Pantaleo et al. BMC Cancer 2012, 12:231 http://www.biomedcentral.com/1471-2407/12/231 Page 3 of 5 Table 1 Data describing the main cardiotoxic events reported in clinical trials of tumor angiogenesis inhibitors Reference Drug N of pts Events Types of events Ranpura V et al. [6] Bevacizumab in pts 1853 61 (3.3 %) ATE (all-grade) Meta-analysis of 20 RCTs with a variety of 5558 111 (2.0 %) ATE (high-grade) advanced solid tumors 2322 34 (1.5 %) Cardiac ischemia Richards CJ et al. [7] Sunitinib 6936 186 (4.1 %) Congestive heart failure Choueiri TK et al. [8] Sunitinb and Sorafenib 9837 122 (1.4 %) ATE Meta-analysis of 10 studies in pts with advanced 1.3 % for Sunitinib; cancer 1.7 % for Sorafenib (NS) Chu TF et al. [15] Sunitinib in pts 75 8 (11 %) Cardiovascular events affected 36 6 (8 %) Congestive heart failure by GIST 75 10 (28 %) LVEF reduction (at least 10 %) 7 (19 %) LVEF reduction (15 % or more) 35 (47 %) Hypertension Telli ML et al. [16] Sunitinib in pts affected 48 7 (15 %) Heart failure by mRCC and GIST Di Lorenzo G et al. [17] Sunitinib in pts 175 66 (37.7 %) Hypertension G1-2 affected by mRCC 17 (9.7 %) Hypertension G3 12 (6.9 %) LVEF dysfunction 33 (18.9 %) of which Cardiac abnormalities 12 (6.9 %) LVEF G3 and/or Congestive heart failure Schmidinger M et al. [18] Sunitinib (Su) 74 25 [11 in Su; 14 in So] (33.8 %) of which: Cardiac event and Sorafenib (So) 12 (16.2 %) Biochemical signs and ECG in pts with mRCC 13 (17.6 %) of which changes only 7 (9.4 %) Clinical symptoms (angina, dyspnea, dizziness) Life-threatening clinical symptoms LVEF dysfunction and/or CHF (<1 %-33.8 %) [5,7], and ATEs (3.3 % overall; 2 % high-grade with bevacizumab and 1.4 % high-grade with sunitinib and sorafenib) [6,8]. Several authors have concluded that LVEF dysfunction and/or CHF is more frequent in patients with a history of hypertension or coronary artery disease than those without, even though a careful cardiac assessment at baseline was not always reported. The molecular mechanisms of TKI cardiotoxicity have not been extensively investigated, but seem to be related to the inhibition of kinases that have a crucial role in nor- mal cardiovascular development [19]. The role of BRAF in the heart is not well understood. RAF1 seems to inhibit two pro-apoptotic kinases with ERK-independent effects: apoptosis signal-regulating kinase 1 (ASK1) and mamma- lian sterile 20 kinase 2 (MST2), which are both involved in oxidant stress-induced injury. If sorafenib disrupts the RAF1–ASK1 and/or RAF1–MST2 interactions, cardio- toxicity might be an even greater concern than if only the ERK cascade is inhibited [20]. To examine the in vivo role of Raf-1 in the heart, Yamaguchy et al. generated cardiac muscle–specific Raf-1–knockout (Raf CKO) mice with Cre-loxP–mediated recombination [21]. The mice demon- strated left ventricular systolic dysfunction and heart dila- tation, related to a significant increase in the number of apoptotic cardiomyocytes and fibrosis. The molecular mechanism of ATE has not been well investigated, but it seems to depend on multiple actions of VEGF on vascular walls, and maybe also on components of the coagulation cascade. VEGF stimulates endothelial cell proliferation and promotes endothelial cell survival, thereby helping to main- tain vascular integrity. VEGF-signaling inhibition leads to a decrease in the regenerative capacity of endothelial cells, and causes cell wall defects that expose pro-coagulant phospholipids on the luminal plasma membrane or un- cover the matrix, favoring thrombosis. VEGF-inhibitors may also inhibit nitric oxide and prostacyclin, increase endothelial cell apoptosis, and promote pro-coagulant changes and proliferation of vascular smooth muscle cells. Finally, VEGF-inhibitors may increase the risk of ATE by increasing the hematocrit and blood viscosity via overpro- duction of erythropoietin [3,22]. The absence of cardiovascular risk factors or any per- sonal or family history of cardiac disease in our patient increases the suspicion of a correlation between his car- diovascular disease and sorafenib treatment. His cardiac function had been investigated and found to be normal before starting sorafenib, because his primary surgery was performed under extracorporeal circulation. He did not develop hypertension (average blood pressure before and during treatment: 125/80 mmHg) or other risk factors during sorafenib treatment (blood glucose level about 86 mg/dl, total cholesterol level about 141 mg/dl, HDL cholesterol level about 53 mg/dl, LDL cholesterol level about 75 mg/dl, and triglyceride level about 90 mg/dl). He therefore developed at least two critical sub-occlusive lesions during the 30 months after the start of treatment, which is a very short time period, considering the usual