Skip Navigation

Cardiovascular Research 2002 54(2):302-314; doi:10.1016/S0008-6363(02)00262-6
© 2002 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Shimizu, A.
Right arrow Articles by Centurion, O. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shimizu, A.
Right arrow Articles by Centurion, O. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2002, European Society of Cardiology

Electrophysiological properties of the human atrium in atrial fibrillation

Akihiko Shimizu* and Osmar Antonio Centurion1

The Faculty of Health Sciences, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan

* Corresponding author. Tel./fax: +81-836-222-856 ashimizu{at}yamaguchi-u.ac.jp

Received 30 August 2001; accepted 11 January 2002


   Abstract
Top
 Abstract
1. Introduction
 2. The electrophysiological...
 3. The electrophysiological...
 4. Modifying factors of...
 5. The electrophysiological...
 6. Conclusion
 References
 
It has been reported that ectopic foci from the pulmonary veins can initiate atrial fibrillation (AF) and can also act as drivers for maintaining AF. However, not all patients with atrial arrhythmias initiate AF. A substrate for atrial propensity to AF is required for AF initiation and maintenance. Thus, we reviewed and discussed mainly the electrophysiological properties observed in AF. Abnormal atrial electrograms during sinus rhythm and abnormal responses of the atrium elicited by programmed stimulation have been observed more frequently in patients with paroxysmal AF than in those without. A shorter atrial effective refractory period, greater dispersion of the atrial refractoriness and atrial conduction delay are also of electrophysiologic significance in the genesis of AF. Electrical remodeling is likely to be a final common pathway that ultimately supervenes. Even if atrial electrical remodeling facilitates AF initiation and AF perpetuation, the initiation of AF requires a trigger. Further investigation into the electrophysiological properties in AF will be needed in order to contribute to the future development of an appropriate treatment.

KEYWORDS Antiarrhythmic agents; Arrhythmia (mechanisms); Mapping; Supraventr. arrhythmia


   1. Introduction
Top
 Abstract
 1. Introduction
2. The electrophysiological...
 3. The electrophysiological...
 4. Modifying factors of...
 5. The electrophysiological...
 6. Conclusion
 References
 
Since the beginning of this century, the debate on ectopic foci versus reentry as the mechanism underlying atrial fibrillation (AF) in humans has continued. Recently, the mechanism of atrial fibrillation (AF) is considered to be a spiral wave with a continuously changing pattern of the activation wave front [1,2], that is, a random multiple reentry [3,4] of independent wavelets wandering in the atria around arcs of refractory tissue [5,6] or the accentuation of focal activity originating mainly from the pulmonary veins (PVs) [7–10] or the superior vena cava [11], ligament of Marshall [12,13].

Although a reentrant activation sequence of multiple wavelets has been demonstrated in human AF by epicardial mapping just before the surgical treatment of this arrhythmia [5,14], the method is not suitable or feasible for diagnostic or investigational purposes in the clinical electrophysiologic laboratory. In addition, once AF is induced in the laboratory, pharmacologic or electrical cardioversion is required to restore sinus rhythm. However, these interventions make it impossible to repeat the baseline study for the mechanism of AF. Therefore, clinical electrophysiologic studies have become focused mainly on the electrophysiologic properties of the substrates in the atrial muscle during sinus rhythm and on the atrial electrical responses elicited by the premature stimulation method. However, many fundamental aspects of this arrhythmia have been poorly understood until quite recently.

In recent years, a wealth of new information has been published on the genesis of AF, especially arrhythmogenic PVs as the triggers of AF [7–10], and on electrical remodeling [15–21] of the electrophysiologic properties in the atrial muscle as modifying factors of AF. Furthermore, a possible genetic basis of AF has been suggested in some cases [22], although little is known about its electrophysiology. Approaches to the surgical management have improved and have provided information about the clinical determinants of AF [6,23,24]. Information has been obtained about post-operative AF [25] and the response to implanted devices, such as both atrial pacemakers [26–32] and atrial defibrillators [33,34].

Generally, arrhythmias are generated by the presence of substrates, triggers, or modifying factors for arrhythmias. Therefore, this review was designed to investigate the electrophysiologic properties of the substrates and triggers, and modifying factors of the electrophysiological properties of AF and the electrophysiologic properties during AF.


   2. The electrophysiological properties of the substrate in AF
Top
 Abstract
 1. Introduction
 2. The electrophysiological...
3. The electrophysiological...
 4. Modifying factors of...
 5. The electrophysiological...
 6. Conclusion
 References
 
The investigation was based on the recordings of local abnormal atrial electrograms during sinus rhythm and their characteristic distribution, and on several abnormal responses elicited by premature atrial stimulation

2.1 Atrial endocardial mapping during sinus rhythm
At the time of atrial endocardial mapping during sinus rhythm, an abnormally prolonged and fractionated right atrial electrogram may reflect slow and anisotropic conduction through the diseased atrial muscle [35]. The first attempt to define the quantitative characteristics of the normal atrial endocardial electrograms was made by Tanigawa et al. [36]. The atrial mapping technique was performed with a bipolar catheter electrode array with a 10-mm interelectrode distance, and the atrial endocardial electrograms were filtered from 50 to 1000 Hz. They recorded atrial electrograms from the anterior, lateral, posterior and medial aspects of the high, middle and low RA (Fig. 1). The duration of the atrial electrogram was defined as the time from the beginning of the earliest electrical activity that deviated from the stable baseline to the last point of the atrial electrogram that crossed the baseline. The number of fragmented deflections was measured by counting the number of downward deflections [36] (Fig. 2). In subjects with normal sinus node function and without paroxysmal AF, the mean duration and mean number of fragmented deflections were 74±11 ms and 3.9±1.3 (mean±S.D.), respectively. Atrial electrograms with values >2 times the S.D. of the mean values were considered abnormal. Therefore that number would be the mean plus 2 times the S.D. for the number of deflections, i.e. 3.9+2x1.3=6.5. Tanigawa et al. defined the atrial electrogram as abnormal when either the duration was >100 ms, there were eight or more fragmented deflections, or both.


Figure 1
View larger version (39K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Mapping sites in the right atrium. Atrial electrograms were recorded from 12 endocardial sites in each patient. SVC, superior vena cava; IVC, inferior vena cava; Ao, aorta; PA, pulmonary artery; LA, left atrium; RV, right ventricle; LV, left ventricle (reproduced by permission from Tanigawa et al. [36]).

 

Figure 2
View larger version (14K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Six atrial electrograms recorded at different right atrial sites in a patient with sick sinus syndrome but without PAF (A, B, C), and in a patient with both sick sinus syndrome and PAF (D, E, F). The diagonal arrows represent the onset and offset of local electrical activity and the horizontal arrows represent the downward deflection. Electrogram A was recorded from the high lateral right atrium and shows an abnormal atrial electrogram, 130 ms in duration with 10 fragmented deflections. Electrogram B was recorded from the middle lateral right atrium and shows an abnormal atrial electrogram, 110 ms in duration with six fragmented deflections. Electrogram C was recorded from the low lateral right atrium and shows a normal atrial electrogram, 80 ms in duration with two fragmented deflections. Electrogram D was recorded from the high posterior right atrium and shows an abnormal atrial electrogram, 110 ms in duration with nine fragmented deflections. Electrogram E was recorded from the middle posterior right atrium and shows an abnormal atrial electrogram, 105 ms in duration with eight fragmented deflections. Electrogram F was recorded from the low posterior right atrium and shows an abnormal atrial electrogram, 100 ms in duration with eight fragmented deflections (reproduced by permission from Centurion et al. [39]).

 
There are certain limitations to the catheter mapping technique of the RA during sinus rhythm. The 12 sites used may not be enough to detect abnormal atrial electrograms. The interelectrode distance of bipolar catheters, filter-frequency settings [37], high-gain recordings and motion at the electrode–tissue interface with the cardiac movement [38] may affect the recording of the atrial endocardial electrograms and might generate certain features of the fractionated electrogram. Catheters with a 10-mm interelectrode distance can record more distant electrical activity. No method can discriminate with certainty the local activation from the electrotonic activity or far-field effects. The filter setting is known to influence the amplitude of the electrogram. They have not measured their amplitude of the electrogram. In addition, one of the major problems in determining the number of deflections is the noise level. What should be considered as a real deflection (2x or 10x the noise level)? Finally, since left atrial catheter mapping was not performed, further investigation is needed to shed light on this issue.

2.2 Abnormal atrial electrograms
2.2.1 Distribution
Centurion et al. [39] quantitatively measured 1195 atrial endocardial electrograms in 101 patients to determine the sites in the RA where the electrical activity is likely to be abnormal. They then correlated the distribution of abnormal atrial electrograms with the likelihood of paroxysmal AF developing in patients with sick sinus syndrome. Of the 130 abnormal atrial electrograms recorded, 84 (65%) were found in the high RA, 30 (23%) in the middle RA, and 16 (12%) in the low RA (Fig. 3). Furthermore, 88% of the abnormal atrial electrograms were recorded in the posterolateral high RA. They concluded that the greater the extent of the compromised atrial muscle, the greater the likelihood that paroxysmal AF would develop.


