July 09, 2017
Sleep-related breathing disorders, ranging from habitual snoring to the increased upper airway resistance syndrome to sleep apnea, are now recognized as major health problems. The majority of patients have excessive daytime sleepiness and tiredness. Neuropsychological dysfunction results in poor work performance, memory impairment, and even depression.
Until recently, the coexistence of cardiovascular and cerebrovascular diseases with sleep-related breathing disorders was thought to be the result of shared risk factors, such as age, sex, and obesity. However, in the past 5 years there have been important advances in understanding the pathophysiology of sleep-related breathing disorders, including habitual snoring, increased upper airway resistance syndrome, and sleep apnea. Sleep-related breathing disorders have been recognized as important causes of morbidity and mortality. Among adults, sleep apnea is more common than asthma. In the United States, approximately 12 million people 30 to 60 years of age have obstructive sleep apnea and 38,000 die each year from cardiovascular disease attributed to sleep related breathing disorders. Among the approximately 31 million US citizens aged 65 years and older, nearly 7.5 million have sleep apnea, including 46% with moderate or severe disease. Among nursing home residents, up to half have clinically important sleep apnea.
In two recent studies, approximately 40% to 50% of outpatients with asymptomatic or mildly symptomatic congestive heart failure had obstructive sleep apnea or Cheyne-Stokes respiration with central sleep apnea. Sleep-related breathing disorders may contribute to progression of heart failure and worsen its prognosis.
In this article, we review the cardiovascular consequences of sleep-related breathing disorders, including the acute effects of apnea on the cardiovascular system, and the associations between sleep-related breathing dis- orders and hypertension, cardiac arrhythmias, pulmonary hypertension, and congestive heart failure. Epidemiologic studies have demonstrated that sleep- related breathing disorders are an independent risk factor for hypertension, probably resulting from a combination of intermittent hypoxia and hypercapnia, arousals, increased sympathetic tone, and altered baroreflex control during sleep. Sleep apnea may lead to the development of cardiomyopathy and pulmonary hypertension. Early recognition and treatment of sleep-related breathing disorders may improve cardiovascular function.
There are several types of sleep-related breathing disorders. Sleep apnea is defined as repetitive prolonged cessation of airflow associated with sleep arousal and at times with oxygen desaturation. Sleep apnea can be obstructive, in which respiratory effort persists despite occlusion of the oropharyngeal airway; central, in which both respiratory efforts and airflow cease; or a mixed central/obstructive pattern. Hypopnea is defined as a greater than 50% reduction in air flow with either an oxygen desaturation of greater than 3% or an arousal. A respiratory effort-related arousal event occurs when increasing effort leads to an arousal from sleep that does not meet the criteria for apnea or hypopnea. Increasing respiratory effort or out-of-phase breathing is the hallmark of in- creased upper airway resistance syndrome. However, the measurement of respiratory effort during sleep is difficult, because there are no non-invasive ways to measure increased resistance to breathing. Current techniques include respiratory inductance plethysmography and measurement of nasal pressure, change in pulse transit time is being evaluated as a measure of increased respiratory effort. Because there is night-to-night variability in the frequency of respiratory events in patients with milder forms of sleep-related breathing disorders, a “negative” polysomnogram does not rule out sleep-related breathing disorders in a symptomatic patient.
The usual daytime manifestations of sleep-related breathing disorders are excessive sleepiness, fatigue, un- refreshing sleep, and poor concentration. The constellation of obstructive sleep apnea, oxygen desaturation, and excessive sleepiness has been termed the obstructive sleep apnea syndrome.
A recent statement of the American Academy of Sleep Medicine and the American Thoracic Society outlined the diagnostic criteria for sleep-related breathing disorders. Obstructive sleep apnea-hypopnea syndrome requires excessive daytime sleepiness that is not better explained by other factors, as well as five or more obstructed breathing events (apnea, hypopnea, or respiratory effort-related arousals) per hour during sleep. The number of these events per hour of sleep determines the Respiratory Disturbance Index (RDI). The severity is rated as mild when there are 5 to 15 events per hour, moderate at 15 to 30 per hour, and severe at greater than 30 events per hour.
Apneic or hypopneic events are commonly associated with oxygen desaturation and are terminated by arousal. These repetitive events are associated with substantial changes in sympathetic discharge and in intrathoracic pressure that affect cardiovascular function.
Acute and transient effects of sleep-related breathing disorders on the cardiovascular system.
In normal subjects, systemic blood pressure decreases approximately 10% to 15% during sleep, with the greatest reductions occurring in non-rapid eye movement (non- REM) stages 3 and 4. Cardiac output also decreases by approximately 10% during non-REM sleep. The decrease in cardiac output results from reductions in heart rate and stroke volume. Because systemic blood pressure decreases substantially in conjunction with a less pronounced decrease in cardiac output, systemic vascular resistance probably declines slightly during non-REM sleep.
