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Sleep-disordered breathing (SDB), a disorder characterized
by repetitive partial or complete collapse of the upper airway during sleep, is frequent among middle-aged and older persons in the United States and other developed countries.
Among state employees in Wisconsin 30 to 60 yr of age,
Young and colleagues (1) estimated that 2% of women and
4% of men meet the criteria for the clinical syndrome of SDB.
Moreover, regular snoring, perhaps an indicator of the earliest
stages of SDB, affects far higher percentages. The unfortunate
trend of rising obesity in the United States predicts that SDB
may become even more common (2). In this issue of the Journal, Kraiczi and coworkers (3) address a common clinical
problem related to SDB
the treatment of hypertension.
SDB has a number of adverse effects on health, including an increased risk for hypertension. The association of SDB with hypertension was first noted in clinic-based studies, which showed a high prevalence of hypertension in patients with SDB and of SDB in patients with hypertension (4, 5). Confirmatory epidemiologic evidence soon followed (6, 7). The most recent data come from the Sleep Heart Health Study, a multicenter prospective cohort study of SDB and risk for hypertension and cardiovascular diseases. The initial, cross-sectional findings from this study have provided strong confirmation of the link between SDB and hypertension (8). In the study's 6,132 participants, all 40 yr of age and above, the apnea-hypopnea index was associated with hypertension (odds ratio, 1.37 [95% confidence interval, 1.02-1.82]) comparing the highest and lowest categories, after adjusting for potential confounding factors. A weaker and nonsignificant association was observed for the arousal index. Because the study is prospective in design, it will be possible to evaluate whether SDB is an independent risk factor for incident hypertension and to characterize the rise of blood pressure with age in relation to the apnea-hypopnea index, the disease-defining metric for SDB.
The mechanisms underlying the association of SDB with
hypertension remain to be established. One leading hypothesis is that SDB increases sympathetic neural traffic. Clinic-based studies indicate that patients with untreated SDB exhibit elevated muscle sympathetic nerve activity during sleep
and wakefulness (9, 10). Such patients also have higher levels
of plasma and urinary catecholamines in comparison with control subjectsa finding that lends support to the hypothesized
role of the sympathetic nervous system (9, 11). Furthermore,
effective treatment with continuous positive airway pressure
(CPAP) has been shown to improve autonomic function and
lower sympathetic tone significantly (12, 13).
The heightened sympathetic drive in SDB has been attributed to the combination of recurrent intermittent hypoxia and arousal from sleep. In a sample of patients with moderate to severe SDB, Leuenberger and colleagues (10) have shown that the occurrence of an apnea is associated with a transient rise in sympathetic activity, followed by an increase in arterial blood pressure. Because the phasic changes in sympathetic activity and blood pressure in these patients were attenuated by hyperoxia, the authors concluded that intermittent hypoxia, acting through arterial chemoreflexes, is a predisposing factor for the increase in sympathetic tone and elevation of arterial blood pressure. Some researchers, however, have questioned the role of hypoxia and have suggested that arousal from sleep may be the primary determinant for the elevation in blood pressure (14, 15). In one recent study, Brooks and colleagues (16) showed that sleep disruption, induced by auditory stimuli, was associated with an increase in systolic and diastolic arterial pressure during sleep that was similar in magnitude to that typically observed after obstructive apneas. Whether the observed increase in sympathetic activity, mediated either by hypoxia and/or arousal, plays an important role in elevating daytime blood pressure in persons with SDB remains unclear.
A second possible mechanism that may explain the observed relationship between SDB and hypertension is an impairment in vascular endothelial function in patients with SDB (17). Investigation of vascular endothelial vasodilation, as assessed by forearm blood flow and vascular resistance, indicates that endothelium-dependent vascular relaxation in patients with SDB is reduced during wakefulness (18). Finally, there are also emerging data suggesting that the disruption of sleep and the hypoxic stress that accompanies SDB may also be associated with a number of metabolic abnormalities that are well recognized as independent risk factors for hypertension, including impaired glucose tolerance, insulin resistance, and altered corticotropic function (19, 20).
