cardiac electrical remodeling

Cardiac electrical remodeling in healthand diseaseMichael J. Cutler, Darwin Jeyaraj and David S. Rosenbaum

The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, USA

Review

Electrical remodeling of the heart takes place in responseto both functional (altered electrical activation) andstructural (including heart failure and myocardial infarc-tion) stressors. These electrophysiological changes pro-duce a substrate that is prone to malignant ventriculararrhythmias. Understanding the cellular and molecularmechanisms of electrical remodeling is important inelucidating potential therapeutic targets designed toalter maladaptive electrical remodeling. For example,altered patterns of electrical activation lead primarilyto electrical remodeling, without significant structuralremodeling. By contrast, secondary remodeling arises inresponse to a structural insult. In this article we reviewcardiac electrical remodeling (predominantly in the ven-tricle) with an emphasis on the mechanisms causingthese adaptations. These mechanisms suggest noveltherapeutic targets for the management or preventionof the most devastating manifestation of heart disease,sudden cardiac death (SCD).

IntroductionCardiovascular death rates have fallen in recent years, butthe proportion of cardiovascular death that is attributableto SCD continues to rise [1]. It is estimated that theincidence of SCD is approximately 350 000 events per yearin the United States. The most common etiology of SCD isthe development of malignant ventricular arrhythmiasresulting from complex structural and electrical remodel-ing that follows myocardial injury, most commonly second-ary to coronary artery disease. Cardiac remodeling is oftenan adaptive response to a functional or structural stressorand plays an important role in both cardiovascular healthand disease. These adaptations initially compensate,thereby maintaining cardiac performance, but over timethey can become maladaptive, causing progressive pumpfailure and/ormalignant arrhythmias. Structural remodel-ing of the heart has been extensively reviewed and isbeyond the scope of this paper [2,3].

In addition to remodeling of the mechanical and con-tractile properties of the heart, it has been more recentlyappreciated that diverse disease states can remodel keyelectrophysiological properties of the heart. Electricalremodeling takes place in both the atria and the ventricles.Electrical remodeling in the atria has been linked to atrialarrhythmias such as atrial fibrillation, as recentlyreviewed [4,5]. Electrical remodeling in the ventricle pro-duces an electrophysiological substrate for the develop-

Corresponding author: Rosenbaum, D.S. ([email protected])

174 0165-6147/$ – see front matter � 2010 Elsevier Ltd. All rights reserved. doi:10

ment of potentially lethal ventricular arrhythmias. Inthis article we therefore review cardiac electrical remodel-ing primarily in the ventricle, with an emphasis on themechanisms responsible for these adaptations. We alsodiscuss possible novel therapeutic targets for managingthe consequences of ventricular electrical remodeling in-cluding ventricular arrhythmias which lead to SCD.

Basic electrophysiological properties of the heartNormal electrical conduction in the heart allows for thecoordinated propagation of electrical impulses that initiatecontraction of the atria and ventricles. The surface elec-trocardiogram (ECG) is a reflection of these cellular elec-trical events (Figure 1). For example, atrial depolarizationis represented by the p-wave on the ECG. Ventriculardepolarization and repolarization represent the QRS com-plex and the T-wave, respectively. At the cellular level, thecardiac action potential (AP) is characterized by the inter-play of depolarizing and repolarizing currents (Figure 1).In ventricular myocytes (i.e. QRS complex and T wave)activation of Na+ currents causes rapid depolarization(phase 0) followed by a brief period of repolarization (phase1) secondary to activation of the transient outward K+

current (Ito). Subsequently, depolarization is maintained(phase 2) by a balance of inward L-type Ca2+ current (ICa-L)and outward K+ currents (primarily IKr but also IKs).Finally, repolarization (phases 3 and 4) occurs in responseto inactivation of ICa-L and the activation of multipleoutward K+ currents (IKr, IKs and IK1). The following sec-tions consider how these electrical properties of the heartremodel in health and disease.