Figure 3
View larger version (36K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Sites in the right atrium with abnormal atrial electrograms in the controls (group 1, white circles), in patients with sick sinus syndrome but without tachyarrhythmias (group 2, triangles), and in patients with both sick sinus syndrome and PAF (group 3, black circles). One symbol represents one abnormal atrial electrogram (reproduced by permission from Centurion et al. [39]).

 
Pathologic studies have demonstrated that patients with sinoatrial block without PAF had lesions localized to the sinus node and its vicinity. On the other hand, patients with bradycardia–tachycardia syndrome have been found to have more diffuse lesions of the atrium [40]. Electrophysiologic studies conducted in this investigation were found to be in accordance with earlier histologic findings [39]. The electrophysiologic observations reported in patients with partial atrial standstill [41–43] however, have been of particular interest. Ezaki et al. [41] observed that neither electrical activity nor electrical activation by electrical stimulation of ≤10 V was present in the RA of their patients, except for the low RA. Zipes and Dejoseph [42] reported a patient in whom no right atrial activity could be recorded, and atrial pacing was accomplished only from the low atrial septum. Effendy et al. [43] reported a patient whose atrial standstill was present only in the high RA. Therefore, it appears that the high RA may be more diseased than the lower regions of the RA in these patients with partial atrial standstill. Irrespective of the presence or absence of paroxysmal AF in the patients [39], a significantly greater number of abnormal atrial electrograms have been recorded in the high RA. It is difficult to provide a simple explanation for the characteristic distribution of the abnormal atrial electrograms.

From birth, the basic structure of a small amount of connective tissue beneath the endothelial lining of both atria is altered by proliferation of smooth muscle cells and elastic and collagen fibers. This process, called endocardial hypertrophy by Bharati and Lev [44], is more diffuse in the left atrium and more focally distributed in the RA. By maturity, there is an increase in elastic and collagenous fibers in the atrial subendocardium. At all times, the endocardial hypertrophy is more marked in the posterior wall of the atria [44]. Anderson et al. [45] have shown that during the development of the internodal atrial myocardium, the sinoatrial ring and the sinus venosus are positioned in the posterior atrial wall. These findings may partially support the electrophysiologic findings of this study. Another important factor to be considered is the mechanical force of the blood entering the RA. Miyatake et al. [46] observed, by using a real-time two-dimensional Doppler flow imaging technique, that the blood flow pathway into the RA lies mainly along the posterior right atrial wall. This may account in part for the significantly higher number of abnormal atrial electrograms observed in the high RA.

2.2.2 Mechanism
During conduction of a propagating impulse, axial current flows from one myocardial cell to the adjacent cell through the gap junctions of the disks, which normally have a relatively low resistance [47]. Conduction perpendicular to the long axis of atrial muscle fibers can be delayed due to the higher effective axial resistance in the direction perpendicular to the fiber orientation [48]. This higher axial resistance results in part from fewer and shorter intercalated disks in a side-to-side direction than in an end-to-end direction. When atrial myocardial fiber bundles are separated by connective tissue, the conduction properties may be altered because of the effects on axial resistance, leading to anisotropic discontinuous propagation [49].

Spach et al. [50] reported that depressed conduction velocity reduced the amplitude and broadened the duration of the extracellular electrogram in the canine Purkinje system. In a computer model of electrogram generation, it was demonstrated that decreased conduction velocity was responsible for increased electrogram width, while increased intracellular resistance was responsible for the fractionated nature of the electrogram [51]. It was suggested that the occurrence of reentry in a given region of the atrium depends on both spatial differences in membrane properties and anatomic complexities such as a nonuniform anisotropic atrium, in which the connective tissue separates the muscle bundles [49]. Histologic studies in patients with paroxysmal AF have shown fibrodegenerative changes in the atrial muscle, muscle loss in the internodal tracts, and fibrous thickening of the pericardium [52]. In addition, detailed pathologic quantification in patients with both AF and sick sinus syndrome has disclosed an extensive fibrosis of the atrial muscle in the approaches to the sinus node and internodal tracts [53]. Fibrosis may indeed play a crucial role in AF, especially in elderly people. Furthermore, Polontchouk et al. have shown that there are also changes in the gap junction expression and distribution [54].

Therefore, an abnormally prolonged and fractionated atrial electrogram recorded in patients undergoing endocardial catheter mapping during sinus rhythm may reflect inhomogeneous local electrical activity related to a delayed and nonuniform anisotropic conduction through diseased atrial muscle [36].

2.3 Electrophysiologic findings by programmed atrial stimulation
The programmed atrial stimulation method has been most widely performed in studies with paroxysmal AF. The atrial refractory period (A-ERP) and the extent of its dispersion can be determined through use of the programmed atrial stimulation method. This method also allows eliciting of several abnormal responses of the atrial muscle, such as repetitive atrial firing, fragmented atrial activity, and intra-atrial conduction delay. The interval between the longest and shortest coupling interval that elicited one of these indicators of atrial vulnerability is often referred to as the zone of each indicator [55,56]. Patients with paroxysmal AF not only have been found to have a higher incidence of, but also to have significantly wider zones of, repetitive atrial firing, fragmented atrial activity and conduction delay than the control subjects [55–57].

2.3.1 Repetitive atrial firing
Several clinical studies have demonstrated that repetitive atrial firing is a common finding in patients with paroxysmal AF [58,59]. According to Wyndham et al. [60], repetitive atrial firing is defined as the occurrence of two or more successive atrial complexes with a return cycle of <250 ms and a subsequent cycle length of <300 ms (Fig. 4). The occurrence of repetitive atrial firing requires the presence of a short refractory period at the pacing site and prolongation of the maximum conduction delay [59,61]. The mechanism of repetitive atrial firing appears to be a local reentry around the point of stimulation in a double circuit ‘figure-of-eight’ pattern, as has been shown in experimental studies that have used a rabbit atrium and an open-chest dog [62]. Other mechanisms, such as triggered activity or enhanced automaticity, also have been described as possible mechanisms [63].


Figure 4
View larger version (22K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Surface leads I, aVF and V1 and intracardiac recordings from high right atrium (HRA), coronary sinus (CS) and His bundle electrogram (HBE). Extrastimulus introduced at coupling interval of 240 ms with a driving cycle length of 500 ms induced repetitive atrial firings (RAF) (reproduced by permission from Shimizu et al. [108]).

 
Because repetitive atrial firing can be induced in patients with paroxysmal AF or flutter, as well as in controls, some investigators have stated that this is not a specific phenomenon [56,60,64]. Nevertheless, patients with AF demonstrated a higher incidence of repetitive atrial firing and a significantly wider repetitive atrial firing zone than did the control subjects, suggesting the existence of a common electrophysiologic mechanism in both paroxysmal AF and repetitive atrial firing [57].

Repetitive atrial firing often precedes atrial flutter or degenerates to AF [59,64–66]. Recently, Saksena et al. [66] performed simultaneous catheter mapping of right and left atrial regions at the onset and during sustenance of spontaneous AF and found that spontaneous AF was initiated by atrial premature contractions (APCs) arising from different right or left atrial regions in patients with structural heart disease. They further found that the initial region of atrial activation in AF was in proximity to the region of the APC origin. Organized and repetitive electrical activation is frequently observed in both the right and left atria at the AF onset. Although electrically-induced AF may have different activation patterns than spontaneous AF at the onset in many patients, both types of AF demonstrate organization and the earliest atrial activation in the proximity of the initiating APC.

2.3.2 Fragmented atrial activity
A single atrial extrastimulus often results in widening of the local atrial electrogram. It has been demonstrated that fragmentation and slowing of conduction in response to premature stimulation are related to paroxysmal AF [55,56,67]. Presumably, the mechanism of fragmented atrial activity is similar to that of the abnormal atrial electrogram, as previously described [36,47–54].

Ohe et al. [55] defined fragmented atrial activity elicited by atrial extrastimuli as the occurrence of disorganized atrial activity ≥150% of the duration of the local atrial electrogram of the basic beat recorded in the RA (Fig. 4). The duration of the local atrial electrogram and the induction zone of fragmented atrial activity are greater in patients with PAF than in controls [55,56]. Electrophysiologic studies performed in patients with chronic sustained lone AF after electric cardioversion also have shown a wider fragmented atrial activity zone than that in controls [57].

2.3.3 Conduction delay
The slowing of intra-atrial conduction is considered to be one of the most important requirements for the initiation of reentry and, thus, for AF or atrial flutter to develop [56,64]. A significantly wider zone of the intra-atrial conduction delay was observed in patients with paroxysmal AF than in the controls [56,67].

