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THE PRESENT AND FUTURE

COUNCIL PERSPECTIVES

Arrhythmia-Induced Cardiomyopathies
Mechanisms, Recognition, and Management
Rakesh Gopinathannair, MD, MA,* Susan P. Etheridge, MD,y Francis E. Marchlinski, MD,zFrancis G. Spinale, MD, PHD,x Dhanunjaya Lakkireddy, MD,k Brian Olshansky, MD{

ABSTRACT

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Arrhythmia-induced cardiomyopathy (AIC) is a potentially reversible condition in which left ventricular dysfunction is

induced or mediated by atrial or ventricular arrhythmias. Cellular and extracellular changes in response to the culprit

arrhythmia have been identified, but specific pathophysiological mechanisms remain unclear. Early recognition of AIC and

prompt treatment of the culprit arrhythmia using pharmacological or ablative techniques result in symptom resolution

and recovery of ventricular function. Although cardiomyopathy in response to an arrhythmia may take months to years to

develop, recurrent arrhythmia can result in rapid decline in ventricular function with development of heart failure,

suggesting residual ultrastructural abnormalities. Reports of sudden death in patients with normalized left ventricular

ejection fraction cast doubt on the complete reversibility of this condition. Several aspects of AIC, including specific

pathophysiological mechanisms, predisposing factors, optimal therapeutic strategies to prevent ultrastructural changes,

and long-term risk of sudden death remain unresolved and need further research. (J Am Coll Cardiol 2015;66:1714–28)

© 2015 by the American College of Cardiology Foundation.

I dentifying, stabilizing, and correcting the causesof cardiomyopathy improves outcomes and qual-ity of life in patients with systolic heart failure

(HF). Arrhythmias can initiate or exacerbate acuteHF in patients with pre-existing heart disease. Lesswell recognized is the effect of persistent tachycardiaor frequent ectopy on cardiomyopathy in patientswith or without concomitant heart disease (1–3). Early

e views expressed in this paper by the American College of Cardiolo

uncil do not necessarily reflect the views of the Journal of the America

m the *Division of Cardiovascular Medicine, University of Louisville, Lou

iversity of Utah, Salt Lake City, Utah; zDivision of Cardiology, Unive

epartment of Internal Medicine, University of South Carolina, Charleston, S

nsas, Kansas City, Kansas; and the {Mercy Heart and Vascular Institute, M

. Spinale’s research is supported by National Institutes of Health (NIH) gra

ard from the Veterans Affairs Health Administration. Dr. Gopinathannair

iomed; and has served on speakers bureaus for Pfizer/Bristol-Myers Squibb

bster, Boston Scientific, St. Jude Medical, and Medtronic. Dr. Marchlinski

ston Scientific, and Medtronic; and has received lecture honoraria from Bio

dical, and Medtronic. Dr. Spinale’s research is supported by NIH grants

ard from the Veterans Affairs Health Administration. Dr. Lakkireddy has s

Jude Medical, BiosenseWebster, and Bristol-Myers Squibb; and has served

hansky has served as a consultant to Boston Scientific, Medtronic, Da

arin, Boehringer Ingelheim, On-X, Abbott Vascular, and Sanofi. Dr. Et

evant to the contents of this paper to disclose.

ten to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Vale

nuscript received May 26, 2015; revised manuscript received July 28, 201

nt.onlinejacc.org/ by Rakesh Gopinathannair on 10/09/2015

recognition of the relationship of culprit arrhythmiato cardiomyopathy is paramount in providing treat-ment that improves symptoms, left ventricular ejec-tion fraction (LVEF), and functional status.

This state-of-the-art review addresses the signifi-cance, mechanisms, diagnosis, current managementstrategies, and prognosis of arrhythmia-induced car-diomyopathy (AIC).

gy’s (ACC’s) Electrophysiology Section Leadership

n College of Cardiology or the ACC.

isville, Kentucky; yDivision of Pediatric Cardiology,

rsity of Pennsylvania, Philadelphia, Pennsylvania;

outh Carolina; kDivision of Cardiology, University of

ercy Medical Center North Iowa, Mason City, Iowa.

nts HL057952, HL059165, and HL095608 and a merit

has served as a consultant to St. Jude Medical and

. Dr. Marchlinski’s research is sponsored by Biosense

has served on advisory boards for Biosense Webster,

sense Webster, Biotronik, Boston Scientific, St. Jude

HL057952, HL059165, and HL095608; and a merit

erved as a speaker and consultant to Janssen, Pfizer,

on advisory boards for Atritech and SentreHeart. Dr.

iichi-Sankyo, Biotronik, Cardionomics, BioControl,

heridge has reported that she has no relationships

ntin Fuster.

5, accepted August 17, 2015.

https://s3.amazonaws.com/ADFJACC/JACC6615/JACC6615_fustersummary_07

http://crossmark.crossref.org/dialog/?doi=10.1016/j.jacc.2015.08.038&domain=pdf

http://dx.doi.org/10.1016/j.jacc.2015.08.038

AB BR E V I A T I O N S

AND ACRONYM S

AET = atrial ectopic

tachycardia

AF = atrial fibrillation

AIC = arrhythmia-induced

cardiomyopathy

AT = atrial tachycardia

AV = atrioventricular

BNP = B-type natriuretic

peptide

HF = heart failure

JET = junctional ectopic

tachycardia

LV = left ventricle/ventricular

LVEF = left ventricular

ejection fraction

NT-proBNP = N-terminal

pro-B-type natriuretic peptide

PJRT = permanent junctional

reciprocating tachycardia

PVC = premature ventricular

complex

J A C C V O L . 6 6 , N O . 1 5 , 2 0 1 5 Gopinathannair et al.O C T O B E R 1 3 , 2 0 1 5 : 1 7 1 4 – 2 8 Arrhythmia-Induced Cardiomyopathy

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WHAT IS AIC?

AIC is a condition in which atrial or ventriculartachyarrhythmias or frequent ventricular ectopy re-sult in left ventricular (LV) dysfunction, leading tosystolic HF (1,2). The hallmark of this condition ispartial or complete reversibility once arrhythmiacontrol is achieved. AIC can be classified into 2 cate-gories: one in which arrhythmia is the sole reason forventricular dysfunction (arrhythmia induced) andanother in which the arrhythmia exacerbates ventric-ular dysfunction and/or worsens HF in a patient withconcomitant heart disease (arrhythmia mediated) (3).