Electrical remodeling of the heartElectrical remodeling can be divided into primary andsecondary remodeling (Figure 2). Primary electrical remo-deling describes the remodeling that primarily takes placein response to a functional insult, such as an alteredsequence of electrical activation. For example, duringright ventricular pacing the normal sequence of electricalactivation is altered because the initiating electrical im-pulse arises from ventricular myocytes in the right ven-tricle and not through the specialized Purkinje system. Ingeneral, this type of electrical remodeling takes place inthe absence of a primary structural insult to the myocar-dium [6,7]. By contrast, secondary electrical remodelingdevelops as a result of a structural alteration such as heartfailure (HF), hypertrophy, or myocardial infarction. Themechanisms responsible for primary and secondary elec-trical remodeling are complex and remain to be fully

.1016/j.tips.2010.12.001 Trends in Pharmacological Sciences, March 2011, Vol. 32, No. 3

mailto:[email protected]

http://dx.doi.org/10.1016/j.tips.2010.12.001

[()TD$FIG]

IKr

IKs

IK1

ICa-LIto

INa

Basic ECG

P waveT wave

Ventricularaction potential

QRS complex

TRENDS in Pharmacological Sciences

Figure 1. Example of basic ECG and ventricular AP. Top panel: the ECG is a

graphical representation of a coordinated sequence of electrical events in the heart

during each heart beat. Atrial depolarization produces the P wave, whereas

ventricular depolarization and repolarization produced the QRS complex and T

wave, respectively. Bottom panel: the ventricular AP consists of an interplay of

depolarizing and repolarizing currents. Abbreviations: INa, sodium current; ICa-L, L-

type Ca2+ current; Ito, transient outward K+ current; IKr, rapid component of the

delayed rectifier K+ current; IKs, slow component of the delayed rectifier K+ current;

IK1, inward rectifier K+ current.

Review Trends in Pharmacological Sciences March 2011, Vol. 32, No. 3

elucidated. However, recent research has shown thatprimary electrical remodeling also takes place in theabsence of structural remodeling, and this has providedimportant insights into the mechanisms underlying elec-trical remodeling of the heart in disease [8]. Furthermore,understanding the cellular and molecular mechanisms ofelectrical remodeling is important in elucidating potentialtherapeutic targets. Utilizing these insights to developtherapies designed to alter maladaptive electrical remo-[()TD$FIG]

Cardiac electrica

Primaryremodeling

Mechanisms

Ionic changes

Electrophysiologychanges

Causes Ventricular pacingConduction system dysfu

APD prolongation

↓ Ito, ICa, and Cx43

Mechanical stretchAngiotension IIElectrotonus

? E-C coupling prote

Figure 2. Schematic of primary and secondary remodeling. Abbreviations: INa-L, late so

component of the delayed rectifier K+ current; INCX, sodium–calcium exchanger current;

receptor.

deling could transform the management of malignantarrhythmias.

Primary electrical remodelingFor the purpose of this review we define electrical remo-deling as a persistent change in the electrophysiologicalproperties of the heart in response to a change in thesequence of electrical activation. As stated above, whenthese changes occur in the absence of significant structuralchanges they are referred to as primary electrical remodel-ing. Changes in the rate of electrical activation can alsolead to primary electrical remodeling. This review willprimarily focus on the role of an altered sequence ofelectrical activation; the reader is referred to recentreviews on the role of altered rate of activation in primaryelectrical remodeling [9,10].

Nearly 30 years ago Rosenbaum et al. described remo-deling of cardiac repolarization in response to alteredactivation [11]. Specifically, following prolonged right ven-tricular (RV) pacing the polarity of the T wave on the ECGwas persistently inverted even when normal activationwas restored (Figure 3). This phenomenon was termed‘cardiac memory’ because the T-wave polarity ‘remem-bered’ the QRS polarity during the previous period ofpacing [11]. Cardiac memory reflects significant remodel-ing of myocardial repolarization taking place within min-utes to hours of altered electrical activation (i.e. short-termmemory) [12]. Furthermore, long periods of altered activa-tion induce a greater magnitude of T-wave remodeling thatpersists for weeks to months (i.e. long-term memory) [12].Understanding the mechanisms underlying cardiac mem-ory, a clinical manifestation of primary electrical remodel-ing, could provide insights into themechanisms underlyingmore complex electrical remodeling (i.e. secondary remo-deling) that takes place following structural insults such asmyocardial infarction.

l remodeling

nctionMyocardial infarction

HypertrophyHeart failure

APD prolongationConduction slowing

E-C coupling changes

Complex signaling pathways

↓ Ito, Ikr, and Cx43

↓ RyR and SERCA2a↑ INa,L, INCX

↓ ↔ ICa

Secondaryremodeling

ins


dium current. ICa-L, L-type Ca2+ current; Ito, transient outward K+ current; IKr, rapid

Cx43, Connexin 43; SERCA2a, sarcoplasmic reticulum Ca2+ ATPase; RyR, ryanodine

175

[()TD$FIG]

µV/seg

0

0

+70

-70

Endpacing

20 Days403010


Figure 3. ECG changes in T-wave memory. Graph of T-wave polarity and representative ECGs during right ventricular pacing and for 40 days post pacing. After progressive

periods of pacing, a progressive and persistent change in polarity of the T wave takes place. This change in T-wave polarity persists for several days after the cessation of

pacing. Adapted from Rosenbaum et al. [11].


