Download Atrial Remodeling and Atrial Fibrillation

Atrial Remodeling and Atrial Fibrillation
Mechanisms and Implications
Stanley Nattel, MD; Brett Burstein, BSc; Dobromir Dobrev, MD
A
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trial fibrillation (AF) is the most common arrhythmia in
clinical practice. It can occur at any age but is very rare
in children and becomes extremely common in the elderly,
with a prevalence approaching 20% in patients ⬎85 years of
age.1 AF is associated with a wide range of potential
complications and contributes significantly to population
morbidity and mortality. Present therapeutic approaches to
AF have major limitations, including limited efficacy and
significant adverse effect liability. These limitations have
inspired substantial efforts to improve our understanding of
the mechanisms underlying AF, with the premise that improved mechanistic insights will lead to innovative and
improved therapeutic approaches.2
Our understanding of AF pathophysiology has advanced
significantly over the past 10 to 15 years through an increased
awareness of the role of “atrial remodeling.” Any persistent
change in atrial structure or function constitutes atrial remodeling. Many forms of atrial remodeling promote the occurrence or maintenance of AF by acting on the fundamental
arrhythmia mechanisms illustrated in Figure 1. Both rapid
ectopic firing and reentry can maintain AF. Reentry requires
a suitable vulnerable substrate, as well as a trigger that acts on
the substrate to initiate reentry. Ectopic firing contributes to
reentry by providing triggers for reentry induction. Atrial
remodeling has the potential to increase the likelihood of
ectopic or reentrant activity through a multitude of potential
mechanisms. This article reviews the types of atrial remodeling, their underlying pathophysiology, the molecular basis
of their occurrence, and finally, their potential therapeutic
significance.
which (like rapid focal firing) produces fibrillatory activity by
virtue of an irregular, fractionated atrial response (Figure 2B).
Fibrillatory activity can also be an intrinsic consequence of
the AF-maintaining mechanism, when AF is maintained by
multiple simultaneous functional reentry circuits (Figure 2C).
Atrial Remodeling and Reentry
Figure 3 illustrates the fundamental determinants of reentry
and the effects of atrial remodeling. Figure 3A shows the
initiation of reentry in a schematic circuit. An ectopic beat
encounters refractory tissue when propagating in one direction, while able to conduct in faster-recovering tissue in the
other direction (“unidirectional block”). For reentry to be
maintained (Figure 3B), the impulse must traverse the entire
circuit slowly enough for all points to regain excitability, ie,
the conduction time has to be greater than the longest
refractory period in the circuit. Conduction time is determined by circuit path length and conduction velocity: Long
path lengths and slow conduction increase circuit time, which
makes it more likely that all points will have recovered
excitability early enough to be reactivated by the reentering
impulse. The recovery of excitability is governed by the
refractory period: Short refractory periods increase the likelihood that tissue will be available for reactivation when the
reentering impulse passes through. The “wavelength,” or
distance traveled by an impulse in 1 refractory period (given
as the product of refractory period and conduction speed), is
a useful concept to relate the determinants of reentry. The
wavelength approximates the shortest path length for reentry
and determines the size of functional reentry circuits. Factors
that reduce the atrial wavelength decrease reentry-circuit
dimensions, which increases the potential number of simultaneous circuits and augments the probability of AF
maintenance.
The ways in which atrial remodeling can promote reentry
are illustrated at the bottom of Figure 3 (for a detailed
description of the underlying physiology, see reference 4).
Atrial refractoriness depends on cardiac action potential
duration (APD), because the Na⫹ channels that govern
cardiomyocyte excitability inactivate when cells are depolarized and require repolarization to ⬇⫺60 mV for channel
Physiological Mechanisms by Which
Remodeling Promotes AF
The mechanisms underlying AF are portrayed schematically
in Figure 2. AF can be maintained by rapid focal firing, which
may itself be regular but result in fibrillatory activity because
of wave breakup in portions of the atrium that fail to follow
1:1 conduction (Figure 2A).3 In addition to their potential role
as an AF driver, ectopic foci can contribute to AF by acting
on vulnerable reentrant substrates to initiate AF. One form of
reentrant AF involves a single, rapidly firing reentrant circuit,
From the Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal (S.N., B.B.), Montreal, Quebec, Canada;
Department of Pharmacology and Therapeutics, McGill University (S.N., B.B.), Montreal, Quebec, Canada; and Department of Pharmacology and
Toxicology (D.D.), Dresden University of Technology, Dresden, Germany.
Correspondence to Stanley Nattel, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8. E-mail
[email protected]
(Circ Arrhythmia Electrophysiol. 2008;1:62-73.)
© 2008 American Heart Association, Inc.