EPIDEMIOLOGY

The incidence and prevalence of AIC are uncertain,but AIC appears underrecognized. Atrial fibrillation(AF) is present in 10% to 50% of patients with HF;many patients with cardiomyopathy and AF haveworsening symptoms and ventricular function solelydue to poorly controlled ventricular rates (4). In 2studies of adult patients with focal atrial tachycardia(AT), the incidence of AIC was 8.3% to 10% (5,6),whereas 28% had AIC in a pediatric multicenter studyof atrial ectopic tachycardia (AET) (7). The incidenceof AIC was 9% to 34% in patients with frequent pre-mature ventricular complexes (PVCs) and/or non-sustained ventricular tachycardia referred forelectrophysiological evaluation (8–10).

PATHOPHYSIOLOGY, MECHANISMS, AND

PREDISPOSING FACTORS

PATHOPHYSIOLOGY: INSIGHTS FROM ANIMAL

MODELS. Chronic rapid pacing has long been recog-nized to cause HF in animal models (11). LV remod-eling and HF occur in a time-dependent and highlypredictable manner, similar to the phenotype of AIC(12–18). Due to the rapidly progressive and predict-able nature of pacing to induce cardiomyopathy, thenatural history of LV remodeling and failure, neuro-hormonal activation and signaling, and cell viabilityand molecular pathways have been examined indetail. The Central Illustration shows the natural his-tory and contributing cellular and molecular events inrapid pacing–induced cardiomyopathy and HF.

LV REMODELING AND HF. During the early phase(the first 3 to 7 days) of rapid pacing, LV dilationoccurs, with a decline in LVEF (12–15). This earlyremodeling phase is not accompanied by compro-mises in cardiac output or systemic perfusion pres-sures. By the second week, LV dilation, a fall in LVEF,and elevations in central venous and pulmonary

ded From: http://content.onlinejacc.org/ by Rakesh Gopinathan

capillary wedge pressures and systemicvascular resistance ensue (12–17). EventuallyHF develops.

Whereas initial manifestations are adap-tive, sustained rapid pacing affects LVload-ejection relationships, specifically, thepre-load recruitable LV stroke–work relation-ship (17), the LV systolic wall stress–ejectionrelationship, and the slope of the LV end-systolic pressure–volume relationship (18).LV dilation and dysfunction are accompaniedby a decline in intrinsic myocardial contractilefunction.

NEUROHORMONAL ACTIVATION. Rapid pacingin animals results in a predictable, time-dependent change in neurohormonal path-ways and synthesis and release of bioactivepeptides (19–25). The levels of plasma atrialnatriuretic peptide and B-type natriureticpeptide (BNP) increase early, concomitantwith LV dilation (19,21); eventually natri-uretic peptide levels plateau or decrease,likely due to suppression of synthesis and
increased degradation by endopeptidases. Anotherhallmark is activation of sympathetic pathways,resulting in norepinephrine spillover (20,21). Consis-tent with the phenotype of progressive LV failure,rapid pacing invariably causes activation of therenin-angiotensin-aldosterone system (20,25). Otherbioactive molecules activated and released includeendothelin and inflammatory cytokines such astumor necrosis factor alpha (24).
Whereasmediators of vasoconstriction are induced,mediators of vasodilation, such as the response tonitric oxide, become impaired (22,23). Several keyaspects regarding these temporal changes in theneurohormonal/bioactive signaling pathways holdrelevance. First, shifts in key neurohormonal path-ways, such as the natriuretic peptides and the renin-angiotensin-aldosterone system, likely reflect shiftsin underlying LV functional status from a “compen-sated” to a “decompensated” state. Thus, neurohor-monal measurements may serve as useful biomarkersfor the progressive nature/status of AIC. Secondly, it islikely that stimulation of key pathways, such as theadrenergic and cytokine systems, contribute directlyto myocardial dysfunction.

CELL SIGNALING AND VIABILITY. Under normalconditions, increased contraction frequency causesa progressive rise in myocardial contractile perfor-mance due to appropriate changes in Ca2þ handlingand in the myofilament response to Ca2þ. However,this positive force–frequency relationship is blunted

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CENTRAL ILLUSTRATION Schematic Illustration of the Natural History and Pathophysiology of Rapid Pacing–InducedDilated Cardiomyopathy and Heart Failure

CytoplasmCa2+

L-Type Ca2+ Channel

Ca2+ ATPase

Myocyte

ECM

~ >7 Days

~ 1-3 Weeks

~ >3 WeeksDefects in Ca++ Handling and Severe Contractile Dysfunction

Initial Tachyarrhythmia Stimulus

Extracellular Matrix Remodeling

Cellular Remodeling,Contracile Dysfunction, Viability

Cellular and Molecular Events Natural History Time

Compensatory PhaseLV pump function normalSympathetic system activation

Gopinathannair, R. et al. J Am Coll Cardiol. 2015; 66(15):1714–28.

In response to rapid pacing in animals, left ventricular (LV) remodeling and heart failure occur in a time-dependent and highly predictable manner, similar to the

phenotype of arrhythmia-induced cardiomyopathy. Several cellular and molecular events in response to the initial tachyarrhythmia stimulus take place over a period of

approximately 3 to 4 weeks and involve both extracellular matrix (ECM) and myocyte remodeling. Specifically, there is loss of normal extracellular matrix and

architecture. This, coupled with alterations in cellular growth and viability, defects in Ca2þ handling, and neurohormonal activation, results in LV dilation and severe

contractile dysfunction. The natural history of rapid pacing–induced cardiomyopathy progresses from a compensatory phase (approximately >7 days) to an LV

dysfunction phase (approximately 1 to 3 weeks) to an LV failure phase (approximately >3 weeks), characterized by progressive LV dilation and dysfunction and

increasing neurohormonal activation. ATPase ¼ adenosine triphosphatase; RAAS ¼ renin-angiotensin-aldosterone system.

Gopinathannair et al. J A C C V O L . 6 6 , N O . 1 5 , 2 0 1 5

Arrhythmia-Induced Cardiomyopathy O C T O B E R 1 3 , 2 0 1 5 : 1 7 1 4 – 2 8

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with pacing-induced cardiomyopathy (26), withaccompanied prolongation of myocardial Ca2þ tran-sients and defects in Ca2þ cycling (27). These changesin the force-frequency relation and Ca2þ handling area manifestation of prolonged rapid pacing and arepresent when definable changes in LV systolic func-tion have already occurred (27–30). The summation ofchanges in Ca2þ handling results in fundamental de-fects in the excitation-contraction coupling process,leading to defects in absolute myocyte contractilefunction and inotropic responsiveness (27–30).

ntent.onlinejacc.org/ by Rakesh Gopinathannair on 10/09/2015

In isolated myocyte preparations, intrinsic defectsin the rate and extent of shortening, as well as defectsin the rate of relaxation, have been identified as car-diomyopathy develops and progresses (20,28,31).Changes in cellular growth and viability ensue (32,33).Chronic rapid pacing induces several proapoptoticcascades (34). LV dilation is not associated with anabsolute increase in myocyte cross-sectional area butrather with lengthening of individual myocytes, withalterations in cytoskeletal architecture (20,29,31,35).If these changes in myocyte function and viability


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were placed in a temporal context, then LV myocyteremodeling (cell shape and architecture) is likely tooccur early, followed by abnormalities in excitation-contraction and changes in cell viability.

