Resynchronization effects and clinical outcomes during left bundle branch area pacing with and without conduction system capture

Abstract Background Left bundle branch area pacing (LBBAP) includes left bundle branch pacing (LBBP) and left ventricular (LV) septal myocardial pacing (LVSP). Hypothesis The study aimed to assess resynchronization effects and clinical outcomes by LBBAP in heart failure (HF) patients with cardiac resynchronization therapy (CRT) indications. Methods LBBAP was successfully performed in 29 consecutive patients and further classified as the LBBP‐group (N = 15) and LVSP‐group (N = 14) based on the LBBP criteria and novel LV conduction time measurement (LV CT, between LBBAP site and LV pacing (LVP) site). AV‐interval optimized LBBP or LVSP, or LVSP combined with LVP (LVSP‐LVP) was applied. LV electrical and mechanical synchrony and clinical outcomes were assessed. Results All 15 patients in the LBBP‐group received optimized LBBP while 14 patients in the LVSP‐group received either optimized LVSP (5) or LVSP‐LVP (9). The LV CT during LBBP was significantly faster than that during LVP (p < .001), while LV CT during LVSP were similar to LVP (p = .226). The stimulus to peak LV activation time (Stim‐LVAT, 71.2 ± 8.3 ms) and LV mechanical synchrony (TSI‐SD, 35.3 ± 9.5 ms) during LBBP were significantly shorter than those during LVSP (Stim‐LVAT 89.1 ± 19.5 ms, TSI‐SD 49.8 ± 14.4 ms, both p < .05). Following 17(IQR 8) months of follow‐up, the improvement of LVEF (26.0%(IQR 16.0)) in the LBBP‐group was significantly greater than that in the LVSP‐group (6.0%(IQR 20.8), p = .001). Conclusions LV activation in LBBP propagated significantly faster than that of LVSP. LBBP generated superior electrical and mechanical resynchronization and better LVEF improvement over LVSP in HF patients with CRT indications.

activation pattern or synchrony, while LVSP produces a slower LV activation without direct recruitment of the conduction system. 4 The differences of electrical characteristics between LBBP and LVSP have been investigated. 5,6 Although LBBP has well been defined, 7 direct LBB capture may not always be achievable, especially when the operator limits the number of lead screw-in attempts or due to anatomical variation between patients. It remains unknown whether LVSP can provide clinical benefits similar to LBBP in HF patients. In the present study, we developed a practical technique to measure LV conduction time for assessing whether the pacing captured LBB or not. Therefore, the objectives of this study were to evaluate the therapeutic effects of LBBAP in HF patients with CRT indications and assess the electrical characteristics and mechanical resynchronization in LBBAP with a comparison between LBBP and LVSP.

| Patient selection
Twenty-nine consecutive patients with symptomatic HF and CRT indications were prospectively enrolled from July 2019 to June 2021.
All patients received standard medications for HF treatment for at least 3 months and conformed to the following inclusion criteria: LV ejection fraction (LVEF) ≤ 40%, QRSd ≥130 ms with LBBB or intraventricular conduction delay (IVCD).
The study protocol was approved by the hospital ethics committee and conformed with the Declaration of Helsinki. Informed consent has been obtained from each patient.

| Device programming and pacing optimization
In two patients in whom the LV lead was not successfully implanted due to the severe distortion of coronary vein or phrenic nerve stimulation, a dual-chamber pacemaker was implanted. For the patients with CRT-D, the LBBAP lead was inserted to the RV IS-1 connector port and the RV lead IS-1 connector pin was capped.
LBBAP was delivered using bipolar pacing.
After device implantation, 12-lead ECGs were recorded during different pacing modes including LBBAP with optimized AV interval (optimized LBBAP with AV delay sweeping from 80 ms to the intrinsic PR interval to determine the optimal AV interval) and LBBAP combined with LV pacing (LBBAP-LVP) based on V-V delay sweeping from −40 to 40 ms. Among patients in whom LBBP was achieved, optimized LBBP with an AV interval that produced the shortest paced-QRSd was applied. In patients who received LVSP, optimized LVSP and LVSP-LVP, whichever produced the shortest paced-QRSd was chosen as the final pacing mode ( Figure 1).

| Data collection and follow-up
Baseline data before enrollment were collected, including demographics, medical history, HF-related medications, plasma level of B-type natriuretic peptide (BNP), New York Heart Association (NYHA) classification, ECG parameters, echocardiogram parameters, and HF hospitalization.  At follow-up, intracardiac EGM and 12-lead ECG were simultaneously recorded at working outputs (3V/0.4 ms) of LBBAP and LVP in 27 patients with a LV CS lead. EGMs during LBBAP and LVP were analyzed to confirm LBBP or LVSP as following: The conduction time (CT1) from LBBAP to the activation detected by the distal electrodes of LV lead was compared with the interval (CT2) from LVP to the activation detected by the LBBAP lead electrodes ( Figure 2). If the value of CT2 minus CT1 (ΔC T ) was ≥20 ms, LBBP was assumed because the paced activation propagation through the conduction system is faster (a shorter CT1) than that through the myocardial tissue (a longer CT2) (Figure 2A). If the ΔCT was <20 ms, then the LVSP was further confirmed because the activation propagation time without the conduction system direct capture was similar between the LVSP to the LVP site and the LVP to the LVSP site ( Figure 2B).

