electrophysiological remodeling in heart failure ... · aiba t electrophysiological reverse...

Electrophysiological Remodeling in Heart FailureDyssynchrony vs. Resynchronization

Takeshi Aiba MD PhD�1, Gordon F. Tomaselli MD�2, Wataru Shimizu MD PhD�1

�1Division of Arrhythmia and Electrophysiology, Department of Cardiology,

National Cerebral and Cardiovascular Center�2Division of Cardiology, the Johns Hopkins University School of Medicine

The electrophysiological hallmark of cells and tissues isolated from failing hearts isprolongation of action potential duration (APD) and conduction slowing. In human studiesand a number of animal models of heart failure, functional downregulation of K currents andalterations in depolarizing Na and Ca currents and transporters are demonstrated. Alterationsin intercellular ion channels and matrix contribute to heterogeneity of APD and conductionslowing. The changes in cellular and tissue function are regionally heterogenous particularlyin the heart failure with dyssynchronous LV contraction (DHF). Furthermore, �-adrenergicsignaling and modulation of ionic currents is blunted in heart failure.

Cardiac resynchronization therapy (CRT) partially reversed the DHF-induced down-regulation of K current and improved Na channel gating. CRT significantly improved Cahomeostasis especially in myocytes from late-activated, lateral wall, and restores the DHF-induced blunted �-adrenergic receptor responsiveness. CRT abbreviated DHF-inducedprolongation of APD in the lateral wall myocytes and reduced the LV regional gradient ofAPD, and suppressed development of early afterdepolarizations.

In conclusion, CRT partially restores DHF-induced ion channel remodeling, abnormal Cahomeostasis, blunted �-adrenergic response and regional heterogeneity of APD, thus maysuppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well asimprove mechanical performance of the heart.(J Arrhythmia 2010; 26: 79–90)

Key words: Ion channels, Calcium handling, Heart failure, Remodeling, Electrophysiology

Introduction

Heart failure is highly prevalent, accounting formore than 250,000 deaths annually in the UnitedStates and 100,000 in Japan. The incidence andprevalence has continued to increase with the aging

of the population.1,2) Despite remarkable improve-ments in medical therapy, the prognosis of patientswith myocardial failure remains poor with almost20% of patients dying within one year of initialdiagnosis and greater than 80% eight-year mortality.Of the deaths in patients with heart failure, up to50% are sudden and unexpected; indeed, patients

Address for correspondence: Takeshi Aiba MD PhD, Division of Arrhythmia and Electrophysiology, Department of Cardiology, National

cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita 565-8565, Japan. Phone: 06-6833-5012 FAX: 06-6872-7486 E-mail:

[email protected]

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Aiba T Electrophysiological Reverse Remodeling by CRT

Review Article

with heart failure have 6–9 times the rate of suddencardiac death of the general population.1)

Heart failure is associated with anatomic andfunctional remodeling of cardiac tissues in bothanimal models and humans, which alters cardiacelectrophysiology. Indeed, abnormalities of atrialand ventricular electrophysiology in diseased humanhearts have been recognized for over four decades.Remodeling of myocyte electrophysiology in heartfailure is well described; recent data suggests that thepattern of electrical and mechanical activation mayinfluence this remodeling.

Heart Failure and Electrical Remodeling

Prolongation of APD and development of EADsThe hallmark of cells and tissues isolated from

failing hearts independent of the cause is prolon-gation of action potential duration (APD).3–9) Theaction potential reflects a delicate balance betweenthe activity of several depolarizing and repolarizingionic currents, transporters, and exchangers, whichare not uniformly expressed in the ventricular wall(Figure 1). The prolongation of APD in heart failureis heterogeneous, exaggerating the physiologicalinhomogeneity of electrical properties in the failingheart.4,10) The action potential prolongation in heartfailure is highly arrhythmogenic with frequentearly afterdepolarizations (EADs) that are notobserved in ventricular myocytes isolated fromcontrol hearts.

Kþ channel remodelingKþ current downregulation is a regular finding in

the failing heart. The detailed changes in currentsand channels vary with the model of heart failure;however, the consistent effect is the generation ofheterogeneous prolongation of APD.

