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Basic Science for the Clinical Electrophysiologist
Cardiac Ion Channels
Augustus O. Grant, MB, ChB, PhD
T
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he analysis of the molecular basis of the inherited cardiac
arrhythmias has been the driving force behind the identification of the ion channels that generate the action potential. The genes encoding all the major ion channels have
cloned and sequenced. The studies have revealed greater
complexity than heretofore imagined. Many ion channels
function as part of macromolecular complexes in which many
components are assembled at specific sites within the membrane. This review describes the generation of the normal
cardiac action potential. The properties of the major ionic
currents are the examined in detail. Special emphasis is
placed on the functional consequences of arrhythmiaassociated ion channel mutations. The review concludes with
a glimpse of the directions in which this new electrophysiology may lead.
phase 0 is much slower than that in the working myocardial
cells and results in slow propagation of the cardiac impulse in
the nodal regions (␪⫽0.1 to 0.2 m/s). Cells in the HisPurkinje system may also show phase 4 depolarization under
special circumstances. The characteristics of the action potential change across the myocardial wall from endocardium,
midmyocardium, to epicardium. Epicardial cells have a
prominent phase 1 and the shortest action potential. The
action potential duration is longest in the midmyocardial
region.2 The average duration of the ventricular action potential duration is reflected in the QT interval on the ECG.
Factors that prolong the action potential duration (eg, a
decrease in outward K⫹ currents or an increase in inward late
Na⫹ current) prolong the action potential duration and the QT
interval on the ECG. The QT interval of males and females is
equal during early childhood. However, at puberty the interval of males shortens.3 Studies have focused on the longer
QT interval of females and the possible reduction in K⫹
channel function. However, a definitive conclusion has not
been made.
The Cardiac Action Potential
The normal sequence and synchronous contraction of the
atria and ventricles require the rapid activation of groups of
cardiac cells. An activation mechanism must enable rapid
changes in heart rate and also respond to the changes in
autonomic tone. The propagating cardiac action potential
fulfils these roles. Figure 1 illustrates the 5 phases of the
normal action potential:
General Properties of Ion Channels
The generation of the action potential and the regional
differences that are observed throughout the heart are the
result of the selective permeability of ion channels distributed
on the cell membrane. The ion channels reduce the activation
energy required for ion movement across the lipophilic cell
membrane. During the action potential, the permeability of
ion channels changes and each ion, eg, X, moves passively
down its electro-chemical gradients (⌬V⫽[Vm⫺Vx,] where
Vm is the membrane potential and Vx the reversal potential of
ion X) to change the membrane potential of the cell. The
electrochemical gradient determines whether an ion moves
into the cell (depolarizing current for cations) or out of the
cell (repolarizing current for cations). Homeostasis of the
intracellular ion concentrations is maintained by active and
coupled transport processes that are linked directly or indirectly to ATP hydrolysis.
Ion channels have 2 fundamental properties, ion permeation and gating.4 Ion permeation describes the movement
through the open channel. The selective permeability of ion
channels to specific ions is a basis of classification of ion
channels (eg, Na⫹, K⫹, and Ca2⫹ channels). Size, valency,
and hydration energy are important determinants of selectivity. The selectivity ratio of the biologically important alkali
cations is high. For example, the Na⫹:K⫹ selectivity of
1. Phase 4, or the resting potential, is stable at ⬇⫺90 mV
in normal working myocardial cells.
2. Phase 0 is the phase of rapid depolarization. The
membrane potential shifts into positive voltage range.
This phase is central to rapid propagation of the cardiac
impulse (conduction velocity, ␪⫽1 m/s).
3. Phase 1 is a phase of rapid repolarization. This phase
sets the potential for the next phase of the action
potential.
4. Phase 2, a plateau phase, is the longest phase. It is
unique among excitable cells and marks the phase of
calcium entry into the cell.
5. Phase 3 is the phase of rapid repolarization that restores
the membrane potential to its resting value.1
The action potentials of pacemaker cells in the sinoatrial
(SA) and atrioventricular (AV) nodes are significantly different from those in working myocardium. The membrane
potential at the onset of phase 4 is more depolarized (⫺50
to ⫺65 mV), undergoes slow diastolic depolarization, and
gradually merges into phase 0. The rate of depolarization in
From the Cardiovascular Division, Department of Medicine, Duke University Medical Center, Durham, NC.
Correspondence to Augustus O. Grant, Box 3504, Cardiovascular Division, Department of Medicine, Duke University Medical Center, Durham, NC
27710. E-mail [email protected]
(Circ Arrhythmia Electrophysiol. 2009;2:185-194.)
© 2009 American Heart Association, Inc.
Circ Arrhythmia Electrophysiol is available at http://circep.ahajournals.org
185
DOI: 10.1161/CIRCEP.108.789081
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April 2009
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Figure 1. Membrane currents that generate the a normal action
potential. Resting (4), upstroke (0), early repolarization (1), plateau (2), and final repolarization are the 5 phases of the action
potential. A decline of potential at the end of phase 3 in pacemaker cells, such as the sinus node, is shown as a broken line.
The inward currents, INa, ICa, and If, are shown in yellow boxes;
the sodium-calcium exchanger (NCX) is also shown in yellow. It
is electrogenic and may generate inward or outward current.
IKAch, IK1, Ito, IKur, IKr, and IKs are shown in gray boxes. The
action potential duration (APD) is approximately 200 ms. Reproduced with permission from Stanley and Carlsson.44
sodium channels is 10:1. Ion channels do not function as
simple fluid-filled pores, but provide multiple binding sites
for ions as they traverse the membrane. Ions become dehydrated as they cross the membrane as ion-binding site
interaction is favored over ion–water interaction. Like an
enzyme–substrate interaction, the binding of the permeating
ion is saturable. Most ion channels are singly occupied during
permeation; certain K⫹ channels may be multiply occupied.
The equivalent circuit model of an ion channel is that of a
resistor. The electrochemical potential, ⌬V is the driving
force for ion movement across the cell membrane. Simple
resistors have a linear relationship between ⌬V and current I
(Ohm’s Law, I⫽⌬V/R⫽⌬Vg, where g is the channel conductance). Most ion channels have a nonlinear current-voltage
relationship. For the same absolute value of ⌬V, the magnitude of the current depends on the direction of ion movement
into or out of the cells. This property is termed rectification
and is an important property of K⫹ channels; they pass little
outward current at positive (depolarized) potentials. The
molecular mechanism of rectification varies with ion channel
type. Block by internal Mg⫹ and polyvalent cations is the
mechanism of the strong inward rectification demonstrated
by many K⫹ channels.5
Gating is the mechanism of opening and closing of ion
channels and is their second major property. Ion channels are
also subclassified by their mechanism of gating: voltagedependent, ligand-dependent, and mechano-sensitive gating.
