REVIEWS

Innovative approaches to
anti-arrhythmic drug therapy
Stanley Nattel* and Leif Carlsson‡
Abstract | Normal cardiac function requires an appropriate and regular beating rate
(cardiac rhythm). When the heart rhythm is too fast or too slow, cardiac function can be
impaired, with derangements that vary from mild symptoms to life-threatening
complications. Irregularities, particularly those involving excessively fast or slow rates,
constitute cardiac ‘arrhythmias’. In the past, drug treatment of cardiac arrhythmias has
proven difficult, both because of inadequate effectiveness and a risk of serious
complications. However, a variety of recent advances have opened up exciting possibilities
for the development of novel and superior approaches to arrhythmia therapy. This article
will review recent progress and future prospects for treating two particularly important
cardiac arrhythmias: atrial fibrillation and ventricular fibrillation.

*Department of Medicine
and Research Center,
Montreal Heart Institute
and Université de Montréal,
5000 Belanger Street,
Montreal, Quebec,
Canada H1T 1C8.
‡
AstraZeneca Research
& Development,
Integrative Pharmacology,
Pepparedsleden 1,
S-431 83 Mölndal, Sweden.
Correspondence to S.N.:
e-mail:
stanley.nattel@icm-mhi.org
doi:10.1038/nrd2112
The normal heart beats approximately 100,000 times a
day, with beating rates finely tuned to the body’s needs.
When the beating rate is inappropriately rapid or slow
because of abnormalities in cardiac rhythm referred to as
‘cardiac arrhythmias’, cardiac function can be impaired,
producing derangements varying from mild symptoms
to severe life-threatening complications.
Two particularly important cardiac arrhythmias
with major clinical implications are atrial fibrillation
(AF) and ventricular fibrillation (VF) (FIG. 1). AF is the
most common arrhythmia in the population1,2, and the
complex mechanisms leading to abnormal firing in AF
are being rapidly elucidated3. Its age-related occurrence
rate is growing alarmingly with the ageing of the popula-
tion, and it is estimated that if present trends continue
more than 15 million Americans will be affected by AF
by 20504. It is also a common identifiable cause of stroke
(the single most common factor in stroke of the elderly)
and is associated with particularly severe strokes5. VF is
the most common cause of sudden cardiac death, and is
estimated to kill about 600,000 individuals per year in
Europe and the United States combined.
Anti-arrhythmic drugs have been used for more than
a hundred years, ever since quinidine was identified as
the active ingredient in Cinchona bark and subsequently
achieved widespread use in the 1920s6. Currently avail-
able anti-arrhythmic drug options include less than a
dozen rather old agents, the majority of which were spe-
cifically designed to target ion channels, with the most
recent launch more than 5 years ago. Anti-arrhythmic
drug use has decreased over the past 15 years because
of problems with side effects, particularly a paradoxi-
cal capacity to create more serious rhythm disorders
than the ones being treated, a phenomenon called ‘pro-
arrhythmia’6. Pro-arrhythmia is largely due to powerful
effects of the drugs on ion channels, often in cardiac
regions other than the arrhythmic zone being treated,
which create unexpected derangements in the presence
of a vulnerable substrate and induce rhythm instability.
Because of the potentially devastating effect of
arrhythmias, even low-probability events that occur
in predisposed individuals at crucial times can be very
dangerous, and pro-arrhythmic potential is a serious
limitation of presently used anti-arrhythmic agents.
There is therefore a major unmet need for drugs that
will control arrhythmias more safely and effectively. New
developments in our understanding of the molecular
and biophysical factors controlling cardiac rhythm — as
well as rapidly advancing approaches to high-through-
put screening (HTS) of molecular libraries, intelligent
chemical modification of substance structure to achieve
desired profiles of action, and cell and gene therapy
— are creating exciting opportunities in anti-arrhythmic
therapeutic innovation. This paper reviews emerging
findings that promise the development of new types of
safer and more effective anti-arrhythmic compounds,
addressing in particular drugs that target the two very
important arrhythmias, AF and VF, illustrated in FIG. 1.
Key basic concepts
The cellular basis of cardiac electrical activity is the car-
diac action potential (AP), which is based on ion fluxes

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 REVIEWS

through specific membrane structures, particularly ion
channels (BOX 1). The ‘firing’ or depolarization of cardiac
cells and closely associated cardiac electrical conduction
depends on the movement of positive ions into the cell
(Na+ for atrial and ventricular tissue, Ca2+ for nodal
structures such as the sino-atrial node (SAN) and the
atrioventricular (AV) node). Once a cardiac cell is fired
by being depolarized from its normally negative resting
a Normal heart
SAN LA AV node
0 mV SAN RA
mV
intracellular potential to a positive value (causing a phase
of the AP called ‘phase 0’), it goes through a series of reg-
ulated repolarizing steps (AP phases 1 and 3), separated
by a relatively flat phase of the AP (phase 2), to get back
to its resting potential (BOX 1). Cardiac cells are gener-
ally inexcitable once they have fired, and the time taken
from initial depolarization to repolarization (called AP
duration (APD)) imposes a limit (called the refractory
period (RP)) on how soon a cell can be re-excited. APD
is controlled by the rate of repolarization, which depends
on the balance between inward movement of Na+ and
Ca2+ that tends to keep the cell depolarized and outward
movement of K+ through a series of highly specialized

mV
0 mV channels with typical time-dependent opening and
–50 –60 closing properties.
The underlying cause of cardiac arrhythmias is
AV node
Atrium
abnormal impulse formation or impulse propagation
Atrium Ventricle (FIG. 2) resulting from defective (overactive or underac-
30 mV 30 mV tive) function of cardiac ion channels and exchangers.
mV

