6.

04 Cardiac Physiology and Pharmacology

R J Sommer, Bates College, Lewiston, ME, USA
2010 Elsevier Ltd. All rights reserved.

6.04.1 Introduction 51
6.04.2 Myocardial Excitation and Contraction 51
6.04.2.1 Generation and Spread of Excitation 51
6.04.2.2 Ionic Basis of Cardiac Action Potentials 53
6.04.2.3 ExcitationContraction Coupling 54
6.04.2.4 Relaxation of Contraction 55
6.04.3 Autonomic Regulation of Cardiac Excitation and Contraction 56
6.04.3.1 Sympathetic Modulation of the Heartbeat 56
6.04.3.2 Parasympathetic Modulation of the Heartbeat 57
6.04.4 Compartmentation 58
6.04.5 Classification and Mechanisms of Arrhythmias 59
6.04.5.1 Abnormal Impulse Generation 59
6.04.5.2 Abnormal Impulse Conduction 62
6.04.5.3 Genetic Basis of Arrhythmias 62
6.04.6 Classification and Mechanisms of Action of Antiarrhythmic Agents 63
6.04.6.1 Conventional Antiarrhythmic Agents 64
6.04.6.1.1 Class I and III antiarrhythmic agents 64
6.04.6.1.2 Class II antiarrhythmic agents 64
6.04.6.1.3 Class IV antiarrhythmic agents 64
6.04.6.2 Novel Antiarrhythmic Agents and Approaches 64
6.04.6.2.1 Atrial-selective agents 64
6.04.6.2.2 Gap junction modulators 64
6.04.6.2.3 Preventing heart failure and arrhythmias 65
6.04.6.2.4 Future directions 66
References 66

6.04.1 Introduction content of the first edition of this chapter, written by

Under normal circumstances, the hearts rate and force
of contraction is tightly regulated to meet the circula-
tory demands of the body. The sympathetic and
parasympathetic nervous systems are primary regula-
tors of cardiac output but a number of integrated
systems of the body including the renal system, adre-
nal glands, vascular endothelium, immune system, and
cardiac tissue itself play important roles in regulating
circulation and hydroelectrolytic homeostasis. This
chapter describes the cellular and molecular basis of
myocardial excitationcontraction coupling, explains
how the autonomic nervous system regulates excita-
tioncontraction coupling, and examines emerging
information on the mechanisms of arrhythmias and
the new pharmacologic approaches being taken to
treat arrhythmias and chronic heart failure. Much of
the organizational structure and some informational
Sheu and Colecraft (1997), has been retained; how-
ever, significant revisions and additions have been
made to include dramatic advancements in under-
standing the molecular biology of ion channels, the
autonomic receptor signaling pathways, and the
genetic basis of some forms of arrhythmias.
6.04.2 Myocardial Excitation and
Contraction
6.04.2.1 Generation and Spread of
Excitation
The ability of the heart to contract is intrinsic. Unlike
neurons and skeletal muscle fibers, cardiac muscle
does not depend upon nervous system stimulation to
initiate an action potential (AP). Instead, autorhyth-
mic cells of the intrinsic cardiac conduction system

51
52 Introduction to Cardiovascular Biology

generate and distribute impulses throughout the heart
in a coordinated fashion from the atria to the ventri-
cles. In a healthy heart, the sinoatrial (SA) node,
located at the junction between the superior vena
cava and the right atrium, sets the pace for the heart,
generating an AP approximately 75 times every
minute. However, in the absence of extrinsic neural
and hormonal factors the SA node generates approxi-
mately 100 APs per minute. The pacemaker cells of
the SA node are not homogenous in terms of their rate
of AP generation and the exact position of the leading
pacemaking site within the node shifts depending on
conditions such as autonomic nerve stimulation
(Boyett et al. 2000; Schuessler et al. 1996). For a
detailed review of the SA node, the interested reader
is referred to Dobrzynski et al. (2007).
Once an AP has been initiated in the SA node, gap
junction channels allow ions to pass rapidly to adjacent
cells, directly transmitting the current through both
the conducting cells of the internodal pathway and the
contractile cells of the left and right atria. Atria and
ventricles abut one another but are not connected by
gap junctions. Thus, the atrioventricular (AV) node,
located immediately above the tricuspid valve, is the
only electrical connection between the upper and
the lower chambers (Figure 1). Within the AV node,
the rate of impulse propagation is slowed, at least in
part, due to differential expression of the number of

0
3
Superior SA node 4
vena cava

Atrium

AV node
Overshoot
1
0 2

3
mV
Phase 0
Tricuspid Purkinje 4
valve
100 Resting potential
Mitral
valve

Ventricle

R
Action potential phases
0: Upstroke
1: Early-fast repolarization
2: Plateau T
3: Repolarization
4: Diastole ECG P

Q S
PR QT
200 ms
Figure 1 Schematic diagram of cardiac action potentials (APs) in different regions of the heart. The cumulative electrical
activity of the heart is manifested on the body surface as the ECG. The P wave is generated by atrial depolarization, the QRS
by ventricular muscle depolarization, and the T wave by ventricular repolarization. Action potential phases: 0, upstroke; 1,
early fast repolarization; 2, plateau; 3, repolarization; 4, diastole resting potential. (Mason, J. W.; Hondeghem, L. M. Ann.
N.Y. Acad. Sci. 1984, 432, 162176.)

