Supplement to Journal of The Association of Physicians of India ■ Published on 1st of Every Month 1st August, 2016 11

Pathophysiology of Atrial Fibrillation -

Current Concepts
Ashish Nabar1, Irshad Pathan2

The pathophysiology of AF has

Abstract been studied extensively and is a
Atrial fibrillation (AF) is the most common supraventricular tachycardia subject of continuing research so
and its incidence increases with age. The pathophysiology of AF has been that better preventive and curative
therapies can be developed. The
studied extensively and is a subject of continuing research. The primary
onset and sustenance of AF involves
pathologic change seen in AF is progressive fibrosis of the atria and hence
focal atrial ectopic activity and
structural remodeling, is the mainstay in many forms of AF. Dilation of the
reentry mechanisms through the
atria can be due to almost any structural abnormality of the heart which
atrial tissue, a result of various
includes valvular heart disease, hypertension or congestive heart failure.
electrical and structural remodeling
Electrical remodeling promotes AF by acting on fundamental arrhythmia
processes. AF is a progressive
mechanism: focal ectopic activity and reentry. Rapidly firing foci initiating disease which in it itself may
paroxysmal AF arise most commonly from the atrial myocardial sleeves induce further structural changes
that extend into pulmonary veins. The evolution of AF from paroxysmal to and worsening of the underlying
persistent to permanent forms through atrial remodeling can be caused disease (ventricular function), thus
by the arrhythmia itself and/or progression of underlying heart disease. creating a vicious circle. 3
The development of functional reentry substrates contribute to persistent
A patient who presents for the
AF. AF-related reentry is currently thought to occur through two main first time with symptomatic AF is
concepts: (1) the leading- circle concept and (2) spiral wave reentry. The considered as first diagnosed AF.
multiple wavelets hypothesis, particularly in advanced structural and Clinically, recurrent AF is classified
electrical remodelling are present, maintains AF survival, causing the based on presentation and duration
most frequent common final pathway in sustained AF. of the episodes (Table 1).
AF may be asymptomatic and
recorded on incidental ECG, Holter
Introduction study or cardiac implantable

A trial fibrillation (AF) is a

supraventricular tachycardia
characterized electrically by a
chaotic atrial activation and a
resultant mechanically ineffective
atrial contraction. Due to a
variable number of the total (>300
bpm) atrial impulses conducting
through the atrioventricular
node, the ventricular (heart) rate
tends to be fast and irregular.
Epidemiologically, it is the most
common arrhythmia encountered
in clinical practice, affecting about
2% to 3% of the population. The
number of new cases each year Fig. 1: ECG showing Atrial Fibrillation with Fast Ventricular Tachycardia
increases with age, such that it
affects about 8% of the peopleover
the age of 80 years. AF was first Cardiac Electrophysiologist, Arrhythmia Associates, Visiting Cardiologist, Seth GS Medical College and KEM
1

