AER 6.1 Mark E Josephson Tribute

Arrhythmia & Electrophysiology Review Volume 6 • Issue 1 • Spring 2017

Volume 6 • Issue 1 • Spring 2017

www.AERjournal.com

Personal Perspectives of Mark E Josephson Alfred Buxton, Hugh Calkins, David Callans, Philippa Hill, Demosthenes Katritsis, Frank Marchlinski, John Miller, Fred Morady, Edward Rowland, William Stevenson, Charles Swerdlow, Hein Wellens, Peter Zimetbaum, Douglas Zipes

Electrophysiological Testing for the Investigation of Bradycardias Demosthenes G Katritsis and Mark E Josephson

Mahaim Accessory Pathways Demosthenes G Katritsis, Hein J Wellens, Mark E Josephson

Dedicated to the Memory of

Mark E Josephson 1943–2017

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Volume 6 • Issue 1 • Spring 2016

Editor-in-Chief Demosthenes Katritsis Athens Euroclinic, Athens, Greece

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Implantable Devices

Andrew Grace

Karl-Heinz Kuck

Angelo Auricchio

University of Cambridge, UK

Asklepios Klinik St Georg, Hamburg, Germany

Fondazione Cardiocentro Ticino, Lugano, Switzerland

Charles Antzelevitch

Lankenau Institute for Medical Research, Wynnewood, US

Carsten W Israel

Sunny Po

JW Goethe University, Germany

Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, US

Warren Jackman

Carina Blomström-Lundqvist

Uppsala University, Uppsala, Sweden

University of Oklahoma Health Sciences Center, Oklahoma City, US

Johannes Brachmann

Pierre Jaïs

ALFA – Alliance to Fight Atrial Fibrillation, Venice-Mestre, Italy

Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute (LIRYC), France

Frédéric Sacher

Klinikum Coburg, II Med Klinik, Germany

Pedro Brugada

University of Brussels, UZ-Brussel-VUB, Belgium

Josef Kautzner

Antonio Raviele

Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute (LIRYC), France

Alfred Buxton

Beth Israel Deaconess Medical Center, Boston, US

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Hugh Calkins

Samuel Lévy

John Hopkins Medical Institution, Baltimore, US

Aix-Marseille University, France

Barts Health NHS Trust, London Bridge Hospital, London, UK

A John Camm

Cecilia Linde

William Stevenson

St George’s University of London, UK

Karolinska University, Stockholm, Sweden

Riccardo Cappato

Gregory YH Lip

Richard Schilling

Brigham and Women’s Hospital, Harvard Medical School, US

IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

University of Birmingham, UK

Richard Sutton

Ken Ellenbogen

Francis Marchlinski

University of Pennsylvania Health System, Philadelphia, US

National Heart and Lung Institute, Imperial College, London, UK

Virginia Commonwealth University School of Medicine, US

Jose Merino

Sabine Ernst

Hospital Universitario La Paz, Madrid, Spain

Royal Brompton and Harefield NHS Foundation Trust, London, UK

Andreas Götte

St Vincenz-Hospital Paderborn and University Hospital Magdeburg, Germany

Fred Morady Cardiovascular Center, University of Michigan, US

Sanjiv M Narayan

Stanford University Medical Center, US

Juan Tamargo University Complutense, Madrid, Spain

Panos Vardas Heraklion University Hospital, Greece

Marc A Vos University Medical Center Utrecht, Netherlands

Katja Zeppenfeld

Hein Heidbuchel

Mark O’Neill

Antwerp University and University Hospital, Antwerp, Belgium

St. Thomas’ Hospital and King’s College London, London, UK

Leiden University Medical Center, Netherlands

Gerhard Hindricks

Carlo Pappone

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, US

University of Leipzig, Germany

IRCCS Policlinico San Donato, Milan, Italy

Douglas P Zipes

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Contents

Foreword

5

Mark E Josephson The Elegance of Genius Demosthenes Katritsis, Editor-in-Chief Athens Euroclinic, Athens, Greece

Guest Editorial

6

Mark E Josephson: Characteristics of Leadership David Callans Section of Cardiac Electrophysiology, Division of Cardiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

9

Mark E Josephson: Clinical Investigator John M Miller Indiana University School of Medicine; Indiana University Health, Indianapolis, USA

Personal Perspective

13

“What Would He Do Next?”

Alfred Buxton Beth Israel Deaconness Medical Center, Boston, USA

14

Getting to the Heart of the Matter Hugh Calkins John Hopkins Medical Institution, Baltimore, USA

To Know Mark was to Love Him Philippa Hill Bruin Biometrics, Los Angeles, USA

15

Mark E Josephson: A Tribute to His Work on Ventricular Arrhythmias Francis Marchlinski University of Pennsylvania Health System, Philadelphia, USA

17

A Brash, Politically Incorrect, Opinionated and Brilliant Friend Fred Morady Cardiovascular Center, University of Michigan, Ann Arbor, USA

A Gifted Teacher Edward Rowland St Bartholomew’s Hospital, London, UK

18

Mark Josephson: Pioneer, Educator and Mentor to a Generation of Cardiac Electrophysiologists William G Stevenson Cardiac Arrhythmia Program, Brigham and Women’s Hospital; Harvard Medical School, Boston, USA

19

Mark Josephson and the ICD: A Personal Perspective Charles D Swerdlow Cedars-Sinai Medical Center, Los Angeles, USA

21

Mark E Josephson: The Boston Years Peter Zimetbaum Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, USA

23

Shared Moments Hein Wellens University of Maastricht, the Netherlands

A Brilliant Pioneer and Leader Douglas P Zipes Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, USA

Diagnostic Electrophysiology & Ablation

24

Electrophysiological Testing for the Investigation of Bradycardias Demosthenes G Katritsis1 and Mark E Josephson2 1. Athens Euroclinic, Athens, Greece; 2. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

29

Mahaim Accessory Pathways Demosthenes G Katritsis,1 Hein J Wellens,2 Mark E Josephson3

1. Athens Euroclinic, Athens, Greece, 2. Cardiovascular Research Institute, Maastricht, the Netherlands, 3. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

4

© RADCLIFFE CARDIOLOGY 2017

Foreword

Mark E Josephson The Elegance of Genius…

T

hree years ago I accepted an invitation by Mark Josephson to get attached to his Department as a part-time scientist, “in order to have fun” in his own words. Apart from being educated by his book and publications,

I had in the past co-authored with him a number of papers that had provided a firsthand opportunity to appreciate his impressive mental capacity, and almost unlimited knowledge on arrhythmias. Living and working with him, however, was perhaps the most exciting experience in my whole professional life. Mark was not just an investigator, a clinician, a teacher, an electrophysiology and ablation expert, an inspiring chief. Mark was simply a genius. Anything else is an understatement, perhaps except from the fact that, in addition, he was also an incredibly honest, politically incorrect person of uncompromising intellectual dignity.

Demosthenes G Katritsis

In this special issue of the journal, leaders who knew and had worked with Mark present their personal reflection on this giant in the field. Electrophysiologists of the world owe so much to this brilliant mind. He will live forever in every published paper that contains one figure with electrograms from the human heart. Mark the friend, however, will be deeply missed.

Demosthenes Katritsis, Editor-in-Chief, Arrhythmia & Electrophysiology Review Athens Euroclinic, Athens, Greece

DOI: 10.15420/aer.2017.6.1:ED1 ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

5

Guest Editorial

Mark E Josephson: Characteristics of Leadership

M

ark Josephson is without a doubt the most fascinating person I have ever met.

I am proud to have had a close friendship with him and I miss him immensely.

I have written in the past about his amazing academic contributions, but in a

way I am relieved that this is not my topic today. I will instead talk about the unique aspects of his personality that allowed him to be a great leader in the field of electrophysiology and a powerful influence on the personal development of those of us who had the great good fortune of interacting with him closely.

David J Callans

Section of Cardiac Electrophysiology, Division of Cardiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

Total Recall

often made others uncomfortable – it was a very exacting, difficult

Mark’s intellect seems to have been the driving force of much of his

way to think, requiring discipline and an intact ego structure. Some

behaviour. His gifts were substantial. He apparently had a total recall

found his constant challenging and superior intellect difficult

memory on all sorts of topics, not only cardiac electrophysiology and

to bear. Nonetheless, these are the qualities that drove him to

electrocardiography, but details of individual patients, Patriots football,

fundamentally change the practice of electrophysiology.

fine wine and much more internal medicine than I have ever mastered. He was in the habit of pretending that this was all

Mark’s time in the Public Health Service at Staten Island exposed

completely natural, and that he “never read anything”. I knew that his

him to intracardiac recording techniques, which at that time were

depth and breadth of knowledge was acquired the old fashioned way,

used primarily for understanding abnormalities in the conduction

however, by intense study. In addition to recall, he had blazing

system. It was revolutionary when Mark used these techniques

analytical skills, which he applied, again, to any number of topics from

to study ventricular tachycardia (VT), including stimulating and

complex intracardiac tracings to interpersonal relationships.

recording from the left ventricle during ongoing tachycardia. In a

We occasionally differed on the topic of whether or not someone was

(distant) analogy, I remember being told by my young son’s hockey

to be trusted, either intellectually or personally. I would come to my

coach that we adults do everything we can to avoid ice, even when

conclusions after much consideration, he after a millisecond. I would

wearing study shoes. They were teaching our children how to do

try to change his opinion on people, thinking that he must have

acrobatics on ice, despite wearing thin skates. In the same way,

overlooked a key element, but he never faltered. Without exception,

although almost everyone else in the world was deathly afraid of VT,

when more information became available I would end up realising he

Mark realised that the only way to understand this enemy well

had been right all along.

enough to devise therapy was to spend some time with it. From rigorous physiological investigation (anatomic and electrical

Encouraging Revolution

substrate of VT, electrical stimulation during VT to determine the

So, what would one set out to accomplish, equipped with such

nature of the circuit) arose important therapeutic concepts:

formidable skills? I often wonder what it must have felt like from

subendocardial resection, followed by catheter ablation of VT. This

Mark’s perspective – thinking so very quickly must have made the

progression of physiology to therapeutic concept could only have

efforts of 'neurotypicals' seem agonisingly slow. It must have been

been conceived by a quite limited number of investigators, but also

clear to him that genius has the responsibility of encouraging

required a great deal of work to bring to fruition. Mark and the

revolution, and that is what he did. His overriding creative principles

all-star team he constructed, first at the University of Pennsylvania,

were to never accept the limitations of the present and to always

then at Beth Israel Deaconess, provided the required mixture of

question everything, even one’s own work. These forceful principles

creative spark and sweat equity.

6

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Mark E Josephson: Characteristics of Leadership

Figure 1: Mark was known as “The Sheriff” in his Boston years. He felt a deep commitment to preserving the intellectual honesty of cardiac electrophysiology.

It took great courage to do this, and a sense of balance to prevent being labeled as a pariah.

Figure 2: Mark was always recruiting like-minded people to join forces with him. Who could refuse this guy?

training involved. At the end of the discussion, the interviewer asked with reverent appreciation for the human struggle of running “Is there

Intellectual Dignity

anything I can do for you?” The runner answered “Run with me.” Mark

Mark was always questioning, even some of the very concepts he

did not need my meager input to understand the intricacies of mind

had brought to life. He seemed to have taken responsibility for the

experiments about the nature of the VT circuit, but it was lonely to

intellectual dignity of our field (see Figure 1). He cautioned against

think about it by himself (see Figure 2).

blind acceptance of guideline-based patient care, particularly in the setting of primary prevention implantable defibrillator (ICD) therapy.

And so, I and many others benefitted greatly from his attempts. What

This was not because he did not believe in this powerful technology,

were the rules of engagement? Never be anything less than completely

but because he wanted it to be better. He abhorred the loss of

honest. Always try your very hardest. It was nonsense to think that we

physiological basis for much of the current practice of interventional

could keep up with Mark and it would have been ridiculous for him to

electrophysiology, particularly as applied to ablation of atrial

expect this. He was passionate about each of us becoming the best

fibrillation. He constantly strove to remind us that physiological

possible version of ourselves, both professionally and personally. What

understanding must precede therapy. He was righteously indignant

were the rewards? In addition to learning physiology in real time as it

about the casual relationship to truth that too many clinical research

was being made from an expert teacher, the rewards for me included

manuscripts appear to have. To the very end of his life, he was always

one of the most meaningful friendships of my adult life. I would have

questioning our fundamental concepts and improving on available techniques. In 2016 he wrote important manuscripts exposing some of our misconceptions about recording of intracardiac electrograms, particularly as this applies to VT substrate mapping and the nature of the VT circuit.

How did this all get translated on a personal level? You might expect that Mark’s fierce expectations would overwhelm all possibility for close relationships. That is in fact what I expected, as a beginning student of electrophysiology. At a time when his lectures were completely undecipherable to me, he was deeply interested in trying to bring me into his life and work. I remember hours in his Gladwyne house, sitting around a table with him drawing figures of the VT circuit (How is VT initiated? How do we understand the response to stimulation? Are the VT circuit barriers fixed or functional?) which certainly inspired an enthusiasm for learning, but was far above my ability to grasp. It reminds me of a quote from a famous long-distance runner, who was being interviewed about the arduous hours of

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Figure 3: Mark (here seen with the author and another disciple, Bruce Hook), like all amazing mentors, always made us feel stronger than we thought we were!

7

Guest Editorial always seemed to make me feel like I was so much stronger/smarter/ better than I really was (see Figure 3). I ache for the loss of his counsel and support.

Reaching Out I was fortunate to have been close to him, but Mark was not about closing ranks to an inner sanctum. He was always reaching out, teaching, recruiting, encouraging. One of the enduring monuments to his love for teaching was the legacy of electrocardiography and intracardiac recording courses that he taught with his dear friend and kindred spirit Hein Wellens. Over 7,000 students participated in the rite of passage of interpreting tracings at the board over 35 years of courses throughout the world (see Figure 4). A remarkable number Figure 4: Mark 'at the board' interpreting intracardiac electrograms with his first grandchild, who even at this tender age was an expert in distinguishing SVT mechanisms.

of these students admitted that they finally felt like a real cardiologist only after passing this milestone.

On 11 January 2017 we lost a transformative leader and a great friend.

We have inherited what seems a tragically large responsibility

walked through fire for Mark, and I knew he would have done the same

to represent what Mark Josephson stood for, but we bear it with joy

and even more for me. He was fiercely loyal, incredibly honest and

in dedication to his memory. n

David J Callans Section of Cardiac Electrophysiology, Division of Cardiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

DOI: 10.15420/aer.2017.6.1:ED2

8

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Guest Editorial

Mark E Josephson: Clinical Investigator

M

ark E Josephson entered the world of clinical cardiac electrophysiology (EP) almost at its inception (1972); with so much to learn and so many directions one could take, he dived into the field with unbridled enthusiasm and an uncommon

– perhaps almost unique – aptitude for asking questions and finding ways to answer them.

