Atrial Remodeling And Atrial Fibrillation: Mechanistic Interactions And Clinical Implications
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Credits:Bandar Al Ghamdi, MD, Walid Hassan, MD, FACP, FACC,
FCCP, FAHA
King Faisal Specialist Hospital and research centre, Riyadh, Saudi Arabia.
Address for correspondence: Walid Hassan, MD, FCCP, FACC, FACP, FAHA. Consultant and Head Adult Cardiology, MBC 16, King Faisal Specialist Hospital & Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia.
Atrial fibrillation (AF) is the most common arrhythmia in
clinical practice. The prevalence of AF increases dramatically with age and is
seen in as high as 9% of individuals by the age of 80 years. In high-risk
patients, the thromboembolic stroke risk can be as high as 9% per year and is
associated with a 2-fold increase in mortality. Although the pathophysiological
mechanism underlying the genesis of AF has been the focus of many studies, it
remains only partially understood. Conventional theories focused on the
presence of multiple re-entrant circuits originating in the atria that are
asynchronous and conducted at various velocities through tissues with various
refractory periods. Recently, rapidly firing atrial activity in the muscular
sleeves at the pulmonary veins ostia or inside the pulmonary veins have been
described as potential mechanism,. AF results from a complex interaction
between various initiating triggers and development of abnormal atrial tissue
substrate. The development of AF leads to structural and electrical changes in
the atria, a process known as remodeling. To have effective surgical or
catheter ablation of AF good understanding of the possible mechanism(s) is
crucial.
Once initiated, AF alters atrial electrical and structural
properties that promote its maintenance and recurrence. The role of atrial
remodeling (AR) in the development and maintenance of AF has been the subject
of many animal and human studies over the past 10-15 years. This review will
discuss the mechanisms of AR, the structural, electrophysiologic, and
neurohormonal changes associated with AR and it is role in initiating and
maintaining AF. We will also discuss briefly the role of inflammation in AR and
AF initiation and maintenance, as well as, the possible therapeutic
interventions to prevent AR, and hence AF, based on the current understanding
of the interaction between AF and AR.
Atrial fibrillation (AF) is the most common arrhythmia in
clinical practice. The prevalence of AF increases dramatically with age and is
seen in as high as 9% of individuals by the age of 80 years [1]. In
high-risk patients, the thromboembolic stroke risk can be as high as 9% per
year and is associated with a 2-fold increase in mortality [1,
2].
Twenty percent of patients with paroxysmal atrial fibrillation (PAF), defined
as AF lasting 7 days (and spontaneous conversion), progress to chronic
(persistent or permanent) AF, defined as lasting 30 days [1
- 5].
Although the pathophysiological mechanism underlying the
genesis of AF has been the focus of many studies, it remains only partially
understood. Conventional theories focused on the presence of multiple
re-entrant circuits originating in the atria that are asynchronous and
conducted at various velocities through tissues with various refractory periods
[2].
Recently, rapidly firing atrial activity in the muscular
sleeves at the pulmonary veins ostia or inside the pulmonary veins have been
described as potential mechanism for AF [3]. AF results from a complex
interaction between various initiating triggers and development of abnormal
atrial tissue substrate [6]. The development of AF leads to structural and electrical
changes in the atria, a process known as remodeling. These changes further
perpetuate the existence and maintenance of this arrhythmia (i.e., “atrial
fibrillation begets atrial fibrillation”) [4].
There has been an increase interest in AF surgical and
catheter ablation in the past 15 years aiming to reduced its morbidity and
mortality. However these procedures have limited success and are not without
risk.
To have effective surgical or catheter ablation of AF good
understanding of the possible mechanism(s) is crucial. Once initiated, AF
alters atrial electrical and structural properties that promote its maintenance
and recurrence. The role of atrial remodeling in the development and
maintenance of AF has been the subject of many animal and human studies over
the past 10-15 years. This review will discuss the mechanisms of atrial
remodeling (AR), the structural, electrophysiologic, and neurohormonal
changes associated with AR and it is role in initiating and maintaining AF. We
will also discuss briefly the role of inflammation in AR and AF initiation and
maintenance, as well as, the possible therapeutic interventions to prevent AR,
and hence AF, based on the current understanding of the interaction between AF
and AR.
Atrial
remodeling refers to structural and functional
changes in the atrial myocytes in response to internal or external stimuli. Atrial
remodeling may also be described as a time-dependent
adaptive regulation of cardiac myocytes in order to maintain
homeostasis against external stressors [7]. The strength and the
duration of exposure to the "stressors plays a major role in determining
the extent of AR [8]. Exposure to external stressors for a short period of time
(<30 minutes) may lead to responses at the ionic/genomic level, which is
usually reversible [9]. Mid-term exposure (< or = 1 week) [10] may result in changes at the cellular level which are usually
reversible; however long-term exposure (>5 weeks) [11] may result in changes at the cellular/ extracellular
matrix level (e.g. apoptosis and fibrosis) and is usually irreversible).
Atrial remodeling may occur in response
to tachycardia with high rates of cell depolarization as in patients with AF.
In this case, AF is initially maintained by ectopic activity or single-circuit
reentry in a given patient, but the high atrial rates induce spatially
heterogeneous refractoriness abbreviation which creates conditions favorable to
multiple-circuit reentry. This multiple reentry circuits reentry may then
become the AF-maintaining mechanism. Thus, multiple-circuit reentry may be a
final common pathway AF mechanism in many patients. Hence the term “AF begets
AF” [4].
Atrial remodeling may also occur in
response to volume/pressure overload such as in heart failure
syndromes. Specific stressors, such as diastolic dysfunction,
ischemia, and valvular diseases, e.g. mitral stenosis and mitral regurgitation,
impose excess pressure and/or volume load on the atrial myocytes, which
responds with a range of adaptive, as well as maladaptive, processes
[7]. These processes include myocyte growth, hypertrophy,
necrosis, and apoptosis, alterations in the composition of extracellular
matrix, recalibration of energy production and expenditure, changes
in the expression of cellular ionic channels and atrial hormones and
reversal to a fetal gene program. These changes promote a cascade of reactions, which lead to AR with structural, functional, electrical,
metabolic, and neurohormonal consequences [7].
