Skip to main content
NCBI home page
PLOS One logoLink to PLOS One
. 2020 Feb 19;15(2):e0228731. doi: 10.1371/journal.pone.0228731

Differences in right-to-left vs left-to-right interventricular conduction times in patients indicated to cardiac resynchronization therapy

David Pospisil 1,2,, Tomas Novotny 1,2,#, Jiri Jarkovsky 3,#, Barbora Farkasova 1,2,#, Milan Kozak 1,2, Lubomir Krivan 1,2, Jitka Vlasinova 1,2, Petr Kala 1,2, Milan Sepsi 1,2,*,#
Editor: Giuseppe Coppola4
PMCID: PMC7029862  PMID: 32074118

Abstract

Introduction

Differences in conduction times from right ventricle to left ventricle and from left ventricle to right ventricle respectively were observed during biventricular devices implantation when changing pacing vector direction. In this article the phenomenon of interventricular conduction time differences is described and assessed in relationship to various clinical and electrophysiological parameters.

Methods

In 62 consecutive patients (9 females) interventricular conduction times between right and left ventricle in both directions were measured during cardiac resynchronization therapy device implantation procedure. Complex pacing protocol was performed.

Results

Investigated individuals was divided into 3 subgroups according to type of interventricular conduction pattern and statistically tested with various clinical data. Substantial differences in right-to-left vs left-to-right conduction times (> 5 ms, range 7–72 ms) were observed in 24 (39%) of all patients. They were more common in patients with dilated cardiomyopathy (20 of 38, 53%) compared to 4 (17%) of 24 patients with coronary artery disease (p = 0.011). The phenomenon occurred more often in hypertensive patients (p = 0.012). Other tested factors were nonsignificant.

Conclusions

There are almost no data on this topic. The occurrence of conduction difference phenomenon is quite common in dilated cardiomyopathy while it is rare in coronary artery disease. We assume the diffuse nature of the disease and the way of remodeling of myocardium play the main role. Knowledge of this phenomenon could be useful in personalized cardiac resynchronization therapy optimization.

Introduction

There are series of unanswered questions in the field of cardiac resynchronization therapy and various known approaches how to describe interventricular conduction delays. Interventricular conduction delay (IVCD) is a descriptor of interventricular electrical dyssynchrony between right ventricle (RV) and left ventricle (LV). It is measured between pacing lead in RV and sensing lead in LV. There are studies which found direct proportional relationship between measure of IVCD and reverse remodeling [1] or responsiveness to CRT (2).

Differences in conduction times from right ventricle to left ventricle and from left ventricle to right ventricle respectively were observed by our group during biventricular devices implantation. In this paper we show detailed description of this phenomenon and its relationship to various clinical factors.

Materials and methods

The investigated group consisted of individuals who fulfilled indication criteria to CRT system implantation according to ESC Guidelines. All of them signed informed consents and agreed with CRT implantation and periprocedural pacing protocol.

Implantation procedure

As usually, right atrial (RA) bipolar lead was implanted into the appendage. Right ventricular (RV) bipolar lead was placed in RV apex or septum according to physician’s decision. Left ventricular (LV) quadripolar (rarely bipolar) lead was implanted preferably in lateral or posterolateral position. The final decision of its placement resulted from several parameters evaluation—acceptable R wave voltage, pacing threshold and good vein anchorage position with no phrenic nerve stimulation tested at maximum output (10 V).

Conduction measurement protocol

All measurements were done using Biotronik ICS 3000 Operation / Implant module (Biotronik GmbH & Co.KG Berlin Germany). Conduction times were measured automatically using “Conduction times” tool integrated into the ICS 3000 Pacing System Module application.

Pacing vectors between RV and LV leads were tested and conduction times measured. We used bipolar mode only. In case of using quadripolar LV lead it meant to pace RV and to measure conduction times in LV lead—bipolarly coupled proximal & middle proximal, middle proximal & middle distal and middle distal & rings consecutively. Then LV lead was paced and conduction to RV lead measured. The following LV quadrupolar lead couples were paced consecutively: proximal & middle proximal, middle proximal & middle distal and middle distal & distal ring. Thus, using a quadrupolar electrode it was possible to create 6 unique vectors compared to only two when using a bipolar electrode.

