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Molecular genetics of arrhythmias and cardiovascular conditions associated with arrhythmias

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NASPE HISTORY SERIES Molecular Genetics of Arrhythmias and Cardiovascular Conditions Associated with Arrhythmias CHARLES ANTZELEVITCH From the Masonic Medical Research Laboratory, Utica, New York Introduction Recent years have witnessed significant strides in our understanding of the genetic ba- sis of inherited arrhythmic disorders. Advances in molecular genetics have enabled the identification of the genetic basis and pathogenesis of a wide variety of cardiovascular diseases. With progres- sive expansion of our knowledge base, genetic di- agnosis and screening will in time become part of standard clinical practice. This brief review sum- marizes our present understanding of the genetic basis for disease and the genetic factors that con- tribute to the manifestation and pathogenesis of arrhythmic disorders. Basic Principles Hereditary information is encoded in DNA via a sequence of purine (adenine, guanine) and pyrimidine (cytosine, thymine) bases. The heredi- tary unit is called a gene and consists of a segment of DNA that encodes for a specific protein. There are 30,000 to 35,000 genes in the human genome 1 and each individual has two copies of each gene called alleles. The genes are distributed among 23 pairs of chromosomes including 22 pairs of au- tosomes (chromosomes 1 to 22) and one pair of sex chromosomes, X and Y. Females have two X chromosomes, while males carry one X and one Y chromosome. Each parent contributes one of each chromosome pair and thus one copy of each gene. The site at which a gene is located on a particular chromosome is referred to the genetic locus. The information on the DNA is translated into protein through a translational code passed through mes- senger ribonucleic acid (mRNA), in which three bases, referred to as a codon, encode for a specific amino acid. The transcribed mRNA serves as the template that determines sequence of amino acids in the resulting protein. DNA nucleotide sequences generally remain constant when passed from parent to offspring. Base sequence changes are referred to as muta- Supported by grants from the National Institutes of Health (HL 47678), the American Heart Association, New York State Affil- iate, and the Masons of New York State and Florida. Address for reprints: Charles Antzelevitch, Ph.D., Gordon K. Moe Scholar, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, New York 13501. Fax: (315) 735-5648; e-mail: [email protected] tions. Environmental factors, including radiation, chemicals, drugs, and errors introduced by the DNA synthetic and editing enzymes, can result in mutations. Mutations can take the form of a deletion or translocation of a large segment of a chromosome, in which case multiple genes may be eliminated or altered. Alternatively a mutation may be limited to minor alterations in the DNA sequence ranging from the substitution of a sin- gle nucleotide to the deletion or addition of multi- ple nucleotides. Hereditary diseases are generally classified into three broad categories: 1) chromo- somal abnormalities; 2) single gene or monogenic disorders and 3) polygenic disorders or complex traits that are the result of interactions between defects in multiple genes. Monogenic disorders exhibit Mendelian pat- terns of inheritance and are generally classified as: 1) autosomal dominant; 2) autosomal reces- sive; and 3) X linked (dominant or recessive). The majority of single gene diseases display an auto- somal dominant mode of inheritance, in which case approximately half of family members are af- fected. Monogenic disorders with an autosomal re- cessive inheritance are secondary to mutations in both copies of the gene; in which case only 25% of offspring exhibit the phenotype, 50% carry the mutation, and 25% are normal. With X linked in- heritance, only males generally exhibit the dis- ease, whereas females do not show the phenotype, unless the mutation involves a major protein, in which case females could exhibit the clinical phe- notype. In diseases secondary to mitochondrial DNA mutations, inheritance is from the mother, because mitochondrial DNA is primarily inherited from the ovum. Polygenic disorders are caused by mutations in multiple genes. Single nucleotides alterations, referred to as single nucleotide polymorphisms (SNP), occur with a frequency of approximately 1 per 600 bp and account for morphological distinc- tions, susceptibility to disease, as well as response to drugs and other therapeutic modalities. Poly- genic disorders underlie the majority of the cardio- vascular diseases, but unlike monogenic diseases, are much more difficult to map. Genetic heterogeneity refers to the observation that different mutations in the same (allele het- erogeneity) or different genes (locus heterogene- ity) can cause the same phenotype. Within a given Reprinted from PACE November 2003, Vol. 26, and JCE November 2003, Vol. 14. PACE and JCE are published by Blackwell Publishing. Heart Rhythm (2004) 42C–56C ©2004 Heart Rhythm Society
Transcript
Page 1: Molecular genetics of arrhythmias and cardiovascular conditions associated with arrhythmias

NASPE HISTORY SERIES

Molecular Genetics of Arrhythmias and CardiovascularConditions Associated with ArrhythmiasCHARLES ANTZELEVITCHFrom the Masonic Medical Research Laboratory, Utica, New York

IntroductionRecent years have witnessed significant

strides in our understanding of the genetic ba-sis of inherited arrhythmic disorders. Advances inmolecular genetics have enabled the identificationof the genetic basis and pathogenesis of a widevariety of cardiovascular diseases. With progres-sive expansion of our knowledge base, genetic di-agnosis and screening will in time become part ofstandard clinical practice. This brief review sum-marizes our present understanding of the geneticbasis for disease and the genetic factors that con-tribute to the manifestation and pathogenesis ofarrhythmic disorders.

Basic PrinciplesHereditary information is encoded in DNA

via a sequence of purine (adenine, guanine) andpyrimidine (cytosine, thymine) bases. The heredi-tary unit is called a gene and consists of a segmentof DNA that encodes for a specific protein. Thereare 30,000 to 35,000 genes in the human genome1

and each individual has two copies of each genecalled alleles. The genes are distributed among 23pairs of chromosomes including 22 pairs of au-tosomes (chromosomes 1 to 22) and one pair ofsex chromosomes, X and Y. Females have two Xchromosomes, while males carry one X and one Ychromosome. Each parent contributes one of eachchromosome pair and thus one copy of each gene.The site at which a gene is located on a particularchromosome is referred to the genetic locus. Theinformation on the DNA is translated into proteinthrough a translational code passed through mes-senger ribonucleic acid (mRNA), in which threebases, referred to as a codon, encode for a specificamino acid. The transcribed mRNA serves as thetemplate that determines sequence of amino acidsin the resulting protein.

DNA nucleotide sequences generally remainconstant when passed from parent to offspring.Base sequence changes are referred to as muta-

Supported by grants from the National Institutes of Health (HL47678), the American Heart Association, New York State Affil-iate, and the Masons of New York State and Florida.

