Atrial fibrillation – where do we stand today?

REVIEW

Atrial ®brillation ± where do we stand today?

S . B . O L S S O NDepartment of Cardiology, University Hospital, Lund, Sweden

Abstract. Olsson SB (University Hospital, Lund,

Sweden). Atrial ®brillation ± where do we standtoday? J Intern Med 2001; 250: 19±28.

2 The basic underlying mechanisms behind atrial

®brillation (AF), the most abundant therapydemanding cardiac dysrhythmia, have until recently

being largely unknown. Once established, AF is not

only self-perpetuating but also self-destructive,prompting rapid treatment against possible initiating

mechanisms. Recent observations reveal that the

ectopic beats, initiating AF, often originate in the

walls of the pulmonary veins and that the deterior-ation of the ectopic impulse to AF may be linked to an

impaired inferoposterior interatrial conduction. The

underlying mechanisms behind these functionaldefects are still obscure. The observations has how-

ever, permitted evaluation of new types of treatment,

directly interfering with the newly veri®ed ®ndings.

Keywords: ablation, atrial ®brillation, atrium, heart,

pacing.

Introduction

Understanding the mechanisms behind a disease is aprerequisite for designing the best principles of

treatment. In dysrhythmology, this has been dras-

tically evidenced during the last decades for patientssuffering from monomorphic re-entrant or focal

tachydysrhythmias, several of them which can be

eradicated using catheter ablation, a method which,because of its safety and low morbidity, has now

become widely accepted.

Although the last decade has seen a substantialexpansion in our knowledge, we are still far from a

complete understanding of the mechanisms behindatrial ®brillation (AF), the most common supraven-

tricular tachydysrhythmia necessitating treatment.

The pieces of the AF puzzle are, however, successivelyfalling in place, allowing the exploration and clinical

application of new principles of treatment and the

discontinuation of earlier, inadequate techniques.The present review aims at giving a personal and

comprehensive interpretation of some recent, prom-

ising new ®ndings concerning the AF mechanism,

whose clinical applications have already been tested

or will shortly be tested. This said, the reader is

reminded that knowledge in this area is rapidlyexpanding and the `best before date' of the opinions

given may already be close in time.

What can we learn from populationstudies?

Several population studies have analysed possible

underlying disorders in patients with AF. Although

statistical signi®cance is not always reached, ischae-mic heart disease (IHD) is often found to be more

common amongst patients with AF than in controlpopulations [1]. The true nature of the relation is,

however, obscured by the inherent haemodynamic

differences between AF and normal sinus rhythm(SR). It is thus quite possible that the increased

ventricular rates observed in AF patients induce

ischaemic symptoms in patients with otherwise silentischaemia. Furthermore, as a result of different

mortalities and different diagnostic precisions, even

a direct comparison between the prevalence of AF,

Journal of Internal Medicine 2001; 250: 19±28

ã 2001 Blackwell Science Ltd 19

IHD and their combinations allows only a limited

interpretation of possible associations amongst these

®ndings. Ischaemic heart disease is a common ®ndingalso in control populations and it may in fact be

possible that the association between AF and IHD is

in fact largely coincidental. The association betweenhypertension and AF can be regarded in a similar

way. In addition, in most cases direct mechanistic

relations between IHD or hypertension and AF are farfrom obvious. Therefore, patients with ìdiopathic' or

`lone' AF and those who have IHD or hypertension

probably coincidental to AF, constitute the vastmajority of all cases with AF. Consequently, we are

not today aware of the true mechanism behind AF in

most patients suffering from this most common of alltherapy-demanding cardiac dysrhythmias!

One dysrhythmia ± several clinical patterns

Two distinct clinical patterns of AF are well recog-

nized. One group of individuals may repeatedlydevelop AF, but almost always relapse spontaneously

back to SR. They contrast markedly with the othergroup, in which the dysrhythmia relapses in spite of

repeated efforts to re-establish SR and never seems to

transform back to SR without medical assistance.Originating in these old clinical observations, recent

studies have strongly underlined the importance of

distinguishing between mechanisms which initiatedysrhythmia and those perpetuating it. Also, the old

classi®cation of chronic contra paroxysmal AF is

today being questioned. The most appealing classi-®cation of AF would be the one based on the true

underlying mechanism, the knowledge of which is

still not available. Instead, a clinical classi®cation,distinguishing AF which may spontaneously revert

to a reliable SR from the ones which either need

medical help to do so, or it is believed will never do so,is becoming increasingly more accepted [2].

