Molecular Basis of Arrhythmias Manish Shah, Fadi G. Akar ...tibbits/courses/K812/Circ-Review05.pdf · Molecular Basis of Arrhythmias Manish Shah, MD; Fadi G. Akar, PhD; Gordon F

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DOI: 10.1161/CIRCULATIONAHA.104.494476 2005;112;2517-2529 Circulation

Manish Shah, Fadi G. Akar and Gordon F. Tomaselli Molecular Basis of Arrhythmias

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Molecular Basis of ArrhythmiasManish Shah, MD; Fadi G. Akar, PhD; Gordon F. Tomaselli, MD

Abstract—The characterization of single gene disorders has provided important insights into the molecular pathogenesisof cardiac arrhythmias. Primary electricalal diseases including long-QT syndrome, short-QT syndrome, Brugadasyndrome, and catecholaminergic polymorphic ventricular tachycardia have been associated with mutations in a varietyof ion channel subunit genes that promote arrhythmogenesis. Pathological remodeling of ionic currents and networkproperties of the heart critical for normal electrical propagation plays a critical role in the initiation and maintenance ofacquired arrhythmias. This review focuses on the molecular and cellular basis of electrical activity in the heart undernormal and pathophysiological conditions to provide insights into the fundamental mechanisms of inherited andacquired cardiac arrhythmias. Improved understanding of the basic biology of cardiac arrhythmias holds the promise ofidentifying new molecular targets for the treatment of cardiac arrhythmias. (Circulation. 2005;112:2517-2529.)

Key Words: arrhythmia � electrophysiology � genetics � ion channels � molecular biology

Normal heart rhythm requires the finely orchestratedactivity of a number of ion channels and transporters

and the orderly propagation of electrical impulses throughoutthe myocardium; disruption of either can have severe conse-quences, resulting in potentially lethal heart rhythm distur-bances. Indeed, it is surprising that arrhythmias do not occurmore frequently in the setting of structural heart disease,which results in a host of electrophysiological changes thatrender the heart more vulnerable to electrical instability. Thisreview focuses on the molecular and cellular basis of excit-ability, conduction, and electrical recovery in the heart undernormal and pathophysiological conditions, with the goal ofproviding insights into the fundamental mechanisms of car-diac arrhythmias and the identification of appropriate targetsfor antiarrhythmic therapy.

Molecular and Cellular Basis ofCardiac Excitability

Ion channels are multisubunit transmembrane protein com-plexes that perform the seemingly paradoxical task of medi-ating the exquisitely selective flux of millions of ions persecond across cell membranes. These macromolecules are thefundamental functional units of biological electricality in allexcitable cells. In the past 2 decades most of the relevant ionchannel genes encoding the major or pore-forming (�)subunits and many of the ancillary (�) subunits correspond-ing to ionic currents in the heart have been cloned, sequenced,and functionally characterized (Figure 1). A growing numberof inherited arrhythmias have been linked to mutations in ionchannel subunit genes. Other heritable cardiac diseases thatalter the structure of the heart may change the level ofexpression or function of 1 or more of these ion channelgenes, enhancing the risk of arrhythmias. Many of these ion

channel subunits serve as molecular targets for drugs used inthe treatment of cardiovascular diseases. We are just begin-ning to discover that subtle variations in gene sequences thatoccur in a significant proportion of the population (ie,polymorphisms) may dramatically and potentially lethallyalter the response to drugs that act on ion channels.1,2

Myocardial cells have a characteristically long actionpotential that is sculpted by the orchestrated activity ofmultiple ion channels and transporters (Figure 2). Depolariz-ing currents, primarily sodium and calcium, are responsiblefor the action potential upstroke and maintenance of theaction potential plateau, and repolarizing currents, primarilypotassium, in concert with a reduction in depolarizing cur-rents are responsible for restoration of the resting membranepotential (��80 mV). A number of electrogenic transporterscontribute to the action potential profile; the magnitude anddirection of the current depend on the transmembrane voltageand concentration gradient of the ions being transported.

Rare Disease Paradigm: MonogenicElectric DiseasesPrimary electrical diseases of the heart refer to rare inheritedcardiac arrhythmias in the absence of structural abnormalitiesof the heart that are associated with mutations in ion channelgenes. The long-QT syndrome (LQTS), short-QT syndrome(SQTS), Brugada syndrome, and catecholaminergic poly-morphic ventricular tachycardia (CPVT) are primary electri-cal diseases and constitute a significant minority of cases ofsudden cardiac death (SCD) in the young (Table). Importantinsights into the pathogenesis of cardiac arrhythmias havebeen gleaned from the molecular characterization of mono-genic inherited arrhythmia syndromes. The ion channel basisof congenital LQTS was verified with the discovery of

From the Department of Medicine, Johns Hopkins University, Baltimore, Md.Correspondence to Gordon F. Tomaselli, MD, Department of Medicine, Johns Hopkins University, Division of Cardiology, 844 Ross Bldg, 720 Rutland

Ave, Baltimore, MD 21205-2196. E-mail [email protected]© 2005 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.104.494476

2517

Basic Science for Clinicians



disease-causing mutations in KCNH2 (hERG) and SCN5A(Nav1.5), the genes encoding the cardiac delayed rectifier(IKr) and sodium (INa) currents, respectively. The recentidentification of overlap syndromes with mutations in a singlegene producing distinct inherited arrhythmias (eg, mutationsin SCN5A producing LQTS and Brugada syndrome) furtheradds to the phenotype complexity of the rare monogenicarrhythmia syndromes. This may be the result of interactionsof the expressed genes with the environment or the effect ofother “modifier genes” that alter the susceptibility of anindividual to the expression of a specific phenotype.