Atrial structural and ultra-structural changes due
to rapid atrial rates
Rapid atrial rate is associated with structural and ultra-structural
changes in both right and left atria. Starting with the structural changes; in
clinical practice there is a clear relationship between AF and atrial
dilatation. For many years atrial dilatation has been recognized as a
predictive factor for the development of AF [12]. On the other hand, atrial
diameters have been shown to further increase when AF is present. Sanfillipo et
al. [13] demonstrated an
increase in atrial diameters of almost 40% during a mean follow-up of 20.6
months in patients with AF and in the absence of structural heart disease. In
addition, it has been demonstrated that atrial diameters may decrease after
conversion of AF to sinus rhythm. [14, 15].
Rapid atrial pacing for 6 weeks in healthy dogs was shown
to result in progressive biatrial enlargement [16]. Furthermore
AF results in loss of atrial contraction and the recovery of this function may
take weeks to months to be seen after cardioversion depending on the duration
of the previous episode of AF [17].
In terms of atrial ultra-stractural changes due to high
atrial rates, chronic experimental AF leads to extensive changes in atrial
ultra-structure. The nature and time course of these alterations have been elaborately
investigated in goats by Ausma et al.[18 ] in which after 9 to 23 weeks of artificially maintained AF, they
found marked changes in atrial cellular substructures, including loss of
myofibrils, accumulation of glycogen, changes in mitochondrial shape and size,
fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin. These
changes were present in up to 92% of studied atrial cells and are considered to
be a sign of dedifferentiation rather than degeneration, that is, the cells
seemed to have changed to a fetal phenotype.
There are few studies describing atrial ultra-structural
changes in humans suffering AF. Bailey et al. [19] reported the first study
in which the atrial myocardium of living patients with AF was examined. They
obtained atrial tissue from patients undergoing valve surgery for rheumatic
valve disease. Of the 44 patients included, 32 were in AF, of whom 18 had AF
for more than 5 years at the time of surgery. They observed that long-term AF
was characterized by loss of muscle mass, which they described as diffuse
atrophy. The presence of rheumatic heart disease, however, may have importantly
influenced the structural abnormalities that were seen.
Mary-Rabine et al. [20] described the relationship between atrial cellular
electrophysiology, function, and ultra-structure in 121 patients undergoing
cardiac surgery, of whom 23 had AF. Atrial biopsies obtained from patients with
AF showed ultra-structural abnormalities such as loss of myofibrils and
disorganization of sarcoplasmic reticulum. However, interpretation of these
changes is difficult because AF was associated with higher patient age and
atrial dilatation, factors independently associated with these structural
changes [21].
Brundel et al. [22] evaluated atrial
tissue of patients with normal ventricular function undergoing coronary artery
bypass grafting and compared patients with persistent AF, paroxysmal AF, and
sinus rhythm. In patients with paroxysmal and persistent AF, contraction bands
were observed, which were virtually absent in patients with sinus rhythm. In
patients with AF, degenerative features such as clumping of nuclear chromatin
and the presence of lysosome-like bodies were present. Furthermore, only in
patients with persistent AF, were hibernating atrial myocytes found,
characterized by glycogen accumulation and the dispersion of nuclear chromatin.
Apart
from these intracellular changes, alterations in expression of atrial
intercellular gap junctions have been described during AF. These gap junctions
are responsible for the cell-to-cell propagation of electrical conduction and
consist of 2 connexons, each formed by 6 proteins called connexins. In the
heart, connexin 43 is the most abundant, whereas connexin 40 is mainly present
in the atrium [23]. Whether
AF-induced changes in these connexins play a significant role in atrial
remodeling remains a subject of debate [23].
AF
has been shown to be associated with a net increase [24, 25] or decrease [26, 27]
in connexin 40 expression with redistribution to the lateral borders of the
atrial myocytes. This may result in anisotropy and dispersion of atrial
conduction, thus favoring an environment vulnerable to AF.
Atrial remodeling due heart failure or other causes of
increased atrial volume /pressure overload is characterized primarily by biatrial
dilatation, which is considered an important factor in the genesis of atrial
arrhythmias in these patients. In the presence of acute or chronic stress
or injury, the atria stretch and stiffen [28, 29]. Larger atrial size means that more circuits can
be accommodated and that long-wavelength circuits that are too large
for a normal atrium can be supported. Atrial dimensions are a
particularly important determinant of the occurrence of
multiple-circuit reentry [30]. In canine models, Shi. et
al. [31] showed that five weeks of rapid ventricular pacing (220-240
beats per minute) resulted in an increase of 80.2% and 61.2% in left and right
atrial diastolic area, respectively, as measured by transthoracic
echocardiography. This biatrial dilatation was associated with a decrease in
atrial contractile function, which was reflected by a decrease in left and
right fractional area shortening of 41.8% and 33.7%, respectively. Similar
results were obtained by Power et al. [32] who found a 100% increase in diastolic left atrial
cross-sectional area in sheep after 6 weeks of rapid ventricular pacing. In
patients with diastolic dysfunction, there is also a clear relationship between
the magnitude of diastolic dysfunction and left atrial diameter and volume
which could explain the propensity to develop AF in patients with hypertension
and diastolic dysfunction [33, 34].
Atrial volume
or pressure overload results in atrial
dilatation which is accompanied by changes in atrial ultrastructure, also in
the absence of atrial arrhythmia [23]. The
development of rapid ventricular pacing–induced congestive heart failure (CHF)
in dogs is associated with atrial interstitial fibrosis, cellular hypertrophy,
loss of myofibrils, and signs of necrosis [11]. These processes were shown to be irreversible after cessation of
pacing and consequent recovery of the systolic ventricular function [35].
Verheule et al. [36] showed that chronic atrial dilatation in dogs due to
experimental mitral regurgitation in the absence of overt CHF results in atrial
fibrosis, signs of chronic inflammation, and increased accumulation of
glycogen.
Aimé-Sempé et al. [37] investigated human specimens of dilated right atrial
myocardium and found signs of apoptosis and myolysis in patients with AF as
well as in patients with a decreased left ventricular ejection fraction (LVEF)
who were in sinus rhythm. These included a disrupted sarcomeric apparatus with
replacement by glycogen granules, the presence of large Terminal deoxynucleotidyl
Transferase Biotin-dUTP Nick End Labeling (TUNEL)-positive nuclei with
condensed chromatin indicating the presence of DNA breakage and the decreased
expression of antiapoptotic proteins.
