Predictive Value of Septal Flash for Reduction of Left Ventricular Systolic Function as Reflected by Global Longitudinal Strain Using Echocardiography in Patients With Isolated Complete Left Bundle-Branch Block

Yonghuai Wang; Guangyuan Li; Chunyan Ma; Zhengyu Guan; Xuanyi Jin; Yang Li; Shuang Liu; Jun Yang

doi:10.1253/circj.CJ-17-1422

Abstract

Background: Septal leftward motion followed by a counter motion during early systole is known as septal flash (SF) in patients with isolated complete left bundle-branch block (cLBBB). This study aimed to determine the predictive value of SF for reduction of left ventricular (LV) global systolic function using 2D speckle-tracking echocardiography (2D STE) in cLBBB patients.

Methods and Results: The study group of 41 patients with isolated cLBBB and preserved LV ejection fraction and 41 age- and sex-matched control subjects were studied. The presence of SF and LV global longitudinal strain (GLS) were defined and measured using 2D STE. Multivariate logistic regression analysis identified the presence of SF as an independent factor predicting LV GLS >−20% in isolated cLBBB patients (odds ratio, 1.38; 95% confidence interval, 1.10–1.72; P=0.005). LV GLS in cLBBB patients with SF further decreased over time, whereas LV GLS did not decrease in patients without SF. The presence of SF was shown to be an independent factor predicting the reduction of LV global systolic function (relative reduction in LV GLS >15% from baseline to 2-year follow-up) (odds ratio, 1.27; 95% confidence interval, 1.06–1.50; P=0.008).

Conclusions: Assessment of SF by 2D STE may be an easy and effective method of predicting the reduction in LV global systolic function in isolated cLBBB patients.

Complete left bundle-branch block (cLBBB), an electrical conduction disorder, exists in different patient populations.¹^,² Some patients with cLBBB have other underlying cardiac abnormalities, such as heart failure (HF) and coronary artery disease (CAD), but cLBBB may occur in apparently healthy and asymptomatic individuals without any evidence of heart disease, a condition known as isolated cLBBB. Although the prevalence of isolated cLBBB in the general population is 0.1%, the patients are at an increased risk of cardiovascular diseases and have a higher cardiac mortality rate.³

It has been reported that cLBBB may have different prognoses. Some patients may have preserved left ventricular (LV) systolic function, but other patients may have progressive reduction of LV systolic function and ultimately develop HF.⁴^–⁸ It has even been suggested that the presence of cLBBB may be an early sign of dilated cardiomyopathy.⁸ Therefore, it is important to evaluate isolated cLBBB patients who are at risk for developing HF by early detection of LV systolic dysfunction. Evaluating isolated cLBBB patients at risk for developing HF may be helpful for counseling patients about their prognosis.⁹

In HF patients with cLBBB, it has been shown that septal flash (SF) is associated with a more favorable response to cardiac resynchronization therapy (CRT).¹⁰^–¹³ SF involves a pre-ejection leftward contraction of the septum, followed by a lengthening motion towards the right ventricle (RV), which can be visualized on echocardiography in some patients with cLBBB.¹⁰^,¹⁴ A previous study based on experimental ablation-induced cLBBB revealed that SF may negatively contribute to LV stroke work.¹⁵ Thus, abnormal septal motion may affect LV function in cLBBB patients; however, the effect of SF on the reduction of LV function in isolated cLBBB patients is unclear. Therefore, we hypothesized that isolated cLBBB patients with SF may have worse LV systolic function compared with patients without SF, and the presence of SF may predict the reduction of LV global systolic function in isolated cLBBB patients.

In view of that hypothesis, we used 2D speckle-tracking echocardiography (2D STE) to measure LV global longitudinal strain (GLS) in the present study.

