cardiac resynchronization therapy

Mechanistic insights into the benefits of multisite pacing in cardiac resynchronization therapy: The importance of electrical substrate and rate of left ventricular activation Manav Sohal, MBBS,*† Anoop Shetty, MD,* Steven Niederer, PhD,* Angela Lee, PhD,* Zhong Chen, MBBS,* Tom Jackson, MBBS,* Jonathan M. Behar, MBBS,* Simon Claridge, MBBS,* Julian Bostock, PhD, FHRS,† Eoin Hyde, PhD,* Reza Razavi, MD,* Frits Prinzen, PhD,‡ C. Aldo Rinaldi, MD, FHRS*†Q1 Fromthe *DivisionofImagingSciencesandBiomedicalEngineering,King’sCollegeLondon,London,United Kingdom, †Cardiovascular Department, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom, and ‡Maastricht University Medical Center, Cardiovascular Research Institute (CARIM), Maastricht, The Netherlands.
BACKGROUNDQ3 Multisite left ventricular (LV) pacing (MSPQ4 ) is proposed as an alternative to conventional single-site LV pacing in cardiac resynchronization therapy (CRT). Reports on the benefits of MSP have been conflicting. A paradigm whereby not all patients derive benefit from MSP is emerging. OBJECTIVE Wesoughttocomparethehemodynamicandelectrical effects of MSP with the aim of identifying a subgroup of patients more likely to derive benefit from MSP. METHODS Sixteen patients with implanted CRT systems incorporating a quadripolar LV pacing lead were studied. Invasive hemodynamic and electroanatomic assessment was performed during the following rhythms: baseline (non-CRT); biventricular (BIV) pacing delivered via the implanted CRT system (BIVimplanted); BIV pacing delivered via an alternative temporary LV lead (BIValternative); dual-vein MSP delivered via 2 LV leads; MultiPoint Pacing delivered via 2 vectors of the quadripolar LV lead. RESULTS Seven patients had an acute hemodynamic response (AHR) of o10% over baseline rhythm with BIVimplanted and were deemed nonresponders. AHR in responders vs nonresponders was 21.4%
10.4% vs 2.0%
5.2% (P o .001). In responders, neither form of MSP provided incremental hemodynamic benefit over BIVimplanted. Dual-vein MSP (8.8%
5.7%; P ¼ .036 vs BIVimplanted) and MultiPoint Pacing (10.0%
12.2%; P ¼ .064 vs BIVimplanted) both improved AHR in nonresponders. Seven of 9Q5
responders to BIVimplanted had LV endocardial activation characterizedbyafunctionallineofblock Q6 duringintrinsicrhythmthatwas abolished with BIV pacing. All these patients met strict criteria for left bundle branch block (LBBB). No nonresponders exhibited this line of block or met strict criteria for LBBB. CONCLUSION Patients not meeting strict criteria for LBBB appear most likely to derive benefit from MSP. KEY WORDS Cardiac resynchronization therapy; Multisite pacing; Noncontact mapping; Left bundle branch block; Acute hemodynamic response ABBREVIATIONS AHR ¼ acute hemodynamic response; AV ¼ atrioventricular; BIV ¼ biventricular; BIValternative ¼ biventricular pacing delivered via the temporary left ventricular lead; BIVimplanted ¼ biventricular pacing delivered via the implanted cardiac resynchronization therapy system; CRT ¼ cardiac resynchronization therapy; DSM ¼ dynamic substrate mapping; LBBB ¼ left bundle branch block; LV ¼ left ventricle/ventricular; LVendoAT10-90¼timedelaybetweenthe10thand90thcentilesof activation; LVendoATtotal ¼ total LV endocardial activation time; MPP ¼ MultiPoint Pacing; MSP ¼ multisite pacing; RV ¼ right ventricular (Heart Rhythm 2015;0:-1–9) I 2015 Heart Rhythm Society. All rights reserved.
Introduction Cardiac resynchronization therapy (CRT) for patients with systolic heart failure and electrical dyssynchrony is one of the major advances in cardiovascular medicine in the past 20 years.1,2 Despite extensive efforts, the rate of response to CRT has remained static, and current guidelines reflect the fact that the strongest evidence is in patients with left bundle
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This work was partly supported by the NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London.Addressreprintrequests andcorrespondence: Dr Manav Sohal, Division of Imaging Sciences and Biomedical Engineering, Rayne Institute, King’s College London, 4th Floor, Lambeth Wing, St. Thomas’ Hospital, Westminster Bridge Rd, London SE1 7EH, United Kingdom. E-mail address: manav.sohal@gstt.nhs.uk.
