CLINICAL RESEARCH: HEART RHYTHM DISORDER
Functional Characterization of Atrial Electrograms in Sinus Rhythm Delineates Sites of Parasympathetic Innervation in Patients With Paroxysmal Atrial Fibrillation
Nicolas Lellouche, MD1,
Eric Buch, MD1,
Andrew Celigoj, BS,
Carin Siegerman, PhD,
David Cesario, MD, PhD,
Carlos De Diego, MD,
Aman Mahajan, MD, PhD,
Noel G. Boyle, MD, PhD,
Isaac Wiener, MD,
Alan Garfinkel, PhD and
Kalyanam Shivkumar, MD, PhD*
UCLA Cardiac Arrhythmia Center, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
Manuscript received February 5, 2007;
revised manuscript received March 5, 2007,
accepted March 14, 2007.
* Reprint requests and correspondence: Dr. Kalyanam Shivkumar, UCLA Cardiac Arrhythmia Center, Division of Cardiology, Department of Medicine, 47-123 CHS, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, California 90095-1679. (Email: kshivkumar{at}mednet.ucla.edu).
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Abstract
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Objectives: This study sought to characterize left atrial (LA) sinus rhythm electrogram (EGM) patterns and their relationship to parasympathetic responses during atrial fibrillation (AF) ablation.
Background: The mechanistic basis of fractionated LA EGMs in patients with paroxysmal AF is not well understood.
Methods: We analyzed 1,662 LA ablation sites from 30 patients who underwent catheter ablation for paroxysmal AF. Pre-ablation EGM characteristics (number of deflections, amplitude, and duration) were measured in sinus rhythm. Parasympathetic responses during radiofrequency application (increase of atrial-His interval by  10 ms or decrease of sinus rate by 20%) were assessed at all sites. We also prospectively studied the effect of adenosine, a pharmacological agent mimicking acetylcholine signaling in myocytes, on LA EGMs. Finally, we performed mathematical simulations of atrial tissue to delineate possible mechanisms of fractionated EGMs in sinus rhythm.
Results: A specific pattern of pre-ablation sinus rhythm EGM (deflections 4, amplitude 0.7 mV, and duration 40 ms) was strongly associated with parasympathetic responses (sensitivity 72%, specificity 91%). The sites associated with these responses were found to be located mainly in the posterior wall of the LA. Adenosine administration and mathematical simulation of the effect of acetylcholine were able to reproduce a similar EGM pattern.
Conclusions: Parasympathetic activation during AF ablation is associated with the presence of pre-ablation high-amplitude fractionated EGMs in sinus rhythm. Local acetylcholine release could potentially explain this phenomenon.
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Abbreviations and Acronyms
| | AF = atrial fibrillation | | A–H = atrial-His | | CART = classification and regression tree | | CFAE = complex fractionated atrial electrogram | | EGM = electrogram | | HAFE = high-amplitude fractionated electrogram | | LA = left atrial/atrium | | LAFE = low-amplitude fractionated electrogram | | PV = pulmonary vein | | RA = right atrial/atrium | | RF = radiofrequency |
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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet the underlying mechanisms remain poorly understood. Experimental (1) and clinical (2) studies have shown that parasympathetic activation can induce and maintain AF. Further, parasympathetic denervation during AF ablation has been associated with improved clinical outcomes (3). Studies of intracardiac electrograms (EGMs) in the left atrium (LA) during AF have shown complex fractionated atrial electrograms (CFAEs) (4), and an ablation strategy targeting these sites to cure AF has been shown to confer clinical benefit (5).
Fractionated LA EGMs also have been observed during sinus rhythm in paroxysmal AF patients (6). These fractionated sites have been targeted during catheter ablation of AF (6). Some investigators have suggested that CFAE may be in part related to parasympathetic innervation (7,8). However, CFAEs recorded during AF are potentially a dynamic phenomenon, and the role of acetylcholine in their genesis requires further investigation.
