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1/Gap junction modulation is a major determinantof the mechanism and organisation of ventricularfibrillation and a potential therapeutic target

European Journal of Arrhythmia & Electrophysiology. 2019;5(Suppl. 1):abstr1

Background: Mechanisms that maintain ventricular fibrillation (VF) remain debated. There are both clinical and experimental data to support the existence of rotational drivers (RDs), though other conflicting studies have not demonstrated such drivers and suggested that VF is the result of disorganised myocardial activation. Abnormal electrical coupling between cardiomyocytes through gap junctions (GJ) has been considered an important factor in initiation and maintenance of VF and pre-treatment with GJ couplers has been shown to reduce VF inducibility.

Purpose: We hypothesised that the underlying mechanism of VF is determined by the degree of GJ coupling, and that changes in GJ coupling can shift or modify the predominant mechanism of fibrillation along the spectrum between disorganised activity and organised drivers. We postulated that increased organisation of VF is critical to its termination.

Methods: Thirty Sprague-Dawley rat hearts were explanted, perfused ex vivo and VF induced with burst pacing and 30 μM pinacidil. Optical mapping of transmembrane potential was performed at baseline and the effects of GJ coupling on VF dynamics were studied in an acute VF model by perfusing with increasing concentrations of a GJ uncoupler; carbenoxolone (0–50 µM, CBX, n=10) or a GJ coupling-enhancer; rotigaptide (0–80 nM, RTG, n=10). A chronic diffuse fibrosis model (n=10) was generated with 4 weeks of in vivo angiotensin infusion (500 nm/kg/min). Fibrillation dynamics were quantified using phase analysis, phase singularity (PS) tracking and our novel method of global fibrillation organisation quantification, frequency dominance index (FDI), which is defined as the power ratio of highest amplitude dominant frequency in the frequency spectrum.

Results: RTG increased average rotations per RD (Baseline: 2.86 ± 0.10 versus 80 nM: 5.66 ± 0.43, p<0.001) whilst CBX caused a reduction (Baseline: 3.77 ± 0.39 versus 50 µM: 0.26 ± 0.26, p<0.001). Maximum rotations for a RD increased with RTG (5.4 ± 0.45 versus 48.20 ± 12.32, p<0.001) and decreased with CBX (8.0 ± 1.3 versus 0.3 ± 0.3, p<0.001). Proportion of time PSs were detected in VF increased with RTG
(0.44 ± 0.06 versus 0.93 ± 0.02, p<0.001) and decreased with CBX
(0.61 ± 0.9 versus 0.03 ± 0.02, p<0.001). RTG reduced meander of longest duration RD (20.6 ± 1.68 versus 11.51 ± 0.77 pixels, p<0.001) for PS >5 rotations. FDI increased with RTG (0.53 ± 0.04 versus 0.78 ± 0.3, p<0.001) and decreased with CBX (0.60 ± 0.05 versus 0.17 ± 0.03, p<0.001). In the diffuse fibrosis group, in comparison to baseline RTG 80 nM increased FDI (0.35 versus 0.65, p<0.001) and terminated VF in 40% of hearts.

Conclusion: The degree of GJ coupling is a key determinant of the underlying mechanism of VF. RTG organised fibrillation and stabilised RDs in a concentration-dependent manner whilst CBX disorganised VF. Enhancing GJ coupling with RTG in diseased hearts with fibrosis can terminate VF. GJ coupling may be a potential therapeutic target in VF.

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