Delayed trans-septal activation results in comparable hemodynamic effect of left ventricular and biventricular endocardial pacing insights from electroanatomical mapping

Bostock, Reza Razavi, Frits Prinzen and C. Aldo RinaldiManav Sohal, Anoop Shetty, Steven Niederer, Zhong Chen, Tom Jackson, Eva Sammut, Julian

Ventricular and Biventricular Endocardial Pacing: Insights from Electro-Anatomical MappingDelayed Trans-Septal Activation Results in Comparable Hemodynamic Effect of Left

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DOI: 10.1161/CIRCEP.113.001152

1

Delayed Trans-Septal Activation Results in Comparable Hemodynamic Effect

of Left Ventricular and Biventricular Endocardial Pacing:

Insights from Electro-Anatomical Mapping

Running title: Sohal et al.; Endocardial CRT and delayed trans-septal activation

Manav Sohal, MRCP1,2; Anoop Shetty, MD1,2; Steven Niederer, PhD1; Zhong Chen, MRCP1;

Tom Jackson, MRCP1; Eva Sammut, MRCP1; Julian Bostock, MSc2; Reza Razavi MD1;

Frits Prinzen, PhD3; C. Aldo Rinaldi, MD1,2

1Division of Imaging Sciences and Biomedical Engineering, King’s College; 2Cardiovascular Department, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom; 3Maastricht

University Medical Center, Cardiovascular Research Institute (CARIM), Maastricht, the Netherlands

Correspondence:

Dr Manav Sohal

King’s College London

Division of Imaging Sciences and Biomedical Engineering

Rayne Institute, 4th Floor Lambeth Wing

St. Thomas’ Hospital

Westminster Bridge Road

London SE1 7EH

United Kingdom

Tel: 0044(0) 207 188 8382

Fax: 0044(0) 207 188 5442

Email: [email protected]

Journal Subject Codes: [11] Other heart failure, [110] Congestive, [120] Pacemaker, [106] Electrophysiology

;

2222

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DOI: 10.1161/CIRCEP.113.001152

2

Abstract:

Background - We sought to compare left ventricular (LVepi) and biventricular epicardial pacing

(BIVepi) with left ventricular (LVendo) and biventricular endocardial pacing (BIVendo) in patients

with chronic heart failure with an emphasis on the underlying electrophysiological mechanisms

and hemodynamic effects.

Methods and Results - 10 patients with chronically implanted cardiac resynchronization devices

underwent temporary LVendo and BIVendo pacing with an LV endocardial roving catheter. A

pressure wire and non-contact mapping array were placed to the LV cavity to measure

LVdP/dtmax and perform electroanatomical mapping. At the optimal endocardial position the

acute hemodynamic response (AHR) was superior to epicardial stimulation, the AHR to BIVendo

pacing and LVendo pacing being comparable (21±15% vs 22±17%; P=NS). During intrinsic

conduction QRS duration (QRSd) was 185±30ms, endocardial LV total activation time

(LVTAT) 92±27ms and trans-septal activation time (TSAT) 60±21ms. With LVendo pacing

QRSd (187±29ms; P=NS) and endocardial LVTAT (91±23ms; P=NS) were comparable to

intrinsic conduction. There was no significant difference in endocardial LVTAT between LVendo

and BIVendo pacing (91±23 vs 85±15ms; P=NS). Assessment of isochronal maps identified slow

trans-septal conduction with both LVendo and BIVendo pacing resulting in activation of almost the

entire LV endocardium prior to septal breakout thereby limiting any possible fusion with either

pacing mode.

Conclusions - The equivalent AHR to LVendo and BIVendo pacing may be explained by prolonged

trans-septal conduction limiting electrical fusion. The optimal AHR was associated with

predominantly LV pre-excitation and depolarization. Our results suggest that LV pacing alone

may offer a viable endocardial stimulation strategy to achieve cardiac resynchronization.

Key words: pacing, heart failure, cardiac resynchronization therapy, left bundle branch block, electroanatomic mapping

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DOI: 10.1161/CIRCEP.113.001152

3

Background

The last two decades have seen cardiac resynchronization therapy (CRT) establish itself as a

powerful tool in selected heart failure patients with evidence of electrical dyssynchrony.