mV Both causes can involve abnormal ion channel func-

RV LV
–70 –80
Ventricle
1 second
b Atrial fibrillation c Ventricular fibrillation
Figure 1 | Electrical functioning of the heart. a | Normal heart. The heart has its
own pacemaker: the sino-atrial node (SAN), which produces regular electrical impulses
at an appropriate rate (normally 60–100 per min, but faster in situations of stress). The
impulse spreads across the right atrium (RA) and left atrium (LA) and towards the atrio-
ventricular node (AV node), where its velocity is reduced before passing on to the left
(LV) and right (RV) ventricles, in which contraction and therefore ventricular pumping
is triggered. Representative action potentials are shown from SAN and atria (left) and
from AV node and ventricles (right), respectively. b | Atrial fibrillation. The upper
cardiac chambers (atria) can develop sustained, very rapid (400–600 per min) and
irregular firing called atrial fibrillation (AF; for a detailed discussion, see REF. 1). These
waves of activity bombard the AV node, which filters the impulses, but they still reach
the ventricles at an inappropriately rapid rate (typically about 150 per min). Untreated,
the maintenance of such a rapid rate is likely to cause the heart to fail over time. In
addition, the atria do not contract effectively during AF, resulting in inadequate
ventricular filling and a coagulation-favouring state, increasing the chances that a clot
will dislodge and go to the brain (causing a stroke) or to other vital organs. c | Ventricular
fibrillation. Ventricular fibrillation (VF) resembles AF in producing rapid, irregular
waves that control ventricular activity. However, unlike AF, against which the ventricles
are protected by the filtering function of the AV node, VF directly fires the ventricles at
400—600 per min. Such rapid activity is incompatible with effective cardiac pumping,
and VF is rapidly lethal if not arrested. The most common explanation of both VF and
AF is multiple simultaneous functional re-entry waves (for a presentation of the
mechanism of re-entry, see FIG. 3).
tion and defective intracellular ion handling that can
accelerate or retard diastolic depolarization, produce
inward currents that generate after-depolarizations or
create conditions for re-entry arrhythmias. Enhanced
automaticity (FIG. 2A) refers to a regional exaggeration
of normal cellular capacity to fire spontaneously, and
causes cardiac rhythm to be dictated by a site other
than the normal SAN pacemaker. After-depolarizations
are abnormal depolarizations falling during AP phases
2 or 3 (early after-depolarizations (EADs)), or phase
4 (delayed after-depolarizations (DADs)) (FIG. 2B,C).
EADs are caused by factors that impair repolariza-
tion, allowing for re-activation of inward currents that
depolarize the cell prematurely. DADs are caused by
abnormal Ca2+ leakage from subcellular stores during
the resting phase (phase 4), which causes enhanced
movement of Na+ into the cell in exchange for the excess
Ca2+. Re-entry (FIG. 3) is akin to an electrical short-cir-
cuit that depends on the balance between refractory
and conduction properties. Most ion channels deter-
mining cardiac electrical activity have been molecularly
defined and the crucial ion currents involved in vari-
ous forms of cardiac arrhythmias are largely known7,
as are the mechanisms by which presently used anti-
arrhythmic agents work 8 (FIG. 4). If novel candidate
currents for anti-arrhythmic action can be established,
automated HTS methods can identify potent and selec-
tive blockers from small-molecule libraries9. The key
question that has to be answered in order to use this
powerful technology is: which ion channels are the
best candidates for new anti-arrhythmic drug devel-
opment? In the discussion below, we present a number
of promising new targets, including ion channels that
can be specifically targeted in the atria, ion channels
that are specifically involved in triggering ventricular
arrhythmias due to acute myocardial ischaemia, and
ion channels that generate or modulate spontane-
ous activity. We also outline the lessons that can be
learned from inherited arrhythmia syndromes, and
briefly discuss potential alternative strategies such as
gene therapy and ‘upstream therapy’ — the prevention

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Box 1 | The action potential and ion currents during depolarization

The action potential (AP; red line), here depicted for a
typical atrial or ventricular cell, reflects the changing Ito↑
Early
electrical potential differences across cardiac cell repolarization Plateau (2)
membranes as a function of time, and is controlled by (1) ICaL↓
the flow of ions through ion channels (grey boxes with IKur↑
IKs↑
arrow up: outward currents; yellow boxes with arrow 0
down: inward currents). In the rested state (diastole, IKr↑
phase 4), ion pumps maintain a higher outside INa↓
concentration of Na+ and Ca2+ and a higher inside

mV
concentration of K+. The cell is impermeable to Na+ and Final
Ca2+, but is permeable to K+ through a channel Upstroke IKACh↑ repolarization (3)
+
(0)
designated IK1. As a result, positively charged K ions If↓
IK1↑
flow slowly out of the cell, keeping the interior
IKACh↑ Pacemaker
negative. When the membrane potential reaches a function
crucial threshold voltage, the cells ‘fire’ as positive ions IK1↑
(Na+ in the case of atrium and ventricle, Ca2+ in the APD
–80
case of the sino-atrial and atrioventricular nodes) Resting
NCX↓
(4) 0.2 seconds
enter the cell and rapidly bring the cell to a
‘depolarized’, positive potential (a process known as IK1
the AP upstroke or AP phase 0). The large current (INa) INa
through Na+ channels provides the electrical energy Ito
IKur
for rapid conduction in the mammalian heart. ICaL
2+
Following depolarization, Ca enters the cell through IKr
the L-type Ca2+-channel (ICaL), helping the cell to IKs
remain depolarized after initial depolarization and NCX
If
inducing mechanical contraction. During the ‘plateau’ IKACh
2+ +
phase of the AP (phase 2), inward Ca and outward K
currents are relatively balanced. To bring the cell back
to its resting state (‘repolarization’), an outward flow of K+ has to occur and is produced by a series of K+ currents known
by their time-dependent properties as transient-outward (Ito) and ultra-rapid (IKur), rapid (IKr), and slow (IKs) delayed-
rectifier currents. Rapidly activating K+ currents such as Ito and IKur are responsible for very rapid initial repolarization
(phase 1), whereas slower components (IKr and IKs) primarily determine terminal repolarization (phase 3), which brings
the cell back to its resting state. The time elapsed between AP upstroke and the return to the resting potential is
referred to as AP duration (APD; green bracket). Cells are unable to manifest a normal AP upstroke during the
depolarized phase of the AP, a period of relative inexcitability called the refractory period, corresponding roughly to the
APD. Some cells have a ‘pacemaker current’, If, allowing them to depolarize gradually during phase 4 to ‘threshold’,
causing repetitive spontaneous firing at a frequency characteristic of the tissue. The extra Na+ and Ca2+ which have
entered the cell during the AP are extruded (and the K+ which has left the cell is brought back in) by exchanging
intracellular Na+ for extracellular K+ (through the Na+,K+-pump) and Na+ for Ca2+ (by an exchanger called the Na+,Ca2+-
exchanger (NCX)). The acetylcholine-regulated K+ current IKACh is an inward rectifier current with time and voltage
dependent properties roughly similar to those of IK1. The timing of each current in relation to the AP is shown in the
schematic below.

of arrhythmogenic remodelling. A list of new anti-
arrhythmic agents, along with molecular structures,
target, therapeutic indication, stage of development
and manufacturer, is provided in TABLE 1.
Atrial-selective drug targets
The most common mechanism of AF is complex atrial
reentry1 (FIG. 3). An effective way to prevent or terminate
re-entry is to increase the RP. The RP can be increased by
drugs that inhibit K+-channels, making cells take longer
to repolarize to their rested state, and the drugs that
have traditionally been used to prolong the RP (such as
quinidine, sotalol and dofetilide) target IKr6. The problem
with IKr as a target is that it is crucial for repolarization
in all parts of the heart, and in predisposed patients IKr
blockers destabilize ventricular repolarization and cause
potentially lethal EAD-related arrhythmias (FIG. 2C)10,11.
There has therefore been a search for newer agents with
atrial-selective actions.
One interesting potential target is IKur, carried by
Kv1.5 subunits (FIG. 4), which in humans has a significant
role in the atria12,13 but is absent in the ventricles13–15.
Its inhibition should delay atrial repolarization and RP
without affecting ventricular tissue (and therefore be
free of the risk of ventricular pro-arrhythmia). Many
pharmaceutical companies have developed IKur block-
ers16 and some compounds are approaching or have
entered clinical trials. One representative of this group is
AVE0118 (Sanofi-Aventis), which initially was believed
to be a specific IKur blocker but later found to block Ito
and IKACh as well. AVE0118 has shown excellent anti-
arrhythmic efficacy in a goat model of persistent AF17.
Another example that very recently entered clinical test-
ing is XEN-D0101 (Xention), which is highly selective
for IKur and has demonstrated anti-arrhythmic efficacy
in two canine AF models18,19.
A key issue will be whether IKur block effectively pro-
longs the atrial AP, because the AP changes induced by

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IKur block will predominantly delay early repolarization A Accelerated normal automaticity
(phases 1 and 2, BOX 1) and move the plateau (phase 2) to
a more positive potential. A more positive plateau activates
more IKr and consequently accelerates late repolarization
(phase 3). The acceleration of phase 3 can totally offset 0
the delaying of phases 1 and 2, causing no net AP pro-
longation20,21. However, in rapidly firing fibrillating tissue

mV
and with atrial remodelling the role of IKr is small and IKur
block prolongs the AP. Another issue is potential accessory
effects on non-cardiac tissue as Kv1.5 is found in vascu-
lar, neural and pancreatic tissues as well as the heart22–24. –80
However, no such effects have been seen in preclinical
studies and results in humans will be a crucial test. B Delayed after-depolarizations
Another potentially interesting target is the acetyl-
choline-related K+ current, IKACh (carried by Kir3.1/3.4
heterotetramers, FIG. 4). IKACh is normally small or absent
in the absence of the parasympathetic neurotransmitter 0
acetylcholine. When acetylcholine is released from para-
sympathetic nerves, it activates IKACh, which has strong
b

mV
atrial AP-shortening and AF-promoting effects. Recent
studies have shown that AF alters IKACh properties, caus-
ing the channel to open even in the absence of acetylcho-
a
line25,26 and resulting in APD abbreviation that promotes –80
AF27. IKACh is absent in the ventricles: blocking IKACh has no
effect on ventricular-cell currents or APs27. IKACh blockers C Early after-depolarizations
therefore might suppress AF without causing ventricular
pro-arrhythmia. Efforts to develop IKACh blockers are still
in their infancy, but one candidate molecular series is
being developed28 and is approaching clinical testing. 0
Na+-channel blockade is highly effective in terminat-
ing AF by causing primary re-entry waves to extinguish29.
RSD1235 (vernakalant; Cardiome) is a recently devel-
mV

oped atrial-selective agent30 that rapidly stops recent-

onset AF in ~50% of patients in clinical Phase II and
III studies31. Its mechanisms of action are incompletely
understood, but INa inhibition with favourable kinetics32
probably has an important role. AZD7009 (AstraZeneca)
is another atrial-selective agent with both Na +- and
K+-current blocking properties33, but it has been with-
drawn from development because of extra-cardiac side
effects. For a more detailed discussion of atrial-selective
and other new targets for AF, the interested reader is
referred to a recent review34.
Ischaemia-specific targets
Acute myocardial ischaemia causes highly arrhyth-
mogenic changes in cardiac electrical properties35,36
which strongly promote ventricular tachycardias and
ventricular fibrillation and lead to a high incidence of
sudden death in minutes to hours36.
In ischaemic tissue, APD is shortened, resting poten-
tial is reduced (causing INa inactivation and reducing the
energy available for impulse conduction) and cell-to-cell
coupling is impaired (FIG. 5). Attempts to prevent sud-
den death by suppressing premature beats that trigger
re-entry37,38 or by K+-channel blocking drugs that pre-
vent re-entry by increasing APD6,8 have failed. Efforts
have shifted to implantable cardioverter-defibrillator
devices in high-risk individuals39 and measures to com-
bat ischaemia (such as β-adrenoceptor blockers and
revascularization procedures)40.
–80
Figure 2 | Cellular mechanisms of abnormal impulse
formation and arrhythmia. A | Normal automaticity in a
spontaneously depolarizing pacemaker cell: the cell
reaches a critical threshold voltage (threshold potential,
red line), at which the Na+ current is strong enough to lead
to the initiation of an action potential (‘fire the cell’; solid
line). Accelerated normal automaticity causes a faster
spontaneous firing rate than normal and results when cells
increase their rate of depolarization and, as a consequence,
spontaneous pacemaker frequency (dashed line), such as
when local disease induces an increased If (see BOX 1).
B | After-depolarizations of a typical ventricular cell: after-
depolarizations are abnormal ‘hump-like’ depolarizations.
If they arise after the final repolarization of the cell they are
called delayed after-depolarizations (DADs; dashed line, a)
and are generally due to abnormal intracellular Ca2+ release
that results in an excessive inward current carried by the
Na+,Ca2+ exchanger. If the DAD is large enough to reach
threshold, it will cause abnormal extra beating (dashed
line, b) before the next expected action potential (solid
line). C | When after-depolarizations occur before
complete AP repolarization, they are called ‘early after-
depolarizations’ (EADs) and result from abnormalities in
repolarization that prolong the AP. APs of two cells are
shown: a cell (upper trace) that fails to repolarize,
generating repeated EADs that cause the adjacent cell
to fire repeatedly (lower trace).

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However, the occurrence of sudden arrhythmic death
due to acute myocardial ischaemia and consequent ven-
tricular fibrillation, particularly as an initial presenting
event, remains significant. Developments in our under-
standing of the mechanisms causing ischaemia-induced
electrical dysfunction and arrhythmias (FIG. 5) have
opened up some interesting new therapeutic possibilities.
The adenosine-triphosphate sensitive (KATP) K+ channel,
composed of the Kir6.2 and SUR2A subunits (FIG. 4), is a
metabolic sensor that opens during myocardial ischaemia,
and has a key role in ischaemic APD shortening41. KATP
has a complex role, mediating cardioprotective as well as
arrhythmogenic functions. Recent work has shown that
these actions can be dissociated, with cardioprotective
function mediated largely by a mitochondrial KATP chan-
nel and electrical changes due to a sarcolemmal chan-
nel42. Organic compounds (for example, HMR 1883 and
HMR1098/clamikalant; Sanofi-Aventis) selectively block
sarcolemmal KATP channels43, suppress ischaemia-induced
electrocardiographic changes44 and prevent associated
ventricular fibrillation45. Because of the selectivity of
their action for acutely ischaemic tissue, they are poten-
tially promising for the prevention of ischaemic sudden
arrhythmic death. If such compounds prove to be suf-
ficiently selective as to be both safe in relatively low-risk
patients and effective against ischaemic arrhythmias, they
could be given chronically to patients with coronary artery
disease in order to prevent ischaemia-induced malignant
arrhythmias should an ischaemic event ensue.
The Brugada syndrome is a familial condition that,
like acute myocardial ischaemia, involves elevation of
the ST segment on the electrocardiogram (reflecting
abnormal local repolarization; see also FIG. 6b) and
an increased risk of sudden death due to ventricular
fibrillation 46. As in acute myocardial ischaemia 47,
electrophysiological deterioration in the Brugada syn-
drome can be precipitated by Na+-channel blocking
drugs48. Many genotyped cases involve loss-of-func-
tion mutations in cardiac Na+ channels and it has been
suggested that a key pathophysiological event is very
rapid repolarization in the outer (epicardial) layer of
heart muscle, which has a very large Ito early in the
AP, in the face of reduced inward INa to keep the cell
depolarized49. Similar pathophysiology might occur
in acute ischaemia, and ventricular tachyarrhythmic
death in both acute ischaemia and Brugada syndrome
could be amenable to prevention by Ito blockers. At
present, no selective Ito blockers are available; however,
the development of compounds targeting the under-
lying Kv4.3–KChIP2 subunit complex could produce
interesting new therapeutic possibilities.
Finally, improved understanding of the basic mecha-
nisms of cell-to-cell coupling and their pharmacological
manipulation has yielded new approaches to ischaemia-
related uncoupling of intercellular communication.
Targets that control spontaneous activity
A number of specific cardiac currents are involved in
the generation or regulation of spontaneous activity and
abnormalities in these currents can cause abnormal local
cellular activity that generates arrhythmias (FIG. 2).
1038 | DECEMBER 2006 | VOLUME 5
© 2006 Nature Publishing Group
Re-entry
I
II
b d
0 II
mV
a c
–60
–80 RP I
Figure 3 | Re-entry. Re-entry as an electrical short-
circuit between two cells: re-entry depends on the
balance between refractory and conduction properties
of two adjacent tissue zones (I and II) that are
connected, as shown in the inset. The solid lines
represent action potential recordings (a and b,
respectively) from zones I (lower trace) and II (upper
trace) of the tissue without arrhythmia, and dashed
potentials show recording with a re-entrant extra beat.
Re-entry occurs when an impulse (b) leaves one cell (II
here) and arrives in another zone (I) before cells in the
latter zone have fully repolarized (and therefore are
refractory), setting up a delayed activation (c) of zone I
(red dashed line). If a cell in zone II has now recovered its
excitability, this action potential (c) can propagate to
initiate an action potential (d) in zone II. This process can
occur repeatedly, causing a sustained rapid rhythm
(‘tachycardia’). In order for this mechanism to be
maintained, the time for the impulse to traverse the
circuit has to be longer than the time required for cells
to regain excitability after initial firing as determined
by their refractory period (RP).
Hyperpolarization-activated nonselective cation chan-
nels. A K+ current showing time-dependent inactiva-
tion was initially believed to have a key role in cardiac
pacemaking, but subsequent studies suggested that the
current involved carries both Na+ and K+ in a relatively
non-selective fashion and is activated in a time-depend-
ent way at negative potentials50. Because of its unusual
ion-selectivity and voltage-dependent properties the
current was initially named If for ‘funny current’50. The
underlying channel subunits have been cloned and
named hyperpolarization-activated, cyclic nucleotide-
gated cation channel (HCN) subunits. Four isoforms are
known, with HCN4 being particularly important in car-
diac pacemaking51, although various ionic currents con-
tribute to pacemaking function52. Recently developed,
highly selective If inhibitors such as ivabradine (Servier)
(FIG. 4)53 might be useful for cardiac arrhythmias result-
ing from abnormally increased pacemaker function in
regions that do not normally pace the heart54.
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 REVIEWS

