Arrhythmia-Induced Cardiomyopathies

15 Pages·2015·1.18 MB·English

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 66, NO. 15, 2015
ª2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2015.08.038
THE PRESENT AND FUTURE
COUNCIL PERSPECTIVES
Arrhythmia-Induced Cardiomyopathies
Mechanisms, Recognition, and Management
RakeshGopinathannair,MD,MA,*SusanP.Etheridge,MD,yFrancisE.Marchlinski,MD,z
FrancisG.Spinale,MD,PHD,xDhanunjayaLakkireddy,MD,kBrianOlshansky,MD{
ABSTRACT
Arrhythmia-inducedcardiomyopathy(AIC)isapotentiallyreversibleconditioninwhichleftventriculardysfunctionis
inducedormediatedbyatrialorventriculararrhythmias.Cellularandextracellularchangesinresponsetotheculprit
arrhythmiahavebeenidentified,butspecificpathophysiologicalmechanismsremainunclear.EarlyrecognitionofAICand
prompttreatmentoftheculpritarrhythmiausingpharmacologicalorablativetechniquesresultinsymptomresolution
andrecoveryofventricularfunction.Althoughcardiomyopathyinresponsetoanarrhythmiamaytakemonthstoyearsto
develop,recurrentarrhythmiacanresultinrapiddeclineinventricularfunctionwithdevelopmentofheartfailure,
suggestingresidualultrastructuralabnormalities.Reportsofsuddendeathinpatientswithnormalizedleftventricular
ejectionfractioncastdoubtonthecompletereversibilityofthiscondition.SeveralaspectsofAIC,includingspecific
pathophysiologicalmechanisms,predisposingfactors,optimaltherapeuticstrategiestopreventultrastructuralchanges,
andlong-termriskofsuddendeathremainunresolvedandneedfurtherresearch. (JAmCollCardiol2015;66:1714–28)
©2015bytheAmericanCollegeofCardiologyFoundation.
I
dentifying,stabilizing,andcorrectingthecauses recognition of the relationship of culprit arrhythmia
ofcardiomyopathyimprovesoutcomesandqual- to cardiomyopathy is paramount in providing treat-
ity of life in patients with systolic heart failure ment that improves symptoms, left ventricular ejec-
(HF). Arrhythmias can initiate or exacerbate acute tionfraction(LVEF),andfunctionalstatus.
HF in patients with pre-existing heart disease. Less This state-of-the-art review addresses the signifi-
wellrecognizedistheeffectofpersistenttachycardia cance, mechanisms, diagnosis, current management
or frequent ectopy on cardiomyopathy in patients strategies, and prognosis of arrhythmia-induced car-
withorwithoutconcomitantheartdisease(1–3).Early diomyopathy(AIC).
TheviewsexpressedinthispaperbytheAmericanCollegeofCardiology’s(ACC’s)ElectrophysiologySectionLeadership
CouncildonotnecessarilyreflecttheviewsoftheJournaloftheAmericanCollegeofCardiologyortheACC.
Fromthe*DivisionofCardiovascularMedicine,UniversityofLouisville,Louisville,Kentucky;yDivisionofPediatricCardiology,
University of Utah, Salt Lake City, Utah; zDivision of Cardiology, University of Pennsylvania, Philadelphia, Pennsylvania;
xDepartmentofInternalMedicine,UniversityofSouthCarolina,Charleston,SouthCarolina;kDivisionofCardiology,Universityof
Kansas,KansasCity,Kansas;andthe{MercyHeartandVascularInstitute,MercyMedicalCenterNorthIowa,MasonCity,Iowa.
Dr.Spinale’sresearchissupportedbyNationalInstitutesofHealth(NIH)grantsHL057952,HL059165,andHL095608andamerit
awardfromtheVeteransAffairsHealthAdministration.Dr.GopinathannairhasservedasaconsultanttoSt.JudeMedicaland
Abiomed;andhasservedonspeakersbureausforPfizer/Bristol-MyersSquibb.Dr.Marchlinski’sresearchissponsoredbyBiosense
Webster,BostonScientific,St.JudeMedical,andMedtronic.Dr.MarchlinskihasservedonadvisoryboardsforBiosenseWebster,
BostonScientific,andMedtronic;andhasreceivedlecturehonorariafromBiosenseWebster,Biotronik,BostonScientific,St.Jude
Medical,andMedtronic.Dr.Spinale’sresearchissupportedbyNIHgrantsHL057952,HL059165,andHL095608;andamerit
awardfromtheVeteransAffairsHealthAdministration.Dr.LakkireddyhasservedasaspeakerandconsultanttoJanssen,Pfizer,
St.JudeMedical,BiosenseWebster,andBristol-MyersSquibb;andhasservedonadvisoryboardsforAtritechandSentreHeart.Dr.
Olshanskyhasserved asa consultant to BostonScientific,Medtronic,Daiichi-Sankyo,Biotronik, Cardionomics,BioControl,
Amarin,BoehringerIngelheim,On-X,AbbottVascular,andSanofi.Dr.Etheridgehasreportedthatshehasnorelationships
relevanttothecontentsofthispapertodisclose.
Listentothismanuscript’saudiosummarybyJACCEditor-in-ChiefDr.ValentinFuster.
ManuscriptreceivedMay26,2015;revisedmanuscriptreceivedJuly28,2015,acceptedAugust17,2015.
JACC VOL. 66, NO. 15, 2015 Gopinathannairetal. 1715
OCTOBER 13, 2015:1714–28 Arrhythmia-InducedCardiomyopathy
WHAT IS AIC? capillary wedge pressures and systemic ABBREVIATIONS
vascular resistance ensue (12–17). Eventually AND ACRONYMS
AIC is a condition in which atrial or ventricular HFdevelops.
AET=atrialectopic
tachyarrhythmias or frequent ventricular ectopy re- Whereas initial manifestations are adap-
tachycardia
sult in left ventricular (LV) dysfunction, leading to tive, sustained rapid pacing affects LV
AF=atrialfibrillation
systolic HF (1,2). The hallmark of this condition is load-ejection relationships, specifically, the
AIC=arrhythmia-induced
partial or complete reversibility once arrhythmia pre-loadrecruitableLVstroke–workrelation-
cardiomyopathy
controlisachieved.AICcanbeclassifiedinto2cate- ship (17), the LV systolic wall stress–ejection
AT=atrialtachycardia
gories:oneinwhicharrhythmiaisthesolereasonfor relationship, and the slope of the LV end-
AV=atrioventricular
ventricular dysfunction (arrhythmia induced) and systolic pressure–volume relationship (18).