gap junction channels, their cellular location, and the
specific type of connexin proteins that form the gap
junctions (Desplantez et al. 2007). This delay allows
time for ventricular filling. From the AV node, cardiac
APs are rapidly conducted through the AV bundle
(Bundle of His) to the right and left bundle branches
to a rapidly conducting network of Purkinje fibers that
supply the ventricular myocardium (Figure 1). Again,
the excitation is transferred from the Purkinje network
to the myocardial cells by means of gap junctions
between the fiber terminals and the ventricular myo-
cytes, resulting in the rapid and nearly simultaneous
activation of the two ventricles.
The cumulative electrical activity of the heart can
be recorded by electrodes placed on the body surface
generating an electrocardiogram (ECG). An ECG is a
composite of all the APs generated by the cells of the
cardiac conduction system and the contracting myo-
cytes at a given time. Note that the APs from differing
cardiac cell types have different characteristic shapes,
which when combined form a series of three deflection
waves per heartbeat recorded on the ECG (Figure 1).
Primarily, the P wave is generated by depolarization of
the atria while the QRS complex results from depolar-
ization of the ventricles. The T wave coincides with
ventricular repolarization. The QT interval spans the
period from the beginning of ventricular depolarization
to the end of repolarization, and thus reflects the dura-
tion of ventricular APs. It is important to consider that a
single type of abnormality detected by an ECG, such as
a long QT interval, could be the manifestation of one of
several diverse causes such as overstimulation of the
sympathetic nervous system, loss of function mutation
in hERG K channels (KV11.1), or gain of function
mutation in Na channels (NaV1.5).
6.04.2.2 Ionic Basis of Cardiac Action
Potentials
Differential concentrations of ions (primarily Na,
K, Ca2, and Cl) inside versus outside of cardiac
cells result in electrochemical gradients across the
cell membrane that are necessary for normal cardiac
function. At rest, the Na, Ca2 exchanger (NCX)
and Na, K ATPase pump maintain higher extra-
cellular concentrations of Na and Ca2 and a higher
intracellular concentration of K. Cardiac cells are
impermeable to Na and Ca2, but are permeable to
K. As a result, positively charged K ions flow
slowly out of the cell (current designated as IK1),
and keep the interior of cardiac cells negatively
charged relative to the exterior. The resting
Cardiac Physiology and Pharmacology 53
membrane potential of atrial and ventricular myo-
cytes and Purkinje fibers range from 70 to 95 mV.
SA node and AV node cells have resting membrane
potentials of 50 to 60 mV. Resting potentials of
SA and AV node cells are not stable but exhibit
spontaneous, slow depolarization that, upon reaching
a threshold voltage, trigger an influx of Ca2, further
depolarizing the cell. This depolarization is the fir-
ing of an AP. In myocytes, as opposed to node cells,
the upstroke (phase 0) of an AP results from a rapid
influx of Na (Figure 2).
Immediately following this influx of positive
ions, the cell begins to return to its resting voltage
(repolarization) by moving K out of the cell, which
creates multiple time-dependent K currents
(Figure 2). Transient-outward (Ito) and ultra-rapid
(IKur) K currents are primarily responsible for
rapid early repolarization (phase 1) of the AP.
During phase 2, Ca2 enters the myocyte through
voltage-gated L-type Ca2 channels (CaV1.2) and
initiates mechanical contraction of the myocyte. At
this time, inward Ca2 (ICaL) and outward K cur-
rents are relatively balanced to form the AP plateau
(phase 2). Slower rectifying currents (IKr and IKs),
created by the movement of K outward by hERG
(KV11.1) and KVLQT1 (KV7.1) K channels, med-
iate terminal repolarization (phase 3) and bring the
cell back to resting potential (phase 4). The resting
potential is maintained in myocardial cells by IK1
and IKACh currents until an influx of ions from a
neighboring cell triggers the next AP.
No AP trigger is needed in pacemaker cells
because the pacemaker current, If, spontaneously
depolarizes node cells during phase 4. When first
discovered, If was labeled the funny current for a
number of its unusual features. If is activated at
hyperpolarized voltages (40 to 50 mV), has
mixed permeability to Na and K, and is activated
by cAMP (Accili et al. 2002; DiFrancesco and Borer
2007). A relatively new family of ion channels,
the hyperpolarization-activated cyclic nucleotide-
gated (HCN) channels, carries the If current and
have become novel targets for the development of
pure heart rate-lowering drugs such as Ivabradine
(Tardif 2007).
Cardiac cells are at least partially protected from
early reexcitation because they cannot undergo
depolarization during a refractory period that exists
for most of the time from initial depolarization to
final repolarization (termed the AP duration, APD)
(Figure 2). However, this also means that any nor-
mal change in heart rate requires a change in APD.
54 Introduction to Cardiovascular Biology
Early
repolarization (1)
0
mV
INa Upstroke (0)
IKACh
IK1
80
Resting (4)
IK1
INa
Ito
IKur
ICaL
IKr
IKs
NCX
If
IKACh
Figure 2 Ion currents during an action potential (AP) for a typical atrial or ventricular cell. Outward currents are indicated
with an arrow pointing up. Inward currents are indicated with an arrow pointing down. The timing of each current in relation
to the AP is shown. APD, action potential duration; NCX, Na/Ca2 exchanger. (Nattel, S.; Carlsson, L. Nat. Rev. Drug Discov.
2006, 5, 10341049.)
Depolarization is dominated by a single type of ion
channel (Na in the case of atrial and ventricle cells,
Ca2 in the case of the SA and AV node cells);
however, plateau and repolarization phases result
from complex interactions between many inward
depolarizing and outward repolarizing currents
carried by various types of ion channels
(Figure 2). This multifaceted system of repolariza-
tion provides many points for fine control of APD;
however, it also exposes many targets to perturba-
tion by disease or drugs.
6.04.2.3 ExcitationContraction Coupling
2
Ca is the central regulator of excitationcontraction
coupling. The influx of Ca2 via voltage-dependent
L-type Ca2 channels during phase 2 of the AP triggers
the release of large amounts of Ca2 from the sarco-
plasmic reticulum (SR). This process is termed Ca2-
induced Ca2-release (CICR) and is mediated by
ryanodine receptors (RyR2) of the SR (for review, see
Bers 2002). RyR2s are Ca2 release channels, ligand-
activatedby Ca2, and are found within a macromole-
cular complex that includes calmodulin, calstabin 2
(FKBP12.6), cyclic adenosine monophosphate
Ito
Plateau (2)
ICaL
IKur
IKs
IKr
Final
repolarization (3)
IKACh
IK1
Pacemaker
If function
APD
0.2 sec NCX
(cAMP)-dependent protein kinase (PKA), Ca2/
calmodulin-dependent protein kinase (CaMKII), pro-
tein phosphatases 1 and 2A, and A-kinase anchoring
protein (AKAP) (Bers 2006; Marx et al. 2000).
Calstabin 2 stabilizes RyR2 in a closed state until
PKA-mediated phosphorylation of RyR2 facilitates
the dissociation of calstabin 2, increasing SR Ca2
release (Brillantes et al. 1994). The elevation in the free
intracellular Ca2 concentration is directly responsible
for initiating the interaction of thin actin and thick
myosin filaments which leads to muscle contraction
(Figure 3). The thin filaments contain two regulatory
proteins, tropomyosin and troponin (Tn), in addition to
actin. There are three Tn proteins each of which has a
unique function: Tn C binds Ca2, Tn I affects -
tropomyosin so as to prevent the interaction of actin
and myosin, and Tn T attaches the other two Tn units
to tropomyosin. In the absence of Ca2, Tn works
through tropomyosin to prevent the interaction
between actin and myosin. The elevated Ca2 concen-
tration from CICR results in the diffusion of Ca2 to the
myofibrils where it binds to the Tn C subunit of the
Tntropomyosin complex. This causes a conforma-
tional change in the Tn molecule that shifts the
tropomyosin strand, exposing the myosin-binding
 Cardiac Physiology and Pharmacology 55

Strain

Plasma membrane Integrin

Ca2+
Troponin C
Troponin T
Troponin I Actin

Thin filament
-Tropomyosin

Myosin-binding -Myosin
protein C heavy chain
Thick filament
PEVK region

Calsarcin 1
T-cap Calcineurin

MLP
Titin
cGMP
PDES -Actinin
PKG
Z-disk

Figure 3 Myofilament and structural proteins of a cardiac sarcomere. Ca2 binds regulatory sites on Tn C, resulting in a
conformational change in Tn I which releases -tropomyosin from its position of blocking actin and myosin binding. Activated
myosin heads strongly attach to actin filaments, forming multiple cross bridge attachments that contract the myofilament by
sliding the actin filament toward the center of the sarcomere. Mechanical stimuli are transduced by clustered membrane
integrins that couple to proteins of the Z-disk (shaded) that bind contractile filaments. cGMP, cyclic GMP; MLP, muscle LIM
protein; PDE5, phosphodiesterase 5; PKG, cGMP-dependent protein kinase; T-cap, titin cap. (Mudd, J. O.; Kass, D. A. Nature
2008, 451, 919928.)

sites on the actin, allowing actin and myosin to inter-
act. The binding of myosin heads to actin filaments
forms multiple cross bridge attachments that con-
tract the myofilament by sliding the actin filament
toward the center of the sarcomere (Figure 3).
6.04.2.4 Relaxation of Contraction
Relaxation of myocardial contraction is achieved
by multiple processes which serve to reduce the cyto-
solic concentration of Ca2 back to resting levels.
First, Ca2 influx is mostly terminated by inactivation
of ICaL during the plateau (phase 2) of the AP. L-type
Ca2 channels undergo Ca2-dependent inactivation,
most likely mediated by calmodulin binding to the
pore-forming region of the L-type Ca2 channel
(Bodi et al. 2005). Second, a combination of RyR2
inactivation and partial depletion of SR Ca2 stores
turns off Ca2 release from the SR (Bers 2002). Third,
the Ca2-ATPase pump of the SR (SERCA2)
removes most of the elevated Ca2 from the cyto-
plasm. SERCA2 uses ATP to pump Ca2 back into
the SR where it is reversibly buffered by the Ca2-
binding protein, calsequestrin.
SERCA2 activity is regulated by the phosphory-
lation state of the protein phospholamban (PLB), an
SR membrane protein (Simmerman and Jones 1998).
Phosphorylation of PLB by any of several kinases
56 Introduction to Cardiovascular Biology

relieves PLBs inhibition of SERCA2, enhancing receptors (- and -AR) (Hartzell 1998). However, it is
Ca2 sequestration in the SR. Fourth, proteins pre- signaling of -ARs, via one of the most well-known
sent on the sarcolemma serve to transport Ca2 out molecular pathways, that regulates heart rate (chrono-
of the cell. The primary transport system for the tropy), contractility (inotropy), and relaxation
efflux of Ca2 from myocardial cells is the NCX (lusitropy). Initially, signaling of -ARs was thought
which uses the Na gradient to transport three Na to be a simple linear cascade, initiated primarily by  1-
ions into and one Ca2 ion out of the cell (Sheu and AR stimulation, but it is now recognized to be a com-
Blaustein 1992). Finally, there are also the ATP- plex network that utilizes both 1-AR and 2-ARs and
dependent Ca2 pump (Carafoli 1987) and mito- has cross talk with numerous other pathways
chondrial Ca2 uniporter (Gunter et al. 1994; Maack (Saucerman and McCulloch 2006). The classical
and ORourke 2007) that move small amounts of understanding of -AR signaling is that norepinephr-
Ca2 outside of the cell and into the mitochondria, ine, or other -AR agonist, binding leads to -AR
respectively. As the cytosolic concentration of Ca2 activation of the stimulatory G protein, Gs, facilitating
decreases, Ca2 dissociates from Tn C, reestablishing exchange of GTP for GDP and dissociation of the 
the tropomyosin blockade of actin and myosin bind-
subunits. The activated Gs sub-
ing, leading to muscle relaxation and diastole.
6.04.3 Autonomic Regulation of
Cardiac Excitation and Contraction
6.04.3.1 Sympathetic Modulation of the
Heartbeat
Sympathetic innervation is found throughout the heart
subunit from the 
unit then directly interacts with all isoforms of adenylyl
cyclase (AC) expressed in cardiac tissue (Smit and
Iyengar 1998) to stimulate production of cAMP and
activation of PKA. PKA-dependent phosphorylation
of numerous cardiac proteins, including L-type Ca2
channels (CaV1.2) (Hulme et al. 2003), Na channels
(NaV1.5) (Herfst et al. 2004), RyR2 (Marx et al. 2000),
PLB (Simmerman and Jones 1998), and Tn 1 (Kentish
et al. 2001) increases both contractile and relaxation
and acts via stimulation of both - and -adrenergic responses (Figure 4). To increase heart rate you must

NE, epinephrine, isoproterenol

1-AR 2-AR sarcolemma

AC AC
ICa Gs GRK2 Gs GRK2 Gi PI3K

-arrestin -arrestin
CaMKII cAMP PDE4D cAMP PDE4D ERK Akt

apoptosis PDE PKA PDE PKA apoptosis

CREB
If RyR TnI PLB ICa

ICER
transcription
chronotropy lusitropy inotropy
CaN NFATc hypertrophy nucleus

Figure 4 Functional consequences of cardiac -AR signaling. Historically, cardiac -AR signaling was known to act only
through the 1-AR-AC-cAMP-PKA signaling axis (bold arrows) to acutely regulate heart rate (chronotropy), contractility
(inotropy), and relaxation rate (lusitropy). Recent evidence additionally demonstrates an important role for  2-AR signaling
and long-term cardiac remodeling including regulation of hypertrophy and apoptosis. AC, adenylylcyclase; CaMKII, Ca2/
calmodulin-dependent kinase II; cAMP, cyclic adenosine monophosphate; CaN, calcineurin; CREB, cAMP response
element-binding factor; ICa, Ca2 current; ERK, extracellular-signal-regulated kinase; ICER, inducible cAMP early repressor;
GRK2, G-protein receptor kinase 2; Gi, G inhibitory protein; Gs, G stimulatory protein; NFATc, nuclear factor of activated
T cells; PDE, phosphodiesterase; PDE4D, phosphodiesterase 4D; PI3K, phosphatidyl-inositol 3-OH-kinase; PKA, cAMP-
dependent protein kinase; PLB, phospholamban; RyR, ryanodine receptor; TnI, troponin I. (Saucerman, J. J.; McCulloch,
A. D. Ann. N.Y. Acad. Sci. 2006, 1080, 348361.)
 Cardiac Physiology and Pharmacology 57

cycle through contracting the heart and relaxing the 6.04.3.2 Parasympathetic Modulation of
heart faster. The duality of increasing both contraction the Heartbeat
and relaxation is achieved by the diverse effectors of
The stimulatory effects of the sympathetic nervous
the -AR signaling pathway. Phosphorylation of L-
type Ca2 channels increases the inward flow of Ca2
(ICaL) and phosphorylation of PLB enhances SR Ca2
stores, so more Ca2 is delivered to the myofilaments
during subsequent APs. Phosphorylation of PLB and
Tn I increases the rates of SR Ca2 uptake and dis-
sociation of Ca2 from Tn C, respectively, enhancing
the rate of relaxation.
system are generally opposed by the parasympa-
thetic nervous system. The parasympathetic left
and right vagus nerves terminate in intracardiac
ganglia that go onto richly innervate atrial myocar-
dium, SA and AV nodes, and the ventricular
conduction system (Randall and Wurster 1993).
Although less dense, there is significant parasympa-
thetic innervation of the ventricular myocardium
The classical -AR activation pathway (Gs-AC-
cAMP production) can also increase heart rate
independently of phosphorylation (Figure 4).
Increased cAMP levels increase If which increases
pacemaker cells spontaneous depolarization rates
(Accili et al. 2002). cAMP directly binds to a cyclic
nucleotide-binding domain on the cytoplasmic C-
terminus of the HCN channel, which carries If.
HCN channels have opening kinetics consistent
(Standish et al. 1994) and muscarinic acetylcholine
receptors (mAChR), primarily of the M2 subtype,
are expressed throughout all areas of the heart,
including the ventricles (Loffelholz and Pappano
1985). However, following mAChR activation, atrial
and node cells readily display decreased contractile
and impulse initiation and propagation responses,
whereas, ventricular myocyte response is evident,
or at least more prominent, only in the presence of
with a model of combined allosteric and voltage-
dependent gating (Altomare et al. 2001). This model
proposes that HCN channels can be in an open or
closed state, and each of the channels four voltage
sensors can be in a reluctant or willing state. The
probability of the channel being in the open state
increases each time one voltage sensor switches to
the willing state and cAMP binds preferentially to
open channels and locks them in an open state
elevated cAMP levels and/or sympathetic (-AR)
stimulation (Harvey and Belevych 2003). These
tissue-specific differences are thought to be
mediated by different mechanisms that follow one
of two general paradigms. The first mechanism, in
SA node and atrial cells, involves mAChRs directly
coupled to inward rectifying K channels (KACh)
via PTX-sensitive G proteins (Go/Gi family)
(Tamargo et al. 2004). Upon mAChR activation, G
(Altomare et al. 2001; DiFrancesco 1999). protein 
subunits activate IKACh by directly bind-
In just the last several years, non-classical -AR ing the cytoplasmic N- and C-termini of KACh
signaling pathways that are cAMP/PKA-indepen- (Tamargo et al. 2004). Activation of IKACh hyperpo-
dent have been discovered. These new forms of larizes the membrane potential, slowing the
-AR signaling often cause long-term effects such
as cardiac hypertrophy and apoptosis (Figure 4)
(Saucerman and McCulloch 2006). One non-
classical signaling pathway is both dependent and
independent of PKA. It is Ca2-calmodulin-
dependent kinase II (CaMKII) which is activated
by PKA-induced increases in intracellular Ca2
and can also be activated as a result of Gs acting
directly on Ca2 channels (Yatani et al. 1987).
CaMKII is an important mediator of cardiac myo-
cyte apoptosis (Zhu et al. 2003) and is an attractive
therapeutic target for heart failure (HF)
spontaneous firing rate of the pacemaker cells and
decreasing atrial cell contraction. The second
mechanism, found throughout the heart, involves
indirect regulation of ion channel activity through
modulation of cAMP levels (Harvey and Belevych
2003). mAChR activation decreases cAMP synthesis
and increases cAMP degradation by direct inhibi-
tion of AC subtypes 5 and 6 (AC5/6) by  subunit of
Go/Gi and increased production of phosphodiester-
ase (PDE) via production of nitric oxide and cyclic
GMP, respectively (Figure 5a) (Harvey and
Belevych 2003).
(Saucerman and McCulloch 2006). Unlike 1- Paradoxically, under a variety of conditions,
ARs, 2-ARs signal via Gs and G inhibitory (Gi)
proteins and increase extracellular-signal-regu-
lated kinase (ERK) phosphorylation, a likely
cause of myocyte hypertrophy (Figure 4) (Baillie
et al. 2003; Molkentin and Dorn 2001).
mAChR activation has been reported to increase
strength of contraction and/or cause rebound
increases in heart rate. One potential explanation is
that mAChRs differentially regulate different iso-
forms of AC (Harvey and Belevych 2003). It is
58 Introduction to Cardiovascular Biology

AC
(a) s 5/6 i/o M2
i/o
ATP
CM Ca2+
cAMP
PKA 5-AMP NOS3

PDE2 NO L-arginine

sGC

cGMP GTP
ATP PO4

stimulatory
Ca2+ inhibitory

AC AC
(b) 1 s 5/6 i/o M2 4/7 s 1
i/o
ATP ATP
cAMP cAMP
PKA

ATP PO4

stimulatory
Ca2+ inhibitory

Figure 5 Proposed signaling pathways responsible for mAChR (M2) inhibition of cAMP-dependent ion channel responses
(a) and both inhibitory and stimulatory responses through differential regulation of specific AC isoforms (b). (Harvey, R. D.;
Belevych, A. E. Brit. J. Pharmacol. 2003, 139, 10741084.)

known that  subunit of Gi inhibits AC5 and AC6 but 6.04.4 Compartmentation
not group 2 ACs (AC2, AC4, and AC7) (Smit and
Iyengar 1998; Sunahara et al. 1996). Furthermore, In recent years, the importance of cellular compart-
AC5 and AC6 are inhibited by 
subunit, whereas ments has become apparent. We now know the
group 2 ACs are stimulated by 
subunit binding plasma membrane is a heterogeneous environment,
(Hanoune et al. 1997). Belevych and colleagues pro-
pose that the net response to mAChR activation is a
balance between inhibition and facilitation of cAMP-
dependent responses mediated by specific isoforms of
AC (Figure 5b) (Harvey and Belevych 2003). This
hypothesis is supported, in part, by the observation
that AC5 null mice have elevated heart rates, indi-
cating that more parasympathetic inhibition, rather
with lipid rafts and microdomains. Caveolae, or little
caves of membrane invaginations, and the larger
membrane invaginations of the transverse (T) tubu-
lar system of ventricular myocytes, located near the
SR terminal cisternae, form microdomains or com-
partments that concentrate ions and/or effectors of
signal transduction systems (Balijepalli et al. 2006;
Saucerman and McCulloch 2006). Interestingly,
than sympathetic stimulation, is mediated by AC5 2-ARs are almost exclusively located in caveolae,
(Okumura et al. 2003). but  1-ARs are not (Rybin et al. 1999). Using green
 Cardiac Physiology and Pharmacology 59

