Physiol Rev 85: 33– 47, 2005;
doi:10.1152/physrev.00005.2004.
Inherited and Acquired Vulnerability to Ventricular
Arrhythmias: Cardiac Na⫹ and K⫹ Channels
COLLEEN E. CLANCY AND ROBERT S. KASS
Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Medical College
of Cornell University, and Department of Pharmacology, College of Physicians and Surgeons of Columbia
University, New York, New York
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I. Introduction
II. Long QT Syndrome
III. Na⫹ Channelopathies: INa, the Fast Voltage-Gated Na⫹ Channel
A. Mutations can result in multiple phenotypes
B. The heterogeneous myocardial substrate
C. Mutations and/or polymorphisms may increase susceptibility to drug-induced arrhythmias
IV. K⫹ Channelopathies: IKs, the Slowly Activating Component of the Delayed Rectifier K⫹ Current
A. Mutations in KCNQ1 or KCNE1 can underlie long QT syndrome
B. Cellular consequences of IKs channel blockade
C. Blockade of IKs and ␤-adrenergic stimulation
V. K⫹ Channelopathies: IKr, the Rapidly Activating Component of the Delayed Rectifier
A. Cellular consequences of IKr blockade by mutations and/or drugs
B. HERG channels are promiscuous drug targets
C. State-specific block of IKr
D. Gene-specific triggers and treatments
VI. Summary
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Clancy, Colleen E., and Robert S. Kass. Inherited and Acquired Vulnerability to Ventricular Arrhythmias: Cardiac
Na⫹ and K⫹ Channels. Physiol Rev 85: 33– 47, 2005; doi:10.1152/physrev.00005.2004.—Mutations in cardiac Na⫹ and
K⫹ channels can disrupt the precise balance of ionic currents that underlies normal cardiac excitation and
relaxation. Disruption of this equilibrium can result in arrhythmogenic phenotypes leading to syncope, seizures, and
sudden cardiac death. Congenital defects result in an unpredictable expression of phenotypes with variable
penetrance, even within single families. Additionally, phenotypically opposite and overlapping cardiac arrhythmogenic syndromes can stem from one mutation. A number of these defects have been characterized experimentally
with the aim of understanding mechanisms of mutation-induced arrhythmia. Improving understanding of abnormalities may provide a basis for the development of therapeutic approaches.
I. INTRODUCTION
Meticulously timed opening and closing of cardiac
ion channels results in cardiac electrical excitation and
relaxation that is coupled to rhythmic contraction of the
heart (Fig. 1). Abnormalities resulting from pharmacological agents or congenital defects can undermine the cardiac electrical syncytium, resulting in the development of
debilitating arrhythmias that act to destabilize coordinated contraction and lead to the failure of sufficient
pressure for blood circulation (85).
Cardiac excitation originates in the sinoatrial node
and propagates through the atria into the atrial-ventricular node. The impulse then enters the Purkinje conduction
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system, which delivers the excitatory wave to the ventricles. Ventricular excitation spreads from the endocardium to the epicardium and is coupled to the contraction
of the ventricles that generates systolic blood pressure.
The wave of excitation that spreads over the heart reflects
membrane depolarization of cardiac myocytes (Fig. 1),
due primarily to the activation of fast voltage-dependent
Na⫹ channels that underlie the action potential (AP) upstroke. Activation is followed by a long depolarized plateau phase that permits Ca2⫹-induced Ca2⫹ release from
the sarcoplasmic reticulum, binding of Ca2⫹ to contractile
proteins on the sarcomeres, and coordinated contraction
(systole). Repolarization follows due to time- and voltagedependent activation of K⫹ currents. Relaxation of con-
0031-9333/05 $18.00 Copyright © 2005 the American Physiological Society
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COLLEEN E. CLANCY AND ROBERT S. KASS
drug-provoked Brugada syndrome (29, 40, 125, 140). Prolongation of the action potential duration (APD) (delayed
repolarization) results in long QT intervals and may result
in morphological changes in the T wave that can provide
insight as to the underlying cellular mechanism of APD
prolongation (40, 139, 142).
Individuals displaying ECG abnormalities may be at
higher risk of lethal arrhythmias associated with syncope
and sudden death. Many such arrhythmic events are rate
dependent and may be linked to sudden changes in heart
rate due to exercise or auditory stimulation that may
trigger life-threatening arrhythmias (99, 142).
FIG. 1. Electrical gradients in the myocardium can be detected on
the body surface electrocardiogram (ECG) and reflect underlying cellular ionic current gradients. A: illustration of a single cardiac cycle ECG
detected as electrical gradients on the body surface. B: schematic representation of the ventricular action potential gradients detected on the
body surface ECG. C: ionic currents responsible for the different phases
of the action potential and the genes that encode for them. Darkened
shapes are indicative of relative current amplitude, duration, and direction. The shape of the current is also aligned with its approximate time
of action during the ECG (A) and the cardiac ventricular action potential
(B). (Modified from Clancy CE and Kass RS. J Clin Invest 110: 1075–
1077, 2002; and The Sicilian Gambit. Circulation 84: 1831–1851, 1991.)
traction is coupled to the electrical repolarization phase,
which allows filling of the ventricles (diastole) before the
next excitation. Each of these electrical processes can be
detected on the body surface electrocardiogram (ECG) as
a signal average of the temporal and spatial gradients
generated during each phase (Fig. 1) (9, 40, 85). Electrical
excitation gradients in the atria (atrial depolarization)
manifest on the ECG as P waves, while gradients of
ventricular depolarization are seen as the QRS complex.
Gradients in ventricular repolarization are reflected in the
T wave.
Electrocardiographic abnormalities are related to
changes in cellular AP morphologies, which may be due
to altered cell-to-cell coupling, heart disease, congenital
ion channel abnormalities, drug intervention, or electrolyte imbalance (9, 40, 85). Conduction abnormalities can
be detected as changes in the QRS complex. Widening of
the QRS reflects reduced conduction velocity, which typically stems from altered Na⫹ channel function (121). ST
segment elevation reflects transmural voltage gradients
during the AP plateau, a hallmark of congenital forms or
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Long QT syndrome (LQTS) is a collection of cardiac
disorders characterized by a prolongation of the QT interval on the ECG and can be divided into two primary
clinical categories: inherited and acquired. The acquired
form of LQTS generally results from pharmacological
therapeutic intervention, often for the purpose of treating
disorders unrelated to cardiac dysfunction. Many medications, including antihistamines, antipsychotics, antibiotics, and antiarrhythmics, can predispose patients to lethal
arrhythmias (26). Acquired forms of LQTS may also result
from electrical or structural abnormalities arising from
other rhythm disorders, cardiac ischemia, and a range of
cardiomyopathies. Inherited forms of LQTS are predominantly autosomal dominant, although less common autosomal recessive forms exist and typically result in more
severe phenotypes. Romano-Ward syndrome is typically
autosomal dominant and predominantly heterozygous, although some more severe homozygous forms exist (131).
Romano-Ward is distinguishable from Jervell LangeNielsen syndrome, since the latter is autosomal recessive
and always accompanied by hearing loss (22). The inherited, or congenital, LQTS results from mutations in genes
coding for cardiac proteins including ion channels, accessory subunits, and associated modulatory proteins, responsible for orchestrating the AP in the heart. To date,
five genes have been implicated in Na⫹ and K⫹ channel
linked LQTS (Table 1).
III. Naⴙ CHANNELOPATHIES: INa, THE FAST
VOLTAGE-GATED Naⴙ CHANNEL
Voltage-gated Na⫹ channels cause the rapid depolarization that marks the rising phase of APs in the majority
of excitable cells. At negative membrane potentials, channels typically reside in closed and available resting states
that represent a nonconducting conformation. Depolarization results in activation of the voltage sensors and
channel opening, allowing for ion passage. Subsequent to
channel activation, channels enter inactivated states that
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II. LONG QT SYNDROME
CARDIAC Na⫹ AND K⫹ CHANNELS AND VENTRICULAR ARRHYTHMIAS
TABLE
1.
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Na⫹ and K⫹ channel LQT-associated genes and proteins
Type
LQT1
LQT2
LQT3
LQT5
LQT6
Gene
Protein
KCNQ1
KCNQ1, KvLQT1, ␣-subunit
of IKs
KCNH2 (hERG)
HERG or ␣-subunit
of IKr
SCN5A
Nav1.5 or ␣-subunit
of INa
KCNE1
KCNE1, MinK or ␤-subunit
of IKs
KCNE2
MiRP1 or ␤-subunit
of IKr
INa, fast voltage-gated Na⫹ channel; IKs, slowly activating component of the delayed rectifier K⫹ current; IKr, rapidly activating component of
the delayed rectifier K⫹ current.
Many mutations in the cardiac voltage-gated Na⫹
channel isoform NaV1.5 have been shown to underlie several disease phenotypes including the LQTS type 3 (LQT3),
Brugada syndrome (BrS), and isolated cardiac conduction
disease (ICCD). Mutations underlying these clinical syndromes are scattered throughout the channel (Fig. 2).
In general, Na⫹ channel-linked LQTS stems from mutation-induced disruption of channel inactivation, as was
originally identified in the ⌬KPQ mutation, a three-amino
acid deletion in the intracellular linker between domains
III and IV of NaV1.5. This motif is known to be critical for
fast inactivation of the channel, and the mutation results
in persistent noninactivating current (11, 20). The noninactivating component of INa acts to prolong the plateau of
the AP and may allow for the development of arrhythmogenic triggered activity, referred to as early afterdepolarizations (EADs) (27) (Fig. 3).
While ⌬KPQ is one example of altered gating, several
recent studies suggest that mutation-induced gain of function in cardiac INa can exist in at least three distinct forms
(Fig. 4). The most common is due to transient inactivation
failure as in ⌬KPQ, which underlies sustained Na⫹ channel activity over the plateau voltage range (9, 19). A
second is due to steady-state channel reopening called
window current (20), because reopening occurs over voltage ranges for which steady-state inactivation and activation overlap. A third original mechanism was demonstrated in channels containing the I1768V mutation, which
⫹
FIG. 2. The cardiac Na channel is
involved in multiple arrhythmogenic syndromes. Shown is a schematic representation of the voltage-gated cardiac Na⫹
channel (NaV1.5), in which mutations can
lead to the LQT3 form of long QT syndrome (LQTS), Brugada syndrome (BrS),
and isolated cardiac conduction disorder
(ICCD) or mixed combinations of
disorders.
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are nonconducting and refractory. Repolarization is required to alleviate inactivation with isoform-specific time
and voltage dependence.
SCN5A encodes the cardiac isoform (NaV1.5) of the
voltage-gated Na⫹ channel, which is a heteromultimeric
protein complex consisting of four heterologous domains,
each containing six transmembrane spanning segments.
Positive residues are clustered in the S4 segments and
comprise the voltage sensor (52, 119) (Fig. 2). The intracellular linker between domains three and four, DIII/DIV,
includes a hydrophobic isoleucine-phenylalanine-methionine (IFM) motif, which acts as a blocking inactivation
particle and occludes the channel pore, resulting in channel
inactivation subsequent to channel opening (119, 134). Recent studies also suggest a role for the COOH terminus in
channel inactivation in brain and cardiac isoforms (NaV1.1
and NaV1.5, respectively) (31, 66, 74). The S5 and S6 transmembrane segments of each domain comprise the putative
channel pore and associated ion selectivity filter (120, 138).
There has been renewed interest in the study of
voltage-gated Na⫹ channels since the recent realization
that genetic defects in Na⫹ channels can underlie idiopathic clinical syndromes (41). Interestingly, all Na⫹
channel-linked syndromes are characterized by episodic
attacks and heterogeneous phenotypic manifestations
(59, 116). These defective channels suggest themselves as
prime targets of disease and perhaps even mutation-specific pharmacological interventions (19, 41).
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COLLEEN E. CLANCY AND ROBERT S. KASS
does not result in an obvious gain of channel function (30,
44, 83). However, under nonequilibrium conditions during
repolarization, channel reopening results from faster recovery from inactivation at membrane potentials that facilitate the activation transition (30). Mutation-induced
⫹
FIG. 4. Na channel-linked LQTS mutations result in a gain of function and can stem from at least three distinct mechanisms. A: the most
common is due to transient inactivation failure as in ⌬KPQ, readily seen in the single-channel gating, which underlies sustained Na⫹ channel activity
over the plateau voltage range (9, 19). Wild-type (WT) and ⌬KPQ mutant channels are shown in the top four and bottom five traces, respectively.
Mutant channels exhibit two distinct forms of abnormal gating compared with WT. [From Clancy and Rudy (28).] B: the E1295K mutation shifts the
voltage dependence of steady-state channel reopening called window current into voltages relevant during the action potential plateau (20).
Reopening occurs over voltage ranges for which steady-state inactivation and activation overlap (top). Window current is easily observable by
implementing a slow positive voltage ramp. [From Abriel et al. (4).] C: a third original mechanism was demonstrated in channels containing the
I1768V mutation, which does not result in an obvious gain of channel function (30, 44, 83). However, under nonequilibrium conditions during
repolarization, channel recovery from inactivation states that occur subsequent to opening is faster at membrane potentials that facilitate the
activation transition (30). Mutation induced faster recovery from inactivation results in channels that reopen during repolarization and that the
resulting current amplitude rivals that of bursting channels. [From Clancy et al. (30).]
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FIG. 3. The effect of ⌬KPQ mutation on the whole cell action
potential. Wild-type (WT) Na⫹ channels activate and then rapidly enter
nonconducting inactivation states where they remain throughout the
action potential plateau (left). The ⌬KPQ mutation results in a fraction
of channels that transiently fail to inactivate resulting in persistent Na⫹
current (INa) during the action potential plateau (right), which prolongs
the action potential duration (compare with WT on left). In both panels,
action potentials are shown in the top and corresponding Na⫹ current
below at high gain (peak current ⬎300 ␮A/␮F in both WT and mutant
cases). [Modified from Clancy and Rudy (28).]
faster recovery from inactivation results in channels that
reopen during repolarization, and the resulting current
amplitude rivals that of bursting channels. Simulations
have demonstrated that late current due to channel reopening causes severe prolongation of the AP plateau and
arrhythmic triggers (30).
Recently, several studies have focused on the role of
the intracellular COOH terminus of the Na⫹ channel in
voltage-gated Na⫹ channel inactivation (31, 66). Notably,
gene defects associated with LQT3 located in this region
disrupt inactivation in a manner similar to mutations that
affect the DIII/DIV linker inactivation gate. LQT3 mutations in this region (E1784K, 1795insD, Y1795C) evoke
small, sustained currents similar to ⌬KPQ (8, 82, 125).
Unlike LQTS that is associated with a gain of Na⫹
channel function, loss of Na⫹ channel function underlies
the BrS phenotype. BrS is an arrhythmic syndrome characterized by right bundle branch block, ST segment elevation on the ECG, and ventricular tachyarrhythmias often resulting in sudden death (14). Mutations in NaV1.5
have been linked to BrS and characteristically cause a
reduction in INa (21, 42). This reduction in INa has been
shown to occur by several mechanisms in BrS, including
reduced rates of recovery from inactivation, faster inactivation subsequent to channel opening, and protein trafficking defects (29, 35, 82, 125, 129).
ICCD is observed on the ECG in a widening of the
QRS complex, indicating delays in ventricular excitation
CARDIAC Na⫹ AND K⫹ CHANNELS AND VENTRICULAR ARRHYTHMIAS
(42, 121). They are associated with bradycardia and may
manifest as syncope. Mutations in NaV1.5 have been
shown to cause ICCD and typically result from a depolarizing shift of the Na⫹ channel activation curve (42, 121).
This shift most likely results from a reduction in the rate
of channel activation or decreased channel sensitivity to
the voltage required for activation. Mutant channels may
require a greater amount of time to reach depolarized
membrane potentials at which the maximum INa occurs.
The lag in activation of ICCD mutant Na⫹ channels would
result in a reduction of the AP upstroke velocity, a primary determinant of conduction velocity (88, 105).
The relationship between genetic mutations and clinical syndromes is becoming increasingly complex as the
revelation of novel mutations suggests paradoxical phenotypic overlap or exclusivity. Recently, at least three loci
in the cardiac sodium channel have been identified where
the same mutation can result in different disease phenotypes. An insertion of an aspartic acid residue (1795insD)
in the COOH terminus of NaV1.5 can result in either BrS or
LQTS (125). Additionally, mutation of the same residue to
a histidine (Y1795H) or cysteine (Y1795C) results in BrS
and LQTS, respectively, indicating the proximal region of
the COOH terminus as a potentially important structure in
Na⫹ channel function (82).
The mutation of a glycine to arginine (G1406R)
DIII-S5 linker region to DIII-S6 resulted in either BrS or
ICCD in several families (56). Expression studies resulted
in no current, although no trafficking errors were detected, suggesting a potential modifier gene or genes affecting NaV1.5 function.
The deletion of a lysine (⌬K1500) in the III-IV linker
of NaV1.5 is associated with BrS, LQTS, and ICCD (42).
LQTS is typically associated with gain-of-function Na⫹
channel mutations while BrS and ICCD are typically associated with loss-of-function resulting in reduced INa.
The fact that single mutations can underlie disparate phenotypes begs the question of underlying mechanisms.
How can a single mutation simultaneously result in seemingly paradoxical syndromes (i.e., gain-of-function LQTs
and loss-of-function BrS)?
B. The Heterogeneous Myocardial Substrate
One explanation may stem from the intrinsic heterogeneity of the underlying myocardial substrate with
which mutant Na⫹ channels interact (Fig. 5). The ventricular myocardium is comprised of at least three distinct
cell types referred to as epicardial, midmyocardial (M),
and endocardial cells, which exhibit distinct electrophysiological properties (60).
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FIG. 5. Cellular electrical abnormalities manifest as clinical syndromes. A: mutation-induced changes in epicardial action potential (AP)
morphologies (thick line) cause dispersion of plateau potentials and a
voltage gradient (ƒVm, arrows) (WT, thin line). This gradient will manifest on the ECG as ST segment elevation, indicative of BrS. B: mutations
may prolong AP duration (APD) in myocardial (M) cells (thick line)
compared with WT (thin line). The delay in repolarization (⌬APD ⫽ 60
ms) is reflected as QT prolongation on the ECG, a hallmark of LQTS.
(Modified from Clancy CE and Kass RS. J Clin Invest 110: 1075–1077,
2002.)
Epicardial cells display a characteristic spike and
dome morphology due to large transient outward K⫹ current (Ito) and short APD resulting from a high density of
the slowly activating component of the delayed rectifier
K⫹ current (IKs) (60). Mutations that act to reduce INa in
the presence of large repolarizing currents (Ito and IKs)
may result in premature plateau repolarization (BrS phenotype) and APs with distinctive triangular morphology
or in APs with prominent coved domes (29, 35, 60, 140).
Ito and IKs are smaller in M cells and are unable to
overwhelm the mutation induced by reduced INa. Selective loss of the AP plateau in epicaridal cells results in
dispersion of plateau potentials across the ventricular
wall. This gradient generates ST segment elevation on the
ECG, which is a diagnostic indicator of BrS (21, 140).
Clinically, ST segment elevation is observed in right precordial leads of BrS patients, consistent with the large Ito
density in right ventricular epicardium (35, 140). In M
cells, the noninactivating component of INa, in the presence of smaller repolarizing currents, acts to prolong the
plateau of the AP (29) and may allow for the development
of arrhythmogenic EADs (LQT phenotype). APD prolongation is reflected in a prolonged QT interval on the ECG,
indicative of the LQTS.
C. Mutations and/or Polymorphisms May Increase
Susceptibility to Drug-Induced Arrhythmias
Within the context of arrhythmia, pharmacogenomic
considerations are important to determine the potential
for genetic heterogeneity to directly affect drug targets
and interfere with drug interactions. Mutations or polymorphisms may directly interfere with drug binding (62)
or can result in a physiological substrate that increases
predisposition to drug-induced arrhythmia (113).
Use-dependent block of voltage-gated Na⫹ channels
results in preferential reduction of current at fast pacing
rates (62). This property is potentially useful in reducing
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A. Mutations Can Result in Multiple Phenotypes
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COLLEEN E. CLANCY AND ROBERT S. KASS
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mutations were more sensitive to blockade by mexilitene,
a drug with similar properties to lidocaine, than wild-type
channels (130). In three mutations, ⌬KPQ, N1325S, and
R1644H, mexilitene displayed a higher potency for blocking late Na⫹ current than peak Na⫹ current (130).
We found that flecainide, but not lidocaine, showed a
more potent interaction with a COOH-terminal D1790G
LQT3 mutant than with wild-type channels and a correction of the disease phenotype (4, 62). The precise mechanism underlying these differences is unclear. Lidocaine
has a pKa of 7.6 – 8.0 and thus may be up to 50% neutral at
physiological pH. In contrast, flecainide has a pKa of ⬃9.3,
leaving ⬍1% neutral at pH 7.4 (46, 100, 118). Thus one
possibility underlying differences in the voltage dependence of flecainide- and lidocaine-induced modulation of
cardiac Na⫹ channels is restricted access to a common
site that is caused by the ionized group of flecainide.
Another possibility is that distinctive inactivation gating
defects in the D1790G channel may underlie these selective pharmacological effects. Indeed, we recently found
mutations that promote inactivation (shift channel availability in the hyperpolarizing direction) enhance flecainide block. Interestingly, our data also showed that flecainide sensitivity is mutation, but not disease, specific (62).
These studies are important in the demonstration
that effects of flecainide segregate in a mutation-specific
manner that is not correlated with disease phenotype,
suggesting that it may not be an effective agent for diagnosing or treating genetically based disease. The nature of
the interaction between pharmacological agents and wildtype cardiac Na⫹ channels has been extensively investigated. However, the new findings of drug action on mutant channels in LQTS and BrS have stimulated a renewed
interest in a more detailed understanding of the molecular
determinants of drug action, with the specific aim of
developing precise, disease-specific therapy for patients
with inherited arrhythmias.
IV. Kⴙ CHANNELOPATHIES: IKs, THE SLOWLY
ACTIVATING COMPONENT OF THE
DELAYED RECTIFIER Kⴙ CURRENT
IKs, the slowly activating component of the delayed
rectifier K⫹ current, is a major contributor to repolarization of the cardiac AP (49). Moreover, IKs is a dominant
determinant of the physiological heart rate-dependent
shortening of APD (37, 117, 127, 141). Sympathetic stimulation and resulting fast pacing results in short diastolic
(recovery) intervals that prevent complete deactivation of
IKs, resulting in the build-up of instantaneous IKs repolarizing current at the AP onset (37, 117, 127, 141). At slower
rates, less repolarizing current exists during each AP due
to sufficient time between beats to allow for complete
deactivation of IKs (37, 117, 127, 141).
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runaway excitation by reducing Na⫹ current and thereby
decreasing the likelihood of reexcitation. The unpredictable outcomes of pharmacological intervention with mutant channels must be investigated to develop appropriate
treatments, since a Na⫹ channel blocker may be ineffective, or overly effective, in interacting with mutant channels.
Genetic mutations or polymorphisms may affect drug
binding by altering the length of time that a channel
resides in a particular state. For example, the epilepsy
associated R1648H mutation in NaV1.1 reduces the likelihood that a mutant channel will inactivate and increases
the channel open probability (64). Hence, an anticonvulsant that interacts with open channels will have increased
efficacy, while one that interacts with inactivation states
may have reduced efficacy. However, even this type of
analysis may not predict actual drug-receptor interactions
(61, 62). The I1768V mutation increases the cardiac Na⫹
channel isoform propensity for opening, suggesting that
an open channel blocker would be more effective, but in
fact, the mutation is in close proximity to the drug-binding
site, which may render open channel blockers nontherapeutic (61, 62).
Local anesthetic molecules such as lidocaine and
flecainide block Na⫹ channels and have been used therapeutically to manage cardiac arrhythmias (89, 90, 136).
Despite the prospective therapeutic value of the inherent
voltage- and use-dependent properties of channel block
by these drugs in the treatment of tachyarrhythmias, their
potential has been overshadowed by toxic side effects
(91, 133). However, Na⫹ channel blockers have proven
useful as a diagnostic tool and in treatment of BrS and
LQT3 (15). Na⫹ channel blockade by flecainide is of particular interest as it had been shown to reduce QT prolongation in carriers of some LQT3 mutations and to
evoke ST segment elevation, a hallmark of the BrS, in
patients with a predisposition to the disease (15). Thus, in
the case of LQT3, flecainide has a potential therapeutic
application, whereas for BrS it has proven useful as a
diagnostic tool. However, in some cases, flecainide has
been reported to provoke BrS symptoms (ST segment
elevation) in patients carrying LQT3 mutations (81). Furthermore, flecainide preferentially blocks some LQT3- or
BrS-linked mutant Na⫹ channels (5, 43, 62, 126). Investigation of the drug interaction with these and other LQT3
and BrS linked mutations may indicate the usefulness of
flecainide in the detection and management of these disorders and determine whether or not it is reasonable to
use this drug to identify potential disease-specific mutations.