However, when applying internationally recognized selection criteria for CRT there is a non-

response rate of 30-40%.1, 2 CRT is conventionally delivered as biventricular pacing with

endocardial stimulation of the right ventricle and epicardial left ventricular (LV) stimulation via

the coronary sinus (BIVepi). Clinical studies have shown similar outcomes with LV and BIV

pacing suggesting that epicardial LV only pacing (LVepi) may be as beneficial as BIVepi.3 A

recent canine study suggested delayed trans-septal activation results in the majority of LV

depolarisation occurring prior to any contribution from right ventricular (RV) stimulation

thereby limiting fusion of electrical wave-fronts.4 LV pacing alone has potential advantages over

BiV pacing as it may preserve intrinsic conduction, avoid detrimental effects of RV pacing and

reduce the number of electrodes making implantation less technically challenging. Endocardial

LV pacing (BIVendo) pacing is not limited by CS anatomy and has been shown to improve acute

and medium-term CRT response5-8 due to a more physiological electrical and mechanical

propagation.9, 10 The relative effect of endocardial pacing (LVendo) alone compared to BIVendo

pacing is not well defined. We therefore sought to compare the hemodynamic effects of LVepi

and BIVepi with LVendo and BIVendo pacing in patients with chronic heart failure with an

emphasis on the underlying electrophysiological mechanisms that might explain the response to

these different pacing modalities.

Methods

The study was approved by the local ethics committee and informed consent was obtained from

each patient. The study population consisted of 10 patients with a chronically implanted CRT

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DOI: 10.1161/CIRCEP.113.001152

4

system in-situ for at least three months (St Jude Medical, Sylmar, CA, USA). All patients

fulfilled standard criteria for CRT (NYHA class II-IV drug refractory he

pacing). Patients with a mechanical aortic valve or significant peripheral vascular disease were

excluded. Baseline assessment included NYHA functional class, ECG and 2D echocardiography

prior to the original CRT implant. Each patient’s heart failure etiology was confirmed on the

basis of clinical history, coronary angiography and/or cardiac magnetic resonance (CMR)

imaging. In all cases a temporary LV endocardial lead was used to perform LV endocardial

stimulation.

Invasive Hemodynamic and Electro-anatomical Study

The protocol used has previously been described.11 Patients were lightly sedated using diazepam

(5-10mg). A steerable 6Fr Livewire decapolar catheter (St Jude Medical, Sylmar, CA, USA)

was passed from the left femoral artery retrogradely to the LV cavity to stimulate multiple sites

within the LV. A non-contact mapping (NCM) array was passed retrogradely into the LV cavity

and an 0.014 inch diameter high fidelity Certus PressureWire and PhysioMon software (RADI

Medical Systems, Uppsala, Sweden) with a 500Hz frequency response and 50Hz filter

bandwidth were used to assess real-time mean peak LVdP/dtmax.7

Acute Hemodynamic Measurement

LVdP/dtmax was recorded for at least 20 s to ensure steady-state conditions during any pacing

modality. LVdP/dtmax during atrial pacing (AAI) or RV pacing (if the patient was in AF) at 5-10

beats above intrinsic rate was used as baseline. A waiting period of at least 20 s was respected

after any change in pacing settings or lead position to achieve hemodynamic stabilization. These

methods have previously been shown to reliably measure LVdP/dtmax.12-17 Results at each pacing

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DOI: 10.1161/CIRCEP.113.001152

5

site were expressed as a percentage change from baseline. To minimize baseline drift in AHR the

baseline was reassessed prior to and after every change in pacing modality and comparisons were

made to a mean of these two readings. Data from premature ventricular complexes were

discarded.

Pacing protocol

A pacing protocol was performed: (5-10bpm above intrinsic rate, paced and sensed AV delay

100ms, AAI pacing as baseline and repeated after each pacing mode):

i)DDD-RV only

ii)DDD-LV only from the chronic epicardial CS lead (LVepi)

iii)DDD-BIV from the chronically implanted epicardial LV lead plus RV pacing with 0ms V-V

delay (BIVepi)

iv) LV only pacing from the endocardial catheter at multiple endocardial sites (LVendo)

v) LV endocardial and RV endocardial pacing from multiple LV endocardial sites with 0ms V-

V delay (BIVendo)

BIVendo and LVendo stimulation was repeated with the LV roving catheter in a random order in up

to 4 different LV endocardial positions including anterior, lateral, and posterior sites. Capture

was verified for each pacing modality by looking for a change in QRS morphology at a paper

speed of 200mm/s. This was also validated with reference to LV pacing by analysis of the

activation wavefront on non-contact mapping. For the purposes of this study the endocardial

position producing the best AHR with BiVendo pacing was chosen as the position used for

analysis.

