Progression of incomplete toward complete left bundle branch block: A clinical and electrocardiographic analysis

Abstract Background Complete left bundle branch block (cLBBB) is associated with increased cardiovascular mortality and heart failure. On the contrary, the clinical relevance of incomplete left bundle branch block (iLBBB) is less known. This study investigated the profile and outcome of iLBBB patients and assessed the risk of progression to cLBBB. Methods Patients diagnosed with iLBBB between July 2013 and April 2018 were retrospectively included. Subsequently, echo‐ and electrocardiographic examinations at time of iLBBB diagnosis and during follow‐up, as well as progression to non‐strict cLBBB and strict cLBBB, were evaluated. Results The study enrolled 321 patients (33% female, age 74 ± 11 years). During the follow‐up of 21 (8;34) months, 33% of iLBBB patients evolved to non‐strict cLBBB and 27% to strict cLBBB. iLBBB patients who evolved to non‐strict or strict cLBBB were older, had more frequently reduced left ventricular ejection fraction, and had more often QRS notching/slurring in the lateral leads and inferior leads, compared to patients without progression to cLBBB. In multivariate analysis, only QRS notching/slurring in the lateral leads was independently associated with progression to non‐strict cLBBB (odds ratio 4.64, p < .001) and strict cLBBB (odds ratio 9.6, p < .001). iLBBB patients with QRS notching/slurring had a progression rate to non‐strict cLBBB of 52% and 49% to strict cLBBB. Conclusion Among patients with iLBBB, up to one third of the patients progress to cLBBB within a period of 2 years. The presence of QRS notching/slurring in the lateral leads during iLBBB was the strongest predictor for progression toward cLBBB.


| INTRODUC TI ON
Complete left bundle branch block (cLBBB) is associated with increased cardiovascular mortality, sudden cardiac death, and heart failure (Surkova et al., 2017). Therefore, the presence of cLBBB on the electrocardiogram (ECG) raises clinical awareness and often warrants further cardiac investigations and clinical follow-up.
Incomplete LBBB (iLBBB) is most often defined by a QRS morphology reminiscent of cLBBB, but with a QRS duration (QRSD) <120 ms (Surawicz, Childers, Deal, & Gettes, 2009). The clinical profile and natural history of patients with iLBBB are poorly investigated and remain therefore largely unknown (Willems et al., 1985). This study aims to assess (a) the clinical profile of iLBBB patients, (b) the rate and risk factors of progression to cLBBB, and (c) the outcome of iLBBB patients.

| Patient selection and iLBBB definition
The study enrolled all adult in-and outpatients diagnosed with iLBBB on standard twelve-lead ECG at the Gent University Hospital between July 2013 and April 2018. The study was approved by the Ethics Committee of the Gent University Hospital.
Patients with suspicion of iLBBB diagnosis were screened by scanning the hospital digital ECG database (Muse Cardiology Information System, GE Healthcare) using the following criteria: (a) QRSD ≥110 and <120 ms; (b) negative QRS complex in leads V1 and V2; (c) absence of q waves in leads I, V5, and V6 (any of two); and (d) R-wave peak time >60 ms in leads I, aVL, V5, and V6 (any of two) (GE Healthcare, 2008).
Subsequently, all ECGs were visually analyzed. iLBBB diagnosis was manually confirmed by two independent cardiologists according to compliance to the American Heart Association (AHA) criteria (Table 1): (a) QRSD ≥110 and <120 ms; (b) R-wave peak time >60 ms in leads V4, V5, and V6; and (c) absence of q waves in leads I, V5 and V6 (Surawicz et al., 2009). In case of borderline QRSD, measurements were manually confirmed using digital calipers. When multiple ECGs were available within a short follow-up time, iLBBB diagnosis was withheld if confirmed on sequential ECGs.

| Electrocardiographic analysis
ECGs were recorded at a paper speed of 25 mm/s and a calibration of 10 mm/mV with MAC 5,500 ECG recording devices (GE healthcare). ECG characteristics were digitally analyzed by the 12SL algorithm (GE Healthcare) including QRSD; maximum R-wave amplitude and R-wave peak time (  . The presence of QRS notching and slurring in the lateral and inferior leads was assessed by two independent investigators, experienced in ECG-reading.

