Continuous Positive Airway Pressure and Cardiovascular Events in Patients with Obstructive Sleep Apnea
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- Pataka, A. & Riha, R.L. Curr Cardiol Rep (2013) 15: 385. doi:10.1007/s11886-013-0385-z
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The obstructive sleep apnea syndrome (OSAS) is associated with the development/worsening of cardiovascular disease. OSAS is considered to be an independent risk factor for hypertension and is linked to increased mortality in the context of coronary heart disease, the development of cardiac arrhythmias and increased risk of developing mild pulmonary hypertension. OSAS is also associated with cerebrovascular mortality and morbidity. In heart failure, OSAS can lead to worsening of symptoms. Treatment of OSAS using positive airways pressure therapy (PAP) has been shown in randomized, controlled trials in selected populations to reduce some, but not all of these cardiovascular and cerebrovascular risks. Unequivocal evidence of causality for OSAS in the development, progression, and outcomes of these disorders in all individuals suffering from them, is lacking. Good quality long-term morbidity and mortality data for the effects of OSAS on cardiometabolic health and the impact of PAP treatment are likewise limited.
KeywordsContinuous positive airway pressureCPAPObstructive sleep apneaHeart failureCardiovascular diseaseCerebrovascular diseaseReview
Obstructive sleep apnea syndrome (OSAS) is a highly prevalent chronic condition associated with an increased risk of cardiovascular morbidity and mortality . OSAS serves as an excellent example of the close interaction between the respiratory, cardiac, metabolic, and neurological systems. In addition to the impact OSAS has on excessive daytime sleepiness, deficits in cognitive performance, mood and behavior, OSAS has been implicated in the etiopathogenesis of a wide spectrum of cardiovascular diseases (CVD). These include systemic and pulmonary hypertension, congestive cardiac failure, arrhythmias, atherosclerosis, ischemic heart disease, and stroke. Apart from hypertension, it is difficult to prove whether or not OSAS is an independent risk factor for all-cause CVD. There is evidence that implicates OSAS in the development of CVD, but whether this constitutes a true causal relationship remains controversial. OSAS is associated with metabolic dysfunction that increases the risk for cardiac disease, ie, diabetes, hypertension. In addition, OSAS and CVD share a number of common risk factors including aging, male gender, and obesity.
Currently the treatment of choice for OSAS is considered to be continuous positive airway pressure (CPAP) therapy. CPAP therapy is the mainstay of treatment for OSA and is delivered using a mask, attached by a hose to an air compressor, which delivers a constant positive pressure throughout the respiratory cycle. This acts as a pneumatic splint, keeping the airway open. CPAP has been shown to improve ventilator function, objective and subjective measures of daytime somnolence, and quality of life in patients with mild to severe OSA .
This review discusses the link between OSAS and cardiovascular disease, describing potential responsible mechanisms and the impact of CPAP treatment on associated morbidity and mortality.
Obstructive sleep apnea syndrome (OSAS) affects 3%–7% of adult men and 2%–5% of adult women in the general population . The prevalence of the disease can vary depending on differences in techniques used for monitoring sleep and breathing, variability in definitions and different sampling methods and up to 20% of the population is considered to have obstructive events during sleep that do not result in daytime symptoms. Epidemiological studies have shown that OSAS is linked to cardiovascular disease (CVD), hypertension, stroke, and Type 2 diabetes [4–9]. OSAS patients have also been shown to have a higher incidence of nocturnal disturbances in cardiac rhythm, eg, heart block, atrial fibrillation, ventricular ectopy . An association between OSAS and incident AF has also been described . OSAS is extremely common in patients who have suffered a stroke (43%–72%) . Among patients with heart failure (HF), the prevalence of OSAS is in the order of 11%–53 % [12–14]. In severe heart failure, Cheyne-Stokes breathing (CSB) can occur, characterized by waxing and waning, central apneic events during sleep (cessation of effort and breathing). The prevalence of central sleep apnea (CSA) and CSB is 15%–37% in severe heart failure, whereas in the general population it is less than 1% [13–16].
OSAS is characterized by obstruction of the upper airway during sleep, resulting in complete or partial breathing pauses (apneas or hypopneas respectively) accompanied by oxygen desaturation and arousal from sleep.
