Remarkable response to cardiac resynchronization therapy via left bundle branch pacing in patients with true left bundle branch block

Abstract Background Left bundle branch pacing (LBBP) has been suggested as an alternative means to deliver cardiac resynchronization therapy (CRT). Hypothesis LBBP may deliver resynchronization therapy along with an advantage over traditional biventricular (BiV) pacing in clinical outcomes. Methods Heart failure patients who presented LBBB morphology according to Strauss's criteria and received successful CRT procedure were enrolled in the present study. Propensity score matching was applied to match patients into LBBP‐CRT group and BiV‐CRT group. Then, the electrographic data, the echocardiographic data and New York heart association (NYHA) class were compared between the groups. Results Twenty‐one patients with successful LBBP procedure and another 21 matched patients with successful BiV‐CRT procedure were finally enrolled in the study. The QRS duration (QRSd) was narrowed from 167.7 ± 14.9 ms to 111.7 ± 12.3 ms (P < .0001) in the LBBP‐CRT group and from 163.6 ± 13.8 ms to 130.1 ± 14.0 ms (P < .0001) in the BiV‐CRT group. A trend toward better left ventricular ejection fraction (LVEF) was recorded in the LBBP‐CRT group (50.9 ± 10.7% vs 44.4 ± 13.3%, P = .12) compared to that in the BiV‐CRT group at the 6‐month follow‐up. A trend toward better echocardiographic response was documented in patients receiving LBBP‐CRT procedure (90.5% vs 80.9%, P = .43) and more super CRT response was documented in the LBBP‐CRT group (80.9% vs 57.1%, P = .09) compared to that in the BiV‐CRT group. Conclusions LBBP‐CRT can dramatically improve the electrical synchrony in heart failure patients with LBBB. Meanwhile, compared with the traditional BiV‐CRT, it has a tendency to significantly improve LVEF and enhance the NYHA cardiac function scores.

Later on, Zhang et al reported that LBBP was clinically feasible and effective in a small cohort of heart failure patients with LBBB. 6 Recently, several nonrandomized studies suggested that LBBP-CRT has some advantages in restoring electrical synchrony over BiV-CRT leading to better CRT response.
New criteria to define the presence of a "true" LBBB have been proposed by Strauss et al, which include a QS or rS morphology in V1 to V2, a duration ≥140 ms for men and ≥ 130 ms for women, along with mid-QRS notching or slurring in ≥2 leads among I, aVL, V1, V2, V5, and V6. 7 Studies had shown that patients with heart failure and LBBB met the Strauss's criteria had good response to BIV. More evidences are needed to confirm whether LBBP-CRT is superior to BIV-CRT in this special patient population. In this study, we evaluated the ability of LBBP to deliver resynchronization in patients with strictly defined LBBB and indications for CRT.

| Patient selection
This was a prospective, observational study. Heart failure patients presented LBBB morphology met Strauss's criteria, with left ventricular ejection fraction(LVEF) ≤35%, New York Heart Association (NYHA) functional class II to IV and successful CRT procedure in Xiamen Cardiovascular Hospital, Xiamen University from January, 2018 to December, 2019 were recruited in the present study. Since February 2018, LBBP was offered as an alternative choice for CRT in patients with typical LBBB in our center. The operator discussed the nonstandard but potentially more physiological pacing approach with the patients and obtained informed consent before the LBBP-CRT procedure. All the patients that received successful LBBP-CRT procedure were included. Patients who received successful BiV-CRT during the study period were selected as control by using 1 to 1 propensity score matching to minimize bias based on gender, etiology and LV enddiastolic diameter (LVEDD). Patients with previous pacemaker implanted, followed up irregularly or less than 6 months, and could not provide informed consent were excluded. The approval of the Ethics Committee of Xiamen Cardiovascular Hospital, Xiamen University was obtained prior to patient enrollment, and informed consent was obtained from all participants. The trial was conducted in accordance with the principles of the Declaration of Helsinki.