EXTRACELLULAR REMODELING. Although remodel-ing occurs within the myocyte, robust changes alsooccur within the extracellular matrix (35,36). Specif-ically, there is a loss of normal fibrillar collagen con-tent and distribution (35,36), which, in turn, initiatesalterations in myocyte support and alignment withinthe LV wall. Concomitantly, the capacity of myocytesto bind to the extracellular matrix is diminished (35),suggesting that abnormalities in the extracellularmatrix–integrin interface have occurred. Increasedmatrix metalloproteinase activity and expressioncontribute to loss of normal extracellular matrixsupport and architecture (37). Activation of matrixmetalloproteinases precedes the defects in myocytecontractile function (37). These findings suggest thatthe likely mechanism for LV remodeling is loss ofnormal myocardial extracellular matrix structure,composition, and function.

IMPLICATIONS OF ANIMAL STUDIES. Chronic rapidpacing in animals causes dilated cardiomyopathyresembling clinical AIC. With rapid atrial pacing inpigs, an atrioventricular (AV) conduction pattern ismaintained and ventricular dyssynchrony as thestimulus for adverse remodeling and HF is unlikely(12,13,20). However, rapid ventricular pacing, wheremyocardial dyssynchrony is inevitable, results in amore rapid and precipitous fall in LV systolic perfor-mance (14–17). Thus, the tachycardia stimulus is suf-ficient to drive the cardiomyopathy process, wherebyelectrical dyssynchrony would constitute an additivefactor accelerating the process.

Phases and structural milestones that occur withchronic arrhythmias in animal models translate toclinical forms of AIC. Specifically, there is an adaptive/compensatory phase whereby LV dilation, extracel-lular matrix remodeling, and neurohormonal systemactivation occurs but severe LV dysfunction does not.This phase could be identified in patients by LV imag-ing and biomarker profiling and is followed by a phasein which LV dysfunction becomes manifest and asso-ciated with defects in excitation-contraction couplingand LV myocyte remodeling and dysfunction. Thisphase likely represents a critical transition when thisprocess may not completely reverse, leading toneurohormonal activation accompanied by the fullpathophysiological spectrum of HF.

Several challenges and limitations exist in trans-lating animal data to humans. The time coursefor development of AIC and HF in patients with


otherwise structurally normal hearts is usuallymonths to years, which is quite different from theacute changes seen in pacing models. Some ar-rhythmias (e.g., AF and PVCs) may have mecha-nisms leading to AIC that are not explained fullyby rapid-pacing animal models (10,38–40). Althoughultrastructural changes may explain the initial de-velopment of AIC, the relationship between identifi-able ultrastructural changes and the mechanisms bywhich cardiomyopathy develops are less clear. Anoverview of the current understanding of the rela-tionship between arrhythmias and cardiomyopathy,from mechanisms to management and prognosis, isshown in Figure 1.

ARRHYTHMIA AND PATIENT CHARACTERISTICS. Ar-rhythmia characteristics contributing to AIC includearrhythmia type (Table 1), rate, duration, rhythm ir-regularity, persistence (5,41–43), and concomitantheart disease (44). An arrhythmia that is insidious,persistent, and well tolerated is more likely to resultin AIC (5). Lack of persistent tachycardia from auto-nomic influences and resultant slower rates duringsleep are likely to be the reasons that AIC is rare ornonexistent with inappropriate sinus tachycardia andpostural orthostatic tachycardia syndrome (POTS),although the average heart rate can be >100 beats/min. There is no specific heart rate cutoff at which AICdevelops. The rate is not well defined, may be agedependent, and is likely lower than initially sus-pected. Little is known about patient factors thatincrease vulnerability to AIC, but one report hasindicated that patients with a homozygous deletionpolymorphism in the angiotensin-converting enzyme(DD) gene had a higher propensity to develop AICwhen faced with persistent tachycardia, suggesting apotential genetic link (45). In a longitudinal study ofpatients with high PVC burden, those who developedcardiomyopathy had wider PVC QRS width versusthose who did not, suggesting baseline myocardialfiber disruption that portends an increased risk (46).

CLINICAL FEATURES AND DIAGNOSIS

The key diagnostic feature of AIC is the presence of apathological tachycardia or persistent arrhythmia(PVC) in the presence of an otherwise unexplainedcardiomyopathy. The relationship of arrhythmia tocardiomyopathy can be difficult to determine be-cause an arrhythmia could exist for years before itsrecognition and before cardiomyopathy develops.Although a high index of clinical suspicion may pointto subtle diagnostic clues, the condition may go un-recognized for years. The presentation can be lateonly after manifest systolic HF develops. Similarly, if

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FIGURE 1 Overview of the Current Understanding of AIC, From Mechanisms to Management and Prognosis

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– Confirms diagnosis of AIC

No significant improvement in LV function —Not AIC

Follow up:1. Maintain sinus rhythm/strict rate control2. Close surveillance to avoid arrhythmia recurrence3. Continue beta–blockers/ACE inhibitors4. Follow–up imaging (echo and/or MRI)

No evidence of persistent ultra–structural changesby echo or cardiac MRI

Persistent ultra–structural changes:1. LV dimensions2. Evidence for fibrotic changes in MRI3. Development of LV hypertrophy

Good prognosis

– Close surveillance– Continue beta– blockers/ACE inhibitors

Persistent tachyarrhythmias or frequent ventricular ectopy can lead to dilated cardiomyopathy and decompensated heart failure in patients with or without

concomitant structural heart disease. Cellular and extracellular changes in response to the culprit arrhythmia have been identified (see Central Illustration),

but specific pathophysiological mechanisms have not been well elucidated. Early recognition of the relationship of a culprit arrhythmia to cardiomyopathy

and aggressive arrhythmia control results in improved symptoms, left ventricular (LV) ejection fraction, and functional status and helps establish the

diagnosis of arrhythmia-induced cardiomyopathy (AIC). Cellular and extracellular ultrastructural changes can, however, persist and can contribute to a rapid

decline in cardiac function with arrhythmia recurrence. Close surveillance is thus crucial to ensure good long-term prognosis. ACE ¼ angiotensin-converting

enzyme; MRI ¼ magnetic resonance imaging; PVC ¼ premature ventricular complex.



