1

Mechanism of Abnormal Septal Motion in Left Bundle Branch

Block: Role of Left Ventricular Wall Interactions and Myocardial

Scar

Brief title: Modifiers of Septal Motion in Left Bundle Branch Block

John M. Aalen a, b, c, f, MD; Espen W. Remme a, b, d, MSc, Dr.ing.; Camilla K. Larsen a, b, c, f,

MD; Oyvind S. Andersen a, b, c, f, MD; Magnus Krogh a, d, MSc; Jürgen Duchenne g, h, MSc;

Einar Hopp e, MD, PhD; Stian Ross b, c, MD; Ahmed S. Beela g, h, MD; Erik Kongsgaard b, c,

MD, PhD; Jacob Bergsland a, d, MD, PhD; Hans H. Odland b, c, MD, PhD; Helge Skulstad a, b,

c, f, MD, PhD; Anders Opdahl c, MD, PhD; Jens-Uwe Voigt g, h, MD, PhD; Otto A. Smiseth a,

b, c, f, MD, PhD, FACC.

Total word count: 5331

a Institute for Surgical Research, b Center for Cardiological Innovation, c Department of

Cardiology, d The Intervention Center, e Division of Radiology and Nuclear Medicine, Oslo

University Hospital, f Institute of Clinical Medicine, University of Oslo, Oslo, Norway, g Department of Cardiovascular Sciences, University of Leuven, and h Department of

Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium

Funding:

Dr Aalen was supported by a grant from the Norwegian Health Association. Drs Larsen and

Andersen were recipients of clinical research fellowships from the South-Eastern Norway

Regional Health Authority. Professor Voigt holds a personal research mandate of the Flemish

Research Council. Professor Voigt and Mr Duchenne were further supported by a grant of the

University of Leuven. Dr Beela received a research grant from the Egyptian Ministry of

Higher Education.

Disclosures:

Professor Smiseth is co-inventor, but has no longer ownership of the patent “Method for

myocardial segment work analysis”, which was used to calculate myocardial work in the

clinical study. The other authors report no conflicts.

Address for correspondence:

Otto A. Smiseth, MD, PhD

Department of Cardiology

Oslo University Hospital, Rikshospitalet

N-0027 Oslo, Norway

Phone: + 47 23 07 00 00

Fax: + 47 23 07 39 17

E-mail: otto.smiseth@ous-hf.no

Acknowledgments:

The authors thank Surgical Nurse Aurora Pamplona for her contribution to the animal

experiments.

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Abstract:

Objectives: This study sought to investigate how regional left ventricular (LV) function

modifies septal motion in left bundle branch block (LBBB).

Background: In LBBB the interventricular septum often has marked pre-ejection shortening,

followed by immediate re-lengthening (rebound stretch). This motion, often referred to as

septal flash, is associated with positive response to cardiac resynchronization therapy (CRT).

Methods: In 10 anesthetized dogs we induced LBBB by radiofrequency ablation and

occluded the circumflex (CX) (n=10) and left anterior descending (LAD) (n=6) coronary

arteries, respectively. Myocardial dimensions were measured by sonomicrometry and

myocardial work by pressure-segment length analysis. In 40 heart failure patients with LBBB,

including 20 with post-infarct scar and 20 with non-ischemic cardiomyopathy, myocardial

strain was measured by speckle-tracking echocardiography and myocardial work by pressure-

strain analysis. Scar was assessed by cardiac magnetic resonance imaging with late

gadolinium enhancement.

Results: During LBBB each animal showed typical septal flash with pre-ejection shortening

and rebound stretch, and reduced septal systolic shortening (p<0.01). CX occlusion caused

LV lateral wall dysfunction and abolished septal flash due to loss of rebound stretch

(p<0.0001). Furthermore, CX occlusion restored septal systolic shortening to similar level as

before induction of LBBB and substantially improved septal work (p<0.001). LAD occlusion,

however, accentuated septal flash by increasing rebound stretch (p<0.05).

Consistent with the experimental findings, septal flash was absent in patients with LV lateral

wall scar due to lack of rebound stretch (p<0.001), and septal systolic shortening and septal

work far exceeded values in non-ischemic cardiomyopathy (p<0.0001). Septal flash was

present in most patients with anteroseptal scar.

Conclusions: LV lateral wall dysfunction and scar abolished septal flash and markedly

improved septal function in LBBB. Therefore, function and scar in the LV lateral wall should

be taken into account when using septal motion to evaluate dyssynchrony.

Condensed abstract:

Septal flash is a characteristic feature of left bundle branch block (LBBB) and predicts

response to cardiac resynchronization therapy (CRT), but is not consistently present. In the

present clinical and experimental study, we evaluated the effect of ischemia on septal motion

during LBBB. LV lateral wall ischemia abolished septal flash and septal work improved

markedly. Similar findings were present in patients with LV lateral wall scar. During septal

ischemia, however, septal flash was preserved. These findings suggest that LV lateral wall

function is important when evaluating dyssynchrony and future studies should investigate

how this is related to CRT response.