Circ Arrhythmia Electrophysiol is available at http://circep.ahajournals.org
62
DOI: 10.1161/CIRCEP.107.754564
Nattel et al
Mechanisms and Consequences of Atrial Remodeling
Figure 1. General schema representing AF mechanisms and the
role of remodeling.
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availability to return (Figure 3C). APD is determined by the
balance between inward currents (primarily Ca2⫹, which
tends to keep the cell depolarized) and outward currents
(primarily K⫹, which tends to repolarize) during the action
potential plateau. Atrial remodeling can abbreviate APDs and
refractory periods in either way: Sustained rapid atrial activation, as occurs during AF, reduces inward L-type Ca2⫹
current (ICaL) and also enhances outward K⫹ currents.4 These
actions are major contributors to clinically relevant AF
promotion.5,6
Atrial conduction slowing can result from changes in
sarcolemmal (cell membrane) Na⫹ channels, gap junction
channels (connexins), or tissue structure (Figure 3D). Normal
impulse conduction depends on the balance between the
energy for conduction provided by tissue firing (the current
“source”) and the dissipation of this energy by the downstream tissue that has to be fired (the current “sink”). The
energy source for conduction derives from the large phase 0
Na⫹ current (INa). Energy dissipation is minimized by having
good electrical coupling between cardiac cells (provided by
low-resistance gap junction channels that connect cell ends in
a longitudinal fashion) and a high resistance to lateral current
leakage (ensured by a continuous cable-like organization of
cardiomyocyte bundles). Atrial tachycardia appears to suppress expression of the atrial-selective connexin-40.7 There is
also evidence that atrial tachycardia remodeling (ATR) re-
63
duces INa.8 Congestive heart failure (CHF), a strong promoter
of atrial remodeling that facilitates fibrillation, causes atrial
tissue fibrosis that interferes with local atrial conduction by
disturbing the continuous cable-like arrangement of
cardiomyocytes.9,10
Atrial dilation increases the amount of atrial tissue that can
accommodate reentry circuits (Figure 3E). 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.11 Atrial enlargement can occur with both atrial
tachycardia– and CHF-related remodeling12 and is an important clinical predictor of AF maintenance.13 However, atrial
dilation is not essential for the maintenance of CHF-related
AF: After full hemodynamic recovery from CHF, fibrosis
remains, and sustained AF is still inducible, despite the
absence of atrial dilation.10
Atrial Remodeling and Ectopic Activity
Figure 4 illustrates the principal mechanisms that generate
ectopic activity. The spontaneous firing rate of potentially
automatic atrial foci is determined by the slope of phase 4
depolarization, which establishes the time required to reach
threshold potential and generate a spontaneous action potential. If the atrial cell firing rate is slower than the sinus node
rate, no ectopic activity occurs. When the slope of phase 4 is
accelerated, the spontaneous rate increases, and ectopic beats
or sustained tachycardias may occur. Increased atrial expression of ion channel subunits that underlie a potentially
important contributor to phase 4 depolarization, the “funny
current” (I f ), 4 has been observed in both atrial
tachycardia–related14 and CHF-related15 remodeling; however, there has been no direct demonstration of enhanced
automaticity due to accelerated phase 4 depolarization in AF.
Abnormalities in cellular Ca2⫹ handling, particularly Ca2⫹
overload, can cause delayed afterdepolarizations (DADs;
Figure 4B), which are spontaneous hump-shaped depolarizations after full cellular repolarization. DADs differ from
Figure 2. Principal mechanisms that can produce
AF. Reentry involves a vulnerable substrate,
which requires a trigger for reentry initiation. Ischemia, inflammation, and dilation make atria
more vulnerable to AF. AF that results from any
mechanism causes tachycardia-induced remodeling. Even if AF is initially maintained by ectopic
activity or single-circuit reentry in a given patient,
ATR-induced spatially heterogeneous refractoriness abbreviation creates conditions favorable to
multiple-circuit reentry, which may then become
the AF-maintaining mechanism. Thus, multiplecircuit reentry may be a final common pathway
AF mechanism in many patients. RA indicates
right atrium; PVs, pulmonary veins; LA, left
atrium; RP, refractory period; and WL,
wavelength.
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Figure 3. Basis for reentry and
its promotion by remodeling. A,
A premature beat blocks in stillrefractory cardiac tissue but
propagates through tissue that
has already recovered. B, Conditions for maintenance of reentry.
C, Mechanisms involved in
shortening refractoriness. D,
Mechanisms of remodelinginduced conduction slowing. E,
Remodeling-induced atrial dilation promotes AF by increasing
circuit path space so that larger
reentry circuits can be supported (left) and/or a larger number of circuits can be maintained
(right). RP indicates refractory
period.
spontaneous phase 4 depolarization in both shape and mechanism. When DADs become large enough to reach threshold
potential, they cause cell firing, either as the single ectopic
beat illustrated in Figure 4B or as a sustained tachycardia.
