Biophysical Modeling to Simulate the Response to Multisite Left Ventricular Stimulation Using a Quadripolar

Biophysical Modeling to Simulate the Response to Multisite Left Ventricular Stimulation Using a Quadripolar Pacing Lead STEVEN A. NIEDERER, PH.D.,* A.K. SHETTY,
M.B.B.S.,*,† G. PLANK, PH.D.,‡ J. BOSTOCK, M.B.B.S.,† R. RAZAVI, M.D.,*,† N.P. SMITH, PH.D.,*,§ and C.A. RINALDI, M.D.,*,† From the *Imaging Sciences & Biomedical
Engineering Division, King’s College London, London, United Kingdom; and †Department of Cardiology, St Thomas’ Hospital, London, United Kingdom; ‡Institut f¨ur
Biophysik, Medizinische Universit¨at Graz, Graz, Austria; and §Computing Laboratory, University of Oxford, Oxford, United Kingdom
Background: Response to cardiac resynchronization therapy (CRT) is reduced in patients with posterolateral scar. Multipolar pacing leads offer the ability to select
desirable pacing sites and/or stimulate from multiple pacing sites concurrently using a single lead position. Despite this potential, the clinical evaluation and
identification of metrics for optimization of multisite CRT (MCRT) has not been performed. Methods: The efficacy of MCRT via a quadripolar lead with two left ventricular
(LV) pacing sites in conjunction with right ventricular pacing was compared with single-site LV pacing using a coupled electromechanical biophysical model of the human
heart with no, mild, or severe scar in the LV posterolateral wall. Result: The maximum dP/dtmax improvement from baseline was 21%, 23%, and 21% for standard CRT versus
22%, 24%, and 25% for MCRT for no, mild, and severe scar, respectively. In the presence of severe scar, there was an incremental benefit of multisiteversus standard CRT
(25% vs 21%, 19% relative improvement in response). Minimizing total activation time (analogous to QRS duration) or minimizing theactivationtimeofshort-
axisslicesoftheheartdidnotcorrelatewithCRTresponse.Thepeakelectrical activation wave area in the LV corresponded with CRT response with an R2 value between 0.42 and
0.75. Conclusion: Biophysical modeling predicts that in the presence of posterolateral scar MCRT offers an improved response over conventional CRT. Maximizing the
activation wave area in the LV had the most consistent correlation with CRT response, independent of pacing protocol, scar size, or lead location. (PACE 2012; 35:204–
214) biomedical engineering, computing, CRT
Introduction Cardiac resynchronization therapy (CRT) is an effective treatment for medically refractory patients with heart failure and left branch bundle block.1–3
Despite the mortality, morbidity, and quality of life benefits, 30–40% of patients still fail to respond to CRT.4 One potential strategy to improve response is
multisite left ventricular (LV) stimulation that has the capacity to produce simultaneous recruitment of a larger volume of viable myocardium and thus more effectively
re
Disclosures: Anoop Shetty receives a St. Jude Medical educational grant and Christopher Rinaldi receives St. Jude educational support and is on advisory boards for St.
Jude Medical and Medtronic. Address for reprints: Steven Niederer, Biomedical Engineering Department, The Rayne Institute, St Thomas’ Hospital, London SE1 7EH, United
Kingdom. Fax: 44-0-2071885442; e-mail: steven.niederer@kcl.ac.uk Received June 12, 2011; revised August 2, 2011; accepted September 5, 2011. doi: 10.1111/j.1540-
8159.2011.03243.x
verse dyssynchrony. While multisite CRT (MCRT) has been previously applied using two separate LV pacing leads,5 new lead technologies allow multisite stimulation to be
delivered through a single multipolar lead.6,7 Specifically, the cathodal programmability available with a quadriploar lead (Quartet LV lead
model1458Q,St.JudeMedical,Sylmar,CA,USA) allows stimulation of the LV myocardium using multiple vectors. The four LV lead electrodes can act as cathodes and two as
anodes and the right ventricular (RV) coil can act as an anode giving 10 possible different pacing configurations. The lead has a 4.0-Fr tip and 4.7-Fr maximum body
diameter with three ring electrodes (M2, M3, P4) located 20, 30, and 47 mm from the distal electrode (D1). The lead can be used in a conventional way for single-site
LV stimulation but the multiple vectors available have been shown to be useful in overcoming problems with phrenic nerve stimulation and high capture thresholds.6,7 In
addition, this quadripolar lead has the ability to perform true multisite pacing of the LV using two different vectors with a
C 2011, The Authors. Journal compilation C 2012 Wiley Periodicals, Inc. 204 February 2012 PACE, Vol. 35
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Figure 1. Heart geometry and coronary venous anatomy. (A) Electrode position and label and (B) the region LV posterolateral scar in blue.