During normal activation of the ventricle through theHis–Purkinje system there is rapid electrical activation ofboth ventricles to produce synchronized mechanical con-traction. In disease states that affect the cardiac conduc-tion system or ventricular pacing, impulse propagationtakes place through cell-to-cell conduction. Themyocardialregion from which activation initiates serves as the source;the remainder of the myocardium becomes the sink. Thisgenerates a source–sink mismatch in which downstreamdepolarizing myocytes exert an electrotonic influence thatprolongs repolarization in the myocytes adjacent to thesource [13–15]. Consequently, there is AP prolongation inregions adjacent to the site of altered activation, andshortening in distal regions [15]. The altered repolariza-tion gradients that develop probably cause a change in T-wave polarity. Electrotonus occurs within minutes afteronset of altered activation and serves as a trigger forelectrical remodeling (i.e. ion channel changes). Themechanisms responsible for specific ion-channel remodel-ing in response to electrotonus is an active area of investi-gation. For example, attenuation of the epicardial phase 1notch is evident within minutes after the onset of alteredactivation [14,16]. This is due to a decrease in the transientoutward K+ current (Ito) in myocardial regions adjacent tosite of altered activation [17]. The importance of Ito remo-deling in short-term cardiac memory is supported by theobservation that treatment with the Ito blocker 4-amino-pyridine prevents short-term memory, and that neonataldogs which lack Ito are resistant to cardiac memory [17,18].

Another important consequence of altered electrical ac-tivation is changes in the mechanical contractile propertiesof the heart, a process known as stretch-dependent remo-deling [19]. Specifically, myocardial regions adjacent to thesite of altered activation exhibit reduced mechanicalstrain, whereas distal regions are under significantly great-er strain [8,19]. Our laboratory recently investigatedwhether the changes in regional mechanical straininduce electrical remodeling through a mechano-electrical

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feedbackmechanism. Interestingly, we found that the mostsignificant AP remodeling took place in myocardial regionsthat were under enhanced mechanical strain [8]. Thesefindings were also evident in the pacing-induced model ofdyssynchronous HF, in which the late-activated lateral leftventricle region exhibits themost significantAP remodeling[20]. Furthermore, recent studies have revealed that shortperiods of mechanical stretch can also induce cardiac mem-ory [21]. These observations suggest an important role formechanical strain/stretch in inducing cardiac electricalremodeling.

Myocardial stretch is a potent stimulus for the localrelease of angiotensin II, and treatment with angiotensin-receptor blockers attenuates the development of ‘short-term’ memory [22,23]. Importantly, angiotensin II wasrecently shown to decrease Ito in isolated epicardial myo-cytes. Following incubation with angiotensin II, Ito densitywas reduced with altered kinetics, and attenuation of thephase 1 notch was evident in epicardial myocytes [23].Furthermore, the angiotensin II type 1 receptor (AT1)colocalizes with the a subunit (Kv4.3) of the channelcarrying Ito, and exposure to angiotensin II causes inter-nalization of the AT1–Kv4.3 complex [24]. Angiotensin IIalso controls b-subunit (KChIP2) expression throughCREB-mediated transcriptional regulation [25–27]. There-fore, angiotensin-converting enzyme (ACE) inhibitors orangiotensin receptor blockers could have a beneficial rolein prevention of cardiac memory.

In contrast to short-term memory, the ionic bases ofchronic remodeling are complex and involve altered out-ward K+ currents, inward Ca2+ currents, and changes inthe quantity and distribution of cardiac gap junctions. Theremodeling of the early-activated region following long-term pacing has been extensively studied; however,changes in the late-activated region remain to be fullyelucidated. In long-term memory, remodeling of Ito resultsin a decreased current density, altered activation threshold(i.e. more positive), and delayed recovery from inactivation


