Author + information
- Received September 25, 2017
- Revision received December 29, 2017
- Accepted December 29, 2017
- Published online February 28, 2018.
- Paul Garabelli, MD,
- Stavros Stavrakis, MD, PhD,
- John F.A. Kenney and
- Sunny S. Po, MD, PhD∗ ()
- Section of Cardiovascular Diseases and Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- ↵∗Address for correspondence:
Dr. Sunny S. Po, Heart Rhythm Institute, University of Oklahoma Health Sciences Center, 1200 Everett Drive, TCH 6E103, Oklahoma City, Oklahoma 73104.
Objectives The authors intended to investigate if 28-mm cryoballoon (CB) ablation also modifies the 4 major atrial ganglionaated plexi (GP).
Background The major atrial GP facilitate the initiation and maintenance of atrial fibrillation (AF). The 28-mm CB covers a large surface area of the left atrium and probably the GP areas.
Methods High-frequency stimulation (20 Hz) was delivered to the area of anterior right GP (ARGP), inferior right GP, superior left (SLGP), and inferior left GP (ILGP). Positive GP sites were defined as a prolongation of R-wave to R-wave (RR) interval during AF by >50%. The area of each GP before and after CB ablation was compared.
Results A total of 18 patients with paroxysmal AF who underwent CB and radiofrequency ablation and had positive GP sites were reviewed. The Wilcoxon signed-rank test was used to assess the effects of CB ablation on each GP. There was a statistically significant difference in the area of all 4 GP after CB ablation: 1) ARGP area: 2.9 cm2 (interquartile range [IQR]: 2.1 to 3.5 cm2) pre-CB, 0.1 cm2 (IQR: 0 to 0.6 cm2) post-CB, p = 0.0002; 2) inferior right GP area: 2.1 cm2 (IQR: 0.9 to 2.9 cm2) pre-CB, 0.5 cm2 (IQR: 0 to 1.7 cm2) post-CB, p = 0.001; 3) SLGP area: 1.4 cm2 (IQR: 0.6 to 2.4 cm2) pre-CB, 0 cm2 (IQR: 0 to 0 cm2) post-CB, p = 0.0002; and 4) ILGP area: 1.3 cm2 (IQR: 0.3 to 2.2 cm2) pre-CB, 0.3 cm2 (IQR: 0 to 1.6 cm2) post-CB, p = 0.008.
Conclusions The surface area of all 4 of the major atrial GP was substantially reduced by CB ablation. The SLGP and ARGP had the largest, whereas the ILGP had the least percent of reduction following CB ablation. Part of the therapeutic effects of CB ablation may result from modifying the 4 major atrial GP.
The cardiac autonomic nervous system (ANS) is composed of a network of autonomic neurons and nerves. It regulates vascular tone, contractility, and electrophysiology by transducing and integrating the afferent and efferent autonomic impulses (1,2). The neural network of the cardiac ANS converges at several ganglionated plexi (GP) embedded in epicardial fat pads. In human atria, the 4 major atrial GP are located in close proximity to the pulmonary veins (PVs). Preclinical and clinical studies have indicated that the cardiac ANS facilitates the initiation and maintenance of atrial fibrillation (AF) (3–6).
Standard circumferential PV isolation, the cornerstone of AF ablation, transects the 4 major atrial GP, suggesting that GP ablation may account for at least part of the antiarrhythmic effects of AF ablation (7). AF ablation using the second-generation (28-mm) cryoballoon (CB) has been shown to be noninferior to radiofrequency (RF) ablation (8), and the area at the PV antrum and left atrium (LA) covered by the CB is substantially larger than that covered by point-by-point RF ablation (9). In the present study, we sought to measure the extent of GP ablated by 28-mm CB ablation. We defined the area of the 4 major atrial GP by delivering high-frequency stimulation (HFS) to the presumed anatomic GP site before and after CB ablation.
