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TOPIC REVIEW ARTICLE

Quadripolar Leads inCardiac Resynchronization Therapy

Wouter M. van Everdingen, MD, Maarten J. Cramer, MD, PHD, Pieter A. Doevendans, MD, PHD,Mathias Meine, MD, PHD

ABSTRACT

Fro

the

Ma

Despite the benefit of cardiac resynchronization therapy (CRT) in patients with heart failure and conduction delay, a

considerable number of patients do not respond substantially. Left ventricular lead position is an important factor in

response, restricted by the patient’s specific anatomy and local pathophysiology. Quadripolar leads could enhance

response to CRT, offering 4 pacing locations along the distal end of the lead. Several quadripolar leads are available, all

with different shapes and electrode spacing. Electrodes can be positioned in an ideal pacing location, determined by

delayed mechanical or electrical activation, and away from phrenic nerve stimulation, high pacing thresholds, and

fibrosis. Implantation is safe, with comparable or even lower complication rates compared with standard bipolar leads.

Studies on biventricular pacing with quadripolar leads show apparent variations in acute hemodynamic response between

pacing configurations, implying a patient-specific response. Pacing with an optimal pacing vector of a quadripolar

lead benefits acute hemodynamic response. Multipoint pacing, pacing the left ventricle with 2 of 4 electrodes, could

further enhance response. However, larger trials are needed to confirm these results, and results on long-term outcome

of CRT with quadripolar leads and the benefit of multipoint pacing are warranted. We conclude that quadripolar leads are

an important improvement in the treatment of heart failure patients with CRT. (J Am Coll Cardiol EP 2015;1:225–37)

© 2015 by the American College of Cardiology Foundation.

C ardiac resynchronization therapy (CRT) hasproven its benefit for a selection of heartfailure patients by reducing mortality and

morbidity, according to renewed guidelines (1,2).CRT improves prognosis in patients with dilatedcardiomyopathy by inducing reverse remodelingthrough electromechanical resynchronization. Un-fortunately, a considerable proportion of patients(approximately 30% to 40%) show no significantresponse to CRT (1). Suboptimal left ventricular(LV) lead position is an important factor for dimin-ished CRT response (3). Besides targeting of theposterolateral wall and avoiding apical segments,the optimal position depends on several patient-specific factors (4,5). Even if the ideal pacing locationis known, lead placement in or near this location isdifficult.

m the Department of Cardiology, University Medical Center Utrecht, Utre

y have no relationships relevant to the contents of this paper to disclose

nuscript received May 20, 2015; revised manuscript received June 26, 20

Formerly, only unipolar and bipolar leads wereavailable for transvenous epicardial LV pacing, with2 electrodes placed at the tip of the lead. Theseleads need to be wedged in a distal vessel or activelyfixed by dedicated systems. The anatomy of the cor-onary sinus and its side branches, lead instability,local pacing parameters, and phrenic nerve stimula-tion (PNS) could restrict lead placement. Optionsto overcome suboptimal positioning are available(thoracoscopic placement) or emerging, such asendocardial pacing, implantation of multiple LVleads, and quadripolar leads.

Quadripolar LV leads have 4 electrodes along thedistal end. These leads can pace the LV wall, viatransvenous access, at several locations and multiplevectors along the lead. Optimal pacing sites (i.e., thelatest mechanical or electrical activated region) could

cht, the Netherlands. The authors have reported that

.

15, accepted July 2, 2015.

ABBR EV I A T I ON S

AND ACRONYMS

AHR = acute hemodynamic

response

AV = atrioventricular

BiQ = biventricular pacing with

a quadripolar lead

CONV = conventional

biventricular pacing with a

bipolar lead or distal pacing

vector of a quadripolar lead

(i.e., tip electrodes)

CRT = cardiac

resynchronization therapy

EAM = electroanatomic map

MPP = multipoint pacing

(i.e., multiple points on a

quadripolar lead)

PNS = phrenic nerve

stimulation

QLV = Q-wave (on

electrocardiogram) to left

ventricular depolarization (on

intracardiac electrogram)

VTI = velocity time integral

VV = interventricular

van Everdingen et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 1 , N O . 4 , 2 0 1 5

Quadripolar Leads in CRT A U G U S T 2 0 1 5 : 2 2 5 – 3 7

226

more easily be reached during and even afterimplantation. Suboptimal sites can be avoi-ded, such as areas with fibrosis due tomyocardial infarction or areas with PNS(Central Illustration). These properties comewithout compromising lead stability, as thetip can be wedged in a distal part of the veinwhile other electrodes are placed near theoptimal pacing site. Moreover, quadripolarLV leads have the ability of multipoint pacing(MPP), pacing the LV with 2 of 4 availableelectrodes. Quadripolar leads therefore rein-force the discussion about optimal pacingsites, multisite pacing, and timing optimiza-tion, because a single quadripolar lead canoffer multiple pacing options. This paper re-views background information, recentdevelopments, and future implications aboutoptimizing CRT with a quadripolar lead.

Based on a systematic search in BioMedCentral, Cochrane Library, and PubMed,all relevant papers in English about CRTand quadripolar leads published betweenDecember 2000 and May 2015 were selected.Further studies were sought through a

manual search of secondary sources, including ref-erences from primary papers. All studies and trials onmultipolar and quadripolar leads regarding acute,short-term, and long-term results were regarded asrelevant. Furthermore, technical specifications ofcurrent quadripolar leads and delivery systems weresought on manufacturers’ web sites or by communi-cation with their representatives.

