- Email: [email protected]
Low-level carotid baroreflex stimulation suppresses atrial fibrillation by inhibiting left stellate ganglion activity in an acute canine model
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Low-level carotid baroreflex stimulation suppresses atrial fibrillation by inhibiting left stellate ganglion activity in an acute canine model Mingyan Dai, MD,*†‡ Mingwei Bao, MD, PhD,*†‡ Yijie Zhang, MD,*†‡ Lilei Yu, MD, PhD,*†‡ Quan Cao, MD,*†‡ Yanhong Tang, MD, PhD,*†‡ He Huang, MD, PhD,*†‡ Xi Wang, MD, PhD,*†‡ Dan Hu, MD, PhD, FHRS, FAHA,*†‡§ Congxin Huang, MD, PhD, FHRS, FACC, FESC*†‡ From the *Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China, †Cardiovascular Research Institute, Wuhan University, Wuhan, People’s Republic of China, ‡Hubei Key Laboratory of Cardiology, Wuhan, People’s Republic of China, and §Masonic Medical Research Laboratory, Utica, New York. BACKGROUND Low-level carotid baroreflex stimulation (LL-CBS) appears to have a potential antiarrhythmogenic effect. OBJECTIVE The purpose of this study was to investigate effects of short-term LL-CBS on an atrial fibrillation (AF) canine model.
(P o .05). The activation of LSG, decrease in high frequency, and increase in low frequency and low frequency/high frequency ratio induced by RAP were also reversed by LL-CBS (P o .05). After 6hour RAP, plasma norepinephrine and angiotensin II concentrations were significantly lower in the LL-CBS group than in the control group (P o .05). Group 2: The AF duration was shortened and the average AF cycle length was prolonged markedly in both subgroups (P o .01) by LL-CBS.
METHODS Group 1: Anesthetized dogs underwent 6 hours of rapid atrial pacing (RAP) with concomitant LL-CBS in last 3 hours (LL-CBS group; n ¼ 7) or without (control group; n ¼ 6). Effective refractory period (ERP), ERP dispersion, and window of vulnerability to AF were determined. Left stellate ganglion (LSG) neural activity and heart rate variability were analyzed. Group 2: In subgroup 1, sustained AF was induced by injecting acetylcholine (Ach; 10 mM) into the anterior right ganglionated plexus at baseline and after 3hour LL-CBS (n ¼ 7) or sham operation (n ¼ 6). In subgroup 2, Ach was applied onto the right atrial appendage. The time of duration of AF and the average AF cycle length were determined in both subgroups.
KEYWORDS Low-level carotid baroreflex stimulation; Atrial fibrillation; Left stellate ganglion; Autonomic remodeling; Autonomic nervous system
RESULTS Group 1: LL-CBS reversed the RAP-induced ERP shortening and increase in ERP dispersion and window of vulnerability
(Heart Rhythm 2016;0:0–10) I 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia that results in significant morbidity and mortality.1 Antiarrhythmic drugs, electrical cardioversion, and catheter ablation techniques have been used to treat AF, while clinical outcomes are far from satisfactory. In recent years, the The first 2 authors contributed equally to this work. This work was supported by the National Science and Technology Pillar Program of China (grant no. 2011BAI11B12), Independent Research Project of Wuhan University (grant no. 2042016kf0138), and the National Natural Science Foundation of China (grant nos. 81570460 and 81500668). Address reprint requests and correspondence: Dr Congxin Huang, Department of Cardiology, Cardiology Research Institute, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan 430060, Hubei, People’s Republic of China.. E-mail address: [email protected].
CONCLUSION LL-CBS can reverse RAP-induced atrial electrical remodeling and suppress electrically or mechanically induced AF with Ach, and the anti-AF effect is attributed to attenuation of autonomic nerve remodeling, including inhibition of the LSG activity.
autonomic nervous system was validated to play an important role in the initiation and maintenance of AF.2 Varieties of interventions on the modulation of the autonomic nervous system have shown potential for AF control.3 Carotid baroreflex stimulation (CBS) modulates the autonomic nervous system by sympathetic suppression as well as vagal activation.4 Recent studies found that moderate CBS that decreased blood pressure (BP) and heart rate showed proarrhythmic effects including shortening of the effective refractory period (ERP).5 In contrast, our recent studies demonstrated that low-level CBS (LL-CBS) without BP or heart rate reduction exhibited antiarrhythmic potential. LL-CBS prolonged ERP and monophasic action potential duration of the left atrium in rabbits and suppressed local AF inducibility by high-frequency (HF) stimulation during the
1547-5271/$-see front matter B 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.hrthm.2016.08.021
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refractory period in canines.6,7 In this study, we further investigate the effects of LL-CBS on AF induced by different methods and its underlying mechanism.
Methods The detailed methods are described in the Online Supplement.
Animal preparation All animal studies were reviewed and approved by the ethics committee of the Renmin Hospital of Wuhan University and followed the guidelines outlined by the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Thirty-eight adult mongrel dogs (weighing 16–20 kg) were anesthetized with Na-pentobarbital (30 mg/kg) and ventilated with room air by a positive pressure respirator (MAO01746, Harvard Apparatus, Holliston, MA). Normal saline at 50–100 mL/h was infused to replace spontaneous fluid losses. Core body temperature was maintained at 36.5° C ± 1.5°C. Standard surface electrocardiograms and BP were monitored continuously. The depth of anesthesia was monitored by checking heart rate, breathing rate, and the toepinch response. The procedures of animal preparations and bilateral thoracotomy as well as positions of electrodes at multiple atrial and pulmonary vein (PV) sites have been communicated in detail elsewhere (Figures 1A and 1B).8 All recordings were displayed on a computer-based, electrophysiology system (LEAD 2000, Jinjiang, Inc, XXXX, China).
LL-CBS We have previously described the methods for LL-CBS.6 Electrodes were positioned once the location was identified in which stimulation (frequency 20 Hz; stimulus duration 2 ms) of 45 V could elicit an abrupt decrease of 410% in systolic BP from baseline (Figures 1C and 1D). The intensity of LL-CBS was set to 80% of the threshold (V) to cause systolic BP reduction. The threshold was reassessed every 1 hour to adjust the voltage for LL-CBS.6
Study protocol 1: LL-CBS in the 6-hour RAP model Group 1 (n ¼ 14): After determination of the baseline values of ERP and WOV, rapid atrial pacing (RAP) was delivered at 1000 beats/min (2 × threshold) at the left atrial appendage for 6 hours. After each pacing hour, RAP was temporarily stopped for 10–15 minutes to measure the ERP and AF inducibility. LL-CBS was applied concomitantly during the last 3 hours of the 6-hour RAP in the LL-CBS group (n ¼ 8). Six other animals that underwent 6-hour RAP without LLCBS served as the control group. During ERP measurements, AF was induced by the S1-S2 protocol. The difference between the longest and the shortest S1-S2 interval that induced AF was defined as the window of vulnerability (WOV). We chose ΣWOV as the quantitative measurement of AF inducibility of the whole heart, which was considered as the sum of WOVs at all 7 recording sites. Before RAP and
Heart Rhythm, Vol 0, No 0, Month 2016 after 3-hour and 6-hour RAP, left stellate ganglion (LSG) neural activity was recorded (Figures 1E and 1F) for 15 minutes and heart rate variability (HRV) power spectral was analyzed. After 3-hour and 6-hour RAP, 5 mL venous blood was collected (Figure 1G) for plasma norepinephrine (NE) and angiotensin II (Ang II) tests. LSG samples of all animals were obtained from the recording sites for immunohistochemistry analysis of tyrosine hydroxylase (TH) and growthassociated protein 43 (GAP43).
