Recent studies tighten the link between OSA and hypertension, which are leading to more targeted therapies.
OSA affects approximately 4% of middle-aged adults and up to 50% of elderly persons.1,2 Of the approximately 75,000 patients seen annually in sleep disorder centers, roughly 75% are diagnosed with OSA.3 Projections of the prevalence of OSA in the United States range from 7 to 18 million people.3
OSA is a potentially life-threatening condition characterized by repeated collapse of the upper airway during sleep, cessation of breathing, and clinical associations with a variety of disease states, including hypertension. The spectrum and severity of clinical presentations of OSA are extremely variable.
Apnea and hypopnea cause temporary elevations in blood pressure in association with blood-oxygen desaturation, arousal, and sympathetic activation, and may cause elevated blood pressure during the daytime and, ultimately, sustained hypertension.1,4 Epidemiologic data support a link between obesity and hypertension as well as between OSA and hypertension. For example, untreated OSA predisposes to an increased risk of new hypertension, and treatment of OSA lowers blood pressure, even during the daytime.4
Pathogenesis of OSA and OSA-Associated Hypertension
Despite the prevalence of OSA, the pathogenetic mechanisms of this disorder remain incompletely understood. The occurrence of upper airway obstruction during sleep and not wakefulness implicates the removal of the wakefulness stimulus to breathe as a key factor underlying upper airway obstruction during sleep. Most of the data on sleep effect are derived from studies during non-REM (NREM) sleep, given the difficulty in achieving REM during invasive studies in the laboratory environment.
The reduction of tonic upper airway dilating muscle activity caused by sleep is associated with reduced upper airway caliber and increased pharyngeal wall compliance.5 The mechanical corollary of decreased caliber is an increase in upper airway resistance.7 In addition to increased resistance, increased pharyngeal wall compliance during sleep in snorers is manifested by the occurrence of inspiratory flow limitation as flow plateaus during inspiration.6
The combination of increased resistance and inspiratory flow limitation leads to an increased work of breathing, hypoventilation, and frequent arousals from sleep, and ensuing excessive daytime sleepiness. This has been described as a distinct clinical entity referred to as the upper airway resistance syndrome.7
The ability of the ventilatory control system to compensate for added loads is essential for the preservation of chemoreceptor homeostasis; however, immediate compensation for added loads is compromised during NREM sleep. Therefore, resistive loading results in decreased tidal volume and minute ventilation and, consequently, alveolar hypoventilation with subsequent elevation of arterial Paco2.8 Furthermore, NREM sleep abolishes the ability of upper airway dilating muscles to respond to negative pressure.
In awake humans and animals, application of negative pressure to the upper airway elicits a reflex activation of the genioglossus muscle, presumably dilating the upper airway. The fact that this reflex is absent during NREM sleep suggests that sleep eliminates a protective reflex that maintains upper airway patency in the face of narrowing or deformation.9,10 The mechanical consequences of such reflex activation have not yet been determined.
The pathogenic mechanisms responsible for hypertension in patients with OSA are believed to include activation of the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS); oxidative stress; and systemic and vascular inflammation, all of which could link OSA to a sustained increase in blood pressure.3
OSA has been associated with hypertension in clinical reports since the early 1980s.11-14 Although some studies found an independent association between snoring and hypertension,15,16 others found that this relationship may be explained by the confounding effects of age, sex, or obesity.17,18 Two recent studies demonstrated that a self-reported history of snoring is associated with an increased incidence of hypertension in middle-aged men and women.19,20 Other studies have used polysomnography, a more objective measure of OSA.21-24 Most of these studies found an association between OSA and hypertension, independent of age, sex, and other potential confounding factors.22,23 With the exception of the reports from the Wisconsin Sleep Cohort Study of middle-aged employed persons,24,25 most previous studies were based on a small number of patients in clinical settings.