DESIGN OF QUADRIPOLAR LEADS

Several quadripolar leads have been developed withvarious shapes (Figure 1) and electrode spacing(Figure 2). Boston Scientific (St. Paul, Minnesota)offers 3 different leads with different curvatureand different electrode spacing. Biotronik (Berlin,Germany) and Medtronic Inc. (Minneapolis, Minne-sota) offer leads with different curvatures but similarelectrode spacing. St. Jude Medical (St. Paul, Minne-sota) has 1 option available. Straight leads aredesigned for smaller distal veins, whereas curvedleads are meant to be fixated in larger veins. Posi-tioned in a target vessel, practical electrode spacingof these leads may be smaller. Total and effectiveinterelectrode distance can be of importance.Although never documented, the total electrodespacing may overextend the target vessel, resulting inproximal electrodes positioned in the coronary sinusor great cardiac vein instead of 1 of the tributary

veins. Moreover, a pre-shaped lead design mayimprove positioning of proximal electrodes (Figure 1).Pre-shaped leads therefore improve functionality, asan unstable position in the larger cardiac veinscould increase the distance to the myocardium,resulting in high pacing thresholds. Moreover, a pre-shaped lead design may improve positioning ofproximal electrodes, which is offered by all manu-facturers (Figure 1). A short (interelectrode) distancediminishes the benefit of extra electrodes, as elec-trodes could still cause PNS or be placed on scar tis-sue. However, the position of the second and thirdelectrode of the Attain Performa leads of Medtronic(1.3 mm apart) were chosen because of lower PNSthresholds at small interelectrode distances (6).Although there are 4 pacing sites, electromechani-cally only 3 separate spots can be stimulated withthis lead. Moreover, in case of high pacing thresholdsof the proximal electrode (e.g., due to vessel diam-eter), only 2 functionally different bipolar vectors canbe used. Two leads of Boston Scientific have the samelimitation, as 3 proximal electrodes are positionedclose together. Due to the spiral shape, at least 1electrode should be placed close to the myocardium,whereas others may become unusable.

The manufacturers also differ in the location ofcorticosteroid on quadripolar leads. The leads ofMedtronic have steroid reservoirs near all 4 elec-trodes. Both Biotronik leads have a corticosteroidcoating on the entire lead with a steroid reservoir atthe tip. Boston Scientific and St. Jude Medical supplyleads with steroid reservoirs at the tip of the lead.Besides small and clinically irrelevant differencesfound in a small animal study (7), the effect of ste-roids on the long-term performance of transvenousLV leads is unknown. Steroids are especially benefi-cial for the long-term impedance of screw-in leads.

All leads should fit through a 7-F introducer;however, not all leads are compatible with a 5-F innerguide, as most are wider (maximal width: Biotronik:4.8-F, St. Jude Medical: 5.1-F, Medtronic: 5.3-F, andBoston Scientific: 5.2-F). Although leads are coatedand therefore compatible with the inner guide forsmooth introduction, the electrodes are not coatedand may cause friction.

As all manufacturers have IS-4 compatible devices,all combinations of quadripolar leads and dedi-cated devices can be used. However, 2 cases haveshown that problems may arise when using quad-ripolar leads and CRT defibrillator devices of differentmanufacturers, resulting in unacceptable highimpedance levels at the 3 proximal quadripolar elec-trodes (8). The high impedance is probably a resultof misalignment of these electrodes within the spring

FIGURE 1 Overview of Currently Available Quadripolar Leads

Photographic overview of current quadripolar leads, with respect to curvature. Boston Scientific: (A) Acuity X4 Spiral L, (B) Spiral S, and

(C) Straight; Medtronic: Attain Performa (D) 4298, (E) S 4598, and (F) S 4398; St. Jude Medical: (G) Quartet; Biotronik: (H) Sentus,

(I) Sentus (straight).

CENTRAL ILLUSTRATION Drawing/Graphical Representation of a Heart, Viewed From the Lateral Side

van Everdingen, W.M. et al. J Am Coll Cardiol EP. 2015; 1(4):225–37.

A quadripolar lead is wedged in a distal cardiac vein. The distal electrode (1) is positioned close to an area of myocardial infarction and an area of

phrenic nerve stimulation, whereas 2, 3, and 4 are positioned near the optimal pacing site. The latter is possibly defined by electroanatomical

mapping or speckle tracking echocardiography. IVC¼ inferior vena cava; LV¼ left ventricle; PNS¼phrenic nerve stimulation; RV¼ right ventricle.

J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 1 , N O . 4 , 2 0 1 5 van Everdingen et al.A U G U S T 2 0 1 5 : 2 2 5 – 3 7 Quadripolar Leads in CRT

227

FIGURE 2 Electrode Spacing of Quadripolar Leads

Graphical presentation of electrode spacing of current options of quadripolar leads. Boston

Scientific: (A) Acuity X4 Spiral L, (B) Spiral S, and (C) Straight; St. Jude Medical: (D) Quartet

1458Q; Medtronic: (E) Attain Performa (4298, 4398, and S 4598); Biotronik: (F) Sentus.

van Everdingen et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 1 , N O . 4 , 2 0 1 5

Quadripolar Leads in CRT A U G U S T 2 0 1 5 : 2 2 5 – 3 7

228

contacts in the connector block of the device (8). Thisissue needs to be resolved so that operators can selectthe preferred (quadripolar) lead for the target vesseland optimal pacing location, independent of thechosen device.