BNP=B-typenatriuretic
anotherinwhichthearrhythmiaexacerbatesventric- LVdilationanddysfunctionareaccompanied
peptide
ulardysfunctionand/orworsensHFinapatientwith byadeclineinintrinsicmyocardialcontractile
HF=heartfailure
concomitantheartdisease(arrhythmiamediated)(3). function.
JET=junctionalectopic
NEUROHORMONALACTIVATION. Rapidpacing tachycardia
EPIDEMIOLOGY
in animals results in a predictable, time- LV=leftventricle/ventricular
dependent change in neurohormonal path- LVEF=leftventricular
The incidence and prevalence of AIC are uncertain,
ways and synthesis and release of bioactive ejectionfraction
but AIC appears underrecognized. Atrial fibrillation
peptides (19–25). The levels of plasma atrial NT-proBNP=N-terminal
(AF) is present in 10% to 50% of patients with HF; pro-B-typenatriureticpeptide
natriuretic peptide and B-type natriuretic
many patients with cardiomyopathy and AF have peptide (BNP) increase early, concomitant PJRT=permanentjunctional
worseningsymptomsandventricularfunctionsolely reciprocatingtachycardia
with LV dilation (19,21); eventually natri-
due to poorly controlled ventricular rates (4). In 2 PVC=prematureventricular
uretic peptide levels plateau or decrease,
studiesofadultpatientswithfocalatrialtachycardia complex
likely due to suppression of synthesis and
(AT), the incidence of AIC was 8.3% to 10% (5,6),
increased degradation by endopeptidases. Another
whereas28%hadAICinapediatricmulticenterstudy
hallmark is activation of sympathetic pathways,
ofatrialectopic tachycardia(AET)(7).The incidence
resulting in norepinephrine spillover (20,21). Consis-
of AIC was 9% to 34% in patients withfrequent pre-
tent with the phenotype of progressive LV failure,
mature ventricular complexes (PVCs) and/or non-
rapid pacing invariably causes activation of the
sustained ventricular tachycardia referred for
renin-angiotensin-aldosterone system (20,25). Other
electrophysiologicalevaluation(8–10).
bioactive molecules activated and released include
PATHOPHYSIOLOGY, MECHANISMS, AND endothelin and inflammatory cytokines such as
PREDISPOSING FACTORS tumor necrosis factor alpha (24).
Whereasmediatorsofvasoconstrictionareinduced,
PATHOPHYSIOLOGY: INSIGHTS FROM ANIMAL mediators of vasodilation, such as the response to
MODELS. Chronic rapid pacing has long been recog- nitric oxide, become impaired (22,23). Several key
nized to cause HF in animal models (11). LV remod- aspects regarding these temporal changes in the
eling and HF occur in a time-dependent and highly neurohormonal/bioactive signaling pathways hold
predictable manner, similar to the phenotype of AIC relevance. First, shifts in key neurohormonal path-
(12–18). Due to the rapidly progressive and predict- ways,suchasthenatriureticpeptidesandtherenin-
able natureofpacingtoinduce cardiomyopathy,the angiotensin-aldosterone system, likely reflect shifts
natural history of LV remodeling and failure, neuro- in underlying LV functional status from a “compen-
hormonal activation and signaling, and cell viability sated” to a “decompensated” state. Thus, neurohor-
and molecular pathways have been examined in monalmeasurementsmayserveasusefulbiomarkers
detail. The CentralIllustration shows the naturalhis- fortheprogressivenature/statusofAIC.Secondly,itis
toryandcontributingcellularandmoleculareventsin likely that stimulation of key pathways, such as the
rapidpacing–inducedcardiomyopathyandHF. adrenergic andcytokine systems, contribute directly
LV REMODELING AND HF. During the early phase tomyocardialdysfunction.
(the first 3 to 7 days) of rapid pacing, LV dilation CELL SIGNALING AND VIABILITY. Under normal
occurs, with a decline in LVEF (12–15). This early conditions, increased contraction frequency causes
remodeling phase is not accompanied by compro- a progressive rise in myocardial contractile perfor-
mises in cardiac output or systemic perfusion pres- mance due to appropriate changes in Ca2þ handling
sures.Bythesecondweek,LVdilation,afallinLVEF, and in the myofilament response to Ca2þ. However,
and elevations in central venous and pulmonary this positive force–frequency relationship is blunted
1716 Gopinathannairetal. JACC VOL. 66, NO. 15, 2015
Arrhythmia-InducedCardiomyopathy OCTOBER 13, 2015:1714–28
CENTRALILLUSTRATION SchematicIllustrationoftheNaturalHistoryandPathophysiologyofRapidPacing–Induced
DilatedCardiomyopathyandHeartFailure
Cellular and Molecular Events Natural History Time
Myocyte
Initial Tachyarrhythmia
ECM Compensatory Phase
Stimulus
LV pump function normal ~ >7 Days
Sympathetic system activation
Extracellular Matrix
Remodeling
~ 1-3 Weeks
Cellular Remodeling,
Contracile Dysfunction,
Viability
Ca2+ ATPase L-Type Ca2+
Channel
Defects in Ca++ Handling ~ >3 Weeks
and Severe Contractile
Dysfunction
Cytoplasm
Ca2+
Gopinathannair, R. et al. J Am Coll Cardiol. 2015; 66(15):1714–28.
