Europace (2008) 10, 1133–1137

doi:10.1093/europace/eun193

REVIEW

Role of potassium currents in cardiac arrhythmias

Ursula Ravens1* and Elisabetta Cerbai2
1
Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology, Dresden, Germany;
and 2Centro Interuniversitario di Medicina Molecolare, University of Florence, Florence, Italy
Received 29 April 2008; accepted after revision 4 July 2008; online publish-ahead-of-print 24 July 2008

KEYWORDS Abnormal excitability of myocardial cells may give rise to ectopic beats and initiate re-entry around an
Potassium channels; anatomical or functional obstacle. As Kþ currents control the repolarization process of the cardiac
Ventricular fibrillation; action potential (AP), the Kþ channel function determines membrane potential and refractoriness of
Torsades de pointes; the myocardium. Both gain and loss of the Kþ channel function can lead to arrhythmia. The former
Atrial fibrillation; because abbreviation of the active potential duration (APD) shortens refractoriness and wave length,
Genetic polymorphism; and thereby facilitates re-entry and the latter because excessive prolongation of APD may lead to
Drugs; torsades de pointes (TdP) arrhythmia and sudden cardiac death. The pro-arrhythmic consequences of
Remodelling malfunctioning Kþ channels in ventricular and atrial tissue are discussed in the light of three pathophy-
siologically relevant aspects: genetic background, drug action, and disease-induced remodelling. In the
ventricles, loss-of-function mutations in the genes encoding for Kþ channels and many drugs (mainly
hERG channel blockers) are related to hereditary and acquired long-QT syndrome, respectively, that
put individuals at high risk for developing TdP arrhythmias and life-threatening ventricular fibrillation.
Similarly, down-regulation of Kþ channels in heart failure also increases the risk for sudden cardiac
death. Mutations and polymorphisms in genes encoding for atrial Kþ channels can be associated with
gain-of-function and shortened, or with loss-of-function and prolonged APs. The block of atrial Kþ chan-
nels becomes a particular therapeutic challenge when trying to ameliorate atrial fibrillation (AF). This
arrhythmia has a strong tendency to cause electrical remodelling, which affects many Kþ channels.
Atrial-selective drugs for the treatment of AF without affecting the ventricles could target structures
such as IKur or constitutively active IK,ACh channels.

Introduction and a plateau phase (phase 2), in which repolarization is

Regular excitation is generated in the sino-atrial node and
spreads throughout the heart in an orderly manner,
whereas disorganization of electrical activity is the basis
of atrial or ventricular fibrillation. Arrhythmias are caused
by the perturbation of physiological impulse formation,
impaired impulse conduction, or disturbed electrical
recovery. Abnormal excitability of myocardial cells may
give rise to ectopic beats and initiate re-entry around an
anatomical or functional obstacle (reviewed in Jalife1).
The long-lasting action potential (AP) of the working
myocardium maintains a refractory state for as long as the
muscle contracts and thus ensures rhythmic pump function.
Typical cardiac APs consist of five distinct phases (Figure 1).
In phase 0, Naþ influx triggers a rapid depolarization
followed by an early fast repolarization phase (phase 1)
* Corresponding author: Institut für Pharmakologie und Toxikologie,
Fetscherstr. 74, 01307 Dresden, Germany. Tel: þ49 351 4586300; fax: þ49
351 4586315.
E-mail address: ravens@rcs.urz.tu-dresden.de
slowed due to the activation of inward Ca2þ current.
During the final rapid repolarization phase (phase 3),
membrane potential returns to the resting level (phase 4).
The various potassium (Kþ) currents are repolarizing
outward currents. Their major contributions to the cardiac
AP are control of stable resting membrane potential and
termination of the AP.
Potassium channels
Ions traverse the lipid bilayer of the plasmalemma along their
electrochemical gradient via hydrophilic ion channels. These
ion channels open and close in a voltage- and time-dependent
manner (activation, inactivation, or deactivation) and pass
ions only in the open state. After-repolarization, some chan-
nels must recover from inactivation before they become
available for re-opening, and during this time, the myocardial
cells remain refractory for re-excitation.
Potassium channels form the largest family of ion
channel proteins. Determining and depending on membrane

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008.
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 1134 U. Ravens and E. Cerbai

