Article
Reference
Evolution of post–pulmonary vein isolation atrial fibrillation inducibility at redo ablation: Electrophysiological evidence of extra–pulmonary
vein substrate progression
JOHNER, Nicolas, et al.
Abstract
The goals of this study were to study the evolution of post–pulmonary vein isolation (PVI) AF inducibility (AFI) after AF ablation and to compare patients with organized atrial tachycardia recurrence (OATr) versus those with paroxysmal or persistent AF recurrence.
JOHNER, Nicolas, et al. Evolution of post–pulmonary vein isolation atrial fibrillation inducibility at redo ablation: Electrophysiological evidence of extra–pulmonary vein substrate progression.
Heart Rhythm, 2019, vol. 16, no. 8, p. 1160-1166
DOI : 10.1016/j.hrthm.2019.02.026 PMID : 30818093
Available at:
http://archive-ouverte.unige.ch/unige:135842
Disclaimer: layout of this document may differ from the published version.
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1
Evolution of Post-Pulmonary Vein Isolation Atrial Fibrillation
1
Inducibility at Redo Ablation: Electrophysiological Evidence of
2
Extra-Pulmonary Vein Substrate Progression
3
Short title: AF inducibility progression after redo-PVI 4
5
Authors: Nicolas Johner1*, MD, Dipen C. Shah1*, MD, FHRS, Georgios Giannakopoulos1, MD, Anne Girardet2, MD, Mehdi Namdar1, MD, PhD.
*Both authors contributed equally as first authors.
Affiliations: 1. Cardiology Division, Geneva University Hospitals, Geneva, Switzerland. 2.
Pediatrics Division, Geneva University Hospitals, Geneva, Switzerland.
Correspondence: Prof. Dipen C. Shah, Cardiology Division, Geneva University Hospitals, 6
Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland.
7
Tel: +41-223727202. Fax: +41-223727229. Email: dipen.shah@hcuge.ch 8
Word count: 4’957 9
Disclosures: Nicolas Johner: educational grants from Boston Scientific, Abbott, Cardinal 10
Health. Dipen C. Shah: consultant fees from Biosense Webster, Biotronik, St. Jude Medical 11
and Boston Scientific; research grants from Biosense Webster, St. Jude Medical and Boston 12
Scientific via the Cardiology Division; Speaker Board member fees from Biosense Webster, 13
St. Jude Medical and Boston Scientific. Mehdi Namdar: consultant fees and travel grants 14
from Boston-Scientific, Biotronik and Biosense-Webster.
15 16
17
2
Abstract
18
BACKGROUND: The electrophysiological substrate underlying atrial fibrillation (AF) progression remains difficult to identify.
OBJECTIVE: To study the evolution of post-pulmonary vein isolation (PVI) AF inducibility (AFI) after AF ablation, and compare patients with recurrence as organized atrial tachycardia (OATr) vs paroxysmal (pAF) and persistent AF (peAF).
METHODS: We studied 99 patients who underwent de novo AF ablation (p1) and redo (p2) for recurrent AF (AFr) or OATr. Stepwise AF ablation was performed at p1 and p2: 1) PVI, 2) coronary sinus defragmentation, 3) left atrium (LA) defragmentation. Burst-pacing followed each step, with AFI defined as sustained AF>5 min, triggering the next step. OATr patients underwent OAT ablation and inducibility testing post-redo-PVI. Inducibility progression (IP) was defined as AFI at further steps of p2 compared to p1.
RESULTS: Among AFr patients, 34/72 (47%) exhibited post-PVI IP versus 2/27 (7.4%) OATr patients (p=0.0002). Stratification for peAF/pAF/OATr showed consistent association
between recurrence phenotype and IP. PV reconnection incidence was 90%, without
association with recurrence type or IP. LA volume was larger in patients with IP versus no IP (86.7±25.3 versus 72.0±28.9 ml, p=0.001). RA dimensions increased between p1 and p2 in patients with IP versus no IP, and in AFr versus OATr.
CONCLUSION: Patients with AFr after first ablation exhibit IP more frequently at redo compared to patients with OATr. IP correlates with more advanced AFr type, larger LA volumes and progressive RA enlargement. PV reconnection is not associated with AFr.
Changes in post-PVI AFI may accurately indicate progression of extra-PV AF-maintaining substrate.
Keywords: Atrial fibrillation, atypical atrial flutter, catheter ablation, pulmonary vein isolation, 19
recurrence, inducibility, prognosis.
20 21
3 22
Introduction
23
Catheter ablation is a successful treatment option for both paroxysmal and persistent atrial 24
fibrillation (AF). However, studies have reported single procedure arrhythmia recurrence 25
rates of approximately 50% at 1 year1. While durable pulmonary vein isolation (PVI) is 26
established as the primary goal of catheter ablation, the role of PV reconnection in AF 27
recurrence (AFr) remains unclear. In a recent meta-analysis2, 58.6% of patients without AFr 28
exhibited ≥ 1 PV reconnection at repeat electrophysiology study, compared to 85.5% of 29
patients with AFr. While PV reconnection was associated with an increased risk of 30
recurrence, it was neither necessary nor sufficient for AFr to occur. It is likely that a 31
significant proportion of post-ablation AFr has other underlying mechanisms, including 32
unrecognized, untreated or progressive extra-PV AF substrate maintaining AF. The 33
electrophysiological substrate underlying AF persistence and progression has remained 34
difficult to identify beyond the clinical AF phenotype. Likewise, there is no established 35
procedural outcome to define AF ablation success beyond PVI.
