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Novel Therapeutic Targets in the Management of
Atrial Fibrillation
Abhishek Maan, Moussa Mansour, David D. McManus, Vickas V. Patel, Alan Cheng, Jeremy
N. Ruskin, E. Kevin Heist
Am J Cardiovasc Drugs. 2014;14(6):403-421.
Abstract and Introduction
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia, contributing to increased morbidity and reduced survival through its
associations with stroke and heart failure. AF contributes to a four- to fivefold increase in the risk of stroke in the general population
and is responsible for 10–15 % of all ischemic strokes. Diagnosis and treatment of AF require considerable health care resources.
Current therapies to restore sinus rhythm in AF are suboptimal and are limited either by their proarrhythmic effects or by their
procedure-related complications. These limitations have necessitated identification of newer therapeutic targets to expand the
treatment options. There has been a considerable amount of research interest in investigating the mechanisms of initiation and
propagation of AF. Despite extensive research focused on the pathogenesis of AF, a thorough understanding of various pathways
mediating initiation and propagation of AF still remains limited. Research efforts focused on the identification of these pathways and
molecular mediators have generated a great degree of interest for developing more targeted therapies. This review discusses the
potential therapeutic targets and the results from experimental and clinical research investigating these targets.
Introduction
Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice, contributing to increased morbidity and
reduced survival through its associations with stroke, thromboembolism and heart failure.[1–3] Current antiarrhythmic drugs remain
limited in their efficacy and carry the risk of adverse effects, including proarrhythmia.[4,5] The landmark discovery by Haïssaguerre et
al.[6] that arrhythmogenic triggers in the pulmonary veins contributed to some cases of AF led to the development of pulmonary vein
isolation as an effective interventional therapy for symptomatic drug-refractory AF. Catheter ablation, although efficacious, remains
limited because of its invasive nature and possible procedural complications.[7,8] The current medical and invasive AF rhythm control
strategies necessitate research focused on the identification of newer therapeutic targets to expand available treatment options.
Despite the fact that the pathophysiology of AF has been extensively investigated for almost a century, the precise mechanisms
leading to and maintaining AF still remains elusive.[9] This review focuses on the ° mechanisms of AF that might represent targets
for future novel AF therapies.
Structural and Electrical Remodeling as Therapeutic Targets
Structural and electrical remodeling appear to be the key synergistic mechanisms contributing to the arrhythmogenic substrate
underlying AF. Atrial fibrosis is the hallmark of arrhythmogenic structural remodeling.[10–12] Atrial fibrosis can also be seen as a
convergent pathological end point in a variety of settings, including the aging process,[13] valvular disease,[14] ischemic heart
disease[15] and cardiac dysfunction.[16] Multiple pathways, including the renin-angiotensin-aldosterone system (RAAS), and
proinflammatory factors are potential targets for prevention of atrial fibrosis. Increased collagen deposition has been observed in
patients with lone AF as compared with control patients in sinus rhythm (SR). [17] RAAS has been shown to be a predominant
pathway implicated in myocardial fibrosis in the settings of congestive heart failure (CHF), myocardial infarction (MI), cardiomyopathy
and hypertensive heart disease.[18] The adverse effects of RAAS seem to be predominantly mediated by increased production of
angiotensin II (Ang II) (Fig. 1). Electrical remodeling in AF refers to the changes in electrophysiological properties as a result of AF.
This process is facilitated by the alteration in ion-channel expression and function. This pathophysiological process is believed to
occur as a compensatory mechanism to avoid Ca++ overload which adversely affects the viability of cardiac myocytes. This
maladaptive mechanism (although autoprotective to an extent) further increases the susceptibility to develop sustained episodes of
AF.[19,20]
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Figure 1.
Explaining molecular pathways mediating atrial fibrosis and electrical remodeling changes leading to atrial fibrillation (AF). AGE
advanced glycation end products, Ang II angiotensin II, AP-1 activator protein-1, APD action potential duration, CHF congestive
heart failure, Cx connexin, DM diabetes mellitus, ERK extracellular signal-regulated kinase, HTN hypertension, JNK c-Jun
NH2-terminal kinase, MAP mitogen-activated protein, miRNA microRNA, NADPH nicotinamide adenine dinucleotide phosphate,
NF- B nuclear factor kappa-light-chain-enhancer of activated B cells, PKC protein kinase C, RAAS renin-angiotensin-aldosterone
system, RAGE receptor for advanced glycation end products, ROS reactive oxygen species, TGF 1 transforming growth factor- 1
Electrical remodeling can be envisioned as the result of short-term and long-term processes. The short-term factors which act within
minutes to hours include (a) intracellular Ca++ increase which leads to inactivation of the L-type Ca++ channel and (b) post-translation
modification of ion channels and neurohumoral factors which affect channel function.
The long-term factors which contribute to the electrical remodeling act over a period of days to weeks and include (a) alteration in
gene transcription and protein expression, (b) disturbances in Ca++ homeostasis and (c) increases in the oxidative stress and
fibrosis.
Therapeutic agents which can target these short- and long-term mechanisms facilitating electrical remodeling can be of potential
interest as novel treatment options for suppression of AF.
Angiotensin II-mediated Atrial Fibrosis
Ang II has been well characterized as a profibrotic molecule that is implicated in cardiomyocyte apoptosis and reactive interstitial
fibrosis.[21] Ang II-mediated atrial dilatation with focal atrial fibrosis leading to AF has been observed in transgenic mice with cardiacrestricted angiotensin-converting enzyme (ACE) overexpression.[22] Overproduction of Ang II promotes upregulation of mitogenactivated protein (MAP) kinase signaling, an important downstream mediator that further leads to altered gap-junctional coupling and
conduction properties.[23,24] Ang II has also been demonstrated to mediate cardiac hypertrophy by upregulation of c-Jun
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NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK).[25]
In a mouse model, an increase in the production of Ang II by rapid electrical stimulation was found to be associated with increased
expression of connexin 43 (Cx43). This effect was also associated with upregulation of MAP kinases, suggesting their activation
could play a key role as mediators of adverse electrical and structural remodeling in AF. The final effect of Cx43-mediated alteration
of gap junctions is believed to lead to an alteration in conduction properties that is proarrhythmic.[26] A clinical study has suggested
that a decrease in the ratio of atrial Cx40 to Cx43 is correlated with chronic AF, so this may be secondary to either a rise in Cx43 or
loss of Cx40.[27]
The role of matrix metalloproteinases (MMPs) is also being increasingly recognized in the extracellular matrix (ECM) remodeling
which leads to atrial dilatation and contributes to the pathogenesis of AF. MMP expression and regulation, which are regulated at
various steps, are relevant in matrix turnover and structural remodeling further contributing to AF. MMP-1 is primarily responsible for
degradation of collagen components, and a decrease in its level is associated with an increased degree of atrial fibrosis.[28]
Overexpression of MMP-9 is also observed to be another key process in the pathogenesis of AF via increasing atrial fibrosis.[29]
Ang II has been demonstrated to mediate an increase in the level of MMP-9.[30] Similarly, the profibrotic role of Ang II is further
substantiated by its inhibition in the levels of MMP-1.[31]
Myeloperoxidases (MPOs) have also generated a keen degree of interest in the pathogenesis of atrial fibrosis. The potency of
MPOs to generate reactive oxygen species (ROS) and free radicals has been believed to be central to their role in perpetuation of
AF. The mechanistic link between MPOs and AF development was clarified by Rudolph et al.[32] in their experiments. The
investigators observed that the angiotensin II-treated mpo
mice were protected against the fibrotic remodeling of the atria as
compared with the wild-type mice. The role of MPOs was further confirmed by a dose-dependent increase in the AF vulnerability
when the wild-type and mpo
mice were exposed to the intravenous infusion of MPOs.[32]
In addition to the effects of Ang II leading to structural remodeling of atrial tissue, there is further evidence that it also contributes to
electrical remodeling.[33–35] Ang II has been demonstrated to modulate the inward calcium (ICa) current density by activation of
protein kinase C (PKC) and induction of phosphoinositide-3-kinase (PI3K)-dependent pathways.[36,37] Another recently published
study found that Ang II also increased the L-type calcium channel (LCC) density by upregulating the transcription of LCC messenger
RNA (mRNA) via PKC, ROS and cyclic adenosine monophosphate response element-binding protein pathways.[36]
Therapeutic Interventions Targeting the Renin-angiotensin-aldosterone System
On the basis of the established relationship of RAAS, atrial fibrosis and AF, angiotensin-converting enzyme inhibitors (ACEIs) and
angiotensin receptor blockers (ARBs) have been investigated in the context of primary and secondary AF prevention. Li et al.[37]
investigated the mechanistic effect of ACEIs on atrial remodeling in a canine ventricular tachypacing (VTP)-induced CHF model and
observed that the administration of enalapril was associated with a significant decrease in tissue concentration of Ang II and also
reduced the expression of the phosphorylated form of ERK. The administration of enalapril was also associated with attenuation of
atrial fibrosis and conduction heterogeneity.[37] Similar experiments by Shi et al.[38] also investigated the role of enalapril in
attenuation of atrial fibrosis in a VTP-induced CHF canine model. Atrial fibrosis was estimated with left atrium (LA) functional area
shortening (FAS) (measured on transthoracic as systolic area – diastolic area/systolic area × 100), and AF inducibility was measured
by the effective refractory period (ERP) and AF duration. The treatment with enalapril was observed with attenuation of atrial fibrosis
which further correlated with histological evidence as well as echocardiographic measurement of FAS.[38] Another study, by Saygili
et al.,[39] observed that, in cultured atrial myocytes exposed to stretch, treatment with the ARB losartan prevented stretch-induced
and consequently angiotensinmediated atrial hypertrophy. In addition, losartan also attenuated stretch-induced alterations in I K1, IKur,
and I to density and thereby prevented stretch-induced decreases in action potential duration (APD).
In addition to these salutatory effects of ACEIs/ARBs on atrial fibrosis, Chen et al. [40] demonstrated that these agents also mitigated
local Ang II-induced automaticity in isolated rabbit pulmonary vein tissue preparations and isolated cardiomyocytes. Further
investigations by Shetty and DelGrande [41] also observed that the ARBs irbesartan and valsartan reduced local Ang II-mediated
norepinephrine spillover in rat atria, and thereby led to a decrease in conduction heterogeneity and inducibility of AF. Endothelial
dysfunction also has a pertinent role in the pathogenesis of AF; an increased expression of adhesion molecules mediated by Ang II
has been demonstrated in the fibrillating atria. Goette et al.[42,43] used a rapid atrial pacing model in pigs to show treatment with
ACEIs abrogated the increased expression of adhesion molecules, further supporting the role of ACE inhibition in mitigating the
endothelial dysfunction.
Clinical Studies
A recently published meta-analysis of 14 clinical trials including 92,817 patients demonstrated that RAAS inhibition with an ACEI was
associated with a modest decrease in the incidence of new-onset AF as compared with conventional therapy or placebo [relative
risk (RR) 0.79, 95 % confidence interval (CI) 0.62–1.00, p = 0.05]. ARBs showed a similar effect in reduction of AF (RR 0.78, 95
%CI 0.66–0.92, p = 0.009).[44] The authors of this meta-analysis acknowledged that although there was a modest degree of benefit
of RAAS inhibition in the prevention of AF, the overall quality of evidence of these findings was low.
