Download cardiac potassium channel subtypes: new roles in repolarization

Physiol Rev 94: 609 – 653, 2014
doi:10.1152/physrev.00022.2013
CARDIAC POTASSIUM CHANNEL SUBTYPES: NEW
ROLES IN REPOLARIZATION AND ARRHYTHMIA
Nicole Schmitt, Morten Grunnet, and Søren-Peter Olesen
The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences,
University of Copenhagen, Copenhagen, Denmark; Acesion Pharma, Copenhagen, Denmark; and Lundbeck A/S,
Valby, Denmark
L
I.
II.
III.
IV.
V.
INTRODUCTION
ION CHANNELS IN ATRIAL AND...
MECHANISMS AND ETIOLOGY...
PHARMACOLOGICAL TOOLS...
CONCLUSIONS AND PERSPECTIVES
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635
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I. INTRODUCTION
The heart functions as a mechanical pump ensuring a continuous systemic and pulmonary blood supply. The circulation provides the essential transport of nutrients, antibodies, hormones, and other chemical mediators, as well as the
exchange of gases and removal of waste products. Under
normal physiological, i.e., nondiseased conditions, the
heart works steadily and uninterruptedly, only changing
rate according to changes in systemic needs. A human heart
thus performs ⬃100,000 successful and coordinated contractions every day. These contractions are controlled by
electrical signals, known as action potentials, which trigger
an intracellular signaling pathway referred to as the excitation-contraction coupling leading to the muscle contraction
(41). The tight electrical control of cardiac contractions also
means that imbalances can lead to disturbances in the heart
rhythm. In fact, under certain conditions, a single inappropriate electrical signal can obliterate proper cardiac function and ultimately develop into sudden cardiac arrest. Any
deviation from the normal stable heart rhythm is categorized as an arrhythmia (from Greek a ⫹ rhythmos ⫽ loss of
rhythm). Arrhythmias are often diagnosed based on irreg-
ularities of the surface electrocardiogram (ECG), which
macroscopically depicts the electrical activity of the heart.
The ECG is divided into different phases (FIGURE 1) that
reflect the depolarization and repolarization of atria and
ventricles.
Arrhythmias span the entire spectrum from the simplest
isolated event of a diminutive palpitation to uncoordinated
chaotic signaling recognized as fibrillations. The latter is
especially dangerous in a context where fibrillation propagates in the ventricles. Unless quickly terminated, ventricular fibrillation can result in sudden cardiac death, as it invalidates coordinated pumping activity. Arrhythmias are,
however, unusual events in young and middle-aged people,
which is comforting and also indicates the presence of a
broad safety margin and tight control of the complicated
and multifaceted processes of electrical signaling and excitation-contraction coupling. In combination with partly
overlapping functions for a number of the proteins involved
in these mechanisms, this ensures a high level of fidelity and
stability in the cardiac system.
The high lipophilicity of cell membranes, including those of
cardiac myocytes, provides an effective separation barrier
between the cell interior and the extracellular surroundings.
The cell membrane is impermeable to the hydrophilic ions,
but special transmembrane proteins such as ion channels
and transporters enable the different ion species to permeate selectively, and they form the basis for a controlled
0031-9333/14 Copyright © 2014 the American Physiological Society
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Schmitt N, Grunnet M, Olesen S-P. Cardiac Potassium Channel Subtypes: New
Roles in Repolarization and Arrhythmia. Physiol Rev 94: 609 – 653, 2014;
doi:10.1152/physrev.00022.2013.—About 10 distinct potassium channels in the
heart are involved in shaping the action potential. Some of the K⫹ channels are primarily
responsible for early repolarization, whereas others drive late repolarization and still
others are open throughout the cardiac cycle. Three main K⫹ channels drive the late repolarization
of the ventricle with some redundancy, and in atria this repolarization reserve is supplemented by
the fairly atrial-specific KV1.5, Kir3, KCa, and K2P channels. The role of the latter two subtypes in
atria is currently being clarified, and several findings indicate that they could constitute targets for
new pharmacological treatment of atrial fibrillation. The interplay between the different K⫹ channel
subtypes in both atria and ventricle is dynamic, and a significant up- and downregulation occurs in
disease states such as atrial fibrillation or heart failure. The underlying posttranscriptional and
posttranslational remodeling of the individual K⫹ channels changes their activity and significance
relative to each other, and they must be viewed together to understand their role in keeping a stable
heart rhythm, also under menacing conditions like attacks of reentry arrhythmia.
SCHMITT, GRUNNET, AND OLESEN
lated in shape, with a less pronounced plateau phase and a
more sliding repolarization phase. Action potentials recorded from sinoatrial and atrioventricular nodes exhibit a
third kind of shape with a slow onset enabling pacemaker
activity. This is accomplished by a sliding resting membrane
potential that will elicit spontaneous activity when depolarization is sufficient to reach the threshold for initiation of
action potentials. Keeping in mind that ion channels confer
the unique signature of action potentials, it follows that a
thorough understanding of the regulation and interaction
between these channels is a prerequisite for the perception
of cardiac function in both a physiological and a pathophysiological context. Representative examples of action
potentials obtained from human atria and ventricles are
shown in FIGURE 2.
QRS
Complex
R
PQ Interval
T
Q
S
QT Interval
FIGURE 1. Electrocardiogram (ECG) hallmarks. ECG from an individual in normal sinus rhythm. The schematic drawing below
(adapted from Wikimedia Commons) illustrates the phases of the
ECG. The P-wave represents depolarization of the atria, the QRS
complex the depolarization of the ventricles, and the T-wave the
repolarization of the ventricles.
electrical communication across the cell membrane as the
ions carry electrical charges. Fast transient changes in ion
permeability generate action potentials and thereby excitability. This is primarily achieved by delicate control of the
opening and closing of a number of different ion channels in
various parts of the heart. Cardiac action potentials are different from their neuronal counterparts by having an extended
plateau phase that will last for several hundred milliseconds in
humans and thereby secure the necessary Ca2⫹ dynamic for
appropriate contractions and time for the heart chambers to
empty their blood volume. The morphology of the cardiac
action potential varies in shape and duration according to the
location in the heart (reviewed in Ref. 305).
Ventricular action potentials have a relative stable plateau
phase and what is recognized as a domelike shape. The
exact action potential shape varies to a minor but significant
degree in different parts of the ventricle and throughout the
ventricular wall. Furthermore, the shape varies over time
depending on heart rate, as a fast heart rate speeds up repolarization. Atrial action potentials appear more triangu-
610
Ion channels are, as stated, of paramount significance for
electrical signaling in excitable cells. A thorough insight
into the function and regulation of cardiac ion channels is
therefore important for the understanding of cardiac
physiology and pathophysiology. This review has consequently been devoted to giving a detailed description of
cardiac ion channel function and regulation with special
emphasis on repolarizing K⫹ channels and their role in
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P
ST
Segment
PQ
Segment
The stability of cardiac electrical signaling is secured by
some degree of redundancy in combination with the tight
regulation of ion channels as stated above. The various K⫹
channels involved in repolarization of the action potential
represent a good example of such partial redundancy. The
most thoroughly investigated example is from the ventricles, where three different K⫹ currents participate in the
same phase of repolarization. These currents are called IKr,
IKs, and IK1, and albeit different in nature, due to different
biophysical properties these currents all have a profound
and overlapping impact on repolarization of the action potential. This phenomenon has been described as the “repolarization reserve” (364) to emphasize the partly overlapping function and, in this context, the redundancy of the
system (FIGURE 2). Various K⫹ channels also participate in
the repolarization of atrial action potentials, so there is an
equivalent atrial repolarization reserve, including a number
of additional K⫹ channel subtypes (FIGURE 2). Some K⫹
channels are believed to be exclusively present in the atria
and therefore play important roles for the triangulated
shape of atrial action potentials compared with their more
domelike ventricular counterparts. Examples of K⫹ channels selectively expressed in the atria encompass Kir3.1/
Kir3.4 as responsible for IKACh, KV1.5 as responsible for
IKur, and, more recently, Ca2⫹-activated K⫹ channels accountable for IKCa and two-pore domain K⫹ channels K2P
underlying Ileak (51, 102, 122, 132, 166, 250, 302, 471).
Due to their limited distribution, these channels have gained
significant interest for many years in the continuing effort to
find a treatment for atrial fibrillation without concomitant
ventricular adverse effects.
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
Sinus node
Right atrium
Left atrium
Atrioventricular
node
Left ventricle
Right ventricle
–50
0 mV
mV
–50
01 2
100 ms
3
4
mV
01
100 ms
2
Ito
3
4
IKs
IKr
IK1
IKATP
IKur
IKACh
IKCa
ITASK
arrhythmia. To obtain better perspectives on the nature
of arrhythmias and the role of ion channels in this context, we include an introduction to the mechanisms and
etiology of arrhythmias. Finally, we cover pharmacological treatments of arrhythmias and the general application of pharmacological tools to obtain better physiological understanding of the heart.
II. ION CHANNELS IN ATRIAL AND
VENTRICULAR CARDIOMYOCYTES
The different cardiac ion channels play well-defined roles in
shaping the action potential. Although the overall principle
is the same in all mammalian cells, the role of repolarizing
currents differs significantly. In the heart, it is widely dic-
tated by the great differences in heart rate among species.
Humans have a resting heart rate of ⬃60 beats/min (bpm),
whereas mice have a heart rate of ⬃600 bpm, which requires repolarizing K⫹ channels with different kinetics.
Within the same species, the ion channel expression and
thereby the shape and length of the action potential also
varies significantly in subregions of the heart, as shown in
FIGURE 2. These local differences, especially between atria
and ventricles, but also in sinoatrial (SA) and atrioventricular (AV) node, the conduction system and across the ventricular wall, are crucial for the function of these subregions
and for the stability of the heart rhythm.
The following section gives a short account of the ion channels responsible for shaping action potential in atria and
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0 mV
FIGURE 2. Cardiac action potential and repolarizing currents that underlie the repolarization reserve in atria and ventricles. Original traces from an action potential recording
in human atrial trabecula (left) and ventricular septum (right). Note that the atrial resting membrane potential (RMP) is more positive than the ventricular RMP (indicated by
the red dotted line). K⫹ current contributions
to the different phases (0 – 4) of the action
potential are shown below with an approximate physiological time course. The current
amplitudes are arbitrary and do not reflect
their relative size.
SCHMITT, GRUNNET, AND OLESEN
ventricle with focus on potassium channels. A more detailed
description is included for two subtypes of K⫹ channels that
traditionally have received relatively little attention. These
are the Ca2⫹-activated K⫹ channels and two-pore domain
K⫹ channels. We further elaborate on the role of accessory
subunits, posttranslational modifications, and epigenetic
regulation for the major repolarizing potassium currents.
A. Cardiac Action Potential: The Classic
Orchestra
1. Phase 0
The abrupt shift in membrane potential in a positive direction (depolarization) that initiates the systolic period is
called phase 0 and is driven by influx of Na⫹, INa, through
the NaV1.5 channel encoded by the gene SCN5A. The channels are rather insensitive to tetrodotoxin (TTX), which
blocks many neuronal NaV channels (126, 482). The
NaV1.5 current is by far the dominating Na⫹ current in the
human heart, but TTX-sensitive currents have been reported (99, 365, 393, 502). Discrete expression patterns
have been shown by immunohistochemistry for NaV1.1,
NaV1.5 channels open at potentials positive to ⫺55 mV,
show a steep voltage dependency, and activate very quickly
(126). In addition to the fast peak current, NaV1.5 channels
also conduct a persistent current due to slow or incomplete
inactivation at intermediate potentials (23). Although this
persistent or window current only makes up 0.1–1% of the
total current (441), it can significantly impact the action
potential morphology and arrhythmogenesis (37, 451).
The NaV1.5 channels are encoded by the same gene
throughout the heart, but functional differences exist between atria and ventricle. The voltage for half-inactivation
of NaV1.5 channels is more negative in atria compared with
ventricles in canine and guinea pig (59, 243), and the resting
membrane potentials differ between the two regions, which
impacts Na⫹ channel availability and conduction velocity.
2. Phase 1
The initial depolarization is followed by a transient repolarization termed phase 1, which is most prominent in atria
and the ventricular epicardium. This early repolarization is
caused by inactivation of NaV1.5 channels in combination
Table 1. Cardiac potassium currents
Current
Pore Forming
␣-Subunit
Gene
Other Channel
Names
Topology
Phase
Ito, fast
KV4.3
KCND3
6 TM tetramer
1
Ito, slow
IKur
IKr
KV1.4
KV1.5
KV11.1
KCNA4
KCNA5
KCNH2
6 TM tetramer
6 TM tetramer
6 TM tetramer
1
1 (1–3)
3 (3–4)
IKs
Kv7.1
KCNQ1
6 TM tetramer
3 (2–4)
IK1
IKAch
IKATP
Kir2.1
Kir3.1/Kir3.4
Kir6.1
KCNJ2
KCNJ3/KCNJ5
KCNJ11
2 TM tetramer
2 TM tetramer
6 TM tetramer
3 (3–4)
3
0–3
Ileak
IKCa
K2P3.1
KCa2.x
KCNK3
KCNN1-KCNN3
4 TM dimer
6 TM tetramer
0–4
0–4
ERG1, hERG,
LQT2
KvLQT1, KCNQ1,
LQT1, SQT2
GIRK2
GIRK1/GIRK4
TASK-1
SK1, SK2, SK3
Comment
Reference Nos.
Additional obligatory
subunit KChIP2
Reviewed in 311
Atria-specific
Additional obligatory
subunit KCNE1
Atria-specific
Additional obligatory
subunit SUR2A
TM, transmembrane segment.
612
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133, 415
Reviewed in 359
Reviewed in 433
Reviewed in 266,
464
98, 285
Reviewed in 113
Reviewed in 24
Reviewed in 166
Reviewed in 153
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The cardiac action potential is divided into five distinct
phases (phase 0 – 4, as indicated below the action potentials
in FIGURE 2). The underlying endogenous currents and their
molecular correlates are described below. TABLE 1 gives an
overview of potassium currents, their pore-forming ion
channel subunits, the principle channel topology, and the
genes encoding the channels. For stringency, we follow the
nomenclature recommendations of the International Union
of Basic and Clinical Pharmacology (IUPHAR) (145, 450,
483), although trivial channel names, included in TABLE 1,
are widely used in the field.
NaV1.2, NaV1.3, NaV1.4, and NaV1.6 (encoded by the
genes SCN1A, SCN2A, SCN3A, SCN4A, and SCN6A, respectively) (210, 452). Furthermore, the NaV1.8 channel
protein encoded by SCN10A was reported to be expressed
in working myocardium and the cardiac conduction system
(475). Others, however, have found its expression restricted
to intracardiac neurons (436), and the impact of NaV1.8 on
the cardiac sodium current is debated (256). Whereas
NaV1.5 is the main depolarizing current in atria, conduction system, and ventricle, it is absent in the core of the
nodes where CaV currents are suggested to serve this function, albeit with slower kinetics (271, 305, 323).
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
Selectively in atria, an additional ultra-rapid current called
IKur contributes to early repolarization. IKur is conducted by
KV1.5 potassium channels, and silencing KV1.5 in human
atrial myocytes by antisense oligonucleotides causes a major reduction of the IKur current (122, 359, 397). Due to its
slow and partial inactivation, IKur plays a role during all
phases 1–3, being partly responsible for the triangular action potential shape.
3. Phase 2
The long-lasting depolarized plateau in phase 2 of the cardiac action potential is a prerequisite for excitation-contraction coupling and is caused by a balance between outward K⫹ currents and inward currents through voltagegated Ca2⫹ channels. The latter are located in the t tubules,
and the Ca2⫹ influx through these channels activates ryanodine receptors located just below in the sarcoplasmic reticulum. The ensuing Ca2⫹-dependent Ca2⫹ release from
intracellular stores triggers muscle contraction (41). There
are two types of CaV channels displaying different expression patterns: the CaV1.2 (L-type, gene CACNA1C) ubiquitously expressed in the heart, and the CaV3 (T-type) suggested to contribute to the pacemaker function in the nodes
(30, 309, 323, 398, 496). CaV3 exists in three isoforms:
CaV3.1, 3.2, and 3.3. CaV3 channels activate at potentials
positive to ⫺50 mV and inactivate quickly, whereas CaV1.2
channels require potentials positive to ⫺30 mV and inactivate slowly, making them the key driver of phase 2 (30,
339). Phase 2 is terminated by a voltage- and Ca2⫹/calmodulin-dependent slow inactivation of CaV1.2 combined with
the simultaneous activation of K⫹ channels (40, 97).
