Cardiovasc Toxicol DOI 10.1007/s12012-011-9141-z Timely Recognition of Cardiovascular Toxicity by Anticancer Agents: A Common Objective of the Pharmacologist, Oncologist and Cardiologist Francesca Bonura • Daniela Di Lisi • Salvatore Novo • Natale D’Alessandro Springer Science+Business Media, LLC 2011 Abstract Both conventional and new anticancer drugs can frequently cause adverse cardiovascular effects, which can span from subclinical abnormalities to serious lifethreatening and sometimes fatal events. This review examines the principal basic and clinical elements that may be of profit to identify, prevent and treat such toxicities. Clearly, the accomplishment of such objectives requires the strong commitment and cooperation of different professional figures including, but not limited to, pharmacologists, oncologists and cardiologists. The aspect of anticancer drug cardiotoxicity seems to be somehow underestimated, mainly due to inadequate reporting of adverse reactions from oncology drugs in the post-marketing setting. Thus, the implementation of pharmacovigilance is indispensable to rapidly and fully assess the safety of newer agents in real-life patients. Keywords Cardiotoxicity Echocardiography Tissue Doppler New anticancer drugs F. Bonura (&) D. Di Lisi S. Novo Department of Cardiology, Policlinico P. Giaccone, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy e-mail: [email protected] D. Di Lisi e-mail: [email protected] S. Novo e-mail: [email protected] N. D’Alessandro Section of Pharmacology ‘‘P. Benigno’’, Department for Health Promotion Sciences ‘‘G, D’Alessandro’’, University of Palermo, Palermo, Italy e-mail: [email protected] Introduction Medical therapy of patients with cancer is a section of medicine in continuous growth, and in recent years, there has been an impressive development of new anticancer drugs. Disappointingly, both the new and conventional anticancer therapies can result in adverse cardiac and vascular effects, which can span from subclinical abnormalities to serious life-threatening and sometimes fatal events. The issue of cardiovascular risk has become of greater concern than in the past in the light of the increased use of adjuvant combination therapies along with the improved life expectancy of cancer patients. This review wants to examine the principal basic and clinical elements that may be of profit to identify and reduce the likelihood of cardiovascular toxicity from both conventional and new oncology drugs. Cardiovascular Toxicity of Molecularly Targeted Anticancer Agents Several anticancer drugs have been associated with some form of cardiotoxicity (Table 1). Introduction of targeted agents has for multiple reasons, not least because of the economic costs, rendered anticancer therapy even more complex. In contrast to the limited selective mechanisms of most conventional drugs, the targeted molecules are directed to interfere with genetic alterations specific of cancer cells and thus, in principle, are effective with low toxicity. They include monoclonal antibodies (mAb) that selectively target growth factor receptors or their ligands and small organic molecules which can inhibit a more or less broad spectrum of receptor or non-receptor tyrosine kinases (TKs) and, in some cases, of serine/threonine kinases. Novel agents have also been developed to interact Cardiovasc Toxicol Table 1 Cardiovascular toxicities from anticancer agents Drug(s) Principal clinical manifestations Principal mechanism(s) Amsacrine QT prolongation Interference with cardiac HERG currents Anthracyclines and anthraquinones LV dysfunction, CHF Oxidative stress Notes Increased risk with cumulative doses Arsenic trioxide QT prolongation Interference with cardiac HERG currents Bevacizumab Hypertension, thromboembolism Block of VEGF Bleomycin Pericarditis, ischaemic heart disease Likely related to oxidative stress Capecitabine, 5-fluorouracil Ischaemia, infarction, arrhythmias Vasospasm (inhibition of endothelial NO synthase? responsibility of metabolites and degradation products?) Cisplatin Arrhythmias, CHF, ischaemia/infarction Hypomagnesaemia, coronary artery fibrosis? Not firmly established, confounded by concomitant drugs Cyclophosphamide Haemorrhagic myopericarditis, CHF, arrhythmias Endothelial injury Observed at doses [ 120–170 mg/Kg Cytarabine Angina, pericarditis Unknown Etoposide Ischaemia/infarction Vasospasm Imatinib LV dysfunction, CHF, arrhythmias Inhibition of Abl kinase Methotrexate CHF, arrhythmias, ischaemia/infarction Unknown Case reports only Mitomycin C CHF Oxidative stress Increased risk with cumulative doses C 30 mg/m2 Multikinase inhibitors (sorafenib, sunitinib) Hypertension, ischaemia/ infarction, LV dysfunction, arrhythmias Anti-angiogenesis, inhibition of relevant cardiac kinases, hypothyroidism Tamoxifen Thromboembolism Oestrogenic activity Taxanes Hypotension, arrhythmias, CHF Hypersensitivity reactions (especially to cremophor EL, vehicle of paclitaxel), microtubule stabilization Can aggravate the cardiac toxicity of doxorubicin Trastuzumab LV dysfunction, CHF, arrhythmias Inhibition of HER2 signalling in the heart Concomitant administration aggravates the cardiac toxicity of other agents such as the anthracyclines Vinca alkaloids Ischaemia/infarction Vasospasm Not firmly established with some other functions, such as those of the proteosome, the histone deacetylases or the farnesyl transferases, which are now recognized to be frequently dysregulated in cancer. The targeted approaches have improved the management of different neoplastic diseases, with the best results having been obtained in chronic myeloid leukaemia, gastrointestinal stromal tumours (GIST) and breast cancer. However, in general, they have not shown to lead to cures or longterm survival for most intractable cancers; whatever the relevance of the blocked mechanism is, the genetic instability of cancer cells enables them to switch to adaptation changes and alternative signalling pathways that stimulate cell proliferation and survival, so that resistance eventually develops. Reasonably, multi-targeted agents might be less Not firmly established likely to run into problems of drug resistance than singletargeted ones; subsequently, many efforts of drug design are also oriented in this direction. On the whole, it has been calculated that there are approximately 500 novel anticancer agents under preclinical or clinical development or already on the market [1]. Importantly, in contrast to initial expectations, targeted agents have shown to be frequently associated with severe toxicities. They can affect also the cardiovascular system with manifestations