| Progression toward cLBBB
Progression to cLBBB was assessed on follow-up ECGs by two independent ECG readers. Assessment of progression toward cLBBB in patients with valvular disease was considered prior to valvular surgery to exclude iatrogenic cLBBB. To define cLBBB, a non-strict cLBBB definition (QRSD ≥120 ms, QS or rS in lead V1 and monophasic R wave with the absence of q waves in leads V5 and V6) (Surkova et al., 2017) and a strict cLBBB definition (QRSD ≥120 ms; QS or rS in lead V1; broad notched or slurred R wave in leads I, aVL, V5, or V6; and absence of q waves in leads V5 en V6) (Brignole et al., 2013) were used (Table 1).

| Echocardiographic and dyssynchrony assessments
Echocardiographic examinations within a 3-month window of first iLBBB diagnosis were used for echocardiographic analysis. Left ventricular dimensions were measured in conventional parasternal views: left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD). Left ventricular mass (LVM) was calculated using the Devereux formula (Lang et al., 2015). LVEDD, LVESD, and LVM were indexed for body surface area (BSA).
Mechanical dyssynchrony was assessed by the presence of septal flash (SF). SF refers to a pre-ejection leftward motion of the septum, followed by septal rebound stretch due to contraction of the lateral left ventricular wall and is considered a typical pattern of cLBBB-induced mechanical dyssynchrony (Smiseth, Russell, & Skulstad, 2012). Two echocardiographic experts, blinded to the ECGs, reviewed all echocardiographic studies offline (EchoPAC version 7.1.13 and Xcelera viewer R3 version 3.3.1). The presence of SF was assessed visually and by M-mode in apical window and parasternal long axis and short axis. This visual assessment of SF has previously been validated with low inter-and intra-observer variability (Corteville et al., 2017).

| Statistical analysis
Categorical variables are expressed as absolute number (percentage). Continuous variables are expressed as mean ± standard deviation in case of Gaussian distribution or median (1st and 3rd quartile) if data are non-Gaussian distributed. Normality was tested using the Shapiro-Wilk test. To compare means of two variables, Student's t test and Mann-Whitney U test were used. Comparison of categorical variables among groups was performed by chi square test.
Significant and near significant variables in univariate analysis were subsequently tested in a multivariate analysis using multiple logistic regression. Odds ratios (OR) are expressed with (95% confidence interval). Statistical significance was set at a 2-tailed probability level of <.05. All statistical analyses were performed using SPSS software (version 25.0, IBM).

| Clinical, electro-, and echocardiographic characterization of iLBBB patients
The study enrolled 321 patients diagnosed with iLBBB on a standard twelve-lead ECG. Mean age of the patients was 74 ± 11 years, and 33% of the patients were female. Coronary artery disease was present in 143 (45%) and valvular heart disease in 73 (23%) patients. Median QRSD at iLBBB diagnosis was 112 (110;116) ms.
QRS notching and slurring in the lateral and inferior leads were observed in 123 (38%) and 82 (26%) iLBBB patients, respectively. Echocardiographic studies within a 3-month window of iLBBB diagnosis were available in 243 patients. Mean LVEDD was 54 ± 9 mm, and 119 (51%) of the patients had a normal LVEF. Of interest, SF was detected in only 6 (2.5%) of iLBBB patients. Clinical, electro-, and echocardiographic characteristics of all iLBBB patients are summarized in Table 2.

| Progression rate to cLBBB
Sequential ECG recordings were available in 215 patients with a median follow-up period of 21 (8;34) months. Out of 215 patients, 72 (33%) patients showed progression from iLBBB to non-strict cLBBB and 57 (27%) patients evolved to strict cLBBB. Representative ECG tracings are shown in Figure 1. Of interest, in only 6 (3%) patients, recovery to normal QRS was observed.

| Clinical predictors of progression toward cLBBB
iLBBB patients who evolved to non-strict or strict cLBBB were older (75.8 ± 9.6 and 76.4 ± 9.6 years) compared to patients without progression to cLBBB (71.9 ± 11 years, p = .007 and p = .016, respectively). No differences in gender distribution, anthropometric characteristics, or underlying heart disease were detected between patients with and without progression toward cLBBB.
Comparison of all clinical characteristics between iLBBB patients with and without progression to strict or non-strict cLBBB is summarized in Table 3.

