Sleep and Cardiovascular Disease:An Overview

Atul Malhotra and Joseph Loscalzo

From the Pulmonary & Critical Care and Sleep MedicineDivisions, Brigham and Women's Hospital and HarvardMedical School, Boston, MA, and Cardiovascular Division,Department of Medicine, Brigham and Women's Hospitaland Harvard Medical School, Boston, MA.Address reprint requests to Atul Malhotra, MD,

Department of Medicine, Brigham and Women's Hospitaland Harvard Medical School, 75 Francis Street, Boston,MA 02115. E-mail: amalhotra1@partners.org0033-0620/$ - see front matter© 2009 Elsevier Inc. All rights reserved.doi:10.1016/j.pcad.2008.10.004

C onsiderable progress has beenmade regardingthe interactions between sleep and cardiovas-

cular diseases.1-3 Historically, a number of abnor-malities have been linked with sleep apnea but arelikely a reflection of the comorbidities associatedwith morbid obesity rather than causal.4 Morerecently, however, certain sleep disorders have beenproven to cause cardiovascular disease; for example,obstructive sleep apnea has now been definitivelyproven to cause systemic hypertension5-10 andpossibly myocardial infarction,11 congestive heartfailure,12 stroke13,14 and death.15-18 In addition,cardiovascular diseases can disrupt sleep, as is thecase in patients with congestive heart failure whoexperience paroxysmal nocturnal dyspnea fromCheyne-Stokes breathing.19 As is discussed in thisissue of the Progress in Cardiovascular Disease(PCD), the science is rapidly evolving regardingour understanding of the mechanisms underlyingand linking these phenomena.

Sleep deprivation is exceedingly common inmodern society with compelling data suggestingprogressive reductions in sleep duration for NorthAmericans over the past several decades. In someseries, only 3% of children were actually acquiringthe recommended 9 hours of sleep per night.20

Although the neurocognitive consequences of sleepdeprivation are well known and well esta-blished,21,22 emerging data suggest major meta-bolic23-25 and cardiovascular consequences tochronic partial sleep restriction.26 As discussed inthis issue of PCD, sleep deprivation in physiologicalstudies can induce impairments in insulin sensi-tivity27 and hormonal changes that can mediateincreases in hunger and appetite.25 Indeed epide-miologic studies have also shown increases in bodyweight in short sleepers as compared with thosewho sleep 7 to 8 hours per night, although theprecise mechanisms remain unclear.24 Some dataalso suggest that short sleepers have an increasedincidence of myocardial infarction26 and all-causemortality28 as compared with conventional slee-

Progress in Cardiovascular Diseases, Vol. 51, No. 4 (January/Fe

pers, independent of known confounding vari-ables. Interestingly, long sleepers (N9 hours pernight) also appear to have an excess risk ofcomplications.29 The epidemic of chronic partialsleep restriction is likely to become recognized as apublic health problem owing to the severecomplications that are increasingly appreciated.Public education of the health effects of sleepdeprivation should be a priority.Obstructive sleep apnea (OSA) is a highly

prevalent condition with well-established neuro-cognitive and cardiovascular sequelae.1 Although4% of North American middle-aged men and 2%of North American women have symptomaticsleep apnea according to a frequently cited 1993article,30 these figures likely represent under-estimates. Since 1993, the prevalence of obesityhas increased considerably,31-33 the technologyhas improved to detect more subtle respiratoryevents,34 and the data have evolved such thatlimiting the definition of OSA based on symptomsof sleepiness is likely inappropriate. Because of thenumerous associated comorbidities, the proof ofapnea-attributable complications has been chal-lenging. Three lines of investigation have led tothis proof of causation: mechanistic animalstudies, large well-controlled human epidemiolo-gic studies, and human interventional studies.First, using elegant animal models, Brooks et al10

