Incidence and Duration of Unintentional Neuromodulation Effects After Pulmonary Vein Isolation in Patients With Atrial Fibrillation. (UNCOVER-PVI)

Incidence and Duration of Unintentional Neuromodulation Effects After Pulmonary Vein Isolation in Patients With Atrial Fibrillation. (UNCOVER-PVI)

Pulmonary vein isolation (PVI) is a proven, high-efficiency treatment for atrial fibrillation (AF). Performed, among others, using cryoablation, pulsed field ablation (PFA) or radiofrequency (RF) ablation. It has been shown that its effectiveness significantly increases when the PVI procedure is combined with cardioneuroablation (CNA). The autonomic nervous system - ganglionated plexi (GP), the target of the CNA, are the endings of the vagal nerve and are located in the neighborhood of the pulmonary veins ostia. Places that, in many cases, are unintentionally damaged during PVI. Varying degrees of injury to the GP during PVI indicate that the group of patients undergoing PVI is heterogeneous in this regard, and the effectiveness of PVI may vary. Vagal nerve endings damage during CNA abolishes or modifies its activity, which is manifested by the acceleration of sinus rhythm and increased atrioventricular conduction efficiency. Unintended CNA is not observed in every PVI procedure. The severity of the unintended CNA effect and its duration also vary.

THE STUDY OBJECTIVES:

1. Frequency of unintentional CNA occurrence during PVI
2. Duration effect of CNA after unintentional CNA
3. Evaluation of the relationship between the different kinds of energy - cryo, pulsed field) and RFwith the unintentional CNA frequency occurrence and durability effect
4. Clinical significance evaluation of the new assessment method of the CNA effectiveness with the measure of the cSNRT and the sinus rate after its return, measured before and after PVI
5. Assessment of clinical significance for CNA evaluation of the electrophysiological parameters of AV node conduction efficiency, such as PQ interval, AH interval, HV interval, and Wenckebach's point. Parameters will be examined before and after PVI.
6. PVI efficacy evaluation with the AF and Sick Sinus Syndrome treatment, especially with the elimination of the indications for the PM implantation (sinus bradycardia, AV conduction disorders)
7. Assessment of sinus rhythm maintenance after PVI with unintentional CNA and without unintentional CNA
8. Assessment of ventricular rate control during AF burden after unintentional CNA
9. The search for new parameters evaluating the effectiveness and degree of CNA, such as the change in SR frequency after its return, may prove helpful and allow for resignation or significantly reduce the use of the complicated protocol of extracardiac vagal ganglion stimulation (ECVS) as a method to verify the effectiveness CNAs.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Procedure: ablation- pulmonary vain isolation- crioablation; Procedure: Electrophysiological study (EPS); Diagnostic test: Holter EKG; Other: Questionnaire; Procedure: ablation- pulmonary vain isolation- pulsed field ablation (PFA); Procedure: ablation- pulmonary vain isolation- radiofrequency ablation (RF)

Detailed Description

This is a multi-centre, prospective, observational study, which will include patients with paroxysmal or persistent atrial fibrillation qualified for PVI by the European Society of Cardiology guidelines. Pulmonary veins will be isolated with three kinds of energies: cryo, pulsed field and RF. The study group will consist of four subgroups:

1. Patients undergoing cryoablation of pulmonary veins with paroxysmal or persistent AF with ongoing AF during ablation
2. Patients undergoing cryoablation of pulmonary veins with paroxysmal AF, in sinus rhythm during the procedure
3. Patients undergoing pulmonary veins isolation with PFA with paroxysmal AF, in sinus rhythm during the procedure
4. Patients undergoing RF ablation of the pulmonary veins using an electroanatomical system with paroxysmal AF, in sinus rhythm during the procedure

The effect of unintentional neuromodulation will be assessed based on the following:

1. ECG Holter monitoring performed before and after the procedure in all groups
2. Parameters assessed in EPS before and after the procedure in groups 2,3, and 4.

The long-term effect of neuromodulation and its impact on maintaining sinus rhythm will be assessed based on the following:

1. The Holter ECG monitoring in groups 2,3, and 4.
2. The interview in all groups after three months of observation.

PROTOCOL STUDY:

GROUP 1:

1. Holter ECG prior to PVI
2. Holter ECG after PVI
3. Survey after three months of observation.

GROUPS 2,3 AND 4:

1. Holter ECG prior to PVI
2. EPS prior to PVI
3. EPS after PVI
4. Holter ECG prior to PVI
5. Holter ECG after three to six months of observation
6. Survey after three months of observation.