Hospital, Mumbai, Maharashtra; 2Senior Resident, Department of Cardiology, Seth GS Medical College and
documented by ECG in 1909 by KEM Hospital, Mumbai, Maharashtra
Thomas Lewis (Figure 1). 1,2
12 Supplement to Journal of The Association of Physicians of India ■ Published on 1st of Every Month 1st August, 2016
Table 1: Classification of atrial
fibrillation
AF category Defining characteristics
Paroxysmal Continuous AF that stop on
its own and lasts <48 hours
Persistent Continuous AF that last
more than 7 days and
requires cardioversion
Long- Episodic Persistent AF
standing known for >1 year
persistent
Permanent AF episode more than 1
year duration (accepted or
therapy failure)
electronic device episode log
(pacemaker or cardioverter-
defibrillator ), when it is referred
to as silent AF.
In addition to the above AF
categories, the American Heart
A s s o c i a t i o n ( A H A) d e s c r i b e s
additional AF categories based on
underlying related disease. 4
Lone AF: AF occurs in absence
of clinical or echocardiographic
findings of other cardiovascular
disease causing left atrial (LA)
enlargement or related pulmonary
disease.
Nonvalvular AF: AF in absence
of rheumatic mitral valve disease,
a prosthetic heart valve, or mitral
valve repair.
Secondary AF: AF occurs in the
setting of a primary condition
that may be the cause of AF, such
as acute myocardial infarction,
cardiac surgery, pericarditis,
myocarditis, hyperthyroidism,
pulmonary embolism, pneumonia,
or other acute pulmonary disease.
Pathophysiology of AF
Structural remodeling:
Structural remodeling, particularly
fibrosis, is the mainstay in many
forms of AF. The primary pathologic
change seen in AF is progressive
fibrosis of the atria. This fibrosis
is primarily due to atrial dilation.
Dilation of the atria can be due to
almost any structural abnormality
of the heart that can cause a rise
in the pressure within the heart.
This includes valvular heart
disease (such as mitral stenosis,
mitral regurgitation, and tricuspid
regurgitation), hypertension or
congestive heart failure. Also, any
inflammatory state that affects the
heart can cause fibrosis of the atria.
For example, sarcoidosis or an
autoimmune disorder that creates
autoantibodies against myosin
heavy chains can cause atrial
inflammation and subsequent atrial
fibrosis. Recently, mutation of the
lamin AC gene has been found to be
associated with fibrosis of the atria
that can lead to atrial fibrillation.
Dilated atria leads to the
activation of the renin aldosterone
angiotensin system (RAAS) and
subsequent increase in deposition
of matrix metalloproteinases and
disintegrin in the atrial walls.
RAAS further initiates multiple cell
signaling cascades that promote
increased intracellular calcium,
apoptosis, cytokine release and
inflammation, oxidative stress,
and production of growth-related
factors that also stimulate fibrosis,
as well as possible modulation of ion
channel and gap-junction dynamics.
Angiotensin II, angiotensin-
c o n ve r t i n g e n z y m e [ A C E ] , a n d
aldosterone which are components
of RAAS are synthesized locally
in the atrial myocardium and
are increased during AF. 5 This
leads to atrial remodeling and
fibrosis, with loss of atrial muscle
mass. These changes are not
sudden, experimental studies
have demonstrated that patchy
atrial fibrosis may precede the
occurrence of AF andis progressive.
Reactive interstitial fibrosis
separates muscle bundles, whereas
reparative fibrosis replaces dead
cardiomyocytes, interfering with
electric continuity and slowing
conduction. Fibroblasts can couple
electrically to cardiomyocytes and
when increased in number, promote
reentry and/or ectopic activity.
Fibrosis causes paroxysmal AF
progression to permanent forms. 6
Triggers for Atrial Fibrillation:
Electrical remodeling promotes
AF by acting on fundamental
arrhythmia mechanism: focal
ectopic activity and reentry. In
this context two principles gained
attention: factors triggering the
onset and factors perpetuating AF.
Ectopic focal discharges often
initiate AF. Rapidly firing foci
initiating paroxysmal AF arise
most commonly from the atrial
myocardial sleeves that extend
i n t o p u l m o n a r y v e i n s . At r i a l
myocardial fibres are oriented
in disparate directions, and
possess unique anatomical and
electrophysiological features for
their arrhythmogenic nature. The
r e l a t i ve l y d e p o l a r i z e d r e s t i n g
p o t e n t i a l s i n p u l m o n a r y ve i n
myocyte promote sodium channel
inactivation and to the abrupt
changes in fiber orientation and
thus favors reentry. These myocytes
also demonstrate abnormal
automaticity and triggered activity
that could promote rapid focal
firing. Although the pulmonary
veins are the most common sites
for ectopic focal triggers, they can
also arise elsewhere, including
the posterior LA, ligament of
Marshall, coronary sinus, venae
cavae, septum, and appendages. 7
The evolution of AF from
paroxysmal to persistent to
permanent forms through atrial
remodeling can be caused by
the arrhythmia itself and/or
progression of underlying heart
disease. Atrial electrical properties
are modified by affecting expression
and function of ion-channels,
pumps, and exchangers, thus a
reentry prone substrate is created
which promotes arrhythmia.
This concept is known as atrial
remodeling and was first tested
in animal models showing that
long-term rapid atrial pacing or
maintenance of AF favors the
occurrence and maintenance of AF
(‘AF Begets AF’). 8 The development
of functional reentry substrates,
which are reversible on AF
 Supplement to Journal of The Association of Physicians of India ■ Published on 1st of Every Month 1st August, 2016 13