Study protocol 2: LL-CBS on electrically or mechanically induced AF with acetylcholine Group 2: In subgroup 1 (n ¼ 13), to induce paroxysmal AF that closely resembles the paroxysmal AF observed in patients initiated by rapid focal firing from the PV-atrial junctions, we injected acetylcholine (Ach; 10 mM, 0.5 mL) into the anterior right ganglionated plexus (ARGP) as previously described.9 In subgroup 2 (n ¼ 11), applying Ach onto the atrial appendage induces sustained AF that shows focal characteristics arising from non-PV sites.10 Three hours of LL-CBS was applied in the LL-CBS group (n ¼ 7 and n ¼ 6 in subgroups 1 and 2), while sham operation was performed in the control group (n ¼ 6 and n ¼ 5 in subgroups 1 and 2) (Figures 1H and 1I). The time duration of AF and the average AF cycle length were analyzed.
Statistical analysis Data are presented as mean ± SEM. In group 1, paired t tests were used for comparisons within the LL-CBS group or control group. A multivariate analysis of variance was used for comparisons between the LL-CBS group and the control group. In group 2, an analysis of variance for repeated measures was used to compare changes before and after 3hour LL-CBS.
Results The detailed results are described in the Online Supplement. During LL-CBS, BP and heart rate were stably maintained at the same level as baseline (Table 1). The average CBS threshold that induced a BP reduction of 410% was 2.5 ± 0.3 V (n ¼ 21) without any change during 3-hour LLCBS. The intensity of LL-CBS, which was 80% of the threshold, was 2.0 ± 0.2 V (n ¼ 21).
ERP In both LL-CBS and control groups, ERPs of all sites were markedly shortened by RAP in the first 2 or 3 hours (Figure 2). From the third hour on, ERPs in the control group were kept stable at an obviously lower level than at baseline. While in the LL-CBS group, compared to the level at the 3rd hour, ERPs were remarkably prolonged after initiating LL-CBS.
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Figure 1 Schematic plot of the electrodes at multiple sites (A and B), representative examples of CBS (C and D), representative examples of LSG (E) and LSG recording electrodes (F), and experimental design flowchart in group 1 (G) and group 2 (H and I). A plastic barrier was used to isolate the RAA from the RA (panel B). Ach ¼ acetylcholine; AF ¼ atrial fibrillation; ARGP ¼ anterior right ganglion plexus; BP ¼ blood pressure; BS ¼ baseline; CBS ¼ carotid baroreflex stimulation; IVC ¼ inferior vena cava; LA ¼ left atrium, LAA ¼ left atrial appendage; LIPV ¼ left inferior pulmonary vein; LL-CBS ¼ low-level carotid baroreflex stimulation; LPA ¼ left pulmonary artery; LSG ¼ left stellate ganglion; LSPV ¼ left superior pulmonary vein; LV ¼ left ventricle; RA ¼ right atrium; RAA ¼ right atrial appendage; RIPV ¼ right inferior pulmonary vein; RSPV ¼ right superior pulmonary vein; RV ¼ right ventricle; SVC ¼ superior vena cava.
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Table 1
Blood pressure and heart rate recordings in group 1 Baseline
3h
6h
Variable
LL-CBS group
Control group
LL-CBS group
Control group
LL-CBS group
Control group
Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart rate (beats/min)
133 ± 4 86 ± 3 145 ± 8
132 ± 3 84 ± 3 141 ± 9
127 ± 4 87 ± 5 140 ± 8
125 ± 4 82 ± 4 137 ± 5
125 ± 5 85 ± 4 141 ± 10
121 ± 3 81 ± 3 134 ± 7
Values are presented as mean ± SD. n ¼ 8 for the LL-CBS group and n ¼ 6 for the control group. BP ¼ blood pressure; LL-CBS ¼ low-level carotid baroreflex stimulation.
ERP dispersion
LSG neural activity
In group 1, ERP dispersion of the control group was significantly increased after the 1st pacing hour (P o .01) and then stabilized during the 2nd to 6th pacing hours. The increase in ERP dispersion induced by RAP was reversed by LL-CBS. ERP dispersion of the LL-CBS group markedly decreased at the 4th hour (P o .05) and stabilized during the 5th and 6th hours (P o .05 for both, compared to the 3rd hour; Figure 2).
Typical examples of LSG neural discharge recordings at baseline and after 3 and 6 hours in both LL-CBS and control groups are shown in Figure 4A. Quantitative analysis revealed that the frequency of LSG neural discharges increased progressively (P o .05) in the control group, while the 3-hour LL-CBS reversed the frequency increase (P o .05; Figure 4B, a). The amplitude of LSG neural discharges significantly increased after 6hour RAP (P o .05) in the control group. In comparison with the 3rd hour, 3-hour LL-CBS induced a significant decrease in the amplitude (P o .05) in the LL-CBS group (Figure 4B, b).
ΣWOV and AF vulnerability In group 1, when ERPs were measured, AF was reproducibly induced in 6 of 8 and 5 of 6 animals in LL-CBS and control groups, respectively. The induced AF terminated spontaneously and could be reinduced as programmed stimulation continued. Thus, ΣWOV was determined only in those animals with AF inducibility. In the control group, ΣWOV gradually increased (7 ± 4 seconds at baseline vs 135 ± 13 seconds at the 6th hour). From the 4th hour on, ΣWOV increased significantly as compared with that at baseline (P o .05), while LL-CBS reversed the increase in ΣWOV by RAP. Three-hour LL-CBS steadily narrowed ΣWOV from 93 ± 23 to 16 ± 5 seconds (P o .05 compared to the 3rd hour; Figure 2). The number of dogs with continued AF after discontinuing RAP is listed in Online Supplemental Table 1. The duration of self-persistent AF was not affected by LLCBS, which is consistent with a previous study.11
HRV power spectral Figure 3 shows that in group 1, 3-hour RAP significantly increased low-frequency (LF) components and LF/HF ratio in both LL-CBS and control groups (P o .01). HF components exhibited decreased tendency after 3-hour RAP in both groups. In the control group, LF components and LF/HF ratio extended to a higher level at the 6th hour and HF components maintained at the same level at the 3rd hour, while in the LL-CBS group, the decrease in HF components and the increase in LF components and LF/HF ratio were reversed after 3-hour LL-CBS.
Plasma NE and Ang II In group 1, after 3-hour LL-CBS, plasma NE and Ang II concentrations were significantly decreased in the LL-CBS group (P o .05), while there were no significant differences in plasma NE and Ang II concentrations between the end of the 3rd and the 6th hour in the control group (P 4 .05).
Immunohistochemical studies Figure 5A compares the immunohistochemical staining results of LSG between the LL-CBS group and the control group in group 1. There was no significant difference in the density of either TH-positive or GAP43-positive nerves between the 2 groups (Figure 5B).