In a study of 15 patients with an atrial septal defect,
who were in sinus rhythm and had a dilated RA , structural abnormalities including hypertrophy and cell degeneration
were observed only in the presence of elevated RA pressures [38].
Also, ultra-structural changes in
heart-failure-induced remodeling characterized by degenerative changes,
including cellular edema, nuclear pyknosis, and contraction band
necrosis leading to cell loss [29].
Electrophysiological studies comparing heart
failure-induced AR with atrial tachycardia-induced AR have shown
significant differences in electrophysiological properties between
these two types. These differences depend mostly on the changes in the
ionic channels during the remodeling process [7].
Atrial electrophysiological changes due to rapid atrial
rates
Olsson et al. [39] found short right atrial monophasic action potentials in
patients immediately after conversion of AF to sinus rhythm. Boutjdir et al. [40] and Le Heuzey et al. [41] found short atrial refractory periods with loss of
physiological adaptation to high rates in atrial appendages of patients with
chronic AF undergoing surgery.
In 1995, two independent studies showed changes in atrial
electrophysiology as a consequence of AF. Wijffels et al. [4] demonstrated that repeated induction of AF in goats
resulted in progressive duration of the induced paroxysms, together with
shortening of the atrial refractory period and loss, or even reversal of, its
physiological adaptation to rate. Similarly, Morillo et al. [16] demonstrated that rapid atrial
pacing for 6 weeks in dogs resulted in shortening of atrial refractory periods,
an increased inducibility and stability of AF, together with an increase in P
wave duration and a decrease in atrial conduction velocity.
Shortening of refractoriness in combination with a decrease
in conduction velocity results in a shorter atrial wavelength, which is the
product of these two parameters. This could be an explanation for the increased
duration of AF, because according to the multiple wavelet theory, a short
wavelength will result in smaller wavelets which would increase the maximum
number of wavelets, given a certain atrial surface. Furthermore, chronic atrial
tachycardia depresses sinus node function which, may reduce the stability of
sinus rhythm and increase the stability of AF [42].
Changes in atrial electrophysiology favoring an increased
inducibility of AF have been described as a consequence of long-term pacing or
repeated induction of the arrhythmia. An increased heterogeneity of atrial
conduction and atrial refractoriness, which provides a substrate for reentry,
may occur after only 24 hours of rapid atrial pacing [43].
As well as these research data, several studies have also
investigated atrial electrical remodeling in humans. Short-term artificially
induced AF in humans results in shortening of atrial refractoriness [44]. In
addition, in patients with persistent AF, atrial refractoriness has been shown
to be shorter when compared with controls [45, 46] and to prolong after conversion
to sinus rhythm [47, 48].
Shortening of the atrial refractory period and the atrial
action potential may be caused by a net decrease of inward ionic currents (Na+
or Ca++), a net increase of outward currents (K+), or a combination
of both [23]. In dogs subjected to 42 days of rapid atrial pacing, Yue
et al. [49] demonstrated a
reduction in the L-type calcium current (ICa,L) and the transient
outward potassium current (Ito). The inward rectifier K+
current (IK1) and the components of the delayed rectifier current (IKur, IKr,
IKs) were unchanged. In addition, they demonstrated a decrease of the mRNA
expression of the L-type calcium channel a1c subunit, as well as Kv4.3
(encoding for Ito) [50].
Human studies also demonstrated a decrease in ICa,L and Ito
in patients with AF undergoing cardiac surgery [51, 54]. The
reduction in ICa,L may be explained by a decreased expression of the L-type
calcium channel a1c subunit [55, 57].
Brundel et al. [58] reported a decreased protein expression of the L-type
calcium channel, a finding that could not be confirmed by others [59].
Reduced mRNA and/or protein concentrations of several potassium channels have
also been reported [58, 61].
Despite these findings, a pivotal role of atrial electrical
remodeling in the progressive nature of clinical AF has never been proven.
Furthermore, experimental atrial electrical remodeling is complete within hours
to days, whereas the development of sustained AF generally takes at least 1
week. This indicates that other factors must be involved [23].
A study in
thirty-five patients with a left-sided accessory pathway and without a prior
history of AF where after successful ablation, the effective refractory periods
(ERPs) and conduction times of the right atrium (RA), left atrium(LA), and the
PVs were determined. Afterwards, AF was induced and maintained for a period of
15 min. Thereafter, the stimulation protocol was repeated. It was found that
new-onset; short-lasting AF creates electrical characteristics similar to those
of patients with AF. However, these alterations are pronounced in the PVs
compared with the atria, indicating that “AF begets AF in the PVs” [53].
Electrophysiological changes due to volume/ pressure
overload AR
Increased ventricular and atrial pressures during the
development of CHF may modulate atrial electrophysiology by causing myocardial
stretch. This phenomenon is called mechanoelectric feedback or
contraction-excitation coupling and has been demonstrated in animal studies as
well as in humans [23].
In the setting of an acute rise in the atrial pressure, several
studies have demonstrated changes in atrial refractoriness because of an acute
rise in atrial pressure. However, there is disagreement whether refractory
periods shorten or prolong. In dogs, an acute rise in atrial pressure caused by
(near) simultaneous atrioventricular (AV) pacing [63] or by saline infusion [64] resulted in prolongation of atrial effective refractory
period (AERP). In contrast, Solti et al. [65] reported a decrease of AERP along with an increase of
atrial conduction times. Similarly, acute atrial volume overload in rabbits
resulted in shortening of AERP [66] and a decrease of atrial conduction velocity [67]. Although
the results of these studies are conflicting, all report an enhanced
susceptibility to AF during an acute rise in atrial pressure.
The effects of chronic heart failure producing
long-standing atrial hemodynamic overload on atrial electrophysiologic
properties are even less well established. Li et al. [11] evaluated
the processes underlying the enhanced propensity of AF during the development
of pacing-induced CHF in a dog model. They induced CHF by rapid ventricular
pacing over 5 weeks. When compared with controls, the dogs with CHF had a
dramatically increased duration of AF induced by burst pacing (535 ± 82 vs 8 ±
4 seconds). When comparing the AERP between the groups, at longer basic cycle
lengths AERP was comparable between both groups, whereas at shorter cycle
lengths, AERP was slightly longer in the CHF group. However, this
prolongation of AERP is not likely responsible for the enhanced inducibility
and sustenance of AF during CHF. Li et al. also observed a dispersion of atrial
conduction in the CHF dogs, caused by extensive interstitial atrial fibrosis,
resulting in an environment vulnerable to reentry [11]. Comparable results were
obtained in sheep with ventricular pacing–induced CHF [31]. During 6 weeks of pacing left,
but not right AERP was prolonged and the susceptibility to AF initially increased.
