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.
Highlights
Remodelling of ventricular tissue is an adaptive response to trauma, disease and ageing
We used (i) freshly isolated neonatal rat ventricular cardiomyocytes (NRVMs), and (ii) a modified version of the mathematical model of these cells created by Korhonen et al.[43] including the adaptations made by Hou et al.[44]
Cx43↓ resulted in a dose-dependent reduction in Cx43 RNA and protein levels (Supplementary Fig. S2), conduction velocity (CV) and wavelength (λ, defined as: APD80 × CV; Supplementary Fig. S3)
Summary
Remodelling of ventricular tissue is an adaptive response to trauma, disease and ageing. Wavebreaks can occur in structurally homogeneous cardiac tissue as a result of dynamically induced functional heterogeneity, such as AP duration (APD) alternans when such heterogeneity is large enough to cause electrotonic load imbalance, a feature promoted by electrical remodelling[5,6,7,8,9]. In this paper a head-to-head, synergistic in silico-in vitro approach was applied for studying the mechanisms underlying arrhythmias in remodelled ventricular tissue, focusing on the effects of Cx43 down-regulation and diffuse cardiac fibrosis For this purpose, we used (i) freshly isolated neonatal rat ventricular cardiomyocytes (NRVMs), and (ii) a modified version of the mathematical model of these cells created by Korhonen et al.[43] including the adaptations made by Hou et al.[44]. Programmed electrical stimulation and voltage mapping, together with an interactive data exchange strategy, were used to investigate whether and how these features of ventricular remodelling affected electrical impulse generation and propagation as well as arrhythmia initiation and complexity
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