Aortic valve implantation-induced conduction block as a framework towards a uniform electrocardiographic definition of left bundle branch block

Enrolled in the study were all patients with AVI-induced LBBB (LBBB_AVI), including both patients with TAVR- and SAVR-induced LBBB, at Ghent University Hospital between January 2013 and June 2019. All patients with a primary TAVR and SAVR procedure and without pre-existing LBBB were screened. Exclusion criteria were pre-procedural ventricular pacing and peri-procedural permanent pacemaker implant. Presence of acute LBBB was scored within 24 h following TAVR/SAVR.

A control group of LBBB patients (LBBB_control) consisted of randomly selected LBBB patients at Ghent University Hospital. LBBB_control patients were matched for age, sex, left ventricular ejection fraction (LVEF), history of coronary artery disease (CAD) and acute coronary syndrome to the LBBB_AVI group in a 2:1 ratio. In both the AVI and control groups, LBBB was defined according to broad conventional criteria (QRS duration (QRSD) ≥ 120 ms, QS or rS in lead V1 and absence of Q waves in leads V5 and V6) [16]. The study was approved by the ethics committee of Ghent University Hospital.

Electrocardiograms (ECGs) were recorded at a sweep speed of 25 mm/s and a calibration of 10 mm/mV, and digitally stored in the MUSE ECG database (GE Healthcare, Chicago, IL, USA). All ECGs were independently reviewed by two investigators and classified according to three currently used LBBB definitions: European Society of Cardiology 2013 (ESC 2013) [9], Strauss et al. [1] and American Heart Association 2009 (AHA 2009) [10] (see Electronic Supplementary Material, Fig. S1). Continuous electrocardiographic characteristics (QRSD, QRS axis, R wave peak time (RWPT)) were digitally analysed by the Marquette 12SL algorithm (GE Healthcare) [17]. RWPT was defined according to the Minnesota Code [18].

Based on our observations in LBBB_AVI, we adapted currently used LBBB criteria and propose a revised definition of LBBB. The revised definition was validated in consecutive LBBB patients (broad criteria) who underwent implantation of a CRT device at Ghent University Hospital according to current guidelines (LVEF ≤ 35%) [9] and who were categorised as CRT super-responders (LBBB_CRT) based on improvement in LVEF to > 45% after at least 6 months of CRT therapy at a prospective echocardiographic examination between October 2018 and August 2020. All pre-implant ECGs were reviewed by an investigator blinded to the revised LBBB criteria.

A total of 59 LBBB_AVI patients (34 TAVR and 25 SAVR patients, median age 82 years, 42% male) were enrolled in the study. The characteristics of the TAVR and SAVR patients are shown in the Electronic Supplementary Material (Table S1). All patients had severe aortic valve stenosis with an aortic valve area < 1.0 cm² as the indication for TAVR/SAVR. Pre-procedural conduction disease (left anterior/posterior hemiblock or intraventricular conduction delay) was observed in 8 (15%) patients. All patients developed LBBB immediately during implantation or within 24 h post-procedure. Except for age, no significant differences were observed between TAVR and SAVR patients.

With the occurrence of LBBB_AVI, QRSD increased from 94 (86;100) ms to 148 (140;160) ms (p < 0.001) (Tab. 1). An LBBB QRSD of ≥ 130 ms was observed in 98% of patients and, with regard to the Strauss definition, 95% of patients met the sex-specific QRSD cut-off (Tab. 2). Notably, 100% of females had a QRSD ≥ 130 ms and 88% of males had a QRSD ≥ 140 ms. QRSD in LBBB_AVI males was longer than in females (154 [145;162] ms vs 145 [138;153] ms, p = 0.006). No other electrocardiographic differences were observed between the sexes. In a multivariate linear regression model including age, height, weight, sex, CAD and end-diastolic diameter, only male sex was independently associated with increased QRSD (β = 11.49; p = 0.039). The baseline frontal QRS axis shifted from 9 (−15;45)° to −15 (−37;11)° post-AVI (p = 0.001). In 72% of LBBB_AVI patients with a normal QRS axis (90%), a leftward shift was observed.