Methods

Study Population

The subject cases were selected from individuals who underwent regular annual checkups at a medical examination center from March 2013 to December 2014. The checkup included blood pressure, standard 12-lead ECG, echocardiography, computed tomography and series of conventional biochemical indicator including blood glucose and blood lipids. We enrolled asymptomatic subjects with cLBBB on standard 12-lead ECG and no other evidence of heart disease. cLBBB in the included patients was thought to result from a primary conduction abnormality. The following patients were excluded: an arrhythmia other than cLBBB (ventricular pre-excitation, atrioventricular conduction abnormalities, atrial fibrillation, and paced rhythms); abnormal heart structure (valvular dysfunction, congenital heart disease, restrictive, hypertrophic, or dilated cardiomyopathy); pericardial effusion; LV ejection fraction (LVEF) <52% in males or <54% in females;¹⁶ history of CAD defined as ever suffering from chronic stable angina, unstable angina, non-ST-segment elevation myocardial infarction or ST-segment elevation acute myocardial infarction;¹⁷ positive results on an exercise test; familial history of dilated cardiomyopathy or with other risk factors, such as alcohol, drugs, toxins, myocarditis and so on;¹⁸ severe kidney disease defined as estimated glomerular filtration rate <30 mL/min/1.73 m² for at least 3 months, history of renal transplantation, or severe acute renal failure with dialysis requirement;¹⁷ severe chronic liver disease or history of liver transplantation; hypertension; hyperlipidemia; hyperglycemia; hyperthyroidism; hypothyroidism; pulmonary hypertension; malignancy; autoimmune disease; infection; and poor echocardiographic or ECG images. Age- and sex-matched healthy controls in sinus rhythm with the same exclusion criteria were enrolled during the study period for comparison. A total of 41 isolated cLBBB patients (23 females; mean age, 57.5±8.7 years) and 41 age- and sex-matched control subjects (26 females; mean age, 56.5±5.7 years) were enrolled. Smoking history was defined as persons who reported smoking at least 100 cigarettes during their lifetime, according to the 2011 Centre of Disease Control and Prevention Criteria,¹⁹ and the smoking histories of the groups were matched. Written informed consent was given by each subject and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

Electrocardiography

Baseline standard supine 12-lead ECGs were recorded at a calibration of 10 mm/mV and a paper speed of 25 mm/s using a standard GE Healthcare device (type MACC 5500; Waukesha, WI, USA). cLBBB was defined as follows: (1) QRS duration ≥140 ms in males or ≥130 ms in females; (2) QS or rS in leads V1 and V2; and (3) mid-QRS complex slurring or notching in ≥2 of contiguous leads V1, V2, V5, V6, I, and aVL.¹ The ECGs were identified by 2 cardiologists and any disagreements were resolved by a 3rd observer.

Echocardiography

All patients had standard echocardiographic examinations in the left decubitus position using a Vivid 7 ultrasound system equipped with a 2–4 MHz phased-array probe (GE Healthcare). Standard 2D cine loops were recorded for offline analysis using an EchoPAC work station (GE Healthcare), with a frame rate of 57–72 frames/s. All echocardiography images were acquired and measured by 2 experienced cardiologists who were blinded to any clinical data.

According to the recommendations of the American Society of Echocardiography,¹⁶ LVEF (biplane modified Simpson method), left atrial volume index (LAVI), mitral E, mitral A, average mitral E’, LV isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT), and ejection time (ET) intervals were assessed. Mitral E/A, mitral E/ E’, and LV index of myocardial performance (IMP) were calculated, as follows: IMP=(ICT+IRT)/ET.

Interventricular mechanical delay (IVMD) is the difference between the time interval from the onset of the QRS wave on a surface ECG to the beginning of ejecting blood from the LV and RV, which was measured by pulsed-wave Doppler spectrum in the LV and RV outflow tracts.

2D STE When image analyses by 2D STE of the apical views were performed offline, the endocardial boundary of the LV was delineated manually, after which the software automatically drew the epicardial boundary.²⁰ The widths of the regions of interest were adjusted manually to match the endocardial and epicardial boundaries. Automatic frame-by-frame tracking of speckle patterns during the cardiac cycle yielded a measure of strain in the 18 segments of the LV. Subjects with inadequate tracking of more than 1 segment in at least 1 apical view were excluded from the study. LV GLS was calculated and obtained by averaging all LV segmental values in all apical views. LV GLS <−20% is expected in a healthy person, and LV GLS >−20% is abnormal.¹⁶ LV septal LS was calculated by averaging 6 segmental values of the septum and the average of the other 12 segmental values of LV was calculated as LV non-septal LS.

