Release of Acetylcholine From the Ganglionated Plexus During the Thaw Phase of Cryoballon Pulmonary Vein Ablation (GP RESPONSE Study)

Atrial Fibrillation Clinical Trial

Official title:

Systemic Release of Acetylcholine From the Autonomic Ganglionated Plexus: a Proposed Mechanism of Induced Hypotension During the Thaw Phase of Cryoballon Pulmonary Vein Ablation (GP RESPONSE Study)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03636100
• Other study ID #: GP Response
• Status: Terminated
• Start date: August 15, 2018
• Est. completion date: October 11, 2019

Study information

• Verified date: October 2021
• Source: Saint Luke's Health System
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Determine whether the presence of acetylcholine in the systemic circulation, correlates with the hypotensive response observed during the thaw phase of cryoballoon ablation.

Description:

This will be a two-phase (feasibility and primary study phases), prospective observational study with pulmonary vein ablation applications during which a hypotensive response is not observed serving as within-subject controls. A total of 14 patients age 18-80 with atrial fibrillation undergoing first time cryoballoon ablation will be enrolled. Exclusion criteria are any prior left atrial ablation or cardiac surgery, a hemoglobin level of < 12.0 g/dL, or refusal or inability to provide informed consent.

The ablation procedure will be carried out per routine clinical practice by one operator. Two cryoballoon applications targeting 180 seconds per application will be performed per vein. Applications may be abbreviated at the discretion of the operator for indications such as balloon temperatures reaching the mid -50s C, esophageal temperatures approaching 20 C, or a decrease in diaphragmatic movement during phrenic nerve pacing. Application times may be extended to 200 to 240 seconds, also at the discretion of the operator, if within-freeze target temperatures (such as -30 C by 30 seconds or -40 C by 60 seconds) are not met.

A hypotensive response will be defined as a transient ≥ 20% decrease in systolic blood pressure from baseline (start of thaw) during the thaw phase and up to 60 seconds post-end of thaw (balloon deflation). A partial hypotensive response will be defined as a transient 10-19% decrease in systolic blood pressure. For all patients, the time from the end of the cryoballoon freeze to the end of the thaw, to the onset of the hypotensive response, and to blood pressure recovery within 10% of baseline will be recorded. Blood pressure and heart rate will be recorded at each time point. For the first 4 patients (phase I), blood samples of 2-3mL each will be drawn from the mid-right atrium at baseline and then at 30, 60 and 90 seconds after the end of each cryoballoon freeze application. Samples will also be drawn at onset of hypotension and 30 seconds later (superseding the drawing of other samples in the first 90 seconds post-end of freeze), and at blood pressure recovery. Samples will be drawn within 10 seconds of each specified time point; or will not be obtained and will be marked as a missing data point. If more than 20% of the specified data are missing for a given subject, that subject will be excluded from analysis. The samples will then be run on a commercially available 96-well colorimetric assay kit by Cell Biolabs Inc (catalog number STA-603) to assay for acetylcholine.

If the first phase of the study demonstrates the presence of acetylcholine at one or more time points during the thaw phase of 20% or more of cryoballoon applications during which a hypotensive response is observed, the study will proceed to phase 2. The results will be used to determine the optimal time point(s) at which to obtain samples during the second phase of the study (remaining 10 patients), with an anticipated need for 2-4 samples per cryoballoon application, one at start of thaw, another at a determined time point, and when there is a hypotensive response at the onset of hypotension and at blood pressure recovery. An interim report will be produced detailing the observations of phase 1 and specifying the plan for obtaining samples in phase 2.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 7
• Est. completion date: October 11, 2019
• Est. primary completion date: October 11, 2019
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• patients with atrial fibrillation undergoing first time cryoballoon ablation

• age 18-80

Exclusion Criteria:

• any prior left atrial ablation or cardiac surgery

• hemoglobin level of <12.0 g/dL

• refusal or inability to provide informed consent

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

Device:
• Cryoballoon ablation
Cryoballoon ablation using standard equipment and techniques

Locations

Country	Name	City	State
United States	Saint Luke's Mid America Heart Institute	Kansas City	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Saint Luke's Health System

Country where clinical trial is conducted

United States, 

References & Publications (13)

Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res. 2014 Apr 25;114(9):1453-68. doi: 10.1161/CIRCRESAHA.114.303211. Review. — View Citation

Bordignon S, Fürnkranz A, Dugo D, Perrotta L, Gunawardene M, Bode F, Klemt A, Nowak B, Schulte-Hahn B, Schmidt B, Chun KR. Improved lesion formation using the novel 28 mm cryoballoon in atrial fibrillation ablation: analysis of biomarker release. Europace. 2014 Jul;16(7):987-93. doi: 10.1093/europace/eut400. Epub 2014 Jan 19. — View Citation