Keywords: Cardiac Resynchronization Therapy, Heart Failure, Left Bundle Branch Block,

Myocardial Work, Septal Flash, Strain

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Abbreviations:

CMR = cardiac magnetic resonance

CRT = cardiac resynchronization therapy

CX = circumflex coronary artery

ECG = electrocardiogram

GLS = global longitudinal strain

LA = left atrial

LAD = left anterior descending coronary artery

LBBB = left bundle branch block

LGE = late gadolinium enhancement

LV = left ventricular

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Introduction:

Cardiac resynchronisation therapy (CRT) causes reverse left ventricular (LV)

remodelling and improves survival in heart failure patients with left bundle branch block

(LBBB) (1). Using current ECG-based selection criteria, however, only about 50-70% of

patients show positive response. A number of different imaging-based criteria have been

tested to optimize selection of patients for CRT, but so far none are proven to add clinical

value (2).

Observational studies of patients with LBBB have shown an association between

abnormal septal motion and positive response to CRT (3-9). Therefore, it was proposed to use

abnormal septal motion by echocardiography as a means to identify patients who are likely to

benefit from CRT. The characteristic features of septal motion in LBBB are marked pre-

ejection contraction with leftward motion of the septum, followed by immediate re-

lengthening (rebound stretch) and subsequent paradoxical rightward motion (10,11). This

contraction pattern is often referred to as septal flash (4). As shown previously, pre-ejection

shortening is mainly due to active septal contraction (12), whereas rebound stretch is the

result of contractions in late activated remote myocardium (3,11,13). Furthermore, as

suggested by mathematical simulation studies (14), reduction of LV lateral wall contractility

may reduce septal rebound stretch and increase septal shortening in LBBB.

About one third of patients with wide QRS and LBBB do not demonstrate septal flash

(7,15), suggesting that non-electrical factors have major influence on septal motion in LBBB.

Since septal pre-ejection shortening and rebound stretch are dependent on active contraction

in the septum and LV lateral wall, respectively, we hypothesized that a shift in the balance of

forces between the two parts of the ventricle would modify septal flash and septal pump

function. To address the specific hypothesis that impairment of LV lateral wall function

would attenuate rebound stretch and therefore abolish septal flash, we occluded the

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circumflex coronary artery (CX) in acutely instrumented, anesthetized dogs. We also induced

septal ischemia to determine if impairment of septal function would shift the balance of forces

in favour of the LV lateral wall and modify septal flash accordingly. To investigate the same

hypothesis in patients, we compared patients with LBBB and non-ischemic cardiomyopathy

to patients with LBBB and post infarct myocardial scar.

Methods:

Experimental study

Animal preparation:

Ten mongrel dogs of either sex and body weight of 40±4 kg were anesthetized by

propofol and opioids (single dose methadone 0.2 mg/kg, followed by propofol 3-4 mg/kg and

a bolus of fentanyl 2-3 μg/kg, thereafter continuous infusion of propofol 0.2-1 mg/kg/min and

fentanyl 5-40 μg/kg/hour). The animals were ventilated and surgically prepared as previously

described (16), including partial splitting of the pericardium from apex to base and loose

resuturing of the pericardial edges after completed instrumentation. Cardiac and aortic

pressure catheters and catheter for radiofrequency ablation were introduced via peripheral

vessel incisions and a left atrial (LA) pressure catheter was introduced via the LA appendage.

To obtain LV lateral wall ischemia we occluded the proximal part of the CX by an adjustable

extravascular occluder cuff (n=5) or intravascular balloon inflation (n=5). Similarly, septal

ischemia was obtained by proximal left anterior descending coronary artery (LAD) occlusion

(adjustable occluder (n=1) or balloon inflation (n=5)). In animals with both LAD and CX

occlusion (n=6), the protocol was varied so that LAD was occluded first in 4 animals and CX

first in 2 animals. In one animal the posterior descending coronary artery (PDA) was occluded

simultaneously as LAD to obtain adequate septal ischemia. The National Animal

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Experimentation Board approved the study. The animals were supplied by the Center for

Comparative Medicine (Oslo University Hospital, Rikshospitalet, Oslo, Norway).

Pressures, dimensions and electromyograms

LV pressure was measured by a 5F micromanometer-tipped catheter (model MPC 500,

Millar Instruments Inc., Houston,TX, USA). The LV micromanometer was zero referenced to

LA pressure measured via a fluid-filled catheter during diastasis, using extrasystolic beats

with long diastoles.

