Submit Manuscript    >>    Login | Register

Atrial Remodeling And Atrial Fibrillation: Mechanistic Interactions And Clinical Implications


Atrial Remodeling And Atrial Fibrillation: Mechanistic Interactions And Clinical Implications
Quick View
Credits:Bandar Al Ghamdi, MD, Walid Hassan, MD, FACP, FACC, FCCP, FAHA
King Faisal Specialist Hospital and research centre, Riyadh, Saudi Arabia.

Address for correspondence: Walid Hassan, MD, FCCP, FACC, FACP, FAHA. Consultant and Head Adult Cardiology, MBC 16, King Faisal Specialist Hospital & Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia.

Abstract

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. The prevalence of AF increases dramatically with age and is seen in as high as 9% of individuals by the age of 80 years. In high-risk patients, the thromboembolic stroke risk can be as high as 9% per year and is associated with a 2-fold increase in mortality. Although the pathophysiological mechanism underlying the genesis of AF has been the focus of many studies, it remains only partially understood. Conventional theories focused on the presence of multiple re-entrant circuits originating in the atria that are asynchronous and conducted at various velocities through tissues with various refractory periods.  Recently, rapidly firing atrial activity in the muscular sleeves at the pulmonary veins ostia or inside the pulmonary veins have been described as potential mechanism,. AF results from a complex interaction between various initiating triggers and development of abnormal atrial tissue substrate. The development of AF leads to structural and electrical changes in the atria, a process known as remodeling. To have effective surgical or catheter ablation of AF good understanding of the possible mechanism(s) is crucial.


Once initiated, AF alters atrial electrical and structural properties that promote its maintenance and recurrence. The role of atrial remodeling (AR) in the development and maintenance of AF has been the subject of many animal and human studies over the past 10-15 years. This review will discuss the mechanisms of AR, the structural, electrophysiologic, and neurohormonal changes associated with AR and it is role in initiating and maintaining AF. We will also discuss briefly the role of inflammation in AR and AF initiation and maintenance, as well as, the possible therapeutic interventions to prevent AR, and hence AF, based on the current understanding of the interaction between AF and AR.

Introduction

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. The prevalence of AF increases dramatically with age and is seen in as high as 9% of individuals by the age of 80 years [1]. In high-risk patients, the thromboembolic stroke risk can be as high as 9% per year and is associated with a 2-fold increase in mortality [1, 2]. Twenty percent of patients with paroxysmal atrial fibrillation (PAF), defined as AF lasting 7 days (and spontaneous conversion), progress to chronic (persistent or permanent) AF, defined as lasting 30 days [1 - 5].


Although the pathophysiological mechanism underlying the genesis of AF has been the focus of many studies, it remains only partially understood. Conventional theories focused on the presence of multiple re-entrant circuits originating in the atria that are asynchronous and conducted at various velocities through tissues with various refractory periods [2].


Recently, rapidly firing atrial activity in the muscular sleeves at the pulmonary veins ostia or inside the pulmonary veins have been described as potential mechanism for AF [3]. AF results from a complex interaction between various initiating triggers and development of abnormal atrial tissue substrate [6]. The development of AF leads to structural and electrical changes in the atria, a process known as remodeling. These changes further perpetuate the existence and maintenance of this arrhythmia (i.e., “atrial fibrillation begets atrial fibrillation”) [4].


There has been an increase interest in AF surgical and catheter ablation in the past 15 years aiming to reduced its morbidity and mortality. However these procedures have limited success and are not without risk.


To have effective surgical or catheter ablation of AF good understanding of the possible mechanism(s) is crucial. Once initiated, AF alters atrial electrical and structural properties that promote its maintenance and recurrence. The role of atrial remodeling in the development and maintenance of AF has been the subject of many animal and human studies over the past 10-15 years. This review will discuss the mechanisms of atrial remodeling (AR), the structural, electrophysiologic, and neurohormonal changes associated with AR and it is role in initiating and maintaining AF. We will also discuss briefly the role of inflammation in AR and AF initiation and maintenance, as well as, the possible therapeutic interventions to prevent AR, and hence AF, based on the current understanding of the interaction between AF and AR.

Artial remodeling

Atrial remodeling refers to structural and functional changes in the atrial myocytes in response to internal or external stimuli. Atrial remodeling may also be described as a time-dependent adaptive regulation of cardiac myocytes in order to maintain homeostasis against external stressors [7]. The strength and the duration of exposure to the "stressors plays a major role in determining the extent of AR [8]. Exposure to external stressors for a short period of time (<30 minutes) may lead to responses at the ionic/genomic level, which is usually reversible [9]. Mid-term exposure (< or = 1 week) [10] may result in changes at the cellular level which are usually reversible; however long-term exposure (>5 weeks) [11] may result in changes at the cellular/ extracellular matrix level (e.g. apoptosis and fibrosis) and is usually irreversible).


Atrial remodeling may occur in response to tachycardia with high rates of cell depolarization as in patients with AF. In this case, AF is initially maintained by ectopic activity or single-circuit reentry in a given patient, but the high atrial rates induce spatially heterogeneous refractoriness abbreviation which creates conditions favorable to multiple-circuit reentry. This multiple reentry circuits reentry may then become the AF-maintaining mechanism. Thus, multiple-circuit reentry may be a final common pathway AF mechanism in many patients. Hence the term “AF begets AF” [4].


Atrial remodeling may also occur in response to volume/pressure overload such as in heart failure syndromes. Specific stressors, such as diastolic dysfunction, ischemia, and valvular diseases, e.g. mitral stenosis and mitral regurgitation, impose excess pressure and/or volume load on the atrial myocytes, which responds with a range of adaptive, as well as maladaptive, processes [7]. These processes include myocyte growth, hypertrophy, necrosis, and apoptosis, alterations in the composition of extracellular matrix, recalibration of energy production and expenditure, changes in the expression of cellular ionic channels and atrial hormones and reversal to a fetal gene program. These changes promote a cascade of reactions, which lead to AR with structural, functional, electrical, metabolic, and neurohormonal consequences [7].

Structural and ultra-structural changes in atrial remodeling


Atrial structural and ultra-structural changes due to rapid atrial rates

Rapid atrial rate is associated with structural and ultra-structural changes in both right and left atria. Starting with the structural changes; in clinical practice there is a clear relationship between AF and atrial dilatation. For many years atrial dilatation has been recognized as a predictive factor for the development of AF [12]. On the other hand, atrial diameters have been shown to further increase when AF is present. Sanfillipo et al. [13] demonstrated an increase in atrial diameters of almost 40% during a mean follow-up of 20.6 months in patients with AF and in the absence of structural heart disease. In addition, it has been demonstrated that atrial diameters may decrease after conversion of AF to sinus rhythm. [14, 15].


Rapid atrial pacing for 6 weeks in healthy dogs was shown to result in progressive biatrial enlargement [16]. Furthermore AF results in loss of atrial contraction and the recovery of this function may take weeks to months to be seen after cardioversion depending on the duration of the previous episode of AF [17].


In terms of atrial ultra-stractural changes due to high atrial rates, chronic experimental AF leads to extensive changes in atrial ultra-structure. The nature and time course of these alterations  have been elaborately investigated in goats by Ausma et al.[18 ] in which after 9 to 23 weeks of artificially maintained AF, they found marked changes in atrial cellular substructures, including loss of myofibrils, accumulation of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin. These changes were present in up to 92% of studied atrial cells and are considered to be a sign of dedifferentiation rather than degeneration, that is, the cells seemed to have changed to a fetal phenotype.


There are few studies describing atrial ultra-structural changes in humans suffering AF. Bailey et al. [19] reported the first study in which the atrial myocardium of living patients with AF was examined. They obtained atrial tissue from patients undergoing valve surgery for rheumatic valve disease. Of the 44 patients included, 32 were in AF, of whom 18 had AF for more than 5 years at the time of surgery. They observed that long-term AF was characterized by loss of muscle mass, which they described as diffuse atrophy. The presence of rheumatic heart disease, however, may have importantly influenced the structural abnormalities that were seen.


Mary-Rabine et al. [20] described the relationship between atrial cellular electrophysiology, function, and ultra-structure in 121 patients undergoing cardiac surgery, of whom 23 had AF. Atrial biopsies obtained from patients with AF showed ultra-structural abnormalities such as loss of myofibrils and disorganization of sarcoplasmic reticulum. However, interpretation of these changes is difficult because AF was associated with higher patient age and atrial dilatation, factors independently associated with these structural changes [21].


Brundel et al. [22] evaluated atrial tissue of patients with normal ventricular function undergoing coronary artery bypass grafting and compared patients with persistent AF, paroxysmal AF, and sinus rhythm. In patients with paroxysmal and persistent AF, contraction bands were observed, which were virtually absent in patients with sinus rhythm. In patients with AF, degenerative features such as clumping of nuclear chromatin and the presence of lysosome-like bodies were present. Furthermore, only in patients with persistent AF, were hibernating atrial myocytes found, characterized by glycogen accumulation and the dispersion of nuclear chromatin.


Apart from these intracellular changes, alterations in expression of atrial intercellular gap junctions have been described during AF. These gap junctions are responsible for the cell-to-cell propagation of electrical conduction and consist of 2 connexons, each formed by 6 proteins called connexins. In the heart, connexin 43 is the most abundant, whereas connexin 40 is mainly present in the atrium [23]. Whether AF-induced changes in these connexins play a significant role in atrial remodeling remains a subject of debate [23].


AF has been shown to be associated with a net increase [24, 25] or decrease [26, 27] in connexin 40 expression with redistribution to the lateral borders of the atrial myocytes. This may result in anisotropy and dispersion of atrial conduction, thus favoring an environment vulnerable to AF.

Atrial structural and ultra-structural changes due to volume/pressure overload

Atrial remodeling due heart failure or other causes of increased atrial volume /pressure overload is characterized primarily by biatrial dilatation, which is considered an important factor in the genesis of atrial arrhythmias in these patients. In the presence of acute or chronic stress or injury, the atria stretch and stiffen [28, 29]. Larger atrial size means that more circuits can be accommodated and that long-wavelength circuits that are too large for a normal atrium can be supported. Atrial dimensions are a particularly important determinant of the occurrence of multiple-circuit reentry [30]. In canine models, Shi. et al. [31] showed that five weeks of rapid ventricular pacing (220-240 beats per minute) resulted in an increase of 80.2% and 61.2% in left and right atrial diastolic area, respectively, as measured by transthoracic echocardiography. This biatrial dilatation was associated with a decrease in atrial contractile function, which was reflected by a decrease in left and right fractional area shortening of 41.8% and 33.7%, respectively. Similar results were obtained by Power et al. [32] who found a 100% increase in diastolic left atrial cross-sectional area in sheep after 6 weeks of rapid ventricular pacing. In patients with diastolic dysfunction, there is also a clear relationship between the magnitude of diastolic dysfunction and left atrial diameter and volume which could explain the propensity to develop AF in patients with hypertension and diastolic dysfunction [33, 34].


Atrial volume or pressure overload results in atrial dilatation which is accompanied by changes in atrial ultrastructure, also in the absence of atrial arrhythmia [23]. The development of rapid ventricular pacing–induced congestive heart failure (CHF) in dogs is associated with atrial interstitial fibrosis, cellular hypertrophy, loss of myofibrils, and signs of necrosis [11]. These processes were shown to be irreversible after cessation of pacing and consequent recovery of the systolic ventricular function [35].


