The recently identified genetic short QT syndrome is characterised by abbreviated QT intervals on the electrocardiogram, an increased risk of atrial and ventricular arrhythmias, and an increased risk of sudden death. Although the short QT syndrome has been suggested to provide a paradigm for increasing understanding of the role of potassium channels in ventricular fibrillation, the basis for arrhythmogenesis in the short QT syndrome is incompletely understood. There are no animal models that accurately reproduce a short QT phenotype, and whilst in vitro electrophysiology of short QT mutant channels provides a route to greater understanding of the effects of short QT mutants on action potential repolarisation, on its own, this approach is insufficient to explain how arrhythmias arise and are maintained at the tissue level. Consequently, this thesis is concerned with the use of the viable alternative; in silico (computational) modelling to elucidate how the short QT syndrome facilitates the genesis and maintenance of ventricular arrhythmias and its effects on ventricular contraction. Using extant biophysical data on changes induced by the short QT mutations and data from BHF-funded in vitro electrophysiology, three novel mathematical models of the first three variants of the short QT syndrome were developed; a Markov chain model for short QT variant 1, a Markov chain model for short QT variant 2 and a Hodgkin-Huxley model for short QT variant 3. These models were incorporated into single cell and anatomically detailed tissue and organ computer models to elucidate how these variants lead to ventricular arrhythmias. The developed short QT models were then incorporated into electromechanically coupled single cell and tissue models to investigate the effects of the short QT mutants on ventricular contraction. It was found that each short QT variant uniquely increased the transmural dispersion of action potential duration across the ventricular wall, increased the temporal window of tissue vulnerability to premature excitation stimulus, leading to increased susceptibility to re-entrant arrhythmia.

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A solution to distinguish ventricular fibrillation and ventricular flutter from other arrhythmias and from disturbances caused by body motion or muscle activity with the use of a neural network has been investigated. Ventricular fibrillation and ventricular flutter occurs when the cardiac muscle cells are not triggered by the cardiac conduction system, but rather by ectopic foci preventing a synchronized contraction of the cardiac muscle cells and therefore inhibiting the hearts capability to properly pump blood. Two different methods, gradient descent and quasi-Newton, used by the network for learning was tested and preprocessing methods used on the input data before introducing it to the network was evaluated. Gradient descent makes use of the gradient to the error function with regards to its weights and updates the network in the direction which the output error by the network decreases the most. Quasi-Newton update the network roughly in the Newton direction by iteratively build up an approximation to the Hessian of the error function with the use of information from the gradient. The preprocessing methods used were: Threshold Crossing Intervals (TCI) which looks at the time between baseline crossings of the ECG signal. Mean Absolute Value (MAV) which computes the mean absolute value of the normalized ECG signal. Spectral Analysis which takes into account different properties of the frequency spectrum of ventricular fibrillation and normal sinus rhythm. VF-filter which assumes VF to be sinusoidal and computes the leakage after the ECG signal has been bandstop filtered around the mean frequency. Period and Amplitude Information of the maximum amplitude of the input frequency spectrum and its period. It was found that the networks that used the preprocessed signal was a poor classifier for the arrhythmias partially because ventricular fibrillation was not easily separable from the arrhythmias by the implementaion of the preprocessed inputs given.

Spatio-temporal variation in activation rates during ventricular fibrillation (VF)provides insight into mechanisms of sustained re-entry during VF. This study had three objectives related to spatio-temporal dynamics in activation rates during VF. The first objective was to quantify spatio-temporal variability in activation rates,that is, in dominant frequencies, computed from epicardial electrograms recorded during VF in swine. Results showed that temporally and spatially, dominant frequencies variedas much as 20% of the mean dominant frequency, and the mean dominant frequencies increased during first 30 sec of VF. These results suggest that activation rates are nonstationary during VF. The second objective of the study was to develop a new stimulation protocol for quantifying restitution of action potential duration (APD) by independently controlling diastolic intervals (DI). A property of cardiac cells that determines spatio-temporal variability in dominant frequencies is restitution of APD, which relates APD to the previous DI. Independent control of DI permits explicit determination of the role of memory in restitution. Restitution functions quantified using mathematical models of activation and our stimulation protocol, showed significant hysteresis. That is, for adiastolic interval, the action potential durations were as much as 15% longer during periods when the DI were decreasing than when the DI were increasing. We verified the feasibility of implementing our protocol experimentally in isolated and perfused rat hearts with action potentials recorded using floating glass microelectrodes. The third objective of our study was to verify that spatio-temporal variability in dominant frequencies during VF could be modified using spatially distributed pacing strength stimuli. Simulated VF was induced in 400x400 and 400x800 matrices of cells. Electrical function of cells was simulated using the Luo-Rudy model. Stimulators were arranged in the matrices such that there were 5 rows of line stimulators. Results showed that it was possible to modify activations in almost 54% of the area and to modify spatio-temporal variability in activation during VF into a desired pattern by the use of synchronized pacing from multiple sites. These results support further exploration of distributed stimulation approach for potential improvements in defibrillation therapy.

