Sleep Disordered Breathing and the Heart

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Robert D. Ballard, MD Medical Director, Sleep Disorders Center National Jewish Medical and Research Center Professor of Medicine University of Colorado Denver

Learning Objectives 

1. Define obstructive sleep apnea and Cheyne-Stokes breathing.
2. Review data linking sleep disordered breathing to cardiovascular disease.
3. Explain the appropriate uses of continuous positive airway pressure and nocturnal supplemental   oxygen therapy in the treatment of sleep disordered breathing.
4. Discuss the impact of treating sleep disordered breathing on the risk of cardiovascular sequelae.

• Introduction 
• Sleep Disordered Breathing
• Obstructive Sleep Apnea
• Cheyne -Stokes Respiration
• Summary
• References

Introduction

Extensive evidence has accumulated during the last several years linking sleep disordered breathing to cardiovascular disease. We will review currently available data addressing this association, with the hope that this review will convince the reader that sleep disordered breathing is an important contributor to cardiovascular disease, and that effective therapy of sleep disordered breathing reduces the risk for cardiovascular sequelae.

• Introduction  
• Sleep Disordered Breathing
• Obstructive Sleep Apnea   
• Cheyne -Stokes Respiration
• Summary 
• References

Sleep Disordered Breathing

It appears that the two major types of sleep disordered breathing with relevance to cardiovascular disease are obstructive sleep apnea and Cheyne-Stokes respiration. Obstructive sleep apnea is apparently much more common than Cheyne-Stokes respiration, and has been much more widely investigated. We will, therefore, begin our discussion with obstructive sleep apnea. 

Obstructive Sleep Apnea

Obstructive sleep apnea is a uniquely human disorder, brought on by the collapse of the pharyngeal airway during sleep. This collapse appears to result at least partly from sleep-associated reduction in the activity of pharyngeal dilator muscles. In the patient with anatomic predisposition toward narrowing of their pharynx (such as due to a large tongue or long palate), this can result in total occlusion during sleep, despite continuing respiratory efforts (Figure 1). By convention, the absence of airflow for at least 10 seconds in the presence of continuing inspiratory effort is defined as an obstructive apnea (Figure 2 ). Obstructive hypopneas are defined by at least a 30% reduction in airflow or effort, which lasts for at least 10 seconds and triggers a 4% reduction in oxygen saturation (Figure 3 ). Obstructive apneas and hypopneas during sleep are typically tallied together, to yield the apnea/hypopnea index (the combined number of apneas and hypopneas per hour of sleep). An apnea/hypopnea index of less than 5 is regarded as normal, an apnea/hypopnea index in the range of 5 to 15 events per hour is defined as mild sleep apnea, an apnea/hypopnea index in the range of 15 to 30 events is defined as moderately severe sleep apnea, while an apnea/hypopnea index of greater than 30 events per hour is commonly regarded as severe sleep apnea.

Potential Pathophysiologic Links between Obstructive Sleep Apnea and Cardiovascular Disease
Recent studies have provided strong evidence that untreated obstructive sleep apnea can be associated with several physiologic processes that could increase the risk for cardiovascular disease. First, it has been well established that obstructive sleep apnea is associated with increased sympathetic activation. A number of studies have determined that obstructive sleep apnea patients have increased sympathetic activation of peripheral vasculature.1 This is most pronounced in association with obstructive apneas and hypopneas during sleep, when affected patients demonstrate marked acute increases in systemic blood pressure. However, obstructive sleep apnea patients also have evidence of augmented sympathetic activity that persists throughout wakefulness.2 There is also evidence that effective therapy for obstructive sleep apnea can reduce the level of sympathetic activation, both during sleep and during wakefulness.3

Recent studies have also suggested that obstructive sleep apnea patients may have vascular endothelial dysfunction. Ultrasound studies have suggested that obstructive sleep apnea patients frequently have thickening of peripheral arterial walls, as well as impaired endothelial-dependent vascular dilation in response to reperfusion.4 Such findings strongly suggest a role for obstructive sleep apnea in the promotion of vascular pathology.

In addition, evidence is accumulating that obstructive sleep apnea represents a state of oxidative stress, with increased levels of reactive oxygen species that could trigger a proinflammatory cytokine cascade.5 In particular, it has been shown that proinflammatory cytokines such as TNF-alpha, IL-6, and IL-8, as well as the adhesion molecules ICAM-1 and VCAM-1, are all increased in the presence of obstructive sleep apnea. There is also evidence that effective therapy of obstructive sleep apnea can reduce these proinflammatory cytokines. Finally, it has recently been noted C-reactive protein is a strong marker of cardiovascular risks, if not a direct participant in vascular endothelial damage. It has recently been shown that C-reactive protein levels are elevated in patients with obstructive sleep apnea6, again signifying a potential association between obstructive sleep apnea and cardiovascular risk.