| Echocardiographic predictors of progression toward cLBBB
iLBBB patients evolving toward non-strict cLBBB and strict cLBBB had more frequently a reduced LVEF (58% vs. 41%, p < .036 and 55% vs. 41%, p < .068, respectively). No large differences in echocardiographic left ventricular dimensions were observed between patients with and without progression to non-strict cLBBB and strict cLBBB.
Comparison of all echocardiographic characteristics between iLBBB patients with and without progression to strict or non-strict cLBBB is summarized in Table 3.

| Electrocardiographic predictors of progression toward cLBBB
iLBBB patients evolving to non-strict cLBBB and strict cLBBB had more often QRS notching/slurring in the lateral leads (65% vs. 31%, p < .001 and 79% vs. 31%, p < .001, respectively). Likewise, QRS notching/slurring in the inferior leads was more frequently observed in patients evolving to non-strict cLBBB and strict cLBBB (33% vs. 20%, p = .036 and 35% vs. 20%, p = .028, respectively) compared to iLBBB patients without progression to cLBBB. Differences in QRSD between patients with and without evolution toward cLBBB  Surawicz et al., 2009;Surkova et al., 2017;Brignole et al., 2013. TA B L E 1 Electrocardiographic criteria to diagnose incomplete and complete LBBB a were small (114 vs. 112 ms, p < .05). No differences in R-wave peak time, QRS axis, PR, QT, and QTc intervals were observed between groups. Comparison of all electrocardiographic characteristics between iLBBB patients with and without progression to strict or non-strict cLBBB is summarized in

| Multivariate analysis to predict progression toward cLBBB
In a multiple logistic regression model including QRS notching/slurring in the lateral and inferior leads, age, LVM, LVEF, and QRSD, only QRS notching/slurring in the lateral leads was independently associated with progression toward non-strict cLBBB and strict cLBBB (OR 4.6 [2.15;10.02], p < .001 and OR 9.6 [3.77;24.41], p < .001, respectively) ( Table 3). No collinearity was found among notching/slurring in the lateral and inferior leads (variance inflation factor <1.5).
Differences in clinical, echo-, and electrocardiographic characteristics between iLBBB patients with and without QRS notching/slurring in the lateral leads are summarized in Table 4. Of interest, although the prevalence of SF among iLBBB patients was low, 5 out of 6 (83%) iLBBB patients with SF had QRS notching/slurring in the lateral leads. In female iLBBB patients with SF (3), lateral QRS notching/slurring was observed in all patients.
iLBBB patients with QRS notching/slurring had a progression rate toward non-strict cLBBB of 52%, and 49% to strict cLBBB, indicating that most of the patients evolving to cLBBB fulfilled strict cLBBB criteria. However, in iLBBB patients without QRS notching/ slurring, progression to non-strict cLBBB was only 20% and 10% to strict LBBB, meaning that merely half of the patients evolving toward cLBBB fulfilled strict cLBBB criteria (Figure 2).

| Outcome in iLBBB patients
Follow-up data were available in 301 out of 321 patients. During a median follow-up period of 31 (21;47) months, 101 (34%) patients died. None of the clinical, echo-, or electrocardiographic parameters was independently of age associated with increased mortality.

| Main findings
To the best of our knowledge, this is the first study assessing progression from iLBBB to cLBBB. We show that among iLBBB patients, 26.5%-33.5% of the patients reveal evolution to cLBBB, depending on whether a strict or non-strict cLBBB definition is used, respectively. The presence of QRS notching/slurring during iLBBB is the strongest predictor for progression toward cLBBB, independent of cLBBB definition. As such, patients with iLBBB and QRS notching/slurring in the lateral leads represent a population at high risk for the development of cLBBB.