Mutations in ion channels have also been implicated inmultisystem disorders associated with abnormal ventricularrepolarization and an enhanced risk of SCD, such asAndersen and Timothy syndromes.3,4 Heritable forms ofstructural ventricular disease may be associated with atrialarrhythmias and an increased risk of SCD. These disordersinclude hypertrophic and dilated cardiomyopathies and ar-rhythmogenic right ventricular dysplasia, which have been

linked to mutations in sarcomeric, cytoskeletal, and intercel-lular junction proteins, respectively. Linking these syndromesto their genetic and molecular basis not only offers thepractitioner tools to accurately diagnose rare disorders butalso provides novel markers for assessing risk of SCD.Unfortunately, more far-reaching screening strategies, riskstratification schemes, and molecular therapeutics have beenlimited by the unexpectedly wide spectrum of clinical phe-notypes associated with even single gene abnormalities.

The mechanisms of arrhythmias associated with mutationsin ion channel genes are relatively straightforward comparedwith rhythm disturbances that occur in the context of acquiredstructural heart disease. Altered functional expression of ioniccurrents, often referred to as electrical remodeling, is prom-inently associated with arrhythmias in complex polygenicdisorders such as atrial fibrillation (AF) and ventriculararrhythmias associated with heart failure (HF) and myocar-dial ischemia/infarction. For example, the electrical remod-eling characteristic of the failing heart enhances the predis-

Figure 1. K� channel assembly. a, FourKv �-subunits (each with 6 transmem-brane domains). b, �-Subunit proteinsmay be cytoplasmic proteins or trans-membrane spanning proteins that inter-act with �-subunits. c, �-Subunits tet-ramerize to form a K�-selectiveholochannel. �-Subunit proteins interactwith �-subunits in various stoichiometricratios to modulate channel function.

Figure 2. Depolarizing and repolarizingionic currents that underlie ventricularand atrial action potentials (AP) in humanheart. Each phase of the action potentialis labeled. A schematic of the timecourse of each current is shown, and thegene/(gene product) that underlies thecurrent is indicated.

2518 Circulation October 18, 2005



position to both atrial5 and ventricular6 arrhythmias andincreases the risk of lethal proarrhythmic complications ofantiarrhythmic drugs.

LQTS and Other Syndromes ThatAlter RepolarizationCongenital LQTS is an inherited disorder characterized byprolonged ventricular repolarization on the ECG (ie, QTprolongation) and a predilection for ventriculartachyarrhythmias. Syncope and sudden death in LQTS pa-tients may result from a distinctive polymorphic ventriculartachycardia (VT) called torsades de pointes (TdP). Thispolymorphic VT has a characteristic undulating axis that candegenerate into ventricular fibrillation (VF), culminating indeath. TdP is commonly initiated with abrupt increases insympathetic tone as might occur with fright, emotionaldistress, or physical activity. It has been suggested thattriggers may be genotype specific.

The prevalence of LQTS is estimated to be between 1 in3000 to 5000 individuals, with onset of symptoms typicallyoccurring within the first 2 decades of life. LQTS has a widespectrum of presentations, ranging from marked prolongationof the QT interval and recurrent syncope to subclinical formswith borderline QT prolongation and no arrhythmias.7 Per-haps the most difficult challenge in managing patients withLQTS is assessing their risk for SCD. Even now in thepostgenomic era, clinical features such as congenital deaf-ness, a prior history of syncope and/or tachyarrhythmia,female gender, family history of SCD, and the degree of QTprolongation are important determinants of the risk of SCD.8

In 1995, through a combination of positional cloning andcandidate gene approaches, Keating and colleagues9,10 de-scribed mutations in ion channel genes in the autosomaldominant form of LQTS. Over the last decade, hundreds ofdistinct mutations in disease genes at 6 additional loci havebeen linked to the LQTS. Of the 6 disease genes that havebeen identified, 2 encode K� channel �-subunits, 2 encode

K� channel �-subunits, and 1 encodes the voltage-gated Na�

channel. Recently, a mutation in ankyrin B (ANK2), ascaffolding protein, has been described in LQTS4, the onlynonchannel disease gene described,11 although this proteinclearly influences the functional expression of a number ofion channel and transporter proteins.

LQTS is characterized by genetic heterogeneity. Alteredexpression and/or function of ion channel subunits couldresult in action potential prolongation by either enhancingdepolarizing or reducing repolarizing currents. The details ofthe changes depend on the specific genotype, but the finalcommon pathway is action potential prolongation and de-creased repolarizing reserve, resulting in a diminished capac-ity of the ventricular cell to respond to additional stresses thatimpair repolarization such as hypokalemia, hypomagnesemia,and drugs with class III antiarrhythmic action.

Na� and K� currents have disparate effects on the actionpotential duration: increases in INa tend to depolarize themyocyte and therefore lengthen the action potential; alterna-tively, reduced K current also lengthens the action potential.The molecular genetics of LQTS are consistent with thefunctional effects on the ion channel genes; mutations inSCN5A tend to increase function (gain-of-function muta-tions), whereas mutations in K� channel genes reduce oreliminate the function of the gene product or alter itstrafficking to the cell membrane. In some cases, mutantchannels retain the ability to combine with normal subunitsand in doing so render the holochannel nonfunctional andtherefore reduce the pool of functional subunits from whichintact functional K� channels can be synthesized (dominantnegative effect). In fact, as predicted by the autosomaldominant inheritance, only 1 copy of the mutated gene isnecessary to produce the clinical syndrome.

