Potassium Channel

Remodeling in Heart
Disease
Vincent Algalarrondo, MD, PhDa,b,c, Stanley Nattel, MDa,b,c,*

KEYWORDS
 Cardiac repolarization  Heart disease  Potassium  Potassium channel  Arrhythmia
 Atrial Fibrillation

KEY POINTS
 Cardiac repolarization and underlying ionic mechanisms are substantially altered by heart disease.
 In hypertrophy, myocardial infarction, and heart failure, potassium channels and currents are down-
regulated and repolarization is delayed, creating a substrate for ventricular tachyarrhythmia.
 Mechanisms leading to arrhythmia with potassium channel downregulation include early afterdepo-
larizations, reduced cardiomyocyte resting membrane resistance, and increased repolarization
heterogeneity.
 A variety of extracardiac conditions (eg, hypokalemia, class III antiarrhythmic drugs) further reduce
repolarization reserve and increase the arrhythmic risk in patients with heart disease.
 In atrial fibrillation, the combined effects of reduced calcium current and increased potassium cur-
rent reduce action potential duration and refractory period and promote reentry, while hyperpola-
rizing the resting membrane potential, stabilizing reentrant rotors.

INTRODUCTION shorten the cardiomyocyte refractory period to

Potassium channels are substantially altered in
cardiovascular diseases (for an overview, see
Table1). Teleologically, the types of potassium
channel remodeling could be classified into 2 gen-
eral secondary categories. The first type of remod-
eling, occurring in the ventricles with heart failure
(HF), aims to prolong the action potential (AP) to in-
crease calcium entry into the cytoplasm and
compensate cardiomyocyte contraction. The sec-
ond type of remodeling process, typically occur-
ring in atria during atrial fibrillation (AF), aims to
allow cardiomyocytes to sustain very high activa-
tion rates. These pathophysiologic processes are
complex and include redundancy and negative
feedback. Although apparently designed to main-
tain cardiac homeostasis, they also induce elec-
trophysiologic alterations that lead to potentially
serious arrhythmias. Therefore, understanding
them is of value for cardiologists in daily practice.
In addition, K1 channel remodeling can be
induced by a host of other cardiac and extracar-
diac conditions.

Disclosures: V. Algalarrondo received scholarship funding from St. Jude Medical, Biotronik, Boston, Medtronic
and Sorin.
Funding Sources: Canadian Institutes of Health Research (6957 and 44365, S. Nattel) and Heart and Stroke
cardiacEP.theclinics.com

Foundation of Canada (S. Nattel). Fédération Française de Cardiologie (V. Algalarrondo).

a
Department of Medicine, Research Center, Montreal Heart Institute, University of Montreal, 5000 Belanger
Street East, Montreal, Quebec H1T 1C8, Canada; b Department of Pharmacology and Therapeutics, McGill Uni-
versity, 3655 Promenade Sir-William-Osler, Montréal, Québec H3G 1Y6, Canada; c Faculty of Medicine, Univer-
sity Duisburg-Essen, Hufelandstr. 55, Essen 45122, Germany
* Corresponding author. Montreal Heart Institute, University of Montreal, 5000 Belanger Street East, Mon-
treal, Quebec H1T 1C8, Canada.
E-mail address: stanley.nattel@icm-mhi.org

Card Electrophysiol Clin - (2016) -–-

http://dx.doi.org/10.1016/j.ccep.2016.01.006
1877-9182/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
2 Algalarrondo & Nattel

Table 1
Main disease-related modifications in KD currents in pathologic situations

Ventricular Atrial
Hypertrophy Heart Failure Myocardial Infarction Fibrillation
Current Density Exercise Overload Atria Ventricle Border Zone Normal Zone Atria PVa
APD 4 [ — [ [ [ Y Y
Ito 4 Y Y Y Y/4b Y Y Y
IKurc — — — — — — Y(?)d —
IK1 [ Y 4 Y Y Y [ Y
IKr 4 Y 4 4 Y Y 4 [
IKs 4 — Y Y Ye Y 4 [
IKss [ Y — 4 — — — —
Iff — — Y — — — — —
IK(Ach,c) c
— — — — — — [ —
IK(ATP) — — — — — [ ?d —
ISK — — — [ — [ 4 d
[
IK2P c
— — — — — — [ —