Verheule et al. [36] showed that chronic atrial dilatation in dogs due to experimental mitral regurgitation in the absence of overt CHF results in atrial fibrosis, signs of chronic inflammation, and increased accumulation of glycogen.


Aimé-Sempé et al. [37] investigated human specimens of dilated right atrial myocardium and found signs of apoptosis and myolysis in patients with AF as well as in patients with a decreased left ventricular ejection fraction (LVEF) who were in sinus rhythm. These included a disrupted sarcomeric apparatus with replacement by glycogen granules, the presence of large Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL)-positive nuclei with condensed chromatin indicating the presence of DNA breakage and the decreased expression of antiapoptotic proteins.


In a study of  15 patients with an atrial septal defect, who were in sinus rhythm and had a dilated RA , structural abnormalities including hypertrophy and cell degeneration were observed only in the presence of elevated RA pressures [38].


Also, ultra-structural changes in heart-failure-induced remodeling characterized by degenerative changes, including cellular edema, nuclear pyknosis, and contraction band necrosis leading to cell loss [29].

Electrophysiological changes in atrial remodeling

Electrophysiological studies comparing heart failure-induced AR with atrial tachycardia-induced AR have shown significant differences in electrophysiological properties between these two types. These differences depend mostly on the changes in the ionic channels during the remodeling process [7].


Atrial electrophysiological changes due to rapid atrial rates

Olsson et al. [39] found short right atrial monophasic action potentials in patients immediately after conversion of AF to sinus rhythm. Boutjdir et al. [40] and Le Heuzey et al. [41] found short atrial refractory periods with loss of physiological adaptation to high rates in atrial appendages of patients with chronic AF undergoing surgery.


 In 1995, two independent studies showed changes in atrial electrophysiology as a consequence of AF. Wijffels et al. [4] demonstrated that repeated induction of AF in goats resulted in progressive duration of the induced paroxysms, together with shortening of the atrial refractory period and loss, or even reversal of, its physiological adaptation to rate. Similarly, Morillo et al. [16] demonstrated that rapid atrial pacing for 6 weeks in dogs resulted in shortening of atrial refractory periods, an increased inducibility and stability of AF, together with an increase in P wave duration and a decrease in atrial conduction velocity.


Shortening of refractoriness in combination with a decrease in conduction velocity results in a shorter atrial wavelength, which is the product of these two parameters. This could be an explanation for the increased duration of AF, because according to the multiple wavelet theory, a short wavelength will result in smaller wavelets which would increase the maximum number of wavelets, given a certain atrial surface. Furthermore, chronic atrial tachycardia depresses sinus node function which, may reduce the stability of sinus rhythm and increase the stability of AF [42].


Changes in atrial electrophysiology favoring an increased inducibility of AF have been described as a consequence of long-term pacing or repeated induction of the arrhythmia. An increased heterogeneity of atrial conduction and atrial refractoriness, which provides a substrate for reentry, may occur after only 24 hours of rapid atrial pacing [43].


As well as these research data, several studies have also investigated atrial electrical remodeling in humans. Short-term artificially induced AF in humans results in shortening of atrial refractoriness [44]. In addition, in patients with persistent AF, atrial refractoriness has been shown to be shorter when compared with controls [45, 46] and to prolong after conversion to sinus rhythm [47, 48].


Shortening of the atrial refractory period and the atrial action potential may be caused by a net decrease of inward ionic currents (Na+ or Ca++), a net increase of outward currents (K+), or a combination of both [23]. In dogs subjected to 42 days of rapid atrial pacing, Yue et al. [49] demonstrated a reduction in the L-type calcium current (ICa,L) and the transient outward potassium current (Ito). The inward rectifier K+ current (IK1) and the components of the delayed rectifier current (IKur, IKr, IKs) were unchanged. In addition, they demonstrated a decrease of the mRNA expression of the L-type calcium channel a1c subunit, as well as Kv4.3 (encoding for Ito) [50].


Human studies also demonstrated a decrease in ICa,L and Ito in patients with AF undergoing cardiac surgery [51, 54]. The reduction in ICa,L may be explained by a decreased expression  of the L-type calcium channel a1c subunit [55, 57].


Brundel et al. [58] reported a decreased protein expression of the L-type calcium channel, a finding that could not be confirmed by others [59]. Reduced mRNA and/or protein concentrations of several potassium channels have also been reported [58, 61].


Despite these findings, a pivotal role of atrial electrical remodeling in the progressive nature of clinical AF has never been proven. Furthermore, experimental atrial electrical remodeling is complete within hours to days, whereas the development of sustained AF generally takes at least 1 week. This indicates that other factors must be involved [23].


A study in thirty-five patients with a left-sided accessory pathway and without a prior history of AF where after successful ablation, the effective refractory periods (ERPs) and conduction times of the right atrium (RA), left atrium(LA), and the PVs were determined. Afterwards, AF was induced and maintained for a period of 15 min. Thereafter, the stimulation protocol was repeated. It was found that new-onset; short-lasting AF creates electrical characteristics similar to those of patients with AF. However, these alterations are pronounced in the PVs compared with the atria, indicating that “AF begets AF in the PVs” [53].


Electrophysiological changes due to volume/ pressure overload AR

Increased ventricular and atrial pressures during the development of CHF may modulate atrial electrophysiology by causing myocardial stretch. This phenomenon is called mechanoelectric feedback or contraction-excitation coupling and has been demonstrated in animal studies as well as in humans [23].


In the setting of an acute rise in the atrial pressure, several studies have demonstrated changes in atrial refractoriness because of an acute rise in atrial pressure. However, there is disagreement whether refractory periods shorten or prolong. In dogs, an acute rise in atrial pressure caused by (near) simultaneous atrioventricular (AV) pacing [63] or by saline infusion [64] resulted in prolongation of atrial effective refractory period (AERP).  In contrast, Solti et al. [65] reported a decrease of AERP along with an increase of atrial conduction times. Similarly, acute atrial volume overload in rabbits resulted in shortening of AERP [66] and a decrease of atrial conduction velocity [67]. Although the results of these studies are conflicting, all report an enhanced susceptibility to AF during an acute rise in atrial pressure.


The effects of chronic heart failure producing long-standing atrial hemodynamic overload on atrial electrophysiologic properties are even less well established. Li et al. [11] evaluated the processes underlying the enhanced propensity of AF during the development of pacing-induced CHF in a dog model. They induced CHF by rapid ventricular pacing over 5 weeks. When compared with controls, the dogs with CHF had a dramatically increased duration of AF induced by burst pacing (535 ± 82 vs 8 ± 4 seconds). When comparing the AERP between the groups, at longer basic cycle lengths AERP was comparable between both groups, whereas at shorter cycle lengths, AERP was slightly longer in the CHF group. However, this prolongation of AERP is not likely responsible for the enhanced inducibility and sustenance of AF during CHF. Li et al. also observed a dispersion of atrial conduction in the CHF dogs, caused by extensive interstitial atrial fibrosis, resulting in an environment vulnerable to reentry [11]. Comparable results were obtained in sheep with ventricular pacing–induced CHF [31]. During 6 weeks of pacing left, but not right AERP was prolonged and the susceptibility to AF initially increased. However, the sheep became less susceptible to AF induced by an extra-stimulus, although the duration of AF, when induced, was longer.


Boyden et al. [68] found no differences in the action potential duration and shape in the right atrium and only a slightly increased duration in the left atrium of cats with cardiomyopathy when compared with controls. Furthermore, the diseased atria had a substantially increased amount of inexcitable cells and showed structural abnormalities including fibrosis, cellular hypertrophy, and degeneration. In dogs with artificially induced right atrial enlargement caused by tricuspid regurgitation, they found no difference in the right atrial action potential, although the susceptibility and duration of AF was significantly increased when compared with controls. However, there was no spontaneously occurring AF [69].


On the other hand, Verheule et al. [70] found prolonged atrial refractory periods but unchanged atrial conduction velocity in dogs 1 month after the induction of mitral regurgitation. Dogs with pacing-induced CHF had an enhanced inducibility of atrial tachycardia with foci located along the crista terminalis and pulmonary veins. The focal nature of specific types of AF recently has gained a lot of interest. These findings indicate that the development of CHF may evoke atrial foci, leading to AF [71].


Patients with dilated atria have been shown to have a shorter atrial action potential with lower amplitude than patients in whom the atria have normal dimensions [72]. However, this finding may partly be due to the presence of AF in 25% of patients with the dilated atria, which apart from underlying heart disease, shortens AERP [4]. In contrast, Calkins et al. [73] found no change in AERP during simultaneous AV pacing. However, an acute increase of the atrial pressure by two simultaneous AV beats resulted in a shortening of AERP [74]. These results were not influenced by the presence or absence of autonomic blockade.


In addition, chronic hemodynamic load may lead to changes in atrial electrophysiology. Patients with AF and mitral valve regurgitation were shown to have an increased AERP. This prolongation was not related to arrhythmia history, that is, patients with chronic or paroxysmal AF and mitral regurgitation also had longer AERP than patients suffering the same arrhythmia without valve disease [58, 75].


Sparks et al. [76] investigated the effect of VVI pacing in patients during sinus rhythm in the presence of an AV block. Chronic AV dissociation also resulted in prolongation of AERP and an impairment of left atrial contractility, [77] processes which were reversible after reestablishing AV synchrony by DDD pacing. Experimental CHF in dogs decreases the densities of atrial ICaL, Ito, and IKs. The net result of the decrease of repolarizing potassium currents and the decrease of depolarizing calcium current results in a slight prolongation of the atrial refractory period and action potential, but only at higher rates. Furthermore, the Na+/Ca+ exchanger current increases, which may promote delayed afterdepolarization induced ectopic activity and indirectly influence atrial refractoriness [78]. Le Grand et al. [72] found a decrease in ICaL in humans with dilated atria whereas others [79] found no change. In addition, reported changes in Ito and other potassium currents are conflicting. Some authors [80] have reported an increase; others [72, 81] have found a decrease of Ito in dilated atria. In addition, the inward rectifier current IK1 was found to be reduced [82] or unchanged [72]. The discrepancies of these findings may be explained by the variety of underlying cardiac disease, use of medication, and the presence of AF.

Neurohormonal disturbances in atrial remodeling

In addition to the role in the electrophysiologic and hemodynamic function of the heart, the atria also have an endocrinologic function.


AR is associated with neurohormonal changes that include increase in angiotensin II (Ang-II), aldosterone, transforming growth factor-beta1, [83] atrial natriuretic peptide (ANP), [84] brain natriuretic peptide (BNP), [85, 86] and sympathetic hyperinnervation [87].      


The neurohormonal changes resulted from rapid atrial rates and volume/pressure overload will be elaborated below.


Neurohormonal disturbances due to rapid atrial rates

High atrial rates are associated with increase plasma levels of atrial natriuretic peptide (ANP). [88, 89] ANP is elevated not only in the acute phase [90] but also when the arrhythmia is chronic. [91] ANP is secreted by right and left atria, has diuretic effects, reduces peripheral vascular resistance, reduces the sympathetic tone, and suppresses the renin-angiotensin-aldosterone axis. [92] Therefore ANP reduces the preload and protects the atria from hemodynamic overload. The exact mechanism by which an atrial arrhythmia results in secretion of ANP is unknown, although it has been demonstrated that atrial stretch is an important factor [93, 94].


Atrial remodeling due to rapid atrial rates, at least in part, depends on angiotensin II–dependent pathways [94, 96]. Angiotensin II is a potent promoter of fibrosis, leading to cardiac fibroblast proliferation and, thus may play an important role in the formation of a substrate vulnerable to AF.


