aritmia & apnea obstructiva

8/12/2019 Aritmia & Apnea Obstructiva

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Hindawi Publishing CorporationPulmonary MedicineVolume , Article ID ,pageshttp://dx.doi.org/.//

Review ArticleAtrial Arrhythmias in Obstructive Sleep Apnea:Underlying Mechanisms and Implications in the Clinical Setting

David Filgueiras-Rama,1,2 Miguel A. Arias,3ngel Iniesta,1 Eduardo Armada,4

Jos L. Merino,2 Rafael Peinado,1 and J. L. Lpez-Sendn5

Cardiac Electrophysiology Unit, Department o Cardiology, Hospital Universitario La Paz, Paseo de la Castellana ,st oor, Madrid, Spain

Robotic Cardiac Electrophysiology and Arrhythmia Unit, Hospital Universitario La Paz, Madrid, Spain Cardiac Arrhythmia and Electrophysiology Unit, Department o Cardiology, Hospital Virgen de la Salud, oledo, SpainAcute Cardiac Care Unit, Department o Cardiology, Hospital Universitario La Paz, Madrid, Spain Department o Cardiology, Hospital Universitario La Paz, Madrid, Spain

Correspondence should be addressed to David Filgueiras-Rama; [email protected]

Received January ; Accepted March

Academic Editor: RodoloAlvarez-Sala

Copyright David Filgueiras-Rama et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive interruption o ventilation during sleep causedby recurrent upper airway collapse, which leads to intermittent hypoxia. Te disorder is commonly undiagnosed despite itsrelationship with substantial cardiovascular morbidity and mortality. Moreover, the effects o the disorder appear to be particularlydangerous in young subjects. In the last decade, substantial clinical evidence has identied OSA as independent risk actor orboth bradyarrhythmias and tachyarrhythmias. o date the mechanisms leading to such arrhythmias have not been completelyunderstood. However, recent data rom animal models and new molecular analyses have increased our knowledge o the eld,which might lead to uture improvement in current therapeutic strategies mainly based on continuous positive airway pressure.Tis paper aims at providing readers a brie and specic revision o current knowledge about the mechanisms underlying atrialarrhythmias in OSA and their clinical and therapeutic implications.

1. Introduction

Obstructive sleep apnea (OSA) is a relevant health problem

because o its high prevalence and concomitant severe effectsin the general population []. Although the disorder is mainlypresent in obese men, other clinical characteristics such asage years or older, smoking, and alcohol consumptionare also common []. OSA is characterized by repetitiveinterruption o ventilation during sleep caused by recurrentupper airway collapse, which is associated with increasingrespiratory efforts and intermittent arterial oxygen desatu-ration. Nocturnal arousals, loud intermittent snoring, andincreased daytime sleepiness are the main symptoms [].Obstructive apneas and hypopneas are considered signicanti they last or more than seconds. Such episodes can berecorded and quantied by a polysomnography study, which

remains the standard technique or the diagnosis. Currently,international guidelines consider the diagnosis o OSA inthe presence o an apnea-hypopnea index and persistent

respiratory effort during the episodes[].Cardiovascular morbidity and mortality signicantly

increase in patients with untreated severe OSA []. Moreover,the effects o the disorder appear to be particularly dangerousin young subjects [, ]. Substantial evidence supports theassociation between OSA and cardiovascular diseases, amongwhich atrial arrhythmias and conduction disorders are oparticular interest [,]. Abnormalities such as hypoxia orsympathovagal imbalance are consistently present in OSAand have been associated with atrial arrhythmias [, ].Moreover, undercontinuous positive airwaypressure (CPAP)treatment, it has been shown the disappearance o both atrialbrillation (AF) and heart block in patients with severe OSA
http://dx.doi.org/10.1155/2013/426758http://dx.doi.org/10.1155/2013/426758


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Mechanisms of atrial arrhythmias in

obstructive sleep apnea

Hypoxemia Hypercapnia

Acute atrial

stretch

Acute

diastolic

dysfunction

Autonomic

dysregulation

Proinammatory

state

Negative

intrathoracic

pressure

Acute changes in

atrial

electrophysiology

Atrial

electromechanical

remodeling

Modulation ofatrial

substrate

Atrial

heterogeneity

Hypertension

hypertrophy

Chronic

diastolic

dysfunction

F : Diagram o mechanisms involved in atrial arrhythmias in patients with obstructive sleep apnea.

