DOI: 10.1161/CIRCEP.112.971317

1

Effect of Bipolar Electrode Spacing on Phrenic Nerve Stimulation and Left

Ventricular Pacing Thresholds: An Acute Canine Study

Running title: Biffi et al.; Short bipolar pacing to avoid PNS in CRT

Mauro Biffi, MD1; Laurie Foerster, BS2; William Eastman, BS2; Michael Eggen, PhD2;

Nathan A Grenz, BS2; John Sommer, BS2; Tiziana De Santo, MSc3; Tarek Haddad, MSc2;

Annamaria Varbaro, MS3; Zhongping Yang, PhD2

1Institute of Cardiology, University of Bologna, Bologna, Italy;2Medtronic Inc., Minneapolis, MN;3Medtronic Italia S.p.A, Rome, Italy

Address for correspondence:

Mauro Biffi, MD

Institute of Cardiology

University of Bologna

Via Massarenti 9

40138 Bologna

Italy

Tel: +39 051 6363531

Fax: +39 051 344859

E-mail: mauro.biffi@aosp.bo.it

Journal Subject Codes: [110] Congestive; [22] Ablation/ICD/surgery; [120] Pacemaker

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Annamaria Varbaro, MS3; Zhongping Yang, PhD2

e of Cardiology, University of Bologna, Bologna, Italy;2Medtronic Inc., MinneapMN;3Medtronic Italia S.p.A, Rome, Italy

DOI: 10.1161/CIRCEP.112.971317

2

Abstract:

Background - Phrenic Nerve Stimulation (PNS) is a common complication of cardiac

resynchronization therapy (CRT) when left ventricular (LV) pacing occurs via a coronary vein.

The purpose of this study was to evaluate effects of bipolar electrode spacing on PNS and LV

pacing threshold.

Methods and Results - Electrophysiology (EP) catheters with standard (2mm-5mm-2mm) or

modified (1mm-5mm-1mm) inter-electrode spacing was respectively inserted in a

posterior/lateral cardiac vein in a randomized order in six anesthetized dogs via jugular access.

The phrenic nerve was dissected via a left mini-thoracotomy and repositioned over the vein, as

close as possible to one of the electrodes. The presence of PNS was verified (i.e. PNS threshold

<2V at 0.5 ms in unipolar configuration). Bipolar pacing was delivered using the electrode

closest to the phrenic nerve as the cathode, and multiple bipolar electrode spacing configurations

were tested. During bipolar pacing, PNS threshold increased as bipolar electrode spacing was

reduced (p<0.05), while LV pacing thresholds did not change significantly (p>0.05). Compared

with a standard bipolar electrode spacing of 20mm for LV leads, 1mm and 2mm bipolar

electrode spacing resulted in a PNS threshold increase of 5.5±2.2V (p=0.003) and 2.8±1.7V

(p<0.001), respectively. Similarly, PNS threshold increased by 6.5±3.7V with 1mm and by

3.8±1.9V with 2mm bipolar pacing (both p<0.001), as compared to unipolar pacing.

Conclusions - This study suggests that reducing LV bipolar electrode spacing from the standard

20 mm to 1 or 2 mm may significantly increase the PNS threshold without compromising LV

pacing thresholds.

Key words: bipolar electrode spacing; cardiac resynchronization therapy; phrenic nerve stimulation

eeeeriririrififififiedededed ( ( ((iii.i e.e.e.e. P PPPNSNSNSNS tthrhrhrhresesss

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p V

respectively. Similarly, PNS th y y

he phrenic nerve as the cathode, and multiple bipolar electrode spacing configur

d. During bipolar pacing, PNS threshold increased as bipolar electrode spacing w

<0.05), while LV pacing thresholds did not change significantly (p>0.05). Comp

dard bipolar electrode spacing of 20mm for LV leads, 1mm and 2mm bipolar

pacing resulted in a PNS threshold increase of 5.5±2.2V (p=0.003) and 2.8±1.7V

respectively. Similarly, PNS threshold increased by 6.5±3.7V with 1mm and by

DOI: 10.1161/CIRCEP.112.971317

3

Cardiac resynchronization therapy (CRT) is an established treatment of heart failure due to left

ventricular (LV) systolic dysfunction with evidence of electrical and mechanical dyssynchrony