IKATP IKr IKs IKACh Ito IKur IK1 If

Na+

hERG KvLQT1 Kv4.3 Kv1.5 Kir2.1 HCN4

Kir6.2 Kir3.1 Kir3.4

MiRP1 KCR1 minK M2 G-protein KChIP2.2 MiRP1

SUR2A
K+ K+ K+ K+ K+ K+ K+ K+
Clamikalant NS1643 HMR-1556 NIP-151 XEN-D0101 (blocker) Ivabradine (blocker)
(blocker) (agonist) (blocker) (blocker) Phase I Phase III

L-364,373
(agonist)

Calstabin2
2+
SR Ca JTV519
RyR2 (stabilizer of
RyR channels)

RSD1235 (vernakalant)
(blocker) GsMTx4 Mibefradil Rotigaptide (agonist)
Phase III iv/II oral (blocker) (blocker) Phase II
INa + ICaT

Nav1.5 Cav3.1/3.2
Cytosol

β β SAC SAC ?
Gap junction Extracellular space
Na+ + Ca2+

Connexin
Connexon

Drug Preclinical Drug Clinical trials (phase indicated) Drug Withdrawn from market/clinical trials

Figure 4 | Ion currents, ion channel subunits and ion transporters implicated in arrhythmogenesis. Schematic of a
cardiac cell, depicting ion channels and ion transporters that are targeted by investigational drugs. SR, sarcoplasmic
reticulum; SAC, stretch activated channel.

Stretch-operated channels. The electrophysiological of stretch-activated cation channels61, was therefore a

characteristics of cardiomyocytes are sensitive to changes
in mechanical stress, and mechanical stimuli (such as
tissue stretch) can modulate electrical activity55,56. This
interrelationship, commonly called ‘mechanoelectri-
cal feedback’, might be involved in the triggering of
various atrial and ventricular tachyarrhythmias55,56.
For example, AF is often associated with atrial enlarge-
ment57–59. Furthermore, in patients with diminished
ventricular function, transient myocardial stretch can
elicit ventricular tachycardias and promote fibrillation.
Mechanoelectrical feedback involves several currents,
including cation fluxes across non-selective stretch-acti-
vated channels found in a variety of cardiac cell types60.
Exploration of stretch-activated channels as targets for
anti-arrhythmic therapy has until recently been hampered
by a lack of specific blockers or modulators. The isolation
of GsMTx4, a peptide from the venom of the tarantula
Grammostola spatulata, a selective and potent inhibitor
significant advance. The d-enantiomer is more resistant
to hydrolysis by endogenous proteases and possesses
identical pharmacological activity to the l-enantiomer62.
GsMTx4 is highly effective in suppressing AF promotion
by stretch in an isolated rabbit heart model, at concentra-
tions without effects on action potential characteristics
or refractoriness63. GsMTx4 inhibition of the stretch-
activated channel does not seem to involve traditional
lock-and-key protein-protein interactions, but more of
a bilayer-dependent mechanism that modifies channel
gating64. Stretch-activated channels are sensitive to the
local lipid environment, so increased membrane fluidity,
as occurs following acute addition of polyunsaturated
fatty acids, might attenuate stretch-induced vulnerability
to AF by altering physicochemical properties of cardiac
membranes. A protective effect of dietary fish oil against
AF in the rabbit atrial-stretch model has recently been
demonstrated65.

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Table 1a | New anti-arrhythmic drugs in development

Agent and chemical structure Mechanism Therapeutic Stage of Company Refs
of action implications/ development
indications
IKr/IKs Maintenance of SR Phase III Procter &
O N N CH3 blockade Gamble
N
O N O
Cl N

Azimilide

Multichannel Maintenance of SR Phase III Sanofi Aventis

blockade
O O
H
O N
N
S
HCL
O
O

Dronedarone

Multichannel Conversion of AF/ Phase II Sanofi Aventis

O blockade maintenance of SR
O N

O
HO
OH
O

SSR149744C

IKur/Ito/IKACh Conversion of AF Phase II Sanofi Aventis 17

CH3
H blockade
O N
O
O
N N
H

AVE0118

Multichannel Conversion of AF Phase II Solvay

COO–
blockade Pharmaceuticals
•
–OOC
H COOH
+
N N •2
HOOC
2
Tedisamil

Na+/atrial Conversion of AF/ Phase II/III Cardiome 30

O potassium maintenance of SR Pharma/Astellas
O channel Pharma
blockade

N OH

RSD1235
(Vernakalant)

AF, atrial fibrillation; SR, sinus rhythm.