LV dimensions were measured as circumferential segment lengths by sonomicrometry

using 2 mm wide crystals (Sonometrics Corporation, London, Ontario, Canada) implanted in

the inner third of the myocardium in the interventricular septum and in the posterior, anterior

and lateral LV walls. Apical and basal crystals were added to allow measurement of LV

volume (17). The ultrasonic crystals were combined with a bipolar electrode for recording of

intramyocardial electromyograms. This enabled simultaneous assessment of myocardial

electrical and mechanical activation. Data were sampled at 200 Hz.

Experimental protocol:

LBBB was induced by radiofrequency ablation as previously described (12).

Measurements were obtained during sinus rhythm or atrial pacing prior to and after 61±16

seconds of complete CX occlusion and after 42±16 seconds of complete LAD occlusion.

Data analysis:

Values are given as average of three consecutive heart beats. Systolic shortening was

measured as end-diastolic minus end-systolic dimension. End-diastole was defined as onset

septal shortening following myocardial electrical activation as determined by the septal

electromyogram. Septal pre-ejection shortening, rebound stretch and ejection shortening were

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measured as indicated in Figure 1. LV lateral wall pre-ejection lengthening was defined as the

corresponding stretch seen simultaneously with septal pre-ejection shortening. Systolic stretch

index was calculated as the sum of systolic stretch in septum and LV lateral wall (18).

Segmental myocardial work was estimated as the pressure-segment length loop area. Work

performed during counter-clockwise rotation was defined as positive and work during

clockwise rotation, reflecting stretching of the segment, was considered negative. Work for a

given segment was defined as the sum of positive and negative work.

Clinical study

Study population:

Forty heart failure patients with LBBB were recruited from the Department of

Cardiology at Oslo University Hospital, Oslo, Norway and University Hospitals Leuven,

Leuven, Belgium. All patients were planned for CRT implantation. Patients were separated

based on non-ischemic (n=20) and ischemic (n=20) cause of cardiomyopathy and the latter

was further divided into a posterolateral (n=10) and anteroseptal scar group (n=10) based on

predominant scar location. Cardiac magnetic resonance (CMR) imaging with late gadolinium

enhancement (LGE) ruled out previous myocardial infarction in 17 out of 20 non-ischemic

patients. In the remaining 3 patients, a coronary angiogram without signs of significant

coronary artery disease was performed within the last 10 months. CMR with LGE was

performed in 8 out of 10 patients in the posterolateral scar group and all 10 patients in the

anteroseptal scar group. For posterolateral scar patients not undergoing CMR (n=2), scar was

assessed echocardiographically by an experienced reader. Medical history, clinical

examination, ECG and echocardiography were obtained in all participants. LBBB was defined

according to Strauss (19).

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The study was approved by the Regional Ethics Committees and written, informed

consent was obtained from all study participants.

Echocardiography and strain analysis:

A Vivid E9 or E95 ultrasound scanner (GE Vingmed Ultrasound, Horten, Norway)

was used to acquire two dimensional (2D) grey-scale echocardiographic images from

parasternal and apical views. Average frame rate was 60±9 frames/s. Ventricular volumes and

LV ejection fraction were calculated by the biplane Simpson’s method.

Global and segmental longitudinal strain analyses were performed by speckle tracking

echocardiography (Echopac, GE Vingmed Ultrasound, Horten, Norway). Segmental strains

were obtained from the average septal and LV lateral wall strain curves in single wall analysis

in the apical 4-chamber view. Systolic shortening was measured at end-systole. Septal pre-

ejection shortening, rebound stretch, ejection shortening, and systolic stretch index were

measured similar to the experimental study (Figure 1).

Estimation of regional work:

An index of segmental myocardial work was calculated by LV pressure-strain analysis

using a semi-automated analysis tool (Echopac, version 202, GE Vingmed Ultrasound,

Horten, Norway). The method, which includes a non-invasive estimate of LV pressure, was

validated previously and is described in detail in the validation paper (20). Similar to the

experimental study, work for a segment was calculated as the sum of positive and negative

work.

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CMR and scar analysis:

Patients were scanned with a 1.5 or 3.0 Tesla unit (in Oslo: Aera or Skyra, Siemens,

Erlangen, Germany; in Leuven: Ingenia, Philips Healthcare, Best, the Netherlands), using a

phased array coil. LGE images in long- and short axis projections were obtained during steady

state after intravenous injection of 0.15 mmol/kg gadoterate meglumine (Doteram™, Guerbet,

Villepinte, France). An experienced radiologist visually interpreted the LGE images to

determine if myocardial infarct was present. Infarct size was thereafter quantified

semiautomatically in Segment software v2.0 R5270 (21) using a stack of short axis slices, and

polar maps were constructed using a 17 segment model (22). Myocardial infarct size was

reported as percentage of the total amount of tissue per segment. Anteroseptal wall infarct was

defined as the average infarct size of the LV anterior and septal segments, whereas

posterolateral wall infarct was defined as the average infarct size of the LV posterior and

lateral wall segments.