We performed a retrospective review of the first 20 patients in whom both RF and CB ablative technologies were used to treat paroxysmal AF at the University of Oklahoma Health Sciences Center. At that time, our standard of care for CB ablation included mapping and ablation of GP using HFS delivered through an RF ablation catheter. HFS with fixed frequency and strength (20 Hz, 0.1-msec pulse width, 100 V; Grass, Warwick, RI) was delivered to the presumed 4 major atrial GP locations, as shown in Figure 1 (7). The superior left GP (SLGP) is located near the junction of the left superior PV (LSPV), LA, and left pulmonary artery. The anterior right GP (ARGP) is located near the anterior aspect of the right superior PV (RSPV)-LA junction, between the RSPV and mitral annulus. We designated it as ARGP to emphasize that it is not located at the junction between the RSPV and the posterior wall of the LA. The inferior right GP (IRGP) is situated at the inferior aspect of the LA, below the lower edge of the right inferior PV (RIPV) and adjacent to the crux of the heart. The inferior left GP (ILGP) is situated at the inferior aspect of the LA posterior wall. The location of the ILGP varies significantly, ranging from being adjacent to the left inferior PV (LIPV) to >2 cm away from the inferior left PV (Figure 1B). Notably, because it stimulates both the atrial myocardium and neural elements, HFS invariably induced AF if the patient presented to the electrophysiology laboratory in sinus rhythm. After AF was induced by brief (<2 s) HFS, the first 10 beats of RR interval in AF during HRS were averaged, positive GP sites were defined as a prolongation of the RR interval during AF by >50% (7). Sites where prolongation of RR interval could not be elicited by HFS were not tagged as a GP-negative site unless the contact force was >5 g.
Electrophysiological study and ablation procedure
All patients underwent computed tomography angiography and transesophageal echocardiography the day before ablation. All ablation procedures were performed under general anesthesia (sevoflurane, desflurane, or propofol) with a paralytic agent used for induction only. Invasive arterial blood pressure, oxygen saturation, and electrocardiogram were monitored continuously throughout the procedure. Both femoral veins were used for vascular access via the modified Seldinger technique. Multi-electrode catheters were positioned at the right atrial appendage, coronary sinus, and para-Hisian area. A single transseptal puncture was performed under fluoroscopy and intracardiac echocardiography guidance. The activated clotting time was between 300 and 350 s.
A fast anatomic map was created using a PentaRay catheter or a SmartTouch ThermoCool catheter (Biosense Webster, Diamond Bar, California). The standard practice of RF ablation to treat AF at the University of Oklahoma is to deliver HFS at the presumed GP sites. HFS-positive and HFS-negative sites were tagged with different colors on the electroanatomic map. All HFS sites must have a contact force ≥5 g and all HFS sites displayed on the electroanatomic map were acquired at the end of expiration phase during mechanical ventilation. In all cases, individual GP mapping is considered complete if HFS-negative points encompass an area of HFS-positive points. The endpoint of RF ablation at each site is to eliminate the vagal response elicited by HFS. In the present study, which includes the first 20 patients undergoing ablation using both CB and RF technologies, HFS-positive sites were not ablated before CB ablation. This practice was based on the uncertainty about the adverse effect of applying CB to the same area immediately after RF ablation. The sheath was then exchanged for the 12-F steerable transseptal sheath (FlexCath, CryoCath, Medtronic Inc., Minneapolis, Minnesota) over a stiff guidewire (0.032-inch, 180-cm, Rossen J-tip). The 28-mm CB (Arctic Front Advance, Medtronic Inc.) and the inner circular catheter (Achieve mapping catheter, Medtronic Inc.) were used in all patients for PV isolation (PVI) (8,9).
After guiding the balloon toward the respective PV ostia, adequate occlusion was confirmed with 50% diluted contrast through the CB catheter’s central lumen. Each freeze was initiated while using the proximal seal technique to ensure a more antral freeze. No effort was made to intentionally direct the CB to cover the presumed GP area. PV potentials were monitored using the Achieve catheter. Nonstacked 180-s freezes were delivered to each PV. If a clear time to PVI effect was observed within the first 30 s, the number of therapies was reduced to 1 lasting 180 s. For all cases, CB ablation was performed in the following order: LSPV, LIPV, RIPV, and ultimately the RSPV. Esophageal temperature monitoring was performed in all cases, and the probe was adjusted to the appropriate CB location. CB duration was stopped for an esophageal temperature of 30°C. The right phrenic nerve was also monitored during right PV lesions via direct palpation of the right hemidiaphragmatic excursion by right subclavian/superior vena cava pacing.