Figure 1 Inward, depolarizing and outward, repolarizing currents that underlie the atrial and ventricular action potential. Inward currents:
INa sodium current; ICa,L L-type calcium current; Ito transient outward current; IKur ultra rapidly activating delayed rectifier current; IKr and IKs
rapidly and slowly activating delayed rectifier current; IK1 inward rectifier current; IK,ACh acetylcholine-activated potassium current. Note
that IKur is present in atria only. Phase 0, rapid depolarization; phase 1, rapid early repolarization phase; phase 2, slow repolarization
phase (‘plateau’ phase); phase 3, rapid late repolarization phase; phase 4, resting membrane potential. Adapted from The Sicilian gambit.28

potential, Kþ channels can also be activated by ligand Potassium channels—differences between

binding, and hence are divided into voltage- and ligand-gated
channels. The ion-conducting pore of a Kþ channel is formed
by four a-subunits that co-assemble as homo- or hetero-
tetramers with different biophysical properties. Their gating
characteristics are further modulated by ancillary subunits.
Cardiac Kþ channels are further classified according to
their function (cf. Figure 1). (i) The transient outward
current Ito exhibits rapid activation and subsequent
inactivation during the early repolarization phase. (ii) The
delayed rectifier channels conduct at least three different
currents IKur, IKr, and IKs. All three currents activate at posi-
tive potentials with distinct time courses, i.e. ultrarapid,
rapid, and slow, respectively. Inactivation of IKur and IKs is
slow, whereas that of IKr is extremely fast. Contribution of
each of these currents to repolarization depends on the
number of open channels and the electrochemical driving
force that declines as the membrane potential returns to
its resting level. In the course of repolarization, IKr recovers
rapidly from inactivation into an open state which deacti-
vates very slowly, so that this current exhibits inward
rectification.2 Therefore, IKr increases again at negative
potentials and strongly accelerates final repolarization.
(iii) The major classical cardiac inward rectifier K þcurrent
is IK1. This channel is always open and conducts Kþ better
into than out of the cell. Atrial myocytes also express an
acetylcholine-dependent channel that conducts IK,ACh
in response to the stimulation of G-protein-coupled mus-
carinic (M2) and adenosine (A1) receptors. The activation
of IK,ACh hyperpolarizes the membrane and shortens the
active potential duration (APD). The third inward rectifier
channel in cardiomyocytes is closed under physiological
metabolic conditions and is activated when the cells are
deprived of intra-cellular adenosine triphosphate. Similar
to IK,ACh, IK,ATP causes profound APD shortening.
atrium and ventricle
Despite general similarity in the mechanisms of AP gener-
ation, APs exhibit distinct shapes in atrial and ventricular
myocardium (Figure 1). The most striking differences are
that (i) the plateau phase occurs at more negative potentials
and (ii) overall APD is shorter in atrial when compared with
ventricular cells. These differences are due to the non-
uniform distribution of ion channels, including Kþ channels.
For instance, IKur is detected only in atrial but not in ventri-
cular myocytes, although the Kv1.5 protein is abundant in
both chambers. Rapid activation of IKur in the positive poten-
tial range following the AP upstroke may offset depolarizing
ICa,L and hence leads to the less positive plateau phase
in atrial than ventricular cells. The acetylcholine-activated
inward rectifying current IK,ACh, too, is not detected in
ventricle.
Contribution of K1 channel function to
arrhythmias
Because of their impact on membrane potential and
refractoriness, Kþ currents play a prominent role in arrhyth-
mogenesis. An increase in Kþ currents abbreviates APD and
thereby facilitates re-entry. Conversely, impaired Kþ current
amplitudes prolong APD with contrasting outcome, whereas
moderate prolongation maintains the myocardium in a refrac-
tory state and is actually considered an anti-arrhythmic
mechanism (class III anti-arrhythmic action according to the
classification of Vaughan Williams), excessive prolongation
predisposes to early after-depolarizations that may trigger
torsades de pointes arrhythmias (TdP). This form of
arrhythmia may either resolve spontaneously or deteriorate
into ventricular fibrillation causing sudden cardiac death.