Few aspects of EP escaped his indelible influence. In this short paper, I will attempt to touch on some of the high points of his astounding career as a clinical investigator.

John M Miller

Indiana University School of Medicine; Indiana University Health, Indianapolis, USA

The Electrocardiogram

information can be extracted by masters such as Josephson and

In the entire realm of his work, Dr Josephson’s greatest love was

Wellens. In the later years of his career, he was invited along with Prof

the simple electrocardiogram (ECG). His discernment, based on

Wellens to provide a regular contribution to the prestigious journal

the ECG, into the patient’s history and disease processes was

Heart Rhythm – ‘Josephson and Wellens’ ECG Lessons: A Monthly Visit

legendary. Among the more important and insightful contributions

to the 12-Lead ECG’. Here, they retrieved some of the choice jewels

he made to our understanding of heart disease and arrhythmias

from their treasures of ECGs obtained over the prior half-century,

from the ECG are: observations of alternating preexcitation patterns

sharing their insights into how the ECG could yield important and

in patients with Wolff-Parkinson-White (WPW) pattern who had more

often surprising information about the patient and their proper

1

diagnosis and management. These pearls bear careful reading by the

and a patient with 1:2 conduction AV using an AV pathway;2 the

serious student of electrophysiology. Josephson was often heard to

than one accessory atrioventricular (AV) accessory pathway (AP), 3

nature of electrocardiographic ‘left atrial enlargement’; multiple ECG

state something like the following: “The ECG never lies, but it doesn’t

manifestations of ventricular tachycardia (VT) in the same patient;4,5

always tell you all it knows.”

use of the 12-lead ECG to localise exit sites of post-infarction VT

6,7

and

premature ventricular complexes;8 studies on electrical alternans in 9

A couple of anecdotes are worth sharing here. In preparing our 1988

wide complex tachycardias; a highly useful method of distinguishing

paper on correlation of the 12-lead ECG with ‘site of origin’ of VT, some

VT from supraventricular tachycardia (SVT) with aberration in left

of the ECGs had been recorded as a long continuous strip from which

bundle branch block (LBBB) wide-QRS tachycardias;

10

variations in

I had to cut several complexes of individual leads and affix them to

the ECG expression of atrial flutter;11 differentiation of insertion sites

paper in a standard 12-lead ECG format. In one case, I had inadvertently

of atriofascicular

pathways;12

classification of which portion of which

mounted a lead V5 upside down; as I was reviewing a stack of these

coronary artery was affected in myocardial infarction;13,14 features of

ECGs with Dr Josephson, he immediately noted the error. I was of

the ECG in what appears to be right ventricular outflow tract ectopy

course very embarrassed and apologetic but he was not as bothered

and VT that correlate with difficult catheter ablation;15 distinction of

by it as I was, knowing what it should look like. He could also name

the causes of T-wave inversion (post-pacing cardiac memory versus

from which patient most of the ECGs came. In another instance,

ischaemia),16 and whether LBBB was new or old (with implications for

during a regular Monday ECG conference in a darkened room, a fellow

patients with chest pain and LBBB on

ECG).17

was squirming uncomfortably at the front of the room trying to analyse an ECG projected on the screen that showed an atrial

Throughout his career, Dr Josephson gave courses on ECG

bradycardia, incomplete right bundle branch block and mild right

interpretation with his close friend Prof Hein Wellens; most EP fellows

ventricular hypertrophy. At that moment, Dr Josephson burst into the

of the last 25 years have attended these legendary courses and come

room looking for one of the other fellows; he glanced at the ECG on

away with a new appreciation of this old tool and how much

the screen and blurted out the diagnosis (sinus venosus atrial septal

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

9

Guest Editorial

Figure 1: Diagram Showing How Recordings are Made Pre- and Post-left Ventricular Endocardial Resection for Treatment of Ventricular Tachycardia At left, the left ventricle is shown opened at the time of surgery. A stylised ventricular tachycardia (VT) circuit is shown; a 4 x 5 electrode array records electrograms during VT as well as sinus rhythm immediately prior to resection of 2–3 mm of endocardium in a region where the VT has been mapped. Centre, the resection has been accomplished, removing endocardial layers along with some of the VT circuit. At right, the electrode array is positioned as before, but now recording from tissue deep to where the endocardium had been removed.

defect) and the name of the patient (one of his). Such was his command of the ECG. Although most cardiologists interpret the ECG well, and some even interpret it expertly, Dr Josephson interpreted and understood the ECG deeply, as do but a few others.

Supraventricular Arrhythmias Dr Josephson started his investigative career with supraventricular

Figure 2: Recordings from 20-bipolar Electrode Array As shown in Figure 1. A: During ventricular tachycardia (VT), diastole is shaded yellow; green arrows denote diastolic potentials during VT. B: Recorded during sinus rhythm immediately prior to endocardial resection, blue arrows point to split potentials and red arrows to late potentials (recorded after the end of the QRS complex [dashed red line]). These split and late potentials correspond in size and morphology to the diastolic potentials during VT in the same recording electrodes. C: after endocardial resection, split and late potentials are gone (removed with specimen) and electrograms recorded during the QRS complex are much larger than before after removal of interposed scar. A 1 mV calibration signal is at right. SR = sinus rhythm.

arrhythmias such as SVT and atrial fibrillation (AF) and flutter. In a general overview on paroxysmal SVT18 – on which he was the sole

and exit block out of, the PV were obtained,30,31 as well as correlating

author – he showed even this early in his career (1978) how extensive

acute PV reconnection after ablation with poorer outcomes;32 a case

his understanding of this family of arrhythmias was (as well as how

in which AF was contained within a PV after isolation;33 and pointing

much was still unknown). Among his favourite arrhythmias was AV

out the frequency of aortic wall injury during AF ablation procedures.34

nodal reentrant tachycardia (AVNRT), on which he published

From the start of his career to its end, despite his plethora of other

extensively throughout his career. The first of these studies investigated

investigative interests, his attention was never very far from SVTs.

whether the atrium was a necessary component in AV nodal reentry.

19

Following this were investigations into upper and lower common

Ventricular Tachycardia

pathways between the tachycardia circuit and atrium (above) and His

The area of clinical investigation for which Dr Josephson is most

bundle (below);20,21 using the ∆HA interval (HA during SVT versus HA

renowned is VT. In the 1970s, post-infarction VT was a major problem

during ventricular pacing at the SVT rate) to distinguish AV nodal

without a good solution. Antiarrhythmic drugs were palliative at best,

reentry from orthodromic SVT using a septal AP;22 variations in

and neither catheter ablation nor implantable defibrillators had been

retrograde conduction pathways in AVNRT, in which he showed that

developed. Dr Josephson believed that effective treatment might hinge

retrograde conduction did not necessarily have the same atrial

on a better understanding of the nature of the arrhythmia – which at that

activation pattern during SVT and retrograde conduction with

time was poor. He and his colleagues began a series of investigations

ventricular pacing;23,24 the origin of accelerated junctional rhythm

that not only changed many aspects of the care of patients with VT, but

during slow pathway ablation for

AVNRT;25

that standard slow pathway

eventually those with many other types of arrhythmias (to which the

ablation of AVNRT suffices in patients with earliest retrograde

principles learned in VT investigation could be applied). The first studies

activation in the coronary

sinus;26

the unusual rhythm disturbance of

he published in this area were an astounding series of four landmark

1:2 AV conduction during sinus rhythm coexisting with typical AV

papers, appearing in Circulation over a span of 13 months.4,35–37 This was

nodal reentry (which many thought

impossible);27

and his final major

a planned series (the first is entitled ‘Recurrent Sustained Ventricular

work on AVNRT, in which he matter-of-factly corrected some of his

Tachycardia. 1. Mechanisms’) setting forth the state of the art at that

own prior work in the light of newer

evidence.28

Dr Josephson also

time, and showing that:

added to knowledge and practice in a paper on selection of sites for ablation of APs in WPW, in particular using the unipolar electrogram;29

• VT in this setting was due to reentry;

the previously-noted atriofascicular AP insertion study;12 and several

• Reentry occurred on the endocardium;

papers investigating AF. These included evaluating the success of AF

• Reentry did not involve the proximal His-Purkinje system; and

ablation by pulmonary vein (PV) isolation when entrance block into,

• Reentry occurred in a relatively small area.

10

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Mark E Josephson: Clinical Investigator

These findings led directly to surgical treatment of VT by excising

lidocaine in man.53 A few years later, the previously-mentioned work on

endocardial tissue proven to be essential for ongoing arrhythmia;

mechanisms of VT appeared as the first of many regarding this

finally, a cure for VT was possible.38,39 A series of papers followed this

arrhythmia. Following this were papers describing continuous electrical

– where circuits

activity during VT;54 the mechanism of ventricular fibrillation;55 structure

were, patterns of activation during VT, what accounted for multiple QRS

and ultrastructure of surgically-removed specimens from VT patients;56

morphologies of VT, observations about ‘dead-end’ conduction

and the meaning of endocardial late potentials.57 A series of

pathways with 2:1 conduction during VT – and led to innovations in

monumental papers on resetting and entrainment of arrhythmias

providing further insights into the behaviour of VT

This, in turn, paved the

began in 198558 and continued for a decade thereafter, including

way for subsequent work in catheter ablation of VT, in which Dr

resetting response patterns;59,60 resetting in the presence of fusion;61

technique, resulting in improved outcomes.

Additional investigations

comparing results of single-beat resetting versus entrainment;62

involved the aforementioned use of the ECG during VT to localise exit

predictability of overdrive pacing to terminate VT;63 and investigation as

Josephson was an active investigator. sites from circuits,

6,7

43

42

5,40,41

pace-mapping to corroborate activation

to whether functional or fixed lines of conduction block are present in

mapping;44,45 and one of his favourite studies, the effect of endocardial

VT.64 The lessons learned from these studies provide substantial help

tissue resection on electrograms at sites of reentry.

46

In this study, a

in some cases of complex reentry, which are increasingly encountered

multipolar electrode array was positioned on a portion of endocardium

after ablation of AF. Dr Josephson provided a lucid explanation of the

to which VT had been mapped during the procedure; recordings were

mechanism of the rare but important disorder known as paroxysmal

made during sinus rhythm (and usually also VT); the endocardium was

AV block.65 He also contributed to the development of the first

then removed by undermining with scissors; and finally, the array was

electroanatomical mapping system.66

placed back in the same position where recordings were repeated during sinus rhythm (see Figure 1). This showed that endocardial late

Dr Josephson participated in investigations into drug therapy of

potentials (recorded after the end of the QRS complex) that correlated

arrhythmias and the adverse effects of these drugs; cardiovascular

with mid-diastolic potentials during VT were located on the endocardial

genetics; animal models of arrhythmias; heart failure; valvular heart

surface (present prior to resection, absent after), and that the larger

disease; device-based therapy of atrial and ventricular arrhythmias;

signals seen during the QRS complex were recorded from deeper

clinical trials in arrhythmia therapy; and healthcare economics.

layers, with their amplitudes decreased by endocardial scar (see Figure 2). He also participated in studies of VT in the absence of structural

Conclusion

heart disease47 as well as in the setting of congenital heart disease

The panoply of contributions by Dr Josephson to our understanding of

(repaired tetralogy of Fallot, Ebstein anomaly).

48,49

One of his last

cardiac arrhythmias is far too broad to recount in a short paper. Even

battles against VT was in the form of prophylactic catheter ablation of

in failing health in his last two years here, he continued to develop new

VT to try to prevent shocks from implanted defibrillators;

50

he always

ideas about ways to investigate arrhythmias. His contributions to the

believed prevention was a better strategy than rescue (analogy:

field are large, both in number and impact; practically every procedure

preventing injury by preventing a motor vehicle accident, versus

that a practicing electrophysiologist does on any given day has been

rescue by airbag), so this study was a natural fit for him.

influenced by Dr Josephson’s work. These accomplishments were of course important to him; far more important were his relationships

Mechanisms and Tools of Investigation

with his family, colleagues and trainees. Ever the advocate and friend,

Dr Josephson was known for his earnest search for a more thorough

he never saw himself as too important or busy to help someone

understanding of the mechanisms of arrhythmias, strongly believing

understand a difficult point, or offer patient care or career advice when

that correct therapy depended on knowing the correct diagnosis.

asked. A good clinical investigator does good work; an exceptional

While this seems self-evident, some electrophysiologists still perform

investigator inspires those with whom he works to launch out onto

catheter ablation procedures based on a presumption of a diagnosis

their own investigative paths. Dr Josephson was clearly among the

and mechanism (reentry versus automaticity, for instance), rather than

exceptional. Thus it is that, through his students – who he taught how

taking the extra few seconds or minutes needed to prove the case. A

to think and ask questions – his work continues.

long and ultimately unsuccessful procedure can result from a strategy of presumption, if incorrect. Dr Josephson penned two perspective

Lastly, although Dr Josephson made many new discoveries and

papers entitled ‘Electrophysiology at a Crossroads’51,52 that set forth

devised new therapies in his investigative career, some of the

his reservations about how EP practices had evolved from mechanism-

conclusions he made from these studies turned out to be less than

and evidence-based care to what was expedient and economically

completely correct; he was big enough to own up to these and

driven; these are required reading in many training programmes.

criticise his own prior work. A pioneer in any field, like an explorer in new territory, occasionally goes down a seemingly promising path that

Dr Josephson’s research into mechanisms of arrhythmias was spread

eventually leads nowhere. Far more often than not, however,

throughout his career, starting with a publication on the effects of

Dr Josephson led us down a path of new discovery and we find, in

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

11

Guest Editorial looking back, that the ‘hits’ far outnumbered the ‘misses’. It is difficult

how we would be practicing EP today, were it not for the contributions

to imagine where our knowledge about arrhythmias would be, and

of this one man. His legacy as a pioneer in our field is secure. n

John M Miller Indiana University School of Medicine; Indiana University Health, Indianapolis, USA

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Josephson ME, Caracta AR, Lau SH. Alternating type A and type B Wolff-Parkinson-White syndrome. Am Heart J 1974;87:363–6.

DOI:10.1016/0002-8703(74)90079-9; PMID:4812374 Josephson ME, Seides SF, Damato AN. Wolff-ParkinsonWhite syndrome with 1:2 atrioventricular conduction. Am J Cardiol 1976;37:1094–6. DOI:10.1016/0002-9149(76)90431-8; PMID:1274872 Josephson ME, Kastor JA, Morganroth J. Electrocardiographic left atrial enlargement. Electrophysiologic, echocardiographic and hemodynamic correlates. Am J Cardiol 1977;39:967–71.

