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ORIGINALARTICLE

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 coro-

nary artery disease management. In this setting, sleep apnea syn-

drome, which includes obstructive sleep apnea and central sleep

apnea, is being increasingly recognized as a potentially modifiable

risk factor for coronary artery disease. Emerging evidence points

toward a cause and effect relationship between sleep apnea syn-drome 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 inflammatory 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 Cardiol2008;7: 248253)

Obstructive sleep apnea (OSA) and central sleep apnea(CSA) characterize the sleep apnea syndrome (SAS).SAS is a focus of intense research with its intriguing inter-plays between cardiovascular disease (CVD) and metabolicdysregulation. It serves as a potentially modifiable risk factorfor CVD. The risk factor profile of CVD has added an arrayof novel risk factors over the years and global risk assessmentis becoming the standard of care in CVD management,incorporating newer risk factors into the existing models forrisk stratification.1,2 They serve as prognostic tools andpresent 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

association between SAS and CVD offers an opportunity forimproving medical outcomes. This paper reviews the patho-physiology of SAS and its association with the above-men-tioned medical disorders. Evidence from recent trials on thetherapeutic implications of treating SAS is also reviewed.

PathophysiologyMany complex factors interact to initiate and sustain

SAS. Despite having overlapping yet distinct pathophysiolo-gies, both OSA and CSA are highly prevalent in cardiovas-cular patients.7 CSA is characterized by a loss of respiratorydrive with repetitive cycles of hyperventilation that result indecreased arterial carbon dioxide levels below the apneathreshold.8 OSA is associated with dysfunction or loss ofupper airway tone during sleep. An increased airway resis-tance with a tendency for airway collapse and a crowdedpharyngeal space initiate the process of OSA.9 Episodes ofapnea 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 absenceof treatment, this continues in a cyclical pattern. The nasalcontinuous positive airway pressure (CPAP) is the currentstandard of treatment for OSA. A combination of fragmentedsleep with frequent arousals, negative intrathoracic pressureagainst an occluded pharynx, hypoxemia, hypercapnia, andautonomic oscillations contribute to the altered cardiovascu-lar physiology seen in association with SAS.

OSA and Cardiovascular PhysiologyThe cardiovascular physiology is altered due to the

periodic and repetitive stress imposed by sleep apnea. Suchstresses have mechanical, hemodynamic, autonomic, neural,

and inflammatory origins. Both OSA and CSA result inaltered blood gas physiology and catecholamine surges,which have important clinical consequences. In OSA, sus-tained respiratory effort against an occluded airway in theabsence of ventilation leads to increased negative intratho-racic pressure and enhanced vagal tone. The repetitive respi-ratory effort against a closed upper airway (the Muellermaneuver) leads to the increased negative intrathoracic pres-sures, to the tune of65 mm Hg. This may further contributeto autonomic and hemodynamic instability. Muellers maneu-ver is an objective measure of upper airway narrowing. Thismaneuver is performed by trying to inhale at the end ofcomplete exhalation, with the nose and mouth closed. In the

From *Internal Medicine Department, Memorial University Medical Center,Savannah, Georgia; Savannah Center for Respiratory and Critical CareMedicine, Savannah, Georgia; and Department of MedicinePulmo-nary, Allergy and Critical Care Medicine, Emory University, Atlanta,Georgia.

Reprints: Satish Bhadriraju, MD, Memorial University Medical Center, 1101Lexington Avenue, Savannah, GA 31404. E-mail: drbkm@yahoo.com.