(1, 2). The mechanism of improvement with CRT is based on the stimulation of the mostly

delayed LV sites (3-5). Phrenic nerve stimulation (PNS) is a major complication that may result

in withdrawal of CRT. PNS is observed in 33-37% of patients (6-8) and, although it is actively

addressed in different ways during implantation (6), it may be difficult to overcome in the long-

term management of CRT patients (9-11). Indeed, about 15% of patients need to be re-evaluated

after hospital discharge because of PNS occurrence at follow up (9-11), and about 6.6%

eventually report PNS symptoms at long-term follow up despite multiple attempts to avoid PNS

(10).

Device manufacturers have developed approaches to manage PNS, such as electronic

repositioning, multiple pacing vectors and modification of the pacing output, but no definite

solution has fully addressed this demanding challenge (12). We sought to investigate the

physiologic principles of PNS occurrence in an animal model, to develop a comprehensive

strategy aimed at PNS avoidance in the clinical practice.

Methods

This was an acute open chest study on six anesthetized adult dogs. The dogs were premedicated

with morphine (1mg/kg IM) and anesthesia was induced with propofol (120 mg IV) and

isoflurane to effect. ECG limb leads were placed and connected to an EP recording station

(Prucka, GE Medical Systems, US) for monitoring.

A jugular access was obtained and a standard Attain catheter (Model 6216A, Medtronic)

was introduced in the coronary sinus to perform a venogram (Figure 1A). An ICD lead (Model

), and about 6.6%

ple attttttttem tttpts ttott avovovovoidididid

v n

ng, multiple pacing vectors and modification of the pacing output, but no definit

a

i i l f PNS i i l d l t d l h i

vice manufacturers have developed approaches to manage PNS, such as electron

ng, multiple pacing vectors and modification of the pacing output, but no definit

as fully addressed this demanding challenge (12). We sought to investigate the

i i l f PNS i i l d l t d l h i

DOI: 10.1161/CIRCEP.112.971317

4

6935, Medtronic) was implanted in the right ventricle (RV) via jugular access to provide an

anodal electrode for unipolar measurements and to guarantee backup pacing, if necessary.

Decapolar EP catheter with standard (2mm-5mm-2mm) inter-electrode spacing

(Medtronic Torqr, Model 041590CS) and modified (1mm-5mm-1mm) inter-electrode spacing

was placed into a posterior/lateral cardiac vein, respectively, in a randomized order under

fluoroscopic guidance. The phrenic nerve was dissected via a left mini-thoracotomy and

repositioned over the vein, as close as possible to one of the electrodes. Radiopaque markers

(Model V60 U-Clips, Medtronic) were placed next to the nerve to document nerve location on

fluoroscopy after the chest was closed (Figure 1B). During pacing, PNS was detected using

tactile feel by placing a hand directly on the chest and the presence of PNS was verified (i.e. PNS

threshold <2V at 0.5 ms in unipolar configuration). Once the phrenic nerve was repositioned,

unipolar electrical measurements of PNS and LV pacing (LVP) thresholds were taken using all

the ten electrodes of the EP catheters as cathodes and the coil of the implanted RV lead as anode.