such as cardiac dysfunction, arrhythmias, hypertension and thromboembolic events. Nonetheless, in many cases, the real dimension of this problem is not fully defined, owing to various reasons which, as it will be discussed further, include: Cardiovasc Toxicol • • • issues of screening for cardiovascular toxicity through better predictive preclinical models; paucity of prospective clinical studies specifically addressed to monitor cardiovascular events; need to identify the best clinical approaches and criteria to evaluate the various types of cardiovascular toxicity. Last but not least, it should be noted that there exists a strong inadequacy of reporting adverse reactions from oncology drugs in the post-marketing setting [2]. However, the pharmacovigilance detection methods are indispensable to rapidly and fully assess the safety of newer agents in real-world patients, as highlighted by the recent experience with the osteonecrosis of the jaw by bisphosphonates [3]. Cardiac Dysfunction from Targeted Agents From a mechanistic point of view, it is reasonable that such toxicity can ensue when the relevant targeted factor in cancer cells performs an important physiological function also in cardiomyocytes or other cardiovascular cells [1]. Examples of such ‘‘on-target’’ toxicity are represented by trastuzumab and, possibly, imatinib with their effects on HER2 and Abl kinase, respectively. In the case of more pleiotropic agents, ‘‘off-target’’ toxicities might also be encountered if their activities include targets not relevant for anticancer effects but responsible for cardiovascular functions. The mechanisms of the cardiac toxicity associated with the multikinase inhibitors sunitinib or sorafenib are not completely understood, but they might reflect on- and/or off-target effects. Clearly, cardiac toxicity cannot be considered as a class effect of all the molecularly targeted approaches, and, for example, there are no major basic or clinical concerns regarding the inhibitors (like erlotinib or gefitinib) of epidermal growth factor receptor (EGFR) TKs as relevant targets frequently adopted in the new therapies [1]. Trastuzumab and Other HER2 Inhibitors Trastuzumab, a humanized mAb, blocks activation of the human epidermal growth factor receptor 2 (HER2); HER2 is over-expressed in about 25–30% of breast cancer patients, and trastuzumab has clinical efficacy in such patients both in the metastatic and adjuvant setting. However, the mAb can lead to cardiac toxicity, manifesting as a reduction in LV systolic function. It can severely aggravate the cardiac toxicity of other anticancer agents, especially the anthracyclines [4]. In a pivotal trial in women with metastatic breast cancer, it was shown that combining trastuzumab with doxorubicin and cyclophosphamide caused CHF (NYHA class III or IV) in 16% of patients compared to the incidence of 3, 2 or 1% in patients receiving doxorubicin and cyclophosphamide, trastuzumab and paclitaxel or paclitaxel alone, respectively [5]. The cardiac toxicity from trastuzumab is mainly related to the fact that HER2 and its ligand neuregulin activate signals (like the ERK, PI3 K/AKT and FAK pathways) that promote cardiomyocyte proliferation and anti-apoptosis during development, as well as contractility in adults [6, 7]. HER2 signalling may also play an important role in the autonomic regulation of the heart [8]. Disappointingly, preclinical studies in mice could not detect trastuzumab cardiotoxicity because the mAb does not recognize ErbB2, the HER2 homologue in mice. Though trastuzumab binds primate HER2, the preclinical toxicology studies were done with healthy primates that had not been treated with anthracyclines [9]. Relevantly to the clinical situation, it is now clear that mice that have a targeted deletion of ErbB2 in the heart develop a dilated cardiomyopathy with advanced age and are particularly sensitive to hypertensive loads or anthracycline treatments [10]. As opposed to the anthracycline cardiotoxicity, clinical trastuzumab-associated cardiac dysfunction does not appear to be related to cumulative dose; fortunately, it often recovers with treatment discontinuation, and rechallenge is tolerated. Thus, one may distinguish two types of anticancer treatment-related cardiac dysfunction: type I and type II cardiotoxicity. Type I cardiotoxicity is associated with anthracyclines and results, at least to some degree, in myocyte destruction and clinical heart failure. Type II cardiotoxicity is a phenomenon that is not unique to trastuzumab, but it also occurs with different kinase inhibitors, and results in a loss of contractility (presumably a form of stunning or hibernation) that is less likely to be associated with myocyte death or clinical heart failure and, in general, is reversible [11, 12]. However, there are still different uncertainties regarding the trastuzumab cardiotoxicity [13]. In the absence of formal guidelines or consensus statements to predict, prevent and treat trastuzumab cardiomyopathic effects, proposed recommendations include a careful assessment of cardiac ejection fraction (EF) prior to initiating the treatment, avoidance of concurrent administration of trastuzumab with anthracyclines and regular monitoring of symptoms and cardiac function during and for several years after therapy. Increased vigilance is needed for higher-risk patients. Interestingly, a study on a frequent HER2 gene polymorphism (Ile655Val), though limited in size, has suggested that the Val allele significantly increases the risk of trastuzumab-induced cardiotoxicity [14], thus underlining the necessity of pharmacogenetic research in this particular field. Lapatinib is a small organic molecule that acts as an inhibitor of EGFR and HER2 TKs and is currently approved for treatment of refractory HER2-positive Cardiovasc Toxicol advanced breast cancer. Existing clinical evidence indicates that it is less cardiotoxic than trastuzumab, a fact that might depend on the different selection characteristics of the patients exposed to trastuzumab or lapatinib thus far, and, at molecular level, on the inherent differences between the action mechanisms of the mAb and lapatinib [1]. In fact, lapatinib would be able to induce cardiac protection by stimulation of AMP-activated protein kinase (AMPK), a key regulator of energy metabolism in the heart, while trastuzumab does not [15]. Imatinib and Other Abelson Kinase (Abl) Inhibitors Imatinib targets the kinase of the causal fusion protein BcrAbl in chronic myeloid leukaemia and also c-Kit and PDGFR-a and -b in GIST. Abl kinase inhibits apoptosis, and studies in mouse models have shown that imatinib