Ca2⫹ enters cells through L-type Ca2⫹ channels with each
action potential, so rapid firing rates increase Ca2⫹ entry and
can induce DAD-related tachyarrhythmias (so-called triggered activity). CHF promotes atrial DADs16,17 by enhancing
cellular Ca2⫹ loading.17 Pulmonary veins may be particularly
prone to triggered activity,18 although the evidence for this is
controversial.19
Early afterdepolarizations (EADs; Figure 4C) occur when
action potentials become abnormally prolonged, which allows ICaL to recover from inactivation and to generate abnormal depolarizations at plateau potentials. Although EADs are
most characteristic of Purkinje fiber tissue and long-QT
syndrome ventricular tachyarrhythmias,20 EAD-related arrhythmias can also occur at the atrial level.21,22 Investigators
have yet to demonstrate a clear role for EAD-related mechanisms in atrial remodeling.
Components of Atrial Remodeling
Although many processes can alter atrial properties and
promote AF, animal models and clinical studies have provided insights into 2 major forms of atrial remodeling: ATR,
which occurs with rapid atrial tachyarrhythmias such as AF
and atrial flutter, and atrial structural remodeling (ASR),
which is associated with CHF and other fibrosis-promoting
conditions.
Molecular Basis of Atrial Remodeling
Atrial Repolarization Abnormalities
Figure 4. Basic mechanisms of ectopic impulse generation by
(A) enhanced automaticity, (B) DADs, and (C) EADs.
The recognition that AF alters atrial electrophysiological
properties, promoting AF induction and maintenance, was an
important advance in AF pathophysiology.2,23 AF induces
electrical remodeling primarily by virtue of a very rapid atrial
rate and associated ATR.2,4 Whether AF can produce additional forms of remodeling, particularly when the arrhythmia
Nattel et al
Mechanisms and Consequences of Atrial Remodeling
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Figure 5. Mechanisms underlying ATR. Rapid
atrial rates increase potentially cytotoxic Ca2⫹
loading. Autoprotective ICaL reductions occur via
rapidly developing functional changes (ICaL inactivation) and more slowly developing changes in
gene and protein expression. Decreased ICaL
reduces Ca2⫹ loading but decreases APD. Diminished APD shortens refractoriness and reduces
the wavelength (WL), which allows for smaller
and more atrial reentry circuits, thus making AF
unlikely to terminate. Atrial tachycardia also
increases inward-rectifier currents such as IK1
and IKACh,c, which further reduces APD and promotes AF. RP indicates refractory period; WL,
wavelength.
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remains sustained for prolonged periods, remains uncertain.24
Figure 5 summarizes the molecular mechanisms that underlie
ATR promotion of reentrant AF. ATR abbreviates atrial
refractoriness by decreasing APD, primarily by ICaL downregulation5 but also via increased inward-rectifier K⫹ currents
such as the background current IK1 and a constitutively active
form of acetylcholine-dependent K⫹ current (IKACh).6,25,26 In
addition, ATR impairs atrial contractility, principally by
causing Ca2⫹-handling abnormalities,27 which causes atrial
dilation12 that further promotes reentry.
L-Type Ca2ⴙ Current
The abrupt ⬇8-fold increase in atrial rate with the onset of AF
substantially increases Ca2⫹ loading. Atrial cardiomyocytes
respond by reducing Ca2⫹ influx via ICaL to prevent potentially
cytotoxic Ca2⫹ overload, but reduced ICaL decreases APD and
wavelength, which favors AF perpetuation (Figure 5). Initially, rapid APD shortening occurs because of functional ICaL
inactivation. Sustained AF causes more persistent ICaL decreases, predominantly via downregulation of ICaL poreforming ␣-subunit mRNA28 but possibly also via posttranscriptional mechanisms such as protein dephosphorylation
and breakdown.29,30 In addition, intracellular Ca2⫹ handling is
altered, which contributes to loss of APD rate dependence
and favors reentry-facilitating alternans behavior.31 Some
studies at the protein level have confirmed ATR-induced
reductions in Cav1.2 ␣-subunit abundance,28,32 whereas others suggest unchanged ␣-subunit protein.29,33,34 Investigators
have also detected reduced expression of ␤1, ␤2a, ␤2b, ␤3, and
␣2␦2 accessory ICaL subunits.29,33,35,36 Decreased expression of
the endogenous antioxidant glutathione, the major cellular
reducing agent, accompanies enhanced S-nitrosylation.37
Cav1.2 S-nitrosylation is increased in AF, and exogenously
applied glutathione partially restores AF-related ICaL reductions.37 Thus, oxidative stress could play an important role in
ICaL changes. Recent findings also suggest increased atrial
expression of ZnT-1, a protein originally associated with zinc
homeostasis, in ATR.38,39 ZnT-1 suppresses ICaL via presently
unknown mechanisms.38 Protein kinases attach phosphate
groups to proteins, which causes phosphorylation that controls protein function. Altered regulation of ICaL by src-type
tyrosine kinases may also cause ICaL dysregulation.34
Inward-Rectifier Kⴙ Currents
The cardiomyocyte resting membrane potential is set by
background K⫹ conductances, primarily inward rectifiers, and
becomes more negative in AF.25,26,40 The main background
conductance that controls atrial resting potential is designated
IK1 and is formed by Kir2-family subunits, especially Kir2.1.
