Arterial thrombotic events, including myocardial infarction, are associated with treatment with bevacizumab. The mechanism is unclear, but it is thought that anti-vascular endothelial growth factor (VEGF) therapy may decrease the capability of endothelial cells to regenerate in response to trauma, leading to defects in the interior vascular lining with exposure of subendothelial collagen, increasing the risk of thrombotic events (Kamba and McDonald 2007; Kilickap et al. 2003).

Furthermore, antiangiogenic therapy is known to cause hypertension by mechanisms which are not fully understood. It is possibly related to VEGF inhibition, which decreases nitric oxide production in the arterioles (Kamba and McDonald 2007). Nitric oxide is a natural vasodilator, and blocking its production leads to increased peripheral vascular resistance and blood pressure. Angiogenesis is an important component of the normal adaptive response to pressure load, and inhibition of VEGF signaling may be even more serious in hypertensive patients (Izumiya et al. 2006; Shiojima et al. 2005).

Human epidermal growth factor receptor 2 (HER2) has an essential role in the development of the embryonic heart (Erickson et al. 1997; Lee et al. 1995a), and HER2 is expressed on adult myocardiocytes (Strasser et al. 2001; Zhao et al. 1998). Preclinical experiments have shown that activation of the HER2 receptor induced by its ligand neuregulin promotes cardiomyocyte survival (Zhao et al. 1998). Cardiotoxicity of trastuzumab is most likely secondary to inhibition of HER2 receptor on cardiomyocytes, thereby interfering with their normal growth and repair, whereas there is little evidence of cell death in the adult myocardium due to HER2 inhibition, which may explain the reversibility of trastuzumab cardiotoxicity (Crone et al. 2002; Ewer and O’Shaughnessy 2007; Ozcelik et al. 2002; Suter et al. 2007). However, other mechanisms not involving HER2 signaling may also be operating (Guglin et al. 2008).

These antibodies target the epidermal growth factor receptor (EGFR), and no cardiotoxicity has been reported with these two drugs.

Lapatinib cardiotoxicity is likely related to HER2 inhibition, as mentioned previously for trastuzumab. However, the risk associated with lapatinib is smaller. The difference may be due to the fact that monoclonal antibodies cause antibody dependent cellular and complement-dependent cytoxicity which could augment cardiotoxicity (Imai and Takaoka 2006). Moreover, differential inhibition and/or activation by lapatinib compared to trastuzumab of downstream signaling pathways may also be responsible (Spector et al. 2007).

Animal studies have shown cardiotoxicity in cardiomyocytes. Cardiotoxicity is most likely due to Abl inhibition in cardiomyocytes (Force et al. 2007; Kerkela et al. 2006). This seems to lead to induction of endoplasmic reticulum stress response, although the mechanisms are not clear. The endoplasmic reticulum stress response leads to cellular apoptosis. Imatinib-induced cardiotoxicity in patients is still an issue of debate (Breccia 2011).

Like imatinib, dasatinib inhibits Abl, and the mechanism of cardiotoxicity may be similar. However, dasatinib inhibits a number of other kinases, which may be involved in the cardiotoxicity (Chen et al. 2008).

Nilotinib, like imatinib and dasatinib, inhibits Abl. However, it seems to have a favorable toxicity profile, and the only cardiotoxicity reported is QT prolongation.

Sunitinib is a multi-target tyrosine kinase inhibitor. It has been shown in human and animal studies to cause mitochondrial damage in cardiomyocytes (Chu et al. 2007) (see Fig. 6), with ensuing heart failure and cardiomyopathy in a minority of patients. These symptoms improve with discontinuation of the agent and are responsive to heart failure therapy. Animal studies suggest that sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase (Kerkela et al. 2009). Further work has also suggested that sunitinib cardiotoxicity is caused by inhibition of ribosomal kinase leading to activation of the intrinsic apoptotic pathway (Force et al. 2007). Hypertension may also play a role (Chu et al. 2007; Khakoo et al. 2008).

Sorafenib is also a multi-target tyrosine kinase inhibitor, and it may cause cardiac damage by the same mechanisms as sunitinib. However, sorafenib also causes inhibition of the Raf kinases which may lead to enhanced cardiomyocyte apoptosis and fibrosis of the heart (Yamaguchi et al. 2004).

These drugs target the EGFR tyrosine kinase, and no cardiotoxicity has been reported with these two drugs.

