ORIGINAL ARTICLE

Sleep Apnea Syndrome

Implications on Cardiovascular Diseases
Satish Bhadriraju, MD,* Carlton R. Kemp, Jr, MD, Mani Cheruvu, PhD,* and Srinivas Bhadriraju, MD

Abstract: Global risk assessment is the standard of care for coronary artery disease management. In this setting, sleep apnea syndrome, which includes obstructive sleep apnea and central sleep apnea, is being increasingly recognized as a potentially modiable risk factor for coronary artery disease. Emerging evidence points toward a cause and effect relationship between sleep apnea syndrome and medical conditions like insulin resistance, hypertension, heart failure, and myocardial ischemia. The effects of sleep apnea on coronary artery disease can be independent of many traditional risk factors. Continuous positive airway pressure has been shown to decrease inammatory markers that are elevated in sleep apnea syndrome. Well-designed randomized controlled clinical trials are needed to better establish the role of sleep apnea in the genesis and progression of coronary artery disease. Key Words: sleep apnea, cardiovascular disease, continuous positive airway pressure (Crit Pathways in Cardiol 2008;7: 248 253)

association between SAS and CVD offers an opportunity for improving medical outcomes. This paper reviews the pathophysiology of SAS and its association with the above-mentioned medical disorders. Evidence from recent trials on the therapeutic implications of treating SAS is also reviewed.

Pathophysiology
Many complex factors interact to initiate and sustain SAS. Despite having overlapping yet distinct pathophysiologies, both OSA and CSA are highly prevalent in cardiovascular patients.7 CSA is characterized by a loss of respiratory drive with repetitive cycles of hyperventilation that result in decreased arterial carbon dioxide levels below the apnea threshold.8 OSA is associated with dysfunction or loss of upper airway tone during sleep. An increased airway resistance with a tendency for airway collapse and a crowded pharyngeal space initiate the process of OSA.9 Episodes of apnea lead to a state of hypoxia and hypercapnia (Fig. 1). This leads to arousal accompanied by a surge of sympathetic activity that results in resumption of breathing. In the absence of treatment, this continues in a cyclical pattern. The nasal continuous positive airway pressure (CPAP) is the current standard of treatment for OSA. A combination of fragmented sleep with frequent arousals, negative intrathoracic pressure against an occluded pharynx, hypoxemia, hypercapnia, and autonomic oscillations contribute to the altered cardiovascular physiology seen in association with SAS.

bstructive sleep apnea (OSA) and central sleep apnea (CSA) characterize the sleep apnea syndrome (SAS). SAS is a focus of intense research with its intriguing interplays between cardiovascular disease (CVD) and metabolic dysregulation. It serves as a potentially modiable risk factor for CVD. The risk factor prole of CVD has added an array of novel risk factors over the years and global risk assessment is becoming the standard of care in CVD management, incorporating newer risk factors into the existing models for risk stratication.1,2 They serve as prognostic tools and present opportunities as therapeutic targets. SAS is fast emerging as a risk factor for coronary artery disease (CAD), with a contributory/causative role in CAD,3 hypertension,4 heart failure (HF),5 and insulin resistance.6 Exploring the
From *Internal Medicine Department, Memorial University Medical Center, Savannah, Georgia; Savannah Center for Respiratory and Critical Care Medicine, Savannah, Georgia; and Department of MedicinePulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia. Reprints: Satish Bhadriraju, MD, Memorial University Medical Center, 1101 Lexington Avenue, Savannah, GA 31404. E-mail: drbkm@yahoo.com. Copyright 2008 by Lippincott Williams & Wilkins ISSN: 1535-282X/08/0704-0248 DOI: 10.1097/HPC.0b013e31818ae644