Recent findings revealed the differential properties of
certain drugs on mutant and wild-type cardiac Na⫹ channels. One such example is the preferential blockade by
flecainide of persistent INa in the ⌬KPQ Na⫹ channel
mutant (75). It was also shown that some LQT-associated
CARDIAC Na⫹ AND K⫹ CHANNELS AND VENTRICULAR ARRHYTHMIAS
A. Mutations in KCNQ1 or KCNE1 Can Underlie
Long QT Syndrome
phosphatase 1 (PP1) to the channel. The complex then
regulates the phosphorylation of Ser-27 in the NH3 terminus of KCNQ1 (67). PKA phosphorylation of IKs considerably increases current amplitude, by increasing the rate
of channel activation and reducing the rate of channel
deactivation (53, 54, 67). Each of these outcomes acts to
increase the channel open probability leading to increased current amplitude and faster cardiac repolarization.
Mutations in either KCNQ1 or KCNE1 can reduce IKs
amplitude resulting in abnormal cardiac phenotypes and
the development of lethal arrhythmias (Fig. 6B) (112).
Reduction of IKs during the delicate plateau phase of the
AP disrupts the balance of inward and outward current
leading to delayed repolarization. Prolongation of APD
manifests clinically as forms of LQTS that are characterized by extended QT intervals on the electrocardiogram.
Gene defects in KCNQ1 and KCNE1 are associated with
distinct disease forms, LQT1 and LQT5, respectively (12,
13, 24, 76).
More than 30 mutations have been identified in
KCNQ1 or KCNE1, and many act to reduce IKs through
dominant negative effects (12, 13, 104), reduced responsiveness to ␤-AR signaling (1, 54), or alterations in channel gating (22, 86, 112, 137) (Fig. 6B). Mutations in KCNQ1
cause LQTS by a reduction in or loss of IKs, resulting in
reduced repolarizing current during the AP (77, 131).
These mutations often act by dominant negative suppres-
FIG. 6. A: sympathetic regulation of
slowly activating component of delayed
rectifier K⫹ current (IKs) requires a macromolecular signaling complex. KCNQ1 and
KCNE1 coassemble to form IKs. Sympathetic stimulation results in the activation
of protein kinase A (PKA) that is recruited
to the channel COOH terminus in conjunction with protein phosphatase 1 (PP1) by
Yotiao (an AKAP scaffolding protein). PKA
phosphorylation of serine-27 (arrow) ensues and IKs is upregulated, allowing for
rate-dependent adaptation of the APD.
Both KCNQ1 and KCNE1 are targets for
pharmacological agents. B: a schematic
representation of KCNQ1 mutations linked
to LQT1. Mutations are most commonly
found in KCNQ1 and are scattered
throughout the channel. KCNE1 (mink)
are mutations linked to LQT5 and can affect repolarization by altering channel gating or by disrupting sympathetic regulation of the channel.
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The first LQTS locus (LQT1) was linked to mutations
in KCNQ1, a gene coding for a voltage-gated K⫹ channel
␣-subunit. IKs results from coassembly of KCNQ1 (KvLQT1) and KCNE1 (minK) (10, 95). KCNQ1 was identified
by positional cloning and mapped by linkage analysis to
chromosome 11 (131). KCNQ1 shares topological homology with other voltage-gated K⫹ channels with 676 amino
acids that form six transmembrane domains and a poreforming region. Four identical ␣-subunits form a tetramer
with a central ion-conduction pore. KCNQ1 and its ancillary subunit, KCNE1, have been shown to recapitulate the
gating properties of native IKs (55).
The contribution of IKs to regulation of APD is augmented by the sympathetic branch of the autonomic nervous system, which increases IKs through primary and
secondary effects on channel gating kinetics (53, 54, 67,
128) (Fig. 6A). ␤-Adrenergic receptor (␤-AR) stimulation
acts to increase the heart rate, which results in ratedependent shortening of the APD resulting from the slow
deactivation of IKs (as described above). IKs amplitude is
also directly mediated by ␤-AR stimulation through protein kinase A (PKA) phosphorylation (53, 54, 67). A
leucine zipper motif in the COOH terminus of KCNQ1
coordinates the binding of a targeting protein yotiao (85,
86), which in turn binds to and recruits PKA and protein
39
40
COLLEEN E. CLANCY AND ROBERT S. KASS
Physiol Rev • VOL
with the clinical manifestation of arrhythmias associated
with LQT1 and LQT5, which tend to occur due to sudden
increases in heart rate. This strongly suggests that investigation of congenital forms of electrical abnormalities
may act as a paradigm for drug-induced forms of clinical
syndromes.
B. Cellular Consequences of IKs Channel Blockade
Some pure class III compounds block both native and
heterologously expressed IKs current. Chromanol 293B
and the benzodiazepine L7, which are distinct in their
chemical structures, as well as the diuretic agent indapamide were some of the first compounds discovered to
selectively block IKs (17, 47, 65). The application of Chromanol 293B revealed that IKs inhibition appears to have
rate-independent effects on human and guinea pig myocytes (17). Chromanol 293B exhibits slow binding kinetics
to open channels and blocks IKs in a voltage-dependent
manner, favoring positive potentials (65). It is possible
that this type of voltage and time dependence of druginduced IKs blockade might have less proarrhythmic potency compared with other compounds. Azimilide, a class
III compound which blocks both IKr and IKs, also appears
to have rate-independent effects that are maintained under ischemic or hypoxic conditions, properties of potential clinical significance (48). Some evidence suggests that
IKs blockers can prolong QT intervals in a dose-dependent
manner, an effect that is exacerbated when administered
in combination with isoproterenol (107).
The sensitivity of IKs to blockade by chromanol 293B
and XE991 is modulated by the presence of KCNE1 (16).
KCNE1 is itself a distinct receptor for the IKs agonists
stilbene and fenamate (16), which bind to an extracellular
domain on KCNE1. Stilbene and fenamate have been
shown to be useful in reversing dominant negative effects
of some LQT5 COOH-terminal mutations and restoring IKs
channel function (3). On the other hand, L364,373, a 1,4benzodiazepine compound, is an effective agonistic on
KCNQ1 currents only in the absence of KCNE1 (92).