When discrepancies were noted across models, results documented on human samples are reported.
Abbreviations: [, current is increased; Y, current is decreased; 4, current is unchanged; APD, action potential duration;
Ito, transient outward K1 current; IK1, inward rectifier K1 current; IK2P, 2-pore-domain K1 current; IKur, ultrarapid rectifier
K current; IKr, delayed rectifier K1 current; IKs, slow rectifier K1 current; IKss, steady-state outward K1 current; IK(ACh),
1

acetylcholine-dependent K1 current; ISK, small calcium-activated K1 current; PV, pulmonary veins.

a
Compared with the left atrium.
b
Ito is reduced initially then return to normal within 2 months.
c
Atrial-specific currents.
d
Conflicting results.
e
ERG, KvLQT1 and minK are down regulated at day 2 after MI then ERG and KvLQT1 normalized at day 5 after MI,
whereas minK remains downregulated.
f
In sinoatrial node.
Data from Refs.7,12,30,73,74

Cardiac repolarization is in itself a complex pro-
cess. Current state of the art recognizes more than
10 different types of cardiac K1 currents, and
more than 20 types of K1 channels are known to
be expressed in the heart.1,2 Herein, we aim to
present the K1 channel remodeling processes in
4 common pathologic situations: cardiac hypertro-
phy, HF, myocardial infarction (MI), and AF. Spe-
cific regional remodeling profiles such as the
border zone of the MI scar and the pulmonary
veins (PVs) are also detailed.
OVERVIEW OF THE REMODELING PROCESSES
OF POTASSIUM CHANNELS IN PATHOLOGIC
SITUATIONS
Remodeling of K1 Currents Associated with
Hypertrophy
Hypertrophy
Cardiac hypertrophy is an adaptive response
to volume or pressure overload that occurs in
various pathologic situations (hypertension,
valvular ischemic or congenital heart diseases).
In hypertensive patients, there is a weak but signif-
icant correlation between QTc interval and blood
pressure and hypertrophic indices like the Cornell
voltage indices.3 It is also known that hypertensive
patients with prolonged QTc intervals are at
increased risk of cardiovascular morbidity and
mortality.4 In patients with successful antihyper-
tensive therapy, left ventricular mass reduction is
correlated with a decrease in the QTc interval5;
for a review, see Ref.6 In experimental models of
cardiac hypertrophy, prolongation of repolariza-
tion has been documented by longer QTc intervals
and AP durations (APDs). In patch clamp analysis,
total K1 current amplitudes are similar in cardiac
hypertrophy subjects and controls, but because
the membrane capacitance is larger in hypertro-
phy, the resulting K1 current densities are reduced
in cardiac hypertrophy.7 This phenomenon has
been documented for transient outward K1 cur-
rent (Ito), IK1 and slow rectifier K1 current (IKs):
compared with control, proteins and transcripts
 Potassium Channel Remodeling in Heart Disease
are unchanged in cardiac hypertrophy but current
densities are lower because the cells are larger (for
Ito: Kv4.2, Kv4.3 and KChIP2; for IK1: Kir2.1 and
Kir2.2).7 For IKs, downregulation is observed at
the transcript and the protein levels, especially in
the epicardium. Finally, Iss amplitude (noninacti-
vating current) is increased in cardiac hypertrophy
but not enough to restore a normal Iss current den-
sity.7 Together, these results suggest downregula-
tion of repolarizing K1 current densities in cardiac
hypertrophy owing to pressure overload. This
downregulation prolongs the APD; this could be
proarrhythmic and may explain, at least in part,
the correlation between hypertrophy, QTc interval,
and cardiovascular events.
Exercise-induced hypertrophy
In contrast with hypertrophy owing to chronic
pressure overload, exercise-induced hypertrophy
does not modify corrected QTc interval and QTc in-
terval dispersion in professional athletes.8 How-
ever, T wave morphology is commonly altered in
trained athletes, suggesting that repolarization is
remodeled in cardiac hypertrophy owing to exer-
cise. In 2010, Yang and colleagues9 reported an
