Studies of ischaemia and reperfusion in cardiac hypertrophy

Richardson, Simon, .Ph.D.

Abstract

Cardiac hypertrophy may be associated with an enhanced susceptibility to ischaemic/reperfusion injury but the mechanisms remain unresolved. There is evidence for an increased dependence on glucose metabolism in cardiac hypertrophy, which may be beneficial in normoxia but detrimental in ischaemia. The role of glycogen, the major endogenous substrate during ischaemia, to the enhanced susceptibility of the hypertrophied heart to ischaemic/reperfusion injury is unclear. Work in this thesis investigates the role of glycogenolysis to the severity of ischaemia, and assesses oxidative substrate utilisation following reperfusion, in the hypertrophied heart.

Pressure overload cardiac hypertrophy was induced surgically in male Sprague-Dawley rats by intra-renal constriction. A moderate hypertrophy was observed nine weeks post surgery as evidenced by between a 4 and 25 % increase in heart weight: tibia length ratio. Hearts were perfused in an isovolumic mode, and function was recorded. ¹³C-NMR spectroscopy was performed on extracts from hypertrophied and control hearts reperfused with ¹³C labelled substrates to determine the profile of substrate use.

Glycogen content was unchanged in hypertrophied hearts compared to control hearts and there was no evidence for glycogen loading in the presence of physiological substrates and insulin. In addition, no further glycogen loading occurred when insulin concentrations were increased to pharmacological levels. Provision of other carbohydrate substrates, such as lactate, did result in a further increase in myocardial glycogen content.

Hypertrophied hearts experienced the same extent of ischaemia as controls with no evidence of increased ischaemic injury, implying that a compensated model of hypertrophy was generated in this study. Myocardial function decreased during low flow ischaemia and stopped during global ischaemia, but contracture was not observed. The severity of ischaemia was the determining factor in the degree of glycogen degradation. Increased glycogen degradation during ischaemia did not correlate with increased ischaemic injury, suggesting that the availability of glycogen for energy provision limited ischaemic injury.

Recovery on reperfusion was markedly improved in the presence of insulin. This improvement appeared to be mediated by the inotropic actions of insulin rather than by alterations in substrate provision. The profile of substrate use in hypertrophied hearts during reperfusion was found to be the same as that in controls.

No metabolic alterations were observed in the hypertrophied heart that enhanced susceptibility to ischaemic/reperfusion injury, implying that compensated hypertrophy is a beneficial response of the heart.

Citation

Richardson, S. .. Studies of ischaemia and reperfusion in cardiac hypertrophy. (Thesis). University of Hull. https://hull-repository.worktribe.com/output/4217972

• Thesis Type: Thesis
• Deposit Date: May 4, 2016
• Publicly Available Date: Feb 23, 2023
• Keywords: Biological sciences
• Public URL: https://hull-repository.worktribe.com/output/4217972
• Additional Information: Department of Biological Sciences, The University of Hull
• Award Date: Aug 1, 2002