Angiotensin II acts by binding to two discrete receptor subtypes, angiotensin type I (AT1R) and type II (AT2R) receptors. The signaling cascades coupled to AT1Rs and AT2Rs are distinct and often have opposing actions. AT1Rs mediate the profibrotic effects of angiotensin II by stimulating fibroblast proliferation, cardiomyocyte hypertrophy, and apoptosis [97]. AT1R signaling through the Shc/Grb2/SOS adapter-protein complex activates the small GTPase protein Ras, which initiates mitogen-activated protein kinase phosphorylation cascades that are centrally involved in remodeling [98, 99]. AT1R activation stimulates phospholipase C. Phospholipase C breaks down membrane phosphoinositol bisphosphate (PIP2) into diacylglycerol and inositol 1,4,5-trisphosphate (IP3) [98]. Diacylglycerol activates protein kinase C, and IP3 causes intracellular Ca++ release, both of which promote remodeling. Signal transduction also occurs through the JAK/STAT pathway, activating transcription factors such as activator protein-1 and nuclear factor-B. AT2R activation inhibits mitogen-activated protein kinases [99] via dephosphorylating actions of phosphotyrosine phosphatase and protein phosphatase 2A and produces antiproliferative and survival-promoting effects that oppose AT1R-mediated changes.


Angiotensin II mediates cardiac fibrosis in a variety of cardiac pathologies, including hypertensive heart disease, CHF, myocardial infarction, and cardiomyopathy [100]. Transgenic mice with cardiac-restricted ACE overexpression show marked atrial dilation with focal fibrosis and AF [101]. Aldosterone promotes fibrosis through its action on cardiac fibroblasts [101] and matrix metalloproteinases (MMPs) [102, 103]. Thus, the neurohormonal changes have an important role in the genesis and the progression of AR, [104 - 106] which lead to the development and maintenance of AF [104, 107, 108].

Neurohormonal disturbances due to volume/pressure overload

Natriuretic peptides defend against excess salt and water retention, inhibit vasoconstrictor peptides, promote vascular relaxation, and inhibit the sympathetic neural system. These neurohormones have been shown to be important markers in the assessment of clinical severity and prognosis of CHF [86, 109]. Patients with CHF have high plasma concentrations of both ANP and BNP. These concentrations are associated with the degree of left ventricular dysfunction and may raise a factor 30 in patients with New York Heart Association Class IV CHF [110]. ANP is mainly secreted from the cardiac atria but during CHF, a proportion is also produced in the ventricles [111]. Several experimental pacing–induced CHF studies have demonstrated an increase in circulating ANP and BNP during the development of CHF [112, 113].


Mechanical stretch of atria is the strongest stimulator for ANP secretion, which is augmented by endothelin and inhibited by nitric oxide (NO).However, longstanding AF in severe LV dysfunction and development of atrial fibrosis can cause depletion of ANP stores [114, 115].


AR is associated with increase BNP level. The association between BNP and LA volume in predicting AF was demonstrated in post-thoracotomy patients where patients with larger LA volume and higher BNP levels had higher incidence of post-operative AF [116, 117].


The development of atrial fibrosis during CHF is angiotensin-mediated. In dogs subjected to rapid ventricular pacing, administration of enalapril resulted in attenuation of pacing-induced changes in angiotensin II concentrations, atrial fibrosis, and impairment of atrial contractility [118, 119].


No direct effect of ACE inhibiting drugs or angiotensin II blockers on atrial refractoriness have been established in patients. However, potential benefits of these drugs in arrhythmia burden in patients with CHF have been reported. Administration of the ACE inhibitor trandolapril reduced the incidence of AF in patients with systolic dysfunction after myocardial infarction, [120] Data from heart failure trials indicate that treatment with an ACE inhibitor [121] or angiotensin II blocker [122] reduces the risk of developing AF in patients with left ventricular dysfunction. Furthermore, these effects have been shown to be independent of changes in blood pressure.

The role of systematic inflammation in atrial remodeling and AF initiation and perpetration

Recent studies have indicated that inflammation might play a significant role in the initiation, maintenance, and perpetuation of AF. Inflammatory cells have been demonstrated to infiltrate atrial tissue of patients with AF [123, 124]. Inflammatory markers such as C-reactive protein (CRP), tumour necrosis facort, interlukin and cytokines have been shown to be elevated in patients with  AF [125, 126]. Elevation of CRP and IL-6 might also contribute to generation and perpetuation of AF, as evidenced by marked inflammatory infiltrates, myocyte necrosis, and fibrosis found in atrial biopsies of patients with lone AF [124, 126 - 129]. Complement activation has also been described in a cohort of patients with AF without other associated inflammatory diseases [128]. It has been suggested in 1 population-based cohort of 1,011 patients who were followed up to 4 years, that in the absence of high baseline complement component levels (C3 and C4) a high baseline CRP level is not significantly associated with a high incidence of AF [130].


The exact mechanism of inflammation leading to tissue remodeling in AF patients is unclear and warrants further research. It is thought that AF leads to myocyte calcium overload, promoting atrial myocyte apoptosis. C-reactive protein might then act as an opsonin that binds to atrial myocytes, inducing local inflammation and complement activation. Tissue damage then ensues and fibrosis sets in [129, 131, 132]. Specifically, in the presence of Ca++ ions, CRP binds to phosphatidylcholine. Long-chain acylcarnitines and lysophosphatidylcholines are generated from phosphatidylcholine and can further contribute to membrane dysfunction by inhibiting the exchange of sodium and calcium ions in sarcomeres. This can eventually lead to the maintenance of AF [129 - 131].


The inflammatory cascade and catecholamine surge associated with surgery might play a prominent role in initiating atrial tachyarrhythmias after cardiac surgery. It has been reported to occur in up to 40% of patients undergoing cardiac bypass surgery (CABG) or up to 50% of patients undergoing cardiac valvular surgery [3, 4]. After cardiac surgery, the complement system is activated and pro-inflammatory cytokines are released. Bruins et al. [128] found that IL-6 rises initially and peaks at 6 h after surgery and a second phase occurs in which CRP levels peak on post-operative day 2, with complement-CRP complexes peaking on postoperative day 2 or 3. The incidence of atrial arrhythmias follows a similar pattern and peaks on post-operative day 2 or 3 [4,127, 133, 134]. Another study correlated leukocytosis to an increased incidence in AF in post-operative cardiovascular patients [132].


Burzotta et al. [135] discovered that the development of postoperative AF was linked to 174G/C polymorphism of the IL-6 promoter gene. In this particular study of 110 patients undergoing CABG, genetic analysis revealed that the GG genotype was associated with higher IL-6 plasma levels and subsequently, a greater inflammatory burden. Similarly Gaudino et al. [136] established a genetic link between inflammation and AF and found that the GG genotype was an independent predictor of postoperative AF.


The notion that the inflammatory process plays a role in AF has garnered much attention in many recent studies and is now a well-established connection. Many clinicians now consider inflammation to be an independent risk factor for the initiation and maintenance of AF [123]. Studies are currently underway in an attempt to attenuate the inflammatory burden in patients with AF by novel therapeutic interventions.


Agents with potential anti-inflammatory effects such as ACEI, statins, steroids, omega 3 fatty acids, and vitamin C have increasingly recognizable roles in prevention of AF. This will be discussed in the next section.

Potential therapeutic interventions to prevent or reverse AR

Reversal of AR is possible, especially if it is in an early stage. The earlier the restoration of sinus rhythm by medication, electrical cardioversion, catheter ablation or even surgery, the better the outcome, in term of reverse remodeling.


Medical interventions


The angiotensin converting enzyme inhibitors (ACEI) and the angiotensin receptor blockers (ARBs)

The ACEI and ARBs are antihypertensive medications which may improve LV systolic and diastolic function; and have beneficial effects on AR [137]. However, it appears that altering renin-angiotensin-aldosterone system has strong effects on AR, which extends beyond their beneficial effects on blood pressure regulation. AR structural remodeling appeared reversible with quinapril, which occurrs in parallel with an improvement in arterial stiffness but independent of blood pressure changes [138]. Angiotensin-converting enzyme inhibition has been shown to have important beneficial effects on electrical remodeling [139, 140], atrial stretch [138, 141], interstitial fibrosis [142 - 144] and inflammation [144 - 146]. ACEI has been shown to prevent first and recurrent AF in patients with hypertension [122] and LV dysfunction [120 - 122, 147, 148]. Patients with persistent AF who were treated with amiodarone plus irbesartan had a lower rate of recurrence of AF than did patients treated with amiodarone alone [149]. A number of large clinical trials have shown a beneficial impact of ACE inhibition on AF, however, the AF was not the primary end point in these studies [122, 148, 150 - 156]. The meta-analysis of 11 studies, which included 56,308 patients, were identified: 4 in heart failure, 3 in hypertension, 2 in patients following cardioversion for AF, and 2 in patients following myocardial infarction. Overall, ACEIs and ARBs reduced the relative risk of AF by 28% (95% confidence interval [CI] 15% to 40%, p = 0.0002). Reduction in AF was similar between the two classes of drugs (ACEI: 28%, p = 0.01; ARB: 29%, p = 0.00002) and was greatest in patients with heart failure (relative risk reduction [RRR] = 44%, p = 0.007). Overall, there was no significant reduction in AF in patients with hypertension (RRR = 12%, p = 0.4), although one trial found a significant 29% reduction in patients with left ventricular (LV) hypertrophy [157].


In patients with AF, an ACE-dependent increase in the amounts of activated Erk1/Erk2 in atrial interstitial cells was noted [104]. The effectiveness of angiotensin blocker to reverse AR and suppress AF lies in its ability to modulate the Ang-II–activated Erk1/Erk2 proteins, thereby effectively inhibiting interstitial fibrosis [119, 139, 140].


Animal studies showed that the use of angiotensin blockers can mitigate increase in interstitial fibrosis and LA pressure; reduce myolysis, loss of contractile proteins, and LA dysfunction; and shorten the duration of AF [119, 139, 140]. Administration of the angiotensin-converting enzyme (ACE) inhibitor captopril attenuated shortening of AERP after 3 hours of rapid atrial pacing in dogs [139]. In the TRACE (Trandolapril Cardiac Evaluation) trial [120], 2.8% of patients in the trandolapril arm developed AF versus 5.3% (p _ 0.05) in the placebo arm; similarly, patients randomized to enalapril in SOLVD (Studies Of Left Ventricular Dysfunction) [121] had a 78% relative risk reduction in developing AF (P Value0.0001).


There are a few studies linking reduction in AF with an administration of an ARB. In one prospective study, addition of irbesartan to amiodarone resulted in lower recurrence of AF after DCCV in patients with normal ejection fraction (79.52% vs. 55.91%, p _ 0.007) [149] Subset analysis of Val-Heft (the Valsartan Heart Failure Trial) [150] and (Candesartan in Heart Failure) [148] showed a reduction in the incidence of AF in patients receiving ARBs compared with placebo. Current evidence does not support the administration of statins and ACEIs /ARBs for the sole purpose of preventing AF, because many of the current published reports available were retrospective and observational in nature, with limited sample size [123].


Aldosterone receptor antagonists

Aldosterone receptor antagonists, such as spironolactone and eplerenone, appear to have a beneficial impact in modifying the extracellular matrix, especially in terms of collagen deposition and fibrosis.Spironolactone has been shown to reverse the effects of AR by reducing atrial hyperexcitability, [108] inhibition of vascular Ang-I/Ang-II conversion, [108] and attenuation of atrial fibrosis [159 - 161].