36
AF inducibility by burst-pacing has been investigated as a method to indirectly assess the 37
substrate responsible for AF maintenance. Studies have shown a correlation between AF 38
inducibility and AFr during follow-up3. However, the significance of AF inducibility progression 39
from the first ablation procedure (p1), post-PVI, to the second procedure for recurrence (p2), 40
post-redo PVI, has not been evaluated. While AF inducibility at baseline may provide a global 41
evaluation of the substrate of AF, inducibility testing immediately after confirmed PVI should 42
reliably exclude the role of the PVs and provide selective information about the extra-PV 43
substrate.
44
We therefore sought 1) to assess the evolution of post-PVI AF inducibility from the first (p1) 45
to the subsequent ablation procedure (p2) in paroxysmal and persistent AF patients with 46
arrhythmia recurrence after catheter ablation, 2) to determine the relationship of post-PVI AF 47
4 inducibility with clinical evolution: arrhythmia recurrence as an organized atrial tachycardia 48
(OAT) versus paroxysmal AF versus persistent AF and 3) to compare these groups (AFr vs 49
OATr and IP vs no IP) with regards to the prevalence of PV reconnection, clinical and 50
echocardiographic characteristics.
51 52
Methods
53
Study population
54A retrospective analysis was performed on all AF patients who underwent a first AF ablation 55
procedure followed by a redo procedure for supraventricular arrhythmia recurrence between 56
2009-2017 at our institution. Written informed consent was obtained for the ablation 57
procedures and for analysis of procedural data. The protocol was approved by the 58
institutional review board.
59
The only exclusion criterion was an incomplete inducibility protocol at p1 or p2, precluding 60
the evaluation of AF inducibility progression.
61
Electrophysiology study and ablation strategy
62All antiarrhythmic drugs were discontinued 5 half-lives before the procedures, except 63
amiodarone which was discontinued for ≥72h. A 10-electrode catheter (2-5-2 mm electrode 64
spacing, St Jude Medical, Saint Paul, MN) was placed with its tip in the distal coronary sinus 65
(CS)/great cardiac vein and all electrodes within the CS so that the tip was placed at 2-4 66
o’clock around the mitral annulus on the left anterior oblique view. Another identical catheter 67
was placed with its base in the high right atrium (RA) and its tip against the anterolateral RA 68
free wall.
69
After trans-septal puncture, stepwise AF ablation was performed in the following order: 1) 70
PVI, 2) fractionated potentials ablation in the CS and great cardiac vein and 3) fractionated 71
potentials ablation in the left atrium (LA) until elimination of fractionation. An irrigated-tip 72
5 ablation catheter (Thermocool SmartTouch, Biosense Webster, Diamond Bar, CA) was used 73
for radiofrequency delivery and a 20-electrode catheter (Lasso, Biosense Webster) for PV 74
mapping. In the absence of “spontaneous” AF termination (during or immediately after 75
ablation), each ablation step was followed by electrical cardioversion. AF inducibility testing 76
was performed in sinus rhythm. The standardized induction protocol consisted of 8-paced 77
beat sequences delivered from the LA appendage or the distal CS with 1-2 ms stimulus 78
duration, 25 mA bipolar output and decremental S1-S1 intervals from 350 ms down to 2:1 79
local capture (or 180 ms) by steps of 10 ms. Inducibility was considered positive when 80
sustained AF > 5 min was induced, in which case the next ablation step in the algorithm was 81
performed. In case of non-inducibility (including induced self-terminating AF < 5 min), the 82
induction protocol was repeated with burst pacing from the RA. When non-inducibility was 83
confirmed, no further ablations were performed, except to complete PVI in the event of early 84
reconnection.
85
Definition of outcomes
86Arrhythmia recurrences were detected by routine post-ablation follow-up, which included 87
periodic clinic visits with 12-lead ECG at 1, 3, 6 and 12 months, 24-hour Holter monitoring at 88
1 and 3 months and exercise testing and transthoracic echocardiography at 3 months.
89
AFr/OATr was defined as ECG-documented AF/OAT or at least 1 AF/OAT episode > 30 90
seconds on Holter recording. All procedures, including p2, were performed for recurrent 91
symptomatic arrhythmia refractory to antiarrhythmic drug therapy and/or electrical 92
cardioversion. PV reconnection was defined as an absence of entry block at PV Lasso 93
mapping.
94
For each patient, AF inducibility, defined as induced sustained AF > 5 min, was assessed 95
after each ablation step (PVI, CS defragmentation and LA defragmentation) of both p1 and 96
p2. Inducibility progression (IP) was defined as the persistence of AF inducibility following a 97
later step of p2 as compared to p1 (Figure 1); for example, AF inducibility post-redo PVI at p2 98
was considered equivalent (same step) to post-PVI inducibility at p1 (e.g. Figure 1, Example 99
6 2). Similarly, in the absence of PV reconnection, inducibility prior to CS lesions at p2, i.e. at 100
baseline, was considered equivalent to post-PVI inducibility at p1. Controls with OATr 101
underwent the same induction protocol following redo PVI or prior to extra-PV AF ablation in 102
the absence of PV reconnection. OAT was defined as sustained regular monomorphic atrial 103
tachyarrhythmia with a fixed reentrant or focal mechanism confirmed at electrophysiology 104
study. Induced sustained OATs were ablated following established approaches4. Inducibility 105
testing was repeated following OAT ablation and termination, until no sustained organized 106
arrhythmia was inducible. In case of induced sustained AF in a patient with clinical OATr, the 107
usual AF ablation algorithm was applied and AF inducibility was assessed stepwise without 108
taking into account previous OAT ablation lesions.
109
Echocardiography
110A transthoracic echocardiogram was performed within 24 hours before each procedure. All 111
recorded video loops were reviewed by one experienced echocardiographer blinded to the 112
study’s objectives and patient outcomes. All measurements were performed off-line using a 113
dedicated software (Xcelera, Philips Medical Systems, Andover, MA). Atrial volumes were 114
calculated using the biplane area-length method for the left atrium and the single plane area- 115
length method for the right atrium in accordance with current guidelines.