causes a modest, but reproducible, decline in cardiac contractility along with cardiomyocyte death, due to its impact on c-Abl kinase in the same cells [1, 16]. A redesigned imatinib, devoid of Bcr-Abl inhibitory capacity, has demonstrated conserved therapeutic efficacy in a GIST mouse model with a marked reduction in cardiotoxicity [17]. However, other authors have suggested that imatinib may be not cardiotoxic in animals at clinically relevant concentrations [18]. The clinical cardiac toxicity of imatinib and of newer Abl inhibitors, like dasatinib and nilotinib, is under scrutiny. In any case, imatinib appears to be less cardiotoxic in humans than in mice, though some clinical cases of imatinib-related CHF have been reported [19, 20]. So far, dasatinib and nilotinib have been associated mainly with an increased risk of QT interval prolongation [21]. Multikinase Inhibitors: Sunitinib and Sorafenib Sunitinib and sorafenib are multikinase inhibitors currently indicated in the treatment of renal cell carcinoma. Sunitinib is approved for GIST, and sorafenib is now considered a standard agent for hepatocellular carcinoma. In a phase I/II trial, eight out of 75 (11%) patients with imatinib-resistant GIST treated with sunitinib underwent major cardiac events, such as heart failure (in 8% of patients), myocardial infarction or cardiovascular death. Decline in left ventricle ejection fraction (LVEF) of 15% or more occurred in 19% of the patients and hypertension ([150/100 mm Hg) in 47% [22]. LV dysfunction might be due, in part, to direct cardiomyocyte toxicity, with mitochondrial impairment, exacerbated by hypertension. Importantly, CHF and LV dysfunction generally responded to sunitinib being withheld and institution of medical management, so that afterwards, the majority of the patients were able to resume the drug [22]. In clinical trials, sorafenib was associated with acute coronary syndromes, including myocardial infarction, in 2.9% of patients versus 0.4% of placebo-treated patients [1]. Detailed cardiovascular monitoring during treatment with sunitinib or sorafenib may reveal early signs of myocardial damage. In a study on 74 patients with metastatic renal cell carcinoma treated with either sunitinib or sorafenib, 11 treated with sunitinib and 14 with sorafenib experienced a cardiac event; 13 of these 25 event patients had typical clinical symptoms, which included typical angina, dyspnoea at exertion and dizziness. Among these, seven were seriously compromised and required treatment in intermediate or intensive care units. ECG changes were found in 12 of the 25 event patients. All patients recovered after cardiovascular management and were considered eligible for continuation of the treatment [23]. Close monitoring is recommended as a prudent approach until large studies and post-marketing surveillance will clearly define the nature and rate of sunitinib- or sorafenib-associated cardiovascular effects, especially in patients with cardiac risk factors, such as advanced age or previous history of coronary disease [24]. Multikinase inhibitors can cause also hypothyroidism, which can aggravate their cardiotoxicity [25]. Sunitinib targets mainly vascular endothelial cell growth factor receptors (VEGFR) 1–3, platelet-derived growth factor receptors PDGFR a and b, stem cell factor KIT receptor, FMS-like tyrosine kinase-3 (FLT-3), colonystimulating factor-1 receptor (CSF-1R) and the product of the human RET gene. While VEGFR inhibition is responsible for the anti-angiogenetic as well as the hypertensive effect (see below) of sunitinib, other targets of sunitinib, such as FLT-3, CSF-1R, KIT and RET, are not known to be expressed in the adult heart. Possible cardiac effects of PDGFR inhibition in cancer patients have to be elucidated. Sunitinib cardiotoxicity does not appear to be due in a major way to its ability of inhibiting AMPK or also the ribosomal S6 kinase RSK1 [26]. Sorafenib, alongside VEGFR, PDGFR, KIT and FLT-3, inhibits the Raf kinases that trigger the cell proliferation and survival MEK/ERK pathway and have a protective role in the heart. Interestingly, gain-of-function mutation of Raf-1 and other components of the Raf pathway are causal in some cases of hypertrophic cardiomyopathy (Noonan and LEOPARD syndromes) [27]. However, the involvement of RAF-1 and BRAF in the myocyte toxicity of sorafenib has been recently questioned [28]. Arterial Hypertension (AH) and Thromboembolic Events from Anti-Angiogenic Agents Tumour neo-angiogenesis is a complex process that is indispensable for cancer growth and involves a Cardiovasc Toxicol disequilibrium between pro-angiogenetic factors, such as the potent VEGF-A (hereinafter referred to as VEGF), and anti-angiogenetic ones. At present, there are available on the market the anti-VEGF monoclonal antibody bevacizumab and the small organic molecules sunitinib and sorafenib, which, as already said, are multikinase inhibitors targeting also the VEGF receptors. Bevacizumab is indicated for the treatment of advanced colorectal, non-small cell lung, breast and renal cancers. Other VEGFR inhibitors currently awaiting approval include vatalanib, vandetanib (also an EGFR inhibitor), pazopanib and axitinib, the latter two being both VEGFR and PDGFR inhibitors [29]. AH, possibly associated with proteinuria, is a very frequent adverse effect of these anti-angiogenetic agents [30, 31]; it has been proposed that bevacizumab-induced hypertension might even represent a prognostic factor for clinical outcome in advanced colorectal cancer patients receiving first-line treatment with the drug [32]. However, the incidence of this AH may not be exactly known since the conventional measurement of arterial pressure in medical centres does not always permit the diagnosis of AH, suggesting the usefulness of auto-measurement of arterial pressure in patients treated with anti-angiogenetic agents. Further AH incidence has been reported according to the criteria (grades) of NCI-CTCAE (National Cancer Institute-Common Terminology Criteria for Adverse Events) and not according to those commonly accepted by the international scientific societies (C140 mmHg and/or 90 mmHg or use of an antihypertensive treatment irrespectively of the arterial pressure values) [51]. Nevertheless, in a recent meta-analysis on 12,656 patients, the incidence of all-grade hypertension in patients receiving bevacizumab was 23.6% (95% CI: 20.5–27.1) with 7.9% (95% CI: 6.1–10.2) being high grade (grade 3 or 4). The risk of high-grade hypertension may vary with tumour types, with relative risks ranging from 2.49 (95% CI: 0.94–6.59) in patients with mesothelioma to 