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

Abstract

Aims Conflicting data exist supporting differing mechanisms for sustaining ventricular fibrillation (VF), ranging from disorganized multiple-wavelet activation to organized 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 fibrosis (CF), diffuse fibrosis (DiF), and patchy fibrosis (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 organized fibrillation in a concentration-dependent manner; increasing FDI (0 nM: 0.53 ± 0.04, 80 nM: 0.78 ± 0.03, P < 0.001), increasing RA-sustained VF time (0 nM: 44 ± 6%, 80 nM: 94 ± 2%, P < 0.001), and stabilized RAs (maximum rotations for an RA; 0 nM: 5.4 ± 0.5, 80 nM: 48.2 ± 12.3, P < 0.001). GJ uncoupling with carbenoxolone progressively disorganized VF; the FDI decreased (0 µM: 0.60 ± 0.05, 50 µM: 0.17 ± 0.03, P < 0.001) and RA-sustained VF time decreased (0 µM: 61 ± 9%, 50 µM: 3 ± 2%, P < 0.001). In CF, VF activity was disorganized and the RA-sustained VF time was the lowest (CF: 27 ± 7% vs. PF: 75 ± 5%, P < 0.001). Global fibrillatory organization measured by FDI was highest in PF (PF: 0.67 ± 0.05 vs. CF: 0.33 ± 0.03, P < 0.001). PF harboured the longest duration and most spatially stable RAs (patchy: 1411 ± 266 ms vs. compact: 354 ± 38 ms, P < 0.001). DiF (n = 11) exhibited an intermediately organized 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 organization in VF, ranging between globally organized fibrillation sustained by stable RAs and disorganized, possibly multiple-wavelet driven fibrillation with no RAs.

Toward Mechanism-Directed Electrophenotype-Based Treatments for Atrial Fibrillation

“…All the above-mentioned mechanisms may be relevant and important in sustaining AF, and the predominant AF mechanism in an individual is dependent on the specific nature of the underlying atrial substrate. We recently systematically demonstrated that a spectrum of ventricular fibrillation (VF) mechanisms exists, and that the mechanism sustaining VF is determined by the underlying substrate of the ventricular myocardium (Handa et al, 2020b). We reported a continuous range of fibrillation "electrophenoypes" that can sustain VF, influenced by the substrate spectrum that incorporates the degree of gap junction coupling and the specific pattern of fibrosis.…”

“… Proposed electrophenotype spectrum for myocardial fibrillation. Recent experimental data suggest that VF mechanisms exist along a continuum, ranging organized VF, sustained by focal drivers, through to disorganized VF, sustained by multiple meandering wavefronts ( Handa et al, 2020b ). The specific fibrillation electrophenotype is determined by the underlying substrate or electroarchitecture, with the pattern of fibrosis and gap junction coupling being two important determinants.…”

“…The proposed paradigm is that AF mechanisms exist along a similar continuous spectrum, and thus treatments need to be tailored and targeted toward the specific AF electrophenotype to be successful. Figure adapted and reproduced from Eckstein et al (2008) and Handa et al (2020b) , with permission from Oxford University Press and Elsevier.…”

“…However, such a tailored approach to AF treatment is critically dependent on the ability to accurately identify the AF electrophenotype in patients. Much of the work on AF and VF mechanisms, including our own, has been performed with high-resolution optical mapping ( Davidenko et al, 1992 ; Muñoz et al, 2007 ; Roney et al, 2018 ; Handa et al, 2020b ). The problem of low spatial resolution clinical data, which has hampered the interpretation of human AF data ( King et al, 2017 ; Roney et al, 2017 ), would need to be overcome, and novel approaches for handling fibrillation data would be required.…”

“…Figure adaptedand reproduced fromEckstein et al (2008) andHanda et al (2020b), with permission from Oxford University Press and Elsevier.…”