minimum 5-ms delay between them. With an RV electrode also used, this allows up to three ventricular sites to be paced at the same time, thus increasing the points of
early activation in the heart. Despite the options provided to this quadriploar lead, it is important to note that, giventherelativecloseproximityoftheelectrodes,
increasing the number of pacing sites may not necessarily produce a significant improvement. Furthermore,theincreasednumberofpacingsites and the corresponding increase
in the temporal and spatial pacing combinations means that optimizing such a device for a specific patient is a challenge in itself. The number of potential pacing
permutations greatly limits the capacity to comprehensively evaluate all combinations or optimizetheleadthroughtrialanderrorinasingle patient, thus necessitating
improved optimization algorithms. The difficulty in both testing and validating such algorithms is that while safety studies of multisite pacing are currently being
performed, there are currently no clinical data on the hemodynamic effect of multisite stimulation using the quadriploar lead. In silico biophysical models allow the
possibility to test multiple pacing parameters.8 To provide an initial prediction of the efficacy of multisite pacing with a quadripolar lead and to facilitate the
proposal of optimization algorithms, we applied this approach to evaluate the effects of multisite pacing in a computational coupled electromechanical human heart
model (see Fig.1).ThemodelsimulatessingleormultisiteLV pacing in conjunction with right ventricular (RV) pacing and can be tested in the presence of no, moderate, or
severe LV transmural posterolateral scar. These simulations predict the contractile ability of the heart for each pacing combination, measured using the maximum rate
of pressure increaseduringventricularsystole(dP/dtmax),and provide a quantitative evaluation of the effects of MCRT compared with conventional CRT. Using
a complete set of pacing combinations, we then evaluate three potential optimization algorithms basedontotalactivationtime,cumulativefraction of activated volume, and
activation time of shortaxis slices, parallel to the base of the heart (see Fig. 2). Methods Modeling Methods The computational model is based on a coupled
electromechanical human heart model developed previously8 using invasive data from a 60-year-old female with New York Heart Association class III heart failure, an LV
ejection fraction (LVEF) of 25%, and left bundle branch block (QRS duration of 154 ms). The mechanics and electrophysiology model were validated preand post-CRT
against endocardial activation patterns derived from noncontact mapping (Ensite), magnetic resonance imaging (MRI) derived wall motion, and pressure catheter measures.
In this study, two simplifying assumptions were made to reduce confounding factors. The heart was assumed to have no native activation and the myocardium was treated
as homogenous. Simulations were performed using the bidomain approximation of myocardial electrical activation in the heart. Simulations were performed using CARP9
(http://carp.medunigraz.at) on the UK National HPC resource HeCTOR (www.hector.ac.uk).Theelectrophysiologymodel had 35 million and 26 million extra and intracellular
degrees of freedom, respectively, and 208 million elements, and took approximately 3 hours to solve using 512 cores. Mechanics simulations were performed using CMISS
(www.cmiss.org) on ORAC at the Oxford e-Research Center (www.oerc.ox.ac.uk). Pacing Model To simulate pacing, we manually aligned the coronary venous anatomy from
steady-state free precession MRI with the model geometry derived
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Figure 2. Heart model activation cross sections. (A) The activation patterns, where white regions are activated and black regions inactivated for evenly spaced 10-mm
slices taken from the heart model in (B). (C) The point of first activation at 15 ms in slice 3, the point (marked with a yellow x) and time where the first loop of
activation is formed at 92 ms, the point when the LV is fully activated at 104 ms, and the time just prior to full slice activation at 139 ms.