OSA and Cardiovascular Physiology

The cardiovascular physiology is altered due to the periodic and repetitive stress imposed by sleep apnea. Such stresses have mechanical, hemodynamic, autonomic, neural, and inammatory origins. Both OSA and CSA result in altered blood gas physiology and catecholamine surges, which have important clinical consequences. In OSA, sustained respiratory effort against an occluded airway in the absence of ventilation leads to increased negative intrathoracic pressure and enhanced vagal tone. The repetitive respiratory effort against a closed upper airway (the Mueller maneuver) leads to the increased negative intrathoracic pressures, to the tune of 65 mm Hg. This may further contribute to autonomic and hemodynamic instability. Muellers maneuver is an objective measure of upper airway narrowing. This maneuver is performed by trying to inhale at the end of complete exhalation, with the nose and mouth closed. In the

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Sleep Apnea and Cardiovascular Implications

Loss of respiratory drive

CSA

OSA

Respiratory effort against occluded airway

Cardiac effects:
PaO2 PaCO2 pH Tachycardia LV failure Arrhythmias Hypertension Hypoxic vasoconstriction Myocardial structural alterations

Arousal Fragmented sleep Myocardial oxygen demand Vagal tone Pleural pressure Left ventricular end diastolic pressure Cardiac output
FIGURE 1. Pathophysiology of sleep apnea syndrome.

absence of obstruction, negative pleural pressure, lung parenchymal pressure, thoracic airway pressure, and upper airway pressure are in equilibrium. However, in the presence of signicant occlusion between the thoracic and upper airway, there is a disruption in this equilibrium.10 Mueller maneuver acts to increase afterload placed on the left ventricle. Furthermore, in patients with CAD, the Mueller maneuver may induce localized myocardial ischemia or unmasked vulnerable myocardial region.11 Augmented intrathoracic pressure leads to higher intracardiac pressures, leading to increasing ventricular wall tension and afterload.12 In addition, increased venous return results in a leftward shift of the interventricular septum, resulting in reduced left ventricular end-diastolic volume.13 Concurrent processes involving repetitive hypoxemia and consequent arousals further augment the heightened sympathetic state and effect the cardiovascular function.14 Frequent uctuations in autonomic tone and sleep stage-specic hemodynamic oscillations adversely impact the cardiovascular function. Sleep stage-specic hemodynamic oscillations are observed in the 2 stages of physiologic sleep, namely, rapid eye movement (REM) and non-REM (NREM). REM sleep is vagotonic although NREM is predominantly parasympathetic. REM has phasic and tonic components.
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Sudden bursts of sympathetic activity occur in phasic REM, leading to increase in heart rate and blood pressure. Sympathetic tone predominates during the day, whereas parasympathetic dominance is seen during nighttime. As a reection of this, heart rate and blood pressure measurements are observed to peak in the early morning. Daytime sympathetic tone and heart rate variability are more pronounced in patients with sleep apnea.15 The frequent sympathetic surges set the stage for many cardiovascular consequences associated with sleep disordered breathing, including hypertension and arrhythmias.

Sleep Apnea and Hypertension

Both hypertension and sleep apnea are increasingly common clinical conditions. It is reported that about 50% of OSA patients are hypertensive and 30% of hypertensive patients have OSA.4 Wisconsin Sleep Cohort, a prospective study evaluated the association between OSA and hypertension. The study revealed a 3-fold increased risk of developing new onset hypertension in patients with an apnea-hypopnea index of 15 or more. This association was independent of age, sex, BMI, and antihypertensive medications. Participants were evaluated 4 years after the initial sleep study.16 In the Sleep Heart Health study (SHHS), a large cross-sectional

