Cardiovascular Pathology 23 (2014) 7184

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Cardiovascular Pathology

Review Article

Atrial brillation from the pathologists perspective

Domenico Corradi
Department of Biomedical, Biotechnological, and Translational Sciences (S.Bi.Bi.T.), Unit of Pathology, University of Parma, Parma, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Atrial brillation (AF), the most common sustained cardiac arrhythmia encountered in clinical practice, is
Received 13 November 2013 associated with increased morbidity and mortality. Electrophysiologically, it is characterized by a high rate of
Received in revised form 3 December 2013 asynchronous atrial cell depolarization causing a loss of atrial contractile function and irregular ventricular
Accepted 7 December 2013
rates. For a long time, AF was considered as a pure functional disorder without any structural background.
Only in recent years, have new mapping and imaging techniques identied atrial locations, which are very
Keywords:
Atrial brillation
often involved in the initiation and maintenance of this supraventricular arrhythmia (i.e. the distal portion of
Structural remodeling the pulmonary veins and the surrounding atrial myocardium). Morphological analysis of these myocardial
Fibrosis sites has demonstrated signicant structural remodeling as well as paved the way for further knowledge of AF
Cardiomyocyte natural history, pathogenesis, and treatment. This architectural myocardial disarrangement is induced by the
Genetics arrhythmia itself and the very frequently associated cardiovascular disorders. At the same time, the structural
Upstream therapy remodeling is also capable of sustaining AF, thereby creating a sort of pathogenetic vicious circle. This review
focuses on current understanding about the structural and genetic bases of AF with reference to their
classication, pathogenesis, and clinical implications.
2014 Elsevier Inc. All rights reserved.

1. Background and aims
Atrial brillation (AF) is the most common sustained arrhythmia
with undisputed individual and social sequelae. Electrophysiologically,
it is characterized by a high rate (400600 beats/minute) of
asynchronous atrial cell depolarization causing a loss of atrial
contractile function and irregular ventricular rates [1]. Its prevalence
in the developed world is approximately 1.52% of the general
population, with the average age of patients with this arrhythmia
being 75 to 85 years. In both genders, lifetime risks for the
development of AF are about one in four people aged 40 and older,
this magnitude being similar to that for congestive heart failure (one in
ve people, for the same interval) [2]. Recent evidence suggests a trend
of increased incidence and prevalence over time for AF which cannot
merely be explained by an aging population. In fact, in addition to well-
known conditions capable of favoring this arrhythmic disorder (i.e.,
valvular disease, congestive heart failure, lung disease, coronary artery
disease, hypertension, diabetes mellitus, and thyroid disease) [3] new
risk factors are emerging, such as obesity and obstructive sleep apnea,
which might signicantly predispose to AF [4]. However, in approx-
imately 1213% of cases, AF occurs without any clinically detectable
abnormalities (lone or idiopathic AF) [5]. In turn, AF is associated
with a 5-fold increased risk of ischemic stroke as a consequence of a
thrombus formation in the left atrial appendage [6].
The nature of this manuscript does not imply a specic nancial support.
Department of Biomedical, Biotechnological, and Translational Sciences (S.Bi.Bi.T.),
Unit of Pathology, University of Parma, Via Gramsci 14, 43126 Parma, Italy. Tel.: +39
0521 702390; fax: +39 0521 292710.
E-mail address: domenico.corradi@unipr.it.
AF was long thought to represent a purely functional disorder
without any distinctive anatomical characterization. However, in
recent years, new mapping and imaging techniques have identied
atrial sites which are predominantly involved in AF initiation and
maintenance, i.e., the pulmonary veins (PVs) and the surrounding left
atrial posterior wall (Fig. 1) [7,8]. Ablation procedures performed in
these specic left atrial sites has very often proved efcient in
restoring sinus rhythm in patients suffering from AF [9]. This
increased understanding of AF pathogenesis has also generated
great curiosity about its underlying histopathologic substrate and, as
a consequence, its electrophysiologic implications [10]. Therefore, AF
has been seen in a new light according to which it is not a purely
functional disease but rather the result of diverse histological changes
capable of sustaining this arrhythmic disorder [11].
This review article will focus on current understanding about the
structural and genetic bases of AF as seen from the perspective of a
morphologist. Their clinical implications will also be discussed. A
complete PubMed search was performed in order to identify original
manuscripts focusing on structural remodeling in AF and published
between 1973 and 2014. Selected study papers, recently published
review articles, editorials from peer-reviewed journals, book sections).
In addition, the reference lists of each searched publication were
reviewed. All of these were full-text English-language manuscripts.
2. Classication and natural history of atrial brillation
Currently, AF is classied by the American College of Cardiology/
American Heart Association/European Society of Cardiology (ACC/
AHA/ESC) as paroxysmal, persistent, long-standing persistent, or