Thalidomide is associated with the development of bradycardia. The mechanism remains unclear. It has been suggested to be due to the central sedative effects of the drug or to vasovagal activation. Thalidomide reduces the level of TNF-alpha which causes inhibition of the dorsal motor neurons including the nucleus of the vagus nerve. This could conceivably lead to over-reactivity of the parasympathetic nervous system leading to bradycardia. In some patients, thalidomide may cause hypothyroidism which may also lead to bradycardia (Fahdi et al. 2004; Kaur et al. 2003).

Radiation-associated heart disease includes a wide spectrum of cardiac disease, and combined disease of the coronary arteries, the heart valves, the myocardium, and the conductive system may occur (Adams et al. 2003; Aleman et al. 2007). These conditions usually only become symptomatic 10–15 years after exposure of the heart to irradiation, leading to an increased risk of (fatal) cardiovascular events after for instance mediastinal irradiation for Hodgkin lymphoma and after irradiation for left-sided breast cancer; symptomatic abnormalities may develop much earlier. (Hancock et al. 1993a; Stewart et al. 1995; Adams et al. 2004; Boivin et al. 1992; Carlson et al. 1991; Clarke et al. 2005; Darby et al. 2003, 2005; Giordano et al. 2005; Glanzmann et al. 1998; Gustavsson et al. 1990; Hojris et al. 1999; Lee et al. 2000; Lipshultz and Sallan 1993; Lund et al. 1996; Paszat et al. 1998; Piovaccari et al. 1995; Rutqvist and Johansson 1990; Swerdlow et al. 2007; Taylor et al. 2006). The reported incidence of injury is thus clearly related to the endpoints being considered. It is often useful to stratify the various endpoints (albeit somewhat imperfectly) into categories as shown in Table 4.

The long delay before expression of serious damage probably explains why the radiation sensitivity of the heart has previously been underestimated.

Information on mortality from cardiovascular diseases (CVDs) has been available in many countries for quite some time, whereas the information of incidence rates of CVD has been scarce. Gradually, incidence rates of several CVDs have become available. In addition, incidence rates of hospitalization for ischemic heart disease (Reinders et al. 1999) and of utilization of valve surgery, percutaneous interventions, and coronary bypass graft surgery among patients with HL (Hull et al. 2003) compared with general population rates, have been used as surrogate markers for CVD incidence.

Epidemiological studies on survivors of Hodgkin lymphoma show relative risk estimates for cardiac deaths in the range of 2–7, depending on the age of the patients (increased risks for irradiation at young age), the radiation therapy methods used, and the follow-up time (Hancock et al. 1993a; Adams et al. 2003; Boivin et al. 1992; Swerdlow et al. 2007; Aleman et al. 2003). In a Dutch study 3- to 5-fold increased standardized incidence ratios (SIR) of various heart diseases were observed in patients treated for Hodgkin lymphoma before the age of 41 years relative to the general population, even after a follow-up of more than 20 years (Aleman et al. 2007). The 25-year cumulative incidence of heart failure or cardiomyopathy with death from any cause as competing risk following mediastinal radiotherapy only was 6.8 %. The persistence of increased risk over prolonged follow-up time is of concern because this implies increasing absolute excess risks over time, due to the rising incidence of cardiovascular diseases with age.

Increased morbidity from cardiac diseases has been widely reported after treatment for breast cancer, especially using older radiotherapy techniques (Adams et al. 2003; Verheij et al. 1994; Gaya and Ashford 2005; Senkus-Konefka and Jassem 2007). The early breast cancer trialists’collaborative group (EBCTCG) evaluated the effects of local treatment on death from breast cancer and other causes in a collaborative meta analysis evaluating 42,000 women. This study showed a clear benefit of radiotherapy for local control and risk of death from breast cancer. However, there was, at least with some of the older radiotherapy regimens, a significant excess of nonbreast-cancer mortality in irradiated women [rate ratio 1.12; standard error (SE) 0.04] mainly from heart disease (rate ratio 1.27; SE 0.07) (Clarke et al. 2005).