Electro-anatomical mapping

Analysis of the non-contact mapping data was performed by 2 independent observers blinded to

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DOI: 10.1161/CIRCEP.113.001152

6

the hemodynamic results. Endocardial maps were obtained at baseline and in each pacing

configuration. The virtual unipolar electrograms recorded at 1200Hz (temporal resolution of

0.83ms) from the endocardial surface were used to measure the endocardial left ventricular total

activation time (LVTAT).18 The high pass filter was set at 8Hz. The onset of LV activation was

defined as the first peak negative dV/dt at any point in the LV and the end of LV activation was

defined as the time of the latest peak negative unipolar electrogram on the virtual endocardial

surface. The trans-septal activation time (TSAT) was defined as the time from the onset of the

earliest QRS complex to the time of the first detected LV endocardial breakthrough as described

previously by Auricchio et al.19

Statistical Analysis

Statistical analysis was performed on PASW Statistics 20 (SPSS Inc, Chicago, IL, USA). Data

were analyzed using generalized estimating equations using an exchangeable correlation

structure, to explore the extent of differences between pacing methods. Pacing methods were

compared to each other and to avoid type 1 errors, P values were corrected using the Bonferroni

adjustment. Descriptive results are expressed as mean± SD.

Results

Patient demographics (table 1)

Baseline characteristics are shown in table 1. All patients were male with a mean age of 62 ± 8

yrs. The mean LVEF was 26 ± 8% and there were equal numbers of ischemic and non-ischemics

(5/5). The mean QRS duration was 186±27 ms and morphology was LBBB in 9 and RV paced

rhythm in the remaining patient. The epicardial LV lead was in a lateral or postero-lateral

position in 8 (80%) patients and in an anterior position in 2 (20%) patients. Table 2 displays the

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DOI: 10.1161/CIRCEP.113.001152

7

epicardial LV lead positions for each patient along-side the optimal LV endocardial pacing

position in each case. There was concordance in four cases (table 2).

Acute hemodynamic response (figure 1 and table 3):

LV dP/dtmax whilst AAI pacing 5-10 beats above intrinsic rate was taken as the baseline to which

all pacing measurements were compared in each patient. Table 3 shows the mean (SD)

percentage increase in LV dP/dtmax for each pacing mode over baseline. Compared to baseline,

LVepi pacing from the chronically implanted epicardial lead gave a 10±14% increase in LV

dP/dtmax. BIVepi pacing increased LV dP/dtmax over baseline by 15±15% whilst LVendo and

BIVendo pacing increased LV dP/dtmax over baseline by 22±17% and 21±15% respectively. The P

value for the overall test for variability across all pacing modalities was significant at 0.001

(figure 1). BIVepi increased LV dP/dtmax by a mean of 4.1% (95% CI 1.2 to 7.0). However the

AHR to BIVendo pacing and LVendo pacing were comparable with a mean difference of 1.1%

(95% CI -5.5 to 7.8). At the optimal endocardial position, hemodynamics were superior to

epicardial stimulation with a mean difference of 6.2% (95% CI 0.5 to 11.8 for BIVendo vs BIVepi

pacing).

QRS duration, LVTAT and Transeptal Activation Times (TSAT) (figure 1 and table 3):

Intrinsic QRSd was 185±30ms and the intrinsic endocardial LVTAT was 92±27ms. Four

patients exhibited a type I pattern of endocardial activation (homogenous spread from the septum

to lateral wall) whilst 6 patients exhibited a type II pattern of activation (characterized by a line

of functional block between the septum and lateral wall).19 TSAT in intrinsic rhythm was

60±21ms and lengthened with RV pacing to 71±13ms (mean difference 10.4, 95% CI 0.6 to

20.2). Figure 2 demonstrates the delay in endocardial breakout on the left side of the

interventricular septum following RV pacing. LVepi pacing resulted in a similar QRSd to

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DOI: 10.1161/CIRCEP.113.001152

8

intrinsic (187±25ms vs 185±30ms) and a similar endocardial LVTAT (93±17). BIVepi however,

significantly reduced QRSd to 142±12ms (mean difference -42.3; 95% CI -61.0 to -23.6) and

shortened endocardial LVTAT to 72±15ms (mean difference -20.1; 95% CI -41.4 to 1.2)

suggesting a degree of fusion of RV and LV wavefronts. The mean QRSd and endocardial

LVTAT with LVendo pacing were comparable to intrinsic rhythm (187±29ms and 91±23ms

respectively). BIVendo pacing from the same position as LVendo reduced QRSd over intrinsic

rhythm to 155±28ms however there was no significant difference between the endocardial

LVTAT between LVendo and BIVendo pacing (91±23 vs 85±15ms; mean difference -5.9; 95% CI -

14.6 to 2.8).

