A clinical approach to arrhythmias revisited in 2018
Neth Heart J
A clinical approach to arrhythmias revisited in 2018
L. Jordaens 0
0 Department of Cardiology, University Hospital , Ghent , Belgium
Understanding arrhythmias and their treatment is not always easy. The current straightforward approach with catheter ablation and device therapy is an amazing achievement, but does not make management of underlying or other cardiac disease and pharmacological therapy unnecessary. The goal of this paper is to describe how much of the knowledge of the 1980s and early 1990s can and should still be applied in the modern treatment of patients with arrhythmias. After an introduction, this review will focus on paroxysmal atrial fibrillation and a prototype of 'idiopathic' ventricular arrhythmias, two diseases with a striking similarity, and will discuss the arrhythmogenesis. The ECG continues to play an important role in diagnostics. Both diseases are associated with a structurally normal heart; the autonomic nervous system plays an important role in triggering arrhythmias at both the atrial and ventricular level.
Arrhythmia mechanisms; Autonomic nervous system; Atrial fibrillation; Outflow tract arrhythmias; Ventricular extrasystoles
Recently, some concerns were expressed on the recent
developments in arrhythmia management in general, and on
the way clinical electrophysiology is evolving in particular
]. This is a good reason to reemphasise some ideas on the
clinical approach, and how this could help us in
improving our understanding of atrial fibrillation (AF) and some
important ventricular arrhythmias. This paper will review
whether the very basic principles of the approach to
arrhythmias (Fig. 1) as developed by Philippe Coumel can
still be applied in the area of two frequently occurring
arrhythmias, at the atrial and ventricular level, namely
paroxysmal AF and ventricular extrasystoles of the outflow tract
]. These two prototypes were selected as they share
some features, as similar changes in the substrate make the
arrhythmia more cumbersome to treat.
Conventional approach to arrhythmogenesis: normal impulses and arrhythmias
Understanding the genesis of arrhythmias
(arrhythmogenesis) was not considered to be too difficult some 40 years
ago, in the era before the advent of clinical
electrophysiology with its ablation and implantable defibrillators. We
only had the electrocardiogram at our disposal. Normal
impulse generation in the sinus node and conduction through
the specialised conduction tissue in the heart leads to
electromechanical coupling, and the heart pumps the blood
through the blood vessels. A calcium-mediated action
potential governs normal impulse formation in the sinus node
and in the atrioventricular (AV) node, while all other
myocardial tissue is dependent on a sodium-channel mediated
action potential. When this nice mechanism is disturbed,
arrhythmias are encountered as the consequence of abnormal
impulse generation or conduction, mainly due to re-entry
]. Automaticity, triggered activity, or bidirectional and
unidirectional block were not considered too complicated
to be part of the general medical curriculum. The work of
Wellens and Durrer with programmed stimulation allowed
us to study some of these mechanisms, especially re-entry,
in depth .
Fig. 1 The original concept
of Coumel on the left (a), and
its generally well-known
final form (b), as the triangle of
Coumel, explaining how the
interaction of substrate,
triggers and the autonomic nervous
system are important in
arrhythmogenesis. (Modified after [
Conventional therapy (from the 1960s to early 1990s)
The widespread and well-taught pharmacological
antiarrhythmic treatment at that time was only seldom subjected
to randomised clinical trials [
]. You did not have to be
a cardiologist to understand antiarrhythmic drug
classification. However, for the more ambitious amongst us, a new
scientific approach, the Sicilian Gambit, (like a move in
a chess game), was proposed, the precursor of guidelines
on this matter [
]. One should be able to identify the weak
link of the rhythm disturbance, select the appropriate drug,
and beat the arrhythmia. If this is impossible, some daring
(and exceptional) antiarrhythmic surgery could be done in
a few centres of excellence, both for atrial and ventricular
Arrival of clinical electrophysiology (the late 1980s and the 1990s)
It was more or less at this moment that new options were
added to our therapeutic arsenal. Class Ic drugs proved to be
dangerous, at least for patients with ischaemic heart disease
], but fortunately Michel Mirowski introduced the
implantable cardioverter-defibrillator [
warned me at that time that serious research on
arrhythmias would be endangered, as there was no longer a need
to understand, something they had observed with research
on renal diseases after the arrival of dialysis. Luckily, this
was not the case, as the almost simultaneous introduction of
catheter ablation was a real boost for research on
arrhythmias, and defibrillators proved to be nice ECG recorders,
disclosing the arrhythmias involved in the genesis of
sudden death [
]. A new subspeciality was born, clinical
electrophysiology, and our generation was very glad to be
part of it. In the long run, this magnificent technological
revolution created a new generation of highly qualified
cardiologists, the electrophysiologists, completely focussed on
catheter ablation and device therapy (sometimes only on
one of these aspects), but unfortunately, sometimes with
limited knowledge on antiarrhythmic drugs, which now
seemed less often necessary.
