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Ventricular fibrillation mechanism and global fibrillatory organisation are determined by gap junction coupling and fibrosis pattern

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Title: Ventricular fibrillation mechanism and global fibrillatory organisation are determined by gap junction coupling and fibrosis pattern
Authors: Handa, B
Li, X
Baxan, N
Roney, C
Shchendrygina,, A
Mansfield, C
Jabbour, R
Pitcher, D
Chowdhury, RA
Peters, N
Ng, FS
Item Type: Journal Article
Abstract: Aims Conflicting data exist supporting differing mechanisms for sustaining ventricular fibrillation (VF), ranging from disorganised multiple-wavelet activation to organised rotational activities (RAs). Abnormal gap junction (GJ) coupling and fibrosis are important in initiation and maintenance of VF. We investigated whether differing ventricular fibrosis patterns and the degree of GJ coupling affected the underlying VF mechanism. Methods and Results Optical mapping of 65 Langendorff-perfused rat hearts was performed to study VF mechanisms in control hearts with acute GJ modulation, and separately in three differing chronic ventricular fibrosis models; compact (CF), diffuse (DiF) and patchy (PF). VF dynamics were quantified with phase mapping and frequency dominance index (FDI) analysis, a power ratio of the highest amplitude dominant frequency in the cardiac frequency spectrum. Enhanced GJ coupling with rotigaptide (n = 10) progressively organised fibrillation in a concentration-dependent manner; increasing FDI (0nM: 0.53±0.04, 80nM: 0.78±0.03, p < 0.001), increasing RA sustained VF time (0nM:44±6%, 80nM: 94±2%, p < 0.001) and stabilised RAs (maximum rotations for a RA; 0nM:5.4±0.5, 80nM: 48.2±12.3, p < 0.001). GJ uncoupling with carbenoxolone progressively disorganised VF; the FDI decreased (0µM: 0.60±0.05, 50µM: 0.17±0.03, p < 0.001) and RA-sustained VF time decreased (0µM: 61±9%, 50µM: 3±2%, p < 0.001). In CF, VF activity was disorganised and the RA-sustained VF time was the lowest (CF: 27±7% versus PF: 75±5%, p < 0.001). Global fibrillatory organisation measured by FDI was highest in PF (PF: 0.67±0.05 versus CF: 0.33±0.03, p < 0.001). PF harboured the longest duration and most spatially stable RAs (patchy: 1411±266ms versus compact: 354±38ms, p < 0.001). DiF (n = 11) exhibited an intermediately organised VF pattern, sustained by a combination of multiple-wavelets and short-lived RAs. Conclusion The degree of GJ coupling and pattern of fibrosis influences the mechanism sustaining VF. There is a continuous spectrum of organisation in VF, ranging between globally organised fibrillation sustained by stable RAs and disorganised, possibly multiple-wavelet driven fibrillation with no RAs. Translational perspective Multiple competing mechanisms have been proposed for sustaining VF. We reframed conflicting mechanisms reported in sustaining fibrillation and defined them as part of a continuum of varying global organisation, with some sustained by stable rotationalactivities. The underlying cardiac electroarchitecture, namely gap junction coupling and fibrosis, were important determinants of the VF mechanism. Characterising the VF mechanism and its relationship to the cardiac electroarchitecture may facilitate a patient-tailored treatment approach towards VF prevention in VF survivors. Organised fibrillation sustained by stable rotational activities could be considered for targeted ablation. Disorganised fibrillation dynamics may be better suited for conventional pharmacotherapy.
Issue Date: 1-Apr-2021
Date of Acceptance: 6-May-2020
URI: http://hdl.handle.net/10044/1/80086
DOI: 10.1093/cvr/cvaa141
ISSN: 0008-6363
Publisher: Oxford University Press (OUP)
Start Page: 1078
End Page: 1090
Journal / Book Title: Cardiovascular Research
Volume: 117
Issue: 4
Copyright Statement: © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited
Sponsor/Funder: British Heart Foundation
British Heart Foundation
British Heart Foundation
British Heart Foundation
Rosetrees Trust
Rosetrees Trust
Imperial College Healthcare NHS Trust- BRC Funding
British Heart Foundation
Funder's Grant Number: RG/16/3/32175
PG/16/17/32069
PG/16/17/32069
RG/16/3/32175
A1173/ M577
A1407/ M645
RDB02
RE/18/4/34215
Keywords: Cardiovascular System & Hematology
1102 Cardiorespiratory Medicine and Haematology
Publication Status: Published
Online Publication Date: 2020-05-13
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine