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Part of the highly regarded Braunwald's family of cardiology references,Clinical Arrhythmology and Electrophysiology, 3rd Edition, offerscomplete coverage of the latest diagnosis and management optionsfor patients with arrhythmias.Expanded clinical content, clear illustrations, and dynamic videoskeep you fully abreast of current technologies, new syndromes and diagnostic procedures, new information on molecular genetics, advances in ablation, and much more. A true gift from the God of Education!
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Executive Director
Cardiac Electrophysiology
Prairie Heart Institute of Illinois
Medical Director
Cardiac Electrophysiology Laboratory
HSHS St. John’s Hospital
Springfield, Illinois

Professor of Medicine
Krannert Institute of Cardiology
Indiana University School of Medicine
Clinical Cardiac Electrophysiology
Indiana University Health
Indianapolis, Indiana


Distinguished Professor
Professor Emeritus of Medicine, Pharmacology, and Toxicology
Director Emeritus
Division of Cardiology and the Krannert Institute of Cardiology
Indiana University School of Medicine
Indianapolis, Indiana


1600 John F. Kennedy Blvd.
Ste 1600
Philadelphia, PA 19103-2899


ISBN: 978-0-323-52356-1

Copyright © 2019 by Elsevier, Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance
Center and the Copyright Licensing Agency, can be found at our website:
This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).

Knowledge and best practice in this field are constantly changing. As new research and experience broaden
our understanding, changes in research methods, professional practices, or medical treatment may become
Practitioners and researchers must always re; ly on their own experience and knowledge in evaluating
and using any information, methods, compounds, or experiments described herein. In using such
information or methods they should be mindful of their own safety and the safety of others, including
parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most
current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be
administered, to verify the recommended dose or formula, the method and duration of administration,
and contraindications. It is the responsibility of practitioners, relying on their own experience and
knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each
individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume
any liability for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.
Previous editions copyrighted 2012 and 2009.
Library of Congress Control Number: 2018945138

Publishing Director: Dolores Meloni
Senior Content Development Manager: Katie DeFrancesco
Publishing Services Manager: Catherine Jackson
Book Production Specialist: Kristine Feeherty
Design Direction: Renee Duenow

Printed in China
Last digit is the print number: 9


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As always, we would like to thank our families for their support during the writing of this book,
since it meant time away from them:
Ziad F. Issa:
My wife, Dana, and my sons, Tariq and Amr
John M. Miller:
My wife, Jeanne, and my children, Rebekah, Jordan, and Jacob
Douglas P. Zipes:
My wife, Joan, and my children, Debbie, Jeff, and David
We also thank the Elsevier support team that helped bring this edition to fruition.

F O R E WO R D
Disturbances in cardiac rhythm occur in a large proportion of the
population. Arrhythmias can have sequelae that range from life-shortening to inconsequential. Sudden cardiac deaths and chronic disability
are among the most frequent serious complications resulting from
The eleventh edition of Braunwald’s Heart Disease: A Textbook of
Cardiovascular Medicine includes an excellent section on rhythm disturbances carefully edited and largely written by Douglas Zipes and
Gordon Tomaselli, the most accomplished and respected investigators
and clinicians in this field. However, there are many subjects that simply
cannot be discussed in sufficient detail, even in a 2000-page, densely
packed book. For this reason, the current editors and I decided to
commission a series of companions to the parent title. We were extremely
fortunate to enlist Dr. Zipes’ help in editing and writing Clinical Arrhythmology and Electrophysiology. Dr. Zipes, in turn, enlisted two talented
collaborators, Drs. Ziad F. Issa and John M. Miller, to work with him
to produce this excellent volume.
This third edition is superbly illustrated, with the number of figures
and tables increasing substantially from its predecessor. What has not
changed, however, is the very high quality of the content, which is
accurate, authoritative, and clear; second, it is as up-to-date as last
month’s journals; and third, the writing style and illustrations are consistent throughout with little, if any, duplication. As this important
branch of cardiology has grown, so has this book.

The first seven chapters (“Molecular Mechanisms of Cardiac Electrical Activity,” “Cardiac Ion Channels,” “Electrophysiological Mechanisms
of Cardiac Arrhythmias,” “Electrophysiological Testing: Tools and Techniques,” “Conventional Intracardiac Mapping Techniques,” “Advanced
Mapping and Navigation Modalities,” and “Ablation Energy Sources”)
provide a superb introduction to the field. This is followed by 24 chapters
on individual arrhythmias, each following a similar outline. Here, the
authors lead us from a basic understanding of the arrhythmia to its
clinical recognition, natural history, and management. The latter is
moving rapidly from being largely drug-based to device-based, although
many patients receive combination device-drug therapy. These options,
as well as ablation therapy, are clearly spelled out as they apply to each
arrhythmia. The final chapter discusses the complications of catheter
ablation of cardiac arrhythmias.
We are proud to include Clinical Arrhythmology and Electrophysiology
as a companion to Braunwald’s Heart Disease, and we are fully confident
that it will prove to be valuable to cardiologists, internists, investigators,
and trainees.
Eugene Braunwald, MD
Peter Libby, MD
Robert Bonow, MD
Douglas Mann, MD
Gordon Tomaselli, MD


The third edition of Clinical Arrhythmology and Electrophysiology maintains its unique style, written by just the three of us. Once again, we
can “explain, integrate, coordinate, and educate in a comprehensive,
cohesive fashion while avoiding redundancies and contradictions.” We
liken it to a comprehensive travel guide written by an expert who has
actually stayed in that unique hotel or eaten in that special restaurant.
We have experienced the progress first-hand, from basic science to
clinical application, and are able to pass on our experiences to you. In
addition, as before, readers have the opportunity to delve deeper into
basic mechanisms or invasive procedures…or not…depending on the
level of interest.
We have thoroughly revised and updated all chapters. In addition,
we have greatly expanded the book by increasing the total number of


pages from 700 to over 1100 and increased the number of figures to
almost 1000 in print and over 200 online. A unique feature of our book
are 74 new videos that take the reader into our electrophysiology labs
to become a “fly on the wall” observing electrophysiology procedures.
We believe the adage that “one picture is worth a thousand words,” and
we invite you to learn with us during actual procedures.
Our textbook, written as a companion to the Braunwald’s Heart
Disease series, is for learners of all stages. We hope you enjoy, learn,
and expand your care of arrhythmia patients.
Ziad F. Issa
John M. Miller
Douglas P. Zipes

1 Molecular Mechanisms of Cardiac Electrical Activity, 1

19 Atypical Bypass Tracts, 677

2 Cardiac Ion Channels, 15

20 Paroxysmal Supraventricular Tachycardias, 697

3 Electrophysiological Mechanisms of Cardiac
Arrhythmias, 51


4 Electrophysiological Testing: Tools and Techniques, 81

Wide Complex Tachycardias, 730

22 Ventricular Arrhythmias in lschemic Heart Disease, 748

Idiopathic Focal Ventricular Tachycardia, 816


Fascicular Ventricular Tachycardia, 858


Ventricular Tachycardia in Nonischemic Dilated
Cardiomyopathy, 869

8 Sinus Node Dysfunction, 238


Bundle Branch Reentrant Ventricular Tachycardia, 897

9 Atrioventricular Conduction Abnormalities, 255


Epicardial Ventricular Tachycardia. 907

10 lntraventricular Conduction Abnormalities. 286


Arrhythmias in Hypertrophic Cardiomyopathy, 925



Ventricular Tachycardia in Arrhythmogenic Right
Ventricular Cardiomyopathy, 942

5 Conventional lntracardiac Mapping Techniques, 125
6 Advanced Mapping and Navigation Modalities, 155
7 Ablation Energy Sources, 206

Focal Atrial Tachycardia, 305

12 Typical Atrial Flutter, 339

13 Macroreentrant Atrial Tachycardia, 375

30 Ventricular Arrhythmias in Adults With Congenital
Heart Disease, 968

14 Atrial Tachyarrhythmias in Adults With Congenital
Heart Disease, 407


15 Atrial Fibrillation, 421

32 Complications of Catheter Ablation of Cardiac
Arrhythmias, 1042

16 Inappropriate Sinus Tachycardia, 549

17 Atrioventricular Nodal Reentrant Tachycardia, 560

Ventricular Arrhythmias in Inherited
Channelopathies, 976

Index, 1068

18 Typical Atrioventricular Bypass Tracts, 599

Marep11jan aawrnfleH ay

B R AU N WA L D ’ S H E A R T D I S E A S E

Cardiovascular Intervention

Diabetes in Cardiovascular Disease

Myocardial Infarction

Cardiovascular Therapeutics

Heart Failure

Preventive Cardiology

Chronic Coronary Artery Disease


Valvular Heart Disease

Clinical Lipidology

Mechanical Circulatory Support

Vascular Medicine





Braunwald’s Heart Disease Review and Assessment


Atlas of Cardiovascular Computed

Atlas of Nuclear Cardiology

Atlas of Cardiovascular Magnetic
Resonance Imaging

Cardiovascular Magnetic Resonance

Essential Echocardiography

Molecular Mechanisms of Cardiac
Electrical Activity
Ionic Equilibrium, 1
Transmembrane Potentials, 1
Cardiac Action Potential, 2
Fast Response Action Potential, 3
Slow Response Action Potential, 8
Excitability, 8
Refractoriness, 9

Propagation, 10
Intracellular Propagation, 10
Intercellular Propagation, 10
Anisotropic Conduction, 11
Source-Sink Relationship, 11
Safety Factor for Conduction, 12
Excitation-Contraction Coupling, 12


its own Eion. The contribution of each ion type to the overall Em at any
given moment is determined by the instantaneous permeability of the
plasma membrane to that ion. The larger the membrane conductance
to a particular ion, the greater is the ability of that ion to bring the Em
toward its own Eion. Hence the Em is the average of the Eion of all the
ions to which the membrane is permeable, weighed according to the
membrane conductance of each individual ion relative to the total ionic
conductance of the membrane.1