In contrast with the normal physiologic effect of sleep on the cardiovascular system, the hemodynamic response to apnoeic stimuli is more complex. The acute hemodynamic consequences of obstructive sleep apnea include systemic and pulmonary hypertension, increased left ventricular afterload, and decreased cardiac output. These changes are primarily the result of sympathetic stimulation, alterations in intra-thoracic pressure, and hypoxia and hypercapnia.
Neurohumoral Response to Apnea.
Apnoeic events result in brief surges in sympathetic nervous system activity, vasoconstriction, and transient hypertension. Systemic blood pressure is usually lowest during the early to middle portion of most apneic episodes. A gradual increase in pressure is then observed, and a sudden elevation occurs after termination of apnea.
During apneic episodes that are 35 to 40 seconds in duration, cardiac output decreases by approximately one-third. After termination of apnea, cardiac output increases by 10% to 15% above baseline. The combination of increasing systemic pressure and decreasing cardiac output indicates that systemic vascular resistance increases during apnea. Systemic vasoconstriction is believed to be mediated by alpha sympathetic neural activity, because patients with Shy-Drager syndrome, who are sympathetically denervated, have minimal changes in heart rate or systemic pressures in response to apnea. During hypoxia and at the termination of apnea, serum catecholamine levels increase, causing acute elevation in pulmonary and systemic blood pressures. Some of these alterations persist during wakefulness. The sympathetic neural response to apnea is, in large part, related to hypoxemia and hypercapnia, although cardiac sympathetic function and integrity, as assessed with radionuclide imaging, are impaired in sleep apnea. During the apnoeic period, heart rate slows in proportion to the duration of apnea and the degree of oxyhemoglobin desaturation. Increased vagal efferent activity partly mediates these reductions in heart rate, as atropine usually ameliorates apnea-related bradycardia. The resumption of ventilation is associated with a rapid increase in heart rate, presumably in response to a decrease in vagal tone.
Brady and tachy arrhythmias are common during sleep in patients with obstructive sleep apnea syndrome. In addition, several other types of arrhythmias can occur, including sinus pauses of 2 to 13 seconds in duration, ventricular ectopy, and complete heart block. Whereas supraventricular bradyarrhythmias and tachyarrhythmias during sleep is mainly the result of an alteration in sympathetic nervous system tone, ventricular arrhythmias are related to marked hypoxia, because they usually occur when oxyhemoglobin saturation falls below 60%.
Increased venous return causes a leftward shift of the interventricular septum (ventricular interdependence), thereby reducing left ventricular compliance and decreasing left ventricular end-diastolic volume. Further, the decrease in intrathoracic pressure delays blood leaving the intratharacic aorta, hence increasing left ventricular afterload. The combination of decreased left ventricular end- diastolic volume and increased left ventricular afterload results in decreased stroke volume and cardiac output. As a result of these hemodynamic changes and the surges in catecholamine levels, systemic blood pressure increases cyclically during sleep.
Effect of Hypoxia.
Changes in blood oxygen tension are sensed primarily by the carotid chemoreceptors, which, when activated, lead to bradycardia, arteriolar constriction in many vascular beds, and increased secretion of catecholamines. Hypoxia induced systemic vasoconstriction occurs during apnea, especially when the oxyhemoglobin saturation falls below 65%. The resulting hypertension is transient.
Pulmonary vasoconstriction occurs in response to alveolar hypoxia in order to match lung perfusion with ventilation. In patients with obstructive sleep apnea, recurrent episodes of hypoxemia during sleep lead to repeated acute increases in pulmonary artery pressures However, fewer than 20% of these patients develop sustained daytime pulmonary hypertension (mean pulmonary artery pressure greater than 20 mm Hg). Right ventricular hypertrophy can occur in patients with more marked obstructive sleep apnea and oxygen desatu- ration. However, overt pulmonary hypertension with right ventricular failure is seen primarily in patients with obstructive sleep apnea who also have chronic alveolar hypoventilation and hypercapnia.
Chronic cardiovascular effects of sleep-related breathing disorders.
Sleep-related breathing problems are associated with several cardiovascular diseases. Although a review by Wright et al on the health effects of obstructive sleep apnea dismissed these effects, citing the lack of controlled prospective studies, several recent epidemiologic studies and trials have demonstrated a strong association between sleep-related breathing disorders and cardiovascular disease that is independent of shared risk factors, such as obesity, age, and male sex.
More than half of patients with obstructive sleep apnea have systemic hypertension compared with an expected prevalence of 20% in middle-aged obese men. Approximately 25% of patients with hypertension have obstructive sleep apnea. For example, one study found that 30% of hypertensive men had sleep apnea, with an apnea index greater than 10, compared with only 9% of controls.
A greater prevalence of cardiovascular complications is seen throughout the spectrum of sleep-related breathing disorders, from snoring to obstructive sleep apnea. A study of 3,323 Danish men found an association between self-reported snoring and blood pressure, but the association was lessened when other risk factors were taken into account. Lindberg et al prospectively studied 2,668 men aged 30 to 69 years for the development of hypertension in relation to snoring, excessive daytime sleepiness, and other known cardiovascular risk factors during a 10-year follow-up period. Of the habitual snorers, 12.5% reported that they had developed hypertension, compared with 7.4% of the remaining subjects.
