Influence of Pacing Site Characteristics on Response to Cardiac

Influence of Pacing Site Characteristics on Response to Cardiac

Resynchronization Therapy Wong et al: Pacing Site Scar and CRT Response

Jorge A. Wong, MD1; Raymond Yee, MD1; John Stirrat, BMSc2; David Scholl, BSc2;

Andrew D. Krahn, MD1; Lorne J. Gula, MD, MSc1; Allan C. Skanes, MD1;

Peter Leong-Sit, MD1; George J. Klein, MD1; David McCarty, MB BCh1;

Nowell Fine1, MD1; Aashish Goela, MD3; Ali Islam, MD3; Terry Thompson, PhD4,5,6;

Maria Drangova, PhD2,5,6; James A. White, MD1,2,4,5

1Division of Cardiology, Department of Medicine, University of Western Ontario (UWO), 2Imaging Laboratories - Robarts Research Institute, UWO

3Department of Medical Imaging, Schulich School of Medicine and Dentistry 4Lawson Health Research Institute, UWO,

5Biomedical Imaging Research Centre (BIRC), UWO 6Department of Medical Biophysics, UWO, London, Ontario, Canada

Correspondence to: Dr James A. White 3T-7T MRI Unit - Robarts Research InstitutePO Box 5015, 100 Perth Drive London, Ontario, Canada, N6A 5K8Tel: 519-931-5244 Fax: 519 931-5262 E-mail [email protected]

DOI: 10.1161/CIRCIMAGING.111.000146

Journal Subject Codes: 110, 120, 30, 106

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Abstract

Background—Transmural scar occupying left ventricular pacing regions has been associated

with reduced response to cardiac resynchronization therapy (CRT). However, spatial influences

of lead tip delivery relative to scar at both pacing sites remains poorly explored. This study

evaluated scar distribution relative to left ventricular (LV) and right ventricular (RV) lead tip

placement through co-registration of Late Gadolinium Enhancement (LGE) MRI and cardiac

computed tomography (CT) findings. Influences on CRT response were assessed by serial

echocardiography.

Methods and Results—Sixty patients receiving CRT underwent pre-implant LGE-MRI, post-

implant cardiac CT and serial echocardiography. Blinded segmental evaluations of mechanical

delay, percent scar burden, and lead tip location were performed. Response to CRT was defined

as a reduction in LVESV 15% at 6 months. The mean age and LVEF were 64±9 years and

25±7%, respectively. Mean scar volume was higher among CRT non-responders for both the

LV [23±23 vs. 8±14% (p=0.01) and RV pacing regions [40±32 vs. 24±30% (p=0.04)].

Significant pacing region scar was identified in 13% of LV pacing regions and 37% of RV

pacing regions. Absence of scar in both regions was associated with an 81% response rate,

compared to 55%, 25% and 0%, respectively when the RV, LV or both pacing regions contained

scar. LV pacing region dysynchrony was not predictive of response.

Conclusions—Myocardial scar occupying the LV pacing region is associated with non-response

to CRT. Scar occupying the RV pacing region is encountered at higher frequency and appears to

provide a more intermediate influence on CRT response.

Key Words: cardiac resynchronization therapy, cardiac magnetic resonance imaging, late

gadolinium enhancement, dyssynchrony, cardiac computed tomography, scar, response

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Abbreviations:

LV = Left Ventricle

RV = Right Ventricle

EF = Ejection Fraction

CRT = Cardiac Resynchronization Therapy

NYHA = New York Heart Association

CAD = Coronary Artery Disease

ICM = Ischemic Cardiomyopathy

DCM = Dilated Cardiomyopathy

QOL = Quality of Life

6-MWT = 6 minute walk test

MLWH = Minnesota Living with Heart Failure

DE-MRI = Delayed Enhancement Magnetic Resonance Imaging

EDV = End Diastolic Volume

ESV = End Systolic Volume

LBBB = Left Bundle Branch Block

RBBB = Right Bundle Branch Block

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Systolic heart failure is the leading cause of cardiovascular morbidity and mortality in North

America, consuming over $20 billion per year of global health care expenditures1. Therapeutic

strategies currently include cardiac resynchronization therapy (CRT), a permanent pacing

therapy aimed at correcting dysynchronous mechanical activation of the left ventricle (LV)

through simultaneous pacing of the right ventricular (RV) septum and the lateral wall (via a

coronary sinus lead).2 While CRT has been shown to reduce symptoms and mortality in select

heart failure patients2-9 up to 30-40% of candidates may not respond.10, 11 Reasons for response

failure appear multi-factorial, with 3 dominant variables implicated to date: i) lack of LV

dyssynchrony12, 13, ii) geographic placement of the LV lead14-19, and iii) scar within the LV

pacing region.20-22 Preliminary evidence similarly suggests absence of RV pacing region (ie:

septal wall) scar to be of importance for achieving response.23, 24 However, the relative and

combined influence of these variables on response to CRT has not been well studied.

In this prospective cohort study we combine findings from Late Gadolinium Enhancement

(LGE) Magnetic Resonance Imaging (MRI) and Cardiac-gated Computerized Tomography

(CCT) to achieve accurate geographic registration of myocardial scar and lead tip location for

both the LV and RV pacing leads. These findings are correlated to CRT response, as assessed by

serial echocardiography.

Methods

Study Population

Ninety-three consecutive patients referred for CRT between January 2008 and March 2011 at the

London Health Sciences Centre were screened for study eligibility. Inclusion criteria were: age

18 years, LV ejection fraction (EF) 35%, QRS duration 120 ms, NYHA class II and on

maximal tolerated medical therapy for 6 weeks. Exclusion criteria were: myocardial infarction

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or revascularization procedure 3 months, standard contraindications to MRI, and a GFR

30ml/min/1.73 m2.

Of all screened patients 63 satisfied study entry criteria and successfully completed baseline

evaluations. Screened patients were excluded for the following reasons; renal insufficiency (12),

existing pacemaker or implantable cardiac defibrillator (ICD) system (16), and severe

claustrophobia (2). Patients were classified according to cardiomyopathy etiology. Ischemic

cardiomyopathy (ICM) was defined as those with prior myocardial infarction (admission for

chest pain with cardiac marker elevation and/or development of new Q waves on ECG) or an

invasive coronary angiogram with obstructive coronary artery disease (CAD) ( 1 coronary artery

with 70% stenosis). Those patients not meeting these criteria were classified as dilated

cardiomyopathy (DCM).

Study Protocol

All patients received baseline clinical evaluations followed by LGE-MRI and a baseline

echocardiogram within 4 weeks of device implantation. An ECG-gated CCT was performed at

the 3-month device interrogation visit to establish lead tip location. A repeat echocardiogram

and clinical evaluation was performed at 3 and 6-months. Clinical evaluations, each performed

by an experienced research nurse, included a 12-lead ECG, NYHA class determination, 6-minute

walk test (6-MWT)25 and a quality of life (QOL) assessment using the Minnesota Living With

Heart Failure (MLWH) questionnaire.26 All imaging studies were blindly analyzed using to the

same 16-segment cardiac model27 with the use of standardized anatomic markers (RV insertion

site) to provide consistent segmental assignment. Using this model 2 geographic regions were

pre-defined: “Paced segment”; the segment below the pacing portion of the LV or RV lead tip,

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and: “Pacing region”; the paced segment plus corresponding segments sharing 50% of an

adjacently located border. For example, if the LV paced segment was segment 11 (mid

inferolateral wall) the LV pacing region was defined by segments 5, 10, 11, 12, 15 and 16.

The study protocol was approved by the University of Western Ontario’s ethics review board,

and all patients provided informed consent.

LGE-MRI Protocol and Image Analysis

LGE-MRI was performed using a 3.0 Tesla scanner (Trio or Verio, Siemens Medical Solutions,

Germany) equipped with a 32-channel cardiac coil. Retrospectively gated, breath-held cine

imaging was performed in serial short axis planes from the atrio-ventricular annulus to apex in

addition to 2, 3 and 4-chamber views. Typical pulse sequence parameters were: slice thickness 6

mm, gap 2 mm, TE 1.8 ms, flip angle 50, matrix 256 x 213, temporal resolution 30-35 ms, iPAT

= 2. Ten to fifteen minutes following 0.2 mmol/kg gadolinium chelate (Gadovist�, Bayer Inc.

Canada) administration, LGE imaging was performed using a standard inversion-recovery

gradient pulse sequence in matched slice orientations. The inversion time was manually adjusted

to provide optimal nulling of the normal myocardium, as previously described.28 Typical pulse

sequence parameters were: slice thickness = 6 mm, gap = 2 mm, TR = 800 ms, TE = 3.9 ms, flip

angle = 20 degrees, matrix 256 x 205, iPAT = 2.

CMR images were analyzed using commercially available visualization and analysis software

(CMR42, Circle Cardiovascular Imaging, Calgary, Canada). Short axis cine images were

analyzed to determine segmental measures of time to maximal wall thickening using FDA-

approved commercial software (CMR42, Circle Cardiovascular Inc., Calgary). Semi-automated

endocardial and epicardial contour tracing was performed throughout the cardiac cycle (all

phases) with the time to maximal wall thickness (TmWT) determined for each myocardial

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segment, as previously described.21 As shown in Figure 1, 90 radial spokes (15 per segment)

were projected from the center of the LV with wall thickness calculated as the linear difference

in length from its intersection of the endocardial and epicardial borders. For each segment the

mean of 15 radial measurements were used to provide a mean wall thickness at each of the

cardiac phases. TmWT of the LV paced segment was defined as the time in milliseconds (ms)

required to reach maximal wall thickness for this segment, identified by CCT analysis.