The aim of our study was first to characterize LA EGM patterns during sinus rhythm in patients with paroxysmal AF. Second, we sought to determine specific EGM patterns during sinus rhythm that predicted parasympathetic responses during ablation. We also studied the effect of adenosine, which mimics acetylcholine signaling (9), on LA EGMs in humans. Finally, we performed mathematical modeling of atrial tissue with areas simulating acetylcholine effect.
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Methods
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Patients.
We retrospectively studied 30 patients referred to our center for a first paroxysmal AF ablation between January 2003 and January 2006. All patients were in sinus rhythm at baseline and during ablation. Digoxin and antiarrhythmic agents were discontinued for at least 5 half-lives, or 3 months in the case of amiodarone, before the procedure. Exclusion criteria were permanent pacing, recent myocardial infarction, renal failure requiring dialysis, thyroid dysfunction, and previous AF ablation. Our institutional review board approved the study.
LA mapping and ablation.
All patients underwent transesophageal echocardiography, no more than 24 h before the procedure, to exclude atrial thrombus. Electrophysiological studies, mapping, and ablation were performed in sinus rhythm. For recording and stimulation, multipolar recording catheters were positioned in the coronary sinus, right atrium (RA), His bundle region, and apex of the right ventricle. Access to the LA was obtained by transseptal puncture, after which systemic anticoagulation was achieved with intravenous heparin to maintain activated clotting time between 250 and 350 s. All procedures were done under general anesthesia using isoflurane or sevoflurane.
Before ablation, patients underwent electroanatomical mapping using the CARTO system and 8-mm-tip Navistar catheter (Biosense Webster, Diamond Bar, California) to define the 3-dimensional anatomy of the LA and pulmonary veins (PVs).
After completing reconstruction of chamber geometry, we performed radiofrequency (RF) ablation in sinus rhythm. The EGMs from ablation sites were recorded using a 12-bit analog-to-digital amplifier at 977 samples/s using a 30- to 500-Hz bandpass filter on a Cardiolab platform (GE Medical Systems, Waukesha, Wisconsin).
The RF applications were delivered with a temperature setting of 50°C and power output of 50 W for 15 to 20 s per ablation site. Power was limited to 30 W in the posterior LA wall. A decrease in EGM amplitude of at least 25% was sought at each site. If this end point was not achieved after 2 RF applications, further energy application was not attempted at those sites. All patients underwent wide-area circumferential ablation encircling PVs (corresponding to the antrum region) and an ablation line from the left inferior PV to the mitral isthmus. The locations of sites associated with parasympathetic response were recorded.
EGM analysis.
At each ablation site, we measured the following parameters just before RF application: heart rate, atrial-His (A–H) interval (defined as the time from earliest reproducible rapid atrial deflection in the His bundle catheter to onset of the His deflection) (10), and characteristics of the atrial EGM (duration, amplitude, and number of deflections). Duration was defined as the time from the earliest local electrical activity to the point of final return to baseline. Amplitude was the voltage difference between highest and lowest deflections of each EGM. Number of deflections was determined by counting the number of turning points (positive to negative direction or vice versa) in each EGM.
A significant parasympathetic response during RF application was defined as 20% decrease of heart rate (10) or 10 ms increase of A–H interval (11). Each measurement was taken as the average of 3 stable cardiac complexes. If multiple RF applications were delivered at the same anatomical site, only the first was included in the analysis. Two independent experts measured intervals with online calipers.
Adenosine and LA EGMs.
Eight patients referred for electrophysiology study and catheter ablation between April 2004 and February 2006 were included in this prospective part of the study. Inclusion criteria were age 18 years, need for LA access, and sinus rhythm during ablation. Exclusion criteria were asthma, permanent pacing, and prior atrial ablation procedures. Antiarrhythmic drugs were discontinued before the procedure. All patients provided written informed consent, and our institutional review board approved the study.