Scientific advances of the last two decades
The insights into cardiac anatomy and functioning
improved considerably. On the one hand, a growing basic
knowledge, based on experimental animal studies, the
development of molecular cardiology, and the fast evolution in
genetics, improved our understanding of cardiomyopathies
and diseases associated with arrhythmias [
the other hand, the developments in engineering,
electroanatomic mapping, and advances in imaging techniques
as echocardiography and magnetic resonance proved to
be extremely helpful in the diagnostics and therapy of
bradyarrhythmias and tachyarrhythmias, and cardiology in
Antiarrhythmic treatment finally entered or re-entered
the phase of randomised trials, often with disappointing
results, so that over the last three decades only a few of
the active antiarrhythmic drugs that were developed and
investigated (e. g. azimilide, dronedarone and vernakalant)
were actually put on the market, and then not always in
all countries. This really did not help to improve the care
of patients when catheter ablation or device therapy were
unsuccessful, so, for instance with an incomplete effect of
AF ablation or inappropriate shocks from implanted
defibrillators. The real progress was not in the niche corner of
a new antiarrhythmic, but rather with the advanced
understanding of when and how to prescribe or avoid flecainide
or amiodarone, with or without a beta-blocker, and how to
treat background pathology and heart failure [
Electrocardiography versus imaging?
ECG interpretation remains important. This is not only the
case for the 12-lead ECG, but also for Holter analysis,
which lost much of its glory at the ventricular level after the
CAST (Cardiac Arrhythmia Suppression Trial), as a matter
of fact, without good reason [
]. Its use for AF detection
is in my opinion not standardised, even if the guidelines
and working parties for ablation have tried to make it so
]. This makes evaluation and understanding of AF
interventions very difficult. A Holter is also a scientific tool
providing information on the autonomic nervous system
(ANS) . Apart from the arrhythmia, mechanisms for
arrhythmogenesis are hidden in the recording, and should be
Imaging has evolved, with advanced body surface
mapping, and processing of echocardiography and magnetic
resonance. However, the real mechanism behind the
arrhythmia is still not clarified. Moreover, the noninvasive
technologies are not really assisting the general cardiologist,
who has to make the first therapeutic decisions and also
decide whether to transfer the patient to the
electrophysiologist. His computer screen will finally display scars, barriers,
rotors and wave fronts.
Atrial arrhythmias: paroxysmal atrial fibrillation
AF is present in more than 20% of the population at a
certain moment [
]. Other atrial arrhythmias all seem
somehow related to AF: when not treated circus movement
tachycardia, as in the Wolff-Parkinson–White syndrome in the
young, often leads to AF at a higher age and there is an
association between AVNRT, atrial flutter and AF [
extrasystoles predispose to AF. The breakthrough in
understanding this disease is rather recent, with the discovery
of spontaneous activity in the pulmonary veins [
wonders how much of the hitherto described physiology
remains valid, and how much is really applicable in the
clinical situation. The focus will be on the patient with
paroxysmal AF. Can the pathogenesis of AF be described
in terms of triggers, autonomic activity and substrate, or is
the presence of triggers enough to have AF?
The trigger Pulmonary veins are structures coated by
muscular sleeves, which are remnants of the primitive heart,
drawn into the lung tissue when the lungs are shaped
during our early life. It is therefore not surprising that these
muscular sleeves show spontaneous pacemaker activity, or
that they form an electrical continuum with the adjacent
atrium. Pulmonary vein isolation (PVI) has indeed become
the cornerstone of effective interventional AF therapy [
The presence of multiple supraventricular extrasystoles on
a Holter might be a good marker that PVI is the road to take.