[17]. Furthermore, the rapid component of the delayedrectifier current (IKr) is remodeled in ‘long-term’ memory[28]. Specifically, the normal transmural gradient of great-er IKr in the epicardium compared to the endocardium isreversed in long-term memory [28]. In addition to theremodeling of outward K+ currents, long-term memory isassociated with remodeling of the inward L-type Ca2+

current (ICa,L) [29]. Indeed, treatment with L-type Ca2+-channel blockers has been shown to attenuate both short-and long-term cardiac memory [29]. Interestingly, only inlong-term cardiac memory is the function of the L-typeCa2+ channel remodeled, and thus the role of ICa,L in short-term memory is not clear. In long-term cardiac memoryICa,L activates at a more positive membrane voltage, andrecovery from inactivation is prolonged; both effects willprolong AP duration (APD) [29]. It is postulated that themechanisms responsible for these changes in ICa,L aresecondary to the reduction of KChIP2, which has recentlybeen shown to be an accessory subunit for the L-type Ca2+

channel [30].Furthermore, Patel et al. demonstrated remodeling of

the gap-junction protein connexin 43 (Cx43) followingprolonged RV pacing [31]. They found reduced Cx43 ex-pression primarily in the early activated myocardial seg-ments. By contrast, Spragg et al. showed that Cx43 proteinexpression is not decreased in the late-activated myocar-dial segments, but its localization is lateralized with areduction in conduction velocity in these regions [32].The mechanisms responsible for Cx43 remodeling remainunclear, but angiotensin II has been suggested to be amodulator of Cx43 in cardiac memory. Whether experi-mental agents that augment gap junction conduction willhave a role in attenuating cardiac memory remains to beexplored.

In summary, primary electrical remodeling takes placein response to alteration in the pattern of electrical activa-tion (Figure 2). These changes alter electrotonic flow andmyocardial strain throughout the heart, triggering distinctmyocardial remodeling in the early-activated versus late-activated regions. Electrotonic remodeling is apparent inearly-activated regions, whereas mechanical strain-depen-dent remodeling takes place in the late-activated regions.These triggers underlie remodeling of repolarization viachanges in the expression and function of multiple ioniccurrents and gap junctions. Moreover, angiotensin II isimportant in the transduction of altered myocardialstretch into remodeling of ionic currents and gap junctions.It is likely that other mechanisms are also involved inregulating primary electrical remodeling, and this is anactive area of investigation. The molecular mechanismsdriving remodeling of ionic currents and gap junctions incardiac memory remain unclear. However, it was recentlyshown that the remodeling of KChIP2 (accessory subunit ofIto and ICa,L) in cardiac memory is mediated through thetranscription factor CREB [33]. Furthermore, CREB ex-pression is modulated by both angiotensin II binding to theAT1 receptor and by the intracellular actions of Ca2+ [33].Finally, this could explain why treatment with both angio-tensin receptor and L-type Ca2+-channel antagonists canattenuate the development of cardiac memory. Futurestudies that examine ionic and calcium-handling remodel-

ing in regions after primary electrical remodeling willprovide important insights into common molecularmechanisms.

Secondary electrical modelingOne of the most devastating manifestations of cardiovas-cular disease (e.g. HF myocardial infarction) is SCD sec-ondary to fatal arrhythmias. The mechanisms responsiblefor these arrhythmias are complex and involve electricalremodeling of the myocardium in response to a structuralinsult, referred to as secondary electrical remodeling(Figure 2). In particular, secondary electrical remodelinginvolves alterations of numerous ion channels, excitation–

contraction (EC)-coupling [i.e. altered sarcoplasmic reticu-lum (SR) Ca2+ cycling], and intercellular gap junctions.One of the hallmarks of secondary electrical remodeling isrepolarization abnormalities, specifically a prolongation ofAPD. The ionic mechanisms responsible for remodeling ofthe cardiac AP involve a complex interplay between alteredoutward K+ currents (Ik), inward Ca2+ currents (ICa) andthe late component of the inward Na+ current (INa). Inaddition to altered current densities, the spatial distribu-tion of IK, ICa and INa are altered, most notably in HF.These changes markedly alter normal repolarization gra-dients in the heart and can contribute to the developmentof abnormal heart rhythms (arrhythmogenesis) [34]. It isimportant to note that secondary electrical remodeling isnot restricted to ventricular myocytes but is frequentlyseen in Purkinje cells and the atrial myocardia. In fact,electrical remodeling of Purkinje cells is believed to pro-duce a substrate that is particularly prone to the develop-ment of triggered ventricular arrhythmias [35]. Inaddition, electrical remodeling of atrial myocytes increasessusceptibility to atrial arrhythmias such as atrial fibrilla-tion [36].