[, ]. In this work we aim at reviewing the current knowledgeabout the mechanisms underlying atrial disorders in OSAand their implications in clinical practice, in such a way thatclinicians will be able to establish a mechanistic link rommolecular basis to animal models and clinical setting.

2. Mechanisms of Increased Risk of AtrialArrhythmias in OSA

Different abnormalities have been involved in the patho-genesis o atrial arrhythmias and increased cardiovascularrisk in patients with OSA []. Signicantly relevant is thestrong association between tachyarrhythmias, especially AFand OSA []. Tus hypoxia, hypercapnia, negative intratho-racic pressure, autonomic alterations, inammation, increasein intravascular volume, and lef ventricular diastolic dys-unction are likely implicated in a multiactorial processleading to unctional and structural changes prompt to atrialarrhythmias(Figure ).

Hypoxemia signicantly impairs relaxation o lef andright ventricles in healthy humans rendered hypoxemic bybreathing a variable nitrogen/oxygen mixture []. Similarly,intermittent apnea-induced hypoxemia documented duringa polysomnographic study has been associated with signi-

cant hemodynamic changes in lef and right ventricular unc-tions [,]. Tus, the severity o apnea-related hypoxemiais associated with a gradual deterioration o lef ventricularlling, which may explain the presence o lef ventricularhypertrophy in patients with OSA and no history o hyper-tension[,]. Experimental evidence rom animal modelshas yielded some clues about the molecular mechanismsleading to diastolic dysunction. Tus, intermittent hypoxiaseems to increase both oxidative stress and susceptibilityo the heart to such a stress [, ]. In addition, myocytehypertrophy, apoptosis,and multiocal inarcts have been alsoassociated with lef ventricular dysunction[]. Interestingly,hypoxia-induced deterioration o lef ventricular lling is

signicantly correlated with acute atrial changes. In a ratmodel o obesity and acute OSA, increases in lef ven-tricular end diastolic pressure during obstructive apneacorrelated with signicant lef atrial enlargement moni-tored by echocardiography []. Moreover, in the samestudy Iwasaki et al. tried to elucidate the main mechanismleading to reproducibly inducible AF in those animals. odo so, they tested our different interventions consistingo pharmacologic autonomic blockade, ventilatory muscleparalysis, balloon occlusion o the inerior vena cava, andsaline injection as control. Autonomic blockade partiallydecreased AF inducibility compared with control. However,only prevention o lef atrial dilatation by balloon occlusiono the inerior vena cava was associated with signicantsuppression o AF inducibility []. Te latter suggests thatacute atrial dilatation due to apnea-related increase in lef

ventricular end diastolic pressure may prompt the atria to AF.Te results are especially relevant since acute atrial stretch

has been traditionally associated with increased vulnerabilityto AF. Moreover, resumption o sinus rhythm is consistentlyachieved afer releasing the atrial stretch []. Te latter hasimportant clinical implications in spite o the act that mech-anisms underlying stretch-induced AF are highly complexand not completely understood []. Tereore, AF might beterminated or prevented by correcting apnea-induced acute

hemodynamic changes in the lef atrium.In addition, hypoxia may affect atrial electrophysiology

by modiying conduction velocity and atrial reractoriness.However, data rom different animal models have yieldeddivergent results, which preclude identiying conclusiveeffects [, ]. High levels o hypercapnia may also affectatrial electrophysiology by slowing atrial conduction andincreasing atrial reractoriness. Upon returning to normo-capnia, reractoriness rapidly returns to baseline levels whileconduction slowing still persists. Although it is difficultto reproduce in vivo responses to acute hypoxemia andhypercapnia, hypercapnia-related electrophysiology changeshave been associated with AF in the sheep intact heart [].