However, the sheep became less susceptible to AF induced by an extra-stimulus,
although the duration of AF, when induced, was longer.
Boyden et al. [68] found no differences in the action potential duration and
shape in the right atrium and only a slightly increased duration in the left
atrium of cats with cardiomyopathy when compared with controls. Furthermore,
the diseased atria had a substantially increased amount of inexcitable cells
and showed structural abnormalities including
fibrosis, cellular hypertrophy, and degeneration. In dogs with artificially
induced right atrial enlargement caused by tricuspid regurgitation, they found
no difference in the right atrial action potential, although the susceptibility
and duration of AF was significantly increased when compared with controls.
However, there was no spontaneously occurring AF [69].
On the other hand, Verheule et al. [70] found prolonged atrial refractory periods but unchanged
atrial conduction velocity in dogs 1 month after the induction of mitral
regurgitation. Dogs with pacing-induced CHF had an enhanced inducibility of
atrial tachycardia with foci located along the crista terminalis and pulmonary
veins. The focal nature of specific types of AF recently has gained a lot of
interest. These findings indicate that the development of CHF may evoke atrial foci,
leading to AF [71].
Patients
with dilated atria have been shown to have a shorter atrial action potential
with lower amplitude than patients in whom the atria have normal dimensions [72].
However, this finding may partly be due to the presence of AF in 25% of patients
with the dilated atria, which apart from underlying heart disease, shortens
AERP [4]. In contrast, Calkins et al. [73]
found no change in AERP during simultaneous AV pacing. However, an acute
increase of the atrial pressure by two simultaneous AV beats resulted in a
shortening of AERP [74]. These results were not influenced by the presence
or absence of autonomic blockade.
In addition,
chronic hemodynamic load may lead to changes in atrial electrophysiology.
Patients with AF and mitral valve regurgitation were shown to have an increased
AERP. This prolongation was not related to arrhythmia history, that is,
patients with chronic or paroxysmal AF and mitral regurgitation also had longer
AERP than patients suffering the same arrhythmia without valve disease [58, 75].
Sparks et al. [76] investigated the effect of VVI pacing in patients during
sinus rhythm in the presence of an AV block. Chronic
AV dissociation also resulted in prolongation of AERP and an impairment of left
atrial contractility, [77] processes
which were reversible after reestablishing AV synchrony by DDD pacing. Experimental
CHF in dogs decreases the densities of atrial ICaL, Ito, and IKs. The net
result of the decrease of repolarizing potassium currents and the decrease of
depolarizing calcium current results in a slight prolongation of the atrial
refractory period and action potential, but only at higher rates. Furthermore,
the Na+/Ca+ exchanger current increases, which may
promote delayed afterdepolarization induced ectopic activity and indirectly
influence atrial refractoriness [78]. Le Grand et al. [72] found a decrease in ICaL in humans with
dilated atria whereas others [79] found no change. In addition, reported changes in Ito
and other potassium currents are conflicting. Some authors [80] have reported an increase; others
[72, 81]
have found a decrease of Ito in dilated atria. In addition,
the inward rectifier current IK1 was found to be reduced [82] or unchanged [72]. The discrepancies of
these findings may be explained by the variety of underlying cardiac disease,
use of medication, and the presence of AF.
In addition to the role in the electrophysiologic and
hemodynamic function of the heart, the atria also have an endocrinologic
function.
AR is associated with neurohormonal changes that include
increase in angiotensin II (Ang-II), aldosterone, transforming growth
factor-beta1, [83]
atrial natriuretic peptide (ANP), [84] brain natriuretic peptide (BNP), [85, 86] and
sympathetic hyperinnervation [87].
The neurohormonal changes resulted from rapid atrial rates
and volume/pressure overload will be elaborated below.
Neurohormonal
disturbances due to rapid atrial rates
High atrial rates are associated with increase plasma levels
of atrial natriuretic peptide (ANP). [88, 89] ANP is elevated not only in the
acute phase [90] but also
when the arrhythmia is chronic. [91] ANP is secreted by right and left atria, has diuretic
effects, reduces peripheral vascular resistance, reduces the sympathetic tone,
and suppresses the renin-angiotensin-aldosterone axis. [92] Therefore ANP reduces
the preload and protects the atria from hemodynamic overload. The exact
mechanism by which an atrial arrhythmia results in secretion of ANP is unknown,
although it has been demonstrated that atrial stretch is an important factor [93, 94].
Atrial remodeling due to
rapid atrial rates, at least in part, depends on angiotensin II–dependent
pathways [94, 96]. Angiotensin II is a
potent promoter of fibrosis, leading to cardiac fibroblast proliferation and,
thus may play an important role in the formation of a substrate vulnerable to
AF.
Angiotensin II acts by binding to two discrete receptor subtypes, angiotensin type I (AT1R) and type II (AT2R) receptors. The
signaling cascades coupled to AT1Rs and AT2Rs are distinct and often
have opposing actions. AT1Rs mediate the profibrotic effects of
angiotensin II by stimulating fibroblast proliferation, cardiomyocyte
hypertrophy, and apoptosis [97]. AT1R signaling through the Shc/Grb2/SOS adapter-protein complex activates the small GTPase
protein Ras, which initiates mitogen-activated protein kinase
phosphorylation cascades that are centrally involved in remodeling [98, 99]. AT1R activation stimulates
phospholipase C. Phospholipase C breaks down membrane phosphoinositol
bisphosphate (PIP2) into diacylglycerol and inositol
1,4,5-trisphosphate (IP3) [98]. Diacylglycerol activates protein
kinase C, and IP3 causes intracellular Ca++ release, both
of which promote remodeling. Signal transduction also occurs through
the JAK/STAT pathway, activating transcription factors such as
activator protein-1 and nuclear factor-B. AT2R activation inhibits
mitogen-activated protein kinases [99] via dephosphorylating actions of phosphotyrosine phosphatase and protein phosphatase 2A
and produces antiproliferative and survival-promoting effects that
oppose AT1R-mediated changes.