fluorescent protein-based technology, real-time ima- 6.04.5 Classification and

ging of living cells has demonstrated discrete Mechanisms of Arrhythmias
localization patterns for several second messengers,
such as Ca2, cAMP, and PKA (Zhang et al. 2002). Arrhythmias can be classified based on their properties
Using this technique, -AR stimulation was observed
to induce gradients of cAMP in the regions of T
tubule membranes (Zaccolo and Pozzan 2002).
Furthermore, computational modeling has predicted
that concentrations of Ca2 in the T tubule micro-
domain may be 100 to 1000 times that of the bulk
cytosol (Shannon et al. 2004). Compartmentation of
Ca2 likely explains the observation that Ca2-
dependent signaling pathways are not themselves
triggered by alterations in Ca2 concentration that
occur during myocardial contraction and relaxation
(Mudd and Kass 2008).
Functional compartmentation, or localization
of particular signaling and regulatory molecules
near one another in multi-protein complexes, is
accomplished by a number of scaffolding and adap-
tor proteins (Pawson and Nash 2003; Pawson and
Scott 1997). Not only do these proteins ensure that
upon activation the enzyme is near its specific
targets (spatial regulation), but also carry shut-off
proteins (temporal regulation) and/or means to
integrate the signal with other pathways (cross-
talk regulation) (Beene and Scott 2007). Two
scaffolding proteins with particular importance for
the cardiovascular system are the A-kinase anchor-
at the molecular, cellular, or clinical levels (Table 1).
In general, arrhythmias occur because of abnormal
impulse generation and/or abnormal impulse conduc-
tion. Both abnormalities may result from intrinsic
heart disease, some drug exposures, or inherited
disorders. This section discusses important mechan-
isms of abnormal impulse generation and conduction.
It also includes a section on the genetic basis of
arrhythmias. Work in this area has identified particu-
lar molecules whose dysfunction leads to arrhythmias
(Table 1) and moved the entire field from empirically
derived, often less than satisfactory, treatments toward
mechanism-based therapeutics that hold great poten-
tial (Knollmann and Roden 2008).
6.04.5.1 Abnormal Impulse Generation
Triggered activity is an abnormality of impulse gen-
eration in which impulses are initiated by oscillations
in membrane potential which arise following the
upstroke of a preceding action potential. These oscil-
lations in membrane potential are referred to as
afterdepolarizations and are of two types: early
afterdepolarizations (EADs) or delayed afterdepolar-
izations (DADs). EADs occur during the plateau or
ing proteins (AKAPs) and -arrestins. More than 50
AKAPs exist with significant structural diversity,
yet all bind PKA and other signaling enzymes to
form multi-protein complexes at specific subcellu-
lar sites (Beene and Scott 2007). The first AKAP
discovered was found in the macromolecular
complex of RyR2 (Marx et al. 2000) and facilitates
SR Ca2 release. It is also known that AKAP15
directly anchors PKA to L-type Ca2 channels
repolarization phases (phase 2 or 3) of the AP while
DADs occur after the completion of repolarization.
When afterdepolarizations are large enough to reach
a threshold value, they result in the generation of
triggered APs. Thus, in contrast to automaticity in
which the rhythm can be generated in the absence of
any preceding electrical activity, triggered rhythms
require at least one AP preceding them (Waldo and
Wit 1993).
and is needed for -AR-stimulated-phosphoryla- Experimentally, EADs have been induced in
tion of L-type Ca2 channels and subsequent preparations exposed to hypoxia, hypercapnia, and
increase in ICaL (Hulme et al. 2003). More than 20 high levels of catecholamines which are all conditions
proteins have been shown to be targeted by - present in the ischemic or infarcted myocardium
arrestins (Lefkowitz and Shenoy 2005). (Binah and Rosen 1992). Triggered APs during the
Importantly for the heart, -arrestin acts as a scaf- plateau and early repolarizing phases have an upstroke
fold that enables ERK phosphorylation through Gi carried by ICaL, due to inactivation of the fast inward
signaling in response to 2-AR stimulation Na channels at depolarized potentials. In contrast,
(Figure 2) (Perry et al. 2002) and allows for the triggered APs occurring during late phase 3 of repo-
dynamic movement of active phosphodiesterase larization have upstrokes caused by the fast inward
4D (PDE4D) from the cytosol to -ARs to create INa, due to the partial reactivation of the fast Na
a localized sink for cAMP degradation and thus channels at repolarized membrane potentials. The
dampen PKA activity (Houslay et al. 2007). amplitude of EADs and thus their likelihood of
Table 1 Mechanism-based approach to antiarrhythmic drug therapy

Phenotype
Disease- Possible acquired Potential mechanism-
Mechanism Molecular Cellular Clinical associated genes syndrome specific drug therapy

Failure of channel closing Destabilized Increased APD, Long QT interval (mostly SCN5A, CAV3, Drug-induced LQTS Blocker of Na
or inactivation Na-channel EADs at rest) SCN4B channels
inactivation
Destabilized DAD-mediated Catecholaminergic RYR2 Arrhythmia in heart Stabilizers of ryanodine
ryanodine automaticity, polymorphic VT CASQ2 failure, channels; blocker
channels premature Atrial and ventricular phenocopied by of Ca2-activated
Ca2 release arrhythmia, bradycardia digitalis intoxication arrhythmogenic
from SR processes
Abnormal L-type Increased APD, Timothy syndrome (extreme CACNA1C Drug-induced LQTS Blocker of Ca2
Ca2-channel EADs LQTS and extracardiac channels
inactivation effects)
Increased repolarizing K Failure of fast IKr Decreased APD SQTS (with AF and VF) KCNH2 (HERG) AF induced by vagal Blocker of affected
current inactivation stimulation K channel
IKs activated at KCNQ1
more negative
voltages
Increased IK1 KCNJ2
secondary
to failure of
normal inward
rectification
Increased non-selective ND Decreased AF ND AF Blocker of stretch-
stretch current APD, DADs activated channels
(such as spider
toxin MTx-4)
Decreased current as Decreased Na Loss of AP Increased PR and SCN5A SCD during therapy Activator of peak Na
a result of abnormal current dome in QRS duration (slow with Na-channel current; blocker of
channel gating or epicardial conduction), ST-segment blockers, especially transient outward
decreased cell-surface cells elevation, VF (Brugada in ischemic heart current
protein expression syndrome) disease
Decreased Isolated conduction-system
slope of AP disease (PR and QRS
upstroke prolongation, bundle
branch block, AV nodal
block
Decreased K Increased APD, LQTS (often with exertion) KCNQ1, KCNH2, Drug-induced LQTS Activator of affected
current EADs KCNE1, K channel
KCNE2, KCNJ2
ND AF KCNA5 AF
 Decreased L- Decreased APD Combined SQTS and CACNA1C, ND Activator of peak Ca2
type Ca2 Brugada syndrome CACNB2 current
current
Decreased ND AF GJAS Some VT in ischemic Activation of gap
connexin heart disease junction
channel conductance
current
Decreased Slowed Sinus-node dysfunction HCN4 Bradycardia Activation of
pacemaker pacemaker pacemaker current
current rate
Abnormal targeting of Ca2 ND DADs AF, VF, bradycardia, type 4 ANK2 Drug-induced LQTS ND
control proteins LQTS
Cardio-myopathic lesions, Cytoskeletal- ND Dilated cardiomyopathy, LMNA, DMD, Viral carditis ND
associated with protein heart block, AF, VF DES, SGCD,
arrhythmias dysfunction ACTN2, VCL,
CLP, LDB3
Sarcomere- EADs or DADs Mostly hypertrophic cardio- MYH7, MYBPC3, Acquired cardiac
protein in some cases myopathy: myofibrillar TNNT2, TNNI3, hypertrophy
dysfunction disarray, nonconcentric TPM1, MYL2,
ventricular hypertrophy, MYL3, ACTC1,
AF, VT TTN
Desmosome- ND Arrhythmogenic right PKP2, DSP, JUP, ND
protein ventricular DSG2, DSC2,
dysfunction cardiomyopathy DES
Metabolism and Cytoplasmic Hypertrophic LAMP2, PRKAG2 WolffParkinson
lysosomal aggregates cardiomyopathy, White syndrome
protein due to ventricular preexcitation
dysfunction defective
lysosomes