Electrophysiological catheters were placed in the right ventricle, coronary sinus, and His bundle. Multipolar recording catheters, containing either 5 or 10 pairs of closely spaced bipolar electrodes (St. Jude Medical, Minnetonka, Minnesota), were placed in the RA and the LA along the posterior wall via the transseptal approach. The EGMs were recorded immediately before and during adenosine administration, with catheter stability confirmed by biplane fluoroscopy. Adenosine was infused in a central venous bolus, with complete AV dissociation used as an end point to indicate drug effect. The EGMs were recorded and analyzed as described above.
Mathematical simulation.
The single atrial cell action potential was simulated using the Jacquemet modification (12) of the original Courtemanche model (13). Cells were resistively coupled to each other in a 5 x 5-cm-square sheet. To simulate fibrosis, longitudinal areas of conduction block were added, forcing the wavefront to propagate in a zigzag manner. To simulate parasympathetic innervation, regions with acetylcholine were assigned an additional outward potassium current, IKACh (14), which is also activated by adenosine, as well as a lower diffusion coefficient, resulting in slower conduction. All simulations used point stimulation with cycle length 400 ms. The EGMs were computed from the integral of the transmembrane potential. Further details of the mathematical simulation methods can be found in the Online Appendix.
Statistical analysis.
Continuous variables are expressed as mean ± standard deviation, except in figures, where they are shown as mean ± standard error of the mean. Categorical variables are expressed as numbers or percentages. Comparisons were 2-tailed, and p < 0.05 was considered statistically significant. The EGM analysis was performed using classification and regression tree (CART) methodology (15). The CART model identified variables allowing EGMs to be classified successively into subsets, which best predicted occurrence of parasympathetic response during ablation. A 5-fold cross-validation was carried out on the CART results. A random person effects logistic model was used to estimate the degree of within-subject correlation among multiple observations from the same patient. The number of EGM deflections before and after adenosine administration was compared by the nonparametric Wilcoxon signed rank test.
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Results
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Thirty patients (54 ± 15 years, 77% male) were included for ablation EGM analysis. Patient characteristics are described in Table 1.
EGM characteristics and parasympathetic response.
We analyzed 1,754 ablation sites, an average of 59.1 per patient. Ninety-two ablations were excluded because the A–H interval could not be measured. The remaining 1,662 sites were included in the final analysis. Parasympathetic responses were observed at a total of 184 (11.1%) sites. These responses corresponded with increased A–H interval in 71% of sites, decreased sinus rate in 23%, and both in 6%. Twenty-nine patients (97%) showed at least 1 site with a parasympathetic response during AF ablation.
Using CART analysis, we found that the best single predictor of parasympathetic response was the number of EGM deflections at the ablation site (Fig. 1). The presence of at least 4 EGM deflections was the first branch of the prediction tree for parasympathetic response. For the 956 sites with 4 deflections, the next most useful predictor was EGM amplitude 0.7 mV. Sites with amplitude above this cutoff were more likely to be associated with a parasympathetic response. Finally, for the 289 sites with 4 deflections and amplitude 0.7 mV, the last branch of the tree was EGM duration 40 ms, which was the weakest predictor. The EGM characteristics that best predicted parasympathetic response during ablation, in order of importance, were number of deflections 4, amplitude 0.7 mV, and duration 40 ms.
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Figure 1 Classification and Regression Tree Model
Likelihood of parasympathetic response (PR) according to pre-ablation electrogram characteristics. The total number of ablation sites (n = 1,662) is represented by the pie diagram at the top. The shaded area of each pie diagram is proportional to the number of sites in that group showing a parasympathetic response to ablation. According to this tree analysis, we defined 3 electrogram patterns: normal, low-amplitude fractionated electrogram (LAFE), and high-amplitude fractionated electrogram (HAFE).