Recently, biatrial pacing has been developed as a technique for simultaneous activation of the RA and left atrium to reduce the intra-atrial conduction delay [26,27]. This has been reported to prevent the recurrence of AF in paced patients with a marked intra-atrial conduction delay [68]. Thus, these facts indicate that the intra-atrial conduction delay can play an important role in the onset of AF.

2.4 Abnormal atrial electrograms and atrial vulnerability with programmed atrial pacing
To evaluate the relationship among abnormal atrial electrograms recorded during sinus rhythm, repetitive atrial firing and fragmented atrial activity elicited by atrial premature stimuli [69], the patients were divided either by the presence of sick sinus syndrome and paroxysmal AF or on the basis of the presence or absence of abnormal atrial electrograms. A significantly greater vulnerability of the atrial muscle to AF was demonstrated in patients who had abnormal atrial electrograms than in those who did not have them [69]. Abnormal atrial electrograms showed specificity and positive predictive accuracy for the inducibility of AF.

2.5 The atrial refractory period and dispersion of atrial refractoriness
It is generally believed that patients with paroxysmal AF have relatively shorter A-ERPs and a relatively wider dispersion of atrial refractoriness [70]. Simpson et al. [71] found no association between ERP and a history of paroxysmal AF or the ability of an early cycle premature beat to induce AF. Some researchers have found shorter A-ERPs in patients with paroxysmal AF [64], whereas others have not [70,72]. By determining the refractory periods at four different atrial sites, the dispersion of refractoriness was studied and no significant difference was found between patients with and without paroxysmal AF [61]. The same results were shown in patients with sinus node dysfunction and paroxysmal AF by Luck and Engel [70]. On the other hand, Michelucci et al. [73] found a wider dispersion of atrial refractoriness in idiopathic AF. These discrepancies may be partly related to the different underlying cardiac disease in patients studied, yet they also suggested that simple comparison of the refractory period or the dispersion of refractoriness might not be enough.

The A-ERPs were significantly shorter at pacing sites where repetitive atrial firing was induced than at sites where it was not induced [61]. Attuel et al. [74] stated that an increase in the vulnerability of the atrium to develop fibrillation was found to be linked to an absence, or near absence, of the physiologic adaptation of the refractory period to increasing pacing rates. Ramdat Misier et al. [75] studied AF intervals at multiple sites in the RA of patients undergoing antiarrhythmic surgery. They found that both a shorter refractory period and a larger dispersion in refractoriness are responsible for the recurrence of AF. The increase in the dispersion of refractoriness has been nicely determined in patients with idiopathic AF, using decapolar catheters [76]. Gaita et al. [77] also reported that electrical activity during AF showed a significant spatial inhomogeneity, which was more evident in patients with paroxysmal AF. Nonhomogeneous recovery of excitability has been observed at the cellular level, studied by microelectrode technique, in isolated human atrial specimens from patients with AF [78].

2.6 Site-dependent differences in electrophysiological properties
It has been observed that atrial extrastimuli are more likely to induce AF when delivered from the high RA than from the coronary sinus [79]. The repetitive atrial firing zone has been shown to be greater when the extrastimulus is delivered from the high RA than from the coronary sinus [61]. The mechanism of this phenomenon is not fully understood. It may be related to site-dependent differences in how the impulse propagates within the atrial myocardium and activates sites critical for the initiation of AF or repetitive atrial firing [80]. The presence of site-specific conduction delay can be explained on the basis of non-uniform atrial anisotropy. In addition, site-dependent dispersion of refractoriness also appears to be an important factor in the electrophysiological properties of AF [80].

2.7 Limitation of the programmed atrial stimulation method
Electrophysiologic study of the atrial muscle by using programmed stimulation has several limitations. The catheter electrode contact with the atrial endocardium seems to be one of the major problems due to the movement of the catheter with cardiac motion causing recording artifacts on the atrial electrogram and affecting the stimulation strength used for measuring the effective and functional refractory periods of the atrial muscle. Atrial vulnerability to repetitive atrial firing, AF, or both is supposed to be present also in the left atrium, but few data on this issue have been collected. The vulnerability of the other parts of the left atrium remains to be investigated. The recording of fragmented atrial activity was performed only at the high RA. Because the recording of the high RA covers a limited area of the high lateral atrium, it is possible that the electrical abnormality of the atrial area is overlooked. The sensitivity, specificity, positive and negative predictive values of the repetitive atrial firing and the fragmented atrial activity for the spontaneous episode of AF remain controversial in spite of numerous studies. The exact mode of initiation and progression of the AF wavelets remain to be defined, due to the limitations of the current recording techniques of the endocardial atrial electrogram.


   3. The electrophysiological properties of triggers in AF
Top
 Abstract
 1. Introduction
 2. The electrophysiological...
 3. The electrophysiological...
4. Modifying factors of...
 5. The electrophysiological...
 6. Conclusion
 References
 
Research on the mechanisms and management of AF has exploded over the past 5 years, with much important work having been done in man. Especially, the work of Jais and Haissaguerre has opened the new era of electrophysiologic studies and therapies for AF to us [7,8].

Surgical therapy has been applied to the treatment of AF for almost two decades. At present, the most commonly used approach is the maze operation developed by Cox [6,23]. In this operation, critically located incisional lines prevent AF. Currently, these lines also are drawn during operations using radiofrequency current [81–84]. Thus, Haissaguerre et al. [84] investigated a staged anatomical approach using radiofrequency catheter ablation lines to prevent paroxysmal AF and they noticed that successful radiofrequency catheter ablation of paroxysmal AF was feasible using linear atrial lesions complemented by focal ablation targeted at arrhythmogenic foci.

From previous studies, a focal mechanism was considered to be very unlikely [5,6,85]. Jais et al. and Haissaguerre et al. [7,8] first documented that paroxysmal AF could be initiated by ectopic beats from the PVs. Chen et al. [9] more deeply investigated the electrophysiologic characteristics of both the ectopic beats originating from the PVs and the atrium and found that the electrophysiologic characteristics of the PVs were different from those in the atria. The major source of ectopic beats initiating paroxysmal AF is from PVs. However, Chen's group reported one subgroup of focal AF is a right atrial focal AF that they observed in 4.7–6.2% of patients who had clinically documented attacks of paroxysmal AF [11,86]. The ligament of Marshall may be the origin of focal AF in some patients [13,87].

There is the possibility that ectopic foci from the PVs can also act as drivers for maintaining AF according to the electrophysiologic findings from the surgical [25] or catheter ablation [88–90] of the PV orifices in patients with chronic AF. PV isolation may be curative for chronic AF, suggesting that AF-induced atrial electrical remodeling might be reversible after the elimination of the focal source or modification of the anatomical substrate.


   4. Modifying factors of the electrophysiologic properties of the atrium
Top
 Abstract
 1. Introduction
 2. The electrophysiological...
 3. The electrophysiological...
 4. Modifying factors of...
5. The electrophysiological...
 6. Conclusion
 References
 
It has been shown that the initiation, maintenance, and termination of AF were affected by many modifying factors of the electrophysiologic properties at the atrium (e.g. aging, AF itself, underlying heart disease, drugs, autonomic nerve system, etc.).

4.1 Aging
The increase in prevalence of AF in elderly persons has been reported to be associated with degeneration of the atrial muscle in pathologic studies [91]. Spach and Dolber [92] found evidence in the human atrial muscle of an age-related electrical uncoupling of the side-to-side connections between bundles, related to the proliferation of extensive collagenous tissue septa in intercellular spaces [92]. The zone of repetitive atrial firing, of fragmented atrial activity, and of intra-atrial conduction delay did not significantly change with aging [93]. Though this would mean that the refractory period increased, which would reduce vulnerability for AF, the longest coupling interval giving rise to these indicators of atrial vulnerability was prolonged significantly in correlation with age. Therefore a premature atrial beat, even with a long coupling interval, could induce AF, suggesting that the atrial muscle is more prone to develop AF with advancing age.

4.2 AF itself (electrical remodeling)
Developments in our understanding of AF over the last several years have led to the recognition that AF itself modifies the atrial properties (AF begets AF) [15] in a way that promotes the occurrence and maintenance of the arrhythmia. This process has been termed ‘atrial electrical remodeling’ [15]. Thus, once initiated, AF causes alterations in atrial electrical properties, including both rapid functional change and slower alternation in the ionic channel gene expression [19,20]. Electrical remodeling decreases the A-ERP in a heterogenous way, thus decreasing the size and stability of the functional atrial reentry waves and promoting multiple-circuit reentry. Whatever the initial cause of AF, electrical remodeling is likely a final common pathway that ultimately supervenes [94]. In the regional change in the atrial electrophysiologic properties related to AF, the electrophysiologic changes observed in the patients with paroxysmal AF appear to behave as if in transition from the control state to chronic AF, suggesting progressive changes in the atrial electrophysiologic properties [95]. The electrical changes were reversed within 24 h after conversion [16]. However, no return to normal atrial electrophysiology was demonstrated after long episodes of sinus rhythm in patients who previously had sustained AF [17].