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved. http://dx.doi.org/10.1016/j.hrthm.2015.07.012
branch block (LBBB), QRS duration 4150 ms, and little or no scar.3 CRT is generally accepted to achieve its therapeutic benefit by electrical resynchronization of the left ventricle (LV). It has been hypothesized that LV stimulation from 41 site, multisite pacing (MSP), may allow more complete synchronizationandimproveresponse.4 Severalstudieshave evaluated the acute hemodynamic effects of delivering CRT with MSP, either via 2 anatomically separated LV leads (dual-vein MSP) or via 2 vectors of a single multipolar LV lead (MultiPoint Pacing [MPP], St. Jude Medical, St. Paul, MN), with conflicting results.5–10 Some authors have shown an improvement in hemodynamics with MSP, whereas others have shown little incremental benefit if the single LV pacing siteQ7 is optimized.7,11 We have previously shown a small but nonsignificant improvement in acute hemodynamics with MSP (either multivein or multipolar) compared to standard CRT.12 Data from canine studies have shown that MSP (from up to 7 sites) produces little incremental acute hemodynamic benefit whenresponsetosingle-site LVpacingisfavorable.13 Inthis study, we sought to assess whether either form of MSP resulted in the correction of suboptimal hemodynamic response to CRT or whether biventricular (BIV) pacing from an alternative site was sufficient. We also sought to evaluate the electrical rationale for any hemodynamic improvement with the use of noncontact electroanatomic mapping in intrinsic rhythm and during pacing.
Methods The study was approved by the local ethics committee, and each patient provided written informed consent. The study population consisted of 16 patients with a chronically implanted CRT system (with a quadripolar LV lead) in situ for at least 3 months (St. Jude Medical). Data comparing the effect of endocardial pacing and MSP in part of this cohort have been previously reported.12 Inclusion and exclusion criteria and CRT system implant details can be found in the online supplemental material.
Hemodynamic and electroanatomic study A second temporary coronary sinus pacing lead was implanted along with a noncontact mapping array (EnSite 3000, St. Jude Medical) and high-fidelity pressure wire capable of recording LVdP/dtmaxQ8 (both into the LV cavity; see the online supplemental material).
Measurement of acute hemodynamic response LVdP/dtmax was recorded for at least 20 seconds to ensure steady-state conditions during any pacing configuration. LVdP/dtmax during atrial pacing (AAI) or right ventricular (RV) pacing (if the patient was in atrial fibrillation)at5–10 beats above the intrinsic rate was used as baseline. A waiting period of at least 20 seconds was observed after any change in pacing settings to achieve hemodynamic stabilization. These methods have previously been shown
to reliably measure LVdP/dtmax.14–16 Results for each pacing protocol were expressed as a percentage change from baseline. To minimize baseline drift in acute hemodynamic response (AHR), baseline was reassessed immediately before and after every change in pacing configuration. The mean of these 2 readings (immediately before and after each pacing intervention) served as the reference to which particular pacing intervention was compared. Data from premature ventricular complexes were discarded.
Pacing protocol A pacing protocol was performed with an atrioventricular (AV) delay of 100 ms (when in sinus rhythm) and with simultaneous RV and LV stimulation (VV interval = 0 ms). Where multisite stimulation was performed via 2 electrodes of the quadripolar LV lead, the delay between the 2 electrodes was set at the lowest possible interval (5 ms). In the present analysis, the AHR to the following pacing configurations was compared ( F1 Figure 1):
1. BIV pacing delivered via the implanted CRT system (BIVimplanted; Figure 1A) was compared to baseline. Patients were deemed acute responders if the AHR to BIV pacing was Z10% over baseline.16 2. In those patients who did not exhibit a favorable acute response to CRT delivered via the implanted system, BIVimplanted (Figure 1B) was compared to BIV pacing delivered via the temporary LV lead (BIValternative) and then either MPP (Figure 1C) or dual-vein MSP (Figure 1D). 3. The same comparison was also made in patients with a favorable acute response to BIVimplanted.
Assessment of electrical data LVendocardialactivationinintrinsicrhythmwasassessedin all patients. Isopotential maps derived from the EnSite array were analyzed to determine whether patients exhibited a line of functional conduction block, as first described by Auricchio et al.17 The following electrical parameters were recorded for each pacing configuration (see the online supplemental material):
1. Paced QRS duration. 2. LV transmural conduction time (TMCT). 3. Total LV endocardial activation time (LVendoATtotal). Endocardial maps were obtained at baseline and in each pacing configuration. 4. Time delay between the 10th and 90th centiles of activation (LVendoAT10-90).
The last 3 variables were derived from the customdeveloped MATLAB code (MathWorks, Natick, MA).
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Assessment of endocardial substrate The dynamic substrate mapping (DSM) function of the EnSite system was used to identify areas of scar and/or slow conduction (see the online supplemental material).