The molecular, cellular, and clinical phenotypes associated with fundamental molecular defects are indicated, together with the genetic and acquired arrhythmia syndromes that probably have
the same pathophysiology. This information has led to specific interventions that are predicted or have been established to be antiarrhythmic. ACTC1, cardiac 2-actinin; AF, atrial fibrillation;
ANK2, ankyrin 2; APD, action potential duration; AV, atrioventricular; CACNA1C, L-type Ca2 channel 1C subunit; CACNB2, L-type Ca2 channel 2-subunit; CASQ2, cardiac calsequestrin 2;
CAV3 caveolin 3; CLP cardiac LIM protein; DAD, delayed afterdepolarization; DES, desmin; DMD, dystrophin; DSC2, desmocollin 2; DSG2, desmoglein 2; DSP, desmoplakin; EAD, early
afterdepolarization; GJA5, gap junction protein-5 (also known as connexin 40); HCN4, hyperpolarization-activated cyclic-nucleotide-gated K channel 4; JUP, junction plakoglobin (also known
as -catenin); KCN, K channel; LAMP2, lysosomal-associated membrane protein 2; LDB3, LIM-domain-binding 3; LMNA, lamin A; LQTS, long-QT syndrome (QT-interval prolongation and
torsades de pointes-type polymorphic VT); MYBPC3, cardiac myosin-binding protein C; MYH7, -myosin heavy chain; MYL, myosin light chain; ND, not determined; PKP2, plakophilin 2;
PRKAG2, AMP-activated protein kinase-
2; SCGD, -sarcoglycan; SCN, voltage-gated Na channel; SR, sarcoplasmic reticulum; SQTS, short-QT syndrome (QT-interval shortening associated
with AF and VF); TNNI3, cardiac troponin I; TNNT2, cardiac troponin T; TPM1, -tropomyosin; TTN, titin; VCL, vinculin; VF, ventricular fibrillation; VT, ventricular tachycardia. (Knollman, B. C.;
Roden, D. M. Nature 2008, 451, 929936.
62 Introduction to Cardiovascular Biology
initiating triggered arrhythmias are enhanced by slow
heart rates (Damiano and Rosen 1984). Triggered
rhythms are commonly subdivided into those occur-
ring when the heart rate is slow (long QT-interval-
associated arrhythmias) and when it is rapid (catecho-
laminergic polymorphic ventricular tachycardia).
DADs are transient depolarizations occurring
after repolarization of the AP and have been
observed under a number of experimental conditions,
all of which are associated with an increase in intra-
cellular Ca2. These conditions include cardiac
glycoside intoxication, elevated extracellular Ca2
concentration, and administration of catecholamines
(Ferrier 1977). When the heart rate is high, subthres-
hold DADs can build to reach the threshold for firing
a triggered AP. Thus, tachycardias triggered by
DADs can be expected after an increase in sponta-
neous or pacing-induced rate (Binah and Rosen
1992). This property of DADs demonstrates an
important difference between normal automaticity
in Purkinje fibers and DAD-induced triggered
activity. While rapid pacing and overdrive stimula-
tion suppress normal automaticity, DAD-induced
arrhythmias undergo overdrive excitation such that
pacing at a rate faster than the triggered activity
results in an increase in the rate of the arrhythmia.
The underlying ionic mechanisms responsible for
DADs have been extensively studied. Abnormalities
in the sequestration and release of Ca2 by the SR
are important factors contributing to elevated intra-
cellular Ca2 and increased risk of DADs (Bers 2002,
2006). Most ventricular tachycardias in HF patients
are initiated by altered Ca2 handling in the myo-
cytes, including SR Ca2 leak and activation of NCX
(Bers 2006).
6.04.5.2 Abnormal Impulse Conduction
Normally in the intact heart, the impulse generated by
the SA node dies out after sequentially activating the
atria and the ventricles via the AV conduction system
because it encounters refractory tissue that it has just
excited and also because it meets the inexcitable
fibrous annulus. Reentrant excitation occurs when
there is continuous excitation in an electrical circuit
without independent triggering of each beat.
Reentrant circuits can be small (micro-reentry) or
large (macro-reentry), and require heterogeneity in
the electrophysiological properties of tissue in the
circuit, such as differences in refractory periods or in
conduction velocity. Stable reentrant circuits are ana-
tomical structures and can often be cured by ablation
(Morady 1999). Random reentry occurs with no fixed
circuit but travels from cell to cell as soon as the
neighboring cell repolarizes. Atrial fibrillation and
ventricular fibrillation (AF and VF) are often caused
by random reentry mechanisms. Atrial flutter, mono-
morphic ventricular tachycardias, AV nodal reentrant
tachycardia, and sinus node reentrant tachycardia are
caused by ordered reentry mechanisms.
Underlying cellular and molecular mechanisms of
reentry include a wide range of conditions from
acquired injury or ischemia, to inherited congenital
structural defects and channelopathies, to changes
in the expression levels of gap junction or structural
proteins (Wolf and Berul 2006). Any condition that
slows conduction in a subset of myocytes, such as an
elevated resting membrane potential that partially or
completely inactivates fast Na channels requiring
propagation to depend on the more slow L-type
Ca2 channels, can result in an AP arriving at neigh-
boring cells post their refractory period and be
treated as a new impulse for propagation.
6.04.5.3 Genetic Basis of Arrhythmias
Studying relatively rare genetic diseases that cause
familial cardiomyopathies and/or arrhythmias have
helped define molecular constituents and underlying
mechanisms of common arrhythmias (Knollmann
and Roden 2008; Nattel and Carlsson 2006). For
example, long-QT syndrome (LQTS) was first
described in the 1950s as a familial disease with
long QT-interval, normal heart structure, and
increased risk of sudden cardiac death (SCD). Most
investigators thought the condition resulted from an
autonomic imbalance (Rosen 1998). Today, we know
that loss-of-function mutations in ion channel
subunits underlying IKr, IKs, IK1 and gain-of-function
mutations in INa and ICaL increase APD and can
cause life-threatening polymorphic ventricular
tachycardia known as torsade de pointes (Nattel and
Carlsson 2006; Sanguinetti and Tristani-Firouzi
2006). The most common mutation responsible
for this disease is found in the gene HERG
(KCNQ1), which codes the -subunit of the channel
that conducts the slow delayed rectifier K current,
IKs (Curren et al. 1995). This and other mutations
that inactivate inward K currents delay the ability
of the cell to return to normal resting potential,
delaying repolarization and increasing APD. Gain-
of-function in Na channel activity (often incom-
plete inactivation) results in a small but persistent
inward current during phase 2 that prolongs the APD
 Cardiac Physiology and Pharmacology 63