demonstrated that the induction of sleep apnea in

bruary), 2009: pp 279-284 279

280 MALHOTRA AND LOSCALZO

the tracheostomized dog led to elevations ofsystemic blood pressure, which were then rever-sible with the elimination of apnea. Second, inlarge-scale human epidemiologic studies, obstruc-tive sleep apnea has an increased prevalence aswell as incidence of systemic hypertension,independent of known confounders.7,9 A dose-response relationship of increasing risk of hyper-tension with increasing severity of sleep apnea hasbeen observed. Longitudinal analyses have showna tripling of risk of incident hypertension over thecourse of 4 years among moderate OSA patients ascompared with carefully matched controls.7 Theapnea-hypopnea index, a common metric of sleepapnea severity, has greater predictive value forhypertension than does body mass index in somestudies.5 Third, interventional studies using nasalcontinuous positive airway pressure (CPAP) havedemonstrated improvement in hypertension withtreatment of OSA.35 Although the magnitude ofthe effect is quite variable across different studies,the bulk of the evidence suggests importantimprovements in blood pressure with sleepapnea therapy.36 Nocturnal surges in bloodpressure, which may provide a substrate forplaque rupture, are known to occur duringobstructive apnea.37 However, these intermittentsurges in blood pressure and the impact of theirelimination have been less carefully studied in theOSA arena. Patients with drug refractory hyper-tension also have marked improvements in bloodpressure with sleep apnea therapy in some smallstudies.38,39 Thus, although further work isrequired, OSA now has a proven causal effect onsystemic blood pressure elevation.

Regarding potential mechanisms, a number ofissues are addressed in this issue of PCD.Autonomic factors are likely important,3,40,41 butnewer data suggest important roles for inflamma-tory factors, oxidative stress, and metabolicfactors, among others. Acute hemodynamicalterations in OSA result from sustained breathingefforts during pharyngeal collapse yielding mark-edly negative intrathoracic pressure, hypoxemia,and arousal from sleep.1,2 Negative intrathoracicpressure increases transmural cardiac pressure,effectively increasing ventricular wall tension andafterload.42 In addition, augmented venous returnand increased pulmonary arterial pressures fromhypoxemia may elevate right ventricular pres-sures, resulting in a leftward shift of the

interventricular septum.43,44 The concomitanthypoxemia and arousals from sleep lead tosympathetic surges augmenting blood pressureand heart rate. Thus, each episode of obstructiveapnea may yield impaired left ventricular filling,elevated ventricular afterload, and increasedmyocardial oxygen demand in patients withhypoxemia.45 Institution of CPAP decreases leftventricular afterload and venous return, andminimizes hypoxemia and sympathoexcitation.46

As detailed in this issue of PCD, recurrenthypoxemia followed by reoxygenation resemblesischemia reperfusion events, and the reoxygena-tion phase yields reactive oxygen species.47

Endothelial cells are particularly vulnerable tooxidative stress because reactive oxygen speciesdecrease nitric oxide (NO) production and mayinactivate bioavailable NO, thus reducing theprotective effect of endothelium-derived NO.48,49

Intermittent hypoxemia also activates nuclearfactor κB producing a proinflammatory environ-ment, potentially promoting atherosclerosis.50

Indeed, the degree of hypoxemia predicts thedegree of endothelial dysfunction in OSA.51

OSA has been linked to congestive heart failure,stroke, atrial fibrillation, and myocardial infarc-tion in some cross-sectional studies.12,52,53 Recentlongitudinal studies suggest an important inci-dence of stroke in OSA independent of knownconfounding variables.13,14,54 Although long-termfollow-up studies have suggested reduced risk offatal and nonfatal cardiovascular events in OSApatients treated with CPAP as compared withuntreated patients, such studies are complicatedto interpret.55,56 Presumably, the CPAP-adherentpatients are highly motivated, well-educatedpeople who are more likely to take their medica-tions or call their physician in case of problems;that is, such studies are susceptible to the healthyparticipant bias.57 Thus, randomized trials will berequired to draw any definitive conclusions. Suchtrials are difficult to design both logistically andethically as discussed in this issue of PCD. Becauseof the known symptomatic benefits of CPAP,many practitioners are reluctant to withholdCPAP from affected patients for long periodsawaiting vascular events in the context of aclinical trial. By contrast, asymptomatic OSApatients are unlikely to be adherent with CPAPin the long term,58,59 making a definitive studydifficult to design.

281SLEEP AND CARDIOVASCULAR DISEASE: AN OVERVIEW

With regard to congestive heart failure, thesituation is quite complicated. Patients withcongestive heart failure frequently have abnorma-lities observed during sleep recordings.60,61

Roughly one third of CHF patients with leftventricular dysfunction will have evidence ofobstructive sleep apnea, whereas another thirdwill have evidence of Cheyne-Stokes respirations(CSRs, a form of central apnea).60 In some studies,the overall prevalence of sleep disordered breath-ing is 50%, with a predominance of CSR overOSA.61 In many cases, the distinction betweenOSA and CSR is difficult to make in congestiveheart failure, leading some investigators to suggestthe term sleep disordered breathing (SDB) be usedto describe both forms of breathing abnormality.62

Breathing abnormalities are also quite commonduring the sleep of patients with diastolic heartfailure.63 Although the prevalence of SDB in CHFis quite high, the importance of this conditionremains controversial.64-67 Although some data