Address for reprints: Charles Antzelevitch, Ph.D., Gordon K.Moe Scholar, Masonic Medical Research Laboratory, 2150Bleecker Street, Utica, New York 13501. Fax: (315) 735-5648;e-mail: [email protected]

tions. Environmental factors, including radiation,chemicals, drugs, and errors introduced by theDNA synthetic and editing enzymes, can resultin mutations. Mutations can take the form of adeletion or translocation of a large segment of achromosome, in which case multiple genes maybe eliminated or altered. Alternatively a mutationmay be limited to minor alterations in the DNAsequence ranging from the substitution of a sin-gle nucleotide to the deletion or addition of multi-ple nucleotides. Hereditary diseases are generallyclassified into three broad categories: 1) chromo-somal abnormalities; 2) single gene or monogenicdisorders and 3) polygenic disorders or complextraits that are the result of interactions betweendefects in multiple genes.

Monogenic disorders exhibit Mendelian pat-terns of inheritance and are generally classifiedas: 1) autosomal dominant; 2) autosomal reces-sive; and 3) X linked (dominant or recessive). Themajority of single gene diseases display an auto-somal dominant mode of inheritance, in whichcase approximately half of family members are af-fected. Monogenic disorders with an autosomal re-cessive inheritance are secondary to mutations inboth copies of the gene; in which case only 25%of offspring exhibit the phenotype, 50% carry themutation, and 25% are normal. With X linked in-heritance, only males generally exhibit the dis-ease, whereas females do not show the phenotype,unless the mutation involves a major protein, inwhich case females could exhibit the clinical phe-notype. In diseases secondary to mitochondrialDNA mutations, inheritance is from the mother,because mitochondrial DNA is primarily inheritedfrom the ovum.

Polygenic disorders are caused by mutationsin multiple genes. Single nucleotides alterations,referred to as single nucleotide polymorphisms(SNP), occur with a frequency of approximately 1per 600 bp and account for morphological distinc-tions, susceptibility to disease, as well as responseto drugs and other therapeutic modalities. Poly-genic disorders underlie the majority of the cardio-vascular diseases, but unlike monogenic diseases,are much more difficult to map.

Genetic heterogeneity refers to the observationthat different mutations in the same (allele het-erogeneity) or different genes (locus heterogene-ity) can cause the same phenotype. Within a given

Reprinted from PACE November 2003, Vol. 26, and JCE November 2003, Vol. 14. PACE and JCE are published by Blackwell Publishing. Heart Rhythm (2004) 42C–56C©2004 Heart Rhythm Society

Page 2: Molecular genetics of arrhythmias and cardiovascular conditions associated with arrhythmias

INHERITED ARRHYTHMIAS

family, a single mutation is usually responsible forthe disorder in all affected family members. Anexample is the long QT syndrome in which sevendifferent genes (locus heterogeneity) with multi-ple mutations in each (allelic heterogeneity) giverise to prolongation of the QT interval in the ECG.The majority of single gene disorders involve a sin-gle nucleotide or point mutation. A point mutationmay result from a substitution of one nucleotidefor another, leading to a change in the amino acidsequence (missense mutation); or conversion of acodon that encodes for an amino acid to a stopcodon, causing truncation of the protein (trun-cated or nonsense mutation); or elimination of astop codon resulting in elongation of the protein(elongated mutant); or it may change the codonwithout changing amino acid sequence (synony-mous mutation). All genes during transcriptionand translation are read from 5′ to 3′ orientationwith each triplet of bases (codon) coding for a spe-cific amino acid.

Table I.

Genetic Disorders Causing Cardiac Arrhythmias in the Absence of Structural Heart Disease (Primary Electrical Diseas)

Rhythm Inheritance Locus Ion Channel Gene

VentricularLQT syndrome (RW) TdP AD

LQT1 11p15 IKs KCNQ1, KvLQT1LQT2 7q35 IKr KCNH2, HERGLQT3 3p21 INa SCN5ALQT4 4q25 ANKB, ANK2LQT5 21q22 IKs KCNE1, minKLQT6 21q22 IKr KCNE2, MiRP1LQT7 17q23 IK1 KCNJ2, Kir 2.1

LQT syndrome (JLN) TdP AR11p15 IKs KCNQ1, KvLQT121q22 IKs minK

Catecholaminergic VT VT AD 1q42 RYR2AR 1p13-p11 CASQ2

Brugada syndrome VT/VF AD 3p21 INa SCN5A3p22-25

SupraventricularAtrial fibrillation AF AD 10q22 –

AD 11p15 IKs KCNQ1, KvLQT1Atrial standstill SND, AF AD 3p21 INa SCN5AAbsent sinus rhythm SND, AF AD – –WPW AVRT AD – PRKAG2Conduction disordersProgressive Conduction AVB AD 19q13Disease 3p21 INa SCN5A

AD = autosomal dominant; AF = atrial fibrillation; AR = autosomal recessive; AVB = atrioventricular block; AVRT = atrioventricularre-entrant tachycardia; JLN = Jervell and Lange—Nielsen; LQT = Long QT, RW = Romano-Ward; SND = sinus node dysfunction;TdP = Torsade de pointes; VF = ventricular fibrillation; VT = ventricular tachycardia; WPW = Wolff-Parkinson-White syndrome.

Numerous genetic and environmental fac-tors can affect expression of a gene mutation.When these factors mask the phenotype, pene-trance is said to be low. Thus, penetrance refersto the percentage of individuals within a familywho display the phenotype after inheriting themutation.

Molecular Genetics of Arrhythmias andCardiovascular Conditions Associated withArrhythmias

Cardiac arrhythmias generally result from ab-normalities in four classes of protein: 1) ion chan-nels, exchangers, and their modulators (primaryelectrical disease); 2) cell-to-cell junction proteins,such as those responsible for arrhythmogenic rightventricular cardiomyopathy (ARVC); 3) contractilesarcomeric proteins, such as those responsible forhypertrophic cardiomyopathy (HCM); and 4) cy-toskeletal proteins, which are responsible for di-lated cardiomyopathy (DCM). Tables I-IV present a

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Table II.