All the measured parameters as well as demographic and clinical data will be recorded in the study database.

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

• Study Contact: Name: Przemysław Skoczyński, PhD; Phone Number: +48602753043; Email: przeskocz@tlen.pl
• Study Contact Backup: Name: Bruno Hrymniak, MD; Phone Number: +48603766801; Email: bruno.hrymniak@gmail.com

Study Locations

• Poland
  • Dolnośląskie
    • Wrocław, Dolnośląskie, Poland, 50-981
      • Recruiting
      • 4th Military Hospital, Cardiology Department
      • Sub-Investigator: Bartosz Biel, MD
      • Contact: Przemysław Skoczyński, PhD; Phone Number: +48602753043; Email: przeskocz@tlen.pl
      • Contact: Bruno Hrymniak, MD; Phone Number: +48603766801; Email: bruno.hrymniak@gmail.com
      • Principal Investigator: Przemysław Skoczyński, PhD
      • Sub-Investigator: Bruno Hrymniak, MD
      • Sub-Investigator: Bartosz Skonieczny, MD
      • Sub-Investigator: Krystian Josiak, PhD
      • Sub-Investigator: Dorota Zyśko, Profesor
      • Sub-Investigator: Dariusz Jagielski, PhD
  • Śląskie
    • Dąbrowa Górnicza, Śląskie, Poland, 41-300
      • Recruiting
      • Polish-American Heart Clinics Cardiovascular Center in Dąbrowa Górnicza, American Heart of Poland Group
      • Contact: Sebastian Stec, PhD; Phone Number: +48600298022; Email: smstec@wp.pl
      • Principal Investigator: Sebastian Stec, PhD
      • Sub-Investigator: Antoni Wileczek, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The study group will consist of patients aged 18-85. With paroxysmal or persistent atrial fibrillation. Qualified for PVI according to the guidelines of the European Society of Cardiology.

Description

Inclusion Criteria:

• Patients qualified for PVI due to paroxysmal or persistent atrial fibrillation.
• Signed and dated written informed consent prior to admission to the trial.

Exclusion Criteria:

• Any underwent cardiac ablation.
• A history of cardiac surgery.
• Pregnancy.
• Diseases affecting the autonomic nervous system.
• Change in heart rhythm during PVI, with no conversion to the primary rhythm at the end of the procedure.
• Cardiac pacing during Holter ECG monitoring.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group 1; Patients undergoing cryoablation of pulmonary veins with paroxysmal or persistent AF with ongoing AF during ablation.	Procedure: ablation- pulmonary vain isolation- crioablation; Pulmonary vein isolation is the electrical isolation of the pulmonary veins from the left atrium. It can be performed using the cryoablation technique. The procedure begins with venous access through the femoral vein through which catheters and electrodes are inserted. Then, the left atrium is accessed through a transseptal puncture and the pulmonary veins are isolated using a cryoablation balloon. Cryoablation procedures are performed under local anesthesia. The procedure is performed using X-ray fluoroscopy.; Procedure: Electrophysiological study (EPS); In the electrophysiological study (EPS), electrophysiological parameters such as the recovery time of sinus rhythm (SNRT), Wenckebach's point, AH and HV intervals are measured. The examination begins with venous access through the femoral vein. Then, diagnostic electrodes are inserted into the right atrium, right ventricle and coronary sinus, with which electrophysiological tests are performed. The SNRT is measured after 60 seconds of atrial pacing with a 600ms cycle. The Wencjabach point is determined by stimulation in the incremental protocol. AV and HV intervals are measured during sinus rhythm using an electrode placed on the bundle of His. EPS is performed under local anesthesia. EPS will be performed both before and after pulmonary vein isolation. In patients with atrial fibrillation, during ablation, only the HV interval will be measured. The procedure is performed using X-ray fluoroscopy.; Diagnostic test: Holter EKG; Holter ECG is a 24-hour, non-invasive ECG recording using a portable recorder and electrodes placed on the patient's chest. The Holter ECG will be performed three times: on the day preceding and on the first day after pulmonary veins isolation, and after 3 months of observation.; Other: Questionnaire; The survey will be conducted after 3 months of observation and will include questions about the number of hospitalizations due to atrial fibrillation, heart palpitations, changes in pharmacotherapy.
Group 2; Patients undergoing cryoablation of pulmonary veins with paroxysmal AF, in sinus rhythm during the procedure.	Procedure: ablation- pulmonary vain isolation- crioablation; Pulmonary vein isolation is the electrical isolation of the pulmonary veins from the left atrium. It can be performed using the cryoablation technique. The procedure begins with venous access through the femoral vein through which catheters and electrodes are inserted. Then, the left atrium is accessed through a transseptal puncture and the pulmonary veins are isolated using a cryoablation balloon. Cryoablation procedures are performed under local anesthesia. The procedure is performed using X-ray fluoroscopy.; Procedure: Electrophysiological study (EPS); In the electrophysiological study (EPS), electrophysiological parameters such as the recovery time of sinus rhythm (SNRT), Wenckebach's point, AH and HV intervals are measured. The examination begins with venous access through the femoral vein. Then, diagnostic electrodes are inserted into the right atrium, right ventricle and coronary sinus, with which electrophysiological tests are performed. The SNRT is measured after 60 seconds of atrial pacing with a 600ms cycle. The Wencjabach point is determined by stimulation in the incremental protocol. AV and HV intervals are measured during sinus rhythm using an electrode placed on the bundle of His. EPS is performed under local anesthesia. EPS will be performed both before and after pulmonary vein isolation. In patients with atrial fibrillation, during ablation, only the HV interval will be measured. The procedure is performed using X-ray fluoroscopy.; Diagnostic test: Holter EKG; Holter ECG is a 24-hour, non-invasive ECG recording using a portable recorder and electrodes placed on the patient's chest. The Holter ECG will be performed three times: on the day preceding and on the first day after pulmonary veins isolation, and after 3 months of observation.; Other: Questionnaire; The survey will be conducted after 3 months of observation and will include questions about the number of hospitalizations due to atrial fibrillation, heart palpitations, changes in pharmacotherapy.
Group 3; Patients undergoing pulmonary veins isolation with PFA with paroxysmal AF, in sinus rhythm during the procedure.	Procedure: Electrophysiological study (EPS); In the electrophysiological study (EPS), electrophysiological parameters such as the recovery time of sinus rhythm (SNRT), Wenckebach's point, AH and HV intervals are measured. The examination begins with venous access through the femoral vein. Then, diagnostic electrodes are inserted into the right atrium, right ventricle and coronary sinus, with which electrophysiological tests are performed. The SNRT is measured after 60 seconds of atrial pacing with a 600ms cycle. The Wencjabach point is determined by stimulation in the incremental protocol. AV and HV intervals are measured during sinus rhythm using an electrode placed on the bundle of His. EPS is performed under local anesthesia. EPS will be performed both before and after pulmonary vein isolation. In patients with atrial fibrillation, during ablation, only the HV interval will be measured. The procedure is performed using X-ray fluoroscopy.; Diagnostic test: Holter EKG; Holter ECG is a 24-hour, non-invasive ECG recording using a portable recorder and electrodes placed on the patient's chest. The Holter ECG will be performed three times: on the day preceding and on the first day after pulmonary veins isolation, and after 3 months of observation.; Other: Questionnaire; The survey will be conducted after 3 months of observation and will include questions about the number of hospitalizations due to atrial fibrillation, heart palpitations, changes in pharmacotherapy.; Procedure: ablation- pulmonary vain isolation- pulsed field ablation (PFA); Pulmonary vein isolation is the electrical isolation of the pulmonary veins from the left atrium. It can be performed using the pulsed field ablation (PFA) technique. The procedure begins with venous access through the femoral vein through which catheters and electrodes are inserted. Then, the left atrium is accessed through a transseptal puncture and the pulmonary veins are isolated with a PFA electrode. PFA procedures are performed under general anesthesia. The procedure is performed using X-ray fluoroscopy.
Group 4; Patients undergoing RF ablation of the pulmonary veins using an electroanatomical system with paroxysmal AF, in sinus rhythm during the procedure.	Procedure: Electrophysiological study (EPS); In the electrophysiological study (EPS), electrophysiological parameters such as the recovery time of sinus rhythm (SNRT), Wenckebach's point, AH and HV intervals are measured. The examination begins with venous access through the femoral vein. Then, diagnostic electrodes are inserted into the right atrium, right ventricle and coronary sinus, with which electrophysiological tests are performed. The SNRT is measured after 60 seconds of atrial pacing with a 600ms cycle. The Wencjabach point is determined by stimulation in the incremental protocol. AV and HV intervals are measured during sinus rhythm using an electrode placed on the bundle of His. EPS is performed under local anesthesia. EPS will be performed both before and after pulmonary vein isolation. In patients with atrial fibrillation, during ablation, only the HV interval will be measured. The procedure is performed using X-ray fluoroscopy.; Diagnostic test: Holter EKG; Holter ECG is a 24-hour, non-invasive ECG recording using a portable recorder and electrodes placed on the patient's chest. The Holter ECG will be performed three times: on the day preceding and on the first day after pulmonary veins isolation, and after 3 months of observation.; Other: Questionnaire; The survey will be conducted after 3 months of observation and will include questions about the number of hospitalizations due to atrial fibrillation, heart palpitations, changes in pharmacotherapy.; Procedure: ablation- pulmonary vain isolation- radiofrequency ablation (RF); Pulmonary vein isolation is the electrical isolation of the pulmonary veins from the left atrium. It can be performed using the radiofrequency ablation (RF) technique. The procedure begins with venous access through the femoral vein through which catheters and electrodes are inserted. Then, the left atrium is accessed through a transseptal puncture and the pulmonary veins are isolated with a RF electrode. RF procedures are performed under local anesthesia. The procedure is performed using X-ray fluoroscopy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acceleration and maintenance of a faster sinus rhythm after PVI	Based on EPS before and after PVI and Holter ECG before and after PVI and after 3 months of follow-up.	3 months of follow-up
Improvement of AV conduction efficiency and its durability after PVI	Based on EPS before and after PVI and Holter ECG before and after PVI and after 3 months of follow-up.	3 months of follow-up
Recurrence of AF during the observation period.	Based on Holter ECG and survey after 3 months of follow-up.	3 months of follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AF recurrence with the need to increase doses of heart rate control drugs.	Based on survey after 3 months of follow-up.	3 months of follow-up