The electrode on the EP catheters with the lowest PNS threshold in unipolar configuration was

identified as the targeted phrenic nerve electrode (TPNE), which was considered to be closest to

the phrenic nerve (Figure 1B). Finally, Bipolar pacing was delivered using TPNE as cathode (the

electrode closest to the phrenic nerve), in order to test nine bipolar electrode spacing

configurations of the decapolar EP catheters . In each configuration PNS and LV Pacing (LVP)

thresholds were measured at 0.5ms pulse width by an amplitude step down protocol from 10V to

0.1V by pacing at 130 bpm using the analyzer (Model 2290, Medtronic Inc).The LV pacing

impedance at 5V and 0.5 ms, and the R-Wave were also measured using the same pacing

analyzer in all bipolar configurations. The surface EKG was used during the stimulation protocol

to validate true LV capture: anodal stimulation was always discarded for the measurement of

ument nerve locatitititionooo

NS was dddd tttetectttet dd d ususususininining

e

<

e g

c a

d th EP th t ith th l t PNS th h ld i i l fi ti

by placing a hand directly on the chest and the presence of PNS was verified (i.e

<2V at 0.5 ms in unipolar configuration). Once the phrenic nerve was reposition

ectrical measurements of PNS and LV pacing (LVP) thresholds were taken usingV

ctrodes of the EP catheters as cathodes and the coil of the implanted RV lead as a

d th EP th t ith th l t PNS th h ld i i l fi ti

DOI: 10.1161/CIRCEP.112.971317

5

LVP threshold. The actual bipolar electrode spacings were also measured on the EP catheter in

all bipolar configurations. This study setting closely mimics clinical practice in the worst-case

scenario, where the pacing lead is in proximity of the phrenic nerve. The study was reviewed and

approved by Medtronic’s Institutional Animal Care and Use Committee.

Statistical Analysis

A Parametric Survival Model was used to study the effect of cathode distance from phrenic nerve

for the unipolar configuration due to the fact that unipolar threshold greater than 10 V were

censored. Additionally a random effects term was incorporated into the survival model to

account for the multiple observations within a canine. A Linear mixed-effects model with

canines as the random effect was utilized to understand the effect of electrode spacing on

observed electrical measurements and safety margin. Natural cubic splines with 2 knots located

at the 1/3 and 2/3 percentiles of the predictor variables were used to address nonlinear

relationships in both models described above. To compare the effect of pacing configuration on

thresholds for both PNS and LV, a linear mixed-effects model that accounts for different

variances across the different levels of the predictor was used to account for the observed

heteroscedasticity across the pacing configurations. A Bonferroni correction was applied to the

alpha level for the multiple comparisons made across pacing configuration. All P-values for the

models described above were generated using Likelihood ratio tests. P-values < 0.05 were

considered significant.

All analysis was performed in the statistical analysis software R version 2.14.2.

Results

LVP and PNS threshold were measured in 6 dogs; the 1/5/1 mm catheter was not used in 1/6

e survival model totototo

d-efffectstt m dodddellll witititithhhh

t

l

a

p o

f b th PNS d LV li i d ff t d l th t t f diff t

the random effect was utilized to understand the effect of electrode spacing onf

lectrical measurements and safety margin. Natural cubic splines with 2 knots lo

and 2/3 percentiles of the predictor variables were used to address nonlinear

ps in both models described above. To compare the effect of pacing configuratio

f b th PNS d LV li i d ff t d l th t t f diff t

DOI: 10.1161/CIRCEP.112.971317

6

canines due to a surgical complication. Overall, 110 LVP threshold and 110 PNS threshold

measurements were carried out on the 6 animals.

Effect of cathode distance from phrenic nerve in the unipolar configuration

Figure 2 shows the effect of cathode distance from the TPNE (“phrenic nerve”) location on the

unipolar PNS and LVP threshold @ 0.5 ms to the RV coil. The PNS and LVP threshold was

positively correlated with the cathode distance from the TPNE, (p<0.001, respectively). The

effect of cathode distance from the TPNE on the unipolar PNS threshold is significantly stronger

than that on the LVP threshold (p<0.001). The unipolar PNS thresholds rapidly increased while

the cathode moving away from the TPNE and reached a maximum of 10 V@0.5 ms at the

distance greater than 20 mm. However, the unipolar LVP thresholds appeared stable while

cathode distance to the TPNE was less than 20mm then increasing while cathode distance to the

TPNE was greater than 20mm. In fact, both unipolar PNS and LVP threshold showed large

variability at TPNE distance > 20 mm likely due to phrenic nerve anatomy (i.e. divergence in the

course of the phrenic nerve from coronary vein) (13) and to the larger vein diameter when

located more proximally (i.e. poor electrode contact) : in this experimental setting the TPNE was

located at the distal end of the decapolar catheter .

