Regeneration of the cardiac conduction system

Thesis

Arrhythmias are a hallmark of myocardial infarction (MI) and increase mortality risk for patients. The cardiac conduction system is increasingly implicated in arrhythmias but how it is altered following MI is not well understood. I hypothesised that there is an impairment of the conduction system in adult infarcted hearts whereas it is rapidly restored in regenerative neonatal hearts to maintain normal rhythm.

In this thesis, I demonstrate complete conduction system restoration during neonatal mouse heart regeneration, versus pathological remodelling at non-regenerative stages that map onto the adult heart wound-healing response. By developing tissue-cleared whole- organ imaging and analysis approaches, I initially performed the first description and quantitative characterisation of the intact 3D architecture of the post-natal murine ventricular conduction system. Next, following MI injury, I identified global disruption to the His/Purkinje network, disorganised bundling of conduction fibres and regional loss of connexin-40 one week after birth which contrasted with regeneration of the network and restoration of fibres at immediate post-natal stages. Enriched single-cell RNA-sequencing revealed distinct transcriptional signatures of infarcted regenerating versus non-regenerating conduction cells. I identified that conduction cells undergo transition at a transcriptional and protein level to regenerate the network, as compared to sustained electrical alterations during fibrotic repair. I found that this manifests functionally via transition from normal rhythm to pathological conduction delay beyond the regenerative window. Finally, modelling the non- regenerative phenotype in the infarcted human heart implicated these changes as causative for bundle branch block and increased dyssynchrony of ventricular contraction, as is observed in MI patients.

Collectively, the findings of this thesis characterise conduction system growth and maturation following birth, identify pathophysiological electrical remodelling in the His/Purkinje network after MI, elucidate the cellular and molecular profiles of the regenerating conduction system, and demonstrate the consequence of MI-induced conduction system damage for clinical arrhythmogenesis.

Authors: Sayers, J

• DOI: 10.5287/ora-ry2r8xwav
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Connexin; 3D Imaging; Arrhythmia; Myocardial Infarction; Purkinje; Heart Regeneration; Remodelling; Single-cell RNA-sequencing; Electrical Conduction