IMPLANTATION AND LONG-TERM USE

Implantation and long-term use of quadripolarleads seems safe (9). Quadripolar leads have a lowercomplication rate compared with conventionalbipolar leads (Table 1) (9,10). Even in cases of minordislocation, alternative pacing vectors may beselected, circumventing the need for a secondaryinvasive procedure and thereby reducing complica-tions (11) Although Behar et al. (9) even found a lowerall-cause mortality rate in patients with quadripolarleads compared with bipolar leads, their results areon the basis of a registry: a comparison of non-randomized cohorts. Selection bias could have drivenresults, as baseline characteristics show that thepercentage of patients with ischemic cardiomyopathyand patients not in sinus rhythm were higher in thegroup with bipolar leads. Both are associated with areduced response to CRT (12,13). Moreover, simplebaseline and follow-up characteristics, such as ejec-tion fraction, end-systolic volumes, New York Heart

Association functional class, and QRS width andmorphology, are unknown. Comparison of bothgroups is, therefore, difficult. Nevertheless, the re-sults are interesting (Table 1), as a reduced mortalityrate is compelling for full implementation in clinicalpractice. Unfortunately, most studies focus solely onthe quadripolar leads, without comparison to bipolarleads. Moreover, most used the quadripolar lead ofeither St. Jude Medical or Medtronic, whereas per-formance of other leads has received little attention(9–11,14–16). Results of the MORE-CRT (MOreREsponse on Cardiac Resynchronization TherapyWith MultiPoint Pacing) trial (17), a randomizedcomparison of quadripolar versus bipolar leads onperformance and outcome, are therefore warranted.

OPTIMIZING LEAD PLACEMENT

The benefit of quadripolar leads lies in the additionalpacing options. More pacing options facilitateplacement in a stable position, while avoiding areaswith fibrosis or PNS (Central Illustration). Severalstudies have demonstrated the benefit of finding theoptimal site for LV lead positioning, in terms of acutehemodynamic benefit, echocardiographic reverseremodeling, and long-term clinical outcome (Table 2)(3,18–20).

AVOIDING PNS

As the left phrenic nerve is located close to theposterolateral side of the pericardium, PNS in theconventionally targeted midposterior and lateralpositions is a common finding (21). PNS due to LVpacing is seen in 13% to 33% of patients during CRTimplantation with bipolar LV leads, with 10%requiring lead revision (22,23). Although program-ming of the pacing stimulus may overcome PNS, leadplacement can be restricted (22). Phrenic nerveinvolvement can also occur after implantation, due tolead dislodgement or intrathoracic displacement ofthe heart due to patient positioning (22). Hypotheti-cally, PNS may occur due to a changed anatomicposition of the heart after reverse remodeling. Assummarized in Table 1, the percentage of PNSrequiring lead revision is between 0.0% to 0.3%among quadripolar leads. A large, multicenter, pro-spective study showed a lower prevalence of PNSrequiring lead revision among quadripolar leadscompared with bipolar leads (11). A lower amount oflead revisions means even fewer possible complica-tions due to a second intervention, which is animportant clinical benefit.

TABLE

1St

udieson

Per

form

ance

andCo

mplica

tion

sof

CRTWithaQua

dripolar

LVLe

ad

FirstAut

hor

(Ref

.#)

Des

ign

NSu

bjec

tsTy

peof

Qua

dripolar

Lead

Follow

-Up

(Mea

nin

Mon

ths)

Succes

sful

Implan

tation

Complications

Rep

ositioning

Lead

Displac

emen

tPN

SReq

uiring

Lead

Rev

ision

Beh

aret

al.(9)

Reg

istry/co

hort.

Multicenter

721

Qua

dripolar

(n¼

357)

vs.

bipo

larlead

s(n

¼36

4)Qua

rtet

SJM

(n¼

706),

AttainMed

tron

ic(n

¼15)

28.8

96.1%

vs.95.1%

;p¼

0.51

*2.0%

vs.5.2%

;p¼

0.03

1.7%

vs.4.6%;

p¼

0.03

0%

vs.4.4%

;p<

0.001

Aria

set

al.(10)

Prospe

ctive

sing

lecenter

42Qua

dripolar

(n¼

21)vs.

bipo

larlead

s(n

¼21)

Qua

rtet

SJM

910

0%

vs.10

0%

LVlead

prob

lems:

42.9%

vs.23

.8%;

p¼

0.326

4.8%

vs.9.5%;

p¼

1.0

0%

vs.0%

Crossley

etal.(11)

Prospe

ctive

multicenter

1,124

Qua

dripolar

only

AttainMed

tron

ic6.6

97.6%

3%0.4%

0.3%

Forleo

etal.(15)

Prospe

ctive

multicenter

154

Qua

dripolar

only

Qua

rtet

SJM

15.3

97.4%

*2.7%

2.7%

0%

Meh

taet

al.(16)

Prospe

ctive

sing

lecenter

40Qua

dripolar

only

Qua

rtet

SJM

695%

*3%

0%

Sperzelet

al.(14)

Prospe

ctive

multicenter

75Qua

dripolar

only

Qua

rtet

SJM

1594.6%

4.3%

4.3%

0%

*Nope

rcen

tage

ofallco

mplications

know

n,co

mplications

aredivide

dinto

lead

disp

lacemen

tan

dPN

Srequ

iring

lead

revision

.