The rapid and slow components of the delayed rectifierpotassium current IKr and IKs are critical to phase 3 (Figure 2)of the ventricular action potential and are mutated in differentforms of LQTS. IKs is formed by the coassembly of the

Primary Electric Diseases Producing Ventricular Arrhythmias

Chromosome Gene Protein Frequency SCD Incidence Inheritance Pattern LQTS

LQTS

LQT1 11p15 KCNQ1 KvLQT1 (IKs) �50% 0.30%/y AD, AR

LQT2 7q35 KCNH2 hERG (IKr) 30–40% 0.60%/y AD

LQT3 3p21 SCN5A Na channel 5–10% 0.56%/y AD

LQT4 4q25 ANK2 Ankyrin B Rare AD

LQT5 21q22 KCNE1 minK (IKs) Rare AD/AR

LQT6 21q22 KCNE2 MiRP1 (IKr) Rare AD

LQT7 17 KCNJ2 IK1 Rare AD

SQTS

SQTS 7 KCNH2 hERG (IKr) Rare AD

SQTS 11 KCNQ1 KvLQT1 (IKs) Rare AD

Idiopathic VF (Brugada syndrome) 3 SCN5A (�30) Na channel AD

CPVT

CPVT1 1q42–43 RYR2 Cardiac ryanodine receptor AD

CPVT2 1p11-p13.3 CASQ2 Calsequestrin AR

CPVT3? ? ? ? AD

AD indicates autosomal dominant; AR, autosomal recessive.

Shah et al Molecular Basis of Arrhythmias 2519



KCNQ1 (KVLQT1) and the KCNE1 (minK accessory sub-unit) gene products. KCNE1 is 1 of 2 genes on chromosome21 mutated in LQTS. Mutations in KCNQ1 and KCNE1 arealso associated with the Jervell Lange-Nielsen (autosomalrecessive) variants of LQTS.

LQTS2 is caused by mutations in a potassium channelknown as the human ether a-go-go–related gene (hERG),which is encoded by KCNH2 after the effects of the gene onDrosophila. hERG putatively combines with MiRP-1 en-coded by KCNE2 to generate IKr

12; mutations in KCNE2 mayalso produce LQTS. IKr is the target of a number of clinicallyimportant antiarrhythmic drugs with so-called class III (QT-interval prolonging) action, such as sotalol, dofetilide, andamiodarone. The hERG channel also has a cyclic nucleotidebinding domain in its C-terminus providing a link to theadrenergically mediated triggering of arrhythmic events.Mutations or polymorphisms in KCNQ1, KCNE1, KCNE2,and KCNH2 have been associated with autosomal dominantand recessive forms of LQTS13 and apparently acquired,drug-induced TdP.

Andersen syndrome is a rare sporadic or autosomal dom-inant disorder characterized by periodic paralysis, cardiacarrhythmias, short stature, scoliosis, clinodactyly, and dys-morphic facies.14 Patients with Andersen syndrome exhibit anumber of ventricular arrhythmias including TdP and bidi-rectional VT, thus sharing an electrophysiological functionaldefect with the canonical forms of LQTS. Mutations inKCNJ2, the gene that encodes the �-subunit of the inwardrectifier K� channel (Kir2.1), have been identified in severalfamilies with this syndrome.3 Hence, an ion channel that isessential for normal cardiac excitability also appears to playa critical role in development.

Timothy syndrome is a rare sporadic disorder characterizedby multiorgan dysfunction, including cardiac arrhythmias,congenital heart disease, syndactyly, immune deficiency, andautism. Patients with Timothy syndrome exhibit severe pro-longation of QT interval and have a predilection for life-threatening ventricular arrhythmias. De novo missense muta-tions in the L-type Ca2� channel �-subunit, Cav1.2, that havebeen described in Timothy syndrome result in maintainedinward Ca2� currents by causing nearly complete loss ofvoltage-dependent channel inactivation.4 This gain-of-function mutation results in prolongation of the cardiac actionpotential and likely serves as the mechanism for arrhythmiasusceptibility.

The importance of correlating protein function with spe-cific mutations and clinical phenotype is illustrated by theKCNQ1 gene mutation resulting in a gain of function of IKs,leading to accelerated repolarization, short QT intervals, andSCD.15 Mutations in the KCNQ1 gene have now beenassociated with 3 diseases including LQTS, SQTS, andfamilial AF. To add to the complexity of genotype-phenotypecorrelation is the description of a single large family withnocturnal death, ECG features of LQTS, and familial idio-pathic VF. Genetic analysis revealed an identical mutation inthe cardiac Na� channel in affected individuals that wasassociated with an overlap syndrome exhibiting features ofboth LQTS and idiopathic VF.16 Experimental and simulationstudies of this SCN5A mutation suggest mechanisms that may

produce both electrophysiological phenotypes.16,17 Such stud-ies highlight the hazards of predicting phenotype on the basisof grouping of mutations by genetic loci or by associationwith a single gene mutation.

TdP leading to SCD remains the most feared manifestationof LQTS. Reduced repolarization reserve due to previouslydescribed ion channel mutations contributes to action poten-tial prolongation. The extended plateau phase results inrepolarization instability; thus, slight increases in depolariz-ing current can generate secondary depolarizations during theplateau or early repolarization phases of the action potentialknown as early afterdepolarizations (EADs).18 The resultingEADs may initiate polymorphic VTs.19 Well-described spa-tial differences in action potential duration or dispersion ofrepolarization have been proposed as a mechanism for TdPresulting from functional reentry (Figure 3). Spatial differ-ences in action potential duration create pockets of inexcit-able myocardium (secondary to extended refractory periods)that form regions of block and promote reentrant arrhythmias.Pharmacological models of LQTS have shown exaggerateddispersion of repolarization across the transmural wall, lead-ing to local block and polymorphic reentrant arrhythmias.19,20

EAD-mediated triggered activity and functional reentry arenot mutually exclusive mechanisms, and both may contributeto the genesis of TdP.