An experienced investigator, blinded to patient identity, visually scored each myocardial

segment to identify those with “any myocardial scar”, defined as unequivocal signal

enhancement of the myocardium not felt to be due to image artifact. Quantitative assessment of

myocardial scar was performed by trained core-lab personnel using a signal-threshold based

analysis, and reported for the entire LV (total percent scar) and for each myocardial segment.

This was done using a Signal Threshold versus Reference Myocardium (STRM) approach, as

previously described29, 30, where a signal threshold of 5SD above the mean signal of normal

myocardium was used to define scar. With respect to the referenced myocardial region; careful

attention was paid to avoid tissue-blood and tissue-fat interfaces, and select only homogeneous

regions of signal-nulled tissue.

CCT Imaging Protocol and Image Analysis

Cardiac CT imaging was performed using a 64-slice CT scanner (Lightspeed VCT, GE Medical

Systems, USA) using standard acquisition protocols.31 As part of an expanded study protocol

(although not required for lead localization) contrast enhancement was employed with 80-100 cc

of iodinated contrast agent (VisipaqueTM (iodixanol), Amersham Health, Princeton, NJ)

administered. Typical imaging parameters were: slice thickness 0.625 mm, tube voltage 120 kV,

and tube current 550 mA, followed by a 40 cc saline flush. Image reconstruction was performed

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using retrospective ECG-gating to obtain the optimal phase for lead visualization with

overlapping 0.75 mm cross-sectional images reconstructed at 0.5mm and image matrix of 512 x

512 pixels.

Segmental assignment of the LV and RV lead tips were performed by a blinded interpreter using

a 3D multi-planar reconstruction (OsiriX, Version 3.7.1), as shown in Figure 2. To minimize

artifact related to the CRT lead system we reconstructed images using a 2.5mm slice thickness

and displayed this dataset using 3D multi-planar reconstruction (MPR), averaging signal of 4

consecutive slices (MIP thickness 10mm). The tips of the LV and RV lead were separately

localized on axial images and orthogonal short and long-axis projections generated. Using a

radial grid manually over-laid on the short axis view to mark standard segmental assignments

according to the AHA 16-segment model (6 basal, 6 mid and 4 apical)27 the segmental position

of the LV and RV leads were determined. The corresponding long axis view was used to

determine its basal, mid or apical position (equal division of the LV into 3 zones). For the LV

lead, pacing lead polarity (ie: ring to tip versus tip to ring) was incrementally considered to

ensure that the pacing portion of the lead was scored.

Echocardiography Imaging Protocol and Image Analysis

Standard 2D echocardiography was performed at baseline, 3 and 6 months using a 3.5 MHz

transducer (S5-1, Philips, Bothell, WA, USA) on commercially available equipment (iE33,

Philips, Eindhoven, Netherlands). Digitally captured images were stored for offline analysis

using the Xcelera software suite version 3.1 (Philips, Eindhoven, Netherlands). All imaging was

performed at end-expiration. The LV end-diastolic volume (LVEDV) and LV end-systolic

volume (LVESV) were determined using the biplane method of discs method (modified

Simpson’s technique)32 by an experienced, blinded echocardiographer.

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CRT device implantation

CRT devices with defibrillator capability were implanted in the standard fashion in all patients.

The LV pacing lead was inserted transvenously into the coronary sinus and positioned according

to standard clinical practice. The RV septal lead was routinely placed to the apical septal

segment in accordance with the site’s conventional practice. V-V intervals were set to 0 ms with

A-V intervals programmed to the manufacturer’s nominal settings. These settings were not

adjusted during the first 6-months of therapy.

Definition of Response to CRT

The primary outcome, echocardiographic response to CRT, was defined as a reduction in the

LVESV 15% at 6-months post implantation. Pre-defined thresholds for the following clinical

variables were used to define secondary clinical endpoints: NYHA functional class improvement

by 1 class, 6-MWT increase by 30m or 10%, and QOL score improvement (reduction) by 10

points.

Inter-observer and Intra-observer Reproducibility

Inter-observer and intra-observer reproducibility measures for scar analysis in this population

have been reported separately from our laboratory.30 To assess reproducibility of dysynchrony

measurement 10 randomly selected cases underwent blinded evaluations by 2 investigators

followed by a repeat evaluation by the first investigator on a separate day.

Statistical Methods

Continuous variables are expressed as the mean ± SD, while medians with 25th and 75th

percentiles are provided for non-normally distributed data. Categorical variables are expressed

as simple proportions. Univariate analysis to test for differences between responders and non-

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responders to CRT was performed using the Mann-Whitney U test for continuous variables and

Fisher’s Exact Test for categorical variables. Similar analyses were performed for improvement

in NYHA, 6-minute walk test and QOL. All endpoints were assessed at 6 months post CRT

device implantation. We constructed a multivariate logistic regression model to assess the

incremental association of MRI and baseline clinical variables to predict to occurrence of non-

response to CRT using backward stepwise selection (p<0.10 for entry and p>0.05 for removal).

