Optimization of CRT programming using non‐invasive electrocardiographic imaging to assess the acute electrical effects of multipoint pacing

Abstract Aim Quadripolar lead technology and multi‐point pacing (MPP) are important clinical adjuncts in cardiac resynchronization therapy (CRT) pacing aimed at reducing the rate of non‐response to therapy. Mixed results have been achieved using MPP and it is critical to identify which patients require this approach and how to configure their MPP stimulation, in order to achieve optimal electrical resynchronization. Methods & Results We sought to investigate whether electrocardiographic imaging (ECGi), using the CARDIOINSIGHT ™ inverse ECG mapping system, could identify alterations in electrical resynchronization during different methods of device optimization. In no patient did a single form of programming optimization provide the best electrical response. The effects of utilizing MPP were idiosyncratic and highly patient specific. ECGi activation maps were clearly able to discern changes in bulk LV activation during differing MPP programming. In two of the five subjects, MPP resulted in more rapid activation of the left ventricle compared to standard CRT; however, in the remaining three patients, the use of MPP did not appear to acutely improve electrical resynchronization. Crucially, this cohort showed evidence of extensive LV scarring which was well visualized using both CMR and ECGi voltage mapping. Conclusions Our work suggests a potential role for ECGi in the optimization of non‐responders to CRT, as it allows the fusion of activation maps and scar analysis above and beyond interrogation of the 12 lead ECG.


| BACKG ROU N D
Cardiac resynchronization therapy (CRT) aims to restore regional activation synchrony and enhance cardiac contractility and the mechano-energetic efficiency of the heart. 1 Multi-point pacing (MPP) has been developed as a tool to reduce the rate of nonresponse. [2][3][4] Intuitively, activating the heart from multiple locations could achieve more effective resynchronization; bypassing scarred myocardium and enabling the recruitment of a greater proportion of the left ventricle, resulting in increased conduction velocities and a reduction in the total activation time. 5 Whilst some authors have shown improvements in acute hemodynamics 6 and chronic echocardiographic remodeling, 2,4 recent data have suggested that its efficacy may be confined to a small proportion of patients and that its effect is conditional on specific electrical and anatomical 7,8 parameters and programming. 3 We sought to investigate how myocardial activation varied during programming optimization and whether non-invasive body surface mapping technology might be capable of identifying patients who may derive the most benefit from MPP.

| ME THODS
Patients on optimal medical therapy (OMT) meeting European Society of Cardiology (ESC) 9 and/or Heart Rhythm Society (HRS) 10  The following day after implantation, each patient underwent an iterative CRT optimization procedure, guided by non-invasive body surface mapping, looking to identify the optimal pacing settings.

| Non-invasive body surface mapping
A non-invasive electrophysiological mapping study was performed using a high resolution electrocardiographic mapping system (ECVUE, CardioInsight Technologies Inc. Medtronic), as previously described. 11 The patient's baseline presenting rhythm--either intrinsic sinus rhythm or RV paced rhythm--was first analysed using directional activation maps. 12 Further mapping was undertaken using nominal CRT programming, before echo guided device optimisation was attempted. Finally, both local and extended bipolar MPP was used to further optimize the delivery of biventricular pacing. The ECSYNC software calculates four parameters assessing electrical activation:  Given the primary objective of CRT is to restore regional activation synchrony, we defined the optimal activation pattern as that which achieved the most effective degree biventricular resynchronization whilst simultaneously minimizing both biventricular and LV activation times. Electrical synchrony is specifically assessed by VVsync, where a figure of 0 represents identical LV and RV activation time. 13 As such, the optimal pacing figuration was that which achieved a VVsync approaching 0, whilst also minimizing LV and BiV activation times.
Epicardial voltage maps were also collected, in order to identify any areas of low voltage which may indicate areas of myocardial scar and fibrosis. Where possible, these were correlated against CMR data, see Figure 1.

| Device optimisation
The patient's baseline presenting rhythm--either intrinsic sinus rhythm or RV paced rhythm--was first analyzed using directional activation maps. 12 Subsequently, mapping was undertaken using Next, an echo guided iterative approach to device optimization was employed. The AV interval was optimized according to the maximal improvement in LV diastolic filling. An AV interval of 200 ms was first programmed followed by decrements of 20 ms until 60 ms.
Once the optimal AV and VV intervals had been established and programmed, differing MPP settings were then acutely programmed.
During each configuration, a non-invasive electro-anatomical mapping was obtained. The SJM CRT toolkit™ (St. Jude Medical Inc.) was used to identify the RV-paced to LV-sensed timings for each of the poles on the quadripolar lead. MPP was then programmed to pace the pole with the longest delay first and the pole with the shortest delay second. The right ventricular lead was always paced last. We delivered MPP with 5, 10, and 20 ms delays between each stimulus using both a local bipole configuration-distal (D1) to mid 2 (M2) and proximal (P4), and an extended bipole configuration-D1 to RV coil and P4 to RV coil. This resulted in our testing 6 MPP settings per patient; 3 local and 3 extended bipole. In order to test the different MPP vectors for capture threshold and phrenic nerve stimulation, a number of standard biventricular recordings were also performed which served as comparators for individual patients.