Statistical analysis:

Values are presented as mean ± standard deviation (SD). If not otherwise stated,

comparisons within the same group were performed by paired samples t-tests, whereas

comparisons between two groups were performed by independent samples t-tests. A value of

p<0.05 was considered significant for the experimental study. Since comparison of each of

the two ischemic groups to the non-ischemic group in the clinical study was not orthogonal,

we used Bonferroni correction so that only a value of p<0.025 was considered significant.

IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp was used for the

analyses.

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Results:

Experimental study

In each animal induction of LBBB caused abnormal septal motion with pre-ejection

shortening followed by rebound stretch and marked reduction in septal systolic shortening

(Table 1). A representative septal strain trace is displayed in Figure 1.

Occlusion of CX caused marked hypokinesia in the LV lateral wall (p<0.0001), and

abolished septal flash due to loss of rebound stretch (p<0.0001) (Figures 2 and 3, Table 1).

Furthermore, CX occlusion restored septal systolic shortening to values similar to control

recordings prior to induction of LBBB (4.2±1.3 vs. 4.0±2.6 mm, respectively, NS) (Figure 3).

Figure 4 shows how progressive reduction in LV lateral wall systolic shortening during

increasing ischemia was associated with progressive decrease in septal rebound stretch,

illustrating the tight coupling between contractile function in early-activated septum and late-

activated LV lateral wall.

Occlusion of the LAD, on the other hand, increased septal rebound stretch (p<0.05)

and caused marked reduction in septal systolic shortening (p<0.02) (Figure 2, Table 1). Septal

pre-ejection shortening was maintained during LAD occlusion. There was no significant

change in LV lateral wall shortening.

Figure 5A shows a grossly abnormal pressure-segment length loop for the septum with

lengthening during part of systole, which is typical for LBBB. The systolic lengthening

implies that work was performed by other parts of the ventricle to stretch the septum, which

by definition is negative septal work, and is indicated by the gray-shaded part of the loop.

During CX occlusion, septal function improved markedly as the septum performed positive

work throughout the entire heart cycle (Figure 5A, Table 1). During LAD occlusion, however,

septal dysfunction was aggravated as indicated by marked increase in rebound stretch and

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septum behaved as a net passive structure during most of systole (Table 1). The supplemental

video illustrates beat-to-beat changes in the septal and LV lateral wall pressure-segment

length loops with CX occlusion during LBBB.

Clinical study

All patients were in sinus rhythm with ECG features of LBBB and there were similar

QRS-duration and LV ejection fraction among the groups (Table 2). Patients with

posterolateral scar had largest LV volumes, whereas patients with anteroseptal scar had lowest

absolute values for global longitudinal strain (GLS) (Table 2).

For the group of patients with posterolateral scar undergoing CMR, gadolinium

enhanced tissue represented 61±26% of LV posterolateral wall and 13±9% of the anteroseptal

wall. For the anteroseptal scar group, gadolinium enhanced tissue represented 32±18% of the

anteroseptal wall and 6±7% of the posterolateral wall.

As expected, LV lateral wall shortening was substantially reduced in the posterolateral

scar group (p<0.001 vs. non-ischemic group) (Figure 2, Table 2). Similar to the observations

in the experimental study with CX occlusion, rebound stretch was completely absent in

patients with posterolateral scar (p<0.001 vs. non-ischemic group), and septal systolic

shortening was substantially larger (p<0.0001 vs. non-ischemic group) (Figure 2 and Figure 6,

Table 2). In patients with anteroseptal scar, however, septal rebound stretch was present

(Table 2).

Segmental pressure-strain loop analysis showed marked differences between patients

with posterolateral scar and non-ischemic patients. As illustrated in Figure 5B, non-ischemic

LBBB patients had deformed septal pressure-strain loops, indicating reduced positive work

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and a substantial portion of negative work. This was accompanied by a large pressure-strain

loop area in the LV lateral wall, reflecting increased lateral wall work. In patients with

posterolateral scar there was markedly lower LV lateral wall work (p<0.002) (Table 2). This

was, similar to the experimental findings, associated with a large septal pressure-strain loop

area, reflecting that the septum performed more positive work (p<0.001) (Figure 5B).

Discussion:

The present study demonstrates that abnormal septal contraction pattern in LBBB can

be enhanced or aggravated by purely mechanical factors. In experimental LBBB, induction of

LV lateral wall ischemia gradually abolished septal rebound stretch and improved septal

systolic shortening to similar values as recordings during normal conduction, whereas

induction of septal ischemia increased rebound stretch and caused reduction of septal systolic

shortening. This interaction between septal and LV lateral wall function in LBBB was

confirmed in the clinical study by the observation that patients with LBBB and LV lateral

wall scar had apparently normal septal contraction pattern. In patients with LBBB and

anteroseptal scar there was abnormal septal motion, essentially similar to patients with LBBB

and non-ischemic cardiomyopathy.