1054-8807/$ see front matter 2014 Elsevier Inc. All rights reserved.
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72 D. Corradi / Cardiovascular Pathology 23 (2014) 7184
Fig. 1. Trigger points for atrial brillation. Postero-inferior view of the heart showing
the most (red abbreviations) and the less (black abbreviations) common atrial trigger
points for atrial brillation. Abbreviations: CS, coronary sinus; CVs, caval veins; LAPW,
left atrial posterior wall; LM, ligament of Marshall; PVs, pulmonary veins.
permanent merely on the basis of its (often presumed) duration.
Paroxysmal AF is dened as recurrent AF (2 episodes) that terminates
spontaneously within 7 days. Persistent AF is dened as AF, which is
sustained beyond 7 days, or lasts less than 7 days but necessitates
pharmacologic or electrical cardioversion. Long-standing persistent AF
is dened as continuous AF of greater than 1-year duration. Permanent
AF refers to a group of patients where a decision has been made not to
pursue restoration of sinus rhythm by any means, including catheter or
surgical ablation [12]. Although widely used, this classication has
been questioned by some groups particularly on the basis of its
simplistic approach which fails in expounding on the real underlying
atrial substrate. On this basis, in order to improve the use of both
ablation and medical treatment strategies, patients suffering from AF
should additionally be categorized in terms of underlying etiology
(and potential substrate), risk factors, and mechanisms [13]. Seen
from a morphologic standpoint, a further weak point of the present
classication is that, in the real world, there is a denite
clinicopathologic continuum from paroxysmal to permanent AF,
while a subdivision based on arrhythmia duration with specic cut-
offs forces patients into rigid and heterogeneous categories.
A structural remodeling affecting the atrial myocardial architecture
seems to play a crucial role in the initiation and maintenance of AF.
Aging itself and several non-arrhythmic diseases such as hypertension,
heart failure, valve disorders, diabetes, and thyroid dysfunctions may
induce both important histological and ultrastructural changes in the
atrial myocardium [11]. Clinically, the rst signs of AF usually arise
after months/years of remodeling and are very often preceded by
asymptomatic arrhythmic episodes. In addition, once AF has taken
place, also the cardiomyocyte electrophysiology are modied (so-
called electrophysiological remodeling, see below) [14]. When
established, AF behaves as a progressive disease where the arrhythmia
itself may induce both further structural changes and deterioration of
the underlying above-mentioned diseases, thereby creating a kind of
vicious circle that does nothing but make the myocardial architecture
distortion worse [15]. In this scenario, paroxysmal AF may progress to
persistent or even permanent AF, whereas structural remodeling
seems to be reversible only during the rst phases of the arrhythmic
disorder. In any event, the degree of structural remodeling appears to
be crucial because it may reach a point of no return beyond which sinus
rhythm cannot be restored [14].
Interestingly, the atrial distribution of structural remodeling seems
to modify over the natural history of AF. Hassaguerre et al. observed
that PVs are a major source of ectopic beats and can frequently initiate
paroxysms of AF (triggered AF episodes). In this situation, the
anatomical and electrical isolation of PVs has become a foundation
of ablation techniques [1618]. However, the success of this PV
isolation is limited in some patients with paroxysmal AF and,
especially, in the great majority of those subjects with persistent/
permanent AF, very likely because of more extensive atrial remodel-
ing additionally involving extra-PV locations [19,20]. The most
frequent sites of non-PV atrial triggers include the posterior wall of
the left atrium, the superior vena cava, the coronary sinus, the
ligament of Marshall, and the region adjacent to the atrioventricular
valve annuli (Fig. 1). Furthermore, the atrial ganglionated plexi may
play a signicant role in the pathogenesis of AF [21].
The high rate of recurrences after PV isolation alone in patients
with persistent and long-standing persistent AF, has led to the
identication of further strategies aimed at improving outcomes [18].
The logic for these procedures is the fact that persistent AF seems to
become pathogenetically less dependent on the PV [22] since its
triggers and re-entry sites are commonly found in the left atrial
myocardium around the PVs, probably as a result of greater structural
remodeling which, in chronic conditions, involves the surrounding
atrial myocardium [23]. Consequently, although targeting the triggers
located in PVs may often be sufcient in patients with paroxysmal AF,
further ablation specically targeting the altered anatomical substrate
responsible for maintaining AF may be required in chronic
conditions [18].
3. Morphologic ndings of atrial structural remodeling in
atrial brillation
Large population-based investigations have associated left atrial
size to the risk of developing AF. The Framingham study, which
prospectively followed up adults after routine surveillance M-mode
echocardiograms, showed that left atrial size is an independent risk
factor for the subsequent development of AF with a hazard ratio of
1.39 for every 5-mm incremental increase in left atrial size [24]. The
Cardiovascular Health Study Left atrial revealed that a diameter N5 cm
was associated with a relative risk of 4.05 (1.958.35) for the
development of AF [25]. At the same time, evidence from echocar-
diographic prospective studies also supports the fact that AF itself can
lead to atrial dilatation. AF occurring in patients with lone AF induces
a slow and progressive increase in left atrial size which is independent
of left ventricular changes [26]. With the passing of time, this dilation
further worsens, also because of the frequent superimposition of
additional structural heart diseases, such as mitral valve dysfunctions
[12]. There are contradictory data regarding right atrial enlargement
in AF even though in the RACE study, performed in a patient
population suffering from lone AF, both atria were enlarged with
the left more that the right one [2629]. On this basis, AF and atrial
dilatation may take part in a vicious cycle which would lead to the
maintenance of this arrhythmia [30].
From the histopathologic standpoint, the enlarged atrial walls are
the site of profound morphologic changes affecting both the
cardiomyocyte component and the myocardial interstitium (Fig. 2A
and B). These modications have been documented by both
experimental and clinical studies [11]. The most evident modication
in atrial cardiomyocytes is a progressive loss of sarcomeres starting
from the perinuclear area and extending eccentrically towards the
sarcoplasm (so-called myocytolysis) (Fig. 2C). Sometimes this
empty perinuclear area is lled with abundant glycogen granules
 D. Corradi / Cardiovascular Pathology 23 (2014) 7184 73

Fig. 2. The histopathology of atrial structural remodeling in atrial brillation. (A, B) Medium-power view of an autopsy normal (A) and atrial brillation remodeled (B) left atrium.
This latter shows moderate-to severe architectural disarray in terms of both cardiomyocyte and interstitial changes. (C, D) A variable amount of cardiomyocytes display perinuclear
loss of myobrils (so-called myocytolysis, arrows) with (C) or without (D) glycogen granules accumulation (deeper red color). (E, F, G) Increasing degrees of interstitial brosis
(red color, arrows) as collagen bers that surround single or small groups of cardiomyocytes. (H) Sometimes the adventitial/periadventitial spaces are expanded as a consequence of
collagen tissue deposition (so-called perivascular brosis, red color, arrows). Stainings: A, B, and D: hematoxylineosin, C: periodic acid-Schiff, E through H: Van Gieson staining for
collagen bers. Original magnications: A, B, and E through H, 20 (bar is 200 m); C and D, 40 (bar is 50 m).

(Fig. 2D). A lower cardiomyocyte oxygen supply/demand ratio in AF
would induce a metabolic shift from the use of fatty acids to the use of
glucose. This intra-cardiomyocyte pathologic accumulation of glyco-
gen could represent the result of metabolic excess of glucose or of
altered glycogen catabolism with varying degrees of glycogen
accumulation (Fig. 3) [31]. Interestingly, experimental studies have
shown that a quantitatively different number of cardiomyocytes
partially regain their fetal phenotype by means of an active process of
re-expressing some embryonic-type structural proteins (such as
smooth muscle actin) and the simultaneous decrease in proteins
distinctive of the adult cardiomyocyte (e.g., titin and cardiotin)
[3133]. Re-expression of smooth-muscle actin has immunohisto-
chemically been conrmed in human left atrial biopsies from patients
suffering from AF and mitral valve disease [34]. Ultrastructurally, in
addition to conrming all of the changes observed histologically,
transmission electron microscopy may document elongated mito-
chondria with characteristic longitudinally oriented cristae as well as
the homogeneous distribution of nuclear heterochromatin (Fig. 4)
[31]. Within certain limits, atrial cardiomyocytes in AF do not display
patent histopathological degenerative ndings (e.g. cytoplasmic
74 D. Corradi / Cardiovascular Pathology 23 (2014) 7184

Fig. 3. The spectrum of glycogen granule accumulation in atrial brillation cardiomyocytes. (A) Myocytolytic cardiomyocytes with no or very mild glycogen perinuclear lling
(arrow). (B) High-power view of a group of cardiomyocytes with increased sarcoplasmic glycogen (arrow)but still without any sign of myocytolysisor with early deposition of
glycogen granules into the perinuclear myocytolytic area (arrowheads). (C) Myocytolytic cardiomyocyte with moderate perinuclear glycogen. (D) Large-size cardiomyocyte with
severe glycogen accumulation (arrow) into a sarcoplasm with only few peripheral myobrils. Some myocytolytic bers with no signicant perinuclear glycogen are also detectable
(arrowhead). Staining: A through D, periodic acid Schiff. Original magnications: A through D, 40 (bar is 50m).