The lipid bilayer of the cell membrane is hydrophobic and impermeable
to water-soluble substances such as ions. Hence, for the hydrophilic
ions to be able to cross the membrane, they need hydrophilic paths
that span the membrane (i.e., pores), which are provided by transmembrane proteins called ion channels. Once a hydrophilic pore is available,
ions move passively across the membrane, driven by two forces: the
electrical gradient (voltage difference) and chemical gradient (concentration difference). The chemical gradient forces the ions to move from
a compartment of a higher concentration to one of lower concentration.
The electrical gradient forces ions to move in the direction of their
inverse sign (i.e., cations [positively charged ions] move toward a negatively charged compartment, whereas anions [negatively charged ions]
move toward a positively charged compartment). Because the chemical
and electrical gradients can oppose each other, the direction of net ion
movement will depend on the relative contributions of chemical
gradient and electrical potential (i.e., the net electrochemical gradient),
so that ions tend to move spontaneously from a higher to a lower
electrochemical potential.1
The movement of an ion down its chemical gradient in one direction across the cell membrane results in build-up of excess charge carried
by the ion on one side of the membrane, which generates an electrical
gradient that impedes (repels) continuing ionic movement in the same
direction. When the driving force of the electrical gradient across the
membrane becomes equal and opposite to the force generated by the
chemical gradient, the ion is said to be in electrochemical equilibrium,
and the net transmembrane flux (or current) of that particular ion is
zero. In this setting, the membrane electrical potential is called the
equilibrium potential (Eion) (“reversal potential” or “Nernst potential”)
of that individual ion. Any further current flow would reverse the balance
of forces and therefore reverse the current direction until equilibrium
is restored, hence the name “reversal potential.”2 The Eion for a given
ion measures the voltage that the ion concentration gradient generates
when it acts as a battery, and it depends on its concentration on either
side of the membrane and the temperature. At membrane voltages
more positive to the reversal potential of the ion, passive ion movement
is outward, whereas it is inward at a membrane potential (Em) more
negative to the Nernst potential of that channel.1
When multiple ions across a membrane are removed from their
electrochemical equilibrium, each ion will tend to force the Em toward

All living cells, including cardiomyocytes, maintain a difference in the
concentration of ions across their membranes. There is a slight excess
of positive ions on the outside of the membrane and a slight excess of
negative ions on the inside of the membrane, resulting in a difference
in the electrical charge (i.e., voltage, potential difference, or electrical
gradient) across the cell membrane, called the Em (also known as membrane voltage or transmembrane potential). A membrane that exhibits
an electrical gradient is said to be polarized.
In nonexcitable cells, and in excitable cells in their baseline states
(i.e., not conducting electrical signals), the Em is held at a relatively
stable value, called the resting Em. All cells have a negative resting Em
(i.e., the cytoplasm is electrically negative relative to the extracellular
fluid), which arises from the interaction of ion channels and ion pumps
embedded in the membrane that maintain different ion concentrations
on the intracellular and extracellular sides of the membrane.
When an ion channel opens, it allows ion flux across the membrane
that generates an electrical current (I). This current affects the Em,
depending on the membrane resistance (R), which refers to the ratio
between the Em and electrical current, as shown in Ohm’s law: E = I ×
R, or R = E/I. Resistance arises from the fact that the membrane impedes
the movement of charges across it; hence the cell membrane functions
as a resistor (i.e., when current is passed through the membrane, there
is a voltage drop that is predictable from Ohm’s law). Conductance
describes the ability of a membrane to allow the flux of charged ions
in one direction across the membrane. The more permeable the membrane is to a particular ion, the greater is the conductance of the membrane to that ion (Table 1.1). Membrane conductance (g) is the reciprocal
of resistance: g = 1/R.
Because the lipid bilayer of the cell membrane is very thin, accumulation of charged ions on one side gives rise to an electrical force





Molecular Mechanisms of Cardiac Electrical Activity

Definitions Related to Electrical Properties of Cell Membranes




Charge (electric charge, Q)


Voltage (potential difference, V)

Volt (V)

Current (I)
Resistance (R)

Amperes (A)
Ohm (Ω)

Conductance (g)

Siemen (S)

Capacitance (C)


Membrane potential (transmembrane
potential, membrane voltage, Em)
Equilibrium potential of an ion (Eion)
(reversal potential, Nernst potential)

Volt (V)

• The physical property of matter that causes it to experience a force (electrostatic attraction or
repulsion) in the presence of other matter.
• There are two types of electric charges: positive and negative. Like charges repel and unlike attract.
• A separation of unlike charge in space; the greater the amount of charge separated, the larger the
voltage, and the greater the tendency for the charges to flow toward each other.
• Voltage is always measured at one point with respect to another point. There cannot be a voltage
at one point in space.
• Voltage is the ability to drive an electric current across a resistance.
• A flow of electrical charges.
• A measure of the difficulty with which current flows in a circuit; the greater the difficulty, the
greater the resistance.
• A measure of the ease with which current flows in a circuit.
• Conductance is the reciprocal of the resistance.
• The ability of a body to store an electrical charge.
• A material with a large capacitance holds more electric charge at a given voltage, than one with
low capacitance.
• The difference in electrical potential between the interior and the exterior of a biological cell.

Ionic current (Iion)
Capacitive current (nonfaradaic
current, double-layer current)

Volt (V)

Amperes (A)

• The value of the Em at which diffusive and electrical gradients for a particular ion counterbalance,
so that there is no net ion flow across the membrane (i.e., electrochemical equilibrium).
• In other words, equilibrium potential is the membrane potential necessary to maintain a given
concentration difference or the membrane potential that will result from maintenance of a given
concentration difference.
• An ion will be in electrochemical equilibrium if Em = Eion.
• Electrical current generated by the flux of charged ions across the cell membrane.
• The electric current generated by the movement of electrons toward and away from the surfaces of
the cell membrane.
• This current does not involve movement of charged ions across the cell membrane, it only causes
accumulation (or removal) of electrical charges on membrane surface.

(potential) that pulls oppositely charged particles toward the other side.
Hence the cell membrane functions as a capacitor (i.e., capable of separating and storing charge). Although the absolute potential differences
across the cell membrane are small, they give rise to enormous electrical
potential gradients because they occur across a very thin surface. As a
consequence, apparently small changes in Em can produce large changes
in potential gradient and powerful forces that are able to induce molecular
rearrangement in membrane proteins, such as those required for opening
and closing ion channels embedded in the cell membrane. The capacitance of the membrane is generally fixed and unaffected by the molecules
that are embedded in it. In contrast, membrane resistance is highly
variable and depends on the conductance of ion channels embedded
in the membrane.3
The sodium (Na+), potassium (K+), calcium (Ca2+), and chloride
(Cl−) ions are the major charge carriers, and their movement across
the cell membrane creates a flow of current that generates excitation
and signals in cardiac myocytes. The electrical current generated by the
flux of an ion across the membrane is determined by the membrane
conductance to that ion (gion) and the potential (voltage) difference
across the membrane. The potential difference represents the potential
at which there is no net ion flux (i.e., the Eion) and the actual Em: current
= gion × (Em − Eion).
By convention, an inward current increases the electropositivity
within the cell (i.e., causes depolarization of the Em [to become less
negative]) and can result from either the movement of positively charged
ions (most commonly Na+ or Ca2+) into the cell or the efflux of nega-

tively charged ions (e.g., Cl−) out of the cell. An outward current increases
the electronegativity within the cell (i.e., causes hyperpolarization of
the Em [to become more negative]) and can result from either the movement of anions into the cell or the efflux of cations (most commonly
K+) out of the cell.
Opening and closing of ion channels can induce a departure from
the relatively static resting Em, which is called depolarization if the interior
voltage rises (becomes less negative) or hyperpolarization if the interior
voltage becomes more negative. The most important ion fluxes that
depolarize or repolarize the membrane are passive (i.e., the ions move
down their electrochemical gradient without requiring the expenditure
of energy), occurring through transmembrane ion channels. In excitable
cells a sufficiently large depolarization can evoke a short-lasting all-ornone event called an action potential, in which the Em very rapidly
undergoes specific and large dynamic voltage changes.
Both resting Em and dynamic voltage changes such as the action
potential are caused by specific changes in membrane permeabilities
for Na+, K+, Ca2+, and Cl−, which, in turn, result from concerted changes
in functional activity of various ion channels, ion transporters, and ion

During physiological electrical activity, the Em is a continuous function
of time. The current flowing through the cell membrane, at each instant,
is provided by multiple channels and transporters carrying charge in



Molecular Mechanisms of Cardiac Electrical Activity

opposite directions because of their different ion selectivity. The algebraic summation of these contributions is referred to as net transmembrane current.
The cardiac action potential reflects a balance between inward and
outward currents. When a depolarizing stimulus (typically generated
by an electric current from an adjacent cell) abruptly changes the Em
of a resting cardiomyocyte to a critical value (the threshold level), the
properties of the cell membrane and ion conductances change dramatically, precipitating a sequence of events involving the influx and efflux
of multiple ions that together produce the action potential of the cell.
In this fashion an electrical stimulus is conducted from one cell to the
cells adjacent to it.4
Unlike skeletal muscle, cardiac muscle is electrically coupled so that
the wave of depolarization propagates from one cell to the next, independent of neuronal input. The heart is activated by capacitive currents
generated when a wave of depolarization approaches a region of the
heart that is at its resting potential. Unlike ionic currents, which are
generated by the flux of charged ions across the cell membrane, capacitive currents are generated by the movement of electrons toward and
away from the surfaces of the membrane. These electrotonic potential
changes are passive and independent of membrane conductance. The
resulting decrease in positive charge at the outer side of the cell membrane reduces the negative charge on the intracellular surface of the
membrane. These charge movements, which are carried by electrons,
generate a capacitive current. When an excitatory stimulus causes the
Em to become less negative and beyond a threshold level (approximately
−65 mV for working atrial and ventricular cardiomyocytes), Na+ channels activate (open) and permit an inward Na+ current (INa), resulting
in a rapid shift of the Em to a positive voltage range. This event triggers
a series of successive opening and closure of selectively permeable ion
channels. The direction and magnitude of passive movement (and the
resulting current) of an ion at any given transmembrane voltage are
determined by the ratio of the intracellular and extracellular concentrations and the reversal potential of that ion, with the net flux being
larger when ions move from the more concentrated side.
The “threshold potential” is the lowest Em at which opening of enough
Na+ channels (or Ca2+ channels in the setting of nodal cells) is able to
initiate the sequence of channel openings needed to generate a propagated action potential. Small (subthreshold) stimuli depolarize the
membrane in proportion to the strength of the stimulus and cause only
local responses because they do not open enough Na+ channels to generate depolarizing currents large enough to activate nearby resting cells
(i.e., insufficient to initiate a regenerative action potential). On the
other hand, when the stimulus is sufficiently intense to reduce the Em
to a threshold value, regenerative action potential results, whereby
intracellular movement of Na+ depolarizes the membrane more, a process
that increases conductance to Na+ more, which allows more Na+ to
enter, and so on. In this fashion the extent of subsequent depolarization
becomes independent of the initial depolarizing stimulus, and more
intense stimuli do not produce larger action potential responses; rather,
an all-or-none response results.4
Electrical changes in the action potential follow a relatively fixed
time and voltage relationship that differs according to specific cell types.
Although the entire action potential takes only a few milliseconds in
nerve cells, the cardiac action potential lasts several hundred milliseconds. The course of the action potential can be divided into five phases
(numbered 0 to 4). Phase 4 is the resting Em, and it describes the Em
when the cell is not being stimulated.
During the cardiac action potential, membrane voltages fluctuate
in the range of −94 to +30 mV (Fig. 1.1). With physiological external
K+ concentration, the reversal potential of K+ (EK) is approximately
−94 mV, and passive K+ movement during an action potential is out of

