PhD Candidate University of Toronto Toronto, Ontario, Canada
Background:
Introduction: Cancer therapy-related cardiac dysfunction (CTRCD) remains a debilitating consequence of chemotherapy and a competing risk factor for mortality in cancer survivors. Treatments for breast cancer, especially anthracyclines such as doxorubicin, can introduce a >15% risk of CTRCD, which can lead to heart failure with poor prognosis. Strategies to determine CTRCD pathogenesis and identify those at risk are warranted.
Rationale: Our unpublished clinical data have revealed elevated circulating markers of inflammation and endothelial dysfunction in breast cancer patients who later developed CTRCD. Intriguingly, these markers were elevated even before the initiation of chemotherapy, which led us to hypothesize that the tumour itself may trigger systemic vascular inflammation and endothelial dysfunction, predisposing patients to CTRCD.
METHODS AND RESULTS: To test this hypothesis, we utilized the MMTV-PyMT mouse model of breast cancer and wild-type (WT) littermates. At baseline, tumour-bearing mice display comparable cardiac function to WT mice, but exhibited compromised microvascular architecture, with reduced vessel density, vessel percent area, and increased lacunarity in the heart. To assess the impact of cancer on cardiotoxic outcomes, female MMTV-PyMT mice and WT littermates were randomized to receive three weekly 5mg/kg injections of doxorubicin (Dox) or vehicle (Veh) and were followed by echocardiography. At 5-weeks after the initiation of treatment, WT+Dox mice had a significant decline in cardiac function or ejection fraction (EF: 72.7±0.5% vs 76.6±0.2%). This decline was slightly more pronounced in tumour-bearing mice, both with and without Dox (71.1±0.9% and 72.7±0.5%, respectively). Additionally, tumour-bearing mice had a significantly elevated heart weight:tibia length ratio, compared to WT controls (102±2.5mg and 105±1.6mg vs 93.9±1.7mg and 95.4±1.2mg). Importantly, Importantly, increasing tumour burden correlated with EF decline (r² = -0.425, p = 0.038). Furthermore, cardiac gene expression analyses revealed a significant increase in genes related to inflammation (IL-1β, IL-6, Ly6G, Myeloperoxidase), cardiac stress (Nppa) and endothelial activation (P-selectin) in tumour-bearing mice, with Ly6G and myeloperoxidase being more pronounced in MMTV+Dox mice.
Conclusion: These findings suggest that breast cancer may prime the cardiovascular system for injury by promoting inflammation, endothelial dysfunction, and microvascular remodeling—factors that may exacerbate doxorubicin-induced cardiotoxicity. Our ongoing studies aim to profile systemic inflammation during chemotherapy to further elucidate this tumour–heart axis and identify early biomarkers of CTRCD vulnerability.