The time-to-peak systolic longitudinal strain (Ts) was measured as the interval from the onset of the QRS to the peak negative systolic of LV longitudinal strain throughout the cardiac cycle. Ts-SD is the standard deviation (SD) of Ts from 18 LV segments. Ts-Dif is the maximal difference in Ts between any 2 of 18 segments of the LV.¹⁷

Assessment of Septal Flash

The presence of SF was assessed by 2D STE in the apical 4-chamber and long-axis views. SF was defined as the presence of an early pre-ejection shortening peak before the prominent late-systolic shortening peak in any segment of the septum according to the longitudinal strain curve from the single-wall recordings using 2D STE (Figure), just like cLBBB-1 (Leenders et al²¹ classified septal deformation patterns in CRT candidates with cLBBB into 3 patterns: cLBBB-1, double systolic shortening peak; cLBBB-2, early pre-ejection shortening peak followed by prominent systolic stretch; and cLBBB-3, pseudonormal shortening with a late-systolic shortening peak and less pronounced end-systolic stretch). We further assessed the extent of SF and scored it as the number of involved septal myocardial segments (total of 6 segments).

Figure.

Septal flash (SF) on 2D speckle-tracking echocardiography. Note the septal strain curve and M-mode strain color-map of (A) cLBBB patients with SF (arrow; similar pattern to cLBBB-1); and (B) cLBBB patients without SF. cLBBB, complete left bundle branch block.

Follow-up

We followed these patients with examinations approximately every 6 months for 2 years. During the routine follow-up, all the patients had their blood pressure and a series of conventional biochemical indicators measured, and underwent standard 12-lead ECG, echocardiography, computed tomography, which was same as the annual checkup every time. We further assessed LV global systolic function (GLS and LVEF) and ventricular synchrony (IVMD and Ts-SD) in the patients until the final follow-up visit (2 years). If the absolute LVEF of the patients was <52% in males or <54% in females or there was a relative reduction of LVEF >10% from baseline to the follow-up visit, the patients were hospitalized to delay progressive worsening of LV systolic function and improve health-related quality of life by pharmacological therapy or even CRT according to the guideline for the Management of Heart Failure reported by American College of Cardiology Foundation/American Heart Association.²² If not, the patients had only outpatient visits and received appropriate medical treatment according to their condition. The reduction in LV global systolic function was defined as a relative reduction in GLS >15% from baseline to 2-year follow-up.²³

Reproducibility

Intra- and interobserver variabilities for LV GLS were examined in 10 randomly selected patients. To assess intraobserver variability, the same observer, blinded to the initial measurements, repeated the measurements after more than 4 weeks had elapsed. In addition, a 2nd independent observer repeated the measurements twice to assess interobserver variability.

Statistical Analysis

All statistical analyses were performed using SPSS 17.0 software package (SPSS version 17, SPSS Inc., Chicago, IL, USA). Continuous data are presented as the mean±SD, and categorical variables as the frequency (percentage). Normality plots with tests were performed using the Shapiro-Wilk test. An independent samples Student’s t-test was used to compare the differences in continuous variables between 2 groups. Categorical variables were compared using a chi-square or Fisher exact test, as appropriate. Comparisons among ≥3 groups were assessed using one-way analysis of variance, and comparisons between groups were performed by post hoc analysis of variance using Scheffe’s method. Selections of independent variables for the prediction of LV GLS >−20% and reduction of LV global systolic function in patients with isolated cLBBB were performed using multivariate logistic regression analyses, and the associations were expressed as the odds ratio (OR) and 95% confidence interval (CI). Bland-Altman analysis was used to estimate intraobserver and interobserver variabilities. For all parameters, P<0.05 (two-tailed) was considered statistically significant.