However, the pulmonary veins are not the only structures
acting as a trigger—the superior vena cava, the coronary
sinus, and Marshall’s ligament are all structures which can
act as triggers, be it to a much lesser degree. The same can
be said of the already-mentioned supraventricular
The substrate Larger atria will more easily sustain AF than
smaller ones, allowing multiple wavelets to re-enter [
The importance of this substrate is seen in the different
outcome after PVI in paroxysmal versus persistent AF
patients. In the latter form, the atria are larger, atrioventricular
valves show more regurgitation, and more associated
cardiovascular disease is seen. Even when these two forms
might be the expression of a continuum, it is clear that
all conditions stretching the atria (hypertension, valvular
diseases, hyperthyroidism, excessive sports) will create
inflammation, hypertrophy and fibrosis, probably preparing
a setting to sustain re-entry when the triggers are active
]. This explains why all electrocardiographic and
imaging indices showing larger atria or atrial overload
(Pwave duration, longer signal averaged P waves, P-wave
dispersion, left atrial volume) will be helpful in predicting the
outcome of cardioversion, drug therapy and PVI . The
same holds for the extent of atrial fibrosis as shown with
magnetic resonance imaging, the holy grail of AF
]. Therefore, it is clear that careful assessment of
the substrate before PVI is useful: a normal sized atrium is
highly predictive for a successful procedure [
The ANS The physiology of the autonomic innervation of
the heart is intriguing. Bradycardia and tachycardia promote
their own automaticity, not necessarily related to the ANS
. The sinus node, the atria and the AV node are
controlled by the vagal and adrenergic nervous system. Apart
from its effects on heart rate, the ANS contributes to
inhomogeneous activation of the atria, and has effects on
conduction and repolarisation creating or maintaining the
arrhythmia. Coumel made a very clear and didactic
distinction between vagally induced and adrenergic mediated
forms of AF [
]; the first occurred in the setting of a
normal heart, at rest, while the second typically occurred during
exercise, and suggested the presence of a more
pathological and damaged substrate. The first type of AF was not to
be treated with beta-blockers, while this was considered to
be the perfect therapy for the second type. From a clinical
point of view, only a minority of AF patients seem to
correspond to these prototypes, and many are mixed [
]. Is the
role of the ANS then only marginal? In specific situations,
the influence of the ANS can be more pronounced, as in
postoperative situations, where vagal withdrawal, with
sudden adrenergic changes, can provoke AF [
]. Epicardial fat
pad ablation was found to be successful to prevent AF after
coronary bypass [
]. According to some, PVI should be
completed by additional ablation of the autonomic ganglia,
while a recent surgical trial was negative [
]. It cannot
be excluded that the success of large circumferential
ablation (as opposed to segmental PVI) is due to modulation
of the antra, where many of these structures are situated
]. Furthermore, beta-blocking agents are the only drugs
withstanding the scrutiny of the Cochrane review of
antiarrhythmic drugs, with a significant reduction of AF
recurrence, and a low incidence of side effects [
I feel that the influence of the ANS should still be assessed
in all patients, even when this is limited to a simple Holter
Ventricular arrhythmias: the outflow tract
Sudden cardiac death is very often the end result of an
interaction of the three factors in the triangle of Coumel
]. Risk stratification, which was extremely popular in
the late 1990s, was largely neglected after the observation
that a low left ventricular ejection fraction (LVEF) was the
more important parameter, but has now been taken up again
as it becomes clear that the old flowcharts are not so good
in modern times as expected, e. g. for non-ischaemic
]. The role of the ANS becomes
increasingly clear when the impact of beta-blockers is
considered on event-free survival, for example in heart
failure . Neuromodulation (left-sided stellectomy, thoracic
epidural anaesthesia) is being studied, especially in patients
at high risk [
This review will now focus on a particular condition in
the normal heart, first described by Gallavardin, and also
well studied by Coumel, namely extrasystoles originating
in the outflow tract. When occurring as tachycardia, it was
called ‘tachycardie en salves’, and more recently ‘repetitive
monomorphic tachycardia’ [
Fig. 2 Holter recording of
a professional cyclist with
symptomatic atrial fibrillation and
dizziness. a Bradycardia at rest,
with a short episode of slow
conduction of atrial flutter or
fibrillation. b During exercise
atrial flutter, with suddenly 1:1
conduction. c Continuation of b,
with slowing of the
atrioventricular conduction at the end
This variant of ventricular extrasystoles or tachycardia is
almost ubiquitous, with a typical left bundle branch
morphology and inferior axis [
]. The reason for the
omnipresence of this kind of extrasystole is the fact that the outflow
tract of the primitive embryonic heart (the venous sinus
horn) serves as a pacemaker, and retains the capacity to
generate electrical activity in later life, in a different way
than the other myocardial cells [
]. The sinus node should
take the lead, and suppress its activity. It might be
postulated that in the presence of other factors, these extrasystoles
become important again and might even lead to sustained
tachycardia (Fig. 2), and to tachycardiomyopathy [
The trigger Whether these extrasystoles are due to