AF increases expression levels of Kir2.1 mRNA25,35 and
protein,35 which enlarges IK1.
The inward-rectifier K⫹ current IKACh mediates cardiac
vagal effects: Acetylcholine released from vagal nerve endings activates IKACh, which causes APD abbreviation and
cell-membrane hyperpolarization. Increased vagal activity
strongly promotes AF by stabilizing atrial reentrant rotors,41
and clinical AF often begins under vagotonic conditions.42
ATR alters the IKACh system such that agonist-stimulated IKACh
(as occurs with vagal activation) is reduced, but agonistindependent (“constitutive”) IKACh (IKACh,c) activity is enhanced.6,26,43,44 IKACh,c enhancement is due to increased singlechannel open probability caused by slowed channel closure.44
mRNA and protein expression of Kir3 subunits underlying
IKACh are unchanged in experimental ATR,43,44 whereas in AF
patients, they are decreased,26 so increased IKACh,c is not due to
increased expression of the underlying ion channel subunits.
Inhibition of protein kinase C (PKC) reduces IKACh,c activity,
and PKC⑀ protein is upregulated in AF,45 which suggests that
increased protein kinase C–mediated phosphorylation is important for AF-induced IKACh,c augmentation. IKACh,c blockade
suppresses ATR-induced APD abbreviation and AF promotion,6 which indicates that IKACh,c plays an important role in
arrhythmogenesis.
The ATP-sensitive inward-rectifier K⫹ current (IKATP) is an
important contributor to ischemia-induced electrophysiological abnormalities, and relative ischemia is a potential con-
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Figure 6. Major profibrotic signaling pathways
involved in atrial fibrosis. Interaction between
pathways produces positive feedback that is
important in fibrosis development. ␣␤ Indicates
integrin receptor ␣- and ␤-subunits; Ang II, angiotensin II; AP-1, activator protein-1; DAG, diacylglycerol; ERK 1/2, extracellular signal-related
kinase 1/2; Grb2, growth factor receptor binding
protein 2; JAK, Janus kinase; JNK, c-Jun
N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK 1/2, mitogen-activated/ERK
kinase 1/2; MMP, matrix metalloproteinase;
NF-␬B, nuclear factor-␬B; PKC, protein kinase C;
PDGFR, PDGF receptor; PIP2, phosphatidylinositol bisphosphate; PLC, phospholipase C; PP2A,
protein serine/threonine phosphatase 2A; PTP,
phosphotyrosine phosphatase; Shc, src homologous and collagen protein; SMAD, SMA- and
MAD-related proteins; SOS, son of sevenless
protein; STAT, signal transducers and activators
of transcription; TAK1, TGF-␤1–activated kinase
1; TF, transcription factor; TGF-␤R, TGF-␤
receptor; IP3, inositol 1,4,5-trisphosphate; and
TIMP, tissue inhibitor of matrix metalloproteinase.
tributor to ATR. IKATP amplitude is increased under ischemic
conditions in cells from AF patients,46 whereas IKATP enhancement by agonists such as rilmakalim is reduced.47 Variable
expression changes of the IKATP pore-forming Kir6.2 subunit
observed in AF32,48 underscore the complexity of IK,ATP
regulation.