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the arrhythmia is detected early but a nonaggressiveapproach is taken, progressive worsening of symp-toms and insidious development of cardiomyopathyensue. It can be difficult to determine whether anarrhythmia is the initiator or consequence of car-diomyopathy in a patient with tachycardia and HF.Thus, AIC raises a “chicken or egg” question (47).Frequently, the arrhythmia is considered secondaryand is not treated effectively when, in fact, arrhythmiacontrol is necessary for full recovery.

History, physical examination, and clinical in-vestigations should focus on determining the etiologyof cardiomyopathy. Specific patient characteristicsmay suggest a higher likelihood of AIC. Patients withAIC have a smaller LV end-diastolic diameter and


mass index versus those with pre-existing dilatedcardiomyopathy and concomitant tachyarrhythmia(48,49). Cardiac magnetic resonance imaging (CMR)may help differentiate AIC from dilated cardiomyop-athy. In a study of 27 patients with frequent PVCsand cardiomyopathy, 22 had improvement in LVEFfollowing PVC suppression; 5 did not. Four of the5 patients with LVEF that did not improve had evi-dence for late gadolinium enhancement, suggestingunderlying scar (8). Campos et al. (49) comparedpatients with irreversible nonischemic dilated car-diomyopathy, reversible PVC-mediated cardiomyo-pathy, and patients with PVCs and normal LVEFwho underwent electroanatomic mapping. Theseinvestigators noted that those with irreversible

TABLE 1 Causes of Arrhythmia-Induced Cardiomyopathy

Supraventricular

Atrial fibrillation

Atrial flutter

Atrial tachycardia

AV nodal re-entrant tachycardia

AV re-entrant tachycardia

Permanent junctional reciprocating tachycardia

Junctional ectopic tachycardia

Ventricular

Idiopathic ventricular tachycardia

Fascicular tachycardia

Ectopy

Frequent premature ventricular contractions

Frequent premature atrial contractions

Pacing

Persistent rapid atrial and/or ventricular pacing

Adapted with permission from Gopinathannair et al. (2).

AV ¼ atrioventricular.


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cardiomyopathy had a significantly larger percentageof the LV endocardium with abnormal unipolarvoltage (64% vs. 5.2% for the reversible group and0.1% for the normal LVEF group). An abnormal uni-polar voltage area $32% of LV endocardium predictedthe irreversibility of cardiomyopathy with >95%sensitivity and specificity, but prospective validationis lacking (49).

Serial assessment of the N-terminal pro-BNP(NT-proBNP) ratio (NT-proBNP at baseline/NT-proBNP during follow-up) can differentiate AIC fromirreversible dilated cardiomyopathy. Forty patientswith AF or atrial flutter with ventricular rates >100beats/min and LVEF <40% were cardioverted, andNT-proBNP was measured on day 1 and weekly for4 weeks. An NT-proBNP ratio cutoff >2.3 at 1 week,suggesting rapid decline in NT-proBNP levels, wasassociated with reversible cardiomyopathy, with anaccuracy of 90% (50).

When AIC cannot be easily differentiated fromdilated cardiomyopathy with consequent tachy-cardia, treatment for both problems becomes neces-sary (2). The diagnosis may be evident only afterrestoration and maintenance of sinus rhythm or afteraggressive rate control.

PRINCIPLES OF MANAGEMENT

AIC management should focus on concerted attemptsto eliminate or control the arrhythmia, with the goalof improving symptoms, reversing LV dysfunction,and preventing arrhythmia recurrence (1,5,43,51,52).A favorable response to arrhythmia elimination/control establishes the diagnosis of AIC. Along with


arrhythmia control, use of neurohormonal antago-nists can result in favorable ventricular remodeling.Controversy remains about the need to continuethese medications if there is complete recovery ofLVEF with arrhythmia control.

AIC ASSOCIATED WITH SPECIFIC

ARRHYTHMIAS IN ADULTS

ATRIAL FIBRILLATION. AF is the most commoncause of AIC in adults (1,43). Of patients presentingwith HF, 10% to 50% have AF (4,53), and many suchpatients likely have a component of AIC. The mech-anisms underlying development or progression ofcardiomyopathy in patients with persistent AF havenot been elucidated clearly (39). Rapid heart rates,loss of atrial contraction, and rhythm irregularity maycontribute (1,39,40,54). Persistent tachycardia canimpair myocardial contractility, either directly orthrough alterations in cellular and neurohormonalmechanisms. Resting tachycardia, as well as a rapidincrease in heart rate with exercise, can impair dia-stolic filling. Lack of atrial contribution to ventricularfilling can further worsen diastolic function. A viciouscycle can thus develop, with HF and associated in-creases in left-sided filling pressures and functionalmitral regurgitation resulting in mechanoelectricalchanges in the left atrium, perpetuating AF and car-diomyopathy (54).

Management of AF consists of rate and/or rhythmcontrol. In those with AF and cardiomyopathy, theideal target heart rate remains uncertain. For thosewith permanent AF, lenient rate control (resting heartrate <110 beats/min) has been advocated over strictrate control (resting heart rate <80 beats/min andheart rate with moderate exercise <110 beats/min)(55). However, in the RACE II (Rate Control Efficacy inPermanent Atrial Fibrillation II) trial (55), most pa-tients were rate controlled before enrollment (base-line heart rate 96 beats/min) and were asymptomaticwithout cardiomyopathy. Follow-up was short, anddevelopment of AIC was not specifically considered.

Several methods are available for AF rate control(56). Achieving adequate rate control may requiredrug combinations and frequent regimen changes(57). However, these data may not directly applyto AF-mediated AIC because rate irregularity maycontribute to symptoms and facilitate development ofAIC (40). Although AV nodal ablation with pacemakerimplantation can provide effective rate control (58)and regularize the rate, this strategy changes ven-tricular activation, even if cardiac resynchronizationtherapy is used; therefore, it should only be con-sidered if rhythm and/or rate control cannot be

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established. In contrast, electrical or pharmacologicalcardioversion, antiarrhythmic drugs, and catheterablation can achieve rhythm control. In AF-mediatedcardiomyopathy, restoration and maintenance of si-nus rhythm can hasten clinical recovery and reversecardiomyopathy over several months (1,40,59).