These unresolved pathogenic considerations are relevant to
the treatment of hypertension in persons with SDB. In this issue, Kraiczi and colleagues (3) provide findings from a treatment trial of hypertension in persons with SDB. Using a balanced incomplete block design, researchers investigated five
agents in 40 patients: atenolol (
1-selective -blocker), amlodipine (calcium channel blocker), enalapril (angiotensin converting enzyme inhibitor), losartan (angiotensin receptor inhibitor), and hydrochlorothiazide (diuretic). Participants were
assigned at random to receive two of the drugs, each for 6 wk,
while not receiving CPAP. Blood pressure was assessed in the
clinic and by ambulatory monitoring; breathing during sleep
was reevaluated during treatment. Due in part to the study's
design, these findings could potentially inform the approach to
managing hypertension in patients with SDB and provide insights into the pathogenic mechanisms linking SDB to hypertension through the differing modes of action of the drugs.
The investigators found that clinic diastolic blood pressure,
the primary outcome measure, was most reduced by atenolol.
The reductions of systolic blood pressure in the clinic were not
significantly different across the five drugs, although atenolol
was associated with the greatest reduction. Ambulatory blood
pressure monitoring showed greater reduction of nighttime
systolic and diastolic blood pressures by atenolol and more
comparable reductions of the daytime systolic and diastolic
blood pressures. The authors interpret the findings as consistent with the hypothesized role of the sympathetic nervous
system in the pathogenesis of hypertension associated with
SDB. For the clinical management of hypertension in patients with untreated SDB, the results imply that a -blocker may be the optimal therapy.
Limitations of the study, however, call for caution in interpretation of the findings and in offering strong recommendations for clinical practice. First, the report is somewhat silent on the characteristics of the participants. We are told that they were obese, having a mean body mass index (BMI) of 29.5 kg/ m2, and a mean desaturation index of 43 per hour, but distributions are not provided for these key factors, or for age. The report also does not provide information on the characteristics of those receiving the various drugs, even though in view of the limited sample size, there is little guarantee that randomization resulted in perfectly comparable groups. Second, key features of the design are not fully justified, including the sample size and the choice of diastolic blood pressure in the clinic as the primary outcome measure. Ambulatory blood pressure monitoring and conventional plethysmography provide complementary information, and, in persons with SDB, 24-h monitoring provides data across the night when the typical nocturnal drop in blood pressure does not occur uniformly (12, 21). Results of 24-h monitoring, which includes sleep, may be more appropriate than single measurements as an index of hypertension and of the potential risk of target organ damage in the hypertension associated with SDB (22). Third, the design did not include additional randomization to CPAP, thereby limiting the generalizability of the findings for clinical purposes. Use of CPAP has been shown to decrease sympathetic activity and blood pressure during sleep (12).
To date, only a few studies have examined and compared
the effectiveness of different pharmacologic regimens in the
management of hypertension in patients with SDB. The general conclusion from these studies is that in the majority of
cases most antihypertensive drugs effectively reduce daytime
blood pressure (23). Studies that have compared several
drug regimens suggest that the decrease in blood pressure by
-blockade may be more than that observed with other agents.
However, as in the present study, the difference in magnitude
change in blood pressure between -blockers and other agents
is small and of unclear clinical significance (26, 27).
We do agree with the overall interpretation offered by
Kraiczi and colleagues (3) for their findings: there is support for overactivity of the sympathetic nervous system as a mechanism underlying the association of SDB with hypertension.
While awaiting more definitive evidence for this hypothesis,
clinicians may choose to give preference to -blockers in the
treatment of hypertension in persons with SDB. Nevertheless,
drug therapy should be coupled with aggressive management
of sleep-disordered breathing.
Departments of Epidemiology,Johns Hopkins School of Hygiene and Public Health
Division of Pulmonary Medicine, Johns Hopkins School of Medicine Baltimore, Maryland
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