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Table 1b | New anti-arrhythmic drugs in development

Agent and chemical structure Mechanism of Therapeutic Stage of Company Refs
action implications/ development
indications
Connexin Ventricular Phase II Wyeth/Zealand 84–86
O
H modulator arrhythmia Pharma
O N C
HO H3C
C NH2
O H
HN HN
O CH3
C C
H O O O
H N C C NH
N H

HO H

Rotigaptide

XEN-D0101 IKur blockade Maintenance of SR Phase I Xention

Structure not disclosed

JTV519 Promotes Animal studies Preclinical Japan Tobacco 18,19

Structure not disclosed calstabin 2– show efficacy in AF
RyR2 binding

NIP-151 IKACh blockade Maintenance of SR Preclinical Nissan 178

Structure not disclosed Pharmaceuticals

O SAN inhibitor SR control Phase III Servier 53

H3CO
OCH3
N N
H3CO CH3
OCH3
Ivabradine

GsMTx4 Blockade of Animal studies Preclinical 61

Polypeptide stretch-activated show efficacy in AF
channels
IKr activator Long QT syndrome Preclinical NeuroSearch AS 91
OH OH
H H
N N

CF3 CF3

NS1643

O IKs blockade Atrial arrhythmias Preclinical Sanofi-Aventis 103,104

S
F N
O
F O OH
F
O

HMR-1556

H3C IKs activator Long QT syndrome Preclinical Merck Research 92

O
N Labs

F N
H

L-364,373

AF, atrial fibrillation; SAN, sino-atrial node; SR, sinus rhythm

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a Loss of plateau dome b Normal cell-to-cell coupling hypertrophy, and inherited arrhythmogenic diseases
because of INa/Ito imbalance: such as catecholaminergic polymorphic ventricular
block Ito and/or IKATP tachycardia (CPVT)66. By promoting after-depolariza-
0 tions (FIG. 2B), Ca2+-handling abnormalities can lead to
arrhythmias including atrial and ventricular fibrillation.
Ca 2+ handling is a crucial and complex cardio-
myocyte function. Effective contraction requires rapid
mV

Impaired coupling in ischaemia

–60
–80
Cells depolarized by K+ loss
through IKATP: block IKATP Improve coupling with connexin activator
Figure 5 | Promising targets for ischaemia-selective anti-arrhythmics. a | Diagram of
a normal ventricular action potential (AP; grey) and an action potential affected by acute
myocardial ischaemia (dashed line). Acute ischaemia shortens the duration of the AP and
causes depolarization of the resting membrane potential. The ion channels that carry IKATP
and Ito are potential drug targets. IKATP has It is well-documented role in ischaemia-induced
intracellular K+ loss and AP abbreviation. The role of Ito in acute ischaemia is not fully
established, but based on related physiology in the Brugada syndrome it might also be an
interesting target for ischaemia-induced arrhythmias. b | Impaired cell-to-cell coupling
in ischaemia. Cells (depicted by red boxes) are connected with each other by specialized
gap junctions that maintain electrical continuity (top), allowing for the propagation of an
action potential between cells (direction of propagation shown by arrow). Coupling is
impaired by ischaemia, causing failure of propagation that results in an inability of the
propagating impulse to initiate effective action potentials (bottom), promoting impulse
blockade and the occurrence of re-entry. Connexin activators can reverse ischaemia-
induced coupling abnormalities, improving conduction and suppressing arrhythmias.
Targeting the Ca2+-handling machinery
Abnormalities in intracellular Ca2+ handling occur in a
range of arrhythmogenic conditions, including congestive
heart failure (CHF), ischaemic heart disease, myocardial
increases in free cytoplasmic Ca2+ concentration, but
effective relaxation requires rapid restoration of low
Ca2+ concentrations in diastole (the relaxed phase of the
cardiac cycle, corresponding roughly to AP phase 4).
Efficient Ca2+ handling is maintained by a complex set
of intracellular Ca2+ stores, transporters and channels.
Many membrane electrical functions are regulated by
Ca2+, so abnormalities in Ca2+ handling can be highly
arrhythmogenic. Key components of the Ca2+-handling
machinery include the sarcoplasmic reticulum (SR)
Ca2+-release channel or ryanodine receptor (the cardiac
form is known as RyR2), the RyR2-binding molecule
calstabin 2, the SR Ca2+-ATPase (the cardiac form is
known as SERCA2A) and the SERCA2A-regulatory
molecule phospholamban (for details, see BOX 2).
Calstabin 2 is a crucial modulator of RyR2 func-
tion (FIG. 4) and depletion of calstabin 2 from the RyR2
complex (as occurs in congestive heart failure) leads to
hyperactive RyRs and Ca2+ leak67,68. By contrast, strate-
gies that increase calstabin 2 binding attenuate Ca2+ leak,
inhibit DADs and suppress triggered arrhythmias69. The
1,4-benzothiazepine JTV519 (Japan Tobacco), which
promotes calstabin 2–RyR2 binding, reduces diastolic
Ca2+ leak, prevents adrenergically mediated polymor-
phic ventricular arrhythmias and sudden cardiac death
in calstabin 2+/– haplosufficient mice70,71. JTV519 also

a Long QT syndromes b Brugada syndrome

ECG ECG

ST segment

AP Epicardial
AP
1s
Arrhythmic beat

Endocardial
Epicardial

Figure 6 | Examples of genetically based arrhythmia syndromes. a | Long QT syndrome. Long QT syndromes cause
paroxysmal ventricular tachyarrhythmias of characteristic, polymorphic morphology (Torsades de Pointes, electrocardiogram
(ECG) in upper panel) by impairing repolarization and causing arrhythmogenic early after-depolarizations (EADs) and
ectopic beats (action potential (AP) recordings s in lower panel). b | Brugada syndrome. The top panel shows a typical
Brugada ECG. The horizontal green lines delineate the ‘ST segment’. The characteristic electrocardiographic ST segment
elevation (dashed line, as opposed to normal ECG depicted by the solid line) is believed to be due to rapid repolarization in
the Brugada syndrome of the outer (epicardial) layer of the heart (see lower panel, the Brugada syndrome epicardial AP is
shown by the dashed line; a normal epicardial AP is shown by the black line). Rapid epicardial repolarization in Brugada
syndrome patients results from the large epicardial Ito, which overpowers a diminished Na+ current caused by the Na+
channel loss-of-function mutation that underlies Brugada syndrome. Electrical current flows from normally repolarizing
inner-layer (endocardial, red line) cells to the early-repolarizing epicardium. The resulting large voltage gradient produces
depolarization and reactivation of the endocardial cell, causing extra beats that can initiate ventricular tachyarrhythmias90.

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Box 2 | Cardiac Ca2+ flux in health and disease