Voltage-Gated Kⴙ Currents
The transient outward K⫹ current (Ito) is consistently decreased in ATR.4 The functional consequences of Ito downregulation are unclear; however, Ito activates quickly and
produces an outward-current component that can oppose
inward Na⫹ current during the action potential upstroke, so Ito
downregulation may facilitate wave propagation by indirectly
increasing action potential amplitude. Decreased Ito parallels
reductions in both mRNA and protein expression of its
pore-forming Kv4.3 subunit.28 Increased calpain-mediated
proteolysis may also contribute by degrading Kv4.3 proteins.30,49 The Ca2⫹-dependent protein phosphatase calcineurin suppresses Kv4.3 gene transcription via nuclear
factor of activated T-cell (NFAT)– dependent mechanisms,50
and calcineurin activity is increased in AF.51
Reported AF-associated changes in the ultrarapid delayed
rectifier IKur have been inconsistent.4 The role of IKur in atrial
repolarization depends strongly on action potential morphology and is increased with the short-duration, triangular action
potentials that occur in AF.52 Oxidant production is increased
in ATR and AF,53,54 and Kv1.5 currents are inhibited by
oxidation by S-nitrosylation,55 which may contribute to IKur
suppression in AF. The delayed-rectifier currents IKr and IKs
are not changed in experimental ATR,5 and information from
AF patients is lacking, likely because of difficulties in
recording IKr and IKs in human atrial cardiomyocytes isolated
by the “chunk” method.56
Atrial Conduction Abnormalities
Structural Remodeling and Fibrosis
Extensive evidence indicates that structural remodeling, particularly interstitial fibrosis, is an important contributor to the
AF substrate.57 The regulatory mechanisms that underlie
atrial extracellular matrix remodeling are incompletely understood, and the precise signaling pathways that lead to
structural changes may vary in different heart disease paradigms. Several secreted factors are known to be profibrotic.
In addition to their individual effects, they often act synergistically.58 Angiotensin II and transforming growth factor-␤1
(TGF-␤1) are well-established profibrotic molecules, and
recent evidence points to significant roles for platelet-derived
growth factor (PDGF) and connective tissue growth factor
(CTGF). Figure 6 depicts the interplay of various signaling
systems.
Angiotensin II
Angiotensin II mediates cardiac fibrosis in a variety of
cardiac pathologies, including hypertensive heart disease,
CHF, myocardial infarction, and cardiomyopathy. Transgenic
mice with cardiac-restricted ACE overexpression show
marked atrial dilation with focal fibrosis and AF.59 Angiotensin II acts by binding to 2 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.57
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.60 The
mitogen-activated protein kinases ERK (extracellular signalrelated kinase)-1 and -2, p38, and JNK (c-Jun N-terminal
Nattel et al
Mechanisms and Consequences of Atrial Remodeling
kinase) activate transcription factors (Elk-1, c-jun, and c-fos)
that modulate gene expression. In addition, AT1R activation
stimulates phospholipase C. Phospholipase C breaks down
membrane phosphoinositol bisphosphate (PIP2) into diacylglycerol and inositol 1,4,5-trisphosphate (IP3). Diacylglycerol activates protein kinase C, and IP3 causes intracellular
Ca2⫹ 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 kinases60 via dephosphorylating actions of
phosphotyrosine phosphatase and protein phosphatase 2A
and produces antiproliferative and survival-promoting effects
that oppose AT1R-mediated changes. The balance between
the 2 counterregulatory angiotensin II receptor subtypes
(AT1R and AT2R) may have important therapeutic
implications.
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Transforming Growth Factor ␤1
TGF-␤1 is secreted by both cardiomyocytes and fibroblasts
and acts as a primary downstream mediator of angiotensin II
effects in both autocrine (influencing the cell that produces
angiotensin II/TGF-␤1) and paracrine (influencing adjacent
cells) manners.61 Angiotensin II induces TGF-␤1 synthesis,
which potently stimulates fibroblast activity. In turn, TGF-␤1
reciprocally enhances the production of angiotensin II and
additional profibrotic factors to create positive feedback.61
TGF-␤1 acts primarily through the SMAD protein (homolog
of the Drosophila protein “mothers against decapentaplegic,”
or MAD, and the Caenorhabditis. elegans protein, SMA)
pathway to stimulate fibroblast activation and collagen deposition.62 Cardiac overexpression of constitutively active
TGF-␤1 causes selective atrial fibrosis, atrial conduction
heterogeneity, and AF promotion.63
Platelet-Derived Growth Factor
PDGF, a PDGF/vascular endothelial growth factor family
member, stimulates fibroblast proliferation and differentiation. Occupation of PDGF receptors causes them to dimerize,