The AF-CHF (Atrial Fibrillation and CongestiveHeart Failure) trial randomized 1,376 patients with AF(70% persistent) and HF to either a rhythm control(amiodarone with cardioversion) or a rate controlstrategy. The mean LVEF was 27% and patients werefollowed for 37 months. A rhythm control strategyusing antiarrhythmic drugs did not improve all-causemortality or prevent worsening HF. However, the AF-CHF patient population may not fully represent theAIC population because 40% of patients in the ratecontrol arm were in sinus rhythm during follow-up(60). The CAFÉ-II (Controlled Study of Rate VersusRhythm Control in Patients With Chronic AF andHeart Failure) study randomized 61 patients withpersistent AF (median duration of 14 months) andmoderate LV dysfunction to a rate control andrhythm control strategy (amiodarone with cardio-version). During a follow-up of 1.2 years, 66% ofpatients maintained sinus rhythm, whereas 90%achieved target rate control (<80 beats/min at restand <110 beats/min with 6-min walk). Rhythm con-trol was superior to rate control in improving LVfunction, pro-BNP levels, and quality of life (61). At-tempts to control rate might not be as aggressive orcarefully monitored in the real world as in clinicaltrials. It is also possible that side effects and proar-rhythmic risks from antiarrhythmic drugs may offsetany salutary effects from restoring and maintainingsinus rhythm (62).

Restoring and maintaining sinus rhythm by cath-eter ablation of AF can improve and reverse AIC(63,64). Pulmonary vein isolation appears superior toAV node ablation and biventricular pacing in patientswith drug-refractory AF and HF (64). A systematicreview of 19 studies (n ¼ 914) evaluating AF ablationin patients with concomitant LV dysfunction showedthat sinus rhythm was maintained in 57% aftera single procedure, with an increase to 82% with>1 procedure and/or use of antiarrhythmic drugs (65).LVEF increased by 13.3% (95% CI: 11% to 16%), sug-gesting the effectiveness of catheter ablation formaintaining sinus rhythm and reversing AIC.

The recent AATAC-AF (Ablation vs. Amiodaronefor Treatment of Atrial Fibrillation in Patients WithCongestive Heart Failure and an Implanted ICD/CRTD)trial randomized 203 patients with persistent AFwith HF and cardiomyopathy (LVEF <40%) to eitheramiodarone or catheter ablation. During a 24-month


follow-up, 70% of patients in the ablation arm werefree of AT/AF (vs. 34% in the amiodarone arm[p < 0.001]) and had significant improvements inmortality, hospitalization rates, and quality of life.LVEF improved 9.6 � 7.4% in the ablation arm versus4.2 � 6.2% in the amiodarone arm (p < 0.01) (66).Catheter ablation thus offers an effective rhythmcontrol strategy and avoids potentially toxic long-termantiarrhythmic therapy. The available data argue forcatheter ablation as the best choice for rhythm controlin patients with AF-mediated AIC.

ATRIAL FLUTTER. Atrial flutter is more difficult torate control than AF, given less concealed conductioninto the AV node. Therefore, despite intense efforts atpharmacological rate control, minimal exertion canlead to rapid ventricular rates. Given the inherentdifficulty with rate control and the high success rateand low risk of complications with catheter ablation(67,68), ablation to eliminate atrial flutter is recom-mended when AIC is suspected. For those in whomcatheter ablation is not feasible or desired, cardio-version with antiarrhythmic therapy or aggressiverate control should be used.

SUPRAVENTRICULAR TACHYCARDIAS. Persistent sup-raventricular tachycardias can result in AIC by severalmechanisms (5). Near simultaneous AV relationshipscan have a negative hemodynamic effect. A curativestrategy by catheter ablation should be pursuedwhenever possible as first-line therapy for supra-ventricular tachycardia-mediated AIC. Successfulcatheter ablation can normalize LVEF and is usuallyassociated with excellent long-term outcomes (5,6).

PVCs AND VENTRICULAR TACHYCARDIA. Idiopathicventricular tachycardia and, more commonly, fre-quent PVCs can lead to AIC in patients withoutstructural heart disease and can exacerbate car-diomyopathy in patients with structural disease(10,52,69,70). PVCs associated with cardiomyopathyusually arise in the right or left ventricular outflowtract, but PVCs from non–outflow tract sites can alsoresult in AIC (10,46,52).

The mechanism of PVC-mediated AIC is not fullyunderstood. A large animal model using a pacingprotocol to simulate paroxysmal PVCs produced anAIC phenotype that resolved completely within 2 to 4weeks after pacing cessation. Tissue analysis did notshow evidence of inflammation, fibrosis, or apoptosis,suggesting that PVC-induced cardiomyopathy instructurally normal hearts could be a functional ab-normality (38). Potential mechanisms postulatedinclude ventricular dyssynchrony, especially relatedto a left bundle branch block PVC morphology,abnormal Ca2þ handling from the short coupling


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intervals, and abnormal ventricular filling from thepost-PVC pause (10,37,38).

The development of cardiomyopathy with atrialpremature depolarizations (71) and the absence ofconvincing site-specific association in PVC-mediatedAIC suggest that it may not be a simple matter of LVdyssynchrony. The causal relationship between PVCsand AIC has been firmly established on the basis ofreversal of the cardiomyopathy with suppressionand/or elimination of PVCs (72,73).

The most prominent predictor of cardiomyopathyin patients with frequent PVCs appears to be thedaily burden of PVCs. A high PVC burden has beenvariably defined as ranging from >10,000 to 25,000PVCs/day and as >10% to 24% of total heartbeats/day (74–76). There appears to be a threshold burdenof approximately 10,000 PVCs/day for developingAIC. Ventricular function can improve if the PVCburden is reduced to <5,000/day (72). This is animportant target when elimination of all PVCs maynot be possible, especially in the setting of multi-form PVCs.

Retrospective studies suggest multiple potentialpatient and PVC characteristics associated with thedevelopment of AIC (9,10,74,77,78). These character-istics include male sex, increased body mass index,asymptomatic PVCs, higher PVC coupling intervaldispersion, interpolated PVCs, and presence ofretrograde P waves (10,77–80). In a study of patientswith high PVC burden followed for 14 months, 17(38%) developed AIC. A PVC QRS duration >153 msand non–outflow tract origin predicted developmentof AIC (46). Importantly, most patients with frequentPVCs will not develop cardiomyopathy (76). Cur-rently, although an important goal of future investi-gation, no risk profile defines a group of patientsrequiring prophylactic PVC elimination to preventAIC. However, it is advisable for patients with ahigh PVC burden to have periodic echocardiographicassessments to confirm stable LV chamber size andfunction.

