Basis and treatment of cardiac arrhythmias

Handbook of

Experimental Pharmacology

Volume 171

Editor-in-Chief

K. Starke, Freiburg i. Br.

Editorial Board

G.V.R. Born, London

M. Eichelbaum, Stuttgart

D. Ganten, Berlin

F. Hofmann, München

W. Rosenthal, Berlin

G. Rubanyi, Richmond, CA

Basis and Treatment

of Cardiac Arrhythmias

Contributors

M.E. Anderson, C. Antzelevitch, J.R. Balser, P. Bennett,

M. Cerrone, C.E. Clancy, I.S. Cohen, J.M. Fish, I.W. Glaaser,

T.J. Hund, M.J. Janse, C. January, R.S. Kass, J. Kurokawa,

J. Lederer, S.O. Marx, A.J. Moss, S. Nattel, C. Napolitano,

S. Priori, G. Robertson, R.B. Robinson, D.M. Roden,

M.R. Rosen, Y. Rudy, A. Shiroshita-Takeshita, K. Sipido,

Y. Tsuji, P.C. Viswanathan, X.H.T. Wehrens, S. Zicha

Editors

Robert S. Kass and Colleen E. Clancy

123

Robert S. Kass Ph. D.

David Hosack Professor and Chairman

Columbia University

Department of Pharmacology

630 W. 168 St.

New York, NY 10032

USA

e-mail: [email protected]

Colleen E. Clancy Ph. D.

Assistant Professor

Department of Physiology and Biophysics

Institute for Computational Biomedicine

Weill Medical College of Cornell University

1300 York Avenue

LC-501E

New York, NY 10021

e-mail: [email protected]

With 60 Figures and 11 Tables

ISSN 0171-2004

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Preface

In the past decade, major progress has been made in understanding mecha￾nisms of arrhythmias. This progress stems from much-improved experimen￾tal, genetic, and computational techniques that have helped to clarify the roles

of specific proteins in the cardiac cycle, including ion channels, pumps, ex￾changer, adaptor proteins, cell-surface receptors, and contractile proteins. The

interactions of these components, and their individual potential as therapeu￾tic targets, have also been studied in detail, via an array of new imaging and

sophisticated experimental modalities. The past 10 years have also led to the

realization that genetics plays a predominant role in the development of lethal

arrhythmias.

Many of the topics discussed in this text reflect very recently undertaken

research directions including the genetics of arrhythmias, cell signaling mole￾cules as potential therapeutic targets, and trafficking to the membrane. These

new approaches and implementations of anti-arrhythmic therapy derive from

many decades of research as outlined in the first chapter by the distinguished

professors Michael Rosen (Columbia University) and Michiel Janse (University

of Amsterdam). The text covers changes in approaches to arrhythmia therapy

over time, in multiple cardiac regions, and over many scales, from gene to

protein to cell to tissue to organ.

New York, May 2005 Colleen E. Clancy and Robert S. Kass

List of Contents

History of Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . 1

M. J. Janse, M.R. Rosen

Pacemaker Current and Automatic Rhythms:

Toward a Molecular Understanding . . . . . . . . . . . . . . . . . . . . 41

I.S. Cohen, R.B. Robinson

Proarrhythmia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

D.M. Roden, M.E. Anderson

Cardiac Na+ Channels as Therapeutic Targets

for Antiarrhythmic Agents . . . . . . . . . . . . . . . . . . . . . . . . . 99

I.W. Glaaser, C.E. Clancy

Structural Determinants of Potassium Channel Blockade

and Drug-Induced Arrhythmias . . . . . . . . . . . . . . . . . . . . . . 123

X.H.T. Wehrens

Sodium Calcium Exchange as a Targetfor Antiarrhythmic Therapy . . . 159

K.R. Sipido, A. Varro, D. Eisner

A Role for Calcium/Calmodulin-Dependent Protein Kinase II

in Cardiac Disease and Arrhythmia . . . . . . . . . . . . . . . . . . . . 201

T. J. Hund, Y. Rudy

AKAPs as Antiarrhythmic Targets? . . . . . . . . . . . . . . . . . . . . 221

S.O. Marx, J. Kurokawa

β-Blockers as Antiarrhythmic Agents . . . . . . . . . . . . . . . . . . . 235

S. Zicha, Y. Tsuji, A. Shiroshita-Takeshita, S. Nattel

Experimental Therapy of Genetic Arrhythmias:

Disease-Specific Pharmacology . . . . . . . . . . . . . . . . . . . . . . 267

S.G. Priori, C. Napolitano, M. Cerrone

Mutation-Specific Pharmacology of the Long QT Syndrome . . . . . . . 287

R.S. Kass, A. J. Moss

VIII List of Contents

Therapy for the Brugada Syndrome . . . . . . . . . . . . . . . . . . . . 305

C. Antzelevitch, J.M. Fish

Molecular Basis of Isolated Cardiac Conduction Disease . . . . . . . . . 331

P.C. Viswanathan, J.R. Balser

hERG Trafficking and Pharmacological Rescue

of LQTS-2 Mutant Channels . . . . . . . . . . . . . . . . . . . . . . . . 349

G.A. Robertson, C.T. January

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

List of Contributors

(Addresses stated at the beginning of respective chapters)

Anderson, M.E. 73

Antzelevitch, C. 305

Balser, J.R. 331

Cerrone, M. 267

Clancy, C.E. 99

Cohen, I.S. 41

Eisner, D. 159

Fish, J.M. 305

Glaaser, I.W. 99

Hund, T. J. 201

Janse, M. J. 1

January, C.T. 349

Kass, R.S. 287

Kurokawa, J. 221

Marx, S.O. 221

Moss, A. J. 287

Napolitano, C. 267

Nattel, S. 235

Priori, S.G. 267

Robertson, G.A. 349

Robinson, R.B. 41

Roden, D.M. 73

Rosen, M.R. 1

Rudy, Y. 201

Shiroshita-Takeshita, A. 235

Sipido, K.R. 159

Tsuji, Y. 235

Varro, A. 159

Viswanathan, P.C. 331

Wehrens, X.H.T. 123

Zicha, S. 235

HEP (2006) 171:1–39

© Springer-Verlag Berlin Heidelberg 2006

History of Arrhythmias

M. J. Janse1 (✉) · M.R. Rosen2

1The Experimental and Molecular Cardiology Group, Academic Medical Center, M 051,

University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

[email protected]

2Center for Molecular Therapeutics, Department of Pharmacology, College of Physicians

and Surgeons, Columbia University, 630 W 168th Street, PH7West-321,

New York NY, 10032, USA

1 Introduction .................................... 2

2 Methods to Record the Electrical Activity of the Heart ............. 4

2.1 The Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2.2 The Interpretation of Extracellular Waveforms . . . . . . . . . . . . . . . . . 6

2.3 The Recording of Transmembrane Potentials . . . . . . . . . . . . . . . . . . 10

2.4 Mapping of the Spread of Activation During Arrhythmias . . . . . . . . . . . 11

3 Some Aspects of Cardiac Anatomy Relevant for Arrhythmias . . . . . . . . . 12

3.1 Atrioventricular Connections . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3.2 Specialized Internodal Atrial Pathways . . . . . . . . . . . . . . . . . . . . . . 14

4 Mechanisms of Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

4.1 Re-entry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

4.2 Abnormal Focal Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

5 Some Specific Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

5.1 Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

5.2 Atrioventricular Re-entrant Tachycardia . . . . . . . . . . . . . . . . . . . . . 24

5.3 Atrioventricular Nodal Re-entrant Tachycardia . . . . . . . . . . . . . . . . . 26

5.4 Ventricular Tachycardia, Fibrillation and Sudden Death . . . . . . . . . . . . 28

6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Abstract A historical overview is given on the techniques to record the electrical activ￾ity of the heart, some anatomical aspects relevant for the understanding of arrhythmias,

general mechanisms of arrhythmias, mechanisms of some specific arrhythmias and non￾pharmacological forms of therapy. The unravelling of arrhythmia mechanisms depends,

of course, on the ability to record the electrical activity of the heart. It is therefore no

surprise that following the construction of the string galvanometer by Einthoven in 1901,

which allowed high-fidelity recording of the body surface electrocardiogram, the study

of arrhythmias developed in an explosive way. Still, papers from McWilliam (1887), Gar￾rey (1914) and Mines (1913, 1914) in which neither mechanical nor electrical activity was

recorded provided crucial insights into re-entry as a mechanism for atrial and ventricular

2 M. J. Janse · M.R. Rosen

fibrillation, atrioventricular nodal re-entry and atrioventricular re-entrant tachycardia in

hearts with an accessory atrioventricular connection. The components of the electrocardio￾gram, and of extracellular electrograms directly recorded from the heart, could only be well

understood by comparing such registrations with recordings of transmembrane potentials.