There is some evidence that obstructive sleep apnea may represent a “hypercoagulable state,” which could also predispose patients to the development of vascular disease. Studies have demonstrated that obstructive sleep apnea is associated with platelet activation and increased levels of fibrinogen, which could denote augmented clotting tendencies.7 Finally, recent studies have demonstrated that obstructive sleep apnea can be associated with insulin resistance and glucose intolerance in a manner that is directly proportional to the severity of obstructive sleep apnea.8, 9 Observations such as these may explain previous reports of an increased risk for the diagnosis of diabetes in obstructive sleep apnea patients, even after controlling for other risk factors. When taken together, all of these findings seem to offer credible pathways by which the presence of obstructive sleep apnea could promote increased cardiovascular risk.

Obstructive Sleep Apnea and Cardiovascular Risk
As already noted, it is well established that obstructive apneas and hypopneas often trigger significant surges in systemic blood pressure in association with the discreet, sleep-associated events. However, there is also compelling evidence that obstructive sleep apnea increases the risk for diurnal hypertension. Three large studies assessed the risk for hypertension in patients sampled from the general population or referred to a sleep disorders center with the suspicion of sleep apnea.10-12 These studies concur that the presence of obstructive sleep apnea increases the relative risk for hypertension by a factor of 1.5 to threefold, even after correcting for other risk factors such as age, gender, and body mass index. In particular, one of these studies followed patients longitudinally, with repeat assessments for sleep apnea and the development of hypertension at 4 year intervals.10 This study revealed that the risk for developing hypertension during a 4 year follow-up period increased with a linear relationship to apnea/hypopnea index, such that those patients with an apnea/hypopnea index of at least 15 events per hour had a 2.89 fold greater risk of developing hypertension over 4 years of follow-up than did those patients with no events.  

The apparent association between obstructive sleep apnea and hypertension might at least partially explain other studies that have reported an increased risk for cardiovascular disease in patients with obstructive sleep apnea. Partinen and Guilleminault followed 198 obstructive sleep apnea patients over 7 years after treatment with either a tracheotomy or with encouragement to lose weight, although as a group they did not lose significant weight.13 The relative risk for developing new cardiovascular disease in the “weight-loss” group after adjustment for body mass index was 2.3 in comparison with the tracheotomy group. Of additional interest, 56% of all obstructive sleep apnea patients had an already diagnosed cardiovascular disorder at the time of entry into this study, emphasizing the need for early diagnosis and therapy of sleep apnea.

These findings were further supported by results from the Sleep Heart Health Study, in which 6,424 free living individuals underwent overnight polysomnography.14 Those patients with an apnea/hypopnea index greater than 11 had a relative risk of 1.42 for the prevalence of cardiovascular disease in comparison with those patients demonstrating an apnea/hypopnea index <1.3. This increase in risk persisted despite correction for age, race, gender, smoking status, presence of self-reported diabetes and hypertension, body-mass index, total cholesterol, and HDL cholesterol levels.
In this same study14, it is also found that an apnea/hypopnea index of at least 11 events per hour increased the risk for self-reported congestive heart failure 2.38 fold in comparison to patients with an apnea/hypopnea index of 1.3 or less. Obstructive sleep apnea was more strongly associated with self-reported congestive heart failure than either stroke or coronary heart disease. Numerous other studies have also suggested an association between obstructive sleep apnea and congestive heart failure. Combining the results of six case series in which a total of 680 congestive heart failure patients underwent nighttime polysomnography (Table 1 ), 29% of the study patients were found to have obstructive sleep apnea.15 This link is further supported by observations from numerous case series of unselected obstructive sleep apnea patients that left ventricular dysfunction is common, and that ventricular function typically improves in response to effective therapy with continuous positive airway pressure (CPAP).

Therapy of Obstructive Sleep Apnea and Its Effect Upon Cardiovascular Disease
At present, the most effective therapy for obstructive sleep apnea continues to be CPAP. This incorporates the administration through a nasal or full-face mask of positive airway pressure that pneumatically splints the pharynx open during sleep, thereby preventing obstructive apneas and hypopneas. Although compliance with CPAP therapy has been an issue, it is widely accepted that if one complies with this therapy it will control obstructive sleep apnea greater than 90% of the time.
Two studies have assessed the impact of therapy with effective levels of CPAP vs. sub-therapeutic, or “sham”, CPAP upon blood pressure. Becker and colleagues16 observed no important change in blood pressure after 9 weeks of “sham” CPAP therapy, whereas mean, diastolic, and systolic blood pressures all decreased significantly (mean reductions of approximately 10 mmHg), both at night and during the day, in patients treated with effective levels of CPAP. In a similar study, Pepperell and associates17 observed that one month of effective CPAP therapy reduced 24-hour mean arterial blood pressure by 2.5 mmHg, whereas sub-therapeutic CPAP allowed blood pressure to increase 0.8 mmHg during the same period. Finally, there was an interesting report by Logan and colleagues18 that obstructive sleep apnea was detected in 84% of patients with refractory hypertension. Two months of CPAP therapy yielded an 11 mmHg reduction in 24-hour mean systolic blood pressure.
These observations strongly suggest that not only is obstructive sleep apnea associated with increased prevalence of hypertension and increased risk for developing new hypertension, but that effective therapy of obstructive sleep apnea can significantly reduce blood pressure, even in those patients with diagnosed refractory hypertension.

