Cardiac Resynchronization Therapy using Left-Bundle-Branch Area and Left Ventricular Pacing

Background: Cardiac resynchronization therapy via biventricular pacing is an established therapy for patients with heart failure. However, high nonresponder rates and inability to predict response remains a challenge. Recently left bundle branch area pacing (LBBAP) has been shown to be feasible and may also improve clinical outcomes. In this article we describe the new technique (sequential LBBAP followed by left ventricular pacing, LOT-CRT) and assess the feasibility of LOT-CRT. Methods: The RV implantation site was positioned and the LBBAP lead was implanted using our methods. The QRS duration (QRSd) at baseline, during LBBAP, biventricular pacing, and LOT-CRT was measured. Results: LOT-CRT was successful in 5 patients (age 71.8 ± 5.1 years, men 3, ischemic 3). The QRSd at baseline was 158.0 ± 13.0 ms and signicantly narrowed to 117.0 ± 6.7 ms during LOT-CRT (P < 0.01). During 3-month follow-up, LV ejection fraction improved from 32.8 ± 5.2 % to 45.0 ± 5.1% (P < 0.01), and New York Heart Association functional class changed from 3.25 ± 0.5 to 2.5 ± 0.6 (P < 0.05). A decrease in left ventricular end-diastolic dimension was observed, with widening from (68.2 ± 12.3) mm at baseline to (62.2 ± 11.3) mm at pacing (P < 0.05). The length of operation time was (152.0 ± 31.1) min. Conclusions: The study demonstrates that LOT-CRT is clinically feasible in patients with systolic HF and LBBB. LOT-CRT was associated with signicant narrowing of QRSd and improvement in LV function, especially in patients with ischemic cardiomyopathy. In patients with LBBB and cardiomyopathy, LOT-CRT resulted in signicant electrical resynchronization in these patients. In our study, which included 60 % of patients with severe ischemic cardiomyopathy, LOT-CRT resulted in high clinical and echocardiographic response rates. Our results indicated that those patients with LBBB and higher overall scar burden might be the desired candidates of LOT-CRT.


Background
Cardiac resynchronization therapy (CRT) via biventricular pacing (BVP) is known to improve clinical outcomes, and decreases all-cause mortality, particularly in patients with left bundle branch block (LBBB), and reduced left ventricular function [1] , [2]. Permanent His bundle pacing (HBP) has been shown to overcome LBBB, and is being considered as a viable alternative to BVP in patients requiring CRT [3]. However, HBP may be associated with high pacing thresholds to capture the distal His bundle and/or correct LBBB [4].
Recently several groups have shown the feasibility of left bundle branch area pacing (LBBAP) as an alternative choice to HBP in patients with LBBB by pacing the LBB region beyond the block site with a stable threshold and narrow QRS duration (QRSd) [5][6][7]. However, it is unknown whether the clinical e cacy of LBBAP with an appropriate AV delay would be the same as or better than LV epicardial pacing or cardiac resynchronization therapy.
We hypothesized that electrical resynchronization measured by narrowing of the QRS complex can be accomplished more effectively by LBBAP followed by sequential LV pacing (LBB-Optimized LV pacing, LOT-CRT). The aim of our study is to assess the feasibility and e cacy of LOT-CRT to improve electrical resynchronization in patients qualifying for CRT and evaluate clinical and echocardiographic response rates.

Methods
This study was approved by Ethics Committee of Xinhua Hospital A liated to Shanghai Jiao tong University School of Medicine (approval number: XHEC-D-2020-148) and performed in accordance with the Declaration of Helsinki.

Patient's selection
Patients with chronic LBBB by Strauss criteria [8], optimal medical therapy-refractory New York Heart Association (NYHA) class III to IV heart failure(HF) symptoms and a baseline left ventricular ejection fraction (LVEF, calculated by Simpson method) ≤ 35% were enrolled in Shanghai Xinhua Hospital from April 1, 2019 to June 1, 2020.
Patients were excluded if they had a history of previous valve intervention, end-stage renal disease, previous heart transplantation, left ventricular assist device, metastatic cancer, moderate or severe valve disease, life-expectancy less than 1 year.
All patients submitted written informed consent and demonstrated an understanding of LOT-CRT as a nonstandard approach to achieve physiologic pacing, and their data were analyzed prospectively.