Assessment of the isochronal activation maps of the LV during the various pacing modes

demonstrated fusion of electrical wave-fronts with BIVepi pacing (figure 3). LVepi pacing

resulted in minimal fusion of RV and LV activation wave fronts. No significant fusion was seen

with BIVendo pacing and the activation maps were strikingly similar to LVendo pacing (figure 3).

The non-contact maps identified slow trans-septal conduction during both LVendo and BIVendo

pacing. This resulted in activation of almost the entire LV endocardium prior to septal breakout,

thereby limiting any possible fusion with either pacing mode. With BIVepi pacing, endocardial

breakthrough from the epicardial LV lead was sufficiently delayed to allow fusion of electrical

wave fronts.

Discussion

The present study provides new insights into the electrical mechanisms of epicardial and

endocardial CRT. The principal findings of our study are as follows: 1) trans-septal LV

activation was prolonged during both intrinsic rhythm and RV pacing (equivalent to

approximately 33% of the QRSd); 2) there was no significant difference between the AHR

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DOI: 10.1161/CIRCEP.113.001152

9

derived from LVendo and BIVendo at the optimal site whereas BIVepi appeared superior to LVepi

pacing; 3) Endocardial LVTAT and LV endocardial activation patterns were comparable

between BIVendo and LVendo pacing suggesting minimal fusion of LV and RV wave-fronts. 4)

LVendo pacing may be equivalent to BiVendo pacing.

Endocardial pacing hemodynamics and electrical changes

BIVendo stimulation at the optimal site gave a superior AHR to epicardial pacing which was site

specific. LVendo stimulation at a short AV delay produced a similar AHR to BIVendo pacing

(22±17% vs 21±15%, P=NS) suggesting no incremental benefit in BIVendo over LVendo pacing

(when pacing at a short AV delay) in comparison to epicardial stimulation. Our findings may be

explained on the basis of the long trans-septal activation times seen in our patients with LBBB so

that by the time the RV pacing impulse had broken through the septum into the LV cavity

(approximately 70msecs) the majority of LV endocardial activation had already occurred. This is

supported by examination of the isochronal activation maps of BIVendo and LVendo pacing which

were almost identical, suggesting an absence of fusion (figure 3). The short AV interval of

100ms used in our study may explain the apparent lack of fusion seen with LVendo/epi pacing and

the PR interval in our group was 182±19ms therefore at an AV delay of 100ms one would not

expect any fusion from intrinsic activation via the right bundle branch. A reduction in QRSd

was noted with BIVendo pacing but endocardial LVTAT remained similar between LV and

BIVendo pacing. The surface QRSd represents a summation of LV and RV activation times and

therefore the QRS reduction seen with BIV pacing may reflect a reduction in RV (and not LV)

activation time. We measured only LV endocardial activation time (and not epicardial) and the

reduction may be related to changes occurring in the epicardium as has been shown in the canine

model.4 We saw divergent findings for LVepi and BIVepi pacing with an improvement in AHR

Vendo over LVendo papapapacic

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DOI: 10.1161/CIRCEP.113.001152

10

with BIVepi pacing over LVepi accompanied by a reduction in both QRSd and endocardial

LVTAT. The electrical findings may be accounted for by the fact that pacing from the

epicardium resulted in a sufficient delay to compensate for prolonged trans-septal conduction

thereby allowing fusion of electrical wave-fronts from RV and LV stimulation. A reduction in

RV activation time (which was not measured) may have also contributed to the reduction in

QRSd with BIVepi pacing (the reduction in QRSd between LVepi and BIVepi was greater than

the reduction between LVendo and BIVendo). Our results would suggest a mismatch between

hemodynamic response and electrical paramaters with the best hemodynamic response being

relatively equal between LVendo and BIVendo pacing, however with epicardial pacing this differed.

This may suggest that optimal pacing LV endocardially may only require a single lead. The long

TSAT seen in our group would suggest that most LV depolarization occurs via the LV pacing

impulse in both LVendo and BIVendo modes.