In addition, two recent studies have suggested that CPAP therapy in patients with obstructive sleep apnea and concurrent congestive heart failure can lead to improvement in cardiac function and quality of life. Kaneko and colleagues19 followed 12 obstructive sleep apnea patients with congestive heart failure who were treated for one month with effective level CPAP. The treated patients demonstrated a 10 mmHg reduction in daytime systolic blood pressure in conjunction with an improvement in left ventricular ejection fraction from 25 to 34%. No such changes were observed in a control group of 12 similar patients. In a similar fashion, Mansfield and colleagues20 evaluated the effects of 3 months of effective CPAP therapy upon quality of life and cardiac function in 19 obstructive sleep apnea patients with congestive heart failure. CPAP therapy lead to a 5% improvement in left ventricular ejection fraction and improvement in quality of life as measured by both SF36 in chronic heart failure questionnaires, whereas the control group of 21 patients remained unchanged.

All of these observations might explain the interesting observations of Peker and associates21, who monitored the incidence of cardiovascular disease over 7 years in middle-aged men diagnosed with obstructive sleep apnea. Of interest, cardiovascular disease was already present in 37% of patients formally diagnosed with obstructive sleep apnea vs. only 7% of those patients referred for the evaluation of sleep apnea, but with a subsequently negative polysomnogram. Over the next 7 years only 7% of effectively treated obstructive sleep apnea patients developed new cardiovascular disease, as opposed to 57% of inadequately treated sleep apnea patients. These results suggest that efficient treatment of obstructive sleep apnea reduces the excess risk of cardiovascular disease in this population.

• Introduction  
• Sleep Disordered Breathing
• Obstructive Sleep Apnea   
• Cheyne -Stokes Respiration
• Summary 
• References

Cheyne-Stokes Respiration

The crescendo/decrescendo periodic breathing pattern of Cheyne-Stokes respiration was first observed in association with congestive heart failure by Dr. John Cheyne in 1818. This respiratory pattern has been widely described since that time, and recent evidence suggests that it is the most common respiratory abnormality in patients with congestive heart failure (Figure 4). This periodic breathing pattern appears to result when a low baseline carbon-dioxide level leads to a “hypocapnic apnea” with transition to sleep, during which carbon-dioxide levels rise to the apneic threshold. Once this occurs, respiratory effort resumes but is typically followed by “ventilatory overshoot,” which leads to recurrence of hypocapnia and often a subsequent arousal from sleep (Figure 5). With return to sleep, the cycle repeats itself. Potential contributors to this pathophysiologic process could include; 1) increased ventilatory drive often seen in congestive heart failure; 2) hypoxia as a result of ventilation-perfusion abnormalities and low lung volumes; 3) reduction in functional residual capacity with subsequent “underdamping”; 4) upper airway instability, and; 5) a circulatory time delay between the alveolar units of the lungs and the peripheral chemoreceptors that is typical of congestive heart failure. The relative contributions of these different mechanisms are likely quite variable, but it is clear that Cheyne-Stokes respiration is common in patients with congestive heart failure. If one combines the results of 6 different studies which performed polysomnography in unselected patients with congestive heart failure (Table 1 ), 259 out of 680 subjects, or 38%, were found to have Cheyne-Stokes respiration.15

Morbidity of Cheyne-Stokes Respiration in Congestive Heart Failure
Several studies have demonstrated that Cheyne-Stokes respiration can impair sleep quality, and two studies by Hanley and colleagues22, 23 have demonstrated this condition to be associated with a reduction in sleep duration, increased sleep disruption, a tendency toward lighter stages of sleep, and daytime sleepiness. It has also been demonstrated that Cheyne-Stokes respiration is associated with cyclic increases in blood pressure and heart rate in a fashion quite similar to that observed with obstructive sleep apnea.24 It has also been observed that Cheyne-Stokes respiration in congestive heart failure is associated with increases in sympathetic activity that exceed those observed with congestive heart failure alone.25

Several studies have suggested that Cheyne-Stokes respiration can be associated with increased mortality in the congestive heart failure population. Hanley and colleagues23 followed 16 congestive heart failure patients for up to 4.5 years. They observed that in 9 patients with Cheyne-Stokes respiration there was a 55% mortality and 2 patients required urgent heart transplants during less than 4.5 years of follow-up. In comparison, the 7 patients without Cheyne-Stokes respiration demonstrated only a single death (14% mortality). Lanfranchi and colleagues26 followed 62 congestive heart failure patients for up to 28 months. Fifteen of these 62 patients (24%) died of cardiac causes during this follow-up. Their analysis revealed that Cheyne-Stokes respiration with an apnea/hypopnea index of at least 30 events per hour and left atrium enlargement were the only significant independent predictors of mortality.