Transient outward Kþ current (Ito)Although expressed cardiac Kþ channels vary in

different species. Transient outward potassium cur-rent (Ito) down regulation is the most consistent ioniccurrent change in failing hearts.3,5,6,8,11) As Ito is anearly transient current; it may not directly affect theventricular APD in large mammalian hearts as itdoes in rodent ventricle. Interestingly, downregula-tion of Ito in cells isolated from terminally failinghuman hearts is not associated with a change in itsvoltage dependence or kinetics.3) The molecularmechanism of Ito downregulation in heart failure islikely to be multifactorial. Reduced steady-statelevels of Kv4 mRNA are highly correlated withfunctional downregulation of Ito in human heartfailure.6,11–14) In a canine model, tachycardia down-regulates Ito expression, with the Ca2þ/calmodulin-dependent protein kinase II (CaMKII) and calcineur-in/nuclear factor of activated T-cells (NFAT) sys-tems playing key Ca2þ-sensing and signal-transduc-ing roles in rate-dependent Ito control.15)

Inward rectifier Kþ current (IK1)Reduced inward IK1 density in heart failure may

contribute to prolongation of APD and enhancedsusceptibility to spontaneous membrane depolari-zations including delayed afterdepolarizations(DADs)7,10,16,17) Changes in IK1 functional expres-sion are more variable than Ito, and controversial.

CACNA1C (Cav1.2)

SCN5A (Nav1.5)

Current Gene (Protein)

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Figure 1 Ionic basis for altered ventricular action potential by heart failure.Schematic of inward and outward ionic currents, pumps, and exchangers, which inscribe the mammalian ventricular action potential. A

schematic of the time course of each current is shown (left), and the gene product that underlies the current is indicated (right).

J Arrhythmia Vol 26 No 2 2010

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Even within the same experimental model of heartfailure induction (e.g. pacing-tachycardia), inconsis-tencies have been observed across species: reducedIK1 density in canine5,10) but no change in rabbit.18)

In terminal human heart failure, IK1 is significantlyreduced at negative voltages,3) but the underlyingbasis for such downregulation appears to be post-transcriptional in light of the absence of changes inthe steady-state level of Kir2.1 mRNA.6)

The molecular basis of IK1 downregulation inheart failure remains controversial without consistentchanges in the expression of Kir2 family of genes.Even the specific subunit(s) that underlie IK1 vary asfunction of species and cardiac chamber, althoughKir2.1 and 2.2 knockout19) and Kir2.1 dominantnegative overexpressing mice20) exhibit prolongedAPDs.

Delayed rectifier Kþ currents (IKr and IKs)The delayed rectifier Kþ currents play a prom-

inent role in the late phase of repolarization,21)

therefore changes in either the slow (IKs) or fast(IKr) activating components of this current couldcontribute significantly to action potential prolonga-tion in heart failure. Reduced IK density, sloweractivation, and faster deactivation kinetics havebeen observed in hypertrophied feline ventricles.22)

Downregulation of both IKr and IKs have beenreported in a rabbit model of rapid ventricularpacing heart failure,8) whereas IKs but not IKr wasdownregulated in all layers of the left ventricularmyocardium in a canine model of same tachy-pacing heart failure.10) The molecular basis for IKdown regulation in heart failure remains uncertain.Previous study measured mRNA levels of the genesencoding the � subunits for the rapidly (HERG) andslowly (KvLQT1) activating components of IK innormal and failing canine hearts and found nostatistical difference.6)

Ca2þ currents and Ca2þ transientsAltered Ca2þ homeostasis underlies abnormalities

in excitation-contraction coupling and arrhythmicrisk in heart failure. Intracellular [Ca2þ] and theaction potential are intricately linked by a variety ofCa2þ-mediated cell surface channels and transporterssuch as L-type Ca2þ current (ICa-L), IK, Ca2þ-activated Cl� current, and Naþ/Ca2þ exchanger(NCX). ICa-L density is unchanged or reduced inheart failure, the latter typically occurring in moreadvanced disease.23) Remarkably in human heartfailure baseline ICa-L density is consistently un-changed;24) although single channel studies suggesta reduction in channel number with an increase in

open probability perhaps due to altered phosphor-ylation or subunit composition.25) The molecularbases of changes in the density of ICa-L areincompletely understood, subunit mRNA expressionin heart failure is variable.26) The complexity of themolecular Ca channel remodeling is highlighted byreports of isoform switching of both �1C27) and �subunits in the failing heart.28)