Genetic Basis for Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Protein Gene Function Locus Inheritance

ARVC1 Ryanodine RYR2 Calcium Release 14q24.3 ADReceptor 2 Channel

ARVC2 1q42 ADARVC3 14q11-q12 ADARVC4 2q32 ADARVD5 3p23 ADARVD6 10p12-p14 ADARVD7 10q22 ADARVC8 Desmoplakin DSP Adherens junction 6p28 AD

proteinNaxos disease Plakoglobin JUP Cell junction 17q21 AR

AD = Autosomal dominant; AR = Autosomal recessive.

list of known genetic disorders divided along thesedisease phenotypes.

Primary Electrical DiseaseIon Channelopathies

Ion channels consist of proteins and glycopro-teins that form transmembrane pores that permitthe flow of ions along the electrochemical gradi-ent that exists across the plasma membrane. Theresulting current effects a voltage change across themembrane, which regulates the contractile func-tion of the cell. Numerous currents contribute tothe development of the action potential. Defects inany one of these ion channel currents can distortthe action potential, thus creating the substrate forthe development of cardiac arrhythmias. A great

Table III.

Genetic Basis for Hypertrophic Cardiomyopathy (HCM)

Protein Gene Locus Estimated Frequency Inheritance

β-Myosin heavy chain MYH7 14q12 35% ADMyosin binding protein-C MYBPC3 11p11.2 20% ADCardiac troponin T TNNT2 1q32 20% ADCardiac troponin I TNN13 19p13.2 5% ADα-tropomyosin TPM1 15q22.1 5% ADEssential myosin light chain MYL3 3p21.3 <5% ADRegulatory myosin light chain MYL2 12q23-24.3 <5% ADCardiac α-actin ACTC 15q11 <5% ADTitin TTN 2q24.1 <5% ADα-Myosin heavy chain MYH6 14q1 Rare ADCardiac troponin C TNNC1 3p21.3-3p14.3 Rare AD

AD = Autosomal dominant.

deal of work has been done in recent years to elu-cidate the role of ion channelopathies in the Bru-gada, long QT and short QT syndromes.

Brugada Syndrome

Brugada syndrome was first described as anew clinical entity in 1992.2 The electrocardio-graphic features of the syndrome include: 1) anaccentuated J wave appearing principally in theright precordial leads (V1-V3) and taking the formof an ST segment elevation, often followed by anegative T wave; 2) very closely coupled extrasys-toles; and 3) rapid polymorphic ventricular tachy-cardia (VT), which at times may be indistinguish-able from ventricular fibrillation (VF). The ECGsign of Brugada syndrome is dynamic and often

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Table IV.

Genetic Basis for Dilated Cardiomyopathy (DCM)

Gene Symbol Locus Inheritance

Sarcomeric/CytoskeletalCardiac α-actin ACTC 15q11-14 AD Also causes HCMβ-myosin heavy chain MYH7 14q11-13 AD Also causes HCMCardiac troponin T TNNT2 1q32 AD Also causes HCMα-tropomyosin TPM1 15q22.1 AD Rare. Also causes HCMTitin TTN 2q24.1 AD Rare. Also causes HCMCytoskeletalβ-Sarcoglycan SGCB 4q12 AD Limb-girdle muscular dystrophyδ-Sarcoglycan SGCD 5q33-34 AD Limb-girdle muscular dystrophy

AR Limb-girdle muscular dystrophyα-Sarcoglycan SGCA 17q21 AD Limb-girdle muscular dystrophyDystrophin DMD Xp21 X-linked Muscular dystrophyMuscle LIM protein M L P 11q15.1 AD Rare. Founder effect

(CSRP3)Intermediary filamentsDesmin DES 2q35 AD Also causes RCM and desminopathiesαB-crystallin CRYAB 11q35 DesminopathyNuclear ProteinsLamin A/C LMNA 1q21.2 AD DCM, Conduction defect, muscular dystrophy,

lipodystrophy, insulin resistanceEmerin EMD Xq28 X-linkedCell junction moleculesDesmoplakin DSP 6p23-25 AR Also cases ARVCUnknownTaffazin (G4.5) TAZ Xq28 X-linked Ventricular non-compaction

1q322q14-222q313p22-256q23-249q13-2210q21-23

AD = Autosomal dominant; AR = Autosomal recessive.

concealed, but can be unmasked by potent sodiumchannel blockers such as flecainide, ajmaline, pro-cainamide, disopyramide, propafenone, and pilsi-cainide.3−5 A consensus report dealing with diag-nostic criteria for Brugada syndrome has recentlybeen published.6 Sudden unexplained death syn-drome (SUDS), a disorder most prevalent in south-east Asia, and Brugada syndrome have been shownto be phenotypically, genetically, and functionallythe same disorder.7

In addition to sodium channel blockers, afebrile state, vagotonic agents, α-adrenergic ago-nists, β-adrenergic blockers, tricyclic antidepres-sants, first generation antihistaminics (dimenhy-drinate), alcohol intoxication, insulin+glucose,and cocaine toxicity can unmask Brugada syn-

drome or lead to accentuation of ST segment el-evation in patients with the syndrome.3,8−15

Cellular and Ionic Mechanisms

Rebalancing of the currents active at the end ofPhase 1, is thought to underlie the accentuation ofthe action potential notch in right ventricular epi-cardium, which is responsible for the augmentedJ wave and ST segment elevation associated withBrugada syndrome (see 16 for references). In largermammals, the presence of a transient outward cur-rent (Ito)-mediated spike and dome morphology,or notch, in ventricular epicardium, but not en-docardium, creates a transmural voltage gradientresponsible for the inscription of the electrocar-diographic J wave (Fig. 1A).17,18 The ST segment

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Figure 1. Schematic representation of right ventricular epicardial action potential changes thought to underlie theelectrocardiographic manifestation of Brugada syndrome. Modified from reference 18 with permission.

