Abstract:
The research presented in this thesis extends our understanding of the spread of electrical activation in the heart and its relationship to cardiac structure. This has been achieved by successfully combining three powerful techniques: (i) intramural mapping of optical and extracellular potentials (ii) 3D reconstruction of myocardial tissue architecture in regions of the heart from which high-density intramural electrical mapping data have been acquired, and (iii) experiment-specific computer modelling. The work has produced several novel outcomes. For the first time, transmembrane potentials have been compared with extracellular potentials at adjacent intramural sites in the intact LV. Intramural extracellular potential mapping has been used to reconstruct 3D electrical activation sequences in the LV at much higher spatial resolution than has previously been reported. Moreover, because these data are registered directly to 3D myocardial architecture imaged throughout the same tissue volume, it has been possible to probe the relationship between LV structure and electrical vents across a range of scales. Experiment-specific computer models that incorporate detailed 3D structural information have also been used to interpret and integrate experimental data. Finally, we have demonstrated that a cardiopulmonary bypass preparation provides a physiologically stable experimental platform for intramural optical mapping in large hearts which can be used during ventricular tachycardia and fibrillation. The principal scientific findings of this research are: 1. The electrical properties that determine extracellular potential fields and the spread of electrical activation in LV myocardium are orthotropic, and are associated with distinct microstructural axes. The propagation of activation from an intramural point stimulus is most rapid in the myofibre direction. However, transverse to this, activation spreads preferentially in the direction of muscle layers and is slowest normal to the myolaminae. These findings challenge the widespread assumption that electrical coupling in ventricular myocardium is uniform transverse to the local myocyte axis. 2. While structurally detailed computer models that incorporate orthotropic intracellular and extracellular conductivities capture key features of the 3D extracellular potentials generated during electrical activation, there is strong evidence that active propagation in normal LV myocardium is discontinuous at the tissue level not captured by continuum modelling.