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Title: Biochemical adaptations in cardiac hypertrophy
Author: Clarke, Samantha Jayne
ISNI:       0000 0001 3558 4788
Awarding Body: University of Hull
Current Institution: University of Hull
Date of Award: 2001
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Cardiac hypertrophy is the adaptive response of the heart to chronic overload. The metabolic adaptations that occur during hypertrophy are initially beneficial, but can ultimately deteriorate into heart failure. The mechanisms underlying this are unknown. Evidence of impaired energy reserve, which may be caused by changes in the profile of substrate use, has been implicated in the transition of compensatory hypertrophy to heart failure. The work of this thesis characterises the alterations in substrate utilisation that occur in the heart, secondary to pressure-overload induced cardiac hypertrophy, the their implications on heart function. Pressure-overload hypertrophy was induced surgically in male Sprague- Dawley rats by inter-renal ligation. 13C-NMR spectroscopy was performed on extracts from hypertrophied and control hearts perfused with 13C-labelled substrate mixtures to determine the profile of substrate utilisation. Nine weeks pressure- overload achieved a moderate hypertrophy, evidenced by a 10-15% increase in heart mass to tibia length. The hypertrophied hearts showed an increased reliance on glucose and endogenous substrate contribution to TCA cycle oxidation for the production of ATP (15.0% versus 11.0%) compared to control hearts. Prolonged fifteen weeks pressure-overload resulted in further metabolic changes including impaired long-chain fatty acid oxidation and the accumulation of long-chain acylcarnitines. Alteration in substrate utilisation preceded any change in heart function and is strong evidence to suggest that impaired substrate delivery at the level of the mitochondria in cardiac hypertrophy plays an important role in the development of heart failure and is not a secondary phenomenon. At high workloads both hypertrophied and control hearts, showed similar profiles of substrate use, with glucose being the predominant substrate utilised for TCA cycle oxidation. At high workloads, hypertrophied hearts initially exhibited significantly higher mechanical function, but was not sustained, suggesting that physiological changes were becoming detrimental. This study highlights that sequential metabolic adaptations occur during the development of hypertrophy and precede any functional abnormality, providing potential prognostic markers.
Supervisor: Seymour, Anne-Marie Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biological sciences