The pharynx is the site of upper airway (UA) obstruction and is commonly characterized by anatomical abnormalities such as increased tongue size, enlarged tonsillar tissue, enlarged lateral pharyngeal walls, and increased total soft tissue.
During inspiration, the size of the pharyngeal lumen depends on the balance between narrowing forces resulting from intrapharyngeal suction pressure and dilating forces generated principally by UA muscles. In normal subjects at sleep onset, there is a reduction in pharyngeal luminal area, a reduction in UA muscle activity and decreased intraluminal pressure during inspiration - all of which are exaggerated in OSAS. Passive gravitational forces generated by craniofacial structure or adipose tissue are also thought to compromise the UA. UA resistance is also thought to increase due to loss of caudal traction on UA structures during sleep. Surface mucosal factors may influence airway patency especially in subjects with mucosal inflammation from repetitive trauma, resulting in loss of UA sensation .
OSAS can lead to abnormalities in cardiovascular autonomic regulation, variability in blood pressure, and changes in heart rate (HR). Increased sympathetic nervous activity, reduced baroreflex sensitivity, and increased vascular stiffness have also been demonstrated, even in asymptomatic patients. The pathophysiology is currently incompletely understood but is thought to arise as a result of repetitive hypoxemia, hypercapnia, and changes in intrathoracic pressure that lead to increases in blood pressure (BP) and elevated levels of circulating catecholamines, the effect being greatest in those with the most frequent and severe oxygen desaturations during sleep. Most patients with OSAS have concomitant obesity and metabolic dysregulation, which may independently contribute to these effects on the cardiovascular system.
Pathophysiological Mechanisms Linking Cardiovascular Events with OSAS
As briefly mentioned above, OSAS can result in chronic abnormalities in cardiovascular autonomic regulation during sleep, which also manifest during wakefulness, as evidenced by increased sympathetic nervous system activity, reduced baroreflex sensitivity, heart rate and blood pressure variability. Recurrent nocturnal apneas are followed by sympathetic activation, which persists into wakefulness. Reduction in intra-thoracic pressure (negative intra-thoracic pressure), due to ineffective inspiratory efforts, affects the heart by increasing left ventricular transmural pressure and left ventricular afterload. Venous return is enhanced, resulting in right ventricular distension and leftward shift of the inter-ventricular septum. This combination of diminished left ventricular pre-load and augmented left ventricular afterload together reduces stroke volume and can compromise cardiac function.
Arousals at the termination of an obstructive apnea are accompanied by an increase in ventilation that precedes an increase in heart rate and blood pressure. This increase in ventilatory drive co-activates cardiovascular sympathetic neurons. Arousals serve to activate upper airway dilator muscles and prevent asphyxiation, but they also contribute to surges in heart rate and blood pressure. However, some studies have shown that this chain of events can occur independently of arousals at the termination of an apnea .
Intermittent hypoxia at night leads to tonic elevation of sympathetic neural activity by the augmentation of peripheral chemoreflex sensitivity. Apnea and CO2 retention amplify this effect. These effects are engaged after several seconds into the apnea. Intermittent hypoxia and sleep fragmentation are key features in systemic inflammation and oxidative stress in OSAS. Inflammation and oxidative stress play an important role in the development of endothelial dysfunction, atherosclerosis, and cardiovascular disease . During hypoxia, cells adapt to a low oxygen environment and the post apneic reoxygenation suddenly increases the oxygen in the cells. This results in the production of reactive oxygen species (ROS), which promote oxidative stress. OSA also leads to excessive platelet activation, hypercoagulability, increased hematocrit (probably due to nocturnal hypoxemia), elevated fibrinogen levels and whole blood viscosity predisposing to clot formation . OSA patients have an elevated concentration of atrial natriuretic peptide and this is related to the degree of hypoxemia- induced increases in pulmonary artery pressure and negative intrathoracic pressure swings. This increase in ANP probably contributes to nocturia, which is a common feature of OSAS.
Patients with heart failure (HF) may have both OSAS and central sleep apnea (CSA). Nocturnal rostral fluid shift is thought to contribute to the pathogenesis of both OSAS and CSA in patients with HF. During sleep, part of the peripheral fluid shifts into the neck, increasing neck circumference, thereby predisposing to OSA. There is also limited evidence to suggest that some fluid may be distributed into the lungs, thus stimulating the pulmonary irritant receptors and leading to hypocapnia, which can predispose to central apneas .