is normally isoelectric due to the absence of trans-mural voltage gradients at the level of the actionpotential plateau. Accentuation of the right ven-tricular action potential notch under pathophysi-ological conditions leads to exaggeration of trans-mural voltage gradients and thus to accentuationof the J wave or to J point elevation. If the epicardialaction potential continues to repolarize before thatof endocardium, the T wave remains positive, giv-ing rise to a saddleback configuration of the ST seg-ment elevation. Further accentuation of the notchis accompanied by a prolongation of the epicardialaction potential causing it to repolarize after en-docardium, thus inversion of the T wave (Fig. 1B).The down-sloping ST segment elevation, or accen-tuated J wave, observed in the experimental wedgemodels often appears as an R′, suggesting that theappearance of a right bundle branch block (RBBB)morphology in Brugada patients may be due atleast in part to early repolarization of right ven-tricular (RV) epicardium, rather than to impulseconduction block in the right bundle.19 Despite theappearance of a typical Brugada sign, the electro-physiological changes shown in Fig. 1B do not give

rise to an arrhythmogenic substrate. The arrhyth-mogenic substrate is thought to develop with a fur-ther shift in the balance of current leading to loss ofthe action potential dome at some epicardial sitesbut not others (Fig. 1C). This results is the develop-ment of a marked transmural dispersion of repolar-ization, creating a vulnerable window, which canbe captured by a premature impulse or extrasys-tole to trigger a reentrant arrhythmia. Loss of theaction potential dome in epicardium is generallyheterogeneous, leading to the development of epi-cardial dispersion of repolarization. Conduction ofthe action potential dome from sites at which it ismaintained to sites at which it is lost causes localre-excitation via Phase 2 reentry (Fig. 1D), lead-ing to the development of a very closely-coupledextrasystole, which captures the vulnerable win-dow across the wall, thus triggering a circus move-ment reentry in the form of VT/VF.20,21 Supportfor these hypotheses derives from experiments in-volving the arterially perfused RV wedge prepa-ration20 and from recent studies in which MAPelectrodes where positioned on the epicardialand endocardial surfaces of the right ventricular

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outflow tract (RVOT) in patients with Brugadasyndrome.22,23

An interesting aspect of Brugada syndrome isthat despite equal genetic transmission of the dis-ease, the clinical phenotype is eight to ten timesmore prevalent in males than in females. The ba-sis for this sex related distinction was recentlyshown to be due to a more prominent transient out-ward current (Ito)-mediated action potential notchin the RV epicardium of males versus females.24

The more prominent Ito causes the end of Phase 1of the RV epicardial action potential to repolarizeto more negative potentials in tissue and arteriallyperfused wedge preparations from males, facilitat-ing loss of the action potential dome and the devel-opment of Phase 2 reentry and polymorphic VT.

A rebalancing of currents active at the end ofPhase 1 underlies the unmasking of the syndromein response to drugs. Vagotonic agents, IK-ATP ac-tivators and hypokalemia achieve this by aug-menting outward currents, whereas sodium chan-nel blockers, β-blockers, cocaine, antidepressants,and antihistamines like terfenadine are likely toaccomplish this by reducing inward currents.

Genetic Factors Underlying Brugada Syndrome

Inheritance of Brugada syndrome is via an au-tosomal dominant mode of transmission. The firstand only gene to be linked to Brugada syndrome isSCN5A, the gene encoding for the α subunit of thecardiac sodium channel gene.25 Nearly five dozenmutations in SCN5A have been linked to the syn-drome over the past 4 years (see references 16,26–28 for references). Approximately two dozen ofthese have been studied in expression systems andshown to result in loss of function due either to:(1) failure of the sodium channel to express; (2) ashift in the voltage- and time-dependence of INa ac-tivation, inactivation, or reactivation; (3) entry ofthe sodium channel into an intermediate state ofinactivation from which it recovers more slowly;or (4) accelerated inactivation of the sodium chan-nel. The premature inactivation of the sodiumchannel is observed at physiological temperatures,but not at room temperature.29 Because this char-acteristic of the mutant channel is exaggerated attemperatures above the physiological range, it wassuggested that the syndrome may be unmasked,and that patients with Brugada syndrome may be atan increased risk during a febrile state.29 A numberof Brugada patients displaying fever induced poly-morphic VT have since been identified (see ref-erence 30 for references). Another locus on chro-mosome 3, close to but distinct from SCN5A, hasrecently been linked to the syndrome31 in a largepedigree in which the syndrome is associated withprogressive conduction disease, a low sensitivityto procainamide, and a relatively good prognosis.

Genotype-Phenotype Correlation in BrugadaSyndrome

Limited data are available concerninggenotype-phenotype correlation s in patients withBrugada syndrome. A recent study suggests thatelectrocardiographic parameters, such as longerconduction intervals (PQ and HV) on baselineECG can distinguish carriers of sodium channelmutations from noncarriers.32

Long QT Syndrome (LQTS)The long QT syndrome (LQTS) is character-

ized by the appearance of long QT intervals in theECG, an atypical polymorphic ventricular tachy-cardia known as torsade de pointes (TdP), and ahigh risk for sudden cardiac death (SCD).33−35 Con-genital LQTS can be further subdivided into sevengenotypes distinguished by mutations in at leastsix different ion genes and a structural anchoringprotein located on chromosomes 3, 4, 7, 11, 17,and 21 (Table I).36−41 Acquired LQTS is a term longreserved for a syndrome similar to the congenitalform but caused by exposure to drugs that prolongthe duration of the ventricular action potential,42

or QT prolongation secondary to bradycardia oran electrolyte imbalance. In recent years this syn-drome has been extended to encompass the re-duced repolarization reserve attending remodelingof the ventricular myocardium that accompaniesdilated and hypertrophic cardiomyopathies.43−47

Cellular Mechanisms Underlying LQTS

Amplification of spatial dispersion of repo-larization within the ventricular myocardium sec-ondary to an increase of transmural and transseptaldispersion of repolarization and the developmentof early after depolarization (EAD) induced trig-gered activity, underlie the substrate and triggerfor the development of TdP arrhythmias observedunder LQTS conditions (Figs. 2 and 3).48;49 Modelsof the LQT1, LQT2, and LQT3 form of the long QTsyndrome have been developed using the caninearterially perfused left ventricular wedge prepara-tion (Fig. 2).50 These models have shown that inthese three forms of LQTS, preferential prolonga-tion of the M cell action potential duration (APD)leads to an increase in the QT interval as well as anincrease in transmural dispersion of repolarization(TDR), the latter providing the substrate for the de-velopment of spontaneous as well as stimulationinduced torsade de pointes (TdP).

LQT1 is the most prevalent of the congenitallong QT syndromes.51 LQT1 can be mimicked us-ing an IKs blocker (chromanol 293B) together witha β-adrenergic agonist (isoproterenol). Chromanol293B alone leads to uniform prolongation of APDin all three cell types with little change in TDR.