As with primary electrical remodeling, downregulationof Ito is one of the most reproducible events during second-ary electrical remodeling in the ventricle [37]. The primaryeffect of diminished Ito on the AP is a slowing of earlyrepolarization, primarily changing the shape of the APwith variable effect on APD. By contrast, the delayedrectifier K+ currents (i.e. IKr and IKs) are largely responsi-ble for phase 3 repolarization in cardiomyocytes. In sec-ondary electrical remodeling, changes in IK1, IKr and IKs

are variable and appear to be related to the underlyingcause of electrical remodeling (i.e. ischemic vs non-ische-mic cardiomyopathy) [38]. Recently it was shown thataltered expression of microRNAs might explain some ofthe IK changes seen in secondary remodeling [39,40]. Inparticular, miR-133 expression was shown to be increasedin the diabetic heart. Importantly, it was shown that miR-133 acts to inhibit translation of HERG (a subunit of IKr)[39]. In a separate study, miR-1 expression was increasedin the infarcted heart, causing inhibition of Kir2.1 (asubunit of IK1) [40]. These microRNAs represent excitingnew therapeutic targets for the management of secondaryremodeling and its associated risk of arrhythmia.

Pharmacological blockade of IK has shown limited prom-ise in the management of arrhythmia risk in secondaryelectrical remodeling. By contrast, exciting new preclinicaltrials have shown promise for gene therapies targeting IK

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in secondary remodeling. In a porcine model, focal genetransfer in the border zone of myocardial infarction tosilence IKr has been shown to abolish ventricular arrhyth-mias [41]. Moreover, overexpression of mir-1 and miR-133was shown to decrease the risk of arrhythmias in models ofdiabetes and myocardial infarction, respectively [39,40].

Increasing evidence demonstrates that increased ICa,Ldensity is an important mechanism for APD prolongationin mild to moderate hypertrophy [42]. However, in severehypertrophy and HF, ICa-L is unchanged or decreasedcompared to control, highlighting the complexity of APDprolongation in HF. Themost common alteration of ICa,L inHF is delayed ICa,L inactivation, secondary to diminishedCa2+-dependent inactivation. For example, the amount ofCa2+ released from the sarcoplasmic reticulum is dimin-ished in HF, which results in diminished Ca2+-dependentICa,L inactivation. Also, Wang et al. [43] recently demon-strated that the slowed ICa,L inactivation in HF requiresCa2+-calmodulin-dependent kinase (CAMKII). Interest-ingly, animal models of HF have enhanced/re-expressionof fetal T-type Ca2+ current (ICa,T). It is postulated thatICa,T might enhance cardiac automaticity in HF [44,45].Unfortunately, clinical trials investigating the use of L-type Ca2+ channel antagonists in humans have failed toshow a mortality benefit or reversal of secondary electricalremodeling [46].

Remodeling of INa is variable in HF, with reports ofincreased, unchanged and decreased peak INa [36]. Thesechanges have very little impact on APD: instead theseprimarily alter conduction velocity. By contrast, the latecomponent of the INa,L, which accounts for only 1% of peakINa, is increased in HF. Importantly, increased INa,L (asoccurs in patients with long QT syndrome type III) canincrease APD in HF, thereby contributing to arrhythmo-genesis in HF. Therapies targeted at blocking INa,L haveshown promise in the management of secondary remodel-ing, and this is an active area of investigation [47,48].

The sodium–calcium exchanger (NCX) is an electrogen-ic, bidirectional transporter (moving three Na+ ions acrossthe membrane in exchange for one Ca2+ ion). In mild tomoderate hypertrophy NCX expression is increased butINCX is decreased. Increased NCX expression in hypertro-phy is hypothesized to bemediated by calcineurin [49], andaltered targeting of NCX to the sarcolemma is postulatedto cause decreased INCX. By contrast, NCX expression andfunction are increased in HF; these have been linked to thedevelopment of delayed afterdepolarizations (DADs) andtriggered ventricular arrhythmias [50]. The role of phar-macological blockade of NCX in the management of sec-ondary electrical remodeling is unknown because there areno INCX blockers available for clinical use at this time.Preclinical investigation of the selective NCX blocker SEA-0400 has shown mixed results in the management ofsecondary electrical remodeling [51].

