Outcomes of left bundle branch area pacing compared to His bundle pacing and right ventricular apical pacing in Japanese patients with bradycardia

Abstract Background His bundle pacing (HBP) and left bundle branch area pacing (LBBAP) emerge as better alternatives to right ventricular apical pacing (RVAP) in patients with bradycardia requiring permanent cardiac pacing. We aimed to compare the clinical outcomes of LBBAP, HBP, and RVAP in Japanese patients with bradycardia. Methods A total of 424 patients who underwent successful pacemaker implantation (HBP, n = 53; LBBAP, n = 75; and RVAP, n = 296) were retrospectively enrolled in this study. The primary study endpoint was the cumulative incidence of heart failure hospitalization (HFH) during the follow‐up. Results The success rate for implantation was higher in the LBBAP group than in the HBP group (94.9% and 81.5%, respectively). Capture threshold increase >1V during the follow‐up occurred in the HBP and RVAP groups (9.4% and 5.1%, respectively), while it did not in the LBBAP group. The cumulative incidence of HFH was significantly lower in the LBBAP group than the RVAP (adjusted hazard ratio, 0.12 [95% confidence interval: 0.02–0.86]; p = .034); it did not differ between the HBP and RVAP groups (adjusted hazard ratio, 0.48 [95% confidence interval: 0.17–1.34]; p = .16). Advanced age, mean percent right ventricular pacing (per 10% increase), left ventricular ejection fraction <50%, and RVAP were associated with HFH. Conclusions Compared to RVAP and HBP, LBBAP appeared more feasible and effective in patients with bradycardia requiring permanent cardiac pacing.


| INTRODUC TI ON
Permanent cardiac pacing is the most effective treatment for patients with chronic high-degree atrioventricular block (AVB) and symptomatic sick sinus syndrome.Right ventricular apical pacing (RVAP) has been widely used for these patients.However, RVAP causes electronic and mechanical dyssynchrony, associated with an increased risk of heart failure. 1 Although different right ventricular (RV) site (e.g., the septum and outflow tract) pacing had been attempted to overcome these limitations, meta-analyses have not demonstrated the superiority of alternative RV pacing to RVAP. 2,3][6][7][8][9][10] His bundle pacing (HBP) has demonstrated its feasibility and clinical benefits compared with RAVP. 4,5Despite these advantages, HBP has some limitations in terms of technical aspects (e.g., relatively lower procedural success rates and a high and unstable pacing threshold in 5% to 10% of patients). 4,5On the other hand, left bundle branch area pacing (LBBAP) emerges as a new physiological pacing therapy that can generate a comparably narrow-paced QRS complex and left ventricular activation with a low, stable pacing threshold. 6The collective term "LBBAP" encompasses left bundle branch pacing (LBBP), left fascicular pacing (LFP), and left ventricular septal pacing (LVSP). 7is categorization arises from challenges in differentiation and the limited clinical data highlighting their differences.Previous studies reported that LBBP was superior to LVSP in enhancing pacing characteristics, such as LVAT and QRS duration. 8,9LVSP was not part of the success criteria for LBBAP in initial studies, [10][11][12][13][14][15][16][17][18][19] while the latest consensus document has included LVSP for LBBAP. 74][15][16][17][18][19][20] Although previous studies compared clinical outcomes between LBBAP and HBP, little data are available regarding the feasibility and efficacy of LBBAP in Japanese subjects.Therefore, the current study sought to investigate the clinical outcomes of LBBAP compared with HBP and RVAP in Japanese patients with bradycardia requiring permanent cardiac pacing.

| Study population
This was a retrospective, observational study at Kokura Memorial Hospital, Kitakyushu, Japan.From June 2018 and June 2021, a total of 481 consecutive patients underwent de novo permanent pacemaker implantation for bradycardia indications. 21In the present study, we retrospectively sought to enroll patients undergoing RVAP, HBP, and LBBAP among them.The choice of pacing technique (i.e., RVAP, RV septum pacing, HBP, or LBBAP) was determined based on the operator's professional judgment.Patients with (1) ≤20 years old, (2) RV septum pacing, (3) leadless pacemaker implantation, (4)   implantable cardioverter defibrillator implantation, or (5) cardiac resynchronization therapy were excluded.The research protocol received approval from the ethics committee at Kokura Memorial Hospital and adhered to the principles outlined in the Declaration of Helsinki.Written informed consent was waived because of the retrospective study design.This study was registered with http:// www.umin.ac.jp, unique identifier UMIN000053252.

