Prospective evaluation of clinical safety and ecacy of left bundle branch area pacing in comparison with right ventricular sepal pacing

AVB ventricular block, LBB left bundle branch, LBBB left bundle branch block, LBBaP left bundle branch area pacing, branch block, septum pacing, sick sinus syndrome, are given as range), mean


Background
Pacemaker therapy has been used for more than half a century in patients with bradycardia arrhythmias.
Conventional right ventricular apical pacing (RVAP) is easily successful, good pacing parameters, and less lead dislodgement, but it is related to high risk for heart failure and atrial brillation [1,2] due to ventricular electromechanical dyssynchrony. Pursuit of alternate right ventricular pacing sites (septum or out ow tract) do not lead to ventricular synchrony and has not been con rmed to be superior to RVAP [3].
Cardiac resynchronization Therapy (CRT) based on biventricular pacing (BVP) can shorten the left and right ventricular delays and improve ventricular systolic function, however, approximately 30 and 40% of patients have no clinical bene t or no response to conventional biventricular CRT [4], moreover there was no signi cant improvement in cardiac function in patients with right bundle branch block (RBBB) [5], even leading to deterioration of cardiac function in patients with narrow QRS duration [6]. His bundle pacing (HBP) can maintain ventricular synchronized contraction via pacing the native His-Purkinje system directly, emerging as a viable alternative for CRT with physiological restoration of electrical synchrony [7].
However, there are still some challenges of HBP, including high capture thresholds, electrode dislocation and lower success rates particularly in patients with bundle branch block (BBB) or infranodal block [8,9].
Thus, left bundle branch area pacing (LBBaP) as another physiological pacing form was rstly proposed in 2017 [10]. Subsequently, the narrow paced QRS duration (QRSd), good ventricular mechanical synchrony and a low capture threshold of LBBaP has been con rmed by several studies [11,12]. However, the results of comparison of left ventricular (LV) function such as left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) between LBBaP and right ventricular pacing (RVP) were inconsistent in several studies [13,14]. In this study, we aimed to evaluate the clinical safety, e cacy and LV function of LBBaP compared to RVSP.