Inresponsetorapidpacinginanimals,leftventricular(LV)remodelingandheartfailureoccurinatime-dependentandhighlypredictablemanner,similartothe
phenotypeofarrhythmia-inducedcardiomyopathy.Severalcellularandmoleculareventsinresponsetotheinitialtachyarrhythmiastimulustakeplaceoveraperiodof
approximately3to4weeksandinvolvebothextracellularmatrix(ECM)andmyocyteremodeling.Specifically,thereislossofnormalextracellularmatrixand
architecture.This,coupledwithalterationsincellulargrowthandviability,defectsinCa2þhandling,andneurohormonalactivation,resultsinLVdilationandsevere
contractiledysfunction.Thenaturalhistoryofrapidpacing–inducedcardiomyopathyprogressesfromacompensatoryphase(approximately>7days)toanLV
dysfunctionphase(approximately1to3weeks)toanLVfailurephase(approximately>3weeks),characterizedbyprogressiveLVdilationanddysfunctionand
increasingneurohormonalactivation.ATPase¼adenosinetriphosphatase;RAAS¼renin-angiotensin-aldosteronesystem.
with pacing-induced cardiomyopathy (26), with Inisolatedmyocytepreparations,intrinsicdefects
accompanied prolongation of myocardial Ca2þ tran- intherateandextentofshortening,aswellasdefects
sientsanddefectsinCa2þcycling(27).Thesechanges intherateofrelaxation,havebeenidentifiedascar-
intheforce-frequencyrelationandCa2þhandlingare diomyopathy develops and progresses (20,28,31).
a manifestation of prolonged rapid pacing and are Changesincellulargrowthandviabilityensue(32,33).
present when definable changes in LV systolic func- Chronic rapid pacing induces several proapoptotic
tionhavealreadyoccurred(27–30).Thesummationof cascades (34). LV dilation is not associated with an
changes in Ca2þhandlingresults in fundamental de- absoluteincreaseinmyocytecross-sectionalareabut
fects in the excitation-contraction coupling process, ratherwithlengtheningofindividualmyocytes,with
leading to defects in absolute myocyte contractile alterations in cytoskeletal architecture (20,29,31,35).
functionandinotropicresponsiveness(27–30). If these changes in myocyte function and viability
JACC VOL. 66, NO. 15, 2015 Gopinathannairetal. 1717
OCTOBER 13, 2015:1714–28 Arrhythmia-InducedCardiomyopathy
wereplacedinatemporalcontext,thenLV myocyte otherwise structurally normal hearts is usually
remodeling (cell shape and architecture) is likely to months to years, which is quite different from the
occur early, followed by abnormalities in excitation- acute changes seen in pacing models. Some ar-
contractionandchangesincellviability. rhythmias (e.g., AF and PVCs) may have mecha-
nisms leading to AIC that are not explained fully
EXTRACELLULAR REMODELING. Although remodel-
by rapid-pacing animal models (10,38–40). Although
ing occurs within the myocyte, robust changes also
ultrastructural changes may explain the initial de-
occur within the extracellular matrix (35,36). Specif-
velopment of AIC, the relationship between identifi-
ically,thereisalossofnormalfibrillarcollagencon-
able ultrastructural changes and the mechanisms by
tentanddistribution(35,36),which,inturn,initiates
which cardiomyopathy develops are less clear. An
alterationsinmyocytesupportandalignmentwithin
overview of the current understanding of the rela-
theLVwall.Concomitantly,thecapacityofmyocytes
tionship between arrhythmias and cardiomyopathy,
tobindtotheextracellularmatrixisdiminished(35),
from mechanisms to management and prognosis, is
suggesting that abnormalities in the extracellular
showninFigure1.
matrix–integrin interface have occurred. Increased
matrix metalloproteinase activity and expression ARRHYTHMIA AND PATIENT CHARACTERISTICS. Ar-
contribute to loss of normal extracellular matrix rhythmia characteristics contributing to AIC include
support and architecture (37). Activation of matrix arrhythmia type (Table 1), rate, duration, rhythm ir-
metalloproteinases precedes the defects in myocyte regularity, persistence (5,41–43), and concomitant
contractilefunction(37).Thesefindingssuggestthat heart disease (44). An arrhythmia that is insidious,
the likely mechanism for LV remodeling is loss of persistent,andwelltoleratedismorelikelytoresult
normal myocardial extracellular matrix structure, in AIC (5). Lack of persistent tachycardia from auto-
composition,andfunction. nomic influences and resultant slower rates during
sleep are likely to be the reasons that AIC is rare or
IMPLICATIONS OF ANIMAL STUDIES. Chronic rapid
nonexistentwithinappropriatesinustachycardiaand
pacing in animals causes dilated cardiomyopathy
postural orthostatic tachycardia syndrome (POTS),
resembling clinical AIC. With rapid atrial pacing in
although the average heart rate can be >100 beats/
pigs, an atrioventricular (AV) conduction pattern is
min.ThereisnospecificheartratecutoffatwhichAIC
maintained and ventricular dyssynchrony as the
develops. The rate is not well defined, may be age
stimulus for adverse remodeling and HF is unlikely
dependent, and is likely lower than initially sus-
(12,13,20). However, rapid ventricular pacing, where
pected. Little is known about patient factors that
myocardial dyssynchrony is inevitable, results in a
increase vulnerability to AIC, but one report has
morerapidandprecipitousfallinLVsystolicperfor-
indicated that patients with a homozygous deletion
mance(14–17).Thus,thetachycardiastimulusissuf-
polymorphismintheangiotensin-convertingenzyme
ficienttodrivethecardiomyopathyprocess,whereby
(DD) gene had a higher propensity to develop AIC
electricaldyssynchronywouldconstituteanadditive
whenfacedwithpersistenttachycardia,suggestinga
factoracceleratingtheprocess.
potentialgeneticlink(45).Inalongitudinalstudyof
Phases and structural milestones that occur with
patientswithhighPVCburden,thosewhodeveloped
chronic arrhythmias in animal models translate to
cardiomyopathy had wider PVC QRS width versus
clinicalformsofAIC.Specifically,thereisanadaptive/
those who did not, suggesting baseline myocardial
compensatory phase whereby LV dilation, extracel-
fiberdisruptionthatportendsanincreasedrisk(46).