| Statistical analysis
Normally distributed continuous variables were expressed as mean ± SD. Between-group comparisons and within-group comparisons were made using independent-sample T-test and paired-sample Ttest, respectively. Non-normally distributed continuous variables were expressed as median (interquartile range, IQR) and were compared using the Mann-Whitney U-test. Categorical variables were expressed as numbers and percentages, and were compared using the χ 2 test or Fisher's exact test. All tests were two-tailed and p < .05 was considered statistically significant. All statistical analysis was carried out by SPSS 25 (IBM Corp.). were all in the LVSP group (p = .017 vs. the LBBP group). There were no significant differences in other baseline data between the two groups (Supporting Information: Table S1). All 15 patients in the LBBP group received optimized LBBP, while 5 of 14 patients in the LVSP group received optimized LVSP and the remaining 9 LVSP-LVP.

| Electrical characteristics of LBBAP
ECG characteristics during intrinsic rhythm and different pacing modes at follow-up were shown in Figure 3A,B and Supporting Information: Table S2. The paced-QRSd and Stim-LVAT during optimized LBBP were significantly shorter than those in intrinsic rhythm (both p ＜ .001), and also significantly shorter than those during optimized LVSP (both p = .005 vs. during LBBP, respectively). In patients with optimized LVSP, the paced-QRSd and Stim-LVAT were significantly shorter than those during intrinsic rhythm (p = .001, p = .013, respectively). However, LVSP-LVP could further shorten paced-QRSd and Stim-LVAT (compared with those during optimized LVSP, p = .010, p = .129, respectively; compared with those in intrinsic rhythm, both p < .001).

| Echocardiographic mechanical synchrony during LBBAP
As shown in Figure 3C,D and Supporting Information: Table S2, there was no significant difference in TSI-SD and IVMD under intrinsic rhythm between the two groups (p = .133, .242, respectively). Compared with intrinsic rhythm, both the pacing modes of optimized LBBAP and LBBAP-LVP significantly shortened IVMD and TSI-SD. TSI-SD during optimized LBBP in the LBBP group was significantly smaller than that during optimized LVSP in the LVSP group (p = .003). In the LBBP group, TSI-SD during the optimized LBBP trended smaller than that during LBBP-LVP (p = .064). In the LVSP group, there was no significant difference in TSI-SD between optimized LVSP and LVSP-LVP. No significant difference in IVMD was observed between optimized LBBAP and LBBAP-LVP or between LBBP and LVSP. Supporting Information: Figure S1 showed the LV mechanical synchrony evaluated by TSI in two patients during different pacing modes.

| Clinical findings during follow-up
The average follow-up time was 17 (IQR 8) months. The proportion of ventricular pacing was 99.4 ± 0.6% (range 98% to 100%). As shown in  Table S3). All patients had at least one hospitalization for HF in the 1-year period before LBBAP. During follow-up, no patients in the LBBP group were hospitalized for HF, and two patients (one nonresponder and one moderate-responder) in the LVSP group experienced one HF hospitalization.

| Pacing parameters and procedure-related complications during follow-up
There was no significant difference in LBBAP capture threshold between postimplantation and at follow-up in both the two groups (Supporting Information: Table S4). No procedure related complications such as IVS perforation, lead dislocation, and obvious lead displacement were observed.

| DISCUSSION
The present study demonstrated a significant improvement in cardiac function and favorable clinical effects of LBBAP in patients with HF and CRT indications, which is consistent with previous findings. [10][11][12] Furthermore, the present study has several new findings. First, the study utilized intracardiac EGM to assess LV conduction time (CT) during pacing in addition to using LVAT and ECG morphology to further confirm LBBP and LVSP. The activation in the LV during LBBP propagated faster than that during LVSP. Second, LBBP provided better LV electrical and mechanical synchrony than LVSP. Third, the study found that the CRT response rate and the improvement of LVEF in the LBBP group were greater than those in the LVSP group.
Poor improvement in LVEF was mainly found in the patients with IVCD. fashion. In addition, the term of LBBAP has been adopted and the LBBP and LVSP share similar ECG characteristics at a certain level. Therefore, the difference in resynchronization therapy between LBBP and LVSP in HF patients at relatively long-term follow-up is still unknown. The present study utilized a practical technique of LV CT measurement to differentiate LBBP from LVSP, especially during follow-up. As a result, we were able to compare clinical outcomes between LBBP and LVSP, the two pacing modalities of LBBAP.

