Author + information
- Received August 26, 2016
- Revision received January 2, 2017
- Accepted January 12, 2017
- Published online April 26, 2017.
- Mu Qin, MDa,
- Yu Zhang, MDa,
- Xu Liu, PhDa,∗ (, )
- Wei-Feng Jiang, MDa,
- Shao-Hui Wu, MDa and
- Sunny Po, MD, PhDb
- aDepartment of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China
- bDepartment of Medicine and Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- ↵∗Address for correspondence:
Dr. Xu Liu, Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University. No.241 West Huaihai Road, Shanghai 200030, China.
Objectives This study sought to determine if anatomic atrial ganglionated plexus (GP) ablation leads to long-term sinus rate (SR) increase and improves quality of life in patients with symptomatic sinus bradycardia (SB).
Background Atrial GP ablation has been demonstrated to increase SR in our previous study. Atrial GP ablation may also be effective in treating patients with symptomatic SB.
Methods Sixty-two patients with symptomatic SB were recruited: Group A included patients <50 years of age (n = 40); Group B included patients ≥50 years of age (n = 22). All patients underwent anatomic ablation of the main atrial GP, and 24-h Holter monitoring and quality-of-life assessment were performed during 1 year of follow-up. Quality of life was accessed by the Medical Outcomes Study Short-Form 36 Health Survey.
Results Although SR markedly increased in all patients after GP ablation, the increase was significantly greater in patients <50 years of age than in patients ≥50 years of age (19.3 ± 9.9 beats/min vs. 10.8 ± 5.4 beats/min; p = 0.001). The right anterior GP and the GP at the junction of the aorta and superior vena cava made the greatest contributions to SR increase among all GP. The mean and minimal SR increased significantly after ablation and remained elevated for 12 months only in Group A patients. Although symptoms and quality of life improved in all patients, 5 of the 8 domains of the Medical Outcomes Study Short-Form 36 Health Survey did not show obvious improvements in patients of Group B at 12 months.
Conclusions Anatomic atrial GP ablation effectively increased SR and improved quality of life in patients <50 years of age with symptomatic SB.
Sinus bradycardia (SB) is a common clinical problem and serves as a potential risk of cardiovascular events. Although both European and American guidelines recommend cardiac pacing for severely symptomatic SB patients (1,2), younger patients may have to undergo multiple generator exchanges as well as lead revision, extraction, or replacement, exposing them to potential serious complications such as infection. Unfortunately, the mechanism underlying symptomatic SB in younger patients remains unclear. Our preliminary study showed that atrial ganglionated plexus (GP) ablation significantly increased sinus rate (SR) and improved symptoms in 11 patients (mean age 45.9 yrs) with symptomatic SB (3), suggesting that abnormal autonomic activity may play a role in the genesis of symptomatic SB. Thus, ablation of the major atrial GP potentially may serve as an alternative approach to treat patients with symptomatic SB. This prospective study therefore investigated the long-term effects (12 months) of autonomic denervation by ablation of the major atrial GP in patients with symptomatic SB.
This study protocol was approved by the Institutional Ethics Committee at the Shanghai Chest Hospital and was conducted in compliance with the protocol and in accordance with standard institutional operating procedures. Patients who met all the inclusion criteria and were willing to participate were enrolled after providing written informed consent.
Sixty-two consecutive patients with symptomatic SB (dizziness, fatigue, and palpitation) at Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University were prospectively enrolled. Patients were excluded if they had structural heart disease, with any atrial or ventricular arrhythmia, drug-induced SB, sinus pause >2.0 s, positive atropine test, corrected sinus node recovery time (cSNRT) >525 ms, or a history of ablation procedures to treat atrial tachyarrhythmias. A positive atropine test was defined as SR <90 beats/min within 20 min, junctional rhythm, or sinus pause after intravenous administration of 0.03 mg/kg atropine. Therefore, the study population included only patients with symptomatic SB who did not meet the criteria for pacemaker implantation. Because the incidence of sick sinus syndrome has been reported to be about 3-fold higher in subjects 55 to 64 years of age (0.10% to 0.37%) than in those 45 to 54 yrs of age (0.06% to 0.12%) (4), sick sinus syndrome and other pathological conductive disorders are associated with increasing age and ablation would be ineffective for these patients. Furthermore, GP ablation showed greater effects in patients <50 years of age than in older patients in our previous study (3). Based on these observations, patients with class I indications for a pacemaker were strictly excluded. Group A (patients <50 yrs of age) and Group B (patients >50 yrs of age) were pre-specified in this study. All patients provided written informed consent for the electrophysiological study and ablation.