Copyright 2008 by Lippincott Williams & WilkinsISSN: 1535-282X/08/0704-0248DOI: 10.1097/HPC.0b013e31818ae644

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absence of obstruction, negative pleural pressure, lung paren-chymal pressure, thoracic airway pressure, and upper airwaypressure are in equilibrium. However, in the presence ofsignificant occlusion between the thoracic and upper airway,there is a disruption in this equilibrium.10 Mueller maneuveracts to increase afterload placed on the left ventricle. Further-more, in patients with CAD, the Mueller maneuver mayinduce localized myocardial ischemia or unmasked vulnera-ble myocardial region.11 Augmented intrathoracic pressureleads to higher intracardiac pressures, leading to increasingventricular wall tension and afterload.12 In addition, in-

creased venous return results in a leftward shift of theinterventricular septum, resulting in reduced left ventricularend-diastolic volume.13 Concurrent processes involving re-petitive hypoxemia and consequent arousals further augmentthe heightened sympathetic state and effect the cardiovascularfunction.14

Frequent fluctuations in autonomic tone and sleepstage-specific hemodynamic oscillations adversely impact thecardiovascular function. Sleep stage-specific hemodynamicoscillations 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 predominantlyparasympathetic. REM has phasic and tonic components.

Sudden bursts of sympathetic activity occur in phasic REM,leading to increase in heart rate and blood pressure. Sympa-thetic tone predominates during the day, whereas parasym-pathetic dominance is seen during nighttime. As a reflectionof this, heart rate and blood pressure measurements areobserved to peak in the early morning. Daytime sympathetictone and heart rate variability are more pronounced in pa-tients with sleep apnea.15 The frequent sympathetic surges setthe stage for many cardiovascular consequences associatedwith sleep disordered breathing, including hypertension andarrhythmias.

Sleep Apnea and HypertensionBoth hypertension and sleep apnea are increasingly

common clinical conditions. It is reported that about 50% ofOSA patients are hypertensive and 30% of hypertensivepatients have OSA.4 Wisconsin Sleep Cohort, a prospectivestudy evaluated the association between OSA and hyperten-sion. The study revealed a 3-fold increased risk of developingnew onset hypertension in patients with an apnea-hypopneaindex of 15 or more. This association was independent of age,sex, BMI, and antihypertensive medications. Participantswere evaluated 4 years after the initial sleep study.16 In theSleep Heart Health study (SHHS), a large cross-sectional

Loss of respiratory drive

Respiratory effort

against

occluded airway

CSA OSA

PaO2PaCO2pH

Arousal

Fragmented sleep

Myocardial oxygen demand

Vagal tone

Pleural pressure

Left ventricular end diastolic pressure

Cardiac output

Cardiac effects:Tachycardia

LV failure

Arrhythmias

Hypertension

Hypoxic vasoconstriction

Myocardial structural alterations

FIGURE 1. Pathophysiology of sleep apnea syndrome.

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study, the odds ratio for hypertension, comparing the highestcategory of apnea-hypopnea index (AHI) (30/hr) with thelowest category (1.5/h) was 1.37 (95% CI, 1.031.83; Pfortrend 0.005).17 A recent study has shown a 2-fold increased riskfor hypertension for adults in their fourth-sixth decade having asleep duration of less than 5 hours each night (hazard ratio, 2.10;

95% CI, 1.582.79).18

Thus, the weight of clinical evidencefavors OSA as a risk factor for hypertension. Exploring themechanisms behind this association will provide an opportunityto further enhance the existing therapeutic approaches.

Many mechanisms have been postulated to understandthe role of OSA as a causative factor for hypertension.Hypoxia is a known stimulant of vascular endothelial growthfactors (VEGFs) that are elevated in OSA.19 They promoteangiogenesis in vivo at high blood concentrations20 and arepotent mediators of capillary leakage. Such physiology, me-diated by elevated VEGF levels may impact CVD by wors-ening clinical conditions like hypertension. Repeated apneasand hypopneas lead to exaggerated sympathetic tone that

creates wide excursions in blood pressure. Sympathetic toneis also altered in patients with OSA by other mechanisms.Elevated urinary and circulating catecholamine levels, andhigh levels of muscle sympathetic nerve activity (MSNA) areobserved in these patients.21 Repeated episodes of hypoxia,hypercapnia, and apnea result in chemoreflex activation andconsequent MSNA increase during sleep.22,23 A causal rela-tionship between OSA and hypertension has been suggestedby studies that evaluated the impact of treating OSA onhypertension management: CPAP use for a year has shown todecrease VEGF levels in comparison with no treatment24;CPAP treatment was shown to decrease urinary and plasmacatecholamine levels25; CPAP therapy also lowered MSNA.26

