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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

Role of MFBs in reentry initiation: insights from the in silico model.(a) Voltage and (b) alternans phase maps of in silico NRVM cultures corresponding to the experimental group with the lowest CV, containing different percentages of randomly distributed MFBs. Alternans was not observed in monolayers with 100% cardiomyocytes (a1,b1); in the presence of 10% MFBs, some portions of the monolayer began to show unstable alternans (a2,b2). In this scenario wavebreaks could occur, but these failed to develop into reentrant circuits. With 15% MFBs (a3,b3) a limited number of large APIs began to form and; unstable reentry could be initiated. With 25% MFBs (a4,b4), multiple APIs started to form, which evolved dynamically giving rise to stable reentrant circuits. Raising the percentage of MFBs to 30% further increased the pro-arrhythmicity of the substrate (a5,b5).
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f6: Role of MFBs in reentry initiation: insights from the in silico model.(a) Voltage and (b) alternans phase maps of in silico NRVM cultures corresponding to the experimental group with the lowest CV, containing different percentages of randomly distributed MFBs. Alternans was not observed in monolayers with 100% cardiomyocytes (a1,b1); in the presence of 10% MFBs, some portions of the monolayer began to show unstable alternans (a2,b2). In this scenario wavebreaks could occur, but these failed to develop into reentrant circuits. With 15% MFBs (a3,b3) a limited number of large APIs began to form and; unstable reentry could be initiated. With 25% MFBs (a4,b4), multiple APIs started to form, which evolved dynamically giving rise to stable reentrant circuits. Raising the percentage of MFBs to 30% further increased the pro-arrhythmicity of the substrate (a5,b5).

Mentions: Having made the association between reentry initiation, the complexity of reentry patterns and API formation, the origin of these APIs was investigated next. Specifically, the combinatorial effects of structural discontinuities (MFBs) and functional instabilities (high frequency pacing-induced alternans) on the onset of reentry were studied in silico. As shown in Fig. 5a–h, in monolayers with 30% randomly distributed MFBs, APIs only occurred at cycle lengths <333 ms and their number increased with a further decrease in cycle length. For investigations into the role of structural discontinuities in API formation, computer simulations of NRVM cultures containing different percentages of MFBs and a CV of ~7.9 cm/s (i.e., the lowest CV analysed) were performed. High-frequency paced NRVM cultures without MFBs showed that APD alternans was practically absent (Fig. 6a1,b1) and wavebreaks were not observed. In monolayers with 10% randomly distributed MFBs, APD alternans began to appear (Fig. 6a2,b2). Large APIs emerged when ~15% of the cells were MFBs (Fig. 6a3,b3). Stable API-mediated reentry was observed in monolayers containing ≥ 25% MFBs (Fig. 6a4,b4,a5,b5), and at > 40% MFBs conduction block occurred. Thus, the presence of interspersed MFBs above a certain critical percentage could be recognized as a factor involved in the formation of APIs. Taken together, our data indicate the co-occurrence of (i) tissue heterogeneity (e.g., diffuse fibrosis) and (ii) CV slowing below a certain threshold (e.g., by Cx43 down-regulation) is required for successful API formation upon high-frequency pacing. Furthermore, increased numbers of MFBs lowers the threshold of CV reduction and decreased CV lowers the threshold of fibrosis necessary for API formation.


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)

Role of MFBs in reentry initiation: insights from the in silico model.(a) Voltage and (b) alternans phase maps of in silico NRVM cultures corresponding to the experimental group with the lowest CV, containing different percentages of randomly distributed MFBs. Alternans was not observed in monolayers with 100% cardiomyocytes (a1,b1); in the presence of 10% MFBs, some portions of the monolayer began to show unstable alternans (a2,b2). In this scenario wavebreaks could occur, but these failed to develop into reentrant circuits. With 15% MFBs (a3,b3) a limited number of large APIs began to form and; unstable reentry could be initiated. With 25% MFBs (a4,b4), multiple APIs started to form, which evolved dynamically giving rise to stable reentrant circuits. Raising the percentage of MFBs to 30% further increased the pro-arrhythmicity of the substrate (a5,b5).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Role of MFBs in reentry initiation: insights from the in silico model.(a) Voltage and (b) alternans phase maps of in silico NRVM cultures corresponding to the experimental group with the lowest CV, containing different percentages of randomly distributed MFBs. Alternans was not observed in monolayers with 100% cardiomyocytes (a1,b1); in the presence of 10% MFBs, some portions of the monolayer began to show unstable alternans (a2,b2). In this scenario wavebreaks could occur, but these failed to develop into reentrant circuits. With 15% MFBs (a3,b3) a limited number of large APIs began to form and; unstable reentry could be initiated. With 25% MFBs (a4,b4), multiple APIs started to form, which evolved dynamically giving rise to stable reentrant circuits. Raising the percentage of MFBs to 30% further increased the pro-arrhythmicity of the substrate (a5,b5).
Mentions: Having made the association between reentry initiation, the complexity of reentry patterns and API formation, the origin of these APIs was investigated next. Specifically, the combinatorial effects of structural discontinuities (MFBs) and functional instabilities (high frequency pacing-induced alternans) on the onset of reentry were studied in silico. As shown in Fig. 5a–h, in monolayers with 30% randomly distributed MFBs, APIs only occurred at cycle lengths <333 ms and their number increased with a further decrease in cycle length. For investigations into the role of structural discontinuities in API formation, computer simulations of NRVM cultures containing different percentages of MFBs and a CV of ~7.9 cm/s (i.e., the lowest CV analysed) were performed. High-frequency paced NRVM cultures without MFBs showed that APD alternans was practically absent (Fig. 6a1,b1) and wavebreaks were not observed. In monolayers with 10% randomly distributed MFBs, APD alternans began to appear (Fig. 6a2,b2). Large APIs emerged when ~15% of the cells were MFBs (Fig. 6a3,b3). Stable API-mediated reentry was observed in monolayers containing ≥ 25% MFBs (Fig. 6a4,b4,a5,b5), and at > 40% MFBs conduction block occurred. Thus, the presence of interspersed MFBs above a certain critical percentage could be recognized as a factor involved in the formation of APIs. Taken together, our data indicate the co-occurrence of (i) tissue heterogeneity (e.g., diffuse fibrosis) and (ii) CV slowing below a certain threshold (e.g., by Cx43 down-regulation) is required for successful API formation upon high-frequency pacing. Furthermore, increased numbers of MFBs lowers the threshold of CV reduction and decreased CV lowers the threshold of fibrosis necessary for API formation.

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