Electrophysiological study and ablation procedure
Specific anatomic ablation of the 4 major left atrial GP and aorta-superior vena cava (Ao-SVC) GP was performed as described (3). Briefly, catheter ablation was performed under the guidance of an electroanatomic mapping system (CARTO, Biosense Webster, Diamond Bar, California). After completed the electroanatomic mapping of the left atrium was complete and pulmonary vein (PV) ostia identified, presumed GP clusters were ablated 1 to 2 cm outside the PV-left atrium junctions at the following sites: the left superolateral area (left superior GP [LSGP]), the left inferoposterior area (left inferior GP [LIGP]), the right superoanterior area (right anterior GP [RAGP]), the right inferoposterior area (right inferior GP [RIGP]), and the Ao-SVC fat pad (Ao-SVC GP), and in that sequence (Figure 1) (3,5,6).
Radiofrequency (RF) power output was up to 40 W, at 43°C, with 20- to 30-s duration for each lesion and saline infusion rate of 20 to 25 ml/min. The endpoint was ablation of atrial electrical activity (peak-to-peak bipolar electrogram <0.1 mV), or elimination of vagal response at the sites where vagal responses were elicited by RF applications. A positive vagal response was defined as a >20% decrease in heart rate (HR) during SR or atrioventricular conduction block.
After the ablation procedure, patients were hospitalized for at least 3 days, with cardiac rhythm continuously monitored for the first 48 h. Outpatient visits and 24-h Holter monitoring were scheduled at 3, 6, and 12 months and every 6 months thereafter. The mean HR and HR variability (HRV) were analyzed by 24-h Holter monitoring before the procedure and 1 week and 3, 6 and 12 months after ablation. Autonomic modulation was assessed by frequency-domain HRV analysis with commercially available software (MemCalc/CHIRAM, GMS, Tokyo, Japan). Frequency-domain analysis was performed by a fast Fourier transformation of the NN intervals. The low frequency (LF) (range 0.04 to 0.15 Hz), high frequency (HF) (range 0.15 to 0.40 Hz), and LF-HF ratio were calculated by frequency-domain analysis.
The Medical Outcomes Study Short-Form 36 Health Survey (SF-36) was used to assess quality of life (QoL) at baseline and 12 months after ablation (7). The self-administration mode was strictly followed for QoL surveys. The SF-36 assesses 8 specific QoL domains, namely physical functioning, role limitations due to physical health, bodily pain, general health, vitality, social functioning, role limitations due to emotional problem, and mental health. For each subscale, scores were transformed to a scale ranging from 0 to 100, with lower scores representing a lower QoL.
Each patient subjectively assessed his or her SB-related symptom, including dizziness, fatigue, and palpitation, on a score of 1 to 10 points (mild to severe). The total SB-related symptom score for each patient was calculated as the sum of all scores for individual symptoms.
Continuous variables were expressed as mean ± SD and compared using independent samples t tests or non-parametric test, whereas discrete variables were expressed as percentages and compared using chi-square tests. One-way analysis of variance was used for multiple comparisons of normally distributed data. All tests of significance were 2 sided, with a probability value <0.05 considered significant. All statistical analyses were performed using SPSS version 18.0 (IBM, Armonk, New York) and GraphPad software Prism 5 version 5.01 (GraphPad Software, La Jolla, California).
The 62 patients enrolled included 42 men and 20 women; of these 40 were <50 years of age (mean age 42.1 ± 7.7 yrs) and 22 were ≥50 yrs of age (mean age 58.3 ± 8.1 yrs). Their baseline demographic and clinical characteristics, as well as the results of atropine and electrophysiology tests, are shown in Table 1. Left ventricular ejection fraction, diastolic diameter, and left atrial size were similar in the 2 age groups. On atropine tests, the Group A had significantly larger increases in SR a significantly higher maximum SR and a shorter time to maximum SR than the older group (p < 0.001 each). Electrophysiology tests before ablation no significant between group differences in cSNRT and atrial and atrioventricular node effective refractory periods (Table 1).