Due to the number of events we limited covariates to comply with the general rule that 10 events

should be available for each variable tested.33,34 Reproducibility analyses were performed using

both linear regression analysis and Bland and Altman analysis. Sample size calculations were

performed a-priori based upon available literature20,23 and adequate power was ensured for the

selected primary outcome. All statistical tests were two-tailed and p value of <0.05 was regarded

as significant. S-Plus (version 8.0, Insightful Software, Seattle, WA) was used to perform the

statistical analyses.

Results

Baseline Patient Characteristics

Sixty of the 63 enrolled patients (95%) completed study follow-up and were included in final

analysis. Three patients did not complete initial (3-month) follow-up; two dying - one due to

heart failure and one due to device-unrelated sepsis - and one patient voluntarily withdrawing

from the study. Baseline patient characteristics are summarized in Table 1. The mean age was

64±9 years with 16 (27%) being female. The median baseline NYHA was 3 (IQR 3, 3). Referral

etiology was ICM in 25 patients (42%) and DCM in 35 (58%).

Baseline non-LGE MRI findings revealed a mean LVEF of 25.3±7.1%. No significant

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differences in septal to LV paced segment mechanical delay was identified between ICM and

DCM cohorts (p=0.22). Mean segmental TmWT values for all 16 myocardial segments are

graphically shown in Figure 3. Univariate analysis showed the following to be associated with

non-response to CRT; lower GFR (p=0.04), higher NYHA class (p=0.04), ischemic

cardiomyopathy (p=0.01) and right bundle branch block (RBBB) (p=0.02). No dysynchrony

measure was predictive of CRT response.

Echocardiographic and Clinical Response to CRT

The primary endpoint was met in 42 patients (70%) at 6-months. Secondary endpoints were

achieved as follows; Improvement 1 NYHA class in 37 patients (62%), increase in 6-MWT

30m or by 10% in 37 patients (62%), and a reduction in MLWH score 10 in 39 patients

(65%).

CRT Lead Tip Locations by CCT

The RV lead tip was delivered to the apical septal segment in 100% of patients. The LV lead tip

was delivered to a posterolateral wall segment (basal or mid) in the majority of patients (59.0%),

a finding that was consistent between ICM and DCM cohorts (58.6% and 59.1%, respectively).

A graphical illustration of RV and LV lead placement for the population is shown in Figure 3.

Patients achieving the primary outcome were more likely to have had the LV lead placed on a

posterolateral wall segment (83%) versus those without response (50%).

Scar Burden and Distribution by LGE-MRI

Analysis of LGE imaging confirmed a higher prevalence and total burden of myocardial scar in

those with ICM versus those with DCM (Table 2). Overall, 25 patients with ICM (100%) and

27 patients with DCM (77%) showed any visible scar by LGE-MRI. Similarly, the mean total

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scar burden was significantly higher among those with ICM versus DCM (26.2±14.5% versus

5.9±7.2, p<0.001). Segmental scar analysis, shown in Figure 3, revealed the burden of scar to be

highest among the septal wall segments, irrespective of cardiomyopathy etiology.

The prevalence of transmural scar ( 50% wall thickness) within the LV paced segment was 7%,

with a prevalence of 22% for the RV paced segment. The prevalence of significant pacing

region (paced segment plus adjacent segments) scar, defined as 25% scar by volume, was 13%

for the LV pacing region and 37% for the RV pacing region. Patient examples are shown in

Figure 4.

Pacing Site Scar and Response to CRT

Total scar burden was not statistically different between those achieving and not achieving the

primary outcome (Table 2). This finding was consistent for both ischemic and non-ischemic

cohorts.

The results of segmental scar analysis among responders and non-responders are shown in Table

2. The mean scar volume of the LV pacing region was significantly lower in responders versus

non-responders (p=0.01) with a similar finding identified for the RV pacing region (p=0.04).

Thirty-four patients had no significant scar (<25%) in either the LV or RV pacing regions. Of

these patients 19% failed to achieve CRT response at 6-months (ie: response rate 81%). Twenty-

two patients had significant scar in the RV pacing region with 45% of this group having non-

response (ie: response rate 55%). Eight patients had significant scar in the LV pacing region with

75% having non-response (ie: response rate 25%). Among these patients 4 had significant scar in

both the LV and RV pacing regions, 100% having non-response to CRT at 6-months. The

relationship between pacing region scar and CRT response is graphically shown in Figure 5.

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LV pacing region scar 25% was the strongest independent predictor of CRT non-response

following adjustment for cardiomyopathy etiology with an odds ratio of 7.2 (95% CI 1.2 to 43.8,

p=0.03). By multivariate analysis, when LV and RV pacing region scar were entered into the

same model only LV pacing region scar remained predictive with an odds ratio of 7.7 (95% CI

1.3 to 46.3, p=0.03).

Secondary endpoints were achieved with high frequency among those with no scarring of LV or

RV pacing regions. Among these patients a reduction of NYHA class 1 was achieved in 82%,

an increase in 6MHW 30m in 82%, and a reduction in MLWH score 10 in 96% of patients.

While a trend towards reduction in these outcomes was seen among those with scarring of LV

and/or RV pacing regions, these differences were not statistically significant.

