Site-Dependent Intra-Atrial Conduction Delay
Relationship to Initiation of Atrial Fibrillation
Background Atrial dysrhythmia patients have exaggerated intra-atrial conduction delays and prolonged relative refractoriness in response to atrial premature depolarizations (APDs). Furthermore, atrial fibrillation (AF) is more readily inducible by APDs from the high right atrium (HRA) than the coronary sinus (CS). In this study, we postulated that site-specific intra-atrial conduction delays can explain why AF is initiated more from the HRA than from the CS.
Methods and Results We examined 17 patients (age, 49±22 years) without a history of atrial flutter, AF, or structural heart disease. Programmed stimulation was carried out from the HRA and distal CS, and bipolar recordings were made at the HRA, His bundle, posterior triangle of Koch, and CS. More prolongations in conduction and relative refractoriness in all intra-atrial sites were observed during HRA than CS APDs. AF was induced in 8 patients after HRA and not CS stimulation. During HRA stimulation, patients with AF inducibility exhibited significant prolongation of conduction to the posterior triangle of Koch and marked broadening of the posterior triangle of Koch electrogram compared with CS stimulation. In patients without AF inducibility, the posterior triangle of Koch electrogram width was the same during HRA and CS stimulation.
Conclusions The existence of site-dependent intra-atrial conduction delays and site-dependent dispersion of refractoriness appears to be a common property of the atrial myocardium and does not necessarily forecast AF inducibility. However, the presence of nonuniform anisotropic characteristics of the posterior triangle of Koch may be critical for AF induction.
Significant evidence suggests that the apparent chaotic pattern of atrial activation during AF is the result of multiple reentrant wavelets that propagate, become extinct, or fractionate within the atrial tissue.1 2 3 Essential elements of reentry include unidirectional conduction delay or block and recovery of excitability proximal to the area of block. Critically timed premature atrial impulses falling into the atrial relative refractory period at a point when inhomogeneous dispersion of conduction and refractoriness is present may initiate reentry circuits, leading to AF.4 Prior studies have demonstrated that individuals with clinical histories of atrial dysrhythmias have increased intra-atrial conduction times in response to atrial extrastimuli compared with normal control subjects.5 6 In addition, it has been observed that atrial extrastimuli are more likely to induce AF when delivered from the HRA than from the CS.7 8 The mechanism of this phenomenon, however, is not fully understood. It may be related to site-dependent differences in the way the impulse propagates within the atrial myocardium and activates sites critical for the initiation of AF. In addition to a proposed effect on impulse propagation by the atrial fiber geometry,9 other intracellular or intercellular factors might account for nonuniform anisotropic conduction, which in turn may facilitate reentry phenomena. Therefore, we undertook the present study to examine the hypothesis that the readiness of AF induction by HRA rather than CS stimulation is due to the presence of site-specific conduction delays in the atrial myocardium.
We studied 17 patients with histories of symptomatic rapid palpitations or previously documented supraventricular tachycardias who were referred to our center for invasive electrophysiological evaluation and treatment. None of the patients had a documented history of atrial flutter or AF; however, some of the reported unexplained episodes of palpitations could have been secondary to atrial arrhythmias. The patients had no evidence of structural heart disease as assessed by two-dimensional echocardiograms, and their surface ECGs showed no evidence of intra-atrial conduction delays during sinus rhythm. The study group included 5 men and 12 women whose mean age (±SD) was 49±22 years.
Electrophysiological studies were carried out by means of the following catheters: a 6F 5-mm-spaced quadripolar electrode catheter placed in the HRA, a 7F steerable 2/5/2-mm-spaced quadripolar electrode catheter positioned at the posterior triangle of Koch at the level of the CS ostium (slow pathway region, P1 location, as previously described10 ), a 6F 2-mm-spaced decapolar electrode catheter placed in the AV junction along the tendon of Todaro and positioned to obtain the largest His bundle deflection in the distal electrode pair, and a 5-mm-spaced decapolar electrode catheter in the CS with the proximal electrode at the ostium. Fig 1⇓ shows a schematic of the catheter positions.
The distal electrode pairs of the HRA and CS catheters were used for bipolar stimulation. The stimulus output had a pulse width of 2 ms and was consistently set at twice the diastolic threshold. Threshold values ranged from 0.2 to 0.8 mA for the HRA stimulation and from 0.5 to 1.2 mA for the distal CS stimulation. Particular care was taken to ensure continuous capture of the atrial tissue when threshold values were determined.