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 Role of potassium currents in cardiac arrhythmias
Therefore, both gain and loss of Kþ channel function can
lead to arrhythmia. Malfunction of Kþ channels may be
due to diverse causes such as mutations in the encoding
genes for any of the subunits, drug actions, or remodelling
in adaptation to heart disease. These three factors will be
discussed first for ventricular and, subsequently, for atrial
arrhythmias.
Ventricular arrhythmias
Arrhythmogenic potential of K1 channel mutations
The number of mutations identified in Kþ channel-encoding
genes that have been related to arrhythmias is increasing
rapidly. The consequences of missense mutations include
faulty protein folding and disturbed co-assembly between
subunits and therefore early degradation, disruption of
trafficking or defects in plasmalemmal integration, altered
voltage dependency, or impaired ion selectivity of the
channel. These adverse effects reduce repolarizing Kþ
currents and thereby delay the repolarization process. The
resulting long-cardiac APD or long-QT interval in the electro-
cardiogram predisposes a patient to TdP arrhythmias. There-
fore, patients with the hereditary long-QT syndrome (LQTS)
are at increased risk for sudden cardiac death. Mutations in
the genes for KvLQT1 (IKs) and hERG (IKr) account for 80–90%
of all hereditary LQTS, although mutations that cause LQTS
were also discovered in other ion channels, in ion-handling,
or associated proteins (for recent review, see Saenen and
Vrints3). As mentioned above, rare gain-of-function mutations
in hERG and KvLQT1 shorten cardiac APs and also give rise
to potentially lethal arrhythmias (short-QT syndrome).
Arrhythmogenic potential of K1 channel blockers
Many drugs used in cardiac and non-cardiac diseases prolong
APs and give rise to acquired LQTS. Besides underlying heart
disease, several factors predispose to drug-induced TdP.
These include female gender, long-QT interval at baseline,
bradycardia, low Kþ and Mg2þ plasma levels, old age, and
the increased incidence of heart disease. Similar to con-
genital LQTS, the actual incidence of drug-induced TdP is
low and that of proven drug-associated syncope or sudden
cardiac death is even lower.4 The absolute incidence of
cardiotoxicity of any drug must be judged in relation to
the severity of the treated disease: a high risk may be
perfectly acceptable when treating a life-threatening
condition, whereas even a very low incidence as reported
for non-sedating antihistaminic drugs is not acceptable as
these drugs are widely prescribed for minor complaints.
Nevertheless, the increasing number of drugs recognized
to cause acquired LQTS has become a concern for patients,
physicians, and safety regulation authorities.
Almost all drugs with reported QT-prolongation and
TdP are blockers of potassium channels, particularly IKr
channels.5 In fact, hERG channels are sensitive to block by
a surprisingly large variety of agents, and block of hERG
channels is so common that drug safety agencies require
data on hERG channel block for new drugs when filed for
registration. hERG screening tests are performed at very
early stages in drug development and even promising new
compounds are usually abandoned when testing positive.
This is not always justified, because the block of IKr may in
part be compensated by changes in opposing currents
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1135
(increase in ‘repolarization reserve’).6,7 Although there
appears to be no strict concentration–response relationship
for triggering TdP, drug plasma concentrations should not be
allowed to rise above the therapeutic level and interference
with drug metabolism or excretion should be avoided.
Even in asymptomatic patients, a genetic predisposition
related to congenital LQTS may exacerbate drug action
that turns the otherwise borderline QT interval into overt
prolongation. Some polymorphisms, for instance, in the
gene encoding for a common ancillary subunit (i.e. the
KCNE2 gene) have normal function at baseline, but are
susceptible to block by sulfamethoxazole that imposes no
prolongation in healthy individuals.8
Arrhythmogenic exacerbation frequently occurs due to
pharmacokinetic interactions by co-administered drugs
that interfere with biotransformation and excretion of a
previously tolerated drug resulting in excessive plasma
concentrations. If the parent compound is more effective
than the metabolite in producing a pro-arrhythmic event,
inhibition of drug metabolizing enzymes will enhance
arrhythmogenicity. Conversely, if the metabolite is more
effective, induction of enzymes is pro-arrhythmogenic.
The antifungal agent, ketoconazole for instance, interferes
with biotransformation of the non-sedating antihistaminic
terfenadine into a metabolite that does not prolong the