Brugada SyndromeIdiopathic VF in the setting of right ventricular ECG abnor-malities and the absence of structural heart disease is oftenreferred to as Brugada syndrome. The syndrome of suddendeath with unexplained right precordial ECG abnormalitieswas described as early as the 1950s.21 In the 1990s, Brugadaand Brugada22 described a cohort of patients that had noapparent structural heart disease, right ventricular ECG ab-normalities, and a propensity to die suddenly. It is nowrecognized that idiopathic VF with right precordial ECGabnormalities is worldwide in distribution, with a highprevalence in Southeast Asia,23,24 where it exhibits a strikingmale predominance (8:1),23 distinct from that in Westerncohorts.25,26 Idiopathic VF is a highly lethal disease with a40% survival at 5 years in high-risk patients.25–27

Patients with Brugada syndrome exhibit a spectrum ofright precordial ST abnormalities in leads V1 through V3 frommost (type I) to least (type III) severe in both appearance andprognosis. An ST-segment pattern is referred to as spontane-ous if it is present on the resting ECG; however, the ECGchanges are dynamic, and patterns may vary in the samepatient. Thus, repeated recordings may be required to makethe diagnosis. Antiarrhythmic drugs with class I action(flecainide, procainamide, ajmaline) have been used to un-mask and exaggerate the ST-segment changes in IVF.

The Brugada syndrome has been linked to mutations in theNa� channel �-subunit, SCN5A,28 but the syndrome is genet-ically heterogeneous. In the largest genotyped cohort reportedto date, only 42% of 200 subjects (probands and familymembers) and only 20% of probands harbored SCN5Amutations.25 There have been �30 different mutations inSCN5A that have been associated with Brugada syndrome. Aconsistent theme has been the functional reduction in peak




Na� current; however, mutations have been described thatproduce overlap syndromes of Brugada syndrome and LQTSassociated with multiple defects in channel function.16 Theproposed mechanisms of the ECG abnormalities and arrhyth-mia induction in the SCN5A-linked forms of Brugada syn-drome involve the imbalance of ionic currents during phase 1repolarization. The deep phase 1 notch in the epicardial actionpotential, particularly prominent in the right ventricle, rendersit susceptible to the effects of a reduction in the Na� current.The reduction in Na� current establishes a steep voltagegradient across the right ventricular wall (J-point elevationand ST-segment changes) due to short-circuiting of theepicardial action potential with extreme shortening. Theimbalance of currents allows for reactivation of the rightventricular epicardium by neighboring regions of myocardi-um, with longer action potentials producing functional reen-try, commonly referred to as phase 2 reentry.29 Support forthis hypothesis in humans comes from a small study ofmonophasic action potential recordings in patients with Bru-gada syndrome during chest surgery.30

Catecholaminergic PolymorphicVentricular TachycardiaCPVT is a heritable disorder that presents as exercise- orstress-induced ventricular arrhythmias, syncope, or suddendeath. Originally described in children,31 more recent studiessuggest that ventricular arrhythmias may begin in adult-hood.32–34 In patients with CPVT who have been monitoredduring exercise, several types of malignant ventricular ar-rhythmias have been described, including polymorphic VT,bidirectional VT (exhibiting a beat-to-beat alternation of theQRS axis), and VF. This syndrome is genetically heteroge-neous, with both autosomal dominant and autosomal reces-sive transmission. Disease-causing mutations in RYR232,34

and calsequestrin (CSQ)35 have been identified, the former

segregating as dominant and the latter as recessive traits.More than 20 different mutations in functionally importantdomains of RYR2 have already been described in CPVT.32–34

There are a number of families with mutations that do notmap to either the RYR2 or CSQ loci; thus, there is at least 1and probably several additional disease genes associated withthis disorder. RYR2 and CSQ are molecules that are central tonormal Ca2� homeostasis of the cardiac myocyte. Mutationsthat produce functional abnormalities in either of thesemolecules can produce cellular Ca2� overload and lead toarrhythmias induced by abnormalities of repolarizationknown as delayed afterdepolarizations (DADs). DADs occurat the completion of the cardiac action potential and areinitiated by abnormal Ca2� release from the sarcoplasmicreticulum and subsequent activation of a transient inwarddepolarizing current, which drives the transmembrane poten-tial toward 0 mV (Figure 4). Inherited abnormalities in theryanodine receptor or associated proteins have been shown toresult in a leaky sarcoplasmic reticulum and cytosolic cal-cium overload, thus providing a link between abnormalcalcium handling and triggered arrhythmias.36 Notably, HF ischaracterized by abnormalities of calcium handling andincreased sympathetic tone and may also exhibit DAD-induced triggered ventricular arrhythmias.37

Familial Supraventricular Arrhythmias andConduction System DiseaseFamilial forms of AF were first described over 6 decadesago.38,39 Since then, a number of families with heritable AFhave been described. Linkage analysis of 4 families withautosomal dominant AF identified 2 genetic loci, 10q22-q24and 6q14-q16; however, candidate gene approaches have yetto identify specific gene(s).40,41 Recently, several Chinesekindreds with autosomal dominant AF have been linked tomutations in KCNQ1 and KCNE2.42,43 In contrast to LQTS1,

Figure 3. Molecular mechanism of TdP in inherited LQTS. Mutations in ion channel subunits result in reduced repolarizing current lead-ing to action potential duration prolongation, QT interval prolongation, afterdepolarizations, and increased dispersion of repolarization.These factors act to create a proarrhythmic substrate that can result in TdP.




both mutations are associated with a gain of function in abackground current composed of KCNQ1 and KCNE2 in cellexpression systems, predicting shortening of the atrial actionpotential duration, which is consistent with the electricalremodeling observed in rapid atrial pacing–induced AF.44–46

Patients with KCNQ1-associated familial AF did not exhibitQT shortening but instead had modest prolongation of the QTinterval consistent with a divergent effect of KCNQ1 muta-tions on IKs and the background K� current, highlighting theimportance of additional genetic and/or environmental con-tributors to the electrophysiological phenotype.42 Shorteningof the atrial action potential leads to a reduction in thewavelength of conduction through atrial tissue and, in thesetting of inhomogeneous shortening, the possibility forfunctional reentry and or rapid conduction in the setting of aprimary driver (so-called mother rotor47) for AF.