AttainMed

tron

ic¼

AttainPe

rformalead

(Med

tron

ic);CM

P¼

cardiomyo

pathy;

PNS¼

phrenicne

rvestim

ulation;

Qua

rtet

SJM

¼14

58Q,Q

uartet

(St.Jude

Med

ical).

J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 1 , N O . 4 , 2 0 1 5 van Everdingen et al.A U G U S T 2 0 1 5 : 2 2 5 – 3 7 Quadripolar Leads in CRT

229

CIRCUMVENTING SCAR TISSUE

Patients with ischemic cardiomyopathy are morefrequent nonresponders to CRT (22). Both scar tissuenear the LV lead and total scar burden influence theresponse to CRT (12). Pacing in a region of scar tissuecan even deteriorate LV function, as proven by acutehemodynamic experiments and by long-term follow-up (24,25). Pacing in scarred regions results in slow oreven absent electrical wave front propagation andreduces the effect of biventricular pacing. Avoidinglead placement in scarred regions is, therefore, animportant determinant of response that is directlyrelated to the implantation procedure (26). Thequadripolar lead can aid in this process; whenever asuccessful lead position is limited by venous anatomyand results in the tip placed near scar tissue, theadditional electrodes may offer important alterna-tives. Forleo et al. (27) found no differences in long-term volumetric and clinical response betweenischemic and nonischemic patients with quadripolarleads. Their results could indicate that the in-crease of pacing options benefits response rate inischemic patients. There was even a trend toward ahigher decrease of end-systolic volume in non-ischemic patients. Larger trials are needed to provethese results.

IMAGING-GUIDED LEAD PLACEMENT

Two recent trials (i.e., TARGET [Targeted Left Ven-tricular Lead Placement to Guide Cardiac Resynch-ronization Therapy] and STARTER [Speckle TrackingAssisted Resynchronization Therapy for ElectrodeRegion]) proved the benefit of LV lead positioningof a bipolar lead while knowing the latest con-tracting segment (on the basis of peak radial strainderived by speckle tracking echocardiography)(3,18). Both studies found an increased benefit ofthe echocardiographic strategy on survival andechocardiographic response. Even in the controlgroup, a large proportion of leads were placedconcordant or adjacent. When lead positioning inboth groups was compared to response, optimalplacement was strongly associated with survival andresponse. Nevertheless, reaching the pre-definedtarget with bipolar leads can be difficult, as thesetrials showed that 10% to 15% of leads wereplaced remote from the intended area. Moreover,7% to 23% of leads were placed apically, which wasnot part of the echocardiographic protocol. Quad-ripolar leads could facilitate imaging-guided leadplacement, increasing the chance to reach theintended target.

TABLE 2 Studies on Comparison of Response to CRT With a Quadripolar LV Lead (Alternative Vector or Multipoint Pacing) to Conventional Biventricular Pacing

First Author (Ref. #) Design NPacing

Configuration Parameter(s) Main Result Remarks

Jones et al. (37) Intraoperative 22 BiQ Bioreactancemeasurement: CI

Large variations betweenBiQ electrodes within veins

Fixed AV delay

Asbach et al. (38) Intraoperative 16 BiQ vs. CONV dP/dtmax BiQ improves AHR: 31.3% vs.28.2%; p < 0.001

1 optimized AV delay per patient

Thibault et al. (40) Intraoperative 19 MPP vs. CONV dP/dtmax MPP with proximal and distalelectrode: greatest benefit

1 optimized AV delay per patient

Pappone et al. (42) Intraoperative 42 MPP vs. BiQ SW (pressure-volumeloops) and dP/dtmax

MPP improves AHR:SW: 27.2% vs. 19.4%; p ¼ 0.018dP/dt: 15.9% vs. 13.5%; p < 0.001

2 BiQ vs. 7 MPP settings,Fixed AV delay

Zanon et al. (43) Intraoperative 29 MPP vs. CONV dP/dtmax Average increase of best sitewith MPP (1,231 �267 mm Hg/s) higher thanCONV (1,200 � 267 mm Hg/s)

Fixed AV delay, multipleveins per patient

CabreraBueno et al. (59)

Post-implantation 51 BiQ vs. CONV Echo: CO BiQ improves CO: 4.33 vs.4.16 l/min; p ¼ 0.058

10 patients best CO with BiQ vector

Optimized AV delay foreach setting

Osca et al. (36) Post-implantation 27 BiQ vs. CONV Transthoracic impedanceelectrocardiography:CI, CO, and SV

No significant differenceBiQ and CONV

Optimized AV and VV delayfor each setting

Rinaldi et al. (41) Post-implantation 40 MPP vs. CONV Echo, STE: peak radial strainCW-Doppler: VTI of LVOT