Bipolar recordings filtered at 30 to 500 Hz were obtained from all intra-atrial sites (a total of 12 electrograms: 1 at the HRA, 5 along the tendon of Todaro, 5 along the CS, and 1 from the posterior triangle of Koch). An analog-to-digital sampling rate of 1 kHz was applied before digital storage and analysis. Measurements were performed at a sweep speed of 200 mm/s with electronic calipers and with the same gain setting maintained in all recordings. To ensure the reproducibility of the measurements, two investigators analyzed the tracings. The precision of repeated measurements was estimated to be 10 ms.
Atrial pacing at drive cycles of 600 and 450 ms followed by programmed atrial extrastimuli (APDs) was performed from the HRA and distal CS until the atrial ERP was reached. Local atrial delay at each site and for each atrial extrastimulus was calculated as the difference between the local atrial response at each site (A1A2) and the stimulus coupling interval (S1S2): A1A2−S1S2. The range of relative refractoriness at each intra-atrial site was defined as the range of coupling intervals that started with the initial local delay (A1A2 >S1S2) at stimulus site and A1A2distant site>A1A2stimulus site and ended with the atrial ERP. The duration of local intracardiac electrograms was assessed at the posterior triangle of Koch by measuring from the beginning of the first deflection from the isoelectric line to the end of the last deflection from the isoelectric line.
The statistical analysis was based on Newman-Keuls parametric tests for multiple comparisons, preceded by two-factor ANOVA to test for the presence of differences between groups. The null hypothesis was rejected at a value of P<.05. Data are expressed as mean±SEM.
Programmed atrial extrastimuli were delivered at the HRA and distal CS until the atrial ERP was reached. Conduction times in response to APDs were determined in the HRA, in the AV junction along the tendon of Todaro, along the CS, and in the posterior triangle of Koch. Marked intra-atrial conduction delays were observed in all sites when APDs were delivered at the HRA, whereas CS stimulation at the same coupling intervals was accompanied by much shorter conduction times to all intra-atrial sites. Of note, during the paced drives of 600 and 450 ms from either the HRA or the CS, there was no evidence for intra-atrial conduction delays at any site (ie, S1S1=A1A1) in any of the patients.
Fig 2⇓ displays a typical three-dimensional isochronal landscape of the intra-atrial anisotropic conduction observed in a single patient during HRA stimulation (top) and CS stimulation (bottom). For each APD coupling interval, the conduction time from the HRA (or the distal CS) to each intra-atrial site is plotted as a function of the latter. This figure displays a prominent conduction delay associated with increased APD prematurity that is seen during HRA stimulation and not CS stimulation.
It is further shown that during HRA extrastimuli, conduction delays occur over a wider range of intervals, suggesting that partial atrial refractoriness is encountered much sooner than in CS stimulation. Alternatively, the slowing of conduction may not represent local partial refractoriness at the recording sites; rather, it might be due to the presence of an area of slow conduction between the HRA and the recording sites. Fig 3⇓ summarizes the relative refractoriness data from all 17 patients: The mean range of relative refractoriness at each intra-atrial site was consistently higher during HRA stimulation, at least twice the values recorded during CS stimulation (P<.03).
The presence of local latency at the stimulus site may influence the degree of conduction delay at the rest of the sites. To normalize for latency at the stimulus site, we subtracted the maximal (A1A2−S1S2) value of the stimulus site from the maximal (A1A2−S1S2) values of the remaining intra-atrial sites. The means of such normalized conduction times from all 17 patients are presented in Fig 4⇓. It is apparent that HRA stimulation was followed by an approximately fivefold increase in intra-atrial conduction times to all sites compared with CS stimulation (P<.01).
During HRA stimulation, AF was induced in 8 patients. Atrial flutter or AF never was observed as a result of CS stimulation in any of the 17 patients. Fig 5⇓ shows an example of AF induction after an early-coupled right APD. There was no difference in the mean (±SD) age of patients with AF induction versus those without AF induction (50±21 versus 48±25 years, P>.8). Although there seemed to be a trend, there was no statistical difference in the maximal latency at the stimulus site between the groups with and without AF induction. During HRA extrastimuli, the local maximal latency was 10±3 ms in the group without AF induction versus 22±8 ms in the AF group (P>.1). Similarly, during CS extrastimuli, the local maximal latency was 16±7 ms in the group without AF induction versus 30±9 ms in the AF group (P>.1).