Angiotensin II
mediates cardiac fibrosis in a variety of cardiac pathologies,
including hypertensive heart disease, CHF, myocardial infarction,
and cardiomyopathy [100]. Transgenic mice with
cardiac-restricted ACE overexpression show marked atrial dilation
with focal fibrosis and AF [101]. Aldosterone
promotes fibrosis through its action on cardiac fibroblasts [101] and matrix metalloproteinases (MMPs) [102,
103]. Thus, the
neurohormonal changes have an important role in the genesis and the
progression of AR, [104 - 106] which
lead to the development and maintenance of AF [104, 107, 108].
Natriuretic peptides defend against excess salt and water
retention, inhibit vasoconstrictor peptides, promote vascular relaxation, and
inhibit the sympathetic neural system. These neurohormones have been shown to
be important markers in the assessment of clinical severity and prognosis of
CHF [86, 109]. Patients with CHF have
high plasma concentrations of both ANP and BNP. These concentrations are
associated with the degree of left ventricular dysfunction and may raise a
factor 30 in patients with New York Heart Association Class IV CHF [110].
ANP is mainly secreted from the cardiac atria but during CHF, a proportion is
also produced in the ventricles [111]. Several experimental
pacing–induced CHF studies have demonstrated an increase in circulating ANP and
BNP during the development of CHF [112, 113].
Mechanical stretch of atria is the strongest stimulator for
ANP secretion, which is augmented by endothelin and inhibited by nitric oxide
(NO).However, longstanding AF in severe LV dysfunction and development of
atrial fibrosis can cause depletion of ANP stores [114, 115].
AR is
associated with increase BNP level. The association between BNP and LA volume
in predicting AF was demonstrated in post-thoracotomy patients where
patients with larger LA volume and higher BNP levels had higher
incidence of post-operative AF [116, 117].
The development
of atrial fibrosis during CHF is angiotensin-mediated. In dogs subjected to
rapid ventricular pacing, administration of enalapril resulted in attenuation
of pacing-induced changes in angiotensin II concentrations, atrial fibrosis,
and impairment of atrial contractility [118, 119].
No direct
effect of ACE inhibiting drugs or angiotensin II blockers on atrial
refractoriness have been established in patients. However, potential benefits
of these drugs in arrhythmia burden in patients with CHF have been reported.
Administration of the ACE inhibitor trandolapril reduced the incidence of AF in
patients with systolic dysfunction after myocardial infarction, [120]
Data from heart failure trials indicate that treatment with an ACE inhibitor [121] or angiotensin II blocker [122]
reduces the risk of developing AF in patients with left ventricular
dysfunction. Furthermore, these effects have been shown to be independent of
changes in blood pressure.
Recent studies
have indicated that inflammation might play a significant role in the
initiation, maintenance, and perpetuation of AF. Inflammatory
cells have been demonstrated to infiltrate atrial tissue of patients with AF [123, 124]. Inflammatory markers such as C-reactive protein (CRP),
tumour necrosis facort, interlukin and cytokines have been shown to be elevated
in patients with AF [125, 126]. Elevation of CRP and IL-6
might also contribute to generation and perpetuation of AF, as evidenced by
marked inflammatory infiltrates, myocyte necrosis, and fibrosis found in atrial
biopsies of patients with lone AF [124, 126 - 129]. Complement activation has also been described in a cohort
of patients with AF without other associated inflammatory diseases [128]. It
has been suggested in 1 population-based cohort of 1,011 patients who were followed
up to 4 years, that in the absence of high baseline complement component levels
(C3 and C4) a high baseline CRP level is not significantly associated with a
high incidence of AF [130].
The exact mechanism of inflammation leading to tissue remodeling in AF patients is unclear and
warrants further research. It is thought that AF leads to myocyte calcium
overload, promoting atrial myocyte apoptosis. C-reactive protein might then act
as an opsonin that binds to atrial myocytes, inducing local inflammation and complement activation. Tissue damage then ensues and
fibrosis sets in [129, 131, 132].
Specifically, in the presence of Ca++ ions, CRP binds to
phosphatidylcholine. Long-chain acylcarnitines and lysophosphatidylcholines are
generated from phosphatidylcholine and can further contribute to membrane
dysfunction by inhibiting the exchange of sodium and calcium ions in
sarcomeres. This can eventually lead to the maintenance of AF [129 - 131].
The inflammatory cascade and catecholamine surge associated
with surgery might play a prominent role in
initiating atrial tachyarrhythmias after cardiac surgery. It has been reported
to occur in up to 40% of patients undergoing cardiac bypass surgery (CABG) or
up to 50% of patients undergoing cardiac valvular surgery [3, 4]. After cardiac
surgery, the complement system is activated and pro-inflammatory cytokines are
released. Bruins et al. [128] found that IL-6 rises
initially and peaks at 6 h after surgery and a second phase occurs in which CRP
levels peak on post-operative day 2, with complement-CRP complexes peaking on
postoperative day 2 or 3. The incidence of atrial arrhythmias follows a similar
pattern and peaks on post-operative day 2 or 3 [4,127, 133, 134]. Another study correlated leukocytosis to an
increased incidence in AF in post-operative cardiovascular patients [132].
Burzotta
et al. [135] discovered that the development of
postoperative AF was linked to 174G/C polymorphism of the IL-6 promoter gene.
In this particular study of 110 patients undergoing CABG, genetic analysis
revealed that the GG genotype was associated with higher IL-6 plasma levels and
subsequently, a greater inflammatory burden. Similarly Gaudino et al. [136] established a genetic link between inflammation and AF
and found that the GG genotype was an independent predictor of postoperative
AF.
The
notion that the inflammatory process plays a role in AF has garnered much
attention in many recent studies and is now a well-established connection. Many
clinicians now consider inflammation to be an independent risk factor for the
initiation and maintenance of AF [123]. Studies are currently
underway in an attempt to attenuate the inflammatory burden in patients with AF
by novel therapeutic interventions.
Agents
with potential anti-inflammatory effects such as ACEI, statins, steroids, omega
3 fatty acids, and vitamin C have increasingly recognizable roles in prevention
of AF. This will be discussed in the next section.