The SEER database (surveillance, epidemiology, and end-results cancer registries) analysis also provides evidence of increased risk of myocardial infarction due to radiotherapy (Darby et al. 2005; Paszat et al. 1998). In a cohort of 308,861 women treated for early breast cancer, tumor laterality had no influence on subsequent mortality for women who did not receive radiotherapy. However, for women irradiated in the period of 1973–1982, there was a significant increase in cardiac mortality for left versus right-sided tumor (1.2 at <10 years, 1.42 at 10–14 years and 1.58 at >15 years). For women irradiated between 1983 and 1992, these risks had decreased to 1.04 at <10 years and 1.27 at >10 years.

Another large study (n > 4,000) investigated treatment-specific incidence of cardiovascular diseases in 10-year survivors of breast cancer treated from 1970 to 1986 in the Netherlands (Hooning et al. 2007). When comparing breast cancer patients who did or did not receive radiotherapy, radiation to the internal mammary chain was associated with significantly increased risk of cardiovascular disease (estimated mean, fractionated dose to the heart 6–15 Gy), while for breast irradiation alone no increased risk was observed (estimated mean, fractionated dose to the heart <7 Gy). For patients treated before 1979, radiation was associated with hazard ratios (HR) of 2.6 and 1.7 for myocardial infarct and congestive heart failure, respectively. For patients irradiated after 1979, the risk of myocardial infarct declined toward unity but the risks for congestive heart failure and valvular dysfunction remained significantly increased (HR 2.7 and 3.2, respectively). Smoking and radiotherapy together were associated with a more than additive effect on risk of myocardial infarction (HR = 3.04).

In concert, these studies suggest that radiotherapy for left-sided breast cancer has the potential to increase the risk of cardiac morbidity and mortality, but that these risks are markedly reduced with newer radiation therapy techniques. However, since radiotherapy-induced heart disease is generally believed to not be clinically manifest until >10–15 years post radiotherapy, and since the follow-up duration is shorter in the studies using more modern techniques (vs. the older techniques), additional follow-up is needed to be confident that the more modern techniques are indeed “safe”. The interaction between the duration of follow-up, the ‘era of the radiotherapy’ (taken as a surrogate for the ‘modern-ness’ of the radiotherapy techniques), and the RR of a cardiac event associated with radiotherapy, is shown in Fig. 7. Nevertheless, we are reassured that the more modern approaches markedly reduce the volume of heart exposed to radiotherapy, and that the available data suggest modern radiotherapy for breast cancer is not associated with a marked increase in cardiac events (albeit with modest follow-up time).

Many factors appear to influence the risk of CVDs. Table 1 summarizes the association between various risk factors and the different cardiac events. The highest relative risks are reported for those treated at young age (Aleman et al. 2007; Mulrooney et al. 2009; Hooning et al. 2007; Chen et al. 2008; Swerdlow et al. 2007; Myrehaug et al. 2008) and only slightly increased risks or no increased risks are reported in patients treated at 65 years or older (Swerdlow et al. 2007).

Although radiation damage to the coronary arteries may be immediate, clinical manifestation of damage does not usually appear until 10 or more years after radiation exposure.

Radiation may cause damage to the vascular endothelium of large arteries and therefore lead to accelerated atherosclerosis and an increased risk of vascular stenosis and thromboembolism.

Because of reduction of the arterial lumen to variable degrees, a spectrum of clinical manifestations of ischemic heart disease may be observed such as stable angina pectoris, unstable angina, myocardial infarction, and chronic ischemic heart disease.

An American study including 961 stage I-II breast cancer patients treated from 1977 to 1995 treated with conventional tangential beam radiation treatment (RT) showed that a statistically significant higher prevalence of stress test abnormalities was found among left (27 of 46; 59 %) versus right-side irradiated patients (3 of 36; 8 %; P < 0.001) at a median follow-up of 12 years. Furthermore, 19 of 27 of left-sided abnormalities were in the left anterior descending artery territory. Thirteen left-side irradiated patients also underwent cardiac catheterization revealing 12 of 13 with coronary stenoses (92 %) and 8 of 13 with coronary stenoses (62 %) solely in the left anterior descending artery (Correa et al. 2007; Tsibiribi et al. 2006a, b; Shapiro et al. 1998).

Furthermore, an increased risk of restenosis after coronary artery stenting has been reported in patients treated with thoracic radiation for lymphoma (Schomig et al. 2007; Manojlovic et al. 2008; Halyard et al. 2009).

Increased risks of valvular problems (valvular regurgitation in the aortic or mitral valve, and sometimes aortic stenosis) with or without clinical symptoms have been reported following radiotherapy for Hodgkin lymphoma (Aleman et al. 2007; Chen et al. 2011; Adams et al. 2004; Glanzmann et al. 1998; Lund et al. 1996; Heidenreich et al. 2003; Jones et al. 2007).

There are conflicting data following treatment for breast cancer (Hooning et al. 2007; Harris et al. 2006). Progressive valvular dysfunction has also been shown during long-term follow-up after treatment for Hodgkin lymphoma with mediastinal radiotherapy and/or anthracyclines (Wethal et al. 2009). Hodgkin lymphoma patients also have a significantly higher risk (SIR 8.4) of requiring valve surgery 15–20 years after radiotherapy (Hull et al. 2003).

Acute pericarditis is nowadays uncommon because of improved radiation techniques and lower radiation doses to smaller cardiac volumes. Patients may present with pleuritic chest pain, fever, tachycardia, a pericardial rub, and characteristic electrocardiographic abnormalities. These symptoms and pericardial effusions may resolve spontaneously. Symptomatic treatment analgesic and anti-inflammatory drugs are usually applied to relieve the pain. Constrictive pericarditis does however develop in a minority of patients. Medical treatment may temporarily alleviate symptoms of heart failure, but patients may need a pericardiectomy (Cosset et al. 1991; Bertog et al. 2004; Galper et al. 2010).

In the past, when generally larger radiation fields were used, for instance, in Hodgkin lymphoma treatment pericarditis was seen relatively frequently. In the early Stanford study, the risk of (a) symptomatic pericarditis was 20 % following whole-heart irradiation to 30 Gy, versus 7 % with the placement of a left-ventricular block at 15 Gy, and 2.5 % with a subcarinal block at 25–35 Gy (Carmel and Kaplan 1976).

Another European study including patients treated several decades ago has estimated that 4.8 % of Hodgkin lymphoma patients treated enveloped pericarditis approximately 18 years post-radiation therapy; the cumulative incidence for pericardial disease requiring surgery in these patients rose from only 0.1 % at 5 years post- radiation therapy to 1.3 % at 25 years from treatment (Galper et al. 2010).

More recently, a variety of dose-volume-histogram-based parameters were reported to be related to pericardial effusion for patients treated for esophageal cancer (Wei et al. 2008; Martel et al. 1998). Martel et al. (1998) implicated fraction size, mean, and maximum dose as a predictors for pericarditis. Wei et al. (2008) reported that a variety of DVH-based parameters (e.g., V3 to V50 and mean dose) predicted for pericardial effusions. The dosimetric parameters were highly correlated with each other, making comparisons of their predictive abilities difficult. See for detailed information Table 5.

Anthracyclines are used to treat a wide range of cancers including breast, uterine, ovarian and lung cancers, leukemias, and lymphomas. The incidence of anthracycline cardiotoxicity depends on the medication and the cumulative dose. For doxorubicin the reported incidence of heart failure is 3–5 % with doses of 400 mg/m², 7–26 % with doses of 550 mg/m², and 18–48 % with doses of 700 mg/m² (Wouters et al. 2005; Swain et al. 1997; Von Hoff et al. 1979). A 5 % risk of cardiomyopathy is seen with a cumulative dose of doxorubicin of 450 mg/m², of daunorubicin of 900 mg/m², of epirubicin of 935 mg/m², and of idarubicin of 223 mg/m² (Wouters et al. 2005; Keefe 2001), and these doses are generally regarded as the maximum lifetime cumulative dose allowed. However, no threshold dose exists below which no left ventricular dysfunction is seen. Liposomal doxorubicin, epirubicin, and idarubicin seem to have a lower incidence of heart failure. However, the longer the follow-up, the higher the incidence of cardiac dysfunction is reported to be. A higher risk is reported with intravenous high single doses, drug infusion lasting <30 min, prior radiotherapy involving the heart, use of other concomitant agents such as cyclophosphamide, trastuzumab or paclitaxel, female gender, young and old age, and underlying cardiovascular disease (Aleman et al. 2007; Myrehaug et al. 2008; Leonard et al. 2009; Lipshultz et al. 1995, 2008; Moser et al. 2006; Stickeler et al. 2009; Trudeau et al. 2009).

Acute anthracycline cardiotoxicity occurs in <1 % of patients, and manifests immediately after infusion as a reversible depression of myocardial function (Giantris et al. 1998; Wouters et al. 2005). Discontinuation of the anthracycline often leads to improvement in the cardiac function.