Study design
This study was performed in Xiangtan Central Hospital with consecutive pacemaker-indicated patients who received LBBaP or RVSP from February 2019 to May 2020, according to 2013 ESC/EHRA Guidelines on cardiac pacing. Exclusion criteria consisted of (a) previously implanted with cardiac devices (b) underwent cardiac resynchronization therapy (CRT) (c) moderate to severe valvular diseases (d) acute or old myocardial infarction (e) severe liver, kidney or lung dysfunction. All surgical methods were performed in accordance with relevant guideline [15] and hospital regulations. And the protocol of this prospective was approved by the Research Ethics Committee of Xiangtan central Hospital, and all patients had submitted written informed consent. Procedure LBBaP: Axillary vein angiography was performed through the left cubital vein to guide the axillary vein puncture (Fig. 1a). If this method failed, the loach guide wire(Merit Medical Systems. Inc.)was sent through the femoral vein to the left subclavian vein to guide the axillary vein puncture under X-rays ( Fig. 1b). Then, the 6-pole ventricular electrode Synaptic Medical was implanted into the right ventricle through the right femoral vein, of which the purpose was to provide protective pacing and to predetermine the His bundle region by intracardiac electrogram (EGM) with the 6-pole ventricular electrode and uoroscopic image (Fig. 2a). The C315 HIS sheath (Medtronic Inc., Minneapolis, MN) with the lead (model 3830, Medtronic Inc., Minneapolis, MN) was inserted into the His bundle region through the left axillary vein access under the guidance of position of the 6-pole ventricular electrode to mark the His bundle potential (Fig. 2a). Using the His bundle region as a marker, subsequently, the C315 sheath with the 3830 lead was advanced 1 to 1.5cm toward right ventricular (RV) apex in right anterior oblique (RAO) 30 projection (Fig. 2b). The morphology of QRS wave at baseline in LBBaP was shown in Fig. 3a. Unipolar paced QRS morphology in lead V1 appeared W-shaped at an output of 2V/0.42 ms, which was acted as the ideal point for lead implantation (Fig. 3b). Next, the pacing lead tip was screwed towards the left side of septum perpendicularly with 8 to 10 clockwise rotation. During the lead screwing process, the cathode ring of the lead was intermittently paced and the W-shaped "notch" morphology in V1 lead gradually shifted and nally disappeared and the paced QRS morphology changed from left bundle branch block (LBBB) to RBBB, and the lead advancement was stopped (Fig. 3b,3c,3d), and left bundle branch (LBB) could be recorded (Fig. 3e). At the same time, we closely monitored output threshold and pacing impedance to avoid septum lead perforation. The stimulus to peak left ventricular activation time (S-PLVAT) in lead V5 was also measured. Finally, successful LBBaP manifested as a paced QRS morphology of RBBB pattern with short QRSd, and S-PLVAT was no change with low and high output (Fig. 3f, 3g). In addition, LBB potential or premature ventricular contraction (PVC) originated from the left side of septum could be observed during the lead screwing procedure (Fig. 2b). Postoperative images of LBBaP and contrast injection through the sheath showed in Fig. 4. RVSP: The loach guide wire (Merit Medical Systems. Inc.) was sent to the right ventricular out ow tract (RVOT) through the left axillary vein access, and the C315 S10 sheath (Medtronic Inc., Minneapolis, MN) was inserted into the RVOT. Then, the guide wire and inner sheath was pulled out and slowly retracted the delivery sheath to the middle or low septum of the right ventricle. Next, the lead (model 3830, Medtronic Inc, Minneapolis, MN) was delivered through the sheath to the RV septum. Finally, the lead was screwed towards the middle site of ventricular septum perpendicularly with 4 to 6 clockwise rotation. The schematic representation of RVSP was shown in Programming Atrioventricular (AV) delay programming should be individualized for those patients with BBB. Before discharge, a series of sensed and paced AV delays, ranging from 100 ms to intrinsic PR interval in 10 ms increment, were tested for those patients until BBB appeared. AV delay was considered optimum when BBB was corrected and the QRSd was minimum Fig. 5. We routinely turned on the automatic AV search/VIP function in the remaining patients Date collecting and follow-up Baseline patient characteristics were collected at enrolment. ECG and intracardiac EGM pattern, QRSd, S-PLVAT, uoroscopy dose, procedure duration (de ned as the time from sterilization to the end of the operation) and imaging data were recorded during implantation. Pacing parameters (capture threshold, sensing amplitude and impedance) were recorded at implantation and during follow-ups.
Echocardiography were performed by specialists before implantation and during follow-up. The distance from the the onset of the QRS to the blood ow starting point of the left ventricular out ow tract (LVOT) was measured as aortic pre-ejection in interval (APEI), to the blood ow starting point of the RVOT as pulmonary pre-ejection interval (PPEI), and the absolute value of the difference between APEI and PPEI was de ned as the interventricular mechanical delay (IVMD). And interventricular dyssynchrony was considered present if IVMD was more than 40 ms. Intraventricular dyssynchrony was de ned as the septal-posterior wall motion delay (SPWMD) of more than 130 ms, which was measured by M-mode as the difference between the time of maximum displacement of the septum and the posterior wall of the left ventricle. Complications such as pocket infection, hematoma, and late lead dislodgment were monitored during follow-up visits. Pacing parameters would be tested at 1 month and several months (6 to 24) after operation. Echocardiography would be performed at several months (6 to 24) after operation.