MPP increases peak strain and VTIStrain: 18.3% vs. 9.3%; p < 0.001VTI: 13.5 cm vs. 10.9 cm; p < 0.01

VTI: 13 patientsFixed AV delay8 MPP vs. 1 CONV setting

Rinaldi et al. (46) Post-implantation 41 MPP vs. CONV Echo, TDI: Ts-SD MPP decreases Ts-SD:35.3 � 36.4 ms vs. 50.2 �

29.1 ms; p < 0.001

Fixed AV delay8 MPP vs. 1 CONV setting

Calo et al. (35) Post-implantation andlong-term outcome

22 BiQ vs. CONV ECG: QRS durationEcho: VTI, MPI, MR, EF,

ESV, EDV, and NYHAfunctional class at6-month follow-up

BiQ higher VTI, MPI, less MR,and shorter QRS-durationcompared with CONV.

No effect on long-term outcome

7 BiQ vs. 3 CONV setting,fixed AV delay

Pappone et al. (47) Short-term outcome 43 MPP vs. CONV Echo: EF, ESV, EDV, andNYHA functional classat 3-month follow-up

MPP improves response:DESV: �21.0 vs. �12.6; p ¼ 0.03;DEF: þ9.8% vs. þ2.0%;

p < 0.001; DNYHA: �1.05 vs.�0.72; p ¼ 0.006

Optimal MPP configurationdetermined by SW

CONV: distal or proximal electrode

AHR ¼ acute hemodynamic response; BiQ ¼ biventricular pacing with a quadripolar lead; CI ¼ cardiac index; CO ¼ cardiac output; CONV ¼ conventional biventricular pacing with a quadripolar lead;CW ¼ continuous wave; dP/dtmax ¼ maximal rate of left ventricular pressure rise; ECG ¼ electrocardiogram; Echo ¼ echocardiogram; EDV ¼ end-diastolic volume; EF ¼ ejection fraction; ESV ¼ end-systolicvolume; LVOT ¼ left ventricular outflow tract; MPI ¼ myocardial performance index; MPP ¼ multipoint pacing; MR ¼ mitral regurgitation; NYHA ¼ New York Heart Association; STE ¼ speckle trackingechocardiography; SV ¼ stroke volume; SW ¼ stroke work; TDI ¼ tissue Doppler imaging; Ts-SD ¼ standard deviation of time to peak contraction; VTI ¼ velocity time integral.

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ELECTROANATOMICAL-GUIDED PLACEMENT

Delayed activated segments can also be found bydetermining the delay in electrical depolarization.The Q-wave to left ventricular depolarization (QLV)interval is used for this purpose, by determining therecorded timing of onset of the QRS complex (“Q”) onthe electrocardiogram and the local depolarization atthe LV lead electrode (“LV”). As an interindividualparameter, QLV is related to acute response, reverseremodeling, and long-term outcome (28–30). LongQLV intervals (>95 ms) were associated with an in-crease in reverse remodeling and quality of life (28).Longer QLV intervals also result in higher maximalrate of left ventricular pressure rise (dP/dtmax), with a10-ms increase in QLV leading to a 1.7% to 2.0% in-crease in dP/dtmax (29,31). Zanon et al. (30) confirmedthe strong positive correlation of QLV and dP/dtmax

within individual patients. QLV could therefore beused in combination with quadripolar leads, as theelectrode with the highest QLV can be selected forbiventricular pacing. Although the difference in QLVwithin a single vein can be relatively small, the dif-ferences in dP/dtmax are significant (32). Figure 3 il-lustrates QLV within a vein for 2 separate patientsusing 2 different quadripolar leads.

Latest activated regions can also be mapped usingelectroanatomic mapping (EAM) systems. ExistingEAM systems have been used to find the latest acti-vated region, using dedicated catheters within thecoronary sinus and its side branches (Figure 4) (33).Areas with PNS can also be detected and thereforeavoided during lead placement. The (acute) hemo-dynamic and clinical benefit of this method is un-known, but would be promising on the basis of theresults of studies on QLV and acute hemodynamic

FIGURE 3 Electroanatomical Recordings of 2 Quadripolar Leads

(A and D) Electrocardiogram (ECG), intracardiac electrogram (IEGM) of intrinsic rhythm, obtained with the Prucka EP system (GE Medical

Systems, Milwaukee, Wisconsin). (B, C, E, F) Fluoroscopy images of 2 implantations of cardiac resynchronization therapy with quadripolar leads.

Images A to C represent a case with an implanted Medtronic Attain Performa S 4598; note the comparable Q-wave to left ventricular

depolarization (QLV) interval of intrinsic rhythm of electrodes LV2 and LV3 (134 and 136 ms, respectively). The differences between the

QLV intervals of the St. Jude Medical Quartet lead (D to F) are notably larger (152, 162, 175, and 179 ms). LAO ¼ left anterior oblique; LV ¼ left

ventricular; RAO ¼ right anterior oblique; RV ¼ right ventricular.

J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 1 , N O . 4 , 2 0 1 5 van Everdingen et al.A U G U S T 2 0 1 5 : 2 2 5 – 3 7 Quadripolar Leads in CRT

231

response (30). Figure 4 is an excellent example of thebenefits of quadripolar leads in combination withEAM, as the lead is wedged apically while theproximal electrode is positioned in the area withlatest depolarization. However, accessibility by a thinguidewire used for EAM does not guarantee success-ful lead placement.