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study, the odds ratio for hypertension, comparing the highest category of apnea-hypopnea index (AHI) (30/hr) with the lowest category (1.5/h) was 1.37 (95% CI, 1.031.83; P for trend 0.005).17 A recent study has shown a 2-fold increased risk for hypertension for adults in their fourth-sixth decade having a sleep duration of less than 5 hours each night (hazard ratio, 2.10; 95% CI, 1.58 2.79).18 Thus, the weight of clinical evidence favors OSA as a risk factor for hypertension. Exploring the mechanisms behind this association will provide an opportunity to further enhance the existing therapeutic approaches. Many mechanisms have been postulated to understand the role of OSA as a causative factor for hypertension. Hypoxia is a known stimulant of vascular endothelial growth factors (VEGFs) that are elevated in OSA.19 They promote angiogenesis in vivo at high blood concentrations20 and are potent mediators of capillary leakage. Such physiology, mediated by elevated VEGF levels may impact CVD by worsening clinical conditions like hypertension. Repeated apneas and hypopneas lead to exaggerated sympathetic tone that creates wide excursions in blood pressure. Sympathetic tone is also altered in patients with OSA by other mechanisms. Elevated urinary and circulating catecholamine levels, and high levels of muscle sympathetic nerve activity (MSNA) are observed in these patients.21 Repeated episodes of hypoxia, hypercapnia, and apnea result in chemoreex activation and consequent MSNA increase during sleep.22,23 A causal relationship between OSA and hypertension has been suggested by studies that evaluated the impact of treating OSA on hypertension management: CPAP use for a year has shown to decrease VEGF levels in comparison with no treatment24; CPAP treatment was shown to decrease urinary and plasma catecholamine levels25; CPAP therapy also lowered MSNA.26 Two randomized placebo (subtherapeutic CPAP)-controlled trials showed that the use of CPAP improved both daytime and nighttime blood pressure readings in comparison with that by placebo.27,28 The association between OSA and hypertension is gaining prominence. OSA has been recognized as a cause for underdiagnosed hypertension.29 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure includes OSA as an important identiable cause of hypertension.30 The existing evidence encourages considering OSA in the evaluation of all hypertensive patients.

CI, 1.0315.74).36 Although both tachyarrhythmias and bradyarrhythmias may be seen in association with SAS, AF is of particular interest. AF is triggered nocturnally and displays a strong circadian pattern.37 SHHS showed a 4-fold increase in prevalence of AF in subjects with an AHI 30.36 Atrial overdrive pacing has been considered as an alternative to CPAP therapy for cardiac arrhythmias in select patients. Garrigue et al38 reported that nocturnal atrial overdrive pacing, at a rate of 15 beats/min faster than the mean nocturnal heart rate, reduced the AHI by 60% in patients who had received pacemakers for symptomatic sinus bradycardia or tachyarrhythmias or bradyarrhythmias. To explain the effect of atrial overdrive pacing on cardiovascular physiology, 2 mechanisms have been suggested.39 The rst mechanism considers mitigation of nocturnal hypervagotonia and resultant stabilization of respiration by acting on cardiac and sympathetic efferent neurons. The other mechanism suggests that overdrive pacing may improve cardiac output and relieve pulmonary congestion, which in turn can decrease the work of breathing. However, 2 subsequent studies failed to demonstrate a benet of atrial overdrive pacing in OSA.40,41 As such, there is no direct evidence to support atrial overdrive pacing as a treatment option for OSA. CSA may be a target for this option in future studies that will continue to explore alternatives to CPAP.

Sleep Apnea and Heart Failure

Advances in understanding SAS in patients with congestive HF has generated and reignited the efforts to establish the relationship between SAS and HF.5 Observational data associates both OSA and CSA with HF.42,43 Cross-sectional data from SHHS demonstrated a signicant association of sleep disordered breathing with HF (OR for upper vs. lower quartile, 2.38; 95% CI, 1.22 4.62).44 Although OSA may lead to HF, the reverse is also true; thus, there exists a paradoxical relationship between both entities. Acute depression of cardiac function with obstructive apneas may lead to long-term cardiac structural remodeling, weakening the cardiac muscle, and potentially participating in the pathogenesis of HF.45 On the other hand, HF patients may show periodic breathing, which can lead to upper airway collapse.46,47 OSA can lead to progression of HF by promoting a physiological state of heightened stress on the cardiovascular system with repeated nocturnal desaturations, elevations in central sympathetic outow, and hypertension. OSA leads to an increase in negative intrathoracic pressure, which leads to the leftward shift of the interventricular septum, resulting in reduced end diastolic volume and increased left HF.48 CPAP has been shown to acutely reverse these effects.49 Patients with moderate-severe OSA show left ventricular hypertrophy50 and diastolic dysfunction.51 CSA is seen in 25% to 40% of patients with HF. This is associated with regular periodic waxing and waning of tidal volumes. This breathing pattern is called Cheyne-Stokes respiration (CSR). CSR with CSA (CSR-CSA) is seen in 30% to 40% of HF.42,52 Growing evidence indicates that CSR-CSA inuences the main pathophysiological reasons behind increased mortality in HF patients.5355 Thus, this has become an attractive therapeutic target for improving outcomes in HF patients with
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Sleep Apnea and Cardiac Arrhythmias