116
Statistical analysis
117Continuous variables are expressed as mean (± standard deviation). Categorical variables 118
are expressed as values (percentages). Measures of association are reported as odds ratios 119
(OR, 95% confidence intervals). The Kolmogoroff-Smirnov test was performed to test for 120
normal distribution. Continuous variables were compared using paired and unpaired two- 121
tailed t-test (Welch approximation) if normally distributed and Mann-Whitney U-test in case of 122
non-normal distribution. Categorical variables were compared using Pearson’s Chi-squared 123
test in case of expected frequencies > 5 in all subcategories and the Fischer exact test if not.
124
The primary objective of the study was to assess the association between IP and recurrence 125
7 type (AFr vs OATr). Multivariable logistic regression was used to adjust for possible
126
confounding factors including baseline characteristics, amiodarone therapy and time from p1 127
to p2. Statistical significance was defined at α < 0.05.
128 129
Results
130
Of the 110 patients screened for eligibility, 99 were included in the study. The remaining 11 131
were excluded due to incomplete inducibility testing precluding the evaluation of IP. Out of 27 132
patients with OATr, 19 were assessed for AF inducibility prior to any ablation and 8 were 133
assessed following ablation of a baseline OAT.
134
Baseline clinical characteristics (at time of p1) of the cohort are summarized in Table 1. At 135
p1, 48 (48%) patients presented persistent AF and 51 (52%) paroxysmal AF. Arterial 136
hypertension was more prevalent in patients with AFr compared to OATr: 40 of 72 (55.6%) 137
vs 9 of 27 (33.3%), p=0.049 (univariate analysis not shown in Table 1), and was an 138
independent predictor of AFr when adjusting for other baseline characteristics, IP and 139
amiodarone therapy (Table 1): OR=5.5 (95% CI: 1.1-29.2), p=0.043.
140
Median time from p1 to p2 was 14.3 (IQR 6.3-26.7) months and did not differ significantly 141
between groups: 13.7 (IQR 6.5-26.5) months in paroxysmal AF with AFr, 9.9 (IQR 4.3-26.4) 142
in paroxysmal AF with OATr, 19.3 (IQR 8.7-29.9) in persistent AF with AFr and 9.9 (IQR 4.1- 143
21.0) in persistent AF with OATr, p=0.75.
144
Redo procedural outcomes are reported in Supplemental results.
145
Inducibility progression
146Figure 2 and Supplemental Tables 1-3 show after which step of the stepwise protocol the 147
procedures were terminated due to non-inducibility of AF, at p1 and p2 in each subgroup 148
(AFr vs OATr).
149
8 Of the 99 patients, 36 (36%) exhibited IP from p1 to p2 while 63 did not. IP was more
150
prevalent in patients with AFr compared to OATr (Figure 3A): 34 of 72 (47.2%) vs 2 of 27 151
(7.4%) exhibited IP, respectively, p=0.0002, OR=11.2 (95% CI: 2.5-50.8). The association 152
persisted when adjusting for baseline characteristics as well as for time from p1 to p2 and 153
amiodarone therapy before each procedure: OR=19.1 (95% CI: 3.1-118.4), p=0.002 (Table 154
1). Likewise, a comparable result was found when excluding from analysis the patients with 155
OATr who underwent OAT ablation prior to AF inducibility testing: 34 of 72 (47.2%) patients 156
with AFr vs 2 of 19 (10.5%) patients with OATr presented IP, p=0.004, OR=7.6 (95% CI: 1.6- 157
71.3). Among patients with persistent AF at p1 (N=48), those with clinical recurrence as 158
persistent AF presented IP more often compared to those with recurrence as paroxysmal AF 159
and as OAT (Figure 3B): 19 of 29 (66%), 1 of 4 (25%) and 2 of 15 (13%), respectively, 160
p=0.001. In patients with paroxysmal AF at p1 (N=51), those who progressed to persistent 161
AF at p2 presented more IP compared to those with recurrent paroxysmal AF and those with 162
OAT (Figure 3C): 3 of 3 (100%), 11 of 36 (31%) and 0 of 12 (0%), respectively, p=0.001.
163
Among all AFr (N=72), patients with persistent AF at p1 more frequently exhibited IP than 164
patients with paroxysmal AF at p1: 20 of 33 (61%) vs 14 of 39 (36%) p=0.04.
165
Pulmonary vein reconnection
166PV reconnection (at least 1 PV) was present in 89 of 99 (89.9%) patients: 40 (40.4%) left 167
superior PVs, 70 (70.7%) right superior PVs, 55 (55.6%) right inferior PVs and 35 (35.4%) 168
left inferior PVs. Interestingly, PV reconnection was not more frequent with AFr, as compared 169
to OATr: 65 of 72 (90.3%) patients versus 24 of 27 (88.9%), respectively, p=1.0. See 170
Supplemental results for further analysis.
171
Echocardiographic parameters
172Echocardiographic parameters at p1 and p2 are summarized in Table 2 and Supplemental 173
Table 4. Patients with IP (N=36) exhibited a larger LA volume compared to patients without 174
9 IP (N=63) at both p1 and p2, regardless of the clinical phenotype (Table 2). There were no 175
significant changes in LA volume from p1 to p2 in both groups (p>0.3).
176
Interestingly, patients with IP exhibited a significant RA surface and volume increase from p1 177
to p2 compared to patients without IP (Table 2). The same was true for patients with AFr 178
compared to patients with OATr.