Measurement protocol was divided into four parts:

  1. To assess dependency of particular pacing rings location to interventricular conduction time all above mentioned vectors were tested.

  2. To rule out voltage dependency of interventricular conduction times an incremental voltage test was performed. Pacing pulse width was set to 0.4 ms. Lowest pacing voltage was rounded to the closest upper whole number value over recently measured pacing threshold, then increased with 1 V steps up to 10 V. Pacing rate was set to 90 BPM to avoid intrinsic activation. Each pacing phase was long enough to reach stable interventricular conduction times.

  3. To assess the influence of pacing rate on interventricular conduction time duration an incremental pacing test was performed. Pacing was started at heart rate equivalent to the closest upper ten of the intrinsic heart rate and then increased in 10 BPM steps up to 140 BPM. Pacing voltage in the test was set to double value of pacing threshold. Each pacing phase was long enough to reach stable interventricular conduction times.

  4. To assess interventricular conduction during natural ventricular activation the atrial lead was paced incrementally. Initial pacing rate was equal to intrinsic heart rate rounded up to the closest ten. Pacing rate was then increased by 10 BPM steps up to 140 BPM or reaching the Wenckebach point. Pacing voltage in the test was set to double value of pacing threshold. Each pacing phase was long enough to reach stable interventricular conduction times. Conduction times to both ventricular leads were measured during atrial pacing. Interventricular conduction time differences at particular pacing rates were computed.

An average value was computed from at least five consecutive conduction times.

Statistical analysis

Numerical data are presented as mean ± standard deviation. Fisher’s exact test was used for categorical variables and Mann/Whitney test for continuous variables (alpha = 0.05). Statistical software used: IBM SPSS 25.0.0.1 (IBM Corporation, 2018). For analysis, subjects group was divided to three parts based on computed difference value. Group “RV→LV≈LV→RV”–bidirectionally comparable conduction with differences ≤ ±5 ms (n = 39). Group “RV→LV>LV→RV”–negative difference value—faster conduction from the left ventricle to the right ventricle (n = 12) and Group “RV→LV<LV→RV”—positive difference value—faster conduction from the right ventricle to the left ventricle (n = 11).

Together with meeting requirements of Helsinki’s declaration the Ethics committee of Brno University Hospital and Masaryk University approved the project design and related patient informed consent.

Results

In the period from February 2015 to March 2017 sixty-two patients (9 females, 15%), were recruited. Clinical characteristics are shown in Table 1.

Table 1. Characteristics of investigated group.

RV→LV ≈ LV→RV RV→LV > LV→RV RV→LV < LV→RV p-value
(N = 39) (N = 12) (N = 11)
Gender—N (%)
Females 5 (12.8%) 2 (16.7%) 2 (18.2%) 0,883
Males 34 (87.2%) 10 (83.3%) 9 (81.8%)
Age—mean (± SD) 66 ±9 62 ±9 62 ±8 0,708
Ejection fraction—mean (± SD) (%) Median (5–95 percentile) 27.4 ± 4.9; 30.0 (20.0; 35.0) 28.3 ± 6.3; 30.0 (17.0; 35.0) 28.6 ± 6.7; 30.0 (15.0; 35.0) 0,535
NYHA Class—N (%)
I 1 (2.6%) 1 (8.3%) 0 (0.0%) 0,658
II 15 (38.5%) 6 (50.0%) 4 (36.4%)
III 23 (59.0%) 5 (41.7%) 7 (63.6%)
IV 0 (0.0%) 0 (0.0%) 0 (0.0%)
Etiology—N (%)
DCM 19 (48.7%) 11 (91.7%) 8 (72.7%) 0,011
ICM 20 (51.3%) 1 (8.3%) 3 (27.3%)
Rhythm at implantation—N (%)
Sinus rhythm 38 (97.4%) 8 (66.7%) 10 (90.9%) 0,060
Atrial fibrillation 1 (2.6%) 3 (25.0%) 1 (9.1%)
Ventricular escape rhythm 0 (0.0%) 1 (8.3%) 0 (0.0%)
QRS complex duration—mean (± SD) (%) Median (5–95 percentile) 146.2 ± 22.0; 150.0 (90.0; 172.0) 153.8 ± 20.8; 150.0 (110.0; 195.0) 152.1 ± 14.3; 155.0 (120.0; 175.0) 0,796
Type of bundle branch block—N (%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
RBBB 4 (10.3%) 0 (0.0%) 1 (9.1%) 0,516
LBBB 34 (87.2%) 12 (100.0%) 10 (90.9%)
Other 1 (2.6%) 0 (0.0%) 0 (0.0%)
Position of lead in right ventricle—N (%)
Apex 17 (43.6%) 6 (50.0%) 2 (18.2%) 0,210
Septum 22 (56.4%) 6 (50.0%) 9 (81.8%)
Position of lead in left ventricle—N (%)
Anterior 3 (7.7%) 0 (0.0%) 0 (0.0%) 0,099
Lateral 30 (76.9%) 6 (50.0%) 8 (72.7%)
Posterolateral 6 (15.4%) 6 (50.0%) 3 (27.3%)
Hypertension—N (%) 29 (74.4%) 6 (50.0%) 3 (27.3%) 0,012
Diabetes mellitus—N (%) 11 (28.2%) 4 (33.3%) 1 (9.1%) 0,297
Hyperlipoproteinemia—N (%) 19 (48.7%) 4 (33.3%) 4 (36.4%) 0,555
Vascular brain disease—N (%) 3 (7.7%) 0 (0.0%) 0 (0.0%) 0,238
Ischemic disease of lower extremities—N (%) 1 (2.6%) 0 (0.0%) 0 (0.0%) 0,626
Chronic renal insufficiency—N (%) 8 (20.5%) 2 (16.7%) 0 (0.0%) 0,111
Chronic hepatopathy—N (%) 2 (5.1%) 1 (8.3%) 0 (0.0%) 0,506
Chronic obstructive pulmonary disease—N (%) 2 (5.1%) 0 (0.0%) 0 (0.0%) 0,388
Open in a new tab