Comparison with previous studies

Our findings of improved hemodynamic response with endocardial CRT are in keeping with

other groups. Strik et al demonstrated in a chronic canine heart failure model improved

hemodynamics as a result of LV endocardial pacing compared to conventional epicardial CRT

which could be explained by the shorter path length and more rapid conduction resulting from

endocardial LV pacing.20 Derval et al found better hemodynamic effects with LVendo versus

LVepi and in keeping with our study showed that there is not one pacing site (or combination of

pacing sites) that is best for all patients.6 The benefits of LV endocardial pacing seen in our

patients are likely to be due to a reduction in total LV activation time (endocardial and epicardial

activation) with the reduction predominantly in epicardial LV activation time (which we did not

specifically measure in this study. Our findings of slow trans-septal conduction are strikingly

yny amic respop nse bebebebeini

cardidiiialalll ppacacininii g g ttththisisisis ddddifif

uggest that optimal pacing LV endocardially may only require a single lead. The

n i

o

gs of impro ed hemod namic response ith endocardial CRT are in keeping it

ugggggegegegestststs tthahahahattt opppptitititimal pacing LV endocarddddiaiaialll y may onlyyy reqqquiuiuire a single lead. The

n innn n our group wwouuulddd sugggggggest ttt tththt aaat moosttt LVV depppolololaaara iizaaation ococcuuurrss via thhhe LLV pppaaaci

boththhh LVLVLVLVendo a ddndd BIBIBIB VVVVendo mmmmoddododes.

on wiii hthth prpp evvvioioioous stut dididies

ff iim ded hh dod iic iithth dnd didi lal CRCRTT iin kk ipi itit




DOI: 10.1161/CIRCEP.113.001152

11

similar to those recently found in canines.4 Strik et al found a TSAT of 67±9ms in a canine

model of LBBB and pacing induced dysynchrony compared to 60±21ms in our patients with

LBBB and heart failure. In the same study there was no incremental benefit in BIV compared to

LV only pacing and this was due to predominant LV stimulation in both modes due to long

trans-septal activation times. This is in keeping with our findings with endocardial stimulation

where we saw no incremental benefit with RV and LV pacing due to apparent lack of fusion with

both modalities. Our results do however differ in that we found an incremental hemodynamic

benefit with BIVepi compared to LVepi associated with a reduction in the LVTAT and a degree of

fusion of wave fronts, which may be explained by much longer endocardial LVTAT than in the

dogs. Additionally, we saw that there was a delay between epicardial stimulation and endocardial

breakthrough (as seen in figure 3) thereby allowing for a delay in trans-septal conduction and

resulting in fusion of RV and LV wave fronts. We saw minimal fusion with LVepi pacing and

this may have been as a result of the short AV delay used in the study (100ms) versus the longer

mean PR interval (182ms) in intrinsic rhythm. The short AV delay when the RV was paced with

BIVepi pacing may have provided a sufficient head start and therefore earlier breakthrough into

the LV endocardium. The difference may also be explained by the differences between the

animal model in our patients with chronic heart failure, significantly dilated ventricles and the

presence of scar (50% of our patients were ischemic). Also the PR interval in our patients of over

180ms is longer in comparison to the canine model and likely explains the difference on the basis

of fusion with BIVepi pacing.

Human studies comparing LVepi pacing with BIVepi pacing would also seem to suggest

that there is little difference in terms of acute hemodynamics or medium-term clinical response

between the two.3, 21-23 We found a small (but statistically significant) benefit in AHR with

he LVTAT and a ddddegegee

ardiaal lll LVLVLVLVTATATATATTTT ththhthanananan iin

tionally, we saw that there was a delay between epicardial stimulation and endoc

g as seen in f ure there allowing for a delay in trans-septal conduction an

n fusion of RV and LV wave fronts. We saw minimal fusion with LVepi pacing

ave been as a result of the short AV delay used in the study (100ms) versus the lo

nter al (182ms) in intrinsic rh thm The short AV dela hen the RV as paced

tiononononalalalllylylyy, weweww ssawawawaw that there was a delay bebebebetwween epicardidd al sssstitt mulation and endoc

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ntte lal ((181822m )s) ii iinttriin isi hh thth ThTh hsh tt AVAV dd lel hhe thth RVRV ded




DOI: 10.1161/CIRCEP.113.001152

12

BIVepi pacing over LVepi pacing. The reason behind this may lie behind the fact that we

utilized a short AV delay of 100ms compared to a long mean intrinsic PR interval of 182ms.

This meant that we saw minimal fusion with LVepi pacing (see figure 3) and this in turn may

have attenuated the AHR. Auricchio et al also studied the differences in LVdP/dtmax between

LVepi and BIVepi pacing and found LVepi to be associated with a slightly greater AHR.24

Crucially, pacing was performed in VDD mode (atrial sensing) and so did not control for heart

rate which is one of the key determinants that affects absolute values of LVdP/dtmax.

Additionally, most LV leads were positioned apically and this has been shown to attenuate the

response to BIV stimulation.25 These differences may also explain why our results vary in this

respect.

