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

• Published in: Scientific reports 2016-04, Vol.6 (1), p.24334-24334, Article 24334
• Main Authors: Majumder, Rupamanjari, Engels, Marc C., de Vries, Antoine A. F., Panfilov, Alexander V., Pijnappels, Daniël A.
• Format: Article
• Language: English
• Subjects: 13/106; 13/89; 38/44; 45/77; 631/1647/767/1657; 631/57/2266; Action potential; Animal models; Animals; Arrhythmia; Arrhythmias, Cardiac - physiopathology; Cardiac arrhythmia; Cells, Cultured; Connexin 43; Disease Models, Animal; Fibrosis; Gap junctions; Heart diseases; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Heterogeneity; Humanities and Social Sciences; Islands; multidisciplinary; Myocardium; Neonates; Rats; Science; Stochasticity; Ventricle
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep24334

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.