MECHANISMS

DRUG DISCOVERY

TODAY

DISEASE

Drug Discovery Today: Disease Mechanisms Vol. 1, No. 1 2004

Editors-in-Chief

Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA

Tamas Bartfai – Harold L. Dorris Neurological Research Center and The Scripps Research Institute, USA

Cardiovascular diseases

Inherited and acquired long QTsyndromes: new insights andevolving technologyTimothy J. Kamp*, Craig T. JanuaryDepartments of Medicine and Physiology, University of Wisconsin-Madison, Madison, WI 53792, USA

The long QT syndrome is characterized by prolonga-

tion of the cardiac action potential resulting in

increased heterogeneity of repolarization and early

afterdepolarizations, which trigger the life-threatening

ventricular arrhythmia torsades de pointes. Advances

in understanding the specific ion channel-related gene

mutations linked to the congenital long QT syndrome

and mechanisms underlying the acquired long QT syn-

drome are described, along with emerging technolo-

gies to study these diseases.

*Corresponding author: (T.J. Kamp) tjk@medicine.wisc.edu

1740-6765/$ � 2004 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddmec.2004.08.014

Section Editor:Pascal J. Goldschmidt-Clermont— Duke University MedicalCenter, Durham, NC, USA

The field of cardiology stemmed from the need for clinicians with

expertise in reading a novel test: the electrocardiogram (EKG). TheEKG remains a workhorse for cardiologists interested in predicting

outcomes. Prolongation of ventricular electrical activity, or long QT,whether caused by genetic predisposition, electrolyte disturbances or

drugs, is a crucial EKG marker for risk of arrhythmias. Here Kamp andJanuary, experts in basic and clinical cardiac electrophysiology, provide

remarkable insight into the molecular and genetic components of ioniccurrents that are essential for cardiac repolarization, and they explain

mechanisms by which gene mutations lead to arrhythmogenesis. Drug-induced QT prolongation, whose etiology nearly always involves the

block of HERG K+ channels, creates a sizeable risk for patients andthreatens drug development. Pharmacophore models, models involving

human embryonic stem cells and pharmacogenetics represent new

tools for understanding how genetic determinants underlie a patient’sresponse to therapeutic drugs and susceptibility to side effects.

and acquired forms that typically manifest on an electrocar-

Introduction

Long QT syndrome (LQTS) occurs in (inherited) congenital

diogram by a prolonged QT interval with characteristic ST-T

wave abnormalities, and by symptoms including palpita-

tions, syncope, seizures and sudden death. The congenital

forms include the Romano-Ward (autosomal dominant

inheritance), the Jervell and Lang-Nielsen (autosomal reces-

sive associated with sensorineural deafness), and the Ander-

sen (autosomal dominant associated with dysmorphic

features and periodic paralysis) syndromes. Congenital LQTS

classically involves the multi-generational transmission of

one of seven defective genes that encode ion channel sub-

unit proteins, or the signaling protein ankyrin-B. Congenital

LQTS is rare, occurring perhaps in 1 in 5000 live births, but

represents a major cause of sudden death in otherwise

healthy children and young adults. Acquired LQTS is typi-

cally associated with exposure to certain drugs but also can

occur in various heart diseases, and it can be exacerbated by

electrolyte and metabolic abnormalities such as hypokalemia

or ischemia. Acquired LQTS can occur commonly as a result

of exposure to arsenic trioxide and certain antiarrhythmic

drugs, but for most drugs acquisition of LQTS is a thought

to be a rare response. The present review will describe the

contemporary understanding of the molecular defects under-

lying congenital LQTS and the mechanisms of arrhythmo-

genesis in acquired LQTS.

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Drug Discovery Today: Disease Mechanisms | Cardiovascular diseases Vol. 1, No. 1 2004

Cardiac action potential and early afterdepolarizations

The action potential in cardiac myocytes is the electrical

signal triggering contraction. Multiple ion channels and

electrogenic membrane transporters provide the ionic cur-

rents that result in the precisely regulated cardiac action

potential (Fig. 1). Inward depolarizing currents passing

through voltage-dependent Na+ and Ca2+ channels are

responsible for the rapid upstroke of the action potential.