Initiation of AF ± role of ectopic foci

Although it has long been recognized, that most

episodes of AF follow premature atrial beats, it isonly in the last few years that this knowledge has

had an impact on our methods of treating the

dysrhythmia [3]. A focal source of AF localized atthe entrance of the pulmonary veins into the left

atrium was thus identi®ed in selected patients, in

whom the dysrhythmia could be cured by catheter

ablation technique. Later, independent groups

reported that the rapidly ®ring `focus' was most

often localized a few mm into the upper pulmonaryveins and slightly more often in the left one [4±6],

the impulse thus being conducted along the

myocardial shafts, extending from the left atrialmyocardium [7] (Fig. 1). In these studies, several

patients had dysrhythmia of multiple origins, some

of which were situated in the atrial wall and thusoutside the pulmonary veins (Fig. 2). Provided that

experienced persons carry out the procedures when

elective ablation of these foci is attempted, roughlythree out of four patients will be free from dysrhyth-

mia during a limited follow-up time. A speci®c side-

effect of this treatment was, however, quicklyreported, namely ablation-related localized obstruc-

tion of the pulmonary vein. This undesirable effect

has prompted alternative ablation techniquesattempting to induce a conduction block between

the left atrium and the pulmonary veins [8].

Although the electrophysiologically veri®ed local-ization of a focal origin of AF may suggest that these

patients have extranodal pacemaker cells localized inthe pulmonary venous walls, microscopic examina-

tion of this tissue in humans has failed its presence.

Histological, electrophysiological and immunohisto-

Fig. 1 The pulmonary venous±left atrial junction area depicted

from behind. Note that myocardial sleeves extend into the

pulmonary veins. Reproduced with permission [7].

S . B . O L S S O N20

ã 2001 Blackwell Science Ltd Journal of Internal Medicine 250: 19±28

logical methods applied in rats, guinea-pigs andhuman embryonic specimens do, however, suggest

that cells with pacemaker characteristics may in fact

exist at the junction between the pulmonary veins

and the true atrium [9±11]. In contrast, the obser-vations of conduction block and localized differences

in refractoriness within the atrial muscle sleeve,

veri®ed ®ndings associated with the `focal origin' of

(A)

(B)

Fig. 2 Localization of ectopic origin

of atrial ®brillation in two studies

(A and B). Note the obvious agree-

ment with the spatial distributionof pressure sensitive vagal recep-

tors, seen in the lower part of the

®gure (C). For further informationsee text. Reproduced with permis-

sion [4, 6, 12].

A T R I A L F I B R I L L A T I O N1 21


AF, allow speculations on other mechanisms than a

true monocellular origin of the dysrhythmia [6].

Interestingly, the spatial distribution of ÀF foci'coincides markedly with the distribution of pressure-

sensitive receptors, mediating their response via

vagal nerve ®bres [12] (Fig. 2). Any possible relationbetween the function of these receptors and the

ectopic origin of AF remains, however, to be clari®ed.

The initial substrate ± role of theinteratrial conduction

Although AF is initiated by atrial ectopic beats and

paroxysms of the arrhythmia may be eliminated by

abolishing these beats, it should be remembered thatmost such beats do not initiate AF. Therefore, the

development of the dysrhythmia may also demand

an initial substrate, where the conduction of theimpulse ®nds the prerequisites needed to allow

deterioration into AF. Circumstances promoting

such signal deterioration include slow conduction,

dissociation of the wavefront and increased disper-

sion of refractoriness, especially when all these occurwithin a small area.

A common ®nding in patients with paroxysmal AF

is a prolongation of the P-wave, indicating either amarked enlargement of the atria, or global or localized

slowing of conduction along the activation of the

atria. Interestingly, a spatial vector analysis of globalatrial excitation by Platonov et al. suggests a speci®c,

localized and common pathoelectrophysiological

®nding in patients with paroxysmal AF even withoutan obvious P-wave in their study prolongation [13].

The spatial envelope of the signal-averaged P-wave in

their study was thus compatible with impaired right-to-left inferoposterior interatrial conduction, i.e. in a

region where muscle bundles connecting the two

atria were elegantly described by Bourgery almost200 years ago [14] (Fig. 3). Further invasive studies

by Platonov et al. have in fact localized the interatrial

(a) (b)

Fig. 3 Macroscopic interatrial myocardial connections of the human atrium identi®ed in a lithograph from the early nineteenth century.