Procedural Details
The RV de brillator lead was rst implanted in the RV to provide backup ventricular pacing should the patient develop transient complete atrioventricular block during the LBBAP lead placement. Subsequently, the LV lead was implanted in the standard fashion targeting sites with maximal LV delay. Then, LBBAP was performed using the Select Secure pacing lead. The uoroscopy duration for the entire procedure, LBBAP lead implant and LV lead implant were separately recorded.
Once this site is identi ed, the pacing lead is advanced deep into the septum while monitoring unipolar pacing impedance, electrogram characteristics and paced QRS morphology.
Additionally, the lead orientation can be displayed in various projections. During the initial LBBAP lead xation, if the lead torques back, it will mean that the lead and sheath are not oriented orthogonal to the RV septum. Generally, the sheath and the lead are oriented such that the lead is pointing towards 12-1 O'clock direction right anterior oblique 30° view and 2-3 O'clock direction in left anterior oblique 30° view [14].
In addition to uoroscopic views, signi cant rise in unipolar pacing impedance above 900 Ohms would suggest that the lead is directing to an oblique direction and need re-oriented. If several attempts were made to achieve LBBAP, prior sites were tagged in the mapping system or uoroscopic view to prevent re-engaging in the same site. Once the lead position was nalized, 1-2 ml of contrast was injected through the delivery sheath to visualize the septal wall and the approximate depth of the lead under left anterior oblique uoroscopic view.

Device Connection and Programming
In patients with normal sinus rhythm undergoing CRT-de brillators, the LBBAP lead was connected to the pace-sense portion of RV port and a bipolar LV lead in the LV port. The pace-sense portion of the spliced ICD lead (DF-1) was capped. In patients with normal sinus rhythm undergoing CRT-pacemakers (P), the LBBAP lead was connected to the RV port and the LV lead to the LV port.

Implant Measurements
The pacing output required to maximally narrow the QRS (BBB correction threshold) and LBB capture threshold (without BBB correction) was assessed and recorded at a pulse width of 1.0 ms. The QRSd at baseline, during LBBAP, BVP (via RV de brillator lead, when available) and LBB-Optimized LV pacing were measured on the EP recording system at 100 mm/s. The interval from the onset of QRS to the maximal de ection of LV electrogram (LVAT) during native LBBB pacing and during LBBAP was documented.

Clinical follow-up
Patients were seen for routine clinical follow-up at standard time periods (every 3 months). Functional status was assessed by NYHA classi cation. Device thresholds were checked and adjusted as needed to maximize battery longevity. The pacing threshold, impedance and R wave amplitude were measured. According to previous literature [15], the high pacing threshold was de ned as pacing threshold over 2.5 V/0.4 ms, increased threshold over 1.0 V compared with the baseline after the procedure and at follow-up. Echocardiographic indices, including LVEF, LV end-diastolic dimensions, pulmonary artery systolic pressure were recorded pre-implant and at follow-up.

Statistical analysis
Continuous variables were given as mean ± SD or median. Paired comparisons were made using a Student t test if the data were normally distributed, and with the Wilcoxon signed-rank test for nonparametric data. Paired categorical data (NYHA functional class) were compared using the Wilcoxon test. P ≦ 0.05 was considered signi cant.

Results
Seven out of the 12 screened patients were excluded from the study according to the exclusion criteria. Consequently, 5 patients were registered into the LOT-CRT cohort.
Baseline characteristics Among 5 patients, three patients (60%) were male. All patients had cardiomyopathy (2 with nonischemic and 3 with ischemic), and 2 patients had paroxysmal atrial brillation. Hypertension was present in all the patients. The mean age was 71.8 ± 5.1 years, and the baseline characteristics of patients are provided in Table 1. The baseline LVEF and the baseline QRSd with LBBB were 32.8 ± 5.2 % and 158.0 ± 13.0 ms respectively ( Figure 1A).