After completion of PVI based on elimination of all PV potentials recorded by the circular Achieve mapping catheter positioned at the PV-LA junction (Figure 2), the 28-mm CB was exchanged for the RF ablation catheter. HFS was first delivered along the border set by pre-CB HFS-positive points, followed by retesting the entire previously HFS-positive area. HFS-positive and HRS-negative sites after CB ablation were tagged in different colors. The remaining positive sites were then ablated using RF current (20 to 25 W, 30 to 40 s) until a positive vagal response could no longer be elicited as previously described (7).
Upon Institutional Review Board approval, a retrospective review of CB and RF ablation cases was performed. The respective electroanatomic maps were analyzed at a CARTO workstation (Biosense Webster). All HFS points were displayed as 2 mm in diameter. The baseline area (cm2) of individual GP was defined as the area bordered by HFS-positive points of the presumed GP site. Measurement was made offline by a software function (“measurement of area”) provided by CARTO, which measures the area within the contour anchored by 3 points selected by the operator. The contour of the area can be adjusted to provide the best reasonable estimate of the area of interest. In the present study, the contour delineating area was adjusted to pass the center of the HFS-positive points along the border of the presumed GP area (Figure 3). If the HFS-positive area was relatively large or its shape could not be reliably represented by the contour anchored by 3 points, this HFS-positive area was divided into 2 areas, and each area was measured separately (Figures 3A and 3B). Points acquired by excessive contact force, leading to distortion of the LA geometry and errors of surface area calculation, were deleted from the map. All measurements were performed independently by 2 electrophysiologists. The values measured by both electrophysiologists were averaged for data analysis.
Categorical data are presented as percentages and continuous data are presented as mean ± SD (for normally distributed data) or median and interquartile range (for non-normally distributed data). Correlation between the respective GP areas obtained by the 2 independent reviewers was evaluated by Pearson's correlation coefficient. The areas of the respective GP, as well as the number of sites where HFS was delivered, before and after CB were compared using the Wilcoxon signed rank test. The percent change of the area of the respective GPs after ablation was compared among groups using the Kruskal-Wallis test, and p values <0.05 were considered statistically significant. Statistical analysis was performed with SAS 9.3 software (SAS Institute, Inc., Cary, North Carolina).
The first 20 patients with paroxysmal AF who underwent CB and RF ablation were reviewed. Of those, 2 patients only received HFS stimulation on 1 GP before ablation due to unstable blood pressure during AF with rapid ventricular rate (n = 1) and bleeding complication caused by the FlexCath sheath (n = 1). Eighteen patients had HFS-positive sites in the baseline state and were therefore included for analysis. Baseline characteristics of the patient population reviewed are displayed in Table 1. The average CHADS2-VASc score (Congestive heart failure (C = CHF), H = Hypertension, A = Age >75, D = Diabetes, S = Stroke, V = Vascular Disease, A = age 65–74, SC = sex category) was 2.4, and the average LA size was 4.4 cm.
PVI was successfully accomplished in all 18 patients, evidenced by disappearance of the PV potential recorded by a circular catheter (Figure 2). Both entrance and exit block were verified. No vagal response was elicited by CB application in any of the 18 patients. All patients received at least 2 CB freezes for each PV. The mean freeze duration for the LSPV, LIPV, RSPV, and RIPV was 449 ± 161 s, 391 ± 134 s, 408 ± 141 s, and 372 ± 102 s, respectively. Figures 3 to 5⇓⇓ show typical examples of the area of HFS-positive sites before and after CB ablation. The correlation between the measurements made by 2 independent reviewers was excellent (Pearson correlation coefficient = 0.994, 0.994, 0.991, and 0.987 for ARGP, IRGP, SLPG, and ILGP, respectively). A comparison of the GP area before and after CB ablation is shown in Table 2. All GP showed a statistically significant reduction in ability to induce a vagal response after CB ablation, suggestive of modification of this autonomic substrate (Figure 6). The number of sites where HFS was delivered after CB ablation was not different from that before CB ablation (ARGP: 11.3 ± 2.6 before, 14.1 ± 3.1 after; IRGP: 8.4 ± 3.4 before, 10.6 ± 5.0 after; SLGP: 7.5 ± 4.1 before, 7.3 ± 2.7 after; ILGP: 6.9 ± 2.0 before, 8.1 ± 2.8 after; p > 0.05 for all). The SLGP and ARGP had the largest percent of reduction, whereas the ILGP had the least percent of reduction after CB ablation. The latter observation can be explained by greater variation of the location of the ILGP (Figure 1B). When the ILGP is located adjacent to the inferior-posterior aspect of the LIPV, ILGP is likely in the range of CB ablation (Figure 5A). On the contrary, the ILGP was not affected by CB ablation if it was located at a distance from the LIPV (Figure 5B). In all patients, the remaining HFS-positive sites after CB ablation were ablated with RF current as part of our standard care.