Statistical analysis Statistical analyses were performed using PASW Statistics 21 (SPSS Inc, Chicago, IL). Changes in hemodynamics and electrical parameters between pacing configurations were compared using repeated-measures analysis of variance with a Bonferroni correction applied for any post hoc comparisons in the event of an overall significant effect across comparators (so as to avoid type 1 errors). P values less than .05 were deemed statistically significant.
Results Baseline characteristics and procedural outcome Sixteen patients were studied, and their characteristics are listed inT1 Table 1. All patients underwent full hemodynamic
assessment, and electroanatomic analysis was possible in 13 patients, along with previously unreported vascular disease precluded passage of the array in 1 patient, 1 patient developed recurrent ventricular tachycardia on passage of the array into the LV, and the third experienced technical malfunction of the array system Q9 . All patients were men with a mean age of 65
7years.Elevenpatients (69%) had an ischemic etiology. The mean QRS duration was 164
39 ms. Twelve patients (75%) had LBBB according to conventional criteria, and 4 patients (25%) were dependent on RV pacing. When applying a more strict definition of LBBB as advocated by Strauss et al20 to the 12 patients meeting conventional criteria for LBBB, 7 were classified as complete LBBB and 5 as nonspecific interventricular conduction delay. The position of the chronically implanted lead was lateral/posterolateral in 14 patients and anterior in 2. The position of the second LV lead was anterior in 15 cases and lateral in the remaining case. There were no procedure-related complications.
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Figure 1 Schematic of the pacing configurations assessed in the study. The leads are labeled in panel A, and the stars reflect sites of stimulation. A: Biventricular pacing delivered via the chronically implanted system. B: Biventricular pacing delivered via the second temporary CS pacing lead passed via the femoral vein. C: MPP delivered via 2 vectors of the quadripolar lead (the vectors chosen were distal tip to RV coil and most proximal ring to RV coil). D: Triventricular pacing using the distal bipoles of both CS leads. CS ¼ XXXX; LV ¼ left ventricular; MPP ¼ MultiPoint Pacing; RV ¼ right ventricular.
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Comprehensive electroanatomic assessment Assessment of LV endocardial activation during intrinsic rhythm identified a line of functional conduction block in 7 patients. The functional nature of conduction block was verified by its absence during subsequent pacing protocols. All 7 patients met strict electrocardiographic criteria for LBBB. Functional lines of conduction block were not identified in any of the remaining 9 patients.
Electrical substrate analysis Delayed-enhancement cardiac magnetic resonance imaging was available in 10 patients, 7 of whom had at least 2
segments with subendocardial scar. The geographical location of this was closely mirrored by DSM findings in all 7 patients, with both methods providing concordant data with regard to the presence of leads with or without scar. In all 7 patients with scar on cardiac magnetic resonance imaging, scar distribution was in keeping with prior myocardial infarction (as opposed to midmyocardial or epicardial scar).
Ahr BIVimplanted resulted in an AHR of 12.9%
12.9%, and this was not significantly different to BIValternative (10.7%
15.1%; P ¼ .422); BIValternative was superior in 7 patients. Seven patients had an AHR of o10% with BIVimplanted and were therefore deemed acute nonresponders. Across the whole cohort, the AHR with dual-vein MSP was 17.7%
12.7% and the AHR with MPP was 15.3%
11.2% (P ¼ .215 for a significant difference between all 3 pacing configurations).
Impact of dual-vein MSP and MPP on AHR in responders to BIVimplanted (Figure 2A)
F2 Q10Neither dual-vein MSP nor MPP signi ficantly improved AHR in patients who acutely responded to BIVimplanted (BIVimplanted 21.4%
10.4%; dual-vein MSP 24.6%
12.5%; MPP 19.5%
8.8%; P ¼ .389 and P ¼ .517 vs BIVimplanted, respectively).
Impact of BIValternative and MSP on AHR in nonresponders to BIVimplanted (Figures 2B and Figure 3) F3AHRwas2.0%
5.2%innonresponderstoBIVimplanted and 21.4%
10.4% in responders (Po.001). BIV pacing from an alternative site was not sufficient to improve AHR in nonresponders to BIVimplanted (AHR BIValternative 1.3%
5.6%; P ¼ .797). Dual-vein MSP (8.8%
5.7%; P ¼ .036
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Table 1 Patient characteristicsQ14 Characteristic Value Age (y) 65
7 Sex: male 16 (100) Etiology Ischemic 11 (69) Nonischemic 5 (31) NYHA class II 5 (31) III 11 (69) LV ejection fraction* (%) 25
7 QRS duration (ms) 164
39 QRS morphology LBBB 7 (44) IVCD 5 (31) RV paced 4 (25) Chronic LV lead position Lateral/posterolateral 11 (69) Nonlateral/posterolateral 5 (31) Values are presented as mean
SD or as n (%). IVCD ¼ interventricular conduction delay; LBBB ¼ left bundle branch block;LV¼leftventricular;NYHA¼NewYorkHeartAssociation;RV¼right ventricular. *Derived from 2-dimensional echocardiography using the modified Simpson’s biplane method.