Inter-observer and Intra-observer Reproducibility

Good inter-observer reproducibility was seen for the measurement of dysychrony by SD16-

TmWT. The Pearson correlation coefficients for intra- and inter-observer measurements were

0.87 and 0.85, respectively. Corresponding Bland and Altman analyses showed non-significant

bias of -3.4 ms (-45.6 to 38.7 ms) and 19.4 (-22.9 to 61.7 ms), respectively.

Discussion

In this prospective, multimodality imaging study analyzing the effects of regional scar in relation

to lead tip localization on CRT response, the primary findings were as follows: 1. Scar in the LV

pacing region was observed in a minority of patients but was associated with a low CRT

response; 2. Scar occupying the RV pacing region was seen more commonly and was associated

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with intermediate CRT response; 3. Presence of scar in both pacing regions was associated with

no response, whereas absence of scar in these regions was associated with the highest response

rate.

The over-arching goal of CRT is to advance electro-mechanical activation of the lateral wall

such that it becomes physiologically synchronous with the septal wall. If accomplished this

therapy can realize substantial improvement in stroke volume and cardiac performance.5 Studies

to date evaluating optimal patient selection and CRT delivery have focused primarily on

characteristics of the posterolateral wall, suggesting scar in this region to be associated with

lower rates of LV remodeling. 21, 22, 35, 36 Such findings led to the recent reporting of the first

randomized control trial of targeted LV lead placement in CRT.37 In this study, a reported 15%

improvement in CRT response was observed when LV leads were targeted to dysynchronous but

non-scarred myocardial segments; the latter defined by surrogate echocardiographic markers of

viability. Our current study presents the most comprehensive evaluation of scar burden relative

to lead tip delivery to date and confirms that scar within the LV pacing region, encountered in

approximately 1 out of 8 cases, is an important impediment to CRT response. Scar within the RV

pacing region is more common, being encountered in 1 out of 3 cases. This finding did not

provide an independent influence on CRT response among those also having LV pacing region

scar. However, a reduction in CRT response was appreciated among the whole population when

significant RV pacing region scar was present.

The potential relevance of RV pacing region scar was highlighted in a recent study by Duckett,

et al. that evaluated the feasibility of achieving a mid-septal RV pacing position among 50

consecutive patients receiving CRT. In this study a more conventional apical position was

conceded to in those patients with poor R-wave pacing amplitudes ( 5 mV) and identified that

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these patients had a 67% prevalence of septal scar by LGE imaging versus 33% in those where

adequate voltages were achieved. Septal wall scar by LGE imaging was associated with a lower

rate of LV remodeling at 6-months (20% versus 56%, p=0.02) within the context of this lead

placement strategy.24 Segmental characterization of LV lead position, LV dysynchrony or LV

pacing region scar were not evaluated. By comparison, our current study shows that the delivery

of both LV and RV pacing leads to non-scarred myocardium provides a robust 81% response

rate to CRT, versus 55% when significant scar is present in the RV pacing region, 25% when in

the LV pacing region, and 0% when present in both pacing regions.

The septal-predominant distribution of myocardial injury found among this referral population is

not unexpected. ICM patients are anticipated to be at higher likelihood of both heart failure and

LBBB when irreversible injury is realized in the LAD-territory (ie: septal wall). Similarly,

patients with DCM preferentially demonstrate non-ischemic fibrosis of the septum in advanced

stages of disease, a finding associated with worse prognosis.38 Irrespective of etiology,

mechanisms relating septal scar to non-response in CRT can be envisioned. First, electro-

mechanical advancement of the lateral wall is aimed at reducing afterload effects on the septum,

and re-engaging its contribution to stroke volume. Such contribution may not be enlisted if the

septum is substantially injured, limiting its capacity to augment stroke volume. Second, the aim

of RV paced stimulation to activate the LV myocardium simultaneous to paced stimulation of the

lateral wall may be violated by interposed scar. An introduction of electro-mechanical

dispersion can therefore be theorized. This latter concept presents one plausible role for

directing RV lead tips to alternate and viable geographic targets - similar to that proposed for the

LV lead. Indeed, the concept of mid-septal or RV outflow tract pacing has been shown to be

both feasible39-42 and potentially of clinical value24, 42. In a study by Haghjoo, et al. patients

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otherwise receiving optimal LV pacing (ie: those with LV leads delivered to the posterolateral

wall) had significantly higher CRT response rates when the RV lead was placed to the high

(basal) septum compared with conventional apical placement (70% vs. 30%, p=0.01).40 Further,

Duckett, et al., showed that mid-septal pacing was associated with improved response rate

compared with apical pacing (70% vs. 30%, p=0.01).24 However, whether the selective

placement of the RV lead to viable myocardial targets improves outcomes in this population

remains to be evaluated.