P value—statistical significance of differences among investigated groups; Fisher's exact test for categorical variables, Mann-Whitney test for continuous variables (alpha = 0.05). Group “RV→LV≈LV→RV”–bidirectionally comparable conduction with differences ≤ ±5 ms; Group “RV→LV>LV→RV”–faster conduction from the left ventricle to the right ventricle; Group “RV→LV<LV→RV”–faster conduction from the right ventricle to the left ventricle; SD—Standard Deviation; NYHA—New York Heart Association; DCM—Dilated cardiomyopathy; CAD—Coronary Artery Disease; RBBB—Right bundle branch block; LBBB—Left bundle branch block;

The patients were divided into 3 subgroups based on interventricular conduction times difference values. Fig 1 shows values of interventricular conduction times difference and its distribution in the study population.

Fig 1. Differences in interventricular conduction times sorted by differences value (whole study group N = 62).

Fig 1

Open in a new tab

Dashed line define group borders: Group RV→LV≈LV→RV—bidirectionally comparable conduction with differences ≤ ±5 ms (n = 39). Group RV→LV>LV→RV—negative difference value—faster conduction from the left ventricle to the right ventricle (n = 12) and Group RV→LV<LV→RV—positive difference value—faster conduction from the right ventricle to the left ventricle (n = 11). * Conduction time difference was -72 ms.

The conductions were considered as similar if differences were ≤ ±5 ms (n = 39)–the Group “RV→LV = LV→RV”. Faster conduction from the left ventricle to the right ventricle–(the Group “RV→LV>LV→RV”) was observed in 12 patients and absolute values of interventricular conduction differences ranged from 7 to 72 ms. Faster conduction from the right ventricle to the left ventricle–(the Group “RV→LV<LV→RV”) was observed in 11 patients and absolute values of interventricular conduction differences ranged from 6 to 32 ms.

In Fig 2 similar data are shown separately for patients with dilated cardiomyopathy (DCM, n = 38) and coronary artery disease (CAD, n = 24) etiology of heart failure.

Fig 2.

Fig 2

Open in a new tab

Panel A: Interventricular conduction time differences in patients sorted by its value in DCM (N = 38) group. Dashed line defines DCM subgroup borders. See Fig 1 for groups definitions. DCM patients belongs to: Group RV→LV≈LV→RV (N = 19), group RV→LV>LV→RV (N = 11), group RV→LV<LV→RV (N = 8). Panel B: Interventricular conduction time differences in patients sorted by its value in CAD (N = 24) group. Dashed line defines CAD subgroup borders. CAD patients belongs to: Group RV→LV≈LV→RV (N = 20), group RV→LV>LV→RV (N = 1), group RV→LV<LV→RV (N = 3).

