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J Am Coll Cardiol, 2001; 38:355-363
© 2001 by the American College of Cardiology Foundation
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CLINICAL STUDY

Prevalence, characteristics and clinical implications of regular atrial tachyarrhythmias in patients with atrial fibrillation: insights from a study using a new implantable device

Carsten W. Israel, MD*, Joachim R. Ehrlich, MD*, Gerian Grönefeld, MD*, Armin Klesius, MD*, Thomas Lawo, MDb, Bernd Lemke, MDb and Stefan H. Hohnloser, MD, FACC, FESC*

* Department of Medicine, Division of Cardiology, J. W. Goethe University, Frankfurt, Germany
b the Department of Medicine, Division of Cardiology, Ruhr-University Bochum, Bergmannsheil, Bochum, Germany

Manuscript received September 14, 2000; revised manuscript received April 5, 2001, accepted April 11, 2001.

Reprint requests and correspondence: Dr. Stefan H. Hohnloser, Department of Medicine, Division of Cardiology, J. W. Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
Hohnloser{at}em.uni-frankfurt.de


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

This study prospectively analyzed atrial tachyarrhythmia (AT) organization and antitachycardia pacing (ATP) success in patients with an implanted device for AT therapy.

BACKGROUND

In patients with atrial fibrillation (AF), the incidence of regular, slow ATs amendable by ATP is unknown.

METHODS

Forty patients with previously documented AT (70% with AF) received a new pacemaker with atrial electrogram (AEG) storage and atrial ATP capabilities for standard pacing indications. The AEGs acquired during the first month (study phase 1) were classified into high (type I), intermediate (type II) and low (type III) degrees of organization. Atrial ATP was then activated, and treated AT episodes were retrieved three and six months after implantation (study phase 2).

RESULTS

Of 824 AEGs retrieved before ATP activation (study phase 1), 351 (43%) were classified as type I, 47% as type II and 10% as type III. Episodes of AT starting as type I (35%) and type II or III (65%) maintained their type over 1 min in 73%. All patients with an exclusive history of AF also showed type I AEGs. In 361 subsequently treated AT episodes (study phase 2), ATP was successful in 62% of type I and 34% of type II episodes, but not in type III (p < 0.0001).

CONCLUSIONS

The majority of patients with a history of AF show not only disorganized but also highly organized AT episodes, which can be successfully terminated by ATP.

Abbreviations and Acronyms
  AEG = atrial electrogram
  AF = atrial fibrillation
  AT = atrial tachyarrhythmia
  ATP = antitachycardia pacing
  AV = atrioventricular
  CI = confidence interval
  GEE = Generalized Estimating Equation

Different approaches to improve treatment of atrial tachyarrhythmias (ATs), such as new antiarrhythmic drugs, catheter ablation techniques, atrial pacing for prevention of AT onset, atrial overdrive pacing and internal atrial defibrillation, are currently under investigation. Antiarrhythmic drug treatment of AT is limited by a relatively low success rate of maintaining sinus rhythm and proarrhythmic side effects (1). Atrial defibrillation, on the other hand, is highly effective in restoring sinus rhythm, but the associated discomfort and pain limit its widespread use (2). The possibility of automatically pace-terminating ATs by an implanted device is a promising new therapeutic avenue. However, atrial antitachycardia pacing (ATP) will terminate only regular AT, such as atrial flutter, but not atrial fibrillation (AF) (3). Knowledge of AT organization is derived from atrial electrograms (AEGs) in animal models (4), recordings during human electrophysiologic studies (5,6) and temporary atrial leads implanted during cardiac surgery (7). It is not known how many spontaneous ATs during daily life consist of regular, relatively slow episodes, which may be amendable by painless termination by ATP. Moreover, it is unclear whether the degree of AT organization is stable over a short period. Accordingly, it is unknown whether automatic atrial ATP should be applied early after onset of AT, before it disorganizes, or later to allow for spontaneous conversion to more organized rhythms or eventually to sinus rhythm. Thus, this prospectively designed study evaluated the degree of AT organization during the first minute after its onset, as well as the success rate of automatic atrial ATP related to AT organization, using an implanted device with dedicated capabilities for AT monitoring and treatment.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Study group.   Patients with a class I indication for permanent pacemaker therapy, according to accepted guidelines (8), and ATs documented by rest electrocardiography or 24-h Holter monitoring within three months before implantation were eligible for the study. Records were kept for antiarrhythmic drug treatment before and after pacemaker implantation. All patients gave written, informed consent. The study protocol was approved by the institutional ethical committees.

