Modelling chemotherapy-induced cardiotoxicity with live myocardial slices: from bedside to bench and back again

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Netherlands Heart Institute & Dutch Heart Foundation (Dekker Senior Clinical Scientist 2019) Introduction Cancer therapy related cardiac dysfunction (CTRCD) is a common side-effect of many oncological regimens. The prevention, diagnosis and treatment of CTRCD requires a well-orchestrated management by a multidisciplinary team composed by oncologists, cardiologists, radiologists, but less often translational scientists. Purpose In this work, we investigated the translational potential of live myocardial slices derived from a patient presenting with acute biventricular failure, with no history of cardiovascular disease, who had previously received neo-adjuvant chemotherapy containing doxorubicin (240 mg/m2) and trastuzumab, for the treatment of a breast carcinoma. In contrast to anthracycline cardiotoxicity, which is often permanent, cardiac dysfunction caused by trastuzumab is commonly reversible after cessation of treatment. Herein, we provide a novel side-by-side comparison of myocardial function ex vivo and clinical outcomes in the patient. Methods After several days on extracorporeal life support and inotropic therapy, the patient’s cardiac function did not improve. The patient was ultimately implanted with a left- and right-ventricular assist device (LVAD and RVAD, respectively). Live myocardial slices were produced from the apical biopsy obtained during LVAD implantation and cultured in a biomimetic system under physiological mechanical and electrical conditions. Slices were subsequently exposed to doxorubicin, trastuzumab or vehicle (0.1% DMSO) for a continued period of 7 days. Contractile force was recorded continuously, and a custom-made stimulation protocol applied every 24h. To evaluate responsiveness to inotropes, slices were incubated with milrinone before culture termination. Calcium transients and action potentials were determined optically using calcium and voltage-sensitive dyes. Results Continued exposure to either doxorubicin or trastuzumab limited the recovery of contractility in myocardial slices. In contrast, vehicle controls showed a robust recovery and development of stronger contractile forces. Doxorubicin-treated slices were less responsive to stimulation, displayed increased stimulation threshold and were less able to follow pacing at higher frequencies. Optical mapping revealed that exposure to doxorubicin led to the development of abnormal calcium handling. In parallel to the ex vivo findings, RVAD/LVAD-mediated cardiac unloading and the absence of any chemotherapy drug, resulted in a significant recovery of right-ventricular function, enabling RVAD removal within 2 weeks. Conclusions The complex nature of chemotherapy-induced cardiotoxicity imposes numerous challenges in clinical decision-making. In this unique case, patient care could be paralleled by concomitant state-of-the-art ex vivo tissue culture. We observed that myocardial tissue slices could partially recapitulate clinical observations, highlightings the promising synergy between translational science and personalized patient care.