The amplitude of the calcium transient (CaT) andits rate of decay are reduced in intact preparationsand cells isolated from failing ventricles.29) System-atic comparisons of the CaT profile and dynamics incells isolated from different regions of the failingheart are limited. Sarcoplasmic reticulum Ca2þ-ATPase (SERCA2a), its inhibitor phospholamban(PLN) and NCX are primary mediators of Ca2þ

removal from the cytoplasm. In heart failure,ventricular myocytes exhibit a greater reliance onNCX for removal of Ca2þ from the cytosol and anincrease in NCX function,30) which leads to defec-tive SR Ca2þ loading.31) Altered NCX function inheart failure significantly influences CaT and actionpotential dynamics.32) SR Ca2þ release is alsodefective in the failing heart and is associated withaltered regulation of the ryanodine receptor(RyR).33) Hyperphosphorylation of RyR by proteinkinase A34) or CaMKII35) may increase diastolicCa2þ leak and generate spontaneous Ca2þ wavesunderlying triggered arrhythmias in heart failure.The role of RyR regulation and gating in alteredsystolic function and arrhythmic risk in heart failureremains controversial.36–38) Recently, increased in-ositol 1,4,5-trisphosphate receptors (InsP3Rs) ex-pression has been suggested to be a generalmechanism that underlies remodeling of Ca2þ

signaling during heart disease, and in particular, intriggering ventricular arrhythmia during hypertro-phy.39) On the other hand, CaMKII� contributes tocardiac decompensation by enhancing RyR2-medi-ated SR Ca2þ leak and that attenuating CaMKII�activation can limit the progression to heart fail-ure.40) The heart failure-mediated alterations inRyR2 function mimic the changes caused by post-translational modification by reactive oxygen spe-cies, thus redox modification of RyR may contributeto SR Ca2þ leak in chronic heart failure.41)

Naþ channel and late INaStudies of Naþ current (INa) in a canine infarct

model of heart failure revealed a significant downregulation of the current, an acceleration of itsinactivation properties, and a slowing of its recoveryfrom inactivation in myocytes isolated from theinfarct border zone.42) Normal impulse formation


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and conduction depend on the fast inward INa. Also,an increase in the late component of Na current(late INa) can markedly prolong APD and promotepolymorphic VT. Therefore, changes in INa densityand kinetics may predispose to arrhythmias either bydisrupting conduction and/or prolonging repolariza-tion.

In a canine model of ischemic heart failure,significant downregulation of INa, acceleration of itsinactivation properties, and slowing of its recoveryfrom inactivation were observed.42) A significantincrease in the late INa was demonstrated in human

and canine heart failure.43,44) A recent study hasshown that intracellular Ca2þ CaMKII signalingincreases late INa by slowing inactivation kineticsand shifting steady state inactivation.45–47) Theconsequence of increased Naþ influx or decreasedefflux in heart failure particularly in the setting ofregionally variable lengthening of the APD isheterogenous cytosolic Naþ loading and subsequentactivation of ‘reverse mode’ NCX. NCX functioningin the reverse mode in response to increased [Naþ]imay be adaptive promoting an increase influx inactivator Ca2þ (Figure 2).

cAMP

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Figure 2 Intracellular Ca2þ cycling and associated signaling pathways in cardiomyocytes.On a beat-by-beat basis, a CaT is elicited by the influx of a small amount of Ca2þ through the ICa-L and the

subsequent large-scale Ca2þ release from the SR through the ryanodine receptor (RyR). During diastole,

cytosolic Ca2þ is taken up into the SR by the phospholamban (PLN)-regulated SERCA2a pump. �-adrenergic

receptor (�-AR)-mediated PKA stimulation regulates this Ca2þ cycling by phosphorylating ICa-L, RyR, and