Therapy for PVC-mediated AIC should be targetedat suppressing or eliminating the PVCs and shouldinclude antiarrhythmic therapy and catheter abla-tion. Beta-blockade and non–dihydropyridine cal-cium channel blockade are low-risk therapies, butthey have limited effectiveness. Beta-blockers arefrequently considered first-line treatment because ofthe benign nature of the treatment. Dofetilide, mex-iletine, sotalol, or amiodarone may be more effective,although they have greater risk of side effects andproarrhythmia. Antiarrhythmic drug use is frequentlyreserved for patients who fail or are reluctant to un-dergo catheter ablation.


Catheter ablation has emerged as the definitivetherapy for PVC-mediated AIC, with success ratesranging from 70% to 90% (52). Elimination of PVCswith ablation has been shown to improve LVEF,ventricular dimensions, mitral regurgitation, andfunctional status. In an observational series, ablationwas superior to antiarrhythmic therapy in reducingPVCs and improving LVEF (51). Successful ablation ofPVCs can improve the efficacy of cardiac resynchro-nization therapy in nonresponders (81). The elimi-nation of high PVC burden (>10%) in patients withimpaired LVEF can be associated with improvementof function, even when structural cardiac abnormal-ities are present (72,73,82).

MANAGEMENT IN ADULTS—SUMMARY. Our approachto manage patients with suspected AIC is to attemptcareful and aggressive control of rate and rhythm,with the focus on arrhythmia elimination by cath-eter ablation whenever possible. The only tachyar-rhythmias that do not appear to require aggressivetreatment to prevent AIC are sinus tachycardia andPOTS. Continued therapy with neurohormonal an-tagonists is advisable for favorable remodeling, al-though the duration of such therapy is not welldefined (83).

AIC IN CHILDREN

In children, dilated cardiomyopathy is the mostcommon reason for heart transplant (84). Nearly40% of children with cardiomyopathy undergo hearttransplant or die within 2 years of presentation (85).AIC must be considered in this setting. In the largestpediatric series of AIC, AET (59%) and permanentjunctional reciprocating tachycardia (PJRT; 23%) werethe most common arrhythmias represented. Ventric-ular arrhythmias were uncommon (86).

Tachyarrhythmias are a reversible cause of car-diomyopathy from fetal life onward (87–90). Childrenoften present late because they fail to recognize pal-pitations or are unable to verbalize symptoms andcome to medical attention only after the developmentof HF. Compared with adults, different arrhythmiamechanisms are represented in pediatric AIC.

Supraventricular arrhythmias are more commonthan ventricular arrhythmias in children and there-fore are more frequently associated with AIC. In thenewborn, a single, sustained episode of typical sup-raventricular tachycardia may be unrecognized untilHF symptoms emerge; thus, neonates may presentwith decreased LV function, or even shock. In thisgroup, prognosis and recovery of cardiac function areexcellent after control of supraventricular tachy-cardia. This is in contrast to the more incessant

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tachycardias, for which control is more challengingand recovery less rapid.

Etiologically, sustained rapid rates, QRS duration,AV dyssynchrony, and heart rate irregularity all couldcontribute to AIC, yet not all children with incessanttachycardia develop AIC. In children, the tachycar-dias most often associated with AIC have a narrowQRS complex and 1:1 AV conduction. Heart rateirregularity occurs in pediatric AIC as salvos oftachycardia interspersed with periods of sinusrhythm, rather than as the persistent heart rate ir-regularity seen in AF.

As evident in many cardiac conditions, geneticfactors may underlie the development of AIC. Serum-and glucocorticoid-regulated kinase 1 (SGK1), acomponent of the cardiac phosphatidylinositol 3-kinase signaling pathway has proarrhythmic effectsand has been linked to biochemical and functionalchanges in the cardiac Naþ channel. These effects arereversed by treatment with ranolazine, which blocksthe late Naþ current (91). Conversely, inhibition ofSGK1 in the heart protects against fibrosis, HF, andNaþ channel alterations after hemodynamic stress.One might speculate that an underlying cardio-myopathic process is unmasked by a tachyarrhythmiaor that genetic factors are responsible for botharrhythmic and myopathic outcomes. Recent advan-cement in our understanding of channelopathicconditions and the overlapping of arrhythmic andmyopathic phenotypes seen in some patients lendscredibility to this theory (92–95). Mutations in thecardiac Naþ channel and in the ryanodine receptor,long known to be involved in arrhythmogenesis,can now be linked to abnormalities of contractilefunction (92).PEDIATRIC ARRHYTHMIAS ASSOCIATED WITH AIC.

Atr ia l ectop ic tachycard ia . AET is the most com-mon arrhythmia associated with AIC in children (96).Although P-wave morphology and axis usually differfrom sinus rhythm, AET foci near the sinus node arehard to differentiate from sinus tachycardia, espe-cially in patients with HF, when tachycardia is ex-pected. Increased automaticity is the most likelymechanism; others include triggered activity andmicro-reentry (97–100). AET usually occurs withoutstructural heart disease but has been described aftercongenital heart disease surgery (100) and in thesetting of channelopathies (101).

In a multicenter study of 249 children with AET,28% had AIC (7). The cardiomyopathy varied fromasymptomatic mild LV dysfunction to the need forHF medications in 52%; 3 required extracorporealmembrane oxygenation (7). Multiple antiarrhythmicmedications or combinations of medications were


used, with beta-blockers being the most commonfirst-line therapy. No trends emerged to define themost successful medication. Catheter ablation waseffective in 81% of patients in whom it was used.The use of electroanatomic mapping for ablationimproved success (102) and decreased recurrence(103).

Spontaneous resolution of AET can occur, espe-cially in those presenting within the first year of life,where 74% had resolution (7). Ablation proved safeand effective, but the investigators suggested a trialof medical therapy in the youngest patients, in whomablation may have more risk (104,105) and whenspontaneous resolution is more likely.Permanent junctional reciprocating tachycardia. PJRTis an accessory pathway–mediated tachycardia with along RP interval that occurs predominantly in infantsand children. The pathway can be located anywherein the AV junction but is usually posteroseptal (106).Pathways are tortuous and slow conducting; thus,tachycardia is often incessant.