As the current study was a retrospective analysis of the impact of CB ablation on GP, patients in this study were not followed as rigorously as those in prospective studies. On the basis of our standard care, patients were followed by symptoms of atrial arrhythmias as well as periodic Holter monitoring (24 h), event monitoring (1 week), or by transcutaneous rhythm monitoring (Zio patch, 2 weeks). Discontinuation of antiarrhythmic agents was not mandated if no arrhythmia was detected. The mean follow-up period was 1.9 ± 0.8 years. Two patients received a repeat AF ablation procedure; 3 patients had documented recurrence of atrial tachyarrhythmias; 6 patients remained on antiarrhythmic agents but without symptoms or confirmed atrial tachyarrhythmias; 6 patients remained free of atrial tachyarrhythmias without taking antiarrhythmic agents; 1 patient was lost to follow-up. The outcome of the study patients is not different from our anecdotal experience in paroxysmal AF ablation.
It is known that the cardiac ANS facilitates the genesis and maintenance of AF. However, adding GP ablation to circumferential PVI yielded conflicting results. Katritsis et al. (10) randomized 242 patients with paroxysmal AF to circumferential PVI alone, anatomic GP ablation alone, and circumferential PVI plus anatomic GP ablation. After 2 years of follow-up, freedom from AF or atrial tachycardia was achieved in 56%, 48%, and 74% of patients in the PVI, GP ablation, and PVI + GP ablation groups, respectively (p = 0.0036), indicating additional benefits provided by GP ablation. GP ablation alone had a similar success rate to that of circumferential PVI, indicating that GP ablation is beneficial in certain patients. On the contrary, the AFACT (Atrial Fibrillation Ablation and Autonomic Modulation Via Thorascopic Surgery) trial, randomizing mostly persistent AF patients (many with markedly enlarged LA or failed prior ablation) to surgical circumferential PVI (CPVI) versus CPVI + GP ablation, showed no additional benefits but more adverse events in the CPVI + GP group (11). Conflicting results from these 2 largest GP ablation trials suggest that GP ablation should be performed in an earlier stage of AF before advanced structural remodeling occurs.
Not surprisingly, the CB has been postulated to affect the cardiac ANS. Vagal reactions manifesting as bradycardia and hypotension during CB-based PVI were encountered in 36% to 50% of ablations (12). Oswald et al. (13) were the first to investigate the CB effect on the cardiac ANS at the PV ostia using the first-generation balloon in 14 patients. Similar to RF ablation studies, they used heart rate variability (HRV) as a marker of cardiac ANS modulation. They hypothesized that heart rate slowing, suggestive of a vagal response, might be induced by stretch of the LA tissue, direct damage to cardiac neural tissue during the thawing phase, or hyperemia at the CB-tissue interface (13). Yorgun et al. (14) studied the vagal response during CB ablation. In their group of 145 patients, they observed vagal reactions (e.g., sinus bradycardia or atrioventricular block) in 59% of patients. They found a decrease in AF recurrence in a subgroup of patients with paroxysmal and persistent AF that exhibited vagal response, suggesting modulation of the cardiac ANS through inadvertent GP injury. Similarly, Aytemir et al. (15) compared first-generation CB to second-generation CB, the latter of which covers more atrial tissue during a freeze. They found that vagal responses tended to be predictive for lower late AF recurrence, but their data did not reach statistical significance (hazard ratio: 0.574; 95% confidence interval: 0.335 to 1.002; p = 0.055). In the present study, we did not observe a vagal response induced by CB ablation, similar to our observation on GP ablation using RF current (7). In our patients, HFS was delivered during AF and under general anesthesia. In the CB ablation patients reported by others, patients were mostly in sinus rhythm under mild sedation. Differences in defining vagal responses and different mode of sedation and anesthesia may account for the differences in the incidence of CB ablation–induced “vagal responses.”