The time and voltage-dependent decay of these inward Na+

and Ca2+ currents, plus activation of various outward K+

currents, cause repolarization of the myocyte. A variety of

different K+ channel proteins are responsible for the diverse

Figure 1. Relationship between surface electrocardiogram (EKG),

ventricular action potential (AP) and ionic currents (I). The interval

from the beginning of the Q wave to the end of the T wave defines the

electrocardiographic QT interval, which reflects the duration of the

underlying ventricular action potential. Selected ionic currents respon-

sible for generating the ventricular action potential are schematically

shown with inward currents below the dashed zero current line and

outward currents above.

46 www.drugdiscoverytoday.com

K+ currents observed in the myocytes. The K+ channels have

different properties with regard to their gating such as the

voltage range over which they open (activation) or close

(deactivation or inactivation) and the kinetics of opening

and closing. For example, IKr and IKs are the rapid and slowly

activating delayed rectifier currents that differentially con-

tribute to later phases of ventricular repolarization, and pass

through HERG (human ether-a-go-go-related gene; also

known as KCNH2) and KvLQT1 + MinK (KCNQ1 + KCNE1)

K+ channels, respectively. The inward rectifier current, IK1,

contributes to maintaining the cell at the resting membrane

potential, which is approximately the reversal potential for

K+, and passes through Kir2.1 (KCNJ2) channels. There are

numerous other ionic currents that make more minor con-

tributions to the cardiac action potential and these are

described in more detail elsewhere [1]. In addition, cardiac

ion channels and transporters typically exist as multisubunit

protein complexes which also can be associated with macro-

molecular signaling complexes to provide the appropriately

regulated and finely tuned ionic currents.

The action potential duration (APD) is the time from initial

depolarization of the myocyte until it fully repolarizes. The

APD is determined by the dynamic balance between inward

and outward currents, and so decreasing outward currents or

increasing inward currents can delay repolarization to pro-

long APD. Changes in the APD are part of normal cardiac

physiology such as rate-adaptation, for example, APD

decreases as heart rate increases. On the surface electrocar-

diogram, the QT interval represents the aggregate action

potential duration for ventricular myocardium (Fig. 1). LQTS

is due to pathological prolongation of APD, and this underlies

the clinical importance of careful measurement of the QT

interval on the electrocardiogram [2].

Prolongation of APD in some cardiac myocytes can result

in secondary depolarizations in late phases of the action

potential called early afterdepolarizations (EADs), as shown

in Fig. 2A. Certain cardiac myocyte cell types are more prone

to the generation of EADs such as Purkinje fibers of the

conduction system and M cells of the midmyocardium

[3,4]. EADs occur when repolarization is delayed long enough

at plateau voltages to allow recovery of a fraction of inacti-

vated L-type Ca2+ channels, which then reopen to provide

added inward current initiating the EAD [5]. An EAD can, in

some circumstances, excite nearby more polarized myocar-

dium to reach threshold to trigger another action potential,

and if this triggered action potential is propagated through

the heart it causes a premature ventricular beat. In the setting

of the LQTS, there is exaggerated heterogeneity of APD

throughout the heart, and therefore, premature triggered

ventricular beats can lead to complex reentrant circuits of

excitation resulting in a form of polymorphic ventricular

tachycardia (Fig. 2B) [6,7]. On the surface electrocardiogram

a rapid ventricular tachycardia with a changing QRS axis is

Vol. 1, No. 1 2004 Drug Discovery Today: Disease Mechanisms | Cardiovascular diseases

Figure 2. Early afterdepolarization and related ventricular arrhythmia. (a) An action potential recorded from a human embryonic stem cell-derived

cardiomyocyte under basal conditions and after block of IKr with E-4031, which results in action potential prolongation and an early afterdepolarization (EAD;

arrow). Reproduced, with permission, from Ref. [27]. (b) An ECG from a patient receiving the antiarrhythmic agent quinidine that resulted in QT prolongation,

premature ventricular beats and the initiation of torsades de pointes (Tds).

observed, hence the name torsades de pointes or ‘‘twisting of

the points.’’ The ionic mechanisms and complex whole-heart

electrophysiology underlying this form of triggered arrhyth-

mia and other basic mechanisms of arrhythmogenesis are

described in more detail by Akar and Tomaselli [6]. Clinically,

torsades de pointes is often self-limited and produces symp-

toms of palpitations and syncope, but it can also degenerate

into ventricular fibrillation and result in sudden cardiac

death.