Results

We excluded 1 patient with cLBBB and 1 control because of inadequate tracking quality of more than 1 segment in at least 1 apical view during the analysis of images by 2D-STE. In the remaining 80 subjects (40 cLBBB patients, 40 control subjects), there were potentially 1,413 segments that could be tracked to obtain strain measurements. Of these, 27 segments (1.88%) were excluded from the analysis for inadequate tracking quality.

The baseline characteristics of the study population are shown in Table 1. There was no difference between the isolated cLBBB patients and healthy controls.

Table 1. Baseline Characteristics and LV Echocardiographic Findings of the Study Population

Variables	cLBBB (n=40)	Controls (n=40)	P value
Age (years)	57.5±8.7	56.5±5.6	0.54
Female [n (%)]	23 (57.5)	26 (65.0)	0.49
Body surface area (m²)	1.69±0.16	1.65±0.16	0.35
Smoking history	9 (22.5)	7 (17.5)	0.58
Heart rate (beats/min)	69.3±10.4	66.1±9.6	0.16
Systolic BP (mmHg)	124.9±11.3	121.4±10.5	0.41
Diastolic BP(mmHg)	76.9±8.1	74.1±8.6	0.31
Fasting blood glucose (mmol/L)	5.58±1.17	5.35±0.72	0.33
LDL-C (mmol/L)	2.78±0.43	2.68±0.68	0.30
Triglycerides [median (IQR)]	1.42 (1.07, 2.18)	1.39 (0.98, 1.79)	0.32
HDL-C (mmol/L)	1.12±0.21	1.20±0.26	0.43
Total cholesterol (mmol/L)	4.37±0.63	4.31±0.67	0.75
Echocardiography
LV end-diastolic diameter (mm)	51.37±4.99	41.59±7.58	<0.001
LVEF (%)	60.12±5.55	65.23±4.18	<0.001
LAVI (mL/m²)	34.07±6.18	29.55±4.15	0.01
Mitral E/A	0.79±0.27	1.34±0.39	<0.001
Mitral average E’ (cm/s)	4.97±1.62	9.88±2.48	<0.001
Mitral E/ E’	13.69±4.69	8.94±3.10	<0.001
LV index of myocardial performance	1.01±0.20	0.51±0.09	<0.001
LV GLS (%)	−18.47±2.51	−21.82±1.23	<0.001
LV GLS >−20% [n (%)]	29 (72.5)

A, late diastolic flow velocity; BP, blood pressure; E, early diastolic flow velocity; E’, early diastolic annular velocity; GLS, global longitudinal strain; HDL-C, high-density lipoprotein-cholesterol; LAVI, left atrial volume index; LDL-C, low-density lipoprotein-cholesterol; LV, left ventricular.

LV Function in Isolated cLBBB

The effect of isolated cLBBB on LV function is shown in Table 1. These patients had significantly decreased LV systolic function compared with the healthy subjects, including LV GLS, LVEF, and IMP(P<0.001 for all). Moreover, the mitral E/ E’ of the patients with isolated cLBBB was significantly increased (P<0.001).

Septal Flash in Isolated cLBBB

Of the 40 isolated cLBBB patients, 22 (55.0%) exhibited the SF phenomenon: 3-, 4-, 5-, and 6-segment involvement of SF was found in 6 (27.3%), 2 (9.1%), 3 (13.6%), and 11 (50.0%) patients, respectively. There were no patients with 1- or 2-segment involvement of SF.

Septal Flash and LV Function in Isolated cLBBB

Of the 40 isolated cLBBB patients, 29 (72.5%) had a LV GLS >−20%. When we compared the age, sex, heart rate, QRS duration, LV end-diastolic diameter, LV mass index, mitral average E’, E/E’, E/A, Ts-SD, IVMD and the presence of SF between patients with LV GLS >−20% and those with a LV GLS <−20%, we observed that the incidence of SF and mitral average E/E’ were significantly increased in patients with a LV GLS >−20% compared with the patients with a LV GLS <−20% (72.4% vs. 9.1%, P=0.001; 14.63±5.14 vs.11.49±2.31, P=0.02). Multivariate logistic regression analysis was performed to predict LV GLS >−20%. After adjusting for related factors, such as age, sex, heart rate QRS duration, LV end-diastolic diameter, LV mass index, mitral average E›, E/E›, E/A, Ts-SD and IVMD, we found that only the presence of SF entered the final regression model and the presence of SF was the independent factor for LV GLS >−20% (P=0.005, OR=1.38, 95% CI=1.10–1.72, Table 2).