PLN. In normal hearts, sympathetic stimulation activates the �1-adrenergic receptor, which in turn stimulates

the production of cAMP by adenylyl cyclase and thereby activates PKA. PKA phosphorylates PLN and RyR,

both of which contribute to an increased intracellular CaT and enhanced cellular contractility. PP1 and PP2A

regulate the dephosphorylation process of these Ca2þ regulatory proteins (RyR, PLN and ICa-L). The PLN

hypophosphorylation inhibits SERCA2a activity, thereby decreasing SR Ca2þ uptake. The increased Ca2þ

level in the cytosol activates CaMKII, which affects the functions of RyR and PLN. Activation or deactivation

of these molecules at a node in the signaling cascade affects beat-by-beat Ca2þ cycling, and such maneuvers

have recently been highlighted as potential new therapeutic strategies against heart failure. Increased INCX,

reduced IK1 and residual coupling to �-AR signaling may predispose to arrhythmogenic DADs.


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There are no consistent changes in cardiac Naþ

channel subunit expression in heart failure, however,aberrant splicing of Nav1.5 transcripts has beenreported in failing human ventricular myocardium.48)

Changes in INa are likely to depend on the specificdisease etiology, and may have profound implica-tions for arrhythmogenesis given the relative abun-dance and importance of this current to wavefrontpropagation.

Connexin and Purkinje fiber remodeling in heartfailure

Slowed intraventricular conduction is a prominentfeature of heart failure and is associated with areduction in the density, altered distribution andpost-translational modification of the major cardiacgap junction protein (connexin 43, Cx43).49) Similarfindings have been observed in hypertrophied andischemic human ventricular myocardium, Cx43 isdownregulated and redistributed from the interca-lated disk to the entire cell border (lateraliza-tion),50–52) a pattern observed in early cardiacdevelopment. Downregulation and lateralization ofCx43 in heart failure49) is progressive with durationof tachypacing53) and associated with conductionslowing. The mechanism of Cx43 downregulation isnot completely understood but may involve alteredrennin-angiotensin signaling54,55) changes in bindingpartners56,57) or altered membrane domain localiza-tion.58) In tachypacing-induced heart failure, Cx43down regulation is associated with a reduction inCx43 mRNA.

Synchronous activation of the ventricles requiresconduction over the His-Purkinje network. Ioniccurrent remodeling is distinct in different regions ofthe failing heart. In heart failure changes in ioniccurrents of Purkinje cell include a reduction of Itoand IK1 density with slowing of ICa-L decay. Therewere no significant changes in IKr or IKs but Purkingcell exhibit a reduction in repolarizing reserve inheart failure manifest by APD prolongation andexaggerated prolongation of the duration in thepresence of class III antiarrhythmic drugs. InPurkinje fibers downregulation of KV4.3, KV3.4,Kir2.1 mRNA and protein was observed consistentwith the Kþ current changes.59) Pacing induced heartfailure in the canine model slowed conduction inPurkinje fiber false tendons with an associatedreduction in NaV1.5, Cx40, Cx43 and phospho-Cx43 protein levels. Immunohistochemistry revealedreduced Cx40, Cx43 and phospho-Cx43 protein atthe intercalated disk.59) The changes in electrophy-siological properties of Purkinje fiber may serve as asubstrate for ventricular arrhythmia; moreover, re-

duction in conduction in the Purkinje network mayresult in dyssynchronous activation of the ventricleand progression of the heart failure phenotype.

CRT and Reverse Electrical Remodeling

In heart failure with dyssynchronous contraction(DHF), bi-ventricular (V) pacing referred to as CRTimproves symptoms and reduces mortality in subsetsof patients,60) CRT is widely applied in patients withDHF, but the electrophysiological consequences ofCRT are not well understood. Therefore, to answerthese questions, using a canine model of pacing-induced DHF and CRT we investigated theseelectrical differences and mechanistic insights incellular, molecular and genetic level.