14.80 (95% CI: 0.92–238.51) in patients with breast cancer [31]. Though the mechanism of AH is not fully understood, it clearly involves the blocking of the physiological effects of VEGF at the level of the vascular walls, through reduction in the number of terminal arterioles and capillaries (microvascular rarefaction) as well as inhibition of endothelial NO synthase and of NO release following vasodilatatory stimuli. An increase in arterial pressure is constant during the first weeks of treatment in both normotensive and hypertensive patients; it frequently reaches the stage of AH in normotensive patients and makes controlling of AH in already hypertensive individuals more difficult. AH from anti-angiogenetic agents is dose dependent, generally manageable by antihypertensive agents and rarely compromises the continuation of the anti-angiogenetic treatment. However, in some cases, serious, short-term complications, such as malignant or severe refractory AH and reversible posterior leukoencephalopathy associated with serious AH, have been reported. The long-term consequences of AH from anti-angiogenetic agents have not been evaluated. As already noticed, it is conceivable that elevated arterial pressure can lead to more serious cardiotoxicity if cardiac damage is present. Irrespective of the mechanism, it is worth noting that bevacizumab aggravated the cardiotoxicity of doxorubicin in a phase II study on patients with advanced soft tissue sarcomas [33]. Thromboembolism, especially at arterial sites (Arterial Thromboembolic Events, ATEs), and haemorrhage have also emerged as significant toxicities associated with the use of angiogenesis inhibitors. These events may reflect the maintenance and protection role of VEGF for endothelial cells where, independently of angiogenesis and cell proliferation, VEGF regulates the expression of components of the thrombolytic and coagulation pathways. Loss of these protective effects may result more crucial when anti-VEGF agents are associated with chemotherapy, which, per se, frequently causes haemostatic activation. The risks of thromboembolic events associated with bevacizumab-, sunitinib- or sorafenib-based therapies have been recently reviewed [34]. Overall, the incidence of ATEs due to bevacizumab, although low (2–3%), is double respect to that observed in chemotherapy-only-treated patients and with a significant difference. Since this increased risk of ATEs in bevacizumab-treated patients seems to be mainly related to older age, history of previous ATE and ECOG performance status, these variables should be taken into account before starting the anti-angiogenic treatment. The risk of venous thrombotic events (VTEs) from bevacizumab might be comparable [35, 36] or, according to a recent meta-analysis [37], moderately superior (RR 1.33, 95% CI: 1.13–1.56, P \ 0.001) to that of patients treated with standard chemotherapy. Some points remain to be clarified, which might lead to underestimation of such risk. Considering the yet relatively small numbers of patients exposed to sunitinib or sorafenib, data on the rates of thromboembolic events from these molecules are less mature than those on bevacizumab. Thalidomide and lenalidomide, two multi-mechanism drugs that can also inhibit angiogenesis by interfering with VEGF signalling and by other activities, have been shown to significantly increase the frequency of VTEs in multiple myeloma patients [38, 39]. Serious haemorrhagic complications have been observed in patients with non-small cell lung carcinoma receiving bevacizumab or other anti-VEGF agents. Risk factors suggested to be associated with developing haemoptysis include tumour cavitation, squamous cell histology and central tumour location [40]. Patients with congenital Cardiovasc Toxicol bleeding diathesis, acquired coagulopathy or receiving fulldose anticoagulation should receive bevacizumab only with great caution. The thromboembolic profile has to be especially estimated also in elderly patients [41]. QT Interval Prolongation and Oncology Therapies QT interval prolongation is a potentially severe effect because it may lead to fatal arrhythmias (torsade de pointes and ventricular fibrillation). It is recognized as a frequent complication of different conventional anticancer agents, which include the anthracyclines, 5-fluorouracil, amsacrine, the taxanes, some platinum compounds and arsenic trioxide [42]. Newer compounds with possible QT prolongation effects include some histone deacetylase inhibitors (such as depsipeptide, the cinnamic acid hydroxamates panobinostat and LAQ824; however, vorinostat, which is marketed for the treatment of cutaneous T cell lymphoma, has no documented QT effects but can cause non-specific ECG changes), TK inhibitors (such as lapatinib, dasatinib, nilotinib, sunitinib, vandetanib and XL647), protein kinase C inhibitors (enzastaurin) and farnesyl protein transferase inhibitors (L-778123 and lonafarnib). For most of these agents, the effective clinical significance of these effects needs to be better assessed. On the basis of preclinical and early clinical studies, QT effects and other cardiovascular toxicities are anticipated also for some vascular disrupting agents, such as combretastatin A4 phosphate and the flavone acetic derivative vadimezan [43–45]. The structural characteristics leading to QT toxicity have not been fully delineated, though the existence of a relationship with a given therapeutic class is not likely. Nevertheless, one of the most frequent mechanisms of QT prolongation is that, owing to its three-dimensional configuration, an agent may be able to interact with human ether-a-go-go-related gene potassium ion channels (HERG K?), which allow for the rapid component of myocardial repolarization. However, not all drugs that block HERG K? cause QT prolongation limiting the sensitivity of this marker. On the other hand, there are several identified factors that may predispose cancer patients to QT prolongation; they include advanced age, cardiac abnormalities inherent to cancer population, high prevalence of comorbid diseases that may independently increase the risk of QT prolongation, electrolyte disturbances due to severe nausea or vomiting, starvation, concomitant medications with other agents that predispose to QT abnormalities (like 5-HT3 receptor antagonists, antipsychotics and antidepressants) and many others [44, 45]. The measurement of QT is affected by variability and lack of standardization. Biological sources of QT variance include gender, circadian rhythm, autonomic tone, physical activity levels, food ingestion and, in particular, heart rate, as QT