lular matrix remodeling, and neurohormonal system
activationoccursbutsevereLVdysfunctiondoesnot. CLINICAL FEATURES AND DIAGNOSIS
ThisphasecouldbeidentifiedinpatientsbyLVimag-
ingandbiomarkerprofilingandisfollowedbyaphase ThekeydiagnosticfeatureofAICisthepresenceofa
inwhichLVdysfunctionbecomesmanifestandasso- pathological tachycardia or persistent arrhythmia
ciatedwithdefectsinexcitation-contractioncoupling (PVC) in the presence of an otherwise unexplained
and LV myocyte remodeling and dysfunction. This cardiomyopathy. The relationship of arrhythmia to
phaselikelyrepresentsacriticaltransitionwhenthis cardiomyopathy can be difficult to determine be-
process may not completely reverse, leading to cause an arrhythmia could exist for years before its
neurohormonal activation accompanied by the full recognition and before cardiomyopathy develops.
pathophysiologicalspectrumofHF. Althoughahighindexofclinicalsuspicionmaypoint
Several challenges and limitations exist in trans- to subtle diagnostic clues, the condition may go un-
lating animal data to humans. The time course recognized for years. The presentation can be late
for development of AIC and HF in patients with onlyaftermanifestsystolicHFdevelops.Similarly,if
1718 Gopinathannairetal. JACC VOL. 66, NO. 15, 2015
Arrhythmia-InducedCardiomyopathy OCTOBER 13, 2015:1714–28
FIGURE1 OverviewoftheCurrentUnderstandingofAIC,FromMechanismstoManagementandPrognosis
Persistent tachyarrhythmia or frequent ventricular ectopy (PVC)
No known structural heart disease Underlying structural heart disease
Patient and arrhythmia characteristics
– Adverse cellular, cytoskeletal, neurohormonal, and proapoptotic changes
(see Central Illustration)
– Other mechanisms (ventricular dyssynchrony, abnormal Ca2+ handling, etc.)
Development of left ventricular (LV) dysfunction,
dilated cardiomyopathy, and heart failure —
arrhythmia–induced cardiomyopathy (AIC)
– Suppression/elimination of arrhythmia by rate
and/or rhythm control
– Heart failure therapy
– Heart failure resolution and LV function recovery No significant improvement in LV function —
– Confirms diagnosis of AIC Not AIC
Follow up: No evidence of persistent ultra–structural changes Good prognosis
1. Maintain sinus rhythm/strict rate by echo or cardiac MRI
control
2. Close surveillance to avoid arrhythmia
recurrence Persistent ultra–structural changes: – Close surveillance
3. Continue beta–blockers/ACE inhibitors 1. LV dimensions – Continue beta–
4. Follow–up imaging (echo and/or MRI) 2. Evidence for fibrotic changes in MRI blockers/ACE inhibitors
3. Development of LV hypertrophy
Persistenttachyarrhythmiasorfrequentventricularectopycanleadtodilatedcardiomyopathyanddecompensatedheartfailureinpatientswithorwithout
concomitantstructuralheartdisease.Cellularandextracellularchangesinresponsetotheculpritarrhythmiahavebeenidentified(seeCentralIllustration),
butspecificpathophysiologicalmechanismshavenotbeenwellelucidated.Earlyrecognitionoftherelationshipofaculpritarrhythmiatocardiomyopathy
andaggressivearrhythmiacontrolresultsinimprovedsymptoms,leftventricular(LV)ejectionfraction,andfunctionalstatusandhelpsestablishthe
diagnosisofarrhythmia-inducedcardiomyopathy(AIC).Cellularandextracellularultrastructuralchangescan,however,persistandcancontributetoarapid
declineincardiacfunctionwitharrhythmiarecurrence.Closesurveillanceisthuscrucialtoensuregoodlong-termprognosis.ACE¼angiotensin-converting
enzyme;MRI¼magneticresonanceimaging;PVC¼prematureventricularcomplex.
thearrhythmiaisdetectedearlybutanonaggressive mass index versus those with pre-existing dilated
approach is taken, progressive worsening of symp- cardiomyopathy and concomitant tachyarrhythmia
toms and insidious development of cardiomyopathy (48,49). Cardiac magnetic resonance imaging (CMR)
ensue. It can be difficult to determine whether an mayhelpdifferentiateAICfromdilatedcardiomyop-
arrhythmia is the initiator or consequence of car- athy. In a study of 27 patients with frequent PVCs
diomyopathy in a patient with tachycardia and HF. and cardiomyopathy, 22 had improvement in LVEF
Thus, AIC raises a “chicken or egg” question (47). following PVC suppression; 5 did not. Four of the
Frequently, the arrhythmia is considered secondary 5 patients with LVEF that did not improve had evi-
andisnottreatedeffectivelywhen,infact,arrhythmia dence for late gadolinium enhancement, suggesting
controlisnecessaryforfullrecovery. underlying scar (8). Campos et al. (49) compared
History, physical examination, and clinical in- patients with irreversible nonischemic dilated car-
vestigationsshouldfocusondeterminingtheetiology diomyopathy, reversible PVC-mediated cardiomyo-
of cardiomyopathy. Specific patient characteristics pathy, and patients with PVCs and normal LVEF
maysuggestahigherlikelihoodofAIC.Patientswith who underwent electroanatomic mapping. These
AIC have a smaller LV end-diastolic diameter and investigators noted that those with irreversible
JACC VOL. 66, NO. 15, 2015 Gopinathannairetal. 1719
OCTOBER 13, 2015:1714–28 Arrhythmia-InducedCardiomyopathy
arrhythmia control, use of neurohormonal antago-
TABLE1 CausesofArrhythmia-InducedCardiomyopathy
nists can result in favorable ventricular remodeling.
Supraventricular
Controversy remains about the need to continue
Atrialfibrillation
these medications if there is complete recovery of
Atrialflutter
LVEFwitharrhythmiacontrol.
Atrialtachycardia
AVnodalre-entranttachycardia
AIC ASSOCIATEDWITH SPECIFIC
AVre-entranttachycardia
Permanentjunctionalreciprocatingtachycardia ARRHYTHMIAS IN ADULTS
Junctionalectopictachycardia
Ventricular ATRIAL FIBRILLATION. AF is the most common
Idiopathicventriculartachycardia
cause of AIC in adults (1,43). Of patients presenting
Fasciculartachycardia
withHF,10%to50%haveAF(4,53),andmanysuch
Ectopy
patients likely have a component of AIC. The mech-
Frequentprematureventricularcontractions
Frequentprematureatrialcontractions anisms underlying development or progression of
Pacing cardiomyopathy in patients with persistent AF have
Persistentrapidatrialand/orventricularpacing not been elucidated clearly (39). Rapid heart rates,
lossofatrialcontraction,andrhythmirregularitymay
AdaptedwithpermissionfromGopinathannairetal.(2).