Whether QLV or a similar parameter is the idealtool for (quadripolar) lead positioning can be dis-cussed. For a homogenous activation of the LV, the(very) last activated region is hypothetically subop-timal. Pacing the latest activated region will requiremore time to depolarize the entire LV. Nevertheless,pacing in a “late” activated region is beneficial toacute and long-term response, as proven by QLV(28,30). Moreover, CRT depends on biventricularpacing, with fusion between right ventricular (RV)and LV pacing. Mafi Rad et al. (34) have shown that

the order of activated regions due to RV pacing candiffer from intrinsic activation. Therefore, the delaybetween RV pacing and LV capture may be moreimportant than QLV.

OPTIMIZING PACING CONFIGURATION OF

A QUADRIPOLAR LEAD

Several studies have assessed the effects of opti-mizing pacing configurations of a quadripolar lead(Table 2). Most studies focus on parameters for acutehemodynamic response, whereas only 1 reports re-sults on short- or long-term response.

Calo et al. (35) compared echocardiographic find-ings (e.g., velocity time integral [VTI] of the LVoutflow tract) and QRS duration, and found signifi-cant improvements of all parameters with optimizedbiventricular pacing using a quadripolar lead (BiQ)

FIGURE 4 Electroanatomical Map of the Coronary Sinus With NavX EnSite

(A) Coronary venogram of a patient undergoing cardiac resynchronization therapy implantation. (B) X-ray of final LV lead placement.

(C) Coronary venous electroanatomic map during intrinsic ventricular activation together with the corresponding unipolar electrograms

collected from the regions of earliest and latest activation. The coronary sinus and all side branches have been mapped. Connecting the LV lead

to EnSite NavX allowed real-time visualization and navigation of the lead to the latest activated region in the electroanatomic map. Note the

large difference in local depolarization between proximal and distal sites in the ALV. The proximal electrode of the quadripolar lead was

positioned in the area with latest depolarization. Printed with permission of Dr. K. Vernooy, MD, PhD, MUMC, Maastricht, the Netherlands.

AIV ¼ anterior interventricular vein; ALV ¼ anterolateral vein; IIV ¼ inferior interventricular vein; ILV ¼ inferolateral vein; RA ¼ right atrial;

other abbreviations as in Figure 3.

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compared with conventional biventricular pacingusing distal pacing vectors (CONV). Conventionalvectors were distal pacing vectors of the quadripolarlead, using a combination of electrode D1, M2, or theRV coil, thus mimicking a standard bipolar lead. Twostudies used noninvasive measurement of cardiacindex to evaluate CRT with a quadripolar lead andfound a widespread response to tested pacing set-tings, but no significant differences between BiQ andCONV pacing (36,37).

Studies on invasively measured hemodynamicresponse of CRT with quadripolar leads reportapparent differences between pacing vectors. Asbachet al. (38) found a significant increase of dP/dtmax in

12 of 16 patients with BiQ versus CONV. Shetty et al.(39) used quadripolar leads to test differences indP/dtmax within a coronary vein and between veins.For individual patients, acute hemodynamic response(AHR) within a vein varied between pacing elec-trodes. When patient data was combined, the overalldifference between vectors was nonsignificant.

Only 1 small study reported short-term responseof biventricular pacing using CRT with a quadripolarlead. Calo et al. (35) optimized quadripolar pacingconfigurations using echocardiography in 22 pa-tients. They found no differences in New York HeartAssociation functional class or reverse remodeling(>15% decrease in LV end-systolic volume) after

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6 months between 11 patients with optimizedBiQ pacing and 11 patients with optimized CONVpacing.

OPTIMIZING MPP

Currently, 1 manufacturer has a CRT defibrillator de-vice with MPP capability (Unify Quadra MP, St. JudeMedical). MPP is programmable as “simultaneously”(minimal delay of 5 ms) or with programmable interleft ventricular electrode delays. Compared withimplanting multiple LV leads, implanting a singlequadripolar lead will not increase procedure durationand fluoroscopy time.

Several smaller studies recently published favor-able results on the hemodynamic, electrical, andmechanical response of MPP (Table 2) (40–43). Rinaldiet al. (41) used echocardiographic-derived VTI ofcontinuous wave Doppler of the LV outflow tract. VTIhas a low signal-to-noise ratio and requires numerousiterations to make reliable estimations of LV function(44). Also, a short and nonphysiological atrioven-tricular (AV) delay (25 ms) was used, and some set-tings with long inter left ventricular electrode delayswere compared (up to 80 ms). This may have led topacing in already depolarized myocardium, as themaximal spacing between 2 electrodes (47 mm)combined with the conduction velocity (0.84 m/s) ofpatients with dilated cardiomyopathy would lead to atheoretical maximum delay of 56 ms (45). However,myocardial fibrosis in between electrode positionsmay result in longer delays. Besides VTI, Rinaldi et al.(41) compared peak radial strain derived by speckletracking echocardiography and found higher valuesfor MPP compared with CONV pacing (18.3 � 7.4% vs.9.3 � 5.3%; p < 0.001). The same group publishedresults of reduced dyssynchrony assessed with tissueDoppler imaging with MPP compared with conven-tional biventricular pacing (46). However, 8 non-randomized MPP settings were compared to only 1conventional setting in both studies. Thereby, thechance of defining outlying results of MPP as an op-timum increased.