AP. Thus, co-medication of the two drugs results in a high
plasma concentration of terfenadine leading to acquired
LQTS. Such an interaction applies for many drugs that
inhibit cytochrome P450 enzymes and even grapefruit
juice may interfere (reviewied in Priori et al. 4).
Intuitively, cardiac drugs and, in particular, anti-
arrhythmics that prolong APD (class III action according to
the Vaughan Williams classification) are expected to produce
an increased risk not only because of their mechanism of
action but also because they are given to patients with dis-
eased hearts that are per se at a high risk for rhythm disturb-
ances. However, drugs for treating non-cardiac diseases such
as antihistamines, antibiotics, antipsychotic, or prokinetic
agents also may increase risk. Comprehensive lists of drugs
with reported or suspected risk for TdP are available in the
internet (for instance, http://www.qtdrugs.org/).
Disease-induced remodelling
Heart failure is associated with a plethora of ventricular
ionic changes that predispose to arrhythmias (for recent
review, see Nass et al. 9). These remodelling processes
include electrophysiological changes that lead to APD
prolongation, especially in the endocardial region. We and
others have shown that Ito amplitude is down-regulated,
but other Kþ currents (IKr, IKs, and IK1) are depressed as
well.10,11 Reduced Kþ currents increase the propensity for
early after-depolarizations, dispersion of repolarization,
and ventricular arrhythmias, thereby significantly increasing
the risk of sudden cardiac death in heart failure patients. In
contrast, delayed after-depolarizations occurring at high
intra-cellular Ca2þ load may initiate triggered activity
and induce ventricular tachycardia, particularly in non-
ischaemic heart failure patients, and decreased IK1 enhances
the propensity for triggered activity.12 Kþ channel down-
regulation also contributes to enhanced sensitivity of
failing myocardium to other triggering factors such as
hypokalaemia, ischaemia, and anti-arrhythmic agents with
 1136
class III effects. In addition, overexpression of pacemaker
channels may predispose ventricular myocytes from failing
hearts to enhanced automaticity.13
Atrial arrhythmias
Atrial fibrillation (AF) is initiated when a suitable trigger
meets an appropriate substrate. The underlying pathophy-
siological mechanisms include ectopic electrical activity
and single or multiple re-entry circuits. Re-entry often
develops in large fibrotic atria associated with valvular
disease or heart failure, whereas in seemingly healthy
hearts, rapid local ectopic activity initiating in the pulmon-
ary veins can give rise to re-entry circuits.
Arrhythmogenic potential of K1 channel mutations
In contrast to the vast majority of several hundreds of known
Kþ channel mutations being associated with LQTS, there
are, but a few, mutations directly linked to familial AF
(Table 1). Nevertheless, LQTS patients may also exhibit poly-
morphic atrial tachyarrhythmias.14 Although in the ventri-
cles loss-of-function mutations predominantly predispose
to chaotic electrical activity, the Kþ channel mutations
associated with AF exhibit—with one exception—gain-of-
function, leading to abbreviation of the APD and facilitating
re-entry. In the individual studies, gain-of-function was
verified by expressing mutated channels in cell lines and
measuring increased Kþ current density when compared
with wild-type channels (reviewed in Roberts15). For the
loss-of-function mutation, it was demonstrated that mice
expressing the mutated channels had long APs with early
after-depolarizations and were more prone to stress-induced
arrhythmias.16 Recent evidence from a genome-wide associ-
ation study identified three novel single nucleotide poly-
morphisms that confer predisposition to AF.17 Moreover, a
systematic candidate gene-based analysis of the gene
encoding for hERG discovered a hitherto unknown variant,
which strongly associated with AF.18
Arrhythmogenic potential of drugs acting
on K1 channels
Vagal nerve stimulation induces AF because of shortening of
the refractory period due to acetylcholine release and sub-
sequent activation of IK,ACh. In analogy, drugs that shorten
APD by activating Kþ currents are expected to predispose
to AF. However, much less is known about the actual inci-
dence of drug-induced AF than of TdP in the case of LQTS.
As outlined above, prolongation of atrial APD by the block
of Kþ channels, as, for instance, with cesium, may also
Table 1 Mutations in genes encoding for potassium channel proteins associated with familial atrial fibrillation
Gene (Protein) Current Mutation Amino acid change
KCNA5 (Kv1.5) IKur 1123G!T E375X
KCNH2 (Kv11.1) IKr 1764C!G N588K
KCNQ1 (Kv7.1) IKs 418A!G S140G
KCNQ1 (Kv7.1) IKs 491G!A V141M
KCNQ1 (Kv7.1) IKs 40C!T R14C
KCNE2 IKs 79C!T R27C
KCNJ2 (Kir2.1) IK1 277G!A V93I