Interventricular conduction differences were significantly higher in DCM subgroup compared to CAD subgroup (11 ±13 ms vs 3 ± 4 ms, p = 0.01). If difference up to 5 ms was considered normal, then marked conduction difference was observed in 20 (53%) of 38 patients with DCM vs 4 (17%) of 24 patients with CAD. Presence of interventricular conduction difference is statistically significantly related to cardiomyopathy etiology (p = 0.011).

Hypertension was more common in the Group A compared to B and C (74.4% vs 50% and 27.3%, p = 0.012).

Relationships to other clinical parameters (including QRS duration, ejection fraction or bundle branch block type) were not statistically significant.

Discussion

In our study we assessed differences in conduction times from RV to LV and from LV to RV respectively in patients indicated for CRT. Pronounced differences (often up to 35 ms) were observed in substantial part of patients with DCM, while this phenomenon was much less common in patients with CAD.

It is well known that pathologic delay between activation of RV and LV during sinus rhythm with spontaneous conduction exists in heart failure patients with interventricular conduction disturbances. It is a descriptor of interventricular electrical dyssynchrony between right ventricle (RV) and left ventricle (LV). Several studies found direct proportional relationship between measure of IVCD and reverse remodeling [1] or responsiveness to CRT [2]. Interestingly, all these studies worked with right to left conduction times. According to our knowledge there are data neither on conduction times in the opposite direction, i.e. from LV to RV, nor on differences between both directions.

There was no notable difference in conduction time duration among any pacing vectors in concordant direction, at least at given distance between the proximal and distal rings of the LV lead. In other words, conduction times were similar throughout all the vectors in the same patient. Moreover, interventricular conduction times did not differ neither in relationship to pacing voltage nor to pacing rate (see Fig 3). There are no existing trials to compare these results with.

Fig 3. Examples of pacing protocol results in four selected patients.

Fig 3

Open in a new tab

Panel A shows interventricular conduction time differences at different pacing rates. Panel B shows interventricular conduction time differences at different pacing voltages. Particular individual values do not substantially change neither in relationship to pacing rate nor to pacing voltage.

As mentioned above differences in conduction times in both directions were present in 53% of DCM patients compared to only 17% of CAD patients. Moreover, the absolute values of the differences were much higher in the DCM group. The reason is unclear. We can hypothesize that the particular way of remodeling of myocardium in the particular disease play the main role in the conduction differences. Histopathologic examination of hearts from end stage of cardiomyopathy shows reactive (interstitial and perivascular) fibrosis prevailing among patients with idiopathic DCM [3]. In contrast, a greater prevalence of replacement fibrosis is present in patients with CAD [4]. This special distinct pattern of diffuse fibrosis in DCM suggests a more generalized dysfunction which leads to slower conduction through myocardium [5].

Observation of less frequent hypertension in patients with interventricular conduction difference phenomenon is likely a collateral chance finding.

There are several approaches of interventricular conduction assessment. Several authors equal to several approaches. The main thing is that interventricular delay, in general, has been proven as it has its role in left ventricular remodeling [6] or prediction of CRT clinical response many times [7,8,9]. Other studies worked with RV to LV measurements. Since the resynchronization therapy is based mainly on preexcitation of the left ventricle to obtain synchronous ventricular contraction, it can be assumed there will be a relation with LV—RV conduction parameters or presence of some type of the difference with clinical outcome as well.

Knowledge of interventricular conduction differences might have important clinical impact. They are simple to measure with common implantation equipment during implantation procedure. In default settings a CRT device is programmed to pace LV and RV simultaneously [10,11]. Studies of LV offset for CRT programming have been disappointing [12]. In this regard implication of LV-RV vs RV-LV conduction differences could lead to more consistent results. To verify this concept further investigation is needed.

Limitations

The group of patients is small, nevertheless this is a pilot study. The proportion of DCM and CAD was not equivalent similarly to other studies [13,14]. Due to small numbers it was not possible to perform any sex related comparisons.

Conclusion

The occurrence of differences in right-to-left vs left-to-right conduction times in patients indicated to cardiac resynchronization therapy is not rare. It was observed more often in patients with DCM compared to CAD. Knowledge of this phenomenon could be useful in optimization of ventricular timing in CRT patients.