Voltage-gated ion channels change their conductance in
response to variations in membrane potential. Voltagedependent gating is the commonest mechanism of gating
observed in ion channels. A majority of ion channels open in
response to depolarization. The pacemaker current channel (If
channel) opens in response to membrane hyperpolarization.
The steepness of the voltage dependence of opening or
activation varies between channels. Sodium channels increase
their activation by ⬇e-fold (2.73) for 4 mV of depolarization;
in contrast, the K⫹ channel activation increase e-fold for 5
mV of depolarization.4
Ion channels have 2 mechanism of closure. Certain channels like the Na⫹ and Ca2⫹ channels enters a closed inactivated state during maintained depolarization. To regain their
ability to open, the channel must undergo a recovery process
at hyperpolarized potentials. The inactivated state may also
be accessed from the closed state. Inactivation is the basis for
refractoriness in cardiac muscle and is fundamental for the
prevention of premature re-excitation. The multiple mechanisms of inactivation are discussed below. If the membrane
potential is abruptly returned to its hyperpolarized (resting)
value while the channel is open, it closes by deactivation, a
reversal of the normal activation process. These transitions
may be summarized by the following state diagram (as
proposed for the Na⫹ channel6):
The C3 I transition may occur from multiple closed states.
However, because these states are nonconducting, the kinetics of transition between them are difficult to resolve with
certainty.
Ligand-dependent gating is the second major gating mechanism of cardiac ion channels. The most thoroughly studied
channel of this class is the acetylcholine (Ach)-activated K⫹
channel. Acetylcholine binds to the M-2 muscarinic receptor
and activates a G protein–signaling pathway, culminating in
the release of the subunits G␣i and G␤␥. The G␤␥ subunit
activates an inward-rectifying K⫹ channel, IKAch that abbreviates the action potential and decreases the slope of diastolic
depolarization in pacemaker cells. IKAch channels are most
abundant in the atria and the SA and atrioventricular nodes.
IKAch activation is a part of the mechanism of the vagal
control of the heart. The ATP-sensitive K⫹ channel, also
termed the ADP-activated K⫹ channel, is a ligand-gated
channel distributed abundantly in all regions of the heart. The
open probability of this channel is proportional to the [ADP]/
[ATP] ratio. This channel couples the shape of the action
potential to the metabolic state of the cell. Energy depletion
Grant
Table 1.
Current
Cardiac Ion Channels
187
Membrane Currents That Generate the Action Potential
Description
AP Phase
Activation Mechanism
Clone
Gene
Nav1.5
SCN5A
␣-subunit of action potential inward current channels
INa
Sodium current
Phase 0
Voltage, depolarization
ICa,L
Calcium current, L-type
Phase 2
Voltage, depolarization
Cav1.2
CACNA1C
ICa,T
Calcium current, T-type
Phase 2
Voltage, depolarization
Cav3.1/3.2
CACNA1G
KCND2/3
␣-subunit of action potential outward (K⫹) current channels
Ito,f
Transient outward current, fast
Phase 1
Voltage, depolarization
KV 4.2/4.3
Ito,s
Transient outward current, slow
Phase 1
Voltage, depolarization
KV 1.4/1.7/3.4
KCNA4
KCNA7
KCNC4
IKur
Delayed rectifier, ultrarapid
Phase 1
Voltage, depolarization
KV 1.5/3.1
KCNA5
IKr
Delayed rectifier, fast
Phase 3
Voltage, depolarization
HERG
KCNH2
IKs
Delayed rectifier, slow
Phase 3
Voltage, depolarization
KVLQT1
KCNQ1
IK1
Inward rectifier
Phase 3 & 4
Voltage, depolarization
Kir 2.1/2.2
KCNJ2/12
IKATP
ADP activated K⫹ current
Phase 1 & 2
关ADP兴/关ATP兴1
Kir 6.2 (SURA)
KCNJ11
IKAch
Muscarinic-gated K⫹ current
Phase 4
Acetylcholine
Kir 3.1/3.4
KCNJ3/5
Background current
All Phases
Metabolism, stretch
TWK-1/2
KCNK1/6
TASK-1
KCNK3
KCNC1
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IKP
IF
Pacemaker current
Phase 4
during ischemia increases the [ADP]/[ATP] ratio, activates
IK ATP, and abbreviates the action potential. The abbreviated
action potential results in less force generation and may be
cardioprotective. This channel also plays a central role in
ischemic preconditioning.
The mechanosensitive or stretch-activated channels are the
least studied. They belong to a class of ion channels that can
transduce a physical input such as stretch into an electric
signal through a change in channel conductance. Acute
cardiac dilatation is a well-recognized cause of cardiac
arrhythmias. Stretch-activated channel are central to the
mechanism of these arrhythmias. Blunt chest wall impact at
appropriately timed portions of the cardiac cycle may also
result in PVCs or ventricular fibrillation (the VF of commotio
cordis). The channels that transduce the impact into an
electric event are unknown.
The major ion channels that shape the action potential have
been cloned and sequenced. Table 1 lists the clones of the
primary ␣-subunits of the major ion channels. Over the past
2 decades, the focus of research has been the relationship
between channel structure and function, including the molecular underpinnings of the permeation and gating processes.
Recent studies have focused on molecular suprastructures of
which ion channels are a part.7,8 The channels are not
randomly distributed in the membrane, but tend to cluster at
the intercalated disc in association with modulatory subunits.
The sodium channel has a binding site for the structural
protein ankryin and mutations that affects its binding site
result in LQTS or Brugada syndrome.9
Sodium Channels
Sodium channels are the arch-type of voltage-gated ion
channels.10 The human cardiac sodium channel hNaV1.5 is a
Voltage, hyperpolarization
TRAAK
KCNK4
HCN2/4
HCN2/4
member of the family of voltage-gated sodium channels
(hNaV1 to 9). The channel consists of a primary ␣- and
multiple secondary ␤-subunits. When studied in a mammalian expression system, the ␣-subunit of hNaV1.5 is sufficient
to generate sodium current with features characteristic of the
current in native cells. The ␤1-subunit increases the level of
expression and alters the gating of the neuronal sodium
channel. An analogous role of the ␤1 subunit for the cardiac
sodium channel has not been established.
The sodium channel consists of 4 homologous domains,
DI – DIV11,12 arranged in a 4-fold circular symmetry to form
the channel (Figure 2). Each domain consists of 6 membranespanning segments, S1 through S6. The membrane-spanning
segments are joined by alternating intra- and extracellular
loops. The loops between S5 and S6 of each domain termed
the P loops curve back into the membrane to form the pore.