interval duration decreases as cardiac frequency increases. Different formulas have therefore been developed to mathematically correct QT for heart rate variability (QTc), but they are considered inaccurate, and there is no consensus on which of them is preferable. In addition, there is no established threshold below which QT interval prolongation can be considered free of pro-arrhythmic risk. Overall, emphasis has recently been put on the need of better preclinical and early clinical criteria and approaches to evaluate the risk of QT toxicity from novel anticancer drugs [43, 44]. Principal Diagnostic Investigations to Study Cardiotoxicity Guidelines for anthracycline cardiotoxicity monitoring propose left ventricular ejection fraction (LVEF) measurement as the gold standard parameter for decision-making. However, its prediction power for late development of cardiomyopathy is not strictly accurate or timely. Traditionally, the detection of anticancer-induced cardiotoxicity has been based on the measurement of resting LVEF or LV fractional shortening (LVFS). In many studies, cardiac toxicity is assumed if (a) LVEF drops more than 10% from the baseline to values below 50%, (b) LVEF drops more than 20% from the baseline despite still having normal function or (c) LVEF drops below 45% [46]. Another method used is the classification of functional cardiotoxicity on the basis of both clinical and echocardiographic criteria. Functional cardiotoxicity is defined as mild (a decrease in LVEF [10% from the baseline with a final value [50%), moderate (a decrease in LVEF [10% from the baseline with a final value \ 50% and no symptoms nor signs of heart failure) and severe (a decrease in EF [10% from the baseline with a final value \50% and symptoms or signs of heart failure or a decrease in EF of any percentage leading to a final value \40% irrespective of symptoms or signs of heart failure) [47]. These parameters are, however, not sensitive enough to detect the subtle changes in myocardial function which occur in early cardiotoxicity. A certain proportion of damaged, dysfunctional myocardium to cause a change in global systolic function that will exceed the sensitivity threshold of these parameters is needed. At the point when changes are detected, functional deterioration already proceeds rapidly and is mostly irreversible. Therefore, new methods are needed to reliably detect early myocardial injury during or shortly after oncological therapies [48]. Currently, multiple tests are available for the monitoring of anthracycline cardiotoxicity (Table 2). At the moment, it is difficult to define the best method to assess the cardiotoxicity due to new anticancer drugs. Cardiovasc Toxicol Table 2 Principal diagnostic investigations for cardiotoxicity Electrocardiogram Benefits Disadvantages Easily reproducible Often non-specific abnormalities Early electrical alterations Not invasive Endomyocardial biopsy Radionuclide angiocardiography Echocardiogram LVEF (Simpson’s rule) Histological diagnosis Invasive method Useful for ‘‘type 1’’ cardiotoxicity Possibly inapplicable for ‘‘type 2’’ cardiotoxicity Excellent for evaluation of ejection fraction Expensive Easily reproducible Operator-dependent Not invasive Doppler blood flow Early diagnosis of diastolic dysfunction Influenced by loading conditions Easily reproducible TDI Very early diagnosis of diastolic an systolic dysfunction Operator dependent Not influenced by loading conditions TEI index Measure of global (systolic and diastolic) function without geometrical assumptions Operator dependent Strain Changes in tissue deformation Need of further validation Need of further validation Strain rate ECHO stress MRI Assesses left ventricular function contractile reserve Published studies appear controversial Detects changes in ventricular function and toxic effects Expensive Of value in patients with limited echocardiographic imaging windows Delayed enhancement Biomarkers Assessing scar and fibrosis Need of further validation Possible value as early disease markers and, in some cases, also as pathophysiologic determinants Ability to evaluate cardiotoxicity induced by non-classical therapeutic agents? Need of further validation Electrocardiogram Endomyocardial Biopsy Examination Signal-averaged electrocardiography (ECG) is a noninvasive diagnostic technique intensively used to especially monitor the cardiotoxic effects that can occur during or shortly (within hours) after administration of chemotherapeutic drugs. These include non-specific ST-T-wave changes, decreased QRS voltage and prolongation of the QT interval and rhythm disturbances. Acute cardiac arrhythmias have been observed in association with the administration of taxol [49], doxorubicin [50], cisplatin [51], 5-fluorouracil [52] and other drugs. Atrial fibrillation, a common finding in elderly patients, may be due to patient stress but can also be induced by various drugs, including anticancer agents [53]. In a recent study on anthracycline-induced cardiotoxicity, the ECG changes were compared with the findings on echocardiography (ECHO). The anthracycline treatment was associated with changes in electrical activity of the myocardium, like prolonged QTc interval and decreased QRS voltage, which could correlate with LV dysfunction in ECHO [54]. Endomyocardial biopsy examination requires a small sample of right ventricular myocardium for analysis by a skilled histopathologist. Although it provides histological diagnosis along with grading of severity of disease (based on the Billingham’s score), it has multiple shortcomings [55]. This method can possibly be used only for type I cardiotoxicity because type II, exemplified by trastuzumab, differs from the former in that it may not be associated with identifiable structural cardiomyocytes changes and appears to be mostly reversible. Moreover, considering that there are now a few non-invasive alternative methods, endomyocardial biopsy examinations are increasingly becoming a scarcely used technique. Radionuclide Angiocardiography Scintigraphic parameters of both systolic and diastolic cardiac function have been recommended to assess cardiac injury. Equilibrium radionuclide angiocardiography (ERNA) has shown to be a reliable and reproducible test Cardiovasc Toxicol for monitoring and evaluating LV function in patients undergoing doxorubicin chemotherapy [56]. It is among the earliest and most widely used methods for this purpose. Serial monitoring using ERNA allows for the detection of a predetermined decrease in LVEF that predicts subsequent cardiac dysfunction [57]. A prospective study on doxorubicin cardiotoxicity using