Data Availability

The data underlying this study are available from the Harvard Dataverse using the following URL: https://doi.org/10.7910/DVN/ARGMZ9.

Funding Statement

This work was supported by the Ministry of Health, Czech Republic - conceptual development of research organization (FNBr, 65269705) and MUNI/A/1446/2019. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Sassone B, Gabrieli L, Saccà S, Boggian G, Fusco A, Pratola C, et al. Value of right ventricular-left ventricular interlead electrical delay to predict reverse remodelling in cardiac resynchronization therapy: the INTER-V pilot study. Europace. 2010. January;12(1):78–83. 10.1093/europace/eup347 [DOI] [PubMed] [Google Scholar]
  • 2.Gold MR, Singh JP, Ellenbogen KA, Yu Y, Wold N, Meyer TE, et al. Interventricular Electrical Delay Is Predictive of Response to Cardiac Resynchronization Therapy. JACC Clin Electrophysiol. 2016. August;2(4):438–47. 10.1016/j.jacep.2016.02.018 [DOI] [PubMed] [Google Scholar]
  • 3.Leeuw N, Ruiter DJ, Balk AHMM, Jonge N, Galama JMD, Melchers WJG. Histopathologic findings in explanted heart tissue from patients with end-stage idiopathic dilated cardiomyopathy. Transpl Int. 2001. September;14(5):299–306. [DOI] [PubMed] [Google Scholar]
  • 4.Hare JM, Walford GD, Hruban RH, Hutchins GM, Deckers JW, Baughman KL. Ischemic cardiomyopathy: Endomyocardial biopsy and ventriculographic evaluation of patients with congestive failure, dilated cardiomyopathy and coronary artery disease. J Am Coll Cardiol. 1992. November;20(6):1318–25. 10.1016/0735-1097(92)90243-g [DOI] [PubMed] [Google Scholar]
  • 5.Glukhov A V., Fedorov V V., Kalish PW, Ravikumar VK, Lou Q, Janks D, et al. Conduction Remodeling in Human End-Stage Nonischemic Left Ventricular Cardiomyopathy. Circulation. 2012. April 17;125(15):1835–47. 10.1161/CIRCULATIONAHA.111.047274 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Gold MR, Birgersdotter-Green U, Singh JP, Ellenbogen KA, Yu Y, Meyer TE, et al. The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy. Eur Heart J. 2011; 10.1093/eurheartj/ehr329 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Gold MR, Yu Y, Wold N, Day JD. The role of interventricular conduction delay to predict clinical response with cardiac resynchronization therapy. Heart Rhythm. 2017; 10.1016/j.hrthm.2017.10.016 [DOI] [PubMed] [Google Scholar]
  • 8.Coppola G, Ciaramitaro G, Stabile G, DOnofrio A, Palmisano P, Carità P, et al. Magnitude of QRS duration reduction after biventricular pacing identifies responders to cardiac resynchronization therapy. Int J Cardiol. 2016. October;221:450; 10.1016/j.ijcard.2016.06.203 [DOI] [PubMed] [Google Scholar]
  • 9.Carità P, Corrado E, Pontone G, Curnis A, Bontempi L, Novo G, et al. Non-responders to cardiac resynchronization therapy: Insights from multimodality imaging and electrocardiography. A brief review. Int J Cardiol. 2016. December;225:402–7; 10.1016/j.ijcard.2016.09.037 [DOI] [PubMed] [Google Scholar]
  • 10.St. Jude Medical. St. Jude Medical Online Product Manuals [Internet]. Frontier User’s Manual. 2015 [cited 2019 Sep 9]. p. 34. https://manuals.sjm.com/
  • 11.Medtronic. Medtronic Online Manual Library [Internet]. Claria MRI /CLARIA MRI Quad CRT-Ds. 2018 [cited 2019 Sep 9]. p. 440. http://manuals.medtronic.com/manuals/
  • 12.Horst IAH, Bogaard MD, Tuinenburg AE, Mast TP, de Boer TP, Doevendans PAFM, et al. The concept of triple wavefront fusion during biventricular pacing: Using the EGM to produce the best acute hemodynamic improvement in CRT. Pacing Clin Electrophysiol. 2017. July;40(7):873–82. 10.1111/pace.13118 [DOI] [PubMed] [Google Scholar]
  • 13.Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001. March 22;344(12):873–80. 10.1056/NEJM200103223441202 [DOI] [PubMed] [Google Scholar]
  • 14.McSwain RL, Schwartz RA, DeLurgio DB, Mera F V., Langberg JJ, Leon AR. The Impact of Cardiac Resynchronization Therapy on Ventricular Tachycardia/Fibrillation: An Analysis from the Combined Contak-CD and InSync-ICD Studies. J Cardiovasc Electrophysiol. 2005. November;16(11):1168–71. 10.1111/j.1540-8167.2005.40719.x [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Giuseppe Coppola

