Vagal tone augmentation to the atrioventricular node in humans: Efficacy and safety of burst endocardial stimulation
Article Outline
Background
Control of atrioventricular (AV) nodal conduction by endocardial stimulation of efferent AV nodal vagal fibers [atrioventricular nodal vagal stimulation (AVNS)] is a promising approach for long-term device-based modulation of ventricular rate during atrial fibrillation (AF). However, few data on the efficacy of AVNS delivered as high-frequency stimulus packages (burst AVNS) in humans are available.
Objective
The purpose of this study was to determine whether burst AVNS can to modulate AV nodal conduction during AF and whether burst AVNS delivered during sinus rhythm (SR) in the effective atrial refractory period allows safe implantation of a permanent lead in a position suitable for AVNS.
Methods
Twenty patients (10 in SR and 10 in AF) who were candidates for dual-chamber pacemaker implantation for sick sinus syndrome were enrolled in the study. The posteroseptal right atrium was mapped to identify a location at which burst AVNS would achieve AV nodal conduction modulation (lengthening of PR interval in SR and reduction of ventricular rate in AF). Subsequently, a lead was screwed in at that site and burst stimulation (pulse rate 50 Hz, burst duration 180 ms) was delivered at different burst rates, pulse durations, and amplitudes.
Results
In all SR patients, PR-interval prolongation was evoked at 90 and 120 bursts/minute with pulse durations ≤1 ms. Specifically, the mean voltages required to obtain PR-interval prolongation and advanced AV block were 4.3 ± 2.2 V and 5.4 ± 1.8 V (at 90 bursts/minute and 1 ms), respectively. Similarly, ventricular rate reduction was obtained in all AF patients, starting from 90 bursts/minute and 0.5-ms pulse duration (at 5.4 ± 1.8 V). Ventricular arrhythmias were never induced during AVNS.
Conclusion
Endocardial right atrial burst AVNS reduces ventricular rate during AF. Burst AVNS delivered during SR in the effective atrial refractory period allows optimization of lead positioning for AVNS.
Keywords: Atrial fibrillation, Atrioventricular node, Burst stimulation, Vagal stimulation
Abbreviations: AF, atrial fibrillation, AV, atrioventricular, AVNS, atrioventricular nodal vagal stimulation, EARP, effective atrial refractory period, SR, sinus rhythm
Introduction
Atrioventricular (AV) nodal conduction can be instantaneously and reversibly modulated by high-frequency stimulation of epicardial vagal ganglionated plexuses in both animals and humans.1, 2, 3, 4 Control of AV nodal conduction by endocardial stimulation of efferent AV nodal vagal fibers [atrioventricular nodal vagal stimulation (AVNS)] through placement of a standard pacing lead in close proximity to the coronary sinus ostium has been demonstrated to be feasible and effective.5, 6, 7 It also has been suggested to be a promising approach to long-term device-based modulation of ventricular rate during atrial fibrillation (AF) in humans.8 The feasibility and efficacy of acute and chronic AVNS using both continuous stimulation and high-frequency stimulus packages (burst AVNS) have been demonstrated in animals.9, 10 However, few data are available on the efficacy of acute burst AVNS in humans.2 Although a technique for implantation of standard pacing leads during AF in a position suitable for AVNS has been proposed in an animal study,7 implantation during sinus rhythm (SR) has never been described. Adequately delivered burst AVNS could permit implantation of the lead, with no additional risk of inducing atrial arrhythmias, during high-frequency stimulation tests. The aim of the present study was to determine whether (1) burst AVNS can significantly modulate AV nodal conduction in humans in the acute setting and (2) burst AVNS delivered during SR within the effective atrial refractory period (EARP) allows optimization of lead positioning for AVNS without inducing arrhythmias.
