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

Figures

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  Figure 1. Enhanced GJ coupling regularizes VF to VT. Representative ECGs in response to (A) RTG (0–80 nM) with progressive regularization of VF to VT and (B) CBX (0–50 µM) with progressive VF disorganization on ECG. (C) Representative phase maps with tracked RAs in VF in response to RTG 80 nM showing existence of spatially stable RAs. (D) Representative phase maps in VF in response to CBX 50 µM showing disorganized myocardial activation only.

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  Figure 2. The degree of GJ coupling influences the stability of RAs. Representative RA heat map in (A) RTG- and (B) CBX-treated hearts in VF. (C) Progressive increase in maximum rotations for a single RA in RTG group in comparison to decrease with CBX. (D) Increase in percentage of VF time driven by RAs at increasing RTG concentrations comparative to decrease with CBX. Data from RTG (n = 10) and CBX (n = 10) hearts. Statistical analysis with repeated measures ANOVA, post hoc Bonferroni, P-values are in comparison to baseline, **P < 0.01 and ***P < 0.001.

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  Figure 3. Enhanced GJ coupling increases the global fibrillatory organization. Representative DF maps in response to (A) RTG and (B) CBX in VF. The DF of the largest organized region or the m-DF is indicated below in hertz (Hz). (C) A graph showing an increase in the FDI in RTG-treated hearts in comparison to (D) decrease with CBX. Data from RTG (n = 10) and CBX (n = 10) hearts. Statistical analysis with repeated measures ANOVA, post hoc Bonferroni, P-values are in comparison to baseline, ***P < 0.001. m-DF, maximal DF.

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  Figure 4. Validation of differing ventricular fibrosis models. (A) Representative ECG traces in differing fibrosis models in VF. (B) Representative mid-LV axial histological sections of fibrotic areas (dark red) and normal tissue (orange to pink), scale—black bar corresponds to 1 mm. (C) Histological LV fibrosis quantification. (D) Representative mid-LV short-axis slices with LGE. Data in (C) from select hearts; sham (n = 4), CF (n = 7), DiF (n = 7), and PF (n = 7) hearts. Statistical analysis with ANOVA post hoc Bonferroni multiple comparisons test, ***P < 0.001.

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  Figure 5. The pattern of fibrosis influences the stability of RAs in fibrillation. (A) Representative RA heat maps for differing fibrosis models; CF, DiF, and PF hearts in VF. (B) Percentage of VF time driven by RAs and (C) maximum duration for a single RA in the PF group is higher in comparison to sham surgery, CF and DiF groups. Data from sham surgery (n = 5), CF (n = 11), DiF (n = 11), and PF (n = 13) hearts. Statistical analysis with ANOVA, post hoc Bonferroni multiple comparisons test, *P < 0.05, **P < 0.01, ***P < 0.001.

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  Figure 6. PF anchors RAs and sustains the most globally organized fibrillation. (A) Representative DF maps in differing fibrosis groups; CF, DiF, and PF hearts in VF. The DF of the largest organized region or the m-DF is indicated below in hertz (Hz). (B) A graph showing the highest FDI in the PF group in comparison to DiF and CF. (C) Two representative PF hearts showing the mapped surface with fibrosis border in view (left), phase processed RA heat maps (middle), and corresponding histological cross-section from the shaded region (pink, pale yellow = normal myocardium, dark red = fibrosis, scale—black bar = 1 mm). Data from sham surgery (n = 5), CF (n = 11), DiF (n = 11), and PF (n = 13) hearts. Statistical analysis with ANOVA, post hoc Bonferroni multiple comparisons test, **P < 0.01, ***P < 0.001. m-DF, maximal DF.

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  Figure 7. The meander of RAs is lowest in PF and reduces with enhanced GJ coupling. Representative tracked paths of the longest duration RA (threshold—>5 rotations) in (A) RTG-treated group and (B) differing fibrosis groups; CF, DiF, and PF (left) and the corresponding centre shift from initiation to termination site over time (right). Data from RTG (n = 10) treated hearts in (A) and sham surgery (n = 5), CF (n = 11), DiF (n = 11), and PF (n = 13) hearts in (B). Statistical analysis with repeated measures ANOVA, post hoc Bonferroni, P-values are in comparison to baseline in (A) and ANOVA, post hoc Bonferroni multiple comparisons test in (B). *P < 0.05 and ***P < 0.001.