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Data from the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study further support the benefit of RAAS
antagonism for prevention of AF. The LIFE investigators showed that, despite similar reductions in blood pressure, patients in the
losartan arm had a lower incidence of new-onset AF than patients in the atenolol arm (6.8 vs. 10.1 per 1,000 patient-years; RR 0.67,
95 % CI 0.55–0.83, p<0.001).[45] Further analyses from this study also showed that a greater degree of regression of left ventricular
hypertrophy (LVH) with the use of losartan as compared with atenolol might also be responsible for prevention of AF. A greater
degree of LVH regression might contribute to greater improvement in left atrial hemodynamics and dilatation. These additional
mechanisms also seem pertinent in the beneficial effects of losartan in the LIFE study. Similarly, in a broad CHF patient population,
candesartan was found to be more effective in prevention of new-onset AF as compared with placebo [5.55 % patients developed
new-onset AF in the candesartan arm vs. 6.74 % in the placebo arm; odds ratio (OR) 0.81, 95 % CI 0.66–0.99, p = 0.048] in the
Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trial.[46]
Contrary to these beneficial effects of ACE inhibition particularly for prevention of new-onset AF, the results of the Gruppo Italiano
per lo Studio della Sopravvivenzanell'Infarto Miocardico-Atrial Fibrillation (GISSI-AF) trial showed that valsartan did not reduce the
recurrence rates for AF in patients with pre-existing cardiovascular diseases.[47] The Atrial Fibrillation Clopidogrel Trial with
Irbesartan for Prevention of Vascular Events (ACTIVE-I) trial investigated the impact of irbesartan on a composite of adverse
cardiovascular events (stroke, MI, death from vascular causes as the primary outcome). The rate of this outcome was observed to
be similar for both irbesartan and placebo [5.4 % per 100 patient-years in each; hazard ratio (HR) with irbesartan 0.99, 95 % CI
0.91–1.08, p = 0.85]. The use of irbesartan also did not have a significant effect in reducing the rate of hospitalization due to heart
failure in this study.[48] The Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) trial aimed to investigate the impact
of olmesartan on the AF burden (measured by transtelephonic electrocardiograms) in patients with paroxysmal AF without any
coexisting structural heart disease. During a 12-month follow-up period, the use of olmesartan was not observed to have any
beneficial effect in decreasing AF burden (p = 0.77). Similarly, the secondary outcomes of the trial (quality of life, time to develop
persistent AF, and rate of cardiovascular hospitalizations) were also not affected by the use of olmesartan as compared with
placebo.[49]
The lack of clinically beneficial effects with the use of ARBs for prevention of AF suppression was further substantiated by the
results of the Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II). In this open-labeled randomized trial,
symptomatic and asymptomatic recurrences of AF episodes were assessed in patients with paroxysmal AF who received either
candesartan or amlodipine. At a follow-up period of 1-year, the frequency of total AF was 2.1 ? 3.8 days/month in the candesartan
group as compared with 2.4 ± 4.4 days/month in the amlodipine group, p = 0.51. The use of candesartan was also not found to have
a significant effect on the frequency of cardiovascular events, left atrial dimensions and subsequent development of persistent
AF.[50]
Aldosterone Antagonists
Aldosterone antagonists have also been investigated in both pre-clinical and clinical studies as potential therapeutic antagonists of
the RAAS system. The role of these agents might be even more relevant in AF, considering the evidence of intracardiac production
of aldosterone, which has been shown to upregulate the gene expression of ACE[51] and may also have a direct role in fibrosis[52]
and electrophysiological changes.[53] There is also evidence from clinical studies which supports the finding that patients with AF
have a relatively higher serum level of aldosterone as compared with patients in SR,[54] and these levels decrease after SR is
restored in AF patients.[55]
Milliez et al.[56] investigated the role of a 1-month treatment regimen of spironolactone alone and in combination with lisinopril and
atenolol in a 3-month post-MI rat model using echocardiographic and P-wave measurements on electrocardiogram. Spironolactone
was observed to mitigate the atrial fibrosis measured by increased LA mass and also decreased the post-MI elevation in left
ventricular end-diastolic pressure, which was measured as a covariate in this study. The authors in this study also speculated a
superior efficacy of spironolactone, particularly in reducing the atrial fibrosis once it had occurred.[56] This observation could be
potentially explained by the fact that once atrial fibrosis has ensued, it might become relatively less sensitive to the hemodynamic
alterations and to the activity of the RAAS agents.[57] Another study, by Shroff et al.,[58] further elucidated the role of eplerenone in a
VTP-induced CHF model. The results from this study indicated that selective aldosterone blockade using eplerenone was
associated with improvement in diastolic dysfunction and reduced AF inducibility by prolongation of atrial ERP. The investigators in
this study speculate that the prolongation of atrial ERP with the use of eplerenone could be due to its additional ionic-modulation
properties.[58]
Clinical Studies
These findings were further supported by a retrospective analysis of the Eplerenone in Mild Patients Hospitalization and Survival
Study in Heart Failure (EMPHASIS-HF) study. In this study, randomization to eplerenone was observed to be associated with a
decreased incidence of new-onset AF as compared with placebo (2.7 vs. 4.5 %, HR 0.58, 95 % CI 0.35–0.96, p = 0.034).[59]
Another recently published study, by Ito et al.,[60] investigated the efficacy of eplerenone on clinical outcomes of 161 patients with
long-standing persistent AF who underwent radio-frequency ablation; after a follow-up period of 24 months, eplerenone was
observed to be associated with a greater incidence of freedom from AF (60 vs. 40 % in the non-eplerenone group, p = 0.011).
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Although these data are from small observational studies, spironolactone may be potentially useful in reducing AF recurrences,[61]
AF burden and hospitalizations necessitated by cardioversion.[62] Further studies focused on investigation of additional mechanisms
of aldosterone antagonists and larger clinical studies validating these findings are still needed to make a compelling
recommendation for encouraging the use of these agents for prevention of AF ( ).
Table 1. Pre-clinical mechanisms and data from clinical studies on ACEIs, ARBs and aldosterone antagonists
Agent
Mechanism of action
Clinical evidence
References
ACEIs
Decrease Ang II production
Meta-analysis demonstrated benefit in reducing new-onset AF [44]
ARBs
Attenuates Ang II-mediated
downstream effects
(a) Beneficial effects seen in LIFE and CHARM trials,
negative evidence from GISSI-AF trial
[45–49]
(b) Lack of beneficial effect in reducing cardiovascular
outcomes in patients with AF in the ACTIVE I trial (irbesartan)
(c) Lack of efficacy in suppressing AF in the ANTIPAF trial
(olmesartan)
Aldosterone
antagonists
Decrease cardiac
production of aldosterone
Reduction in new-onset AF with eplerenone in EMPHASIS-HF
[59, 60]
trial, decreased AF recurrences after catheter ablation
ACEI angiotensin-converting enzyme inhibitor, AF atrial fibrillation, Ang II angiotensin II, ARB angiotensin receptor blocker
Effect of Pioglitazone on Atrial Fibrosis
Recently, there has been a great degree of interest in the role of peroxisome proliferator-activated receptor (PPAR- ) agonists. The
activation of these receptors has been observed to reduce the expression of pro-inflammatory cytokines such as interleukin (IL)-1
and IL-6, inducible nitric oxide, tumor necrosis factor- (TNF- ) and MMP-9 by inhibition of transcription factors which bind to nuclear
factor kappa-light-chain-enhancer of activated B cells (NF- B) in monocytes and macrophages.[63,64] Similarly, this receptor also
leads to a decreased production of TNF- by downregulating the function of NF- B.[65] Shimano et al.[66] investigated the role of
pioglitazone in comparison and combination with candesartan for its role in mitigation of atrial fibrosis and prevention of AF based on
a VTP-induced CHF rabbit model. The investigators observed that the treatment with pioglitazone was associated with attenuation of
atrial fibrosis, significant reductions in the interatrial activation time and duration of AF as compared with controls. These changes in
the pioglitazone group were comparable with those in the candesartan group. In the group which received the combination of
pioglitazone and candesartan, no additional reduction in attenuation of atrial fibrosis and reduction in AF was observed. The findings
that both pioglitazone and candesartan decreased the expression of transforming growth factor- 1 (TGF- 1), TNF- and the
phosphorylated form of ERK suggest that they might have a common underlying antifibrotic mechanism.[66] Another study, by Xu et
al.,[67] showed that pioglitazone reduced age-related atrial fibrosis and AF propagation by upregulating the gene expression of
antioxidant molecules such as superoxide dismutase (SOD-2) and heat shock protein (hsp 70) and by preventing hyperactivity of
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase responsible for free-radical generation. This study also highlighted
the role of pioglitazone in decelerating cardiac apoptosis which was predominantly mediated by the activation of bad signaling
pathway molecule via the phosphoinositide-3 kinase pathway. Pioglitazone also led to inhibition of caspases-3 and 9, which are also
relevant molecules implicated in cardiac apoptosis.[67] A recently published study by Gu et al.[68] on cultured atrial myocytes
demonstrated that pioglitazone attenuated Ang II-induced connective tissue growth factor (CTGF) expression and proliferation of
atrial fibroblasts. This study also demonstrated these effects were mediated by at least partial if not complete inhibition of the
TGF- 1/Smad2/3 pathway.[68] Further investigations, by Takahashi et al.,[69] also demonstrated the beneficial effect of pioglitazone
in attenuating hypertrophy-mediated atrial fibrosis by repression of monocyte chemoattractant protein-1, which was observed to be a
key profibrotic molecule involved in atrial fibrosis.
Clinical Studies
Gu et al.[70] also investigated the role of pioglitazone in 150 patients with type 2 diabetes mellitus (DM) who underwent catheter
ablation for drug-refractory paroxysmal AF. After a mean follow-up duration of 22.9 ± 5.1 months following index ablation, SR was
maintained in 44/51 patients (86.3 %) in the pioglitazone group versus 70/99 patients (70.7 %) in the control group (p = 0.034).
Transforming Growth Factor- 1 (TGF- 1)
TGF- 1 is another key mediator of atrial fibrosis which is also observed to be a primary downstream mediator of Ang II effects.
[71,72] Pre-clinical studies based on treatment of human atrial tissue with Ang II have demonstrated an overexpression of TGF- 1
mRNA.[73,74] Furthermore, there is accumulating evidence that Ang IImediated overexpression of TGF- 1 could also be facilitated
by multiple mechanisms such as overexpression of TGF- 1 mRNA[74] and activation of MAP kinase by either Ca++- or
PKC-dependent pathways.[75] TGF- 1 predominantly acts through the mothers against decapentaplegic (Drosophila protein)
(SMAD) signaling pathway to stimulate collagen production.[76,77] An increased atrial expression of TGF- 1 has been observed in
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the VTPinduced CHF animal model.[78] Targeted overexpression of TGF- 1 in mice has been observed as a key mediator of
selective atrial fibrosis, conduction heterogeneity further leading to AF propagation.[79,80]
Therapeutic Interventions on TGF- 1
Considering the central role of TGF- 1 as a mediator of atrial fibrosis, it is intuitive to believe that anti-TGF- 1 therapies could be
potentially useful to inhibit atrial fibrosis and hence prevent the development of AF. Pirfenidone, 5-methyl-1-phenyl-2 (1H)-pyridone,
was investigated by Lee et al.[81] in a VTP-induced CHF canine model. Induction of CHF was found to be associated with increased
degree of atrial fibrosis and atrial conduction heterogeneity as compared with controls, whereas the treatment with pirfenidone
resulted in decreased atrial fibrosis, conduction heterogeneity and hence reduced AF vulnerability. Furthermore, pirfenidone was
also found to reduce the TGF- 1-mediated downstream expression of various MAP kinases studied on cytokine profile in this
study.[81] Treatment with pirfenidone was also observed to be associated with a decrease in MMP-9 and tissue inhibitor of
metalloproteinase-4 levels, further supporting its potential as an antifibrotic agent. Yamazaki et al.[82] also demonstrated the
beneficial effects of pirfenidone in an Ang II-mediated cardiac hypertrophy model in mice and demonstrated its efficacy in mitigating
Ang II-mediated perivascular and interstitial fibrosis and TGF- 1 expression; additionally, pirfenidone also attenuated the expression
of mineralocorticoid receptors. Various other models investigating pulmonary fibrosis have also studied the antifibrotic role of
pirfenidone.[83–85] In the future, more robust pre-clinical and clinical studies are likely to help clarify the relevance of pirfenidone as a
novel agent for prevention of AF ( ).