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U. Ravens and E. Cerbai
induce AF;19 however, unlike ventricular fibrillation, this
arrhythmias is not immediately life threatening.
Disease-induced remodelling
Atrial fibrillation has a strong tendency to become persistent.
Persistent AF is thought to develop because of ‘remodelling’,
which refers to any change in the atrial function that pro-
motes AF or occurs as a consequence of the arrhythmia20
and involves alterations in myocardial structural and electro-
physiological properties. Structural remodelling includes
interstitial fibrosis and is closely related to the renin–
angiotensin–aldosterone system.21 Electrical remodelling
comprises triangularization of the AP shape, shortening of
APD, and lack of adaptation of APD to cycle length and is
due to alterations in the ion channel function as well as
changes in Ca2þ handling of the cardiomyocytes.11,22
Reduced refractoriness supports multiple wavelet re-entry
and generation of sustained, high-frequency spiral waves
(‘rotors’) with fibrillatory conduction, which are thought to
contribute to sustained AF.23
Electrical remodelling by AF affects depolarizing currents
(with reduced ICa,L, unaffected conventional INa, and acti-
vated sodium/calcium exchanger) as well as repolarizing
Kþ currents with Ito and IKur current densities being
decreased. The contribution of IKr and IKs to electrical remo-
delling is less clear, because their presence in the human
atrium is difficult to assess experimentally.24 Basal activity
of the inwardly rectifying IK1 current is enhanced, but
acetylcholine-activated IK,ACh current is reduced. Moreover,
a component of constitutively active IK,ACh that activates in
the absence of any agonist is detected in persistent AF and
may contribute to AP shortening.25 The contribution of
other ion channels (chloride channels, TASK-1, and so on)
to AF pathophysiology is still unknown.
Atrial fibrillation-induced changes in Kþ current amplitude
need not necessarily be due to corresponding alteration in
the gene expression, but can be caused by AF-induced
effects on protein kinases and phosphatases that modify
channel phosphorylation status (see, for instance, Christ
et al. 6) or by enhanced protein degradation through pro-
teases.21 There is some controversy in the literature con-
cerning the expression of Kþ channels in remodelled atria
(see Dobrev and Ravens,22 for references): mRNA and
protein expression of Ito channels are always found
depressed, IKur channels are not changed or decreased; IKr
channels are not altered or decreased and IKs channels are
decreased or increased; inward rectifier Kþ channels for
IK1 are enhanced, for IK,ACh and IK,ATP decreased.26,27 More-
over, these discrepant findings do not always go in line
Change Origin References
Loss-of-function Mostly Caucasian Olson et al.16
Gain-of-function — Hong et al.29
Gain-of-function Chinese Chen et al.30
Gain-of-function Caucasian Hong et al.31
Gain-of-function (stretch) — Otway et al.32
Gain-of-function Chinese Yang et al.33
Gain-of-function Chinese Xia et al.34
 Role of potassium currents in cardiac arrhythmias
with the actually measured changes in the current ampli-
tude, indicating that AF-induced channel dysregulation
must have occurred. Although ancillary subunits of Kþ
channels profoundly affect their expression and biophysi-
cal properties, little is presently known about AF-induced
remodelling in these regulatory proteins.
The Kþ currents, IKur and IK,Ach, have recently attracted
special attention because they are confined to atrial
myocardium and hence their blockade is not expected to
cause pro-arrhythmic effects in the ventricles. In the past
decade, several new compounds were developed for the
prolongation of effective refractory period by the block of
IKur, however, the efficacy of most of these new drugs
in converting AF back to SR has been rather disappointing,
possibly due to low IKur amplitude in AF. With regard to
IK,ACh channels, we have recently reported that these
channels develop constitutive activity during human AF, i.e.
these channels become activated, despite the absence of
stimulating acetylcholine.25 Constitutively active IK,ACh can
hyperpolarize the membrane and hence contribute to persist-
ence of AF by stabilization of rotors. Therefore, selectively
targeting constitutively active IK,ACh channels only may pre-
serve physiological stimulation by vagal nerves and could
serve as a promising remodelling-related drug target.
Acknowledgements
The authors gratefully acknowledge helpful comments by Dobromir
Dobrev and Niels Voigt.
Conflict of interest: none declared.
Funding
This work was supported by a grant from the Fondation
Leducq and by a European Union grant (NORMACOR,
LSHM-CT-2006-018676).
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