Electrophysiological mechanisms behind the differential cardiotoxicity of chemotherapeutic agents Bortezomib and Carfilzomib

Background and Purpose: Bortezomib and Carfilzomib are first- and second-generation proteasome inhibitors that revolutionized the treatment of multiple myelomas. Despite their efficacy, they have been associated with off-target adverse events. Carfilzomib has a high rate of cardiovascular adverse events including heart failure, hypertension, ischemic heart diseases and arrhythmias. On the other hand, Bortezomib is known to cause peripheral neuropathy but has a safer cardiac profile. The mechanism behind the differential cardiac toxicity of Bortezomib and Carfilzomib is not completely understood. Thus, we aim to investigate the chronic effect of low nanomolar concentrations of Bortezomib and Carfilzomib on the electrophysiology of human-induced pluripotent-derived cardiomyocytes.Methods and Results: in-house differentiated human-induced pluripotent-derived cardiomyocytes were incubated with Bortezomib or Carfilzomib for 16 h. Patch-clamp experiments were conducted to record spontaneous action potentials and ionic currents. Carfilzomib affected the electrophysiology of spontaneous action potentials by altering the calcium and potassium currents, without affecting the sodium current. Bortezomib showed a milder effect on action potentials, probably due to a lack of effect on the potassium current IKr and an opposite compensatory effect on the calcium and sodium currents.Conclusion: this study proposes a novel potential pro-arrhythmic mechanism that may contribute to elucidate the differential cardiotoxicity of Bortezomib and Carfilzomib.