from cine MRI. The coronary venous anatomy providedthelocationforthequadripolarleadthat was introduced into the model. RV septal (RVS) and apical (RVA) lead positions
were introduced in the center of the RV. All electrodes are shown in Figure 1A. LV pacing was between the D1 (cathode) and M2 (anode) or M3 (cathode) and P4
(anode)electrodes.RVpacingwasbetweentheRV tip (cathode) in the septum or apex position and theRVcoil(anode).Stimulationwassimulatedby
raisingthecathodalelectrodeto2Vfor0.5msand grounding the anodal electrode.
Scar Model Simulations were performed using the model with no scar or in the presence of a transmural basal LV posterolateral scar with a 60-mm diameter, as shown in
Figure 1B. Scar was simulated by reducing conduction and decreasing anisotropy.10 Conduction velocities decrease by approximately 50% between viable tissue and scar.11
From the cable equation conduction, velocity is proportional to the square route of conductivity (the inverse of resistance).12 Hence, scar was simulated by a 50% or a
90% decrease in the conductivity value corresponding to 30% or 70% decrease in conduction velocity, for mild andseverescar,respectively.Thequadripolarlead was placed
across the scar with the most distal pole D1 out of the scar, M2 on the scar border, and M3 and P4 basally within the scar.
Cardiac Function and Efficacy of CRT The efficacy of each pacing mode was evaluated using the change in dP/dtmax as a metric
of improvement. RV apical pacing dP/dtmax was used as a baseline, as the model had no intrinsic activation. We normalized all CRT responses by dP/dtmax calculated for
an instantaneous homogenous activation pattern.
Simulations For standard CRT (single LV stimulation site and RV stimulation), simulations were performed withtheLVorRVsitepacedfirstwitha5-,15-,30-, or 45-ms delay. For
MCRT (two LV pacing sites andoneRV),thethreestimulationswereseparated by two delays, one delay interval was always 5 ms andtheotherdelayintervalwas5,15,30,or45ms. The
sites could be paced in any order except that the RV site had to be paced either before or after the LV pacing. Activation times for combinations of pacing sites were
calculated by combining activation patterns from each individual site as described in the online supplement.
Optimization Algorithms QRS duration has been reported to correlate with CRT response13–17 and provide an effective metric of asynchrony to identify CRT candidates.4
To test this hypothesis, we compared CRT responsewithQRSduration,usingtotalactivation time of both ventricles as an analog of QRS
duration.Previousstudieshaveshownthatpacing the LV only increased QRS duration, potentially due to late activation of the RV.18 To account for this effect we provide
results for activation times, both for the combined LV and RV and for the LV alone.
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Figure 3. Standard CRT pacing response: top panel corresponds to pacing the RV first, and bottom panel pacing the LV first with increasing intervals between the two. Red
lines correspond to septal and blue lines apical RV pacing. Triangle and square symbols correspond to LV pacing from the apex or base, respectively.
