Ripple-AT Study: A multicenter and randomized study comparing 3D mapping techniques during atrial

tachycardia ablations

Short Title: Randomized Ripple AT

Vishal Luther PhD MRCP1, Sharad Agarwal MD2, Anthony Chow PhD FRCP3, Michael Koa-Wing PhD

MRCP1, Nuno Cortez-Dias PhD MD4, Luís Carpinteiro PhD MD4, João de Sousa PhD MD4, Richard

Balasubramaniam MD5, David Farwell MD6, Shahnaz Jamil-Copley PhD MRCP7, Neil Srinivasan PhD

MRCP3, Hakam Abbas BSc3, James Mason BSc2, Nikki Jones BSc5, George Katritsis MBChB BSc1,

Phang Boon Lim PhD MRCP1, Nicholas S. Peters MD FHRS1, Norman Qureshi PhD MRCP1, Zachary

Whinnett PhD MRCP1, Nick Linton PhD MRCP1, Prapa Kanagaratnam PhD FRCP1

Institutional Affiliations:

1. Imperial College Healthcare, London, UK;

2. Papworth Hospital, Cambridge, UK.

3. Barts Heart Centre, London, UK;

4. Hospital de Santa Maria, Lisbon, Portugal;

5. Royal Bournemouth & Christchurch Hospital, Bournemouth, UK;

6. Essex Cardiothoracic Centre, Basildon, UK;

7. Nottingham University Hospital, Nottingham, UK

Address for correspondence: Professor Prapa Kanagaratnam, Department of Cardiology, Mary

Stanford Wing, St. Marys Hospital, Imperial College Healthcare NHS Trust, London W2 1NY, United

Kingdom. Telephone: +44 (0) 203 312 3783 Email: p.kanagaratnam@imperial.ac.uk

This abstract received the “Eric N. Prystowsky Fellows Clinical Research Award” at Heart Rhythm

Society 2019. This abstract presentation also received a “Late Breaking Research Award” at Asia-

Pacific Heart Rhythm Society 2018.

Journal Subject Terms: Arrhythmia, Atrial Fibrillation, Electrophysiology

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ABSTRACT

Background: Ripple Mapping (RM) is an alternative approach to activation mapping

of atrial tachycardia (AT) that avoids electrogram (EGM) annotation. We tested

whether RM is superior to conventional annotation based local activation time (LAT)

mapping for AT diagnosis in a randomized and multicenter study (NCT02451995).

Methods: Patients with AT were randomized to either RM or LAT mapping using the

CARTO3v4 CONFIDENSE™ system. Operators determined the diagnosis using the

assigned 3D mapping arm alone, before being permitted a single confirmatory

entrainment manuever if needed. A planned ablation lesion set was defined. The

primary endpoint was AT termination with delivery of the planned ablation lesion set.

The inability to terminate AT with this first lesion set, the use of more than one

entrainment manuever, or the need to crossover to the other mapping arm were

defined as failure to achieve the primary endpoint.

Results: 105 patients from 7 centres were recruited with 22 patients excluded due to

premature AT termination, non-inducibility or LAA thrombus. 83 patients (RM=42,

LAT=41) completed mapping and ablation within the two groups of similar

characteristics (RM vs LAT: prior ablation or cardiac surgery n=35 (83%) vs n=35

(85%) p=0.80). The primary endpoint occurred in 38/42pts (90%) in the RM group

and 29/41 (71%) in the LAT group (p=0.045). This was achieved without any

entrainment in 31/42pts (74%) with RM and 18/41pts (44%) with LAT (p=0.01). Of

those patients who failed to achieve the primary endpoint, AT termination was

achieved in 9/12pts (75%) in the LAT group following crossover to RM with

entrainment, but 0/4 pts (0%) in the RM group crossing over to LAT mapping with

entrainment (p=0.04).

Conclusion: RM is superior to LAT mapping on the CARTO3v4 CONFIDENSE™

system in guiding ablation to terminate AT with the first lesion set, and with reduced

entrainment to assist diagnosis.

Keywords: Mapping, Atrial Tachycardia, Ablation, Ripple Mapping, CARTO

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INTRODUCTION

The incidence of atrial tachycardia (AT) has increased with the rising numbers of

atrial fibrillation (AF) ablation.1 3D mapping and ablation for patients with

symptomatic ATs is proven to be superior to pharmacological therapy and is the

recommended first line treatment.2

The current gold standard approach to AT mapping relies on the annotation of local

activation time (LAT) of each intra-cardiac electrogram (EGM) collected within a pre-

specified window of interest (WOI) based on the tachycardia cycle length (TCL).3

This approach can be prone to error, especially in areas of low voltage related to

prior ablation, surgery or myopathy where EGM annotation can be challenging.4 3D

mapping systems continue to develop algorithms to overcome the challenges of LAT

mapping in these areas without addressing the fundamental limitations related to

annotation. Ripple Mapping (RM) is now an established alternative approach to

activation mapping on the CARTO3 CONFIDENSE™ platform (Biosense Webster,

Inc) that does not require electrogram annotation or a window of interest.5-7

Furthermore, as Ripple Maps can be played over a color display of bipolar voltage, it

can demonstrate how activation navigates through areas of low voltage.8 Recent

non-randomized studies have suggested that RM can improve diagnostic accuracy

compared to standard LAT mapping approaches.8, 9

In this study we prospectively randomized patients with AT to test whether RM is

superior to LAT mapping on the CARTO3 version4 (v4) CONFIDENSE™ platform in

diagnosing the mechanism of AT to guide the delivery of radiofrequency ablation.