Each S4 segment has a positively charged amino acid at every
third or fourth position and acts as the sensor of the transmembrane voltage. The movement of these charges across the
membrane during channel gating generates small currents that
can be recorded at high resolution. Transmission of the voltage
sensor transition to S-5 has been suggested as the critical element
of channel gating.
The highly potent neurotoxin tetrodotoxin (TTX) and the
systematic mutation of residues in the loop have enabled the
tentative identification of the amino acid residues that are
critical for ion permeation; these residues include aspartate,
glutamate, lysine, and alanine (D, E, K, and A) contributed by
D1 through D4, respectively. The lysine (K) in domain III is
critical for Na:K selectivity. Mutation of multiple residues in
D4 renders the channel noncation selective.
Each sodium channel opens very briefly (⬍1 ms) during
more than 99% of depolarizations.13,14 The channel occasion-
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Circ Arrhythmia Electrophysiol
April 2009
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Figure 2. Putative transmembrane organization of the sodium channel. The channel consists of 4 homologous domains, D1 through
D1V. The amino and carboxyl termini are intracellular. The positive charges (⫹) on the fourth transmembrane segment are evident, as
are the extended extracellular loops between S5 and S6 of each domain. Examples of loci at which functionally characterized mutations cause Brugada syndrome, LQT3, the overlap syndrome (Brugada syndrome/LQT3), and isolated conduction system disease are
also shown. Reproduced with permission from Herbert and Chahine.46
ally shows alternative gating modes consisting of isolated
brief openings occurring after variable and prolonged latencies and bursts of openings during which the channel opens
repetitively for hundreds of milliseconds. The isolated brief
openings are the result of the occasional return from the
inactivated state. The bursts of openings are the result of
occasional failure of inactivation.13,15 Sodium channel mutations that favor these slow gating modes are the basis of a
subgroup of the long QT syndromes (LQT3).16
Sodium channel inactivation is a multifaceted process that
may occur in the time frame of milliseconds, seconds, or tens
of seconds, depending on the duration of the antecedent
depolarization.17 In response to depolarization lasting tens of
milliseconds, the process is fast. Intermediate and slow
inactivation develops over hundreds of milliseconds, for
example during the course of the normal action potential and
in response to trains of action potentials. The fraction of
channels available for opening (1-the inactivated fraction),
denoted by h⬁, varies from ⬇1 at ⫺90 mV to zero at ⬇⫺40
mV. The structural basis of fast sodium channel inactivation
resides in the interdomain linker between DIII and DIV
(ID111/IV). The primary amino acid sequence of this region
is highly conserved between species and sodium channel
subtypes. The tertiary structure of the region has been
resolved by NMR spectroscopy.18 The putative form is that of
a tilting disk that folds into the membrane to occlude the pore.
The amino acid triplet isoleucine, phenylalanine, methionine
(IFM) is crucial for inactivation; the mutation IFM3 QQQ
abolishes inactivation.19 The receptor site to which the triplet
binds has not been identified. The carboxyl terminus also
plays an important role in sodium channel inactivation.
The cardiac sodium channel has consensus sites for phosphorylation by protein kinase (PKA), protein kinase C (PKC),
and Ca-calmodulin kinase. Data on the effects of PKA on the
INa are controversial, with some studies reporting a decrease
in current whereas others report an increase.20 –22 Phosphorylation of the channel by PKC results in a decrease in INa.
Modulation the Na⫹ channel by glycerol-3phosphate dehydrogenase like1 kinase was recently established by the
identification of a kindred with Brugada syndrome and a
mutation in the enzyme.23 In vitro expression showed that
enzyme action is associated with a decrease in INa.
Mutations in cardiac sodium channel gene SCN5A have
been associated with LQTS, Brugada syndrome, primary
cardiac conduction system disease (PCCP), and dilated cardiomyopathy (Table 4).24 The long QT syndrome is the result
of defects in inactivation that enhance the late component of
sodium current. The late component of current is more
sensitive to block by class 1 antiarrhythmic drugs than the
peak current. Mexiletine and flecainide decrease the late
component of sodium current and restore the QT interval
toward normal.25,26 They have been used to treat patients with
LQT3, particularly in the neonatal period and in children
when ICD implantation may prove technically challenging.
Sodium channel mutations have been described in 20% of
patients with Brugada syndrome.27 The mutations reduce the
Na⫹ current as a result of synthesis of nonfunctional proteins,
failure of the protein to be targeted to the cell membrane or
accelerated inactivation of the channel. As a subgroup, the
patients with Na⫹ channel mutations that produce Brugada
syndrome have H-V interval prolongation at electrophysiology study. The mechanism of ST segment elevation and T
wave inversion in the syndrome is controversial. One group
view the syndrome as primarily a repolarization abnormality28;
others view the Na⫹ channel variant as a conduction defect.29
Slow conduction from endocardium to epicardium results in
delayed epicardial activation. The sequence of transmural
repolarization is reversed, resulting in the ST-T wave
changes. The mutations associated with primary cardiac
conduction disease also reduce the Na⫹ current.30 The clinical
syndromes include sinus node dysfunction, atrial standstill,
AV block, and fascicular (infra-Hisian) block. Overlap syndromes of LQT3, Brugada syndrome, and PCCD may occur
in the same kindred or individual.31 The mechanisms by
Grant
Table 2. A Comparison of the L-Type and T-Type
Ca2ⴙ Channels
Table 3.
L-Type
T-Type
Low Em (⬇⫺30 mV)
High Em (⬇⫺60 mV)
Activation
Range
Inactivation
Range
Low Em (⬇⫺40 mV)
Hyperpolarized
Voltage dependence
Slow
Fast
关Ca2⫹兴 i dependent
Yes
No
Pharmacologic sensitivity
Dihydropyridnes
Yes
No
Cd
High
Low
Ni
Low
High
Isoproternol
Yes
No
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which Na⫹ defects result in dilated cardiomyopathy are not
well understood.32 Long standing conduction delay and asynchronous contraction may be contributory.
The cardiac sodium channel is the substrate for the action
of class 1 antiarrhythmic drugs (Table 3). Open and inactivated channels are more susceptible to block than resting
channels. The differential block may be the result of a
difference in binding affinity or state-dependent access to the
binding site.33,34 Binding of antiarrhythmic drug occurs primarily during the action potential. This block is dissipated in
the interval between action potentials. Because a fast heart
rate is associated with abbreviation of the diastolic period and
insufficient time for recovery, block accumulates (ie, it is
use-dependent). Class 1 antiarrhythmic drugs may be classified according to the kinetics of unbinding, with various
drugs showing fast, intermediate, or slow unbinding
kinetics.35
Calcium Channels
Calcium ions are the principal intracellular signaling ions.
