Efficacy on resynchronization and longitudinal contractile function comparing His-bundle pacing with conventional biventricular pacing: a substudy to the His-alternative study

Abstract

Aims

His-bundle pacing has emerged as a novel method to deliver cardiac resynchronization therapy (CRT). However, there are no data comparing conventional biventricular (BiV)-CRT with His-CRT with regard to effects on mechanical dyssynchrony and longitudinal contractile function.

Methods and results

Patients with symptomatic heart failure, left ventricular ejection fraction ≤ 35%, and left bundle branch block (LBBB) by strict ECG criteria were randomized 1:1 to His-CRT or BiV-CRT. Two-dimensional strain echocardiography was performed prior to CRT implantation and at 6 months after implantation. Differences in changes in mechanical dyssynchrony (standard deviation of time-to-peak in 12 midventricular and basal segments) and regional longitudinal strain in the six left ventricular walls were compared between the BiV-CRT and His-CRT groups.

In the on-treatment analysis, 31 received BiV-CRT and 19 His-CRT. In both groups, mechanical dyssynchrony was significantly reduced after 6 months [BiV group from 120 ms (±45) to 63 ms (±22), P < 0.001, and His group from 116 ms (±54) to 49 ms (±11), P < 0.001] but no significant differences in changes could be demonstrated between groups [−9.0 ms (−36; 18), P = 0.50]. Global longitudinal strain (GLS) improved in both groups [BiV group from −9.1% (±2.7) to −10.7% (±2.6), P = 0.02, and His group from −8.6% (±2.1) to −11.1% (±2.0), P < 0.001], but no significant differences in changes could be demonstrated from baseline to follow-up [−0.9% (−2.4; −0.6), P = 0.25] between groups. There were no regional differences between groups.

Conclusion

In heart failure, patients with LBBB, BiV-CRT, and His-CRT have comparable effects with regard to improvements in mechanical dyssynchrony and longitudinal contractile function.

Graphical Abstract

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Introduction

Cardiac resynchronization therapy (CRT) is a well-established treatment for patients with symptomatic heart failure and left bundle branch block (LBBB).¹ Resynchronization by conventional biventricular (BiV)-pacing (BiV-CRT) is obtained by pacing the septum of the right ventricle (RV) endocardially and the left ventricle (LV) epicardially from the coronary sinus. However, it is not always possible to place the LV lead in an optimal position due to anatomical challenges, high pacing thresholds, phrenic nerve stimulation, or suboptimal pacing configuration.²

Methods for physiologic pacing such as His-pacing (His-CRT) may overcome some of these limitations.³ By pacing the bundle of His, one can utilize the native conduction system, which in theory leads to a more physiologic correction of electromechanical dyssynchrony. His-CRT is considered an alternative to BiV-pacing in case of lead implantation failure in current guidelines (IIA indication).⁴

Two recent randomized pilot studies His-SYNC⁵ and His-alternative⁶ have compared BiV-CRT with His-bundle pacing in patients with severe heart failure. Both studies suggested similar or better outcome in terms of more efficient LV remodelling with His-CRT in on-treatment analysis. Thus, it may be that His-CRT is more efficient in resynchronizing the LV compared with BiV-CRT; however, this is poorly elucidated.

Two-dimensional strain echocardiography deformation analysis can be performed to assess electromechanical dyssynchrony as well as to characterize subtle contractile changes after CRT.⁷ The current study was a substudy to the His-alternative study and aimed to investigate (i) whether patients receiving His-pacing obtain a more synchronous contractile function, compared with those receiving BiV-pacing, and (ii) whether this translates to improved longitudinal contractile function.