extensive study of cardiac repolarization in a
swim training mouse model. Although myocytes
had a 17% increase in membrane capacitance
with exercise training, most of the electrical pa-
rameters were similar between trained mice and
controls: ECG intervals were similar and APDs
were unchanged. Using patch clamp methods,
the authors documented that K1 and Ca21 cur-
rents increased in parallel with each other, result-
ing in unchanged AP shapes in exercise. The
increased current densities were due to increased
transcription and translation of channel subunits.
The voltage-gated properties were unaltered. In
contrast with hypertrophy caused by pressure
overload, the repolarization remodeling in exercise
parallels cardiac hypertrophy and returns to
normal if training is stopped.
Remodeling of K1 Currents Associated with
Congestive Heart Failure
Between one-third and one-half of HF-related
deaths are caused by ventricular tachyarrhyth-
mias, and sudden death prevention is crucial in
HF. QTc prolongation occurs in HF10 and is asso-
ciated with an increased sudden death rate in
ischemic cardiomyopathy.11 In experimental HF
models, the APs are prolonged and early afterde-
polarization have been reproducibly documented
(Figs. 1A and 3A; for a review, see Ref.12). APD
prolongation is induced by downregulation of the
main “classical” cardiac K1 currents: Ito, slow
(IKS) and rapid delayed rectifier K1 current (IKr),
3
and IK1, although there are some discrepancies
among studies. These discrepancies could be
caused by differences in the HF models or to
time-course differences in electrophysiologic
remodeling after the onset of HF.13 Table 2 sum-
marizes the changes in messenger RNA (mRNA)
and protein expression in various models.
Because the classical K1 currents are downregu-
lated, other K1 currents could play an important
role in the repolarization of remodeled myocytes.
For instance, inhibition of the small conductance
Ca21-activated K1 current small calcium-
activated K1 current (ISK) has been recently re-
ported to prolong APD by 9% in failing human
hearts, suggesting a compensatory role.14 This
report supports previous results in HF rabbits, in
which increased cytosolic Ca21 in HF seems to
activate ISK, thus reducing APD and compensating
for the HF-induced reduction in repolarization
reserve (Fig. 2).14–16
Reduced repolarizing currents induce proarrhyth-
mic consequences in several ways. First, increased
duration of repolarization may induce early afterde-
polarizations (see Fig. 1A). Early afterdepolariza-
tions are triggered if AP is prolonged in the
specific voltage and time window that allows either
the late Ca21 current ICaL or the Na1 current INa to
reactivate and generate a new AP.12 In HF patients,
repolarization reserve is reduced and the addition of
class III antiarrhythmic drugs or hypokalemia may
trigger early afterdepolarizations and ventricular
tachyarrhythmias more easily. The downregulation
of inward rectifying IK1 current increases the mem-
brane resistance in the phase 4 of the AP, increasing
the risk that a delayed afterdepolarization will
generate an arrhythmia (see Fig. 1B).
Remodeling of K1 Currents Associated with
Myocardial Infarction
MI causes changes in K1 current expression, den-
sity and function. In most cases, the proarrhythmic
substrate in ischemic cardiomyopathy results from
a heterogeneous scar where islands of living cells,
called the border zone, are partially surrounded by
fibrotic tissue.
Remodeling in the myocardial infarction border
zone
Post MI border zone remodeling is characterized
by prolonged repolarization owing to global down-
regulation of K1 currents that promotes early after-
depolarizations (Fig. 3B; see Table 1). Remodeling
begins within the first days after MI and is
observed in both Purkinje cells and cardiomyo-
cytes. It tends to recover after the MI episode for
Ito, IKr, and IKs. The a-subunit expression for these
3 currents normalizes after the acute episode.
4 Algalarrondo & Nattel