CRT and arrhythmic eventsIs CRT pro-arrhythmic or anti-arrhythmic? Soon

after starting bi-V pacing, QT prolongation anddevelopment of Torsades de pointes, the arrhythmiacharacteristic of the long QT syndrome, has beenreported.61) LV epicardial pacing further increasedQTc and JTc intervals compared to Bi-V pacing.62)

In an acute study using a canine wedge preparation,reversal of activation by the epicardial pacingcompared to the endocardial pacing increased QT,JT interval and transmural dispersion of repolariza-tion, creating the substrate for TdP under long-QTcondition.63) On the other hand, whether chronicCRT alters the QT interval and QT dispersion, andwhether such changes relate to the risk of developingarrhythmic events are still controversial.64)

In patients with advanced heart failure and aprolonged QRS interval, CRT decreases the com-bined risk of death from any cause or first hospital-ization and, when combined with an ICD, signifi-cantly reduces mortality.65) Compared with ICD-only, CRT with defibrillator (CRT-D) prevents heartfailure events in relatively asymptomatic patientswith low ejection fraction.66) ICD strongly suppressessudden cardiac death but cannot prevent arrhythmicevents, and continuous RV pacing rather results inadverse LV remodeling and reduce systolic func-tion.67) On the contrary, some small clinical studieshave shown ventricular arrhythmias were decreasedespecially in patients with CRT responder during theinitial 12 months after implant.68,69) Therefore, CRTis expected to have some beneficial effects not onlyin heart failure but also in arrhythmias.

CRT and regional effects on action potentialsand ionic currents

Action potential prolongation in DHF is most


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prominent in cells isolated from the late-activatedlateral LV wall. CRT significantly shortens theaction potential in lateral myocytes and reduces theLV regional heterogeneity in APD (Figure 3).13)

Action potential prolongation in DHF is highlyarrhythmogenic with frequent EADs that were notobserved in myocytes isolated from control hearts.CRT dramatically reduces the frequency of EADsin cells isolated from both the anterior and lateralLV.

The mechanisms of regional action potentialremodeling in the DHF and CRT are controversial.At the molecular level, tumor necrosis factor-�(TNF-�) and CaMKII were increased in DHFprominently in the lateral wall and these differenceswere absent in CRT.70) TNF-� decreases Ito andprolongs the APD in rat ventricular myocytes.71)

Recently, Xie et al. suggested an increased oxidativestress in heart failure induced CaMKII activation andtriggers of ventricular arrhythmias.72) CaMKII influ-ences Ca2þ current, SR function,73,74) and increasespersistent Naþ current45–47) resulting in prolongationof APD.75) It is possible and indeed likely, that otherregional alterations in Ca2þ handling or increasedpersistent Naþ current contribute to regional dif-

ferences in the APD and action potential profile inDHF, and the regionally-specific effects of bi-Vpacing on this phenotype.

Kþ current changes associated with CRT arevariable (Figure 4). The down regulation of Ito isregionally uniform in the left ventricle in DHF and isunique among regulated Kþ currents in heart failurein that it is not reversed by CRT. In parallel, Kv4.3and KChIP2 mRNA and protein expression are downregulated in DHF without restoration by CRT.13)

CRT even in the setting of continued heart failurepartially restores IK1 density and decreases mem-brane resistance and in the setting of improved Ca2þ

handling in CRT may reduce the frequency ofarrhythmogenic DADs. Kir2.1 mRNA and proteinlevels are partially restored by CRT in the caninemodel; suggesting that different mechanisms ofregulation of current are operative in some animalmodels and human HF. CRT partially restores DHF-induced downregulation of IK density in bothanterior and lateral LV myocytes without a signifi-cant change in mRNA or protein levels of KvLQT1or minK compared with DHF, whereas ERG mRNAlevel was restored by CRT in either the anterior orlateral LV wall.13)

ANT

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Figure 3 Regional heterogeneity of action potential and Ca transient in DHF and its restoration by CRT.A: DHF prolongs action potential duration (APD), reduces peak amplitude and prolongs decay of Ca transient (CaT) especially in the cells

isolated from LV lateral wall. CRT abbreviates DHF-induced prolongation of APD and restores amplitude and decay of CaT in the lateral

cells, thus reduced regional heterogeneity of repolarization and Ca handling. B: Frequency of early afterdepolarizations (EADs) in

myocytes from DHF are higher than in normal cells, whereas CRT significantly reduces the frequency of EADs.


