Three-dimensional mapping of electrical propagation in the heart: experimental and mathematical model based analysis

Abstract

In this thesis, mathematical modelling, instrumentation development and experimental studies are combined to effect two advances in the study of cardiac electrophysiology. Firstly, we outline a method that will enable microstructural information gathered using extended confocal microscopy to be incorporated into whole heart models of electrical propagation. A structured finite element technique is used to solve the bidomain equations on a realistic representation of myocardial architecture. The effects of intercellular gaps in the tissue on electrical propagation, and the response of myocardium to defibrillation-strength shocks, are examined. It is shown that myocardium is not a transversely isotropic electrical medium as has been widely assumed. Instead it is most appropriately viewed as orthotropic, with different electrical properties assigned to three microstructurally defined orthogonal axes. It is also concluded that the intercellular tissue gaps provide a likely mechanism for activation of a critical volume of tissue during defibrillation. Secondly, a novel imaging system is presented which enables transmembrane potentials to be recorded simultaneously at multiple sites through the heart wall. While heart surface optical recordings of transmembrane potential have been widely used in studies of normal and pathological heart rhythms, it is difficult to obtain information about propagation processes deep within the heart wall. A probe constructed from optical fibers is used to deliver excitation light to and collect fluorescence from 6 tissue sites each spaced 1mm apart. For individual channels, excitation is provided by the 488nm line of a watercooled argon-ion laser, while the fluorescence of a voltage-sensitive dye is split at 600nm and imaged into separate photodiodes for later signal ratioing. The system has been sucessfully used to record intramural action potentials in the isolated rabbit heart and is designed to be easily expandable to accommodate multiple optical probes. The fluorescence collection volume of the fibre-optic probe has been characterised in rhodamine solution using two-photon microscopy. These data are compared with corresponding results obtained with two flat cleaved optical fibres in solution and in stained heart tissue. The results demonstrate that the effective collection depth in cardiac tissue for our optrodes was 100μm, but that this is dependent on the type of optical fibre used to fabricate the optrode. These techniques developed in this research provide a basis for more systematic study of the initiation and termination of reentrant electrical activity in the heart. Future research that builds on the original findings presented in this thesis is discussed.