Two randomized placebo (subtherapeutic CPAP)-controlled

trials showed that the use of CPAP improved both daytimeand nighttime blood pressure readings in comparison withthat by placebo.27,28

The association between OSA and hypertension isgaining prominence. OSA has been recognized as a cause forunderdiagnosed hypertension.29 The Seventh Report of theJoint National Committee on Prevention, Detection, Evalua-tion, and Treatment of High Blood Pressure includes OSA asan important identifiable cause of hypertension.30 The exist-ing evidence encourages considering OSA in the evaluationof all hypertensive patients.

Sleep Apnea and Cardiac Arrhythmias

Heightened sympathetic tone has also been postulatedas an underlying mechanism for increased incidence of car-diac arrhythmias and OSA.31 The most common arrhythmiasduring sleep include nonsustained ventricular tachycardia,sinus arrest, second degree atrioventricular conduction blockand frequent (2 beats/min) premature ventricular contrac-tions.3235 Data from clinical studies suggest a causal rela-tionship between OSA and cardiac arrhythmias. The SHHSsuggested a direct relationship between the severity of sleepdisordered breathing and a higher risk of having nocturnalcomplex arrhythmias (24-fold). This association was inde-pendent of age, sex, BMI, and CAD as observed by theincreased likelihood of atrial fibrillation (AF) (OR, 4.02; 95%

CI, 1.0315.74).36 Although both tachyarrhythmias and bra-dyarrhythmias may be seen in association with SAS, AF is ofparticular interest. AF is triggered nocturnally and displays astrong circadian pattern.37 SHHS showed a 4-fold increase inprevalence of AF in subjects with an AHI 30.36 Atrialoverdrive pacing has been considered as an alternative to

CPAP therapy for cardiac arrhythmias in select patients.Garrigue et al38 reported that nocturnal atrial overdrive pac-ing, at a rate of 15 beats/min faster than the mean nocturnalheart rate, reduced the AHI by 60% in patients who hadreceived pacemakers for symptomatic sinus bradycardia ortachyarrhythmias or bradyarrhythmias.

To explain the effect of atrial overdrive pacing oncardiovascular physiology, 2 mechanisms have been suggested.39

The first mechanism considers mitigation of nocturnal hyper-vagotonia and resultant stabilization of respiration by actingon cardiac and sympathetic efferent neurons. The other mech-anism suggests that overdrive pacing may improve cardiacoutput and relieve pulmonary congestion, which in turn can

decrease the work of breathing. However, 2 subsequentstudies failed to demonstrate a benefit of atrial overdrivepacing in OSA.40,41 As such, there is no direct evidence tosupport atrial overdrive pacing as a treatment option for OSA.CSA may be a target for this option in future studies that willcontinue to explore alternatives to CPAP.

Sleep Apnea and Heart FailureAdvances in understanding SAS in patients with con-

gestive HF has generated and reignited the efforts to establishthe relationship between SAS and HF.5 Observational dataassociates both OSA and CSA with HF.42,43 Cross-sectionaldata from SHHS demonstrated a significant association of sleepdisordered breathing with HF (OR for upper vs. lower quartile,

2.38; 95% CI, 1.224.62).44 Although OSA may lead to HF, thereverse is also true; thus, there exists a paradoxical relationshipbetween both entities. Acute depression of cardiac function withobstructive apneas may lead to long-term cardiac structuralremodeling, weakening the cardiac muscle, and potentially par-ticipating in the pathogenesis of HF.45 On the other hand, HFpatients may show periodic breathing, which can lead to upperairway collapse.46,47