A B (RP) and/or a slowed conduction

velocity (CV) are the main
mechanisms contributing to the
perpetuation of either one or
multiple reentrant circuits. The
Early Afterdepolarization (EAD) Delayed Afterdepolarization (DAD)
electrical and structural remodeling
Fig. 2: Focal ectopy / triggered process promotes shortening of
activity. (A) EAD based on refractoriness of atrial tissue and
prolonged repolarisation; thereby decreases the wavelength
(B) DAD based on altered (WL) of reentry-circuits. The WL is
Ca2+-handling the product of the refractory period
(RP) and the conduction velocity
termination (reverse remodeling)
(CV) [WL = RP×CV].
contribute to persistent AF. As atrial
disease progresses to irreversible Fig. 3: Leading circle concept. AF-related reentry is currently
structural changes, AF becomes Activity in form of a reentry thought to occur through two main
permanent. 9 circuit establishes itself in concepts: (i) the leading- circle
a smallest possible loop concept and (ii) spiral wave reentry.
Potential mechanics for ectopic that permits the wave These mechanisms may underlie
firing (trigger): The resting to propagate. Inside the
AF perpetuation once continuously
potential of normal atrial cell is leading circle, multiple
impulses propagating firing sources or triggers such as
maintained by high resting K +
centripetally render the the PVs are eliminated. 13
permeability through the inward
core tissue refractory and Leading Circle concept: (Figure 3)
rectifier K + current (IK1). Although
extinguish The mechanism involves a reentrant
normal human atrial cells also
manifest pacemaker current closed during diastole but can open activity which is functional and
(If ), it is overwhelmed by much if they are functionally defective exists without the need of an
larger IK1, and does not manifest or if the sarcoplasmic reticulum is anatomical obstacle. The shorter the
automaticity. Enhanced automaticity Ca2 + overloaded. When one Ca2 + wavelength, the larger the number
is caused by changes in this balance ion is released during diastole, it of simultaneous reentry circuits
resulting from decreased (IK1) and/ is exchanged for three extracellular that the atria can accommodate.
or enhanced (If). 10 Na+ ions by the Na+- Ca2+ exchanger, Conversely, increasing wavelength
causing a net depolarizing inward reduces the number of possible
Early afterdepolarizations (EAD)
positive-ion movement (called circuits. This reentry circuit makes
(Figure 2) involve abnormal
transient inward current [Iti]) that smallest possible loop that allows
secondary cell membrane
underlies DADs. Congestive heart the wave to propagate. Inside the
depolarizations during
failure, one of the most common leading circle, multiple impulses
repolarization phases. EAD are
causes ofAF, produces atrial cell propagating centripetally render
caused mainly by action potential
Ca2 + overload and DADs. 12 the core tissue refractory and
duration (APD) prolongation. This
extinguish. Conversely, centrifugal
allows L-type Ca2+ current (ICaL) to Reentry-Maintenance of
propagation of impulses at the
recover from inactivation, leading AF: Reentry requires a suitable
leading edge of the leading circle
to inward movement of Ca2 + ions vulnerable substrate, as well as a
depolarizes adjacent tissue as fast
causing EAD. EADs caused by trigger, that acts on the substrate.
as possible. 14
atrial APD prolongation underlies Such substrates can be caused
the increased prevalence of AF by altered electrical properties Spiral wave Reentry: (Figure 4)
in congenital long-QT syndrome (functional reentry) or by fixed A spiral wave rotating around
patients. 11 structural changes (anatomical a microreentrant circuit adapts
reentry). Numerous cardiac a shape of a rotor. Reentry is
Delayed afterdepolarizations
conditions may cause structural the result of periodic activity
