- Title
- Understanding anthracycline-induced cardiotoxicity: mechanisms, detection and treatment
- Creator
- Chen, Dongqing (Kelly)
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2025
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Heart disease costs over $7 billion annually in Australia. Cancer therapy-related cardiovascular toxicity (CTR-CVT) is an emerging cause of cardiovascular disease (CVD) that could add millions more to the healthcare budget. CTR-CVT refers to a broad spectrum of CV manifestations that include left ventricular (LV) fibrosis, dysfunction and heart failure (HF), as well as arrhythmias, myocardial ischemia, hypertension and pericarditis (see Appendix 1). Cancer therapy-related cardiovascular toxicity (CTR-CVT) is an active process with an “asymptomatic” stage that can progressively lead to irreversible overt heart failure (HF) (see Appendix 1). Anthracycline chemotherapies, especially doxorubicin, are among the most used anticancer drugs; listed by World Health Organisation as essential medicines2. However, doxorubicin is associated with cardiotoxicities, mostly occurring in the first 12 months of treatment3, 4 with 2 year mortality of up to 60%3, affecting between 10-40% of cancer patients5. Most importantly, this form of cardiotoxicity is preventable and reversible. Even though doxorubicin-induced cardiotoxicity (DIC) has been known since the 1960s, there are no cardioprotective agents in routine clinical use. There is, however, accumulating clinical and preclinical data that suggest an interdependence and biological overlap, based on commonality of risk factors (e.g. smoking, obesity, aging and diet) and pathophysiological mechanisms (e.g. inflammation, redox stress, abnormal metabolism and mitochondrial dysfunction) between the anti-cancer effects and the cardiotoxicity associated with doxorubicin. Various cardiovascular medications, including angiotensin-modulating agents, β-antagonists, and statins, have all been suggested, and tested, as oncological adjuvant treatments for prevention of cardiotoxicities6-10. However, no conclusive evidence for their efficacy has been shown. One of the identified strategies for the work in this thesis is firstly, to discover therapeutic targets and strategies that could be used synergistically for both cardio protection and anti-cancer effects. Secondly, I addressed the utility of potential new biomarkers, FSTL3 and sST2 for effectiveness in identifying likelihood of patients that will have hospital readmission due to MACE. The investigations are firstly, to elucidate the ability of these biomarkers in cardiovascular diseases prior to determining their role in predicting early onset CTR-CVT. Chapter 1 provides background information on the scope of the problem of CTR-CVT. I also discussed the various pathomechanism(s) of doxorubicin-induced cardiotoxicity and current strategies for cardioprotection. This chapter also highlights the potential overlapping mechanisms of PARP1 inhibition and doxorubicin-mediated cardiotoxicity, providing rationale for Chapter 2 Chapter 2 is original work (manuscript submitted and under revision for publication) assessing the potential cardioprotective effects of PARP-1 inhibitor, olaparib for doxorubicin-induced cardiotoxicity. Olaparib showed significant increase in doxorubicin-mediated reduction in human cardiomyocyte in vitro as well as improvement in cardiac function in vivo. Elucidation of the mechanism(s) for cardioprotection, showed that cGAS-STING pathway is involved in olaparib-associated cardioprotection in doxorubicin-induced cardiotoxic model. Chapter 3 introduces a novel potential therapeutic target and secreted biomarker for cardiovascular complications, Follistatin-like 3 (FSTL3). The background of this chapter provides critical insight into the possible dual effects of FSTL3: in cancer and cardiovascular pathophysiology. FSTL3 is an emerging target and biomarker, but there is still a paucity of data on the prognostic role of FSTL3 in heart failure and CTR-CVT. Chapter 4 provides preliminary assessment of the therapeutic role of FSTL3 in doxorubicin-induced cardiotoxicity (DIC). Results from this chapter demonstrates direct relationship between DIC-mediated increases in FSTL3 secreted levels, suggesting a potential role of FSTL3 as a biomarker. Neutralisation of FSTL3 partly rescues DIC, while maintaining the anti-cancer effects of doxorubicin in vitro. Given the potential role of FSTL3 as a biomarker, Chapter 5 investigates the prognostic value of FSTL3 in predicting major adverse cardiovascular events (MACE), all-cause mortality within 1 year in patients with high-risk cardiovascular disease. While investigation of the role of FSTL3 in CTR-CVT will be for future directions and beyond the scope of this thesis due to the duration of follow-up, my findings indicate that FSTL3 could potentially be used as a prognostic marker for MACE for patients living with through and beyond cancer. Chapter 6 reviews current biomarkers under investigation for CTR-CVT and introduces the potential role of soluble Suppression of Tumorigenicity-2 (sST2) as a biomarker for various cardiovascular disease. In Chapter 7, similar to Chapter 5, I evaluated the prognostic role of sST2 in predicting MACE within 1 year in patients with high risk cardiovascular disease. These data are in support of the future investigations of sST2 in predicting CTR-CVT as well as longer-term prediction of adverse cardiac events in patients living with through and beyond cancer. Chapter 8 summarises the major findings of my thesis, discuss the limitations and future directions.
- Subject
- anthracycline-induced cardiotoxicity; cardioprotection; pathomechanism; detection and treatment
- Identifier
- http://hdl.handle.net/1959.13/1517780
- Identifier
- uon:57180
- Rights
- Copyright 2025 Dongqing (Kelly) Chen
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 15 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 426 KB | Adobe Acrobat PDF | View Details Download |