Study Limitations

This study is limited by its small sample size, however given the highly invasive and time-

consuming nature of the study the size was limited to the smallest size needed to provide

significant results in this proof of principle study. Ideally a range of AV delays and VV delays

would have been assessed but this was not possible because of time constraints and will need to

be assessed in future studies. Our study used a short AV delay of 100ms and this may in some

part explain the results. With such a short AV delay there was likely to be little intrinsic fusion

in the LV only modes (intrinsic PR interval was over180ms). At a short AV delay, LV and BIV

endocardial pacing appear equivalent, although we cannot rule out the possibility that at different

AV delays this may have differed due to ‘LV fusion’ pacing. Our measures of LV activation

were endocardial and we did not study epicardial activation specifically. We do, however, have

data on QRS duration which is a measure of total electrical activation of the heart. We did not

specifically look at areas of myocardial scar in relation to lead positioning in our patients may

n shown to attenuuuatatatatee

hy ourur rresesulullltststt vvara y y yy inininin

m

g

res lts in this proof of principle st d Ideall a range of AV dela s and VV del

miiiitaaaations

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g gg nature off f thhheee sssts udddy yy hhthe siiize was lllimii iiti edddd to ththhhe smallestt sizii e nennn dedd ddedd to prpp ovovovovidididde

ltlt iin tthihi ff fof iri iiplle tt dd IdId llll fof AAVV ddella dnd VVVV ddell




DOI: 10.1161/CIRCEP.113.001152

13

which may be important in determining both the optimal epicardial and endocardial stimulation

sites. There was concordance between epicardial and endocardial lead position in only four cases

meaning that comparisons between endocardial and epicardial CRT should be made with caution

and the benefits of LV endocardial pacing seen in this study may be related to the lack of being

constrained by coronary venous anatomy and so being able to pace from a more optimal position.

Our assessment of CRT response using AHR may not necessarily translate into chronic response,

however, previous work from our institution has suggested a good correlation with chronic

response albeit predominantly in non ischemic patients.17

Clinical implications

Our findings may have important implications for the practice of endocardial CRT. This type of

CRT may become more prevalent in an attempt to improve CRT response. Our results would

suggest that in such patients LVendo pacing may be a viable treatment strategy and that in

patients not requiring an RV lead (for potential defibrillation) it may be reasonable to implant an

LV lead alone.

Conclusion

Endocardial LV pacing from the optimal site is hemodynamically superior to conventional

epicardial CRT, but biventricular endocardial pacing did not produce an incremental

hemodynamic benefit over endocardial LV pacing alone. This may be due to long trans-septal

activation times resulting in lack of fusion of LV and RV wavefronts. Indeed the optimal

hemodynamic response would appear to be associated with predominantly LV pre-excitation and

depolarization. Our results suggesting that LV pacing alone may offer a viable endocardial

stimulation strategy to achieve CRT.

g p

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a

a

one

gs mmmmayayaya hhhhavavava ee immmportant implications for tttheheheh practice of eeendocococo ardial CRT. This typ

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DOI: 10.1161/CIRCEP.113.001152

14

Conflict of Interest Disclosures: Drs. Sohal and Shetty are supported by an educational grant from St. Jude Medical. Dr. Niederer receives research support from Boston Scientific Corp.Professor Razavi receives research support from Philips Healthcare. Professor Prinzen has received research grants from Medtronic Inc., Boston Scientific Corp., MSD, Biological Delivery System (Cordis) and EBR Systems. Dr. Rinaldi receives research support form St. Jude Medical and Medtronic Inc. All other authors state that they have no conflicting interests to declare.

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ininnnoooo J,J,J,J, AAAAbrbrbrbrahahahahamamamam WWWWT,T,T,T,SSutteteeer r r r J,J,J,J, MMMMururururilililillolololo JJJJ. ReReReRe2008888;1;1;1117171717:2:222606060608-8-8-8-2626262616

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t B,B,B,B, DDDDuchaaarmrmrr e AA,AA Harel F, White M, O'MMMeaara E, Guerrrrtititiin MCMCMCMC, Lavoie J, Frasure-MMMM, GGuerra P, MaMM clcllcle L,LL,L RRRRivivivivarrrrd d d d LL,LL RRoyy DDD, TaTalaaajijijij c MM,MM KKKKhahhahaiririry yy PP. LLLLefefefeft veveveentntntrririicucucuulalalaar r veuuusu bbbbiventricullarr pacaacing innnn patiennntss withhh heaeart fffaiaiaiailululurre aaannnd a QQRSSS comppppllel xx 122000ds. CiCCiCircrcrccululululatatata ioiooonnn. 202020011111;1; 24242424:2:2:2:287878787444-2828282881818181