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Autonomic neural inputs to ganglionated plexi occurringduring apnea may initiate AF. However, the exact mech-anisms leading to AF are extremely difficult to elucidatebecause o the anatomic and physiological complexity othe sympathetic and parasympathetic innervation o theheart []. Ganglionated plexi neural activity progressively

increases beore the onset o AF, which associates withshortening o the atrial reractory period []. Te latterallows nonconducted premature stimuli at baseline to activatethe atrium and probably generate heterogeneity [], whichleads to reentry and AF. Moreover, either the blockade oboth arms o the autonomic nervous system or ablation opericardiac at pad containing ganglionated plexi inhibits theoccurrence o apnea-induced AF, similar to the previouslymentioned effect o releasing atrial stretch []. However,acute effects o autonomic blockade may not last in thelong term, rendering AF reinducible afer several weeks oablation-based autonomic denervation []. It is difficult todetermine whether autonomic inputs or atrial stretch playsthe main role in initiating and sustaining AF. Model-baseddifferences on the presence or absence o negative intratho-racic pressure during apnea might be responsible or morestretch-dependent or autonomic deregulation-dependent AF[,].

Negative intrathoracic pressure occurs during OSA dueto ineffective inspiratory efforts against the occluded upperairway. Animal models simulating clinical OSA incorporatenegative intrathoracic pressure during tracheal occlusion,which leads to shortening o the atrial effective reractoryperiod and action potential duration[,]. Such electro-physiological changes increase AF susceptibility, which seemsto be partially mediated by vagal activation. Te latter isurther supported by a high rate o AF prevention uponatropine or vagotomy[]. Concomitant changes in sympa-thetic activity and atrial pressure have been also documented[,], which may increase atrial susceptibility to AF in thepresence o vagal activation. Acetylcholine-mediated AF isacilitated by isoproterenol, which decreases the threshold oacetylcholine concentration or AF induction and increasesAF duration []. Similarly, increases in lef atrial pressureand atrial dilatation decrease the conduction velocity andincrease the degree o spatial heterogeneities in conduction,which acilitates reentry and AF []. Both phenomena, alongwith vagal activation may generate an optimal substrateto initiate and sustain AF. Additionally, in the presence ohypoxia it might be expected a signicant role o the AP-

sensitive K+ current (K-AP). However, its role seems to bemuch less prominent and probably overcome by the vagal-mediated activity[].

Inammation may acilitate AF in patients with atrialsubstrate suitable to develop the arrhythmia. It is also possiblea direct effect o inammatory markers on ionic channelsand signaling pathways involved in the development oatrial brosis, both leading to AF []. Interestingly, asinammatory cytokines rise the risk o AF concomitantlyincreases []. Intermittent hypoxia and hypercapnia inanimal models result in systemic inammation and increasesin interleukin- (IL-)[]. Te mechanism by which IL-may be produced in hypoxic conditions is the upregulation

o transcription actors NF-B (nuclear actor kappa-light-chain-enhancer o activated B cells) and NF-IL (nuclearactor or IL- expression)[]. In addition, increases in IL- precede increases in C-reactive protein (CRP), which is aninammatory mediator involved in releasing new proinam-matory cytokines. Patients with OSA show markedly elevated

monocyte and neutrophil NF-B activity[]. Tereore, aproinammatory state may lead to higher susceptibility toAF in OSA patients. Moreover, inammation is common inOSA patients, including elevated levels o proinammatorycytokines. umor necrosis actor-(NF-) and IL- levelsare elevated in OSAindependent o obesity [, ]. However,the initial trigger driving the elevation o proinammatorycytokines in OSA patients has not been completely eluci-dated. Some evidence supports the role o both sides o theautonomic nervous system andhypoxia as the main initiationmechanisms[].