Fig. 1. (A) Compared with normal ac-

tion potential (AP) (1), the reduced
K1 currents in ventricular pathology
prolong the action potential duration
(APD) (2); this may induce early after-
depolarizations (3) that can trigger an
ectopic AP (4). (B) Reduced IK1 (1)
reduces resting membrane conduc-
tance, which increases membrane
resistance R. Since the voltage change
(V) induced by any membrane current
(I) is influenced by the membrane
resistance (V 5 IR), any given depola-
rizing current during a delayed after-
depolarization will induce a stronger
depolarization in pathologic condi-
tion than in normal (2), thus more
easily reaching the threshold poten-
tial of the myocyte to trigger an
ectopic AP (3). (C) Propagation of
ectopic activations according to
timing and APD variability. APDs in
3 cells (from 1 to 3) at 4 different
ectopic beat coupling intervals (from
A to D) are represented. If AP vari-
ability is high as often occurs in dis-
ease states (lower panel), premature
beats with coupling conditions B
and C arrive when some cell(s) are
refractory whereas other(s) are
available for activation, which may
induce unidirectional block and
reentry (asterisk). AERP, atrial effec-
tive refractory period; DAD, de-
layed afterdepolarization; EAD, early
afterdepolarization.

Table 2
Changes reported in mRNA and protein expression of KD currents in heart failure

Reference Subunit mRNA Changes Model/Remarks

Kääb et al,75 1998 Kv4.3 Y; HERG, Kv1.4, Kir2.1 4 Human heart
Wang et al,76 1998 Kir2.1, Kir2.2, Kir2.3 4 Human heart
Borlak and Thum,77 2003 Kv4.3, Kv1.5, K2P 1.1, Kir2.1, Kir3.4, Human heart
Kir6.2 Y; ERG 4; KvLQT1, Mink [
Zicha et al,78 2004 Kv4.3 Y; KChiP2 4 Human and dog hearts, proteins
correspond with mRNA
Akar et al,79 2005 Kv4.3 Y; KChiP2, KvLQT1, Mink, Dog heart; proteins correspond with
Kir2.1 4; Kv1.4, ERG [ mRNA but not to current
Rose et al,80 2005 Kv1.4, Kv4.2, KChIP2, Kir2.1 Y; Kv4.3, Tachypacing in rabbit; proteins:
ERG, KvLQT1, Mink 4 Kv1.4, Kv4.2, Kv4.3, KChIP2, Kir2.1
KvLQT1 4
Tsuji et al,41 2006 Kv1.4, Kv4.3, KvLQT1, minK Y; AVB in rabbit; proteins correspond
ERG 4 with mRNA
Yang et al,81 2015 — Rat with AVF. proteins: SK3 [ SK2 4

Abbreviations: Y, decrease; [, increase; 4, no change; AVB, atrioventricular block; AVF, arteriovenous fistula; mRNA,
messenger RNA.
Data from Refs.41,75–81
Potassium Channel Remodeling in Heart Disease 5

Fig. 2. Consequences of repolariza-

tion reserve on action potentials
(APs) and the associated surface elec-
trocardiograph (ECG). Under normal
conditions (A), individual reductions
of IKr or IKs induce only a minor pro-
longation of AP duration (APD) and
QT interval because of repolarization
reserve. (B) When this compensatory
effect is impaired (eg, in heart disease
with reduced IKr and/or IKs) (C), the
APD prolongation is enhanced, as is
as the risk of early after depolariza-
tions (dashed red line).