Taken together, these observations indicate that abnormal septal motion in LBBB is

determined not only by electrical conduction delay, but also by the balance of contractile

forces between septum and LV free wall. Our findings help to explain why a substantial

number of LBBB patients do not have septal flash (7), and suggest that function and structure

of the LV lateral wall should be taken into account when using septal contraction pattern to

evaluate LV dyssynchrony.

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Terminology and mechanisms of abnormal septal motion in LBBB

Abnormal early-systolic septal motion in LBBB was defined as septal beaking by

Dillon et al (1974) who used M-mode echocardiography (23). Somewhat later the same

phenomenon was imaged by tissue Doppler echocardiography and the color change of early-

systolic septal thickening/thinning was referred to as septal flash (4). Mechanisms behind

abnormal septal motion in LBBB have been debated. Rapid leftward motion of the septum at

onset systole has been attributed to right ventricular (RV) contraction preceding LV

contraction, causing RV pressure to transiently exceed LV pressure and septum moves

leftwards analogous to a passive membrane (24,25). Subsequently, when LV pressure exceeds

RV pressure, the septum is pushed towards the RV and accounts for paradoxical rightward

motion of the septum in LBBB. The proposed mechanism for leftward motion of the septum

was challenged by studies from our group, which concluded that the pre-ejection septal

shortening was mainly due to active septal contraction (12,26). This was based upon the

observation that the septum was contracting against rising LV pressure and rising trans-septal

pressure, which is not compatible with passive motion. Furthermore, the LV pressure-segment

length relation was shifted upwards during pre-ejection, indicating stiffening of the

myocardium. This was confirmed in the present study as illustrated in Figure 5A (upper left

panel). Walmsley et al (27) in a simulation study, argued in favor of a passive mechanism.

When taking the different studies into account, it seems likely that a passive mechanism is

superimposed on the active pre-ejection septal contraction and may contribute to the abnormal

leftward shift of the septum in LBBB.

As shown previously, septal rebound stretch is due to contraction in the LV lateral

wall (3,11,13). This mechanism was supported by the observation in the present study that

rebound stretch and paradoxical rightward septal motion were lost during LV lateral wall

ischemia (Figure 3). Unfortunately, the term septal flash is used inconsistently in the

14

literature, and therefore it may be preferable to specify the abnormal motion rather than using

a term such as septal flash.

Modifiers of abnormal septal motion in LBBB

Mathematical simulation studies have suggested that septal contraction patterns typical

for LBBB can be modified by changing regional LV contractility (14). The present study

shows that this mechanism is operative in the in vivo heart as indicated by the tight coupling

between septal rebound stretch and contractile function in the LV lateral wall in the

experimental study, and the observation that septal contraction pattern was apparently normal

in patients with scar in the LV lateral wall.

Enhanced septal deformation pattern during LV lateral wall ischemia and scar was

reflected in marked improvement in septal work estimated by septal pressure-dimension

analysis. Therefore, not only septal deformation pattern, but also septal pump function was

markedly improved when the LV lateral wall was dysfunctional. In a recent study of patients

with LBBB we also demonstrated a strong afterload dependency of septal motion (28). In that

study we showed aggravation of septal dysfunction with enhanced septal rebound stretch

during acute elevation of aortic pressure (28). Therefore, septal contraction pattern in LBBB

is modified by non-electrical factors, which need to be taken into account when using septal

contraction pattern as marker of electrical dyssynchrony.

In the present clinical study, there was no difference in rebound stretch between non-

ischemic patients and patients with anteroseptal scars, which is in apparent contradiction to

the experimental data where septal ischemia increased septal rebound stretch. This difference

between the acute dog experiments where ischemic myocardium is relatively elastic (29) and

post infarct patients may be due to increased stiffness of the scar as stiff tissue is less prone to

stretch. Furthermore, most of the patients with anteroseptal scar had apical aneurysms that

15

could potentially absorb displaced blood due to shortening in the LV lateral wall and thereby

lead to less stretch in the mid and basal portions of the septum.

Despite proximal LAD occlusion in the experimental study and anteroseptal scar in the

clinical study, there were no differences in pre-ejection septal shortening as compared to no

ischemia, which is somewhat unexpected assuming this is an active contraction. This could in

part be explained by the fact that septal pre-ejection shortening occurs against low LV

pressure representing only a small amount of work and, hence, can still be performed by a

weakened segment. In accordance with this, it was shown by Lyseggen et al that short-lasting

pre-ejection shortening was preserved in ischemic segments (30) and furthermore, computer

modeling studies of LBBB have shown that septal pre-ejection shortening was present despite

reduced septal contractility (14). However, collaterals preventing complete septal ischemia in

the dog model and substantial amounts of viable myocardium, especially in the basal and

inferior parts of the septum in anteroseptal scar patients, have likely affected our results. This

does not necessary limit clinical relevance as scar in the entire septum is rare, also after LAD-

infarcts (31).