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Figure 2. Transmembrane action potentials and transmural electrocardiograms (ECG) in control and LQT1 (A), LQT2(B), and LQT3 (C) models of LQTS (arterially-perfused canine left ventricular wedge preparations). Isoproterenol +chromanol 293B - an IKs blocker, d-sotalol + low [K+]o, and ATX-II - an agent that slows inactivation of late INa are usedto mimic the LQT1, LQT2 and LQT3 syndromes, respectively. Panels A - C depict action potentials simultaneouslyrecorded from endocardial (Endo), M and epicardial (Epi) sites together with a transmural ECG. BCL = 2000 ms.Transmural dispersion of repolarization across the ventricular wall, defined as the difference in the repolarizationtime between M and epicardial cells, is denoted below the ECG traces. (Panels D-F) Effect of isoproterenol in the LQT1,LQT2 and LQT3 models. In LQT1, isoproterenol (Iso) produces a persistent prolongation of the APD90 of the M cell andof the QT interval (at both 2 and 10 minute), whereas the APD90 of the epicardial cell is always abbreviated, resultingin a persistent increase in TDR (D). In LQT2, isoproterenol initially prolongs (2 minute) and then abbreviates the QTinterval and the APD90 of the M cell to the control level (10 minute), whereas the APD90 of epicardial cell is alwaysabbreviated, resulting in a transient increase in TDR (E). In LQT3, isoproterenol produced a persistent abbreviationof the QT interval and the APD90 of both M and epicardial cells (at both 2 and 10 minute), resulting in a persistentdecrease in TDR (F). *P < 0.0005 versus control; †P < 0.0005, ††P < 0.005, †††P < 0.05, versus 293B, d-Sotalol (d-Sot),or ATX-II. (Modified from references 52, 54, and 55 with permission).

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Figure 3. Cellular mechanism for thedevelopment of torsade de pointes in thelong QT syndrome.

Although the QT interval is prolonged, TdP neveroccurs under these conditions, nor can it be in-duced. Addition of isoproterenol results in abbre-viation of epicardial and endocardial APD whilethe M cell APD either prolongs or remains thesame. The dramatic increase in TDR provides thesubstrate for the development of spontaneous aswell as stimulation induced TdP.52 These resultshighlight the fact that the problem with the longQT syndrome is not the long QT interval, but ratherthe increase in TDR that often accompanies theprolongation of the QT interval. The combinationof IKs block and β-adrenergic stimulation creates abroad based T wave in the perfused wedge, similarto that observed in patients with LQT1. These find-ings correlate well with the high sensitivity of con-genital LQTS patients, especially LQT1 patients, tosympathetic stimulation.33,53

The second most prevalent form of congeni-tal LQTS is LQT2, involving a defect in IKr. Re-duced levels of IKr are also responsible for mostcases of acquired LQTS. In the canine ventricularwedge model, d-sotalol is used to mimic this vari-ant of the syndrome. Although all three cell typesexhibit an increase in APD when IKr is blocked,the M cell prolongs to a greater degree, resultingin an increased TDR and spontaneous as well asstimulation induced TdP. If IKr block is accompa-nied by hypokalemia, a deeply notched or bifur-cated T wave is observed in the wedge preparation,similar to that seen in patients with LQT2. Isopro-terenol further exaggerates TDR and increases theincidence of TdP in this model.

Use of ATX-II to augment late INa providesa model of LQT3. The APD of each of the threecell types in the perfused wedge is prolonged withATX-II, leading to a delay in the onset of theT wave.54 Since the M cell has a higher density

of late INa, the APD prolongation is more pro-nounced in this region, especially at slower stim-ulation rates. As in the other forms of LQTS, ex-aggerated prolongation of APD in the M region re-sults in an increase in TDR and induction of TdP.β-adrenergic stimulation abbreviates APD of allcell types under these conditions, causing an ame-liorative effect in this model of LQTS. TDR is im-portantly reduced owing to the fact that the APDof the M cell abbreviates more than that of epi-cardium or endocardium.55

The arrhythmogenic effects of sympathetic ac-tivation display a very different time-course inthe case of LQT1 and LQT2, both in experimentalmodels and in the clinic.49,56,57 In LQT1, isopro-terenol produces an increase in TDR that is mostprominent during the first 2 minutes, but whichpersists, although to a lesser extent, during steadystate. TdP incidence is enhanced during the ini-tial period as well as during steady state. In LQT2,isoproterenol produces only a transient increasein TDR that persists for less than 2 minutes. TdPincidence is therefore enhanced only for a brief pe-riod of time. These differences in time-course mayexplain the important differences in autonomicactivity and other gene-specific triggers that con-tribute to events in patients with different LQTSgenotypes.51,53,57

Genetic Basis for LQTS

Two patterns of inheritance have been de-scribed in the congenital LQT syndrome: 1) auto-somal recessive disease, described by Jervell andLange Nielsen (JLN) in 1957, which is associatedwith deafness; and 2) autosomal dominant disease,described by Romano and Ward (RW), which isnot associated with deafness and is more commonthan the recessive form.

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Initial efforts to identify genes responsible forlong QT intervals used positional cloning tech-niques on chromosomal DNA from members offamilies with congenital Romano-Ward syndrome.The first long QT syndrome gene (LQT1) wasmapped to the short arm of chromosome 11 ina locus proximal to the Harvey ras-1 gene (11p15.5).58,59 Cloning and heterologous expression ofthe LQT1 gene 5 years after its initial mapping, re-vealed a potassium channel termed KCNQ1 (pre-viously KvLQT1) with activation and inactivation(gating) kinetics resembling those of IKs.40 It con-sists of 16 exons spanning 400 kb, which form 6transmembrane segments. Despite its genetic link-age to LQTS, the current generated by KCNQ1alone could not, however, fully reproduce featuresof IKs like its sensitivity to blockade by Chromanol293B, a compound with Class III antiarrhythmicactivity, or its slow kinetics of activation. By 1993,evidence for genetic heterogeneity in LQTS wasaccumulating.60,61 The identification of the Ether-a-Go-Go (EAG) channel,62 named on the basis ofthe drosophila leg-shaking phenotype,63 led to thecloning of a human EAG related channel (KCNH2,HERG) mapped to chromosome 7.64 Through acandidate gene approach and positional cloning,a second (LQT2) and a third (LQT3) LQTS lo-cus were mapped to 7q35-36 and 3p21-24 respec-tively.65 LQT2 was linked to mutations in HERG.39

Expression studies revealed that HERG currentshad some of the pharmacological and gating prop-erties of IKr,66 making it a likely candidate forcongenital and acquired forms of LQTS.67 LQT3was linked to mutations in SCN5A,65 the cardiacsodium channel gene.