(Bennett et al. 1995). Discovering that different mole- (Vaughan Williams 1970). Class I agents block the
cular mechanisms could be responsible for LQTS inward sodium current, INa, responsible for the AP
explained why only some patients responded to upstroke (phase 0) and are divided into subclasses
treatment with Na channel blocking agents, and based on their ability to alter APD; class II agents
ushered in a new era of mechanism-based approaches
to antiarrhythmic drug therapy (Table 1)
(Knollmann and Roden 2008).
In addition to inherited disease, several common
medications can prolong the QT interval and induce
torsade de pointes (De Bruin et al. 2005). Torsade de
pointes is frequent in patients treated with the antiar-
rhythmic drug quinidine (as high as 9%), but occurs
in about 1 out of 120 000 patients treated with the
block -AR receptors; class III agents prolong APD,
primarily through blocking the late phase 3 repolar-
izing currents, IKr and IKs; and class IV agents block
L-type calcium channels (Table 2). Although widely
used, this classification system is not ideal. Many
antiarrhythmic drugs have multiple actions and do
not fit into a single class. For example, amiodarone
prolongs APD by potently inhibiting the outward
rapid K current, IKr, but also inhibits sodium chan-
non-antiarrhythmic drugs that can induce the effect
(Haverkamp et al. 2000; Vitola et al. 1998). Although
rare in non-antiarrhythmic drugs, the risk level of
torsade de pointes is unacceptable for patients being
treated for non-life-threatening conditions and sev-
eral agents (cisapride, sertindole, grepafloxacin,
terfenadine, and astemizole) were restricted in their
use or completely removed from the market
(Sanguinetti and Tristani-Firouzi 2006). These
structurally diverse agents all bind and block hERG
channels (Sanguinetti and Tristani-Firouzi 2006). It
is now common practice for pharmaceutical compa-
nies to screen compounds for hERG channel binding,
ability to alter hERG current in cells, or ability to
alter QT intervals in animals during drug develop-
ment (Sanguinetti and Mitcheson 2005).
6.04.6 Classification and
Mechanisms of Action of
Antiarrhythmic Agents
Antiarrhythmic drugs are commonly classified by the
Vaughan WilliamsSingh system, which groups
drugs according to their electrophysiologic effects
Table 2 Vaughan WilliamsSingh antiarrhythmic drug classification system with prototypical
agents listed for each class
Class Action
Ia Sodium channel antagonists
Prolong action potential duration (APD)
Ib Less potent sodium channel antagonists
No change or shortening of APD
Ic Potent sodium channel antagonists
No change or mild APD prolongation
nel, -adrenergic receptor, and calcium channel
actions (Singh and Hauswirth 1974; Singh and
Vaughan Williams 1970). Thus, amiodarone could
be categorized into any one of the four Vaughan
WilliamsSingh classes. Lack of class specificity and
additional concerns about the Vaughan Williams
Singh classification system are discussed in detail by
members of the Sicilian Task Force (Members of the
Sicilian Gambit 1994; Rosen 1998; Task Force of the
Working Group on Arrhythmias of the European
Society of Cardiology 1991). They gathered in 1991
to devise a new antiarrhythmic drug classification
system. Their proposal, the Sicilian Gambit, empha-
sizes individual drug characteristics (actions on ion
channels, autonomic and purinergic receptors, and
clinical effects), rather than class groupings, in order
to promote treatment based on known mechanisms of
arrhythmic disease and drug action (Members of the
Sicilian Gambit 1994; Rosen 1998; Task Force of the
Working Group on Arrhythmias of the European
Society of Cardiology 1991). Unfortunately, their
approach produced a complex system that has lim-
ited the Sicilian Gambits usefulness as a means of
classification (Reiffel 1997). However, the Sicilian
Agents
Quinidine, procainamide, disopyramide
Lidocaine, mexiletine
Propafenone, flecainide, moricizine
II -Adrenergic receptor antagonists Propranolol, esmolol
III Prolong APD Amiodarone, sotalol, dofetilide
IV Calcium channel antagonists Verapamil, diltiazem
64 Introduction to Cardiovascular Biology
Gambits original intent of target-specific, mechan-
ism-based drug development and use is now being
realized as many of the ion channel subunits that
mediate cardiac currents have been identified,
cloned, and physiologically characterized.
6.04.6.1 Conventional Antiarrhythmic
Agents
6.04.6.1.1 Class I and III antiarrhythmic
agents
Only class I and III agents (Na and K channel
blockers) are effective in terminating or preventing
recurrences of AF (Levy 2001), the most common
form of sustained arrhythmia. However, these agents
can themselves induce life-threatening ventricular
arrhythmias. The Cardiac Arrhythmia Suppression
Trial (CAST), terminated early in 1989 because
patients being treated with potent Na channel block-
ers, encainide and flecainide, had two- to three-fold
increases in mortality versus placebo controls (CAST
Investigators 1989), and several subsequent studies
(SWORD (SWORD Investigators 1996), AFFIRM
(AFFIRM Investigators 2002), RACE (RACE
Investigators 2002)) have shown no mortality benefit
to restoring normal sinus rhythm in AF patients with
either class I or class III antiarrhythmic agents. It is
likely that the toxicities and proarrhythmic risks of
the agents negate the benefits of chronically suppres-
sing the AF (Morrow et al. 2007). Out of necessity, class
I and III antiarrhythmic agents continue to be used for
both acute and chronic cessation of atrial and ventricu-
lar fibrillations, but novel pharmaceutical agents and
non-pharmacological approaches, such as ablation ther-
apy and implantable cardioverter defibrillators, are
increasing (Bardy et al. 2005; Morady 1999).
6.04.6.1.2 Class II antiarrhythmic agents
6.04.6.1.3 Class IV antiarrhythmic agents
Ca2 channel antagonists are used most often to treat
hypertension and angina, but are also effective against
the treatment of a wide variety of supraventricular
tachycardias. There are three chemical classes of cal-
cium channel antagonists: phenylalkylamines (e.g.,
verapamil), benzothiazepines (e.g., diltiazem), and
dihydropyridines (e.g., nifedipine). Each class binds
to distinct, high affinity binding sites in close proxi-
mity to one another on the 1 subunit of L-type Ca2
channels (for review see Striessnig et al. 1998). The 1
subunit forms the conduction pore, voltage sensor, and
gating apparatus of the channel (Bodi et al. 2005). Four
separate L-type 1 subunit genes have been identified:
CaV1.1 (1S), 1.2 (1C), 1.3 (1D), and 1.4 (1F). Only
CaV1.2 is expressed at high levels in cardiac myocytes
and may explain the differential responses of skeletal,
smooth and cardiac muscle to class IV agents
(Catterall et al. 2005).
6.04.6.2 Novel Antiarrhythmic Agents and
Approaches
6.04.6.2.1 Atrial-selective agents
Currently available antiarrhythmic agents target the
same channels (primarily IKr) in atrial and ventricular
cells and it is their action in the ventricles as opposed
to the atria that can lead to lethal arrhythmias. Newer
agents, such as XEN-D0101 (Xention), that specifi-
cally target Kv1.5 subunits, found in atrial but not
ventricular cells (Feng et al. 1997) and carry the
ultrarapid delayed rectifier current (IKur), are
promising compounds to treat AF without causing
ventricular arrhythmias (Figure 6) (Nattel and
Carlsson 2006). Another selective target is the acet-
ylcholine-related K current (IKACh) carried by
Kir3.1/3.4 heterotetramers (Figure 6). Normally
inactive until stimulated by the parasympathetic sys-
tem, IKACh is constitutively active and contributes to
-AR blocking agents have well-established effects
on arrhythmias that involve the AV node (Task
Force of the Working Group on Arrhythmias of the
European Society of Cardiology 1991). Blocking
sympathetic stimulation decreases conduction velo-
city and increases refractoriness of conduction cells
as well as decreasing myocardial cell contraction rate.
basal inward rectifier K current in chronic AF
(Dobrev et al. 2005). IKACh is atrial selective and has
no effect on ventricular current or APD (Cha et al.
2006). IKACh blockers, NIP-141 and 142, are
currently in pre-clinical trials (Hashimoto et al.
2007; Matsuda et al. 2006).
-ARs antagonists have become important agents in 6.04.6.2.2 Gap junction modulators
the prevention of many forms of heart disease, Gap junctions are aggregates of voltage-gated, cellcell
including arrhythmias (Ellison and Gandhi 2005). channels, with each channel constructed from two
See Section 6.04.6.2.3 for more information on the hemichannels and each hemichannel comprised of six
use of -AR blocking agents to slow the progression connexin subunits (Desplantez et al. 2007). There are at
of HF to reduce arrhythmia formation. least three different connexin types expressed in the
 Cardiac Physiology and Pharmacology 65