the cell. On the other hand, because the calculated reversal potential of
a cardiac Ca2+ channel (ECa) is +64 mV, passive Ca2+ flux is into the cell.
In normal atrial and ventricular myocytes and in His-Purkinje fibers,
action potentials have very rapid upstrokes, mediated by the fast inward
INa. These potentials are called fast response potentials. In contrast, action
potentials in the normal sinus and atrioventricular (AV) nodal cells
and many types of diseased tissues have very slow upstrokes, mediated
by a slow inward, predominantly L-type voltage-gated Ca2+ current
(ICaL), rather than by the fast inward INa (Fig. 1.2). These potentials have
been termed slow response potentials.

Fast Response Action Potential

Phase 4: The Resting Membrane Potential
The Em of resting atrial and ventricular cardiomyocytes remains steady
throughout diastole. The resting Em is caused by the differences in ionic
concentrations across the membrane and the selective membrane permeability (conductance) to various ions. Large concentration gradients
of Na+, K+, Ca2+, and Cl− across the cell membrane are maintained by
the ion pumps and exchangers (Table 1.2).4
Under normal conditions, the resting membrane is most permeable
to K+ and relatively impermeable to other ions. K+ has the largest resting
membrane conductance (gK is 100 times greater than gNa) because of
the abundance of open K+ channels at rest, whereas Na+ and Ca2+ channels are generally closed. Thus K+ exerts the largest influence on the
resting Em. As a consequence, the resulting Em is almost always close to
the K+ reversal potential (Em approximates EK). The actual resting Em
is slightly less negative than EK because the cell membrane is slightly
permeable to other ions.
The inwardly rectifying K+ (Kir) channels underlie an outward K+
current (IK1) responsible for maintaining the resting potential near the
EK in atrial, His-Purkinje, and ventricular cells, under normal conditions. Kir channels preferentially allow currents of K+ ions to flow into
the cell with a strongly voltage-dependent decline of K+ efflux (i.e.,
reduction of outward current) on membrane depolarization. As such,
IK1 is a strong rectifier that passes K+ currents over a limited range of
Em. At a negative Em, IK1 conductance is much larger than that of any
other current; thus it clamps the resting Em close to the reversal potential
for K+ (EK) (see Chapter 2 for detailed discussion on the concept of
rectification). IK1 density is much higher in ventricular than in atrial
myocytes, a feature that largely prevents the ventricular cell from having
diastolic membrane depolarization and pacemaker activity. By contrast,
IK1 is almost absent in sinus and AV nodal cells, thus allowing for relatively more depolarized resting diastolic potentials compared with atrial
and ventricular myocytes (Table 1.3). The effect of outward K+ current
to resist membrane depolarization (keeping voltage fixed) is sometimes
referred to as a voltage clamping effect.2
A unique property of Kir currents is the unusual dependence of
rectification on extracellular K+ concentration. Specifically, with an

Intracellular and Extracellular
Ion Concentrations and Equilibrium
Potentials in Cardiomyocytes




Potential (mV)






Molecular Mechanisms of Cardiac Electrical Activity















200 A/F



5 A/F


1.5 A/F


10 A/F





1 A/F



1 A/F




1 A/F



Time (msec)



Time (msec)


Fig. 1.1 Contribution of Depolarizing Inward and Repolarizing Outward Currents to the Atrial and
Ventricular Action Potential (AP). The top panel from the atrial (left) and ventricular (right) myocytes. The
five phases of the AP are labeled: 0 = upstroke of the AP represents depolarization of the membrane; 1 =
initial repolarization; 2 = plateau phase; 3 = late repolarization; 4 = the resting (diastolic) phase. The rate of
change of the AP is directly proportional to the sum of the underlying transmembrane ion currents (lower
panels). Inward currents (blue) depolarize the membrane, whereas outward currents (red) contribute to
repolarization. Compared with an atrial AP, the ventricular AP typically has longer duration, higher plateau
potential (phase 2), and more negative resting membrane potential (phase 4). ICa, L-type Ca2+ current; INa,
Na+ current; INCX, Na+-Ca2+ exchanger; IKr, rapidly activating delayed rectifier K+ current; IKs, slowly activating
delayed rectifier K+ current; IKur, ultrarapidly activating delayed rectifier K+ current; IK1, inward rectifier K+
current; Ito, transient outward K+ current. (With permission from Oudit GY, Backx PH. Voltage-gated
potassium channels. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 7th ed.
Philadelphia: Elsevier; 2018.)


Molecular Mechanisms of Cardiac Electrical Activity


SA nodal










100 mV


0.2 sec
Fig. 1.2 Action Potential Waveforms, Displaced in Time to Reflect the Temporal Sequence of Propagation, Vary in Different Regions of the Heart. AV, Atrioventricular (node); Endo, endocardial; Epi, epicardial;
LV, left ventricle; Mid, midmyocardial; RV, right ventricle; SA, sinoatrial. (Modified with permission from
Nerbonne JM. Heterogeneous expression of repolarizing potassium currents in the mammalian myocardium.
In Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 5th ed. Philadelphia: Saunders;


Regional Differences in Cardiac Action Potential


Sinus Nodal Cell

Atrial Muscle Cell

AV Nodal Cell

Purkinje Fiber

Ventricular Muscle Cell

Resting potential (mV)
Action potential amplitude (mV)
Action potential duration (msec)

−50 to −60
+60 to +70
100 to 300

−80 to −90
+110 to +120
100 to 300

−60 to −70
+70 to +80
100 to 300

−90 to −95
300 to 500

−80 to −90
+110 to +120
200 to 300

AV, Atrioventricular.

increase in extracellular K+, the IK1 current-voltage relationship shifts
nearly in parallel with the EK and leads to a crossover phenomenon.
One important consequence of such behavior is that at potentials positive to the crossover, K+ conductance increases rather than decreases,
against an expectation based on a reduced driving force for K+ ions as
a result of elevated extracellular K+ concentration.5
The resting Em is also powered by the Na+-K+ adenosine triphosphatase (ATPase) (the Na+-K+ pump), which helps to establish concentration gradients of Na+ and K+ across the cell membrane. Under
physiological conditions, the Na+-K+ pump transports two K+ ions into
the cell against its chemical gradient and three Na+ ions outside against

its electrochemical gradient at the expense of one ATP molecule. Because
the stoichiometry of ion movement is not 1 : 1, the Na+-K+ pump is
electrogenic and generates a net outward movement of positive charges
(i.e., an outward current). At faster heart rates, the rate of Na+-K+
pumping increases to maintain the same ionic gradients, thus counteracting the intracellular gain of Na+ and loss of K+ with each
Ca2+ does not contribute directly to the resting Em because the voltageactivated Ca2+ channels are closed at the hyperpolarized resting Em.
However, changes in intracellular free Ca2+ concentration can affect
other membrane conductance values. Increases in intracellular Ca2+



Molecular Mechanisms of Cardiac Electrical Activity

levels can stimulate the Na+-Ca2+ exchanger (INa-Ca), which exchanges
three Na+ ions for one Ca2+ ion; the direction depends on the Na+ and
Ca2+ concentrations on the two sides of the membrane and the Em
difference. At resting Em and during a spontaneous sarcoplasmic reticulum Ca2+ release event, this exchanger would generate a net Na+ influx,
possibly causing transient membrane depolarizations.

Phase 0: The Upstroke—Rapid Depolarization
On excitation of an atrial, ventricular, or Purkinje cardiomyocyte by
electrical stimuli from adjacent cells, its resting Em (approximately
−85 mV) depolarizes, leading to opening (activation) of Na+ channels
from its resting (closed) state and enabling a large and rapid influx of
Na+ ions (inward INa) into the cell down their electrochemical gradient.
As a consequence of increased Na+ conductance, the excited membrane
no longer behaves like a K+ electrode (i.e., exclusively permeable to K+)
but more closely approximates an Na+ electrode, and the Em moves
toward the ENa (see Table 1.2). Once an excitatory stimulus depolarizes
the Em beyond the threshold for activation of Na+ channels (approximately −65 mV), the activated INa is regenerative and no longer depends
on the initial depolarizing stimulus. As a consequence, the influx of
Na+ ions further depolarizes the membrane and thereby increases conductance to Na+ more, which allows more Na+ to enter the cell (thus
Normally, activation of Na+ channels is transient; fast inactivation
(closing of the channel pore) starts simultaneously with activation, but
because inactivation is slightly delayed relative to activation, the channels remain transiently (less than 1 millisecond) open to conduct INa
during phase 0 of the action potential before it closes. In addition, the
influx of Na+ into the cell increases the positive intracellular charges
and reduces the driving force for Na+. When the ENa is reached, no
further Na+ ions enter the cell.
The rate at which depolarization occurs during phase 0 (i.e., the
maximum rate of change of voltage over time [dV/dtmax]) is a reasonable approximation of the rate and magnitude of Na+ entry into the
cell and a determinant of conduction velocity for the propagated action
potential (see later).
The threshold for activation of ICaL is approximately −30 to −40 mV.
Although ICaL is normally activated during phase 0 by the regenerative
depolarization caused by the fast INa, ICaL is much smaller than the peak
INa. Furthermore, the amplitude of ICaL is not maximal near the action
potential peak because of the time-dependent nature of ICaL activation,
as well as the low driving force (Em − ECa) for ICaL. Therefore ICaL contributes little to the action potential until the fast INa is inactivated, after
completion of phase 0. As a result, ICaL affects mainly the plateau of
action potentials recorded in atrial and ventricular muscle and HisPurkinje fibers. On the other hand, ICaL plays a prominent role in the
upstroke of slow response action potentials in partially depolarized
cells in which the fast Na+ channels have been inactivated.