Table 2. Role of various potentially therapeutic agents based on experimental studies
Therapeutic
agent
Mechanism of
action
Comments
References
Pioglitazone
PPAR- agonist
Decreases pro-inflammatory cytokine (TNF- , IL-6 and MMP-9)
production
[63–70]
Pirfenidone
Anti-TGF- 1 agent
Decreases TGF- 1-mediated activation of kinases and attenuates
atrial fibrosis
[81–85]
Statins
Antioxidant,
pleiotropic effects
Decrease Ang II-mediated free-radical production and inhibit
rac1-mediated activation of NADPH oxidase
[151]
PUFAs
Modulates membrane Counteract arrhythmogenic effect of atrial stretch by modulating
fluidity
membrane proteins and regulate MAP kinase activity
[152–155]
Ang II angiotensin II, IL-6 interleukin-6, MAP mitogen-activated protein, MMP matrix metalloproteinase, NADPH nicotinamide
adenine dinucleotide phosphate, PPAR- peroxisome proliferator-activated receptor, PUFA polyunsaturated fatty acid, TGF- 1
transforming growth factor- 1, TNF- tumor necrosis factorRecent investigations by Barter et al.[86] have also identified histone deacetylases (HDACs) as regulatory mediators of the
profibrotic function of TGF- 1 at the gene-expression level. Several genes (such as smad2, 3 and 7) which regulate matrix turnover
in response to TGF- 1 are selectively regulated by HDACs. Selective inhibition of HDACs was demonstrated to suppress the
induction of profibrotic signals (disintegrin and metalloproteinase-12) which are driven by TGF- 1.[86] In addition, Liu et al.[87]
showed that global HDAC inhibition could reverse atrial fibrosis and inducible atrial arrhythmias. In this study, mice that were ~3
months old already had established atrial fibrosis and inducible atrial arrhythmias. After treatment with the global HDAC inhibitor
trichostatin A daily for 2 weeks, the percentage of atrial fibrosis and arrhythmia burden were reduced in the experimental group when
compared with wild-type littermate mice. Interestingly, the degree of ventricular hypertrophy and diastolic dysfunction were not
affected by the HDAC inhibitor, but along with a reduction in atrial fibrosis, there was an increase in Cx40 gap junctions in the atrium
of mice treated with HDAC inhibitor. These observations support the role of HDACs as key mediators of profibrotic proliferation
signal in fibroblasts which are activated by TGF- 1.
While it is intuitive to be optimistic about the role of antifibrotic therapy in AF, it is also important to be cognizant about the limitations
of the role of atrial fibrosis in pathogenesis of AF. There is also a further need to better understand the relationship between the
extent of atrial fibrosis and the threshold for AF initiation. Knowledge of a precise mechanism by which atrial fibrosis leads to
conduction heterogeneity and development of AF will help clarify whether atrial fibrosis is the central event in the pathogenesis of
AF.
MicroRNAs
Recently there has been a rapid evolution in the field of microRNAs (miRNAs) as novel mediators of various cardiovascular
conditions at the molecular level. miRNAs are non-coding RNAs that are 19–25 nucleotides in length that repress gene expression
at the post-transcriptional level by acting on the 30-untranslated region of RNAs.[88,89]
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As discussed in the previous sections, structural atrial remodeling results from an imbalance between the anti- and profibrotic
pathways; similarly, certain miRNAs can be visualized as mediators of antifibrotic and others as mediators of profibrotic processes.
Xu et al.[90] investigated the expression profile of various miRNAs in three groups of dogs (adult and aged dogs in SR and aged
dogs with persistent AF induced by rapid atrial pacing) and observed that, as compared with adult dogs, the expression of
miRNA-21 and 29 was significantly increased in the older dogs whereas the expression of miRNA-1 and 133 was downregulated;
when the aged SR group was compared with the aged AF group, miRNA-1, 21 and 29 showed an increased expression, while
miRNA-133 showed downregulation in the aged AF group. The investigators in this study also observed that miRNA-1 was also
implicated in increased apoptosis by repressing the levels of hsp 60 and hsp 70 and this proapoptotic effect of miRNA-1 was
attenuated by miRNA-133 through deactivation of caspase-9.[90]
Another recently published study, by Dawson et al.,[91] using a VTP-induced HF model in dogs, observed that the atrial expression
of miRNA-29 was downregulated in AF as compared with SR. The mechanisms linking miRNA-29 to AF were further clarified in a
knockdown model where the absence of miRNA-29 was associated with upregulation of collagen producing genes (COL1A1 and
COL3A1).[91] Upregulation of miRNA-21 in rat atria was associated with atrial fibrosis and subsequent development of AF. These
findings were confirmed by the lesser amount of atrial fibrosis in an atrial miRNA-21 knockdown model.[92] miRNA-21 promotes
cardiac fibrosis by upregulating the activity of cardiac ERK and MAP kinases through the inhibition of sprouty homologue 1.[93]
The role of miRNAs has also been thought to be particularly relevant in mediating the process of electrical remodeling. From a
conceptual standpoint, it is now widely agreed upon that electrical remodeling of atrial tissue results in shortening of atrial ERP, which
further favors the generation of AF due to re-entry. A simplified way to visualize this process could be an imbalance mediated by two
important alterations.
The first change is the reduction of L-type Ca++ (I CaL) and transient outward K+ (Ito) currents which are primarily responsible for
decreasing the plateau phase of the atrial action potential.[94,95] The second relevant process involved with shortening of the
terminal phase of the action potential is an increase in the inward rectifier K + current (I K1).[96] In a study by Yue et al.[97] investigating
the ionic mechanisms underlying propagation of AF in a canine model, the alteration in current density was found to be related to the
reduction in functional channels without any alterations in the other properties of ion channels such as voltage, time and frequency
dependence. These findingswere further supported by another study, by Gaborit et al.,[98] which compared the ion-channel gene
expression profiles in patients with AF and SR and observed that AF patients had a disproportionate upregulation in functional Kir
2.1 current compared with the overexpression of its codingmRNA(twofold increase vs. 20 %increase), suggesting that
post-transcriptional modification of the Kir 2.1 channel subunit may be responsible for these changes. The results of these two key
hypothesis-generating studies were further validated in a mouse model of AF by Yu et al.,[99] who reported an increased expression
of miR-328 in AF as compared with SR and forced overexpression of miR-328 led to an increased propensity to develop AF
mediated by diminished L-type Ca++ current, which was mediated by downregulation of the genes coding (CACNA1C and
CACNB1) the cardiac L-type Ca++ channel by miR-328.
Clinical Studies
A recently published investigation by McManus et al.[100] based on analysis of the Framingham study reported that circulating
miRNA-328 levels were significantly lower in the patients with prevalent AF as compared with patients without AF (8.76 vs. 7.75, OR
1.21, 95 % CI 1.09–1.33, p<0.001).
The mechanistic basis of miRNAs leading to ionic remodeling and thereby shortening of atrial APD was investigated by Luo et
al.,[101] who observed that miR-26 was downregulated in samples from animals and patients with AF accompanied by an
upregulation of I K1/KIR 2.1 protein. Investigations by Ling et al.[102] have also implicated the role of miRNA-499 in the pathogenesis
of AF; on the basis of the comparison of miRNA expression profile in AF versus SR patients, the levels of miRNA-499 were
observed to be upregulated in AF as compared with SR patients. Upregulation of miRNA-499 was also accompanied by
downregulation of the small conductance calcium-activated potassium channel-3 (SK3), which was further confirmed by transfection
experiments with miRNA-499. While the exact role of the SK3 channel is still under investigation, it is believed to be involved with
electrical remodeling changes mediating the development of AF. Apart from being implicated in these two fundamental pathways of
structural and electrical remodeling leading to AF, miRNAs are also being investigated as mediators in the cardiac apoptotic pathway
in response to oxidative stress (miRNA-133).[103] Based on data from these studies, it is conceivable that various miRNA molecules
could very well turn out to be not only therapeutic targetsbut also potential biomarkers in AF ( ).
Table 3. Role of various miRNAs in the pathogenesis of atrial remodeling leading to AF
miRNA
Function and role in AF
References
miRNA-1
Upregulated in AF, increases apoptosis in cardiomyocytes by repressing heat shock proteins (hsp
60 and hsp 70)
[90]
miRNA-21
Repression of sprouty-1 and upregulation of phosphorylated ERKs
[92, 93]
miRNA-29
Downregulated in AF leading to increased expression of collagen genes (COL1A1 and COL3A1)
[91]
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miRNA-133
Downregulated in AF, attenuates the proapoptotic function of miRNA-1 by deactivation of
caspase-9, some relevance in oxidative stress-mediated AF
miRNA-328
Increased expression of miR-328 in AF, diminished L-type Ca++ current mediated by
[99, 100]
downregulation of the genes coding (CACNA1C and CACNB1) decreasing APD and promoting AF
miRNA-499
Increased expression in AF leading to downregulation of function of SK3 channels leading to
decrease in repolarization currents
[103]
[102]
AF atrial fibrillation, APD action potential duration, ERK extracellular signal-regulated kinase, miRNA micro ribonucleic acid, SK3
small conductance calcium-activated potassium channel-3
Role of Ion Channels as Potential Targets in Atrial Fibrillation (AF)
Normal cardiac electrical activity (reflected by APD) is facilitated by the proper functioning of the ion channels. Electrical remodeling
reflected by a reduction in APD is a key process in promoting initiation and propagation of AF. The intracellular resting potential of
atrial cells is maintained at a negative value by a large resting K+ permeability, which in turn is governed by the principal cardiac
inward-rectifier current I K1. I K1 is composed of Kir 2.1 subunits which are overexpressed in chronic AF.[104,105] Another inwardrectifier K+ current, I KACh, is upregulated by vagal activation and mediates the effects of acetylcholine. The upregulation of both
these currents leads to shortening of APD and thereby provides an electrical basis for AF pathogenesis.[106] The increased
activation of IKACh is mediated by its reduced inhibition by the protein kinase (PKC isoform ).[107]
Upon activation, the cells are depolarized by the rapid entry of Na+ through the Na+ channels, which generates a large inward-flowing
current (I Na). Following this phase, the cells undergo brief repolarization, which is mediated by the outward flow of K+ via the Ito
channel. This phase is followed by the plateau phase, during which there is a balance between the inward current I CaL (mediated by
Ca++ entry through the L-type Ca++ channel). Reduction in ICaL contributes to shortening of APD and is of particular relevance in the
pathogenesis of re-entry-mediated AF.[108] The plateau phase of APD is also of key interest in the pathogenesis of AF mediated by
altered impulse formation, which is believed to be caused by ''afterdepolarization.'' Early afterdepolarizations (EADs) are a result of
an impairment of action potential repolarization which leads to a prolongation of the plateau phase. These EADs are mediated by
either an excess of inward currents (ICaL or late INa) or decreased activity of I to which mediates early repolarization.[109]
The plateau phase is followed by the late repolarization which is mediated by the rapid (IKr) and slow (I Ks ) K+ currents. Additionally,
this phase is also mediated by the ultrarapid delayed rectifier current (I Kur) in the atrial cells. The activity of I Kur in turn is mediated by
the Kv 1.5 channel. This phase is also of relevance in the role of delayed afterdepolarizations (DADs), which are initiated by the
activity of Na+-Ca++ exchanger (NCX) and an abnormal Ca++ leak from the subcellular stores (i.e., sarcoplasmic reticulum). The
DADs are further mediated by the dysfunction of ryanodine receptor 2 (RyR2) in the patients with AF.[110] In the experimental
models of AF, hyperphosphorylation of RyR2 by protein kinase A (PKA) seems to contribute to both an increased activation as well
as its increased sensitivity to cytosolic Ca++ [111–113] (Fig. 2, ).