Effect of bipolar electrode spacing on bipolar PNS and LVP threshold, pacing impedance

and R-wave

Figure 3 shows the random correlation of bipolar PNS and LVP thresholds to the bipolar

electrode spacing when the TPNE was used as the cathode (the electrode closest to phrenic

nerve). PNS threshold was significantly inversely related to bipolar electrode spacing (p<0.001,

Fig.3 B), while no association was found for LVP threshold ( p=0.640; Figure 3A). Figure 4 and

5 show LV pacing impedance and R-wave amplitude relationship with the bipolar electrode

s rapidly increased dd d wwa

10 VVVV@0@0@0@0 55.55 ms at tttthehehehe

r e

s t

h h i f i ) (13) d t th l i di t h

reater than 20 mm. However, the unipolar LVP thresholds appeared stable while

stance to the TPNE was less than 20mm then increasing while cathode distance t

greater than 20mm. In fact, both unipolar PNS and LVP threshold showed large

at TPNE distance > 20 mm likely due to phrenic nerve anatomy (i.e. divergence

h h i f i ) (13) d t th l i di t h

DOI: 10.1161/CIRCEP.112.971317

7

spacing when the TPNE was used as the cathode. A decrease of LV pacing impedance and a

decrease of the intrinsic R-wave were respectively observed as the bipolar electrode spacing

shortened ( p<0.001, Figure 4; p=<0.001, Figure 5).

Figure 6 summarizes the comparison of pacing configurations: the unipolar pacing was

compared respectively to the 1mm-spaced, 2 mm-space and 20 mm-spaced (this last is

commonly available in clinical practice using market-released LV leads) bipolar pacing using

the TPNE as cathode. The pacing configuration affected the PNS thresholds (p<0.001). However,

the pacing configuration did not affect LVP thresholds (p=0.130). As compared with 20mm of

standard bipolar electrode spacing, 1mm and 2mm bipolar electrode spacing resulted in a PNS

threshold increase of 5.5±2.2V (p=0.003) and 2.8±1.7V (p<0.001), respectively. Similarly, PNS

threshold increased by 6.5±3.7V with 1mm and by 3.8±1.9V with 2mm bipolar pacing (both

p<0.001), as compared to unipolar TPNE pacing. The trend of the bipolar configuration was

clear: a shorter electrode spacing resulted in significantly higher PNS thresholds (Figure 6).

Effect of bipolar electrode spacing on safety margin of bipolar PNS to LVP

Figure 7 shows the significant relationship of the difference between the bipolar PNS and LVP

thresholds to the bipolar electrode spacing with the TPNE as the cathode. The difference between

PNS and LVP threshold is significantly inversely related to the bipolar electrode spacing

(p<0.001).

Figure 8 shows the effect of the bipolar electrode spacing on the probability to achieve a

safety margin greater than 3 V at the worst case scenario, using the TPNE as the cathode (closest

to phrenic nerve). This safety margin is obtained reliably in all the cases using 1mm bipolar

electrode spacing. The success rate dropped dramatically for bipolar electrode spacing > 6 mm,

which are those typically employed for LV leads in clinical practice.

compared with 20m0m0m0mm

pacingggg resulllltettt dddd inn aaaa P

n

n t

a a

o )

bi l l t d i f t i f bi l PNS t LVP

ncrease of 5.5±2.2V (p=0.003) and 2.8±1.7V (p<0.001), respectively. Similarly,

ncreased by 6.5±3.7V with 1mm and by 3.8±1.9V with 2mm bipolar pacing (botV

as compared to unipolar TPNE pacing. The trend of the bipolar configuration wa

orter electrode spacing resulted in significantly higher PNS thresholds (Figure 6)

bi l l t d i f t i f bi l PNS t LVP

DOI: 10.1161/CIRCEP.112.971317

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Discussion

The main finding of our study is that both the distance from the LV cathode to the phrenic nerve