Phase 1: Early Repolarization
Phase 0 is followed by phase 1 (early repolarization), during which the
membrane repolarizes rapidly and transiently to almost 0 mV (early
notch), partly because of the inactivation of INa and concomitant activation of several outward currents. The transient outward K+ current (Ito)
is mainly responsible for phase 1 of the action potential. Ito rapidly
activates (with time constants less than 10 milliseconds) by depolarization and then rapidly inactivates (25 to 80 milliseconds for the fast
component of Ito [Ito,f ], and 80 to 200 milliseconds for the slow component of Ito [Ito,s]). The influx of K+ ions via Ito channels partially
repolarizes the membrane, thus shaping the rapid repolarization (phase
1) of the action potential and setting the height of the initial plateau
(phase 2) (see Fig. 1.1). In addition, an Na+ outward current through

the Na+-Ca2+ exchanger operating in reverse mode likely contributes to
this early phase of repolarization.4

Phase 2: The Plateau
Phase 2 (plateau) represents a delicate balance between the depolarizing
inward currents (ICaL and a small residual component of inward INa)
and the repolarizing outward currents (ultrarapidly [IKur], rapidly [IKr],
and slowly [IKs] activating delayed outward rectifying currents) (see
Fig. 1.1). Phase 2 is the longest phase of the action potential, lasting
tens (atrium) to hundreds of milliseconds (His-Purkinje system and
ventricle). The plateau phase is unique among excitable cells and marks
the phase of Ca2+ entry into the cell. It is the phase that most clearly
distinguishes the cardiac action potential from the brief action potentials
of skeletal muscle and nerve.4,7,8
ICaL is activated by membrane depolarization, is largely responsible
for the action potential plateau, and is a major determinant of the
duration of the plateau phase. ICaL also links membrane depolarization
to myocardial contraction. L-type Ca2+ channels activate on membrane
depolarization to potentials positive to −40 mV. ICaL peaks at an Em of
0 to +10 mV and tends to reverse at +60 to +70 mV, following a bellshaped current-voltage relationship.
Na+ channels also make a contribution, although minor, to the plateau
phase. After phase 0 of the action potential, some Na+ channels occasionally fail to inactivate or exhibit prolonged opening or reopening
repetitively for hundreds of milliseconds after variable and prolonged
latencies, resulting in a small inward INa (with a magnitude of less than
1% of the peak INa). This persistent or “late” INa (INaL), along with ICaL,
helps to maintain the action potential plateau.9
IKr and IKs are activated at depolarized membrane potentials. IKr
activates relatively fast (in the order of tens of milliseconds) on membrane depolarization, thus allowing outward diffusion of K+ ions in
accordance with its electrochemical gradient, but voltage-dependent
inactivation thereafter is very fast. Hence only limited numbers of channels remain in the open state, whereas a considerable fraction resides
in the nonconducting inactivated state. The fast voltage-dependent
inactivation limits outward current through the channel at positive
voltages and thus helps to maintain the action potential plateau phase
that controls contraction and prevents premature excitation. However,
as the voltage becomes less positive at the end of the plateau phase of
repolarization, the channels recover rapidly from inactivation; this
process leads to a progressive increase in IKr amplitudes during action
potential phases 2 and 3, with maximal outward current occurring
before the final rapid declining phase of the action potential.10
IKs, which is approximately 10 times larger than IKr, also contributes
to the plateau phase. IKs activates in response to membrane depolarization to potentials positive to −30 mV and gradually increases during
the plateau phase because its time course of activation is extremely
slow, slower than any other known K+ current. In fact, steady-state
amplitude of IKs is achieved only with extremely long membrane depolarization. Hence the contribution of IKs to the net repolarizing current
is greatest late in the plateau phase, particularly during action potentials
of long duration. Importantly, although IKs activates slowly compared
with action potential duration, it is also slowly inactivated. As heart
rate increases, IKs increases because channel deactivation is slow and
incomplete during the shortened diastole. This allows IKs channels to
accumulate in the open state during rapid successive action potentials
and mediate the faster rate of repolarization. Hence IKs plays an important role in determining the rate-dependent shortening of the cardiac
action potential.5
IKur is detected only in human atria but not in the ventricles, such
that it is the predominant delayed rectifier current responsible for atrial
repolarization and is a basis for the much shorter duration of the action


Molecular Mechanisms of Cardiac Electrical Activity

potential in the atrium. IKur activates rapidly on depolarization in the
plateau range and displays outward rectification, but it inactivates slowly
during the time course of the action potential.
The Na+-Ca2+ exchanger operating in forward mode (three Na+ ions
in for one Ca2+ ion out) and the Na+-K+ pump provide minor current
components during phase 2.
Importantly, during the plateau phase, membrane conductance to
all ions falls to rather low values. Thus less change in current is required
near plateau levels than near resting potential levels to produce the
same changes in Em. In particular, K+ conductance falls during the plateau
phase as a result of inward rectification of IK1 (i.e., voltage-dependent
decline of K+ efflux and hence reduction of outward current) on membrane depolarization, in spite of the large electrochemical driving force
on K+ ions during the positive phase of the action potential (phases 0,
1, and 2). This property allows membrane depolarization following
Na+ channel activation, slows membrane repolarization, and helps to
maintain a more prolonged cardiac action potential. This also confers
energetic efficiency in the generation of the action potential.11,12

Phase 3: Final Rapid Repolarization
Phase 3 is the phase of rapid repolarization that restores the Em to its
resting value. Phase 3 is mediated by the increasing conductance of the
delayed outward rectifying currents (IKr and IKs), the inwardly rectifying
K+ currents (IK1 and acetylcholine-activated K+ current [IKACh]), and
time-dependent inactivation of ICaL (see Fig. 1.1). Final repolarization
during phase 3 results from K+ efflux through the IK1 channels, which
open at potentials negative to −20 mV.4

Phase 4: Restoration of Resting Membrane Potential
During the action potential, Na+ and Ca2+ ions enter the cell and depolarize the Em. Although the Em is quickly repolarized by the efflux of
K+ ions, restoration of transmembrane ionic concentration gradients
to the baseline resting state is necessary. This is achieved by the Na+-K+
ATPase (Na+-K+ pump, which exchanges two K+ ions inside and three
Na+ ions outside) and by the Na+-Ca2+ exchanger (INa-Ca, which exchanges
three Na+ ions for one Ca2+ ion).4
Reduction of cytosolic Ca2+ concentration during diastole is achieved
by the reuptake Ca2+ by the sarcoplasmic reticulum via activation of
the sarco/endoplasmic reticulum calcium-ATPase calcium pump
(SERCA), in addition to extrusion across the sarcolemma via the Na+Ca2+ exchanger. In the human heart under resting conditions, the time
required for cardiac myocyte depolarization, contraction, relaxation,
and recovery is approximately 600 milliseconds.

Regional Heterogeneity of the Action Potential
Substantial differences in expression levels of ion channels underlie the
considerable heterogeneity in action potential duration and configuration between cardiomyocytes located in different regions of the heart.
The characteristics of the action potential differ in atrial versus ventricular myocardium, as well as across the ventricular myocardial wall
from endocardium, midmyocardium, to epicardium (see Fig. 1.2).

Atrioventricular Heterogeneity of the Action Potential
Compared with the atrium, ventricular myocytes maintain a slightly
more hyperpolarized resting Em (approximately −85 mV vs. −80 mV).
In addition, the action potential duration is longer, the plateau phase
reaches a more depolarized Em (approximately +20 mV), and phase 3
repolarization curve is steeper in ventricular myocytes as compared
with the atrial action potential (see Table 1.3).
The differences in action potential configuration between atria and
ventricles are mainly related to differences in ionic current densities
and ion channel expression (especially K+ channels) between ventricular


and atrial myocytes. Although IKr and IKs densities are similar in atrial
and ventricular myocytes, IKur is detected only in human atria and not
in the ventricles. In fact, IKur is the predominant delayed rectifier current
responsible for human atrial repolarization, with only small contribution of IKr and IKs.
Furthermore, the density of Ito is twofold higher in the atria compared with ventricular myocytes. In addition, Ito subtypes (Ito,f and Ito,s)
are differentially expressed in the heart. Ito,f is the principal subtype
expressed in human atrium. Conversely, Ito,s is larger and Ito,f is smaller
in the ventricles compared with atrial tissue.8
The markedly higher densities of Ito,f, together with the expression
of IKur, accelerate the early phase of repolarization and lead to lower
plateau potentials and shorter action potential durations in atrial as
compared with ventricular cells.13
IK1 density is much higher in ventricular than in atrial myocytes,
and this explains the steep repolarization phase in the ventricles (where
the more abundant IK1 plays a larger role in accelerating the terminal
portion of repolarization) and the shallower phase in the atria. Furthermore, the higher IK1 channel expression underlies the hyperpolarized
resting Em in ventricular myocytes, and prevents the ventricular cell
from exhibiting pacemaker activity.14
Several other K+ channels are atrial selective and potentially contribute significantly to the atrial, but not ventricular, action potential.
These include IKACh, two-pore K+ channels (K2P), and small-conductance
Ca2+-activated K+ (SK) channels.