Early onset chronic progressive anthracycline cardiotoxicity, usually presenting within 1 year of anthracycline treatment, occurs in 1–3 % of patients. Late onset chronic anthracycline cardiotoxicity occurs at least 1 year after anthracycline treatment in 1.6–5 %, and even higher incidence figures are reported for children, depending on what severity of symptoms are required for the diagnosis. However, it may not become clinically evident until 10–20 or even 30 years after treatment. Chronic progressive cardiotoxicity typically presents as dilated cardiomyopathy (Lipshultz et al. 2008).

Cyclophosphamide is an alkylating agent commonly used in the treatment for a variety of nonmalignant and malignant conditions including breast cancer, leukemia, lymphoma, multiple myeloma, mycosis fungoides, neuroblastoma, ovarian cancer, and retinoblastoma (Floyd et al. 2005). Cyclophosphamide has been associated with heart failure in 7–28 % of patients (Goldberg et al. 1986; Gottdiener et al. 1981; Pai and Nahata 2000; Braverman et al. 1991). The risk is dose related, occurring mainly in patients receiving >150 mg/kg and >1.5 g/m²/day. It occurs within 1–10 days after the administration (Pai and Nahata 2000), and the clinical manifestations range from asymptomatic pericardial effusions to overt heart failure and myopericarditis (Gottdiener et al. 1981; Braverman et al. 1991). Cardiac failure following cyclophosphamide usually resolves over 3–4 weeks and is treated with supportive care (Floyd et al. 2005). Risk factors include previous anthracycline treatment and mediastinal radiotherapy (Goldberg et al. 1986; Pai and Nahata 2000).

Ifosfamide has been associated with cardiotoxicity in 17 % of patients (Pai and Nahata 2000; Quezado et al. 1993), occurring mainly in patients receiving doses >12.5 g/m² (Pai and Nahata 2000). Heart failure occurred within 6–23 days after treatment.

Fluorouracil is mainly used in the treatment for patients with cancer of the digestive tract especially colorectal cancer and head and neck cancer. Fluorouracil has been associated with symptoms of cardiotoxicity in 1–18 % of patients, most commonly as angina-like chest pain, but ischemic ECG changes may be seen in up to 68 % (Yeh and Bickford 2009; de Forni et al. 1992; Wacker et al. 2003; Jensen and Sorensen 2006; Keefe et al. 1993; Labianca et al. 1982; Tsavaris et al. 2002). In rare cases myocardial infarction, arrhythmias, heart failure, cardiogenic shock, and sudden death have been reported (Meyer et al. 1997; Van Cutsem et al. 2002). The overall mortality of symptomatic fluorouracil cardiotoxicity has been estimated at 2.2–13 % (de Forni et al. 1992; Wacker et al. 2003; Keefe et al. 1993; Labianca et al. 1982; Tsavaris et al. 2002; Robben et al. 1993). Cardiac events generally occur within 5 days after administration. The risk of cardiotoxicity is associated with high doses (>800 mg/m²), continuous infusion, prior cardiovascular disease or mediastinal radiotherapy, and concurrent chemotherapy (de Forni et al. 1992; Kosmas et al. 2008; Jensen and Sorensen 2006; Labianca et al. 1982; Tsavaris et al. 2002; Meyer et al. 1997; Van Cutsem et al. 2002; Cardinale et al. 2006a, b; Rezkalla et al. 1989).

Capecitabine, an oral prodrug of fluorouracil, has been associated with cardiotoxicity with an incidence of 3–9 % (Kosmas et al. 2008; Van Cutsem et al. 2002; Ng et al. 2005; Saif et al. 2008; Walko and Lindley 2005). Typically, angina symptoms occurred 4–5 days after therapy (Jensen and Sorensen 2006) with ischemic ECG changes present in many cases (Cardinale et al. 2006a; Frickhofen et al. 2002; Schnetzler et al. 2001), but without echocardiography or coronary angiogram abnormalities (Yeh and Bickford 2009; Cardinale et al. 2006a; Schnetzler et al. 2001). Prior fluorouracil cardiotoxicity and possibly prior symptoms of coronary artery disease were risk factors (Labianca et al. 1982; Saif et al. 2008; Frickhofen et al. 2002; Schober et al. 1993).