Clinical Implications

Our findings add justification for lead navigation approaches to optimal myocardial targets in

CRT. Several studies to date, inclusive of the current study, demonstrate that characteristics of

the LV pacing region strongly influence response to CRT21, 36, 37, 43-45 and support that lead

delivery to viable targets may be a pre-requisite for response to occur. We found that without

image-guidance the delivery of this lead to a scarred myocardial region occurs in 13% of cases

with 75% of these patients failing to respond. Navigation strategies to guide the LV lead to

viable targets is therefore of potential importance for this cohort. While the role of RV lead

navigation to optimal septal targets remains uncertain, recognition that scar within this region

may contribute to response failure justifies expanded exploration within larger cohort studies.

Study Limitations

This study must be considered in recognition of several limitations. First, this was a single-

center cohort study and was not sufficiently sized to evaluate clinical outcomes beyond the

surrogate of LV remodeling at 6-months. Second, while not the focus of the current paper, the

MRI-derived measure of mechanical dyssynchrony used in this study, adopted from Marsan, et

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al.21 has not undergone rigorous clinical validation versus other measures of dyssynchrony, such

as tissue Doppler or strain imaging. Finally, signal-threshold based scar quantification is

inherently dependent upon user-selected regions for referencing of “normal” myocardium. In

this study we employed an STRM-based technique with careful attention to the selection of the

reference region. We also selected a higher signal threshold ( 5SD) to maximize

reproducibility, as previously described.30, 46 These technical factors must always be considered

when comparing values of scar burden between otherwise comparable studies. Alternate

techniques, such as the Full-Width Half of Maximum, may offer slightly superior reproducibility

in those with ischemic cardiomyopathy.30, 46 However, the inclusion of patients with dilated

cardiomyopathy in this study, a cohort recognized to have inconsistent results using this

technique30, limited analysis to an STRM-based approach.

Conclusions

Scar within the LV and RV pacing regions is associated with a lower response rate to CRT at 6-

months. Strategies aimed at the selective placement of pacing leads to non-scarred myocardial

targets appear justified.

Acknowledgements

The authors would like to thank Samuel Siu for his assistance in reviewing this manuscript and

Linda Marziali, Kris Carter (RN), Kim Krueger (RMT) and John Butler (RMT) for their

important contributions to this work.

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Sources of Funding

Dr White is supported by a Clinician Scientist award with the Heart and Stroke Foundation of

Ontario, Canada. Dr Drangova is supported by a Career Scientist award from the Heart and

Stroke Foundation of Ontario. Dr Krahn is a Career Investigator of the Heart and Stroke

Foundation of Ontario. This research was supported in part by Heart and Stroke Foundation

grant # NA6488 (PI: J.A.W.), the Canada Foundation of Innovation Leaders Opportunity Fund

and the Ontario Research Fund, Imaging in Cardiovascular Therapeutics grant.

Disclosures

Dr White receives in-kind research support from Bayer, Inc. Canada, and has received

consultative fees from Medtronic, Inc. There are no other conflicts of interest or financial

relationships to disclose.

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42. Haghjoo M, Bonakdar HR, Jorat MV, Fazelifar AF, Alizadeh A, Ojaghi-Haghjghi Z, Esmaielzadeh M, Sadr-Ameli MA. Effect of right ventricular lead location on response to cardiac resynchronization therapy in patients with end-stage heart failure. Europace. 2009;11:356-363.

43. Taylor AJ, Elsik M, Broughton A, Cherayath J, Leet A, Wong C, Iles L, Butler M, Pfluger H. Combined dyssynchrony and scar imaging with cardiac magnetic resonance imaging predicts clinical response and long-term prognosis following cardiac resynchronization therapy. Europace. 2010;12:708-713.

ER, Schalij MJMJMJMJMJMJMJ, eeeeeadadadadadadad pppppppososososososositititititititioioioioioioion,n,n,n,n,n,n, aaaaaaandndndndndndndure pppppppatatatatatatatieieieieieiei ntntntntntntnts s s s s ss unununuunuu d

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nG, Prasad SK, Lyne J, Smith G, Burman ED, Khan M, Sh pPennell DJ Cardiovascular magnetic resonance fibrosis

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44. Ypenburg C, Roes SD, Bleeker GB, Kaandorp TA, de Roos A, Schalij MJ, van der Wall EE, Bax JJ. Effect of total scar burden on contrast-enhanced magnetic resonance imaging on response to cardiac resynchronization therapy. Am J Cardiol. 2007;99:657-660.

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46. Flett AS, Hasleton J, Cook C, Hausenloy D, Quarta G, Ariti C, Muthurangu V, Moon JC. Evaluation of techniques for the quantification of myocardial scar of differing etiology using cardiac magnetic resonance. JACC Cardiovasc Imaging. 2011;4:150-156.



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Table 1. Non-MRI baseline patient characteristics, presented for the total population and for those with and without response to CRT (defined as a 15% reduction in LVESV at 3 or 6 months).