20 Dec 2019

PONE-D-19-32599

Differences in right-to-left vs left-to-right interventricular conduction times in patients indicated to cardiac resynchronization therapy

PLOS ONE

Dear  Dr. Sepsi

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We would appreciate receiving your revised manuscript by Feb 03 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Giuseppe Coppola

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Additional Editor Comments (if provided):

Kind author, your manuscript underwent three different reviewers; your paper is quite interesting but it does present some methodological problems.

We cannot accept as it is; you will find all the comments and criticisms underlined by reviewers.

We hope you could answer point by point to resubmit a revised version of your manuscript.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear author,

the paper is well written and the topic is very interesting. The protocol is clear and precise while results appear hard to understand after a single reading and should be improved considering that they seem to be a long list of figures and tables description.

Moreover an important limitation of this study is the small number of enrolled patients.

At least, have you any data about response to resynchronization according to difference between inter-ventricular delay?

Regarding this topic I would like to suggest this paper regarding QRS index that can be considered a surrogate of reduced interventricular conduction delay: Magnitude of QRS duration reduction after biventricular pacing identifies responders to cardiac resynchronization therapy.

Coppola G, Ciaramitaro G, Stabile G, DOnofrio A, Palmisano P, Carità P, Mascioli G, Pecora D, De Simone A, Marini M, Rapacciuolo A, Savarese G, Maglia G, Pepi P, Padeletti L, Pierantozzi A, Arena G, Giovannini T, Caico SI, Nugara C, Ajello L, Malacrida M, Corrado E.

Int J Cardiol. 2016 Oct 15;221:450-5.

Reviewer #2: The paper from Sepsi and coll. is quite interesting but it does present some methodological problems.

1. The position of the RV lead could have had an impact on results. It is not simply a matter of how many RV leads have been implanted in a group or in another, but that changing the RV lead position IN THAT patients could have lead to completely different results and this impacts negatively on the study itself

2. The definition itself of "septal RV lead" is quite generical: which part of the septum? Hissian, parahissiam, septal RVOT? Again, this could have changed everything

3. The conclusions on correction on RV-LV lead delay (or viceversa; page 17, lines 213 - 214) and results of CRT is too simplicistic. FREEDOM Trial on use of QuickOpt did not demonstrate any benefit from this approach (it is almost the same concept, because the algorhitm measure the RV-LV delay during RV pacing and LV-RV delay during LV pacing and adjusts the VV interval so that the activation front is simultaneous)

Furthermore, I do not understand (Abstract, page 8, line 30) what does that < 5 ms mean: could the Authors make it clearer or at least explain in the revision letter the meaning of this statement.

Finally, the whole manuscript needs a deep english language revision because some passages are unclear.

Reviewer #3: Cardiac resynchronization therapy (CRT) is an established treatment for patients with heart failure (HF), impaired left ventricular (LV) function, and wide QRS complex.

Pospisil et al. described the phenomenon of interventricular conduction time differences and assessed relationship to various clinical and electrophysiological parameters. In fact the differences in conduction times from right ventricle to left ventricle and from left ventricle to right ventricle respectively were observed during biventricular devices implantation when changing pacing vector direction. In this study a pronounced differences (often up to 35 ms) were observed in substantial part of patients with dilatative cardiomyopathy (DCM), while this phenomenon was much less common in patients with coronary artery disease (CAD). The study is very interesting, presented in an appropriate fashion and are supported by interesting data. A limitation is represented by the small sample number (62 patients) to draw conclusions although the idea from a pathophysiological point of view is acceptable. Moreover it would be interesting to point out that other studies have also previously evaluated importance of CRT (see: “Non-responders to cardiac resynchronization therapy: Insights from multimodality imaging and electrocardiography. A brief review”, Doi: 10.1016/j.ijcard.2016.09.037). This would certainly increase the the article's quality.