Docetaxel is employed in the treatment of breast cancer and prostate cancer. It has been reported to be associated with heart failure in 2.3–8 % of patients (Martin et al. 2005; Marty et al. 2005). Myocardial ischemia has been reported to occur in 1.7 % of patients (Yeh and Bickford 2009; Vermorken et al. 2007).

Paclitaxel is used in patients with lung cancer, ovarian cancer, and breast cancer. It has been reported to be associated with ischemia in 5 % of patients (Rowinsky et al. 1991) and with myocardial infarction in 0.5 % (Arbuck et al. 1993). The cardiac events occurred up to 14 days after paclitaxel administration (Arbuck et al. 1993), and risk factors were previous cardiac disease including hypertension and coronary artery disease. Paclitaxel has also been associated with bradycardia, which is usually without clinical significance, but may in rare cases have clinically significant hemodynamic effects. Hypersensitivity reactions with histamine release have been implicated, and premedication to prevent hypersensitivity reactions may prevent bradycardia as well.

Vinca alkaloids, used in the treatment of lymphomas, nonsmall cell lung cancer, breast cancer, and testicular cancer, have also been incriminated. Significantly (2 fold or more) increased risks of death from myocardial infarction (Swerdlow et al. 2007) or more general cardiovascular diseases (Tukenova et al. 2010) have been reported.

Bevacizumab is a monoclonal antibody that inhibits the activity of human VEGF. It is approved for use in the setting of first-line metastatic colon cancer in combination with intravenous FU-based chemotherapy. It is also used in the treatment of nonsmall cell lung cancer and brain tumors. Bevacizumab has been associated with heart failure in 1.7–3 % of patients (Miller et al. 2005, 2007). Moreover, arterial thrombotic events have been reported in 3.8 % of patients with myocardial infarctions in 0.6 % (Scappaticci et al. 2007). Arterial thrombotic events could occur at any time during therapy, and they did not seem to be related to dose or cumulative exposure. Risk factors were older age and prior arterial thrombotic events (Scappaticci et al. 2007). The most common cardiotoxicity with bevacizumab treatment is, however, hypertension, which is reported to occur in 4–35 % of patients (Miller et al. 2005, 2007; Cobleigh et al. 2003; Hurwitz et al. 2004; Johnson et al. 2004; Kabbinavar et al. 2005; Pande et al. 2007; Yang et al. 2003). Hypertension might develop at any time during therapy, and higher dose has been suggested as a risk factor (Kabbinavar et al. 2005). Most patients can continue bevacizumab in combination with antihypertensive drugs.

Trastuzumab, used in patients with breast cancer, is associated with cardiomyopathy in 2–7 % of patients when the drug is used alone. However, when trastuzumab is used with paclitaxel the incidence is 2–13 %, and when used with an anthracycline it is up to 27 % (Ewer and O’Shaughnessy 2007; Suter et al. 2007; Gianni et al. 2007; Guarneri et al. 2006; Perez et al. 2008a; Romond et al. 2005; Seidman et al. 2002; Slamon et al. 2001; Tripathy et al. 2004; Vogel et al. 2002). Risk factors are age >50, pretreatment borderline left ventricular ejection fraction, prior cardiovascular disease, and prior treatment with anthracyclines to higher cumulative doses (287 mg/m² vs. 257 mg/m² for doxorubicin, 480 mg/m² vs. 422 mg/m² for epirubicin) (Suter et al. 2007; Guglin et al. 2008; Gianni et al. 2007; Guarneri et al. 2006; Perez et al. 2008a, b; Seidman et al. 2002; Tan-Chiu et al. 2005). Hence, increased cardiac stress seems to increase the risk of trastuzumab associated cardiac side effects, which may explain why it appears to be more frequent in clinical practice than in controlled trials (McArthur and Chia 2007). Trastuzumab cardiotoxicity is not dose related, and it is frequently reversible. However, if combined with anthracyclines, the frequency and risk of anthracycline induced myocyte death might increase (Zuppinger et al. 2007).