To a lesser extent, the Ca2⫹ influx in the early part of phase
2 is also transported by the electrogenic Na⫹/Ca2⫹ exchanger encoded by the SLC8A1 gene. The stoichiometry of
this cotransporter is 3 Na⫹ for 1 Ca2⫹, which results in a net
movement of a positive charge with a reversal potential
around ⫺30 mV causing influx of Ca2⫹ and extrusion of
Na⫹ during phase 2 in normal hearts (20, 41, 273).
4. Phase 3
Phase 3 represents the repolarization from plateau phase to
resting membrane potential. The repolarization is caused by
the balance between inactivating Ca2⫹ current and rising
K⫹ channels tilting quickly towards the latter. In humans
and other large mammals, three different potassium currents called IKr, IKs, and IK1 are mainly responsible for
repolarization. They have diverse but partly overlapping
functions, and to stress the latter they have often been called
the “repolarization reserve” (FIGURE 2) (364).
IKr is conducted by the channel protein KV11.1, also known
as ERG1 or just hERG for the human variant. The KV11.1
channel is the gene product of KCNH2, and it exists in
several splice variants called KV11.1a, KV11.1b, and
KV11.1-uso (233). Functional IKr is likely to consist of a
mixture of both KV11.1a and KV11.1b (232, 255). The
presence of accessory ␤-subunits might further be necessary
to recapitulate native IKr, and two of these called KCNE1
and KCNE2 have been described to interact with KV11.1
(2, 280). The proposed interaction with KCNE1 has been
substantiated by immunoprecipitations from horse heart,
indicating a direct interaction (124), whereas the interaction with KCNE2 remains controversial (116).
IKs is conducted by the pore forming ␣-subunit KV7.1
(KCNQ1) in a complex with the ␤-subunit KCNE1 (also
known as mink or IsK) (29, 266, 376). KV7.1 channels can
potentially interact with all ␤-subunits in the KCNE family
(KCNE1–5) (279), since although at different levels, all five
subunits are expressed in the heart and modulate the function of KV7.1 in vitro.
IK1 is conducted via Kir2.x proteins. This channel family
consists of four members Kir2.1 (IRK1/KCNJ2), Kir2.2
(IRK2/KCNJ12), Kir2.3 (IRK3/KCNJ4), and Kir2.4 (IRK4/
KCNJ14) (47, 53, 226, 413, 421).
Intriguingly, the partly overlapping function of these three
currents driving phase 3 repolarization occurs on the basis
of very different gating properties. The voltage-gated current IKr is characterized by a relatively fast activation upon
depolarization, but as the inactivation is another 10-fold
faster, it renders the channel virtually nonconductive during
phases 0 –2 of the action potential (346). The opposite is
true in phase 3, where the initial repolarization will release
IKr from inactivation and reopen the channel. The subsequent deactivation or closure of the channel is a slow process allowing IKr to conduct current during both phase 3
and the early part of the diastolic phase 4 of the action
potential. Although IKs is also voltage-gated, it displays very
different biophysical properties. IKs opens at potentials positive to ⫺20 mV and activates slowly. Both the slow activa-
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with activation of transient voltage-gated K⫹ currents (Ito)
that can further be divided into Ito,fast and Ito,slow (470).
Both are activated at potentials above ⫺30 mV and show
inactivation. The differences in the two Ito components exhibit in their kinetics of inactivation and recovery from
inactivation (Ito,fast: ␶inactivation ⫽ ␶recovery ⫽ 20 –100 ms;
Ito,slow: ␶inactivation ⫽ hundreds of ms, ␶recovery ⫽ seconds)
(311, 335). The pore-forming subunit of Ito,fast is KV4.2 and
KV4.3 channels, encoded by the genes KCND2 and
KCND3, respectively. Additionally, the accessory subunits
KChIP2 and DPP6 are necessary to recapitulate native
Ito,fast (165). In large mammals, Ito,fast is primarily formed
by KV4.3 ⫹ KChIP2, and the latter shows a stronger epicardial than endocardial expression, causing the Ito gradient across the ventricular wall (367, 399). The K⫹ channel
constituting Ito,slow is KV1.4 (KCNA4) (311). Functionally,
the fast repolarization in phase 1 contributes to increasing
the driving gradient for Ca2⫹ into the cardiac myocytes.
SCHMITT, GRUNNET, AND OLESEN
In addition to the “repolarization reserve currents” IKr, IKs,
and IK1, other potassium currents can have a significant
impact on repolarization of cardiac action potentials. Especially important for the atria are IKur (see phase 1) and
IKACh. IKACh is generally believed to be atria specific, and
endogenous IKAch channels are composed of Kir3.1/Kir3.4
(or GIRK1/GIRK4) proteins encoded by KCNJ3 and
KCNJ5 genes. IKAch is directly activated by interaction with
the ␤␥ part of Gi proteins connected to muscarinic receptors
(178). Release of acetylcholine following vagal stimulation
leads to activation of the cardiac muscarinic receptors. Kir3.1/
Kir3.4 channels play an important role in the sinoatrial node,
where an increased K⫹ conductance will give rise to a slower
depolarization of the pacemaker potential and a reduction of
the heart rate (281, 358). Furthermore, Kir3.1/Kir3.4 channels
are important for atrial repolarization. Activation of the channels causes a shortening of the atrial action potential. The
channel is also activated by adenosine and seems via this mechanism to be able to also repolarize both atrial (445) and ventricular cardiomyocytes (246).
Finally, IKATP should be mentioned as a potentially important cardiac repolarizing current. The channel is composed
of the pore-forming ␣-subunit Kir6.2 (KCNJ11) in association with the ␤-subunit SUR2A (ABCC9) (59a, 124a). The
channel is abundant throughout the heart, but generally
closed due to ATP inhibition at the intracellular surface.
Under normal physiological conditions, the intracellular
614
ATP level is sufficiently high to inhibit the channels, but
during hypoxia and ischemia, the intracellular ATP level
drops and may result in an activation of Kir6.2 channels
(189a). Kir6.2 channels have a membrane topology similar
to Kir2.x channels conducting IK1, albeit with less rectification, so they can conduct current throughout phases 0 –3
resulting in triangulation of the action potential.
5. Phase 4
Phase 4 describes the interval between full repolarization
and the initiation of the next action potential. In this diastolic interval, the cardiac myocytes are at resting membrane potential, and the charge movements are primarily
conducted via various K⫹ channels, including Kir2.x and
two-pore motif leak channels. Additional K⫹ channels with
slow deactivation kinetics, including KV11.1 and KV7.1,
also remain open in the initial part of phase 4. These K⫹
currents will counteract possible depolarizing events from
delayed afterdepolarizations. However, the inhibitory force
of the K⫹ conductances is not enough to withstand massive
depolarizing stimuli arising from a new wave of action potentials. Prolongation of the effective refractory period
through K⫹ channel inhibition and Na⫹ channel inactivation remains the more efficient mechanism.
It is worth mentioning that the duration and degree of hyperpolarization in phase 4 will impact the morphology of
the subsequent action potential. The reason is that both
Ca2⫹ and Na⫹ channels undergo voltage- and time-dependent release from inactivation. The number of Na⫹ and
Ca2⫹ channels that can be engaged in a subsequent action
potential will therefore increase with duration and extent of
hyperpolarization in phase 4.
B. Cardiac Action Potential: New Players
In addition to the well-described currents, in recent years
Ca2⫹-activated small conductance K⫹ channels (KCa2.x)
and various two-pore domain channels (K2P) have proven
to be important cardiac K⫹ channels contributing in particular to atrial repolarization.
1. Ca2⫹-activated K⫹ channels
For many years, Ca2⫹-activated K⫹ channels were regarded
as absent from cardiac tissue or at least not present in cardiomyocytes. There is increasing evidence of an important
functional role for some subtypes of Ca2⫹-activated K⫹
channels in the heart. After a brief introduction to the family of Ca2⫹-activated K⫹ channels and the pharmacological
tools applied to reveal their function, we will provide an
overview of the literature evidence for the significance of
these channels in cardiac tissue.
Ca2⫹-activated K⫹ channels are divided into three subfamilies originally classified according to single-channel
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tion kinetics and the right-shifted activation curve are
largely caused by the presence of the KCNE1 ␤-subunit.
Importantly and in contrast to IKr, IKs barely inactivates
(195, 403). These properties enable IKs to build up slowly
during phase 2 and to become one of the key K⫹ conductances in phase 3. The third current, IK1, is not endowed
with an inherent voltage sensor in the protein (175). However, Kir2.x channels are indirectly voltage sensitive, as the
outflow of K⫹ through the channel is accompanied by
Mg2⫹ and polyamines such as spermine that will block the
channel deep in the pore (120, 164, 258, 432). The more
positive the membrane potential becomes, the stronger the
inhibition and Kir2.x channels do not conduct K⫹ at potentials more positive than ⫺20 mV, i.e., in phases 0 –2. When
phase 3 repolarization has reached a value of approximately ⫺40 mV, the Kir2.x channels will be released from
the Mg2⫹/spermine inhibition, and IK1 will contribute particularly to repolarization in the late part of phase 3 (258).
IK1 stays open during diastole and is important for setting
the resting membrane potential. This is emphasized by the
fact that ventricles with high IK1 expression have a resting
membrane potential of approximately ⫺80 mV, while the
maximum diastolic potential in nodes lacking IK1 is about
⫺50 mV (380). The relative conductances of the three repolarizing currents IKr, IKs, and IK1 during the atrial and
ventricular action potential and their partly overlapping
functions are illustrated in FIGURE 2.
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
KCa2.x channels are composed of four ␣-subunits. Each
subunit has six transmembrane segments with amino- and
carboxy-termini located intracellularly (435) (FIGURE 3B).
Cardiac KCa2.x channels can consist of KCa2.1, KCa2.2, and
KCa2.3 homotetramers or heterotetramers (425). Functional KCa2.x channels in cardiac tissue have been described
in humans, mice, rats, guinea pigs, rabbits, and dogs (101,
102, 245, 295, 328, 426, 471). KCa2.x (and KCa3.x) channels represent a special family of K⫹ channels, since they are
voltage insensitive and gated solely by free intracellular
conductance resulting in big- (KCa1.1/BK/KCNMA1), intermediate- (KCa3.1/IK/KCNN4), and small-conductance (KCa2.1/SK1/KCNN1, KCa2.2/SK2/KCNN2, KCa2.3/
SK3/KCNN3) potassium channels (39, 161, 449) (FIGURE 3A).
To date, only KCa2.x channels have been established as
functional in surface membranes of cardiomyocytes, while
BK channels have been demonstrated to be important in
mitochondrial membranes (17, 37, 38, 444). Since only
KCa2.x channels have been associated with arrhythmia, the
following description will focus on this channel type.
A
KCa2.3 (NP_002240)
KCa2.2 (NP_067627)
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KCa2.1 (NP_002239)
KCa3.1 (NP_002241)
KCa1.1 (NP_001014797)
200
150
100
B
50
0
C
nA
mV
1
–100
–50
50
100
–15
–15
CaM
2
–15
D
% Residual current
100
75
50
IC50 = 91 nM
25
0
10
100
[NS8593] (nM)
1,000
FIGURE 3. Overview of KCa channels. A: phylogenetic tree of KCa channel proteins (GenBank accession
numbers to the right). The x-axis denotes amino acid substitution per 100 residues (ClustalW alignment
performed with MegAlign, DNASTAR program package). B: topological model of a KCa2.x subunit with
calmodulin (CaM) (top) and a tetramer (bottom). C: representative whole cell current recordings of HEK293
cells stably expressing KCa2.3 channels. Both traces represent recordings upon application of 200-ms voltage
ramps (every 5 s) from a holding potential of 0 mV to potentials from ⫺100 to ⫹100 mV with 1 ␮M Ca2⫹ in
the pipette. Traces were recorded just after break-in (trace 1) and after 60 s (trace 2). [From Grunnet et al.
(157). Copyright 2001, with permission from Elsevier.] D: inhibition of KCa2.3 channel activity by the tool
compound NS8593. [From Strøbaek et al. (408).]
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SCHMITT, GRUNNET, AND OLESEN
Ca2⫹ concentration ([Ca2⫹]i) (FIGURE 3C). Consequently,
KCa2.x channels can integrate changes in secondary messenger activity, i.e., [Ca2⫹]i with changes in membrane K⫹
conductance (449). KCa2.x channels do not form complexes
with traditional K⫹ channel ␤-subunits, but constitutively
bind calmodulin at the carboxy-terminus of the ␣-subunit.
Half-maximal activation appears at ⬃300 nM [Ca2⫹]i, and
Ca2⫹ binding is a cooperative event illustrated by the steep
Hill coefficient of 4 –5 (468). The Ca2⫹ source for activation
of KCa2.x channels is likely L-type CaV channels that are
physically coupled to Ca2⫹-activated K⫹ channels in both
cardiac and neuronal tissue eventhough Ca2⫹ can also arise
from intracellular stores (159, 260).
The first indirect evidence for the presence of cardiac
KCa2.x channels appeared more than 40 years ago. In a
technical report from Edgewood Arsenal, Maryland,
apamin was tested in isolated, perfused hearts from rhesus monkeys and mongrel dogs as well as and in intact
animals (437). The studies demonstrated clear antiarrhythmic effect without concomitant change in blood
pressure (437). These studies were conducted using a bee
venom batch in which the different components were not
entirely separated, and before apamin was known as a
specific ion channel inhibitor (136). It is probably for
these reasons that the interesting findings did not lead to
follow-up studies for decades.
Sporadic indications of a Ca2⫹-activated K⫹ current were
occasionally reported (115), but it was not until 1999 that
616
It has further been demonstrated that pharmacological inhibition of IKCa is antiarrhythmic in species such as rat,
guinea pig, and rabbit in a model applying isolated perfused
hearts. Additional antiarrhythmic effect of KCa2.x inhibition was demonstrated in acute burst-induced AF in vivo in
rats (102). KCa2.x channel inhibition can also prolong the
atrial effective refractory period in rats in vivo. This prolongation is associated with an antiarrhythmic effect (396).
These effects were additionally confirmed in a more clinically relevant setting using aged spontaneously hypertensive rats (101). These rats exhibited atrial remodeling and
thereby increased susceptibility to atrial tachyarrhythmias
(75). The efficacy of KCa2.x channel inhibition and the observed antiarrhythmic effect were similar in hypertensiveinduced atrial remodeled rats and in young normotensive
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Specific pharmacological tools have successfully been used
to address KCa2.x channel function, with the bee venom
apamin as the gold standard. Apamin inhibits all three subtypes of KCa2.x channels at nanomolar concentrations, although with different potency (156, 409). The toxin does
not show affinity for the other members of the Ca2⫹-activated K⫹ channel family or for Ca2⫹, Na⫹, and Cl⫺ channels. Therefore, apamin has been considered a fingerprint or
state-of-the-art inhibitor of KCa2.x channels. Whereas in
noncardiac tissue such as neurons, skeletal muscle, hepatocytes, and T lymphocytes, apamin is used broadly as a tool
to address the physiological roles of KCa2.x channels, the
experiences from using the large apamin molecule as a tool
compound on cardiac tissue are less convincing (28, 46,
101, 191, 354, 396). A number of alternatives to apamin
exist, including peptide toxins such as scorpion toxins scyllatoxin and tamapin (406, 465), and small organic molecules such as tubocurarine, UCL1684, or N-(pyridin-2-yl)4-(pyridin-2-yl)thiazol-2-amine (138, 248, 366, 465). A
completely different class of selective KCa2.x channel inhibitors was introduced by the small organic compound
NS8593, which has a different binding site than apamin
(194, 400, 408) (FIGURE 3D). NS8593 acts as a negative
gating modifier that decreases the Ca2⫹ sensitivity by rightward shifting the Ca2⫹-activation curve (408).
the first convincing data for cardiac KCa2.x channels were
presented. Wang et al. (444) reported evidence for KCa2.3
subunits and corresponding IKCa currents in a myocyte cell
line derived from rat ventricles (444). In 2003, Xu et al.
(471) demonstrated apamin-sensitive currents recorded
from human and mouse atrial myocytes, while almost no
IKCa could be measured in ventricular myocytes from mice.
The results were obtained with a remarkably low apamin
concentration of only 50 pM (471). In 2005, Tuteja et al.
