physicians is in deciding the level of severity at which patients with obstructive sleep apnea (OSA) should be treated. There is particular uncertainty about the need for, and the effectiveness of, treatment in mild cases. To help define the role of nasal continuous positive airway pressure (CPAP) treatment in mild OSA we undertook a randomized controlled cross-over trial of CPAP in patients with an apnea- hypopnea index (AHI) of 5 - 30 (mean, 12.9 +/- 6.3 SD). Twenty-four-hour blood pressure and neurobehavioral function were measured at baseline, after 8 wk of treatment with CPAP, and after 8 wk of treatment with an oral placebo tablet. Twenty-eight of 42 patients enrolled in the study completed both treatment arms. Baseline characteristics were not different between those who completed the study and those who did not complete the study. Patients used CPAP for a mean (SD) of 3.53 (2.13) h per night and the mean AHI on the night of CPAP implementation was 4.24 (2.9). Nasal CPAP improved self-reported symptoms of OSA, including snoring, restless sleep, daytime sleepiness, and irritability (in-house questionnaire), more than did placebo, but did not improve objective (Multiple Sleep Latency Test) or subjective (Epworth Sleepiness Scale) measures of daytime sleepiness. We found no benefit of CPAP over placebo in any tests of neurobehavioral function, generic SF-36 (36-item Short Form Medical Outcomes Survey) or sleep-specific (Functional Outcomes of Sleep Questionnaire) quality of life questionnaires, mood score (Profile of Moods States and Beck Depression Index), or 24-h blood pressure. However, the placebo tablet resulted in a significant improvement in a wide range of functional variables compared with baseline. This placebo effect may account for some of the treatment responses to CPAP observed previously in patients with mild OSA.

A Randomized Controlled Trial of Continuous Positive Airway Pressure in Mild Obstructive Sleep Apnea

Daytime pulmonary hypertension (PH) is relatively common in obstructive sleep apnea (OSA) and is thought to be associated with pulmonary vascular remodeling (PRm). The extent to which PH is reversible with treatment is uncertain. To study this, we measured pulmonary hemodynamics (Doppler echocardiography) in 20 patients with OSA (apnea-hypopnea index [AHI] 48.6 +/- 5.2/h, mean +/- SEM) before and after 1 and 4 mo of CPAP treatment (compliance 4.7 +/- 0.5 h/night). Patients had normal lung function, and no cardiac disease or systemic hypertension. Doppler studies were performed at three levels of inspired oxygen concentration (11%, 21%, and 50%) and during incremental increases in pulmonary blood flow (10, 20, and 30 microg/kg/min dobutamine infusions). Treatment resulted in a decrease in pulmonary artery pressure (Ppa, 16.8 +/- 1.2 mm Hg before CPAP versus 13.9 +/- 0.6 mm Hg after 4 mo CPAP, p < 0.05) and total pulmonary vascular resistance (231.1 +/- 19.6 versus 186.4 +/- 12.3 dyn. s. cm(-)(5), p < 0.05). The greatest treatment effects occurred in the five patients who were pulmonary hypertensive at baseline. The pulmonary vascular response to hypoxia decreased after CPAP (DeltaPpa/DeltaSa(O(2)) 10.0 +/- 1.6 mm Hg before versus 6.3 +/- 0.8 mm Hg after 4 mo CPAP, p < 0.05). The curve of Ppa versus cardiac output (Q), derived from the incremental dobutamine infusion, shifted downward in a parallel fashion during treatment. Systemic diastolic blood pressure also fell significantly. Improvements in pulmonary hemodynamics were not attributable to changes in left ventricular diastolic function or Pa (O(2)). We conclude that CPAP treatment reduces Ppa and hypoxic pulmonary vascular reactivity in OSA and speculate that this may be due to improved pulmonary endothelial function.

Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea.

We compared the effects of sustained isocapnic hypoxia (SIH; 20 min) and repetitive isocapnic hypoxia (RIH; 10 2-min episodes) on ventilation (VI), genioglossal (EMGgg) and diaphragmatic electromyographic (EMGdi) activities, and supraglottic airway resistance in 11 normal supine male subjects (36.6 +/- 2.2 yr) during wakefulness. Seven of the subjects had control measurements on a separate day. Desaturation was similar (arterial O2 saturation 80-84%) in the SIH and RIH protocols. SIH and RIH caused a biphasic ventilatory response: early augmentation of VI (169.5 +/- 6.9 and 168.9 +/- 4.3% of baseline, respectively; not significant) followed by a significant roll-off (VI after 20 min of cumulative hypoxia 153 +/- 4.0 and 150.8 +/- 10.2% respectively; not significant). Moving-time-average EMGdi signals (peak inspiratory and phasic) demonstrated a similar biphasic response in the two protocols. Mean EMGgg responses, however, differed. During SIH, peak inspiratory EMGgg increased early and remained elevated. Phasic and tonic EMGgg signals showed a similar trend. During RIH, early augmentation of peak inspiratory and phasic EMGgg signals was followed by a marked roll-off in activity such that by the 10th hypoxic episode neither value increased above baseline. In the 2-min periods between hypoxic episodes, there was a progressive suppression of peak inspiratory and phasic EMGgg values below baseline. Supraglottic airway resistance did not change significantly during either SIH or RIH. VI and phasic EMGs did not change during control experiments. We conclude that in awake normal male subjects SIH and RIH cause similar biphasic responses in VI and EMGdi activity. Phasic EMGgg activity responses differ between SIH and RIH: EMGgg remains augmented during SIH, whereas during RIH early augmentation is followed by marked suppression.