Methods
Study population
Patients undergoing dual-chamber pacemaker implantation for sick sinus syndrome who had a structurally normal heart and no cardiovascular drug treatment were enrolled in the study. Diagnosis of sick sinus syndrome was based on the presence of symptoms compatible with cerebral hypoperfusion and documentation of sinus bradycardia, pauses, or chronotropic incompetence on ECG Holter recording. Patients in SR on implantation were assigned to group A. Patients affected by paroxysmal AF who were in AF at the time of implantation were assigned to group B. Patients with basal AV nodal dysfunction (PR interval >200 ms), history of permanent AF, or, in the case of group B, slowly conducted AF (mean ventricular rate <100 bpm) and those with a history of cardiac valve replacement were excluded from the study. All patients gave informed consent, as approved by the local ethics committee in accordance with the Declaration of Helsinki.
Implantation procedure and tests
Surgery was performed with patients under local anesthesia. At the beginning of the implantation procedure, the ventricular lead was placed at the right ventricular apex using standard technique. The following tests were performed in order to identify an atrial location suitable for standard pacing/sensing and for AVNS through high-frequency stimulation.
The subclavian vein was punctured and a diagnostic electrophysiology catheter was inserted (model 041002JM, Medtronic, Inc., Minneapolis, MN, USA) and advanced to the right atrium. The coronary sinus was cannulated to identify the location of the ostium, and fluoroscopic images were collected. The catheter was connected to an external high-frequency stimulator (computer-controlled stimulation system with custom-made software developed in LabVIEW, National Instruments, Houston, TX, USA), slowly withdrawn, and positioned below the coronary sinus ostium. This area was tested delivering cardiac stimulation according to the protocol described below. In case of unsatisfactory dromotropic effect, the catheter was positioned behind the coronary sinus ostium, and the stimulation test was repeated in this area.
Once the target site had been identified, a standard bipolar screw-in lead (model 4076, Medtronic) was positioned at the tip of the temporary electrode, under fluoroscopic guidance, with a standard stiff stylet previously hand-shaped to a Josephson-like curve.
To verify the absence of ventricular capture caused by high-output atrial pacing and thus ensure safety, pacing was delivered through the atrial lead (amplitude 10 V at 1.5 ms, pacing rate 20 bpm more than ventricular rate). An AAI pacing mode was applied in group A (SR patients), whereas asynchronous pacing was used in group B (AF patients). Finally, standard tests (P-wave amplitude, pacing threshold, impedance measurements) were performed to verify that electrical characteristics were suitable for permanent pacing.
In case of satisfactory electrical measures and reproducible dromotropic effect with the permanent lead, the electrophysiology catheter was withdrawn, and the complete protocol of high-frequency stimulation was applied to characterize the effects of AVNS.
Stimulation protocol
A train of square-wave impulses was delivered to each test location through the distal dipole of the electrophysiology catheter: amplitude 10 V, pulse duration 1 ms, biphasic waveform (95% positive and 5% negative), pulse-to-pulse interval 20 ms (i.e., pulse rate 50 Hz), burst duration 180 seconds (10 pulses), and 90 bursts/minute. In the case of AF (group B), this stimulation pattern resulted in asynchronous high-frequency stimulation, whereas for SR patients (group A), the first pulse of each burst ensured constant atrial capture, resulting in fixed-rate overdrive pacing, with the following pulses of the burst falling in the EARP. In group A, atrial overdrive pacing (at 90 bursts/minute) was applied before high-frequency burst stimulation to measure the reference PR interval in the absence of AVNS (Figure 1).
Figure 1.
ECG (lead II) and endocardial electrogram recorded at the coronary sinus ostium (CSO). Atrial pacing (90 bpm) is delivered by the permanent lead screwed in behind the CSO. A: Burst stimulation (50 Hz) during the effective atrial refractory period is initiated at the asterisk. B: 2:1 AV block is evoked after a few bursts and disappears immediately after stimulation is interrupted (#).
In order to characterize the negative dromotropic effect, the previously described high-frequency stimulation was delivered through the permanent lead with bipolar configuration, varying the following parameters: pulse duration 0.2, 0.5, and 1 ms; burst rate 70, 90, and 120 bursts/minute (for patients in SR, only rates higher than the sinus rate were tested). For each setting, the pulse amplitude was increased in steps of 1 V (up to maximum of 10 V) after every 5 bursts in SR patients and 20 bursts in AF patients, in order to assess the voltage corresponding to the following:
In both groups, backup ventricular pacing (VVI at 40 bpm) was ensured in order to avoid prolonged complete AV block. In group A patients, atrial pacing at 120 bpm was also preliminarily delivered to exclude the occurrence of spontaneous advanced AV block at the rates tested. If an arrhythmia was induced, stimulation was immediately interrupted.
