Abstract
Introduction: Following myocardial infarction (MI) a process of adverse cardiac remodelling occurs leading to impaired function and eventually heart failure. Improving understanding of cardiac remodelling progression will aid in identifying targets for therapeutic intervention. Additionally, there is a need to design cardioprotective interventions against ischemia reperfusion (I/R) injury in failing hearts. Strategies targeting the adrenergic receptor (AR) signalling pathways are cardioprotective, whether such interventions are protective in the failing heart or in combination with cardioplegic arrest is not presently known.Methods: MI was induced in Wistar rats by occlusion of the left anterior descending coronary artery. Animals were recovered for 3-days, 2-weeks, or 4 weeks. Cardiac function was assessed by echocardiography. Blood and tissue samples were collected for metabolomics, histology, electron microscopy (EM) and proteomics. Cardioprotection against I/R injury was assessed ex-vivo in healthy and failing hearts. Pre-conditioning drugs targeting AR pathways were given prior to I/R, with or without cardioplegic arrest.
Results: Functional impairment was evident at 3-days, with further deterioration at later time-points. Cardiomyocyte loss alongside increased collagen deposition occurred over-time in the infarct area, with subtle changes in remote areas. EM showed a time-dependent increase in telocytes within the extracellular matrix of the infarcted area. There were extensive cardiac proteome changes during early remodelling which markedly decreased during the later stages. Interestingly, there were changes in cardiac proteome and blood metabolites in response to sham surgery. Targeting the α1A-ARs conferred protection against I/R injury in healthy and failing hearts. Targeting β-ARs pathways provided additional protection to cardioplegic arrest, the underlying mechanism(s) involving modulation of the mitochondrial permeability transition pore.
Conclusion: This work comprehensively characterised the cardiac remodelling process over-time following MI, providing new insights into disease progression. It has also shown the potential of targeting AR pathways to protect the heart against I/R injury as occurs in cardiac surgery.
| Date of Award | 20 Jun 2023 |
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| Original language | English |
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| Supervisor | Massimo Caputo (Supervisor) & Saadeh Suleiman (Supervisor) |