If the bulk of the heart is rapidly and synchronously activated, then late activation of peripheral regions that prolongQRS durationmay confound relationships between
QRS and CRT response. Maximizing the peak rate of volume activation may minimize bulk activation asynchrony and lead to improved cardiac function. To test this
hypothesis, we calculated derivative of the cumulative activation curve and plotted this against CRT response. The length dependence of cardiac muscle combined with
the circumferential fiber direction in the mid-LV wall means that effective LV contraction may be achieved when a continuous strand of activated myocardium is formed
around the circumference of the LV. When all myocardiumisactivatedinsuchaloop,thelength dependence of the muscle will spatially regulate tension development so that
during isovolumetric contractionmusclelengthismaintained,allowing it to generate higher tension and hence improved dP/dtmax. To test if activation loops in the LV
correlate with dP/dtmax in seven short-axis slices, we evaluated the time that the first loop of myocardium around the LV is activated, when the whole of the slice is
activated in both the LV and
RV, and when the whole of the slice in the LV is activated. Results Baseline Results Maximum dP/dtmax was calculated for a homogenous instantaneous activation of the
myocardium, resulting in a theoretical maximum dP/dtmax of 1,295 mmHg/s. Baseline dP/dtmax (RV apical pacing) was 906, 885, and 825 mmHg/s for no, mild, and severe
scar or 0.7, 0.683, and 0.64 of the maximum value. Single-Site and Multisite LV stimulation Figures 3 and 4 show the fraction of the theoretical maximum dP/dtmax
reached with standard CRT and MCRT in the presence of no, mild, and severe scar, for different combinations ofLVandRVpacinglocationsanddelayintervals. Standard CRT
caused a 21%, 23%, and 21% change in dP/dtmax from pacing combination D1M2 5-ms RVS, M3-P4 15-ms RVA, and M3-P4 45-ms RVA for no scar, mild scar, and severe scar,
respectively. These changes correspond to an absolute increase of 0.150, 0.154, and 0.133 in the fraction of maximum dP/dtmax reached for no
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Figure 4. Multisite CRT pacing: red lines correspond to septal and blue apical RV pacing, and triangle and squares symbols correspond to the variable time interval
being first or second, respectively.
scar,mildscar,andseverescarcases,respectively. MCRT (two LV and one RV stimulation sites) caused a 22%, 24%, and 25% change in dP/dtmax from pacing combination D1-M2
5ms M3-P4 5ms RVS, M3-P4 5ms D1-M2 5ms RVS and M3-P4 5ms
D1-M245msRVSfornoscar,mildscar,andsevere scar, respectively. These changes correspond to an absolute increase of 0.153, 0.164, and 0.162 in the fraction of maximum
dP/dtmax reached for no scar, mild scar, and severe scar cases,
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Figure5. (A)HemodynamiceffectofstandardversusMCRTdependentonthepresenceandseverityofposterolateral scar. With difference between standard versus MCRT labeled. (B)
Comparison of optimal pacing combinations from Figures 3 and 4, for conventional CRT (CCRT, gray lines) and multipolar CRT (MCRT, black lines) for no (solid line), 50%
(dashed line), and 90% (dash dot line) scar.
respectively. Thus, in the presence of severe scar, there was a benefit with multisite versus conventional CRT (25% vs 21% representing a 19% relative improvement in
the change in dP/dtmax). Figure 5 compares the optimal response from conventional CRT compared to multisite pacing.
CRT Efficacy and QRS Duration To test if minimizing either biventricular or LV activation time is a potential method for optimizing lead timings or positions, we
plotted totalandLVactivationtimeagainstpacingefficacy inboththeconventionalandMCRTsimulationsin Figure 6.
Volume Activation Figure 7 plots the peak rate of volume activation (the rate of change of the fraction of the myocardial volume that is activated) for each
pacingandscarcombination,inthewholeheartor only in the LV against the normalized dP/dtmax.
LV Activation Time To evaluate the formation of continuous strands of activated tissue, we calculated the time taken for short-axis slices of the heart or the LV to
become fully activated or the time taken for the first loop of continuous activation around the LV to form. Figure 8 shows the correlations between these times and
dP/dtmax.
Discussion Thisisthefirsthumanbiophysicalmodelthat hastestedtheefficacyofmultisiteLVpacingusing a quadripolar lead. The model predicts that: (1) preexcitation of the LV
in regions of slow conduction improves hemodynamic response to CRT, (2) multisite CRT offers moderate improvements in acute hemodynamic response over conventional CRT
but that this is the case only in the presence of scar, (3) minimizing QRS duration or activation times of short-axis slices provide a poor indicator of CRT response,
and (4) cumulative volume activation maps provide a potential metric of CRT response that is robust to cases with scar.