The first intracellular potentials were recorded with microelectrodes in 1949 by Coraboeuf

and Weidmann. It is remarkable that the interpretation of extracellular electrograms was

still controversial in the 1950s, and it was not until 1962 that Dower showed that the trans￾membrane action potential upstroke coincided with the steep negative deflection in the

electrogram. For many decades, mapping of the spread of activation during an arrhythmia

was performed with a “roving” electrode that was subsequently placed on different sites

on the cardiac surface with a simultaneous recording of another signal as time reference.

This method could only provide reliable information if the arrhythmia was strictly regular.

When multiplexing systems became available in the late 1970s, and optical mapping in the

1980s, simultaneous registrations could be made from many sites. The analysis of atrial

and ventricular fibrillation then became much more precise. The old question whether an

arrhythmia is due to a focal or a re-entrant mechanism could be answered, and for atrial

fibrillation, for instance, the answer is that both mechanisms may be operative. The road

from understanding the mechanism of an arrhythmia to its successful therapy has been

long: the studies of Mines in 1913 and 1914, microelectrode studies in animal prepara￾tions in the 1960s and 1970s, experimental and clinical demonstrations of initiation and

termination of tachycardias by premature stimuli in the 1960s and 1970s, successful surgery

in the 1980s, the development of external and implantable defibrillators in the 1960s and

1980s, and finally catheter ablation at the end of the previous century, with success rates

that approach 99% for supraventricular tachycardias.

Keywords Electrocardiogram · Extracellular electrograms · Transmembrane potentials ·

Re-entry · Focal activity · Tachycardias · Fibrillation

1

Introduction

The diagnosis of cardiac arrhythmias and the elucidation of their mechanisms

depend on the recording of the electrical activity of the heart. The study

of disorders of the rhythmic activity of the heart started around the fifth

century b.c. in China and in Egypt around 3000 b.c. with the examination of

the peripheral pulse (for details see Snellen 1984; Acierno 1994; Lüderitz 1995;

Ziskind and Halioua 2004). In retrospect, it is easy to recognize atrioventricular

(AV) block, represented by the slow pulse rate observed by Gerber in 1717

(see Music et al. 1984), or atrial fibrillation manifested by the irregular pulse

described by de Senac (1749). The recording of arterial, apical and venous

pulsations, notably by MacKenzie (1902) and Wenckebach (1903), provided

a more rational basis for diagnosing many arrhythmias. Still, the concept

that disturbances in the electrical activity of the heart were responsible for

abnormal arterial and venous pulsations was not universally known at the turn

of the nineteenth century. For example, MacKenzie observed that the A wave

disappeared from the venous curve during irregular heart action, and wrote, in

History of Arrhythmias 3

1902 under the heading of “The pulse in auricular paralysis”, “I have no clear

idea of how the stimulus to contraction arises, and so cannot definitely say how

the auricle modifies the ventricular rhythm. But as a matter of observation I

can with confidence state that the heart has a very great tendency to irregular

action when the auricles lose their power of contraction.”

The first demonstration of the electrical activity of the heart was made

accidentally by Köllicker and Müller in 1856. Following the experiments of

Matteuci in 1842, who used the muscle of one nerve-muscle preparation as

a stimulus for the nerve of another, thereby causing its muscle to contract

(see Snellen 1984), they also studied a nerve-muscle preparation from a frog

(sciatic nerve and gastrocnemius muscle). Accidentally, the sciatic nerve was

placed in contact with the exposed heart of another frog, and they observed

the gastrocnemius muscle contract in synchrony with the heartbeat. They saw

immediately before the onset of systole a contraction of the gastrocnemius,

and in some preparations a second contraction at the beginning of diastole.

Although Marey (1876) first used Lipmann’s capillary electrometer to record

the electrical activity of the frog’s heart, the explanation for this activity was

provided by the classic experiments of Burdon-Sanderson and Page (1879,

1883). They also used the capillary electrometer together with photographic

equipment to obtain recordings of the electrical activity of frog and tortoise

hearts. They placed electrodes on the basal and apical regions of the frog heart

and observed two waves of opposite sign during each contraction. The time

interval between the two deflections was in the order of 1.5 s. By injuring the

tissue under one of the recording sites, they obtained the first monophasic

action potentials and showed how, in contrast to nerve and skeletal muscle,

there is in the heart a long period between excitation and repolarization [“...

if either of the leading-off contacts is injured ... the initial phase is followed

by an electrical condition in which the injured surface is more positive, or

less negative relatively to the uninjured surface: this condition lasts during

the whole of the isoelectric period ...” (Burdon-Sanderson and Page 1879)].

