Local impedance measurement: results of the LOCALIZE trial and role as a marker of effective radiofrequency ablation

Author name: Moloy Das.
Institution: Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, UK.
Corresponding Author: Dr Moloy Das, Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK.
Email: moloy.das@doctors.org.uk

Abstract:

Radiofrequency ablation aims to create myocardial tissue damage through tissue heating, and contiguous transmural ablation lesions are often required, including for pulmonary vein isolation (PVI) for atrial fibrillation (AF).  Although there have been advances over recent years in delivering durable PVI, this cannot yet be guaranteed.  Local impedance (LI) measurement is a recently developed metric that provides information on direct tissue effect during ablation.  Pre-clinical and early clinical studies have supported the clinical utility of LI drop during ablation as a marker of lesion efficacy.

The LOCALIZE trial evaluated the relationship between LI drop and both acute and chronic PV conduction block.  Following initial encirclement of the pulmonary veins and a 20-minute waiting period, sites of acute PV reconnection were correlated to LI drop values in a segmental model.  Study participants underwent a repeat left atrial mapping procedure after 3 months to identify sites of chronic PV reconnection.  LI drop was found to be predictive of acute PV conduction block, with lower LI drop values required for conduction block in the thinner posterior/inferior region than the thicker anterior/roof region.  Preliminary data regarding durable PV conduction block indicate similar findings, with full results awaited. LI drop showed greater predictive value compared to generator impedance drop.

The LOCALIZE trial has therefore demonstrated the clinical utility of LI drop for acute and durable PVI and may allow more tailored and efficient radiofrequency energy delivery during these procedures.

Introduction:

The aim of radiofrequency ablation is to create focal myocardial tissue damage through tissue heating.  For many arrhythmias, for example cavotricuspid isthmus ablation for typical right atrial flutter, a contiguous, transmural line of ablation lesions creating an electrical barrier is required to successfully treat the rhythm abnormality.

Since the pulmonary veins were first described as the primary sources of AF triggers,¹ pulmonary vein isolation (PVI) has become the primary ablation strategy for both paroxysmal and persistent atrial fibrillation (AF).² However, while acute isolation of the pulmonary veins is readily achieved, it has proved more challenging to deliver durable PVI.  This is important because it has been shown that the number of reconnected PVs relates to clinical outcome, with increasing PV reconnection leading to a higher risk of AF recurrence.³ Conversely, excessive energy delivery increases the risk of damage to extra-cardiac structures.

There has therefore been a major focus on improving delivery of radiofrequency energy, particularly for PVI, with the aim of helping operators to titrate ablation applications more effectively and safely.  A number of studies assessing new advances in PVI ablation technology have involved a repeat left atrial mapping study 2-3 months after an initial PVI procedure to assess the proportions of patients and pulmonary veins with reconnection.  As shown in Table 1, significant progress has been made from the early years of AF ablation, with successive reductions in the proportion of patients and pulmonary veins found to have reconnection at repeat left atrial study.  This has occurred with the introduction of 3D mapping systems, contact force-sensing catheters, ablation lesion quality markers such as force time integral (FTI) and Ablation Index, and recently temperature-guided ablation using a novel irrigated catheter.^4-10  Although use of lesion quality markers such as Ablation Index and Lesion Size Index has resulted in improved clinical outcomes,^11-14 durable PVI cannot yet be assured and therefore the search for superior ablation lesion quality markers continues.

Table 1

Local impedance measurement

Generator impedance drop, as measured by the radiofrequency generator, has been used for many years as a marker of effective lesion formation and has been shown to correlate with the lesion size in an animal model.¹⁵ Furthermore, smaller generator impedance drops have been found to be associated with sites of pulmonary vein reconnection.^16-18  However, generator impedance is measured from the tip of the ablation catheter to the return patch on the body surface and is therefore limited by the large field of view, which can be affected by body habitus, changes in thoracic impedance including uneven respiratory patterns, fluid shifts and tissue oedema.^19-21

A novel local impedance (LI) metric was therefore developed within the Rhythmia electroanatomic mapping system, with the aim of providing a more focused impedance measurement.²²  This was modelled on the ability of weekly electric fish to sense objects within their vicinity.  Local impedance is measured by creating a local electric field through injection of current from the distal tip electrode to the proximal ring electrode of the IntellaNav MiFi OI ablation catheter.  As the tip of the catheter approaches cardiac tissue there is a distortion in the electric field causing a change in the LI.  This is calculated from the mini-electrode voltage and the known current injection.