Abnormal Ca2+ handling is a hallmark of altered ECcoupling in secondary electrical remodeling, resulting indecreased contractile force, impaired relaxation, and in-creased susceptibility to ventricular arrhythmias. Im-paired sarcoplasmic reticulum (SR) Ca2+ release iscaused by impaired gating properties of the ryanodinereceptor (RyR) complex, with variable alteration in RyR

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protein expression [52]. The exact mechanisms underlyingabnormal RyR Ca2+ are complex and probably involvemultiple pathways. For example, hyperphosphorylationof RyR causes a loss of FKBP12.6–RyR binding, and thishas been shown to increase RyR Ca2+ leak [53]. BothCAMKII and cAMP-dependent kinase (PKA) phosphory-late RyR, but there remains debate over which is thepredominant pathway mediating RyR leak in secondaryelectrical remodeling [53–57]. In addition, other mechan-isms including oxidative stress and altered S-nitrosylationof the RyR have been implicated in enhanced RyR Ca2+

leak [58,59]. For example, reduced S-nitrosylation of RyRenhances diastolic calcium sparks in isolated myocytes.However, the mechanisms responsible for this observationare controversial. Whether enhanced RyR Ca2+ leak ordiastolic calcium sparks in isolated myocytes translateto arrhythmogenesis in the intact heart is an active areaof investigation. Spontaneous diastolic SR Ca2+ release inthe intact heart can cause DADs via INCX. Importantly,abnormal RyR release properties have been linked toDADs and triggered ventricular arrhythmias [60]. Howev-er, enhanced RyR Ca2+ leak in isolation is unlikely to besufficient to produce arrhythmias in the intact heart.Increasing evidence indicates increased SR Ca2+ loadingis necessary for enhanced RyR Ca2+ leak to produce ar-rhythmia [61].

Impaired SR Ca2+-reuptake is a common finding insecondary electrical remodeling and is related to decreasedsarcoplasmic reticulum Ca2+ ATPase (SERCA2a) expres-sion and function [62]. Also, decreased phosphorylation ofphospholamban (PLB) secondary to reduced b-adrenergicsensitivity enhances PLB inhibition of SERCA2a. There isincreasing evidence that decreased SERCA2a expressionand/or function enhances arrhythmia risk [63–65]. In par-ticular, our laboratory recently showed that SERCA2aexpression is an important mechanism in the developmentof arrhythmogenic cardiac alternans. Moreover, increasingSERCA2a expression suppresses cardiac alternans andreduces arrhythmia susceptibility.

Therapies targeting abnormal SR Ca2+ handling are notcurrently available in clinical practice. However, preclini-cal trials have shown promise for therapies targeting RyRand SERCA2a function [66,67]. Abnormalities in EC cou-pling increase both arrhythmia risk and cause contractiledysfunction and therapies targeting these abnormalitieshave great potential to ameliorate the effects of bothstructural and electrical remodeling.

Gap junctions provide low-resistance electrical couplingbetween adjacent cardiac myocytes and allow movement ofions and small molecules between cells. The intercellularchannel of gap junctions is composed of two hemi-channelconnexons each composed of six connexin protein subunits.Connexin 43, the major subtype of connexin in the ventri-cles, exhibits heterogeneous expression throughout theheart. These heterogeneities are important in defining re-gional differences in electrophysiological properties withinthe heart [68]. Importantly, remodeling of gap junctions hasbeen demonstrated in multiple models of secondary electri-cal remodeling and has been linked to arrhythmia risk[69–72]. InHFboth lateralization and decreased expressionof connexin43 (Cx43), the major subtype of connexin in the


ventricle, have been described. Decreased expression andlateralization of Cx43 decreases conduction velocity andincreases dispersion of repolarization, both of which pro-vide the substrate for arrhythmias. Therapies targetinggap junctions are an active area of investigation, but thesehave not yet reached clinical testing. However, a peptidedesigned to enhance gap junction conduction, rotigaptide,was shown in preclinical testing to reduce susceptibility toarrhythmogenic cardiac alternans [73]. These observa-tions highlight the potential for therapies targeting gap-junction remodeling.

Concluding remarksElectrical remodeling of the heart takes place in responseto both functional (i.e. altered electrical activation) andstructural (i.e. HF, myocardial infarction) stressors. Theseelectrophysiological changes produce a substrate that isprone to malignant ventricular arrhythmias. Understand-ing the cellular and molecular mechanisms of electricalremodeling is important in elucidating potential therapeu-tic targets designed to alter maladaptive electrical remo-deling. The development of such therapies couldrevolutionize the management of malignant arrhythmias.

AcknowledgmentsThis work was supported by grant RO1-HL54807 from the US NationalInstitutes of Health.

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