Systemic hypertension has been found in a number of studies to be more common among patients with OSAS, compared with those without OSAS. Hypertension in OSAS patients is more difficult to treat by conventional means than in non-apneic patients. A dose–response relationship between the severity of OSA and hypertension has been found even after controlling for age, sex, body mass index, and antihypertensive medications . However, in the Sleep Heart Health Study after adjustment for body mass index, OSAS severity was not a significant predictor of future hypertension, although an apnea/hypopnea index (AHI) > 30 influenced hypertension . These conflicting observations may be attributed to differences in the patient populations studied.
Many mechanisms may mediate the development of hypertension in OSAS, including repetitive hypoxemia, hypercapnia, and changes in intrathoracic pressure that lead to increases in blood pressure (BP) and elevated levels of circulating catecholamines. One possible important mechanism includes changes in aortic stiffness . Treating OSAS with continuous positive airway pressure (CPAP) results in a reduction of BP in both hypertensive and normotensive patients: the effect being greatest in those with frequent oxygen desaturations during sleep [24, 25••].
Left ventricular hypertrophy can occur as a consequence of longstanding hypertension. One study to date has undertaken echocardiography in 40 matched controls, 40 hypertensive subjects, and 40 patients with OSAS, demonstrating that patients with OSAS and hypertension had similar degrees of left ventricular hypertrophy and left ventricular impairment. After 26 weeks of therapy, cardiac function improved in the OSAS patients. However, the trial was not randomized and transthoracic echocardiography is more operator-dependent and more prone to error than radionuclide echocardiography. Nevertheless, the results are intriguing .
Current recommendations and guidelines suggest that patients with resistant hypertension should be evaluated for possible OSAS [25••]. In one study, more than 70% of patients with resistant hypertension suffered from OSAS compared with less than 40% with controlled systemic hypertension . The effect of antihypertensive medications on nocturnal blood pressure in OSAS is small with beta-blockers being the most effective. Their mechanism of action may lie in reducing sympathetic overactivity .
Treatment studies of hypertension in OSAS should be interpreted with caution. There are methodological differences among the different studies, including different study populations, sample sizes, outcome measures (single measure or 24-hour blood pressure measurements) and duration of follow-up. Most of the studies enrolled patients regardless of their baseline blood pressure (and not specifically because of hypertension). The studies that involved patients with known systemic hypertension and OSA did not find a reduction of systemic blood pressure after CPAP initiation [27, 28]. Furthermore, CPAP application in patients with elevated AHI but without excessive daytime sleepiness failed to reduce blood pressure [29, 30, 31••].
OSAS may contribute to the development of pulmonary hypertension when there is coexisting daytime hypoxemia, but not in patients with nocturnal hypoxemia alone. OSAS associated with pulmonary hypertension is mild and results from hypoxic vasoconstriction resulting in vascular remodeling. Some authors speculate that hyper-reactivity to hypoxia, left ventricular diastolic dysfunction, and left atrial enlargement have additional roles in its pathogenesis. Structural and functional changes in the right ventricle have been reported in OSAS patients, but their clinical significance is uncertain. Right ventricular failure is uncommon in OSA and more likely to be present if there is coexisting chronic hypoxic respiratory disease, morbid obesity or left-sided heart disease. CPAP therapy reduces pulmonary artery systolic pressure in patients with OSAS [32, 33].
Coronary Artery Disease
Patients with a history of myocardial infarction (MI) have a 2- to 3- fold higher incidence of OSAS. Patients with a nocturnal onset of MI had 6- fold higher odds ratio of OSAS than those with MI-onset during the daytime [34, 35].