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METHODS

Study designThe Ripple-AT study (clinicaltrials.gov ID: NCT02451995) was a multi-centre,

prospective, and randomized study comparing RM vs LAT guided AT ablation.

Centers experienced in the 3D mapping of ATs and using the CARTO3v4

CONFIDENSE™ module (which includes CARTO Ripple Mapping as a module)

volunteered for participation. All operators received formal training in the use of RM,

and undertook at least 4 consecutive RM guided AT ablations prior to commencing

the randomized study. All procedures were performed with informed consent and

institutional approval at each site was granted for this study. The data that support

the findings of the study are available from the corresponding author upon

reasonable request.

Patients were recruited from those referred for paroxysmal/persistent AT ablation.

Subjects were excluded if the documented ECG was consistent with typical cavo-

tricuspid isthmus dependent flutter. Patients were block randomized into an

unblinded 1:1 mapping design of either RM or LAT mapping to guide ablation.

Randomisation was performed via a sealed envelope.

A decapolar catheter was placed in the coronary sinus (CS) and a suitable CS

reference was selected. Burst pacing down to 200ms from different CS poles was

used to induce AT if in sinus rhythm at the start. The CS activation pattern in AT was

used to decide on the first chamber to map. CARTO3v4 CONFIDENSE™ (Biosense,

Inc). was used for mapping with a Lasso Nav (Biosense, Inc) or Pentaray Nav

(Biosense, Inc) as per operator discretion. A point density to color the entire

geometry with a color threshold of 5mm was targeted. Criteria for including points on

the map using CONFIDENSE Continuous Mapping™ included a cycle length stability

within a 5% range of the TCL, an electrode position stability within 2 mm, an LAT

stability filter at 3 milliseconds and tissue proximity to the endocardial surface. While

industry support was offered to assist with operating the CARTO system, they

provided no assistance in interpreting the activation map to which each patient was

randomized.

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Randomized to Ripple Mapping: RM presents the entire EGM as a white moving bar on the surface geometry with the

height correlating to the EGM voltage amplitude at that time point. Every bipolar

EGM from each point is aligned relative to the reference signal, and the Ripple map

of all points is then played through time, with activation understood as the movement

of bars traverses from one area to the next.

The approach to RM undertaken by operators in this arm of the study is presented in

Table 1. Details of how this approach was developed can be seen in previous

published studies.7, 8 EGM deflections above 0.07mV were displayed as Ripple bars,

but could be adjusted down to 0.03mV to review very low voltage activation. The

bars were clipped above 0.30mV to allow easier visualisation. The map was played

as a continuous loop spanning two tachycardia cycle lengths. EGM data from the

same tachycardia cycle is presented as a Ripple Map by aligning the EGMs

according to their corresponding reference EGM from the same cycle.

In this arm of the study, during the geometry and electro-anatomical map acquisition,

the bipolar voltage map was displayed and the LAT map remained hidden to all lab

staff. The voltage display was set empirically to 0.30mV-0.30mV (such that tissue

<0.30mV was colored red, and tissue >0.30mV was colored purple). The voltage

color scale was manually reduced from 0.30mV to identify the surface voltage

threshold supporting wave-fronts of Ripple bars. In doing so, areas supporting ripple

wavefronts were displayed in purple, and the remaining non-conducting areas

without ripple bars in red (e.g. 0.15mV-0.15mV, where tissue below 0.15mV

appeared red, and tissue above 0.15mV appeared purple). Every potential ripple

activation wave front was studied to determine the AT mechanism. In complex cases

the ‘design line’ tool dialogue box was activated, which allowed the operator to

manually draw out the path of the visualised activation direction across the entire

geometry chamber (as small white arrows), in order to plan the ablation approach.

Randomized to LAT Mapping:Conventional activation mapping involves the measurement of the “local activation

time” of each EGM. This denotes the numerical difference in timing between a

component of a sampled EGM and a stable reference signal, the values of which are

plotted on the 3D map according to a rainbow color bar that spans the interval of the

mapped tachycardia. Annotation of LAT requires a timing “window of interest” (WOI)

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to ensure that EGMs from the same beat are compared. A WOI is defined by

specifying a timing interval both before and after the reference point. The position of

the reference point in relation to the window is arbitrary. The color red is used to

represent the earliest measurement of LAT within the specified window, and purple

the latest. In a re-entrant tachycardia, the concept of “early” and “late” is a misnomer,

because any given area of activation will have other sites that are activated before or

after that location, and the red area of earliest activation will be adjacent to a purple

area of latest activation (i.e. early meets late).

The CARTO3v4 CONFIDENSE™ module offers several features to enhance LAT

mapping. This includes Wavefront™ annotation, an automated algorithm that

assigns timing annotation at the maximal negative distal unipolar derivative within

the time-window spanned by the corresponding bipolar EGM. In addition, there is an

algorithm to enable an automated WOI recompute, which allows the WOI and the

subsequent LAT of each projected point to be re-calculated at any time during map

acquisition. There is also a “map consistency” filter, which determines the

consistency of each measured LAT point relative to its neighbouring points, and

highlights outlier points with LAT’s very different to its surrounding neighbours for

review and deletion/re-annotation as required.

