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Abstract

This thesis describes the development and validation of mathematical models of the human cardiovascular system suitable for the study of short-term haemodynamic effects.

The basis of the model development is a large-scale mathematical representation of the controlled circulatory system which is capable of investigating short-term dynamics resulting from the administration of drugs which have rapid effects upon the heart and blood vessels. This model comprised a 19th order representation of the uncontrolled circulatory dynamics, so that overall, with neural control and pharmacokinetic and local pharmacodynamic models added, it was of 61st order with 178 parameters. A comprehensive and systemic programme of validation has been undertaken upon these models. Principal features of this validation programme include: investigating the nature of the sources of data used in specifying model parameters and initial values of model variables, in particular identifying the magnitude of uncertainty associated with such data; performing a series,of empirical tests, examining the ability of the model to reproduce the principal features of response observed in dynamic experimental data corresponding to a wide range of physiological and pharmacological investigation; and using the results of such validation tests to highlight areas of structural uncertainty in the model, specifically relating to the representation of neural control mechanisms.

Whilst such large-scale mathematical models have substantial heuristic potential, more compact representations are required if such models are to find potential clinical application. The Associated problems of model reduction are therefore discussed.

The result of this model reduction process is a smaller model which includes an 8-segment representation of the uncontrolled circulatory dynamics. The development of this reduced form is fully described, as is the programme of model validation which parallels that performed upon the original large-scale model. Particular emphasis is placed on the role of this more compact model to test alternative hypotheses regarding the neural control of peripheral resistance.

The programme of work described in this thesis constitutes an exemplar of the role of validation and the processes by which it is implemented in the context of large-scale physiological systems.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science > QA Mathematics Q Science > QM Human anatomy
Departments:	School of Science & Technology > School of Science & Technology Doctoral Theses Doctoral Theses

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