Kampaktsis PN, Oikonomou EK, Y Choi D, Cheung JW. Efficacy of ganglionated plexi ablation in addition to pulmonary vein isolation for paroxysmal versus persistent atrial fibrillation: a meta-analysis of randomized controlled clinical trials. J Interv Card Electrophysiol. 2017 Dec;50(3):253-260. doi: 10.1007/s10840-017-0285-z. Epub 2017 Sep 8. Review. — View Citation

Kellogg DL Jr, Zhao JL, Coey U, Green JV. Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin. J Appl Physiol (1985). 2005 Feb;98(2):629-32. — View Citation

Ketels S, Houben R, Van Beeumen K, Tavernier R, Duytschaever M. Incidence, timing, and characteristics of acute changes in heart rate during ongoing circumferential pulmonary vein isolation. Europace. 2008 Dec;10(12):1406-14. doi: 10.1093/europace/eun287. Epub 2008 Oct 19. — View Citation

Kojodjojo P, O'Neill MD, Lim PB, Malcolm-Lawes L, Whinnett ZI, Salukhe TV, Linton NW, Lefroy D, Mason A, Wright I, Peters NS, Kanagaratnam P, Davies DW. Pulmonary venous isolation by antral ablation with a large cryoballoon for treatment of paroxysmal and persistent atrial fibrillation: medium-term outcomes and non-randomised comparison with pulmonary venous isolation by radiofrequency ablation. Heart. 2010 Sep;96(17):1379-84. doi: 10.1136/hrt.2009.192419. — View Citation

Kuck KH, Brugada J, Fürnkranz A, Metzner A, Ouyang F, Chun KR, Elvan A, Arentz T, Bestehorn K, Pocock SJ, Albenque JP, Tondo C; FIRE AND ICE Investigators. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med. 2016 Jun 9;374(23):2235-45. doi: 10.1056/NEJMoa1602014. Epub 2016 Apr 4. — View Citation

Kuck KH, Fürnkranz A, Chun KR, Metzner A, Ouyang F, Schlüter M, Elvan A, Lim HW, Kueffer FJ, Arentz T, Albenque JP, Tondo C, Kühne M, Sticherling C, Brugada J; FIRE AND ICE Investigators. Cryoballoon or radiofrequency ablation for symptomatic paroxysmal atrial fibrillation: reintervention, rehospitalization, and quality-of-life outcomes in the FIRE AND ICE trial. Eur Heart J. 2016 Oct 7;37(38):2858-2865. Epub 2016 Jul 5. — View Citation

Lemery R. Bradycardia with cooling and cryo: A reminder of the autonomic effects of cold stimuli on the heart. Heart Rhythm. 2016 May;13(5):1018-1019. doi: 10.1016/j.hrthm.2015.12.049. Epub 2016 Jan 6. — View Citation

Nakagawa H, Scherlag BJ, Patterson E, Ikeda A, Lockwood D, Jackman WM. Pathophysiologic basis of autonomic ganglionated plexus ablation in patients with atrial fibrillation. Heart Rhythm. 2009 Dec;6(12 Suppl):S26-34. doi: 10.1016/j.hrthm.2009.07.029. Epub 2009 Oct 24. — View Citation

Peyrol M, Barraud J, Koutbi L, Maille B, Trevisan L, Martinez E, Lévy S, Paganelli F, Franceschi F. Vagal Reactions during Cryoballoon-Based Pulmonary Vein Isolation: A Clue for Autonomic Nervous System Modulation? Biomed Res Int. 2016;2016:7286074. doi: 10.1155/2016/7286074. Epub 2016 May 3. Review. — View Citation

Sun L, Dong JZ, DU X, Bai R, Li S, Salim M, Ma CS. Prophylactic Atropine Administration Prevents Vasovagal Response Induced by Cryoballoon Ablation in Patients with Atrial Fibrillation. Pacing Clin Electrophysiol. 2017 May;40(5):551-558. doi: 10.1111/pace.13072. Epub 2017 Apr 25. — View Citation

Yanagisawa S, Inden Y, Mizutani Y, Fujii A, Kamikubo Y, Kanzaki Y, Ando M, Funabiki J, Murase Y, Takenaka M, Otake N, Hattori T, Shibata R, Murohara T. Vagal response in cryoballoon ablation of atrial fibrillation and autonomic nervous system: Utility of epicardial adipose tissue location. J Arrhythm. 2017 Aug;33(4):275-282. doi: 10.1016/j.joa.2017.03.001. Epub 2017 Apr 24. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Individual acetylcholine levels	With each subject serving as their own control, acetylcholine levels between ablation applications will be compared followed by a hypotensive response vs those that are not using paired T-tests.	1 day
Secondary	Group acetylcholine levels	Acetylcholine levels will be compared for the entire study group for applications followed by a hypotensive response vs those that are not. For this analysis each application will be treated as an independent unit and independent T-test will be used to compare acetylcholine levels.	1 day