In this arm of the study, during the geometry and electro-anatomical map acquisition,

the LAT and bipolar voltage maps were displayed and the Ripple Map remained

hidden to all lab staff. The WOI was set from the start, spanning between 90-100%

of the TCL and either around the reference signal, or the surface p wave.10

Operators were able to adjust the WOI as required using the automated recalculation

function for the complete electroanatomic map. Automated annotation of activation

timing was assigned using the CONFIDENSE Wavefront™ algorithm in all cases. In

the absence of a sharp negative slope >0.03mV in unipolar signal, a grey square

was projected as the system could not automatically assign LAT. After all points

were collected, the Map Consistency filter was used as required. The static LAT map

was then visualised as a 2 color propagation map (red and blue). Additional manual

LAT re-annotation or deletion was allowed at sites where propagation remained

unclear on the map. In a re-entrant circuit, an “early meets late” algorithm could be

applied to interpolate between early and late sights on the map considered re-

entrant.

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DiagnosisThe AT diagnosis was considered macro-re-entrant if it travelled continuously around

the mapped atrial chamber (where head met tail), whilst small loop circuits were

contained within a single plane (i.e. anterior wall). Both focal/localised re-entrant

circuits appeared to emanate from a small focus, spreading radially away and often

involving low voltage and fractionated EGMs at the break-out site.

Ablation:A diagnosis was made using the mapping arm assigned and a strategy for ablation

was planned. Power controlled (25–35 W) radiofrequency energy was delivered

(Stockert ۛ 70 RF generator, Biosense Webster) through an irrigated ablation catheter

(ThermoCool SmartTouch, Biosense Webster) at the putative target for AT ablation.

EndpointsThis study protocol was applied only to the first map collected (i.e. AT1). The primary

endpoint of the study was “AT termination with the first ablation set”. The “first

ablation set” encompassed all the ablation lesions delivered to target the AT based

on the studied activation map. For example, if the mapping approach suggested LA

roof dependency, the “first ablation set” would have been a roof line(s) and AT

termination following this ablation set alone would achieve the primary endpoint. If

AT1 changed to AT2 with ablation (defined as a sustained change in CS activation or

cycle length), this was also considered to have met the primary endpoint.

Cases where the tachycardia 1) terminated to sinus rhythm or 2) degenerated to

atrial fibrillation/alternating ATs, before mapping was completed, were excluded from

analysis. The objective of this study was to assess the diagnostic efficacy in the

acute setting only, therefore no long-term data was collected.

EntrainmentIn this study protocol, operators were asked to make a diagnosis with RM or LAT

alone, and entrainment was restricted in order to allow a fair comparison of the two

mapping approaches in isolation. Thus, if the operator was confident of the AT

diagnosis and ablation strategy from the 3D map, no entrainment was performed. A

single entrainment manuever was allowed where the operator had some diagnostic

uncertainty, in order to validate the diagnosis before ablation. For example, if the

mapping approach suggested peri-mitral macro-re-entry, entrainment from CS

proximal and CS distal would have been permissible as a single confirmatory

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entrainment manuever. If the diagnosis remained uncertain, or if ablation failed to

terminate AT, this was considered a failure to meet the primary endpoint of the

study. Crossover to the other mapping arm of the study and additional entrainment

mapping was open as per operator discretion.

StatisticsA prior non-randomized study demonstrated a diagnostic yield using RM compared

to LAT maps of 90% vs. 65%.9 Assuming the same effect size, in order to detect a

difference between arms with 80% power at the 5% two-tailed significance level, this

required at least 40 patients in each group. A sample size of at least 80 patients was

targeted.

Categorical variables were expressed as percentages. Continuous variables were

expressed as mean ± 1 standard deviation for parametric data and/or median (lower

quartile – upper quartile) for non-normal data. Categorical data were analysed using

either a Fishers Exact Test or Chi Squared test where appropriate. Unpaired data

were analysed using a Student’s T-test for parametric data and Mann Whitney U test

for non-normal data. A two-sided p value was determined where applicable and a

value of p≤0.05 was considered significant.

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RESULTS

Figure 1 summarises the study design and number of patients in each arm. A total of

105 patients were recruited from 7 centers (6 UK; 1 Portugal) participating in this

study. Of these patients, 22 were excluded. This was due premature termination of

AT whilst mapping (n=6), AT non-inducibility (n=9), or degeneration to alternating

ATs/atrial fibrillation prior to the delivery of ablation (n=4). Left atrial appendage

thrombus on TOE seen at the start of the procedure (n=3) resulted in immediate

procedural cessation.

The remaining 83 patients completed mapping and AT ablation as per the assigned

randomized arm, and these were used for subsequent analysis. This included 42

patients in the RM group and 41 patients in the LAT group.

The baseline demographics, prior ablation history, and mapping details between the

two groups were similar, and is summarised in Table 2. (RM vs LAT: (65±9yrs) vs

(65±10yrs) p=0.78; prior atrial ablation n=32 (76%) vs n=33 (80%) p=0.83 – this

included prior pulmonary vein isolation n=30 (71%) vs n=29 (71%); linear

lesions/complex fractionated atrial electrogram ablation n=20 (48%) vs n=12 (29%)

p=0.13; prior right atrial ablation only n=2 (5%) vs n=4 (10%) p=0.65. Patients with

prior cardiac surgery without ablation included (RM vs LAT) n=3 (7%) vs n=2 (5%)

p=0.66. Therefore, the total number of patients with potential iatrogenic scar causing

AT (prior ablation or cardiac surgery) included RM n=35 (83%) vs LAT n=35 (85%)

p=0.80.