Ventricular Regional Heterogeneity of the Action Potential
Action potential differences exist among the different layers across the
ventricular wall, between the left and right ventricles, and from the
apical region to the base.
Three distinct action potential waveforms have been distinguished
from three predominant cell types contributing to the transmural heterogeneity of ventricular repolarization: the epicardial, midmyocardial,
and endocardial cardiomyocytes. The most notable differences among
these three layers are the prominent phase 1 notch and the spike and
dome morphology of epicardial and midmyocardial action potentials
compared with endocardium. The action potential duration of epicardial
myocytes is shorter than that of endocardial myocytes. The duration
of the action potential is longest in midmyocardial myocytes.8,14
The distinct notch phase in the action potential waveform of epicardial myocytes has mainly been attributed to the regional differences in Ito density across the myocardial wall. In human ventricles,
Ito densities are much higher in the epicardium and midmyocardium
than in the endocardium. Furthermore, although both Ito,f and Ito,s are
expressed in the ventricle, Ito,f is more prominent in the epicardium
and midmyocardium than in the endocardium, whereas Ito,s is mainly
present in the endocardium and Purkinje cells. A prominent Ito-mediated
action potential notch in ventricular epicardium but not endocardium produces a transmural voltage gradient during early ventricular
repolarization that registers as a J wave or J point elevation on the
electrocardiogram (ECG).8,14
Some experimental studies in wedge preparations strongly suggest the
presence of a subpopulation of cells in the midmyocardium (referred to
as the M cells) that exhibits distinct electrophysiological (EP) properties,
although the presence of M cells has not been consistently confirmed
by intact heart experiments. The putative M cells appear to have the
longest action potential duration across the myocardial wall, largely
attributed to their weaker IKs current but stronger late INa and Na+-Ca2+
exchanger currents. Hence the M cells have been proposed to underlie
the EP basis for transmural ventricular dispersion of repolarization and
the T wave on the surface ECG, with the peak of the T wave (in wedge
preparations) coinciding with the end of epicardial repolarization and



Molecular Mechanisms of Cardiac Electrical Activity

the end of the T wave coinciding with the end of repolarization of the
M cells. Although the role of M cells under physiological conditions
remains controversial, these cells appear to have a significant role in
arrhythmogenesis under a variety of pathological conditions, such as
the long QT and Brugada syndromes, secondary to exaggeration of
transmural repolarization gradients.
In addition to the transmural action potential gradient that exists
across the three layers of myocardium in the left and right ventricles,
the right ventricular (RV) action potential duration overall is shorter
and the spike and dome morphology is more pronounced compared
with that of the left ventricle (LV). These differences have been attributed to higher Ito densities in the right than in the left ventricular
Evidence also suggests an apicobasal ventricular action potential
heterogeneity. Action potential duration appears to be shorter in LV
base compared with the apex. Larger Ito and IKs in apical compared with
basal myocytes likely underlie those observations.14

Slow Response Action Potential
In normal atrial and ventricular myocytes and in the His-Purkinje
fibers, action potentials have very rapid upstrokes mediated by the
fast inward INa. These potentials are called fast response potentials. In
contrast, action potentials in the normal sinus and AV nodal cells
and many types of diseased tissue have very slow upstrokes, mediated
predominantly by the slow inward ICaL, rather than by the fast inward
INa (see Fig. 1.2). These potentials have been termed slow response
As noted, action potentials of pacemaker cells in the sinus and AV
nodes are significantly different from those in working atrial and ventricular myocardium. Slow response action potentials are characterized
by a more depolarized Em at the onset of phase 4 (−50 to −65 mV),
slow diastolic depolarization during phase 4, and reduced action potential
amplitude. Furthermore, the rate of depolarization in phase 0 is much
slower than that in the working myocardial cells, resulting in reduced
conduction velocity of the cardiac impulse in the nodal regions (see
Table 1.3). Cells in the His-Purkinje system can also exhibit phase 4
depolarization under special circumstances (when Na+ channels are
inactivated by pathological processes).

clock” (also referred to as the “voltage clock” or “ion channel clock”)
refers to the time- and voltage-dependent membrane ion channels
underlying pacemaking activity, including the decay of the outward
rectifier K+ current and the activation of several inward currents (If, ICaL,
ICaT, and INa).
Newer evidence suggests that the sarcoplasmic reticulum, a major
Ca2+ store in sinus nodal cells, can function as a physiological clock
(the so-called calcium clock) within the cardiac pacemaker cells and
has a substantial impact on late diastolic depolarization.15,17
There remains some degree of uncertainty about the relative role
of If versus that of intracellular Ca2+ cycling in controlling the normal
pacemaker cell automaticity. Furthermore, the interactions between the
membrane clock and the intracellular calcium clock and cellular mechanisms underlying this internal Ca2+ clock are not completely elucidated.
A further debate has arisen around their individual (or mutual) relevance
in mediating the positive and negative chronotropic effects of neurotransmitters. Nevertheless, these interactions are of fundamental
importance for understanding the integration of pacemaker mechanisms
at the cellular level (see Chapter 3 for detailed discussion on the mechanisms of automaticity and pacemaker activity).14

Phase 0: The Upstroke—Slow Depolarization
IK1 is almost absent in sinus and AV nodal cells, thus allowing for relatively more depolarized resting diastolic potentials (−50 to −65 mV)
compared with atrial and ventricular myocytes and facilitating diastolic depolarization mediated by the inward currents (e.g., If ). At the
depolarized level of the maximum diastolic potential of pacemaker
cells, most Na+ channels are inactivated and unavailable for phase
0 depolarization. Consequently, action potential upstroke is mainly
achieved by ICaL.15
L-type Ca2+ channels activate on depolarization to potentials positive
to −40 mV, and ICaL peaks at 0 to +10 mV. The peak amplitude ICaL is
less than 10% that of INa, and the time required for activation and
inactivation of ICaL is approximately an order of magnitude slower than
that for INa. As a consequence, the rate of depolarization in phase 0
(dV/dt) is much slower and the peak amplitude of the action potential
is less than that in the working myocardial cells.


Phase 4: Diastolic Depolarization

The sinus and AV nodal cells lack the inward rectifier K current (IK1),
which acts to stabilize the resting Em in the normal working atrial and
ventricular myocardium and Purkinje fibers. Sinus and AV nodal excitable cells exhibit a spontaneous, slow, and progressive decline in the
Em during diastole (spontaneous diastolic depolarization or phase 4
depolarization) that underlies normal automaticity and pacemaking
function. Once this spontaneous depolarization reaches threshold
(approximately −40 mV), a new action potential is generated.15
The ionic mechanisms responsible for diastolic depolarization and
normal pacemaker activity in the sinus node are still controversial.
Originally, a major role was attributed to the decay of the delayed K+
conductance (an outward current) activated during the preceding action
potential (the IK-decay theory). This model of pacemaker depolarization
lost favor upon the discovery of the “funny” current (If ), sometimes
referred to as the pacemaker current. If is a hyperpolarization-activated
inward current that is carried largely by Na+ and, to a lesser extent, K+
ions. Once activated, If depolarizes the membrane to a level where the
Ca2+ current activates to initiate an action potential.15,16
Other ionic currents gated by membrane depolarization (i.e., ICaL
and T-type Ca2+ current [ICaT]), nongated and nonspecific background
leak currents, and a current generated by the Na+-Ca2+ exchanger have
also been proposed to be involved in pacemaking. The “membrane

Excitability of a cardiac cell describes the ease with which the cell responds
to a stimulus with a regenerative action potential. A certain minimum
charge must be applied to the cell membrane to elicit a regenerative
action potential (i.e., the stimulus should be sufficiently intense to reduce
the Em to the threshold value). Excitability is inversely related to the
charge required for excitation.
Excitability of a cardiac cell depends on the passive and active properties of the cell membrane. The passive properties include the membrane
resistance and capacitance and the intercellular resistance. The most
important determinant of reduced excitability is the reduced availability
of Na+ channels. The more negative the Em is, the more Na+ channels
are available for activation, the greater the influx of Na+ into the cell
during phase 0, and the greater the conduction velocity. In contrast,
membrane depolarization to levels of −60 to −70 mV can inactivate
half the Na+ channels, and depolarization to −50 mV or less can inactivate all the Na+ channels, thereby rendering Na+ channels unavailable
for mediating an action potential upstroke and thus reducing tissue
excitability (Fig. 1.3).
Reduced excitability is physiologically observed during the relative
refractory period (occurring during phase 3 of the action potential,
before full recovery of Em). At less negative potentials of the cell membrane, a portion of Na+ channels will still be inactivated and unavailable

100% rested






% I Na

(% rested) 40


Molecular Mechanisms of Cardiac Electrical Activity



100% inactivated


Full recovery time


Effective refractory period

refractory period





Resting potential (mV)
Fig. 1.3 Cellular Excitability. Relationship between transmembrane
action potential from single ventricular muscle fiber and excitability of
fiber to cathodal stimulation. Amplitudes of peak sodium current (INa)
and proportion of Na+ channels in the resting state are depicted as a
function of resting membrane potential. I, Inactivation of Na+ channels;
R, recovery of Na+ channels. (Redrawn from Rosen MS, Wit AL, Hoffman
BF. Electrophysiology and pharmacology of cardiac arrhythmias. I. Cellular electrophysiology of the mammalian heart. Am Heart J. 1974;88:380.)

for activation. As a result, initiation of a propagating action potential
will require a larger-than-normal stimulus. Even then, INa and phase 0
of the resulting action potential are reduced, and conduction of a premature stimulus occurring during that period is slowed.
On the other hand, supernormal excitability can be observed during
a brief period at the end of phase 3 of the action potential. During the
supernormal period, excitation is possible in response to an otherwise
subthreshold stimulus; that same stimulus fails to elicit a response earlier
and later than the supernormal period. Two factors are responsible for
supernormality: the availability of fast Na+ channels and the proximity
of the Em to threshold potential. During the supernormal phase of
excitability, the cell has recovered enough to respond to a stimulus (i.e.,
an adequate number of Na+ channels is available for activation). At the
same time, because the Em is still reduced, it requires only a little additional depolarization to bring the fiber to threshold; thus a stimulus
that is smaller than is normally required is now able to elicit an action
potential. However, because Na+ channels are still not fully activated,
the resulting action potential is still somewhat reduced from normal
in amplitude and propagation velocity.18 In general, the later the second
stimulus comes, the more the Na+ channels are reactivated, and the
more rapid the upstroke of the second action potential.
Reduced membrane excitability can occur in certain pathophysiological conditions, including genetic mutations that result in loss of Na+
channel function, Na+ channel blockade with class I antiarrhythmic
drugs, and acute myocardial ischemia.19
Action potentials with reduced upstroke velocity resulting from
partial inactivation of Na+ channels are called “depressed fast responses.”
Importantly, refractoriness in cells with reduced Em can outlast voltage
recovery of the action potential (i.e., the cell can still be refractory or
partially refractory after the resting Em returns to its most negative value).