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CRT restores Ca2þ current and handlingIn DHF there are intraventricular regional changes

in ICa-L that are partially restored by CRT.13) DHFproduced a reduction peak ICa-L density and slowedcurrent decay in myocytes isolated from the late-activated lateral LV wall. In contrast, peak ICa-Ldensity in anterior myocytes was increased com-pared with non-failing controls, thus DHF producedregional heterogeneity of Ca2þ current density andkinetics. CRT restored the peak current density butdid not alter the ICa-L decay in the lateral cells,eliminating the anterior-lateral ICa-L density gradient.Neither DHF nor CRT exhibit consistent changes inCa2þ channel subunit mRNA or protein levels.

In canine pacing DHF, CaT amplitudes are de-pressed and kinetics slowed particularly in cellsisolated from the late-activated lateral LV myocar-dium and partially restored by CRT (Figure 3).13) InDHF, mRNA and protein levels of SERCA2a, PLNand RyR2 were down regulated and NCX upregulated without a change in CRT. There were alsono regional differences in mRNA and proteinexpression in any of these mediators of Ca2þ handlingin DHF and CRT, suggesting that the global and

regional differences of Ca2þ handling function inDHF and its restoration by CRT are post translational.

The mechanisms underlying the differences inregional remodeling of Kþ currents and Ca2þ

handling in DHF remain obscure. Plotnikov et al.reported that cardiac dyssynchrony by left ventric-ular pacing (120–150 bpm for 3 weeks) produced aslower decay of ICa inactivation.76) Moreover, thisphenomenon was suppressed by a �-adrenergicblockade. These findings suggest that DHF-inducedchanges of ICa inactivation kinetics might bemediated by regionally heterogeneous �-adrenergicreceptor stimulation. Furthermore, the Ca2þ-han-dling proteins are functionally regulated by phos-phorylation, prominently by key intracellular en-zymes protein kinase A and CaMKII,73,74,77) and avariety of phosphatases which may be regionallyregulated.70)

Reduced �-adrenergic receptor (�-AR) function isa key feature of heart failure. CRT restores the DHF-induced baseline reduction of ICa,L and the bluntedresponse to �-adrenergic (�1 � �2) receptor stim-ulation. Moreover, CRT improves baseline Ca2þ

handling and its adrenergic responsiveness, which

p<0.05 vs. Normal# p<0.05 vs. DHF

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Aiba T et al: Circulation 2009;119:1120-1130

††

mV

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Figure 4 CRT partially reverses DHF-induced downregulation of IK1, IK but not Ito.A-C. DHF significantly reduces the inward rectifier IK1, the delayed rectifier (IK) and transient outward Kþ currents (Ito) in both anterior

and lateral cells. CRT partially restores the DHF-induced reduction of IK1 and IK but not Ito in both anterior and lateral cells, D. These

functional changes are consistent with changes in steady state Kþ channel mRNA subunit and protein expressions.


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may contribute to improvement in contractility andaltered arrhythmia susceptibility.78) These electro-physiological data is consistent to previous molecu-lar results that CRT increased �1=�2-AR ratio. And,this restoration is the result of augmentation of �1

receptor abundance and reduction in G�i signalingmediated by an increase in the inhibitory regulator ofG protein signaling, RGS3, in CRT (Figure 5).79)

Gene expression changes by CRTSeveral studies have described regional changes in

signaling and protein expression in DHF, notably instress-response kinases and cytokines with enhancedlevels in the late-activated, lateral wall.49,70,80) Insome instances CRT can reverse these changes andproduce salutary effects on overall LV function.70) Inorder to better understand the breadth of signalingchanges, transcriptomic changes in DHF and CRThave demonstrated that genes in mitochondrial

energetic pathways are similarly over representedin the lists of downregulated genes in the failingLV.81) In contrast, genes localized in nucleus andrelated to transcriptional regulation are over repre-sented in the genes up regulated in failing LV.