Pre-clinical work assessing this new measure demonstrated three important findings.  Firstly, the LI value starts to rise as the catheter tip approaches cardiac tissue, with an increase seen from approximately 2mm away.²²  As the catheter tip comes in contact with tissue and then pushes deeper into it, there is a steeper rise (Figure 1A).  This is irrespective of catheter angulation.  Secondly, LI drop seen during ablation correlated better with lesion depth and diameter than FTI in vitro, and than generator impedance drop in vivo (Figure 1B).  Finally, local impedance drops associated with a steam pop were significantly larger (59 [46-73]Ω) than successful 31W (18 [11-26]Ω) or 50W (28 [18-49Ω) lesions.²³

Figure 1: Graphics showing the relationships between (A) LI and engagement with cardiac tissue, and (B) LI drop and ablation lesion size

Subsequent clinical studies have confirmed the utility of this metric. The first clinical study was published by Martin et al, and demonstrated lower baseline local impedance in dense scar compared to healthy tissue or blood pool and a linear correlation between starting LI and maximum LI drop during ablation.²⁴  The median LI drops for successful lesions, as assessed by lack of local tissue capture with pacing, were significantly larger than for unsuccessful lesions in both the left ventricle and left atrium.  A further study by Gunawardene et al confirmed significant differences in baseline LI between high-voltage areas and intermediate-voltage areas, low-voltage areas and blood pool, with a stronger correlation between starting LI and LI drop than for generator impedance and generator impedance drop.²⁵

The findings of these initial studies were corroborated and extended by a number of studies published in 2020.  Sasaki et al demonstrated that the absolute and percentage LI drops were significantly greater at effective ablation sites compared to ineffective sites during cavotricuspid isthmus ablation.²⁶  A study by Masuda and colleagues identified that the impedance drop at acute reconnection sites following initial encirclement of the pulmonary veins was significantly lower than at non-gap sites (12±7 vs. 23±12Ω, P<0.001), whereas there was no difference in generator impedance drop.²⁷  The CHARISMA registry, involving 5 centres in Italy, confirmed differences in the LI between the blood pool, high-voltage areas and low-voltage areas in patients with AF, and also demonstrated an association between LI drop and ablation success but not for generator impedance drop.²⁸  These findings were replicated in ventricular tissue in a study by Munkler et al, with baseline LI and again found to differentiate between scarred and healthy myocardium, and larger LI drops seen for VT-terminating ablations compared to non-terminating ablations, with again no difference seen for generator impedance drop.²⁹

These retrospective studies therefore provided evidence of the clinical utility of LI measurement for acute success during catheter ablation but prospective, systematic data on its role in creating durable radiofrequency lesions remained lacking.

The LOCALIZE trial

Objective and study design

In order to gain further insights into the utility of LI drop for predicting durable ablation lesions, the ‘Electrical Coupling Information from the RHYTHMIA HDx™ Mapping System and DIRECTSENSE™ Technology in the Treatment of Paroxysmal Atrial Fibrillation — A Non-Randomized, Prospective Study: LOCALIZE’ trial was designed.  The aim of this study was to evaluate the association between LI drop and PVI segment block at two time points: after first pass encirclement of the PVs (acute block) and at chronic assessment after 3 months (durable block) in patients with paroxysmal AF.³⁰ This study was designed as a single arm, non-randomised, prospective, international multi-centre clinical trial (clinicaltrials.gov NCT03232645).

Patients with paroxysmal AF were enrolled at 6 centres in 4 European countries.  At the index procedure, an electroanatomical map of the left atrium was created with the Orion high-density mapping catheter and PVI was performed using point-by-point ablation with an IntellaNav MiFi OI ablation catheter, with operators blinded to LI information.  Radiofrequency power and application durations were at the discretion of operators. Following a 20-minute waiting period after initial encirclement of ipsilateral PV pairs, a left atrial activation map during coronary sinus pacing was created to identify acute gaps within anatomical segments of the PVI rings.  These gaps were annotated and re-ablated with operators now unblinded to LI data.