DOI:10.1016/S0002-9149(77)80209-9; PMID:141202 Josephson ME, Horowitz LN, Farshidi A, et al. Recurrent sustained ventricular tachycardia. 4. Pleomorphism. Circulation 1979;59:459–68. DOI:10.1161/01.CIR.59.3.459; PMID:761327 Miller JM, Kienzle MG, Harken AH, Josephson ME. Morphologically distinct sustained ventricular tachycardias in coronary artery disease: significance and surgical results. J Am Coll Cardiol 1984;4:107–39. DOI:10.1016/S0735-1097(84)80124-2; PMID:6501715 Josephson ME, Horowitz LN, Waxman HL, et al. Sustained ventricular tachycardia: role of the 12-lead electrocardiogram in localizing site of origin. Circulation 1981;64:257–72.

DOI:10.1161/01.CIR.64.2.257; PMID:7249295 Miller JM, Marchlinski FE, Buxton AE, Josephson ME. Relationship between the 12-lead electrocardiogram during ventricular tachycardia and endocardial site of origin in patients with coronary artery disease. Circulation 1988;77:759– 66. DOI:10.1161/01.CIR.77.4.759; PMID:3349580 Josephson ME. The origin of premature ventricular complexes– role and limitations of the 12-lead electrocardiogram. Int J Cardiol 1982;2:87–90. DOI:10.1016/0167-5273(82)90013-4; PMID:6182117 Kremers MS, Miller JM, Josephson ME. Electrical alternans in wide complex tachycardias. Am J Cardiol 1985;56:305–8.

DOI:10.1016/0002-9149(85)90854-9; PMID:4025170 Kindwall KE, Brown J, Josephson ME. Electrocardiographic criteria for ventricular tachycardia in wide complex left bundle branch block morphology tachycardias. Am J Cardiol 1988;61:1279–83. DOI:10.1016/0002-9149(88)91169-1; PMID:3376886 Milliez P, Richardson AW, Obioha-Ngwu O, et al. Variable electrocardiographic characteristics of isthmus-dependent atrial flutter. J Am Coll Cardiol 2002;40:1125–32. DOI:10.1016/ S0735-1097(02)02070-3; PMID:12354439 Gandhavadi M, Sternick EB, Jackman WM, et al. Characterization of the distal insertion of atriofascicular accessory pathways and mechanisms of QRS patterns in atriofascicular antidromic tachycardia. Heart Rhythm 2013;10:1385–92. DOI:10.1016/j. hrthm.2013.07.009; PMID:23851064 Zimetbaum PJ, Krishnan S, Gold A, et al. Usefulness of ST-segment elevation in lead III exceeding that of lead II for identifying the location of the totally occluded coronary artery in inferior wall myocardial infarction. Am J Cardiol 1998;81:918–9.

DOI:10.1016/S0002-9149(98)00013-7; PMID:9555783 Zimetbaum PJ, Josephson ME. Use of the electrocardiogram in acute myocardial infarction. N Engl J Med 2003;348:933–40.

DOI:10.1056/NEJMra022700; PMID:12621138 Hachiya H, Hirao K, Sasaki T, et al. Novel ECG predictor of difficult cases of outflow tract ventricular tachycardia: peak deflection index on an inferior lead. Circ J 2010;74:256–61.

PMID:20009358 Shvilkin A, Ho KK, Rosen MR, Josephson ME. T-vector direction differentiates postpacing from ischemic T-wave inversion in precordial leads. Circulation 2005;111:969–74. DOI:10.1161/01.

CIR.0000156463.51021.07; PMID:15710753 Shvilkin A, Bojovic B, Vajdic B, et al. Vectorcardiographic and electrocardiographic criteria to distinguish new and old left bundle branch block. Heart Rhythm 2010;7:1085–92.

DOI:10.1016/j.hrthm.2010.05.024; PMID:20493964 Josephson ME. Paroxysmal supraventricular tachycardia: an electrophysiologic approach. Am J Cardiol 1978;41:1123–6.

DOI:10.1016/0002-9149(78)90868-8; PMID:665519 Josephson ME, Kastor JA. Paroxysmal supraventricular tachycardia: is the atrium a necessary link? Circulation 1976;54:430–5. DOI:10.1161/01.CIR.54.3.430; PMID:181173 Miller JM, Rosenthal ME, Vassallo JA, Josephson ME. Atrioventricular nodal reentrant tachycardia: studies on upper and lower 'common pathways'. Circulation 1987;75:930–40.

DOI:10.1161/01.CIR.75.5.930; PMID:3568310 Anselme F, Poty H, Cribier A, et al. Entrainment of typical AV nodal reentrant tachycardia using para-Hisian pacing: evidence for a lower common pathway within the AV node. J Cardiovasc Electrophysiol 1999;10:655–61. DOI:10.1111/j.1540-8167.1999. tb00242.x; PMID:10355921 Miller JM, Rosenthal ME, Gottlieb CD, et al. Usefulness of the delta HA interval to accurately distinguish atrioventricular nodal reentry from orthodromic septal bypass tract tachycardias. Am J Cardiol 1991;68:1037–44. DOI:10.1016/00029149(91)90492-4; PMID:1927917 Anselme F, Hook B, Monahan K, et al. Heterogeneity of retrograde fast-pathway conduction pattern in patients with

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atrioventricular nodal reentry tachycardia: observations by simultaneous multisite catheter mapping of Koch's triangle.

Circulation 1996;93:960–8. DOI:10.1161/01.CIR.93.5.960; PMID:8598087 Anselme F, Papageorgiou P, Monahan K, et al. Presence and significance of the left atrionodal connection during atrioventricular nodal reentrant tachycardia. Am J Cardiol 1999;83:1530–6. DOI:10.1016/S0002-9149(99)00142-3; PMID:10363866 Boyle NG, Anselme F, Monahan K, et al. Origin of junctional rhythm during radiofrequency ablation of atrioventricular nodal reentrant tachycardia in patients without structural heart disease. Am J Cardiol 1997;80:575–80. DOI:10.1016/S00029149(97)00424-4; PMID:9294984 Chen J, Anselme F, Smith TW, et al. Standard right atrial ablation is effective for atrioventricular nodal reentry with earliest activation in the coronary sinus. J Cardiovasc Electrophysiol 2004;15:2–7. DOI:10.1046/j.1540-8167.2004.03299.x; PMID:15028065 Germano JJ, Essebag V, Papageorgiou P, Josephson ME. Concealed and manifest 1:2 tachycardia and atrioventricular nodal reentrant tachycardia: manifestations of dual atrioventricular nodal physiology. Heart Rhythm 2005;2:536–9.

DOI:10.1016/j.hrthm.2005.01.025; PMID:15840482 Katritsis DG, Josephson ME. Classification of electrophysiological types of atrioventricular nodal re-entrant tachycardia: a reappraisal. Europace 2013;15:1231–40.

DOI:10.1093/europace/eut100; PMID:23612728 Grimm W, Miller J, Josephson ME. Successful and unsuccessful sites of radiofrequency catheter ablation of accessory atrioventricular connections. Am Heart J 1994;128:77–87.

DOI:10.1016/0002-8703(94)90013-2; PMID: 8017289 Essebag V, Baldessin F, Reynolds MR, et al. Non-inducibility post-pulmonary vein isolation achieving exit block predicts freedom from atrial fibrillation. Eur Heart J 2005;26:2550–5.

DOI:10.1093/eurheartj/ehi577; PMCID:PMC1361286 Essebag V, Wylie JV Jr, Reynolds MR, et al. Bi-directional electrical pulmonary vein isolation as an endpoint for ablation of paroxysmal atrial fibrillation. J Interv Card Electrophysiol 2006;17:111–7. DOI:10.1007/s10840-006-9057-x; PMCID:PMC1937574 Anter E, Contreras-Valdes FM, Shvilkin A, et al. Acute pulmonary vein reconnection is a predictor of atrial fibrillation recurrence following pulmonary vein isolation. J Interv Card Electrophysiol 2014;39:225–32. DOI:10.1007/s10840-013-9864-9; PMID:24532109 Josephson ME. Isolation of atrial fibrillation to a pulmonary vein.

Europace 2003;5:365–6. DOI:10.1016/S1099-5129(03)00092-8 Tung P, Hong SN, Chan RH, et al. Aortic injury is common following pulmonary vein isolation. Heart Rhythm 2013;10:653–8.

DOI:10.1016/j.hrthm.2013.01.012; PMID:23318348 Horowitz LN, Josephson ME, Farshidi A, et al. Recurrent sustained ventricular tachycardia 3. Role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation 1978;58:986–97. DOI:10.1161/01.

CIR.58.6.986; PMID:709782 Josephson ME, Horowitz LN, Farshidi A, Kastor JA. Recurrent sustained ventricular tachycardia. 1. Mechanisms. Circulation 1978;57:431–40. DOI:10.1161/01.CIR.57.3.431; PMID:624152 Josephson ME, Horowitz LN, Farshidi A, et al. Recurrent sustained ventricular tachycardia. 2. Endocardial mapping.

Circulation 1978;57:440–7. DOI:10.1161/01.CIR.57.3.440; PMID:624153 Harken AH, Josephson ME, Horowitz LN. Surgical endocardial resection for the treatment of malignant ventricular tachycardia. Ann Surg 1979;190:456–60. PMID:485619; PMCID:PMC1344508 Josephson ME, Harken AH, Horowitz LN. Endocardial excision: a new surgical technique for the treatment of recurrent ventricular tachycardia. Circulation 1979;60:1430–9.

DOI:10.1161/01.CIR.60.7.1430; PMID:498470 Miller JM, Kienzle MG, Harken AH, Josephson ME. Subendocardial resection for ventricular tachycardia: predictors of surgical success. Circulation 1984;70:624–31.

DOI:10.1161/01.CIR.70.4.624; PMID:6478565 Miller JM, Vassallo JA, Hargrove WC, Josephson ME. Intermittent failure of local conduction during ventricular tachycardia.

Circulation 1985;72:1286–92. DOI:10.1161/01.CIR.72.6.1286; PMID:4064273 Hargrove WC, 3rd, Miller JM, Vassallo JA, Josephson ME. Improved results in the operative management of ventricular tachycardia related to inferior wall infarction. Importance of the annular isthmus. J Thorac Cardiovasc Surg 1986;92:726–32.

PMID:3762202 El-Shalakany A, Hadjis T, Papageorgiou P, et al. Entrainment/ mapping criteria for the prediction of termination of ventricular tachycardia by single radiofrequency lesion in patients with coronary artery disease. Circulation 1999;99:2283–9.

DOI:10.1161/01.CIR.99.17.2283; PMID:10226094 Josephson ME, Waxman HL, Cain ME, et al. Ventricular activation during ventricular endocardial pacing. II. Role of

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pace-mapping to localize origin of ventricular tachycardia.

Am J Cardiol 1982;50:11–22. DOI:10.1016/0002-9149(82)90003-0; PMID:7090993 Waxman HL, Josephson ME. Ventricular activation during ventricular endocardial pacing: I. Electrocardiographic patterns related to the site of pacing. Am J Cardiol 1982;50:1–10.

DOI:10.1016/0002-9149(82)90002-9; PMID:7090991 Miller JM, Tyson GS, Hargrove WC 3rd, et al. Effect of subendocardial resection on sinus rhythm endocardial electrogram abnormalities. Circulation 1995;91:2385–91.

DOI:10.1161/01.CIR.91.9.2385; PMID:7729025 Buxton AE, Marchlinski FE, Doherty JU, et al. Repetitive, monomorphic ventricular tachycardia: clinical and electrophysiologic characteristics in patients with and patients without organic heart disease. Am J Cardiol 1984;54:997–1002.

DOI:10.1016/S0002-9149(84)80133-2; PMID:6496364 Harken AH, Horowitz LN, Josephson ME. Surgical correction of recurrent sustained ventricular tachycardia following complete repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 1980;80:779–81. PMID:7431975 Obioha-Ngwu O, Milliez P, Richardson A, et al. Ventricular tachycardia in Ebstein's Anomaly. Circulation 2001;104:E92–4.

DOI:10.1161/hc4301.098011; PMID:11684642 Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007;357:2657–65. DOI:10.1056/NEJMoa065457; PMID:18160685; PMCID:PMC2390777 Josephson ME. Electrophysiology at a crossroads. Heart Rhythm 2007;4:658–61. DOI:10.1016/j.hrthm.2006.12.045; PMID:17467638 Josephson ME. Electrophysiology at a crossroads: A revisit.

Heart Rhythm 2016;13:2317–22. DOI:10.1016/j.hrthm.2016.07.024; PMID:27542727 Josephson ME, Caracta AR, Lau SH, et al. Effects of lidocaine on refractory periods in man. Am Heart J 1972;84:778–86.

DOI:10.1016/0002-8703(72)90071-3; PMID:4669900 Josephson ME, Horowitz LN, Farshidi A. Continuous local electrical activity. A mechanism of recurrent ventricular tachycardia. Circulation 1978;57:659–65. DOI:10.1161/01.

CIR.57.4.659; PMID:630672 Josephson ME, Spielman SR, Greenspan AM, Horowitz LN. Mechanism of ventricular fibrillation in man. Observations based on electrode catheter recordings. Am J Cardiol 1979;44:623–31. DOI:10.1016/0002-9149(79)90279-0; PMID:484493 Fenoglio JJ Jr, Pham TD, Harken AH, et al. Recurrent sustained ventricular tachycardia: structure and ultrastructure of subendocardial regions in which tachycardia originates.

Circulation 1983;68:518–33. DOI:10.1161/01.CIR.68.3.518; PMID:6223722 Vassallo JA, Cassidy D, Simson MB, et al. Relation of late potentials to site of origin of ventricular tachycardia associated with coronary heart disease. Am J Cardiol 1985;55:985–9.

DOI:10.1016/0002-9149(85)90731-3; PMID:3984886 Almendral JM, Gottlieb C, Marchlinski FE, et al. Entrainment of ventricular tachycardia by atrial depolarizations. Am J Cardiol 1985;56:298–304. DOI:10.1016/0002-9149(85)90853-7; PMID:4025169 Almendral JM, Rosenthal ME, Stamato NJ, et al. Analysis of the resetting phenomenon in sustained uniform ventricular tachycardia: incidence and relation to termination. J Am Coll Cardiol 1986;8:294–300. PMID:3734253 Almendral JM, Stamato NJ, Rosenthal ME, et al. Resetting response patterns during sustained ventricular tachycardia: relationship to the excitable gap. Circulation 1986;74:722–30.

DOI:10.1161/01.CIR.74.4.722; PMID:3757186 Rosenthal ME, Stamato NJ, Almendral JM, et al. Resetting of ventricular tachycardia with electrocardiographic fusion: incidence and significance. Circulation 1988;77:581–8.

DOI:10.1161/01.CIR.77.3.581; PMID:3342489 Callans DJ, Hook BG, Josephson ME. Comparison of resetting and entrainment of uniform sustained ventricular tachycardia.

Further insights into the characteristics of the excitable gap.