Table 4. Role of various ion-channels in various phases of action potential and pathogenesis of AF
Ion
channel
Role in action potential
Relevance in pathogenesis of AF
IK1
Maintains the negative resting
membrane potential
Increased in AF because of increased expression of Kir 2.1, which could be
mediated by decreased expression of miR-26 and miR-101
IKACh
Inward current, mediates vagal
effects
Increased expression detected in AF, believed to play a relevant role in vagally
mediated AF
Increase mediated by enhanced open probability of Kir 3.1 (GIRK1) and Kir 3.4
(GIRK2), which is mediated by reduced inhibition by PKC (PKC ) and
increased activation of PKC
INa
Responsible for rapid action
potential depolarization (Phase
0)
Decreased INa leads to slowing of conduction and promotes re-entry-mediated
AF
Ito
Mediates brief rapid
repolarization phase (Phase 1)
Definite role in the pathogenesis of AF remains unclear, speculated to be atrialselective target, also believed to be a mediator in AF-related ionic remodeling
ICaL
Mediates the plateau phase,
inward Ca++ current (Phase 2)
Phosphorylated form observed to hyperactive and hypersensitive to cytosolic
Ca++
PKA-mediated hyperphosphorylation of RyR2 is seen in AF models
Reduction favors shortening of APD and AF perpetuation
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IKs
Slow component of delayed
rectifier current (Phase 3)
Alterations in delayed-rectifier current speculated to be involved in AF,
reduction in IKs could lead to shortening of APD and promote AF
IKr
Rapid component of delayed
rectifier current (Phase 3)
Contributes to the delayed-rectifier current and thus could promote
development of AF
If
Contributes to Phase 4
Limited data, unclear role
NCX
Contributes to Phase 4 and also
Mediates the initiation of DADs, increased expression is reported in AF
implicated in Ca++ homeostasis
AF atrial fibrillation, APD action potential duration, DADs delayed afterdepolarizations, GIRK G-protein coupled inwardly-rectifying
potassium channels, NCX Na+-Ca++ exchanger, PKA protein kinase A, PKC protein kinase C, RyR2 dysfunction of ryanodine
receptor 2
Figure 2.
Role of ion channels in action potential duration and pathogenesis of atrial fibrillation (AF). PartArepresents the role of various ion
channels in various phases of action potential. Afterdepolarizations occurring after full repolarization [delayed afterdepolarizations
(DADs); part B] and incomplete repolarization [early afterdepolarizations (EADs); part C] mediate the pathogenesis of AF by causing
premature beats. Conditions which promote spontaneous re-entry of electrical impulses are shown in the figure D. Re-entry is
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initiated by a premature beat (indicated by a yellow star), acting on interconnected zones of tissue with two alternate conduction
pathways that have different refractory periods. The numbers 1, 2, and 3 in part D represent different sites of electrical activation.
(Modified and reproduced with permission from Dobrev et al. [110])
Abnormal release of Ca++ from sarcoplasmic reticulum has also been demonstrated to be a local trigger generator and also
mediates re-entry leading to AF.[114] This release of intracellular Ca++ is dynamically regulated by the frequency of open state of
RyR2. The probability of open state of RyR2 is modulated by the accessory binding proteins (FK506 binding protein 12.6,
calmodulin, sorcin) as well as posttranslational modifications (especially phosphorylation). Ca++/calmodulin-dependent protein
kinase II (CaMKII) is an important mediator of phosphorylation of RyR2. The phosphorylated form of RyR2 facilitates an open state
of RyR2 and thereby governs the abnormal Ca++ release and re-entry driven AF.[115]
Azimilide
Azimilide is a class III multichannel blocker which has been demonstrated to have electrophysiological effects on the repolarization
phase of cardiac APD. At varying concentrations, it was observed to have inhibitory action on I Kr, IKs and I KACh.[116,117]
Azimilide showed initial promising results in suppressing AF in the four randomized, placebo-controlled clinical trials [referred to as
the Supraventricular Arrhythmia Study (SVA 1–4)].[118] However, the subsequent studies such as the Azimilide-CardiOversion
Maintenance Trial-II (A-COMETII)[119] and the clinical trial by Page et al.[120] did not show a significant benefit of azimilide in
suppressing AF. Considering its lack of beneficialfindings inAFprevention, the future development of azimilide has been
discontinued.
JTV-519/K201/Multichannel Blocker
JTV-519/K201 is a multichannel blocker which inhibits the activity of I Kr and I KACh [121] and also stabilizes RyR2.[122] In a pre-clinical
study by Nakaya et al.,[123] JTV-519 was observed to decrease the prolongation in APD induced experimentally by carbachol. The
addition of JTV-519 to the guinea-pig atrial cells in this study also increased the carbachol-induced shortening in ERP. Both these
mechanisms contribute to the efficacy of JTV-519 in mitigating the perpetuation of AF.[123] The antiarrhythmic potential of JTV-519
was further demonstrated on the activity of pulmonary veins in isolated cardiomyocytes by Chen et al..[124] This was mediated by its
inhibition of I CaL and NCX currents in the pulmonary veins [125] ( ).
Table 5. Summary of various investigational agents, respective targets and their developmental status
Investigational agent
Mode of action/target
channels
Development
status
Comments
Multi-channel blocker
JTV-519/K201 (Aetas
Pharma) [122–125]
Ranolazine [128, 129]
Multi-channel blocker, also
Phase II
stabilizes RyRs. Blocks I Kr
Phase II study has been completed
Believed to have
antiarrhythmic action by
INa blockade
Currently being investigated in combination with
dronedarone in the HARMONY trial
Phase II
Atrial-selective blocker
AVE-0118 (Sanofiaventis) Kv 1.5 blocker, also blocks
Phase I
[126]
IKur
Non-selective blocker of Kv 1.5, also blocks
other Kv channels
XEN D 0101
(Xention/Galapagos NV)
[127]
Kv 1.5 blocker
Phase I
Atrial-selective blocker of Kv 1.5, prolongs atrial
APD, lack of effect on QTc
NyK 1001 (Nyken) [156,
157]
hsp 70 inducer
Phase II
Promotes anti-apoptotic and anti-inflammatory
actions of hsp
ISIS-CRPRx (Isis
Pharmaceuticals) [159]
C-reactive protein inhibitor Phase II
Anti-inflammatory action
Potentially anti-inflammatory in action, could have
relevant role in post-operative AF
Mechanism remains
investigational
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BMS 914392
Unknown mechanism
(Bristol-Myers Squibb) [175]
Phase II
Currently being investigated for
pharmacokinetics properties and drug interaction
with metoprolol and diltiazem
F 373280 (Pierre Fabre)
[176]
Unknown mechanism
Phase II
Being investigated for maintenance of SR after
electric cardioversion of patients with persistent
AF and cardiac failure
OPC-108459 (Otsuka
Pharmaceutical) [177]
Unknown mechanism
Phase II
Currently being investigated in the CADENCE
215 study for its efficacy in paroxysmal and
persistent AF patients
AF atrial fibrillation, APD action potential duration, hsp heat shock protein, QTc corrected QT interval, RyRs ryanodine receptors, SR
sinus rhythm
Atrial-selective Agents
An important limitation of multichannel blockers for the treatment of AF is the risk of ventricular arrhythmias. This limitation has
necessitated the development of ''atrialselective'' agents with a promising efficacy and a better safety profile. Blockage of I KACh and
I Kur has been considered to be a promising atrial-selective approach for the management of AF. AVE-0118 is a potent inhibitor of
I KACh and prolongs the ERP, which contributes to its efficacy in suppressing AF. Since I KACh is constitutively expressed in AF and
also tends to be atrial selective, AVE-0118 offers the benefit of being a selective target drug without affecting ventricular
depolarization.[126] XEN D 0101 is another ''atrial-selective'' agent which increases the APD by its inhibition of K v 1.5 and I Kur.[127]
Both these agents are in phase I of their development.
Recently, there has been a renewed interest in the role of ranolazine as an antiarrhythmic agent for AF suppression. Ranolazine,
although a multichannel blocker, has also been shown to be a potent inhibitor of the activity of I Na in the atrial myocytes.[128] The
clinical efficacy of ranolazine as a primary agent as well as in combination with dronedarone for treatment of paroxysmal AF is being
investigated in the HARMONY (a study to evaluate the effect of ranolazine and dronaderone when given alone and in combination in
patients with paroxysmal atrial fibrillation) trial.[129]
Receptor for Advanced Glycation End Products (RAGE)
The role of receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of AF inDM. Both the presences
of DM as well as the degree of glycemic control in diabetes have been shown to be relevant risk factors for the pathogenesis of
AF.[130,131] There is emerging evidence that the activation of the advanced glycation end products (AGE)-RAGE axis has a relevant
role in oxidative stress and inflammation-mediated pathogenesis of AF.[132]
In a study by Kato et al.,[133] the atrial tissue from diabetic rats revealed a remarkably increased degree of fibrosis and an increased
expression of RAGE. In this study, the development of atrial fibrosis was further accompanied by upregulation of CTGF, suggesting
its role as a mediator of atrial fibrosis. Another study, by Candido et al.,[134] also found that atrial tissue from diabetic rats
demonstrated increased production of AGE with increased expression of RAGE and RAGE-3; these changes were also
accompanied by upregulation in the gene and protein expression of CTGF. The profibrotic role of AGE was further supported by the
AGE-RAGE axis-mediated upregulation of MMPs production and alteration in the cross-linking of type 1 collagen and laminin.