Table 2. Factors Associated With LV GLS >−20% on Multivariate Analysis

Covariates	Presence of SF	Constant
β	0.32	−3.28
SE	0.11	1.41
Wald	7.79	5.4
P value	0.005	0.02
OR	1.37	0.04
95% CI	1.10–1.71

Data presented as odds ratio (OR) and 95% confidence intervals (CI). Abbreviations as in Table 1.

In the analyses regarding the effect of SF, we observed that LV systolic function was and inter- and intraventricular mechanical synchrony was further decreased and worse, respectively, in patients with SF than in patients without SF (P<0.05 in all; Table 3).

Table 3. Effect of SF on LV Function and Synchrony

Variables	SF (n=22)	No SF (n=18)	Controls (n=40)	P value
Heart rate (beats/min)	67.4±9.2	71.6±11.5	66.1±9.6	0.19
QRS duration (ms)	159.36±11.27*	153.16±10.42*	116.9±8.9	<0.001
LAVI (mL/m²)	34.98±6.32*	33.14±5.62*	29.55±4.15	0.01
Mitral E/A	0.83±0.33*	0.74±0.16*	1.34±0.39	<0.001
Mitral average E’ (cm/s)	4.80±2.04*	5.17±0.99*	9.88±2.48	<0.001
Mitral E/ E’	14.45±5.61*	12.81±3.24*	8.94±3.10	<0.001
LV end-diastolic diameter (mm)	52.02±5.15*	50.58±4.81*	41.59±7.58	<0.001
LV mass index (g/m²)	80.14±15.59*	76.67±12.98*	64.54±13.88	<0.001
LV stroke volume (mL)	61.88±12.05*^,†	65.79±10.57*	52.13±8.03	<0.001
LVEF (%)	58.42±4.77*^,†	62.19±5.85	65.23±4.18	<0.001
LV index of myocardial performance	1.04±0.22*	0.97±0.18*	0.51±0.09	<0.001
LV septal longitudinal strain (%)	−15.78±2.31*^,†	−19.18±3.30*	−21.86±1.83	<0.001
LV non-septal longitudinal strain (%)	−18.73±4.32*^,†	−20.08±2.64	−20.91±1.76	0.02
LV GLS (%)	−17.31±1.95*^,†	−19.89±2.42*	−21.82±1.23	<0.001
LV GLS >−20%	21 (95.5)^†	8 (44.4)
Ts-Dif (ms)	199.55±61.17*	183.00±57.80*	101.93±27.50	<0.001
Ts-SD (ms)	66.78±17.27*^,†	55.64±9.58*	33.11±5.84	<0.001
IVMD (ms)	66.77±14.26*^,†	54.56±20.45*	5.97±1.09	<0.001

*P<0.05 vs. controls; ^†P<0.05 vs. no SF. EF, ejection fraction; IVMD, interventricular mechanical delay; SF, septal flash; Ts, time-to-peak longitudinal systolic strain; Ts-SD, standard deviation of Ts from 18 segments of the LV; Ts-Dif, maximal difference in Ts between any 2 of the 18 segments of the LV. Other abbreviations as in Table 1.

Follow-up

The median duration of follow-up for the isolated cLBBB patients was 23 months, with a range of 10–25 months. At the final follow-up visit, 4 patients (10%) were excluded from the follow-up analysis: atrial fibrillation (n=1); atrioventricular conduction abnormality (n=1); hyperthyroidism (n=1); and death from acute pneumonia (n=1); 1 event occurred in the group of patients with SF, and 3 occurred in the group of patients without SF (4.5% vs. 16.7%, P=0.46).