and bipolar electrode spacing affect the PNS threshold: the farther the LV cathode from the

phrenic nerve, or the shorter the bipolar electrode spacing, the lower the chance of PNS. The

difference between PNS threshold and LVP threshold was used to provide a “PNS safety margin”

in order to relate the results to clinical practice. Indeed, a difference 3V is associated with

freedom from PNS-related complications in the majority of clinical reports (6, 8, 10,11), which

involved about 600 patients. This safety margin was obtained reliably in all the cases using 1

mm bipolar electrode spacing and keeping the TPNE as cathode (Fig.8). The success rate

dropped dramatically for bipolar electrode spacing > 6 mm, which are those typically employed

for LV pacing in clinical practice. Two strategies for PNS management are highlighted by this

study: placing the LV cathode remote from the TPNE or shortening the bipolar electrode spacing

with the LV cathode at TPNE.

PNS needs to be managed at the same pacing sites that are deemed optimal for CRT (6,

7, 9, 11). When PNS is detected at implantation, several approaches are used: moving the lead to

a different position in the vein, programming the LV cathode to a different electrode in devices

featuring this technology or lowering the LV output to avoid PNS when the other options have

failed (6, 11, 14). LV lead repositioning to another vein is the last resort and is possible only

when other coronary veins are suitable for LV lead placement.

Each of these approaches has its own drawbacks: LV lead placement at an alternative site

poses an increased risk of a suboptimal LVP threshold and of LV lead dislodgement with need

for repeated surgery (6, 8). Surgery increases the risk of complications due to increased risk of

infection (15). Abandoning the target site or loss of capture because of a high LVP threshold may

yyy in all the cases uuuusisisisinn

8). The successs raatetetete

r l

i

p

V

S d b d h i i h d d i l f CRT

ramatically for bipolar electrode spacing > 6 mm, which are those typically empl

ing in clinical practice. Two strategies for PNS management are highlighted by

ing the LV cathode remote from the TPNE or shortening the bipolar electrode sp

V cathode at TPNE.

S d b d h i i h d d i l f CRT

DOI: 10.1161/CIRCEP.112.971317

9

cause failure to achieve CRT and clinical improvement (4,5).

Our observations highlight the need to develop new strategies for PNS management

through implant techniques and lead technology.

Impact of cathode distance from the phrenic nerve in unipolar configuration

PNS threshold has a linear relationship with distance from the phrenic nerve (Figure 2). This is

the physiological background for the strategy most commonly used in clinical practice to avoid

PNS: placement of the LV cathode far from the phrenic nerve. Nowadays this is achieved by re-

programming the LV cathode in multi-electrode leads in order to maintain lead stability and

decrease the risk of lead dislodgement (6, 8-10, 14). This strategy has not proved to ensure PNS

avoidance in 100% of patients (10-12, 16), most likely owing to the electrode spacing of bipolar

LV leads, that ranges from 10 to 20 mm, whereas our observation dictates that the LV cathode

needs to be at least 20~30 mm far from the TPNE. To overcome this limitation , a quadripolar S-

shaped LV lead that spans a length of approximately 50 mm from the tip to the proximal

electrode and allows 10 pacing configurations has been developed (16). The preliminary short-

term experience with this lead in highly trained centers reported that during implantation 5/75

(6.6%) patients had the lead placed at a vein different than the target one because of PNS that

could not be managed by re-programming (16). Moreover, the incidence of PNS at 7.5V when

programming the LV cathode 30 mm or 47 mm from the lead tip was 14% and 23%,

respectively, with an average PNS threshold around 5 ± 2 V (16). The LVP threshold in those

settings was respectively 2.5V and 3.5V on average, meaning that a 3V difference between PNS

and LVP threshold was not obtained in all patients, and that PNS avoidance was a trade-off with

a high LVP threshold. This represents a potential limitation in managing PNS at follow up (10).