Inducibility of AF In group 2, after Ach was injected into the ARGP at baseline, AF occurred spontaneously in 5 of 7 animals in the LL-CBS group and in 5 of 6 animals in the control group (Figure 1H). After 3 hours, in the LL-CBS group, spontaneous AF occurred in 2 of 7 animals while in 5 of 6 animals in the control group. Three-hour LL-CBS significantly decreased the AF duration as well as increased the AF cycle length (P o .01). In contrast, no significant difference was observed in those indexes between baseline and after 3 hours in the control group (P 4 .05) (Figures 6A and 6B). After the application of Ach onto the right atrial appendage with a moist gauze pad, AF occurred spontaneously in 1 of 6 animals in the LL-CBS group and no animal in the control group at baseline. No spontaneous AF occurred in the LL-CBS group after 3-hour stimulation, nor in the control group. While after mechanical stimulation, AF was induced in all animals. The AF duration was shortened and the AF cycle length were prolonged significantly after 3-hour LL-CBS (P o .01 for both), while neither AF duration nor AF cycle length was altered in the control group (P 4 .05) (Figures 6C and 6D). In 4 other canines, mechanical stimulation alone without Ach was unable to induce AF.
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Figure 2 Changes in mean ERP, cumulative WOV (∑WOV), and ERP dispersion in group 1. *P o .05 and **P o .01 vs baseline; △P o .05 and △△P o .01 vs the 3rd hour of RAP. ERP ¼ effective refractory period; RAP ¼ rapid atrial pacing; WOV ¼ window of vulnerability. Other abbreviations as in Figure 1.
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Figure 3 Changes in heart rate variability power spectral at baseline and after 3-hour and 6-hour RAP in group 1. *P o .05; **P o .01. HF ¼ high frequency; HF (nu) ¼ (HF power/TP − VLF power) × 100; LF ¼ low frequency; LF (nu) ¼ (LF power/TP − VLF power) × 100; nu ¼ normalized units; RAP ¼ rapid atrial pacing. Other abbreviations as in Figure 1.
Discussion Main findings
In the present study, we observed that LL-CBS exerted antiAF effects in 3 acute canine models. LL-CBS decreased ∑WOV and reversed the acute atrial electrical remodeling induced by RAP. The underlying mechanisms might be autonomic nervous and humoral regulation. First, the HRV power spectral analysis indicated that acute RAP induced the LF and LF/HF increase as well as the HF decrease. LL-CBS reversed the changes. Second, direct LSG neural discharge
Figure 4
recordings exhibited that acute RAP aroused the activation of LSG neural activity, which was drawn back to baseline state by LL-CBS. Third, compared with the control group, the plasma NE and Ang II concentrations of the LL-CBS group were significantly decreased after 3-hour LL-CBS. Finally, we demonstrated that LL-CBS substantially shortened the duration and increased the cycle length of AF induced by electrical or mechanical stimulation with strong Ach stimulation, regardless of whether Ach was injected into the ARGP or applied locally onto the right atrial appendage.
Effect of LL-CBS on LSG activity. *P o .05; **P o .01. Abbreviations as in Figure 1.
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Figure 5 Immunohistochemical staining (A) and comparison of TH-positive or GAP43-positive nerves (B) of LSG. n ¼ 8 for the LL-CBS group and n ¼ 6 for the control group. GAP43 ¼ growth-associated protein 43; LL-CBS ¼ low-level carotid baroreflex stimulation; TH ¼ tyrosine hydroxylase.
Autonomic remodeling in the acute AF model by RAP It is accepted that aside from structural changes (changes in autonomic innervation), autonomic remodeling includes alterations in autonomic nerve activity and neurochemistry.12,13 The concept of “AF begets AF” (atrial electrical remodeling) has been widely accepted,14 and the intrinsic cardiac autonomic nervous system (ICANS) is a critical element in the initial phase of AF.8 Yu et al15 illustrated that the vicious cycle of atrial electrical remodeling and autonomic remodeling was crucial in facilitating the maintenance of AF in the first few hours after onset. In the present study, the HRV power spectral analysis provided specific evidence of autonomic remodeling induced by RAP. The increasing LF components and LF/HF ratio indicated the increase in cardiac sympathetic tone, while the decreasing HF components represented the suppression of parasympathetic tone. Previous studies in anesthetized animals suggested the activation of atrial ganglionated plexi (ICANS) during RAP.15 Being components of cardiac neuronal hierarchy, ICANS and extrinsic cardiac autonomic nervous system (ECANS) inevitably interact with each other.16 Choi et al17 simultaneously recorded the activity of ICANS and ECANS in ambulatory canine models and found frequent interactions between ICANS and ECANS and simultaneous activation of
them before onsets of paroxysmal atrial tachyarrhythmia. In this study, direct neural recordings confirmed the activation of LSG, which is the sympathetic component of ECANS, during RAP, which is consistent with the result of a previous study.18 It indicated the activation of sympathetic ECANS in the initial phase of AF induced by RAP. Thus, it can be inferred that ECANS and ICANS might interact with each other via a local neuron pathway and together undergo the autonomic remodeling processes of AF.
Possible mechanism of LL-CBS suppressing AF Carotid baroreflex originates from carotid baroreceptors that detect changes in stretch of arterial wall, and the signals are transmitted to the central nervous system, integrated and converted from excitatory to inhibitory, and then transmitted to peripheral tissues.4 CBS bypasses mechanotransduction and produces sustained afferent input into the brain and consequently results in a suppression of sympathetic outflow and an activation of vagal tone.19 On account of the linear relationship between the intensity of CBS and the reduction in BP in a certain range,19 we define LL-CBS as subthreshold stimulation with which BP is not affected. In spite of having no effect on BP, LL-CBS exhibited modulation of the autonomic nervous system and attenuation of RAP-induced
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Figure 6 Changes in AF duration and AF CL by 3-hour LL-CBS in group 2. AF cycle length is defined as the average interval of the first 20 atrial electrograms during AF. *P o .05; **P o .01. AF ¼ atrial fibrillation; CL ¼ cycle length; LL-CBS ¼ low-level carotid baroreflex stimulation.
atrial electrical remodeling in anesthetized rabbits.6 In the present study, the concrete effect of LL-CBS on AF and its possible underlying mechanisms were further investigated in canine models. A particularly striking and potentially important finding was that direct neural recordings confirmed the inhibiting effect of LL-CBS on LSG activity. Shen et al demonstrated that chronic low-level vagal nerve stimulation (LL-VNS) suppressed AF via downregulating LSG nerve activity and caused LSG remodeling including reduction of TH-positive ganglion cells.20,21 In acute RAP models, stellate ganglion stimulation facilitates AF induction and exacerbates electrical remodeling, and conversely, unilateral stellate ganglionectomy can inhibit AF initiation.22 In this study, the activation of LSG during RAP is substantially withdrawn to basal levels after 3-hour LL-CBS. The capability of suppressing sympathetic components of ECANS of LL-CBS may account for the reverse of electrical remodeling and suppression of AF induction. Notably, previous studies show that prolonged strong CBS may chronically reduce BP, which is more effective than adrenergic blockade for α1- and β1,2-adrenergic receptors,19 and it could lower BP reduction during adrenergic blockade with an additional 10 mm Hg in parallel with reduction in plasma NE concentrations to control values.23 However, whether LL-CBS is more effective than the pharmacological β-blockade in suppressing AF and produces further benefit in the setting of β-blockade remains unknown.