MPP has been compared with conventional pacingwith a quadripolar lead. However, in most cases MPPwas compared to only 1 or 2 unifocal pacing vectors(40,42). Pappone et al. (42) compared pressure-volume loops obtained with MPP to CONV pacingand found significant increase with MPP. However,they compared a large number of MPP configurations(7) to a limited amount of conventional configura-tions (2). Thibault et al. (40) reported heterogeneouseffects of MPP, ranging from detrimental to benefi-cial, compared to conventional CRT. Zanon et al. (43)

used quadripolar LV leads and found a slight butsignificant increase in dP/dtmax with MPP, comparedto unifocal proximal and distal pacing. Although theyrepeated measurements, there was no comparison tobaseline and physiological variation over time couldtherefore have influenced results.

Only one follow-up study focused on the effects ofMPP on echocardiographic response. Pappone et al.randomized 41 patients to conventional biventricularpacing or MPP (47). The group receiving MPP had ahigher percentage of echocardiographic respondersafter 3 months (76% vs. 50%). Ejection fractionimproved and end-systolic volume was reducedcompared with the conventional pacing group(Table 2). The authors suggested that the favorableresponse could be attributed to the patients withischemic cardiomyopathy, as MPP may have led tomore homogenous electrical depolarization in ven-tricles with fibrotic tissue in these patients.

REMARKS ON REPORTED RESULTS

As can be appreciated from Table 2, only a few studiesdirectly compared BiQ to CONV. The added benefit ofquadripolar leads to standard bipolar leads on AHRneeds further study. Recent studies do show thatAHR varies significantly between pacing vectorsof a quadripolar lead, implying a patient-specificapproach to vector selection (37,38). A quadripolarlead can therefore be beneficial, if stimulation at theadditional electrodes is at least feasible. Both pacingand PNS thresholds are as important as the benefit inAHR. Reports on available pacing vectors are variable.Asbach et al. (38) reported an average of 9 of 10possible vectors, tested in 16 patients. Unfortunately,they did not report specific cut-offs. Surprisingly,Sperzel et al. (14) found that only 20% of patients hadat least 9 possible pacing vectors without PNS andwith good pacing threshold. A total of 89% of patientshad at least 3 (of 10) possible vectors compared with53% with 3 or more conventional vectors, with a cut-off for pacing threshold #2.5 V and PNS $7.5 V.

Anodal capture is a confounder in results on pacingwith quadripolar leads. Stimulation on an electrodepair (i.e., cathode and anode) is meant to depolarizemyocardium at the cathodal electrode. However, withsubstantial output, the anodal site could also bedepolarized. Trolese et al. (48) reported changes inQRS width and morphology using pacing vectors witha similar cathode and different anodes of the quad-ripolar lead. The changes could be ascribed to anodalcapture (49). If anodal electrodes have low thresh-olds, intended bipolar stimulation could lead to dualsite stimulation. This affects QRS width as well as

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AHR and makes comparison between vectors prob-lematic. Comparison of vectors with the RV coil asanode could be a solution.

The absence of AV and interventricular (VV)delay optimization is an important limitation ofresults on AHR. As AV and VV delay optimizationsignificantly influence AHR, published studies onhemodynamic assessment without optimization aredifficult to interpret (50). As can be appreciatedfrom Table 2, a large proportion of studies use afixed AV and/or VV delay. The increase of the he-modynamic improvement of the optimal pacingvector may be underestimated because a longer VVdelay (with LV pre-activation) will be beneficialduring LV pacing with the more basal electrodes ofthe quadripolar lead. Using different electrodes of aquadripolar lead or even MPP with a quadripolarlead would require intensive study protocols, withmultiple AV and/or VV delays for each vector. Pro-tocols become even more time consuming when thecomparison of a larger range of configurations re-quires iterations or curve fitting to reduce the riskof bias (44).

Most studies on quadripolar leads primarily focuson MPP, neglecting optimal single-site LV pacing.Animal experiments show that AHR of an optimalsingle pacing position could only be matched byadding a total of 6 pacing sites to a suboptimal pacingposition (51). So, 1 optimally placed (quadripolar) leadis better than adding a pacing site. If the ideal pacingsite is reached, which is even more likely withquadripolar leads, thoracoscopic epicardial place-ment, or the emerging endocardial approach, an extrapacing site may be obsolete. Shetty et al. (52)confirmed this hypothesis, as they found a signifi-cant increase of AHR while pacing a single endocar-dial site compared with MPP. Perhaps only a subset ofpatients would be eligible to respond to MPP. Un-fortunately, none of the currently published studieswere designed to identify markers for response toMPP. MPP is thought to depolarize the myocardiumwith a more homogenous electrical wave front, andcould be beneficial in ventricles with heterogeneousconduction delays, for example due to fibrosis. Thiswas confirmed in a group of CRT patients withposterolateral scar (53). Another small study showedthat 2 of (only) 3 patients converted to responderswith MPP, compared with conventional CRT (54).Patient selection for MPP could be of interest, as MPPcan also have detrimental effects on LV function (40).Whether patients with heterogeneous conductiondelays and/or previous myocardial infarction orsimply nonresponders are eligible for MPP is ofinterest.