During a cardiac cycle, once an action potential is initiated, the cardiomyocyte becomes inexcitable to stimulation (i.e., unable to initiate
another action potential in response to a stimulus of threshold intensity)
for some duration of time (which is generally slightly shorter than the
duration of the “true” action potential duration) until its membrane




200 250

300 350


Fig. 1.4 Cellular Refractory Periods. See text for details. (Redrawn
from Rosen MS, Wit AL, Hoffman BF. Electrophysiology and pharmacology of cardiac arrhythmias. I. Cellular electrophysiology of the mammalian
heart. Am Heart J. 1974;88:380.)

has repolarized to a certain level. With repolarization, Na+ channels
normally recover rapidly from inactivation (within 10 milliseconds)
and are ready to open again. Refractoriness is determined, in part, by
the action potential duration and the Em, and the degree of refractoriness primarily reflects the number of Na+ channels that have recovered
from their inactive state. The period of refractoriness to stimulation is
physiologically necessary for the mechanical function of the heart; it
allows only gradual recovery of excitability, thus permitting relaxation
of cardiac muscle before subsequent activation. In addition, the refractory period acts as a protective mechanism by preventing multiple,
compounded action potentials from occurring (i.e., it limits the frequency
of depolarization and heart rate). Therefore refractoriness is a determinant of susceptibility to arrhythmias. In general, shorter refractoriness
facilitates reentry and arrhythmias.9
There are different levels of refractoriness during the action potential
(Fig. 1.4). During the absolute refractory period (which extends over
phases 0, 1, 2, and part of phase 3 of the action potential), no stimulus,
regardless of its strength, can reexcite the cell. After the absolute refractory period, a stimulus can cause some cellular depolarization, but it
does not lead to a propagated action potential. The sum of this period
(which includes a short interval of phase 3 of the action potential) and
the absolute refractory period is termed the effective refractory period
(ERP, ending during phase 3 at an Em of approximately −60 mV). The
ERP is followed by the relative refractory period, which extends over the
middle and late parts of phase 3 (at an Em of approximately −60 mV
during phase 3) to the end of phase 3 of the action potential. During
the relative refractory period, initiation of a second action potential is
more difficult but not impossible; a larger-than-normal stimulus can
result in activation of the cell and lead to a propagating action potential
(Fig. 1.5). However, the upstroke of the new action potential is less
steep and of lower amplitude and its conduction velocity is reduced
compared with normal. As noted, there is a brief period in phase 3, the
supernormal period, during which excitation is possible in response to
an otherwise subthreshold stimulus (supernormal excitability).18
In pacemaking tissues, INa is predominantly absent and excitability
is mediated by the activation of ICaL. After inactivation, the transition
of Ca2+ channels from the inactivated to the closed resting state (i.e.,
recovery from inactivation) is relatively slow. The time constant for
recovery from inactivation depends on both the Em and the intracellular
Ca2+ concentration (typically 100 to 200 milliseconds at −80 mV and
low intracellular Ca2+ concentration). This means that ICaL must recover
from inactivation between action potentials. As a result, excitability in



Molecular Mechanisms of Cardiac Electrical Activity


Vm (mV)



100 msec
Fig. 1.5 Excitability as a Function of Latency. The changes in action
potential amplitude and shape of the upstroke as action potentials are
initiated at different stages of the relative refractory period of the preceding excitation. (Redrawn from Rosen MS, Wit AL, Hoffman BF.
Electrophysiology and pharmacology of cardiac arrhythmias. I. Cellular
electrophysiology of the mammalian heart. Am Heart J. 1974;88:380.)

pacemaking cells may not be recovered by the end of phase 3 of the
action potential and full restoration of maximum diastolic potential
because L-type Ca2+ channels require longer time to recovery from
inactivation to be able to mediate the upstroke of a new action potential.
In other words, sinus and AV nodal cells remain refractory for a time
interval that is longer than the time it takes for full membrane repolarization to occur, a phenomenon termed postrepolarization refractoriness. This can also occur in working myocardium during some disease
states such as myocardial infarction.

Cardiac excitation involves generation of the action potential by individual cells, followed by propagation of the electrical impulse along the
cardiac muscle fiber and rapidly from cell to cell throughout the cardiac
tissue. Conduction velocity refers to the speed of propagation of the
action potential through cardiac tissue. The conduction velocity varies
in cardiac tissues, ranging from 0.05 m/s in the atrioventricular node
(AVN), to 0.5 m/s in atrial and ventricular working myocardium, 2 m/s
in the bundle branches, and up to 4 m/s in Purkinje fibers.20 In most
regions of the heart, conduction does not occur as a continuous process;
rather, the propagating electrical wavefronts interact with structural
boundaries that exist at the cellular level (cell membranes, intercellular
gap junctions, the three-dimensional [3-D] arrangement of cardiomyocytes), as well as at the more macroscopic level (microvasculature, connective tissue barriers, trabeculation).21,22

Intracellular Propagation
Once initiated, the action potential propagates along the cell membrane
until the entire cardiomyocyte is depolarized. The velocity of propagation increases with increasing cell diameter, action potential amplitude,
and the initial rate of the rise of the action potential.
An action potential traveling along a cardiac muscle fiber is propagated by local circuit currents, much as it does in nerve and skeletal
muscle. Conduction velocity along the cardiac fiber is directly related
to the action potential amplitude (i.e., the voltage difference between
the fully depolarized and the fully polarized regions) and the rate of
change of potential (i.e., the rate of rise of phase 0 of the action potential

[dV/dt]). These factors depend on the amplitude of INa, which, in turn,
is directly related to the Em at the time of stimulation, the availability
of Na+ channels for stimulation, and the size of the Na+ electrochemical
potential gradient across the cell membrane.
Normally, the charge flow across depolarizing ion channels (INa) is
significantly larger than the charge needed to excite the same cell, providing sufficient extra stimulatory current to drive propagation forward.
This property (referred to as “propagation reserve” or “safety of propagation”) helps to maintain action potential propagation under different
physiological and pathophysiological conditions.23 Working atrial and
ventricular myocardium and, in particular, Purkinje fibers have high
concentrations of Na+ channels (Purkinje fibers contain up to 1 million
Na+ channels per cell), which help to generate a large depolarizing
current flow (INa) during the action potential. The large INa spreads
quickly within and between cells to support rapid conduction.
Reduction of membrane excitability leads to a reduction in the rate
or amplitude of depolarization (INa) during phase 0 of the action potential. Conduction velocity decreases monotonically with progressive
reduction of membrane excitability. When the safety factor for conduction falls to less than 1 (i.e., the source current becomes less than the
current necessary for excitation of downstream tissue), conduction can
no longer be sustained, and failure (conduction block) occurs.
In tissues with slow response action potentials (sinus and AV nodes),
the upstroke of the action potential is formed by ICaL instead of INa.
Because ICaL has lower amplitude and slower activation kinetics than
INa, slow response action potentials exhibit reduced amplitudes and
upstroke velocities. Hence slow conduction (approximately 0.1 to 0.2 m/s)
and prolonged refractoriness are characteristic features of nodal tissues.
These cells also have a reduced safety factor for conduction, which
means that the stimulating efficacy of the propagating impulse is low,
and conduction block occurs easily.

Intercellular Propagation
Propagation of action potentials from one cell to adjacent cells is achieved
by direct ionic current spread (without electrochemical synapses) via
specialized, low resistance intercellular connections (gap junctional
channels) located mainly in arrays within the intercalated disks. Gap
junctions facilitate impulse propagation throughout the heart, so that
the heart behaves electrically as a functional syncytium, resulting in a
coordinated mechanical function.22
Gap junctional channels connect neighboring cells and allow biochemical and low-resistance electrical coupling. Although the resistivity
of the gap junctional membrane for the passage of ions and small
molecules and for electrical propagation is several orders of magnitude
lower compared with uncoupled cell membranes, gap junction coupling
provides a resistance pathway that is several orders of magnitude higher
than the cytoplasmic intracellular resistivity (conduction delay is approximately 0.21 to 0.27 milliseconds at gap junctions, and 0.05 to 0.1 milliseconds at the cell membrane).24 As a consequence, impulse propagation
along single cell chains of cardiomyocytes is saltatory, in which the
high-resistance intercellular junctions alternate with the low cytoplasmic
resistance. However, this feature is lost in intact multicellular tissue due
to lateral gap junctional coupling which serves to average local small
differences in activation times of individual cardiomyocytes at the excitation wavefront.19
The number, size, and molecular composition of the gap junction
channels contribute to the specific propagation properties of a given
tissue. Tissue-specific connexin expression and gap junction spatial
distribution, as well as the variation in the structural composition of
gap junction channels, allow for a greater versatility of gap junction
physiological features and enable disparate conduction properties in
cardiac tissue.25


Molecular Mechanisms of Cardiac Electrical Activity

Three different connexins are prominently expressed in the atrial
and ventricular myocardium: connexin 40 (Cx40), connexin 43 (Cx43),
and connexin 45 (Cx45), named for their molecular masses. A fourth
connexin has been described in the AVN (Cx31.9). Cx40 gap junction
channels exhibit the largest conductance and Cx45 the smallest. The
myocytes of the sinus node and AVN are equipped with small, sparse,
and dispersed gap junctions containing Cx45, a connexin that forms
low conductance channels, thus underlying the relatively poor intercellular coupling in nodal tissues, a property that is linked to slowing of
conduction. In contrast, atrial myocardium gap junctions consist mainly
of Cx43 and Cx40, ventricular myocardium of Cx43, and the and Purkinje fibers of Cx40.24,25
Importantly, there is a high redundancy in connexin expression in
the heart with regard to conduction of electrical impulse, and a large
reduction of intercellular coupling is required to cause major slowing
of conduction velocity. It has been shown that a 50% reduction in Cx43
does not alter ventricular impulse conduction. Cx43 expression must
decrease by 90% to affect conduction, but even then conduction velocity
is reduced only by 20%.25,26
Similar to its behavior during reduced membrane excitability, conduction velocity decreases monotonically with reduction in intercellular
coupling. Of note, partial gap junctional uncoupling was shown to
result in conduction velocities that are over an order of magnitude
slower than those obtained during a maximal reduction of excitability
before conduction failure develops.19,23
An alternative to the generally accepted understanding of gap
junction–mediated intercellular impulse propagation is the electric field
mechanism (also referred to as “ephaptic transmission”). Electrical field
coupling (ephaptic coupling) refers to the initiation of an action potential
in a nonactivated downstream cell by the electrical field caused by an
activated upstream cell. This model postulates that activation spreads
along tracts of cardiac cells in a saltatory fashion driven by the negative
potential that develops in the restricted cleft space between cells when
an action potential develops in the prejunctional membrane. The large
INa in the proximal side of an intercellular cleft at the intercalated disks
(where Na+ channels are concentrated) generates a negative extracellular
potential within the cleft, which depolarizes the distal membrane and
activates its Na+ channels. Thus propagation can continue downstream
in the absence of gap junctions, provided there is a large INa at the
intercalated disk and a narrow (2 to 5 nm) intercellular cleft that separates the two opposing cells. Computer simulation studies suggest that,
under certain conditions, ephaptic coupling may play a role in cardiac
impulse propagation, and that ephaptic transmission can explain the
insensitivity of conduction velocity to reduced intercellular gap junction
coupling. However, the importance and contribution of ephaptic transmission to action potential propagation in normal cardiac tissue are
currently unclear and remain difficult to define.22,24,25