During depolarization of the cell membrane, calcium ICaL
Extracellular NCX
enters the cell via activated L-type Ca2+-channels. The Ca2+
2+ 2+
resulting Ca influx promotes intracellular Ca release
from subcellular stores in the sarcoplasmic reticulum
(SR) by Ca2+-induced Ca2+ release, which greatly
amplifies the initial signal118,119. Ca2+-induced Ca2+
release occurs via specialized Ca2+-release channels, also Na+
Ca2+ PKA
called ryanodine receptors (RyRs) because of their initial
identification via high-affinity binding of the toxin Calstabin 2 CamKII
PP1
ryanodine. Ca2+ release occurs via unitary events called RyR2
119 SERCA
‘sparks’, reflecting activation of clusters of RyRs . The
RyR (the cardiac form is RyR2) constitutes part of a large
macromolecular complex of key accessory proteins P –PLB P P PLB– P
including calmodulin, calstabin 2 (FKBP12.6), protein
2+
kinase A (PKA), Ca /calmodulin-dependent protein
kinase (CaMKII) and protein phosphatases 1 (PP1) and
Ca2+
2A120. Calmodulin is a key Ca2+-binding protein that
regulates the action of key intracellular enzymes such as
the kinase CaMKII and the protein phosphatase
calcineurin. Protein kinase A and CaMKII are both
stimulated by adrenergic activation and phosphorylate
key intracellular regulatory proteins. Calstabin 2 binds to Ca2+
and stabilizes the open and closed states of the RyR.
SR Ca2+ stores are determined by the rate of SR Ca2+
uptake and the rate of Ca2+ release. Ca2+ uptake occurs P –PLB P P PLB– P
via the SR Ca2+-ATP’ase, SERCA (cardiac form is
SERCA2A). SERCA function is negatively regulated by Cytosol SR PP1 SERCA
phospholamban (PLB), but PLB phosphorylation removes
2+
this inhibitory influence. Diastolic Ca leak from
dysfunctional RyRs causes a loss of SR Ca2+, reducing contractility, but might still facilitate delayed after-depolarizations
(DADs) by causing excess diastolic Ca2+ concentrations. In a seminal paper, Marx et al. suggested that in the failing heart RyR
‘hyperphosphorylation’ causes calstabin unbinding, increases RyR Ca2+ sensitivity and makes RyRs functionally ‘leaky’121. RyR
phosphorylation can result from PKA action at a specific serine120 or CaMKII-induced threonine-phosphorylation122.
Abnormalities in intracellular Ca2+ handling occurs in conditions such as congestive heart failure, ischaemic heart disease,
myocardial hypertrophy and atrial fibrillation, as well as in inherited arrhythmogenic diseases such as catecholaminergic
polymorphic ventricular tachycardia (CPVT) in which obvious structural heart disease is absent123. Spontaneous diastolic
Ca2+ release triggers Na+,Ca2+ exchange (NCX), which mitigates Ca2+ loading by extruding Ca2+ in exchange for extracellular
Na+. NCX carries three Na+-ions in for each single Ca2+ ion extruded, and therefore causes movement of one extra positive
ion into the cell for each functional cycle. This excess movement of positive ions into the cell depolarizes the cell
membrane, causing arrhythmic DADs as illustrated in FIG. 3. In addition, NCX activation by abnormal cellular Ca2+ handling
is believed to potentially participate in early after-depolarizations formation.

reduces AF inducibility in dogs with sterile pericardi-
tis72. Atrial cardiomyocytes from patients with chronic
AF or from dogs with pacing-induced AF show RyR2
hyperphosphorylation and calstabin 2 unbinding, which
are corrected by JTV51973. JTV519 might therefore be an
important potential lead structure for identification of
compounds targeting calstabin 2–RyR2 binding.
Another important enzyme which forms part of the
RyR2 macromolecular complex is the Ca2+/calmodulin-
dependent protein kinase (CaMKII), which has been
shown to contribute to arrhythmogenesis in conditions
such as Torsades de Pointes (TdP). TdP is a potentially life-
threatening ventricular arrhythmia that is associated with
abnormal repolarization, EADs and myocardial re-entry.
Because of the very rapid rate of TdP, it can cause ventricu-
lar ischaemia and/or irregular re-entry that degenerates
into ventricular fibrillation74. CaMKII increases L-type
Ca2+-channel open probability, potentially facilitating
channel reactivation that causes EADs, effects attenuated
by CaMKII inhibitors75,76. CaMKII inhibition therefore
constitutes a potential novel anti-arrhythmic strategy,
although we are not aware of effective and non-toxic lead
compounds presently under study.
Targeting intercellular coupling mechanisms
Gap junctions contain clusters of closely packed
hemichannel subunits that connect adjacent cells to
allow intercellular communication by the passage of ions
and small molecules, producing the continuous syncytial
function of myocardial tissue. The conducting structures
formed by oligomerization of transmembrane spanning
proteins are named connexins, six of which constitute
an individual connexon. Of >20 connexin genes in the
genome, connexins 43, 40 and 45 are the most abundantly
expressed in the myocardium. Connexin 43 dominates in
working ventricular and atrial myocytes. Connexin 40 is
also expressed in atrium, and along with connexin 45 in
conduction tissue. Changes in gap-junction organization,
expression and function create a substrate for arrhyth-
mias77, and abnormalities in connexins occur in a range

