Department of Engineering
Biomedical Engineering Group
University Road, Leicester LE1 7RH, England, UK
Tel: +44 (0)116 252 5053
Fax: +44 (0)116 252 2619
Email: [email protected]
Dr. Fernando S. Schlindwein BEng, MSc, CEng, PhD, DSc
Reader in Biomedical Engineering
Professor Nitish Thakor,
Editor-in-Chief
Medical & Biological Engineering & Computing
16 May 2017
Dear Professor Thakor,
Thank you for considering our work “The temporal behavior and consistency of bipolar
atrial electrograms in human persistent atrial fibrillation” suitable for publication at
Medical & Biological Engineering & Computing upon minor corrections. The valuable
comments from the referees certainly helped to improve the quality of the work. We are
thankful for their comments and positive feedback. We believe we have addressed all the
points raised by the reviewers and, as a result, we made the amendments in the manuscript
following the referees’ considerations.
We hope that, after these changes, the editorial board and reviewers will agree that this study
contributes to our understanding of CFAE-guided AF ablation that will be of significant
interest to your readers. Please find below our considerations regarding each of the referees’
comments and actions taken.
We look forward to hearing from you at your earliest convenience.
Yours sincerely,
Dr. Fernando S. Schlindwein
BEng, MSc, CEng, PhD, DSc
Reader in Biomedical Engineering
Biomedical Engineering Group
Department of Engineering, University of Leicester
We would like to thank the reviewers for their comments and suggestions, for highlighting
the important points discussed below, and for the valuable suggestions in addressing those in
the manuscript. We believe the amendments incorporated into the manuscript address all the
suggestions and we hope the revised manuscript is now acceptable for publication in Medical
& Biological Engineering & Computing.
Addressing the comments from Reviewer #1:
Reviewer #1: A very well analysed and compiled article. There is a focused question,
which is adequately answered. There have been so many approaches to ablation of
persistent A Fib- no standardisation, widely varying results, high recurrences (which
get higher over time).
Hence this article showing the fallacy of using short time intervals for CFAE is useful in
this regard.
AUTHORS: Thank you for the positive feedback and opinion that the study is well analysed
and compiled. We are glad that the reviewer agrees that this is a controversial topic, and that
we managed to convey the message properly.
Addressing the comments from Reviewer #2:
Reviewer #2: This manuscript presents a quantitative study on the AEG behaviors in
different window sizes and consecutive segments in a window from 18 patients with
persistent AF. The findings showed that the currently accepted 2.5s window size for
CARTO criteria would not be long enough for optimal results. The work has certain
clinical significance.
AUTHORS: Thank you for your feedback and opinion that the study is clinically relevant.
Reviewer #2: How were the total 797 AEGs, p.4, distributed among those 18 patients?
Had each patient contributed about the same amount AEGs recordings, or some
patients contributed much more and some others did much less?
AUTHORS: The authors are grateful for the opportunity to give more details about this
relevant point. Although two of the patients (8 and 10) had had more AEGs collected than the
others, each of the remaining patients accounts for a similar number of AEGs used in this
study, as shown on the table below. We feel that the AEGs collected provide a good and
balanced representation of the population in this study. In addition, the AEGs have been
collected in different anatomical sites, as illustrated in Figure 4D, which provides a thorough
description of the left atrium. This discussion and the table shown below have been included
in the “Methods” section:
Pre-ablation Post-ablation
Total
# (%)
# (%)
# (%)
Patient 1
17 (4%)
11 (3%)
28 (4%)
Patient 2
21 (5%)
17 (5%)
38 (5%)
Patient 3
17 (4%)
9 (3%)
26 (3%)
Patient 4
18 (4%)
12 (4%)
30 (4%)
Patient 5
34 (7%)
28 (8%)
62 (8%)
Patient 6
24 (5%)
16 (5%)
40 (5%)
Patient 7
28 (6%)
20 (6%)
48 (6%)
Patient 8
49 (11%)
54 (16%)
103 (13%)
Patient 9
26 (6%)
22 (6%)
48 (6%)
Patient 10
53 (12%)
31 (9%)
84 (11%)
Patient 11
19 (4%)
12 (4%)
31 (4%)
Patient 12
15 (3%)
12 (4%)
27 (3%)
Patient 13
27 (6%)
20 (6%)
47 (6%)
Patient 14
15 (3%)
7 (2%)
22 (3%)
Patient 15
33 (7%)
20 (6%)
53 (7%)
Patient 16
16 (4%)
15 (4%)
31 (4%)
Patient 17
16 (4%)
16 (5%)
32 (4%)
Patient 18
27 (6%)
20 (6%)
47 (6%)
Total
455
342
797
Reviewer #2: The limitation of the study should include that the patient sample size (18)
is small.