179 180
Discussion
181
The main findings of this study are: 1) an evolution of post-PVI AF inducibility between p1 182
and p2 with progression of inducibility in 36% of all patients, 2) patients with AFr after a first 183
catheter ablation of AF exhibit more frequent progression of post-PVI AF inducibility at redo 184
compared to controls who present for OATr (OR 11.2), 3) IP is associated with a more 185
advanced clinical AFr phenotype (persistent AF vs. paroxysmal AF), 4) in patients with AFr, 186
IP is more prevalent in initially persistent AF patients compared to paroxysmal AF patients, 5) 187
a larger LA volume at baseline is associated with a higher rate of IP, 6) an increase in RA 188
surface and volume during follow-up is associated with both IP and AFr as opposed to OATr, 189
7) arterial hypertension is associated with AFr rather than OATr, and, 8) there was no 190
association between PV reconnection and recurrence phenotype or inducibility phenotype.
191
Pulmonary vein reconnection in arrhythmia recurrence after ablation
192While there is a large body of evidence showing that aiming to achieve complete PVI at de 193
novo AF ablation improves rhythm control5, the determinants and mechanisms of ablation 194
success and arrhythmia recurrence have remained elusive.
195
The present study did not show any association between PV reconnection and arrhythmia 196
recurrence phenotype (OAT, paroxysmal AF or persistent AF). This result is comparable to a 197
recent study6 where 90 patients with arrhythmia recurrence (45 AF, 45 OAT) after AF 198
ablation underwent a clinically indicated repeat procedure. There was no significant 199
10 difference in the rate of PV reconnection between OATr and AFr (75.6% vs. 64.4%
200
respectively, p=0.36). Likewise, studies comparing patients with AFr to patients without 201
arrhythmia recurrence have shown at most a weak association between AFr and PV 202
reconnection2, and some of the larger studies failed to detect any association5,7. 203
Several explanations have been proposed. It is possible that the efficacy of PVI is mediated 204
by the incidental ablation of AF substrate located near the PV ostia including ganglionated 205
plexi and rotors. Another, not mutually exclusive explanation, is that extra-PV triggers and 206
substrate are responsible for a proportion of AFr regardless of PV reconnection status. In the 207
present study, the absence of correlation between PV reconnection and post-PVI IP is 208
compatible with the latter hypothesis, even though we could not exclude insufficient power to 209
detect a weak association.
210 211
Post-PVI AF inducibility progression may indicate extra-PV substrate progression
212The rationale for testing AF non-inducibility by burst-pacing, with positive inducibility defined 213
by a minimum duration of induced AF (> 5 min in this study), is to assess the capacity of the 214
cardiac tissue to maintain and sustain AF. A normal heart should either not sustain AF at all 215
or for a shorter period of time, probably in the order of a few seconds for experimental 216
animals such as goats. Human studies have shown that the majority of patients with healthy 217
hearts do not sustain AF for ≥ 5 minutes8, though the proportions varied with the induction 218
protocol. Therefore, induced sustained AF after stepwise ablation may be related to the 219
presence and extent of residual AF-maintaining substrate and eventually a marker of 220
structural and electrophysiological remodeling. AF inducibility at procedure end has been 221
reported to correlate, though modestly, with AFr following de novo catheter ablation3. In 222
addition, inducibility has been shown to decline with adjunctive ablation beyond PVI9. 223
Inducibility of sustained AF has therefore been used as a procedure endpoint in various 224
stepwise AF ablation protocols9. Finally, recent evidence has suggested that AF non- 225
11 inducibility may be a better indicator of outcome than AF termination10,11. Nevertheless, more 226
data is needed to determine the limits of AF inducibility and sustainability in health and 227
disease and how it relates to clinical outcomes after ablation.
228
The present study shows that AF inducibility after redo-PVI progresses compared to the 229
index procedure in a large proportion of patients with AFr but does so in very few patients 230
with OATr in contrast to PV reconnection. Moreover, the association remains strong when 231
adjusting for baseline characteristics, including AF type (paroxysmal vs persistent) at de 232
novo ablation, time from p1 to p2 and amiodarone therapy. This shows that the recurrence 233
phenotype is associated with a different electrophysiological behavior of extra-PV tissue and 234
not PV reconnection. In addition, the prevalence of IP consistently increases with more 235
advanced recurrence phenotypes (persistent AF > paroxysmal AF > OAT). It is therefore 236
likely that the differences in inducibility are related to differences in the extent and/or 237
importance of extra-PV AF substrate and its progression. In support of this interpretation, IP 238
was associated with a larger LA volume, and the prevalence of hypertension was higher in 239
patients with AFr compared to OATr. Moreover, this study shows that RA surface/volume 240
increases from p1 to p2 in patients with AFr compared to OATr, as well as in patients with IP 241
compared to no IP. This finding suggests that the RA could harbor extra-PV substrate in a 242
significant proportion of patients who exhibit unfavorable arrhythmia outcomes after PVI.
243
Several studies have investigated the progression of extra-PV substrate after ablation using 244
different approaches. LA volume has been reported to decrease following PVI and the effect 245
was more pronounced in patients without recurrence12. Likewise, magnetic resonance 246
imaging (MRI)-based atrial sphericity – a measure of atrial structural remodeling – was 247
associated with AF type and recurrence13. MRI studies have also consistently reported an 248
association between the extent of LA late gadolinium enhancement (LGE) – an established 249
measure of myocardial fibrosis – before ablation and worse post-ablation rhythm outcomes.
250
However, fibrosis progression and its relation with rhythm outcomes and AF inducibility have 251
not been assessed and remain a promising area for further study. Finally, non-PV AF- 252
12 triggering foci have been identified as a predictor of AFr after ablation and were reported to 253
increase in prevalence at redo procedures14. 254
Clinical implications
255The absence of association between PV reconnection and recurrence phenotype adds to the 256
growing evidence supporting the inference that PV reconnection does not play an 257
instrumental role in AFr after ablation in a significant proportion of patients. In contrast, 258
hypertension was associated with an increased risk of recurrent AF, which supports the 259
practice of optimal risk factor control as an adjunctive intervention in rhythm control 260
strategies.