The median AT cycle lengths were similar between groups (RM vs LAT: 267ms (LQ

240, UQ 298) vs 260ms (LQ 231, UQ 278) p=0.20). Multipolar catheters (Lasso and

Pentaray) were used for mapping in almost all cases (a linear Smarttouch catheter

was used in the non-coronary cusp in a focal AT) with similar median point densities

between groups (RM vs LAT: 2681points (LQ 1722, UQ 3647) vs 2219 points (LQ

1453, UQ 3232) p=0.44. The Pentaray was the most preferred mapping catheter

(RM vs LAT: n=27 (64%) vs n=26 (63%) p=0.93).

Figure 2 summarises the key endpoints of the study. The primary endpoint of

termination of AT with the first ablation set occurred in 38/42pts (90%) in the RM

group and 29/41 (71%) in the LAT group (p=0.045). This was achieved with the 3D

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map alone, i.e. without entrainment in 31/42pts (74%) in the RM group and 18/41pts

(44%) in the LAT group (p=0.01). AT1 changed to AT2 with ablation in 6pts in both

groups, and the AT2 map confirmed a different mechanism and ablation target in all

cases. 1pt in each group failed to terminate with ablation where entrainment

confirmed the same diagnosis as the map. Where the primary endpoint was not met

(i.e. those without a diagnosis based on the 3D mapping method, or where the first

ablation set failed to terminate AT), AT termination was achieved in n=9/12 (75%)

patients crossing from LAT to a combination of RM and entrainment mapping, and in

n=0/4 (0%) patients crossing from RM to a combination of LAT and entrainment

mapping (p=0.04).

Where the primary endpoint was met, left sided ATs were predominantly identified in

both groups (RM vs LAT: n=31/38 (82%) vs n=24/29 (83%) p=0.90). Macro/small

loop re-entrant mechanisms were more common in both groups (RM vs LAT: 27/38

(71%) vs 22/29 (76%) p=0.87; with the remaining diagnosed as focal/localized re-

entrant (RM vs LAT: 11/38 (29%) vs 7/29 (24%)).

There were no procedural complications in either groups in this study.

Figure 3 (and supplementary video 1) illustrates a case of a patient randomized to

Ripple Mapping. A complex LA circuit circumnavigating around an island of probable

scar <0.15mV was observed on the anterior wall, determined by the absence of

Ripple wave-fronts through it. A second circuit was also observed around the mitral

annulus (supplementary video 1). Both these circuits were dependent on a narrow

and slowly conducting isthmus between the inferior border of this island and the

mitral annulus, and transecting this isthmus terminated tachycardia. This case

demonstrates how Ripple Mapping is used to define putative scar on the map by

functional assessment, and then exploiting the concurrent display of activation and

scar to define the optimal ablation site.

There were 4/42 cases which failed to meet the primary endpoint in the RM group.

One case was peri-mitral (confirmed with entrainment) where MI block could not be

achieved. One case terminated with ablation after further diagnostic mapping. One

case targeted a septal source without effect. The last case involved extensive low

voltage substrate/scar from multiple prior ablations where a roof substrate was

targeted without effect.

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Figures 4, 5, 6 & 7 (and corresponding supplementary videos 2, 3, 4) highlight cases

of patients randomized to LAT mapping that did not meet the primary endpoint. The

cases in Figures 4 and 5 are from patients with prior surgical Atrial Septal Defect

repair, and illustrate issues related to LAT color interpolation. In Figure 4, several

early and late sites colored red and purple are seen on the final LAT display. As

these early and late sites were in close proximity, the operator applied the “early

meets late” tool to interpolate the colors between these sites and produce a uniform

pattern. When propagation was played, the operator observed continuous rotation

around scar on the anterolateral wall suggestive of small loop re-entry. However,

split potentials were identified along the circuit, implying wave-front collision, not

observed on the propagation display. Given this uncertainty, the operator crossed

over to RM. The Ripple Map demonstrated that a line of conduction block prevented

small loop re-entry. Thus, the appearance of re-entry was false, and a consequence

of over-interpolation creating the impression of re-entry.

In figure 5, the full color coded spectrum was observed within a small area

collocating with an area of low voltage consistent with the lateral surgical cannulation

site. The propagation map demonstrated wavefront turning around this site, and

sampled EGMs were fractionated, leading the operator to again consider small loop

re-entry. This site was ablated without effect. The patient crossed over to RM, where

no rotational activity was seen, rather splitting of activation on either side of this

region of probable scar. Post procedure, a band of false color interpolation spanning

the full rainbow spectrum was appreciated on the LAT map between the apparent

early and late sites on the map. This created the appearance of a slowly moving

backward wave-front and this false appearance of wavefront turning on the

propagation display. As RM does not require a WOI and does not interpolate, this

error was avoided.

Figure 6 depicts an iatrogenic AT post extensive AF ablation where the LAT WOI

had been set equally around the CS reference EGM. The subsequent activation

pattern appeared focal in origin from within the LAA. Given the absence of EGMs of

interest, this diagnosis was uncertain, and entrainment revealed this site was outside

the circuit. RM did not demonstrate focal activation from the LAA, rather activation

breakout from probable scar near the posterior floor. Post procedure, after multiple

arbitrary post hoc adjustments of the LAT WOI, it revealed a similar activation

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pattern as seen with RM. This case highlights how setting the WOI is arbitrary and

can be misleading in complex cases. As RM does not require a WOI, this limitation

can be avoided.