Posterolateral scar and CRT response

In patients evaluated for CRT, septal rebound stretch has been suggested as a

functional substrate for CRT (3), and in support for this concept it was shown that

normalization of septal motion after CRT implantation is a predictor of long term survival (7).

The finding that reduced contractility in the LV lateral wall markedly improved septal

contraction pattern raises the question whether such patients experience favorable effect from

CRT. In fact, there is convincing evidence that patients with posterolateral scar do not

respond to CRT (32-34). This has been attributed to lack of efficient pacing as the LV lead is

placed over fibrotic tissue and was supported by the observation that lead location outside

16

scar tissue improved acute response to CRT in animals with LBBB and CX infarction (35).

However, a mathematical simulation study showed that the benefit of CRT was small in

patients with LV lateral wall scar, even when pacing in an optimal location (36). Thus,

absence of septal dysfunction as target for CRT, which implies less potential for improvement

of LV function by resynchronization, may also contribute to lack of response in patients with

posterolateral scars (14).

Clinical implications:

Currently, ECG is the only dyssynchrony parameter used routinely in the evaluation of

CRT candidates. The finding in the present study of apparently normal septal contraction

pattern in patients with LV lateral wall scar in spite of wide QRS and typical LBBB

morphology, implies that abnormal septal motion pattern has limited sensitivity for

identifying patients with electrical dyssynchrony. This, however, does not necessarily

represent a limitation of septal motion analysis to improve selection of patients for CRT. As

suggested by the insights provided by the present study, when heart failure patients with

LBBB do not have abnormal septal contraction pattern, one should search for scar in the LV

lateral wall. In addition, apparently normal septal contraction pattern implies that the potential

for improvement of LV function with CRT is less than in patients with abnormal septal

motion. Possibly, patients with LBBB and absence of septal flash should not receive CRT.

Whether this will be useful diagnostic approaches when evaluating patients for CRT, should

be further explored in future prospective studies.

Limitations:

The experimental part of the study was performed in an acute animal model during

general anesthesia and extensive instrumentation. Furthermore, the clinical part of the study

17

was cross-sectional with relatively small size of patient groups and acute ischemia in the

experimental study is different from post-infarct scar in the clinical study. In total, however,

the present investigation with a combined experimental and clinical design was well suited to

determine the role of LV lateral wall scar and function in generation of abnormal septal

contraction patterns in LBBB.

Conclusions:

The present study demonstrates that septal contraction pattern in LBBB is determined

by contractile function in the LV lateral wall. When patients with LBBB and wide QRS do

not have abnormal septal contraction pattern, one should search for scar in the LV lateral wall.

Therefore, evaluation of septal function may be important not only to use typical abnormal

contraction pattern to favor CRT, but also to use apparently normal septal contractions to raise

suspicion of LV lateral wall scar with less likelihood of good response to CRT. Future studies

should explore if these proposed strategies will provide added clinical value when selecting

patients for CRT.

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Clinical perspectives:

Competency in Medical Knowledge: LV lateral wall function is an important

determinant of abnormal septal motion and reduced septal function in LBBB.

Competency in Patient Care and Procedural Skills: Patients with LBBB and apparent normal

septal motion should be examined for scar in the LV lateral wall.

Translational Outlook 1: There is need for prospective trials to evaluate whether LBBB

patients without septal flash should receive CRT.

Translational Outlook 2: Future studies should explore whether imaging has added value on

top of ECG for dyssynchrony assessment in CRT candidates.

19

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Figure legends:

Figure 1. Septal deformation during left bundle branch block

Experimental study: Pressure and septal strain traces after induction of LBBB in a

representative animal. AVC=aortic valve closure; AVO=aortic valve opening;

ECG=electrocardiogram; LBBB=left bundle branch block; LV=left ventricular; LA=left

atrial; MVC=mitral valve closure; MVO=mitral valve opening.

Figure 2. Determinants of abnormal septal motion in left bundle branch block

Upper panels: Strain traces from representative animal during LBBB (left), LBBB with CX

occlusion (middle) and LBBB with LAD occlusion (right). Please note how septal rebound

stretch is lost and septal systolic shortening markedly improved with LV lateral wall

ischemia.

Lower panels: Strain traces and LGE-CMR images from representative LBBB patients (left:

non-ischemic cardiomyopathy; middle: LV lateral wall scar; and right: anteroseptal scar).