vacuoles, secondary lysosomes and lipid droplets) therefore the
above-mentioned muscle cell changes have not been considered to be
strictly degenerative. On this basis, Ausma et al. have hypothesized
that they may simply exemplify an adaptive dedifferentiation
toward an incomplete fetal phenotype that, within bounds, may act
as a survival state [31]. The dedifferentiated cardiomyocytes in AF
share several resemblances with those in the adaptive response to
inadequate coronary blood ow hibernating myocardium, which
strongly suggests that these modications are part of a non-specic
cardiomyocyte protective mechanism [35].
In AF, the myocardial interstitium is usually occupied by varying
amounts of collagen I bers which organize around single or small
groups of cardiomyocytes, thereby generating a spiderweb-like
network (Fig. 3EG). Some degrees of perivascular brosis may also
be detected in peripheral coronary artery branches (Fig. 3H) [36]. In
patients with mitral disease and AF, we found that this marked
interstitial collagen deposition was accompanied by decreased atrial
myocardial capillary density [36].
In a goat AF model, Ausma et al. investigated the time course of the
atrial structural remodeling and found that it takes place progres-
sively over time, with full changes being reached approximately 16
weeks after atrial burst stimulation [37]. The same group found that
partial reverse structural remodeling is a partially possible slow
process. About 4 months after stopping AF: (i) most of the
cardiomyocytes with severe myocytolysis had almost normalized
(even though a large proportion of them still showed mild sarcomere
loss), (ii) the adult-type expression of cell proteins had only partially
recovered, iii) interestingly, the degree of brosis was almost
superimposable on that seen during AF [38]. These data rank
interstitial brosis rst among the most urgent histopathologic
modications to be prevented.
In patients with mitral disease and AF, we showed a gradient in the
distribution of structural remodeling in terms of both cardiomyocyte
and interstitial changes. Although qualitatively similar, the above-
described changes were not homogeneously distributed throughout
the left atrial myocardium but were greater in the left atrial posterior
wall than in the corresponding left atrial appendage [34,36]. This
asymmetric myocardial injury could be justied by two main
explanations: (i) the close anatomical position of the left atrial
posterior wall to the PV orices, an area subjected to an intense stress
(ii) according to Laplaces law, the atrial free wall is characterized by a
higher tension, as compared to the left atrial appendage (since the
internal diameter of the left atrium is greater than its appendage
diameter while the internal left atrial and appendage pressures are
similar) [36].
Over the past few years, we have quantied structural remodeling
of the left atrial posterior wall in patient populations affected by
persistent AF associated with structural heart disease (mitral-valve
dysfunction) [34,36,39,40] and, more recently, in persistent idiopathic
AF (unpublished data). We found that these changes were milder in
the latter than in the former category of patients. These data further
strengthen the idea that the degree of structural remodeling is related
both to the natural history of AF and the presence of potential
associated disorders themselves capable of haemodynamically over-
loading the left atrial chamber. Unlike the key study by Frustaci et al.
on the pathology of lone AF [41], we could not nd any signicant sign
of inammation in our atrial endomyocardial biopsies from idiopathic
AF patients (unpublished data). However, the two AF populations
were not fully comparable in terms of AF time course, therefore we
cannot rule out the possibility that the interstitial brosis that we
documented could have potentially been caused by previous
myocarditis (at least in a fraction of cases). Our prior morphometric
quantications of left atrial (posterior wall, Fig. 1) structural
remodeling in AF patients are summarized in Table 1 [34,36,39,40].
As already stated, PVs are involved in the initiation and maintenance
of AF. Clinical investigations have shown that up to 94% of the triggers
initiating AF originate within one or more PVs and may interact with the
surrounding left atrial substrate through discrete or wide fascicles [42].
In fact, irregular atrial sleeves of cardiomyocyteswith potential
spontaneous electrical activity - extend over the veno-atrial junction
 D. Corradi / Cardiovascular Pathology 23 (2014) 7184 75

Fig. 4. Ultrastructure of atrial structural remodeling in atrial brillation. (A) Medium-power view of a myocytolytic cardiomyocyte whose perinuclear space (asterisk) is essentially
empty with some mitochondria (arrowhead). The remaining myobrils (arrow) surround the periphery of the myocytolytic area. (B) The perinuclear space in myocytolytic
cardiomyocytes is sometimes lled by abundant glycogen granules (arrowhead) and a variable number of mitochondria (arrow). (C) Detail of a myocytolytic cardiomyocyte with
copious glycogen (asterisk), mitochondria (arrowhead), and, peripherally, some altered myobrils (arrow). (D) The mitochondria are very often altered with the more frequent
change being an elongated shape with longitudinally oriented cristae (arrow). Glycogen granules (arrowhead) are located between the mitochondria. (E) The interstitium between
cardiomyocytes (asterisks) is variably occupied by collagen bers (arrows). (F) High-power detail of the collagen bers shown in E; they appear longitudinally (arrow) or
transversally (arrowhead) cut. Ultrastructurally, in view of their shape, pattern of distribution, and typical cross striation, these bers are in keeping with collagen type I. Original
magnications: A and B, 2800 (bar is 5,000 nm); C, 11,000 (bar is 1000 nm); D and F, 44,000 (bar is 200 nm); E, 5600 (bar is 2000 nm). Abbreviations: N, nucleus; L, lipofuscins;
M, mitochondrion.