| Differences in electrical and mechanical synchrony and clinical effects between LBBP and LVSP
In the present study, we developed a unique technique using intracardiac EGMs recorded by the LBBAP lead and the LV CS lead to measure the LV CT between the two sites during pacing. The study found that the CT during LBBP was significantly shorter than that during LVP, suggesting the recruitment of the conduction system during LBBP while LVP generates activation that propagates slowly via myocardial tissue. On the other hand, the CT during LVSP was similar to that during LVP, suggesting that both have a slower activation propagation. By using paced QRS morphology, LVAT and LV CT, we were able to confirm LBBP and LVSP during follow-up and compare the clinical effects of LBBP and LVSP. Our findings in LV CT and ECG LVAT are consistent with previous findings that LBBP generates better LV electrical synchrony than LVSP. 4,14,15 In the study by Hou et al. 15 using single-photon emission computed tomography myocardial perfusion imaging to evaluate LV mechanical synchrony of LBBAP, it was found that LV mechanical synchrony in patients with a LBB potential were better than those without a LBB potential, suggesting that LBBP has better LV mechanical synchrony than LVSP. The present study also showed better LV synchrony during LBBP than that during LVSP though both LBBP and LVSP generated better LV mechanical synchrony than during intrinsic rhythm. Both LBBP and LVSP, whether combined with LVP or not, had similar improved IVMD, implying that the Superior LV electrical and mechanical synchrony during LBBP may explain the results of the present study that showed a better improvement in LVEF and a higher super response rate with LBBP than with LVSP. Better implantation tools and techniques should be developed to achieve a high success rate of LBBP.

| Achieving optimized LBBP and LVSP
In the LBBP group, optimized LBBP was utilized in all patients by choosing an appropriate AV delay, which resulted in super response to CRT in all patients. This result was likely due to the restoration of the native LV conduction system and physiological LV synchrony, as well as the fusion of LV activation with the native right ventricular activation.
Surprisingly, our study found that the LV TSI-SD during LBBP appeared better than LBBP-LVP, suggesting that adding LVP to LBBP (LOT-CRT 12 ) may not be needed in patients with LBBB. This is because LBBP can fully restore the functionality of the LBB. In patients with LVSP (the LVSP group), pacing options include (1) optimized LVSP, or (2) LVSP-LVP which could achieve further shortening of QRSd in some patients. The present study found that some patients with optimized LVSP could also experience super response. The explanations may include (1) LVSP with a relatively narrow QRSd and short LVAT may have a delayed recruitment of the conduction system or (2) the slow conduction through IVS in patients with LBBB could be bypassed by LVSP. 16 The study also observed that some of these patients with LVSP-LVP still showed only moderate or no CRT response, especially in the patients with IVCD. In the His-SYNC study, His-CRT did not show significant advantage over biventricular pacing-CRT (BiVP-CRT). 17 One of the main reasons was that His-CRT could not obtain resynchronization in patients with IVCD. IVCD suggests not only diffuse intraventricular conduction disturbance, but also myocardial disease. CRT for patients with IVCD still needs investigations. Prospective, randomized studies in a large and broad HF population should be conducted to determine the superiority of optimized LBBAP or LBBAP-LVP over BiVP-CRT in patients with CRT indications.

| LIMITATIONS
First, this is a single-center, observational study. The comparison between LBBP versus LVSP in a nonrandomized fashion with a small sample size could lead to inclusion bias, which could also have an impact on the comparison of the baseline data and CRT response rate of the two groups. HF patients with LBBB and IVCD were all enrolled in the present study, which made the study cohort some heterogenous.
While the present study used the existing LBBP criteria and new LV conduction time measurement to differentiate LBBP from LVSP, further validation in more patients is needed. Moreover, an additional LV pacing lead doesn't seem to be necessary for patients with direct LBB capture and LBBP-LVP was not performed. However, because BiVP is recommended by current guidelines for patients with CRT indications and the safety and effectiveness of LBBP need to be further verified. Therefore, LV pacing lead was implanted as a backup.
Although the present study showed that the electrical and mechanical resynchronization of LBBP-LVP was not superior to that of optimized LBBP, further investigations are needed to determine whether LBBP-LVP can provide additional therapeutic benefits. Besides, the success rate of LBBP in this study was around 60%, which might be due to the enrollment of patients with IVCD in the study cohort and the limitation of the number of lead screw-in attempts.

| CONCLUSIONS
The present study found that LBBP had superior electrical and mechanical synchrony and clinical effects over LVSP in HF patients with CRT indications. Importantly, the present study utilized the measurement of LV conduction time, which can enhance the current LBBP criteria to differentiate LBBP from LVSP. Furthermore, the study suggests that optimized LBBP is an effective CRT in HF patients with LBBB in whom LBBP-LVP may not be necessary. Moreover, LVSP can be an alternative when LBBP cannot be achieved, and LVSP-LVP should be considered if LVSP-LVP generates narrower QRSd.