They regulate excitation– contraction coupling, secretion, and
the activity of many enzymes and ion channels. [Ca2⫹]i is
highly regulated despite its marked fluctuation between
systole and diastole. Calcium channels are the principal portal
of entry of calcium into the cells; a system of intracellular
storage sites, and transporters such as the sodium-calcium
exchanger (NCX), also play important roles in [Ca2⫹]i
regulation. In cardiac muscle, 2 types of Ca2⫹ channels, the
L- (low threshold type) and T-type (transient-type), transport
Ca2⫹ into the cells. The L-type channel is found in all cardiac
cell types. The T-type channel is found principally in pacemaker, atrial, and Purkinje cells. The unqualified descriptor
Ca2⫹ channel refers to the L-type channel. Table 2 contrasts
the properties of the two types of channels.
A combination of as many as 5 subunits, ␣1, ␣2, ␤, ␥, and
␦, unite to form the channel in its native state. The ␣1c
subunit, Cav1.2, is the cardiac-specific subunit. The ␤ subunit
increases channel expression ⬇10-fold and accelerates the
activation and inactivation kinetics. Ca2⫹ channels have a
similar structure to the sodium channel: 4 homologous
domains each consisting of 6 membrane-spanning segments.
Cardiac Ion Channels
189
Classification of Antiarrhythmic Drug Actions
Class
Unbinding Kinetics
Effect on
APD
Example
Procainamide
1A
Intermediate
APD1
1B
Fast
APD 3
Lidocaine
1C
Slow
APD2,3
Flecainide
APD
Metoprolol
APD1
Dofetelide, Ibutilide
APD1,3
Verapamil
II (␤-blocker)
⫹
III (K channel
blocker)
IV (Ca⫹ channel
blocker)
Slow
The P-loop of each domain contributes a glutamate residue
(E) to the pore structure. These residues (EEEE) are critical
for calcium selectivity; the channel can be converted from a
Ca2⫹-sensitive channel to one with high monovalent cation
sensitivity by mutating a glutamate residue.36 Several molecular mechanisms contribute to a complex system of inactivation. Membrane depolarization decreases the fraction (d⬁) of
channels available for opening; d⬁ varies from 1 at ⬇⫺45
mV to 0 at zero mV. The carboxyl terminus has multiple
Ca2⫹ binding sites and Ca-calmodulin– dependent kinase
activity. Ca2⫹ in the immediate vicinity of the channel and
phosphorylation also play roles in the inactivation of the
channel. Reuptake of Ca2⫹ by the sarcoplasmic reticulum
during prolonged depolarization can result in the recovery
from Ca2⫹-dependent inactivation and enable secondary depolarization. This may be the basis for the early afterdepolarizations, EADs that trigger polymorphic VT in LQTS. The
overall kinetics of the Ca channel is important in controlling
contractility in response to various patterns of stimulation. At
low (depolarized) membrane potentials, recovery of ICa from
inactivation between action potentials is slow; ICa declines in
response to repetitive stimulation and a negative staircase of
contractility is observed. At normal resting potentials, recovery of ICa from inactivation is fast, and ICa may increase
progressively during repetitive stimulation. This positive
staircase or rate-dependent potentiation of contractility is
Ca2⫹-dependent. It is the result of enhanced loading of the
sarcoplasmic reticulum and may be facilitated by calmodulin
kinase II– dependent phosphorylation.
Timothy syndrome is a multi-system disease with LQTS,
cognitive abnormalities, immune deficiency, hypoglycemia,
and syndactyly that is the result of mutations of CaV1.2.37 The
mutation of glycine to arginine converts a neighboring serine
to a consensus site for phosphorylation by calmodulin kinase.
The phosphorylation of this site promotes a slow gating mode
of the calcium channel, increasing Ca2⫹ entry and resulting in
cytotoxicity.38 A sudden death syndrome that combines the
features of Brugada syndrome, including the characteristic
ECG pattern, and a short QT interval has been described
recently.39 The syndrome results from a loss of function of the
␣1- or ␤2b subunit of the L-type Ca2⫹ channel.
The Ca2⫹ channel is the target for the interaction with class
IV antiarrhythmic drugs. The principal class IV drugs are the
phenylalkylamine, verapamil and the benzothiazepine, diltiazem. Both drugs block open and inactivated Ca2⫹ channels;
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they cause use-dependent block of conduction in cells with
Ca2⫹-dependent action potentials such those in the SA- and
AV nodes and slow the sinus node rate. However, the
hypotensive effects of verapamil may cause an increase in
sympathetic tone and increase the heart rate. A third class of
Ca2⫹ channel blockers, the dihydropyridines, block open
Ca2⫹ channels. However, the kinetics of recovery from block
is sufficiently fast that they produce no significant cardiac
effect but effectively block the smooth muscle Ca2⫹ channel
because of its low resting potential.
Potassium Channels
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Cardiac K⫹ channels fall into 3 broad categories: Voltagegated (Ito, IKur, IKr, and IKs), inward rectifier channels (IK1,
IKAch, and IKATP), and the background K⫹ currents (TASK-1,
TWIK-1/2). It is the variation in the level of expression of
these channels that account for regional differences of the
action potential configuration in the atria, ventricles, and
across the myocardial wall (endocardium, midmyocardium,
and epicardium). K⫹ channels are also highly regulated and
are the basis for the change in action potential configuration
in response to variation in heart rate.
Voltage-gated K⫹ channels consist of principal ␣-subunits
and multiple ␤-subunits. The channel functional units also
include the complementary proteins KV-channel associated
protein, KChAP, and the KV channel interacting protein,
KChIP. The major subfamilies of ␣-subunits include KVN.x
(n⫽1 to 4), the HERG channel (gene KCNH2), and KvLQT1
(gene KCNQ1). They are important in generating outward
current in the heart. Members of the KVN.x subfamily may
coassemble to form hetero-multimers through conserved
amino-terminal domains. In contrast, members of the HERG
and KvLQT1 subfamilies assemble as homotetramers. The ␣subunits that coassemble to form the various types of K⫹
channels and their role in the generation of the action
potential are summarized in Table 1. Most ␤-subunits have
been cloned and sequenced. They have oxio-reductase activity. The ␣-subunits can generate voltage dependent K⫹
current when expressed in heterogonous systems. However,
the accessory subunits are required to recapitulate the K⫹
currents seen in native cells. KChAP (KCHAP) and KChIP
(KCNIP2) may increase channel activity independent of
transcription and alter channel kinetics. The structure of
voltage-gated K⫹ channels is similar to 1 of the 4 domains
of voltage-gated Na⫹ and Ca2. The amino acid sequence
glycine-tyrosine-glycine GYG is the sequence requirement
for K⫹ selectivity.