Of the remaining 36 patients, 3 had absolutely reduced LVEF (<52% in males or <54% in females) or relatively reduced LVEF (>10% [all in the group of patients with SF]), 2 had newly-diagnosed hypertension (1 in the group of patients with SF and 1 in the group of patients without SF), 1 patient complained of mild angina and presented with a positive exercise test (in the group of patients without SF), 3 had newly-diagnosed diabetes mellitus (1 in the group of patients with SF and 2 in the group of patients without SF), and 3 had newly-diagnosed hyperlipidemia (2 in the group of patients with SF and 1 in the group of patients without SF). The medications of these patients are shown in Table 4.

Table 4. Medical Treatments During Follow-up

Medications	SF (n=20)	No SF (n=16)	P value
Aspirin [n (%)]	0	1 (6.3)	0.44
β-blockers [n (%)]	1 (5.0)	2 (12.5)	0.57
ACE/ARB [n (%)]	1 (5.0)	2 (12.5)	0.57
Diuretics [n (%)]	1 (5.0)	0	1.00
Calcium-channel blocker [n (%)]	1 (5.0)	0	1.00
Nitrates [n (%)]	0	1 (6.3)	0.44
Statin [n (%)]	2 (10.0)	1 (6.3)	1.00
Metformin [n (%)]	1 (5.0)	1 (6.3)	1.00
Acarbose [n (%)]	1 (5.0)	2 (12.5)	0.57

ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; SF, septal flash.

In the 36 patients, 13 (36.1%) had a relative reduction in LV GLS >15% from baseline to 2-year follow-up, and the incidence was significantly higher in the isolated cLBBB patients with SF compared with the patients without SF [11 (55.0%) vs. 2 (12.5%), P=0.01]. LV systolic function, including GLS, septal LS, non-septal LS and LVEF, in the isolated cLBBB patients with SF, but not the patients without SF, further decreased over time (P<0.05 in all; Table 5). The inter- and intraventricular mechanical synchrony did not change significantly over time in any of the patients. Multivariate logistic regression analysis was performed to predict the reduction in LV global systolic function. After adjusting for related factors, such as age, sex, QRS duration, LV end-diastolic diameter, LV stroke volume, mitral E/A and E/E’, we found that only the presence of SF entered the final regression model and the presence of SF was the independent risk factor for a reduction in LV global systolic function (P=0.008, OR=1.27, 95% CI=1.06–1.50, Table 6).

Table 5. Left Ventricular Function and Synchrony During Follow-up

Variables	All (n=36)		No SF (n=16)		SF (n=20)
Variables	Baseline	Follow-up	Baseline	Follow-up	Baseline	Follow-up
Heart rate (beats/min)	69.8±10.5	70.4±11.5	72.18±11.7	70.5±8.4	67.9±9.2	70.4±10.8
LAVI (mL/m²)	34.04±5.31	34.21±5.14	33.47±5.64	33.82±4.87	34.51±5.12	34.67±5.02
Mitral E/A	0.79±0.27	0.74±0.36*	0.73±0.16	0.73±0.21	0.84±0.33	0.75±0.26*
Mitral E/ E’	13.75±4.77	13.18±3.88	12.65±3.28	12.07±2.45	14.68±5.66	14.05±4.25
LV end-diastolic diameter (mm)	51.15±5.15	51.74±4.23	50.22±4.84	50.08±3.98	51.88±5.40	53.71±3.73*^,†
LV mass index (g/m²)	78.85±13.06	79.14±12.94	75.88±12.68	75.00±12.69	81.93±14.35	83.45±13.58
LVEF (%)	60.32±5.52	57.00±6.16*	62.83±5.90	60.56±5.33	58.31±4.37	53.77±6.40*^,†
LV GLS (%)	−18.49±2.63	−17.51±2.37*	−20.07±2.51	−20.08±2.58	−17.22±2.00	−15.14±2.09*^,†
LV septal longitudinal strain (%)	−17.25±3.31	−16.51±3.08*	−19.03±3.47	−18.99±2.57	−15.82±2.42	−13.94±2.79*^,†
LV non-septal longitudinal strain (%)	−20.40±5.11	−18.13±4.02*	−20.99±2.80	−21.03±3.76	−19.93±3.88	−16.61±2.89*^,†
Ts-SD (ms)	62.12±15.34	67.85±17.82	55.97±9.44	56.58±14.14	67.03±17.48	75.46±18.65
IVMD (ms)	59.97±18.56	58.41±16.11	52.50±20.80	50.74±15.91	65.95±14.44	65.47±13.23

*P<0.05 vs. before follow-up; ^†P<0.01 vs. before follow-up. Abbreviations as in Tables 1,3.

