Sleep Apnea and Hypertension
Thomas G. Pickering, MD, DPhil, Mt. Sinai School of Medicine, 50 East 98th Street, New York, NY 10029
How many of us, when we are first taking a history from a hypertensive patient, ask about sleep habits and snoring? My guess is, not many. Sleep disordered breathing is not on the radar of most clinicians, and for good reasons. In the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) report,1 which is the standard guideline for the evaluation of hypertension in the United States, sleep apnea is not mentioned as a possible cause of hypertension, and most major textbooks of hypertension also pay little attention to it. Despite this, there is convincing evidence for an association and recent evidence that sleep apnea is a primary risk factor for the development of hypertension. We spend about one third of our lives asleep; we are all aware that the blood pressure (BP) falls in most people during sleep, and yet our mindset is that hypertension is a daytime disease. Numerous studies using 24-hour monitoring of BP have demonstrated that the nocturnal fall of BP is not a universal finding, and that variants of the normal dipping pattern may have pathologic consequences.
A wide spectrum of severity of sleep-disordered breathing has been recognized, with snoring at the benign extreme, and obstructive sleep apnea at the other. These conditions are relevant to the present discussion not only because they affect the changes of BP occurring during sleep, but also because they are significant risk factors for cardiovascular disease. The study of sleep apnea has largely been undertaken by pulmonologists, and as a result of the compartmentalization of contemporary medical science, their significance has not been fully appreciated by researchers or clinicians in the field of cardiovascular disease.
Obstructive sleep apnea is a disorder in which there are repeated episodes of partial (hypopnea) or complete (apnea) cessation of breathing during sleep. Such episodes may be of central origin, or due to mechanical obstruction of the airways, or to a combination of the two. By definition, apneas or hypopneas lasting at least 10 seconds are considered to be of clinical significance, although they usually last for 20–30 seconds and can last for more than a minute. The apnea/hypopnea index (AHI, also known as the Respiratory Distress Index, or RDI) is the average number of apneas and hypopneas per sleep hour.
Most apneic episodes are caused by collapse of the pharyngeal airway.2 This is the narrowest part of the airway, and the most dependent on muscle tone to maintain its patency. Muscle tone relaxes during sleep, and this may result in narrowing of the upper airway during inspiration, and hence snoring. This collapse of the airway also leads to increased respiratory effort and arousal. The arousal restores the muscle tone of the upper airways, allowing the subject to fall asleep once more. In this way the cycle of sleep and arousal may be repeated throughout the night. Not surprisingly, agents that relax skeletal muscle such as alcohol and benzodiazepines tend to exacerbate sleep apnea.
EPIDEMIOLOGY OF SLEEP APNEA AND HYPERTENSION
Since sleep apnea often goes undiagnosed, studies of its epidemiology need to be population-based surveys. The Wisconsin Sleep Cohort Study is the best example of such a study, in which Young et al.3 estimated the prevalence of sleep-disturbed breathing in a cohort of working middle-aged adults aged 30–60 years. The main finding was that 2% of women and 4% of men have sleep apnea (defined as an AHI score of 5 or more and daytime sleepiness). The prevalence of an AHI of ≥5 increases with age, reaching a maximum at the age of about 70.4
Both sleep apnea and hypertension are common, and not surprisingly there are many individuals who have both conditions. Furthermore, both are closely linked to obesity (particularly central obesity, as seen in the metabolic syndrome), so there is a cluster of related syndromes—hypertension, sleep apnea, diabetes, and the metabolic syndrome. Thus about 60% of sleep apnea patients are hypertensive,5 and conversely, about 30% of hypertensive patients have sleep apnea.6–9 The Wisconsin Sleep Cohort Study10,11 found a linear relationship between 24 hour BP and AHI that was independent of confounding factors such as body mass index. One of the issues is the causal linkage between sleep apnea and hypertension. The largest study of this is the Sleep Heart Health Study,12 which is a prospective study of the relationship between sleep apnea and cardiovascular morbidity. In an initial cross-sectional study of 6132 subjects aged ≥40,12 there was a dose-response relationship between the AHI score and the prevalence of hypertension, although some of it was attributable to the effects of increased body mass index. The association between sleep apnea and hypertension was seen in both sexes, at older and younger ages, and among normal and overweight groups.
To establish sleep apnea as an independent risk factor for the development of essential hypertension it is necessary to be able to demonstrate that it precedes and predicts the onset of hypertension, and that there is a dose-response relationship between the two. This has been achieved most convincingly by the Wisconsin Sleep Cohort Study,13 which found a consistent dose-response relationship, even after controlling for age, sex, body mass index, and antihypertensive medications.