Similar to the experimental study, there is no rebound stretch and instead markedly improved

septal deformation in the patient with LV lateral wall scar, whereas septal rebound stretch is

present in the patient with anteroseptal scar.

AVC=aortic valve closure; CX=circumflex coronary artery; LAD=left anterior descending

coronary artery; LBBB=left bundle branch block; LGE-CMR=late gadolinium-enhanced

cardiac magnetic resonance; LV=left ventricular.

Figure 3. Effect of left ventricular lateral wall ischemia on septal flash

Upper panels: Parasternal M-mode images from representative animal during normal

conduction (left), LBBB (middle) and LBBB with CX occlusion (right). Please note how

25

septal flash is abolished with LV lateral wall ischemia due to loss of paradoxical rightward

septal motion.

Lower panels: Strain traces from representative animal during normal conduction (left),

LBBB (middle) and LBBB with CX occlusion (right). Similar to the paradoxical rightward

septal motion, septal rebound stretch (arrow) is lost with LV lateral wall ischemia and septal

systolic shortening restored to similar levels as normal conduction.

AVC=aortic valve closure; CX=circumflex coronary artery; LBBB=left bundle branch block;

LV=left ventricular.

Figure 4. Stepwise reduction in left ventricular lateral wall contractility during left

bundle branch block

Strain traces from representative animal before (left panel) and during increasing LV lateral

wall ischemia (right panels). The gradual loss of contractility in the LV lateral wall is closely

followed by decrease in septal rebound stretch and increase in septal systolic shortening.

AVC=aortic valve closure; LBBB=left bundle branch block; LV=left ventricular.

Figure 5. Septal pump function during left bundle branch block and left ventricular

lateral wall ischemia

A) Experimental study: Representative pressure-segment length loops from a dog after

induction of LBBB. The area of the loops reflects myocardial work where positive work is

performed during counter-clockwise rotation (segmental shortening) and negative work

during clockwise rotation (segmental lengthening). Please note how septal systolic function

improves markedly during LV lateral wall ischemia as the loop rotates counterclockwise

during systole and performs a large positive work.

26

B) Clinical study: Representative pressure-strain loops from two LBBB patients (to the left

patient with non-ischemic cardiomyopathy and to the right patient with LV lateral wall scar).

The loops resemble the experimental observations in A).

LBBB=left bundle branch block; LV=left ventricular.

Figure 6. Septal versus left ventricular lateral wall shortening in left bundle branch

block

Upper panel: Experimental study. During LBBB there is reduced septal and maintained LV

lateral wall systolic shortening. With LV lateral wall ischemia, however, the negative impact

from the LV lateral wall on the septum is removed and septal shortening improves markedly.

Lower panel: Clinical study. The findings in patients with non-ischemic cardiomyopathy as

compared to patients with LV lateral wall scar, resemble those from the experimental study.

LBBB=left bundle branch block; LV=left ventricular.

Supplemental video. Negative crosstalk between septum and left ventricular lateral wall

in left bundle branch block

The video displays beat-to-beat changes in septal and LV lateral wall pressure-segment length

loops in a representative animal immediately after onset of CX occlusion. The negative

impact of the LV lateral wall on the septum is removed as the LV lateral wall becomes

increasingly ischemic and allows the septal loop to perform predominantly positive work.

CX=circumflex coronary artery; LBBB=left bundle branch block; LV=left ventricular.

27

Tables:

Table 1. Hemodynamic variables for animals after induction of left bundle branch block

(LBBB)

LBBB

(n=10)

LBBB and CX

occlusion

(n=10)

LBBB

(n=6)

LBBB and LAD

occlusion (n=6)

Heart rate (bpm) 117 ± 15 121 ± 15 112 ± 16 125 ± 14

QRS duration (ms) 107 ± 4 110 ± 5 107 ± 4 108 ± 5

Peak LV pressure

(mmHg)

88 ± 9 74 ± 10* 92 ± 9 78 ± 7*

LV end diastolic

pressure (mmHg)

9 ± 5 13 ± 5* 9 ± 3 12 ± 5 *

LV dP/dt max

(mmHg/s)

1011 ± 120 877 ± 124* 1050 ± 132 902 ± 100*

LV stroke volume (ml) 19 ± 5 15 ± 4* 21 ± 4 13 ± 4*

LV stroke work

(mmHg·ml)

1257 ± 383 769 ± 370* 1499 ± 228 743 ± 221*

Septal pre-ejection

shortening (mm)

2.7 ± 1.0 2.4 ± 0.7* 2.8 ± 1.1 2.9 ± 0.9

Septal rebound stretch

(mm)

1.4 ± 0.6 0.2 ± 0.2* 1.5 ± 0.3 2.7 ± 1.2*

Septal ejection

shortening (mm)

1.5 ± 0.9 2.4 ± 0.8* 1.8 ± 0.9 0.4 ± 0.5*

Septal systolic

shortening (mm)

1.1 ± 1.4 4.2 ± 1.3* 2.4 ± 1.6 0.3 ± 1.5*

28

Values are mean ± standard deviation. Segmental data are circumferential. *p<0.05 vs.