Statistical analysis
Continuous data are expressed as mean ± SD. Differences between mean data were compared by t-test for Gaussian variables and by Mann-Whitney nonparametric test for nongaussian variables. Differences in proportions were compared by Chi-square analysis. P <.05 was considered significant for all tests. All statistical analyses were performed using SPSS software (SPSS, Inc., Chicago, IL, USA).
Results
Twenty patients undergoing dual-chamber pacemaker implantation who were not receiving cardiovascular drug treatment were included in the study. Ten patients in SR at the time of implantation were assigned to group A. In this group, diagnosis of sick sinus syndrome was based on the patients' age and their presentation with symptomatic sinus bradycardia and chronotropic incompetence, as evidenced by monotonic daily heart rate profile on ECG Holter recording. In 6 of 10 patients, sinus pauses longer than 3 seconds were recoded and correlated with syncopal episodes. The remaining 10 patients, assigned to group B, were affected by tachy-brady syndrome and were in AF at the time of implantation.
Baseline characteristics of the study population are listed in Table 1. Except for a trend toward a higher proportion of males in group A (P = .057), no differences were found between the groups. The posteroseptal right atrium was mapped with the diagnostic catheter, and the negative dromotropic effect of high-frequency burst stimulation was verified as defined in the Methods section. This was achieved in all patients in groups A (Figure 1) and B (Figure 2), after no more than five attempts. In one group A patient, AF was induced during the mapping test and spontaneously terminated a few minutes later. The procedure was completed during SR, and the atrial lead was successfully implanted in the target position (Figure 3). The occurrence of ventricular capture by high-output atrial pacing (amplitude 10 V, pulse duration 1.5 ms) was excluded in all patients, and the adequacy of pacing parameters was verified in both groups: group A (P-wave amplitude 3.7 ± 2.0 mV, pacing threshold 0.9 ± 0.2 V, impedance 615 ± 21 Ω); group B (pacing impedance 703 ± 25 Ω). In no cases was repositioning needed because of a lack of negative dromotropic effect or unsatisfactory pacing parameter.
Table 1. Baseline clinical parameters of the two patient groups
| Parameter | Group A: patients in sinus rhythm (n = 10) | Group B: patients in atrial fibrillation (n = 10) |
|---|---|---|
| Male gender (n) | 9 | 4 |
| Age (years) | 73 ±10 | 74±6 |
| QRS duration (ms) | 95±8 | 106±21 |
| PR interval (ms) | 172±25 | 179±15⁎ |
| Left ventricular ejection fraction (%) | 62±4 | 62±7 |
⁎Measured from patient's previous sinus rhythm ECG recording. |
Figure 2.
Asynchronous burst stimulation (90 bursts/minute) during rapidly conducted atrial fibrillation (mean ventricular rate 160 bpm) starts at the asterisk. Progressive burst voltage increase allows significant ventricular rate reduction, as seen in the second line (mean ventricular rate 80 bpm). Third line shows ventricular rate increase after vagal stimulation is interrupted (#).
Figure 3.
Anteroposterior (A) and latero-lateral (B) X-ray views. The permanent ventricular passive fixation lead is implanted in the right ventricular apex. The second lead is screwed in at the right atrial septum (asterisk) behind the coronary sinus ostium, a location suitable for both standard atrial pacing/sensing and AVNS.
