Bortezomib is an antitumor compound that inhibits proteasome activity. It is able to impair the activation of nuclear factor (NF)-jB, blocking the degradation of inhibitory jB (IjB), which is required for NF-jB translocation into the nucleus and activation of target genes. NF-jB is important for cell survival, regulating the expression of genes involved in apoptosis, such as BCL2 and BCL2L1, cell cycle progression, inflammation and angiogenesis (Richardson et al, 2003). In 2006, we treated 69 patients with bortezomib, either alone or as combination therapy. Bortezomib therapy is known to be associated with neurological side effects and thrombocytopenia (Richardson et al, 2003); however, we noticed an unexpected increase of cardiac complications, ranging from heart failure to onset of arrhythmias. Only one single case of heart failure (Voortman & Giaccone, 2006) and one asymptomatic arrhythmia (Berenson et al, 2007) following bortezomib therapy have been reported to date. All except one of our bortezomib-treated patients were receiving at least a second line therapy, and some of them had previously received anthracycline-containing regimens. Eight (11Æ6%) of the 69 patients developed serious cardiac side effects requiring medication, hospitalisation or the implant of a pacemaker (see Table I). All patients underwent cardiovascular screening before receiving bortezomib and no clinically significant abnormalities were present. The only conditions that were identified as common to all the patients were bortezomib administration and age> 60 years. All eight patients who experienced cardiotoxicity underwent at least four cycles of bortezomib, strengthening the hypothesis of a direct connection with the drug. Each cycle included bortezomib 1Æ3 mg/m2 on days 1, 4, 8 and 11 and the recycling period was 3 weeks. The onset of cardiac symptoms was never recorded before a cumulative dose of 20Æ8 mg/m2 of bortezomib. The ubiquitin-proteasome system is responsible for nonlysosomal degradation of intracellular proteins, including key regulators of cell cycle, angiogenesis and apoptosis, and transcription factors, which regulate crucial mechanisms of plaque formation and rupture. Additionally, the presence of a reduced proteasome activity is associated with an increased rate of apoptosis in smooth muscle cells, determining atherosclerotic plaque instability by weakening of the fibrous cap and enlargement of the necrotic core (Versari et al, 2006). Furthermore, NF-jB activation plays an essential role in the intracellular signal transduction of the second window of protection of delayed ischaemic preconditioning in the myocardium, leading to myocardial cytoprotection (Jancso et al, 2005). Therefore, bortezomib may simultaneously cause atherosclerotic plaque progression and tendency to rupture, and facilitate ischaemic heart complications by reducing/abrogating myocardial preconditioning. Additionally, although bortezomib was found to reduce the onset of delayed arrhythmias following coronary ligation in the canine model by upregulating