abnormal calcium currents or not, or to delayed activity with
afterdepolarisation or enhanced automaticity is important
when we are looking for a medical therapy [
has an important diagnostic role, and calcium antagonists
may be effective in suppressing extrasystoles [
]. It is not
clear in clinical practice whether the latter is due to a
direct activity on the action potential, or whether the result is
due to an effect on the heart rate. There is no reason to
believe (in contrast to what is published in the guidelines) that
outflow tract arrhythmias from the left or right side would
behave in a different way [
]. The ECG plays an
important role in diagnostics, for localisation of the origin, and
the Holter discloses the burden of the arrhythmia, which is
important for decision-making [
The substrate Right ventricular outflow tract arrhythmias
are considered benign (and were also called benign
ventricular tachycardia), indicating that the myocardium is
considered to be healthy [
]. This means that no structural
heart disease should be detected, that the ECG shows no
signs of the Brugada syndrome, that no signs of
arrhythmogenic heart disease are present, and so on. Exercise testing
shows no signs of ischaemia. Valvular disease should be
absent, but the extrasystoles might increase or provoke
insufficiency, creating a difficult to interpret haemodynamic
perturbation during echocardiography. Nevertheless, it is clear
that this kind of extrasystoles might coexist with a
pathological heart. Extrasystoles from the outflow tract may
provoke ventricular fibrillation or tachycardia in coexistent
ischaemic heart disease (even during acute infarction), dilated
cardiomyopathy, Brugada syndrome, congenital heart
disease, and in arrhythmic right ventricular cardiomyopathy
Abnormalities on magnetic resonance and
echocardiography are only seldom detected, and with the present
technology can be considered anecdotal. Nevertheless, it is
hypothesised that many athletes seen with outflow tract
tachycardia have developed fibrosis over time, making re-entry
]. This fibrosis is reflected in a longer QRS
duration, and impacts on repolarisation [
]. It is unlikely
that all the athletes in our study had ARVC, or hypertrophic
cardiomyopathy, as further invasive and noninvasive studies
did not show clues for additional pathology.
The ANS Neurohumoral factors play an important role in
the occurrence of arrhythmias and in the development of
symptoms. Extrasystoles appear typically at a certain heart
rate, and disappear at higher frequencies. A close relation
Fig. 3 Drug study of a marathon
runner with syncope. The 6th
complex shows a ventricular
extrasystole, negative in lead I,
and positive in the inferior leads.
The transition is very early,
indicating a left ventricular
origin. After isuprel infusion,
a fast sustained tachycardia
occurs, initiated by a similar left
ventricular complex, while the
VT suggests a right ventricular
outflow tract origin
was detected between the heart rate and duration of
ventricular runs, and even with the coupling interval of the first
]. Exercise testing often results in more,
rather than in less arrhythmias, which is to be considered
abnormal. Infusion of isoprenaline may provoke the
arrhythmia spontaneously (Fig. 3), or facilitate inducibility, which
could suggest support for triggered activity and re-entry as
a mechanism. More advanced Holter analysis shows that
altered dynamics of the heart rate, as caused by
sympathetic activation, may precondition the heart to ventricular
The ESC guidelines give no real clues for reliable drug
therapy, but there is agreement that medical therapy is
]. Beta-blocking agents also yield
disappointing results. It might be that the endpoint set for successful
therapy is wrong: beta-blockers probably do not erase the
arrhythmia (i. e. the trigger) but they may still be capable of
preventing some complications, and play a role in the
prevention of heart failure [
]. Many patients with outflow
tract arrhythmias also suffer from other arrhythmias, often
heavily influenced by adrenergic tone: AV-nodal re-entry
and AF [
]. The advantages of beta-blockade may
outweigh the disadvantages of the class Ic agents, which are
advocated in the guidelines. They may also be necessary
after catheter ablation.
Fig. 4 Coexistent
ventricular tachycardia (VT) in a
patient with arrhythmogenic right
(ARVC), and ventricular
extrasystoles (VPB) originating
in the right ventricular outflow
It is concluded that for the daily, clinical, but also for the
advanced interventional management of patients a
consideration of the classical three mechanisms of
arrhythmogenesis remains useful. Both electrocardiography and imaging
(Fig. 4) remain important to come to a correct diagnosis
in both the examples discussed here, knowing that
imaging will not reveal many abnormalities at first glance. The
autonomic nervous system plays a role in both conditions,
and its importance is sometimes difficult to quantify.
Further, the parallelism of arrhythmogenesis in atrial and
ventricular arrhythmias as described in this selective review
is striking. Attempts to prevent atrial and ventricular
overloading, and fibrosis (if possible) are of the highest
importance. Beta-blockers remain safer than other antiarrhythmic
drugs and may prevent benign arrhythmias from becoming
Finally, clinical electrophysiology provides us with
important tools to improve this conventional approach. More
refined mapping is necessary, and devices are magnificent
recorders. We will need electrophysiology specialists who
know a lot about the basics and other areas of cardiology
to make progress.
Conflict of interest L. Jordaens declares that he has no competing
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