AF is predominantly accompanied by decreased protein contents of the L-type Ca2+ channel [19], sarcoplasmic reticular Ca2+-ATPase gene [20] and several potassium channels. Reductions in the L-type Ca2+ channels correlate with the A-ERP and rate adaptation [19]. Alterations in the gene expression of proteins involved in the calcium homeostasis occur only in patients with long-term persistent AF. In the absence of underlying heart disease, the changes are rather secondary than primary to AF [96]. Altered gene expression is an important component of the electrical remodeling process and may contribute to repolarization abnormalities in AF [97]. In patients with paroxysmal AF these reductions were observed predominantly at the protein level and not at the mRNA level, suggesting a post-transcriptional regulation [98].

In general, the expression of connexins is related to the construction of the gap junctions. The major connexins expressed in mammalian myocardium are connexin40 (Cx40) and connexin45 (Cx45) in atrium and conduction system [54,99]. As Cx40 is known to influence the conduction properties of atrial tissue and the vulnerability for AF, attenuated gap junctional remodeling with conduction slowing might be another factor in the tachycardia-induced increase in the stability of AF [54,99]. The change in expression and distribution of Cx40, results in microscopic changes in conduction properties with the generation of small areas of conduction blocks and dispersion of conduction, which stabilizes AF. The above data support the notion that conduction through the atria may be slowed while the intrinsic conduction velocity is normal [18].

4.3 Underlying heart disease
4.3.1 Wolff–Parkinson–White syndrome
AF assumes a great clinical importance in the setting of Wolff–Parkinson–White (WPW) syndrome because of the potential risk for ventricular fibrillation, circulatory collapse, and sudden death. However, the pathogenesis of AF in WPW syndrome remains unclear. Electrophysiologic evidence has been reported suggesting that AF can occur as a result of atrioventricular reciprocating tachycardia [100]. Atrial vulnerability has been found to be enhanced at short cycle lengths [100]. Therefore, abolishing atrioventricular reciprocating tachycardia should reduce the incidence of AF in patients with WPW syndrome. In addition, it has been suggested that the accessory atrioventricular pathways may participate directly in the induction of AF [101].

On the other hand, Fujimura et al. [102] reported longer intra-atrial conduction times and shorter atrial functional refractory periods in the patients with WPW syndrome associated with paroxysmal AF than in those without paroxysmal AF. Konoe et al. [103] demonstrated a significantly longer duration and greater number of fragmented deflections of atrial electrograms in patients with AF associated with WPW syndrome than in those with WPW syndrome alone. These findings suggest that the intrinsic electrical abnormalities of the atrial muscle may play an important role in the occurrence of paroxysmal AF in patients with WPW syndrome. Jackmann et al. [101] suggested, by using accessory pathway potential recordings, that the accessory connection site to the atrium functions as a network of fibers where AF originates. However, since clinical AF did not occur in patients without organic heart disease after surgical ablation of the accessory pathway [100], one should be cautious in concluding that intrinsic abnormality of the atrial muscle is the definitive factor for the development of AF. In addition, so far there is no information that the triggers (or short bursts of reentry) of AF cannot occur any longer after the ablation of the accessory pathway.

4.3.2 Other underlying heart diseases
The other arrhythmic mechanisms (e.g. atrial flutter, AV node reentry, atrial tachycardia) and all the other cardiac conditions (e.g. hypertension, valve disease, thyrotoxicosis, congestive heart failure (CHF), etc.) are also important modifying factors for the electrophysiologic properties of the atrial muscle. However, there has been little information on the relationship between the electrophysiologic substrate and underlying cardiac diseases. AF was induced in 11% of patients with hypertrophic cardiomyopathy during electrophysiologic study [104]. Patients with hypertrophic cardiomyopathy are prone to develop AF due to worsening diastolic dysfunction and left atrial dilatation rather than as a primary electrical phenomenon [105]. Li et al. [106] demonstrated a unique study to test the hypothesis that AF maintained by different substrates responds differently to antiarrhythmic-drug therapy. In this study, dofetilide was highly effective in inducting AF by atrial burst pacing in dogs with CHF but was totally ineffective in dogs with RAP. Epicardial mapping showed that CHF-related AF was often due to macroreentry, with dofetilide terminating AF by causing block in the reentry circuit. These results indicate that electrophysiological properties of AF are different for the different types of underlying disease in AF.

4.4 Effects of drugs on the atrial electrophysiologic properties
The class I antiarrhythmic drugs have been studied most extensively regarding their effects on the electrophysiologic properties of the atrium. Intravenous administration of disopyramide (2 mg/kg) suppressed completely the induction of repetitive atrial firing in 56–59% [107,108] of patients with paroxysmal AF. The zones of repetitive atrial firing and fragmented atrial activity have been shown to be significantly decreased by disopyramide [108] and cibenzoline [109]. Disopyramide has been shown to reduce the zone of conduction delay as a result of prolongation of the atrial refractory period, in spite of prolongation of the conduction time at the basic cycle length [108] (Fig. 5). In addition, both quinidine and procainamide have been reported to prolong the action-potential duration and refractory periods in human atrial muscle preparations [110]. Flecainide has been reported to prolong the effective refractory period of the atrial muscle and to slow intra-atrial conduction by ~20% [111]. Among newer class III antiarrhythmic drugs, E-4031, pure IKr channel blocker, has been found to prolong the atrial refractory period in patients with paroxysmal AF. This prolongation tends to be greater at sites where repetitive atrial firing has been abolished by the drug, than at sites where the repetitive atrial firing was unchanged or newly induced [112].


Figure 5
View larger version (18K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Relation between the coupling interval (S1–S2) and intra-atrial conduction time from the extrastimulus artifact to the corresponding atrial electrogram (S2–A2) at baseline and after disopyramide in a patient with PAF. Measurement of the maximum conduction delay (MCD), conduction delay zone (CDZ) and longest coupling interval (LCI) eliciting conduction delay at baseline and after disopyramide are also shown. Disopyramide diminished the MCD from 45 to 25 ms because of prolongation of atrial refractory period from 240 to 290 ms, in spite of prolongation of the conduction time from 100 to 120 ms at the basic cycle length. Disopyramide also prolonged the LCI from 270 to 310 ms, but reduced the CDZ from 30 to 20 ms (reproduced by permission from Shimizu et al. [108]).

 
Calcium channel blockers have been shown to have no effect on the electrophysiologic properties of the atrial tissue in the normal human heart [113]. Shenasa et al. [114] reported that verapamil and diltiazem prolonged the duration of electrically induced AF. In addition, Kumagai et al. [115] reported that verapamil increased the intra-atrial conduction delay without affecting the effective refractory period of the RA in patients with paroxysmal AF. Most recently, Isomoto et al. [116] demonstrated that verapamil increased the inducibility and duration of repetitive atrial firing and augmented the fragmented atrial activity in patients without a history of paroxysmal AF, but with intra-atrial conduction delay at baseline study.

Administration of calcium channel blockers before the initiation of AF, can blunt or prevent the electrophysiological remodeling that accompanies AF [117]. Calcium overload also has been suggested to be an important factor in the initiation of arrhythmia [118]. Verapamil can attenuate short-term (less than 24 h) tachycardia-induced shortening and mal-adaptation of A-ERP and reduce the inducibility of AF. However, verapamil cannot prevent long-term (more than 1 week) tachycardia-induced change of atrial electrophysiological properties [119]. Furthermore, verapamil increases the duration of AF in the dogs either before or after long-term rapid atrial pacing [118]. Though almost none of this deals with the human study, these findings are consistent with previously described reports [114–116]. Furthermore, Ramanna et al. [120] recently demonstrated that verapamil caused a shortening of the refractoriness and an increase in the spatial dispersion of refractoriness in patients with chronic AF.

Isoproterenol may prevent the initiation of reentrant arrhythmias by improving the conduction within the cardiac tissue [108,121].


   5. The electrophysiological properties during AF
Top
 Abstract
 1. Introduction
 2. The electrophysiological...
 3. The electrophysiological...
 4. Modifying factors of...
 5. The electrophysiological...
6. Conclusion
 References
 
5.1 Mapping
Little information is available about the patterns of activation during AF in humans, though mapping studies in animals have suggested that AF is based on multiple reentering wavelets. Konings et al. [5] reconstructed and classified the patterns of human right atrial activation during electrically-induced AF in patients with WPW syndrome undergoing surgery for interruption of their accessory pathway(s). They concluded that three types of RA activation during AF were identified. Thus, these various types of AF in humans appear to be characterized by different numbers and dimensions of the intra-atrial reentrant circuits [5]. On the other hand, Ikeda et al. [2] recently reported that a single meandering functional reentrant wave front could result in rapid and irregular electrogram activity in human atrial tissues.