into the PV wall and have electrical activity [43]. The sleeves (whose
size is up to 25 mm in length) mainly consist of circularly or spirally
oriented bundles of cardiomyocytes that interconnect with each other
in a continuous pattern with some gaps throughout [44]. Even though
no node-like cells have been found in human hearts, PVs are capable of
sustaining automaticity. Several mechanisms have been associated
with PV arrythmogenicity. Experimentally, triggered activity and
irregular high-frequency rhythms have been observed following
ryanodyne infusion, atrial stretching, rapid atrial pacing and congestive
heart failure, but, seemingly, not in normal PV cardiomyocytes. It
cannot be ruled out that re-entry mechanisms are involved in the
genesis of spontaneous PV activity [4547].
Some studies have indicated that amyloidosis is a possible group of
disorders capable of bringing about atrial structural remodeling and
thus providing a substrate for AF. A peculiar atrial-limited variant
known as isolated atrial amyloidosis (IAA), whose bril proteins are
found in the atrial interstitium and consist of atrial natriuretic peptide
(ANP) [48,49]. Rcken et al. investigated IAA in right atrial
appendages taken from subjects undergoing heart surgery, and
found that amyloid was more common in patients suffering from AF
than in those in sinus rhythm (especially in women with mitral valve
disease) and increased with age. In addition, the amount of the
material that was immuno-reactive to ANP correlated inversely with
the amount of interstitial brosis [48]. However, further focused
investigations need to be performed in order to conrm the role of
amyloidosis as a substrate for AF.
Finally, in this scenario of intense tissue remodelling, several
experimental and clinical investigations have explored whether in AF
there was any sign of cardiomyocyte death, in particular apoptosis.
Unfortunately, they have reached the most varied conclusions. It
should be noted that this heterogeneity in conclusions might be
imputable to diverse factors including exceedingly dissimilar patient
populations (or experimental designs) and different methods (with
many limitations) to detect apoptotic cardiomyocytes. However,
despite these disparate results, it seems that the event marking a
watershed between the absence and presence of apoptosis might be
the development of such a severe left ventricular failure capable of
provoking further atrial hemodynamic overload [11,5052].
76 D. Corradi / Cardiovascular Pathology 23 (2014) 7184
Table 1
Morphometric quantication of the left atrial structural remodeling in atrial brillation based on previous studies
References Patient Interstitial Perivascular
population brosis, % brosis, %
[36] PAF-MVD 7.163.23* (2.33-14.69) 0.320.25 (0-0.97)
[34] PAF-MVD 7.493.34* (2.33-14.69) 0.340.31 (0-1.60)
[39] PAF-MVD 8.22.2# (4.5-12.0)
[40] PAF-MVD 10.45.1 (3.8-24.7)
[34,36,39,40] Controls 0-2.75 0.07-2.03
Data from patients are expressed as average value its standard deviation, with range values in brackets. Control data are expressed as the overall min/max range obtained from the
four studies. Abbreviations: PAF-MVD, persistent atrial brillation and mitral valve disease. *: statistically different from controls and the corresponding left atrial appendage; :
statistically different from controls; #: statistically different from the corresponding left atrial appendage (no control group in this study); : statistically different from controls and
mitral valve regurgitation in sinus rhythm patients (no left atrial appendage samples in this study); : statistically different from controls (no left atrial appendage samples in this
study).
4. Connexins and atrial brillation
Five of the 21 connexin (Cx) isoforms in the human genome are
found in the heart (Cx37, Cx40, Cx43, Cx45, and Cx50) [53]. The atria
have Cx40, Cx43, and Cx45, with Cx40 being the most expressed (and
two to three times more expressed in the right atrium than in the left
atrium) [53,54]. Under normal conditions, Cx40 is heterogeneously
distributed throughout the atrial myocardium. Cx43 is distributed
homogeneously in the left atrium and right atrium, and its expression
in the right atrium is similar to that of Cx40 [54]. The sinoatrial node and
atrioventricular node cardiomyocytes are equipped with small dispersed
gap junctions mainly constituted of Cx45. These peculiar gap junctions
probably imply poor inter-cardiomyocyte coupling and are the cause of
the slower impulse speed within the nodes, and the sequential
contraction of the atria and the ventricles [55]. Unitary conductance is
relatively high in Cx40 gap junctions (200 pS), lowest in Cx45 junctions
(30 pS), and intermediate in Cx43 channels (120 pS) [53].
The difculty in detecting Cx45 has hampered efforts to determine
its levels in normal or pathological atria; however, they do seem to be
lower than those of either of the other two Cxs [53,54,56].
Unlike the ventricles, which in essence have a single Cx isoform
(Cx43), the presence of multiple connexon isoforms leads to many
different types of gap junction channel combinations, each of which
has its own electrical characteristics [57].
Unfortunately, atrial quantication of Cx in AF, each time, has
reported the expression of Cx40 and Cx43 as increased, decreased or
unaltered [5864]. This inconsistency is probably the consequence of
the large number of Cx combinations in the atrial myocardium and, as
a result, their different electrical properties. The single investigation of
Cx expression (e.g., by immunohistochemistry, Western blotting, etc.)
does not take into consideration the real spatial combination of the
multiple Cxs involved in gap junction structure, thereby being a too
supercial method of evaluating the real functional contribution of
these proteins to this cell-to-cell formation [53]. Nevertheless, the
assessment of Cx43 distribution pattern throughout the myocardium
may provide precious information on possible gap junction myocar-
dial remodeling [65].
5. Pathogenetic links between atrial brillation and development
of atrial morphologic changes
The pathogenesis of the myocardial damage in AF is dependent on
multiple factors and, very likely, multifactorial with different
mechanisms superimposing one on another. These factors contribute
differently depending on the main underlying cause of AF.
Two main key factors capable of modifying myocardial structure
and function in AF would seem to be atrial tachycardia, with a high
rate of cell depolarization, and volume/pressure overload leading to
increasing atrial wall stretch [66].
In addition to being the cause of most of the early electrophys-
iological changes [11], cardiomyocyte Ca 2+ overload may also activate
Cardiomyocyte Myocytolytic Capillary density,
transverse diameter, m cardiomyocytes, % No/mm2
830106* (670-1020)
19.01.5 (16.3-21.2) 19.97.7* (6.9-33.8)
18.62.1 (15.6-26.4) 15.13.1# (7.9-20.1)
18.61.5 (15.6-21.2) 20.85.6 (11.1-32.9) 923107 (732-1144)
10.2-14.8 0-2.8 1,276-1,514
the proteolytic activity of Ca 2+-activated neutral proteases, rst of all
calpain, which seems to be one of the main players in provoking the
myocytolysis found in AF cardiomyocytes [67]. Interestingly, this
protein localizes in the nuclear area as well as in the intercalated discs
and, after appropriate stimuli, can cleave both cardiomyocyte
cytoplasmic and membrane-associated proteins [68]. It may also
degrade L-type Ca 2+ channels and factors involved in excitation-
contraction coupling and may trigger particular mechanisms leading
to cell death [69].
Atrial interstitial brosis may be the result of non-specic scar-like
reparative mechanisms following cardiomyocyte necrosis or, more
interestingly, be secondary to reactive bro-proliferative signaling
pathways [70,71]. Angiotensin II (AngII), through its AngII type 1
receptors (AT1) has the potential of inducing, each time, cardiomyo-
cyte hypertrophy [72], endothelial changes [73], vasoconstriction
[74], apoptotic cardiomyocyte death [75], and myocardial brosis
[66,76]. Transforming growth factor-1 (TGF-1) is one of the major
downstream mediators of AngII, both of which quickly increase after
ventricular tachypacing-induced chronic heart failure [77]. Interest-
ingly, in constitutively active TGF-1 transgenic mice, TGF-1 activity
in itself does not seem to promote signicant amounts of brosis in
the ventricular myocardium. On the contrary, a selective interstitial
brosis is stimulated in the atrial myocardium, thus suggesting a
particular susceptibility of atrial cells to this cytokine [78].
Mechanical stretch can itself induce in broblast AngII and TGF-1
expression, therefore greatly inuencing the atrial structural remo-
delling and its propensity to arrhythmic disorders [79]. Cardiac
broblasts are highly receptive in sensing, integrating and reacting to
mechanical stimuli, being capable of coupling mechanical input to
functional responses. This mechanically induced up-regulation of
extracellular matrix production may be induced through the
autocrine or paracrine action of probrotic factors [80]. Cardiomyo-