Heightened sympathetic tone has also been postulated as an underlying mechanism for increased incidence of cardiac arrhythmias and OSA.31 The most common arrhythmias during sleep include nonsustained ventricular tachycardia, sinus arrest, second degree atrioventricular conduction block and frequent (2 beats/min) premature ventricular contractions.3235 Data from clinical studies suggest a causal relationship between OSA and cardiac arrhythmias. The SHHS suggested a direct relationship between the severity of sleep disordered breathing and a higher risk of having nocturnal complex arrhythmias (2 4-fold). This association was independent of age, sex, BMI, and CAD as observed by the increased likelihood of atrial brillation (AF) (OR, 4.02; 95%

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CSR-CSA. Sin et al42 showed that patients with HF and CSR showed improved LV function and transplant-free survival when treated with CPAP. The same was not true in the group that had HF but not associated with CSR. The Canadian Continuous Positive Airway Pressure for Patients with Central sleep Apnea and Heart Failure (CANPAP) trial was a multicenter randomized controlled trial that involved 258 patients with HF and CSA. The use of CPAP resulted in attenuation of CSA, improved nocturnal oxygenation, left ventricular function, and submaximal exercise tolerance (initial, but transient). However, improvement in these physiological parameters did not translate into mortality benet in this group of patients with CSA and HF.56 A follow-up study after 2 years showed that the primary outcome of combined mortality and cardiac transplantation did not differ in the treated and control groups. But, proponents in favor of the trial point out that the study may not have been adequately powered to elicit important clinical differences. Drawing conclusions from the beta-blocker and spironolactone trials in HF, the authors of the CANPAP trial argue that given adequate patient numbers, it may be possible to see clinically important outcomes.56 Bradley,57 in his insightful article, analyzed the ndings from CANPAP trial and drew comparisons to the beta-blocker trials. In the studies that used Metoprolol, although initial trial results (n 383) had no mortality benet,58 the subsequent trials with a larger patient population (n 3991) showed clear survival benet.59 Similarly, in the trials that used carvedilol, although initial trial results (n 301) had demonstrated no mortality benet,60 the subsequent trials showed a clear survival benet (n 2289).61 Arzt et al62 in a post hoc analysis of the CANPAP trial showed mortality benet in patients who achieved an AHI 15 events per hour with the use of CPAP. The CANPAP trial was done in an era when medical management of HF was being optimized with widespread use of betablockers, spironolactone, and angiotensin-converting enzyme inhibitors. The additional benet of CPAP therapy over and above the optimal medical regimen of present day HF management will have to be determined by larger randomized control trials.