Given the strong association between OSA and obesity, some investigators have cautioned that even in studies controlling for body mass index (BMI) (see sidebar), there is a potential for residual confounding, because fat distribution may be the strongest confounding component of obesity.26
|Body mass index (BMI) is a nutritional parameter that can be used to diagnose protein-calorie malnutrition. This index is independent of height, and the same standards apply to both men and women. BMI may be determined from the use of a nomogram or calculated by using the following formula:
BMI (kg/m2) = weight (kg) ÷ Height (m2)
• A BMI >28 defines significant obesity, while a BMI of 20 to 25 is considered normal. A BMI <18 implies moderate malnutrition.
Association in a Large Community-Based Study
Investigators performed a large-scale, cross-sectional analysis of 6,132 subjects aged Ž40 years recruited from ongoing population-based sleep studies.27 The objective of the analysis was to assess the association between OSA and hypertension in a large cohort of middle-aged and older persons. The main outcome measure was the apnea-hypopnea index (AHI), the average number of apneas plus hypopneas per hour of sleep, with hypopnea defined as a >30% reduction in airflow or thoracoabdominal excursion accompanied by a >4% drop in oxyhemoglobin saturation, obtained by unattended home polysomnography. Other outcome measures included arousal index; percentage of time below 90% oxygen saturation; history of snoring; and presence of hypertension, defined as a resting blood pressure of at least 140/90 mm Hg or use of antihypertensive medication.
The mean systolic and diastolic blood pressure and prevalence of hypertension increased significantly with increasing OSA measures, although some of this association was explained by BMI. After adjusting for demographics and anthropometric variables (including BMI, neck circumference, and waist-to-hip ratio), as well as for alcohol use and cigarette smoking, the odds ratio for hypertension, comparing the highest category of AHI (>30 per hour) with the lowest category (<1.5 per hour), was 1.37. The corresponding estimate comparing the highest and lowest categories of percentage of sleep time below 90% oxygen saturation (>12% vs <0.05%) was 1.46. In stratified analyses, associations of hypertension with either measure of OSA were seen in both men and women, older and younger ages, all ethnic groups, and among normal-weight and overweight individuals. Weaker and nonsignificant associations were observed for the arousal index or self-reported history of habitual snoring.
This well-designed analysis of a large study population provides compelling evidence of the association between OSA and hypertension in middle-aged and older individuals of different sexes and ethnic backgrounds.
More Research Is Needed
The mechanisms underlying the association between OSA breathing with hypertension remain to be established. One leading hypothesis is that OSA increases sympathetic neural traffic. Patients with untreated OSA exhibit elevated muscle sympathetic nerve activity during sleep and wakefulness. Such patients also have greater levels of plasma and urinary catecholamines in comparison with control subjects—a finding that lends support to the hypothesized role of the sympathetic nervous system. Furthermore, effective treatment with CPAP has been shown to improve autonomic function and lower sympathetic tone.28 Appropriate CPAP can resolve OSA in many patients. CPAP works by pneumatically splinting the collapsible upper airway. Although effective, CPAP is uncomfortable or intolerable for some patients, and variable patient compliance remains a significant problem. Studies have found that up to 25% of patients discontinue CPAP therapy.29-31
A second possible mechanism that may explain the observed relationship between OSA and hypertension is an impairment in vascular endothelial function in patients with OSA.32 Endothelium-dependent vascular relaxation in patients with OSA is reduced during wakefulness. The disruption of sleep and the hypoxic stress that accompany OSA may also be associated with a number of metabolic abnormalities that are well recognized risk factors for hypertension. These include impaired glucose tolerance, insulin resistance, and altered corticotropic function.
Mounting evidence indicates that treatment of sleep apnea using positive airway pressure, palatonasal surgery, and weight reduction corrects the associated hypertension.33 Interestingly, antihypertensive therapy appears to be less effective.33,34
Further research is needed to more definitively assess the relationship between OSA and hypertension. Clear elucidation of the pathogenic mechanisms of hypertension in patients with OSA may lead to new, more targeted therapies, and offer improved quality of life to those who suffer from OSA and its comorbidities.
John D. Zoidis, MD, is a contributing writer for Sleep Review.
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