[135–138]
AGE-RAGE interaction has also been demonstrated to have a pro-inflammatory role by activation of pleiotropic transcription factor
NF- B.[139] Data from the animal studies, epidemiological studies and various clinical trials suggest that inflammation plays a pivotal
role in the pathophysiology of AF,[140,141] and there is also interesting evidence that inflammation could also partly be mediated by
the arrhythmia itself.[142] The link between the activation of AGE-RAGE axis is particularly relevant as a therapeutic target for
antioxidant molecules. Yamagishi et al.[143] demonstrated that N-acetylcysteine (NAC) was found to inhibit the AGE-induced
apoptosis, which in turn was mediated by AGE-induced upregulation of p53 protein in a mesangial cell-based model.
Clinical Studies
Ozaydin et al.[144] investigated the role of NAC in a double-blind prospective trial in 115 patients undergoing coronary artery bypass
grafting (CABG) and/or valve surgery who were randomized to receive either placebo or NAC; the patients in NAC arm had a
significantly lower incidence of post-operative AF (5.2 %) as compared with the placebo arm (21.1 %, p = 0.019). A meta-analysis of
eight randomized controlled trials including 578 patients also demonstrated beneficial effects of NAC in reducing the incidence of
post-operative AF (OR 0.62, 95 % CI 0.41–0.93, p = 0.021) as compared with controls.[145]
Oxidative Stress Pathway and Targets in AF
Oxidative stress is another key area of interest that appears to have a relevant role in the pathogenesis of AF.[141] Mihm et al.[146]
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were some of the first investigators to observe a significantly greater degree of oxidative damage in AF as compared with SR in the
patients who underwent cardiovascular operations. The results from this study also identified myofibrillar creatine kinase (MM-CK) to
be a potential target of oxidative injury, with decreased activity levels in AF as compared with SR. Further results of this study also
demonstrated higher levels of 3-nitrotyrosine (peroxynitrite biomarker) and protein carbonyl (hydroxy radical biomarker), implicating
their role in oxidation-mediated injury in the atrial tissue of AF patients. These findings were further supported by the study of Kim et
al.,[147] which investigated transcriptional profiles from human atrial tissue obtained from AF patients undergoing Maze procedure.
They found an increased expression of genes associated with the production of ROS, which was accompanied by a simultaneous
decreased expression of genes related to antioxidant protection (glutathione peroxidase 1 and heme oxygenase 2).
These results supporting the role of increased oxidative damage in the atrium of patients with AF were further supported by Lenaerts
et al.,[148] who reported an increased NADPH oxidase-mediated superoxide production in a sheep model of persistent AF. These
changes were also paralleled by increased mRNA expression of the NADPH regulator protein Rac1, suggesting its role as a key
mediator for increased NAPH oxidase activity.[148] Based on the mechanistic link between oxidative stress and AF, the role of
antioxidants has been investigated for both preventive and treatment purposes, particularly in the setting of post-operative AF. A
protective role of vitamin C on atrial remodeling has been observed to be mediated by its potency to decrease the production of
peroxynitrite[149] and attenuation of the oxidative effects of peroxide on the atrial tissue.[150]
Statins have also been investigated for their additional role as antioxidants in suppression of AF which is mediated by oxidative
stress. Yagi et al.[151] demonstrated that treatment with pitavastatin was protective against Ang II-mediated atrial superoxide
production and rac1-mediated activation of NADPH oxidase. Similar to the pleiotropic actions of statins, polyunsaturated fatty acids
(PUFAs) have also been demonstrated to have multiple antiarrhythmic effects. PUFAs have been demonstrated to counteract the
arrhythmogenic effects of atrial stretch by regulating membrane fluidity and modulating the properties of various membrane
proteins.[152] PUFAs have also been demonstrated to have direct electrophysiological effects on various ion channels [153,154] and a
regulatory effect on MAP kinase function.[155]
Heat shock protein 70, C-reactive protein (CRP) and adenosine are some other relevant mediators of therapeutic interest in
inflammation-mediated AF. NyK 1001, which is an inducer of hsp 70, is currently being investigated for its anti-inflammatory
properties,[156,157] Increased levels of CRP after catheter ablation have been found to be associated with a greater recurrence of
AF.[158] ISIS-CRPRx is currently being investigated as a novel CRP inhibitor in the phase II studies.[159] Increased release of
adenosine has also been found to be implicated in the pathogenesis of post-operative AF by shortening of atrial ERP.
Trabodenoson is being investigated as an antagonist of these arrhythmogenic effects of adenosine.[160]
Clinical Studies
Currently available clinical data on the efficacy of vitamin C and E as antioxidants is limited because of the absence of larger
randomized controlled trials and are mostly based on observations from smaller retrospective studies. In a relatively recent
meta-analysis of five randomized controlled trials incorporating 567 patients, Harling et al.[161] showed that the prophylactic use of
vitamin C and E prior to cardiac surgery significantly reduced the incidence of post-operative AF (OR 0.43, 95 % CI 0.21–0.89).
The role of statins in the prevention of post-operative AF was supported by the finding from the Atrial Fibrillation Suppression Trials
(AFIST I–III). On the basis of a multivariate analysis of patients enrolled in these studies, the use of statins was found to be
associated with a reduction in post-operative AF (adjusted OR 0.60, 95 % CI 0.37–0.99), and this effect was suggested to be dose
dependent (adjusted OR 0.45, 95 % CI 0.21–0.99 for a dose of atorvastatin 40 mg).[162] These findings were further supported by
the results of the Atorvastatin for Reduction of MYocardial Dysrhythmia After (ARMYDA-3) trial based on 200 patients without prior
history of AF and statin intake undergoing elective cardiac surgery who were randomized to receive statins or placebo for 7 days
prior to the procedure. After a follow-up of 30 days, the patients in the atorvastatin arm had a reduced incidence of AF (35 vs. 57 %,
p = 0.003) as compared with the placebo group.[163] Current clinical evidence for the beneficial effects of PUFAs for prevention of
AF remains limited and contradictory on the basis of available data. In a randomized controlled trial based on 160 patients, a 5-day
treatment course of N-3 fatty acids prior to CABG and continued until the day of discharge was found to be associated with a lower
incidence of new-onset AF (15.2 vs. 33.3 %, OR 0.35, 95 % CI 0.16–0.76, p = 0.013) as compared with controls.[164] These
beneficial effect of PUFAs for preventing AF were not observed in the recently concluded larger, multicenter Omega-3 Fatty Acids
for Prevention of Post-operative Atrial Fibrillation (OPERA)[165] and Omega-3 Fatty Acid for Inhibition of Supraventricular Arrhythmia
(FISH) trials.[166]
The lack of efficacy of PUFAs for prevention of AF was further substantiated by the results of the OM8 (efficacy and safety of
prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial) trial,
which compared a regimen of omega-3 fatty acids (prescription omega-3 at 8 g/day for a week, followed by 4 g/day thereafter until
24 weeks) with placebo in reducing the symptomatic recurrence of AF in paroxysmal and persistent AF patients. After a follow-up
interval of 24 weeks, the use of omega-3 fatty acids was not observed to reduce the study end point (HR 1.22, 95 % CI 0.98–1.52,
p = 0.08) in both paroxysmal and persistent AF patients.[167]
Connexins as Molecular Targets
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Connexins are ubiquitous proteins which have also generated a great degree of interest as mediators of electrical remodeling. Each
connexin consists of four -helical transmembrane domains (TMI–TM4), two extracellular loops (EL1 and EL2), a cytoplasmic loop
(CL) between TM2 and TM3, and cytoplasmic amino-terminal (NT) and carboxy-terminal (CT) domains.[168] Six connexins join
together to form a hemichannel, which docks with a hemichannel on an adjacent cell to form a gap junction. Alteration in the
expression of connexins leads to an impaired conduction across gap junctions and contributes to the development of AF.[169]
Two connexin molecules, namely, Cx40 and Cx43, are believed to be the main mediators of conduction heterogeneity and
disturbances as part of atrial electrical remodeling.[169–171] Cx40 is of particular interest in the pathogenesis of AF because of its
selective expression in the atrium.[169] Early investigations by Bagwe et al.[172] reported altered atrial activation and increased
P-wave duration in Cx40 knockout mice, and the authors speculated these changes in atrial conduction could be due to alteration of
intercellular coupling and possibly secondary to the ion-channel independent effects of connexin alteration. In addition to reduced
quantitative expression of Cx40, an alteration in regional distribution and lateralization of Cx40 was also found to be associated with
regional heterogeneity in atrial conduction and an increased tendency to develop re-entry mediated AF.[173]
Almeida et al.[174] observed increased upregulation of Cx40 mRNA in a mouse model with hyperthyroidism, which was further
associated with increased atrial depolarization velocity and an upregulation of Cx40 expression suggesting that Cx40 could be a
relevant mediator of interest in the pathogenesis of AF in the setting of hyperthyroidism. Some other agents which are also being
investigated for their potential efficacy for suppressing AF are BMS 914392,[175] F373280[176] and OPC-108459.[177] Currently, the
mechanism of these agents remains to be elucidated.
Future Directions
Limitations in the current drug- and catheter ablation-based therapies for AF have sparked great interest in identification of various
molecular pathways mediating structural and electrical atrial remodeling leading to AF. Future research efforts will help clarify the
relationship between the degree of atrial fibrosis, conduction heterogeneity and predisposition to develop AF.
Further data from trials investigating ACE and aldosterone inhibition as ''upstream'' therapies will yield useful information regarding
the use of these agents for prevention of AF. In the coming years, further pre-clinical studies will also help uncover new pathways of
potential interest. Research in the field of miRNA is rapidly evolving and is of considerable interest with respect to a
biomarker-based diagnostic approach in the patients with AF; pre-clinical studies supplemented with data from clinical trials will help
advance the role of miRNAs from ''bench to bedside.'' A better understanding of oxidative stress, ion-channel remodeling and
alterations of connexins will not only help identify the relevance of these individual pathways in the pathogenesis of AF, but will also
help uncover key interrelationships between these pathways that ultimately result in the substrates responsible for driving AF.
Sidebar
Key Points
Limitations of current therapeutic options for atrial fibrillation (AF) necessitate research and development of newer agents.
Modification of atrial fibrosis has generated considerable interest as a potential target for several agents as ''upstream
therapies''.
Atrial selective ion channel blockers are also of potential as promising agents for suppression of AF without an increased risk
of development of ventricular arrhythmias.
This review discusses the role of various therapeutic agents in development as novel agents in the management of AF.
References
1. Benjamin EJ, Chen PS, Bild DE, et al. Prevention of atrial fibrillation: report from a national heart, lung, and blood institute
workshop. Circulation. 2009;119:606–18.
2. Miyasaka Y, Barnes ME, Gersch BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980
to 2000, and implications on the projections for future prevalence. Circulation. 2006;114:119–25.
3. Benjamin EJ, Wolf PA, D'Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham heart study.
Circulation. 1998;98:946–52.
4. Kochiadakis GE, Marketou ME, Igoumenidis NE, et al. Amiodarone, sotalol, or propafenone in atrial fibrillation: which is
preferred to maintain normal sinus rhythm? Pacing Clin Electrophysiol. 2000;23:1883–7.
5. Singh BN, Singh SN, Reda DJ, et al. Sotalol amiodarone atrial fibrillation efficacy trial (SAFE-T) investigators. N Engl J Med.
2005;352:1861–72.
2015-04-29 08:05
14 iš 22
6. Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the
pulmonary veins. N Engl J Med. 1998;339:659–66.
7. Maan A, Shaikh AY, Mansour M, et al. Complications from catheter ablation of atrial fibrillation. A systematic review. Crit Pathw
Cardiol. 2011;10:76–83.