radionuclide angiography found that patients with normal baseline EF at rest but abnormal EF under exertion appeared to be at increased risk of cardiac heart failure [58]. Though the number of studies supporting an additional benefit for the detection of chemotherapy-induced cardiac damage with specific myocardial tracers is limited to date, these techniques appear to be more sensitive than LVEF measurements. Increased 111Inantimyosin uptake, reflecting myocyte damage, as well as 123 decreased myocardial I-metaiodobenzylguanidine (MIBG) uptake, indicating cardiac adrenergic denervation, may be useful in identifying both the early and late cardiac sequelae due to treatment with anthracyclines [59, 60]. Role of Echocardiography (ECHO) Among non-invasive examinations, ECHO provides a wide spectrum of information on cardiac morphology and function. Standard parameters measured in systole and diastole are LV dimensions, right ventricular anterior wall (RVAW), interventricular septum (IVS) and LV posterior wall (LVPW) thickness. LVEF is calculated using the modified Simpson’s rule with a value of 50% or more being considered as normal [61]. LV fractional shortening is calculated from the LV dimensions; a value of [28% is considered normal. Using the apical four-chamber view, peak early (E wave) and late (A wave, after atrial contraction) diastolic Doppler blood flow velocities of the mitral valve can be measured. Accordingly, the E/A ratio is calculated from these measured peak velocities. However, although used frequently, the sensitivity of serial measurement of cardiac function by ECHO is limited by inherent variability [62, 63]. Tissue Doppler imaging (TDI) using ECHO is a technique that allows for measurements of velocity at any point along the ventricular wall during the cardiac cycle. TDI allows for the measurement of maximal systolic endocardial velocity and strain rate. When compared with conventional measures of LVEF, TDI-derived parameters are less influenced by loading conditions, such as the change in intravascular volume that occurs with chemotherapy in combination with trastuzumab. Thus, TDI is a feasible imaging modality that might provide improved sensitivity in detecting early subclinical LV dysfunction. Recently, the potential application of TDI for the early detection of anthracycline- and trastuzumab-mediated cardiac dysfunction was validated in a murine model. It was shown that TDI was abnormal in mice receiving doxorubicin or doxorubicin plus trastuzumab as early as 24 h after treatment and that it predicted ensuing LV systolic dysfunction with increased mortality [64]. TDI may become a regularly and more widely used non-invasive method to detect subclinical cardiotoxicity emerging after chemotherapy [65]. In addition to traditional parameters of LV systolic and diastolic function, the Tei index can be calculated, and TDI-derived longitudinal systolic (Sa) and early diastolic (Ea) velocities can be measured. The Tei index is calculated as the sum of the isovolumetric contraction time (ICT) and isovolumetric relaxation time (IRT) divided by the ejection time (ET) [66]. The longitudinal Sa and Ea velocities are obtained online using spectral TDI in the apical 4-chamber view placing a 5 mm pulsed wave sample volume at the level of the lateral mitral annulus [67]. Respiratory manoeuvres (e.g. end expiratory apnoea) are used where possible to enhance data quality. If used at the baseline, the manoeuvres are repeated on subsequent studies to maintain consistency. Each parameter is measured from 3 to 5 consecutive beats and averaged [68]. Overall, the Tei index is a measure of global (systolic and diastolic) function without geometrical assumptions, correlating well with invasive measurements and has been validated in the assessment of ventricular function with higher values conferring poorer prognosis [69]. The Tei index increases after therapy with anthracyclines in the majority of the patients (78.8%), indicating that early myocardial alteration is more frequent than that previously recognized [70, 71], although this may not predict functional cardiotoxicity in terms of EF and symptoms and signs of heart failure [47, 72]. New ECHO methods quantifying regional deformation like strain and strain rate imaging are promising tools, which have the potential to sensitively monitor cardiac function and, thus, guide anticancer therapy and preventive measures to avoid unnecessary myocardial damage [73, 74]. The aim of a recent study was to investigate whether changes in tissue deformation, assessed by myocardial strain and strain rate (SR), are able to identify LV dysfunction earlier than conventional ECHO measures in patients treated with trastuzumab [75]. There were no overall changes in 3D-EF, 2D-EF, myocardial E-velocity or strain. However, significant reductions were seen for TDI SR, 2D-SR and 2D radial SR. The conclusion was that myocardial deformation can identify preclinical myocardial dysfunction earlier than conventional measures in women treated with trastuzumab for breast cancer. TDI, allowing to measure parameters such as myocardial velocity, deformation (strain) or deformation rate (strain rate), can reliably detect early abnormalities in both regional and global myocardial function. Further validation in larger prospective studies is needed. Cardiovasc Toxicol Stress ECHO Cardiac Biomarkers Stress ECHO can assess LV function contractile reserve. Exercise ECHO is an optimal tool to unmask coronary artery disease in the general population and may also be of importance in patients treated with some chemotherapeutic agents (e.g. 5-fluorouracil or capecitabine) and by radiation therapy, which is able to provoke accelerated coronary atherosclerosis. Experiences on exercise ECHO in this clinical setting are, however, scanty until now [76, 77]. Low-dose dobutamine stress ECHO has been shown to be useful for the identification of myocardial viability and the prediction of LV contractile recovery after coronary revascularization in patients with coronary artery disease [78]. It has been suggested that abnormalities of myocardial adrenergic neuron activities may occur early in anthracycline cardiotoxicity before any appreciable systolic dysfunction. The presence of this early adrenergic derangement might explain the impaired myocardial responsiveness to dobutamine even when standard ECHO parameters do not reveal any alteration [79]. Other studies have shown that dobutamine stress ECHO could detect subtle changes in LV function due to anthracycline cardiotoxicity [80–84]. Cardiac biomarkers are molecules that are released into the blood when there