Anisotropic Conduction
Anisotropy refers to directionally dependent conduction velocity. Isotropic conduction is uniform in all directions; anisotropic conduction
is not. Anisotropy is a normal feature of heart muscle and is related to
the differences in longitudinal and transverse conduction velocities,
which are attributable to the lower resistivity of myocardium in the
longitudinal (parallel to the long axis of the myocardial fiber bundles)
versus the transverse direction (eFig. 1.1).25
In normal adult working myocardium, a given cardiomyocyte is
electrically coupled to an average of approximately 11 adjacent cells,
with gap junctions being predominantly localized at the intercalated
discs at the ends of the rod-shaped cells. Lateral (side-to-side) gap
junctions in nondisc lateral membranes of cardiomyocytes are much
less abundant and occur more often in atrial than ventricular tissues.


This particular subcellular distribution of gap junctions is a main determinant of anisotropic conduction in the heart; a wavefront must traverse
more cells in the transverse direction than over an equivalent distance
in the longitudinal direction because cell diameter is much smaller than
cell length. In addition, less intercellular gap junctional coupling occurs
and hence greater resistance and slower conduction transversely than
A further level of anisotropy exists in the normal working myocardium secondary to discontinuities of 3-D myocyte architecture at the
tissue scale. The myocardium is not a continuum. Distinct layers or
bundles of myocytes are evident in the atria and ventricles, at dimensions ranging from approximately 100 µm to several millimeters.22 The
myocardial tissue is not uniformly connected transverse to the myofiber
direction. Ventricular myocytes are arranged in layers four to six cells
thick (referred to as sheets, myolaminae, or sheetlets) that are separated
by clefts of connective tissue, across which there is little direct cell-tocell coupling. These layers form a branching network. In addition to
the laminar myocyte architecture, transmural myofiber rotation adds
further complexity to cellular organization. In a normal heart, myocardial
fiber direction changes (gradually) from the endocardium to the epicardium by nearly 90 degrees. A lower axial resistivity in the longitudinal
myofiber and myolaminar orientation than in the transverse direction
further exacerbates electrical anisotropy.22

Source-Sink Relationship
Source-sink relationships reflect the interplay between the main factors
influencing source current (the rate of rise of the upstroke and amplitude of the action potential) and those that influence the current requirements of the sink (the membrane resistance, the difference between
the resting and threshold potentials, cell-to-cell coupling, and tissue
During action potential propagation, an excited cell serves as a source
of electrical charge for depolarizing neighboring unexcited cells. The
requirements of adjacent resting cells to reach the threshold Em constitute
an electrical sink (load) for the excited cell. For propagation to succeed,
the excited cell must provide sufficient charge to bring the Em at a site
in the sink from its diastolic value to the threshold. Once threshold is
reached and an action potential is generated, the load on the excited
cell is removed, and the newly excited cell switches from being a sink
to being a source for the downstream tissue, thus perpetuating the
process of action potential propagation. Action potentials are “regenerative” because they can be conducted over large distances without attenuation. Propagation will continue to be successful as long as the active
sources can generate enough current to satisfy local sinks. Alternatively,
if the sink overwhelms the source, propagation will fail.27
The current provided by the source must reach the sink. The pathway
between the source and the sink includes intracellular resistance (provided by the cytoplasm) and intercellular resistance (provided by the
gap junctions). Extracellular resistance plays a role, but it can often be
neglected. The coupling resistance is mainly determined by resistance
of the gap junctions. Therefore the number and distribution of gap
junctions, as well as the conductance of the gap junction proteins (connexins) and the geometry of the source-sink relationship, are important
factors for propagation of the action potential.21,28
A major cause for source-sink mismatch is an abrupt change in
the structure of the cellular network, such as that which occurs at the
Purkinje fiber–ventricular muscle junction. Each Purkinje fiber (source)
transfers the impulse to hundreds or thousands of ventricular cardiomyocytes (sink). This mismatch can potentially result in dispersion of the source current to many neighboring cells (sink), and in
each of these the accumulated charge may be too low to trigger an
action potential, leading to conduction failure.12,29 Nonetheless, in a


Molecular Mechanisms of Cardiac Electrical Activity


eFig. 1.1 Anisotropic Conduction. Progression of activation wavefronts
in blocks of ventricular myocardium with longitudinal fiber orientation
are shown. A wavefront stimulated (asterisk) at the left edge progresses
more rapidly (wider isochrone spacing, [A]) than one starting perpendicularly (B) because of more favorable conduction parameters in the
former direction.




Molecular Mechanisms of Cardiac Electrical Activity

normal heart, the local structure of the cellular network and abrupt
changes in geometric properties are not of magnitude to provide
sufficient sink-source mismatch and cause conduction block of the
normal action potential because the safety factor for conduction is
large (i.e., there is a large excess of activating current over the amount
required for propagation). However, when the action potential is abnormal, the unexcited area has decreased excitability (e.g., in the setting
of acute ischemia), or both, anatomical impediments can result in
conduction block.19,30
Reduction of intercellular coupling can improve the safety of propagation despite the presence of significant source-sink mismatch. For
example, this is realized in the sinus node, where a small current source
(sinus node) meets a large sink (atrium). At the sinus node/atrium
border, there is only little expression of connexins, which protects the
excitatory current generated in the sinus node from downstream
Importantly, such tissue structures can exhibit directional asymmetry
in source-sink relationships. The source is smaller than the sink in the
orthodromic direction but larger than the sink in the opposite direction. Depending on the size of the source-sink mismatch, this results
in either local conduction delay or conduction block at the junction
during orthodromic conduction.27,31,32
Furthermore, the shape of the wavefront is a major determinant of
efficiency of propagation. Due to source-sink balance, conduction velocity is dependent on wave curvature (Fig. 1.6). A convex wavefront, as
might be observed after point stimulation, has a smaller source and a
larger sink because the local excitatory current supplied by the cells in
the front of a convex wave diverges into a larger membrane area downstream. Conversely, a concave activation front produces a source-sink
mismatch that favors the source, resulting in a high safety factor and
more rapid impulse transmission. Hence, as wavefront curvature
increases, conduction velocity decreases.24,33

Safety Factor for Conduction
The safety factor for conduction predicts the success of action potential
propagation and is based on the source-sink relationship. The safety
factor is defined as the ratio of the current generated by the depolarizing
ion channels of a cell (source) to the current consumed during the
excitation cycle of a single cell in the tissue (sink). Thus the safety factor









Fig. 1.6 Wave Curvature and Source-Sink Balance. (A) Flat wavefronts
have source-sink balance, whereas (B) convex wavefronts have a smaller
source and a larger sink. (C) The curvature of a spiral wave increases
as one moves along the wavefront toward the spiral center (the curvature
at point 3 is greater than at point 2, which is greater than at point 1).
At the innermost aspect of the wavefront, the source is too small to
excite the adjacent sink; the result is a core of unexcited cells around
which rotation occurs. Color bar indicates percentage depolarization;
gray indicates subthreshold voltage. (From Spector P. Principles of cardiac
electric propagation and their implications for re-entrant arrhythmias.
Circ Arrhythmia Electrophysiol. 2013;6:655–661.)

for propagation is proportional to the excess of source current over the
sink needs. By this definition, conduction fails when the safety factor
drops to less than 1 and becomes increasingly stable as it rises to
more than 1.
Membrane excitability, intercellular coupling, and tissue structure
have a huge influence on the safety of propagation. The safety factor
decreases monotonically as membrane excitability is reduced. In addition, the safety factor tends to be low for propagation that occurs from
a smaller cell to a larger cell or from a relatively small number of cells
to a larger number of cells.
On the other hand, although reduction of intercellular coupling
between the source cell and the sink leads to slowing of conduction, it
is associated with improved safety of conduction. Uncoupling the source
cells from neighboring cells prevents the source from becoming overwhelmed by sink demand. As cells become less coupled, there is greater
confinement of depolarizing current to the depolarizing source cell,
with less electrotonic load and axial flow of charge to the downstream
“sink” cells. As a result, individual cells depolarize with a high margin
of safety, but conduction proceeds with long intercellular delays. At
such low levels of coupling, conduction is very slow but, paradoxically,
very robust. Due to the high safety factor, extremely slow conduction
velocities can be sustained in tissue with greatly reduced intercellular

Excitation-contraction coupling describes the physiological process by
which electrical stimulation of the cardiomyocytes (the action potential)
results in a mechanical response (muscle contraction). The contraction
of a cardiac myocyte is governed primarily by intracellular Ca2+ concentration (Fig. 1.7). Ca2+ enters the cell during the plateau phase of
the action potential through the L-type Ca2+ channels that line areas
of specialized invaginations known as transverse (T) tubules. Although
the rise in intracellular Ca2+ is small and not sufficient to induce contraction, the small amount of Ca2+ entering the cell via ICaL triggers a
massive release of Ca2+ from the sarcoplasmic reticulum (the major
store for Ca2+) into the cytosol by opening the ryanodine receptor 2
(RyR2) channels (present in the membrane of the sarcoplasmic reticulum) in a process known as calcium-induced calcium release (CICR).
Approximately 75% of Ca2+ present in the cytoplasm during contraction
is released from the sarcoplasmic reticulum.
Each junction between the sarcolemma (T tubule) and sarcoplasmic
reticulum, where 10 to 25 L-type Ca2+ channels and 100 to 200 RyRs
are clustered, constitutes a local Ca2+ signaling complex (called a
“couplon”). When a Ca2+ channel opens, local cytosolic Ca2+ concentration rises in less than 1 millisecond to 10 to 20 µM in the junctional
cleft, and this activates RyR2 to release Ca2+ from the sarcoplasmic
reticulum. The close proximity of the RyR2 to the T tubule enables
each L-type Ca2+ channel to activate four to six RyR2s and generate a
“Ca2+ spark.” Ca2+ influx via ICaL simultaneously activates approximately
10,000 to 20,000 couplons in each ventricular cardiomyocyte with every
action potential.35
CICR raises cytosolic Ca2+ levels from approximately 10−7 M to
approximately 10−5 M. The free Ca2+ binds to troponin C, a component
of the thin filament regulatory complex, and thus causes a conformational change in the troponin-tropomyosin complex, such that troponin
I exposes a site on the actin molecule that is able to bind to the myosin
ATPase located on the myosin head. This binding results in ATP hydrolysis that supplies energy for a conformational change to occur in the
actin-myosin complex. The result of these changes is a movement
(ratcheting) between the myosin heads and the actin, such that the
actin and myosin filaments slide past each other and thereby shorten