In animal models, Milliez et al. [160] demonstrated that spironolactone attenuated atrial fibrosis, caused by chronic CHF in rats, more than did lisinopril and atenolol. The role of spironolactone and eplerenone on arrhythmia prevention was inferred from the RALES (Randomized ALdactone Evaluation Study) [161] and EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study) [162]  trials where patients treated with these drugs had lower rates of sudden cardiac deaths. No studies have been done to assess the direct effects of aldosterone antagonists on AF prevention and treatment.


Beta blockers

The effect of beta-blockers on AR and AF suppression has not been well studied. Metoprolol and carvedilol can attenuate LV remodeling [163 - 165]. In a double-blind, placebo-controlled study in 394 patients with persistent AF who underwent cardioversion, metoprolol CR/XL was effective in preventing relapse into atrial fibrillation or flutter [166].


Statins

Statins are highly effective and widely used lipid-lowering agents in clinical practice but they also display a number of pleiotropic properties beyond cholesterol lowering. These pleiotropic effects include anti-inflammatory, antioxidant, atrial remodeling attenuation, ion channel stabilization, and autonomic nervous system regulation [167].


In animal and human studies and in human studies [168 - 171] Simvastatin has been shown to reduce the propensity to AF possibly through its antioxidant effects [166, 168].


Two studies have evaluated the role of statin treatment in animal models of HF. Firstly, Shiroshita-Takeshita et al. [168] demonstrated that simvastatin effectively attenuates atrial structural remodeling and AF promotion in a dog model of tachycardiomyopathy. Furthermore, Okazaki et al. [172] showed that atorvastatin attenuates atrial oxidative stress and prevents atrial electrical and structural remodeling in rat hypertensive HF induced by chronic inhibition of NO synthesis.


During the past few years, the association between statin use and development of AF has been examined in different clinical settings [167, 173, 174].  Recent meta-analysis by Liu et al. [167] on this issue showed different results between randomized clinical trials (RCTs) and observational studies, suggesting that statins maybe effective in AF prevention, especially in postoperative patients. Therefore, larger RCTs with longer follow-up periods and more sensitive methods of AF detection are urgently needed. Recently, a review by Abi Nasr et al. [175] provided an overview of the evidence regarding AF management in elderly patients with CHF. The authors discussed treatments for the underlying disease, prevention of thromboembolism, rate or rhythm control, as well as nonpharmacological therapy that may be effective in some patients. In their review, they noted the possible role of statins in maintaining sinus rhythm in persistent lone-AF patients.


A post-hoc analysis from the Sudden Cardiac Death in Heart Failure Trial (SCDHeFT) [176] also demonstrated similar findings. After adjusting for several confounding factors, statin use was independently associated with a significant reduction (28%) in the relative risk of AF or atrial flutter during a follow-up period of 45.5 months.


These results are similar to a study by Hanna et al. [177] which reported the result of a registry of 25,268 patients with reduced left ventricular ejection fraction (LFEF <OR = 40%), that demonstrated a 31 % reduction in the odds of AF prevalence with statin. Recently also, another observational study by Adabag et al. [178] added new evidence to this issue. There are three large ongoing RCTs (GISSI-HF, CORONA and UNIVERSE) [179] which hopefully will provide us more clear data with respect to the role of statins in AF prevention in patients with HF.


Vitamin C

Vitamin C is a potent water-soluble antioxidant [180, 181] which has been recently shown to ameliorate electrical remodeling in animal studies and to decrease the incidence of postoperative AF in patients undergoing cardiac surgery [182]. However, no data exists with respect to AF due to other causes.


It was demonstrated that Vitamin C exerts favourable electrophysiological effects, ameliorating the shortening of the AERP. Furthermore, Vitamin C inhibits nitrotyrosine formation in the atrial tissue, indicating an effective antioxidant action. In a pilot study, the investigators showed that oral administration of vitamin C significantly reduces the incidence of postoperative AF in patients undergoing coronary artery bypass graft surgery (CABG) [182].


A small study in 44 patients who underwent successful electrical cardioversion of persistent AF with one to one randomization to either oral Vitamin C administration or no additional therapy, the AF recurred one week after the successful cardioversion in 4.5% of patients in the Vitamin C group compared to 36.3% in the control group (P value 0.024). Compared to baseline values, inflammatory indices decreased significantly in the Vitamin C group but not in the control group. CRP and fibrinogen levels were higher in patients who relapsed into AF compared to patients who maintained sinus rhythm [183]. So the role of vitamin C in prevention and treatment of patients with AF is still unclear and needs further RCTs to evaluate the issue.


Glucocorticoids

Most of the initial studies involving glucocorticoid therapy in AF were conducted in patients undergoing cardiovascular surgery, and the results were equivocal. Early studies by Chaney et al. [184] did not find any significant benefit of steroid administration to patients undergoing coronary artery bypass graft surgery (CABG); however, Yared et al. [185] in a study of 216 patients undergoing cardiothoracic surgery, found that dexamethasone administration perioperatively decreased the incidence of post-operative AF in the first few days after surgery. Inflammatory markers (i.e., CRP, IL-6, and so forth) were not measured in this study.


Yared et al. [186] reported on the outcome of 78 patients undergoing combined CABG and valve surgery who were randomized to receive either dexamethasone or placebo before surgery. In this study, dexamethasone did not affect the incidence of perioperative AF. However, it did modulate the release of several inflammatory and acute-phase response mediators that are associated with adverse outcomes. Most recently, a group from Finland showed in a prospective, randomized, double-blind study, that the use of 100 mg cortisone, given intravenously immediately before cardiac surgery and continued for 3 consecutive days, significantly decreased the incidence of AF after cardiac surgery by 15% [187].


In a prospective trial which examined the effects of adding methylprednisolone to propafenone in AF patients undergoing pharmacological cardioversion to assess the recurrence rate, the methylprednisolone-treated group experienced an 80% decrease in CRP levels (p < 0.001) within the first month, which was maintained throughout the duration of the study. This corresponded to a reduction of AF recurrence from 50% in the placebo group to 9.6% in the methylprednisolone group (p < 0.001) [188].


Unsaturated Fatty Acids (UFAs)

Fish oil, and omega-3 fatty acids in particular, have been found to reduce plasma levels of triglycerides and increase levels of high-density lipoprotein in patients with marked hypertriglyceridemia, and a pharmaceutical-grade preparation has recently received approval from the US Food and Drug Administration to market for this purpose [189]. However, in both bench research studies and clinical trials, evidence for clinically significant antiarrhythmic properties has also been detected in association with omega-3 fatty acid intake [189].


The consumption of fish and fish oils appears in some large-scale clinical trials to have beneficial effects on survival, particularly or at least in ischemic substrates and in populations without high ambient consumption of fish intake [190, 191].


Clinical data supporting antiarrhythmic properties of fish oils have also been obtained from studies examining surrogate markers of lethal sustained ventricular arrhythmias, such as incidence of premature ventricular complexes, and from other arrhythmias, such as atrial tachycardia and atrial fibrillation [189]. 


In a double-blind, placebo-controlled study in 65 patients with cardiac arrhythmias but without evidence of CAD or heart failure, the incidences of atrial and ventricular premature complexes, couplets, and triplets were reduced over a 6-month period among those randomized to treatment with 3 g/day of fish oil providing 1 g of omega-3 fatty acids, compared with those randomized to 3 g/day of olive oil as a placebo [192]. Similarly, in a study in 40 patients with dual-chamber pacemakers who had paroxysmal atrial tachyarrhythmia recorded at periodic monitoring, treatment with 1 g/day of omega-3 fatty acids for 4 months significantly reduced the number of atrial tachyarrhythmia episodes by 59% (p = 0.037) and the burden by 67% (p = 0.029) without change in device programming or pharmacologic therapy [193]. During the 4-month follow-up after discontinuation of the omega-3 fatty acid therapy, both the number of episodes and burden of duration increased to levels comparable to pretreatment values.


Risk of atrial fibrillation was also inversely associated with fish intake in a prospective population-based cohort of 4,815 adults aged ≥65 years [194]. A total of 980 cases of incident atrial fibrillation were diagnosed from hospital discharge records and annual ECGs at 12-year follow-up. A 28% lower risk of atrial fibrillation was associated with consumption of tuna or other broiled or baked fish 1 to 4 times weekly compared with intakes of <1 time monthly. Risk was 31% lower when fish was consumed ≥5 times weekly. Adjusting for a history of, or the presence of, MI or congestive heart failure did not change the results. This study also confirmed a significant relation between plasma phospholipid EPA and DHA concentrations and consumption of tuna or other broiled or baked fish. In contrast, consumption of fried fish or fish sandwiches did not significantly influence risk of atrial fibrillation nor did it relate to plasma phospholipid concentration of EPA and DHA. An additional trial in atrial fibrillation is ongoing [195].


The incidence of atrial fibrillation has also been reported to be reduced by fish oils when used following coronary artery bypass surgery [196]. In a prospective study, 160 patients were randomized to receive polyunsaturated fatty acids (2 g/day) or placebo control, starting 5 days before surgery and continuing until hospital discharge [196].  The incidence of atrial fibrillation was 33.3% in the control group and 15.2% in the fish oil group (p = 0.013), and hospital stay was 1 day shorter in the fish oil group (p = 0.017).


There are several mechanisms through which n-3 FA could prevent arrhythmias. The n-3 FA is incorporated into myocyte membranes and may influence ion channel function. N-3 FA inhibits voltage-gated sodium channels in cardiomyocytes, resulting in a longer relative refractory period and an increased voltage required for depolarization which reduces heart rate [197]. N-3 FA also maintains the integrity of L-type calcium channels, preventing cytosolic calcium overload during periods of ischemic stress [198]. On other hand n-3 FA improves left ventricular efficiency and reduces blood pressure which could indirectly decrease heart rate [199].


Other medications

The interest in reverse remodeling has resulted in the development of new medications, one of which is Omapatrilat, a vasopeptidase inhibitor. In a canine model of tachycardia-induced congestive heart failure, chronic treatment with omapatrilat maintained myocardial ATP, the high-energy currency, and protected adenylate and creatine kinase phosphotransfer capacity. Omapatrilat-induced bioenergetic protection was associated with maintained atrial and ventricular structural integrity, albeit without full recovery of the creatine phosphate pool [200].


Alagebrium chloride (ALT-711) is a novel compound that breaks glucose crosslinks and may improve ventricular and arterial compliance. In 23 patients with diastolic heart failure,  sixteen weeks of treatment with alagebrium (ALT 17) resulted in a decrease in left ventricular mass and improvements in left ventricular diastolic filling and quality of life in patient with diastolic HF [201].  Alagebrium also improved total arterial compliance in older humans with vascular stiffening [202, 203]. Whether ALT-711 has the potential of reversing AR and reducing vulnerability to AF induced by arterial stiffness requires further investigation.


Electrical cardioversion

Conversion of AF to sinus rhythm, whether by electrical cardioversion or radiofrequency ablation, has been shown to reduce LA size [204 - 207] and improve LA function [208, 209]. Reversal of electrical remodeling can usually be rapidly achieved, [210, 211] but vulnerability to the recurrence of AF depends on the amount of atrial fibrosis and the size of the LA [204]. Normalization of atrial structure and function generally lags behind the reversal of electrical remodeling [211].