A microarray study comparing intraventricularchanges in gene expression in DHF and CRTrevealed that dyssynchrony-induced changes in geneexpression were more pronounced in the anteriorcompared with the lateral LV. The genes thatexhibited regional heterogeneity with dyssynchronyare involved in critical cellular processes such asmetabolic pathways, extracellular matrix remodel-ing, and myocardial stress responses. Remarkably,dyssynchrony-induced regional expression changeswere reversed to levels in normal hearts by CRT,with prominent reversal of dysregulation of expres-sion of transcripts with metabolic and cell signalingfunction (Figure 6).82)

Chakir K, Aiba T et al: Circulation 2009; 119:1231-40.

β1-ARβ2-AR

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Figure 5 CRT restores DHF-induced blunted �-AR responsiveness.A: Peak L-type Ca2þ current (ICa) at baseline, after isoproterenol (ISO: �1þ2) or zinterol +CGP-29712A (�2) AR stimulation. CRT

restored DHF-induced blunted response to �-AR (�1 � �2) stimulation. B: Both �1 and �2 mRNA expressions were decreased in DHF,

whereas �2 remained reduced but �1 was increased in CRT, thus CRT increased �1=�2-AR ratio. C: Protein regulation of G�i and RGS

proteins. Membrane G�i was increased in DHF and CRT, whereas RGS2 and RGS3 were markedly upregulated in CRT but not in DHF.

D: Schematic crosstalk of �1 and �2-AR signaling pathway. CRT suppressed DHF-induced enhanced G�i signaling by upregulation of

RGS2 and RGS3.


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Conclusions

Electrophysiological remodeling of the failingheart involves changes in both active membraneproperties of heart cells and network attributes of themyocardium. The pattern of electrical activation andmechanical contraction impact the cellular and tissuephysiology and all seem to exaggerate the normalheterogeneity of electrophysiological properties ofthe heart when it is failing. The remodeling posesunique and complex challenges to the treatment ofarrhythmias in the failing heart. Studies of antiar-rhythmic therapy have targeted ion channels and thecardiac action potential as well as changes in thecardiac interstitium with variable success.

CRT alters electrical activation of the failing heartthat exhibits intraventricular conduction delays andresynchronizes mechanical contraction. CRT un-doubtedly benefits some patients, improving symp-toms of heart failure and reduces sudden death whenimplemented with defibrillator therapy. The reversalof the exaggerated electrophysiological heterogene-

ity of the failing heart would suggest that CRT isantiarrhythmic, however this has yet to be demon-strated clinically.

Acknowledgments

The work was supported by NIH P01 HL 077180 (to G.F.T)

and HL 072488 (to G.F.T), and grant from Medtronic Japan (to

T.A). Gordon Tomaselli is the Michel Mirowski M.D. Professor in

Cardiology. The authors thank Drs. Andreas S. Barth, Khalid

Chakir, and David A. Kass for excellent support.

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DHF Normal + CRT

-3.0 3.0

0

100

200

300

400

500

600

Normal DHF CRT

Num

ber

of d

ereg

ulat

edge

nes

per

arra

y(A

NT

vs.

LA

T)

p=0.09

p<0.01 p<0.01

Normal DHF CRTA B

Barth AS, Aiba T et al: Circ Cardiovasc Genet 2009;2:371-8

C

Figure 6 CRT reverses DHF-induced regional differences in gene expression.A: Heat map of regional (anterior vs. lateral) changes in gene expression in DHF and CRT. Unsupervised clustering of 1050 transcripts

reveals a gene expression pattern in CRT that more closely resembles Normal than DHF. B: Pseudoimages of a representative 44K feature

microarrays from Normal, DHF and CRT hearts with RNA from anterior and lateral regions labeled in a 2-color format. Red and green

dots represent statistically significant transcript between anterior and lateral wall, respectively. C: DHF shows a dramatic increase in the

regional heterogeneity of gene expression that is corrected by CRT.


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