Device specifications.   In all patients, a DDDRP pacemaker system (AT500 model 7253, Medtronic Inc., Minneapolis, Minnesota) was implanted. This system offers DDDR pacing with automatic atrial ATP (adaptive ramp and burst-plus protocols) and storage capabilities for 35 AT episodes. The ATs are automatically stored using a detection algorithm combining the rate with P:R pattern information (PR LogicTM, Medtronic). An automatic algorithm adjusts the atrial sensitivity after each sensed or paced atrial event to avoid ventricular far-field oversensing. Each episode report contains an AT summary and marker annotations with atrial and ventricular beat-to-beat cycle length of 144 cycles. Simultaneously, a bipolar AEG recorded through the implanted atrial lead is stored for up to 4 s at the onset of the AT episode and for up to 4 s at confirmation of AT persistence 1 min later.

Data acquisition.   This prospective study comprised two successive phases. During the first phase (first month after implantation), AEGs of up to 35 AT episodes per patient (AT cycle length <360 ms) were stored by the devices; ATP functions remained deactivated. One month after implantation, the second phase started with activation of ATP modalities for AT episodes lasting >1 min. During the subsequent five-month period, only AT episodes treated by ATP were acquired. Stored AT episodes were downloaded on disk, subsequently printed out and analyzed. Antitachycardia pacing was delivered for slow, regular AT episodes (median cycle length 220 to 360 ms, difference between second longest and second shortest AA interval ≤25% of median AA interval). Antitachycardia pacing was programmed to eight sequences of adaptive ramp (91% of AA interval, 10-ms decrement, 4 initial beats), six sequences of burst-plus (91% of AA interval, 84% S1S2, 20-ms S2S3, 10-ms decrement, 8 initial beats) and four sequences of a more aggressive burst-plus protocol (91% of AA interval, 75% S1S2, 20-ms S2S3, 10-ms decrement, 15 initial beats).

Analysis of episodes and definitions.   Stored electrograms were manually analyzed (by Dr. Israel) in the following way: 1) Confirmation of sustained AT; episodes consisting of nonsustained AT, only oversensing artifacts or severe undersensing precluding reliable evaluation of sensed potentials and cycle lengths were excluded from analysis. 2) Evaluation of AT type at onset and at confirmation of AT persistence; AT classification on the basis of AEG morphology, including cycle length information (modified from [9]) (Table 1), was prospectively used to define three types of AT (Fig. 1): type I—highly organized AT, defined as a discrete deflection of constant morphology with an isoelectric line between signals and a minimal cycle length ≥200 ms; type II—intermediate type of organization, so classified if morphology and cycle length did not meet the definition of either type I or type III (e.g., an AT with discrete monomorphic narrow signals and a minimal cycle length <200 ms or an AT with polymorphic deflections and a clear isoelectric line); and type III—disorganized AT, defined as polymorphic deflections without an isoelectric line between signals and a minimal cycle length <200 ms. Each stored AEG (at AT onset and AT confirmation 1 min later) was assigned to one type of AT. If there were clearly two different types of AT on one AEG, two types of AT were classified. 3) Evaluation of atrial ATP success; for each AT episode treated by ATP, the reliability of marker annotations was evaluated using the periods with simultaneous AEG storage. The type of AT immediately before ATP was classified (see earlier text). Primary termination of AT was defined as immediate termination of the arrhythmia after ATP. Secondary AT termination was defined, as suggested in previous studies (10), as arrhythmia termination within 30 s after ATP. In addition, the atrial cycle length had to be changed after ATP by ≥20 ms.


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  		Table 1 Classification of Atrial Tachyarrhythmias on the Basis of Atrial Electrograms

 


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  		Figure 1 Classification of atrial tachyarrhythmia (AT) on the basis of analysis of stored bipolar electrograms. a) Type I: highly organized AT with discrete deflections of constant morphology, an isoelectric line between signals and a minimal cycle length ≥200 ms. b) Type II: intermediate type of organization not meeting the definition of type I or type III. c) Type III: disorganized AT with polymorphic deflections, no isoelectric line between signals and a minimal cycle length <200 ms. AS = atrial sense; FD = fibrillation detection interval; FS = fibrillation sense; TF = tachycardia/fibrillation (overlap zone); TS = tachy sense.

