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Islands of spatially discordant APD alternans underlie arrhythmogenesis by promoting electrotonic dyssynchrony in models of fibrotic rat ventricular myocardium.

Majumder R, Engels MC, de Vries AA, Panfilov AV, Pijnappels DA - Sci Rep (2016)

Bottom Line: However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail.At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced.This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Cardiology, Department of Cardiology, Heart Lung Centre Leiden, Leiden University Medical Enter, Leiden, the Netherlands.

ABSTRACT
Fibrosis and altered gap junctional coupling are key features of ventricular remodelling and are associated with abnormal electrical impulse generation and propagation. Such abnormalities predispose to reentrant electrical activity in the heart. In the absence of tissue heterogeneity, high-frequency impulse generation can also induce dynamic electrical instabilities leading to reentrant arrhythmias. However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail. Here, arrhythmogenesis was studied using in vitro and in silico monolayer models of neonatal rat ventricular tissue with 30% randomly distributed cardiac myofibroblasts and systematically lowered intercellular coupling achieved in vitro through graded knockdown of connexin43 expression. Arrhythmia incidence and complexity increased with decreasing intercellular coupling efficiency. This coincided with the onset of a specialized type of spatially discordant action potential duration alternans characterized by island-like areas of opposite alternans phase, which positively correlated with the degree of connexinx43 knockdown and arrhythmia complexity. At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced. This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity.

No MeSH data available.


Related in: MedlinePlus

Complexity of electrical activation patterns increases with decreasing CV.Comparison of (a) CV, (b) arrhythmia incidence and (c) arrhythmia complexity (i.e., number of PSs) in NRVM monolayers in silico (red bars) and in vitro (blue bars) at different levels of intercellular coupling and in the presence of 30% interspersed MFBs (N > 9). Statistical analysis was performed by comparing LV.PpLuc↓-transduced cell cultures (negative control) with cell cultures exposed to different amounts of LV.Cx43↓. Statistical significance was expressed as follows: *P < 0.05, #P < 0.001. Relationship between arrhythmia complexity and (d) CV or (e) wavelength (λ), defined as: APD80 × CV. (f) Pseudocolor plots of phase maps from the in silico (top panel) and in vitro (bottom panel) datasets. The small black circles indicate the locations of PSs.
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f1: Complexity of electrical activation patterns increases with decreasing CV.Comparison of (a) CV, (b) arrhythmia incidence and (c) arrhythmia complexity (i.e., number of PSs) in NRVM monolayers in silico (red bars) and in vitro (blue bars) at different levels of intercellular coupling and in the presence of 30% interspersed MFBs (N > 9). Statistical analysis was performed by comparing LV.PpLuc↓-transduced cell cultures (negative control) with cell cultures exposed to different amounts of LV.Cx43↓. Statistical significance was expressed as follows: *P < 0.05, #P < 0.001. Relationship between arrhythmia complexity and (d) CV or (e) wavelength (λ), defined as: APD80 × CV. (f) Pseudocolor plots of phase maps from the in silico (top panel) and in vitro (bottom panel) datasets. The small black circles indicate the locations of PSs.

Mentions: High-frequency electrical pacing (3.5 Hz) of our fibrotic NRVM monolayers with the highest degree of Cx43↓ in vitro led to complex arrhythmias, i.e., reentrant arrhythmias with multiple phase singularities (PSs; points in the phase map where the phase is indeterminate, around which activation wave fronts hinge and progress through a complete cycle from −π to +π; Fig. 1). In order to develop mechanistic insights into the underlying basis of these arrhythmias in a more subtle, precise, controllable and reproducible manner, we employed our in silico model. The first step involved validation of this model.


Islands of spatially discordant APD alternans underlie arrhythmogenesis by promoting electrotonic dyssynchrony in models of fibrotic rat ventricular myocardium.

Majumder R, Engels MC, de Vries AA, Panfilov AV, Pijnappels DA - Sci Rep (2016)

Complexity of electrical activation patterns increases with decreasing CV.Comparison of (a) CV, (b) arrhythmia incidence and (c) arrhythmia complexity (i.e., number of PSs) in NRVM monolayers in silico (red bars) and in vitro (blue bars) at different levels of intercellular coupling and in the presence of 30% interspersed MFBs (N > 9). Statistical analysis was performed by comparing LV.PpLuc↓-transduced cell cultures (negative control) with cell cultures exposed to different amounts of LV.Cx43↓. Statistical significance was expressed as follows: *P < 0.05, #P < 0.001. Relationship between arrhythmia complexity and (d) CV or (e) wavelength (λ), defined as: APD80 × CV. (f) Pseudocolor plots of phase maps from the in silico (top panel) and in vitro (bottom panel) datasets. The small black circles indicate the locations of PSs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4829862&req=5

f1: Complexity of electrical activation patterns increases with decreasing CV.Comparison of (a) CV, (b) arrhythmia incidence and (c) arrhythmia complexity (i.e., number of PSs) in NRVM monolayers in silico (red bars) and in vitro (blue bars) at different levels of intercellular coupling and in the presence of 30% interspersed MFBs (N > 9). Statistical analysis was performed by comparing LV.PpLuc↓-transduced cell cultures (negative control) with cell cultures exposed to different amounts of LV.Cx43↓. Statistical significance was expressed as follows: *P < 0.05, #P < 0.001. Relationship between arrhythmia complexity and (d) CV or (e) wavelength (λ), defined as: APD80 × CV. (f) Pseudocolor plots of phase maps from the in silico (top panel) and in vitro (bottom panel) datasets. The small black circles indicate the locations of PSs.
Mentions: High-frequency electrical pacing (3.5 Hz) of our fibrotic NRVM monolayers with the highest degree of Cx43↓ in vitro led to complex arrhythmias, i.e., reentrant arrhythmias with multiple phase singularities (PSs; points in the phase map where the phase is indeterminate, around which activation wave fronts hinge and progress through a complete cycle from −π to +π; Fig. 1). In order to develop mechanistic insights into the underlying basis of these arrhythmias in a more subtle, precise, controllable and reproducible manner, we employed our in silico model. The first step involved validation of this model.

Bottom Line: However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail.At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced.This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Cardiology, Department of Cardiology, Heart Lung Centre Leiden, Leiden University Medical Enter, Leiden, the Netherlands.

ABSTRACT
Fibrosis and altered gap junctional coupling are key features of ventricular remodelling and are associated with abnormal electrical impulse generation and propagation. Such abnormalities predispose to reentrant electrical activity in the heart. In the absence of tissue heterogeneity, high-frequency impulse generation can also induce dynamic electrical instabilities leading to reentrant arrhythmias. However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail. Here, arrhythmogenesis was studied using in vitro and in silico monolayer models of neonatal rat ventricular tissue with 30% randomly distributed cardiac myofibroblasts and systematically lowered intercellular coupling achieved in vitro through graded knockdown of connexin43 expression. Arrhythmia incidence and complexity increased with decreasing intercellular coupling efficiency. This coincided with the onset of a specialized type of spatially discordant action potential duration alternans characterized by island-like areas of opposite alternans phase, which positively correlated with the degree of connexinx43 knockdown and arrhythmia complexity. At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced. This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity.

No MeSH data available.


Related in: MedlinePlus