Circulation 1993;87:1229–38. DOI:10.1161/01.CIR.87.4.1229; PMID:8462149 Callans DJ, Hook BG, Mitra RL, Josephson ME. Characterization of return cycle responses predictive of successful pacingmediated termination of ventricular tachycardia. J Am Coll Cardiol 1995;25:47–53. DOI:10.1016/0735-1097(94)00361-S; PMID:7798525 Callans DJ, Zardini M, Gottlieb CD, Josephson ME. The variable contribution of functional and anatomic barriers in human ventricular tachycardia: an analysis with resetting from two sites. J Am Coll Cardiol 1996;27:1106–11. DOI:10.1016/07351097(95)00585-4; PMID:8609328 Lee S, Wellens HJ, Josephson ME. Paroxysmal atrioventricular block. Heart Rhythm 2009;6:1229–34. DOI:10.1016/j. hrthm.2009.04.001; PMID:19632639 Ben-Haim SA, Osadchy D, Schuster I, et al. Nonfluoroscopic, in vivo navigation and mapping technology. Nat Med 1996;2:1393–5. DOI:10.1038/nm1296-1393; PMID: 8946843

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Personal Perspective

Alfred Buxton Beth Israel Deaconess Medical Center, Boston, USA

“What Would He Do Next?”

I met Mark Josephson in 1973 when he came to the Hospital of the

and used these cases to expand and refine our understanding of the

University of Pennsylvania (HUP) as a cardiology fellow. He had just

underlying physiology.

completed 2 years at the US Public Health Service Hospital on Staten Island where he began his career in clinical electrophysiology.

Two major changes took place in clinical electrophysiology in the 1980s:

I was beginning medical internship at the same time. Even though

the introduction of the implantable cardioverter-defibrillator (ICD) and

Mark was among the most junior members of the cardiopulmonary

the introduction of catheter ablation (initially using direct current shock,

division he quickly became one of the leaders, both by force of his

then radiofrequency energy). Characteristically, Mark was initially

personality, as well as a remarkable series of observations

skeptical of each, before embracing them, and utilising them fully and

encompassing broad areas of clinical electrophysiology, including

skillfully. Nevertheless, a common theme drove him crazy about each of

supraventricular (SVT) and ventricular tachycardias (VT). In the

these therapeutic modalities: indiscriminate, unphysiological use.

1970s at our clinical cardiology conferences, Mark and colleagues

Regarding the ICD, he felt that it is often used inappropriately, without

described exciting new observations almost on a weekly basis.

regard to the individual patient’s overall clinical situation – he was

These observations formed the basis for much of the practice of

staunchly against blind adherence to practice guidelines, without

clinical electrophysiology, not only in that decade, but to the present

attempts to comprehend individual patients’ arrhythmic tendencies and

time. For myself, as someone interested in asking questions, this

mechanisms (i.e., underutilisation of diagnostic electrophysiological

was an incredibly stimulating environment, and Mark was a most

studies). Second, he both practiced and preached against empiric

exciting mentor and role model.

catheter ablation without first exploring a patient’s physiology. That is, he did not believe in “Learning While Burning”. Rather, his philosophy could

Subsequently, from 1979 to 1981 when I served my electrophysiology

probably be expressed as “Learn Before You Burn”.

fellowship, the work of the EP lab continued to expand. During this time surgical therapy for ventricular tachycardia was growing

I spent about 22 years training under, and then working alongside, Mark.

enormously, and both patients and electrophysiologists came to HUP

I also spent 18 years working at institutions separate from Mark. I think

from all over the US and abroad. The mantra of Mark, which carried

his influence on me (and I suspect this is true for most of the many

over to the entire lab, was to study everyone possible, and enroll

others who trained under him) can best be summed up in this way:

everyone possible into a research protocol. These were times before

regardless of his physical presence, I have never done an EP study or

catheter ablation existed: therapeutic efforts were aimed at

ablation without him at my side, thinking, “What would he do next?”

appropriate drug choices, based on physiology as we then understood

Almost every time I care for a patient, I think, “What would he do?” For

it. Direct EP therapy was limited to the operating room for patients

me, this will never end. What greater tribute could there be for a

with VT as well as SVT – we routinely operated on patients with Wolff-

physician, electrophysiologist and teacher. I am extremely grateful for

Parkinson-White syndrome. Mark loved studying patients with SVT,

the time we had together. I will miss him sorely. n

DOI: 10.15420/aer.2017.6.1:PP1 ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

13

Personal Perspective

Hugh Calkins

Philippa Hill

John Hopkins Medical Institution, Baltimore, USA

Bruin Biometrics, Los Angeles, USA

Getting to the Heart of the Matter

To Know Mark was to Love Him

I have always held Mark Josephson in the highest of regard. He was

I was fortunate to work for Dr Josephson at the Beth Israel Hospital in

a true giant in the field. As an electrophysiology fellow I read his

Boston as my first job in the US after leaving the UK. My interview

famous text book on electrophysiology from cover to cover. I first met

with Mark was a taste of the man – his flair for the dramatic, the need

Mark when I was a junior faculty member at the University of

to shock you and see your response. But more importantly his

Michigan. I was assigned the high honour of picking him up at the

kindness. My friendship with this amazing man endured from that

airport. He showed enormous interest in me and in the research

first meeting. I learned so much more about him over the next few

projects I was working on. Ever since then I have looked forward to

years – we shared laughs, a love of Motown music and more

reading his articles and catching up with him at medical meetings. A

importantly the love of learning in the challenging world of

particularly memorable meeting was at the South African Heart

electrophysiology. A lot of fellows came through the labs and to my

Association meeting. Mark and Joan had just returned from a high-

great amusement one of the greatest compliments in a true MEJ

end game park and were in tremendous spirits. Beth and I shared a

back-handed manner when a fellow got the answer wrong he would

wonderful bus ride with them to the conference. One of Mark’s most

look at me with a wry grin and say to them, "Even she knows the

important qualities was that he always said exactly what he thought

answer to that" – me, a mere cardiac technician. What a compliment

about a given topic. Whether it was the indiscriminate use of ICDs or

from the man himself. It didn’t matter who you were, what level in the

the less than perfect results of AF ablation you could count on Mark

hierarchy you were, as long as you showed passion and enthusiasm.

to get to the heart of the matter. He was also an outstanding speaker.

To know Mark was to love him, and I'm honoured to be part of the group of people who can say they knew him. n

I am sorry that my fellowship predated his ECG meetings. I am sure I would have learned a lot if I had been lucky enough to attend one of these courses. n

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Personal Perspective

Mark E Josephson: A Tribute to His Work on Ventricular Arrhythmias

D

r Josephson was passionate about the study of ventricular arrhythmias and bold in his pioneering approach to their evaluation and management. Programmed right ventricular stimulation to test for antiarrhythmic drug efficacy was already pushing

the risk limits for the invasive management of cardiac arrhythmias in the 1970s.

Francis Marchlinski

University of Pennsylvania Health System, Philadelphia, USA

Catheter-based Mapping to Characterise Ventricular Tachycardia

continued to champion the role of the lowly but critically important 12-lead ECG in helping us pinpoint the origin of VT.

Catheter-based mapping of the left ventricle (LV) to characterise the substrate and origin of ventricular tachycardia (VT) was thought to

I always refer those interested in the subject to Mark’s epic work

involve a much greater level of risk and therefore not to be pursued.

published in Circulation in 1981. 6 The paper had 11 figures, each with

Mark proved the naysayers wrong with his careful and methodical

multiple 12-lead ECGs, helping the reader understand how the

approach to evaluating the LV endocardium.

12-lead ECG QRS pattern could help regionalise the area of interest to focus more detailed mapping.

What made these early efforts even more remarkable was that left ventricular mapping was performed with a nonsteerable, quadripolar

A year later, Mark also detailed the role of pace mapping in patients

catheter. Sampling each of the ‘12 Josephson endocardial sites’ with

with VT, making observations that have stood the test of time.7 He

the catheter tip localisation guided only by fluoroscopy was frequently

pointed out that long activation times from the site of earliest

a daunting task but always accomplished. Abnormal, late, split and

activation during VT (isthmus sites) were mimicked by the long

fractionated electrograms, diastolic activation and continuous

stimulus to QRS interval during pace mapping and that the production

electrical activity would become part of the electrophysiology lexicon

of grossly disparate 12-lead ECG patterns was frequently observed

in describing the VT substrate and circuit.

during pacing from closely adjacent areas within the scar. Years

1–3

later, other investigators would echo the value of his early This early work also revealed the subendocardium to be a critical

observations and emphasise their importance in localising the best

component of most post-MI VTs. This would lead to the surgical

sites for VT ablation. 8,9

‘peeling’ of the subendocardial layer of infarcted myocardium extending from the edge of the more densely scarred aneurysm to

Resetting with Fusion – the Hallmark of Reentry

The ‘Pennsylvania Peel’ was established as the

In the mid-1980s Mark worked with a young trainee in his lab at that

eliminate VT.

4,5

surgical technique to cure infarct-related VT.

time, Dr Jesus Almendral from Madrid. They introduced extrastimuli during VT to characterise the resetting response of scar-related

Championing the Diagnostic Value of the 12-lead ECG

VT.10,11 The ability to reset the VT after surface electrocardiogram

Throughout his efforts to understand the physiological mechanisms

activation (resetting with fusion) represents the hallmark of reentry.12

related to the initiation and maintenance of VT, Dr Josephson also

The list of accomplishments and key observations goes on and on.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

(ECG) or intracardiac recordings had already indicated onset of

15

Personal Perspective During his more than 45 year of working on ventricular arrhythmias

be skeptical of technology or treatment trends that avoided

the ground-breaking efforts which improved our understanding of

physiological confirmation in their development and use. He was

ventricular arrhythmia pathogenesis and treatment would number in

selfless with his time, always accessible and enthusiastically

the hundreds; all seminal in nature, clearly described and moving

supportive but always challenging us to get it right. We had a

the needle of care worldwide.

‘hotline’ to Mark over the last 25 years, which linked us immediately to him for academic discussion, challenge and advice, no matter

An Inspirational Mentor

what the geographical or institutional differences. This hotline has

Perhaps, gifts of equal value to his enormous scientific legacy,

been sadly disconnected and he is very much missed. We find

were his ability to inspire and his skill in mentoring. Mark both

solace in knowing that he blazed the path, showed us the way and

inspired us and indicated that we had the responsibility to join him

served as a role model for how things should be done. We will

in the effort to inch the field forward. He taught us to challenge

follow in his footsteps and tip our academic hats to our friend and

accepted treatment strategies that were based on opinion and

mentor as we continue the important effort to inch the study of

dogma but not sound physiological principles. He encouraged us to

ventricular arrhythmias forward. n

Francis Marchlinski University of Pennsylvania Health System, Philadelphia, USA

1.

2.

3.

4.

Josephson ME, Horowitz LN, Farshidi A. Continuous local electrical activity: a mechanism of recurrent ventricular tachycardia. Circulation 1978;57:659–6. DOI: 10.1161/01.

CIR.57.4.659; PMID: 630672 Cassidy DM, Vassallo JA, Marchlinski FE, et al. Endocardial mapping in humans in sinus rhythm with normal left ventricles: activation patterns and characteristics of electrograms. Circulation 1984;70:37–42. DOI: 10.1161/01.

CIR.70.1.37; PMID: 6723010 Cassidy DM, Vassallo JA, Miller JM, et al. Endocardial catheter mapping in patients in sinus rhythm: relationship to underlying heart disease and ventricular arrhythmias.

Circulation 1986;73:645–52. DOI: 10.1161/01.CIR.73.4.645; PMID: 3948367 Josephson ME, Harken AH, Horowitz LN. Endocardial excision: a new surgical technique for the treatment of recurrent ventricular tachycardia. Circulation 1979;60:1430–9.

DOI: 10.1161/01.CIR.60.7.1430; PMID: 498470

5.

6.

7.

8.

Horowitz LN, Harken AH, Kastor JA, Josephson ME. Ventricular resection guided by epicardial and endocardial mapping for treatment of recurrent ventricular tachycardia. N Engl J Med 1980;302:589–93. DOI: 10.1056/ NEJM198003133021101; PMID: 7351905 Josephson ME, Horowitz LN, Waxman HL, et al. Sustained ventricular tachycardia: role of the twelve-lead electrocardiogram in localizing site of origin. Circulation 1981;64:257–72. DOI: 10.1161/01.CIR.64.2.257; PMID: 7249295 Josephson ME, Waxman HL, Cain ME, et al. Ventricular activation during ventricular endocardial pacing. II. Role of pace-mapping to localize origin of ventricular tachycardia.

Am J Cardiol 1982;50:11–22. DOI: 10.1016/0002-9149(82)900030; PMID: 7090993 Brunckhorst CB, Delacretaz E, Soejima K, et al. Identification of the ventricular tachycardia isthmus after infarction by pace mapping. Circulation 2004;110:652–9. DOI: 10.1161/01.

CIR.0000138107.11518.AF; PMID: 15289385

9.

de Chillou C, Groben L, Magnin-Pouli I, et al. Localizing the critical isthmus of postinfarct ventricular tachycardia: the value of pace-mapping during sinus rhythm. Heart Rhythm 2014;11:175–81. DOI: 10.1016/j.hrthm.2013.10.042; PMID: 24513915 10. Almendral J, Rosenthal ME, Stamato N, et al. Analysis of the resetting phenomenon in sustained uniform ventricular tachycardia: incidence and relation to termination. J Am Coll Cardiol 1986;8:294–300. PMID: 3734253 11. Almendral J, Gottlieb C, Rosenthal ME, et al. Entrainment of ventricular tachycardia: explanation for surface electrocardiographic phenomena by analysis of electrograms recorded within the tachycardia circuit. Circulation 1988;3:569– 80. DOI: 10.1161/01.CIR.77.3.569; PMID: 3342488 12. Josephson ME, Almendral J, Callans DJ. Resetting and entrainment of reentrant ventricular tachycardia associated with myocardial infarction. Heart Rhythm 2014;11:1239–49. DOI: 10.1016/j.hrthm.2014.03.046; PMID: 24681116

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Personal Perspective

Fred Morady

Edward Rowland

Cardiovascular Center, University of Michigan, Ann Arbor, USA

St Bartholomew’s Hospital, London, UK

A Brash, Politically Incorrect, Opinionated and Brilliant Friend

A Gifted Teacher

I met Mark for the first time over 30 years ago. I had completed my

specialty. Some achieve it through an eponymous syndrome or the

training only 1–2 years earlier and was amazed to discover that Mark

invention of a classic operational procedure. Mark Josephson’s name

was only a few years older than me. At that point, I had published one

was known to throughout the world of cardiac electrophysiology, and

or two clinical research studies dealing with electrophysiology issues,

through most of cardiology, because he was central to virtually all

whereas Mark already had established himself as a prolific investigator

aspects of the modern investigation and management of cardiac

and a leader in the field of clinical cardiac electrophysiology. Hardly a

arrhythmias from its beginning in the 1970s. Since those early days

month would go by without another study from Mark and his group

Mark Josephson’s name was on numerous classic scientific papers,

at the University of Pennsylvania appearing in Circulation. His status

conferences were incomplete without his presence, and any

as a pioneer in the field is undisputed. It is incredible to think back to

discussion on the mechanism of most arrhythmias had to encompass

how his early work shook up the cardiology community. I have a

Mark’s contribution to our better understanding. A week spent with

distinct memory of a debate that Mark had with a prominent icon in

him in the hospital during his meetings and rounds was an education

the field of electrocardiography and arrhythmia management at a

in a determination to be the best. Even a day spent at the courses

national American Heart Association meeting in the late 1970s. Mark

where Mark held court was something of a rite of passage. Here one

was quite literally and shockingly accused of advocating torture when

could glimpse his determination, an inquisitive mind backed up by

he defended the practice of programmed ventricular stimulation to

huge experience and learning.