Lapatinib is used in the treatment of disseminated breast cancer. It has been reported to be associated with symptomatic (grade 3 or 4 heart failure) cardiotoxicity in 0.2 % of patients and with asymptomatic events (>20 % decrease in left ventricular ejection fraction without symptoms) in 1.4 % of patients (Perez et al. 2008b). The risk was increased in patients with prior anthracycline treatment (2.2 %) or prior trastuzumab treatment (1.7 %). The mean time to onset of symptoms was 13 weeks. Lapatinib has also been reported to cause QT prolongation in 16 % of patients treated with varying doses (Yeh and Bickford 2009). Lapatinib thus seems to be less cardiotoxic than trastuzumab. This may partly be due to selection bias in the trials of patients receiving lapatinib, but recent data indicate an underlying molecular mechanism for the apparent difference in cardiotoxicity, as lapatinib, but not trastuzumab protects against TNF-alpha-induced cardiomyocyte death (Spector et al. 2007).

Imatinib, used in the treatment of chronic myeloid leukemia and in gastro-intestinal stromal tumors, has been associated with rare heart failure (Kerkela et al. 2006). The incidence of clinical heart failure in patients treated with imatinib has been reported as 0.5–1.7 % (Atallah et al. 2007; Hatfield et al. 2007). Whether the imatinib-associated cardiotoxicity is reversible or not is still unknown.

Dasatinib, also used in the treatment of chronic myeloid leukemia, has been reported to be associated with heart failure in 2–4 % of patients, and QT prolongation has been reported to occur in 2–3 % of patients treated with dasatinib (Yeh and Bickford 2009).

Sunitinib, simultaneously approved for the treatment of renal cell carcinoma, and gastrointestinal stroma tumor, has been associated with left ventricular dysfunction in 4–11 % of patients, with symptomatic heart failure in 2.7–8 % (Chu et al. 2007; Khakoo et al. 2008). The mean time to the development of heart failure varied between 22 days and 27 weeks, and the only risk factor was prior coronary artery disease. Although heart failure responded to medical therapy, it did not seem to be fully reversible (Khakoo et al. 2008). Moreover, sunitinib has been associated with hypertension in 5 to 47 % (Chu et al. 2007), in different clinical trials, with grade 3 occurring in 2–8 % (Chu et al. 2007; Burstein et al. 2008; Demetri et al. 2006; Motzer et al. 2006a, b, 2007; Azizi et al. 2008).

Sorafenib, approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma, causes hypertension in a significant number of patients. The overall incidence in a recent meta analysis was 23.4 %, with grade 3 and 4 reported in 2.1–30.7 % in different studies (Wu et al. 2008). Sorafenib has also been associated with myocardial ischemia in 3 % of patients in clinical trials, which is significantly higher than in patients treated with placebo (Yeh and Bickford 2009; Escudier et al. 2007).

Kinase Inhibition Determines TKI-induced Toxicity to Normal Tissue:

Vorinostat is approved for the treatment of cutaneous T cell lymphomas. Vorinostat had been reported to be associated with QT prolongation in 3.5–6 % of patients (Yeh and Bickford 2009; Olsen et al. 2007). Risk factors are female gender, older age, previous myocardial ischemia, heart failure, electrolyte imbalances, bradycardia, and medication with QT prolonging drugs (Yeh and Bickford 2009; Vorchheimer 2005).

Thalidomide is used in the treatment of multiple myeloma. Bradycardia has been associated with thalidomide treatment in 2–55 % of patients. Most patients are asymptomatic, but some patients may experience fatigue, syncope, or dizziness. Patients developing third-degree atrioventricular block need a permanent pacemaker.

Arsenic trioxide is used in the treatment of certain leukemias. QT prolongation has been reported in patients treated with arsenic trioxide in 26–93 % of patients (Barbey et al. 2003; Huang et al. 1998; Ohnishi et al. 2002; Shigeno et al. 2005; Singer 2001; Unnikrishnan et al. 2004; Westervelt et al. 2001). The QT interval has been reported to be prolonged from 1 to 5 weeks after treatment and then returned to baseline (Soignet et al. 2001).

Direct effects of chemotherapy on coronary arteries are rare.

Fluoropyrimidines (i.v. 5 fluoro-uracil (5FU) or oral capecitabine), may cause myocardial ischemia and decreased contractility of the heart (Kosmas et al. 2008; Tsibiribi et al. 2006a, b; Manojlovic et al. 2008). A spasm of the coronary arteries is often considered to be the most important cause. The underlying mechanism is not fully elucidated yet. Experimental studies in rabbits indicate that a spasm of the coronary arteries is not the only mechanism of 5FU cardiotoxicity, and that apoptosis of myocardial and endothelial cells can result in inflammatory lesions mimicking toxic myocarditis (Tsibiribi et al. 2006a, b).