5.2 AF intervals
Recordings of electrograms have demonstrated short and variable fibrillation intervals similar to ventricular fibrillation. Opthof et al. [123] found that there was no diastolic interval between successive action potentials and that there was only a small difference in refractory periods during ventricular fibrillation.

In contrast to ventricular fibrillation, larger variations in local fibrillation intervals have been observed during AF [124]. Possible explanations for this have included either variation in the local refractory periods or the presence of a significant excitable gap [125]. Mapping of AF intervals in both canine and human AF suggested that there was a high degree of spatial organization of wave fronts [76,77] and that cells did not re-excite as soon as their refractory periods ended [6]. In the investigation of a correlation between the local AF intervals and local ERP, Ramanna et al. [76] used the mean local fibrillatory interval by measuring through the detection of intrinsic negative deflection in the unipolar electrogram recorded at the right atrial free wall and the right atrial appendage, as an index of local refractoriness. On the other hand, Kim et al. found that the AF intervals were longer than the ERPs, suggesting that reflex changes might shorten ERP in the intact heart [125]. Furthermore, Gaits et al. proposed that the mean AF intervals did not correlate with the mean ERPs [77].

Patients with idiopathic AF showed increased dispersion of refractoriness, which may be the substrate for the observed enhanced inducibility and spontaneous occurrence of AF [76]. Botteron et al. [126] demonstrated that AF in the intact human heart was organized over a length scale consistent with reentrant excitation by using a novel method to measure the spatial organization of atrial activation during AF. This preliminary result suggests a relationship between the measured spatial organization and the clinical course of the arrhythmia [126].

Zrenner et al. [127] analyzed the electrophysiologic characteristics of paroxysmal AF and chronic AF in the human RA. They found that the majority of endocardial breakthrough points were located in the septal region and coincided anatomically with the major interatrial connection routes. Coexistence of reentrant and apparently focal activation determined the maintenance of AF in the RA in paroxysmal AF, whereas random reentry was documented more frequently in the patients with chronic AF. Furthermore, they [128] demonstrated that differences in activation of the left and right surfaces of the interatrial septum and the preferential use and filtering effect of the interatrial connections played a significant role in explaining the differences in activation patterns of the left and right atria in patients with AF.

In typical human atrial flutter, the crista terminalis, eustachian ridge, and tricuspid annulus have been already identified as barriers to conduction. From clinical observation, it is apparent that there is a relationship between atrial fibrillation and atrial flutter in patients with atrial arrhythmias. Thus, the atrial anatomy and its relationship to the electrophysiological findings, and the role of partial or complete conduction barriers around which reentry can and cannot occur, may be of importance for AF as well [129].


   6. Conclusion
Top
 Abstract
 1. Introduction
 2. The electrophysiological...
 3. The electrophysiological...
 4. Modifying factors of...
 5. The electrophysiological...
 6. Conclusion
References
 
Abnormal atrial electrograms during sinus rhythm and abnormal responses of the atrium elicited by programmed stimulation have been observed more frequently in patients with paroxysmal AF than in those without. A shorter A-ERP, greater dispersion of the atrial refractoriness and atrial conduction delay are also of electrophysiologic significance in the genesis of AF. Even if atrial electrical remodeling facilitates AF initiation and AF perpetuation, the initiation of AF requires a trigger. Since AF is not initiated in all patients with atrial arrhythmias, a substrate for atrial propensity to AF also is required for AF initiation. Further investigation into the electrophysiological properties in AF will be needed in order to contribute to the future development of an appropriate treatment.

Time for primary review 32 days.


   Notes
 
1 Present address: The Department of Hemodynamics and Electrophysiology, Sanatorio Migone-Battilana, Eligio Ayala 1293, Asuncion, Paraguay. Back


   References
Top
 Abstract
 1. Introduction
 2. The electrophysiological...
 3. The electrophysiological...
 4. Modifying factors of...
 5. The electrophysiological...
 6. Conclusion
 References
 