The left ®gure, looking at the heart from its front, depicts clearly the muscle ®bres connecting the medial part of the right atrial appendix

and the anterior part of the left atrial wall. Although later studies have failed to verify its existence in all hearts, this muscle bundle, named

the Bachmann bundle after being rediscovered almost 100 years later, is regarded as a ubiquitous interatrial bridge. The right ®gure, aposterior view of the heart, illustrates the multiple and variable tiny connections between the left atrial myocardium and the right atrial

wall in the close vicinity of the coronary sinus ostium ± the Bourgery±Platonov bundles. Reproduced from a lithograph, based on an

original painting by N.H. Jacob and published by Bourgery et al. [14].

S . B . O L S S O N22


conduction defect to this area [15] and documented

initial ®brillatory activity in its vicinity in sponta-

neous or pacing-induced attacks of AF [16].The relation between deteriorated interatrial con-

duction and atrial dysrhythmia has hitherto been

restricted to the observation of impaired conductionalong the anterior interatrial connection, namely the

Bachmann bundle [17]. As myocardial connections

of potential prodysrhythmic importance are almostalways identi®ed as eponyms, it seems pertinent

hereafter to identify the inferoposterior interatrial

connections as the Bourgery±Platonov bundles.Interatrial conduction is, however, complex, not

only occurring via the Bachman and Bourgery±

Platonov bundles, but perhaps also in followingmuscle ®bres in the wall of the coronary sinus [18]

or even via the interatrial muscular continuity

which can be identi®ed histologically around thefossa ovalis (Fig. 4). There is an important marked

interindividual variability not only of the micro-

scopic ®bres in the wall of the coronary sinus [18],

but also of the Bachmann [19] and Bourgery±Platonov bundles (P.G. Platonov, LB Mitrofanova,

L.V. Chireikin and S.B. Olsson,3 unpublished data).

Whether this variability is of prodysrhythmicimportance remains to be veri®ed.

The importance of impaired interatrial conduction

in paroxysmal AF is further evidenced by the resultsof dual site uni- or biatrial pacing [20±22]. Today, the

choice of pacing sites is not based upon prior

localization of conduction defects or the suppressionof induced dysrhythmia. Irrespective of whether

multisite pacing is performed from two positions in

the right atrium, each of which is in the vicinity of theinferoposterior and anterocranial interatrial connec-

tions, or the right and left atrium, respectively, the

majority of patients report a prophylactic antidys-rhythmic effect of the treatment [22]. Pacing at these

Fig. 4 Schematic illustration of the localization of the right atrial insertions of interatrial myocardial connections. The connecting positions

are indicated by adding symbols in red to an original drawing of an autopsied heart [54]. Microscopic ®bres running in the wall of the

coronary sinus connect with the right atrial wall at its ostium. More microscopic interatrial connections are found along the raphae of theinteratrial septum, surrounding the fossa ovalis in the present view (see also Fig. 3). The macroscopic connections, the Bachmann bundle

and the Bourgery±Platonov bundles are attached to the right atrial myocardium at many places in the anterior and inferoposterior parts of

the septum, respectively (BB and BP). Reproduced with permission [53].



sites will, however, favourably effect the overall

interatrial conduction. The genuine antidysrhythmic

effect of selectively bridging the impaired inferopos-terior interatrial conduction remains to be clari®ed.

The probable role of impaired interatrial conduc-

tion is evidenced in Fig. 5, which illustrates thedevelopment of AF during rapid pacing of the left

atrium, mimicking the effect of a `focal discharge'

from a leftsided pulmonary vein. The onset of®brillation coincides with a pronounced impulse

delay in the inferoposterior conduction (courtesy of

Dr O. Kongstad).

Perpetuation of AF

As evidenced from studies in animals [23, 24] and

induced [25] or spontaneous AF in man [26], it is

now generally accepted that AF is perpetuated by

multiple interfering re-entry phenomena. The pre-

requisites for AF perpetuation depend on the grossanatomy, the arrangement of myocardial ®bres as

well as the electrophysiological characteristics of

individual cells and interactions between adjacentcells. The re-entry of the electrical wavefront may

thus occur around anatomical, electrophysiological

or functional obstacles. Although the excitationpattern gives an impression of randomness,

independent studies with different techniques have

in fact veri®ed that AF indeed implies a predictableactivation of major parts of the epicardial atrial

surface [26±28]. Although these and earlier cited

studies on AF excitation have almost exclusively usedeither epicardial or endocardial recordings, evidence

exists that, in addition to the two-dimensional

Fig. 5 Initiation of atrial ®brillation by incremental pacing in the distal part of the coronary sinus (CS1-2) in a patient suffering from