Until further evidence is provided, the mechanism of the LLCBS effect has not been clearly established yet. With regard to the induction of AF by strong cholinergic stimulation, LL-CBS also showed a preventive effect. Linz et al5 showed that in normotensive anesthetized pigs, strong electrical baroreflex stimulation resulted in a pronounced shortening of atrial refractoriness because baroreflex stimulation shifted the autonomic balance toward vagal predominance. And they recently further validated that LL-CBS, but not high-level CBS, could suppress negative thoracic pressure–induced ERP shortening and AF inducibility in an acute porcine model of sleep apnea,24 which is consistent with the results in our model. The effects of LL-CBS on AF are in contrast to those of strong baroreflex stimulation, which is similar to vagal nerve stimulation. The possible mechanism might be that the ECANS suppresses neural activity in the ICANS and suppresses AF.14,25 LL-VNS could suppress ARGP stimulation–induced sinus rate slowing and suppress AF via inhibiting ARGP discharges.14,26 Given that LL-CBS is validated to inhibit ganglionated plexus activity,7 we assume that LL-CBS inhibits electrically or mechanically induced AF with strong cholinergic stimulation in a similar way as LL-VNS. Thus, combining the previous results with the present study, it would be reasonable to assume that the suppression of ICANS as well as sympathetic components of ECANS underlies the mechanism of an anti-AF effect of LL-CBS.
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Probably because of the short period of time, there was no significant difference in the expression of TH and GAP43 between the LL-CBS group and the control group according to immunohistochemical staining. Although HRV is rather an indirect index of the autonomic nervous activity,27 the marked decrease in LF components and LF/HF ratio after LL-CBS is consistent with suppression of the sympathetic activity. The reduction in plasma NE concentration after LLCBS further corroborated the sympathetic suppression. Moreover, the decrease in plasma Ang II concentrations revealed an inhibitory effect of LL-CBS on the reninangiotensin-aldosterone system (RAAS). This result is consistent with the concept that suppression of renin secretion contributes to the chronic CBS-mediated BP reduction.28 As the RAAS activation is considered a promoting factor of electrical remodeling in the early phase of AF,29 LL-CBS– mediated Ang II reduction may also account for the anti-AF effect. However, this hypothesis remains to be tested in further studies, such as whether Ang II infusion during LLCBS would counteract the anti-AF effect.
Clinical implications This study provided a striking evidence that LL-CBS might serve as a new approach to prevent AF. The results also remind us to pay attention to AF occurrence among patients in the ongoing clinical trials of CBS on resistant hypertension and heart failure. Notably, as the sympathetic overactivity is a common promoting factor among cardiovascular diseases such as hypertension, chronic heart failure, and AF, LL-CBS may become a potent device therapy to reduce mortality and morbidity of such diseases.
Study limitations This study illustrated that short-term LL-CBS can protect against AF, but several limitations existed. First, we examined the effects of LL-CBS on AF in acute canine models, while the long-term effect of LL-CBS on AF remains uncertain. Second, we performed HRV analysis, which is an indirect index to represent the parasympathetic activity, rather than direct neural recordings from vagal nerves. Third, in this study, AF models were made in canines with normal arterial pressure. Considering that the intensity of CBS necessary to reduce BP may be different in normotensive from hypertensive subjects, the stimulus intensity used in this study may cause additional BP reduction in hypertensive subjects. In that case, LL-CBS should be redefined and the dual effects of LL-CBS on AF and BP control would benefit patients with hypertension complicated with AF.
Conclusion LL-CBS can reverse atrial electrical remodeling induced by RAP and suppress electrically or mechanically induced AF with Ach. The mechanism is attributed to attenuation of the autonomic nerve remodeling, including inhibition of the LSG activity. The suppression of RAAS may also account for the anti-AF effect.
9
Appendix Supplementary data Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.hrthm. 2016.08.021.
References 1. Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 2011;57:e101–e198. 2. Shen MJ, Choi EK, Tan AY, Lin SF, Fishbein MC, Chen LS, Chen PS. Neural mechanisms of atrial arrhythmias. Nat Rev Cardiol 2012;9:30–39. 3. Linz D, Ukena C, Mahfoud F, Neuberger HR, Bohm M. Atrial autonomic innervation: a target for interventional antiarrhythmic therapy? J Am Coll Cardiol 2014;63:215–224. 4. Iliescu R, Tudorancea I, Lohmeier TE. Baroreflex activation: from mechanisms to therapy for cardiovascular disease. Curr Hypertens Rep 2014;16:453. 5. Linz D, Mahfoud F, Schotten U, Ukena C, Neuberger HR, Wirth K, Bohm M. Effects of electrical stimulation of carotid baroreflex and renal denervation on atrial electrophysiology. J Cardiovasc Electrophysiol 2013;24:1028–1033. 6. Dai M, Bao M, Liao J, Yu L, Tang Y, Huang H, Wang X, Huang C. Effects of low-level carotid baroreflex stimulation on atrial electrophysiology. J Interv Card Electrophysiol 2015;43:111–119. 7. Liao K, Yu L, Zhou X, Saren G, Wang S, Wang Z, Huang B, Yang K, Jiang H. Low-level baroreceptor stimulation suppresses atrial fibrillation by inhibiting ganglionated plexus activity. Can J Cardiol 2015;31:767–774. 8. Lu Z, Scherlag BJ, Lin J, Niu G, Fung KM, Zhao L, Ghias M, Jackman WM, Lazzara R, Jiang H, Po SS. Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing. Circ Arrhythm Electrophysiol 2008;1:184–192. 9. Po SS, Scherlag BJ, Yamanashi WS, Edwards J, Zhou J, Wu R, Geng N, Lazzara R, Jackman WM. Experimental model for paroxysmal atrial fibrillation arising at the pulmonary vein-atrial junctions. Heart Rhythm 2006;3:201–208. 10. Scherlag BJ, Hou YL, Lin J, Lu Z, Zacharias S, Dasari T, Niu G, Ghias M, Patterson E, Jackman WM, Lazzara R, Po SS. An acute model for atrial fibrillation arising from a peripheral atrial site: evidence for primary and secondary triggers. J Cardiovasc Electrophysiol 2008;19:519–527. 11. Yu L, Scherlag BJ, Li S, Fan Y, Dyer J, Male S, Varma V, Sha Y, Stavrakis S, Po SS. Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve: a noninvasive approach to treat the initial phase of atrial fibrillation. Heart Rhythm 2013;10:428–435. 12. Nattel S, Harada M. Atrial remodeling and atrial fibrillation: recent advances and translational perspectives. J Am Coll Cardiol 2014;63:2335–2345. 13. Chen PS, Chen LS, Cao JM, Sharifi B, Karagueuzian HS, Fishbein MC. Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death. Cardiovasc Res 2001;50:409–416. 14. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation 1995;92:1954–1968. 15. Yu L, Scherlag BJ, Sha Y, Li S, Sharma T, Nakagawa H, Jackman WM, Lazzara R, Jiang H, Po SS. Interactions between atrial electrical remodeling and autonomic remodeling: how to break the vicious cycle. Heart Rhythm 2012;9: 804–809. 16. Armour JA. Cardiac neuronal hierarchy in health and disease. Am J Physiol Regul Integr Comp Physiol 2004;287:R262–R271. 17. Choi EK, Shen MJ, Han S, Kim D, Hwang S, Sayfo S, Piccirillo G, Frick K, Fishbein MC, Hwang C, Lin SF, Chen PS. Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs. Circulation 2010;121: 2615–2623. 18. Wang S, Zhou X, Huang B, Wang Z, Zhou L, Chen M, Yu L, Jiang H. Spinal cord stimulation suppresses atrial fibrillation by inhibiting autonomic remodeling. Heart Rhythm 2016;13:274–281. 19. Lohmeier TE, Irwin ED, Rossing MA, Serdar DJ, Kieval RS. Prolonged activation of the baroreflex produces sustained hypotension. Hypertension 2004;43:306–311. 20. Shen MJ, Shinohara T, Park HW, et al. Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines. Circulation 2011;123:2204–2212.