Negative dromotropic effect in group A
In all group A patients, AV conduction with a 1:1 pattern was observed during atrial pacing at 120 bpm, thus excluding the occurrence of spontaneous advanced AV block at the rates tested. The stimulation protocol was performed in the whole group (Figure 4). During stimulation tests with the permanent lead, atrial arrhythmias were never induced. Tests performed by delivering 120 bpm induced PR-interval prolongation in all patients at 1- and 0.5-ms pulse durations (mean voltage 3.4 ± 1.8 V and 4.3 ± 2.5 V, respectively) and in 8 of 10 patients at 0.2 ms (at 5.1 ± 2.2 V). The same protocol evoked advanced AV block in 8 patients at 1 ms (at 4.3 ± 1.6 V) and in 7 patients at 0.5 and 0.2 ms (at 5.0 ± 2.2 V and 6.4 ± 2.8 V, respectively). Stimulation at 90 bursts/minute produced PR-interval prolongation in all patients at 1 ms (mean voltage 4.3 ± 2.2 V), in 8 patients at 0.5 ms (at 4.5 ± 1.9 V), and in 6 patients at 0.2-ms pulse duration (at 6.0 ± 2.0 V). The same burst rate elicited advanced AV block in 8 patients at 1 ms (at 5.4 ± 1.8 V), in 7 patients at 0.5 ms (at 6.0 ± 2.2 V) and in 4 patients at 0.2 ms (at 6.8 ± 2.2 V). Stimulation at 70 bursts/minute evoked PR-interval prolongation in 7 patients at 1 ms (mean voltage 6.3 ± 1.7 V), in 6 patients at 0.5 ms (at 7.0 ± 1.9 V), and in 3 patients at 0.2 ms (at 7.7 ± 0.6 V). The same protocol elicited advanced AV block in 4 patients at 1 ms (at 6.4 ± 3.4 V), in 2 patients at 0.5 ms (at 8.0 ± 0.6 V), and in no patients at 0.2-ms pulse duration. Overall, for patients in group A, the amplitude that elicited advanced AV block exceeded the voltage that elicited PR-interval prolongation by 2.1 ± 1.2 V.
Figure 4.
A: Number of group A subjects in whom AV nodal conduction modulation (lined bars) and advanced AV block (solid bars) were functionally induced at different pulse durations and burst rates. B: Mean voltages (group A) needed to functionally induce AV nodal conduction modulation (lined bars) and advanced AV block (full bars) at different pulse durations and burst rates. C: Same as panel A for patients in group B. D: Same as panel B for patients in group B. AF = atrial fibrillation; SR = sinus rhythm.
Negative dromotropic effect in group B
Asynchronous burst stimulation with 120 bursts/minute induced ventricular rate modulation in all patients at 1- and 0.5-ms pulse duration (mean voltage 4.1 ± 1.7 V and 4.6 ± 1.4 V, respectively) and in 9 of 10 patients at 0.2 ms (at 6.3 ± 2.8 V). The same stimulation protocol produced complete AV block in all patients at 1 ms (at 5.6 ± 2.1 V), in 9 patients at 0.5 ms (at 6.2 ± 1.8 V), and in 6 patients at 0.2 ms (at 7.3 ± 1.8 V).
Asynchronous AVNS at 90 bursts/minute induced ventricular rate modulation in all patients at 1 and 0.5 ms (at 4.7 ± 1.8 V and 5.4 ± 2.2 V) and in 7 patients at 0.2 ms (at 6.6 ± 2.4 V). The same burst rate produced complete AV block in 9 patients at 1 ms (at 6.1 ± 2.0 V), in 7 patients at 0.5 ms (at 6.4 ± 1.0 V), and in 4 patients at 0.2 s (at 7.5 ± 1.0 V). Burst stimulation at 70 bursts/minute induced ventricular rate modulation in 8 patients at 1 and 0.5 ms (at 5.1 ± 2.0 V and 6.8 ± 2.1 V, respectively) and in 6 patients at 0.2 ms (at 7.8 ± 1.7 V). At the same rate, stimulation produced complete AV block in 7 patients at 1 ms (at 7.0 ± 2.2 V) and in 4 patients at 0.5- and 0.2-ms pulse duration (at 7.8 ± 2.2 V and 8.8 ± 1.0 V). The mean difference between voltages eliciting advanced AV block and those eliciting ventricular rate reduction was 1.9 ± 1.4 V.
Tolerability and safety
No atrial or ventricular arrhythmias were induced by AVNS through the permanent lead. Only 1 of 20 patients referred chest pain during stimulation at amplitudes higher than 8 V. No pericardial effusions, other complications, or lead dislodgments were observed after lead implantation or before hospital discharge in the study population.