OSA can lead to progression of HF by promoting aphysiological state of heightened stress on the cardiovascularsystem with repeated nocturnal desaturations, elevations incentral sympathetic outflow, and hypertension. OSA leads toan increase in negative intrathoracic pressure, which leads to

the leftward shift of the interventricular septum, resulting inreduced end diastolic volume and increased left HF.48 CPAPhas been shown to acutely reverse these effects.49 Patientswith moderate-severe OSA show left ventricular hypertro-phy50 and diastolic dysfunction.51 CSA is seen in 25% to40% of patients with HF. This is associated with regularperiodic waxing and waning of tidal volumes. This breathingpattern is called Cheyne-Stokes respiration (CSR). CSR withCSA (CSR-CSA) is seen in 30% to 40% of HF.42,52 Growingevidence indicates that CSR-CSA influences the main pat-hophysiological reasons behind increased mortality inHF patients.5355 Thus, this has become an attractive thera-peutic target for improving outcomes in HF patients with

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CSR-CSA. Sin et al42 showed that patients with HF and CSRshowed improved LV function and transplant-free survivalwhen treated with CPAP. The same was not true in the groupthat had HF but not associated with CSR. The CanadianContinuous Positive Airway Pressure for Patients with Cen-tral sleep Apnea and Heart Failure (CANPAP) trial was a

multicenter randomized controlled trial that involved 258patients with HF and CSA. The use of CPAP resulted inattenuation of CSA, improved nocturnal oxygenation, leftventricular function, and submaximal exercise tolerance (ini-tial, but transient). However, improvement in these physio-logical parameters did not translate into mortality benefit inthis group of patients with CSA and HF.56 A follow-up studyafter 2 years showed that the primary outcome of combinedmortality and cardiac transplantation did not differ in thetreated and control groups. But, proponents in favor of thetrial point out that the study may not have been adequatelypowered to elicit important clinical differences. Drawingconclusions from the beta-blocker and spironolactone trials in

HF, the authors of the CANPAP trial argue that givenadequate patient numbers, it may be possible to see clinicallyimportant outcomes.56 Bradley,57 in his insightful article,analyzed the findings from CANPAP trial and drew compar-isons to the beta-blocker trials. In the studies that usedMetoprolol, although initial trial results (n 383) had nomortality benefit,58 the subsequent trials with a larger patientpopulation (n 3991) showed clear survival benefit.59 Sim-ilarly, in the trials that used carvedilol, although initial trialresults (n 301) had demonstrated no mortality benefit,60 thesubsequent trials showed a clear survival benefit (n 2289).61 Arzt et al62 in a post hoc analysis of the CANPAPtrial showed mortality benefit in patients who achieved anAHI 15 events per hour with the use of CPAP. TheCANPAP trial was done in an era when medical managementof HF was being optimized with widespread use of beta-blockers, spironolactone, and angiotensin-converting enzymeinhibitors. The additional benefit of CPAP therapy over andabove the optimal medical regimen of present day HF man-agement will have to be determined by larger randomizedcontrol trials.

Metabolic Dysregulation in Sleep Apnea andCardiovascular Risk

Insulin resistance is observed in association with sleepdisordered breathing.63 Cross-sectional data from the SHHS

and Wisconsin Sleep Cohort also revealed insulin resistanceto be associated with sleep apnea.64,65 The pathophysiologyof such association may be related to sleep fragmentationand repetitive hypoxemia.66 This association is independentof obesity67 and all other constituents of the metabolic syn-drome.68 Treatment with CPAP has been shown to restoreinsulin sensitivity, more so in nonobese patients.69 However,there is conflicting data about the efficacy of using CPAP tocorrect the insulin resistance.70 Because the evidence lends tothe association of OSA with insulin resistance, further re-search is needed to define this relationship more precisely.Larger trials may be needed to clarify the role of CPAPtreatment for sleep apnea-induced insulin resistance.

