Cardiovascular disease remains the primary cause of morbidity and mortality in the UK and EU, accounting for more than 2.0 million deaths per year across the EU. The economic consequences of cardiovascular disease are equally grave, with a total estimated annual health care expenditure of €109.7 billion in the EU, rising to €192.5 billion if informal health care costs and productivity losses are taken into account. The precise mechanisms underlying arrhythmogenesis in heart failure are not fully understood, however there is an increasing body of evidence identifying the Purkinje fibre (PF) network as both a major source and contributor to the sustenance of ventricular arrhythmias. Mathematical models of the electrical action potentials (APs), and their propagation through the cardiac conduction system, compliment, and present a unique alternative to, experimental observations and investigation. They enable fundamental physiological mechanisms to be dissected and theories rigorously tested in a consistent and efficient manner. In this thesis, a 3D wedge model of the canine Purkinje-ventricular junction (PVJ) is developed incorporating details of the transmural AP heterogeneity, tissue geometry, and fibre orientation of the left ventricular free wall, completed with a single PF entering the endocardium. The relationships between the tissue heterogeneity; AP conduction velocity; and the safety of conduction at the junction are explored and pharmacological effects on conduction through the junction are studied. A new mathematical model for the AP of the canine PF cell is developed to support the construction of the PVJ model and additionally, a new model for the AP of the human PF cell is developed. Biophysically detailed, species specific models are necessary for a complete understanding of the cardiac conduction system, yet PF models have been largely neglected since the early work of DiFrancesco & Noble in 1985. The models are proven in the analysis and dissection of the mechanisms underlying experimental phenomena including the Bowditch effect; rate dependence of the AP; and overdrive suppression.
|Date of Award||1 Aug 2011|
- The University of Manchester
|Supervisor||Henggui Zhang (Supervisor)|