Further genetic heterogeneity emerged withthe mapping of a fourth LQTS locus (LQT4)to chromosome 4q25-27.68 The causal gene wasonly recently identified as ANKB (also knownas ANK2), which encodes ankyrin-B.37 Mutationsin ankyrin B disrupt cellular localization of thesodium pump, the sodium/calcium exchanger andthe inositol-1,4,5-triphosphate receptors, reducetheir expression levels and affect Ca+2 signalingin adult cardiac myocytes.37 This finding suggeststhat mutations other than those in ion channelscan cause cardiac arrhythmias.

The search for ancillary proteins co-assembling with KCNQ1 to generate electricalcurrents with the properties of IKs, led to the iden-tification of a fifth LQTS locus. KCNE1 (minK),a small single transmembrane spanning proteininitially cloned in 1988 from rat kidney,69 wasmapped to chromosome 21 and linked to LQT5.70

LQT5 has been linked to both JLN (homozygous)and RW (heterozygous) syndromes.41;70 Recentyears have witnessed the emergence of severalmembers of the KCNE family of small protein

genes. These proteins have proved to be impor-tant modulators of IKr and IKs activity and ofpharmacological responsiveness and have beenlinked to two new congenital forms of the long QTsyndrome. The multifunctional role of the KCNEfamily of channel modulators is exemplifiedby KCNE2, a MinK related peptide (MiRP1).KCNE2 is structurally similar to KCNE1, but morespecifically targets HERG as a cofactor. It can alsoassociate with other genes to form the transientoutward current Ito.71 Mutations in KCNE2 havebeen linked to RW syndrome, representing a sixthform of LQTS (LQT6).

Mutations in KCNJ2, encoding Kir2.1 or IK1channels has recently been linked to LQT7, alsoknown as Andersen’s syndrome.38 Andersen’s syn-drome is a rare autosomal dominant inherited dis-order characterized by periodic paralysis, cardiacarrhythmias, LQT, and dysmorphic features suchas short stature, scoliosis, clinodactylym, hyper-teletorism, low set or slanted ears, micrognathia,and broad forehead.38 The causal gene is KCNJ2,located on chromosome 17q23, which encodes forKir2.1 channels, expressed in skeletal and cardiacmuscles. Kir2.1 or IK1 is a strong inward rectifiedpotassium channel that maintains the resting po-tential and contributes to final repolarization of theaction potential. Electrophysiological studies indi-cate the mutant protein exerts a dominant negativeeffect on Kir2.1 function with an ultimate decreasein potassium current.

The autosomal recessive forms of LQTS,which are associated with sensorineuronal deaf-ness, have been linked to mutations in thegenes encoding IKs current, namely KCNQ1 andKCNE1.72 It is less common than the Romano-Ward syndrome but is associated with a more ma-lignant course and longer QT interval. The pheno-type can also arise in recessive forms if differentmutations in the same gene are inherited from theparents (compound heterozygote).

Genotype-Phenotype Correlation in LQTS

Recent studies have identified ECG charac-teristics that are suggestive of specific genotypes(Fig. 2).51,73−75 LQT1 patients generally exhibitsymptoms during physical activity, such as swim-ming and have a broad-based T wave, whereasthose with LQT2 commonly develop symptomsfollowing an auditory stimulus and the T wavesare of low voltage and often bifurcated or notched.In contrast, patients with LQT3 experience eventsduring sleep and the ECG shows a late appearingT wave with a long isoelectric ST segment.

Mutations also carry prognostic significanceand in all three groups (LQT1,2, and 3) there isa correlation between cardiac events and the QTcinterval. In general patients with LQT1 and LQT2

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have a higher risk of cardiac events than patientswith LQT3. LQT3 patients have fewer events, butthey are typically more lethal.76 In addition, re-sponse to drug therapy seems to correlate with thegenotype.

While β-blockers are considered the first lineof therapy in patients with LQT1, they have notbeen shown to be beneficial in LQT3. Prelimi-nary data suggest LQT3 patients might benefit fromNa+1 channel blockers, such as mexiletine andflecainide, but long-term data are not yet avail-able.77,78 Experimental data have shown that mex-iletine reduces transmural dispersion and pre-vents TdP in LQT3 as well as LQT1 and LQT2,suggesting that agents that block the late sodiumcurrent may be effective in all forms of LQTS.52,79

Clinical trial data are not as yet available.

Acquired LQTS

Acquired LQTS is iatrogenic caused by drugs,electrolyte abnormalities, or cardiomyopathies.Several factors increase the risk of developingLQTS syndrome in response to drugs. These in-clude bioavailability of the drug, interaction withother medications that affect the same or differentrepolarizing currents, and the presence of SNPsor mutations. SNPs play a major role in determin-ing pharmacodynamics and pharmacokinetics ofdrugs and thus influence the risk of developingTdP. SNPs and some mutations in genes knownto cause LQTS, may be silent until unmasked bythe use of IKr blockers. These patients are said tohave a forme fruste of the congenital disease.80 Re-cent identification of a common SNP that predis-poses to drug induced arrhythmias in the AfricanAmerican population, serves as an example.80 Anycombination of genetic and environmental factors(drug, electrolyte abnormalities) that reduce the“repolarization reserve” of the ventricles below asafe threshold will place patients at risk for TdP.81

Progressive Familial Heart BlockFamilial heart block, an autosomal dominant

disease of the cardiac conduction system, usuallystarts out as bundle branch block with subsequentgradual progression to complete heart block. Twoforms are recognized. In type I, the onset is earlyand the disease progresses rapidly. In type II, theonset is later in life; the QRS complex is narrowand AV nodal block predominates. Clinical fea-tures of the disease include syncope, SCD, andStokes-Adams attacks. A locus has been identifiedin a large family of Portuguese descent on chro-mosome 19q13. As discussed earlier, mutations inSCN5A have been identified in some families withfamilial heart block.3,82,83

Catecholaminergic Polymorphic VentricularTachycardia

Ryanodine receptors are responsible for re-lease of calcium from the sarcoplasmic reticu-lum (SR) in response to calcium entering the cell.Mutations in ryanodine receptors (RYR2) havebeen shown to cause ARVC type 2 (ARVD2)84−86

and familial polymorphic ventricular tachycardia(FPVT).84 FPVT, also referred to as catecholamin-ergic VT, is an autosomal-dominant inherited dis-ease with a high mortality rate (∼30%) by age 30.Phenotypically, it is characterized by runs of bidi-rectional and polymorphic ventricular tachycardiain response to vigorous exercise in the absence ofevidence of structural myocardial disease. A re-cessive form of FPVT also has been described andmapped to the calsequestrin 2 (CASQ2) gene at lo-cus 1p13.3-p11.87 Calsequestrin is an intralumi-nal SR calcium binding proteins and its dysfunc-tion interferes with the ability of the SR to handlecalcium.