AF catheter ablation

In 57 consecutive patients with symptomatic drug-refractory AF, radiofrequency ablation reverted 39 (68%) to sinus rhythm [206]. This was accompanied by a significant reduction in LA antero-posterior dimension (4.5 ± 0.3 cm vs. follow-up 4.2 ± 0.2 cm, p < 0.01), and LA volume (59 ± 12 ml vs. follow-up 50 ± 11 ml, p < 0.01) at 3 months follow-up. In contrast, patients who remained in AF after catheter ablation had increased LA size at 3 months follow-up (4.5 ± 0.3 cm to 4.8 ± 0.3 cm, p < 0.05; 63 ± 7 ml to 68 ± 8 ml, p < 0.05). In a cohort study of 251 consecutive patients with paroxysmal (n=179) or permanent (n=72) AF who underwent circumferential PV ablation , Paponi et al. [212] reported no significant relationship between ablation success and clinical variables such as age, AF duration, presence of heart disease, or ejection fraction. Also the LA size did not seem to influence the outcome in paroxysmal AF patients, whereas in patients with permanent AF the likelihood for ablation failure was increased in the presence of LA dilation. They concluded that the fact that their technique was able to eradicate AF, regardless of its duration or the presence of structural heart disease, suggests that AF-induced atrial electrical remodeling may be reversible after the elimination of the focal source or arrhythmogenic substrate.


Catheter ablation of AF may also results in recovery of sinus node function in patients with persistent AF with prolonged sinus pauses [213]. 

Cardiac surgery and surgical AF ablation

Mitral valve surgery for valvular stenosis or regurgitation can relieve LA pressure and volume overload with reduction of LA size and improved LA function [208].  AF patients who underwent LA reduction together with mitral valve surgery had lower AF recurrence after 3 months when compared to those who did not have LA reduction [214]. Further reduction in LA size was seen in those who remained in sinus rhythm when compared to those who had persistent or recurrent AF [214]. Successful surgical ablation of AF (Maze procedure) has been shown to reduce neurohormonal activation as evidenced by a decrease in ANP, BNP, and angiotensin II [215, 216]. MAZE III procedure has been demonstrated to reduce LA size and improve LA transport function and LV diastolic function [217].

Conclusion

AR is an important and increasingly recognizable factor in the development and maintenance of AF. It is likely that AR is playing an integral part in the cascade of the events that lead to AF development.


Understanding of AR mechanisms may help in the management and hopefully prevention of AF. The extent of AF burden reduction and other adverse clinical outcomes with prevention and reversal of AR remains to be proven. The measures to prevent or reverse AR at its early stages need to be studied further with large CRT. If proven successful these measures may result in significant reduction in the AF burden and its major impact on public health care.