Methods

Study population

Inclusion criteria

The His-alternative study was a double-blinded randomized (1:1) pilot study of 50 symptomatic heart failure patients with LBBB comparing His-CRT with BiV-CRT. All patients were included at Copenhagen University Hospital—Rigshospitalet, Denmark, between September 2018 and May 2020. Inclusion criteria were severe heart failure with left ventricular ejection fraction (LVEF) ≤ 35%, age ≥ 18 years, New York Heart Association functional class II–III, despite optimized medical therapy, and LBBB by strict ECG criteria. QRS widths for women were >130 ms and for men >140 ms. Additionally, the criteria included QS or rS pattern in leads V₁, V₂, and mid-QRS plateau phase and/or notching in at least 2 of leads V₁, V₂, V₅, V₆, I, and aVL. Figure 1 shows a flow chart of the patients entering the study and the subsequent crossover between groups. Procedural techniques for placement of the His and LV leads have previously been described in detail.⁶

Exclusion criteria

Patients were excluded if they had an existing BiV-pacing system, permanent atrial fibrillation, severe kidney disease with estimated glomerular filtration rate < 30 mL/min, acute myocardial infarct or coronary artery bypass graft within 3 months before assessment, and unwillingness to participate.

Blinding

Patients were blinded as to which intervention they received. Likewise, the staff that performed the echocardiographic examinations and subsequent off-line analysis were blinded to study groups.

Echocardiography

All patients had a standard echocardiography performed 1–7 days before CRT implantation and at the 6-month follow-up visit, including grayscale images optimized for 2D strain analysis (55–90 frames/s). All echocardiographic studies were performed on a GE Vivid E95 with the use of a 3.5-MHz ultrasound probe (GE Healthcare Ultrasound, Horten, Norway), and a standard protocol for CRT patients were used. Off-line analysis was performed by experienced readers with the use of Echopac version 204.71 (GE Healthcare Ultrasound).

Longitudinal strain

Two-dimensional strain echocardiography was performed in the apical four-, three-, and 2-chamber view as previously described.⁸ The reference points were adjusted to the beginning of the QRS complex. Aortic valve closure and opening were defined using a pulsed-wave Doppler ultrasound in the LV outflow tract with a 2-mm sample volume. The endocardial border was traced in end-systole, and the automatically generated region of interest was adjusted to exclude the pericardium. The accuracy and integrity of speckle tracking were automatically detected and visually ascertained. In the case of inaccurate or poor tracking, the tracing in the region of interest was adjusted. Segments with persistent poor tracking were excluded from the analysis (8%). See Supplementary data online, appendix, for longitudinal strain traces from the four-chamber view in two representative patients before and after BiV-CRT and His-CRT.

Mechanical dyssynchrony

Time-to-peak strain was measured in basal and midventricular segments in each wall, and the mechanical dyssynchrony index was calculated by the standard deviation of all 12 segments (TTPSD12)⁹—Figure 2.

Global longitudinal strain

Longitudinal peak systolic strain was measured in basal, midventricular, and apical segments and calculated into an averaged regional score for each wall (septal, lateral, inferior, anterior, posterior, and anteroseptal). Global longitudinal strain (GLS) was calculated by averaging all 18 segmental peak systolic strain values—Figure 2 and supplemental Figure 1.

Myocardial work

Systemic blood pressure was measured by a brachial artery cuff preceding echocardiography. After measurement of longitudinal strain, constructive myocardial work was calculated using an integrated algorithm in the post processing software. Constructive work is defined as the sum of the positive work performed by the LV during myocardial shortening in systole and the negative work by lengthening of the myocardium during isovolumetric relaxation. The septal-to-lateral work ratio was then calculated as the regional constructive work done by the septal wall divided with the constructive work done by the lateral wall.

LBBB contraction patterns

Identification of a typical LBBB contraction pattern was performed as previously described from the four-chamber view.¹⁰ The following criteria were required for a study to be read as a typical LBBB pattern: (i) early shortening of at least one basal or mid-ventricular segment in the septal wall and early stretching in at least one basal or midventricular segment in the lateral wall; (ii) early septal peak shortening (within the first 70% of the ejection phase); and (iii) lateral wall peak shortening after aortic valve closure. If one of these three criteria was not present, the patient was categorized as having an atypical LBBB pattern.

The presence of septal flash (SF) and apical rocking was visually assessed.