261
In addition, the results support the hypothesis that post-PVI AF inducibility represents a 262
measure of the extra-PV AF-maintaining substrate. Changes in AF inducibility may reflect the 263
evolution of the underlying electrophysiological substrate, which has so far remained difficult 264
to estimate. Therefore, evaluation of AF inducibility after stepwise ablation may provide an 265
efficient procedural endpoint as well as useful prognostic information, which may allow more 266
selective management strategies, including more aggressive risk factor treatment in selected 267
patients. Moreover, our results suggest that the development of stable OAT, typically 268
reentrant atrial tachycardia, correlates with lack of post-PVI inducibility and of substrate 269
progression thus requiring typically limited redo ablation if any for anti-AF efficacy.
270
Finally, the consistent association between the type of arrhythmia at recurrence, IP and RA 271
surface/volume progression may warrant further investigation into the role of RA remodeling 272
and EP substrate in AFr and progression.
273
Study limitations
274This is an observational study in which patients who underwent a clinically indicated redo 275
procedure were retrospectively selected. Therefore, the study population does not include 276
the entire population of patients with arrhythmia recurrence following AF ablation and the 277
results should be interpreted accordingly. Likewise, this study provides no data on patients 278
13 without arrhythmia recurrence. Further studies are required to delineate the causal relations 279
between recurrence phenotype, IP and the observed risk factors.
280
While the prognostic value of non-inducibility after AF ablation has been repeatedly 281
reported(3), the evidence remains conflicting and shows a relatively weak predictability of 282
AFr. Of note, because AF non-inducibility was actively pursued as part of the stepwise 283
ablation strategy, evaluating the prognostic significance of inducibility with respect to 284
arrhythmia recurrence after de novo ablation is beyond the scope of this study. The 5-minute 285
cut-off used to define sustained induced AF, i.e. positive inducibility, represents an arbitrary 286
compromise between practical limitations, sensitivity and specificity. Previous studies have 287
used variable cut-off durations ranging from 10 seconds to 10 minutes. The implications of 288
using different cut-offs and stimulation protocols remain unclear. Therefore, AF inducibility 289
should be interpreted within the context of the induction protocol that was used.
290
It should be noted that the lesion sets performed at p1 versus p2 differ between patients due 291
to the stepwise protocol. However, the same procedure algorithm was applied to all patients 292
included in the study. In addition, potential biases should be mitigated by the analysis of IP, 293
which establishes inducibility at p1 as the baseline for each patient.
294
Finally, the analysis of atrial size is limited by the reliance on echocardiography and the 295
intrinsic limitations of echocardiography should be considered when interpreting the present 296
findings. Interobserver variability was, however, minimized through systematic and blinded 297
review of all images by a single echocardiographer.
298 299
Conclusions
300
Patients with AFr after a first catheter ablation of AF (including PVI) exhibit a progression of 301
immediate post-redo-PVI AF inducibility at the repeat procedure compared to patients who 302
present for OATr without association between PV reconnection and recurrence phenotype.
303
IP is associated with a more severe clinical AFr phenotype and is more prevalent in initially 304
14 persistent AF patients compared to paroxysmal AF patients. A larger LA volume is
305
associated with a higher rate of IP, and arterial hypertension is associated with AFr rather 306
than OATr. RA surface and volume increase are associated with AFr and IP. Changes in 307
post-PVI AF inducibility therefore may reflect the evolution of the underlying extra-PV 308
electrophysiological AF maintaining substrate.
309 310
Funding sources
311
Department of Medicine Scholarship, University Hospital of Geneva.
312
Unrestricted grants to the Cardiology Service from Biosense Webster, Abbott-St Jude, 313
Boston Scientific.
314
Dipen C. Shah is supported by the Swiss National Science Foundation.
315 316
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360 361
Table 1. Baseline characteristics (at first procedure, unless otherwise specified)
All patients
(N=99)
Recurrence phenotype Inducibility phenotype
AF (N=72)
OAT (N=27)
P (adjusted)
IP (N=36)
No IP (N=63)
P (adjusted)
Age (y) 61±11 62±11 60±11 0.3 63±10 60±11 0.3
Male gender 66 (67%) 48 (63%)
18
(78%) 0.6 24
(67%)
42
(67%) 0.5
Persistent AF 48 (48%) 33 (46%)
15
(56%) 0.07 22
(61%)
26
(41%) 0.043*
16 Paroxysmal
AF 51 (52%) 39
(54%)
12 (44%)
14 (39%)
37 (59%)
Comorbidity
Arterial
hypertension 49 (49%) 40
(56%) 9 (33%) 0.043* 21 (58%)
28
(44%) 0.6
Diabetes
mellitus 8 (8%) 5 (7%) 3 (11%) 0.9 2 (6%) 6 (10%) 0.5
Organic heart
disease 19 (19%) 13
(18%) 6 (22%) 0.8 8 (22%) 11
(17%) 0.2
Prior
stroke/TIA 5 (5%) 3 (4%) 2 (7%) 0.3 1 (3%) 4 (6%) 1.0
CHADS2-
VASc score≥2 45 (45%) 34 (47%)
11
(41%) 0.9 18
(50%)
27
(43%) 0.6
LVEF≤50% 19 (19%) 12
(17%) 7 (26%) 0.8 4 (11%) 15
(24%) 0.1
Amiodarone†
at p1 15 (15%) 9 (13%) 6 (22%) 0.4 3 (8%) 12
(19%) 0.3
Amiodarone†
at p2 18 (18%) 11
(15%) 7 (26%) 0.1 8 (22%) 10
(16%) 0.4
Time to p2, months (median, IQR)
14.3(6.3- 26.7)
15.3 (7.5- 28.6)
9.9 (3.9- 26.1) 0.5
20.9 (9.5- 31.1)
10.8 (5.2- 25.1)
0.1
IP 36 (36%) 34
(47%) 2 (7.4%) 0.002* - - -
Recurrent AF 72 (73%)
- - - 34
(94%)
38
(60%) 0.002*
AF denotes atrial fibrillation; IP, inducibility progression; IQR, interquartile range; LA, left atrium; LVEF, left ventricular ejection fraction; OAT, organized atrial tachycardia; p1, first procedure; p2, second procedure; RA, right atrium; TIA, transient ischemic attack.