References

  1. Page RL. Clinical practice. Newly diagnosed atrial fibrillation. N Engl J Med 2004; 351:2408 –16. CrossRef  PubMed
  2. Falk R. Atrial fibrillation. N Engl J Med 2001; 344:1067–78. CrossRef  PubMed
  3. Haisguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary vein. N Engl J Med 1998; 339:659–66. CrossRef  PubMed
  4. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation 1995; 92: 1954–68.
  5. Korantzopoulos P, Kolettis T, Siogas K, Goudevenos J. Atrial fibrillation and electrical remodeling: the potential role of inflammation and oxidative stress. Med Sci Monit 2003; 9:RA225–9.
  6. Oral H, Pappone C, Chung A, Good E, Bogun F, Pelosi F, Bates ER, Lehmann MH, Vicedomini G, Augello G, Agricola E, Sala S, Santinelli V, Morady F. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med 2006; 354: 934–41. CrossRef  PubMed
  7. Casaclang-Verzosa G, Gersh BJ, Tsang TSM . Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation. J Am Coll Cardiol 2008; 51:1-11. CrossRef  PubMed
  8. Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation: mechanisms and implications . Circ Arrhythm Electrophysiol 2008;1 :62-73. CrossRef
  9. Goette A, Honeycutt C, Langberg JJ. Electrical remodeling in atrial fibrillation : Time course and mechanisms. Circulation 1996;94:2968-2974.
  10. Ausma J, Litjens N, Lenders MH, Duimel H, Mast F, Wouters L, Ramaekers F, Allessie M, Borgers M. Time course of atrial fibrillation-induced cellular structural remodeling in atria of the goat. J Mol Cell Cardiol 2001;33:2083-2094. CrossRef  PubMed
  11. Li DS, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs—atrial remodeling of a different sort Circulation 1999;100:87-95.
  12. Van der Velden HMW, van der Zee L, Wijffels MC, et al: Atrial fibrillation in the goat induces changes in monophasic action potential and mRNA expression of ion channels involved in repolarization. J Cardiovasc Electrophysiol 11:1262- 1269, 2000. CrossRef  PubMed
  13. Sanfilippo AJ, Abascal VM, Sheehan M, et al: Atrial enlargement as a consequence of atrial fibrillation. A prospective echocardiographic study Circulation 82:792- 797, 1990. Circulation 82:792- 797.
  14. Van Gelder IC, Crijns HJ, Van Gilst WH, et al: Decrease of right and left atrial sizes after direct current electrical cardioversion in chronic atrial fibrillation. Am J Cardiol 67:93- 95, 1991. CrossRef  PubMed
  15. Gosselink AT, Crijns HJ, Hamer HP, et al: Changes in left and right atrial size after cardioversion of atrialfibrillation: Role of mitral valve disease. J Am Coll Cardiol 22:1666- 1672, 1993.
  16. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacingStructural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation 1995;91:1588-1595.
  17. Manning WJ, Silverman DI, Katz SE, et al: Impaired left, atrial mechanical function after cardioversion: Relation to the duration of atrial fibrillation. J Am Coll Cardiol 23:1535- 1540, 1994.
  18. Ausma J, Wijffels M, Thone F, Wouters L, Allessie M, Borgers M. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat Circulation 1997;96:3157-3163.
  19. Bailey GW, Braniff BA, Hancock EW, et al: Relation of left atrial pathology to atrial fibrillation in mitral valvular disease. Ann Intern Med 69:13- 20, 1968.
  20. Mary-Rabine L, Albert A, Pham TD, et al. The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure Circ Res 1983;52:188-199.
  21. Kistler PM, Sanders P, Fynn SP, et al: Electrophysiologic and electroanatomic changes in the human atrium associated with age. J Am Coll Cardiol 44:109-116, 2004. CrossRef  PubMed
  22. Brundel BJ, Ausma J, Van Gelder IC, et al: Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation. Cardiovasc Res 54:380-389, 2002. CrossRef  PubMed
  23. Bas A. Schoonderwoerd, Isabelle C. Van Gelder, Dirk J. Van Veldhuisen, Maarten P. Van den Berg, and Harry J.G.M. Crijns. Electrical and Structural Remodeling: Role in the Genesis and Maintenance of Atrial Fibrillation Progress in Cardiovascular Diseases, Vol. 48, No. 3 (November/December), 2005: pp 153-168.
  24. Polontchouk L, Haefliger JA, Ebelt B, et al: Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. J Am Coll Cardiol 38: 883- 891, 2001. CrossRef  PubMed
  25. Wetzel U, Boldt A, Lauschke J, et al: Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart 91:166-170, 2005. CrossRef  PubMed
  26. Kostin S, Klein G, Szalay Z, et al: Structural correlate of atrial fibrillation in human patients. Cardiovasc Res 54:361-379, 2002. CrossRef  PubMed
  27. Nao T, Ohkusa T, Hisamatsu Y, et al: Comparison of expression of connexin in right atrial myocardium in patients with chronic atrial fibrillation versus those in sinus rhythm. Am J Cardiol 91:678-683, 2003. CrossRef  PubMed
  28. Hoit BD, Shao Y, Gabel M. Left atrial systolic and diastolic function accompanying chronic rapid pacing-induced atrial failure Am J Physiol 1998;275:H183-H189.
  29. Khan A, Moe GW, Nili N, et al. The cardiac atria are chambers of active remodeling and dynamic collagen turnover during evolving heart failure J Am Coll Cardiol 2004;43:68-76. CrossRef  PubMed
  30. Zou R, Kneller J, Leon LJ, Nattel S. Substrate size as a determinant of fibrillatory activity maintenance in a mathematical model of canine atrium. Am J Physiol (Heart Circ Physiol). 2005; 289: H1002–H1012. CrossRef  PubMed
  31. Shi Y, Ducharme A, Li D, Gaspo R, Nattel S, Tardif JC. Remodeling of atrial dimensions and emptying function in canine models of atrial fibrillation Cardiovasc Res 2001; 52:217-225. CrossRef  PubMed
  32. Power JM, Beacom GA, Alferness CA, et al: Susceptibility to atrial fibrillation: A study in an ovine model of pacing-induced early heart failure. J Cardiovasc Electrophysiol 9:423- 435, 1998. CrossRef  PubMed
  33. Matsuda M, Matsuda Y: Mechanism of left atrial enlargement related to ventricular diastolic impairment in hypertension. Clin Cardiol 19:954-959, 1996. CrossRef  PubMed
  34. Pritchett AM, Mahoney DW, Jacobsen SJ, et al: Diastolic dysfunction and left atrial volume: A population- based study. J AmColl Cardiol 45:87- 92, 2005. CrossRef  PubMed
  35. Shinagawa K, Shi YF, Tardif JC, et al: Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs. Circulation 105:2672- 2678, 2002. CrossRef  PubMed
  36. Verheule S, Wilson E, Everett T, et al: Alterations in atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation. Circulation 107:2615- 2622, 2003.
  37. Aime-Sempe C, Folliguet T, Rucker-Martin C, et al: Myocardial cell death in fibrillating and dilated human right atria. J Am Coll Cardiol 34:1577- 1586, 1999. CrossRef  PubMed
  38. Fenoglio Jr JJ, Pham TD, Hordof A, et al: Right atrial ultrastructure in congenital heart disease. II. Atrial septal defect: Effects of volume overload. Am J Cardiol 43:820- 827, 1979. CrossRef  PubMed
  39. Olsson SB, Cotoi S, Varnauskas E: Monophasic action potential and sinus rhythm stability after conversion of atrial fibrillation. Acta Med Scand 190:381-387, 1971.
  40. Boutjdir M, Le Heuzey JY, Lavergne T, et al: In homogeneity of cellular refractoriness in human atrium: Factor of arrhythmia? Pacing Clin Electrophysiol 9:1095-1100, 1986. CrossRef  PubMed
  41. Le Heuzey JY, Boutjdir M, Gagey S, et al: Cellular aspects of atrial vulnerability, in Attuel P, Coumel P, Janse MJ (eds): The atrium in health and disease. Mount Kisco, NY, Futura Publishing, 1989, pp 81-94.
  42. Elvan A, Wylie K, Zipes DP: Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling. Circulation 94: 2953- 2960, 1996.
  43. Fareh S, Villemaire C, Nattel S: Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling. Circulation 98:2202- 2209, 1998.
  44. Daoud EG, Bogun F, Goyal R, et al: Effect of atrial fibrillation on atrial refractoriness in humans. Circulation 94:1600- 1606, 1996.
  45. Franz MR, Karasik PL, Li C, et al: Electrical remodeling of the human atrium: Similar effects in patients with chronic atrial fibrillation and atrial flutter. J Am Coll Cardiol 30:1785- 1792, 1997. CrossRef  PubMed
  46. BJ, Van Gelder IC, Henning RH, et al: Ionchannel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation 103:684-690, 2001.
  47. Pandozi C, Bianconi L, Villani M, et al: Electrophysiological characteristics of the human atria after cardioversion of persistent atrial fibrillation. Circulation 98:2860-2865, 1998.
  48. Yu WC, Lee SH, Tai CT, et al: Reversal of atrial electrical remodeling following cardioversion of long-standing atrial fibrillation in man. Cardiovasc Res 42:470- 476, 1999. CrossRef  PubMed
  49. Yue L, Feng J, Gaspo R, Li G-R, Wang Z, Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res. 1997;81:512–525.
  50. Yue L, Melnyk P, Gaspo R, Wang Z, Nattel S. Molecular mechanisms underlying ionic remodeling in a dog model of atrial fibrillation. Circ Res. 1999;84:776-784.
  51. Van Wagoner DR, Pond AL, Lamorgese M, et al: Atrial L-type Ca2+ currents and human atrial fibrillation . Circ Res 85:428- 436, 1999.
  52. Bosch RF, Zeng X, Grammer JB, et al: Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc Res 44:121- 131, 1999. CrossRef  PubMed
  53. Skasa M, Jungling E, Picht E, et al: L-type calcium currents in atrial myocytes from patients with persistent and non-persistent atrial fibrillation. Basic Res Cardiol 96:151-159, 2001. CrossRef  PubMed
  54. Workman AJ, Kane KA, Rankin AC: The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation. Cardiovasc Res 52:226- 235, 2001. CrossRef  PubMed
  55. 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 (In Process Citation). J Am Coll Cardiol 33:1231-1237, 1999. CrossRef  PubMed
  56. Brundel BJ, Van Gelder IC, Henning RH, et al: Gene expression of proteins influencing the calcium homeostasis in patients with persistent and paroxysmal atrial fibrillation. Cardiovasc Res 42:443- 454, 1999. CrossRef  PubMed
  57. Van Gelder IC, Brundel BJ, Henning RH, et al:Alterations in gene expression of proteins involved in the calcium handling in patients with atrial fibrillation. J Cardiovasc Electrophysiol 10: 552- 560, 1999. CrossRef  PubMed
  58. Brundel BJ, Van Gelder IC, Henning RH, et al: Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation 103:684-690, 2001.
  59. Schotten U, Haase H, Frechen D, et al: The L-type Ca2+-channel subunits alpha1C and beta2 are not downregulated in atrial myocardium of patients with chronic atrial fibrillation. J Mol Cell Cardiol 35:437- 443, 2003. CrossRef  PubMed
  60. Van Wagoner DR, Pond AL, McCarthy PM, et al: Outward K+ current densities and Kv15 expression are reduced in chronic human atrial fibrillation. Circ Res 80:772-781, 1997.
  61. Brundel BJ, Van Gelder IC, Henning RH, et al: Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: Differential regulation of protein and mRNA levels for K+ channels. J Am Coll Cardiol 37:926- 932, 2001. CrossRef  PubMed
  62. Rostock T, Steven D, Lutomsky B, Servatius H, Drewitz I, Klemm H, Müllerleile K, Ventura R, Meinertz T, Willems S. Atrial fibrillation begets atrial fibrillation in the pulmonary veins on the impact of atrial fibrillation on the electrophysiological properties of the pulmonary veins in humans. J Am Coll Cardiol. 2008 Jun 3;51(22):2161-2.
  63. Kaseda S, Zipes DP: Contraction-excitation feedback in the atria: A cause of changes in refractoriness. J Am Coll Cardiol 11:1327-1336, 1988.
  64. Satoh T, Zipes DP: Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation. J Cardiovasc Electrophysiol 7:833- 842, 199.
  65. Solti F, Vecsey T, Kekesi V, Juhasz-Nagy A. The effect of atrial dilatation on the genesis of atrial arrhythmias Cardiovasc Res 1989;23:882-886. CrossRef  PubMed
  66. Ravelli F, Allessie M: Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart. Circulation 96:1686-1695, 1997.
  67. Eijsbouts SC, Majidi M, van Zandvoort M, et al: Effects of acute atrial dilation on heterogeneity in conduction in the isolated rabbit heart. J Cardiovasc Electrophysiol 14:269- 278, 2003.
  68. Boyden PA, Tilley LP, Albala A, et al: Mechanisms for atrial arrhythmias associated with cardiomyopathy: A study of feline hearts with primary myocardial disease. Circulation 69:1036-1047, 1984.
  69. Boyden PA, Hoffman BF: The effects on atrial electrophysiology and structure of surgically induced right atrial enlargement in dogs. Circ Res 49:1319- 1331, 1981.
  70. Verheule S, Wilson E, Everett T, et al: Alterations in atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation. Circulation 107:2615- 2622, 2003.
  71. Fenelon G, Shepard RK, Stambler BS: Focal originof atrial tachycardia in dogs with rapid ventricular pacing–induced heart failure. J Cardiovasc Electrophysiol 14:1093- 1102, 2003. CrossRef  PubMed
  72. Le Grand BL, Hatem S, Deroubaix E, et al: Depressed transient outward and calcium currents in dilated human atria. Cardiovasc Res 28:548- 556, 1994. CrossRef  PubMed
  73. Calkins H, el-Atassi R, Leon A, et al. Effect of the atrioventricular relationship on atrial refractoriness in humans. Pacing Clin Electrophysiol 1992; 15: 771–778. CrossRef  PubMed
  74. Calkins H, el-Atassi R, Kalbfleisch S, Langberg J, Morady F. Effects of an acute increase in atrial pressure on atrial refractoriness in humans. Pacing Clin Electrophysiol 1992; 15: 1674–1680. CrossRef  PubMed
  75. Tieleman RG, Van Gelder IC, Tuinenburg AE, et al: Infra- and post operative atrial refractory periods in relation to atrial arrhythmia history and the presence of mitral regurgitation. Pacing Clin Electrophysiol (Part II)816, 1999 (abstr).