SF was defined as a short initial septal contraction during the isovolumic contraction. ApRock was defined as movement of the apex septally while the septum moves leftward, followed by a movement laterally during ejection phase when with lateral wall contraction, i.e. a septal-to-lateral rocking.¹¹

Response to CRT was defined as a reduction in left ventricular end systolic volume (LVESV) of ≥15%.

AV delay settings

All patients were implanted with a CRT-system from Abbott. Capture of His and the left bundle was ensured by shortening the atrio-ventricular (AV) delay below the measured delay between the beginning of the p-wave on ECG and by local His-deflection; mean sAV 78 ms (±19), pAV 91 ms (±27).

In the BiV-group, a default setting was used 110 ms after atrial sensing and 160 ms after atrial pacing and simultaneous pacing of RV and LV. It was tested that this setting assured BiV-pacing, and it was also tested whether fusion could be an option with the use of the SyncAVTM algorithm (with RV + LV simultaneously and offset −30 to −60 ms). If it was possible to achieve fusion with a clear reduction in QRS width (>20 ms), this was programmed. AV delays were mean sAV 138 ms (±56) and pAV 180 ms (±46).

Placements of LV leads

For placements of the LV leads, no standard projections were used; instead, the projections that gave the best individual long-axis and short-axis views (RAO 15–30° and LAO 25–40°) were used. Solely, quadripolar LV leads from Abbott were used.

Statistical analysis

Continuous variables [reported as mean ± standard deviation (SD)] were compared using a two-sample t-test after testing for normality. Categorical variables (reported as percentages) were tested for differences using χ² statistics. Paired two-sample t-tests were used to investigate the changes in measures of time-to-peak LV dyssynchrony and strain values within the same patient over time. A random effect for the individual patient was added to the model, and the model runs with only the variable for LV dyssynchrony/strain difference. P < 0.05 was considered statistically significant. All statistical analyses were performed using an open statistical software (R version 4.1.0).

Ethics

The His-alternative study was approved by the regional Danish Ethics Committee (approval no. H-18005323). Written informed consent was obtained from every patient, and the study was conducted according to the Declaration of Helsinki. The study was registered at ClinicalTrials.gov with the identifier NCT03614169.

Results

Baseline characteristics according to intervention arm: intention-to-treat and actual on-treatment, respectively, are shown in Table 1. All patients were implanted with a CRT device, and all patients were followed for 6 months. Eight patients crossed over to the opposite intervention group: seven patients randomized to His-CRT were instead implanted with an LV lead. In six cases, it was possible to find a His-signal but the threshold for capturing the left bundle was too high (typically >5–10 V and often with only intermittent capture). In the last case, it was not possible to identify a His-signal nor to capture the left bundle. One patient randomized to BiV-CRT had a dissection in the CS ostium, and it was deemed too risky to proceed that way, and instead, a His-lead was implanted with capture of the left bundle. Accordingly, 31 patients received BiV-CRT and 19 received His-CRT. The location of the active cathode of the LV leads was as follows: basal, 1 o’clock (1 patient); basal, 2 o’clock (2 patients); basal, 3 o’clock (2 patients); mid, 2 o’clock (1 patient); mid, 3 o’clock (20 patients); mid, 4 o’clock (4 patients); and distal, 3 o’clock (1 patient). The types of leads are as follows: 1456Q (4 patients), 1458Q (11 patients), and 1458QL (16 patients). Two patients in the BiV-CRT group experienced complications. One had early device endocarditis which required extraction of the CRT device, and at 2 months, a right-sided system was implanted with no further complications. The other had LV lead dislodgement after 3 weeks, and consequently, the LV lead was replaced with no further complications. Follow-up was performed at 6 months for both patients as planned. No patients in the His-CRT group experienced complications. The results reported in this manuscript are based on the on-treatment analysis.

There were more women in the group receiving His-CRT (23% vs. 58%, P = 0.02), and patients in the His-group were less likely to be treated with a mineralocorticoid receptor antagonist (81 vs. 47, P = 0.03). There were no significant differences in baseline mechanical dyssynchrony [120 ms (±45) vs. 116 ms (±54), P = 0.75] or GLS between groups [−9.1% (±2.7) vs. −8.6% (±2.1), P = 0.49]. In total, 89% receiving BiV-CRT were responders while 88% in the His-CRT group were responders (P = 1.0).