8. Gupta A, Perera T, Ganesan A, et al. Complications of catheter ablation of atria fibrillation: a systematic review. Circ Arrhythm
Electrophysiol. 2013;6:1082–8.
9. Nattel S. From guidelines to bench: implications of unresolved clinical issues for basic investigations of atrial fibrillation
mechanisms. Can J Cardiol. 2011;27:19–26.
10. Li D, Fareh S, Leung TK, et al. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort.
Circulation. 1999;100:87–95.
11. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented
goats. Circulation. 1995;92:1954–68.
12. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res.
2002;54:230–46.
13. Anyukhovsky EP, Sosunov EA, Chandra P, et al. Age-associated changes in electrophysiologic remodeling: a potential
contributor to initiation of atrial fibrillation. Cardiovasc Res. 2005;66:353–63.
14. Cong H, Li X, Ma L, et al. Angiotensin II receptor type 1 is upregulated in atrial tissue of patients with rheumatic valvular
disease with atrial fibrillation. J Thorac Cardiovasc Surg. 2010;140(2):298–304.
15. Sinno H, Derakchan K, Libersan D, et al. Atrial ischemia promotes atrial fibrillation in dogs. Circulation. 2003;107:1930–6.
16. Ohtani K, Yutani C, Nagata S, et al. High prevalence of atrial fibrosis in patients with dilated cardiomyopathy. J Am Coll
Cardiol. 1995;25:1162–9.
17. Frustaci A, Chimenti C, Bellocci F, et al. Histological substrate of atrial biopsies in patients with atrial fibrillation. Circulation.
1997;96:118–84.
18. Weber KT, Brilla CG, Campbell SE, et al. Myocardial fibrosis: role of angiotensin II and aldosterone. Basic Res Cardiol.
1993;88(Suppl 1):107–24.
19. Schotten U, Verheule S, Kirchof P, et al. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol
Rev. 2011;91:265–325.
20. Nattel S, Burnstein B, Dobrev D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ Arrhythm
Electrophysiol. 2008;1:62–73.
21. Wang X, Lu J, Khaidakov M, Mitra S, et al. Delineation of the effects of angiotensin type 1 and 2 receptors on HL-1
cardiomyocyte apoptosis. Apoptosis. 2012;17:908–15.
22. Xiao HD, Fuchs S, Campbell DJ, et al. Mice with cardiacrestricted angiotensin-converting enzyme (ACE) have atrial
enlargement, cardiac arrhythmia, and sudden death. Am J Pathol. 2004;165:1019–32.
23. Sugden PH, Clerk A. ''Stress-responsive'' mitogen-activated protein kinases (c-Jun N–terminal kinases and p38
mitogenactivated protein kinases) in the myocardium. Circ Res. 1998;83:345–52.
24. Inoue N, Ohkusa T, Nao T, et al. Rapid electrical stimulation of contraction modulates gap junction protein in neonatal rat
cultured cardiomyocytes: involvement of mitogen-activated protein kinases and effects of angiotensin II-receptor antagonist.
J Am Coll Cardiol. 2004;44:914–22.
25. Yano M, Kim S, Izumi Y, et al. Differential activation of cardiac c-jun amino-terminal kinase and extracellular signal-regulated
kinase in angiotensin II-mediated hypertension. Circ Res. 1998;83:752–60.
26. Peters NS, Coromilas J, Severs NJ, et al. Disturbed connexin 43 gap junction distribution correlates with the location of
reentrant circuits in the epicardial border zone of healing infarcts that cause ventricular tachycardia. Circulation.
1997;95:988–96.
27. Kanagaratnam P, Cherian A, Stanbridge RD, et al. Relationship between connexins and atrial activation during human atrial
2015-04-29 08:05
15 iš 22
fibrillation. J Cardiovasc Electrophysiol. 2004;15:206–16.
28. Anne W, Willms R, Roskams T, et al. Matrix metalloproteinases and atrial remodeling in patients with mitral valve disease and
atrial fibrillation. Cardiovasc Res. 2005;67:655–66.
29. Nakano Y, Niida S, Dote K, et al. Matrix metalloproteinase-9 contributes to human atrial remodeling during atrial fibrillation. J
Am Coll Cardiol. 2004;43:818–25.
30. Rouet-Benzineb P, Gontero B, et al. Angiotensin II induces nuclear factor-kappa B activation in cultured neonatal rat
cardiomyocytes through protein kinase C signaling pathway. J Mol Cell Cardiol. 2000;32:1767–78.
31. Brilla CG, Zhou G, Matsubara L, et al. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II
and aldosterone. J Mol Cell Cardiol. 1994;26:809–20.
32. Rudolph V, Andrié RP, Rudolph TK, et al. Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation. Nat Med.
2010;16:470–4.
33. Tsai CT, Wang DL, Chen WP, et al. Angiotensin II increases expression of alpha 1 C subunit of L-type channel through a
reactive oxygen species and cAMP response element-binding protein-dependent pathway in HL-1 myocytes. Circ Res.
2007;100:1476–85.
34. Tsai CT, Chiang FT, Chen WP, et al. Angiotensin II induces complex fractionated electrogram in a cultured atrial myocyte
monolayer mediated by calcium and sodium-calcium exchanger. Cell Calcium. 2011;49:1–11.
35. Bosch RF, Zeng X, Grammer JB, et al. Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc Res.
1999;44:121–31.
36. De Mello WC, Monterrrubio J. Intracellular and extracellular angiotensin II enhance the L-type calcium current in the failing
heart. Hypertension. 2004;44:360–4.
37. Li D, Shinagawa K, Pang L, et al. Effects of angiotensin-converting enzyme inhibition on the development of the atrial
fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation. 2001;104:2608–14.
38. Shi Y, Li D, Tardif JC, et al. Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure.
Cardiovasc Res. 2002;54:456–61.
39. Saygili E, Rana OR, Saygili E, et al. Losartan prevents stretch-induced electrical remodeling in cultured atrial neonatal
myocytes. Am J Physiol Heart Circ Physiol. 2007;292:H2898–905.
40. Chen YJ, Chen YC, Tai CT, et al. Angiotensin II and angiotensin II receptor blocker modulate the arrhythmogenic activity of
pulmonary veins. Br J Pharmacol. 2006;147:12–22.
41. Shetty SS, DelGrande D. Differential inhibition of the prejunctional actions of angiotensin II in rat atria by valsartan, irbesartan,
eprosartan, and losartan. J Pharmacol Exp Ther. 2000;294:179–86.
42. Goette A, Bukowska A, Lendeckel U, et al. Angiotensin II receptor blockade reduces tachycardia-induced atrial adhesion
molecule expression. Circulation. 2008;117:732–42.
43. Le Blanc C, Mironneau C, Barbot C, et al. Regulation of vascular L-type Ca2+ channels by phosphatidylinositol 3,4,5trisphosphate. Circ Res. 2004;95:300–7.
44. Khatib R, Joseph P, Briel M, et al. Blockade of the reninangiotensin-aldosterone system (RAAS) for primary prevention of
non-valvular atrial fibrillation: a systematic review and metaanalysis of randomized controlled trials. Int J Cardiol.
2013;165:17–24.
45. Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent
stroke compared to atenolol: the losartan intervention for end point reduction in hypertension (LIFE) study. J Am Coll Cardiol.
2005;45:712–9.
46. Ducharme A, Swedberg K, Pfeffer MA, CHARM Investigators, et al. Prevention of atrial fibrillation in patients with
symptomatic chronic heart failure by candesartan in the candesartan in heart failure: assessment of reduction in mortality and
morbidity (CHARM) program. Am Heart J. 2006;152:86–92.
47. GISSI-AF Investigators. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med. 2009;360:1606–17.
2015-04-29 08:05
16 iš 22
48. The ACTIVE I investigators. Irbesartan in patients with atrial fibrillation. N Engl J Med. 2011;364:928–38.
49. Goette A, Schön N, Kirchhof P, et al. Angiotensin II-antagonist in paroxysmal atrial fibrillation (ANTIPAF) trial. Circ Arrhythm
Electrophysiol. 2012;5:43–51.
50. J Rhythm II investigators. Randomized trial of angiotensin IIreceptor blocker vs. dihydropiridine calcium channel blocker in
the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II study). Europace. 2011;13:473–9.
51. Harada E, Yoshimura M, Yasue H, et al. Aldosterone induces angiotensin-converting-enzyme gene expression in cultured
neonatal rat cardiocytes. Circulation. 2001;104:137–9.
52. Mizuno Y, Yoshimura M, Yasue H, et al. Aldosterone production is activated in failing ventricle in humans. Circulation.
2001;103:72–7.
53. Tillman HC, Schumacher B, Yasenyev O, et al. Acute effects of aldosterone on intracardiac monophasic action potentials. In
J Cardiol. 2002;84:33–9.
54. Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of cardiovascular events in patients with primary
aldosteronism. J Am Coll Cardiol. 2005;45:1243–8.
55. Goette A, Hoffmanns P, Enayati W, et al. Effect of successful electrical cardioversion on serum aldosterone in patients with
persistent atrial fibrillation. Am J Cardiol. 2001;88:906–9.
56. Milliez P, Deangelis N, Rucker-Martin C, et al. Spironolactone reduces fibrosis of dilated atria during heart failure in rats with
myocardial infarction. Eur Heart J. 2005;26:2193–9.
57. Brooks WW, Bing OH, Robinson KG, et al. Effect of angiotensin-converting enzyme inhibition on myocardial fibrosis and
function in hypertrophied and failing myocardium from the spontaneously hypertensive rat. Circulation. 1997;96:4002–10.
58. Shroff SC, Ryu K, Martovitz NL, et al. Selective aldosterone blockade suppresses atrial tachyarrhythmias in heart failure. J
Cardiovasc Electrophysiol. 2006;17:534–41.
59. Swedberg K, Zannad F, McMurray JJ, EMPHASIS-HF Study Investigators, et al. Eplerenone and atrial fibrillation in mild
systolic heart failure: results from the EMPHASIS-HF (Eplerenone in mild patients hospitalization and survival study in heart
failure) study. J Am Coll Cardiol. 2012;59:1598–603.
60. Ito Y, Yamasaki H, Naruse Y, et al. Effect of eplerenone on maintenance of sinus rhythm after catheter ablation in patients with
long-standing persistent atrial fibrillation. Am J Cardiol. 2013;111:1012–8.
61. Dabrowski R, Borowiec A, Smolis-Bak E, et al. Effect of combined spironolactone- -blocker ± enalapril treatment on
occurrence of symptomatic atrial fibrillation episodes in patients with a history of paroxysmal atrial fibrillation (SPIR-AF study).
Am J Cardiol. 2010;106:1609–14.
62. Williams RS, deLemos JA, Dimas V, et al. Effect of spironolactone on patients with atrial fibrillation and structural heart
disease. Clin Cardiol. 2011;34:415–9.
63. Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator-activated receptor-gamma is a negative regulator of
macrophage activation. Nature. 1998;39:79–82.
64. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature.
1998;391:82–6.
65. Takano H, Nagai T, Asakawa M, et al. Peroxisome proliferator-activated receptor activators inhibit lipopolysaccharide-induced
tumor necrosis factor-alpha expression in neonatal rat cardiac myocytes. Circ Res. 2000;87:596–602.
66. Shimano M, Tsuji Y, Inden Y, et al. Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates
atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure. Heart Rhythm. 2008;5:451–9.