These types of studies illustrate the importance of accessory subunits in determining the pharmacological properties of IKs.
C. Blockade of IKs and ␤-Adrenergic Stimulation
In a model of acquired LQTS (IKs blockade by chromanol 293B), the addition of the ␤-adrenergic agonist
isoproterenol induced the development of torsades de
pointes (107). These results are consistent with the clinical findings that cardiac events are more likely to be
associated with sympathetic nervous stimulation in LQT1
patients than either in LQT2 or LQT3 patients (99). Moreover, ␤-blockers are reported to reduce cardiac events
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sion of normal subunits, which results in a significant
reduction in current. In other instances, there is a complete loss of current, which has been demonstrated to
result from the assembly of nonfunctional channels or the
failure of channels to traffic to the plasma membrane (12,
13, 33, 71). Mutations can also alter channel-gating properties, which typically manifest as either reduction in the
rate of channel activation, such as R539W KCNQ1 (25),
R555C KCNQ1 (23), or an increased rate of channel deactivation including S74L (114), V47F, W87R (13), KCNE1
and W248R KCNQ1 (39). An LQTS-associated KCNQ1
COOH-terminal mutation, G589D, disrupts the leucine zipper motif and prevents cAMP-dependent regulation of IKs
(67). The reduction of sensitivity to sympathetic activity
likely prevents appropriate shortening of the APD in response to increases in heart rate.
As with KCNQ1, homozygous mutations in KCNE1
can cause the more severe Jervell and Lange-Nielsen phenotype (114), while heterozygous mutations can manifest
via dominant-negative suppression or changes in channel
kinetics resulting in reduced outward K⫹ current (87).
KCNE1 has recently been shown to be required for cAMPdependent regulation of IKS (54). Even though KCNQ1
phosphorylation is independent of coassembly with
KCNE1, transduction of the phosphorylated channel into
the physiologically required increase in reserve channel
activity requires the presence of KCNE1 (54). Several
LQT-5 linked point mutations of KCNE1 can severely
disrupt the important physiologically relevant functional
consequences KCNQ1 phosphorylation including the
D76N and W87R mutations (54). Both the D76N and W87R
mutations reduce basal current density when expressed
with WT KCNQ1 subunits (54). This effect would be expected to reduce repolarizing current, prolong cellular
APs, and contribute to prolonged QT intervals in mutation
carriers even in the absence of sympathetic nervous system (SNS) stimulation. However, in addition, the mutations would be expected to eliminate or reduce physiologically important reserve K⫹ channel activity in the face
of SNS stimulation. The W87R mutation speeds channel
deactivation kinetics, which then are not slowed by
cAMP. Thus the data suggest that the W87R mutation
eliminates the important cAMP-dependent accumulation
of channel activity that is the normal response to the SNS.
The D76N mutation ablates functional regulation of the
channels by cAMP. The result is an expected delay in the
onset of repolarization that is more pronounced in the
face of SNS stimulation.
Despite their distinct origins, congenital and druginduced forms of LQTS related to alterations in IKs are
remarkably similar. In either case, reduction in IKs results
in prolongation of the QT interval on the ECG without an
accompanying broadening of the T wave, as observed in
other forms of LQTS (40). Reduced IKs leads to the loss of
rate-dependent adaptation in APD, which is consistent
CARDIAC Na⫹ AND K⫹ CHANNELS AND VENTRICULAR ARRHYTHMIAS
41
V. Kⴙ CHANNELOPATHIES: IKr, THE RAPIDLY
ACTIVATING COMPONENT OF THE
DELAYED RECTIFIER
HERG (Human ether-a-go-go related gene) has been
implicated in the chromosome 7-linked LQT2 syndrome
(84, 112). HERG encodes a typical voltage-gated K⫹ channel pore-forming ␣-subunit, but with unique and physiologically significant biophysical and structural characteristics. HERG rapidly inactivates and slowly deactivates,
resulting in the passage of little outward current but
significant transient current upon repolarization that contributes to AP shortening (84, 85).
While HERG is widely accepted as the ␣-subunit of
IKr, marked differences exist between native IKr current
and HERG-induced currents in heterologous expression
systems in terms of gating (2, 143), regulation by external
K⫹ (2, 68, 106), and sensitivity to antiarrhythmics (96, 97).
These data suggest the presence of a modulating subunit
that coassembles with HERG to reconstitute native IKr
currents. A candidate is the minK-related protein 1
(MiRP1 ⫽ KCNE2), which when coexpressed with HERG,
results in currents similar to native IKr (2) (Fig. 7). Coexpression with MiRP1 causes a ⫹5310 mV depolarizing
shift in steady-state activation, accelerates the rate of
deactivation, and causes a decrease in single-channel conductance from 13 to 8 pS (2). However, a specific and
selective interaction of HERG and MiRP1 in the myocardium has not yet been demonstrated (132), and other
Physiol Rev • VOL
FIG. 7. Human ether-a-go-go related gene (HERG; A) and KCNE2
(B) in the long QT syndrome. A schematic representation of mutations
in HERG. Mutations have been found throughout the channel and generally result in loss of channel function.
factors may contribute to the functional differences between native IKr current and HERG-induced currents in
heterologous expression systems. Several alternatively
spliced ERG1 variants have been demonstrated in the
heart (58, 63), and there is evidence for posttranslational
modification of HERG proteins (79, 80).
More than 50 mutations in HERG have been linked to
the congenital LQTS (84, 112) (Fig. 7). Defects in the
HERG pore have been shown to have heterogeneous cellular phenotypes. Mutations in HERG resulting in LQTS
result in a reduction in K⫹ current, either by dominantnegative suppression, nonfunctional channels, or trafficking errors (84, 112). Pore mutations may result in a loss of
function, sometimes due to a trafficking defect (78) and
may or may not coassemble with WT HERG subunits to
exert dominant negative effects (94, 112). Other defects in
the channel pore give rise to altered channel kinetics
leading to decreased repolarizing current (38, 109).
Nearby mutations in the S4-S5 linker have been shown to
variably affect activation (98). Mutations in the Per-ArntSim (PAS) domain located in the NH3-terminal region of
HERG, which normally interacts with the channel and
reduces the rate of deactivation, alter deactivation kinet-
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dramatically in LQT1 patients (108). Under normal circumstances, ␤-adrenergic stimulation increases Ca2⫹ current, which acts to prolong APD, but a concomitant increase in IKs shortens APD. Hence, a controlled feedback
system exists to prevent excessive APD prolongation
(45). However, in the presence of mutations that reduce
IKs, appropriate APD shortening in response to ␤-adrenergic stimulation may fail to occur and increase arrhythmia susceptibility.