van nnn DeDeDeD ururursesesennn CJCJCJCJ,,,, vavavannn MiMiMiddddddddenenendododod rprprp LLLLBB,B vvvananan HHHHunununnninininik kk A,A,A,A KKKKuiuiuipepepeerrr r M,MM,M, AAAAurururiciciccchchchioioio AAAA, WW. TrTranananssssssepepeptatatall cococondnducucuctitiononon aaasss ananan iimpmpmpororortatatantntnt ddetetetererermiminananantntnt ffororor cccararardidiacacac rrresesesynynynchchrororoninizazaza

reeveveala eddded bbbby y exe tetet nssivivvi e e elelllecectrtrt iciciicallal mappappipiingg iiin thhthhe e dydydydyssssyny chchhhroonoousus ccana ininii e e heeara t.t. CC




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tricular electric accctitititivavvvnanananatotototomimimimicccc mamamamappppppppinininingg.g.g CCCiCirrrr

lder BM, Meijer A, Bracke FA. Stimulation rate and the optimal interventricularr .n

dm cu

lder BM Bracke FA Meijer A Laker eld LJ Pijls NH Effect of optimi ing the

lderererer BBBBMM,M MMMeiiijejejer A, Bracke FA. Stimulatatatioioioi n rate and theh optptptptimii al interventricularrininini gggg cardiaaaacccc rereresysss nccnchrhrhrononononizzatatata ioioioon n thththeree apapapy yy in ppatieeentntntntssss wiwithththth ccchrhhrononono ic aatrtrtrtriaiaiaalll fibrbrbrililili lalalatitititiono .nnn n EElE ectrophysiool. 20202008;33;31:56666999-9 575574.

d MAAAA, vaavavann Geldldlder BBBMMMM, Brararaackkckcke FAAAA, vavavan ZuZZZ ddndderrrtttt AAAAAAAA, vaaannn n StStStS ratttet n AHAHAHAH. AcAAA ttute mic efefefeffefefef ctctctsss ofofofof ccccararardidididiacacacc rrrresesesynynynynchc rorororoninininizazazazatittit onnn ttthhhererererapapapapy yyy ininini ppppatatatatieieeientntntsss wiwiwiw thththth pppoooooooorr r leleleleftfttft vvvenenenntricuring gg ca drddiac sususuurgggery.yy JJJ CaCC rd SSSSurggg. 2020202 09999 22;244:4 585858555-5 5959595 0.00

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20. Strik M, Rademakers LM, van Deursen CJ, van Hunnik A, Kuiper M, Klersy C, Auricchio A, Prinzen FW. Endocardial left ventricular pacing improves cardiac resynchronization therapy in chronic asynchronous infarction and heart failure models. Circ Arrhythm and Electrophysiol.2012;5:191-200.

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25. Singh JP, Klein HU, Huang DT, Reek S, Kuniss M, Quesada A, Barsheshet A, Cannom D, Goldenberg I, McNitt S, Daubert JP, Zareba W, Moss AJ. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial. Circulation. 2011;123:1159-1166.

heart failure: Resusuuultltltlts

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DOI: 10.1161/CIRCEP.113.001152

17

Table 1: Patient characteristics

Characteristic

Age (years) 62 ± 8 Gender n(%) Male 10 (100)

Female 0 (0)Etiology n(%) Ischemic 5 (50)

Non-ischemic 5 (50)NYHA class n(%) Class II 4 (40)

Class III 6 (60)LV ejection fraction* (%) 26 ± 8 Intrinsic PR interval (ms) 182 ± 19 QRS duration (ms) 185 ± 30QRS morphology n(%) LBBB 9 (90)

RV paced 1 (10) Epicardial LV lead position n(%) Lateral 4 (40)

Posterolateral 4 (40) Anterior 2 (20)

derived from 2D echocardiography using the modified Simpson’s biplane method Continuous variables are expressed as mean ± standard deviation

Table 2: Comparison between the position of the chronically implanted epicardial LV lead and the optimal position for LV endocardial pacing

Patient Epicardial lead position Optimal endocardial lead position

1 Posterolateral Posterolateral2 Posterolateral Inferoseptal3 Lateral Lateral4 Posterolateral Lateral5 Anterior Lateral6 Lateral Posterior7 Lateral Septal8 Lateral Septal9 Posterolateral Posterolateral10 Anterior Anterior

RV paced 1 (10)

fro

RV pacededed 1 (10)LLLLV V V V lead posooo itioioioi n n(n(n(n %)%)%) Laaateteterar l 4 (40)0)0))