Despite all attempts to optimise, the LAT map in figure 7 was considered

uninterpretable, with multiple early and late sites. This was mapped from a patient

with prior mitral valvuloplasty and extensive low voltage atrial tissue. EGMs sampled

within the map were frequently long duration and multicomponent. Despite being in

close proximity, sites have been labelled as early and late due to overlapping EGMs

spanning a large portion of the set WOI. This case highlights the challenge of having

to annotate a single LAT to represent multi-component fractionated EGMs. Ripple

Mapping does not annotate, rather it presents all EGM components in its entirety.

Following crossover to RM, a breakout of activation from an extensive area of low

voltage along the posterior roof was appreciated and a decision to perform a

posterior box lesion resulted in AT termination.

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DISCUSSION

This study is the first prospective, multicenter and randomized study comparing 3D

activation mapping techniques. We show that operators experienced with LAT

mapping on the CARTO3v4 CONFIDENSE™ platform had a higher rate of AT

termination using Ripple Mapping, and achieved this with less reliance on

entrainment support.

The effectiveness of mapping tachycardia activation using LAT is proven. Published

studies document ~85% success rates in AT termination using this approach1. LAT

mapping has seen recent advances, including automated annotation to the

maximum negative unipolar EGM derivative within the period of bipolar activation,

and its incorporation with high point density. However, most of these published

studies have combined LAT with entrainment mapping such that the efficacy of LAT

mapping in isolation remains unknown. Furthermore, these studies did not report

whether ablation had been delivered at multiple incorrect sites prior to eventual AT

termination. This is the first study to measure the efficacy of LAT mapping in

isolation, without entrainment, and following the delivery of only the first ablation set.

This study demonstrated acute AT termination with first lesion set in 71% with LAT

mapping, and in only 44% without entrainment. The figures highlight three sources

for error in relation to LAT mapping that likely explain this ~30% failure rate,

including: (1) incorrect color interpolation; (2) window of interest errors and (3) mis-

annotation.

Interpolation algorithms assign the average activation time between mapped points

in order to display an interpretable propagation pattern on the assumption that

activation is uniform; however, these estimates of timing can be misleading,

especially in areas of conduction delay or block, as seen in Figure 4. “Backward

wave-fronts” are a specific interpolation error observed in macro-re-entrant circuits,

and caused the problems demonstrated in Figure 5. These occur at sites where

“early” and “late” do not quite meet, and interpolation of colors between these

apparent early and late sites occur, resulting in a slowly moving wave-front in

reverse to the true direction of activation.

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A windows of interest (WOI) is required to ensure that EGM LATs from the same

cycle are compared. However, the process of setting this window is arbitrary, with

different color coded activation patterns generated depending on the setting, as

shown in Figure 6. Whilst methods to standardise this approach around the surface

p-wave have been considered, they are only applicable in non-focal mechanisms,

which is not known at the start of the case.10 Furthermore, in diseased tissue with

prolonged conduction times, no matter how the window is set, being limited to a

single cycle can lead to very late activating sites being erroneously displayed as

early in the WOI with respect to the next cycle of activation, resulting in more than

one early site on the map.11 Ripple Mapping is the only contact-mapping system

which currently reviews more than a single tachycardia cycle length. The CARTO3v4

LAT maps used in this study present their WOI as a color bar. A WOI color wheel

has also been proposed to solve the challenges of setting a WOI. Rotation of this

wheel has the equivalent effect of sliding the WOI without causing a full map re-

compute. In principle, this can avoid some errors related to the WOI as considered

above. However, several studies have reported on a high prevalence of small

pseudo-re-entrant circuits from continuously rotating the wheel, some of which were

misdiagnosed as localized/small loop re-entry and inappropriately ablated.12, 13

Mis-annotation of LAT can lead to a complete change in the color coded pattern. The

advent of high point density acquisition with algorithms that filter out points with

inconsistent timings in relation to neighbouring LAT measurements have reduced

annotation errors. However, these errors remain prevalent, particularly in areas of

low voltage containing multicomponent EGMs as in Figure 7. Manual checking and

re-annotation of LAT when >2000points are collected is time consuming and

impractical during clinical procedures.

Whilst all 3D-mapping systems continue to develop algorithms to overcome these

limitations to LAT mapping, Ripple Mapping offers a completely alternative activation

mapping approach. RM presents activation information without the need for

annotation of activation time or setting of a window of interest, and does not

interpolate between unmapped sites.5 Patients randomized to RM in this study

achieved AT termination in 90% with the first ablation set (p=0.045).

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This superiority was partly attributable to avoiding these errors associated with LAT

mapping. It was also consequent to a unique means of studying activation in areas

of low voltage and scar. There remains no consensus on a voltage parameter to

differentiate between active and non-conducting tissue (i.e. either true scar from

fibrosis or areas of functional block dependant on the wave-front direction and atrial

rate) using endocardial mapping. LAT maps apply an arbitrary pre-set voltage

threshold to display scar, and display areas below this threshold as grey tags to

blank the color-coded map.14 With RM, displaying activation wave-fronts on a colored

voltage map enables a novel approach to defining this voltage parameter that

differentiates electrically active myocardium from non-conducting tissue (voltage

thresholding).8 The example in Figure 3 is a case where only the common isthmus of

the dual-loop tachycardia needed to be ablated. This was possible because of the

simultaneous display of activating and non-conducting myocardium during

tachycardia that helped determine the optimal site for ablation. This can be

particularly helpful in peri-mitral tachycardias in which conventional mitral isthmus

lines can be avoided.