| Procedures
Right ventricular apical pacing was performed in a standard fashion; RV leads were implanted at the RV apex using a hand-shaped style.
7]10,11 HBP was utilized to position the sheath at the base of the tricuspid annulus in the right ventricle.Screw-in was performed at the location where the His bundle potential was detected on the unipolar lead.A successful HBP was determined by the detection of the His bundle potential without surpassing a pacing capture threshold of 3.5 V/0.4 ms or 3 V/1 ms.If failed, RV septum pacing was undergone.We defined selective HBP when the QRS waveform appeared with latency from the pacing spike on the 12-lead ECG and nonselective HBP when it did not. 22 the other hand, LBBAP involved positioning the sheath 1.5-2 cm distal to the His bundle in preparation for screw-in.When targeting the left ventricular septum, we monitored the pacing waveform in V1 lead and observed a transition from "W" waveform to "rSR" or "QR."For depth verification, contrast was injected through the sheath.The R-wave peak time in V6 (V6RWPT) was assessed in a 12-lead electrocardiogram just after the procedure. 7Notably, V6RWPT represented the interval from the onset of the pacing spike to the peak of the R wave in the V6 lead. 22Successful LBBAP was characterized by the emergence of R waveforms such as "rSR," "qR," "QR," and "Qr" in the V1 lead.Moreover, if the intrinsic QRS was either normal or right bundle branch block (RBBB), V6RWPT of ≤85 ms was required.In instances where the intrinsic QRS had conduction disturbances other than RBBB, V6RWPT of ≤100 ms was necessary.For a specific LBBP classification, the V6RWPT was defined as ≤75 ms if the intrinsic QRS was normal or RBBB, or ≤80 ms if other conduction disturbances were evident. 7Patients who did meet the criteria of LBBP were categorized as LVSP.In cases where LBBAP was unsuccessful, RV septum pacing was performed.

| Data collection and follow-up
Electrical performance (e.g., pacing capture thresholds, pacing impedances, sensed R-wave amplitudes, and %RV pacing) was assessed at outpatient visits at 1, 3, 6, and 12 months and then yearly postimplantation or via remote monitoring devices when feasible.Percent RV pacing was determined at the end of follow-up, censored to an earlier date if the primary outcomes occurred.Lead-related complications, including infection, dislodgement, loss of capture, and early battery depletion, were also tracked over the follow-up.Delta QRS duration means the difference between paced QRS duration and intrinsic QRS duration.Clinical follow-up data were systematically gathered from medical records or via telephone contact with the patients, their families, or referring physicians.Pacing-induced cardiomyopathy (PICM) was defined as left ventricular ejection fraction (LVEF) <40% or a necessity for biventricular pacing (BVP) upgrade. 23

| Study endpoints and definitions
The primary study endpoint was the cumulative incidence of heart failure hospitalization (HFH) during the follow-up.HFH was defined as an unplanned hospitalization for worsening heart failure or de novo heart failure events. 24The secondary endpoints included (1)   all-cause death, (2) cardiac death, (3) a need for BVP upgrade; and (4) major cardiovascular events (MACE; a composite of all-cause death, HFH, and a need for BVP upgrade).Also, we assessed the cumulative incidence of HFH between the CSP (LBBAP and HBP) and RVAP groups.Death was regarded as cardiac death unless other noncardiac death could be identified.

| Statistical analysis
Data are presented as median (lower and upper qualities) for continuous variables and number (percentage) for categorical variables.
Group comparisons were performed by the one-way analysis of variance or Kruskal-Wallis test for continuous variables, the chi-square test, or Fisher's exact test for categorical variables, as appropriate.
Cumulative incidence rates of study endpoints were estimated using Kaplan-Meier curves and compared by the log-rank test.Hazard ratios (HRs) with 95% confidence intervals (CIs) of ( 1

| Baseline clinical characteristics
The baseline clinical characteristics are summarized in Table 1.
Compared with the LBBAP and HBP groups, the RVAP group had a higher prevalence of prior atrial fibrillation (32.1% vs. 13.3% vs. prior HFH, LVEF, and medication at discharge did not differ among the three groups.

| DISCUSS ION
The main findings of the present study can be summarized as follows: (1)   1.