  1. Davidenko J.M, Pertsov A.V, Salomonsz R, Baxter W, Jalife J. Stationary and drifting spiral waves of excitation in isolated cardiac muscle. Nature (1992) 355:349–351.[CrossRef][Medline]
  2. Ikeda T, Czer L, Trento A, et al. Induction of mandering functional reentrant wave front in isolated human atrial tissues. Circulation (1997) 96:3013–3020.[Abstract/Free Full Text]
  3. Moe G.K, Rheinboldt W.C, Abildskov J.A. A computer model of atrial fibrillation. Am Heart J (1964) 67:200–220.[CrossRef][Web of Science][Medline]
  4. Allessie M.A, Lammers W.J.E.P, Bonke F.I.M, Hollen S.J. Cardiac electrophysiology and arrhythmias. Zipes D.P, Jalife J, eds. (1985) Orlando, FL: Grune and Stratton. 256–276.
  5. Konings K.T.S, Kirchhof C.J.H.J, Smeets J.R.L.M, et al. High-density mapping of electrically induced atrial fibrillation in humans. Circulation (1994) 89:1665–1680.[Abstract/Free Full Text]
  6. Cox J.L, Canavan T.E, Schuessler R.B, et al. The surgical treatment of atrial fibrillation, II: intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg (1991) 101:406–426.[Abstract]
  7. Haissaguerre M, Jaise P, Sha D.C, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med (1998) 339:659–666.[Abstract/Free Full Text]
  8. Jais P, Haissaguerre M, Shah D.C, et al. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation (1997) 95:572–576.[Abstract/Free Full Text]
  9. Chen S.A, Hsieh M.H, Tai C.T, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiologic characteristics, pharmacologic responses, and effects of radiofrequency ablation. Circulation (1999) 100:1879–1886.[Abstract/Free Full Text]
  10. Lu T.M, Tai C.T, Hsieh M.H, et al. Electrophysiologic characteristics in initiation of paroxysmal atrial fibrillation from a focal area. J Am Coll Cardiol (2001) 37:1658–1664.[Abstract/Free Full Text]
  11. Chen S.A, Tai C.T, Chen J.Y, et al. Right atrial focal atrial fibrillation: electrophysiologic characteristics and radiofrequency catheter ablation. J Cardiovasc Electrophysiol (1999) 10:328–335.[Web of Science][Medline]
  12. Kim D.T, Lai A.C, Hwang C, et al. The ligament of Marshall: a structural analysis in human hearts with implications for atrial arrhythmias. J Am Coll Cardiol (2000) 36:1324–1327.[Abstract/Free Full Text]
  13. Hwang C, Wu T.J, Doshi R.N, Peter C.T, Chen P.S. Vein of marshall cannulation for the analysis of electrical activity in patients with focal atrial fibrillation. Circulation (2000) 101:1503–1505.[Abstract/Free Full Text]
  14. Brugada J, Gursoy S, Brugada P, et al. Cibeazoline transforms random reentry into ordered reentry in the atria. Eur Heart J (1993) 14:267–272.[Abstract/Free Full Text]
  15. Wijffels M.C, Kirchhof C.J, Dorland R, Allessie M.A. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation (1995) 92:1954–1968.[Abstract/Free Full Text]
  16. Manios E.G, Kanoupakis E.M, Chlouverakis G.I, et al. Changes in atrial electrical properties following cardioversion of chronic atrial fibrillation: relation with recurrence. Cardiovasc Res (2000) 47:244–253.[Abstract/Free Full Text]
  17. Rodriguez L.M, Timmermans C, Wellens H.J. Are electrophysiological changes induced by longer lasting atrial fibrillation reversible? Observations using the atrial defibrillator. Circulation (1999) 100:113–116.[Abstract/Free Full Text]
  18. Tieleman R.G, Crijns H.J. The ‘second factor’ of tachycardia-induced atrial remodeling. Cardiovasc Res (2000) 46:364–366.[Free Full Text]
  19. Brundel B.J, Van Gelder I.C, Henning R.H, et al. Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation (2001) 103:684–690.[Abstract/Free Full Text]
  20. Lai L.P, Su M.J, Lin J.L, et al. Down-regulation of L-type calcium channel and sarcoplasmic reticular Ca(2+)-ATPase mRNA in human atrial fibrillation without significant change in the mRNA of ryanodine receptor, calsequestrin and phospholamban: an insight into the mechanism of atrial electrical remodeling. J Am Coll Cardiol (1999) 33:1231–1237.[Abstract/Free Full Text]
  21. Brundel B.J.J.M, Van Gelder I.C, Tuinenburg A.E, et al. Endothelin system in human persistent and paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol (2001) 12:737–742.[CrossRef][Web of Science][Medline]
  22. Brugada R, Tapscott T, Czernuszewicz G.Z, et al. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med (1997) 336:905–911.[Abstract/Free Full Text]
  23. Cox J.L, Boineau J.P, Schuessler R.B, Kater K.M, Lappas D.G. Five-year experience with the Maze procedure for atrial fibrillation. Am Thorac Surg (1993) 56:814–824.[Abstract]
  24. Kosakai Y, Kawaguchi A.T, Isobe F, et al. Modified Maze procedure for patients with atrial fibrillation undergoing simultaneous open heart surgery. Circulation (1995) 92(suppl_II):359–364.[Abstract/Free Full Text]
  25. Sueda T, Imai K, Ishii O, et al. Efficacy of pulmonary vein isolation for the elimination of chronic atrial fibrillation in cardiac valvular surgery. Thorac Surg (2001) 71:1189–1193.[Abstract/Free Full Text]
  26. Levy T, Fotopoulos G, Walker S, et al. Randomized controlled study investigating the effect of biatrial pacing in prevention of atrial fibrillation after coronary artery bypass grafting. Circulation (2000) 102:1382–1387.[Abstract/Free Full Text]
  27. Fan K, Lee K.L, Chiu C.S, et al. Effects of biatrial pacing in prevention of postoperative atrial fibrillation after coronary artery bypass surgery. Circulation (2000) 102:755–760.[Abstract/Free Full Text]
  28. Delfaut P, Saksena S, Prakash A, Krol R.B. Long-term outcome of patients with drug-refractory atrial flutter and fibrillation after single- and dual-site right atrial pacing for arrhythmia prevention. J Am Coll Cardiol (1998) 32:1900–1908.[Abstract/Free Full Text]
  29. Saksena S, Delfaut P, Prakash A, Kaushik R.R, Krol R.B. Multisite electrode pacing for prevention of atrial fibrillation. J Cardiovasc Electrophysiol (1998) 9:S155–162.[Web of Science][Medline]
  30. D'Allonnes G.R, Pavin D, Leclercq C, et al. Long-term effects of biatrial synchronous pacing to prevent drug-refractory atrial tachyarrhythmia: a nine-year experience. J Cardiovasc Electrophysiol (2000) 11:1081–1091.[Web of Science][Medline]
  31. Leclercq J.F, De Sisti A, Fiorello P, et al. Is dual site better than single site atrial pacing in the prevention of atrial fibrillation? PACE (2000) 23:2101–2107.[Medline]
  32. Chung M.K, Augostini R.S, Asher C.R, et al. Ineffectiveness and potential proarrhythmia of atrial pacing for atrial fibrillation prevention after coronary artery bypass grafting. Ann Thorac Surg (2000) 69:1057–1063.[Abstract/Free Full Text]
  33. Wellens H.J, Lau C.P, Luderitz B, et al. Atrioverter: an implantable device for the treatment of atrial fibrillation. Circulation (1998) 98:1651–1656.[Abstract/Free Full Text]
  34. Timmermans C, Levy S, Ayers G.M, et al. Spontaneous episodes of atrial fibrillation after implantation of the Metrix Atrioverter: observations on treated and nontreated episodes. J Am Coll Cardiol (2000) 35:1428–1433.[Abstract/Free Full Text]
  35. Spach M.S, Dolber P.C. Relating extracellular potentials and their derivatives to anisotropic propagation at microscopic level in human cardiac muscle: evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res (1986) 58:356–371.[Abstract/Free Full Text]
  36. Tanigawa M, Fukatani M, Konoe A, et al. Prolonged and fractionated right atrial electrograms during sinus rhythm in patients with paroxysmal atrial fibrillation and sick sinus node syndrome. J Am Coll Cardiol (1991) 17:403–408.[Abstract]
  37. Waxman H.L, Sung R.J. Significance of fragmented ventricular electrograms observed using intracardiac recording techniques in man. Circulation (1980) 62:1349–1356.[Free Full Text]
  38. Ideker R.E, Lofland G.K, Bardy G.H, et al. Late fractionated potentials and continuous electrical activity caused by electrode motion. PACE (1983) 6:908–914.[Medline]
  39. Centurion O.A, Fukatani M, Konoe A, et al. Different distribution of abnormal endocardial electrograms within the right atrium in patients with sick sinus syndrome. Br Heart J (1992) 68:596–600.[Abstract/Free Full Text]
  40. Thery C, Gosselin B, Lekieffre J, Warembourg H. Pathology of sinoatrial node. Correlations with electrocardiographic findings in 111 patients. Am Heart J (1977) 93:735–740.[CrossRef][Web of Science][Medline]
  41. Ezaki H, Ohkawa S, Miyagawa A, Ueda K, Sugiura M. A histopathologic study of the conduction system in an elderly patient with partial atrial standstill. Jpn Heart J (1987) 28:933–940.[Medline]
  42. Zipes D.P, Dejoseph R.L. Dissimilar atrial rhythms in man and dog. Am J Cardiol (1973) 32:618–628.[CrossRef][Web of Science][Medline]
  43. Effendy F.N, Bolognesi R, Bianchi G, Visioli O. Alternation of partial and total atrial standstill. J Electrocardiol (1979) 12:121–127.[CrossRef][Web of Science][Medline]
  44. Bharati S, Lev M. Atrial fibrillation: mechanisms and management. Falk R.H, Podrid P.J, eds. (1992) New York: Raven Press. 15–39.
  45. Anderson R.H, Becker A.E, Wenink A.C.G, Janse M.J. The conduction system of the heart: structure, function and clinical implication. Wellens H.J.J, Lie K.I, Janse M.D, eds. (1976) Leiden: H.E. Stenfert Kroese B.V. 3–28.
  46. Miyatake K, Izumi S, Shimizu A, et al. Right atrial flow topography in healthy subjects studied with real-time two-dimensional Doppler flow imaging technique. Am Coll Cardiol (1986) 7:425–431.[Abstract]
  47. Fozzard H.A. The heart. Berne R.M, ed. (1979) vol. 1. Baltimore: American Physiological Society. 335–356. Handbook of physiology. Section 2: the cardiovascular system.
  48. Spach M, Miller W.T, Geselowitz D.B, et al. The discontinuous nature of propagation in normal canine cardiac muscle: evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. Circ Res (1981) 48:39–54.[Free Full Text]
  49. Spach M.S, Miller W.T, Dolber P.C, et al. The functional role of structural complexities in the propagation of depolarization in the atrium of the dog: cardiac conduction disturbances due to discontinuities of effective axial resistivity. Circ Res (1982) 50:175–191.[Free Full Text]
  50. Spach M.S, Barr R.C, Serwer G.A, Kootsey J.M, Johnson E.A. Extracellular potential related to intracellular action potentials in the dog Purkinje system. Circ Res (1972) 30:505–511.[Abstract/Free Full Text]
  51. Lesch M.D, Spear J.F, Simsom M.B. A computer model of the electrogram: what causes fractionation? J Electrocardiol (1988) 21(suppl II):S69–73.[CrossRef][Web of Science][Medline]
  52. Davis M.J, Pomerance A. Pathology of atrial fibrillation in man. Br Heart J (1972) 34:520–525.[Free Full Text]
  53. Kaplan B.M, Langendorf R, Lev M, Pick A. Tachycardia–bradycardia syndrome (so-called ‘sick sinus syndrome’): pathology, mechanisms, and treatment. Am J Cardiol (1973) 31:497–508.[CrossRef][Web of Science][Medline]
  54. Polontchouk L, Haefliger J.A, Ebelt B, et al. Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. J Am Coll Cardiol (2001) 38:883–891.[Abstract/Free Full Text]
  55. Ohe T, Matsuhisa M, Kamakura S, et al. Relation between the widening of the fragmented atrial activity zone and atrial fibrillation. Am J Cardiol (1983) 53:1219–1222.
  56. Shimizu A, Fukatani M, Tanigawa M, Mon M, Hashiba K. Intra-atrial conduction delay and fragmented atrial activity in patients with paroxysmal atrial fibrillation. Jpn Circ J (1989) 53:1023–1030.[Medline]
  57. Kumagai K, Akimitsu S, Kamahira K, et al. Electrophysiological properties in chronic lone atrial fibrillation. Circulation (1991) 84:1662–1668.[Abstract/Free Full Text]
  58. Centurion O.A, Isomoto S, Fukatani M, et al. Relationship between atrial conduction defects and fractionated atrial endocardial electrograms in patients with sick sinus syndrome. PACE (1993) 16:2022–2033.[Medline]
  59. Cosio F, Lovet A, Vidal J. Mechanism and clinical significance of atrial repetitive responses in man. PACE (1983) 6:53–59.[Medline]
  60. Wyndham C, Amat-y-Leon F, Wu D, et al. Effects of cycle length on atrial vulnerability. Circulation (1977) 55:260–267.[Abstract/Free Full Text]
  61. Shimizu A, Konoe A, Tanigawa M, et al. Electrophysiologic characteristics of repetitive atrial firing: atrial extrastimulus at four sites. Jpn J Cardiac Pacing Electrophysiol (1993) 9:126–131.
  62. Boineau J, Schenessler R, Mooney C, et al. Natural and evoked atrial flutter due to circus movement in dogs: role of abnormal atrial pathways, slow conduction, non-uniform refractory period distribution and premature beats. Am J Cardiol (1980) 45:1167–1181.[CrossRef][Web of Science][Medline]
  63. Johnson N.J, Rosen M.R. Cardiac arrhythmias: where do we go from here? Brugada P, Wellens H, eds. (1987) Mt. Kisko, NY: Futura Publisher. 129–145.
  64. Cosio F.G, Palacios J, Vidal J.M, et al. Electrophysiologic studies in atrial fibrillation. Slow conduction of premature impulses: a possible manifestation of the background for reentry. Am J Cardiol (1983) 51:122–130.[CrossRef][Web of Science][Medline]
  65. Shimizu A, Nozaki A, Rudy Y, Waldo A.L. Onset of induced atrial flutter in the canine pericarditis model. J Am Coll Cardiol (1991) 17:1223–1234.[Abstract]