cytes themselves can interact and inuence the myocardial broblast.
Three further potential mediators of structural remodeling still under
consideration are the platelet-derived growth factor, the ANP, and the
highly promising galectin-3 [11,81].
Several inammatory markerssuch as C-reactive protein (CRP),
tumor necrosis factor alpha (TNF), interleukin 2, interleukin 6 (IL-6),
interleukin 8 (IL-8), and monocyte chemoattractant protein 1 (MCP-
1)have been found as linked with AF (e.g. in post-operative AF) and
its outcome [82]. However, many unsolved points remain in the
knowledge of the relationship between AF and inammation. First,
there are no univocal results regarding inammatory marker levels
and natural history of atrial brillation. In fact, the great majority of
them seem not to increase with the transition from paroxysmal to
persistent or permanent AF. TNF is the only molecule that may show
a graded increase from paroxysmal to persistent/permanent AF
[83,84]. Second, wondering whether inammation is the cause or
consequence of AF is probably the chicken and egg conundrum.
Based on the available literature, very likely, both hypotheses are
true. Inammation would represent a signicant trigger for the
 D. Corradi / Cardiovascular Pathology 23 (2014) 7184
arrhythmia and, at the same time, AF would create an inammatory
environment [84]. Third, it is unclear whether inammation in AF
reects a local or systemic process. Only very limited data are
available on this subject, yet. Liuba et al. found higher IL-8 plasma
levels in femoral vein, right atrial, and coronary sinus blood, but not in
PV blood samples, this nding being in keeping with a systemic source
of inammation [85]. Marcus et al. found higher CRP levels in the left
atrium than in the corresponding coronary sinus and concluded that
trans-cardiac cytokine gradients in AF would arise by sequestration of
inammatory cytokines in the heart [86]. Forth, there are contrasting
results as to whether inammation reects AF or the potential
underlying disease [84,87]. Lastly, there is much convincing evidence
that inammation plays an important role in the pro-thrombotic state
associated with AF. The mechanism linking these two phenomena
would involve activated inammatory cells (i.e., monocytes, macro-
phages, and lymphocytes) which trigger endothelial dysfunction,
platelet activation, and increase brinogen production (for details see
reference [84]).
Several lines of evidence support an association between oxidative
stress and AF induction and maintenance [11,88,89]. In the myocar-
dium, increased levels of ROS such as superoxide and H2O2 have been
found to be associated with AF [9093]. The oxidized GSSG/reduced
glutathione and oxidized cysteine/reduced cysteine ratios have been
found increased in the blood of patients with AF [94]. Increased ROS
levels result in damage to proteins, lipids, and DNA, and potentiate
inammation. In addition, ROS are also implicated in cardiac
structural and electrical remodeling. In fact, it has been shown that
hydroxyl radical (OH) and peroxynitrate (ONOO) mediate
oxidative damage of myobrils in AF [95,96]. With regard to atrial
electrical remodeling, this has been found to be associated with
intracellular calcium overload [97,98]. Carnes et al., in a dog model,
showed that AF induced by rapid pacing decreased myocardial tissue
ascorbate levels and increased protein nitration [99]. Coronary artery
bypass surgery, which is often complicated by post-operative AF, is
associated with an increase in oxidized glutathione and lipid
peroxidation [94,100,101].
In patients with persistent AF and mitral valve disease, our group
documented higher myocardial tissue levels of the inducible oxidative
stress marker heme oxygenase 1 (HO-1), compared to controls.
Interestingly, HO-1 was more expressed where the structural
remodeling peaked (left atrial posterior wall vs left atrial appendage)
[39,40]. Very recently, in comparison with controls, we have also
found both HO-1 overexpression and greater 3-nitrotyrosine levels in
the left and right atrial free walls of individuals with idiopathic
persistent AF (unpublished data).
However, despite the correlative link between oxidative stress and
AF, systemic anti-oxidant therapy in patients with AF has not met
with much achievement in clinical trials [102,103]. Possible explana-
tions are that oxidative stress is either not part of the pathogenic
cascade of arrhythmogenesis, or our available antioxidant treatments
are not targeting the specic pathogenic source of oxidative stress in
arrhythmia [102,104]. In addition, as already said for inammation, it
is still largely unclear whether oxidative stress is the cause,
consequence or both in AF [11]. Further investigations are necessary
to elucidate detailed mechanisms involving oxidative stress in the
pathogenesis of AF.
As already stated, in addition to the cardiovascular diseases that
are traditionally accepted as being related to AF, other conditions may
also act as risk factors for this supraventricular arrhythmia as well as
being players in its pathogenesis [105].
The Veterans Health Administration Hospitals study reported that
the incidence of AF in patients with diabetes mellitus was 14.9%, this
being signicantly higher than that of hypertension. Diabetes mellitus
is a strong and independent risk factor for the occurrence of AF, with
an odds ratio of 2.13 (Pb.0001) [106,107]. The precise pathogenetic
mechanisms that cause AF in diabetes mellitus patients are still
77
unknown. The supposed mechanisms linking diabetes mellitus and AF
include autonomic remodeling, structural remodeling, electrical
remodeling, and insulin resistance. With regard to structural
remodeling, in a diabetes mellitus rat model Kato et al. showed
brosis in the atria with formation of anchoring points for reentry
circuits and changes in the forward propagation of brillatory
wavelets, thereby causing atrial fractionated potentials and conduc-
tion delay [108]. A study in which atrial tissue was collected from
diabetes mellitus patients, atrial samples biopsied during coronary
artery bypass graft surgery displayed mitochondrial dysfunction
causing oxidative stress which could also be involved in the formation
of hyperglycemia-associated AF substrates, leading to atrial interstitial
brosis [109]. It has been demonstrated that the advanced glycation
end products (AGEs) and AGE receptors (RAGEs) (both constituting
the AGERAGE system) facilitate the interstitial collagen deposition in
atrial myocardium of diabetes mellitus rats by inducing up-regulation
of the expression of connective tissue growth factors, and, as a
consequence, cause myocardial structural remodeling [110]. Interest-
ingly, in the atrial myocardium of rats with induced diabetes mellitus,
the expression of Cx43 was elevated and its phosphorylation was
decreased, this leading to disorders of intercellular electrical coupling
and consequent atrial arrhythmia [111].
AF is one of the most frequent rhythm disturbance in the setting of
hyperthyroidism with its prevalence ranging from 2% to 20% [112]. If
compared with a population with normal thyroid function and a 2.3%
prevalence of AF, the prevalence of AF in overt hyperthyroidism is
13.8% [113,114]. Shimizu et al. showed that in a cohort of patients
with hyperthyroidism analyzed for age distribution, AF prevalence
increased stepwise in each decade, peaking at about 15% in patients
N70 years, therefore demonstrating that hyperthyroidism-related AF
is more common with advancing age [113]. A number of potential
mechanisms of AF in hyperthyroidism have been suggested including
elevation of left atrial pressure as a result of increased left ventricular
mass and impaired ventricular relaxation, increased atrial ectopic
activity, and ischemia secondary to raised resting heart rate [115
117]. Interestingly, it has recently been shown that both hypothy-
roidism and hyperthyroidism lead to increased AF vulnerability in a
rat thyroidectomy model. In fact, hypothyroidism and hyperthyroid-
ism, while inducing opposite electrophysiological changes in heart
rates and atrial effective refractory period, both signicantly increase
AF susceptibility [118].
The association of episodic heavy alcohol (ethanol) use with the
onset of AF has long been designated as holiday heart syndrome
[119]. However, more recently, it has been suggested that even
habitual heavy alcohol consumption could be associated with a risk of
AF [120]. Kodama et al. conducted a meta-analysis of studies related to
alcohol consumption and AF to summarize the estimated risk of AF
related to alcohol. In a recent meta-analysis performed by Kodama et
al. on 14 previous studies, the pooled estimate for AF for highest vs.
lowest alcohol intake in individual investigations was 1.51 (Pb.05)
and a positive relationship between AF risk and heavy alcohol intake
was consistently found in all stratied analyses. In addition, in a linear
regression model, the pooled estimated for an increment of 10g per