Mechanical dyssynchrony

Overall, no differences in the resynchronizing effect of the two pacing approaches were found. In both groups, mechanical dyssynchrony was significantly improved after 6 months [BiV group from 120 ms (±45) to 63 ms (±22), P < 0.001, and His-group from 116 ms (±54) to 49 ms (±11), P < 0.001] but no significant differences in changes could be demonstrated between the His group and BiV group [−9.0 ms (−36; 18), P = 0.50]. Figure 3A shows changes in time-to-peak dyssynchrony from baseline to follow-up in each of the two groups.

In all patients who were categorized as having a typical LBBB contraction, the pattern was abolished at 6 months indicating successful resynchronization. In line with these findings, QRS duration was significantly reduced in both groups [168 ms (±15) vs. 134 ms (±19), P ≤ 0.001, and 163 ms [±14] vs. 129 ms [±14], P < 0.001] and to a similar degree with a mean difference in changes of −1.5 ms (−13.6; 10.6), P = 0.81, comparing the His group with the BiV group.

Longitudinal contraction

The effect on longitudinal contraction was comparable between groups globally and regionally. GLS improved in both groups [BiV group from −9.1% (±2.7) to −10.7% (±2.6), P = 0.02, and His -group from −8.6% (±2.1) to −11.1% (±2.0), P < 0.001], but no significant differences could be demonstrated in changes from baseline to follow-up [−0.9% (−2.4; −0.6), P = 0.25] between groups. Similarly, there were no differences in changes between groups when comparing each of the LV walls (P < 0.05, for all). Specifically, the difference in changes in regional septal wall strain was 0.5% (−1.8; 2.7), P = 0.68, and the difference in changes in lateral wall strain was −0.2% (−2.4; 2.1), P = 0.86, comparing the His group with the BiV group. Figure 3B shows LV regional and global changes in longitudinal strain from baseline to follow-up in each of the two groups.

A significant reversal in the septal-to-lateral ratio was observed after CRT (0.82 ± 0.34 vs. 0.97 ± 0.30, P = 0.03) but no differences were found between groups with a mean difference in changes in a septal-to-lateral ratio of 0.04 (−0.20; 0.28), P = 0.75, comparing the His-CRT group with the BiV-CRT group.

LBBB contractile patterns

Forty-four patients (88%) had a typical LBBB contraction pattern: 28 in the BiV group (90%) and 16 in the His group (84%), P = 0.66. After CRT, we found a difference in changes in TTPSD12 of −44 ms (−69; −19), P = 0.003, comparing the patients with typical patterns with the patients with atypical patterns. GLS after CRT in the patients with typical patterns compared with those with atypical patterns showed a difference in changes of −1.5% (−4.7; 1.7), P = 0.30. Forty-two patients (84%) had early septal peak shortening in the pre-ejection phase (SF), and in 41 patients (82%), an ApRock could be observed. These patterns were evenly distributed among treatment groups at baseline—16/19 (84%) vs. 26/31 (84), P = 1, and 15/19 (79%) vs. 26/31 (84%), P = 0.73, respectively. Except for one patient, no patients showed SF or ApRock at 6 months. In line with these findings, a significant reversal was also observed in the septal-to-lateral work ratio after CRT (0.76 ± 0.28 vs. 1.04 ± 0.31, P < 0.001) but no difference was found between groups with a mean difference in changes in the septal-to-lateral work ratio of −0.12 (−0.33; 0.08), P = 0.22, comparing the His-CRT group with the BiV-CRT group.

Discussion

The clinical role for His-pacing in CRT is still to be established, and information regarding the effect of His-CRT compared with conventional BiV-CRT is lacking.

In this substudy of the His-alternative pilot, we compared the effect of the two pacing approaches with regard to the effect on electromechanical dyssynchrony and longitudinal contraction after 6 months. This has not been investigated in previous studies.