The 59 LBBB_AVI patients were matched to 118 LBBB_control patients. The characteristics of LBBB_AVI and LBBB_control patients are shown in Tab. 1. Representative ECGs are shown in Fig. 1. No clinical or echocardiographic differences were observed between the two groups.

All LBBB_AVI patients presented with QRS notching/slurring in the lateral leads (I, aVL, V5 or V6), whereas this was present in only 85% (100) of the LBBB_control group (p = 0.001). Inferior (lead II, III or aVF) and septal (lead V1 or V2) QRS notching/slurring was also more prevalent in the LBBB_AVI group (83% vs 70%, p = 0.067 and 20% vs 5%, p = 0.002, respectively).

Overall, QRSD was not significantly different between the two groups, neither was RWPT. However, patients with LBBB QRSD ≥ 130 ms (98% vs 86%, p = 0.007) and patients meeting the Strauss sex-specific QRSD cut-off (95% vs 81%, p = 0.012) were more frequently observed in the LBBB_AVI group.

Of all LBBB_AVI patients, 100% met the ESC 2013 and 95% the Strauss LBBB definition, whereas only 17% of patients met the AHA 2009 definition (Tab. 2, Fig. 2). Low concordance with the AHA definition is explained by the low prevalence of QRS notching/slurring combined in all four lateral leads (54%, Tab. 2). Interestingly, except for one patient, all LBBB_AVI patients had QRS notching in at least two lateral leads (I, aVL, V5 or V6). Furthermore, only 27% of patients had an RWPT > 60 ms in both leads V5 and V6, contributing to the low agreement with the AHA 2009 definition. When the analysis was restricted to the first three AHA 2009 criteria only, 48–53% of LBBB_AVI patients fulfilled the AHA 2009 definition. The presence of a Q wave in lead aVL minimally reduced adherence to the AHA 2009 definition (Tab. 2).

In the LBBB_control group, concordance with the different definitions was significantly lower than in the LBBB_AVI group: ESC 2013 85% (p = 0.001) and Strauss 68% (p < 0.001) (Tab. 2, Fig. 2). The lower agreement with the different LBBB definitions is explained by: (1) lower prevalence of lateral notching/slurring (85% vs 100%, p = 0.001) and (2) the higher number of patients with a shorter QRSD (QRSD ≥ 130 ms, 86% vs 98%, p = 0.007) in the LBBB_control group. Only 7% of patients fulfilled the AHA 2009 definition (p = 0.035, compared to LBBB_AVI). As in the LBBB_AVI group, low concordance with the AHA 2009 criteria is caused by a low combined prevalence of QRS notching/slurring in all four lateral leads (31%) and most patients not meeting the RWPT criterion (83%).

Comparison of LBBB_AVI patients and LBBB_control patients with lateral QRS notching/slurring is shown in the Electronic Supplementary Material (Table S2).

No differences in frontal QRS axis, nor in QRSD and number of patients with QRSD ≥ 130 ms were observed between the LBBB_AVI group and the LBBB_control group with lateral notching. Furthermore, concordance with the different LBBB definitions was comparable between LBBB_AVI patients and LBBB_control patients with lateral notching, but not when comparing LBBB_AVI versus LBBB_control without lateral notching.

Clinical, echo- and electrocardiographic characteristics of the 33 CRT responders (median age 61 (48;71) years, 52% male) are summarised in Tab. 3. During a median follow-up of 53 (20;77) months, as per definition, LVEF increased from 27 ± 5.9% to 54 ± 7.5% (p < 0.001). Except for an increased QRSD (160 [155;173] ms vs 148 [140;160] ms, p < 0.001) and a higher prevalence of QRS notching/slurring in all four lateral leads (76% vs 54%, p = 0.047) in the LBBB_CRT group, no differences in electrocardiographic features or agreement with the LBBB definitions were observed between LBBB_AVI and LBBB_CRT.

This study assesses and reviews electrocardiographic features of LBBB in a population with proximal LBBB, i.e. patients with AVI-induced LBBB. As all LBBB_AVI patients had lateral QRS notching/slurring, QRS notching/slurring in the lateral leads is fundamental in the diagnosis of proximal LBBB. The LBBB_AVI group showed high concordance with ESC 2013 and Strauss definitions, but low agreement with the AHA 2009 definition. Our observations in LBBB_AVI were compared to matched LBBB patients from a general population, showing a higher number of patients with QRSD ≥ 130 ms, a higher prevalence of lateral QRS notching/slurring and a higher concordance with LBBB definitions in the LBBB_AVI group.