P=0.596 for a difference between protocols
A
P=0.027 for a difference between protocols
P=0.797
P=0.036
P=0.064
B
Figure 2 Hemodynamic response to each pacing protocol in responders (A) and nonresponders (B) to BIVimplanted. BIValternative ¼ biventricular pacing delivered via the temporary left ventricular lead; BIVimplanted ¼ biventricular pacing delivered via the implanted cardiac resynchronization therapy system; LVdP/dtmax ¼ XXXX; MPP ¼ MultiPoint Pacing; MSP ¼ multisite pacing.
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vs BIVimplanted) and MPP (10.0%
12.2%; P ¼ .064 vs BIVimplanted) both improved AHR in nonresponders to BIVimplanted. Figure 3 shows the hemodynamic response to each pacing intervention for each individual nonresponder. In all but 1 patient, both forms of MPP resulted in hemodynamic improvement over BIVimplanted.
Characteristics of responders vs nonresponders to BIVimplanted (Table 2) T2 The intrinsic QRS duration was significantly lower in nonresponders to BIVimplanted (131
21 ms vs 188
25 ms; P o .001). The range of QRS duration was 150–228 ms in responders and 121–174 ms in nonresponders. No nonresponder patients met strict criteria for LBBB and all exhibited scar. Five patients had their chronically implanted LV lead in a region of scar on DSM, and of these, 4 failed to respond to BIV pacing from that site. There was a trend toward a lack of favorable AHR when pacing in scar with BIVimplanted (P ¼ .106). LVendoATtotal did not differ significantly, but LVendoAT10-90 was significantly shorter in responders (86%
7% vs 77%
6%; P ¼ .015). Notably, there was no shortening in LVendoAT10-90 with
either form of MSP as compared to BIVimplanted in responders,whereas areduction was seen with both forms ofMSP in nonresponders ( F4 Figure 4). There was a negative correlation between LVendoAT10-90 and AHR (r ¼0.57; P o .001). Discussion This is the first human study to look specifically at the question as to whether dual-vein MSP or MPP is superior and also identifies a group of patients in whom MSP might create a positive response to CRT. The main findings are as follows:
1. Where there is attenuated AHR to BIVimplanted, pacing fromanothersiteisoflittlebenefitwhereasbothMPPand dual-vein MSP do improve AHR. There is little to choose between MPP and dual-vein MSP hemodynamically. 2. Patients with little or no scar and strict LBBB are highly likely to show a favorable acute response to BIVimplanted with the addition of more pacing sites, producing no incremental hemodynamic benefit. 3. A consistent feature inpatients with goodAHRamong all pacingconfigurationsisfasteractivationofthebulkofthe LV endocardium (as opposed to the total activation delay).
Comparison with other studies There are conflicting reports on the additional acute hemodynamic benefits of MSP compared to conventional BIV pacing. Before the advent of multipolar lead technology, studies on MSP focused on the use of 2 LV leads. Pappone et al6 studied 14 patients with heart failure with currently accepted class I indications for CRT (LBBB with QRS duration 4150 ms) and found that dual-site LV stimulation (patients were paced VDD with leads in the posterior and lateral branches of the CS Q11 ) improved LVdP/dtmax over and abovepacing from either site alone buttheimprovement was dependenton findingtheoptimalAVinterval.Padelettietal7 compared true triventricular pacing with conventional CRT delivered at the better of the 2 sites tested. They did not demonstrate any benefit from MSP over conventional CRT
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Figure 3 Hemodynamic response to each pacing protocol in each individual nonresponder to BIVimplanted. BIVimplanted ¼biventricular pacing delivered via the implanted cardiac resynchronization therapy system; LVdP/dtmax¼XXXX; MPP¼MultiPoint Pacing; MSP¼multisite pacing.