Acquired Arrhythmias: AFIn contrast to rare monogenic arrhythmias, the most frequentcardiac rhythm disorders commonly occur in the context ofstructural heart disease. Acquired arrhythmias are dependenton complex interactions between the myocardial substrateand triggers that define the overall risk of arrhythmia suscep-tibility (Figure 5). The risk of cardiac arrhythmias is in partgenetically determined; population-based studies of suddendeath demonstrate an increased risk of SCD among patientswho have a parental history of cardiac arrest.48,49 The geneticbasis for this increased risk is not limited to variations in thedisease genes implicated in rare inherited arrhythmia syn-dromes. Polymorphisms of genes that alter the structure orexcitability of the arrhythmic myocardial substrate, as well asthose that generate triggers (eg, metabolism and energyutilization, thrombosis, and inflammation), will influencearrhythmic risk.

The single most important factor contributing to the risk ofcommon acquired arrhythmias is the presence of structuralheart disease. For example, myocardial infarction with scarformation and left ventricular dysfunction are both associatedwith dramatic increases in arrhythmia susceptibility. Struc-tural and electrical remodeling in response to myocardialinjury, altered hemodynamic loads, and changes in neurohor-monal signaling can lead to alterations in ion channel func-tion, intracellular calcium handling, intercellular communica-tion, and the composition of the intercellular matrix, all of

Figure 4. DAD-mediated CPVT. Mutations in the ryanodinereceptor (RyR) result in leakage of Ca2� from sarcoplasmic retic-ulum (SR) into cytoplasm. High cytosolic [Ca2�] drives the Na�-Ca2� exchanger (NCX) in the forward mode, resulting in a depo-larizing current that contributes to DAD. Similar mechanismsmay be opertive in HF.

Figure 5. Key elements contributing tothe development of acquired arrhyth-mias. Lethal arrhythmias occur as theresult of multiple “hits” and are the resultof complex gene-environment interac-tions. An individual has a risk based onthe genetic makeup, and that risk isaffected by external stressors, theresponse of the myocardium to suchstressors, and iatrogenic factors.




which conspire to create a substrate for both atrial andventricular arrhythmias. A number of other concomitantfactors, including electrolyte imbalance, neurohumoral acti-vation, pharmacological therapy, and ischemia, can serve astriggers for arrhythmia initiation.

AF is associated with multiple cellular and tissue electro-physiological changes that promote the maintenance andrecurrence of the arrhythmia after cardioversion.50,51 Theprogressive nature of AF lends support to the hypothesis thatelectrical and structural remodeling are key components ofarrhythmogenesis. Several distinct types of remodeling havebeen associated with AF. Atrial tachycardia–induced remod-eling is associated with shortening of atrial refractoriness. Incontrast, atrial remodeling in the aged and failing heart isassociated with prominent fibrosis, producing heterogeneousslowing of conduction velocity in the heart and prolongationof atrial refractoriness. In either case, there is a reduction inthe cardiac wavelength (�), which is defined as the physicaldistance traveled by an electrical impulse in one refractoryperiod and mathematically is the product of the conductionvelocity and refractory period (or action potential duration).Reentry is critically dependent on the wavelength beingshorter than the total length of the reentrant pathway (pathlength). If the wavelength exceeds the path length, reentrycannot be established because as the wavelength approachesthe path length, the wave head encroaches on the refractorytail, resulting in termination of reentrant activation. A reduc-tion in wavelength improves the stability of a reentrant circuitand increases the allowable number of independent reentrantcircuits in a given area of tissue, thereby promoting theconditions necessary for existence of multiple reentrantcircuits.

Three main mechanisms have been proposed for theinitiation and maintenance of AF. Rapid firing from a singleectopic focus (eg, pulmonary veins) can produce atrialtachycardia, AF, and atrial electrophysiological remodelingthat serves to perpetuate AF (“AF begets AF”).51 A singlereentrant circuit or mother rotor may drive activation of theatria with fibrillatory conduction, with the result of interac-tion of the high-frequency activation wave fronts with het-erogeneous atrial tissue generating random propagation of theactivation wave(s), producing characteristically irregularrhythm. Ectopic activation and single reentry circuits mayboth be mechanistically linked through remodeling of theatria to the multiple wavelet mechanism of AF.52 The latter isthe result of a number of distinct electrical circuits activatingthe atria. Indeed, these mechanisms are not mutually exclu-sive. In fact, the multiple wavelet reentry hypothesis has beenproposed as a final common pathway for AF.

Reduced functional expression of L-type Ca2� channels45 isthought to underlie the shortening of action potential durationassociated with tachycardic remodeling of the atria. Reduc-tions in the transient outward current (Ito) and alterations inthe inward rectifier current (IK1) and acetylcholine-sensitiveK� channels (IKACh)53 have been noted in AF models; how-ever, their electrophysiological significance remains un-clear.44,46 The altered functional expression of these ioniccurrents is spatially inhomogeneous, tending to further exag-gerate the electrophysiological heterogeneity of the atria.50,54

Atrial tachycardia may also influence currents that hastenrefractoriness in pulmonary vein myocytes and serve as atrigger or source of AF.55 Disparities in the time course ofshortening of atrial refractoriness and susceptibility toAF suggest that other factors may be important intachycardia-induced atrial remodeling. The importance ofalterations in intracellular Ca2� homeostasis in atrial myocyteremodeling has recently been demonstrated. In a mouse atrialcell line, rapid stimulation in vitro led to reduction ofsarcolemmal L-type Ca2� channel expression and structuralchanges (myolysis and nuclear condensation).56 Studies inhumans suggest that atrial tachycardia remodeling may beclinically significant and to some degree reversible, with bothacute57 and chronic58 normalization of atrial refractorinessand improvement in sinus node function.