A second important observation was that by partially warming the surface “...

the initial phase (i.e. of the electrogram) is unaltered but the terminal phase

begins earlier and is strengthened” (Burdon-Sanderson and Page 1879).

Heidenhain introduced the term arrhythmia as the designation for any dis￾turbance of cardiac rhythm in 1872. With the introduction of better techniques

to record the electrical activity of the heart, the study of arrhythmias developed

in an explosive way. We will limit this brief account to those studies in which

the electrical activity was documented, even though we will make an exception

for a number of seminal papers on the mechanisms of arrhythmias in which

neither mechanical nor electrical activity was recorded (McWilliam 1887a,b,

1889; Garrey 1914; Mines 1913b, 1914). We will pay particular attention to

the early studies, nowadays not easily accessible, and will not attempt to give

a complete review of all arrhythmias.

4 M. J. Janse · M.R. Rosen

2

Methods to Record the Electrical Activity of the Heart

2.1

The Electrocardiogram

In 1887, Waller was the first to record an electrocardiogram from the body

surface of dog and man (see Fig. 1). He used Lippmann’s capillary electrome￾ter, an instrument in which in a mercury column borders on a weak solution

of sulphuric acid in a narrow glass capillary. Whenever a potential difference

between the mercury and the acid is applied, changed or removed, this bound￾ary moves (see Snellen 1995). The capillary electrometer was sensitive, but

slow. Einthoven constructed his string galvanometer, which was both sensitive

and rapid, based on the principle that a thin, short wire of silver-coated quartz

placed in a narrow space between the poles of a strong electromagnet will move

whenever the magnetic field changes as a consequence of change in the current

flowing through the coils. During the construction of the string galvanometer,

Einthoven was aware of the fact that Ader in 1897 also had used an instrument

with a string in a magnetic field as a receiver of Morse signals transmitted

by undersea telegraph cables. In Einthoven’s first publication on the string

galvanometer, he did quote Ader (Einthoven 1901). It is often suggested that

Einthoven merely improved Ader’s instrument. However, as argued by Snellen

(1984, 1995), Ader’s instrument was never used as a galvanometer, i.e. as an

instrument for measuring electrical currents, and if it had, its sensitivity would

have been 1:100,000 that of the string galvanometer. To quote Snellen (1995):

“... the principle of a conducting wire in a magnetic field moving when a cur￾rent passes through it, had been known from Faraday’s time if not earlier, that

is three quarters of a century before Ader. Equalizing all possible instruments

which use that principle is perhaps just as meaningless as to put a primitive

horse cart on a par with a Rolls Royce, because they both ride on wheels.”

Figure 1 shows electrocardiograms recorded with the capillary electrometer

byWaller and by Einthoven, Einthoven’smathematical correction of his tracing,

and the first human electrocardiogram recorded by Einthoven with his string

galvanometer (Einthoven 1902, 1903).

Remarkably, Einthoven constructed a cable which connected his physiolog￾ical laboratory with the Leiden University hospital, over a distance of a mile

(Einthoven 1906). This should have created a unique opportunity to collabo￾rate with clinicians and document the electrocardiographic manifestations of

a host of arrhythmias. Unfortunately, according to Snellen (1984):

Occurrence of extrasystoles had the peculiar effect that Einthoven could

warn the physician by telephone that he was going to feel an intermission

of the pulse at the next moment. It seems that this annoyed the clinician

who was poorly co-operative anyway; in fact, after only a few years he

cut the connection to the physiological laboratory. This must have been

History of Arrhythmias 5

Fig. 1 Panel 1: Waller’s recording of the human electrocardiogram using the capillary elec￾trometer.t, time; h, external pulsation of the heart; e, electrocardiogram.Panel 2: Einthoven’s

tracing published in 1902 also with the capillary electrometer, with the peaks called A, B, C,

and D. In the lower tracing, Einthoven corrected the tracing mathematically, and now used

the terminology P, Q, R, S and T. Panel 3: One of the first electrocardiograms recorded with

the string galvanometer as published in 1902 and 1903 by Einthoven. (Reproduced from

Snellen 1995)

a blow to Einthoven, although in 1906 and 1908 he had already collected

two impressive series of clinical tracings. Precisely at this time, a young

physician and physiologist from London approached him who needed

to improve his registration method of the relation between auricular

and ventricular contraction in what ultimately proved to be auricular

fibrillation. This was Thomas Lewis.

There is no doubt that Lewis was foremost in introducing Einthoven’s instru￾ment into clinical practice and in experiments designed to unravel mechanisms

of arrhythmias (see later). Einthoven always appreciated Lewis’s work. When