Background: Modulation of ischemia-dependent pathways alters electrophysiological evolution of ventricular fibrillation(VF). Hypothesis: 1)There is regional disease-related expression of KATP-channels in human cardiomyopathic hearts. 2)KATP-channel blockade promotes spontaneous VF termination by attenuating spatiotemporal dispersion of refractoriness(ΔERP). Methods and Results: Electric mapping of control(n=6) and treatment(n=9) (10 μmol/L glibenclamide) isolated human cardiomyopathic hearts was performed. Spontaneous defibrillation and KATP-subunit gene expression were studied. Spontaneous VF termination occurred in 1/6 control and 7/8 treated hearts (P=0.026). After 180 seconds of ischemia, LV transmural dispersion in VF cycle length was observed(p=0.001), which was attenuated by glibenclamide. There was greater gene expression of all KATP-subunit on the endocardium compared with the epicardium(P<0.02). In ischemic rat heart model, ΔERP was verified with pacing protocols (36±5ms vs 4.9±4ms, p=0.019). Conclusions: KATP channel subunit gene expression is heterogeneously altered in the cardiomyopathic human heart. Blockade of KATP channels promotes spontaneous defibrillation by attenuating ischemia-dependent ΔERP during VF.

Background: Modulation of ischemia-dependent pathways alters electrophysiological evolution of ventricular fibrillation(VF). Hypothesis: 1)There is regional disease-related expression of KATP-channels in human cardiomyopathic hearts. 2)KATP-channel blockade promotes spontaneous VF termination by attenuating spatiotemporal dispersion of refractoriness(ΔERP). Methods and Results: Electric mapping of control(n=6) and treatment(n=9) (10 μmol/L glibenclamide) isolated human cardiomyopathic hearts was performed. Spontaneous defibrillation and KATP-subunit gene expression were studied. Spontaneous VF termination occurred in 1/6 control and 7/8 treated hearts (P=0.026). After 180 seconds of ischemia, LV transmural dispersion in VF cycle length was observed(p=0.001), which was attenuated by glibenclamide. There was greater gene expression of all KATP-subunit on the endocardium compared with the epicardium(P<0.02). In ischemic rat heart model, ΔERP was verified with pacing protocols (36±5ms vs 4.9±4ms, p=0.019). Conclusions: KATP channel subunit gene expression is heterogeneously altered in the cardiomyopathic human heart. Blockade of KATP channels promotes spontaneous defibrillation by attenuating ischemia-dependent ΔERP during VF.

Ventricular fibrillation is one of the leading causes for Sudden Cardiac Death and is characterized by multiple activation wavefronts. Multiple activation wavefronts originate from a reentrant circuit which requires the presence of a unidirectional block in the path of a propagating excitation wave. It has been proposed that at the cellular level beat to beat alternation in the action potential duration at rapid pacing rates can result in a conduction block. Various mechanisms have been postulated to show the mechanisms of alternans. We use simulated activation in a one dimensional tissue fiber to show the existence of a new mechanism via which alternans can result. We used a new pacing protocol to eliminate alternans at the pacing site, and thus eliminating restitution of action potential duration at this site to reveal existence of alternans down the fiber. Effects on alternans of manipulations of specific ionic currents such as the sodium current (INa), calcium current (ICaL), potassium current (Ikr) and of the diffusion co-efficient (Dx) which simulates reduced expression of connexin 43 were determined. Decrease in sodium conductance, i.e. in excitability by half caused the alternans to occur at the pacing site itself even though APD restitution was eliminated. An increase or decrease in calcium current (ICaL) eliminated alternans throughout the fiber. The use of a novel pacing approach in investigation of alternans, as in this study, furthers our understanding of the mechanism of alternans and may prove helpful in the development of better anti-arrhythmic drugs in the future.

Spatio-temporal variation in action intervals during ventricular fibrillation (VF) suggestthat the excitable gap may also be distributed spatio-temporally. The observation leadus to hypothesize that distributed pacing can be used to modify and entrain electricalactivation during VF. We tested this hypothesis using simulated VF and animal studies. We simulated VF in a 400 by 400 cell matrix. Simulation results showed that activationpattern could be entrained using spatially distributed stimulation. Up to a certain limit,increasing stimulus strength and density led to improved entrainment. Best entrainmentwas obtained by pacing at a cycle length similar to the intrinsic cycle length. In order to verify whether activation could be entrained experimentally, eight opticallyisolated biphasic TTL addressable stimulators were fabricated. Distributed stimulationwas tested during electrically induced VF in two canines and two swine. Resultsshowed that electrical activation could be entrained in both species. Similar to that insimulation, better entrainment was obtained with denser pacing distribution and atpacing cycle length similar to the intrinsic cycle length. As expected, entrainment wasaffected by tissue thickness. Our results show that spatio-temporally distributed pacingstrength stimuli can be used to modify activation patterns during VF.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 109-117).

Thesis (M.S.)--University of Alabama at Birmingham, 2007. / Description based on contents viewed Oct. 5, 2007; title from title screen. Includes bibliographical references (p. 19-20).