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21. Chen PS, Chen LS, Fishbein MC, Lin SF, Nattel S. Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ Res 2014;114:1500–1515. 22. Zhou QHJ, Guo Y, Zhang F, Yang X, Zhang L, Xu X, Wang L, Wang H, Hou Y. Effect of the stellate ganglion on atrial fibrillation and atrial electrophysiological properties and its left-right asymmetry in a canine model. Exp Clin Cardiol 2013;18:38–42. 23. Lohmeier TE, Hildebrandt DA, Dwyer TM, Iliescu R, Irwin ED, Cates AW, Rossing MA. Prolonged activation of the baroreflex decreases arterial pressure even during chronic adrenergic blockade. Hypertension 2009;53:833–838. 24. Linz D, Hohl M, Khoshkish S, Mahfoud F, Ukena C, Neuberger HR, Wirth K, Bohm M. Low-level but not high-level baroreceptor stimulation inhibits atrial fibrillation in a pig model of sleep apnea [published online ahead of print May 28, 2016]. J Cardiovasc Electrophysiol. 〈doi:10.1111/jce.13020〉. 25. Zhang Y, Ilsar I, Sabbah HN, Ben David T, Mazgalev TN. Relationship between right cervical vagus nerve stimulation and atrial fibrillation inducibility:
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therapeutic intensities do not increase arrhythmogenesis. Heart Rhythm 2009;6: 244–250. Yu L, Scherlag BJ, Li S, Sheng X, Lu Z, Nakagawa H, Zhang Y, Jackman WM, Lazzara R, Jiang H, Po SS. Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia. J Cardiovasc Electrophysiol 2011;22:455–463. Goldstein DS, Bentho O, Park MY, Sharabi Y. Low-frequency power of heart rate variability is not a measure of cardiac sympathetic tone but may be a measure of modulation of cardiac autonomic outflows by baroreflexes. Exp Physiol 2011;96:1255–1261. Lohmeier TE, Iliescu R. Lowering of blood pressure by chronic suppression of central sympathetic outflow: insight from prolonged baroreflex activation. J Appl Physiol (1985) 2012;113:1652–1658. Nakashima H, Kumagai K, Urata H, Gondo N, Ideishi M, Arakawa K. Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation. Circulation 2000;101:2612–2617.
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Low-level carotid baroreflex stimulation suppresses atrial fibrillation by inhibiting left stellate ganglion activity in an acute canine model Mingyan Dai, MD,*†‡ Mingwei Bao, MD, PhD,*†‡ Yijie Zhang, MD,*†‡ Lilei Yu, MD, PhD,*†‡ Quan Cao, MD,*†‡ Yanhong Tang, MD, PhD,*†‡ He Huang, MD, PhD,*†‡ Xi Wang, MD, PhD,*†‡ Dan Hu, MD, PhD, FHRS, FAHA,*†‡§ Congxin Huang, MD, PhD, FHRS, FACC, FESC*†‡ From the *Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China, †Cardiovascular Research Institute, Wuhan University, Wuhan, People’s Republic of China, ‡Hubei Key Laboratory of Cardiology, Wuhan, People’s Republic of China, and §Masonic Medical Research Laboratory, Utica, New York. BACKGROUND Low-level carotid baroreflex stimulation (LL-CBS) appears to have a potential antiarrhythmogenic effect. OBJECTIVE The purpose of this study was to investigate effects of short-term LL-CBS on an atrial fibrillation (AF) canine model.
(P o .05). The activation of LSG, decrease in high frequency, and increase in low frequency and low frequency/high frequency ratio induced by RAP were also reversed by LL-CBS (P o .05). After 6hour RAP, plasma norepinephrine and angiotensin II concentrations were significantly lower in the LL-CBS group than in the control group (P o .05). Group 2: The AF duration was shortened and the average AF cycle length was prolonged markedly in both subgroups (P o .01) by LL-CBS.
METHODS Group 1: Anesthetized dogs underwent 6 hours of rapid atrial pacing (RAP) with concomitant LL-CBS in last 3 hours (LL-CBS group; n ¼ 7) or without (control group; n ¼ 6). Effective refractory period (ERP), ERP dispersion, and window of vulnerability to AF were determined. Left stellate ganglion (LSG) neural activity and heart rate variability were analyzed. Group 2: In subgroup 1, sustained AF was induced by injecting acetylcholine (Ach; 10 mM) into the anterior right ganglionated plexus at baseline and after 3hour LL-CBS (n ¼ 7) or sham operation (n ¼ 6). In subgroup 2, Ach was applied onto the right atrial appendage. The time of duration of AF and the average AF cycle length were determined in both subgroups.
KEYWORDS Low-level carotid baroreflex stimulation; Atrial fibrillation; Left stellate ganglion; Autonomic remodeling; Autonomic nervous system
RESULTS Group 1: LL-CBS reversed the RAP-induced ERP shortening and increase in ERP dispersion and window of vulnerability
(Heart Rhythm 2016;0:0–10) I 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia that results in significant morbidity and mortality.1 Antiarrhythmic drugs, electrical cardioversion, and catheter ablation techniques have been used to treat AF, while clinical outcomes are far from satisfactory. In recent years, the The first 2 authors contributed equally to this work. This work was supported by the National Science and Technology Pillar Program of China (grant no. 2011BAI11B12), Independent Research Project of Wuhan University (grant no. 2042016kf0138), and the National Natural Science Foundation of China (grant nos. 81570460 and 81500668). Address reprint requests and correspondence: Dr Congxin Huang, Department of Cardiology, Cardiology Research Institute, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan 430060, Hubei, People’s Republic of China.. E-mail address: [email protected].
CONCLUSION LL-CBS can reverse RAP-induced atrial electrical remodeling and suppress electrically or mechanically induced AF with Ach, and the anti-AF effect is attributed to attenuation of autonomic nerve remodeling, including inhibition of the LSG activity.
autonomic nervous system was validated to play an important role in the initiation and maintenance of AF.2 Varieties of interventions on the modulation of the autonomic nervous system have shown potential for AF control.3 Carotid baroreflex stimulation (CBS) modulates the autonomic nervous system by sympathetic suppression as well as vagal activation.4 Recent studies found that moderate CBS that decreased blood pressure (BP) and heart rate showed proarrhythmic effects including shortening of the effective refractory period (ERP).5 In contrast, our recent studies demonstrated that low-level CBS (LL-CBS) without BP or heart rate reduction exhibited antiarrhythmic potential. LL-CBS prolonged ERP and monophasic action potential duration of the left atrium in rabbits and suppressed local AF inducibility by high-frequency (HF) stimulation during the
1547-5271/$-see front matter B 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.hrthm.2016.08.021
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refractory period in canines.6,7 In this study, we further investigate the effects of LL-CBS on AF induced by different methods and its underlying mechanism.