Some o the mechanisms involved in tachyarrhythmiashave been also associated with bradyarrhythmias or asystolein patients with severe OSA. In act, bradycardia, signicantpauses (> s) and some degree o conduction block are highlyprevalent in OSA patients []. Te occurrence and degree obradycardia during apnea depends on the degree o hypox-emia resulting rom these apneas. Furthermore, increased

vagal efferent activity appears to cause the bradycardia, whichcan be prevented by intravenous atropine[]. Paroxysmalparasympathetic discharges are more pronounced duringrapid eye movement (REM) sleep, which even in healthyyoung subjects have been associated with marked bradycar-dia and prolonged asystolic pauses []. In patients with OSAmarked bradycardia may occur particularly in REM state,during which longer breathing pauses and greater degreeso oxyhemoglobin desaturation occur. In addition, in OSAthere is lack o normal lung expansion during ventilation,which prevents attenuation o parasympathetic dischargesby vagolytic properties o normal lung expansion []. Teinuence o parasympathetic tone is urther supported byclinical electrophysiological studies revealing no evidence oradvanced sinus node disease or atrioventricular conductionsystem dysunction, which suggest that prolongedventricularasystole during OSA is not due to xed or anatomic diseaseo the sinus node or the atrioventricular conduction system[]. Animal models aimed at studying AF in OSA have alsoshown slowing o the heart rate concurrent with increasedblood pressure afer the initiation o apnea [, ]. Teeffects are compatible with simultaneous increases in cardiac

parasympathetic and vasoconstrictingsympathetic tone, sim-ilar to the diving reex seen in mammals, during which thebody responds to apnea by increasing sympathetic tone to theperipheral vasculature and parasympathetic tone to the heart[].

3. Clinical Significance of Atrial Arrhythmiasin OSA Patients

In the early s a potential relationship between OSA andAF emerged rom an observational, uncontrolled study byGuilleminault et al., in which the use o -hour holter


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electrocardiography identied a prevalence o nocturnalparoxysms o AF o% in OSA patients compared with thegeneral population prevalence o . to % []. Te samestudy reported sinus arrest lasting or more than . secondsand second-degree atrioventricular conduction block in %and % o OSA patients, respectively.

In a large cohort o patients who underwent theirrst diagnostic polysomnogram study and urther averageollows up o . years, obesity and OSA were independentrisk actors or incident AF in individuals


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: Risk o atrial arrhythmias in obstructive sleep apnea.

Author, year Design Study population Diagnostic

method o

patients Cardiac monitoring Results

Guilleminault et

al., [] Uncontrolled S evere OSA PSG h holter ECG

Nocturnal paroxysms oAF in % o OSApatients

Sinus arrest and AV blockin % and % o OSApatients

Gami et al., []

Observationalretrospective

Adults underwenta st PSG study.No AF at baseline

PSG N/A. Medicalindex diagnostic codesor AF

Obesity and OSA wereindependent risk actorsor incident AF

Mooe et al., []

Observationalprospective

PatientsunderwentCABG surgery

PSG Prospective monitoring

until discharge

AHI was associatedwith signicant higherrisk o postsurgical AF

Ng et al., []Meta-analysis(observational

studies)

Patientsunderwent PVI

PSG/Berlinquestionnaire

/h holter ECGEvent monitor/recorderelephone ollow-upECG

OSA led to greater AFrecurrence rates afer PVI

Simantirakis etal., []


Moderate-severeOSA

PSG Implantable loop

recorder

Cardiac pauses > s andbradycardicepisodes []. AF recurrenceswere also reduced in the ollowup o patients with atrial utterwho underwent radiorequency ablation o cavotricuspidisthmus (CI) and proper CPAP therapy []. However,CPAP was only protective rom AF recurrences when AF wasnot present prior to CI ablation.

Te exact mechanisms or preventing AF recurrences byCPAP therapy are not understood. Beyond preventing upperairway obstruction, correcting hypoxemia, and decreasing

the AHI, CPAP therapy seems to attenuate oxidative stressand systemic inammation [], which has been associatedwith both incident AF and AF recurrences afer catheterablation [,].