AV¼atrioventricular. contribute (1,39,40,54). Persistent tachycardia can
impair myocardial contractility, either directly or
through alterations in cellular and neurohormonal
mechanisms. Resting tachycardia, as well as a rapid
cardiomyopathyhadasignificantlylargerpercentage
increase in heart rate with exercise, can impair dia-
of the LV endocardium with abnormal unipolar
stolicfilling.Lackofatrialcontributiontoventricular
voltage (64% vs. 5.2% for the reversible group and
fillingcanfurtherworsendiastolicfunction.Avicious
0.1% for the normal LVEF group). An abnormal uni-
cycle can thus develop, with HF and associated in-
polarvoltagearea$32%ofLVendocardiumpredicted
creases in left-sided filling pressures and functional
the irreversibility of cardiomyopathy with >95%
mitral regurgitation resulting in mechanoelectrical
sensitivityandspecificity,butprospectivevalidation
changes in the left atrium, perpetuating AF and car-
islacking(49).
diomyopathy(54).
Serial assessment of the N-terminal pro-BNP
Management of AFconsists of rate and/or rhythm
(NT-proBNP) ratio (NT-proBNP at baseline/NT-
control. In those with AF and cardiomyopathy, the
proBNPduringfollow-up)candifferentiateAICfrom
ideal target heart rate remains uncertain. For those
irreversible dilated cardiomyopathy. Forty patients
withpermanentAF,lenientratecontrol(restingheart
with AF or atrial flutter with ventricular rates >100
rate <110 beats/min) has been advocated over strict
beats/min and LVEF <40% were cardioverted, and
rate control (resting heart rate <80 beats/min and
NT-proBNP was measured on day 1 and weekly for
heart rate with moderate exercise <110 beats/min)
4 weeks. An NT-proBNP ratio cutoff >2.3 at 1 week,
(55).However,intheRACEII(RateControlEfficacyin
suggesting rapid decline in NT-proBNP levels, was
Permanent Atrial Fibrillation II) trial (55), most pa-
associated with reversible cardiomyopathy, with an
tients were rate controlled before enrollment (base-
accuracyof90%(50).
lineheartrate96beats/min)andwereasymptomatic
When AIC cannot be easily differentiated from
without cardiomyopathy. Follow-up was short, and
dilated cardiomyopathy with consequent tachy-
developmentofAICwasnotspecificallyconsidered.
cardia, treatment for both problems becomes neces-
Several methods are available for AF rate control
sary (2). The diagnosis may be evident only after
(56). Achieving adequate rate control may require
restorationandmaintenanceofsinusrhythmorafter
drug combinations and frequent regimen changes
aggressiveratecontrol.
(57). However, these data may not directly apply
PRINCIPLES OF MANAGEMENT to AF-mediated AIC because rate irregularity may
contributetosymptomsandfacilitatedevelopmentof
AICmanagementshouldfocusonconcertedattempts AIC(40).AlthoughAVnodalablationwithpacemaker
toeliminateorcontrolthearrhythmia,withthegoal implantation can provide effective rate control (58)
of improving symptoms, reversing LV dysfunction, and regularize the rate, this strategy changes ven-
and preventing arrhythmia recurrence (1,5,43,51,52). tricular activation, even if cardiac resynchronization
A favorable response to arrhythmia elimination/ therapy is used; therefore, it should only be con-
control establishes the diagnosis of AIC. Along with sidered if rhythm and/or rate control cannot be
1720 Gopinathannairetal. JACC VOL. 66, NO. 15, 2015
Arrhythmia-InducedCardiomyopathy OCTOBER 13, 2015:1714–28
established.Incontrast,electricalorpharmacological follow-up, 70% of patients in the ablation arm were
cardioversion, antiarrhythmic drugs, and catheter free of AT/AF (vs. 34% in the amiodarone arm
ablationcanachieverhythmcontrol.InAF-mediated [p < 0.001]) and had significant improvements in
cardiomyopathy, restoration and maintenance of si- mortality, hospitalization rates, and quality of life.
nus rhythm can hasten clinical recovery and reverse LVEFimproved9.6(cid:2)7.4%intheablationarmversus
cardiomyopathyoverseveralmonths(1,40,59). 4.2 (cid:2) 6.2% in the amiodarone arm (p < 0.01) (66).
The AF-CHF (Atrial Fibrillation and Congestive Catheter ablation thus offers an effective rhythm
HeartFailure)trialrandomized1,376patientswithAF controlstrategyandavoidspotentiallytoxiclong-term
(70% persistent) and HF to either a rhythm control antiarrhythmic therapy. The available data argue for
(amiodarone with cardioversion) or a rate control catheterablationasthebestchoiceforrhythmcontrol
strategy.ThemeanLVEFwas27%andpatientswere inpatientswithAF-mediatedAIC.
followed for 37 months. A rhythm control strategy ATRIAL FLUTTER. Atrial flutter is more difficult to
usingantiarrhythmicdrugsdidnotimproveall-cause ratecontrolthanAF,givenlessconcealedconduction
mortalityorpreventworseningHF.However,theAF-
intotheAVnode.Therefore,despiteintenseeffortsat
CHF patient population may not fully represent the
pharmacological rate control, minimal exertion can
AIC population because 40% of patients in the rate
lead to rapid ventricular rates. Given the inherent
control arm were in sinus rhythm during follow-up difficulty withrate controlandthe highsuccessrate
(60). The CAFÉ-II (Controlled Study of Rate Versus
and low risk of complications with catheter ablation
Rhythm Control in Patients With Chronic AF and (67,68), ablation to eliminate atrial flutter is recom-
Heart Failure) study randomized 61 patients with mended when AIC is suspected. For those in whom
persistent AF (median duration of 14 months) and catheter ablation is not feasible or desired, cardio-
moderate LV dysfunction to a rate control and
version with antiarrhythmic therapy or aggressive
rhythm control strategy (amiodarone with cardio-
ratecontrolshouldbeused.