CPVI made by standard point-by-point RF ablation transects the 4 major atrial GP (Figure 1) (7). The left PVI line can transect the ILGP in a relatively small LA. Kenigsberg et al. (9) used electroanatomic mapping to measure the surface area of the LA before and after 28-mm CB ablation. The mean distance from proximal PV to the CB ablation edge was approximately 2 cm. Up to 73% of the LA posterior wall was ablated by the CB. It clearly showed that CB ablation covers a substantially larger area of the LA than that of RF ablation, which probably is a major contributor to the success of CB ablation. Although we did not measure voltage reduction after CB ablation, in the study by Kenigsberg et al. (9), the presumed anatomic location of the ARGP and SLGP, as well as part of the ILGP and IRGP, was also covered by the CB, consistent with our observations. Hence, there is no surprise that CB ablation nearly eliminated the vagal response of SLGP and ARGP that are in close proximity to the LSPV and RSPV, respectively. Although HFS is neither sensitive nor specific for detecting GP and there was no histological proof of injury to the autonomic ganglia embedded in GP, our findings strongly indicate that CB ablation is capable of modifying the cardiac ANS. Because GP are embedded in the epicardial fat pad, elimination of HFS responses also suggests the presence of transmural lesions made by CB. Therefore, both larger areas of transmural lesion formation and GP modification may contribute to the success of CB ablation.
First, based on the nature of the data analysis, there may be an inherent bias in the area measurement portion of the study. We appreciate the possibility that the surface area measured by the software provided by the CARTO mapping system may not reflect the true topology of the surface of the entire LA. However, the area of the GP is relatively small, with the largest GP area being 3.5 cm2, minimizing the measurement error of a flat surface versus a curved surface. In most of the cases, no HFS-positive site could be identified in the ARGP and SLGP area after CB ablation. The inherent measurement bias, which is most profound in measuring the GP area after CB ablation, is therefore minimized. In addition, the results were consistent and highly correlated between 2 independent reviewers.
Second, the accuracy of the area measurement was dependent on the number and quality of points taken during electroanatomic mapping at the beginning of the study. Although the vagal response elicited by HFS is highly reproducible if stimulated repeatedly (5–7), the exact location of points tagged and displayed on the CARTO system can vary due to spiration, various arrhythmias, or cardiac output. These problems were minimized by taking all HFS points at the end expiration phase during AF and excluding points with less than 5 g of contact force and points protruding outside the merged computed tomographic CARTO image.
Third, the ablation outcome of the study patients was assessed according to our standard care, not based on the rigorous follow-up procedures recommended for prospective studies. HRV measurement is no longer part of our standard care after AF ablation because all ablation techniques lead to similar HRV changes. The decision of discontinuation of antiarrhythmic agents was made by the operator, referring physician, and patient, leading to a high percentage of patients continuing their antiarrhythmic drugs despite the absence of symptoms or confirmed atrial tachyarrhythmias. Regardless, the number of the subjects in the current study is too small to draw any outcome conclusion.
The 28-mm CB is effective at modifying the cardiac ANS as measured with the markedly decreased vagal responses to HFS of the 4 major atrial GP. In addition to covering substantially large areas of the LA, modification of the cardiac ANS may also contribute to the antiarrhythmic effects of CB ablation.
COMPETENCY IN MEDICAL KNOWLEDGE: Previous studies have shown that hyperactivity of the cardiac ANS facilitates the initiation and maintenance of AF. In this study, we showed that in addition to covering large areas of the LA, 28-mm CB ablation also significantly modified all of the 4 major atrial GP, suggesting that modification of cardiac ANS may also contribute to the therapeutic effect of CB ablation.
TRANSLATIONAL OUTLOOK: Future preclinical and clinical studies focusing on the histological changes of the autonomic neurons within the major atrial GP are needed to verify GP neuronal injury caused by CB ablation.
Dr. Garabelli has received speaking honoraria from Medtronic. Drs. Po and Stavrakis have received equipment donations from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institution and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- atrial fibrillation
- autonomic nervous system
- anterior right ganglionated plexi
- ganglionated plexi
- high-frequency stimulation
- inferior right ganglionated plexi
- inferior left ganglionated plexi
- left atrium
- left inferior pulmonary vein
- left superior pulmonary vein
- pulmonary vein isolation
- right superior pulmonary vein
- superior left ganglionated plexi
- Received September 25, 2017.
- Revision received December 29, 2017.
- Accepted December 29, 2017.
- 2018 American College of Cardiology Foundation
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