Familial Atrial FibrillationAtrial fibrillation (AF) may be familial when

it presents in the young or in individuals withno apparent cause. Inheritance of familial AF isautosomal dominant and the first locus identifiedwas localized to chromosome 10q22-24.88 The firstcausal gene identified for familial AF is KCNQ1,which is also responsible for LQT1 syndrome. ThisAF mutation causes a gain of function, in contrastto the loss of function observed in patients withLQT1.89

Familial Wolf-Parkinson-White SyndromeFamilial Wolf-Parkinson-White (WPW) syn-

drome, a rare syndrome with autosomal dom-inant mode of inheritance, is characterized bypre-excitation, palpitations, and syncope due tosupraventricular arrhythmias. When found in con-junction with HCM it has been linked to PRKAG2,TNNI3, or MYBPC3 mutations.90,91,92 It has alsobeen reported in patients with Pompe disease,caused by mutations in α-1,4-glucosidase,93 andin Leber’s hereditary optic neuropathy, which iscaused by mutations in mitochondrial DNA.94

Genetic Disease of Ventricular MyocardiumAssociated with Arrhythmia

Diseases of the ventricular muscle are classi-fied into four groups based on their phenotypiccharacteristics: 1) arrhythmogenic right ventric-ular dysplasia; 2) hypertrophic; 3) dilated; and4) restrictive cardiomyopathies.

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Arrhythmogenic Right VentricularCardiomyopathy/Dysplasia (ARVC/ARVD)ARVC is a disorder of the myocardium charac-

terized by progressive loss of myocytes and fibro-fatty replacement.95 The disease is commonly lim-ited to the right ventricle, but may involve the leftventricle or interventricular septum in advancedcases. ARVC often presents with ventricular ar-rhythmias originating in the right ventricle, andless commonly with heart failure. Arrhythmias areusually minor during adolescence, and progress tomore serious ventricular arrhythmias during thethird and fourth decade of life. A characteristicfinding is the presence of epsilon wave as well asdepolarization and repolarization abnormalities inthe right precordial leads of the ECG. VT usuallytakes the form of monomorphic VT, although poly-morphic VT with electrocardiographic features ofBrugada syndrome has been described in a smallsubset of ARVC patients.96 ARVC is a commoncause of SCD of the young in Italy, but less so inthe United States.97

ARVC is a genetic disorder with autosomaldominant inheritance in the majority of cases; anautosomal recessive form has been described inconjunction with palmoplantar keratoderma andwoolly hair (Naxos disease).98 Recent studies sug-gest that familial polymorphic ventricular tachy-cardia or catecholaminergic polymorphic ventric-ular tachycardia may be phenotypic variants ofARVC.99

Molecular Genetics of ARVD

Autosomal dominant ARVC has been mappedto eight chromosomal loci, but only three puta-tive genes have been identified (Table II). Thethree genes are RYR2,99 which encodes for the car-diac ryanodine receptor and DSP,100 which codesfor desmoplakin and plakoglobin.98 Mutations inRYR2 are also known to cause catecholaminer-gic (stress induced) ventricular tachycardia, whichmay be a phenotypic variant of ARVC.101 The ryan-odine receptor is a tetrameric protein comprisedof 4 RYR2 polypeptides and 4 FK506-binding pro-teins. It is located on the sarcoplasmic reticulumand is the major source of calcium required for car-diac muscle excitation-contraction coupling. Theactivity of the channel is regulated through phos-phorylation by PKA and its hyperphosphorylationinactivates the channel.102

A mutation in exon 7 of DSP which modifiesa putative phosphorylation site in the N-terminaldomain binding plakoglobin, was recently iden-tified in an Italian family with ARVC.100 Desmo-plakin is a large protein comprised of 2,871 aminoacids and a major component of desmosomes atcell-cell junctions, in particular in epidermal cells

and in cardiac myocytes. The gene responsiblefor autosomal recessive form of ARVC, Naxos dis-ease, is JUP, which encodes for plakoglobin.98

Plakoglobin together with desmoplakin anchorsintermediary filaments to desmosomes. The phe-notype was first described in a family in the Naxosisland in Greece and mapped to 17q21.

Hypertrophic Cardiomyopathy (HCM)HCM is diagnosed clinically by the presence

of cardiac hypertrophy in the absence of an in-creased external load. The most common form isusually diagnosed between the ages of 10 and 25,but has been reported much later in life as well asin infants under 1 year of age.103 Clinical manifes-tations range from minimal to severe heart failure,which may not develop until the third or fourthdecades of life. The majority of patients are asymp-tomatic or mildly symptomatic with predominantsymptoms being dyspnea, chest pain, palpitation,or syncope. Cardiac arrhythmias, in particular AFand nonsustained ventricular tachycardia are rela-tively common and WPW syndrome is uncommon.SCD and severe systolic heart failure are uncom-mon. SCD often occurs as the first manifestationof HCM in the young, asymptomatic and appar-ently healthy individual.104,105 HCM is the mostcommon cause of SCD in young competitive ath-letes, accounting for approximately one third of allSCD.104 This fact notwithstanding, HCM is a rela-tively benign disease.106

Cardiac hypertrophy, myocyte disarray, andinterstitial fibrosis are considered major determi-nants of mortality and morbidity in HCM.107 Hy-pertrophy and myocyte disarray are more promi-nent in the interventricular septum, but scatteredmyocyte disarray is often present throughout themyocardium.108

HCM is a genetically heterogeneous diseasewith an autosomal dominant mode of inheritanceand a prevalence of about 1:500.109 Approximatelytwo thirds of patients have a family history ofHCM (familial) and in the remainder, HCM is spo-radic. Familial and sporadic cases are both causedby mutations in contractile sarcomeric proteins(Table III).110,111 Because hypertrophy is a com-mon response to a variety of stimuli, a pheno-type of hypertrophy in the absence of an increasedexternal load could also occur due to mutationsother than those in sarcomeric proteins, includingmetabolic disorders,112 mitochondrial diseases,113

and triplet repeat syndromes 114 and congenitalheart diseases.115

Seminal work of Christine and Jonathan Sei-dman pioneered the elucidation of the molecu-lar genetic basis of HCM. In 1990, an arginine toglutamine substitution at codon 403 (R403Q) inthe β-myosin heavy chain (MyHC) was identified