The type of atrial remodeling that predisposes to AF iscontext dependent. For example, experimental congestive HFmodels that promote AF are associated with atrial actionpotential prolongation and prominent alterations in conduc-tion, arguing for structural or intercellular ion channel remod-eling as a prominent feature of AF in HF. Fibrosis inter-spersed between myocyte bundles is a prominent feature ofHF-induced AF models. In animal models of AF associatedwith HF, quantitative and qualitative changes in the intersti-tium have been documented. Atrial collagen synthesis isincreased and matrix metalloproteinases are activated inHF.59,60 In fact, in the pacing tachycardia HF model, the atriaexhibit a more intense inflammatory and fibrotic phenotypethan the ventricles.61 Intercellular ion channels or connexinsat gap junctions are major determinants of conduction veloc-ity and directional differences in wave front propagation(referred to as anisotropy). In AF they have been shown to bemore heterogeneously distributed and in some studies de-creased. These spatial heterogeneities in connexin expressionmay contribute to wave front fragmentation and increaseddispersion of repolarization. Some studies have shown thatconnexin40, an isoform prominently expressed in the atrium,is decreased and more heterogeneously distributed in animalmodels of AF,62 although this is not a universal finding.63 Ina recent study, 2 polymorphisms of the human connexin40gene have been linked to indices of increased spatial disper-sion of atrial refractoriness and an increased risk of AF.64

Such changes in tissue architecture and heterogeneities in cellcoupling produce slowed and heterogeneous conduction andmay act to increase dispersion of repolarization, thus creatinga substrate ripe for reentry (Figure 6). Reversal of HF inanimal models has been associated with resolution of ionicremodeling in atrium but persistence of atrial fibrosis andsusceptibility to induced AF.65 Thus, fibrosis appears to besufficient to generate a profibrillatory substrate in the atrium.

The pulmonary veins contain myocytes that are a source ofectopic activity that may trigger or maintain atrial arrhyth-mias in humans. Indeed, isolation of the pulmonary veinsfrom the body of the left atrium has proven to be curative insome patients with AF.66 The diseased atrium is associatedwith both structural and functional remodeling of the pulmo-nary veins. Animal models of tachycardia-induced HF arecharacterized by enhanced susceptibility to atrial tachycardia,with a focal origin often in the pulmonary veins.67 DADs




have been recorded in pulmonary vein myocytes, suggestingtriggered activity related to Ca2� overload as a mechanism ofpulmonary vein ectopic activity68; a relevant molecular cor-relate of DAD-mediated triggered activity is upregulation ofthe electrogenic Na�-Ca2� exchanger in atrial myocytesisolated from failing hearts.69

Several studies support the relevance of the electrophysi-ological remodeling in experimental AF to human arrhyth-mia. Action potential shortening with downregulation of Ca2�

currents has been demonstrated in cells isolated from humanatria.45 Altered atrial refractory period dynamics have beendemonstrated in patients who have undergone induction ofAF under controlled conditions in the electrophysiologylaboratory.57 Patients with HF undergoing electroanatomicmapping exhibit regional conduction disturbances and en-hanced susceptibility to AF.70 Atrial extracellular matrixremodeling in the explanted hearts of patients undergoingcardiac transplantation reveals increased atrial fibrosis, down-regulation of tissue inhibitor of matrix metalloproteinase-2,upregulation of matrix metalloproteinase-2, and an increasedlevel of collagen type I.71 These data suggest that remodelingof tissue structure may constitute a promising target withantifibrillatory action. Angiotensin-converting enzyme inhib-itors will reduce atrial fibrosis and AF inducibility in animalmodels, and post hoc analysis of HF treatment trials suggeststhat angiotensin-converting enzyme inhibitor treatment isassociated with a lower incidence of AF. The utility ofinhibiting the renin-angiotensin-aldosterone pathway awaitstesting in randomized clinical trials.

Acquired Ventricular ArrhythmiasAction potential prolongation is an electrophysiological hall-mark of ventricular myocytes isolated from failing or hyper-trophied hearts, independent of etiology. It is not surprising,however, that different models of ventricular dysfunction areassociated with distinct patterns of remodeling of ion channelfunctional expression. There are at least 2 mechanisms thatserve to explain the prolongation in action potential durationand alteration of action potential dynamics in the hypertro-phied and failing heart, downregulation of repolarizing K�

currents, and alterations in intracellular calcium handling (forreview, see Tomaselli and Marban6).

Functional downregulation of K� currents has been exten-sively documented in human and animal models of HF. Theaggregate electrophysiological effect is a reduction in repo-larization reserve, rendering the ventricular myocardiumsusceptible to EADs and functional reentry resulting fromexaggerated temporal and spatial dispersion of repolarization.Downregulation of each of the major repolarizing K� cur-rents, Ito, IKr, IKs, and IK1, has been described in HF. Thespecific impact on the action potential duration and actionpotential dynamics as well as the molecular mechanisms ofreduction in current density varies depending on the speciesand etiology of HF. Ito is a rapidly activating and inactivatingrepolarizing current that occurs early in the plateau phase andis likely to have an indirect effect on action potential durationthrough its effects on ensuing plateau currents. Computermodels of the cardiac action potential reveal impaired actionpotential duration rate adaptation in cells with diminished Ito,suggesting that sudden changes in heart rate as seen withpremature ventricular contractions can result in enhancedspatial differences in action potential duration.72 IKr and IKs areprominent repolarizing currents active during the plateauphase of the action potential and are altered in HF. Down-regulation of both components of the delayed rectifier hasbeen reported in models of cardiac hypertrophy and HF.73–75

The inward rectifier current, IK1, is responsible for setting theresting membrane potential and contributes to the terminalphase of repolarization. Ventricular myocytes isolated fromfailing human hearts and some animal models of HF demon-strate reduced IK1 density.76,77 In addition to prolongation ofthe action potential duration, alterations in the resting mem-brane current that accompanies reduced IK1 density mayenhance automaticity in failing ventricular myocytes.78