The transient outward current is composed of a K⫹ current
Ito1 and a Ca2⫹-activated chloride current, Ito2. The former
has fast and slow components, Ito,f and Itos. Itof is the principal
subtype expressed in human atrium; Ito,f and Itos are expressed
in the ventricle. Myocardial regions with relatively short
action potentials such as the epicardium, right ventricle, and
the septum have higher levels of Ito expression. Compared to
other voltage-gated K⫹ channels, activation of Ito is fast
(activation time constant ⬍10 ms). The rate of inactivation is
variable and highly voltage-dependent. ␣-adrenergic stimulation reduces Ito in human myocytes through PKA-dependent
phosphorylation. Chronic ␣-adrenergic stimulation and an-
giotensin II also reduces channel expression. The influence of
a reduction of Ito on the action potential duration varies with
species; in rodents, a reduction in Ito prolongs the action
potential duration. In large mammals, a reduction in Ito shifts
the plateau to more positive potentials increasing the activation of the delayed rectifier and promoting faster repolarization. In a rodent model of hypothyroidism the action potential
prolongation is associated with a reduction of Ito. The current
is also reduced in human heart failure but is associated with
a prolongation of the action potential duration. Because the
level of the plateau is set by Ito, modulators that decrease Ito
shift the plateau into the positive range of potentials. This
decreases the electro-chemical driving force for Ca2⫹ and
hence ICa.
The delayed rectifier K⫹ currents IKur, IKr, and IKs are
slowly activating outward currents that play major roles in the
control of repolarization. The deactivation of these channels
is sufficiently slow that they contribute outward current
throughout phase 3 repolarization. IKur is highly expressed in
atrial myocytes and is a basis for the much shorter duration of
the action potential in the atrium. IKr is differentially expressed, with high levels in the left atrium and ventricular
endocardium. IKs is expressed in all cell types, but is reduced
in midmyocardial myocytes. These cells have the longest
action potential duration across the myocardial wall. The
␣-subunits that make up the delayed rectifier currents are
summarized in Table 1. ␤-subunits are associated with IKr and
IKs. MinK-Related Peptide-1 (MiRP-1) and MinK are the
most thoroughly studied. MiRP-1 and MinK are singlemembrane spanning peptides with extracellular amino termini. The ␤-subunits are nonconducting but regulate
␣-subunit function, including gating, response to sympathetic
stimulation, and drugs. ␤-adrenergic stimulation regulates IKr
through activation of protein kinase A and elevation of
c-AMP. The former effect is inhibitory; the latter is stimulatory through binding to the cyclic nucleotide binding domain
of the channel. ␣-adrenergic stimulation is inhibitory.
␤-adrenergic stimulation increases IKs through PKAdependent phosphorylation. This action involves a complex
of PKA, protein phosphatase1, and the adaptor protein
yotaio.7 Ion channel mutations that disrupt the function of the
complex result in the action potential prolongation of LQT1.
␤-adrenergic blockers indirectly regulate this complex and
are important therapeutic options in LQT1.
The inward rectifier channel current Ik1 sets the resting
membrane potential in atrial and ventricular cells. Channel
expression is much higher in the ventricle and protects the
ventricular cell from pacemaker activity. The strong inward
rectification of the Ik1 limits the outward current during
phases 0, 1, and 2 of the action potential. This limits the
outward current during the positive phase of the action
potential and confers energetic efficiency in the generation of
the action potential. Because block of the outward current by
intracellular Mg⫹ and the polyamines is relieved during
repolarization, Ik1 makes a significant contribution to phase 3
repolarization.
The acetylcholine-activated K⫹ channel is a member of the
G protein– coupled inward rectifying potassium channels.
The channel is highly expressed in the SA and AV nodes, and
Grant
Table 4.
Cardiac Ion Channels
191
The Genetic Basis of Inherited Arrhythmias
Type
Gene
Protein
Functional Alteration
LQT1
KCNQ1
IKs potassium channel ␣-subunit
Loss of function
Loss of function
LQTS
LQT2
KCNH2
IKr potassium channel ␣-subunit
LQT3
SCN5A
INa cardiac sodium channel ␣-subunit
Gain of function
LQT4
ANK2
Ankyrin-B
Loss of function
LQT5
KCNE1
IKs potassium channel ␤-subunit
Loss of function
LQT6
KCNE2
IKr potassium channel ␤-subunit
Loss of function
LQT7
KCNJ2
IK1 potassium channel subunit
Loss of function
LQT8
CACNA1C
Calcium channel ␣-subunit
Gain of function
Short QT syndrome
S4T1
KCNH2
IKr potassium channel ␣-subunit
Gain of function
S4T2
KCNQ1
IKs potassium channel ␣-subunit
Gain of function
S4T3
KCNJ2
IK1 potassium channel subunit
Gain of function
Loss of function
Brugada syndrome
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BrS1
SCN5A
INa sodium channel ␣-subunit
BrS2
GPD1L
G-3PD 1⫺
Altered function
BrS3
CACNA1C
ICa calcium channel ␣-subunit
Loss of function
BrS4
CACNB2b
ICa calcium channel ␤-subunit
Loss of function
BrS other
ANKRYN-B
Ankryin-B
Altered function
RYR2
Cardiac ryanodine receptor
Gain of function
CASQ2
Calsequestrin
Gain of function
Catecholaminergic polymorphic VT
Idiopathic sick sinus syndrome
HCN4
If pacemaker channel subunit
Loss of function
SCN5A
INa cardiac sodium channel ␣-subunit
Loss of function
SCN5A
INa cardiac sodium channel ␣-subunit
Loss of function
KCNQ1
IKs potassium channel ␣-subunit
Gain of function
KCNE2
IKr potassium channel ␤-subunit
Gain of function
Cardiac conduction disease
Familial atrial fibrillation
KCNJ2
IK1 potassium channel subunit
Gain of function
KCNH2
IKr potassium channel ␣-subunit
Gain of function
atria, but low in ventricle. Activation of IKAch hyperpolarizes
the membrane potential and abbreviates the action potential.
Phase 4 depolarization of pacemaker cells is slowed. The
channel structure is similar to that of IK1. The binding of
acetylcholine to the M2 muscarinic receptor activates the G
protein Gi and the release of the subunits Gi␣ and G␤␥. The
dissociated G␤␥ subunit binds to the channel and activities it.