AUTHORS: We agree with the reviewer that this study involved a small number of patients,
and that additional points would help to validate the results. However, as the main objective
of this study was to investigate the spatio-temporal behavior of AEGs according the CARTO
criteria during persAF, we do believe that this limitation is partially overcome considering
that the number of points collected from the 18 patients, providing information from a
balanced distribution of different LA anatomical sites, as illustrated in Figure 4D. Further
studies with a more representative population needs to be performed to consolidate which
measurement is better or can get better ablation outcome.
This discussion has been included in the “Limitation” section, as suggested by the reviewer.
Reviewer #2: Another limitation of the study is that the AEG recording (duration) was
limited to 8s as maximum by the existing device(s). The conclusion (which although has
some clinical significance) from this study is light, as it was only found that the AEG
recording (analyzing) duration should be longer than 2.5s; but what would be the
optimal duration? Would the optimal duration be possibly longer than 8s? If these
questions can be answered, the significance of the study would be much greater.
AUTHORS: We acknowledge that, from the nature of the proposed study design, it is
challenging to infer about the optimal AEG duration for CFAE classification. As mentioned
by the reviewer, we were limited to 8 seconds as maximum AEG duration by the existing
devices. Naturally, longer AEG recording durations would facilitate the investigation of the
‘optimum’ segment length for proper CFAE classification. Unfortunately, few – if none –
devices permit such analysis, and we believe that the results found in the present work are
relevant and timely, as they can be applied with the technology currently available.
With regard to the estimation of the ‘optimal duration’, our results show both (i) how fast the
behavior based on the CARTO criteria changes - the best fit exponential shown in Figure 4C,
with a time constant of 2.8 s and (ii) how fast the results of the attributes (ICL, ACI, SCI)
converge, as shown in Figure 5B. Both results support the conclusion that AEG recording
durations longer than 2.5 s should be used for CFAE classification using the CARTO criteria.
Furthermore, the convergence of the parameters with increasing time shown in Figure 5B
indicates that 5 s long segments already produce results that are quite similar to those
obtained using 8 s. We had intended to leave for the reader to judge what is ‘optimal’, but, as
we were kindly invited by the referee to expand on this – for which we are thankful – we are
suggesting that 5 s is sufficient and 7.5 s is close to the ‘optimum’. Further studies should be
conducted to verify our results that CFAE maps using the CARTO criteria with longer
recording durations correspond to fibrosis area estimated from image analysis, such as late
gadolinium enhancement of LA in magnetic resonance imaging, as we had already suggested
in the “Limitations” section.
The above discussion has been included in the manuscript. In the “Discussion” section, the
following discussion was included:
“Our results show both (i) how fast the behavior based on the CARTO criteria changes – the
best fit exponential shown in Figure 4C, with a time constant of 2.8 s – and (ii) how fast the
results of the attributes (ICL, ACI, SCI) converge, as shown in Figure 5B. Both results
support the conclusion that AEG recording durations longer than 2.5 s should be used for
CFAE classification using the CARTO criteria. Although it can be challenging to infer what
is ‘optimal’, we would suggest that 5 s is sufficient and 7.5 s is close to the ‘optimum’
duration for analysis based on the results shown in Figure 5B.”
The following paragraph was added in the “Limitations” section.
“We acknowledge that, from the nature of the proposed study design, it is challenging to infer
about the optimal AEG duration for CFAE classification. In the present study, the maximum
AEG duration was limited to 8 s by the existing devices. Naturally, longer AEG recording
durations would facilitate the investigation of the ‘optimum’ segment length for proper CFAE
classification. Unfortunately, few – if none – devices permit such analysis, and the results
found in the present work are relevant and timely, as they can be applied with the technology
currently available.”
Addressing the comments from Reviewer #4:
Reviewer #4: The structure and content of the paper are correct, being only necessary a
minor change: paragraphs of the paper should be aligned to both sides (left and right).
AUTHORS: We appreciate the positive feedback. The manuscript has been justified, and the
text is now evenly distributed between the margins.