In conclusion, given the overall work, I accept manuscript with minor revision concerning a small implementation of bibliography, reporting the aforementioned work and other.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Giosue Mascioli

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Feb 19;15(2):e0228731. doi: 10.1371/journal.pone.0228731.r002

Author response to Decision Letter 0

16 Jan 2020

PLoS ONE Brno, January 8, 2020

Editorial Office

Dear editor,

Please find attached our revised manuscript called

Differences in right-to-left vs. left-to-right interventricular conduction times in patients indicated for cardiac resynchronization therapy

by David Pospisil et al., (PONE-D-19-32599).

Thank you for your invitation to submit a revised version of the manuscript. We highly appreciate the opportunity to respond to reviewer’s suggestions on the paper to clarify all questions and to meet PLoS ONE’s publication criteria. We look forward to hearing from you regarding our submission. We would be glad to respond to any further questions and comments that you may have.

Best regards

On behalf of all the authors

Milan Sepsi, MD, PhD

Department of Internal Medicine and Cardiology

University Hospital Brno, Masaryk University, Jihlavska 20, 625 00 Brno, Czech Republic

Phone: +420 777 227 346, Fax: +420 53223 2611, E-mail: sepsi.milan@fnbrno.cz

Response to Reviewer #1:

Dear reviewer,

thank you for your valuable time and useful contribution. We highly appreciate your inputs you given to improve the manuscript. We hope you will find our explanations and manuscript edits enough to your convenience. A point-by-point reactions to your comments and critics are written below directly into received texts using blue colored italic font. Attached file “Revised Manuscript with Track Changes” contains marked revisions made in the manuscript.

Dear author,

the paper is well written, and the topic is very interesting. The protocol is clear and precise while results appear hard to understand after a single reading and should be improved considering that they seem to be a long list of figures and tables description.

According to your proposition some corrections of the text have been applied. Nevertheless, the text of the “Results” section is quite short, substantial part of information is present in figures and their captions (which are inserted in the text of the manuscript immediately following the paragraph in which the figure is first cited).

Moreover, an important limitation of this study is the small number of enrolled patients.

We agree that the number is small and we have commented it in the limitations. Nevertheless, as a pilot study it can be sufficient to draw conclusions from a pathophysiological point of view. It is clear it deserves a further study on larger set of patients.

At least, have you any data about response to resynchronization according to difference between inter-ventricular delay?

Unfortunately, not yet. We are preparing a study to evaluate the phenomenon according to QRS width and responsiveness to CRT rigorously.

Regarding this topic I would like to suggest this paper regarding QRS index that can be considered a surrogate of reduced interventricular conduction delay: Magnitude of QRS duration reduction after biventricular pacing identifies responders to cardiac resynchronization therapy.

Coppola G, Ciaramitaro G, Stabile G, DOnofrio A, Palmisano P, Carità P, Mascioli G, Pecora D, De Simone A, Marini M, Rapacciuolo A, Savarese G, Maglia G, Pepi P, Padeletti L, Pierantozzi A, Arena G, Giovannini T, Caico SI, Nugara C, Ajello L, Malacrida M, Corrado E.

Int J Cardiol. 2016 Oct 15;221:450-5.

We find suggested paper very interesting regarding our topic and it has been added to the manuscript.

Response to Reviewer #2:

Dear Dr. Mascioli,

thank you for your valuable time and useful contribution. We highly appreciate your inputs you given to improve the manuscript. We hope you will find our explanations and manuscript edits enough to your convenience. A point-by-point reactions to your comments and critics are written below directly into received texts using blue colored italic font. Attached file “Revised Manuscript with Track Changes” contains marked revisions made in the manuscript.

Reviewer #2: The paper from Sepsi and coll. is quite interesting, but it does present some methodological problems.

1. The position of the RV lead could have had an impact on results. It is not simply a matter of how many RV leads have been implanted in a group or in another, but that changing the RV lead position IN THAT patients could have lead to completely different results and this impacts negatively on the study itself.