Table 1. Potential Reasons That Sleep Issues Have No

Concern Response

Clinicianfactors

Lack of awarenessby physicians

Traditionally no teamedical school and

Lack of classic symptomssuch as sleepiness in CHF80

Routine, thoroughin medical history

Concerns about confoundingof OSA by covariates,such as obesity in prior studies4

Large, rigorous stunow shown indepeeffects of OSA7

Lack of mechanistic research,particularly for sleep deprivation

Data are evolving;field is young

Lack of definitivemulticenter RCTs

Ethical barriers to wtherapy in symptomOSA patientsPoor adherence anlack of efficacy inasymptomatic OSA

Patientfactors

Lack of awarenessby patients

Traditionally lack oon sleep duration aof sleep disorders

Reluctance to undergodiagnostic testing

Sleep study is innoto many diagnostic

Reluctance to use CPAP orother positive airwaypressure devices

Some patients feelAdherence is compother chronic mediBed partner is oftewith alleviation of sNewer technologiemasks, and humid

suggest an important attributable mortality to CSRin CHF, other data suggest no major association.Thus, further study is clearly required.

A number of points deserve emphasis aboutSDB in CHF. First, optimization of medicaltherapy is a cornerstone of treatment,68 as anumber of studies have shown resolution of CSRwith adequate dosing of cardiac medications.Second, positive airway pressure has a numberof hemodynamic influences, including reductionsin cardiac preload and cardiac afterload,42,45,69

improvements in oxygenation, suppression ofcatecholamine release, and improvements in leftventricular function.70-72 Third, the data regar-ding CPAP therapy for SDB in CHF are equivo-cal.73 In OSA, the existing studies are quite smallbut do suggest some improvement in left ven-tricular ejection fraction with CPAP.74,75 In CSR,the largest study showed no improvement intransplant-free survival in CHF patients with CSRtreated with CPAP as compared with medically

t Been Embraced by the Cardiology Community

Potential Solution

ching inresidency

Enhanced medical education

questioning High index of suspicion

dies havendent

Interventional studies help to showtreatment of sleep apnea per seis important35

Further research

ithholdingatic

Further researchDevelop better treatmentsLarge-scale studies

d potential

patientsf importance placednd symptoms

Public educationLay press

cuous comparedtests in cardiology

Patient educationDevelopment of newer technologiesto diagnose sleep disordersin the home

much better. Develop better technologiesarable tocal therapies81

Provide more definitive data

n happynoring

Patient education

s with blowers,ifiers are available

Intensive support82

282 MALHOTRA AND LOSCALZO

treated controls.73 Thus, CPAP cannot currentlybe recommended for CSR. Fourth, newer devicesare under development to stabilize breathingacutely during sleep19,76,77; however, outcomedata are currently lacking for these newer devices.Fifth, cardiac resynchronization therapy has beenshown to improve both central and obstructiveapnea, although the magnitude of the benefit issomewhat variable.78,79 Thus, OSA and CSR arehighly prevalent in CHF, although the approach tomanagement beyond optimization of medicaltherapy remains unclear.

In summary, sleep is an evolving disciplinemaking some exciting contributions to thecardiovascular literature. Compelling data revealimportant effects of sleep deprivation, obstructivesleep apnea, and CSRs on cardiovascular andmetabolic health. Despite these compelling data,however, sleep issues have not been embraced bythe cardiology community (see Table 1). For theclinician, an appreciation for the importance ofthese conditions is now required to provideoptimal patient care. For the clinical researcher,a number of interventional studies need to beperformed to determine how best to reduce therisk caused by various sleep disorders. For thebasic scientist, as reviewed in this issue of PCD,we are just beginning to understand the mechan-isms underlying the various cardiovascular man-ifestations of sleep disturbances. For theepidemiologist, the public health impact of sleepapnea (partially as a result of the obesitypandemic) and chronic partial sleep deprivationneeds to be become general knowledge. For juniorfaculty and trainees, the sleep field represents amajor opportunity as the discipline is in seriousneed of talented young investigators and clini-cians. Clearly, we all have work to do.

Acknowledgments

Atul Malhotra is supported by NIH P50HL060292, AG024837-01, RO1-HL73146, RO1-HL085188, and AHA Established InvestigatorAward. Joseph Loscalzo is supported by NIHR01-HL58796, R37-HL061795, N01-HV28178,PO1-HL081587, and V54-HL070819. Atul Mal-hotra has received consulting and/or researchfunding from Respironics, Restore Medical,Inspiration Medical, NMT Medical, Pfizer, ApnexMedical, Sepracor, Itamar Medical and Cephalon.

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