Few in the medical world get to be a household name in their

induce ventricular tachycardia. Perhaps to the dismay of this ‘expert’, Mark’s pioneering efforts were quickly adopted into standard clinical

Asking colleagues their memories of Mark produced "gifted teacher"

practice, as have many of his other contributions to the field.

as the most common reply – of that there can be no doubt.

His deductive skills, emphasising the importance of the ECG and

Although Mark tragically is no longer with us, my strong memories of

using other information, especially intracardiac electrograms, to

this brash, politically incorrect, opinionated and brilliant friend

confirm these deductions was the cornerstone of much of his

remain embedded in my mind. n

teaching. At times it was harsh, but it was never any more demanding of others than the demands he made of himself. Like all highly intelligent individuals he was never hide-bound by rules or received wisdom. Evidence and deductive reasoning were necessary to prove the point. Much of this extended to his life outside medicine. Playing golf with Mark was always an interesting and entertaining experience, where passion, determination and enthusiasm were not inhibited by a rule book!

All those involved in or affected by heart rhythm abnormalities whether clinical staff, patients or administrators owe Mark Josephson a huge debt of gratitude. n

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Personal Perspective

Mark Josephson: Pioneer, Educator and Mentor to a Generation of Cardiac Electrophysiologists

I

n January 2017 we lost a giant in cardiac electrophysiology, whose work and teachings touched all of us working in the field. Mark Josephson’s early work, building on the work of Hein Wellens in using programmed stimulation and catheter mapping to understand

scar-related ventricular tachycardias, led the way to surgical and then catheter ablation as a viable therapy for that arrhythmia. His seminal observations are many and catalogued in ‘The Josephson School’ a wonderful book with 59 Chapters and extensive commentary devoted to his research.1 In the area of scar-related VT alone his work characterising electrograms in infarct scars and defining their relation to reentry circuits led to the development of substrate mapping techniques in common use today. His attention to the details of recording techniques helped establish the standards for electrophysiology studies. His investigational studies are not limited to ventricular arrhythmias but extend across the spectrum of cardiac electrophysiology. He was a superb observer with a talent for recognising subtle, unexpected

William G Stevenson

Cardiac Arrhythmia Program, Brigham and Women’s Hospital; Harvard Medical School, Boston, USA

events and delving deep to explore their potential mechanisms and significance.

I first met Mark Josephson in the early 1980s at his conference in

From a review of Mark’s publications one would appreciate only part of

Philadelphia, which I attended as a trainee. He was an inspiring figure,

his impact on the field. He was a tireless and inspiring teacher in the

with his incisive commentary and enthusiasm for the field. It was

clinic, on the wards, in the electrophysiology laboratory, and in countless

there that I first heard Al Waldo explain entrainment, which he

conferences and scientific meetings. His passion for electrocardiography

illustrated by drawing diagrams on a large flip chart. The discussion

and electrophysiology inspired more than a generation of physicians

was spirited! Mark brought people together, then pushed them with

and investigators who can be found in academic institutions and clinics

intellectual rigour. He used this approach with everyone from medical

around the world. He was a mentor and friend to those who trained

students to senior investigators. He routinely challenged conventional

under him, as well as to those who did not have that opportunity but

thinking, pushing the field forward.

sought his advice. He will be greatly missed. n

William G Stevenson Cardiac Arrhythmia Program, Brigham and Women’s Hospital; Harvard Medical School, Boston, USA

1.

The Josephson School: A Legacy of Important Contributions to Electrophysiology. Wellens HJ, Buxton AE, Marchlinski FE, Zimetbaum P (eds). Minneapolis, US: Cardiotext Publishing, 2015.

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Personal Perspective

Mark Josephson and the ICD: A Personal Perspective

M

ark Josephson dedicated his career to the prevention of premature sudden cardiac death (SCD). Toward that goal, he was an early adopter of the implantable cardioverter defibrillator (ICD) and indefatigable advocate for better ICD

technology,1 both as a clinical tool and as living laboratory to study SCD in ambulatory patients. With characteristic intellectual integrity and analytical rigour, he sought an honest and balanced appraisal of the life-saving benefits and serious complications of this unique therapy.

Charles D Swerdlow

Cedars-Sinai Medical Center, Los Angeles, USA

Balanced Evaluation of the ICD

Honesty with Evidence – Honesty with Patients

Although better known for his transformative contributions to

Dr Josephson sought to apply rigorous evidence to clinical care, yet

arrhythmia mechanisms, mapping and ablation, Dr Josephson

he retained a deeply human connection to his patients at risk for SCD.

participated in investigational studies of the first implantable

He interpreted practice guidelines through their stated intent, to

and served as a principal investigator for the MUSTT

assist in clinical decision-making;9 he was deeply troubled by the

(Multicenter Unsustained Tachycardia Trial) foundational trial of

trend to accept guidelines as canonical dictums that absolved

4

defibrillator

2,3

In one of the first systematic

physicians of cognitive responsibilities; and he discriminated

analyses of ICD far-field electrograms (EGMs), he stressed

unambiguously between those based on valid evidence and those he

5

judged to be based on inconsistent evidence, omission of relevant

and he actively encouraged research to predict spontaneous VT in

evidence or incorrect interpretation of evidence. In this context, he

ambulatory patients based on ICD EGMs.

contributed to an incisive critique of the inconclusive and statistically

primary-prevention ICD therapy.

morphological disparities between spontaneous and induced VT;

flawed evidence for primary-prevention ICDs in patients with As enthusiasm for ICDs began to soar in the mid-1990s, Dr Josephson

nonischaemic cardiomyopathy,8 a critique supported by the recent

provided a vital, clear-thinking counterbalance. He emphasised the role

Danish ICD Study in Patients with Dilated Cardiomyopathy (DANISH).10

of preventive, ablative therapy, both in conjunction with interruptive

He questioned the wisdom of some primary-prevention guidelines

ICD therapy to reduce shocks and as a curative alternative in patients

that required implanting 15 to 20 ICDs to save one life; and

6

he consistently supported research to improve risk stratification.

Dr Josephson spotlighted critical issues related to overestimating the

He emphasised that competing comorbidities and advanced age

benefits of ICD therapy and under-appreciating its limitations: early

precluded ICDs from prolonging life in some guideline-indicated

observational studies used appropriate ICD therapy as a surrogate for

patients, even if their ICDs prevented SCD.8 In this context, Dr Tung

prevention of SCD. With his mentees Joseph Germano and Roderick

penned a critical admonition with Dr Josephson as senior author:

with single-vessel coronary disease and haemodynamically stable VT.

Tung, Dr Josephson played a vital role in exposing this fallacy by emphasising that, in randomised control trials, appropriate ICD

“ With modern medicine, less emphasis has been placed on the

therapies occurred two to three times as frequently as SCD in control

physician-patient dialogue where concerns and expectations are

groups.7

Based on then limited evidence, they highlighted the reasons

freely exchanged. Physicians should understand that choosing

for this difference in event rates, unnecessary appropriate ICD therapy

longevity with potential tradeoffs in device-related complications

for self-terminating VT and device

proarrhythmia,7,8

were confirmed in subsequent studies.

both of which

and quality of life is a personal decision that must be individually tailored to patient preference. … It is ethically imperative that we are honest with the data, so that we can be honest with our patients.”

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

19

Personal Perspective An Inspirational Teacher

the intricate stories concealed within complex arrhythmias; and I

I first met Dr Josephson when he visited my fellowship programme,

witnessed his lucid expositions inspire students – including me – to

but I didn’t really get to know Mark until 2004, when he asked me to

seek out the stories hidden in our own patients’ tracings.

teach interpretation of ICD EGMs at the ‘How to Approach Complex Arrhythmias’ course he gave with Hein Wellens. Twice a year, for the

Mark was devoted to his gracious and inspirational wife Joan. They

next 12 years, I did my best to honour his implicit mandate – to

were inseparable, and she attended every course. Each Sunday

develop a systematic approach to ICD EGMs that complemented the

morning, I drank coffee with Joan as she recounted stories of Mark’s

systematic approach to ECGs he taught with Hein. By serendipity, I

deep personal investment in his fellows and his loving devotion as a

had a ringside seat to master teachers in action. I studied how,

father. I showed her the latest pictures of my two sons, and she

beyond Mark’s occasional frustration with fools, he provided strategic

offered practical and insightful parenting advice.

and strategically timed clues when a student struggled with a tracing.

Invariably, these clues framed the solution, yet required students to

Over years, Mark became my friend and mentor. In that process,

complete the analysis and thus permitted them to walk away with a

surpassing even his encyclopaedic knowledge and towering intellect,

sense of mastery. At each course, I sat humbled by the blinding speed

Mark’s humanity and moral compass became my greatest teacher.

and penetrating power of Mark’s reasoning, the depth and ken of his

For me, his integrity, empathy and compassion continue to shine like

analyses; I marvelled at the casual elegance with which he unravelled

a beacon, illuminating my path. n

Charles D Swerdlow Cedars-Sinai Medical Center, Los Angeles, USA

1.

2.

3.

4.

Josephson ME, Callans DJ, Buxton AE. The role of the implantable cardioverter-defibrillator for prevention of sudden cardiac death. Ann Intern Med 2000;133:901–10. DOI: 10.7326/0003-4819-133-11-200012050-00015; PMID: 11103061 Hargrove WC, 3rd, Miller JM, Josephson ME. Use of the automatic implantable cardioverter-defibrillator. N Engl J Med 1986;315:63–4. DOI: 10.1056/NEJM198607033150113; PMID: 3713785 Marchlinski FE, Flores BT, Buxton AE, et al. The automatic implantable cardioverter-defibrillator: efficacy, complications, and device failures. Ann Intern Med 1986;104:481–8.

DOI: 10.7326/0003-4819-104-4-481; PMID: 3954276 Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med

5.

6.

7.

1999;341:1882–90. DOI: 10.1056/NEJM199912163412503; PMID: 10601507 Monahan KM, Hadjis T, Hallett N, et al. Relation of induced to spontaneous ventricular tachycardia from analysis of stored far-field implantable defibrillator electrograms. Am J Cardiol 1999;83:349–53. DOI: 10.1016/S0002-9149(98)00867-4; PMID: 10072222 Almendral J, Josephson ME. All patients with hemodynamically tolerated postinfarction ventricular tachycardia do not require an implantable cardioverterdefibrillator. Circulation 2007;116:1204–12. DOI: 10.1161/ CIRCULATIONAHA.106.670067; PMID: 17768304 Germano JJ, Reynolds M, Essebag V, Josephson ME. Frequency and causes of implantable cardioverterdefibrillator therapies: is device therapy proarrhythmic? Am J Cardiol 2006;97:1255–61. DOI: 10.1016/j.amjcard.2005.11.048; PMID: 16616037

8.

Tung R, Zimetbaum P, Josephson ME. A critical appraisal of implantable cardioverter-defibrillator therapy for the prevention of sudden cardiac death. J Am Coll Cardiol 2008;52:1111–21. DOI: 10.1016/j.jacc.2008.05.058; PMID: 18804736 9. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/ HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 2008;117:e350–408. DOI: 10.1161/CIRCUALTIONAHA.108.189742; PMID: 18483207 10. Køber L, Thune JJ, Nielsen JC, et al. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med 2016;375:1221–30. DOI: 10.1056/NEJMoa1608029; PMID: 27571011

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Personal Perspective

Mark E Josephson: The Boston Years

M

ark Josephson came to Beth Israel Hospital from the University of Pennsylvania in 1992, having firmly established a reputation as a master clinician, scientist and educator. He had built one of the premier electrophysiology (EP) services in the

world in Pennsylvania and had become Chief of Cardiology there by the age of 35. In those days, Beth Israel was well known for its interventional cardiology and cardiac imaging but had not yet committed to the development of a modern EP section. The buzz surrounding Mark’s arrival predicted an outspoken, larger than life and irreverent character who would profoundly change the place.

Peter Zimetbaum

Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, USA

Intellectual Excitement

called ‘The Josephson Scholars – Four Decades of Clinical EP’, and

That turned out to be an understatement. As a Beth Israel resident

nearly 200 of his mentees and their mentees came to Boston from

at the time, I can remember his chagrin and frustration as he

across the country and around the world. Mark often proudly

realised how behind we were. Perhaps it was the need to catch us

referred to his “academic children and grandchildren,” and he

up or just his irrepressible passion for EP, but he brought an

received much recognition for his role as mentor, including the

intellectual excitement to the Division of Cardiovascular Medicine

American Heart Association’s prestigious Eugene Braunwald

that was electric. From the start he was everywhere – teaching at

Academic Mentorship Award. Upon getting the award, Mark

the bedside, in ECG conference and in the laboratory. He insisted on

reflected that mentoring is about more than helping people advance

the education of everyone from lab technicians and nurses to

professionally: “You have to love people; you have to care about

housestaff, fellows and cardiology attendings. No one got a pass –

people and want to see them grow and be happy.”

not even the then chief of cardiology, whom he quizzed on the details of reentry during his first cardiology grand rounds.

Tough Love His style was very much tough love, however; his approach to life

In short order, EP began to rival interventional cardiology for

was to question, to debate, to agree to disagree. Mark started the

fellowship applicants, fellows were talking about arrhythmia

practice and we continue it of meeting early every morning as an EP

mechanisms on rounds, and old attendings were embracing new

service and review the cases for the day and the patients on the

ways of managing arrhythmias. In fact, at age 80, Paul Zoll stood

ward service. The fellows quickly learn to bring all the tracings and

next to Mark in the EP lab as he performed the first ventricular

be ready to interpret them with both a diagnosis and an explanation

tachycardia (VT) ablation at Beth Israel on a patient of Paul's whose

of the physiology. This morning meeting ritual is about education

VT was no longer suppressed on medication.

and clinical excellence. It keeps us honest in our approach to patient care, allows us to teach one another, creates a cohesive service and,

A Valued Mentor

in effect, creates a family. It embodies all the principles Mark stood

For me personally, Mark was the best doctor I had – and have –ever

for as an academic physician. It is one of the places where Mark

worked with. He’s a big part of the reason that I’ve spent 25 years –

shared his brilliance with us and helped us learn to think more

the entirety of my career – here at Beth Israel Deaconess Medical

deeply and rigorously. It is no surprise that many EP programmes in

Center (BIDMC). And I’m not alone in having considered Mark a

Boston and, I suspect, wherever his former fellows have landed now

valued mentor and friend. A few years ago, we held a symposium

have similar morning meetings.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

21

Personal Perspective Ultimately Mark’s commitment to the care of patients, the education

Josephson scholar award – a three-year award given to a faculty

of young doctors, and the pursuit of academic excellence resulted in

member committed to the principles of humanism in medicine. The

his selection as Chief of Cardiovascular Medicine in 2001, a position

second is the first chair in cardiac electrophysiology at Harvard

he held until 2016.

