Central Sleep Apnea in Congestive Heart Failure: Prevalence, Mechanisms, Impact, and Therapeutic Options

Shahrokh Javaheri, M.D.


Semin Respir Crit Care Med. 2005;26(1):44-55. 

In This Article

Mechanisms of Periodic Breathing and Central Sleep Apnea in Systolic Heart Failure

In patients with systolic heart failure, periodic breathing, defined earlier, occurs during wakefulness, even during exercise, but most commonly in sleep. In the setting of heart failure, periodic breathing reflects the failure of the negative feedback system, which normally operates, both during wakefulness and during sleep, to maintain homeostasis of normal stable breathing. Central apnea, however, is invariably unique to the state of sleep; hence, central sleep apnea. Even though central apnea has been described to occur during "wakefulness," at the time of its occurrence, the patient is commonly dozing, and if brain waves happen to be monitored, slowing of brain waves can be observed, though the epoch as a whole may be classified as wakefulness. In this regard, therefore, state of sleep provides the appropriate environment for development of apnea, both obstructive and central sleep apnea, of course by different mechanisms. Central sleep apnea is the result of unmasking the apneic threshold and a drop in the prevailing PCO2 below the apneic threshold resulting in cessation of breathing. Obstructive sleep apnea is due to upper airway occlusion, which is the result of failure in neuromuscular drive to maintain patency of the upper airway.

I emphasize, however, that the preceding description is a simplification of a complex set of pathophysiological processes that control breathing during sleep. There is considerable overlap with both central and obstructive sleep apnea commonly occurring in the same patient. This has been a major reason why we and others have described predominance of central or obstructive sleep apnea in patients with heart failure.[9,12]

As an example, upper airway narrowing and occlusion have been observed during the course of central apnea.[18,19] Therefore, the upper airway becomes vulnerable to closure, in the nadir of the ventilatory cycle of periodic breathing, resulting in mixed apneas.[20] Furthermore, patients with heart failure who are prone to upper airway occlusion (e.g., more obese subjects), will develop obstructive or mixed apneas in the setting of background periodic breathing.

Mathematical and experimental models[21,22,23,24,25,26,27,28,29,30] of the negative feedback system contributing to breathing homeostasis predict that increased arterial circulation time (which delays the transfer of information regarding changes in PO2 and PCO2 from pulmonary capillary blood to the chemoreceptors); enhanced gain of the chemoreceptors (enhanced CO2/O2 chemosensitivity, the high responders); and enhanced plant gain (decreased functional residual capacity) collectively increase the likelihood of periodic breathing. These three factors may all be present in systolic heart failure. It is therefore not surprising that heart failure is so conducive to development of period breathing. In systolic heart failure, effective arterial circulation time is increased (for a variety of reasons, such as pulmonary congestion, left atrial and ventricular enlargement, and diminished stroke volume); function residual capacity is decreased (again for a variety of reasons, such as pleural effusion, cardiomegaly, pulmonary congestion, and edema); and hypercapnic /hypoxic ventilatory responses may be increased. The latter has been shown to be one of the distinguishing features between those heart failure patients with or without significant periodic breathing and central apnea during sleep.[31] This is because in individuals with increased sensitivity to carbon dioxide, the chemoreceptors elicit a large ventilatory response whenever the partial pressure of carbon dioxide rises. The consequent intense hyperventilation, by driving the PCO2 below the apneic threshold, results in central apnea. Due to central apnea, PCO2 rises. Therefore, the cycles of hyperventilation and hypoventilation are maintained.

In any case, because these alterations in the negative feedback system controlling breathing are not necessarily state (sleep or wake) specific, periodic breathing may occur both during wakefulness and sleep, though most frequently during sleep. This is because sleep has profound effects on control of breathing. Sleep may promote periodic breathing because of the assumption of the supine position and also because of its own specific effects. Examples are: reduction in cardiac output further prolonging arterial circulation time, reduction in functional residual capacity and metabolic rate, both of which increase underdamping, increasing the likelihood of developing periodic breathing. As was already noted, sleep also has a profound effect on the genesis of central apnea.

The mechanisms involved in the genesis of central apnea relate specifically to the state of sleep and removal of wakefulness drive on breathing, which unmasks the apneic threshold.[32,33,34,35,36] The apneic threshold is defined as the level of PCO2 below which rhythmic breathing ceases. The difference between two PCO2 set points, the PCO2 at the apneic threshold minus the prevailing PCO2, is a critical factor for occurrence of central apnea. The smaller this difference, the greater the likelihood of central apnea occurrence.

Normally, with onset of sleep, ventilation decreases and PCO2 increases. As long as the prevailing PCO2 is above the apneic threshold, rhythmic breathing continues. However, in some patients with heart failure, prevailing PCO2 does not rise during sleep,[36,37] and central sleep apnea occurs because of the proximity of the prevailing PCO2 to the apneic threshold.[35,36] The reason for the lack of normally observed sleep-induced rise in PCO2 in some patients with heart failure is not clear. I believe, however, that it could be due to the lack of normally observed sleep-induced decrease in ventilation, presumably because of increased venous return in the supine position. In heart failure patients with severe left ventricular diastolic dysfunction (and stiff left ventricle), which invariably accompanies systolic dysfunction, when venous return increases, pulmonary capillary pressure can rise. This results in an increase in respiratory rate and ventilation, preventing the normally observed rise in PCO2.

Several studies[38,39,40] have shown that subjects with heart failure and low arterial PCO2 have a high probability of developing central sleep apnea during sleep. Predictive value of a low arterial PCO2 (≤ 35 mm Hg) is ~80%.[40] It is emphasized that although a low awake arterial PCO2 is highly predictive of central sleep apnea, it is not a prerequisite. Many patients with heart failure and central sleep apnea have normal awake PCO2.[40,41] What is important is the proximity of the apneic threshold to the arterial PCO2.[35,36]

Another implication of the difference between apneic threshold and the prevailing PCO2, may relate to the gender difference in prevalence of central apnea in congestive heart failure. Combining the results of several studies,[10,11,12,13,14] 40% of the male subjects have central sleep apnea, which is significantly higher than the 18% prevalence of central sleep apnea in female subjects (Fig. 2). However, in women with congestive heart failure and systolic dysfunction, risk of central sleep apnea was six times higher in those 60 years or older when compared with those less than 60 years of age.[12] Premenopausal women have a lower apneic threshold than men,[42] and this may be in part the reason for a lower prevalence of central apnea in premenopausal females than in males with heart failure.

Prevalence of obstructive (OSA) and central (CSA) sleep apnea in men and women with systolic heart failure. The prevalence of CSA is much less in females than in males. A similar trend is found in OSA, though not statistically significant. Data are compiled from Javaheri et al,[7] Hanly et al,[8] Javaheri et al,[9] Tremel et al,[10] Solin et al,[11] with permission from Javaheri.[1]


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