| Patient characteristics
A total of five patients were enrolled in the study.

| Body surface mapping
The effect of changing AV delays, VV delays, the LV pacing vector, and finally the addition of MPP are shown in Table 1. In no patient did a single form of optimization provide the best electrical response.
The mean electrical response using each strategy is shown in Table 1.
Epicardial voltage mapping showed the presence of scar in all of the ischemic patients which corresponded to LGE on MRI in the 3 cases where MRI was performed, see Figure 1. MPP had divergent effects on electrical activation in different patients that are described below.

| Electrical effect of MPP
In this patient with extensive lateral scar, intrinsic activation was again characterized by typical LBBB propagation with delayed lateral LV wall activation (see Figure 3). Despite this patient having a broad QRS,

| Electrical effect of MPP
The pattern of LBBB activation with delayed activation in the lateral LV wall can again be observed on the baseline ECGi maps (see Figure 4). Interestingly this patient also had the longest LV and BiV activation time of the entire cohort but the shortest VVsync, suggesting activation in both ventricles was retarded.
Activation was clearly delayed in the apical region, denoted by the blue isochrones on the activation map. This area corre-

| Electrical effect of MPP
ECGi analysis of the intrinsic rhythm confirms activation is again delayed in the lateral LV wall (see Figure 5). Extended Bipolar MPP appears to offer a superior degree of resynchronization to conventional CRT.

| Case 5
Age 83 The patient had long-standing AF and had undergone implantation of a VVI pacing system in conjunction with an AV junction ablation.

| Electrical effect of MPP
Baseline activation in this case demonstrates the pattern of activation typically associated with RV apical pacing (see Figure 6). The dark blue isoch-

| D ISCUSS I ON
Our series demonstrates that non-invasive mapping technology is able to accurately delineate the divergent electrical effects of programming optimization. Evaluation of the 12 lead ECG alone during biventricular pacing is frequently challenging due to the merging wave fronts 16 and provides only a general overview of ventricular electrical activation. 11 ECGi activation maps were clearly able to discern changes in bulk LV activation during differing MPP programming. In addition, voltage mapping was able to delineate areas of fibrotic tissue with showed good correlation with areas of scar defined using LGE CMR.
Some degree of discrepancy between these modalities was expected as CMR can struggle to detect areas of homogenous microscopic diffuse fibrosis due to the low resolution of the image. In addition, ECGi is more sensitive at detecting zones of epicardial and transmural fibrosis but may not always be able to detect sub-endocardial scar.
CRT delivered with nominal settings always proved superior to baseline activation and this improvement may explain why the majority of patients who receive CRT improve, without undergoing programming optimization. In three of our cohorts, the degree of biventricular resynchronization was further enhanced with iterative echo guided optimization of the AV and VV intervals. Whilst there is evidence to support this strategy, 14,15,17 larger studies have failed to consistently prove it's efficacy. 18,19 Our results would suggest that optimization of the AV and  Our analysis with ECGi mapping confirms that this tool is capable of detecting subtle changes in activation pattern achieved using different device optimization strategies. Furthermore, our findings suggest that traditional CRT with nominal settings is able to largely restore biventricular electrical synchronicity in selected patients and may explain the consistent response rate of 50%-70%

| LI M ITATI O N S
to conventional CRT.
Amongst carefully selected patients; however, the use of optimal device programming can achieve a superior degree of electrical resynchronization when compared to conventional CRT with nominal settings. However, these strategies are not without cost. Echo guided device optimization can be expensive and time consuming 29 whilst MPP is associated with a reduction in battery longevity. 30 Neither strategy has been consistently shown to be superior to conventional CRT with nominal settings in large multicenter studies. 7,8,18,19 Our analysis suggests that judicious use of device reprogramming optimization may be a useful strategy; however, the main issue remains identifying which patients may require this approach and then successfully optimizing their programming to achieve optimal electrical resynchronization. ECGi is a non-invasive technique capable of accurately delineating the electrical effects of CRT pacing as well as the presence and distribution of myocardial scar. Our work suggests a potential a role for this tool in the optimization of non-responders to CRT, as it allows the fusion of activation maps and scar analysis above and beyond interrogation of the 12 lead ECG. Peter Mountney who contributed to preparation and analysis of CMR and ECGi data allowing the comparison of these two modalities.

CO N FLI C T S O F I NTE R E S T S
Authors declare no conflict of interests for this article.