Minor perturbations in depolarizing currents during theplateau phase of the action potential, a period of low currentflow and high membrane resistance, can tilt the balance infavor of secondary depolarizations that result in triggeredarrhythmias. In fact, animal studies of HF in which actionpotential duration prolongation is provoked with pharmaco-

Figure 6. Myocardial remodeling and thedevelopment of AF. In response to HF orrapid pacing, atrial tissue remodels, withchanges in active (cellular) and passive(intercellular) properties. Conductionvelocity (CV) is reduced in congestive HF(CHF), and action potential duration(APD) is shortened with rapid pacing,both of which result in shortening of thecardiac wavelength (�) and the creationof a proarrhythmic substrate (see text fordetails). Cx40 indicates connexin40.




logical agents demonstrate enhanced susceptibility toafterdepolarization-mediated ventricular tachyarrhythmias.79

Abnormalities in intracellular Ca2� handling that charac-terize failing myocardium are responsible for altered ventric-ular mechanics and increased electrical instability. The ven-tricular action potential and intracellular Ca2� homeostasisare linked through a number of mechanisms, includingCa2�-mediated inactivation of the L-type Ca2� channel, acti-vation of a variety of Ca2�-sensitive transporters, and theNa�-Ca2� exchanger. Cells isolated from failing human heartsexhibit no change or a slight decrease in L-type Ca2� currentdensity.76,80–85 Increased Na�-Ca2� exchanger current densityand protein expression have been reported in the ventricles insome models of HF.86,87 Increased Na�-Ca2� exchangercurrent may contribute to the production of arrhythmias byaltering the action potential profile or contributing to thegenertion of DADs and triggered arrhythmias. Indeed, humanHF studies have correlated increased expression of Na�-Ca2�

exchanger protein with increased incidence of DAD-mediated ventricular arrhythmias.88 Preliminary evidencesuggests that selective pharmacological inhibition of theNa�-Ca2� exchanger may be a promising target for correctingcellular excitation-contraction coupling defects89 and reduc-ing triggered activity in HF.90

Alterations in ionic currents that accompany structuralheart disease affect the steady state as well as the dynamicbehavior of the action potential. In response to increased heartrates, myocardial cells dynamically adapt (shorten) theiraction potential duration. Electric restitution refers to thedependence of the action potential duration on the previousdiastolic interval. This dependence is exaggerated in HF suchthat subtle changes in diastolic interval produce markeddifferences in action potential duration,91 accounting for largebeat-to-beat changes in action potential duration or enhancedtemporal lability of repolarization.92 Abnormal electricalrestitution properties have been hypothesized to account forthe transition from stable reentrant monomorphic VT to VF.93

Pharmacological treatment with Ca2� channel blockers andbretylium have been shown to flatten the restitution slope(�1), reduce wave break, and prevent VF.94

Cellular electrophysiological abnormalities are prominentin the structurally diseased heart and are complicated by thepresence of abnormalities of the electrical network propertiesof the heart. The altered composition of the interstitium andintercellular coupling reduce conduction velocity in the fail-ing heart. Slowed conduction velocity leading to shortenedwavelengths and reduced cellular coupling may be an impor-tant contributor to the production of reentrant ventriculararrhythmias in HF. Electrophysiological indices of depressedconduction velocity, including delayed paced ventricularactivation and fractionated electrograms, are observed indiseased hearts at risk for SCD.95–97 The molecular determi-nants of conduction velocity in myocardial tissue include thequantity and pattern of fibrous tissue, the density and distri-bution of gap junctions, and the availability of Na� current,98

all of which are altered in some models of HF. In histologicalstudies of failing human hearts, increased density and patternsof tissue fibrosis correlate with depressed conduction velocityand increased directional differences in wave front propaga-

tion (tissue anisotropy).99 Areas of patchy fibrosis with long,dense groups of strands create isolating barriers and discon-tinuities that may cause unidirectional block, wave break, andreentry.100

In addition to fibrosis, the speed and direction of wave frontpropagation are significantly influenced by the location anddensity of gap junctions. Alterations in the density and distribu-tion of gap junction channel proteins have been described inischemic, hypertrophic, and dilated hearts.98,101,102 Connexin43the major gap junction protein in the ventricle, is redistributedfrom the intercalated disk to the lateral cell border, accounting inpart for abnormal conduction in HF.98,103 Such a change inconnexin expression may promote reentry by slowing conduc-tion velocity and/or uncoupling myocytes. Poor electrotoniccoupling between adjacent cells in the diseased heart contributesto regional inhomogeneities of action potential duration, predis-posing to local conduction block and reentrant excitation.104,105

Alterations in Na� current may also contribute to conduc-tion slowing in the diseased heart. Myocardial infarctionmodels have shown slow conduction and reduced expressionof Na� current in regions adjacent to the infarcted tissueshortly after coronary artery ligation.106 Several chronicinfarction models have been associated with a reduction inNa� current density.107 Further functional and molecularstudies will be required to elucidate the relative contributionof interstitial changes, ionic remodeling, and cell-to-cellcoupling to conduction velocity and arrhythmogenesis.

The manifestations of coronary artery disease create dis-tinct and time-varying changes in the myocardium thatenhance the risk of arrhythmias. The time course of cellularelectrophysiological changes after coronary artery ligationhas been characterized in infarcted tissue and in areas remotefrom the infarct. Clearly, scar formation after myocardialinfarction is a major contributor to arrhythmia susceptibility.However, the healing phase preceding scar formation is alsoassociated with an increased risk of sustained ventriculartachyarrhythmias. The acute electrophysiological response ofcells adjacent to the infarcted territory is progressive short-ening of action potential duration, followed by a return tonear-normal action potential duration by 2 months.108 Cellsisolated from noninfarcted regions demonstrate cellular hy-pertrophy and action potential duration prolongation. Actionpotential duration prolongation is thought to be secondary todownregulation of repolarizing currents and upregulation ofdepolarizing calcium currents (L-type Ca2� current).109,110

Studies of paired myocytes isolated from the epicardialborder zone of a myocardial infarction have shown decreasedside-to-side coupling with no change in overall connexin43expression.111 Heterogeneities in action potential durationand altered coupling between infarct border zone tissue andsurrounding myocardium create a region of conduction slow-ing susceptible to local conduction block necessary forreentrant excitation.