Methods The detailed methods are described in the Online Supplement.
Animal preparation All animal studies were reviewed and approved by the ethics committee of the Renmin Hospital of Wuhan University and followed the guidelines outlined by the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Thirty-eight adult mongrel dogs (weighing 16–20 kg) were anesthetized with Na-pentobarbital (30 mg/kg) and ventilated with room air by a positive pressure respirator (MAO01746, Harvard Apparatus, Holliston, MA). Normal saline at 50–100 mL/h was infused to replace spontaneous fluid losses. Core body temperature was maintained at 36.5° C ± 1.5°C. Standard surface electrocardiograms and BP were monitored continuously. The depth of anesthesia was monitored by checking heart rate, breathing rate, and the toepinch response. The procedures of animal preparations and bilateral thoracotomy as well as positions of electrodes at multiple atrial and pulmonary vein (PV) sites have been communicated in detail elsewhere (Figures 1A and 1B).8 All recordings were displayed on a computer-based, electrophysiology system (LEAD 2000, Jinjiang, Inc, XXXX, China).
LL-CBS We have previously described the methods for LL-CBS.6 Electrodes were positioned once the location was identified in which stimulation (frequency 20 Hz; stimulus duration 2 ms) of 45 V could elicit an abrupt decrease of 410% in systolic BP from baseline (Figures 1C and 1D). The intensity of LL-CBS was set to 80% of the threshold (V) to cause systolic BP reduction. The threshold was reassessed every 1 hour to adjust the voltage for LL-CBS.6
Study protocol 1: LL-CBS in the 6-hour RAP model Group 1 (n ¼ 14): After determination of the baseline values of ERP and WOV, rapid atrial pacing (RAP) was delivered at 1000 beats/min (2 × threshold) at the left atrial appendage for 6 hours. After each pacing hour, RAP was temporarily stopped for 10–15 minutes to measure the ERP and AF inducibility. LL-CBS was applied concomitantly during the last 3 hours of the 6-hour RAP in the LL-CBS group (n ¼ 8). Six other animals that underwent 6-hour RAP without LLCBS served as the control group. During ERP measurements, AF was induced by the S1-S2 protocol. The difference between the longest and the shortest S1-S2 interval that induced AF was defined as the window of vulnerability (WOV). We chose ΣWOV as the quantitative measurement of AF inducibility of the whole heart, which was considered as the sum of WOVs at all 7 recording sites. Before RAP and
Heart Rhythm, Vol 0, No 0, Month 2016 after 3-hour and 6-hour RAP, left stellate ganglion (LSG) neural activity was recorded (Figures 1E and 1F) for 15 minutes and heart rate variability (HRV) power spectral was analyzed. After 3-hour and 6-hour RAP, 5 mL venous blood was collected (Figure 1G) for plasma norepinephrine (NE) and angiotensin II (Ang II) tests. LSG samples of all animals were obtained from the recording sites for immunohistochemistry analysis of tyrosine hydroxylase (TH) and growthassociated protein 43 (GAP43).
Study protocol 2: LL-CBS on electrically or mechanically induced AF with acetylcholine Group 2: In subgroup 1 (n ¼ 13), to induce paroxysmal AF that closely resembles the paroxysmal AF observed in patients initiated by rapid focal firing from the PV-atrial junctions, we injected acetylcholine (Ach; 10 mM, 0.5 mL) into the anterior right ganglionated plexus (ARGP) as previously described.9 In subgroup 2 (n ¼ 11), applying Ach onto the atrial appendage induces sustained AF that shows focal characteristics arising from non-PV sites.10 Three hours of LL-CBS was applied in the LL-CBS group (n ¼ 7 and n ¼ 6 in subgroups 1 and 2), while sham operation was performed in the control group (n ¼ 6 and n ¼ 5 in subgroups 1 and 2) (Figures 1H and 1I). The time duration of AF and the average AF cycle length were analyzed.
Statistical analysis Data are presented as mean ± SEM. In group 1, paired t tests were used for comparisons within the LL-CBS group or control group. A multivariate analysis of variance was used for comparisons between the LL-CBS group and the control group. In group 2, an analysis of variance for repeated measures was used to compare changes before and after 3hour LL-CBS.
Results The detailed results are described in the Online Supplement. During LL-CBS, BP and heart rate were stably maintained at the same level as baseline (Table 1). The average CBS threshold that induced a BP reduction of 410% was 2.5 ± 0.3 V (n ¼ 21) without any change during 3-hour LLCBS. The intensity of LL-CBS, which was 80% of the threshold, was 2.0 ± 0.2 V (n ¼ 21).
ERP In both LL-CBS and control groups, ERPs of all sites were markedly shortened by RAP in the first 2 or 3 hours (Figure 2). From the third hour on, ERPs in the control group were kept stable at an obviously lower level than at baseline. While in the LL-CBS group, compared to the level at the 3rd hour, ERPs were remarkably prolonged after initiating LL-CBS.
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Dai et al 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242
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Figure 1 Schematic plot of the electrodes at multiple sites (A and B), representative examples of CBS (C and D), representative examples of LSG (E) and LSG recording electrodes (F), and experimental design flowchart in group 1 (G) and group 2 (H and I). A plastic barrier was used to isolate the RAA from the RA (panel B). Ach ¼ acetylcholine; AF ¼ atrial fibrillation; ARGP ¼ anterior right ganglion plexus; BP ¼ blood pressure; BS ¼ baseline; CBS ¼ carotid baroreflex stimulation; IVC ¼ inferior vena cava; LA ¼ left atrium, LAA ¼ left atrial appendage; LIPV ¼ left inferior pulmonary vein; LL-CBS ¼ low-level carotid baroreflex stimulation; LPA ¼ left pulmonary artery; LSG ¼ left stellate ganglion; LSPV ¼ left superior pulmonary vein; LV ¼ left ventricle; RA ¼ right atrium; RAA ¼ right atrial appendage; RIPV ¼ right inferior pulmonary vein; RSPV ¼ right superior pulmonary vein; RV ¼ right ventricle; SVC ¼ superior vena cava.
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Table 1
Blood pressure and heart rate recordings in group 1 Baseline
3h
6h
Variable
LL-CBS group
Control group
LL-CBS group
Control group
LL-CBS group
Control group
Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart rate (beats/min)
133 ± 4 86 ± 3 145 ± 8
132 ± 3 84 ± 3 141 ± 9
127 ± 4 87 ± 5 140 ± 8
125 ± 4 82 ± 4 137 ± 5
125 ± 5 85 ± 4 141 ± 10
121 ± 3 81 ± 3 134 ± 7
Values are presented as mean ± SD. n ¼ 8 for the LL-CBS group and n ¼ 6 for the control group. BP ¼ blood pressure; LL-CBS ¼ low-level carotid baroreflex stimulation.