The binding of adenosine to the P1 receptor also results in the
release of G␤␥ and activation of the channel. Methylxanthines
such as theophylline block the P1 receptor and antagonized
the effects of adenosine. Coexpression of the inward rectifier
K⫹ channel Kir6.x and sulfonylurea receptor yield channels
with properties similar to the native IKATP.
Mutations of the genes encoding cardiac K⫹ channels are
the principal causes of arrhythmias that result from abnormal
repolarization (Table 4).40 Mutations of KCNQ1, the gene
encoding KvLQT1, and KCNH2, the gene encoding HERG,
account for more than 80% of autosomal dominant LQTS
(Romano-Ward syndrome). Bilateral neurosensory deafness
is a part of the autosomal recessive form (Jervell and
Lange-Nielsen syndrome). Mutations of the ␣-subunit
KCNJ2 and the ␤-subunits of KVLQT1 and HERG are minor
causes of LQTS. A majority of these mutations have a
dominant negative effect, coassembling with normal subunits, but impairing their function. Polymorphisms of the
genes encoding the K⫹ channels may increase susceptibility
to drug-induced LQTS. Gain of function mutations of IKr, IKs,
IK1 cause marked acceleration of repolarization and the short
QT syndrome. Mutations of these subunits have also been
associated with familial atrial fibrillation.
Cardiac K⫹ channels are the targets for the action of class
III antiarrhythmic drugs. The HERG channel is very susceptible to block by a broad range of drugs that are not primarily
used to treat cardiac arrhythmias, including antipsychotics,
and the macrolide antibiotics. The potent K⫹ channel blocking action of quinidine, procainamide, and disopyramide
account for their QT- prolonging action and occasionally
torsade de pointes. HERG blockers produce greater blockade
192
Circ Arrhythmia Electrophysiol
April 2009
at slow heart rates; block tends to dissipate during the rapid
heart rates of a tachycardia, so called reverse-use dependence.
Amiodarone is exceptional in that it produces K⫹ channel
blockade that shows little use dependence. Although antiarrhythmic drugs have fallen out of favor for the management
for ventricular tachycardia, they retain an important role in
the prevention of recurrences of atrial fibrillation. The discovery of the atrial-specific distribution of IKur has made this
channel a target for novel therapies for atrial fibrillation. The
drug vernakalant is a IKur/Na channel blocker and is undergoing review by the FDA for the acute termination of atrial
fibrillation.
Hyperpolarization-Activated Cyclic Nucleotide
Gated Channel
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Autorhythmicity is one of the most characteristic features of
cardiac cells and resides in the pacemaker cells of the
specialized conducting system, including the SA and AV
nodes, and His-Purkinje system. Pacemaker activity initiates
and sustains electric activity of the heart independent of the
underlying innervation. Phase 4 diastolic depolarization is
characteristic of pacemaker cells. Many ion channels contribute to phase 4 depolarization: the K⫹ channel current activated during the preceding action potential, a background
Na⫹ current, the sodium-calcium exchange, the If channel,
and the L- and T-type Ca2⫹ channels. However, the If current
channel is unique to this process. Unlike other voltage-gated
channels, If is activated by hyperpolarization negative to ⬇40
mV. The channel is not very selective for Na⫹ over K⫹ and
has a reversal potential (Er) of ⫺10 to ⫺20 mV. Therefore, it
carries inward current throughout the range of pacemaker
potential. The phase 4 depolarization reduces the membrane to
the threshold for the regenerative activation of ICa,T and ICaL.
The genes encoding If channels have been cloned and
sequenced in the past decade. If channels (hyperpolarizationactivated cyclic nucleotide gated [HCN]I–HCN4) are members of a family of cyclic nucleotide activated voltage-gated
channels. Although members of this family of channels are
expressed in heart and brain, HCN2 and HCN4 are expressed
in the heart. Expression is both developmentally and regionally regulated. Neonatal cardiac ventricular myocytes that
show pacemaker activity predominantly expressed HCN2.
Expression of HCN2 declines in adulthood. HCN4 is the
subtype primarily expressed in the sinus node, AV node, and
ventricular conducting system. Knockout of the HCN4 gene
is embryonic lethal. Channels are formed by the assembly of
4 ␣-subunits, each with a structure analogous to that of the
voltage gated K⫹ channels. Binding of cAMP to this domain
shift the voltage dependence of If activation to more depolarized potentials and increase the rate of pacemaker discharge. Protons shift the activation of If to more hyperpolarized potentials and slow pacemaker activity. The If channel is
the target for a new class of bradycardic agents, eg, ivabradine. They have the advantage over ␤- blockers in that they
slow the heart rate without the disadvantage of negative
inotropy or hypotension. They have proved effective in the
management of patients with chronic stable angina.
Isolated reports of mutations in the HCN4 gene have
appeared recently. One kindred had idiopathic sinus brady-
cardia and chronotrophic incompetence.41 Severe bradycardia, QT prolongation, and torsade de pointes have been
described in another family. If expression is upregulated in
cardiac hypertrophy and congestive heart failure. This response may contribute to the arrhythmias observed in these
disease states.
Gap Junction Channels
That cardiac tissues are made up of discrete cells was a
seminal observation in cell biology. The rapid conduction of
the cardiac impulse required the presence of low resistance
connections between cardiac cells.42 The propagation velocity in a uniform cable is inversely related to the intercellular
(internal) resistance; low internal resistance favors rapid
conduction. Gap junction channels form the low resistance
connections between cardiac cells.43 In the young, gap junctions are widely distributed over the surface of cells. Cells
become elongated and arranged in parallel bundles in the
adult heart, and gap junctions become localized principally at
the ends of cells. The density of gap junctions is lower at the
lateral margins of cells, particular conduction system myocytes. This nonuniform distribution of gap junctions changes
the pattern and safety of conduction. Propagation occurs
rapidly through the cytoplasm of cells and slows at the
intercellular junctions, ie, conduction is discontinuous. Conduction is faster in the longitudinal direction, with velocity
ratios of 3 to 8 for longitudinal direction compared with the
transverse direction. The higher density of gap junction in the
longitudinal direction results in unloading of the excitatory
current during propagation. Longitudinal conduction is more
likely to fail. Conduction is more sustained in the transverse
direction and can occur at very slow rates.
Each of a pair of neighboring cells contributes hemichannels or connexons to the junction. The connexons are
made up of 6 connexins. These are the fundamental building
blocks of the junction. Three types of connexins are expressed in heart and are defined on the basis of their
molecular weight: connexin 40, connexin 43, and connexin
45 (molecular weights 40, 43, and 45 kDa). Connexin 43 is
the principal connexin expressed in the heart. Regional
differences in the type and distribution of connexins are
important determinants of the passive spread of excitation
over boundaries such as those of the SA and AV nodes. The
connexins may assemble as homomultimeric or heteromultimeric channels.