which activates a tyrosine kinase that forms part of the PDGF
receptor molecule. This tyrosine kinase phosphorylates intracellular domains of the PDGF receptor (autophosphorylation). Autophosphorylation activates PDGF receptors, initiating signaling via mitogen-activated protein kinase, JAK/
STAT, and phospholipase C pathways shared with TGF-␤1
and angiotensin II. PDGF appears to underlie atrium-selective
fibroblast hyperresponsiveness, which may explain why atria
are much more susceptible to fibrotic remodeling than
ventricles.64
Connective Tissue Growth Factor
CTGF is a member of the CCN (cyr61, ctgf, nov) protein
family and a major downstream effector of TGF-␤1 fibrosis
promotion. Areas with active myocardial remodeling show
coordinate CTGF expression with TGF-␤1.65 CTGF is upregulated by both angiotensin II66 and TGF-␤1,67 and it
directly activates fibroblasts.66
Profibrotic Signaling in AF Paradigms
Atrial angiotensin II expression increases rapidly in
tachycardia-induced CHF.68 Renin-angiotensin-aldosterone
67
inhibition by ACE inhibitors,69 AT1R blockers,70 or aldosterone antagonists71 prevents atrial fibrosis and associated AF
promotion. Atrial TGF-␤1 is activated rapidly during
tachypacing-induced CHF,72 and TGF-␤1 inhibition by pirfenidone attenuates remodeling and AF.73 Pathway analysis
has implicated CTGF as a potentially important atrial fibrotic
mediator.74 There is a delicate balance between matrix
metalloproteinases and tissue inhibitors of metalloproteinases
in extracellular matrix degradation, and important changes in
the tissue inhibitor of metalloproteinases/matrix metalloproteinase system are seen in AF.74 –76
Leukocyte infiltration and increased cell death occur in
CHF-induced ASR.72 Oxidant stress is enhanced in AF,53,54
which promotes fibrosis through both cell death and proinflammatory pathways. Rac1 GTPase, a small G-protein
NADPH oxidase regulator that increases oxidant stress, is
upregulated in AF and produces atrial fibrosis–related AF in
mice.77 Statins, which inhibit Rac1 GTPase, prevent ASR,
possibly by antioxidant mechanisms.78
Ion Channels Involved in Atrial Conduction
Gap Junction Remodeling
Relatively little is certain about atrial gap junction remodeling; results reported in the literature vary widely.4 Some of
the discrepancies may relate to differences in the duration of
AF and the nature of the underlying cardiac pathology.79
Spatially heterogeneous connexin-40 remodeling occurs in
the well-established goat AF-remodeling system,7 consistent
with clinical evidence for genetically controlled variability in
connexin-40 as a determinant of AF predisposition.80,81
Sodium Channel Remodeling
INa is reduced in canine ATR, with corresponding decreases in
mRNA and protein expression.8,28 However, studies in AF
patients have not confirmed INa downregulation.35
Ectopic Impulse Formation
Ca2⫹-related triggered activity caused by abnormal Ca2⫹
handling is a strong candidate mechanism to underlie AFgenerating ectopic foci. The main determinants of cellular
Ca2⫹ handling are illustrated in Figure 7. Ca2⫹ enters cells
principally via Ca2⫹ influx through L-type Ca2⫹ channels.
Ca2⫹ entry triggers opening of SR Ca2⫹-release channels
(commonly called ryanodine receptors, or RyRs), which
causes substantial Ca2⫹-induced Ca2⫹ release. The Ca2⫹ that
has entered the cytoplasm during systole is removed in
diastole by 2 primary mechanisms: (1) active pumping back
into the sarcoplasmic reticulum (SR) via SR Ca2⫹-ATPase (or
SERCA), and (2) extrusion across the cell membrane through
the Na⫹-Ca2⫹ exchanger (NCX). NCX transfers 3 Na⫹ ions
into the cell for every Ca2⫹ ion exported, which yields a net
inward (depolarizing) current. SERCA is regulated by the
associated protein phospholamban, which inhibits SERCA
function. Phospholamban phosphorylation reduces its
SERCA-inhibitory capacity and enhances SR Ca2⫹ uptake.
The accessory protein FKBP12.6 binds to and stabilizes RyR
function, which prevents diastolic RyR reopening. Hyperphosphorylated RyRs lose FKBP12.6 binding, which causes
arrhythmogenic diastolic SR Ca2⫹ leak. Any cause of diastol-
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Circ Arrhythmia Electrophysiol
April 2008
Figure 7. Diagram of the cellular Ca2⫹-handling
system. CSQ indicates calsequestrin.
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ic Ca2⫹ leak, including cell Ca2⫹ overload and RyR dysfunction due to FKBP12.6 unbinding, increases diastolic [Ca2⫹]i
and enhances Ca2⫹ extrusion via NCX-mediated exchange.
Enhanced diastolic NCX activity produces a depolarizing
current that causes DADs. Calsequestrin is the main SR
Ca2⫹-binding protein. Ca2⫹ binding by calsequestrin allows
the SR to maintain large Ca2⫹ stores without excessive free
Ca2⫹ concentration. Calsequestrin deficiency impairs SR Ca2⫹
binding and function, which promotes Ca2⫹-release events
and DADs.