Reversal of AR is possible, especially if it is in an early
stage. The earlier the restoration of sinus rhythm by medication, electrical
cardioversion, catheter ablation or even surgery, the better the outcome, in
term of reverse remodeling.
Medical interventions
The angiotensin converting enzyme inhibitors (ACEI) and the
angiotensin receptor blockers (ARBs)
The ACEI and ARBs are antihypertensive medications which
may improve LV systolic and diastolic function; and have beneficial
effects on AR [137]. However, it appears
that altering renin-angiotensin-aldosterone system has strong
effects on AR, which extends beyond their beneficial effects on blood pressure
regulation. AR structural remodeling appeared reversible with
quinapril, which occurrs in parallel with an improvement in arterial stiffness
but independent of blood pressure changes [138]. Angiotensin-converting
enzyme inhibition has been shown to have important beneficial
effects on electrical remodeling [139, 140], atrial stretch
[138, 141], interstitial fibrosis [142 - 144] and inflammation
[144 - 146]. ACEI has been
shown to prevent first and recurrent AF in patients with
hypertension [122] and LV
dysfunction [120 - 122, 147, 148]. Patients with persistent AF who
were treated with amiodarone plus irbesartan had a lower rate of
recurrence of AF than did patients treated with amiodarone alone [149]. A number of large
clinical trials have shown a beneficial impact of ACE inhibition on
AF, however, the AF was not the primary end point in these studies [122, 148, 150 - 156]. The meta-analysis of 11 studies, which included 56,308
patients, were identified: 4 in heart failure, 3 in hypertension, 2
in patients following cardioversion for AF, and 2 in patients
following myocardial infarction. Overall, ACEIs and ARBs reduced the
relative risk of AF by 28% (95% confidence interval [CI] 15% to 40%, p = 0.0002). Reduction in AF was similar between the two classes of
drugs (ACEI: 28%, p = 0.01; ARB: 29%, p = 0.00002) and was greatest
in patients with heart failure (relative risk reduction [RRR] = 44%,
p = 0.007). Overall, there was no significant reduction in AF in
patients with hypertension (RRR = 12%, p = 0.4), although one trial
found a significant 29% reduction in patients with left ventricular
(LV) hypertrophy [157].
In patients with AF, an ACE-dependent increase in the
amounts of activated Erk1/Erk2 in atrial interstitial cells was noted
[104]. The effectiveness of angiotensin blocker to
reverse AR and suppress AF lies in its ability to modulate the
Ang-II–activated Erk1/Erk2 proteins, thereby
effectively inhibiting interstitial fibrosis [119,
139, 140].
Animal studies showed that the use of
angiotensin blockers can mitigate increase in interstitial fibrosis
and LA pressure; reduce myolysis, loss of contractile proteins, and
LA dysfunction; and shorten the duration of AF [119,
139, 140]. Administration of
the angiotensin-converting enzyme (ACE) inhibitor captopril attenuated
shortening of AERP after 3 hours of rapid atrial pacing in dogs [139].
In the TRACE (Trandolapril Cardiac Evaluation) trial [120], 2.8% of patients in the trandolapril arm developed AF
versus 5.3% (p _ 0.05) in the placebo arm; similarly, patients randomized to
enalapril in SOLVD (Studies Of Left Ventricular Dysfunction) [121] had a 78% relative risk
reduction in developing AF (P Value0.0001).
There are a few studies linking reduction in AF with an
administration of an ARB. In one prospective study, addition of irbesartan to
amiodarone resulted in lower recurrence of AF after DCCV in patients with
normal ejection fraction (79.52% vs. 55.91%, p _ 0.007) [149] Subset analysis of Val-Heft (the Valsartan Heart Failure Trial)
[150] and (Candesartan in
Heart Failure) [148] showed a reduction in
the incidence of AF in patients receiving ARBs compared with placebo. Current
evidence does not support the administration of statins and ACEIs /ARBs for the
sole purpose of preventing AF, because many of the current published reports
available were retrospective and observational in nature, with limited sample
size [123].
Aldosterone receptor antagonists
Aldosterone receptor antagonists, such as
spironolactone and eplerenone, appear to have a beneficial impact in
modifying the extracellular matrix, especially in terms of collagen
deposition and fibrosis.Spironolactone has been shown to reverse
the effects of AR by reducing atrial hyperexcitability, [108] inhibition of vascular Ang-I/Ang-II
conversion, [108] and attenuation of atrial fibrosis [159
- 161].
In animal models, Milliez et al. [160] demonstrated that
spironolactone attenuated atrial fibrosis, caused by chronic CHF in rats, more
than did lisinopril and atenolol. The role of
spironolactone and eplerenone on arrhythmia prevention was inferred
from the RALES (Randomized ALdactone Evaluation Study) [161] and EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy
and Survival Study) [162] trials where
patients treated with these drugs had lower rates of sudden cardiac
deaths. No studies have been done to assess the direct effects of
aldosterone antagonists on AF prevention and treatment.
Beta blockers
The effect of
beta-blockers on AR and AF suppression has not been well studied.
Metoprolol and carvedilol can attenuate LV remodeling [163 - 165].
In a double-blind, placebo-controlled study in 394 patients with
persistent AF who underwent cardioversion, metoprolol CR/XL was effective in
preventing relapse into atrial fibrillation or flutter [166].
Statins
Statins are
highly effective and widely used lipid-lowering agents in clinical practice but
they also display a number of pleiotropic properties beyond cholesterol lowering.
These pleiotropic effects include anti-inflammatory, antioxidant, atrial
remodeling attenuation, ion channel stabilization, and autonomic nervous system
regulation [167].
In animal and human studies and in human studies [168 - 171] Simvastatin has been shown to reduce the propensity
to AF possibly through its antioxidant effects [166,
168].
Two studies have evaluated the role of statin treatment in
animal models of HF. Firstly, Shiroshita-Takeshita et al. [168] demonstrated that simvastatin
effectively attenuates atrial structural remodeling and AF promotion in a dog
model of tachycardiomyopathy. Furthermore, Okazaki et al. [172] showed that atorvastatin
attenuates atrial oxidative stress and prevents atrial electrical and
structural remodeling in rat hypertensive HF induced by chronic inhibition of
NO synthesis.
