Self-organization of conducting pathways explains electrical wave propagation in cardiac tissues with high fibrosis

Abstract

Cardiac fibrosis occurs in many forms of heart disease and is considered to be one of the main arrhythmogenic factors. Regions with a high density of fibrosis are likely to cause blocks of wave propagation that give rise to dangerous cardiac arrhythmias. Therefore, studies of the wave propagation through these regions are very important, yet the precise mechanisms leading to arrhythmia formation in fibrotic cardiac tissue remain poorly understood. Particularly, it is not clear how wave propagation is organized at the cellular level, as experiments show that the regions with a high percentage of fibrosis (65-75%) are still conducting electrical signals, whereas geometric analysis of randomly distributed cells predicts connectivity loss at 40% at the most (percolation threshold). To address this question, we used a joint in vitro-in silico approach, which combined experiments in neonatal rat cardiac monolayers with morphological and electrophysiological computer simulations. We have shown that the main reason for sustainable wave propagation in highly fibrotic samples is the formation of a branching network of cardiomyocytes. We have successfully reproduced the morphology of conductive pathways in computer modelling, assuming that cardiomyocytes align their cytoskeletons to fuse into cardiac syncytium. The electrophysiological properties of the monolayers, such as conduction velocity, conduction blocks and wave fractionation, were reproduced as well. In a virtual cardiac tissue, we have also examined the wave propagation at the subcellular level, detected wavebreaks formation and its relation to the structure of fibrosis and, thus, analysed the processes leading to the onset of arrhythmias.\n\nAuthor summaryCardiac arrhythmias are one of the major causes of death in the industrialized world. The most dangerous ones are often caused by the blocks of propagation of electrical signals. One of the common factors that contribute to the likelihood of these blocks, is a condition called cardiac fibrosis. In fibrosis, excitable cardiac tissue is partially replaced with the inexcitable connective tissue. The precise mechanisms leading to arrhythmia formation in fibrotic cardiac tissue remain poorly understood. Therefore, it is important to study wave propagation in fibrosis from cellular to tissue level. In this paper, we study fibrosis of high density in experiments and computer simulations. We have observed a paradoxical ability of the tissue with extremely high fibrosis (up to 75% of fibroblasts) to conduct electrical signals and contract synchronously, whereas geometric analysis of randomly distributed cells predicted connectivity loss at 40% at the most. To explain this phenomenon, we have studied the patterns that cardiac cells form in the tissue and reproduced their self-organisation in a computer model. Our virtual model also took into account the polygonal shapes of the spreading cells and explained high arrhythmogenicity of fibrotic tissue.