Entrainment enhances our electrophysiological understanding of the AT circuit prior

to ablation, and this study does not advocate entrainment avoidance.15 However,

entrainment does have limitations in areas of low voltage due to pacing latency, non-

capture, and can cause degeneration to AF.16 In this study, patients randomized to

RM underwent significantly less entrainment than those in the LAT group (p=0.01),

as operators felt more confident to ablate the AT based on the Ripple Map alone.

Entrainment appears to be essential to LAT mapping to help overcome the core

limitations of this approach, whilst with RM it was more supportive by confirming a

diagnosis.

RM looks very different to conventional LAT activation maps. There is a learning

curve, and each operator (who had extensive experience in LAT mapping and

entrainment) received 2-3hrs of formal training in RM on a workstation with example

cases. This was followed by 4 consecutive clinical cases where operators made a

diagnosis with RM first, with the improved diagnostic efficacy of RM already apparent

at that stage.9 These operators did not need technical support from industry

representatives to make these diagnoses. We would consider similar training to be

essential for other operators aiming to replicate the results seen in this study.

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Whilst this study was specific to mapping EGMs within the atria, RM is also suited to

mapping EGMs within the ventricle. We and others have shown how RM can be

used to follow late potentials through channels of slow conduction that might support

re-entry.17, 18 Ripple Mapping to study VT and substrate during sinus rhythm has a

very different workflow due to the main challenge being differentiating local and far-

field EGMs.

Limitations:The objective of this study was to assess the diagnostic efficacy of each mapping

technique in the acute setting, and does not consider the best approach to achieve

long-term freedom from AT. The analysis of long-term outcomes of patients

randomised to each mapping arm would require a different protocol that prohibited

crossover to the other mapping arm during the entire case, and mandated post-

ablation inducibility testing (which was performed at operator discretion in this

protocol) and treatment of any subsequent ATs using the same mapping approach.

These cases were all performed on the CARTO3v4 CONFIDENSE™ platform, and

some of the findings might not apply to other mapping software.

Approximately 20% of patients recruited were not included in the study analysis due

to tachycardia termination before mapping was started/completed. We excluded

these patients as the ATs were not stable and therefore our endpoint of acute

termination during ablation would not have been robust. The best approach to

achieve acute success and long-term benefit in this group of patients needs further

study.

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CONCLUSION

This prospective, randomized and multi-center study demonstrates that Ripple

Mapping is superior to LAT mapping on the CARTO3v4 CONFIDENSE™ platform in

achieving acute atrial tachycardia termination using the first delivered ablation set,

with reduced reliance on entrainment to assist diagnosis.

Sources of Funding: The study was funded by a clinical study grant from Biosense Webster

and a British Heart Foundation Clinical Research Training Fellowship award (no. FS/15/12/31239).

Disclosures: Imperial Innovations holds Intellectual Property relating to Ripple Mapping on behalf

of PK and NL, who have also received royalties from Biosense Webster. PK, NL, SJC and VL have

received consulting fees with respect to Ripple Mapping from Biosense Webster. The remaining

authors have nothing to disclose.