Data from the Wisconsin Sleep Cohort Study indicate a higher all-cause and cardiovascular mortality among patients with severe OSAS . A higher incidence of cardiovascular events was found in patients with untreated severe OSAS than in those treated with CPAP, those with mild-moderate disease or healthy individuals . OSAS patients have an increased risk of angina or myocardial infarction and those with untreated severe OSAS were found to have a higher incidence of fatal and non-fatal cardiovascular events (myocardial infarction, acute coronary syndrome, and stroke) than patients treated with CPAP [1, 37, 38]. Patients who have both OSAS and known coronary artery disease run a greater risk of adverse cardiovascular outcomes (cardiac death, reinfarction, target vessel revascularization) than those without OSAS . Chronic intermittent hypoxia may induce atherosclerosis and a correlation between the AHI and atherosclerotic plaque volume has been shown in a few studies. Systemic inflammation, oxidative stress and endothelial dysfunction also contribute to atherogenesis . In addition, swings in intrathoracic and cardiac transmural pressures secondary to apneic events, sympathetic vasoconstriction, elevations in blood pressure, and intermittent hypoxia may trigger plaques to rupture. Mueller’s maneuver, which simulates the effects of an obstructive apnea, was found to cause more pronounced reductions in left ventricular ejection fraction (LVEF) in patients with known coronary artery disease than in those without. This suggests that a diseased myocardium is more vulnerable to the adverse effects of upper airways obstruction than a normal one . Treatment of OSAS using CPAP has been shown to reduce the incidence of cardiovascular events, including those related to coronary artery disease . CPAP treatment has been associated with a lower frequency of ST-segment depression and relief of nocturnal angina in patients with CAD and OSAS [43, 44].
OSAS is associated with cerebrovascular disease, including stroke [45, 46]. The Sleep Heart Health Study showed an increase in coronary artery disease, CHF, and stroke with increasing severity of OSAS . However, a surrogate marker of incipient stroke, the transient ischemic attack (TIA), has been shown to have variable increase in prevalence in OSAS patients [47, 48]. Once again, the negative intra-thoracic pressure swing during apneas have been shown to decrease cerebral blood flow predisposing to ischemic changes in some patients and alterations in the tension of the vessel wall, which may lead to changes in vascular shear forces and the development of cerebral angiopathy. Heavy snoring independently increases the risk of carotid atherosclerosis . Systemic hypertension, heart disease, impaired vascular endothelial function, hypercoagulability, and a proinflammatory state are risk factors for stroke that may be exacerbated by the presence of OSAS. Stroke patients with OSAS have an increased risk of premature death, a higher risk of long-term mortality, and a more than 2-fold increase in the cumulative incidence of nonfatal cardiovascular events, particularly another ischemic stroke [50–53, 54•].
CPAP treatment reduces the incidence of death in stroke patients with OSAS [51–53, 54•, 55–58] and provides protection against the appearance of new non-fatal events, similar to patients with no or mild disease [54•]. CPAP-treated patients have been shown to have a greater improvement in depression, wellbeing, nocturnal blood pressure, and nonfatal cardiovascular events [55, 56]. However, long-term compliance with CPAP was low, negating the benefits [54•, 58].
OSAS occurs commonly in HF patients, although CSA may be more frequent . Apart from the chronic effects on systemic blood pressure, OSA  may promote LV hypertrophy, diastolic and systolic dysfunction and HF. Several mechanisms are involved, including hypoxia, increased sympathetic drive, increased LV wall stress during each obstructed inspiratory effort and increased aldosterone secretion. Cheyne-Stokes respiration (a form of CSA) can also result in sleep disruption and sleep fragmentation resulting in excessive daytime somnolence. However, patients with OSAS and HF have significantly less subjective daytime sleepiness compared with the general population; the reasons for this are unclear . CPAP has been shown to be ineffective (no improvement in alertness, or fall in blood pressure) in the absence of excessive daytime sleepiness [61, 62]. In acute heart failure, The European Heart Failure guidelines recommend the use of positive airways pressure (PAP), which has been shown to reduce the need for intubation and improve short-term mortality in acute pulmonary edema [63–66]. This form of treatment is applied irrespective of the presence of sleep disordered breathing.