Medical School called the Josephson–Ben Haim Chair in Cardiac Electrophysiology. Mark was very proud of this honour and gratified to

An Enduring Legacy

know that the future occupants of this chair would have his legacy to

Mark’s spirit will live on at the BIDMC in countless ways – but two

uphold and continue to ensure a vibrant environment for the training

enduring symbols have been created; the first is the Joan and Mark

of young physicians and the relentless pursuit of innovation. n

Peter Zimetbaum Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, USA

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Personal Perspective

Douglas P Zipes Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, USA

A Brilliant Pioneer and Leader Mark Josephson was a leader; not just a leader, but a brilliant pioneer leader breaking new ground in multiple areas of electrophysiology, including research, patient care and teaching. We were friends since his early days at Penn Medicine, Philadelphia, when he was working with Len Horowitz as his collaborator. I watched his maturation and contributions over the next 40 years in all three areas. His textbook is one of a kind: a single authored electrophysiology teaching gem that will never be duplicated. His teaching seminars with Hein Wellens, known for the Socratic method initiated by Pick and Langendorf many years ago, will also never be replicated. Mark’s most recent contributions to teaching have been a plea – a demand, really – to harken back to our roots as electrophysiologists, to teach and learn physiology, not just implantation or ablation procedures. I couldn't agree more.

So often our attributes become our failings, and Mark’s was his outspokenness. He never said things in a mean or vindictive manner, but always spoke his mind on a particular issue. Those colleagues fortunate enough to have known Mark had a friend in their corner for life. Those learners privileged to have taken his course or read his book had a teacher they will never forget.

Mark has left a legacy that will guide our specialty for many years to come. n

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Shared Moments Professor Wellens has written memorials about Mark Josephson for Heart Rhythm and European Heart Journal and has also prepared a book about the Josephson school. n

“ I remember many

moments from the 40 years that Mark and I worked together. This is one from a drink together after a long day of giving a course.”

–

Hein Wellens

–

University of Maastricht, the Netherlands

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23

Diagnostic Electrophysiology & Ablation

Electrophysiological Testing for the Investigation of Bradycardias Demosthenes G Katritsis 1 and Mark E Josephson 2 1. Athens Euroclinic, Athens, Greece; 2. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

Abstract In this article we review the role of electrophysiological testing in patients presenting with bradycardia due to sinus node or atrioventricular node disease. In sinus bradycardia the role of electrophysiology studies is not established. In AV conduction disturbances, an electrophysiology study may be necessary both for the establishment of atrioventricular block as the main cause of symptoms, and for identification of the anatomic site of block that may dictate the potential need of permanent pacing.

Keywords Electrophysiological tests, bradycardia, atrioventricular node, sinus node, AV conduction Disclosure: The authors have no conflicts of interest to declare.

Received: 7 November 2016 Accepted: 2 March 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(1):24–8. DOI: 10.15420 /aer.2016:34:2 Correspondence: Dr DG Katritsis, Athens Euroclinic, 9 Ahanassiadou Street, Athens 11521, Greece. E: dkatrits@dgkatritsis.gr

In patients with syncope or episodes of palpitations and heart disease, an electrophysiology study (EPS) may be of value by means of potential induction of sustained ventricular tachyarrhythmias.1,2 Programmed ventricular stimulation may be useful in the context of risk stratification of ischaemic patients with left ventricular ejection fraction (LVEF) 30–40 %, and there has been some evidence that it might also be of predictive value in revascularised patients with ST-segment elevation myocardial infarction and LVEF ≤30 %.3,4 In patients investigated for bradycardias, either due to sinus node or atrioventricular (AV) conduction disturbances, the role of EPS is not well defined. Most of the time, the criteria used for indications of permanent pacing are symptoms and electrocardiographic findings. However, there are certain occasions on which an EPS is mandatory either for the establishment of diagnosis or for appropriate implementation of prophylactic pacing.

Sinus Bradycardia Early studies on limited patient cohorts had suggested that corrected sinus node recovery time (c-SNRT) may be useful in predicting the development of syncope and the need of permanent pacing in patients with bradycardia. A marked prolongation of the c-SNRT and an absent or blunted response to atropine and exercise suggest impaired sinus node function.5 However, a wide range of ‘normal’ c-SNRTs has been published, and it seems that only very prolonged c-SNRTs (>800 ms) have reasonable predictive ability.6 When considering conventional upper limits, such as 500–550 ms, the sensitivity of the test in asymptomatic patients with dizziness or no symptoms who will need a pacemaker in the future is only 50–65 %.7 The sinoatrial conduction time (SACT) is an insensitive indicator, being prolonged in only 40 % of our patients with clinical findings of sinus node dysfunction.5 The ACCF/AHA/HRS 2012 Guidelines on Device-based Therapy recommend EP testing in patients with syncope of unexplained origin for the detection of clinically significant abnormalities of sinus node function (IIa-C indication for permanent pacing),8 whereas the ESC 2013 Guidelines on Pacing and Cardiac Resynchronization Pacing do not consider the value of EPS established in this setting.9

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AV Conduction Disturbances Diagnosis The ECG appearance of first- or second-degree block may be due to junctional (His bundle) extrasystoles that are concealed (not conducted to the atria or ventricles), but render a portion of the conduction system refractory to propagation of a sinus beat. The observance of junctional premature depolarisations on the surface ECG suggests that concealed His bundle extrasystoles are responsible for the apparent A-V block, but a His-bundle recording is the only method of positive identification (see Figure 1).

Anatomic Site of Block High-grade block can occur anywhere in the AV conduction system, and the width of the QRS complex and the configuration of conducted beats and/or escape beats are of only limited value in localising the site of block. A narrow QRS complex is most compatible with an AV nodal or intra-His problem, and a wide QRS complex is most compatible with an infra-His problem; however, a wide QRS complex certainly may occur with A-V nodal or intra-His disease in the presence of coexistent bundle branch block.10 Approximately 70 % of type II blocks (i.e. consecutive, non-conducted P waves without changes in the PR interval) are associated with bundle branch block, whereas 30 % are associated with a narrow QRS complex, and are therefore within the His bundle.11 All type II blocks are infranodal, i.e. below the AV node or N zone, but not all infranodal blocks are type II blocks.12 Although 2:1 or higher degrees of block (e.g. 3:1 and 4:1) have traditionally been classified as type II block, the site of those blocks cannot be reliably determined by the surface ECG. A 2:1 block in the context of bundle branch block does not necessarily indicate infranodal block, since in 15–20 % of patients the block is in the AV node. Thus pacing may not be required in asymptomatic patients with this pattern and an EPS may be useful (see Table 1). Symptomatic patients with type I block and a bundle branch block should also be considered for an EPS to determine the site of block. Multiple levels of A-V block spontaneously or during pacing may also coexist in the same patient, and they can produce a confusing ECG picture that is extraordinarily difficult to

© RADCLIFFE CARDIOLOGY 2017

Electrophysiological Testing for Bradycardias interpret without an EPS. Combined A-V nodal and infra-His block has been described as the mechanism in alternate 2:1 block and prolonged PR intervals.13 Finally, the presence of phase 4 block can be suspected by observing prolonged ventricular asystole and the absence of type I block in long tracings. Absence of sinus slowing is usually a criterion for type II block because a vagal surge can cause simultaneous sinus slowing and AV nodal block, which can superficially resemble type II block. Significant PR prolongation before and after block and prolonged P-P intervals during ventricular asystole are indicative of vagal block that is a benign condition, rather than paroxysmal AV block, i.e. pause-dependent phase 4 AV block which is potentially dangerous for syncope.14 A definitive diagnosis of phase 4 AV block require His bundle recordings.11 Specific loss-of-function SCN5A mutations demonstrate varied competing gating effects that reduce sodium current density and enhance slow inactivation with selective slowing of conduction velocity, in a way that may result in isolated progressive conduction system disease without provoking tachyarrhythmias.15 Initial EPS in mutation carriers with AV block revealed prolonged HV but normal A-H intervals, thus suggesting infra-Hisian block, but progressive AV block due to SCN5A mutations can be both supra- and infra-Hisian. Thus, an EPS may useful in this setting. Several different types of muscular dystrophies, such as Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy (Erb’s muscular dystrophy), myotonic dystrophy type 1 (Steinert’s disease) and desmin-related myopathy, are also associated with progressive conduction defects. An EPS may identify patients in need of permanent pacing, and improve survival of these patients.16

Figure 1: Pseudo-type II infra-His Block Secondary to a Concealed His Bundle Depolarisation in a Patient with Right Bundle Branch Block and Left-Axis Deviation II V1 AH

His

A

CS

V

H

A

AH A

A

V

V V

II, V1: 12-lead ECG leads; His: His bundle; CS: coronary sinus. Reproduced with kind permission from Josephson, 2016.34

Table 1: Recommendations for Electrophysiology Study in Selecting Patients for Permanent Pacing ACCF/AHA/HRS 2012 Guidelines on Device-based Therapy8 Recommendations for Acquired Atrioventricular Block in Adults Asymptomatic second-degree AV block at intra- or infra-His levels found at electrophysiological study.

IIa-B

Recommendations for Permanent Pacing in Chronic Bifascicular Block Incidental finding at electrophysiological study of pacing-induced infra-His block that is not physiological.

IIa-B

ESC 2013 Guidelines on Pacing and CRT9 Indication for pacing in persistent bradycardia Pacing second-degree type 1 acquired AV block which causes symptoms or is found to be located at intra- or infra-His levels at electrophysiological study.

IIa-C

Figure 2: Markedly Prolonged H-V Interval in the Presence of a Normal Overall P-R Interval

Prediction of High-Grade AV Block H-V Interval Bifascicular block, specifically right bundle branch block (RBBB) with left-axis deviation, is the most common ECG pattern preceding complete heart block in adults. 5 Early studies on patients with bifascicular or trifascicular block have reported an overall incidence of progression to complete heart block of approximately 1–2 % per year.17–20 Patients with syncope, in particular, may have a 17 % cumulative incidence of complete AV block within the next 5 years.19 The evaluation of the patient with bundle branch block or fascicular block necessarily involves testing the integrity of the remaining fascicle, and the simplest method of assessing this His–Purkinje reserve is the measurement of basal H-V intervals (normal <55 msec).

In the presence of bundle branch block, with or without additional fascicular block, the H-V interval should be normal as long as conduction is unimpaired in the remaining fascicle. Most patients developing complete infra-His block have prolonged H-V intervals (>70 ms),18–20 and prolongation of the HV interval by ≥13 ms is strongly associated with AV block following transcatheter aortic valve replacement. 21 Thus, analysis of H-V interval was the factor initially evaluated as a predictor of subsequent heart block. However, an H-V interval >70 ms may not independently predict development of complete heart block,19 and approximately 50 % of patients with RBBB and left anterior hemiblock, and 75 % of patients with left bundle branch block (LBBB) have prolonged H-V intervals. 22 This finding alone, therefore, is nonspecific as a predictor of the development of high-grade heart block, because the incidence of heart block is low, yet the presence of prolonged H-V interval is great. In our experience, approximately 70 % of patients with H-V intervals ≥100 msec, develop second- or third-degree infra-His block

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PR

200 msec

I

aVF V1 A HRA

MRA

A

A HBE

RVA

88

H 90

V

V

T

The P-R interval is at the upper limits of normal (200 msec), and the QRS complex is prolonged with a pattern of interventricular conduction defect of the LBBB type. The H-V interval is 90 msec. Reproduced with kind permission from Josephson, 2016.34

within the next two years. However, H-V intervals in excess of 100 msec are uncommon. Thus, such marked H-V prolongation, although highly predictive, is insensitive.

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Diagnostic Electrophysiology & Ablation Figure 3: Prolonged P-R Interval with a Normal H-V Interval

Figure 5: Effect of Procainamide on H-V Interval 1 aVF

1

V1 2

HRA HBE

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H–V 70 msec

RVA A

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Procainamide 1,000 mg

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aVF

45 V

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V1 HRA

T The P-R interval is 290 msec, and the QRS complex is prolonged with a pattern of right bundle branch block and left anterior fascicular block. The H-V interval is normal at 45 msec, but the A-H interval is prolonged at 210 msec. Reproduced with kind permission from Josephson, 2016.34

Figure 4: Normal H-V Interval in Left Bundle Branch Despite P-R Prolongation and Marked QRS Complex Widening LBBB

PR .230

I

II

III

VI 30

HBE

T

150 A H50 V

300 msec

The P-R interval is 230 msec and QRS complex 210 msec, yet the H-V interval is normal (50 msec). The P-R prolongation is due to A-V nodal delay (A-H interval = 150 msec).

Reproduced with kind permission from Josephson, 2016.34

Of note, the surface ECG may not allow accurate assessment of the H-V interval. Although a short P-R interval (i.e. ≤160 msec) makes a markedly prolonged H-V interval (i.e. ≥100 msec) unlikely, and a P-R interval of >300 msec almost always means at least some AV nodal conduction abnormality,23 intermediate values do not correlate with the H-V interval (see Figure 2). In the presence of RBBB and left anterior hemiblock or LBBB with or without left anterior hemiblock, a normal P-R interval can easily ‘conceal’ a significantly prolonged H-V interval, and a prolonged P-R interval can be the result of a prolonged A-H interval only (see Figure 3).

Most patients who have LBBB have prolonged H-V intervals, regardless of the length of the accompanying P-R interval. Conversely, a long P-R interval does not automatically mean a long H-V interval (see Figure 4).

