Multi-scale modelling and simulations into the mechanisms linking neuronal nitric oxide synthase and atrial fibrillation

Thesis

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its incidence is projected to rise due to population ageing and increasing prevalence of associated risk factors. AF alters, or remodels, the affected atrial tissue, promoting future occurrences of itself and increasing resistance to treatment. Mechanisms underlying AF initiation and remodelling are not well understood. Recent experimental evidence indicates that decreased levels of the neuronal isoform of Nitric Oxide Synthase (nNOS) may be related to AF onset and precede remodelling. However, the potential mechanisms cannot be easily elucidated with experiments alone. Furthermore, experiments are complicated by inter-subject variability, which is particularly important in human studies due to the wide heterogeneity of the human population.

In this thesis, I use multi-scale modelling and simulations in synergy with experimental information to investigate mechanistic links between nNOS and AF at the level of ionic currents/cellular action potential/whole atria in human. First, I construct populations of models spanning experimentally-observed variability in human atrial myocytes under control conditions. Second, I use those populations of control models to identify key ionic mechanisms underpinning nNOS-mediated regulation of the cellular action potential in human atrial myocytes. I show that two of those currents – I_Kur and I_K1 – play a key role in explaining the phenotypic shortening of the action potential observed under nNOS inhibition conditions and preceding AF-induced tissue remodelling. Finally, I build models of human whole atria and establish that this action potential shortening leads to the establishment of a vulnerable substrate, and hence is the main mechanism of pro-arrhythmia at this level. Overall, I provide a picture of nNOS-mediated mechanisms related to AF onset from ionic currents to the whole organ level.

Authors: Muszkiewicz, A

• DOI: 10.5287/ora-zg2k0xa2w
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford