Optimization of nonresponders to left bundle branch area pacing using electrical dyssynchrony mapping

Abstract

Background

Left bundle branch area pacing (LBBAP) is a new approach to resynchronization in patients with heart failure (HF). Treatment of LBBAP nonresponders by optimizing programming has not been studied.

Objective

This study aimed to assess the effects of optimization on left ventricular (LV) size and systolic function in LBBAP nonresponders.

Methods

We studied 41 patients with systolic HF and attempted LBBAP 6.5 ± 4.3 months post-implantation. Nonresponders (pre-cardiac resynchronization therapy [CRT] ejection fraction [EF] < 45% and increase in EF < 5%) and incomplete responders (increase in EF > 5% but final EF < 45%) to LBBAP were included. Electrical dyssynchrony was assessed using a novel measure called cardiac resynchronization index (CRI). Patients with R waves in V1 were classified as left bundle branch pacing (LBBP) and those without R waves in V1 as deep septal pacing. Patients were programmed to optimal atrioventricular delay, ventricular–ventricular delay, and pacing mode (LBBAP-only, biventricular, or LV-only). Echocardiograms before CRT, before optimization, and 8.2 ± 4.4 months after optimization were read in blinded fashion.

Results

Most patients had LV leads (90.2%). LBBP was present in 41.5% and deep septal pacing in 58.5% of patients. CRI increased from 59.8% ± 25.9% to 84.5% ± 16.7%. CRT optimization significantly improved LV EF from 34.0% ± 7.0% to 37.0% ± 6.4% (P < .0001), end-systolic volume from 83.1 ± 38.9 to 72.7 ± 35.5 mL (P < .001), end-diastolic volume from 124.9 ± 46.3 to 112.9 ± 46.8 mL (P < .001), and global longitudinal strain from −10.5 ± 3.2 to −11.5 ± 3.0 (P = .01).

Conclusion

CRT programming to optimal CRI significantly improves LV systolic function, end-systolic volume, end-diastolic volume, and global longitudinal strain in nonresponders and incomplete responders to LBBAP, offering a non-invasive, practical clinical approach to improving response in patients having LBBAP.

Key Findings.

• ▪Nonresponders and incomplete responders to left bundle branch area pacing (LBBAP) (predominantly LBBAP–optimized cardiac resynchronization therapy [LOT-CRT]) are 60% resynchronized.
• ▪Based on QRS morphology in lead V1, deep septal pacing is present in 58.5% of patients studied ∼6 months after device implantation.
• ▪Optimization of electrical synchrony using electrical dyssynchrony mapping (EDM) achieves 85% resynchronization and significantly improves left ventricular size and systolic function.
• ▪EDM is a noninvasive, practical approach to correcting residual dyssynchrony and improving heart function in patients receiving LBBAP and LOT-CRT.

Introduction

Left bundle branch area pacing (LBBAP) is an emerging and rapidly growing alternative to standard cardiac resynchronization therapy (CRT). It offers more physiologic resynchronization by engaging the left bundle branch (LBB) or its fascicles and more rapidly and homogeneously depolarizing the left ventricular (LV) myocardium.¹ LBBAP has been shown in some studies to provide superior response with respect to electrical resynchronization as measured with QRS duration (QRS_d), LV function, and LV remodeling compared with biventricular (BiV) pacing (BVP) in patients with heart failure (HF) with LBBB.^2,3 However, other studies have shown improved acute hemodynamic⁴ and echocardiographic⁵ response with BVP compared with LBBAP. 2 modest-sized randomized trials showed conflicting results with respect to clinical outcomes,^6,7 possibly because of substantial differences in study design and patient population.⁸ In addition, it is debated whether LBBAP alone, or in combination with an LV lead (LOT-CRT), is better.

Nonresponse to CRT has been studied extensively, occurs in approximately 30%–35% of patients, and has not markedly changed over the past 2 decades.^9,10 The rate of nonresponse to LBBAP has not been well-characterized, and there is no established approach to treatment. We have developed a methodology based on the concept of wavefront fusion called electrical dyssynchrony mapping (EDM) for optimization of device programming in patients with CRT.¹¹ Studies of nonresponders and incomplete responders using EDM have demonstrated significant improvements in EF of ∼4%–6% and concomitant significant improvements in LV remodeling, LV strain, and mechanical synchrony.^12,13 The present study is designed to use EDM for determination of electrical resynchronization in nonresponders and incomplete responders to LBBAP and LOT-CRT, and to assess the effects of optimization on LV size and systolic function.

Methods

Patient population

We have developed a standard clinical protocol for CRT/conduction system pacing (CSP) optimization. Patients with a new CRT/CSP device and patients referred for nonresponse to CRT/CSP undergo EDM and are reprogrammed to optimal device settings if applicable. Electrocardiograms (ECGs) and echocardiograms (at least 3 months post-implantation in patients with a new device) are obtained before optimization and at least 4 months post-optimization. This study is a retrospective review of the patients who had LBBAP, were nonresponders or incomplete responders, had echos done in the appropriate timeframe, and were optimized as part of this clinical protocol. Nonresponders had improvement in LV ejection fraction (LVEF) of ≤5%, and incomplete responders had improvement in LVEF of >5% with final LVEF of ≤45%. All patients had a SelectSecure™ Model 3830 (n = 38) CSP lead or an OmniaSecure™ (n = 3) combined CSP/defibrillator lead (Medtronic Inc, Minneapolis, MN) placed in the interventricular septum to achieve LBBAP. All patients were clinically stable, had LVEF of ≤45%, underlying QRS_d (or paced QRS_d if in complete heart block [CHB]) of ≥120 ms, and were New York Heart Association (NYHA) class II to ambulatory class IV HF on optimal medical therapy pre-CRT. This study was approved by the Allina Health Institutional Review Board (IRB# 1993435). The research adhered to the Declaration of Helsinki as revised in 2013. Informed consent was waived by the institutional review board because this study is a retrospective review of an existing clinical protocol at our institution.

LBBAP classification

We use the term LBBAP to include all patients who had a lead placed in the proximal or mid deep septum to achieve LV activation via the LBB or its fascicles. We defined left bundle capture by a paced QRS complex in lead V1 with qR, QR, Qr, or r’ morphology and called these patients LBB-pacing (LBBP) as previously described.^4,5 Patients not meeting these criteria had a Q wave, often broad, in V1 and were categorized as deep septal pacing (DSP). All patients with an LV lead in addition to an LBBAP lead were defined as having LBBAP-optimized CRT (LOT-CRT) regardless of the V1 morphology during LBBAP only.

EDM and CRT optimization

The methodology for calculating cardiac resynchronization index (CRI) and generating EDMs has previously been described.11, 12, 13 In this study, we use the same methodology except that we have reduced the number of electrodes utilized to capture data from 9 anterior and 9 posterior to 6 anterior and 3 posterior. This change has simplified the efficiency of data collection and analysis without significantly altering CRI values. This methodology is based on the concept of electrical fusion of native, right ventricular-paced (RVp), and LV-paced (LVp) wavefronts, and manifests on the surface ECG as electrocardiographic cancellation. We quantify ED by CRI, a number between 0 and 100% that compares ED at any given setting to ED during native LBBB conduction for each patient.

Patients had device interrogation and ECG with CRT turned off to assess native conduction. Electrograms from the 6 anterior and 3 posterior leads were superimposed. QRS area under the curves (AUC) was measured using a proprietary algorithm that automatically marked the beginning and end of the QRS complex, calculated the area between multiple pairs of anterior/posterior electrograms, and averaged the results over 3 heartbeats. CRI was defined as percent change in absolute AUC compared with native conduction. For patients with CHB, RVp or LVp at short atrioventricular delay (AVD) was substituted for native conduction. CRI was measured at multiple combinations of AVD and ventricular–ventricular delay (VVD). EDM plotted atrial sensed/paced-to-LBBAP intervals (A-LBBAP) on the y-axis and atrial sensed/paced-to-LVp intervals (A-LVp) on the x-axis. CRI values were color-coded and plotted using MATLAB (Mathworks Inc., Natick, MA) to generate ED maps. In patients without an LV lead, atrial-to-LBBAP delay and LBBAP-to-RV apical paced delay were plotted. Patients were programmed to optimal CRI, with clinician judgement used to determine LV-only vs BVP if CRI values were similar at both pacing modalities. Acquisition of the data required for optimization typically took 30–60 minutes.

Echocardiographic analysis

Echocardiograms were obtained before device implantation, prior to CRT optimization, and 8.2 ± 4.4 months post-optimization. Echocardiograms were read by a scientist blinded to patient name and time of acquisition (pre-CRT, pre-, or post-CRT optimization). LV volumes and LVEF were measured using Simpson’s biplane method. Speckle-tracking echocardiography was used to measure global longitudinal strain (GLS) (2D Cardiac Performance Analysis, TomTec Imaging Systems, Unterschleißheim, Germany) as previously described.¹⁴ GLS was calculated as the average of basal, mid, and apical peak strain from apical 4-chamber, 3-chamber, and 2-chamber views.

Statistical analysis

Continuous variables were expressed as mean ± standard deviation, and categorical variables as count (percentage), unless otherwise noted. Comparisons of variables between groups were performed using paired Student’s t-tests and one-way analysis of variance as appropriate. Comparisons in CRI and echocardiographic variables were made separately, between non-responder and incomplete responder subgroups, and between LBBP and DSP subgroups. GraphPad Prism version 10.6.1 (GraphPad Software, Boston, MA) was used for data analysis, and a 2-sided P-value of ≤.05 was considered statistically significant.

Results

Baseline characteristics

Table 1 shows baseline characteristics of the 41 patients studied. Patients were studied 6.5 ± 4.3 months post-CSP implant. 26 patients (63.4%) were nonresponders, and 15 (36.6%) were incomplete responders. 17 patients (41.5%) had LBBP, and 24 (58.5%) had DSP. LOT-CRT was present in 37 patients (90.2%). Mean pre-CRT EF was 29.4% ± 6.2%, and QRS_d was 159 ± 24 ms. Patients were on guideline-directed medical therapy with 28 (66.3%) on renin–angiotensin system blockers and 36 (87.8%) on beta blockers.

Table 1.

Baseline characteristics (pre-cardiac resynchronization therapy unless noted)

Demographics
Age (years)	77.8 ± 10.6
Men: n = 24 (58.5%)	79.9 ± 8.8
LVEF (BP %)	29.4 ± 6.2
ECG
LBBB	23 (56.1%)
IVCD	2 (4.9%)
V Paced (CHB/AF)	16 (39.0%)
QRS Duration (ms)	159 ± 24
Comorbidities
Ischemic heart disease	18 (43.9%)
Chronic kidney disease	12 (29.3%)
Diabetes	14 (34.1%)
Hypertension	32 (78.0%)
Atrial fibrillation	22 (53.7%)
CV Medications
ACE-I/ARB/ARNI	28 (66.3%)
β-Blockers	36 (87.8%)
MRN	16 (39.0%)
SGLT2i	21 (51.2%)

ACE-I = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; CHB = complete heart block; CRT = cardiac resynchronization therapy; ECG = electrocardiogram; IVCD = intraventricular conduction delay; LBBB = left bundle branch block; LVEF = left ventricular ejection fraction; MRN = mineralocorticoid receptor antagonist; SGLT2i = sodium-glucose transporter 2 inhibitor.

ED at different device settings

Figure 1A shows an ED map in a 54-year-old female nonresponder (EF improvement of 2.4% with LBBAP). She had a CRI of 34% programmed LBBAP-only (LBBAP lead pacing of 60 ms ahead of apical RVp lead) with AVD of 120 ms. CRI improved to 77% with a decrease in AVD to 40 ms, and EF increased from 35% to 45%. ECGs showed a marked decrease in QRS amplitude with optimization. Figure 1B shows an ED map in a 93-year-old male nonresponder (EF improvement of 3.8% with device implantation) with underlying LBBB (QRS, 148 ms), DSP, and LOT-CRT. He was programmed at baseline to adaptive CRT with simultaneous BVP (VVD = 0) at an AVD of 120 ms. CRI was 63% at baseline and 29% with LBBAP-only. He was optimized to a VVD of −30 ms (LVp ahead). CRI improved to 98%. EF improved from 43% pre-optimization to 48% post-optimization. ECGs during LBBAP-only and at optimal BVP setting demonstrate loss of Q waves in V1–V3 and reduction in QRS amplitude with optimization.

Figure 1.

Electrical dyssynchrony maps (EDMs) and electrocardiograms (ECGs) in cardiac resynchronization therapy (CRT) nonresponders. A: EDM in a patient with left bundle branch area pacing (LBBAP) lead, right ventricular apical lead, and no left ventricular (LV) lead. Decreasing atrioventricular delay (AVD) from 120 to 40 ms resulted in large improvements in cardiac resynchronization index (CRI) and ejection fraction (EF). B: EDM with CRI values plotted at all practical combinations of A-LBBAP and A-LVp intervals. Red area marks CRI of >80%. Patient was programmed at baseline with AVD of 120 ms and simultaneous biventricular pacing (VV = 0 ms). He was optimized to AVD of 120 ms with LV preactivation of 30 ms (VV = −30 ms) with large improvements in CRI and EF. AVD = atrioventricular delay; CRI = cardiac resynchronization index; LBBAP = left bundle branch area pacing; LV = left ventricle.

Programming changes and effects on CRI

Figure 2 shows patient programming at baseline and after optimization. In all patients, a change in programming was made after performing EDM. At baseline, LBBAP programming was bipolar. In 10 patients (24.4%), programming was automatically determined using the AdaptiveCRT algorithm (Medtronic Inc). Baseline setting was defined in these patients as the most prevalent setting based on device interrogation. 27 patients (65.9%) were programmed BVP with a mean VVD of +8 ms (range, −20 to +40 ms). 6 patients (14.6%) were programmed LBBAP-only, and 4 of these 6 did not have an LV lead. 8 patients (19.5%) were programmed LV-only at baseline. BVP was continued in 24 patients (88.9%) initially programmed BiV, with changes in VVD ranging from +50 ms (additional RV preactivation) to −50 ms (additional LV preactivation). LBBAP was the optimal setting in 7 patients (17.1%) (and 4 of the 7 patients did not have an LV lead). Figure 3 shows the average CRI for LBBAP-only, baseline, and final settings in the 37 patients with LOT-CRT. CRI with LBBAP alone (50.4% ± 33.7%) was not significantly different (P = .134) from CRI baseline (61.3% ± 24.4%). CRI at optimal setting (83.6% ± 17.2%) was significantly (P < .0001) higher than CRI at LBBAP-only and baseline settings. The 4 patients without an LV lead had DSP. CRI improved in these patients by 46% ± 36% by modifying AVD. In patients with LBBP, CRI significantly improved (P < .00001) from 50.1% ± 33.2% during LBBAP alone to 87.1% ± 12.7% at final setting by programming LOT-CRT. QRS_d did not significantly change with optimization (143.8 ± 14.9 to 141.6 ± 10.6 ms, P = not significant).

Figure 2.

Device programming pre- and post-optimization. Programmed device settings at baseline and after optimization are shown. Final programming was based on the highest CRI. BiV = biventricular pacing; LBBAP = left bundle branch area pacing; LV = left ventricle.

Figure 3.

CRI in patients with LBBAP–optimized CRT (LOT-CRT). CRI with LBBAP-only (50.4%) and at baseline (61.3%) was similar and significantly lower than CRI at optimal device setting in 37 patients with LOT-CRT (83.6%). CRI = cardiac resynchronization index; LBBAP = left bundle branch area pacing.

Echocardiographic response to CRT optimization

CRI for the entire cohort of patients was 54.1% with LBBAP alone and significantly (P < .0001) increased from 59.8% ± 25.9% at baseline to 84.5% ± 16.7% at the final optimized setting. Table 2 and Figure 4 show echocardiographic variables pre-implant, pre-optimization, and post-optimization. Changes in echocardiographic variables with device implantation and with optimization respectively were as follows: LVEF increase 4.6% ± 4.3% (P < .0001) and 3.0% ± 4.5% (P < .0001), LVESV decrease 9.7 ± 23.7 mL (10.4%; P = not significant) and 10.4 ± 17.9 mL (12.6%; P < .01), LVEDV decrease 6.1 ± 30.6 mL (4.6%; P < .05) and 12.0 ± 23.6 mL (9.6%; P < .001), and LV GLS improvement of 1.2 ± 3.5 (13.2%; P < .05) and 1.0 ± 2.4 (9.5%; P < .05). Changes with optimization in EF (4.2% ± 4.6% vs 0.9% ± 3.4%; P = .02) significantly differed between nonresponders and incomplete responders, whereas changes in LVESV (−11.8 ± 18.5 mL vs −10.2 ± 11.7 mL; P = .76), LVEDV (−10.3 ± 27.0 mL vs −15.0 ± 16.9 mL; P = .55), and LV GLS (−1.6 ± 1.8 vs −0.1 ± 3.0; P = .051) were not significantly different. CRI values improved from LBBAP-only to final device setting in nonresponders (45.3% to 84.5%) and in incomplete responders (69.7% to 84.4%) with P = .053 for changes between groups. Changes in EF (2.8% ± 5.1% vs 3.3% ± 4.1%; P = .74), LVESV (−8.7 ± 18.8 mL vs −11.2 ± 17.8 mL; P = .67), LVEDV (−11.8 ± 19.0 mL vs −11.4 ± 27.2 mL; P = .96), and LV GLS (−0.9 ± 2.5 vs −1.1 ± 2.4; P = .80) were not significantly different in patients with DSP vs LBBP respectively. CRI values improved from LBBAP-only to final device setting in the LBBP group (50.1% to 87.1%) and in the DSP group (59.2% to 81.1%) with a P-value of .22 for changes between groups.

Table 2.

Echo variables in left bundle branch area pacing non-responders and incomplete responders pre- and post-optimization

Variable	Pre-implantation (A)	Pre-optimization (B)	Post-optimization (C)	P-value (A–B)	P-value (B–C)	P-value (A–C)
LVEF (%)	29.4 ± 6.2	34.0 ± 7.0	37.0 ± 6.4	<.0001	<.0001	<.0001
LVEDV (mL)	130.93 ± 43.88	124.87 ± 46.27	112.85 ± 46.84	<.05	<.001	<.0001
LVESV (mL)	92.78 ± 33.97	83.11 ± 38.87	72.67 ± 35.48	ns	<.01	<.01
Longitudinal strain	-9.1 ± 2.9	-10.5 ± 3.2	-11.5 ± 3.0	<.05	<.05	<.0001

P-values calculated using pairwise paired Student’s t-test between groups.

LVEF = left ventricular ejection fraction; LVEDV = left ventricular end diastolic volume; LVESV = left ventricular end systolic volume; ns: not significant.

Figure 4.

Changes in LV systolic function and size with device implantation and with optimization. LVEF, LV volumes, and LV global longitudinal strain significantly improved with both device implantation (except for left ventricular end-systolic volume) and with optimization of device programming using EDM.

Discussion

We demonstrate that patients with LBBAP and nonresponse or incomplete response are ∼60% electrically resynchronized at baseline settings and can be optimized to 84.5% resynchronization with EDM. This is achieved by altering AVD during LBBAP-only, fusing the LBBAP wavefront with the LVp wavefront during BVP, or pacing LV-only at the optimal AVD. LBBAP alone results in 50% resynchronization and, in the majority of patients, does not achieve optimal electrical synchrony. CRT optimization using EDM results in significant improvements in LV systolic function and LV size.

Nonresponse and incomplete response to LBBAP

The nonresponse rate for CRT is ∼30%–35%.¹⁰ CRT nonresponders have a poor prognosis with a higher hospitalization rate, and mortality increased 3.3- and 3.5-fold that of responders.¹⁵ Nonresponders often (44% of the time) receive no additional intervention and infrequently (18.5% of the time) undergo AV and/or VV optimization.¹⁵ Additionally, excess costs for nonresponders are ∼$6000–$10,000 in the first 2 years after device implantation.¹⁶ We estimate that another 30%–35% of patients are incomplete responders who still have significant LV dyssynchrony and abnormal EF despite an improvement in EF of >5% with CRT and have called these patients incomplete responders.^12,13 The nonresponse and incomplete response rates for LBBAP have not been well-characterized, and there is no demonstrated effective approach to treatment of CSP nonresponders. In a multicenter retrospective observational cohort study, EF response of <5% was found in 27% of 202 patients treated with LBBAP.¹⁷ This study was notable for a very heterogeneous patient population, which included 39% of patients with LBBB and 14%–17% of patients each receiving IVCD, RBBB, RV-paced, and narrow QRS. Shroff et al¹⁸ found that 18.6% of their 59 patients with LBBAP had an LVEF improvement of <10% at 12 months post-implantation. However, this was a highly selected group of patients since non-LBBB and ischemic cardiomyopathy patients were excluded. In the consecutive cohort study by Zhu et al,¹⁹ nonresponse rates (EF improvement at 6 months < 5%) in 68 patients having LBBP and 38 with DSP were ∼27% and ∼52%, respectively. Of note, this study included >80% of patients with nonischemic cardiomyopathy. In most previous small randomized controlled studies of LBBAP, the vast majority of patients had non-ischemic cardiomyopathy.²⁰ In the CSPOT trial, 21% of 34 patients evaluated for chronic response to LOT-CRT by echocardiography were nonresponders with EF improvement of <5% at 6 months.⁵ This patient group differed from patient groups in most other studies of LBBAP in that it included a high percentage (47%) of patients with IVCD. A better estimate of the true nonresponse and incomplete response rate to LBBAP will require much larger and more diverse populations than those studied thus far.

In the present study, we demonstrate significant improvements in EF of 3%, LVESV of 10.2 mL, LVEDV of 11.8 mL, and strain of −1.2% with optimization of LBBAP nonresponders and incomplete responders. The EF improvement is lower than the 4.5%¹² and 6.2%¹³ we found in previous studies of EDM optimization of CRT nonresponders and incomplete responders. Changes in LVESV (10.5 mL and 13.4 mL) and global longitudinal LV strain (−1.0% and −1.0%) in our previous studies of CRT nonresponders and incomplete responders were similar to those found in the present study. 1 potential reason for the lower magnitude of EF response in this study is that 39% of the patients in the present study had either atrial fibrillation or CHB. LV-only pacing was not a reasonable option in these patients as they had no native wavefront to fuse with the LVp wavefront, limiting the potential optimization choices. We have previously demonstrated consistently high CRI values of ∼90% in patients with CRT during LV-only pacing.²¹ We did not program many patients with LV-only as we found VVDs during BVP that produced high CRI values.

LBBAP alone

For LBBAP alone to fully resynchronize the heart, a number of criteria need to be met, including absence of distal or diffuse conduction system block, engagement of the conduction system fibers with the LBBAP lead, and stable lead position over time. Previous studies have demonstrated that these criteria are often not met. Patients with IVCD, ischemic CM and/or septal scar are more likely to have diffuse conduction system disease or conduction system block distal to the LBBAP lead insertion point.²² LBBAP physiologic lead location is difficult to compare across studies. This is because a variety of different categories of lead location have been used (selective LBB pacing, non-selective LBB pacing, LV septal pacing, DSP); the category is usually defined at the time of implantation; and the functional lead resynchronization effect can change with time, programmed pacing outputs, and switching from unipolar to bipolar pacing.^1,23 Lead position over time can change as a result of macrodislodgement or microdislodgement and micromovement with resultant loss of LBB pacing. Although macrodislodgement is infrequent with lumenless 3830-type leads (0.3%–1.5%),¹ micromovement and loss of true LBB capture occurs in ∼5%–10% of patients over several years in some studies.^24,25 We could not identify the presence or loss of true LBB capture in the present study as we did not have a detailed assessment of LBB lead physiologic location at the time of implant. In our study, LBBAP lead location was defined based on QRS morphology in V1 as either LBB pacing (r’) or DSP (Q) at the time of EDM, approximately 8.0 months after implantation. This classification is the same as that used in the CSPOT echo study, where 55% of patients were found to have LBBP and 45% have DSP,⁵ and in the PhysioSync-HF Study, where ∼1/3 of 57 patients had no terminal R wave in VI immediately post implant and another ∼1/3 of patients had a terminal R wave in V1 immediately post implant but not at 12 months.⁶ Our findings of 41.5% LBBP and 58.5% DSP in the present study are not very dissimilar from those found in these studies. The percentage of patients with LBBP was low in our study compared with the MELOS study, which reported successful LBBP in 89.6% of patients.²⁶ Reasons for our lower percentage of successful LBBP include assessment of LBB pacing on ∼6-month post-implant ECG and not at the time of implantation, ECG recording during chronic bipolar pacing, and exclusion of super-responders (who will likely have a much higher success rate). Although QRS morphology in V1 during LBBAP-only differed between the LBBP and DSP groups (by definition), CRI was similar in the 2 groups during LBBAP-only, and we were able to achieve similar improvements in CRI, LV size, and systolic function in patients of the LBBP and DSP groups by tailoring programming to the individual patient to achieve optimal wavefront fusion. In the 4 patients in our study without an LV lead, the only optimization approach available was a change in atrial-to-LBBAP timing and/or a change in LBBAP-to-RV apical timing. In these patients, optimal CRI was achieved with LBBAP programmed far ahead of RV apical pacing and LBBAP programmed at short AVD to ensure complete LV capture with the LBBAP lead without fusion with the native wavefront.

LOT-CRT

In our study, the majority (90.2%) of patients had LOT-CRT. In these patients, baseline programming was determined by the implanting physician at the time of implant. Baseline CRI was 61.3%, which was not significantly higher than the 50.4% CRI with LBBAP only (P = .134). However, we were able to achieve a significantly higher CRI (P < .0001) of 82.6% ± 18.9% by altering the VVD during BVP. The fact that the vast majority of nonresponders and incomplete responders needed fusion of LBBAP and LVp wavefronts to achieve optimal synchrony provides evidence that LBBAP is not fully depolarizing the LV myocardium via the conduction system fibers. Part of the depolarization is likely from cell-to-cell electrical transmission, and it is this component of the LBBAP wavefront that requires fusion with the LVp wavefront.

Our finding of substantially improved electrical synchrony, LV size, and LV systolic function with optimal VVD during LOT-CRT is consistent with other studies showing that LOT-CRT may be a better option than LBBAP alone in patients with systolic HF. In 1 study of 38 consecutive patients with CRT-P indications, HF, and EF of ∼34%, LOT-CRT produced an additional 20 ms of QRS narrowing compared with LBBAP.²⁷ Patients who benefited most were those with a classic CRT indication (NYHA HF class ≥ II, LVEF ≤ 35%, LBBB and QRS ≥ 130 ms), a larger LV and a higher NYHA HF class. In the CSPOT multicenter trial,⁴ 48 patients with HF with advanced conduction system disease and low EF underwent assessment of hemodynamic response to standard CRT, LBBAP alone, and LOT-CRT. Improvement in QRS_d and LV dP/dt was significantly greater with LOT-CRT as compared with LBBAP (unipolar and bipolar). In addition, the improvement in LV dP/dt as compared with LBBAP was most prominent in patients with QRS of >171 ms and patients with DSP, suggesting that the more diseased the conduction system and the less effective the LBB capture, the greater the need for an LV lead and LOT-CRT.