(426) demonstrated biochemical evidence in mouse hearts
for all three KCa2.x channel subtypes. Here KCa2.1 and
KCa2.2 subunits revealed an atria-selective distribution
(426). In 2007, the first circumstantial evidence of a relationship between KCa2.x channel and arrhythmia was provided (328). This study demonstrated increased membrane
trafficking of KCa2.2 channels to pulmonary vein sleeves
after burst pacing and a corresponding progressive shortening of action potentials as a consequence of increased IKCa.
In 2009, more direct evidence of IKCa association to AF was
given (245). Prolongation of atrial action potentials was
observed in KCa2.2 knockout mice, and this was associated
with a counterintuitive proarrhythmic effect. A likely explanation for the latter could be the sustained and sliding repolarization observed in the knockout mice (triangulation),
which is associated with increased propensity for inducible
early afterdepolarizations (EAD) under certain conditions.
As mentioned, these findings were surprising since prolongation of the atrial effective refractory period is normally
considered antiarrhythmic (304). Later in 2009, a new
study failed to show any functional role for cardiac KCa2.x
channels in rat, dog, and humans under normal physiological conditions, since 100 nM apamin did not affect atrial or
ventricular action potential duration in single cardiomyocytes
or multicellular preparations, even in conditions with high
[Ca2⫹]i (295). One year later, the first clinical link between
KCa2.x channels and atrial fibrillation (AF) appeared. A genome-wide association study including 1,355 individuals with
lone AF and 12,844 unaffected controls concluded that common gene variants in the area comprising KCNN3 (the gene
encoding KCa2.3) are connected to AF (118).
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
controls (101) (FIGURE 3C). Information regarding functional KCa2.x channels in remodeled human hearts is
sparse. Two articles written in Chinese indicate the presence
of apamin-sensitive currents in cardiomyocytes isolated
from AF patients in sinus rhythm at the time of the recordings. Furthermore, the apamin-sensitive currents are suggested to be upregulated in persistent AF patients (244,
484). A new study comparing human atrial tissue from
patients in sinus rhythm and in AF shows that the KCa2.x
channel inhibitor NS8593 prolongs the atrial action potential and refractory period (L. Skibsbye, C. Poulet, J. G.
Diness, B. H. Bentzen, L. Yuan, U. Kappert, K. Matschke,
E. Wettwer, U. Ravens, M. Grunnet, T. Christ, and T. Jespersen, unpublished data).
Two-pore domain K⫹ (K2P) channel proteins are a relatively
new addition to the superfamily of potassium channels
(333). These channels are widely expressed and are major
determinants of background K⫹ conductance in the cells in
which they are present. They set the negative resting potential of eukaryotic cells under a range of normal and pathophysiological conditions (166, 315). This section will provide a brief introduction to the family of K2P channels,
followed by an account of the possible significance of these
channels in human atria.
Fifteen K2P channel subtypes are known to date, divided
into subclasses by homology (FIGURE 4A). Functionally,
they lack voltage dependence, but are instead regulated by
lipids, temperature, pH, oxygen, membrane stretch, anesthetics, and second messengers (166, 237). Their widely
used trivial names arise from functional attributes such
as tandem of “P domains in a weak inward-rectifier K⫹
channel” (TWIK), “TWIK-related channel” (TREK), or
“TWIK-related acid-sensitive K⫹ channel” (TASK), to
name a few. Functional channels are composed of two subunits, each comprising four transmembrane segments and
two pore-forming (P) domains. The structures of K2P1.1
and K2P4.1 were solved in 2012 (54, 257) (FIGURE 4B).
Assembly with traditional K⫹ channel ␤-subunits leading to
functional changes has been proposed (217). The channels
are so-called leak or background channels that conduct currents at all phases in the cardiac action potential (FIGURE 2).
This conductance ensures the stabilization of the resting
membrane potential (Em) towards the equilibrium potential
of potassium. Open K2P channels will probably both antagonize early afterdepolarizations and play a role in tuning
NaV channel availability (16).
The K2P channels have been described in a variety of species
including human, rat, mouse, guinea pig, and dog (reviewed
in Ref. 166). In human hearts, mRNA expression has been
shown for K2P1.1 (TWIK-1/KCNK1), K2P3.1 (TASK-1/
KCNK3), K2P4.1 (TRAAK/KCNK4), K2P5.1 (TASK-2/
KCNK5), K2P15.1 (TASK-5/KCNK15), and K2P17.1
K2P3.1 was originally described by Duprat et al. (109) in
1997. Functional characterization revealed a K⫹-selective,
voltage-independent channel (FIGURE 4C). Furthermore,
the channels were highly sensitive to changes in external
pH near physiological values (109) and were inhibited by
the endocannabinoid anandamide (270). Meanwhile,
more selective tool compounds have been developed (356,
407). The aromatic carbonamide A293 (Sanofi-Aventis)
was shown to inhibit K2P3.1 currents at low concentrations
(IC50 222 ⫾ 38 nM in Xenopus laevis oocytes). Furthermore, A293 increased the action potential duration in rat
ventricular myocytes, although under nonphysiological
conditions (356). It should be mentioned that a controversy
exists regarding the contribution of K2P3.1 in rat atria and
ventricles. Kim et al. (215) observed a similar expression
pattern in the chambers using Northern blot analysis,
whereas Liu and Saint (253) reported a more prominent
expression in atria compared with ventricles employing
quantitative PCR. Evidence for protein expression is sparse
due to the lack of specific antibodies in the field (107).
Most of the studies on cardiac K2P3.1 function have used
mouse cardiomyocytes. In mice, the channel shows a predominantly ventricular expression (107). Taking advantage
of a K2P3.1 mouse knockout model, Donner et al. (107)
showed that K2P3.1(⫺/⫺) mice display prolongation of the
rate-corrected QT interval and reduced heart rat variability.
Assessment of time and frequency domains as well as baroreceptor reflex revealed sympathovagal imbalances (107)
increasing the impact of sympathetic stimulation in
K2P3.1(⫺/⫺) mice. In a follow-up study, the same group
showed that the key electrophysiological parameters such
as electrical conduction and refractoriness were unchanged
in K2P3.1(⫺/⫺) mice, yet the heart rate response after premature ventricular contractions was significantly abolished.
The authors suggested that the baroreceptor reflex in
K2P3.1(⫺/⫺) is diminished either due to sympathetic predominance or an impaired cardiac parasympathetic activity
(342). In a parallel study employing A293, Decher et al.
(95) also reported that ITASK plays a role in modulation of
cardiac action potential duration and that genetic silencing
of K2P3.1 leads to broadened QRS complexes in a mouse
knockout model (95).
The results obtained from the K2P3.1 knockout mouse
model only partially translate to human physiology given
the predominant atrial expression in humans (131, 250).
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2. Two-pore domain K⫹ channels
(TASK-4/KCNK17) (21, 94, 131, 325, 327). Most experimental and functional evidence in human heart is reported
for K2P1.1 and K2P3.1, the latter being predominantly expressed in the atrium and the atrioventricular node (117,
131, 250). Hence, K2P3.1 has been added to the list of
prominent candidates for developing atria-selective drugs.
The following section will give an account of the current
knowledge about K2P3.1 function in the heart.
SCHMITT, GRUNNET, AND OLESEN
A
K2P10.1 (NP_612190)
K2P2.1 (NP_001017424)
K2P4.1 (NP_201567)
K2P5.1 (NP_003731)
K2P17.1 (NP_113648)
K2P7.1 (NP_203133)
K2P1.1 (NP_002236)
K2P6.1 (NP_004814)
K2P12.1 (NP_071338)
K2P13.1 (NP_071337)
K2P9.1 (NP_057685)
K2P15.1 (NP_071753)
K2P16.1 (NP_001128577)
K2P18.1 (NP_862823.1)
180
160
140
120
100
B
80
60
40
20
0
C
K2P3.1
mock
200pA
K2P1.1
100 ms
100 mV
-80 mV
-120 mV
FIGURE 4. Overview of K2P channels. A: phylogenetic tree of K2P channel proteins. Alignment is as in
Figure 3. In red are channels for which mRNA expression has been reported in the human heart (see text for
details). B: ribbon representation of the recently resolved K2P1.1 structure based on Protein Data Bank ID
3UKM (283). Transmembrane segments of one subunit are colored (TM1, blue; TM2, purple; TM3, pink;
TM4, red). The so-called C-helix located just below the lipid surface is labeled in green; the lipid bilayer is
indicated by the black bar. (Picture was generated with Protean 3D, DNASTAR program package.)
C: representative patch-clamp recordings of CHO-K1 cells transiently expressing K2P3.1, or mock-transfected
cells. Current was recorded during 500-ms voltage-clamp pulses from ⫺120 to 100 mV in 20-mV steps from
a holding potential of ⫺80 mV.
618
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K2P3.1 (NP_002237)
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
Limberg et al. (250) investigated the role of K2P3.1 channels
in human atria. They showed that a current carried by
K2P3.1, ITASK, accounts for ⬃40% of background current
in human atrial myocytes isolated from healthy humans.
Furthermore, applying a mathematical model adapted to
atrial action potential, the authors showed that changes in
ITASK may alter the duration of the atrial action potential
(250).
Despite the apparent role of K2P channels for setting
the resting membrane potential and participating in repolarization, only a few reports exist on disease-associated mutations in these channels. Lafrenière et al. (229)
reported a dominant-negative mutation in K2P18.1
(TRESK/KCNK18) linked to a form of familial migraine.
An abstract written in German alludes to a gain-of-function
K2P17.1 (TASK-4/KCNK17) variant associated with conduction defects (127).
Of note, Barbuti et al. (27) described a role for K2P3.1
channels in the arrhythmic effects of inflammatory phospholipid platelet-activating factor (PAF) in mice. PAF is
released upon reperfusion after ischemic events and triggers
arrhythmia (262). Barbuti et al. (27) showed that PAF action induced spontaneous beats, EADs, and prolonged depolarization similar to previous observations in canine cardiomyocytes. These effects involved PKC-dependent block
of K2P3.1 (27). The same group recently reported an association between K2P3.1 inhibition with atrial fibrillation in
a canine model of peri-operative AF (113). However, the
study did not irrevocably show whether K2P3.1 inhibition
contributed to arrhythmogenesis or whether it was secondary to AF induction in this specific animal model (173).
In addition, it should be kept in mind that K2P3.1 function
has also been related to other pathophysiological conditions such as ischemia, cancer development, inflammation
and epilepsy (reviewed in Ref. 44). Hence, therapeutic value
has to be carefully considered given the wide distribution of
these channels in tissues other than the heart. Although
K2P3.1 channels are attractive candidates for the development of atrial-specific drugs, further studies are warranted
to elucidate whether K2P3.1 inhibitors are antiarrhythmic
or proarrhythmic.
C. Striking the Wrong Note: Genetic
Variation Causing Arrhythmia
Several ventricular and supraventricular arrhythmias such
as long and short QT syndromes (LQTS, SQTS), Brugada
syndrome (BrS), Andersen’s syndrome, and AF have been
associated with impaired potassium channel function (reviewed in Ref. 311). Disease-associated mutations in the
genes encoding the repolarizing potassium channels of the
heart have been instrumental in understanding the channels’ physiological function and their role in pathophysiological conditions. TABLE 2 gives an overview of potassium
channel subunits associated with arrhythmia.
In the case of ventricular arrhythmias, loss-of-function of
potassium conductance leads to action potential prolongation and syndromes such as the LQTS. Vice versa,
gain-of-function results in shortening action potential
duration and SQTS (174). Supraventricular arrhythmias
such as AF show a more complex pattern as both loss-offunction and gain-of-function mutations in a single potassium channel have been described (e.g., Ref. 79), as
well as mutations showing a mixed phenotype of AF and
QT prolongation (265). AF as well as LQTS are generally
considered to be driven by triggered activity and electrical reentry. In both conditions, action potential prolongation tends to increase the triggered activity, whereas
action potential shortening, as it is observed in AF and in
SQTS, promotes reentry.
In general, the heart rate corrected QT interval (QTc) is
considered to be a measure of ventricular repolarization.
Its prolongation has been associated with an increased
risk of sudden cardiac death (494), although its predictive value for ventricular arrhythmia is debated and the
concept of TRIaD (triangulation, reverse use depen-
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The latter observation supports the notion that K2P3.1 may
be a valuable target candidate for the development of drugs
against atrial fibrillation. Inhibition of K2P3.1 is speculated
to prolong action potential duration and effective refractory period and to suppress atrial arrhythmias. Recently,
several antiarrhythmic drugs have been applied to K2P3.1
channels. Carvedilol inhibited heterologously expressed
K2P3.1 with IC50 ⫽ 0.83 ␮M in mammalian Chinese hamster ovary (CHO) cells (405). The class III antiarrhythmic
drug amiodarone was shown to inhibit K2P3.1 channels in
Xenopus laevis oocytes (IC50 ⫽ 0.4 ␮M) without changing
rectification properties (139). Also dronedarone inhibits
K2P3.1 channels in both Xenopus laevis oocytes (IC50 ⫽
18.7 ␮M) and CHO cells (IC50 ⫽ 5.2 ␮M) (379). A more
specific drug, A1899 (Aventis), was recently reported. The
compound inhibited K2P3.1 as an open-channel blocker
with an IC50 ⫽ 7 nM in CHO cells, and bound to the closely
related K2P9.1 with a 10-fold lower affinity. Furthermore,
A1899 did not affect a large panel of other channels expressed in human cardiomyocytes (407). The recent publication of the human K2P1.1 crystal structure could enable
the development of specific drugs (257).
Very recently, impaired K2P3.1 function was postulated as
an arrhythmogenic substrate (247). Transient knockdown
of K2P3.1 expression affected atrial size in a zebrafish
model. Furthermore, reduced K2P3.1 current prolonged
atrial action potential duration in cardiac action potential
modeling, which was potentiated by reciprocal changes in
activity of other ion channel currents (247).
SCHMITT, GRUNNET, AND OLESEN
Table 2. Potassium channel mutations associated with arrhythmia
Protein/Subunit
Gene
Current
Effect of Mutation
Type of Arrhythmia
Reference Nos.
Familial atrial fibrillation
Early-onset lone atrial fibrillation
Early-onset lone atrial fibrillation
Early-onset lone atrial fibrillation
Long QT syndrome
Short QT syndrome
Long QT syndrome
Short QT syndrome
Long QT syndrome
Andersen Syndrome
Short QT syndrome
Atrial fibrillation
Atrial fibrillation
Long QT syndrome
Conduction defect
298, 322
79
79
321
298, 377
55, 298
298, 442
34, 298
298, 348
298, 348
298, 355
467
64
478
127
Long QT syndrome
Early-onset lone atrial fibrillation
Long QT syndrome
Atrial fibrillation
Atrial fibrillation
Long QT syndrome
Brugada syndrome
Atrial fibrillation
Brugada syndrome
298, 307
319
2, 298
477
264, 489
316
96, 296
360
317
␣-Subunits
KCNA5
IKur
KV4.3
KV11.1
KCND3
KCNH2
Ito
IKr
KV7.1
KCNQ1
IKs
Kir2.1
KCNJ2
IK1
Kir3.4
KCNJ5
IKAch
K2P17.1
KCNK17
ITASK
Loss of function
Gain of function
Gain of function
Loss of function
Gain of function
Loss of function
Gain of function
Loss of function
Loss of function
Gain of function
Gain of function
Loss of function
Loss of function
Gain of function
␤-Subunits
KCNE1
KCNE1
KCNE2
KCNE2
KCNE3
KCNE3
KCNE5
KCNE5
IKs
IKs
IKr
IKs
IKr/Ito
IKs
Ito
IKs
Ito
Loss of function
Gain of function
Loss of function
Gain of function
Gain of function
Loss of function
Gain of function
Gain of function
Gain of function
If more than two reports exist, the original reference is provided together with a link to a mutation database or
relevant review.
dence, instability and dispersion) has been suggested
(184, 186, 187). However, there is increasing evidence
that prolongation of the mean QT interval is associated
with AF (330). A recent study including digital ECGs
from more than 300,000 persons confirmed that the QTc
interval length is a predictive parameter for the susceptibility of AF (308). Of note, both shortened and in particular prolonged QTc interval duration are risk factors for
AF (308). This association was strongest for lone AF
cases, a condition in which other predisposing diseases
such as hypertension, diabetes, ischemic, and/or valvular
heart diseases are absent (66, 67). The study indicates
that QTc prolongation is an inherent characteristic of an
individual’s cardiac electrophysiology and that prolonged QTc can predispose to AF (308). Vice versa, Johnson et al. (199) have previously shown a prevalence of
early-onset atrial fibrillation in congenital LQTS. Hence,
ventricular and atrial arrhythmia phenotypes seem to
overlap, although knowledge about the mechanisms on
the cellular and molecular levels is only slowly accumulating.