*Independent predictors (p<0.05).
†AADs other than amiodarone were discontinued 5 half-lives before the procedures and were therefore not included in the model for adjustment.
362 363
17 Table 2. Echocardiographic parameters
All patients
(N=99)
Recurrence phenotype Inducibility phenotype
AF (N=72)
OAT (N=27)
p IP
(N=36)
No IP (N=63)
p
LA volume at
p1 (ml) 79.4±28.0 79.6±28.0 78.7±28.7 0.9 88.3±27.4 73.9±27.1 0.008*
LA volume at
p2 (ml) 77.8±28.4 77.1±27.9 79.9±30.3 0.7 86.7±25.3 72.0±28.9 0.001*
LA volume progression (ml)
-3.2±17.5 -5.2±17.7 3.4±15.3 0.09 -0.4±17.1 -5.0±17.6 0.3
RA volume at
p1 (ml) 69.5±26.2 68.8±27.7 71.6±21.7 0.3 75.9±31.9 65.5±21.2 0.1
RA volume at
p2 (ml) 70.4±31.1 73.9±33.4 59.5±19.7 0.1 84.4±35.1 61.7±25.0 <0.001*
RA volume progression (ml)
1.5±19.9 4.7±19.9 -9.6±16.1 0.002* 7.6±15.6 -2.5±21.5 0.005*
AF denotes atrial fibrillation; IP, inducibility progression; LA, left atrium; OAT, organized atrial tachycardia; p1, first procedure; p2, second procedure; RA, right atrium.
*Significant difference between two groups (p<0.05).
364 365 366 367 368 369 370
18
Figure legends
371
Figure 1. Examples illustrating how inducibility progression was defined. AF inducibility 372
refers to inducible sustained AF lasting > 5 minutes. AF denotes atrial fibrillation; CS, 373
coronary sinus; LA, left atrium; P1, de novo AF ablation; P2, redo-procedure; PVI, pulmonary 374
vein isolation.
375
Figure 2. Sankey diagram showing the procedure step after which AF non-inducibility was 376
achieved at procedure 1 (p1) and 2 (p2). Band width is proportional to the number of patients 377
in each trajectory (indicated on the sides); red indicates inducibility progression. For the 378
purpose of this graph, the 6 patients who did not undergo additional AF-directed ablation 379
despite AF inducibility were classified as non-inducible after the next (virtual) ablation step 380
and are indicated by obelisks (†).
381
Figure 3. Proportion of patients exhibiting IP from de novo AF ablation (N=99) to repeat 382
procedure for AFr vs OATr (A). Proportion of patients exhibiting IP from de novo persistent 383
AF ablation (N=48) (B) or de novo paroxysmal AF ablation (N=51) (C) to repeat procedure 384
for persistent AF vs paroxysmal AF vs OAT. Error bars indicate 95% CI. AF denotes atrial 385
fibrillation; CI, confidence interval; IP, inducibility progression; OAT, organized atrial 386
tachycardia.
387 388 389 390 391 392 393 394
19 Figure 1.
395
396 397
Figure 2 398
399
20 400
Figure 3.
401
402
1
Supplemental Material
Evolution of Post-Pulmonary Vein Isolation Atrial Fibrillation Inducibility at Redo Ablation: Electrophysiological Evidence of extra-PV substrate Progression
Authors: Nicolas Johner1*, MD, Dipen C. Shah1*, MD, FHRS, Georgios Giannakopoulos1, MD, Anne Girardet2, MD, Mehdi Namdar1, MD, PhD.
*Both authors contributed equally as first authors.
Affiliations: 1. Cardiology Division, Geneva University Hospitals, Geneva, Switzerland. 2.
Pediatrics Division, Geneva University Hospitals, Geneva, Switzerland.
Correspondence: Prof. Dipen C. Shah, Cardiology Division, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland.
Tel: +41-223727202. Fax: +41-223727229. Email: dipen.shah@hcuge.ch
2
Supplemental results
Antiarrhythmic drug therapy before procedure 1 and 2
Beside amiodarone (Table 1), anti-arrhythmic drug therapy and rate-control medication, which were discontinued 5 half-lives before the procedures, included, before p1, flecainide in 19/99 (19%) patients, sotalol in 5/99 (5%), dronedarone in 2/99 (2%), beta-blocker in 50/99 (51%), non-dihydropyridin calcium channel blocker in 9/99 (9%), and digoxin in 3/99 (3%);
before p2, medication included flecainide in 13/99 (13%) patients, sotalol in 4/99 (4%), propafenone in 1/99 (1%), beta-blocker in 69/99 (70%), non-dihydropyridin calcium channel blocker in 11/99 (11%), and digoxin in 9/99 (9%).
Electroanatomical mapping
Electroanatomical mapping (CARTO system, Biosense Webster or Rhythmia mapping system, Boston Scientific, Marlborough, MA) was used in 21/99 (21%) patients at p1. At p2, electroanatomical mapping was used in 47/99 (47%) patients, including 21/27 (78%) OATr and 26/72 (36%) AFr.