ECG characteristics and pacing parameters
Individual electrocardiographic responses to RV, LV, and LBBAP at the time of implantation are shown in Table 2  The mean follow-up time was 296 ± 201 days. Overall, LBBAP capture threshold, R-wave amplitude, and lead impedance were 0.74 ± 0.25 V, 13.36 ± 5.23 mV, and 533.73 ± 32.31 Ω during 1-month follow-up (P > 0.05, respectively, between at the time of device implantation and at the follow-up visit). During LOT-CRT, QRSd was stable and no signi cant difference was observed between at the 3-month follow-up visit and at the time of device implantation (P > 0.05). The ventricular pacing rates were 99%. The latest success rate was 100%. No patients showed signs of dislodgement, loss of capture, infections, embolism, or stroke associated with the implantation.
Transthoracic echocardiogram (Figure2C) evaluation data at baseline and 1-month follow-up, 3-month follow-up were available in all 5 patients receiving successful LOT-CRT. As shown in Table 3, the left ventricular end-diastolic dimension (68.2 ± 12.3 mm vs.62.2 ± 11.3 mm, P=0.017) and LVEF (32.8 ± 5.2% vs. 45.0 ± 5.1%, P=0.008) were improved at the 3-month follow-up visit. The symptoms and the median NYHA classi cation score were improved signi cantly from 3.2 ± 0.45 to 2.4 ± 0.55 (P=0.016).  Anatomical de nition CRT using BVP (BVP-CRT) is as an integral part of the therapy for patients with HF with reduced LVEF and BBB, particularly LBBB [16]. However, up to a third of patients treated with BVP-CRT are still considered non-responders [17]. The reasons for BVP-CRT nonresponse are many but include LV scar burden and distribution, suboptimal LV stimulation site, sex, and limited electrical or mechanical dyssynchrony [18]. Patients with ischemic cardiomyopathy experience a similar response rate to BVP-CRT as their nonischemic counterparts [19]. However, higher overall scar burden, a larger number of severely scarred segments, and greater scar density near the LV lead tip portend an unfavorable response to BVP-CRT in ICM patients [20]. There is evidence that CRT is not salutary in patients with posterolateral scar[21].

Electrophysiological de nition
Permanent LBBAP is an effective form of physiologic pacing with high success rates in patients with intact His-Purkinje conduction [7]. . LOT-CRT offers the advantage to use the LV lead in addition to LBBAP in a potential scenario of progression of conduction disease.
In patients with LBBB and cardiomyopathy, LOT-CRT resulted in signi cant electrical resynchronization in these patients. In our study, which included 60 % of patients with severe ischemic cardiomyopathy, LOT-CRT resulted in high clinical and echocardiographic response rates. Our results indicated that those patients with LBBB and higher overall scar burden might be the desired candidates of LOT-CRT.

Limitations
First, it is time consuming. The duration of operation time was 152 ± 31 min, and the time of X-ray uoroscopy was 26.2 ± 5.9 min, both are longer than previous report (117 ± 48 and 16.4 ± 12.3 min) [7]. Second, this study includes a small sample in a single center. Third, this study had a short follow-up interval. We expect long-term favorable clinical bene ts. Furthermore, this study enrolled only 3 ischemic patients. Although this uncontrolled nonrandomized study does not provide su cient data to support this conclusion, we observed signi cant echocardiographic and clinical improvement in these patients with HF treated with LOT-CRT.

Conclusions
The study demonstrates that LOT-CRT is clinically feasible in patients with systolic HF and LBBB. LOT-CRT was associated with signi cant narrowing of QRS duration and improvement in LV function, especially in patients with ICM.

Consent for publication
Not applicable.

Availability of data and materials
Data are available from the corresponding author upon reasonable request due to privacy or other restrictions.

Funding
None.
Authors' contributions XFF was the study advisor. XFF and LCY designed the study. MY collected data and performed TTE. RZ analysed the data. XFF, RZ, BL, MY, YQH, and QFL performed the procedures. RZ was the main investigator and provided the rst draft. YGL critically revised the manuscript.XFF provided the nal draft. All authors read and approved the nal manuscript.