Nilotinib and imatinib significantly reduced beats per minute in human cardiac organoids at 24 hours (p<0.0001 and p=0.0213, respectively), demonstrating their utility for modeling cardiotoxicity.
Does exposure to imatinib or nilotinib alter functional parameters in human cardiac organoids?
Human cardiac organoids serve as a viable animal-free platform to detect early cardiotoxic signatures of tyrosine kinase inhibitors.
Abstract Background – Reliable in vitro prediction and modelling of cardiotoxicity remain major challenges in the field of cardio-oncology, and growing ethical pressures are accelerating the development of animal-free, human-relevant systems capable of accurately detecting cardiotoxic signatures. Human cardiac organoids (hCOs), derived from pluripotent stem cells, are capable of autonomous electrical and mechanical function, and therefore hold potential as an emerging platform for mechanistic and functional assessment of drug-induced cardiotoxicity. Among agents known to cause cardiac adverse events are tyrosine kinase inhibitors (TKIs), leading to arrhythmias, QT prolongation, and impaired cardiac function in patients. Here, we evaluate the effects of two clinically relevant TKIs – imatinib and nilotinib – on hCO function, with nilotinib in particular having been associated with cardiovascular complications in clinics. Methods – hCOs were exposed to imatinib or nilotinib for either 24 or 48 hours (h), with unstimulated controls. Functional parameters, including beats per minute (BPM), contraction amplitude, contraction duration, time to peak, and peak to peak intervals, were quantified using an automated video-based motion analysis. Results – At 24h, imatinib caused a modest, but significant reduction in BPM (p = 0.0213), whereas nilotinib induced a more pronounced effect (p 0.0001). By 48h, nilotinib, not imatinib, further suppressed hCO BPM, indicating progressive impairment of rhythmic activity. Additionally, nilotinib treatment led to a moderate reduction in contraction amplitude after 48h of treatment (p = 0.0715). At both time points, contraction duration slightly increased only upon nilotinib treatment. Furthermore, peak to peak interval remained relatively stable at 24h in both treatment groups, but was significantly prolonged by nilotinib at 48h (p = 0.0011). Time to peak showed minimal changes across both conditions. Conclusion – These findings showed that hCOs can reflect early and progressive functional disturbances in contractility in response to cancer therapy, mirroring clinically observed cardiotoxic signatures of the respective drugs. This highlights the value of hCOs as an animal-free, human-relevant, platform for modelling cancer therapy-induced cardiotoxicity.
Appels et al. (Fri,) conducted a other in Cancer therapy-induced cardiotoxicity. Imatinib and nilotinib vs. Unstimulated controls was evaluated on Functional parameters including beats per minute (BPM), contraction amplitude, contraction duration, time to peak, and peak to peak intervals. Nilotinib and imatinib significantly reduced beats per minute in human cardiac organoids at 24 hours (p<0.0001 and p=0.0213, respectively), demonstrating their utility for modeling cardiotoxicity.