  76. Sparks PB, Mond HG, Vohra JK, et al: Electrical remodeling of the atria following loss of atrioventricular synchrony: A long-term study in humans. Circulation 100:1894- 1900, 1999.
  77. Sparks PB, Mond HG, Vohra JK, et al: Mechanical remodeling of the left atrium after loss of atrioventricular synchrony. A long-term study in humans. Circulation 100:1714- 1721, 1999.
  78. Li D, Melnyk P, Feng J, et al. Effects of experimental heart failure on atrial cellular and ionic electrophysiology Circulation 2000;101:2631-2638.
  79. Cheng TH, Lee FY, Wei J, et al: Comparison of calcium-current in isolated atrial myocytes from failing and nonfailing human hearts. Mol Cell Biochem 157:157- 162, 1996. CrossRef  PubMed
  80. 80. Schreieck J, Wang Y, Overbeck M, et al: Altered transient outward current in human atrial myocytes of patients with reduced left ventricular function. J Cardiovasc Electrophysiol 11:180- 192, 2000. CrossRef  PubMed
  81. Mansourati J, Le Grand B: Transient outward current in young and adult diseased human atria. Am J Physiol 265:H1466-H1470, 1993.
  82. Koumi S, Arentzen CE, Backer CL, et al: Alterations in muscarinic K+ channel response to acetylcholine and to G protein–mediated activation in atrial myocytes isolated from failing human hearts. Circulation 90:2213- 2224, 1994.
  83. Hanna N, Cardin S, Leung TK, Nattel S. Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure Cardiovasc Res 2004;63:236-244. CrossRef  PubMed
  84. Dietz JR. Mechanisms of atrial natriuretic peptide secretion from the atrium Cardiovasc Res 2005;68:8-17. CrossRef  PubMed
  85. Tsioufis C, Stougiannos P, Taxiarchou E, et al. The interplay between haemodynamic load, brain natriuretic peptide and left atrial size in the early stages of essential hypertension J Hypertens 2006;24:965-972. CrossRef  PubMed
  86. Omland T, Aakvaag A, Bonarjee VV, et al: Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Circulation 1996, 93:1963- 1969.
  87. Miyauchi Y, Zhou S, Okuyama Y, et al. Altered atrial electrical restitution and heterogeneous sympathetic hyperinnervation in hearts with chronic left ventricular myocardial infarction: implications for atrial fibrillation Circulation 2003;108:360-366. CrossRef  PubMed
  88. Schiebinger RJ, Linden J: Effect of atrial contraction frequency on atrial natriuretic peptide secretion. Am J Physiol 251:H1095-H1099, 1986.
  89. Schiebinger RJ, Li Y, Cragoe Jr EJ: Calcium dependency of frequency-stimulated atrial natriuretic peptide secretion. Hypertension 23:710-716, 1994.
  90. Roy D, Paillard F, Cassidy D, et al: Aerial natriuretic factor during atrial fibrillation and supraventricular tachycardia. J Am Coll Cardiol 9:509- 514, 1987.
  91. Van Den Berg MP, Crijns HJ, Van Veldhuisen DJ, et al: Atrial natriuretic peptide in patients with heart failure and chronic atrial fibrillation: Role of duration of atrial fibrillation. Am Heart J 135:242- 244, 1998. CrossRef  PubMed
  92. Levin ER, Gardner DG, Samson WK: Natriuretic peptides. N Engl J Med 339:321-328, 1998. CrossRef  PubMed
  93. Edwards BS, Zimmerman RS, Schwab TR, et al: Atrial stretch, not pressure, is the principal determinant controlling the acute release of atrial natriuretic factor. Circ Res 62:191-195, 1988.
  94. Christensen G, Leistad E: Atrial systolic pressure, as well as stretch, is a principal stimulus for release of ANF. Am J Physiol 272:H820-H826, 1997.
  95. Cardin S, Li D, Thorin-Trescases N, et al: Evolution of the atrial fibrillation substrate in experimental congestive heart failure: Angiotensin-dependent and -independent pathways. Cardiovasc Res 60: 315- 325, 2003. CrossRef  PubMed
  96. Goette A, Arndt M, Rocken C, et al: Regulation of angiotensin II receptor subtypes during atrial fibrillation in humans. Circulation 101:2678- 2681, 2000.
  97. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008; 51: 802–809. CrossRef  PubMed
  98. Nattel S. Electrophysiological remodeling: are ion channel static players or dynamic movers ? J Cardiovasc Electrophysiol. 1999;10:1553-1556. CrossRef  PubMed
  99. Hunyady L, Catt KJ. Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol Endocrinol. 2006; 20: 953–970. CrossRef  PubMed
  100. Xiao HD, Fuchs S, Campbell DJ, Lewis W, Dudley SC Jr, Kasi VS, Hoit BD, Keshelava G, Zhao H, Capecchi MR, Bernstein KE. Mice with cardiac-restricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death. Am J Pathol. 2004; 165: 1019–1032.
  101. Stockand JD, Meszaros JG. Aldosterone stimulates proliferation of cardiac fibroblasts by activating Ki-RasA and MAPK1/2 signaling Am J Physiol Heart Circ Physiol 2003;284:H176-H184.
  102. Rude MK, Duhaney T-AS, Kuster GM, et al. Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes Hypertension 2005;46:555-561. CrossRef  PubMed
  103. Anne W, Willems R, Roskams T, et al. Matrix metalloproteinases and atrial remodeling in patients with mitral valve disease and atrial fibrillation Cardiovasc Res 2005;67:655-666. CrossRef  PubMed
  104. Goette A, Staack T, Rocken C, et al. Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation J Am Coll Cardiol 2000;35:1669-1677. CrossRef  PubMed
  105. Thai H, Castellano L, Juneman E, et al. Pretreatment with angiotensin receptor blockade prevents left ventricular dysfunction and blunts left ventricular remodeling associated with acute myocardial infarction Circulation 2006;114:1933-1939. CrossRef  PubMed
  106. Wong GC, Marcotte F, Rudski LG. Impact of chronic lisinopril therapy on left atrial volume versus dimension in chronic organic mitral regurgitation Can J Cardiol 2006;22:125-129.
  107. Madrid AH, Peng J, Zamora J, et al. The role of angiotensin receptor blockers and/or angiotensin converting enzyme inhibitors in the prevention of atrial fibrillation in patients with cardiovascular diseases: meta-analysis of randomized controlled clinical trials Pacing Clin Electrophysiol 2004;27:1405-1410. CrossRef  PubMed
  108. Shroff SC, Ryu K, Martovitz NL, Hoit BD, Stambler BS. Selective aldosterone blockade suppresses atrial tachyarrhythmias in heart failure J Cardiovasc Electrophysiol 2006;17:534-541. CrossRef  PubMed
  109. Gottlieb SS, Kukin ML, Ahern D, et al: Prognostic importance of atrial natriuretic peptide in patients with chronic heart failure. J Am Coll Cardiol 13: 1534- 1539, 1989.
  110. Burnett Jr JC, Kao PC, Hu DC, et al: Atrial natriuretic peptide elevation in congestive heart failure in the human. Science 231:1145- 1147, 1986. CrossRef  PubMed
  111. Yasue H, Yoshimura M, Sumida H, et al: Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 90:195-203, 1994.
  112. Moe GW, Angus C, Howard RJ, et al: Pathophysiological role of changing atrial size and pressure in modulation of atrial natriuretic factor during evolving experimental heart failure. Cardiovasc Res 24: 570- 577, 1990. CrossRef  PubMed
  113. Brunner-La Rocca HP, Woods RL, Kaye DM, et al: Divergent effects of ANP and BNP in acute heart failure: Evidence for a putative BNP-selective receptor? J Hypertens 20:1195- 1201, 2002. CrossRef  PubMed
  114. Hayashi M, Tsutamoto T, Wada A, et al. Intravenous atrial natriuretic peptide prevents left ventricular remodeling in patients with first anterior acute myocardial infarction J Am Coll Cardiol 2001;37:1820-1826. CrossRef  PubMed
  115. Van den Berg MP, Tjeerdsma G, Jan de Kam P, Boomsma F, Crijns HJ, van Veldhuisen DJ. Longstanding atrial fibrillation causes depletion of atrial natriuretic peptide in patients with advanced congestive heart failure Eur J Heart Fail 2002;4:255-262. CrossRef  PubMed
  116. Osranek M, Fatema K, Qaddoura F, et al. Left atrial volume predicts the risk of atrial fibrillation after cardiac surgery: a prospective study J Am Coll Cardiol 2006;48:779-786. CrossRef  PubMed
  117. Wazni OM, Martin DO, Marrouche NF, et al. Plasma B-type natriuretic peptide levels predict postoperative atrial fibrillation in patients undergoing cardiac surgery Circulation 2004;110:124-127. CrossRef  PubMed
  118. 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 104:2608- 2614, 2001. CrossRef  PubMed
  119. Shi Y, Li D, Tardif JC, Nattel S. Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure Cardiovasc Res 2002;54:456-461. CrossRef  PubMed
  120. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction Circulation 1999;100:376-380.
  121. Vermes E, Tardif JC, Bourassa MG, et al. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials Circulation 2003;107:2926-2931. CrossRef  PubMed
  122. 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;45:712-719. CrossRef  PubMed
  123. T. Issac, H. Dokainish, N. Lakkis. Role of Inflammation in Initiation and Perpetuation of Atrial FibrillationA Systematic Review of the Published Data.Journal of the American College of Cardiology, Volume 50, Issue 21, Pages 2021-2028.
  124. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation Circulation 1997;96:1180-1184.
  125. Psychari SN, Apostolou TS, Sinos L, Hamodraka E, Liakos G, Kremastinos DT. Relation of elevated C-reactive protein and interleukin-6 levels to left atrial size and duration of episodes in patients with atrial fibrillation Am J Cardiol 2005;95:764-767. CrossRef  PubMed
  126. Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation Circulation 2001;104:2886-2891. CrossRef  PubMed
  127. Ommen S, Odell J, Stanton M. Atrial arrhythmias after cardiothoracic surgery. N Engl J Med 1997;336:1429 –34. CrossRef  PubMed
  128. Bruins P, Velthuis H, Yazdanbakhsh AP, et al. Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia. Circulation 1997;96:3542– 8.
  129. Aviles R, Martin D, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003;108:3006 –10. CrossRef  PubMed
  130. Dernellis J, Panaretou M. Effects of C-reactive protein and the third and fourth components of complement (C3 and C4) on incidence of atrial fibrillation. Am J Cardiol 2006;97:245– 8. CrossRef  PubMed
  131. Dernellis J, Panaretou M. C-reactive protein and paroxysmal atrial fibrillation: evidence of the implication of an inflammatory process in paroxysmal atrial fibrillation. Acta Cardiologica 2001;56:375– 80. CrossRef  PubMed
  132. Abdelhadi RH, Gurm HS, Van Wagoner DR, Chung MK. Relation of an exaggerated rise in white blood cells after coronary bypass or cardiac valve surgery to development of atrial fibrillation postoperatively. Am J Cardiol 2004;93:1176–8. CrossRef  PubMed
  133. Korantzopoulos P, Kolettis T, Siogas K, Goudevenos J. Atrial fibrillation and electrical remodeling: the potential role of inflammation and oxidative stress. Med Sci Monit 2003; 9:RA225–9.
  134. Gabay C, Kushner I. Acute phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340:448 –54. CrossRef  PubMed
  135. Burzotta F, Lacoviella L, Di Castelnuovo A, et al. Relation of the 174 G/C polymorphism of interleukin-6 to interleukin-6 plasma levels and to length of hospitalization after surgical coronary revascularization. Am J Cardiol 2001;88: 1125– 8. CrossRef  PubMed
  136. Gaudino M, Andreotti F, Zamparelli R, et al. The 174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation 2003;108:195–9. CrossRef
  137. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden Am J Cardiol 2002;90:1284-1289. CrossRef  PubMed
  138. Tsang TS, Barnes ME, Abhayaratna WP, et al. Effects of quinapril on left atrial structural remodeling and arterial stiffness Am J Cardiol 2006;97:916-920. CrossRef  PubMed
  139. Nakashima H, Kumagai K, Urata H, Gondo N, Ideishi M, Arakawa K. Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation Circulation 2000;101:2612-2617.
  140. Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation J Am Coll Cardiol 2003;41:2197-2204. CrossRef  PubMed
  141. Mattioli AV, Bonatti S, Monopoli D, Zennaro M, Mattioli G. Influence of regression of left ventricular hypertrophy on left atrial size and function in patients with moderate hypertension Blood Press 2005;14:273-278. CrossRef  PubMed
  142. Weber KT, Brilla CG, Campbell SE, Guarda E, Zhou G, Sriram K. Myocardial fibrosis: role of angiotensin II and aldosterone Basic Res Cardiol 1993;88(Suppl Brooks WW, Bing OH, Robinson KG, Slawsky MT, Chaletsky DM, Conrad CH. Effect of angiotensin-converting enzyme inhibition on myocardial fibrosis and function in hypertrophied and failing myocardium from the spontaneously hypertensive rat Circulation 1997;96:4002-4010.
  143. Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease Circulation 2000;102:1388-1393.
  144. Xu ZG, Lanting L, Vaziri ND, et al. Upregulation of angiotensin II type 1 receptor, inflammatory mediators, and enzymes of arachidonate metabolism in obese Zucker rat kidney: reversal by angiotensin II type 1 receptor blockade Circulation 2005;111:1962-1969. CrossRef  PubMed
  145. Anand IS, Latini R, Florea VG, et al. C-reactive protein in heart failure: prognostic value and the effect of valsartan Circulation 2005;112:1428-1434. CrossRef  PubMed
  146. Fliser D, Buchholz K, Haller H. Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation Circulation 2004;110:1103-1107. CrossRef  PubMed
  147. Murray KT, Rottman JN, Arbogast PG, et al. Inhibition of angiotensin II signaling and recurrence of atrial fibrillation in AFFIRM Heart Rhythm 2004;1:669-675. CrossRef  PubMed