Discussion
Ventricular rate control during AF may result in improved hemodynamic status and quality of life.11, 12, 13, 14 The present study confirms the efficacy of burst AVNS in modulating AV nodal conduction, both during atrial paced rhythm and during AF, when a permanent endocardial lead is used in humans in the acute setting. Although epicardial vagal stimulation has proved effective in acute and chronic studies,1, 3, 9 the endocardial approach appears to be more attractive in clinical practice because it is less invasive and can be implemented using standard pacing catheters and devices.6, 9 However, endocardial AVNS presents two main drawbacks: it requires more energy than the epicardial approach,8 and it may engender a risk of inducing arrhythmias because it stimulates myocardial tissue.
Burst AVNS drains the battery less than continuous pulse delivery; indeed, at a given pulse amplitude exceeding the threshold for vagal stimulation, battery drainage is proportional to the duration of stimulation.
In our study, AVNS was able to induce ventricular rate modulation in all AF patients at 90 bursts/minute and in 80% of patients at 70 bursts/minute.
AVNS enables control of ventricular rate and improvement of hemodynamic response with respect to rapidly conducted AF. However, it is associated with marked ventricular irregularity.15 AVNS in combination with VVI pacing has been seen to regularize the ventricular rate16 by fully eliminating anterograde propagation of fibrillatory impulses.17, 18 Notably, combining AVNS and VVI pacing can be even more beneficial if associated to biventricular pacing because this approach avoids the abnormal contraction pattern, with its negative hemodynamic consequences, caused by right ventricular apical pacing.
Burst AVNS synchronized to the ventricular electrogram during AF has been proposed in order to minimize the risk of inducing ventricular fibrillation in the event of accidental ventricular capture, lead positioning close to the coronary sinus ostium, or atrial lead dislodgment. In addition, burst AVNS enables concurrent assessment of atrial rhythm. In the event of SR recovery, prompt interruption of high-frequency stimulation would avoid the reinduction of atrial arrhythmias.
However, both continuous and R-wave–synchronized burst stimulation would induce atrial arrhythmias in SR patients, which would prevent them from undergoing the mapping procedure necessary to identify a favorable site for AVNS at the time of implantation. This could constitute an important limitation in patients with episodes of rapidly conducted AF, as these patients may frequently be in SR at the time of implantation. It has recently been shown that more than 40% of heart failure patients with no history of AF in whom cardiac resynchronization therapy (and therefore atrial lead implantation) is indicated experience ex novo AF episodes during follow-up, as detected by the implantable device diagnostics.19, 20 In these patients, AF induces loss of atrial contribution and rapid, irregular ventricular rate; indeed, it has been found to be the most frequent cause of resynchronization therapy discontinuation, accounting for 18% of the overall biventricular pacing population.21 One possible approach to delivering vagal stimulation while avoiding atrial arrhythmias may be application of burst AVNS during the EARP, a method proposed by Schauerte et al2 for the investigation of vagal stimulation in SR patients.
In the present study, this kind of stimulation proved to be a feasible and safe technique for preimplantation testing in SR patients in that it was able to identify atrial positions suitable for AVNS without inducing atrial arrhythmias or symptoms. However, atrial synchronized AVNS achieved by delivering high-amplitude (up to 30 V) short trains (50 ms) of high-frequency (200 Hz) electrical stimuli through a temporary catheter electrode placed in a standard coronary sinus location, although effective, has been shown to elicit symptoms in conscious subjects,2 which limits the potential application of this technique to anesthetized patients. In the present study, preliminary mapping and the use of screw-in leads allowed us to evoke a vagal reflex by applying low voltages (<10 V) while causing symptoms in almost no patients.
In the majority of SR patients, modulation of AV nodal conduction was evoked by burst stimulation at 90 bursts/minute, demonstrating that the preimplantation test does not require extremely fast and uncomfortable overdrive atrial pacing. Nonetheless, future studies are warranted to verify whether the stimulation parameters resulting in negative dromotropic effect in SR at the time of implant may also ensure adequate ventricular rate reduction during AF during follow-up.