paroxysmal atrial ®brillation. The left activation of the left atrium is explored by electrodes CS 3±4 to CS 9±10. There are two recording

positions in the right atrium, at a high lateral position (HRA1-2) and across the anterior part of the septum (HBED and HBEP). The atrialactivity noted in the septal leads can be interpreted as either right-sided septal signals or far-®eld left-sided atrial activity. Note that the

increasing prolongation of the time to attain high lateral right atrial activation at ®rst () is not followed by the anticipated atrial activity

after a further shortening of the pacing interval. Instead, there is a deterioration of the conducted impulse in the right atrium (AF) whilstthe left atrium and perhaps also the anterior part of the septum follow the pacing throughout the recording. The exact location of the

transformation to ®brillation cannot be de®ned. Courtesy of Dr Ole Kongstad.

S . B . O L S S O N24


re-entry along the atrial wall, endo-epicardial

re-entrant phenomena can also occur [26, 29].

When the prerequisites for maintaining AF nolonger exist, the dysrhythmia is interrupted and SR

may reappear. Although this is readily accepted

after only short periods as part of a common clinicalform of AF, it has also been observed after AF of very

long duration. Spontaneous relapse to SR have been

observed even after several decades [30]. Thisphenomenon has mainly been observed in patients

with advanced mitral valve disease and may be

linked to advanced ®brosis of the left atrial myocar-dium, thus implying that the substrate for main-

taining AF has vanished. However, some patients

did not have valve disease, but suffered from diabetesof long duration. It may be speculated that, in these

cases, spontaneous interruption of AF is associated

with diabetic neuropathy and abolishment of thenormal vagal nervous discharge ± another subtle

indicator of the importance of vagal nervous activity

in AF.

The wavelength concept

Great interest has been paid to a number of factors,

possibly in¯uencing the self-sustaining properties ofAF. Understanding this mechanism has bene®ted

from the so-called `wavelength' concept. Thus,

although AF is perpetuated by multiple, concomitantand mostly incomplete re-entrant excitation waves, a

grossly simpli®ed approach to describe the inherent

basic components of this dysrhythmia can be applied.Assuming an electrophysiologically homogenous

tissue, and knowing the conduction velocity (CV)

and refractory period (RP) allows an estimate of thetheoretical distance of the shortest possible complete

re-entrant circuit, the wavelength [31]:

Wavelength � CV� RP

Although this model is a marked simpli®cation of the

actual circumstances, experimental studies do indeedverify that AF in a canine model demands a

constellation between the inherent factors of this

concept, compatible with the existence of a criticalmaximal length of the re-entry loop being required in

order to become sustained [31]. The principle shows

in an easily understandable manner that re-entrydemands a certain amount of myocardium to be

sustained. The role of atrial size, CV and RP in

different settings of AF merits further exploration.

The role of repolarization

From the wavelength concept it is easy to understandthat a decreased refractory state of the tissue, caused

by an acceleration of repolarization, is a prodysrhyth-

mic phenomenon in AF. Provided other circum-stances are unchanged, the theoretical wavelength

will thus diminish, allowing a larger number of

concomitant re-entry phenomena. This mechanism isthe probable explanation of the propensity to AF seen

in patients with hyperthyroid disease. Thus,

increased thyroid activity shortens the repolarizationof atrial myocardial cells during physiological heart

rates in animals [32] and human atrial repolarization

is affected by decreased levels of thyroid hormones[33] in a way similar to that seen in animals [32].

Since the very ®rst recordings of monophasic action

potentials from the intact human heart, accelerationof atrial repolarization has been observed in patients

with AF [34]. The true nature of this patho-electro-

physiological ®nding remained, however, obscureuntil a few years ago, when it was convincingly linked

to a rate-dependent inability to handle properly the

intracellular ¯ux of calcium [35]. Further studiesprovide evidence that this so called èlectrical remod-

elling' develops over days to weeks and is followed by

structural myocardial changes [36]. The true role ofthese changes and their potential reversibility is,

however, still largely unexplored [37].