Anatomic GP ablation in LA and RA
The duration of fluoroscopy was similar in patients <50 yrs of age and ≥50 yrs of age (13 ± 3 min vs. 14 ± 5 min; p > 0.05). Vagal responses (VR) were more frequent and intense in areas of the RAGP, LSGP, and Ao-SVC GP during ablation, with more than 90% of RF applications at these sites eliciting VR. Because 1 of the endpoints of ablation was to eliminate the VR elicited by ablation, RF applications were significantly fewer and shorter in the LIGP and RIGP than in other areas (p < 0.001) (Figures 2A and 2C). However, there were no significant differences between the 2 groups in the number and duration of RF applications at each GP region (p > 0.05) (Figures 2B and 2D). Particularly, ablation at the RAGP area often caused bradycardia with a >5-s sinus pause (Group A: 22.5%, 9 of 40 patients; Group B: 18.2%, 4 of 22 patients) associated with syncope in 9 of 62 (14.5%) patients.
Following sequential GP ablation, mean SR markedly increased in the entire patient cohort, from 47.3 ± 5.7 beats/min to 63.5 ± 8.4 beats/min (p < 0.001). To evaluate the effects of individual GP on SR, we analyzed SR increases after each GP ablation in whole patients (Figure 3A). There were no obvious increase in the mean SR after ablation of the LSGP, LIGP, and RIGP, but RAGP and Ao-SVC GP ablation greatly increased the SR from 49.4 ± 5.5 beats/min to 55.6 ± 7.4 beats/min (p < 0.05) and from 55.7 ± 7.1 beats/min to 63.6 ± 8.4 beats/min (p < 0.05), respectively (Figure 3). Further analysis found that 21 of the 62 patients showed SR increases >60 beats/min after RAGP ablation (RAGP[+] patients), with SR in these patients being significantly higher after than before ablation (63.6 ± 3.7 beats/min vs. 46.8 ± 5.6 beats/min; p < 0.05) (Figure 3B). Subsequent ablation of Ao-SVC GP produced additional effects on SR increases (70.6 ± 8.5 beats/min vs. 63.4 ± 4.3 beats/min; p < 0.05) in these patients. In addition, 31 of 40 patients showed significant SR increasing only after the Ao-SVC GP was ablated (Ao-SVC GP[+] patients), with SR in these patients increasing from 51.4 ± 5.2 beats/min to 61.5 ± 5.4 beats/min (p < 0.05) (Figure 3C). Subgroup analysis showed that SR increased significantly after sequential ablation in all patients of Group A, with the mean SR increase in this group being significantly greater than that in patients of Group B (19.3 ± 9.9 vs. 10.8 ± 5.4; p = 0.001). However, in Group B patients, RAGP and Ao-SVC GP ablation did not significantly alter mean SR, with only 12 of these patients showing SR > 60 beats/min after sequential ablation (data not shown).
Patients underwent Holter monitoring 3 days, and 3, 6, and 12 months, after ablation. In the entire patient cohort, both mean SR (64.6 ± 6.0 beats/min vs. 48.3 ± 6.1 beats/min; p < 0.01) and minimal SR (54.9 ± 5.8 beats/min vs. 43.7 ± 6.1 beats/min; p < 0.01) were significantly higher 3 days after than before ablation, with both remaining stable for 12 months (Figures 4A and 4B). In subgroup analysis, Group A patients experienced significantly higher increases in mean and minimal SR than Group B patients did during the follow-up period (Figures 5A and 5B). Both mean and minimal SR were significantly higher in Group B patients 3 days after than before ablation (p < 0.05) (Table 2), but these increases did not remain stable through 12 months of follow-up (p < 0.05) (Figures 5A and 5B).
The HF component of HRV, representing parasympathetic activities, decreased significantly in all patients, a decrease that persisted for 12 months after ablation (Figure 4C). In subgroup analysis, this decrease was greater in Group A patients than in Group B patients from 3 days to 12 months after ablation (Figure 5C). Group A patients had higher LF-HF ratio after ablation than Group B patients did from 3 days to 12 months after the procedure, and ratio was steadily close to 1, suggesting improved autonomic balance (Figures 4D and 5D, Table 2).