day of alcohol consumption was 1.08 (Pb.001) [121]. Over the last few
years, a number of mechanisms by which alcohol consumption would
relate to the development of AF have been proposed: a direct toxic
effect on cardiac myocytes, a hyperadrenergic state which is reached
during both drinking and withdrawal of alcohol, an impaired vagal
tone, an increase in intra-atrial conduction time (which is also
testied by a P-wave prolongation) [122125].
6. Architectural atrial structural remodeling and its propensity to
develop atrial brillation
There are no conduction system bers between the two nodes and
through the remaining atrial myocardium. This is why, because of this
78 D. Corradi / Cardiovascular Pathology 23 (2014) 7184
peculiar architecture of the atria, a cardiac impulse is rst generated in
the sinoatrial node and is subsequently conducted throughout the
working atrial myocardium to the atrioventricular node following
well-dened routes in a non-uniform anisotropic way, that is to say,
strictly dependent on the anatomic orientation of the myocardial
bers. Among these routes, the terminal crest and anterior limbus of
the oval fossa are the main paths for this favored anisotropic
conduction which is a consequence of the cylindrical-like shape of
adult cardiomyocytes, the heterogeneous distribution of gap junc-
tions, and the muscle bundle orientation along the major axis of atrial
cardiomyocytes [126].
In epicardial maps of acute AF and persistent AF, Allessie et al.
found that the main feature of the substrate of longstanding AF was a
signicant increase in longitudinal dissociation, in terms of lines of
block running parallel to the atrial musculature [17]. The term
longitudinal dissociation originally referred to any kind of asyn-
chronous or non-uniform propagation along the longitudinal axis of a
portion of the A-V conducting system [127]. In patients with
longstanding AF they found electrical longitudinal dissociation of
neighboring muscle bundles and the amount of this phenomenon was
more than six times higher than in acute AF. On the contrary they
failed to nd any rotors or foci that could explain the persistence of AF.
As a whole, these ndings provide evidence that in persistent AF, the
route of the brillating waves is largely inuenced by the underlying
architecture of the atrial myocardium (e.g., interstitial brosis) [17].
In addition to longitudinal dissociation of atrial muscle bundles,
endocardial-epicardial dissociation may be considered a further
determinant for the establishment of a substrate capable of favoring
persistent AF. Electric dissociation between the endocardial and
epicardial myocardial layers during AF is a vital condition for
transmural conduction of the brillation waves. In fact, only in the
presence of this dissociation, electric activity in one single layer of the
atrial wall can meet excitable muscle in the opposite layer [128].
Since during persistent AF, waves with a focal spread of activation
are frequently observed, De Groot et al. have recently investigated
whether these waves originate from focal activity (ectopic impulse
formation or microreentry) or may be considered as an epicardial
breakthrough of waves directly propagating in deeper layers of the
atrial myocardial wall. Compared to acute AF, they found a fourfold
greater incidence of epicardial breakthroughs in patients with long-
standing AF, thereby implying the presence of a three-dimensional
substrate where the brillation waves frequently cross over from the
endocardial to the epicardial layers [129].
On the basis of the above observations, in recent times, Eckstein et
al. have proposed a new pathogenetic hypothesis according to which
structural heart disease, and AF itself, would induce structural
remodeling by disrupting side-to-side cardiomyocyte connections
not only between muscle bundles (longitudinal dissociation) but also
between the epicardial and endocardial layers (endocardial-epicardial
dissociation). As already stated, this progressive loss of endoepicardial
electric connections would result in a signicant increase in
endocardial-epicardial dissociation, produce a three-dimensional
structural substrate for AF, and increase the functional surface
available for brillation waves [128].
7. The genetics of atrial brillation
The idea that AF could be a heritable disease dates back to the mid-
20th century, even though only over the last decade has the
underlying transmissible component been extensively explored and
partially described [130,131]. Several genetic data and epidemiologic
observations are strongly in keeping with the concept of AF as a
disorder with genetic basis.
Data from the Framingham study reported that there was an
increased risk of AF in offsprings with at least 1 parent affected by AF,
compared to those without parental disease [132]. Arnar et al. found
that the relative risk of AF among relative pairs declined incremen-
tally, from 1.77 in rst-degree relatives to 1.36, 1.18, 1.10, and 1.05 in
second- through fth-degree relatives, respectively, (Pb.001) [133]. In
a patient population of 1,137 same-sex twin pairs (monozygotic and
dizygotic) in which one or both members had AF, Christophersen et al.
demonstrated that, compared to dizygotic, monozygotic twins had a
signicantly shorter event-free survival time (hazard ratio, 2.0; 95%
CI, 1.33.0) and estimated that the heritability of AF due to additive
genetics was 62% (5568%) [134]. Ellinor et al. explored the extent of
familial aggregation in patients with lone AF and found that family
members had an increased relative risk of AF, compared to the general
population: sons (risk ratio 8.1; 95% condence interval 2.032),
daughters (9.5; 1.367), brothers (70; 47102), sisters (34; 1480),
mothers (4.0; 2.56.5) and fathers (2.0; 1.23.6) [135]. Darbar et al. at
the Mayo Clinic found that at least 5% of all patients with AF and 15%
with lone AF had a positive family history (in rst- or second-degree
relatives) [136].
Three main methods have been applied in investigating the
genetics of AF. The genetic linkage analysis is a powerful tool to
detect the chromosomal location of disease genes and is based on the
fact that genes that are physically located close on a chromosome
remaining linked during meiosis. Therefore, AF may be studied as a
monogenic disease in which different members of a family have AF as
a primary electrical disease. This method is appropriate when dealing
with a family of two or three generations in which AF segregates
across generations and exhibits a Mendelian-like pattern of inheri-
tance [137]. The main monogenic mutations and rare variants
associated with AF are listed in Table 2 [137161]. Gene association
studies explore the correlation between a particular disease status
and a genetic variation in order to identify candidate genes (or
genome regions) that may potentially be linked to a specic disease.
In this scenario, a higher frequency of a single-nucleotide polymor-
phism (SNP) allele or genotype in a series of individuals affected with
a disease can be interpreted as potentially increasing the risk of that
given specic disease [162]. The main results from gene association
studies in AF are shown in Table 3 [163176]. In addition to testing for
association in candidate genes, genome-wide association studies
also identify several SNPs and loci for complex phenotypes in inter-
genic regions [177]. The AF susceptibility loci assessed by genome-
wide association studies are listed in Table 4 [178185].
As shown in Tables 2, 3, and 4, in recent years, several monogenic
mutations have been described by candidate gene tests. Even though
efcient in understanding the pathogenesis of some forms of AF, they
are limited in explaining the heritability of this supraventricular
arrhythmia since they only refer to sporadic or familial cases of AF. On
the contrary, genome-wide association studies are more efcient in
recognize genetic loci associated with an increased risk of for AF [186].
Additional identication of AF susceptibility loci as well as biological
pathways linking the disease with its genetic background will very
likely allow us to propose AF risk scores on the basis of the genetic
variants. For a more extensive treatment of AF genetics, some
comprehensive articles on this subject have recently been published
in the English-language literature [131,137,186190].
8. Structural remodeling in atrial brillation and its implications
for clinical practice
It is well known that traditional anti-arrhythmic agents classes I
(i.e., ecainide, propafenone) and III (i.e., amiodarone, dofetilide,
sotalol), which were initially developed to treat ventricular
arrhythmias, may also be effective in restoring sinus rhythm when
the onset of AF is recent. However, the overall risk of relapse is
considerable and depends particularly on the duration of the
arrhythmia and structural remodeling establishment [191]. In
addition, the Atrial Fibrillation Follow-up Investigation of Rhythm
Management (AFFIRM) study showed that the rhythm-control
 D. Corradi / Cardiovascular Pathology 23 (2014) 7184 79

