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NEJM Editorial

Cardiac Pacing - A Novel Therapy for Sleep Apnea?

Sleep apnea, which is characterized by frequent episodes of apnea or hypopnea during sleep, is among the most common chronic disorders in adults. Sleep apnea associated with hypersomnolence is conservatively estimated to affect 2 to 4 percent of the middle-aged population of the United States, but the proportion of this population in whom polysomnography would provide evidence of sleep apnea, defined as an apnea-hypopnea index of five or more episodes per hour of sleep, is approximately five times as great.1 Although the clinical importance of sleep apnea that is not overtly symptomatic remains controversial, there is evidence that it is associated with daytime sleepiness2 and an increased risk of hypertension and cardiovascular disease.3,4

In most sleep laboratories, more than 90 percent of patients with sleep apnea have obstructive sleep apnea, for which treatment includes mechanical therapies, such as continuous positive airway pressure or the use of oral appliances at night, or surgery to enlarge the airway. These therapies are often poorly tolerated or unacceptable to patients, especially in the absence of marked daytime sleepiness. Drug therapy for obstructive sleep apnea has proved ineffective.5 However, since serotonin has an excitatory effect on motor neurons that innervate the muscles of the upper airway,6 serotonergic agents are promising as potential therapeutic agents in obstructive sleep apnea. Selective serotonin-reuptake inhibitors do cause a moderate reduction in the apnea-hypopnea index, although this effect has little clinical value.5 The report in this issue of the Journal by Garrigue et al.7 that atrial overdrive pacing caused a 60 percent reduction in the apnea-hypopnea index in a small group of patients with sinus-node dysfunction and sleep apnea is therefore of considerable interest. Although pacemaker insertion is unlikely to become an acceptable therapy for sleep apnea, this finding suggests that efficacious therapies for obstructive sleep apnea other than those that mechanically maintain airway patency may be possible.

The mechanism underlying this unexpected finding is unknown, and its generalizability to the typical patient with sleep apnea is uncertain. Although the demographic characteristics of the patients studied, who were predominantly middle-aged and older men, are typical of patients with sleep apnea, the characteristics of the sleep apnea itself are unusual. Approximately half the patients had predominantly central, rather than obstructive, sleep apnea. Even among those with predominantly obstructive apnea, the proportion of episodes of central apnea was unusually high. It is unclear whether this high incidence of central apnea is related to the underlying cardiac disorder. Although cyclic bradycardia-tachycardia during sleep is common in obstructive sleep apnea, true sinus-node dysfunction is most often the result of sclerodegenerative changes in the cardiac conduction system and is not known to be associated with sleep apnea. In a minority of cases, however, sinus-node dysfunction is "extrinsic," resulting from generalized autonomic dysfunction, which may be associated with sleep apnea.8 Most of the patients studied had documented left ventricular systolic dysfunction. Although it is not stated whether the observed pattern of central apnea was typical of Cheyne-Stokes respiration, the mild degree of ventricular dysfunction and the absence of clinical symptoms of heart failure argue strongly against Cheyne-Stokes respiration due to heart failure as the cause of sleep apnea.

It is interesting that both central and obstructive apnea showed similar improvement with atrial pacing. Obstructive sleep apnea is characterized by the collapse during sleep of an airway that is, in most cases, narrowed even during waking hours, and episodes of obstructive apnea are typically accompanied by vigorous respiratory efforts, leading many to consider obstructive sleep apnea a predominantly anatomical disorder. In contrast, central sleep apnea reflects a transient loss of respiratory effort during sleep. Although in some respects the two forms of apnea are quite different, a dichotomous view of them is overly simplistic. Upper airway obstruction itself is capable of inducing central apnea, presumably through reflexes originating in sensory neurons of the upper airway.9

A more important mechanism common to central and obstructive sleep apnea is related to the respiratory role of many muscles of the upper airway, such as the genioglossus, which maintain the patency of the airway during inspiration by stiffening or dilating the pharynx. Activation of the genioglossus muscle appears to parallel that of the diaphragm, and cyclic decreases in the activity of both muscles have been demonstrated not only in central sleep apnea but also in obstructive sleep apnea.10 The anatomical propensity of the airway to collapse is likely to determine whether central or obstructive apnea develops in persons with such cyclic decreases in respiratory effort, although differential activation of the motor neurons that innervate the various respiratory muscle groups may also have a role. Obesity is probably the most important anatomical cause of sleep apnea. In the light of the fact that the association between sleep apnea and obesity diminishes with age, central mechanisms may play a more important part in the pathophysiology of sleep apnea in elderly populations.

Such a central mechanism, affecting both respiratory rhythm and pharyngeal motor-neuron activity, would provide the most likely explanation for the reported equivalence in the improvement of central and obstructive apnea during atrial overdrive pacing.7 Since pacing apparently caused no change in sleep patterns - nor would it have been expected to do so - it is unlikely that sleep-related loss of the wakefulness stimulus to breathe was mitigated by pacing. It has long been known that the stimulation of carotid baroreceptors causes a decrease in the respiratory rate,11 although the effect of this barorespiratory reflex on the activity of pharyngeal muscles is not known. Garrigue et al. do not report the hemodynamic effects of pacing, but if pacing reduced blood pressure, either as a result of impaired cardiac function or as a response to increasing cardiac output, a diminution of the barorespiratory reflex might have increased the central respiratory drive.

Whereas the effects of pulmonary vagal afferent neurons on the heart rate are widely recognized and fairly well understood, the possible effects of cardiac afferent neurons on respiration have received little attention. Given the demonstrated efficacy of atrial overdrive pacing in preventing vagally mediated atrial arrhythmias and syncope in some patients, the authors conclude that atrial pacing at the rates used in this study (a mean of 72 beats per minute) is itself vagolytic, although nothing in the literature cited justifies this conclusion. It remains an intriguing hypothesis, however, that atrial pacing directly influences signaling from cardiac vagal or sympathetic afferent neurons. These afferents are known to be important in regulating blood pressure and heart rate.12 Although their effect on respiration is unknown, cardiac vagal afferents form synapses in the nucleus of the tractus solitarius,12 an important component of the medullary respiratory control center.6 Pulmonary vagal afferents to this area inhibit respiration, and the speculation that cardiac vagal afferents also inhibit respiration presents a testable hypothesis. Cardiac sympathetic afferents may also be relevant, since norepinephrine, like serotonin, has an excitatory effect on respiratory motor neurons, including those that innervate the pharyngeal muscles.6

The results that Garrigue and colleagues obtained with overdrive pacing in a small and highly selected group of patients with sinus-node dysfunction must be considered preliminary. Nonetheless, they are tantalizing because they imply that novel nonmechanical treatment options may be found for sleep apnea and because they suggest that the heart may be important in controlling respiration. Confirmation of these results and elucidation of the mechanisms involved will enhance our understanding of cardiorespiratory interaction and the pathophysiology of sleep apnea. Identification of the specific neural pathways involved may advance efforts to develop much-needed pharmacologic therapies for sleep apnea.

Daniel J. Gottlieb, M.D., M.P.H.

Boston University School of Medicine

Boston, MA 02118

References

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