The benefit of MPP depends on the location of theextra pacing site. The ideal location for an extrastimulus for MPP is unknown. Ploux et al. (51)showed that pacing the latest activated site (duringpacing with the previous implanted leads) is of in-cremental hemodynamic benefit. Implanting anadditional lead at the latest electrical activated re-gion during conventional biventricular pacing wouldbe an interesting method for future patient trials.This concept is not feasible for quadripolar leads, asthe electrode spacing and location is limited to 1 vein.Shetty et al. (52) found no significant differences inAHR between MPP (with quadripolar leads) ormultisite pacing (with multiple LV leads), althoughtheir sample size was small (n ¼ 15). As shown byFigure 3 and by Mafi Rad et al. (34), the electricaldelays along the optimal vein can be quite similar.Stimulating 2 spots with relatively comparable elec-trical delays is probably not beneficial. It is thereforeinteresting to define the relation between the elec-trical delays between quadripolar electrodes andthe benefit to MPP. Pappone et al. (42) found that theelectrode pair with the largest anatomical spacingwas optimal in 71% of patients, compared withthe pair with the largest interelectrode delay. Anexpected overlap between both strategies was notreported. Nevertheless, it is an interesting result,as anatomical spacing merely resembles posi-tion, whereas the electrical delay is a functionalparameter.

ONGOING STUDIES

Two ongoing studies onMPP are the MultiPoint PacingIDE study and the MORE-CRT trial (17,55). The firsttrial is designed to include 506 patients with a CRTindication (55), comparing the effects on response andcomplications of CRT with a quadripolar lead to CRTwith a standard bipolar lead. The MORE-CRT trial iseven larger, enrolling 1,250 patients (17). This multi-center study will investigate the clinical effects of CRTwith a quadripolar lead compared with a bipolar lead.The effect of MPP on nonresponders at 6-monthfollow-up will also be investigated.

FUTURE DIRECTIONS

Multipolar leads are currently restricted to 4 elec-trodes, possibly due to limitations in maximal leaddiameter and device header size. Future de-velopments could overcome these restrictions andopen the door for hexapolar or even octapolar leads.Additional electrodes increase the number of pacingoptions and will only increase the success rate of CRT

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implantation. Several short distanced dipoles forexample (like the 2 middle electrodes in Medtronicquadripolar leads), could reduce the chance of PNS.Optimization however, becomes even more timeconsuming without a proper surrogate parameter(beside QLV). Whether multisite pacing on more than2 sites could be beneficial for a selection of patients iscontroversial. First, the benefit of 1 extra pacing siteshould be investigated thoroughly. The extra pacingsites can also be positioned in the coronary sinus forleft atrial sensing (56). Left atrial sensing could causethe right atrial electrode to become obsolete inpatients without atrial arrhythmia.

Lead positioning strategies could be optimizedby incorporating results of imaging and electro-anatomic modalities. If scar tissue, delayed activa-tion (either mechanical or electrical), PNS, andpacing thresholds are incorporated in the venogramduring implantation, an implanting physiciancould choose the optimal position and lead forthe patient’s specific anatomy (33,57). The quad-ripolar lead with a specific shape and distance be-tween electrodes could then be selected to achievean optimal mid or basal position with more prox-imal electrodes, whereas distal electrodes arewedged near the apex. A heterogeneous choice ofleads, as currently available, is therefore practical.Figure 4 displays a possible strategy using EAM toguide the operator in choosing a lead with elec-trodes placed in the area with maximal electricaldelay.

Optimization of CRT configuration is complicatedby the additional electrodes and pacing options(e.g., MPP) of a quadripolar lead. Automated optimi-zation algorithms based on electrical delays could

incorporate the electrode with longest QLV andacceptable pacing threshold without PNS for optimalquadripolar pacing configuration. However, thebenefit of AV and VV delay optimization is debatable,as a meta-analysis of several optimization techniquesfound no apparent benefit (58).

CONCLUSIONS

The benefit of quadripolar leads over conventionalbipolar leads has been underlined by recent trials.Quadripolar LV leads have lower complication ratesand more pacing options, thereby reducing the fre-quency of PNS, circumventing fibrosis, and facili-tating reaching a pre-defined optimal position. Leadsare available in various models and different elec-trode spacing, with an expected heterogeneity in use.On the basis of acute hemodynamic studies and asmall randomized trial, quadripolar leads can improveacute and short-term response to CRT. Currently, 1manufacturer offers MPP, a pacing modality that canhave benefit in certain cases. Its application is uncleardue to methodological shortcomings and contradic-tory results of recent studies, besides the unknownideal substrate for MPP. Results of ongoing and futurecomparative studies on quadripolar leads regardingboth acute hemodynamic response and long-termoutcome are warranted.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Wouter M. van Everdingen, Department of Cardiol-ogy, University Medical Center Utrecht, HP E.03.8.20,Heidelberglaan 100, P.O. Box 85500, 3508 GAUtrecht, the Netherlands. E-mail: w.m.vaneverdingen@umcutrecht.nl.

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KEY WORDS cardiac resynchronizationtherapy, lead, multipoint pacing, phrenicnerve stimulation, quadripolar