PV reconnection
Subdivision into recurrent AF type did not show any difference in the prevalence of PV reconnection: 88.9% vs 95.0% vs 84.4% PV reconnection in recurrent OAT, paroxysmal AF and persistent AF, respectively, p=0.3. Likewise, there was no difference in IP prevalence between patients with and without PV reconnection: 32 of 89 (36.0%) versus 4 of 10 (40%), respectively, p=1.0. The same was true when considering the number of reconnected PVs in each patient: average 2.1±1.2 vs 2.0±1.1 reconnected PVs (p=0.8) in patients with IP vs without IP, respectively, and 2.0±1.1 vs 2.1±1.1 (p=0.7) reconnected PVs in patients with recurrent AF vs recurrent OAT, respectively.
3 Among 65 recurrent AF patients with PV reconnection, 22 (34%) progressed from non-
inducible AF post-PVI to inducible AF post-redo PVI, in contrast with 0 of 27 (0%) patients with OATr (p=0.001) but similarly to 3 of 7 (43%) patients with AFr without PV reconnection (p=0.7).
Redo ablation procedural outcomes
Out of 72 patients with AFr, 23 (32%) had persistently inducible sustained AF at redo procedure end (of which 2 underwent only redo-PVI and 2 stopped at CS defragmentation);
26 (36%) exhibited AF non-inducibility following redo-PVI (of which 3 had inducible OAT), 9 (13%) had AF non-inducibility following CS defragmentation, 14 (19%) had AF non-
inducibility following LA defragmentation (of which 1 had inducible OAT).
In 27 patients with OATr, a total of 53 different OATs were observed, representing an average 2.0±1.4 different OATs per patient, 94% of which were macroreentries and 6% had a focal mechanism; 48 (91%) were left atrial, 4 (7%) were CTI-dependent typical atrial flutter, and 1 (2%) originated from the superior vena cava. LA OATs whose circuit anatomy was delineated (N=23) were most commonly locally reentrant around PV ostia (26%), followed by perimitral (17%), roof-dependent (17%), and dual-loop with one perimitral loop and one roof- dependent loop (9%). Other mechanisms included focal atrial tachycardia (13%), local reentry involving endo-epicardial CS connections (9%) and septal reentry (9%).
On the 53 identified OATs, ablation at narrowest accessible isthmus confirmed/identified by entrainment mapping resulted in termination to sinus rhythm in 23 (43%); 9 (17%) were ablated in sinus rhythm and were subsequently non-inducible, 8 (15%) ablations resulted in a change of activation sequence, 5 (9%) had no detectable effect, 2 (4%) resulted in a cycle length increase > 20 ms. Six of the 53 identified OATs (11%) were not ablated due to incomplete mapping followed by failure to re-induce the arrhythmia after spontaneous termination, or location of the isthmus at the AV node region. Of the 27 patients with OATr,
4 final rhythm outcome at procedure end was sinus rhythm with no inducible arrhythmia in 20 (74%), residual inducibility of 1 or more OAT(s) in 6 (22%) and residual inducibility of AF following successful ablation of OAT and AF-directed ablations in 1 (4%).
Supplemental tables
(below)
5 Supplemental Table 1. Ablation targets at p1 and p2, by recurrence and IP group.
Recurrence phenotype Inducibility phenotype Procedure 1 All patients
(N=99)
AF recurrence (N=72)
OAT recurrence (N=27)
IP (N=36)
No IP (N=63)
AF ablation
PVI only 56 (57%) 46 (64%) 10 (37%) 24 (67%) 32 (51%)
PVI + CS only 10 (10%) 8 (11%) 2 (7%) 6 (17%) 4 (6%)
PVI + CS + LA 33 (33%) 18 (25%) 15 (56%) 6 (17%) 27 (43%)
Other arrhythmias targeted
CTI 33 (33%) 27 (38%) 6 (22%) 13 (36%) 20 (32%)
Non-CTI-dependent left atrial flutter
1 (1%) 1 (1%) 0 (0%) 1 (3%) 0 (0%)
Non-CTI-dependent right atrial flutter
2 (2%) 2 (3%) 0 (0%) 2 (6%) 0 (0%)
Left focal AT/PAC 2 (2%) 0 (0%) 2 (7%) 0 (0%) 2 (3%)
Right focal AT/PAC 1 (1%) 1 (1%) 0 (%) 1 (3%) 0 (0%)
Procedure 2 All patients (N=99)
AF recurrence (N=72)
OAT recurrence (N=27)
IP (N=36)
No IP (N=63)
AF ablation
Redo-PVI only 51 (52%) 28 (39%) 23 (85%) 2 (6%) 49 (78%)
PVI + CS only 13 (13%) 11 (15%) 2 (7%) 10 (28%) 3 (5%)
PVI + CS + LA 35 (35%) 33 (46%) 2 (7%) 24 (67%) 11 (17%)
Other arrhythmias targeted
CTI 22 (22%) 18 (25%) 4 (15%) 8 (22%) 14 (22%)
Non-CTI-dependent left atrial flutter
33 (33%) 10 (14%) 23 (85%) 5 (14%) 28 (44%)
Non-CTI-dependent right atrial flutter
2 (2%) 2 (3%) 0 (0%) 1 (3%) 1 (2%)
Left focal AT/PAC 6 (6%) 3 (4%) 3 (11%) 2 (6%) 4 (6%)
Right focal AT/PAC 2 (2%) 1 (1%) 1 (4%) 0 (0%) 2 (3%)
AF denotes atrial fibrillation; AT, atrial tachycardia; CTI, cavotricuspid isthmus; IP, inducibility progression; LA, left atrium; OAT, organized atrial tachycardia; PAC, premature atrial complex;
PVI, pulmonary vein isolation.