Current controversy in defining LBBB is primarily related to the difficulty in identifying patients with ‘true’ electrocardiographic LBBB. As studies over the past century have included patients with various types of conduction delay (proximal vs distal, focal vs diffuse), this obviously resulted in heterogeneous LBBB electrocardiographic patterns and criteria. Furthermore, most current LBBB definitions are derived from the same 1985 consensus criteria [19], but with different adaptations and interpretations (Electronic Supplementary Material, Fig. S1).

Although the importance of QRS notching/slurring was acknowledged even in early LBBB definitions [1, 20, 21], CRT was fundamental to the understanding of the relationship between electro-mechanical dyssynchrony in LBBB and a subset of LBBB electrocardiographic patterns with lateral QRS notching/slurring (‘true’ LBBB) [1, 13]. Patients without ‘true’ LBBB morphology were shown to demonstrate less electromechanical dyssynchrony [22], and absence of QRS notching/slurring resulted in less clinical and echocardiographic improvement than in true LBBB patients [6]. Experimental animal studies [14], His bundle pacing [23] and recent mapping studies [15] were able to link these ‘true’ LBBB electrocardiographic patterns with QRS notching to a proximal block in the LBB.

In our procedure-induced LBBB population, QRS notching/slurring was the most distinctive electrocardiographic characteristic of proximal LBBB. Our findings are in line with observational TAVR studies [24, 25] and a recent mapping study by Upadhyay et al., showing that QRS notching had the highest sensitivity and best negative predictive value to diagnose proximal LBBB [15]. Moreover, most proximal LBBBs were correctable by His bundle pacing in their study, indicating that in these patients no distal conduction disease was present. In contrast, LBBB patients without lateral notching demonstrated an intact proximal left conduction system and their LBBB was not correctable by His bundle pacing [15]. These findings suggest that an LBBB pattern without notching/slurring most likely reflects ‘distal block’ [1].

The question remains whether the presence of lateral QRS notching/slurring in a non-AVI-induced LBBB population also corresponds to proximal conduction disease of the left bundle. However, as uniformity was observed among LBBB_AVI patients and LBBB_control patients with lateral notching, these findings suggest pathophysiological similarities between the two groups and corroborate the evidence of a proximal block in all LBBB patients when notching/slurring is present.

AVI-induced LBBB implies an unequivocal proximal block and is therefore well suited for defining proximal LBBB. Based on our findings in LBBB_AVI, we selected and adapted currently used criteria (Fig. 3).

The ESC 2013 and Strauss definitions identify most LBBB_AVI patients. However, 5–14% of our proximal LBBB patients did not reach the computer-simulation-based Strauss QRSD thresholds of 130 and 140 ms for females and males, respectively. As such, QRS prolongation with a lower limit of 120 ms is preferable to define proximal LBBB. Although the ESC 2013 definition provides excellent sensitivity (100% of LBBB_AVI patients fulfilling the definition), the specificity might still be improved by adding the requirement of QRS notching/slurring in at least two lateral leads and the ancillary criterion of a leftward and superior oriented frontal QRS axis: 98% of LBBB_AVI patients had QRS notching/slurring in at least two lateral leads and 85% of patients had a QRS axis ≤ 30°. As AVI-induced LBBB patients and CRT super-responders both represent a ‘true’ LBBB electromechanical substrate within the large spectrum of left ventricular dysfunction, excellent compliance (97%) with the proposed criteria among CRT super-responders corroborates our revised LBBB definition.

A potential drawback in LBBB_AVI patients for studying the characteristics and definition of LBBB may relate to the age and co-morbidity in this particular population. Studying LBBB in a population with an unaffected myocardial substrate could overcome these issues. However, the almost identical observations in LBBB_AVI, matched LBBB_control with lateral notching and LBBB_CRT patients argue against important myocardial substrate differences between these populations. In acute LBBB, as in LBBB_AVI, electrical remodelling might affect electrocardiographic characteristics and alter LBBB features over time. However, this mainly involves changes in repolarisation features rather than changes in QRS features [30].