During the past few years, the association between statin
use and development of AF has been examined in different clinical settings [167, 173, 174]. Recent meta-analysis by Liu et al. [167] on this issue showed
different results between randomized clinical trials (RCTs) and observational
studies, suggesting that statins maybe effective in AF prevention, especially
in postoperative patients. Therefore, larger RCTs with longer follow-up periods
and more sensitive methods of AF detection are urgently needed. Recently, a
review by Abi Nasr et al. [175]
provided an overview of the evidence regarding AF management in elderly patients
with CHF. The authors discussed treatments for the underlying disease,
prevention of thromboembolism, rate or rhythm control, as well as
nonpharmacological therapy that may be effective in some patients. In their
review, they noted the possible role of statins in maintaining sinus rhythm in
persistent lone-AF patients.
A post-hoc analysis from the Sudden Cardiac Death in Heart
Failure Trial (SCDHeFT) [176] also demonstrated similar findings. After adjusting for several
confounding factors, statin use was independently associated with a significant
reduction (28%) in the relative risk of AF or atrial flutter during a follow-up
period of 45.5 months.
These results are similar to a study by Hanna et al. [177] which reported the result of a
registry of 25,268 patients with reduced left ventricular ejection fraction (LFEF
<OR = 40%), that demonstrated a 31 % reduction in the odds of AF prevalence
with statin. Recently also, another observational study by Adabag et al. [178] added new evidence to this
issue. There are three large ongoing RCTs (GISSI-HF, CORONA and UNIVERSE) [179] which hopefully will provide us more clear
data with respect to the role of statins in AF prevention in patients with HF.
Vitamin C
Vitamin C is a potent water-soluble antioxidant [180, 181] which has
been recently shown to ameliorate electrical remodeling in animal studies and
to decrease the incidence of postoperative AF in patients undergoing cardiac
surgery [182]. However, no data exists
with respect to AF due to other causes.
It was demonstrated that Vitamin C exerts favourable
electrophysiological effects, ameliorating the shortening of the AERP.
Furthermore, Vitamin C inhibits nitrotyrosine formation in the atrial tissue,
indicating an effective antioxidant action. In a pilot study, the investigators
showed that oral administration of vitamin C significantly reduces the
incidence of postoperative AF in patients undergoing coronary artery bypass
graft surgery (CABG) [182].
A small study in 44 patients who underwent successful
electrical cardioversion of persistent AF with one to one randomization to
either oral Vitamin C administration or no additional therapy, the AF recurred one
week after the successful cardioversion in 4.5% of patients in the Vitamin C
group compared to 36.3% in the control group (P value 0.024). Compared to
baseline values, inflammatory indices decreased significantly in the Vitamin C
group but not in the control group. CRP and fibrinogen levels were higher in
patients who relapsed into AF compared to patients who maintained sinus rhythm [183].
So the role of vitamin C in prevention and treatment of patients with AF is still
unclear and needs further RCTs to evaluate the issue.
Glucocorticoids
Most of the initial studies involving glucocorticoid
therapy in AF were conducted in patients undergoing cardiovascular surgery, and
the results were equivocal. Early studies by Chaney et al. [184] did
not find any significant benefit of steroid administration to patients
undergoing coronary artery bypass graft surgery (CABG); however, Yared et al. [185] in
a study of 216 patients undergoing cardiothoracic surgery, found that
dexamethasone administration perioperatively decreased the incidence of
post-operative AF in the first few days after surgery. Inflammatory markers
(i.e., CRP, IL-6, and so forth) were not measured in this study.
Yared et al. [186] reported on the outcome of 78 patients undergoing combined
CABG and valve surgery who were randomized to receive either dexamethasone or
placebo before surgery. In this study, dexamethasone did not affect the
incidence of perioperative AF. However, it did modulate the release of several
inflammatory and acute-phase response mediators that are associated with
adverse outcomes. Most recently, a group from Finland showed in a prospective,
randomized, double-blind study, that the use of 100 mg cortisone, given
intravenously immediately before cardiac surgery and continued for 3 consecutive
days, significantly decreased the incidence of AF after cardiac surgery by 15% [187].
In a prospective trial which examined the effects of adding
methylprednisolone to propafenone in AF patients undergoing pharmacological
cardioversion to assess the recurrence rate, the methylprednisolone-treated
group experienced an 80% decrease in CRP levels (p < 0.001) within the first
month, which was maintained throughout the duration of the study. This
corresponded to a reduction of AF recurrence from 50% in the placebo group to
9.6% in the methylprednisolone group (p < 0.001) [188].
Unsaturated Fatty Acids (UFAs)
Fish oil, and omega-3 fatty acids in particular, have been
found to reduce plasma levels of triglycerides and increase levels of
high-density lipoprotein in patients with marked hypertriglyceridemia, and a
pharmaceutical-grade preparation has recently received approval from the US
Food and Drug Administration to market for this purpose [189]. However, in both bench
research studies and clinical trials, evidence for clinically significant
antiarrhythmic properties has also been detected in association with omega-3
fatty acid intake [189].
The consumption of fish and fish oils appears in some
large-scale clinical trials to have beneficial effects on survival,
particularly or at least in ischemic substrates and in populations without high
ambient consumption of fish intake [190, 191].
Clinical data supporting antiarrhythmic properties of fish
oils have also been obtained from studies examining surrogate markers of lethal
sustained ventricular arrhythmias, such as incidence of premature ventricular
complexes, and from other arrhythmias, such as atrial tachycardia and atrial
fibrillation [189].
In a double-blind, placebo-controlled study in 65 patients
with cardiac arrhythmias but without evidence of CAD or heart failure, the
incidences of atrial and ventricular premature complexes, couplets, and
triplets were reduced over a 6-month period among those randomized to treatment
with 3 g/day of fish oil providing 1 g of omega-3 fatty acids, compared with
those randomized to 3 g/day of olive oil as a placebo [192]. Similarly, in a study in
40 patients with dual-chamber pacemakers who had paroxysmal atrial
tachyarrhythmia recorded at periodic monitoring, treatment with 1 g/day of
omega-3 fatty acids for 4 months significantly reduced the number of atrial
tachyarrhythmia episodes by 59% (p = 0.037) and the burden by 67% (p = 0.029)
without change in device programming or pharmacologic therapy [193].
During the 4-month follow-up after discontinuation of the omega-3 fatty acid
therapy, both the number of episodes and burden of duration increased to levels
comparable to pretreatment values.