Fig. 3. Schematic summarizing the

principal alterations in the action po-
tential (AP) and corresponding K1
currents alterations in 4 situations:
heart failure (HF; A), border zone of
the myocardial infarction (MI; B),
atrial fibrillation (AF; C) and pulmo-
nary veins (D). Blue numbers indicate
AP phases. Red are changes in pathol-
ogy (A–C) or differences in pulmonary
vein versus atrium (D).
6 Algalarrondo & Nattel
However, this recovery is incomplete and the b-
subunit minK remains downregulated in the longer
term, which would accelerate IKs inactivation and
decrease its amplitude (for a review see Ref.12).
Remodeling in the normal zones of hearts with
prior myocardial infarction
Studies of zones remote from the MI scar zone
have been performed in small animal models (rab-
bit and rat). APD prolongation leads to triggered
activity and spatial refractoriness heterogeneity.
As in the border zone, APD prolongation is caused
by downregulation of the main K1 currents. Math-
ematical modeling of border and normal zones in
MI ventricles highlights the interplay between the
2 zones and the crucial role of refractoriness het-
erogeneity in generating a substrate for arrhythmia
(Fig. 1C).17
Remodeling of K1 Currents Associated with
Atrial Fibrillation
Remodeling of K1 currents in atrial fibrillation
AF, the most common sustained cardiac
arrhythmia, results from a variety of conditions,
like ectopic activity in the PVs and atrial remodel-
ing in HF and hypertension. By itself, AF induces
electrical remodeling that shortens atrial refractory
periods and promotes AF (“AF begets AF”18). This
remodeling has been reproduced in experimental
models by performing high-rate atrial pacing. It
has been shown that K1 current changes play a
key role in the pathogenesis of AF. The remodeling
process begins within the first day after the onset
of AF and results in complex modifications of the
atrial AP (see Fig. 3C). During the initial phase of
repolarization (phase 1), APD is prolonged
because of the downregulation of Ito; ultrarapid
rectifier K1 current (IKur) was documented as
reduced or unchanged.12 Thereafter, the
combining effects of stable IKr/IKs, decreased ICaL
and increased IK1/acetylcholine-dependent K1
current [IK(Ach)]/2-pore-domain K1 current (IK2P)
induce a shortening of phases 2 and 3 of the AP.
IK1 increases also occur, paralleling upregulation
of Kir2.1 (KCNJ2) mRNA and protein. This upregu-
lation is associated with a decreased expression
of microRNAs 1 and 26 (miR-1 and miR-26) both
in humans and in experimental models.19,20 Simi-
larly, decreases in Ito density parallel the downre-
gulation of Kv4.3 mRNA and protein. Several
reports in experimental models suggest that
reduced miR-1 and increased miR-301a may
decrease the expression of KCND2 (Kv4.2), and
that increased miR-133 may reduce the expres-
sion of KChIP2 (for further reviews, see Refs.2,21).
The upregulation of IK(Ach) has been docu-
mented both in experimental models and in AF
patients.22 This increased IK(Ach) is caused by acti-
vation of the basal current (with downregulation of
the carbachol-induced current); Kv3.1 mRNA and
protein remain stable. Functional upregulation of
constitutive IK(Ach) seems to be caused by changes
in regulation by protein kinase C isoforms.23
Two-pore domain K1 channels (K2P) have been
recently identified as potential contributors to AF
pathophysiology. Expressed mostly in the atria,
these channels are regulated by various factors,
including lipids, pH, temperature, or membrane
stretch (but not voltage) and thus they conduct a
background current throughout the AP. The elec-
trophysiologic role of the cardiac K2P channel
K2P3.1 was first characterized in mice.24 Recently,
Schmidt and colleagues25 documented that
K2P3.1 transcripts, protein, and the corresponding
IK2P current are upregulated in the atria of patients
with chronic AF, contributing to AP abbreviation.
The contribution of small conductance calcium-
activated potassium channels in AF is still contro-
versial. It was first documented that increased ISK
was associated with arrhythmia and that pharma-
cologic inhibition of ISK was antiarrhythmic in
experimental models.26,27 In subsequent reports,
however, ISK inhibition did not modify AP shape
and the expression of SK2 and SK3 subunits
was reduced in human AF atria.27 Therefore, the
precise role of ISK in human AF remains to be
clarified.
Remodeling of K1 currents in pulmonary veins
Following the observations from Haı̈ssaguerre and
colleagues28 of the crucial role of PVs in the initia-
tion of AF, basic research characterized further the
electrophysiology of the myocardial sleeves in
PVs.29,30 Anatomically, myocardial fibers extend
from left atria to PVs for 1 to 3 cm, with a specific
structure that transits from a linear to a circular or-
ganization. At the cellular level, PV cardio-
myocytes have distinct properties, including
decreased phase 0 upstroke velocity and short
APD, and the fibers have a specific organization
(Fig. 3D).29–32 PV sleeve cardiomyocytes also
have small background IK1 that could lead to de-
polarization and spontaneous activity.30,33
Furthermore, as compared with the left atrium,
PVs show lower expression of Kir3.1 and Kir3.4