 
Statistical analysis.   This was a prospective observational study with the primary end points of 1) the incidence of highly organized AEGs in patients with a history of AT, including AF; and 2) ATP success rate in relation to AT organization. Secondary end points were 1) the incidence of organized AT (type I) in patients with a history of AF only; 2) transition from organized to less organized AT, and vice versa, during the first minute of the AT episode; and 3) the potential influence of various clinical factors (e.g., position of the atrial bipolar lead, gender, age, pacing indication, presence of coronary artery disease, valvular disease, hypertension, left ventricular ejection fraction, left atrial diameter, class I or III antiarrhythmic drug treatment) on the AT type. All data were analyzed using the Statistical Package for Social Sciences (SPSS, version 8.0), and the statistical software packages SAS 11 and S-plus 12 (SAS, Cary, North Carolina). The Student t test or Fisher exact test for categorical data was used, where appropriate. The Generalized Estimating Equation (GEE [11]) was used to compensate for the different number of episodes from each patient and to calculate an adjusted percentage of AT type occurrence with 95% confidence intervals (CIs). Stepwise logistic regression with the occurrence of type I AT and ATP success as the dependent variable was performed to assess the independent contributions of the aforementioned clinical variables. A p value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Study group.   Forty patients (19 women and 21 men, age 68 ± 9 years) with a class I indication for permanent pacing (26 with sick sinus syndrome, 10 with atrioventricular [AV] block, 3 with planned AV node ablation, 1 with hypersensitive carotid sinus) and electrocardiographically documented AT were enrolled in this study. A history of AT consisted of AF alone in 28 patients (paroxysmal in 26, persistent in 2), atrial flutter in combination with AF in 3, atrial flutter alone in 7 and ectopic atrial tachycardia in 2. Before pacemaker implantation, 3 ± 1 (range 1 to 7) antiarrhythmic drugs had been used for treatment of AT. Antiarrhythmic drug therapy at enrollment consisted of amiodarone (n = 5), sotalol (n = 5), flecainide (n = 1), beta-blocker (n = 11), calcium antagonist (n = 4) and digoxin (n = 4) and was kept constant during follow-up. Underlying cardiac disease was present in 32 (80%) of 40 patients: coronary artery disease in 14, hypertension in 20, valvular disease in 9 and cardiomyopathy in 3. Mean left ventricular ejection fraction was 0.55 (<0.40 in 7 patients). Mean left atrial diameter was 45 mm (≥45 mm in 22 patients). Pacemaker implantation was successfully completed in all 40 patients, with the atrial lead positioned at the right atrial free wall in 25 patients (lateral in 15, anterior in 10) and in the right atrial appendage in 15 patients.

Type of AT.   Episodes of AT were stored during the first study phase in 21 patients. Of these, one patient was excluded because of insufficient signal quality during AF, resulting in false detection of AF termination and new-onset AF. Another patient was excluded because of inappropriate AT detection caused by atrial runs of three to five beats, alternating with two to three sinus beats. Thus, analysis of AT type during study phase 1 is based on 432 AT episodes in 19 patients. For these 432 AT episodes, 804 AEGs were stored: 392 at AT onset and 412 at AT confirmation 1 min later. Twenty AEGs showed two AT types. Thus, a total of 824 AT types were classified (Fig. 2). Type I was found in 351 (43%), type II in 392 (47%) and type III in 81 AEGs (10%). The distribution of AT type among individual patients is shown in Figure 3. Using the GEE method, the adjusted prevalence of type I AT was 47.5% (95% CI 37.5% to 57.7%), 42.1% (95% CI 29.6% to 55.7%) for type II AT and 9.6% (95% CI 4.9% to 18.1%) for type III AT.



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  		Figure 2 Episodes of atrial tachyarrhythmia (AT) (solid bar = type I; shaded bar = type II; open bar = type III) at onset and confirmation of AT persistence 1 min later on the atrial electrogram (AEGM).

 


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  		Figure 3 Number of type I (highly organized) or type II/III (less organized) atrial tachyarrhythmia (AT) episodes on the atrial electrogram at onset (left) and after 1 min of AT (right).

 
Type of AT at onset and confirmation.   In 279 episodes recorded during study phase 1, AEG analysis confirmed correct AT detection at both AT onset and AT confirmation 1 min later (Fig. 3). Of these, 97 AT episodes (35%) started as type I. At confirmation, 72 (74%) of 97 episodes remained as type I, whereas 25 (26%) of 97 had degenerated into type II or III. Of the 182 (65%) of 279 episodes that started as type II or III, 51 (28%) became organized secondarily into type I AT within 1 min and 131 (72%) remained unchanged. Thus, 203 (73%) of 279 AT episodes exhibited the same degree of organization 1 min after onset, whereas 76 (27%) of 297 AT episodes changed during this period.

