Risicovoorspelling en modellering van cardiotoxiciteit gerelateerd aan kankertherapie

As survival rates of cancer patients significantly improved, the side effects of oncological treatments have emerged as a significant area of concern. This thesis is situated in the overlay between oncology and cardiology, namely cardio-oncology, providing insights into models and markers of cardiovascular adverse events of different cancer treatment modalities. We evaluated the predictors of cancer-therapy related cardiotoxicity by looking into the experiences of a state-of-the-art cardio-oncology clinic, studying cardiovascular event rates following curative radiotherapy for breast cancer, and exploring the incidence and predictors of anthracycline induced cardiotoxicity (AIC) in an all-comer breast cancer population. Our findings indicate that current risk prediction models for cardiotoxicity are inadequate, while baseline measurements of troponin and NTproBNP in all patients undergoing anthracycline treatment, independent of initial risk assessments, seemed useful. Contrary to common belief, heart failure and atrial fibrillation were already common in the first ten years following radiotherapy for curative treatment of unilateral breast cancer. Additionally, an artificial intelligence tool for ECGs was tested in the context of AIC. Next, we developed an in vitro disease model using patient-derived induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) to evaluate susceptibility to AIC and investigate underlying disease mechanisms. Apoptosis and especially autophagy were identified as critical contributors to AIC. Importantly, one needs to keep the broad applicability of the in vitro model into account as it could be used to study the detrimental effects on other (cardiac) cell types and/or other cancer drugs. Finally, we characterized mouse models to study inflammation and autophagy in AIC, as well as immune checkpoint inhibitor-related myocarditis, helpful for further elucidation of disease pathways and development of therapeutics to prevent cardiotoxicity. We strongly believe these comprehensive insights significantly advanced our understanding of cardiotoxicity mechanisms and suggested more precise and effective disease models to study cancer therapy-related cardiotoxicity. Moving forward, further research is necessary to validate our results in future small animal experiments, as well as independent and eventually larger patient populations.