After 3 months, patients were invited to return for a protocol-mandated left atrial mapping procedure, irrespective of symptoms in the intervening period.  A further left atrial activation map during coronary sinus pacing was created, with identification of late PV reconnection sites.  After annotation, these sites were re-ablated with operators unblinded to LI information.

Study analysis

Ipsilateral PV rings were divided into 8 anatomical segments (16 segments per patient) (Figure 2). The median LI drop within each segment was calculated offline, with the minimum LI and median/minimum generator impedance drops also calculated. Comparisons were then made between blocked and reconnected segments, both acutely and at the 3-month mapping procedure. Optimal LI drop thresholds for predicting PVI segment block were assessed using receiver operating characteristic (ROC) curve analysis.

Figure 2: Segmental approach used for analysis of conduction block vs. gap. (Left) PA view of the left atrial electroanatomic map created for a study participant, with tags indicating the planned PVI ring and segments (blue tags: boundaries of segments; pink tags: segment centres). (Right) Diagram depicting the 16-segment model, with 8 segments per ipsilateral PV ring (R=right, L=left, S=Superior, A=Anterior, I=Inferior, P=Posterior).

Results

60 patients completed the initial PVI procedure, with all PVs in all patients (240/240 PVs) successfully isolated at the end of the procedure. Electroanatomic maps were reviewed offline for adequate PV conduction beyond the planned PVI ring prior to ablation in order to ensure accurate discrimination between blocked and reconnected segments, resulting in the inclusion of 55 patients in the analysis.

Relationship between LI drop and acute PV conduction block

When considering all PVI segments, acutely blocked segments had a significantly larger median LI drop compared to reconnected segments (19.7 [14.1–26.8] vs. 10.4 [7.0–14.7]Ω, P<0.001; Figure 3, Left panel). This was also true for segments with inter-lesion distance (ILD) ≤6mm (19.8 [14.1–27.1] vs. 10.6 [7.8–14.7]Ω, P<0.001; Figure 3, Right panel), with the majority of outlying values accounted for by ILD such that the largest LI drop associated with a PV reconnection site was 20.1Ω.

Figure 3: Box-and-whisker plots of LI drop for acutely blocked and acute gaps segments, for (A) all segments and (B) segments with a maximum ILD of ≤6mm. Blue crosses denote outliers and the black dashed line indicates the optimal LI drop value from ROC curve analysis.

Due to the known differences in tissue thickness between the anterior and posterior regions of the left atrium, a regional analysis was undertaken. Anterior and superior segments were grouped together, as were posterior and inferior segments.  Considering segments with ILD ≤6mm, acutely blocked segments had a significantly larger LI drop compared to reconnected segments in both regions (anterior/roof segments: 22.4 [16.5–28.4] vs. 10.8 [8.2–14.9]Ω, P<0.001; posterior/

inferior segments: 17.5 [12.6–25.6] vs. 10.5 [7.5–12.2]Ω, P<0.001). Furthermore, the median LI drop for blocked anterior/roof segments was significantly higher than for blocked posterior/inferior segments (P<0.001).  These findings are shown graphically in Figure 4.

Figure 4: Box-and-whisker plots of LI drop for acutely blocked and acute gaps segments with a maximum ILD of ≤6mm: (Left) anterior/superior segments; (Right) posterior/inferior segments. Blue crosses denote outliers. The orange and blue dashed lines indicate the optimal LI drop value from ROC curve analysis for anterior/superior segments and posterior/inferior segments, respectively.

In receiver operator characteristic curve analysis, the optimal LI cut-off value identified for the anterior/roof region was 16.1Ω and for the posterior/inferior region was 12.3Ω. These values were highly predictive of acute conduction block (positive predictive values of 96.3% and 98.1%, respectively). In the anterior/roof region, 60% of lesions reached an LI drop of >16.1Ω, taking an average time of 10.4±7.1sec, while 69% of ablations reached an LI drop of >12.3Ω in the posterior/inferior region, taking 8.2±6.3sec. In comparison, the average application duration in the study while blinded to LI information was 28.3±7.6sec.

Comparison between LI and generator impedance for acute PV conduction block

When comparing LI with generator impedance, median LI drop had a larger area under the curve in ROC curve analysis and a greater magnitude of difference between acutely blocked and reconnected segments than median generator impedance drop. Furthermore, pre-ablation starting LI had a significant and strong correlation to LI drop during ablation (r=0.66, P<0.0001), with each 2Ω increase in starting LI associated with an approximately 1Ω larger LI drop. In comparison, the correlation between starting generator impedance and generator impedance drop during ablation was significant but weaker (r=0.34, P<0.0001).

Relationship between LI drop and durable PV conduction block

Full results of the analysis of the relationship between LI drop and durable PV conduction block at left atrial mapping after 3 months are awaited. However, data presented at the Heart Rhythm Society Scientific Sessions 2020 for the first 44 study participants indicated similar findings for durable PV conduction block as for acute conduction block, with similar optimal values for the anterior/roof region (16.9Ω) and the posterior/inferior region (14.2Ω) identified from ROC curve analysis.³¹

Discussion

While there has been significant progress in refining the delivery of radiofrequency energy to achieve transmural ablation lesions through developments in 3D mapping, contact force-sensing catheters and composite lesion quality markers, the ability to deliver consistent, durable PVI has remained elusive. This may in part relate to the inherent limitations of even the most advanced composite markers, as they only incorporate input ablation factors such as power, contact force and application duration.^7,32  Assessment of direct tissue response to radiofrequency energy delivery has proved more challenging, with tissue temperature measurement limited by catheter tip irrigation, although novel catheter designs may allow this with greater accuracy.^10,33  Generator impedance measurement has inherent limitations due to its wide field of view and potential for significant differences between patients as well as within an individual patient over the course of an ablation procedure.^19-21

Local impedance measurement is a promising technology, supported by pre-clinical data and clinical evidence of an association between LI drop and acute ablation success.  However, the LOCALIZE trial provides evidence that the magnitude of LI drop is predictive of both acute and durable PVI segment conduction block.³⁰  This is a critical finding which confirms the clinical utility of LI drop in the objective of delivering durable PVI safely and efficiently.  The threshold values identified for acute PVI segment block provide a very high positive predictive value for achieving this, and therefore allow radiofrequency energy delivery to be tailored to create effective lesions.   Importantly, the thinner posterior/inferior region required smaller LI drops for acute conduction block compared to the thicker anterior/superior region, enabling operators to further refine ablation delivery without excessive over-ablation which can compromise safety.  While the full results from analysis of the relationship between LI drop and durable PVI segment conduction block are awaited, initial results indicate very similar findings to those for acute conduction block, with a likelihood of only small adjustments to the thresholds identified for acute block.³¹

There were a number of other important findings from the LOCALIZE trial.  Firstly, starting LI was shown to have a significant, strong and positive correlation to LI drop.  Not only was this stronger than for generator impedance, but this finding indicates that starting LI can play a significant role in pre-ablation planning prior to initiating RF energy delivery.  Accordingly, at each ablation lesion site, steps can be taken to ensure that there is adequate catheter-tissue coupling as indicated by the starting LI value, with a predictable LI drop once ablation is commenced.  This again facilitates intra-procedural efficiency.

Secondly, the optimal threshold values identified for acute PVI segment block were reached relatively quickly in an average of 8-10 seconds depending on left atrial region.  Although the optimal values associated with durable PVI conduction block may prove to be slightly higher, the time to reach these is likely to remain relatively short and certainly shorter than conventional application durations of 20-40 seconds.  This is also a critical finding which has the potential to significantly reduce both total ablation time and procedural duration.

Conclusion:

Optimising radiofrequency energy delivery to improve outcomes for ablation procedures such as PVI remains a major target.  Following initial pre-clinical and clinical data supporting the role of LI measurement, the LOCALIZE trial has confirmed the clinical utility of LI drop for predicting acute PVI conduction block.  Although results for prediction of chronic PVI conduction block are not yet available, initial reports suggest similar findings and the final data are eagerly anticipated.

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