Overall, none of the patients experienced complications such as tamponade, death, myocardial infarction, or stroke. Compared with ablation before, the SB-related symptom score of whole patients was significantly lower 12 months after than before ablation. All patients in Group A had symptom improvement, and the score of decrease showed significant when compared with Group B (Figures 6C and 6D). Of the 22 Group B patients, 18 (81.8%) patients completed the entire follow-up, whereas 3 (13.6%) required pacemaker implantation due to serious SB-related symptoms before the end of follow-up. An additional patient, a 59-year-old woman, experienced paroxysmal atrial fibrillation and underwent a PV isolation (PVI) procedure at 5 months after ablation. Thirteen patients (59.1%) reported improvements in their SB-related symptoms, although 5 continued to experience paroxysmal palpitations, which were associated with lower mean SR (48.7 ± 2.1 beats/min vs. 54.2 ± 4.6 beats/min; p < 0.05) and minimal SR (43.4 ± 1.4 beats/min vs. 48.3 ± 3.6 beats/min; p < 0.05) than others, these 5 patients had positive VR during ablation.
Quality of life
Analysis of the entire patient cohort 12 months after ablation showed significant improvements in 7 of the 8 subscales of the SF-36 (p < 0.05 each) (Figure 6A). Although the 2 groups showed similar scores at baseline, Group A patients showed significant improvements in all 8 subscales, whereas Group B patients showed significant improvements in only 3 of the 8 subscales, at the 12-month follow-up. All measures of the SF-36 showed a larger magnitude of improvement in Group A than in patients of Group B (Figure 6B).
The main findings of present study are: 1) anatomically guided atrial autonomic ablation yielded better clinical outcomes, including increased SR and improved QoL, in younger (<50 yrs of age) than in older (≥50 yrs of age) symptomatic SB patients without any complications; and 2) RAGP and Ao-SVC GP are the GP predominant in modulating sinus node function in patients with symptomatic SB.
Cardiac autonomic nervous system and SR
The cardiac autonomic nervous system (ANS) contains 2 main components: the extrinsic and intrinsic ANS, which regulate various physiologic functions of the heart. GP, as integral parts of the intrinsic ANS, are usually embedded in the fat pads located on the epicardium and form a complex interacting network that regulates HR and heart rhythm. The RAGP has been reported to mainly control the function of the SA node; electrical stimulation of the RAGP reduces SR and shortens the effective refractory period of adjacent atrial tissue without affecting atrioventricular nodal conduction (5,8). The main neural pathway between the left vagosympathetic trunk and the SA node has been reported to sequentially traverse the LSGP and RAGP before proceeding to the SA node. The RAGP integrates the vagosympathetic trunks to modulate sinus rhythm, and the LSGP modulates the SA node mainly through an RAGP-dependent pathway (5,6). We previously reported that, during PVI, ablation of the sites at the PV antrum adjacent to the RAGP often elicited prolonged bradycardia. Patients showing this bradycardic response during ablation had higher HRs after the ablation procedure (3). In the present study, VR was again observed during GP ablation, particularly at the RAGP and Ao-SVC GP, consistent with the notion that RAGP may serve as a “gateway” for the cardiac ANS to modulate the sinus node.
Most efferent vagal fibers to the atria have been found to travel through a fat pad located between the medial superior vena cava and the proximal aorta, corresponding to the Ao-SVC GP in the present study, and then project onto the RAGP and RIGP (9). Moreover, ablation of this GP was found to suppress the effects of vagal stimulation on SR slowing (10). Our preliminary study also showed that ablation of the Ao-SVC GP resulted in a profound vagal response, followed by an increase in SR (3). In the present study, Ao-SVC GP ablation after RAGP ablation resulted in additional SR increases, suggesting that the Ao-SVC GP is critical in modulating sinus nodal function through both RAGP-dependent and -independent pathways.
Anatomic GP modification and clinical outcomes
In treating syncope, anatomic GP ablation was found to require shorter procedure and fluoroscopy times than endocardial high-frequency stimulation (HFS)–guided ablation, with the 2 having identical success rates (4). In the present study, the GP area before ablation was not identified by HFS, both because HFS was difficult to perform in patients not under general anesthesia and because HFS at the regions innervated by both sympathetic and parasympathetic neural elements may not elicit any vagal response (11). In addition, up to one-third of autonomic nerve fibers are located distant from the major GP (12). Stimulating these nerves in adjacent regions, such as the PV antrum, also resulted in vagal responses. However, our ablation targets were the autonomic neurons in the GP. These ablated autonomic neurons were unlikely to regenerate. GP ablation guided by anatomic location, rather than relying on HFS, is widely used for atrial fibrillation, because the locations of the major atrial GP vary minimally among patients (11).