In the majority of patients, advanced AV block was evoked by further increasing the voltage above the value for AV nodal conduction modulation. Specifically, we recorded a mean voltage increase of approximately 2 V in both groups of patients. These values confirm our previous experience with continuous AVNS.6
In this study, successful implantation of the permanent lead was achieved in all patients, confirming our previous findings on the feasibility of AVNS delivery by means of standard pacing catheters and devices.6 In our preliminary experience, we also reported acceptable procedural and fluoroscopy times with the adopted procedure (24 ± 18 minutes and 8 ± 7 minutes, respectively).
To avoid any bias in the present study, we enrolled patients with a structurally normal heart who were not receiving cardiovascular drug treatment. However, the target population for long-term AVNS includes heart failure patients requiring ventricular rate reduction during AF.
Previous work on an animal model of heart failure has shown that, despite an attenuation of vagal response during stimulation at the preganglionic level, direct stimulation of the postganglionic neuron produces responses equal to or greater than those seen in controls.22 Whether this occurs in humans is unknown. However, these findings suggest that endocardial AVNS may be equally or even more effective in heart failure patients.
Moreover, inotropic drugs or beta-blockers are expected to influence the AVNS threshold, and further extensive analyses should be performed to test AVNS efficacy in different settings. Nonetheless, in our preliminary study performed in heart failure patients,6 no significant interaction between beta-blockers and AVNS efficacy was observed.
Study limitations
In the present study, we tested AVNS delivered during the EARP with a fixed burst duration of 180 ms and did not find that atrial arrhythmias were induced, except for one case of AF during the mapping procedure. In this case, the burst may have been delivered outside the refractory period, and shortening the burst length might have prevented induction of the arrhythmia. However, we did not investigate the relationship between burst duration, AVNS efficacy, and the potential induction of atrial arrhythmias or the effects of AVNS on the length of atrial arrhythmia episodes.23, 24
Because Soos et al25 showed that vagal stimulation exerts maximal effects in the range from 40 to 50 Hz, we tested only the 50-Hz pulse rate, which is available in standard pacemakers and implantable defibrillators. In addition, we did not test voltages higher than 10 V or multiple-impulse waveforms; therefore, we cannot exclude the possibility that values outside of the ranges tested may yield different results in terms of efficacy, symptoms, or arrhythmic risk.
Clinical implications
The possibility of using a single, adequately positioned lead to deliver two therapies, atrial pacing and AVNS for AV nodal conduction modulation (i.e., a sort of inverse ventricular pacing), could represent a new therapeutic strategy for device-based management of some clinical arrhythmic patterns. This therapeutic approach may have clinical advantages in patients who could potentially benefit from rate control therapy as an alternative to irreversible complete AV ablation and subsequent pacemaker dependency. Heart failure patients with AF especially would benefit from AVNS. Clinical experience in such patients suggests that AF may be triggered by periods of volume overload.26 Alternatively, it is possible that AF events initiate periods of hemodynamic deterioration, which recent data suggest may occur more often than previously suspected.26 In addition, in patients with implantable defibrillators, AV nodal conduction modulation by AVNS could facilitate the differentiation of atrial tachycardias from ventricular arrhythmias, thus permitting the reduction of inappropriate shocks, which have been shown to impact heavily on mortality,27 quality of life,28 and overall device longevity.
Conclusion
Endocardial posteroseptal right atrial burst AVNS through a permanent endocardial lead enables reduction of ventricular rate during AF. Burst AVNS delivered during SR allows optimal lead positioning for AVNS, without inducing arrhythmias. These results provide further evidence for the development of device-based control of ventricular rate during AF. However, further studies are warranted to investigate the efficacy of long-term AVNS in humans.
Acknowledgment
We thank Tiziana De Santo (Clinical Service Team, Medtronic Italy) for careful statistical analysis of the data.
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A. Della Scala, Dr. Valsecchi, S. Canonaco, and Dr. Kornet are employees of Medtronic, Inc.,
PII: S1547-5271(10)00060-3
doi:10.1016/j.hrthm.2010.01.029
© 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