Table 6. Factors Associated With a Reduction in LV Global Systolic Function on Multivariate Analysis^a

Covariate	Presence of SF	Constant
β	0.26	−5.02
SE	0.12	2.14
Wald	5.22	5.49
P value	0.02	0.02
OR	1.3	0.007
95% CI	1.04–1.63

Data presented as OR and 95% CI. ^aReduction in LV global systolic function defined as relative reduction in LV GLS >15% from baseline to 2-year follow-up. Abbreviations as in Tables 1,2.

Reproducibility of LV GLS

Mean differences in intraobserver variability of LV GLS were 0.39% (95% CI: −0.88 to 0.60%). Mean differences in interobserver variability were 0.70% (95% CI: −1.46 to 1.24%).

Discussion

In the present study we evaluated global systolic function using 2D STE in patients with isolated cLBBB and thus assessed SF. We found that SF correlated with the decrease in LV GLS in patients with isolated cLBBB, and that the presence of SF independently predicted a reduction in LV global systolic function in patients with isolated cLBBB.

2D STE can reliably assess LV systolic function by obtaining myocardial strain based on the tracking of speckles in grayscale 2D echocardiographic images. 2D STE-derived LV GLS is the recommended parameter for clinical assessment of LV global systolic function according to the American Society of Echocardiography.¹⁶ LV GLS can identify early subclinical changes and offer incremental data about LV systolic function even though the LVEF may be within the normal range.

Previous studies have shown that LV systolic function in isolated cLBBB patients is impaired based on LVEF by conventional echocardiography or IMP by tissue Doppler imaging.²⁴^,²⁵ Our results were consistent with that previous work and we further evaluated LV global systolic function by measuring LV GLS using 2D STE. Interestingly, we found that the LV GLS in isolated cLBBB patients was significantly decreased. The mechanisms underlying the effect of cLBBB on LV systolic function might be explained by the following inferences. First, cLBBB can lead to electric activation asynchrony and further mechanical asynchrony, which may impair the ability of the LV to fill with or eject blood.²^,²⁶ Moreover, cLBBB may lead to LV remodeling, asymmetric myocardial hypertrophy, and LV dilatation.²¹^,²⁷ In addition, asynchronous electric activation may affect coronary flow, myocardial perfusion, oxygen demand, and glucose metabolism, which may ultimately result in worsened myocardial performance.²⁸^–³¹

It has been reported that SF can predict a favorable response to CRT in HF patients with cLBBB.¹⁰^–¹² This abnormal septal motion may be related to a more inhomogeneous electrical activation, which results in worse myocardial performance. Gjesdal et al¹⁵ expounded the mechanisms underlying SF using a cLBBB-induced canine model and revealed that the pre-ejection leftward contraction of the septum may be an active process and the following lengthening motion towards the RV may be attributed to LV lateral wall contraction and septal flattening. The pre-ejection contraction of the septum pushes the blood towards the mitral valve, making the valve close completely and simultaneously push the blood against the lateral wall with passive stretching. In contrast, the late activated lateral wall contracts to stretch the early contractive septum rather than contributing to blood ejection. As a consequence, the interaction of the abnormal LV septal and lateral wall motion is similar to the function of a ventricular aneurysm, which leads to ineffective contraction and wastes energy for LV systole.¹⁵ Indeed, our study highlighted the negative effect of the SF phenomenon on LV systolic function in isolated cLBBB patients using 2D STE. The change in LV GLS may provide a significantly incremental value for a single individual even with the LVEF within the normal range. Moreover, we followed up these patients and found that the presence of SF was an independent factor predicting the reduction in LV global systolic function.