Molecular defects underlying congenital LQTS

Because dozens of ion channels and electrogenic membrane

transporters contribute to the delicate balance of currents

responsible for repolarization of the cardiac action potential,

mutations in a variety of genes could theoretically cause

delayed repolarization and congenital LQTS. At the present

time, mutations in seven different genes have been identified

as causing LQTS (see Table 1). Romano-Ward syndrome

occurs with autosomal dominant inheritance and is now

characterized as LQT1-LQT6, referring to six genes involved

Table 1. Genetic defects responsible for inherited long QT synd

Disease Current Chromosome Defe

Romano-Ward (autosomal dominant)

LQT1 IKs, # amplitude 11p15.5 KvLQ

LQT2 IKr, # amplitude 7q35–36 HERG

LQT3 INa, " late current 3p21–24 SCN5

LQT4 altered cell Ca2+ 4q25–27 ANKB

LQT5 IKs, # amplitude 21q22.1–22.2 MinK

LQT6 IKr, " deactivation 21q22.1–22.2 MiRP

Andersen Syndrome (autosomal dominant + dysmorphic features + per

LQT7 IK1, # amplitude 17q23 Kir2.1

Jervell & Lange-Nielsen (autosomal recessive + sensorineural deafness)

JLN1 IKs, # amplitude 11p15.5 KvLQ

JLN2 IKs, # amplitude 21q22.1–22.2 MinK

in its genesis. Loss of function mutations in K+ channel-

related genes resulting in decreased repolarizing current are

responsible for LQT1,2,5, and 6. By contrast, LQT3 is due to

gain of function mutations in the cardiac Na+ channel lead-

ing to altered kinetics and increased late inward Na+ current.

LQT4 is due to mutations in the membrane adapter protein

ankyrin-B and is unique as it does not directly involve an ion

channel subunit. This ankyrin-B mutation is postulated to

disrupt the cellular organization of several ion transporters

and thus interfere with Ca2+ cycling in the myocytes [8].

Sometimes called LQT7, Andersen’s syndrome is due to a loss

of function in the Kir2.1 channel, which is characterized by

modest QT prolongation with ventricular arrhythmias, as

well as dysmorphic features and periodic paralysis of skeletal

muscle. More than 200 mutations have been reported for

LQT1-7. The vast majority of these mutations are single

nucleotide changes that cause single amino acid substitutions

(missense mutations). The most common forms of LQTS are

LQT1 and LQT2. Homozygous mutations in two of the LQTS

genes described above, KvLQT1 (KCNQ1) or MinK (KCNE1),

rome (LQTS)

ctive gene GenBank accession no. Key reference

T1 (KCNQ1) NM000218 [28]

(KCNH2) NM000238 [29]

a (hNaV1.5) NM198056 [30]

NM001148 [31] [8]

(KCNE1) NM000219 [32]

1 (KCNE2) NM005472 [33]

iodic paralysis)

(KCNJ2) NM000891 [34]

T1 (KCNQ1) NM000218 [35]

(KCNE1) NM000219 [36]

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Drug Discovery Today: Disease Mechanisms | Cardiovascular diseases Vol. 1, No. 1 2004

produce the Jervell and Lange-Nielsen phenotype JLN1 and

JLN2, respectively, which we associated with deafness. Occa-

sional spontaneous gene mutations (no familial genetic pat-

tern), and recently a germ-line (somatic) mosaicism,

emphasize the genetic variability [9,10].