Te effects o CPAP therapy have been also studied inpatients with OSA and bradyarrhythmia. Cornerstone seriesby Guilleminault et al. in the early s initially suggestedthat preventing upper airway obstruction by tracheostomycompletely abolished conduction disturbances at monthso ollowup []. Case reports have also documented com-plete reversion o second-degree atrioventricular block aferinitiation o CPAP treatment[]. During polysomnographythe vast majority o the apnea-associated bradyarrhythmias

occur during rapid eye movement sleep and signicantdesaturation o at least %. Both CPAP and BPAP drasticallydecrease the AHI and bradyarrhythmias []. More accurateollowup using implantable loop recorders shows that the ini-tiation o CPAP therapy tends to reduce the total number othe recorded episodes in the short term while in the long termbradycardia episodes are completely abolished []. CPAPtherapy also has the capability to decrease the Q correctedinterval dispersion present at baseline in patients with mod-erate to severeOSA []. Te lattermight have implicationsinpreventing bradycardia-related early aferdepolarizations and

ventricular arrhythmias leading to nocturnal sudden death(see able with supplementary inormation about effects


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: Effects o CPAP therapy on atrial arrhythmia outcomes in OSA patients.

Author, year Design Study population Diagnostic

method o

patientsCardiacmonitoring

Results

Kanagala et al.,[]


PatientsunderwentAF/AFL DC

shock

PSG

Hospital recordsPhone interviewsECG

Medical visits

AF recurrences in % oOSA treated with CPAPAF recurrences in % o

untreated patients

Abe et al., []

Nonrandomizedprospective

Adults underwentPSG study

PSG ECG monitoring

during PSG

CPAP prevented AF, sinusbradycardia/pauses inpatients with moderate tosevere OSA

Naruse et al., []


PatientsunderwentPVI isolation

PSG

-lead ECG h holter ECGPortable ECGmonitoring

Untreated OSA showedhigher recurrence o AFafer ablation

Koehler et al.,[]


OSA patientswithbradyarrhythmia

PSG ECG monitoring

during PSG

CPAP and BPAPdrastically decreasedbradyarrhythmias

Simantirakis et

al., []

Observational

prospective

Moderate-severe

OSA PSG

Implantable loop

recorder

Long-term CPAP therapy

completely abolishedbradycardia episodes

AF: atrial brillation; AFL: atrial utter; CPAP: continuous positive airway pressure; OSA: obstructive sleep apnea; PSG: polysomnography; PVI: pulmonaryvein isolation.

o CPAP therapy on atrial arrhythmia outcomes in OSApatients).

However, one importantlimitation o CPAP therapy is thepoor long-term acceptance o treatment. Approximately %o patients are no longer complaint with the treatment afer years[]. However, it seems that patients with the mostsevere sleep apnea are more likely to be complaint. Te mostcommon reason or discontinuing is intolerance o the mask

[]. Moreover, mask leak is a major independent predictoro CPAP compliance; thereore reducing mask leak predictsgood compliance with CPAP therapy[].

Finally, based on the benets o CPAP therapy and sucha requent undiagnosed disorder in the general population,screening or OSA in patients with both AF and atrialutter appears to be a reasonable clinical strategy i either aclinical or catheter-based rhythm control strategy is pursued.It seems also reasonable to identiy patients with apnea-related bradyarrhythmias, since appropriate treatment maycompletely abolish its presence.

5. Conclusions and Future Directions

Atrial arrhythmias are highly prevalent in patients withmoderate to severe obstructive sleep apnea, which has beenidentied as independent risk actor or both bradyarrhyth-mias and tachyarrhythmias. Hypoxia, hypercapnia, auto-nomicdysunction, acuteatrial stretch, negative intrathoracicpressure, and inammation are some o the mechanismsleading to arrhythmia. However, complete understanding osuch mechanisms is still ongoing and urther research basedon animal models is needed. CPAP therapy has demonstratedsignicant improvement in preventing and even abolishingatrial arrhythmias. However, it is necessary to improve anddevelop alternatives to conventional CPAP, which help to

prevent current high rates o treatment discontinuation in thelong-term.

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