  148. Ducharme A, Swedberg K, Pfeffer MA, 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. CrossRef  PubMed
  149. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study Circulation 2002;106:331-336. CrossRef  PubMed
  150. Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT) Am Heart J 2005;149:548-557. CrossRef  PubMed
  151. The SOLVD Investigators Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure N Engl J Med 1991;325:293-302.
  152. The Captopril Prevention Project (CAPP) Study Group Effect of angiotensin-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPP) randomized trial Curr Hypertens Rep 1999;1:466-467.
  153. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity: the Swedish Trial in Old Patients with Hypertension-2 study Lancet 1999;354:1751-1756. CrossRef
  154. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial Lancet 2004;363:2022-2031. CrossRef
  155. Pizzetti F, Turazza FM, Franzosi MG, et al. Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: the GISSI-3 data Heart 2001;86:527-532. CrossRef  PubMed
  156. Torp-Pedersen C, Kober L. Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular function after acute myocardial infarction. TRACE study group. Trandolapril Cardiac Evaluation Lancet 1999;354:9-12.
  157. Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis J Am Coll Cardiol 2005;45:1832-1839. CrossRef  PubMed
  158. Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure Circulation 2000;101:594-597.
  159. Brilla CG, Matsubara LS, Weber KT. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism J Mol Cell Cardiol 1993;25:563-575. CrossRef  PubMed
  160. 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;26:2193-2199. CrossRef  PubMed
  161. Fraccarollo D, Galuppo P, Hildemann S, Christ M, Ertl G, Bauersachs J. Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction J Am Coll Cardiol 2003;42:1666-1673. CrossRef  PubMed
  162. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction N Engl J Med 2003;348:1309-1321. CrossRef  PubMed
  163. Palazzuoli A, Quatrini I, Vecchiato L, et al. Left ventricular diastolic function improvement by carvedilol therapy in advanced heart failure J Cardiovasc Pharmacol 2005;45:563-568. CrossRef  PubMed
  164. Kobayashi M, Machida N, Mitsuishi M, Yamane Y. Beta-blocker improves survival, left ventricular function, and myocardial remodeling in hypertensive rats with diastolic heart failure Am J Hypertens 2004;17:1112-1119. CrossRef  PubMed
  165. Waagstein F, Stromblad O, Andersson B, et al. Increased exercise ejection fraction and reversed remodeling after long-term treatment with metoprolol in congestive heart failure: a randomized, stratified, double-blind, placebo-controlled trial in mild to moderate heart failure due to ischemic or idiopathic dilated cardiomyopathy Eur J Heart Fail 2003;5:679-691. CrossRef  PubMed
  166. Kuhlkamp V, Schirdewan A, Stangl K, Homberg M, Ploch M, Beck OA. Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study J Am Coll Cardiol 2000;36:139-146. CrossRef  PubMed
  167. Liu T, Li L, Korantzopoulos P, Liu E, Li G. Statin use and development of atrial fibrillation: A systematic review and meta-analysis of randomized clinical trials and observational studies. Int J Cardiol 2008;126:160–70. CrossRef  PubMed
  168. Shiroshita-Takeshita A, Brundel BJ, Burstein B, et al. Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure. Cardiovasc Res 2007;74:75–84. CrossRef  PubMed
  169. Kumagai K, Nakashima H, Saku K. The HMG-CoA reductase inhibitor atorvastatin prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model Cardiovasc Res 2004;62:105-111. CrossRef  PubMed
  170. Siu C-W, Lau C-P, Tse H-F. Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversion Am J Cardiol 2003;92:1343-1345. CrossRef  PubMed
  171. Young-Xu Y, Jabbour S, Goldberg R, et al. Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease Am J Cardiol 2003;92:1379-1383. CrossRef  PubMed
  172. Okazaki H,Minamino T,Wakeno M, et al. Statin prevents structural and electrical atrial remodeling in rat hypertensive heart failure induced by chronic inhibition of NO synthesis. Circulation 2007;116(Suppl II):140.
  173. Kostapanos MS, Liberopoulos EN, Goudevenos JA, Mikhailidis DP, Elisaf MS. Do statins have an antiarrhythmic activity? Cardiovasc Res 2007;75:10–20. CrossRef  PubMed
  174. Savelieva I, Camm J. Statins and polyunsaturated fatty acids for treatment of atrial fibrillation. Nat Clin Pract Cardiovasc Med 2008;5:30–41. CrossRef  PubMed
  175. Abi Nasr I, Mansencal N, Dubourg O. Management of atrial fibrillation in heart failure in the elderly. Int J Cardiol 2008;125:178–82. CrossRef  PubMed
  176. Dickinson MG, Hellkamp AS, Ip JH, et al. Statin therapy was associated with reduced atrial fibrillation and flutter in heart failure patients in SCD-HEFT. Heart Rhythm 2006;3(Suppl):S49. CrossRef
  177. Hanna IR, Heeke B, Bush H, et al. Lipid-lowering drug use is associated with reduced prevalence of atrial fibrillation in patients with left ventricular systolic dysfunction. Heart Rhythm. 2006;3:881-886. CrossRef  PubMed
  178. Adabag AS, Nelson DB, Bloomfield HE. Effects of statin therapy on preventing atrial fibrillation in coronary disease and heart failure. Am Heart J 2007;154:1140–5. CrossRef  PubMed
  179. Celik T, Iyisoy A, Dogru MT, Isik E, et al, Statin use in chronic heart failure: Waiting for the results of large prospective outcome trials. Int J Cardiol. Vol132, Issue1, 6 February 2009, Pages 122-124. CrossRef  PubMed
  180. Korantzopoulos P and Galaris D, The protective role of vitamin C on endothelial dysfunction, J Clin Basic Cardiol 6 (2003), pp. 3–6.
  181. Johnston CS and Cox SK, Plasma-saturating intakes of vitamin C confer maximal antioxidant protection to plasma, J Am Coll Nutr 20 (2001), pp. 623–627.
  182. Carnes CA, Chung MK, Nakayama T, Nakayama H, Baliga RS, Piao S, Kanderian A, Pavia S, Hamlin RL, McCarthy PM, Bauer JA, Van Wagoner DR. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res 2001;89: e32–e38. CrossRef  PubMed
  183. Korantzopoulos P, Kolettis TM, Kountouris E, Dimitroula V, Karanikis P, Pappa E, Siogas K, Goudevenos JA. Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation. Int J Cardiol 2005;102:321–326. CrossRef  PubMed
  184. Chaney MA, Nikolov MP, Blakeman B, Bakhos M, Slogoff S. Pulmonary effects of methylprednisolone in patients undergoing coronary artery bypass grafting and early tracheal extubation. Anesth Analg 1998;87(1):27-33. CrossRef
  185. Yared JP, Starr NJ, Torres FK, Bashour CA, Bourdakos G, Piedmonte M, Michener JA, Davis JA, Rosenberger TE. Effects of single dose, postinduction dexamethasone on recovery after cardiac surgery. Ann Thorac Surg. 2000; 69: 1420–1424. CrossRef  PubMed
  186. J.P. Yared, M.H. Bakri and S.C. Erzurum et al., Effect of dexamethasone on atrial fibrillation after cardiac surgery: prospective, randomized, double-blind, placebo-controlled trial, J Cardiothorac Vasc Anesth 21 (2007), pp. 68–75. CrossRef  PubMed
  187. Halonen J, Halonen P and Jarvinen O et al., Corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial, JAMA 297 (2007), pp. 1562–1567. CrossRef  PubMed
  188. Dernellis J, Panaretou M. Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation Eur Heart J 2004;25:1100-1107. CrossRef  PubMed
  189. Reiffel JA, McDonald A.: Antiarrhythmic effects of Omega-3 fatty acids. Am J Cardiol 2006;98 (suppl): 50i-60i. CrossRef
  190. Lee KW, Hamaad A, MacFadyen RJ, Lip GY. Effects of dietary fat intake in sudden death: reduction of death with omega-3 fatty acids. Curr Cardiol Rep 2004;6: 371–378. CrossRef  PubMed
  191. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, Franzosi MG, Geraci E, Levantesi G, Maggioni AP, et al. Early protection against sudden death by omega-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002;105: 1897–1903. CrossRef  PubMed
  192. Singer P and Wirth M, Can omega-3 polyunsaturated fatty acids reduce cardiac arrhythmias? Results of a clinical trial, Prostaglandins Leukot Essent Fatty Acids 71 (2004), pp. 153–159. CrossRef
  193. Biscione F, Totteri A, De Vita A, Lo BF and Altamura G, Effect of omega-3 fatty acids on the prevention of atrial arrhythmias [in Italian], Ital Heart J Suppl 6 (2005), pp. 53–59.
  194. Mozaffarian D, Psaty BM, Rimm EB, LemaitreRN, Burke GL, Lyles MF, Lefkowitz D and Siscovick DS, Fish intake and risk of incident atrial fibrillation, Circulation 110 (2004), pp. 368–373. CrossRef  PubMed
  195. Harrison RA and Elton PJ, Is there a role for long-chain ?3 or oil-rich fish in the treatment of atrial fibrillation?, Med Hypotheses 64 (2005), pp. 59–63. CrossRef  PubMed
  196. Calo L, Bianconi L, Colivicchi F, Lamberti F, Loricchio ML, de Ruvo E, Meo A, Pandozi C, Staibano M and Santini M., N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial, J Am Coll Cardiol.
  197. Leaf, A; Kang, JX; Xiao, YF; Billman, GE. N-3 Fatty acids in the prevention of cardiac arrhythmias. Lipids. 1999;34(suppl):S187–S189. CrossRef  PubMed
  198. Hallaq, H; Smith, TW; Leaf, A. Modulation of dihydropyridine-sensitive calcium channels in heart cells by fish oil fatty acids. Proc Natl Acad Sci U S A. 1992;89:1760 –1764. CrossRef
  199. Charnock, JS; McLennan, PL; Abeywardena, MY. Dietary modulation of lipid metabolism and mechanical performance of the heart. Mol Cell Biochem. 1992;116:19–25. CrossRef  PubMed
  200. Cha Y-M, Dzeja PP, Redfield MM, Shen WK, Terzic A. Bioenergetic protection of failing atrial and ventricular myocardium by vasopeptidase inhibitor omapatrilat Am J Physiol Heart Circ Physiol 2006;290:H1686-H1692. CrossRef  PubMed
  201. Little WC, Zile MR, Kitzman DW, Hundley WG, O’Brien TX, Degroof RC. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure J Card Fail 2005;11:191-195. CrossRef  PubMed
  202. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness Arterioscler Thromb Vasc Biol 2005; 25: 932-943. CrossRef
  203. Liu J, Masurekar MR, Vatner DE, et al. Glycation end-product cross-link breaker reduces collagen and improves cardiac function in aging diabetic heart Am J Physiol Heart Circ Physiol 2003;285:H2587-H2591.
  204. Hagens VE, Van Veldhuisen DJ, Kamp O, et al. Effect of rate and rhythm control on left ventricular function and cardiac dimensions in patients with persistent atrial fibrillation: results from the RAte Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study Heart Rhythm 2005; 2:19-24. CrossRef  PubMed
  205. Reant P, Lafitte S, Jais P, et al. Reverse remodeling of the left cardiac chambers after catheter ablation after 1 year in a series of patients with isolated atrial fibrillation Circulation 2005;112:2896-2903.
  206. Tops LF, Bax JJ, Zeppenfeld K, Jongbloed MR, van der Wall EE, Schalij MJ. Effect of radiofrequency catheter ablation for atrial fibrillation on left atrial cavity size Am J Cardiol 2006;97:12. CrossRef  PubMed
  207. Beukema WP, Elvan A, Sie HT, Misier AR, Wellens HJ. Successful radiofrequency ablation in patients with previous atrial fibrillation results in a significant decrease in left atrial size Circulation 2005;112: 2089-2095. 20-1222.
  208. Sanders P, Morton JB, Kistler PM, Vohra JK, Kalman JM, Sparks PB. Reversal of atrial mechanical dysfunction after cardioversion of atrial fibrillation: implications for the mechanisms of tachycardia-mediated atrial cardiomyopathy Circulation 2003;108: 1976-1984. CrossRef  PubMed
  209. Thomas L, Boyd A, Thomas SP, Schiller NB, Ross DL. Atrial structural remodelling and restoration of atrial contraction after linear ablation for atrial fibrillation Eur Heart J 2003;24:1942-1951. CrossRef  PubMed
  210. Raitt MH, Kusumoto W, Giraud G, McAnulty JH. Reversal of electrical remodeling after cardioversion of persistent atrial fibrillation J Cardiovasc Electrophysiol 2004; 15:507-512.
  211. Kinebuchi O, Mitamura H, Shiroshita-Takeshita A, et al. Temporal patterns of progression and regression of electrical and mechanical remodeling of the atrium Int J Cardiol 2005;98:91-98. CrossRef  PubMed
  212. Pappone C, Oreto G, Rosanio S, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: Efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001; 104:2539-44. CrossRef  PubMed
  213. Hocini M, Sanders P, Deisenhofer I, et al Reverse Remodeling of Sinus Node Function After Catheter Ablation of Atrial Fibrillation in Patients With Prolonged Sinus Pauses . Circulation 2003;108 :1172-1175. CrossRef  PubMed
  214. Hornero F, Rodriguez I, Buendia J, et al. Atrial remodeling after mitral valve surgery in patients with permanent atrial fibrillation J Card Surg 2004; 19:376-382. CrossRef  PubMed
  215. Watanabe T, Takeishi Y, Hirono O, et al. C-reactive protein elevation predicts the occurrence of atrial structural remodeling in patients with paroxysmal atrial fibrillation Heart Vessels 2005;20:45-49. CrossRef  PubMed
  216. Albage A, Kenneback G, van der Linden J, Berglund H. Improved neurohormonal markers of ventricular function after restoring sinus rhythm by the MAZE procedure Ann Thorac Surg 2003;75:790-795. CrossRef  PubMed
  217. Lonnerholm S, Blomstrom P, Nilsson L, Blomstrom-Lundqvist C. Atrial size and transport function after the MAZE III procedure for paroxysmal atrial fibrillation Ann Thorac Surg 2002;73:107-111. CrossRef  PubMed


Biosense Webster
event date
Introduction to AFib
Ablation Specialist

View Ablation Specialists