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Table 2 Electroanatomic characteristics of responders vs nonresponders to BIVimplanted
Characteristic
Responders (n ¼ 9) (n ¼ 7 for EAM data)
Nonresponders (n ¼ 7) (n ¼ 6 for EAM data) P Baseline QRS duration (ms) 188
25 131
21 o.001 Baseline QRS morphology 7 LBBB* 6 IVCD .003 2 RVP 1 RVP Line of functional block during intrinsic rhythm Yes 7 Yes 0 o.001 No 0 No 6 TMCT during BIVimplanted (ms) 58
22 61
19 .779 LVEndoATtotal (ms) 64
15 66
19 .817 LVEndoAT10-90 as a percentage of LVEndoATtotal 77
6 86
7 .015 BIVimplanted ¼ biventricular pacing delivered via the implanted cardiac resynchronization therapy system; EAM ¼ electroanatomic mapping; IVCD ¼ interventricularconductiondelay;LBBB¼leftbundlebranchblock;LVendoAT10-90¼timedelaybetweenthe10thand90thcentilesofactivation;LVendoATtotal¼ total LV endocardial activation time; RVP¼ right ventricular pacing; TMCT¼ transmural conduction time.
SohaletalMultisitePacinginHumans5
delivered at the optimal AV interval.7 Further mechanistic insights were provided by Ginks et al,21 who used noncontact electroanatomic mapping and cardiac magnetic resonance imaging to demonstrate that patients with scar seemed to respond best to MSP. With the introduction of multipolar LV leads it is possible to deliver MSP with just 3 implanted leads (right atrial, RV, and LV) using 2 vectors of the quadripolar lead to achieve dual-site stimulation of the LV MPP. Thibault et al10 were the first to demonstrate an
increase in LVdP/dtmax with MPP in all but 2 of 19 patients. Therewasamarkedheterogeneityofresponseintermsofthe optimal pacing vectors, but use of the distal and most proximal electrode seemed to provide the best response most frequently. Across the entire cohort, standard CRT improved LVdP/dtmax by 13.3% over baseline while the best MSP configuration improved this to 17.5%. The investigators presented the individual data for each case and the magnitudeofchangewashighlyvariable,withmanypatients
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P=0.257 for a difference between protocols
A
P=0.011 for a difference between protocols
P=0.797
P=0.031
P=0.049
B
Figure4 LVEndoAT10-90 foreachpacingprotocolinresponders(A)andnonresponders(B)toBIVimplanted.BIValternative¼biventricularpacingdeliveredvia the temporary left ventricular lead; BIVimplanted ¼ biventricular pacing delivered via the implanted cardiac resynchronization therapy system; LV ¼ left ventricular; LVendoAT10-90 ¼ time delay between the 10th and 90th centiles of activation; MPP ¼ MultiPoint Pacing; MSP ¼ multisite pacing.
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Figure5 Indicative bull’s-eye plots of simulated left ventricular endocardial activation patterns in responders (panels A–D) and nonresponders (panels E–H) tobiventricularpacing.Blackdottedlinesrepresentthe10thcentileofactivation,andmagentadottedlinesrepresentthe90thcentile.A¼anterior;I¼inferior;L ¼ lateral; S ¼ septal. A: Activation during intrinsic rhythm is characterized by a line of functional block (white line) that obligates activation to spread inferoapicallyinaU-shapedpattern.B:Biventricularpacingwith2wavesofactivation(1septaltolateraland1lateraltoseptal)abolishingthelineofblockseen duringintrinsicrhythm(panelA).CandD:Dual-veinMSP(panelC)andMPP(panelD)withactivationpatternssimilartothatofbiventricularpacing.Thereis littlechangeinactivationdelaybetweenthe10thand90thcentiles.E:Activationduringintrinsicrhythmwithnolineofblockandhomogeneousspreadfromthe septum to the lateral wall. F: Activationwith biventricular pacing and no appreciableimprovement in time taken to activate the bulk of the endocardium. G and H: Some improvement in activation delay between the 10th and 90th centiles is seen with both dual-vein MSP (panel G) and MPP (panel H).