Standard and MCRT As shown in Figure 3, in the absence of scarapproximately0.85ofthemaximumdP/dtmax could be achieved with either standard or MCRT. It was only in the
presence of posterolateral scar that MCRT showed a benefit. As the level of scar increased, the optimal response between multisite and standard CRT diverged (25% vs
21%, representing a relative increase of 19%). As the level of scar increased, the optimal combination of poles locations in both the LV and RV changed for both
standard and MCRT demonstrating the impact of scar on optimal lead placement. Figure3showsthatiftheRV(apicalorseptal) is the first site to be activated then regardless
of the severity of posterolateral scar, increasing the delay interval decreases CRT efficacy. In the presence of scar preexciting, the LV with
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Figure 6. Plot of normalized pressure against LV or biventricular activation time for conventional and MCRT in the presence of no scar, 50%, and 90% scar. Point
symbols correspond to pacing from RVA (square), RVS (circle), D1-M2 (triangle), or M3-P4 (diamond) first. Solid points correspond to RVA as opposed to RVS pacing.
standard CRT improves response, regardless of LV or RV pacing location, consistent with earlier studies that showed an improved benefit of LV preexcitation over
simultaneous LV and RV pacing.19,20 Similarly for MCRT in the absence of posterolateral scar, the model predicts no significant benefit from LV preexcitation and limited
benefit in the presence of mild scar for any pacing lead combination (Fig. 4). Only in the presence of severe scar was a benefit seen in preexciting the LV for MCRT. The
effect of RV septal or apical pacing remains controversial.21,22 In standard CRT, RV septal pacing has been shown to provide no benefit over RV apical pacing.23
Consistent with these results, the model predicted no clear benefit from RV septal or apical pacing for standard CRT. Interestingly, there was a consistently better
responsetoCRTwithRVseptalpacingasopposed to apical pacing in the MCRT simulations. Figures 3 and 4 predict that in a clinical context, when temporal optimization may
be
unavailableorlimited,MCRTprovidesanoptimal or near optimal outcome in 85% of pacing combinations for near simultaneous activation compared to 71% of pacing
combinations for conventional CRT. Meaning MCRT may provide a more robust outcome in the absence of temporal optimization. Pacing in Scar Consistent with canine24 and
human25 studies, the model results predict that with optimal pacingtimingandlocation,CRTinthepresenceof scarcanstillsignificantlyimprovepumpfunction. Specifically, the
model predicts that, with lead capture, pacing in scarred regions and thus preexciting the scarred myocardium often results in an optimal site. Controversy remains on
the detrimental effects of pacing in or near scar26–28; however, these conflicting results could be due to differences in capture of the scarred region, as if
electrical activation fails to propagate from the pacing site then patients will receive no benefit.
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Figure 7. Correlation between CRT response and peak rate of cumulative activation for conventional CRT and MCRT in the presence of no scar, 50%, and 90% scar.
Notablyleadpositionoptimizationstrategieshave resulted in apparently conflicting conclusions. Previous reports have suggested that pacing in or near regions of scar
compromises response26,27 conversely an alternate strategy proposes pacing at the point of latest mechanical contraction maximizes response.29–31 Although not
explicitly inconsistent, in many cases, slow conduction in scar will result in the last region to contract being one that is scarred or compromised; this location is
then either an optimal or a poor pacing location depending on the doctrine adopted. The modelpredictsthatifthescarredregionhasviable but slow conduction then
preexciting the scarred region can result in an optimal response; thus, the optimal increase in dP/dtmax for standard and MCRT was achieved by first pacing from D1 to
M2 in the absence of scar, but in the presence of scar, it was optimal to pace first from M3 to P4, whichwaslocatedinthemiddleofthescarregion. This is in keeping with
noncontact mapping data from our institution where LV preexcitation in areas of slow conduction improved hemodynamic response.32
Apical versus Basal Pacing There has been much interest recently in the position of the LV pacing lead for CRT in terms of an apical or basal pacing site. Recent data
from the MADIT-CRT trial showed that leads placed in the apical region were associated with an unfavorable outcome.33 For standard CRT simulations, with a single LV
stimulation site, the optimal site was basal in models with mild or severe scar. In models without scar, there was marginal difference between apical and basal pacing.
For MCRT, pacing at both apical and basalsitesisperformedsoonecannotdifferentiate betweenapicalandbasalLVpacing.Onepotential advantage of this type of lead, especially
in patients with scar, thus may be the ability to achieve a stable apical position within a coronary sinus branch and to perform basal stimulation using the proximal
electrodes.