(DAD) (Figure 2) are caused by
substrates for reentry, basically of a stable, meandering self-
abnormal diastolic release of
mediated by atrial enlargement sustained uninterrupted spiral
Ca2 + from sarcoplasmic reticulum
a n d f i b r o s i s . At r i a l d i m e n s i o n wave reentry. A premature ectopic
stores. Specialized sarcoplasmic
affects the amount of tissue that can activity within the atrium initiates
reticulum Ca2 + channels (called
accommodate reentry circuits and a wavefront, which collides
ryanodine receptors [RyRs]) release
makes long pathways available. with the previous sinus beat
Ca2 + in response to transmembrane
A s h ort en e d r e fr a ct ory p e r i od which is in its refractory and
Ca2 + entry. RyRs are normally
14 Supplement to Journal of The Association of Physicians of India ■ Published on 1st of Every Month 1st August, 2016
A B C
D E F with each other and/or extinguish
Fig. 4: Spiral wave model. Top: A
schematic illustration of
the activation (with arrows)
and repolarisation (inner
curvature without arrows)
front of a meandering
self-sustained spiral
wave rotating around a
microreentrant circuit
(dotted circle). Bottom:
Various trajectories of
the spiral wave. Of note,
these trajectories produce
irregular local activation
pattern and frequency. A:
Circular; B: Hypocycloidal;
C: Epicycloidal; D:
Hypermeandering; E:
Cycloidal; F: Linear
recovery period. The propagation
o f t h e e c t o p i c wa ve f r o n t m a y
collide and block the edge of
not-recovered refractory tissue.
When the refractory tissue regains
excitability, it is activated by the
premature wavefront, generating
a curve continuously following
the recovery front until a complete
revolution is achieved. The point,
where excited and refractory
tissues collide is called the “phase
singularity”. The radius of the
wavefront curvature decreases
towards the vortex of the rotor
where conduction velocity is very
high. These rotors are also thought
to act as periodic background foci
generating wavefronts, which may
break up into multiple wavelets
when encountering anatomical
obstacles such as orifices or scar
tissue. 15
M u l t i p l e wa ve l e t h y p o t h e s i s /
multiple circuit reentry: When a
wa ve f r o n t c o l l i d e s w i t h i s l e t s
or strands of refractory tissue,
it divides and fractionates into
independent and eventually
unstable daughter wavelets. These
daughter wavelets show a very
r a p i d a c t i v i t y w i t h a va r i a b l e
and very short cycle length, may
divide again, fuse, block, collide
when encountering refractory
tissue (functional block) or sites
of slow conduction. As long as
number of wavefronts does not
decline below a critical level, the
multiple wavelets will sustain
the tachyarrhythmia, particularly
when advanced structural and
electrical remodelling processes are
present, maintaining its survival.
This causes the most frequent
common final pathway in sustained
AF. 16
Neural / Autonomic Nervous
System: Parasympathetic
stimulation causes vagal discharge
which enhances acetylcholine-
d e p e n d e n t K + c u r r e n t ( I K ACh) ,
reducing atrial action potential
duration and refractoriness,
increasing the susceptibility to
reentry mechanism. Sympathetic
stimulation causes β-adrenoceptor
a c t i va t i o n i n c r e a s e s d i a s t o l i c
Ca2 + leak and promotes DAD by
hyperphosphorylating RyR2s,
which promotes automaticity
a n d t r i g g e r e d a c t i v i t y . At r i a l
s y m p a t h e t i c h y p e r i n n e r va t i o n
occurs in persistent AF patients.
Au t o n o m i c n e u r a l r e m o d e l i n g
contributes to positive feedback
loops that promote AF persistence
and recurrence. Plexi of autonomic
ganglia that constitute the intrinsic
cardiac autonomic nervous system
are located in epicardial fat near
the pulmonary vein-LA junctions