  66. Saksena S, Prakash A, Krol R.B, Shankar A. Regional endocardial mapping of spontaneous and induced atrial fibrillation in patients with heart disease and refractory atrial fibrillation. Am J Cardiol (1999) 84:880–889.[CrossRef][Web of Science][Medline]
  67. Hashiba K, Tanigawa M, Fukatani M, et al. Electrophysiologic properties of atrial muscle in paroxysmal atrial fibrillation. Am J Cardiol (1989) 64:20–23.
  68. Daubert C, Berder V, Gras D. Atrial tachyarrhythmias associated with high degree intra-atrial conduction block: prevention by permanent atrial resynchronization. Eur J Card Pacing Electrophysiol (1994) 1:35–44.
  69. Centurion O.A, Shimizu A, Isomoto S, et al. Repetitive atrial firing and fragmented atrial activity elicited by extrastimuli in the sick sinus syndrome with and without abnormal atrial electrograms. Am J Med Sci (1994) 307:247–254.[Web of Science][Medline]
  70. Luck J.C, Engel T.R. Dispersion of atrial refractoriness in patients with sinus node dysfunction. Circulation (1979) 60:404–412.[Abstract/Free Full Text]
  71. Simpson R.J Jr., Amara I, Foster J.R, Woelfel A, Gettes L.S. Thresholds, refractory periods, and conduction times of the normal and diseased human atrium. Am Heart J (1988) 116:1080–1090.[CrossRef][Web of Science][Medline]
  72. Dobmeyer D.J, Stine R.A, Leier C.V, Schaal S.F. Electrophysiologic mechanism of provoked atrial flutter in mitral valve prolapse syndrome. Am J Cardiol (1985) 56:602–604.[CrossRef][Web of Science][Medline]
  73. Michelucci A, Padeletti L, Fradella G.A. Atrial refractoriness and spontaneous or induced atrial fibrillation. Acta Cardiol (1982) 37:333–344.[Web of Science][Medline]
  74. Attuel P, Childers R, Cauchemez B, et al. Failure in the rate adaptation of the atrial refractory period: its relationship to vulnerability. Int J Cardiol (1982) 2:179–197.[CrossRef][Web of Science][Medline]
  75. Ramdat Misier A.R, Opthof T, van Hemel N.M, et al. Increased dispersion of ‘refractoriness’ in patients with idiopathic paroxysmal atrial fibrillation. J Am Coll Cardiol (1992) 19:1531–1535.[Abstract]
  76. Ramanna H, Hauer R.N.W, Wittkampf F.H.M, et al. Identification of substrate of atrial vulnerability in patients with idiopathic atrial fibrillation. Circulation (2000) 101:995–1001.[Abstract/Free Full Text]
  77. Gaita F, Calo L, Riccardi R, et al. Different patterns of atrial activation in idiopathic atrial fibrillation: simultaneous multisite atrial mapping in patients with paroxysmal and chronic atrial fibrillation. J Am Coll Cardiol (2001) 37:534–541.[Abstract/Free Full Text]
  78. Boutjdir M, Le Heuzey J.Y, Lavergne T, et al. Inhomogeneity of cellular refractoriness in human atrium: factor of arrhythmia? PACE (1986) 9:1095–1100.[Medline]
  79. Josephson M.E. Clinical cardiac electrophysiology: techniques and interpretations. (1993) Philadelphia: Lea and Febiger. 275–310.
  80. Papageorgiou P, Monahan K, Boyle N, et al. Site-dependent intra-atrial conduction delay: relationship to initiation of atrial fibrillation. Circulation (1996) 94:384–386.[Abstract/Free Full Text]
  81. Gaita F, Riccardi R, Cab L, et al. Atrial mapping and radiofrequency catheter ablation in patients with idiopathic atrial fibrillation. Electrophysiological findings and ablation results. Circulation (1998) 97:2136–2145.[Abstract/Free Full Text]
  82. Haissaguerre M, Gencel L, Fischer B, et al. Successful catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol (1994) 5:1045–1052.[Web of Science][Medline]
  83. Swartz J.F, Pellersels G, Silvers J, Patten L, Cervantez D. A catheter-based curative approach to atrial fibrillation in humans (abstract). Circulation (1994) 90:I–335.
  84. Haissaguerre M, Jais P, Shah D.C, et al. Right and left atrial radiofrequency catheter therapy of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol (1996) 7:1132–1144.[Web of Science][Medline]
  85. Holm M, Johansson R, Brandt J, Luhrs C, Olsson S.B. Epicardial right atrial free wall mapping in chronic atrial fibrillation: documentation of repetitive activation with a focal spread, a hitherto unrecognized phenomenon in man. Eur Heart J (1997) 18:290–310.[Abstract/Free Full Text]
  86. Tsai C.F, Tai C.T, Hsieh M.H, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of radiofrequency ablation. Circulation (2000) 102:67–74.[Abstract/Free Full Text]
  87. Tai C.T, Hsieh M.H, Tsai C.F, et al. Differentiating the ligament of Marshall from the pulmonary vein musculature potentials in patients with paroxysmal atrial fibrillation: electrophysiological characteristics and results of radiofrequency ablation. PACE (2000) 23:1493–1501.[Medline]
  88. Popone C, Rosanio S, Oreto G, et al. Circumferential radiofrequency ablation of pulmonary vein ostia: a new anatomic approach for curing atrial fibrillation. Circulation (2000) 102:2619–2628.[Abstract/Free Full Text]
  89. Rosanio S, Pappone C, Vicedomini O, et al. Chronic atrial fibrillation. Is it a curable condition? Eur Heart J (2001) 22:361. Abstract.
  90. Kumagai K, Yasuda T, Tojo H, et al. Role of rapid focal activation in the maintenance of atrial fibrillation originating from the pulmonary veins. PACE (2000) 23:1823–1827.[Medline]
  91. Davis M.J, Pomerance A. Pathology of atrial fibrillation in man. Br Heart J (1972) 34:520–525.[Free Full Text]
  92. Spach M.S, Dolber P.C. Relating extracellular potentials and their derivatives to anisotropic propagation at microscopic level in human cardiac muscle: evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res (1986) 58:356–371.[Abstract/Free Full Text]
  93. Isomoto S, Fukatani M, Konoe A, et al. The influence of advancing age on the electrophysiological changes of the atrial muscle induced by programmed atrial stimulation. Jpn Circ J (1992) 56:776–782.[Medline]
  94. Nattel S, Li D, Yue L. Basic mechanisms of atrial fibrillation—very new insights into very old ideas. Annu Rev Physiol (2000) 62:51–77.[CrossRef][Web of Science][Medline]
  95. Tse H.F, Lau C.P, Ayers G.M. Heterogenous changes in electrophysiologic properties in the paroxysmal and chronically fibrillation human atrium. J Cardiovasc Electrophysiol (1999) 10:125–135.[Web of Science][Medline]
  96. Brundel B.J.J.M, Van Gelder I.C, Henning R.H, et al. Gene expression of proteins influencing the calcium homeostasis in patients with persistent and paroxysmal atrial fibrillation. Cardiovasc Res (1999) 42:443–454.[Abstract/Free Full Text]
  97. Grammer J.B, Bosch R.F, Kuhlkamp V, Seipel L. Molecular remodeling of Kv4.3 potassium channels in human atrial fibrillation. J Cardiovasc Electrophysiol (2000) 11:626–633.[Web of Science][Medline]
  98. Brundel B.J.J.M, Van Gelder I.C, Henning R.H, 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 (2001) 37:926–932.[Abstract/Free Full Text]
  99. Dupont E, Ko Y, Rothery S, et al. The gap-junctional protein connexin 40 is elevated in patients susceptible to postoperative atrial fibrillation. Circulation (2001) 103:842–849.[Abstract/Free Full Text]
  100. Sung R.J, Castellanos A, Mallon S.M. Mechanism of spontaneous alternation between reciprocating tachycardia and atrial flutter-fibrillation in the Wolff–Parkinson–White syndrome. Circulation (1977) 56:409–416.[Free Full Text]
  101. Jackmann W, Yeung-Lai-Wah J, Friday K, et al. Tachycardia originating in accessory pathway networks mimicking atrial flutter and fibrillation. J Am Coll Cardiol (1986) 7:6A. Abstract.
  102. Fujimura O, Klein G.J, Yee R, Sharma A.D. Mode of onset of atrial fibrillation in the Wolff–Parkinson–White syndrome: how important is the accessory pathway? J Am Coll Cardiol (1990) 15:1082–1086.[Abstract]
  103. Konoe A, Fukatani M, Tanigawa M, et al. Electrophysiological abnormalities of the atrial muscle in patients with manifest Wolff–Parkinson–White syndrome associated with paroxysmal atrial fibrillation. PACE (1992) 15:1040–1052.[Medline]
  104. Fananapazir L, Tracy C.M, Leon M.B, et al. Electrophysiologic abnormalities in patients with hypertrophic cardiomyopathy: a consecutive analysis in 155 patients. Circulation (1989) 80:1259–1268.[Abstract/Free Full Text]
  105. Greenspan A.M. Hypertrophic cardiomyopathy and atrial fibrillation: a change of perspective. J Am Coll Cardiol (1990) 15:1286–1287.[Web of Science][Medline]
  106. Li D, Benardeau A, Nattel S. Contrasting efficacy of dofetilide in differing experimental models of atrial fibrillation. Circulation (2000) 102:104–112.[Abstract/Free Full Text]
  107. Ito M, Gnodera S, Hashimoto J, et al. Effect of disopyramide on initiation of atrial fibrillation and relation to effective refractory period. Am J Cardiol (1989) 63:561–566.[CrossRef][Web of Science][Medline]
  108. Shimizu A, Fukatani M, Tanigawa M, et al. Mechanism of the suppression of repetitive atrial firing by isoproterenol: comparison with disopyramide. Int J Cardiol (1994) 43:175–183.[CrossRef][Web of Science][Medline]
  109. Esato M, Shimizu A, Chun Y.-H, et al. Electrophysiologic effects of a class I antiarrhythmic agent, cibenzoline, on the refractoriness and conduction of the human atrium in vivo. Cardiovasc Pharmacol (1996) 28:321–327.[CrossRef][Web of Science][Medline]
  110. Hoffman B.F, Rosen M.R, Wit A.L. Electrophysiology and pharmacology of cardiac arrhythmias. VII. Cardiac effects of quinidine and procainamide. Am Heart J (1975) 90:117–122.[CrossRef][Web of Science][Medline]
  111. Vik-Mo H, Ole-Jorgen O, Lund-Johansen P. Electrophysiologic effects of flecainide acetate in patients with sinus node dysfunction. Am J Cardiol (1982) 50:1090–1094.[CrossRef][Web of Science][Medline]
  112. Shimizu A, Fukatani M, Konoe A, et al. Electrophysiologic effects of new class III antiarrhythmic agent (E4031) on the conduction and refractoriness of the in-vivo human atrium. Cardiovasc Res (1993) 27:1333–1338.[Abstract/Free Full Text]
  113. Singh B.N, Nademanee K. Use of calcium antagonists for cardiac arrhythmias. Am J Cardiol (1987) 59:153B–162B.[CrossRef][Medline]
  114. Shenasa M, Kust T, Fromer M, et al. Effect of intravenous and oral calcium antagonists (diltiazem and verapamil) on sustenance of atrial fibrillation. Am J Cardiol (1988) 62:403–407.[CrossRef][Web of Science][Medline]
  115. Kumagai K, Matsuo K, Ono M, et al. Effects of verapamil on electrophysiological properties in paroxysmal atrial fibrillation. PACE (1993) 16:309–316.[Medline]
  116. Isomoto S, Shimizu A, Konoe A, et al. Effects of intravenous verapamil on atrial vulnerability. Jpn Circ J (1994) 58:1–8.[Medline]
  117. Tieleman R.G, De Langen C, Van Gelder I.C, et al. Verapamil reduces tachycardia-induced remodeling of the atria. Circulation (1997) 96:1542–1550.[Abstract/Free Full Text]
  118. Ravens U, Himmel H.M. Drugs preventing Na+ and Ca2+ overload. Pharmacol Res (1999) 39:167–174.[CrossRef][Web of Science][Medline]
  119. Lee S.H, Yu W.C, Cheng J.J, et al. Effect of verapamil on long-term tachycardia-induced atrial electrical remodeling. Circulation (2000) 101:200–206.[Abstract/Free Full Text]
  120. Ramanna H, Elvan A, Wittkampf F.H.M, et al. Increased dispersion and shortened refractoriness caused by verapamil in chronic atrial fibrillation. J Am Coll Cardiol (2001) 37:1403–1407.[Abstract/Free Full Text]
  121. Ngnyen N, Yang P, Huycke E.C, et al. Effects of beta-adrenergic stimulation on atrial latency and atrial vulnerability in patients with supraventricular tachycardia. Am J Cardiol (1988) 61:1031–1036.[CrossRef][Web of Science][Medline]
  122. Opthof T, Ramdat Misier A.R, Coronel R, et al. Dispersion of refractoriness in canine ventricular myocardium: effects of sympathetic stimulation. Circ Res (1991) 68:1204–1215.[Abstract/Free Full Text]
  123. Allessie M.A, Kirchhof C, Scheffer G.J, Chorro F, Brugada J. Regional control of atrial fibrillation by rapid pacing in conscious dogs. Circulation (1991) 84:1689–1697.[Abstract/Free Full Text]
  124. Kim K.B, Rodefeld M.D, Schuessler R.B, Cox J.L, Boineau J.P. Circulation. (1996) 94:2961–2967.
  125. Botteron G.W, Smith J.M. Quantitative assessment of the special organization of atrial fibrillation in the intact human heart. Circulation (1996) 93:513–518.[Abstract/Free Full Text]
  126. Zrenner B, Ndrepepa G, Karch M.R, et al. Electrophysiologic characteristics of paroxysmal and chronic atrial fibrillation in human right atrium. J Am Coll Cardiol (2001) 38:1143–1149.[Abstract/Free Full Text]
  127. Ndrepepa G, Zrenner B, Schreieck J, et al. Left atrial fibrillation with regular right atrial activation and a single left-to-right electrical interatrial connection: multisite mapping of dissimilar atrial rhythms. J Cardiovasc Electrophysiol (2000) 11:587–592.[CrossRef][Web of Science][Medline]
  128. Roithinger F.X, Lesh M.D. What is the relationship of atrial flutter and fibrillation? PACE (1999) 22:643–654.[Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
S.-M. Chaldoupi, P. Loh, R. N.W. Hauer, J. M.T. de Bakker, and H. V.M. van Rijen
The role of connexin40 in atrial fibrillation
Cardiovasc Res, October 1, 2009; 84(1): 15 - 23.
[Abstract] [Full Text] [PDF]