The conductance of gap junctional channels is regulated in
health and disease states. Protein kinase A phosphorylation
and low pH decrease junctional conductance. The latter may
be an important contributing factor to slow conduction during
acute ischemia. With aging, the density of gap junctions
declines and cells become separated by connective tissue
septa. This favors the occurrence of slow conduction, fractionated extracellular electrograms, and block.
Gap junctions are the targets for a new class of antiarrhythmic drugs.44 An antiarrhythmic peptide (AAP) inhibits ischemia-induced conduction slowing. An analog rotigaptide prevents ischemia-induced ventricular tachycardia.
Grant
Future Directions
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The cloning and sequencing of the ion channel genes that
regulate the action potential hold the promise that these genes
could be manipulated to treat arrhythmias. Proof of principle
has been established. The initial problem approached is the
control of the ventricular response in atrial fibrillation.
␤-adrenergic blockers are the most widely used drugs used to
control the ventricular response in atrial fibrillation. Adrenergic inhibition decreases intracellular [cAMP] and the Ca2⫹
current. This would slow conduction over the AV node.
Donahue and colleagues developed an indirect strategy to
decrease sympathetic activity in AV nodal cells.45 They
inserted the inhibitory G protein G␣i into an adenoviral
vector. The adenoviral vector-G␣i construct was infused in
the AV nodal artery of pigs with atrial fibrillation. G␣i over
expression decreased the heart rate in atrial fibrillation by
20% compared to the drug-free state. Persistence of the effect
was limited and the delivery of vector would be challenging
in the clinical situation.
Sick sinus syndrome is the most common cause for
permanent pacemaker implantation. A genetic strategy to
treat sinus node failure would be attractive. In an earlier
contribution to this series, Rosen and colleagues have provided a state of the art review on the genetic approach to the
development of biological pacemakers by manipulating the
HCN4 gene.47 The biological pacemakers have relatively
slow rates. The initial effort is focused on biological pacemaker that will complement rather than replace the normal
sinus node pacemaker.
Disclosures
Dr Grant has received honoraria from Boston Scientific, Medtronic,
St Jude Medical, and Sanofi Aventis.
References
1. Hoffman BF, Cranefield PF. Electrophysiology of the Heart. New York:
McGraw-Hill Book Company; 1960:1–323.
2. Antzelevitch C, Dumaine R. Electrical heterogeneity in the heart: physiological, pharmacological and clinical implications. In: Handbook of
Physiology. New York: Oxford University Press; 2002: Chapter 17.
3. Rautaharju PM, Zhou SH, Wong S, Calhoun HP, Berenson GS, Prineas
R, Davignon A. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol. 1992;8:690 – 695.
4. Hille B. Ionic Channels of Excitable Membranes. Sunderland: Sinauer
Associates Inc; 1984:249 –271.
5. Lopatin AN, Makhina EN, Nichols CG. Potassium channel block by
cytoplasmic polyamines as the mechanism of intrinsic rectification.
Nature. 1994;372:366 –369.
6. Leblanc N, Hume JR. Sodium current-induced release of calcium from
cardiac sarcoplasmic reticulum. Science. 1990;248:372–376.
7. Marx SO, Kurokawa J, Reiken S, Motoike H, D’Armiento J, Markes AR,
Kass RS. Requirement of a Macromolecular Signaling Complex for ␤
Adrenergic Receptor Modulation of the KCNQ1-KCNE1 Potassium
Channel. Science. 2002;295:496 – 499.
8. Delmar M, Duffy HS, Sorgen PL, Taffet SM, Spray DC. Molecular
organization and regulation of the cardiac gap junction channel connexin43. In: Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: Elsevier Inc; 2004.
9. Mohler PJ, Splawski I, Napolitano C, Bottelli G, Sharpe L, Timothy K,
Priori SG, Keating MT, Bennett V. A cardiac arrhythmia syndrome
caused by loss of ankyrin-B function. Proc Natl Acad Sci U S A. 2004;
101:9137–9142.
10. Hodgkin AL, Huxley AF. A quantitative description of membrane current
and its application to conduction and excitation in nerve. J Physiol.
1952;117:500 –544.
Cardiac Ion Channels
193
11. Noda M, Shimizu S, Tanabe T, Takai T, Kayano T, Ikeda T, Takahashi
H, Nakayama H, Kanaoke Y, Minamino N, Kangawa R, Matsuo H,
Raftery MA, Hirose T, Inayama S, Hayashida H, Miyata T, Numa S.
Primary structure of electrophorus electricus sodium channel deduced
from cDNA sequence. Nature. 1984;312:121–127.
12. Li RA, Tomaselli F, Marbin E. Sodium Channels. In: Cardiac electrophysiology: from cell to bedside. 2004. Elsevier, Inc., Philadelphia, PA.
13. Patlak JB, Ortiz M. Slow currents through single sodium channels of
adult rat heart. J Gen Physiol. 1985;86:89 –104.
14. Grant AO, Starmer CF. Mechanisms of closure of cardiac sodium
channels in rabbit ventricular myocytes: Single-channel analysis. Circ
Res. 1987;60:897–913.
15. Zilberter YI, Starmer CF, Starobin J, Grant AO. Late Na channels in cardiac
cells: The physiological role of background Na channels. Biophys J. 1994;
67:153–160.
16. Bennett PB, Yazawa K, Makita N, George AL Jr. Molecular mechanism
for an inherited cardiac arrhythmia. Nature. 1995;376:683– 685.
17. Richmond JE, Featherstone DE, Hartmann HA, Ruben PC. Slow inactivation in human cardiac sodium channels. Biophys J. 1998;74:
2945–2952.
18. Rohl CA, Boeckman FA, Baker C, Scheuer T, Catterall WA, Klevit RE.
Solution structure of the sodium channel inactivation gate. Biochemistry.
1999;38:855– 861.
19. West JW, Patton DE, Scheuer T, Wang Y, Goldin AL, Catterall WA.
A cluster of hydrophobic aminoacid residues required for fast Na⫹channel inactivation. Proc Natl Acad Sci U S A. 1992;89:10910 –10914.
20. Ono K, Kiyosue T, Arita M. Isoproterenol, DBcAMP and forskolin
inhibit cardiac sodium current. Am J Physiol. 1989;256:C1131–C1137.
21. Kirstein M, Eickhorn R, Kochsiek K, Langenfeld H. Dose-dependent
alteration of rat cardiac sodium current by isoproterenol: results from
direct measurements on multicellular preparations. Eur J Physiol. 1996;
431:395– 401.