Relatively little is known about the molecular basis for
abnormal Ca2⫹ handling in AF. The expression levels of
calsequestrin, RyRs, and phospholamban are preserved in
AF.29,35,82 NCX expression may be upregulated,35,83 which
accelerates Ca2⫹ extrusion from the cytoplasm at the expense
of larger DAD-generating inward currents produced by electrogenic Ca2⫹ removal. The phosphorylation states of several
key Ca2⫹-handling proteins are altered in AF. Protein kinase
A (PKA) and Ca2⫹ calmodulin kinase II (CaMKII) hyperphosphorylation of phospholamban,84 along with decreased
sarcolipin84,85 (another SERCA inhibitor), enhances SR Ca2⫹
uptake, which reduces diastolic [Ca2⫹]i load at the expense of
promoting SR Ca2⫹ overload. Protein kinase A– overexpressing mice have hyperphosphorylated phospholamban and
RyRs and develop AF.86 Besides enhanced phosphorylation
by kinases, phospholamban and RyR2 hyperphosphorylation
may also result from reduced dephosphorylation. Protein
phosphatase 1 (PP1) is a key dephosphorylating enzyme. PP1
function is inhibited in AF by increased activity of an
endogenous inhibitor, phosphatase inhibitor protein-1 (I-1).87
I-1 is activated by protein kinase A phosphorylation. I-1
protein kinase A phosphorylation is increased 10-fold in AF,
to a level that completely inhibits SR-bound PP1 activity.84
IP3 receptor (IP3R2)-mediated SR Ca2⫹ release may amplify
Ca2⫹ leak via RyRs to promote atrial arrhythmogenesis,88 and
IP3R2 protein expression is increased by ATR.89 IP3R2coupled atrial SR Ca2⫹-release enhancement and related
arrhythmogenesis90 may thus be an important contributor to
AF-related ectopic activity.
Figure 8 summarizes the interplay between various Ca2⫹
homeostasis–related factors in AF. We have already discussed the role of Ca2⫹ loading and associated ionic changes
in ATR-induced reentry promotion. Protein hyperphosphorylation due to enhanced I-1, CaMKII, or protein kinase A
function,82,84,86 along with decreased SR-bound PP1 activity,84 causes arrhythmogenic dysfunction of RyR/FKBP12.6
and SERCA/phospholamban complexes. Calmodulin and calcineurin are Ca2⫹-regulated proteins that play key roles in
remodeling, and nitric oxide and NADPH oxidase control
oxidation-state changes that regulate remodeling and Ca2⫹
handling. Both reentry and focal driver mechanisms related to
triggered activity contribute to CHF-induced AF.4,16,17
CaMKII-mediated phospholamban hyperphosphorylation
contributes to SR Ca2⫹ overload in CHF, causing spontaneous
Ca2⫹-release events and DAD-related triggered activity.17
Figure 8. Processes related to Ca2⫹ homeostasis abnormalities
that participate in AF promotion. Components that lead to reentry are indicated by stippled fill and italics. PKA indicates protein
kinase A; NADPHO, NADPH oxidase; and PLN, phospholamban.
Nattel et al
Mechanisms and Consequences of Atrial Remodeling
Potential Therapeutic Implications
Extensive evidence implicates atrial remodeling as an important player in the pathophysiology of AF.2,4 Therefore, atrial
remodeling may have significant therapeutic implications.
Therapeutic Consequences of ATR
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Implications for Traditional Therapeutic Approaches
The changes in ion channel function caused by ATR alter the
response to antiarrhythmic drugs, which in general makes AF
more drug-resistant.91 A poorer response of more prolonged AF
has been shown for both Na⫹ and K⫹ channel52,92,93 blockers.
Early detection and termination of AF increases the clinical
effectiveness of pharmacological cardioversion.92 However,
electrical cardioversion is highly effective in restoring sinus
rhythm irrespective of AF duration, and the value of an early
termination strategy for electrical cardioversion is unclear. Implantable atrial defibrillators permit rapid detection and termination of AF. A strategy of early cardioversion reduces atrial
remodeling,94 prevents atrial dysfunction,95 reduces atrial size,96
and may prolong sinus rhythm maintenance after cardioversion.96,97 However, there is little clinical evidence for the
practical value of an early cardioversion strategy.94
Table.
