attributable 
to longer duration of recording events. However, given the lack of an overall statistical difference for all grade and high grade cardiac events, it is unlikely that analysis of events per-unit of PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19645759 time will yield useful information. There are two possible explanations for our finding: Firstly, cardiotoxicity is usually underreported in clinical trials; in our search, 87.3% of prospective clinical trials are excluded because data on cardiotoxicity is unavailable. Secondly, only six prospective randomized controlled trials are included to investigate the risk of cardiotoxicity associated with bortezomib, thus the power to investigate the risk is small. Nevertheless, because bortezomib are increasingly used in the routine treatment of cancer patients and in the setting of clinical trials in combination with other agents, it is important for oncologists and primary care physicians to be aware of the incidence and risk of cardiotoxicity associated with bortezomib to monitor and treat it appropriately. The pathogenesis of bortezomib related cardiotoxicity is currently unknown. Multiple distinct mechanisms could be involved in the pathogenesis of cardiotoxicity. Bortezomib is known to worsen ischemic heart disease. The presence of reduced proteasome activity is associated with an increased rate of apoptosis in smooth muscle cells, resulting in atherosclerotic plaque instability due to weakening of the fibrous cap and enlargement of the necrotic core. This causes increased propensity of the atherosclerotic plaque to rupture resulting in ischemic complications. Cell culture experiments have demonstrated that bortezomib causes significant structural abnormalities within the mitochondria of the cardiomyocytes resulting in decreased adenosine triphosphate synthesis and reduced cardiac contractility. Thus bortezomib treatment can result in significant left ventricular contractile dysfunction. The reversibility of cardiac failure on stopping bortezomib and negative findings on angiography lends further credence to this theory. As cardiac complications are rarely reported as side effects of bortezomib, the treatment for this adverse event is still under debate. According to the US package insert for bortezomib, patients with risk factors for, or existing heart disease should be closely monitored when prescribing bortezomib. In several case reports of patients with congestive hear failure, pro-brain natriuretic peptide concentrations have been shown to be elevated, while cardiac enzymes, such as creatinine phosphokinase and troponin I, does not significantly increase. As a result, whether pro-BNP or cardiac enzymes could be used to monitor the cardiotoxicity associated with bortezomib is still unknown. More studies are still needed to address this issue. 7 Cardiotoxicity Associated with Bortezomib There are several challenges and limitations in this analysis. Firstly, we only have access to the available data published in the clinical trials, so there are patient variables that are not known, such as co-morbidities, previous treatment exposure, concomitant medications, and dose interruptions. Secondly, the reporting of cardiotoxicity are lacking in many studies, leading to their purchase TMS exclusion from analysis. Adverse events, unlike efficacy outcomes, are rarely predetermined for systematic data collection in clinical trials. Therefore, reporting of adverse events depends highly on the investigators, and could likely be confounded by other variab
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