Our results showed that the extent of SF in isolated cLBBB patients varied, which may be related to different levels of conduction block within the left bundle conduction system.¹⁰ The cLBBB patients with a larger extent of SF may have a proximal block in the left bundle. Accordingly, electrical activation from the RV to the LV by slow cell-to-cell conduction reaches the LV endocardium and creates a breakthrough site in the middle and apical portions of the septum. Thus, these patients have a much longer trans-septal time. In contrast, the cLBBB patients with a smaller SF may have preserved activation within the proximal left bundle via one or more septal branches of the His-Purkinje system and may have a near-normal trans-septal time.²⁶ The correlation between the extent of SF and LV systolic function, however, warrants further investigation with a larger sample size.

Leenders et al²¹ classified septal deformation patterns in CRT candidates with cLBBB into 3 patterns and reported that cLBBB-1 was associated with a more favorable response to CRT. It seems there are many similarities between SF and cLBBB-1. However, when we tried to identify the characteristic septal deformation patterns in our research, we found that there were few patients to include in cLBBB-2. We speculated that the heterogeneity may relate to different study populations because we included isolated cLBBB patients with preserved LVEF rather than the patients who were candidates for CRT with cLBBB. Therefore, SF may be a more effective way to predict the reduction in LV global systolic function in isolated cLBBB patients.

During follow-up of the isolated cLBBB patients, we found that 3 of them developed absolute or relatively reduced LVEF. All of these patients had SF, and all had involvement of 6 myocardial segments of the septum. When further comparing the LV global systolic function, we found that the patients with SF significantly decreased over time and the presence of SF was an independent factor predicting deterioration of LV global systolic function. These results further confirmed the prognostic value of SF for deterioration of LV global systolic function in isolated cLBBB patients, thus emphasizing the importance of close monitoring of isolated cLBBB patients with SF. During the follow-up period, a relative reduction in LV GLS was found in 13 patients, but only 3 patients developed absolute or relatively reduced LVEF. This further confirmed the incremental value of 2D STE for predicting a deterioration of LV global systolic function in isolated cLBBB patients.

Clinical Implications

Isolated cLBBB patients may have different prognoses. Some patients may develop LV systolic dysfunction or even HF. Therefore, it is important to differentiate these 2 groups of patients. The assessment of SF by 2D STE may be an easy and effective way of predicting a deterioration of LV global systolic function in isolated cLBBB patients. It may help not only with counseling the patients about their prognosis, but also for performing early additional treatment or special management.

Study Limitations

There were diverse limitations to our study. First, there are currently no recognized standards for the definition of a reduction in LV global systolic function using GLS. In the present study, we referred to the standard from an expert consensus on cancer therapy reported by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. It is recommended that a reduction in GLS >15% from baseline is very likely to be abnormal during chemotherapy.²³ It remains to be further analyzed using special standards.

In addition, we did not analyze the correlation between the extent of SF and LV systolic function because of the limited number of patients. We will investigate this correlation in a corollary study with sufficient sample size.

Furthermore, it is also worth mentioning that we obtained the results of this work only with use of the EchoPAC work station (GE Healthcare). Different software may use different tracking techniques, which may make a subtle difference.

Moreover, in the present study, the recommendations were based on a preliminary study given the limited sample size and follow-up duration, and the potential link to subsequent HF has not been made. Therefore, a prospective trial with a longer follow-up period and a larger number of patients from a multicenter study should be designed to validate the findings.

Conclusions

Isolated cLBBB patients with SF may be at risk of a reduction in LV systolic function. Assessment of SF by 2D STE may be an easy and effective way to help counsel such patients about their prognosis. Isolated cLBBB patients with SF should receive special attention and undergo regular follow-up. This is a preliminary study and some larger and longer prospective studies are necessary to verify these results.

Disclosures of Interests

The authors have no conflicts of interest to disclose.

Financial Support

This work was supported by the National Natural Science Foundation of China (Project number 81401413); and Fund for Scientific Research of The First Hospital of China Medical University (Project number fsfh1312).

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