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exhibiting only small benefits in LVdP/dtmax. No specific testing of optimal lead position was performed. Similarly, Pappone et al22 used pressure-volume loops to assess MPP. They found that MPP delivered via the widest anatomically separated vectors resulted in improvement in both LVdP/ dtmax and stroke work and this translated to improvement in LV reverse remodeling and NYHA status at 3 months as compared to conventional CRT.23 Findings similar to those of the present study have been demonstrated in a canine model of heart failure and LBBB. Ploux et al13 studied 9 dogs and found that the introduction of up to 7 LV epicardial pacing sites led to an incremental reduction in electrical parameters (LV total activation time and QRS duration), but this did not translate to a consistent stepwise improvement in LVdP/dtmax. High response to single-site LV pacing could not be improved further with multi-site LV pacing. This is in keeping with our findings that in those patients not meeting strict criteria for LBBB, MSP resulted in a more favorable hemodynamic response than did conventional CRT. In the canine experimental model, pacing was performed in DOO configuration and ventricular pacing wasLVonly. We tested true BIV pacing in humans, but there is a growing evidence base suggesting that DDDLV pacing provides hemodynamic benefits equivalent to those provided by BIV stimulationQ12 .24 Inaddition,important findings inthecanine model described have been replicated in humans.25,26
Possible reasons for lack of universal response with MSP The present findings may explain some of the diversity of results in the aforementioned studies because they suggest thatthereisasubgroupofpatientsinwhomMSPmightbeof some benefit. This subgroup appears to consist of patients with nonstrict LBBB and little or no scar. In these patients both forms of MSP produced a significant improvement in AHR over BIV pacing, but this was not the case for patients with strict LBBB and no scar. Our data are novel in providing a possible explanation for this. There was a strong association between strict LBBB and lack of scar, with favorable response to BIVimplanted. While the total LV endocardial activation delay was not different between responders and nonresponders, responders did have a significantlyshorterdelaybetweenthe10thand90thcentiles of activation, suggesting that it is the rate of activation that is important; this is consistent with predictions from previous modeling studies.27 Notably, neither form of MSP resulted in any further improvement in AHR in responders to BIVimplanted, whereas an additional site of stimulation did produce an incremental improvement in AHR in nonresponders. One possible explanation is shown inF5 Figure 5. All the patients meeting strict criteria for LBBB exhibited LV endocardial activation characterized by a line of functional block in intrinsic rhythm, whereas this was absent in nonresponders (Figure 5A). Overcoming the line of functional block in patients with strict LBBB allows for more rapid activation of most of the LV endocardium with BIVimplanted
(Figure 5B), and little or no incremental benefit is achieved with the addition of additional LV pacing sites (Figures 5C and 5D). As this potential target for correction (functional block) is absent in patients without strict LBBB (Figure 5E), single-site pacing alone may not be sufficient to activate the majority of the endocardium quickly, thereby necessitating the addition of another pacing site to produce any form of tangible hemodynamic benefit(Figures 5F–5H). The use of conventional CRT in patients with narrower QRS duration (up to 130 ms) has been debated with several nonrandomized studies showing potential benefit.28–30 Enthusiasm for CRT implantation in this group was summarily tempered by the largest randomized trial of CRT in patients with narrow QRS complex (o130 ms).31 The EchoCRT study showed no benefit from CRT and even a signal for excess mortality. Prespecified subgroup analysis showed that even in patients with QRS duration Z120 ms (and who would all still meet current implant criteria), these findings remained consistent. The nonresponders to BIVimplanted in our study had a mean QRS duration of 131
21 ms, and all responders had a QRS duration of 4150 ms. In nonresponders, we were able to achieve improved acute response with some form of MSP in all but 1 patient. A paradigm shift away from predicting responders toward better treating patients less likely to respond is currently the subject of much interest. The data presented in this study supporttheconceptthatpatientsnotmeetingstrictcriteriafor LBBB and having a QRS duration of o150 ms may do better with MSP.
MPP or dual-vein MSP? Our data do not show a clear hemodynamic benefit with 1 form of MSP over the other. It should be noted that a major limitation of multivein pacing at the present time is the requirement of a Y connector and this is fraught with limitations relating to current drain and impedance drop.32 Thereisanincreasingrealizationthatminimizingtheamount of implanted hardware also mean that MPP may be a more attractive method of implementing MSP.
Study limitations The main limitation is the small study cohort size. Given the highly invasive and time-consuming nature of the study, it was necessary to limit the cohort to the minimum number needed to generate significant results. For the same reasons, the effect of AV and VV interval variation was not investigated and this may have some bearing on the results. With respect to VV intervals, it is possible that preexcitation of the second LV stimulus with either form of MSP may have resynchronizedLV activationmore (with potentially an increase in the rate of LV activation). This hypothesis is certainly worthy of further study. In addition, BIV pacing was performed from 2 sites and it may be possible that these did not include the “optimal” site. Finally, it is not certain that LVdP/dtmax predicts long-term outcome and acute results should be extrapolated with a degree of caution.
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Conclusion In patients with strict LBBB and no scar, conventional CRT deliveredfromasinglesiteisassociatedwithfavorableacute response with no incremental benefit from the addition of additional LV pacing sites. In patients without true LBBB, both forms of MSP improve hemodynamic response. No single form of MSP is superior in terms of hemodynamic response. Faster activation of the majority of LV endocardium (as opposed to the total delay) appears a key determinant of AHR and the presence of lines of functional conduction block may be the electrical therapeutic target that modulates this phenomenon.
Uncited references 18; 19
Appendix Supplementary data Supplementary material cited in this article is available online at http://dx.doi.org/10.1016/j.biopsych.2013.11.018.