Type of AT and success of ATP.   During the study phase 2, ATP was activated in all patients, and 395 treated AT episodes were retrieved from the devices. The majority of episodes were treated immediately after 1 min of AT persistence; 78% of episodes were treated within 10 min after AT onset. Of these 395 episodes, 34 were excluded because of high-degree atrial undersensing or frequent ventricular far-field oversensing. Of the remaining 361 treated AT episodes (Fig. 4), 217 (60%) were type I and 86 (24%) were type II. Fifty-eight treated AT episodes (16%) showed type III organization. These were eventually treated on the basis of relatively regular (e.g., 2:1) undersensing of AF potentials. Atrial ATP terminated 135 of 217 type I AT episodes (62%, primary termination in 19%, secondary termination in 43%) (Fig. 5). Type II AT was successfully terminated in 29 (34%) of 86 episodes: 1 episode with primary termination and 28 episodes with secondary termination. Type III AT episodes could not be terminated by ATP.



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  		Figure 4 Antitachycardia pacing success rates in types I, II and III of atrial tachyarrhythmia (AT) episodes.

 


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  		Figure 5 Examples of atrial antitachycardia (ATP). (A) Primary termination of regular atrial tachyarrhythmia (AT) (type I, cycle length 260 ms) by burst-plus pacing. (B) Primary termination of type I AT (cycle length 250 ms) by ramp pacing. (C) Secondary termination of type I AT (cycle length 250 ms). After the last paced beat, there are four AT cycles before the AT ceases. Details are from stored AT episodes immediately before first ATP (with AEG) and during last ATP (no AEG available) (paper speed 25 mm/s). AP = atrial pace; AS = atrial sense; FDI = fibrillation detection interval; FS = fibrillation sense; TF = tachycardia/fibrillation (overlap zone); VP = ventricular pace; VS = ventricular sense.

 
Organized AT in patients with a history of AF.   From the 28 patients with surface electrocardiographic documentation of AF only, 14 had 471 AT episodes stored by the device (patients 6 to 19 in Fig. 6). Ten patients showed both type I and type II or III on AEG, whereas in four patients, all stored AEGs showed type I AT organization. Of these 471 AT episodes, 157 (33%) consisted of type I, 275 (58%) type II and 39 (8%) type III. Of 12 patients with documented AF together with atrial flutter (n = 3) or AT other than AF (n = 9), five (2 with exclusively atrial flutter and 3 with atrial flutter and AF) had 332 AT episodes stored by the device. Of these, 192 (58%) showed type I, 101 (30%) type II and 39 (11%) type III characteristics.



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  		Figure 6 Distribution of atrial tachyarrhythmia (AT) types (solid bar = type I; open bar = type II; shaded bar = type III) among individual patients. In patients 1 and 2, only atrial flutter was previously documented, whereas in patients 3 to 5, atrial fibrillation (AF) and atrial flutter were documented. The only previously documented AT in patients 6 to 19 was AF.

 
Influence of clinical factors on AT type and ATP success.   On univariate analysis, antiarrhythmic treatment (class IC and III drugs) was associated with a higher percentage of type I AT episodes (54% vs. 28%, p < 0.01) and a lower percentage of type II or III AT episodes (39% vs. 52%, p < 0.01 and 7% vs. 20%, p < 0.01, respectively). However, all patients receiving antiarrhythmic drug therapy exhibited type I and also type II or III AT episodes. On stepwise logistic regression, no clinical variable, including antiarrhythmic medication and atrial lead position, was significantly related to the prevalence of type I versus type II or III AT. No clinical factors, including age, antiarrhythmic drug treatment, left atrial diameter and left ventricular function, showed a significant correlation with ATP success.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Main study findings.   This study demonstrates that in patients with a history of AF alone or atrial flutter and AF, a large proportion of spontaneous ATs show highly (43%) or intermediately (48%) organized AT. Most AT episodes (73%) remained within the same degree of organization after 1 min of AT persistence; 26% of type I ATs degenerated into less organized forms and 28% of type II or III ATs became secondarily organized into type I. Atrial ATP successfully terminated 62% of type I ATs, whereas type II was only pace-terminable in 34%. Type III could not be terminated by pacing.