Effects of sustained and repetitive isocapnic hypoxia on ventilation and genioglossal and diaphragmatic EMGs.

STUDY OBJECTIVES Changes in cardiovascular measures such as heart rate (HR) and pulse transit time (PTT) have been advocated as sensitive markers of autonomic arousal from sleep. In animal studies, alerting stimuli produce particularly marked skin vascular responses. We hypothesized that changes in skin vascular conductance would provide more sensitive markers of autonomic arousal during sleep compared to central cardiovascular response measures such as HR and PTT. DESIGN Cardiovascular responses to auditory-induced arousals were recorded during overnight sleep studies. SETTING Sleep disorders unit in a 270-bed teaching hospital. PARTICIPANTS Eleven young healthy male subjects. INTERVENTIONS Throughout ovemight sleep studies, auditory tones (5-second duration, 54-90 decibels, 22-56 per subject) were presented during non-rapid-eye-movement sleep. Beat-by-beat HR, PTT, laser-Doppler fingertip skin blood flow (SBF) and finger and ear photoplethysmogram pulse wave amplitudes (PWA) were measured in the 20 seconds preceding and 30 seconds following each tone and compared to control measurements obtained during 50-second periods of recording with no stimulus (no tone, 6-22 per subject). Electroencephalographic (EEG) arousals were scored according to standard criteria (American Sleep Disorders Association) into no discemible, 3- to 10-second duration, or 10- to 15-second duration arousals. Poststimulus cardiovascular measurements were expressed as a percentage of the prestimulus mean and response magnitudes quantified from peak responses and the area under the poststimulus response curve. The ability of each cardiovascular response measure to discriminate EEG arousals (EEG changes lasting more than 3 seconds) was assessed from the area under the receiver operating characteristic (ROC) curve. MEASUREMENTS AND RESULTS There were no significant changes in any cardiovascular parameter during control recordings. In contrast to all other parameters, finger PWA and SBF decreased following tones that produced no discernible EEG arousal (P < 0.05). A significant HR rise and decreases in all cardiovascular measures occurred with greater than 3-second arousals, with longer duration arousals generally exhibiting larger responses. Conventional EEG arousals (greater than 3 seconds) were relatively poorly detected from HR responses (ROC area HR rise 0.80 +/- 0.04) compared to changes in SBF (0.85 +/- 0.02), PTT (0.85 +/- 0.03) and finger PWA (0.90 +/- 0.01). CONCLUSIONS Decreases in skin vascular conductance (finger PWA and SBF) provide sensitive markers of autonomic arousal during sleep. They are at least as sensitive as PTT for detecting conventionally scored EEG arousals and may be more sensitive in detecting "subcortical" arousals.

Noninvasive cardiovascular markers of acoustically induced arousal from non-rapid-eye-movement sleep.

To ascertain whether sleep-disordered breathing (SDB) in the elderly is associated with increased mortality, a prospective cohort study with 4-year follow-up was conducted at a retirement village complex in Sydney, Australia. The subjects were 163 non-demented retirement village residents. Logistic regression was used to assess SDB and co-morbidity as independent predictors of mortality. Respiratory disturbance index (RDI) was measured in the home; those subjects with RDIs > or = 15 were classified as having SDB. Co-morbidity was measured by an index of Burden of Illness based on the medical history obtained at baseline. At 4 years, 27% (4/15) of those subjects with RDIs > or = 15 and 22% (33/148) of those with RDIs < 15 were dead. RDI had an odds ratio (OR) of 1.00 (95% CI: 0.96, 1.04). Burden of Illness had an OR of 1.90 (95% CI: 1.34, 2.71). Adjustment for age and sex did not alter these findings. Significant predictors of mortality from the illness measure were a history of hypertension, Parkinson's disease and other severe illnesses (usually cancer). RDI was not a predictor of mortality in this population of non-demented seniors, where the prevalence of high levels of RDI was low.

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N. A. Saunders

Papers

A Randomized Controlled Trial of Continuous Positive Airway Pressure in Mild Obstructive Sleep Apnea

Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea.

Effects of sustained and repetitive isocapnic hypoxia on ventilation and genioglossal and diaphragmatic EMGs.

Noninvasive cardiovascular markers of acoustically induced arousal from non-rapid-eye-movement sleep.

Four-year follow-up of mortality and sleep-related respiratory disturbance in non-demented seniors.