ERP dispersion
LSG neural activity
In group 1, ERP dispersion of the control group was significantly increased after the 1st pacing hour (P o .01) and then stabilized during the 2nd to 6th pacing hours. The increase in ERP dispersion induced by RAP was reversed by LL-CBS. ERP dispersion of the LL-CBS group markedly decreased at the 4th hour (P o .05) and stabilized during the 5th and 6th hours (P o .05 for both, compared to the 3rd hour; Figure 2).
Typical examples of LSG neural discharge recordings at baseline and after 3 and 6 hours in both LL-CBS and control groups are shown in Figure 4A. Quantitative analysis revealed that the frequency of LSG neural discharges increased progressively (P o .05) in the control group, while the 3-hour LL-CBS reversed the frequency increase (P o .05; Figure 4B, a). The amplitude of LSG neural discharges significantly increased after 6hour RAP (P o .05) in the control group. In comparison with the 3rd hour, 3-hour LL-CBS induced a significant decrease in the amplitude (P o .05) in the LL-CBS group (Figure 4B, b).
ΣWOV and AF vulnerability In group 1, when ERPs were measured, AF was reproducibly induced in 6 of 8 and 5 of 6 animals in LL-CBS and control groups, respectively. The induced AF terminated spontaneously and could be reinduced as programmed stimulation continued. Thus, ΣWOV was determined only in those animals with AF inducibility. In the control group, ΣWOV gradually increased (7 ± 4 seconds at baseline vs 135 ± 13 seconds at the 6th hour). From the 4th hour on, ΣWOV increased significantly as compared with that at baseline (P o .05), while LL-CBS reversed the increase in ΣWOV by RAP. Three-hour LL-CBS steadily narrowed ΣWOV from 93 ± 23 to 16 ± 5 seconds (P o .05 compared to the 3rd hour; Figure 2). The number of dogs with continued AF after discontinuing RAP is listed in Online Supplemental Table 1. The duration of self-persistent AF was not affected by LLCBS, which is consistent with a previous study.11
HRV power spectral Figure 3 shows that in group 1, 3-hour RAP significantly increased low-frequency (LF) components and LF/HF ratio in both LL-CBS and control groups (P o .01). HF components exhibited decreased tendency after 3-hour RAP in both groups. In the control group, LF components and LF/HF ratio extended to a higher level at the 6th hour and HF components maintained at the same level at the 3rd hour, while in the LL-CBS group, the decrease in HF components and the increase in LF components and LF/HF ratio were reversed after 3-hour LL-CBS.
Plasma NE and Ang II In group 1, after 3-hour LL-CBS, plasma NE and Ang II concentrations were significantly decreased in the LL-CBS group (P o .05), while there were no significant differences in plasma NE and Ang II concentrations between the end of the 3rd and the 6th hour in the control group (P 4 .05).
Immunohistochemical studies Figure 5A compares the immunohistochemical staining results of LSG between the LL-CBS group and the control group in group 1. There was no significant difference in the density of either TH-positive or GAP43-positive nerves between the 2 groups (Figure 5B).
Inducibility of AF In group 2, after Ach was injected into the ARGP at baseline, AF occurred spontaneously in 5 of 7 animals in the LL-CBS group and in 5 of 6 animals in the control group (Figure 1H). After 3 hours, in the LL-CBS group, spontaneous AF occurred in 2 of 7 animals while in 5 of 6 animals in the control group. Three-hour LL-CBS significantly decreased the AF duration as well as increased the AF cycle length (P o .01). In contrast, no significant difference was observed in those indexes between baseline and after 3 hours in the control group (P 4 .05) (Figures 6A and 6B). After the application of Ach onto the right atrial appendage with a moist gauze pad, AF occurred spontaneously in 1 of 6 animals in the LL-CBS group and no animal in the control group at baseline. No spontaneous AF occurred in the LL-CBS group after 3-hour stimulation, nor in the control group. While after mechanical stimulation, AF was induced in all animals. The AF duration was shortened and the AF cycle length were prolonged significantly after 3-hour LL-CBS (P o .01 for both), while neither AF duration nor AF cycle length was altered in the control group (P 4 .05) (Figures 6C and 6D). In 4 other canines, mechanical stimulation alone without Ach was unable to induce AF.
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Dai et al 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 Q8 468 469 470
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Figure 2 Changes in mean ERP, cumulative WOV (∑WOV), and ERP dispersion in group 1. *P o .05 and **P o .01 vs baseline; △P o .05 and △△P o .01 vs the 3rd hour of RAP. ERP ¼ effective refractory period; RAP ¼ rapid atrial pacing; WOV ¼ window of vulnerability. Other abbreviations as in Figure 1.
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Figure 3 Changes in heart rate variability power spectral at baseline and after 3-hour and 6-hour RAP in group 1. *P o .05; **P o .01. HF ¼ high frequency; HF (nu) ¼ (HF power/TP − VLF power) × 100; LF ¼ low frequency; LF (nu) ¼ (LF power/TP − VLF power) × 100; nu ¼ normalized units; RAP ¼ rapid atrial pacing. Other abbreviations as in Figure 1.
Discussion Main findings
In the present study, we observed that LL-CBS exerted antiAF effects in 3 acute canine models. LL-CBS decreased ∑WOV and reversed the acute atrial electrical remodeling induced by RAP. The underlying mechanisms might be autonomic nervous and humoral regulation. First, the HRV power spectral analysis indicated that acute RAP induced the LF and LF/HF increase as well as the HF decrease. LL-CBS reversed the changes. Second, direct LSG neural discharge
Figure 4
recordings exhibited that acute RAP aroused the activation of LSG neural activity, which was drawn back to baseline state by LL-CBS. Third, compared with the control group, the plasma NE and Ang II concentrations of the LL-CBS group were significantly decreased after 3-hour LL-CBS. Finally, we demonstrated that LL-CBS substantially shortened the duration and increased the cycle length of AF induced by electrical or mechanical stimulation with strong Ach stimulation, regardless of whether Ach was injected into the ARGP or applied locally onto the right atrial appendage.
Effect of LL-CBS on LSG activity. *P o .05; **P o .01. Abbreviations as in Figure 1.
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Dai et al 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698
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Figure 5 Immunohistochemical staining (A) and comparison of TH-positive or GAP43-positive nerves (B) of LSG. n ¼ 8 for the LL-CBS group and n ¼ 6 for the control group. GAP43 ¼ growth-associated protein 43; LL-CBS ¼ low-level carotid baroreflex stimulation; TH ¼ tyrosine hydroxylase.