620
Major challenges in elucidating these mechanisms are the
often observed 1) low penetrance in families and 2) variable expressivity in mutation carriers. As illustrated in
FIGURE 5, penetrance describes the extent to which all
mutation carriers within a family develop the clinical
symptoms of the respective disease. Variable expressivity
designates the degree to which individuals with the same
genotype express a certain phenotype. Congenital LQTS
is a paradigm for such an arrhythmia with incomplete
penetrance and variable expressivity (reviewed in Ref.
141). It has been recognized that additional factors contribute to the manifestation of the arrhythmia and the
observable symptoms. The impact of factors such as gender, age, seasonal changes, circadian rhythm, and triggers such as auditory stimuli or exercise, or physiological
challenges such as hypokalemia have been reported (42,
89, 152, 165, 227, 290, 414, 486). Beyond environmental modifiers, the presence of additional genetic modifiers
is well-recognized. Both compound heterozygosity and
digenic heterozygosity have been described (381, 453). A
recent study has shown that LQTS patients with multiple
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KV1.5
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
ion channel function and hence cardiac rhythm. Yet,
these nonsynonymous variants of potassium channel
genes also present in the healthy population may act as
modulators of the cardiac action potential and as a “second hit” when the individual faces physiological challenges (reviewed in Ref. 141).
A
B
Noteworthy, the increasing availability of genomic data is
challenging the concept of channelopathies as monogenic
disease as well as aiding understanding of the basis of arrhythmia. Analyses of continuously updated exome data
provided by the NHLI GO Exome Sequencing Project (ESP)
currently holding data from 6500 individuals (119a) revealed that many previously disease-associated mutations
are in fact variants that occur frequently in the general
population (14, 363). Hence, these variants might not be
the underlying cause of the disease.
C
Genotype-negative
ECG phenotype
Genotype-positive
ECG + cardiac event
FIGURE 5. Complexity of genetics traits. A: complete penetrance:
the genotype of an individual correlates completely with the diagnostic and clinical phenotype. B: incomplete penetrance: not all genotype-positive individuals display ECG and clinical phenotypes. C: incomplete penetrance combined with variable expressivity: genotypepositive individuals display ECG, but not clinical phenotype. [From
Guidicessi and Ackerman (141). Copyright 2013, with permission
from Elsevier.]
mutations in the known LQT genes had a higher rate of
life-threatening cardiac events (291). Yet, a general picture emerges that shifts the focus from monogenic inheritance, where very rare variants with a frequency ⬍0.1%
in the general population are considered disease causing,
to oligogenic (0.1% to ⬍ 5%) or polygenic (common
variants ⬎5%) inheritance patterns. It seems that the
more frequent the genetic variant, the lower its effect on
Solid conclusions regarding a causative link between
genomic variant and disease require a combination of 1)
detailed analysis of frequency in the general population,
2) algorithms to predict the pathogenic effects of the
variant (reviewed in Ref. 420), 3) verification of findings
in independent cohorts, 4) often laborious and time-consuming experimental knowledge using suitable in vitro
assays, and 5) evaluation of cosegregation in families.
The latter is often hampered by small family sizes, lack of
Mendelian inheritance, lack of penetrance, and/or variable expressivity.
A wealth of publications on variants and mutations, functional data, and possible new players important for cardiac
rhythm are continuously being released, which challenges
the attempts to see the larger picture of the disease-causing
processes. For a decade, Napolitano and Wilson (298) have
put tremendous effort into maintaining a large annotated
database listing mutations and common variants associated
with cardiac arrhythmia. Owing to the complexity of the
genetic traits, the availability of genomic data, and the ever
improving systems for functional characterization, it is
likely that the field will benefit from continuous efforts to
collect all available data, including negative findings, in
such an arrhythmia database maintained by the scientific
community. Such information would be valuable as a guide
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Several recent genome-wide association studies (GWAS)
followed the hypothesis that traits such as heart rate or QTc
interval used as markers for arrhythmia are associated with
single-nucleotide polymorphisms (SNPs) (reviewed in Refs.
282, 394). The analysis of many common genetic variants
in different individuals led to the identification of a number
of candidate genes such as KCNN3 encoding KCa2.3 (SK3)
channels (118). Although this association has been supported by other studies (70, 320), no disease-causing mutations in the exons or splice sites of KCNN3 have been
reported to date.
SCHMITT, GRUNNET, AND OLESEN
to understanding the physiological/pathophysiological
mechanisms of arrhythmia, as well as for risk stratification
of affected family members.
D. Tuning the Instruments
1. Posttranscriptional mechanisms
Alternative splicing of mRNA transcripts has been described for most of the repolarizing potassium channels of
the heart. Accordingly, several isoforms with different functional phenotypes exist (22, 200, 223, 327, 402, 404, 460,
469, 499). The alternative splicing increases the redundancy of the channels, but also helps to diversify the function of the multimeric proteins. Some isoforms are highly
expressed in the heart but, surprisingly, exert dominantnegative effect on channel function when coexpressed in
heterologous expression systems (201, 228, 287). Differential expression of KV7.1 isoforms KV7.1-iso1 and KV7.1iso2 across the human ventricular wall has been suggested
to contribute to action potential heterogeneity (338).
Whereas the total expression level in the endocardial, midmyocardial, and epicardial layers was similar, the proportion of the dominant-negative KV7.1-iso2 was higher in
midmyocardial tissue. Mimicking the experimentally determined ratios in heterologous expression systems indicated a
drastically reduced midmyocardial IKs compared with that
in the epicardium. (338). Consequently, endo- and epicardial myocytes are reported to have shorter action potentials
(57, 251). Recently, Lee et al. (234) determined the effect of
amiloride on the ratio of these KV7.1 isoforms in canine
endocardial, midmyocardial, and epicardial ventricular
myocytes. Whereas the drug led to decreased expression
levels of KV7.1-iso1 in endocardial and epicardial layers,
KV7.1-iso1 was increased in midmyocardium. The authors
further investigated the impact of these changes on action
potential duration using simulations of human ventricular
action potentials. Their results supported the earlier find-
622
Assembly of different KV11.1 isoforms in the native channel
complex influences the kinetics (233) and pharmacological
sensitivity (231) and has been implicated in arrhythmia
(372, 422). Accordingly, a number of splice-site mutations
have been associated with arrhythmia (298).
An additional regulatory mechanism, nonsense-mediated
mRNA decay (NMD), has been described for KV11.1 channels. NMD is an RNA surveillance mechanism that selectively degrades mRNA transcripts that have in-frame premature termination codons. Nonsense mutations have been
implicated in human disease (289), and NMD is thought to
serve as a “cellular vacuum cleaner” that protects the cell
from the potentially harmful effects of truncated proteins
by eliminating mRNAs with premature termination
codons. NMD occurs when translation terminates 50 –55
nucleotides upstream of the 3’-most exon-exon junction
(33). Gong and co-workers investigated LQT2 nonsense
mutations that showed a decrease in mutant mRNAs by
NMD, thereby altering the amount of mRNA available for
subsequent KV11.1 protein generation. It was suggested
that the degradation of premature termination codons containing mRNA transcripts by NMD represents a new class
of LQT2 pathogenic mechanism (148, 149, 410, 487). Yet
of all the channel proteins involved in cardiac excitability
described above, this mechanism has been exclusively described for KV11.1 channels.
Traditionally, the field has focused on the protein encoding
sequence of DNA and paid only scant attention to 5’- or
3’-untranslated regions (UTR). This changed with the discovery of so-called microRNAs. These small noncoding
RNAs are part of the epigenetic control of gene expression
that also encompasses DNA methylation and histone modifications (143). The binding of miRNAs to the 3’-UTR of
their targets can lead to degradation of target mRNAs or
repression of target mRNA translation. A number of cardiovascular-specific miRNAs have been described (reviewed in Ref. 45). A very interesting feature is the fact that
miRNAs may regulate multiple targets simultaneously,
which allows for complex and cooperative regulation of
several channel proteins whose functions are tightly connected. Also, several miRNAs can bind to the same target,
which increases the level of regulatory control. Although
the field is only emerging, several miRNAs have been linked
to the regulation of the cardiac repolarizing potassium
channels (216). Hence, changed miRNAs levels in disease
conditions may have an impact on cardiac excitability. Examples are the downregulation of miR-1 in atrial fibrillation leading to increased IK1 currents (140) or the upregulation of miR-301a in a diabetic mouse model leading to
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The delicate act of keeping the heart beat stable under all
conditions is quite sensitive to changes in the function of the
key ion channels. The expression and activity of the channels may vary significantly as a consequence of posttranscriptional and epigenetic changes. Furthermore, the channel function is also drastically influenced by the proteins’
exact subcellular localization within cardiac myocytes; the
complexes they form with accessory subunits, kinases, and
phosphatases; and posttranslational modifications. As elaborated above, channel function can change due to mutations, yet also due to electrical remodeling and presence of
drugs. Below we will give a short account of some of these
important mechanisms that influence the function of the
channel on its way from the gene in the nucleus to the
surface-expressed protein, and their significance for cardiac
repolarization. FIGURE 6 gives a summarized picture of the
outlined regulatory mechanisms.
ings that transmural differences in IKs density might be explained by the ratio of the two isoforms (234, 338) and
indicated that amiloride may lead to a reduction of the
transmural IKs gradient (234).
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
K+
K+
Kinase
K+
Phosphatase
P
Ub
Vesicle
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pH
Lysosome
Ub
Ub
Ub
Ub
Proteasome
Golgi
ER
Vesicles
Translation repression
miRNA
Nucleus
RISC
Alternatice splicing
RISC
DNA
pre-miRNA
miRNA
Mutually exclusive exons
NMD
STOP
AUG
RNA
Exon skipping
Alternative 5’ donor sites
Cap
Ex1
Ex2
Ex3
Ex4
(A)n PolyA
Distance
>55 nucleotides
Potential NMD Targets
≤55 nucleotides
Non NMD Targets
Alternative 3’ donor sites
Intron retention
FIGURE 6. Postranscriptional and posttranslational regulatory mechanisms. After transcription in the nucleus, mRNA is processed, alternatively spliced, and translated into protein, unless degraded via, e.g.,
nonsense-mediated mRNA decay (NMD) or miRNA mediated translation repression. Proteins are folded in the
ER. Misfolded proteins are degraded in the proteasome (indicated by the dashed line), whereas correctly
assembled proteins are processed in the Golgi apparatus, where glycosylation may occur. Mature channel
complexes are transported in vesicles to the plasma membrane. Targeting signals in the protein may guide the
membrane protein to a specific location within the cardiomyocyte, e.g., t tubules or intercalated discs. The potassium
␣-subunit can interact with accessory subunits and undergo additional posttranslational modifications such as phosphorylation (P) and ubiquitination (Ub). Ubiquitinated proteins are endocytosed and degraded in the proteasome (via lysosomes). Alternatively, the channel can be recycled to the membrane in recycling vesicles (not shown).
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SCHMITT, GRUNNET, AND OLESEN
decreased Ito (332). An overview of known miRNAs affecting cardiac potassium currents is given in TABLE 3.
Further research exploring these outline mechanisms will
hopefully shed additional light on the determinants of low
penetrance and variable expressivity in arrhythmia research.
2. Posttranslational regulation of potassium channels
in protein complexes
Potassium channels are often pictured as isolated membrane proteins, but it is well recognized that they are part of
Of all the cardiac ion channel complexes, the IKs channel
has probably received the most attention due to its regulation by the KCNE family of ␤-subunits. The interaction
with KCNE1 (29, 376) leads to dramatic changes in biophysical properties such as a major increase of macroscopic
current, slowed activation, and shift of the voltage dependence of activation to more depolarized potential (reviewed
in Ref. 464). The exact mode of interaction between these
subunits and their stoichiometry has been intensively studied and is still a matter of debate. The interaction seems to
be dynamic with variable stoichiometry and interaction
sites (reviewed in Ref. 464). In addition to KCNE1, the
␣-subunit is able to interact with all five members of the
KCNE channel family in heterologous expression systems
(197). The relative expression of KCNE genes in human
hearts is KCNE4 ⫽ KCNE1 ⬎ KCNE3 ⬎ KCNE2 ⬎
KCNE5 (35). Despite this, the only functionally important
interaction is probably KV7.1/KCNE1, as KCNE4 and
KCNE5 significantly right-shift the activation curve for the
channel complex, rendering them nonfunctional under normal physiological conditions (15, 158, 160). The interaction with KCNE2 and KCNE3 seems to be most important
in non-cardiac tissue (35, 195), although mutations in
KCNE2 and KCNE3 genes have been associated with cardiac arrhythmia (see below), pointing to a functional role of
these subunits in the heart (96, 116, 264, 316, 477).
Table 3. microRNAs regulating cardiac potassium channels
miRNA
Target
Gene/Protein
miR-1
Ito
KCND2/KV4.2
miR-26
IK1
IK1
KCNJ2/Kir2.1
KCNJ2/Kir2.1
miR-133
Ito
ND
IKr
KCNH2/KV11.1
IK1
Ito
KCNJ2/Kir2.1
KCND2/KV4.2
miR-212
miR-301a
Comment
Reference Nos.
Deletion of miR-1 leads to widened QRS complex, effect mediated via
transcription factor Irx5 (mouse model)
Reduced miR-1 level in atrial fibrillation leads to increased IK1 (human)
Reduced miR-1 level in atrial fibrillation leads to increased IK1 (human,
and canine and mouse models)
Increased miR133 level leads to decreased Ito possibly by an indirect
mechanism involving KChIP2 (mouse model)
Increased miR133 level leads to decreased KV11.1 protein levels and
reduced IKr (guinea pig model)
Downregulates Kir2.1 and IK1 (HeLa cells)
Increased miR-301a levels lead to decreased KV4.2 protein level,
direct binding to 3’UTR (diabetic mouse model, db/db)
497
ND, not determined.
624
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267
278
387
144
332
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Adding another level of complexity, Amin et al. (12) reported that common variants in the 3’-UTR of the KCNQ1
gene encoding KV7.1 modified disease severity in LQTS
patients in an allele-specific manner. As KV7.1 channels are
composed of tetramers, in a heterozygous mutation carrier
channels will be formed from two healthy and two mutant
subunits, provided that wild-type and mutant alleles are
expressed equally well. The authors found several SNPs in
the 3’-UTR of the KCNQ1 gene. With the assumption that
the SNPs exert no effect on expression, the balance between
normal and mutant subunits within each channel should be
equal. However, the authors suggested a model in which the
subunits carrying the disease-modifying SNPs were suppressed, which would affect the balance between wild-type
and mutant channel subunits. Such suppression could be
mediated by miRNAs that bind to consensus sites in the
3’-UTR. Depending on which nucleotide sequence favors
the binding of miRNAs, then the balance of wild-type and
mutant subunits relies on whether the “suppressive” SNP
variants reside on the normal or mutant allele. Accordingly,
an increased expression of the mutant allele would enhance
the disease phenotype of the patient, while an increased
expression of the wild-type allele could possibly result in an
asymptomatic phenotype (12).
large complexes. They form multimolecular complexes
with each other as well as with accessory subunits, anchoring proteins, and regulatory kinases and phosphatases. The
association with non-pore-forming proteins, so-called
␤-subunits, helps to regulate and modify the function of the
␣-subunit, likely in a temporal and spatial manner. A number of excellent recent review articles have covered the composition and regulation by accessory subunits for the protein complexes underlying Ito, IKur, IKAch, IKr, and IKs currents (268, 311, 359, 433, 464).
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
In addition, these multiprotein complexes link membrane
proteins to intracellular proteins and contain components
of the cytoskeleton and extracellular matrix proteins. Furthermore, cardiac myocytes are polarized cells with most
ion channels localized at specific subdomains such as the
t-tubular invaginations or intercalated disks. Hence, highly
regulated trafficking and targeting mechanisms are crucial
to achieving these specific locations. The mechanism and
the current view on where the potassium channel complexes
are located within the surface membrane of cardiomyocytes
are reviewed in Reference 26.
Protein activity is not only controlled by the rates of protein
biosynthesis and protein degradation, but also by specific
and selective covalent processing, i.e., posttranslational
modification (PTM) such as phosphorylation, which modulates molecular interactions, protein localization, and stability. TABLE 4 lists the current knowledge on PTMs for the
major repolarizing currents of the heart.