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H–V 100 msec

HBE RVA In the contra state (top) the patient manifests right bundle branch block and right-axis deviation with an H-V of 70 msec. After 1,000 mg of procainamide (bottom), the H-V markedly prolongs to 100 msec. Reproduced with kind permission from Josephson, 2016.34

Pharmacological Challenge The administration of pharmacological agents known to impair His– Purkinje conduction (e.g. procainamide) may unmask poor His–Purkinje system reserve. In normal persons as well as in most persons with moderately prolonged (55–80 msec) H-V intervals, procainamide typically produces a 10–20 % increase in the H-V interval.24 An increase of greater magnitude, including (a) doubling of the H-V interval, (b) a resultant H-V interval exceeding 100 msec, or (c) the precipitation of second- or third-degree infra-His block, all represent evidence of propensity for spontaneous infra-His block (see Figures 5 and 6). However, the incidence of provocation of AV block by procainamide is low, and the test may be useful in cases with borderline prolongation of the HV interval but its diagnostic yield is rather limited.25–27 Other drugs may also be used in order to provide additional information about the His-Purkinje reserve. If the conduction improves with atropine or exercise, or worsens with carotid sinus massage, the block is in the AV node. If the conduction worsens with atropine or exercise or improves with carotid sinus massage, the block is in His or bundle branches.22 The value of adenosine or ATP testing for induction of asystole due to latent sinus nodal disease AV block in patients investigated for unexplained syncope is not established, and these drugs have little or no effect on the His-Purkinje system.28,29 However, there has been evidence that induction of cardiac pauses (due to AV block or sinoatrial block >10 sec by an IV bolus of 20 mg ATP) indicates the need for DDD pacing in patients with unexplained syncope.30,31 Adenosine may also be used although its effects are not identical to those of ATP.29,32

Atrial Pacing The use of atrial pacing to stress the His–Purkinje system may provide further information beyond that of the basal H-V interval. Most normal patients will not exhibit second- or third-degree infra-His block at any time during incremental pacing, particularly at rates less than 150 bpm.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Electrophysiological Testing for Bradycardias Figure 6: Effect of Procainamide on H-V Response to Pacing

1 aVF V1 PCL

340 msec

HRA A HBE

A

V H

V H

RVA

Procainamide 1,000 mg 1 aVF PCL

400 msec

V1 HRA A

H

A

H

V

HBE RVA

Top: Before procainamide, 1:1 conduction is present at a paced cycle length (PCL) of 340 msec. Bottom: After procainamide pacing at 400 msec results in block below the His. Reproduced with kind permission from Josephson, 201634

Figure 7: Unmasking of Decreased Infra-His Conduction Reserve by Atrial Pacing NSR

BCL 600

BCL 400

2 V1

HRA

A

A

A

A

A A

A

A A

A

A

A

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HV

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Left panel (during sinus rhythm), a right bundle branch block configuration is seen with a normal H-V interval of 50 msec. Centre panel, atrial pacing (arrows) at a cycle length of 600 msec results in an increase in the H-V interval to 65 msec. Right panel, atrial pacing (arrows) at a cycle length of 400 msec precipitates infra-His type I second-degree block. Reproduced with kind permission from Josephson, 2016.34

Physiologically, this occurs because the shortening of His–Purkinje refractoriness had decreased paced cycle lengths or because A-V nodal block developed at shorter paced cycle lengths, which thus protects the His–Purkinje system, even H-V prolongation during atrial pacing at rates less than 150 bpm. Second- or third-degree block within the His–Purkinje system in the absence of a changing A-H interval at paced cycle lengths of 400 msec or greater is abnormal and suggests a high risk for A-V block (see Figure 7). In patients who develop block

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

distal to the His bundle induced by atrial pacing at rates of 150 bpm or less, there is a 33 % progression to high-grade A-V block within the next 3 years.33 However, data on this procedure, in order to guide the decision for permanent pacing, are limited.

Table 1 presents current recommendations of learned societies for the utility of EPS in the selection of patients with AV conduction disturbances for permanent pacing. In Table 2 we have summarised all

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Diagnostic Electrophysiology & Ablation Table 2: Indications for Electrophysiology Study of Atrioventricular Block 1. Suspicion of concealed AV junctional extrasystoles 2. Asymptomatic type I second degree AV block with bundle branch block 3. Asymptomatic second degree AV block with bundle branch block 4. Questionable diagnosis of type II block with a narrow QRS complex 5. Suspicion of bradycardia-dependent (phase 4) infranodal block 6. Transient second degree AV block with bundle branch block in patients with inferior myocardial infarction where the site of block is suspected to be in the His-Purkinje system rather than the AV node 7. Third degree AV block with a fast ventricular rate 8. Progressive conduction disease due to neuromuscular disorders or suspected SCN5A mutations

indications of EPS for diagnostic purposes in patients with apparent or suspected AV conduction abnormalities.

Conclusion In sinus bradycardia the role of EPS is not established. In AV conduction disturbances, there are certain occasions in which an EPS is necessary

1.

2.

3.

4.

5.

6.

7.

8.

9.

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D Electrophysiologic evaluation and follow-up characteristics of patients with recurrent unexplained syncope and presyncope. Am J Cardiol 1985;55:703–8. DOI: 10.1016/00029149(85)90140-7; PMID: 3976512 Morady F, Shen E, Schwartz A, et al. Long-term follow-up of patients with recurrent unexplained syncope evaluated by electrophysiologic testing. J Am Coll Cardiol 1983;2:1053–9.

PMID: 6630777 Buxton AE, Lee KL, Hafley GE, et al. Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: an analysis of patients enrolled in the multicenter unsustained tachycardia trial. Circulation 2002;106:2466–72. DOI: 10.1161/ 01.CIR.0000037224.15873.83; PMID: 12417544 Zaman S Narayan A, Thiagalingam A, et al. Long-term arrhythmia-free survival in patients with severe left ventricular dysfunction and no inducible ventricular tachycardia after myocardial infarction. Circulation 2014;129:848–54. DOI: 10.1161/CIRCULATIONAHA. 113.005146; PMID: 24381209 Josephson ME. Electrophysiologic evaluation of sinus node function. In: Clinical Cardiac Electrophysiology. Fifth Edition.

Philadelphia, US: Wolters Kluwer, 2016; 72–85.

Menozzi C, Brignole M, Alboni P, et al. The natural course of untreated sick sinus syndrome and identification of the variables predictive of unfavorable outcome. Am J Cardiol 1998;82:1205–9. DOI: 10.1016/S0002-9149(98)00605-5; PMID: 9832095 Gann D, Tolentino A, Samet P. Electrophysiologic evaluation of elderly patients with sinus bradycardia: a long-term follow-up study. Ann Intern Med 1979;90:24–29. PMID: 420459 Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2012;126:1784-800. DOI: 10.1161/ CIR.0b013e3182618569; PMID: 22965336 Brignole M, Auricchio A, Baron-Esquivias G, et al.

2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 2013;15:1070–118. DOI: 10.1093/europace/eut206. PMID: 23801827

for the appropriate diagnosis, and allows both the avoidance of unnecessary permanent pacing and the appropriate implementation of prophylactic pacing. n

Clinical Perspective • The value of electrophysiology studies in patients with sinus bradycardia is not established. A marked prolongation of the corrected sinus node recovery time (>800 ms) is a highly predictive but insensitive sign for sick sinus syndrome.

• In patients with atrioventricular node conduction disturbances an electrophysiology study may be necessary to define the site of block.

• An H-V interval >70 ms is a nonspecific predictor of development of high-grade atrioventricular block. An H-V interval >100 ms is highly predictive but insensitive.

• Adenosine triphosphate/adenosine, procainamide and atrial pacing have a rather limited diagnostic yield in patients with AV conduction disturbances.

10. P uech P, Wainwright RJ. Clinical electrophysiology of atrioventricular block. Cardiol Clin 1983;1:209–24.

PMID: 6544636 11. Barold SS, Hayes DL. Second-degree atrioventricular block: a reappraisal. Mayo Clin Proc 2001;76:44–57. DOI: 10.4065/76.1.44; PMID: 11155413 12. Antoniadis AP, Fragakis NK, Maligkos GC, Katsaris GA. InfraHisian block as cause of Wenckebach’s phenomenon in an asymptomatic middle-aged man. Europace 2010;12:898–902.

DOI: 10.1093/europace/eup450; PMID: 20106798 13. Feldman R, Horowitz LN, Josephson ME. Two-to-one A-V block with four-to-three A-V nodal Wenckebach, a form of spontaneous multilevel block. J Electrocardiol 1978;11:181–4.

PMID: 660022 14. Lee S, Wellens HJ, Josephson ME. Paroxysmal atrioventricular block. Heart Rhythm 2009;6:1229–34.

15. Katritsis D. Progressive cardiac conduction disease. In: Zipes DP, Jalife J. Cardiac Electrophysiology: From Cell to Bedside. Sixth edition. Elsevier; 2014: 1035–42.

16. Wahbi K, Meune C, Porcher R, et al. Electrophysiological study with prophylactic pacing and survival in adults with myotonic dystrophy and conduction system disease. JAMA 2012;307: 1292–301. DOI: 10.1001/jama.2012.346; PMID: 22453570 17. Dhingra RC, Wyndham C, Amat-y-Leon F, et al. Incidence and site of atrioventricular block in patients with chronic bifascicular block. Circulation 1979;59:238–46. DOI: 10.1161/ 01.CIR.59.2.238; PMID: 758992 18. Dhingra RC, Palileo E, Strasberg B, et al. Significance of the HV interval in 517 patients with chronic bifascicular block. Circulation 1981;64:1265–1271. DOI: 10.1161/01.

CIR.64.6.1265; PMID: 7296798 19. McAnulty JH, Rahimtoola SH, Murphy E, et al. Natural history of “high-risk” bundle-branch block: final report of a prospective study. N Engl J Med 1982;307:137–43. DOI: 10.1056/ NEJM198207153070301; PMID: 7088050 20. Scheinman MM, Peters RW, Suave MJ, et al. Value of the H-Q interval in patients with bundle branch block and the role of prophylactic permanent pacing. Am J Cardiol 1982;50:1316–22.

PMID: 7148708 21. Rivard L, Schram G, Asgar A, et al. Electrocardiographic and electrophysiological predictors of atrioventricular block after transcatheter aortic valve replacement. Heart Rhythm 2015;12:321–9. DOI: 10.1016/j.hrthm.2014.10.023; PMID: 25446155 22. Josephson ME. Clinical relevance of intraventricular conduction disturbances. In: Clinical Cardiac Electrophysiology. Fifth Edition. Philadelphia, US: Wolters Kluwer, 2016;130–9.

23. J osephson ME, Wellens HJ. Episodic dizziness in a 74-yearold woman. Heart Rhythm 2014;11:2329–30. DOI: 10.1016/ j.hrthm.2014.08.018; PMID: 25454060 24. Josephson ME, Caracta AR, Ricciutti MA, et al.

Electrophysiologic properties of procainamide in man.

Am J Cardiol 1974;33:596–603. PMID: 4820891 25. Tonkin AM, Heddle WF, Tornos P. Intermittent atrioventricular block: procainamide administration as a provocative test.

Aust N Z J Med 1978;8:594–602. PMID: 285680 26. Twidale N, Heddle WF, Tonkin AM. Procainamide administration during electrophysiology study—utility as a provocative test for intermittent atrioventricular block. Pacing Clin Electrophysiol 1988;11:1388–97. PMID: 2462213 27. Gang ES, Denton TA, Oseran DS, et al. Rate-dependent effects of procainamide on His-Purkinje conduction in man. Am J Cardiol 1985;55:1525–9. PMID: 4003294 28. Brignole M, Sutton R, Menozzi C, et al. Lack of correlation between the responses to tilt testing and adenosine triphosphate test and the mechanism of spontaneous neurally mediated syncope. Eur Heart J 2006;27:2232–9.

DOI: 10.1093/eurheartj/ehl164; PMID: 16864606 29. Lerman BB, Belardinelli L. Cardiac electrophysiology of adenosine. Basic and clinical concepts. Circulation 1991;83:1499–509. DOI: 10.1161/01.CIR.83.5.1499; PMID: 2022011 30. Brignole M, Gaggioli G, Menozzi C, et al. Adenosine-induced atrioventricular block in patients with unexplained syncope: the diagnostic value of ATP testing. Circulation 1997;96:3921–7.

DOI: 10.1161/01.CIR.96.11.3921; PMID: 9403616 31. Flammang D, Church TR, De Roy L, et al. Treatment of unexplained syncope: a multicenter, randomized trial of cardiac pacing guided by adenosine 5’-triphosphate testing. Circulation 2012;125:31–6. doi: 10.1161/ CIRCULATIONAHA.111.022855; PMID: 22086879 32. Fragakis N, Antoniadis AP, Saviano M, et al. The use of adenosine and adenosine triphosphate testing in the diagnosis, risk stratification and management of patients with syncope: current evidence and future perspectives. Int J Cardiol 2015;183:267–73. DOI: 10.1016/j.ijcard.2015.01.089; PMID: 25725201 33. Dhingra RC, Wyndham C, Bauernfeind R, et al. Significance of block distal to the His bundle induced by atrial pacing in patients with chronic bifascicular block. Circulation 1979;60:1455–64. DOI: 10.1161/01.CIR.60.7.1455; PMID: 498473 34. Josephson ME. Clinical Cardiac Electrophysiology. Fifth Edition. Philadelphia, US: Wolters Kluwer, 2016.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Diagnostic Electrophysiology & Ablation

Mahaim Accessory Pathways Demosthenes G Katritsis, 1 Hein J Wellens, 2 Mark E Josephson 3 1. Athens Euroclinic, Athens, Greece, 2. Cardiovascular Research Institute, Maastricht, the Netherlands, 3. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

Abstract The term Mahaim conduction is conventionally used to describe decrementally conducting connections between the right atrium or the AV node and the right ventricle in or close to the right bundle branch. Although such pathways are rare, their unique properties make their diagnosis and treatment cumbersome. In this article we review the published evidence, and discuss the electrocardiographic and electrophysiological characteristics as well as the anatomy and origin of these fibres.

Keywords Mahaim; accessory; pathway Disclosure: The authors have no conflicts of interest to declare.

Received: 7 November 2016 Accepted: 2 March 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(1):29–32. DOI: 10.15420 /aer.2016:35:1 Correspondence: Dr DG Katritsis, Athens Euroclinic, 9 Ahanassiadou Street, Athens 11521, Greece. E: dkatrits@dgkatritsis.gr

In 1941, Mahaim and Winston described the histology of anomalous connections that arise from the AV node and insert into the right ventricle.1 This was the first description of nodoventricular or so-called Mahaim accessory pathways. Accessory pathways with decremental conduction properties that connected the atrium to the right bundle branch (RBB) were subsequently mapped mainly at the lateral aspect of the tricuspid annulus, and thus the term atriofascicular was also adopted.2-4 We know now that decrementally conducting connections can be between the right atrium or the AV node and the right ventricle in or close to the RBB.5-7 Thus, although they are anatomically distinct from the initially described nodoventricular pathway, they present with similar electrocardiographic and electrophysiological characteristics and the term ‘Mahaim’ has been adopted to describe pathways with the following features:

ECG during tachycardia Although, typically, antidromic atrioventricular reentrant tachycardia over a Mahaim fibre has a left bundle branch (LBBB) morphology (see Figure 2), various QRS patterns and axis may occur (see Figure 3). 6,7 It seems that these pathways insert into or near the RBB, and variations in the frontal plane axis can be explained by the location of the exit of the RBB and a variable degree of fusion of ventricular activation between anterograde conduction over the pathway and, following retrograde invasion into the RBB, partial anterograde left ventricular activation over the left-sided conduction system, especially the anterior fascicle (see Figure 4). The various QRS patterns and rate changes seen during the change from short to long V-A tachycardia can be explained by the mode of retrograde conduction over the bundle branch system.6,7

Electrophysiological Properties • Baseline normal QRS or different degrees of manifest preexcitation with left bundle branch block morphology; • Programmed atrial pacing leading to obvious manifest preexcitation following an increase in A-V interval along with shortening of H-V interval at shorter pacing cycle lengths; and • Right bundle electrogram preceding His bundle activation during anterograde pre-excitation and supraventricular tachycardia (SVT).