BP PATTERNS IN SLEEP APNEA
It might be expected that repeated interruptions of breathing during the night, together with the arousals from sleep, would result in an absence of the normal dipping pattern of BP. It is certainly true that nocturnal BP is more variable in patients with sleep apnea,11 and some studies have reported an absence of any decrease of BP during the night or even an increase.14 However, the correlation between sleep apnea and nondipping is not close: the discovery of nondipping on a 24-hour BP recording is not a reliable screening test for sleep apnea, and many apneic patients retain the dipping pattern. Another important consequence of sleep apnea is refractory hypertension. One study15 found sleep apnea to be present in 83% of patients whose BP remained uncontrolled while taking a combination of three or more antihypertensive drugs, titrated to maximally recommended doses.
Sleep Apnea and Prognosis
It is generally thought that sleep apnea is an independent risk factor for both coronary and cerebrovascular morbidity, although prospective data on this is relatively limited at the present time. For example, some of the earlier studies indicating an increased morbidity in sleep apnea were retrospective analyses that had incomplete follow-up, or many of the patients had a diagnosis of cardiovascular disease at baseline.16 One prospective Swedish study17 of 408 patients with known coronary heart disease found that an AHI >10 was associated with an increased risk of cardiovascular events (death, stroke, and myocardial infarction). A second Swedish cohort18 was followed for 7 years, and found that sleep apnea at baseline was independently associated with a 4.9-fold increased risk of cardiovascular events (including new onset of hypertension, coronary, and cerebrovascular events).
Mechanisms of Hypertension in Sleep Apnea
Some of the strongest evidence linking sleep apnea to hypertension comes from a series of animal studies in rats and dogs. In the rat, repetitive episodes of hypoxia administered for 7 hours a day result in a persistent increase of BP and left ventricular mass.19 A role for the carotid chemoreceptors as the afferent stimulus was demonstrated by showing that surgical denervation of the chemoreceptors prevented the increase of BP.20 The role of the sympathetic nervous system as the efferent mediator was shown by sympathectomy using adrenal demedullation and 6-hydroxy dopamine, which also prevented the increase of BP.20,21 The renin-angiotensin system may also play a role, since when it is suppressed by a high-salt diet, the hypoxia-induced hypertension no longer occurs.22 In dogs, obstructing a tracheostomy to simulate apnea causes an acute increase of BP of about 20 mm Hg, which lasts for several hours, and is exacerbated by prior sleep deprivation.23 The BP increase can be blocked by pharmacologic blockade of the autonomic nervous system with hexamethonium, showing that it is mediated by the sympathetic nervous system rather than mechanical factors related to changes of intrathoracic pressure.
There is also evidence that the sympathetic nervous system plays an important role in the hypertension of patients with sleep apnea. Thus, 24-hour urine catecholamine levels are increased24 as are plasma levels measured during the day.25,26 Sympathetic nerve activity is also increased even while awake, 14,26,27 and may increase further during sleep, along with the BP.14
The cardinal manifestations of the obstructive sleep apnea syndrome are snoring and daytime sleepiness28; however, both may be denied or minimized by the patient. Snorers may be unaware of the sounds of their nightly battle to breathe unless there is a listener to tell them. There are at least two problems with sleepiness as a symptom. One is that patients may develop sleepiness so slowly over years that they forget what normal alertness is like. The other is that sleep deprivation is so common in our society that sleepiness is ubiquitous and thus nonspecific. The observation of someone who has seen the patient's sleep behavior (and daytime alertness) can be very helpful to the clinician. Witnessed obstructive events during sleep in a habitual snorer are a strong predictor of clinically important sleep apnea. Morning headaches are characteristic of sleep apnea, and are usually of relatively short duration (less than 30 minutes).29 They are related to the severity of AHI, and may be relieved by continuous positive airway pressure (CPAP, which maintains the patency of the upper airway during sleep) or surgery.
Examination of the prototypical patient with sleep apnea reveals a hypertensive, obese, middle-aged male with a large neck. Routine laboratory data are generally not helpful. The gold standard for diagnosing sleep apnea is polysomnography, which is usually performed in a sleep laboratory, but which can also be recorded with an ambulatory system in the home. The increasing awareness of sleep apnea has meant that sleep laboratories are inundated with requests for polysomnography tests, so waiting lists are long. Attempts are being made to develop less elaborate screening tests, but so far none have emerged that have found much acceptance.
There are two general issues when it comes to treating hypertensive patients who have sleep apnea: first, treatment of the underlying condition, and second, treating the hypertension itself. Since many of these patients will have the metabolic syndrome, attention should be paid to general hygienic measures such as weight loss and exercise. Another major issue concerns the effects of relieving the apneic episodes by surgery or nasal CPAP on blood pressure. Effective treatment of sleep apnea by CPAP has been shown to markedly and acutely decrease BP and sympathetic traffic during sleep, although chronic effects of CPAP treatment are less clear. The majority of studies have shown that blood pressure is lowered after starting CPAP, but almost none of them have been adequately powered randomized trials.5 While CPAP is the definitive treatment, it is poorly tolerated by many patients; other modalities of treatment include weight loss, and sleeping on the side as opposed to the back, in some cases wearing a belt with a tennis ball in the small of the back. Surgery has its advocates, but the results are disappointing.