Using noninvasive techniques, the dominatingatrial cycle length (DACL) during AF can be estimated

[38, 39], and used as an index of the refractory stateof the ®brillating atrial myocardium [40±42]. The

DACL may thus be used as a crude measure of the

actual level of remodelling, a long duration meaningthat remodelling is minimal and a short duration

indicating pronounced remodelling. Interestingly, AF

of recent onset and with suf®cient long ®brillatorycycle length is converted to SR more often by a class 3

antidysrhythmic drug than those with shorter ®bril-

latory cycles [43]. Furthermore, in patients withlong-lasting AF and a very short DACL, the sponta-

neous diurnal variability of DACL [44] is minimal as

is the DACL-prolonging effect of a Ca-blocker [45],suggesting that the remodelling developed in these

patients may well be irreversible. It would therefore

be tempting to believe that assessment of the degree ofremodelling by measuring the DACL could

distinguish between patients who would or would

not successfully maintain a stable SR following



cardioversion. DACL fails, however, to discriminate

these patient groups more convincingly than meas-

urements of left atrial size (C.J. Meurling, A. Roijer,J.E.P. Waktare, C.J. Lindholm, M.P. Ingemansson,

J. Carlson, M. Stridh, L. SoÈrnmo and S.B. Olsson,

unpublished data). Interestingly, however, combi-ning information from DACL and atrial size improves

the accuracy of prognosis regarding the long-term

maintenance of sinus rhythm, although it stillremains far from useful for individual patients (C.J.

Meurling et al., unpublished data). A natural conclu-

sion from these observations is that factors other thanatrial size and the degree of myocardial remodelling

are more important for long-term success in main-

taining SR once remodelling is fully developed.Several electrophysiological and structural factors

of probable importance for generating and maintain-

ing AF remain to be better clari®ed. The degree of®brosis of the atrium [47], dispersion of refractoriness

[48], slowing and variability of conduction velocity

[49] and the role of the so called `pulmonary venousectopism' during permanent AF are such examples.

It is possible that the prodysrhythmic role of vagalnervous discharge is linked to its effect on atrial myo-

cardial repolarization. The acethyl-choline released

from vagal nerve endings markedly accelerates

atrial myocardial repolarization [50]. Furthermore,as the atrial vagal innervation is probably inhom-

ogenous in humans and dogs [51], it is probable

that vagal discharge enhances the spatial dispersionof atrial repolarization. Whether this is the mech-

anism in patients who have clinically evident AF

occurrence linked to periods of increased vagalactivity [52] remains to be veri®ed. This and earlier

cited observations on a possible link between AF and

vagal dependence [12, 30, Fig. 2] do, however,motivate detailed exploration of this hitherto largely-

unexplored relation.

The role of atrial size

An unfavourable relation between the theoretically-calculated wavelength and the actual atrial size may,

of course, also be caused by a genuine enlargement of

the atria without any primary change of atrialmyocardial refractoriness or impulse-conduction.

Although enlargement of the atria is commonlyobserved in patients with AF, it may be blamed on an

Fig. 6 Three-dimensional drawing of atrial myocardium and the interatrial connections. For further information see text.

S . B . O L S S O N26


underlying disorder or as being caused by the

dysrhythmia. Recently, evidence of the importance

of atrial size in the development of AF has beenreported from a large-sized prospective population

study [53]. Thus, healthy individuals in SR show an

increased risk of developing AF, related to the leftatrial diameter. In comparison with those who had

left atrial diameters below 3 cm, the relative risk of

developing AF was 1.5 for those whose left atriameasured 3±4 cm and 2.6 in those whose left atrial

sizes were 4±5 cm. Left atrial enlargement must thus

be regarded as a strong and presumably primary riskfactor for developing AF.

Atrial fabrillation ± a multidimensionalproblem

Based upon current knowledge of the differentfactors involved in the initiation and continuance

of AF, it must be considered uncommon that only

one factor is responsible for the dysrhythmia in anindividual patient. Global atrial electrophysiology

and morphology10 (Fig. 6), cellular electrophysiologyand cell-to-cell interaction as well as subcellular

changes, not to mention modulation by variability of

the autonomous nervous discharge, are thus obvi-ous factors of prodysrhythmic importance in differ-

ent phases of AF. That these factors must all be

considered together makes interpretation of mecha-nisms behind AF a true multidimensional problem.

The interaction between individually veri®ed

pathoelectrophysiological and structural pro®brilla-tory factors is still poorly explored. Furthermore, the

importance of various factors differs at different

stages of dysrhythmia, underlining the need forfurther knowledge before a genuine and mechanis-

tically correct treatment may be designed. Finally,

whilst knowledge of the few pathophysiologicalmechanisms discussed in the present paper may

appear adequate in considering the possible

treatment of AF, these constitute only a few of thedifferent clues in today's exploration of the back-

ground of this common dysrhythmia [54].

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Correspondence: Prof. S. Bertil Olsson, Department of Cardiology,University Hospital, SE-221 85 Lund, Sweden (fax: +46 46±15 78

57).

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