These modifications may provide an important feedback
mechanism for regulating the number of functional complexes upon external stimuli from, e.g., hormones and the
autonomic nervous system, which will significantly influence cardiac signaling. The greater our understanding of the
signaling pathways, the more complex the picture may become. Several studies have shown that common genetic
variants in the components that modulate potassium channel function such as G protein-coupled receptors or kinases
may have an influence on cardiac signaling. SNPs in the
genes encoding ␣2 and ␤1 adrenergic receptors, ADRA2C
and ADRB1, respectively, have been linked to the LQTS
disease phenotype (reviewed in Ref. 141). Furthermore, a
recent study on chronic AF in humans showed a chamberspecific upregulation of ␤1 adrenergic receptors, which led
to dramatic effects on several repolarizing currents, foremost IKs (150).
Other regulatory pathways such as the nitric oxide pathway
also seem to be linked to cardiac arrhythmia. Arking et al.
(19) were the first to establish a link between the age, gender, and heart rate corrected QT-interval with SNPs in the
gene encoding nitric oxide synthase 1 adapter protein
(NOS1AP, also known as CAPON) (19). The SNP
rs10494366 located in the upstream region of the coding
region achieved genome-wide significance. This finding has
been replicated in several large independent populations of
both European ancestry and other ethnicities. In those studies, several additional NOS1AP SNPs were found to be
significantly linked to the QTc interval (1, 18, 114, 274,
306, 343, 352). Noteworthy, NOS1AP SNPs reached
higher significance compared with SNPs in genes known to
be causes of LQTS and SQTS (306, 343). Furthermore,
NOS1AP has been linked to sudden cardiac death (205,
326).
Analyzing the protein complexes and their regulation in the
cellular network will help our understanding of the complex regulation of cardiac excitability.
III. MECHANISMS AND ETIOLOGY OF
ARRHYTHMIAS
Arrhythmia in its broadest sense describes every type of
abnormal heart rhythm ranging from gentle transient palpitations to devastating fibrillations. Ultimately, fibrillation
in the ventricles can result in sudden cardiac arrest. A subdivision of arrhythmias encompasses bradycardia and
tachycardia, representing too slow or too rapid heart rates,
respectively. Heart rates are species dependent, and humans
are considered bradycardiac when having fewer than 60
bpm and tachycardic with more than 100 bpm. In brady- or
tachycardia the individual can either have a regular rhythm
triggered by the sinus node (sinus rhythm), or an irregular
arrhythmia governed by other mechanisms. In AF, the atrial
rhythm is ⬎200 bpm. While not lethal, it is associated with
thromboembolic events and an increased risk of cardiac
death in a longer perspective (36). This increased morbidity
and mortality is the result of the reduced ejection fraction
during tachycardia and blood stasis in the fibrillating atria
increasing the propensity of thrombosis and stroke (461).
Ventricular arrhythmias are significantly more serious as
they directly influence the pumping capacity of the heart. A
ventricular tachyarrhythmia can be both monomorphic and
polymorphic in origin and can eventually develop into fibrillation. In ventricular fibrillation, the electrical activity of
the cardiac cells occurs in a completely uncoordinated manner and pumping ceases.
From a mechanistic perspective, tachyarrhythmic events are
obligate depending on two phenomena: a triggering event
for initiation and a substrate for sustainability. In the following, we give a thorough overview of triggers and substrates. This includes an introduction to the spiral wave and
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In 2012, Milstein et al. (285) used a multipronged approach
to show a large macromolecular complex involving both
Kir2.1 and NaV1.5 channels. They thereby revealed an extraordinarily tight connection between the IK1 current controlling the resting membrane potential and INa, whose
availability, effect on cell excitability, action potential duration, and velocity of impulse propagation are governed by
the membrane potential set by IK1 (285). Noteworthy, the
postsynaptic density, discs large and zonula occludens-1
(PDZ) domain protein SAP97 is a component of this macromolecular complex (285). The same anchoring protein
has previously been shown to interact with KV1.5 in both
heterologous expression systems (292) and cardiomyocytes, where it seems to stabilize the channels in the plasma
membrane (72). This opens up for the possibility of even
larger macromolecular complexes also involving IKur channels.
SCHMITT, GRUNNET, AND OLESEN
Table 4. Posttranslational modifications of cardiac potassium channels
␣-Subunit
KV1.5
KV4.3
KV11.1
Kir2.1
IKur
Ito
IKs
IKr
IK1
Kir2.2
IK1
Kir3.1
IKAch
Kir3.4
IKAch
Kir6.2
IKATP
K2P3.1
Ileak
Modification
Enzyme
Acetylation
Glycosylation
Palmitoylation
Sumoylation
Nitrosylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Src
EGFR kinase
Src
p90RSK
PKC
CaMKII
CaMKII
PKA
PKC
Dephophorylation
Ubiquitination
Deubiquitination
PP1
Nedd4-2
USP2
Glycosylation
Glycosylation
Phosphorylation
Phosphorylation
Ubiquitination
Acetylation
Nitrosylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Glycosylation
Glycosylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Phosphorylation
Ubiquitination
Phosphorylation
Phosphorylation
Phosphorylation
PAT
Ubc9
Amino Acid
Position(s)
C604
N290
C593
K221, K536
C331, C346
n.d.
Y136
Y108
S516, S550
T503
S550
S27
S409, T513, S464,
S577
(S27)
P660, Y662
(P660, Y662)
Src
Nedd4-2
N598, N629
N598
S283, S890, T895,
S1137
Y475
P1075, Y1077
PKA
PTK
PKA
PKC
C76
S425
Y242
S425
S64A, T353A
PKA
N119
PKA
PKC
PKC
CaMKI
CaMKII
CaMKII
PKC
PKA
PKC
PKC
Src
RhoK
S185
S191
S372
T180
T381
S336
Species
h
h
r
h
h
h
h
h
h
h
r
h
h
h
h
h,gp
h
Native
⫹
⫹
⫹
⫹
⫹
—
—
—
—
—
(ventricle)
(atria)
(atria)
—
(ventricle)
(heart)
—
—
—
276
196
225
—
—
—
341
147
419
—
⫹ (gp heart)
—
⫹ (atria)
—
—
⫹ (ventricles)
⫹ (atria)
⫹ (atria)
—
⫹ (atria)
⫹ (atria)
—
⫹ (atria)
⫹ (atria)
⫹ (atria)
—
—
—
—
—
—
—
Only direct posttranslational modifications that have been reported in either mammalian cell systems or
cardiac tissue are listed. References are given for the first report on the respective modification. If known, the
amino acid position referring to full-length protein and enzyme are given. Note that some regulatory pathways
act via accessory subunits not included in this list. CaMK, calmodulin-dependent kinase; EGFR, epidermal
growth factor receptor; gp, guinea pig; h, human; Nedd4, neuronal precursor cell-expressed developmentally
downregulated 4; PAT, palmitoyl acyltransferase; PKA, protein kinase A; PKC, protein kinase C; PP1, protein
phosphatase 1; PTK, phosphotyrosine kinase; p90RSK, p90 ribosomal S6 kinase; r, rat; RhoK, Rho kinase;
USP2, ubiquitin-specific protease 2.
626
493
382
198
38
313
182
495
495
261
349
80
385
276
208
—
⫹ (gp ventricles)
—
h
h
h
h
h,gp
m
h
r
h
r
h
m
h
r
r
h
r
r
r
h
h
m
r
m
Reference Nos.
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5
429
146
459
491
236
214
212
329
281
281
272
281
281
281
272
32
249
417
43
294
386
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KV7.1
Current
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
leading circle theories explaining reentry-based arrhythmias to understand the role of the repolarizing currents in
these arrhythmias.
A. Triggers of Arrhythmias
The initiation of an arrhythmia requires a triggering event.
Abnormal focal automaticity constitutes a typical trigger.
Several areas of the heart have the intrinsic capability for
automaticity or pacemaker activity, but under normal circumstances the sinoatrial node has the fastest pacemaker
rate and will therefore be the area that determines the heart
rate. Impulse generation in areas outside the sinoatrial or
atrioventricular nodes is called abnormal automaticity, and
the abnormal pacing site is called an ectopic focus. Several
factors can increase the risk of abnormal automaticity, such
as increased sympathetic drive, acute myocardial ischemia,
or electrical remodeling leading to changed ion channel distribution (51, 358). Areas around the left and right pulmonary veins are especially sensitive to triggering events (167).
The increased likelihood of focal (nonreentrant) arrhythmias
around pulmonary veins is explained by several factors: specialized cells with pacemaker activity are located here, and the
resting membrane potential is more depolarized as a consequence of reduced IK1 current (111, 238). Abnormal focal
activity can also be initiated by early afterdepolarizations
(EADs), which are inappropriate secondary depolarizations
taking place during the normal repolarization phase of the
cardiac action potential (phase 3) (FIGURE 7). EADs are
primarily due to reactivation of the voltage-gated CaV1.2
channels (L-type Ca2⫹ channels). These channels are activated during the initial depolarization of the action potential (phase 0) and will subsequently undergo inactivation in
a time-, voltage-, and Ca2⫹-dependent manner. The inacti-
Accelerated normal automaticity
Another source of abnormal focal activity is delayed afterdepolarizations (DADs) (FIGURE 7). A DAD describes inappropriate depolarizations in the time interval from complete repolarization of an action potential to the upstroke of
a subsequent action potential, i.e., during the diastolic interval or phase 4. The mechanistic understanding of DADs
relies on inappropriate activity of the Na⫹/Ca2⫹ exchanger.
This cotransporter has a stoichiometry of 3 Na⫹ exchanged
for 1 Ca2⫹, implying electrogenic transport. The exchanger
is the main exit pathway for Ca2⫹ having entered the car-
EAD
DAD
0 mV
250 ms
-80 mV
Normal atrial AP
Arrythmic APs
FIGURE 7. Triggers for arrhythmia: accelerated normal automaticity (left), delayed afterdepolarizations
(DADs) (middle), and early afterdepolarizations (EADs). For details, see text. [Modified from Iwasaki et al. (190)
with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health.]
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vation is released by the hyperpolarization of the membrane
potential and reduction in [Ca2⫹]i in phase 3. If release from
inactivation takes place while the membrane potential is
still sufficiently depolarized to allow for activation of the
CaV1.2 channels, the result is inappropriate reopening that
will prompt an EAD (392, 474, 488). The critical time
interval during repolarization that allows for reactivation
of the CaV1.2 channels is recognized as the “vulnerable
window.” This normally lies from 30 to 90% of full repolarization of the action potential (APD30-APD90). EADs
typically originate in ventricular tissue zones with extended
action potentials, such as the Purkinje system, but can also
be observed in atrial tissue as triggers for atrial fibrillation
(58, 378, 473). It is worth mentioning that it is not simply
the action potential duration per se that governs whether an
EAD might commence. The exact morphology of the action
potential in the repolarizing phase 3 is probably more important (184). Delayed repolarization seen as a prolongation of the APD30-APD90 interval will increase triangulation of action potentials and thereby also the time interval
for the vulnerable window. This augments the probability
for EADs. A typical situation for EAD-triggered arrhythmias in both atria and ventricles is the LQTS (199).
SCHMITT, GRUNNET, AND OLESEN
diomyocyte through L-type Ca2⫹ channels. The Na⫹/Ca2⫹
exchanger removes one Ca2⫹ in exchange for the inward
movement of three Na⫹, which generates a net inward
transport of positive ions resulting in a depolarizing current. The effect of this current can normally be counteracted
by the large resting K⫹ conductances. In situations with
excessive intracellular Ca2⫹ load, this electrogenic exchange generates a depolarization recognized as a DAD
(183, 295, 434, 503). Intracellular Ca2⫹ overload can be
subsequent to Ca2⫹ leak from mutant ryanodine receptors
(RyR) in the sarcoplasmic reticulum, which can result in
catecholaminergic polymorphic ventricular tachycardia
and concomitant fibrillation (347). Hyperphosphorylation
of RyR as a consequence of increased sympathetic drive can
also provoke phase 4 Ca2⫹ overload and DADs (106). Congestive heart failure is another source of Ca2⫹ overload and
fibrillation (481).
unidirectional blocks and the involvement of obstacles or
substrates in the development of arrhythmia (FIGURE 8).
Almost 50 years ago, a mathematical description and the
first modeling of functional reentry was provided, including
the notion that the substrate did not necessarily have to be
of anatomical origin (286, 303). A historical overview in
combination with an excellent description of theories for
reentry-based arrhythmias is given by Comtois et al. (81).
On the background of these classical experiments, two different theories have been developed to explain reentrybased arrhythmias: the leading circle and spiral wave theories. A brief introduction to both phenomena is useful to
facilitate the understanding of the role of ion channels in
re-entry mechanisms.
Allessi and co-workers (8 –11) were the first to demonstrate
and describe functional reentry based on experimental evidence, from which they developed the leading circle model:
“The smallest possible pathway in which the impulse can
continue to circulate is the circuit in which the stimulating
efficacy of the circulating wavefront is just enough to excite
the tissue ahead which is still in its relative refractory
phase.” The principle is illustrated in FIGURE 9A. In the
situation of an unidirectional block (illustrated by the gray
square), the leading circle can be defined as the smallest
possible circle of continuous propagating electrical activity
(illustrated by the heavy black arrow), which is exactly
sufficient in length to reach is original point of initiation at
the time point when absolute refractoriness has ended and
reexcitation can be evoked. It follows that a smaller circle
will reach the starting point at a time point when absolute
refractoriness still prevails, hence making reexcitation impossible, so the reentry will terminate. Impulses traveling
longer circles will have longer turn-around time, and hence
the reentry activity will be dominated by the shortest possible circle that therefore receives the name, the leading
circle. The length of such a leading circle is called the wavelength (WL), and this is equal to the product of the effective
refractory period (ERP) and conduction velocity (CV) as
WL ⫽ ERP ⫻ CV. A reduced wavelength will mean that
B. Substrates for Reentry-Based
Arrhythmias
In order for sustained arrhythmias to occur, the triggering
event must subsequently initiate a self-sustained episode of
action potential propagation. A change in the conduction
properties of the cardiac tissue is a prerequisite for such an
activity, and that is called a substrate. Substrates can be
anatomical obstacles in nature or based on electrophysiological heterogeneity. The shared denominator is that independently of its origin, the substrate will allow for sustained
excitation and propagation of action potentials. Such a situation can arise if the tissue is allowed to regain excitability
before the propagating wave of electrical signals meets its
starting point. Situations that will prompt this are slow
propagation of electrical signals or if the signal has to travel
a long path to again reach its starting point. The resulting
self-sustained and uninterrupted propagation of electrical
signals is denoted a reentry-based arrhythmia. A more detailed description of the nature of different substrates is
given in the section describing remodeling.
The concept of reentry in the context of fibrillation has been
known for more than a century, as have the ideas about
1
2
4
3
Normal
628
Re-entry
FIGURE 8. Reentry arrhythmias. Propagation of normal action potential (left) and
conditions for a reentrant excitation (right).
In normal tissue, the electrical signals
travel down each branch with equal velocity. If the two branches are connected, the
signals will encounter refractory tissue and
will not progress. Yet, if one branch exhibits
a unidirectional block (indicated in red) (2),
the electrical signal will travel down only one
branch (1). If the signal enters the common
branch at a time where it is not refractory,
retrograde signaling (3) and re-excitation
can occur resulting in self-sustained propagation (4).
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1. The leading circle
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
A
B
C
CELL 2
D
2. The spiral wave
APD reduction
Passive
activity
1. Curvature and/or
twisting effect
2. Reduced excitability
by effective refractory
period
FIGURE 9. Substrates for reentry arrhythmias. A: concept of leading circle. The gray block represents a unidirectional block, and the
leading circle is defined as the smallest possible circle of continuous
self-propagating electrical activity (black arrow). Inside the leading
circle, smaller wavelets (small arrows) form and maintain the central
core in a refractory state. B: concept of spiral wave. The spiral wave
describes a continuous, rapid movement of electrical signals that
rotates around a central core. C: the degree of cell-cell coupling will
determine the relative impact neighboring cells can exert on each
other and thereby also the relative difference in action potential duration (APD) between cells. Black lines represent APD in uncoupled cells
that can be of various lengths. If cells increase coupling via gap junctions, the result is a compensatory effect of APD as a consequence of
net depolarizing current flowing from cell 2 to cell 1, thereby increasing
APD in cell 1 and decreasing APD in cell 2 as represented by the red
dotted lines. The degree of cell-cell coupling will thereby determine the
effect on relative APD difference between neighboring cells. This can
create a current sink that can serve as a passive central sink area in a
spiral wave. D: electrotonic effects in a simple spiral wave showing the
inner core region. For detailed explanation, see text. [From Comtois et
al. (81) by permission of Oxford University Press.]