The molecular mechanisms by which mutations in these

genes produce alterations in ionic currents are manifold. The

magnitude and kinetics of a given ionic current are due to the

number of channels inserted in the surface membrane, the

intrinsic gating and permeability properties of the channel,

and the regulation of these intrinsic properties by signaling

pathways. Thus, mutations can impact channel function by

altering biophysical, biochemical or biogenic properties, and

there are multiple ways to impact each property. For example,

the number of channels in the surface membrane is regulated

at the level of transcription, translation, trafficking of the

channel to the surface membrane, and degradation of the

protein. Most of our understanding of the effects of muta-

tions in the implicated ion channels or associated proteins

come from heterologous expression studies where the

mutant protein is expressed in a cultured mammalian cell

line or Xenopus oocytes, and the resulting ionic currents and

membrane channels characterized by both biophysical and

biochemical approaches. As an example, the LQT2 syndrome

results from a wide variety of different mutations in the HERG

K+ channel that reduce macroscopic IKr by various mechan-

isms including a reduction in trafficking of the channels to

the surface membrane and various alterations in channel

gating [11]. Furthermore, the tetrameric structure of the

HERG channel can lead to a dominant negative effect by

the mutant allele.

Limitations of current understanding of congenital LQTS

Dramatic advances in our understanding of congenital LQTS

have occurred in the last decade with the identification of

seven different causative genes. However, a simple correla-

tion of genotype with phenotype is not yet possible, and only

�60–70% of the clinically identified cases of LQTS presently

can be linked to known genetic loci [12]. Thus additional new

genes or mutations in gene regions not usually sequenced are

likely to arise [13].

Genotyping has brought additional questions with the

identification of individuals in families harboring the known

mutation but exhibiting normal QT intervals. As clinical

symptoms correlate with QT prolongation [14], individuals

with normal QT intervals tend to be silent carriers. Therefore,

there are important modifying genetic and environmental

factors that impact on disease manifestation, which remain

to be defined. The situation is even more complicated in that

a single genetic mutation in a gene might have dramatically

different consequences depending on the different common

polymorphisms that make-up the ‘‘background’’ of that par-

ticular gene [15]. The paroxysmal nature of events and symp-

48 www.drugdiscoverytoday.com

toms is also poorly understood. Research has identified

several modifying factors that increase the tendency toward

arrhythmias including hypokalemia, being female, and hor-

monal changes [14,16,17]. The activity of the autonomic

nervous system probably plays a crucial role in triggering

events, and differences in the settings of clinical events have

been identified such that in LQT1 and LQT2, events are more

common with exercise or emotional stimulation than in

LQT3, in which events tend to occur during sleep [18].

Acquired LQTS

The idea that drugs and diseases can affect the QT interval

and ST-T waves is nearly as old as the electrocardiogram itself.

Acquired LQTS occurs when a condition arises to cause a

prolonged QT interval, often with associated ventricular

arrhythmias. Multiple different factors have been linked to

the acquired LQTS, and these might act alone or often in

concert to produce the underlying action potential prolonga-

tion. Certain drugs, electrolyte abnormalities, ischemia and

congestive heart failure, starvation, and bradycardia can lead

to or accentuate acquired LQTS. Interestingly, some patient

groups might have increased risk for acquired LQTS, such as

post-menarche females, carriers of the KCNE2 mutation T8A

(threonine to alanine), and patients with altered drug meta-

bolism. These differences in the risk of developing a long QT

interval in the population have in part been attributed to

differences in what has been termed ‘‘repolarization reserve’’

[19]. The concept is that the many ionic currents that main-

tain normal cardiac repolarization vary between patients, but

collectively they lead to a normal range of action potential

durations in the basal state. However, after provocative sti-

muli (e.g. a drug or altered electrolytes), the variations

become greater, and thus some patients could be more sus-

ceptible to acquired LQTS. A corollary of this is that poly-

morphisms or silent mutations in ion channel and related

genes can contribute to altered repolarization reserve,

although this remains an area of controversy.

Drug-induced long QT and HERG channel block

Drug-induced LQTS is an infrequent complication of phar-

macological therapy, but the resulting potentially fatal ven-

tricular arrhythmias have focused great attention on this

problem. Beginning with Class III antiarrhythmic drugs,

which were intended to cause lengthening of APD, refractori-

ness and the QT interval, a diverse range of other drugs have

now been implicated in QT prolongation. A major challenge

in detecting unwanted QT prolongation associated with a

therapeutic agent is the often-times rare nature of this side

effect. As a consequence of this unintentional drug side effect,

several medications have been removed from the market or

had their use severely limited, and concern about this poten-

tial toxicity has also ended the development of countless

other lead compounds and new medications.