| The pathophysiology of QRS notching in the lateral leads
QRS notching/slurring has been proposed as diagnostic criterion to define "true cLBBB" and differentiate cLBBB from QRS prolongation with cLBBB-like pattern caused by left ventricular hypertrophy (Strauss, Selvester, & Wagner, 2011). Several cLBBB definitions and guidelines on conduction disorders consider mid-QRS notching/slurring as a key feature to diagnose "true cLBBB" (Brignole et al., 2013;Surawicz et al., 2009). According to the work of Strauss et al., QRS notching during cLBBB represents slowing of the right to left septal conduction, which occurs typically in cLBBB (Strauss et al., 2011). In electromechanical experiments in dogs with varying degrees of mechanically induced iLBBB, reversal of septal activation (right to left activation) could be documented if sufficient degree of iLBBB was accomplished (Rodriguez & Sodi-Pallares, 1952). On the surface ECG, this reversal of septal activation was associated with widening of the QRS complex, disappearance of q waves in the lateral leads, and appearance of notching and/or slurring in the lateral leads. Minor degrees of iLBBB caused only a delay in left ventricular activation but did not change the leftto-right septal depolarization front, nor revealed the above mentioned ECG features. Identical electrocardiographic changes were observed during progressive impairment of left bundle branch conduction with increasing heart rates in patients with rate-dependent iLBBB (Barold, Linhart, Hildner, Narula, & Samet, 1968;Schamroth & Bradlow, 1964).

| Evolution of iLBBB to cLBBB
Data on progression from iLBBB to cLBBB are scarce, although one could assume that iLBBB might be a precursor of cLBBB. In this single-center cohort study of iLBBB patients, we showed that up to one third of iLBBB patients evolved to cLBBB during a median follow-up of 21 months. However, among iLBBB patients with QRS notching in the lateral leads, progression toward cLBBB occurred in half of the patients, whereas only 10%-20% of the patients evolved to cLBBB when QRS notching was absent. Therefore, from a clinical point of view, the presence of QRS notching identifies a population at high risk for evolution toward cLBBB. Whether this evolution to cLBBB translates into worse outcome needs to be further determined.

| QRS notching/slurring as criterion to define "true" iLBBB
Our findings that QRS notching is associated with progression to cLBBB combined with the existing evidence that QRS notching

TA B L E 3 (Continued)
Notching/slurring in lateral leads (n = 123) TA B L E 4 Differences in clinical, echo-, and electrocardiographic characteristics between iLBBB patients with and without QRS notching in the lateral leads F I G U R E 2 Evolution to cLBBB in iLBBB patients with and without QRS notching/slurring in the lateral leads in iLBBB is associated with reversed septal activation, raises the question whether QRS notching should be considered as a major diagnostic criterion to define "true" iLBBB. Indeed, the difficult electrocardiographic distinction between iLBBB and left ventricular hypertrophy has been a matter of debate since long (Willems et al., 1985). The presence of QRS notching/slurring might differentiate "true iLBBB" from QRS prolongation with iLBBB-like pattern caused by left ventricular hypertrophy. Previous pathological work showed that 75% of iLBBB patients with presence of QRS notching in the lateral leads had truly injury to the proximal part of the left bundle branch, at its junction with the atrioventricular bundle (Unger, Greenblatt, & Lev, 1968 Finally, all above-mentioned findings suggest that iLBBB and cLBBB are entities within the same pathophysiologic spectrum of conduction delay in the left bundle branch and presumably only differ by the degree of impaired left ventricularconduction.

| LI M ITATI O N S
Our population represents a hospital population and therefore both prevalence of iLBBB and progression to cLBBB in the general population might differ from our population. Given the retrospective study design, echocardiographic data were not retrieved for all patients and not all patients had paired data for clinical, echo-, and electrocardiographic follow-up variables, which may have limited our analyses. Especially, the assessment of SF was hampered by the limited availability of high-quality echocardiographic data and the restricted echocardiographic follow-up. Furthermore, we did not investigate the impact of clinical events during follow-up on the natural history of progression from iLBBB to cLBBB. This could have given us a better understanding on when and why progression to cLBBB is to be expected. Follow-up time was limited in our study.
As one might assume that progression rates to cLBBB will be even higher during longer follow-up, further investigation on outcome in iLBBB patients is needed.

| CON CLUS ION
In this single-center registry of iLBBB patients, we showed that up to one third of patients reveal evolution to cLBBB during a median follow-up of 21 months. The presence of QRS notching/slurring in the lateral leads during iLBBB was the strongest predictor for progression toward cLBBB, independent of the used cLBBB definition. As such, the presence of QRS notching/slurring during iLBBB on the twelvelead ECG identifies a population at high risk for the development of cLBBB.

CO N FLI C T O F I NTE R E S T
All authors declare that they have no conflict of interest.