With the development of high-resolution mapping studies
and more advanced in silico modeling, it has become evident that reentry explained by spiral waves is more likely to
reveal the true nature of reentry-based arrhythmias compared with the leading circle theory. This includes observed
properties such as dynamic core behavior, electrogenic
source-sink relations, electrotonic interactions, and the predicted response to Na⫹ channel inhibition (class I antiarrhythmics) (81, 91, 286, 457).
The concept of a spiral wave has been developed and described by a number of groups (93, 219, 340, 395, 455). In
its most simple form, a spiral wave can be described as a
continuous, rapid movement of electrical signals that rotates around a central core. An important difference between the leading circle and the spiral wave is that the latter
operates with a curved wave front as shown in FIGURE 9.
Depolarizing activity originates from a central core, marked
by the largest and more heavily dotted circle in FIGURE 9B,
and propagates away from the center. The curved depolarization wavefront is depicted by the solid black line and
direction of propagation indicated by the black arrows.
Since the depolarizing part of the wave is radiating outward, each cell will have to excite more than one cell when
moving away from the core. This generates a source to sink
mismatch and consequently decreases propagation velocity.
The depolarization will naturally be followed by a repolar-
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CELL 1
more circles can be included within a given tissue area,
thereby increasing the risk of reentry-based arrhythmias, so
a reduction in WL is considered proarrhythmic. By the same
argument, a prolongation of the WL will be antiarrhythmic.
This is the basic principle accounting for the efficacy of
classic class III antiarrhythmics. These drugs prolong action
potential duration by inhibition of the K⫹ channels responsible for phase 3 repolarization (108, 389). ERP is consequently increased, and provided that CV is unchanged, it
leads to increased WL and diminished risk of reentry
(FIGURE 9) (301). This principle is particularly valid for
atrial arrhythmias, whereas in ventricles it has unambiguously been shown that K⫹ channel inhibition can also lead
to an increased heterogeneity in the ventricular action
potential duration, and this is profibrillatory (17, 82, 353).
In the context of AF, it should also be mentioned that structural remodeling leading to atrial enlargement or dilatation
is considered proarrhythmic, the reason being that increased tissue area is equivalent to a relative reduction in
WL. Physical or electrical atrial remodeling can be caused
by valve stenosis, insufficiency, congestive heart failure, or
tachycardia and is an important clinical cause of sustained
AF (176, 390). The leading circle theory is fascinating in its
simplicity and is good for illustrating class III antiarrhythmic efficacy, but from a biophysical perspective, it is probably not the most accurate representation of re-entry based
arrhythmias.
SCHMITT, GRUNNET, AND OLESEN
3. Implications for modes of drug action
An important reality check on the two reentry theories of
leading circle versus spiral wave is how they encompass the
effects of antiarrhythmic compounds. The leading circle
easily explains how the class III compounds inhibiting repolarizing K⫹ currents cause an increased ERP and concomitant increase in WL (WL ⫽ ERP ⫻ CV), which according to the theory should be antiarrhythmic. When explaining the efficacy of K⫹ channel inhibitors on the basis of
spiral wave reentry, the situation is more complex, although
this model also predicts an antiarrhythmic effect. The exact
630
outcome will, however, depend on which type of K⫹ current is targeted. In general, reduced action potential duration will tend to accelerate and thereby stabilize rotors (31).
From this perspective, an antiarrhythmic effect is expected
when blocking K⫹ currents, especially when targeting IK1
(373). Other antiarrhythmic effects of K⫹ channel inhibition are explained by an increase in the core area and meandering (31). Yet, in principle, K⫹ current inhibition can
also result in formation of additional spiral waves, especially in ventricular tissue. In situations with sufficient excitable tissue, this could lead to fibrillatory activity (134,
362, 412).
In attempts to explain the efficacy of class I compounds
represented by Na⫹ channel inhibitors, the leading circle
theory falls short. Na⫹ channel inhibitors are divided into
class Ia, Ib, or Ic according to their effects on Na⫹ channel
kinetics being intermediate, fast, or slow, respectively, and
on the different effects on action potential morphology
(284, 318). All classes will decrease CV, and class Ib will
further decrease ERP. Recalling WL ⫽ ERP ⫻ CV, it follows that Na⫹ channel inhibitors will decrease WL via both
parameters, and thereby should be proarrhythmic. Although all antiarrhythmics can comprise proarrhythmic
properties under certain circumstances, the overall antiarrhythmic effects of class I compounds seem to be in opposition to the leading circle description of reentry. In contrast, antiarrhythmic effects of class I compounds are easily
explained from the spiral wave perspective. Na⫹ channel
inhibition is expected to increase core size and meandering
and to decrease curvature (211, 221). Na⫹ channel inhibition will also diminish the source-to-sink mismatch in the
core area of the spiral wave. Altogether these effects should
terminate reentry-based arrhythmias (81). It should be noticed that the concepts presented above primarily apply to
atrial tissue. In ventricles, the larger muscle mass complicates the nature of reentry, as will be discussed in the section
on ventricular fibrillation.
Finally, it should be mentioned that during the last 60 years,
the spiral wave and leading circle theories have gained most
attention for explaining the principles of multiple circuit
reentry. There is, however, also more recent experimental
evidence to support single reentry circles, mainly in the
areas of mitral valves and pulmonary veins as the foundation of especially atrial fibrillation. Depending on the conditions, single reentry, multiple reentry, and ectopic foci can
all impact reentry-based arrhythmias to various degrees
(301).
C. Atrial and Ventricular Fibrillation
Having introduced triggers, substrates, and unidirectional
block as prerequisites for the development of fibrillation, in
this section we give a short introduction to the etiology of
atrial and ventricular fibrillation.
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ization front represented by the solid red line. As a consequence of the curvature of the wave, there is a point or area
where the depolarizing and repolarizing fronts meet. This
point is termed the phase singularity of the spiral wave and
is represented by the inner dashed circle (FIGURE 9B) (81). In
the leading circle, the central core is believed to be nonexcitable due to refractoriness obtained from centripetal
wavelets originating from the leading circle (represented by
black arrows pointing inward in FIGURE 9A). This notion
was originally based on measuring very short action potentials with reduced amplitude in the central core (11). Later
studies showed that the true nature of the core is better
represented by the spiral wave theory describing an excitable but nonexcited core (188, 192, 206). From a biophysical perspective, this is explained by the phase singularity
that represents such an excitable area of tissue, which is,
however, nonexcited due to the nature and rotation of the
spiral wave. Outside this area of phase singularity, there
will be a larger area (represented by the outer dashed circle
in FIGURE 9B) characterized by electrotonic activity, i.e., a
movement of depolarization that can spread from cell to cell
but does not have sufficient amplitude to reach the threshold for activation of new action potentials. This area of
passive activity will serve as a current sink for surrounding
tissue. As a consequence of cell-cell coupling, there is a
reduction in action potential duration in the surrounding
tissue that serves as a source for the passive central sink
area. The principle is illustrated in FIGURE 9, C AND D.
These electrotonic properties and the faster repolarization
as a consequence of the shortened action potential duration
have been demonstrated to be pro-arrhythmic by stabilizing
rotor behavior and preventing wave breaks (74, 92). The
combined effect of core size, wave curvature, and electrotonic properties will have important impact on the wave tip
dynamics. A final important notion about the spiral wave
theory is the inclusiveness of meandering, i.e., the turning
and winding movement of the wave front through the cardiac tissue. To a large degree, the exact trajectory of a given
spiral wave will depend on the wave tip dynamics (123,
207, 458). Generally, a very stable core with a minimum of
meandering is considered proarrhythmic (213). This is explained by the reduced chance for moving into refractory
tissue and thereby the decreased likelihood of wave-breaks
that can terminate the re-entry.
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
Although not devastating per se, AF can significantly influence life quality, and the disease is associated with a longterm increased risk of death (204). The uncoordinated
movements of the atria during AF result in impaired ventricular filling and blood stasis and thrombosis in the atrial
appendices. The condition predisposes to heart failure
and thromboembolic stroke, respectively (443, 461). The
severe consequences of stasis are emphasized by the fact
that the risk of stroke is increased by fivefold for patients
with AF compared with unaffected individuals. It is further estimated that 15% of all stroke incidences are attributable to AF, a number that increases significantly
with age (461). In contrast to AF, ventricular fibrillation
(VF) is less common but more serious in nature. VF
causes an immediate severe reduction in ventricular ejection fraction due to the fast contractions not being coordinated in the different parts of the ventricle. Systemic
need for circulation cannot be met, and if continued, VF
will result in sudden cardiac death. According to both the
spiral wave and leading circle theories for reentry-based
arrhythmias, inhibition of K⫹ channels should prolong
ERP and exhibit antiarrhythmic effects. This is, however,
not necessarily the reality in ventricular arrhythmia, as
demonstrated by the SWORD clinical trial (Survival
With Oral D-Sotalol) that was preterminated due to increased mortality (440). The proarrhythmic effect of Dsotalol and other more traditional class III compounds
can be explained be several factors. Excessive prolongation of action potentials, especially in situations introducing an extended and slowly decaying phase 3-repolarization, will promote reactivation of voltage-gated Ca2⫹
channels. This is exactly the basis for EADs that can
trigger an arrhythmic event such as the polymorphic ventricular tachycardia, also described as torsades de pointes
(TdP), which can eventually degenerate into VF (377).
An additional mechanistic problem from using class III
compounds for the treatment of VF is the reverse use-
dependency associated with many of these drugs (108).
Reverse use-dependency describes the phenomenon that
the efficacy of the drugs in prolonging the action potentials is poor in tachycardia and good in bradycardia,
where there is no need for the drug to function and where
the risk of EAD-based triggering of arrhythmias is maximal. It should be mentioned that whereas a delayed repolarization can be antiarrhythmic, a slowed depolarizing phase (triangulation) is proarrhythmic, and a common problem with K⫹ channel blocking compounds is
that they induce both effects (185). The multichannel
blocker amiodarone is a fairly safe compound that prolongs the QT interval (indicating prolonged ventricular
action potentials), does not induce triangulation, demonstrates no reverse use-dependency, and has very diminutive probability for inducing TdP (209).
In addition to the increased risk of inducing EADs by inappropriate inhibition of repolarization K⫹ channels leading
to triangulation, the large muscle mass in ventricles, compared with atria, further adds to the increased propensity
for pro-arrhythmic effects of K⫹ channel inhibition. Electrical heterogeneities among cardiac cells can exist along
several axes including the transmural, left-right, and apicobasal axes (50). As described earlier, such electrical heterogeneities can constitute a substrate for arrhythmias as
prominent as those obtained by anatomical remodeling or
infarcts. This type of heterogeneity can also arise from acute
myocardial ischemia and chronic myocardial infarction
(25, 87, 447). In the literature, transmural voltage gradients
in particular have received continued interest. In different species including humans, it has been suggested that the ventricular wall is sufficient in thickness to encompass three different
areas of cells named endocardial, mid-myocardial, and epicardial areas (56, 293, 427). Particularly the mid-myocardial cells
have been speculated as having prolonged action potentials
that can cause electrical heterogeneity during repolarization.
This heterogeneity is also recognized as action potential dispersion and can be increased under conditions such as ischemia, bradycardia, and drug application (241, 427).
To recapitulate, the research in new pharmacological treatments of ventricular tachycardia and VF has been rather
unsuccessful, although it has led to a much better understanding of how to avoid pro-arrhythmic effects of new
drugs. The current first-line treatment for ventricular arrhythmia is therefore often devices and classical anti-arrhythmic drugs as adjuncts (83, 84). A detailed description
of new attempts is given in the section on pharmacological
tools.
D. Remodeling
One of the consequences of sustained fibrillation or congestive heart failure is that these conditions predispose to further fibrillation by inducing changes in the physiological
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AF is by far the most common sustained cardiac arrhythmia
and accounts for approximately one-third of hospitalizations related to heart rhythm disturbances (129). The overall lifetime risk for getting AF is ⬃25% in the general population (254). In a historical perspective, AF was first described in 1906, and characterized as rapid uncoordinated
electrical activation of the atria (130). Several classification
systems are now used to describe various forms of AF.
These include categories such as acute, paroxysmal, intermittent, constant, chronic, persistent, and permanent.
When a patient encounters two or more episodes, the AF is
considered recurrent. Should the recurrent AF terminate
and revert to sinus rhythm spontaneously within a week,
the designation paroxysmal is used. If AF continues for
longer than 7 days, it is categorized as persistent. Finally,
AF can become permanent. This is a clinical definition for
ongoing AF resistant to cardioversion or for very long-term
AF for which cardioversion has not been attempted.
SCHMITT, GRUNNET, AND OLESEN
and anatomical properties of the cardiac tissue. It should be
accentuated that fibrillatory events per se can change the
overall distribution and function of ion channels in a quantitative and qualitative fashion without evident structural
changes. This process is known as electrical remodeling.
Hence, we will subsequently give an account of essential
changes in ion channel function and distribution as a consequence of remodeling.
1. Atrial remodeling
AF is a condition that tends to develop or progress over
time. A consequence of especially sustained AF is remodeling of the atria. The changes encompass both structural and
electrical alternations. Structural remodeling primarily involves atrial dilatation, hypertrophy, and increased amount
and changed distribution of fibrotic tissue not able to conduct electrical signals (60, 61, 71). Electrical remodeling is
the consequence of an overall qualitative and quantitative
change in ion channel distribution. The combined effects of
structural and electrical remodeling result in AF being a
self-perpetuating disease if left untreated. The reason for
this is that remodeling increases the propensity for triggering events that can initiate future incidences of AF. This will
happen in combination with the tissue becoming more vulnerable to electrical disturbances and the development of
larger areas of nonconducting tissue that can serve as a
substrate for reentry-based AF. Consequently, patients with
episodes of paroxysmal AF can progress into persistent and
permanent AF, a phenomenon that has been characterized
as “AF begets AF” (7, 105, 303, 456). In addition to being
a direct outcome of tachypacing and AF, remodeling of
atria can also arise as a secondary effect from cardiac diseases that are not directly related to arrhythmia. These
could be congestive heart failure and acute myocardial infarction (300). The following description of remodeling focuses on effects on ion channels as a direct consequence of
AF. A brief overview of the effects of remodeling is given in
FIGURE 10.
At first sight remodeling might be perceived as a condition
resulting in nothing but an unfavorable outcome. Despite
the damaging long-term consequences, however, there are
acute beneficial effects associated with remodeling. In AF
tissue, atrial contraction is significantly increased due to the
high frequent initiation of action potentials and corresponding influx of Ca2⫹. A very consistent observation in
632
Upregulation of K⫹ channels is also a prominent contributor to the action potential shortening associated with
tachypacing and AF. Several studies showed increased
mRNA and protein levels for Kir2.1 channels that are the
main component of IK1 (132, 172, 331, 492). In contrast,
IK1 is downregulated or unchanged when remodeling is
based on myocardial infarction or congestive heart failure
(240, 345). This notion emphasizes the complexity of
changes and the importance of the condition that provokes
the remodeling. It seems justifiable to hypothesize that there
may be different types of AF based on the biological mechanism causing the disease. The upregulation of IK1 during
AF will contribute to a further reduction in action potential
duration and ERP, which is proarrhythmic. Furthermore, it
has been demonstrated that increased IK1 can increase the
curvature of spiral waves and thereby stabilize rotors and
reentry arrhythmias (74, 373).
Also Kir3.1/3.4 responsible for IKACh is affected by remodeling. The constitutive component of this channel is normally tiny, and a significant IKACh normally requires an
increased parasympathetic or vagal tone. Vagal activation
is proarrhythmic as the IKACh activation leads to a shortening of ERP and stabilization of rotors (81, 220, 480). A
reduction of IKACh has been reported in conjunction with
AF, but it has also been suggested that the constitute component of IKACh is increased as a consequence of AF remodeling leaving a sustained vagally independent current activity that would be proarrhythmic (104, 438).