The main findings were that there were no significant differences in the degree of resynchronization when comparing His-CRT with BiV-CRT, and, secondly, the improvement in longitudinal function from baseline to 6 months follow-up was not significantly different between modalities neither regionally nor globally. This study indicates comparable effects for His-CRT and BiV-CRT in patients fulfilling strict LBBB criteria with severe heart failure.

In the present study, QRS duration with His-CRT was not significantly different from BiV-CRT which is in contrast to other studies with His-CRT, e.g. the His-SYNC study.⁵ The main reason for this discrepancy was that we also saw a substantial reduction in QRS width with BIV-CRT which most probably was due to patient selection. The His-alternative study included only ‘ideal’ patients for CRT. Another reason was that we reported the actual QRS duration from the pacing spike to the end of the QRS when there was non-selective His-capture (most of the ECG’s), while in the His-SYNC study, a corrected QRS was reported discarding the initial (pseudo-delta) part of the QRS. This part corresponds roughly in time to the H-V interval.

Retrospective series¹² and comparisons of acute haemodynamic effects¹³ have shown promising results for His-CRT. Current guidelines for CRT recommend to consider His-pacing as an alternative to conventional BiV-pacing if this approach is not possible.⁴ While larger randomized clinical studies are yet to be conducted, two randomized pilot studies comparing His-CRT with BiV-CRT were recently published. In the His-SYNC pilot trial, 41 patients with bundle branch block (85% LBBB) and heart failure were randomized to either His-CRT or BiV-CRT.¹⁴ No significant differences in LV reverse remodelling could be demonstrated, but the on-treatment analysis indicated a better effect of His-pacing with regard to changes in LVEF and reduction in QRS duration.

In the primary intention-to-treat analysis of the current study, no differences between pacing modalities were demonstrated; however, in line with the findings of His-Sync, on-treatment analysis showed a trend towards more efficient LV reverse remodelling in the His-CRT group compared with the BiV-CRT group. Together, the two pilot studies support the hypothesis that capture of the native conduction system may translate into better electromechanical resynchronization, which again leads to a more effective LV reverse remodelling and contraction.

Electromechanical resynchronization

CRT is an electrical intervention aimed at solving an electrical problem hereby restoring mechanical synchrony and cardiac function. Time-to-peak strain analysis is useful for evaluation of the mechanical treatment effect.^15,16 The degree of resynchronization after CRT predicts LV reverse remodelling and long-term outcome. In MADIT-CRT, a reduction in mechanical dyssynchrony of 20 ms was associated with a 7% risk reduction of a primary outcome.¹⁷ In contrast, patients with persistent or worsened dyssynchrony after BiV-CRT have been demonstrated to have a particular poor prognosis.¹⁵ In the current study, patients were carefully selected with regard to the underlying electrical substrate, i.e. all had LBBB by strict ECG criteria. Accordingly, patients had significant mechanical dyssynchrony prior to CRT and a high degree of resynchronization [on average reduced by −61 ms (±42)] was observed after 6 months. Of note, this improvement was comparable to what has previously been observed among patients with LBBB and highest benefit from CRT.¹⁷

There were no differences in the magnitude of resynchronization between patients receiving BiV-CRT and His-CRT at 6 months follow-up, and no differences were observed in the reduction in QRS duration. Thus, the different electrical activation sequences caused by the two different pacing approaches did not translate into measurable differences in mechanical dyssynchrony.