Collaborators and Investigators

• Sponsor: 4th Military Hospital

Publications and helpful links

General Publications

• Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomstrom-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021 Feb 1;42(5):373-498. doi: 10.1093/eurheartj/ehaa612. No abstract available. Erratum In: Eur Heart J. 2021 Feb 1;42(5):507. Eur Heart J. 2021 Feb 1;42(5):546-547. Eur Heart J. 2021 Oct 21;42(40):4194.
• Katritsis DG, Pokushalov E, Romanov A, Giazitzoglou E, Siontis GC, Po SS, Camm AJ, Ioannidis JP. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial. J Am Coll Cardiol. 2013 Dec 17;62(24):2318-25. doi: 10.1016/j.jacc.2013.06.053. Epub 2013 Aug 21.
• Aksu T, Guler TE, Bozyel S, Yalin K, Gopinathannair R. Why is pulmonary vein isolation not enough for vagal denervation in all cases? Pacing Clin Electrophysiol. 2020 May;43(5):520-523. doi: 10.1111/pace.13922. Epub 2020 May 2.
• Sakamoto S, Schuessler RB, Lee AM, Aziz A, Lall SC, Damiano RJ Jr. Vagal denervation and reinnervation after ablation of ganglionated plexi. J Thorac Cardiovasc Surg. 2010 Feb;139(2):444-52. doi: 10.1016/j.jtcvs.2009.04.056. Epub 2009 Sep 9.
• Yorgun H, Aytemir K, Canpolat U, Sahiner L, Kaya EB, Oto A. Additional benefit of cryoballoon-based atrial fibrillation ablation beyond pulmonary vein isolation: modification of ganglionated plexi. Europace. 2014 May;16(5):645-51. doi: 10.1093/europace/eut240. Epub 2013 Aug 16.

Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2021
• Primary Completion (Anticipated): December 23, 2023
• Study Completion (Anticipated): December 23, 2023

Study Registration Dates

• First Submitted: December 23, 2022
• First Submitted That Met QC Criteria: December 23, 2022
• First Posted (Estimate): January 10, 2023

Study Record Updates

• Last Update Posted (Estimate): January 10, 2023
• Last Update Submitted That Met QC Criteria: December 23, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: pulmonary vains isolation, catdioneuroablation, cardioneuromodultion
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation
• Other Study ID Numbers: UNCOVER-PVI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: The data will be collected in a database accessible only to the named researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No