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REFERENCES

1. Chae, S.; Oral, H.; Good, E.; Dey, S.; Wimmer, A.; Crawford, T.; Wells, D.; Sarrazin, J. F.; Chalfoun, N.; Kuhne, M.; Fortino, J.; Huether, E.; Lemerand, T.; Pelosi, F.; Bogun, F.; Morady, F.; Chugh, A., Atrial tachycardia after circumferential pulmonary vein ablation of atrial fibrillation: mechanistic insights, results of catheter ablation, and risk factors for recurrence. J Am Coll Cardiol 2007, 50, 1781-7.2. Zhang, X. D.; Gu, J.; Jiang, W. F.; Zhao, L.; Zhou, L.; Wang, Y. L.; Liu, Y. G.; Liu, X., Optimal rhythm-control strategy for recurrent atrial tachycardia after catheter ablation of persistent atrial fibrillation: a randomized clinical trial. Eur Heart J 2014, 35, 1327-34.3. Jais, P.; Shah, D. C.; Haissaguerre, M.; Hocini, M.; Peng, J. T.; Takahashi, A.; Garrigue, S.; Le Metayer, P.; Clementy, J., Mapping and ablation of left atrial flutters. Circulation 2000, 101, 2928-34.4. Del Carpio Munoz, F.; Buescher, T. L.; Asirvatham, S. J., Teaching points with 3-dimensional mapping of cardiac arrhythmias: teaching point 3: when early is not early. Circ Arrhythm Electrophysiol 2011, 4, e11-4.5. Linton, N. W.; Koa-Wing, M.; Francis, D. P.; Kojodjojo, P.; Lim, P. B.; Salukhe, T. V.; Whinnett, Z.; Davies, D. W.; Peters, N. S.; O'Neill, M. D.; Kanagaratnam, P., Cardiac ripple mapping: a novel three-dimensional visualization method for use with electroanatomic mapping of cardiac arrhythmias. Heart Rhythm 2009, 6, 1754-62.6. Jamil-Copley, S.; Linton, N.; Koa-Wing, M.; Kojodjojo, P.; Lim, P. B.; Malcolme-Lawes, L.; Whinnett, Z.; Wright, I.; Davies, W.; Peters, N.; Francis, D. P.; Kanagaratnam, P., Application of ripple mapping with an electroanatomic mapping system for diagnosis of atrial tachycardias. J Cardiovasc Electrophysiol 2013, 24, 1361-9.7. Koa-Wing, M.; Nakagawa, H.; Luther, V.; Jamil-Copley, S.; Linton, N.; Sandler, B.; Qureshi, N.; Peters, N. S.; Davies, D. W.; Francis, D. P.; Jackman, W.; Kanagaratnam, P., A diagnostic algorithm to optimize data collection and interpretation of Ripple Maps in atrial tachycardias. Int J Cardiol 2015, 199, 391-400.8. Luther, V.; Linton, N. W.; Koa-Wing, M.; Lim, P. B.; Jamil-Copley, S.; Qureshi, N.; Ng, F. S.; Hayat, S.; Whinnett, Z.; Davies, D. W.; Peters, N. S.; Kanagaratnam, P., A Prospective Study of Ripple Mapping in Atrial Tachycardias: A Novel Approach to Interpreting Activation in Low-Voltage Areas. Circ Arrhythm Electrophysiol 2016, 9, e003582.9. Luther, V.; Cortez-Dias, N.; Carpinteiro, L.; de Sousa, J.; Balasubramaniam, R.; Agarwal, S.; Farwell, D.; Sopher, M.; Babu, G.; Till, R.; Jones, N.; Tan, S.; Chow, A.; Lowe, M.; Lane, J.; Pappachan, N.; Linton, N.; Kanagaratnam, P., Ripple mapping: Initial multicenter experience of an intuitive approach to overcoming the limitations of 3D activation mapping. J Cardiovasc Electrophysiol 2017, 28, 1285-1294.10. De Ponti, R.; Verlato, R.; Bertaglia, E.; Del Greco, M.; Fusco, A.; Bottoni, N.; Drago, F.; Sciarra, L.; Ometto, R.; Mantovan, R.; Salerno-Uriarte, J. A., Treatment of macro-re-entrant atrial tachycardia based on electroanatomic mapping: identification and ablation of the mid-diastolic isthmus. Europace 2007, 9, 449-57.11. Ju, W.; Yang, B.; Chen, H.; Zhang, F.; Gu, K.; Yu, J.; Li, M.; Yang, G.; Cao, K.; Chen, M., Mapping of focal atrial tachycardia with an uninterpretable activation map after extensive atrial ablation: tricks and tips. Circ Arrhythm Electrophysiol 2014, 7, 598-604.12. Luther, V.; Sikkel, M.; Bennett, N.; Guerrero, F.; Leong, K.; Qureshi, N.; Ng, F. S.; Hayat, S. A.; Sohaib, S. M.; Malcolme-Lawes, L.; Lim, E.; Wright, I.; Koa-Wing, M.; Lefroy, D. C.; Linton, N. W.; Whinnett, Z.; Kanagaratnam, P.; Davies, D. W.; Peters, N. S.; Lim, P. B., Visualizing Localized Reentry With Ultra-High Density Mapping in Iatrogenic Atrial Tachycardia: Beware Pseudo-Reentry. Circ Arrhythm Electrophysiol 2017, 10.

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Ripple Mapping of an Atrial Tachycardia – Diagnostic Steps

Mapping • Multipolar mapping - Lasso/PentaRay

• Colour threshold 5mm: point density = no grey areas (usually >2000points).

• Only “points projected” displayed (visualisation set-up)

• Annular points tagged and mitral/tricuspid annulus removed

Ripple Setup • Ripple Preferences: Show bars above - 0.07mV; Clip bars above - 0.30mV

• Selected point viewer: 2 cycle lengths played

Surface Voltage thresholding • Bipolar voltage map displayed - set empirically at to 0.3mV – 0.3mV on custom settings

• Play Ripple Map and reduce voltage limits in 0.05mV steps (i.e. 0.25mV – 0.25mV; continued down to 0.05mV – 0.05mV as required) until no ripple wave-fronts in red areas (non-activating tissue)

• Ripple bar wave-fronts should only visible in purple areas

Identifying mechanism • Study ripple activation in small patches of geometry. Use design lines with arrowheads to mark these wave-fronts throughout the entire chamber

• Follow the arrows backwards to identify focal source or re-entrant circuit.

• Reduce “Show bars above” to 0.03mV - study activation in areas of interest, to locate 1) earliest bar of focal source or 2) narrowest isthmus of re-entrant circuit.

Table 1: Protocol for Atrial Tachycardia diagnosis using Ripple Mapping

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Table 2: Baseline demographics and mapping details

RM - Ripple Mapping; LAT – Local Activation Time; RA – right atrium; LA – left atrium; PVI – pulmonary vein isolation; CFAE – complex fractionated atrial electrogram; AT – atrial tachycardia; denotes 3 missing values; denotes 4 missing values.

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Baseline CharacteristicsAssigned Group

p valueRM LAT

No of Patients 42 41

Prior atrial ablation or cardiac surgery (%) 83 85 1.00

Age (yrs) 65±9 65±10 0.78

Prior atrial ablation (%)(RA or LA) 76 80 0.80

Prior PVI (%) 71 71 NA

Prior LA substrate ablation (e.g. lines/CFAE) (%) 48 29 0.12

Prior RA ablation only (%) 5 10 0.43

Prior cardiac surgery without ablation (%) 7 5 1.00

AT cycle length/ ms, median 267* 260* 0.2

Pentaray use (%) 64 63 0.93

Collected Points, median 2681* 2219 0.44

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Figure Legends:

Figure 1: Study design and patient numbers

Figure 2: Results of acute ablation outcomes.