is something wrong with the heart. During an abnormal cardiac event, like a heart attack, or even angina, the heart muscle is put under great stress and the heart muscle fibres release molecules that are never normally produced. These molecules enter into the bloodstream and can be detected in a blood test. Non-invasive biochemical tests for early detection of cardiotoxicity are an interesting field addressed by different papers in the published literature. Magnetic Resonance Imaging (MRI) Among other applications, MRI is considered as an ideal tool to study acute myocardial injuries. One can successfully visualize the site and extent of myocardial infarction by imaging the necrotic area and associated oedema using T2- and contrast-enhanced T1-weighted MRI [84]. Furthermore, in a study on MRI in acute myocarditis, myocardial inflammation produced an increase in signal intensity in contrast-enhanced T1-weighted MRI [85]. Late contrast enhancement in the myocardium is a reliable marker of either scar tissue or of the capillary leakage that occurs early during myocardial damage. This phenomenon is widely used in cardiology to identify post-infarction scar, as well as viable myocardium. MRI may have the potential to image both changes in ventricular function and toxic effects on the myocardial tissue. In a study on patients receiving anthracyclines, MRI could detect early changes in myocardial contrast enhancement along with slight deterioration in cardiac function [86]. There is an advantage of MRI in patients with limited ECHO imaging windows. A comparison of the wall motion assessment by ECHO and MRI proved the comparable accuracy of both methods [87]. Recently, it was demonstrated that delayed contrast enhancement imaging using cardiac MRI could detect early changes in the myocardium due to trastuzumab-induced cardiotoxicity [88]. This finding merits further study. Natriuretic Peptides The family of natriuretic peptides includes atrial natriuretic peptide (ANP), which is dominant in cardiac atria, and brain natriuretic peptide (BNP), primarily released from the ventricles. The corresponding pro-hormones split into inactive N-terminal (NT-pro-ANP and NT-pro-BNP) and the biologically active ANP and BNP peptides. Increased quantities of these peptides are released in response to increased myocardial wall stress induced by volume overload, as important indicators of severe as well as early symptomless heart failure. The distinct peptides may possibly reflect different aspects of the process (diastolic versus systolic dysfunction) [89, 90]. They might also represent an early sign of cardiotoxicity secondary to chemotherapy and radiation treatment, although the data are controversial and their role in this respect has to be further clarified [91–95]. Combining continuous wave Doppler ultrasound and NT-pro-BNP monitoring may be useful to monitor the immediate haemodynamic changes that occur after trastuzumab therapy [96]. Troponins Circulating levels of both cardiac troponin T (cTnT) and I (cTnI) have been correlated in humans to the extent of myocardial injury from various aetiologies and especially used as tests for myocardial infarction [97]. Early elevations of serum cardiac troponins have been also reported after chemotherapy, predicting subsequent subclinical and clinical cardiac morbidity. On the basis of a significant body of clinical evidence, troponins can be considered as well-established markers of myocardial non-ischaemic damage from drugs. However, their monitoring requires frequent sampling, as it has not been possible to identify a single time point for their evaluation [95]. Troponin I might be superior to troponin C to early detect cardiac injury associated with anthracycline therapy [98]. A recent study on 251 breast cancer patients has shown that elevation of troponin I identifies trastuzumab-treated patients Cardiovasc Toxicol who are at risk of cardiotoxicity and are unlikely to recover from cardiac dysfunction despite heart failure therapy [99]. Other Markers Cardiac endothelial cells contribute to regulate cardiac performance, and endothelin-1 (ET-1) is a central substance in this mechanism. ET-1, first identified as a vasoconstrictor, has pleiotropic effects in the heart where it triggers hypertrophic, proliferative and cell survival responses. In an early small study, progressive elevation of its plasma levels occurred before deterioration of LVEF in patients who subsequently developed CHF from doxorubicin [100]. In contrast, another study on patients with Hodgkin’s or nonHodgkin’s lymphoma has shown that ET-1 levels decreased significantly after anthracycline therapy and remained low after 1 year. These findings were accompanied by worsening of left ventricular function [101]. In studies on mice, block of ET-1 activities [102, 103] inhibited doxorubicin-induced cardiomyopathy, suggesting that endothelin may play a role in mediating the cardiotoxic effects of the anthracycline. Thus, the pathophysiological and predictive role of ET-1 in anthracycline cardiomyopathy remains to be better clarified. Cardiotrophin-1 (CT-1), a member of the interleukin 6 family of cytokines, is capable of promoting both the proliferation and the survival of embryonic or neonatal cardiac myocytes. It is synthesized in the heart in response to mechanical stretch and other forms of injury. At first, it may provide myocardial protection, but in the chronic course, it induces myocyte hypertrophy and collagen synthesis, thus participating in the ventricular structural changes that ultimately result in heart failure. Circulating CT-1 levels are elevated in patients with hypertension, valve diseases, coronary artery diseases and congestive heart failure [104]. However, despite the possible interest in CT-1, both as a disease marker and a pathophysiological determinant, there are no systematic studies on the behaviour of CT-1 plasma levels in the context of clinical toxicity from anticancer drugs [104, 105]. Other promising markers of cardiomyocyte impairment, like the heart-type fatty acid-binding protein (H-FABP) [106], are awaiting validation for their use in cardiooncology. Collectively, however, the clinical value of biochemical parameters for the early diagnosis and prognostic judgement of cardiotoxicity from anthracyclines and, possibly, from the newer anticancer drugs remains a controversial issue. A New Area of Interest: The Use of Induced Pluripotent Stem Cells (iPS Cells) Different studies propose that chemotherapy induces cardiotoxicity by inadvertently interrupting the homoeostasis of cardiac stem cells and depleting the resident cardiac stem cells