67. Xu D, Murakoshi N, Igarashi M, et al. PPAR-c activator pioglitazone prevents age-related atrial fibrillation susceptibility by
improving antioxidant capacity and reducing apoptosis in a rat model. J Cardiovasc Electrophysiol. 2012;23:209–17.
68. Gu J, Liu X, Wang QX, Guo M, et al. Beneficial effects of pioglitazone on atrial structural and electrical remodeling in vitro
cellular models. J Mol Cell Cardiol. 2013;65:1–8.
69. Takahashi N, Kume O, Wakisaka O, et al. Novel strategy to prevent atrial fibrosis and fibrillation. Circ J. 2012;76:2318–26.
2015-04-29 08:05
17 iš 22
70. Gu J, Liu X, Wang X, et al. Beneficial effect of pioglitazone on the outcome of catheter ablation in patients with paroxysmal
atrial fibrillation and type 2 diabetes mellitus. Europace. 2011;13:1256–61.
71. Chen K, Mehta JL, Li D, et al. Transforming growth factor receptor endoglin is expressed in cardiac fibroblasts and
modulates the profibrogenic actions of angiotensin II. Circ Res. 2004;95:1167–73.
72. Schutz Jel J, Witt SA, Glascock BJ, et al. TGF-beta 1 mediates the hypertrophic cardiomyocyte growth induced by
angiotensin II. J Clin Invest. 2002;109:787–96.
73. Kupfahl C, Pink D, Friedrich K, et al. Angiotensin II directly increases transforming growth factor beta1 and osteopontin and
indirectly affects collagen mRNA expression in the human heart. Cardiovasc Res. 2000;46:463–75.
74. Lee AA, Dillmann WH, McCulloch AD, et al. Angiotensin II stimulates the autocrine production of transforming growth
factor-beta 1 in adult rat fibroblasts. J Mol Cell Cardiol. 1995;27:2347–57.
75. Booz GW, Dostal AE, Singer HA, et al. Involvement of protein kinase C and Ca2+ in angiotensin II-induced mitogenesis of
cardiac fibroblasts. Am J Physiol. 1994;267(5 Pt 1):C1308–18.
76. Hao J, Wang B, Jones SC, et al. Interactions between angiotensin II and Smad proteins in fibroblasts in failing heart and in
vitro. Am J Physiol Heart Circ Physiol. 2000;279:H3020–30.
77. Evans RA, Tian YC, Steadman R, et al. TGF-beta 1 mediated fibroblast-myofibroblast terminal differentiation-the role of
SMAD proteins. Exp Cell Res. 2003;282:90–100.
78. Hanna N, Cardin S, Leung TK, et al. Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacinginduced congestive heart failure. Cardiovasc Res. 2004;63:236–44.
79. Verheule S, Sato T, Everett T 4th, et al. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial
fibrosis caused by overexpression of TGF-beta 1. Circ Res. 2004;94:1458–65.
80. Nakajima J, Nakajima HO, Salcher O, et al. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth
factor-beta (1) transgene in the heart. Circ Res. 2000;86:571–9.
81. Lee KW, Everett TH 4th, Rahmutula D, et al. Pirfenidone prevents the development of a vulnerable substrate for atrial
fibrillation in a canine model of heart failure. Circulation. 2006;16:1703–12.
82. Yamazaki T, Yamashita N, Izumi Y, et al. The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy
in mice. Hypertens Res. 2012;35:34–40.
83. Iyer SN, Wild JS, Schiedt MJ, et al. Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J
Lab Clin Med. 1995;125:779–85.
84. Iyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on transforming growth factor-beta gene expression at the
transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther. 1999;291:367–73.
85. Iyer SN, Margolin SB, Hyde DM, et al. Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a
three-dose bleomycin-hamster model. Exp Lung Res. 1998;24:119–32.
86. Barter MJ, Pybus L, Litherland GJ, et al. HDAC-mediated control of ERK- and PI3K-dependent TGF- -induced extracellular
matrix-regulated genes. Matrix Biol. 2010;29:602–12.
87. Liu F, Levin MD, Peternko B, et al. Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac
hypertrophy independent of angiotensin. J Mol Cell Cardiol. 2008;45:715–23.
88. Catalucci D, Latronico MV, Condorelli G. MicroRNAs control gene expression: importance for cardiac development and
pathophysiology. Ann N Y Acad Sci. 2008;1123:20–9.
89. Thum T, Catalucci D, Bauersachs J. MicroRNAs: novel regulators in cardiac development and disease. Cardiovasc Res.
2008;79:562–70.
90. Xu GJ, Gan TY, Tang BP, et al. Changes in microRNAs expression are involved in age-related atrial structural remodeling and
atrial fibrillation. Chin Med J (Engl). 2013;126:1458–63.
91. Dawson K, Wakili R, Ordög B, et al. MicroRNA29: a mechanistic contributor and potential biomarker in atrial fibrillation.
Circulation. 2013;127:1466–75.
2015-04-29 08:05
18 iš 22
92. Cardin S, Guasch E, Luo X, et al. Role for MicroRNA-21 in atrial profibrillatory fibrotic remodeling associated with
experimental postinfarction heart failure. Circ Arrhythm Electrophysiol. 2012;5:1027–35.
93. Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in
fibroblasts. Nature. 2008;456:980–4.
94. Skasa M, Jüngling E, Picht E, et al. L-type calcium currents in atrial myocytes from patients with persistent and non-persistent
atrial fibrillation. Basic Res Cardiol. 2001;96:151–9.
95. Lai LP, Su MJ, Lin JL, et al. Down-regulation of L-type calcium channel and sarcoplasmic reticular Ca (2+)-ATPase mRNA in
human atrial fibrillation without significant change in the mRNA of ryanodine receptor, calsequestrin and phospholamban: an
insight into the mechanism of atrial electrical remodeling. J Am Coll Cardiol. 1999;33:1231–7.
96. Atienza F, Almendral J, Moreno J, et al. Activation of inward rectifier potassium channels accelerates atrial fibrillation in
humans: evidence for a reentrant mechanism. Circulation. 2006;114:2434–42.
97. Yue L, Feng J, Gaspo R, et al. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ
Res. 1997;81:512–25.
98. Gaborit N, Steenman M, Lamirault G, et al. Human atrial ion channel and transporter subunit gene-expression remodeling
associated with valvular heart disease and atrial fibrillation. Circulation. 2005;112:471–81.
99. Lu Y, Zhang Y, Wang N, et al. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation.
2010;122:2378–87.
100. McManus DD, Lin H, Tanriverdi K, et al. Relations between the circulating microRNAs and atrial fibrillation: data from the
Framingham offspring study. Heart Rhythm. 2014;11:663–9.
101. Luo X, Pan Z, Shan H, et al. MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial
fibrillation. Clin Invest. 2013;123:1939–51.
102. Ling TY, Wang XL, Chai Q, et al. Regulation of the SK3 channel by microRNA-499-potential role in atrial fibrillation. Heart
Rhythm. 2013;10:1001–9.
103. Xu C, Lu Y, Pan Z, Chu W, et al. The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on
apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes. J Cell Sci. 2007;120:3045–52.
104. Dobrev D, Graf E, Wettwer E, et al. Molecular basis of down-regulation of G-protein coupled inward rectifying K (?) current (I
K, Ach) in chronic human atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced I (K, Ach) and muscarinic
receptor-mediated shortening of action potentials. Circulation. 2001;104:2551–7.
105. Pandit SV, Berenfeld O, Anumonwo JM, et al. Ionic determinants of functional reentry in a 2-D model of human atrial cells
during simulated chronic atrial fibrillation. Biophys J. 2005;88:3806–21.
106. Kneller J, Zou R, Vigmond EJ, et al. Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine
atrial cells with realistic ionic properties. Circ Res. 2002;90:E73–87.
107. Voigt N, Friedrich A, Bock M, et al. Differential phosphorylation-dependent regulation of constitutively active and muscarinic
receptor-activated IKACh channels in patients with chronic atrial fibrillation. Cardiovasc Res. 2007;74:426–37.
108. Wakili R, Voigt N, Kaab S, et al. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest.
2011;121:2955–68.
109. Tang L, Joung B, Ogawa M, et al. Intracellular calcium dynamics, shortened action potential duration, and late-phase 3 early
afterdepolarization in Langendorff-perfused rabbit ventricles. J Cardiovasc Electrophysiol. 2012;23:1364–71.
110. Dobrev D, Carlsson L, Nattel S. Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov. 2012;11:275–91.
111. Dobrev D, Voigt N, Wehrens XH. The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological
and therapeutic implications. Cardiovasc Res. 2011;89:734–43.
112. Vest JA, Wehrens XH, Reiken SR, et al. Defective cardiac ryanodine regulation during atrial fibrillation. Circulation.
2005;111:2025–32.
113. Chelu MG, Sarma S, Sood S, et al. Calmodulin kinase II-mediated sarcoplasmic reticulum Ca++ leak promotes atrial
2015-04-29 08:05
19 iš 22
fibrillation in mice. J Clin Invest. 2009;119:1940–51.
114. Li N, Chiang DY, Wang S, et al. Ryanodine receptor-mediated calcium leak drives progressive development of an atrial
fibrillation substrate in a transgenic mouse model. Circulation. 2014;129:1276–85.
115. Neef S, Dybkova N, Sossalla S, et al. Ca MK II-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in the
right atrial myocardium of patients with atrial fibrillation. Circ Res. 2010;106:1134–44.
116. Takacs J, Iost N, Lengyel C, et al. Multiple cellular electrophysiological effects of azimilide in canine cardiac preparations. Eur
J Pharmacol. 2003;470:163–70.
117. Nishida A, Reien Y, Ogura T, et al. Effects of azilimide on the muscarinic acetylcholine receptor-operated K + current and
experimental atrial fibrillation in guinea-pig hearts. J Pharmacol Sci. 2007;105:229–39.
118. Pritchett EL, Page RL, Connolly SJ, et al. Azilimide Supraventricular Arrhythmia Program 3 (SVA-3) Investigators.
Antiarrhythmic effects of azilimide in atrial fibrillation: efficacy and dose-response. J Am Coll Cardiol. 2000;36:794–802.
119. Lombardi F, Borggrefe M, Ruzyllo W, For the A-COMET-II investigators, et al. Azimilide vs. placebo and sotalol for persistent
atrial fibrillation: the A-COMET-II (Azimilide-CardiOversion Maintenance Trial-II) trial. Eur Heart J. 2006;18:2224–31.
120. Page RL, Pritchett EL, Connolly SJ, SVA-4 Investigators, et al. Azimilide for the treatment of atrial fibrillation, atrial flutter, and
paroxysmal supraventricular tachycardia: results of a randomized trial and insights on the concordance of symptoms and
recurrent arrhythmias. J Cardiovasc Electrophysiol. 2008;19:172–7.
121. Hasumi H, Matsuda R, Shimamoto K, et al. K201, a multichannel blocker, inhibits clofilium-induced torsades-de pointes and
attenuates an increase in repolarization. Eur J Pharmacol. 2007;555:54–60.
122. Kaneko N, Matsuda R, et al. Pharmacological characteristics and clinical applications of K201. Curr Clin Pharmacol.
2009;4:126–31.
123. Nakaya H, Furosawa Y, Ogura T, et al. Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and
experimental atrial fibrillation in guinea-pig hearts. Br J Pharmacol. 2000;131:1363–72.
