Sunitinib causes dose‐dependent negative functional effects on myocardium and cardiomyocytes

Study Type – Aetiology (case control) Level of Evidence 2b What's known on the subject? and What does the study add? The multikinase inhibitor sunitinib causes cardiotoxic side effects in a substantial number of treated patients. Previously, data from clinical studies suggested that these side effects are more frequently found in patients with a lower body mass index, but the reasons for this toxic effect remain elusive. In this study we determined, in a human multicellular model, that sunitinib causes an impairment of the contractile function of cardiomyocytes in a dose‐dependent manner. Furthermore, we found that sunitinib induces alterations in calcium homeostasis in cardiomyocytes. In addition, an increased production of reactive oxygen species after exposure of cardiomyocytes to this drug was detected. These findings suggest that measurement of plasma concentration might help to control cardiotoxic side effects and optimize a more personalized application of this drug. OBJECTIVES To examine the acute effects of sunitinib on inotropic function, intracellular Ca 2+ transients, myofilament Ca 2+ sensitivity and generation of reactive oxygen species (ROS) in human multicellular myocardium and isolated mouse cardiomyocytes. To search for microRNAs as suitable biomarkers for indicating toxic cardiac effects. PATIENTS AND METHODS After exposure to sunitinib (0.1–10 µg/mL) developed force, diastolic tension and kinetic variables were assessed in isolated human myocardium. Changes in myocyte sarcomere length, whole‐cell calcium transients, myofilament force‐Ca 2+ relationship, and ROS generation were examined in isolated ventricular mouse cardiomyocytes. Microarray and realtime‐PCR were used to screen for differentially expressed microRNAs in cultured cardiomyocytes that were exposed for 24 h to sunitinib. RESULTS We found that higher concentrations of sunitinib (1 and 10 µg/mL) decreased developed force at 30 minutes 76.9 + 2.8 and 54.5 + 6.3%, compared to 96.1 + 2.6% in controls ( P < 0.01). Sunitinib exposure significantly decreased sarcomere shortening and Ca2+ transients. Myofilament Ca 2+ sensitivity was not altered, while ROS levels were significantly increased after exposure to the drug. MicroRNA expression patterns were not altered by sunitinib. CONCLUSIONS Sunitinib elicits a dose‐dependent negative inotropic effect in myocardium, accompanied by a decline in intracellular Ca 2+ and increased ROS generation. In clinical practice, these cardiotoxic effects should be considered in cases where cardiac concentrations of sunitinib could be increased.