In CSB, CPAP can improve left ventricular ejection fraction  and quality of life. Several studies have shown that PAP improves exercise capacity, cardiac function, and nocturnal oxygenation, whilst decreasing circulating catecholamine levels in patients with HF and CSA. CPAP prevents pharyngeal narrowing and occlusion and reduces the degree of CSB [68, 69]. In CSA the pharyngeal airway also narrows and may even occlude, such that increased negative airway pressure must be generated in order for respiration to resume. This results in hyperpnea, followed by hypocapnia and generates ongoing CSA. In the Canadian Positive Airway Pressure (CANPAP) trial 258 patients who had HF and CSA were randomly assigned to receive CPAP or no CPAP for 2 years . The CPAP group had a greater reduction in the AHI, as well as greater improvement in mean nocturnal arterial oxygen saturation, LVEF%, and the 6-minute walk distance than the control group. However, there were no differences in the number of hospitalizations, quality of life, or transplant-free survival . In CANPAP there was an early divergence of transplantation rates in the first 18 months, favoring the control group that reversed after 18 months to favor the CPAP group. This was probably due to the potential adverse effect of CPAP on some patients with low filling pressures that lead to a reduction in cardiac output and increased mortality risk.
A post-hoc analysis of the CANPAP results demonstrated a time-dependent alleviation in CSA in some CHF patients with a further reduction in AHI after 12 weeks of CPAP treatment without further adjustment of CPAP pressure . However, in patients with HF and OSA, CPAP suppresses obstructive apneas immediately . This probably indicates that the approach to treatment with CPAP should differ between heart failure patients with OSAS and those with CSA. In some patients, the decision to treat should be based on potential long-term benefits.
New variants of PAP, such as adaptive servo-ventilation (ASV) and bilevel positive airway ventilation (BiPAP) have also been used in patients with HF and OSAS/CSA. BiPAP has improved cardiac function to a greater degree in HF patients with OSAS than CPAP . ASV has also been shown to be more effective than CPAP in reducing sleep disordered breathing, augmenting cardiac function, and improving exercise capacity, the 6-minute walk distance, and quality of life (especially vitality/energy). ASV has overall higher treatment compliance [74, 75]
OSAS has been associated with cardiac arrhythmias such as atrial fibrillation, non-sustained ventricular tachycardia, atrioventricular block complex ventricular ectopy, and cardiac pauses [76, 77]. Bradyarrhythmias have been reported in 18%–50%  of patients with severe OSAS. Apnea and hypoxia induce vagal activation resulting in bradyarrhythmias. Bradycardia is mainly related to the duration of apnea and the degree of hypoxemia. Nocturnal bradyarrhythmias in OSAS patients should be treated with CPAP prior to implantation of a pacemaker. CPAP abolishes nocturnal ventricular asystole and bradycardia in most patients with OSAS .
Ventricular arrhythmias are more common in OSA patients with left ventricular dysfunction and may be more evident during apneas . There is a high prevalence of OSAS in patients with atrial fibrillation (AF). Obesity and OSAS are considered independent risk factors for incident AF in patients less than 65 years old. Patients presenting with nocturnal cardiac arrhythmias should be evaluated for possible OSAS. Treatment of OSAS with CPAP significantly reduced arrhythmia recurrence in AF .
The use of atrial overdrive pacing to reduce the number of apneic events in OSAS was an association initially reported with great optimism, but has since been disproven in well-conducted studies [80–82]. In the context of HF, a reduction in CSA by using a pacemaker can be explained by an increase in heart rate with consequent improvements in cardiac output. Obstructive apneas do not decrease . When the effect of CPAP was compared with that of atrial overdrive pacing (AOP) in patients with OSAS without heart failure, AOP was ineffective in reducing obstructive events . In patients with OSAS and heart failure, AOP exerted a mild effect on respiratory events in some heart failure patients with OSA, but was not effective for the treatment of respiratory disturbances during sleep .
OSAS is implicated in the development of cardiovascular disease, including systemic hypertension, mild pulmonary hypertension, coronary artery disease, cerebrovascular events, and nocturnal cardiac arrhythmias. CPAP treatment is effective in at least partially reducing the risk of adverse cardiovascular and cerebrovascular disease through a number of effects such as lowering the severity of proatherogenic inflammation, improving nocturnal oxygenation, and reducing sympathetic drive. However, evidence for unequivocal causality and long-term reduction in mortality is lacking and further studies are essential to establish whether early identification and treatment of OSAS truly reduces cardiovascular morbidity and mortality.
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Conflict of Interest
Athanasia Pataka declares that she has no conflict of interest.
Renata L. Riha declares that she has no conflict of interest.
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This article does not contain any studies with human or animal subjects performed by any of the authors.