124. Chen YJ, Chen YC, Wongcharoen W, et al. Effect of K201, a novel antiarrhythmic drug on calcium handling and
arrhythmogenic activity of pulmonary vein cardiomyocytes. Br J Pharmacol. 2008;153:915–25.
125. Chen YJ, Chen SA, Chen YC, et al. Electrophysiology of single cardiomyocytes isolated from rabbit pulmonary veins:
implication in initiation of focal atrial fibrillation. Basic Res Cardiol. 2002;97:26–34.
126. Christ T, Wettwer E, Voigt N, et al. Pathology-specific effects of the I Kur/Ito/I KACh blocker AVE 0118 on ion channels in human
chronic atrial fibrillation. Br J Pharmacol. 2008;154:1619–30.
127. Ford J, Milenes J, Wettwer E, Christ T, et al. Human electrophysiological and pharmacological properties of XEN-D 0101: a
novel atrial-selective Kv1.5/IKur inhibitor. J Cardiovasc Pharmacol. 2013;61:408–15.
128. Antzelevitch C, Burashinkov A, Siccouri S, et al. Electrophysiological basis for the antiarrhythmic actions of ranolazine. Heart
Rhythm. 2011;8:1281–90.
129. A study to evaluate the effect of ranolazine and dronedarone when given alone and in combination in patients with paroxysmal
atrial fibrillation (HARMONY). 2014 http://clinicaltrials.gov/show/NCT01522651. Accessed 06 July 2014.
130. Iguchi Y, Kimura K, Shibazaki K, et al. HbA1c and atrial fibrillation: a cross-sectional study in Japan. Int J Cardiol.
2012;156:156–9.
131. Movahed MR, Hashemzadeh M, Jamal MM. Diabetes mellitus is a strong, independent risk for atrial fibrillation and flutter in
addition to other cardiovascular disease. Int J Cardiol. 2005;105:315–8.
132. Aksnes TA, Schmieder RE, Kjeldsen SE, et al. Impact of newonset diabetes mellitus on development of atrial fibrillation and
heart failure in high-risk hypertension (from the VALUE trial). Am J Cardiol. 2008;101:634–8.
133. Kato T, Yamashita T, Sekiguchi A, et al. AGEs-RAGE system mediates atrial structural remodeling in the diabetic rat. J
Cardiovasc Electrophysiol. 2008;19:415–20.
134. Candido R, Forbes JM, Thomas MC, et al. A breaker of advanced glycation end products attenuates diabetes-induced
myocardial structural changes. Circ Res. 2003;92:785–92.
2015-04-29 08:05
20 iš 22
135. Mukherjee R, Heeron AR, Lowry AS, et al. Selective induction of matrix metalloproteinases and tissue inhibitor of
metalloproteinases in atrial and ventricular myocardium in patients with atrial fibrillation. Am J Cardiol. 2006;97:532–7.
136. Tanaka S, Avigad G, Brodsky B, et al. Glycation induces expansion of the molecular packing of collagen. J Mol Biol.
1988;203:495–505.
137. Huijberts MS, Wolffenbuttel BH, Boudier HA, et al. Aminoguanidine treatment increases elasticity and decreases fluid
filtration of large arteries from diabetic rats. J Clin Invest. 1993;92:1407–11.
138. Tsilibary EC, Charonis AS, Reger LA, et al. The effect of nonenzymatic glucosylation on the binding of the main
noncollagenous NC1 domain to type IV collagen. J Biol Chem. 1988;263:4302–8.
139. Hoffman MA, Drury S, Fu C, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S
100/Calgranulin polypeptides. Cell. 1999;97:889–901.
140. Friedrichs K, Klinke A, Baldus S. Inflammatory pathways underlying atrial fibrillation. Trends Mol Med. 2011;17:556–63.
141. Korantzopoulos P, Kolettis TM, Galaris D, et al. The role of oxidative stress in the pathogenesis and perpetuation of atrial
fibrillation. Int J Cardiol. 2007;115:135–43.
142. Marcus GM, Smith LM, Glidden DV, et al. Markers of inflammation before and after curative ablation of atrial flutter. Heart
Rhythm. 2008;5:215–21.
143. Yamagishi S, Inagaki Y, Okamoto T, et al. Advanced glycation end product-induced apoptosis and overexpression of vascular
endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells. J Biol Chem.
2002;277:20309–15.
144. Ozaydin M, Peker O, Erdogan D, et al. N-acetylcysteine for the prevention of postoperative atrial fibrillation: a prospective,
randomized, placebo-controlled pilot study. Eur Heart J. 2008;29:625–31.
145. Gu WJ, Wu ZJ, Wang PF, et al. N-acetyl cysteine supplementation for the prevention of atrial fibrillation after cardiac surgery:
a meta-analysis of eight randomized controlled trials. BMC Cardiovasc Disord. 2012;12:10.
146. Mihm MJ, Yu F, Carnes CA, et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation.
Circulation. 2001;104:174–80.
147. Kim YH, Lim DS, Lee JH, et al. Gene expression profiling of oxidative stress on atrial fibrillation in humans. Exp Mol Med.
2003;35:336–49.
148. Lenaerts I, Driesen RB, Blanco NH, et al. Role of nitric oxide and oxidative stress in a sheep model of persistent atrial
fibrillation. Europace. 2013;15:754–60.
149. Carnes CA, Chung MK, Nakayama T, et al. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical
remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res. 2001;89:E32–8.
150. Lin YK, Lin FZ, Chen YC, et al. Oxidative stress on pulmonary vein and left atrium arrhythmogenesis. Circ J.
2010;74:1547–56.
151. Yagi S, Akaike M, Aihara K, et al. Endothelial nitric oxide synthase-independent protective action of statin against angiotensin
II-induced atrial remodeling via reduced oxidant injury. Hypertension. 2010;55:918–23.
152. Ninio DM, Murphy KJ, Howe PR, et al. Dietary fish oil protects against stretch-induced vulnerability to atrial fibrillation in a
rabbit model. J Cardiovasc Electrophysiol. 2005;16:1189–94.
153. Li GR, Sun HY, Zhang XH, et al. Omega-3 polyunsaturated fatty acids inhibit transient outward and ultra-rapid delayed rectifier
K+currents and Na+current in human atrial myocytes. Cardiovasc Res. 2009;81:286–93.
154. Boland LM, Drzewiecki MM, et al. Inhibitory effects of polyunsaturated fatty acids on Kv4/KChIP potassium channels. Am J
Physiol Cell Physiol. 2009;296:C1003–14.
155. Savelieva I, Camm J. Statins and polyunsaturated fatty acids for treatment of atrial fibrillation. Nat Clin Pract Cardiovasc Med.
2008;5:30–41.
156. Mandal K, Torsney E, Poloniecki J, et al. Association of high intracellular, but not serum, heat shock protein 70 with
postoperative atrial fibrillation. Ann Thorac Surg. 2005;79:865–71.
2015-04-29 08:05
21 iš 22
157. Announcement of Phase IIb development of NyK-1001 by Nyken. http://www.nyken.com/2009.html. Accessed 06 July 2014.
158. Lin YJ, Tsao HM, Chang SL, et al. Prognostic implications of the high-sensitive C-reactive protein in the catheter ablation of
atrial fibrillation. Am J Cardiol. 2010;105:495–501.
159. Development of ISIS-CRPRX. http://isispharm.com/backup/Pipeline/Therapeutic-Areas/Cardiovascular.htm#ISIS-CRPRx.
Accessed 06 July 2014.
160. Morrison CF, Elzein E, Jiang B, et al. Structure-affinity relationship of 50-aromatic ethers and 50-aromatic sulfides as partial
A1 adenosine agonists, potential supraventricular anti-arrhythmic agents. Bioorg Med Chem Lett. 2004;14:3793–7.
161. Harling L, Rasoli S, Vecht JA, et al. Do antioxidant vitamins have an anti-arrhythmic effect following cardiac surgery? A
meta-analysis of randomised controlled trials. Heart. 2011;97:1636–42.
162. Lertsburapa K, White CM, Kluger J, et al. Preoperative statins for the prevention of atrial fibrillation after cardiothoracic
surgery. J Thorac Cardiovasc Surg. 2008;135:405–11.
163. Patti G, Chello M, Candura D, et al. Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation in patients
undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac
surgery) study. Circulation. 2006;114:1455–61.
164. Calò L, Bianconi L, Colivicchi F, et al. N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass
surgery: a randomized, controlled trial. J Am Coll Cardiol. 2005;45:1723–8.
165. Wu JH, Marchioli R, Silletta MG, et al. Plasma phospholipid omega-3 fatty acids and incidence of postoperative atrial
fibrillation in the OPERA trial. J Am Heart Assoc. 2013;21(2):e000397.
166. Sandesara CM, Chung MK, Van Wagoner DR, et al. A randomized, placebo-controlled trial of omega-3 fatty acids for
inhibition of supraventricular arrhythmias after cardiac surgery: the FISH trial. J Am Heart Assoc. 2012;1:e000547.
167. Kowey PR, Reiffel JA, Ellenbogen KA, et al. Efficacy and safety of prescription omega-3 fatty acids for the prevention of
recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA. 2010;304:2363–72.
168. Evans WH, Martin PE. Gap-junctions: structure and functions. Mol Membr Biol. 2002;19:121–36.
169. Gollob MH, Jones DL, Krahn AD, et al. Somatic mutations in the connexin 40 gene (gja 5) in atrial fibrillation. N Engl J Med.
2006;354:2677–88.
170. Poelzing S, Rosenbaum DS. Altered connexin 43 expression produce arrhythmia substrate in heart failure. Am J Physiol
Heart Circ Physiol. 2004;287:H1762–70.
171. Yang LQ, Liu X, Zhang XL, et al. Connexin 40 nonsense mutation in familial atrial fibrillation. Int J Mol Med. 2010;26:605–10.
172. Bagwe S, Berenfeld O, Vaidya D, et al. Altered right atrial excitation and propagation in connexin 40 knockout mice.
Circulation. 2005;112:2245–53.
173. Hsieh MH, Lin YJ, Wang HH, et al. Functional characterization of atrial electrograms in a pacing-induced heart failure model of
atrial fibrillation: importance of regional atrial connexin40 remodeling. Cardiovasc Electrophysiol. 2013;24:573–82.
174. Almeida NA, Cordeiro A, Machado DS, et al. Connexin40 messenger ribonucleic acid is positively regulated by thyroid
hormone (TH) acting in cardiac atria via the TH receptor. Endocrinology. 2009;150:546–54.
175. Effect of BMS-914392 on pharmacokinetics of metoprolol. http://clinicaltrials.gov/show/NCT01211821. Accessed 06 July
2014.
176. Efficacy and safety study of F 373280. http://clinicaltrials.gov/show/NCT01831. Accessed 06 July 2014.
177. Ascending dose study of OPC-108459 intravenous infusion in patients with paroxysmal and persistent atrial fibrillation:
CADENCE 215. http://clinicaltrials.gov/show/NCT01483183. Accessed 06 July 2014.
Acknowledgements
Supported in part by The Deane Institute for Integrative Research in Atrial Fibrillation at Massachusetts General Hospital.
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Am J Cardiovasc Drugs. 2014;14(6):403-421. © 2014 Adis Springer International Publishing AG
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