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Box 3 | Gap-junction coupling enhancers as anti-arrhythmic agents
In 1980, Aonuma and coworkers124 identified a bovine atrial hexapeptide with anti-
arrhythmic activity in cultured myocardial cell clusters, designating it anti-arrhythmic
peptide (AAP). The unique AAP amino-acid sequence (H2N-Gly-Pro-4Hyp-Gly-Ala-Gly-
COOH) was later determined. AAP was found not to act on ion currents; rather, anti-
arrhythmic actions were attributable to improved intercellular coupling by increased
gap-junctional conductivity125–127. Subsequently, synthetic analogues have been
synthesized by altering the amino-acid sequence, exchanging single amino acids and
producing propionyl derivatives such as the pentapeptide HP-5128,129. Structure–
activity relationships were established, allowing Dhein and others to synthesize the
structural analogue AAP10127. AAP10 inhibited ischaemia-induced conduction
alterations and reduced dispersion in epicardial repolarization127. AAP10 might act
through G-protein-coupled receptor-mediated activation of protein kinase Cα and
phosphorylation of Connexin 43130.
Practical application remained elusive because of poor enzymatic stability of available
AAPs, rendering assessment of in vivo anti-arrhythmic efficacy difficult. A major step
forward was the development of the stable AAP analogues cyclo-AAP10 and
rotigaptide (ZP123) by retro-all-d-amino acid design, resulting in markedly longer
plasma half-lives than traditional AAPs131,132. Rotigaptide attenuates atrial and
ventricular conduction-slowing during acidosis and metabolic stress, reduces action
potential dispersion and prevents re-entrant ventricular tachycardia induction during
acute myocardial infarction133–136. By contrast, rotigaptide does not influence focal
ventricular tachycardia or triggered activity136.
Rotigaptide is currently in early clinical testing for management of atrial and
ventricular arrhythmias. As for all peptide drugs, a major hurdle still to overcome is poor
bioavailability resulting from intestinal absorption barriers137. Attempts to circumvent
this difficulty and to permit practical chronic oral therapy have not been very successful
to date, hampered by factors such as toxicity of absorption enhancers, inter-individual
variability in absorption and manufacturing costs. If this challenge can be overcome,
gap-junction enhancers could become a practical and important addition to the
anti-arrhythmic pharmacopoeia.
of arrhythmia models78–81. Conduction velocity begins to
be perceptibly reduced when gap-junction coupling is
reduced by >50% — for example, a two-thirds reduction
in coupling decreases conduction speed by ~30%82.
Increasing gap-junctional coupling could be anti-
arrhythmic by improving cell-to-cell communication
and thereby improving conduction velocity. Anti-
arrhythmic peptides that act by enhancing coupling were
first identified in 198083. By an interesting series of steps
(BOX 3), this led to the identification of the stable ana-
logue rotigaptide (Zealand Pharma/Wyeth). Rotigaptide
improves ventricular conduction and prevents arrhyth-
mia generation in the face of acute myocardial ischae-
mia84–86. Rotigaptide might also improve other forms of
arrhythmias involving gap junction dysfunction, an area
under active investigation. To date, no clear adverse or
toxic effects of gap-junction enhancement have been
reported, and the main obstacles to therapeutic applica-
tion are pharmacokinetic: poor bioavailability and rapid
breakdown in the plasma.
Inherited arrhythmia syndromes as a paradigm for new
therapeutic approaches. There has been a remarkable
increase in our understanding of the molecular and
genetic basis of inherited lethal arrhythmias over the
past decade (TABLE 2)87, which has provided a wealth
of newer and more specific targets for anti-arrhythmic
therapy. In addition to the relatively uncommon pure
congenital arrhythmia syndromes, common genetic
1044 | DECEMBER 2006 | VOLUME 5
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polymorphisms might reproduce some of the abnor-
malities of monogenic arrhythmic syndromes and con-
tribute to an even more substantial portion of the overall
sudden death burden88. These insights have resulted in
more specific tools for genetic testing, clinical diagnosis
and risk stratification as, for example, in the long QT
syndromes (LQTS). A number of specific paradigms for
inherited arrhythmia mechanisms have been developed,
including the LQTS, the short QT syndrome (SQTS), the
Brugada syndrome and CPVT89,90.
The LQTS (FIG. 6a) promote sudden death by
impairing ventricular repolarization, and the genetic
abnormalities leading to this syndrome include loss-of-
function mutations in subunits underlying IKr, IKs, IK1 and
gain-of-function mutations in INa and ICaL (for details, see
TABLE 2). Drugs are being developed that accelerate repo-
larization by directly enhancing function of IKr (NS1643)
or IKs (L-364,373)91,92. Careful use of these compounds
will be needed to avoid creating a SQTS, but they are the-
oretically ideal agents for the targeted therapy of patients
at risk of arrhythmias due to repolarization defects.
Arrhythmias in some LQTS, particularly the IKs-deficiency
forms, are triggered by adrenergic stimulation, probably
because of the crucial role of IKs as a ‘brake’ against exces-
sive ICaL-induced plateau prolongation by adrenergic
stimulation93. Anti-adrenergic therapy will become bet-
ter targeted by evolving pharmacogenomic approaches
to guiding therapy. Defective channel-protein trafficking
causes most forms of the IKr-deficient LQTS (termed
LQT2)78,94,95, and might contribute to the causation of
other inherited arrhythmia syndromes96. Agents have
been identified that rescue defectively trafficked mutant
channels by improving their delivery to the cell mem-
brane97,98. Although the initially identified compounds
(such as E-4031) were also channel blockers, which
would have made dose titration difficult, recently iden-
tified agents (such as fexofenadine) promote channel
trafficking without directly affecting channel function95.
Such agents could be used to correct the expression
of mutated ion channels in many LQTS patients and
therefore provide safe and effective protection against
VF precipitated by TdP.
By contrast, the SQTS is caused by gain-of-function
mutations in K+ channels that accelerate repolarization
and reduce APD/RP, favouring re-entry (FIG. 3) by making
it easier for the re-entering impulse to find excitable tis-
sue at all points in the potential re-entry circuit99–101. The
development of agents that specifically inhibit the result-
ing abnormal current would seem to be an ideal therapy
for SQTS. For IKr, highly selective blockers (such as dofe-
tilide (Pfizer)) are well established102, and highly selective
IKs blockers (such as HMR-1566 (Sanofi-Aventis)) have
recently been developed103,104. Agents that selectively
inhibit IK1 might be of great interest for IK1 gain-of-func-
tion SQTS and other arrhythmic conditions associated
with IK1 enhancement, but none are presently known.
The Brugada syndrome (FIG. 6b) is associated with
loss-of-function INa mutations, and is believed to pro-
duce arrhythmias when Ito overpowers INa 90. There is
evidence that Ito inhibition can counteract the associ-
ated electrical and arrhythmic phenotype105, and the
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Box 4 | Prevention of arrhythmogenic remodelling: ‘upstream therapy’

Alterations in cardiac structure and function — so-called arrhythmogenic remodelling — lead to acquired cardiac
arrhythmia syndromes138,139. Remodelling-induced abnormalities in cardiac structure and electrical function strongly
predispose to atrial fibrillation (AF) and ventricular fibrillation (VF). Treatments are being developed to target
remodelling, guided by the notion that more direct targeting of the arrhythmic substrate will produce novel treatment
approaches that are safe and effective. This approach, sometimes called ‘upstream therapy’, aims to prevent arrhythmia-
generating abnormalities upstream of the final electrical product.
Atrial structural remodelling
Many clinical conditions associated with AF are characterized by prominent atrial fibrosis. In experimental congestive
heart failure (CHF), atrial fibrosis associated with prominent local conduction slowing, which favours the occurrence of
re-entry, seems to be crucial to an increased capacity to maintain AF140,141. The atrial rennin–angiotensin system is strongly
activated by CHF142,143, and its inhibition by converting-enzyme inhibitors142,143 or angiotensin-receptor blockers144
prevents atrial fibrosis and associated AF promotion. Agents interfering with the rennin–angiotensin system have been
applied clinically for AF prevention with apparent success, particularly for patients with structural-remodelling
conditions such as CHF or hypertension145.
Effects of oxidative stress and inflammation
There is evidence for a role of oxidative stress146,147 and inflammation143 in AF-associated remodelling. Both tissue
oxidation and inflammation can alter ion-channel function and contribute to tissue fibrosis, and antioxidant interventions
might prevent atrial remodelling146. Although not indicated for maintenance of sinus rhythm in AF patients, anti-
inflammatory drugs such as glucocorticoids can prevent atrial remodelling148 and the recurrence of clinical AF149.
However, these are not accepted indications and are still experimental. Cholesterol-lowering statin drugs have anti-
oxidant and anti-inflammatory properties and are also effective in preventing atrial remodelling150. They are not indicated
or used specifically for prevention of AF recurrence but many AF patients are given statins for other reasons. As above,
these are not accepted indications and are still experimental.
Atrial-tachycardia remodelling
Rapid atrial firing rates, as occur during AF, change ion-channel function and atrial electrophysiology, and increase
susceptibility to AF induction and maintenance151. Mibefradil, a T-type Ca2+-channel blocker, and amiodarone, a
particularly effective anti-AF drug that also has T-type Ca2+-channel blocking action, reduce atrial tachycardia
remodelling and prevent remodelling-associated AF152,153. Ongoing work seeks to identify additional drugs that prevent
atrial-tachycardia remodelling and which might be useful in preventing AF recurrence. Anti-inflammatory and anti-
oxidant drugs might also work for this indication146,148,150.
Ventricular remodelling
Efforts to prevent ventricular arrhythmogenic remodelling have been more limited to date than those targeting atrial
remodelling. An endothelin-receptor A antagonist prevented prolongation of the duration of the action potential, ionic
remodelling, QT-interval prolongation and ventricular arrhythmias, and improved overall survival in cardiomyopathic
hamsters154. Most present effort is being targeted at functional alterations, like Ca2+-release channel phosphorylation and
SERCA downregulation, caused by ventricular remodelling, rather than remodelling development per se.