Vol. 1, No. 1 2004 Drug Discovery Today: Disease Mechanisms | Cardiovascular diseases

The mechanism of this untoward drug-induced QT pro-

longation has almost universally been block of HERG K+

channels, or IKr, which is analogous to the congenital syn-

drome LQT2 associated with loss of function mutations in the

HERG gene. Assays based on the expression of normal HERG

channels in mammalian cell lines (such as HEK293 cells [20])

have now provided easy screening technologies to detect

compounds capable of high affinity HERG channel block

and the risk of drug-induced LQTS and Table 2 summarizes

our experience with available drugs. The situation is more

complicated as not only are parent compounds capable of

blocking HERG channels, but also metabolites of some drugs

can exert high affinity HERG channel block which might be

exacerbated by various drug–drug interactions impacting

drug metabolism. For example, the non-sedating antihista-

mine astemizole is metabolized rapidly mostly to desmethy-

lastemizole, which is equipotent to the parent compound for

HERG channel block and has a prolonged elimination time;

thus it is the dominant cause of astemizole induced QT

prolongation [21]. Another example is terfenadine, which

also causes drug-induced QT prolongation. Normally its near

complete first pass metabolism to terfenadine-carboxylate

Table 2. Drug block of HERG channels expressed in HEK293cellsa

Drug IC50

Astemizole 0.9 nM

Desmethylastemizole 1.0 nM

Cisapride 6.5 nM

E-4031 7.7 nM

Halofantrine 21.6 nM

Norastemizoleb 27.7 nM

Droperidol 32.2 nM

N-desbutylhalofantrine 71.9 nM

Verapamil 143 nM

Flecainide 279 nM

Mibefradil 460 nM

Cocaine 7.2 mM

HIV protease inhibitorsc 8.2–15.3 mM

Diltiazem 17.8 mM

Fexofenadine 65.1 mM

4-AP 1.1 mM

Nifedipine No effect

Losartan No effect

Ethanol No effect

a Data obtained using whole-cell patch clamp experiments performed at the University of

Wisconsin-Madsion (e.g. see Zhou et al.) [21]. Additional information on drugs associated

with acquired LQTS can be found at www.torsades.org and www.longqt.org.b Partial block.c Lopinavir, Nelfinavir, Ritanovir, Saquinavir.

(fexofenadine), which has a markedly reduced HERG channel

block potency, results in minimal drug-induced QT prolon-

gation and acquired LQTS. However, co-administration of

ketoconazole can inhibit first pass metabolism by blocking a

cytochrome P450 isoform to allow significant levels of terfe-

nadine to be reached in the circulation with an increased risk

of acquired LQTS. Thus acquired LQTS can be caused by direct

block of HERG channels by a drug or metabolites, their effects

on drug metabolism, and combinations of multiple HERG

blocking drugs. Similarly, the risk of manifesting drug-

induced LQTS is also dependent on several associated factors

that also affect the QT interval, such as hypokalemia, heart

failure, being female, and bradycardia. Finally, it is important

to realize that not every drug causing high affinity block of

HERG channels has a significant incidence of LQTS, with

examples being verapamil and amiodarone. These drugs

block additional channels that might offset the effect of

HERG channel block, such as Ca2+ channels. Therefore, the

composite profile of drug action on the cardiac action poten-

tial and vulnerability to EADs will probably remain crucial in

understanding the true risk of drug-induced LQTS.

Summary and conclusions

Research on the genetic basis of congenital LQTS has pro-

vided remarkable insight into the molecular components and

ionic currents that are essential for repolarization of cardiac

action potentials. Multiple new genes encoding ion channel

and associated subunit proteins have been discovered.

Furthermore, the understanding of cellular and tissue

mechanisms in which these mutations lead to arrhythmo-

genesis has advanced. Despite this progress, many important

questions remain. Why do some family members who inherit

a disease-associated mutation have a normal QT interval and

are clinically unaffected? Can the emerging technologies

associated with genomics and proteomics assist in explaining

variable penetrance? Ultimately, one goal is to be able to

accurately risk-stratify individual patients, to determine

appropriate therapy. Risk varies with the loci affected, with

better survival in LQT1 than LQT2 and LQT3 [14]. However,

it seems probable that even at a given loci, different muta-

tions in a gene will impart distinct risk profiles [22]. Loci or

mutation specific therapy might emerge to treat patients

with congential LQTS [23,24,11]. Will newer therapies using

gene delivery or even cell delivery to stabilize repolarization

obtain clinical relevance in this disease? Finally, not all

cases of LQTS have been successfully genotyped, suggesting

that additional new genes or associated with LQTS await

discovery.