Table 2
Main monogenic mutations and rare variants associated with atrial brillation

Gene/ Gene name Chromosomes Functional consequences Atrial brillation pathogenetic mechanism References
Locus

ABCC9 ATP-binding cassette, sub-family 12p12.1 Retention of adenosine-triphosphate- Defective responses to adrenergic stress [137,138]
C (CFTR/MRP), member 9 induced inhibition of K+ current
GJA1 gap junction protein, alpha 1, 6q22.31 Dominant negative effect on gap Decreased conduction velocity [137,139]
43kDa junctions
GJA5 gap junction protein, alpha 5, 1q21.1 Dominant negative effect on gap Decreased conduction velocity [140]
40kDa junctions
KCNA5 potassium voltage-gated 12p13 Loss-of-function effect on IKur currents Delayed atrial action potential repolarization [141]
channel, shaker-related
subfamily, member 5
KCNE2 potassium voltage-gated 21q22.12 Gain-of-function effect on IKr currents Enhanced atrial action potential repolarization [142]
channel, Isk-related family,
member 2
KCNE3 potassium voltage-gated 11q13.4 Increased activity of Kv4.3/KCNE3 and Faster cardiac action potential repolarization and thus [143]
channel, Isk-related family, Kv11.1/KCNE3 generated currents vulnerability to re-entrant wavelets
member 3
KCNE5 KCNE1-like Xq22.3 Gain-of-function effect on IKs Enhanced atrial action potential repolarization [144]
KCNH2 potassium voltage-gated 7q36.1 Gain-of-function effect on IKr currents Increase of the repolarizing currents active during the [145]
channel, subfamily H (eag- early phases of the action potential leading to its shorter
related), member 2 duration
KCNJ2 potassium inwardly-rectifying 17q24.3 Gain-of-function effect on IK1 currents Enhanced atrial action potential repolarization [146]
channel, subfamily J, member 2
KCNQ1 potassium voltage-gated 11p15.5 Gain-of-function effect on IKs currents Enhanced atrial action potential repolarization [147149]
channel, KQT-like subfamily,
member 1
LMNA lamin A/C 1q22 [150,151]
NPPA natriuretic peptide A 1p36.21 Shortened action potential duration and Enhanced atrial action potential repolarization [152]
effective refractory period
NUP155 nucleoporin 155kDa 5p13 Inhibitation of the export of Hsp70 Reduced atrial action potential duration [137,153]
messenger RNA and nuclear import of
Hsp70 protein
RYR2 ryanodine receptor 2 (cardiac) 1q43 Gain-of-function defect in RyR2 Defects in calcium ion handling [137,154]
SCN1B sodium channel, voltage-gated, 19q13.1 Loss-of-function effect on INa currents Reduced SCN5A-mediated current and altered channel [137,154]
type I, beta subunit gating
SCN2B sodium channel, voltage-gated, 11q23 Loss-of-function effect on INa currents Reduced SCN5A-mediated current and altered channel [137,155]
type II, beta subunit gating
SCN5A sodium channel, voltage-gated, 3p21 Gain-of-function effect on INa currents Delayed atrial action potential repolarization [156]
type V, alpha subunit
TBX5 T-box 5 12q24.1 Enhanced DNA binding and activation of [157,158]
both the NPPA (ANP) and Cx40 promoter
Unknown Unknown 6q14-q16 Unknown [159]
Unknown Unknown 10q22-q24 Unknown [160]
Unknown Unknown 10p11-q21 Unknown [161]

strategy offers no gain in survival over the rate-control strategy
(with beta-blockers, calcium-channel blockers) [192]. Interestingly,
a subsequent AFFIRM sub-study examining the relationships
between sinus rhythm, treatment and survival demonstrated that,
although sinus rhythm is associated with a signicant reduction in
the risk of death, the anti-arrhythmic pharmacologic strategy was
associated with increased mortality, and the investigators therefore
supposed that the benecial anti-arrhythmic effects on survival may
be annulled by the signicant adverse effects (e.g., proarrhythmic
and negative inotropic effects) [193].
Over the last few years, new pharmacologic targets have emerged
from our current knowledge concerning AF-related structural remo-
deling and its pathophysiology. Among the various morphologic
changes that take place throughout the natural history of AF,
interstitial brosis seems to be the most lasting tissue injury as it is
virtually unaltered by sinus rhythm restoration and, as it is capable of

Table 3
Main results from gene association studies in atrial brillation

Gene Gene name Locus References

ACE Angiotensin I converting enzyme D/D [163,164]

AGT Angiotensinogen (serpin peptidase inhibitor, clade A, member 8) M235T, G-6A, G-217A, T174M, 20C/C [163166]
eNOS Nitric oxide synthase 3 (endothelial cell) 2786C, G894T [163167]
GJA5 Gap junction protein, alpha 5, 40kDa -44AA/+71GG [168]
GNB3 Guanine nucleotide binding protein (G protein), beta polypeptide 3 C825T [169]
IL10 Interleukin 10 A-592C [170]
IL6 Interleukin 6 G-174C [171]
KCNE1 minK Potassium voltage-gated channel, Isk-related family, member 1 38G [167,172]
KCNH2 Potassium voltage-gated channel, subfamily H (eag-related), member 2 K897T [173]
KNCE5 KCNE1-like 97T [174]
MMP2 Matrix metallopeptidase 2 C1306T [170]
SCN5A Sodium channel, voltage-gated, type V, alpha subunit H558R [175]
SLN Sarcolipin C-65G [176]
80 D. Corradi / Cardiovascular Pathology 23 (2014) 7184

Table 4
Atrial brillation susceptibility loci assessed by genome-wide association studies

Locus Top SNP Nearest gene Nearest gene name References

9q22 rs10821415 C9orf3 Chromosome 9 open reading frame 3 [178]