| Comparison of technical aspects between HBP and LBBAP
His bundle pacing is a physiological alternative to RVAP with improved clinical outcomes. 4However, successful HBP with an adequate capture threshold is more technically challenging than RVAP because of the much smaller potential target area for lead, so its procedural and fluoroscopy times are prolonged compared to the RVAP. 4 Consistently, the present study demonstrated that the HBP group had longer procedural and fluoroscopy times than the RVAP group.Although further improvement in devices and techniques might mitigate these limitations, it seems impossible to make procedural and fluoroscopy times for HBP shorter than those for RVAP.
In contrast, LBBAP has an obvious advantage over HBP in terms of technical aspects as follows: (1) the site of pacing can be positioned distal to the pathological or vulnerable region within the conduction system, and (2) it is easier to perform LBBAP than HBP owing to the reduced requirement for precision needed in lead placement. 6In the present study, the procedural and fluoroscopy times were comparable between the LBBAP and RVAP groups.Also, the technical success rate was higher in the LBBAP group than in the HBP group (94.9% vs. 81.0%), in line with previous studies. 7,26,27ven these results, LBBAP might be more feasible than HBP from a technical viewpoint.
TA B L E 3 Clinical events during the follow-up.The number of patients with event was counted until the end of follow-up.The cumulative 2-year incidence was estimated by the Kaplan-Meier method.HRs with 95% CIs of (1) the LBBAP group relative to the RVAP and HBP groups and (2) the HBP group relative to the RVAP group for the outcome measures were estimated throughout the entire follow-up period by the Cox proportional hazard models.

Outcomes
a Adjusted for the following variables: age, male gender, body mass index, atrioventricular block, hypertension, dyslipidemia, diabetes mellitus, left ventricular ejection fraction <50%, hemodialysis, prior arterial fibrillation, prior coronary artery graft bypass, prior percutaneous coronary intervention, prior heart failure hospitalization, and percent right ventricular pacing.Abbreviations: BVP, biventricular pacing; CI, confidence interval; HFH, heart failure hospitalization; HR, hazard ratio; MACE, major cardiovascular events; NA, not applicable.Other abbreviations as in Table 1.
F I G U R E 2 Cumulative 2-year incidence of heart failure hospitalization.Abbreviations as in Table 1.

| Complications associated with physiological pacing
Most complications associated with cardiac pacing occur in the periprocedural phase, but a sizable risk remains during the long-term follow-up. 289][30] Vijayaraman et al. 29 reported that His capture threshold increase >1V was noted in 12% of patients during 5-year follow-up; the need for lead revisions and generator change was higher in the HBP group than in the RVAP group (6.7% vs. 3.0% and 9.0% vs. 1.0%, respectively).In LBBAP, the lead is positioned slightly distal to the His bundle and is screwed deep within the left ventricular septum. 6These features lead to excellent results of electronic parameters (e.g., narrow QRS duration and stable pacing threshold).However, data on the long-term lead performance of LBBAP are still scarce.The current study demonstrated that threshold elevation >1V occurred in the HBP and RVAP groups, while it did not in the LBBAP group.Although these results suggested the advantage of LBBAP over HBP in real-world practice, further studies are warranted to assess the long-term safety and efficacy of LBBAP because of the shorter follow-up duration and relatively small study population.

| Clinical outcomes after physiological pacing
Chronic RV pacing potentially leads to dyssynchronous ventricular activation and subsequent LV dysfunction (i.e., PICM); PICM occurs in ≈12% of patients with chronic RV pacing, although with a significant range between studies. 31Physiological pacing such as HBP and LBBAP is a novel technique directly activating the specialized conduction system and has reduced all-cause mortality and HFH compared to RVAP. 4,11,12,30,31A recent meta-analysis reported that pacing parameters (capture threshold and R wave amplitude) might be better in LBBAP than in HBP. 32To date, however, there is little evidence comparing clinical outcomes between HBP and LBBAP.The present study demonstrated that (1) the LBBAP group showed a significantly lower incidence of HFH than the RVAP group, while the HBP group did not; (2) PICM contributed to 26.7% of HFH cases, although without any PICM cases in the HBP and LBBAP groups.Notably, in the present study, the cumulative incidence of HFH was not significantly lower in the HBP group than in the RVAP group; most HFH occurred in the HBP group beyond 1-year after implantation.These results might be explained by inherent limitations of HBP (e.g., HBP capture threshold increase in the chronic phase).In the current study, pacing failure attributable to an increased capture threshold constituted 50% of HFH cases in the HBP group.Furthermore, 17% of the HBP group comprised selective HBP, potentially leading to an elevated capture threshold when compared to the LBBAP group.
Although these findings might contribute to no significant differences in HFH occurrence between the HBP and RVAP groups, it is Abbreviation: %RV, percent right ventricular.Other abbreviations as in Table 1.
prudent to interpret our results with caution due to the relatively limited sample size of the HBP group.Yet, it is noteworthy that PICM did not occur in the HBP and LBBAP groups.Also, the CSP group had a lower incidence of HFH than in the RVAP group, which was in line with the previous study. 10These results highlighted the clinical advantages of physiological pacing over RVAP.