Like congenital LQTS, the understanding of the acquired

LQTS has dramatically advanced. In particular, drug-induced

QT prolongation has been a focus of vigorous investigations,

which have revealed that nearly all of these compounds act

by blocking HERG K+ channels. Patient-to-patient variability

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Drug Discovery Today: Disease Mechanisms | Cardiovascular diseases Vol. 1, No. 1 2004

in the susceptibility to drug-induced QT prolongation exists,

and undoubtedly is due, in part, to differences in the genetic

background contributing to repolarization. HERG block,

although crucial, does not always produce acquired LQTS,

as noted above. This raises the question of how much HERG

block is acceptable and under what associated conditions, an

issue presently being addressed through the International

Conference on Harmonization (ICH 57B step2 revisions

and related E14 guidelines), partnership of regulatory agen-

cies and industry.

A variety of strategies have emerged to avoid the potential

for drug-induced LQTS. A major focus has been on direct

(patch clamp studies) and indirect (competitive displacement

of radio-labeled compounds, rubidium flux, biochemical

assay) screening using heterologously expressed normal HERG

channels. Other efforts have focused on site-directed muta-

genesis to precisely define the structure-activity relationship

for compounds that block HERG channels and pharmaco-

phore models with the goal of understanding the precise

structural determinants necessary for HERG block [25]. Ulti-

mately, the field of pharmacogenetics will provide under-

standing of how genetic determinants underlie a patient’s

response to therapeutic drugs and susceptibility to side effects.

Further progress in our understanding of both congenital

and acquired LQTS will require continued advances in model

systems to investigate these human syndromes. Although

heterologous expression studies of cloned ion channel genes

in mammalian cells or Xenopus oocytes have provided major

breakthroughs, these model systems fall short of providing a

complete understanding of the effects in the intact heart. In

the case of screening compounds for the risk of QT prolonga-

tion, isolated canine Purkinje fibers have been widely used, but

this screening strategy has limitations as it failed to identify the

risk of LQTS associated with the now withdrawn antihista-

mine, terfenadine [26], although HERG-based cellular assays

showed it to be a potent channel blocker. The use of animal

models in drug toxicity or the creation of transgenic mice,

although important, is limited by the complexity and number

of animals that can be studied. Furthermore, small animal

hearts such as the mouse cannot easily reproduce some reen-

trant arrhythmias found in larger hearts such as the human

heart. Transgenic rabbits will provide larger hearts, which

exhibit action potentials more comparable to man, including

a prominent IKr. However, the ideal model will study the

mutation, drug or other provocative LQTS stimuli in an envir-

onment that most closely mimics the human heart both at the

cellular and multicellular level. The desired model system

should be highly reproducible, spare animal use, and be amen-

able to high throughput approaches for screening. A promis-

ing new approach utilizes human cardiomyocytes derived

from human embryonic stem cells in vitro (see action poten-

tials shown in Fig. 2A) [27]. Human embryonic stem cell-

derived cardiomyocytes might ultimately permit the study

50 www.drugdiscoverytoday.com

of the electrophysiological effects of human mutations in

LQTS and might offer a powerful new approach to screening

for drugs capable of causing drug-induced QT prolongation.

Research in tissue engineering might eventually permit the in

vitro generation of multicellular cardiac preparations from

stem cell-derived cells that will mimic the complex nature

of heart tissue. In the past decade, remarkable progress has

been made linking genetic mutations and drugs to ion channel

alterations and to LQTS phenotype, but much work remains

before we truly understand the mechanisms underlying LQTS.

Acknowledgments

The excellent support of Thankful Sanftleben in preparation

of this manuscript is acknowledged. Support was provided by

NHLBI R21HL72089 (TJK), P01HL47053 (TJK), and NHLBI

R01 HL60723 (CTJ).

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