References 1. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 2. ClelandJG,DaubertJC,ErdmannE,etal.Theeffectofcardiacresynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–1549. 3. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update incorporatedintotheACCF/AHA/HRS 2008guidelines fordevice-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2012;9:1737–1753. 4. Rinaldi CA, Burri H, Thibault B, Curnis A, Rao A, Gras D, Sperzel J, Singh JP, Biffi M,Bordachar P, Leclercq C. Areview of multisite pacing to achieve cardiac resynchronization therapy. Europace 2015;17:7–17. 5. Rinaldi CA, Leclercq C, Kranig W, et al. Improvement in acute contractility and hemodynamics with multipoint pacing via a left ventricular quadripolar pacing lead. J Interv Card Electrophysiol 2014;40:75–80. 6. PapponeC,RosanioS,OretoG,etal.Cardiacpacinginheartfailurepatientswith left bundle branch block: impact of pacing site for optimizing left ventricular resynchronization. Ital Heart J 2000;1:464–469. 7. Padeletti L, Colella A, Michelucci A, Pieragnoli P, Ricciardi G, Porciani MC, Tronconi F, Hettrick DA, Valsecchi S. Dual-site left ventricular cardiac resynchronization therapy. Am J Cardiol 2008;102:1687–1692. 8. Rogers DP, Lambiase PD, Lowe MD, Chow AW. A randomized double-blind crossover trial of triventricular versus biventricular pacing in heart failure. Eur J Heart Fail 2012;14:495–505. 9. Leclercq C, Gadler F, Kranig W, Ellery S, Gras D, Lazarus A, Clementy J, Boulogne E, Daubert JC. A randomized comparison of triple-site versus dual-site ventricular stimulation in patients with congestive heart failure. J Am Coll Cardiol 2008;51:1455–1462. 10. Thibault B, Dubuc M, Khairy P, Guerra PG, Macle L, Rivard L, Roy D, Talajic M, Karst E, Ryu K, Paiement P, Farazi TG. Acute haemodynamic comparison of multisite and biventricular pacing with a quadripolar left ventricular lead. Europace 2013;15:984–991. 11. van Gelder BM, Bracke FA. Acute hemodynamic effects of single and dual site leftventricularpacingemployingadualcathodalcoronarysinuslead.PacingClin Electrophysiol 2015;38:558–564. 12. Shetty AK, Sohal M, Chen Z, et al. A comparison of left ventricular endocardial, multisite, and multipolar epicardial cardiac resynchronization: an acute haemodynamic and electroanatomical study. Europace 2014;16:873–879. 13. Ploux S, Strik M, van Hunnik A, van Middendorp L, Kuiper M, Prinzen FW. Acute electrical and hemodynamic effects of multisite left ventricular pacing for
cardiac resynchronization therapy in the dyssynchronous canine heart. Heart Rhythm 2014;11:119–125. 14. van Gelder BM, Bracke FA, Meijer A, Pijls NH. The hemodynamic effect of intrinsic conduction during left ventricular pacing as compared to biventricular pacing. J Am Coll Cardiol 2005;46:2305–2310. 15. Shetty AK, Duckett SG, Ginks MR, et al. Cardiac magnetic resonance-derived anatomy, scar, and dyssynchrony fused with fluoroscopy to guide LV lead placement in cardiac resynchronization therapy: a comparison with acute haemodynamic measures and echocardiographic reverse remodelling. Eur Heart J Cardiovasc Imaging 2013;14:692–699. 16. Duckett SG, Ginks M, Shetty AK, Bostock J, Gill JS, Hamid S, Kapetanakis S, Cunliffe E, Razavi R, Carr-White G, Rinaldi CA. Invasive acute hemodynamic responsetoguideleftventricularleadimplantationpredictschronicremodelingin patients undergoing cardiac resynchronization therapy. J Am Coll Cardiol 2011;58:1128–1136. 17. Auricchio A, Fantoni C, Regoli F, Carbucicchio C, Goette A, Geller C, Kloss M, Klein H. Characterization of left ventricular activation in patients with heart failure and left bundle-branch block. Circulation 2004;109:1133–1139. 18. Voss F, Steen H, Bauer A, Giannitsis E, Katus HA, Becker R. Determination of myocardial infarct size by noncontact mapping. Heart Rhythm 2008;5:308–314 Q13 . 19. Sohal M, Amraoui S, Chen Z, Sammut E, Jackson T, Wright M, O’Neill M, Gill J, Carr-White G, Rinaldi CA, Razavi R. Combined identification of septal flash and absence of myocardial scar by cardiac magnetic resonance imaging improves prediction of response to cardiac resynchronization therapy. J Intervt Card Electrophysiol 2014;40:179–190. 20. Strauss DG, Selvester RH, Wagner GS. Defining left bundle branch block in the era of cardiac resynchronization therapy. Am J Cardiol 2011;107:927–934. 21. Ginks MR, Shetty AK, Lambiase PD, et al. Benefits of endocardial and multisite pacing are dependent on the type of left ventricular electric activation pattern and presence of ischemic heart disease: insights from electroanatomic mapping. Circ Arrhythm Electrophysiol 2012;5:889–897. 