Hence, owing to the variability of both coronary vein and phrenic nerve anatomy, a strategy

ntain lead stability y y y a

not ppproved ddd tottt ennnnsusususure

i b

h o

e o

d ll 10 i fi ti h b d l d (16) Th li i h

in 100% of patients (10-12, 16), most likely owing to the electrode spacing of b

hat ranges from 10 to 20 mm, whereas our observation dictates that the LV catho

e at least 20~30 mm far from the TPNE. To overcome this limitation , a quadripo

lead that spans a length of approximately 50 mm from the tip to the proximala

d ll 10 i fi ti h b d l d (16) Th li i h

DOI: 10.1161/CIRCEP.112.971317

10

based on a multi-electrode LV lead with conventional bipolar electrode spacing in the range of

10 to 20 mm does not seem to provide a comprehensive approach to manage PNS.

Impact of electrode spacing on PNS threshold and implications for a PNS-avoidance

strategy

We observed an inverse relationship of PNS threshold with bipole electrode spacing (Figure 3B),

that warrants a PNS-LVP threshold difference above 3V at a spacing < 2mm (Fig. 7,8).

This allows the implanting physician to keep the LV cathode at the target site for CRT (though

being the TPNE), thus minimizing the risk of non-response to CRT (5, 17-20), which carries the

risk of significant morbidity and mortality (1, 2, 5, 19, 20). Furthermore, this approach is neutral

on the LVP threshold compared to longer/standard electrode spacing (Fig. 6B), thus minimizing

the risk of a high LVP threshold and loss of ventricular capture when pacing elsewhere than lead

tip (16). Our results are in complete agreement with the recently published experience by Wecke

et al (21) that reported similar results in a canine model, using a networked multi-electrode LV

lead. They demonstrated (21) that a very short pacing dipole ( 1mm), obtained by pacing

between adjacent segments of networked electrodes, can achieve PNS avoidance in 100% of the

worst-case scenarios (Phrenic nerve dissected and positioned above the LV lead).

Practical implications: We believe that our study provides the rationale for the development of

multi-electrode LV leads with a 1 to 2 mm bipolar electrode spacing to maximize PNS

management either at implant or at follow up. The short-spaced dipole could be part of either

multi-electrode or active fixation leads, where all the efforts are focused to avoid both a high

LVP threshold and PNS at the same time. The advantage of such an approach is the use of an

already established and reliable LV lead technology, whereas the new lead technology described

by Wecke et al (21) might be vulnerable to the risks of any new highly sophisticated electronic

17-20), which cararararririrr e

re, thihihihis approach iiiissss ne

P i

a a

u W

h e

d t t d (21) th t h t i di l ( 1 ) bt i d b i

P threshold compared to longer/standard electrode spacing (Fig. 6B), thus minimid

a high LVP threshold and loss of ventricular capture when pacing elsewhere tha

ur results are in complete agreement with the recently published experience by W

hat reported similar results in a canine model, using a networked multi-electrode

d t t d (21) th t h t i di l ( 1 ) bt i d b i

DOI: 10.1161/CIRCEP.112.971317

11

technology.

Study Limitations: This was an acute animal study which requires confirmation firstly in acute

human studies and later during long-term follow-up. The healthy animals used in the study could

not mimic a high LVP threshold due to ischemic scars, that could possibly alter the study results.

We used commercially available electrophysiology catheters, both standard and modified, to

provide a shorter bipolar electrode spacing instead of leads designed for chronic pacing. This

catheter and electrode design may have increased the LV pacing threshold compared to

conventional LV pacing leads due to unpredictable electrode contact with the myocardium. PNS

was determined via tactile feel and this may not reflect the clinical perception of PNS felt by

patients. The phrenic nerve was surgically repositioned over a coronary vein and this difference

from physiological conditions could impact the contact between the nerve and the catheter within

the vein.

Conflict of Interest Disclosure: Dr. Biffi has received modest honoraria from Medtronic, Boston Scientific, and Biotronik for scientific presentations at Medical Simposia and for Educational Activity. All the other authors are employees of Medtronic.