Total Population (N=60) ICM (N=25) DCM (N=35)

Variables All patients (N=60)

Response (N=42)

No Response (N=18)

p Response (N=13)

No Response (N=12)

p Response (N=29)

No Response

(N=6)

p

Age (years) 64±9 63±10 66±8 .35 66±8 69±7 0.61 61±10 61±10 0.99

Female sex 16(27%) 14(33%) 2(11%) .07 2(15%) 1(8%) 0.53 12(41%) 1(17%) 0.26

Hypertension 34(57%) 25(59%) 9(50%) .34 9(69%) 5(42%) 0.16 16(55%) 4(67%) 0.48

Diabetes mellitus 19(32%) 13(31%) 6(33%) .54 7(54%) 3(25%) 0.14 6(21%) 3(50%) 0.16

Hyperlipidemia 37(62%) 25(59%) 12(67%) .41 9(69%) 8(67%) 0.61 16(55%) 4(67%) 0.48

Smoking 22(37%) 14(33%) 8(44%) .30 3(23%) 5(42%) 0.29 11(38%) 3(50%) 0.46

Any prior revascularization

14(23%) 9(21%) 5(28%) .41 4(31%) 5(42%) 0.44 5(17%) 0(0%) 0.37

GFR (ml/min/1.73m2) 68±16 71±17 61±12 .04* 66±8 68±6 0.17 72±17 64±11 0.33

Atrial fibrillation 9(15%) 5(12%) 4(24%) .23 2(15%) 3(27%) 0.42 3(10%) 1(17%) 0.55

QRS morphology

QRS duration (ms) 159±21 162±20 151±23 .08 156±24 147±19 0.34 165±18 161±30 0.71

LBBB 48(81%) 36(86%) 12(71%) .16 9(69%) 8(73%) 0.60 27(93%) 4(67%) 0.13

RBBB 5(8%) 1(2%) 4(24%) .02* 1(8%) 2(18%) 0.43 0(0%) 2(33%) 0.02*

Non-specific delay 6(10%) 5(12%) 1(6%) .44 3(23%) 1(9%) 0.36 2(7%) 0(0%) 0.68

NYHA functional class 2.8±0.5 2.7±0.6 2.9±0.2 .04* 2.8±0.7 2.9±0.3 0.73 2.6±0.6 3.0±0.0 0.12

Class II 18(30%) 17(40%) 1(6%) .01* 4(31%) 1(8%) 0.10 13(45%) 0(0%) 0.09

Class III 39(65%) 22(52%) 17(94%) 7(54%) 11(92%) 15(52%) 6(100%)

Class IV 3(5%) 3(7%) 0(0%) 2(15%) 0(0%) 1(3%) 0(0%)

Medications

ACE inhibitor 43(72%) 31(74%) 12(67%) .40 12(92%) 8(67%) 0.14 19(66%) 4(67%) 0.67

ARB 20(33%) 13(31%) 7(39%) .38 1(8%) 5(42%) 0.06 12(41%) 2(33%) 0.54

ACE inhibitor or 57(95%) 40(95%) 17(94%) .66 12(92%) 11(92%) 0.74 28(97%) 6(100%) 0.83

(4(4(4(4(4(4(42%2%2%2%2%2%2%) ) ) ) ) ) ) 0.0.0.0.0.0.0.4444444

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ARB

Beta-blocker 54(90%) 38(90%) 16(89%) .59 11(85%) 11(92%) 0.53 27(93%) 5(83%) 0.44

Diuretic 50(83%) 34(81%) 16(89%) .36 11(85%) 10(83%) 0.67 23(79%) 6(100%) 0.29

Continuous data are expressed as mean ±SD, categorical data as n (%). ICM = Ischemic cardiomyopathy; DCM = Dilated cardiomyopathy; PCI = percutaneous coronary intervention; CABG = coronary artery bypass grafting; MI = Myocardial infarction, GFR = Glomerular Filtration Rate; LBBB, left bundle-branch block; NYHA = New York Heart Association; CRT = Cardiac resynchronization therapy; ACE = angiotensin-converting enzyme



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Table 2. Baseline MRI characteristics of the study population and for those with and without response to CRT, stratified according to cardiomyopathy Etiology.

Variable Total Population (N=60) ICM (N=25) DCM (N=35)

Response (N=42)

No-response (N=18)

P Response (N=13)

No-response (N=12)

P Response (N=29)

No-response (N=6)

P

LV volumes / mass

LV EF (%) 26±6 24±9 .48 26±7 25±9 .89 26±6 21±6 .22

LV EDV (mL) 275±78 320±68 .02* 266±55 324±67 .02* 279±87 312±77 .31

LV ESV (mL) 206±71 245±64 .03* 197±52 214±56 .04* 210±78 252±84 .29

LV mass (g) 191±41 229±66 .03* 186±34 214±72 .41 194±44 258±43 .004

LV mass – indexed (g/m2) 96±20 105±27 .28 92±15 101±30 .65 98±22 114±22 .16

Dyssynchrony

SD16 TmWT (ms) 151±48 144±51 .88 169±71 138±54 .22 143±33 154±45 .43

Septal to LVp segment delay (ms) 323±159 303±192 .54 310±179 279±217 .57 328±152 346±144 .82