In a recent review, 27% of patients with PJRT pre-sented in fetal life, 7% with hydrops, a fetal mani-festation of AIC (107). Isolation of the AV junction is acontinuing process that may not be complete at birth,and the presence of accessory connections crossingthe annulus fibrosis could result in persistent peri-natal supraventricular tachycardia. Although mostchildren with PJRT present with palpitations or arenoted to have rapid heart rates, 18% presented withAIC in a series of 194 children (107). Cardiomyopathyis more likely to occur in children with longer RPinterval/cycle length ratios, consistent with an acces-sory pathway with slow retrograde conduction and awide, excitable gap (108). PJRT is often incessant, andthose with incessant PJRT had longer RP intervals,were younger at diagnosis, and more often had AIC(107). The clinical course of PJRT is not benign, andspontaneous resolution is unlikely (107).

A number of antiarrhythmic medications are used,but a single most effective agent has not emerged(107). Beta-blockers are the common first choice,likely reflecting physician comfort, rather thanproven efficacy. Complete tachycardia suppressionwith medications varies from 25% in the recent series(107) to >80% in a study using regimens that includedamiodarone (109). Medical therapy is commonly usedin neonates and infants, whereas older childrenundergo ablation. Catheter ablation is the primarytreatment for PJRT, with reported success ratesof 90% (107). Thus, the role for medical therapy islimited to the neonate and small infant as a tempo-rary measure to allow for the rare patient with spon-taneous resolution, to suppress the tachycardia, and


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to prevent AIC and allow time and growth beforeundertaking catheter ablation.Junctional ectopic tachycardia. Junctional ectopictachycardia (JET), most commonly seen in smallchildren following congenital heart surgery (110), isdue to abnormal automaticity in the region of the AVjunction. JET unassociated with cardiac surgery canpresent at any age, and congenital JET, presenting ininfancy, is associated with high morbidity and mor-tality (110–112). In an early study, mortality was 34%,with sudden death occurring in infants (113). Ina multicenter study of nonoperative JET, overallmortality was low, with all deaths occurring inchildren #6 months of age (114). Although only 16%presented with HF, the tachycardia was incessant in>40%. JET can be incessant or paroxysmal, althoughinfants <6 months of age are more likely to haveincessant tachycardia.

Medical management is commonly undertaken(89%) as the first step but was variably effective, witha variety of drugs used. Beta-blockers were the mostcommon first-line agent, but the majority required $2drugs for control, with complete suppression seen inonly 11%. Amiodarone alone or in combination wascited as the most effective for rate or rhythm control.Catheter ablation for JET can be accomplished withthe preservation of AV nodal conduction (115,116),and cryoablation has been associated with successrates similar to those of radiofrequency ablation butwithout AV block (114,117).Ventr i cu la r tachycard ia and PVCs . Although rarein children, ventricular tachycardia can result in AIC.Incessant ventricular tachycardia of infancy occurs inassociation with ventricular Purkinje cell tumors orhistiocytoid or lymphocytoid tumors (118–121). Bothleft and right ventricular tachycardias can result inpediatric AIC (86), and there are reports of PVC-induced AIC in children (122,123). The burden ofectopy needed, or other features associated with AICrisk, have not been defined.

AIC IN CHILDREN—SUMMARY. Tachyarrhythmias re-sulting in AIC in children differ from those in theadult. There is a predictable pattern of resolutionwith treatment, and although previous small reportshave described weeks to months for functional re-covery and years for reverse remodeling, the mediantime to recovery in a larger study was <2 months (86).Recovery seems independent of treatment strategy(ablation vs. medical therapy). Recovery is predict-able following arrhythmia control, and failure of re-covery should instigate a search for factors, such assubclinical arrhythmia recurrence or an underlyingcardiomyopathy.


RECOVERY, PROGNOSIS, AND IMPACT OF

RECURRENT ARRHYTHMIA ON AIC

Clinical and animal studies have documented theresolution of signs and symptoms of HF and recoveryof LV dysfunction with termination of culpritarrhythmia. In several large animal models of pacing-induced cardiomyopathy, cessation of pacing resul-ted in significant improvements in LV function and arelative normalization of neurohormonal systems(13,32,36,124,125). For example, LV volumes and sys-tolic performance progress toward normalcy andbiomarker measurements of renin-angiotensin acti-vation fall sharply by 7 to 14 days following cessationof rapid pacing. Clinically, studies have shown thatrecovery from AIC usually happens over weeks toseveral months following arrhythmia suppression(1,9,52,83).

In 75 patients with PVC-mediated cardiomyopathywith successful catheter ablation, LVEF normalized in5 � 6 months, with 68% recovering by 4 months (9). Asimilar time course to recovery of LVEF was seen inanother study of 24 patients with AIC (predominantlyfrom AT) (1). Elimination of PVCs in patients with AICresulted in progressive improvement in LVEF andclinical profile, irrespective of underlying structuralheart disease (82).

Although AIC was originally considered a com-pletely reversible form of cardiomyopathy, severalobservations have cast doubt on whether the im-provement in LVEF in AIC really means “cure.”Whether myocardial structure and function fullynormalize remains unresolved. Resolution of HF andrecovery of LVEF may not imply normalization of LVstructure and function. Identifying predictors of re-covery has therefore been of great interest. Earlyimprovement (>25% improvement in 1 week) ofLVEF following catheter ablation was predictive ofcomplete normalization in LVEF during long-termfollow-up (126). In a study of 69 patients with AICfrom outflow tract PVCs, significant PVC suppression(>80% reduction in PVC burden and always <5,000PVCs/day) showed LVEF improvement comparableto complete elimination (72). Long-standing andpersistent AIC prior to recognition and curative ther-apy of the culprit arrhythmia could result in irrevers-ible adverse LV remodeling and can limit completerecovery (83). Another major factor affecting recoveryand outcomes is the effect of recurrent arrhythmia. Ina study of 24 patients with AIC and New YorkHeart Association functional class III/IV HF, the me-dian time from onset of arrhythmia to cardiomyopathyand development of HF was 4.2 years. As one would

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expect, aggressive rate and/or rhythm control ofthe culprit arrhythmia resulted in significant im-provement in LVEF and resolution of HF in all patientswithin 6 months. Five of 24 patients developedrecurrent arrhythmia, and all had a rapid decline inLVEF (within 6 months of arrhythmia recurrence) withrecurrence of HF, which was again reversed withaggressive arrhythmia control.