Therapy of Cheyne-Stokes Respiration and its Effect Upon Cardiac Disease
Numerous studies have assessed the effects of CPAP upon Cheyne-Stokes respiration in congestive heart failure. These studies have predictably demonstrated that 1 to 3 months of therapy with CPAP at 10 to 12 cmH2O can yield significant improvement in sleep disordered breathing, while also improving cardiac function and quality of life indicators. Sin and colleagues27 conducted an interesting study in which 66 patients with congestive heart failure were randomized to receive either nightly CPAP or usual therapy. For the entire group of patients, a 60% relative risk reduction in mortality and cardiac transplantation rate was observed for those patients who complied with CPAP therapy. Effective use of CPAP yielded significant improvement in left ventricular ejection fraction after 3 months of therapy and a relative risk reduction of 81% in the combined mortality and cardiac transplantation rate for those patients with Cheyne-Stokes respiration. These studies therefore confirm that CPAP therapy improves cardiac function in congestive heart failure patients with Cheyne-Stokes respiration, and can apparently reduce the combined mortality and cardiac transplantation rates in congestive heart failure patients with Cheyne-Stokes respiration.

Oxygen Therapy for Cheyne-Stokes Respiration
Although it has not been as widely studied, there is also substantial evidence that nocturnal supplemental oxygen therapy can improve respiratory pattern during sleep in congestive heart failure patients with Cheyne-Stokes respiration. Franklin and associates28 treated 20 patients with Cheyne-Stokes respiration (16 of whom also had congestive heart failure) with supplemental oxygen via nasal canula at 1 to 5 liters per minute or 60% inspired oxygen via a Venturi mask. Oxygen therapy in this study reduced the median apnea/hypopnea index from 33.5 to 5 events per hour, with 17 out of 20 patients demonstrating at least 50% reduction in frequency of central apneas. However, it was not clear that sleep quality was improved by this therapy.

Krachman and associates29 subsequently evaluated 9 congestive heart failure patients with Cheyne-Stokes respiration, in random order administering supplemental oxygen via nasal canula at 2 liters per minute or nasal CPAP at 9cm of water. The oxygen therapy reduced the apnea/hypopnea index from 44 events per hour to 18 events per hour while CPAP therapy reduced the apnea/hypopnea index to 15 events per hour, with no significant difference between the two modalities. There was a slight reduction in total sleep time and sleep efficiency in those patients treated with CPAP.  

These studies suggest that both CPAP and supplemental oxygen therapy can be useful in treating sleep disordered breathing in congestive heart failure patients with Cheyne-Stokes respiration (Figure 6) , although only CPAP therapy has been observed to benefit cardiac function and quality of life. More recent studies have also evaluated the efficacy of bi-level positive airway pressure30 and “adaptive servo-ventilation,”31 both of which appear to be as effective as CPAP therapy. A variety of medications has also been utilized to treat Cheyne-Stokes respiration in congestive heart failure, but the only possibly useful medication is theophylline. Unfortunately, this medication has also been observed in numerous studies to disrupt sleep.  

• Introduction    
• Sleep Disordered Breathing
• Obstructive Sleep Apnea   
• Cheyne -Stokes Respiration
• Summary 
• References

Summary

In conclusion, there is clear evidence that obstructive sleep apnea has adverse effects upon blood pressure, cardiovascular status, and probably cardiovascular mortality. There is also evidence that effective therapy with CPAP can improve blood pressure and cardiac function in adult obstructive sleep apnea patients. Obstructive sleep apnea likely occurs in 30% of all congestive heart failure patients, while Cheyne-Stokes respiration occurs in at least 40% of congestive heart failure patients. The pattern of Cheyne-Stokes respiration with congestive heart failure appears to be associated with increased morbidity and excess mortality. Both CPAP and supplemental oxygen appear to be effective therapies for Cheyne-Stokes respiration in congestive heart failure, but only CPAP has been shown to improve cardiac function and quality of life.

• Introduction  
• Sleep Disordered Breathing
• Obstructive Sleep Apnea   
• Cheyne -Stokes Respiration
• Summary 
• References

References:

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