69
ATR Suppression as an Antiarrhythmic Principle
ATR is a potentially interesting antiarrhythmic drug target. Both
the T-type Ca⫹ channel blocker mibefradil98 and amiodarone99
suppress ATR, whereas ICaL,98 K⫹99, and Na⫹ channel99 blockers
are ineffective, and it has been suggested that ATR suppression
may contribute to the superior efficacy of amiodarone in AF.99
Bepridil, an L- and T-type Ca2⫹ channel blocker, also suppresses
ATR,100 an action that may explain its unusual ability to convert
long-standing AF.101 Inflammation and tissue oxidation are
believed to be important mediators in atrial remodeling.102 Drugs
with antiinflammatory and antioxidant properties, such as glucocorticoids103 and statins,78 suppress ATR and have shown
some clinical value in preventing AF recurrence.104,105 ATR
suppression may thus prove to be a useful principle as either a
primary or adjunct property of new antiarrhythmic drugs. In
addition, understanding the ionic basis of ATR may allow for the
development of novel ionic targets for antiarrhythmic drug
development, such as IKACh,c.6
Therapeutic Consequences of ASR
Initial experiments suggested the potential value of angiotensin-production inhibition in the prevention of ASR-related
ASR-Targeted Therapies for AF
Drug(s)
ACE inhibitors
AT1R blockers
Spironolactone/eplerenone
Pirfenidone
Statins
n-3 PUFAs
HSP inducers
Action
Decrease angiotensin II production
Prevent AT1R stimulation
Aldosterone antagonists
Antifibrotic, antagonizes TGF-␤1 action
HMG-CoA reductase inhibitors, antioxidant and
antiinflammatory actions
Antioxidant, antiinflammatory actions
Augment endogenous HSP production
Summary of Findings
Experimental
Suppressed apoptosis, fibrosis, and AF maintenance in dogs
with ventricular tachypacing–induced CHF
Clinical
Decreased AF in patients with left ventricular dysfunction after
myocardial infarction
Decreased AF in patients with left ventricular dysfunction
Meta-analysis: Prevented AF in patients with left ventricular
dysfunction or hypertrophy
Experimental
Reduced AF promotion and fibrosis in dogs with atrial
tachypacing, rapid ventricular response, and
tachycardiomyopathy
Clinical
Meta-analysis: Prevented AF in patients with left ventricular
dysfunction or hypertrophy
Experimental
Decreased atrial ectopy and fibrosis after MI in rats
Decreased AF maintenance and fibrosis in dogs with
tachypacing-induced CHF
Experimental
Decreased fibrosis and AF vulnerability in dogs with ventricular
tachypacing–induced CHF
Experimental
Reduced AF promotion and fibrosis in dogs with ventricular
tachypacing–induced CHF
Clinical
Four of 5 clinical trials showed reduced AF incidence
Experimental
Reduced atrial fibrosis and AF in dogs with ventricular
tachypacing–induced CHF
Experimental studies
Suppressed AF-substrate in dogs with ventricular
tachypacing–induced CHF
HMG-CoA indicates 3-hydroxy-3-methylglutaryl coenzyme A; PUFAs, polyunsaturated fatty acids; and HSP, heat shock protein.
References
68, 69
106
107
108
109
108
110
111
73
112
113
114
115
70
Circ Arrhythmia Electrophysiol
April 2008
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AF69 and received support from clinical trial evidence.106 A
variety of elements involved in ASR-inducing signaling have
been targeted subsequently in both clinical and experimental
studies, as summarized in the Table.68,69,73,106 –115 The interested reader is referred to recent detailed reviews of this
approach.57,116 The results to date have been promising, but
evidence from randomized prospective, controlled clinical
trials will be needed before the precise role of ASR-targeting
interventions in clinical AF management can be appreciated.
In addition to atrial fibrosis, CHF and many other AFinducing conditions cause atrial dilation. The inhibition of
nonselective stretch-sensitive cation channels suppresses AF
in a rabbit model of stretch-induced AF,117 which suggests
potential additional ionic targets for AF prevention. Finally,
abnormal atrial Ca2⫹ handling occurs in CHF17 and other AF
paradigms82 and may play an important role in AF-initiating
and -maintaining ectopic activity. Compounds such as JTV519, which improve FKBP12.6 binding and stabilization of
RyR function,118 may prove to be prototypes for new drugs
with efficacy against a variety of arrhythmias, including some
forms of AF.
7.
8.
9.
10.
11.
12.
13.
14.
Conclusions
Considerable progress has been made in understanding the
mechanisms underlying atrial remodeling. These insights
have potentially important implications for our understanding
of the pathophysiology of AF and for the development of new
therapeutic approaches.
Acknowledgments
The authors thank France Thériault for excellent secretarial help.
15.
16.
17.
Sources of Funding
This study was supported by the Canadian Institutes of Health
Research, the Quebec Heart and Stroke Foundation, the German
Federal Ministry of Education and Research (Atrial Fibrillation
Competence Network grant 01Gi0204), and the Leducq EuropeanNorth American Research Alliance network award (Fondation
Leducq).
18.
Disclosures
20.
Dr Nattel is listed as an inventor on intellectual property belonging
to the Montreal Heart Institute: “Statin drugs to treat atrial fibrillation” and “Acetylcholine-dependent current as a novel ionic target
for AF.” Dr Dobrev and B. Burstein report no conflicts.
19.
21.
22.
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KEY WORDS antiarrhythmia agents
䡲 ion channels 䡲 remodeling
䡲
arrhythmia
䡲
electrophysiology
Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications
Stanley Nattel, Brett Burstein and Dobromir Dobrev
Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017
Circ Arrhythm Electrophysiol. 2008;1:62-73
doi: 10.1161/CIRCEP.107.754564
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