Integrative computational approach to the role Of myocardial structure in myocardial function and dysfunction
Lead Research Organisation:
University of Leeds
Department Name: Institute of Membrane & Systems Biology
Abstract
We are trying to discover how the complex three-dimensional structure of the heart muscle effects the conduction of electrical excitation that drives each heart beat.
It has been shown, by us and others, that the muscle cells of the heart are organised into an intricate highly complex structural network, which is paradoxically both highly regular and highly variable. Structure is known to influence the spread of electricity in both health and disease, but the details of this are not known. Structural changes through the heart wall together with differences in electrical properties are thought to play a role in the success or failure of defibrillation.
Investigating cardiac electrical conduction is a challenge in living people as it would require imaging the structure and excitation of the beating heart.
We will investigate this question using the rabbit as an animal model. We will probe the microscopic structure of the normal and diseased heart using medical imaging methods and we will record the movement of excitation through the heart using dyes which change colour depending on voltage. This information will be analysed using a sophisticated computer model. We will address the important question: how is the heart rhythm affected by heart structure?
It has been shown, by us and others, that the muscle cells of the heart are organised into an intricate highly complex structural network, which is paradoxically both highly regular and highly variable. Structure is known to influence the spread of electricity in both health and disease, but the details of this are not known. Structural changes through the heart wall together with differences in electrical properties are thought to play a role in the success or failure of defibrillation.
Investigating cardiac electrical conduction is a challenge in living people as it would require imaging the structure and excitation of the beating heart.
We will investigate this question using the rabbit as an animal model. We will probe the microscopic structure of the normal and diseased heart using medical imaging methods and we will record the movement of excitation through the heart using dyes which change colour depending on voltage. This information will be analysed using a sophisticated computer model. We will address the important question: how is the heart rhythm affected by heart structure?
Technical Summary
I will explore the role of local myocardial structure in cardiac excitation and arrhythmia.
The arrangement of the ventricular myocytes is controversial. In a leading model myocytes are arranged as regularly helically coursing fibres running through sheets. Structural studies show that sheets belong to two populations (of positive or negative orientation), have a complex distribution, vary in form between individuals and have localised regions of sudden orientation change. Ventricular electrophysiological propagation is significantly influenced by both by fibre orientation and local sheet structure, and these and other heterogeneities are believed to play a role in the success or failure of defibrillation. Detailed understanding of normal and deranged cardiac excitation requires the integration of knowledge of individual myocyte electrophysiology, cell interconnectivity, the 3D structural arrangement of myocytes and the of the purkinje system.
I will acquire structural and functional data from experimental studies of selected regions of the normal rabbit myocardium, at high spatial resolution. This will be extended to the whole left ventricle, at lower spatial resolution. These data will be built into an integrative structural computational model (virtual tissue). Electrophysiological propagation will be simulated, based upon experimental recordings and using the virtual tissue. Structural changes in the diseased myocardium will be incorporated by manipulation of the normal model, based on published rabbit studies and from our exploration of canine cardiomyopathy. This will also allow the exploration of interspecies differences in the normal and diseased heart.
Structure will be analysed using DT-MRI and three-dimensional histology. The distribution of gap junctions and ion channels (as a marker of myocyte sub-type) will be mapped using immunohistochemistry and in situ hybridisation. These data will be complemented by recording the monophasic action potential and optical recording using voltage sensitive dyes. A multi-layered and detailed virtual tissue will be constructed and then used for the simulation of normal and abnormal electrical propagation. We will explore the roles of the anatomic distribution of fibres, sheets, gap junctions and cell types in electrical propagation. Electrophysiology recording will be used to refine the model, and the model will be used to redirect the recording studies.
The outputs are i) detailed structural data, ii) a structural and simulation model, and iii) the knowledge from electrophysiological recording and simulation. These will add to the scientific understanding of the mechanisms of arrhythmia which will, in turn, facilitate development of therapies. Specifically the results may find application in clinical defibrillation studies.
The arrangement of the ventricular myocytes is controversial. In a leading model myocytes are arranged as regularly helically coursing fibres running through sheets. Structural studies show that sheets belong to two populations (of positive or negative orientation), have a complex distribution, vary in form between individuals and have localised regions of sudden orientation change. Ventricular electrophysiological propagation is significantly influenced by both by fibre orientation and local sheet structure, and these and other heterogeneities are believed to play a role in the success or failure of defibrillation. Detailed understanding of normal and deranged cardiac excitation requires the integration of knowledge of individual myocyte electrophysiology, cell interconnectivity, the 3D structural arrangement of myocytes and the of the purkinje system.
I will acquire structural and functional data from experimental studies of selected regions of the normal rabbit myocardium, at high spatial resolution. This will be extended to the whole left ventricle, at lower spatial resolution. These data will be built into an integrative structural computational model (virtual tissue). Electrophysiological propagation will be simulated, based upon experimental recordings and using the virtual tissue. Structural changes in the diseased myocardium will be incorporated by manipulation of the normal model, based on published rabbit studies and from our exploration of canine cardiomyopathy. This will also allow the exploration of interspecies differences in the normal and diseased heart.
Structure will be analysed using DT-MRI and three-dimensional histology. The distribution of gap junctions and ion channels (as a marker of myocyte sub-type) will be mapped using immunohistochemistry and in situ hybridisation. These data will be complemented by recording the monophasic action potential and optical recording using voltage sensitive dyes. A multi-layered and detailed virtual tissue will be constructed and then used for the simulation of normal and abnormal electrical propagation. We will explore the roles of the anatomic distribution of fibres, sheets, gap junctions and cell types in electrical propagation. Electrophysiology recording will be used to refine the model, and the model will be used to redirect the recording studies.
The outputs are i) detailed structural data, ii) a structural and simulation model, and iii) the knowledge from electrophysiological recording and simulation. These will add to the scientific understanding of the mechanisms of arrhythmia which will, in turn, facilitate development of therapies. Specifically the results may find application in clinical defibrillation studies.
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| Stephen Gilbert (Principal Investigator / Fellow) |