In this News Brief emerging evidence about sleep-disordered breathing or “sleep apnea” as a “risk factor” for cardiovascular disease will be highlighted. Traditionally, the main “modifiable” risk factors for cardiovascular disease have included smoking, hypertension, diabetes, and hyperlipidemia. More recently physical inactivity has been added to the list of modifiable risk factors. Family history and age are unmodifiable risk factors. Whether sleep apnea will ever meet the strict epidemiological criteria required to be a well-accepted risk factor is unclear. Additionally, although sleep-disordered breathing is not the typical exercise- or activity-related topic discussed in the News Briefs section of Exercise and Sport Sciences Reviews, members of American College of Sports Medicine (especially those who work with patients) should be well versed about “risk factors” in general. Finally, our students should have up-to-date information on emerging concepts about cardiovascular disease. In this context, emerging evidence suggests that sleep-disordered breathing and sleep apnea are frequently associated with cardiovascular disease, or may in fact contribute to the progression of cardiovascular disease, especially hypertension.
What is sleep apnea? Sleep apnea is the temporary but frequent cessation of breathing during sleep that is associated with a fall in arterial o2 saturation, a rise in arterial Co2 and a rise in arterial pressure. Obstructive apneas are caused by a collapse of the upper airway, most often at the level of the soft palate or base of the tongue, which occurs when the wakefulness “drive” to upper airway muscles is withdrawn. Even though the individual continues to make respiratory efforts during this obstruction, little or no airflow occurs. Obstructive apneas usually terminate when arousal from sleep restores the waking level of muscle tone, reestablishes patency of the upper airway, and allows breathing to resume (often accompanied by a loud snort or snore). Frequent apneas affect both the quantity and quality of sleep. Not surprisingly, excessive daytime sleepiness is one of the most commonly reported symptoms in people with sleep apnea. The frequency of events varies from person to person; however, in severe sleep apnea, events can occur as frequently as once·min−1. More than five apneas or hypopneas·h−1 of sleep, in conjunction with symptoms, are usually considered clinically significant.
One of the first studies to document an association between sleep apnea and hypertension came from Hla et al. (1). This was a cross-sectional study from the Wisconsin Sleep Cohort Study of Wisconsin state employees. In this study mean systolic pressure was significantly higher among those with sleep apnea (defined as greater than five apneas or hypopneas·h−1 of sleep) in comparison to those without significant sleep-disordered breathing. Systolic and diastolic pressures were on average 5–8 mm Hg higher during both wakefulness and sleep in those with sleep-disordered breathing. Additionally, arterial pressure was more variable during sleep in those with sleep apnea and a history of snoring, and the odds ratio for the occurrence of hypertension was associated with the number of apnea or hypopneic episodes per hour in a dose-response fashion. The authors conclude that their data indicate an association between hypertension and sleep apnea that is independent of obesity, age, and gender in a community-based adult population.
Evidence for a casual relationship between sleep disordered breathing and hypertension comes from Wright et al. (10), Peppard et al. (8), and Lavie et al. (5). In these studies a prospective association between sleep-disordered breathing and the development of hypertension over time was shown, and the theoretical and integrative aspects of sleep apnea and how it might contribute to cardiovascular disease were discussed.
Morgan et al. (6) investigated potential causal mechanisms that might be responsible for the apparent association between sleep-disordered breathing and hypertension. When humans are apneic during sleep they become both hypoxic and hypercapnic, so Morgan and colleagues studied the neurocirculatory responses to combined hyperoxia and hypercapnia. They found that muscle sympathetic nerve traffic (which causes vasoconstriction in skeletal muscle) and blood pressure both rose dramatically during combined hypoxia and hypercapnia. They also demonstrated that this sympathetic activation was long lasting and persisted for up to 1 h after return to room air breathing. By contrast, exposure to hypercapnia alone caused a sustained increase in sympathetic activity that subsided quickly after the resumption of room air breathing. Subsequently, other investigators have shown that combined hypoxia and hypercapnia or hypoxia alone can evoke long-lasting sympathetic activation, and that repeated exposures to these conditions appear to evoke even more impressive and sustained increases in sympathetic vasoconstrictor activity and blood pressure. There is also emerging evidence from a variety of laboratories, but most notably from Mikael Sander and Jim Hansen at the Copenhagen Muscle Research Center, suggesting that when robust, young, healthy individuals are exposed to extreme altitude (>4000 m) for prolonged periods of time there is marked and continuous sympathetic activation. This sympathetic activation also persists for days or even weeks before it subsides after a return from high altitude (Sander, personal communication, 2002).