Possteerollaaterrrralalal 444 (4404 ))) Annteeerior 2 ((((20202020)

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DOI: 10.1161/CIRCEP.113.001152

18

Table 3: Hemodynamic and electrical parameters compared across pacing modalities

Modality % change in

dP/dtmax

over baseline

QRSd

(ms)

Mean change

in QRSd

over baseline

TSAT

(ms)

Mean change

in TSAT

over baseline

LVTAT

(ms)

Mean change

in LVAT

over baseline

Baseline n/a 185±30 n/a 60±21 92±27

RV 1±3 195±30 10.0

(0.9 to 19.1; P=0.035)

71±13 10.4

(0.6 to 20.2; P=0.040)

93±26 1.6

(-8.6 to 11.8; P=0.730)

LVepi 10±14 187±25 2.3

(-11.9 to 16.5; P=0.723)

93±17 1.8

(-19.6 to 23.2; P=0.853)

BiVepi 15±15 142±12 -42.3

(-61.0 to -23.6; P=0.001)

72±15 -20.1

(-41.4 to 1.2; P=0.062)

LVendo 22±17 187±29 2.8

(-10.2 to 15.8; P=0.639)

91±23 -0.4

(-21.5 to 20.7; P=0.967)

BiVendo 21±15 155±28 -30.1

(-47.0 to -13.2; P=0.003)

85±15 -6.3

(-21.4 to 8.8; P=0.369)

Abbreviations: LVepi – AV synchronous LV pacing from the epicardial LV lead; BiVepi – AV synchronous biventricular pacing using the chronically implanted CRT system; LVendo – AV synchronous LV pacing from the temporary endocardial LV pacing catheter; BiVendo – AV synchronous biventricular stimulation using the temporary endocardial LV pacing catheter for LV stimulation; QRSd – QRS duration; TSAT –transseptal activation time; LVAT – endocardial LV activation time

2020020 222.2; ; ; ; P=P=P=P=0.0.0.0.040404040)0)0)0)

22.22 3

(---11.9 to 161116.555;;; P=P=P=P=0.0.0.0.77727 3)3)3)3)

-4442.2.2.2 3333

(-(-6161 0.0 ttoo -22-2233.6;6; PP=0=0 0.00101))




DOI: 10.1161/CIRCEP.113.001152

19

Figure Legends:

Figure 1: Mean change from baseline in dP/dtmax, QRS duration and LV activation time for each

pacing modality. This is displayed as the percentage mean change each variable resulting from

pacing in each pacing configuration, compared with baseline (AAI pacing). Abbreviations as for

table 2.

Figure 2: Isochronal map derived from non-contact mapping in a patient with RV pacing

(referenced to RV stimulation artifact). The left hand panel is in a right anterior oblique (RAO)

orientation and the right panel is in a left anterior oblique (LAO) orientation. Septal breakout is

identified as the site of earliest onset in the LV (white colour scale on the map). Inspection of

the scale bar on the left shows that it takes approximately 65ms from the onset of RV stimulation

before septal breakout occurs and begins spreading across the LV.

Figure 3: Isochronal maps from the same patient as figure 2, with LVepi pacing (top panels) and

BIVepi pacing (bottom panels). There is a change in endocardial electrical activation between

LVepi and BIVepi modalities. Inspection of the colour scale bar on the left shows that there is a

delay between epicardial stimulation and endocardial breakthrough and this is sufficient to allow

some fusion of endocardial activation of the LV from RV and LV epicardial stimulation.

Figure 4: Isochronal maps from the same patient as figure 2, with LVendo pacing (top panels)

and BIVendo pacing (bottom panels). Endocardial stimulation results in a broad region of early

activation with both pacing modalities and endocardial activation that is broadly similar for both

(implying minimal fusion of RV and LV stimulation wavefronts).

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-20

-10

0

10

20

30

40

50

60

LVepi BiVepi LVendo BiVendo

Pacing Configuration

Chan

ge in

LV d

P/dt

max

from

bas

elin

e (%

) Overall test of variability across all pacing modes: P=0.012




-40

-30

-20

-10

0

10

20

30



Chan

ge in

QRS

dur

atio

n fr

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asel

ine

(%)

Overall test of variability across all pacing modes: P<0.001




-60

-40

-20

0

20

40

60

80



Chan

ge in

end

ocar

dial

LVAT

from

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elin

e (%

) Overall test of variability across all pacing modes: P<0.001













Documents

Delayed trans-septal activation results in comparable hemodynamic effect of left ventricular and biventricular endocardial pacing insights from electroanatomical mapping