pool. As a result, the heart loses the capability of regeneration and repair and undergoes cardiotoxic effects. This hypothesis is supported by several lines of emerging evidence: the high incidence of cardiotoxicity in paediatric cancer patients who still have more cardiac stem cells in the myocardium; the rescue of anthracycline cardiomyopathy by injection of cardiac stem cells; and the adverse cardiotoxicity induced by inhibitors of oncogenic kinases or pathways that target cardiac stem cells besides cancer cells [107]. The recognition that the adult heart in animals and humans contains a pool of resident primitive cells, which are self-renewing, clonogenic and multipotent in vitro and regenerate myocytes and coronary vessels in vivo, raises the question whether the effects of DOXO on cardiac homoeostasis and repair are primarily directed to the stem cell compartment partially ablating the reserve of functionally competent cardiac progenitor cells (CPCs) [108]. In fact, CPCs are particularly sensitive to oxidative stress and rapidly die by apoptosis. Myocytes are more resistant to ROS formation than CPCs, strengthening the possibility that loss of CPCs together with the reduced generation of a myocyte progeny may be critical in the development of doxorubicin-mediated cardiomyopathy. The growing appreciation that cardiac stem cells represent new targets that contribute to chemotherapy-induced cardiotoxicity opens up novel strategies for overcoming the problem. How might stem cells play a part in repairing the heart? To answer this question, researchers are building their knowledge base about how stem cells are directed to become specialized cells. The potential capability of both embryonic and adult stem cells to develop into myocytes, endothelial and smooth muscle cells is now being explored as part of a strategy to restore heart function in people who have had heart attacks or are affected by congestive heart failure. More evidence for potential stem cell-based therapies for heart disease is provided by a study that showed that human adult stem cells taken from bone marrow are capable of giving rise to vascular endothelial cells when transplanted into rats [109]. The advent of induced pluripotent stem cell (iPS) technology, whereby fully differentiated cells are induced to return to a progenitor state, makes it possible to generate any cell type from any genetic background, increases the utility of stem cell-derived experimental models and negates many of the ethical concerns surrounding embryonic stem cells. Pluripotent stem cells derived from the inner cell mass of early stage embryos have provided a prototype for multilineage repair. However, ethical considerations along with practical limitations have precluded adoption of embryonic stem cell platforms, thereby driving advances in nuclear reprogramming to establish viable alternatives [110]. In Cardiovasc Toxicol this regard, iPS technology may provide an emerging innovation that fulfils the unlimited potential of embryonic stem cells while circumventing the need for embryonic sources [111]. One of the first studies establishing the real potential for using iPS cells in cardiac treatment was conducted by a Mayo Clinic team: It was shown that fibroblasts reprogrammed via a ‘‘stemness-related’’ gene set acquire the capacity to repair and regenerate infarcted hearts [111]. The ultimate goal is to use iPS cells derived from the patients themselves, thus eliminating the risk of rejection and the need of antirejection drugs. In addition, this regenerative medicine strategy might alleviate the demand for organ transplantation limited by donor shortage. Finally, developing iPS cell technology and automated culturing techniques will enable in vitro testing of pharmaceuticals for both efficacy and toxicity over any individual genetic make-up and truly bring the potential of personalized medicine to the clinic. increasingly represents an important challenge for different professional figures and scientists. Understanding the mechanisms responsible for such toxicity may possibly help to design safer drugs or find optimal protective tools. Pharmacologists are also called to develop adequate animal models that better predict drug-induced cardiovascular complications in humans. Such information can offer oncologists the chance to move patients toward less toxic regimens and allow cardiologists to preserve cardiac function. In recent years, many groups have studied the cardiotoxicity and all related issues, because it is an emerging problem that interested many medical specialists. A recent review underlines the importance of close collaboration between oncologist and cardiologist with the aim of balancing the risks of cardiotoxicity with the benefits of oncologic therapy [115]. All the elements presented in our article underline the necessity of further interdisciplinary work in the area of cardio-oncology to improve the survival and quality of life of cancer patients, with particular regard of new area of interest: stem cells and pharmacogenomics. Pharmacogenetics: A New Approach to ‘‘Personalized Medicine’’ Clearly, pharmacogenetics is another emerging field in medical science, which aims to improve the treatment of disease and dramatically reduce the risk of adverse drug reactions, by incorporating genetic information into the treatment decision-making process. For example, patients on doxorubicin show marked interindividual variability in dose tolerance and toxicity. A recent study examined more than 200 polymorphisms in 82 genes with a biologically plausible role in doxorubicin cardiotoxicity. Genetic variants in the ABCC1 and ABCC2 genes (ABC transporters, which encode multidrug resistance-associated proteins member 1 [MRP1] and member 2 [MRP2]) and in the members of the NADPH oxidase complex (genes RAC2 and CYBA) were found to be associated with acute doxorubicin cardiotoxicity [112]. Drug-induced arrhythmias, in particular long QT syndrome and Torsades de Pointes, have been associated with variants in genes encoding cardiac K? and Na? channels [113]. While most authors have been concentrating on mutations in cardiac ion channels, others have also investigated drug metabolizing enzymes on the basis that QT prolongation is increased at higher drug concentrations [114]. Genetic biomarkers can be used to identify high-risk patients and thus prevent serious cardiotoxicity. Conclusions The aspect of cardiovascular toxicity from anticancer agents, including the novel molecularly targeted ones, References 1. Chen, M. H., Kerkelä, R., & Force, T. (2008). 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