Hibernating myocardium, defined as cardiac tissue withreduced baseline blood flow and contractile dysfunction thatrecovers viability on revascularization, is prevalent in patientswith ischemic cardiomyopathy. In fact, it occurs in as manyas 40% to 60% of patients with ischemic heart disease andcontributes to their relatively high risk of SCD.112,113 Hiber-




nating myocardium is a proarrhythmic substrate that isindependent of myocardial necrosis or scar.114 Studies ofelectrical remodeling in models of hibernating myocardiumhave demonstrated prolonged action potential duration andimpaired intracellular Ca2� handling.115,116 Preliminary stud-ies have noted an increase in the depolarizing L-type Cacurrent; however, evaluation of repolarizing K� currents hasnot been reported.116 Reperfusion of ischemic myocardium,as may occur in patients with coronary artery disease, isassociated with increased susceptibility to VF. Electrophysi-ological cell and tissue properties that characterize ischemicand reperfused myocardium help to rationalize the frequencyof reperfusion arrhythmias. During ischemia there is in-creased intracellular resistance and shortened action potentialdurations in whole-tissue preparations.117 Additionally, highintracellular resistance, caused by gap junction uncoupling,results in poor cell-to-cell electrical coupling and conductionslowing. Soon after reperfusion there is a rapid restoration ofaction potential duration to near-normal durations; however,persistent cellular uncoupling enhances spatial differences inrepolarization between the ischemic and nonischemic zones,thus promoting reentry.118 Consistent with this hypothesis,studies have shown multiple reentrant circuits in the ischemicarea during reperfusion-related VF.119

Clinical ImplicationsNovel strategies that leverage our understanding of molecularmechanisms to identify clinical predictors of SCD continue torapidly evolve. Until recently, genetic screening for primaryelectrical diseases was not available to practitioners outsideof specialized academic centers. In 2005, the FAMILION testwas introduced to screen for selected mutations in Na� andK� channels (SCN5A, KCNQ1, KCNH2, KCNE1, KCNE2).Mutations in these genes are thought to account for 50% to75% of cases of congenital LQTS and 15% to 30% ofBrugada syndrome cases. The most recent study to integrateLQTS genotype as a risk-stratifying parameter characterized647 patients with mutations at the LQTS1, LQTS2, andLQTS3 loci and followed them prospectively for their firstcardiac event (syncope, cardiac arrest, or SCD before age 40years). The incidence of a first cardiac event before age 40years was lowest among those patients with mutations at theLQTS1 locus (30%) compared with those with mutations atthe LQTS2 (46%) locus and LQTS3 (42%) locus.120 Progno-sis was accurately assessed with the use of genotype, gender,and corrected QT interval in patients with LQTS. Althoughpromising, the role of genotyping patients with suspectedinherited cardiac arrhythmias remains controversial becausepatients with single gene mutations often exhibit large vari-ability in phenotypic expressivity. Ultimately, genotypingpatients and family members may be useful prognosticallyand in defining genotype-specific antiarrhythmic therapy.

Antiarrhythmic drugs have exhibited limited efficacy in thetreatment of serious arrhythmias and have often been rele-gated to second-line therapy secondary to proarrhythmic sideeffects in patients with structural heart disease. Despite ourimproved understanding of the molecular basis of inheritedcardiac arrhythmias, pharmacotherapeutic targets to specificchannel proteins have both limited efficacy and liabilities that

relate to the pharmacodynamic properties of the drugs andspatial/temporal heterogeneities in channel expression andtherefore action potential profile and duration. Newer thera-peutic agents may target multiple ion channels and useseveral modes of action. In HF, novel drug design will likelyfocus on ion channels, exchangers, and interacting subunitsthat regulate intracellular calcium as well as proteins andpathways that regulate the constitution of tissue structure.

The generation of cardiac arrhythmias requires the pres-ence of a susceptible myocardial substrate and an appropriatetrigger. Although any heart may serve as a substrate for thedevelopment of a potentially serious cardiac arrhythmia, instructurally normal hearts this is rare and requires highlypotent triggers. Alterations of the cellular and tissue electro-physiological properties of the heart mediate enhanced sus-ceptibility to cardiac arrhythmias. These changes includealterations in conduction and changes in the spatial andtemporal features of electrical recovery reflected in the actionpotential. Changes in the functional expression of ioniccurrents and transporters mediate the changes in actionpotential profile and cellular excitability. Extracardiac influ-ences (eg, neurohumoral activation) may modulate the car-diac substrate and serve as arrhythmia triggers in the settingof structural heart disease. An individual’s genetic makeupwill influence one’s risk of development of an arrhythmia,and in rare cases mutations in genes that influence cardiacexcitability are sufficient to cause life-threatening arrhyth-mias. Understanding the basic biology of arrhythmogenesisholds the promise of identifying novel targets for the treat-ment of arrhythmias, including prevention of the develop-ment of structural changes in the heart that form the substratefor cardiac rhythm disturbances.

DisclosureDr Tomaselli has served as a consultant to Pfizer.

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Molecular Basis of Arrhythmias Manish Shah, Fadi G. Akar ...tibbits/courses/K812/Circ-Review05.pdf · Molecular Basis of Arrhythmias Manish Shah, MD; Fadi G. Akar, PhD; Gordon F