Molecular Mechanisms of Cardiac Electrical Activity


















T tubule










200 msec

Fig. 1.7 Excitation-Contraction Coupling. Inset: Diagram showing relationship between transmembrane
action potential (AP), Ca2+ transient, and the contractile response in a ventricular muscle cell. See text for
details. ATP, Ca2+ adenosine triphosphatase; NCX, Na+-Ca2+ exchanger; PLB, phospholamban; RyR, ryanodine
receptor channel; SR, sarcoplasmic reticulum. (Modified with permission from Bers DM. Cardiac excitationcontraction coupling. Nature. 2002;415:198–205.)

the sarcomere length. Ratcheting cycles continue to occur as long as
cytosolic Ca2+ levels remain elevated.
CICR typically induces release of approximately 50% to 60% of
sarcoplasmic reticulum Ca2+ content. RyR2 channels are inactivated by
a feedback mechanism from the rising Ca2+ concentration in the cleft
and, more importantly, by the decline of sarcoplasmic reticulum Ca2+
content (a process referred to as luminal Ca2+- dependent deactivation).
This process ensures that the sarcoplasmic reticulum never is fully
depleted of Ca2+ physiologically.
Relaxation requires the removal of Ca2+ from the cytosol, a process
vital for enabling cardiac chamber relaxation and filling, as well as for
prevention of arrhythmias. At the end of phase 2 of the action potential,
Ca2+ entry into the cell slows, and most of the surplus Ca2+ in the cytosol
is resequestered into the sarcoplasmic reticulum by the SERCA, the
activity of which is controlled by the phosphoprotein phospholamban.
In addition, some of the Ca2+ is extruded from the cell by the sarcolemmal Na+-Ca2+ exchanger and, to a minor degree, the cell membrane
Ca2+ ATPase, to balance the Ca2+ that enters the cell via ICaL. As the
cytosolic Ca2+ concentration drops, Ca2+ dissociates rapidly from the
myofilaments, thus inducing a conformational change in the troponin
complex leading to troponin I inhibition of the actin binding site. At
the end of the cycle, a new ATP binds to the myosin head and displaces
the adenosine diphosphate, and the initial sarcomere length is restored,
thus ending contraction. Recurring Ca2+ release-uptake cycles provide
the basis for periodic elevations of cytosolic Ca2+ concentration and
contractions of myocytes, hence for the orderly beating of the heart.

1. Zaza A. Control of the cardiac action potential: the role of repolarization
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2. Spector P. Principles of cardiac electric propagation and their
implications for re-entrant arrhythmias. Circ Arrhythmia Electrophysiol.
3. Grant AO. Cardiac ion channels. Circ Arrhythmia Electrophysiol. 2009;2:
4. Grant AO. Basic electrophysiology. Card Electrophysiol Clin. 2010;2:
5. Nerbonne JM. Molecular basis of functional myocardial potassium
channel diversity. Card Electrophysiol Clin. 2016;8:257–273.
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7. Chen L, Sampson KJ, Kass RS. Cardiac delayed rectifier potassium
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15. Murphy C, Lazzara R. Current concepts of anatomy and
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Cardiac Ion Channels
Sodium Channels, 16
Structure and Physiology, 16
Function, 18
Regulation, 18
Pharmacology, 18
Inherited Channelopathies, 19
Acquired Diseases, 22
Potassium Channels, 22
Structure and Physiology, 22
Function, 24
Transient Outward Potassium Current, 24
Ultrarapidly Activating Delayed Outward Rectifying Current, 27
Rapidly Activating Delayed Outward Rectifying Current, 27
Slowly Activating Delayed Outward Rectifying Current, 29
Inward Rectifying Current, 31
Acetylcholine-Activated Potassium Current, 32
Adenosine Triphosphate–Sensitive Potassium Current, 33
Two-Pore Potassium Channels, 36
Small-Conductance Calcium-Activated Potassium Channels, 36
Calcium Channels, 37
Structure and Physiology, 37
The α1 Subunit, 38
The β Subunit, 38
The α2δ Subunit, 38
The γ Subunit, 39

Cardiac L-Type Calcium Current, 39
T-Type Calcium Current, 41
Cardiac Pacemaker Current, 42
Structure and Physiology, 42
Function, 42
Regulation, 43
Pharmacology, 43
Inherited Channelopathies, 43
Acquired Diseases, 43
Sarcoplasmic Reticulum Calcium Release Channels (Ryanodine
Receptor 2), 43
Structure and Physiology, 43
Function, 44
Regulation, 45
Pharmacology, 45
Inherited Channelopathies, 46
Acquired Diseases, 46
Cardiac Gap Junctions, 46
Structure and Physiology, 46
Function, 47
Regulation, 48
Pharmacology, 48
Inherited Channelopathies, 48
Acquired Diseases, 48

Ion channels are pore-forming membrane proteins that regulate the
flow of ions passively down their electrochemical gradient across the
membrane. Ion channels are present on all membranes of cells (plasma
membrane) and intracellular organelles (nucleus, mitochondria, endoplasmic reticulum). There are more than 300 types of ion channels in
a living cell. The channels are not randomly distributed in the membrane
but tend to cluster at the intercalated disc in association with modulatory subunits.
Ion channels are distinguished by two important characteristics: ion
permeation selectivity and gating kinetics. Ion channels can be classified
by the strongest permeant ion (sodium [Na+], potassium [K+], calcium
[Ca2+], and chloride [Cl−]), but some channels are less selective or are
not selective, as in gap junctional channels. Size, valency, and hydration
energy are important determinants of selectivity. Na+ channels have a
selectivity ratio for Na+ to K+ of 12 : 1. Voltage-gated K+ and Na+ channels exhibit more than 10-fold discrimination against other monovalent
and divalent cations, and voltage-gated Ca2+ channels exhibit more than
1000-fold discrimination against Na+ and K+ ions and are impermeable
to anions. Ions move through the channel pore at a very high rate (more
than 106 ions/s).

Gating is the mechanism of opening and closing of ion channels
and represents time-dependent transitions among distinct conformational states of the channel protein resulting from molecular movements,
most commonly in response to variations in voltage gradient across
the plasma membrane (termed voltage-dependent gating) and, less
commonly, in response to specific ligand molecules binding to the
extracellular or intracellular side of the channel (ligand-dependent
gating) or in response to mechanical stress such as stretch, pressure,
shear, or displacement (mechanosensitive gating).
Importantly, channel opening and closing are not instantaneous but
usually take time. The transition from the resting (closed) state to the
open state is called activation. Once opened, channels do not remain
in the open state, but instead they undergo conformational transition
in a time-dependent manner to a stable nonconducting (inactivated)
state. Inactivated channels are incapable of reopening and must undergo
recovery or reactivation process back to the resting state to regain
their ability to open. Inactivation curves of the various voltage-gated
ion channel types differ in their slopes and midpoints of inactivation and can overlap, in which case a steady-state or noninactivating
current flows.




Cardiac Ion Channels















Fig. 2.1 The Sodium Channel Macromolecular Complex. See text for discussion. (From Boussy T, Paparella
G, de Asmundis C, et al. Genetic basis of ventricular arrhythmias. Heart Fail Clin. 2010;6:249–266.)

Ion channels differ with respect to the number of subunits of which
they are composed and other aspects of structure. Many ion channels
function as part of macromolecular complexes in which many components are assembled at specific sites within the membrane. For most
ion channels, the pore-forming subunit is called the α subunit, whereas
the auxiliary subunits are denoted β, γ, and so on. Most ion channels
have a single pore; however, some have two.
It is important to note that although cardiomyocytes generally last
the entire human lifetime, the half-lives of ion channels at the membrane
are on the order of hours. The life cycle of cardiac ion channels encompasses many processes, starting from DNA transcription to translation
into proteins, protein modification, protein oligomerization, channel
transport to specific subdomains of the cell membrane (a process known
as forward trafficking), and finally internalization for degradation or
recycling (i.e., retrograde trafficking). Given the quick turnover of channels, the intracellular forward trafficking of channels constitutes a key
regulatory step in controlling the current density of specific channels
and offers targets for therapeutic manipulation of channel function in
the treatment of heart disease. In addition, genetic channelopathies can
result not only from mutations affecting channel structure and function
but also from mutations leading to perturbation of any of the molecular
processes involved in channel trafficking.

Structure and Physiology
The cardiac Na+ channel complex is composed of a primary α and
multiple ancillary β subunits. The approximately 2000-amino-acid α
subunit contains the channel’s ion-conducting pore and controls
channel selectivity for Na+ ions and voltage-dependent gating machinery.
This subunit contains all the drug and toxin interaction sites
identified to date.
Nine genes encode the α subunit of the Na+ channel in humans
(Nav1.1 through Nav1.9). Nav1.5 is the principal cardiac isoform. Nav1.8

and Nav1.9 are primarily expressed peripheral sensory neurons, Nav1.4
in skeletal muscle, and Nav1.6 in the central nervous system.
Nav1.5, encoded by the SCN5A gene, consists of four internally
homologous domains (I to IV) that are connected to each other by
cytoplasmic linkers (Fig. 2.1). Each domain consists of six membranespanning segments (S1 to S6), connected to each other by alternating
intracellular and extracellular peptide loops. The four domains are
arranged in a fourfold circular symmetry to form the channel. The
extracellular l