Patients with HF and low EF needing a defibrillator lead and currently receiving LOT-CRT frequently have chronic atrial fibrillation since they do not require an atrial lead, and thus the 3 headers in the pulse generator can be used for LBBAP, RV apical defibrillator, and LV leads. Patients in sinus rhythm requiring an atrial and RV defibrillator lead can either have a third lead as an LBBAP lead or an LV coronary sinus lead, but not both. With the recent approval of a combined LBBAP and defibrillator lead, the option of LBBAP, defibrillation, and LV pacing leads will be more widely available for patients with low EF, HF, and sinus rhythm. The combination of LBBAP and LV leads in patients needing defibrillation capability offers great flexibility, likelihood of better resynchronization, opportunity to tailor programming specific to a given patient, and ability to adjust programming in response to changes in patient clinical scenario such as infarct, change in native conduction, development of atrial fibrillation, change in lead threshold, or development of side effects such as phrenic nerve stimulation.

CRI, EDM, and residual ED

We quantified electrical synchrony in this study using a novel measure of wavefront fusion and electrocardiographic cancellation called CRI. CRI measures intra-LV synchrony by determining and averaging areas under the paired QRS curves of multiple anterior and posterior electrodes and normalizing this measure of wavefront fusion and cancellation to the synchrony achieved during cell-to-cell electrical transmission (native LBBB conduction or RV-only/LV-only pacing at short AV delay). With LBBAP, there is transmission of the electrical wavefront from the interventricular septum posteriorly and laterally through the specialized conduction system as well as through the myocardium. If the LV is depolarized solely via the conduction system (and CRI is very high), an LV lead (and associated LVp wavefront) is not needed. In contrast, if a portion of the LV myocardium is depolarized more slowly by cell-to-cell transmission, the LVp wavefront is essential in optimizing LV synchrony. ED maps in patients with LOT-CRT and CRI of <80%–90% during LBBAP-only are typical of those seen when there is cell-to-cell wavefront transmission and similar to those generated during standard BVP.¹¹ Use of CRI in LBBAP thus serves to quantify residual LV ED during LBBAP and to determine programming to minimize residual dyssynchrony. An ED map, which displays CRI values across all reasonable and practical AVD and VVD for a given patient, can provide a useful visual aid to help in deciding whether to program a given patient LBBAP alone, BVP at the optimal VVD, or LV-only pacing at the optimal AVD.

Limitations

Patients were optimized an average of 6 months after LBBAP implantation. We cannot completely separate the effect of device implantation on LV remodeling from the effect of optimization at timepoints up to a year post-implantation. However, we have used a similar study design and protocol in standard CRT noresponders and incomplete responders studied ∼4 years after implantation and found results similar to those obtained in this study,¹² suggesting significant improvement on optimization beyond a baseline improvement that might be accounted for by CRT-induced remodeling. In previous studies, EF improved nearly 1% for every 10% improvement in CRI, and that is very similar to what was found in the present study. This was a retrospective, blinded, single-center study of CRT optimization in a modest number of patients. Larger, randomized studies in LBBAP patients are needed.

Conclusion

We demonstrate that nonresponders and incomplete responders to LBBAP, with and without an LV lead, can be optimized using a novel technique called EDM. Electrical synchrony as measured with CRI is 54.1% with LBBAP alone, 59.8% at baseline programming, and improves to 84.5% with optimization of AVD, VVD, and pacing vector. This results in significant improvements in LVEF, LVESV, LVEDV, and LV GLS. EDM offers a practical, noninvasive approach to the effective management of patients with LBBAP.

Disclosures

Dr Bank is a cofounder of Myochron, which owns the patents related to the methods and technologies used in this manuscript. Some of the patents are licensed to Medtronic, and Myochron could receive royalties if the technology is commercialized. The remaining authors have no conflicts of interest to declare.