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as the first causal mutation.116 Over 150 differentmutations in genes encoding 11 different contrac-tile sarcomeric proteins and a few nonsarcomericproteins have been identified (Table III).111 Aninteresting feature of HCM is the presence of asignificant degree of variability in its phenotypicexpression, whether it is the degree of cardiac hy-pertrophy or the risk of SCD. Gene mutations rangefrom MYH7, which are associated with early on-set, extensive hypertrophy, and a high incidenceof sudden death, to MYBPC3, in which hypertro-phy is relatively mild, the onset of clinical symp-toms is late, and the incidence of SCD is low. Thevariability is due in part to factors other than thecausal genes, including SNPs located in coding orregulatory regions of genes and thus, are consid-ered “modifier” genes. Specific modifier genes inHCM are largely unknown but several have beenimplicated, including components of the renin-angiotensin-aldosterone system.

Dilated Cardiomyopathy (DCM)DCM affects 4 per 10,000 individuals and is

the most common cause of congestive heart fail-ure.103 DCM is characterized by dilatation of theleft ventricle and a progressive decline in contrac-tile function. DCM is diagnosed when left ven-tricular ejection fraction is <0.45 and left ven-tricular end-diastolic diameter is >2.7 cm/m2. Pa-tients with DCM are often asymptomatic in earlystages but gradually develop symptoms and signsof heart failure, syncope, cardiac arrhythmias, andSCD. DCM is familial in approximately half of allindex cases with idiopathic DCM117,118 and spo-radic118 in the rest. Familial DCM is commonlyinherited as an autosomal dominant disease,117

which typically manifests clinically during thethird and fourth decades of life. Three X linkedforms of DCM have been identified: Emery- Drei-fuss syndrome, Duchenne/Becker muscular dys-trophy and Barth’s syndrome. X linked DCM issuspected when only male members of a familyexhibit symptoms and signs of DCM and there isno male-to-male transmission.

Emery-Dreifuss muscular dystrophy is char-acterized by progressive skeletal and cardiac my-opathy. The cardiac phenotype of this X linkeddegenerative disorder include cardiomyopathy, ar-rhythmia, SCD, conduction defects, loss of P waveamplitude, and atrial standstill.

Duchenne/Becker muscular dystrophy, diag-nosed in 1 in 3,500 males usually in the firstand second decades of life, is characterized byprogressive degeneration of muscle function lead-ing to progressive skeletal myopathy, early con-tractures, and cardiomyopathy. Duchenne muscu-lar dystrophy is a much more severe form thanBecker muscular dystrophy. Cardiac involvement

includes progressive atrioventricular block, ar-rhythmia, loss of P wave, atrial standstill, DCM,akinesis/dyskinesis of the posterobasal wall of theleft ventricle, and SCD.

Barth syndrome, another X linked disor-der caused by mutations in the gene encodingtaffazin,119 is characterized by skeletal and car-diac myopathy, neutropenia, DCM, and abnormalmitochondria. DCM also occurs in multiorgansdisorders, such as mitochondrial DNA mutations,triplet repeat syndromes, and metabolic disorders.

DCM has been mapped to a wide diversityof loci and genes (Table IV). The predominantmode of inheritance is autosomal dominant, how-ever, autosomal recessive and X linked DCM havealso been reported. The majority of genes linkedto DCM, encode sarcomeric proteins identical tothose responsible for HCM,120 and many are asyet unknown. This notwithstanding, DCM is atpresent, considered a disease of cytoskeletal pro-teins.121

A large array of phenotypes is observed inDCM families due to mutations in a wide vari-ety of genes. For example, mutations in the rod-domain of lamin A/C cause DCM in conjunc-tion with progressive conduction defects, atrial ar-rhythmias, and SCD.122 In contrast, mutations incardiac α-actin, β-MyHC, and cTnT cause DCMwithout other complications, such as conductiondefects or deafness.120 Mutations in desmin andαB-crystallin genes are commonly associated withskeletal myopathy as well as DCM.123 Mutationsin dystrophin gene often lead to skeletal and car-diac myopathy and the severity of the myopathicphenotype is partly determined by the type of mu-tation.124

Cellular Basis for HCM- and DCM-AssociatedArrhythmias

Little information is available regarding theionic and cellular mechanisms responsible for thearrhythmogenic substrate associated with hyper-trophic and dilated cardiomyopathy encounteredclinically. Experimental studies indicate thatchanges in action potential morphology occurunder these conditions as a result of alterationsin the functional expression of depolarizing andrepolarizing currents. Prolongation of the actionpotential is characteristic of cells and tissuesisolated from the ventricles of animals withhypertrophy or heart failure independent of themechanism (see reference 125 for references).Experimental animal models of hypertrophy126,127

and heart failure128 suggest exaggerated regionalinhomogeneity in action potential duration as theprincipal arrhythmogenic substrate. Enhancedspatial and temporal dispersion of monophasicaction potential duration, refractoriness, and

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electrocardiographic QT intervals in hu-mans,110,129 and animals with heart failure130

and biventricular hypertrophy131 have beenreported and are consistent with an exaggerateddispersion of action potential duration as the basisfor the vulnerable window that predisposes to thedevelopment of reentrant arrhythmias. Transmu-ral and transseptal dispersion of repolarizationare in large part responsible for the developmentof the vulnerable window.

Alterations in intracellular [Ca], redistribu-tion of gap junctions and changes in cell size af-fect cell-to-cell coupling. Modified cellular cou-pling and fibrosis can alter anisotropic conduction,leading to further amplification of spatial nonuni-

formities.125 Hemodynamic load may be exagger-ated in the failing and is unlikely to be distributeduniformly across the ventricular wall or through-out the myocardium, resulting in an increaseddispersion of repolarization with arrhythmogenicconsequences.

Defective repolarization and calcium home-ostasis131−134 may also predispose to early and de-layed afterdepolarizations and triggered activity,which can serve as a source of the extrasystolesthat trigger reentry.

Acknowledgment: I wish to acknowledge the assistanceof Dr. Ramon Brugada in formulating the list of mutations con-tained in the Tables.

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