version). During a follow-up of 1.2 years, 66% of
SUPRAVENTRICULAR TACHYCARDIAS. Persistent sup-
patients maintained sinus rhythm, whereas 90%
raventriculartachycardiascanresultinAICbyseveral
achieved target rate control (<80 beats/min at rest
mechanisms (5).Near simultaneous AV relationships
and <110 beats/min with 6-min walk). Rhythm con-
can have a negative hemodynamic effect. A curative
trol was superior to rate control in improving LV
strategy by catheter ablation should be pursued
function, pro-BNP levels, and quality of life (61). At-
whenever possible as first-line therapy for supra-
tempts to control rate might not be as aggressive or
ventricular tachycardia-mediated AIC. Successful
carefully monitored in the real world as in clinical
catheter ablation can normalize LVEF and is usually
trials. It is also possible that side effects and proar-
associatedwithexcellentlong-termoutcomes(5,6).
rhythmicrisksfromantiarrhythmicdrugsmayoffset
any salutary effects from restoring and maintaining PVCsANDVENTRICULARTACHYCARDIA. Idiopathic
sinusrhythm(62). ventricular tachycardia and, more commonly, fre-
Restoring and maintaining sinus rhythm by cath- quent PVCs can lead to AIC in patients without
eter ablation of AF can improve and reverse AIC structural heart disease and can exacerbate car-
(63,64).Pulmonaryveinisolationappearssuperiorto diomyopathy in patients with structural disease
AVnodeablationandbiventricularpacinginpatients (10,52,69,70). PVCs associated with cardiomyopathy
with drug-refractory AF and HF (64). A systematic usually arise in the right or left ventricular outflow
reviewof19studies(n¼914)evaluatingAFablation tract,butPVCsfromnon–outflowtractsitescanalso
inpatientswithconcomitantLVdysfunctionshowed resultinAIC(10,46,52).
that sinus rhythm was maintained in 57% after The mechanism of PVC-mediated AIC is not fully
a single procedure, with an increase to 82% with understood. A large animal model using a pacing
>1procedureand/oruseofantiarrhythmicdrugs(65). protocol to simulate paroxysmal PVCs produced an
LVEF increased by 13.3% (95% CI: 11% to 16%), sug- AICphenotypethatresolvedcompletelywithin2to4
gesting the effectiveness of catheter ablation for weeksafterpacingcessation.Tissueanalysisdidnot
maintainingsinusrhythmandreversingAIC. showevidenceofinflammation,fibrosis,orapoptosis,
The recent AATAC-AF (Ablation vs. Amiodarone suggesting that PVC-induced cardiomyopathy in
for Treatment of Atrial Fibrillation in Patients With structurally normal hearts could be a functional ab-
CongestiveHeartFailureandanImplantedICD/CRTD) normality (38). Potential mechanisms postulated
trial randomized 203 patients with persistent AF include ventricular dyssynchrony, especially related
with HFandcardiomyopathy (LVEF <40%) to either to a left bundle branch block PVC morphology,
amiodarone or catheter ablation. During a 24-month abnormal Ca2þ handling from the short coupling
JACC VOL. 66, NO. 15, 2015 Gopinathannairetal. 1721
OCTOBER 13, 2015:1714–28 Arrhythmia-InducedCardiomyopathy
intervals, and abnormal ventricular filling from the Catheter ablation has emerged as the definitive
post-PVCpause(10,37,38). therapy for PVC-mediated AIC, with success rates
The development of cardiomyopathy with atrial ranging from 70% to 90% (52). Elimination of PVCs
premature depolarizations (71) and the absence of with ablation has been shown to improve LVEF,
convincing site-specific association in PVC-mediated ventricular dimensions, mitral regurgitation, and
AICsuggestthatitmaynotbeasimplematterofLV functionalstatus.Inanobservationalseries,ablation
dyssynchrony.ThecausalrelationshipbetweenPVCs was superior to antiarrhythmic therapy in reducing
and AIC has been firmly established on the basis of PVCsandimprovingLVEF(51).Successfulablationof
reversal of the cardiomyopathy with suppression PVCs can improve the efficacy of cardiac resynchro-
and/oreliminationofPVCs(72,73). nization therapy in nonresponders (81). The elimi-
The most prominent predictor of cardiomyopathy nation of high PVC burden (>10%) in patients with
in patients with frequent PVCs appears to be the impaired LVEF can be associated with improvement
daily burden of PVCs. A high PVC burden has been of function, even when structural cardiac abnormal-
variably defined as ranging from >10,000 to 25,000 itiesarepresent(72,73,82).
PVCs/day and as >10% to 24% of total heartbeats/ MANAGEMENT IN ADULTS—SUMMARY. Our approach
day (74–76). There appears to be a threshold burden
tomanagepatientswithsuspectedAIC isto attempt
of approximately 10,000 PVCs/day for developing
careful and aggressive control of rate and rhythm,
AIC. Ventricular function can improve if the PVC
with the focus on arrhythmia elimination by cath-
burden is reduced to <5,000/day (72). This is an
eter ablation whenever possible. The only tachyar-
important target when elimination of all PVCs may rhythmias that do not appear to require aggressive
not be possible, especially in the setting of multi- treatment to prevent AIC are sinus tachycardia and
form PVCs.
POTS. Continued therapy with neurohormonal an-
Retrospective studies suggest multiple potential
tagonists is advisable for favorable remodeling, al-
patient and PVC characteristics associated with the
though the duration of such therapy is not well
developmentofAIC(9,10,74,77,78).Thesecharacter- defined (83).
istics include male sex, increased body mass index,
asymptomatic PVCs, higher PVC coupling interval AIC IN CHILDREN
dispersion, interpolated PVCs, and presence of
retrogradePwaves (10,77–80).Inastudy of patients In children, dilated cardiomyopathy is the most
with high PVC burden followed for 14 months, 17 common reason for heart transplant (84). Nearly
(38%) developed AIC. A PVC QRS duration >153 ms 40%ofchildrenwithcardiomyopathyundergoheart
and non–outflow tract origin predicted development transplant or die within 2 years of presentation(85).
ofAIC(46).Importantly,mostpatientswithfrequent AICmustbeconsideredinthissetting.Inthelargest
PVCs will not develop cardiomyopathy (76). Cur- pediatric series of AIC, AET (59%) and permanent
rently, although an important goal of future investi- junctionalreciprocatingtachycardia(PJRT;23%)were
gation, no risk profile defines a group of patients the most common arrhythmias represented. Ventric-
requiring prophylactic PVC elimination to prevent ulararrhythmiaswereuncommon(86).