Statistical analysis
The Shapiro-Wilk normal test was applied to verify whether the data followed a normal distribution. Categorical date were described as absolute number and percentage (%). Continuous variables were expressed as mean ± standard deviation or as median with interquartile range (IQR), as appropriate based on data distribution. The χ 2 test or Fisher's exact test was used for categorical data, as appropriate.
Continuous variables were compared with the use of the Student t test if the data were normally distributed, and with the Mann-Whitney U test or the Wilcoxon signed rank test for nonparametric data. A two-sided P-value < 0.05 was considered statistically signi cant. All statistical analyses were performed using IBM SPSS Statistics 26.

ECG and Echocardiography characteristics
A comparison of ECG and echocardiography parameters between the two groups at baseline and last follow-up are shown in Table 2. There was no signi cant difference in QRSd in both the two groups at native-conduction mode, and QRSd had also no difference between the LBBaP capture mode and the LBBaP native-conduction mode (P = .784). But ECG QRSd was much shorter in the LBBaP capture mode compared with that in the RVSP capture mode (108.47 ± 7.64 vs 130.63 ± 13.63 ms, P < .0001). Furthermore, we observed patients with LBBB (n = 5) in the LBBaP group and found that those QRSd was signi cantly narrowed (152.40 ± 6.34 vs 120.00 ± 1.58 ms, P = .001). On the other hand, no statistical differences were noted in paced QRSd between patients with recorded LBB potential and patients without LBB potential (107.42 ± 6.84 vs 110.79 ± 9.03 ms, P = .174).
IVMD at baseline was no difference in both the two groups (  Pacing electrical parameters and complications The comparison and variation trend of lead parameters (capture thresholds, R-wave amplitudes and pacing impedances) in LBBaP group and RVSP group were shown in Fig. 8. Compared with RVSP patients, LBBaP patients had lower capture thresholds at pulse width of 0.4ms (0.59 ± 0.18V vs. 0.71 ± 0.26V, P = 0.011) at implantation, but there was no difference between the two groups during follow-up (0.59 ± 0.21V vs. 0.57 ± 0.22 V, P = 0.673) and remained stable. R-wave amplitudes and pacing impedances did not differ between the two groups (P > .05) at implantation and during follow up, but the R-wave amplitude increased, pacing impedance decreased and remained stable over the follow-up time.
During the implantation procedure, acute lead dislodgement occurred in two patient in the LBBaP group during withdrawal of the sheath, one patient developed septal lead perforation in LBBaP group (see Additional le 1),and nally received RVSP instead. Other implantations such as pocket hematoma, loss of capture, lead removal, or late lead dislodgement were not observed.