that underlie IK(Ach). This K1 channel subunit profile
is associated with lower resting vagal tone at
baseline, greater response to vagal stimulation,
and shorter refractory periods in PVs than in left
atrium.34 The intrinsic ion channel and AP proper-
ties of PVs make them more susceptible to
reentrant arrhythmias. With remodeling, the short
PV AP becomes even shorter; however,
remodeling-induced increases in IK1 should
 Potassium Channel Remodeling in Heart Disease
restore the intrinsically smaller resting potential in
PV cells. Overall, AF-related tachycardia remodel-
ing decreases the AP differences between PV and
left atrial cardiomyocytes and in the absence of
other cardiac pathology the PVs do not play a cen-
tral role in the AF promotion caused by atrial tachy-
cardia remodeling.35
KD CHANNEL REMODELING:
TRANSLATIONAL INTEREST AND CLINICAL
IMPORTANCE
Hypokalemia and K1 Currents in Heart
Disease Patients
Hypokalemia ([K1]<3.6 mmol/L) is a common situ-
ation in daily clinical practice that is associated
with increased morbidity and mortality in patients
with heart diseases like hypertension, MI, resusci-
tation from out-of-hospital cardiac arrest, and
HF.36,37 Whereas low [K1] should enhance extra-
cellular/intracellular K1 gradient, thus increasing
K1 currents, the main effect of hypokalemia’s is
to prolong the QTc interval and APD. This prolon-
gation is caused by hypokalemia-induced reduc-
tions in multiple K1 currents including IKr, IK1,
and Ito. Recently, it was demonstrated that down-
regulation of IKr in hypokalemia is caused, at least
in part, by accelerated internalization and degra-
dation of hERG channels.38 Furthermore, hypoka-
lemia downregulates the Na1–K1 ATPase pump
and increases [Na1]i, which leads to increased
[Ca21]i via activation of the Na1/Ca21 exchanger.
Low [K1]e correspondingly increases the effects
of class III antiarrhythmic drugs by reducing repo-
larization reserve; conversely, high [K1]e protects
against drug-induced torsades de pointes. The
combined proarrhythmic effects of electrolyte
imbalance and/or class III antiarrhythmic agents
multiply the risk of life-threatening arrhythmia if
they occur on top of a predisposed substrate
with reduced repolarization reserve.
Repolarization Reserve
The term “repolarization reserve” refers to the abil-
ity of cardiomyocytes to compensate for the loss
of a repolarizing current by recruiting another one
and thus to minimize the APD prolongation
induced by this loss.39 Repolarization reserve
may result in limited alterations in the AP with K1
channel block, and the surface ECG could be un-
changed compared with normal. However, if this
compensatory mechanism is lost or overridden
by additional repolarization abnormalities, the
resulting effect on the AP, the ECG, and finally
the cardiac arrhythmic risk could be exaggerated
(see Fig. 2). Downregulation of K1 currents and
associated repolarization reserve has been
7
documented in HF,40,41 consistent with the delete-
rious effect of the IKr blocker sotalol in patients
with HF in the Survival With ORal D-sotalol
(SWORD) trial42 and the increased proarrhythmic
risk with sotalol in HF.43 The increased predisposi-
tion to excess APD prolongation with class III
agents may occur without any APD prolongation
at baseline.36 Practically, loss of repolarization
reserve could be detected by recording ECGs
and measuring QTc intervals after the initiation of
class III antiarrhythmic drugs, possibly within a
few hours of the first oral dose. Another phenome-
non that should be considered in the adverse
event risk of class III antiarrhythmic drugs is their
“reverse use dependency.” This “reverse use de-
pendency” means that the APD prolonging effect
is greater for low cardiac frequencies, which in-
creases the risk of EAD-triggered arrhythmia with
bradycardia (for a review see Ref.44).
Specific Targets in Atrial Fibrillation
The upregulation of K1 currents in AF promotes
the arrhythmia and may contribute to its increasing
resistance to drug therapy over time, but may also
create opportunities for new pharmacologic ap-
proaches. In particular, drugs that inhibit inward-
rectifier K1 currents may be particularly interesting
in view of their role in AF perpetuation.45 On the
other hand, downregulation of ionic currents like
IKur may limit the value of targeting them in AF.45
PHARMACOLOGIC MODULATION OF KD
CHANNELS IN HEART DISEASE PATIENTS
Reentry is a crucial arrhythmic mechanism.
Because short refractory periods increase the like-
lihood of reentry, it has long been recognized that
drugs that prolong APD and refractory periods by
blocking K1 channels have antiarrhythmic effects
against reentry. Such drugs were allocated to
class III of the Singh and Vaughan Williams46 anti-
arrhythmic drug classification. After the Cardiac
Arrhythmia Suppression Trial (CAST), class III
agents were widely studied to treat patients with
significant heart diseases. Great successes, but
also great failures, have been recorded in this field
of research.
Amiodarone
Amiodarone blocks IKr and IKs to prolong the APD
(class III action),47 but also blocks Na1 channels to
reduce conduction velocities (class I action),48 has
a noncompetitive blocking effect on b receptors
(class II effect)49 and inhibits ICaL (class IV