| Procedural details
In the LBBP-CRT group, the LBBP lead was implanted by a transventricular septal method in the basal ventricular septum as described elsewhere. 8 Briefly, the Select Secure pacing lead(model 3830, Medtronic Inc., Minneapolis, Minnesota) was introduced through a fixed curve sheath (C315 HIS, Medtronic Inc.) anteroseptally toward the His region to localize His potentials. Temporary His bundle pacing(HBP) was attempted to determine whether LBBB could be corrected. Then the lead was further advanced toward the cardiac apex by 1.0 to 2.0 cm and perpendicularly screwed in. The lead was finally fixed when the paced QRS morphology showed a "QR/Qr" pattern in V1, the stimulus to LV activation time (stim-LVAT) was the shortest and consistent during high and low outputs in V5 or V6, and the capture threshold <1.5 V@0.4 ms 9 . If the LBBP procedure was unsuccessful, traditional BiV-CRT was selected as an alternative pacing modality.
In the BiV-CRT group, a LV lead was positioned with standard technique in the lateral or post-lateral LV vein if possible. 10 RV defibrillator lead or pacing lead was implanted in the right ventricular apex and atrial lead was implanted in the right atrial appendage (RA) in patients with sinus rhythm.

| Device connection and programming
In the LBBP-CRT group, CRT-pacemakers (CRT-P) and CRTdefibrillators (CRT-D) were the first choice for implantation, while DDD or VVI implantation was selected as an alternative in patients with poor economic conditions on the late period of the study. The lead to device connection configurations are showed in Figure 1. All LBBP leads were programmed at tip unipolar pacing with output of 3.0 V@0.4 ms. In patients with sinus rhythm, the PAV/SAV was adjusted to synchronize LBBP with intrinsic right bundle branch conduction in the LBBP-CRT group，while the PAV/SAV was programmed to 130/100 ms and V-V delay was programmed to LV-RV 20 ms in the BiV-CRT group.

| Data collections and follow up
Baseline characteristics and medical history of participants were collected at enrollment. Twelve-lead surface ECG and the intracardiac electrogram (IEGM) were recorded by the GE CardioLab Electrophysiology recording system (GE Healthcare Inc., Marlborough, Massachusetts) at 100 mm/sec. The intrinsic QRSd, the paced QRSd (pQRSd), the stim-LVAT and the QT interval were measured in sequence. The QRSd was measured from the first onset of the complex to the latest offset in all leads. Stim-LVAT was measured from the stimulus to the peak of R-wave in lead V5 or V6. The QT interval was measured from the QRS onset at the earliest deflection in any lead to the end of the T wave in any lead, and the QTc was calculated using the Bazett formula as the duration of the QT interval adjusted for the patient's heart rate. 11 The echocardiographic parameters were documented including LVEF, LVEDD and LV end systolic dimension (LVESD) The LVEF was calculated with the modified Simpson's method (Three measures from each projection were taken, and the average value was recorded). All echocardiographic examinations were performed by the same experienced echocardiographer and analyzed by two independent experienced echocardiographers blinded to the study.
All patients were followed up at 3 months, 6 months and 1 year after implantation. The data of patients' survival status, NYHA functional class, and echocardiographic data were routinely documented and collected. Lead parameters including pacing threshold, R-wave amplitude and impedance were recorded at implantation and each follow-up visit. Possible complications such as infections, pericardial effusion, chronic capture threshold elevation, lead dislodgment and lead deficiencies were routinely tracked.

