Comparison of first‐ and second‐generation leadless pacemakers in patients with sinus rhythm and complete atrioventricular block

The efficacy and safety of leadless cardiac pacemakers (LPMs) as an alternative to conventional transvenous cardiac pacing have been largely reported. The first generation of the MicraTM transcatheter pacing system (VR; Medtronic) was able to provide single‐chamber VVI(R) pacing mode only, with a potential risk of pacemaker syndrome in sinus rhythm patients. A second‐generation system (AV) now provides atrioventricular synchrony through atrial mechanical (Am) sensing capability (VDD mode).


| INTRODUCTION
Leadless pacemakers have been shown to be a feasible and safe option in selected patients. 1,2 Large registries have demonstrated a high implantation success rate, with complications rates in the first 2 months similar to those of transvenous pacemakers (4%-5%) but a significantly lower incidence of long-term complications and pacemaker revisions. [3][4][5] Electrical parameters have also been proven to be stable over time, providing an estimated battery life of approximately 12 years. 6 Several studies have shown the benefit of dual chamber pacing versus single-chamber pacing in patients with high-grade atrioventricular (AV) block on quality of life and hemodynamics, 7-11 but with no difference in mortality or cardiovascular events. [12][13][14] Dual chamber pacing is usually recommended in sinus rhythm patients with high-grade AV block to improve AV synchrony. The first generation of leadless pacemakers however only provided singlechamber ventricular rate responsive pacing.
A second generation of leadless pacemakers has then been developed-the Micra TM AV leadless Transvenous Pacing System (Medtronic, Minneapolis, MN, USA)-and released in 2020, with nominal programming in a ventricular-pacing atrial-tracking mode (VDD) using a proprietary algorithm designed to sense atrial mechanical (Am) contraction, as described in the MARVEL 2 study. 15 Previous studies have demonstrated that this accelerometerbased atrial sensing was feasible and significantly improved AV synchrony in patients with sinus rate and high-grade AV block. 15,16 In this study, we sought to compare the efficacy of first-and second-generation Micra TM leadless pacemakers, and to identify predicting factors for high AV synchrony.

| Study design and patient population
The first 400 consecutive patients with a leadless pacemaker implantation attempt in the CHRU of Tours (France) from July 2015 to May 2022 were retrospectively screened.
Patients were included in this study if their indication for pacemaker implantation was AV block with sinus rhythm. Patients with total ventricular pacing (Vp) < 20% and patients with persistent or permanent atrial fibrillation were excluded.
The AV group consisted of all consecutive patients with a Micra TM AV implantation attempt in the CHRU of Tours (France) from May 2020 to May 2022 meeting these criteria.
The VR group consisted of all consecutive patients with a Micra TM VR implantation attempt in the CHRU of Tours (France) from July 2015 to May 2020 meeting these criteria.
Baseline characteristics were collected from medical files on the date of admission and hospitalization records.
The study was conducted retrospectively, with no impact on patient care, in compliance with the Declaration of Helsinki.
The local ethics committee for human research approved the study protocol. All patients signed informed consent before inclusion.

| Implantation procedure
The implantation procedure was performed according to standard practice. 17 Patients were monitored for at least 24 h following the procedure, with continuous telemetry monitoring, and were discharged after clinical verification of the puncture site, electrocardiogram, chest radiography, and after ensuring the absence of pericardial effusion.

| Follow-up
After implantation, patient and device status were reported at discharge, at 1 month and then at least once a year. Data were censored at the time of the last known follow-up.
Clinical and electrical data were collected from consultation records, and electrical parameters were also collected from reviewing pacemaker interrogations.
Pacemaker settings were at the physician's discretion at first, and the programming strategy for optimizing AV synchrony in second-generation Micra TM was helped as of December 2021 by expert consensus programming guidelines issued by Medtronic.

| Outcomes
Total AV synchrony was defined as the sum of Am-Vs (spontaneous beats tracking an atrial mechanical contraction), Am-Vp (paced beats tracking an atrial mechanical contraction), and AV conduction mode

| Pacemaker syndrome
We sought to evaluate the incidence of pacemaker syndrome in those two groups. Pacemaker syndrome diagnosis was clinical, and defined as the appearance of several symptoms (fatigability, exertional dyspnea, palpitations, decrease in exercise capacity) following device implantation in patients with no synchrony between P waves and QRS complexes on follow-up electrocardiogram(ECG), with a complete reversal of symptoms upon restoration of significant AV synchrony.