The Molecular Mechanisms Behind OSA:Setting the Stage for Clinical Consequences ofAtherogenesis

There is a complex interaction between different mech-anisms that link OSA to cardiovascular risks. Intermittenthypoxia and fragmented sleep may lead to increased inflam-

mation in OSA patients. Cell culture models of intermittenthypoxia indicate an alternate and selective activation ofinflammatory pathways, compared with sustained hypoxiawherein adaptive pathways play a major role.71 Repetitiveepisodes of hypoxemia lead to a state of constant desaturationand reoxygenation. These resemble ischemia-reperfusionevents, with reoxygenation phase generating reactive oxygenspecies.72 The oxidative stress may lead to reduction in thenitric oxide levels, resulting in endothelial dysfunction.71

C-reactive protein, an inflammatory marker, has beenshown to prospectively predict future coronary events inhealthy men and women.73 A direct correlation has beenshown between OSA severity and the levels of C-reactive

protein and interleukin-6.74,75 Tumor necrosis factor-, aninflammatory cytokine, has been linked to insulin resistance76

and atherogenesis,77 and correlates with cardiovascular risk.Tumor necrosis factor-induces endothelial activation in theinitial stages of atherosclerosis, resulting in production ofadhesion molecules that promote monocyte adhesion. Thisstep is critical for vascular disease development.78 Increasedadhesion of lymphocytes to vascular endothelium has beenobserved in OSA patients.79 One consequence of the above-mentioned relationship between OSA, inflammation, and en-dothelial dysfunction is the clinical progression of atheroscle-rosis. In patients with OSA, there is a 5-fold increase in therisk for developing CVD, independent of the traditional risk

factors like age, BMI, hypertension, and smoking.80

Carotidatherosclerosis, regarded as a marker for generalized athero-sclerosis, has been shown to be associated with OSA.8183

Studies have also revealed the independent association be-tween OSA and subclinical CAD assessed by calcificationburden in the coronary arteries.84 The evolution of athero-genesis combined with the nocturnal hemodynamic and neu-rohormonal alterations seen in SAS puts the myocardium atrisk for overt ischemia as well. Coronary events such as acutemyocardial infarction (AMI) and sudden cardiac death followstrong nocturnal patterns. OSA seems to influence this noc-turnal pattern. In patients without coexistent OSA, suddendeath occurred between 6 and 11 AM. In patients who have

coexistent OSA, greater than 50% of sudden cardiac deathshappened during 10 PMto 6 AM.85 Further strengthening thisassociation, a recent study showed that in OSA patients whohad AMI between midnight and 6 AM, sleep apnea wasassociated with a 5-fold greater frequency of infarction,compared with patients who did not have OSA and hadexperienced AMI in the same time interval. The odds ofhaving OSA when AMI occurred between 12 and 6 AMwas6-fold higher than that in the remaining 18 hours of the day(95% CI, 1.327.3; P 0.01). This study draws a cleardistinction in the diurnal variation in the onset of AMI basedon the presence or absence of coexistent OSA.86 However, allthese studies caution that although these are relevant obser-

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vations, they are only associations, and do not prove a causalrelationship between OSA and CAD.

CONCLUSIONDespite a symptomatic quiescence over a long period,

much like in diabetes, the case has been made for sleep to beregarded as providing an autonomic stress test for the heartevery night, with successful treatment of OSA, resulting inthe normalization of impaired autonomic stress responses.87,88

There is growing evidence to link OSA and CVD. Allpatients with hypertension, especially those with difficulty incontrolling hypertension, should be screened for coexistingOSA. There may be unexplored or inadequately understoodmechanisms at the cellular and genetic levels that requirefurther research to better define the relationship betweensleep apnea and CVD. In comparison with several otherwell-established diseases, our understanding of SAS is stillevolving, and further research and development of largedatabases would elucidate many as yet unexplained and

unclear concepts and lead to improved patient care.

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