McGowan, John Victor;
(2024)
The Role of Ischaemic Preconditioning in Protection
Against Doxorubicin-induced Cardiac Dysfunction.
Doctoral thesis (M.D(Res)), UCL (University College London).
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Abstract
Introduction: Doxorubicin (DOX) is a highly effective systemic anticancer therapy, but its clinical utility is limited by dose-dependent cardiotoxicity, leading to left ventricular systolic dysfunction and heart failure. The mechanism of doxorubicin cardiac dysfunction involves DNA damage, oxidative stress and calcium dysregulation, culminating in the activation of multiple programmed cell death pathways and shares common pathways with ischaemia-reperfusion injury (IRI). Ischaemic preconditioning (IPC) has demonstrated efficacy in reducing IRI, therefore, is a potential cardioprotective therapy for DOX-induced cardiac dysfunction. Methods: The ex vivo isolated perfused rat heart model was used to evaluate the effect of DOX on contractile function and potential cardioprotection from IPC. Contractile function and release of lactate dehydrogenase (LDH) and cardiac troponin I (cTnI) were analysed in hearts perfused with DOX for 120 minutes and in a 35-minute regional ischaemia-reperfusion model with DOX during 120-minute reperfusion. Results: High dose DOX (20μM) demonstrated rapid onset of contractile dysfunction, which was not attenuated by IPC. Subsequent experiments identified DOX 7.5μM as the optimal concentration for further cardioprotective studies. IPC appeared to attenuate the DOX 7.5μM-induced increase in left ventricular end-diastolic pressure (LVEDP) (35.1±1.6 vs control 15.9±4.3 mmHg, p<0.01), suggesting a protective effect on diastolic function. However, a DOX-induced significant reduction in heart rate was observed, which may have exacerbated DOX injury. To mitigate this heart rate reduction, subsequent hearts were paced at 300bpm. However, the protective effect of IPC on LVEDP was not reproduced. IPC did not prevent DOX 7.5μM-induced decreases in left ventricular developed pressure. In an ischaemia-reperfusion model, pacing hearts at 300bpm resulted in a high incidence of ventricular fibrillation, confounding the assessment of the cardioprotective effect of IPC on contractile function and infarct size. Conclusion: IPC may protect against DOX 7.5μM-induced diastolic dysfunction. Further study into the effect of IPC in DOX-induced contractile dysfunction is warranted.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | M.D(Res) |
| Title: | The Role of Ischaemic Preconditioning in Protection Against Doxorubicin-induced Cardiac Dysfunction |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10192514 |
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