The Molecular Mechanisms Behind OSA: Setting the Stage for Clinical Consequences of Atherogenesis
There is a complex interaction between different mechanisms that link OSA to cardiovascular risks. Intermittent hypoxia and fragmented sleep may lead to increased inammation in OSA patients. Cell culture models of intermittent hypoxia indicate an alternate and selective activation of inammatory pathways, compared with sustained hypoxia wherein adaptive pathways play a major role.71 Repetitive episodes of hypoxemia lead to a state of constant desaturation and reoxygenation. These resemble ischemia-reperfusion events, with reoxygenation phase generating reactive oxygen species.72 The oxidative stress may lead to reduction in the nitric oxide levels, resulting in endothelial dysfunction.71 C-reactive protein, an inammatory marker, has been shown to prospectively predict future coronary events in healthy men and women.73 A direct correlation has been shown between OSA severity and the levels of C-reactive protein and interleukin-6.74,75 Tumor necrosis factor-, an inammatory cytokine, has been linked to insulin resistance76 and atherogenesis,77 and correlates with cardiovascular risk. Tumor necrosis factor- induces endothelial activation in the initial stages of atherosclerosis, resulting in production of adhesion molecules that promote monocyte adhesion. This step is critical for vascular disease development.78 Increased adhesion of lymphocytes to vascular endothelium has been observed in OSA patients.79 One consequence of the abovementioned relationship between OSA, inammation, and endothelial dysfunction is the clinical progression of atherosclerosis. In patients with OSA, there is a 5-fold increase in the risk for developing CVD, independent of the traditional risk factors like age, BMI, hypertension, and smoking.80 Carotid atherosclerosis, regarded as a marker for generalized atherosclerosis, has been shown to be associated with OSA.81 83 Studies have also revealed the independent association between OSA and subclinical CAD assessed by calcication burden in the coronary arteries.84 The evolution of atherogenesis combined with the nocturnal hemodynamic and neurohormonal alterations seen in SAS puts the myocardium at risk for overt ischemia as well. Coronary events such as acute myocardial infarction (AMI) and sudden cardiac death follow strong nocturnal patterns. OSA seems to inuence this nocturnal pattern. In patients without coexistent OSA, sudden death occurred between 6 and 11 AM. In patients who have coexistent OSA, greater than 50% of sudden cardiac deaths happened during 10 PM to 6 AM.85 Further strengthening this association, a recent study showed that in OSA patients who had AMI between midnight and 6 AM, sleep apnea was associated with a 5-fold greater frequency of infarction, compared with patients who did not have OSA and had experienced AMI in the same time interval. The odds of having OSA when AMI occurred between 12 and 6 AM was 6-fold higher than that in the remaining 18 hours of the day (95% CI, 1.327.3; P 0.01). This study draws a clear distinction in the diurnal variation in the onset of AMI based on the presence or absence of coexistent OSA.86 However, all these studies caution that although these are relevant obser-

Metabolic Dysregulation in Sleep Apnea and Cardiovascular Risk

Insulin resistance is observed in association with sleep disordered breathing.63 Cross-sectional data from the SHHS and Wisconsin Sleep Cohort also revealed insulin resistance to be associated with sleep apnea.64,65 The pathophysiology of such association may be related to sleep fragmentation and repetitive hypoxemia.66 This association is independent of obesity67 and all other constituents of the metabolic syndrome.68 Treatment with CPAP has been shown to restore insulin sensitivity, more so in nonobese patients.69 However, there is conicting data about the efcacy of using CPAP to correct the insulin resistance.70 Because the evidence lends to the association of OSA with insulin resistance, further research is needed to dene this relationship more precisely. Larger trials may be needed to clarify the role of CPAP treatment for sleep apnea-induced insulin resistance.
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vations, they are only associations, and do not prove a causal relationship between OSA and CAD.

CONCLUSION
Despite a symptomatic quiescence over a long period, much like in diabetes, the case has been made for sleep to be regarded as providing an autonomic stress test for the heart every night, with successful treatment of OSA, resulting in the normalization of impaired autonomic stress responses.87,88 There is growing evidence to link OSA and CVD. All patients with hypertension, especially those with difculty in controlling hypertension, should be screened for coexisting OSA. There may be unexplored or inadequately understood mechanisms at the cellular and genetic levels that require further research to better dene the relationship between sleep apnea and CVD. In comparison with several other well-established diseases, our understanding of SAS is still evolving, and further research and development of large databases would elucidate many as yet unexplained and unclear concepts and lead to improved patient care. REFERENCES
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