Investigation into the structural determinants of IKs
block is not yet well understood, and recent studies demonstrate that genetic defects can disrupt drug block (102),
which may aid in the revelation of the drug binding site.
Studies revealed a common site for binding of IKs blockers including Chromanol 293B and L735821 (L7) in the S6
domain (F340) of KCNQ1 (101). Other putative interaction sites in the S6 domain (T312 and A344) and the pore
helix (I337) may lend specificity to pharmacological interactions (101). Interestingly, these binding sites are located
near an aqueous crevice in KCNQ1 that is thought to be
important for interactions with KCNE1 that allosterically
affect pore geometry (55, 122, 123). Drug interaction sites
for channel agonists stilbene and fenamate have been
shown on extracellular domains in KCNE1 (3).
42
COLLEEN E. CLANCY AND ROBERT S. KASS
A. Cellular Consequences of IKr Blockade
by Mutations and/or Drugs
The HERG channel subunit was originally identified
by genetic studies on patients with the congenital LQTS.
Incorporation of mutant HERG subunits in the channel
tetramer generally causes a reduction of IKr, which leads
to prolongation of the ventricular AP (84). A delay in
ventricular repolarization predisposes the heart to arrhythmogenic early afterdepolarizations (6, 7, 28, 36, 51).
Both the cellular effects of these congenital abnormalities and the resulting electrocardiographic abnormalities are analogous to those seen with inhibition of HERG
channels by a variety of compounds. Reductions in IKr
result in prolongation of APD and dispersion of repolarization across the wall of the ventricle, which manifests
on the ECG as prolongation of the QT interval and widening of the T wave, respectively (40). The ECG alterations have been associated with an increased risk of
arrhythmias and sudden cardiac death. Certain factors
can increase the disruption of the repolarization (e.g.,
hypokalemia due to diuretics and sudden changes in pacing rate) and can exacerbate the arrhythmogenic effect of
HERG-blocking drugs. These additional interventions
may result in the appearance of notched T waves on the
ECG (40). The recognition of the fundamental role played
by the K⫹ channels encoded by HERG in cardiac pathophysiology has the potential to improve the understanding of mechanisms of arrhythmogenesis.
B. HERG Channels Are Promiscuous Drug Targets
Recent studies have revealed the molecular basis of
the promiscuity of HERG K⫹ channel drug binding and
have provided further insight into the structure and function of HERG K⫹ channels. IKr is the primary target of
methanesulfonanilides (dofetilide, E-4031, ibutilide, and
MK-499), a group of potent and specific class III antiarPhysiol Rev • VOL
rhythmic drugs that prolong APD (97, 111). HERG channels can also be blocked by an array of other pharmacological agents with diverse chemical structures (80). Experiments suggest the involvement of aromatic residues
in the S6 domain (Y652 and F656) unique to eag/erg K⫹
channels that may underlie the structural mechanism of
preferential block of HERG by a number of commonly
prescribed drugs (69, 70).
Initial investigation of the HERG antagonist binding
site was carried out via site-directed mutagenesis techniques. One study (38) revealed that a single residue,
Ser-620, in the H5 domain of the S5-S6 linker of HERG
altered the sensitivity of the channel to dofetilide. The
altered residue was believed to affect drug binding via an
allosteric effect related to loss of inactivation. A more
recent study (57) reported that Phe-656 in S6 was necessary, although not sufficient, for high-affinity binding of
dofetilide and quinidine, but did not affect binding of
tetraethylammonium and did not disrupt inactivation.
Homology modeling based on crystallographic structure of the bacterial K⫹ channel KcsA (34) predicts that
Phe-656 falls within the HERG pore region. This result
was confirmed and extended in an elegant study by
Mitcheson et al. (69), who identified four residues in
addition to Phe-656 that were crucial for high-affinity
binding by methanesulfonanilides, namely, Tyr-652, Gly648, Val-625, and Thr-623. Using similar homology modeling of HERG channels, the authors showed that the aromatic rings of methanesulfonanilides are likely to interact
with the aromatic rings of Tyr-652 and Phe-656 (69). The
crucial role of Tyr-652 and Phe-656 was confirmed by
studies using cisapride and terfenadine, whereas Gly-648,
Val-625, and Thr-623 were found to be more specific for
methanesulfonanilides (69).
The importance of residues Tyr-652 and Phe-656 was
also demonstrated for the low-affinity ligand choloroquine,
an antimalarial agent that appears to preferentially block
open HERG channels. Block of HERG by chloroquine requires channel opening followed by interactions of the drug
with the aromatic residues in the S6 domain that face the
central cavity of the HERG channel pore (93).
C. State-Specific Block of IKr
The biophysical properties of HERG blockade are
consistent with a discrete state-dependent blocking
mechanism (51, 110). Initial HERG channel studies demonstrated that methanesulfanonilides require channel
opening for access to a presumptive intracellular binding
site (111). Mutations that result in loss of inactivation act
to reduce affinity for methanesulfonanilides, suggesting
that inactivation may be required for drug binding. However, methanesulfanonilides are less effective at inhibiting
HERG K⫹ channels during strong depolarization (e.g.,
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ics of the channel and tend to reduce the amount of time
channels reside in open states, thereby reducing current
(18). Mutations in this region presumably prevent proper
association of the NH2 terminus with the channel and act
to increase the rate of channel deactivation. A particularly
interesting mutation, N629D, results in a “gain-of-function” defect in HERG that leads to loss of C-type inactivation coupled with loss of K⫹ selectivity (57). HERG
contains a pore selectivity sequence that is changed by
the mutation from GFGN to GFGD, allowing for nonspecific passage of monovalent cations.
Mutations in KCNE2 alter the biophysical properties
of IKr and act to reduce current (2, 112). KCNE2 polymorphisms have also been associated with increased affinity
of IKr to blockade by clarithromycin (103).
CARDIAC Na⫹ AND K⫹ CHANNELS AND VENTRICULAR ARRHYTHMIAS
D. Gene-Specific Triggers and Treatments
Although all forms of inherited long-QT that stem
from ion channel mutations act to disrupt repolarization,
the specific genetic loci are indicators of likelihood of
cardiac events stemming from different types of triggers.