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We defined a fractionated atrial EGM during sinus rhythm as an EGM with 4 deflections and duration 40 ms, in accordance with the results of the CART model for predicting parasympathetic response. By further classifying EGMs according to amplitude, we distinguished 3 main types of LA EGMs in sinus rhythm, as shown in Figure 1: 1) normal EGM: number of deflections <4 or duration <40 ms (n = 732); 2) low-amplitude fractionated EGM (LAFE): number of deflections 4 and amplitude <0.7 mV (n = 667); 3) high-amplitude fractionated EGM (HAFE): number of deflections 4, amplitude 0.7 mV, and duration 40 ms (n = 263).
Figure 2
shows each of these patterns and shows examples of observed responses to ablation. As shown in Figure 3, the HAFE pattern was associated with a higher incidence of parasympathetic response during ablation compared with LAFE and normal patterns (51%, 6%, and 1%, respectively). The HAFE pattern before ablation predicted parasympathetic response during ablation with nominal sensitivity, specificity, and positive and negative predictive value of 72%, 91%, 51%, and 96%, respectively.
The 5-fold average cross-validated sensitivity was 71.9%, with a 95% confidence interval of 49.4% to 94.5%. The 5-fold average cross-validated specificity was 91.0%, with a 95% confidence interval of 85.2% to 97.2%. Because the CART analysis assumed that all EGM characteristics were independent, we used a random person effects logistic model to compute the within-subject correlation. This value was 0.0293, indicating that our assumption was reasonable.
After ablation, 17% of LA EGMs classified as HAFE at baseline became normal, 30% remained HAFE, and 53% became LAFE. The number of deflections significantly decreased at HAFE sites after ablation, from 5.5 ± 1.5 to 4.8 ± 1.5 (p < 0.001).
Ablation site location and parasympathetic response.
The locations most commonly associated with A–H prolongation were the junction between the LA and the left superior PV (31%), the posterolateral wall of the LA (18%), and the junction between the LA and the right superior PV (16%). Other sites resulting in A–H prolongation included the septal LA wall (11%), the left inferior PV (7%), and the anterior aspect of the mitral valve annulus (6%). Heart rate reduction was more often seen with ablations near the junction of the LA and left superior PV.
Effect of adenosine on atrial EGMs.
Eight patients (54 ± 11 years, 75% male) with a history of either drug-refractory paroxysmal AF (n = 6) or tachycardia involving an accessory pathway (n = 2) participated in this part of the study. Figure 4
shows catheter locations and atrial EGMs spanning the majority of the surface P-wave for a typical patient. Atrial EGMs were recorded from a total of 55 sites in the LA and 55 sites in the RA. Six sites from each atrium were excluded because of poor signal quality. The EGMs from the remaining 49 LA and RA sites then were analyzed.
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Figure 4 Atrial EGM Recording During Adenosine Infusion
(A) Fluoroscopic image in the left anterior oblique view of typical intracardiac catheter locations during adenosine infusion. (B) Superimposition of the surface electrocardiogram P-wave in lead V1 and atrial EGM. CS = coronary sinus catheter; ICE = intracardiac echocardiography catheter; LA = left atrial catheter; RA = right atrial catheter; RV = right ventricular catheter; other abbreviations as in Figure 2.
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All patients developed transient AV block at adenosine doses of 12 to 36 mg. With adenosine infusion there was no change in surface P-wave duration or intra-atrial conduction time. In 2 patients (25%), AF was induced at the time of adenosine administration. At some sites a striking change in EGM morphology was observed immediately after adenosine infusion (example shown in Fig. 5).
Immediately after adenosine infusion, the number of LA EGM deflections increased from 5.4 ± 3.0 to 7.6 ± 3.4 (p < 0.01), as shown in Figures 6A and 6B. The mean EGM duration (43 ± 9 ms vs. 40 ± 14 ms, p = NS) and amplitude (0.99 ± 0.88 mV vs. 0.86 ± 0.78 mV, p = NS) were not significantly different. As shown in Figure 6C, the average number of EGM deflections also increased significantly in the RA, from 4.4 ± 2.2 to 6.2 ± 3.1 (p < 0.01).