| Definition of CRT response
Echocardiographic response was defined as an LVEF improvement of at least 5% at the 6-month follow-up visit compared to that at baseline. CRT response was defined as an improvement of the patient's symptomatic status, such as decreasing NYHA functional class for at least one grade at the last follow-up compared to the basal value. CRT super-response was defined as a significant improvement in heart function, with the NYHA functional class decreasing to grade I or II, along with greater improvement in LVEF for at least 15% or a final LVEF>45%, and a decrease in LVESD>15%. 12

| Study population
A total of 24 patients underwent LBBP-CRT attempt during this study period, among them 21 were successful in the LBBP procedure resulting in a success rate of 87.5% (supplement data). Three patients failed in LBBP-CRT procedure due to difficulties in screwing the 3830 lead into the deep ventricular septum and subsequent BiV-CRT was successfully performed as an alternative. Twenty-one matched patients with successful BiV-CRT were recruited as control. The mean age was 65.6 ± 8.7 years (range 45 to 82 years), 18 patients (42.9%) were male and 38 patients (90.5%) were diagnosed with nonischemia cardiomyopathy (NICM) in this cohort. Detailed baseline characteristics of the recruited patients in both groups were described in Table 1. No significant differences were noted between LBBP-CRT group and BiV-CRT group based on baseline demographics, echocardiographic measurements and medication.

| Electrographic data
The detailed electrographic data were shown in Table 2. There were no significant differences in QRSd, and QTc at baseline between the LBBP-CRT group and the BiV-CRT group. The paced QRSd and QT interval were narrowed significantly compared to the baseline value in T A B L E 2 Comparison of electrographic data and outcomes n different groups both CRT groups. The QRSd was narrowed from 167.7 ± 14.9 ms to 111.7 ± 12.3 ms (P < 0.0001) after optimizing AV delay in the LBBP-CRT group, while the QRS duration was narrowed from 163.6 ± 13.8 ms to 130.1 ± 14.0 ms (P < .0001) in the BiV-CRT group. The reduction in QRSd was more remarkable in the LBBP-CRT group compared to that in the BiV-CRT group (Figure 2).

| Clinical outcomes
The mean follow-up period was 14.3 ± 7.2 months (ranging from 6 to 27 months). Significant improvements were recorded with respect to baseline measurements for NYHA Class and echocardiographic data at 6 month follow-up in both groups ( Figure 2). All the participants completed the 6 months follow-up with LVEF improved from 30.0 ± 5.0% to 50.9 ± 10.7% (P < .0001), and NYHA Class from 3.0 ± 0.7 to 1.3 ± 0.9 (P < .001) in the LBBP-CRT group. Detailed echocardiographic data were shown in

| Lead parameters
The capture threshold for LBBP lead was significantly lower than Conduction system pacing has emerged as a feasible pacing strategy for CRT in heart failure patients with LBBB. 13 Various studies have demonstrated that HBP can deliver better electrical synchrony compared to BiV-CRT, resulting in improvement of LVEF, life quality and NYHA functional class. [14][15][16][17] However, HBP is technically challenging due to its anatomical location and high capture threshold.. 18  The present study confirmed a better electrical synchrony and remarkable clinical outcomes of LBBP-CRT in heart failure patients complicated with Strauss defined LBBB. Beyond that, LBBP also showed an advantage in low and stable capture threshold over

| LIMITATION
The present study was a nonrandomized study conducted with a relatively small sample size in a single center. Propensity score matching was employed in the current study to correct for selection bias. In the present study, only a trend toward better echocardiographic response was documented in patients receiving LBBP-CRT compared with BiV-CRT. This may due to a relatively small sample size. Powered randomized trials with larger sample size are still needed to verify the results from the present study. The majority of patients recruited had nonischemic cardiomyopathy and thus the study cohort may not broadly represent the heart failure population in daily practice. Though better repolarization homogeneity was shown under LBBP-CRT, differences in iatrogenic arrhythmia could not be demonstrated, which might be due to the relatively small sample size and a short observation period.

| CONCLUSION
Compared with BiV-CRT, LBBP-CRT was remarkable in restoring electrical synchrony in heart failure patients complicated with strictly defined LBBB. A trend toward greater increment in LVEF and NYHA class was documented in this cohort underwent LBBP-CRT. LBBP-CRT procedure is safe and feasible, with low LBBB correction threshold and stable medium-term lead parameters during follow-up.