With respect to differences in ERPs at the two stimulation sites, the CS ERPs were longer on average than the HRA ERPs. In the group without AF induction, the CS ERP was 248±10 ms, and the HRA ERP was 204±5 ms (P=.006). In the AF group, the CS ERP was 231±15 ms, and the HRA ERP was 209±17 ms (P=.04). The numerical differences between the CS ERPs and HRA ERPs were higher in the group without AF induction (43±12 ms) than in the AF group (23±9 ms); however, this trend did not reach statistical significance (P>.1).
Fig 6⇓ displays the intra-atrial conduction times during HRA (top) and CS (bottom) stimulation from a single patient in whom AF was induced. This figure demonstrates two important points. First, the same coupling interval of the HRA APD (270 ms) that induced AF was associated with minimal intra-atrial conduction delays (<20 ms) and no induction of AF when delivered from the CS. Second, although the earliest APD coupling interval (250 ms) was achieved from the CS, the conduction delay it produced (≤40 ms) was much less than that observed (60 to 100 ms) during a less premature APD from the HRA.
We further analyzed the range of relative refractoriness and the conduction delays in all patients grouped according to the presence or absence of AF induction. Fig 7⇓ shows that the range of relative refractoriness was equally prolonged in patients with and without AF during HRA stimulation compared with CS stimulation. Also, within the CS stimulation group, there was no difference in the range of relative refractoriness of all sites from patients with and without AF.
The normalized conduction times to all intra-atrial sites during HRA and CS stimulation also were examined in patients with and without AF. Fig 8⇓ is a plot of the mean maximal delays at each site. Again, conduction delays at all sites were markedly prolonged during HRA stimulation. In addition, during HRA stimulation, the AF group demonstrated a further increase in the conduction delay in the posterior triangle of Koch, whereas there was no statistical difference between the conduction delays in patients with and without AF in the remaining sites (P=.3 for distal CS; P=.4 for CS2). In the AF group and during HRA stimulation, the normalized mean delay measured at the posterior triangle of Koch was 66±13 ms compared with 41±10 ms (P=.04) in the group without AF induction.
To investigate the presence of anisotropic pattern of local activation in the region of the posterior triangle of Koch, we measured the duration of local electrograms recorded at the posterior triangle of Koch during HRA and CS stimulation at the earliest APD coupling interval achieved. In all 17 patients, the duration of the local electrogram was found to be significantly prolonged during HRA stimulation compared with values during CS stimulation (45±2 versus 38±1 ms, P=.003). The width of the local electrogram at the posterior triangle of Koch during HRA and CS stimulation was further examined in relation to AF inducibility. Fig 9⇓ is a plot of the posterior triangle of Koch electrogram width values. It is evident that in patients without AF, there is essentially no difference in the electrogram width during HRA and CS stimulation (38±5 and 37±5 ms, respectively). In contrast, patients in whom AF was induced during HRA stimulation had significantly broader local electrograms during HRA stimulation than during CS stimulation (53±2 versus 39±1 ms, P<.0001).
AF is the most common arrhythmia today11 and can be encountered in patients with and without structural heart disease. The pathophysiological mechanisms responsible for AF are not fully understood, but several lines of evidence suggest that reentry mechanisms are responsible for the genesis of this arrhythmia. Allessie and coworkers,3 12 13 by means of simultaneous multisite mapping, have shown that atrial flutter and AF share an electrophysiological milieu in which the presence of a critical wavelength is necessary to sustain each arrhythmia, with AF requiring a shorter wavelength than atrial flutter. It is common clinical practice to attempt to convert AF by use of drugs that slow intra-atrial conduction and prolong refractoriness. An initial prolongation of the wavelength may convert AF to atrial flutter. Further prolongation of the wavelength may terminate the arrhythmia if the wavelength is too large to fit in the reentry circuit. Often, however, atrial flutter is terminated by a block in a critical zone of poor conduction.14 15
The correlation between the presence of intra-atrial conduction abnormalities and the induction of AF has been well documented. Patients with histories of atrial flutter or AF have been shown to exhibit significant intra-atrial conduction delays during early premature impulses delivered at the right atrium.5 6 As suggested by Simpson et al,16 17 abnormalities of atrial excitability are associated with intra-atrial conduction defects in patients with histories of AF. Furthermore, the induction of AF by right atrial extrastimuli has been associated with the presence of fragmented atrial electrograms at the site of the right atrial stimulation.18 A similar fractionation of electrograms at the AV junction and the ostium of the coronary sinus was seen during atrial flutter induction after early right atrial extrastimuli.7 8 However, CS stimulation at comparable coupling intervals was not accompanied by flutter induction, nor did it produce electrogram fractionation. That observation clearly suggested a role for anisotropic conduction characteristics in certain individuals who may be predisposed to clinical atrial flutter or AF.