and the ligament of Marshall.
Stimulation of the ganglia in
animals elicits repetitive bursts of
rapid atrial activity. Suppression of
autonomic signaling may contribute
to the efficacy of Pulmonary Vein-
directed ablation procedures for
AF. 17
Tachycardiomyopathy: Atrial
contraction contributes ~ 20% of
l e f t ve n t r i c u l a r s t r o k e v o l u m e
at rest. Loss of atrial contraction
may markedly decrease cardiac
output, particularly when
diastolic ventricular filling
is impaired by mitral stenosis,
hypertension, hypertrophic
cardiomyopathy (HCM), or
restrictive cardiomyopathy.
The effects of AF on ventricular
function and the consequences
of LV dysfunction on the atria
lead to a vicious circle, with AF
promoting ventricular dysfunction,
ventricular dysfunction causing
atrial remodeling changes that
promote AF. Hemodynamic
consequences of AF can result
from a variable combination
of suboptimal ventricular rate
control, loss of coordinated atrial
contraction, beat-to-beat variability
in ventricular filling. 18
The pathophysiological
mechanism of tachycardiomyopathy
is the combination of left ventricle
systolic dysfunction inducing a
complex neurohumoral response
and the cardiomyocyte calcium
ion disturbances caused by rapid
electrical ventricular activation.
Neurohormonal activation due
to low cardiac output, results
in marked elevations of plasma
catecholamines, atrial natriuretic
peptide, rennin and aldosterone
levels; further worsening the left
ventricular function. Prolonged
sympathetic activation leads to
adrenergic receptor density and
function disturbances, ion channel
dysfunction, and degenerative
changes in cardiomyocytes. These
processes end in a loss of structural
i n t e g r i t y a n d i n l e f t ve n t r i c l e
enlargement. 19
Thromboembolism: AF
 Supplement to Journal of The Association of Physicians of India ■ Published on 1st of Every Month 1st August, 2016
also confers an increased risk
of stroke and/or peripheral
thromboembolism owing to the
formation of atrial thrombi, usually
in the left atrial appendage (LAA).
In AF, the lack of an organized
atrial contraction can result in
some stagnant blood in the LA
or LAA which leads to thrombus
formation. If the thrombus becomes
mobile and is carried away by
the blood circulation, called an
embolus which proceeds through
smaller arteries until it plugs them
resulting in end organ damage.
Emboli in the brain may result in
an ischemic stroke or a transient
ischemic attack (TIA). More than
90% of cases of thrombi associated
with AF evolve in the LAA. 20
Summary: The pathomechanisms
causing and sustaining AF are
multifactorial and very complex.
The article reviews thebasic
p a t h o p h y s i o l o g y o f A F o ve r a
broad range of levels. The tissue
mechanisms that maintain
thearrhythmia to the relationship
between clinical presentation and
basic mechanisms. Ion channel
and transporter abnormalities
that lead to ectopic impulse
formation, basic models and tissue
determinants of reentry and ion
channel determinants of reentry.
Also the nature and roles of
electric and structural remodeling,
autonomic neural components,
anatomic factors, interactions
b e t we e n a t r i a l a n d ve n t r i c u l a r
functional consequences of AF,
and the basic determinants of
atrial thromboembolism.Symptoms
of AF range from nonexistent
to severe. Patients with AF vary
clinically from no symptoms to
fatigue, palpitations, dyspnea,
hypotension, syncope, or HF.
Frequent hospitalizations,
hemodynamic abnormalities,
and thromboembolic events
related to AF result in significant
morbidity and mortality. Linking
the diversity of risk factors and
pathomechanisms leading to AF
and the understanding of involved
pathophysiological concepts may
yield an improved performance in
AF prevention andtreatment.
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