Patients harboring mutations in KCNQ1 (LQT1) and
KCNE1 (LQT5) are prone to arrhythmia in response to
␤-adrenergic discharge as occurs during exercise, especially swimming (72, 135). In response to ␤-adrenergic
stimulation, there is an accompanying increase in heart
rate coupled to shortening of APD, which allows for
sufficiently long diastolic intervals for filling of the ventricles. This shortening results, in large part, from PKA
phosphorylation of IKs (as described in detail in sect. IV).
A reduction in IKs due to dominant negative mutations,
those that reduce the current through alterations in kinetics, or mutations that disrupt the transduction of PKA
phosphorylation will prevent appropriate shortening of
the AP and may lead to conduction block.
Physiol Rev • VOL
HERG mutations (LQT2), on the other hand, are
associated with auditory triggers and are less heart rate
dependent, with events occurring at both fast and slow
heart rates. While the mechanisms of HERG-linked arrhythmia at slow heart rates have been investigated in
detail (28), the mechanisms underlying auditory induction
of events is elusive. HERG is regulated by cAMP via at
least two distinct pathways (32, 50). Activation of PKA
results in HERG current reduction and a rightward shift of
the activation curve (implying a reduction in current).
However, direct binding of cAMP to HERG has the opposite effect of hyperpolarization of the activation curve and
a current increase (32, 50).
LQT3 resulting from mutations in NaV1.5 are bradycardia-dependent inducers of arrhythmia events. Studies
have shown that mutations that result in a gain of Na⫹
channel function are sufficient to cause events at slow
heart rates as a result of kinetic alterations (27). Current
flowing during the AP plateau through defective Na⫹
channels during the AP plateau results in AP prolongation
in the presence of reduced repolarizing currents and may
trigger arrhythmogenic early afterdepolarizations (27).
While persistent current in wild-type Na⫹ channels is not
regulated by PKA, one study has shown significant regulation of a long QT-associated mutant by PKA (124).
The standard prophylactic therapy for all forms of
LQTS is ␤-adrenergic blockade, although pacemakers, implantable cardioverter defibrillators, and surgical sympathetic ganglionectomy have been used in cases where
patients are resistant to drug therapy (73). A study of the
effectiveness of ␤-adrenergic blockade has shown that
the therapy is gene specific, and although it does not act
to reduce QT intervals per se, blockade does significantly
reduce the likelihood of arrhythmic events in LQT1 and
LQT2 patients (73). ␤-Blockers do not appear to aid in
sudden cardiac death prevention for LQT3 forms of LQTS
(73). Given the bradycardia association of arrhythmic
events in this form of the disease, this result is perhaps
not surprising, but raises the important issue of genespecific therapy and the necessity for identification of
genetic loci of disease.
VI. SUMMARY
In general, the broad diversity in genetic defects
underlying arrhythmia syndromes and potential interactions with pharmacological interventions makes the prediction of treatment outcomes difficult. Variability in response may be due to the presence of gene defects in the
drug targets themselves or influenced by other genetic
heterogeneity. Clinical presentation is determined by complex interactions between pharmacology, causal genes, genetic background (modifier genes), and environmental factors. Although individual modifier genes are largely un-
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⫹60 mV), which promote inactivation (51, 110), and
would therefore be expected to favor drug binding if the
drugs bind to the inactivated state. A possible explanation
for this apparent discrepancy may be that channel opening is required for drug to contact its binding site, which
then becomes accessible as channels inactivate. At positive voltages, extremely rapid inactivation might reduce
the channel open time sufficiently to prevent drug access
to the binding site. This idea has recently been proposed
as a mechanism of flecainide binding to Na⫹ channels,
where channel opening is required for flecainide binding
to inactivated channels (62).
Recovery of HERG from block by methanesulfonanilides is extremely slow, even at negative holding potentials when most channels are in closed states. Using a
mutant HERG (D540K) channel, that has the unusual
property of opening in response to hyperpolarization (98),
it was shown that methanesulfonanilides are trapped in
the inner vestibule by closure of the activation gate. Opening of the channel in response to hyperpolarization allowed release of the drug from its receptor.
HERG trapping of MK-499, despite its large size, suggests that the vestibule of the HERG channel is larger than
the well-studied Shaker K⫹ channel. Indeed, homology
modeling based on the KcsA structure revealed two unusual features of the HERG inner vestibule (the site of
drug block) that are unique among K⫹ channels (69). In
addition, HERG K⫹ channels have two aromatic residues
predicted to face the inner pore, whereas other K⫹ channels lack these residues, or in the case of KCNQ1, contain
only one. As shown in the molecular model of Mitcheson
et al. (69), these residues (Y652 and F656) are crucial for
electrostatic interactions between aromatic rings of Y652/
F652 and the drug molecules.
43
44
COLLEEN E. CLANCY AND ROBERT S. KASS
Address for reprint requests and other correspondence:
C. E. Clancy, Dept. of Physiology and Biophysics, Institute for
Computational Biomedicine, Weill Medical College of Cornell
University, 1300 York Ave., LC-501E, New York, NY 10021 (Email: [email protected]).
9.
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18.
19.
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known, potential modifiers of arrhythmia include, but are
not limited to, gender, electrolyte disturbances, febrile
states, receptor stimulation, channel-associated protein kinases, channel-associated protein phosphatases, and individual electrophysiological and morphological substrates.
Identification of modifier genes will complement the current
studies that increasingly identify and characterize causative
genes, which may improve upon genetically based diagnosis,
risk stratification, and implementation of preventive and
therapeutic interventions in patients with arrhythmia.
Indeed, identification of genetic mutations underlying arrhythmia syndromes and other genetic modifiers
that may identify pharmacological targets or affect treatment efficacy is important but may prove to be less than
half the battle. Establishing a link between abnormalities
or common polymorphisms and manifestation of disease
is a major challenge. Even once the gap is bridged between genotype and phenotype, the challenge to appropriately and cost-effectively treat patients is difficult to
even begin to address. Is it feasible to develop patientspecific treatments that target an individual’s distinct genetic make-up? Certainly not at this juncture, but remarkable developments in pharmacological testing and genotyping with gene chip assays, coupled with targeted
informatics research may allow just such an approach to
be feasible in the future.
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