action).50 These multiple blocking effects likely
contribute to its clinical efficacy and safety.
8 Algalarrondo & Nattel
Clinically, cardiac side effects like torsades de
pointes or HF worsening are unusual, which has
made amiodarone a first-line antiarrhythmic drug
to treat HF patients, illustrating the notion that mul-
tiple channel blockers may have increased safety
in patients with remodeling-related decreases in
repolarization reserve. Clinical efficacy was specif-
ically reported in the AF treatment of HF patients.51
In patients with a high risk of sudden cardiac
death, amiodarone does not prevent sudden
death per se; however, in implantable cardi-
overter–defibrillator carriers, amiodarone plus b-
blockers prevent shocks with greater efficacy
than sotalol or b-blockers alone.
Other Class III Antiarrhythmic Drugs and Heart
Disease
Available class III anti arrhythmic agents include
ibutilide, dofetilide, and sotalol. All block IKr, pro-
longing effective refractory periods with minimal
effects on conduction velocity, and thereby sup-
press reentry.52–56 They also, however, carry a
risk of torsades de pointes (incidence 2.4% for
sotalol, 3.6%–8.3% for ibutilide, and 1%–3% for
dofetilide), which is increased in the presence of
heart disease.45 Predisposing factors for drug-
induced torsades de pointes include female sex,
high drug doses, HF, recent cardioversion, hypo-
kalemia, bradycardia, and elevated baseline
serum creatinine level.57
Sotalol is a mixed class III and class II drug. The
class II action is advantageous to allow for rate
control in addition to the rhythm control effect
owing to class III properties. However, the brady-
cardic action of sotalol may increase the risk of
torsades de pointes. Sotalol may also be useful
to reduce the number of shocks in implantable
cardioverter–defibrillator carriers. Ibutilide was
constructed by comparing sotalol with other b-
blockers and with clofilium phosphate, another
class III antiarrhythmic agent.58 Intravenous ibuti-
lide is used to cardiovert AF and atrial flutter; the
risk of ibutilide-induced long QT syndrome is
enhanced in HF patients.56 Because of the risk of
torsades de pointes with dofetilide, only certified
physicians are authorized to prescribe the drug;
initiation is usually performed in hospital, which
limits its clinical use.
Other Multichannel Blockers and Heart
Diseases
Dronedarone
Dronedarone was constructed on the basis of the
amiodarone structure, designed to retain similar
efficacy while avoiding the leading type of amio-
darone side effect (thyroid disorders). Like
amiodarone, dronedarone blocks INa, ICaL, IKr, IKs,
Ito, IK(ACh), and b-adrenergic receptors59,60 Clini-
cally, the drug has moderate efficacy to maintain
sinus rhythm in AF patients and clearly inferior ef-
ficacy compared to amiodarone. Clinical studies
that included significant numbers of HF patients
(European Trial of Dronedarone in Moderate to Se-
vere Congestive Heart Failure [ANDROMEDA] and
Permanent Atrial Fibrillation Outcome Study Using
Dronedarone on Top of Standard Therapy
[PALLAS]) were interrupted early because of
excess events in the dronedarone group,61 again
highlighting the risks of reduced repolarization
reserve with heart disease. As a consequence,
dronedarone should be avoided for patients with
significant cardiovascular disease.62
Vernakalant
Vernakalant is a multicurrent blocker that was
developed as an atrial selective antiarrhythmic
agent.63 The electrophysiologic profile of vernaka-
lant includes inhibition of IKur, Ito, IKr, IK(ACh), and
INa.64 Vernakalant modestly increases the QTc in-
terval and is contraindicated in patients with a
long QTc.65–67 Current clinical use only involves
intravenous administration to convert AF. The
only clinical report on patients with heart diseases
involved patients undergoing cardiac surgery and
vernakalant was safe.68
Ranolazine
Ranolazine was initially described as a late Na1
current blocker and was primarily evaluated to
treat chronic angina. However, experimental and
clinical studies showed that ranolazine had an
interesting electrophysiologic profile and could
be potentially helpful to treat AF (for a review see
Ref.69). Ranolazine prolongs atrial APD and refrac-
tory periods but does not prolong ventricular repo-
larization in experimental models of hypertrophy
and CHF.56 Ranolazine is a multichannel blocker
that inhibits (peak and late) INa, ICaL, Na1/Ca21
exchanger, IKr, and stabilizes RyR2.70,71 Ranola-
zine was recently tested in a reduced-dose combi-
nation with dronedarone; the combination was
found to have synergistic efficacy with low toxicity
in AF patients.72
SUMMARY
Heart disease produces substantial remodeling of
K1 channels that in general promotes arrhythmia
occurrence. In the case of ventricular arrhythmias,
K1 channel remodeling contributes to the
arrhythmic risk and increases vulnerability to
torsades de pointes with K1 channel inhibiting
drugs. Atrial K1 channel remodeling caused by
AF promotes arrhythmia stability and presents
 Potassium Channel Remodeling in Heart Disease
opportunities for the development of new drugs
targeting atrial inward rectifier K1 currents.
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