Remodeling of KV1.5 channels and thereby IKur in the context of AF is more equivocal. There have been reports of
both a reduction in current density and of no changes (49,
52, 439, 462). It is a paradox that although only modest or
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Changes in electrophysiological parameters are due to redistribution and up- or downregulation of various ion channels. The exact outcome of remodeling depends on the underlying disease and differs according to whether it is introduced by atrial tachypacing or by congestive heart failure
(300). Remodeling can also differ between atria and ventricles,
even when originating from the same condition. The following
section is therefore divided into separate paragraphs covering
atrial and ventricular remodeling, respectively.
different species challenged with AF or tachypacing is a
reduction in voltage-gated L-type Ca2⫹ channels, while Ttype channels seem to be unaffected (485). Ca2⫹ overload is
potentially lethal, and the downregulation of L-type channels can be seen as a logical response serving to reduce Ca2⫹
influx to the myocytes (48, 49, 77, 462, 472). The acute
benefits of decreasing Ca2⫹ overload via a reduction in
L-type Ca2⫹ channels is, however, jeopardized in the longer
perspective. Reduced Ca2⫹ current will decrease the action
potential duration by reducing the plateau phase, meaning a
shorter and also more triangulated action potential. This
will in theory be proarrhythmic, since ERP is reduced and
the risk for EAD-based triggering events is increased. When
it comes to an increased propensity for atrial EADs, the
situation is not quite as simple. Although triangulation enlarges the vulnerable window for reactivation of L-type
Ca2⫹ channels and thereby EADs, the concomitant reduction in channel number will counteract this tendency. Predicting whether the outcome is an increased or decreased
risk for EAD-initiated arrhythmia can be difficult, but EADrelated AF is well-described (58, 378).
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
A
Normal
Decreased number; increased lateralization, heterogeneity of connexins
Remodeled
CV
INa
Substrate for multiple circuit reentry
Normal
Remodeled
APD
IKACh,c
WL:
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RP
Initiation of reentry
ICaL
Increased triggering (?)
IK1
Ca2+ handling abnormalities
Pathophysiology of AF promotion
by atrial-tachycardia remodeling
B
IK1
ATRIAL
TACHYCARDIA
ICa
IKur
IKAch
AP SHORTENING
TRIANGULATION
Ito
FIGURE 10. Remodeling of ionic currents in atrial fibrillation. A: decreased conduction velocity (CV), decreased effective refractory period (ERP), or a combination of both results in a decrease of the wavelength. CV
can be reduced as a consequence of diminished gap junction or subcellular relocation of gap junctions resulting
in increased lateralization that will disturb and reduce normal conduction. Changes in the expression patterns
of a number of ion channels result in action potential shortening and increased triangulation. For details, see
text. [From Nattel et al. (300).] B: ion channel changes associated with atrial remodeling.
no changes in IKur have been observed in association with
AF, the contribution from this current to repolarization
appears very different in AF patients compared with control
individuals in sinus rhythm. IKur inhibition in AF patients
prolongs action potential duration, while a reduction in
action potential duration is observed in sinus rhythm, probably reflecting a changed relative significance of IKur due to
up- and downregulation of other channels (78, 90, 359).
This truly demonstrates the complexity of remodeling and
the importance of considering the entire composition of ion
channels when trying to predict the impact of remodeling of
a single type of current. In the context of lone AF, it should
also be mentioned that some reports have associated loss-
of-function mutations in KCNA5 encoding KV1.5 and
thereby IKur to increased risk for AF (322, 476), and recently KCNA5 gain-of-function mutations (79) have been
reported in a number of lone AF patients.
Very recently, Ling and co-workers (70) reported that atrial
miRNA-499, which is significantly upregulated in AF, leads
to KCa2.3 downregulation by binding of miR-499 to the
3’-UTR of KCNN3, and hence is possibly involved in electrical remodeling in AF.
Downregulation of Ito seems to be a consistent finding in
relation to remodeled atria (48, 439, 462). A decreased Ito
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SCHMITT, GRUNNET, AND OLESEN
can affect action potential duration both directly and indirectly. As expected from a reduction in repolarizing capacity, action potential duration is increased when Ito is downregulated. This has been demonstrated in in silico studies
and in studies employing cardiac atrial myocytes from rabbit and human (275, 463). The indirect mechanism relies on
the fast activation that can oppose depolarizing inward
Na⫹ currents. In a situation of reduced Ito, the balance
between depolarizing and repolarizing currents can change,
thereby resulting in increased action potential amplitude
(299).
Remodeling of the gap junction proteins connexins 40 and
43 is reported in conjunction with tachypacing and AF.
There are some discrepancies in the reports concerning the
overall expression level of connexins, with data indicating
either reduced, enhanced, or unchanged connexin levels
(300). From the perspective of affecting AF, the subcellular
distribution of connexins might be of more importance than
the total expression level, since this could affect conduction
velocity to a larger degree. One of the reported effects of
AF-induced remodeling is translocation of connexins from
intercalated disks to lateral membranes (224, 351). Such
subcellular distributional changes will augment the heterogeneity of impulse propagation and thereby probably increase the propensity for AF.
Finally, some consequences of remodeling that are not directly related to ion channels deserve to be briefly mentioned. Conditions such as acute ischemia, atrial dilation,
and inflammation are likely to contribute to an increased
substrate that will prone the maintenance of AF (299).
Atrial dilation, especially in the left atria, causes tissue enlargements. As a result, more reentry circuits can be encompassed, which is proarrhythmic per se (190). This condition
is observed after tachypacing as well as in heart failure
(390). Another important contributor to increased substrates is generation of fibrotic tissue, which is normally
encountered in heart failure and is associated with the development of AF (239, 391).
2. Ventricular remodeling
A prerequisite for understanding the significance of changes
in ion channel activity is to view them in the broader context of native cells, intact muscles, and intact organs. This is
exemplified when analyzing ventricular remodeling as a
consequence of congestive heart failure. The condition is
634
For K⫹ channels, the most consistent change is a reduction
in the phase 1 repolarizing Ito (300). The change is due to
reduction in the principal ␣-subunit KV4.3, while the expression of the associated ␤-subunit KChIP2 is unaltered (4,
368, 399, 501). Another denominator of heart failure remodeling seems to be a reduction in the phase 3 repolarizing
IK1 encoded by Kir2.1, although findings are not as consistent as observed for Ito (300, 369, 399, 423). Of the two
remaining phase 3 repolarization currents, there may be a
reduction in IKs, whereas IKr is reported to be unaffected
(300, 399).
Remodeling of heart failure ventricles causes a few additional changes: reduction in peak INa but increase in persistent INa,late, decreased connexin 43 expression, and decreased pacemaking If current (3, 375, 428, 430, 431, 500).
The ventricular reduction of HCN2 and HCN4 subunits
conducting If is another example of opposite consequences
of remodeling in atria and ventricles, since these subunits
are upregulated in failing atria (500).
The increased strength of contraction in early remodeling
comes at a price of increased risk of arrhythmias for several
reasons. The downregulation of the repolarizing reserve K⫹
currents will postpone the phase 3 repolarization phase and
increase the vulnerable window for reactivation of voltagegated Ca2⫹ channels. Together with the increased open
probability of these Ca2⫹ channels, the overall consequence
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Nav1.5 channels may also be influenced by remodeling, but
few and conflicting results are reported. Reductions have
been demonstrated in tachypaced dogs, and a significant
16% decrease in peak INa density has also been seen in atrial
right appendage cardiomyocytes isolated from AF patients
compared with controls (135, 401). However, other studies
on atrial tissue from human AF patients did not observe
changes in INa (49, 132).
characterized by severe cardiac impairment and the inability to meet the requirements for proper circulation (300).
Heart failure significantly increases the risk of ventricular
arrhythmias (218). Approximately half of the death incidents in heart failure patients are related to ventricular arrhythmias, and on top of this atrial arrhythmias are a common companion to heart failure (112). Whereas the hallmark of AF was shortened and triangulated atrial action
potentials, the characteristic feature of ventricular remodeling in heart failure is a prolonged ventricular action potential. In the early phase, this will help to partly compensate for reduced ventricular function by improving the contraction strength (370). The prolongation is primarily due
to changes in voltage-gated Ca2⫹ channels and K⫹ channels. Overall, the conductance through voltage-gated Ca2⫹
channels is increased. The number of channels is actually
reduced, but this is more than compensated for by an increased open probability (73). It should also be mentioned
that changes in Ca2⫹ handling proteins other than ion channels occur in heart failure. Expression of the Na⫹/Ca2⫹
exchanger NXC is enhanced by heart failure, while the
expression and function of the Ca2⫹-ATPase SERCA2a located in sarcoplasmic reticulum is downregulated (374,
383, 399). Finally, there is an increased Ca2⫹ leak from the
sarcoplasmic reticulum to the cytosol due to hyperphosphorylation of Ca2⫹-release channels or RyRs (388, 479).
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
is a marked increase risk for EADs that can trigger arrhythmic events (193, 242, 314). As IKr is the main repolarizing
current not downregulated in heart failure myocardium,
there is an excessive risk of action potential prolongation,
triangulation, and arrhythmia when exposing patients to
drugs that inhibit this channel. IKr inhibition is an unintended property of many drugs used in the clinic, and extra
care should be taken with such compounds in the event of
heart failure (424). From the perspective of prolonged ventricular action potentials and increased risk of EADs, heart
failure can be viewed as a kind of acquired LQTS (76).
Furthermore, the remodeling of Ca2⫹ handling proteins
other than ion channels contributes to the proarrhythmic
effects. The combination of increased Ca2⫹ leak from sarcoplasmic reticulum (SR), reduced SR uptake due to decrease SERCA2a function, and increased Na⫹/Ca2⫹ exchanger (NCX) function is problematic for two reasons.
First, the general reduction in SR Ca2⫹ content will decrease
contractile function. Second, the increased cytosolic Ca2⫹
concentration in combination with increased amount of
NCX will increase cellular Ca2⫹ efflux at the expense of
increased Na⫹ uptake. This electrogenic transport can provoke DADs and trigger arrhythmias (300).
Finally, the increase in the persistent Na⫹ current INa,late
will participate in the prolongation of ventricular action
potentials and increase the risk for EADs (428, 430). The
downregulation of HCN subunits and thereby If can
cause bradycardia and contribute to cardiac decompensation (6).
The use of pharmacological tool compounds has been of
immense value for understanding the physiology of cardiac
electrical activity and pathophysiology of cardiac arrhythmias. The following section focuses on initiatives targeting
K⫹ channels and introduces the ideas behind some of the
novel approaches for developing antiarrhythmic drugs and
the experiences with them. The main body will be on strategies for targeting AF, but an outline on new pharmacological treatment of VF by K⫹ channel modulation is also
included.
A. Strategies for Treatment of AF
The two principal strategies for treating AF are rhythm and
rate control, respectively. The aim of rhythm control is to
restore and maintain normal sinus rhythm. In contrast, rate
control aims to reduce the ventricular impact of AF by
protecting the ventricles from the fast atrial electrical activity. In other words, rate control will leave the atria fibrillating and prevent excessive conduction from atria to ventricles. This is accomplished by the application of beta blockers, calcium channel blockers, digoxin, or amiodarone that
prolongs refractoriness in the AV node and slows conduction through the AV node.
Considering these aims, it would be expected that rhythm
control, which targets AF rather than its downstream consequences, would be preferential to rate control. This has,
however, not been justified by trials such as AFFIRM,
RACE, PIAF, STAF, and HOT CAFÉ that compared the
ability of rhythm versus rate control to reduce hard end
points such as stroke and death (68, 137, 181, 324, 466).
The nonsuperiority of rhythm control in these trials is surprising, since it could be expected that reversion of AF to
normal sinus rhythm would decrease blood stasis, reduce
the risk of stroke, and concomitantly improve hemodynamic parameters. An explanation for the nonsuperiority of
rhythm versus rate control might be that the RACE and
AFFIRM trials did not include younger symptomatic AF
patients without underlying heart diseases. Another reason
might be the applied strategy for analyzing the data. Based
on the AFFIRM information, it was demonstrated for example that sinus rhythm was an independent predictor of
reducing the risk of death, but simultaneously increased
overall mortality (hazard ratio ⫽ 1.49) (86, 337). The explanation for this overall increase in mortality is likely due
to the ventricular proarrhythmic effects associated with
some of the drugs developed for rhythm control, as demonstrated by the CAST and SWORD study (110, 119, 440). In
a recent study on 26,130 Canadian AF patients with a longer follow-up, the relative advantages of the two treatment
paradigms were time dependent. The rhythm control group
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The reduction of IK1 has also been associated with proarrhythmia due to increased risk of DADs due to the important function of IK1 in setting the resting membrane potential in the diastole. Under normal conditions, the high open
probability of IK1 at resting membrane potential results in a
correspondingly low membrane resistance. The low resistance will decrease the amplitude of abnormal depolarizations such as DADs. In contrast, when IK1 is reduced, the
diastolic membrane resistance is increased, and a DAD will
result in larger current amplitude with higher chance of
reaching the threshold for evoking a premature action potential (350). These physiological mechanisms emphasize
the somewhat ignored fact that a high diastolic K⫹ conductance can be a very important antiarrhythmic parameter,
both to decrease the likelihood for DADs to elicit inappropriate action potentials, as well as to set the stage for the
next systole by affecting the release from inactivation of
Na⫹ channels. The antiarrhythmic effect of some of the
recent activators of KV11.1 channels and thereby IKr might
be explained by increased diastolic K⫹ conductance (169 –
171). Importantly, this could also be a parameter that discriminates application of KV11.1 activators from short QT
mutations such as KV11.1-N588K (154).
IV. PHARMACOLOGICAL TOOLS FOR
ADDRESSING CARDIAC Kⴙ CHANNEL
FUNCTION
SCHMITT, GRUNNET, AND OLESEN
showed a slight increase in mortality during the first 6
months, equal mortality until year 4, and a lower mortality than the rate control group after 5 years, indicating
a long-term superiority of rhythm control (189). For these
reasons, the search for atrial-selective drugs without extracardiac toxicity and ventricular proarrhythmic effects is the
favorable approach when designing new antiarrhythmic
drugs. The current guidelines also still support restoration
of sinus rhythm in younger AF patients as first-line treatment (128, 129).
Substantial preclinical and clinical information has been
gathered for dronedarone, one of the anti-arrhythmic drug
newcomers. While this drug was developed to preserve the
efficacy of amiodarone and reduce adverse effects by deleting iodine in the molecule, the outcome remained equivocal.
Compared with amiodarone, dronedarone seems less efficacious in a clinical setting. The clinical study ATHENA
comprised patients with paroxysmal or persistent AF
(179). Compared with the placebo group, dronedarone resulted in significant reduction in cardiovascular admissions
and mortality (180). The DIONYSOS study included an
end point of direct comparison of amiodarone and dronedarone. Dronedarone turned out to be less efficacious in
patients with persistent AF, but amiodarone had the advantage of better tolerance (177). Noteworthy, the United
States Food and Drug Administration (FDA) recently issued
a safety announcement stating that the use of dronedarone
can be associated with hepatic failure. Furthermore, dronedarone is counter-indicated for heart failure patients due to
increased premature death in this patient population, as
demonstrated in the preterminated ANDROMEDA study
(222). The diverse experiences with the development of
dronedarone emphasize the need for careful selection of
new antiarrhythmic drugs and thorough preclinical understanding of mode of action. Better patient stratification
might also help new antiarrhythmic drugs to succeed in
passing clinical development.
Current drug discovery and development activities for the
treatment of AF target atrial-specific K⫹ channels or aim at
selective inhibition of atrial Na⫹ channels. This latter ap-
636
1. IKur blockers
Functional IKur is generally believed to be absent from ventricles (13). Thus blocking IKur has been perceived as an
attractive strategy for developing a new drug against AF
(125). However, inhibiting IKur by low concentrations of
4-aminopyrimidine or AVE0118 in atrial trabeculae from
individuals in sinus rhythm led to shortened action potentials. This counterintuitive finding is explained by an elevated plateau potential that allows for more prominent IKr
and IKs activation and thereby accelerated repolarization
(454). The results emphasize the importance of addressing
modulations of ion channels in the perspective of the orchestrated function of all other ion channels in play. This is
further underscored by the fact that inhibition of IKur causes
different effects in remodeled tissue from AF patients. Here
the triangulated action potential gives room for less elevated plateau potentials, and consequently IKur inhibition
increases action potential duration (454). It is still an open
question whether a pure IKur blocker will be sufficient for
AF suppression. It is worth keeping in mind that chronic AF
in humans might reduce KV1.5 expression and thereby IKur
density (78, 439). Also it should be mentioned that the
importance of IKur in humans seems to be less pronounced
than suggested from preclinical animal models (336). In
addition, IKur density is diminished at high atrial heart rates
as seen in AF (122). Furthermore, a safety concern is evident
since it has been demonstrated that loss-of-function mutation in KCNA5 giving rise to reduced IKur is associated with
familial AF (322, 476). A number of KV1.5 channel inhibitors have been or are in development for treating AF, and
the applicability of IKur inhibition as a valid approach for
treating AF is likely to be clarified in the future. Some of
these compounds are AVE0118 (IC50 1.1 ␮M), which also
has affinity for Ito and IKAch (142); DPO-1 as a use-dependent open IKur channel blocker with some affinity for IK1
and IKs (230, 361); and more selective compounds such as
XEN-D0101 and XEN-D0103 with human atrial IKur IC50
values of 241 and 154 nM, respectively (125). It has generally proven difficult to obtain good selectivity among Kv
channel subtypes, as many drugs interact with highly conserved residues in the central cavity. Using alanine-scanning
on KV1.x channels, new drug binding sites have been identified on pockets formed by the backsides of several transmembrane segments, indicating a possible avenue for overcoming this problem (277).