The reason for developing a substrate permissive to intra-atrial reentry need not be related to aging, such as atrial dilatation, intramyocardial fibrosis, or myocyte apoptosis. In addition, intra-atrial conduction delay or block may not necessarily be secondary to fixed anatomic obstacles.19 Functional properties of the atrial tissue, perhaps genetically determined, can be of prime importance in establishing conditions of nonuniform anisotropic conduction and inhomogeneous dispersion of refractoriness that are accountable for reentry phenomena. A particular spatial expression of membrane structures, such as connexins, ion channels, or regulatory proteins, may influence intercellular connections and impulse propagation, thus conferring to the tissue highly anisotropic properties.20 21
In the present study, we examined 17 otherwise healthy individuals with a mean age of 49 years who represented a relatively young population. None of the patients had a history of structural heart disease or a history of documented atrial flutter or AF. Furthermore, the age of patients in whom AF was induced did not differ significantly from that of patients in whom AF was not induced. Again, we confirmed the previously noted observation that AF was induced solely after HRA stimulation and not after CS stimulation. AF was induced in 8 of 17 patients (47%), which may be a high percentage given the prior absence of documented AF. However, all patients had prior histories of palpitations, and it is possible that some of their symptoms could have been due to undocumented episodes of paroxysmal AF or flutter.
Our data suggest that there is a universal pattern of anisotropic conduction within the atrial myocardium. This notion is graphically presented in the isochronal figures of the conduction times and atrial refractoriness (Figs 2 and 6⇑⇑). More specifically, as Fig 4⇑ shows, the maximal time required for a depolarizing impulse after an atrial premature beat to reach all intra-atrial sites is approximately five times longer when the premature beat originates at the HRA instead of the distal CS. We also showed that the range of relative refractoriness at each intra-atrial site during HRA extrastimuli is twice the size of the relative refractoriness at the same sites during CS stimulation (Fig 3⇑). These observations apply similarly to both patients with and without AF induction (Figs 7 and 8⇑⇑). It is possible that a ubiquitous structure, such as the crista terminalis, accounts for the observed delays to the distal intra-atrial sites by intersecting the propagation of the HRA stimulus. Such a role for the crista terminalis as a fixed or functional area of slow conduction was proposed recently.19
In patients in whom AF was induced, it also was noted that during HRA stimulation, the conduction time to the region of the posterior triangle of Koch was significantly prolonged (Fig 8⇑). This observation underscored a potential role of the slow pathway region in determining the inducibility of AF, so we further analyzed the width of the local slow pathway electrograms recorded during the earliest APDs from either site that captured the atria. We found that these electrograms were broader only during HRA stimulation and only in patients with AF inducibility (Fig 9⇑).
Our observations suggest a critical importance of the low right atrium in the genesis of AF. The increased conduction time to that region during HRA stimulation observed only in patients with AF inducibility and the pronounced local conduction delay present only in the same subgroup point to a strong influence of local anisotropic factors in the pathogenesis of AF. The low right atrium has received special attention recently; it appears to be the anatomic area for successful atrial flutter ablation22 23 and radiofrequency catheter modification to control the ventricular rate during AF.24 25 We previously proposed the low right atrium as the critical area required for atrial flutter,8 further corroborating our current observation, given a likely common pathophysiological milieu for both arrhythmias.
In conclusion, we have demonstrated the presence of site-specific dispersion of atrial refractoriness and site-dependent intra-atrial conduction delays that can be explained on the basis of nonuniform atrial anisotropy. Increased relative refractoriness and prolonged conduction times during HRA extrastimulus testing appeared to be common properties of the atrial tissue, regardless of AF induction. Moreover, AF occurrence was strongly associated with further site-specific conduction delays to and within the posterior triangle of Koch. Although this association does not establish a causal relationship, it lends support to the notion that slow conduction in the low right atrium may be required for reentry and may initiate AF. Further studies involving high-density mapping of the posterior triangle of Koch will be necessary to prove whether this particular area is critical to the formation of the AF reentry circuit. The recognition of the existence and importance of nonuniform atrial anisotropy may eventually lead to the development of new treatment avenues for AF.
Selected Abbreviations and Acronyms
|APD||=||atrial premature depolarization|
|ERP||=||effective refractory period|
|HBE||=||His bundle electrogram|
|HRA||=||high right atrium|
- Received November 2, 1995.
- Revision received January 24, 1996.
- Accepted January 29, 1996.
- Copyright © 1996 by American Heart Association
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