LBBB.

CX=circumflex coronary artery; LAD=left anterior descending coronary artery; LBBB=left

bundle branch block; LV=left ventricular.

LV lateral wall pre-

ejection lengthening

(mm)

1.2 ± 0.7 0.8 ± 0.6* 1.1 1.2 ± 0.6 1.1 ± 0.6

LV lateral wall systolic

shortening (mm)

5.0 ± 1.2 0.5 ± 1.0* 4.9 ± 1.2 4.2 ± 1.1

Systolic stretch index

(%)

8.8 ± 3.4 3.5 ± 1.8* 9.6 ± 2.5 12.0 ± 5.6

Septal work

(mmHg·mm)

5 ± 62 108 ± 47* 29 ± 70 -96 ± 72*

LV lateral wall work

(mmHg·mm)

417 ± 84 74 ± 65* 437 ± 98 310 ± 98*

29

Table 2. Characteristics of left bundle branch block (LBBB) patients

Non-ischemic (n=20) Ischemic (n=20)

Posterolateral

scar (n=10)

Anteroseptal

scar (n=10)

Age (years) 65 ± 11 67 ± 6 70 ± 5

Male gender (n) 9 10 8

Height (cm) 169 ± 10 176 ± 8 172 ± 6

Weight (kg) 75 ± 16 87 ± 21 79 ± 20

Heart rate (bpm) 68 ± 11 56 ± 10* 62 ± 8

Systolic blood pressure

(mmHg)

137 ± 25 126 ± 18 123 ± 19

Diastolic blood pressure

(mmHg)

75 ± 12 70 ± 15 63 ± 8*

NYHA class 2.4 ± 0.7 2.6 ± 0.5 2.4 ± 0.7

Medication (n)

ACE-inhibitor/ARB

Beta blocker

Aldosterone antagonists

Loop diuretics

20

19

10

12

9

10

5

6

10

8

4

8

Sinus rhythm (n) 20 10 10

LBBB (n) 20 10 10

QRS duration (ms) 165 ± 16 162 ± 19 167 ± 17

30

Table 2. Characteristics of LBBB patients (continued)

Non-ischemic (n=20) Ischemic (n=20)

Posterolateral

scar (n=10)

Anteroseptal

scar (n=10)

Dimensions end diastole (mm)

Septum

LV internal diameter

LV posterior wall

10 ± 2

63 ± 8

9 ± 2

11 ± 1

71 ± 6*

9 ± 2

9 ± 1

70 ± 11

8 ± 1

LV end diastolic volume (ml) 218 ± 79 313 ± 74* 247 ± 86

LV end systolic volume (ml) 153 ± 65 220 ± 66* 177 ± 67

LV ejection fraction (%) 31 ± 5 31 ± 6 28 ± 6

Global longitudinal shortening

(%)

10.4 ± 2.4 10.4 ± 1.7 8.0 ± 2.4*

Septal pre-ejection shortening

(%)

5.4 ± 1.9 3.8 ± 1.8 5.2 ± 3.3

Septal rebound stretch (%)Ɨ 2.6 ± 2.9 (1.8) 0.0 ± 0.0 (0.0)* 3.2 ± 3.6 (1.7)

Septal ejection shortening (%) 2.3 ± 2.7 9.5 ± 3.8* 2.5 ± 2.5

Septal systolic shortening (%) 2.2 ± 3.5 10.7 ± 4.4* 3.0 ± 3.4

LV lateral wall pre-ejection

lengthening (%)

3.3 ± 2.0 1.5 ± 1.1* 2.4 ± 1.8

LV lateral wall systolic

shortening (%)

12.3 ± 3.6 3.6 ± 1.9* 12.9 ± 4.1

Systolic stretch index (%) 9.0 ± 3.1 4.1 ± 3.6* 7.2 ± 4.3

Septal work (mmHg·%) 7 ± 377 754 ± 453* 46 ± 506

31

Values are mean ± standard deviation. *p<0.025 vs. non-ischemic. ƗDue to lack of normality

and heterogeneity of variance, a Mann-Whitney test was performed and median values given

in brackets for septal rebound stretch.

ACE-inhibitor=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor

blocker; LBBB=left bundle branch block; LV=left ventricular; NYHA class=new york heart

association functional classification.

LV lateral wall work

(mmHg·%)

1552 ± 784 512 ± 468* 1048 ± 697

32

Figure 1

33

Figure 2

34

Figure 3

Figure 4

35

Figure 5A

Figure 5B

36

Figure 6