22. Frohnwieser B, Chen, L-Q, Schreibmayer W, Kallen RG. Modulation of
the human cardiac sodium channel a-subunit by cAMP-dependent protein
kinase and the responsible sequence domain. J Physiol. 1997;498:
309 –318.
23. London B, Michalec M, Mehdi H, Zhu X, Kerchner L, Sanyal S,
Viswanathan PC, Pfahnl AE, Shang LL, Madhusudanan M, Baty CJ,
Lagana S, Aleong R, Gutmann R, Ackerman MJ, McNamara DM, Weiss
R, Dudley SC Jr. Mutation in glycerol-3-phosphate dehydrogenase 1-like
gene (GPD1-L) decreases cardiac Na⫹ current and causes inherited arrhythmias. Circulation. 2007;116:2260 –2268.
24. Clancy CE, Kass RS. Inherited and Acquired Vulnerability to Ventricular
Arrhythmias: Cardiac Na⫹ and K⫹ Channels. Physiol Rev. 2005;85:
33– 47.
25. Schwartz, PJ, Priora SG, Locati EH, Napolitano C, Cantu F, Towbin JA,
Keating MT, Hammoude H, Brown AM, Chen, L-SK, Colatsky TJ. Long
QT syndrome patients with mutations of the SCN5A and HERG genes
have differential responses to Na⫹ channel blockade and to increases in
heart rate. Circulation. 1995;92:3381–3386.
26. Wang DW, Yazawa K, Makita N, George AL Jr, Bennett PB. Pharmacological targeting of long QT mutant sodium channels. J Clin Invest.
1997;99:1714 –1720.
27. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado
D, Gussak I, LeMarec H, Nademanee K, Riera ARP, Shimizu W,
Schulze-Bahr E, Tan H, Wilde A. Brugada Syndrome: Report of the
Second Consensus Conference. Heart Rhythm. 2005;2:429 – 440.
28. Hong K, Bjerregaard P, Gussak I, Brugada R. Short QT syndrome and
atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol. 2005;16:394 –396.
29. Zhang, Z-S, Tranquillo J, Neplioueve V, Bursac N, Grant A. Sodium
channel Kinetic changes that produce Brugada syndrome or progressive
cardiac conduction system disease. Am J Physiol Heart Circ Physiol.
2007;292:H399 –H407.
30. Schott, J-J, Alshinawi C, Kyndt F. Cardiac conduction defects associate
with mutations in SCN5A. Nat Genet. 1999;23:20 –21.
31. Grant AO, Carboni MP, Neplioueva V, Starmer CF, Memmi M,
Napolitano C, Priori S. Long QT syndrome, Brugada syndrome, and
conduction system disease are linked to a single sodium channel
mutation. J Clin Invest. 2002;110:1201–1209.
32. McNair WP, Ku L, Taylor MRG, Fain PR, Dao D, Wolfel E, Mestroni L.
SCN5A mutation associated with dilated cardiomyopathy, conduction
disorder, and arrhythmia. Circulation. 2004;110:2163–2167.
194
Circ Arrhythmia Electrophysiol
April 2009
Downloaded from http://circep.ahajournals.org/ by guest on May 2, 2017
33. Hondeghem LM, Katzung BG Time- and voltage-dependent interactions
of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys
Acta. 1977;472:373–398.
34. Starmer CF, Grant AO. Phasic ion channel blockade: A kinetic and
parameter estimation procedure. Mol Pharmacol. 1985;28:348 –356.
35. Harrison DC. Is there a rational basis for the modified classification of
antiarrhythmic drugs? In: Morganroth J, Moore EN, eds. New Drugs and
Devices. Boston: Martinus Nijhoff; 1985.
36. Heinemann SH, Terlau H, Stuhmer W, Imoto K, Numa S. Calcium
channel characteristics conferred on the sodium channel by single
mutations. Nature. 1992;356:441– 443.
37. Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH,
Sanguinetti MC, Keating MT. Severe arrhythmia disorder caused by
cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A.
2005;102:8089 – 8096.
38. Erxleben C, Liao Y, Gentile S, Chin D, Gomez-Alegria C, Mori Y,
Birnbaumer L, Armstrong DL. Cyclosporin and Timothy syndrome
increase mode 2 gating of CaV1.2 calcium channels through aberrant
phosporylation of S6 helices. Proc Natl Acad Sci U S A. 2006;103:
3932–3937.
39. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC,
Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber
P, Bonaros EP Jr, Burashnikov E, Wu Y, Sargent JD, Schickel S,
Oberheiden R, Bhatia A, Hsu, L-F, Haïssaguerre M, Schimpf R,
Borggrefe M, Wolpert C. Loss-of-function mutations in the cardiac
calcium channel underlie a new clinical entity characterized by
40.
41.
42.
43.
44.
45.
46.
47.
ST-segment elevation, short QT intervals, and sudden cardiac death.
Circulation. 2007;115:442– 449.
Splawski I, Shen, j, Timothy KW, Lehmann MH, Priori S, Robinson JL,
Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT. Spectrum
of mutations in Long-QT syndrome genes KVLQT1, HERG, SCN5A,
KCNE1, and KCNE2. Circulation. 2000;102:1178 –1185.
Herrmann S, Stieber J, Ludwig A. Pathophysiology of HCN channels.
Eur J Physiol. 2007;454.
Rohr S. Role of gap junctions in the propagation of the cardiac action
potential. Cardiovasc Res. 2004;62:309 –322.
Spach M. Anisotropy of cardiac tissue: a major determinant of conduction? J Cardiovasc Electrophysiol. 1999;10:887– 890.
Nattel S, Carlsson L. Innovative approaches to anti-arrhythmic drug
therapy. Nat Rev Drug Discov. 2006;5:1034 –1049.
Donahue JK, Heldman AW, Fraser H, McDonald AD, Miller JM, Rade
JJ, Eschenhagen T, Marban E. Focal modification of electrical conduction
in the heart by viral gene transfer. Nat Med. 2000;6:1395–1398.
Herbert E, Chahine M. Clinical aspects and physiopathology of Brugada
syndrome: review of current concepts. Can J Physiol Pharmacol. 2006;
84:795– 802.
Rosen MR, Brink PR, Cohen IS, Robinson RB. Cardiac pacing from
electronic . . . to biological circulation: arrhythmia and electrophysiology.
Circ Arrhythmia Electrophysiol. 2008;1:54 – 61.
KEY WORDS: action potentials
䡲 genetics 䡲 ion channels
䡲
electrocardiography
䡲
electrophysiology
Cardiac Ion Channels
Augustus O. Grant
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Circ Arrhythm Electrophysiol. 2009;2:185-194
doi: 10.1161/CIRCEP.108.789081
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