Although such pathways are rare, their unique properties as well as the still unanswered questions about their true nature, make them particularly interesting from an electrophysiological point of view.8

Electrocardiographic Features ECG During Sinus Rhythm During sinus rhythm overt pre-excitation is usually absent (see Figure 1). Only subtle ECG abnormalities, such as an rS pattern in lead III, absence of septal Q waves in leads I and V6, and terminal QRS slurring or notching, suggest the presence of Mahaim conduction.9,10 However, patients with short, rapidly conducting fibres may have typical pre-excitation.10

© RADCLIFFE CARDIOLOGY 2017

Nodoventricular or Atriofascicular?

Although the first case of this arrhythmia was studied electrophysiologically by Wellens and published in 1971, and considered to be based on a nodo-ventricular pathway,11 with the advent of surgical and then catheter ablation in the 1980s, it was discovered that most fibres with Mahaim conduction characteristics originated at the lateral aspect of the tricuspid annulus, and the term atriofascicular pathway was adopted.2-5,12-17 However, posteroseptal locations could also be found,7,14 and true nodoventricular fibres have been identified (see Figure 5).1,14,16 In addition, some of these pathways, so-called ‘short’ as opposed to ‘long’ Mahaims, may insert at the ventricle near rather than in the RBB.5-7,18 Thus, pathways with Mahaim characteristics can be atriofascicular, atrioventricular, nodofascicular and nodoventricular, depending on their variable proximal and distal insertions.

Origin The electrophysiological properties of Mahaim pathways are not uniform, and this may reflect the diversity of the limited histology findings.5,18 It seems that most, but not all, of these pathways represent duplications of the AV nodal conducting system and contain nodal

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Diagnostic Electrophysiology & Ablation Figure 2: Induction of Tachycardia by Atrial (left panel) and Ventricular Pacing (right panel)

Figure 1: ECG during Sinus Rhythm and Atrial Pacing Demonstrating Characteristics of Mahaim Conduction

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25 mm/s Left panel: Absence of spontaneous pre-excitation during sinus rhythm. Right panel: Varying degrees of pre-excitation during atrial pacing (right panel). Normal AV nodal conduction (first beat), fusion between nodal and Mahaim conduction (next two beats) and full left bundle branch block appearance due to conduction over the Mahaim pathway (last beat) are shown.

Figure 3: 12-lead ECG of Three Different Patients with Antidromic Tachycardia

Figure 4: Change in QRS Morphology from Short to Long V-A Atrioventricular Re-entrant Tachycardia A

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From left to right: superior, horizontal and normal frontal plane QRS axis ablated from the same sector of the tricuspid annulus (site of ablation between 7 o’clock and 7:30).

Reproduced from Sternick et al, 2014,7 with kind permission.

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tissue, and their association with the R3-2Q mutation in PRKAG2 has been considered as an indication that this gene is involved in the development of the cardiac conduction system.19 They may display spontaneous or post-ablation automaticity,13,20 may respond to adenosine but not to verapamil,21 and their properties may depend on their location and insertion site.5,13

Catheter Ablation Mahaim pathways are typically decremental and conducting only anterogradely. However, retrogradely conducting nodoventricular pathways have been described.22,23 Whether such pathways are classified as ‘true’ Mahaims is a matter of terminology rather than essence. Catheter ablation is accomplished by identifying the proximal

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A: During short V-A AVRT (tachycardia cycle length 300 ms), there is also anterograde activation over the left anterior fascicle to produce a fused QRS complex with a normal axis. B: With retrograde right bundle branch block, anterograde conduction over the left anterior fascicle is no longer possible and conduction to the left ventricle proceeds only via the right free wall. Therefore, the long V-A AVRT (tachycardia cycle length 350ms) has a leftward axis. During the change from short V-A AVRT to long V-A AVRT, the QRS width also increases from 120 to 150 ms. A: atrial electrogram; AF: anterior fascicle; AVN: atrioventricular node; AVRT: atrioventricular reentrant tachycardia; CSp: proximal coronary sinus catheter; HBE: His bundle catheter; HRA: high right atrium catheter; LBB: left bundle branch catheter; M: Mahaim potential; PF: posterior fascicle; RB: right bundle potential; RBB: right bundle branch catheter; RVA: right ventricular apex catheter; V-H: ventriculo-His interval. Reproduced from Gandhavadi et al, 2013,6 with kind permission.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Mahaim Accessory Pathways Figure 5: Site of Ablation of Each Atriofascicular Fibre at the Tricuspid Annulus in 48 Different Antidromic Tachycardias

Figure 6: Atrial Resetting of Tachycardia and Recording of Mahaim Potential I

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The annulus was classified into regions: posterior and postero-septal sites (P), posterolateral sites (PL), lateral sites (L), anterolateral sites (AL) and anteroseptal sites (AS). The QRS frontal plane axis was classified as superior (<-300), horizontal (≤+150 and ≥-300) and normal (>±150). Regardless of the frontal plane axis, most of the cases were ablated at the L and PL regions. There was not a single case with normal frontal plane axis located at the AS region.

Reproduced from Sternick et al, 2014,7 with kind permission.

and distal insertions and, ideally, the recording of a proximal pathway potential at the tricuspid annulus or a distal one on the right ventricular free wall (see Figure 6).5,13-17 Pathway potential recording may be facilitated during atrial pacing. Since most of the Mahaims are mapped on the lateral tricuspid annulus or right free wall underneath the valve, the use of supportive long sheaths that stabilise the ablating catheter may be very helpful.24 Rare true nodoventricular pathways may also be ablated with preservation of AV nodal conduction.25

Conclusion Mahaim pathways are decrementally conducting connections between the right atrium or the AV node and the right ventricle in or close to the right bundle branch. They can be atriofascicular, atrioventricular, nodofascicular and nodoventricular, depending on their variable proximal and distal insertions. Catheter ablation is accomplished by identifying the proximal and distal insertions and, ideally, the recording of a proximal pathway potential at the tricuspid annulus or a distal one on the right ventricular free wall. n

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7.

ahaim I, Winston MR. Recherches d’anatomie compareé et M de pathologie expérimentale sur les connexions hautes du faisceau de His-Tawara. Cardiologia 1941;5:189–260.

Gillette PC, Garson A, Cooley DA, McNamara DG. Prolonged and decremental antegrade conduction properties in right anterior accessory connections: wide QRS antidromic tachycardia of left bundle branch block pattern without Wolff-Parkinson-White configuration in sinus rhythm.

Am Heart J 1982;103:66–74. PMID: 7055047 Klein GJ, Guiraudon GM, Kerr CR, et al. “Nodoventricular” accessory pathway: evidence for a distinct accessory atrioventricular pathway with atrioventricular node-like properties. J Am Coll Cardiol 1988;11:1035–40. DOI: 10.1016/ S0735-1097(98)90063-8; PMID: 3128586 Tchou P, Lehmann MH, Jazayeri M, Akhtar M. Atriofascicular connection or a nodoventricular Mahaim fiber?

Electrophysiologic elucidation of the pathway and associated reentrant circuit. Circulation 1988;77:837–48. DOI: 10.1161/01.

CIR.77.4.837; PMID: 3127077 Haïssaguerre M, Cauchemez B, Marcus F, et al. Characteristics of the ventricular insertion sites of accessory pathways with anterograde decremental conduction properties. Circulation 1995; 91:1077–85. DOI: 10.1161/01.CIR.91.4.1077; PMID: 7850944 Gandhavadi M, Sternick EB, Jackman WM, et al.

Characterization of the distal insertion of atriofascicular accessory pathways and mechanisms of qrs patterns in atriofascicular antidromic tachycardia. Heart Rhythm 2013;10:1385–92. DOI: 10.1016/j.hrthm.2013.07.009; PMID: 23851064 Sternick EB, Lokhandwala Y, Bohora S, et al. Is the 12-lead

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Left panel. Resetting of tachycardia by an atrial extrastimulus. Please note advancement of preexcited ventricular, retrograde His, and atrial electrograms by 22 msec without affecting the retrograde activation sequence. Right panel. Recording of a distal Mahaim potential (arrow) and earliest ventricular activation underneath the tricuspid annulus during atrial pacing and maximum pre-excitation. Reproduced from Giazitzoglou et al, 2008,24 with kind permission.

Clinical Perspective • Mahaim pathways are decrementally conducting connections between the right atrium or the AV node and the right ventricle in or close to the right bundle branch.

• The baseline QRS is normal or displays different degrees of manifest pre-excitation with left bundle branch block morphology.

• Programmed atrial pacing leads to obvious manifest preexcitation following an increase in A-V interval along with shortening of H-V interval at shorter pacing cycle lengths, and right bundle electrogram preceding His bundle activation during antegrade pre-excitation and reentrant tachycardia.

• Catheter ablation is accomplished by identifying the proximal and distal insertions and, ideally, the recording of a proximal pathway potential at the tricuspid annulus or a distal one on the right ventricular free wall.

electrocardiogram during antidromic circus movement tachycardia helpful in predicting the ablation site in atriofascicular pathways? Europace 2014;16:1610–18.

DOI: 10.1093/europace/euu059; PMID: 24681762 8. Katritsis DG, Boriani G, Cosio FG, et al. European Heart Rhythm Association (EHRA) Consensus Document on the Management of Supraventricular Arrhythmias, endorsed

by Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardiaca y Electrofisiologia (SOLAECE).

Eur Heart J 2016; ehw455. DOI: 10.1093/eurheartj/ehw455; PMID: 27856499 9. Sternick EB, Timmermans C, Sosa E, et al. The electrocardiogram during sinus rhythm and tachycardia in patients with anterograde conduction over Mahaim fibers.

The importance of an ‘rS’ pattern in lead III. J Am Coll Cardiol 2004;44:1626–35. DOI: 10.1016/j.jacc.2004.07.035; PMID: 15489095 10. Liao Z, Ma J, Hu J, et al. New observations of electrocardiogram during sinus rhythm on the atriofascicular and decremental atrioventricular pathways. Terminal quantronic resonance system complex slurring or notching.

Circ Arrhythmia Electrophysiol 2011;4:897–901. DOI: 10.1161/ CIRCEP.111.967224; PMID: 21985794 11. Wellens HJJ. Electrical Stimulation of the Heart in the Study and Treatment of Tachycardias. Baltimore, US: University Park Press, 1971; 97–109.

12. Klein LS, Hackett FK, Zipes DP, Miles WM. Radiofrequency catheter ablation of Mahaim fibers at the tricuspid annulus.

Circulation 1993;87:738–47. DOI: 10.1161/01.CIR.87.3.738; PMID: 8443894

13. M cClelland JH, Wang X, Beckman KJ, et al. Radiofrequency catheter ablation of right atriofascicular (Mahaim) accessory pathways guided by accessory pathway activation potentials.

Circulation 1994;89:2655–66. DOI: 10.1161/01.CIR.89.6.2655; PMID: 8205678 14. Grogin HR, Lee RJ, Kwasman M, et al. Radiofrequency catheter ablation of atriofascicular and nodoventricular Mahaim tracts.

Circulation 1994;90:272–81. DOI: 10.1161/01.CIR.90.1.272; PMID: 8026009 15. Heald SC, Davies DW, Ward DE, et al. Radiofrequency catheter ablation of Mahaim tachycardia by targeting Mahaim potentials at the tricuspid annulus. Br Heart J 1995;73:250–7.

DOI: 10.1136/hrt.73.3.250; PMID: 7727185; PMCID: PMC483807 16. Kottkamp H, Hindricks G, Shenasa H, et al. Variants of preexcitation–specialized atriofascicular pathways, nodofascicular pathways, and fasciculoventricular pathways: Electrophysiologic findings and target sites for radiofrequency catheter ablation. J Cardiovasc Electrophysiol 1996;7:916–30.

DOI: 10.1111/j.1540-8167.1996.tb00466.x; PMID: 8894934 17. Cappato R, Schluter M, Weiss C, et al. Catheter-induced mechanical conduction block of right-sided accessory fibers with Mahaim-type preexcitation to guide radiofrequency ablation. Circulation 1994;90:282–90. DOI: 10.1161/01.

CIR.90.1.282; PMID: 8026010 18. Sternick EB, Fagundes ML, Cruz F, et al. Short atrioventricular Mahaim fibers: observations on their clinical, electrocardiographic, and electrophysiologic profile.

J Cardiovasc Electrophysiol 2005;16:127–34. DOI: 10.1046/j.

1540-8167.2004.40508.x; PMID: 15720449 19. Tan HL, van der Wal AC, Campian ME, et al. Nodoventricular accessory pathways in prkag2-dependent familial

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Diagnostic Electrophysiology & Ablation preexcitation syndrome reveal a disorder in cardiac development. Circ Arrhythm Electrophysiol 2008;1:276–81.

DOI: 10.1161/CIRCEP.108.782862; PMID: 19808419 20. Pavlovic´ N, Kühne M, Sticherling C. Slow automaticity of a Mahaim fibre after radiofrequency ablation. Europace 2014;16:1705. DOI: 10.1093/europace/euu286; PMID: 25349224 21. Ellenbogen KA, Rogers R, Old W. Pharmacological characterization of conduction over a Mahaim fiber:

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Evidence for adenosine sensitive conduction. Pacing Clin Electrophysiol 1989;12:1396–404. DOI: 10.1111/j.15408159.1989.tb05054.x; PMID: 2476764 22. Hluchy J, Schlegelmilch P, Schickel S, et al. Radiofrequency ablation of a concealed nodoventricular Mahaim fiber guided by a discrete potential. J Cardiovasc Electrophysiol 1999;10:603–10. DOI: 10.1111/j.1540-8167.1999.tb00718.x; PMID: 10355703 23. Josephson ME. Electrophysiology at a crossroads. Heart

Rhythm 2007;4:658–61. DOI: 10.1016/j.hrthm.2006.12.045; PMID: 17467638 24. G iazitzoglou E, Katritsis DG. Wide-QRS tachycardia inducible by both atrial and ventricular pacing. Hellenic J Cardiol 2008;49:446–50. PMID: 19110934 25. Haissaguerre M, Warin JF, Le Metayer P, et al. Catheter ablation of Mahaim fibers with preservation of atrioventricular nodal conduction. Circulation 1990;82:418–27.

DOI: 10.1161/01.CIR.82.2.418; PMID: 2115408

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