References:

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2. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L, for the Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539-1549.

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with the myoyy cardiuuuum.mmm

rceptiitiion of fff PNPNPNPNSS SS fefefefeltltltlt b

h r

f ,

he phrenic nerve was surgically repositioned over a coronary vein and this differ

ological conditions could impact the contact between the nerve and the catheter

f Interest Disclosure: Dr. Biffi has received modest honoraria from Medtronic,

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fffflulululuenenenencececece oooof f f f papapapacicicicingngngng on frequqq ency of fff phphphphrrrrenon theheeerarararapypypypy EuEuEuEurorororopapappace

6

zable multiple ci confi rations help to overcome high left ventricular acing

-

MN Investigators. The effect of electronic repositioning on left ventricular pacing a

ti l ti E 2011 13 409 415

61-967.

z O, Nof E, Carasso S, Luria D, Bar-Lev D, Tanami N, Eldar M, Glikson M. able multiple pacing configurations help to overcome high left ventricular pacingand avoid phrenic nerve stimulation. Pacing Clin Electrophysiol. 2005;28:1255-

gne J, Healey JS, Krahn AD, Philippon F, Gurevitz O, Swearingen A, Glikson MN Investigators. The effect of electronic repositioning on left ventricular pacing a

ti l ti E 2011 13 409 415

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Figure Legends:

Figure 1. Fluoro image of the coronary vein angiogram (A) and of catheter and phrenic nerve

location (B)

Figure 2 . Effect of cathode distance from the phrenic nerve on both LVP (A) and PNS (B)

iiiinononono J J JJ, ,,, AbAbAbAbrarararahahahaham mmm WTWTWTWT, utter J,JJJ MMMMurilililillolll J. ReReReRes2008888;1;1;1;117171717:2:2:2:2606060608888 2626262616

urg C, van Bommel RJ, Borleffs CJW, Bleeker GB, Boersma E, Schalij MJ, Baxm fr 4

FDP. Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronizati

509 1518

urg C, van Bommel RJ, Borleffs CJW, Bleeker GB, Boersma E, Schalij MJ, Baxm Prognosis After Cardiac Resynchronization Therapy Is Related to the Extent ofr Reverse Remodeling at Midterm Follow-Up. J Am Coll Cardiol. 2009;53:483-4

FZ, Virdee MS, Palmer CR, Pugh PJ, O’Halloran D, Read DA, Begley D, MD, DP. Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronizatihe TARGET Study: A Randomized, Controlled Trial. J Am Coll Cardiol.

509 1518

DOI: 10.1161/CIRCEP.112.971317

14

unipolar threshold. The dashed lines represent the effect in each animal and the solid line

represents the overall trend in the study

Figure 3. Effect of bipolar electrode spacing on bipolar LVP (A) and PNS (B) threshold .The

dashed lines represent the effect in each animal and the solid line represents the overall trend in

the study.

Figure 4. Effect of bipolar electrode spacing on pacing impedance. The dashed lines represent

the effect in each animal and the solid line represents the overall trend in the study..

Figure 5. Effect of bipolar electrode spacing on R-wave amplitude. The dashed lines represent

the effect in each animal and the solid line represents the overall trend in the study.

Figure 6. Comparison of pacing configurations of bipolar and unipolar PNS (A) and LVP (B)

using the TPNE as a cathode. The solid lines represent 95% confidence intervals.

Figure 7. Relationship of the difference between bipolar PNS and LVP threshold. The dashed

lines represent the effect in each animal and the solid line represents the overall trend in the

study.

Figure 8 . Probability of a PNS-LVP threshold difference >3 V, with bipolar electrode spacing.

he dashed lines reprprprpre

d in ththththe tstttuddddy..

E e

n

C i f i fi ti f bi l d i l PNS (A) d LVPf

Effect of bipolar electrode spacing on R-wave amplitude. The dashed lines repre

n each animal and the solid line represents the overall trend in the study.

C i f i fi ti f bi l d i l PNS (A) d LVPf