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Figure 6 Adenosine-Induced Changes in Atrial EGMs
(A) Average number of deflections by patient. (B) Change in deflections from baseline. (C) Effects of adenosine on atrial electrograms. EGM = electrogram; LA = left atrial; RA = right atrial.
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Baseline LA EGMs were classified according to the normal, LAFE, and HAFE patterns. Before adenosine, 35%, 34%, and 31% of the EGMs were normal, LAFE, and HAFE, respectively. After adenosine, 13%, 45%, and 42% were normal, LAFE, and HAFE, respectively.
Mathematical simulation of atrial EGMs.
Mathematical simulations of a small 2-dimensional patch of tissue were performed to provide additional insights into mechanisms underlying EGM fractionation. In normal tissue, the stimulus delivered at the top right corner propagates smoothly to the bottom left corner. The resulting EGM shows a positive deflection from depolarization of the tissue, followed by a negative deflection from repolarization (Fig. 7A). Simulation of fibrosis caused zigzag conduction of the wavefront, resulting in an EGM similar to the LAFE pattern (Fig. 7B). Simulation of areas with acetylcholine effect (IKACh and lowered diffusion) caused an EGM similar to the HAFE pattern (Fig. 7C) (see Online Videos).
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Figure 7 Mathematical Modeling
(Left) (A) Electrograms from normal tissue; (B) fibrotic tissue showing low-amplitude fractionation; (C) tissue exposed to acetylcholine, showing high-amplitude fractionation. (Right) Tissue pattern followed by snapshots of the advancing wavefront. In normal tissue (A), the pattern is homogeneous. In fibrosis (B), gray areas represent inexcitable scar tissue. In tissue exposed to acetylcholine (C), darker shaded areas indicate patches of IKACh and lowered diffusion.
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Discussion
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The first finding of the present study is that 3 main patterns of LA EGMs were seen during sinus rhythm in patients with paroxysmal AF: normal, LAFE, and HAFE. Second, the HAFE pattern was associated with a parasympathetic response during RF ablation. Most of the ablation sites associated with a parasympathetic response were located near LA-PV junctions, the LA posterolateral wall, or the interatrial septum. Finally, EGMs similar to the HAFE pattern were reproduced experimentally with adenosine and in a mathematical model simulating the effect of acetylcholine.
Previous studies have described CFAE in the LA during AF (4) and investigated their mechanisms and role in the maintenance of AF (16). However, different definitions of CFAE during AF have been proposed. Nademanee et al. (5) defined LA CFAE as having at least 2 deflections and an average cycle length of <120 ms. In contrast, Rostock et al. (17) defined CFAE as showing at least 3 deflections or potentials with continuous electrical activity.
Similarly, there is no consistent definition of fractionated atrial EGMs in sinus rhythm. The definition proposed by Sanders et al. (18) was a duration >50 ms. In contrast, Pachon et al. (6) described fractionation in sinus rhythm by a particular pattern on fast Fourier transform analysis.
We characterized LA EGMs with CART analysis, a statistical method using available dependent variables to determine cutoffs that best separate parasympathetic response from nonresponse. In our data, the number of deflections (4) was the strongest predictor of parasympathetic response, followed by amplitude (0.7 mV) and EGM duration (40 ms).
Although the precise mechanisms underlying each of these patterns (normal, LAFE, and HAFE) are not known, some hypotheses can be considered. The first pattern is probably the normal EGM seen in healthy atrial tissue. Conduction is rapid and uniform, creating a simple and sharply inscribed EGM (19).
