In the last decades, sleep medicine experts have been devoting their attention to the cardiovascular consequences of sleep-disordered breathing, particularly obstructive sleep apnea (OSA). This common condition—tightly linked to advanced age, male gender, and obesity—promotes reduction of intrathoracic pressure, intermittent hypoxia, and sleep fragmentation.¹ Chronically, these phenomena trigger important intermediate mechanisms including sympathetic activity, inflammation, and oxidative stress among others that potently explain the increased cardiovascular risk of OSA.² On the other hand, central sleep apnea (CSA), associated with Cheyne-Stokes respiration, is a form of periodic breathing in which central apneas and hypopneas alternate with periods of hyperventilation that have a waxing-waning pattern of tidal volume.³ When the partial arterial pressure of carbon dioxide falls below the threshold level required to stimulate breathing, the central drive to respiratory muscles and airflow cease, and CSA ensues.³ Therefore, CSA was considered a marker of decompensated heart failure (HF).

These traditional views have been recently changed by evidence that chronic conditions characterized by overload fluid—such as those observed in patients with resistant hypertension⁴ and HF⁵—promote overnight rostral leg fluid displacement to the neck, favoring the upper airway collapse and thus, obstructive events. This evidence suggest that cardiovascular diseases may contribute (at least to impair) OSA severity. It was unknown if CSA and associated Cheyne-Stokes respiration may counterintuitively be the cause, and not the consequence, of HF. In an interesting paper, Javaheri and colleagues explored whether these two different types of sleep-disordered breathing (OSA and CSA with or without Cheyne-Stokes breathing) are associated with incident HF in a cohort of 2,865 older men from the MrOS (Osteoporotic Fractures in Men Study). Of note, HF was defined as hospitalization to treat increased intravascular volume or low cardiac output or both. Sensitivity analyses were performed excluding those with a self-report of prevalent HF and truncating the follow-up time to the start of continuous positive airway pressure. The main finding was that only Cheyne-Stokes breathing was associated with a significantly greater chance (odds ratio of 1.90) of developing HF events in a mean follow-up of 7.3 years. The relationship between CSA per se and incident HF failed to reach statistical significance once controlled for confounders. The authors concluded that Cheyne-Stokes respiration, but not obstructive events (OSA), was a strong predictor of incident HF events. These findings apparently contradict the relationship between OSA and incident HF observed in the SHHS (Sleep Heart Health Study).⁷ As pointed out by the elegant editorial⁸ accompanying the article, several differences should be noted between the 2 studies, including the higher age at entry (70 vs. 40 yr) and mean age (76 vs. 62 yr) and the greater proportion of men studied (100 vs. 44%) in MrOS compared with SHHS, respectively. Moreover, participants in MrOS under continuous positive airway pressure treatment at baseline were excluded, thus skewing the population away from severe untreated patients with OSA with HF. In summary, the precise reasons by which only Cheyne-Stokes respiration were associated with increased incident HF are unclear. The authors propose that the intrathoracic pressure swings during the hyperpneic phase of Cheyne-Stokes respiration following a central apnea increase the transmural pressure of the left and right ventricles, which may over time lead to increased ventricular afterload as well as sympathetic activity exacerbations resulting in adverse cardiac remodeling. However, the intrathoracic pressure swings with CSA Cheyne-Stokes breathing are usually much less than those seen in OSA. In addition, sympathetic activity observed in HF patients is also exacerbated in those with OSA.⁹ An alternate but attractive conclusion of the study is that Cheyne-Stokes respiration is a compensatory response to impeding HF in elderly patients.8 In this scenario, Cheyne-Stokes respiration may be a marker of first sign of HF (stage A) in the elderly.

Despite several strengths, the current study has some limitations, including the lack of echocardiogram analyses to appropriately characterize HF diagnosis. As a consequence, the analyses did not distinguish between HF with preserved versus reduced ejection fraction. The focus on male subjects prevented any extrapolation for elderly female patients.

The clinical application of these interesting findings is not entirely clear. Cheyne-Stokes respiration may be a good marker of occult HF in the elderly. Potentially, early identification and treatment of Cheyne-Stokes respiration in elderly patients either by drugs or positive airway pressure devices may prevent overt HF and cardiovascular events. Future randomized trials are warranted.

References

1. Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev 2010;90:47-112.
2. Drager LF, Togeiro SM, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: a cardiometabolic risk in obesity and the metabolic syndrome. J Am Coll Cardiol 2013;62:569-76.
3. Bradley TD, Floras JS. Sleep apnea and heart failure: Part II: central sleep apnea. Circulation 2003;107:1822-6.
4. Friedman O, Bradley TD, Chan CT, Parkes R, Logan AG. Relationship between overnight rostral fluid shift and obstructive sleep apnea in drug-resistant hypertension. Hypertension 2010;56:1077-82.
5. Yumino D, Redolfi S, Ruttanaumpawan P, et al. Nocturnal rostral fluid shift: a unifying concept for the pathogenesis of obstructive and central sleep apnea in men with heart failure. Circulation 2010;121:1598-605.
6. Javaheri S, Blackwell T, Ancoli-Israel S, et al. Sleep-disordered Breathing and Incident Heart Failure in Older Men. Am J Respir Crit Care Med 2016;193:561-8.
7. Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010;122:352-60.
8. Naughton MT. Heart Failure and Sleep-disordered Breathing. The Chicken or the Egg? Am J Respir Crit Care Med 2016;193:482-3.
9. Ueno LM, Drager LF, Rodrigues AC, et al. Effects of exercise training in patients with chronic heart failure and sleep apnea. Sleep 2009;32:637-47.

Keywords: Arterial Pressure, Carbon Dioxide, Cardiac Output, Low, Cardiovascular Diseases, Cheyne-Stokes Respiration, Continuous Positive Airway Pressure, Heart Failure, Heart Ventricles, Hypertension, Hyperventilation, Inflammation, Obesity, Osteoporotic Fractures, Oxidative Stress, Polysomnography, Randomized Controlled Trials as Topic, Respiration, Respiratory Muscles, Risk Factors, Sleep Apnea Syndromes, Sleep Apnea, Obstructive, Sleep Apnea, Central, Sleep Deprivation, Tidal Volume

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