Of course, we considered that RV placement might have a significant impact to the interventricular conduction time and it obviously has. What we want to show is the fact that the differences of RV→LV and LV→RV conduction times are present regardless of RV lead placement in a given position.

2. The definition itself of "septal RV lead" is quite generical: which part of the septum? Hissian, parahissian, septal RVOT? Again, this could have changed everything.

The information on septal vs apical position is based on implanting physician’s declaration. Unfortunately more detailed information on the lead position is not available. The aim of our manuscript is introduction of the phenomenon. Relationships to particular positions would require its study on larger group of patients.

3. The conclusions on correction on RV-LV lead delay (or viceversa; page 17, lines 213 - 214) and results of CRT is too simplicistic. FREEDOM Trial on use of QuickOpt did not demonstrate any benefit from this approach (it is almost the same concept, because the algorhitm measure the RV-LV delay during RV pacing and LV-RV delay during LV pacing and adjusts the VV interval so that the activation front is simultaneous)

The text was modified.

Furthermore, I do not understand (Abstract, page 8, line 30) what does that < 5 ms mean: could the Authors make it clearer or at least explain in the revision letter the meaning of this statement.

In original text, there was a mistake – thank you: we considered interventricular conduction times difference lower than 5 milliseconds (ms) as a bidirectionally comparable conduction (because of measurement error), so. statement < 5 ms corrected to “>5 ms”.

Finally, the whole manuscript needs a deep English language revision because some passages are unclear.

A complete grammar, language and terminology check was done by scientific manuscript editing service to fit the US-English standards. We include PDF file with certification by Proof.Reading.Service.Com Ltd.

Response to Reviewer #3:

Dear reviewer,

thank you for your valuable time and useful contribution. We highly appreciate your inputs you given to improve the manuscript. We hope you will find our explanations and manuscript edits enough to your convenience. A point-by-point reactions to your comments and critics are written below directly into received texts using blue colored font. Attached file “Revised Manuscript with Track Changes” contains marked revisions made in the manuscript.

Reviewer #3: Cardiac resynchronization therapy (CRT) is an established treatment for patients with heart failure (HF), impaired left ventricular (LV) function, and wide QRS complex.

Pospisil et al. described the phenomenon of interventricular conduction time differences and assessed relationship to various clinical and electrophysiological parameters. In fact the differences in conduction times from right ventricle to left ventricle and from left ventricle to right ventricle respectively were observed during biventricular devices implantation when changing pacing vector direction. In this study a pronounced differences (often up to 35 ms) were observed in substantial part of patients with dilatative cardiomyopathy (DCM), while this phenomenon was much less common in patients with coronary artery disease (CAD). The study is very interesting, presented in an appropriate fashion and are supported by interesting data. A limitation is represented by the small sample number (62 patients) to draw conclusions although the idea from a pathophysiological point of view is acceptable.

Moreover, it would be interesting to point out that other studies have also previously evaluated importance of CRT (see: “Non-responders to cardiac resynchronization therapy: Insights from multimodality imaging and electrocardiography. A brief review”, Doi: 10.1016/j.ijcard.2016.09.037).

This would certainly increase the article's quality. In conclusion, given the overall work, I accept manuscript with minor revision concerning a small implementation of bibliography, reporting the aforementioned work and other.

We find the suggested paper very interesting regarding our topic and it has been added to the manuscript.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (24.1KB, docx)

Decision Letter 1

Giuseppe Coppola

23 Jan 2020

Differences in right-to-left vs left-to-right interventricular conduction times in patients indicated to cardiac resynchronization therapy

PONE-D-19-32599R1

Dear Dr. Milan Sepsi,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Giuseppe Coppola

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Manuscript underwent language revision.

Authors have answerd to all reviewrs coments and criticisms when it was possible considering this manuscript a pilot study.

Reviewers' comments:

Acceptance letter

Giuseppe Coppola

28 Jan 2020

PONE-D-19-32599R1

Differences in right-to-left vs left-to-right interventricular conduction times in patients indicated to cardiac resynchronization therapy

Dear Dr. Sepsi:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Giuseppe Coppola

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (24.1KB, docx)

    Data Availability Statement

    The data underlying this study are available from the Harvard Dataverse using the following URL: https://doi.org/10.7910/DVN/ARGMZ9.

    Articles from PLoS ONE are provided here courtesy of PLOS

    RESOURCES