The LAFE pattern may be caused by atrial fibrosis. Fibrosis is a known cause of fractionated, low-amplitude EGMs in the ventricle, and this substrate can predispose to arrhythmias (20). Low-amplitude LA EGMs also have been seen in patients with paroxysmal AF (21). Current evidence suggests that the cellular mechanism relating fibrosis and low-amplitude EGMs is poor tissue coupling and discontinuous conduction (22). Consistent with this, we observed a similar pattern in mathematical simulations of atrial tissue with fibrotic characteristics. Another potential explanation for LAFE in our study is poor tissue-electrode contact. However, we used fluoroscopy, electroanatomical mapping, intracardiac echocardiography, and impedance monitoring to ensure good contact.
The origin of the HAFE pattern remains unclear. In our study, this pattern was associated with a parasympathetic response during AF ablation. Moreover, adenosine produced similar EGMs in the LA posterior wall. Finally, mathematical simulation of an acetylcholine effect on atrial tissue yielded EGMs with the HAFE pattern. Therefore, one explanation for the HAFE pattern could be local effects of acetylcholine in LA tissue.
The parasympathetic system has been recognized to play a role in AF initiation and maintenance (3,23). Parasympathetic activity may promote AF by shortening the atrial refractory period (24) and inducing rapid ectopic activity in the PVs (25). Recently Po et al. (7) suggested that CFAE during AF may be an epiphenomenon of high-frequency PV activity. However, we have shown that fractionated EGMs also are seen during sinus rhythm, presumably in the absence of high-frequency PV or LA activation.
There are several possible mechanisms by which parasympathetic innervation could cause EGM fractionation. Acetylcholine stimulates a potassium current in atrial myocytes, causing hyperpolarization (26), reduced excitability (27), and possibly conduction block between adjacent fiber bundles. Further, acetylcholine can reduce intercellular coupling by inhibiting connexin 43 phosphorylation (28,29). Consistent with this, our mathematical simulation of acetylcholine reproduced the HAFE pattern when the model included both reduced myocyte coupling and shortened action potential duration. Finally, the presence of intercalated parasympathetic nerves also could play a role in the origin of fractionated LA EGMs, as proposed by Pachon et al. (8).
Study limitations.
The location of sites associated with a parasympathetic responses in our study was a function of where ablation was performed, limiting the value of these data. Additionally, some ablation sites with the HAFE pattern were not associated with a parasympathetic response. Ablation at these sites could have been incomplete, and therefore unable to induce a parasympathetic response. Alternatively, mechanisms unrelated to acetylcholine, such as tissue anisotropy and fibrosis, also could cause sinus rhythm fractionation (22,30). Histopathologic and more extensive modeling studies are needed to precisely delineate mechanisms of fractionation not related to parasympathetic innervation. The spatial extent of myocardium that contributes to a given EGM signal is not known, and it is likely that the 8-mm-tip electrode used in this study includes some far-field data. However, the effect of RF is most concentrated at the site of myocardial tissue contact, and therefore the parasympathetic responses elicited at those sites can still be interpreted. Finally, our study was retrospective, and a formal prospective validation of the results has not yet been carried out.
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Conclusions
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High-amplitude fractionated EGMs are associated with parasympathetic activation during AF ablation. One potential cause of this EGM pattern is local tissue effects of acetylcholine. Sites eliciting a parasympathetic response were found to be located in specific areas of the LA, mainly in the posterior wall and septum. Further studies are needed to show whether an ablation strategy targeting these specific sites will be additive to current approaches.
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Appendix
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For accomanying videos and detailed mathematical simulation methods, please see the online version of this article.
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Acknowledgments
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The authors thank Jeffrey A. Gornbein, DrPH, for valuable statistical assistance with the preparation of this manuscript.
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Footnotes
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Supported by grants from the French Society of Cardiology (to Dr. Lellouche), and the American Heart Association, National Affiliate (grant 0430287N), and National Heart, Lung, and Blood Institute (grant R01HL084261) (to Dr. Shivkumar).
1 Drs. Lellouche and Buch contributed equally to this work. 
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References
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