In 69 patients with AF and LVEF <40% who un-derwent catheter ablation, those who maintained si-nus rhythm (65%) had complete recovery of LVEF andmaintained normal LVEF after 28 � 11 months offollow-up, compared with those who had recurrentAF/AT. Interestingly, recovery of LVEF at 6 monthswas similar in both groups, but further improvementwas seen only in the sinus rhythm group (40). Anexample of a patient with recurrent AF and AIC isshown in Table 2, where the time course of LVEFchanges in relation to recurrence of AF is apparent.These data demonstrate that AIC is reversible if theculprit arrhythmia is controlled, but recurrence of thearrhythmia can result in HF and an abrupt decline inLVEF (1).

In patients with AIC who have had resolution ofarrhythmia, echocardiographic evaluations notedpersistently elevated stroke volumes and LV end-systolic and end-diastolic volume indexes, suggest-ing persistent negative remodeling (127). In patientswith AIC from focal AT who had normalization of

TABLE 2 An Example of the Clinical Course of AIC When the

Culprit Arrhythmia Was Not Eliminated: A 54-Year-Old Man With

AF and LVEF of 30%

Time,Months LVEF, % Intervention

0 30 Diuretics, ACE inhibitors, TEE, cardioversion

1 47

6 52 AIC diagnosed

14 — Recurrent AF per patient; did not see a doctor

18 25 Cardioverted; started taking sotalol butdiscontinued due to increased QTcinterval; amiodarone started

23 50

35 20 Admitted with heart failure; recurrent AFwith rapid rates; underwent AF ablation;amiodarone continued

40 55

43 40 LAflutterwithventricular rateof110beats/min;underwent perimitral LA flutter ablation

53 52

63 53 Sinus rhythm; taking amiodarone (200 mgdaily), beta-blockers, ACE inhibitor,warfarin

ACE ¼ angiotensin-converting enzyme; AF ¼ atrial fibrillation; AIC ¼ arrhythmia-induced cardiomyopathy; LA ¼ left atrial; LVEF ¼ left ventricular ejection fraction;TEE ¼ transesophageal echocardiography.


LVEF with successful ablation, CMR scanning 5 yearsafter ablation showed higher LV end-diastolic vol-umes and evidence for diffuse fibrosis compared withpatients with focal AT without AIC and with healthycontrols (128).

Current evidence thus suggests that myocardialstructural and functional impairment can persist inpatients with AIC, even after successful eliminationof the causal arrhythmia and normalization of LVEFand symptoms, suggesting that recovery is incom-plete at an ultrastructural level. The “recovery” fromAIC perhaps represents a transition to another form ofLV remodeling and dysfunction. The mechanismsunderlying these abnormalities, and whether pat-terns of recovery from AIC differ among differentarrhythmias, require further study.

RISK OF SUDDEN DEATH

Long-term survival of patients with AIC followingarrhythmia resolution is likely; however, concernsremain. Sudden cardiac death has been reported inpatients with AIC following symptom recovery andLVEF normalization (1,6,129). Nerheim et al. (1) re-ported 3 patients with AF-mediated AIC who diedsuddenly during follow-up while asymptomatic andhaving preserved LVEF and good functional status.Two patients were on adequate rate control and thethird was on rhythm control. All 3 had index LVEFsthat were markedly lower than those in the rest ofthe study group (n ¼ 24), suggesting a greater riskin patients with severe baseline LV dysfunction (1).Available reports thus have suggested that certainpatients with AIC could be at risk for sudden car-diac death, despite normalization of LVEF. Howev-er, the true risk of sudden death in patients withAIC, especially following arrhythmia suppressionand LVEF recovery, is likely low, and there is nopresent justification for implantable cardioverter-defibrillator (ICD) insertion in patients with revers-ible cardiomyopathy (on the basis of improvementin LVEF).

Close surveillance, as well as continuation ofneurohormonal antagonists to aid positive remodel-ing, is warranted in AIC, even after arrhythmia sup-pression and normalization of LVEF. A follow-up CMRfor assessment of residual fibrosis/scar could providevaluable prognostic information (128). Arrhythmiarecurrence can be devastating (1,6,129).

FUTURE DIRECTIONS

Since the original observations by Philips and Levinein 1949 of the association between rapid AF anda reversible form of HF (130), AIC has become a


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recognized disease entity. Diligent basic and clinicalinvestigations have shed light on the etiology,pathophysiology, clinical features, treatment, andprognosis of AIC. However, several gaps in our un-derstanding still exist. The true incidence and prev-alence of AIC need to be defined. Future researchshould focus on specific pathophysiological mecha-nisms for cardiomyopathy in relation to a particulararrhythmia. Identifying clinical, genetic, and de-mographic characteristics that predispose a particularindividual to AIC in the setting of a culprit arrhythmiawill be crucial for early recognition of this diseaseprocess, before cardiomyopathy develops. Questionsstill exist concerning optimal therapeutic strategies:Is rhythm control really better than rate control forimproving long-term outcomes in AF-mediated AIC?How can we best prevent residual ultrastructural ab-normalities? What are the interrelationships betweenstructural heart disease, arrhythmia, and risk ofsudden death?

THE “BIG PICTURE”: CLINICAL AND

GLOBAL HEALTH IMPACT OF AIC

Heart failure is increasing globally. Tachyarrhythmiasand frequent PVCs remain an important cause ofnonischemic cardiomyopathy and manifest HF thatis partially or completely reversible with control ofthe arrhythmia. However, this condition remainsunder-recognized, often leading to worsening HFand deterioration of LV function. Given that limited


therapeutic options exist for patients with advancedHF, the ability to detect a potentially reversible causeis critical. Raising awareness about this conditionglobally is paramount.

CONCLUSIONS

AIC can affect patients of any age and has a widerange of clinical manifestations, from asymptomatictachycardia or ectopy to cardiomyopathy to end-stage HF. Early recognition is critical, and aggres-sive treatment aimed at controlling or eliminatingthe inciting arrhythmia results in symptom resolu-tion and recovery of ventricular function. However,cellular and extracellular ultrastructural changescan persist and can contribute to a rapid decline incardiac function with arrhythmia recurrence, as wellas confer a risk of sudden cardiac death. Thus,this supposedly “benign” and “reversible” conditionposes unique challenges to the practicing cardiolo-gist. Novel approaches for early detection, as wellas targeted intervention, are warranted and mayultimately improve long-term outcomes for thesepatients.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Rakesh Gopinathannair, Division of CardiovascularMedicine, University of Louisville, 550 South JacksonStreet, ACB/A3L41, Louisville, Kentucky 40202.E-mail: [email protected] [email protected].

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KEY WORDS atrial fibrillation, atrialflutter, catheter ablation, heart failure,heart rate, tachycardia



























































































































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