Septal to LVp segment 130ms 34(81%) 14(78%) .52 10(77%) 9(75%) .64 24(83%) 5(83%) .73

Scar Analysis

Any myocardial scar* 35(83%) 17(94%) .24 13(100%) 12(100%) N/A 22(76%) 5(83%) .58

Total LV scar volume (%) 13±16 17±11 .08 22±8 30±18 .38 6±8 6±4 .68

Total LV pacing region scar (%) 8±14 23±23 .01* 13±20 29±23 .08 5±10 10±20 .85

Total RV pacing region scar (%) 24±30 40±32 .04* 53±31 53±30 .98 12±18 15±18 .56

LVp segment 50% scar 1(2%) 3(17%) .08 1(8%) 3(25%) .26 0(0%) 0(0%) N/A

LVp region 25% scar 2(5%) 6(33%) .01* 1(8%) 5(42%) .06 1(3%) 1(17%) .32

RVp segment 50% scar 8(19%) 5(28%) .33 7(54%) 5(42%) .42 1(3%) 0(0%) .83

RVp region 25% scar 12(29%) 10(56%) .05 9(69%) 9(75%) .55 3(10%) 1(17%) .55

Data expressed as mean ± SD. ICM = Ischemic cardiomyopathy; DCM = Dilated cardiomyopathy; LV = left ventricular; EDV = end-diastolic volume; ESV = end-systolic volume; EF= ejection fraction; SD16 TmWT = Standard Deviation of the Time to Maximal Radial Wall Thickening obtained from all 16 segments; LVpD = Left Ventricular Paced Segment Delay *Defined as the presence of 1 myocardial segment with unequivocal scar, as determined by an experienced, blinded investigator.

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Figure Legends

Figure 1. Example of quantitative wall motion analysis applied to a mid-ventricular short axis

cine image. End-systolic and end-diastolic phases shown to illustrate changes in radial “spokes”

representing wall thickening. The mean length of 15 spokes per myocardial segment were used

to determine the mean wall thickness at each phase of the cardiac cycle.

Figure 2. Example of cardiac-gated CT lead mapping. Left: 3D maximum intensity projection

(MIP) showing the RV lead (open arrow) in the typical apical segment location and the LV lead

(solid arrow) positioned within the anterior interventricular vein. Middle: 3D multi-planar

reconstruction (MPR) in short axis showing both the RV and LV leads relative to the myocardial

soft tissues (dashed lines) with standard chamber segmentation. Right: 3D volume rendering in

the same patient (AP view) showing the LV lead is positioned distant from a calcified

inferolateral transmural scar (inset: corresponding short axis DE-MRI image showing enhancing

scar in white against the normal black myocardium).

Figure 3. Results of segmental analysis showing the segmental prevalence of CRT lead tip

delivery, any myocardial scar, and mean time to maximal wall thickness (SD16-TmWT) for all

patients, ICM, and DCM patients. Shown using the AHA 16-segment model divided into septal

and non-septal segments relevant to the RV and LV pacing leads, respectively.

Figure 4. Late gadolinium enhancement (LGE) images of patients found to have significant scar

(bright signal within myocardium) within the left ventricular pacing region scar (A) and right

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ventricular pacing region (B). Examples provided for both ischemic and non-ischemic patterns

of injury. Left column shows the 4-chamber view (highlighted in red). Middle column shows a

representative short axis view. Right column shows the corresponding signal threshold-based

scar analysis with division into the AHA segment model. Red line corresponds to approximate

position of the 4-chamber view.

Figure 5. Six-month response rate to cardiac resynchronization therapy (CRT) among patients

with i) both leads delivered non-scarred pacing regions, ii) only the right ventricular (RV) lead

delivered to a scarred pacing region, iii) only the left ventricular (LV) lead delivered to a scarred

pacing region, or iv) both the LV and RV lead delivered to scarred pacing regions. CRT

response was defined as a reduction in LV end diastolic volume (LVEDV) by 15% by serial

echocardiography. RVPR = right ventricular pacing region. LVPR = left ventricular pacing

region.

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A)

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Ischemic

Non ischemic

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Terry Thompson, Maria Drangova and James A. WhiteSkanes, Peter Leong-Sit, George J. Klein, David McCarty, Nowell Fine, Aashish Goela, Ali Islam,

Jorge A. Wong, Raymond Yee, John Stirrat, David Scholl, Andrew D. Krahn, Lorne J. Gula, Allan C.Influence of Pacing Site Characteristics on Response to Cardiac Resynchronization Therapy

Print ISSN: 1941-9651. Online ISSN: 1942-0080 Copyright © 2013 American Heart Association, Inc. All rights reserved.

TX 75231is published by the American Heart Association, 7272 Greenville Avenue, Dallas,Circulation: Cardiovascular Imaging

published online June 5, 2013;Circ Cardiovasc Imaging.

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Influence of Pacing Site Characteristics on Response to Cardiac