Organization of AT.   In this study, evaluation of AT organization was based on the analysis of bipolar AEGs recorded at a single site, as a modification of a previously published classification (9). The automatic cycle length annotation added important information to the AEG. Compared with the proposed scheme used in our study, previous classifications of bipolar electrograms of AT (Table 1) are significantly limited, because they do not consider the AT cycle length (9,12), they are restricted to cycle length analysis or signal amplitude variability (13) or they require particular signal post-processing (14,15). The present study demonstrates a high prevalence of organized and relatively slow type I AEGs. In addition, the majority of intermediately organized ATs (type II) were also regular but faster in rate; a minority of type II ATs showed polymorphic or nondiscrete signals or did not display an isoelectric line at baseline. Only 10% of electrograms were disorganized, with a loss of discrete signal morphology (type III). Thus, although human AF has been described as random and disorganized, the present study reveals evidence that even patients with AF show AT episodes with a considerable degree of organization, at least for the first minute after AT onset. This observation is in line with previous studies reporting regularity in direction of wavelet propagation (16,17), as well as temporal and spatial organization during AF (18,19). Of note, in the present study, all 14 patients with an exclusive history of AF who developed an AT episode showed at least one episode of type I on the AEG. These findings indicate that AF organization may vary widely within an individual patient, from highly organized forms suggestive of right atrial flutter to completely disorganized AEG types. Moreover, also during less organized AT episodes, spells of highly organized arrhythmia amendable to ATP may develop. Accordingly, our findings may serve as a conceptual basis to explain the success or failure of pace termination of AT.

Termination of AT by atrial ATP.   The overall success rate of atrial ATP was 46% in our study group. Other studies using implantable devices indicate successful pace termination in 45% to 95% of AT episodes (20,21). According to device programming (treatment only for regular AT episodes with a mean cycle length of 220 to 360 ms), most treated AT episodes showed type I AT, which was terminated by pacing in 62% of cases. In type II AT episodes that met the criteria for ATP treatment, ATP success was significantly lower (34%, p < 0.0001), and type III AT could not be terminated by ATP. Thus, the proposed AT classification, based on AEG morphology and cycle length criteria, correlates well with the success or failure of atrial ATP. As previously reported (10,22–24), secondary pace termination of AT occurred in the present study and was more frequent than primary pace termination.

Transitions between regular and irregular AT.   The present study investigated the time course of spontaneous, paroxysmal AT episodes during daily life by AEG analysis. In terms of the degree of organization, 73% of spontaneous AT episodes were stable, both in episodes starting as organized type I AT (74%) and in those starting as type II or III AT (72%). Thus, a 1-min delay before ATP may avoid unnecessary automatic therapy in short AT episodes, without increasing the proportion of disorganized AT types. Similar observations have been made in different clinical settings. For instance, using temporary leads after cardiac surgery, transitional AF with a mean duration of 9.3 s before the onset of typical atrial flutter was found in 78% of episodes (25). During electrophysiologic study, transitions from AF to atrial flutter (7), and vice versa (6), have been found.

Importance of electrode position and antiarrhythmic drugs.   A higher degree of organization of AF along the trabeculated free right atrial wall, as compared with the septal region or coronary sinus os, has been reported and related to "streaming" of excitation along the crista terminalis (6,7). Organization of AT has also been reported to be dependent on the presence of trabeculated or smooth myocardium at the site of electrogram recording (26,27). However, in the present study using bipolar leads implanted at presumably trabeculated positions, the site of bipolar electrogram recording was not significantly related to the type of AT. In the present study, 11 patients were treated with class I or III antiarrhythmic drugs. Class IC and III antiarrhythmic drugs may substantially lengthen the AF wavelength and convert AF into atypical atrial flutter (28). Accordingly, there was a higher percentage of type I AT episodes in patients receiving class IC antiarrhythmic or amiodarone treatment, but all of them also exhibited type II or III AT episodes.

Study limitations.   In this study, all patients with a history of AT had an indication for permanent pacemaker therapy. Accordingly, our findings cannot be generalized to all patients with AT but no need for pacemaker therapy. Some of the successful secondary terminations by pacing may also represent a coincidence of ATP delivery and spontaneous AT cessation. The AEG recordings were obtained from one endocardial lead located in the right atrium. Thus, no information on the precise electrophysiologic mechanism underlying the observed AT could be derived. This is why we use the term "AT" rather than a more specific diagnosis of the respective atrial arrhythmia.

Conclusions.   A high proportion of patients with a pacemaker show highly or intermediately organized AT episodes, even if AF was the only previously documented arrhythmia. These organized ATs can be successfully terminated by atrial pacing. These findings may serve to derive new strategies of hybrid therapy of AF which merit prospective evaluation in randomized trials.


   Footnotes
 
This study was supported in part by Medtronic Inc., Minneapolis, Minnesota.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

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