development of selective Ito blockers (none of which are
presently known) would present a new and valuable tool
for the Brugada syndrome and related arrhythmias.
CPVTs result when a diastolic Ca 2+ leak occurs,
which is typically caused by mutations affecting RyR2
or the SR Ca 2+ -binding protein calsequestrin 106–109
(BOX 2). This can lead to DADs (FIG. 2B), which, when
large enough, can reach firing threshold and cause trig-
gered activity. Because catecholamines enhance Ca2+
entry into cardiac cells by stimulating β-adrenoceptors,
situations of enhanced adrenergic drive are the
most common triggers for arrhythmias related to
abnormal diastolic Ca2+ release. CPVT responds to
β-adrenoceptor blockers, but arrhythmias can also
occur in the absence of β-adrenergic drive and many
patients require implanted defibrillators to prevent
potentially lethal arrhythmias. The development of
drugs that stabilize the Ca2+-release channel and prevent
diastolic Ca2+ leak, such as JTV51970,71, might produce
valuable new agents for arrhythmic conditions such as
CPVT associated with diastolic Ca2+ leak-related DADs.
These insights could affect future pharmacological
treatment of AF and VF when it becomes possible to
identify patients with arrhythmias due to intracellular
Ca2+ leak and treat them with agents that are specific to
their pathophysiology70–73.
Cell and gene therapy
The limitations in currently available therapy for man-
agement of cardiac arrhythmias have led to considerable
interest in exploring the potential utility of gene- and
cell-transfer therapy. Efforts to date have centred on
approaches to recreate or amplify cardiac pacemaker
activity, to modify electrical conduction and to influ-
ence cardiac repolarization110,111. Strategies that have
been used to create or enhance biological pacemaker
activity in the target region include overexpression of
β2-adrenoceptors to augment adrenergic responsive-
ness, suppression of IK1 to permit a greater effect of
endogenous pacemaker currents, enhancement of If by
transfer of underlying HCN subunits, and cell therapy
(in combination with genetic engineering) to create new
pacemaker cells from mesenchymal or embryonic stem
cells111. Strategies to modify intracardiac conduction

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Table 2 | Genes and functional abnormalities in inherited cardiac arrhythmia syndromes

Locus Gene Protein Functional alteration Mode of inheritance Refs
Long QT syndrome
11p15.5 KCNQ1 IKs potassium channel α-subunit Loss of function Dominant 155
7q35-q36 KCNH2 IKr potassium channel α-subunit Loss of function Dominant 156
3p21 SCN5A INa cardiac sodium channel α-subunit Gain of function Dominant 157
4q25-q27 ANK2 Ankyrin-B Loss of function Dominant 158
21q22.1-q22.2 KCNE1 IKs potassium channel β-subunit Loss of function Dominant 159
21q22.1 KCNE2 IKr potassium channel β-subunit Loss of function Dominant 160
17q23.1-q24.2 KCNJ2 IK1 potassium channel subunit Loss of function Dominant 161
12p13.3 CACNA1C Calcium channel α-subunit Gain of function De novo mutation 162
11p15.5 KCNQ1 IKs potassium channel α-subunit Loss of function Recessive 163
21q22.1-q22.2 KCNE1 IKs potassium channel β-subunit Loss of function Recessive 164
Short QT syndrome
7q35-q36 KCNH2 IKr potassium channel α-subunit Gain of function Dominant 165
11p15.5 KCNQ1 IKs potassium channel α-subunit Gain of function Unknown 166
17q23.1-q24.2 KCNJ2 IK1 potassium channel subunit Gain of function Dominant 167
Brugada syndrome
3p21 SCN5A INa cardiac sodium channel α-subunit Loss of function Dominant 168
Catecholaminergic polymorphic VT
1q42.1-q43 RYR2 Cardiac ryanodine receptor Gain of function Dominant 169
1p13.3-p11 CASQ2 Calsequestrin Gain of function Recessive 170
Idiopathic sick sinus syndrome
15q24-q25 HCN4 If pacemaker channel subunit Loss of function Unknown 171
3p21 SCN5A INa cardiac sodium channel α-subunit Loss of function Recessive 172
Cardiac conduction disease
3p21 SCN5A INa cardiac sodium channel α-subunit Loss of function Dominant 173
Familial atrial fibrillation
11p15.5 KCNQ1 IKs potassium channel α-subunit Gain of function Dominant 174
21q22.1 KCNE2 IKr potassium channel β-subunit Gain of function Dominant 175
17q23 KCNJ2 IK1 potassium channel subunit Gain of function Dominant 176
7q35-q36 KCNH2 IKr potassium channel α-subunit Gain of function Dominant 177

have focussed on interventions that suppress AV nodal
ICaL through gene transfer of adenoviral vectors carry-
ing inhibitory G-protein (Gαi2) to the AV node or by
targeted Gem (a Ras-related small G-protein) gene
transfer to reduce trafficking of ICaL α-subunits to the
sarcolemma110,112. Both interventions reduced ventricu-
lar response rate during AF, in pigs and guinea pigs,
respectively. A few studies have evaluated ion-channel
or engineered cardiomyocyte gene transfer to alter
action potential morphology in canine ventricular
myocytes110. In vitro gene transfer of K+ currents accel-
erates repolarization in ventricular myocytes isolated
from mice, rats and rabbits113–116. Chamber-selective
gene therapy was recently reported in pigs: atrial gene
transfer of a dominant negative KCNH2 mutant elimi-
nated IKr, specifically atrial repolarization, and left the
ventricles unaffected117.
Gene therapy has the promise to provide very specific
modulation of individual currents in selected cardiac
regions. However, the area of arrhythmia gene- and
cell-transfer therapy is presently still in its infancy. None
of the applications described so far have been tested in
humans and we are not aware of any ongoing clinical
trials of gene therapy for cardiac arrhythmia treat-
ment. Major hurdles to circumvent include practical
approaches for successful transfer to the target region in
humans, potential risks of pro-arrhythmia, the control
of amplitude, duration and location of gene expression,
and potential toxic effects of the vector or the transgene,
along with consequences of host immune responses.
Prevention of arrhythmogenic remodelling
During the past 10–15 years, the mechanisms by which a
variety of acquired conditions alter cardiac structure and

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function to induce arrhythmias have been characterized, Conclusions

and are referred to collectively as ‘arrhythmogenic car-
diac remodelling’. A brief description of some aspects of
remodelling and its targeting by innovative anti-arrhythmic
therapies is provided in BOX 4. The prevention of arrhyth-
mogenic remodelling, sometimes called ‘upstream therapy’,
differs from classical anti-arrhythmic drug approaches by
targeting the development of the arrhythmic substrate,
rather than trying to modify the electrical end-product. A
major potential advantage of this approach is that it prom-
ises to be relatively free of pro-arrhythmic risk, and raises
the prospect of providing beneficial effects not only for
arrhythmias but for the underlying cardiac abnormalities.
The field of anti-arrhythmic drug development was
greatly slowed by the recognition of the important
potential risks of classical approaches to anti-arrhyth-
mic therapy6. However, recent developments in under-
standing the mechanisms of cardiac arrhythmias at the
molecular, biophysical and organ level have opened
up unprecedented opportunities for the provision of
safe and effective anti-arrhythmic drug therapy, as
well as for the development of newer pharmacological
approaches. It is hoped that these opportunities will
soon materialize into a broad expansion of the available
pharmaceutical armamentarium.

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Ackowledgements
Supported by the Canadian Institutes of Health Research, the
Quebec Heart and Stroke Foundation and the Mathematics
of Complex Systems and Information Technology (MITACS)
Network of Centers of Excellence.
Competing financial interests
The authors declare competing financial interests: see Web
version for details.
DATABASES
The following terms in this article are linked online to:
Entrez Gene:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
Calstabin 2 | Connexin 40 | Connexin 43 | Connexin 45 |
RyR2 | SERCA2A
OMIM:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
Brugada syndrome
Access to this links box is available online.
VOLUME 5 | DECEMBER 2006 | 1049