IKATP IKr IKs IKACh Ito IKur IK1 If

Na+
Kir6.2 hERG KvLGT1 Kir3.1 Kv4.3 Kv1.5 Kir2.1 HCN4

M2 G-protein
SUR2A Kir3.4 KChlp
MiRP1 KCR1 minK
+ + + + +
2.2
K K K K K K+ K+ K+

Clamikalant Azimilide NIP-141 XEN-D0101 Ivabradine

withdrawn Phase III NIP-142 Phase I Phase III
Preclinical

Vernakalant Dronedarone Mibefradil

Phase II/III Phase III withdrawn GsMTx4
Preclinical Rotigaptide
INa ICaL ICaT Phase II
+
NaV1.5 CaV1.2 CaV3.1/3.2 Connexin

Ahnak SAC SAC

Gap junction
Na+ Ca2+ Ca2+ +

Figure 6 Schematic of cardiac cells depicting ion channel subunits and transporters that are targeted by investigational
drugs. As indicated, drugs are in preclinical, phase II, phase III, or have been withdrawn from clinical trials. SAC, stretch
activated channel. (Nattel, S.; Carlsson, L. Nat. Rev. Drug Discov. 2006, 5, 10341049.)

heart. Connexin 45 is primarily found in SA and AV ventricular tachycardias induced by non-reentrant

node cells. Connexin 40 and 43 are not found in node mechanisms (triggered mechanisms such as DADs,
cells, but are highly expressed in the ventricular con- EADs, and abnormal automaticity) (Pogwizd 1994;
duction system and atrial myocytes. Only connexin 43 Pogwizd et al. 1998). Thus, systolic dysfunction and
is expressed at high levels in ventricle myocytes arrhythmias are not mutually exclusive diseases and
(Desplantez et al. 2007). The tissue-specific distribution use of -AR antagonists to slow the progression of
of connexins makes them attractive targets for novel HF also decreases the risk of arrhythmias.
drug development. Furthermore, alterations in gap The classical view of -AR signaling as a linear
junction kinetics are known to slow conduction velocity pathway (see Section 6.04.3.1) led to the use of inotropic
and promote AF (Kanno and Saffitz 2001). Accordingly, agents to treat both acute and chronic HF. Dobutamine,
drugs that enhance gap junction conduction could be a -AR agonist, is still a mainstay of acute HF manage-
good agents for AF management (Mazzini and ment (Gauthier et al. 2008); however, several large,
Monahan 2008; Nattel and Carlsson 2006). well-controlled clinical trials have demonstrated that
Rotigaptide is a peptide stabilizer of gap junction con-
duction during ischemia (Xing et al. 2003) but does not
affect ischemia-induced focal ventricular tachycardia or
triggered activity in dogs (Xing et al. 2005). Additional
studies will continue to determine whether gap junction
enhancers are clinically viable antiarrhythmic agents.
6.04.6.2.3 Preventing heart failure and
arrhythmias
Many late-stage HF patients also experience
the opposite treatment, -AR antagonism, is clearly the
best treatment for chronic HF (Ellison and Gandhi
2005; Ghali and Lindenfeld 2008). Two to four
thousand patients in each of the Metoprolol
Controlled-Release/Extended-Release Randomized
Intervention Trial (MERIT-HF Investigators 1999),
the Cardiac Insufficiency Bisoprolol Study II (CIBIS-
II Investigators 1999), and the Carvedilol Prospective
Randomized Cumulative Survival trial (Packer et al.
2001) demonstrated a 3435% mortality reduction in
arrhythmias and sudden cardiac death due to -AR antagonist-treated versus placebo-controlled
66 Introduction to Cardiovascular Biology

groups. Today, the American Heart Association and Boyett, M. R.; Honjo, H.; Kodama, I. Cardiovasc. Res. 2000, 47,
658687.
American College of Cardiology recommends the use Brillantes, A. B.; Ondrias, K.; Scott, A.; Kobrinsky, E.;
of -AR antagonists in all patients with symptomatic Ondriasova, E.; Moschella, M. C.; Jayaraman, T.; Landers, M.;
left ventricular dysfunction, yet only one-third of eligi- Ehrlich, B. E.; Marks, A. R. Cell 1994, 77, 513523.
Carafoli, E. Annu. Rev. Biochem. 1987, 56, 395433.
ble patients may be actually receiving -AR antagonist Catterall, W. A.; Perez-Reyes, E.; Snutch, T. P.; Striessnig, J.
therapy for HF (Ansari et al. 2003). The use of -AR Pharmacol. Rev. 2005, 57, 411425.
antagonists to manage HF has not been embraced Cha, T. J.; Ehrlich, J. R.; Chartier, D.; Qi, X. Y.; Xiao, L.; Nattel, S.
Circulation 2006, 113, 17301737.
because it appears counterintuitive to the classical CIBIS-II Investigators. Lancet 1999, 353, 913.
understanding of -AR function (Ellison and Gandhi Curren, M. E.; Splawski, I.; Timothy, K. W.; Vincent, G. M.;
2005). Recent advances in our knowledge of -AR
signaling have revealed a much more complex signaling
network than previously believed (Figure 4) and
should have a great impact on our understanding and
treatment of HF and other cardiac diseases (Saucerman
and McCulloch 2006).
6.04.6.2.4 Future directions
Knollmann and Roden (2008) articulated the opti-
mism of the field that increased knowledge of specific
molecular targets important to normal and dysfunc-
tional cardiac physiology will (1) translate into new,
improved therapies for arrhythmias and other forms
of heart disease; (2) lead to the identification of
genetic markers that will improve cardiovascular dis-
ease screening and preventative measures in the
general population; (3) identify common polymorph-
isms that will lead to personalized medicine for the
most effective treatment for individual patients; and
(4) allow development of pharmaceutical drugs with-
out unintended cardiovascular toxicity.
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