AIC. However, it is advisable for patients with a Tachyarrhythmias are a reversible cause of car-
highPVCburdento have periodic echocardiographic diomyopathyfromfetallifeonward(87–90).Children
assessments to confirm stable LV chamber size and oftenpresentlatebecausetheyfailtorecognizepal-
function. pitations or are unable to verbalize symptoms and
Therapy for PVC-mediatedAICshouldbetargeted cometomedicalattentiononlyafterthedevelopment
at suppressing or eliminating the PVCs and should of HF. Compared with adults, different arrhythmia
include antiarrhythmic therapy and catheter abla- mechanismsarerepresentedinpediatricAIC.
tion. Beta-blockade and non–dihydropyridine cal- Supraventricular arrhythmias are more common
cium channel blockade are low-risk therapies, but than ventricular arrhythmias in children and there-
they have limited effectiveness. Beta-blockers are fore are more frequently associated with AIC. In the
frequentlyconsideredfirst-linetreatmentbecauseof newborn, a single, sustained episode of typical sup-
the benign nature of the treatment. Dofetilide, mex- raventricular tachycardia may be unrecognized until
iletine,sotalol,oramiodaronemaybemoreeffective, HF symptoms emerge; thus, neonates may present
although they have greater risk of side effects and with decreased LV function, or even shock. In this
proarrhythmia.Antiarrhythmicdruguseisfrequently group,prognosisandrecoveryofcardiacfunctionare
reservedfor patientswhofailor arereluctant toun- excellent after control of supraventricular tachy-
dergocatheterablation. cardia. This is in contrast to the more incessant
1722 Gopinathannairetal. JACC VOL. 66, NO. 15, 2015
Arrhythmia-InducedCardiomyopathy OCTOBER 13, 2015:1714–28
tachycardias, for which control is more challenging used, with beta-blockers being the most common
andrecoverylessrapid. first-line therapy. No trends emerged to define the
Etiologically, sustained rapid rates, QRS duration, most successful medication. Catheter ablation was
AVdyssynchrony,andheartrateirregularityallcould effective in 81% of patients in whom it was used.
contributetoAIC,yetnotallchildrenwithincessant The use of electroanatomic mapping for ablation
tachycardia develop AIC. In children, the tachycar- improved success (102) and decreased recurrence
dias most often associated with AIC have a narrow (103).
QRS complex and 1:1 AV conduction. Heart rate Spontaneous resolution of AET can occur, espe-
irregularity occurs in pediatric AIC as salvos of ciallyinthosepresentingwithinthefirstyearoflife,
tachycardia interspersed with periods of sinus where 74% had resolution (7). Ablation proved safe
rhythm, rather than as the persistent heart rate ir- and effective, but the investigators suggested a trial
regularityseeninAF. ofmedicaltherapyintheyoungestpatients,inwhom
As evident in many cardiac conditions, genetic ablation may have more risk (104,105) and when
factorsmayunderliethedevelopmentofAIC.Serum- spontaneousresolutionismorelikely.
and glucocorticoid-regulated kinase 1 (SGK1), a Permanent junctional reciprocating tachycardia.PJRT
component of the cardiac phosphatidylinositol 3- isanaccessorypathway–mediatedtachycardiawitha
kinase signaling pathway has proarrhythmic effects longRPintervalthatoccurspredominantlyininfants
and has been linked to biochemical and functional and children. The pathway can be located anywhere
changesinthecardiacNaþchannel.Theseeffectsare intheAVjunctionbutisusuallyposteroseptal(106).
reversedby treatment withranolazine,whichblocks Pathways are tortuous and slow conducting; thus,
the late Naþ current (91). Conversely, inhibition of tachycardiaisoftenincessant.
SGK1 in the heart protects against fibrosis, HF, and Inarecentreview,27%ofpatientswithPJRTpre-
Naþ channel alterations after hemodynamic stress. sented in fetal life, 7% with hydrops, a fetal mani-
One might speculate that an underlying cardio- festationofAIC(107).IsolationoftheAVjunctionisa
myopathicprocessisunmaskedbyatachyarrhythmia continuingprocessthatmaynotbecompleteatbirth,
or that genetic factors are responsible for both and the presence of accessory connections crossing
arrhythmic and myopathic outcomes. Recent advan- the annulus fibrosis could result in persistent peri-
cement in our understanding of channelopathic natal supraventricular tachycardia. Although most
conditions and the overlapping of arrhythmic and children with PJRT present with palpitations or are
myopathic phenotypes seen in some patients lends noted to have rapid heart rates, 18% presented with
credibility to this theory (92–95). Mutations in the AICinaseriesof194children(107).Cardiomyopathy
cardiac Naþ channel and in the ryanodine receptor, is more likely to occur in children with longer RP
long known to be involved in arrhythmogenesis, interval/cyclelengthratios,consistentwithanacces-
can now be linked to abnormalities of contractile sorypathwaywithslowretrogradeconductionanda
function(92). wide,excitablegap(108).PJRTisoftenincessant,and
PEDIATRIC ARRHYTHMIAS ASSOCIATED WITH AIC. those with incessant PJRT had longer RP intervals,
Atrial ectopic tachycardia.AET is the most com- were younger at diagnosis, and more often had AIC
monarrhythmiaassociatedwithAICinchildren(96). (107). The clinical course of PJRT is not benign, and
AlthoughP-wavemorphologyandaxisusuallydiffer spontaneousresolutionisunlikely(107).