| Risk factors associated with HFH
Previous studies reported that baseline LV function, native QRS duration, RV pacing percentage, and paced QRS duration were primarily associated with the development of PICM. 1,31A mode selection trial reported that the cumulative percent RV pacing strongly predicted HFH in patients with sinus node dysfunction. 1 Consistently, the current study demonstrated that mean %RV pacing contributed significantly to the occurrence of HFH.Notably, despite the higher mean RV pacing rate than other groups, the LBBAP group had a protective impact on HFH compared with RVAP.Also, LVEF <50% was a risk factor for HFH in the current study, which was in line with previous studies. 33current guideline strongly recommends BVP in HF patients with LVEF ≤35%, QRS duration ≥150 ms, and LBBB irrespective of optimal medical treatment. 28However, a recent randomized controlled trial reported the superiority of LBBAP over BVP in LVEF improvement in patients with nonischemic cardiomyopathy and LBBB. 31Although these results should be interpreted with caution because of the small study population, LBBAP might emerge as a first-line approach in patients requiring cardiac pacing in the future, regardless of the baseline LV function.Further larger-scale, randomized studies are warranted to establish the optimal management of those patients.

| Limitations
The present study has several limitations.First, this study was a retrospective study; therefore, the sample size could not be calculated.
Although we performed multivariable Cox models to account for variations in baseline clinical characteristics across the three groups, the inherent potential for bias in this study is inevitable, which might influence the drawn conclusions.Second, the selection of the pacing system was left to operator's discretion.Also, HBP and LBBAP have been available since June 2018 and November 2019, respectively.Thus, the follow-up period of the HBP and LBBAP groups was shorter than the RVAP group.These findings might have biased the conclusions in the present study.Third, echocardiography was performed in 60.6% of cases during the follow-up, which might result in the underestimation of PICM incidence.Fourth, the current study included both selective and nonselective HBP cases.Fifth, we confirmed right bundle branch block in the V1 lead and short V6RWPT in the LBBAP group, while not recording the left bundle branch potential.Finally, extrapolation of our results outside Japan requires caution because this study population consisted solely of Japanese subjects.
) the LBBAP group relative to the RVAP and HBP groups and (2) the HBP group relative to the RVAP group for the outcome measures were estimated throughout the entire follow-up period by a multivariable Cox model.Multivariable models adjusted for the clinically relevant variables as follows: age, male gender, body mass index, AVB, hypertension, dyslipidemia, diabetes mellitus, LVEF <50%, hemodialysis, prior arterial fibrillation, prior coronary artery graft bypass, prior percutaneous coronary intervention, prior HFH, and percent RV pacing.Finally, we sought to identify potential risk factors for HFH by applying the multivariable Cox models, including 5 clinically relevant covariates (pacing mode [HBP, LBBAP, and RVAP], age, prior atrial fibrillation, LVEF [<50% or not], and mean %RV pacing). 1,22,25Statistical analyses for the study were conducted by two physicians (Drs Kono and Kuramitsu) utilizing R software version 3.5.2(R Foundation for Statistical Computing, Vienna, Austria).A twosided p-value of less than .05was deemed to indicate statistical significance.

Table 3
Baseline clinical characteristics.
Procedural and pacing characteristics.
frequently in the LBBAP group than in the HBP group, although without statistical significance; (4) PICM did not occur in the HBP and LBBAP groups; and (5) advanced age, mean %RV pacing (per 10% increase), LVEF <50%, and RVAP (vs.LBBAP) were associated with HFH.TA B L E 2Note: Values are median (lower and upper qualities) or number (percentage).Abbreviations as in Table Factors associated with heart failure hospitalization.
3 Cumulative 2-year incidence of heart failure hospitalization in patients with ventricular pacing >20%.Abbreviations as in Table1.TA B L E 4