In one study, the blood pressure–lowering effect of CPAP was seen only in patients whose blood pressure did not decrease during sleep, “nondippers,” with obstructive sleep apnea syndrome. Some of the effects of CPAP on blood pressure may have been in part the result of weight loss. In one study, patients with sleep apnea who were successfully treated had a substantial reduction in cardiovascular events compared with equally affected patients who refused treatment.
The mechanisms underlying the development of sustained hypertension in sleep-related breathing disorders are not known. Possibilities include hypoxemia, repeated arousals, sustained increases in catecholamine levels and sympathetic tone, enhanced endothelin secretion, and altered eicosanoid activity. Furthermore, carotid chemoreceptors may maintain in- creased peripheral sympathetic activity and blood pressure after cessation of asphyxia or exposure to hypoxia. Increased ventilatory and pressor responsiveness to isocapnic hypoxia has been demonstrated in awake young subjects with mild hypertension. Brief exposure to hypoxia may result in sustained increases in peripheral sympathetic activity.
Coronary Artery Disease.
A greater risk of coronary artery disease in sleep-related breathing disorders is suggested by several retrospective and cross-sectional studies. The prevalence of sleep-related breathing disorders (measured as RDI of 10 or more) was 37% among men and 30% among women with angiographically verified coronary artery disease. In another study, clinically important sleep apnea was found in 50% of patients with coronary artery disease. Nearly 30% of patients with coronary artery disease and concomitant sleep apnea experienced myocardial ischemia during apnea, primarily during REM sleep. Patients with coronary artery disease should be screened for sleep-related breathing disorders.
Idiopathic Cardiomyopathy and Congestive Heart Failure.
Idiopathic cardiomyopathy and congestive heart failure have been reported in patients with obstructive sleep apnea. Left ventricular hypertrophy was more common in 30 normotensive patients with obstructive sleep apnea than in controls. In one study, all 8 patients with congestive cardiomyopathy of unknown origin had obstructive sleep apnea, and 4-week treatment with nasal CPAP increased the mean left ventricular ejection fraction significantly from 37% to 49%.
Respiratory Disturbance Index.
After adjustment for age, body mass index, weight gain, smoking, alcohol consumption, and physical activity, habitual snoring was an independent predictor for the development of hypertension, with an odds ratio of 2.6 [95% confidence interval (CI), 1.5 to 4.5)]. In a cross-sectional study of 805 Wisconsin state employees aged 30 to 60 years, polysomnography data were analyzed in relation to blood pressure measurements made before bedtime and after rising. Compared with subjects who did not have sleep-related breathing disorders, and after adjustment for body mass index, age, and sex, sleep- related breathing disorders were associated with cardio- vascular disease. The dose–response relation be- tween sleep-related breathing disorders, including snoring, and hypertension was independent of known confounders.
Sleep-related breathing disorders were risk factors for cardiovascular diseases in a 10-year prospective study in 3,100 men, in which the age-adjusted mortality was 2.9 (95% CI, 1.3 to 6.7) times greater in men with snoring and excessive daytime sleepiness compared with men who did not have these symptoms. Further adjustment for body mass index, hypertension, cardiac disease, and diabetes reduced the relative risk of cardiovascular mortality to 2.0 (95% CI, 0.8 to 4.7). These studies suggest that snoring and the increased upper airway resistance syndrome may be associated with an increased risk of cardiovascular disease.
The evidence supporting a possible cause–effect relation between obstructive sleep apnea and hypertension comes primarily from intervention studies, which have often observed both acute and chronic reductions in blood pressure after treatment of the sleep disorder.
Two studies found that about one-third of strokes apparently occurred during sleep. Among potential risk factors for stroke in one study, only snoring was significantly associated with stroke in sleep. In the other study, sleep-related breathing disorders were associated with a threefold increase in the risk of stroke.
The hemodynamic changes associated with disordered breathing during sleep may stress the cerebral circulation. In several cross-sectional studies, patients with a history of transient ischemic attacks or stroke have had a greater prevalence of sleep-related breathing disorders than control subjects. However, it is not clear whether sleep-related breathing disorders were an independent risk factor for stroke or increased stroke risk because of associated hypertension.
Sleep-related breathing disorders affect cerebral hemodynamics, including a greater than 50% reduction in cerebral blood flow during apnoeic and hypopneic events. The reduction in blood flow is related to the duration of hypopneas and the degree of oxygen de- saturations. In addition, there is also increased platelet activation and aggregation in the obstructive sleep apnea syndrome.
Sleep-related breathing disorders are a group of conditions that range from simple snoring with sleep disruption, to the increased upper airway resistance syndrome, to sleep apnea. These disorders may be associated with substantial cardiovascular morbidity and mortality, and early recognition and treatment may be effective in reducing these complications.
Francoise Roux, MD, Carolyn D’Ambrosio, MD, Vahid Mohsenin, MD
Updated July 9th 2017
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