Discussion
LBBaP is an other physiological pacing strategy that swiftly recruited the left ventricular His-Purkinje system by advanced actication of the LBB. The QRS duration is a characterization of ventricular activation time and has been accepted as a surrogate indicator for evaluating of ventricular electrical synchrony [16]. Our study shows that ECG QRSd was signi cantly shorter with LBBaP capture mode compared with the RVSP capture mode and did not prolonged in comparsion with native-conduction QRS duration, which represented better ventricular electrical synchrony resulting from LBBaP. This nding was consistent with other studies [17,18]. Signi cantly, as shown in our study, the paced QRSd in the RVSP group (130.63 ± 13.63 ms) was relatively narrow compared to those two studies, which was 154.80 ± 9.85 ms in Chen's study [17], 149.38 ± 19.40 ms in Sun's study [18]. One reason for this difference is that the pacing lead was located in the interventricular septum in our RVP group, while the pacing lead was located in the right ventricular septum or the apex in the other two studies. Another reason for the difference in results may be related to the different implantation methods of RVSP. In these three studies, active xation lead (model 5076; Medtronic Inc) was implanted into the right ventricular septum or apex, while we guided lead (3830, 69 cm, Medtronic Inc) to the middle of the right ventricular septum through delivery sheath (C315 S10, Medtronic Inc). The C315 sheath made the 3830 lead more perpendicular to the septum, and the lead could be screwed deeper into the septum than the 5076 lead. So, the paced QRSd of the RVSP group in our study was similar with the mid-septal pacing (Mid-SP) group (127.20 ± 15.36 ms) in Chen's study [17] and narrower than those of the RVSP group in the three studies. Meanwhile, we optimized AV delay, especially in patients with BBB, to make the paced QRS duration more shorter and to achieve better ventricular electrical synchronization. Interestingly, LBB potential can be recorded during the LBBap implantation procedure, an indication of direct LBBaP [19], but not all LBBaP can observe LBB potential. Our study showed that approximately 68.9% of implants can record LBB potential, which was identical to other studies (60-80%) [11,17,20]. S-PLVAT in V5 lead and paced QRSd were similar in patients with vs without LBB potential recorded in the LBBaP group in our study, which was consistent with Chen's [17]and Cai's results [20], but contradictory with Hou's result [11]. The speci c reasons for this difference are unknown and may be related to the different diagnoses of the included patients, so large sample size and randomized multicenter study with longer term follow-up is needed to obtain conclusive evidence. However, since pacing is intended to correct conduction disease or stimulate the bundle branch to produce rapid conduction with normal or near-normal electrocardiogram, it may not be necessary to record LBB potential, which is consistent with Chen's view [17]. Consequently, Surgical method of LBBaP reported by Zhang JM et al without the guidance of intracardiac electrograms proved to be effective [21].
As is known to all that good ventricular electric synchrony associated with a narrow QRSd leads to good ventricular mechanical contraction synchronization [22,23]. Indeed, subsequent studies have con rmed that LBPaP has better ventricular mechanical synchronization than RVSP. The LV mechanical synchrony of LBBaP was proved to be superior to that of RVSP and to be similar to that of native conduction by using phase analysis of gated SPECT myocardial perfusion imaging in Hou's study [11], 2-D speckle tracking echocardiograph in Sun's study [13], real-time three dimensional echocardiographic (RT-3DE) and tissue Doppler image (TDI) in Cai's study [20]. Our study also demonstrated this result by measuring IVMD and SPWMD. Therefore, LBBaP maintained a good LV electrical-mechanical synchrony, which was similar to normal conduction and signi cantly superior to RVSP.
Theoretically, LV function in patients with LBBaP should be superior to that in patients with RVSP because of LV electrical-mechanical synchrony in LBBaP group was signi cantly better than RVSP group.
Das's study [24] and Zhang' study [14] showed that LBBaP is associated with better LV function (higher LVEF and lower LVEDD, P < .05) during short-middle term follow-up in comparison to RVAP. However, no statistical difference existed in LVEDD and LVEF between the LBBaP and RVSP groups during middleterm follow-up in our study, which were identical to other short term follow-up studies [13,20]. One possible reason for this difference is that patients enrolled into the two studies were different, patients with BBB or AV block were enrolled into Das's study [24] and patients with AV block were enrolled into Zhang's study [14], resulting in most of patients with high ventricular pacing ratio. By subgroup analysis, our study also showed that LV function is better (higher LVEF and lower LVEDD, P < .05) in the LBBaP-H group compared with the RVSP-H group. For those LBBB patients with heart failure, nonrandomized clinical trials have demonstrated that CRT delivered with LBBaP can correct LBBB and signi cantly improve LV function, even better than CRT based on BVP [25][26][27]. Hence, we think that LBBaP may be an option for pacemaker-indicated patients requiring a high ventricular pacing ratio, complicated with heart failure or associated BBB.
In our study, the success rate of LBBaP was 88.2%, which was similar to the success rate (80.5%-100%) of LBBaP in previous studies [11,13,20]. The LBBaP failed in six patients, in two cases, the 3830 lead was pulled which dislocated the lead when removing the C315 delivery sheath. In other three cases, we tried three times and failed to position the lead in the left side of the septum. One patient developed septal lead perforation with a sudden loss of capture and a decrease in lead impedance from 780Ω to 350Ω. The main challenge of LBBaP is to place the lead deep enough in the septum to ensure capture of the LBB, yet not too deep to avoid acute or delayed perforation. Recent documents proposed several methods to monitor lead depth: fulcrum sign, sheath angiography, impedance monitoring, changes in the QRS notch in V1 lead, pacing from the ring electrode and observing xation beats (the ectopic beats of qR/rsR' morphology in V1 lead) [28]. Meanwhile, xation beats is a novel marker for reaching the LBB area. Other complications such as pocket hematoma, loss of capture, lead removal, or late lead dislodgement, ventricular septal coronary damage were not observed in both two groups. The recent study about acute myocardial damage secondary to implantation of lead for the LBBaP found that troponin T levels were signi cantly higher at 12 hours after LBBP surgery than before operation(96.45 ± 11.07 vs.16.59 ± 1.84 ng/L, p < .001)and the number of attempts was an independent risk factor related to the myocardial damage by correlation and regression analysis [29]. Whether the myocardial damage of LBBaP is more serious than that of RVSP, needs to be con rmed in prospective randomized clinical trials. At least, we should pay attention to the damage of ventricular septal coronary and excessive number of attempts should be avoided.
This study showed that the capture threshold with LBBaP was lower at implantation compared to RVSP, but there was no difference between the two groups during short-middle term follow-up and remained stable. R-wave amplitudes and pacing impedances did not differ between the two groups at implantation and during short-middle term follow up, but the R-wave amplitude increased, pacing impedance decreased and remained stable over the follow-up time. It may be that electrode tip of LBBaP causes more myocardial injuries, then excessive myocardial edema in the early stage made the electrode impedance high and R-wave amplitude low at implantation. When the edema was reduced, the impedance gradually decreased, R-wave amplitudes gradually increased and tended to be stable. Other studies also con rmed good pacing parameters for LBBaP [11,14,17].