Risk of atrial fibrillation was also inversely associated
with fish intake in a prospective population-based cohort of 4,815 adults aged
≥65 years [194]. A total of 980 cases of incident atrial fibrillation were
diagnosed from hospital discharge records and annual ECGs at 12-year follow-up.
A 28% lower risk of atrial fibrillation was associated with consumption of tuna
or other broiled or baked fish 1 to 4 times weekly compared with intakes of
<1 time monthly. Risk was 31% lower when fish was consumed ≥5 times
weekly. Adjusting for a history of, or the presence of, MI or congestive heart
failure did not change the results. This study also confirmed a significant
relation between plasma phospholipid EPA and DHA concentrations and consumption
of tuna or other broiled or baked fish. In contrast, consumption of fried fish
or fish sandwiches did not significantly influence risk of atrial fibrillation
nor did it relate to plasma phospholipid concentration of EPA and DHA. An
additional trial in atrial fibrillation is ongoing [195].
The incidence of atrial fibrillation has also been reported
to be reduced by fish oils when used following coronary artery bypass surgery [196].
In a prospective study, 160 patients were randomized to receive polyunsaturated
fatty acids (2 g/day) or placebo control, starting 5 days before surgery and
continuing until hospital discharge [196]. The incidence of atrial
fibrillation was 33.3% in the control group and 15.2% in the fish oil group (p
= 0.013), and hospital stay was 1 day shorter in the fish oil group (p =
0.017).
There are several mechanisms through which
n-3 FA could prevent arrhythmias. The n-3 FA is incorporated into myocyte
membranes and may influence ion channel function. N-3 FA inhibits voltage-gated
sodium channels in cardiomyocytes, resulting in a longer relative refractory
period and an increased voltage required for depolarization which reduces heart
rate [197]. N-3 FA also
maintains the integrity of L-type calcium channels, preventing cytosolic
calcium overload during periods of ischemic stress [198]. On other hand n-3 FA improves left ventricular
efficiency and reduces blood pressure which could indirectly decrease heart
rate [199].
Other medications
The interest in reverse remodeling has resulted in the development
of new medications, one of which is Omapatrilat, a vasopeptidase inhibitor. In
a canine model of tachycardia-induced congestive heart failure,
chronic treatment with omapatrilat maintained myocardial ATP, the
high-energy currency, and protected adenylate and creatine kinase
phosphotransfer capacity. Omapatrilat-induced bioenergetic protection
was associated with maintained atrial and ventricular structural
integrity, albeit without full recovery of the creatine phosphate
pool [200].
Alagebrium chloride (ALT-711) is a novel compound that
breaks glucose crosslinks and may improve ventricular and arterial compliance.
In 23 patients with diastolic heart failure, sixteen weeks of treatment with
alagebrium (ALT 17) resulted in a decrease in left ventricular mass and
improvements in left ventricular diastolic filling and quality of life in
patient with diastolic HF [201]. Alagebrium also
improved total arterial compliance in older humans with vascular
stiffening [202, 203]. Whether ALT-711 has the
potential of reversing AR and reducing vulnerability to AF induced by arterial stiffness requires further investigation.
Electrical cardioversion
Conversion of AF to sinus rhythm, whether by electrical
cardioversion or radiofrequency ablation, has been shown to reduce
LA size [204 - 207] and improve LA function [208, 209].
Reversal of electrical remodeling can usually be rapidly achieved, [210, 211] but
vulnerability to the recurrence of AF depends on the amount of
atrial fibrosis and the size of the LA [204]. Normalization of atrial
structure and function generally lags behind the reversal of
electrical remodeling [211].
AF catheter ablation
In 57 consecutive patients with symptomatic
drug-refractory AF, radiofrequency ablation reverted 39 (68%) to
sinus rhythm [206]. This was accompanied by a significant reduction
in LA antero-posterior dimension (4.5 ± 0.3 cm vs. follow-up 4.2 ±
0.2 cm, p < 0.01), and LA volume (59 ± 12 ml vs. follow-up 50 ± 11 ml, p < 0.01) at 3 months follow-up. In contrast, patients who
remained in AF after catheter ablation had increased LA size at 3
months follow-up (4.5 ± 0.3 cm to 4.8 ± 0.3 cm, p < 0.05; 63 ± 7
ml to 68 ± 8 ml, p < 0.05). In a cohort study of 251
consecutive patients with paroxysmal (n=179) or permanent (n=72) AF
who underwent circumferential PV ablation , Paponi et
al. [212] reported no
significant relationship between ablation success and clinical
variables such as age, AF duration, presence of heart disease, or
ejection fraction. Also the LA size did not seem to influence the
outcome in paroxysmal AF patients, whereas in patients with
permanent AF the likelihood for ablation failure was increased in
the presence of LA dilation. They concluded that the fact that their technique
was able to eradicate AF, regardless of its duration or the presence
of structural heart disease, suggests that AF-induced atrial
electrical remodeling may be reversible after the elimination of the
focal source or arrhythmogenic substrate.
Catheter
ablation of AF may also results in recovery of sinus node function in patients
with persistent AF with prolonged sinus pauses [213].
Mitral valve
surgery for valvular stenosis or regurgitation can relieve LA
pressure and volume overload with reduction of LA size and improved
LA function [208]. AF
patients who underwent LA reduction together with mitral valve
surgery had lower AF recurrence after 3 months when compared to
those who did not have LA reduction [214]. Further reduction in LA size was
seen in those who remained in sinus rhythm when compared to those
who had persistent or recurrent AF [214]. Successful surgical ablation of AF (Maze
procedure) has been shown to reduce neurohormonal activation as
evidenced by a decrease in ANP, BNP, and angiotensin II [215, 216].
MAZE III procedure has been demonstrated to reduce LA size and
improve LA transport function and LV diastolic function [217].
AR is an important and increasingly recognizable factor in
the development and maintenance of AF. It is likely that AR is playing an
integral part in the cascade of the events that lead to AF development.
Understanding of AR mechanisms may help in the management
and hopefully prevention of AF. The extent of AF burden reduction and other
adverse clinical outcomes with prevention and reversal of AR remains
to be proven. The measures to prevent or reverse AR at its early stages need to
be studied further with large CRT. If proven successful these measures may
result in significant reduction in the AF burden and its major impact on public
health care.
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