22. Pappone C, Calovic Z, Vicedomini G, et al. Multipoint left ventricular pacing improves acute hemodynamic response assessed with pressure-volume loops in cardiac resynchronization therapy patients. Heart Rhythm 2014;11:394–401. 23. PapponeC,CalovicZ,VicedominiG,etal.Multipoint leftventricularpacingina single coronary sinus branch improves mid-term echocardiographic and clinical response to cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2015;26(1):58–63. 24. Thibault B, Ducharme A, Harel F, et al. Left ventricular versus simultaneous biventricular pacing in patients with heart failure and a QRS complex 4/¼120 milliseconds. Circulation 2011;124:2874–2881. 25. Strik M, van Deursen CJ, van Middendorp LB, van Hunnik A, Kuiper M, Auricchio A, Prinzen FW. Transseptal conduction as an important determinant for cardiac resynchronization therapy, as revealed by extensive electrical mapping in the dyssynchronous canine heart. Circ Arrhythm Electrophysiol 2013;6:682–689. 26. SohalM,ShettyA,NiedererS,ChenZ,JacksonT,SammutE,BostockJ,RazaviR, Prinzen F, Rinaldi CA. Delayed trans-septal activation results in comparable hemodynamiceffect ofleft ventricular andbiventricular endocardial pacing:insights from electroanatomical mapping. Circ Arrhythm Electrophysiol 2014;7:251–258. 27. Niederer SA, Shetty AK, Plank G, Bostock J, Razavi R, Smith NP, Rinaldi CA. Biophysicalmodelingtosimulatetheresponsetomultisiteleftventricularstimulation using a quadripolar pacing lead. Pacing Clin Electrophysiol 2012;35:204–214. 28. Achilli A, Sassara M, Ficili S, Pontillo D, Achilli P, Alessi C, De Spirito S, Guerra R, Patruno N, Serra F. Long-term effectiveness of cardiac resynchronizationtherapyinpatientswithrefractoryheartfailureand “narrow” QRS.JAmColl Cardiol 2003;42:2117–2124. 29. Bleeker GB, Holman ER, Steendijk P, Boersma E, van der Wall EE, Schalij MJ, Bax JJ. Cardiac resynchronization therapy in patients with a narrow QRS complex. J Am Coll Cardiol 2006;48:2243–2250. 30. Yu CM, Chan YS, Zhang Q, Yip GW, Chan CK, Kum LC, Wu L, Lee AP, Lam YY, Fung JW. Benefits of cardiac resynchronization therapy for heart failure patients with narrow QRS complexes and coexisting systolic asynchrony by echocardiography. J Am Coll Cardiol 2006;48:2251–2257. 31. Ruschitzka F, Abraham WT, Singh JP, et al. Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013;369: 1395–1405. 32. Behar JM, Bostock J, Ginks M, Jackson T, Sohal M, Claridge S, Razavi R, Rinaldi CA. Limitations of chronic delivery of multi-vein left ventricular stimulation for cardiac resynchronization therapy. J Intervt Cardi Electrophysiol 2015;42:135–142.
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CLINICAL PERSPECTIVES The static rate of nonresponse to conventional cardiac resynchronization therapy (CRT) remains substantial, and the list of alternative metrics that have been proposed as better predictors is long and extensively studied but none has been shown to be superior to the electrocardiogram. A paradigm shift away from better predictors of response toward alternative methods of CRT delivery is now an active area of interest. Multisite left ventricular (LV) pacing is one alternative that has been proposed as a means of achieving more complete electrical resynchronization and therefore improved outcomes. We have shown that in patients meeting strict criteria for left bundle branch block (LBBB), conventional CRT provides an excellent hemodynamic response that is not significantly improved with the addition of additional LV stimulation sites. Electroanatomic mapping during intrinsic rhythm and during pacing suggests that the correction of a line of functional block (seenin patients meetingstrict criteria for LBBB) appears tobe themechanism bywhichconventional CRT achieves its therapeutic benefit. Our data also demonstrate that this target is not present in patients not meeting strict criteria for LBBB, and it is in these patients that we were able to demonstrate incremental hemodynamic benefit with the addition of additional LV pacing sites. This improvement appears to be mediated by an increase in the rate of LV activation. These resultssuggestthatthesubsetofpatientswhoareknowntoexhibitattenuatedresponsetoconventionalCRTmayobtainthe most benefit from multisite pacing. This hypothesis needs to be tested in a suitably powered randomized trial.
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