fromsinusrhythm,AETfocinearthesinusnodeare Anumberofantiarrhythmicmedicationsareused,
hard to differentiate from sinus tachycardia, espe- but a single most effective agent has not emerged
cially in patients with HF, when tachycardia is ex- (107). Beta-blockers are the common first choice,
pected. Increased automaticity is the most likely likely reflecting physician comfort, rather than
mechanism; others include triggered activity and proven efficacy. Complete tachycardia suppression
micro-reentry (97–100). AET usually occurs without withmedicationsvariesfrom25%intherecentseries
structuralheart disease but has been described after (107)to>80%inastudyusingregimensthatincluded
congenital heart disease surgery (100) and in the amiodarone(109).Medicaltherapyiscommonlyused
settingofchannelopathies(101). in neonates and infants, whereas older children
In a multicenter study of 249 children with AET, undergo ablation. Catheter ablation is the primary
28% had AIC (7). The cardiomyopathy varied from treatment for PJRT, with reported success rates
asymptomatic mild LV dysfunction to the need for of 90% (107). Thus, the role for medical therapy is
HF medications in 52%; 3 required extracorporeal limited to the neonate and small infant as a tempo-
membrane oxygenation (7). Multiple antiarrhythmic rarymeasuretoallowfortherarepatientwithspon-
medications or combinations of medications were taneous resolution, to suppress the tachycardia, and
JACC VOL. 66, NO. 15, 2015 Gopinathannairetal. 1723
OCTOBER 13, 2015:1714–28 Arrhythmia-InducedCardiomyopathy
to prevent AIC and allow time and growth before RECOVERY, PROGNOSIS, AND IMPACT OF
undertakingcatheterablation. RECURRENT ARRHYTHMIA ON AIC
Junctional ectopic tachycardia.Junctional ectopic
tachycardia (JET), most commonly seen in small Clinical and animal studies have documented the
children following congenital heart surgery (110), is resolutionofsignsandsymptomsofHFandrecovery
duetoabnormalautomaticityintheregionoftheAV of LV dysfunction with termination of culprit
junction. JET unassociated with cardiac surgery can arrhythmia.Inseverallargeanimalmodelsofpacing-
presentatanyage,andcongenitalJET,presentingin induced cardiomyopathy, cessation of pacing resul-
infancy, is associated with high morbidity and mor- tedinsignificantimprovementsinLVfunctionanda
tality(110–112).Inanearlystudy,mortalitywas34%, relative normalization of neurohormonal systems
with sudden death occurring in infants (113). In (13,32,36,124,125).Forexample,LVvolumesandsys-
a multicenter study of nonoperative JET, overall tolic performance progress toward normalcy and
mortality was low, with all deaths occurring in biomarker measurements of renin-angiotensin acti-
children #6 months of age (114). Although only 16% vationfallsharplyby7to14daysfollowingcessation
presented with HF, the tachycardia was incessant in of rapid pacing. Clinically, studies have shown that
>40%.JETcanbeincessantorparoxysmal,although recovery from AIC usually happens over weeks to
infants <6 months of age are more likely to have several months following arrhythmia suppression
incessanttachycardia. (1,9,52,83).
Medical management is commonly undertaken In75patientswithPVC-mediatedcardiomyopathy
(89%)asthefirststepbutwasvariablyeffective,with withsuccessfulcatheterablation,LVEFnormalizedin
avarietyofdrugsused.Beta-blockerswerethemost 5(cid:2)6months,with68%recoveringby4months(9).A
commonfirst-lineagent,butthemajorityrequired$2 similar time course to recovery of LVEF was seen in
drugsforcontrol,withcompletesuppressionseenin anotherstudyof24patientswithAIC(predominantly
only 11%. Amiodarone alone or in combination was fromAT)(1).EliminationofPVCsinpatientswithAIC
citedasthemosteffectiveforrateorrhythmcontrol. resulted in progressive improvement in LVEF and
Catheter ablation for JET can be accomplished with clinical profile, irrespective of underlying structural
the preservation of AV nodal conduction (115,116), heartdisease(82).
and cryoablation has been associated with success Although AIC was originally considered a com-
rates similar to those of radiofrequency ablation but pletely reversible form of cardiomyopathy, several
withoutAVblock(114,117). observations have cast doubt on whether the im-
Ventricular tachycardia and PVCs.Although rare provement in LVEF in AIC really means “cure.”
inchildren,ventriculartachycardiacanresultinAIC. Whether myocardial structure and function fully
Incessantventriculartachycardiaofinfancyoccursin normalizeremainsunresolved.ResolutionofHFand
association with ventricular Purkinje cell tumors or recoveryofLVEFmaynotimplynormalizationofLV
histiocytoid or lymphocytoid tumors (118–121). Both structure and function. Identifying predictors of re-
left and right ventricular tachycardias can result in covery has therefore been of great interest. Early
pediatric AIC (86), and there are reports of PVC- improvement (>25% improvement in 1 week) of
induced AIC in children (122,123). The burden of LVEF following catheter ablation was predictive of
ectopyneeded,orotherfeaturesassociatedwithAIC complete normalization in LVEF during long-term
risk,havenotbeendefined. follow-up (126). In a study of 69 patients with AIC
AIC IN CHILDREN—SUMMARY. Tachyarrhythmias re- fromoutflowtractPVCs,significantPVCsuppression
sulting in AIC in children differ from those in the (>80% reduction in PVC burden and always <5,000
adult. There is a predictable pattern of resolution PVCs/day) showed LVEF improvement comparable
withtreatment, and although previous small reports to complete elimination (72). Long-standing and
have described weeks to months for functional re- persistentAICpriortorecognitionandcurativether-
coveryandyearsforreverseremodeling,themedian apyoftheculpritarrhythmiacouldresultinirrevers-
timetorecoveryinalargerstudywas<2months(86). ible adverse LV remodeling and can limit complete
Recovery seems independent of treatment strategy recovery(83).Anothermajorfactoraffectingrecovery
(ablation vs. medical therapy). Recovery is predict- andoutcomesistheeffectofrecurrentarrhythmia.In
able following arrhythmia control, and failure of re- a study of 24 patients with AIC and New York
covery should instigate a search for factors, such as Heart Association functional class III/IV HF, the me-
subclinical arrhythmia recurrence or an underlying diantimefromonsetofarrhythmiatocardiomyopathy
cardiomyopathy. anddevelopmentofHFwas4.2years.Asonewould