| Statistical analyses
Analyses were performed using JMP software version 9.0 (SAS Institute Inc.  Survival curves were calculated using the Kaplan-Meier method. A two-tailed p < 0.05 was considered significant.

| Baseline characteristics and implantation
The first 400 consecutive patients implanted with a leadless pacemaker in our department were retrospectively screened. Among Baseline characteristics are displayed in Table 1. The two indications for pacemaker implantation were sinus rhythm with AV block and abnormal electrophysiological study. Sinus rhythm with spontaneous AV block was more frequent in the AV group than in the VR group (94% vs. 69%, p = 0.005). Among the 14 patients in the VR group that underwent an electrophysiological study, 11 presented with syncope and bifascicular block, and 3 presented with bifascicular block consecutive to transcatheter aortic valve replacement. All these studies were considered abnormal as they revealed a prolonged HV interval (≥70 ms).
There was no significant difference between the two groups concerning perioperative complications as two major perioperative complications occurred in the VR group and one in the AV group (p = 0.61). In the VR group, one patient had a pericardial effusion requiring urgent pericardiocentesis and ultimately was discharged alive after a short stay in the intensive care unit, and another had a major tricuspid valve dysfunction after the implantation which could also be linked to the prior conventional pacemaker extraction due to T A B L E 1 Baseline characteristics and implantation. device infection. In the AV group, one pericardial effusion occurred but didn't require pericardiocentesis and was closely monitored through repeated echocardiography.
One-year survival rate was similar in the AV and the VR group (87% vs. 85%, respectively, log-rank p = 0.38 ( Figure 1).
Chronic ventricular threshold elevation (>2 V) (4% vs. 4%, p = 1.00) and pacing-induced cardiomyopathy (2% vs. 4%, p = 0.61) incidence were low and comparable between the two groups ( Overall, VR and AV patients were comparable, apart from the former being older. One-year survival rates were similar in these two groups, as were Vp burdens. High AV synchrony was achieved in two-thirds of AV patients, while a minority was switched to VVI mode during follow-up because of poor A4 sensing (15%).
A preoperative E/A ratio on transmitral Doppler lower than 1.2 was found to be the only predictor of high AV synchrony in our cohort.
During the first year post-implantation, there was no pacemaker syndrome in the AV group, compared to five occurrences in the VR group.

| Atrial sensing and atrioventricular synchrony
In our study, total AV synchrony was excellent with a median AV synchrony at 79%, a ratio higher than the 70% considered in Micra TM AV registries and postapproval studies to mean high AV synchrony.
These results are in line with those of the MARVEL 2 Study. Arps et al. 18 achieved higher AV synchrony, but this may be explained by a much lower pacing burden in their cohort, with a 10% median pacing burden, and 66% of their patients paced less than 50% of the time.
This higher AV synchrony might therefore be mostly from preserved AV conduction.
More recently, Chinitz et al. 19 in the AccelAV study and its AccelAV Optimize substudy evaluated total AV synchrony in a cohort of 54 patients with complete AV block and sinus rhythm.
Their results on AV synchrony are close to our findings in patients with similar pacing indications. However, our study is the first to provide a control group to evaluate the benefit of increased AV synchrony with the second-generation Micra TM leadless cardiac pacemaker (LPM).
The influence of the Micra TM AV algorithm on AV synchrony was also studied in our Micra TM AV patients by evaluation of their tracking index. The percentage of synchronous contraction required to maintain the clinical benefit of AV synchronization over time is unknown but is probably not 100%. In our cohort, we arbitrarily considered that a high ratio of AV synchrony was achieved if more than 66% of paced QRS were triggered by the sensing of atrial mechanical contraction by the device.
In our study, 65% of AV patients had a tracking index higher than 66%, with a median tracking index of 78%. The fact that a high tracking index was obtainable in two-thirds of our patients supports the feasibility and efficacy of Micra TM AV programming strategy to improve AV synchrony.
Arps et al. also reported the evaluation of this tracking index, with a lower mean tracking index in their cohort at 45% on the first visit and 54% on the second visit. This index was higher in patients with a pacing burden > 50% (59% at the first visit, 70% at the second visit), comparable to those in our more frequently paced cohort. The reproducibility of these results in patients with high pacing burden is encouraging to support the efficacy of the Micra TM AV algorithm.
The main key to improving AV synchrony in patients implanted Simple guidelines have been recently issued by the manufacturing company to standardize the programming strategy.