7q31 rs3807989 CAV1 Caveolin 1, caveolae protein, 22 kDa [178]
15q24 rs7164883 HCN4 Hyperpolarization activated cyclic nucleotide-gated potassium channel 4 [178]
1q21 rs13376333 KCNN3 Potassium intermediate/small Conductance calcium-activated channel, subfamily N, member 3 [178,179]
4q25 rs2200733 PITX2 Paired-like homeodomain 2 [178,180184]
1q24 rs3903239 PRRX1 Paired related homeobox 1 [178]
14q23 rs1152591 SYNE2 Spectrin repeat containing, nuclear envelope 2 [178]
10q22 rs10824026 SYNPO2L Synaptopodin 2-like [178]
16q22 rs2106261 ZFHX3 Zinc nger homeobox 3 [178,181,185]

interfering with atrial electrical conduction [38,194], it is extremely
important to prevent inter-cardiomyocyte collagen deposition by
reducing atrial stretching (e.g. by means of early mitral valve surgery)
and pharmacologically interfere with the molecular mechanisms
leading to brosis [71]. Inammation and oxidative stress may be two
additional factors involved in the cascade of events leading to
permanent tissue injury, and are therefore to be considered potential
pharmacologic targets [195]. New non-ionic drugs that can potentially
inhibit atrial brosis and cell hypertrophy, and modulate the specic
inammatory/oxidative status, have therefore been proposed as
therapeutic options in AF that could potentially attenuate and delay
atrial structural modications (so-called upstream therapy, Table 5)
[71,99,103,196217].
Over the last few years, a number of clinical trials have been
developed in order to assess the real effect of these classes of drugs
on AF. Upstream treatment with inhibitors of the reninangiotensin
aldosterone system, statins, and n-3 (-3) polyunsaturated fatty
acids may vary the arrhythmia substrate responsible for AF in virtue
of its prevention (or possibly reversal) of structural remodeling and
treatment of the potential underlying cardiovascular disease asso-
ciated with AF. Data from clinical investigations suggest that these
therapies could be valuable for primary prevention of AF. Never-
theless, if renin angiotensin aldosterone system inhibitors or statins
are warranted for proven therapy (e.g., chronic heart failure,
hypertension, coronary artery disease, coronary artery bypass graft,
etc.), there is a bonus that these agents may also prevent AF.
Recommendations for inhibitors of the reninangiotensinaldoste-
rone system and statins use in primary prevention and levels of
evidence have been inserted in the 2010 ESC guidelines on AF
management [196,218]. On the contrary, upstream therapy seems
not to be signicantly efcient in preventing recurrences of AF
(secondary prevention) [197]. This different behavior may be
justied by the fact that, in a patient with clinically evident AF,
structural remodeling (i.e., interstitial brosis) has already set in
and, very likely, upstream therapy cannot only prevent (or retard)
further collagen accumulation without signicantly reversing previ-
ous tissue changes [197].
Given the regional distribution of AF structural remodeling (which
in chronic conditions peaks in the left atrium), catheter ablation may
be an effective non-pharmacological approach to AF and structural
heart disease (Fig. 1). By causing ablation lines of myocardial
destruction, it aims to reduce the remodeled myocardial mass to a
size too small to maintain re-entrant arrhythmogenic circuits [8,9]. As
already stated, the ablation of PVs is very frequently effective in
treating most patients with paroxysmal AF. However, the success of
this ablative procedure is limited in some patients with paroxysmal AF
and, especially, in the great majority of those suffering from
persistent/permanent AF, very likely because of more extensive atrial
remodelling behind the PV-atrial junction [21,82,174,219]. Very
recently, Pump et al. found that in patients with AF and extremely
enlarged left atrium, ablation was effective in non-paroxysmal AF
cases and especially associated with left atrial reverse remodeling and
improved left ventricular ejection fraction [220]. For a more extensive
treatment on ablation of atrial sites in AF, see the two very recent
review articles [21,219].
9. Conclusions
AF is an arrhythmic disorder with signicant structural bases
which, at the same time, are both the result and a condition favoring
the perpetuation of the disease. Due to its extreme structural stability
and negligible regression after restoration of sinus rhythm, collagen
deposition around cardiomyocytes (interstitial brosis) is the most
threatening change in the setting of AF atrial structural remodeling. AF
itself and the often associated cardiovascular disorders are capable of
inducing in the atrial myocardium various degrees of remodeling at
the histologic and ultrastructural level. The extent of structural
remodeling goes hand in hand with the clinical history of AF, with the
rst changes being in the distal PVs and the surrounding myocardium.
As the disease evolves from paroxysmal to chronic, this remodeling

Table 5
"Upstream therapy" for prevention of structural remodelling in atrial brillation (based on animal and human studies)

Pharmacological class Action mechanism Main effects on structural remodelling References

Angiotensin-converting Inhibition of Angiotensin II Improvement of left ventricular diastolic function. Fibrosis production inhibition. [198203]
enzyme (ACE) inhibitors production Benecial effects on inammation, atrial stretch, myocyte metabolism, connexin
distribution and electrical remodelling. Inhibition of myocyte hypertrophy.
Angiotensin II type 1 (AT1) AT1 receptor antagonist Improvement of left ventricular diastolic function. Fibrosis production inhibition. [198,199,204,205]
receptor blockers Inhibition of myocyte hypertrophy.
(sartans)
Spironolactone Aldosterone antagonist Fibrosis production inhibition. [206,207]
Statins 3-hydroxy-3-methylglutaryl Prevention of underlying heart disease by interfering with lipid metabolism. Strong [71,208211]
coenzyme A reductase inhibitor anti-inammatory and anti-oxidant activity. Protection of atrial myocardium during
ischemia. Benecial effects on interstitial brosis.
Ascorbate Anti-oxidant activity Contradictory results on its prevention of AF after cardiac surgery. [99,205,211]
Omega-3 poly-unsaturated Constituent of sh oil with anti- Anti-inammatory and anti-oxidative effect. Inhibitory effect on metalloproteinase 9 [103,210,212
fatty acids inammatory and anti-oxidative activity. Attenuation the development of atrial brosis and inducibility of AF. 215]
activity
Corticosteroids Anti-inammatory activity Suggested in the prevention of atrial brillation post-cardiac surgery. [216,217]
 D. Corradi / Cardiovascular Pathology 23 (2014) 7184
spreads to larger portions of the atrial wall often making both classic
antiarrhythmic dugs and ablation of the sole PV outlets ineffective. On
this basis, the most urgent strategy is preventing the structural
remodelingwith special regard to interstitial brosisby early
treatment of the arrhythmia as well as its underlying cardiovascular
diseases. The association of drugs belonging to the upstream
therapy might potentially be helpful in counteracting and delaying
the myocardial collagen deposition in AF. Finally, a thorough
knowledge of the AF genetic background could break new ground
for future personalized treatments of AF.
Acknowledgments
The author is greatly indebted to Dr. Giorgio Bordin, Hospital
Piccole Figlie, Parma, Italy, for drawing Fig. 1. In addition, the author
would like to thank heartily Ms Gabriella Becchi and Ms Emilia
Corradini, Department of Biomedical, Biotechnological, and Transla-
tional Sciences (S.Bi.Bi.T.), Unit of Pathology, University of Parma, for
their invaluable technical assistance.
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