6 Supplemental Table 2. Stepwise AF inducibility at p1 and p2, by recurrence and IP group.
Recurrence phenotype Inducibility phenotype Procedure 1 All patients AF recurrence OAT recurrence IP No IP AF at baseline 52/99 (53%) 38/72 (53%) 14/27 (52%) 25/36 (69%) 27/63 (43%) ST during/after PVI 9/52 (17%) 6/38 (16%) 3/14 (21%) 3/25 (12%) 6/27 (22%) Sustained induced
AF after PVI 44/99 (44%) 27/72 (38%)† 17/27 (63%) 12/36 (33%) 32/63 (51%)† ST during/after CS
defragmentation 8/43 (19%) 2/26 (8%) 6/17 (35%) 2/12 (17%) 6/31 (19%)
Sustained induced
AF after CS 34/43 (79%) 19/26 (73%)‡ 15/17 (88%) 6/12 (50%) 28/31 (90%)‡
ST during/after LA
defragmentation 9/33 (27%) 5/18 (28%) 4/15 (27%) 2/6 (33%) 7/27 (26%)
Sustained induced
AF after LA 15/33 (45%) 9/18 (50%) 6/15 (40%) 0/6 (0%) 15/27 (56%)
Procedure 2 All patients AF recurrence OAT recurrence IP No IP AF at baseline 29/99 (29%) 29/72 (40%) 0/27 (0%) 18/36 (50%) 11/63 (17%) ST during/after redo-
PVI 1/29 (3%) 1/29 (3%) 0/0 0/18 (0%) 1/11 (9%)
Sustained induced
AF after redo-PVI 50/99 (51%) 46/72 (64%)§ 4/27 (15%) 36/36 (100%)§ 14/63 (22%) ST during/after CS
defragmentation 6/48 (13%) 6/44 (14%) 0/4 (0%) 4/34 (12%) 2/14 (14%)
Sustained induced
AF after CS 37/48 (77%) 35/44 (80%)¶ 2/4 (50%) 26/34 (76%)¶ 11/14 (79%)
ST during/after LA
defragmentation 2/35 (6%) 2/33 (6%) 0/2 (0%) 2/24 (8%) 0/11 (0%)
Sustained induced
AF after LA 20/35 (57%) 19/33 (58%) 1/2 (50%) 17/24 (71%) 3/11 (27%)
ST denotes spontaneous termination.
†1 of which did not undergo CS/LA defragmentation.
‡1 of which did not undergo LA defragmentation.
§2 of which did not undergo CS/LA defragmentation.
¶2 of which did not undergo LA defragmentation.
7 Supplemental Table 3. Time from p1 to p2 by procedure type.
Procedure 1 Number of patients Time from p1 to p2, median (IQR) AF ablation
PVI only N=56 13.3 (6.5-25.6)
PVI + CS only N=10 24.0 (13.3-29.8)
PVI + CS + LA N=33 14.0 (4.8-25.3)
Other arrhythmias targeted
CTI N=33 15.8 (7.8-26.1)
Non-CTI-dependent left atrial flutter N=1 21.9
Non-CTI-dependent right atrial flutter N=2 40.5 (7.2-73.9)
Left focal AT/PAC N=2 27.1 (9.9-44.2)
Right focal AT/PAC N=1 69.4
Procedure 2 Number of patients Time from p1 to p2 (median, IQR) AF ablation
Redo-PVI only N=51 9.3 (4.4-20.0)
PVI + CS only N=13 13.0 (5.5-24.8)
PVI + CS + LA N=35 24.6 (13.3-41.5)
Other arrhythmias targeted
CTI N=22 15.7 (6.6-24.8)
Non-CTI-dependent left atrial flutter N=33 9.9 (3.9-24.6)
Non-CTI-dependent right atrial flutter N=2 46.6 (19.3-73.9)
Left focal AT/PAC N=6 33.2 (9.9-46.5)
Right focal AT/PAC N=2 17.1 (4.4-29.8)
AF denotes atrial fibrillation; AT, atrial tachycardia; CTI, cavotricuspid isthmus; progression; LA, left atrium; PAC, premature atrial complex; PVI, pulmonary vein isolation.
8 Supplemental Table 4. Left and right atrial surface
All patients
(N=99)
Recurrence phenotype Inducibility phenotype
AF (N=72)
OAT (N=27)
p IP
(N=36)
No IP (N=63)
p
LA surface at
p1 (cm2) 23.2±5.3 23.3±5.2 23.0±5.7 0.8 24.0±4.4 22.7±5.7 0.1
LA surface at
p2 (cm2) 23.5±6.2 23.0±5.7 25.1±7.4 0.2 24.9±5.3 22.6±6.5 0.02*
LA surface progression (cm2)
0.05±3.5 -0.3±3.3 1.2±3.9 0.2 1.1±3.4 -0.7±3.4 0.01*
RA surface at
p1 (cm2) 21.4±4.8 21.2±5.1 21.8±4.2 0.4 22.7±5.8 20.5±4.0 0.08
RA surface at
p2 (cm2) 21.2±5.7 21.6±6.2 20.0±4.2 0.4 23.8±6.2 19.6±4.9 <0.001*
RA surface progression (cm2)
0.4±6.1 0.7±5.7 -0.6±7.3 0.048* 1.7±4.6 -0.4±6.7 0.005*
AF denotes atrial fibrillation; IP, inducibility progression from first to second procedure; LA, left atrium;
OAT, organized atrial tachycardia; p1, first procedure; p2, second procedure; RA, right atrium.
*Significant difference between two groups (p<0.05).