| Predictors of atrioventricular synchrony
We found a mitral E/A ratio lower than 1.2 to be the only independent predictor of high AV synchrony.
Our echocardiographic findings need, however, to be analyzed with caution, as only half of our patients had preoperative E/A ratio evaluation, which is harder to interpret in the context of a complete AV block.
Kowlgi et al. 21 found that high atrial synchronous Vp was associated with smaller body indices, a lower proportion of congestive heart failure, and prior cardiac surgery. On the other hand, low atrial synchronous Vp was likely due to small A4-wave amplitude, high Vp burden, and inadequate device reprogramming.
Prior cardiac surgery in our study seemed more of a pejorative parameter. Although there was no statistically significant association, one patient in our cohort underwent cardiac surgery several months after Micra TM AV implantation, and in her case, AV synchrony decreased with a smaller A4-wave amplitude requiring a mode switch to VVI after the cardiac surgery.
Though other studies may be needed to determine predicting factors for high AV synchrony, this highlights the importance of preoperative clinical and echocardiographic evaluation in patients in which Micra TM AV implantation is considered, as it could rule-out patients who would not benefit from such a technology. 22 The echocardiographic assessment is already recommended in Medtronic guidelines, and patients with E/A higher than 1.5 were excluded from post-approval registries, but the application of this recommendation in a real-world setting may deserve to be systematized.

| Pacemaker syndrome
A key finding in our study is the absence of pacemaker syndrome in patients implanted with Micra TM AV, even when switched to VVIR due to poor atrial mechanical sensing. Conversely, in the VR group, five cases of pacemaker syndrome occurred within the first year postimplantation (11%).
Pacemaker syndrome is caused by a mistimed atrial contraction, occurring against a closed AV valve or too close to ventricular contraction leading to a loss of atrial contribution to the cardiac output, and may, therefore, depend on atrial contraction strength.
Patients with strong atrial contraction may be at higher risk of pacemaker syndrome, but also more likely to have better A4 signals, and therefore good AV synchrony in VDD mode. On the other hand, patients with weak atrial contraction may have lower A4 signals, and subsequently be at higher risk of poor AV synchrony in VDD mode, but may also be at lower risk of pacemaker syndrome due to the lower contribution of their atrial contraction to the cardiac output. Our results suggest that Micra TM AV is particularly relevant in preventing pacemaker syndrome, and therefore possible surgical reinterventions, as patients at higher risk may be protected by a good atrial sensing, while patients with poor atrial sensing might be at lower risk of developing this pacing-related complication. This will require confirmation in studies with a longer follow-up, even if pacemaker syndrome appears rapidly in most patients, usually during the first 6 months. 23

| Limitations
We acknowledge several limitations to our work. The main limitation of our study is inherent to its retrospective observational nature, prohibiting any conclusion for causality. as not having a high tracking index and are therefore considered in the 35% of patients who did not achieve high AV synchrony.
The only echocardiographic marker of atrial function available for evaluation in our cohort was the E/A ratio, while the amplitude of the A4 signal has been shown to also correlate with other markers such as atrial contraction excursion or atrial strain. 24 As these parameters were not routinely evaluated in our cohort, the E/A ratio cannot be recommended as the only echocardiographic evaluation to predict AV synchrony and other parameters may be of interest.
The definition of pacemaker syndrome was only clinical, as is usually the case, but this may lead to classification bias, missing other causes for symptoms wrongfully attributed to pacemaker syndrome.
The clinical improvement after restauration of AV synchrony included in our definition, however, strongly suggested the link between AV synchrony and reported symptoms.
Finally, while our study suggests some benefits towards the implantation of second-generation leadless pacemakers, the important cost differential (over €2500 in France) between the two generations of leadless pacemakers must also be considered when discussing the benefits and limits of each device.

| CONCLUSION
In sinus rhythm patients with chronic Vp for complete AV block implanted with an LPM, the addition of an algorithm tracking mechanical atrial contraction resulted in significant AV synchrony in most patients and was associated with no occurrence of pacemaker syndrome. Careful preoperative assessment may be required to select patients who would benefit the most from this technology.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.