Understanding the mechanisms underlying cardiac fibrillation: insights from computational approaches for studying re-entrant circuits in atrial and ventricular fibrillation

Author: Dhani Dharmaprani

Dharmaprani, Dhani, 2020 Understanding the mechanisms underlying cardiac fibrillation: insights from computational approaches for studying re-entrant circuits in atrial and ventricular fibrillation, Flinders University, College of Medicine and Public Health

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Cardiac fibrillation is characterised by aperiodic turbulence of wave propagation. This can occur in the atria, known as atrial fibrillation (AF), or the ventricles, constituting ventricular fibrillation (VF). Despite over 100 years of research, the mechanisms by which these arrhythmias are maintained unfortunately remain incompletely understood, but are of great significance as AF is the most common cardiac arrhythmia in humans, and VF the leading cause of sudden death in the world.

Although the atria and ventricles possess vastly different geometries, ionic mechanisms and global structures, they share similar electrical wave propagation dynamics. A defining characteristic of both AF and VF is the presence of re-entrant circuits that appear during ongoing fibrillation. This has led many to believe that these rotational phenomena play a key role in perpetuating cardiac fibrillation. With this in mind, the primary goal of this research is to investigate the nature of re-entrant events to gain insights into their role in perpetuating cardiac fibrillation, and to explore new avenues for possible treatments.

Chapters 3 and 4 begin by investigating the spatial and temporal stability of re-entrant circuits. It is hypothesised that these sites can be used to create a targeted ablation strategy to treat AF, wherein focal burns are applied at, or in the vicinity of, stable and dominant re-entrant circuits (rotors). Targeting these sites is hoped to result in AF termination or modification. Keeping in line with this thinking, chapter 3 investigates the spatiotemporal stability of rotors using an entropybased mapping approach to determine whether targeted-ablation strategies may be feasible. It was found, however, that there was only a relative stability of the highest 10% of entropy regions, and that an overarching dynamic global instability was present.

Due to the intrinsic instability of re-entrant circuits implied by the findings of the entropy study in chapter 4, the focus of the PhD subsequently moved towards understanding the origin of this instability. The presence of unstable reentrant circuits in fact echoes much of the findings of many independent AF and VF studies conducted thus far. Consequently, Chapters 5-9 aim to collectively understand the unstable nature of reentrant circuits using a branch of mathematics known as stochastic process theory. Specifically, these chapters aim to develop quantitative statistical approaches for understanding the consistently observed, yet unexplained, unstable behaviour of re-entrant circuits plaguing the field for over a century. Collectively, these chapters suggest that cardiac fibrillation should perhaps be redefined as an arrhythmia not governed by singular, autonomous drivers, but instead by the continuous regeneration cycle of phase singularity birth and death.

Keywords: atrial fibrillation, ventricular fibrillation, arrhythmia, mechanism of fibrillation, phase singularities, rotors, stochastic process, Poisson process, entropy, Markov chain

Subject: Cardiology thesis

Thesis type: Doctor of Philosophy
Completed: 2020
School: College of Medicine and Public Health
Supervisor: Anand Ganesan