Figure 3: Randomized to Ripple Mapping. Voltage thresholding defines the critical

isthmus (See also supplementary video 1).

Patient with an idiopathic left AT (262ms). (A). Upper panel - bipolar voltage map set

to 0.30mV– 0.30mV. Tissue with voltage <0.30mV is displayed in red, and >0.30mV

in purple. A large area colored red was seen on the anterior wall. Wave-fronts of

ripple bars (yellow circle) were seen in areas of the voltage map colored red. (B) The

surface voltage limits were reduced until 0.15mV-0.15mV (i.e. red=<0.15mV;

purple=>0.15mV) – here no Ripple bars were seen in areas colored red. At this

voltage setting, an island of red tissue was seen on the anterior wall with ripple bars

circumnavigating clockwise around it (marked out by white arrows). Middle panel –

Ripple markings were sampled around this island, and their corresponding EGMs

spanned the ATCL (3 consecutive EGM cycles shown). Shown in the accompanying

video is a second circuit travelling counter-clockwise around the mitral annulus. Both

circuits were dependent on a narrow isthmus between the inferior border of this

island and the mitral annulus. Lower panel - transecting this critical isthmus with

ablation terminated tachycardia.

Figure 4: Randomized to LAT mapping. Interpolation creates the false impression of

small loop re-entry (See also supplementary video 2).

Patient with a prior surgical ASD repair mapped in AT (260ms) in the right atrium. A)

LAT map (modified AP) with the WOI set either side of the reference signal (-130ms

to +130ms). More than one region of early and late were seen (labelled). B) The

“early meets late” tool was applied (80%-default) and color interpolation between

these early and late sites were filled (dark red). Scar was highlighted as areas with

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peak bipolar voltage amplitude ≤0.03mV and colored grey. All the colors of the LAT

spectrum were seen to progress around a patch of scar on the anterolateral wall

suggestive of small loop re-entry. However, split potentials were identified along the

circuit, implying wave-front collision in the circuit. C) The Ripple Map demonstrated

that a line of conduction block prevented small loop re-entry around this patch of

scar, as evident by a line of double potentials along it (double yellow lines). In fact,

ripple bars rotated around this line of block, creating a “larger loop” re-entry. The

pattern of activation is depicted by white design lines, and can be viewed in the

corresponding video. Entrainment supported this observation – the post pacing

interval was long within the interpolated false small loop circuit seen by the LAT map,

and shortened moving superiorly into larger loop circuit seen with the Ripple Map.

Figure 5: Randomized to LAT mapping. Interpolation creates a false backward

wavefront (See also supplementary video 3).

Another patient with prior surgical ASD repair was mapped in AT (270ms) in the right

atrium. A) The operator observed the full rainbow color spectrum around the lateral

RA corresponding to B) an area of low voltage <0.30mV on the bipolar voltage map

and considered this small loop re-entry based on C) the presence of long and

fractionated EGMs within the circuit and the appearance of wavefront

turning/curvature (although not a complete rotation) on the corresponding LAT

propagation map (see video). However, ablation at this site (red circular VisiTag

disks) was ineffective. D) There was no evidence of wavefront curvature on the

Ripple Map, rather splitting of wavefronts on either side of this region of scar. E) A

band of false color interpolation spanning the full rainbow color spectrum was

evident between the early and late sites on the LAT map (labelled) that created the

appearance of a slowly moving back ward wave-front and the impression of wave-

front turning.

Figure 6: Randomized to LAT mapping. Varying LAT activation patterns when

changing the window of interest (See also supplementary video 4).

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Patient with post AF ablation (PVI, Roof + Mitral isthmus lines, CFAE ablation) AT

(258ms). Upper panel: The WOI was set either side of the reference signal to span

90% of the TCL. The LAT map, seen in AP (A) and PA (B) depicts earliest focal

activation (red) within the left atrial appendage. C) The corresponding voltage map

(PA) demonstrates extensive substrate <0.1mV (colored red). Unlike the LAT map,

RM revealed a breakout of activation from probable scar near the posterior floor

(yellow star), considered the exit of a region of slow conduction supporting a macro-

re-entrant circuit around the mitral annulus (white design lines). D) Adjustment of the

LAT WOI to (-18ms) to (+201ms) revealed the same breakout activation pattern (red

isochrone collocating with yellow star) as suggested by RM, but considered the

mechanism focal rather than part of a macro-re-entrant circuit. AT terminated in the

mid coronary sinus (purple star, snapshot catheter projection applied), presumably

along an epicardial connection of a mitral annular circuit.

Figure 7: Randomized to LAT mapping: Uninterpretable activation pattern

Patient with post-surgical (mitral valvuloplasty) left AT (230ms). The activation

pattern (PA) was uninterpretable with multiple “early” and “late” sites (labelled). The

EGMs from 2 immediately adjacent points are presented. These bipolar EGMs are

low voltage and multicomponent, and span a large portion of the TCL. Their

corresponding unipolar EGMs are also displayed. Despite being in immediate

proximity, the system has annotated one (left) as “early” and the other (right) as

“late” with respect to the set WOI, based on the sharpest unipolar dV/dT within this

long period of bipolar activation. Repeated occurrences of this event have resulted in

this uninterpretable appearance.

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Figure 5:

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