Home page
 EuropaceHome page
O. A. Centurion, A. Shimizu, S. Isomoto, and A. Konoe
Mechanisms for the genesis of paroxysmal atrial fibrillation in the Wolff--Parkinson--White syndrome: intrinsic atrial muscle vulnerability vs. electrophysiological properties of the accessory pathway
Europace, March 1, 2008; 10(3): 294 - 302.
[Abstract] [Full Text] [PDF]

Home page
 ANGIOLOGYHome page
O. Ozdemir, M. Soylu, A. D. Demir, O. Alyan, S. Topaloglu, B. Geyik, and E. Kutuk
Does P-Wave Dispersion Predict the Atrial Fibrillation Occurrence After Direct-Current Shock Therapy?
Angiology, January 1, 2006; 57(1): 93 - 98.
[Abstract] [PDF]

Home page
 ANGIOLOGYHome page
J. Kassotis, L. Voigt, M. Mongwa, and C. V.R. Reddy
Feasibility of Dual-Chamber (DDD) Pacing via a Single-Pass (VDD) Pacing Lead Employing a Floating Atrial Ring (Dipole): Case Series, Future Considerations, and Refinements
Angiology, May 1, 2005; 56(3): 323 - 329.
[Abstract] [PDF]

Home page
 J Am Coll CardiolHome page
H. Morita, K. Kusano-Fukushima, S. Nagase, Y. Fujimoto, K. Hisamatsu, H. Fujio, K. Haraoka, M. Kobayashi, S. T. Morita, K. Nakamura, et al.
Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome
J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1437 - 1444.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
S. Nattel, M. Allessie, and M. Haissaguerre
Spotlight on atrial fibrillation--the 'complete arrhythmia'
Cardiovasc Res, May 1, 2002; 54(2): 197 - 203.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Shimizu, A.
Right arrow Articles by Centurion, O. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shimizu, A.
Right arrow Articles by Centurion, O. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?