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Triggers and reentry propagation of electrical signals in a
changed substrate are the key mechanisms of AF as mentioned above. Inhibition of K⫹ channels has proven effective in prolongation of the effective refractory periods and
interruption of reentry-based arrhythmias. Such compounds constitute the class III antiarrhythmics according to
the Vaughan-Williams classification. The typical class III
drugs are dofetilide and ibutilide, but sotalol and multichannel inhibitors such as amiodarone and dronedarone
also exhibit class III properties (69, 235, 344). All these
drugs inherently influence both atrial and ventricular signaling, and it is evident that many of their adverse effects
would be reduced if they solely targeted atrial ion channels.
proach takes advantage of the fact that resting membrane
potential is more positive in atria compared with ventricles.
Consequently, Na⫹ channels are more inactivated in atria,
which can be exploited to generate state-dependent and
thereby selective inhibitors of atrial Na⫹ channels. Since
this review focuses on K⫹ channels, no further introduction
to state-dependent Na⫹ channel inhibition will be included.
More comprehensive overviews can be found in References
16 and 153.
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
2. IKAch blockers
3. Other concepts
Preclinical evidence points to Ca2⫹-activated KCa2.x channels as a target that possesses functional atrial selectivity,
and KCa2.x channel inhibition has demonstrated to be efficient in terminating acutely induced AF in various animal
models (101, 102, 396). These studies have recently been
extended in dogs with atrial fibrillation induced by atrial
tachypacing. Atrial tachypacing increased whole cell and
single channel KCa2.x current. Pharmacological inhibition
of KCa2.x increased action potential duration in an atrialselective manner and demonstrated antiarrhythmic properties in dogs (357). For a comprehensive overview or recent
development of drugs targeting AF, see also Reference 153.
Some attempts have also been made to investigate the antiarrhythmic potential of modulating the IK1 current. However, since IK1 is by no means an atrial-selective target, it is
debated whether increased or decreased activity will be beneficial. Various studies demonstrated that increasing IK1 is
proarrhythmic due to stabilizing rotors (252, 446). However, antiarrhythmic effects have also been observed after
IK1 activation (252).
B. Strategies for Treatment of VF
In recent years, new developments of K⫹ channel modulators have been sparse as a consequence of the proarrhythmia associated with traditional class III antiarrhythmics
and the current first-line treatment with implantable electronic devices (84, 86, 110, 119). However, there have been
some preclinical approaches investigating the idea of an
increased repolarization reserve as a new principle for treating ventricular arrhythmias. Test molecules have been developed activating all phase 3 repolarizing K⫹ currents IKr,
IKs, and IK1 carried by KV11.1, KV7.1, and Kir2.1, respectively, but it is primarily activators of KV11.1 that have
been thoroughly investigated.
KV11.1 channels show very characteristic inactivation
properties with fast inactivation upon depolarization and
fast recovery from inactivation upon repolarization
(FIGURE 11A). Many KV11.1 channel activators affect these
properties by reducing inactivation or promoting recovery
from inactivation. A reduction in relative inactivation, being equal to a rightward shifted inactivation curve, will
increase the overall KV11.1 current. Compounds with such
properties include NS1643 and NS3623 (both NeuroSearch), PD-307243 (Pfizer), and A-935142 (Abbott) (151,
168, 169, 411, 498). RPR260243 (Sanofi-Aventis) utilizes a
different mechanism of action, as it slows KV11.1 channel
closure (deactivation) corresponding to an increase in macroscopic IKr (203). Importantly, the pharmacological effect
of these compounds is different from the biophysical properties revealed for a KV11.1 channel mutation that has been
associated with the SQTS (154).
The antiarrhythmic properties of this new compound class
were demonstrated experimentally ex vivo and in vivo. In
patch-clamp studies, NS1643 and NS3623 shorten ventricular action potentials when recorded from acutely isolated
single cells (FIGURE 11B), and the same notion holds true in
isolated papillary muscle. Importantly, an increased ability
to withstand triggering activity in the form of mimicked
EADs was also demonstrated (100, 168, 169). Similar results have been obtained with A-935142 in guinea pigs and
dogs (411). PD-118057 has also been tested ex vivo in iso-
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The K⫹ current IKAch composed of Kir3.1/Kir3.4 subunits is
another atrial-selective target that has not been as extensively investigated as KV1.5 channels, but evidence has been
accumulating, particularly in recent years, for this to be an
interesting target (358). As for KV1.5, the rationale for inhibiting this channel is to obtain selective prolongation of
the atrial effective refractory periods. Interesting IKAch inhibitors are NTC-801 with an IC50 of 0.7 nM as well as
NIP-151 and NIP-142 with IC50 values of 1.6 and 640 nM,
respectively (269, 297, 416, 418). Noteworthy, many multichannel inhibitors developed for treatment of AF display
affinity for IKAch. These include amiodarone, dronedarone,
AVE0118, E-4031, vernakalant, sotalol, and flecainide
(121, 142, 163, 288, 448).
The idea about an increased repolarization reserve as an
antiarrhythmic strategy appeared as a logical extension of
the proarrhythmic effects observed by prolonging the ventricular action potential with class III drugs. It was demonstrated that proarrhythmia is primarily due to the inhibition
of KV11.1 channels, and it became a prerequisite in drug
development to screen potential drug candidates for their
ability to inhibit this channel. A number of high-throughput
assays were developed for the purpose, and as a result of
screening hundreds of thousands of compounds for KV11.1
inhibition, a number of activators of this channel also appeared. Several companies pursued the idea that the conditions or diseases associated with prolonged QT intervals
and underlying ventricular action potential prolongations
could be normalized by the application of KV11.1 channel
activators. From a theoretical perspective, the primary antiarrhythmic effects of such compounds would be shortening of the action potential duration and reduced triangulation leading to narrowing of the vulnerable window leaving
less room for EADs that can trigger an arrhythmia. Since
KV11.1 channels deactivate slowly during the early phase 4,
an increased current will further help antagonize DADs
here. Decrease in electronic heterogeneity could be another
beneficial parameter. Relevant indications could be congenital and acquired long QT syndromes, heart failure, and
prolonged QT in association with AF, ischemia, diabetes,
etc.
SCHMITT, GRUNNET, AND OLESEN
A
K+
Slow
Fast
K+
Slow
Fast
K+
Closed
Open
Inactivated
B
b
Control
50
Voltage (mV)
50
0
–50
0
–50
–100
–100
0.0
0.4
c
0.8
Time (s)
1.2
0.0
0.4
d
NS1643
100
50
50
0
0.8
Time (s)
1.2
NS1643
100
Voltage (mV)
Voltage (mV)
Control
100
0
–50
–50
–100
–100
0.0
0.4
0.8
Time (s)
1.2
0.0
0.4
0.8
Time (s)
1.2
0.0
0.4
0.8
Time (s)
1.2
FIGURE 11. KV11.1 pharmacology.
A: KV11.1 gating kinetics. B: activation of
KV11.1 with the tool compound NS1643
in acutely isolated cardiomyocytes from
guinea pig. The response of cardiomyocytes to simulated EADs was assessed after an elicited action potential; a train of
10 –20 50% subthreshold stimuli was applied either at control situations after full
repolarization (a and c) or to induce EADs
at APD90 (b and d). In the absence of
NS1643, subthreshold stimuli applied at
APD90 were able to induce EAD events
every time the protocol was applied, and
prolongation of the action potential was
continued even after cessation of current
injection (b). Upon application of 10 ␮M
NS1643, the premature train of stimuli
was not able to trigger any abnormal activity, and application of the drug thus led to a
stable action potential (d). Superimposed
traces for subthreshold stimuli applied at
APD90 in the absence or presence of
NS1643 are shown in e, left. Current injection protocol is shown in e, right. [B
from Hansen et al. (168).]
e
Voltage (mV)
100
50
0
–50
–100
638
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Voltage (mV)
a
100
CARDIAC POTASSIUM CHANNELS AND ARRHYTHMIA
lated rabbit and canine wedge preparations with somewhat
opposing results. A clear antiarrhythmic effect was observed in the rabbit wedge and included the expected action
potential shortening, but also reduced dispersion. In contrast, canine wedge studies resulted in increased dispersion
and pacing-induced polymorphic ventricular tachycardia
(334, 498). In intact isolated hearts, NS3623 has demonstrated antiarrhythmic properties such as a decrease in QT
variability, and a tendency towards reduced global dispersion when addressed as a reduction in Tpeak-Tend intervals,
as well as a marked reduction in number of extrasystoli
(170).
For KV7.1 channels and IKs, only limited experience is available on pro- or antiarrhythmic effects of increasing this
current, with the benzodiazepine R-L3 being the central
compound. R-L3 reverses pharmacologically induced type
2 LQTS (induced by IKr inhibition), shortens action potential duration, and decreases triangulation. The compound
activates heterologously expressed KV7.1 channels, but has
no effect on the KV7.1/KCNE1 complex that mimics native
IKs (371, 384). R-L3 also reduces the effective refractory
period, which might indicate proarrhythmic activity by increasing the risk for atrial fibrillation (310). More comprehensive overviews of exact mode of actions and anti- and
proarrhythmic properties of KV11.1 and KV7.1 activators
are given in References 155 and 162.
Another innovative approach to address cardiac ion channels has been the development of activators of Ito. Applying
the tool compound NS5806 (NeuroSearch) in isolated canine ventricular myocytes increased peak currents significantly and slowed inactivation kinetics. Furthermore, in
V. CONCLUSIONS AND PERSPECTIVES
The molecular studies of the diverse cardiac potassium
channel subtypes have allowed a detailed picture of their
individual structures and regulatory mechanisms to emerge.
By addressing the significance of accessory subunits and
influence of posttranslational modifications, it has also been
widely possible to translate these molecular correlates into
the endogenous cardiac K⫹ currents. Yet most of the stateof-the-art techniques employ heterologously expressed
channels or depict snap shots of cardiac tissue, and hence
only partially reflect processes in vivo. Accordingly, a larger
challenge that still remains is to understand how these “actors in the still picture” behave in dynamic play and change
their function relative to each other both in the short term
(changes in heart rate, sympathetic tone, Ca2⫹ level, posttranslational modifications) and long term (epigenetic
changes, remodeling). These changes of the basic biological
conditions of the tissue determine whether the stable heart
rhythm is maintained or an arrhythmia is triggered.
We have in this review addressed the concerted action of the
repolarizing cardiac K⫹ currents, while also seeing them as
individual currents. The use of selective pharmacological
tools, both channel-subtype-specific toxins and organic
molecules, has proven valuable to dissect the role of the
individual channels in intact organisms. One result of these
pharmacological studies combined with expression analysis
and other functional investigations is the identification and
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In vivo NS3623 has been tested in anesthetized and conscious guinea pigs. In line with theoretical considerations,
the measured and corrected QT interval was reduced in
both conditions. Furthermore, NS3623 reverses drug-induced QT prolongation (171). In rabbits, NS1643 has demonstrated antiarrhythmic properties in a pharmacological
and nonpharmacological model for ventricular fibrillation.
In the pharmacological model, the combined proarrhythmic effect of the class III drug dofetilide together with the
␣1-adrenergic receptor agonist methoxamine could be prevented by NS1643. In a more physiological model, atrioventricular block and subsequent 3-wk bradypacing resulted in ventricular extrasystoli and short runs of TdP like
arrhythmias. Both conditions could be prevented by
NS1643 (103). Although the models are promising, it
should also be mentioned that proarrhythmic effects have
been associated with KV11.1 channel activators, although
some of these might be unspecific effects (162, 259). In
terms of therapeutic application, KV11.1 channel activators
probably have the highest chance of success in conditions
with extensive action prolongation that can subsequently
be normalized by this new compound class.
coronary-perfused wedge preparations, NS5806 recapitulated the features of Brugada Syndrome phenotype visible
as increase in phase 1 and notch amplitudes (62). The effect
was later shown to be dependent on the presence of the Ito
subunit K channel interacting protein (KChIP) 2 (65, 263).
Accordingly, the transmural KChIP2 gradient across the
ventricular wall led to differential effects of NS5806 in epi-,
mid-, and endocardial cells (65). A study comparing
NS5806 in canine atrial and ventricular myocytes showed a
different response in the atria, where the addition of drug
had only mild effects on phase 1. Instead, the upstroke
velocity was significantly decreased, which could be ascribed to a strong inhibition of INa in the atria (63). Although NS5806 in addition to NaV1.5 does affect other
potassium channels such as KV1.4 and KV1.5, it represents
an interesting tool compound in the context of heart failure
(HF). HF, amongst others, is characterized by an action
potential prolongation due to remodeling the repolarizing
currents Ito and IKs (reviewed in Ref. 88). The reduction in
Ito is due to the reduction of KV4.3 channels (202). NS5806
was used in a tachypaced-induced canine model of heart
failure and was able to restore phase 1 action potential
morphology in wedge preparations from HF dogs (85). Despite the risk of being proarrhythmic, this tool compound
provided a proof-of-concept that Ito activators might be
useful for treatment of HF.
SCHMITT, GRUNNET, AND OLESEN
verification of the fairly atrial-specific repolarizing currents
IKur, IKAch, IKCa, and IK2P. The role of the first two channels
in the atria has been known for a number of years, whereas
the significance of the latter two is new and may pave the
way for new treatment paradigms for AF.
GRANTS
Over the past 20 years, the mutations in single cardiac ion
channels have been a rich source of information about the
role of each channel subtype in arrhythmogenesis and have
fostered the concept of monogenetic arrhythmic diseases.
The significance of these variants is currently being rewritten on the background of the exome data becoming available from large cohorts showing their presence in the general population and calling for a stricter interpretation.
DISCLOSURES
The best translational studies to provide us with an understanding of the specific role of a given K⫹ channel on the
background of the patient’s own biological background use
fresh human cardiac tissue, often removed in open chest
operations with extracorporal circulation. To investigate
specific genetic variants, the use of induced pluripotent stem
cells generated from the patient’s skin biopsies or blood has
fostered hope for the development of true personalized
medicine.
ACKNOWLEDGMENTS
We thank Jonas Bille Nielsen and Lasse Skibsbye (both
from the Danish National Foundation Centre for Cardiac
Arrhythmia) for kindly providing ECG recordings and human cardiac action potentials, respectively.
N. Schmitt and M. Grunnet contributed equally to the present work.
Address for reprint requests and other correspondence:
S.-P. Olesen, The Danish National Research Foundation
Centre for Cardiac Arrhythmia, Dept. of Biomedical Sciences, Faculty of Health and Medical Sciences, Univ. of
Copenhagen, Copenhagen, Denmark (e-mail: [email protected].
dk).
640
M. Grunnet is employed at Lundbeck A/S (Valby, Denmark) and Acesion Pharma (Copenhagen, Denmark).
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The limited penetrance of some of the disease-causing mutations and the fact that both gain-of-function and loss-offunction mutations in the same channel can cause a similar
disease indicate that there are conditions of the cardiac
tissue we probably need to take into consideration for each
patient to understand the outcome of a changed K⫹ channel
function. Great effort is made to generate various disease
models in animals to clarify this issue. Yet, because the
distinct and complex electrophysiological properties of cardiomyocytes differ among species, the use of isolated cardiomyocytes from model animals has limitations. Since certain smaller animals are quite dissimilar to humans, especially from a cardiac point of view, extending the
conclusions to human arrhythmogenesis is applicable only
to a limited degree.
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grant from the Danish National Research Foundation.
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