To quantitatively evaluate anatomic GP modifications, we analyzed the ablation times and number of ablation sites during damage to each GP area. Because 1 endpoint of ablation was to eliminate the VR elicited by ablation, RF applications to the LIGP and RIGP were fewer and of shorter duration. The rates of VR responses during RF applications to the LIGP and RIGP were lower than during RF applications to other GP. However, the number and duration of RF applications to each GP area were similar in the 2 age groups. Although the occurrence of VR during follow-up was less pronounced in patients ≥50 yrs of age, only some of these older patients experienced long-term benefits from GP ablation. Moreover, improvements in quality of life were lower in older than in younger patients. Combined with the nonsignificantly prolonged cSNRT parameter before the procedure in all 62 patients, these findings suggested that: 1) symptomatic bradycardia in our patients was related primarily to an abnormal neural balance; and 2) age may be critical to the success of atrial GP ablation. Hyperactivity of the major atrial GP may play a less important role in the development of bradycardia in patients ≥50 yrs of age than in patients <50 yrs of age. The exact mechanism involved in the genesis of symptomatic SB in this group of patients remains to be elucidated.
Current guidelines discuss symptomatic SB in patients with sick sinus syndrome and vasovagal syncope (1,2), with pacemaker implantation indicated for patients with depressed sinus node automaticity (cSNRT >800 ms) and spontaneous asystole (13). To date, however, no recommendations have been made for symptomatic SB patients without clear sinus node dysfunction. Atrial GP ablation not only improved clinical outcomes and quality, but also avoided multiple pacemaker replacements and unnecessary nonphysiological pacing. Atrial GP ablation may therefore serve as an alternative treatment of patients <50 yrs of age with symptomatic SB but lacking profound sinus node dysfunction. However, patient selection for atrial GP ablation is crucial.
This study had several limitations. First, it was an explorative observational research limited to identifying the age-related effect of ablations in a small patient cohort and over a relatively short follow-up period. Second, although the incidence of complications is approximately 1% in patients undergoing GP ablation to treat AF and does not does not differ significantly in those undergoing GP+PVI and PVI alone (16,17), the risks associated with ablation of the LA remain a concern. Thus, larger-scale studies are needed to further determine the safety of GP ablation in patients with SB. Third, each patient served as his or her own control. Randomized control trials, however, are required to better determine the effects of this GP ablation strategy. Fourth, the present study was not designed to provide complete knowledge about the complicated interactions among atrial GP. Because the sample size was limited, patients underwent only 1 ablation sequence. Larger studies are needed to account for the enormous number of permutations in stepwise GP ablation and to understand the complex interactions among GP. The results presented in this study may assist in defining the complex interactions among GP required for regulation of sinus function. Fifth, there was a lack of direct evidence for identification of autonomic activity before the procedure. Radiolabeled compounds, together with standard γ-cameras and positron emission tomography scanners (14), may be used for noninvasive imaging of neuronal function (14), thereby predicting heart failure (15).
Our data indicate that anatomic atrial GP ablation effectively increased SR and improved QoL in younger patients with symptomatic SB. Its effectiveness suggests it has potential as an alternative treatment for this group of patients. Larger-scale studies are required to determine the safety of this approach.
COMPETENCY IN MEDICAL KNOWLEDGE: SB is a life-threatening condition requiring prompt medical attention. Because the ANS regulates SR, atrial GP may be critical in the treatment of patients with SB. This preliminary study demonstrated that atrial GP ablation greatly increased SR and improved symptoms in nonelderly patients with symptomatic SB.
TRANSLATIONAL OUTLOOK: Better understanding of the relationship between atrial GP and SR may provide an alternative approach to treat younger patients with symptomatic SB.
This research was supported by National Natural Science Foundation of China Grants (Grant No: 81400246) and China Postdoctoral Science Foundation Grant (Grant No: 2015M571570). The funder has designed this study and decided to publish this manuscript. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Qin and Zhang contributed equally to this work.
- Abbreviations and Acronyms
- aorta-superior vena cava
- autonomic nervous system
- ganglionated plexus
- high-frequency stimulation
- heart rate
- heart rate variability
- left inferior ganglionated plexus
- left superior ganglionated plexus
- pulmonary vein ablation
- right superior ganglionated plexus
- right inferior ganglionic plexus
- sinus bradycardia
- Received August 26, 2016.
- Revision received January 2, 2017.
- Accepted January 12, 2017.
- 2017 American College of Cardiology Foundation
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