Optimizing Activation Previous studies have reported that minimizing QRS correlates with CRT response,13,34
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Figure 8. Correlation as defined by the R2 value of a linear fit between the time taken for the whole slice or the first loop to form and the normalized rate of pressure
development for conventional CRT (CCRT) and multipolar CRT (MCRT) with no scar, 50% scar, and 90% scar.
while other studies found no change in QRS despite seeing a response to CRT.35,36 To directly address this issue, we evaluated the correlation between QRS duration,
maximum rate of volume activation, and short-axis slice activation times in both the RV and LV and the LV alone. We found that QRS duration did not consistently
correlate with CRT response. Single-site LV pacing has been reported to prolong QRS while improving CRT response.18 This could be attributable to late activation of
the RV prolonging the QRS while having limited impact on LV function, yet even when the confounding effects of the RV on total activation time were removed (Fig. 6),
the correlation between CRT response and LV activation time in the model was still poor. This relationship was similar for both standard and MCRT with the relationship
deteriorating further in the presence of scar. We hypothesized that minimizing the activationtimeoftheLV,RVandLV,oraloopinashort
axis slice would correlate with CRT response by corresponding to the formation of a continuous contracting region of myocardium that would cause an effective
contraction of the LV. Despite showing a strong correlation of basal activation with CRT response in the absence of scar, this relationship deteriorated rapidly in the
presence of scar, particularly in the MCRT simulations. It is possible that calculating the time of formation of other continuous loops of activating myocardium would
correspond to CRT response. These loops could potentially lie out of the short-axis plane or in loops of myocardium following the direction of principle stress. The
only metric to show a consistent correlation with the CRT response was the peak rate of cumulative activation in the LV. Given an approximate constant conduction
velocity and the continuous smoothly varying LV geometry, this metric corresponds to the peak surface area of the activation wave and maximizing its size
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will synchronize the bulk activation time of the heart. This metric correlated with both standard and MCRT and was independent of scar, RV or LV lead location, and
timing interval. The cumulative activation of the LV is not routinely measured in CRT patients. It can be approximated by evaluating the rate of cumulative volume
contracting, although the relationship between activation time and deformation is dependent on the activation pattern. It is possible that simple patient-specific
activation models could provide a means to evaluate this metric and be used for the model-guided optimization of CRT lead position and timing.
Limitations The model was based on a single patient datasetduetotheneedforasinglecomprehensive and consistent dataset. However, we cannot necessarily assume that all
patients would respond in the same fashion. The patient on whom the model was based, however, was a typical candidate for CRT with a broad left bundle branch block
electrocardiogram and LVEF<35%. In modeling the scar, we assumed a homogenous and discrete region that may not be the case for many patients with ischemic heart
disease that may have multiple and heterogeneous areas of scar. The presence of multiple infarct regions would affect the model predictions. Specifically, the presence
of scarred or compromised regions in close proximity to the RV lead could favor preexcitation of the RV to achieve an optimal
response. Late-enhancement MRI shows us that scar geometry is varied and often complex. In this study, we aimed to investigate the general impact of transmural
posterolateral scar severity on conventional CRT and MCRT efficacy independently from any one individual patients scar geometry. This leads to the use of a defined
analytical description of scar geometry; however, the model results may change for different scar locations or geometries. Multisite pacing was delivered using a
commercially available lead and it is possible that other lead designs would produce a different hemodynamic response. Conclusions This biophysical model, testing the
efficacy of multisite LV pacing using a quadripolar lead, shows that MCRT may offer an improvement in acute hemodynamic response over conventional standard CRT but that
this benefit is only seen in the presence of scar. Posterolateral scar is a well-recognized predictor of poor CRT response and therefore MCRT delivered using such lead
technologies may be a potential way to improve response in the CRT population, especially in patients with ischemic cardiomyopathy. These findings will clearly require
in vivo evaluation.
Acknowledgments: This work was supported by United Kingdom Engineering and Physical Sciences Research Council for support through grants EP/F043929/1 and EP/F059361/1.
The authors are grateful to Paul Ryu for Quartet lead technical specifications.
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