Limitation
Several limitations should be mentioned. First, this is a non-randomized, a single-centre, observational study with a small sample size, therefore, the LBBaP surgery was not representative. Second, the followup time of patients in the two groups was not strictly limited, which may lead to bias of the results. So, randomized multicenter study with larger sample sizes, longer term follow-up is needed for conclusive evidence.

Conclusion
This study demonstrates the clinic safety and e cacy of LBBaP that produces better ventricular electrical-mechanical synchrony than RVSP and con rmed good, stable pacing parameters for LBBaP. Declarations were in charge of statistical analysis. XL drafted the manuscript; JZ, HH and MW revised and commented on the draft and overall responsibility. All authors read and approved the fnal manuscript.

Funding
This study was supported by Science and Technology Department of Hunan Province in China (2018SK52104).

Availability of data and materials
The dataset supporting the conclusions of this article will be available upon request to the corresponding author.
Ethics approval and consent to participate Our study was approved by the Ethics Committee of Xiangtan central Hospital. Written informed consent from every participating patient was obtained.

Consent to publish
Not applicable.  The implantation procedure of LBBaP. Fluoroscopic image of 6-pole RV electrode and its potential at IEGM were recorded. HB potential (the back arrow shows) was identi ed at IEGM and uoroscopic image of the 3830 lead and sheath position were recorded as a reference (a). Fluoroscopic image of LBB area was preliminarily con rmed.The 3830 lead implanted in LBB area successfully and LBB potential (the back arrow shows) can be seen at IEGM, and a paced QRS morphology of RBBB pattern with short QRSd was recorded (b). HB: His bundle; IEGM: intracardiac electrogram; LBBaP: left bundle branch area pacing; LBB: left bundle branch; RV: right ventricular Figure 3 The morphology of QRS wave at baseline (a) in LBBaP, change of the W-shaped "notch" morphology in The optimization of sAV and pAV delays. With the delay of sAV interval, the self LBBB pattern appeared. When the sAV was set at 100ms, the morphology of QRS wave in V1 lead was rSr type, and the QRSd was the narrowest (120ms), and LBBB was corrected (a). With the delay of pAV interval, the morphology of QRS wave changed from RBBB to LBBB. When the pAV was seted at 150ms, the QRSd was the narrowest