Longitudinal contraction

BiV-CRT improves longitudinal contractile function, and this improvement is correlated with favourable LV reverse remodelling and LVEF improvement.¹⁷ The contraction sequence is well described in case of LBBB activation.^18,19 The early-activated septal wall contracts first against the closed aortic valve, and energy is wasted as the opposing lateral free wall is stretched. When the lateral wall is activated, a more forceful contraction is observed due to the regionally increased pre-load.^18,20 Over time, structural changes are observed with decreased septal metabolism and perfusion leading to a more hypokinetic septal wall compared with the lateral wall which has a higher workload and often shows regional hypertrophy.²¹ The septal-to-lateral imbalance in loading conditions and wall contractility is reflected in the strain measurements with a pattern of relatively low septal strain compared with a higher lateral wall strain.⁷

Successful BiV-CRT causes a reversal or redistribution of the septal-to-lateral strain ratio²² and this reversal has been demonstrated to predict better outcome after CRT.^20,23 In the present study, His-CRT showed equally favourable reversal in the septal to lateral ratio and of equal magnitude. Furthermore, there were no differences in regional improvements when comparing LV walls.

Significant improvements were observed in GLS in both groups at follow-up. In patients with LBBB and standard criteria for CRT implantation, responders to CRT with significant LV reverse remodelling (reduction > 15% LVESV) exhibit significant improvements in longitudinal strain of around −2%.⁷ Similar improvements for the overall cohort in the present study were found with concomitant LV remodelling. Changes of this magnitude are likely to be associated with a highly favourable outcome after CRT. In comparison, it was reported from the MADIT CRT that each 1% improvement in GLS was associated with a 24% reduction in the primary outcome.¹⁷

Different LBBB contraction patterns

Deformation patterns based on 2D strain analysis hold useful information beyond the activation delay for prediction of outcome after CRT. Computer simulations indicate that LBBB deformation patterns primarily are determined by wall contractility and the degree of activation delay in the LV.²⁴ If patients do not have a typical LBBB contraction pattern, despite LBBB by ECG, it is either the patient does not have a true LBBB activation or contractility is decreased to such a degree that patterns are abolished.²⁴ Either scenario or a combination of both scenarios is associated with a poor prognosis and is critical to identify. In the current study, 6/50 patients did not have typical LBBB contraction despite LBBB by strict ECG criteria. Indeed, these patients showed less contractile improvement and less improvements with regard to dyssynchrony compared with patients with typical LBBB patterns at baseline. Similar observations were present with ApRock and SF. The fact that all patients (but one) did not have a typical LBBB contraction pattern, SF or ApRock after CRT supports the overall message that resynchronization is obtained to similar levels with both His-CRT and BiV-CRT in patients with LBBB independent of the dyssynchrony parameter used.

Perspectives

While the role for HIS-CRT compared with conventional BIV-CRT is still to be established, the current study suggests that both alternatives result in highly efficient resynchronization and contractile improvement. Despite different mechanisms behind the electromechanical resynchronization, the outcome, as reported in this study, is comparable. Importantly, this study included highly selected patients with LBBB. Conducting a clinical landmark trial comparing the two different pacing approaches may require a very large number of patients in order to demonstrate superiority between the methods. Other outcome parameters such as threshold, battery longevity, and complications will be important to address.

Limitations

The present study was an on-treatment analysis on a relatively small number of patients from a single centre. Larger prospective multicentre studies are warranted to compare His-CRT with conventional BiV-CRT to further establish the role for His-CRT.

Patients in the current study were carefully selected with regard to LBBB by strict ECG criteria, and there was an overrepresentation of patients with non-ischaemic cardiomyopathy; thus, the findings may not be representative for a broader population of CRT candidates.

Myocardial viability or presence of scar tissue was not investigated. It may be important to address this issue in future selection of CRT candidates to support the specific choice of CRT approach.

Conclusions

In selected heart failure patients with strict LBBB, the two different approaches His-CRT and BiV-CRT appear to have comparable effects with regard to improvements in LV electromechanical synchrony and longitudinal contractile performance after 6 months.

Supplementary data

Supplementary data are available at European Heart Journal - Cardiovascular Imaging online.

Funding

This study was funded by a research grant from the Clinical research Unit at the Heart Center, Rigshospitalet, Copenhagen, Denmark and the Alfred Benzon Foundation

Data availability

The data are available from the corresponding author upon reasonable request in accordance with the Danish Data Protection Act and the General Data Protection Regulation and after the approval by the steering committee of the HIS-alternative trial.

References

Author notes