Another interesting article on issues related to sleep apnea (7) comes from the group headed by Virend Somers. In this study the observation that obese humans have increased muscle sympathetic nerve activity was evaluated in obese subjects with and without sleep apnea. The object of this study was to determine whether obesity alone causes increased sympathetic activity (and thus might contribute to hypertension) or if the increased muscle sympathetic nerve activity seen in obesity is frequently attributable to or associated with sleep-disordered breathing because so many obese people have sleep-disordered breathing. To address this issue the authors studied healthy normal-weight subjects and healthy sedentary-obese subjects. Subjects were rigorously screened to exclude people with obvious sleep apnea and hypertension. Despite the screening, overnight sleep studies suggested that about 1/3rd of the 30 obese subjects had obstructive sleep apnea whereas only one of 25 normal subjects had sleep apnea. Sympathetic activity at rest was similar in the normal-weight subjects and obese subjects without sleep apnea. However, in the nine obese subjects with obstructive sleep apnea sympathetic traffic was increased by about 50%. Based on these observations the authors conclude that obesity alone in the absence of sleep apnea is not accompanied by marked increases in sympathetic activity to muscle blood vessels. A subsequent study from Dr. Somers’ group (9) also demonstrated that patients with obstructive sleep apnea have increased C-reactive protein, which is associated with vascular inflammation and may contribute to cardiovascular morbidity and mortality in these patients.
Another potential causal link between sleep apnea and hypertension is the vascular endothelium. There is a growing body of evidence that sleep apnea, probably via the resultant hypoxia, interferes with endothelial function. Endothelium-dependent vasodilatation, an important mechanism in regulation of vascular tone, is impaired persons with sleep apnea syndrome ((3) and (4)). Furthermore, other investigators have observed that plasma endothelin levels are increased and circulating nitric oxide levels are depressed in these individuals (2).
As noted above, sleep apnea has been most closely associated with hypertension. However, it now appears that it may also contribute to sudden death from arrhythmia and congestive heart failure. Although the diagnosis and treatment of this condition can be complex (and include special sleep studies and treatment with continuous positive airway pressure devices during sleep), individuals who report poor sleep quality, snoring, excessive daytime drowsiness, and those who are obese may warrant further evaluation. Emerging evidence also suggests that treatment is effective and can also reduce the cardiovascular problems associated with sleep apnea.
In this News Brief we have reviewed a few ideas related to the association between sleep-disordered breathing and sleep apnea with hypertension. Issues related to obesity with and without sleep apnea have been discussed. The general idea is that sleep apnea (perhaps hypoxia) can evoke long-lasting sympathetic activation and vasoconstriction. This in turn can lead to a cascade of events that contributes to defects in vasomotor regulation and the development of hypertension and perhaps other cardiovascular diseases. From a practical perspective individuals working in the rehabilitation of patients with risk factors for cardiovascular disease should ask simple questions about sleep quality and snoring and have a low index of suspicion that patients with hypertension, obesity, and other elements of the so-called metabolic syndrome might also have sleep apnea. From a basic science perspective sleep apnea also raises many questions about baroreflex and chemoreflex control of the circulation (and how they interact) that are common to exercise.
1. Hla, K.M., Young, T.B. Bidwell, T. Palta, M. Skatrud, J.B. Dempsey. J. Sleep apnea and hypertension. A population-based study. Ann. Intern. Med. 120: 382–388, 1994.
2. Ip, M.C., Lam, B. Chan, L.Y. Zheng, L. Tsang, K.W. Fung, P.C. Lam. W.K. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am. J. Respir. Crit. Care Med. 162: 2166–2171, 2000.
3. Kato, M., Roberts-Thomson, P. Phillips, B.G. Haynes, W.G. Winnicki, M. Accurso, V. Somers. V.K. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation. 102: 2607–2610, 2000.
4. Kraiczi, H., Caidahl, K. Samuelsson, A. Peker, Y. Hedner. J. Impairment of vascular endothelial function and left ventricular filling: association with the severity of apnea-induced hypoxemia during sleep. Chest. 119: 1085–1091, 2001.
5. Lavie, P., Silverberg, D. Oksenberg, A. Hoffstein. V. Obstructive sleep apnea and hypertension: from correlative to causative relationship. J. Clin. Hypertens. 3: 296–301, 2001.
6. Morgan, B.J., Crabtree, D.C. Palta, M. Skatrud. J.B. Combined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. J. Appl. Physiol. 79: 205–213, 1995.
7. Narkiewicz, K., van de Borne, P.J. Cooley, R.L. Dyken, M.E. Somers. V.K. Sympathetic activity in obese subjects with and without obstructive sleep apnea. Circulation. 98: 772–776, 1998.
8. Peppard, P.E., Young, T. Palta, M. Skatrud. J. Prospective study of the association between sleep-disordered breathing and hypertension. N. Engl. J. Med. 342: 1378–1384, 2000.
9. Shamsuzzaman, A.S., Winnicki, M. Lanfranchi, P. Wolk, R. Kara, T. Accurso, V. Somers. V.K. Elevated C-reative protein in patients with obstructive sleep apnea. Circulation. 105: 2462–2464, 2002.
10. Wright Jr., J.T., Redline, S. Taylor, A.L. Aylor, J. Clark, K. O’Malia, B. Graham, G. Liao, G.S. Morton. S. Relationship between 24-H blood pressure and sleep disordered breathing in a normotensive community sample. Am. J. Hypertens. 14: 743–748, 2001.