Autonomic remodeling in the acute AF model by RAP It is accepted that aside from structural changes (changes in autonomic innervation), autonomic remodeling includes alterations in autonomic nerve activity and neurochemistry.12,13 The concept of “AF begets AF” (atrial electrical remodeling) has been widely accepted,14 and the intrinsic cardiac autonomic nervous system (ICANS) is a critical element in the initial phase of AF.8 Yu et al15 illustrated that the vicious cycle of atrial electrical remodeling and autonomic remodeling was crucial in facilitating the maintenance of AF in the first few hours after onset. In the present study, the HRV power spectral analysis provided specific evidence of autonomic remodeling induced by RAP. The increasing LF components and LF/HF ratio indicated the increase in cardiac sympathetic tone, while the decreasing HF components represented the suppression of parasympathetic tone. Previous studies in anesthetized animals suggested the activation of atrial ganglionated plexi (ICANS) during RAP.15 Being components of cardiac neuronal hierarchy, ICANS and extrinsic cardiac autonomic nervous system (ECANS) inevitably interact with each other.16 Choi et al17 simultaneously recorded the activity of ICANS and ECANS in ambulatory canine models and found frequent interactions between ICANS and ECANS and simultaneous activation of
them before onsets of paroxysmal atrial tachyarrhythmia. In this study, direct neural recordings confirmed the activation of LSG, which is the sympathetic component of ECANS, during RAP, which is consistent with the result of a previous study.18 It indicated the activation of sympathetic ECANS in the initial phase of AF induced by RAP. Thus, it can be inferred that ECANS and ICANS might interact with each other via a local neuron pathway and together undergo the autonomic remodeling processes of AF.
Possible mechanism of LL-CBS suppressing AF Carotid baroreflex originates from carotid baroreceptors that detect changes in stretch of arterial wall, and the signals are transmitted to the central nervous system, integrated and converted from excitatory to inhibitory, and then transmitted to peripheral tissues.4 CBS bypasses mechanotransduction and produces sustained afferent input into the brain and consequently results in a suppression of sympathetic outflow and an activation of vagal tone.19 On account of the linear relationship between the intensity of CBS and the reduction in BP in a certain range,19 we define LL-CBS as subthreshold stimulation with which BP is not affected. In spite of having no effect on BP, LL-CBS exhibited modulation of the autonomic nervous system and attenuation of RAP-induced
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Figure 6 Changes in AF duration and AF CL by 3-hour LL-CBS in group 2. AF cycle length is defined as the average interval of the first 20 atrial electrograms during AF. *P o .05; **P o .01. AF ¼ atrial fibrillation; CL ¼ cycle length; LL-CBS ¼ low-level carotid baroreflex stimulation.
atrial electrical remodeling in anesthetized rabbits.6 In the present study, the concrete effect of LL-CBS on AF and its possible underlying mechanisms were further investigated in canine models. A particularly striking and potentially important finding was that direct neural recordings confirmed the inhibiting effect of LL-CBS on LSG activity. Shen et al demonstrated that chronic low-level vagal nerve stimulation (LL-VNS) suppressed AF via downregulating LSG nerve activity and caused LSG remodeling including reduction of TH-positive ganglion cells.20,21 In acute RAP models, stellate ganglion stimulation facilitates AF induction and exacerbates electrical remodeling, and conversely, unilateral stellate ganglionectomy can inhibit AF initiation.22 In this study, the activation of LSG during RAP is substantially withdrawn to basal levels after 3-hour LL-CBS. The capability of suppressing sympathetic components of ECANS of LL-CBS may account for the reverse of electrical remodeling and suppression of AF induction. Notably, previous studies show that prolonged strong CBS may chronically reduce BP, which is more effective than adrenergic blockade for α1- and β1,2-adrenergic receptors,19 and it could lower BP reduction during adrenergic blockade with an additional 10 mm Hg in parallel with reduction in plasma NE concentrations to control values.23 However, whether LL-CBS is more effective than the pharmacological β-blockade in suppressing AF and produces further benefit in the setting of β-blockade remains unknown.
Until further evidence is provided, the mechanism of the LLCBS effect has not been clearly established yet. With regard to the induction of AF by strong cholinergic stimulation, LL-CBS also showed a preventive effect. Linz et al5 showed that in normotensive anesthetized pigs, strong electrical baroreflex stimulation resulted in a pronounced shortening of atrial refractoriness because baroreflex stimulation shifted the autonomic balance toward vagal predominance. And they recently further validated that LL-CBS, but not high-level CBS, could suppress negative thoracic pressure–induced ERP shortening and AF inducibility in an acute porcine model of sleep apnea,24 which is consistent with the results in our model. The effects of LL-CBS on AF are in contrast to those of strong baroreflex stimulation, which is similar to vagal nerve stimulation. The possible mechanism might be that the ECANS suppresses neural activity in the ICANS and suppresses AF.14,25 LL-VNS could suppress ARGP stimulation–induced sinus rate slowing and suppress AF via inhibiting ARGP discharges.14,26 Given that LL-CBS is validated to inhibit ganglionated plexus activity,7 we assume that LL-CBS inhibits electrically or mechanically induced AF with strong cholinergic stimulation in a similar way as LL-VNS. Thus, combining the previous results with the present study, it would be reasonable to assume that the suppression of ICANS as well as sympathetic components of ECANS underlies the mechanism of an anti-AF effect of LL-CBS.
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Low-Level Carotid Baroreflex Stimulation
Probably because of the short period of time, there was no significant difference in the expression of TH and GAP43 between the LL-CBS group and the control group according to immunohistochemical staining. Although HRV is rather an indirect index of the autonomic nervous activity,27 the marked decrease in LF components and LF/HF ratio after LL-CBS is consistent with suppression of the sympathetic activity. The reduction in plasma NE concentration after LLCBS further corroborated the sympathetic suppression. Moreover, the decrease in plasma Ang II concentrations revealed an inhibitory effect of LL-CBS on the reninangiotensin-aldosterone system (RAAS). This result is consistent with the concept that suppression of renin secretion contributes to the chronic CBS-mediated BP reduction.28 As the RAAS activation is considered a promoting factor of electrical remodeling in the early phase of AF,29 LL-CBS– mediated Ang II reduction may also account for the anti-AF effect. However, this hypothesis remains to be tested in further studies, such as whether Ang II infusion during LLCBS would counteract the anti-AF effect.
Clinical implications This study provided a striking evidence that LL-CBS might serve as a new approach to prevent AF. The results also remind us to pay attention to AF occurrence among patients in the ongoing clinical trials of CBS on resistant hypertension and heart failure. Notably, as the sympathetic overactivity is a common promoting factor among cardiovascular diseases such as hypertension, chronic heart failure, and AF, LL-CBS may become a potent device therapy to reduce mortality and morbidity of such diseases.
Study limitations This study illustrated that short-term LL-CBS can protect against AF, but several limitations existed. First, we examined the effects of LL-CBS on AF in acute canine models, while the long-term effect of LL-CBS on AF remains uncertain. Second, we performed HRV analysis, which is an indirect index to represent the parasympathetic activity, rather than direct neural recordings from vagal nerves. Third, in this study, AF models were made in canines with normal arterial pressure. Considering that the intensity of CBS necessary to reduce BP may be different in normotensive from hypertensive subjects, the stimulus intensity used in this study may cause additional BP reduction in hypertensive subjects. In that case, LL-CBS should be redefined and the dual effects of LL-CBS on AF and BP control would benefit patients with hypertension complicated with AF.
Conclusion LL-CBS can reverse atrial electrical remodeling induced by RAP and suppress electrically or mechanically induced AF with Ach. The mechanism is attributed to attenuation of the autonomic nerve remodeling, including inhibition of the LSG activity. The suppression of RAAS may also account for the anti-AF effect.
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Appendix Supplementary data Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.hrthm. 2016.08.021.
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